IRAK4 degrader salt form

Abstract

The present disclosure relates generally to various salt forms and compositions thereof useful for modulating interleukin-1 receptor-associated kinase 4 ("IRAK4") via ubiquitination and / or degradation, and their use in treating various diseases. The disclosure is based, at least in part, on the identification of compounds that modulate targeted ubiquitination of IRAK4 kinase, and methods of using the same in patients in need of treatment for IRAK4-mediated diseases, disorders, or conditions.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 379,391, filed October 13, 2022, the contents of which are incorporated herein by reference.

[0002] The present disclosure relates generally to various salt forms and compositions thereof useful for modulating interleukin-1 receptor-associated kinase 4 ("IRAK4") through ubiquitination and / or degradation, and their use in the treatment of various diseases. [Background technology]

[0003] The ubiquitin-proteasome pathway (UPP) is a critical pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to multiple cellular processes, and its deficiency or imbalance can lead to the pathogenesis of various diseases. The covalent attachment of ubiquitin to specific protein substrates is activated through the action of E3 ubiquitin ligases.

[0004] There are over 600 E3 ubiquitin ligases that promote the ubiquitination of various proteins in vivo, which can be classified into four families: HECT-domain E3s, U-box E3s, monomeric ring E3s, and multisubunit E3s. Generally Li et al. (PLOS One, 2008, 3, 1487) name “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling.”; Berndsen et al. (Nat.Struct.Mol.Biol.,2014,21,301-307) name “New insights into ubiquitin E3 ligase mechanism”;26169771.3.BUSINESS 2 of 1812 397731-010US(170174)Deshaies et al.(Ann.Rev.Biochem.,2009,78,399-434)Name “RING domain E3 ubiquitin ligases.”;Spratt et al. al. (Biochem. 2014, 458, 421-437) entitled "RBR E3 ubiquitin ligases: New structures, new insights, new questions."; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) entitled "Roles of F-box proteins in cancer."

[0005] The UPP plays a vital role in the degradation of short-lived regulatory proteins that are important in various fundamental cellular processes, including the cell cycle, cell surface receptor regulation, and control of ion channels and antigen presentation. This pathway has been implicated in the pathogenesis of several forms of malignancy, several genetic disorders (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), immune surveillance / viral pathology, and muscle wasting. Many diseases are associated with abnormal UPP, negatively affecting the cell cycle and division, cellular responses to stress and extracellular regulators, neuronal network morphogenesis, cell surface receptor regulation, ion channels, secretory pathways, DNA repair, and organelle biogenesis.

[0006] Defects in this process have recently been linked to the development of several diseases, both inherited and acquired. These diseases fall into two major groups: (a) those resulting from the loss of function and subsequent stabilization of specific proteins, and (b) those resulting from gain of function, i.e., the abnormal and accelerated degradation of protein targets.

[0007] UPPs are used to induce selective protein degradation, including the use of fusion proteins to artificially ubiquitinate target proteins and synthetic small molecule probes to induce proteasome-dependent degradation. Bifunctional compounds consist of a target protein-binding ligand and an E3 ubiquitin ligase ligand, which recruit the selected protein to the E3 ubiquitin ligase, leading to proteasome-mediated degradation and subsequent ubiquitination. These drug-like molecules offer the possibility of temporally controlling protein expression. Such compounds can be added to cells or administered to animals or humans to induce the inactivation of target proteins. They may be useful as biochemical reagents and may lead to a new paradigm for treating diseases by eliminating pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(1):40-46). There is a continuing need in the art for effective treatments for diseases, particularly autoinflammatory and autoimmune diseases, which have a high unmet medical need. However, nonspecific effects and the inability to target and regulate specific classes of proteins, such as transcription factors, remain obstacles to developing effective anticancer drugs. Therefore, small molecule therapeutics that exploit E3 ligase-mediated proteolysis to target cancer-associated proteins, such as interleukin-1 receptor-associated kinase 4 ("IRAK4"), hold promise as therapeutics. Therefore, there remains a need to identify compounds that are IRAK4 degraders useful as therapeutics. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Li et al. (PLOS One, 2008, 3, 1487) Name “Genome-wide and functional annotation of human E3 ubiquitin ligases identifies MULAN, a mitochondrial E3 that regulates the organelle's dynamics and signaling.” [Non-patent document 2] Berndsen et al. (Nat.Struct.Mol.Biol.,2014,21,301-307)Name “New insights into ubiquitin E3 ligase mechanism”26169771.3.BUSINESS 2 of 1812 397731-010US(170174) [Non-patent document 3] Deshaies et al. (Ann.Rev.Biochem.,2009,78,399-434) Name “RING domain E3 ubiquitin ligases.” [Non-patent document 4] Spratt et al. (Biochem.2014,458,421-437) Name “RBR E3 ubiquitin ligases: New structures, new insights, new questions.” [Non-patent document 5] Wang et al. (Nat.Rev.Cancer.,2014,14,233-347) Name “Roles of F-box proteins in cancer” [Non-patent document 6] Crews C,Chemistry & Biology,2010,17(6):551-555 [Non-Patent Document 7] Schnnekloth JS Jr.,Chembiochem,2005,6(l):40-46 Summary of the Invention [Means for solving the problem]

[0009] It has now been found that novel salt forms of 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperazin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, as described herein, are useful modulators of targeted ubiquitination of IRAK4 kinase and exhibit desirable properties therefor. In general, the salt forms and pharmaceutically acceptable compositions thereof are useful for treating or lessening the severity of a variety of diseases or disorders, as detailed herein. [Brief explanation of the drawings]

[0010] [Figure 1A] 1 shows XRPD pattern overlays of Form A of Compound 2: a) dry solid; and b)-d) wet cake. [Figure 1B] 1 shows a DSC-TGA overlay of Compound 2 Form A. [Figure 2A] 1 shows XRPD pattern overlays of Form A of Compound 3: a) dry solid; and b)-c) wet cake. [Figure 2B] 1 shows a DSC-TGA overlay of Compound 3 Form A. [Figure 3A] 1 shows XRPD pattern overlays of Form A of Compound 4: a) p-toluenesulfonic acid monohydrate; b)-d) wet cake; and e) dry solid. [Figure 3B] 1 shows a DSC-TGA overlay of Form A of Compound 4. [Figure 4A] 1 shows XRPD pattern overlays of Form A of Compound 5: a) dry solid; and b)-c) wet cake. [Figure 4B]1 shows a DSC-TGA overlay of Form A of Compound 5. [Figure 5A] 1 shows XRPD pattern overlays of Form A of Compound 6: a) to d) wet cake; and e) dry solid. [Figure 5B] 1 shows a DSC-TGA overlay of Form A of Compound 6. [Figure 6A] 1 shows XRPD pattern overlays of Form A of Compound 7: a) maleic acid monohydrate; b)-d) wet cake; and e) dry solid. [Figure 6B] 1 shows a DSC-TGA overlay of Form A of Compound 7. [Figure 7A] 1 shows XRPD pattern overlays of Form A of Compound 8: a) L-tartaric acid; b) to e) wet cake; and f) dry solid. [Figure 7B] 1 shows a DSC-TGA overlay of Form A of Compound 8. [Figure 8A] 1 shows XRPD pattern overlays of Form A of Compound 9: a) fumaric acid; b)-g) wet cake; and g)-h) dry solid. [Figure 8B] 1 shows a DSC-TGA overlay of Form A of Compound 9. [Figure 9A] 1 shows XRPD pattern overlays of Form A of Compound 10: a) citric acid; b) to e) wet cake; and f) dry solid. [Figure 9B] 1 shows a DSC-TGA overlay of Form A of Compound 10. [Figure 10A] 1 shows XRPD pattern overlays of Form A of Compound 11: a) glycolic acid; b) to e) wet cake; and f) dry solid. [Figure 10B] 1 shows a DSC-TGA overlay of Form A of Compound 11. [Figure 11A] 1 shows XRPD pattern overlays of Form A of Compound 12: a) L-Malic acid; b)-g) wet cake; and g)-h) dry solid. [Figure 11B] 1 shows a DSC-TGA overlay of Form A of Compound 12. [Figure 12A] 1 shows XRPD pattern overlays of Form A of Compound 13: a) hippuric acid; b) to e) wet cake; and f) dry solid. [Figure 12B] 1 shows a DSC-TGA overlay of Form A of Compound 13. [Figure 13A] 1 shows XRPD pattern overlays of Form A of Compound 14: a) L-lactic acid; b) to e) wet cake; and f) dry solid. [Figure 13B] 1 shows a DSC-TGA overlay of Form A of Compound 14. [Figure 14A] 1 shows XRPD pattern overlays of Form A of Compound 15: a) benzoic acid; b) to e) wet cake; and f) dry solid. [Figure 14B] 1 shows a DSC-TGA overlay of Form A of Compound 15. [Figure 15A] 1 shows XRPD pattern overlays of Forms A, B, and C of Compound 16: a) succinic acid; b)-f) wet cake; g) Form B dry solid; h) Form C dry solid; and i) Form A dry solid. [Figure 15B] 1 shows a DSC-TGA overlay of Form B of Compound 16. [Figure 15C] 1 shows a DSC-TGA overlay of Form C of Compound 16. [Figure 15D] 1 shows a DSC-TGA overlay of Form A of Compound 16. DETAILED DESCRIPTION OF THE INVENTION

[0011] General Description of Certain Aspects of the Invention: The present disclosure is based, at least in part, on the identification of compounds that modulate targeted ubiquitination of IRAK4 kinase and methods of using same in patients in need of treatment for IRAK4-mediated diseases, disorders, or conditions. The following Compound 1, and salt forms thereof, are disclosed herein: [ka]

[0012] Compound 1, 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperazin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperazin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, functions as a modulator of targeted ubiquitination of IRAK4. Compound 1 is designated I-417, the synthesis of which is described in US Pat. No. 11,352,350, which is incorporated herein by reference in its entirety.

[0013] It would be desirable to provide a solid form of Compound 1 (e.g., as a salt thereof) that imparts properties such as water solubility, stability, and ease of formulation. Accordingly, the present disclosure provides salt forms of Compound 1.

[0014] Salt forms of Compound 1 In some embodiments, an acid and Compound 1 are ionically bonded to form a salt form of Compound 1, as described below. It is believed that the salt form of Compound 1 can exist in various physical forms. For example, the salt form of Compound 1 can be a solution, a suspension, or a solid form. In certain embodiments, the salt form of Compound 1 is a solid form. When the salt form of Compound 1 is a solid form, the compound can be amorphous, crystalline, or a mixture thereof. In certain embodiments, the salt solid form of Compound 1 is crystalline. Exemplary such salt forms of Compound 1 are described in more detail below.

[0015] In some embodiments, the present disclosure provides a salt form of Compound 1 that is substantially free of impurities. Such contaminants may include different forms of Compound 1 or any other impurities that may result from the preparation and / or isolation of Compound 1. In certain embodiments, the salt form of Compound 1 is present at least about 85% by weight. In certain embodiments, the salt form of Compound 1 is present at least about 90% by weight. In still other embodiments of the present disclosure, the salt form of Compound 1 is present at least about 95% by weight.

[0016] According to one embodiment, the salt form of Compound 1 is present in at least about 80, 85, 90, 95, 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the salt form of Compound 1 has an HPLC area percent of total organic impurities of about 20.0 or less, an HPLC area percent of total organic impurities of about 15.0 or less, an HPLC area percent of total organic impurities of about 10.0 or less, an HPLC area percent of total organic impurities of about 5.0 or less, an HPLC area percent of total organic impurities of about 20.0 or less, an HPLC area percent of total organic impurities of about 20.0 or less, or an HPLC area percent of total organic impurities of about 1.5 or less, based on the total area of ​​the HPLC chromatogram. In other embodiments, the salt form of Compound 1 has an HPLC area percent of any single impurity of about 10% or less, an HPLC area percent of any single impurity of about 5% or less, or an HPLC area percent of any single impurity of about 1% or less of the total area of ​​the HPLC chromatogram.

[0017] Structures depicting salt forms of Compound 1 are also intended to include all tautomeric salt forms of Compound 1. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0018] In certain embodiments, the salt form of Compound 1 is a crystalline solid. In other embodiments, the salt form of Compound 1 is a crystalline solid that is substantially free of amorphous Compound 1. In yet other embodiments, the salt form of Compound 1 is a crystalline solid that is substantially free of other crystalline forms of Compound 1 (e.g., crystalline free base and salt forms). In certain embodiments, the crystalline salt form of Compound 1 is present at least about 95% by weight. In yet other embodiments of the present disclosure, the crystalline salt form of Compound 1 is present at least about 99% by weight.

[0019] In some embodiments, the present invention provides a composition comprising Compound 1 in a salt form and a pharmaceutically acceptable carrier or excipient.

[0020] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient a salt form of Compound 1 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0021] In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient a salt form of Compound 1 or a composition thereof. In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient a salt form of Compound 1 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient a salt form of Compound 1 or a composition thereof.

[0022] As described herein, it has been found that salt forms of Compound 1 can exist in at least 15 distinct polymorphic forms. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1 designated herein as Form A of Compound 2. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1 designated herein as Form A of Compound 3. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1 designated herein as Form A of Compound 4. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1 designated herein as Form A of Compound 5. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1 designated herein as Form A of Compound 6. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1 designated herein as Form A of Compound 7. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1 designated herein as Form A of Compound 8. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1 designated herein as Form A of Compound 9. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1, designated herein as Form A of Compound 10. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1, designated herein as Form A of Compound 11. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1, designated herein as Form A of Compound 12. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1, designated herein as Form A of Compound 13. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1, designated herein as Form A of Compound 14. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1, designated herein as Form A of Compound 15. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1, designated herein as Form A of Compound 16. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1, designated herein as Form B of Compound 16. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1, designated herein as Form A of Compound 16.

[0023] Compound 2 (sulfate of Compound 1) According to one embodiment, the present disclosure provides a sulfate salt of compound 1, represented by compound 2: [ka]

[0024] Those skilled in the art will understand that sulfuric acid and compound 1 ionically combine to form compound 2. In some embodiments, compound 2 is a hydrogen sulfate salt. In some embodiments, compound 2 is a sulfate salt. In some embodiments, compound 2 exists as a mixture of hydrogen sulfate and sulfate salts. It is believed that compound 2 can exist in various physical forms. For example, compound 2 can be in solution, suspension, or solid form. In certain embodiments, compound 2 is in solid form. When compound 2 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0025] In some embodiments, the present disclosure provides Compound 2 that is substantially free of impurities. Such impurities or contaminants may include different forms of Compound 2, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 2. In certain embodiments, the Compound 2 form is present at least about 95% by weight. In still other embodiments of the present disclosure, the Compound 2 form is present at least about 99% by weight.

[0026] According to one embodiment, the Compound 2 form is present in at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the Compound 2 form has an HPLC area percent of all organic impurities of about 3.0 or less relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, an HPLC area percent of all organic impurities of about 1.5 or less. In other embodiments, the Compound 2 form has an HPLC area percent of any single impurity of about 1.0% or less relative to the total area of ​​the HPLC chromatogram, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less.

[0027] Structures depicting forms of Compound 2 are also intended to include all tautomeric forms of Compound 2. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0028] It has been found that Compound 2 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0029] In certain embodiments, Compound 2 is a crystalline solid. In other embodiments, Compound 2 is a crystalline solid that is substantially free of amorphous Compound 2. As used herein, the term "substantially free of amorphous Compound 2" means that the compound does not contain a significant amount of amorphous Compound 2. In certain embodiments, crystalline Compound 2 is present at least about 95% by weight. In yet other embodiments of the present disclosure, crystalline Compound 2 is present at least about 99% by weight.

[0030] It has been found that Compound 2 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 2, designated herein as Form A.

[0031] Form A of Compound 2 A method for preparing Form A of Compound 2 is described below.

[0032] In some embodiments, the present disclosure provides Compound 2: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides Compound 2, wherein the compound is substantially free of amorphous Compound 2. In some embodiments, the disclosure provides Compound 2, wherein the compound is substantially free of amorphous Compound 1. In some embodiments, the disclosure provides Compound 2, wherein the compound is substantially free of crystalline forms of Compound 1. In some embodiments, the disclosure provides Compound 2, wherein the compound is substantially free of impurities.

[0033] In some embodiments, Compound 2 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 16.5, 17.5, and 19.7±0.5 degrees two-theta. In some embodiments, Compound 2 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 16.5, 17.5, and 19.7±0.4 degrees two-theta. In some embodiments, Compound 2 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 16.5, 17.5, and 19.7±0.3 degrees two-theta. In some embodiments, Compound 2 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 16.5, 17.5, and 19.7±0.2 degrees two-theta.

[0034] In some embodiments, the present disclosure provides compound 2, which has an XRPD substantially similar to that shown in FIG. 1A (e.g., having peaks at ±0.2 degrees 2-theta).

[0035] In some embodiments, the disclosure provides Compound 2, wherein the compound has a DSC-TGA substantially similar to that shown in Figure 1B (e.g., an endothermic DSC event onset temperature between 240 and 245°C). In some embodiments, the disclosure provides Compound 2, wherein the compound has a DSC event and / or TGA weight loss as set forth in Table 6.

[0036] In some embodiments, the present disclosure provides a composition comprising Compound 2 and a pharmaceutically acceptable carrier or excipient.

[0037] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient Compound 2 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0038] In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 2 or a composition thereof. In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 2 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 2 or a composition thereof.

[0039] Compound 3 (benzenesulfonate salt of Compound 1) According to one embodiment, the present disclosure provides a benzenesulfonate salt of compound 1, represented by compound 3: [ka]

[0040] Those skilled in the art will understand that benzenesulfonic acid and compound 1 ionically bond to form compound 3. In some embodiments, compound 3 is a benzene sulfate salt. It is believed that compound 3 can exist in various physical forms. For example, compound 3 can be in solution, suspension, or solid form. In certain embodiments, compound 3 is in solid form. When compound 3 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0041] In some embodiments, the present disclosure provides Compound 3 that is substantially free of impurities. Such impurities or contaminants may include different forms of Compound 3, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 3. In certain embodiments, the Compound 3 form is present at least about 95% by weight. In still other embodiments of the present disclosure, the Compound 3 form is present at least about 99% by weight.

[0042] According to one embodiment, the Compound 3 form is present in at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the Compound 3 form has an HPLC area percent of all organic impurities of about 3.0 or less relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, an HPLC area percent of all organic impurities of about 1.5 or less. In other embodiments, the Compound 3 form has an HPLC area percent of any single impurity of about 1.0% or less relative to the total area of ​​the HPLC chromatogram, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less.

[0043] Structures depicting forms of Compound 3 are also intended to include all tautomeric forms of Compound 3. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0044] It has been found that compound 3 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0045] In certain embodiments, Compound 3 is a crystalline solid. In other embodiments, Compound 3 is a crystalline solid that is substantially free of amorphous Compound 3. As used herein, the term "substantially free of amorphous Compound 3" means that the compound does not contain a significant amount of amorphous Compound 3. In certain embodiments, crystalline Compound 3 is present at least about 95% by weight. In yet other embodiments of the present disclosure, crystalline Compound 3 is present at least about 99% by weight.

[0046] It has been found that Compound 3 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 3, designated herein as Form A.

[0047] Form A of Compound 3 A method for preparing Form A of Compound 3 is described below.

[0048] In some embodiments, the present disclosure provides compound 3: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides Compound 3, wherein the compound is substantially free of amorphous Compound 3. In some embodiments, the disclosure provides Compound 3, wherein the compound is substantially free of amorphous Compound 1. In some embodiments, the disclosure provides Compound 3, wherein the compound is substantially free of crystalline forms of Compound 1. In some embodiments, the disclosure provides Compound 3, wherein the compound is substantially free of impurities.

[0049] In some embodiments, Compound 3 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 5.6, 11.5, and 16.5±0.5 degrees two-theta. In some embodiments, Compound 3 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 5.6, 11.5, and 16.5±0.4 degrees two-theta. In some embodiments, Compound 3 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 5.6, 11.5, and 16.5±0.3 degrees two-theta. In some embodiments, Compound 3 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 5.6, 11.5, and 16.5±0.2 degrees two-theta.

[0050] In some embodiments, the present disclosure provides compound 3, which has an XRPD substantially similar to that shown in FIG. 2A (e.g., having peaks at ±0.2 degrees 2-theta).

[0051] In some embodiments, the disclosure provides Compound 3, wherein the compound has a DSC-TGA substantially similar to that shown in Figure 2B (e.g., an endothermic DSC event onset temperature between 180 and 185°C). In some embodiments, the disclosure provides Compound 3, wherein the compound has a DSC event and / or TGA weight loss as set forth in Table 6.

[0052] In some embodiments, the present disclosure provides a composition comprising Compound 3 and a pharmaceutically acceptable carrier or excipient.

[0053] In some embodiments, the disclosure provides methods of modulating IRAK4 kinase in a patient, comprising administering to the patient Compound 3 or a composition thereof. In some embodiments, the methods ubiquitinate and / or degrade IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0054] In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 3 or a composition thereof. In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 3 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 3 or a composition thereof.

[0055] Compound 4 (toluenesulfonate of Compound 1) According to one embodiment, the present disclosure provides a toluenesulfonic acid salt of compound 1, represented by compound 4: [ka]

[0056] Those skilled in the art will understand that toluenesulfonic acid and compound 1 ionically bond to form compound 4. In some embodiments, compound 4 is a toluene sulfate salt. It is believed that compound 4 can exist in various physical forms. For example, compound 4 can be a solution, a suspension, or a solid form. In certain embodiments, compound 4 is in a solid form. When compound 4 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0057] In some embodiments, the present disclosure provides Compound 4 that is substantially free of impurities. Such impurities or contaminants may include different forms of Compound 4, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 4. In certain embodiments, the form of Compound 4 is present at least about 95% by weight. In still other embodiments of the present disclosure, the form of Compound 4 is present at least about 99% by weight.

[0058] According to one embodiment, the Compound 4 form is present in at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the Compound 4 form has an HPLC area percent of all organic impurities of about 3.0 or less relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, an HPLC area percent of all organic impurities of about 1.5 or less. In other embodiments, the Compound 4 form has an HPLC area percent of any single impurity of about 1.0% or less relative to the total area of ​​the HPLC chromatogram, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less.

[0059] Structures depicting forms of compound 4 are also intended to include all tautomeric forms of compound 4. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0060] It has been found that compound 4 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0061] In certain embodiments, compound 4 is a crystalline solid. In other embodiments, compound 4 is a crystalline solid that is substantially free of amorphous compound 4. As used herein, the term "substantially free of amorphous compound 4" means that the compound does not contain a significant amount of amorphous compound 4. In certain embodiments, crystalline compound 4 is present at least about 95% by weight. In yet other embodiments of the present disclosure, crystalline compound 4 is present at least about 99% by weight.

[0062] It has been found that Compound 4 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 4, designated herein as Form A.

[0063] Form A of Compound 4 A method for preparing Form A of Compound 4 is described below.

[0064] In some embodiments, the present disclosure provides compound 4: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 4, wherein the compound is substantially free of amorphous compound 4. In some embodiments, the disclosure provides compound 4, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 4, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 4, wherein the compound is substantially free of impurities.

[0065] In some embodiments, Compound 4 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 5.9, 11.9, and 16.5±0.5 degrees two-theta. In some embodiments, Compound 4 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 5.9, 11.9, and 16.5±0.4 degrees two-theta. In some embodiments, Compound 4 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 5.9, 11.9, and 16.5±0.3 degrees two-theta. In some embodiments, Compound 4 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 5.9, 11.9, and 16.5±0.2 degrees two-theta.

[0066] In some embodiments, the present disclosure provides compound 4, which has an XRPD substantially similar to that shown in FIG. 3A (e.g., having peaks at ±0.2 degrees 2-theta).

[0067] In some embodiments, the present disclosure provides a composition comprising compound 4 and a pharmaceutically acceptable carrier or excipient.

[0068] In some embodiments, the disclosure provides compound 4, wherein the compound has a DSC-TGA substantially similar to that shown in Figure 3B (e.g., an endothermic DSC event onset temperature between 190-195°C). In some embodiments, the disclosure provides compound 4, wherein the compound has a DSC event and / or TGA weight loss as set forth in Table 6.

[0069] In some embodiments, the disclosure provides methods of modulating IRAK4 kinase in a patient, comprising administering to the patient Compound 4 or a composition thereof. In some embodiments, the methods ubiquitinate and / or degrade IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0070] In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient a salt form of Compound 4 or a composition thereof. In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 4 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 4 or a composition thereof.

[0071] Compound 5 (ethanesulfonic acid salt of compound 1) According to one embodiment, the present disclosure provides an ethanesulfonic acid salt of compound 1, represented by compound 5: [ka]

[0072] Those skilled in the art will understand that ethanesulfonic acid and compound 1 ionically bond to form compound 5. In some embodiments, compound 5 is an ethanesulfonate salt. It is believed that compound 5 can exist in various physical forms. For example, compound 5 can be in solution, suspension, or solid form. In certain embodiments, compound 5 is in solid form. When compound 5 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0073] In some embodiments, the present disclosure provides Compound 5 that is substantially free of impurities. Such impurities or contaminants may include different forms of Compound 5, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 5. In certain embodiments, the form of Compound 5 is present at least about 95% by weight. In still other embodiments of the present disclosure, the form of Compound 5 is present at least about 99% by weight.

[0074] According to one embodiment, the Compound 5 form is present in at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the Compound 5 form has an HPLC area percent of total organic impurities of about 3.0 or less relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, an HPLC area percent of total organic impurities of about 1.5 or less. In other embodiments, the Compound 5 form has an HPLC area percent of any single impurity of about 1.0% or less relative to the total area of ​​the HPLC chromatogram, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less.

[0075] Structures depicting forms of Compound 5 are also intended to include all tautomeric forms of Compound 5. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0076] It has been found that compound 5 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0077] In certain embodiments, Compound 5 is a crystalline solid. In other embodiments, Compound 5 is a crystalline solid that is substantially free of amorphous Compound 5. As used herein, the term "substantially free of amorphous Compound 5" means that the compound does not contain a significant amount of amorphous Compound 5. In certain embodiments, crystalline Compound 5 is present at least about 95% by weight. In yet other embodiments of the present disclosure, crystalline Compound 5 is present at least about 99% by weight.

[0078] It has been found that Compound 5 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 5, designated herein as Form A.

[0079] Form A of Compound 5 A method for preparing Form A of Compound 5 is described below.

[0080] In some embodiments, the present disclosure provides compound 5: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 5, wherein the compound is substantially free of amorphous compound 5. In some embodiments, the disclosure provides compound 5, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 5, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 5, wherein the compound is substantially free of impurities.

[0081] In some embodiments, Compound 5 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 8.2, and 12.4±0.5 degrees two-theta. In some embodiments, Compound 5 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 8.2, and 12.4±0.4 degrees two-theta. In some embodiments, Compound 5 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 8.2, and 12.4±0.3 degrees two-theta. In some embodiments, Compound 5 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 8.2, and 12.4±0.2 degrees two-theta.

[0082] In some embodiments, the present disclosure provides compound 5, which has an XRPD substantially similar to that shown in FIG. 4A (e.g., having peaks at ±0.2 degrees 2-theta).

[0083] In some embodiments, the present disclosure provides a composition comprising compound 5 and a pharmaceutically acceptable carrier or excipient.

[0084] In some embodiments, the disclosure provides compound 5, which has a DSC-TGA substantially similar to that shown in Figure 4B (e.g., with an endothermic DSC event onset temperature between 195 and 200°C). In some embodiments, the disclosure provides compound 5, which has a DSC event and / or TGA weight loss as set forth in Table 6.

[0085] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient Compound 5 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0086] In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 5 or a composition thereof. In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 5 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 5 or a composition thereof.

[0087] Compound 6 (methanesulfonate salt of compound 1) According to one embodiment, the present disclosure provides a methanesulfonate salt of compound 1, represented by compound 6: [ka]

[0088] Those skilled in the art will understand that methanesulfonic acid and compound 1 ionically bond to form compound 6. In some embodiments, compound 6 is a methanesulfate salt. It is believed that compound 6 can exist in various physical forms. For example, compound 6 can be in solution, suspension, or solid form. In certain embodiments, compound 6 is in solid form. When compound 6 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0089] In some embodiments, the present disclosure provides Compound 6 that is substantially free of impurities. Such impurities or contaminants may include different forms of Compound 6, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 6. In certain embodiments, the form of Compound 6 is present at least about 95% by weight. In still other embodiments of the present disclosure, the form of Compound 6 is present at least about 99% by weight.

[0090] According to one embodiment, the Compound 6 form is present at at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the Compound 6 form has an HPLC area percent of all organic impurities of about 3.0 or less relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, an HPLC area percent of all organic impurities of about 1.5 or less. In other embodiments, the Compound 6 form has an HPLC area percent of any single impurity of about 1.0% or less relative to the total area of ​​the HPLC chromatogram, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less.

[0091] Structures depicting forms of compound 6 are also intended to include all tautomeric forms of compound 6. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0092] It has been found that compound 6 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0093] In certain embodiments, Compound 6 is a crystalline solid. In other embodiments, Compound 6 is a crystalline solid that is substantially free of amorphous Compound 6. As used herein, the term "substantially free of amorphous Compound 6" means that the compound does not contain a significant amount of amorphous Compound 6. In certain embodiments, crystalline Compound 6 is present at least about 95% by weight. In yet other embodiments of the present disclosure, a crystalline salt form of Compound 6 is present at least about 99% by weight.

[0094] It has been found that Compound 6 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 6, designated herein as Form A.

[0095] Form A of Compound 6 A method for preparing Form A of Compound 6 is described below.

[0096] In some embodiments, the present disclosure provides compound 6: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 6, wherein the compound is substantially free of amorphous compound 6. In some embodiments, the disclosure provides compound 6, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 6, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 6, wherein the compound is substantially free of impurities.

[0097] In some embodiments, Compound 6 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 16.5, 19.5, and 21.2±0.5 degrees two-theta. In some embodiments, Compound 6 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 16.5, 19.5, and 21.2±0.4 degrees two-theta. In some embodiments, Compound 6 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 16.5, 19.5, and 21.2±0.3 degrees two-theta. In some embodiments, Compound 6 Form A is characterized in its XRPD pattern by one or more peaks selected from peaks at 3.9, 11.9, and 16.5±0.2 degrees two-theta.

[0098] In some embodiments, the present disclosure provides compound 6, which has an XRPD substantially similar to that shown in FIG. 5A (e.g., having peaks at ±0.2 degrees 2-theta).

[0099] In some embodiments, the present disclosure provides a composition comprising compound 6 and a pharmaceutically acceptable carrier or excipient.

[0100] In some embodiments, the disclosure provides Compound 6, wherein the compound has a DSC-TGA substantially similar to that shown in Figure 5B (e.g., an endothermic DSC event onset temperature between 248 and 253°C). In some embodiments, the disclosure provides Compound 6, wherein the compound has a DSC event and / or TGA weight loss as set forth in Table 6.

[0101] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient a salt form of Compound 6 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0102] In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 6 or a composition thereof. In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 6 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 6 or a composition thereof.

[0103] Compound 7 (maleate salt of Compound 1) According to one embodiment, the present disclosure provides a maleate salt of compound 1, represented by compound 7: [ka]

[0104] Those skilled in the art will understand that maleic acid and compound 1 ionically bond to form compound 7. In some embodiments, compound 7 is a maleate salt. In some embodiments, compound 7 is a hydrogen maleate salt. In some embodiments, compound 7 exists as a mixture of hydrogen maleate and maleate salts. It is believed that compound 7 can exist in various physical forms. For example, compound 7 can be in solution, suspension, or solid form. In certain embodiments, compound 7 is in solid form. When compound 7 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0105] In some embodiments, the present disclosure provides Compound 7 that is substantially free of impurities. Such impurities or contaminants may include different forms of Compound 7, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 7. In certain embodiments, the form of Compound 7 is present at least about 95% by weight. In still other embodiments of the present disclosure, the form of Compound 7 is present at least about 99% by weight.

[0106] According to one embodiment, the compound 7 form is present at at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the compound 7 form has an HPLC area percent of total organic impurities of about 3.0 or less relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, an HPLC area percent of total organic impurities of about 1.5 or less. In other embodiments, the compound 7 form has an HPLC area percent of any single impurity of about 1.0% or less relative to the total area of ​​the HPLC chromatogram, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less.

[0107] Structures depicting forms of compound 7 are also intended to include all tautomeric forms of compound 7. Furthermore, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0108] It has been found that compound 7 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0109] In certain embodiments, compound 7 is a crystalline solid. In other embodiments, compound 7 is a crystalline solid that is substantially free of amorphous compound 7. As used herein, the term "substantially free of amorphous compound 7" means that the compound does not contain a significant amount of amorphous compound 7. In certain embodiments, crystalline compound 7 is present at least about 95% by weight. In yet other embodiments of the present disclosure, crystalline compound 7 is present at least about 99% by weight.

[0110] It has been found that Compound 7 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 7, designated herein as Form A.

[0111] Form A of Compound 7 A method for preparing Form A of Compound 7 is described below.

[0112] In some embodiments, the present disclosure provides compound 7: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 7, wherein the compound is substantially free of amorphous compound 7. In some embodiments, the disclosure provides compound 7, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 7, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 7, wherein the compound is substantially free of impurities.

[0113] In some embodiments, Form A of Compound 7 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 16.5, and 18.5±0.5 degrees two-theta. In some embodiments, Form A of Compound 7 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 16.5, and 18.5±0.4 degrees two-theta. In some embodiments, Form A of Compound 7 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 16.5, and 18.5±0.3 degrees two-theta. In some embodiments, Form A of Compound 7 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 16.5, and 18.5±0.2 degrees two-theta.

[0114] In some embodiments, the present disclosure provides compound 7, which has an XRPD substantially similar to that shown in FIG. 6A (e.g., having peaks at ±0.2 degrees 2-theta).

[0115] In some embodiments, the present disclosure provides a composition comprising compound 7 and a pharmaceutically acceptable carrier or excipient.

[0116] In some embodiments, the disclosure provides compound 7, which has a DSC-TGA substantially similar to that shown in Figure 6B (e.g., with an endothermic DSC event onset temperature between 218 and 223°C). In some embodiments, the disclosure provides compound 7, which has a DSC event and / or TGA weight loss as set forth in Table 6.

[0117] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient Compound 7 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0118] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 7 or a composition thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 7 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the present disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 7 or a composition thereof.

[0119] Compound 8 (L-tartrate salt of Compound 1) According to one embodiment, the present disclosure provides an L-tartrate salt of compound 1, represented by compound 8: [ka]

[0120] Those skilled in the art will understand that L-tartaric acid and compound 1 ionically bond to form compound 8. In some embodiments, compound 8 is an L-bitartrate salt. In some embodiments, compound 8 is an L-tartrate salt. In some embodiments, compound 8 exists as a mixture of L-bitartrate salt and L-tartrate salt. It is believed that compound 8 can exist in various physical forms. For example, compound 8 can be in solution, suspension, or solid form. In certain embodiments, compound 8 is in solid form. When compound 8 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0121] In some embodiments, the present disclosure provides Compound 8 that is substantially free of impurities. Such impurities or contaminants may include different forms of Compound 8, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 8. In certain embodiments, the form of Compound 8 is present at least about 95% by weight. In still other embodiments of the present disclosure, the form of Compound 8 is present at least about 99% by weight.

[0122] According to one embodiment, the Compound 8 form is present at at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the Compound 8 form has an HPLC area percent of all organic impurities of about 3.0 or less relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, an HPLC area percent of all organic impurities of about 1.5 or less. In other embodiments, the Compound 8 form has an HPLC area percent of any single impurity of about 1.0% or less relative to the total area of ​​the HPLC chromatogram, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less.

[0123] Structures depicting forms of compound 8 are also intended to include all tautomeric forms of compound 8. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0124] It has been found that compound 8 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0125] In certain embodiments, compound 8 is a crystalline solid. In other embodiments, compound 8 is a crystalline solid that is substantially free of amorphous compound 8. As used herein, the term "substantially free of amorphous compound 8" means that the compound does not contain a significant amount of amorphous compound 8. In certain embodiments, crystalline compound 9 is present at least about 95% by weight. In yet other embodiments of the present disclosure, crystalline compound 8 is present at least about 99% by weight.

[0126] It has been found that Compound 8 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 8, designated herein as Form A.

[0127] Form A of Compound 8 A method for preparing Form A of Compound 8 is described below.

[0128] In some embodiments, the present disclosure provides compound 8: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 8, wherein the compound is substantially free of amorphous compound 8. In some embodiments, the disclosure provides compound 8, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 8, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 9, wherein the compound is substantially free of impurities.

[0129] In some embodiments, Form A of Compound 8 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 16.5, and 17.5±0.5 degrees two-theta. In some embodiments, Form A of Compound 8 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 16.5, and 17.5±0.4 degrees two-theta. In some embodiments, Form A of Compound 8 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 16.5, and 17.5±0.3 degrees two-theta. In some embodiments, Form A of Compound 8 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 16.5, and 17.5±0.2 degrees two-theta.

[0130] In some embodiments, the present disclosure provides compound 8, which has an XRPD substantially similar to that shown in FIG. 7A (e.g., having peaks at ±0.2 degrees 2-theta).

[0131] In some embodiments, the present disclosure provides a composition comprising compound 8 and a pharmaceutically acceptable carrier or excipient.

[0132] In some embodiments, the disclosure provides compound 8, wherein the compound has a DSC-TGA substantially similar to that shown in Figure 7B (e.g., an endothermic DSC event onset temperature between 250 and 255°C). In some embodiments, the disclosure provides compound 8, wherein the compound has a DSC event and / or TGA weight loss as set forth in Table 6.

[0133] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient Compound 8 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0134] In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 8 or a composition thereof. In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 8 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 9 or a composition thereof.

[0135] Compound 9 (Fumarate of Compound 1) According to one embodiment, the present disclosure provides a fumarate salt of compound 1, represented by compound 9: [ka]

[0136] Those skilled in the art will understand that fumaric acid and compound 1 ionically bond to form compound 9. In some embodiments, compound 9 is a hydrogen fumarate salt. In some embodiments, compound 9 is a fumarate salt. In some embodiments, compound 9 exists as a mixture of hydrogen fumarate and fumarate salts. It is believed that compound 9 can exist in various physical forms. For example, compound 9 can be in solution, suspension, or solid form. In certain embodiments, compound 9 is in solid form. When compound 9 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0137] In some embodiments, the present disclosure provides Compound 9 that is substantially free of impurities. Such impurities or contaminants may include different forms of Compound 9, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 9. In certain embodiments, the form of Compound 9 is present at least about 95% by weight. In still other embodiments of the present disclosure, the form of Compound 9 is present at least about 99% by weight.

[0138] According to one embodiment, the compound 9 form is present at at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the compound 9 form has an HPLC area percent of all organic impurities relative to the total area of ​​the HPLC chromatogram of about 3.0 or less, and in certain embodiments, an HPLC area percent of all organic impurities relative to the total area of ​​the HPLC chromatogram of about 1.5 or less. In other embodiments, the compound 9 form has an HPLC area percent of any single impurity of about 1.0% or less, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less, relative to the total area of ​​the HPLC chromatogram.

[0139] Structures depicting forms of compound 9 are also intended to include all tautomeric forms of compound 9. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0140] It has been found that compound 9 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0141] In certain embodiments, compound 9 is a crystalline solid. In other embodiments, compound 10 is a crystalline solid that is substantially free of amorphous compound 9. As used herein, the term "substantially free of amorphous compound 9" means that the compound does not contain a significant amount of amorphous compound 9. In certain embodiments, crystalline compound 9 is present at least about 95% by weight. In yet other embodiments of the present disclosure, crystalline compound 9 is present at least about 99% by weight.

[0142] It has been found that Compound 9 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 9, designated herein as Form A.

[0143] Form A of Compound 9 A method for preparing Form A of Compound 9 is described below.

[0144] In some embodiments, the present disclosure provides compound 9: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 10, wherein the compound is substantially free of amorphous compound 9. In some embodiments, the disclosure provides compound 9, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 9, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 9, wherein the compound is substantially free of impurities.

[0145] In some embodiments, Form A of Compound 9 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.7, 10.7, and 16.3±0.5 degrees two-theta. In some embodiments, Form A of Compound 9 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.7, 10.7, and 16.3±0.4 degrees two-theta. In some embodiments, Form A of Compound 9 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.7, 10.7, and 16.3±0.3 degrees two-theta. In some embodiments, Form A of Compound 9 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.7, 10.7, and 16.3±0.2 degrees two-theta.

[0146] In some embodiments, the present disclosure provides compound 9, which has an XRPD substantially similar to that shown in FIG. 8A (e.g., having peaks at ±0.2 degrees 2-theta).

[0147] In some embodiments, the present disclosure provides a composition comprising compound 9 and a pharmaceutically acceptable carrier or excipient.

[0148] In some embodiments, the disclosure provides compound 9, which has a DSC-TGA substantially similar to that shown in Figure 8B (e.g., with an endothermic DSC event onset temperature between 266 and 271°C). In some embodiments, the disclosure provides compound 9, which has a DSC event and / or TGA weight loss as set forth in Table 6.

[0149] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient Compound 9 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0150] In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 9 or a composition thereof. In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 9 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 9 or a composition thereof.

[0151] Compound 10 (citrate salt of Compound 1) According to one embodiment, the present disclosure provides a citrate salt of compound 1, designated compound 10: [ka]

[0152] Those skilled in the art will understand that citric acid and compound 1 ionically bond to form compound 10. In some embodiments, compound 10 is a dihydrogen citrate salt. In some embodiments, compound 10 is a hydrogen citrate salt. In some embodiments, compound 10 is a citrate salt. In some embodiments, compound 10 exists as a mixture of dihydrogen citrate salt, hydrogen citrate salt, and citrate salt. It is believed that compound 10 can exist in various physical forms. For example, compound 10 can be in solution, suspension, or solid form. In certain embodiments, compound 10 is in solid form. When compound 10 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0153] In some embodiments, the present disclosure provides Compound 10 that is substantially free of impurities. Such impurities or contaminants may include different forms of Compound 10, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 10. In certain embodiments, at least about 95% by weight of a form of Compound 10 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of a form of Compound 10 is present.

[0154] According to one embodiment, a form of Compound 10 is present in at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, a form of Compound 10 has an HPLC area percent of total organic impurities of about 3.0 or less relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, an HPLC area percent of total organic impurities of about 1.5 or less. In other embodiments, a form of Compound 10 has an HPLC area percent of any single impurity of about 1.0% or less relative to the total area of ​​the HPLC chromatogram, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less.

[0155] Structures depicting forms of compound 10 are also intended to include all tautomeric forms of compound 10. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0156] It has been found that compound 10 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0157] In certain embodiments, Compound 10 is a crystalline solid. In other embodiments, Compound 10 is a crystalline solid that is substantially free of amorphous Compound 10. As used herein, the term "substantially free of amorphous Compound 10" means that the compound does not contain a significant amount of amorphous Compound 10. In certain embodiments, crystalline Compound 10 is present at least about 95% by weight. In yet other embodiments of the present disclosure, crystalline Compound 10 is present at least about 99% by weight.

[0158] It has been found that Compound 10 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 10, designated herein as Form A.

[0159] Form A of Compound 10 A method for preparing Form A of Compound 10 is described below.

[0160] In some embodiments, the present disclosure provides compound 10: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 10, wherein the compound is substantially free of amorphous compound 10. In some embodiments, the disclosure provides compound 10, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 10, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 10, wherein the compound is substantially free of impurities.

[0161] In some embodiments, Form A of Compound 10 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 11.9, and 16.5±0.5 degrees two-theta. In some embodiments, Form A of Compound 10 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 11.9, and 16.5±0.4 degrees two-theta. In some embodiments, Form A of Compound 10 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 11.9, and 16.5±0.3 degrees two-theta. In some embodiments, Form A of Compound 10 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 11.9, and 16.5±0.2 degrees two-theta.

[0162] In some embodiments, the present disclosure provides compound 10, which has an XRPD substantially similar to that shown in Figure 9A (e.g., having peaks at ±0.2 degrees 2-theta).

[0163] In some embodiments, the disclosure provides compound 10, which has a DSC-TGA substantially similar to that shown in Figure 9B (e.g., with an endothermic DSC event onset temperature between 171-176°C). In some embodiments, the disclosure provides compound 10, which has a DSC event and / or TGA weight loss as set forth in Table 6.

[0164] In some embodiments, the present disclosure provides a composition comprising compound 10 and a pharmaceutically acceptable carrier or excipient.

[0165] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient Compound 10 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0166] In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 10 or a composition thereof. In some embodiments, the disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 10 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 10 or a composition thereof.

[0167] Compound 11 (glycolate salt of Compound 1) According to one embodiment, the present disclosure provides a glycolic acid salt of compound 1, designated compound 11: [ka]

[0168] Those skilled in the art will understand that glycolic acid and compound 1 are ionically bonded to form compound 11. In some embodiments, compound 11 is a glycolate salt. It is believed that compound 11 can exist in various physical forms. For example, compound 11 can be in solution, suspension, or solid form. In certain embodiments, compound 11 is in solid form. When the salt form of compound 11 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0169] In some embodiments, the present disclosure provides Compound 11 that is substantially free of impurities. Such impurities or contaminants may include different forms of Compound 11, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 11. In certain embodiments, the form of Compound 11 is present at least about 95% by weight. In still other embodiments of the present disclosure, the form of Compound 11 is present at least about 99% by weight.

[0170] According to one embodiment, the compound 11 form is present in at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the compound 11 form has an HPLC area percent of total organic impurities of about 3.0 or less relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, an HPLC area percent of total organic impurities of about 1.5 or less. In other embodiments, the compound 11 form has an HPLC area percent of any single impurity of about 1.0% or less relative to the total area of ​​the HPLC chromatogram, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less.

[0171] Structures depicting forms of compound 11 are also intended to include all tautomeric forms of compound 11. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0172] It has been found that compound 11 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0173] In certain embodiments, compound 11 is a crystalline solid. In other embodiments, compound 11 is a crystalline solid that is substantially free of amorphous compound 11. As used herein, the term "substantially free of amorphous compound 11" means that the compound does not contain a significant amount of amorphous compound 11. In certain embodiments, crystalline compound 11 is present at least about 95% by weight. In yet other embodiments of the present disclosure, crystalline compound 11 is present at least about 99% by weight.

[0174] It has been found that Compound 11 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 11, designated herein as Form A.

[0175] Form A of Compound 11 A method for preparing Form A of Compound 11 is described below.

[0176] In some embodiments, the present disclosure provides compound 11: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 11, wherein the compound is substantially free of amorphous compound 11. In some embodiments, the disclosure provides compound 11, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 11, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 11, wherein the compound is substantially free of impurities.

[0177] In some embodiments, Form A of Compound 11 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.8, 13.0, and 17.1±0.5 degrees two-theta. In some embodiments, Form A of Compound 11 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.8, 13.0, and 17.1±0.4 degrees two-theta. In some embodiments, Form A of Compound 11 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.8, 13.0, and 17.1±0.3 degrees two-theta. In some embodiments, Form A of Compound 11 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.8, 13.0, and 17.1±0.2 degrees two-theta.

[0178] In some embodiments, the present disclosure provides compound 11, which has an XRPD substantially similar to that shown in FIG. 10A (e.g., having peaks at ±0.2 degrees 2-theta).

[0179] In some embodiments, the disclosure provides compound 11, wherein the compound has a DSC-TGA substantially similar to that shown in Figure 10B (e.g., an endothermic DSC event onset temperature between 197 and 202°C). In some embodiments, the disclosure provides compound 11, wherein the compound has a DSC event and / or TGA weight loss as set forth in Table 6.

[0180] In some embodiments, the present disclosure provides a composition comprising compound 12 and a pharmaceutically acceptable carrier or excipient.

[0181] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient Compound 11 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0182] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 11 or a composition thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 11 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the present disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 11 or a composition thereof.

[0183] Compound 12 (L-malate of Compound 1) According to one embodiment, the present disclosure provides an L-malate salt of compound 1, represented by compound 12: [ka]

[0184] Those skilled in the art will understand that L-malic acid and compound 1 ionically bond to form compound 12. In some embodiments, compound 12 is L-hydrogen malate. In some embodiments, compound 12 is L-malate. It is believed that compound 12 can exist in various physical forms. For example, a salt form of compound 12 can be a solution, a suspension, or a solid form. In certain embodiments, compound 12 is in a solid form. When compound 12 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0185] In some embodiments, the present disclosure provides compound 12 that is substantially free of impurities. Such impurities or contaminants may include different forms of compound 12, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 12. In certain embodiments, a form of compound 12 is present in at least about 95% by weight. In still other embodiments of the present disclosure, a form of compound 12 is present in at least about 99% by weight.

[0186] According to one embodiment, the compound 12 form is present at at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the compound 12 form has an HPLC area percent of all organic impurities of about 3.0 or less relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, an HPLC area percent of all organic impurities of about 1.5 or less. In other embodiments, the compound 12 form has an HPLC area percent of any single impurity of about 1.0% or less relative to the total area of ​​the HPLC chromatogram, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less.

[0187] Structures depicting forms of compound 12 are also intended to include all tautomeric forms of compound 12. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0188] It has been found that compound 12 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0189] In certain embodiments, compound 12 is a crystalline solid. In other embodiments, compound 12 is a crystalline solid that is substantially free of amorphous compound 12. As used herein, the term "substantially free of amorphous compound 12" means that the compound does not contain a significant amount of amorphous compound 12. In certain embodiments, crystalline compound 12 is present at least about 95% by weight. In yet other embodiments of the present disclosure, crystalline compound 12 is present at least about 99% by weight.

[0190] It has been found that Compound 12 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 12, designated herein as Form A.

[0191] Form A of Compound 12 A method for preparing Form A of Compound 12 is described below.

[0192] In some embodiments, the present disclosure provides compound 12: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 12, wherein the compound is substantially free of amorphous compound 12. In some embodiments, the disclosure provides compound 12, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 12, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 12, wherein the compound is substantially free of impurities.

[0193] In some embodiments, Form A of Compound 12 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 10.8, and 16.8±0.5 degrees two-theta. In some embodiments, Form A of Compound 12 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 10.8, and 16.8±0.4 degrees two-theta. In some embodiments, Form A of Compound 12 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 10.8, and 16.8±0.3 degrees two-theta. In some embodiments, Form A of Compound 12 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 10.8, and 16.8±0.2 degrees two-theta.

[0194] In some embodiments, the present disclosure provides compound 12, which has an XRPD substantially similar to that shown in FIG. 11A (e.g., having peaks at ±0.2 degrees 2-theta).

[0195] In some embodiments, the disclosure provides compound 12, wherein the compound has a DSC-TGA substantially similar to that shown in Figure 11B (e.g., an endothermic DSC event onset temperature between 257 and 262°C). In some embodiments, the disclosure provides compound 12, wherein the compound has a DSC event and / or TGA weight loss as set forth in Table 6.

[0196] In some embodiments, the present disclosure provides a composition comprising compound 12 and a pharmaceutically acceptable carrier or excipient.

[0197] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient Compound 12 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0198] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 12 or a composition thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 12 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the present disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 12 or a composition thereof.

[0199] Compound 13 (the hippurate salt of Compound 1) According to one embodiment, the present disclosure provides a hippuric acid salt of compound 1, designated compound 13: [ka]

[0200] Those skilled in the art will understand that hippuric acid and compound 1 ionically bond to form compound 13. In some embodiments, compound 13 is a hippurate salt. It is believed that compound 13 can exist in various physical forms. For example, compound 13 can be in solution, suspension, or solid form. In certain embodiments, compound 13 is in solid form. When compound 13 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0201] In some embodiments, the present disclosure provides compound 13 that is substantially free of impurities. Such impurities or contaminants may include different forms of compound 13, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 13. In certain embodiments, the form of compound 13 is present at least about 95% by weight. In yet other embodiments of the present disclosure, the form of compound 15 is present at least about 99% by weight.

[0202] According to one embodiment, the compound 13 form is present at at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the compound 13 form has an HPLC area percent of all organic impurities of about 3.0 or less relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, an HPLC area percent of all organic impurities of about 1.5 or less. In other embodiments, the compound 13 form has an HPLC area percent of any single impurity of about 1.0% or less relative to the total area of ​​the HPLC chromatogram, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less.

[0203] Structures depicting forms of compound 13 are also intended to include all tautomeric forms of compound 13. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0204] It has been found that compound 13 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0205] In certain embodiments, compound 13 is a crystalline solid. In other embodiments, compound 13 is a crystalline solid that is substantially free of amorphous compound 13. As used herein, the term "substantially free of amorphous compound 13" means that the compound does not contain a significant amount of amorphous compound 13. In certain embodiments, crystalline compound 13 is present at least about 95% by weight. In yet other embodiments of the present disclosure, crystalline compound 13 is present at least about 99% by weight.

[0206] It has been found that Compound 13 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 13 designated Form A.

[0207] Form A of Compound 13 A method for preparing Form A of Compound 13 is described below.

[0208] In some embodiments, the present disclosure provides compound 13: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 13, wherein the compound is substantially free of amorphous compound 13. In some embodiments, the disclosure provides compound 13, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 13, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 13, wherein the compound is substantially free of impurities.

[0209] In some embodiments, Form A of Compound 13 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 16.3, and 20.1±0.5 degrees two-theta. In some embodiments, Form A of Compound 13 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 16.3, and 20.1±0.4 degrees two-theta. In some embodiments, Form A of Compound 13 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 16.3, and 20.1±0.3 degrees two-theta. In some embodiments, Form A of Compound 13 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 16.3, and 20.1±0.2 degrees two-theta.

[0210] In some embodiments, the present disclosure provides compound 13, which has an XRPD substantially similar to that shown in FIG. 12A (e.g., having peaks at ±0.2 degrees 2-theta).

[0211] In some embodiments, the disclosure provides compound 13, wherein the compound has a DSC-TGA substantially similar to that shown in Figure 12B (e.g., an endothermic DSC event onset temperature between 199 and 204°C). In some embodiments, the disclosure provides compound 13, wherein the compound has a DSC event and / or TGA weight loss as set forth in Table 6.

[0212] In some embodiments, the present disclosure provides a composition comprising compound 13 and a pharmaceutically acceptable carrier or excipient.

[0213] In some embodiments, the disclosure provides methods of modulating IRAK4 kinase in a patient, comprising administering to the patient compound 13 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0214] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 13 or a composition thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 13 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the present disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 13 or a composition thereof.

[0215] Compound 14 (L-lactate of Compound 1) According to one embodiment, the present disclosure provides an L-lactate salt of compound 1, represented by compound 14: [ka]

[0216] Those skilled in the art will understand that L-lactic acid and compound 1 are ionically bonded to form compound 14. In some embodiments, compound 14 is a lactate salt. It is believed that compound 14 may exist in various physical forms. For example, compound 14 may be in solution, suspension, or solid form. In certain embodiments, compound 14 is in solid form. When compound 14 is in solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0217] In some embodiments, the present disclosure provides a salt form of Compound 14 that is substantially free of impurities. Such impurities or contaminants may include different forms of Compound 14, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 14. In certain embodiments, the form of Compound 14 is present at least about 95% by weight. In yet other embodiments of the present disclosure, the form of Compound 14 is present at least about 99% by weight.

[0218] According to one embodiment, the compound 14 form is present at at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the compound 14 form has an HPLC area percent of total organic impurities of about 3.0 or less relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, an HPLC area percent of total organic impurities of about 1.5 or less. In other embodiments, the compound 14 form has an HPLC area percent of any single impurity of about 1.0% or less relative to the total area of ​​the HPLC chromatogram, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less.

[0219] Structures depicting forms of compound 14 are also intended to include all tautomeric forms of compound 14. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0220] It has been found that compound 14 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0221] In certain embodiments, compound 16 is a crystalline solid. In other embodiments, compound 14 is a crystalline solid that is substantially free of amorphous compound 14. As used herein, the term "substantially free of amorphous compound 14" means that the compound does not contain a significant amount of amorphous compound 14. In certain embodiments, crystalline compound 14 is present at least about 95% by weight. In yet other embodiments of the present disclosure, crystalline compound 16 is present at least about 99% by weight.

[0222] It has been found that Compound 14 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 14, designated herein as Form A.

[0223] Form A of Compound 14 A method for preparing Form A of Compound 14 is described below.

[0224] In some embodiments, the present disclosure provides compound 14: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 14, wherein the compound is substantially free of amorphous compound 14. In some embodiments, the disclosure provides compound 14, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 14, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 14, wherein the compound is substantially free of impurities.

[0225] In some embodiments, Form A of Compound 14 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 17.1, and 21.0±0.5 degrees two-theta. In some embodiments, Form A of Compound 14 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 17.1, and 21.0±0.4 degrees two-theta. In some embodiments, Form A of Compound 14 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 17.1, and 21.0±0.3 degrees two-theta. In some embodiments, Form A of Compound 14 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 17.1, and 21.0±0.2 degrees two-theta.

[0226] In some embodiments, the present disclosure provides compound 14, which has an XRPD substantially similar to that shown in FIG. 13A (e.g., having peaks at ±0.2 degrees 2-theta).

[0227] In some embodiments, the disclosure provides compound 14, wherein the compound has a DSC-TGA substantially similar to that shown in Figure 13B (e.g., an endothermic DSC event onset temperature between 170-175°C). In some embodiments, the disclosure provides compound 14, wherein the compound has a DSC event and / or TGA weight loss as set forth in Table 6.

[0228] In some embodiments, the present disclosure provides a composition comprising compound 14 and a pharmaceutically acceptable carrier or excipient.

[0229] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient Compound 14 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0230] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 14 or a composition thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 14 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the present disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 14 or a composition thereof.

[0231] Compound 15 (benzoate of Compound 1) According to one embodiment, the present disclosure provides a benzoate salt of compound 1, represented by compound 15: [ka]

[0232] Those skilled in the art will understand that benzoic acid and compound 1 ionically bond to form compound 15. In some embodiments, compound 15 is a benzoate salt. It is believed that compound 15 can exist in various physical forms. For example, compound 15 can be a solution, a suspension, or a solid form. In certain embodiments, compound 15 is in a solid form. When compound 15 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0233] In some embodiments, the present disclosure provides Compound 15 that is substantially free of impurities. Such impurities or contaminants may include different forms of Compound 15, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 15. In certain embodiments, at least about 95% by weight of a form of Compound 15 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of a form of Compound 15 is present.

[0234] According to one embodiment, the compound 15 form is present in at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the compound 15 form has an HPLC area percent of total organic impurities of about 3.0 or less relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, an HPLC area percent of total organic impurities of about 1.5 or less. In other embodiments, the compound 15 form has an HPLC area percent of any single impurity of about 1.0% or less relative to the total area of ​​the HPLC chromatogram, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less.

[0235] Structures depicting forms of compound 15 are also intended to include all tautomeric forms of compound 15. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0236] It has been found that compound 15 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0237] In certain embodiments, compound 15 is a crystalline solid. In other embodiments, compound 15 is a crystalline solid that is substantially free of amorphous compound 15. As used herein, the term "substantially free of amorphous compound 15" means that the compound does not contain a significant amount of amorphous compound 15. In certain embodiments, crystalline compound 15 is present at least about 95% by weight. In yet other embodiments of the present disclosure, crystalline compound 15 is present at least about 99% by weight.

[0238] It has been found that Compound 15 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 15, designated herein as Form A.

[0239] Compound 15 Form A A method for preparing Form A of Compound 15 is described below.

[0240] In some embodiments, the present disclosure provides compound 15: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 15, wherein the compound is substantially free of amorphous compound 15. In some embodiments, the disclosure provides compound 15, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 15, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 15, wherein the compound is substantially free of impurities.

[0241] In some embodiments, Form A of Compound 15 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 17.0, and 20.2±0.5 degrees two-theta. In some embodiments, Form A of Compound 15 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 17.0, and 20.2±0.4 degrees two-theta. In some embodiments, Form A of Compound 15 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 17.0, and 20.2±0.3 degrees two-theta. In some embodiments, Form A of Compound 15 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 17.0, and 20.2±0.2 degrees two-theta.

[0242] In some embodiments, the present disclosure provides compound 15, which has an XRPD substantially similar to that shown in FIG. 14A (e.g., having peaks at ±0.2 degrees 2-theta).

[0243] In some embodiments, the disclosure provides compound 15, which has a DSC-TGA substantially similar to that shown in Figure 14B (e.g., with an endothermic DSC event onset temperature between 149 and 154°C). In some embodiments, the disclosure provides compound 15, which has a DSC event and / or TGA weight loss as set forth in Table 6.

[0244] In some embodiments, the present disclosure provides a composition comprising compound 15 and a pharmaceutically acceptable carrier or excipient.

[0245] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient compound 15 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0246] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 15 or a composition thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 15 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the present disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 15 or a composition thereof.

[0247] Compound 16 (succinate of Compound 1) According to one embodiment, the present disclosure provides a succinate salt of compound 1, represented by compound 16: [ka]

[0248] Those skilled in the art will understand that succinic acid and compound 1 ionically bond to form compound 16. In some embodiments, compound 16 is a hydrogen succinate salt. In some embodiments, compound 16 is a succinate salt. It is believed that compound 16 can exist in various physical forms. For example, compound 16 can be in solution, suspension, or solid form. In certain embodiments, compound 16 is in solid form. When compound 15 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0249] In some embodiments, the present disclosure provides compound 16 that is substantially free of impurities. Such impurities or contaminants may include different forms of compound 16, residual solvent, or any other impurities that may result from the preparation and / or isolation of compound 16. In certain embodiments, a form of compound 16 is present at least about 95% by weight. In yet other embodiments of the present disclosure, a form of compound 16 is present at least about 99% by weight.

[0250] According to one embodiment, the form of Compound 16 is present in at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8 weight percent (wherein the percentages are based on the total weight of the composition). According to another embodiment, the form of Compound 16 has an HPLC area percent of all organic impurities of about 3.0 or less relative to the total area of ​​the HPLC chromatogram, and in certain embodiments, an HPLC area percent of all organic impurities of about 1.5 or less. In other embodiments, the form of Compound 16 has an HPLC area percent of any single impurity of about 1.0% or less relative to the total area of ​​the HPLC chromatogram, an HPLC area percent of any single impurity of about 0.6 or less, and in certain embodiments, an HPLC area percent of any single impurity of about 0.5 or less.

[0251] Structures depicting forms of compound 16 are also intended to include all tautomeric forms of compound 16. Additionally, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon with a C-rich carbon are within the scope of this invention.

[0252] It has been found that compound 16 can exist in various solid forms, exemplary of which include polymorphs as described herein.

[0253] In certain embodiments, compound 16 is a crystalline solid. In other embodiments, compound 16 is a crystalline solid that is substantially free of amorphous compound 16. As used herein, the term "substantially free of amorphous compound 16" means that the compound does not contain a significant amount of amorphous compound 16. In certain embodiments, crystalline compound 16 is present at least about 95% by weight. In yet other embodiments of the present disclosure, crystalline compound 16 is present at least about 99% by weight.

[0254] It has been found that Compound 16 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 16, designated herein as Form A.

[0255] Form A of Compound 16 A method for preparing Form A of Compound 16 is described below.

[0256] In some embodiments, the present disclosure provides compound 16: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 16, wherein the compound is substantially free of amorphous compound 16. In some embodiments, the disclosure provides compound 16, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 16, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 16, wherein the compound is substantially free of impurities.

[0257] In some embodiments, Form A of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 12.9, and 16.2±0.5 degrees two-theta. In some embodiments, Form A of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 12.9, and 16.2±0.4 degrees two-theta. In some embodiments, Form A of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 12.9, and 16.2±0.3 degrees two-theta. In some embodiments, Form A of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.5, 12.9, and 16.2±0.2 degrees two-theta.

[0258] In some embodiments, the present disclosure provides compound 16, which has an XRPD substantially similar to that shown in FIG. 15A (e.g., having peaks at ±0.2 degrees 2-theta).

[0259] In some embodiments, the disclosure provides compound 16, which has a DSC-TGA substantially similar to that shown in Figure 15D (e.g., with an endothermic DSC event onset temperature between 242 and 247°C). In some embodiments, the disclosure provides compound 16, which has a DSC event and / or TGA weight loss as set forth in Table 6.

[0260] In some embodiments, the present disclosure provides a composition comprising compound 16 and a pharmaceutically acceptable carrier or excipient.

[0261] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient compound 16 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0262] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 16 or a composition thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 16 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the present disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 16 or a composition thereof.

[0263] Form B of Compound 16 A method for preparing Form B of Compound 16 is described below.

[0264] In some embodiments, the present disclosure provides compound 16: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 16, wherein the compound is substantially free of amorphous compound 16. In some embodiments, the disclosure provides compound 16, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 16, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 16, wherein the compound is substantially free of impurities.

[0265] In some embodiments, Form B of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.8, 11.1, and 16.5±0.5 degrees two-theta. In some embodiments, Form B of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.8, 11.1, and 16.5±0.4 degrees two-theta. In some embodiments, Form B of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.8, 11.1, and 16.5±0.3 degrees two-theta. In some embodiments, Form B of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.8, 11.1, and 16.5±0.2 degrees two-theta.

[0266] In some embodiments, the present disclosure provides compound 16, which has an XRPD substantially similar to that shown in FIG. 15A (e.g., having peaks at ±0.2 degrees 2-theta).

[0267] In some embodiments, the disclosure provides compound 16, which has a DSC-TGA substantially similar to that shown in Figure 15B (e.g., with an endothermic DSC event onset temperature between 232 and 237°C). In some embodiments, the disclosure provides compound 16, which has a DSC event and / or TGA weight loss as set forth in Table 6.

[0268] In some embodiments, the present disclosure provides a composition comprising compound 16 and a pharmaceutically acceptable carrier or excipient.

[0269] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient compound 16 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0270] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 16 or a composition thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 16 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the present disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 16 or a composition thereof.

[0271] Form C of Compound 16 A method for preparing Form C of Compound 16 is described below.

[0272] In some embodiments, the present disclosure provides compound 16: [ka] wherein the compound is crystalline. In some embodiments, the disclosure provides compound 16, wherein the compound is substantially free of amorphous compound 16. In some embodiments, the disclosure provides compound 16, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the disclosure provides compound 16, wherein the compound is substantially free of crystalline forms of compound 1. In some embodiments, the disclosure provides compound 16, wherein the compound is substantially free of impurities.

[0273] In some embodiments, Form C of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 11.9, and 16.0±0.5 degrees two-theta. In some embodiments, Form C of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 11.9, and 16.0±0.4 degrees two-theta. In some embodiments, Form C of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 11.9, and 16.0±0.3 degrees two-theta. In some embodiments, Form C of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from peaks at 6.0, 11.9, and 16.0±0.2 degrees two-theta.

[0274] In some embodiments, the present disclosure provides compound 16, which has an XRPD substantially similar to that shown in FIG. 15A (e.g., having peaks at ±0.2 degrees 2-theta).

[0275] In some embodiments, the disclosure provides compound 16, which has a DSC-TGA substantially similar to that shown in Figure 15C (e.g., with an endothermic DSC event onset temperature between 240 and 245°C). In some embodiments, the disclosure provides compound 16, which has a DSC event and / or TGA weight loss as set forth in Table 6.

[0276] In some embodiments, the present disclosure provides a composition comprising compound 16 and a pharmaceutically acceptable carrier or excipient.

[0277] In some embodiments, the disclosure provides a method of modulating IRAK4 kinase in a patient, comprising administering to the patient compound 16 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4.

[0278] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signaling pathway involving IRAK4 in a patient, the method comprising administering to the patient Compound 16 or a composition thereof. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering to the patient Compound 16 or a composition thereof, wherein the disease, disorder, or condition is a disease, disorder, or condition mediated by IRAK4. In some embodiments, the present disclosure provides a method of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient Compound 16 or a composition thereof.

[0279] General Methods for Providing Salt Compounds Salt compounds of general formula A (which formula includes, among others, salt compounds 2-16) and / or specific forms thereof are prepared from compound 1 according to the following general scheme. [ka] Scheme 2. Preparation of salts of formula A

[0280] For example, each of Compounds 2-16 and forms thereof is prepared from Compound 1 by combining Compound 1 with an appropriate acid to form the acid salt. Accordingly, another aspect of the present disclosure provides methods for preparing Compounds 2-16 and forms thereof.

[0281] As outlined above, in some embodiments, the present disclosure provides compounds of general formula A: [ka] 1. A method for preparing a salt compound of Compound 1: [ka] with a suitable acid and optionally a suitable solvent under conditions suitable to form a salt of formula A.

[0282] In some embodiments, the suitable acid is sulfuric acid. In some embodiments, the disclosure provides a method for making a sulfate salt of Compound 1. In certain embodiments, the sulfate salt of Compound 1 is Compound 2. In certain embodiments, the sulfate salt of Compound 1 is Form A of Compound 2. In some embodiments, the present invention provides a method for preparing Form A of Compound 2, as described in Example 1 below.

[0283] In some embodiments, the suitable acid is benzenesulfonic acid. In some embodiments, the disclosure provides a method for making a benzenesulfonate salt of Compound 1. In certain embodiments, the benzenesulfonate salt of Compound 1 is Compound 3. In certain embodiments, the benzenesulfonate salt of Compound 1 is Form A of Compound 3. In some embodiments, the present invention provides a method for preparing Form A of Compound 3, as described in Example 1 below.

[0284] In some embodiments, the suitable acid is toluenesulfonic acid. In some embodiments, the disclosure provides a method for making a toluenesulfonate salt of Compound 1. In certain embodiments, the toluenesulfonate salt of Compound 1 is Compound 4. In certain embodiments, the toluenesulfonate salt of Compound 1 is Form A of Compound 4. In some embodiments, the present invention provides a method for preparing Form A of Compound 4, as described in Example 1 below.

[0285] In some embodiments, the suitable acid is ethanesulfonic acid. In some embodiments, the disclosure provides a method for making the ethanesulfonate salt of Compound 1. In certain embodiments, the ethanesulfonate salt of Compound 1 is Compound 5. In certain embodiments, the sulfate salt of Compound 1 is Form A of Compound 5. In some embodiments, the present invention provides a method for preparing Form A of Compound 5, as described in Example 1 below.

[0286] In some embodiments, the suitable acid is methanesulfonic acid. In some embodiments, the disclosure provides a method for making a methanesulfonate salt of Compound 1. In certain embodiments, the methanesulfonate salt of Compound 1 is Compound 6. In certain embodiments, the methanesulfonate salt of Compound 1 is Form A of Compound 6. In some embodiments, the present invention provides a method for preparing Form A of Compound 6, as described in Example 1 below.

[0287] In some embodiments, the suitable acid is maleic acid. In some embodiments, the disclosure provides a method for making a maleate salt of Compound 1. In certain embodiments, the maleate salt of Compound 1 is Compound 7. In certain embodiments, the maleate salt of Compound 1 is Form A of Compound 7. In some embodiments, the present invention provides a method for preparing Form A of Compound 7, as described in Example 1 below.

[0288] In some embodiments, the suitable acid is L-tartaric acid. In some embodiments, the disclosure provides a method for making the L-tartrate salt of Compound 1. In certain embodiments, the L-tartrate salt of Compound 1 is Compound 8. In certain embodiments, the L-tartrate salt of Compound 1 is Form A of Compound 8. In some embodiments, the present invention provides a method for preparing Form A of Compound 8, as described in Example 1 below.

[0289] In some embodiments, the suitable acid is fumaric acid. In some embodiments, the disclosure provides a method for making a fumarate salt of Compound 1. In certain embodiments, the fumarate salt of Compound 1 is Compound 9. In certain embodiments, the sulfate salt of Compound 1 is Form A of Compound 9. In some embodiments, the present invention provides a method for preparing Form A of Compound 9, as described in Example 1 below.

[0290] In some embodiments, the suitable acid is citric acid. In some embodiments, the disclosure provides a method for making a citrate salt of Compound 1. In certain embodiments, the citrate salt of Compound 1 is Compound 10. In certain embodiments, the citrate salt of Compound 1 is Form A of Compound 10. In some embodiments, the present invention provides a method for preparing Form A of Compound 10, as described in Example 1 below.

[0291] In some embodiments, the suitable acid is glycolic acid. In some embodiments, the disclosure provides a method for making a glycolic acid salt of Compound 1. In certain embodiments, the glycolic acid salt of Compound 1 is Compound 11. In certain embodiments, the glycolic acid salt of Compound 1 is Form A of Compound 11. In some embodiments, the present invention provides a method for preparing Form A of Compound 11, as described in Example 1 below.

[0292] In some embodiments, the suitable acid is L-malic acid. In some embodiments, the disclosure provides a method for making the L-malic acid salt of Compound 1. In certain embodiments, the L-malic acid salt of Compound 1 is Compound 12. In certain embodiments, the L-malic acid salt of Compound 1 is Form A of Compound 12. In some embodiments, the present invention provides a method for preparing Form A of Compound 12, as described in Example 1 below.

[0293] In some embodiments, the suitable acid is hippuric acid. In some embodiments, the disclosure provides a method for making the hippuric acid salt of Compound 1. In certain embodiments, the hippuric acid salt of Compound 1 is Compound 13. In certain embodiments, the hippuric acid salt of Compound 1 is Form A of Compound 13. In some embodiments, the present invention provides a method for preparing Form A of Compound 13, as described in Example 1 below.

[0294] In some embodiments, the suitable acid is L-lactic acid. In some embodiments, the disclosure provides a method for producing the L-lactate salt of Compound 1. In certain embodiments, the L-lactate salt of Compound 1 is Compound 14. In certain embodiments, the L-lactate salt of Compound 1 is Form A of Compound 14. In some embodiments, the present invention provides a method for preparing Form A of Compound 14, as described in Example 1 below.

[0295] In some embodiments, the suitable acid is benzoic acid. In some embodiments, the disclosure provides a method for making a benzoate salt of Compound 1. In certain embodiments, the benzoate salt of Compound 1 is Compound 15. In certain embodiments, the benzoate salt of Compound 1 is Form A of Compound 15. In some embodiments, the present invention provides a method for preparing Form A of Compound 15, as described in Example 1 below.

[0296] In some embodiments, the suitable acid is succinic acid. In some embodiments, the present disclosure provides methods for preparing a succinate salt of Compound 1. In certain embodiments, the succinate salt of Compound 1 is Compound 16. In certain embodiments, the succinate salt of Compound 1 is Form A of Compound 16. In some embodiments, the present invention provides methods for preparing Form A of Compound 16, which is described in Example 1 below. In certain embodiments, the succinate salt of Compound 1 is Form B of Compound 16. In some embodiments, the present invention provides methods for preparing Form B of Compound 16, which is described in Example 1 below. In certain embodiments, the succinate salt of Compound 1 is Form C of Compound 16. In some embodiments, the present disclosure provides methods for preparing Form C of Compound 16, which is described in Example 1 below.

[0297] A suitable solvent can be any solvent system (eg, one solvent or mixture of solvents) in which Compound 1 and / or the acid are soluble or at least partially soluble.

[0298] Examples of suitable solvents useful in the methods of the present disclosure include, but are not limited to, protic solvents, aprotic solvents, polar aprotic solvents, or mixtures thereof. In certain embodiments, suitable solvents include ethers, esters, alcohols, ketones, or mixtures thereof. In some embodiments, the solvent is one or more organic alcohols. In some embodiments, the solvent is chlorinated. In some embodiments, the solvent is an aromatic solvent.

[0299] In certain embodiments, suitable solvents are methanol, ethanol, isopropanol, or acetone, which are anhydrous or in combination with water or heptane. In some embodiments, suitable solvents include tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, and acetonitrile. In certain embodiments, suitable solvents are acetonitrile, ethyl acetate, tetrahydrofuran, methanol, or acetone:water (9:1).

[0300] In some embodiments, the suitable solvent is ethyl acetate. In some embodiments, the suitable solvent is methanol. In some embodiments, the suitable solvent is acetonitrile. In some embodiments, the suitable solvent is tetrahydrofuran. In some embodiments, the suitable solvent is acetone:water (9:1).

[0301] In some embodiments, the present disclosure provides a method for preparing a salt compound of general formula A, comprising one or more of the steps of removing a solvent and adding a solvent. In some embodiments, the solvent added is the same as the solvent removed. In some embodiments, the solvent added is different from the solvent removed. Means for removing a solvent are known in the synthetic and chemical arts, including, but not limited to, any of those described herein and in the Examples.

[0302] In some embodiments, the method of preparing the salt compound of general formula A includes one or more steps of heating or cooling the preparation.

[0303] In some embodiments, the method of preparing the salt compound of general formula A includes one or more steps of heating or cooling the preparation.

[0304] In some embodiments, a method for preparing a salt compound of general formula A includes mixing compound 1 with a suitable solvent and stirring the mixture at a specific temperature for a period of time. In some embodiments, the method includes mixing compound 1 with a suitable solvent in a 1:1 molar ratio. In some embodiments, the method includes stirring the mixture at room temperature. In some embodiments, the method includes stirring the mixture for 1, 2, 3, or 4 days.

[0305] In some embodiments, the method for preparing a salt compound of general formula A comprises slowly evaporating the solvent. In some embodiments, the method for preparing a salt compound of general formula A comprises slowly evaporating the solvent by exposure to ambient atmosphere at room temperature. In some embodiments, the method for preparing a salt compound of general formula A comprises evaporating the solvent under a flow of inert gas, such as nitrogen gas.

[0306] In some embodiments, the method of preparing a salt compound of general formula A comprises adding a suitable acid to a solution or slurry of compound 1.

[0307] In some embodiments, the method of preparing the salt compound of general formula A comprises heating.

[0308] In certain embodiments, the salt compound of Formula A precipitates from the mixture. In other embodiments, the salt compound of Formula A crystallizes from the mixture. In other embodiments, the salt compound of Formula A crystallizes from the solution after seeding the solution (i.e., adding crystals of the salt compound of Formula A to the solution).

[0309] The salt compound of formula A can be precipitated from the reaction mixture or produced by removing some or all of the solvent by methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption and reaction, by adding an antisolvent such as heptane, by cooling, or by various combinations of these methods.

[0310] As outlined above, the salt compound of formula A is optionally isolated. It will be understood that the salt compound of formula A can be isolated by any suitable physical means known to those skilled in the art. In certain embodiments, the precipitated solid salt compound of formula A is separated from the supernatant by filtration. In other embodiments, the precipitated solid salt compound of formula A is separated from the supernatant by decanting the supernatant.

[0311] In certain embodiments, the salt compound of Formula A is separated from the supernatant by filtration.

[0312] In certain embodiments, the isolated salt compound of Formula A is air-dried. In other embodiments, the isolated salt compound of Formula A is dried under reduced pressure, optionally at elevated temperature.

[0313] 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 derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the composition of the present invention is such that it is effective to measurably degrade and / or inhibit IRAK protein kinase or a mutant thereof in a biological sample or in a patient. In certain embodiments, the amount of compound in the composition of the present invention is such that it is effective to measurably degrade and / or inhibit IRAK protein kinase or a mutant thereof in a biological sample or in a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0314] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0315] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0316] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of the present invention that, upon administration to a recipient, is capable of providing, directly or indirectly, the compound of the present invention or an inhibitory or degradatively active metabolite or residue thereof.

[0317] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of IRAK protein kinase or a variant thereof.

[0318] As used herein, the term "degradatively active metabolite or residue thereof" means that the metabolite or residue thereof is also a degrader of IRAK protein kinase or a variant thereof.

[0319] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations may be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0320] Any sterile fixed oil can be used for this purpose, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injections, as are natural pharmaceutically acceptable oils such as olive oil and castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, that are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifiers or bioavailability enhancers, that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0321] The pharmaceutically acceptable composition of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.Lubricants such as magnesium stearate are also commonly added.For oral administration in capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents.If necessary, certain sweeteners, flavorings or coloring agents can also be added.

[0322] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum and releasing the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0323] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0324] Topical application for the lower intestinal tract can be effected in a rectal suppository (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

[0325] For topical application, the provided pharmaceutically acceptable composition can be formulated into 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 compounds, emulsifying wax, and water.Alternatively, the provided pharmaceutically acceptable composition can be formulated into 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 ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0326] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or, preferably, as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0327] The pharmaceutically acceptable compositions of this 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 a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0328] Most preferably, the pharmaceutically acceptable compositions of the present invention 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 food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0329] The amount of the compounds of the present invention that can be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, etc. Preferably, provided compositions should be formulated so that a dosage of 0.01-100 mg / kg body weight / day of the compound can be administered to a patient receiving these compositions.

[0330] It should also be understood that the specific dosage and treatment regimen for a particular patient will depend on a variety of factors, including the activity of the specific compound used, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in the composition will also depend on the particular compound in the composition.

[0331] Uses of the Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for degrading and / or inhibiting the kinase activity of one or more enzymes.

[0332] Examples of kinases that may be degraded and / or inhibited by the compounds and compositions described herein and for which the methods described herein are useful include the interleukin-1 receptor-associated kinase (IRAK) family of kinases, members of which include IRAK-1, IRAK-2, and IRAK-4, or mutants thereof. See Li et al., "IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase," PNAS 2002, 99(8), 5567-5572; Flannery et al., "The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signaling," Biochem Pharm 2010, 80(12), 1981-1991 (incorporated by reference in their entireties).

[0333] According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity or degrading protein kinases 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.

[0334] According to another embodiment, the present invention relates to a method for inhibiting the activity of or degrading IRAK-1, IRAK-2 and / or IRAK-4 or mutants thereof in a biological sample, comprising contacting said biological sample with a compound of the present invention or a composition comprising said compound.

[0335] The term "biological sample", as used herein, includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, stool, semen, tears, or other bodily fluids or extracts thereof.

[0336] Inhibition of the activity and / or degradation of a protein kinase, or a protein kinase selected from IRAK-1, IRAK-2 and / or IRAK-4 or variants thereof, in a biological sample is useful for a variety of purposes known to those of skill in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0337] Another embodiment of the invention relates to a method of degrading protein kinases and / or inhibiting protein kinase activity in a patient, comprising administering to said patient a compound of the invention or a composition comprising said compound.

[0338] According to another embodiment, the present invention provides a method for degrading and / or inhibiting the activity of one or more of IRAK-1, IRAK-2 and / or IRAK-4 or mutants thereof in a patient, the method comprising administering to the patient a compound of the present invention or a composition comprising said compound. In another embodiment, the present invention provides a method for treating a disorder mediated by one or more of IRAK-1, IRAK-2 and / or IRAK-4 or mutants thereof in a patient in need of such treatment, the method comprising administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0339] The activity of the compounds utilized in the present invention as degraders and / or inhibitors of IRAK-1, IRAK-2, and / or IRAK-4 or their mutants can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine phosphorylation activity and / or the subsequent functional consequences, or inhibition of the ATPase activity of activated IRAK-1, IRAK-2, and / or IRAK-4 or their mutants. An alternative in vitro assay quantifies the ability of an inhibitor to bind to IRAK-1, IRAK-2, and / or IRAK-4. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / IRAK-1, inhibitor / IRAK-2, or inhibitor / IRAK-4 complex, and determining the amount of bound radiolabel. Alternatively, inhibitor binding can be determined by performing competition experiments in which new inhibitors are incubated with IRAK-1, IRAK-2, and / or IRAK-4 bound to known radioligands.Representative in vitro and in vivo assays useful for assaying IRAK-4 inhibitors include, for example, Kim et al., "A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity," J. Exp. Med. 2007, 204(5), 1025-1036; Lebakken et al., "A Fluorescence Lifetime Based Binding Assay to Characterize Kinase Inhibitors," J. Biomol. Screen. 2007, 12(6), 828-841; Maschera et al., "Overexpression of an enzymatically inactive interleukin-1 receptor-associated kinase activates nuclear factor-κB," Biochem. J. 1999, 339, 227-231; and Song et al., "The kinase activities of interleukin-e receptor associated kinase (IRAK)-1 and 4 are redundant in the control of inflammatory cytokine expression in human and "IRAK-1, IRAK-2, and / or IRAK-4, or mutants thereof," Mol. Immunol. 2009, 46, 1458-1466, each of which is incorporated herein by reference in its entirety. Detailed conditions for assaying the compounds utilized in the present invention as degraders and / or inhibitors of IRAK-1, IRAK-2, and / or IRAK-4, or mutants thereof, are provided in the Examples below.

[0340] The best-characterized member of the IRAK family is the serine / threonine kinase IRAK-4, which is involved in signaling innate immune responses from Toll-like receptors (TLRs) and Toll / IL-1 receptors (TIRs).

[0341] Innate immunity detects pathogens through the recognition of pathogen-associated molecular patterns by TLRs, which then link to adaptive immune responses. TLRs recognize conserved structures of both microbial and endogenous molecules. TLRs that recognize bacterial and fungal components are located on the cell surface, while TLRs that recognize viral or microbial nucleic acids are located on intracellular membranes such as endosomes and phagosomes. Cell surface TLRs can be targeted by small molecules and antibodies, while intracellular TLRs require targeting with oligonucleotides.

[0342] TLRs mediate innate immune responses by upregulating the expression of inflammatory genes in multiple target cells. See, e.g., Sen et al., "Transcriptional signaling by double-stranded RNA: Role of TLR3," Cytokine & Growth Factor Rev. 2005, 16, 1-14 (incorporated by reference in its entirety). While TLR-mediated inflammatory responses are critical for innate immunity and host defense against infection, uncontrolled inflammation is harmful to the host, leading to sepsis and chronic inflammatory diseases such as chronic arthritis, atherosclerosis, multiple sclerosis, cancer, autoimmune disorders such as rheumatoid arthritis, lupus, asthma, psoriasis, and inflammatory bowel disease.

[0343] Upon ligand binding, most TLRs recruit the adaptor molecule MyD88 through their TIR domains and mediate MyD88-dependent pathways. MyD88 then recruits IRAK-4, which participates in the nuclear factor-κB (NF-κB), mitogen-activated protein (MAP) kinase, and interferon-regulatory factor (IL-reg) cascades, leading to the induction of proinflammatory cytokines. NF-κB activation results in the induction of inflammatory cytokines and chemokines, such as TNF-α, IL-1α, IL-6, and IL-8. The kinase activity of IRAK-4 has been shown to play an important role in TLR-mediated immune and inflammatory responses. IRAK4 is a key mediator of innate immune responses orchestrated by interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), IL-33 receptor (IL-33R), and Toll-like receptors (TLRs). Inactivation of IRAK-1 and / or IRAK-4 activity has been shown to result in reduced production of cytokines and chemokines in response to IL-1 and TLR ligand stimulation. For example, Picard et al., “Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency,” Medicine(Baltimore), 2010, 89(6), 043-25; Li, “IRAK4 in TLR / IL-1R signaling: Possible clinical applications,” Eur. J. Immunology2008, 38: 614-618; al.,“Targeting protein kinases for the development of anti-inflammatory drugs,”Curr.Opin.Cell Bio.2009,21:317-324;Flannery et al.,“The interleukin-1 receptor-associated kinases:Critical regulators of innate immune signaling,”Biochem.Pharm.2010,80(12),1981-1991;Gottipati et al.,“IRAK1:A critical signaling mediator of innate immunity,”Cellular Signaling 2008,20,269-276;Kim et al.,“A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity,”J.Exp.Med.2007 204(5),1025-1036;Koziczak-Holbro et al.,“IRAK-4 Kinase Activity Is Required for Interleukin-1(IL-1)Receptor-and Toll-like Receptor 7-mediated Signaling and Gene Expression,”J.Biol.Chem.2007,282(18),13552-13560;Kubo-Murai et al.,“IRAK-4-dependent Degradation of IRAK-1 is a Negative Feedback Signal for TLR-mediated NF-κB Activation,”J.Biochem.2008,143,295-302;Maschera et al.,“Overexpression of an enzymatically inactive interleukin-1-receptor-associated kinase activates nuclear factor-κB,”Biochem.J.1999,339,227-231;Lin et al.,“Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR / IL-1R signalling,”Nature 2010,465(17),885-891;Suzuki et al.,“IRAK-4 as the central TIR signaling mediator in innate immunity,”TRENDS in Immunol.2002,23(10),503-506;Suzuki et al.See, e.g., "Severe impairment of interleukin-1 and Toll-like receptor signaling in mice lacking IRAK-4," Nature 2002, 416, 750-754; Swantek et al., "IL-1 Receptor-Associated Kinase Modulates Host Responsiveness to Endotoxin," J. Immunol. 2000, 164, 4301-4306; Hennessy, E., et al., "Targeting Toll-like receptors: emerging therapeutics?" Nature Reviews, vol. 9, pp: 293-307 (2010); Dinarello, C. "Interleukin-18 and the Pathogenesis of Inflammatory Diseases," Seminars in Nephrology, vol. 27, no. 1, pp: 98-114 (2007) (each of which is incorporated by reference in its entirety herein). Indeed, knockdown mice expressing catalytically inactive mutant IRAK-4 proteins are completely resistant to septic shock and exhibit impaired IL-1 activity. Furthermore, these mice are resistant to joint and bone inflammation / destruction in arthritis models, suggesting that IRAK-4 may be targeted to treat chronic inflammation. Furthermore, while IRAK-4 appears to be important for childhood immunity against some pyogenic bacteria, it has been shown to play a redundant role in protective immunity against most infections in adults, as demonstrated by one study in which patients over the age of 14 lacking IRAK-4 activity did not develop invasive infections. Cohen et al., "Targeting protein kinases for the development of anti-inflammatory drugs," Curr. Opin. Cell Bio. 2009, 21:317-324; Ku et al.,“Selective predisposition to bacterial infections in IRAK-4-deficient children:IRAK-4-dependent TLRs are otherwise redundant in protective immunity,”J.Exp.Med.2007,204(10),2407-2422;Picard et al.,“Inherited human IRAK-4 deficiency:an update,”Immunol.Res.2007,38,347-352;Song et al.,“The kinase activities of interleukin-e receptor associated kinase(IRAK)-1 and 4 are redundant in the control of inflammatory cytokine expression in human cells,”Mol.Immunol.2009,46,1458-1466;Rokosz,L.et al.,“Kinase inhibitors as drugs for chronic inflammatory and immunological diseases:progress and challenges,”Expert Opinions on Therapeutic Targets,12(7),pp:883-903(2008);Gearing,A.“Targeting toll-like receptors for drug development:a summary of commercial approaches,”Immunology and Cell Biology,85,pp:490-494(2007);Dinarello,C."IL-1: Discoveries, controversies and future directions," European Journal of Immunology, 40, pp:595-653 (2010) (each of which is incorporated by reference in its entirety). Because TLR activation elicits IRAK-4 kinase activity, IRAK-4 inhibition provides an attractive target for treating the underlying causes of inflammation in a myriad of diseases.

[0344] Representative IRAK-4 inhibitors include, for example, those described in Buckley et al., Bioorg.Med.Chem.Lett. 2008, 18, 3211-3214; Buckley et al., Bioorg.Med.Chem.Lett. 2008, 18, 3291-3295; Buckley et al., Bioorg.Med.Chem.Lett. 2008, 18, 3656-3660; Powers et al., "Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4," Bioorg.Med.Chem.Lett. 2006, 16, 2842-2845; and Wng et al., "IRAK-4 Inhibitors for Inflammation," Curr. Topics in Med. Chem. 2009, 9, 724-737 (each of which is incorporated herein by reference in its entirety).

[0345] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms appear. In other embodiments, treatment may be administered when symptoms are absent. For example, treatment may be administered to a susceptible individual before symptoms appear (e.g., taking into account a history of symptoms and / or taking into account genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay their recurrence.

[0346] The provided compounds are degraders and / or inhibitors of one or more of IRAK-1, IRAK-2, and / or IRAK-4 and are therefore useful for treating one or more disorders associated with the activity of one or more of IRAK-1, IRAK-2, and / or IRAK-4. Accordingly, in certain embodiments, the present invention provides a method for treating an IRAK-1-mediated, IRAK-2-mediated, and / or IRAK-4-mediated disorder, comprising administering a compound of the present invention or a pharmaceutically acceptable composition thereof to a patient in need thereof.

[0347] As used herein, the terms "IRAK-1-mediated," "IRAK-2-mediated," and / or "IRAK-4-mediated" disorders, diseases, and / or conditions, as used herein, refer to any disease or other deleterious condition in which IRAK-1, IRAK-2, and / or IRAK-4, or one or more mutants thereof, are known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which IRAK-1, IRAK-2, and / or IRAK-4, or one or more mutants thereof, are known to play a role.

[0348] In some embodiments, the compounds and compositions described herein are useful in medicine.

[0349] In some embodiments, the present invention provides a method for treating one or more disorders, diseases and / or conditions, wherein the disorder, disease or condition is cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a genetic disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, a liver disease, a pathological immune condition including T-cell activation, a cardiovascular disorder or a CNS disorder.

[0350] Diseases and conditions that can be treated according to the methods of the present invention include cancer (see, for example, Ngo, V. et al., "Oncogenically active MYD88 mutations in human lymphoma," Nature, vol. 000, pp: 1-7 (2010); Lust, J. et al., "Induction of a Chronic Disease State in Patients With Smoldering of Indolent Multiple Myeloma by Targeting Interleukin 1ss-Induced Interleukin 6 Production and the Myeloma Proliferative Component," Mayo Clinic Proceedings, 84(2), pp: 114-122 (2009)), diabetes, cardiovascular disease, viral diseases, autoimmune diseases such as lupus (see, for example, Dinarello, C. "Interleukin-18 and the Pathogenesis of Inflammatory Diseases," Seminars in Nephrology, vol. 27, no. 1, pp: 98-114 (2007); Cohen et al. al., "Targeting protein kinases for the development of anti-inflammatory drugs," Curr. Opin. Cell Bio. 2009, 21:317-324), and rheumatoid arthritis (see, e.g., Geyer, M. et al., "Actual status of antiinterleukin-1 therapies in rheumatic diseases," Current Opinion in Rheumatology, 22, pp:246-251 (2010)), autoinflammatory syndromes (see, e.g., Hoffman, H. et al., "Efficacy and Safety of Rilonacept (Interleukin-1 Trap) in Patients with Cryopyrin-Associated Periodic Syndromes," Arthritis & Rheumatism, vol. 58, no. 8, pp: 2443-2452 (2008)), atherosclerosis, psoriasis, allergic disorders, inflammatory bowel disease (see, e.g., Cario, E. "Therapeutic Impact of Toll-Like Receptors on Inflammatory Bowel Diseases: A Multiple-edged Sword," Inflamm. Bowel Dis., 14, pp: 411-421 (2008)), inflammation (see, e.g., Dinarello, C. "Interleukin 1 and Interleukin 18 as Mediators of Inflammation and the Aging Process," The American Journal of Clinical Nutrition, 83, pp:447S-455S (2006)), acute and chronic gout and gouty arthritis (see, for example, Terkeltaub, R. "Update on gout: new therapeutic strategies and options," Nature, vol. 6, pp:30-38 (2010); Weaver, A. "Epidemiology of gout," Cleveland Clinic Journal of Medicine, vol. 75, suppl. 5, pp:S9-S12 (2008); Dalbeth, N. et al., "Hyperuricemia and gout: state of the art and future perspectives," Annals of Rheumatic Diseases, 69, pp:1738-1743 (2010); Martinon, F. et al., "Gout-associated uric acid crystals activate the NALP3 inflammasome," Nature, vol.440, pp:237-241(2006);So,A.et al.,“A pilot study of IL-1 inhibition by anakinra in acute gout,”Arthritis Research & Therapy,vol.9,no.2,pp:1-6(2007);Terkeltaub,R.et al.,“The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis:results of a Placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study,”Annals of Rheumatic Diseases,68,pp:1613-1617(2009);Torres, R. et al.,“Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis,”Annals of Rheumatic Diseases, 68, pp:1602-1608 (2009)), neurological disorders, metabolic syndrome (see, e.g., Troseid, M. "The role of interleukin-18 in the metabolic syndrome," Cardiovascular Diabetology, 9:11, pp:1-8 (2010)), immunodeficiency disorders such as AIDS and HIV (see, e.g., Iannello, A. et al., "Role of Interleukin-18 in the Development and Pathogenesis of AIDS," AIDS Reviews, 11, pp:115-125 (2009)), destructive bone disorders (see, e.g., Hennessy, E., et al., “Targeting Toll-like receptors: emerging therapeutics?” Nature Reviews, vol. 9, pp: 293-307 (2010)), osteoarthritis, proliferative disorders, and Waldenstroem's macroglobulinemia (see, e.g., Treon, et al., “Whole genome sequencing reveals a widely expressed mutation (MYD88 L265P) with oncogenic activity in Waldenstroem's macroglobulinemia” 53). rd ASH Annual Meeting;Xu, et al., “A somatic variant in MYD88(L256P) revealed by whole genome sequencing differentiates lymphoplasmacytic lymphoma from marginal zone lymphomas”53 rd ASH Annual Meeting;Yang et al., “Disruption of MYD88 pathway signaling leads to loss of constitutive IRAK1,NK-kB and JAK / STAT signaling and induces apoptosis of cells expressing the MYD88 L265P mutation in Waldenstroem's Macrobulinemia”53 rd ASH Annual Meeting;Iriyama et al., “Clinical significance of genetic mutations of CD79B,CARD11,MYD88,and EZH2 genes in diffuse large B-cell lymphoma patients”53 rdSee ASH Annual Meeting; including, but not limited to, infectious diseases, conditions associated with cell death, pathological immune conditions involving T cell activation, and CNS disorders in patients. In one embodiment, a human patient is treated with a compound of the invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the compound is present in an amount that measurably degrades and / or inhibits the kinase activity of IRAK-1 alone, IRAK-2 alone, IRAK-4 alone, and / or IRAK1 and IRAK4.

[0351] The compounds of the present invention may be used to treat benign or malignant tumors of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, stomach tumors, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, urogenital tract, esophagus, larynx, skin, bone or thyroid, solid tumors, carcinomas, sarcomas, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, in particular colon cancer or colorectal adenoma, tumors of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia Neoplasms of epithelial origin, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's and non-Hodgkin's, breast cancer, follicular adenocarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-driven disorders, MyD88-driven disorders, smoldering low-grade multiple myeloma or hematologic malignancies (leukemia, diffuse large B-cell lymphoma (DLBCL), ABC and malignant lymphoma (MLBCL), chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, AML, MDS.

[0352] In some embodiments, the proliferative disease that can be treated according to the methods of the invention is a MyD88-driven disorder. In some embodiments, the MyD88-driven disorder that can be treated according to the methods of the invention is selected from ABC DLBCL, primary CNS lymphoma, primary extranodal lymphoma, Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia.

[0353] In some embodiments, the proliferative disease that can be treated according to the methods of the present invention is an IL-1 driven disorder, hi some embodiments, the IL-1 driven disorder is smoldering multiple myeloma.

[0354] The compounds according to the present invention are useful for treating inflammatory or obstructive airway diseases, for example, by reducing tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression. Inflammatory or obstructive airway diseases to which the present invention is applicable include asthma of all types and origins, including both intrinsic (non-allergic) and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection. Treatment of asthma is also understood to include treatment of subjects, for example, those under the age of 4 or 5, who present with symptoms of wheezing and have been or can be diagnosed as "wheezing infants," an established patient category of major medical interest, currently often identified as having primary or early-phase asthma.

[0355] The compounds according to the present invention are useful for treating heteroimmune diseases, including, but not limited to, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, house dust mite, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0356] Prophylactic efficacy in the treatment of asthma is evidenced by a reduction in the frequency or severity of symptomatic attacks, e.g., acute asthma or bronchoconstrictor attacks, improved lung function, or improved airway hyperresponsiveness. This may further be evidenced by a reduced need for other symptomatic therapies, such as anti-inflammatory drugs or bronchodilators, aimed at limiting or preventing symptomatic attacks when they occur. The prophylactic effect in asthma may be particularly evident in subjects prone to "morning dip." "Morning dip" is a recognized asthma syndrome characterized by asthma attacks, common in a significant proportion of asthma patients, for example, between 4:00 and 6:00 a.m., a time period typically well removed from previously administered symptomatic asthma treatment.

[0357] The compounds of the present invention can also be used for other inflammatory or obstructive airway diseases and conditions for which the present invention is applicable, including acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, airway diseases or lung diseases (COPD, COAD or COLD), such as chronic bronchitis or its associated dyspnea, emphysema, and exacerbation of airway hyperresponsiveness as a result of other medications, particularly other inhaled medications. The present invention is also applicable to the treatment of bronchitis of any type or genesis (e.g., including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or tuberculous bronchitis). Further inflammatory or obstructive airways diseases to which the present invention is applicable include pneumoconiosis (inflammatory diseases of the lungs, usually occupational, often associated with airway obstruction and caused by repeated inhalation of dust, whether chronic or acute), whatever the type or origin, such as aluminum lung disease, anthracosis, asbestosis, copper lung disease, ptilosis, siderosis, silicosis, tobacco disease and byssinosis.

[0358] With regard to their anti-inflammatory activity, and in particular with regard to the inhibition of eosinophil activation, the compounds of the invention are also useful in the treatment of eosinophil-associated disorders, such as eosinophilia, particularly affecting the airways and / or lungs, and therefore eosinophil-associated disorders of the airways including hypereosinophilia (e.g. including pathological eosinophilic infiltration of lung tissue) and eosinophil-associated disorders of the airways resulting from or occurring concomitantly with, for example, Loeffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophilic asthma, eosinophilic COPD and eosinophil-associated disorders affecting the airways caused by drug reactions.

[0359] The compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, such as psoriasis, generalized pustular psoriasis (GPP), psoriasis vulgaris, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpes dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, hidradenitis suppurativa, Sweet's syndrome, pyoderma gangrenosum, and other inflammatory or allergic conditions of the skin.

[0360] The compounds of the invention may also be used in the treatment of other diseases or conditions, such as diseases or conditions which have an inflammatory component, for example, diseases and conditions of the eye such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis, and inflammatory diseases which involve an autoimmune response or have an autoimmune component or etiology, such as autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active liver disease, and the like. inflammation, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, renal disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, psoriatic keratoconjunctivitis and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathies Arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome, including e.g., idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia , Behçet's disease, Incontinentia pigmenti, Paget's disease, Pancreatitis, Hereditary Periodic Fever Syndromes, Asthma (allergic and non-allergic, mild, moderate, severe, bronchitis, and exercise-induced), Acute Lung Injury, Acute Respiratory Distress Syndrome, Eosinophilia, Hypersensitivity, Anaphylaxis, Sinusitis, Ocular Allergies, Silica-Induced Disease, COPD (Reduction of Damage, Airway Inflammation, Bronchial Hyperresponsiveness, Remodeling or Disease Progression), Lung Disease, Cystic Fibrosis, Acid-Induced Lung Injury, Pulmonary Hypertension, Polyneuropathy, Cataracts, Muscle Inflammation Associated with Systemic Sclerosis, Inclusion Body Myositis, Myasthenia Gravis, Thyroiditis, Addison's Disease,Lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrosis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, myelitis It can be used to treat myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0361] In some embodiments, the inflammatory disease that can be treated according to the methods of the present invention is a disease of the skin, hi some embodiments, the inflammatory disease of the skin is selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpes dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, hidradenitis suppurativa, and other inflammatory or allergic conditions of the skin.

[0362] In some embodiments, inflammatory diseases that may be treated according to the methods of the present invention are selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), adult-onset Still's disease, macrophage activation syndrome (MAS), primary and secondary hemophagocytic lymphohistiocytosis (HLH), familial Mediterranean fever, NLRP12 autoinflammatory syndrome, and osteoarthritis.

[0363] In some embodiments, the inflammatory disease that can be treated according to the methods of the invention is a TH17-mediated disease, hi some embodiments, the TH17-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris, hidradenitis suppurativa, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0364] In some embodiments, inflammatory diseases that can be treated according to the methods of the present invention are selected from ocular conditions such as Sjogren's syndrome, allergic disorders, osteoarthritis, ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis or chronic rhinosinusitis with nasal polyps (CRSwNP).

[0365] In some embodiments, the present invention provides methods for treating TLR / IL-1R-driven autoinflammatory and autoimmune diseases with high unmet medical need, such as hidradenitis suppurativa, atopic dermatitis, and rheumatoid arthritis. Accordingly, in some embodiments, the present invention provides a method for treating hidradenitis suppurativa in a patient in need thereof, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method for treating atopic dermatitis in a patient in need thereof, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method for treating rheumatoid arthritis in a patient in need thereof, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0366] Cardiovascular diseases that may be treated according to the methods of the present invention include, but are not limited to, restenosis, cardiomegaly, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disease, pulmonary embolism, and deep vein thrombosis.

[0367] In some embodiments, neurodegenerative diseases that may be treated according to the methods of the present invention include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative diseases caused by traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation, and graft-versus-host disease.

[0368] Loss of IRAK4 function resulted in reduced Aβ levels in an in vivo mouse model of Alzheimer's disease and was associated with reduced microgliosis and astrogliosis in aged mice. Analysis of microglia isolated from adult mouse brains revealed altered patterns of gene expression associated with changes in microglial phenotype, including increased expression of IRF transcription factors that regulate microglial phenotype. Furthermore, loss of IRAK4 function promoted amyloid clearance mechanisms, including increased expression of insulin-degrading enzymes. Finally, blocking IRAK function restored olfactory behavior (Cameron et al. "Loss of Interleukin Receptor-Associated Kinase 4 Signaling Suppresses Amyloid Pathology and Alters Microglial Phenotype in a Mouse Model of Alzheimer's Disease" Journal of Neuroscience (2012) 32(43), 15112-15123).

[0369] In some embodiments, the present invention provides methods for treating, preventing, and reducing the severity of Alzheimer's disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt or composition thereof.

[0370] In some embodiments, the present invention provides methods of treating disease states commonly associated with transplantation, hi some embodiments, the disease or condition commonly associated with transplantation is selected from organ transplantation, organ transplant rejection, and graft-versus-host disease.

[0371] In some embodiments, the present invention provides methods of treating a metabolic disease, hi some embodiments, the metabolic disease is selected from type 1 diabetes, type 2 diabetes, metabolic syndrome, and obesity.

[0372] In some embodiments, the present invention provides methods of treating a viral disease, hi some embodiments, the viral infection is an HIV infection.

[0373] Furthermore, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt or hydrate or solvate thereof, for the preparation of a medicament for the treatment of a proliferative disease, an inflammatory disease, an obstructive ventilatory disease, a cardiovascular disease, a metabolic disease, a neurological disease, a neurodegenerative disease, a viral disease, or a disorder commonly occurring in association with transplantation.

[0374] Combination therapy Depending on the particular condition, or disease, to be treated, additional therapeutic agents that are normally administered to treat that condition are administered in combination with the compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0375] In certain embodiments, provided combinations or compositions thereof are administered in combination with another therapeutic agent.

[0376] In some embodiments, the present invention provides a method of treating a disclosed disease or condition, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of the disclosed compound and the additional therapeutic agent acts synergistically.

[0377] Examples of drugs in the combinations of the present invention may be combined with, but are not limited to, treatments for Alzheimer's disease, such as Aricept® and Excelon®; treatments for HIV, such as ritonavir; treatments for Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; multiple sclerosis medications for treating MS, such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma, such as albuterol and Singulair®; medications for treating schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine. immunomodulators and immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole and antiparkinsonian agents; drugs for treating cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers drugs for treating liver disease, such as corticosteroids, cholestyramine, interferons, and antivirals; drugs for treating blood disorders, such as corticosteroids, anti-leukemia agents, and growth factors; drugs that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and drugs for treating immune deficiency disorders, such as gamma globulins.

[0378] In certain embodiments, a combination therapy of the invention or a pharmaceutically acceptable composition thereof is administered in combination with a monoclonal antibody or siRNA therapy.

[0379] These additional agents can be administered separately from the provided combination therapy as part of a multiple dose regimen. Alternatively, these agents can be part of a single dosage form, mixed together with the compound of the present invention in a single composition. When administered as part of a multiple dose regimen, the two active agents can be presented simultaneously, sequentially, or at a time interval (usually within 5 hours) between each other.

[0380] As used herein, the terms "combination," "in combination," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, the combination of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form.

[0381] The amount of additional therapeutic agent present in the compositions of the invention will not exceed the amount that would normally be administered in a composition comprising that agent as the only active agent. The amount of additional therapeutic agent in the compositions of the present disclosure preferably ranges from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0382] The one or more other therapeutic agents may be administered separately from the compounds or compositions of the invention as part of a multiple dose regimen. Alternatively, the one or more other therapeutic agents may be part of a single dosage form, mixed together with the compounds of the invention in a single composition. When administered as a multiple dose regimen, the one or more other therapeutic agents and the compounds or compositions of the invention may be administered simultaneously, sequentially, or within a time interval between each other, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18, 20, 21, 22, 23, or 24 hours. In some embodiments, the one or more other therapeutic agents and the compounds or compositions of the invention are administered more than 24 hours apart as a multiple dose regimen.

[0383] In one embodiment, the present invention provides a composition comprising a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents. The therapeutic agents can be administered together with the provided compound or a pharmaceutically acceptable salt thereof, or before or after administration of the provided compound or a pharmaceutically acceptable salt thereof. Suitable therapeutic agents are described in more detail below. In certain embodiments, the provided compound or a pharmaceutically acceptable salt thereof can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before administration of the therapeutic agent. In other embodiments, a provided compound, or a pharmaceutically acceptable salt thereof, can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after administration of the therapeutic agent.

[0384] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, febuxo Tat (Uloric®), sulfasalazine (Azulfidine®), antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as gold thioglucose (Solganal®), gold thiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), as well as "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simpson®), and flunomide (Ventilator®). (registered trademark), certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), "anti-IL-6",anticoagulants such as tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies such as tanezumab (Calcwarmain®), anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binding drugs such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergics or antispasmodics such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists such as albuterol (Ventolin® HFA, Proventil®), trademark HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®) and formoterol (Foradil®), anticholinergics such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids such as beclomethasone dipropionate nates (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®) and flunisolide (Aerobid®), Afviar®, Symbicort®, Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®),Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, IgE antibodies such as omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Em triva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), neveirapine (Viramune®), and etravirine (Intelence®), nucleoside reverse transcriptase inhibitors such as tenofovir (Viread®), (registered trademarks), protease inhibitors such as amprenavir (Agenerase®), (atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and thrombin inhibitors Ripranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), dexamethasone (Decadron®) in combination with bortezomib (Velcade®) and lenalidomide (Revlimid®),Or any combination thereof.

[0385] In another embodiment, the present invention provides a method of treating gout, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from nonsteroidal anti-inflammatory drugs (NSAIDS), such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, colchicine (Colcrys®), corticosteroids, such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, and febuxostat (Uloric®).

[0386] In another embodiment, the present invention provides a method of treating rheumatoid arthritis, comprising administering to a patient in need thereof a combination of a provided compound or a pharmaceutically acceptable salt thereof and nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, sulfasalazine (Azulfidine®), and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as aurothioglucose (Solganal®), aurothiomalate (Myochrysine®) and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine, and the like. (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), rifabutin (Richardson ... )) and one or more additional therapeutic agents selected from adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), and "anti-IL-6" agents such as tocilizumab (Actemra®).

[0387] In some embodiments, the present invention provides methods of treating osteoarthritis, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies, such as tanezumab.

[0388] In some embodiments, the present invention provides methods of treating lupus, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, and the like, antimalarials such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®).

[0389] In some embodiments, the present invention provides methods of treating inflammatory bowel disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheals such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), and the like, laxatives such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®, and anticholinergics or antispasmodics such as dicyclomine (Bentyl®), anti-TNF therapies, steroids, and antibiotics such as Flagyl or ciprofloxacin.

[0390] In some embodiments, the present invention provides a method of treating asthma, comprising administering to a patient in need thereof a combination of a provided compound or a pharmaceutically acceptable salt thereof and an anti-IL-33 antibody, e.g., REGN3500 (SAR440340) or CNTO7160, a beta-2 agonist such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), an anticholinergic agent such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), an inhaled corticosteroid, e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), an inhaled corticosteroid, e.g., ipratropium bromide (Atrovent®), ... and one or more additional therapeutic agents selected from, for example, prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthemanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®, cromolyn sodium (Intal®), methylxanthines such as theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®), and aminophylline, and IgE antibodies such as omalizumab (Xolair®).

[0391] In some embodiments, the present invention provides a method of treating COPD, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof in combination with a beta-2 agonist, such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®), an anticholinergic, such as ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), a methylxanthine, such as tetrofloxacin (Tetrofloxacin), or a steroid. and one or more additional therapeutic agents selected from ophiline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®. In some embodiments, the present invention provides methods of treating eosinophilic COPD, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-IL-33 antibodies, e.g., REGN3500 (SAR440340), or CNTO7160.In some embodiments, the present invention provides methods of treating eosinophilic COPD, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-IL-33 antibodies, e.g., REGN3500 (SAR440340), or CNTO7160.

[0392] In some embodiments, the present invention provides a method of treating HIV, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a nucleoside reverse transcriptase inhibitor, such as zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriv®), or a combination of these compounds or a nucleoside reverse transcriptase inhibitor. a®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®) and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors such as delavirdine (Rescriptor®), efavirenz (Sustiva®), nevairapine (Viramune®) and etravirine (Intelence®), ), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread®), protease inhibitors such as amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), and one or more additional therapeutic agents selected from ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®) and tipranavir (Aptivus®), entry inhibitors such as enfuvirtide (Fuzeon®) and maraviroc (Selzentry®), integrase inhibitors such as raltegravir (Isentress®), and combinations thereof.

[0393] In another embodiment, the present invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0394] In another embodiment, the present invention provides a method of treating a solid tumor, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0395] In another embodiment, the invention provides a method of treating a hematological cancer, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological cancer is DLBCL (Ramirez et al., "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large B-cell lymphoma," Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety).

[0396] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0397] In some embodiments, the present invention provides methods of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a CHOP (cyclophosphamide, Hydrodaunorubicin®, Oncovin® and prednisone or prednisolone) or R-CHOP (rituximab, cyclophosphamide, Hydrodaunorubicin®, Oncovin® and prednisone or prednisolone) chemotherapy regimen.

[0398] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a rituximab / bendamustine chemotherapy regimen.

[0399] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a BTK inhibitor (e.g., ibrutinib).

[0400] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and an anti-CD20 antibody (e.g., rituximab).

[0401] In some embodiments, the invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound, or a pharmaceutically acceptable salt thereof, and an anti-CD79B ADC (e.g., polatuzumab).

[0402] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a BCL2 inhibitor (e.g., venetoclax).

[0403] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and lenalidomide or pomalidomide.

[0404] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor (e.g., umbralisib).

[0405] In some embodiments, the present invention provides a method of treating a T-cell disease or disorder described herein, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor (e.g., umbralisib).

[0406] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a protesome inhibitor (e.g., bortezomib).

[0407] In some embodiments, the present invention provides a method of treating a T-cell disease or disorder described herein, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a protesome inhibitor (e.g., bortezomib).

[0408] In another embodiment, the present invention provides a method of treating multiple myeloma, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from bortezomib (Velcade®) and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor (in combination with lenalidomide (Revlimid®)).

[0409] In another embodiment, the present invention provides a method of treating Waldenstrom's macroglobulinemia, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from chlorambucil (Leukeran®), cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.

[0410] In some embodiments, the one or more other therapeutic agents are hedgehog pathway antagonists. Approved hedgehog pathway inhibitors that can be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both for the treatment of basal cell carcinoma.

[0411] In some embodiments, the one or more other therapeutic agents is a poly ADP-ribose polymerase (PARP) inhibitor. In some embodiments, the PARP inhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib (MDV3800 / BMN673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[0412] In some embodiments, the one or more other therapeutic agents is a histone deacetylase (HDAC) inhibitor. In some embodiments, the HDAC inhibitor is selected from vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); belinostat (Beleodaq®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).

[0413] In some embodiments, the one or more other therapeutic agents is a CDK inhibitor, e.g., a CDK4 / CDK6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib (Ibrance®, Pfizer); ribociclib (Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[0414] In some embodiments, the one or more other therapeutic agents is a folate inhibitor. Approved folate inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly).

[0415] In some embodiments, the one or more other therapeutic agents is a CC chemokine receptor 4 (CCR4) inhibitor. Investigational CCR4 inhibitors that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

[0416] In some embodiments, the one or more other therapeutic agents are isocitrate dehydrogenase (IDH) inhibitors. Investigational IDH inhibitors that may be useful in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[0417] In some embodiments, the one or more other therapeutic agents are arginase inhibitors. Investigational arginase inhibitors that can be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is being tested in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndromes (NCT02732184) and solid tumors (NCT02561234), and CB-1158 (Calithera Biosciences).

[0418] In some embodiments, the one or more other therapeutic agents is a glutaminase inhibitor. Investigational glutaminase inhibitors that can be used in the present invention include CB-839 (Calithera Biosciences).

[0419] In some embodiments, the one or more other therapeutic agents are antibodies that bind to tumor antigens, i.e., proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens that can be used in the present invention include rituximab (Rituxan®, Genentech / BiogenIdec); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and yttrium-90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics); trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); and pertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

[0420] In some embodiments, the one or more other therapeutic agents are topoisomerase inhibitors. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Investigational topoisomerase inhibitors that may be useful in the present invention include pixantrone (Pixuvri®, CTI Biopharma).

[0421] In some embodiments, the one or more other therapeutic agents are inhibitors of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotic agents that may be used in the present invention include venetoclax (Venclexta®, AbbVie / Genentech); and blinatumomab (Blincyto®, Amgen). Other therapeutic agents targeting apoptotic proteins that are undergoing clinical trials and may be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0422] In some embodiments, the one or more other therapeutic agents are androgen receptor inhibitors. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (Xtandi®, Astellas / Medivation); approved inhibitors of androgen synthesis include abiraterone (Zytiga®, Centocor / Ortho); and approved antagonists of the gonadotropin-releasing hormone (GnRH) receptor (degaralix, Firmagon®, Ferring Pharmaceuticals).

[0423] In some embodiments, the one or more other therapeutic agents are selective estrogen receptor modulators (SERMs), which interfere with the synthesis or activity of estrogen. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[0424] In some embodiments, the one or more other therapeutic agents are bone resorption inhibitors. An approved therapeutic agent that inhibits bone resorption is denosumab (Xgeva®, Amgen), an antibody that binds to RANKL and prevents it from binding to its receptor RANK, found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediate bone pathology in solid tumors with bone metastasis. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid (Zometa®, Novartis).

[0425] In some embodiments, the one or more other therapeutic agents are inhibitors of the interaction between two major p53 suppressor proteins, MDMX and MDM2. Investigational inhibitors of p53 suppressor proteins that can be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that equipotently binds and inhibits the interaction of MDMX and MDM2 with p53. ALRN-6924 is currently being evaluated in clinical trials (NCT02909972; NCT02264613) for the treatment of AML, advanced myelodysplastic syndrome (MDS), and peripheral T-cell lymphoma (PTCL).

[0426] In some embodiments, the one or more other therapeutic agents are inhibitors of transforming growth factor beta (TGF-beta or TGFss). Investigational inhibitors of TGF-beta proteins that can be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody undergoing clinical trials for the treatment of various cancers, including breast cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, prostate cancer, and renal cancer (NCT02947165). In some embodiments, the TGF-beta protein inhibitor is fresolimumab (GC1008; Sanofi-Genzyme), which is being tested for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Additionally, in some embodiments, the additional therapeutic agent is a TGF-beta trap, such as those described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. One therapeutic compound currently undergoing clinical trials for the treatment of solid tumors is M7824 (Merck KgaA - formerly MSB0011459X), which is a bispecific anti-PD-L1 / TGFβ trap compound (NCT02699515); and (NCT02517398). M7824 consists of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFβ "trap."

[0427] In some embodiments, the one or more other therapeutic agents are selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody linked to a cytotoxic MMAE (CR011). gpNMB is a protein overexpressed by multiple tumor types that is associated with the metastatic potential of cancer cells.

[0428] In some embodiments, the one or more other therapeutic agents are antiproliferative compounds, such as aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-active compounds, alkylating compounds, histone deacetylase inhibitors, compounds that induce cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, anti-neoplastic antimetabolites, platin compounds, compounds that target / reduce protein or lipid kinase activity and additional anti-angiogenic compounds, compounds that target, reduce or inhibit the activity of protein or lipid phosphatases, gonadorelin agonists, antiandrogens, methionine aminopeptidase inhibitors, matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZd6244 from AstraZeneca, PD181461 and leucovorin from Pfizer.

[0429] In some embodiments, the present invention provides a method of treating Alzheimer's disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from donepezil (Aricept®), rivastigmine (Excelon®), galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

[0430] In some embodiments, the one or more other therapeutic agents are taxane compounds, which cause disruption of microtubules, which are essential for cell division. In some embodiments, the taxane compounds are selected from paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis / Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).

[0431] In some embodiments, the one or more other therapeutic agents are nucleoside inhibitors or therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapidly proliferating cells.

[0432] In some embodiments, the nucleoside inhibitor is trabectedin (a guanidine alkylating agent, Yondelis®, Janssen Oncology), mechlorethamine (an alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics); temozolomide (a prodrug of the alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) Temodar®, Merck); cytarabine injection (ara-C, antimetabolite cytidine analog, Pfizer); lomustine (an alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource) Biotechnology); azacitidine (a pyrimidine nucleoside analog of cytidine, Vidaza®, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (a protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (an asparagine-depleting enzyme, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (antimicrotubule agent, tubulin-based mitotic inhibitor, Halaven®, Eisai); cabazitaxel (antimicrotubule agent, tubulin-based mitotic inhibitor, Jevtana®, Sanofi-Aventis); capacetrin (thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (bifunctional mechlorethamine derivative, thought to form interstrand DNA crosslinks, Treanda®, Cephalon / Teva); ixabepilone (semisynthetic analogue of epothilone B, antimicrotubule agent, tubulin-based mitotic inhibitor, Ixempra®, Bristol-Myers Squibb);Selected from nelarabine (prodrug of a deoxyguanosine analog, a nucleoside metabolism inhibitor, Arranon®, Novartis); clorafabine (prodrug of a ribonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis); and trifluridine and tipiracil (thymidine-based nucleoside analog and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology);

[0433] In some embodiments, the one or more other therapeutic agents are kinase inhibitors or VEGF-R antagonists. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include bevacizumab (Avastin®, Genentech / Roche), an anti-VEGF monoclonal antibody; ramucirumab (Cyramza®, Eli Lilly), an anti-VEGFR-2 antibody; and ziv-aflibercept (Zaltrap®; Regeneron / Sanofi), also known as VEGF trap. VEGFR inhibitors, such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai); Raf inhibitors, such as sorafenib (Nexavar®, Bayer AG and Onyx); dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors, such as covime cobimetanib (Cotellic®, Exelexis / Genentech / Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors, such as imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariadne) Pharmaceuticals; Her2 and EGFR inhibitors such as gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech / Roche / Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim);Osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozantinib (Cometriq®, Exelexis); and multikinase inhibitors, such as sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis); ALK inhibitors, such as crizotinib (Xalkori®, Pfizer); certinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech / Roche); Bruton's tyrosine kinase inhibitors, such as ibrutinib (Imbruvica®, Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin (Rydapt®, Novartis).

[0434] Other kinase inhibitors and VEGF-R antagonists under development that may be used in the present invention include tivozanib (Aveo Pharmaceuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovinitinib (TKI258, Novartis); chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, S.Korea); ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / Takeda).

[0435] In another embodiment, the present invention provides a method of treating organ transplant rejection or graft-versus-host disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from steroids, cyclosporine, FK506, rapamycin, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0436] In another embodiment, the present invention provides a method for treating or lessening the severity of a disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a BTK inhibitor, wherein the disease is selected from the group consisting of inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves' disease, autoimmune thyroiditis, and Schwartz's disease. S. Gren syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylosis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, systemic degeneration hair loss, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous glomerular nephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, foods, insect venom, animal dander, house dust mite or cockroach calyx), type I hypersensitivity, Allergic conjunctivitis, allergic rhinitis, and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, synovitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrosis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, myelitis Myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,Prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorders such as diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma Bone and bone marrow cancers, including but not limited to, lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia or lymphomatoid granulomatosis, Burkitt's lymphoma / leukemia or lymphomatoid granulomatosis, breast cancer, prostate cancer, or cancers of mast cells (e.g., mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), osteosarcoma, colorectal cancer, pancreatic cancer, rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis, Reiter's disease), Nodal disease, Behçet's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastasis, thromboembolic disease (e.g., myocardial infarction, angina pectoris, re-occlusion after angioplasty, restenosis after angioplasty, re-occlusion after aortocoronary artery bypass grafting, restenosis after aortocoronary artery bypass grafting, stroke, transient ischemia, peripheral arterial occlusive disease, pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic thrombocytopenia, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis,Selected from psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0437] In another embodiment, the invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor, wherein the disease is selected from cancer, a neurodegenerative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, and a CNS disorder.

[0438] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor, wherein the disease is a benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, particularly colon carcinoma. or colorectal adenoma or tumors of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, neoplasms of epithelial phenotype, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also called Hodgkin or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma or leukemia, including, for example, Cowden syndrome, Lhermitte-Dudos disease and Banayan-Zonana syndrome, or diseases in which the PI3K / PKB pathway is aberrantly activated; Asthma of any type or origin, including both intrinsic (non-allergic) and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection, acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, chronic bronchitis or associated airway or lung diseases (COPD, COAD or COLD), including dyspnea, emphysema, and exacerbation of airway hyperresponsiveness as a result of other medications, especially other inhaled medications, including acute, arachidic, catarrhal, ulcerative colitis, bronch ... bronchitis of any type or origin, including but not limited to idiopathic, chronic or tuberculous bronchitis, pneumoconiosis of any type or origin (inflammatory disease of the lungs, usually occupational, frequently associated with airway obstruction, caused by repeated inhalation of dust, whether chronic or acute), including aluminosis, anthracosis, asbestosis, copperosis, ptilosis, siderosis, silicosis, tobacco disease and byssinosis, Löffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis,Polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the airways caused by drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpes dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphis, epidermolysis bullosa acquisita, conjunctivitis, and keratoconjunctivitis sicca. and diseases affecting the nose, including vernal conjunctivitis, allergic rhinitis, and inflammatory diseases involving an autoimmune response or having an autoimmune component or cause, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, sclerodoma, Wegener's granulomatosis, dermatomyositis, chronic active Hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine opthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis and glomerulonephritis (with or without nephrotic syndrome, including, for example, idiopathic nephrotic syndrome or minimal change nephropathy), restenosis, cardiac enlargement, atherosclerosis, myocardial infarction, ischemic stroke and congestive heart failure, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and neurodegenerative diseases caused by cerebral ischemia and traumatic injury, glutamate neurotoxicity and hypoxia.

[0439] In some embodiments, the one or more other therapeutic agents are phosphatidylinositol 3-kinase (PI3K) inhibitors. In some embodiments, the PI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpelisib (BYL719, Novartis), taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[0440] In some embodiments, the present invention provides methods of treating AML, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents selected from a FLT3 inhibitor; a targeted agent, such as an IDH inhibitor, an anti-CD33 ADC (e.g., Mylotarg), a BCL2 inhibitor, and a hedgehog inhibitor; and a chemotherapeutic agent, such as AraC, daunorubicin, etoposide, methotrexate, fludarabine, mitoxantrone, azacitidine, and a corticosteroid.

[0441] In some embodiments, the present invention provides a method of treating MDS, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from azacitidine, decitabine, and Revlimid.

[0442] In some embodiments, the present invention provides methods of treating inflammatory skin conditions, such as hidradenitis suppurativa, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-TNF drugs.

[0443] In some embodiments, the present invention provides methods of treating an inflammatory skin condition, such as atopic dermatitis, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from an IL-4 / IL-13 targeted agent, e.g., dupilumab.

[0444] In some embodiments, the present invention provides methods of treating inflammatory skin conditions, such as psoriasis, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-IL-17 and anti-IL-23 antibodies.

[0445] Depending on the particular condition, or disease, to be treated, additional therapeutic agents, which are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0446] The compounds of the present invention can also be effectively used in combination with other antiproliferative compounds, such as aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-active compounds, alkylating compounds, histone deacetylase inhibitors, compounds that induce cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, anti-neoplastic antimetabolites, platin compounds, compounds that target / decrease protein or lipid kinase activity and further anti-angiogenic compounds, compounds that target, decrease or inhibit protein or lipid phosphatase activity, gonadorelin agonists, antiandrogens, methionine aminopeptidase inhibitors, matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease or inhibit the activity of Flt-3; Hsp90 inhibitors, such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors, such as SB715992 or SB743921 from GlaxoSmithKline or pentamidine / chlorpromazine from CombinatoRx; MEK inhibitors, such as ARRY142886 from Array BioPharma, AZd6244 from AstraZeneca, PD181461 and leucovorin from Pfizer.

[0447] The term "aromatase inhibitor," as used herein, refers to a compound that inhibits estrogen production, such as the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. This term includes, but is not limited to, steroids, particularly atamestane, exemestane, and formestane, and nonsteroids, particularly aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is commercially available under the trade name Aromasin™. Formestane is commercially available under the trade name Lentaron™. Fadrozole is commercially available under the trade name Afema™. Anastrozole is commercially available under the trade name Arimidex™. Letrozole is commercially available under the trade name Femara™ or Femar™. Aminoglutethimide is commercially available under the trade name Orimeten™. Combinations of the present invention which include a chemotherapeutic agent that is an aromatase inhibitor are particularly useful for the treatment of hormone receptor positive tumors, such as tumors of the breast.

[0448] In some embodiments, the one or more other therapeutic agents is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis, and glucose uptake. In some embodiments, the mTOR inhibitor is everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[0449] In some embodiments, the one or more other therapeutic agents is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is selected from exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca), and letrozole (Femara®, Novartis).

[0450] The term "antiestrogen," as used herein, refers to a compound that counteracts the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Tamoxifen is commercially available under the trade name Nolvadex™. Raloxifene hydrochloride is commercially available under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combinations of the present invention that include chemotherapeutic agents that are antiestrogens are particularly useful for treating estrogen receptor-positive tumors, such as breast tumors.

[0451] The term "antiandrogen," as used herein, refers to any substance capable of inhibiting the biological effects of androgenic hormones, including, but not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist," as used herein, includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin may be administered under the trade name Zoladex™.

[0452] The term "topoisomerase I inhibitor" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the macromolecular camptothecin conjugate PNU-166148. Irinotecan is commercially available, for example, under the trademark Camptosar™ and can be administered, for example, in that form. Topotecan is commercially available under the trade name Hycamptin™.

[0453] The term "topoisomerase II inhibitors," as used herein, includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations, e.g., Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is commercially available under the trade name Etopophos™. Teniposide is commercially available under the trade name VM26-Bristol. Doxorubicin is commercially available under the trade name Acriblastin™ or Adriamycin™. Epirubicin is commercially available under the trade name Farmorubicin™. Idarubicin is commercially available under the trade name Zavedos™. Mitoxantrone is commercially available under the trade name Novantron.

[0454] The term "microtubule active agents" includes, but is not limited to, taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate and vinorelbine; discodermolide; cochicine and epothilones and their derivatives. Paclitaxel is commercially available under the trade name Taxol™. Docetaxel is commercially available under the trade name Taxotere™. Vinblastine sulfate is commercially available under the trade name Vinblastin RP™. Vincristine sulfate is commercially available under the trade name Farmistin™.

[0455] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is commercially available under the trade name Cyclostin™. Ifosfamide is commercially available under the trade name Holoxan™.

[0456] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including, but not limited to, suberoylanilide hydroxamic acid (SAHA).

[0457] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds such as 5-azacytidine and decitabine, methotrexate and edatrexate, and folate antagonists such as pemetrexed. Capecitabine is commercially available under the trade name Xeloda™. Gemcitabine is commercially available under the trade name Gemzar™.

[0458] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum, and oxaliplatin. Carboplatin is commercially available, e.g., under the trademark Carboplat™, and may be administered, e.g., in that form. Oxaliplatin is commercially available, e.g., under the trademark Eloxatin™, and may be administered, e.g., in that form.

[0459] The term "Bcl-2 inhibitor" as used herein includes, but is not limited to, ABT-199, ABT-731, ABT-737, apogossypol, the pan-Bcl-2 inhibitor Ascenta, curcumin (and analogs thereof), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), genasense (G3139), HA14-1 (and analogs thereof; see WO 2008 / 118802, U.S. Patent Application Publication No. 2010 / 0197686), navitoclax (and analogs thereof; see U.S. Patent Application Publication No. 7,390,799), NH-1 (Shenayng Pharmaceutical In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0460] The term "compounds which target / reduce protein or lipid kinase activity; or protein or lipid phosphatase activity; or further anti-angiogenic compounds", as used herein, refers to protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds which target, reduce or inhibit the activity of platelet derived growth factor receptors (PDGFR), for example compounds which target, reduce or inhibit the activity of PDGFR, in particular compounds which inhibit PDGF receptors, for example N-phenyl 2-pyrimidinamine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds which target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFR); c) compounds which target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), for example compounds which target, reduce or inhibit the activity of IGF-IR d) compounds which target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family or ephrin B4 inhibitors; e) compounds which target, reduce or inhibit the activity of the AXI receptor tyrosine kinase family; f) compounds which target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds which target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds which target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family, such as compounds which target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds which inhibit the c-Kit receptor, such as imatinib;i) Compounds that target, decrease, or inhibit the activity of c-Abl family members, their gene fusion products (e.g., Bcr-Abl kinase) and mutants, such as compounds that target, decrease, or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl 2-pyrimidinamine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC680410; PD173955 (from ParkeDavis); or dasatinib (BMS-35 4825);j) compounds that target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf family of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKb / Akt, Ras / MAPK, PI3K, Syk, TYK2, Btk and TEC families, and / or members of the cyclin-dependent kinase family (CDK), e.g., staurosporine derivatives such as midostaurin; further exemplary compounds include UCN-01, safingo ru, BAY43-9006, bryostatin 1, perifosine; lulumofosine; RO318220 and RO320432; GO6976; lsis3521; LY333531 / LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, for example, compounds that target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors. include imatinib mesylate (Gleevec™) or tyrphostins, such as tyrphostin A23 / RG-50810; AG99; tyrphostin AG213; tyrphostin AG1748; tyrphostin AG490; tyrphostin B44; tyrphostin B44 (+) enantiomer; tyrphostin AG555; AG494; tyrphostin AG556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC680410, adaphostin);l) compounds which target, decrease or inhibit the activity of receptor tyrosine kinases of the epidermal growth factor family (EGFR1, ErbB2, ErbB3, ErbB4 as homo- or heterodimers) and their variants, for example compounds which target, decrease or inhibit the activity of the epidermal growth factor receptor family, in particular compounds, proteins or antibodies which inhibit members of the EGF receptor tyrosine kinase family, such as EGF receptor, ErbB2, ErbB3 and ErbB4, or which bind to EGF or EGF-related ligands, CP358774, ZD1839, ZM105180; m) compounds that target, decrease, or inhibit the activity of the c-Met receptor, e.g., compounds that target, decrease, or inhibit the activity of c-Met, such as rastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, or E7.6.3, and 7H-pyrrolo-[2,3-d]pyrimidine derivatives. n) compounds that target, decrease, or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including, but not limited to, PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-50, and the like; 9, AZD-1480, TG-101348, tofacitinib and ruxolitinib; o) compounds that target, decrease or inhibit the kinase activity of PI3 kinase (PI3K), such as, but not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765 and idelalisib; andand q) compounds that target, decrease, or inhibit the signaling effects of the Hedgehog (Hh) or Smoothened receptor (SMO) pathways, including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (saridegib);

[0461] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are eg inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or a derivative thereof.

[0462] In some embodiments, the one or more other therapeutic agents are growth factor antagonists, such as antagonists of platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists that can be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists that can be used in the present invention include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca).

[0463] The term "PI3K inhibitor", as used herein, includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including, but not limited to, PI3K α, PI3K γ, PI3K δ, PI3K β, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors useful in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictrelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0464] The term "BTK inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0465] The term "SYK inhibitor" as used herein includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0466] Further examples of BTK inhibitor compounds, and conditions treatable by such compounds in combination with the compounds of the invention, can be found in WO 2008 / 039218, U.S. Patent Application Publication No. 2008 / 0108636, WO 2011 / 090760, and U.S. Patent Application Publication No. 2010 / 0249092, each of which is incorporated by reference in its entirety.

[0467] Further examples of SYK inhibitor compounds, and conditions treatable by such compounds in combination with the compounds of the present invention, can be found in WO 2003 / 063794, U.S. Patent Application Publication No. 2004 / 0029902, WO 2005 / 007623, U.S. Patent Application Publication No. 2005 / 0075306, and WO 2006 / 078846, U.S. Patent Application Publication No. 2006 / 0211657 (each of which is incorporated by reference in its entirety).

[0468] Further examples of PI3K inhibitor compounds, and conditions treatable by such compounds in combination with the compounds of the invention, are described in WO 2004 / 019973, U.S. Patent Application Publication No. 2004 / 0106569, WO 2004 / 089925, U.S. Patent Application Publication No. 2004 / 0242631, U.S. Patent No. 8,138,347, WO 2002 / 088112, U.S. Patent Application Publication No. 2004 / 0116421, WO 2007 / 084786, U.S. Patent Application Publication No. No. 2010 / 0249126, WO 2007 / 129161, U.S. Patent Application Publication No. 2008 / 0076768, WO 2006 / 122806, U.S. Patent Application Publication No. 2008 / 0194579, WO 2005 / 113554, U.S. Patent Application Publication No. 2008 / 0275067, and WO 2007 / 044729, U.S. Patent Application Publication No. 2010 / 0087440 (each of which is incorporated by reference in its entirety).

[0469] Further examples of JAK inhibitor compounds, and conditions treatable by such compounds in combination with the compounds of the invention, can be found in WO 2009 / 114512, U.S. Patent Application Publication No. 2009 / 0233903, WO 2008 / 109943, U.S. Patent Application Publication No. 2010 / 0197671, WO 2007 / 053452, U.S. Patent Application Publication No. 2007 / 0191405, WO 2001 / 0142246, U.S. Patent Application Publication No. 2001 / 0053782, and WO 2007 / 070514, U.S. Patent Application Publication No. 2007 / 0135461, each of which is incorporated by reference in its entirety.

[0470] Additional anti-angiogenic compounds include compounds that have another mechanism for their activity, eg, unrelated to protein or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

[0471] Examples of proteasome inhibitors useful in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0472] Compounds which target, decrease or inhibit the activity of a protein or lipid phosphatase are eg inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or a derivative thereof.

[0473] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-γ- or δ-tocopherol, or α-γ- or δ-tocotrienol.

[0474] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acids such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0475] The term "bisphosphonate" as used herein includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etridonic acid is commercially available under the trade name Didronel™. Clodronic acid is commercially available under the trade name Bonefos™. Tiludronic acid is commercially available under the trade name Skelid™. Pamidronic acid is commercially available under the trade name Aredia™. Alendronic acid is commercially available under the trade name Fosamax™. Ibandronic acid is commercially available under the trade name Bondranat™. Risedronic acid is commercially available under the trade name Actonel™. Zoledronic acid is commercially available under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds that inhibit the mammalian target of rapamycin (mTOR) and that possess antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0476] The term "heparanase inhibitor" as used herein refers to a compound that targets, decreases, or inhibits heparin sulfate degradation. This term includes, but is not limited to, PI-88. The term "biological response modifier" as used herein refers to a lymphokine or interferon.

[0477] The term "inhibitor of an oncogenic Ras isoform," such as H-Ras, K-Ras, or N-Ras, as used herein, refers to a compound that targets, reduces, or inhibits the oncogenic activity of Ras; for example, a "farnesyltransferase inhibitor," such as L-744832, DK8G557, or R115777 (Zarnestra™). The term "telomerase inhibitor," as used herein, refers to a compound that targets, reduces, or inhibits the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase are particularly compounds that inhibit the telomerase receptor, such as telomestatin.

[0478] The term "methionine aminopeptidase inhibitors," as used herein, refers to compounds that target, decrease or inhibit the activity of methionine aminopeptidase. Compounds that target, decrease or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or a derivative thereof.

[0479] The term "proteasome inhibitor," as used herein, refers to a compound that targets, decreases, or inhibits the activity of the proteasome. Compounds that target, decrease, or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade™); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda) and MLN341.

[0480] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors)" as used herein includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives, such as the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC683551), BMS-279251, BAY12-9566, TAA211, MMI270B, or AAJ996.

[0481] The term "compounds used in the treatment of hematological malignancies," as used herein, includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase.

[0482] Compounds that target, decrease or inhibit the activity of FLT-3R are compounds, proteins or antibodies that specifically inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0483] The term "HSP90 inhibitor," as used herein, includes, but is not limited to, compounds that target, decrease, or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, decrease, or inhibit HSP90 client proteins via the ubiquitin-proteasome pathway. Compounds that target, decrease, or inhibit the intrinsic ATPase activity of HSP90 are, in particular, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), geldanamycin derivatives; other geldanamycin-related compounds; radicicol, and HDAC inhibitors.

[0484] The term "anti-proliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40), and 2C4 antibodies. Antibodies refer to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, so long as they exhibit the desired biological activity.

[0485] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, particularly in combination with therapies used for the treatment of AML. In particular, the compounds of the present invention can be administered in combination with, for example, farnesyltransferase inhibitors and / or other drugs useful in the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, and PKC412.

[0486] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue that is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Purine analogues include hypoxanthine, 6-mercaptopurine (6-MP) and fludarabine phosphate. Compounds that target, decrease or inhibit the activity of histone deacetylase (HDAC) inhibitors, such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA), inhibit the activity of enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly FR901228), trichostatin A, and compounds disclosed in U.S. Pat. No. 6,552,065, such as N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or a pharmaceutically acceptable salt thereof, particularly the lactate salt. As used herein, somatostatin receptor antagonist refers to compounds that target, treat, or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as any electromagnetic ray (such as X-rays and gamma rays) or particle (such as alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy, and is known in the art. Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, Devita et al., Eds., 4 th Edition, Vol. 1, pp. 248-275 (1993).

[0487] Also included are EDG binders and ribonucleotide reductase inhibitors. The term "EDG binder" as used herein refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to a pyrimidine or purine nucleoside analog, including, but not limited to, fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL), and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0488] Also included are compounds, proteins or monoclonal antibodies of VEGF such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, e.g., rhuMAb and RHUFab, VEGF aptamers, e.g., Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, angiozyme (RPI4610) and bevacizumab (Avastin™).

[0489] Photodynamic therapy, as used herein, refers to a treatment that uses certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0490] Antiangiogenic steroids, as used herein, refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0491] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0492] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

[0493] The compounds of the present invention are also useful as co-therapeutic compounds for use in combination with other active ingredients, such as anti-inflammatory, bronchodilatory, or antihistamine active ingredients, particularly in the treatment of obstructive or inflammatory airway diseases, such as those mentioned hereinabove, e.g., as enhancers of the therapeutic activity of such drugs or as a means of reducing the required dosage or mitigating potential side effects of such drugs. The compounds of the present invention can be mixed with the other active ingredients in a fixed pharmaceutical composition, or can be administered separately, before, simultaneously with, or after the other active ingredients. Thus, the present invention includes combinations of the compounds of the present invention with anti-inflammatory, bronchodilatory, antihistamine, or anti-tussive active ingredients, as described hereinabove, wherein the compounds of the present invention and the active ingredients are in the same or different pharmaceutical compositions.

[0494] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids, such as budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists, such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL284, ONO4057, SB209247; LTD4 antagonists, such as montelukast and zafirlukast; PDE4 inhibitors, such as cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Allophylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801(Celgene), SeICID(TM)CC-10004(Celgene), VM554 / UM565(Vernalis), T-440(Tanabe), KW-4490(Kyowa Hakko Kogyo); A2a agonists; A2b antagonists; and beta-2 adrenergic receptor agonists, such as albuterol (salbutamol), metaproterenol, terbutaline, salmeterol, fenoterol, procaterol, and especially formoterol, and pharmaceutically acceptable salts thereof. Suitable bronchodilator drugs include anticholinergic or antimuscarinic compounds, especially ipratropium bromide, oxitropium bromide, tiotropium salts, and CHF4226 (Chiesi), and glycopyrrolate.

[0495] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratidine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine, and tefenadine.

[0496] Another useful combination of the compounds of the invention with anti-inflammatory agents is with antagonists of chemokine receptors such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, in particular CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, Takeda antagonists such as N-[[4-[[[6,7-dihydro-2-(4-methylphenyl)-5H-benzo-cyclohepten-8-yl]carbonyl]amino]phenyl]-methyl]tetrahydro-N,N-dimethyl-2H-pyran-4-aminium chloride (TAK-770).

[0497] The structures of active compounds identified by code number, generic name or trade name can be obtained from the actual edition of the standard catalogue "The Merck Index" or from databases such as Patents International (e.g. IMS World Publications).

[0498] The compounds of the present invention may also be used in combination with known therapeutic processes, such as the administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for the treatment of tumors that exhibit poor sensitivity to radiation therapy.

[0499] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combination treatments can be in the form of a fixed combination, or the administration of the compounds of the present invention and one or more other therapeutic compounds can be staggered or given independently, or the combined administration of a fixed combination and one or more other therapeutic compounds.The compounds of the present invention can also or additionally be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for tumor treatment.Long-term treatment is equally possible as adjuvant therapy in the context of other treatment strategies, as described above.Other possible treatments are, for example, treatments to maintain the patient's condition after tumor regression or even chemopreventive therapy in at-risk patients.

[0500] These additional agents can be administered separately from the composition containing the compound of the present invention as part of a multiple dose regimen. Alternatively, these agents can be part of a single dosage form, mixed together with the compound of the present invention in a single composition. When administered as part of a multiple dose regimen, the two active agents can be presented simultaneously, sequentially, or at a time interval (usually within 5 hours) between each other.

[0501] As used herein, the terms "combination," "in combination," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0502] The amounts of both the compounds of the invention and additional therapeutic agents (in compositions containing such additional therapeutic agents) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions of the invention should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the compound of the invention can be administered.

[0503] In compositions containing an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention may act synergistically. Thus, the amount of the additional therapeutic agent in such compositions will be less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dose of 0.01 to 1,000 μg / kg body weight / day of the additional therapeutic agent may be administered.

[0504] The amount of one or more other therapeutic agents present in the compositions of the invention may be an amount not exceeding the amount typically administered in a composition containing that therapeutic agent as the only active agent. The amount of one or more other therapeutic agents in the compositions of the present disclosure is preferably in the range of about 50% to 100% of the amount typically administered in a composition containing that agent as the only therapeutically active agent. In some embodiments, the one or more other therapeutic agents are administered at a dosage of about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount typically administered for that agent. As used herein, the phrase "typically administered" refers to the amount of an FDA-approved therapeutic agent approved for administration according to the FDA label insert.

[0505] The compounds of the present invention or pharmaceutical compositions thereof can also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the blood vessel wall after injury). However, patients using stents or other implantable devices are at risk of thrombus formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with the compounds of the present invention is another embodiment of the present invention.

[0506] Representative tumor immunotherapy drugs In some embodiments, the one or more other therapeutic agents are tumor immunotherapeutic agents. As used herein, the term "tumor immunotherapeutic agent" refers to an agent that is effective for enhancing, stimulating and / or upregulating immune response in a subject. In some embodiments, the administration of the tumor immunotherapeutic agent with the compound of the present invention has a synergistic effect in the treatment of cancer.

[0507] The tumor immunotherapeutic agent can be, for example, a small molecule drug, an antibody, or a biological or small molecule. Examples of biological tumor immunotherapeutics include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is a humanized antibody or a human antibody.

[0508] In some embodiments, the tumor immunotherapeutic is (i) an agonist of a stimulatory (including costimulatory) receptor, or (ii) an antagonist of an inhibitory (including costimulatory) signal in T cells, both of which result in the amplification of antigen-specific T cell responses.

[0509] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or costimulatory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or costimulatory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, and R ANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, Includes EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0510] In some embodiments, the tumor immunotherapeutic is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

[0511] In some embodiments, the combination of a compound of the present invention and a tumor immunotherapeutic agent may stimulate a T cell response. In some embodiments, the tumor immunotherapeutic is (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin-9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H.

[0512] In some embodiments, the tumor immunotherapeutic is an antagonist of an inhibitory receptor on NK cells or an agonist of an activating receptor on NK cells, hi some embodiments, the tumor immunotherapeutic is an antagonist of KIR, e.g., lirilumab.

[0513] In some embodiments, the tumor immunotherapeutic agent is a CSF-1R antagonist, such as RG7155 (see WO 2011 / 070024, US Patent Application Publication No. 2011 / 0165156, WO 2011 / 0107553, US Patent Application Publication No. 2012 / 0329997, WO 2011 / 131407, US Patent Application Publication No. 2013 / 0005949, WO 2013 / 087699, US Patent Application Publication No. 2014 / 0336363, WO 2013 / 119 and agents that inhibit or deplete macrophages or monocytes, including, but not limited to, CSF-IR antagonist antibodies including FPA-008 (WO 2011 / 140249, US 2011 / 0274683; WO 2013 / 169264; WO 2014 / 036357, US 2014 / 0079699).

[0514] In some embodiments, the tumor immunotherapeutic agent is selected from agonistic agents that ligate positive costimulatory receptors, blockers that attenuate signaling through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome distinct immunosuppressive pathways within the tumor microenvironment (e.g., block inhibitory receptor engagement (e.g., PD-L1 / PD-1 interactions), deplete or inhibit Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibit metabolic enzymes such as IDO, or reverse / prevent T cell energy or exhaustion), and agents that initiate innate immune activation and / or inflammation at the tumor site.

[0515] In some embodiments, the tumor immunotherapeutic is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, the antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0516] In some embodiments, the tumor immunotherapeutic is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the tumor immunotherapeutic is an antibody or antigen-binding portion thereof that specifically binds to the programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, the antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO 2012 / 145493). In some embodiments, the tumor immunotherapeutic can be pidilizumab (CT-011). In some embodiments, the tumor immunotherapeutic is a recombinant protein called AMP-224, which is composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0517] In some embodiments, the tumor immunotherapeutic agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO 2010 / 077634, U.S. Patent Application Publication No. 2010 / 0203056), durvalumab (MEDI4736), BMS-936559 (WO 2007 / 005874, U.S. Patent Application Publication No. 2009 / 0055944), or MSB0010718C (WO 2013 / 079174, U.S. Patent Application Publication No. 2014 / 0341917).

[0518] In some embodiments, the tumor immunotherapeutic is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, the LAG-3 antibody is BMS-986016 (WO 2010 / 019570, U.S. Patent Application Publication No. 2010 / 0150892, WO 2014 / 008218, U.S. Patent Application Publication No. 2014 / 0093511), or IMP-731 or IMP-321 (WO 2008 / 132601, U.S. Patent Application Publication No. 2010 / 0233183, WO 2009 / 044273, U.S. Patent Application Publication No. 2011 / 0008331).

[0519] In some embodiments, the tumor immunotherapeutic is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO 12 / 32433).

[0520] In some embodiments, the tumor immunotherapeutic is a GITR agonist. In some embodiments, the GITR agonist is an agonistic GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO 2006 / 105021, U.S. Patent Application Publication No. 2007 / 0098719, WO 2009 / 009116, U.S. Patent Application Publication No. 2009 / 0136494), or MK-4166 (WO 2011 / 028683, U.S. Patent Application Publication No. 2012 / 0189639).

[0521] In some embodiments, the tumor immunotherapeutic agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmanitib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); an enzyme that breaks down kynurenine (Kynase, Kyn Therapeutics); and NLG-919 (WO 2009 / 073620, U.S. Patent Application Publication No. 2011 / 0053941, WO 2009 / 132238, U.S. Patent Application Publication No. 2011 / 0136796, WO 2011 / 056652, U.S. Patent Application Publication No. 2012 / 0277217, WO 2012 / 142237, U.S. Patent Application Publication No. 2014 / 0066625).

[0522] In some embodiments, the tumor immunotherapeutic is an OX40 agonist. In some embodiments, the OX40 agonist is an agonistic OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0523] In some embodiments, the tumor immunotherapeutic agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO 2006 / 029879, U.S. Pat. No. 7,501,496).

[0524] In some embodiments, the tumor immunotherapeutic is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic CD40 antibody. In some embodiments, the tumor immunotherapeutic is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonistic CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

[0525] In some embodiments, the tumor immunotherapeutic agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

[0526] In some embodiments, the tumor immunotherapeutic is MGA271 (against B7H3) (WO 2011 / 109400, US 2013 / 0149236).

[0527] In some embodiments, the tumor immunotherapeutic is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimumab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, alatumumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0528] In some embodiments, the tumor immunotherapeutic agent is an immunostimulatory agent. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis have been shown in clinical trials to be able to deregulate activated tumor-reactive T cells and induce durable anti-tumor responses, improving many tumor histologies, including some tumor types not traditionally considered sensitive to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (also known as ONO-4538, MDX1106, and BMS-936558, Opdivo®, Bristol-Myers Squibb) has shown potential to improve overall survival in RCC patients who have experienced disease progression during or after prior antiangiogenic therapy.

[0529] In some embodiments, the immunomodulatory therapeutic specifically induces apoptosis in tumor cells. Approved immunomodulatory therapeutics that may be used in the present invention include pomalidomide (Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenol mebutate (Picato®, LEO Pharma).

[0530] In some embodiments, the tumor immunotherapeutic agent is a cancer vaccine, which is selected from sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-resistant) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex / Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions of melanoma.In some embodiments, the tumor immunotherapeutic agent is an oncolytic virotherapy, e.g., pexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF; Reolysin®, Oncolytics, for many cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell carcinoma (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT00861627). Biotech, a respiratory enteric orphan virus that does not replicate in cells without RAS activation variants of reovirus; enadenotucirev (NG-348, formerly known as PsiOxus, ColoAd1), an adenovirus engineered to express full-length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors, such as in colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036); melanoma (NCT03003676); and ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF, in peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux) GmbH), a vaccinia virus modified to express beta-galactosidase (beta-gal) / beta-glucoronidase or beta-gal / human sodium iodide symporter (hNIS), respectively, in peritoneal carcinomatosis (NCT01443260); in fallopian tube and ovarian cancer (NCT02759588); or in bladder cancer (NCT02365818); CG0070 (Cold Genesys), an adenovirus modified to express GM-CSF.

[0531] In some embodiments, the tumor immunotherapeutics include JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus modified to express cytosine deaminase, which is capable of converting the prodrug 5-fluorocytosine into the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapeutics targeted against difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), a modified adenovirus called Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP (ViraTherapeutics), a vesicular stomatitis virus (VSV) modified to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) (antigen-specific CD8 + may be further modified to express an antigen designed to generate a T cell response).

[0532] In some embodiments, the tumor immunotherapeutic is a T cell engineered to express a chimeric antigen receptor, or CAR. T cells engineered to express such a chimeric antigen receptor are called CAR-T cells.

[0533] CARs are constructed from a binding domain, which may be derived from a natural ligand, a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen fused to an endodomain, which is the functional end of a T cell receptor (TCR), such as the CD3-zeta signaling domain from the TCR, which can generate an activation signal in T lymphocytes. Upon antigen binding, such CARs connect to endogenous signaling pathways in effector cells, generating activation signals similar to those initiated by the TCR complex.

[0534] For example, in some embodiments, the CAR-T cells are one of those described in U.S. Patent No. 8,906,682, the entire contents of which are incorporated herein by reference, which discloses CAR-T cells modified to include an extracellular domain having an antigen-binding domain (such as a domain that binds to CD19) fused to the intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta). When expressed in T cells, the CAR can redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. More than 200 clinical trials are currently underway using CAR-T in a wide variety of applications. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1]

[0535] In some embodiments, the immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor gamma (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as innate immune cell subpopulations that express IL-17, such as NK cells. In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0536] In some embodiments, the immunostimulatory agent is a Toll-like receptor (TLR) agonist or activator. Suitable TLR activators include TLR9 agonists or activators, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that has been tested against B-cell, follicular, and other lymphomas (NCT02254772). TLR8 agonists or activators that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which has been tested against squamous cell carcinoma of the head and neck (NCT02124850) and ovarian cancer (NCT02431559).

[0537] Other tumor immunotherapeutic agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; and MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[0538] In some embodiments, the immunostimulant is selected from elotuzumab, mifamurtide, agonists or activators of Toll-like receptors, and activators of RORγt.

[0539] In some embodiments, the immunostimulating therapeutic agent is recombinant human interleukin-15 (rhIL-15). rhIL-15 is being tested in medical centers as a treatment for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immunostimulating agent is recombinant human interleukin-12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic agent is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex composed of a synthetic form of endogenous IL-15 conjugated to the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which is being tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin-12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0540] In some embodiments, the tumor immunotherapeutic agent is selected from those described in Jerry L. Adams ET.AL., "Big opportunities for small molecules in immuno-oncology," Cancer Therapy 2015, Vol. 14, pages 603-622, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the tumor immunotherapeutic agent is selected from the examples described in Table 1 of Jerry L. Adams ET.AL. In some embodiments, the tumor immunotherapeutic agent is a small molecule that targets a tumor immunotherapy target selected from those listed in Table 2 of Jerry L. Adams ET.AL. In some embodiments, the tumor immunotherapeutic agent is a small molecule drug selected from those listed in Table 2 of Jerry L. Adams ET.AL.

[0541] In some embodiments, the tumor immunotherapeutic agent is selected from small molecule tumor immunotherapeutic agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents," Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the tumor immunotherapeutic agent is an agent that targets a pathway as described in Peter L. Toogood.

[0542] In some embodiments, the tumor immunotherapeutic is selected from those described in Sandra L. Ross et al., "Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing," PLoS ONE 12(8):e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the tumor immunotherapeutic is a bispecific T cell engager (BiTE®) antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, which release cytokines and induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some emb...

Claims

1. 【Chemical 41】 【Chemistry 42】 【Chemistry 43】 【Chemical 44】 【Chemistry 45】 Compound 1 selected from: 【Chemistry 46】 Salt form of.

2. 10. The salt form of claim 1, wherein the salt form is crystalline.

3. 3. The salt form of claim 1 or 2, wherein the salt form is a crystalline solid that is substantially free of amorphous Compound 1.

4. 4. The salt form of any one of claims 1 to 3, wherein the salt form is substantially free of impurities.

5. 5. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 2.

6. 6. The salt form of claim 5, wherein Form A of Compound 2 is characterized in its XRPD pattern by one or more peaks selected from those at 16.5, 17.5, and 19.7 ±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

7. 6. The salt form of claim 5, having an XRPD substantially as shown in FIG. 1A.

8. 5. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 3.

9. 9. The salt form of claim 8, wherein Form A of Compound 3 is characterized in its XRPD pattern by one or more peaks selected from those at 5.6, 11.5, and 16.5 ±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

10. 9. The salt form of claim 8, having an XRPD substantially as shown in Figure 2A.

11. 5. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 4.

12. 12. The salt form of claim 11, wherein Form A of Compound 4 is characterized in its XRPD pattern by one or more peaks selected from those at 5.9, 11.9, and 16.5 ±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

13. 12. The salt form of claim 11, having an XRPD substantially as shown in Figure 3A.

14. 5. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 5.

15. 15. The salt form of claim 14, wherein Form A of Compound 5 is characterized in its XRPD pattern by one or more peaks selected from those at 6.0, 8.2, and 12.4 ±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

16. 15. The salt form of claim 14, having an XRPD substantially as shown in Figure 4A.

17. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 6.

18. 18. The salt form of claim 17, wherein Form A of Compound 6 is characterized in its XRPD pattern by one or more peaks selected from those at 16.5, 19.5, and 21.2 ±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

19. 18. The salt form of claim 17, having an XRPD substantially as shown in Figure 5A.

20. 5. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 7.

21. 21. The salt form of claim 20, wherein Form A of Compound 7 is characterized in its XRPD pattern by one or more peaks selected from those at 6.5, 16.5, and 18.5 ±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

22. 21. The salt form of claim 20, having an XRPD substantially as shown in Figure 6A.

23. 5. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 8.

24. 24. The salt form of claim 23, wherein Form A of Compound 8 is characterized in its XRPD pattern by one or more peaks selected from those at 6.5, 16.5, and 17.5 ±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

25. 24. The salt form of claim 23, having an XRPD substantially as shown in Figure 7A.

26. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 9.

27. 27. The salt form of claim 26, wherein Form A of Compound 9 is characterized in its XRPD pattern by one or more peaks selected from those at 6.7, 10.7, and 16.3 ±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

28. 27. The salt form of claim 26, having an XRPD substantially as shown in Figure 8A.

29. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 10.

30. 30. The salt form of claim 29, wherein Form A of Compound 10 is characterized in its XRPD pattern by one or more peaks selected from those at 6.0, 11.9, and 16.5±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

31. 30. The salt form of claim 29, having an XRPD substantially as shown in Figure 9A.

32. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 11.

33. 33. The salt form of claim 32, wherein Form A of Compound 11 is characterized in its XRPD pattern by one or more peaks selected from those at 6.8, 13.0, and 17.1 ±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

34. 33. The salt form of claim 32, having an XRPD substantially as shown in Figure 10A.

35. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 12.

36. 36. The salt form of claim 35, wherein Form A of Compound 12 is characterized in its XRPD pattern by one or more peaks selected from those at 6.5, 10.8, and 16.8±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

37. 36. The salt form of claim 35, having an XRPD substantially as shown in Figure 11A.

38. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 13.

39. 39. The salt form of claim 38, wherein Form A of Compound 13 is characterized in its XRPD pattern by one or more peaks selected from those at 6.0, 16.3, and 20.1 ±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

40. 39. The salt form of claim 38, having an XRPD substantially as shown in Figure 12A.

41. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 14.

42. 42. The salt form of claim 41, wherein Form A of Compound 14 is characterized in its XRPD pattern by one or more peaks selected from those at 6.5, 17.1, and 21.0 ±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

43. 42. The salt form of claim 41, having an XRPD substantially as shown in Figure 13A.

44. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 15.

45. 45. The salt form of claim 44, wherein Form A of Compound 15 is characterized in its XRPD pattern by one or more peaks selected from those at 6.0, 17.0, and 20.2 ±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

46. 45. The salt form of claim 44, having an XRPD substantially as shown in Figure 14A.

47. The salt form of any one of claims 1 to 4, wherein the salt form is Form A of Compound 16.

48. 48. The salt form of claim 47, wherein Form A of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from those at 6.5, 12.9, and 16.2 ±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

49. 48. The salt form of claim 47, having an XRPD substantially as shown in Figure 15A.

50. The salt form of any one of claims 1 to 4, wherein the salt form is Form B of Compound 16.

51. 51. The salt form of claim 50, wherein Form B of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from those at 6.8, 11.1, and 16.5±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

52. 51. The salt form of claim 50, having an XRPD substantially as shown in Figure 15A.

53. The salt form of any one of claims 1 to 4, wherein the salt form is Form C of Compound 16.

54. 54. The salt form of claim 53, wherein Form C of Compound 16 is characterized in its XRPD pattern by one or more peaks selected from those at 6.0, 11.9, and 16.0 ±0.5 degrees two-theta, ±0.4 degrees two-theta, ±0.3 degrees two-theta, or ±0.2 degrees two-theta.

55. 54. The salt form of claim 53, having an XRPD substantially as shown in Figure 15A.

56. 56. A composition comprising the salt form of any one of claims 1 to 55 and a pharmaceutically acceptable carrier or excipient.

57. 56. A method of degrading IRAK4 protein in a patient or biological sample, comprising administering to said patient or contacting said biological sample with a salt form of any one of claims 1 to 55 or a pharmaceutical composition thereof.

58. 56. A method of treating an IRAK4-mediated disorder, disease or condition in a patient, comprising administering to said patient a salt form or pharmaceutical composition thereof according to any one of claims 1 to 55.

59. 59. The method of claim 58, wherein the IRAK4-mediated disorder, disease or condition is an autoimmune disorder or an inflammatory disorder.

60. The autoimmune or inflammatory disorder may be ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis, allergic rhinitis, hemolytic anemia, aplastic anemia, pure red blood cell anemia, idiopathic thrombocytopenia, or another inflammatory disease involving an autoimmune response or having an autoimmune component or etiology, systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, ulcerative colitis, Crohn's disease or other autoimmune inflammatory bowel disease, irritable bowel syndrome, celiac disease. , periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine opthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome, optionally including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, intrauterine Membranosis, leptospirosis kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hyperchloresterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis, or exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia hypersensitivity, anaphylaxis, sinusitis, silica-induced disease, COPD (reduction of damage, airway inflammation, bronchial hyperresponsiveness, remodeling or disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, type 2 diabetes, appendicitis, atopic dermatitis, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis,Endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrosis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, herpes dermatitis, scleroderma, vitiligo, hypersensitive blood vessels 60. The method of claim 59, wherein the inflammatory disease is selected from the group consisting of rash, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryopyrin-associated periodic syndromes (CAPS), and osteoarthritis.

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