Salt forms of IRAK4 degrading agents

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 the treatment of various diseases.

Description

Cross - Reference to Related Applications

[0001] This application claims the benefit of priority of U.S. Provisional Application No. 63 / 379,391, filed on October 13, 2022, the content of which is incorporated herein by reference. Technical Field

[0002] The present disclosure generally relates to various salt forms and compositions thereof of interleukin - 1 receptor - associated kinase 4 (“IRAK4”) that can be used to regulate IRAK4 via ubiquitination and / or degradation, and their use in treating various diseases. Background Art

[0003] The ubiquitin - proteasome pathway (UPP) is a key pathway for regulating key regulatory proteins and degrading misfolded or abnormal proteins. The UPP is central to multiple cellular processes and, if defective or imbalanced, can lead to the pathogenesis of a variety of diseases. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases.

[0004] There are over 600 E3 ubiquitin ligases that promote the ubiquitination of different proteins in the body and can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multi-subunit E3s. See generally Li et al. (PLOS One, 2008, 3, 1487) titled "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) titled "New insights into ubiquitin E3 ligase mechanism"; Deshaies et al. (Ann. Rev. Biochem., 2009, 78, 399-434) titled "RING domain E3 ubiquitin ligases."; Spratt et al. (Biochem., 2014, 458, 421-437) titled "RBR E3 ubiquitin ligases: new structures, new insights, new questions."; and Wang et al. (Nat. Rev. Cancer, 2014, 14, 233-347) titled "Roles of F-box proteins in cancer."

[0005] The UPP plays a key role in the degradation of short-lived and regulatory proteins that are important in a variety of basic cellular processes, including the regulation of the cell cycle, the regulation of cell surface receptors and ion channels, and antigen presentation. This pathway is associated with the pathogenesis of multiple forms of malignancy, multiple genetic diseases (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), immune surveillance / viral pathogenesis, and the pathology of muscle atrophy. Many diseases are associated with abnormal UPP and negatively impact the cell cycle and division, the cell's response to stress and extracellular regulators, the morphogenesis of neural networks, the regulation of cell surface receptors, ion channels, the secretory pathway, DNA repair, and the biogenesis of organelles.

[0006] Abnormalities in this process have recently been found to be associated with the pathogenesis of a variety of diseases (both hereditary and acquired). These diseases are mainly divided into two categories: (a) those diseases in which certain proteins are stabilized due to loss of function, and (b) those diseases that result from gain of function (i.e., abnormal or accelerated degradation of protein targets).

[0007] The UPP is used to induce selective protein degradation, including the use of fusion proteins to artificially ubiquitinate target proteins and the use of synthetic small molecule probes to induce proteasome-dependent degradation. Bifunctional compounds composed of a target protein-binding ligand and an E3 ubiquitin ligase ligand induce proteasome-mediated degradation of these selected proteins by recruiting the selected proteins to the E3 ubiquitin ligase and subsequent ubiquitination. These drug-like molecules offer the possibility of temporal control of protein expression. Such compounds can induce the inactivation of the protein of interest after being added to cells or administered to animals or humans, can be used as biochemical reagents, and open up new modes of treating diseases by removing pathogenic or carcinogenic proteins (Crews C, Chemistry&Biology, 2010, 17(6):551 - 555; Schnnekloth JS Jr., Chembiochem, 2005, 6(l):40 - 46).

[0008] There is a continuing need in the art for effective treatments for diseases, especially autoinflammatory and autoimmune diseases with a high degree of unmet medical need. However, non-specific effects and the inability to target and regulate certain classes of proteins, such as transcription factors, remain obstacles to the development of effective anticancer agents. Therefore, small molecule therapeutic agents that utilize E3 ligase-mediated protein degradation to target cancer-related proteins, such as interleukin-1 receptor-associated kinase 4 ("IRAK4"), are promising as therapeutic agents. Accordingly, there remains a need to find compounds that can serve as IRAK4 degraders for use as therapeutic agents. Summary of the Invention

[0009] The novel salt forms of 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide as described in this disclosure and compositions thereof have now been found to be useful modulators of the targeted ubiquitination of IRAK4 kinase and exhibit the desired characteristics. Generally, the salt forms and their pharmaceutically acceptable compositions can be used to treat or reduce the severity of a variety of diseases or disorders as described in detail herein. Description of Drawings

[0010] Figure 1A Overlay of XRPD patterns of Form A of Compound 2: a) dry solid; and b)-d) wet cake.

[0011] Figure 1B Overlay of DSC-TGA of Form A of Compound 2 is shown.

[0012] Figure 2A Overlay of XRPD patterns of Form A of Compound 3: a) dry solid; and b)-c) wet cake.

[0013] Figure 2B Overlay of DSC-TGA of Form A of Compound 3 is shown.

[0014] Figure 3A Overlay of XRPD patterns of Form A of Compound 4: a) p-toluenesulfonic acid monohydrate; b)-d) wet cake; and e) dry solid.

[0015] Figure 3B Overlay of DSC-TGA of Form A of Compound 4 is shown.

[0016] Figure 4A Overlay of XRPD patterns of Form A of Compound 5: a) dry solid; and b)-c) wet cake.

[0017] Figure 4B Overlay of DSC-TGA of Form A of Compound 5 is shown.

[0018] Figure 5A Overlay of XRPD patterns of Form A of Compound 6: a)-d) wet cake; and e) dry solid.

[0019] Figure 5B Overlay of DSC-TGA of Form A of Compound 6 is shown.

[0020] Figure 6A XRPD patterns overlay of Form A of Compound 7 are shown: a) Maleic acid monohydrate; b)-d) Wet cake; and e) Dried solid.

[0021] Figure 6B DSC-TGA overlay of Form A of Compound 7 is shown.

[0022] Figure 7A XRPD patterns overlay of Form A of Compound 8 are shown: a) L-Tartaric acid; b)-e) Wet cake; and f) Dried solid.

[0023] Figure 7B DSC-TGA overlay of Form A of Compound 8 is shown.

[0024] Figure 8A XRPD patterns overlay of Form A of Compound 9 are shown: a) Fumaric acid; b)-g) Wet cake; and h) Dried solid.

[0025] Figure 8B DSC-TGA overlay of Form A of Compound 9 is shown.

[0026] Figure 9A XRPD patterns overlay of Form A of Compound 10 are shown: a) Citric acid; b)-e) Wet cake; and f) Dried solid.

[0027] Figure 9B DSC-TGA overlay of Form A of Compound 10 is shown.

[0028] Figure 10A XRPD patterns overlay of Form A of Compound 11 are shown: a) Glycolic acid; b)-e) Wet cake; and f) Dried solid.

[0029] Figure 10B DSC-TGA overlay of Form A of Compound 11 is shown.

[0030] Figure 11A XRPD patterns overlay of Form A of Compound 12 are shown: a) L-Malic acid; b)-g) Wet cake; and h) Dried solid.

[0031] Figure 11B DSC-TGA overlay of Form A of Compound 12 is shown.

[0032] Figure 12A XRPD patterns overlay of Form A of Compound 13 are shown: a) Hippuric acid; b)-e) Wet cake; and f) Dried solid.

[0033] Figure 12BIllustrates the DSC-TGA overlay of Form A of Compound 13.

[0034] Figure 13A Illustrates the XRPD pattern overlay of Form A of Compound 14: a) L-lactic acid; b)-e) wet cake; and f) dry solid.

[0035] Figure 13B Illustrates the DSC-TGA overlay of Form A of Compound 14.

[0036] Figure 14A Illustrates the XRPD pattern overlay of Form A of Compound 15: a) benzoic acid; b)-e) wet cake; and f) dry solid.

[0037] Figure 14B Illustrates the DSC-TGA overlay of Form A of Compound 15.

[0038] Figure 15A Illustrates the XRPD pattern overlay of Forms A, B, and C of Compound 16: a) succinic acid; b)-f) wet cake; g) dry solid of Form B; h) dry solid of Form C; and i) dry solid of Form A.

[0039] Figure 15B Illustrates the DSC-TGA overlay of Form B of Compound 16.

[0040] Figure 15C Illustrates the DSC-TGA overlay of Form C of Compound 16.

[0041] Figure 15D Illustrates the DSC-TGA overlay of Form A of Compound 16. Detailed Description General description of certain aspects of the invention:

[0042] This disclosure is at least partially based on the identification of compounds that modulate the targeted ubiquitination of IRAK4 kinase and methods of using them to treat IRAK4-mediated diseases, disorders, or conditions in patients in need thereof. Compounds 1 and its salt forms are disclosed herein:

[0043] Compound 1, 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-dioxopiperidin-3-yl)-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)prop-2-yn-1-yl)oxy)piperidin-1-yl)methyl)cyclohexyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide has activity as a modulator of the targeted ubiquitination of IRAK4. Compound 1 is designated as I-417 and its synthesis is described in U.S. Patent No. 11,352,350, the entire text of which is incorporated herein by reference.

[0044] It is desired to provide a solid form of Compound 1 (e.g., as its salt), which solid form imparts characteristics such as improved water solubility, stability, and ease of formulation. Accordingly, the present disclosure provides salt forms of Compound 1. Salt forms of Compound 1

[0045] In some embodiments, an acid ionically bonds with Compound 1 to form a salt form of Compound 1, as described below. It is contemplated that the salt forms of Compound 1 can exist in a variety of physical forms. For example, the salt forms of Compound 1 can be in solution, suspension, or solid form. In certain embodiments, the salt forms of Compound 1 are in solid form. When the salt forms of Compound 1 are in solid form, the compound can be amorphous, crystalline, or a mixture thereof. In certain embodiments, the salt solid forms of Compound 1 are crystalline. Exemplary such salt forms of Compound 1 are described in more detail below.

[0046] In some embodiments, the present disclosure provides salt forms of Compound 1 that are substantially free of impurities. Such extraneous materials can 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, there is at least about 85% by weight of the salt form of Compound 1. In certain embodiments, there is at least about 90% by weight of the salt form of Compound 1. In still other embodiments of the present disclosure, there is at least about 95% by weight of the salt form of Compound 1.

[0047] According to one embodiment, the salt form of Compound 1 is present in an amount of at least about 80 wt%, 85 wt%, 90 wt%, 95 wt%, 97 wt%, 97.5 wt%, 98.0 wt%, 98.5 wt%, 99 wt%, 99.5 wt%, 99.8 wt%, where the percentage is based on the total weight of the composition. According to another embodiment, the salt form of Compound 1 contains no more than about 20.0 area % total organic impurities by HPLC, no more than about 15.0 area % total organic impurities by HPLC, no more than about 10.0 area % total organic impurities by HPLC, no more than about 5.0 area % total organic impurities by HPLC, no more than about 2.0 area % total organic impurities by HPLC, no more than about 2.0 area % total organic impurities by HPLC, or no more than about 1.5 area % total organic impurities by HPLC, relative to the total area of the HPLC chromatogram. In other embodiments, the salt form of Compound 1 contains no more than about 10% area % of any single impurity by HPLC, no more than about 5% area % of any single impurity by HPLC, or no more than about 1% area % of any single impurity by HPLC, relative to the total area of the HPLC chromatogram.

[0048] The structures depicted for the salt form of Compound 1 are also intended to include all tautomeric salt forms of Compound 1. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention are within the scope of this disclosure except when hydrogen is replaced with deuterium or tritium or carbon is replaced with 13 C- or 14 C-enriched carbon.

[0049] 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 still 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, there is at least about 95% by weight of the crystalline salt form of Compound 1. In still other embodiments of this disclosure, there is at least about 99% by weight of the crystalline salt form of Compound 1.

[0050] In some embodiments, the present invention provides a composition comprising the salt form of Compound 1 and a pharmaceutically acceptable carrier or excipient.

[0051] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method 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 the modulation of a signal transduction pathway involving IRAK4.

[0052] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient that is associated with the modulation of a signal transduction pathway involving IRAK4, the method comprising administering to the patient a salt form of Compound 1 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 a salt form of Compound 1 or a composition thereof, wherein the disease, disorder, or condition is 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 a salt form of Compound 1 or a composition thereof.

[0053] As described herein, it has been found that the salt forms of Compound 1 can exist in at least fifteen different polymorphs. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 2. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 3. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 4. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 5. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 6. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 7. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 8. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 9. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 10. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 11. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 12. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 13. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 14. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 15. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form A of Compound 16. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form B of Compound 16. In certain embodiments, the present disclosure provides a polymorph of Compound 1, referred to herein as Form C of Compound 16. Compound 2 (sulfate salt of Compound 1)

[0054] According to one embodiment, the present disclosure provides a sulfate salt of Compound 1, represented by Compound 2:

[0055] One of ordinary skill in the art will understand that sulfuric acid ionically bonds with Compound 1 to form Compound 2. In some embodiments, Compound 2 is a bisulfate. In some embodiments, Compound 2 is a sulfate. In some embodiments, Compound 2 exists as a mixture of bisulfate and sulfate. It is contemplated that Compound 2 can exist in a variety of 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.

[0056] In some embodiments, the present disclosure provides Compound 2 that is substantially free of impurities. Such impurities or extraneous materials can include different forms of Compound 2, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 2. In certain embodiments, there is at least about 95% by weight of the form of Compound 2. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of Compound 2.

[0057] According to one embodiment, the form of Compound 2 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the form of Compound 2 contains no more than about 3.0 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram, and in certain embodiments no more than about 1.5 area percent HPLC total organic impurities. In other embodiments, the form of Compound 2 contains no more than about 1.0% area percent HPLC of any single impurity, no more than about 0.6 area percent HPLC of any single impurity, and in certain embodiments no more than about 0.5 area percent HPLC of any single impurity.

[0058] The structures depicted for the form of Compound 2 are also intended to include all tautomeric forms of Compound 2. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention are within the scope of the present disclosure except for the replacement of hydrogen with deuterium or tritium or the replacement of carbon with 13 C- or 14 C-enriched carbon.

[0059] It has been found that Compound 2 can exist in a variety of solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0060] 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 contains no significant amount of amorphous Compound 2. In certain embodiments, there is at least about 95% by weight of crystalline Compound 2. In still other embodiments of the present disclosure, there is at least about 99% by weight of crystalline Compound 2.

[0061] It has been found that Compound 2 can exist in at least one different polymorph. In certain embodiments, the present disclosure provides a polymorph of Compound 2, referred to herein as Form A. Form A of Compound 2

[0062] Methods for preparing Form A of Compound 2 are described below.

[0063] In some embodiments, the present disclosure provides Compound 2: wherein the compound is crystalline. In some embodiments, the present disclosure provides Compound 2, wherein the compound is substantially free of amorphous Compound 2. In some embodiments, the present disclosure provides Compound 2, wherein the compound is substantially free of amorphous Compound 1. In some embodiments, the present disclosure provides Compound 2, wherein the compound is substantially free of the crystalline form of Compound 1. In some embodiments, the present disclosure provides Compound 2, wherein the compound is substantially free of impurities.

[0064] In some embodiments, Form A of Compound 2 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 16.5, 17.5, and 19.7 ± 0.5 degrees 2-θ. In some embodiments, Form A of Compound 2 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 16.5, 17.5, and 19.7 ± 0.4 degrees 2-θ. In some embodiments, Form A of Compound 2 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 16.5, 17.5, and 19.7 ± 0.3 degrees 2-θ. In some embodiments, Form A of Compound 2 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 16.5, 17.5, and 19.7 ± 0.2 degrees 2-θ.

[0065] In some embodiments, the present disclosure provides Compound 2, wherein the compound has an XRPD that is substantially similar to the XRPD Figure 1A depicted in (e.g., having peaks of ± 0.2 degrees 2-θ).

[0066] In some embodiments, the present disclosure provides compound 2, wherein the compound has a DSC-TGA substantially similar to that shown in Figure 1B and having an endothermic DSC event starting at 240 °C - 245 °C). In some embodiments, the present disclosure provides compound 2, wherein the compound has DSC events and / or TGA weight loss as described in Table 6.

[0067] In some embodiments, the present disclosure provides a composition comprising compound 2 and a pharmaceutically acceptable carrier or excipient.

[0068] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 2 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the modulation of a signaling pathway involving IRAK4.

[0069] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient associated with the modulation of a signaling pathway involving IRAK4, the method comprising administering compound 2 or a composition thereof to the patient. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition of a patient, the method comprising administering compound 2 or a composition thereof to the patient, wherein the disease, disorder, or condition is mediated by IRAK4. In some embodiments, the present disclosure provides a method of treating an autoimmune or inflammatory disorder of a patient, the method comprising administering compound 2 or a composition thereof to the patient. Compound 3 (benzenesulfonate of compound 1)

[0070] According to one embodiment, the present disclosure provides the benzenesulfonate of compound 1, which is represented by compound 3:

[0071] One of ordinary skill in the art will understand that benzenesulfonic acid and compound 1 are ionically bonded to form compound 3. In some embodiments, compound 3 is a benzenesulfonate. It is contemplated that compound 3 can exist in a variety of 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.

[0072] In some embodiments, the present disclosure provides compound 3 substantially free of impurities. Such impurities or foreign substances can include different forms of compound 3, residual solvents, or any other impurities that may arise from the preparation and / or isolation of compound 3. In certain embodiments, there is at least about 95% by weight of the form of compound 3. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of compound 3.

[0073] According to one embodiment, the form of compound 3 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the form of compound 3 contains no more than about 3.0 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram, and in certain embodiments no more than about 1.5 area percent HPLC total organic impurities. In other embodiments, the form of compound 3 contains no more than about 1.0% area percent HPLC of any single impurity, no more than about 0.6 area percent HPLC of any single impurity, and in certain embodiments no more than about 0.5 area percent HPLC of any single impurity.

[0074] The structures depicted for the form of compound 3 are also intended to include all tautomeric forms of compound 3. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention are within the scope of the present disclosure except for the replacement of hydrogen with deuterium or tritium or the replacement of carbon with 13 C- or 14 C-enriched carbon.

[0075] It has been found that compound 3 can exist in multiple solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0076] In certain embodiments, compound 3 is a crystalline solid. In other embodiments, compound 3 is a crystalline solid substantially free of amorphous compound 3. As used herein, the term "substantially free of amorphous compound 3" means that the compound contains no significant amount of amorphous compound 3. In certain embodiments, there is at least about 95% by weight of crystalline compound 3. In still other embodiments of the present disclosure, there is at least about 99% by weight of crystalline compound 3.

[0077] It has been found that compound 3 can exist in at least one different polymorph. In certain embodiments, the present disclosure provides a polymorph of compound 3, referred to herein as Form A. Form A of compound 3

[0078] The following describes a method for preparing Form A of Compound 3.

[0079] In some embodiments, the present disclosure provides Compound 3: wherein the compound is crystalline. In some embodiments, the present disclosure provides Compound 3, wherein the compound is substantially free of amorphous Compound 3. In some embodiments, the present disclosure provides Compound 3, wherein the compound is substantially free of amorphous Compound 1. In some embodiments, the present disclosure provides Compound 3, wherein the compound is substantially free of the crystalline form of Compound 1. In some embodiments, the present disclosure provides Compound 3, wherein the compound is substantially free of impurities.

[0080] In some embodiments, Form A of Compound 3 is characterized by one or more peaks in its XRPD pattern selected from those at 5.6, 11.5, and 16.5 ± 0.5 degrees 2-θ. In some embodiments, Form A of Compound 3 is characterized by one or more peaks in its XRPD pattern selected from those at 5.6, 11.5, and 16.5 ± 0.4 degrees 2-θ. In some embodiments, Form A of Compound 3 is characterized by one or more peaks in its XRPD pattern selected from those at 5.6, 11.5, and 16.5 ± 0.3 degrees 2-θ. In some embodiments, Form A of Compound 3 is characterized by one or more peaks in its XRPD pattern selected from those at 5.6, 11.5, and 16.5 ± 0.2 degrees 2-θ.

[0081] In some embodiments, the present disclosure provides Compound 3, wherein the compound has an XRPD substantially similar to that Figure 2A depicted in (e.g., having peaks within ±0.2 degrees 2-θ).

[0082] In some embodiments, the present disclosure provides Compound 3, wherein the compound has a DSC-TGA substantially similar to that Figure 2B depicted in (e.g., having an endothermic DSC event starting at 180°C - 185°C). In some embodiments, the present disclosure provides Compound 3, wherein the compound has DSC events and / or TGA weight loss as described in Table 6.

[0083] In some embodiments, the present disclosure provides a composition comprising Compound 3 and a pharmaceutically acceptable carrier or excipient.

[0084] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 3 or a composition thereof to the patient. 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.

[0085] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient associated with modulation of a signaling pathway involving IRAK4, the method comprising administering compound 3 or a composition thereof to the patient. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering compound 3 or a composition thereof to the patient, wherein the disease, disorder, or condition is 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 compound 3 or a composition thereof to the patient. Compound 4 (tosylate of compound 1)

[0086] According to one embodiment, the present disclosure provides the tosylate of compound 1, which is represented by compound 4:

[0087] One of ordinary skill in the art will understand that tosic acid and compound 1 are ionically bonded to form compound 4. In some embodiments, compound 4 is a tosylate. It is contemplated that compound 4 can exist in a variety of physical forms. For example, compound 4 can be in solution, suspension, or solid form. In certain embodiments, compound 4 is in solid form. When compound 4 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0088] In some embodiments, the present disclosure provides compound 4 substantially free of impurities. Such impurities or extraneous substances can include different forms of compound 4, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound 4. In certain embodiments, there is at least about 95% by weight of the form of compound 4. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of compound 4.

[0089] According to one embodiment, the form of Compound 4 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, wherein the percentages are based on the total weight of the composition. According to another embodiment, the form of Compound 4 contains no more than about 3.0 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities. In other embodiments, the form of Compound 4 contains no more than about 1.0% area percent HPLC of any single impurity, no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity.

[0090] The structures depicted for the form of Compound 4 are also intended to include all tautomeric forms of Compound 4. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention are within the scope of this disclosure except when hydrogen is replaced with deuterium or tritium or 13 C- or 14 carbon is replaced with C-enriched carbon.

[0091] It has been found that Compound 4 can exist in multiple solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0092] 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 contains no significant amount of amorphous Compound 4. In certain embodiments, there is at least about 95% by weight of crystalline Compound 4. In still other embodiments of this disclosure, there is at least about 99% by weight of crystalline Compound 4.

[0093] It has been found that Compound 4 can exist in at least one different polymorph. In certain embodiments, this disclosure provides a polymorph of Compound 4, referred to herein as Form A. Form A of Compound 4

[0094] Methods for preparing Form A of Compound 4 are described below.

[0095] In some embodiments, this disclosure provides Compound 4: Wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 4, wherein the compound is substantially free of amorphous compound 4. In some embodiments, the present disclosure provides compound 4, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the present disclosure provides compound 4, wherein the compound is substantially free of the crystalline form of compound 1. In some embodiments, the present disclosure provides compound 4, wherein the compound is substantially free of impurities.

[0096] In some embodiments, Form A of compound 4 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 5.9, 11.9, and 16.5 ± 0.5 degrees 2-θ. In some embodiments, Form A of compound 4 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 5.9, 11.9, and 16.5 ± 0.4 degrees 2-θ. In some embodiments, Form A of compound 4 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 5.9, 11.9, and 16.5 ± 0.3 degrees 2-θ. In some embodiments, Form A of compound 4 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 5.9, 11.9, and 16.5 ± 0.2 degrees 2-θ.

[0097] In some embodiments, the present disclosure provides compound 4, wherein the compound has an XRPD substantially similar to that Figure 3A depicted therein (e.g., having peaks at ±0.2 degrees 2-θ).

[0098] In some embodiments, the present disclosure provides a composition comprising compound 4 and a pharmaceutically acceptable carrier or excipient.

[0099] In some embodiments, the present disclosure provides compound 4, wherein the compound has a DSC-TGA substantially similar to that Figure 3B depicted therein (e.g., having an endothermic DSC event starting at 190°C - 195°C). In some embodiments, the present disclosure provides compound 4, wherein the compound has DSC events and / or TGA weight loss as described in Table 6.

[0100] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 4 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the modulation of a signaling pathway involving IRAK4.

[0101] In some embodiments, the present disclosure provides methods for treating a disease, disorder, or condition in a patient that is related to the modulation of a signaling pathway involving IRAK4, the method comprising administering Compound 4 or a composition thereof to the patient. In some embodiments, the present disclosure provides methods for treating a disease, disorder, or condition in a patient, the method comprising administering Compound 4 or a composition thereof to the patient, wherein the disease, disorder, or condition is mediated by IRAK4. In some embodiments, the present disclosure provides methods for treating an autoimmune or inflammatory disorder in a patient, the method comprising administering Compound 4 or a composition thereof to the patient. Compound 5 (ethanesulfonate of Compound 1)

[0102] According to one embodiment, the present disclosure provides the ethanesulfonate of Compound 1, which is represented by Compound 5:

[0103] One of ordinary skill in the art will understand that ethanesulfonic acid and Compound 1 are ionically bonded to form Compound 5. In some embodiments, Compound 5 is an ethanesulfonate. It is contemplated that Compound 5 can exist in a variety of 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.

[0104] In some embodiments, the present disclosure provides Compound 5 that is substantially free of impurities. Such impurities or extraneous substances can include different forms of Compound 5, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 5. In certain embodiments, there is at least about 95% by weight of the form of Compound 5. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of Compound 5.

[0105] According to one embodiment, the form of Compound 5 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the form of Compound 5 contains no more than about 3.0 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities. In other embodiments, the form of Compound 5 contains no more than about 1.0% area percent HPLC of any single impurity, no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity.

[0106] The structures depicted for the form of Compound 5 are also intended to include all tautomeric forms of Compound 5. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention are within the scope of this disclosure except where hydrogen is replaced with deuterium or tritium or 13 C- or 14 carbon is replaced with C-enriched carbon.

[0107] It has been found that Compound 5 can exist in multiple solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0108] 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 contains no significant amount of amorphous Compound 5. In certain embodiments, there is at least about 95% by weight of crystalline Compound 5. In still other embodiments of this disclosure, there is at least about 99% by weight of crystalline Compound 5.

[0109] It has been found that Compound 5 can exist in at least one different polymorph. In certain embodiments, this disclosure provides a polymorph of Compound 5, referred to herein as Form A. Form A of Compound 5

[0110] Methods for preparing Form A of Compound 5 are described below.

[0111] In some embodiments, this disclosure provides Compound 5: Wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 5, wherein the compound is substantially free of amorphous compound 5. In some embodiments, the present disclosure provides compound 5, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the present disclosure provides compound 5, wherein the compound is substantially free of the crystalline form of compound 1. In some embodiments, the present disclosure provides compound 5, wherein the compound is substantially free of impurities.

[0112] In some embodiments, Form A of compound 5 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 6.0, 8.2, and 12.4 ± 0.5 degrees 2-θ. In some embodiments, Form A of compound 5 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 6.0, 8.2, and 12.4 ± 0.4 degrees 2-θ. In some embodiments, Form A of compound 5 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 6.0, 8.2, and 12.4 ± 0.3 degrees 2-θ. In some embodiments, Form A of compound 5 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 6.0, 8.2, and 12.4 ± 0.2 degrees 2-θ.

[0113] In some embodiments, the present disclosure provides compound 5, wherein the compound has an XRPD substantially similar to that Figure 4A depicted in (e.g., having peaks at ± 0.2 degrees 2-θ).

[0114] In some embodiments, the present disclosure provides a composition comprising compound 5 and a pharmaceutically acceptable carrier or excipient.

[0115] In some embodiments, the present disclosure provides compound 5, wherein the compound has a DSC-TGA substantially similar to that Figure 4B depicted in (e.g., having an endothermic DSC event starting at 195 °C - 200 °C). In some embodiments, the present disclosure provides compound 5, wherein the compound has DSC events and / or TGA weight loss as described in Table 6.

[0116] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 5 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the modulation of a signaling pathway involving IRAK4.

[0117] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition in a patient related to the modulation of a signal transduction pathway involving IRAK4, the method comprising administering to the patient compound 5 or a composition thereof. In some embodiments, the present disclosure provides methods 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 mediated by IRAK4. In some embodiments, the present disclosure provides methods of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient compound 5 or a composition thereof. Compound 6 (mesylate salt of compound 1)

[0118] According to one embodiment, the present disclosure provides the mesylate salt of compound 1, which is represented by compound 6:

[0119] One of ordinary skill in the art will understand that methanesulfonic acid and compound 1 are ionically bonded to form compound 6. In some embodiments, compound 6 is a mesylate salt. It is contemplated that compound 6 can exist in a variety of 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.

[0120] In some embodiments, the present disclosure provides compound 6 that is substantially free of impurities. Such impurities or foreign substances can include different forms of compound 6, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound 6. In certain embodiments, there is at least about 95% by weight of the form of compound 6. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of compound 6.

[0121] According to one embodiment, the form of Compound 6 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, wherein the percentages are based on the total weight of the composition. According to another embodiment, the form of Compound 6 contains no more than about 3.0 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram and in certain embodiments no more than about 1.5 area percent HPLC total organic impurities. In other embodiments, the form of Compound 6 contains no more than about 1.0 area percent HPLC of any single impurity, no more than about 0.6 area percent HPLC of any single impurity, and in certain embodiments no more than about 0.5 area percent HPLC of any single impurity.

[0122] The structures depicted for the form of Compound 6 are also intended to include all tautomeric forms of Compound 6. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structures of the present invention are within the scope of this disclosure except when hydrogen is replaced with deuterium or tritium or carbon is replaced with 13 C- or 14 C-enriched carbon.

[0123] It has been found that Compound 6 can exist in a variety of solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0124] In certain embodiments, Compound 6 is a crystalline solid. In other embodiments, Compound 6 is a crystalline solid substantially free of amorphous Compound 6. As used herein, the term "substantially free of amorphous Compound 6" means that the compound contains no significant amount of amorphous Compound 6. In certain embodiments, there is at least about 95% by weight of crystalline Compound 6. In still other embodiments of this disclosure, there is at least about 99% by weight of crystalline Compound 6.

[0125] It has been found that Compound 6 can exist in at least one different polymorph. In certain embodiments, this disclosure provides a polymorph of Compound 6, referred to herein as Form A. Form A of Compound 6

[0126] Methods for preparing Form A of Compound 6 are described below.

[0127] In some embodiments, this disclosure provides Compound 6: Wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 6, wherein the compound is substantially free of amorphous compound 6. In some embodiments, the present disclosure provides compound 6, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the present disclosure provides compound 6, wherein the compound is substantially free of the crystalline form of compound 1. In some embodiments, the present disclosure provides compound 6, wherein the compound is substantially free of impurities.

[0128] In some embodiments, Form A of compound 6 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 16.5, 19.5, and 21.2 ± 0.5 degrees 2-θ. In some embodiments, Form A of compound 6 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 16.5, 19.5, and 21.2 ± 0.4 degrees 2-θ. In some embodiments, Form A of compound 6 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 16.5, 19.5, and 21.2 ± 0.3 degrees 2-θ. In some embodiments, Form A of compound 6 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 3.9, 11.9, and 16.5 ± 0.2 degrees 2-θ.

[0129] In some embodiments, the present disclosure provides compound 6, wherein the compound has an XRPD substantially similar to that Figure 5A depicted (e.g., having peaks of ± 0.2 degrees 2-θ) in the XRPD shown.

[0130] In some embodiments, the present disclosure provides a composition comprising compound 6 and a pharmaceutically acceptable carrier or excipient.

[0131] In some embodiments, the present disclosure provides compound 6, wherein the compound has a DSC-TGA substantially similar to that Figure 5B depicted (e.g., having an endothermic DSC onset event at 248 °C - 253 °C) in the DSC-TGA shown. In some embodiments, the present disclosure provides compound 6, wherein the compound has DSC events and / or TGA weight loss as described in Table 6.

[0132] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 6 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the modulation of a signal transduction pathway involving IRAK4.

[0133] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient that is related to the modulation of a signaling pathway involving IRAK4, the method comprising administering to the patient compound 6 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 6 or a composition thereof, wherein the disease, disorder, or condition is 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 6 or a composition thereof. Compound 7 (maleate salt of compound 1)

[0134] According to one embodiment, the present disclosure provides the maleate salt of compound 1, which is represented by compound 7:

[0135] One of ordinary skill in the art will understand that maleic acid and compound 1 are ionically bonded 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 salt and maleate salt. It is contemplated that compound 7 can exist in a variety of 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.

[0136] In some embodiments, the present disclosure provides compound 7 that is substantially free of impurities. Such impurities or extraneous substances can include different forms of compound 7, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound 7. In certain embodiments, there is at least about 95% by weight of the form of compound 7. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of compound 7.

[0137] According to one embodiment, the form of Compound 7 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, wherein the percentages are based on the total weight of the composition. According to another embodiment, the form of Compound 7 contains no more than about 3.0 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram and in certain embodiments no more than about 1.5 area percent HPLC total organic impurities. In other embodiments, the form of Compound 7 contains no more than about 1.0 area percent HPLC of any single impurity, no more than about 0.6 area percent HPLC of any single impurity, and in certain embodiments no more than about 0.5 area percent HPLC of any single impurity.

[0138] The structures depicted for the form of Compound 7 are also intended to include all tautomeric forms of Compound 7. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention are within the scope of this disclosure except when hydrogen is replaced with deuterium or tritium or 13 C- or 14 carbon is replaced with C-enriched carbon.

[0139] It has been found that Compound 7 can exist in multiple solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0140] 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 contains no significant amount of amorphous Compound 7. In certain embodiments, there is at least about 95% by weight of crystalline Compound 7. In still other embodiments of this disclosure, there is at least about 99% by weight of crystalline Compound 7.

[0141] It has been found that Compound 7 can exist in at least one different polymorph. In certain embodiments, this disclosure provides a polymorph of Compound 7, referred to herein as Form A. Form A of Compound 7

[0142] Methods for preparing Form A of Compound 7 are described below.

[0143] In some embodiments, this disclosure provides Compound 7: Wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 7, wherein the compound is substantially free of amorphous compound 7. In some embodiments, the present disclosure provides compound 7, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the present disclosure provides compound 7, wherein the compound is substantially free of the crystalline form of compound 1. In some embodiments, the present disclosure provides compound 7, wherein the compound is substantially free of impurities.

[0144] In some embodiments, Form A of compound 7 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.5, 16.5, and 18.5 ± 0.5 degrees 2-θ. In some embodiments, Form A of compound 7 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.5, 16.5, and 18.5 ± 0.4 degrees 2-θ. In some embodiments, Form A of compound 7 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.5, 16.5, and 18.5 ± 0.3 degrees 2-θ. In some embodiments, Form A of compound 7 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.5, 16.5, and 18.5 ± 0.2 degrees 2-θ.

[0145] In some embodiments, the present disclosure provides compound 7, wherein the compound has an XRPD substantially similar to that Figure 6A depicted therein (e.g., having peaks at ± 0.2 degrees 2-θ).

[0146] In some embodiments, the present disclosure provides a composition comprising compound 7 and a pharmaceutically acceptable carrier or excipient.

[0147] In some embodiments, the present disclosure provides compound 7, wherein the compound has a DSC-TGA substantially similar to that Figure 6B depicted therein (e.g., having an endothermic DSC event starting at 218 °C - 223 °C). In some embodiments, the present disclosure provides compound 7, wherein the compound has DSC events and / or TGA weight loss as described in Table 6.

[0148] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 7 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the modulation of a signal transduction pathway involving IRAK4.

[0149] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient related to the modulation of a signal transduction pathway involving IRAK4, 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 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. Compound 8 (L-tartrate salt of Compound 1)

[0150] According to one embodiment, the present disclosure provides the L-tartrate salt of Compound 1, which is represented by Compound 8:

[0151] One of ordinary skill in the art will understand that L-tartaric acid and Compound 1 are ionically bonded to form Compound 8. In some embodiments, Compound 8 is a hydrogen L-tartrate salt. In some embodiments, Compound 8 is a L-tartrate salt. In some embodiments, Compound 8 exists as a mixture of hydrogen L-tartrate salt and L-tartrate salt. It is contemplated that Compound 8 can exist in a variety of 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.

[0152] In some embodiments, the present disclosure provides Compound 8 substantially free of impurities. Such impurities or extraneous substances can include different forms of Compound 8, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 8. In certain embodiments, there is at least about 95% by weight of the form of Compound 8. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of Compound 8.

[0153] According to one embodiment, the form of Compound 8 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, wherein the percentages are based on the total weight of the composition. According to another embodiment, the form of Compound 8 contains no more than about 3.0 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram and, in certain embodiments, no more than about 1.5 area percent HPLC total organic impurities. In other embodiments, the form of Compound 8 contains no more than about 1.0% area percent HPLC of any single impurity, no more than about 0.6 area percent HPLC of any single impurity, and, in certain embodiments, no more than about 0.5 area percent HPLC of any single impurity.

[0154] The structures depicted for the form of Compound 8 are also intended to include all tautomeric forms of Compound 8. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention are within the scope of this disclosure except when hydrogen is replaced with deuterium or tritium or 13 C- or 14 carbon is replaced with C-enriched carbon.

[0155] It has been found that Compound 8 can exist in multiple solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0156] 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 contains no significant amount of amorphous Compound 8. In certain embodiments, there is at least about 95% by weight of crystalline Compound 9. In still other embodiments of this disclosure, there is at least about 99% by weight of crystalline Compound 8.

[0157] It has been found that Compound 8 can exist in at least one different polymorph. In certain embodiments, this disclosure provides a polymorph of Compound 8, referred to herein as Form A. Form A of Compound 8

[0158] Methods for preparing Form A of Compound 8 are described below.

[0159] In some embodiments, this disclosure provides Compound 8: Wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 8, wherein the compound is substantially free of amorphous compound 8. In some embodiments, the present disclosure provides compound 8, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the present disclosure provides compound 8, wherein the compound is substantially free of the crystalline form of compound 1. In some embodiments, the present disclosure provides compound 9, wherein the compound is substantially free of impurities.

[0160] In some embodiments, Form A of compound 8 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.5, 16.5, and 17.5 ± 0.5 degrees 2-θ. In some embodiments, Form A of compound 8 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.5, 16.5, and 17.5 ± 0.4 degrees 2-θ. In some embodiments, Form A of compound 8 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.5, 16.5, and 17.5 ± 0.3 degrees 2-θ. In some embodiments, Form A of compound 8 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.5, 16.5, and 17.5 ± 0.2 degrees 2-θ.

[0161] In some embodiments, the present disclosure provides compound 8, wherein the compound has an XRPD substantially similar to that Figure 7A depicted therein (e.g., having peaks at ± 0.2 degrees 2-θ).

[0162] In some embodiments, the present disclosure provides a composition comprising compound 8 and a pharmaceutically acceptable carrier or excipient.

[0163] In some embodiments, the present disclosure provides compound 8, wherein the compound has a DSC-TGA substantially similar to that Figure 7B depicted therein (e.g., having an endothermic DSC event starting at 250 °C - 255 °C). In some embodiments, the present disclosure provides compound 8, wherein the compound has DSC events and / or TGA weight loss as described in Table 6.

[0164] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 8 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the modulation of a signaling pathway involving IRAK4.

[0165] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition in a patient that is related to the modulation of a signal transduction pathway involving IRAK4, the method comprising administering to the patient compound 8 or a composition thereof. In some embodiments, the present disclosure provides methods 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 mediated by IRAK4. In some embodiments, the present disclosure provides methods of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient compound 9 or a composition thereof. Compound 9 (fumarate salt of compound 1)

[0166] According to one embodiment, the present disclosure provides the fumarate salt of compound 1, which is represented by compound 9:

[0167] One of ordinary skill in the art will understand that fumaric acid and compound 1 are ionically bonded to form compound 9. In some embodiments, compound 9 is the hydrogen fumarate. In some embodiments, compound 9 is the fumarate salt. In some embodiments, compound 9 exists as a mixture of the hydrogen fumarate and the fumarate salt. It is contemplated that compound 9 can exist in a variety of 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.

[0168] In some embodiments, the present disclosure provides compound 9 that is substantially free of impurities. Such impurities or foreign substances can include different forms of compound 9, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound 9. In certain embodiments, there is at least about 95% by weight of the form of compound 9. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of compound 9.

[0169] According to one embodiment, the form of Compound 9 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, wherein the percentages are based on the total weight of the composition. According to another embodiment, the form of Compound 9 contains no more than about 3.0 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram, and in certain embodiments no more than about 1.5 area percent HPLC total organic impurities. In other embodiments, the form of Compound 9 contains no more than about 1.0 area percent HPLC of any single impurity, no more than about 0.6 area percent HPLC of any single impurity, and in certain embodiments no more than about 0.5 area percent HPLC of any single impurity.

[0170] The structures depicted for the form of Compound 9 are also intended to include all tautomeric forms of Compound 9. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention are within the scope of this disclosure except when hydrogen is replaced with deuterium or tritium or carbon is replaced with 13 C- or 14 C-enriched carbon.

[0171] It has been found that Compound 9 can exist in multiple solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0172] 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 contains no significant amount of amorphous Compound 9. In certain embodiments, there is at least about 95% by weight of crystalline Compound 9. In still other embodiments of this disclosure, there is at least about 99% by weight of crystalline Compound 9.

[0173] It has been found that Compound 9 can exist in at least one different polymorph. In certain embodiments, this disclosure provides a polymorph of Compound 9, referred to herein as Form A. Form A of Compound 9

[0174] Methods for preparing Form A of Compound 9 are described below.

[0175] In some embodiments, this disclosure provides Compound 9: Wherein the compound is crystalline. In some embodiments, the present disclosure provides Compound 10, wherein the compound is substantially free of amorphous Compound 9. In some embodiments, the present disclosure provides Compound 9, wherein the compound is substantially free of amorphous Compound 1. In some embodiments, the present disclosure provides Compound 9, wherein the compound is substantially free of the crystalline form of Compound 1. In some embodiments, the present disclosure provides Compound 9, wherein the compound is substantially free of impurities.

[0176] In some embodiments, Form A of Compound 9 is characterized by one or more peaks in its XRPD pattern selected from those at 6.7, 10.7, and 16.3 ± 0.5 degrees 2-θ. In some embodiments, Form A of Compound 9 is characterized by one or more peaks in its XRPD pattern selected from those at 6.7, 10.7, and 16.3 ± 0.4 degrees 2-θ. In some embodiments, Form A of Compound 9 is characterized by one or more peaks in its XRPD pattern selected from those at 6.7, 10.7, and 16.3 ± 0.3 degrees 2-θ. In some embodiments, Form A of Compound 9 is characterized by one or more peaks in its XRPD pattern selected from those at 6.7, 10.7, and 16.3 ± 0.2 degrees 2-θ.

[0177] In some embodiments, the present disclosure provides Compound 9, wherein the compound has an XRPD substantially similar to that Figure 8A depicted (e.g., having peaks at ±0.2 degrees 2-θ).

[0178] In some embodiments, the present disclosure provides a composition comprising Compound 9 and a pharmaceutically acceptable carrier or excipient.

[0179] In some embodiments, the present disclosure provides Compound 9, wherein the compound has a DSC-TGA substantially similar to that Figure 8B depicted (e.g., having an endothermic DSC event starting at 266°C - 271°C). In some embodiments, the present disclosure provides Compound 9, wherein the compound has DSC events and / or TGA weight loss as described in Table 6.

[0180] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering Compound 9 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the modulation of a signaling pathway involving IRAK4.

[0181] In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition in a patient that is related to modulation of a signal transduction pathway involving IRAK4, the method comprising administering to the patient compound 9 or a composition thereof. In some embodiments, the present disclosure provides methods 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 mediated by IRAK4. In some embodiments, the present disclosure provides methods of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering to the patient compound 9 or a composition thereof. Compound 10 (citrate of Compound 1)

[0182] According to one embodiment, the present disclosure provides the citrate of Compound 1, which is represented by Compound 10:

[0183] One of ordinary skill in the art will understand that citric acid and Compound 1 are ionically bonded to form Compound 10. In some embodiments, Compound 10 is the dihydrogen citrate. In some embodiments, Compound 10 is the hydrogen citrate. In some embodiments, Compound 10 is the citrate. In some embodiments, Compound 10 exists as a mixture of the dihydrogen citrate, the hydrogen citrate, and the citrate. It is contemplated that Compound 10 can exist in a variety of 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.

[0184] In some embodiments, the present disclosure provides Compound 10 that is substantially free of impurities. Such impurities or extraneous substances can include different forms of Compound 10, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 10. In certain embodiments, there is at least about 95% by weight of the form of Compound 10. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of Compound 10.

[0185] According to one embodiment, the form of Compound 10 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the form of Compound 10 contains no more than about 3.0 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram, and in certain embodiments no more than about 1.5 area percent HPLC total organic impurities. In other embodiments, the form of Compound 10 contains no more than about 1.0 area percent HPLC of any single impurity, no more than about 0.6 area percent HPLC of any single impurity, and in certain embodiments no more than about 0.5 area percent HPLC of any single impurity.

[0186] The structures depicted for the form of Compound 10 are also intended to include all tautomeric forms of Compound 10. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention are within the scope of this disclosure except when hydrogen is replaced by deuterium or tritium or carbon is replaced by 13 C- or 14 C-enriched carbon.

[0187] It has been found that Compound 10 can exist in multiple solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0188] 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 contains no significant amount of amorphous Compound 10. In certain embodiments, there is at least about 95% by weight of crystalline Compound 10. In still other embodiments of this disclosure, there is at least about 99% by weight of crystalline Compound 10.

[0189] It has been found that Compound 10 can exist in at least one different polymorph. In certain embodiments, this disclosure provides a polymorph of Compound 10, referred to herein as Form A. Form A of Compound 10

[0190] Methods for preparing Form A of Compound 10 are described below.

[0191] In some embodiments, this disclosure provides Compound 10: Wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 10, wherein the compound is substantially free of amorphous compound 10. In some embodiments, the present disclosure provides compound 10, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the present disclosure provides compound 10, wherein the compound is substantially free of the crystalline form of compound 1. In some embodiments, the present disclosure provides compound 10, wherein the compound is substantially free of impurities.

[0192] In some embodiments, Form A of compound 10 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.0, 11.9, and 16.5 ± 0.5 degrees 2-θ. In some embodiments, Form A of compound 10 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.0, 11.9, and 16.5 ± 0.4 degrees 2-θ. In some embodiments, Form A of compound 10 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.0, 11.9, and 16.5 ± 0.3 degrees 2-θ. In some embodiments, Form A of compound 10 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.0, 11.9, and 16.5 ± 0.2 degrees 2-θ.

[0193] In some embodiments, the present disclosure provides compound 10, wherein the compound has an XRPD Figure 9A substantially similar to that depicted in

[0194] In some embodiments, the present disclosure provides compound 10, wherein the compound has a DSC-TGA Figure 9B substantially similar to that depicted in

[0195] substantially similar to that depicted in

[0196] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 10 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the modulation of a signal transduction pathway involving IRAK4.

[0197] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient related to the modulation of a signal transduction pathway involving IRAK4, the method comprising administering compound 10 or a composition thereof to the patient. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering compound 10 or a composition thereof to the patient, wherein the disease, disorder, or condition is 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 compound 10 or a composition thereof to the patient. Compound 11 (glycolate of compound 1)

[0198] According to one embodiment, the present disclosure provides the glycolate of compound 1, which is represented by compound 11:

[0199] One of ordinary skill 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. It is contemplated that compound 11 can exist in a variety of physical forms. For example, compound 11 can be in solution, suspension, or solid form. In certain embodiments, compound 11 is in solid form. When 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.

[0200] In some embodiments, the present disclosure provides compound 11 that is substantially free of impurities. Such impurities or extraneous substances can include different forms of compound 11, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound 11. In certain embodiments, there is at least about 95% by weight of the form of compound 11. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of compound 11.

[0201] According to one embodiment, the form of Compound 11 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the form of Compound 11 contains no more than about 3.0 area percent HPLC total organic impurities relative to the total area of the HPLC chromatogram, and in certain embodiments no more than about 1.5 area percent HPLC total organic impurities. In other embodiments, the form of Compound 11 contains no more than about 1.0% area percent HPLC of any single impurity, no more than about 0.6 area percent HPLC of any single impurity, and in certain embodiments no more than about 0.5 area percent HPLC of any single impurity.

[0202] The structures depicted for the form of Compound 11 are also intended to include all tautomeric forms of Compound 11. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium or replacing carbon with 13 C- or 14 C-enriched carbon, compounds having the structures of the present invention are within the scope of this disclosure.

[0203] It has been found that Compound 11 can exist in multiple solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0204] 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 contains no significant amount of amorphous Compound 11. In certain embodiments, there is at least about 95% by weight of crystalline Compound 11. In still other embodiments of this disclosure, there is at least about 99% by weight of crystalline Compound 11.

[0205] It has been found that Compound 11 can exist in at least one different polymorph. In certain embodiments, this disclosure provides a polymorph of Compound 11, referred to herein as Form A. Form A of Compound 11

[0206] Methods for preparing Form A of Compound 11 are described below.

[0207] In some embodiments, this disclosure provides Compound 11: Wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 11, wherein the compound is substantially free of amorphous compound 11. In some embodiments, the present disclosure provides compound 11, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the present disclosure provides compound 11, wherein the compound is substantially free of the crystalline form of compound 1. In some embodiments, the present disclosure provides compound 11, wherein the compound is substantially free of impurities.

[0208] In some embodiments, Form A of compound 11 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.8, 13.0, and 17.1 ± 0.5 degrees 2-θ. In some embodiments, Form A of compound 11 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.8, 13.0, and 17.1 ± 0.4 degrees 2-θ. In some embodiments, Form A of compound 11 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.8, 13.0, and 17.1 ± 0.3 degrees 2-θ. In some embodiments, Form A of compound 11 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.8, 13.0, and 17.1 ± 0.2 degrees 2-θ.

[0209] In some embodiments, the present disclosure provides compound 11, wherein the compound has an XRPD Figure 10A substantially similar to that depicted in

[0210] In some embodiments, the present disclosure provides compound 11, wherein the compound has a DSC-TGA Figure 10B substantially similar to that depicted in

[0211] In some embodiments, the present disclosure provides a composition comprising compound 12 and a pharmaceutically acceptable carrier or excipient.

[0212] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 11 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the modulation of a signal transduction pathway involving IRAK4.

[0213] In some embodiments, the present disclosure provides methods for treating a disease, disorder, or condition in a patient that is related to the modulation of a signaling pathway involving IRAK4, the method comprising administering compound 11 or a composition thereof to the patient. In some embodiments, the present disclosure provides methods for treating a disease, disorder, or condition in a patient, the method comprising administering compound 11 or a composition thereof to the patient, wherein the disease, disorder, or condition is mediated by IRAK4. In some embodiments, the present disclosure provides methods for treating an autoimmune or inflammatory disorder in a patient, the method comprising administering compound 11 or a composition thereof to the patient. Compound 12 (L-malate of compound 1)

[0214] According to one embodiment, the present disclosure provides the L-malate of compound 1, which is represented by compound 12:

[0215] One of ordinary skill in the art will understand that L-malic acid and compound 1 are ionically bonded to form compound 12. In some embodiments, compound 12 is the hydrogen L-malate. In some embodiments, compound 12 is the L-malate. It is contemplated that compound 12 can exist in a variety of physical forms. For example, compound 12 can be in solution, suspension, or solid form. In certain embodiments, compound 12 is in solid form. When compound 12 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0216] In some embodiments, the present disclosure provides compound 12 that is substantially free of impurities. Such impurities or extraneous substances can include different forms of compound 12, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound 12. In certain embodiments, there is at least about 95% by weight of the form of compound 12. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of compound 12.

[0217] According to one embodiment, the form of Compound 12 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, wherein the percentages are based on the total weight of the composition. According to another embodiment, the form of Compound 12 contains no more than about 3.0 area percent of total organic impurities by HPLC relative to the total area of the HPLC chromatogram, and in certain embodiments no more than about 1.5 area percent of total organic impurities by HPLC. In other embodiments, the form of Compound 12 contains no more than about 1.0 area percent of any single impurity by HPLC, no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments no more than about 0.5 area percent of any single impurity by HPLC.

[0218] The structure depicted for the form of Compound 12 is also intended to include all tautomeric forms of Compound 12. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the structure of the present invention are within the scope of this disclosure except where hydrogen is replaced with deuterium or tritium or 13 C- or 14 carbon is replaced with C-enriched carbon.

[0219] It has been found that Compound 12 can exist in multiple solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0220] 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 contains no significant amount of amorphous Compound 12. In certain embodiments, there is at least about 95% by weight of crystalline Compound 12. In still other embodiments of this disclosure, there is at least about 99% by weight of crystalline Compound 12.

[0221] It has been found that Compound 12 can exist in at least one different polymorph. In certain embodiments, this disclosure provides a polymorph of Compound 12, referred to herein as Form A. Form A of Compound 12

[0222] Methods for preparing Form A of Compound 12 are described below.

[0223] In some embodiments, this disclosure provides Compound 12: Wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 12, wherein the compound is substantially free of amorphous compound 12. In some embodiments, the present disclosure provides compound 12, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the present disclosure provides compound 12, wherein the compound is substantially free of the crystalline form of compound 1. In some embodiments, the present disclosure provides compound 12, wherein the compound is substantially free of impurities.

[0224] In some embodiments, Form A of compound 12 is characterized by one or more peaks in its XRPD pattern selected from those at 6.5, 10.8, and 16.8 ± 0.5 degrees 2-θ. In some embodiments, Form A of compound 12 is characterized by one or more peaks in its XRPD pattern selected from those at 6.5, 10.8, and 16.8 ± 0.4 degrees 2-θ. In some embodiments, Form A of compound 12 is characterized by one or more peaks in its XRPD pattern selected from those at 6.5, 10.8, and 16.8 ± 0.3 degrees 2-θ. In some embodiments, Form A of compound 12 is characterized by one or more peaks in its XRPD pattern selected from those at 6.5, 10.8, and 16.8 ± 0.2 degrees 2-θ.

[0225] In some embodiments, the present disclosure provides compound 12, wherein the compound has an XRPD substantially similar to that Figure 11A depicted in (e.g., having peaks at ± 0.2 degrees 2-θ).

[0226] In some embodiments, the present disclosure provides compound 12, wherein the compound has a DSC-TGA substantially similar to that Figure 11B depicted in (e.g., having an endothermic DSC event starting at 257 °C - 262 °C). In some embodiments, the present disclosure provides compound 12, wherein the compound has DSC events and / or TGA weight loss as described in Table 6.

[0227] In some embodiments, the present disclosure provides a composition comprising compound 12 and a pharmaceutically acceptable carrier or excipient.

[0228] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 12 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the regulation of a signaling pathway involving IRAK4. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition in a patient that is related to modulation of a signal transduction pathway involving IRAK4, the method comprising administering Compound 12 or a composition thereof to the patient. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition in a patient, the method comprising administering Compound 12 or a composition thereof to the patient, wherein the disease, disorder, or condition is mediated by IRAK4. In some embodiments, the present disclosure provides methods of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering Compound 12 or a composition thereof to the patient. Compound 13 (the hippurate salt of Compound 1)

[0229] According to one embodiment, the present disclosure provides the hippurate salt of Compound 1, which is represented by Compound 13:

[0230] One of ordinary skill in the art will understand that hippuric acid and Compound 1 are ionically bonded to form Compound 13. In some embodiments, Compound 13 is a hippurate salt. It is contemplated that Compound 13 can exist in a variety of 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.

[0231] In some embodiments, the present disclosure provides Compound 13 that is substantially free of impurities. Such impurities or extraneous substances can include different forms of Compound 13, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 13. In certain embodiments, there is at least about 95% by weight of the form of Compound 13. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of Compound 15.

[0232] According to one embodiment, the form of Compound 13 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the form of Compound 13 contains no more than about 3.0 area percent of total organic impurities by HPLC relative to the total area of the HPLC chromatogram, and in certain embodiments no more than about 1.5 area percent of total organic impurities by HPLC. In other embodiments, the form of Compound 13 contains no more than about 1.0 area percent of any single impurity by HPLC relative to the total area of the HPLC chromatogram, no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments no more than about 0.5 area percent of any single impurity by HPLC.

[0233] The structures depicted for the form of Compound 13 are also intended to include all tautomeric forms of Compound 13. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium or 13 C- or 14 replacing carbon with C-enriched carbon, compounds having the structures of the present invention are within the scope of this disclosure.

[0234] It has been found that Compound 13 can exist in multiple solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0235] 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 contains no significant amount of amorphous Compound 13. In certain embodiments, there is at least about 95% by weight of crystalline Compound 13. In still other embodiments of this disclosure, there is at least about 99% by weight of crystalline Compound 13.

[0236] It has been found that Compound 13 can exist in at least one different polymorph. In certain embodiments, this disclosure provides a polymorph of Compound 13, referred to herein as Form A. Form A of Compound 13

[0237] Methods for preparing Form A of Compound 13 are described below.

[0238] In some embodiments, this disclosure provides Compound 13: Wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 13, wherein the compound is substantially free of amorphous compound 13. In some embodiments, the present disclosure provides compound 13, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the present disclosure provides compound 13, wherein the compound is substantially free of the crystalline form of compound 1. In some embodiments, the present disclosure provides compound 13, wherein the compound is substantially free of impurities.

[0239] In some embodiments, Form A of compound 13 is characterized by one or more peaks in its XRPD pattern selected from those at 6.0, 16.3, and 20.1 ± 0.5 degrees 2-θ. In some embodiments, Form A of compound 13 is characterized by one or more peaks in its XRPD pattern selected from those at 6.0, 16.3, and 20.1 ± 0.4 degrees 2-θ. In some embodiments, Form A of compound 13 is characterized by one or more peaks in its XRPD pattern selected from those at 6.0, 16.3, and 20.1 ± 0.3 degrees 2-θ. In some embodiments, Form A of compound 13 is characterized by one or more peaks in its XRPD pattern selected from those at 6.0, 16.3, and 20.1 ± 0.2 degrees 2-θ.

[0240] In some embodiments, the present disclosure provides compound 13, wherein the compound has an XRPD substantially similar to that Figure 12A depicted in (e.g., having peaks of ± 0.2 degrees 2-θ).

[0241] In some embodiments, the present disclosure provides compound 13, wherein the compound has a DSC-TGA substantially similar to that Figure 12B depicted in (e.g., having an endothermic DSC event starting at 199 °C - 204 °C). In some embodiments, the present disclosure provides compound 13, wherein the compound has DSC events and / or TGA weight loss as described in Table 6.

[0242] In some embodiments, the present disclosure provides a composition comprising compound 13 and a pharmaceutically acceptable carrier or excipient.

[0243] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 13 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the regulation of a signal transduction pathway involving IRAK4. In some embodiments, the present disclosure provides methods for treating diseases, disorders, or conditions in a patient related to the modulation of a signal transduction pathway involving IRAK4, the methods comprising administering compound 13 or a composition thereof to the patient. In some embodiments, the present disclosure provides methods for treating a disease, disorder, or condition in a patient, the methods comprising administering compound 13 or a composition thereof to the patient, wherein the disease, disorder, or condition is mediated by IRAK4. In some embodiments, the present disclosure provides methods for treating an autoimmune or inflammatory disorder in a patient, the methods comprising administering compound 13 or a composition thereof to the patient. Compound 14 (L-lactate of Compound 1)

[0244] According to one embodiment, the present disclosure provides the L-lactate of Compound 1, which is represented by Compound 14:

[0245] One of ordinary skill 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. It is contemplated that Compound 14 can exist in a variety of physical forms. For example, Compound 14 can 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 can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0246] In some embodiments, the present disclosure provides Compound 14 substantially free of impurities. Such impurities or extraneous substances can include different forms of Compound 14, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 14. In certain embodiments, there is at least about 95% by weight of the form of Compound 14. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of Compound 14.

[0247] According to one embodiment, the form of Compound 14 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the form of Compound 14 contains no more than about 3.0 area percent of total organic impurities by HPLC relative to the total area of the HPLC chromatogram, and in certain embodiments no more than about 1.5 area percent of total organic impurities by HPLC. In other embodiments, the form of Compound 14 contains no more than about 1.0% area percent of any single impurity by HPLC, no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments no more than about 0.5 area percent of any single impurity by HPLC.

[0248] The structures depicted for the form of Compound 14 are also intended to include all tautomeric forms of Compound 14. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium or replacing carbon with 13 C- or 14 C-enriched carbon, compounds having the structures of the present invention are within the scope of this disclosure.

[0249] It has been found that Compound 14 can exist in multiple solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0250] 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 contains no significant amount of amorphous Compound 14. In certain embodiments, there is at least about 95% by weight of crystalline Compound 14. In still other embodiments of this disclosure, there is at least about 99% by weight of crystalline Compound 16.

[0251] It has been found that Compound 14 can exist in at least one different polymorph. In certain embodiments, this disclosure provides a polymorph of Compound 14, referred to herein as Form A. Form A of Compound 14

[0252] Methods for preparing Form A of Compound 14 are described below.

[0253] In some embodiments, this disclosure provides Compound 14: Wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 14, wherein the compound is substantially free of amorphous compound 14. In some embodiments, the present disclosure provides compound 14, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the present disclosure provides compound 14, wherein the compound is substantially free of the crystalline form of compound 1. In some embodiments, the present disclosure provides compound 14, wherein the compound is substantially free of impurities.

[0254] In some embodiments, Form A of compound 14 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.5, 17.1, and 21.0 ± 0.5 degrees 2-theta. In some embodiments, Form A of compound 14 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.5, 17.1, and 21.0 ± 0.4 degrees 2-theta. In some embodiments, Form A of compound 14 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.5, 17.1, and 21.0 ± 0.3 degrees 2-theta. In some embodiments, Form A of compound 14 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.5, 17.1, and 21.0 ± 0.2 degrees 2-theta.

[0255] In some embodiments, the present disclosure provides compound 14, wherein the compound has an XRPD Figure 13A substantially similar to that depicted in (e.g., having peaks at ± 0.2 degrees 2-theta).

[0256] In some embodiments, the present disclosure provides compound 14, wherein the compound has a DSC-TGA Figure 13B substantially similar to that depicted in (e.g., having an endothermic DSC event starting at 170 °C - 175 °C). In some embodiments, the present disclosure provides compound 14, wherein the compound has DSC events and / or TGA weight loss as described in Table 6.

[0257] In some embodiments, the present disclosure provides a composition comprising compound 14 and a pharmaceutically acceptable carrier or excipient.

[0258] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 14 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the regulation of a signaling pathway involving IRAK4. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient that is related to the modulation of a signal transduction pathway involving IRAK4, the method comprising administering compound 14 or a composition thereof to the patient. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering compound 14 or a composition thereof to the patient, wherein the disease, disorder, or condition is 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 compound 14 or a composition thereof to the patient. Compound 15 (benzoate of Compound 1)

[0259] According to one embodiment, the present disclosure provides the benzoate of Compound 1, which is represented by Compound 15:

[0260] One of ordinary skill in the art will understand that benzoic acid and Compound 1 are ionically bonded to form Compound 15. In some embodiments, Compound 15 is a benzoate. It is contemplated that Compound 15 can exist in a variety of physical forms. For example, Compound 15 can be in solution, suspension, or solid form. In certain embodiments, Compound 15 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.

[0261] In some embodiments, the present disclosure provides Compound 15 that is substantially free of impurities. Such impurities or foreign substances can include different forms of Compound 15, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 15. In certain embodiments, there is at least about 95% by weight of the form of Compound 15. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of Compound 15.

[0262] According to one embodiment, the form of Compound 15 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the form of Compound 15 contains no more than about 3.0 area percent of total organic impurities by HPLC relative to the total area of the HPLC chromatogram, and in certain embodiments no more than about 1.5 area percent of total organic impurities by HPLC. In other embodiments, the form of Compound 15 contains no more than about 1.0 area percent of any single impurity by HPLC relative to the total area of the HPLC chromatogram, no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments no more than about 0.5 area percent of any single impurity by HPLC.

[0263] The structures depicted for the form of Compound 15 are also intended to include all tautomeric forms of Compound 15. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium or 13 C- or 14 replacing carbon with C-enriched carbon, compounds having the structures of the present invention are within the scope of this disclosure.

[0264] It has been found that Compound 15 can exist in multiple solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0265] 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 contains no significant amount of amorphous Compound 15. In certain embodiments, there is at least about 95% by weight of crystalline Compound 15. In still other embodiments of this disclosure, there is at least about 99% by weight of crystalline Compound 15.

[0266] It has been found that Compound 15 can exist in at least one different polymorph. In certain embodiments, this disclosure provides a polymorph of Compound 15, referred to herein as Form A. Form A of Compound 15

[0267] Methods for preparing Form A of Compound 15 are described below.

[0268] In some embodiments, this disclosure provides Compound 15: Wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 15, wherein the compound is substantially free of amorphous compound 15. In some embodiments, the present disclosure provides compound 15, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the present disclosure provides compound 15, wherein the compound is substantially free of the crystalline form of compound 1. In some embodiments, the present disclosure provides compound 15, wherein the compound is substantially free of impurities.

[0269] In some embodiments, Form A of compound 15 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.0, 17.0, and 20.2 ± 0.5 degrees 2-θ. In some embodiments, Form A of compound 15 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.0, 17.0, and 20.2 ± 0.4 degrees 2-θ. In some embodiments, Form A of compound 15 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.0, 17.0, and 20.2 ± 0.3 degrees 2-θ. In some embodiments, Form A of compound 15 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.0, 17.0, and 20.2 ± 0.2 degrees 2-θ.

[0270] In some embodiments, the present disclosure provides compound 15, wherein the compound has an XRPD Figure 14A substantially similar to that depicted in

[0271] In some embodiments, the present disclosure provides compound 15, wherein the compound has a DSC-TGA Figure 14B substantially similar to that depicted in

[0272] In some embodiments, the present disclosure provides a composition comprising compound 15 and a pharmaceutically acceptable carrier or excipient.

[0273] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 15 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the modulation of a signaling pathway involving IRAK4. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient that is related to the modulation of a signal transduction pathway involving IRAK4, the method comprising administering Compound 15 or a composition thereof to the patient. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering Compound 15 or a composition thereof to the patient, wherein the disease, disorder, or condition is 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 Compound 15 or a composition thereof to the patient. Compound 16 (succinate salt of Compound 1)

[0274] According to one embodiment, the present disclosure provides the succinate salt of Compound 1, which is represented by Compound 16:

[0275] One of ordinary skill in the art will understand that succinic acid and Compound 1 are ionically bonded 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 contemplated that Compound 16 can exist in a variety of 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 16 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0276] In some embodiments, the present disclosure provides Compound 16 that is substantially free of impurities. Such impurities or extraneous substances can include different forms of Compound 16, residual solvents, or any other impurities that may result from the preparation and / or isolation of Compound 16. In certain embodiments, there is at least about 95% by weight of the form of Compound 16. In still other embodiments of the present disclosure, there is at least about 99% by weight of the form of Compound 16.

[0277] According to one embodiment, the form of Compound 16 is present in an amount of at least about 97 weight percent, 97.5 weight percent, 98.0 weight percent, 98.5 weight percent, 99 weight percent, 99.5 weight percent, 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, the form of Compound 16 contains no more than about 3.0 area percent of total organic impurities by HPLC relative to the total area of the HPLC chromatogram, and in certain embodiments no more than about 1.5 area percent of total organic impurities by HPLC. In other embodiments, the form of Compound 16 contains no more than about 1.0 area percent of any single impurity by HPLC relative to the total area of the HPLC chromatogram, no more than about 0.6 area percent of any single impurity by HPLC, and in certain embodiments no more than about 0.5 area percent of any single impurity by HPLC.

[0278] The structures depicted for the form of Compound 16 are also intended to include all tautomeric forms of Compound 16. Additionally, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, in addition to replacing hydrogen with deuterium or tritium or replacing carbon with 13 C- or 14 C-enriched carbon, compounds having the structures of the present invention are within the scope of this disclosure.

[0279] It has been found that Compound 16 can exist in multiple solid forms. Exemplary such forms include polymorphs, such as those described herein.

[0280] 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 contains no significant amount of amorphous Compound 16. In certain embodiments, there is at least about 95% by weight of crystalline Compound 16. In still other embodiments of this disclosure, there is at least about 99% by weight of crystalline Compound 16.

[0281] It has been found that Compound 16 can exist in at least one different polymorph. In certain embodiments, this disclosure provides a polymorph of Compound 16, referred to herein as Form A. Form A of Compound 16

[0282] Methods for preparing Form A of Compound 16 are described below.

[0283] In some embodiments, this disclosure provides Compound 16: Wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 16, wherein the compound is substantially free of amorphous compound 16. In some embodiments, the present disclosure provides compound 16, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the present disclosure provides compound 16, wherein the compound is substantially free of the crystalline form of compound 1. In some embodiments, the present disclosure provides compound 16, wherein the compound is substantially free of impurities.

[0284] In some embodiments, Form A of compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 6.5, 12.9, and 16.2 ± 0.5 degrees 2-θ. In some embodiments, Form A of compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 6.5, 12.9, and 16.2 ± 0.4 degrees 2-θ. In some embodiments, Form A of compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 6.5, 12.9, and 16.2 ± 0.3 degrees 2-θ. In some embodiments, Form A of compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 6.5, 12.9, and 16.2 ± 0.2 degrees 2-θ.

[0285] In some embodiments, the present disclosure provides compound 16, wherein the compound has an XRPD Figure 15A substantially similar to that depicted in

[0286] In some embodiments, the present disclosure provides compound 16, wherein the compound has a DSC-TGA Figure 15D substantially similar to that depicted in

[0287] (e.g., having an endothermic DSC event starting at 242 °C - 247 °C). In some embodiments, the present disclosure provides compound 16, wherein the compound has DSC events and / or TGA weight loss as described in Table 6.

[0288] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 16 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the modulation of a signaling pathway involving IRAK4. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition in a patient that is related to modulation of a signaling pathway involving IRAK4, the method comprising administering compound 16 or a composition thereof to the patient. In some embodiments, the present disclosure provides methods of treating a disease, disorder, or condition in a patient, the method comprising administering compound 16 or a composition thereof to the patient, wherein the disease, disorder, or condition is mediated by IRAK4. In some embodiments, the present disclosure provides methods of treating an autoimmune or inflammatory disorder in a patient, the method comprising administering compound 16 or a composition thereof to the patient. Form B of compound 16

[0289] Methods for preparing Form B of compound 16 are described below.

[0290] In some embodiments, the present disclosure provides compound 16: wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 16, wherein the compound is substantially free of amorphous compound 16. In some embodiments, the present disclosure provides compound 16, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the present disclosure provides compound 16, wherein the compound is substantially free of the crystalline form of compound 1. In some embodiments, the present disclosure provides compound 16, wherein the compound is substantially free of impurities.

[0291] In some embodiments, Form B of compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 6.8, 11.1, and 16.5 ± 0.5 degrees 2-θ. In some embodiments, Form B of compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 6.8, 11.1, and 16.5 ± 0.4 degrees 2-θ. In some embodiments, Form B of compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 6.8, 11.1, and 16.5 ± 0.3 degrees 2-θ. In some embodiments, Form B of compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks selected from those at 6.8, 11.1, and 16.5 ± 0.2 degrees 2-θ.

[0292] In some embodiments, the present disclosure provides compound 16, wherein the compound has an XRPD that is substantially similar to the XRPD depicted in Figure 15A (e.g., having peaks of ± 0.2 degrees 2-θ).

[0293] In some embodiments, the present disclosure provides compound 16, wherein the compound has a DSC-TGA that is substantially similar to that depicted in Figure 15B (e.g., having an endothermic DSC event starting at 232°C - 237°C). In some embodiments, the present disclosure provides compound 16, wherein the compound has DSC events and / or TGA weight loss as described in Table 6.

[0294] In some embodiments, the present disclosure provides a composition comprising compound 16 and a pharmaceutically acceptable carrier or excipient.

[0295] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering compound 16 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the modulation of a signaling pathway involving IRAK4. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient associated with the modulation of a signaling pathway involving IRAK4, the method comprising administering compound 16 or a composition thereof to the patient. In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition in a patient, the method comprising administering compound 16 or a composition thereof to the patient, wherein the disease, disorder, or condition is 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 compound 16 or a composition thereof to the patient. Form C of compound 16

[0296] Methods for preparing Form C of compound 16 are described below.

[0297] In some embodiments, the present disclosure provides compound 16: wherein the compound is crystalline. In some embodiments, the present disclosure provides compound 16, wherein the compound is substantially free of amorphous compound 16. In some embodiments, the present disclosure provides compound 16, wherein the compound is substantially free of amorphous compound 1. In some embodiments, the present disclosure provides compound 16, wherein the compound is substantially free of the crystalline form of compound 1. In some embodiments, the present disclosure provides compound 16, wherein the compound is substantially free of impurities.

[0298] In some embodiments, Form C of Compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.0, 11.9, and 16.0 ± 0.5 degrees 2-theta. In some embodiments, Form C of Compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.0, 11.9, and 16.0 ± 0.4 degrees 2-theta. In some embodiments, Form C of Compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.0, 11.9, and 16.0 ± 0.3 degrees 2-theta. In some embodiments, Form C of Compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.0, 11.9, and 16.0 ± 0.2 degrees 2-theta.

[0299] In some embodiments, the present disclosure provides Compound 16, wherein the compound has an XRPD substantially similar to that Figure 15A depicted in (e.g., having peaks at ± 0.2 degrees 2-theta).

[0300] In some embodiments, the present disclosure provides Compound 16, wherein the compound has a DSC-TGA substantially similar to that Figure 15C depicted in (e.g., having an endothermic DSC event starting at 240 °C - 245 °C). In some embodiments, the present disclosure provides Compound 16, wherein the compound has DSC events and / or TGA weight loss as described in Table 6.

[0301] In some embodiments, the present disclosure provides a composition comprising Compound 16 and a pharmaceutically acceptable carrier or excipient.

[0302] In some embodiments, the present disclosure provides a method of modulating IRAK4 kinase in a patient, the method comprising administering Compound 16 or a composition thereof to the patient. In some embodiments, the method ubiquitinates and / or degrades IRAK4 kinase, thereby treating a disease, disorder, or condition associated with the modulation of a signaling pathway involving IRAK4. In some embodiments, the present disclosure provides a method for treating a disease, disorder or condition in a patient related to the modulation of a signal transduction pathway involving IRAK4, the method comprising administering compound 16 or a composition thereof to the patient. In some embodiments, the present disclosure provides a method for treating a disease, disorder or condition in a patient, the method comprising administering compound 16 or a composition thereof to the patient, wherein the disease, disorder or condition is mediated by IRAK4. In some embodiments, the present disclosure provides a method for treating an autoimmune or inflammatory disorder in a patient, the method comprising administering compound 16 or a composition thereof to the patient. General method for providing salt compounds

[0303] According to the general scheme below, salt compounds of general formula A are prepared from compound 1, which formula particularly encompasses salt compounds 2 to 16 and / or their specific forms. Scheme 2. Preparation of salts of formula A

[0304] For example, each of compounds 2 to 16 and their forms is prepared from compound 1 by combining compound 1 with a suitable acid to form the salt of the acid. Accordingly, another aspect of the present disclosure provides a method for preparing compounds 2 to 16 and their forms.

[0305] As generally described above, in some embodiments, the present disclosure provides a method for preparing a salt compound of general formula A: The method comprises the following steps: Combining compound 1: With a suitable acid and optionally a suitable solvent under conditions suitable for forming a salt of formula A.

[0306] In some embodiments, the suitable acid is sulfuric acid. In some embodiments, the present disclosure provides a method for preparing the 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.

[0307] In some embodiments, the suitable acid is benzenesulfonic acid. In some embodiments, the present disclosure provides a method for preparing the 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.

[0308] In some embodiments, a suitable acid is toluenesulfonic acid. In some embodiments, the present disclosure provides a method for preparing the toluenesulfonate of compound 1. In certain embodiments, the toluenesulfonate of compound 1 is compound 4. In certain embodiments, the toluenesulfonate 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.

[0309] In some embodiments, a suitable acid is ethanesulfonic acid. In some embodiments, the present disclosure provides a method for preparing the ethanesulfonate of compound 1. In certain embodiments, the ethanesulfonate of compound 1 is compound 5. In certain embodiments, the ethanesulfonate 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.

[0310] In some embodiments, a suitable acid is methanesulfonic acid. In some embodiments, the present disclosure provides a method for preparing the methanesulfonate of compound 1. In certain embodiments, the methanesulfonate of compound 1 is compound 6. In certain embodiments, the methanesulfonate 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.

[0311] In some embodiments, a suitable acid is maleic acid. In some embodiments, the present disclosure provides a method for preparing the maleate of compound 1. In certain embodiments, the maleate of compound 1 is compound 7. In certain embodiments, the maleate 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.

[0312] In some embodiments, a suitable acid is L-tartaric acid. In some embodiments, the present disclosure provides a method for preparing the L-tartrate of compound 1. In certain embodiments, the L-tartrate of compound 1 is compound 8. In certain embodiments, the L-tartrate 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.

[0313] In some embodiments, a suitable acid is fumaric acid. In some embodiments, the present disclosure provides a method for preparing the fumarate of compound 1. In certain embodiments, the fumarate of compound 1 is compound 9. In certain embodiments, the fumarate 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.

[0314] In some embodiments, a suitable acid is citric acid. In some embodiments, the present disclosure provides a method for preparing the citrate of compound 1. In certain embodiments, the citrate of compound 1 is compound 10. In certain embodiments, the citrate 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.

[0315] In some embodiments, a suitable acid is glycolic acid. In some embodiments, the present disclosure provides a method for preparing the glycolate of compound 1. In certain embodiments, the glycolate of compound 1 is compound 11. In certain embodiments, the glycolate 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.

[0316] In some embodiments, a suitable acid is L-malic acid. In some embodiments, the present disclosure provides a method for preparing the L-malate of compound 1. In certain embodiments, the L-malate of compound 1 is compound 12. In certain embodiments, the L-malate 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.

[0317] In some embodiments, a suitable acid is hippuric acid. In some embodiments, the present disclosure provides a method for preparing the hippurate of compound 1. In certain embodiments, the hippurate of compound 1 is compound 13. In certain embodiments, the hippurate 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.

[0318] In some embodiments, a suitable acid is L-lactic acid. In some embodiments, the present disclosure provides a method for preparing the L-lactate of compound 1. In certain embodiments, the L-lactate of compound 1 is compound 14. In certain embodiments, the L-lactate 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.

[0319] In some embodiments, a suitable acid is benzoic acid. In some embodiments, the present disclosure provides a method for preparing the benzoate of compound 1. In certain embodiments, the benzoate of compound 1 is compound 15. In certain embodiments, the benzoate 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.

[0320] In some embodiments, a suitable acid is succinic acid. In some embodiments, the present disclosure provides a method for preparing the 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 a method for preparing Form A of Compound 16, as 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 a method for preparing Form B of Compound 16, as 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 invention provides a method for preparing Form C of Compound 16, as described in Example 1 below.

[0321] A suitable solvent can be any solvent system (e.g., a single solvent or a mixture of solvents) in which Compound 1 and / or the acid is soluble, or at least partially soluble.

[0322] Examples of suitable solvents that can be used in the methods disclosed in the present invention 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.

[0323] In certain embodiments, a suitable solvent is methanol, ethanol, isopropanol, or acetone, where the solvent is anhydrous or combined with water or heptane. In some embodiments, suitable solvents include tetrahydrofuran, ethyl acetate, dimethylformamide, dimethyl sulfoxide, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, tert-butanol, n-butanol, and acetonitrile. In certain embodiments, a suitable solvent is acetonitrile, ethyl acetate, tetrahydrofuran, methanol, or 9:1 acetone:water.

[0324] In some embodiments, a suitable solvent is ethyl acetate. In some embodiments, a suitable solvent is methanol. In some embodiments, a suitable solvent is acetonitrile. In some embodiments, a suitable solvent is tetrahydrofuran. In some embodiments, a suitable solvent is 9:1 acetone:water.

[0325] In some embodiments, the present disclosure provides a method for preparing a salt compound having General Formula A, the method comprising one or more steps of removing a solvent and adding a solvent. In some embodiments, the added solvent is the same as the removed solvent. In some embodiments, the added solvent is different from the removed solvent. Solvent removal means are known in the synthesis and chemical arts and include, but are not limited to, any of those described herein and in the examples.

[0326] In some embodiments, the method for preparing a salt compound having the general formula A includes one or more steps of heating or cooling the preparation.

[0327] In some embodiments, the method for preparing a salt compound having the general formula A includes one or more steps of agitating or stirring the preparation.

[0328] In some embodiments, the method for preparing a salt compound having the general formula A includes mixing compound 1 and a suitable solvent and agitating or stirring the mixture at a certain temperature for a certain amount of time. In some embodiments, the method includes mixing compound 1 and a suitable solvent in a molar ratio of 1:1. In some embodiments, the method includes agitating or stirring the mixture at room temperature. In some embodiments, the method includes agitating or stirring the mixture for 1, 2, 3, or 4 days.

[0329] In some embodiments, the method for preparing a salt compound having the general formula A includes slowly evaporating the solvent. In some embodiments, the method for preparing a salt compound having the general formula A includes slowly evaporating the solvent by exposing it to the ambient atmosphere at room temperature. In some embodiments, the method for preparing a salt compound having the general formula A includes evaporating the solvent under a stream of an inert gas (such as nitrogen).

[0330] In some embodiments, the method for preparing a salt compound having the general formula A includes the step of adding a suitable acid to a solution or slurry of compound 1.

[0331] In some embodiments, the method for preparing a salt compound having the general formula A includes a heating step.

[0332] In certain embodiments, the salt compound having formula A precipitates from the mixture. In another embodiment, the salt compound having formula A crystallizes from the mixture. In other embodiments, the salt compound having formula A crystallizes from the solution after seeding the solution (i.e., adding crystals of the salt compound having formula A to the solution).

[0333] The salt compound having formula A can be precipitated from the reaction mixture, or by removing a part or all of the solvent by methods such as evaporation, distillation, filtration (such as nanofiltration, ultrafiltration), reverse osmosis, absorption, and reaction, by adding an anti-solvent such as heptane, by cooling, or by different combinations of these methods.

[0334] As generally described above, the salt compound having Formula A is optionally separated. It should be understood that the salt compound having Formula A can be separated by any suitable physical means known to those of ordinary skill in the art. In certain embodiments, the precipitated solid salt compound having Formula A is separated from the supernatant by filtration. In other embodiments, the precipitated solid salt compound having Formula A is separated from the supernatant by decanting the supernatant.

[0335] In certain embodiments, the salt compound having Formula A is separated from the supernatant by filtration.

[0336] In certain embodiments, the separated salt compound having Formula A is dried in air. In other embodiments, the separated salt compound having Formula A is dried under reduced pressure, optionally at elevated temperature. Uses, Formulations, and Administrations Pharmaceutically Acceptable Compositions

[0337] 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 the compound in the composition of the present invention is such that it effectively and measurably degrades and / or inhibits IRAK protein kinase, or a mutant thereof, in a biological sample or a patient. In certain embodiments, the amount of the compound in the composition of the present invention is such that it effectively and measurably degrades and / or inhibits IRAK protein kinase, or a mutant thereof, in a biological sample or 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.

[0338] As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

[0339] 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 formulated therewith. 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), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides 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-polypropylene-block polymers, polyethylene glycol, and lanolin.

[0340] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, ester salt or other derivative of a compound of the present invention, which, when administered to a recipient, is capable of directly or indirectly providing the compound of the present invention or its inhibitory or degradative active metabolite or residue.

[0341] As used herein, the term "its inhibitory active metabolite or residue" means that its metabolite or residue is also an inhibitor of IRAK protein kinase or its mutant.

[0342] As used herein, the term "its degradative active metabolite or residue" means that its metabolite or residue is also a degrader of IRAK protein kinase or its mutant.

[0343] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intra-lesional and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally or intravenously. The sterile injectable form of the composition of the present invention can be an aqueous or oleaginous suspension. These suspensions can be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0344] For this purpose, any mild fixed oil can be employed, including synthetic mono- or di-glycerides of fatty acids. Fatty acids such as oleic acid and its glyceride derivatives can be used in the preparation of injectables, as can natural pharmaceutically acceptable oils such as olive oil or castor oil, especially in their polyoxylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersing agents such as carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans, and other emulsifying agents or bioavailability enhancers (commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms) can also be used for formulation purposes.

[0345] The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, common carriers include lactose and corn starch. Lubricants such as magnesium stearate are typically also added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension for oral use is required, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.

[0346] 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 which is solid at room temperature but liquid at rectal temperature and will thus melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycol.

[0347] The pharmaceutically acceptable compositions of the present invention can also be administered topically, especially when the treatment target includes areas or organs that are readily accessible by topical application, including diseases of the eye, skin or lower intestine. Suitable topical formulations can be readily prepared for each of these areas or organs.

[0348] Topical application for the lower intestine can be in the form of rectal suppository formulations (see above) or in the form of suitable enema formulations. Topical transdermal patches can also be used.

[0349] For topical application, the provided pharmaceutically acceptable compositions can be formulated in a suitable ointment containing the active component 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 compositions can be formulated in a suitable lotion or cream containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include but are not limited to mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0350] 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 preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated in an ointment such as petrolatum.

[0351] The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline with benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0352] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are not administered with food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0353] The amount of the compound of the present invention that can be combined with a carrier material to produce a composition in a single dosage form will vary depending on the host being treated and the specific mode of administration. Preferably, the provided compositions should be formulated such that a dose of the compound of 0.01 - 100 mg / kg body weight / day can be administered to a patient receiving these compositions.

[0354] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician, as well as the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition. Use of the Compounds and Pharmaceutically Acceptable Compositions

[0355] The compounds and compositions described herein can generally be used to degrade one or more enzymes and / or inhibit the kinase activity of one or more enzymes.

[0356] Kinases that are degraded and / or inhibited by the compounds and compositions described herein and that the methods described herein can be directed against include kinases of the interleukin-1 receptor-associated kinase (IRAK) family, members of which include IRAK-1, IRAK-2, and IRAK-4, or mutants thereof. Li et al., "IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase," PNAS [Proceedings of the National Academy of Sciences of the United States of America] 2002, 99(8), 5567-5572; Flannery et al., "The interleukin-1 receptor-associated kinases: Critical regulators of innate immune signaling," Biochem Pharm [Biochemical Pharmacology] 2010, 80(12), 1981-1991, which are incorporated herein by reference in their entireties.

[0357] According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity or degrading a protein kinase in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0358] According to another embodiment, the present invention relates to a method for inhibiting the activity of IRAK-1, IRAK-2, and / or IRAK-4 or mutants thereof in a biological sample or degrading IRAK-1, IRAK-2, and / or IRAK-4 or mutants thereof in a biological sample, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0359] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy materials obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

[0360] Inhibiting the activity of a protein kinase in a biological sample or a protein kinase selected from IRAK-1, IRAK-2, and / or IRAK-4 or mutants thereof and / or degrading a protein kinase in a biological sample or a protein kinase selected from IRAK-1, IRAK-2, and / or IRAK-4 or mutants thereof can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological sample storage, and biological assays.

[0361] Another embodiment of the present invention relates to a method of degrading a protein kinase in a patient and / or inhibiting the activity of a protein kinase in a patient, the method comprising the step of administering to the patient a compound of the present invention, or a composition comprising the compound.

[0362] According to another embodiment, the present invention relates to a method of degrading one or more of IRAK-1, IRAK-2, and / or IRAK-4 in a patient and / or inhibiting the activity of one or more of IRAK-1, IRAK-2, and / or IRAK-4 in a patient, or a mutant thereof, the method comprising the step of administering to the patient a compound of the present invention, or a composition comprising the compound. In other embodiments, the present invention provides a method for treating a disorder mediated by one or more of IRAK-1, IRAK-2, and / or IRAK-4, or a mutant thereof, in a patient in need thereof, the method comprising the step of administering to the patient a compound according to the present invention or a pharmaceutically acceptable composition thereof. Such disorders are described in detail herein.

[0363] The activity of a compound used as a degrader and / or inhibitor of IRAK-1, IRAK-2, and / or IRAK-4 or mutants thereof in the present invention can be determined in vitro, in vivo, or in cell lines. In vitro assays include assays that determine the inhibition of the phosphorylation activity and / or subsequent functional consequences or ATPase activity of activated IRAK-1, IRAK-2, and / or IRAK-4 or mutants thereof. Alternative in vitro assays quantify 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, separating the inhibitor / IRAK-1, inhibitor / IRAK-2, or inhibitor / IRAK-4 complex, and determining the amount of radiolabel bound. Alternatively, inhibitor binding can be determined by running a competition experiment, in which a new inhibitor is incubated with IRAK-1, IRAK-2, and / or IRAK-4 that is bound to a known radioligand.Representative in vitro and in vivo assays useful for determining IRAK-4 inhibitors include those described or disclosed in the following: e.g., 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; Song et al., “The kinase activities of interleukin-e receptorassociated kinase (IRAK)-1 and 4 are redundant in the control of inflammatory cytokine expression in human cells,” Mol. Immunol. 2009, 46, 1458-1466, the respective full texts of which are incorporated by reference in their entireties. Detailed conditions for assaying compounds used as degraders and / or inhibitors of IRAK-1, IRAK-2, and / or IRAK-4 or mutants thereof in the present invention are shown in the following examples.

[0364] The most characterized member of the IRAK family is the serine / threonine kinase IRAK-4. IRAK-4 is involved in the innate immune response signaling from Toll-like receptors (TLRs) and Toll / IL-1 receptors (TIRs).

[0365] Innate immunity detects pathogens by the recognition of pathogen-associated molecular patterns by TLRs, which are then integrated with the adaptive immune response. TLRs recognize conserved structures in 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.

[0366] TLRs mediate innate immune responses by upregulating the expression of inflammatory genes in a variety of target cells. See, e.g., Sen et al., “Transcriptional signaling by double-stranded RNA: role of TLR3 [Transcriptional signaling by double-stranded RNA: role of TLR3],” Cytokine & Growth Factor Rev. [Cytokine and Growth Factor Review] 2005, 16, 1-14, which is incorporated by reference in its entirety. Although TLR-mediated inflammatory responses are crucial 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, and autoimmune disorders (such as rheumatoid arthritis, lupus, asthma, psoriasis, and inflammatory bowel disease).

[0367] Upon binding to ligands, most TLRs recruit the adaptor molecule MyD88 via the TIR domain, mediating the MyD88-dependent pathway. Then, MyD88 recruits IRAK-4, which binds and leads to the induction of pro-inflammatory cytokines in association with the nuclear factor-κB (NF-κB), mitogen-activated protein (MAP) kinase, and interferon regulatory factor cascades. Activation of NF-κB 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 a key role in TLR-mediated immune and inflammatory responses. IRAK4 is a key mediator of the innate immune response coordinated by the interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), IL-33 receptor (IL-33R), and Toll-like receptor (TLR). Inactivation of IRAK-1 and / or IRAK-4 activity has been shown to result in reduced production of cytokines and chemokines in response to stimulation with IL-1 and TLR ligands. See, e.g., 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. Immunology 2008, 38:614-618; Cohen et 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 signalling,” Biochem. Pharm.[Biochemical Pharmacology] 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.[Journal of Biochemistry] 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., “Severe impairment of interleukin - 1 and Toll - like receptor signalling 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, Volume 9, pp. 293 - 307 (2010); Dinarello, C."Interleukin-18 and the Pathogenesis of Inflammatory Diseases," Seminars in Nephrology, Volume 27, Number 1, pp. 98-114 (2007), the respective full texts of which are incorporated herein by reference in their entireties. In fact, knockdown mice expressing catalytically inactive mutant IRAK-4 protein are completely resistant to septic shock and show impaired IL-1 activity. In addition, these mice are resistant to joint and bone inflammation / destruction in an arthritis model, indicating that IRAK-4 can be targeted for the treatment of chronic inflammation. Furthermore, while IRAK-4 appears to be essential for children's immunity against some pyogenic bacteria, it has been shown to play a redundant role in adult protective immunity against most infections, as demonstrated by a study in which patients lacking IRAK-4 activity over the age of 14 did not exhibit 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.[Immunological Research] 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. [Molecular Immunology] 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), the respective full texts of which are incorporated herein by reference in their entireties. Since TLR activation triggers IRAK-4 kinase activity, IRAK-4 inhibition provides an attractive target for the underlying cause of inflammation in numerous diseases.

[0368] Representative IRAK-4 inhibitors include those described and disclosed in the following: e.g., 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; Wng et al., “IRAK-4 Inhibitors for Inflammation,” Curr. Topics in Med. Chem. 2009, 9, 724-737, the respective full texts of which are incorporated herein by reference in their entireties.

[0369] As used herein, the term “treatment / treat / treating” refers to reversing, alleviating a disease or disorder as described herein or one or more of its symptoms, delaying its onset or inhibiting its progression. In some embodiments, treatment may be administered after one or more symptoms have appeared. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual (e.g., based on a symptom history and / or based on genetic or other susceptibility factors) prior to the onset of symptoms. Treatment may also continue after the symptoms have subsided, e.g., to prevent or delay their recurrence.

[0370] The provided compounds are degrader(s) and / or inhibitor(s) of one or more of IRAK-1, IRAK-2, and / or IRAK-4, and thus can be used to treat 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 IRAK-1-mediated, IRAK-2-mediated, and / or IRAK-4-mediated disorders, the method comprising the step of administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof.

[0371] As used herein, the terms "IRAK-1-mediated", "IRAK-2-mediated", and / or "IRAK-4-mediated" disorders, diseases, and / or conditions mean any disease or other adverse condition in which one or more of IRAK-1, IRAK-2, and / or IRAK-4 or a mutant thereof is known to play a role. Accordingly, another embodiment of the invention relates to treating one or more diseases or reducing the severity of one or more diseases in which one or more of IRAK-1, IRAK-2, and / or IRAK-4 or a mutant thereof is known to play a role.

[0372] In some embodiments, the compounds and compositions described herein can be used in medicine.

[0373] In some embodiments, the invention provides methods for treating one or more disorders, diseases, and / or conditions, where the disorder, disease, or condition is cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a genetic disease, a hormone-related disease, a metabolic disorder, a condition related to organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition related to cell death, thrombin-induced platelet aggregation, a liver disease, a pathological immune condition involving T cell activation, a cardiovascular disorder, or a CNS disorder.

[0374] Diseases and disorders that can be treated according to the methods of the present invention include, but are not limited to, cancer in a patient (see, e.g., 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 1β-Induced Interleukin 6 Production and the Myeloma Proliferative Component,” Mayo Clinic Proceedings, 84(2), pp. 114-122 (2009)), diabetes, cardiovascular diseases, viral diseases, autoimmune diseases such as lupus (see, e.g., Dinarello, C. “Interleukin-18 and the Pathogenesis of Inflammatory Diseases,” Seminars in Nephrology, Vol. 27, No. 1, pp. 98-114 (2007); Cohen et 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, e.g., 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., "Hyperuricaemia 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 [Novel gouty arthritis animal model in which hyperalgesia, synovitis and multiple inflammation biomarkers are inhibited by interleukin 1 inhibition]," Annals of Rheumatic Diseases [Annals of Rheumatic Diseases], 68, pp. 1602-1608 (2009)), neurological disorders, metabolic syndrome (see, for example, Troseid, M. "The role of interleukin-18 in the metabolic syndrome [The role of interleukin-18 in the metabolic syndrome]," Cardiovascular Diabetology [Cardiovascular Diabetology], 9:11, pp. 1-8 (2010)), immunodeficiency disorders such as AIDS and HIV (see, for example, Iannello, A. et al., "Role of Interleukin-18 in the Development and Pathogenesis of AIDS [The role of interleukin-18 in the development and pathogenesis of AIDS]," AIDS Reviews [AIDS Reviews], 11, pp. 115-125 (2009)), destructive bone disorders (see, for example, Hennessy, E. et al., "Targeting Toll-like receptors: emerging therapeutics? [Targeting Toll-like receptors: emerging therapeutics?]" Nature Reviews [Nature Reviews], Vol. 9, pp. 293-307 (2010)), osteoarthritis, proliferative disorders, Waldenström macroglobulinemia (see, for example, Treon et al., "Whole genome sequencing reveals a widely expressed mutation (MYD88 L265P) with oncogenic activity in... Macroglobulinemia [Whole genome sequencing reveals a widely expressed mutation (MYD88 L265P) with oncogenic activity in Waldenström macroglobulinemia]" 53 rdASH Annual Meeting [The 53rd 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 [The 53rd 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 Macroglobulinemia [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 Waldenström macroglobulinemia]" 53 rd ASH Annual Meeting [The 53rd 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 rdASH Annual Meeting (the 53rd ASH Annual Meeting); infectious diseases, diseases related to cell death, pathological immune diseases involving T cell activation, and CNS disorders. In one embodiment, a human patient is treated with a compound of the present invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the compound is present in an amount that measurably degrades only IRAK-1, only IRAK-2, only IRAK-4, and / or IRAK1 and IRAK4 kinases and / or inhibits the kinase activity of only IRAK-1, only IRAK-2, only IRAK-4, and / or IRAK1 and IRAK4.

[0375] The compounds of the present invention can be used for treating proliferative diseases selected from the following: benign or malignant tumors, solid tumors, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric cancer, gastric tumors, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, urogenital tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer, or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, particularly colon cancer or colorectal adenoma, head and neck tumors, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasm, epithelioma, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's and non-Hodgkin's, mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-driven disorders, MyD88-driven disorders, smoldering indolent multiple myeloma, or hematological malignancies (including leukemia, diffuse large B cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenström macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B cell lymphoma, AML, MDS).

[0376] In some embodiments, the proliferative disease that can be treated according to the method of the present invention is a MyD88-driven disorder. In some embodiments, the MyD88-driven disorders that can be treated according to the method of the present invention are selected from ABC DLBCL, primary CNS lymphoma, primary extranodal lymphoma, Waldenström macroglobulinemia, Hodgkin lymphoma, primary cutaneous T cell lymphoma, and chronic lymphocytic leukemia.

[0377] In some embodiments, the proliferative disease that can be treated according to the method of the present invention is an IL-1-driven disorder. In some embodiments, the IL-1-driven disorder is smoldering multiple myeloma.

[0378] The compounds according to the invention can be used for treating inflammatory or obstructive airway diseases, thereby reducing, for example, tissue damage, airway inflammation, bronchial hyperreactivity, remodelling or disease progression. Inflammatory or obstructive airway diseases to which the invention is applicable include asthma of any type or cause, including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection. The treatment of asthma should also be understood to include the treatment of, for example, subjects less than 4 or 5 years of age who exhibit wheezing symptoms and are diagnosed or diagnosable as "wheezy infants", which subjects are an established patient category of major medical concern and are now generally identified as patients with incipient or early asthma.

[0379] The compounds according to the invention can be used for treating xenograft immunological diseases. Examples of such xenograft immunological diseases include, but are not limited to, graft-versus-host disease, transplantation, blood transfusion, allergic reactions, allergies (such as allergies to plant pollen, latex, drugs, food, insect poisons, animal hair, animal dander, dust mites or cockroach frass), type I hypersensitivity reactions, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0380] The prophylactic efficacy in the treatment of asthma will be demonstrated by a reduction in the frequency or severity of symptom attacks (such as acute asthma or bronchoconstriction attacks), an improvement in lung function or an improvement in airway hyperreactivity. This can be further demonstrated by a reduction in the need for other symptomatic therapies, such as therapies used or intended to limit or abort symptom attacks (such as anti-inflammatory or bronchodilatory therapies). The benefits of preventing asthma may be particularly evident in subjects prone to "morning dips". "Morning dips" is a recognized asthma syndrome, common in a significant proportion of asthma patients, and is characterized by asthma attacks, for example, between about 4 am and 6 am, i.e., usually at a relatively long time interval from any previously administered symptomatic asthma therapy.

[0381] The compounds of the present invention can be used in other inflammatory or obstructive airway diseases and conditions for which the present invention is applicable, and include acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airway or lung diseases (COPD, COAD or COLD), including chronic bronchitis or associated dyspnea, emphysema, and exacerbation of airway hyperreactivity due to other drug therapies, particularly other inhaled drug therapies. The present invention is also applicable to the treatment of any type or cause of bronchitis, including but not limited to acute bronchitis, peanut aspiration bronchitis, catarrhal bronchitis, croupous bronchitis, chronic bronchitis or tuberculous bronchitis. Other inflammatory or obstructive airway diseases for which the present invention is applicable include any type or cause of pneumoconiosis (an inflammatory, usually occupational lung disease, often accompanied by airway obstruction (either chronic or acute) and caused by repeated inhalation of dust), including, for example, aluminosis, anthracosis, asbestosis, siderosis, ptilosis, siderosis, silicosis, smutosis and byssinosis.

[0382] Regarding anti-inflammatory activity, particularly related to the inhibition of eosinophil activation, the compounds of the present invention can also be used to treat eosinophil-related disorders, such as eosinophilia, particularly eosinophil-related airway disorders (e.g., involving pathological eosinophil infiltration of lung tissue), including hypereosinophilia affecting the airways and / or lungs, and eosinophil-related airway disorders associated with or accompanying, for example: Löffler syndrome, eosinophilic pneumonia, parasite (particularly metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophilic asthma, eosinophilic COPD, and eosinophil-related airway disorders affecting the airways caused by drug reactions.

[0383] The compounds of the present invention can also be used to treat inflammatory or allergic skin conditions, such as psoriasis, generalized pustular psoriasis (GPP), psoriasis vulgaris, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, hidradenitis suppurativa, Sweet Syndrome, pyoderma gangrenosum, and other inflammatory or allergic skin conditions.

[0384] The compounds of the present invention can also be used to treat other diseases or disorders, such as diseases or disorders having an inflammatory component, for example, treating eye diseases and disorders, such as eye allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases in which there is an association with an autoimmune reaction or having an autoimmune component or etiology, including autoimmune blood diseases (such as hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior uveitis and posterior uveitis), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, pulmonary interstitial fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndromes, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome,Such as including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis nephropathy, glaucoma, retinopathy, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, dyschromatosis, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic asthma and non-allergic asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, or exercise-induced asthma), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, ocular allergy, silica-induced diseases, COPD (reducing injury, airway inflammation, bronchial hyperreactivity, remodeling or disease progression), lung diseases, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataract, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia (pneumonitis), pneumonia (pneumonia), polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.,

[0385] In some embodiments, the inflammatory disease that can be treated according to the method of the present invention is a skin disease. In some embodiments, the inflammatory diseases of the skin are selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, hidradenitis suppurativa, and other inflammatory or allergic skin conditions.

[0386] In some embodiments, the inflammatory diseases that can 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.

[0387] In some embodiments, the inflammatory diseases that can be treated according to the methods of the present invention are TH17-mediated diseases. In some embodiments, the TH17-mediated diseases are selected from systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris, hidradenitis suppurativa, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0388] In some embodiments, the inflammatory diseases that can be treated according to the methods of the present invention are selected from Sjogren's syndrome, allergic disorders, osteoarthritis, ocular conditions such as ocular allergy, conjunctivitis, keratoconjunctivitis sicca and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis or chronic rhinosinusitis with nasal polyps (CRSwNP).

[0389] In some embodiments, the present invention provides methods for treating TLR / IL-1R-driven autoinflammatory and autoimmune diseases with high unmet medical needs such as hidradenitis suppurativa, atopic dermatitis and rheumatoid arthritis. Thus, in some embodiments, the present invention provides a method for treating hidradenitis suppurativa in a patient in need thereof, the method 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, the method 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, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0390] The cardiovascular diseases that can be treated according to the methods of the present invention include but are not limited to restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after coronary artery bypass grafting, restenosis after coronary artery bypass grafting, stroke, transient ischemia, peripheral arterial occlusive disorders, pulmonary embolism, and deep vein thrombosis.

[0391] In some embodiments, neurodegenerative diseases that can 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 trauma, glutamate neurotoxicity, hypoxia, epilepsy, diabetes treatment, metabolic syndrome, obesity, organ transplantation, and graft-versus-host disease.

[0392] Loss of IRAK4 function results in reduced Aβ levels in an in vivo mouse model of Alzheimer's disease and is associated with reduced microgliosis and astrogliosis in aged mice. Analysis of microglia isolated from adult mouse brains revealed altered gene expression patterns associated with changes in microglial phenotype, which were associated with the expression of IRF transcription factors that control microglial phenotype. In addition, loss of IRAK4 function also promoted amyloid clearance mechanisms, including increased expression of insulin-degrading enzyme. 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).

[0393] In some embodiments, the present invention provides a method for treating, preventing, or reducing the severity of Alzheimer's disease, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt or composition thereof.

[0394] In some embodiments, the present invention provides a method for treating diseases or conditions commonly associated with transplantation. In some embodiments, diseases or conditions commonly associated with transplantation are selected from organ transplantation, organ transplant rejection, and graft-versus-host disease.

[0395] In some embodiments, the present invention provides a method for treating metabolic diseases. In some embodiments, metabolic diseases are selected from type 1 diabetes, type 2 diabetes, metabolic syndrome, and obesity.

[0396] In some embodiments, the present invention provides a method for treating viral diseases. In some embodiments, the viral infection is an HIV infection.

[0397] 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: proliferative diseases, inflammatory diseases, obstructive respiratory diseases, cardiovascular diseases, metabolic diseases, neurological diseases, neurodegenerative diseases, viral diseases, or disorders commonly associated with transplantation. Combination therapy

[0398] Depending on the particular condition or disease to be treated, an additional therapeutic agent (commonly administered to treat that condition) can be co-administered in combination with the compounds and compositions of the present invention. As used herein, an additional therapeutic agent that is commonly administered to treat a particular disease or condition is referred to as "suitable for the disease or condition being treated".

[0399] In certain embodiments, the provided combination or its composition is co-administered in combination with another therapeutic agent.

[0400] In some embodiments, the present invention provides a method for treating the disclosed diseases or conditions, the method comprising administering to a patient in need an effective amount of a compound as 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 one or more additional therapeutic agents acts synergistically.

[0401] Examples of agents that can also be combined with the combinations of the present invention include, but are not limited to: therapeutic agents for Alzheimer's disease, such as and therapeutic agents for HIV, such as ritonavir; therapeutic agents for Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexyphenidyl, and amantadine; agents for the treatment of multiple sclerosis (MS), such as beta interferon (e.g. and ), and mitoxantrone; therapeutic agents for asthma, such as albuterol and Agents 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 anti-Parkinson's disease agents; agents for treating cardiovascular diseases, such as β-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver diseases, such as corticosteroids, cholestyramine, interferons, and antiviral agents; agents for treating blood disorders, such as corticosteroids, antileukemic agents, and growth factors; agents for prolonging or improving pharmacokinetics, such as cytochrome P450 inhibitors (i.e., metabolic breakdown inhibitors) and CYP3A4 inhibitors (e.g., ketoconazole and ritonavir), and agents for treating immunodeficiency disorders, such as gamma globulin.

[0402] In certain embodiments, the combination therapy of the present invention or a pharmaceutically acceptable composition thereof is administered in combination with a monoclonal antibody or an siRNA therapeutic agent.

[0403] These additional agents can be administered separately from the provided combination therapy as part of a multi-dose regimen. Alternatively, these agents can be part of a single dosage form, mixed together with the compounds of the present invention in a single composition. If administered as part of a multi-dose regimen, the two active agents can be administered simultaneously, sequentially, or within a certain time period (usually within five hours of each other).

[0404] As used herein, the terms "combination", "combined", and related terms refer to the administration of therapeutic agents simultaneously or sequentially in accordance with the present invention. For example, the combination of the present invention can be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form.

[0405] The amount of the additional therapeutic agent present in the composition of the present invention will not exceed the amount typically administered in a composition that contains the therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the composition disclosed by the present invention ranges from about 50% to 100% of the amount typically present in a composition that contains the agent as the sole therapeutic active agent.

[0406] One or more other therapeutic agents can be administered separately from the compounds or compositions of the present invention as part of a multi-dose regimen. Alternatively, one or more other agents can be part of a single dosage form, mixed together with the compounds of the present invention in a single composition. If administered as a multi-dose regimen, one or more other therapeutic agents and the compounds or compositions of the present invention can be administered simultaneously, sequentially, or over a period of time (e.g., within 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 apart from each other). In some embodiments, one or more other therapeutic agents and the compounds or compositions of the present invention are administered as a multi-dose regimen at intervals greater than 24 hours.

[0407] In one embodiment, the present invention provides a composition comprising the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents. The therapeutic agent can be administered together with the provided compound or a pharmaceutically acceptable salt thereof, or can be administered before or after the administration of the provided compound or a pharmaceutically acceptable salt thereof. Suitable therapeutic agents are described in further 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 the therapeutic agent. In other 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 after the therapeutic agent.

[0408] 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 the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents. Such additional therapeutic agents can be small molecules or recombinant biologics and include, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, colchicine corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., probenecid, allopurinol, febuxostat sulfasalazine antimalarials such as hydroxychloroquine and chloroquine methotrexate gold salts such as aurothioglucose aurothiomalate and auranofin D-penicillamine ( or ), azathioprine cyclophosphamide chlorambucil cyclosporine leflunomide and "anti-TNF" agents such as etanercept infliximab golimumab peginesatide and adalimumab "anti-IL-1" agents such as anakinra and rilonacept canakinumab anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab "anti-T cell" agents such as atacicept "anti-IL-6" agents such as tocilizumab diclofenac, cortisone, hyaluronic acid ( or ), monoclonal antibodies such as tanezumab, anticoagulants such as heparin ( or ) and warfarin antidiarrheal agents such as diphenoxylate and loperamide bile acid binders such as cholestyramine, alosetron lubiprostone laxatives such as milk of magnesia, polyethylene glycol and anticholinergic or antispasmodic agents such as dicyclomine β-2 agonists such as salbutamol ( HFA, HFA), levalbuterol orciprenaline pirbuterol acetate terbutaline sulfate salmeterol xinafoate and formoterol anticholinergic agents such as ipratropium bromide and tiotropium bromide inhaled corticosteroids such as beclomethasone dipropionate ( and ), triamcinolone acetonide Mometasone Budesonide and Flunisolide Sodium Cromoglycate Methylxanthines such as Theophylline and Aminophylline, IgE antibodies such as Omalizumab Nucleoside Reverse Transcriptase Inhibitors such as Zidovudine Abacavir Abacavir / Lamivudine Abacavir / Lamivudine / Zidovudine Didanosine Emtricitabine Lamivudine Lamivudine / Zidovudine Stavudine and Zalcitabine Non-Nucleoside Reverse Transcriptase Inhibitors such as Delavirdine Efavirenz Nevirapine and Etravirine Nucleotide Reverse Transcriptase Inhibitors such as Tenofovir Protease Inhibitors such as Amprenavir Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir and Ritonavir Nelfinavir Ritonavir Saquinavir( or ) and Tipranavir Entry Inhibitors such as Enfuvirtide and Maraviroc Integrase Inhibitors such as Raltegravir Doxorubicin Vincristine Bortezomib and Dexamethasone in combination with Lenalidomide or any combination.

[0409] In another embodiment, the present invention provides a method for treating gout, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, colchicine Corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., probenecid, allopurinol, and febuxostat

[0410] In another embodiment, the present invention provides a method for treating rheumatoid arthritis, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., sulfasalazine antimalarial drugs such as hydroxychloroquine and chloroquine methotrexate gold salts such as aurothioglucose aurothiomalate and auranofin D-penicillamine ( or ), azathioprine cyclophosphamide chlorambucil cyclosporine leflunomide and "anti-TNF" agents such as etanercept infliximab golimumab pegol-siltuximab and adalimumab "anti-IL-1" agents such as anakinra and rilonacept antibodies such as rituximab "anti-T cell" agents such as atacicept and "anti-IL-6" agents such as tocilizumab

[0411] In some embodiments, the present invention provides a method for treating osteoarthritis, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, diclofenac, cortisone, hyaluronic acid ( or ) and monoclonal antibodies such as tanezumab.

[0412] In some embodiments, the present invention provides a method for treating lupus, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac and celecoxib, corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., antimalarials such as hydroxychloroquine and chloroquine cyclophosphamide methotrexate azathioprine and anticoagulants such as heparin( or ) and warfarin

[0413] In some embodiments, the present invention provides a method for treating inflammatory bowel disease, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from mesalazine sulfasalazine antidiarrheal agents such as diphenoxylate and loperamide bile acid sequestrants such as cholestyramine, alosetron lubiprostone laxatives such as milk of magnesia, polyethylene glycol and and anticholinergic agents or antispasmodics such as dicyclomine anti-TNF therapy, steroids, and antibiotics such as metronidazole or ciprofloxacin.

[0414] In some embodiments, the present invention provides a method for treating asthma, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-IL-33 antibodies such as REGN3500 (SAR440340) or CNTO 7160, β-2 agonists such as albuterol( HFA, HFA), levalbuterol orciprenaline pirbuterol acetate terbutaline sulfate salmeterol xinafoate and formoterol anticholinergic agents such as ipratropium bromide and tiotropium bromide Inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate ( and ), triamcinolone acetonide mometasone budesonide flunisolide and sodium cromoglycate methylxanthines such as theophylline and aminophylline, and IgE antibodies such as omalizumab

[0415] In some embodiments, the present invention provides a method for treating COPD, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from β-2 agonists such as albuterol ( HFA, HFA), levalbuterol metaproterenol pirbuterol acetate terbutaline sulfate salmeterol xinafoate and formoterol anticholinergic agents such as ipratropium bromide and tiotropium bromide methylxanthines such as theophylline and aminophylline, inhaled corticosteroids such as prednisone, prednisolone, beclomethasone dipropionate ( and ), triamcinolone acetonide mometasone budesonide flunisolide and In some embodiments, the present invention provides a method for treating eosinophilic COPD, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-IL-33 antibodies such as REGN3500 (SAR440340) or CNTO7160. In some embodiments, the present invention provides a method for treating eosinophilic asthma, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-IL-33 antibodies such as REGN3500 (SAR440340) or CNTO 7160.

[0416] In some embodiments, the present invention provides a method for treating HIV, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from nucleoside reverse transcriptase inhibitors such as zidovudine Abacavir Abacavir / lamivudine Abacavir / lamivudine / zidovudine Didanosine Emtricitabine Lamivudine Lamivudine / zidovudine Stavudine And zalcitabine Non-nucleoside reverse transcriptase inhibitors such as delavirdine Efavirenz Nevirapine And etravirine Nucleotide reverse transcriptase inhibitors such as tenofovir Protease inhibitors such as amprenavir Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir and ritonavir Nelfinavir Ritonavir Saquinavir( Or ) and tipranavir Entry inhibitors such as enfuvirtide And maraviroc Integrase inhibitors such as raltegravir And combinations thereof.

[0417] In another embodiment, the present invention provides a method for treating hematological malignancies, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab Cyclophosphamide Doxorubicin Vincristine Prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0418] In another embodiment, the present invention provides a method of treating a solid tumor, comprising administering to a patient in need thereof a compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab Cyclophosphamide Doxorubicin Vincristine Prednisone, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and combinations thereof.

[0419] In another embodiment, the 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 an inhibitor of a Hedgehog (Hh) signaling pathway. In some embodiments, the hematological malignancy 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).

[0420] 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 compound provided herein or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab Cyclophosphamide Doxorubicin Vincristine Prednisone, hedgehog signaling inhibitors, and combinations thereof.

[0421] In some embodiments, the present invention provides a method for treating DLBCL, comprising administering to a patient in need thereof a compound provided herein or a pharmaceutically acceptable salt thereof and CHOP ( Ring Phosphamide, and Splash Nisson or Splash Nisolone) or R-CHOP (rituximab, Ring Phosphamide, and Splash Nisson or Splash Nisolone) chemotherapy regimen.

[0422] In some embodiments, the present invention provides a method for treating DLBCL, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and a rituximab / bendamustine chemotherapy regimen.

[0423] In some embodiments, the present invention provides a method for treating DLBCL, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and a BTK inhibitor (such as ibrutinib).

[0424] In some embodiments, the present invention provides a method for treating DLBCL, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and an anti-CD20 antibody (such as rituximab).

[0425] In some embodiments, the present invention provides a method for treating DLBCL, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and an anti-CD79B ADC (such as polatuzumab).

[0426] In some embodiments, the present invention provides a method for treating DLBCL, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and a BCL2 inhibitor (such as venetoclax).

[0427] In some embodiments, the present invention provides a method for treating DLBCL, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and lenalidomide or pomalidomide.

[0428] In some embodiments, the present invention provides a method for treating DLBCL, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor (such as umbralisib).

[0429] In some embodiments, the present invention provides a method for treating the T cell diseases or deficiencies described herein, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor (such as umbralisib).

[0430] In some embodiments, the present invention provides a method for treating DLBCL, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and a proteasome inhibitor (such as bortezomib).

[0431] In some embodiments, the present invention provides methods for treating the T cell diseases or deficiencies described herein, the methods comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and a proteasome inhibitor (such as bortezomib).

[0432] In another embodiment, the present invention provides methods for treating multiple myeloma, the methods comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from bortezomib and dexamethasone hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, SYK inhibitors, and lenalidomide in combination.

[0433] In another embodiment, the present invention provides methods for treating Waldenström macroglobulinemia, the methods comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from chlorambucil cyclophosphamide fludarabine cladribine rituximab hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0434] In some embodiments, one or more other therapeutic agents are antagonists of the hedgehog pathway. Approved hedgehog pathway inhibitors that can be used in the present invention include sonidegib ( Sun Pharmaceuticals); and vismodegib ( Genentech), both of which are used for the treatment of basal cell carcinoma.

[0435] In some embodiments, one or more other therapeutic agents are poly(ADP-ribose) polymerase (PARP) inhibitors. In some embodiments, the PARP inhibitors are selected from olaparib ( AstraZeneca); rucaparib ( Clovis Oncology); niraparib ( Tesaro, Inc.; talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[0436] In some embodiments, one or more other therapeutic agents are histone deacetylase (HDAC) inhibitors. In some embodiments, the HDAC inhibitor is selected from vorinostat ( Merck); romidepsin ( Celgene); panobinostat ( Novartis); belinostat ( Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide ( HBI-8000, Chipscreen Biosciences, China).

[0437] In some embodiments, one or more other therapeutic agents are CDK inhibitors, such as CDK4 / CDK6 inhibitors. In some embodiments, the CDK 4 / 6 inhibitor is selected from palbociclib ( Pfizer); ribociclib ( Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[0438] In some embodiments, one or more other therapeutic agents are folate inhibitors. Approved folate inhibitors useful in the present invention include pemetrexed ( Eli Lilly).

[0439] In some embodiments, one or more other therapeutic agents are CC chemokine receptor 4 (CCR4) inhibitors. Investigational CCR4 inhibitors useful in the present invention include mogamulizumab ( Kyowa Hakko Kirin, Japan).

[0440] In some embodiments, one or more other therapeutic agents are isocitrate dehydrogenase (IDH) inhibitors. IDH inhibitors that are being investigated and can be used in the present invention include AG120 (Celgene Corporation; NCT02677922); AG221 (Celgene Corporation, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[0441] In some embodiments, one or more other therapeutic agents are arginase inhibitors. Arginase inhibitors that are being investigated and can be used in the present invention include AEB1102 (PEGylated recombinant arginase, Aeglea Biotherapeutics), which is being investigated in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndromes (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[0442] In some embodiments, one or more other therapeutic agents are glutaminase inhibitors. Glutaminase inhibitors that are being investigated and can be used in the present invention include CB-839 (Calithera Biosciences).

[0443] In some embodiments, 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 and can be used in the present invention include rituximab ( Genentech / Biogen Idec); ofatumumab (anti-CD20, GlaxoSmithKline); obinutuzumab (anti-CD20, Genentech); ibritumomab (anti-CD20 and yttrium-90, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Janssen Biotech); dinutuximab (anti-glycolipid GD2, United Therapeutics); trastuzumab (anti-HER2, Genentech); ado-trastuzumab emtansine (anti-HER2, fused with emtansine, Genentech, Inc.); and pertuzumab (anti-HER2, Genentech, Inc.); and vedotin-brentuximab (an anti-CD30 drug conjugate, Seattle Genetics, Inc.).

[0444] In some embodiments, one or more other therapeutic agents are topoisomerase inhibitors. Approved topoisomerase inhibitors that can be used in the present invention include irinotecan ( Merrimack Pharmaceuticals, Inc.); topotecan ( GlaxoSmithKline plc). Topoisomerase inhibitors that are under investigation and can be used in the present invention include pixantrone ( CTI Biopharma Corp.).

[0445] In some embodiments, one or more other therapeutic agents are inhibitors of anti-apoptotic proteins (such as BCL-2). Approved anti-apoptotic agents that can be used in the present invention include venetoclax ( AbbVie Inc. / Genentech, Inc.); and blinatumomab ( Amgen Inc.). Other therapeutic agents that target apoptotic proteins and have been clinically tested and can be used in the present invention include navitoclax (ABT-263, Abbott Laboratories) and BCL-2 inhibitor (NCT02079740).

[0446] In some embodiments, one or more other therapeutic agents are androgen receptor inhibitors. Approved androgen receptor inhibitors that can be used in the present invention include enzalutamide ( Astellas Pharma Inc. / Medivation, Inc.); approved androgen synthesis inhibitors include abiraterone ( Centocor, Inc. / Ortho-McNeil-Janssen Pharmaceuticals, Inc.); approved gonadotropin-releasing hormone (GnRH) receptor antagonists (degarelix, Ferring Pharmaceuticals Inc.).

[0447] In some embodiments, one or more other therapeutic agents are selective estrogen receptor modulators (SERMs) that interfere with estrogen synthesis or activity. Approved SERMs that can be used in the present invention include raloxifene ( Eli Lilly and Company).

[0448] In some embodiments, one or more other therapeutic agents are bone resorption inhibitors. An approved therapeutic agent that inhibits bone resorption is denosumab ( Amgen), an antibody that binds to RANKL and prevents its binding to its receptor RANK, which is present on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, and mediates the bone pathology of solid tumors with bone metastases. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid ( Novartis).

[0449] In some embodiments, one or more other therapeutic agents are inhibitors of the interaction between two major p53 inhibitory proteins (MDMX and MDM2). Inhibitors of p53 inhibitory proteins that are being investigated for use in the present invention include ALRN-6924 (Aileron), a stapled peptide that is capable of equivalently binding to MDMX and MDM2 and disrupting the interaction between MDMX and MDM2 with p53. The efficacy of ALRN-6924 for the treatment of AML, advanced myelodysplastic syndrome (MDS), and peripheral T-cell lymphoma (PTCL) is currently being evaluated in clinical trials (NCT02909972; NCT02264613).

[0450] In some embodiments, one or more additional therapeutic agents are inhibitors of transforming growth factor-β (TGF-β or TGFβ). TGF-β protein inhibitors being studied for use in the present invention include NIS793 (Novartis), an anti-TGF-β antibody being clinically tested for its efficacy in treating various cancers, including breast cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, prostate cancer, and renal cancer (NCT 02947165). In some embodiments, the inhibitor of TGF-β protein is fresolimumab (GC1008; Sanofi-Genzyme), which is being studied 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-β decoy, as described by Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. A therapeutic compound currently in clinical trials for treating solid tumors is M7824 (Merck KgaA - formerly known as MSB0011459X), which is a bispecific anti-PD-L1 / TGFβ decoy compound (NCT02699515); and (NCT02517398). M7824 consists of a fully human IgG1 antibody against PD-L1 that is fused to the extracellular domain of the human TGF-β receptor II and serves as a TGFβ "decoy".

[0451] In some embodiments, one or more additional therapeutic agents are selected from glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) conjugated to the cytotoxic MMAE. gpNMB is a protein overexpressed in a variety of tumor types associated with the metastatic ability of cancer cells.

[0452] In some embodiments, one or more other therapeutic agents are anti-proliferative compounds. Such anti-proliferative compounds include, but are not limited to, aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce the process of cell differentiation; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-tumor antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity and additional anti-angiogenic compounds; compounds that target, reduce or inhibit protein or lipid phosphatase activity; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; anti-proliferative antibodies; heparinase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematological malignancies; compounds that target, reduce or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylamino geldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics); temozolomide Spindle kinesin inhibitors such as SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx); MEK inhibitors such as ARRY142886 (Array BioPharma), AZd6244 (AstraZeneca), PD181461 (Pfizer) and leucovorin.

[0453] In some embodiments, the present invention provides a method for treating Alzheimer's disease, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from donepezil rivastigmine galantamine tacrine memantine

[0454] In some embodiments, one or more other therapeutic agents are taxane compounds, which cause microtubule disruption, and microtubules are essential for cell division. In some embodiments, the taxane compound is selected from paclitaxel ( Bristol-Myers Squibb), docetaxel ( Sanofi-Aventis; Sun Pharmaceutical Industries, Inc., albumin-bound paclitaxel Abraxis BioScience, LLC / Celgene Corporation, cabazitaxel Sanofi-Aventis, and SID530 (SK Chemicals, Co.) (NCT00931008).

[0455] In some embodiments, one or more other therapeutic agents are nucleoside inhibitors, or agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapidly proliferating cells.

[0456] In some embodiments, the nucleoside inhibitor is selected from trabectedin (guanidine alkylating agent, Janssen Oncology), mechlorethamine (alkylating agent, Aktelion Pharmaceuticals); vincristine Eli Lilly and Company; Teva Pharmaceutical Industries Ltd.; Talon Therapeutics); temozolomide (prodrug of alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC), Merck & Co., Inc.); cytarabine injection (ara-C, antimetabolite cytidine analogue, Pfizer Inc.); lomustine (alkylating agent, Bristol-Myers Squibb Company; NextSource Biotechnology); azacitidine (pyrimidine nucleoside analogue of cytidine, Celgene Corporation); empeciclovir (cephalotaxine ester) (protein synthesis inhibitor, Teva Pharmaceutical Industries Ltd.); asparaginase Erwinia chrysanthemi (enzyme for depleting asparagine, Lundbeck; EUSA Pharma); eribulin mesylate (microtubule inhibitor, tubulin-based anti-mitotic agent, Eisai Co., Ltd.); cabazitaxel (microtubule inhibitor, tubulin-based anti-mitotic agent, Sanofi-Aventis; capacetrine (a thymidylate synthase inhibitor, Genentech; bendamustine (a bifunctional nitrogen mustard derivative that is believed to form interstrand DNA crosslinks, Cephalon / Teva; ixabepilone (a semisynthetic analogue of epothilone B, a microtubule inhibitor, a tubulin-based mitotic inhibitor, Bristol-Myers Squibb; nelarabine (a prodrug of a deoxyguanosine analogue, a nucleoside metabolism inhibitor, Novartis; clorafabine (a prodrug of a ribonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, Sanofi-Aventis; and trifluridine and tipiracil (a thymidine-based nucleoside analogue and a thymidine phosphorylase inhibitor, Taiho Oncology).

[0457] In some embodiments, 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 ( Genentech / Roche), an anti-VEGF monoclonal antibody; ramucirumab ( Eli Lilly), an anti-VEGFR-2 antibody and ziv-aflibercept, also known as VEGF Trap ( Regeneron / Sanofi). VEGFR inhibitors such as regorafenib ( Bayer); vandetanib ( AstraZeneca); axitinib ( Pfizer); and lenvatinib ( Eisai); Raf inhibitors such as sorafenib ( Bayer and Onyx); dabrafenib ( Novartis); and vemurafenib ( Genentech / Roche); MEK inhibitors such as cobimetinib ( Exelexis / Genentech / Roche); trametinib ( Novartis); Bcr-Abl tyrosine kinase inhibitors such as imatinib ( Novartis); nilotinib ( Novartis); dasatinib ( Bristol-Myers Squibb Company); bosutinib ( Pfizer Inc.); and ponatinib ( Ariad Pharmaceuticals); Her2 and EGFR inhibitors such as gefitinib ( AstraZeneca); erlotinib ( Genentech / Roche / Astellas); lapatinib ( Novartis); afatinib ( Boehringer Ingelheim); osimertinib (targeting activated EGFR, AstraZeneca); and brigatinib ( Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors such as cabozantinib ( Exelixis); and multi-kinase inhibitors such as sunitinib ( Pfizer); pazopanib ( Novartis); ALK inhibitors such as crizotinib ( Pfizer); ceritinib ( Novartis); and alectinib ( Genentech / Roche); Bruton's tyrosine kinase inhibitors such as ibrutinib ( Pharmacyclics / Janssen); and Flt3 receptor inhibitors such as midostaurin ( Novartis).

[0458] Other kinase inhibitors and VEGF-R antagonists that are being developed and can be used in the present invention include tivozanib (Aveo Pharmaceuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); chiauanib (Chiauanib) (MicroCore BioSciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); ledotinib ( IY5511, Il-Yang Pharmaceuticals, Korea); ruxolitinib ( Incyte Corporation; PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); fruquintinib (Eli Lilly and Company, GlaxoSmithKline); quizartinib (Daiichi Sankyo); and motesanib (Amgen / Takeda).

[0459] In another embodiment, the present invention provides a method of treating organ transplant rejection or graft-versus-host disease, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from the group consisting of steroids, cyclosporine, FK506, rapamycin, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0460] In another embodiment, the present invention provides a method for treating a disease or reducing the severity of a disease, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and a BTK inhibitor, wherein the disease is selected from 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, Sjogren's syndrome, multiple sclerosis, systemic sclerosis, neuroborreliosis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody 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 antibody autoimmune hemolytic anemia, Wegener's granulomatosis, psoriasis, alopecia totalis, Behçet's disease, chronic fatigue, autonomic dysfunction, membranous glomerulonephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative diseases, transplant organ or tissue rejection, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplantation, transfusion, allergic reactions, allergies (e.g., to plant pollen, latex, drugs, foods, insect venoms, animal hair, animal dander, dust mites or cockroach frass), type I hypersensitivity reactions, allergic conjunctivitis, allergic rhinitis and atopic dermatitis, asthma, appendicitis, atopic dermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, 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, tendinitis, 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 / Waldenström macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin lymphoma, Hodgkin lymphoma, plasmacytoma, extranodal marginal zone B cell 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 lymphoma / leukemia or lymphomatoid granulomatosis), breast cancer, prostate cancer or mast cell carcinoma (such as mastocytoma, mast cell leukemia, mast cell sarcoma, systemic mastocytosis), bone cancer, colorectal cancer, pancreatic cancer, bone and joint diseases (including but not limited to rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behçet's disease, Sjögren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases), thromboembolic disorders (such as myocardial infarction, angina pectoris, restenosis after angioplasty, reocclusion after angioplasty, restenosis after coronary artery bypass grafting, reocclusion after coronary artery bypass grafting, stroke, transient ischemia, peripheral arterial occlusive disorder, 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, allergy, Crohn's disease, irritable bowel syndrome, ulcerative colitis, sicca syndrome, tissue transplant rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome), alopecia areata, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolytic and thrombocytopenic states, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenström macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behçet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (such as acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0461] In another embodiment, the present invention provides a method for treating a disease or reducing the severity of a disease, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor, wherein the disease is selected from cancer, neurodegenerative disorders, angiogenesis disorders, viral diseases, autoimmune diseases, inflammatory disorders, hormone-related diseases, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver diseases, pathological immune conditions involving T cell activation, cardiovascular disorders, and CNS disorders.

[0462] In another embodiment, the present invention provides a method for treating a disease or reducing the severity of a disease, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor, wherein the disease is selected from benign or malignant tumors, cancers or solid tumors of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, urogenital tract, esophagus, larynx, skin, bone or thyroid, sarcomas, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, particularly colon cancer or colorectal adenoma or head and neck tumors, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasms, epithelioma, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma (including, for example, non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (also known as Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma or leukemia; diseases including Cowden syndrome, Lhermitte-Duclos disease and Bannayan-Zonana syndrome, or diseases in which the PI3K / PKB pathway is abnormally activated; asthma of any type or etiology, including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial 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, airway or lung diseases (COPD, COAD or COLD), including chronic bronchitis or associated dyspnea, emphysema, and exacerbation of airway hyperreactivity due to other drug therapies, particularly other inhaled drug therapies; bronchitis of any type or etiology, including but not limited to acute bronchitis, peanut aspiration bronchitis, catarrhal bronchitis, croupous bronchitis, chronic bronchitis or tuberculous bronchitis;Any type or cause of pneumoconiosis (an inflammatory, usually occupational lung disease, often associated with airway obstruction (whether chronic or acute) and caused by repeated inhalation of dust), including, for example, aluminosis, anthracosis, asbestosis, siderosis, ostrich plume pneumoconiosis, pulmonary hemosiderosis, silicosis, smutosis, and byssinosis, Löffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infections (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, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, pemphigus, epidermolysis bullosa acquisita, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose (including allergic rhinitis), and inflammatory diseases in which an autoimmune reaction is involved or which have an autoimmune component or etiology, including autoimmune hematological diseases (such as hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (such as ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior uveitis and posterior uveitis), keratoconjunctivitis sicca, and vernal keratoconjunctivitis, pulmonary interstitial fibrosis, psoriatic arthritis, and glomerulonephritis (with or without nephrotic syndrome, such as including idiopathic nephrotic syndrome or minimal change nephropathy); restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke, and congestive heart failure; Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and cerebral ischemia, and neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia.;

[0463] In some embodiments, one or more other therapeutic agents are phosphatidylinositol 3-kinase (PI3K) inhibitors. In some embodiments, the PI3K inhibitor is selected from idelalisib ( Gilead Sciences, Inc.; alpelisib (BYL719, Novartis); taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY 80-6946, Bayer); duvelisib (previously known as IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (previously known as RP5230, TG Therapeutics).

[0464] In some embodiments, the invention provides a method of treating AML, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from: FLT3 inhibitors; targeted agents such as IDH inhibitors, anti-CD33 ADCs (e.g., Mylotarg), BCL2 inhibitors, and Hedgehog inhibitors; and chemotherapy such as AraC, daunorubicin, etoposide, methotrexate, fludarabine, mitoxantrone, azacitidine, and corticosteroids.

[0465] In some embodiments, the invention provides a method of treating MDS, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from azacitidine, decitabine, and lenalidomide.

[0466] In some embodiments, the invention provides a method of treating an inflammatory skin disorder such as hidradenitis suppurativa, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-TNF drugs.

[0467] In some embodiments, the invention provides a method of treating an inflammatory skin disorder such as atopic dermatitis, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from IL-4 / IL-13 targeted agents such as dupilumab.

[0468] In some embodiments, the invention provides a method of treating an inflammatory skin disorder such as psoriasis, the method comprising administering to a patient in need thereof the provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-IL-17 and IL-23 antibodies.

[0469] Depending on the specific disorder or disease to be treated, additional therapeutic agents that are commonly administered to treat that disorder may also be present in the compositions of the invention. As used herein, additional therapeutic agents that are commonly administered to treat a specific disease or disorder are referred to as "suitable for the disease or disorder being treated".

[0470] The compounds of the invention may also advantageously be used in combination with other anti-proliferative compounds. Such anti-proliferative compounds include, but are not limited to, aromatase inhibitors; anti-estrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce the process of cell differentiation; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-tumor antimetabolites; platinum compounds; compounds that target / reduce the activity of protein or lipid kinases and additional anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadorelin agonists; anti-androgens; methionine aminopeptidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; anti-proliferative antibodies; heparinase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematological malignancies; compounds that target, reduce or inhibit the activity of Flt-3; Hsp90 inhibitors such as 17-AAG (17-allylamino geldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics); temozolomide Kinesin spindle protein inhibitors such as SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (Combina Pharmaceuticals); MEK inhibitors such as ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer) and leucovorin.

[0471] The term "aromatase inhibitor" as used herein refers to a compound that inhibits estrogen production, for example, inhibiting the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, especially atamestane, exemestane and formestane, and particularly non-steroids, especially aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is sold under the trade name Aromasin TM and formestane is sold under the trade name Lentaron TM and fadrozole is sold under the trade name Afema TMSold. Anastrozole is sold under the trade name Arimidex TM Sold. Letrozole is sold under the trade name Femara TM or Femar TM Sold. Aminoglutethimide is sold under the trade name Orimeten TM Sold. The combination of the present invention comprising a chemotherapeutic agent as an aromatase inhibitor is particularly useful for treating hormone receptor positive tumors such as breast tumors.

[0472] In some embodiments, one or more other therapeutic agents are mTOR inhibitors which inhibit cell proliferation, angiogenesis and glucose uptake. In some embodiments, the mTOR inhibitor is everolimus ( Novartis); temsirolimus ( Pfizer); and sirolimus ( Pfizer).

[0473] In some embodiments, one or more other therapeutic agents are aromatase inhibitors. In some embodiments, the aromatase inhibitor is selected from exemestane ( Pfizer); anastrozole ( AstraZeneca) and letrozole ( Novartis).

[0474] As used herein, the term "anti - estrogen" refers to a compound that antagonizes estrogen action at the estrogen receptor level. The term includes but is not limited to tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is sold under the trade name Nolvadex TM Sold. Raloxifene hydrochloride is sold under the trade name Evista TM Sold. Fulvestrant can be administered under the trade name Faslodex TM The combination of the present invention comprising a chemotherapeutic agent as an anti - estrogen is particularly useful for treating estrogen receptor positive tumors such as breast tumors.

[0475] As used herein, the term "anti - androgen" refers to any substance capable of inhibiting the biological effects of androgens and includes but is not limited to bicalutamide (Casodex TM ). As used herein, the term "gonadorelin agonist" includes but is not limited to abarelix, goserelin and goserelin acetate. Goserelin can be administered under the trade name Zoladex TM administered.

[0476] As used herein, the term "topoisomerase I inhibitor" includes but is not limited to topotecan, gemitecan, irinotecan, camptothecin and its analogs, 9 - nitro - camptothecin and the macromolecular camptothecin conjugate PNU - 166148. Irinotecan can be, for example, in its commercially available form (e.g., the trademark CamptosarTM ) Administration. Topotecan is sold under the trade name Hycamptin TM and

[0477] As used herein, the term "topoisomerase II inhibitor" includes, but is not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx TM ), daunorubicin, epirubicin, idarubicin, and nemorubicin, anthraquinones such as mitoxantrone and losoxantrone, and podophyllotoxins such as etoposide and teniposide. Etoposide is sold under the trade name Etopophos TM and TM teniposide is sold under the trade name VM 26 - Bristol, doxorubicin is sold under the trade name Acriblastin TM or TM Adriamycin TM and

[0478] The term "microtubule - active agent" refers to microtubule - stabilizing compounds, microtubule - destabilizing compounds, and tubulin polymerization inhibitors, including but not limited to taxanes such as paclitaxel and docetaxel; vinca alkaloids such as vinblastine or vinblastine sulfate, vincristine or vincristine sulfate, and vinorelbine; discodermolide; colchicine and epothilones and their derivatives. Paclitaxel is sold under the trade name Taxol TM and TM docetaxel is sold under the trade name Taxotere TM and TM vinblastine sulfate is sold under the trade name Vinblastin R.P

[0479] As used herein, the term "alkylating agent" includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosoureas (BCNU or Gliadel). Cyclophosphamide is sold under the trade name Cyclostin TM and TM ifosfamide is sold under the trade name Holoxan

[0480] The term "histone deacetylase inhibitor" or "HDAC inhibitor" refers to compounds that inhibit histone deacetylases and have antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0481] 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 folic acid antagonists (such as pemetrexed). Capecitabine is sold under the trade name Xeloda TM and gemcitabine is sold under the trade name Gemzar TM .

[0482] As used herein, the term "platinum compound" includes, but is not limited to, carboplatin, cis-platin / cisplatinum, and oxaliplatin. Carboplatin can be administered, for example, in its commercially available form (such as the trade mark Carboplat TM ). Oxaliplatin can be administered, for example, in its commercially available form (such as the trade mark Eloxatin TM ).

[0483] As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, compounds having inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, the pan-Bcl-2 inhibitor of Ascenta, curcumin (and its analogs), dual Bcl-2 / Bcl-xL inhibitors (Unrestricted Medicines / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogs; see WO 2008 / 118802, US 2010 / 0197686), navitoclax (and its analogs, see US 7,390,799), NH-1 (Shenyang Pharmaceutical University), obatoclax (and its analogs, see WO 2004 / 106328, US 2005 / 0014802), S-001 (Gloria Pharmaceuticals), TW series compounds (University of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0484] As used herein, the term "compound that targets / reduces protein or lipid kinase activity, or protein or lipid phosphatase activity; or additional anti-angiogenic compound" includes, but is not limited to, protein tyrosine kinases and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, reduce or inhibit the activity of platelet-derived growth factor receptor (PDGFR), such as compounds that target, reduce or inhibit the activity of PDGFR, especially compounds that inhibit the PDGF receptor, such as N-phenyl-2-pyrimidin-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit the activity of fibroblast growth factor receptor (FGFR); c) compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, reduce or inhibit the activity of IGF-IR, especially compounds that inhibit the kinase activity of the IGF-I receptor, or antibodies that target the extracellular domain of the IGF-I receptor or its growth factor; d) compounds that target, reduce or inhibit the activity of the Trk receptor tyrosine kinase family, or ephrin B4 inhibitors; e) compounds that target, reduce or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, reduce or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, reduce or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase (which is part of the PDGFR family), such as compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, especially compounds that inhibit the c-Kit receptor, for example imatinib; i) compounds that target, reduce or inhibit the activity of c-Abl family members, their gene fusion products (such as the BCR-Abl kinase) and mutants, such as compounds that target and reduce or inhibit the activity of c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidin-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (Parke Davis); or dasatinib (BMS-354825); j) compounds that target, reduce or inhibit the activity of protein kinase C (PKC) and Raf family members, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC family members, and / or members of the cyclin-dependent kinase family (CDK), including staurosporine derivatives, such as midostaurin; examples of additional compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine;RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531 / LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (PI3K inhibitor) or AT7519 (CDK inhibitor); k) compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors, such as compounds that target, reduce or inhibit the activity of protein tyrosine kinase inhibitors include imatinib mesylate (Gleevec; TM ) or tyrosine phosphorylation inhibitors, such as tyrosine phosphorylation inhibitor A23 / RG-50810; AG 99; tyrosine phosphorylation inhibitor AG 213; tyrosine phosphorylation inhibitor AG 1748; tyrosine phosphorylation inhibitor AG 490; tyrosine phosphorylation inhibitor B44; tyrosine phosphorylation inhibitor B44 (+) enantiomer; tyrosine phosphorylation inhibitor AG 555; AG 494; tyrosine phosphorylation inhibitors AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); l) compounds that target, reduce or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1 ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants, such as compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family are especially compounds, proteins or antibodies that inhibit members of the EGF receptor tyrosine kinase family (such as EGF receptor, ErbB2, ErbB3 and ErbB4) or bind to EGF or EGF-related ligands, CP 358774, ZD1839, ZM 105180; trastuzumab (Herceptin TM ) and cetuximab (Erbitux TM) 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; m) compounds that target, reduce or inhibit the activity of the c-Met receptor, such as compounds that target, reduce or inhibit the activity of c-Met, especially compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or bind to HGF, n) compounds that target, reduce or inhibit the kinase activity of one or more members of the JAK family (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib, and ruxolitinib; o) compounds that target, reduce or inhibit the kinase activity of PI3 kinase (PI3K), including but not limited to ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, buparlisib, pictilisib, PF-4691502, BYL-719, datolisib, XL-147, XL-765, and alpelisib; and q) compounds that target, reduce or inhibit the signal transduction of hedgehog protein (Hh) or smoothened receptor (SMO) pathway, including but not limited to cyclopamine, vismodegib, itraconazole, sonidegib, and IPI-926 (saridegib).

[0485] Compounds that target, reduce or inhibit the activity of protein or lipid phosphatases are, for example, inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or its derivatives.

[0486] In some embodiments, 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 their receptors (EGFR). Approved PDGF antagonists that can be used in the present invention include oratuzumab ( Eli Lilly and Company). Approved EGFR antagonists that can be used in the present invention include cetuximab ( Eli Lilly and Company); necitumumab ( Eli Lilly and Company), panitumumab ( Amgen Inc.); and osimertinib (targeting activated EGFR, AstraZeneca).

[0487] As used herein, the term "PI3K inhibitor" includes, but is not limited to, compounds having inhibitory activity against one or more enzymes in the phosphatidylinositol-3-kinase family, including but not limited to PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, 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, pictilisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and alisertib.

[0488] As used herein, the term "BTK inhibitor" includes, but is not limited to, compounds having inhibitory activity against Bruton's tyrosine kinase (BTK), including but not limited to AVL-292 and ibrutinib.

[0489] As used herein, the term "SYK inhibitor" includes, but is not limited to, compounds having inhibitory activity against spleen tyrosine kinase (SYK), including but not limited to PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0490] Additional examples of BTK inhibitory compounds and the disorders treatable by combination of such compounds with the compounds of the present invention can be found in WO 2008 / 039218, US 2008 / 0108636 and WO 2011 / 090760, US 2010 / 0249092, the entire contents of each of which are incorporated herein by reference.

[0491] Additional examples of SYK inhibitory compounds and the disorders treatable by combination of such compounds with the compounds of the present invention can be found in WO 2003 / 063794, US 2004 / 0029902, WO 2005 / 007623, US 2005 / 0075306, and WO 2006 / 078846, US 2006 / 0211657, the entire contents of each of which are incorporated herein by reference.

[0492] Additional examples of PI3K inhibitory compounds and disorders treatable by combinations of such compounds with the compounds of the present invention can be found in WO 2004 / 019973, US 2004 / 0106569, WO 2004 / 089925, US 2004 / 0242631, US 8,138,347, WO 2002 / 088112, US 2004 / 0116421, WO 2007 / 084786, US 2010 / 0249126, WO2007 / 129161, US 2008 / 0076768, WO 2006 / 122806, US 2008 / 0194579, WO 2005 / 113554, US2008 / 0275067, and WO 2007 / 044729, US 2010 / 0087440, the entire disclosures of each of which are incorporated herein by reference.

[0493] Additional examples of JAK inhibitory compounds and disorders treatable by combinations of such compounds with the compounds of the present invention can be found in WO 2009 / 114512, US 2009 / 0233903, WO 2008 / 109943, US 2010 / 0197671, WO2007 / 053452, US 2007 / 0191405, WO 2001 / 0142246, US 2001 / 0053782, and WO 2007 / 070514, US 2007 / 0135461, the entire disclosures of each of which are incorporated herein by reference.

[0494] Additional anti-angiogenic compounds include compounds having another mechanism of action, such as compounds not related to protein or lipid kinase inhibition, such as thalidomide (Thalomid TM ) and TNP-470.

[0495] Examples of proteasome inhibitors useful for combination with the compounds of the present invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0496] Compounds that target, reduce or inhibit the activity of protein or lipid phosphatases are, for example, inhibitors of phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or derivatives thereof.

[0497] Compounds that induce the process of cell differentiation include, but are not limited to, retinoic acid, α-, γ- or δ-tocopherol, or α-, γ- or δ-tocotrienol.

[0498] As used herein, the term cyclooxygenase inhibitor includes, but is not limited to, Cox-2 inhibitors, 5-alkyl-substituted 2-aryl aminophenylacetic acids and derivatives such as celecoxib (Celebrex TM ), rofecoxib (Vioxx TM ), etoricoxib, valdecoxib or 5-alkyl-2-aryl aminophenylacetic acids such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumicoxib.

[0499] As used herein, the term "bisphosphonate" includes, but is not limited to, etidronic acid (etridonic), clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid. Etidronic acid is sold under the trade name Didronel TM . Clodronic acid is sold under the trade name Bonefos TM . Tiludronic acid is sold under the trade name Skelid TM . Pamidronic acid is sold under the trade name Aredia TM . Alendronic acid is sold under the trade name Fosamax TM . Ibandronic acid is sold under the trade name Bondranat TM . Risedronic acid is sold under the trade name Actonel TM . Zoledronic acid is sold under the trade name Zometa TM . The term "mTOR inhibitor" refers to a compound that inhibits the mammalian target of rapamycin (mTOR) and has antiproliferative activity, such as sirolimus everolimus (Certican TM ), CCI-779 and ABT578.

[0500] As used herein, the term "heparanase inhibitor" refers to a compound that targets, reduces or inhibits the degradation of heparan sulfate. This term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to a lymphokine or interferon.

[0501] As used herein, the term "inhibitor of Ras oncogenic isoforms" (such as H-Ras, K-Ras or N-Ras) refers to a compound that targets, reduces or inhibits the oncogenic activity of Ras; for example, "farnesyltransferase inhibitors" such as L-744832, DK8G557 or R115777 (Zarnestra TM ). As used herein, the term "telomerase inhibitor" refers to a compound that targets, reduces or inhibits the activity of telomerase. Compounds that target, reduce or inhibit the activity of telomerase are especially compounds that inhibit the telomerase receptor, such as telomestatin.

[0502] As used herein, the term "methionine aminopeptidase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of methionine aminopeptidase. Compounds that target, reduce, or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0503] As used herein, the term "proteasome inhibitor" refers to a compound that targets, reduces, or inhibits the activity of the proteasome. Compounds that target, reduce, or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade TM ); carfilzomib ( Amgen); and ixazomib ( Takeda), and MLN 341.

[0504] As used herein, the term "matrix metalloproteinase inhibitor" or ("MMP" inhibitor) includes, but is not limited to, collagen peptidomimetic inhibitors 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, BAY 12-9566, TAA211, MMI270B, or AAJ996.

[0505] As used herein, the term "compound for treating hematological malignancies" includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, reduce, or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferons, 1-β-D-arabinofuranosylcytosine (ara-c), and busulfan; and ALK inhibitors, which are compounds that target, reduce, or inhibit anaplastic lymphoma kinase.

[0506] Compounds that target, reduce, or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) are particularly compounds, proteins, or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin (a staurosporine derivative), SU11248, and MLN518.

[0507] As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce, or inhibit HSP90 client proteins via the ubiquitin proteasome pathway. Compounds that target, reduce, 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) (a geldanamycin derivative); other geldanamycin-related compounds; radicicol; and HDAC inhibitors.

[0508] As used herein, the term "antiproliferative antibody" includes, but is not limited to, trastuzumab (Herceptin TM ), trastuzumab-DM1, erbitux, bevacizumab (Avastin TM ), rituximab PRO64553 (anti-CD40), and 2C4 antibody. Antibody means a complete monoclonal antibody, polyclonal antibody, multispecific antibody formed by at least two complete antibodies, and antibody fragments (as long as they exhibit the desired biological activity).

[0509] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, in particular, in combination with therapies 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 that can be used to treat AML (such as daunorubicin, doxorubicin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin, and PKC412).

[0510] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue, which is a 2'-α-hydroxyribose (cytarabine) derivative of deoxycytidine. Also included are purine analogues of hypoxanthine, 6-mercaptopurine (6-MP), and fludarabine phosphate. Compounds that target, reduce, or inhibit the activity of histone deacetylase (HDAC) inhibitors (such as sodium butyrate and suberoylanilide hydroxamic acid (SAHA)) inhibit the activity of an enzyme called histone deacetylase. Specific HDAC inhibitors include MS275, SAHA, FK228 (formerly known as FR901228), trichostatin A, and the compounds disclosed in US 6,552,065, including but not limited to 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, especially the lactate salt. As used herein, a somatostatin receptor antagonist refers to a compound that targets, treats, or inhibits a somatostatin receptor, such as octreotide and SOM230. Methods of tumor cell destruction refer to methods such as ionizing radiation. The term "ionizing radiation" as mentioned above and below means ionizing radiation in the form of electromagnetic rays (such as X-rays and γ-rays) or particles (such as α-particles and β-particles). Ionizing radiation is provided by radiotherapy, but is not limited thereto, and is well known in the art. See Hellman, Principles of Radiation Therapy, Cancer [Principles of Cancer Radiation Therapy], in Principles and Practice of Oncology [Principles and Practice of Oncology], edited by Devita et al., 4th Edition, Volume 1, pages 248-275 (1993).

[0511] Also included are EDG binders and ribonucleotide reductase inhibitors. As used herein, the term "EDG binder" refers to a class of immunosuppressive agents that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to a pyrimidine or purine nucleoside analogue, including but not limited to fludarabine and / or cytarabine (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for the treatment of ALL), and / or pentostatin. Ribonucleotide reductase inhibitors are especially hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0512] Those compounds, proteins or monoclonal antibodies that also specifically include 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 TM ; Endostatin TM ; anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or an anti-VEGF antibody or an anti-VEGF receptor antibody, such as rhuMAb and RHUFab, a VEGF aptamer such as Macugon; an FLT-4 inhibitor, an FLT-3 inhibitor, a VEGFR-2IgGI antibody, Angiozyme (RPI 4610) and bevacizumab (Avastin TM ).

[0513] As used herein, photodynamic therapy refers to a therapy for treating or preventing cancer using certain chemical substances called photosensitive compounds. Examples of photodynamic therapy include treatment with compounds such as Visudyne TM and porfimer sodium.

[0514] As used herein, an angiogenesis-inhibiting steroid refers to a compound that blocks or inhibits angiogenesis, such as anecortave acetate, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, corticosterone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone and dexamethasone.

[0515] An implant containing a corticosteroid refers to a compound, such as fluocinonide and dexamethasone.

[0516] Other chemotherapeutic compounds include, but are not limited to, alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or other compounds or compounds with other or unknown mechanisms of action.

[0517] The compounds of the present invention can also be used as co-therapeutic compounds in combination with other pharmaceutical substances, such as anti-inflammatory pharmaceutical substances, bronchodilator pharmaceutical substances or antihistamine pharmaceutical substances, in particular for the treatment of obstructive or inflammatory airway diseases (such as those mentioned above), for example as enhancers of the therapeutic activity of such drugs or as a means of reducing the required dose or potential side effects of such drugs. The compounds of the present invention can be mixed with other pharmaceutical substances in a fixed pharmaceutical composition, or can be administered separately, before, simultaneously with or after other pharmaceutical substances. Accordingly, the present invention includes combinations of the compounds of the present invention as described above with anti-inflammatory pharmaceutical substances, bronchodilator pharmaceutical substances, antihistamine pharmaceutical substances or antitussive pharmaceutical substances, the compounds of the present invention and the pharmaceutical substances being present in the same or different pharmaceutical compositions.

[0518] Suitable anti-inflammatory drugs include steroids, especially glucocorticoids, such as budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide or mometasone furoate; non-steroidal glucocorticoid receptor agonists; LTB4 antagonists, such as LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247; LTD4 antagonists, such as montelukast and zafirlukast; PDE4 inhibitors, such as cilomilast ( GlaxoSmithKline; roflumilast (Byk Gulden); V-11294A (Napp); BAY19-8004 (Bayer); SCH-351591 (Schering-Plough); arformoterol (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 β-2 adrenoceptor agonists such as albuterol / salbutamol, orciprenaline, 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 CHF 4226 (Chiesi), and glycopyrronium bromide.

[0519] Suitable antihistamine drugs include cetirizine hydrochloride, paracetamol, clemastine fumarate, promethazine, loratadine, desloratadine, diphenhydramine and fexofenadine hydrochloride, acrivastine, astemizole, azelastine, ebastine, epinastine, mizolastine and terfenadine.

[0520] Other useful combinations of the compounds of the invention are combinations with the following: chemokine receptor (e.g. 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) antagonists, especially CCR-5 antagonists such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, and 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-ammonium chloride (TAK-770).

[0521] The structure of the active compound determined by code number, common name or trade name may be taken from the actual version of the standard compilation "Merck Index" or a database such as Patents International (e.g., IMS World Publications).

[0522] The compounds of the invention may also be used in combination with known treatment procedures (such as administration of hormones or radiation). In certain embodiments, the provided compounds are used as radiosensitizers, especially for treating tumors that exhibit poor sensitivity to radiotherapy.

[0523] The compounds of the invention may be administered alone or in combination with one or more other therapeutic compounds. The possible combination therapies may take the form of a fixed combination, or the administration of the compounds of the invention and one or more other therapeutic compounds may be staggered or given independently of each other, or a combination of a fixed combination and one or more other therapeutic compounds may be administered. The compounds of the invention may additionally or alternatively be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgery, or a combination of these therapies, especially for tumor therapy. Long-term therapy and adjuvant therapy in the context of other treatment strategies are equally possible, as described above. Other possible treatments are therapies for maintaining the patient's condition after tumor regression, or even chemoprevention therapies for patients at risk, for example.

[0524] These additional agents may be administered separately from the composition containing the compound of the invention as part of a multi-dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compound of the invention in a single composition. If administered as part of a multi-dose regimen, the two active agents may be administered simultaneously, sequentially, or within a certain time period (usually within five hours of each other).

[0525] As used herein, the terms "combination", "combined" and related terms refer to the administration of therapeutic agents simultaneously or sequentially according to the invention. For example, the compounds of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms or together in a single unit dosage form. Accordingly, the invention provides a single unit dosage form comprising a compound of the invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0526] The amounts of both the compounds of the invention and the additional therapeutic agents (in those compositions that contain additional therapeutic agents as described above) that may be combined with the carrier material to produce a single dosage form will vary depending on the host being treated and the specific mode of administration. Preferably, the compositions of the invention should be formulated such that a dose of the compound of the invention between 0.01 - 100 mg / kg body weight / day can be administered.

[0527] In those compositions that include an additional therapeutic agent, the additional therapeutic agent and the compounds of the present invention can act synergistically. Accordingly, the amount of the additional therapeutic agent in such compositions will be less than the amount required for a single therapy using only that therapeutic agent. In such compositions, an additional therapeutic agent can be administered at a dose between 0.01 - 1,000 μg / kg body weight / day.

[0528] The amount of one or more other therapeutic agents present in the compositions of the present invention can be no more than the amount typically administered in a composition that includes that therapeutic agent as the sole active agent. Preferably, the amount of one or more other therapeutic agents in the compositions disclosed herein ranges from about 50% to 100% of the amount typically present in a composition that includes that agent as the sole therapeutic active agent. In some embodiments, one or more other therapeutic agents are administered at about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the typical dose of that therapeutic agent. As used herein, the phrase "normal administration" means that the amount of a therapeutic agent approved by the FDA is the dose approved according to the FDA label insert.

[0529] The compounds of the present invention or their pharmaceutical compositions can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents, and catheters. For example, vascular stents have been used to overcome restenosis (narrowing of the blood vessel wall again after injury). However, patients using stents or other implantable devices are at risk of blood clot 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 a compound of the present invention is another embodiment of the present invention. Exemplary immuno - oncology agents

[0530] In some embodiments, one or more other therapeutic agents are immuno - oncology agents. As used herein, the term "immuno - oncology agent" refers to an agent that is effective in enhancing, stimulating, and / or up - regulating the immune response of a subject. In some embodiments, the immuno - oncology agent has a synergistic effect in treating cancer when administered together with the compounds of the present invention.

[0531] Immuno - oncology agents can be, for example, small molecule drugs, antibodies, or biologics or small molecules. Examples of biologic immuno - oncology agents 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 humanized or human.

[0532] In some embodiments, the immuno - oncology agent is (i) an agonist of a stimulatory (including co - stimulatory) receptor or (ii) an antagonist of an inhibitory (including co - inhibitory) signal on T cells, both of which result in the amplification of an antigen - specific T - cell response.

[0533] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory 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 co-stimulatory or co-inhibitory receptors is the family of TNF molecules that bind to cognate TNF receptor family members, which includes 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, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0534] In some embodiments, the immuno-oncology agent 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, for stimulating an immune response.

[0535] In some embodiments, the combination of the compounds of the invention and the immuno-oncology agent can stimulate a T cell response. In some embodiments, the immuno-oncology agent 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.

[0536] In some embodiments, the immuno-oncology agent is an antagonist of an inhibitory receptor on NK cells or an agonist of an activating receptor on NK cells. In some embodiments, the immuno-oncology agent is an antagonist of KIR, such as lirilumab.

[0537] In some embodiments, the immuno-oncology agent is an agent that inhibits or eliminates macrophages or monocytes, including but not limited to CSF-1R antagonists, such as CSF-1R antagonist antibodies, including RG7155 (WO 2011 / 070024, US 2011 / 0165156, WO 2011 / 0107553, US 2012 / 0329997, WO 2011 / 131407, US 2013 / 0005949, WO2013 / 087699, US 2014 / 0336363, WO 2013 / 119716, WO 2013 / 132044, US 2014 / 0079706) or FPA-008 (WO 2011 / 140249, US 2011 / 0274683; WO 2013 / 169264; WO 2014 / 036357, US 2014 / 0079699).

[0538] In some embodiments, the immuno-oncology agent is selected from one or more agents that agonize co-stimulatory receptors, block signals through inhibitory receptors, are antagonists, and systemically increase the frequency of anti-tumor T cells, agents that overcome different immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction), eliminating or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or ex vivo anti-CD25 beads), inhibiting metabolic enzymes (such as IDO), or reversing / preventing T cell anergy or exhaustion) and agents that trigger innate immune activation and / or inflammation at the tumor site.

[0539] In some embodiments, the immuno-oncology agent 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.

[0540] In some embodiments, the immuno-oncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the immuno-oncology agent is an antibody or an 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 immuno-oncology agent can be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1, designated AMP-224.

[0541] In some embodiments, the immuno-oncology 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, US2010 / 0203056), durvalumab (MEDI4736), BMS-936559 (WO 2007 / 005874, US 2009 / 0055944), and MSB0010718C (WO 2013 / 079174, US 2014 / 0341917).

[0542] In some embodiments, the immuno-oncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, the LAG3 antibody is BMS-986016 (WO 2010 / 019570, US 2010 / 0150892, WO 2014 / 008218, US 2014 / 0093511), or IMP-731 or IMP-321 (WO 2008 / 132601, US2010 / 0233183, WO 2009 / 044273, US 2011 / 0008331).

[0543] In some embodiments, the immuno-oncology agent 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).

[0544] In some embodiments, the immuno-oncology agent 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, US 2007 / 0098719, WO 2009 / 009116, US 2009 / 0136494), or MK-4166 (WO 2011 / 028683, US 2012 / 0189639).

[0545] In some embodiments, the immuno-oncology agent is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from epacadostat (INCB024360, Incyte); indoximod (NLG-8189, NewLink Genetics Corporation); capmatinib (INC280, Novartis); GDC-0919 (Genentech / Roche); PF-06840003 (Pfizer); BMS:F001287 (Bristol-Myers Squibb); Phy906 / KD108 (Phytoceutica); Kynase (Kyn Therapeutics); and NLG-919 (WO 2009 / 073620, US 2011 / 0053941, WO 2009 / 132238, US 2011 / 0136796, WO 2011 / 056652, US 2012 / 0277217, WO 2012 / 142237, US 2014 / 0066625).

[0546] In some embodiments, the immuno-oncology agent 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.

[0547] In some embodiments, the immuno-oncology 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, US 7,501,496).

[0548] In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonistic CD40 antibody. In some embodiments, the immuno-oncology agent 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.

[0549] In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

[0550] In some embodiments, the immuno-oncology agent is MGA271 (against B7H3) (WO 2011 / 109400, US 2013 / 0149236).

[0551] In some embodiments, the immuno-oncology agent is abagovomab, adecatumumab, atorvastatin, alemtuzumab, mananamumab, aperolizumab, atezolizumab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, edostate, epratuzumab, indoximod, ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, oratumumab, pembrolizumab, pidilizumab, rituximab, tisotumab, samalizumab, or tremelimumab.

[0552] In some embodiments, the immuno-oncology agent is an immune stimulant. For example, antibodies that block the PD-1 and PD-L1 inhibitory axes can release activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in an increasing number of tumor histologies, including some tumor types that are conventionally considered insensitive to immunotherapy. See, e.g., Okazaki, T. et al. (2013) Nat. Immunol. [Nature Immunology] 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. [Science Translational Medicine] 8. The anti-PD-1 antibody nivolumab ( Bristol-Myers Squibb Company, also known as ONO-4538, MDX1106, and BMS-936558) has shown potential to improve overall survival in patients with RCC who experienced disease progression during or after prior anti-angiogenic therapy.

[0553] In some embodiments, the immunomodulatory therapeutic agent specifically induces apoptosis of tumor cells. Approved immunomodulatory therapeutic agents that can be used in the present invention include pomalidomide ( Celgene Corporation); lenalidomide ( Celgene Corporation); ingenol mebutate ( LEO Pharma A / S).

[0554] In some embodiments, the immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T ( Dendreon Corporation / Valeant Pharmaceuticals), which has been approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec ( BioVex, Inc. / Amgen Inc., previously known as T-VEC), a genetically modified oncolytic virus therapy that has been approved for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions in melanoma. In some embodiments, the immuno-oncology agent is selected from oncolytic virus therapies such as pexastimogene devacirepvec (PexaVec / JX-594, SillaJen Inc. / previously known as Jennerex Biotherapeutics), an engineered thymidine kinase- (TK-) deficient vaccinia virus that expresses GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep ( Oncolytics Biotech, a variant of a respiratory enteric orphan virus (reovirus) that cannot replicate in cells without RAS activation, for multiple 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); enadenotucirev (NG-348, PsiOxus Therapeutics, formerly known as ColoAd1), an adenovirus engineered to express a full-length CD80 and an antibody fragment specific for the T cell receptor CD3 protein, for ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax / formerly known as Oncos Therapeutics), an adenovirus engineered to express GM-CSF, for melanoma (NCT03003676); and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), a vaccinia virus engineered to express β-galactosidase (β-gal) / β-glucuronidase or β-gal / human sodium iodide symporter (hNIS), studied in the following diseases: peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, for bladder cancer (NCT02365818).

[0555] In some embodiments, the immuno-oncology agent is selected from JX-929 (Silajen, Inc. / formerly known as Generex Biotechnology Corporation), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which cytosine deaminase is capable of converting the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (TelagwaRx, Inc. / formerly known as Oncolytics Biotech, Inc.), peptide-based immunotherapeutics targeting difficult-to-treat RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated: Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP (ViraTherapeutics), a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express an antigen designed to enhance antigen-specific CD8 + T cell responses.

[0556] In some embodiments, the immuno-oncology agent is a T cell engineered to express a chimeric antigen receptor or CAR. T cells engineered to express such a chimeric antigen receptor are referred to as CAR-T cells.

[0557] A CAR has been constructed that consists of 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 intracellular domain that functions as the T cell receptor (TCR), such as the CD3-ζ signaling domain from the TCR, which is capable of generating an activation signal in T lymphocytes. Once antigen binding occurs, such CARs engage the endogenous signaling pathway in effector cells and generate an activation signal similar to that initiated by the TCR complex.

[0558] For example, in some embodiments, the CAR-T cells are one of those described in U.S. Patent 8,906,682, the entire text of which is incorporated herein by reference, which discloses CAR-T cells engineered to contain an extracellular domain having an antigen-binding domain (such as a domain that binds CD19) fused to an intracellular signaling domain of the T cell antigen receptor complex ζ chain (such as CD3ζ). When expressed in T cells, the CAR is capable of redirecting antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Over 200 clinical trials are currently underway using CAR-T for a variety of indications. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0559] In some embodiments, the immunostimulant is an activator of retinoic acid receptor-related orphan receptor γ (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of the type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells and in the differentiation of innate immune cell subsets such as NK cells that express IL-17. 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).

[0560] In some embodiments, the immunostimulant is an agonist or activator of a toll-like receptor (TLR). Suitable TLR activators include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that is being investigated for B cell lymphoma, follicular lymphoma, and other lymphomas (NCT02254772). Agonists or activators of TLR8 that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which is being investigated for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0561] Other immuno - oncology 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; lerotilumab (IPH2102 / BMS - 986015, Innate Pharma, Bristol - Myers Squibb), an anti - KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti - NKG2A monoclonal antibody; andelixizumab (GS - 5745, Gilead Sciences), an anti - MMP9 antibody; MK - 4166 (Merck & Co.), an anti - GITR monoclonal antibody.

[0562] In some embodiments, the immunostimulant is selected from elotuzumab, mifamurtide, agonists or activators of toll - like receptors, and activators of RORγt.

[0563] In some embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin - 15 (rhIL - 15). rhIL - 15 has been clinically tested as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immunostimulant 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 (IL15:sIL - 15RA) composed of a synthetic form of endogenous IL - 15 complexed with the soluble IL - 15 binding protein IL - 15 receptor alpha chain, which has been tested in a Phase 1 clinical trial 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), NCT02544724 or NCT02542124.

[0564] In some embodiments, the immuno-oncology 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, pp. 603-622, the content of which is incorporated herein by reference in its entirety. In some embodiments, the immuno-oncology agent is selected from the examples described in Table 1 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule that targets an immuno-oncology target selected from those listed in Table 2 of Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule agent selected from those listed in Table 2 of Jerry L. Adams et al.

[0565] In some embodiments, the immuno-oncology agent is selected from the small molecule immuno-oncology agents described in: Peter L. Toogood, “Small molecule immuno-oncology therapeutic agents,” Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pp. 319-329, the content of which is incorporated herein by reference in its entirety. In some embodiments, the immuno-oncology agent is an agent that targets a pathway as described by Peter L. Toogood.

[0566] In some embodiments, the immuno-oncology agent is selected from those described in: Sandra L. Ross et al., “Bispecific T cell engager antibody constructs can mediate bystander tumor cell killing ”, PLoS ONE 12(8):e0183390, the content of which is incorporated herein by reference in its entirety. In some embodiments, the immuno-oncology agent is a bispecific T cell engager antibody construct. In some embodiments, the bispecific T cell engager antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager The antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager The antibody construct activates T cells. In some embodiments, the bispecific T cell engager The antibody construct activates T cells, which release cytokines inducing upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodiments, the bispecific T cell engager The antibody construct activates T cells, resulting in induction of bystander cell lysis. In some embodiments, the bystander cells are located in a solid tumor. In some embodiments, the lysed bystander cells are close to -activated T cells. In some embodiments, the bystander cells comprise tumor-associated antigen (TAA)-negative cancer cells. In some embodiments, the bystander cells comprise EGFR-negative cancer cells. In some embodiments, the immuno-oncology agent is an antibody that blocks th...

Claims

1. A salt form of Compound 1: Selected from:

2. The salt form according to claim 1, wherein The salt form is crystalline.

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

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

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

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

7. The salt form according to claim 5, having an XRPD substantially as shown in Figure 1A.

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

9. The salt form according to claim 8, wherein, Form A of Compound 3 is characterized by one or more peaks in its XRPD pattern selected from those at 5.6, 11.5, and 16.5 ± 0.5 degrees 2-θ, ± 0.4 degrees 2-θ, ± 0.3 degrees 2-θ, or ± 0.2 degrees 2-θ.

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

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

12. The salt form according to claim 11, wherein, Form A of Compound 4 is characterized by one or more peaks in its XRPD pattern selected from those at 5.9, 11.9, and 16.5 ± 0.5 degrees 2-θ, ± 0.4 degrees 2-θ, ± 0.3 degrees 2-θ, or ± 0.2 degrees 2-θ.

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

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

15. The salt form according to claim 14, wherein, Form A of Compound 5 is characterized by one or more peaks in its XRPD pattern selected from those at 6.0, 8.2, and 12.4 ± 0.5 degrees 2-θ, ± 0.4 degrees 2-θ, ± 0.3 degrees 2-θ, or ± 0.2 degrees 2-θ.

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

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

18. The salt form according to claim 17, wherein Form A of Compound 6 is characterized by one or more peaks in its XRPD pattern selected from those at 16.5, 19.5, and 21.2 ± 0.5 degrees 2-θ, ± 0.4 degrees 2-θ, ± 0.3 degrees 2-θ, or ± 0.2 degrees 2-θ.

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

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

21. The salt form according to claim 20, wherein, Form A of Compound 7 is characterized by one or more peaks in its XRPD pattern selected from those at 6.5, 16.5, and 18.5 ± 0.5 degrees 2-θ, ± 0.4 degrees 2-θ, ± 0.3 degrees 2-θ, or ± 0.2 degrees 2-θ.

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

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

24. The salt form according to claim 23, wherein, Form A of compound 8 is characterized by one or more peaks in its XRPD pattern, said one or more peaks being selected from those at 6.5, 16.5, and 17.5 ± 0.5 degrees 2-θ, ± 0.4 degrees 2-θ, ± 0.3 degrees 2-θ, or ± 0.2 degrees 2-θ.

25. The salt form according to claim 23, which has an XRPD substantially as shown in Figure 7A.

26. The salt form according to any one of claims 1-4, wherein, The salt form is Form A of compound 9.

27. The salt form according to claim 26, wherein, Form A of compound 9 is characterized by one or more peaks in its XRPD pattern, said one or more peaks being selected from those at 6.7, 10.7, and 16.3 ± 0.5 degrees 2-θ, ± 0.4 degrees 2-θ, ± 0.3 degrees 2-θ, or ± 0.2 degrees 2-θ.

28. The salt form according to claim 26, which has an XRPD substantially as shown in Figure 8A.

29. The salt form according to any one of claims 1-4, wherein, The salt form is Form A of compound 10.

30. The salt form according to claim 29, wherein, Form A of compound 10 is characterized by one or more peaks in its XRPD pattern, said one or more peaks being selected from those at 6.0, 11.9, and 16.5 ± 0.5 degrees 2-θ, ± 0.4 degrees 2-θ, ± 0.3 degrees 2-θ, or ± 0.2 degrees 2-θ.

31. The salt form according to claim 29, which has an XRPD substantially as shown in Figure 9A.

32. The salt form according to any one of claims 1-4, wherein, The salt form is Form A of compound 11.

33. The salt form according to claim 32, wherein, Form A of compound 11 is characterized by one or more peaks in its XRPD pattern, said one or more peaks being selected from those at 6.8, 13.0, and 17.1 ± 0.5 degrees 2-θ, ± 0.4 degrees 2-θ, ± 0.3 degrees 2-θ, or ± 0.2 degrees 2-θ.

34. The salt form according to claim 32, which has an XRPD substantially as shown in Figure 10A.

35. The salt form according to any one of claims 1-4, wherein, The salt form is Form A of compound 12.

36. The salt form according to claim 35, wherein, Form A of compound 12 is characterized by one or more peaks in its XRPD pattern, said one or more peaks being selected from those at 6.5, 10.8, and 16.8 ± 0.5 degrees 2-θ, ± 0.4 degrees 2-θ, ± 0.3 degrees 2-θ, or ± 0.2 degrees 2-θ.

37. The salt form according to claim 35, which has an XRPD substantially as shown in Figure 11A.

38. The salt form according to any one of claims 1 - 4, wherein, The salt form is Form A of compound 13.

39. The salt form according to claim 38, wherein, Form A of compound 13 is characterized by one or more peaks in its XRPD pattern, said one or more peaks being selected from those at 6.0, 16.3, and 20.1 ± 0.5 degrees 2-θ, ± 0.4 degrees 2-θ, ± 0.3 degrees 2-θ, or ± 0.2 degrees 2-θ.

40. The salt form according to claim 38, which has an XRPD substantially as shown in Figure 12A.

41. The salt form according to any one of claims 1-4, wherein, The salt form is Form A of compound 14.

42. The salt form according to claim 41, wherein, Form A of compound 14 is characterized by one or more peaks in its XRPD pattern, said one or more peaks being selected from those at 6.5, 17.1, and 21.0 ± 0.5 degrees 2-θ, ± 0.4 degrees 2-θ, ± 0.3 degrees 2-θ, or ± 0.2 degrees 2-θ.

43. The salt form according to claim 41, which has an XRPD substantially as shown in Figure 13A.

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

45. The salt form according to claim 44, wherein Form A of Compound 15 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.0, 17.0, and 20.2 ± 0.5 degrees 2-theta, ± 0.4 degrees 2-theta, ± 0.3 degrees 2-theta, or ± 0.2 degrees 2-theta.

46. The salt form according to claim 44, which has an XRPD substantially as shown in Figure 14A.

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

48. The salt form according to claim 47, wherein, Form A of Compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.5, 12.9, and 16.2 ± 0.5 degrees 2-theta, ± 0.4 degrees 2-theta, ± 0.3 degrees 2-theta, or ± 0.2 degrees 2-theta.

49. The salt form according to claim 47, which has an XRPD substantially as shown in Figure 15A.

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

51. For the salt form according to claim 50, Form B of Compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.8, 11.1, and 16.5 ± 0.5 degrees 2-theta, ± 0.4 degrees 2-theta, ± 0.3 degrees 2-theta, or ± 0.2 degrees 2-theta.

52. The salt form according to claim 50, which has an XRPD substantially as shown in Figure 15A.

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

54. The salt form according to claim 53, wherein, Form C of Compound 16 is characterized by one or more peaks in its XRPD pattern, the one or more peaks being selected from those at 6.0, 11.9, and 16.0 ± 0.5 degrees 2-theta, ± 0.4 degrees 2-theta, ± 0.3 degrees 2-theta, or ± 0.2 degrees 2-theta.

55. The salt form according to claim 53, which has an XRPD substantially as shown in Figure 15A.

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

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

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

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

60. The method according to claim 59, wherein, The autoimmune or inflammatory disorder is selected from the group consisting of: ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis; allergic rhinitis, hemolytic anemia, aplastic anemia, pure red cell anemia, idiopathic thrombocytopenia or another inflammatory disease associated with an autoimmune reaction 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 another autoimmune inflammatory bowel disease, irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior uveitis and posterior uveitis), Sjogren's syndrome, vernal keratoconjunctivitis, pulmonary interstitial fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome,Optionally including idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis nephropathy, glaucoma, retinopathy, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, dyschromatosis, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic asthma, non-allergic asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma or exercise-induced asthma), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, allergic reaction, sinusitis (nasal sinusitis), silica-induced disease, COPD (reducing injury, airway inflammation, bronchial hyperreactivity, remodeling or disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataract, 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, allergy, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis (sinusitis), stomatitis, synovitis, tendinitis, tonsillitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryopyrin-associated periodic syndrome (CAPS), and osteoarthritis.,

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