Polymorphic carbazole derivatives and uses thereof

Abstract

To provide polymorphic carbazole derivatives and uses thereof.SOLUTION: The present invention provides freebase and salt forms, and compositions and methods thereof, useful for treating various conditions in which the aryl hydrocarbon receptor (AHR) is implicated, by the administration of small molecule therapeutics which act as inhibitors of AHR. Compounds provided by this invention are also useful for the study of AHR in biological and pathological phenomena; the study of intracellular signal transduction pathways; and the comparative evaluation of new AHR inhibitors in vitro or in vivo.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 940,481, filed on November 26, 2019, under 35 U.S.C. § 119(e), the content of which is hereby incorporated by reference in its entirety.

[0002] Field of the Invention This application relates to various forms and compositions, and methods useful for treating various AHR - related conditions by administration of small molecule therapeutics that act as inhibitors of the aryl hydrocarbon receptor (AHR).

Background Art

[0003] Background of the Invention The aryl hydrocarbon receptor (AHR) is a transcription factor that binds to HSP90 in the cytoplasm and exists in an inactive state without a ligand. When the AHR binds to a ligand, it translocates to the nucleus, where it dimerizes with ARNT to form a functional transcription factor. AHR / ARNT binds to dioxin response elements (DREs) in the promoters of many genes and modulates gene transcription there. The most well - reported genes regulated by AHR are the cytochrome P450 genes Cyp1b1 and Cyp1a1, and when AHR is activated, the expression of these genes increases significantly. Thus, the mRNA levels of Cyp1b1 and Cyp1a1 are selective read - out information for AHR activation (reviewed in Murray et al., 2014).

[0004] There are many exogenous and endogenous agonists of AHR that activate the receptor. The most well-characterized class of exogenous ligands is dioxins. One of the first characterized endogenous ligands is kynurenine produced by TDO (Opitz 2011) or IDO (Mezrich 2010). Kynurenine is a stable metabolite in the IDO / TDO pathway and is a product of tryptophan catabolism. Kynurenine has been shown to activate AHR, as measured by an increase in the mRNA levels of Cyp1a1 and / or Cyp1b1 in multiple cell types, along with other DRE-induced genes.

[0005] Activation of AHR acts directly on tumor cells and indirectly by causing immunosuppression, thus having a tumor-promoting effect by preventing the body's own immune system from attacking the tumor. For example, activation of AHR via multiple ligands increases the expression of FoxP3 and skews CD4+ T cells towards a suppressive subset called Foxp3+ regulatory T cells (Tregs). These Treg cells inhibit the proliferation of activated T cells (Funatake 2005, among other references). Interestingly, kynurenine has been shown to induce immunosuppressive Tregs via AHR. Kynurenine does not affect the production of Tregs in AHR-null T cells or when an AHR antagonist is added (Mezrich). Activation of AHR, in addition to Tregs, also expands suppressive Tr1 T cells (Gandhi 2010). Expression of IDO has also been shown to be regulated by AHR activation in both tumor cells and T cells, leading to increased immunosuppression (Vogel). There is also a high likelihood of a role for AHR in immunosuppressive myeloid cells (Nguyen 2013). Immunosuppression is often associated with high levels of anti-inflammatory cytokines, and there is evidence that AHR is involved in the activation of many of these cytokines, such as IL-10 (Gandhi 2010, Wagage 2014).

[0006] ​There is still a need to develop inhibitors of AHR for treating diseases, disorders, and conditions associated with AHR. Summary of the Invention Means for Solving the Problems

[0007] Summary of the Invention Here, the compounds and compositions thereof of the present invention have been found to be useful for treating, preventing, and / or reducing the risk of diseases, disorders, or conditions in which aldehyde toxicity is related to lesion formation. Generally, the salt form or free base form, and pharmaceutically acceptable compositions thereof are useful for treating various diseases or disorders or reducing their severity, as detailed herein. Such compounds are represented by the following chemical structure shown as Compound A.

Chemical Formula

[0008] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful for treating various diseases, disorders, or conditions associated with AHR. Such diseases, disorders, or conditions include those described herein.

[0009] The compounds provided by the present invention are also useful for the study of AHR in biological and pathological phenomena, the study of intracellular signal transduction pathways, and the in vitro or in vivo comparative evaluation of new AHR inhibitors. Brief Description of the Drawings

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[0035] **Detailed Description of the Invention** **Summary of Specific Embodiments of the Invention** U.S. Patent Application No. 15 / 958,586, filed on April 20, 2018 and published as U.S. Patent Publication No. 2018-0327411 (the "’411 Publication", which is hereby incorporated by reference in its entirety) on November 15, 2018, describes certain AHR inhibitory compounds. Such compounds include Compound A **Chemical Formula** including.

[0036] Compound A, (3R)-N-[2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4,9-tetrahydro-1H-carbazole-3-amine, is designated as Compound I-40 in the ’411 Publication, and the synthesis of Compound A is detailed in Example 39 of the ’411 Publication and is reproduced herein for ease of reference.

[0037] It is desirable to provide solid forms of Compound A (e.g., as its free base or its salts) that impart characteristics such as improved water solubility, stability, and ease of formulation. Accordingly, the present invention provides both the free base form and the salt form of Compound A **Chemical Formula** both. **Free Base Form of Compound A**

[0038] It is contemplated that Compound A can exist in various physical forms. For example, Compound A can be in solution, suspension, or solid form. In certain embodiments, Compound A is in solid form. When Compound A is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0039] In some embodiments, the present invention provides a form of Compound A that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of foreign matter. Such foreign matter can include various forms of Compound A, residual solvents, or any other impurities that can arise from the preparation and / or isolation of Compound A. In certain embodiments, at least about 95 weight percent of a form of Compound A is present. In still other embodiments of the present invention, at least about 99 weight percent of a form of Compound A is present.

[0040] According to one embodiment, a form of Compound A is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent, where the percentage is based on the total weight of the composition. According to another embodiment, a form of Compound A contains total organic impurities of about 3.0 area percent HPLC or less, relative to the total area of the HPLC chromatogram, and in certain embodiments, contains total organic impurities of about 1.5 area percent HPLC or less. In other embodiments, a form of Compound A contains any single impurity of about 1.0% area percent HPLC or less, about 0.6 area percent HPLC or less, and in certain embodiments, any single impurity of about 0.5 area percent HPLC or less, relative to the total area of the HPLC chromatogram.

[0041] The structures depicted for a certain form of Compound A are also meant to include all tautomeric forms of Compound A. Additionally, the structures depicted herein are also meant to include compounds that differ only in that one or more atoms are enriched with isotopes. For example, substitution of hydrogen by deuterium or tritium, or 13 substitution of carbon by 14 C or

[0042] Compounds having the structures of the present invention are within the scope of the present invention, except for substitution of carbon by

[0043] As used herein, the term "polymorph" refers to the various crystal structures in which a compound, or its salt or solvate, can crystallize.

[0044] In certain embodiments, Compound A is a crystalline solid. In other embodiments, Compound A is a crystalline solid that substantially does not contain amorphous Compound A. As used herein, the term "substantially free of amorphous Compound A" means that the compound does not contain a significant amount of amorphous Compound A. In certain embodiments, at least about 95% by weight of crystalline Compound A is present. In yet other embodiments of the present invention, at least about 99% by weight of crystalline Compound A is present.

[0045] Compound A has been found to be able to exist in at least three distinct polymorphic forms. In certain embodiments, the present invention provides a polymorphic form of Compound A referred to herein as Form A. In certain embodiments, the present invention provides a polymorphic form of Compound A referred to herein as Form B. In certain embodiments, the present invention provides a mixture of Form A and Form B of Compound A. In certain embodiments, the present invention provides a polymorphic form of Compound A referred to herein as Form C.

[0046] In some embodiments, Compound A is amorphous. In some embodiments, Compound A is amorphous and substantially free of crystalline Compound A. Form B of Compound A

[0047] In some embodiments, Form B of Compound A has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table B below. Table B - XRPD Peak Positions for Form B of Compound A [Table 16-1] [Table 16-2]

[0048] In some embodiments, Form B of Compound A is characterized by having one or more peaks selected from the peaks at about 9.5, about 9.8, and about 14.7 degrees 2-theta in its X-ray powder diffraction pattern. In some embodiments, Form B of Compound A is characterized by having two or more peaks selected from the peaks at about 9.5, about 9.8, and about 14.7 degrees 2-theta in its X-ray powder diffraction pattern. In some embodiments, Form B of Compound A is characterized by having all three peaks selected from the peaks at about 9.5, about 9.8, and about 14.7 degrees 2-theta in its X-ray powder diffraction pattern.

[0049] In certain embodiments, the X-ray powder diffraction pattern of Form B of Compound A is substantially similar to the XRPD provided in Figure 1.

[0050] A method for preparing Form B of Compound A is described below. Form C of Compound A

[0051] In some embodiments, Form C of Compound A has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table C below. Table C - XRPD Peak Positions for Form C of Compound A [Table 17-1] [Table 17-2]

[0052] In some embodiments, Form C of Compound A is characterized by having one or more peaks selected from the peaks at about 6.02, about 8.61, and about 10.29 degrees 2-theta in its X-ray powder diffraction pattern. In some embodiments, Form C of Compound A is characterized by having two or more peaks selected from the peaks at about 6.02, about 8.61, and about 10.29 degrees 2-theta in its X-ray powder diffraction pattern. In some embodiments, Form C of Compound A is characterized by having all three peaks selected from the peaks at about 6.02, about 8.61, and about 10.29 degrees 2-theta in its X-ray powder diffraction pattern.

[0053] In certain embodiments, the X-ray powder diffraction pattern of Form C of Compound A is substantially similar to the XRPD provided in Figure 3.

[0054] A method for preparing Form C of Compound A is described below. A mixture of Form A and Form B of Compound A

[0055] In some embodiments, the present invention provides a mixture of Form A and Form B of Compound A having an X-ray powder diffraction pattern substantially similar to the XRPD provided in Figure 24.

[0056] In some embodiments, the mixture of Form A and Form B of Compound A has a TGA substantially similar to the TGA provided in Figure 25. In some embodiments, the mixture of Form A and Form B of Compound A has a DSC substantially similar to the DSC provided in Figure 25.

[0057] A method for preparing a mixture of Form A and Form B of Compound A is described below.

[0058] In some embodiments, the present invention provides Compound A

Chemical formula

[0059] In some embodiments, the present invention provides Compound A which substantially does not contain amorphous Compound A.

[0060] In some embodiments, the present invention provides Compound A which substantially does not contain impurities.

[0061] In some embodiments, the present invention provides Compound A which has an XRPD substantially similar to that shown in Figure 1.

[0062] In some embodiments, the present invention provides Compound A which has an XRPD substantially similar to that shown in Figure 3.

[0063] In some embodiments, the present invention provides Compound A which has an XRPD substantially similar to that shown in Figure 24.

[0064] In some embodiments, the present invention provides a composition comprising Compound A and a pharmaceutically acceptable carrier or excipient.

[0065] In some embodiments, the present invention provides a method of inhibiting AHR, the method comprising administering to the patient a compound A or a composition thereof. In some embodiments, the present invention provides a method of inhibiting AHR in a patient, the method comprising administering to the patient a compound A or a composition thereof. In some embodiments, the present invention provides a method of treating one or more disorders associated with the activity of AHR, the method comprising administering to the patient a compound A or a composition thereof.

[0066] In some embodiments, the present invention provides a method for treating an AHR-mediated disorder, the method comprising administering to a patient in need thereof a compound A or a composition thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease, such as cancer or an inflammatory disorder. Salt form of compound A

[0067] In some embodiments, the acid and compound A ionically bond to form one of the following compounds 1-7. It is contemplated that compounds 1-7 can exist in various physical forms. For example, compounds 1-7 can be in solution, suspension, or solid form. In certain embodiments, compounds 1-7 are in solid form. When compounds 1-7 are in solid form, the compounds can be amorphous, crystalline, or a mixture thereof. Such exemplary solid forms of compounds 1-7 are described in more detail below. Compound 1 (esylate of compound A)

[0068] According to one embodiment, the present invention provides compound 1

Chemical formula

[0069] It is recognized by those skilled in the art that ethanesulfonic acid and Compound A can form Compound 1 by ionic bonding. Compound 1 is contemplated to exist in various physical forms. For example, Compound 1 can be in solution, suspension, or solid form. In certain embodiments, Compound 1 is in solid form. When Compound 1 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0070] In some embodiments, the present invention provides Compound 1 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of foreign matter. Such foreign matter can include excess methanesulfonic acid, excess Compound A, residual solvents, or any other impurities that can result from the preparation and / or isolation of Compound 1. In certain embodiments, at least about 95% by weight of Compound 1 is present. In still other embodiments of the present invention, at least about 99% by weight of Compound 1 is present.

[0071] According to one embodiment, Compound 1 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent, where the percentage is based on the total weight of the composition. According to another embodiment, Compound 1 contains total organic impurities of about 3.0 area percent HPLC or less relative to the total area of the HPLC chromatogram, and in certain embodiments, contains total organic impurities of about 1.5 area percent HPLC or less. In other embodiments, Compound 1 contains any single impurity of about 1.0% area percent HPLC or less, any single impurity of about 0.6 area percent HPLC or less, and in certain embodiments, any single impurity of about 0.5 area percent HPLC or less relative to the total area of the HPLC chromatogram.

[0072] The structure illustrated for Compound 1 is also meant to include all tautomeric forms of Compound 1. Additionally, the structures illustrated herein are also meant to include compounds that differ only in that one or more atoms are enriched in one or more isotopes. For example, substitution of hydrogen with deuterium or tritium, or 13 substitution of carbon with 14 C or carbon enriched in

[0073] Compound 1 has been found to be able to exist in various solid forms. Such exemplary forms include polymorphs such as those described herein.

[0074] In certain embodiments, Compound 1 is a crystalline solid. In other embodiments, Compound 1 is a crystalline solid that substantially does not contain amorphous Compound 1. As used herein, the term “ substantially free of amorphous Compound 1” means that the compound does not contain a significant amount of amorphous Compound 1. In certain embodiments, at least about 95% by weight of crystalline Compound 1 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline Compound 1 is present.

[0075] Compound 1 has been found to be able to exist in at least one distinct polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 1 referred to herein as Form A. In some embodiments, the present invention provides a polymorphic form of Compound 1 referred to herein as Form B.

[0076] In some embodiments, Compound 1 is amorphous. In some embodiments, Compound 1 is amorphous and substantially free of crystalline Compound 1. Form A of Compound 1

[0077] In some embodiments, Form A of Compound 1 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 1 below. Table 1 - XRPD Peak Positions for Form A of Compound 1 [Table 1 - 1] [Table 1 - 2]

[0078] In some embodiments, Form A of Compound 1 is characterized by having one or more peaks selected from the peaks at about 5.8, about 11.6, and about 18.8 degrees 2 - theta in its X - ray powder diffraction pattern. In some embodiments, Form A of Compound 1 is characterized by having two or more peaks selected from the peaks at about 5.8, about 11.6, and about 18.8 degrees 2 - theta in its X - ray powder diffraction pattern. In some embodiments, Form A of Compound 1 is characterized by having all three peaks selected from the peaks at about 5.8, about 11.6, and about 18.8 degrees 2 - theta in its X - ray powder diffraction pattern.

[0079] In certain embodiments, the X - ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 5.

[0080] A method for preparing Form A of Compound 1 is described below. Form B of Compound 1

[0081] In some embodiments, Form B of Compound 1 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 2 below. Table 2 - XRPD Peak Positions for Form B of Compound 1 [Table 2 - 1] [Table 2 - 2]

[0082] In some embodiments, Form B of Compound 1 is characterized by having one or more peaks selected from the peaks at about 5.6, about 11.2, and about 16.9 degrees two-theta in its X-ray powder diffraction pattern. In some embodiments, Form B of Compound 1 is characterized by having two or more peaks selected from the peaks at about 5.6, about 11.2, and about 16.9 degrees two-theta in its X-ray powder diffraction pattern. In some embodiments, Form B of Compound 1 is characterized by having all three peaks selected from the peaks at about 5.6, about 11.2, and about 16.9 degrees two-theta in its X-ray powder diffraction pattern.

[0083] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 7.

[0084] A method for preparing Form B of Compound 1 is described below.

[0085] In some embodiments, the present invention provides Compound 1

Chemical formula

[0086] In some embodiments, the present invention provides Compound 1, and the compound is crystalline.

[0087] In some embodiments, the present invention provides Compound 1, and the compound is a crystalline solid substantially free of amorphous Compound 1.

[0088] In some embodiments, the present invention provides Compound 1, and the compound is substantially free of impurities.

[0089] In some embodiments, the present invention provides Compound 1, which has one or more peaks selected from the peaks at 5.8, about 11.6, and about 18.8 degrees two-theta in its XRPD. In such some embodiments, the present invention provides Compound 1, which has at least two peaks selected from the peaks at about 5.8, about 11.6, and about 18.8 degrees two-theta in its XRPD. In such some embodiments, the present invention provides Compound 1, which is the Compound of Form A.

[0090] In some embodiments, the present invention provides Compound 1, which has an XRPD substantially similar to that shown in FIG. 5.

[0091] In some embodiments, the present invention provides Compound 1, which has one or more peaks selected from the peaks at 5.6, about 11.2, and about 16.9 degrees two-theta in its XRPD. In such some embodiments, the present invention provides Compound 1, which has at least two peaks selected from the peaks at about 5.6, about 11.2, and about 16.9 degrees two-theta in its XRPD. In such some embodiments, the present invention provides Compound 1, which has Form B.

[0092] In some embodiments, the present invention provides Compound 1, which has an XRPD substantially similar to that shown in FIG. 7.

[0093] In some embodiments, the present invention provides a composition comprising Compound 1 and a pharmaceutically acceptable carrier or excipient.

[0094] In some embodiments, the present invention provides methods of inhibiting AHR, comprising administering to the patient Compound 1 or a composition thereof. In some embodiments, the present invention provides methods of inhibiting AHR in a patient, comprising administering to the patient Compound 1 or a composition thereof. In some embodiments, the present invention provides methods of treating one or more disorders associated with activity of AHR, comprising administering to the patient Compound 1 or a composition thereof.

[0095] In some embodiments, the present invention provides a method for treating an AHR-mediated disorder, comprising administering to a patient in need thereof Compound 1 or a composition thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease, e.g., cancer or an inflammatory disorder. Compound 2 (maleate salt of Compound A)

[0096] According to one embodiment, the present invention provides compound 2 [ka] wherein about 1≦x≦about 2.

[0097] Those skilled in the art will recognize that maleic acid and Compound A are ionically bonded to form Compound 2. In some embodiments, Compound A and maleic acid are present in a ratio of about 1:1. In some embodiments, Compound A and maleic acid are present in a ratio of about 2:1. It is contemplated that Compound 2 can exist in various physical forms. For example, Compound 2 can be in a solution, suspension, or 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.

[0098] In some embodiments, the present invention provides Compound 2 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of foreign substances. Such foreign substances may include excess benzenesulfonic acid, excess Compound A, residual solvents, 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 Compound 2 is present. In still other embodiments of the present invention, at least about 99% by weight of Compound 2 is present.

[0099] According to one embodiment, Compound 2 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, Compound 2 contains total organic impurities of about 3.0 area percent HPLC or less relative to the total area of the HPLC chromatogram, and in certain embodiments, contains total organic impurities of about 1.5 area percent HPLC or less. In other embodiments, Compound 2 contains any single impurity of about 1.0% area percent HPLC or less, about 0.6 area percent HPLC or less, and in certain embodiments, about 0.5 area percent HPLC or less relative to the total area of the HPLC chromatogram.

[0100] The structures depicted for Compound 2 are also meant to include all tautomeric forms of Compound 2. In addition, the structures depicted herein are also meant to include compounds that differ only in that one or more isotopically enriched atoms are present. For example, substitution of hydrogen by deuterium or tritium, or substitution of carbon by 13 13 C or 14 14 C enriched carbon, compounds having the structure of the present invention are within the scope of the present invention.

[0101] Compound 2 has been found to be able to exist in at least one distinct polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 2, herein referred to as Form A. In some embodiments, Form A of Compound 2 comprises Compound A and maleic acid in a ratio of about 2:1.

[0102] In certain embodiments, Compound 2 is a crystalline solid. In other embodiments, Compound 2 is a crystalline solid that substantially does not contain amorphous Compound 2. As used herein, the term "substantially free of amorphous Compound 2" means that the compound does not contain a significant amount of amorphous Compound 2. In certain embodiments, at least about 95% by weight of crystalline Compound 2 is present. In yet other embodiments of the present invention, at least about 99% by weight of crystalline Compound 2 is present.

[0103] Compound 2 has been found to be able to exist in at least one distinct polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 2, herein referred to as Form A.

[0104] 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

[0105] 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 - XRPD Peak Positions for Form A of Compound 2

Table 3-1

Table 3-2

[0106] In some embodiments, Form A of Compound 2 is characterized by having one or more peaks selected from the peaks at about 5.3, about 11.3, and about 16.0 degrees two-theta in its X-ray powder diffraction pattern. In some embodiments, Form A of Compound 2 is characterized by having two or more peaks selected from the peaks at about 5.3, about 11.3, and about 16.0 degrees two-theta in its X-ray powder diffraction pattern. In some embodiments, Form A of Compound 2 is characterized by having all three peaks selected from the peaks at about 5.3, about 11.3, and about 16.0 degrees two-theta in its X-ray powder diffraction pattern.

[0107] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 9.

[0108] A method for preparing Form A of Compound 2 is described below.

[0109] In some embodiments, the present invention provides Compound 2 [wherein about 1 ≦ x ≦ about 2]. [wherein about 1 ≦ x ≦ about 2] is provided.

[0110] In some embodiments, the present invention provides Compound 2, and the compound is crystalline.

[0111] In some embodiments, the present invention provides Compound 2, and the compound is a crystalline solid substantially free of amorphous Compound 2.

[0112] In some embodiments, the present invention provides Compound 2, and the compound is substantially free of impurities.

[0113] In some embodiments, the present invention provides Compound 2, which has, in its XRPD, one or more peaks selected from peaks at about 5.3, about 11.3, and about 16.0 degrees two-theta. In some such embodiments, the present invention provides Compound 2, which has, in its XRPD, at least two peaks selected from peaks at about 5.3, about 11.3, and about 16.0 degrees two-theta. In some such embodiments, the present invention provides Compound 2, which is Form A of the compound. In some embodiments, Form A of Compound 2 comprises Compound A and maleic acid in a ratio of about 2:1.

[0114] In some embodiments, the present invention provides compound 2, wherein said compound has an XRPD substantially similar to that depicted in FIG.

[0115] In some embodiments, the present invention provides a composition comprising Compound 2 and a pharmaceutically acceptable carrier or excipient.

[0116] In some embodiments, the present invention provides methods of inhibiting AHR, comprising administering to the patient Compound 2, or a composition thereof. In some embodiments, the present invention provides methods of inhibiting AHR in a patient, comprising administering to the patient Compound 2, or a composition thereof. In some embodiments, the present invention provides methods of treating one or more disorders associated with activity of AHR, comprising administering to the patient Compound 2, or a composition thereof.

[0117] In some embodiments, the present invention provides a method for treating an AHR-mediated disorder, The present invention provides methods for treating AHR-mediated disorders, including administering Compound 2 or a composition thereof to a patient in need thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease, e.g., cancer or an inflammatory disorder. Compound 3 (Mesylate of Compound A)

[0118] According to one embodiment, the present invention provides compound 3

Chem.

[0119] It is recognized by those skilled in the art that methanesulfonic acid and compound A ionically bond to form compound 3. Compound 3 is contemplated to be able to exist in various physical forms. For example, compound 3 can be in solution, suspension, or solid form. In certain embodiments, compound 3 is in solid form. When compound 3 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0120] In some embodiments, the present invention provides compound 3 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of foreign matter. Such foreign matter can include excess sulfuric acid, excess compound A, residual solvents, or any other impurities that may result from the preparation and / or isolation of compound 3. In certain embodiments, at least about 95 wt% of compound 3 is present. In still other embodiments of the present invention, at least about 99 wt% of compound 3 is present.

[0121] According to one embodiment, compound 3 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent, where the percentage is based on the total weight of the composition. According to another embodiment, compound 3 contains up to about 3.0 area percent HPLC total organic impurities, in certain embodiments up to about 1.5 area percent HPLC total organic impurities, relative to the total area of the HPLC chromatogram. In other embodiments, compound 3 contains up to about 1.0% area percent HPLC any single impurity, up to about 0.6 area percent HPLC any single impurity, in certain embodiments up to about 0.5 area percent HPLC any single impurity, relative to the total area of the HPLC chromatogram.

[0122] The structure illustrated for Compound 3 is also meant to include all tautomeric forms of Compound 3. Additionally, the structures illustrated herein are also meant to include compounds that differ only in that one or more isotopically enriched atoms are present. For example, substitution of hydrogen by deuterium or tritium, or 13 C or 14 substitution of carbon by C-enriched carbon, compounds having the structure of the present invention are within the scope of the present invention.

[0123] Compound 3 has been found to be able to exist in at least two distinct polymorphic forms. In some embodiments, the present invention provides a polymorphic form of Compound 3 referred to herein as Form A. In some embodiments, the present invention provides a polymorphic form of Compound 3 referred to herein as Form B.

[0124] In certain embodiments, Compound 3 is a crystalline solid. In other embodiments, Compound 3 is a crystalline solid that substantially does not contain amorphous Compound 3. As used herein, the term "substantially free of amorphous Compound 3" means that the compound does not contain a significant amount of amorphous Compound 3. In certain embodiments, at least about 95 wt% of crystalline Compound 3 is present. In still other embodiments of the present invention, at least about 99 wt% of crystalline Compound 3 is present.

[0125] 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

[0126] 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 - XRPD Peak Positions for Form A of Compound 3 [Table 4-1] [Table 4-2]

[0127] 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 5.6, about 11.2, and about 16.9 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 5.6, about 11.2, and about 16.9 degrees 2-theta. In some embodiments, Compound 3 Form A is characterized in its X-ray powder diffraction pattern by having all three peaks selected from peaks at about 5.6, about 11.2, and about 16.9 degrees 2-theta.

[0128] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG.

[0129] A method for preparing Form A of Compound 3 is described below. Form B of Compound 3

[0130] In some embodiments, Form B of Compound 3 has at least one, two, three, four, or five spectral peaks selected from the peaks listed in Table 5 below. Table 5 - XRPD peak positions for Form B of Compound 3 [Table 5-1]

[0131] In some embodiments, Form B of Compound 3 is characterized by having one or more peaks selected from the peaks at about 6.0, about 12.1, and about 18.1 degrees two-theta in its X-ray powder diffraction pattern. In some embodiments, Form B of Compound 3 is characterized by having two or more peaks selected from the peaks at about 6.0, about 12.1, and about 18.1 degrees two-theta in its X-ray powder diffraction pattern. In some embodiments, Form B of Compound 3 is characterized by having all three peaks selected from the peaks at about 6.0, about 12.1, and about 18.1 degrees two-theta in its X-ray powder diffraction pattern.

[0132] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 13.

[0133] A method for preparing Form B of Compound 3 is described below.

[0134] In some embodiments, the present invention provides Compound 3

Chemical formula

[0135] In some embodiments, the present invention provides Compound 3, and the compound is crystalline.

[0136] In some embodiments, the present invention provides Compound 3, and the compound is a crystalline solid substantially free of amorphous Compound 3.

[0137] In some embodiments, the present invention provides Compound 3, and the compound is substantially free of impurities.

[0138] In some embodiments, the present invention provides Compound 3, which has one or more peaks selected from the peaks at about 5.6, about 11.2, and about 16.9 degrees two-theta in its XRPD. In such some embodiments, the present invention provides Compound 3, which has at least two peaks selected from the peaks at about 5.6, about 11.2, and about 16.9 degrees two-theta in its XRPD. In such some embodiments, the present invention provides Compound 3, which is the Compound of Form A.

[0139] In some embodiments, the present invention provides Compound 3, which has an XRPD substantially similar to that shown in FIG. 11.

[0140] In some embodiments, the present invention provides Compound 3, which has one or more peaks selected from the peaks at about 6.0, about 12.1, and about 18.1 degrees two-theta in its XRPD. In such some embodiments, the present invention provides Compound 3, which has at least two peaks selected from the peaks at about 6.0, about 12.1, and about 18.1 degrees two-theta in its XRPD. In such some embodiments, the present invention provides Compound 3, which has Form B.

[0141] In some embodiments, the present invention provides Compound 3, which has an XRPD substantially similar to that shown in FIG. 13.

[0142] In some embodiments, the present invention provides a composition comprising Compound 3 and a pharmaceutically acceptable carrier or excipient.

[0143] In some embodiments, the present invention provides a method of inhibiting AHR, comprising administering to the patient compound 3 or a composition thereof. In some embodiments, the present invention provides a method of inhibiting AHR in a patient, comprising administering to the patient compound 3 or a composition thereof. In some embodiments, the present invention provides a method of treating one or more disorders associated with the activity of AHR, comprising administering to the patient compound 3 or a composition thereof.

[0144] In some embodiments, the present invention provides a method for treating an AHR-mediated disorder, comprising administering to a patient in need thereof compound 3 or a composition thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease, such as cancer or an inflammatory disorder. Compound 4 (napsylate of Compound A)

[0145] According to one embodiment, the present invention provides Compound 4 [Chemical formula] provides the napsylate of Compound A represented by.

[0146] It is recognized by those skilled in the art that naphthalenesulfonic acid and Compound A form Compound 4 by ionic bonding. It is contemplated that Compound 4 can exist in various physical forms. For example, Compound 4 can be in solution, suspension, or solid form. In certain embodiments, Compound 4 is in solid form. When Compound 4 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0147] In some embodiments, the present invention provides compound 4 that is substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound contains no significant amounts of foreign matter. Such foreign matter can include excess p-toluenesulfonic acid, excess compound A, residual solvents, 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 compound 4 is present. In still other embodiments of the present invention, at least about 99% by weight of compound 4 is present.

[0148] According to one embodiment, compound 4 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, compound 4 contains less than about 3.0 area percent total organic impurities by HPLC, and in certain embodiments, less than about 1.5 area percent total organic impurities by HPLC, relative to the total area of the HPLC chromatogram. In other embodiments, compound 4 contains less than about 1.0% area percent any single impurity, less than about 0.6 area percent any single impurity, and in certain embodiments, less than about 0.5 area percent any single impurity, relative to the total area of the HPLC chromatogram.

[0149] The structures depicted for compound 4 are also meant to include all tautomeric forms of compound 4. In addition, the structures depicted herein are also meant to include compounds that differ only in that one or more atoms are enriched in one or more isotopes. For example, substitution of hydrogen with deuterium or tritium, or substitution of carbon with 13 C or 14 carbon enriched in carbon, compounds having the structures of the present invention are within the scope of the present invention.

[0150] Compound 4 has been found to be capable of existing in at least two distinct solid forms. Such exemplary forms include polymorphs such as those described herein.

[0151] Compound 4 has been found to be able to exist in at least one distinct polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 4, herein referred to as Form A.

[0152] In certain embodiments, Compound 4 is a crystalline solid. In other embodiments, Compound 4 is a crystalline solid 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 invention, at least about 99% by weight of crystalline Compound 4 is present.

[0153] 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

[0154] In some embodiments, Form A of Compound 4 has at least one, two, three, four or five spectral peaks selected from the peaks listed in Table 6 below. Table 6 - XRPD Peak Positions for Form A of Compound 4 [Table 6-1] [Table 6-2]

[0155] In some embodiments, Form A of Compound 4, in its X-ray powder diffraction pattern, has one or more peaks selected from the peaks at about 7.5, about 8.4 and about 20.1 degrees two theta. Characterized by having peaks of numbers. In some embodiments, Form A of Compound 4 is characterized by having two or more peaks selected from the peaks at about 7.5, about 8.4, and about 20.1 degrees 2-theta in its X-ray powder diffraction pattern. In some embodiments, Form A of Compound 4 is characterized by having all three peaks selected from the peaks at about 7.5, about 8.4, and about 20.1 degrees 2-theta in its X-ray powder diffraction pattern.

[0156] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 15.

[0157] A method for preparing Form A of Compound 4 is described below.

[0158] In some embodiments, the present invention provides Compound 4

Chemical formula

[0159] In some embodiments, the present invention provides Compound 4, and the compound is crystalline.

[0160] In some embodiments, the present invention provides Compound 4, and the compound is a crystalline solid substantially free of amorphous Compound 4.

[0161] In some embodiments, the present invention provides Compound 4, and the compound is substantially free of impurities.

[0162] In some embodiments, the present invention provides Compound 4, which has one or more peaks selected from the peaks at about 7.5, about 8.4, and about 20.1 degrees two-theta in its XRPD. In such some embodiments, the present invention provides Compound 4, which has at least two peaks selected from the peaks at about 7.5, about 8.4, and about 20.1 degrees two-theta in its XRPD. In such some embodiments, the present invention provides Compound 4, which is Compound A in Form A.

[0163] In some embodiments, the present invention provides Compound 4, which has an XRPD substantially similar to that shown in FIG. 15.

[0164] In some embodiments, the present invention provides a composition comprising Compound 4 and a pharmaceutically acceptable carrier or excipient.

[0165] In some embodiments, the present invention provides a method of inhibiting AHR, which comprises administering Compound 4 or a composition thereof to a patient. In some embodiments, the present invention provides a method of inhibiting AHR in a patient, which comprises administering Compound 4 or a composition thereof to the patient. In some embodiments, the present invention provides a method of treating one or more disorders associated with the activity of AHR, which comprises administering Compound 4 or a composition thereof to the patient.

[0166] In some embodiments, the present invention provides a method for treating an AHR-mediated disorder, which comprises administering Compound 4 or a composition thereof to a patient in need thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease, such as cancer or an inflammatory disorder. Compound 5 (oxalate salt of Compound A)

[0167] According to one embodiment, the present invention provides Compound 5

Chemical formula

[0168] It is recognized by those skilled in the art that oxalic acid and compound A can form compound 5 by ionic bonding. It is contemplated that compound 5 can exist in various physical forms. For example, compound 5 can be in solution, suspension, or solid form. In certain embodiments, compound 5 is in solid form. When compound 5 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0169] In some embodiments, the present invention provides compound 5 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain significant amounts of foreign matter. Such foreign matter can include excess hydrochloric acid, excess compound A, residual solvents, or any other impurities that can result from the preparation and / or isolation of compound 5. In certain embodiments, at least about 95 weight percent of compound 5 is present. In still other embodiments of the present invention, at least about 99 weight percent of compound 5 is present.

[0170] According to one embodiment, compound 5 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent, where the percentages are based on the total weight of the composition. According to another embodiment, compound 5 contains total organic impurities of about 3.0 area percent HPLC or less, in certain embodiments about 1.5 area percent HPLC or less, based on the total area of the HPLC chromatogram. In other embodiments, compound 5 contains any single impurity of about 1.0% area percent HPLC or less, about 0.6 area percent HPLC or less, in certain embodiments about 0.5 area percent HPLC or less, based on the total area of the HPLC chromatogram.

[0171] The structure illustrated for Compound 5 also includes all tautomeric forms of Compound 5 which means. In addition, the structures illustrated herein also mean including compounds that differ only in that they have one or more atoms enriched with isotopes. For example, substitution of hydrogen with deuterium or tritium, or 13 C or 14 Except for substitution of carbon with C-enriched carbon, compounds having the structure of the present invention are within the scope of the present invention.

[0172] Compound 5 has been found to be able to exist in at least one distinct polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 5 referred to herein as Form A.

[0173] In certain embodiments, Compound 5 is a crystalline solid. In other embodiments, Compound 5 is a crystalline solid that substantially does not contain amorphous Compound 5. As used herein, the term "substantially free of amorphous Compound 5" means that the compound does not contain a significant amount of amorphous Compound 5. In certain embodiments, at least about 95% by weight of crystalline Compound 5 is present. In yet other embodiments of the present invention, at least about 99% by weight of crystalline Compound 5 is present.

[0174] In some embodiments, Compound 5 is amorphous. In some embodiments, Compound 5 is amorphous and substantially does not contain crystalline Compound 5. Form A of Compound 5

[0175] In some embodiments, Form A of Compound 5 has at least 1, 2, 3, 4 or 5 spectral peaks selected from the peaks listed in Table 7 below. Table 7 - XRPD Peak Positions for Form A of Compound 5

Table 7-1

[0176] In some embodiments, Form A of Compound 5 is characterized by having one or more peaks selected from the peaks at about 6.4, about 7.1 and about 12.7 degrees 2-theta in its X-ray powder diffraction pattern. In some embodiments, Form A of Compound 5 is characterized by having two or more peaks selected from the peaks at about 6.4, about 7.1 and about 12.7 degrees 2-theta in its X-ray powder diffraction pattern. In some embodiments, Form A of Compound 5 is characterized by having all three peaks selected from the peaks at about 6.4, about 7.1 and about 12.7 degrees 2-theta.

[0177] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 17.

[0178] A method for preparing Form A of Compound 5 is described below.

[0179] In some embodiments, the present invention provides Compound 5

Chemical formula

[0180] In some embodiments, the present invention provides Compound 5, and the compound is crystalline.

[0181] In some embodiments, the present invention provides Compound 5, and the compound is a crystalline solid substantially free of amorphous Compound 5.

[0182] In some embodiments, the present invention provides Compound 5, and the compound is substantially free of impurities.

[0183] In some embodiments, the present invention provides compound 5, which has one or more peaks selected from the peaks at about 6.4, about 7.1 and about 12.7 degrees two-theta in its XRPD. In such some embodiments, the present invention provides compound 5, which has at least two peaks selected from the peaks at about 6.4, about 7.1 and about 12.7 degrees two-theta in its XRPD. In such some embodiments, the present invention provides compound 5, which is a compound of Form A.

[0184] In some embodiments, the present invention provides compound 5, which has an XRPD substantially similar to that shown in FIG. 17.

[0185] In some embodiments, the present invention provides a composition comprising compound 5 and a pharmaceutically acceptable carrier or excipient.

[0186] In some embodiments, the present invention provides a method of inhibiting AHR, which comprises administering compound 5 or a composition thereof to a patient. In some embodiments, the present invention provides a method of inhibiting AHR in a patient, which comprises administering compound 5 or a composition thereof to the patient. In some embodiments, the present invention provides a method of treating one or more disorders associated with the activity of AHR, which comprises administering compound 5 or a composition thereof to the patient.

[0187] In some embodiments, the present invention provides a method for treating an AHR-mediated disorder, which comprises administering compound 5 or a composition thereof to a patient in need thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease, such as cancer or an inflammatory disorder. Compound 6 (tartrate salt of Compound A)

[0188] According to one embodiment, the present invention provides compound 6

Chemical formula

[0189] It is recognized by those skilled in the art that tartaric acid and Compound A can form Compound 6 by ionic bonding. In some embodiments, Compound A and tartaric acid are present in a ratio of about 1:1. In some embodiments, Compound A and tartaric acid are present in a ratio of about 2:1. It is contemplated that Compound 6 can exist in various physical forms. For example, Compound 6 can be in solution, suspension, or solid form. In certain embodiments, Compound 6 is in solid form. When Compound 6 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0190] In some embodiments, the present invention provides Compound 6 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of foreign matter. Such foreign matter can include excess oxalic acid, excess Compound A, residual solvents, or any other impurities that can result from the preparation and / or isolation of Compound 6. In certain embodiments, at least about 95% by weight of Compound 6 is present. In still other embodiments of the present invention, at least about 99% by weight of Compound 6 is present.

[0191] According to one embodiment, Compound 6 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent, where the percentage is based on the total weight of the composition. According to another embodiment, Compound 6 contains total organic impurities of about 3.0 area percent HPLC or less, in certain embodiments about 1.5 area percent HPLC or less, relative to the total area of the HPLC chromatogram. In other embodiments, Compound 6 contains any single impurity of about 1.0% area percent HPLC or less, about 0.6 area percent HPLC or less, in certain embodiments about 0.5 area percent HPLC or less, relative to the total area of the HPLC chromatogram.

[0192] The structures depicted for Compound 6 are also meant to include all tautomeric forms of Compound 6. Additionally, the structures depicted herein are also meant to include compounds that differ only in that one or more atoms are enriched in one or more isotopes. For example, substitution of hydrogen with deuterium or tritium, or substitution of carbon with 13 C or 14 C enriched carbon, compounds having the structures of the present invention are within the scope of the present invention.

[0193] Compound 6 has been found to be able to exist in at least two distinct polymorphic forms. In some embodiments, the present invention provides a polymorphic form of Compound 6 herein referred to as Form A. In some embodiments, the present invention provides a polymorphic form of Compound 6 herein referred to as Form B. In some embodiments, Form A of Compound 6 contains Compound A and tartaric acid in a ratio of about 1:1. In some embodiments, Form B of Compound 6 contains Compound A and tartaric acid in a ratio of about 2:1.

[0194] In certain embodiments, Compound 6 is a crystalline solid. In other embodiments, Compound 6 is a crystalline solid that substantially does not contain amorphous Compound 6. As used herein, the term "substantially free of amorphous Compound 6" means that the compound does not contain a significant amount of amorphous Compound 6. In certain embodiments, at least about 95% by weight of crystalline Compound 6 is present. In yet other embodiments of the invention, at least about 99% by weight of crystalline Compound 6 is present.

[0195] In some embodiments, Compound 6 is amorphous. In some embodiments, Compound 6 is amorphous and substantially free of crystalline Compound 6. Form A of Compound 6

[0196] In some embodiments, Form A of Compound 6 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 8 below. Table 8 - XRPD Peak Positions for Form A of Compound 6

Table 8-1

Table 8-2

[0197] In some embodiments, Form A of Compound 6 is characterized by having one or more peaks selected from the peaks at about 5.5, about 11.1, and about 18.9 degrees 2-theta in its X-ray powder diffraction pattern. In some embodiments, Form A of Compound 6 is characterized by having two or more peaks selected from the peaks at about 5.5, about 11.1, and about 18.9 degrees 2-theta in its X-ray powder diffraction pattern. In some embodiments, Form A of Compound 6 is characterized by having all three peaks selected from the peaks at about 5.5, about 11.1, and about 18.9 degrees 2-theta in its X-ray powder diffraction pattern.

[0198] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 19.

[0199] A method for preparing Form A of Compound 6 is described below. Form B of Compound 6

[0200] In some embodiments, Form B of Compound 6 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 9 below. Table 9 - XRPD Peak Positions for Form B of Compound 6 [Table 9-1] [Table 9-2]

[0201] In some embodiments, Form B of Compound 6 is characterized by having one or more peaks selected from the peaks at about 6.2, about 6.8, and about 13.5 degrees 2-theta in its X-ray powder diffraction pattern. In some embodiments, Form B of Compound 6 is characterized by having two or more peaks selected from the peaks at about 6.2, about 6.8, and about 13.5 degrees 2-theta in its X-ray powder diffraction pattern. In some embodiments, Form B of Compound 6 is characterized by having all three peaks selected from the peaks at about 6.2, about 6.8, and about 13.5 degrees 2-theta in its X-ray powder diffraction pattern.

[0202] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in FIG. 21.

[0203] A method for preparing Form B of Compound 6 is described below.

[0204] In some embodiments, the present invention relates to Compound 6 [Chemical formula] Provide [wherein about 1 ≦ x ≦ about 2].

[0205] In some embodiments, the present invention provides Compound 6, which is crystalline.

[0206] In some embodiments, the present invention provides Compound 6, which is a crystalline solid substantially free of amorphous Compound 6.

[0207] In some embodiments, the present invention provides Compound 6, which is substantially free of impurities.

[0208] In some embodiments, the present invention provides Compound 6, which has one or more peaks selected from the peaks at about 5.5, about 11.1, and about 18.9 degrees two-theta in its XRPD. In such some embodiments, the present invention provides Compound 6, which has at least two peaks selected from the peaks at about 5.5, about 11.1, and about 18.9 degrees two-theta in its XRPD. In such some embodiments, the present invention provides Compound 6, which is Compound A in Form A. In some embodiments, Form A of Compound 6 comprises Compound A and tartaric acid in a ratio of about 1:1.

[0209] In some embodiments, the present invention provides Compound 6, which has an XRPD substantially similar to that shown in FIG. 19.

[0210] In some embodiments, the present invention provides Compound 6, which has one or more peaks in its XRPD selected from the peaks at about 6.2, about 6.8, and about 13.5 degrees two-theta. In such some embodiments, the present invention provides Compound 6, which has at least two peaks in its XRPD selected from the peaks at about 6.2, about 6.8, and about 13.5 degrees two-theta. In such some embodiments, the present invention provides Compound 6, which has Form B. In some embodiments, Form B of Compound 6 contains Compound A and tartaric acid in a ratio of about 2:1.

[0211] In some embodiments, the present invention provides Compound 6, which has an XRPD substantially similar to that shown in Figure 21.

[0212] In some embodiments, the present invention provides a composition comprising Compound 6 and a pharmaceutically acceptable carrier or excipient.

[0213] In some embodiments, the present invention provides a method of inhibiting AHR, which comprises administering Compound 6 or a composition thereof to a patient. In some embodiments, the present invention provides a method of inhibiting AHR in a patient, which comprises administering Compound 6 or a composition thereof to the patient. In some embodiments, the present invention provides a method of treating one or more disorders associated with the activity of AHR, which comprises administering Compound 6 or a composition thereof to the patient.

[0214] In some embodiments, the present invention provides a method for treating an AHR-mediated disorder, which comprises administering Compound 6 or a composition thereof to a patient in need thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease, such as cancer or an inflammatory disorder. Compound 7 (edisylate of Compound A)

[0215] According to one embodiment, the present invention provides Compound 7 [Chemical formula] Provided is an edisylate of compound A represented by [wherein, about 1 ≦ x ≦ about 2].

[0216] It is recognized by those skilled in the art that ethanedisulfonic acid and compound A ionically bond to form compound 7. In some embodiments, compound A and ethanedisulfonic acid are present in a ratio of about 1:1. In some embodiments, compound A and ethanedisulfonic acid are present in a ratio of about 2:1. Compound 7 is contemplated to be able to exist in various physical forms. For example, compound 7 can be in solution, suspension, or solid form. In certain embodiments, compound 7 is in solid form. When compound 7 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0217] In some embodiments, the present invention provides compound 7 substantially free of impurities. As used herein, the term "substantially free of impurities" means that the compound does not contain a significant amount of foreign matter. Such foreign matter can include excess phosphoric acid, excess compound A, residual solvents, or any other impurities that can result from the preparation and / or isolation of compound 7. In certain embodiments, at least about 95% by weight of compound 7 is present. In still other embodiments of the present invention, at least about 99% by weight of compound 7 is present.

[0218] According to one embodiment, Compound 7 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight percent, where the percentage is based on the total weight of the composition. According to another embodiment, Compound 7 contains total organic impurities of about 3.0 area percent HPLC or less, in certain embodiments about 1.5 area percent HPLC or less, with respect to the total area of the HPLC chromatogram. In other embodiments, Compound 7 contains any single impurity of about 1.0% area percent HPLC or less, about 0.6 area percent HPLC or less, in certain embodiments about 0.5 area percent HPLC or less, with respect to the total area of the HPLC chromatogram.

[0219] The structures depicted for Compound 7 are also meant to include all tautomeric forms of Compound 7. Additionally, the structures depicted herein are also meant to include compounds that differ only in that one or more atoms are enriched in one or more isotopes. For example, substitution of hydrogen with deuterium or tritium, or substitution of carbon with 13 C or 14 C enriched carbon, compounds having the structures of the present invention are within the scope of the present invention.

[0220] Compound 7 has been found to be able to exist in at least one distinct polymorphic form. In some embodiments, the present invention provides a polymorphic form of Compound 7 referred to herein as Form A. In some embodiments, Form A of Compound 7 contains Compound A and ethanedisulfonic acid in a ratio of about 2: 1.

[0221] In certain embodiments, Compound 7 is a crystalline solid. In other embodiments, Compound 7 is a crystalline solid that substantially does not contain amorphous Compound 7. As used herein, the term "substantially free of amorphous Compound 7" means that the compound does not contain a significant amount of amorphous Compound 7. In certain embodiments, at least about 95% by weight of crystalline Compound 7 is present. In yet other embodiments of the present invention, at least about 99% by weight of crystalline Compound 7 is present.

[0222] In some embodiments, Compound 7 is amorphous. In some embodiments, Compound 7 is amorphous and substantially free of crystalline Compound 7. Form A of Compound 7

[0223] In some embodiments, Form A of Compound 7 has at least 1, 2, 3, 4, or 5 spectral peaks selected from the peaks listed in Table 10 below. Table 10 - XRPD Peak Positions for Form A of Compound 7

Table 10-1

[0224] In some embodiments, Form A of Compound 7 is characterized by having one or more peaks selected from the peaks at about 6.6, about 10.4, and about 13.2 degrees 2-theta in its X-ray powder diffraction pattern. In some embodiments, Form A of Compound 7 is characterized by having two or more peaks selected from the peaks at about 6.6, about 10.4, and about 13.2 degrees 2-theta in its X-ray powder diffraction pattern. In some embodiments, Form A of Compound 7 is characterized by having all three peaks selected from the peaks at about 6.6, about 10.4, and about 13.2 degrees 2-theta in its X-ray powder diffraction pattern.

[0225] In certain embodiments, the X-ray powder diffraction pattern is substantially similar to the XRPD provided in Figure 23.

[0226] The method for preparing Form A of Compound 7 is described below.

[0227] In some embodiments, the present invention provides Compound 7 [Chemical formula] [where about 1 ≦ x ≦ about 2]

[0228] In some embodiments, the present invention provides Compound 7, and the compound is crystalline.

[0229] In some embodiments, the present invention provides Compound 7, and the compound is a crystalline solid substantially free of amorphous Compound 7.

[0230] In some embodiments, the present invention provides Compound 7, and the compound is substantially free of impurities.

[0231] In some embodiments, the present invention provides Compound 7, and the compound has one or more peaks selected from the peaks at about 6.6, about 10.4, and about 13.2 degrees 2-theta in its XRPD. In some such embodiments, the present invention provides Compound 7, and the compound has at least two peaks selected from the peaks at about 6.6, about 10.4, and about 13.2 degrees 2-theta in its XRPD. In some such embodiments, the present invention provides Compound 7, and the compound is Compound 7 in Form A. In some embodiments, Form A of Compound 7 contains Compound A and ethanedisulfonic acid in a ratio of about 2:1.

[0232] In some embodiments, the present invention provides Compound 7, and the compound has an XRPD substantially similar to that shown in Figure 23.

[0233] In some embodiments, the present invention provides a composition comprising Compound 7 and a pharmaceutically acceptable carrier or excipient.

[0234] In some embodiments, the present invention provides a method of inhibiting AHR, the method comprising administering to the patient compound 7 or a composition thereof. In some embodiments, the present invention provides a method of inhibiting AHR in a patient, the method comprising administering to the patient compound 7 or a composition thereof. In some embodiments, the present invention provides a method of treating one or more disorders associated with AHR activity, the method comprising administering to the patient compound 7 or a composition thereof.

[0235] In some embodiments, the present invention provides a method for treating an AHR-mediated disorder, the method comprising administering to a patient in need thereof compound 7 or a composition thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease, such as cancer or an inflammatory disorder.

[0236] In some embodiments, the present invention provides a compound selected from Form B of Compound A, Form C of Compound A, Form A of Compound 1, Form B of Compound 1, Form A of Compound 2, Form A of Compound 3, Form B of Compound 3, Form A of Compound 4, Form A of Compound 5, Form A of Compound 6, Form B of Compound 6, and Form A of Compound 7. In such some embodiments, the present invention provides a composition comprising one of the foregoing compound forms and a pharmaceutically acceptable carrier or excipient.

[0237] In such some embodiments, the present invention provides a method of inhibiting AHR, the method comprising administering to the patient the compound of the present invention or a composition thereof. In such some embodiments, the present invention provides a method of inhibiting AHR in a patient, the method comprising administering to the patient the compound of the present invention or a composition thereof. In such some embodiments, the present invention provides a method of treating one or more disorders associated with AHR activity, the method comprising administering to the patient the compound of the present invention or a composition thereof.

[0238] In some such embodiments, the present invention provides a method for treating an AHR-mediated disorder, the method comprising administering to a patient in need thereof a compound or composition of the present invention. In some such embodiments, the AHR-mediated disorder is a proliferative disease, such as cancer or an inflammatory disorder. General method for providing salt compounds

[0239] Compound A is prepared according to the method detailed in the '411 publication, which is hereby incorporated by reference in its entirety. In particular, the salt compounds of general formula X, including salt compounds 1-7 and / or their specific forms, are prepared from Compound A according to the following general scheme.

Chemical formula

[0240] For example, each of and the forms of compounds 1-7 are prepared from Compound A by combining Compound A with an acid suitable for forming the salt of the acid. Accordingly, another aspect of the present invention provides a method for preparing compounds 1-7 and their forms.

[0241] As generally described above, in some embodiments, the present invention provides a salt compound of general formula X

Chemical formula

Chemical formula

[0242] In some embodiments, the suitable acid is ethanesulfonic acid. In some embodiments, the present invention provides a method for preparing the esilate of compound A. In certain embodiments, the esilate of compound A is compound 1. In certain embodiments, the esilate of compound A is Form A of compound 1. In certain embodiments, the esilate of compound A is Form B of compound 1.

[0243] In some embodiments, the suitable acid is maleic acid. In some embodiments, the present invention provides a method for preparing the maleate of compound A. In certain embodiments, the maleate of compound A is compound 2. In certain embodiments, the maleate of compound A is Form A of compound 2.

[0244] In some embodiments, the suitable acid is methanesulfonic acid. In some embodiments, the present invention provides a method for preparing the mesylate of compound A. In certain embodiments, the mesylate of compound A is compound 3. In certain embodiments, the mesylate of compound A is Form A of compound 3. In certain embodiments, the mesylate of compound A is Form B of compound 3.

[0245] In some embodiments, the suitable acid is naphthalenesulfonic acid. In some embodiments, the present invention provides a method for preparing the napsylate of compound A. In certain embodiments, the napsylate of compound A is compound 4. In certain embodiments, the napsylate of compound A is Form A of compound 4.

[0246] In some embodiments, the suitable acid is oxalic acid. In some embodiments, the present invention provides a method for preparing the oxalate of compound A. In certain embodiments, the oxalate of compound A is compound 5. In certain embodiments, the oxalate of compound A is Form A of compound 5.

[0247] In some embodiments, the suitable acid is tartaric acid. In some embodiments, the present invention provides a method for preparing the tartrate salt of Compound A. In certain embodiments, the tartrate salt of Compound A is Compound 6. In certain embodiments, the tartrate salt of Compound A is Form A of Compound 6. In certain embodiments, the tartrate salt of Compound A is Form B of Compound 6.

[0248] In some embodiments, the suitable acid is ethanedisulfonic acid. In some embodiments, the present invention provides a method for preparing the edisylic acid salt of Compound A. In certain embodiments, the edisylic acid salt of Compound A is Compound 7. In certain embodiments, the edisylic acid salt of Compound A is Form A of Compound 7.

[0249] A suitable solvent can be any solvent system (e.g., a single solvent or a solvent mixture) in which Compound A and / or the acid is soluble or at least partially soluble.

[0250] Examples of suitable solvents useful in the present invention include, but are not limited to, protic solvents, aprotic solvents, polar aprotic solvents, or mixtures thereof. In certain embodiments, suitable solvents include ethers, esters, alcohols, ketones, or mixtures thereof. In some embodiments, the solvent is one or more organic alcohols. In some embodiments, the solvent is chlorinated. In some embodiments, the solvent is an aromatic solvent.

[0251] In certain embodiments, suitable solvents are methanol, ethanol, isopropanol, or acetone, and the solvent 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 anhydrous ethanol. In some embodiments, the suitable solvent is MTBE.

[0252] In some embodiments, the suitable solvent is ethyl acetate. In some embodiments, the suitable solvent is a mixture of methanol and methylene chloride. In some embodiments, the suitable solvent is a mixture of acetonitrile and water. 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.

[0253] In some embodiments, the present invention provides a method for preparing a salt compound of general formula X, the method comprising one or more steps of removing a solvent and adding a solvent. In some embodiments, the added solvent is the same as the removed solvent. In some embodiments, the added solvent is different from the removed solvent. Solvent removal means are known in the art of synthesis and chemistry and include, but are not limited to, any of those described herein and in the examples.

[0254] In some embodiments, the method for preparing a salt compound of general formula X comprises one or more steps of heating or cooling the preparation.

[0255] In some embodiments, the method for preparing a salt compound of general formula X involves stirring the preparation or agitating it and includes one or more steps.

[0256] In some embodiments, the method for preparing a salt compound of general formula X involves adding a suitable acid to a solution or slurry of compound A.

[0257] In some embodiments, the method for preparing a salt compound of general formula X involves a heating step.

[0258] In certain embodiments, the salt compound of formula X precipitates from the mixture. In another embodiment, the salt compound of formula X crystallizes from the mixture. In other embodiments, the salt compound of formula X crystallizes from the solution after seeding the solution (i.e., adding crystals of the salt compound of formula X to the solution).

[0259] The salt compound of formula X can precipitate from the reaction mixture or can be produced by removing some or all of the solvent by methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption, and reaction, by adding an anti-solvent such as heptane, by cooling, or by various combinations of these methods. Thereby producing it by removing some or all of the solvent.

[0260] Generally as previously described, the salt compound of formula X is isolated as needed. It will be appreciated that the salt compound of formula X 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 X is separated from the supernatant by filtration. In other embodiments, the precipitated solid salt compound of formula X is separated from the supernatant by decanting the supernatant.

[0261] In certain embodiments, the salt compound of formula X is separated from the supernatant by filtration.

[0262] In certain embodiments, the isolated salt compound of formula X is air-dried. In other embodiments, the isolated salt compound of formula X is dried under reduced pressure, optionally at elevated temperature. Use, formulation and administration and pharmaceutically acceptable compositions

[0263] According to another embodiment, the present invention provides a composition comprising a compound of the present invention, or a pharmaceutically acceptable salt, ester or salt of an ester thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle. The amount of the compound in the composition of the present invention is an amount effective to inhibit AHR to a measurable extent in a biological sample or in a patient. In certain embodiments, the amount of the compound in the composition of the present invention is an amount effective to inhibit AHR to a measurable extent 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.

[0264] As used herein, the term "patient" means an animal, preferably a mammal, most preferably a human.

[0265] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, saturated vegetable fats It contains a partial glyceride mixture of fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and lanolin.

[0266] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of ester or other derivative of the compound of the present invention that can directly or indirectly provide the compound of the present invention or its metabolite or residue with inhibitory activity when administered to a recipient.

[0267] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implantable reservoir. The term "parenteral" as used herein includes injection or infusion techniques into the subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intramedullary, intrahepatic, intralesional and intracranial. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Injectable sterile forms of the compositions of the present invention can be aqueous or oily suspensions. These suspensions can be formulated according to techniques known in the art using appropriate dispersing or wetting agents and suspending agents. Injectable sterile preparations can also be sterile solutions or suspensions in non-toxic parenterally acceptable excipients or solvents, for example as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media.

[0268] For this purpose, any non-irritating fixed oil containing synthetic monoglycerides or diglycerides can be used. Fatty acids, such as oleic acid and its glyceride derivatives, especially their polyoxyethylenated ones, are useful in the preparation of 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 excipients or dispersants generally used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions, such as carboxymethyl cellulose or similar dispersing agents. Other commonly used surfactants generally used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, such as Tween®, Span®, and other emulsifying agents or bioavailability enhancers, can also be used for formulation purposes.

[0269] The pharmaceutically acceptable compositions of the present invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. Excipients useful for oral administration in the form of capsules include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents can also be added.

[0270] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the drug with suitable non-irritating additives that are solid at room temperature but liquid at rectal temperature and thus melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycol.

[0271] The pharmaceutically acceptable compositions of the present invention can also be administered topically, particularly when the target of treatment includes regions or organs that are readily accessible by topical application, including diseases of the eye, skin or lower intestinal tract. Suitable topical formulations are readily prepared for each of these regions or organs.

[0272] Topical application for the lower intestinal tract can be effected with rectal suppository formulations (see above) or with suitable enema formulations. Topical transdermal patches can also be used.

[0273] For topical application, the pharmaceutically acceptable compositions provided can be formulated into suitable ointments containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated into suitable lotions or creams containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0274] For use in the eye, the pharmaceutically acceptable compositions provided 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 benzalkonium chloride. Alternatively, for use in the eye, the pharmaceutically acceptable compositions can be formulated as an ointment, such as petrolatum.

[0275] The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical formulation art and can be prepared as solutions in physiological saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0276] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions of the present invention are administered without food. In other embodiments, the pharmaceutically acceptable compositions of the present invention are administered with food.

[0277] The amount of the compound of the present invention that can be combined with a carrier material to produce a single dosage form composition will vary depending on the host being treated and the particular method of administration. Preferably, the compositions provided should be formulated such that an inhibitor in a dosage between 0.01 and 100 mg / kg (body weight) / day can be administered to a patient to whom these compositions are given.

[0278] 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 compound used, age, body weight, general health status, gender, diet, time of administration, rate of excretion, drug combination, as well as the judgment of the physician administering the treatment and the severity of the particular disease being treated. Also, the amount of the compound of the present invention in the composition will vary depending on the particular compound in the composition. Use of the Compounds and Pharmaceutically Acceptable Compositions

[0279] The activity of the compounds utilized in the present invention as inhibitors of AHR is in vitro Alternatively, it can be assayed in vivo. In vivo assessment of the effectiveness of the compounds of the present invention can be performed using animal models of obesity or metabolic syndrome, such as rodent or primate models. Cell-based assays can be performed using, for example, cell lines isolated from tissues expressing AHR. Furthermore, biochemical assays or mechanism-based assays, such as transcriptional assays, can be performed using purified proteins, Northern blots, RT-PCR, etc. In vitro assays include assays for determining cell morphology, protein expression and / or cytotoxicity, enzyme inhibitory activity, and / or functional consequences of treating cells with the compounds of the present invention. In alternative in vitro assays, the ability of an inhibitor to bind to intracellular proteins or nucleic acid molecules is quantified. Binding of the inhibitor can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / target molecule complex, and determining the amount of bound radiolabel. Alternatively, binding of the inhibitor can be determined by performing a competition experiment in which a new inhibitor is incubated with a purified protein or nucleic acid bound to a known radioligand. Detailed conditions for assaying the compounds utilized in the present invention as inhibitors of AHR are described in the following examples. The foregoing assays are illustrative and are not intended to limit the scope of the present invention. It will be recognized by those skilled in the art that conventional assays can be modified to develop equivalent assays that provide the same results.

[0280] As used herein, the terms "treating," "treat," and "treatment" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder described herein, or one or more symptoms thereof. In some embodiments, treatment can be administered after one or more symptoms have occurred. In other embodiments, treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a symptom history and / or in light of genetic or other susceptibility factors). Treatment can also continue after symptoms have resolved, for example, to prevent or delay their recurrence.

[0281] Compounds and compositions according to the methods of the invention can be administered in any amount and by any route of administration effective to treat or reduce the severity of a metabolic disorder or condition, cancer, bacterial infection, fungal infection, parasitic infection (e.g., malaria), autoimmune disorder, neurodegenerative or neurological disorder, schizophrenia, bone-related disorder, liver disease, or heart disorder.

[0282] In some embodiments, compounds and compositions according to the methods of the invention can be administered in any amount and by any route of administration effective to treat or reduce the severity of a disease associated with AHR.

[0283] The exact amount required varies for each subject depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, etc. The compounds of the present invention are preferably formulated into unit dosage forms in order to facilitate administration and to uniformize the dosage. As used herein, the expression "unit dosage form" refers to physically discrete units of the agent suitable for the patient to be treated. However, it is to be understood that all of the daily uses of the compounds and compositions of the present invention are determined within the scope of sound medical judgment by the attending physician. The specific effective dosage level for 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 the treatment; drugs used in combination with or concurrently with the specific compound used, as well as other factors similar in the medical arts. As used herein, the term "patient" means an animal, preferably a mammal, most preferably a human.

[0284] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, by oral or nasal spray, etc., depending on the severity of the infection being treated. In certain embodiments, the compounds of the present invention can be administered orally or parenterally once or multiple times a day at a dosage level of about 0.01 mg to about 50 mg, preferably about 1 mg to about 25 mg per kg of body weight of the subject per day in order to obtain the desired therapeutic effect.

[0285] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. The liquid dosage forms can contain, in addition to the active compound, inert excipients commonly used in the art, such as, for example, water or other solvents, solubilizers, and emulsifying agents, 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 glycols, and fatty acid esters of sorbitan, and mixtures thereof. Oral compositions can also contain, in addition to inert excipients, adjuvants such as wetting agents, emulsifying agents, and suspending agents, sweetening agents, flavoring agents, and perfuming agents.

[0286] Injectable preparations, for example, injectable aqueous or oleaginous sterile suspensions can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Also, injectable sterile preparations can be sterile solutions, suspensions, or emulsions in a non - toxic parenterally acceptable excipient or solvent, such as, for example, as a sterile solution injectable in a 1,3 - butanediol solution. Acceptable vehicles and solvents that can be used include water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. Further, sterile fixed oils have conventionally been used as a solvent or suspending medium. For this purpose, any bland fixed oil containing synthetic monoglycerides or diglycerides can be used. Further, in the preparation of injectables, fatty acids, such as oleic acid, are used.

[0287] Injectable formulations can be sterilized, for example, by filtration through a bacteria - retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other injectable sterile media before use.

[0288] To prolong the effect of the compounds of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with low solubility in water. And the absorption rate of the compound varies according to its dissolution rate, which in turn can vary according to the crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oily vehicle. Injectable depot forms are prepared by forming a microencapsulation matrix of the compound in a biodegradable polymer, such as polylactide-polyglycolide. Depending on the ratio of the compound to the polymer and the nature of the particular polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0289] Compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing a compound of the present invention with a suitable non-irritating additive or carrier, such as cocoa butter, polyethylene glycol or suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity to release the active compound.

[0290] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is combined with at least one inert pharmaceutically acceptable additive or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, etc., c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) dissolution retardants such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, etc., h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form can also contain buffering agents.

[0291] Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules using additives such as lactose or milk sugar and high molecular weight polyethylene glycol. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells well known in the pharmaceutical formulation art, such as enteric coatings and other coatings. The dosage form can optionally contain opacifying agents and can be a dosage form of a composition that releases only the active ingredient or preferentially releases the active ingredient in a delayed manner in certain parts of the intestinal tract, if necessary. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft and hard gelatin capsules using additives such as lactose or milk sugar and high molecular weight polyethylene glycol.

[0292] The active compound can also be in microencapsulated form using one or more of the additives described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells well known in the pharmaceutical formulation art, such as enteric coatings, controlled release coatings, and other coatings. In such solid dosage forms, the active compound can be mixed with at least one inert excipient, such as sucrose, lactose, or starch. Such dosage forms can also contain, in accordance with normal practice, additional substances other than inert excipients, such as lubricants for tableting and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form can also contain buffering agents. The dosage form can contain, if desired, opacifying agents and can be a dosage form of a composition that releases the active ingredient in a delayed manner, if desired, only in or preferentially in certain parts of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0293] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier and, if necessary, any required preservative or buffer under sterile conditions. Ophthalmic formulations, ear drops, and eye drops are also contemplated to be within the scope of the present invention. Furthermore, the present invention contemplates the use of transdermal patches, which have the additional advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption promoters can also be used to increase the flux of the compound through the skin and its rate can be controlled either by providing a rate-limiting membrane or by dispersing the compound in a polymeric matrix or gel. Methods of Use and Treatment

[0294] According to one embodiment, the present invention relates to a method for inhibiting AHR in a biological sample, the method comprising contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0295] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof, biopsy materials or extracts thereof obtained from mammals, and blood, saliva, urine, feces, semen, tears or other body fluids, or extracts thereof.

[0296] Inhibition of enzymes in biological samples is useful for a variety of purposes known to those of skill in the art. Examples of such purposes include, but are not limited to, biological assays, gene expression studies, and identification of biological targets.

[0297] Another embodiment of the present invention relates to a method for inhibiting AHR in a patient, the method comprising administering to the patient a compound of the present invention or a composition comprising the compound.

[0298] The compounds provided are inhibitors of AHR and are thus useful for treating one or more disorders associated with AHR activity. Accordingly, in certain embodiments, the present invention provides a method for treating an AHR-mediated disorder, the method comprising administering to a patient in need thereof a compound of the present invention or a pharmaceutically acceptable composition thereof. In some embodiments, the present invention provides the use of a compound or solid form of the present invention, or a pharmaceutically acceptable composition thereof, for the treatment of a disease, disorder, or condition described herein.

[0299] As used herein, the term "AHR-mediated" disorder, disease, and / or condition means any disease or other adverse condition in which AHR or a variant thereof is known to play a role, as used herein. Thus, another embodiment of the invention relates to treating or reducing the severity of one or more diseases in which AHR or a variant thereof is known to play a role.

[0300] AHR-mediated disorders are well established in the art. As listed herein, the association between AHR and AHR-mediated disorders, diseases and / or conditions is well established in the relevant art. See, for example: Uyttenhove et al., "Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase" Nature Medicine, 2003 vol. 9(10), 1038; Murray et al., "AH RECEPTOR LIGANDS IN CANCER: FRIEND AND FOE" Nat. Rev. Cancer December 2014, vol. 14(12), pages 801-814; Moon et al., "Targeting the indoleamine 2,3-dioxygenase pathway in cancer" J. ImmunoTherapy of Cancer, 2015 vol 3, page 51; Ishida et al., "Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and "cigarette smoke" Int. J. Cancer July 2015 vol. 15, no.137(2), pages 299-310; Ishida et al., "Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer" Carcinogenesis February 2010 vol. 31(2), pages 287-295。Su et al., "Prognostic value of nuclear translocation of aryl hydrocarbon receptor for non-small cell lung cancer" Anticancer Res. September 2013, vol. 33(9), pages 3953-3961; Peng et al., "Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9" BMC Cell Biol. April 2009 vol. 16; pages 10-27; Jin et al., "Aryl Hydrocarbon Receptor Activation Reduces Dendritic Cell Function during Influenza "Virus Infection" Toxicol Sci. August 2010, vol. 116(2), pages 514-522; Head et al., "The aryl hydrocarbon receptor is a modulator of anti-viral immunity" Biochem. Pharmacol. February 2009 vol. 15; no. 77(4), pages 642-53; Jin et al., "New insights into the role of the aryl hydrocarbon receptor in the function of CD11c + cells during respiratory viral infection" Eur. J. Immunol. June 2014, vol. 44(6), pages 1685-98; Nguyen et al., "Aryl hydrocarbon receptor and kynurenine: recent advances in autoimmune disease research" Front Immunol. October 2014, vol. 29, no. 5, page 551; Esser et al., "The aryl hydrocarbon receptor in immunity" Trends in Immunology, Vol.30, No.9。

[0301] In some embodiments, the present invention provides a method for treating one or more disorders, diseases, and / or conditions, wherein the disorder, disease, or condition is a proliferative disease such as cancer, an inflammatory disorder, or a viral infection.

[0302] In certain embodiments, the present invention provides a method of treating cancer or another proliferative disorder, the method comprising administering a compound or composition of the present invention to a patient having cancer or another proliferative disorder. In certain embodiments, the method of treating cancer or another proliferative disorder comprises administering a compound and composition of the present invention to a mammal. In certain embodiments, the mammal is a human.

[0303] As used herein, the terms “inhibition of cancer” and “inhibition of cancer cell proliferation” refer to inhibiting the growth, differentiation, maturation or survival of cancer cells and / or killing cancer cells, either individually or together with other cancer cells, by inducing cytotoxicity, nutrient depletion or apoptosis.

[0304] Examples of tissues containing cancer cells whose proliferation is inhibited by the compounds and compositions described herein and for which the methods described herein are useful for cancer cells include, but are not limited to, breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, ovary, lung, testis, penis, thyroid, parathyroid, pituitary, thymus, retina, choroid, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary gland, adrenal gland, larynx, esophagus, lymph node, sweat gland, sebaceous gland, muscle, heart, and stomach.

[0305] In some embodiments, the cancer treated by the compounds or compositions of the present invention is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma or colon cancer. In certain embodiments, the cancer is primary effusion lymphoma (PEL).

[0306] The compounds of the present invention are useful for the treatment of proliferative diseases selected from benign or malignant tumors, brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, neck, testis, urogenital tract, esophagus, larynx, skin, bone or thyroid carcinoma, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, or gastrointestinal cancer, particularly colon cancer or colorectal adenoma, or head and neck tumors, epithelial hyperplasia, psoriasis, prostatic hypertrophy, neoplasms, neoplasms with epithelial characteristics, adenomas, adenocarcinomas, keratoacanthomas, epidermoid carcinomas, large cell carcinomas, non-small cell lung cancer, lymphomas, Hodgkin and non-Hodgkin, Waldenström macroglobulinemia, breast cancer, follicular adenocarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, MYD88-induced disorders, DLBCL, ABC DLBCL, IL-1-induced disorders, smoldering type of slowly progressive multiple myeloma, or leukemia.

[0307] In some embodiments, cancers include, but are not limited to, leukemia (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphomas (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenström macroglobulinemia, multiple myeloma, heavy chain disease, and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelioma, lymphangiosarcoma, lymphangioendothelioma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0308] In some embodiments, the cancer is glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0309] In some embodiments, the cancer is acoustic neuroma, astrocytoma (e.g., grade I pilocytic astrocytoma, grade II low-grade astrocytoma, grade III anaplastic astrocytoma, or grade IV glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brainstem glioma, ependymoma, mixed glioma, optic glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type more commonly found in children than in adults, such as brainstem glioma, craniopharyngioma, ependymoma, juvenile pilocytic astrocytoma (JPA), medulloblastoma, optic glioma, pineal tumor, primitive neuroectodermal tumor (PNET), or rhabdoid tumor. In some embodiments, the patient is an adult. In some embodiments, the patient is a child or pediatric patient.

[0310] In another embodiment, cancers include, but are not limited to, mesothelioma, hepatobilliary (liver and biliary duct), bone cancer, pancreatic cancer, skin cancer, head or neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal area cancer, stomach cancer, gastrointestinal tract (stomach, colorectal, and duodenum), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myelogenous leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, non-Hodgkin's lymphoma, spinal axis tumors, brainstem glioma, pituitary adenoma, adrenocortical cancer, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or one or more combinations of the foregoing cancers.

[0311] In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial cancer or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; intrahepatic bile duct cancer; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; undifferentiated thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal tract / stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST); Waldenström macroglobulinemia; or medulloblastoma.

[0312] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), intrahepatic bile duct cancer, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, undifferentiated thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0313] In some embodiments, the cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. Solid tumors generally comprise abnormal tissue masses that typically do not contain cysts or fluid regions. In some embodiments, the cancer is renal cell carcinoma or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma or liver cancer; melanoma; breast cancer; colorectal cancer or colorectal carcinoma; colon cancer; rectal cancer; anal cancer; lung cancer, such as non-small cell lung cancer (NSCLC) or small cell lung cancer (SCLC); ovarian cancer, ovarian epithelial cancer, ovarian carcinoma or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; intrahepatic cholangiocarcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; undifferentiated thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal cancer or pancreatic adenocarcinoma; gastrointestinal stromal tumor (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST); Waldenström macroglobulinemia; or medulloblastoma.

[0314] In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal cancer, colorectal carcinoma, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), intrahepatic cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, undifferentiated thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal cancer, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0315] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial cancer, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), intrahepatic cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, undifferentiated thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal cancer, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0316] In some embodiments, the cancer is hepatocellular carcinoma (HCC). In some embodiments, the cancer is hepatoblastoma. In some embodiments, the cancer is colon cancer. In some embodiments, the cancer is rectal cancer. In some embodiments, the cancer is ovarian cancer or ovarian carcinoma. In some embodiments, the cancer is ovarian epithelial cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In some embodiments, the cancer is intrahepatic cholangiocarcinoma. In some embodiments, the cancer is soft tissue and bone synovial sarcoma. In some embodiments, the cancer is rhabdomyosarcoma. In some embodiments, the cancer is osteosarcoma. In some embodiments, the cancer is undifferentiated thyroid cancer. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer or pancreatic ductal cancer. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumor (MPNST). In some embodiments, the cancer is neurofibromatosis-1 associated MPNST. In some embodiments, the cancer is Waldenström macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0317] In some embodiments, the cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendiceal cancer, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain tumor, astrocytoma, brain and spinal cord tumors, brainstem glioma, central nervous system atypical teratoid / rhabdoid tumor, central nervous system embryonal tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, cancer of unknown primary, central nervous system cancer, cervical cancer, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumor, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, ganglioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor, glioma, hairy cell leukemia, head and neck cancer, heart cancer, hepatocellular cancer, histiocytosis, Langerhans cell cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cavity cancer, liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, AIDS-related lymphoma, macroglobulinemia, male breast cancer, medulloblastoma, medulloepithelioma, melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic squamous neck cancer of unknown primary, midline with NUT geneTract) cancer, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, fungating polyposis, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), myeloma, multiple myeloma, chronic myeloproliferative disorder, nasal cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, paranasal sinus cancer, nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, intermediate pineal parenchymal tumor, pineoblastoma, pituitary tumor, plasma cell neoplasm, pleuropulmonary blastoma, breast cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell cancer, clear cell renal cell carcinoma, renal pelvic cancer, ureteral cancer, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous cell carcinoma of unknown primary in the neck, head and neck squamous cell carcinoma (HNSCC), gastric cancer, supratentorial primitive neuroectodermal tumor, T cell lymphoma, testicular cancer, laryngeal cancer, thymoma, thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, triple negative breast cancer (TNBC), gestational trophoblastic tumor, unknown abnormal primary cancer in childhood, urethral cancer, uterine cancer, uterine sarcoma, Waldenström macroglobulinemia, or Wilms tumor.

[0318] The compounds according to the present invention are useful for treating inflammatory or obstructive airway diseases, for example, to reduce tissue damage, airway inflammation, bronchial hyperreactivity, remodeling or disease progression. Inflammatory or obstructive airway diseases to which the present invention can be applied include both intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and any type or origin of asthma, including asthma induced after bacterial infection. Treatment of asthma also includes treatment of patients diagnosed or diagnosable as "wheezing infants", a patient classification with wheezing symptoms and established primary medical interest, and currently often identified as newly diagnosed or early-phase asthma patients, for example, less than It should be understood to include treatment of subjects under 4 or 5 years of age.

[0319] The prophylactic effectiveness in the treatment of asthma is evidenced by a decrease in the frequency or severity of symptomatic attacks, such as acute asthma or bronchospasm attacks, an improvement in lung function, or an improvement in airway hyperresponsiveness. The prophylactic effectiveness can further be evidenced by a reduction in the requirements for other symptomatic therapies, such as for limiting or interrupting a symptomatic attack when it occurs or for contemplated, e.g., anti-inflammatory or bronchodilatory treatments. The prophylactic benefit in asthma can be evident particularly in subjects who tend to have a "morning dip". The "morning dip" is a recognized asthma syndrome common to a substantial proportion of asthmatic patients and characterized by, for example, asthma attacks between about 4 am and 6 am, i.e., at a time usually substantially remote from previously administered symptomatic asthma therapies.

[0320] The compounds of the present invention can be used for acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive lung, airway or pulmonary diseases (COPD, COAD or COLD) (including associated chronic bronchitis or dyspnea), emphysema, and other inflammatory or obstructive airway diseases and conditions including exacerbation of airway hyperresponsiveness resulting from other drug treatments, particularly other inhaled drug treatments, to which the present invention is applicable. The present invention is applicable to the treatment of bronchitis of any type or origin including, but not limited to, acute, arachidic, catarrhal, croupus, chronic or phthinoid bronchitis. The present invention is also applicable to the treatment of further inflammatory or obstructive airway diseases including, for example, pneumoconiosis of any type or origin including aluminosis, anthracosis, asbestosis, silicosis, blepharoptosis, siderosis, silicosis, tobacco pneumoconiosis and cotton pneumoconiosis (inflammatory, generally occupational lung diseases that often involve airway obstruction, whether chronic or acute, and are caused by repeated inhalation of dust).

[0321] The compounds of the present invention are useful for the treatment of eosinophil-related disorders of the respiratory tract, including eosinophil-related disorders, such as eosinophilia, particularly hypereosinophilia in cases where it affects the respiratory tract and / or lungs, including pathological eosinophilic infiltration of lung tissue, as well as eosinophil-related disorders of the respiratory tract that occur as a result of or simultaneously with, for example, the reflux syndrome, eosinophilic pneumonia, parasitism of parasites (particularly metazoans, including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-Strauss syndrome), eosinophilic granuloma, and eosinophil-related disorders affecting the respiratory tract caused by drug reactions, with respect to their anti-inflammatory activity, particularly with respect to the inhibition of eosinophil activation.

[0322] The compounds of the present invention are also useful for the treatment of inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, pemphigus tumorigenicus, acquired epidermolysis bullosa, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0323] The compounds of the present invention are useful for the treatment of other diseases or conditions, such as diseases or conditions having an inflammatory component, for example, diseases and conditions of the eye, such as eye allergies, conjunctivitis, dry keratoconjunctivitis, and vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis, and inflammatory diseases having an autoimmune component or etiology, including or associated with an autoimmune reaction, or autoimmune hematological disorders (for example, hemolytic anemia, aplastic anemia, erythroblastosis, 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 (for example, ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, pulmonary fibrosis, kidney diseases, glomerular diseases, alcoholic liver diseases, multiple sclerosis, endocrine ophthalmopathy, g Löfgren's syndrome, sarcoidosis, pneumonia, chronic hypersensitivity pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, dry keratoconjunctivitis and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndromes, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with and without nephrotic syndrome including, for example, idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis renal disease, glaucoma, retinal diseases, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle wasting, catabolism disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease , dyschromatosis, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitic, and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, rhinitis, eye allergies, silica-induced diseases, COPD (reduction of injury, airway inflammation, bronchial hyperresponsiveness, remodeling or disease progression), lung diseases, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation associated with systemic sclerosis, dermatomyositis, polymyositis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, and can also be used for the treatment of type 1 or type 2 diabetes.

[0324] In some embodiments, the inflammatory diseases that can be treated according to the methods of the invention are selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndromes (CAPS), or osteoarthritis.

[0325] In some embodiments, the inflammatory diseases that can be treated according to the methods of the invention are selected from TH17-mediated diseases. In some embodiments, the TH17-mediated diseases are selected from inflammatory bowel diseases including systemic lupus erythematosus, multiple sclerosis, Crohn's disease or ulcerative colitis.

[0326] In some embodiments, the inflammatory diseases that can be treated according to the methods of the invention are selected from Sjogren's syndrome, allergic disorders, osteoarthritis. Diseases affecting the eyes, such as eye allergies, conjunctivitis, dry keratoconjunctivitis, and vernal conjunctivitis, and diseases affecting the nose including allergic rhinitis.

[0327] In some embodiments, the inflammatory diseases that can be treated according to the methods of the invention are 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, acquired epidermolysis bullosa, and other inflammatory or allergic conditions of the skin.

[0328] In certain embodiments, the compounds provided are useful for treating viral infections, diseases, or conditions. In some embodiments, the invention relates to retroviral diseases such as HIV-1, HIV-2, human T-cell leukemia virus-I (HTLV-I), HTLV-II, HTLV-III, simian immunodeficiency virus (SIV), lymphadenopathy-associated virus (LAV-2), simian T-lymphotropic virus-I (STLV-I), STLV-II, STLV-III, simian B-lymphotropic (SBL) virus, gibbon ape leukemia virus (GALV), bovine leukemia virus (BLV), equine infectious anemia virus (EIAV), feline leukemia virus (FELV), murine leukemia virus (MuLV), avian leukemia virus (ALV); other viral infections such as the Hepadnaviridae (hepatitis B); Herpesviridae (herpes simplex I, herpes simplex II, varicella-zoster, Epstein-Barr virus and cytomegalovirus); Parvoviridae (human parvovirus B-19); Papovaviridae (human papillomavirus types 1 to 60, JC and BK viruses Methods are provided for treating viral diseases selected from the group consisting of poxviruses (smallpox, vaccinia, cowpox, monkey pox, orf virus, parapoxvirus or orf virus, molluscum contagiosum), as well as cancer, lymphoma and other leukemias. Combination therapy

[0329] Depending on the particular condition or disease being treated, additional therapeutic agents that are normally administered to treat that condition can be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known to be "suitable for the disease or condition being treated".

[0330] In certain embodiments, the compounds or compositions thereof provided are administered in combination with another anti-cancer agent, cytotoxic agent, or chemotherapeutic agent to a patient in need thereof.

[0331] In certain embodiments, the anti-cancer agents or chemotherapeutic agents used in combination with the compounds or compositions of the present invention include, but are not limited to, metformin, phenformin, buformin, imatinib, nilotinib, gefitinib, sunitinib, carfilzomib, salinosporamide A, retinoic acid, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, ifosfamide, azathioprine, mercaptopurine, doxifluridine, fluorouracil, gemcitabine, methotrexate, thioguanine, vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, etoposide, teniposide, tafurposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine, actinomycin, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, plicamycin, mitomycin, mitoxantrone, melphalan, busulfan, capecitabine, pemetrexed, epothilone, 13-cis-retinoic acid, 2-CdA, 2-chlorodeoxyadenosine, 5-azacitidine, 5-fluorouracil, 5-FU, 6-mercaptopurine, 6-MP, 6-TG, 6-thioguanine, abraxane, Accutane®, actinomycin-D, Adriamycin®, Adrucil®, Afinitor®, Agrylin®, Ala-Cort®, aldesleukin, alemtuzumab, ALIMTA, alitretinoin, Alkaban-AQ®, Alkeran®, all-trans retinoic acid, alpha interferon, altretamine, amethopterin, amifostine, aminoglutethimide, anagrelide, Anandron®, anastrozole, arabinosylcytosine, Ara-C, Aranesp®, Aredia®, Arimidex®, Aromasin®, Arranon®, arsenic trioxide, Arzerra™, asparaginase, ATRA, Avastin®, azacitidine, BCG, BCNU, bendamustine, bevacizumab, bexarotene, BEXXAR®, bicalutamide,BiCNU, Blenoxane (registered trademark), bleomycin, bortezomib, busulfan, Busulfex (registered trademark), C225, leucovorin calcium, Campath (registered trademark), Camptosar (registered trademark), camptothecin-11, capecitabine, Carac (trademark), carboplatin, carmustine, carmustine wafer, Casodex (registered trademark), CC-5013, CCI-779, CCNU, CDDP, CeeNU, Cerubidine (registered trademark), cetuximab, chlorambucil, citrovorum factor, cladribine, cortisone, Cosmegen (registered trademark), CPT-11, Cytadren (registered trademark), Cytosar-U (registered trademark), Cytoxan (registered trademark), dacarbazine, dacogen, dactinomycin, darbepoetin alfa, dasatinib, daunomycin, doxorubicin hydrochloride, liposomal doxorubicin, DaunoXome (registered trademark), decadron, decitabine, Delta-Cortef(, Registered Trademark), Deltasone (Registered Trademark), Denilonkin, Diffitox, DepoCyt (Trademark), Dexamethasone, Dexamethasone Acetate, Sodium Dexamethasone Phosphate, Dexazone, Dexrazoxane, DHAD, DIC, Diodecks, Docetaxel, Doxil (Registered Trademark), Doxorubicin, Liposomal Doxorubicin, Droxia (Trademark), DTIC, DTIC-Dome (Registered Trademark), Duralone (Registered Trademark), Efudex (Registered Trademark), Eligard (Trademark), Ellence (Trademark), Eloxatin (Trademark), Elspar (Registered Trademark), Emcyt (Registered Trademark), Epirubicin, Epoetin Alfa, Arbitax, Erlotinib, Erwinia L-Asparaginase, Estramustine, Ethiol, Etopophos (Registered Trademark), Etoposide, Etoposide Phosphate, Eulexin (Registered Trademark), Everolimus, Evista (Registered Trademark), Exemestane, Fareston (Registered Trademark), Faslodex (Registered Trademark), Femara (Registered Trademark), Filgrastim, Floxuridine, Fludara (Registered Trademark), Fludarabine, Fluoroplex (Registered Trademark), Fluorouracil, Fluorouracil (Cream), Fluoxymesterone, Flutamide, Folic Acid, FUDR (Registered Trademark), Fulvestrant, G-CSF, Gefitinib, Gemcitabine, Gemtuzumab, Ozogamicin, Gemzar Gleevec (Trademark), Gliadel (Registered Trademark) Wafer, GM-CSF, Goserelin, Granulocyte Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor, Halotestin (Registered Trademark), Herceptin (Registered Trademark), Hexadrol, Hexalen (Registered Trademark), Hexamethylmelamine, HMM, Hycamtin (Registered Trademark), Hydrea (Registered Trademark), Hydrocort Acetate (Registered Trademark), Hydrocortisone, Sodium Hydrocortisone Phosphate, Sodium Succinate Hydrocortisone, Hydrocortone Phosphate, Hydroxyurea, Ibritumomab, Ibritumomab, Tiuxetan, Idamycin (Registered Trademark), IdarubicinIfex (registered trademark), IFN-alpha, ifosfamide, IL-11, IL-2, imatinib mesylate, imidazole carboxamide, interferon alpha, interferon alpha-2b (PEG conjugate), interleukin-2, interleukin-11, Intron A (registered trademark) (interferon alpha-2b), Iressa (registered trademark), irinotecan, isotretinoin, ixabepilone, Ixempra (trademark), Kidrolase (registered trademark), Lanacort (registered trademark), lapatinib, L-asparaginase, LCR, lenalidomide, letrozole, leucovorin, leukeran, Leukine (trademark), leuprolide, leurocristine, Leustatin (trademark), liposomal Ara-C, Liquid Pred (Registered Trademark), Lomustine, L-PAM, L-Sarcolysin, Lupron (Registered Trademark), Lupron Depot (Registered Trademark), Matulane (Registered Trademark), Maxidex, Mechlorethamine, Mechlorethamine Hydrochloride, Medralone (Registered Trademark), Medrol (Registered Trademark), Megace (Registered Trademark), Megestrol, Megestrol Acetate, Melphalan, Mercaptopurine, Mesna, Mesnex (Trademark), Methotrexate, Methotrexate Sodium, Methylprednisolone, Meticorten (Registered Trademark), Mitomycin, Mitomycin-C, Mitoxantrone, M-Prednisol (Registered Trademark), MTC, MTX, Mustargen (Registered Trademark), Mustine, Mutamycin (Registered Trademark), Myleran (Registered Trademark), Mylocel (Trademark), Mylotarg (Registered Trademark), Navelbine (Registered Trademark), Nelarabine, Neosar (Registered Trademark), Neulasta (Trademark), Neumega (Registered Trademark), Neupogen (Registered Trademark), Nexavar (Registered Trademark), Nilandron (Registered Trademark), Nilotinib, Nilutamide, Nipent (Registered Trademark), Nitrogen Mustard, Novaldex (Registered Trademark), Novantrone (Registered Trademark), Nplate, Octreotide, Octreotide Acetate, Ofatumumab, Oncospar (Registered Trademark), Oncovin (Registered Trademark), Ontak (Registered Trademark), Onxal (Trademark), Oprelvekin, Orapred (Registered Trademark), Orasone (Registered Trademark), Oxaliplatin, Paclitaxel, Protein-Bound Paclitaxel, Pamidronate, Pa Nimumb, Panretin®, Paraplatin®, Pazopanib, Pediapred®, PEG Interferon, Pegaspargase, Pegfilgrastim, PEG-INTRON™, PEG-L-Asparaginase, Pemetrexed, Pentostatin, Phenylalanine Mustard, Platinol®, Platinol-AQ®, Prednisolone, Prednisone, Prelone®, Procarbazine, PROCRIT®, Proleukin®, Prolifeprospan 20 with Carmustine Implant, Purinethol®, Raloxifene, Revlimid®, Rheumatrex®, Rituxan®, Rituximab, Roferon-A® (Interferon Alfa-2a), Romiplostim, Rubex®, Rubidomycin Hydrochloride, Sandostatin®, Sandostatin LAR®, Sargramostim, Solu-Cortef®, Solu-Medrol®, Sorafenib, SPRYCEL™, STI-571, Streptozocin, SU11248, Sunitinib, Sutent®, Tamoxifen, Tarceva®, Targretin®, Tasigna®, Taxol®, Taxotere®, Temodar®, Temozolomide, Temsirolimus, Teniposide, TESPA, Thalidomide, Thalomid®, TheraCys®, Thioguanine, ThioguanineTabloid (registered trademark), thiophosphoramide, Thioplex (registered trademark), thiotepa, TICE (registered trademark), Toposar (registered trademark), topotecan, tamoxifen, Torisel (registered trademark), tositumomab, trastuzumab, Treanda (registered trademark), tretinoin, Trexall (trademark), Trisenox (registered trademark), TSPA, TYKERB (registered trademark), VCR, Vectibix (trademark), Velban (registered trademark), Velcade (registered trademark), VePesid (registered trademark), Vesanoid (registered trademark), Viadur (trademark), Vidaza (registered trademark), vinblastine, vinblastine sulfate, Vincasar Pfs (registered trademark), vincristine, vinorelbine, vinorelbine tartrate, VLB, VM-26, vorinostat, Votrient, VP-16, Vumon (registered trademark), Xeloda (registered trademark), Zanosar (registered trademark), Zevalin (trademark), Zinecard (registered trademark), Zoladex (registered trademark), zoledronic acid, Zolinza, Zometa (registered trademark), or any combination of the foregoing is included.

[0332] In certain embodiments, for the treatment of a proliferative disorder described herein, an immuno-oncology agent can be administered in combination with a compound described herein. As used herein, the term "immuno-oncology agent" refers to an agent effective to enhance, stimulate, and / or upregulate an immune response in a subject. In some embodiments, administering an immuno-oncology agent in combination with a compound described herein has a synergistic effect in the treatment of cancer.

[0333] In some embodiments, a compound described herein is administered sequentially prior to the administration of an immuno-oncology agent. In some embodiments, a compound described herein is administered concurrently with an immuno-oncology agent. In some embodiments, a compound described herein is administered sequentially after the administration of an immuno-oncology agent.

[0334] In some embodiments, a compound described herein can be formulated with an immuno-oncology agent.

[0335] Immuno - oncology agents can be, for example, small - molecule drugs, antibodies, or biomolecules or small molecules. Examples of biological immuno - oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is a humanized monoclonal antibody or a human monoclonal antibody.

[0336] In some embodiments, the immuno - oncology agent is (i) an agonist of a stimulatory (including co - stimulatory) receptor or (ii) an antagonist of an inhibitory (including co - inhibitory) signal on T cells, both of which result in the amplification of an antigen - specific T - cell response.

[0337] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B.B-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors are molecules of the TNF family that bind to members of the TNF receptor superfamily, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, lymphotoxin α / TNFβ, TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0338] In some embodiments, the immuno-oncology agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF, and other immunosuppressive cytokines), or a cytokine that stimulates T cell activation to stimulate an immune response.

[0339] In some embodiments, the combinations of the compounds and immuno-oncology agents described herein can stimulate a T cell response. In some embodiments, the immuno-oncology agent is (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galectin 9, CEACAM-1, BTLA, CD69, galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, or (ii) an agonist of a protein that stimulates T cell activation, such as B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

[0340] 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.

[0341] In some embodiments, the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes, including, but not limited to, CSF-1R antagonists, such as CSF-1R antagonist antibodies including RG7155 (WO11 / 70024, WO11 / 107553, WO11 / 131407, WO13 / 87699, WO13 / 119716, WO13 / 132044) or FPA-008 (WO11 / 140249; WO13169264; WO14 / 036357).

[0342] In some embodiments, the immuno-oncology agent is an agonist agent that ligates a positive co-stimulatory receptor, a blocker that attenuates signaling through an inhibitory receptor, an antagonist, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome distinct immunosuppressive pathways within the tumor microenvironment (e.g., blocking the involvement of inhibitory receptors (e.g., the PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by ex vivo anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell anergy or exhaustion), and agents that cause innate immune activation and / or inflammation at the tumor site.

[0343] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonist CTLA-4 antibody. In some embodiments, the antagonist CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0344] In some embodiments, the immuno-oncology agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the immuno-oncology agent is an antibody or antigen-binding portion thereof that specifically binds to the programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonist PD-1 antibody. In some embodiments, the antagonist PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 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, composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0345] In some embodiments, the immuno-oncology agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonist PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0346] In some embodiments, the immuno-oncology agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonist LAG-3 antibody. In some embodiments, the LAG3 antibody is BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO009 / 44273).

[0347] In some embodiments, the immuno-oncology agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonist CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12 / 32433).

[0348] In some embodiments, the immuno-oncology agent is a GITR agonist. In some embodiments, the GITR agonist is an agonist GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006 / 105021, WO009 / 009116), or MK-4166 (WO11 / 028683).

[0349] In some embodiments, the immuno-oncology agent is an IDO antagonist. In some embodiments, the IDO antagonist is INCB-024360 (WO2006 / 122150, WO07 / 75598, WO08 / 36653, WO08 / 36642), indoximod, or NLG-919 (WO09 / 73620, WO009 / 1156652, WO11 / 56652, WO12 / 142237).

[0350] In some embodiments, the immuno-oncology agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonist OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0351] In some embodiments, the immuno-oncology agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonist OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06 / 029879).

[0352] In some embodiments, the immuno-oncology agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonist CD40 antibody. In some embodiments, the immuno-oncology agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonist CD40 antibody. In some embodiments, the CD40 antibody is lucatumumab or dacetuzumab.

[0353] In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonist CD27 antibody. In some embodiments, the CD27 antibody is balstilimab.

[0354] In some embodiments, the immuno-oncology agent is MGA271 (against B7H3) (WO11 / 109400).

[0355] In some embodiments, the immuno-oncology agent is abagovomab, adecatumumab, afucosylated anti-CD20 antibody, alemtuzumab, anatumomab mafenatox, apo lizumab, atezolizumab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epirubicin, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, ranibizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, tislelizumab, samalizumab, or tremelimumab.

[0356] In some embodiments, the immuno-oncology agent is an immune activator. For example, antibodies that block the PD-1 and PD-L1 inhibitory axes can release activated tumor-reactive T cells and have been shown to induce a durable antitumor response that increases the number of tumor tissues, including some tumor types that were not previously considered sensitive to immunotherapy, in clinical trials. 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 (O NO-4538, MDX1106, and BMS-936558, also known as Opdivo® (Bristol-Myers Squibb), has been shown to potentially improve overall survival in patients with RCC who experienced disease progression during or after prior anti-angiogenic therapy.

[0357] ​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).

[0358] In some embodiments, the immuno-oncology agent is a cancer vaccine. In some embodiments, the cancer vaccine is 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, previously known as T-VEC), which is an approved genetically modified oncolytic virus therapy for the treatment of unresectable cutaneous, subcutaneous, and nodal lesions in melanoma, selected therefrom.In some embodiments, the immuno-oncology agent is PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics, a thymidine kinase-(TK-)deficient vaccinia virus engineered to express GM-CSF for oncolytic virus therapy, e.g., for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep (Reolysin®, Oncolytics Biotech), a mutant of the respiratory enteric orphan virus (reovirus) that does not replicate in cells not activated by RAS in several cancers, including colorectal cancer (NCT01622543), prostate cancer (NCT01619813), head and neck squamous cell carcinoma (NCT01166542), pancreatic adenocarcinoma (NCT00998322), and non-small cell lung cancer (NSCLC) (NCT00861627); enadenotucirev (NG-348, PsiOxus, formerly known as ColoAd1), an adenovirus engineered to express full-length CD80 and antibody fragments specific for the T cell receptor CD3 protein in ovarian cancer (NCT02028117), metastatic or advanced epithelial tumors, e.g., colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF in melanoma (NCT03003676), and peritoneal disease, colorectal cancer or ovarian cancer (NCT02963831); peritoneal carcinomatosis (NCT01443260); beta-galactosidase (beta-gal) / beta-glucoronidase, which has also been studied in fallopian tube cancer, ovarian cancer (NCT02759588), respectively. GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), a vaccinia virus engineered to express either beta-gal / human sodium iodide symporter (hNIS); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818).

[0359] In some embodiments, the immuno-oncology agent is JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which can convert the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapeutic agents targeting refractory RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP (ViraTherapeutics), a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) and further engineered to express an antigen designed to enhance antigen-specific CD8 T cell responses. + In some embodiments, the immuno-oncology agent is a T cell engineered to express a chimeric antigen receptor or CAR. T cells engineered to express such chimeric antigen receptors are referred to as CAR-T cells.

[0360]

[0361] ​A CAR consisting of a binding domain is constructed, and this domain is fused to an endodomain, which is the functional end of a T cell receptor (TCR), such as a CD3-zeta signaling domain derived from the TCR that can generate an activation signal in T lymphocytes, and can be derived from a single-chain variable fragment (scFv), which is a natural ligand derived from a monoclonal antibody specific for a cell surface antigen. When such a CAR binds to an antigen, it links to the endogenous signaling pathway in effector cells and generates an activation signal similar to that initiated by the TCR complex.

[0362] For example, in some embodiments, the CAR-T cell is one of those described in U.S. Patent No. 8,906,682 (June; incorporated herein by reference 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 an intracellular signaling domain of the T cell antigen receptor complex zeta chain (such as CD3 zeta). When expressed in T cells, the CAR can change the target of antigen recognition based on its antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Currently, over 200 clinical trials are underway using CAR-T for a wide range of indications. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0363] In some embodiments, the immune activator is an activator of retinoic acid receptor-related orphan receptor gamma (RORγt). RORγt is a transcription factor that plays a very important role in the differentiation and maintenance of the type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as in the differentiation of subsets of innate immune cells that express IL-17, such as NK cells. In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in a clinical trial for the treatment of solid tumors (NCT02929862).

[0364] In some embodiments, the immunostimulant is an agonist or activator of a toll-like receptor (TLR). Suitable activators of TLR include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that has been studied for follicular B-cell and other lymphomas (NCT02254772). Agonists or activators of TLR8 that can be used in the present invention include Motolimod (VTX-2337, VentiRx Pharmaceuticals), which has been studied for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0365] 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 Squib b), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; and ecaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; MK-4166 (Merck&Co.), an anti-GITR monoclonal antibody are included.

[0366] In some embodiments, the immunostimulant is selected from elotuzumab, mifamurtide, an agonist or activator of a toll-like receptor, and an activator of RORγt.

[0367] In some embodiments, the immune activating therapeutic agent is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been clinically tested as a treatment for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). In some embodiments, the immune activator is recombinant human interleukin 12 (rhIL-12). In some embodiments, the IL-15-based immunotherapeutic agent is being tested in a Phase 1 clinical trial for melanoma, renal cell carcinoma, non-small cell lung cancer and squamous cell carcinoma of the head and neck (NCT02452268), a heterodimeric IL-15 (hetIL-15, Novartis / Admune) composed of a synthetic form of endogenous IL-15 that forms a complex with the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15:sIL-15RA). In some embodiments, the recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0368] 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 entire contents of which are incorporated herein by reference. 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 cancer immunotherapeutic agent is a small molecule drug selected from those listed in Table 2 of Jerry L. Adams ET. AL.

[0369] In some embodiments, the immuno-oncology agent is selected from small molecule immuno-oncology therapeutic agents described in Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents," Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329, the entire content of which is incorporated herein by reference. In some embodiments , the immuno-oncology agent is an agent that targets the pathways described by Peter L. Toogood.

[0370] In some embodiments, the immuno-oncology agent is selected from those described in Sandra L. Ross et al., "Bispecific T cell engager (BiTE(R)) antibody constructs can mediate bystander tumor cell killing", PLoS ONE 12(8): e0183390, the entire content of which is incorporated herein by reference. In some embodiments, the immuno-oncology agent 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 It thereby releases cytokines that induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodiments, a bispecific T cell engager (BiTE®) antibody construct activates T cells, thereby resulting in induction of lysis of bystander cells. In some embodiments, the bystander cells are present in a solid tumor. In some embodiments, the bystander cells to be lysed are present in proximity to BiTE®-activated T cells. In some embodiments, the bystander cells include tumor-associated antigen (TAA)-negative cancer cells. In some embodiments, the bystander cells include EGFR-negative cancer cells. In some embodiments, the immuno-oncology agent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the immuno-oncology agent is tumor-infiltrating T cells that expand ex-vivo. In some embodiments, the immuno-oncology agent is a bispecific antibody construct or a chimeric antigen receptor (CAR) that directly links T cells to tumor-associated surface antigen (TAA).

[0371] In certain embodiments, a combination of two or more therapeutic agents can be administered together with a compound of the invention. In certain embodiments, a combination of three or more therapeutic agents can be administered together with a compound of the invention.

[0372] Other examples of agents that can be combined with the inhibitors of the present invention include, but are not limited to, vitamins and dietary supplements, cancer vaccines, treatments for neutropenia (e.g., G-CSF, filgrastim, lenograstim), treatments for thrombocytopenia (e.g., blood transfusion, erythropoietin), PI3 kinase (PI3K) inhibitors, MEK inhibitors, mTOR inhibitors, CPT1 inhibitors, AMPK activators, PCSK9 inhibitors, SREBP site 1 protease inhibitors, HMG CoA-reductase inhibitors, antiemetics (e.g., 5-HT3 receptor antagonists, dopamine antagonists, NK1 receptor antagonists, histamine receptor antagonists, cannabinoids, benzodiazepines, or anticholinergic agents), treatments for Alzheimer's disease, such as Aricept® and Excelon®; treatments for Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinrole, pramipexole, bromoc riptine, pergolide, trihexephendyl, and amantadine; agents for treating multiple sclerosis (MS), such as beta interferon (e.g., Avonex® and Rebif®), Copaxone®, and mitoxantrone; treatments for asthma, such as albuterol and Singulair®; agents for treating schizophrenia, such as ziprasidone, risperdal, seroquel, and haloperidol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents, such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic Nourishing factors, such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, antiepileptic drugs, ion channel blockers, riluzole, and antiparkinsonian agents; drugs for treating cardiovascular diseases, such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins, fibrate drugs, cholesterol absorption inhibitors, bile acid sequestrants, and niacin; drugs for treating liver diseases, such as corticosteroids, cholestyramine, interferons, and antiviral agents; drugs for treating blood disorders, such as corticosteroids, antileukemic agents, and growth factors; drugs for treating immunodeficiency disorders, such as gamma globulin; and antidiabetic drugs, such as biguanides (metformin, phenformin, buformin), thiazolidinediones (rosiglitazone, pioglitazone, troglitazone), sulfonylureas (tolbutamide, acetohexamide, trazamide, chlorpropamide, glibide, glibenclamide, glimepiride, glycl azide), meglitinides (repaglinide, nateglinide), alpha-glucosidase inhibitors (miglitol, acarbose), incretin mimetics (exenatide, liraglutide, taspoglutide), gastric inhibitory polypeptide analogs, DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin), amylin analogs (pramlintide), and insulin and insulin analogs include.

[0373] In certain embodiments, the compounds or pharmaceutically acceptable compositions thereof of the present invention are administered in combination with antisense agents, monoclonal or polyclonal antibodies or siRNA therapeutics.

[0374] 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 compound of the present invention and one or more additional therapeutic agents. Such additional therapeutic agents can be small molecules or recombinant biological agents, including, for example, acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, etodolac (Lodine®), and celecoxib, colchicine (Colcrys®), corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, etc., probenecid, allopurinol, febuxostat (Uloric®), sulfasalazine (Azulfidine®), anti-malarial drugs such as hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®), methotrexate (Rheumatrex®), gold salts such as aurothioglucose (Solganal®), aurothiomalate (Myochrysine®), and auranofin (Ridaura®), D-penicillamine (Depen® or Cuprimine®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimmune®), leflunomide (Arava®), and "anti-TNF" agents such as etanercept (Enbrel®), infliximab (Remicade®), golimumab (Simponi®), certolizumab pegol (Cimzia®), and adalimumab (Humira®), "anti-IL-1" agents such as anakinra (Kineret®) and rilonacept (Arcalyst®), canakinumab (Ilaris®), anti-Jak inhibitors such as tofacitinib, antibodies such as rituximab (Rituxan®), "anti-T cell" agents such as abatacept (Orencia®), "anti-IL-6" agents such as tocilizumab (Actemra®),Diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies, such as tanezumab, anticoagulants, such as heparin (Calcinparine® or Liquaemin®) and warfarin (Coumadin®), antidiarrheals, such as diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders, such as cholestyramine, alosetron (Lotronex®), lubiprostone (Amitiza®), laxatives, such as milk of magnesia, polyethylene glycol (MiraLax®), Dulcolax®, Correctol® and Senokot®, anticholinergic or antispasmodic agents, such as dicyclomine (Bentyl®), Singulair®, beta-2 agonists, such as albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Xopenex®), metaproterenol (Alupent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Brethai, re (Registered Trademark)), salmeterol xinafoate (Serevent (Registered Trademark)) and formoterol (Foradil (Registered Trademark)), anticholinergics, such as ipratropium bromide (Atrovent (Registered Trademark)) and tiotropium (Spiriva (Registered Trademark)), inhaled corticosteroids, such as beclomethasone dipropionate (Beclovent (Registered Trademark), Qvar (Registered Trademark), and Vanceril (Registered Trademark)), triamcinolone acetonide (Azmacort (Registered Trademark)), mometasone (Asthmanex (Registered Trademark)), budesonide (Pulmocort (Registered Trademark)), and flunisolide (Aerobid (Registered Trademark)), Afviar (Registered Trademark), Symbicort (Registered Trademark), Dulera (Registered Trademark), sodium cromoglycate (Intal (Registered Trademark)), methylxanthines, such as theophylline (Theo-Dur (Registered Trademark), Theolair (Registered Trademark), Slo-bid (Registered Trademark), Uniphyl (Registered Trademark), Theo-24 (Registered Trademark)) and aminophylline, IgE antibodies, such as omalizumab (Xolair (Registered Trademark)), nucleoside reverse transcriptase inhibitors, such as zidovudine (Retrovir (Registered Trademark)), abacavir (Ziagen (Registered Trademark)), abacavir / lamivudine (Epzicom (Registered Trademark)), abacavir / lamivudine / zidovudine (Trizivir (Registered Trademark)), didanosine (Videx (Registered Trademark)), emtricitabine (Emtriva (Registered Trademark)), lamivudine (Epivir (Registered Trademark)), lamivudine / zidovudine (Combivir (Registered Trademark)), stavudine (Zerit (Registered Trademark)), and zalcitabine (Hivid (Registered Trademark)), non-nucleoside reverse transcriptase inhibitors, such as delavirdine (Rescriptor (Registered Trademark)), efavirenz (Sustiva (Registered Trademark)), nevirapine (nevairapine)(V iramune (registered trademark), etravirine (Intelence (registered trademark)), nucleotide reverse transcriptase inhibitors such as tenofovir (Viread (registered trademark)), protease inhibitors such as amprenavir (Agenerase (registered trademark)), atazanavir (Reyataz (registered trademark)), darunavir (Prezista (registered trademark)), fosamprenavir (Lexiva (registered trademark)), indinavir (Crixivan (registered trademark)), lopinavir and ritonavir (Kaletra (registered trademark)), nelfinavir (Viracept (registered trademark)), ritonavir (Norvir (registered trademark)), saquinavir (Fortovase (registered trademark) or Invirase (registered trademark)), and tipranavir (Aptivus (registered trademark)), entry inhibitors such as enfuvirtide (Fuzeon (registered trademark)) and maraviroc (Selzentry (registered trademark)), integrase inhibitors such as raltegravir (Isentress (registered trademark)), doxorubicin (Hydrodaunorubicin (registered trademark)), vincristine (Oncovin (registered trademark)), bortezomib (Velcade (registered trademark)), and dexamethasone (Decadron (registered trademark)) combined with lenalidomide (Revlimid (registered trademark)), or any combination thereof is included.

[0375] In some embodiments, the provided compounds are administered in combination with an antiviral agent, such as acyclovir, pencyclovir, cidofovir, idoxuridine, zidovudine, ribavarin, amantadine, foscarnet, didanosine, acyclovir, ganciclovir, cidofovir, zalcitabine, rimantadine, calacyclovir, famiciclovir, abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine, zidovudine-lamivudine, truvada (zidovudine, lamivudine, abacavir), epzicom (abacavir lamivudine), truvada (tenofovir-emtricitabine), efavirenz, nevirapine, and delavirdine, amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir-ritonavir, nelfinavir, ritonavir, saquinavir, and tipranavir. In some embodiments, the antiviral agent is an anti-influenza agent, such as rimantadine, amantadine, oseltamivir, and zanamivir.

[0376] Those additional agents can be administered separately from the composition containing the compounds of the invention as part of multiple dosing regimens. Alternatively, those agents can be part of a single dosage form, mixed together with the compounds of the invention in a single composition. When administered as part of multiple dosing regimens, the two active agents can be submitted simultaneously, sequentially, or within a time period of each other, usually within 5 hours of each other.

[0377] As used herein, the terms "combination", "combined", and related terms refer to administering therapeutic agents simultaneously or sequentially in accordance with the invention. For example, the compounds of the invention can be administered with another therapeutic agent simultaneously or sequentially, in separate unit dosage forms, or together in a single unit dosage form. Accordingly, the invention provides a single unit dosage form comprising a compound of the invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0378] The amounts of both the provided compounds and additional therapeutic agents, which can be combined with a carrier material to produce a single dosage form (in those compositions containing additional therapeutic agents as described above), will vary depending on the host being treated and the particular method of administration. Preferably, the compositions of the present invention should be formulated such that dosages of the present invention between 0.01 and 100 mg / kg (body weight) / day can be administered.

[0379] In those compositions containing an additional therapeutic agent, the additional therapeutic agent and the compounds of the present invention can act synergistically. Thus, 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, dosages of the additional therapeutic agent between 0.01 and 100 μg / kg (body weight) / day can be administered.

[0380] The amount of the additional therapeutic agent present in the compositions of the present invention is less than the amount that would normally be administered in a composition containing that therapeutic agent as the sole active agent. Preferably, the amount of the additional therapeutic agent in the compositions of the present disclosure is in the range of about 50% to 100% of the amount that is normally present in a composition containing that agent as the sole therapeutically active agent.

[0381] In one embodiment, the present invention provides a composition comprising a compound of the present invention and one or more additional therapeutic agents. The therapeutic agent can be administered together with the compound of the present invention, or can be administered before or after administration of the compound of the present invention. Suitable therapeutic agents are further detailed below. In certain embodiments, the compound of the present invention can be administered up to 5 minutes, 10 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, or 18 hours before the therapeutic agent. In other embodiments, the compound of the present invention 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.

[0382] In some embodiments, the present invention provides a pharmaceutical product comprising at least one compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0383] All features of each aspect of the present invention apply mutatis mutandis to all other aspects.

[0384] To enable a more complete understanding of the invention described herein, the following examples are provided. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

Examples

[0385] As shown in the following examples, in certain exemplary embodiments, the compounds are prepared according to the following general procedures. The general methods illustrate the synthesis of certain compounds of the present invention, but it is understood that the following general methods, as well as other methods known to those skilled in the art, can be applied to all compounds described herein, as well as to each subclass and species of these compounds. General Procedures X-ray powder diffraction (XRPD)

[0386] Configure the X-ray diffraction system in a reflection-type Bragg-Brentano geometry using a line-source X-ray beam. The source provides an incident beam profile that varies in the sample from a narrow line at high angles to a wide rectangle at low angles. Use beam conditioning slits on the X-ray source so that the maximum beam size is less than 10 mm both along the line and perpendicular to the line. The Bragg-Brentano geometry is a para-focusing geometry controlled by a passive divergence slit and a receiving slit, and the sample itself acts as a focusing component with respect to the optical elements. The intrinsic resolution of the Bragg-Brentano geometry is partially determined by the radius of the diffractometer used and the width of the receiving slit. Typically, the X-ray diffraction system is operated so as to obtain a peak width of 0.1° 2θ or less. The axial divergence of the X-ray beam is controlled by 5.0-degree Soller slits in both the incident and diffracted beam paths.

[0387] Prepare the powder sample in a low-background Si holder using light hand pressure to flatten the sample surface and keep it at the same level as the reference surface of the sample holder. Analyze each sample using a continuous scan of 6° 2θ per minute from 2° 2θ to 40° 2θ with an effective step size of 0.02° 2θ. Differential scanning calorimetry (DSC)

[0388] Perform DSC analysis using a TA instrument. Calibrate the instrument temperature using indium. Maintain the DSC cell under a nitrogen purge of approximately 50 mL per minute during each analysis. Place the sample in a standard crimped aluminum pan and heat it from 25 °C to 350 °C at a rate of 10 °C per minute. Thermogravimetric (TG) analysis

[0389] The TG analysis is performed using a TA instrument. The balance of the instrument is calibrated using weights of class M, and temperature calibration is carried out using Almel. The nitrogen purge is approximately 40 mL per minute for the balance and approximately 60 mL per minute for the furnace. Each sample is placed in a pre-tared platinum dish and heated from 20 °C to 350 °C at a rate of 10 °C per minute. Nuclear magnetic resonance (NMR) spectroscopy

[0390] Samples are prepared by dissolving the material in a solvent. The solution is filtered and placed into individual 5 mm NMR tubes for subsequent spectrum acquisition. Primary salt screening

[0391] Salt screening experiments were carried out using 12 acid salt formers with various crystallization techniques (cooling, slurrying, evaporation, and vapor diffusion). The details of the experiments for each salt formation trial are described in Table 11. Table 11. Salt screening experiments

Table 11-1

Table 11-2

Table 11-3

[0392] Form A of Compound 1, Form A of Compound 2, Form B of Compound 3, and Form A of Compound 4 are scaled up, and the details of the experiments are described in Table 12 below. Table 12. Secondary salt screening experiments

Table 12

Chemical formula

[0393] The title compound was prepared according to the steps and intermediates described below and in the '411 publication (which is hereby incorporated by reference in its entirety), for example, Scheme 1. Scheme 1 - Synthesis of Compound A

Chem.

Chem.

[0394] A mixture of 4-chloro-2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine (60.00 mg, 205.68 μmol, 1 equiv), (3R)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (42.14 mg, 226.25 μmol, 1.1 equiv), and DIEA (79.75 mg, 617.05 μmol, 107.48 μL, 3 equiv) in i-PrOH (4 mL) was degassed and purged with N2 three times. The mixture was stirred at 55 °C for 3 h under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Phenomenex Gemini 150*25 mm*10 μm; mobile phase: [water (0.05% HCl)-ACN]; B%: 70% - 100%, 10 min), followed by lyophilization to give (3R)-N-[2-(5-fluoro-3-pyridyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4,9-tetrahydro-1H-carbazol-3-amine (42.07 mg, 75.45 μmol, yield 36.7%, purity 98.8%, 3HCl) as a yellow solid. H NMR (400 MHz, CD3OD) δ ppm 9.46 (s, 1H), 8.81 (d, J = 9.3 Hz, 1H), 8.76 (s, 1 H NMR (400 MHz, CD3OD) δ ppm 9.46 (s, 1H), 8.81 ( d, J = 9.3 Hz, 1H), 8.76 ( s, (1H), 8.12 - 7.92 (m, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.27 (d, J = 7.9 Hz, 1H), 7.08 - 7.00 (m, 1H), 6.99 - 6.90 (m, 1H), 3.34 (s, 1H), 3.31 - 3.25 (m, 2H), 3.18 - 2.79 (m, 3H), 2.44 - 2.21 (m, 2H), 1.42 (d, J = 7.1 Hz, 6H); ES-LCMS m / z 442.2[M+H] + 。 Example 1 - Preparation of Free Base Forms A, B, and C of Compound A

Chemical Structure

[0395] Form B of Compound A was prepared as described above.

[0396] Table B above is reproduced below, listing the X-ray diffraction peaks observed for Form B of Compound A. Table B - XRPD Peak Positions for Form B of Compound A

Table 16-3

Table 16-4

[0397] Figure 1 shows the XRPD pattern of Form B of Compound A.

[0398] Figure 2 shows the TG / DTA trace of Form B of Compound A. Form C of Compound A

[0399] Form C of Compound A was prepared as described above.

[0400] Table C above is reproduced below, listing the X-ray diffraction peaks observed for Form C of Compound A. Table C - XRPD Peak Positions for Polymorph C of Compound A

Table 18 - 1

Table 18 - 2

Table 18 - 3

[0401] Figure 3 shows the XRPD pattern of polymorph C of Compound A.

[0402] Figure 4 shows the TG / DTA trace of polymorph C of Compound A. Mixture of Polymorph A and Polymorph B of Compound A

[0403] Hydrochloride salt of Compound A (7.0 g) was dissolved in a mixture of EtOAc (150 mL) and saturated NaHCO3 solution (200 mL) and stirred at 28 °C for 30 minutes. The mixture was extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over Na2SO4, concentrated to obtain a residue, which was added to MeOH (150 mL) and stirred for 30 minutes. The mixture was filtered, and the filter cake was concentrated to obtain the desired product, which was lyophilized to obtain a mixture of polymorph A and polymorph B of Compound A (6.7 g) as a solid.

[0404] Figure 24 shows the XRPD pattern of the mixture of polymorph A and polymorph B of Compound A.

[0405] Figure 25 shows the TGA / DSC of the mixture of polymorph A and polymorph B of Compound A. Example 2 - Preparation of Polymorph A of Compound 1

Chemical Structure

[0406] Polymorph A of Compound 1 was prepared as described above.

[0407] Table 1 above is reproduced below, and the X-ray diffraction peaks observed for Form A of Compound 1 are described. Table 1 - XRPD Peak Positions for Form A of Compound 1 [Table 1-3] [Table 1-4]

[0408] Figure 5 shows the XRPD pattern of Form A of Compound 1.

[0409] Figure 6 shows the TG / DTA trace of Form A of Compound 1. Form B of Compound 1

[0410] Form B of Compound 1 was prepared as described above.

[0411] Table 2 above is reproduced below, and the X-ray diffraction peaks observed for Form B of Compound 1 are described. Table 2 - XRPD Peak Positions for Form B of Compound 1 [Table 2-3] [Table 2-4]

[0412] Figure 7 shows the XRPD pattern of Form B of Compound 1. Example 3 - Preparation of Form A of Compound 2 [Chemical Structure] <D Form A of Compound 2

[0413] Form A of Compound 2 was prepared as described above.

[0414] Table 3 above is reproduced below, and the X-ray diffraction peaks observed for Form A of Compound 2 are described. Table 3 - XRPD Peak Positions of Polymorph A of Compound 2 [Table 3 - 3] [Table 3 - 4]

[0415] Figure 8 shows the XRPD pattern of polymorph A of Compound 2.

[0416] Figure 9 shows the TG / DTA trace of polymorph A of Compound 2. Example 4 - Preparation of Polymorph A of Compound 3 [Chemical Structure] Polymorph A of Compound 3

[0417] Polymorph A of Compound 3 was prepared as described above.

[0418] Table 4 above is reproduced below, listing the X - ray diffraction peaks observed for polymorph A of Compound 3. described. Table 4 - XRPD Peak Positions of Polymorph A of Compound 3 [Table 4 - 3] [Table 4 - 4]

[0419] Figure 10 shows the XRPD pattern of polymorph A of Compound 3.

[0420] Figure 11 shows the TG / DTA trace of polymorph A of Compound 3. Polymorph B of Compound 3

[0421] Polymorph B of Compound 3 was prepared as described above.

[0422] Table 5 above is reproduced below, and the X-ray diffraction peaks observed for Form B of Compound 3 are described. Table 5 - XRPD Peak Positions for Form B of Compound 3 [Table 5-2]

[0423] Figure 12 shows the XRPD pattern of Form B of Compound 3.

[0424] Figure 13 shows the TG / DTA trace of Form B of Compound 3. Example 5 - Preparation of Form A of Compound 4 [Chemical formula] Form A of Compound 4

[0425] Form A of Compound 4 was prepared as described above.

[0426] Table 6 above is reproduced below, and the X-ray diffraction peaks observed for Form A of Compound 4 are described. Table 6 - XRPD Peak Positions for Form A of Compound 4 [Table 6-3] [Table 6-4]

[0427] Figure 14 shows the XRPD pattern of Form A of Compound 4.

[0428] Figure 15 shows the TG / DTA trace of Form A of Compound 4. Example 6 - Preparation of Form A of Compound 5 [Chemical formula] Form A of Compound 5

[0429] Form A of Compound 5 was prepared as described above.

[0430] Table 7 above is reproduced below, and the X-ray diffraction peaks observed for Form A of Compound 5 are described. Table 7 - XRPD Peak Positions for Form A of Compound 5 [Table 7-2]

[0431] Figure 16 shows the XRPD pattern of Form A of Compound 5.

[0432] Figure 17 shows the TG / DTA trace of Form A of Compound 5. Example 7 - Preparation of Forms A and B of Compound 6 [Chemical formula] Here, X is about 1 or 2. Form A of Compound 6

[0433] Form A of Compound 6 was prepared as described above. It was determined that Form A of Compound 6 contains Compound A and ethanedisulfonic acid in a ratio of about 1:1.

[0434] Table 8 above is reproduced below, and the X-ray diffraction peaks observed for Form A of Compound 6 are described. Table 8 - XRPD Peak Positions for Form A of Compound 6 [Table 8-3]

[0435] Figure 18 shows the XRPD pattern of Form A of Compound 6.

[0436] Figure 19 shows the TG / DTA trace of Form A of Compound 6. Form B of Compound 6

[0437] Form B of Compound 6 was prepared as described above. It was determined that Form B of Compound 6 contains Compound A and ethanedisulfonic acid in a ratio of approximately 2:1.

[0438] Table 9 above is reproduced below, listing the X-ray diffraction peaks observed for Form B of Compound 6. Table 9 - XRPD Peak Positions for Form B of Compound 6

Table 9-3

[0439] Figure 20 shows the XRPD pattern of Form B of Compound 6.

[0440] Figure 21 shows the TG / DTA trace of Form B of Compound 6. Example 8 - Preparation of Form A of Compound 7

Chemical Structure

[0441] Form A of Compound 7 was prepared as described above.

[0442] Table 10 above is reproduced below, listing the X-ray diffraction peaks observed for Form A of Compound 7. Table 10 - XRPD Peak Positions for Form A of Compound 7

Table 10-2

[0443] Figure 22 shows the XRPD pattern of Form A of Compound 7.

[0444] Figure 23 shows the TG / DTA trace of Form A of Compound 7. Example 9 - Solubility Study

[0445] Solubility studies of Form B of Compound A, Form B of Compound 1, Form A of Compound 2, Form B of Compound 3, and Form A of Compound 4 were determined in water, fasted state simulated intestinal fluid (FaSSIF), fed state simulated intestinal fluid (FeSSIF), and fasted state simulated gastric fluid (FaSSGF). The simulated fluids were obtained from biorelevant.com and prepared according to biorelevant.com using biorelevant.com's FaSSIF / FeSSIF / FaSSGF powder (v1, previously known as SIF powder). Samples were prepared by adding an excess of solid to 5 mL of the medium at 37 °C. Samples were withdrawn and filtered at 30 minutes, 120 minutes, and 24 hours and tested for solution concentration using the HPLC parameters described in Table 13 below. Table 13 - HPLC Parameters

Table 13

[0446] The pH of the samples at each time point was also measured. Due to the small sample size, pH paper was used at 30 minutes and 120 minutes, and a pH meter was used at 24 hours. The remaining material from all tests was analyzed by XRPD after 24 hours to determine if any polymorphic form changes occurred. The remaining material from the tests in water was analyzed by NMR after 24 hours to determine if dissociation occurred. Form B of Compound 1 was not analyzed by NMR at 24 hours due to low material availability. The results are shown in Table 14 below. Table 14 - Solubility Studies

Table 14-1

Table 14-2

[0447] As described above, Form A of Compound 2 and Form B of Compound 3 showed the highest solubility in FeSSIF at 24 hours. Example 10 - Stability Study

[0448] Stability studies of Form B of Compound A, Form B of Compound 1, Form A of Compound 2, Form B of Compound 3, and Form A of Compound 4 were conducted at 40 °C / 75% RH. To achieve approximately 75% RH in the chamber, the samples were stored in vials with loose caps in a chamber containing saturated NaCl solution. The chamber was stored in an oven at 40 °C. The samples were analyzed at time points 0, 1 week, 2 weeks, and 4 weeks using the HPLC parameters listed in Table 13. The results are shown in Table 15 below. Table 15 - Stability Study [Table 15-1] [Table 15-2]

[0449] Overall, significant degradation was observed over time for Form B of Compound 3. At the end of the study, it was confirmed that all the solids had lost their crystallinity and became X-ray amorphous. Form B of Compound A and Form B of Compound 1 appeared equally stable at 40 °C / 75% RH. Form A of Compound 4 showed degradation at 1 week and 2 weeks, but the peaks of the degradation products were no longer present at 4 weeks, and the area percentage of the main peak was improved. Form A of Compound 2 was quite stable under these accelerated conditions and lost only about 1.5% area over 4 weeks.

[0450] Although the inventors have described numerous embodiments of the present invention, it is recognized that their basic examples can be modified to provide other embodiments that utilize the compounds and methods of the present invention. Accordingly, it is understood that the scope of the present invention should be defined by the present application and the claims, rather than by the specific embodiments presented by way of illustration. The present invention provides, for example, the following items. (Item 1) Compound 2 in solid form, [Chemical formula] Here, Compound 2 in solid form, where about 1 ≦ x ≦ about 2. (Item 2) The compound according to item 1, wherein the compound is crystalline. (Item 3) The compound according to item 1, wherein the compound is a crystalline solid substantially free of amorphous Compound 2. (Item 4) The compound according to item 1, wherein the compound is substantially free of impurities. (Item 5) The compound according to item 1, having one or more peaks selected from the peaks at about 5.3, about 11.3 and about 16.0 degrees 2-theta in its XRPD. (Item 6) The compound according to item 5, having at least two peaks selected from the peaks at about 5.3, about 11.3 and about 16.0 degrees 2-theta in its XRPD. (Item 7) The compound according to item 6, wherein the compound is Compound A and x is about 2. (Item 8) The compound according to item 1, having an XRPD substantially similar to that shown in Figure 9. (Item 9) A composition comprising the compound according to item 1 and a pharmaceutically acceptable carrier or excipient. (Item 10) A method for inhibiting AHR in a patient in need thereof, comprising administering to the patient the compound according to item 1 or a composition thereof. (Item 11) A method for inhibiting AHR in a biological sample, comprising contacting the biological sample with the compound according to item 1 or a composition thereof. (Item 12) A method for treating an AHR-mediated disorder in a patient in need thereof, comprising administering to the patient the compound according to item 1 or a composition thereof. (Item 13) The method according to item 12, wherein the AHR-mediated disorder is cancer. (Item 14) The method according to item 12, wherein the AHR-mediated disorder is an inflammatory disorder. (Item 15) The method according to item 12, wherein the compound or its composition is administered orally. (Item 16) The compound or its composition is administered in the range of 0.01 to 100 mg / kg per body weight of the patient The method according to item 12. (Item 17) The method according to item 12, further comprising administering an additional therapeutic agent to the patient. (Item 18) Compound A in form A, form B or form C

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Claims

【Claim 1】 The invention described in the specification.

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