Crystalline forms of IRAK degraders

Abstract

To provide: various forms, salts and compositions of compounds useful for the modulation of one or more interleukin-1 receptor-associated kinases ("IRAK") via ubiquitination and / or degradation; and uses of the same in the treatment of various diseases.SOLUTION: The present disclosure is based at least in part on the identification of a compound that modulates targeted ubiquitination of IRAK kinases and methods of using the same to treat an IRAK-mediated disease, disorder or condition in a patient in need thereof. Disclosed herein is compound 1, and salts and solid forms thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Citation of Related Applications This application claims the benefit of U.S. Provisional Application No. 63 / 034,088 (filed June 3, 2020), the contents of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present disclosure relates generally to various forms, salts, and compositions of compounds useful for modulating one or more interleukin-1 receptor-associated kinases ("IRAKs") by ubiquitination and / or degradation, and their use in the treatment of various diseases. [Background technology]

[0003] Background of the Invention The ubiquitin-proteasome pathway (UPP) is a critical pathway that regulates key regulatory proteins and degrades misfolded or abnormal proteins. The UPP is central to numerous cellular processes, and when deficient or imbalanced, it leads to the pathogenesis of various diseases. 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 facilitate the ubiquitination of various proteins in vivo, which can be divided into four families: HECT-domain E3s, U-box E3s, monomeric RING E3s, and multisubunit E3s. Generally, Li et al. (PLOS One, 2008, 3, 1487) titled "Genome-wide and functional annotation of E3s." 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)Title: "New insights into ubiquitin E3 ligase mechanism";26169771.3.BUSINESS 2 of 1812 397731-010US (170174) Deshaies et al. (Ann.Rev.Biochem.,2009,78,399-434) Title "RING domain E3 ubiquitin ligases.";Spratt et al. (Biochem.2014,458,421-437) Title "RBR E3 ubiquitin ligases:new structures, new insights, new questions."; and Wang et al. (Nat. Rev. Cancer., 2014, 14, 233-347) entitled "Roles of F-box proteins in cancer."

[0005] The UPP plays a key role in the degradation of short-lived regulatory proteins important in a variety of fundamental cellular processes, including cell cycle regulation, cell surface receptor and ion channel regulation, and antigen presentation. The pathway is involved in the pathogenesis of several forms of malignancy, several genetic diseases (including cystic fibrosis, Angelman syndrome, and Liddle syndrome), immune surveillance / viral pathogenesis, and muscle wasting. Many diseases are associated with abnormal UPP and adversely affect the regulation of cell cycle and division, cellular responses to stress and extracellular modulators, neuronal network morphogenesis, cell surface receptors, ion channels, secondary pathways, DNA repair, and organelle biogenesis.

[0006] Abnormalities in this process have recently been implicated in the pathogenesis of several diseases, both congenital and acquired. These diseases fall into two major groups: (a) diseases resulting from loss of function leading to the stabilization of specific proteins, and (b) diseases resulting from gain of function (i.e., aberrant or accelerated degradation of protein targets).

[0007] UPP is used to induce selective protein degradation, including the use of fusion proteins to artificially ubiquitinate target proteins and synthetic small molecule probes to induce proteasome-dependent degradation. Bifunctional compounds consisting of a target protein-binding ligand and an E3 ubiquitin ligase ligand induced proteasome-mediated degradation of selected proteins through recruitment to these E3 ubiquitin ligases and subsequent ubiquitination. These drug-like molecules offer the possibility of temporally controlling protein expression. Such compounds can induce the inactivation of target proteins upon addition to cells or administration to animals or humans, and may be useful as biochemical reagents and provide a new paradigm for disease treatment by removing pathogenic or oncogenic proteins (Crews C, Chemistry & Biology, 2010, 17(6):551-555; Schnnekloth JS Jr., Chembiochem, 2005, 6(1):40-46). In this field, there is a continuing need for effective treatment of diseases with poorly met medical needs, especially autoinflammatory and autoimmune diseases.However, non-specific effects and the inability to target and regulate specific classes of proteins (e.g., transcription factors) collectively remain obstacles to the development of effective anti-cancer drugs.Therefore, small molecule therapeutic agents that affect E3 ligase-mediated protein degradation and target cancer-related proteins such as interleukin-1 receptor-associated kinase ("IRAK") hold promise as therapeutic agents.Therefore, there remains a need to find compounds that are IRAK decomposers useful as therapeutic agents. [Prior art documents] [Non-patent literature]

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

[0009] Summary of the Invention It has now been discovered that novel forms of 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-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 and compositions thereof described in the present disclosure are useful modulators of, and exhibit desirable characteristics for, targeted ubiquitination of IRAK kinase. In general, the salt or free base forms, and pharmaceutically acceptable compositions thereof, are useful for treating or lessening the severity of a variety of diseases or disorders detailed herein. [Brief explanation of the drawings]

[0010] [Figure 1A] FIG. 1A shows the XRPD pattern of Form A of Compound 1.

[0011] [Figure 1B] FIG. 1B shows the FT-IR spectrum of Form A of Compound 1.

[0012] [Figure 1C] FIG. 1C shows the 1H-NMR spectrum of Form A of Compound 1.

[0013] [Figure 2A] FIG. 2A shows the XRPD pattern of Form B of Compound 1.

[0014] [Figure 2B]FIG. 2B shows the FT-IR spectrum of Form B of Compound 1.

[0015] [Figure 2C] FIG. 2C shows the 1H-NMR spectrum of Form B of Compound 1.

[0016] [Figure 3A] FIG. 3A shows the XRPD pattern of Form A of Compound 2.

[0017] [Figure 3B] FIG. 3B shows the FT-IR spectrum of Form A of Compound 2.

[0018] [Figure 3C] FIG. 3C shows the 1H-NMR spectrum of Form A of Compound 2.

[0019] [Figure 4A] FIG. 4A shows the XRPD pattern of Form A of Compound 3.

[0020] [Figure 4B] FIG. 4B shows the FT-IR spectrum of Form A of Compound 3.

[0021] [Figure 4C] FIG. 4C shows the 1H-NMR spectrum of Form A of Compound 3.

[0022] [Figure 5A] FIG. 5A shows the XRPD pattern of Form A of Compound 4.

[0023] [Figure 5B] FIG. 5B shows the FT-IR spectrum of Form A of Compound 4.

[0024] [Figure 5C] FIG. 5C shows the 1H-NMR spectrum of Form A of Compound 4. DETAILED DESCRIPTION OF THE INVENTION

[0025] Detailed Description of the Invention General Description of Certain Aspects of the Invention The present disclosure is based, at least in part, on the identification of compounds that modulate targeted ubiquitination of IRAK kinase and methods of using same to treat diseases, disorders, or conditions mediated by IRAK in patients in need thereof. Disclosed herein is Compound 1, as well as salts and solid forms thereof. [ka]

[0026] Compound 1, 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-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, is active as a modulator of targeted ubiquitination of IRAK.

[0027] It would be desirable to provide solid forms of Compound 1 (e.g., as the free base or a salt thereof) that offer characteristics such as improved water solubility, stability, and ease of formulation. Accordingly, the present disclosure provides both the free base and salt forms of Compound 1. The free base form of Compound 1

[0028] It is assumed that Compound 1 can exist in various physical forms. For example, Compound 1 can be in a solution, a suspension, or a solid form. In certain embodiments, Compound 1 is in a solid form. When Compound 1 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0029] In some embodiments, the present disclosure provides forms of Compound 1 that are substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of contaminants. Such contaminants may include different forms of Compound 1, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 1. In certain embodiments, at least about 95% by weight of one form of Compound 1 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of one form of Compound 1 is present.

[0030] According to one embodiment, a form of Compound 1 is present in an amount of at least about 97, at least about 97.5, at least about 98.0, at least about 98.5, at least about 99, at least about 99.5, or at least about 99.8 weight percent (percentages are based on the total weight of the composition). According to another embodiment, a form of Compound 1 contains less than about 3.0 area percent HPLC total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, a form of Compound 1 contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and in certain embodiments, less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0031] A structure depicted for one form of Compound 1 is also meant to encompass all tautomeric forms of Compound 1. In addition, the structure depicted herein is also meant to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure.

[0032] It has been discovered that Compound 1 can exist in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0033] As used herein, the term "polymorph" refers to the different crystalline structures in which a compound, or a salt or solvate thereof, may crystallize.

[0034] In certain embodiments, Compound 1 is a crystalline solid. In other embodiments, Compound 1 is a crystalline solid that is substantially free of amorphous Compound 1. As used herein, the term "substantially free of amorphous Compound 1" means that the compound does not contain significant amounts of amorphous Compound 1. In certain embodiments, at least about 95% by weight of crystalline Compound 1 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline Compound 1 is present.

[0035] It has been discovered that the free base Compound 1 can exist in at least two distinct polymorphic forms. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1, referred to herein as Form A. In certain embodiments, the present disclosure provides a polymorphic form of Compound 1, referred to herein as Form B.

[0036] In some embodiments, Compound 1 is amorphous. In some embodiments, Compound 1 is amorphous and substantially free of crystalline Compound 1. Compound 1 Form A

[0037] In some embodiments, Form A of Compound 1 is a form having at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 1 below. [Table 1]

[0038] In some embodiments, Form A of Compound 1 is characterized in its X-ray powder diffraction pattern by having one or more peaks selected from peaks at about 6.0, about 16.5, about 17.2, about 23.0, and about 23.9 degrees 2-theta. In some embodiments, Form A of Compound 1 is characterized in its X-ray powder diffraction pattern by having two or more peaks selected from peaks at about 6.0, about 16.5, about 17.2, about 23.0, and about 23.9 degrees 2-theta. In some embodiments, Form A of Compound 1 is characterized in its X-ray powder diffraction pattern by having three or more peaks selected from peaks at about 6.0, about 16.5, about 17.2, about 23.0, and about 23.9 degrees 2-theta. In some embodiments, Form A of Compound 1 is characterized in its X-ray powder diffraction pattern as having four or more peaks selected from peaks at about 6.0, about 16.5, about 17.2, about 23.0, and about 23.9 degrees 2-theta. In some embodiments, Form A of Compound 1 is characterized in its X-ray powder diffraction pattern as having five peaks selected from peaks at about 6.0, about 16.5, about 17.2, about 23.0, and about 23.9 degrees 2-theta. As used herein, the term "about," when used in reference to a value of degrees 2-theta, refers to the stated value ±0.2 degrees 2-theta.

[0039] In some embodiments, Form A of Compound 1 is characterized in its X-ray powder diffraction pattern by a relative intensity of each of the spectral peaks listed in Table 1 being greater than 10%, greater than 20%, greater than 30%, or greater than 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 1A.

[0040] A method for preparing Form A of Compound 1 is described below. Form B of Compound 1

[0041] In some embodiments, Form B of Compound 1 is a form having at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 2 below. [Table 2]

[0042] In some embodiments, Form B of Compound 1 is characterized in its X-ray powder diffraction pattern by having one or more peaks selected from peaks at about 3.2, about 16.2, about 16.5, about 17.1, and about 18.2 degrees 2-theta. In some embodiments, Form B of Compound 1 is characterized in its X-ray powder diffraction pattern by having two or more peaks selected from peaks at about 3.2, about 16.2, about 16.5, about 17.1, and about 18.2 degrees 2-theta. In some embodiments, Form B of Compound 1 is characterized in its X-ray powder diffraction pattern by having three or more peaks selected from peaks at about 3.2, about 16.2, about 16.5, about 17.1, and about 18.2 degrees 2-theta. In some embodiments, Form B of Compound 1 is characterized in its X-ray powder diffraction pattern by having four or more peaks selected from peaks at about 3.2, about 16.2, about 16.5, about 17.1, and about 18.2 degrees 2-theta. In some embodiments, Form B of Compound 1 is characterized in its X-ray powder diffraction pattern by having five peaks selected from peaks at about 3.2, about 16.2, about 16.5, about 17.1, and about 18.2 degrees 2-theta. In some embodiments, Form B of Compound 1 is characterized in its X-ray powder diffraction pattern by having a relative intensity of greater than 10%, greater than 20%, greater than 30%, or greater than 40% of each of the spectral peaks listed in Table 2.

[0043] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 2A.

[0044] A method for preparing Form B of Compound 1 is described below.

[0045] In some embodiments, the present disclosure provides crystalline Compound 1. [ka] In some embodiments, the present disclosure provides Compound 1 that is substantially free of amorphous Compound 1.

[0046] In some embodiments, the present disclosure provides Compound 1 that is substantially free of impurities.

[0047] In some embodiments, the present disclosure provides Compound 1 having, in its XRPD, one or more peaks selected from peaks at about 6.0, about 16.5, about 17.2, about 23.0, and about 23.9 degrees two-theta. In some such embodiments, the present disclosure provides Compound 1 having, in its XRPD, at least two peaks selected from peaks at about 6.0, about 16.5, about 17.2, about 23.0, and about 23.9 degrees two-theta. In some such embodiments, the present disclosure provides Compound 1 in Form A. In some embodiments, the present disclosure provides Compound 1 having an XRPD substantially similar to the XRPD depicted in FIG. 1A.

[0048] In some embodiments, the present disclosure provides Compound 1 having, in its XRPD, one or more peaks selected from peaks at about 3.2, about 16.2, about 16.5, about 17.1, and about 18.2 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 1 having, in its XRPD, at least two peaks selected from peaks at about 3.2, about 16.2, about 16.5, about 17.1, and about 18.2 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 1 in Form B. In some embodiments, the present disclosure provides Compound 1 having an XRPD substantially similar to the XRPD depicted in FIG. 2A.

[0049] In some embodiments, the present disclosure provides a composition comprising Compound 1 and a pharmaceutically acceptable carrier or excipient.

[0050] In some embodiments, the disclosure provides methods of modulating one or more IRAK kinases in a patient, the method comprising administering to the patient Compound 1 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades one or more IRAK kinases, thereby treating a disease, disorder, or condition associated with modulation of a signal transduction pathway involving an IRAK kinase.

[0051] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signal transduction pathway involving IRAK kinase in a patient, the method comprising administering to the patient 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 Compound 1 or a composition thereof, wherein the disease, disorder, or condition is mediated by IRAK-1, IRAK-2, and / or IRAK4. In some embodiments, the present disclosure provides a method of treating cancer in a patient, the method comprising administering to the patient Compound 1 or a composition thereof.

[0052] In some embodiments of the above-described methods, Compound 1 is Form A or Form B. In some embodiments, Compound 1 is Form A. In some embodiments, Compound 1 is Form B. Salt forms of Compound 1

[0053] In some embodiments, the acid and Compound 1 ionically bond to form one of Compounds 2-4 below. It is contemplated that Compounds 2-4 can exist in various physical forms. For example, Compounds 2-4 can be in solution, suspension, or solid form. In certain embodiments, Compounds 2-4 are in solid form. When Compounds 2-4 are in solid form, the compounds can be amorphous, crystalline, or a mixture thereof. Exemplary such solid forms of Compounds 2-4 are described in more detail below. Compound 2 (hydrochloride of Compound 1)

[0054] According to one embodiment, the present disclosure provides the hydrochloride salt of compound 1, represented by compound 2. [ka]

[0055] It will be understood by those skilled in the art that hydrochloric acid and Compound 1 ionically combine to form Compound 2. It is believed that Compound 2 can exist in various physical forms. For example, Compound 2 can be in a solution, a suspension, or a solid form. In certain embodiments, Compound 2 is in a solid form. When Compound 2 is in a 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 a form of Compound 2 that is substantially free of impurities. Such impurities or contaminants may include different forms of Compound 2, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 2. In certain embodiments, at least about 95% by weight of one form of Compound 2 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of one form of Compound 2 is present.

[0057] According to one embodiment, a form of Compound 2 is present in an amount of at least about 97, at least about 97.5, at least about 98.0, at least about 98.5, at least about 99, at least about 99.5, or at least about 99.8 weight percent (percentages are based on the total weight of the composition). According to another embodiment, a form of Compound 2 contains less than about 3.0 area percent HPLC total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, a form of Compound 2 contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and in certain embodiments, less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0058] A structure depicted for one form of Compound 2 is also meant to encompass all tautomeric forms of Compound 2. In addition, the structure depicted herein is also meant to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure.

[0059] Compound 2 has been found to be capable of existing in various 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 does not contain significant amounts of amorphous Compound 2. In certain embodiments, at least about 95% by weight of crystalline Compound 2 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline Compound 2 is present.

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

[0062] In some embodiments, Compound 2 is amorphous. In some embodiments, Compound 2 is amorphous and substantially free of crystalline Compound 2. Form A of Compound 2

[0063] In some embodiments, Form A of Compound 2 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 3 below. [Table 3]

[0064] In some embodiments, Compound 2 Form A is characterized in its X-ray powder diffraction pattern by having one or more peaks selected from peaks at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2, and about 23.3 degrees 2-theta. In some embodiments, Compound 2 Form A is characterized in its X-ray powder diffraction pattern by having two or more peaks selected from peaks at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2, and about 23.3 degrees 2-theta. In some embodiments, Compound 2 Form A is characterized in its X-ray powder diffraction pattern by having three or more peaks selected from peaks at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2, and about 23.3 degrees 2-theta. In some embodiments, Compound 2 Form A is characterized in its X-ray powder diffraction pattern by having four or more peaks selected from peaks at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2, and about 23.3 degrees 2-theta. In some embodiments, Compound 2 Form A is characterized in its X-ray powder diffraction pattern by having five or more peaks selected from peaks at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2, and about 23.3 degrees 2-theta. In some embodiments, Compound 2 Form A is characterized in its X-ray powder diffraction pattern by having six or more peaks selected from peaks at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2, and about 23.3 degrees 2-theta. In some embodiments, Form A of Compound 2 is characterized in its X-ray powder diffraction pattern as having seven peaks selected from peaks at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2, and about 23.3 degrees two-theta.

[0065] In some embodiments, Form A of Compound 2 is characterized in its X-ray powder diffraction pattern by a relative intensity of each of the spectral peaks listed in Table 3 being greater than 10%, greater than 20%, greater than 30%, or greater than 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 3A.

[0066] A method for preparing Form A of Compound 2 is described below.

[0067] In some embodiments, the present disclosure provides crystalline Compound 2 [ka] In some embodiments, the present disclosure provides Compound 2 that is substantially free of amorphous Compound 2.

[0068] In some embodiments, the present disclosure provides compound 2 that is substantially free of impurities.

[0069] In some embodiments, the disclosure provides Compound 2 having, in its XRPD, one or more peaks selected from peaks at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2, and about 23.3 degrees two-theta. In some such embodiments, the disclosure provides Compound 2 having, in its XRPD, at least two peaks selected from peaks at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2, and about 23.3 degrees two-theta. In some such embodiments, the disclosure provides Compound 2 in Form A.

[0070] In some embodiments, the present disclosure provides Compound 2 having an XRPD substantially similar to the XRPD depicted in Figure 3A.

[0071] In some embodiments, the present disclosure provides a composition comprising Compound 2 and a pharmaceutically acceptable carrier or excipient.

[0072] In some embodiments, the disclosure provides a method of modulating one or more IRAK kinases in a patient, the method comprising administering to the patient Compound 2 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades one or more IRAK kinases, thereby treating a disease, disorder, or condition associated with modulation of a signal transduction pathway involving an IRAK kinase.

[0073] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signal transduction pathway involving IRAK kinase in a patient, the method comprising administering to the patient Compound 2 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 2 or a composition thereof, wherein the disease, disorder, or condition is mediated by IRAK-1, IRAK-2, and / or IRAK4. In some embodiments, the present disclosure provides a method of treating cancer in a patient, the method comprising administering to the patient Compound 2 or a composition thereof. Compound 3 (Fumarate of Compound 1)

[0074] According to one embodiment, the present disclosure provides a fumarate salt of compound 1, represented by compound 3. [ka]

[0075] It will be understood by those skilled in the art that fumaric acid and compound 1 ionically bond to form compound 3. It is believed that compound 3 can exist in various physical forms. For example, compound 3 can be in solution, suspension, or solid form. In certain embodiments, compound 3 is in a solid form. When compound 3 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0076] In some embodiments, the present disclosure provides forms of Compound 3 that are substantially free of impurities. Such impurities or contaminants may include different forms of Compound 3, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 3. In certain embodiments, at least about 95% by weight of one form of Compound 3 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of one form of Compound 3 is present.

[0077] According to one embodiment, a form of Compound 3 is present in an amount of at least about 97, at least about 97.5, at least about 98.0, at least about 98.5, at least about 99, at least about 99.5, or at least about 99.8 weight percent (percentages are based on the total weight of the composition). According to another embodiment, a form of Compound 3 contains less than about 3.0 area percent HPLC total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, a form of Compound 3 contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and in certain embodiments, less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0078] A structure depicted for one form of compound 3 is also meant to encompass all tautomeric forms of compound 3. In addition, the structure depicted herein is also meant to encompass compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure.

[0079] It has been discovered that Compound 3 can exist in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0080] In certain embodiments, Compound 3 is a crystalline solid. In other embodiments, Compound 3 is a crystalline solid that is substantially free of amorphous Compound 3. As used herein, the term "substantially free of amorphous Compound 3" means that the compound does not contain significant amounts of amorphous Compound 3. In certain embodiments, at least about 95% by weight of crystalline Compound 3 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline Compound 3 is present.

[0081] It has been discovered that Compound 3 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 3, referred to herein as Form A.

[0082] In some embodiments, Compound 3 is amorphous. In some embodiments, Compound 3 is amorphous and substantially free of crystalline Compound 3. Form A of Compound 3

[0083] In some embodiments, Form A of Compound 3 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 4 below. [Table 4]

[0084] In some embodiments, Compound 3 Form A is characterized in its X-ray powder diffraction pattern by having one or more peaks selected from peaks at about 6.4, about 11.9, about 16.2, about 17.2, and about 20.9 degrees 2-theta. In some embodiments, Compound 3 Form A is characterized in its X-ray powder diffraction pattern by having two or more peaks selected from peaks at about 6.4, about 11.9, about 16.2, about 17.2, and about 20.9 degrees 2-theta. In some embodiments, Compound 3 Form A is characterized in its X-ray powder diffraction pattern by having three or more peaks selected from peaks at about 6.4, about 11.9, about 16.2, about 17.2, and about 20.9 degrees 2-theta. In some embodiments, Form A of Compound 3 is characterized in its X-ray powder diffraction pattern as having four or more peaks selected from peaks at about 6.4, about 11.9, about 16.2, about 17.2, and about 20.9 degrees 2-theta. In some embodiments, Form A of Compound 3 is characterized in its X-ray powder diffraction pattern as having five peaks selected from peaks at about 6.4, about 11.9, about 16.2, about 17.2, and about 20.9 degrees 2-theta.

[0085] In some embodiments, Form A of Compound 3 is characterized in its X-ray powder diffraction pattern by a relative intensity of each of the spectral peaks listed in Table 4 being greater than 10%, greater than 20%, greater than 30%, or greater than 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 4A.

[0086] A method for preparing Form A of Compound 3 is described below.

[0087] In some embodiments, the present disclosure provides crystalline Compound 3 [ka] In some embodiments, the present disclosure provides Compound 3 that is substantially free of amorphous Compound 3.

[0088] In some embodiments, the present disclosure provides compound 3 that is substantially free of impurities.

[0089] In some embodiments, the present disclosure provides Compound 3 having, in its XRPD, one or more peaks selected from peaks at about 6.4, about 11.9, about 16.2, about 17.2, and about 20.9 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 3 having, in its XRPD, at least two peaks selected from peaks at about 6.4, about 11.9, about 16.2, about 17.2, and about 20.9 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 3 in Form A.

[0090] In some embodiments, the present disclosure provides compound 3 having an XRPD substantially similar to the XRPD depicted in Figure 4A.

[0091] In some embodiments, the present disclosure provides a composition comprising Compound 3 and a pharmaceutically acceptable carrier or excipient.

[0092] In some embodiments, the disclosure provides a method of modulating one or more IRAK kinases in a patient, the method comprising administering to the patient Compound 3 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades one or more IRAK kinases, thereby treating a disease, disorder, or condition associated with modulation of a signal transduction pathway involving an IRAK kinase.

[0093] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signal transduction pathway involving IRAK kinase in a patient, the method comprising administering to the patient Compound 3 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 3 or a composition thereof, wherein the disease, disorder, or condition is mediated by IRAK-1, IRAK-2, and / or IRAK4. In some embodiments, the present disclosure provides a method of treating cancer in a patient, the method comprising administering to the patient Compound 3 or a composition thereof. Compound 4 (maleate salt of Compound 1)

[0094] According to one embodiment, the present disclosure provides a maleate salt of compound 1, represented by compound 4. [ka]

[0095] It will be understood by those skilled in the art that maleic acid and compound 1 are ionically bonded to form compound 4. It is believed that compound 4 can exist in various physical forms. For example, compound 4 can be in a solution, a suspension, or a solid form. In certain embodiments, compound 4 is in a solid form. When compound 4 is in a solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0096] In some embodiments, the present disclosure provides forms of Compound 4 that are substantially free of impurities. Such impurities or contaminants may include different forms of Compound 4, residual solvent, or any other impurities that may result from the preparation and / or isolation of Compound 4. In certain embodiments, at least about 95% by weight of one form of Compound 4 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of one form of Compound 4 is present.

[0097] According to one embodiment, a form of Compound 4 is present in an amount of at least about 97, at least about 97.5, at least about 98.0, at least about 98.5, at least about 99, at least about 99.5, or at least about 99.8 weight percent (percentages are based on the total weight of the composition). According to another embodiment, a form of Compound 4 contains less than about 3.0 area percent HPLC total organic impurities, and in certain embodiments, less than about 1.5 area percent HPLC total organic impurities, based on the total area of ​​the HPLC chromatogram. In other embodiments, a form of Compound 4 contains less than about 1.0% area percent HPLC of any single impurity, less than about 0.6 area percent HPLC of any single impurity, and in certain embodiments, less than about 0.5 area percent HPLC of any single impurity, based on the total area of ​​the HPLC chromatogram.

[0098] A structure depicted for one form of compound 4 is also meant to encompass all tautomeric forms of compound 4. In addition, the structure depicted herein is also meant to encompass compounds that differ only in the presence of one or more isotopically enriched atoms, for example, the replacement of hydrogen by deuterium or tritium, or 13 C or 14 Compounds having the present structures except for the replacement of a carbon with a C-enriched carbon are within the scope of this disclosure.

[0099] Compound 4 has been found to be capable of existing in various solid forms. Exemplary such forms include polymorphs such as those described herein.

[0100] In certain embodiments, Compound 4 is a crystalline solid. In other embodiments, Compound 4 is a crystalline solid that is substantially free of amorphous Compound 4. As used herein, the term "substantially free of amorphous Compound 4" means that the compound does not contain a significant amount of amorphous Compound 4. In certain embodiments, at least about 95% by weight of crystalline Compound 4 is present. In yet other embodiments of the present disclosure, at least about 99% by weight of crystalline Compound 4 is present.

[0101] It has been discovered that Compound 4 can exist in at least one distinct polymorphic form. In certain embodiments, the present disclosure provides a polymorphic form of Compound 4, referred to herein as Form A.

[0102] In some embodiments, Compound 4 is amorphous. In some embodiments, Compound 4 is amorphous and substantially free of crystalline Compound 4. Form A of Compound 4

[0103] In some embodiments, Form A of Compound 4 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 5 below. [Table 5]

[0104] In some embodiments, Compound 4 Form A is characterized in its X-ray powder diffraction pattern by having one or more peaks selected from peaks at about 3.3, about 6.4, and about 16.7 degrees 2-theta. In some embodiments, Compound 4 Form A is characterized in its X-ray powder diffraction pattern by having two or more peaks selected from peaks at about 3.3, about 6.4, and about 16.7 degrees 2-theta. In some embodiments, Compound 4 Form A is characterized in its X-ray powder diffraction pattern by having three peaks selected from peaks at about 3.3, about 6.4, and about 16.7 degrees 2-theta.

[0105] In some embodiments, Form A of Compound 4 is characterized in that the relative intensity of each of the spectral peaks listed in Table 5 in its X-ray powder diffraction pattern is greater than 10%, greater than 20%, greater than 30%, or greater than 40%. In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 4A.

[0106] A method for preparing Form A of Compound 4 is described below.

[0107] In some embodiments, the present disclosure provides crystalline Compound 4 [ka] In some embodiments, the present disclosure provides Compound 4 that is substantially free of amorphous Compound 4.

[0108] In some embodiments, the present disclosure provides compound 4 that is substantially free of impurities.

[0109] In some embodiments, the present disclosure provides Compound 4 having, in its XRPD, one or more peaks selected from peaks at about 3.3, about 6.4, and about 16.7 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 4 having, in its XRPD, at least two peaks selected from peaks at about 3.3, about 6.4, and about 16.7 degrees 2-theta. In some such embodiments, the present disclosure provides Compound 4 in Form A.

[0110] In some embodiments, the present disclosure provides compound 4 having an XRPD substantially similar to the XRPD depicted in Figure 5A.

[0111] In some embodiments, the present disclosure provides a composition comprising compound 4 and a pharmaceutically acceptable carrier or excipient.

[0112] In some embodiments, the disclosure provides a method of modulating one or more IRAK kinases in a patient, the method comprising administering to the patient Compound 4 or a composition thereof. In some embodiments, the method ubiquitinates and / or degrades one or more IRAK kinases, thereby treating a disease, disorder, or condition associated with modulation of a signal transduction pathway involving an IRAK kinase.

[0113] In some embodiments, the present disclosure provides a method of treating a disease, disorder, or condition associated with modulation of a signal transduction pathway involving IRAK kinase in a patient, the method comprising administering to the patient Compound 4 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 4 or a composition thereof, wherein the disease, disorder, or condition is mediated by IRAK-1, IRAK-2, and / or IRAK4. In some embodiments, the present disclosure provides a method of treating cancer in a patient, the method comprising administering to the patient Compound 4 or a composition thereof. General Method for Providing Salt Compounds

[0114] Salt compounds of general formula A encompassed by the formula, particularly salt compounds 2-4, and / or specific forms thereof, are prepared from compound 1 according to the following general scheme. [ka]

[0115] For example, each of Compounds 2-4 and forms thereof is prepared from Compound 1 by combining Compound 1 with a suitable acid to form a salt of the acid. Accordingly, another aspect of the present disclosure provides methods for preparing Compounds 2-4 and forms thereof.

[0116] As generally described above, in some embodiments, the present disclosure provides a salt compound of general formula A [ka] 1. A method for preparing compound 1 [ka] with a suitable acid and optionally a suitable solvent under conditions suitable to form a salt of formula A.

[0117] In some embodiments, the suitable acid is hydrochloric acid. In some embodiments, the present disclosure provides a method for making the hydrochloride salt of Compound 1. In certain embodiments, the hydrochloride salt of Compound 1 is Compound 2. In certain embodiments, the hydrochloride salt of Compound 1 is Form A of Compound 2.

[0118] In some embodiments, the suitable acid is fumaric acid. In some embodiments, the present disclosure provides a method for making a fumarate salt of Compound 1. In certain embodiments, the fumarate salt of Compound 1 is Compound 3. In certain embodiments, the fumarate salt of Compound 1 is Form A of Compound 3.

[0119] In some embodiments, the suitable acid is maleic acid. In some embodiments, the present disclosure provides a method for making a maleate salt of Compound 1. In certain embodiments, the maleate salt of Compound 1 is Compound 4. In certain embodiments, the maleate salt of Compound 1 is Form A of Compound 4.

[0120] A suitable solvent can be any solvent system (eg, a solvent or mixture of solvents) in which Compound 1 and / or the acid are soluble or at least partially soluble.

[0121] Examples of suitable solvents useful in the method of the present disclosure include, but are not limited to, protic solvents, aprotic solvents, polar aprotic solvents, or mixtures thereof. In certain embodiments, suitable solvents include ethers, esters, alcohols, ketones, or mixtures thereof. In some embodiments, the solvent is one or more organic alcohols. In some embodiments, the solvent is chlorinated. In some embodiments, the solvent is an aromatic solvent.

[0122] In certain embodiments, the suitable solvent is methanol, ethanol, isopropanol, or acetone, which is anhydrous or combined with water or heptane. In some embodiments, suitable solvents include tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, glyme, diglyme, methyl t-butyl ether, t-butanol, n-butanol, and acetonitrile. In some embodiments, the suitable solvent is ethanol. In some embodiments, the suitable solvent is absolute ethanol. In some embodiments, the suitable solvent is MTBE.

[0123] In some embodiments, the suitable solvent is ethyl acetate. In some embodiments, the suitable solvent is methanol. In some embodiments, the suitable solvent is methylene chloride. In some embodiments, the suitable solvent is acetonitrile. In some embodiments, the suitable solvent is isopropanol. In certain embodiments, the suitable solvent is methyl acetate, isopropyl acetate, acetone, or tetrahydrofuran. In certain embodiments, the suitable solvent is diethyl ether. In certain embodiments, the suitable solvent is water. In certain embodiments, the suitable solvent is methyl ethyl ketone. In certain embodiments, the suitable solvent is toluene.

[0124] In some embodiments, the present disclosure provides a method for preparing a salt compound of general formula A, 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. Means for removing solvent are known in the synthetic and chemical arts, including, but not limited to, any of those described herein and in the Examples.

[0125] In some embodiments, the method for preparing the salt compound of general formula A includes one or more steps of heating or cooling the preparation.

[0126] In some embodiments, the method for preparing a salt compound of general formula A includes one or more steps of stirring or agitating the preparation.

[0127] In some embodiments, the method for preparing a salt compound of general formula A includes slowly evaporating the solvent. In some embodiments, the method for preparing a salt compound of 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 of general formula A includes evaporating the solvent under a flow of inert gas, such as nitrogen gas.

[0128] In some embodiments, the method for preparing a salt compound of general formula A comprises adding a suitable acid to a solution or slurry of compound 1.

[0129] In some embodiments, the method for preparing a salt compound of general formula A comprises a heating step.

[0130] In certain embodiments, the salt compound of Formula A precipitates from the mixture. In other embodiments, the salt compound of Formula A crystallizes from the mixture. In other embodiments, the salt compound of Formula A crystallizes from the solution after seeding the solution (i.e., after adding crystals of the salt compound of Formula A to the solution).

[0131] The salt compound of Formula A can precipitate from the reaction mixture or can be produced by removing part or all of the solvent by methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption and reaction, by addition of an anti-solvent such as heptane, by cooling, or by various combinations of these methods.

[0132] As generally described above, the salt compound of formula A is optionally isolated. It will be understood that the salt compound of formula A can be isolated by any suitable physical means known to those skilled in the art. In certain embodiments, the precipitated solid salt compound of formula A is separated from the supernatant by filtration. In other embodiments, the precipitated solid salt compound of formula A is separated from the supernatant by decanting the supernatant.

[0133] In certain embodiments, the salt compound of Formula A is separated from the supernatant by filtration.

[0134] In certain embodiments, the isolated salt compound of formula A is allowed to air dry. In other embodiments, the isolated salt compound of formula A is dried under reduced pressure, optionally at elevated temperature.

[0135] 5. Use, Prescription and Administration Pharmaceutically Acceptable Compositions According to another embodiment, the present invention provides a composition comprising a compound of the present invention, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of compound in the composition of the present invention is an amount effective to measurably degrade and / or inhibit IRAK protein kinase or a mutant thereof in a biological sample or in a patient. In certain embodiments, the amount of compound in the composition of the present invention is an amount effective to measurably degrade and / or inhibit IRAK protein kinase or a mutant thereof in a biological sample or in a patient. In certain embodiments, the composition of the present invention is formulated for administration to a patient in need of such a composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0136] The term "patient", as used herein, means an animal, preferably a mammal, and most preferably a human.

[0137] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions of this invention include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, electrolytes such as salts or protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0138] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of this invention or an inhibitory or degradative active metabolite or residue thereof.

[0139] As used herein, the term "inhibitorily active metabolite or residue thereof" means that a metabolite or residue thereof is also an inhibitor of IRAK protein kinase or a mutant thereof.

[0140] As used herein, the term "degradatively active metabolite or residue thereof" means that the metabolite or residue thereof is also a degrader of IRAK protein kinase or a mutant thereof.

[0141] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0142] For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives, especially in their polyoxyethylated forms, are useful for preparing injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions or suspensions. Other commonly used surfactants, such as Tween®, Span®, and other emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0143] The pharmaceutically acceptable composition of this invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dried corn starch.When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifiers and suspending agents.If desired, certain sweeteners, flavorings or coloring agents can also be added.

[0144] Alternatively, the pharmaceutically acceptable compositions of this invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0145] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0146] Topical application for the lower intestinal tract may be in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches may also be used.

[0147] For topical application, the provided pharmaceutically acceptable composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, the provided pharmaceutically acceptable composition can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0148] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or preferably as a solution in isotonic, pH-adjusted, sterile saline, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated into an ointment such as petrolatum.

[0149] The pharmaceutically acceptable compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may be prepared as solutions in saline using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0150] Most preferably, the pharmaceutically acceptable compositions of this invention are formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of this invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of this invention are administered with food.

[0151] The amount of the compounds of the present invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, etc. Preferably, provided compositions should be formulated so that a dosage of between 0.01 and 100 mg of compound per kg of body weight per day can be administered to a patient receiving these compositions.

[0152] It should also be understood that the specific dosage and treatment regimen for any particular patient will vary depending on a variety of factors, including the activity of the specific compounds employed, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound of the invention in a composition will also vary depending on the particular compound in the composition.

[0153] Uses of the Compounds and Pharmaceutically Acceptable Compositions The compounds and compositions described herein are generally useful for degrading and / or inhibiting the kinase activity of one or more enzymes.

[0154] Examples of kinases that may be degraded and / or inhibited by the compounds and compositions described herein and for which the methods described herein are useful include those of the interleukin-1 receptor-associated kinase (IRAK) family of kinases, members of which include IRAK-1, IRAK-2, and IRAK-4, or mutants thereof. See Li et al., "IRAK-4: A novel member of the IRAK family with the properties of an IRAK-kinase," PNAS 2002, 99(8), 5567-5572; Flannery et al., "The interleukin-1 receptor-associated kinases: Critical "Regulators of innate immune signaling," Biochem Pharm 2010, 80(12), 1981-1991, which is incorporated by reference in its entirety.

[0155] The activity of compounds utilized in the present invention as degraders and / or inhibitors of IRAK-1, IRAK-2, and / or IRAK-4, or mutants thereof, can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine inhibition of either phosphorylation activity and / or the subsequent functional consequences, or the ATPase activity of activated IRAK-1, IRAK-2, and / or IRAK-4, or mutants thereof. An alternative in vitro assay quantifies the ability of an inhibitor to bind to IRAK-1, IRAK-2, and / or IRAK-4. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / IRAK-1, inhibitor / IRAK-2, or inhibitor / IRAK-4 complex, and determining the amount of bound radiolabel. Alternatively, inhibitor binding can be determined by performing comparative experiments in which new inhibitors are incubated with IRAK-1, IRAK-2, and / or IRAK-4 bound to known radioligands. Representative in vitro and in vivo assays useful for assaying IRAK-4 inhibitors include, for example, Kim et al., "A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity," J. Exp. Med. 2007, 204(5), 1025-1036; Lebakken et al., "A Fluorescence Lifetime Based Binding Assay to Characterize Kinase Inhibitors," J. Biomol. Screen. 2007, 12(6), 828-841; Maschera et al., "Overexpression of an enzymatically inactive interleukin-1-receptor-associated ``kinase activates nuclear factor-κB'', Biochem. J. 1999, 339, 227-231; Song et al., ``The kinase activities of interleukin-e receptor associated kinase(IRAK)-1 and 4 are "Redundant in the control of inflammatory cytokine expression in human cells," Mol. Immunol. 2009, 46, 1458-1466, each of which is incorporated herein by reference in its entirety. Detailed conditions for assaying the compounds utilized in the present invention as degraders and / or inhibitors of IRAK-1, IRAK-2, and / or IRAK-4, or mutants thereof, are described in the Examples below.

[0156] The best-characterized member of the IRAK family is the serine / threonine kinase IRAK-4, which is involved in innate immune responses signaled by Toll-like receptors (TLRs) and Toll / IL-1 receptors (TIRs).

[0157] Innate immunity detects pathogens by recognizing pathogen-associated molecular patterns through TLRs, which then lead to adaptive immune responses. TLRs recognize the conserved structures of both microorganisms 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 in intracellular membranes, such as endosomes and phagosomes. Cell surface TLRs can be treated with small molecules and antibodies, while intracellular TLRs require treatment with oligonucleotides.

[0158] TLRs mediate innate immune responses by upregulating the expression of inflammatory genes in multiple target cells. See, e.g., Sen et al., "Transcriptional signaling by double-stranded RNA: role of TLR3," Cytokine & Growth Factor Rev. 2005, 16, 1-14, the entire contents of which are incorporated herein by reference. While TLR-mediated inflammatory responses are important for innate immunity and host defense against infection, uncontrolled inflammation is harmful to the host, leading to sepsis and chronic inflammatory diseases such as chronic arthritis, atherosclerosis, multiple sclerosis, cancer, autoimmune disorders (e.g., rheumatoid arthritis, lupus, asthma, psoriasis, and inflammatory bowel disease).

[0159] Upon ligand binding, most TLRs recruit the adaptor molecule MyD88 via their TIR domains to mediate MyD88-dependent pathways. MyD88 then recruits IRAK-4, which engages the nuclear factor-κB (NF-κB), mitogen-activated protein (MAP) kinase, and interferon regulatory factor (IL-4) cascades, resulting in the induction of proinflammatory cytokines. NF-κB activation results in the induction of inflammatory cytokines and chemokines, such as TNF-α, IL-1α, IL-6, and IL-8. The kinase activity of IRAK-4 has been shown to play an important role in TLR-mediated immune and inflammatory responses. IRAK4 is a key mediator of the innate immune response orchestrated by interleukin-1 receptor (IL-1R), interleukin-18 receptor (IL-18R), IL-33 receptor (IL-33R), and Toll-like receptors (TLRs). Inactivation of IRAK-1 and / or IRAK-4 activity has been shown to result in reduced cytokine and chemokine production in response to IL-1 and TLR ligand stimulation.For example, Picard et al., "Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency", Medicine (Baltimore), 2010, 89(6), 043-25; Li, "IRAK4 in TLR / IL-1R signaling: Possible clinical applications", Eur. J. 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. 2010, 80(12), 1981-1991; Gottipati et al., "IRAK1: A critical signaling mediator of innate immunity", Cellular Signaling 2008, 20, 269-276; Kim et. al.,「A critical role for IRAK4 kinase activity in Toll-like receptor-mediated innate immunity」,J.Exp.Med.2007 204(5),1025-1036;Koziczak-Holbro et al.,「IRAK-4 Kinase Activity Is Required for Interleukin-1(IL-1)Receptor- and Toll-like Receptor 7-mediated Signaling and Gene Expression」,J.Biol.Chem.2007,282(18),13552-13560;Kubo-Murai et al.,「IRAK-4-dependent Degradation of IRAK-1 is a Negative Feedback Signal for TLR-mediated NF-κB Activation」,J.Biochem.2008,143,295-302;Maschera et al., “Overexpression of an enzymatically inactive interleukin-1-receptor-associated kinase activates nuclear factor-κB”, Biochem. J. 1999, 339, 227-231; Lin et al., “Helical assembly in the MyD88-IRAK4-IRAK2 complex in TLR / IL-1R signaling”, 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 signaling in mice lacking IRAK-4",Nature 2002,416,750-754; Swantek et al., “IL-1 See, for example, "Receptor-Associated Kinase Modulates Host Responsiveness to Endotoxin," J. Immunol. 2000, 164, 4301-4306; Hennessy, E., et al., "Targeting Toll-like receptors: emerging therapeutics?" Nature Reviews, vol. 9, pp: 293-307 (2010); Dinarello, C., "Interleukin-18 and the Pathogenesis of Inflammatory Diseases," Seminars in Nephrology, vol. 27, no. 1, pp: 98-114 (2007). Each of these is incorporated herein by reference in its entirety. Indeed, knockdown mice expressing a catalytically inactive mutant IRAK-4 protein are completely resistant to septic shock and exhibit impaired IL-1 activity.Furthermore, these mice are resistant to joint and bone inflammation / destruction in arthritis models, suggesting that IRAK-4 may be a target for treating chronic inflammation. Furthermore, IRAK-4 appears to be essential for childhood immunity to several pyogenic bacteria, but has been shown to play a redundant role in protective immunity against most infections in adults, as demonstrated by studies in which older patients lacking IRAK-4 activity did not develop invasive infections. Cohen et al., "Targeting protein." "kinases for the development of anti-inflammatory drugs",Curr.Opin.Cell Bio.2009,21:317-324;Ku et al.,"Selective predisposition to bacterial infections in IRAK-4-deficient children:IRAK-4-dependent TLRs are otherwise redundant in protective immunity", J.Exp.Med.2007,204(10),2407-2422;Picard et al.,"Inherited human IRAK-4 deficiency:an update",Immunol.Res.2007,38,347-352;Song et al.,"The kinase activities of interleukin-e receptor associated kinase(IRAK)-1 and 4 are redundant in the control of ``inflammatory cytokine expression in human cells'', Mol. Immunol. 2009, 46, 1458-1466; Rokosz, L. et al., ``Kinase inhibitors as drugs for chronic inflammatory and immunological diseases: progress and challenges,” Expert Opinions on Therapeutic Targets, 12(7), pp:883-903 (2008); Gearing, A., “Targeting toll-like receptors for drug development: a summary of commercial approaches,” Immunology and Cell Biology, 85, pp:490-494 (2007); Dinarello, C., “IL-1: Discoveries, controversies and future directions,” European Journal of Immunology, 40, pp:595-653 (2010), each of which is incorporated by reference in its entirety. Because TLR activation induces IRAK-4 kinase activity, IRAK-4 inhibition presents an attractive target for treating the underlying causes of inflammation in a myriad of diseases.

[0160] Representative IRAK-4 inhibitors include, for example, those described in Buckley et al., Bioorg.Med.Chem.Lett. 2008, 18, 3211-3214; Buckley et al., Bioorg.Med.Chem.Lett. 2008, 18, 3291-3295; Buckley et al., Bioorg.Med.Chem.Lett. 2008, 18, 3656-3660; Powers et al., "Discovery and initial SAR of inhibitors of interleukin-1 receptor-associated kinase-4," Bioorg.Med.Chem.Lett. 2006, 16, 2842-2845; Wng et al., "IRAK-4 Inhibitors for Inflammation," Curr. Topics in Med. Chem. 2009, 9, 724-737, each of which is incorporated herein by reference in its entirety.

[0161] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of the symptoms and / or taking into account genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, e.g., to prevent or delay the recurrence of the symptoms.

[0162] The provided compounds are degraders and / or inhibitors of one or more of IRAK-1, IRAK-2, and / or IRAK-4, and are therefore useful for treating one or more disorders associated with the activity of one or more of IRAK-1, IRAK-2, and / or IRAK-4. Accordingly, in certain embodiments, the present invention provides methods for treating an IRAK-1-mediated, IRAK-2-mediated, and / or IRAK-4-mediated disorder, comprising administering to a patient in need thereof a compound of the present invention, or a pharmaceutically acceptable composition thereof.

[0163] As used herein, the terms "IRAK-1-mediated," "IRAK-2-mediated," and / or "IRAK-4-mediated" disorders, diseases, and / or conditions refer to any disease or other deleterious condition in which IRAK-1, IRAK-2, and / or IRAK-4, or one or more mutants thereof, are known to play a role. Accordingly, another embodiment of the present invention relates to treating or lessening the severity of one or more diseases in which IRAK-1, IRAK-2, and / or IRAK-4, or one or more mutants thereof, are known to play a role.

[0164] In some embodiments, the present invention provides methods for treating one or more disorders, diseases, and / or conditions, wherein the disorder, disease, or condition is cancer, a neurodegenerative disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a genetic disorder, a hormone-related disease, a metabolic disorder, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, a liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, or a CNS disorder.

[0165] Diseases and conditions treatable by the methods of the present invention include cancer (see, for example, Ngo, V. et al., "Oncogenically active MYD88 mutations in human lymphoma," Nature, vol. 000, pp: 1-7 (2010); Lust, J. et al., "Induction of a Chronic Disease State in patients With Smoldering of Indolent Multiple Myeloma by Targeting Interleukin 1β-Induced Interleukin 6 Production and the Myeloma Proliferative Component," Mayo Clinic Proceedings, 84(2), pp: 114-122 (2009)), diabetes, cardiovascular disease, viral disease, autoimmune disease, such as lupus (see, for example, Dinarello, C. "Interleukin-18 and the Pathogenesis of Inflammatory Diseases," Seminars in Nephrology, vol. 27, no. 1, pp: 98-114 (2007); Cohen et al., "Targeting protein kinases for the development of anti-inflammatory drugs", Curr. Opin. Cell Bio. 2009, 21: 317-324) and rheumatoid arthritis (see, e.g., Geyer, M. et al., "Actual status of antiinterleukin-1 therapies in rheumatic diseases", Current Opinion in Rheumatology, 22, pp: 246-251 (2010)), autoinflammatory syndromes (see, e.g., Hoffman, H. et al., "Efficacy and Safety of Rilonacept (Interleukin-1 Trap) in Patients with Cryopyrin-Associated Periodic Syndromes," Arthritis & Rheumatism, vol. 58, no. 8, pp: 2443-2452 (2008)), atherosclerosis, psoriasis, allergic disorders, inflammatory bowel disease (see, e.g., Cario, E. "Therapeutic Impact of Toll-Like Receptors on Inflammatory Bowel Diseases: A Multiple-Edged Sword," Inflamm. Bowel Dis., 14, pp: 411-421 (2008)), inflammation (see, e.g., Dinarello, C. "Interleukin 1 and Interleukin 18 as Mediators of Inflammation and the Aging Process," The American Journal of Clinical Nutrition, 83, pp:447S-455S (2006)), acute and chronic gout and gouty arthritis (see, for example, Terkeltaub, R. "Update on gout: new therapeutic strategies and options", Nature, vol. 6, pp:30-38 (2010); Weaver, A. "Epidemiology of gout", Cleveland Clinic Journal of Medicine, vol. 75, suppl. 5, pp:S9-S12 (2008); Dalbeth, N. et al., "Hyperuricemia and gout: state of the art and future perspectives", Annals of Rheumatic Diseases, 69, pp:1738-1743 (2010); Martinon, F. et al., "Gout-associated uric acid crystals activate. the NALP3 inflammasome", Nature, vol. 440, pp: 237-241 (2006); So, A. et al., "A pilot study of IL-1 inhibition by anakinra in acute gout", Arthritis Research & Therapy, vol. 9, no. 2, pp: 1-6 (2007); Terkeltaub, R. et al., "The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study", Annals of Rheumatic Diseases, 68, pp: 1613-1617 (2009); Torres, R. et al., "Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis,” Annals of Rheumatic Diseases, 68, pp:1602-1608 (2009)), neurological disorders, metabolic syndrome (see, e.g., Troseid, M. “The role of interleukin-18 in the metabolic syndrome,” Cardiovascular Diabetology, 9:11, pp:1-8 (2010)), immunodeficiency disorders such as AIDS and HIV (see, e.g., Iannello, A. et al., “Role of Interleukin-18 in the Development and Pathogenesis of AIDS,” AIDS Reviews, 11, pp:115-125 (2009)), destructive bone disorders (see, e.g., Hennessy, E., et al., “Targeting Toll-like receptors: emerging therapeutics?” Nature Reviews, vol. 9, pp:293-307 (2010)), osteoarthritis, proliferative disorders, Waldenstrom's macroglobulinemia (see, e.g., Treon, et al., “Targeting Toll-like receptors: emerging therapeutics?” Nature Reviews, vol. 9, pp:293-307 (2010)), al., “Whole genome sequencing reveals a widely expressed mutation (MYD88 L265P) with oncogenic activity in Waldenstroem's Macroglobulinemia” 53 rd ASH Annual Meeting;Xu, et al., “A somatic variant in MYD88(L256P) revealed by whole genome sequencing differentiates lymphoplasmacytic lymphoma from marginal zone lymphomas” 53 rd ASH Annual Meeting; Yang et al., “Disruption of MYD88 pathway signaling leads to loss of constitutive IRAK1,NK-kB and JAK / STAT signaling and induces apoptosis of cells expressing the MYD88 L265P mutation in Waldenstroem's Macrobulinemia"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 rd See ASH Annual Meeting; including, but not limited to, infectious diseases, conditions associated with cell death, pathological immune conditions involving T cell activation, and CNS disorders. In one embodiment, a human patient is treated with a compound of the invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein the compound is present in an amount that measurably degrades and / or inhibits the activity of IRAK-1 alone, IRAK-2 alone, IRAK-4 alone, and / or IRAK1 and IRAK4 kinases.

[0166] The compounds of the present invention may be used to treat benign or malignant tumors, carcinomas or solid tumors of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone or thyroid gland, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, in particular colon cancer or colorectal adenoma, head and neck tumors, epidermal hyperproliferation, psoriasis, benign prostatic hyperplasia, neoplasia of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's or non-Hodgkin's, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 driven disorders and / or a proliferative disorder selected from MyD88-driven disorder, MyD88-driven disorder, smoldering indolent multiple myeloma, or a hematological malignancy including leukemia, diffuse large B-cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, AML, MDS.

[0167] In some embodiments, the proliferative disease treatable by the methods of the present invention is a MyD88-driven disorder, hi some embodiments, the MyD88-driven disorder treatable by the methods of the present invention is selected from ABC DLBCL, primary CNS lymphoma, primary extranodal lymphoma, Waldenstrom's macroglobulinemia, Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, and chronic lymphocytic leukemia.

[0168] In some embodiments, the proliferative disease that can be treated by the methods of the present invention is an IL-1-driven disorder, hi some embodiments, the IL-1-driven disorder is smoldering multiple myeloma.

[0169] The compounds according to the present invention are useful in the treatment of inflammatory or obstructive airway diseases, for example, by reducing tissue damage, airway inflammation, bronchial hyperactivity, remodeling or disease progression.The inflammatory or obstructive airway diseases to which the present invention is applicable include asthma of any type or origin, including both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection.Treatment of asthma can also be understood as embracing treatment of subjects (for example, those diagnosed or capable of being diagnosed with "wheezing infants" (an established patient category of major medical problems, currently often identified as early or early stage asthma) who show symptoms of wheezing, under the age of 4 or 5 years.

[0170] The compounds according to the present invention are useful in treating heteroimmune diseases. Examples of such heteroimmune diseases include, but are not limited to, graft-versus-host disease, transplantation, blood transfusion, anaphylaxis, allergy (e.g., allergy to plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, house dust mite, or cockroach calyx), type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0171] Prophylactic efficacy in the treatment of asthma is evidenced, for example, by reduced frequency or severity of symptomatic attacks of acute asthma or bronchoconstriction attacks, improved lung function, or improved airway hyperactivity. This may further be evidenced by a reduced need for other symptomatic treatments (e.g., treatments intended to limit or stop symptomatic attacks when they occur, such as anti-inflammatory or bronchodilation therapies). The benefit of prophylaxis in asthma may be particularly evident in subjects prone to "morning depression." "Morning depression" is a recognized symptom of asthma, common to a significant proportion of asthmatics, and characterized by an asthma attack, for example, between 4:00 and 6:00 a.m., i.e., a time usually well removed from any previously administered symptomatic asthma treatment.

[0172] The compounds of the present invention can be used for other inflammatory or obstructive airway diseases and conditions to which the present invention is applicable, including acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD, COAD, or COLD) (including associated chronic bronchitis or dyspnea), emphysema, and exacerbations of airway hyperactivity as a result of other medications (especially other inhaled medications). The present invention is also applicable to the treatment of bronchitis of any type or onset, including, but not limited to, acute, arachidic, keratoconjunctivitis, croupus, chronic, or tuberculous bronchitis. Further inflammatory or obstructive airway diseases to which the present invention is applicable include pneumoconiosis (an inflammatory, generally occupational lung disease, whether chronic or acute, frequently associated with airway obstruction and caused by repeated inhalation of dust) of any type or occurrence, including, for example, aluminum lung disease, anthracosis, asbestosis, stone disease, ptilosis, siderosis, silicosis, tabacosis and byssinosis.

[0173] With regard to their anti-inflammatory activity, particularly with respect to eosinophil activation, the compounds of the present invention are also useful in the treatment of eosinophil-associated disorders, such as eosinophilia, particularly eosinophil-associated disorders of the airways (e.g., involving pathological eosinophil infiltration of lung tissue), including hypereosinophilia affecting the airways and / or lungs, as well as eosinophil-associated disorders of the airways resulting from or associated with, for example, Loffler's syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, eosinophilic asthma, eosinophilic COPD, and eosinophil-associated disorders affecting the airways caused by drug reactions.

[0174] The compounds of the invention are also useful in the treatment of inflammatory or allergic conditions of the skin, such as psoriasis, generalized pustular psoriasis (GPP), psoriasis vulgaris, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, hidradenitis suppurativa, Sweet's syndrome, pyoderma gangrenosum, and other inflammatory or allergic conditions of the skin.

[0175] The compounds of the invention may also be used in the treatment of other diseases or conditions, for example, diseases or conditions which have an inflammatory component, for example, diseases and conditions of the eye such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose including allergic rhinitis, and inflammatory diseases which involve an autoimmune response or have an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, red blood 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 diseases (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary hyaline membrane disease, renal disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, alveolar osteitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (e.g., idiopathic nephrotic syndrome or minimal change nephropathy), Nephrotic syndrome (with or without nephrotic syndrome, including nephrotic change nephropathy), chronic granulomatous disease, endometriosis, leptospirosisRenal disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hyperchlolesterolemia, heart disease, chronic heart failure, mesothelioma, ahidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, ocular allergies, silica-induced disease, COPD (reduction of damage, airway inflammation, bronchial hyperactivity, remodeling, or disease progression), pulmonary disease, cystic fibrosis , acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection Diarrhea, 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 abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis It can be used to treat myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0176] 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 disease of the skin is selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, hidradenitis suppurativa, and other inflammatory or allergic conditions of the skin.

[0177] In some embodiments, the inflammatory disease that can be treated by the methods of this invention is 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.

[0178] In some embodiments, the inflammatory disease that can be treated by the methods of this invention is a TH17-mediated disease, hi some embodiments, the TH17-mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, psoriasis vulgaris, hidradenitis suppurativa, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0179] In some embodiments, the inflammatory disease that can be treated by the methods of this invention is selected from Sjogren's syndrome, allergic disorders, osteoarthritis, ocular allergies, eye conditions such as conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, and diseases affecting the nose such as allergic rhinitis or chronic rhinosinusitis with nasal polyps (CRSwNP).

[0180] In some embodiments, the present invention provides methods for treating TLR / IL-1R-induced autoinflammatory and autoimmune diseases, such as hidradenitis suppurativa, atopic dermatitis, and rheumatoid arthritis, for which there is a significant unmet medical need. Accordingly, in some embodiments, the present invention provides a method for treating hidradenitis suppurativa in a patient in need thereof, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method for treating atopic dermatitis in a patient in need thereof, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method for treating rheumatoid arthritis in a patient in need thereof, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0181] Cardiovascular diseases that may 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 pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disease, pulmonary embolism, and deep vein thrombosis.

[0182] In some embodiments, neurodegenerative diseases that may be treated according to the methods of the present invention include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative diseases caused by trauma, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation, and graft-versus-host disease.

[0183] Loss of IRAK4 function resulted in reduced Aβ levels in an in vivo mouse model of Alzheimer's disease and was associated with reduced microgliosis and astrogliosis in aging mice. Analysis of microglia isolated from adult mouse brains revealed altered patterns of gene expression associated with altered microglial phenotypes, which are associated with the expression of IRF transcription factors that govern microglial phenotype. Furthermore, loss of IRAK4 function also promoted amyloid clearance mechanisms, including increased expression of insulin-degrading enzymes. Finally, blocking IRAK function restored olfactory behavior (Cameron et al., "Loss of Interleukin Receptor-Associated Kinase 4 Signaling Suppresses Amyloid Pathology and Alters Microglial Phenotype in a Mouse Model of Alzheimer's Disease," Journal of Neuroscience (2012) 32(43), 15112-15123).

[0184] In some embodiments, the present invention provides a method of treating, preventing, or lessening the severity of Alzheimer's disease, comprising administering to a patient in need thereof a provided compound, or a pharmaceutically acceptable salt or composition thereof.

[0185] In some embodiments, the present invention provides methods of treating disease conditions commonly associated with transplantation, in some embodiments, the disease or condition commonly associated with transplantation is selected from organ transplantation, organ graft rejection, and graft-versus-host disease.

[0186] In some embodiments, the present invention provides methods of treating a metabolic disorder, in some embodiments, the metabolic disorder is selected from type 1 diabetes, type 2 diabetes, metabolic syndrome, and obesity.

[0187] In some embodiments, the present invention provides a method of treating a viral disease, hi some embodiments, the viral infection is an HIV infection.

[0188] Furthermore, the present invention provides the use of a compound as defined herein, or a pharmaceutically acceptable salt, or hydrate or solvate thereof, for the preparation of a medicament for the treatment of a proliferative disease, an inflammatory disease, an obstructive respiratory disease, a cardiovascular disease, a metabolic disorder, a neurological disease, a neurodegenerative disease, a viral disease, or a disorder commonly occurring in association with transplantation.

[0189] Combination therapy Depending on the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, can be administered in combination with the compounds and compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0190] In certain embodiments, the provided combinations, or compositions thereof, are administered in combination with another therapeutic agent.

[0191] In some embodiments, the present invention provides a method of treating a disclosed disease or condition, comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and simultaneously or sequentially co-administering an effective amount of one or more additional therapeutic agents, such as those described herein. In some embodiments, the method comprises co-administering one additional therapeutic agent. In some embodiments, the method comprises co-administering two additional therapeutic agents. In some embodiments, the combination of a disclosed compound and an additional therapeutic agent(s) acts synergistically.

[0192] Examples of drugs with which the combinations of this invention may be combined include, but are not limited to: drugs for treating Alzheimer's disease, such as Aricept® and Excelon®; drugs for treating HIV, such as ritonavir; drugs for treating Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinirole, pramipexole, bromocriptine, pergolide, trihexephendyl, and amantadine; drugs for treating multiple sclerosis (MS), such as beta interferons (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; drugs for treating asthma, such as albuterol and Singulair®; drugs for treating schizophrenia, such as Zyprexa, Risperdal, Seroquel, and haloperidol; anti-inflammatory drugs, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinsonian agents agents); agents for treating cardiovascular disease, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease, such as corticosteroids, cholestyramine, interferons, and antivirals; agents for treating blood disorders, such as corticosteroids, anti-leukemia agents, and growth factors; agents that prolong or improve pharmacokinetics, such as cytochrome P450 inhibitors (i.e., inhibitors of metabolic degradation) and CYP3A4 inhibitors (e.g., ketokenozole and ritonavir), and agents for treating immune deficiency disorders, such as gamma globulins.

[0193] In certain embodiments, the combination therapy of the invention, or a pharmaceutically acceptable composition thereof, is administered in combination with a monoclonal antibody or siRNA therapeutic agent.

[0194] These additional agents may be administered separately from the combination therapy provided, as part of a multiple dose regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition. When administered as part of a multiple dose regimen, the two active agents may be given simultaneously, sequentially, or within a period of each other, usually within 5 hours of each other.

[0195] As used herein, the terms "combination," "in combination," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, a combination of the invention may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form.

[0196] The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0197] The one or more other therapeutic agents may be administered separately from the compounds or compositions of the invention as part of a multiple dose regimen. Alternatively, the one or more other therapeutic agents may be part of a single dosage form, mixed together with the compounds of the invention in a single composition. When administered as a multiple dose regimen, the one or more other therapeutic agents and the compounds or compositions of the invention may be administered simultaneously, sequentially, or within a period of time from each other, for example, within 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, 18 hours, 20 hours, 21 hours, 22 hours, 23 hours, or within 24 hours of each other. In some embodiments, the one or more other therapeutic agents and the compounds or compositions of the invention are administered more than 24 hours apart as a multiple dose regimen.

[0198] In one embodiment, the present invention provides a composition comprising a provided compound or its pharmaceutically acceptable salt and one or more additional therapeutic agents.The therapeutic agent can be administered together with the provided compound or its pharmaceutically acceptable salt, or can be administered before or after the administration of the provided compound or its pharmaceutically acceptable salt.Suitable therapeutic agents are described in more detail below.In certain embodiments, the provided compound or its pharmaceutically acceptable salt can be administered 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, a provided compound, or a pharmaceutically acceptable salt thereof, can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours after the therapeutic agent.

[0199] In another embodiment, the present invention provides a method of treating an inflammatory disease, disorder, or condition by administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents. Such additional therapeutic agents may be small molecules or recombinant biological agents, such as acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib), colchicine (Colcrys®), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), probenecid, allopurinol, febuxostat, or the like. Drugs that are used include febuxostat (Uloric®), sulfasalazine (Azulfidine®), antimalarials (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®), gold salts (e.g., gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®). (registered trademark)), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents (e.g., etanercept (Enbrel®), infliximab (Remicade®), trademarks), golimumab (Simponi®), certolizumab pegol (Cimzia®) and adalimumab (Humira®), "anti-IL-1" agents (e.g., anakinra (Kineret®) and rilonacept (Arcalyst®)), canakinumab (Ilaris®), anti-Jak inhibitors (e.g., tofacitinib), antibodies (e.g., rituximab (Rituxan®)),"Anti-T cell" agents (e.g., abatacept (Orencia®)), "anti-IL-6" agents (e.g., tocilizumab (Actemra®)), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies (e.g., tanezumab), anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)), antidiarrheal drugs (e.g., diphenoxylate (Lomotil®)), Medications that may be used include: steroids (e.g., steroids), ... 2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhaled corticosteroids (e.g., beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), and flunisolide (Aerobid®)), Afviar®, Symbicort®, Dulera®,Cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline), IgE antibodies (e.g., omalizumab (Xolair®)), nucleoside reverse transcriptase inhibitors (e.g., zidovudine (Retrovir®), abacavir (Ziagen®)), trademark), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors (e.g., For example, delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etravirine (Intelence®), nucleotide reverse transcriptase inhibitors (e.g., tenofovir (Viread®)), protease inhibitors (e.g., amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Darnavir), and benzodiazepine (Darnavir). (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®), entry inhibitors (e.g., enfuvirtide (Fuzeon®) and maraviroc (Selzentry®)), integrase inhibitors (e.g., raltegravir (Isentress®),doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Velcade®), and dexamethasone (Decadron®) in combination with lenalidomide (Revlimid®), or any combination(s) thereof.

[0200] In another embodiment, the present invention provides a method of treating gout, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents selected from nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), colchicine (Colcrys®), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), probenecid, allopurinol, and febuxostat (Uloric®).

[0201] In another embodiment, the present invention provides a method of treating rheumatoid arthritis, comprising administering to a patient in need thereof a combination of a provided compound or a pharmaceutically acceptable salt thereof and nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), sulfasalazine (Azulfidine®), or combinations thereof. antimalarials (e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®)), methotrexate (Rheumatrex®), gold salts (e.g., gold thioglucose (Solganal®), gold thiomalate (Myochrysine®), and auranofin (Ridaura®)), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and “anti-TNF” agents (e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), and Adalimumab (Adalimumab®). tuximab (Humira®)), "anti-IL-1" agents (e.g., anakinra (Kineret®) and rilonacept (Arcalyst®)), antibodies (e.g., rituximab (Rituxan®)), "anti-T cell" agents (e.g., abatacept (Orencia®)), and "anti-IL-6" agents (e.g., tocilizumab (Actemra®)).

[0202] In some embodiments, the present invention provides a method of treating osteoarthritis, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), and monoclonal antibodies (e.g., tanezumab).

[0203] In some embodiments, the present invention provides a method of treating lupus, comprising administering to a patient in need thereof a combination of a provided compound or a pharmaceutically acceptable salt thereof and acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDS) (e.g., aspirin, ibuprofen, naproxen, etodolac (Lodine®) and celecoxib), corticosteroids (e.g., prednisone, prednisolone, methylprednisolone, and hydrocortisone), antimalarials (e.g., hydroxychloroquine (Pl)), and antihistamines (e.g., acetaminophen ... and administering one or more additional therapeutic agents selected from fluticasone (fluticasone), cyclophosphamide (Cytoxan®), methotrexate (Rheumatrex®), azathioprine (Imuran®), and anticoagulants (e.g., heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®)).

[0204] In some embodiments, the present invention provides a method of treating inflammatory bowel disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from mesalamine (Asacol®), sulfasalazine (Azulfidine®), antidiarrheal agents (e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®)), bile acid binders (e.g., cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®)), laxatives (e.g., milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol®, and Senokot®), and anticholinergics or antispasmodics (e.g., dicyclomine (Bentyl®), anti-TNF therapeutics, steroids, and antibiotics (e.g., Flagyl or ciprofloxacin).

[0205] In some embodiments, the present invention provides a method of treating asthma, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and an anti-IL-33 antibody (e.g., REGN3500 (SAR440340) or CNTO). 7160), Singulair®, beta-2 agonists (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), anticholinergics (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent®), Qvar®), and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®), cromolyn sodium (Intal®), methylxanthines (e.g., theophylline (Theo-Dur®, Theolair®, Slo-bid®, Uniphyl®, Theo-24®) and aminophylline), and IgE antibodies (e.g., omalizumab (Xolair®)).

[0206] In some embodiments, the present invention provides a method of treating COPD, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a beta-2 agonist (e.g., albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethaire®), salmeterol xinafoate (Serevent®), and formoterol (Foradil®)), an anticholinergic (e.g., ipratropium bromide (Atrovent®) and tiotropium (Spiriva®)), a methylxanthine (e.g., theofonate), a benzodiazepine (Bordeaux® ... and aminophylline), inhaled corticosteroids (e.g., prednisone, prednisolone, beclomethasone dipropionate (Beclovent®, Qvar®, and Vanceril®), triamcinolone acetonide (Azmacort®), mometasone (Asthmanex®), budesonide (Pulmocort®), flunisolide (Aerobid®), Afviar®, Symbicort®, and Dulera®). In some embodiments, the present invention provides methods of treating eosinophilic COPD, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-IL-33 antibodies (e.g., REGN3500 (SAR440340) or CNTO 7160).In some embodiments, the present invention provides methods of treating eosinophilic asthma, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from anti-IL-33 antibodies (e.g., REGN3500 (SAR440340) or CNTO 7160).

[0207] In some embodiments, the present invention provides a method of treating HIV, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof, as well as a nucleoside reverse transcriptase inhibitor (e.g., zidovudine (Retrovir®), abacavir (Ziagen®), abacavir / lamivudine (Epzicom®), abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine, or a combination thereof. nucleoside reverse transcriptase inhibitors (e.g., delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etravirine (Intelence®)), nucleoside reverse transcriptase inhibitors (e.g., fluvirine (Emtriva®), lamivudine (Epivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerit®), and zalcitabine (Hivid®)), non-nucleoside reverse transcriptase inhibitors (e.g., delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramune®), and etravirine (Intelence®)), nucleoside nucleotide reverse transcriptase inhibitors (e.g., tenofovir (Viread®)), protease inhibitors (e.g., amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®), indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Fortovase® or Invirase®), and tipranavir (Aptivus®)), entry inhibitors (e.g., enfuvirtide (Fuzeon®) and maraviroc (Selzentry®)), integrase inhibitors (e.g., raltegravir (Isentress®)), and combinations thereof.

[0208] In another embodiment, the present invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0209] In another embodiment, the present invention provides a method of treating a solid tumor, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, and combinations thereof.

[0210] In another embodiment, the present invention provides a method of treating a hematological malignancy, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a hedgehog (Hh) signaling pathway inhibitor. In some embodiments, the hematological malignancy is DLBCL (Ramirez et al., "Defining causative factors contributing in the activation of hedgehog signaling in diffuse large bowel disease"). "Large B-cell lymphoma," Leuk. Res. (2012), published online July 17, and incorporated herein by reference in its entirety.

[0211] In another embodiment, the present invention provides a method of treating diffuse large B-cell lymphoma (DLBCL), comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from rituximab (Rituxan®), cyclophosphamide (Cytoxan®), doxorubicin (Hydrodaunorubicin®), vincristine (Oncovin®), prednisone, a hedgehog signaling inhibitor, and combinations thereof.

[0212] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a CHOP (cyclophosphamide, Hydrodaunorubicin®, Oncovin®, and prednisone or prednisolone) or R-CHOP (rituximab, cyclophosphamide, Hydrodaunorubicin®, Oncovin®, and prednisone or prednisolone) chemotherapy regimen.

[0213] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a rituximab / bendamustine chemotherapy regimen.

[0214] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound, or a pharmaceutically acceptable salt thereof, and a BTK inhibitor (e.g., ibrutinib).

[0215] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound, or a pharmaceutically acceptable salt thereof, and an anti-CD20 antibody (e.g., rituximab).

[0216] In some embodiments, the invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound, or a pharmaceutically acceptable salt thereof, and an anti-CD79B ADC (e.g., polatuzumab).

[0217] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof, and a BCL2 inhibitor (e.g., venetoclax).

[0218] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof, and lenalidomide or pomalidomide.

[0219] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof, and a PI3K inhibitor (e.g., umbralisib).

[0220] In some embodiments, the present invention provides a method of treating a T-cell disease or deficiency described herein, comprising administering to a patient in need thereof a provided compound, or a pharmaceutically acceptable salt thereof, and a PI3K inhibitor (e.g., umbralisib).

[0221] In some embodiments, the present invention provides a method of treating DLBCL, comprising administering to a patient in need thereof a provided compound, or a pharmaceutically acceptable salt thereof, and a proteasome inhibitor (e.g., bortezomib).

[0222] In some embodiments, the present invention provides a method of treating a T-cell disease or deficiency described herein, comprising administering to a patient in need thereof a provided compound, or a pharmaceutically acceptable salt thereof, and a proteasome inhibitor (e.g., bortezomib).

[0223] In another embodiment, the present invention provides a method of treating multiple myeloma, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from bortezomib (Velcade®), and dexamethasone (Decadron®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, a SYK inhibitor, in combination with lenalidomide (Revlimid®).

[0224] In another embodiment, the present invention provides a method of treating Waldenstrom's macroglobulinemia, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents selected from chlorambucil (Leukeran®), cyclophosphamide (Cytoxan®, Neosar®), fludarabine (Fludara®), cladribine (Leustatin®), rituximab (Rituxan®), a hedgehog signaling inhibitor, a BTK inhibitor, a JAK / pan-JAK inhibitor, a TYK2 inhibitor, a PI3K inhibitor, and a SYK inhibitor.

[0225] In some embodiments, the one or more other therapeutic agents are hedgehog pathway antagonists. Approved hedgehog pathway inhibitors that can be used in the present invention include sonidegib (Odomzo®, Sun Pharmaceuticals); and vismodegib (Erivedge®, Genentech), both of which are for the treatment of basal cell carcinoma.

[0226] In some embodiments, the one or more other therapeutic agents is a poly ADP-ribose polymerase (PARP) inhibitor. In some embodiments, the PARP inhibitor is selected from olaparib (Lynparza®, AstraZeneca); rucaparib (Rubraca®, Clovis Oncology); niraparib (Zejula®, Tesaro); talazoparib (MDV3800 / BMN 673 / LT00673, Medivation / Pfizer / Biomarin); veliparib (ABT-888, AbbVie); and BGB-290 (BeiGene, Inc.).

[0227] In some embodiments, the one or more other therapeutic agents is a histone deacetylase (HDAC) inhibitor. In some embodiments, the HDAC inhibitor is selected from vorinostat (Zolinza®, Merck); romidepsin (Istodax®, Celgene); panobinostat (Farydak®, Novartis); belinstat (Beleodaq®, Spectrum Pharmaceuticals); entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide (Epidaza®, HBI-8000, Chipscreen Biosciences, China).

[0228] In some embodiments, the one or more other therapeutic agents is a CDK inhibitor, such as a CDK4 / CDK6 inhibitor. In some embodiments, the CDK 4 / 6 inhibitor is selected from palbociclib (Ibrance®, Pfizer); ribociclib (Kisqali®, Novartis); abemaciclib (Ly2835219, Eli Lilly); and trilaciclib (G1T28, G1 Therapeutics).

[0229] In some embodiments, the one or more other therapeutic agents is a folate inhibitor. Approved folate inhibitors useful in the present invention include pemetrexed (Alimta®, Eli Lilly).

[0230] In some embodiments, the one or more other therapeutic agents are CC chemokine receptor 4 (CCR4) inhibitors. CCR4 inhibitors currently under investigation that may be useful in the present invention include mogamulizumab (Poteligeo®, Kyowa Hakko Kirin, Japan).

[0231] In some embodiments, the one or more other therapeutic agents are isocitrate dehydrogenase (IDH) inhibitors. IDH inhibitors currently under investigation that can be used in the present invention include AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[0232] In some embodiments, one or more other therapeutic agents are arginase inhibitors.The arginase inhibitors currently under investigation that can be used in the present invention include AEB1102 (pegylated recombinant arginase, Aeglea Biotherapeutics), which is currently being investigated in Phase 1 clinical trials for acute myeloid leukemia and myelodysplastic syndrome (NCT02732184) and solid tumors (NCT02561234); and CB-1158 (Calithera Biosciences).

[0233] In some embodiments, the one or more other therapeutic agents are glutaminase inhibitors. Glutaminase inhibitors currently under investigation that can be used in the present invention include CB-839 (Calithera Biosciences).

[0234] In some embodiments, the one or more other therapeutic agents are antibodies that bind to tumor antigens, i.e., proteins expressed on the cell surface of tumor cells. Approved antibodies that bind to tumor antigens that can be used in the present invention include rituximab (Rituxan®, Genentech / BiogenIdec); ofatumumab (anti-CD20, Arzerra®, GlaxoSmithKline); obinutuzumab (anti-CD20, Gazyva®, Genentech), ibritumomab (anti-CD20 and yttrium-90, Zevalin®, Spectrum Pharmaceuticals); daratumumab (anti-CD38, Darzalex®, Janssen Biotech), dinutuximab (anti-glycolipid GD2, Unituxin®, United Therapeutics); trastuzumab (anti-HER2, Herceptin®, Genentech); ado-trastuzumab emtansine (anti-HER2, fused to emtansine, Kadcyla®, Genentech); and pertuzumab (anti-HER2, Perjeta®, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Adcetris®, Seattle Genetics).

[0235] In some embodiments, the one or more other therapeutic agents are topoisomerase inhibitors. Approved topoisomerase inhibitors useful in the present invention include irinotecan (Onivyde®, Merrimack Pharmaceuticals); topotecan (Hycamtin®, GlaxoSmithKline). Topoisomerase inhibitors currently under investigation that can be used in the present invention include pixantrone (Pixuvri®, CTI Biopharma).

[0236] In some embodiments, the one or more other therapeutic agents are inhibitors of anti-apoptotic proteins, such as BCL-2. Approved anti-apoptotic agents that can be used in the present invention include venetoclax (Venclexta®, AbbVie / Genentech); and blinatumomab (Blincyto®, Amgen). Other therapeutic agents that target apoptotic proteins that are undergoing clinical trials and can be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0237] In some embodiments, the one or more other therapeutic agents is an androgen receptor inhibitor. Approved androgen receptor inhibitors useful in the present invention include enzalutamide (Xtandi®, Astellas / Medivation). Approved inhibitors of androgen synthesis include abiraterone (Zytiga®, Centocor / Ortho); approved gonadotropin-releasing hormone (GnRH) receptor antagonists (degalarix, Firmagon®, Ferring Pharmaceuticals).

[0238] In some embodiments, the one or more other therapeutic agents are selective estrogen receptor modulators (SERMs), which interfere with the synthesis or activity of estrogen. Approved SERMs useful in the present invention include raloxifene (Evista®, Eli Lilly).

[0239] In some embodiments, the one or more other therapeutic agents are inhibitors of bone resorption. An approved therapeutic agent that inhibits bone resorption is denosumab (Xgeva®, Amgen), an antibody that binds to RANKL and inhibits the binding of RANKL to its receptor RANK, which is found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells and mediates bone pathology in solid tumors with bone metastasis. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid (Zometa®, Novartis).

[0240] In some embodiments, the one or more other therapeutic agents are inhibitors of the interaction between MDMX and MDM2, two major p53 inhibitory proteins. Investigational p53 inhibitor inhibitors that can be used in the present invention include ALRN-6924 (Aileron), a stapled peptide that binds equivalently to MDMX and MDM2 and disrupts their interaction with p53. ALRN-6924 is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS), and peripheral T-cell lymphoma (PTCL) (NCT02909972; NCT02264613).

[0241] In some embodiments, the one or more other therapeutic agents are inhibitors of transforming growth factor-beta (TGF-beta or TGFβ). Investigational inhibitors of TGF-beta proteins that can be used in the present invention include NIS793 (Novartis), an anti-TGF-beta antibody currently being tested in outpatient clinics for the treatment of various cancers, including breast, lung, hepatocellular, colorectal, pancreatic, prostate, and renal cancer (NCT02947165). In some embodiments, the inhibitor of TGF-beta proteins is fresolimumab (GC1008; Sanofi-Genzyme), currently being investigated for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Furthermore, in some embodiments, the additional therapeutic agent is a compound described by Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978. One therapeutic compound currently undergoing clinical trials for the treatment of solid tumors is M7824 (Merck KgaA - formerly MSB0011459X); and (NCT02517398), a bispecific anti-PD-L1 / TGFβ trapping compound (NCT02699515). M7824 consists of a fully human IgG1 antibody against PD-L1 fused to the extracellular domain of human TGF-beta receptor II, which functions as a TGFβ "trapping agent."

[0242] In some embodiments, the one or more other therapeutic agents are selected from glembatumumab vedotin-monomethylauristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) linked to a cytotoxic MMAE. gpNMB is a protein overexpressed by multiple tumor types that is associated with the ability of cancer cells to metastasize.

[0243] In some embodiments, the one or more other therapeutic agents are antiproliferative compounds. Such antiproliferative compounds include, but are not limited to, aromatase inhibitors; antiestrogens; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule-active compounds; alkylating compounds; histone deacetylase inhibitors; compounds that induce cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-neoplastic antimetabolites; platinum compounds; compounds that target / reduce protein or lipid kinase activity, and even anti-angiogenic compounds; compounds that target, reduce or inhibit protein or lipid phosphatases; gonadorelin agonists; antiandrogens; methionine aminopeptides. enzyme inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target Flt-3 and decrease or inhibit its activity; Hsp90 inhibitors (17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma from Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors (such as SB715992 or SB743921 from GlaxoSmithKline, or pentamidine / chlorpromazine from CombinatoRx); MEK inhibitors (such as ARRY142886 from Array BioPharma, AZd6244 from AstraZeneca, PD181461 and leucovorin from Pfizer).

[0244] In some embodiments, the present invention provides a method of treating Alzheimer's disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from donepezil (Aricept®), rivastigmine (Excelon®), galantamine (Razadyne®), tacrine (Cognex®), and memantine (Namenda®).

[0245] In some embodiments, the one or more other therapeutic agents are taxane compounds that cause disruption of microtubules, which are essential for cell division. In some embodiments, the taxane compounds are selected from paclitaxel (Taxol®, Bristol-Myers Squibb), docetaxel (Taxotere®, Sanofi-Aventis; Docefrez®, Sun Pharmaceutical), albumin-bound paclitaxel (Abraxane®; Abraxis / Celgene), cabazitaxel (Jevtana®, Sanofi-Aventis), and SID530 (SK Chemicals, Co.) (NCT00931008).

[0246] In some embodiments, the one or more other therapeutic agents are nucleoside inhibitors or therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or otherwise inhibit rapidly proliferating cells.

[0247] In some embodiments, the nucleoside inhibitor is trabectedin (a guanidine alkylating agent, Yondelis®, Janssen Oncology); mechlorethamine (an alkylating agent, Valchlor®, Aktelion Pharmaceuticals); vincristine (Oncovin®, Eli Lilly; Vincasar®, Teva Pharmaceuticals; Marqibo®, Talon Therapeutics; temozolomide (a prodrug for the alkylating agent 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC), Temodar®, Merck); cytarabine injection (ara-C, an antimetabolite cytidine analog, Pfizer); lomustine (an alkylating agent, CeeNU®, Bristol-Myers Squibb; Gleostine®, NextSource Biotechnology); azacitidine (a pyrimidine nucleoside analog of cytidine, Vidaza®, Celgene); omacetaxine mepesuccinate (cephalotaxine ester) (a protein synthesis inhibitor, Synribo®; Teva Pharmaceuticals); asparaginase Erwinia chrysanthemi (an enzyme that depletes asparagine, Elspar®, Lundbeck; Erwinaze®, EUSA Pharma); eribulin mesylate (a microtubule inhibitor, a tubulin-based antimitotic agent, Halaven®, Eisai); cabazitaxel (a microtubule inhibitor, a tubulin-based antimitotic agent, Jevtana®, Sanofi-Aventis); capacetrin (a thymidylate synthase inhibitor, Xeloda®, Genentech); bendamustine (a bifunctional mechlorethamine derivative, thought to form interstrand DNA crosslinks, Treanda®, Cephalon / Teva); ixabepilone (a semisynthetic analog of epothilone B, a microtubule inhibitor, a tubulin-based antimitotic agent, Ixempra®, Bristol-Myers Squibb); nelarabine (prodrug of a deoxyguanosine analog, an inhibitor of nucleoside metabolism, Arranon®, Novartis); clofarabine (prodrug of a ribonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, Clolar®, Sanofi-Aventis);and triflidine and tipiracil (a thymidine-based nucleoside analog and thymidine phosphorylase inhibitor, Lonsurf®, Taiho Oncology);

[0248] In some embodiments, the one or more other therapeutic agents are kinase inhibitors or VEGF-R antagonists. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include bevacizumab (Avastin®, Genentech / Roche) (an anti-VEGF monoclonal antibody); ramucirumab (Cyramza®, Eli Lilly) (an anti-VEGFR-2 antibody) and ziv-aflibercept (also known as a VEGF scavenger) (Zaltrap®; Regeneron / Sanofi). VEGFR inhibitors (such as regorafenib (Stivarga®, Bayer); vandetanib (Caprelsa®, AstraZeneca); axitinib (Inlyta®, Pfizer); and lenvatinib (Lenvima®, Eisai)); Raf inhibitors (sorafenib (Nexavar®, Bayer) AG and Onyx; dabrafenib (Tafinlar®, Novartis); and vemurafenib (Zelboraf®, Genentech / Roche); MEK inhibitors (such as cobimetanib (Cotellic®, Exelexis / Genentech / Roche); trametinib (Mekinist®, Novartis); Bcr-Abl tyrosine kinase inhibitors (imatinib (Gleevec®, Novartis); nilotinib (Tasigna®, Novartis); dasatinib (Sprycel®, BristolMyersSquibb); bosutinib (Bosulif®, Pfizer); and ponatinib (Inclusig®, Ariadne) Pharmaceuticals); Her2 and EGFR inhibitors (gefitinib (Iressa®, AstraZeneca); erlotinib (Tarceeva®, Genentech / Roche / Astellas); lapatinib (Tykerb®, Novartis); afatinib (Gilotrif®, Boehringer Ingelheim);osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca); and brigatinib (Alunbrig®, Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors (such as cabozantinib (Cometriq®, Exelexis)); and multikinase inhibitors (such as sunitinib (Sutent®, Pfizer); pazopanib (Votrient®, Novartis)); ALK inhibitors (such as crizotinib (Xalkori®, Pfizer); ceritinib (Zykadia®, Novartis); and alectinib (Alecenza®, Genentech / Roche)); Bruton's tyrosine kinase inhibitors (such as ibrutinib (Imbruvica®, Pharmacyclics / Janssen)); and Flt3 receptor inhibitors (such as midostaurin (Rydapt®, Novartis)).

[0249] Other kinase inhibitors and VEGF-R antagonists that are in development and can be used in the present invention include tivozanib (Aveo Pharmaceuticals); vatalanib (Bayer / Novartis); lucitanib (Clovis Oncology); dovitinib (TKI258, Novartis); chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib (Supect®, IY5511, Il-Yang Pharmaceuticals, S. Korea); ruxolitinib (Jakafi®, Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / Takeda).

[0250] In another embodiment, the present invention provides a method of treating organ transplant rejection or graft-versus-host disease, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents selected from steroids, cyclosporine, FK506, rapamycin, hedgehog signaling inhibitors, BTK inhibitors, JAK / pan-JAK inhibitors, TYK2 inhibitors, PI3K inhibitors, and SYK inhibitors.

[0251] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising the step of administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a BTK inhibitor, wherein the disease is selected from the group consisting of inflammatory bowel disease, arthritis, systemic lupus erythematosus (SLE), vasculitis, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, diabetes, myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, and rheumatoid arthritis. thyroiditis), Graves' disease, autoimmune thyroiditis, Sjögren's syndrome, multiple sclerosis, systemic sclerosis, Lyme neuroborreliosis, Guillain-Barré syndrome, acute disseminated cerebrospinal meningitis, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid syndrome, aplastic anemia, autoimmune hepatitis, autoimmune gastritis, pernicious anemia, celiac disease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura, optic neuritis, scleroderma, primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia , Wegener's granulomatosis, psoriasis, alopecia universalis, Behçet's disease, chronic fatigue, autonomic neuropathy, membranous glomerular nephropathy, endometriosis, interstitial cystitis, pemphigus vulgaris, bullous pemphigoid, neuromyotonia, scleroderma, vulvodynia, hyperproliferative disorders, rejection of transplanted organs or tissues, acquired immunodeficiency syndrome (AIDS, also known as HIV), type 1 diabetes, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., to plant pollen, latex, drugs, food, insect venom, animal hair, animal dander, house dust mites, or cockroach calyx) calyx), type I hypersensitivity, 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 abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitisMyocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis, B-cell proliferative disorders (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma / Waldenstrom's macroglobulinemia, splenic marginal zone lymphoma, multiple myeloma (also known as plasma cell myeloma), non-Hodgkin's lymphoma, Hodgkin's lymphoma, plasmacytoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, or lymphomatoid granulomatosis, breast cancer, prostate cancer, or mast cell cancer (e.g., 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 spondyloarthritis (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome, systemic sclerosis, osteoporosis, bone cancer, bone metastases), thromboembolic disorders (e.g., myocardial infarction, angina pectoris, re-occlusion after angioplasty, restenosis after angioplasty, re-occlusion after aortocoronary artery bypass, restenosis after aortocoronary artery bypass, stroke, transient ischemia, peripheral arterial occlusive disorder, Pulmonary embolism, deep vein thrombosis), inflammatory pelvic disease, urethritis, sunburn, sinusitis, pneumonitis, encephalitis, meningitis, myocarditis, nephritis, osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis (cholocystitis), agammaglobulinemia, psoriasis, allergies, Crohn's disease, irritable bowel syndrome, ulcerative colitis, Sjogren's disease, tissue graft rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandulardisease) (also known as autoimmune polyglandular syndrome), autoimmune alopecia, 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, metastatic carcinoma of the liver, leukemia, and rheumatoid arthritis. In some embodiments, the disease is selected from osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom's macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, vitiligo, autoimmune hypopituitarism, Guillain-Barré syndrome, Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory responses (e.g., acute respiratory distress syndrome and ischemia / reperfusion injury), and Graves' disease.

[0252] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising the step of administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor, wherein the disease is selected from cancer, a neurodegenerative disorder, an angiogenic disorder, a viral disease, an autoimmune disease, an inflammatory disorder, a hormone-related disease, a condition associated with organ transplantation, an immunodeficiency disorder, a destructive bone disorder, a proliferative disorder, an infectious disease, a condition associated with cell death, thrombin-induced platelet aggregation, chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), liver disease, a pathological immune condition involving T-cell activation, a cardiovascular disorder, and a CNS disorder.

[0253] In another embodiment, the present invention provides a method of treating or lessening the severity of a disease, comprising the step of administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and a PI3K inhibitor, wherein the disease is a benign or malignant tumor, carcinoma or solid tumor of the brain, kidney (e.g., renal cell carcinoma (RCC)), liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, endometrium, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone, or thyroid, sarcoma, glioblastoma, neuroblastoma, thyroid cancer, or thyroid cancer. tumors, multiple myeloma or gastrointestinal cancer, in particular colon cancer or colorectal adenoma or head and neck tumors, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, neoplasms of epithelial character, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma (including, for example, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma (also called Hodgkin or Hodgkin's disease)), breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma or leukemia, Cowden's syndrome, Lhermitte-Duclots disease Diseases including Banayan-Zonana syndrome or diseases in which the PI3K / PKB pathway is abnormally activated, asthma of any type or onset, including both intrinsic (non-allergic) and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma and asthma induced after bacterial infection, acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, chronic obstructive airway disease or chronic obstructive lung diseasedisease (COPD, COAD or COLD) (including associated chronic bronchitis or dyspnea), emphysema, and exacerbations of airway overactivity as a result of other medications (especially other inhaled medications), bronchitis of any type or onset (including but not limited to acute, arachidic, keratoconjunctivitis, croupus, chronic or tuberculous bronchitis), pneumoconiosis of any type or onset (an inflammatory, generally occupational, lung disease, whether chronic or acute, frequently associated with airway obstruction and caused by repeated inhalation of dust) (including, for example, aluminum lung disease, anthracosis, asbestosis, stone disease, ptilosis, siderosis, silicosis, tabacosis and byssinosis), Loffler's syndromesyndrome), eosinophilic pneumonia, parasitic (especially metazoan) infestations (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophil-related disorders affecting the airways caused by eosinophilic granulomas and drug reactions, psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity 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 involving an autoimmune response or having an autoimmune component or etiology, including autoimmune hematologic disorders (e.g., hemolytic anemia, aplastic anemia, red blood cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma (sc), lerodoma), Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, alveolar osteitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, and and glomerulonephritis (with or without nephrotic syndrome (including, for example, 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, as well as neurodegenerative diseases caused by trauma, glutamate neurotoxicity, and hypoxia.

[0254] In some embodiments, the one or more other therapeutic agents are phosphatidylinositol 3-kinase (PI3K) inhibitors. In some embodiments, the PI3K inhibitor is selected from idelalisib (Zydelig®, Gilead), alpesilib (BYL719, Novartis); taselisib (GDC-0032, Genentech / Roche); pictilisib (GDC-0941, Genentech / Roche); copanlisib (BAY806946, Bayer); duvelisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[0255] In some embodiments, the present invention provides a method of treating AML, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents selected from a FLT3 inhibitor; a targeted agent (e.g., an IDH inhibitor, an anti-CD33 ADC (e.g., Mylotarg), a BCL2 inhibitor, and a hedgehog inhibitor); and a chemotherapeutic agent (e.g., AraC, daunarubicin, etoposide, methotrexate, fludarabine, mitozantrone, azacitidine, and a corticosteroid).

[0256] In some embodiments, the present invention provides a method of treating MDS, comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents selected from azacitidine, decitabine, and Revlimid.

[0257] In some embodiments, the present invention provides a method of treating an inflammatory skin condition (e.g., hidradenitis suppurativa), comprising administering to a patient in need thereof a provided compound, or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents selected from anti-TNF agents.

[0258] In some embodiments, the present invention provides a method of treating an inflammatory skin condition (e.g., atopic dermatitis), comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents selected from an IL-4 / IL-13-targeted agent (e.g., dupilumab). In some embodiments, the present invention provides a method of treating an inflammatory skin condition (e.g., psoriasis), comprising administering to a patient in need thereof a provided compound or a pharmaceutically acceptable salt thereof, and one or more additional therapeutic agents selected from an anti-IL-17 antibody and an anti-IL-23 antibody.

[0259] According to the method of the present invention, the compounds and compositions can be administered in any amount and by any route of administration that is effective for treating or reducing the severity of cancer, autoimmune disorders, proliferative disorders, inflammatory disorders, neurodegenerative or neurological disorders, schizophrenia, bone-related disorders, liver disease, or heart disease.The exact amount required varies from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the specific drug, its mode of administration, etc.The compounds of the present invention are preferably formulated into unit dosage forms for ease of administration and uniformity of dosage.The term "unit dosage form" as used herein refers to a physically separate unit of drug appropriate for the patient to be treated.However, it is understood that the total daily usage amount of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The effective dosage level specific to any particular patient or organism will depend on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound used; the duration of treatment; drugs used in combination or concomitantly with the specific compound used, and similar factors well known in the medical arts.

[0260] The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention can be administered orally or parenterally at dosage levels of about 0.01 mg to about 50 mg per kg of subject body weight per day, preferably about 1 mg to about 25 mg per kg, one or more times daily to obtain the desired therapeutic effect.

[0261] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants such as wetting agents, emulsifiers and suspending agents, as well as sweeteners, flavoring agents and fragrances.

[0262] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be injectable sterile solutions, suspensions, or emulsions in non-toxic, parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic monoglycerides or diglycerides, may be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0263] Injectable preparations can be sterilized prior to use, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other injectable sterile medium.

[0264] To prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The compound release rate can be controlled depending on the ratio of compound to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0265] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of this invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0266] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0267] Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be composed so that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be used as fillers for soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols, etc.

[0268] The active compound may be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is common practice, such dosage forms may contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient(s) only or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0269] Dosage forms for topical or transdermal administration of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers, as needed. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of this invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0270] According to one embodiment, the present invention relates to a method for inhibiting protein kinase activity or degrading protein kinases in a biological sample, comprising the step of contacting said biological sample with a compound of this invention or a composition comprising said compound.

[0271] According to another embodiment, the present invention relates to a method for inhibiting or degrading the activity of IRAK-1, IRAK-2, and / or IRAK-4, or mutants thereof, in a biological sample, comprising the step of contacting said biological sample with a compound of this invention or a composition comprising said compound.

[0272] The term "biological sample," as used herein, includes, but is not limited to, a cell culture or extract thereof; a biopsy or extract thereof obtained from a mammal; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0273] Inhibition and / or degradation of protein kinase or protein kinase activity selected from IRAK-1, IRAK-2, and / or IRAK-4, or mutants thereof, in biological samples is useful for a variety of purposes known to those skilled in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0274] Another embodiment of the invention relates to a method of degrading protein kinases and / or inhibiting protein kinase activity in a patient, comprising administering to said patient a compound of the invention, or a composition comprising said compound.

[0275] According to another embodiment, the present invention relates to a method for degrading and / or inhibiting the activity of one or more of IRAK-1, IRAK-2, and / or IRAK-4, or mutants thereof, in a patient, comprising administering to the patient a compound of the present invention or a composition containing the compound. According to 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 mutants thereof, in a patient in need thereof, comprising administering to the patient a compound of the present invention or a composition containing the compound. Such disorders are described in detail herein.

[0276] Depending upon the particular condition, or disease, being treated, additional therapeutic agents, which are normally administered to treat that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease, or condition, are known as "appropriate for the disease, or condition, being treated."

[0277] The compounds of the present invention can also be advantageously used in combination with other antiproliferative compounds, including, but not limited to, aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-active compounds, alkylating compounds, histone deacetylase inhibitors, compounds that induce cell differentiation processes, cyclooxygenase inhibitors, MMP inhibitors, mTOR inhibitors, antitumor antimetabolites, platin compounds, compounds that target / reduce protein kinase activity or lipid kinase activity and further antiangiogenic compounds, compounds that target, reduce or inhibit the activity of protein phosphatases or lipid phosphatases, gonadorelin agonists, antiandrogens, methionine aminopeptides ... putidase inhibitors; matrix metalloproteinase inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematological malignancies; compounds that target, decrease, or inhibit the activity of Flt-3; Hsp90 inhibitors (e.g., 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (Conforma Therapeutics); temozolomide (Temodal®); kinesin spindle protein inhibitors (e.g., SB715992 or SB743921 (GlaxoSmithKline), or pentamidine / chlorpromazine (CombinatoRx)); MEK inhibitors (e.g., ARRY142886 (Array BioPharma), AZD6244 (AstraZeneca), PD181461 (Pfizer) and leucovorin).

[0278] The term "aromatase inhibitor" as used herein refers to a compound that inhibits estrogen production, for example, the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. This term includes, but is not limited to, steroids, particularly atamestane, exemestane, and formestane, and nonsteroids, particularly aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, and letrozole. Exemestane is commercially available under the trade name Aromasin™. Formestane is commercially available under the trade name Lentaron™. Fadrozole is commercially available under the trade name Afema™. Anastrozole is commercially available under the trade name Arimidex™. Letrozole is commercially available under the trade name Femara™ or Femar™. Aminoglutethimide is commercially available under the trade name Orimeten™. Combinations of the present invention which include a chemotherapeutic agent that is an aromatase inhibitor are particularly useful for the treatment of hormone receptor positive tumors, e.g., breast tumors.

[0279] In some embodiments, the one or more other therapeutic agents is an mTOR inhibitor, which inhibits cell proliferation, angiogenesis, and glucose uptake. In some embodiments, the mTOR inhibitor is everolimus (Afinitor®, Novartis); temsirolimus (Torisel®, Pfizer); and sirolimus (Rapamune®, Pfizer).

[0280] In some embodiments, the one or more other therapeutic agents is an aromatase inhibitor. In some embodiments, the aromatase inhibitor is selected from exemestane (Aromasin®, Pfizer); anastazole (Arimidex®, AstraZeneca), and letrozole (Femara®, Novartis).

[0281] The term "antiestrogen" as used herein refers to a compound that antagonizes the effects of estrogen at the estrogen receptor level. This term includes, but is not limited to, tamoxifen, fulvestrant, raloxifene and raloxifene hydrochloride. Tamoxifen is commercially available under the trade name Nolvadex™. Raloxifene hydrochloride is commercially available under the trade name Evista™. Fulvestrant can be administered under the trade name Faslodex™. The combination of the present invention, which includes a chemotherapeutic agent that is an antiestrogen, is particularly useful for treating estrogen receptor-positive tumors, such as breast tumors.

[0282] The term "antiandrogen," as used herein, relates to any substance capable of inhibiting the biological effects of androgens, including, but not limited to, bicalutamide (Casodex™). The term "gonadorelin agonist," as used herein, includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin can be administered under the trade name Zoladex™.

[0283] The term "topoisomerase I inhibitor" as used herein includes, but is not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin, and the polymeric camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form as it is marketed, for example, under the trademark Camptosar™. Topotecan is marketed under the trade name Hycamptin™.

[0284] The term "topoisomerase II inhibitors", as used herein, includes, but is not limited to, anthracyclines (e.g., doxorubicin (including liposomal formulations such as Caelyx™), daunorubicin, epirubicin, idarubicin, and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is commercially available under the trade name Etopophos™. Teniposide is commercially available under the trade name VM 26-Bristol. Doxorubicin is commercially available under the trade name Acriblastin™ or Adriamycin™. Epirubicin is commercially available under the trade name Farmorubicin™. Idarubicin is commercially available under the trade name Zavedos™. Mitoxantrone is commercially available under the trade name Novantron.

[0285] The term "microtubule active agent" refers to microtubule-stabilizing compounds, microtubule-destabilizing compounds, and microtubulin 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 commercially available under the trade name Taxol™. Docetaxel is commercially available under the trade name Taxotere™. Vinblastine sulfate is commercially available under the trade name Vinblastin RP™. Vincristine sulfate is commercially available under the trade name Farmistin™.

[0286] The term "alkylating agent" as used herein includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosourea (BCNU or Gliadel). Cyclophosphamide is commercially available under the trade name Cyclostin™. Ifosfamide is commercially available under the trade name Holoxan™.

[0287] The term "histone deacetylase inhibitors" or "HDAC inhibitors" relates to compounds which inhibit histone deacetylase and which possess antiproliferative activity, including, but not limited to, suberoylanilide hydroxamic acid (SAHA).

[0288] The term "antineoplastic antimetabolite" includes, but is not limited to, 5-fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylating compounds (e.g., 5-azacytidine and decitabine), methotrexate and edatrexate, and folate antagonists (e.g., pemetrexed). Capecitabine is commercially available under the trade name Xeloda™. Gemcitabine is commercially available under the trade name Gemzar™.

[0289] The term "platin compound" as used herein includes, but is not limited to, carboplatin, cisplatin, cisplatinum and oxaliplatin. Carboplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Carboplat™. Oxaliplatin can be administered, e.g., in the form as it is marketed, e.g., under the trademark Eloxatin™.

[0290] The term "Bcl-2 inhibitor", as used herein, refers 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, Ascenta's pan-Bcl-2 inhibitor, curcumin (and analogs thereof), dual Bcl-2 / Bcl-xL inhibitor (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and analogs thereof; see WO2008 / 118802, US 2010 / 0197686), navitoclax (and analogs thereof, see US 7,390,799), NH-1 (Shenayng Pharmaceutical University), obatoclax (and analogs thereof, see WO2004 / 106328, US 2005 / 0014802), S-001 (Gloria Pharmaceuticals), the TW series of compounds (Univ. of Michigan), and venetoclax. In some embodiments, the Bcl-2 inhibitor is a small molecule therapeutic. In some embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0291] The term "compounds which target / reduce the activity of protein kinases or lipid kinases; or compounds which target / reduce the activity of protein phosphatases or lipid phosphatases; or further anti-angiogenic compounds", as used herein, includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors, or lipid kinase inhibitors, such as a) compounds which target, reduce or inhibit the activity of platelet-derived growth factor receptors (PDGFRs) (e.g., compounds which target, reduce or inhibit the activity of PDGFRs, in particular compounds which inhibit PDGF receptors, such as N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib, SU101, SU6668 and GFB-111); b) compounds which target, reduce or inhibit the activity of fibroblast growth factor receptors (FGFRs); c) compounds which target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR) (e.g., For example, compounds that target, reduce or inhibit the activity of IGF-IR, in particular 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 factors; 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, for example imatinib; h) compounds that target, reduce or inhibit the activity of the C-kit receptor tyrosine kinase, which is part of the PDGFR family (for example compounds that target, reduce or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular 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 (e.g., BCR-Abl kinase) and mutants (e.g., compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products, e.g., N-phenyl-2-pyrimidine-amine derivatives, e.g., imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 (ParkeDavis); or dasatinib (BMS-354825); j) compounds (including staurosporine derivatives, e.g., midostaurin) that target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine / threonine kinases, MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC families, and / or members of the cyclin-dependent kinase family (CDK); further exemplary compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; lsis 3521; LY333531 / LY379196; isoquinoline compounds; FTI; PD184352 or QAN697 (P13K inhibitors) or AT7519 (CDK inhibitors); k) compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors, for example compounds which target, decrease or inhibit the activity of protein-tyrosine kinase inhibitors such as imatinib mesylate (Gleevec™) or tyrphostins (e.g., tyrphostin A23 / RG-50810; AG 99; tyrphostin AG 213; tyrphostin AG 1748; tyrphostin AG 490; tyrphostin B44; tyrphostin B44(+) enantiomer; tyrphostin AG 555; AG; 494; tyrphostin 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, for example, compounds that target, reduce or inhibit the activity of the epidermal growth factor receptor family are, in particular, compounds, proteins or antibodies that inhibit members of the EGF receptor tyrosine kinase family, for example, EGF receptor, ErbB2, ErbB3 and ErbB4, or that bind to EGF or EGF-related ligands (e.g., CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin™), cetuximab (Erbitux™), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3, or E7.6.m) compounds that target, decrease or inhibit the activity of the c-Met receptor, for example, compounds that target, decrease or inhibit the activity of c-Met, in particular compounds that inhibit the kinase activity of the c-Met receptor, or antibodies that target the extracellular domain of c-Met or that bind to HGF; n) compounds that target, decrease or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including, but not limited to, PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-101348, tofacitinib , and ruxolitinib); o) compounds that target, decrease 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, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib); and q) compounds that target, decrease or inhibit the signaling effects of the Hedgehog protein (Hh) or Smoothened receptor (SMO) pathways (including but not limited to cyclopamine, vismodegib, itraconazole, erismodegib, and IPI-926 (salidegib)).

[0292] Compounds which target, decrease or inhibit the activity of protein or lipid phosphatases are eg inhibitors of phosphatase 1, inhibitors of phosphatase 2A or inhibitors of CDC25 (eg okadaic acid or a derivative thereof).

[0293] In some embodiments, the one or more other therapeutic agents are growth factor antagonists, such as antagonists of platelet-derived growth factor (PDGF) or epidermal growth factor (EGF) or its receptor (EGFR). Approved PDGF antagonists that can be used in the present invention include olaratumab (Lartruvo®; Eli Lilly). Approved EGFR antagonists that can be used in the present invention include cetuximab (Erbitux®, Eli Lilly); necitumumab (Portrazza®, Eli Lilly), panitumumab (Vectibix®, Amgen); and osimertinib (targeting activated EGFR, Tagrisso®, AstraZeneca).

[0294] The term "PI3K inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against one or more enzymes of 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, pictorelisib, PF-4691502, BYL-719, dactolisib, XL-147, XL-765, and idelalisib.

[0295] The term "BTK inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against Bruton's tyrosine kinase (BTK), including, but not limited to, AVL-292 and ibrutinib.

[0296] The term "SYK inhibitor," as used herein, includes, but is not limited to, compounds that have inhibitory activity against spleen tyrosine kinase (SYK), including, but not limited to, PRT-062070, R-343, R-333, Excellair, PRT-062607, and fostamatinib.

[0297] Further examples of BTK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention are described in WO 2014 / 023990, each of which is incorporated herein by reference in its entirety. 2008 / 039218, US 2008 / 0108636 and WO 2011 / 090760, US 2010 / 0249092.

[0298] Further examples of SYK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention are described in WO 2005 / 023990, each of which is incorporated herein by reference in its entirety. 2003 / 063794, US 2004 / 0029902, WO 2005 / 007623, US 2005 / 0075306, and WO 2006 / 078846, US 2006 / 0211657.

[0299] Further examples of PI3K inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention are described 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, WO 2007 / 129161, US 2008 / 0076768, WO 2006 / 122806, US 2008 / 0194579, WO 2005 / 113554, US 2008 / 0275067, and WO 2007 / 044729, US 2010 / 0087440.

[0300] Further examples of JAK inhibitor compounds and conditions treatable by such compounds in combination with the compounds of this invention are described in WO 2005 / 023990, each of which is incorporated herein by reference in its entirety. 2009 / 114512, US 2009 / 0233903, WO 2008 / 109943, US 2010 / 0197671, WO 2007 / 053452, US 2007 / 0191405, WO 2001 / 0142246, US 2001 / 0053782, and WO 2007 / 070514, US 2007 / 0135461.

[0301] Additional anti-angiogenic compounds include compounds that have another mechanism for their activity, for example, a mechanism unrelated to protein kinase inhibition or lipid kinase inhibition, such as thalidomide (Thalomid™) and TNP-470.

[0302] Examples of useful proteasome inhibitors for use in combination with the compounds of the invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0303] Compounds which target, decrease or inhibit the activity of protein or lipid phosphatases are eg inhibitors of phosphatase 1, inhibitors of phosphatase 2A or inhibitors of CDC25 (eg okadaic acid or a derivative thereof).

[0304] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-, γ- or δ-tocopherol, or α-, γ- or δ-tocotrienol.

[0305] The term cyclooxygenase inhibitor as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives, such as celecoxib (Celebrex™), rofecoxib (Vioxx™), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acids, such as 5-methyl-2-(2′-chloro-6′-fluoroanilino)phenylacetic acid, lumiracoxib.

[0306] The term "bisphosphonate," as used herein, includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. Etidronic acid is commercially available under the trade name Didronel™. Clodronic acid is commercially available under the trade name Bonefos™. Tiludronic acid is commercially available under the trade name Skelid™. Pamidronic acid is commercially available under the trade name Aredia™. Alendronic acid is commercially available under the trade name Fosamax™. Ibandronic acid is commercially available under the trade name Bondranat™. Risedronic acid is commercially available under the trade name Actonel™. Zoledronic acid is commercially available under the trade name Zometa™. The term "mTOR inhibitors" relates to compounds which inhibit the mammalian target of rapamycin (mTOR) and which have antiproliferative activity, such as sirolimus (Rapamune®), everolimus (Certican™), CCI-779 and ABT578.

[0307] The term "heparanase inhibitor," as used herein, refers to a compound that targets, decreases, or inhibits heparin sulfate degradation. This term includes, but is not limited to, PI-88. The term "biological response modifier," as used herein, refers to lymphokines or interferons.

[0308] The term "inhibitor of Ras oncogenic isoforms" (e.g., H-Ras, K-Ras, or N-Ras) as used herein refers to compounds that target, reduce, or inhibit the oncogenic activity of Ras; for example, "farnesyltransferase inhibitors" such as L-744832, DK8G557, or R115777 (Zarnestra™). The term "telomerase inhibitor" as used herein refers to compounds that target, reduce, or inhibit the activity of telomerase. Compounds that target, reduce, or inhibit the activity of telomerase are particularly compounds that inhibit the telomerase receptor, such as telomestatin.

[0309] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, decreases or inhibits the activity of methionine aminopeptidase. Compounds that target, decreases or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0310] The term "proteasome inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of proteasome. Compounds that target, reduces or inhibit the activity of proteasome include, but are not limited to, bortezomib (Velcade™); carfilzomib (Kyprolis®, Amgen); and ixazomib (Ninlaro®, Takeda), and MLN 341.

[0311] The term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors), as used herein, includes, but is not limited to, collagen peptidomimetic and non-peptidomimetic inhibitors, tetracycline derivatives (e.g., the hydroxamate peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B, or AAJ996).

[0312] The term "compounds used in the treatment of hematological malignancies," as used herein, includes, but is not limited to, FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of FMS-like tyrosine kinase receptor (Flt-3R); interferon, 1-β-D-arabinofuransylcytosine (ara-c) and bisulfan; and ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase.

[0313] Compounds that target, decrease or inhibit the activity of FLT-3R are, in particular, compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0314] The term "HSP90 inhibitor," as used herein, 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 proteosome 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), geldanamycin derivatives; other geldanamycin-related compounds; radicicol, and HDAC inhibitors.

[0315] The term "antiproliferative antibody" as used herein includes, but is not limited to, trastuzumab (Herceptin™), trastuzumab-DM1, erbitux, bevacizumab (Avastin™), rituximab (Rituxan®), PRO64553 (anti-CD40), and 2C4 antibodies. Antibody refers to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity.

[0316] For the treatment of acute myeloid leukemia (AML), the compound of the present invention can be used in combination with standard leukemia therapy, particularly in combination with the therapy used for the treatment of AML.In particular, the compound of the present invention can be administered in combination with farnesyltransferase inhibitors and / or other drugs useful for the treatment of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum and PKC412.

[0317] Other anti-leukemia compounds include, for example, Ara-C, a pyrimidine analogue that is a 2'-alpha-hydroxyribose (arabinoside) derivative of deoxycytidine. Also included are the purine analogue 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 enzymes known as histone deacetylases. Specific HDAC inhibitors include MS275, SAHA, FK228 (previously FR901228), trichostatin A, and the compounds disclosed in US6,552,065, including but not limited to N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salt, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-propenamide or its pharmaceutically acceptable salt, particularly lactate.Somatostatin receptor antagonists as used herein refer to compounds that target, treat or inhibit somatostatin receptors, such as octreotide and SOM230.Tumor cell damaging approaches refer to approaches such as ionizing radiation. The term "ionizing radiation" referred to above and hereinafter means ionizing radiation that occurs as either electromagnetic rays (e.g., X-rays and gamma rays) or particles (e.g., alpha and beta particles). Ionizing radiation is provided in, but is not limited to, radiation therapy and is known in the art. Hellman, Principles of Radiation Therapy, Cancer, in Principles and Practice of Oncology, eds. Devita et al., 4th ed., Vol. 1, pp. 248-275 (1993).

[0318] Also included are EDG binders and ribonucleotide reductase inhibitors.The term "EDG binder" as used herein refers to a class of immunosuppressants that modulate lymphocyte recirculation, such as FTY720.The term "ribonucleotide reductase inhibitor" refers to pyrimidine nucleoside analogs or purine nucleoside analogs, including but not limited to fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (especially in combination with ara-C for ALL) and / or pentostatin.The ribonucleotide reductase inhibitor is particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivative.

[0319] In particular, VEGF compounds, proteins or monoclonal antibodies such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin™; Endostatin™; anthranilic acid amide; ZD4190; ZD6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies (e.g., rhuMAb and RHUFab), VEGF aptamers (e.g., Macugon); FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610), and bevacizumab (Avastin™) are also included.

[0320] Photodynamic therapy, as used herein, refers to the use of certain chemicals known as photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include treatment with compounds such as Visudyne™ and porfimer sodium.

[0321] Antiangiogenic steroids, as used herein, refer to compounds that block or inhibit angiogenesis, such as anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocortisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, desoxycorticosterone, testosterone, estrone, and dexamethasone.

[0322] Corticosteroid-containing implants refer to compounds such as fluocinolone and dexamethasone.

[0323] Other chemotherapeutic compounds include, but are not limited to, plant alkaloids, hormonal compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or miscellaneous compounds or compounds with other or unknown mechanisms of action.

[0324] The compounds of the present invention are also useful as co-therapeutic compounds for use in combination with other drug substances, such as anti-inflammatory, bronchodilator, or antihistamine drug substances, particularly in the treatment of obstructive or inflammatory airway diseases such as those mentioned hereinabove, e.g., as enhancers of the therapeutic activity of such drugs or as a means of reducing the required dosage or potential side effects of such drugs. The compounds of the present invention may be mixed with other drug substances in a given pharmaceutical composition, or may be administered separately, before, simultaneously with, or after the other drug substances. Thus, the present invention includes combinations of the compounds of the present invention, as described hereinabove, with anti-inflammatory, bronchodilator, antihistamine, or antitussive drug substances, wherein the compounds of the present invention and the drug substances are in the same or different pharmaceutical compositions.

[0325] Suitable anti-inflammatory drugs include steroids, in particular glucocorticosteroids (e.g., budesonide, beclomethasone dipropionate, fluticasone propionate, ciclesonide, or mometasone furoate); non-steroidal glucocorticoid receptor agonists; LTB4 antagonists (e.g., LY293111, CGS025019C, CP-195543, SC-53228, BIIL 284, ONO 4057, SB 209247); LTD4 antagonists (e.g., montelukast and zafirlukast); PDE4 inhibitors (e.g., cilomilast (Ariflo® GlaxoSmithKline), roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), Allofylline (Almirall Prodesfarma), PD189659 / PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801 (Celgene), SeICID™ CC-10004 (Celgene), VM554 / UM565 (Vernalis), T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo)); A2a agonists; A2b antagonists; and beta-2 adrenoceptor agonists (e.g., albuterol (salbutamol), metaproterenol, terbutaline, salmeterol Suitable bronchodilator drugs include anticholinergic or antimuscarinic compounds, especially ipratropium bromide, oxitropium bromide, tiotropium salts and CHF 4226 (Chiesi), and glycopyrrolate.

[0326] Suitable antihistamine drug substances include cetirizine hydrochloride, acetaminophen, clemastine fumarate, promethazine, loratadine, desloratidine, diphenhydramine and fexofenadine hydrochloride, activastine, astemizole, azelastine, ebastine, epinastine, mizolastine and tefenadine.

[0327] Other useful combinations of the compounds of the invention with anti-inflammatory drugs are with antagonists of chemokine receptors, such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, in particular CCR-5 antagonists, such as Schering-Plough antagonists SC-351125, SCH-55700 and SCH-D, 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-aminium chloride (TAK-770).

[0328] The structures of active compounds identified by code number, generic name or trade name can be obtained from the current edition of the standard compendium "The Merck Index" or from databases such as Patents International (e.g. IMS World Publications).

[0329] The compounds of the present invention can also be used in combination with known therapeutic processes, such as the administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for the treatment of tumors that exhibit poor sensitivity to radiation therapy.

[0330] The compound of the present invention can be administered alone or in combination with one or more other therapeutic compounds, and possible combination therapy can be in the form of a fixed combination, or the compound of the present invention and one or more other therapeutic compounds are administered alternately or independently, or in the form of a fixed combination administered in combination with one or more other therapeutic compounds.Otherwise or in addition, the compound of the present invention can be administered in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for tumor treatment.As described above, in the context of other treatment strategies, long-term treatment is possible, as well as adjuvant treatment.Other possible treatments are treatments to maintain the patient's condition after tumor regression, or even chemopreventive treatment, for example, in patients at risk.

[0331] These additional agents can be administered separately from the compound-containing compositions of this invention, as part of a multiple dose regimen. Alternatively, these agents can be part of a single dosage form, mixed together with the compound of this invention in a single composition. When administered as part of a multiple dose regimen, the two active agents may be given simultaneously, sequentially, or within a period of each other, usually within 5 hours of each other.

[0332] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention can be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the present invention provides a single unit dosage form comprising a compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0333] The amounts of both the compounds of the present invention and additional therapeutic agents (in compositions containing such additional therapeutic agents) that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Preferably, the compositions of this invention should be formulated so that a dosage of between 0.01-100 mg / kg of body weight per day of the compound of the present invention can be administered.

[0334] In these compositions containing an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention may act synergistically. Therefore, the amount of the additional therapeutic agent in such compositions is less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, the additional therapeutic agent can be administered at a dosage of between 0.01 and 1,000 μg per kg of body weight per day.

[0335] The amount of one or more other therapeutic agents present in the compositions of this invention can be less than or equal to the amount typically administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of one or more other therapeutic agents in the compositions of this disclosure ranges from about 50% to 100% of the amount typically present in a composition comprising that agent as the only therapeutically active agent. In some embodiments, the one or more other therapeutic agents are administered at a dosage that is about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, or about 95% of the amount typically administered for that agent. As used herein, the phrase "typically administered" refers to the amount of an FDA-approved therapeutic agent approved for administration according to the FDA label insert.

[0336] The compounds of this invention, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. For example, vascular stents are used to overcome restenosis (re-narrowing of the blood vessel wall after injury). However, patients using stents or other implantable devices are at risk of blood clot formation or platelet activation. These unwanted effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. An implantable device coated with the compounds of this invention is another embodiment of the present invention.

[0337] Exemplary immuno-oncology agents In some embodiments, the 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 for enhancing, stimulating, and / or upregulating the immune response in a subject. In some embodiments, the administration of an immuno-oncology agent with a compound of the present invention has a synergistic effect in the treatment of cancer.

[0338] The tumor immunotherapeutic agent may be, for example, a small molecule drug, an antibody, or a biological or small molecule. Examples of biological tumor immunotherapeutic 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 a humanized or human antibody.

[0339] In some embodiments, the immuno-oncology agent is either (i) an agonist of a stimulatory (including costimulatory) receptor or (ii) an antagonist of an inhibitory (including co-inhibitory) signal on a T cell, both of which result in amplification of the antigen-specific T cell response.

[0340] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to costimulatory or costimulatory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to costimulatory or co-inhibitory receptors is the TNF family of molecules that bind to cognate TNF receptor family members, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, and OP G, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / D Contains R3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0341] In some embodiments, the tumor immunomodulator is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

[0342] In some embodiments, the combination of a compound of the present invention with an immuno-oncology agent may stimulate a T cell response. In some embodiments, the immuno-oncology agent is (i) an antagonist (e.g., an immune checkpoint inhibitor) of a protein that inhibits T cell activation (e.g., 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 (e.g., B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD28H).

[0343] 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.

[0344] In some embodiments, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, and is a CSF-1R antagonist (e.g., RG7155 (WO 2011 / 070024, US 2011 / 0165156, WO 2011 / 0107553, US 2012 / 0329997, WO 2011 / 131407, US 2013 / 0005949, WO 2013 / 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 Antibodies that can be used include, but are not limited to, CSF-1R antagonist antibodies, including, but not limited to, antibodies against CSF-1R (e.g., CSF-1R antagonist antibodies, e ...

[0345] In some embodiments, the immuno-oncology agent is selected from agonistic agents that ligate positive costimulatory receptors, blocking agents that attenuate signaling via inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome different immunosuppressive pathways within the tumor microenvironment (e.g., blocking the engagement of inhibitory receptors (e.g., PD-L1 / PD-1 interactions), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell energy or exhaustion), and agents that induce innate immune activation and / or inflammation at the tumor site.

[0346] 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.

[0347] In some embodiments, the immuno-oncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by injection. In some embodiments, the immuno-oncology agent is an antibody or antigen-binding portion thereof that specifically binds to the programmed cell 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 called AMP-224, which consists of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0348] 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; WO2010 / 077634, US 2010 / 0203056), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874, US 2009 / 0055944), and MSB0010718C (WO2013 / 079174, US 2014 / 0341917).

[0349] 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 LAG-3 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, US 2010 / 0233183, WO 2009 / 044273, US 2011 / 0008331).

[0350] 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 (WO12 / 32433).

[0351] 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).

[0352] In some embodiments, the tumor immunomodulator is an indoleamine (2,3)-dioxygenase (IDO) antagonist. In some embodiments, the IDO antagonist is selected from the group consisting of 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); an enzyme that breaks down kynurenine (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).

[0353] 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.

[0354] In some embodiments, the tumor immunotherapeutic agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO2006 / 029879, US 7,501,496).

[0355] 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.

[0356] 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.

[0357] In some embodiments, the tumor immunomodulator is MGA271 (B7H3) (WO2011 / 109400, US 2013 / 0149236).

[0358] In some embodiments, the immuno-oncology agent is selected from the group consisting of abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab.

[0359] In some embodiments, the tumor immunotherapy agent is an immunostimulatory agent. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis 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 not previously considered susceptible to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab (Opdivo®, Bristol-Myers Squibb, also known as ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve overall survival in patients with RCC who have experienced disease progression during or after previous antiangiogenic therapy.

[0360] 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 (Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); ingenol mebutate (Picato®, LEO Pharma).

[0361] In some embodiments, the immunomodulatory therapeutic agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), which is approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec (Imlygic®, BioVex / Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodal disease of melanoma.In some embodiments, the immuno-oncology agent is an oncolytic virotherapy such as PexaVec / JX-594 (SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); Reolysin® (Oncolytics) Biotech) (a mutant of respiratory enterovirus (reovirus) that does not replicate in cells that are not activated by RAS in a number of 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); metastatic or advanced epithelial cancers, such as ovarian cancer (NCT02028117), colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036) Enadenotusilev (NG-348, PsiOxus, formerly known as ColoAd1) (an adenovirus engineered to express full-length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein) in tumors; ONCOS-102 (Targovax / formerly Oncos) (an adenovirus engineered to express GM-CSF) in melanoma (NCT03003676) and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux) GmbH) (vaccinia viruses engineered to express beta-galactosidase (beta-gal) / beta-glucoronidase or beta-gal / human sodium iodide symporter (hNIS) were investigated in peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, ovarian cancer (NCT02759588), respectively); or CG0070 (Cold Genesys) (adenovirus engineered to express GM-CSF) in bladder cancer (NCT02365818).

[0362] In some embodiments, the immuno-oncology agents include JX-929 (SillaJen / formerly Jennerex Biotherapeutics) (a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, capable of converting the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil); TG01 and TG02 (Targovax / formerly Oncos) (peptide-based immunotherapeutics targeting refractory RAS mutations); and TILT-123 (TILT Biotherapeutics) (an engineered adenovirus designated Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20); and VSV-GP (ViraTherapeutics) (an engineered adenovirus engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) and targeting antigen-specific CD8 + The virus is selected from vesicular stomatitis virus (VSV), which can be further engineered to express antigens designed to enhance T cell responses.

[0363] In some embodiments, the immuno-oncology agent is a T cell that has been engineered to express a chimeric antigen receptor, or CAR. Such T cells that have been engineered to express a chimeric antigen receptor are called CAR-T cells.

[0364] CARs are constructed that consist of a binding domain, which can be derived from a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen, which is a natural ligand, and fused to an endodomain that is the functional end of a T cell receptor (TCR), such as the CD3-zeta signaling domain derived from the TCR, which can generate an activation signal in T lymphocytes. Upon binding to an antigen, such a CAR links to an endogenous signaling pathway in effector cells, generating an activation signal similar to that initiated by the TCR complex.

[0365] For example, in some embodiments, the CAR-T cells are one of those described in U.S. Pat. No. 8,906,682 (each of which is incorporated by reference herein in its entirety), which discloses CAR-T cells engineered to include an extracellular domain having an antigen-binding domain (such as a domain that binds to CD19) fused to the intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3-zeta). When expressed in T cells, CARs can redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. More than 200 clinical trials are currently underway using CAR-T cells in a wide range of indications [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0366] In some embodiments, the immunostimulatory agent is an activator of retinoic acid receptor-related orphan receptor gamma (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as in the differentiation of IL-17-expressing innate immune cell subsets, such as NK cells. In some embodiments, the activator is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0367] In some embodiments, the immunostimulatory agent is a toll-like receptor (TLR) agonist or activator. Suitable TLR activators include TLR9 agonists or activators, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG currently being investigated for follicular B-cell and other lymphomas (NCT02254772). TLR8 agonists or activators that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which is currently being investigated for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0368] Other immuno-oncology agents that can be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; varilumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck & Co., Inc.), an anti-KIR monoclonal antibody; Co.), and anti-GITR monoclonal antibody.

[0369] In some embodiments, the immunostimulatory agent is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORγt.

[0370] In some embodiments, the immunostimulatory therapeutic agent is recombinant human interleukin-15 (rhIL-15). rhIL-15 is being tested in the clinic as a therapeutic agent for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888), and leukemia (NCT02689453). In some embodiments, the immunostimulatory agent is recombinant human interleukin-12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic agent is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex consisting of a synthetic form of endogenous IL-15 complexed to the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA), which is being tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin-12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0371] 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, pages 603-622, the contents of which are incorporated herein by reference in their 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.

[0372] 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, pages 319-329, the contents of which are incorporated by reference in their entirety. In some embodiments, the immuno-oncology agent is an agent that targets a pathway described in Peter L. Toogood.

[0373] In some embodiments, the tumor immunoagent is selected from those described in Sandra L. Ross et al., "Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing," PLoS ONE 12(8):e0183390, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the tumor immunoagent is a bispecific T cell engager (BiTE®) antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, which release cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, which results in the induction of bystander cell lysis. In some embodiments, the bystander cells are within a solid tumor. In some embodiments, the lysing bystander cells are in the vicinity of the BiTE®-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 tumor immunotherapy agent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the tumor immunotherapy agent is ex vivo expanded tumor-infiltrating T cells.In some embodiments, the tumor immunotherapeutic agent is a bispecific antibody construct or a chimeric antibody receptor (CAR) that directly links T cells to tumor-associated surface antigens (TAAs).

[0374] Exemplary Immune Checkpoint Inhibitors In some embodiments, the immuno-oncology agent is an immune checkpoint inhibitor as described herein.

[0375] The term " checkpoint inhibitor " as used herein refers to an agent that is useful for preventing cancer cells from evading the immune system of patients.One of the main mechanisms of anti-tumor immune destruction is known as " T cell exhaustion ", which is caused by long-term exposure to antigen, which leads to the upregulation of inhibitory receptors.These inhibitory receptors act as immune checkpoints to prevent indiscriminate immune responses.

[0376] PD-1 and co-inhibitory receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), B- and T-lymphocyte attenuator (BTLA; CD272), T-cell immunoglobulin and mucin domain-3 (Tim-3), and lymphocyte-activation gene-3 (Lag-3; CD223) are often referred to as checkpoint regulators. They act as molecular “gatekeepers” that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

[0377] In some embodiments, the immune checkpoint inhibitor is an antibody to PD-1, which binds to the programmed death 1 receptor (PD-1) and prevents this receptor from binding to the inhibitory ligand PDL-1, thus abolishing the tumor's ability to suppress the host's anti-tumor immune response.

[0378] In one embodiment, the checkpoint inhibitor is a biological therapeutic agent or a small molecule. In another embodiment, the checkpoint inhibitor is a monoclonal antibody, a humanized antibody, a fully human antibody, a fusion protein, or a combination thereof. In a further embodiment, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligands, or a combination thereof. In additional embodiments, the checkpoint inhibitor interacts with a ligand of a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, a ligand of the B-7 family, or a combination thereof. In certain embodiments, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In further embodiments, the interleukin is IL-7 or IL-15. In certain embodiments, the interleukin is glycosylated IL-7. In additional aspects, the vaccine is a dendritic cell (DC) vaccine.

[0379] Checkpoint inhibitors include any agent that blocks or inhibits an inhibitory pathway of the immune system in a statistically significant manner. Such inhibitors can include small molecule inhibitors, or can include antibodies or antigen-binding fragments thereof that bind to and block or inhibit immune checkpoint receptors, or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Exemplary immune checkpoint molecules that can be targeted for blockage or inhibition include, but are not limited to, CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, GAL9, LAG3, TIM3, VISTA, KIR, 2B4 (belonging to the CD2 family of molecules), and NK, gamma delta, and memory CD8. +(expressed on all αβ T cells), CD160 (also called BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Checkpoint inhibitors include antibodies or antigen-binding fragments thereof, other binding proteins, biotherapeutics, or small molecules that bind to and block or inhibit the activity of one or more of CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Exemplary immune checkpoint inhibitors include tremelimumab (CTLA-4 blocking antibody) (anti-OX40), PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody), and ipilimumab (anti-CTLA-4 checkpoint inhibitor). Checkpoint protein ligands include, but are not limited to, PD-L1, PD-L2, B7-H3, B7-H4, CD28, CD86, and TIM-3.

[0380] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. In some embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab (Opdivo®), ipilimumab (Yervoy®), and pembrolizumab (Keytruda®). In some embodiments, the checkpoint inhibitor is selected from nivolumab (anti-PD-1 antibody, Opdivo®, Bristol-Myers Squibb); pembrolizumab (anti-PD-1 antibody, Keytruda®, Merck); ipilimumab (anti-CTLA-4 antibody, Yervoy®, Bristol-Myers Squibb); durvalumab (anti-PD-L1 antibody, Imfinzi®, AstraZeneca); and atezolizumab (anti-PD-L1 antibody, Tecentriq®, Genentech).

[0381] In some embodiments, the checkpoint inhibitor is selected from the group consisting of lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab (Keytruda®), or tremelimumab.

[0382] In some embodiments, the immune checkpoint inhibitor is REGN2810 (Regeneron) (an anti-PD-1 antibody studied in patients with basal cell carcinoma (NCT03132636); NSCLC (NCT03088540); cutaneous squamous cell carcinoma (NCT02760498); lymphoma (NCT02651662); and melanoma (NCT03002376)); pidilizumab (CureTech) (an antibody that binds to PD-1, also known as CT-011), which is in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab (Bavencio®, Pfizer / Merck), which is in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer). KGaA) (also known as MSB0010718C, a fully human IgG1 anti-PD-L1 antibody); or PDR001 (Novartis), an inhibitory antibody that binds to PD-1, which is in clinical trials for non-small cell lung cancer, melanoma, triple-negative breast cancer, and advanced, metastatic solid tumors. Tremelimumab (CP-675,206; Astrazeneca) is a fully human monoclonal antibody against CTLA-4 that has been investigated in clinical trials for several indications, including mesothelioma, colorectal cancer, renal cancer, breast cancer, lung and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, squamous cell carcinoma of the head and neck, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, ovarian cancer, cervical cancer, metastatic anaplastic thyroid cancer, urothelial carcinoma, fallopian tube cancer, multiple myeloma, bladder cancer, soft tissue sarcoma, and melanoma. AGEN-1884 (Agenus) is an anti-CTLA4 antibody currently being investigated in a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0383] In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoglobulin mucin-containing protein-3 (TIM-3). TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody currently being investigated in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody currently being investigated in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody currently being investigated in advanced malignancies (NCT02608268).

[0384] In some embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoreceptor with Ig and ITIM domains, i.e., TIGIT, an immunoreceptor on certain T cells and NK cells. TIGIT inhibitors that can be used in the present invention include BMS-986207 (Bristol-Myers Squibb), anti-TIGIT monoclonal antibody (NCT02913313); OMP-313M32 (Oncomed); and anti-TIGIT monoclonal antibody (NCT03119428).

[0385] In some embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte activation gene-3 (LAG-3). LAG-3 inhibitors that can be used in the present invention include BMS-986016, REGN3767, and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is currently being investigated in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody and is currently being investigated in malignant tumors (NCT03005782). IMP321 (Immutep SA) is a LAG-3-Ig fusion protein and is being investigated in melanoma (NCT02676869); adenocarcinoma (NCT02614833); and metastatic breast cancer (NCT00349934).

[0386] Checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists currently being investigated in clinical trials include PF-04518600 / PF-8600 (Pfizer) (agonistic anti-OX40 antibodies) in metastatic kidney cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck) (agonistic anti-OX40 antibody) in a Phase 1 cancer clinical trial (NCT02528357); MCT02318394 and NCT02705482 in advanced solid tumors. These include EDI0562 (Medimmune / AstraZeneca) (agonistic anti-OX40 antibody); MEDI6469 (agonistic anti-OX40 antibody) (Medimmune / AstraZeneca) in patients with colorectal cancer (NCT02559024), breast cancer (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb) (agonistic anti-OX40 antibody) in advanced cancers (NCT02737475).

[0387] The checkpoint inhibitor that can be used in the present invention includes CD137 (also known as 4-1BB) agonist.The CD137 agonist that is currently being investigated in clinical trials includes utomilumab (PF-05082566, Pfizer) (agonistic anti-CD137 antibody) in diffuse large B-cell lymphoma (NCT02951156) and advanced cancer and neoplasm (NCT02554812 and NCT05082566); Urelumab (BMS-663513, Bristol-Myers Squibb) (agonistic anti-CD137 antibody) in melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981).

[0388] The checkpoint inhibitors that can be used in the present invention include CD27 agonists.CD27 agonists currently being investigated in clinical trials include varlilumab (CDX-1127, Celldex Therapeutics) (agonistic anti-CD27 antibody) in squamous cell head and neck cancer, ovarian cancer, colorectal cancer, renal cell carcinoma and glioblastoma (NCT02335918), lymphoma (NCT01460134), and glioma and astrocytoma (NCT02924038).

[0389] Checkpoint inhibitors that can be used in the present invention include glucocorticoid-induced tumor necrosis factor receptor (GITR) agonists. GITR agonists currently being investigated in clinical trials include TRX518 (Leap Therapeutics) (agonistic anti-GITR antibody) in melanoma and other malignant solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis) (agonistic anti-GITR antibody) in solid tumors and lymphomas (NCT02740270); INCAGN01876 (Incyte / Agenus) (agonistic anti-GITR antibody) in advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck) (agonistic anti-GITR antibody) in solid tumors (NCT02132754), and MEDI1873 (Medimmune / AstraZeneca) (human IgG1) in advanced solid tumors (NCT02583165). agonistic hexameric GITR ligand molecules having an Fc domain.

[0390] Checkpoint inhibitors that can be used in the present invention include inducible T cell costimulatory agent (ICOS, also known as CD278) agonists. ICOS agonists currently being investigated in clinical trials include MEDI-570 (Medimmune) (agonistic anti-ICOS antibody) in lymphoma (NCT02520791); GSK3359609 (Merck) (agonistic anti-ICOS antibody) in a phase 1 trial (NCT02723955); and JTX-2011 (Jounce Therapeutics) (agonistic anti-ICOS antibody) in a phase 1 trial (NCT02904226).

[0391] Checkpoint inhibitors that can be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors currently being investigated in clinical trials include lirilumab (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody, in leukemia (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma), in myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to the long cytoplasmic tail three domain (KIR3DL2), in lymphoma (NCT02593045).

[0392] Checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPa). CD47 / SIRPa inhibitors currently being investigated in clinical trials include ALX-148 (Alexo Therapeutics), in a Phase 1 trial (NCT03013218), an antagonistic variant of (SIRPa) that binds to CD47 and blocks CD47 / SIRPa-mediated signaling; TTI-621 (SIRPa-Fc, Trillium Therapeutics), in Phase 1 clinical trials (NCT02890368 and NCT02663518), a soluble recombinant fusion protein generated by linking the N-terminal CD47-binding domain of SIRPa to the Fc domain of human IgG1, which binds to human CD47 and blocks human CD47 from its "do not eat me" message. These include CC-90002 (Celgene), an anti-CD47 antibody, in leukemia (NCT02641002); and Hu5F9-G4 (Forty Seven, Inc.), in colorectal neoplasia and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0393] Checkpoint inhibitors that can be used in the present invention include CD73 inhibitors. CD73 inhibitors currently being investigated in clinical trials include MEDI9447 (Medimmune), an anti-CD73 antibody, in solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody, in solid tumors (NCT02754141).

[0394] Checkpoint inhibitors that can be used in the present invention include agonists of the stimulator of interferon genes protein (STING, also known as transmembrane protein 173 or TMEM173). STING agonists currently being investigated in clinical trials include MK-1454 (Merck), an agonistic synthetic cyclic dinucleotide, in lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonistic synthetic cyclic dinucleotide, in Phase 1 trials (NCT02675439 and NCT03172936).

[0395] Checkpoint inhibitors that can be used in the present invention include CSF1R inhibitors. CSF1R inhibitors currently being investigated in clinical trials include pexidartinib (PLX3397, Plexxikon) (a CSF1R small molecule inhibitor) in colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710), melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumor (GIST), and ovarian cancer (NCT02452424); and pancreatic cancer (NCT03153410), melanoma (NCT031012 54) and solid tumors (NCT02718911); IMC-CS4 (LY3022855, Lilly) (anti-CSF-1R antibody); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxyl]-pyridine-2-carboxylic acid methylamide, Novartis) (an orally available inhibitor of CSF1R) in advanced solid tumors (NCT02829723).

[0396] Checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors currently being investigated in clinical trials include monalizumab (IPH2201, Innate Pharma), an anti-NKG2A antibody, in head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0397] In some embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab. [Example]

[0398] As shown in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures: While the general methods illustrate the synthesis of certain specific compounds of the present disclosure, it is understood that the following general methods, and other methods known to those of skill in the art, can be applied to all compounds and each subclass and species of these compounds as described herein. General Procedure Analysis method X-ray powder diffraction (XRPD)

[0399] XRPD analysis was performed on a PANalytical X'pert Pro equipped with a PIXcel detector (128 channels), scanning samples between 3 and 35°2θ. The material was gently crushed to loosen any aggregates and loaded onto a multiwell plate using a Kapton or Mylar polymer film to support the sample. The multiwell plate was then placed in a diffractometer and analyzed using Cu K radiation (αλ = 1.54060 Å, α = 1.54443 Å, β = 1.39225 Å, α:α ratio = 0.5) in transmission mode (step size 0.0130°2θ, step time 18.87 s) with a generator setting of 40 kV / 40 mA. Data were visualized and imaged using the HighScore Plus 4.7 desktop application (PANalytical, 2017). Polarized Light Microscope (PLM)

[0400] The presence of crystallinity (birefringence) was determined using an Olympus BX53 microscope equipped with cross-polarized lenses and a Motic camera. Images were captured using Motic Images Plus 3.0. All images were recorded using a 20x objective lens unless otherwise noted. Thermogravimetric analysis / differential scanning calorimetry (TGA / DSC)

[0401] Approximately 5–10 mg of material was added to a pre-tared, open aluminum pan and loaded into a TA Instruments Discovery SDT 650 Auto-Simultaneous DSC. The sample was then heated from 30°C to 400°C at a rate of 10°C / min, during which the weight change of the sample was recorded along with the heat flow response (DSC). Nitrogen was used as the sample purge gas at a flow rate of 200 cm. 3 / min. Infrared spectroscopy (IR)

[0402] Infrared spectroscopy was performed on a Bruker ALPHA P spectrometer. Sufficient material was placed in the center of the spectrometer plate and a spectrum was acquired using the following parameters: [Table 6] nuclear magnetic resonance (NMR)

[0403] NMR experiments were performed on a Bruker AVIIIHD spectrometer equipped with a DCH cryoprobe operating at 500.12 MHz. Experiments were performed in deuterated dimethyl sulfoxide, and each sample was prepared to a concentration of approximately 10 mM. High-performance liquid chromatography-ultraviolet detection (HPLC-UV) method [Table 7] Chiral Analysis [Table 8] (Example A1) Preparation of Compound 1 [1-[(4-Methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (Intermediate IQ) [ka] Step 1 - 5-Oxotetrahydrofuran-2-carboxylic acid To a solution of 2-aminopentanedioic acid (210 g, 1.43 mol, CAS number 617-65-2) in HO (800 mL) and HCl (12 M, 210 mL) was added a solution of NaNO (147 g, 2.13 mol) in HO (400 mL) at −5° C. The mixture was stirred at 15° C. for 12 h. Upon completion, the mixture was concentrated, then dissolved in EA (500 mL), filtered, and washed with EA (3×100 mL). The filtrate and washed solution were dried over NaSO, filtered, and concentrated in vacuo to give the title compound (200 g, crude) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ6.43 (s, 1H), 5.02- 4.95 (m, 1H), 2.67 - 2.38 (m, 4H) Step 2 - N-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide To 5-oxotetrahydrofuran-2-carboxylic acid (120 g, 922 mmol), SOCl2 (246 g, 2.07 mol) was slowly added at 0 °C. The mixture was stirred at 85 °C for 3 hours, and then the mixture was stirred at 15 °C for 6 hours. The mixture was concentrated in vacuo. The residue was dissolved in dry DCM (1 L) under N2 at 0 °C. A solution of Et3N (187 g, 1.84 mol) and 4-methoxybenzylamine (101 g, 738 mmol) in DCM (400 mL) was then added, and the mixture was stirred at 15 °C for 3 hours. Upon completion, water (600 mL) was added, and the mixture was extracted with DCM (3 × 300 mL). The combined organic phase was washed with 0.5 M HCl (500 mL), brine (500 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash silica gel chromatography (PE:EA=1:1) to give the title compound (138 g, 60% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.22 - 7.20 (d, J= 8.0, 1H), 6.89 - 6.87 (d, J = 8.0, 1H), 4.90 - 4.86 (m, 1H),4.47 -4.4.36 (m, 2H) 3.81 (s, 3H), 2.67 - 2.64 (m, 1H), 2.59 - 2.54 (m, 2H),2.40 -2.38 (m, 1H);LC-MS(ESI + ) m / z 272.0 (M+Na) + . Step 3 - 3-Hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione A solution of N-[(4-methoxyphenyl)methyl]-5-oxo-tetrahydrofuran-2-carboxamide (138 g, 553 mmol) in anhydrous THF (1500 mL) was cooled to −78° C. Then, t-BuOK (62.7 g, 559 mmol) in anhydrous THF (1000 mL) was slowly added dropwise at −78° C. under a nitrogen atmosphere. The resulting reaction mixture was stirred at −40° C. for 1 hour. Upon completion, the reaction mixture was quenched with saturated NH4Cl solution (100 mL). The mixture was extracted with ethyl acetate (3×1500 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (PE:EA=1:1) to give the title compound (128 g, 92% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ7.39 - 7.32 (m, 2H), 6.89 - 6.81(m, 2H), 4.91 (s, 2H), 4.17 - 4.11 (m, 1H),3.80 (s, 3H), 3.54 (s, 1H), 2.98 -2.87 (m, 1H),2.73 - 2.60 (m, 1H), 2.26 - 2.20 (m, 1H), 1.80 (dq, J = 4.8, 13.1 Hz, 1H). Step 4 - [1-[(4-Methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate To a solution of 3-hydroxy-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (43.0 g, 173 mmol) and pyridine (27.3 g, 345 mmol) in DCM (500 mL) was added trifluoromethylsulfonyl trifluoromethanesulfonate (73.0 g, 258 mmol) dropwise at 0° C. The mixture was stirred at −10° C. under N for 1.5 hours. Upon completion, the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE:EA=20:1 / 8:1) to afford the title compound (45.0 g, 68% yield) as a pale yellow gum. 1 H NMR (400MHz, CDCl3)δ 7.36 (d, J = 8.4 Hz, 2H), 6.85 -6.82 (m, 2H), 5.32 - 5.28 (m, 1H), 4.91 (s,2H), 3.79 (s, 3H), 3.02 - 2.97 (m,1H), 2.79 - 2.74 (m, 1H), 2.41 - 2.35 (m, 2H). 3-(4-Bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione (Intermediate HP) [ka] Step 1 - 2-Bromo-N-methyl-6-nitro-aniline To a solution of 1-bromo-2-fluoro-3-nitro-benzene (40.0 g, 181 mmol, CAS#58534-94-4) in THF (40 mL) was added MeNH2 (2 M, 400 mL). The reaction mixture was stirred at 60 °C for 12 h. Upon completion, the reaction mixture was poured into saturated NaHCO3 (30 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (40.0 g, 95% yield) as a red oil. LC-MS (ESI + ) m / z 230.9 (M+H) + . Step 2 - 3-Bromo-N2-methyl-benzene-1,2-diamine To a mixture of 2-bromo-N-methyl-6-nitroaniline (23.0 g, 99.5 mmol) in EA (300 mL) and HO (10 mL) was added AcOH (100 mL). The mixture was warmed to 50° C. Then, Fe (22.2 g, 398 mmol) was added to the reaction mixture, and the mixture was heated to 80° C. for approximately 4 h. Upon completion, the reaction mixture was filtered and concentrated in vacuo. The residue was diluted with water (100 mL) and extracted with EA (3×200 mL). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo to give the title compound (20.0 g, 99% yield) as a red oil. 1 H NMR (400MHz, DMSO-d6)δ6.73 - 6.70 (m, 1H), 6.68 - 6.60 (m, 2H), 5.02 (s, 2H), 3.67 (s, 1H), 2.58(s,3H). Step 3 - 4-Bromo-3-methyl-1H-benzimidazol-2-one To a mixture of 3-bromo-N2-methyl-benzene-1,2-diamine (20.0 g, 99.4 mmol) in ACN (300 mL) was added CDI (32.2 g, 198 mmol). The reaction mixture was stirred at 85° C. under a N2 atmosphere for 12 hours. Upon completion, the reaction mixture was concentrated in vacuo. The reaction mixture was diluted with water (200 mL), at which time a solid precipitate formed, which was filtered off. The solid was washed with water (1 L) and dried in vacuo to give the title compound (20.0 g, 88% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ11.17 (s, 1H), 7.14 (dd, J = 1.2, 8.0 Hz, 1H),7.00 - 6.95 (m, 1H), 6.93 - 6.87(m, 1H), 3.55 (s, 3H). Step 4 - 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione To a solution of 4-bromo-3-methyl-1H-benzimidazol-2-one (12.0 g, 52.8 mmol) in THF (300 mL) was added t-BuOK (7.12 g, 63.4 mmol). The reaction mixture was stirred at 0° C. for 0.5 h. Then, a solution of [1-[(4-methoxyphenyl)methyl]-2,6-dioxo-3-piperidyl]trifluoromethanesulfonate (20.1 g, 52.8 mmol, Intermediate IQ) in THF (100 mL) was added dropwise. The resulting reaction mixture was stirred at 20° C. under N for 0.5 h. Upon completion, the reaction mixture was quenched with saturated NH4Cl (100 mL) and extracted with ethyl acetate (200 mL). The combined organic layers were washed with brine (2×100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by reverse phase HPLC (0.1% FA) to give the title compound (13.3 g, 55% yield) as a yellow solid. 1 H NMR(400MHz, CDCl3) δ7.38 (d, J = 8.8 Hz, 2H),7.22 (d, J = 8.0 Hz, 1H), 6.84 (d, J = 8.8 Hz, 2H),6.80 (t, J= 8.0 Hz, 1H), 6.48 - 6.40 (d, J = 8.0 Hz, 1H), 5.22 (dd, J =5.2,12.8 Hz, 1H), 5.04 -4.93 (m, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.12 - 2.98(m, 1H), 2.93 - 2.77 (m,1H), 2.62 (dq, J = 4.4, 13.2 Hz, 1H), 2.20 -2.17 (m, 1H). Step 5 - 3-(4-bromo-3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-2,6-dione A mixture of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)-1-[(4-methoxyphenyl)methyl]piperidine-2,6-dione (13.3 g, 29.0 mmol) in a mixed solvent of Toluene (80 mL) and methanesulfonic acid (40 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 120 °C under a N2 atmosphere for 2 hours. Upon completion, the reaction mixture was concentrated in vacuo to remove toluene. 200 mL of ice water was added to the residue, forming a white solid precipitate. The mixture was filtered, and the filter cake was collected and dried in vacuo to give the title compound (7.30 g, 74% yield) as a white solid. 1 H NMR(400MHz, DMSO-d6) δ11.13 (s, 1H), 7.25(d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 7.05 - 6.93(m,1H), 5.41 (dd, J = 5.2, 12.8 Hz, 1H), 3.64 (s, 3H), 2.96 - 2.83 (m,1H),2.78 - 2.59 (m, 2H), 2.08 - 2.00 (m, 1H). tert-Butyl 4-prop-2-ynoxypiperidine-1-carboxylate (Intermediate TM) [ka] A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2.00 g, 9.94 mmol, CAS number 109384-19-2) in anhydrous THF (10 mL) was cooled to 0° C., followed by the addition of NaH (477 mg, 11.9 mmol, 60% oil dispersion). The reaction mixture was stirred at 0° C. for 0.5 hours. 3-Bromoprop-1-yne (1.18 g, 9.94 mmol, 856 μL) was then added. The resulting reaction mixture was stirred at 25° C. for 12 hours. Upon completion, the reaction mixture was quenched with water (1 mL) and then diluted with ethyl acetate (100 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography to give the title compound (2.38 g, 100% yield) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ4.22 (d, J= 2.4 Hz, 2H), 3.84 - 3.75 (m, 2H), 3.73 - 3.70 (m, 1H), 3.15 - 3.09(m, 2H),2.43 (t, J = 2.4 Hz, 1H), 1.93 - 1.82 (m, 2H), 1.61 - 1.50 (m, 2H),1.47(s, 9H). 3-[3-methyl-2-oxo-4-[3-(4-piperidyloxy)prop-1-ynyl]benzimidazol-1-yl]piperidine-2,6-dione (Intermediate APT) Step 1 - tert-Butyl 4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]piperidine-1-carboxylate [ka] A suspension of 3-(4-bromo-3-methyl-2-oxo-benzimidazol-1-yl)piperidine-2,6-dione (300 mg, 887 μmol, Intermediate HP), tert-butyl 4-prop-2-ynoxypiperidine-1-carboxylate (318 mg, 1.33 mmol, Intermediate TM), Pd(PPh)Cl (124 mg, 177 μmol), CuI (33.8 mg, 177 μmol), 4 Å molecular sieves (400 mg), and CsCO (1.16 g, 3.55 mmol) in DMF (5 mL) was degassed under vacuum and purged with N several times, then heated to 80° C. under N for 2 h. Upon completion, the reaction mixture was concentrated in vacuo to remove DMF. The residue was diluted with EA (50 mL) and water (20 mL). The organic layer was then separated, washed with brine (5 mL x 2), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by reverse phase to give the title compound (222 mg, 48% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.09 (s, 1H), 7.10(d, J = 8.0 Hz, 1H), 6.92 (t, J = 8.0 Hz, 1H), 6.69 (d, J=8.0 Hz, 1H), 5.13 (dd, J = 5.2, 12.8 Hz, 1H), 4.39 (s, 2H), 3.76 -3.66 (m, 6H),3.09 - 3.03(m, 2H), 2.94 - 2.84 (m, 1H), 2.82 - 2.71 (m, 1H),2.71 - 2.59 (m,1H), 2.22 - 2.11 (m, 1H), 1.83 - 1.78 (m, 2H),1.57 - 1.49 (m,2H), 1.39 (s, 9H),LC-MS(ESI + ) m / z 441.2 (M+H-56) + . Step 2-3-[3-methyl-2-oxo-4-[3-(4-piperidyloxy)prop-1-ynyl]benzimidazol-1-yl]piperidine-2,6-dione [ka] To a mixture of tert-butyl 4-[3-[1-(2,6-dioxo-3-piperidyl)-3-methyl-2-oxo-benzimidazol-4-yl]prop-2-ynoxy]piperidine-1-carboxylate (1.50 g, 3.02 mmol) in DCM (30 mL) was added TFA (23.1 g, 202 mmol, 15 mL). The reaction mixture was stirred at 20° C. for 1 hour. Upon completion, the reaction mixture was concentrated in vacuo to give the title compound (1.50 g, 97% yield, TFA salt) as a yellow oil. LC-MS (ESI + ) m / z 397.2(M+H) + . 5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (intermediate AEH) [ka] Step 1 - Ethyl 5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate To a solution of ethyl 5-chloropyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg, 886 μmol, CAS number 1224944-77-7) and (1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (144 mg, 1.06 mmol, HCl salt, CAS number 661470-56-0) in ACN (5.00 mL) was added DIPEA (343 mg, 2.66 mmol). The mixture was stirred at 60° C. for 3 h. Upon completion, the reaction mixture was concentrated in vacuo, then diluted with water (5 mL) and extracted with EA (2×10 mL). The combined organic layers were washed with brine (2×30 mL), dried over NaSO, and concentrated in vacuo to give the title compound (180 mg, 70% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ8.38 - 8.18 (m, 2H), 6.12 (s,1H), 5.46 (s, 1H), 4.77 (s, 1H), 4.34 (q, J = 7.2Hz, 2H), 4.06 - 3.87 (m, 2H),3.75 - 3.38 (m, 2H), 2.09 - 1.90 (m, 2H), 1.38 (t,J = 7.2 Hz, 3H). Step 2 - 5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid To a solution of ethyl 5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylate (150 mg, 520 μmol) in MeOH (10.0 mL) and HO (2.00 mL) was added LiOH·HO (43.6 mg, 1.04 mmol). The mixture was stirred at 60° C. for 16 h. Upon completion, the reaction mixture was quenched with water (1 mL) and concentrated in vacuo to remove MeOH. The mixture was then acidified with HCl (1 N) to pH = 5. The aqueous phase was extracted with EA (3 × 5 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound (135 mg, 99% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 11.31 - 9.30(m,1H), 8.32 (d, J = 7.6 Hz, 1H), 8.28 (s, 1H), 6.44 - 6.12 (m, 1H), 5.29 -4.58(m, 2H), 4.00 - 3.85 (m, 2H), 3.77 - 3.49 (m, 2H), 2.20 - 1.97 (m, 2H). Methyl 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexanecarboxylate (Intermediate QS) [ka] Step 1 - Methyl 4-methylsulfonyloxycyclohexanecarboxylate To a mixture of methyl 4-hydroxycyclohexanecarboxylate (1.00 g, 6.32 mmol, CAS#3618-03-9) in DCM (10 mL) was added TEA (831 mg, 8.22 mmol) and MsCl (1.09 g, 9.48 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. Upon completion, the mixture was poured into ice water (50 mL) and extracted with DCM (2 × 30 mL). The combined organic phase was washed with brine (2 × 50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (1.20 g, 80% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3)δ4.91 (t, J = 2.8, 5.2 Hz, 1H), 3.69 (s, 3H), 3.02 (s, 3H), 2.41 - 2.39(m,1H), 2.09 - 1.99 (m, 2H), 1.97 - 1.86 (m, 2H), 1.80 (t, J = 4.4, 9.2Hz, 2H),1.75 - 1.66 (m, 2H). Step 2 - Methyl 4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]cyclohexanecarboxylate To a mixture of 3-(difluoromethyl)-4-nitro-1H-pyrazole (555 mg, 3.40 mmol, Intermediate HS) and methyl 4-methylsulfonyloxycyclohexanecarboxylate (1.20 g, 5.08 mmol) in DMF (30 mL) was added K2CO3 (2.11 g, 15.2 mmol). The reaction mixture was stirred at 80 °C for 12 h. Upon completion, the mixture was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with brine (2 × 40 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography to give the title compound (480 mg, 25% yield) as a brown oil.1 H NMR (400 MHz, CDCl3)δ8.23 (s, 1H), 7.25 - 6.96 (m, 1H), 4.26 - 4.14 (m,1H), 3.76 - 3.65 (m, 3H),2.40 (t, J = 3.6, 12.4 Hz, 1H), 2.36 - 2.17 (m, 4H),1.83 (d, J =3.6, 12.8 Hz, 2H), 1.69 - 1.59 (m, 2H). Step 3 - Methyl 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexanecarboxylate To a mixture of methyl 4-[3-(difluoromethyl)-4-nitro-pyrazol-1-yl]cyclohexanecarboxylate (430 mg, 1.42 mmol) in THF (20 mL) was added Pd / C (100 mg, 10 wt%) under N2. The suspension was degassed under reduced pressure and purged with H2 gas three times. The mixture was stirred under H2 (15 psi) at 25 °C for 12 h. Upon completion, the mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (350 mg, 90% yield) as a brown solid. LC-MS (ESI + ) m / z 274.1 (M+H) + . [4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexyl]methanol (Intermediate TD) [ka] To a mixture of methyl 4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexanecarboxylate (1.20 g, 4.39 mmol, Intermediate QS) in THF (80 mL) and MeOH (10 mL) was added LiBH (191 mg, 8.78 mmol) at 0 °C, and the mixture was then stirred at 60 °C for 1 h. Upon completion, the reaction mixture was poured into water (120 mL) and the aqueous phase was extracted with ethyl acetate (2 × 50 mL). The combined organic phases were washed with brine (2 × 40 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound (860 mg, 79% yield) as a brown solid. 1 H NMR (400 MHz, CDCl3-d) δ7.02 (s,1H), 6.82 - 6.53 (m, 1H), 3.94 (tt, The NMR spectra were as follows: J = 4.0, 12.0 Hz, 1H), 3.50 (d, J = 6.4 Hz, 2H), 2.21 - 2.12 (m, 3H), 2.01 - 1.92 (m, 3H), 1.69 (d, J = 3.6, 12.4 Hz, 2H), 1.56 (tt, J = 3.0, 6.4, 12.0 Hz, 2H), 1.20 - 1.08 (m, 2H). Absolute stereochemistry was randomly assigned, and the compound is the trans isomer. N-[3-(Difluoromethyl)-1-(4-formylcyclohexyl)pyrazol-4-yl]-5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (Intermediate AJB) [ka] Step 1 - N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]-5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide To a solution of 5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (3.71 g, 14.2 mmol, Intermediate AEH) in MeCN (75 mL) was added 1-methylimidazole (4.10 g, 49.9 mmol, 3.98 mL) and [chloro(dimethylamino)methylene]-dimethyl-ammonium hexafluorophosphate (4.80 g, 17.1 mmol). The mixture was stirred at 20° C. for 30 minutes. Then, [4-[4-amino-3-(difluoromethyl)pyrazol-1-yl]cyclohexyl]methanol (3.5 g, 14.2 mmol, Intermediate TD) was added to the mixture, and the reaction mixture was stirred at 20° C. for 2 hours. Upon completion, the reaction mixture was filtered and the filter cake was concentrated in vacuo to afford the title compound (3.80 g, 55% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6)δ9.49 (d, J = 5.2 Hz, 1H), 8.77 (dd, J = 2.4, 8.0 Hz, 1H), 8.39(d, J = 4.0 Hz,1H), 8.25 (d, J = 5.2 Hz, 1H), 7.27 - 6.95 (m,1H), 6.88 -6.40 (m, 1H), 5.32 - 5.01 (m, 1H), 4.76 (d, J = 14.8 Hz,1H), 4.47 (t, J = 5.2Hz, 1H), 4.23 - 4.10 (m, 1H), 3.84 - 3.72 (m, 2H),3.65 - 3.42 (m, 2H), 3.25 (t,J = 5.6 Hz, 2H), 2.07 - 1.90 (m, 4H), 1.89- 1.81 (m, 2H), 1.78 - 1.66 (m, 2H),1.50 - 1.36 (m, 1H), 1.17 - 1.00 (m, 2H); LC-MS (ESI + ) m / z 488.3(M+H) + . Step 2 - N-[3-(Difluoromethyl)-1-(4-formylcyclohexyl)pyrazol-4-yl]-5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide

[0019] To a solution of N-[3-(difluoromethyl)-1-[4-(hydroxymethyl)cyclohexyl]pyrazol-4-yl]-5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (3.80 g, 7.79 mmol) in DCM (78 mL) was added DMP (3.64 g, 8.57 mmol) and the reaction mixture was stirred at 20°C for 3 hours. Upon completion, the reaction mixture was quenched with NaSO (50 mL) and extracted with DCM (2 x 60 mL). The combined organic phase was washed with NaHCO and brine (2 x 20 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound (3.30 g, 87% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6)δ9.60 (s, 1H), 9.49 (d, J = 5.2 Hz, 1H), 8.76 (dd, J = 4.0, 8.0Hz, 1H), 8.40 (d,J = 4.0 Hz, 1H), 8.25 (d, J = 4.8 Hz, 1H), 7.27- 6.94 (m, 1H), 6.88 - 6.40 (m,1H), 5.30 - 5.02 (m, 1H), 4.76 (d, J =14.0 Hz, 1H), 4.29 - 4.14 (m, 1H), 3.85 -3.72 (m, 2H), 3.64 - 3.41 (m, 2H),2.43 - 2.31 (m, 1H), 2.14 - 1.90 (m, 6H),1.88 - 1.73 (m, 2H), 1.48 - 1.24 (m,2H). 5-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-N-(3-(difluoromethyl)-1-((1r,4R)-4-((4-((3-(1-(2,6-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 (Compound 1) [ka] To a solution of 3-[3-methyl-2-oxo-4-[3-(4-piperidyloxy)prop-1-ynyl]benzimidazol-1-yl]piperidine-2,6-dione TFA (52.3 mg, 106 μmol, Intermediate APT) and N-[3-(difluoromethyl)-1-(4-formylcyclohexyl)pyrazol-4-yl]-5-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide (51.4 mg, 106 μmol, Intermediate AJB) in a mixture of DMF (2 mL) and THF (10 mL) was added KOAc (20.8 mg, 212 μmol). After 30 minutes, NaBH(OAc)3 (44.9 mg, 212 μmol) was added to the mixture, and the reaction mixture was stirred at 25 °C for 12 hours. Upon completion, the mixture was concentrated in vacuo. The residue was purified by reverse phase (0.1% FA) to give the title compound as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ11.12 (s, 1H), 9.50 (d, J = 6.4 Hz, 1H),8.78 (d, J= 7.6 Hz, 1H), 8.39 (d, J = 4.4 Hz, 1H), 8.25 (d, J = 5.6 Hz,1H),7.26 - 6.96 (m, 4H), 6.88 - 6.43 (m, 1H), 5.40 (dd, J = 5.2, 12.8Hz, 1H), 5.31- 5.04 (m, 1H), 4.79 - 4.77 (m, 1H), 4.52 (s, 2H), 4.27 - 4.14(m, 1H), 3.84 -3.71 (m, 3H), 3.65 (s, 3H), 3.62 - 3.58 (m, 1H), 3.46 - 3.43(m, 1H), 3.13 - 2.97 (m, 2H),2.97 - 2.79 (m, 2H), 2.78 - 2.68 (m, 2H), 2.68 -2.53 (m, 3H), 2.09 - 1.86 (m,9H), 1.84 - 1.60 (m, 5H), 1.16 - 1.10 (m, 2H);LC-MS(ESI + ) m / z 866.5(M+H) + . (Example A2) IRAK4 degradation in OCI-LY10 (MSD) and hPBMC (flow assay) for compound 1 IRAK4 degradation in the OCI-LY10 assay IRAK4 degradation in OCI-LY10 cells was quantitatively measured using Meso Scale Discovery (MSD) technology. OCI-LY10 cells were seeded into 96-well plates (Corning 3799) at a density of 300,000 cells per well in 100 μL of fresh medium. Compounds were then added to the assay plates in a 1:3 dilution series at final highest concentrations of 1–10 μM for a total of eight doses. The assay plates were then incubated for 4–24 hours at 37°C under 5% CO2. The assay plates were then centrifuged for 5 minutes, and the cell pellets were treated with 100 μL / well of RIPA lysis buffer (Boston BioProducts BP-115D) containing proteinase inhibitors. To prepare MSD assay plates (Meso Scale Discovery catalog number L15XA-3), the plates were coated with 40 μL / well of capture antibody (mouse anti-IRAK4 antibody [2H9], ab119942) at 2 μg / mL in PBS. The plates were then incubated overnight at 4°C, washed three times with 150 μL / well of TBST buffer (Cell Signaling Technology, catalog number 9997S), and blocked with 150 μL / well of blocking buffer (Meso Scale Discovery catalog number R93BA-4). Cell lysates were then added to the MSD assay plates, and the plates were incubated for 1 hour at room temperature. The plates were then washed three times with 150 μL / well of TBST buffer and 25 μL / well of primary detection antibody (rabbit anti-IRAK4 antibody [Y279], Abcam, catalog number ab32511, 1 μg / mL). These assay plates were then incubated for 1 hour at room temperature, washed three times with 150 μL / well of TBST buffer and 25 μL / well of secondary detection antibody, and SULFO-TAG anti-rabbit antibody was added (anti-rabbit antibody from Meso Scale Discovery, catalog number R32AB-1, 1 μg / mL).The assay plates were then incubated for 1 hour at room temperature, washed three times with 150 μL / well of TBST buffer, and 150 μL / well of MSD read buffer (Meso Scale Discovery Catalog No. R92TC-2) was added. The plates were then analyzed using an MSD reader (Meso Scale Discovery, Model Quick Plex SQ 120). The data was then analyzed using GraphPad Prism 7.0 software, and the dose-dependent IRAK4 degradation was fitted using a three-parameter logistic equation to obtain DC. 50 After 4 hours, Compound 1 had a DC of <0.01 μM in the Meso Scale Discovery assay. 50 was demonstrated. hPBMC degradation flow assay Frozen peripheral blood mononuclear cells (PBMCs) were thawed and collected in RPMI containing 10% FBS. On the same day as thawing, PBMCs were plated into 96-well plates at 90 μL per well. Compound plates were prepared and ten-point, 5-fold dilutions were performed with a final DMSO concentration of 0.1%. Test compounds (10 μL per well) were added, sealed, and incubated at 37°C, 5% CO2 for 20 hours (compounds were prepared for the 4-hour treatment and added the next day). After the treatment incubation period (day 1), 1.6% PFA was added to the PBMC plate, placed on a plate shaker for 30 seconds, and incubated at room temperature for 10 minutes. Cells were spun down, washed twice with PBS / 0.5% BSA, pelleted by aspiration, and placed in a -80°C freezer until further processing for flow cytometry. On the day of flow cytometry, the PBMC plate was thawed and samples were transferred to PCR plates. A pre-permeabilization staining cocktail (CD3 Ax488 / CD8 BUV805 / CD14 BUV395 / CD16 / 56 BV711 / CD19 BV785) was added to the samples and incubated at room temperature for 30 minutes. Samples were washed twice and permeabilized with methanol for 10 minutes at 4°C. Samples were washed twice, and a post-permeabilization staining cocktail (CD4 PE / IRAK4 Ax647 BD#560315) was added and incubated at room temperature for 30 minutes. Samples were washed twice with PBS / BSA and run on a BD LSR Fortessa. Mononuclear cells were gated by SSCH / FSCH and single cells. Monocytes were then gated using a CD14 positive gate, and lymphocytes were gated using a CD14 negative gate. To determine absolute DC50 and maximum resolution values, MFI values ​​were normalized to DMSO maximum and 10 μM minimum controls for 20 hours. A 20-hour dose curve was calculated using a four-parameter logistic regression curve fit without constraints (the highest dose was excluded and the lowest was constrained to 0 if a hook effect was observed). After 20 hours, Compound 1 had a DC of <0.01 μM in the flow assay. 50 was demonstrated. Example 1 Preparation of Free Base Forms A and B of Compound 1 [ka]

[0404] Compound 1 is prepared as described elsewhere herein. Compound 1 Form A

[0405] Compound 1 Form A was prepared as follows.

[0406] Approximately 1 g of compound 1 was weighed into a 20 mL vial and transferred to a 100 mL Duran flask, followed by 40 mL of ethanol:water (80:20) to form a slurry. The vial was then capped, sealed with parafilm, and subjected to temperature cycling between ambient temperature (approximately 22 °C) and 40 °C for 72 hours in 4-hour cycles. The material was then filtered under vacuum using a Buchner funnel equipped with a 70.0 mm diameter filter paper. The solid was transferred to a pre-weighed crystallization dish and then dried under vacuum at 40 °C for approximately 12 hours. Approximately 20 mL of the mother liquor was retained in a clean vial.

[0407] Characterization of the resulting material demonstrated crystalline Form A of the free base of Compound 1. The resulting material had a purity of 94.2% as determined by HPLC.

[0408] Table 1 above is reproduced below and lists the X-ray diffraction peaks observed for Compound 1 Form A. [Table 1A]

[0409] FIG. 1A shows the XRPD pattern of Form A of Compound 1.

[0410] FIG. 1B shows the FT-IR spectrum of Form A of Compound 1.

[0411] Figure 1C shows Form A of Compound 1. 1 The H-NMR spectrum is shown. Form B of Compound 1

[0412] Form B of Compound 1 was prepared as follows.

[0413] Approximately 500 mg of the received Compound 1 was weighed into a 20 mL vial, and 20 mL of ethanol:water (93:7) was added, followed by 4 drops of dichloromethane, thereby forming a slurry. The vial was then capped, sealed with parafilm, and subjected to temperature cycling between ambient temperature (approximately 22 °C) and 40 °C for 72 hours in 4-hour cycles. The material was then filtered under vacuum using a Buchner funnel equipped with a 42.5 mm diameter filter paper. The solid was transferred to a pre-weighed vial and then dried under vacuum at 40 °C for approximately 12 hours. Approximately 15 mL of the mother liquor was retained in a clean vial.

[0414] Characterization of the resulting material demonstrated crystalline Form B of the free base of Compound 1. The resulting material had a purity of 94.8% as determined by HPLC.

[0415] Table 2 above is reproduced below and lists the X-ray diffraction peaks observed for Compound 1 Form B. [Table 2A]

[0416] FIG. 2A shows the XRPD pattern of Form B of Compound 1.

[0417] FIG. 2B shows the FT-IR spectrum of Form B of Compound 1.

[0418] Figure 2C shows Form B of Compound 1. 1 The H-NMR spectrum is shown. Example 2 Preparation of Form A of Compound 2 [ka] Form A of Compound 2

[0419] Compound 2 Form A was prepared as follows.

[0420] Approximately 1 g of compound 1 was weighed into a 20 mL vial and transferred to a 100 mL Duran flask, followed by 30 mL of acetonitrile to form a slurry. 1.05 equivalents of HCl in the form of a 1 M stock solution of HCl in THF were added to the slurry. The sample remained a slurry upon addition of the acid. The flask was then capped, sealed with parafilm, and subjected to temperature cycling between ambient temperature (approximately 22 °C) and 40 °C for 72 hours in 4-hour cycles. The material was then filtered under vacuum using a Buchner funnel equipped with a 70.0 mm diameter filter paper. The solid was transferred to a pre-weighed crystallization dish and then dried under vacuum at 40 °C for approximately 12 hours. Approximately 20 mL of the mother liquor was retained in a clean vial.

[0421] Characterization of the resulting material demonstrated anhydrous crystalline Form A of Compound 2. The resulting material had a purity of 92.2% as determined by HPLC.

[0422] Table 3 above is reproduced below and lists the X-ray diffraction peaks observed for Compound 2 Form A. [Table 3A]

[0423] FIG. 3A shows the XRPD pattern of Form A of Compound 2.

[0424] FIG. 3B shows the FT-IR spectrum of Form A of Compound 2.

[0425] Figure 3C shows Form A of Compound 2. 1 The H-NMR spectrum is shown. Example 3 Preparation of Form A of Compound 3 [ka] Form A of Compound 3

[0426] Compound 3 Form A was prepared as follows.

[0427] Approximately 1 g of compound 1 was weighed into a 20 mL vial and transferred to a 100 mL Duran flask, followed by 30 mL of acetone to form a slurry. 1.05 equivalents of fumaric acid in the form of a 1 M stock solution of fumaric acid in THF were added to the slurry. The sample remained a slurry upon addition of the acid. The vial was then capped, sealed with parafilm, and subjected to temperature cycling between ambient temperature (approximately 22 °C) and 40 °C for 72 hours in 4-hour cycles. The material was then filtered under vacuum using a Buchner funnel equipped with a 70.0 mm diameter filter paper. The solid was transferred to a pre-weighed crystallization dish and then dried under vacuum at 40 °C for approximately 12 hours. Approximately 20 mL of the mother liquor was retained in a clean vial.

[0428] Characterization of the resulting material demonstrated anhydrous crystalline Form A of Compound 3. The resulting material had a purity of 92.4% as determined by HPLC.

[0429] Table 4 above is reproduced below and lists the X-ray diffraction peaks observed for Compound 3 Form A. [Table 4A]

[0430] FIG. 4A shows the XRPD pattern of Form A of Compound 3.

[0431] FIG. 4B shows the FT-IR spectrum of Form A of Compound 3.

[0432] Figure 4C shows Form A of Compound 3. 1 The H-NMR spectrum is shown. Without being bound by any particular theory, the integration of the fumarate -CH= peak suggests that the ratio of fumarate to the free base of Compound 1 in Form A of Compound 3 was 1:1. Example 4 Preparation of Form A of Compound 4 [ka] Form A of Compound 4

[0433] Compound 4 Form A was prepared as follows.

[0434] Approximately 1 g of compound 1 was weighed into a 20 mL vial and transferred to a 100 mL Duran flask, followed by 30 mL of acetone to form a slurry. 1.05 equivalents of maleic acid in the form of a 1 M stock solution of maleic acid in THF were added to the slurry. The sample remained a slurry upon addition of the acid. The flask was then capped, sealed with parafilm, and subjected to temperature cycling between ambient temperature (approximately 22 °C) and 40 °C for 72 hours in 4-hour cycles. The material was then filtered under vacuum using a Buchner funnel equipped with a 70.0 mm diameter filter paper. The solid was transferred to a pre-weighed crystallization dish and then dried under vacuum at 40 °C for approximately 12 hours. Approximately 20 mL of the mother liquor was retained in a clean vial. Characterization of the resulting material confirmed anhydrous crystalline Form A of compound 4.

[0435] Table 5 above is reproduced below and lists the X-ray diffraction peaks observed for Compound 4 Form A. The resulting material had a purity of 92.2% as determined by HPLC. [Table 5A]

[0436] FIG. 5A shows the XRPD pattern of Form A of Compound 4.

[0437] FIG. 5B shows the FT-IR spectrum of Form A of Compound 4.

[0438] Figure 5C shows Form A of Compound 4. 1The H-NMR spectrum is shown. Without being bound by any particular theory, the integration of the maleate -CH= peak suggests that the ratio of maleate to Compound 1 free base in Form A of Compound 4 was 1:1. The present invention provides, for example, the following items. (Item 1) Crystalline solid forms of Compound 1 [ka] A crystalline solid form selected from Form A and Form B. (Item 2) 2. The crystalline solid form of item 1, wherein the compound is a crystalline solid that is substantially free of amorphous Compound 1. (Item 3) 2. The crystalline solid form of item 1, wherein the compound is substantially free of impurities. (Item 4) 4. The crystalline solid form according to any one of items 1 to 3, wherein said crystalline solid form is Form A of Compound 1. (Item 5) 5. The crystalline solid form of item 4, having in its X-ray powder diffraction pattern one or more peaks selected from peaks at about 6.0, about 16.5, about 17.2, about 23.0, and about 23.9 degrees two-theta. (Item 6) 5. The crystalline solid form of item 4, having in its X-ray powder diffraction pattern two or more peaks selected from peaks at about 6.0, about 16.5, about 17.2, about 23.0, and about 23.9 degrees two-theta. (Item 7) 5. The crystalline solid form of item 4, having in its X-ray powder diffraction pattern three or more peaks selected from peaks at about 6.0, about 16.5, about 17.2, about 23.0, and about 23.9 degrees two-theta. (Item 8) 5. The crystalline solid form of item 4, having in its X-ray powder diffraction pattern four or more peaks selected from peaks at about 6.0, about 16.5, about 17.2, about 23.0, and about 23.9 degrees two-theta. (Item 9) 5. The crystalline solid form of item 4, having five peaks in its X-ray powder diffraction pattern selected from peaks at about 6.0, about 16.5, about 17.2, about 23.0, and about 23.9 degrees two-theta. (Item 10) 5. The crystalline solid form of item 4, having an X-ray powder diffraction pattern substantially as shown in FIG. 1A. (Item 11) 4. The crystalline solid form according to any one of items 1 to 3, wherein the crystalline solid form is Form B. (Item 12) 12. The crystalline solid form of item 11, having in its X-ray powder diffraction pattern one or more peaks selected from peaks at about 3.2, about 16.2, about 16.5, about 17.1, and about 18.2 degrees two-theta. (Item 13) 12. The crystalline solid form of item 11, having in its X-ray powder diffraction pattern two or more peaks selected from peaks at about 3.2, about 16.2, about 16.5, about 17.1, and about 18.2 degrees two-theta. (Item 14) 12. The crystalline solid form of item 11, having in its X-ray powder diffraction pattern three or more peaks selected from peaks at about 3.2, about 16.2, about 16.5, about 17.1, and about 18.2 degrees two-theta. (Item 15) 12. The crystalline solid form of item 11, having in its X-ray powder diffraction pattern four or more peaks selected from peaks at about 3.2, about 16.2, about 16.5, about 17.1, and about 18.2 degrees two-theta. (Item 16) 12. The crystalline solid form of item 11, having in its X-ray powder diffraction pattern five peaks selected from peaks at about 3.2, about 16.2, about 16.5, about 17.1, and about 18.2 degrees two-theta. (Item 17) 12. The crystalline solid form of item 11, having an X-ray powder diffraction pattern substantially as shown in Figure 2A. (Item 18) Salt forms of Compound 1 [ka] Compound 2 [ka] compound 3 [ka] and compound 4 [ka] A salt form selected from: (Item 19) The salt form of Compound 1 is Compound 2 [ka] 19. The salt form according to item 18, wherein (Item 20) 20. The salt form of item 19, wherein the salt form is crystalline. (Item 21) 20. The salt form of item 19, wherein the salt form is a crystalline solid that is substantially free of amorphous Compound 2. (Item 22) 22. The salt form according to any one of items 19 to 21, wherein the salt form is substantially free of impurities. (Item 23) 23. The salt form according to any one of items 19 to 22, wherein the salt form is Form A of Compound 2. (Item 24) 24. The salt form of item 23, having in its X-ray powder diffraction pattern one or more peaks selected from peaks at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2 and about 23.3 degrees two-theta. (Item 25) 24. The salt form of item 23, having in its X-ray powder diffraction pattern two or more peaks selected from peaks at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2 and about 23.3 degrees two-theta. (Item 26) 24. The salt form of item 23, having in its X-ray powder diffraction pattern three or more peaks selected from peaks at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2 and about 23.3 degrees two-theta. (Item 27) 24. The salt form of item 23, having in its X-ray powder diffraction pattern four or more peaks selected from peaks at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2 and about 23.3 degrees two-theta. (Item 28) 24. The salt form of item 23, having in its X-ray powder diffraction pattern five or more peaks selected from peaks at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2 and about 23.3 degrees two-theta. (Item 29) 24. The salt form of item 23, having six or more peaks in its X-ray powder diffraction pattern at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2 and about 23.3 degrees two-theta. (Item 30) 24. The salt form of item 23, having seven peaks in its X-ray powder diffraction pattern at about 14.1, about 17.0, about 17.3, about 19.0, about 21.0, about 21.2 and about 23.3 degrees two-theta. (Item 31) 24. The salt form according to item 23, having an XRPD substantially as shown in Figure 3A. (Item 32) The salt form of Compound 1 is Compound 3 [ka] 19. The salt form according to item 18, wherein (Item 33) 33. The salt form of item 32, wherein the salt form is crystalline. (Item 34) 33. The salt form of item 32, wherein the salt form is a crystalline solid that is substantially free of amorphous Compound 3. (Item 35) 35. The salt form according to any one of items 32 to 34, wherein the salt form is substantially free of impurities. (Item 36) 36. The salt form according to any one of items 32 to 35, wherein the salt form is Form A of Compound 3. (Item 37) 37. The salt form of item 36, having in its X-ray powder diffraction pattern one or more peaks selected from peaks at about 6.4, about 11.9, about 16.2, about 17.2, and about 20.9 degrees two-theta. (Item 38) 37. The salt form of item 36, having in its X-ray powder diffraction pattern two or more peaks selected from peaks at about 6.4, about 11.9, about 16.2, about 17.2, and about 20.9 degrees two-theta. (Item 39) 37. The salt form of item 36, having in its X-ray powder diffraction pattern three or more peaks selected from peaks at about 6.4, about 11.9, about 16.2, about 17.2, and about 20.9 degrees two-theta. (Item 40) 37. The salt form of item 36, having in its X-ray powder diffraction pattern four or more peaks selected from peaks at about 6.4, about 11.9, about 16.2, about 17.2, and about 20.9 degrees two-theta. (Item 41) 37. The salt form of item 36, having in its X-ray powder diffraction pattern five peaks selected from peaks at about 6.4, about 11.9, about 16.2, about 17.2, and about 20.9 degrees two-theta. (Item 42) 37. The salt form according to item 36, having an XRPD substantially as shown in Figure 4A. (Item 43) The salt form of Compound 1 is Compound 4 [ka] 19. The salt form according to item 18, wherein (Item 44) 44. The salt form of item 43, wherein the salt form is crystalline. (Item 45) 44. The salt form of item 43, wherein the salt form is a crystalline solid that is substantially free of amorphous Compound 4. (Item 46) 46. ​​The salt form according to any one of items 43 to 45, wherein the salt form is substantially free of impurities. (Item 47) 47. The salt form according to any one of items 43 to 46, wherein the salt form is Form A of Compound 4. (Item 48) 48. The salt form of item 47, having in its X-ray powder diffraction pattern one or more peaks selected from peaks at about 3.3, about 6.4, and about 16.7 degrees two-theta. (Item 49) 48. The salt form of item 47, having in its X-ray powder diffraction pattern two or more peaks selected from peaks at about 3.3, about 6.4, and about 16.7 degrees two-theta. (Item 50) 48. The salt form of item 47, having in its X-ray powder diffraction pattern three peaks selected from peaks at about 3.3, about 6.4, and about 16.7 degrees two-theta. (Item 51) 48. The salt form according to item 47, having an XRPD substantially as shown in Figure 5A. (Item 52) 52. A composition comprising the crystalline solid form or salt form according to any one of items 1 to 51, and a pharmaceutically acceptable carrier or excipient. (Item 53) 53. The pharmaceutical composition of item 52, further comprising an additional therapeutic agent. (Item 54) 52. A method of degrading IRAK1, IRAK2 and / or IRAK4 protein kinases in a patient or a biological sample, the method comprising administering to the patient or contacting with the biological sample a crystalline solid form or salt form according to any one of items 1 to 51, or a pharmaceutical composition thereof. (Item 55) 52. A method of treating an IRAK1-mediated, IRAK2-mediated and / or IRAK4-mediated disorder, disease, or condition in a patient, comprising administering to the patient the crystalline solid form or salt form of any one of items 1-51, or a pharmaceutical composition thereof. (Item 56) 56. The method of claim 55, further comprising administering an additional therapeutic agent. (Item 57) 56. The method of claim 55, wherein the IRAK1-, IRAK2- and / or IRAK4-mediated disorder, disease or condition is an inflammatory disorder. (Item 58) The inflammatory disorder is selected from the group consisting of ocular allergy, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis; allergic rhinitis, hemolytic anemia, aplastic anemia, red blood cell anemia, idiopathic thrombocytopenia or another inflammatory disease involving 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 disease, and the like. syndrome, celiac disease, periodontitis, pulmonary hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, alveolar osteitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, nephritis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change nephropathy as appropriate) , chronic granulomatous disease, endometriosis, leptospirosis, kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, ahidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic, non-allergic, mild, moderate, severe, bronchitis, or exercise-induced), acute lung injury, acute respiratory distress syndrome , eosinophilia, hypersensitivity, anaphylaxis, sinusitis, silica-induced disease, COPD (damage, airway inflammation, bronchial hyperresponsiveness, remodeling or reduction in disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, myositis associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, type 2 diabetes, appendicitis, atopic dermatitis, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatitis,Dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, external epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis abscess, 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, stomatitis, synovitis, tendonitis, tonsillitis, vaginitis, vasculitis, vulvitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis 58. The method of item 57, wherein the inflammatory bowel disease is selected from the group consisting of urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, cryopyrin-associated periodic syndromes (CAPS), and osteoarthritis.

Claims

1. Formula A: 【Chemical 1】 1. A method for preparing crystals of a salt of Compound 1: 【Chemistry 2】 with a suitable acid and a suitable solvent; method.

2. The crystalline salt of Formula A has, in its X-ray powder diffraction pattern, three or more peaks selected from peaks at 14.1±0.2, 17.0±0.2, 17.3±0.2, 19.0±0.2, 21.0±0.2, 21.2±0.2 and 23.3±0.2 degrees two-theta: Compound 2: 【Chemistry 3】 The method of claim 1, wherein

3. 2. The method of claim 1, wherein the crystal of the salt has four or more peaks in its X-ray powder diffraction pattern selected from peaks at 14.1±0.2, 17.0±0.2, 17.3±0.2, 19.0±0.2, 21.0±0.2, 21.2±0.2 and 23.3±0.2 degrees two-theta.

4. 2. The method of claim 1, wherein the crystal of the salt has five or more peaks selected from peaks at 14.1±0.2, 17.0±0.2, 17.3±0.2, 19.0±0.2, 21.0±0.2, 21.2±0.2 and 23.3±0.2 degrees two-theta in its X-ray powder diffraction pattern.

5. 2. The method of claim 1, wherein the crystal of the salt has six or more peaks in its X-ray powder diffraction pattern selected from peaks at 14.1±0.2, 17.0±0.2, 17.3±0.2, 19.0±0.2, 21.0±0.2, 21.2±0.2 and 23.3±0.2 degrees two-theta.

6. 2. The method of claim 1, wherein the crystalline salt has seven peaks in its X-ray powder diffraction pattern at 14.1±0.2, 17.0±0.2, 17.3±0.2, 19.0±0.2, 21.0±0.2, 21.2±0.2 and 23.3±0.2 degrees two-theta.

7. The crystalline salt of Formula A has, in its X-ray powder diffraction pattern, three or more peaks selected from peaks at 6.4±0.2, 11.9±0.2, 16.2±0.2, 17.2±0.2, and 20.9±0.2 degrees two-theta: Compound 3: 【Chemistry 4】 The method of claim 1, wherein

8. 8. The method of claim 7, wherein the crystal of the salt has four or more peaks selected from peaks at 6.4±0.2, 11.9±0.2, 16.2±0.2, 17.2±0.2, and 20.9±0.2 degrees two-theta in its X-ray powder diffraction pattern.

9. 8. The method of claim 7, wherein the crystal of the salt has five peaks selected from peaks at 6.4±0.2, 11.9±0.2, 16.2±0.2, 17.2±0.2, and 20.9±0.2 degrees two-theta in its X-ray powder diffraction pattern.

10. The crystals of the salt of formula A have three peaks at 3.3±0.2, 6.4±0.2, and 16.7±0.2 degrees two-theta in their X-ray powder diffraction pattern: Compound 4: 【Chemistry 5】 The method of claim 1, wherein

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