Polymorphic carbazole derivatives and uses thereof

Abstract

This invention provides free base and salt forms, compositions thereof, and methods for treating various symptoms involving AHR by administering small molecule therapeutic agents that act as inhibitors of aryl hydrocarbon receptors (AHR).

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 940,481, filed November 26, 2019, pursuant to 35 U.S. SC §119(e), the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This application relates to various forms and compositions as well as methods for treating various symptoms involving AHR by administering small molecule therapeutic agents that act as inhibitors of aryl hydrocarbon receptors (AHR). Background Technology

[0004] The aryl hydrocarbon receptor (AHR) is a ligand-free transcription factor that exists in an inactive state in the cytoplasm bound to HSP90. Upon ligand binding, the AHR translocates to the nucleus, where it dimers with ARNT to form a functional transcription factor. AHR / ARNT binds to dioxin-responsive elements (DREs) in the promoters of many genes, which regulate gene transcription. Well-documented genes regulated by AHR are the cytochrome P450 genes Cyp1b1 and Cyp1a1, where AHR activation significantly increases the expression of these genes. Therefore, Cyp1b1 and Cyp1a1 mRNA levels are selective reads of AHR activation (reviewed in Murray et al., 2014).

[0005] Numerous exogenous and endogenous AHR agonists exist that activate the receptor. The best-characterized class of exogenous ligands is dioxins. One of the first endogenous ligands characterized was kynurenine, generated from TDO (Opitz 2011) or IDO (Mezrich 2010). Kynurenine is a stable metabolite in the IDO / TDO pathway and is a product of tryptophan degradation. Kynurenine has been shown to activate the AHR, as measured by increased Cyp1a1 and / or Cyp1b1 mRNA levels and other DRE driver genes in various cell types.

[0006] AHR activation has a pro-tumorigenic effect by acting directly on tumor cells and indirectly by inducing immunosuppression, thus preventing the body's own immune system from attacking the tumor. For example, AHR activation via multiple ligands leads to increased FoxP3 expression and causes CD4+ T cells to polarize into a suppressive subset called Foxp3+ T regulatory cells (Tregs). These T-regs inhibit the proliferation of activated T cells (Funatake 2005, other references). Interestingly, kynurenine has been shown to induce immunosuppressive Tregs via AHR. Kynurenine does not affect T-reg generation in AHR-free T cells or when an AHR antagonist (Mezrich) is added. In addition to T-regs, AHR activation also leads to the expansion of suppressive Tr1 T cells (Gandhi 2010). IDO expression has also been shown to be regulated by AHR activation in tumor cells and T cells, leading to increased immunosuppression (Vogel). AHR may also play a role in immunosuppressive bone marrow 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).

[0007] There is still a need to develop AHR inhibitors for the treatment of associated diseases, conditions and symptoms. Summary of the Invention

[0008] It has now been discovered that the compounds and compositions thereof of the present invention can be used to treat, prevent, and / or reduce the risk of diseases, conditions, and symptoms involving aldehyde toxicity in their pathogenesis. Generally, the salt or free base forms and pharmaceutically acceptable compositions thereof can be used to treat or alleviate the severity of a variety of diseases or conditions as described in detail herein. These compounds are represented by the following chemical structure, denoted as Compound A:

[0009]

[0010] The compounds of this invention and pharmaceutically acceptable compositions thereof may be used to treat a variety of diseases, conditions, and symptoms associated with acute heart disease (AHR). These diseases, conditions, and symptoms include those described herein.

[0011] The compounds provided by this invention can also be used to study AHR in biological and pathological phenomena; to study intracellular signal transduction pathways; and to compare and evaluate new AHR inhibitors in vitro or in vivo. Attached Figure Description

[0012] Figure 1 illustrates the XRPD diagram of compound A in form B.

[0013] Figure 2 illustrates the TG / DTA trace of compound A in form B.

[0014] Figure 3 illustrates the XRPD diagram of compound A in form C.

[0015] Figure 4 illustrates the TG / DTA trace of compound A in form C.

[0016] Figure 5 illustrates the XRPD diagram of compound 1 in form A.

[0017] Figure 6 illustrates the TG / DTA trace of compound 1 in form A.

[0018] Figure 7 depicts the XRPD diagram of form B of compound 1.

[0019] Figure 8 depicts the XRPD diagram of compound 2 in form A.

[0020] Figure 9 illustrates the TG / DTA trace of form A of compound 2.

[0021] Figure 10 depicts the XRPD diagram of form A of compound 3.

[0022] Figure 11 illustrates the TG / DTA trace of form A of compound 3.

[0023] Figure 12 depicts the XRPD diagram of form B of compound 3.

[0024] Figure 13 depicts the TG / DTA trace of compound 3 in form B.

[0025] Figure 14 depicts the XRPD diagram of compound 4 in form A.

[0026] Figure 15 illustrates the TG / DTA trace of compound 4 in form A.

[0027] Figure 16 depicts the XRPD diagram of form A of compound 5.

[0028] Figure 17 illustrates the TG / DTA trace of form A of compound 5.

[0029] Figure 18 depicts the XRPD diagram of form A of compound 6.

[0030] Figure 19 illustrates the TG / DTA trace of form A of compound 6.

[0031] Figure 20 depicts the XRPD diagram of form B of compound 6.

[0032] Figure 21 depicts the TG / DTA trace of compound 6 in form B.

[0033] Figure 22 depicts the XRPD diagram of form A of compound 7.

[0034] Figure 23 illustrates the TG / DTA trace of form A of compound 7.

[0035] Figure 24 illustrates an XRPD diagram of a mixture of form A and form B of compound A.

[0036] Figure 25 illustrates the TGA / DSC of a mixture of form A and form B of compound A. Detailed Implementation

[0037] General description of certain aspects of the present invention

[0038] U.S. Patent Application No. 15 / 958,586 (“411 Publication”, filed April 20, 2018, and published November 15, 2018, as U.S. Patent Application Publication No. 2018-0327411, incorporated herein by reference in its entirety), describes certain AHR-inhibiting compounds. These compounds include compound A:

[0039]

[0040] Compound A, (3R)-N-[2-(5-fluoro-3-pyridinyl)-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 publication '411, and the synthesis of compound A is described in detail in example 39 of publication '411, and is reproduced herein for ease of reference.

[0041] It is desirable to provide compound A in a solid form (e.g., as its free base or a salt thereof), which imparts properties such as improved water solubility, stability, and ease of formulation. Therefore, the present invention provides both the free base form and the salt form of compound A:

[0042]

[0043] The free base form of compound A

[0044] Compound A is expected to exist in a variety of physical forms. For example, compound A may be a solution, suspension, or solid. In some embodiments, compound A is in solid form. When compound A is in solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0045] 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 significant amounts of foreign substances. These foreign substances may include different forms of compound A, residual solvents, or any other impurities that may arise from the preparation and / or separation of compound A. In some embodiments, at least about 95% by weight of compound A is present. In still other embodiments of the invention, at least about 99% by weight of compound A is present.

[0046] According to one embodiment, compound A is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, or 99.8% by weight, wherein the percentages are based on the total weight of the composition. According to another embodiment, compound A contains no more than about 3.0% of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in some embodiments, no more than about 1.5% of total organic impurities. In other embodiments, compound A contains no more than about 1.0% of any single impurity relative to the total area of ​​the HPLC chromatogram; contains no more than about 0.6% of any single impurity, and in some embodiments, contains no more than about 0.5% of any single impurity.

[0047] The structures described for the form of compound A are also intended to include all tautomeric forms of compound A. Furthermore, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, those where hydrogen is replaced by deuterium or tritium, or carbon is replaced by... 13 C- or 14 Compounds having the structure of this invention, other than C-enriched carbon substitutions, are within the scope of this invention.

[0048] Compound A has been found to exist in a variety of solid forms. Exemplary forms include polymorphs, such as those described herein.

[0049] As used herein, the term "polymorph" refers to the different crystal structures into which a compound or its salts or solvates can be crystallized.

[0050] In some embodiments, compound A is a crystalline solid. In other embodiments, compound A is a crystalline solid that is substantially free of 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 some embodiments, at least about 95% by weight of crystalline compound A is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound A is present.

[0051] It has been found that compound A can exist in at least three different polymorphic forms. In some embodiments, the present invention provides a polymorphic form of compound A, referred to herein as form A. In some embodiments, the present invention provides a polymorphic form of compound A, referred herein as form B. In some embodiments, the present invention provides a mixture of forms A and form B of compound A. In some embodiments, the present invention provides a polymorphic form of compound A, referred herein as form C.

[0052] In some embodiments, compound A is amorphous. In some embodiments, compound A is amorphous and substantially free of crystalline compound A.

[0053] Form B of compound A

[0054] In some embodiments, compound A in form B has at least 1, 2, 3, 4 or 5 spectral peaks selected from those listed in Table B below.

[0055] Table B - XRPD peak positions of compound A in form B

[0056]

[0057]

[0058] 1 In this table and all subsequent tables, position 2θ is within ±0.2.

[0059] In some embodiments, form B of compound A is characterized by having one or more peaks selected from those at about 9.5, about 9.8, and about 14.7 degrees 2-θ 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 those at about 9.5, about 9.8, and about 14.7 degrees 2-θ in its X-ray powder diffraction pattern. In some embodiments, form B of compound A is characterized by having all three peaks selected from those at about 9.5, about 9.8, and about 14.7 degrees 2-θ in its X-ray powder diffraction pattern.

[0060] In some embodiments, the X-ray powder diffraction pattern of compound A in form B is substantially similar to... Figure 1 XRPD is provided in [the documentation / platform].

[0061] The method for preparing compound A in form B is described below.

[0062] Form C of compound A

[0063] In some embodiments, compound A in form C has at least 1, 2, 3, 4 or 5 spectral peaks selected from those listed in Table C below.

[0064] Table C shows the XRPD peak positions of compound C in form C of compound A.

[0065]

[0066]

[0067] 1 In this table and all subsequent tables, position 2θ is within ±0.2.

[0068] In some embodiments, form C of compound A is characterized by having one or more peaks selected from those at about 6.02, about 8.61, and about 10.29 degrees 2-θ 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 those at about 6.02, about 8.61, and about 10.29 degrees 2-θ in its X-ray powder diffraction pattern. In some embodiments, form C of compound A is characterized by having all three peaks selected from those at about 6.02, about 8.61, and about 10.29 degrees 2-θ in its X-ray powder diffraction pattern.

[0069] In some embodiments, the X-ray powder diffraction pattern of compound A in form C is substantially similar to... Figure 3 XRPD is provided in [the documentation / platform].

[0070] The method for preparing compound A in form C is described below.

[0071] A mixture of form A and form B of compound A

[0072] In some embodiments, the present invention provides a mixture of form A and form B of compound A, the X-ray powder diffraction pattern of which is substantially similar to... Figure 24 XRPD is provided in [the documentation / platform].

[0073] In some embodiments, the TGA of a mixture of form A and form B of compound A is substantially similar to Figure 25 The TGA provided in [the document]. In some embodiments, the DSC of a mixture of form A and form B of compound A is substantially similar to [the document's description]. Figure 25 The DSC provided in the document.

[0074] The method for preparing a mixture of form A and form B of compound A is described below.

[0075] In some embodiments, the present invention provides compound A:

[0076]

[0077] The compound described therein is crystalline.

[0078] In some embodiments, the present invention provides compound A, wherein the compound is substantially free of amorphous compound A.

[0079] In some embodiments, the present invention provides compound A, wherein the compound is substantially free of impurities.

[0080] In some embodiments, the present invention provides compound A, wherein the compound has substantially similar to Figure 1 The XRPD described in the document.

[0081] In some embodiments, the present invention provides compound A, wherein the compound has substantially similar to Figure 3 The XRPD described in the document.

[0082] In some embodiments, the present invention provides compound A, wherein the compound has substantially similar to Figure 24 The XRPD described in the document.

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

[0084] In some embodiments, the present invention provides a method for inhibiting AHR, comprising administering compound A or a composition thereof to the patient. In some embodiments, the present invention provides a method for inhibiting AHR in a patient, comprising administering compound A or a composition thereof to the patient. In some embodiments, the present invention provides a method for treating one or more conditions associated with AHR activity, comprising administering compound A or a composition thereof to the patient.

[0085] In some embodiments, the present invention provides a method for treating an AHR-mediated condition, comprising the step of administering compound A or a combination thereof to a patient in need. In some embodiments, the AHR-mediated condition is a proliferative disease, such as cancer or an inflammatory condition.

[0086] Salt form of compound A

[0087] In some embodiments, the acid and compound A are ionically bonded to form one of compounds 1 to 7, as described below. Compounds 1 to 7 are conceivable to exist in a variety of physical forms. For example, compounds 1 to 7 may be in solution, suspension, or solid form. In some embodiments, compounds 1 to 7 are in solid form. When compounds 1 to 7 are in solid form, the compounds may be amorphous, crystalline, or mixtures thereof. Exemplary solid forms of compounds 1 to 7 are described in more detail below.

[0088] Compound 1 (the ethanesulfonate of compound A)

[0089] According to one embodiment, the present invention provides an ethanesulfonate salt of compound A, represented by compound 1:

[0090]

[0091] Those skilled in the art will understand that ethanesulfonic acid and compound A are ionicly bonded to form compound 1. Compound 1 can exist in a variety of physical forms. For example, compound 1 can be a solution, suspension, or solid. In some 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.

[0092] In some embodiments, the present invention provides a compound 1 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 methanesulfonic acid, excess compound A, residual solvent, or any other impurities that may arise from the preparation and / or separation of compound 1. In some embodiments, at least about 95% by weight of compound 1 is present. In still other embodiments of the invention, at least about 99% by weight of compound 1 is present.

[0093] 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, or 99.8% by weight, wherein the percentages are based on the total weight of the composition. According to another embodiment, compound 1 contains no more than about 3.0% of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in some embodiments, contains no more than about 1.5% of total organic impurities relative to the total area of ​​the HPLC chromatogram. In other embodiments, compound 1 contains no more than about 1.0% of any single impurity relative to the total area of ​​the HPLC chromatogram; contains no more than about 0.6% of any single impurity relative to the total area of ​​the HPLC chromatogram, and in some embodiments, contains no more than about 0.5% of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0094] The structures described for compound 1 are also intended to include all tautomeric forms of compound 1. Furthermore, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, those where hydrogen is replaced by deuterium or tritium, or carbon is replaced by... 13 C- or 14 Compounds having the structure of this invention, other than C-enriched carbon substitutions, are within the scope of this invention.

[0095] Compound 1 has been found to exist in a variety of solid forms. Exemplary forms include polymorphs, such as those described herein.

[0096] In some embodiments, compound 1 is a crystalline solid. In other embodiments, compound 1 is a crystalline solid substantially free of amorphous compound 1. As used herein, the term "substantially free of amorphous compound 1" means that the compound does not contain a significant amount of amorphous compound 1. In some 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.

[0097] It has been found that compound 1 can exist in at least one different 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.

[0098] In some embodiments, compound 1 is amorphous. In some embodiments, compound 1 is amorphous and substantially free of crystalline compound 1.

[0099] Form A of compound 1

[0100] In some embodiments, compound 1 in form A has at least 1, 2, 3, 4 or 5 spectral peaks selected from those listed in Table 1 below.

[0101] Table 1 - XRPD peak positions of form A of compound 1

[0102]

[0103]

[0104] 1 In this table and all subsequent tables, position 2θ is within ±0.2.

[0105] In some embodiments, form A of compound 1 is characterized by having one or more peaks selected from those at about 5.8, about 11.6, and about 18.8 degrees 2-θ 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 those at about 5.8, about 11.6, and about 18.8 degrees 2-θ in its X-ray powder diffraction pattern. In some embodiments, form A of compound 1 is characterized by having all three peaks selected from those at about 5.8, about 11.6, and about 18.8 degrees 2-θ in its X-ray powder diffraction pattern.

[0106] In some embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 5 XRPD is provided in [the documentation / platform].

[0107] The method for preparing compound 1 in form A is described below.

[0108] Form B of compound 1

[0109] In some embodiments, compound 1 in form B has at least 1, 2, 3, 4 or 5 spectral peaks selected from those listed in Table 2 below.

[0110] Table 2 - XRPD peak positions of form B of compound 1

[0111] <![CDATA[Position [°2θ] 1 > d(Angle) strength[%] 5.1 17.2744 1.5 5.6 15.7493 100 8.9 9.9195 1.3 9.5 9.3413 1.2 9.9 8.965 0.1 10.2 8.7059 0.4 10.9 8.1087 1.8 11.2 7.8636 60 12.2 7.2352 0.1 12.8 6.9174 0 13.2 6.6957 3 14.0 6.3029 1.3 14.7 6.0184 0.3 15.0 5.9183 3.2 15.7 5.643 1 16.2 5.4526 0.1 16.9 5.2422 6.7 17.5 5.0508 0 17.9 4.9563 0.2 18.5 4.7908 1.1 19.8 4.4798 0.3 20.9 4.238 1.2 21.6 4.1127 0.1 22.0 4.0401 0.1 22.5 3.9459 0.6 23.7 3.7457 0.3 24.2 3.6719 0.1 24.6 3.6151 0.3 25.6 3.4774 1.8 26.0 3.4236 0.2 26.6 3.3461 0.8 26.8 3.321 0.2 28.4 3.1454 3.2 29.2 3.0548 0.5

[0112] 1 In this table and all subsequent tables, position 2θ is within ±0.2.

[0113] In some embodiments, form B of compound 1 is characterized by having one or more peaks selected from those at about 5.6, about 11.2, and about 16.9 degrees 2-θ 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 those at about 5.6, about 11.2, and about 16.9 degrees 2-θ in its X-ray powder diffraction pattern. In some embodiments, form B of compound 1 is characterized by having all three peaks selected from those at about 5.6, about 11.2, and about 16.9 degrees 2-θ in its X-ray powder diffraction pattern.

[0114] In some embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 7 XRPD is provided in [the documentation / platform].

[0115] The method for preparing compound 1 in form B is described below.

[0116] In some embodiments, the present invention provides compound 1:

[0117]

[0118] In some embodiments, the present invention provides compound 1, wherein the compound is crystalline.

[0119] In some embodiments, the present invention provides compound 1, wherein the compound is a crystalline solid substantially free of amorphous compound 1.

[0120] In some embodiments, the present invention provides compound 1, wherein the compound is substantially free of impurities.

[0121] In some embodiments, the present invention provides compound 1, wherein the compound has one or more peaks selected in its XRPD from peaks at 5.8, about 11.6, and about 18.8 degrees 2-θ. In some such embodiments, the present invention provides compound 1, wherein the compound has at least two peaks selected in its XRPD from peaks at about 5.8, about 11.6, and about 18.8 degrees 2-θ. In some such embodiments, the present invention provides compound 1, wherein the compound is form A.

[0122] In some embodiments, the present invention provides compound 1, wherein the compound has substantially similar to Figure 5 The XRPD described in the document.

[0123] In some embodiments, the present invention provides compound 1, wherein the compound has one or more peaks selected in its XRPD from peaks at 5.6, about 11.2, and about 16.9 degrees 2-θ. In some such embodiments, the present invention provides compound 1, wherein the compound has at least two peaks selected in its XRPD from peaks at about 5.6, about 11.2, and about 16.9 degrees 2-θ. In some such embodiments, the present invention provides compound 1, wherein the compound is form B.

[0124] In some embodiments, the present invention provides compound 1, wherein the compound has substantially similar to Figure 7 The XRPD described in the document.

[0125] In some embodiments, the present invention provides a composition comprising compound 1 and a pharmaceutically acceptable carrier or excipient.

[0126] In some embodiments, the present invention provides a method for inhibiting AHR, comprising administering compound 1 or a composition thereof to the patient. In some embodiments, the present invention provides a method for inhibiting AHR in a patient, comprising administering compound 1 or a composition thereof to the patient. In some embodiments, the present invention provides a method for treating one or more conditions associated with AHR activity, comprising administering compound 1 or a composition thereof to the patient.

[0127] In some embodiments, the present invention provides a method for treating an AHR-mediated condition, comprising the step of administering compound 1 or a combination thereof to a patient in need. In some embodiments, the AHR-mediated condition is a proliferative disease, such as cancer or an inflammatory condition.

[0128] Compound 2 (maleate of compound A)

[0129] According to one embodiment, the present invention provides a maleate salt of compound A, represented by compound 2:

[0130]

[0131] Where approximately 1 ≤ x ≤ approximately 2.

[0132] Those skilled in the art will understand that maleic acid and compound A are ionicly bonded to form compound 2. In some embodiments, the ratio of compound A to maleic acid is about 1:1. In some embodiments, the ratio of compound A to maleic acid is about 2:1. Compound 2 can be present in a variety of physical forms. For example, compound 2 can be in solution, suspension, or solid form. In some embodiments, compound 2 is in solid form. When compound 2 is in solid form, the compound can be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in more detail below.

[0133] In some embodiments, the present invention provides a 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 solvent, or any other impurities that may arise from the preparation and / or separation of compound 2. In some embodiments, at least about 95% by weight of compound 2 is present. In still other embodiments of the invention, at least about 99% by weight of compound 2 is present.

[0134] 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, or 99.8% by weight, wherein the percentages are based on the total weight of the composition. According to another embodiment, compound 2 contains no more than about 3.0% of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in some embodiments, contains no more than about 1.5% of total organic impurities relative to the total area of ​​the HPLC chromatogram. In other embodiments, compound 2 contains no more than about 1.0% of any single impurity relative to the total area of ​​the HPLC chromatogram; contains no more than about 0.6% of any single impurity relative to the total area of ​​the HPLC chromatogram, and in some embodiments, contains no more than about 0.5% of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0135] The structures described for compound 2 are also intended to include all tautomeric forms of compound 2. Furthermore, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, those where hydrogen is replaced by deuterium or tritium, or carbon is replaced by... 13 C- or 14 Compounds having the structure of this invention, other than C-enriched carbon substitutions, are within the scope of this invention.

[0136] It has been found that compound 2 can exist in at least one different polymorphic form. In some embodiments, the present invention provides a polymorphic form of compound 2 referred to herein as form A. In some embodiments, form A of compound 2 comprises compound A and maleic acid in a ratio of about 2:1.

[0137] In some embodiments, compound 2 is a crystalline solid. In other embodiments, compound 2 is a crystalline solid substantially free of amorphous compound 2. As used herein, the term "substantially free of amorphous compound 2" means that the compound does not contain a significant amount of amorphous compound 2. In some embodiments, at least about 95% by weight of crystalline compound 2 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 2 is present.

[0138] It has been found that compound 2 can exist in at least one different polymorphic form. In some embodiments, the present invention provides a polymorphic form of compound 2 referred to herein as form A.

[0139] In some embodiments, compound 2 is amorphous. In some embodiments, compound 2 is amorphous and substantially free of crystalline compound 2.

[0140] Form A of compound 2

[0141] In some embodiments, compound 2 in form A has at least 1, 2, 3, 4 or 5 spectral peaks selected from those listed in Table 3 below.

[0142] Table 3 - XRPD peak positions of compound 2, form A

[0143]

[0144]

[0145] 1 In this table and all subsequent tables, position 2θ is within ±0.2.

[0146] In some embodiments, form A of compound 2 is characterized by having one or more peaks selected from those at about 5.3, about 11.3, and about 16.0 degrees 2-θ 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 those at about 5.3, about 11.3, and about 16.0 degrees 2-θ in its X-ray powder diffraction pattern. In some embodiments, form A of compound 2 is characterized by having all three peaks selected from those at about 5.3, about 11.3, and about 16.0 degrees 2-θ in its X-ray powder diffraction pattern.

[0147] In some embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 8 XRPD is provided in [the documentation / platform].

[0148] The method for preparing compound 2 in form A is described below.

[0149] In some embodiments, the present invention provides compound 2:

[0150]

[0151] Where approximately 1 ≤ x ≤ approximately 2.

[0152] In some embodiments, the present invention provides compound 2, wherein the compound is crystalline.

[0153] In some embodiments, the present invention provides compound 2, wherein the compound is a crystalline solid substantially free of amorphous compound 2.

[0154] In some embodiments, the present invention provides compound 2, wherein the compound is substantially free of impurities.

[0155] In some embodiments, the present invention provides compound 2, wherein the compound has one or more peaks selected in its XRPD from peaks at about 5.3, about 11.3, and about 16.0 degrees 2-θ. In some such embodiments, the present invention provides compound 2, wherein the compound has at least two peaks selected in its XRPD from peaks at about 5.3, about 11.3, and about 16.0 degrees 2-θ. In some such embodiments, the present invention provides compound 2, wherein the compound is form A. In some embodiments, form A of compound 2 comprises compound A and maleic acid in a ratio of about 2:1.

[0156] In some embodiments, the present invention provides compound 2, wherein the compound has substantially similar to Figure 8 The XRPD described in the document.

[0157] In some embodiments, the present invention provides a composition comprising compound 2 and a pharmaceutically acceptable carrier or excipient.

[0158] In some embodiments, the present invention provides a method for inhibiting AHR, comprising administering compound 2 or a composition thereof to the patient. In some embodiments, the present invention provides a method for inhibiting AHR in a patient, comprising administering compound 2 or a composition thereof to the patient. In some embodiments, the present invention provides a method for treating one or more conditions associated with AHR activity, comprising administering compound 2 or a composition thereof to the patient.

[0159] In some embodiments, the present invention provides a method for treating an AHR-mediated condition, comprising the step of administering compound 2 or a combination thereof to a patient in need. In some embodiments, the AHR-mediated condition is a proliferative disease, such as cancer or an inflammatory condition.

[0160] Compound 3 (the methanesulfonate of compound A)

[0161] According to one embodiment, the present invention provides a methanesulfonate salt of compound A, represented by compound 3:

[0162]

[0163] Those skilled in the art will understand that methanesulfonic acid and compound A are ionicly bonded to form compound 3. Compound 3 can exist in a variety of physical forms. For example, compound 3 can be a solution, suspension, or solid. In some 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.

[0164] In some embodiments, the present invention provides a compound 3 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 sulfuric acid, excess compound A, residual solvent, or any other impurities that may arise from the preparation and / or separation of compound 3. In some embodiments, at least about 95% by weight of compound 3 is present. In still other embodiments of the invention, at least about 99% by weight of compound 3 is present.

[0165] 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, or 99.8% by weight, wherein the percentages are based on the total weight of the composition. According to another embodiment, compound 3 contains no more than about 3.0% of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in some embodiments, contains no more than about 1.5% of total organic impurities relative to the total area of ​​the HPLC chromatogram. In other embodiments, compound 3 contains no more than about 1.0% of any single impurity relative to the total area of ​​the HPLC chromatogram; contains no more than about 0.6% of any single impurity relative to the total area of ​​the HPLC chromatogram, and in some embodiments, contains no more than about 0.5% of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0166] The structures described for compound 3 are also intended to include all tautomeric forms of compound 3. Furthermore, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, those where hydrogen is replaced by deuterium or tritium, or carbon is replaced by...13 C- or 14 Compounds having the structure of this invention, other than those enriched by C-carbon substitution, are within the scope of this invention.

[0167] It has been found that compound 3 can exist in at least two different 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.

[0168] In some embodiments, compound 3 is a crystalline solid. In other embodiments, compound 3 is a crystalline solid substantially free of amorphous compound 3. As used herein, the term "substantially free of amorphous compound 3" means that the compound does not contain a significant amount of amorphous compound 3. In some embodiments, at least about 95% by weight of crystalline compound 3 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 3 is present.

[0169] In some embodiments, compound 3 is amorphous. In some embodiments, compound 3 is amorphous and substantially free of crystalline compound 3.

[0170] Form A of compound 3

[0171] In some embodiments, compound 3 in form A has at least 1, 2, 3, 4 or 5 spectral peaks selected from those listed in Table 4 below.

[0172] Table 4 - XRPD peak positions of form A of compound 3

[0173]

[0174]

[0175] 1 In this table and all subsequent tables, position 2θ is within ±0.2.

[0176] In some embodiments, form A of compound 3 is characterized by having one or more peaks selected from those at about 5.6, about 11.2, and about 16.9 degrees 2-θ in its X-ray powder diffraction pattern. In some embodiments, form A of compound 3 is characterized by having two or more peaks selected from those at about 5.6, about 11.2, and about 16.9 degrees 2-θ in its X-ray powder diffraction pattern. In some embodiments, form A of compound 3 is characterized by having all three peaks selected from those at about 5.6, about 11.2, and about 16.9 degrees 2-θ in its X-ray powder diffraction pattern.

[0177] In some embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 10 XRPD is provided in [the documentation / platform].

[0178] The method for preparing compound 3 in form A is described below.

[0179] Form B of compound 3

[0180] In some embodiments, compound 3 in form B has at least 1, 2, 3, 4 or 5 spectral peaks selected from those listed in Table 5 below.

[0181] Table 5 - XRPD peak positions of form B of compound 3

[0182] <![CDATA[Position [°2θ] 1 > d(Angle) strength[%] 6.0 14.7036 100 11.6 7.6195 10 12.1 7.3357 32.3 13.6 6.5115 2.1 14.6 6.0801 3.1 15.6 5.66 2 16.1 5.514 0.6 17.6 5.0376 4.5 18.1 4.8948 12.5 19.8 4.4702 1 20.1 4.4033 3.3 20.8 4.2687 0.2 21.1 4.2034 1.3 21.9 4.0542 2.2 22.2 4.0022 4.2 22.6 3.9386 0.5 23.0 3.8694 0.3 23.5 3.7822 1.2 24.3 3.6649 0.3 25.1 3.5465 1.8 26.9 3.3177 1.9 27.4 3.2583 3 28.3 3.1563 0.9 29.4 3.0401 0.9

[0183] 1 In this table and all subsequent tables, position 2θ is within ±0.2.

[0184] In some embodiments, form B of compound 3 is characterized by having one or more peaks selected from those at about 6.0, about 12.1, and about 18.1 degrees 2-θ 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 those at about 6.0, about 12.1, and about 18.1 degrees 2-θ in its X-ray powder diffraction pattern. In some embodiments, form B of compound 3 is characterized by having all three peaks selected from those at about 6.0, about 12.1, and about 18.1 degrees 2-θ in its X-ray powder diffraction pattern.

[0185] In some embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 12 XRPD is provided in [the documentation / platform].

[0186] The method for preparing compound 3 in form B is described below.

[0187] In some embodiments, the present invention provides compound 3:

[0188]

[0189] In some embodiments, the present invention provides compound 3, wherein the compound is crystalline.

[0190] In some embodiments, the present invention provides compound 3, wherein the compound is a crystalline solid substantially free of amorphous compound 3.

[0191] In some embodiments, the present invention provides compound 3, wherein the compound is substantially free of impurities.

[0192] In some embodiments, the present invention provides compound 3, wherein the compound has one or more peaks selected in its XRPD from peaks at about 5.6, about 11.2, and about 16.9 degrees 2-θ. In some such embodiments, the present invention provides compound 3, wherein the compound has at least two peaks selected in its XRPD from peaks at about 5.6, about 11.2, and about 16.9 degrees 2-θ. In some such embodiments, the present invention provides compound 3, wherein the compound is form A.

[0193] In some embodiments, the present invention provides compound 3, wherein the compound has substantially similar to Figure 10 The XRPD described in the document.

[0194] In some embodiments, the present invention provides compound 3, wherein the compound has one or more peaks selected in its XRPD from peaks at about 6.0, about 12.1, and about 18.1 degrees 2-θ. In some such embodiments, the present invention provides compound 3, wherein the compound has at least two peaks selected in its XRPD from peaks at about 6.0, about 12.1, and about 18.1 degrees 2-θ. In some such embodiments, the present invention provides compound 3, wherein the compound is form B.

[0195] In some embodiments, the present invention provides compound 3, wherein the compound has substantially similar to Figure 12 The XRPD described in the document.

[0196] In some embodiments, the present invention provides a composition comprising compound 3 and a pharmaceutically acceptable carrier or excipient.

[0197] In some embodiments, the present invention provides a method for inhibiting AHR, comprising administering compound 3 or a composition thereof to the patient. In some embodiments, the present invention provides a method for inhibiting AHR in a patient, comprising administering compound 3 or a composition thereof to the patient. In some embodiments, the present invention provides a method for treating one or more conditions associated with AHR activity, comprising administering compound 3 or a composition thereof to the patient.

[0198] In some embodiments, the present invention provides a method for treating an AHR-mediated condition, comprising the step of administering compound 3 or a combination thereof to a patient in need. In some embodiments, the AHR-mediated condition is a proliferative disease, such as cancer or an inflammatory condition.

[0199] Compound 4 (naphthalene sulfonate of compound A)

[0200] According to one embodiment, the present invention provides a naphthalene sulfonate of compound A, represented by compound 4:

[0201]

[0202] Those skilled in the art will understand that naphthalenesulfonic acid and compound A are ionicly bonded to form compound 4. Compound 4 can exist in a variety of physical forms. For example, compound 4 can be a solution, suspension, or solid. In some 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.

[0203] In some embodiments, the present invention provides a compound 4 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 p-toluenesulfonic acid, excess compound A, residual solvent, or any other impurities that may arise from the preparation and / or separation of compound 4. In some embodiments, at least about 95% by weight of compound 4 is present. In still other embodiments of the invention, at least about 99% by weight of compound 4 is present.

[0204] 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, or 99.8% by weight, wherein the percentages are based on the total weight of the composition. According to another embodiment, compound 4 contains no more than about 3.0% of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in some embodiments, contains no more than about 1.5% of total organic impurities relative to the total area of ​​the HPLC chromatogram. In other embodiments, compound 4 contains no more than about 1.0% of any single impurity relative to the total area of ​​the HPLC chromatogram; contains no more than about 0.6% of any single impurity relative to the total area of ​​the HPLC chromatogram, and in some embodiments, contains no more than about 0.5% of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0205] The structures described for compound 4 are also intended to include all tautomeric forms of compound 4. Furthermore, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, those where hydrogen is replaced by deuterium or tritium, or carbon is replaced by... 13 C- or 14 Compounds having the structure of this invention, other than C-enriched carbon substitutions, are within the scope of this invention.

[0206] Compound 4 has been found to exist in at least different solid forms. Exemplary forms include polymorphs, such as those described herein.

[0207] It has been found that compound 4 can exist in at least one different polymorphic form. In some embodiments, the present invention provides a polymorphic form of compound 4 referred to herein as form A.

[0208] In some 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 some embodiments, at least about 95% by weight of crystalline compound 4 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 4 is present.

[0209] In some embodiments, compound 4 is amorphous. In some embodiments, compound 4 is amorphous and substantially free of crystalline compound 4.

[0210] Form A of compound 4

[0211] In some embodiments, compound 4 in form A has at least 1, 2, 3, 4 or 5 spectral peaks selected from those listed in Table 6 below.

[0212] Table 6 - XRPD peak positions of form A of compound 4

[0213]

[0214]

[0215] 1 In this table and all subsequent tables, position 2θ is within ±0.2.

[0216] In some embodiments, form A of compound 4 is characterized by having one or more peaks selected from those at about 7.5, about 8.4, and about 20.1 degrees 2-θ in its X-ray powder diffraction pattern. In some embodiments, form A of compound 4 is characterized by having two or more peaks selected from those at about 7.5, about 8.4, and about 20.1 degrees 2-θ in its X-ray powder diffraction pattern. In some embodiments, form A of compound 4 is characterized by having all three peaks selected from those at about 7.5, about 8.4, and about 20.1 degrees 2-θ in its X-ray powder diffraction pattern.

[0217] In some embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 14 XRPD is provided in [the documentation / platform].

[0218] The method for preparing compound 4, form A, is described below.

[0219] In some embodiments, the present invention provides compound 4:

[0220]

[0221] In some embodiments, the present invention provides compound 4, wherein the compound is crystalline.

[0222] In some embodiments, the present invention provides compound 4, wherein the compound is a crystalline solid substantially free of amorphous compound 4.

[0223] In some embodiments, the present invention provides compound 4, wherein the compound is substantially free of impurities.

[0224] In some embodiments, the present invention provides compound 4, wherein the compound has one or more peaks selected in its XRPD from peaks at about 7.5, about 8.4, and about 20.1 degrees 2-θ. In some such embodiments, the present invention provides compound 4, wherein the compound has at least two peaks selected in its XRPD from peaks at about 7.5, about 8.4, and about 20.1 degrees 2-θ. In some such embodiments, the present invention provides compound 4, wherein the compound is form A.

[0225] In some embodiments, the present invention provides compound 4, wherein the compound has substantially similar to Figure 14 The XRPD described in the document.

[0226] In some embodiments, the present invention provides a composition comprising compound 4 and a pharmaceutically acceptable carrier or excipient.

[0227] In some embodiments, the present invention provides a method for inhibiting AHR, comprising administering compound 4 or a composition thereof to the patient. In some embodiments, the present invention provides a method for inhibiting AHR in a patient, comprising administering compound 4 or a composition thereof to the patient. In some embodiments, the present invention provides a method for treating one or more conditions associated with AHR activity, comprising administering compound 4 or a composition thereof to the patient.

[0228] In some embodiments, the present invention provides a method for treating an AHR-mediated condition, comprising the step of administering compound 4 or a combination thereof to a patient in need. In some embodiments, the AHR-mediated condition is a proliferative disease, such as cancer or an inflammatory condition.

[0229] Compound 5 (oxalate of compound A)

[0230] According to one embodiment, the present invention provides an oxalate of compound A, represented by compound 5:

[0231]

[0232] Those skilled in the art will understand that oxalic acid and compound A are ionicly bonded to form compound 5. Compound 5 can exist in a variety of physical forms. For example, compound 5 can be a solution, suspension, or solid. In some 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.

[0233] In some embodiments, the present invention provides a compound 5 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 hydrochloric acid, excess compound A, residual solvent, or any other impurities that may arise from the preparation and / or separation of compound 5. In some embodiments, at least about 95% by weight of compound 5 is present. In still other embodiments of the invention, at least about 99% by weight of compound 5 is present.

[0234] 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, or 99.8% by weight, wherein the percentages are based on the total weight of the composition. According to another embodiment, compound 5 contains no more than about 3.0% of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in some embodiments, contains no more than about 1.5% of total organic impurities relative to the total area of ​​the HPLC chromatogram. In other embodiments, compound 5 contains no more than about 1.0% of any single impurity relative to the total area of ​​the HPLC chromatogram; contains no more than about 0.6% of any single impurity relative to the total area of ​​the HPLC chromatogram, and in some embodiments, contains no more than about 0.5% of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0235] The structures described for compound 5 are also intended to include all tautomeric forms of compound 5. Furthermore, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, those where hydrogen is replaced by deuterium or tritium, or carbon is replaced by... 13 C- or 14 Compounds having the structure of this invention, other than those enriched by C-carbon substitution, are within the scope of this invention.

[0236] It has been found that compound 5 can exist in at least one different polymorphic form. In some embodiments, the present invention provides a polymorphic form of compound 5 referred to herein as form A.

[0237] In some embodiments, compound 5 is a crystalline solid. In other embodiments, compound 5 is a crystalline solid substantially free of amorphous compound 5. As used herein, the term "substantially free of amorphous compound 5" means that the compound does not contain a significant amount of amorphous compound 5. In some embodiments, at least about 95% by weight of crystalline compound 5 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 5 is present.

[0238] In some embodiments, compound 5 is amorphous. In some embodiments, compound 5 is amorphous and substantially free of crystalline compound 5.

[0239] Form A of compound 5

[0240] In some embodiments, compound 5 in form A has at least 1, 2, 3, 4 or 5 spectral peaks selected from those listed in Table 7 below.

[0241] Table 7 - XRPD peak positions of form A of compound 5

[0242]

[0243]

[0244] 1 In this table and all subsequent tables, position 2θ is within ±0.2.

[0245] In some embodiments, form A of compound 5 is characterized by having one or more peaks selected from those at about 6.4, about 7.1, and about 12.7 degrees 2-θ 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 those at about 6.4, about 7.1, and about 12.7 degrees 2-θ in its X-ray powder diffraction pattern. In some embodiments, form A of compound 5 is characterized by having all three peaks selected from those at about 6.4, about 7.1, and about 12.7 degrees 2-θ in its X-ray powder diffraction pattern.

[0246] In some embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 16 XRPD is provided in [the documentation / platform].

[0247] The method for preparing compound 5 in form A is described below.

[0248] In some embodiments, the present invention provides compound 5:

[0249]

[0250] In some embodiments, the present invention provides compound 5, wherein the compound is crystalline.

[0251] In some embodiments, the present invention provides compound 5, wherein the compound is a crystalline solid substantially free of amorphous compound 5.

[0252] In some embodiments, the present invention provides compound 5, wherein the compound is substantially free of impurities.

[0253] In some embodiments, the present invention provides compound 5, wherein the compound has one or more peaks selected in its XRPD from peaks at about 6.4, about 7.1, and about 12.7 degrees 2-θ. In some such embodiments, the present invention provides compound 5, wherein the compound has at least two peaks selected in its XRPD from peaks at about 6.4, about 7.1, and about 12.7 degrees 2-θ. In some such embodiments, the present invention provides compound 5, wherein the compound is form A.

[0254] In some embodiments, the present invention provides compound 5, wherein the compound has substantially similar to Figure 16 The XRPD described in the document.

[0255] In some embodiments, the present invention provides a composition comprising compound 5 and a pharmaceutically acceptable carrier or excipient.

[0256] In some embodiments, the present invention provides a method for inhibiting AHR, comprising administering compound 5 or a composition thereof to the patient. In some embodiments, the present invention provides a method for inhibiting AHR in a patient, comprising administering compound 5 or a composition thereof to the patient. In some embodiments, the present invention provides a method for treating one or more conditions associated with AHR activity, comprising administering compound 5 or a composition thereof to the patient.

[0257] In some embodiments, the present invention provides a method for treating an AHR-mediated condition, comprising the step of administering compound 5 or a combination thereof to a patient in need. In some embodiments, the AHR-mediated condition is a proliferative disease, such as cancer or an inflammatory condition.

[0258] Compound 6 (tartrate of compound A)

[0259] According to one embodiment, the present invention provides a tartrate salt of compound A, represented by compound 6:

[0260]

[0261] Where approximately 1 ≤ x ≤ approximately 2.

[0262] Those skilled in the art will understand that tartaric acid and compound A are ionicly bonded to form compound 6. In some embodiments, the ratio of compound A to tartaric acid is about 1:1. In some embodiments, the ratio of compound A to tartaric acid is about 2:1. Compound 6 can be present in a variety of physical forms. For example, compound 6 can be in solution, suspension, or solid form. In some 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.

[0263] In some embodiments, the present invention provides a compound 6 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 oxalic acid, excess compound A, residual solvent, or any other impurities that may arise from the preparation and / or separation of compound 6. In some embodiments, at least about 95% by weight of compound 6 is present. In still other embodiments of the invention, at least about 99% by weight of compound 6 is present.

[0264] 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, or 99.8% by weight, wherein the percentages are based on the total weight of the composition. According to another embodiment, compound 6 contains no more than about 3.0% of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in some embodiments, contains no more than about 1.5% of total organic impurities relative to the total area of ​​the HPLC chromatogram. In other embodiments, compound 6 contains no more than about 1.0% of any single impurity relative to the total area of ​​the HPLC chromatogram; contains no more than about 0.6% of any single impurity relative to the total area of ​​the HPLC chromatogram, and in some embodiments, contains no more than about 0.5% of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0265] The structures described for compound 6 are also intended to include all tautomeric forms of compound 6. Furthermore, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, those where hydrogen is replaced by deuterium or tritium, or carbon is replaced by... 13 C- or 14 Compounds having the structure of this invention, other than those enriched by C-carbon substitution, are within the scope of this invention.

[0266] It has been found that compound 6 can exist in at least two different polymorphic forms. In some embodiments, the present invention provides a polymorphic form of compound 6 referred to herein as form A. In some embodiments, the present invention provides a polymorphic form of compound 6 referred to herein as form B. In some embodiments, form A of compound 6 comprises compound A and tartaric acid in a ratio of about 1:1. In some embodiments, form B of compound 6 comprises compound A and tartaric acid in a ratio of about 2:1.

[0267] In some embodiments, compound 6 is a crystalline solid. In other embodiments, compound 6 is a crystalline solid substantially free of amorphous compound 6. As used herein, the term "substantially free of amorphous compound 6" means that the compound does not contain a significant amount of amorphous compound 6. In some embodiments, at least about 95% by weight of crystalline compound 6 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 6 is present.

[0268] In some embodiments, compound 6 is amorphous. In some embodiments, compound 6 is amorphous and substantially free of crystalline compound 6.

[0269] Form A of compound 6

[0270] In some embodiments, form A of compound 6 has at least 1, 2, 3, 4 or 5 spectral peaks selected from those listed in Table 8 below.

[0271] Table 8 - XRPD peak positions of form A of compound 6

[0272]

[0273]

[0274] 1 In this table and all subsequent tables, position 2θ is within ±0.2.

[0275] In some embodiments, form A of compound 6 is characterized by having one or more peaks selected from those at about 5.5, about 11.1, and about 18.9 degrees 2-θ 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 those at about 5.5, about 11.1, and about 18.9 degrees 2-θ in its X-ray powder diffraction pattern. In some embodiments, form A of compound 6 is characterized by having all three peaks selected from those at about 5.5, about 11.1, and about 18.9 degrees 2-θ in its X-ray powder diffraction pattern.

[0276] In some embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 18XRPD is provided in [the documentation / platform].

[0277] The method for preparing compound 6 in form A is described below.

[0278] Form B of compound 6

[0279] In some embodiments, compound 6 in form B has at least 1, 2, 3, 4 or 5 spectral peaks selected from those listed in Table 9 below.

[0280] Table 9 - XRPD peak positions of form B of compound 6

[0281]

[0282]

[0283] 1 In this table and all subsequent tables, position 2θ is within ±0.2.

[0284] In some embodiments, form B of compound 6 is characterized by having one or more peaks selected from those at about 6.2, about 6.8, and about 13.5 degrees 2-θ 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 those at about 6.2, about 6.8, and about 13.5 degrees 2-θ in its X-ray powder diffraction pattern. In some embodiments, form B of compound 6 is characterized by having all three peaks selected from those at about 6.2, about 6.8, and about 13.5 degrees 2-θ in its X-ray powder diffraction pattern.

[0285] In some embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 20 XRPD is provided in [the documentation / platform].

[0286] The method for preparing compound 6 in form B is described below.

[0287] In some embodiments, the present invention provides compound 6:

[0288]

[0289] Where approximately 1 ≤ x ≤ approximately 2.

[0290] In some embodiments, the present invention provides compound 6, wherein the compound is crystalline.

[0291] In some embodiments, the present invention provides compound 6, wherein the compound is a crystalline solid substantially free of amorphous compound 6.

[0292] In some embodiments, the present invention provides compound 6, wherein the compound is substantially free of impurities.

[0293] In some embodiments, the present invention provides compound 6, wherein the compound has one or more peaks selected in its XRPD from peaks at about 5.5, about 11.1, and about 18.9 degrees 2-θ. In some such embodiments, the present invention provides compound 6, wherein the compound has at least two peaks selected in its XRPD from peaks at about 5.5, about 11.1, and about 18.9 degrees 2-θ. In some such embodiments, the present invention provides compound 6, wherein the compound is form A. In some embodiments, form A of compound 6 comprises compound A and tartaric acid in a ratio of about 1:1.

[0294] In some embodiments, the present invention provides compound 6, wherein the compound has substantially similar characteristics to... Figure 18 The XRPD described in the document.

[0295] In some embodiments, the present invention provides compound 6, wherein the compound has one or more peaks selected in its XRPD from peaks at about 6.2, about 6.8, and about 13.5 degrees 2-θ. In some such embodiments, the present invention provides compound 6, wherein the compound has at least two peaks selected in its XRPD from peaks at about 6.2, about 6.8, and about 13.5 degrees 2-θ. In some such embodiments, the present invention provides compound 6, wherein the compound is form B. In some embodiments, form B of compound 6 comprises compound A and tartaric acid in a ratio of about 2:1.

[0296] In some embodiments, the present invention provides compound 6, wherein the compound has substantially similar characteristics to... Figure 20 The XRPD described in the document.

[0297] In some embodiments, the present invention provides a composition comprising compound 6 and a pharmaceutically acceptable carrier or excipient.

[0298] In some embodiments, the present invention provides a method for inhibiting AHR, comprising administering compound 6 or a composition thereof to the patient. In some embodiments, the present invention provides a method for inhibiting AHR in a patient, comprising administering compound 6 or a composition thereof to the patient. In some embodiments, the present invention provides a method for treating one or more conditions associated with AHR activity, comprising administering compound 6 or a composition thereof to the patient.

[0299] In some embodiments, the present invention provides a method for treating an AHR-mediated condition, comprising the step of administering compound 6 or a combination thereof to a patient in need. In some embodiments, the AHR-mediated condition is a proliferative disease, such as cancer or an inflammatory condition.

[0300] Compound 7 (the ethanedisulfonate of compound A)

[0301] According to one embodiment, the present invention provides an ethylene sulfonate of compound A, represented by compound 7:

[0302]

[0303] Where approximately 1 ≤ x ≤ approximately 2.

[0304] Those skilled in the art will understand that ethanedisulfonic acid and compound A are ionicly bonded to form compound 7. In some embodiments, the ratio of compound A to ethanedisulfonic acid is about 1:1. In some embodiments, the ratio of compound A to ethanedisulfonic acid is about 2:1. Compound 7 can be present in a variety of physical forms. For example, compound 7 can be a solution, suspension, or solid. In some 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.

[0305] In some embodiments, the present invention provides a compound 7 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 phosphoric acid, excess compound A, residual solvent, or any other impurities that may arise from the preparation and / or separation of compound 7. In some embodiments, at least about 95% by weight of compound 7 is present. In still other embodiments of the invention, at least about 99% by weight of compound 7 is present.

[0306] 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, or 99.8% by weight, wherein the percentages are based on the total weight of the composition. According to another embodiment, compound 7 contains no more than about 3.0% of total organic impurities relative to the total area of ​​the HPLC chromatogram, and in some embodiments, contains no more than about 1.5% of total organic impurities relative to the total area of ​​the HPLC chromatogram. In other embodiments, compound 7 contains no more than about 1.0% of any single impurity relative to the total area of ​​the HPLC chromatogram; contains no more than about 0.6% of any single impurity relative to the total area of ​​the HPLC chromatogram, and in some embodiments, contains no more than about 0.5% of any single impurity relative to the total area of ​​the HPLC chromatogram.

[0307] The structures described for compound 7 are also intended to include all tautomers of compound 7. Furthermore, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, those where hydrogen is replaced by deuterium or tritium, or carbon is replaced by...13 C- or 14 Compounds having the structure of this invention, other than those enriched by C-carbon substitution, are within the scope of this invention.

[0308] It has been found that compound 7 can exist in at least one different 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 comprises compound A and ethanedisulfonic acid in a ratio of about 2:1.

[0309] In some embodiments, compound 7 is a crystalline solid. In other embodiments, compound 7 is a crystalline solid substantially free of amorphous compound 7. As used herein, the term "substantially free of amorphous compound 7" means that the compound does not contain a significant amount of amorphous compound 7. In some embodiments, at least about 95% by weight of crystalline compound 7 is present. In still other embodiments of the invention, at least about 99% by weight of crystalline compound 7 is present.

[0310] In some embodiments, compound 7 is amorphous. In some embodiments, compound 7 is amorphous and substantially free of crystalline compound 7.

[0311] Form A of compound 7

[0312] In some embodiments, compound 7 in form A has at least 1, 2, 3, 4 or 5 spectral peaks selected from those listed in Table 10 below.

[0313] Table 10 - XRPD peak positions of form A of compound 7 (Compound 7)

[0314]

[0315] 1 In this table and all subsequent tables, position 2θ is within ±0.2.

[0316] In some embodiments, form A of compound 7 is characterized by having one or more peaks selected from those at about 6.6, about 10.4, and about 13.2 degrees 2-θ 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 those at about 6.6, about 10.4, and about 13.2 degrees 2-θ in its X-ray powder diffraction pattern. In some embodiments, form A of compound 7 is characterized by having all three peaks selected from those at about 6.6, about 10.4, and about 13.2 degrees 2-θ in its X-ray powder diffraction pattern.

[0317] In some embodiments, the X-ray powder diffraction pattern is substantially similar to Figure 22 XRPD is provided in [the documentation / platform].

[0318] The method for preparing compound 7 in form A is described below.

[0319] In some embodiments, the present invention provides compound 7:

[0320]

[0321] Where approximately 1 ≤ x ≤ approximately 2.

[0322] In some embodiments, the present invention provides compound 7, wherein the compound is crystalline.

[0323] In some embodiments, the present invention provides compound 7, wherein the compound is a crystalline solid substantially free of amorphous compound 7.

[0324] In some embodiments, the present invention provides compound 7, wherein the compound is substantially free of impurities.

[0325] In some embodiments, the present invention provides compound 7, wherein the compound has one or more peaks selected in its XRPD from peaks at about 6.6, about 10.4, and about 13.2 degrees 2-θ. In some such embodiments, the present invention provides compound 7, wherein the compound has at least two peaks selected in its XRPD from peaks at about 6.6, about 10.4, and about 13.2 degrees 2-θ. In some such embodiments, the present invention provides compound 7, wherein the compound is form A. In some embodiments, form A of compound 7 comprises compound A and ethanedisulfonic acid in a ratio of about 2:1.

[0326] In some embodiments, the present invention provides compound 7, wherein the compound has substantially similar to Figure 22 The XRPD described in the document.

[0327] In some embodiments, the present invention provides a composition comprising compound 7 and a pharmaceutically acceptable carrier or excipient.

[0328] In some embodiments, the present invention provides a method for inhibiting AHR, comprising administering compound 7 or a composition thereof to the patient. In some embodiments, the present invention provides a method for inhibiting AHR in a patient, comprising administering compound 7 or a composition thereof to the patient. In some embodiments, the present invention provides a method for treating one or more conditions associated with AHR activity, comprising administering compound 7 or a composition thereof to the patient.

[0329] In some embodiments, the present invention provides a method for treating an AHR-mediated condition, comprising the step of administering compound 7 or a combination thereof to a patient in need. In some embodiments, the AHR-mediated condition is a proliferative disease, such as cancer or an inflammatory condition.

[0330] In some embodiments, the present invention provides compounds selected from: compound A form B; compound A form C; compound 1 form A; compound 1 form B; compound 2 form A; compound 3 form A; compound 3 form B; compound 4 form A; compound 5 form A; compound 6 form A; compound 6 form B; and compound 7 form A. In some such embodiments, the present invention provides a composition comprising one of the above-described compound forms and a pharmaceutically acceptable carrier or excipient.

[0331] In some such embodiments, the present invention provides a method for inhibiting AHR, comprising administering a compound or composition thereof of the present invention to the patient. In some such embodiments, the present invention provides a method for inhibiting AHR in a patient, comprising administering a compound or composition thereof of the present invention to the patient. In some such embodiments, the present invention provides a method for treating one or more conditions associated with AHR activity, comprising administering a compound or composition thereof of the present invention to the patient.

[0332] In some such embodiments, the present invention provides a method for treating AHR-mediated conditions, comprising the step of administering a compound or a combination thereof of the present invention to a patient in need. In some such embodiments, AHR-mediated conditions are proliferative diseases, such as cancer or inflammatory conditions.

[0333] General methods for providing salt compounds

[0334] Compound A is prepared according to the method described in detail in disclosure '411, which is incorporated herein by reference in its entirety. Salt compounds of general formula X (which particularly cover salt compounds 1 to 7 and / or specific forms thereof) are prepared from compound A according to the following general scheme.

[0335]

[0336] For example, each of compounds 1 to 7 and their forms is prepared from compound A by combining compound A with a suitable acid to form a salt of that acid. Therefore, another aspect of the invention provides a method for preparing compounds 1 to 7 and their forms.

[0337] As described above, in some embodiments, the present invention provides a method for preparing a salt compound of general formula X:

[0338]

[0339] Includes the following steps:

[0340] Compound A:

[0341]

[0342] Combined with a suitable acid and optionally a suitable solvent, under conditions suitable for forming a salt compound of general formula X.

[0343] In some embodiments, a suitable acid is ethanesulfonic acid. In some embodiments, the present invention provides a method for preparing the ethanesulfonate of compound A. In some embodiments, the ethanesulfonate of compound A is compound 1. In some embodiments, the ethanesulfonate of compound A is form A of compound 1. In some embodiments, the ethanesulfonate of compound A is form B of compound 1.

[0344] In some embodiments, a suitable acid is maleic acid. In some embodiments, the present invention provides a method for preparing the maleate salt of compound A. In some embodiments, the maleate salt of compound A is compound 2. In some embodiments, the maleate salt of compound A is in form A of compound 2.

[0345] In some embodiments, a suitable acid is methanesulfonic acid. In some embodiments, the present invention provides a method for preparing a methanesulfonate of compound A. In some embodiments, the methanesulfonate of compound A is compound 3. In some embodiments, the methanesulfonate of compound A is form A of compound 3. In some embodiments, the methanesulfonate of compound A is form B of compound 3.

[0346] In some embodiments, a suitable acid is naphthalenesulfonic acid. In some embodiments, the present invention provides a method for preparing a naphthalenesulfonate of compound A. In some embodiments, the naphthalenesulfonate of compound A is compound 4. In some embodiments, the naphthalenesulfonate of compound A is form A of compound 4.

[0347] In some embodiments, a suitable acid is oxalic acid. In some embodiments, the present invention provides a method for preparing the oxalate of compound A. In some embodiments, the oxalate of compound A is compound 5. In some embodiments, the oxalate of compound A is form A of compound 5.

[0348] In some embodiments, a suitable acid is tartaric acid. In some embodiments, the present invention provides a method for preparing a tartrate of compound A. In some embodiments, the tartrate of compound A is compound 6. In some embodiments, the tartrate of compound A is form A of compound 6. In some embodiments, the tartrate of compound A is form B of compound 6.

[0349] In some embodiments, a suitable acid is ethanedisulfonic acid. In some embodiments, the present invention provides a method for preparing the ethanedisulfonate of compound A. In some embodiments, the ethanedisulfonate of compound A is compound 7. In some embodiments, the ethanedisulfonate of compound A is form A of compound 7.

[0350] A suitable solvent can be any solvent system in which compound A and / or acid are soluble or at least partially soluble (e.g., a solvent or a mixture of solvents).

[0351] Examples of suitable solvents that can be used in this invention include, but are not limited to, protic solvents, aprotic solvents, polar aprotic solvents, or mixtures thereof. In some 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.

[0352] In some embodiments, suitable solvents are methanol, ethanol, isopropanol, or acetone, wherein the solvent is anhydrous or in combination with water or heptane. In some embodiments, suitable solvents include tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, tert-butanol, n-butanol, and acetonitrile. In some embodiments, a suitable solvent is ethanol. In some embodiments, a suitable solvent is anhydrous ethanol. In some embodiments, a suitable solvent is MTBE.

[0353] In some embodiments, a suitable solvent is ethyl acetate. In some embodiments, a suitable solvent is a mixture of methanol and dichloromethane. In some embodiments, a suitable solvent is a mixture of acetonitrile and water. In some embodiments, a suitable solvent is methyl acetate, isopropyl acetate, acetone, or tetrahydrofuran. In some embodiments, a suitable solvent is diethyl ether. In some embodiments, a suitable solvent is water. In some embodiments, a suitable solvent is methyl ethyl ketone. In some embodiments, a suitable solvent is toluene.

[0354] In some embodiments, the present invention provides a method for preparing a salt compound of general formula X, comprising one or more steps of removing a solvent and adding a solvent. In some embodiments, the added solvent is the same as the removed solvent. In some embodiments, the added solvent is different from the removed solvent. Means of removing solvent are known in the fields of synthesis and chemistry, and include, but are not limited to, any of those described herein and in the examples.

[0355] In some embodiments, a method for preparing a salt compound of general formula X includes one or more steps of heating or cooling the preparation.

[0356] In some embodiments, a method for preparing a salt compound of general formula X includes one or more steps of stirring or agitating the preparation.

[0357] In some embodiments, a method for preparing a salt compound of general formula X includes the step of adding a suitable acid to a solution or slurry of compound A.

[0358] In some embodiments, a method for preparing a salt compound of general formula X includes a heating step.

[0359] In some 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 still other embodiments, the salt compound of formula X crystallizes from the solution after solution inoculation (i.e., crystals of the salt compound of formula X are added to the solution).

[0360] Salt compounds of formula X can be generated by methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption and reaction, by adding an antisolvent (e.g., heptane), by cooling or by different combinations of these methods, by precipitation from the reaction mixture or by removing part or all of the solvent.

[0361] As generally described above, salt compounds of formula X are optionally separated. It should be understood that salt compounds of formula X can be separated by any suitable physical means known to those skilled in the art. In some 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 decantation.

[0362] In some embodiments, the salt compound of formula X is separated from the supernatant by filtration.

[0363] In some embodiments, the separated salt compound of formula X is dried in air. In other embodiments, the separated salt compound of formula X is optionally dried at an elevated temperature under reduced pressure.

[0364] Uses, formulations and administration, and pharmaceutically acceptable compositions

[0365] 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 mediator. The amount of the compound in the composition of the present invention is an amount that effectively and measurably inhibits the amount of AHR in a biological sample or patient. In some embodiments, the amount of the compound in the composition of the present invention effectively and measurably inhibits the amount of AHR in a biological sample or patient. In some embodiments, the composition of the present invention is formulated for administration to a patient who requires this composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0366] The term "patient" as used in this article refers to an animal, preferably a mammal, and most preferably a human.

[0367] The term "pharmaceutically acceptable carrier, adjuvant, or mediator" refers to a non-toxic carrier, adjuvant, or mediator that does not impair the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants, or mediators that can be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates), glycine, sorbic acid, potassium sorbate, mixtures of metaglycerol esters of saturated vegetable fatty acids, water, salts or electrolytes (e.g., 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, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol, and lanolin.

[0368] "Pharmaceutical acceptable derivative" means any non-toxic salt, ester, salt of ester or other derivative of the compound of the present invention, which, when administered to a recipient, can directly or indirectly provide the compound of the present invention or its inhibitory metabolites or residues.

[0369] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or through an implanted reservoir. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrasheathic, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of the present invention can be an aqueous or oily suspension. These suspensions can be formulated using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. The sterile injectable formulation can also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable media and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile, non-volatile oils are commonly used as solvents or suspension media.

[0370] For this purpose, any mild, non-volatile oil can be used, including synthetic mono- or diglycerides of glycerol. Fatty acids (such as oleic acid) and their glycerol derivatives can be used to prepare injectable formulations, as can natural, pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylene forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants (such as Tween and Span) and other emulsifiers or bioavailability enhancers, often used to prepare pharmaceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0371] The pharmaceutically acceptable compositions of the present invention can be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. In the case of oral tablets, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifier and a suspending agent. Sweeteners, flavoring agents, or coloring agents may also be added if desired.

[0372] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of rectal suppositories. These can be prepared by mixing the reagent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and thus melts in the rectum to release the drug. These materials include cocoa butter, beeswax, and polyethylene glycol.

[0373] The pharmaceutically acceptable compositions of the present invention can also be applied topically, particularly when the therapeutic target includes diseases of areas or organs easily accessible by topical application, including the eyes, skin, or lower intestine. Suitable topical formulations are readily prepared for each of these areas or organs.

[0374] Topical application to the lower intestine can be achieved with rectal suppositories (see above) or with suitable enema formulations. Topical transdermal patches may also be used.

[0375] For topical application, the provided pharmaceutically acceptable compositions can be formulated into suitable ointments containing active ingredients suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes, and water. Alternatively, the provided pharmaceutically acceptable compositions can be formulated into suitable lotions or creams containing active ingredients suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, hexadecyl ester wax, cetearyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0376] For ocular use, the provided pharmaceutically acceptable composition may 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 ocular use, the pharmaceutically acceptable composition may be formulated as an ointment, such as petrolatum.

[0377] The pharmaceutically acceptable compositions of the present invention can also be administered by nasal aerosol or inhalation. These compositions are prepared according to techniques known in the field of pharmaceutical formulation and can be prepared as saline solutions using benzyl alcohol or other suitable preservatives, bioavailability enhancers, fluorocarbons and / or other conventional solubilizers or dispersants.

[0378] Most preferably, the pharmaceutically acceptable compositions of the present invention are formulated for oral administration. These formulations may or may not be administered with 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.

[0379] The amount of the compounds of the present invention, which can be combined with carrier materials to produce compositions in a single dosage form, will vary depending on the host being treated and the specific method of administration. Preferably, the provided compositions are formulated to allow administration to patients receiving these compositions at doses between 0.01 and 100 mg / kg body weight / day as inhibitors.

[0380] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health condition, sex, diet, timing of administration, excretion rate, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition.

[0381] Use of compounds and pharmaceutically acceptable compositions

[0382] The activity of compounds used as AHR inhibitors in this invention can be determined in vitro or in vivo. In vivo assessment of the efficacy of the compounds of this invention can be performed using animal models of obesity or metabolic syndrome (e.g., rodent or primate models). Cell-based assays can be performed using cell lines isolated, for example, from tissues expressing AHR. Alternatively, biochemical or mechanistic assays can be performed, such as transcriptional assays using purified proteins, Northern blotting, RT-PCR, etc. In vitro assays include measurements of cell morphology, protein expression and / or cytotoxicity, enzyme inhibitory activity, and / or subsequent functional results of cells treated with the compounds of this invention. Alternative in vitro assays quantify the ability of inhibitors to bind to intracellular protein or nucleic acid molecules. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / target molecule complex, and measuring the amount of radiolabeled binding. Alternatively, inhibitor binding can be determined by a competition assay in which a novel inhibitor is cultured alongside purified proteins or nucleic acids that bind to a known radioligand. Detailed conditions for determining the compounds used as AHR inhibitors in this invention are illustrated in the following examples. The above assays are exemplary and not intended to limit the scope of the invention. Those skilled in the art will understand that conventional assays can be modified to develop equivalent assays that yield the same results.

[0383] As used herein, the term "treatment (treat, treating)" refers to reversing, alleviating, delaying the onset of a disease or condition or one or more of its symptoms, or inhibiting its progression, as described herein. In some embodiments, treatment may be administered after one or more symptoms have appeared. In other embodiments, treatment may be administered in the absence of symptoms. For example, susceptible individuals may be treated before the onset of symptoms (e.g., based on a history of symptoms and / or based on genetic or other susceptibility factors). Treatment may also continue after symptoms have subsided, for example, to prevent or delay their recurrence.

[0384] The compounds and compositions according to the method of the present invention may be administered in any amount and by any route of administration for the effective treatment or relief of metabolic disorders or symptoms, cancer, bacterial infections, fungal infections, parasitic infections (e.g., malaria), autoimmune diseases, neurodegeneration or neuropathies, schizophrenia, bone-related disorders, liver diseases or heart diseases, or to alleviate their severity.

[0385] In some embodiments, compounds and compositions according to the methods of the present invention may be administered in any amount and via any route of administration for the effective treatment of AHR-related diseases or to reduce their severity.

[0386] The exact amount required will vary depending on the subject, including species, age, general condition, severity of infection, specific reagent, and method of administration. The compounds of the present invention are preferably formulated in easily administered and uniformly dosed units. As used herein, "dose unit form" refers to a physically discrete unit of reagent suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention will be determined by the attending physician within reasonable medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the condition being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health condition, sex, and diet; the timing, route of administration, and excretion rate of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical field. The term "patient" as used herein refers to an animal, preferably a mammal, and most preferably a human.

[0387] The pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracerebrospinally, vaginally, intraperitoneally, topically (e.g., by powder, ointment, or drops), sublingually, as an oral or nasal spray, etc., depending on the severity of the infection being treated. In some embodiments, the compounds of the present invention can be administered orally or parenterally once or more daily at a dose level of about 0.01 mg / kg to about 50 mg / kg, and preferably about 1 mg / kg to about 25 mg / kg of the subject's body weight per day, to obtain the desired therapeutic effect.

[0388] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol and mixtures thereof. Besides inert diluents, oral compositions may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatizers.

[0389] Injectable formulations, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable formulations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic, parenteral-acceptable diluents or solvents, such as 1,3-butanediol solutions. Acceptable media and solvents that can be used are water, Ringer's solution USP, and isotonic sodium chloride solutions. Furthermore, sterile non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids such as oleic acid are used in the preparation of injectable formulations.

[0390] Injectable formulations can be sterilized, for example, by filtering through a bacterial trap filter, or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0391] To prolong the effect of the compounds of this invention, it is generally necessary to slow down the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using liquid suspensions of poorly water-soluble crystalline or amorphous materials. The absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystal form. Alternatively, delayed absorption of the parenteral form of the compound is achieved by dissolving or suspending the compound in an oil carrier. Injectable reservoir forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer, such as polylactide-polyglycolic acid. The release rate of the compound can be controlled depending on the ratio of the compound to the polymer and the properties of the specific polymer used. Examples of other biodegradable polymers include poly(orthoester) and poly(anhydride). Reservoir-type injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions that are compatible with body tissues.

[0392] Compositions for rectal or vaginal application are preferably suppositories, which can be prepared by mixing the compounds of the invention with a suitable non-irritating excipient or carrier (e.g., cocoa butter, polyethylene glycol, or suppository wax) that is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity to release the active compound.

[0393] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders (e.g., starch, lactose, sucrose, glucose, mannitol, and silicate), b) binders (e.g., carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic), c) humectants (e.g., glycerin), d) disintegrants (e.g., agar, calcium carbonate, potato or cassava starch, alginate, certain silicates, and sodium carbonate), e) solution blockers (e.g., paraffin wax), f) absorption enhancers (e.g., quaternary ammonium compounds), g) wetting agents (e.g., cetyl alcohol and glyceryl monostearate), h) absorbents (e.g., kaolin and bentonite), and i) lubricants (e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate), and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also contain a buffer.

[0394] Similar solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or toffee and high molecular weight polyethylene glycol. Solid dosage forms of tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells (e.g., enteric coatings and other coatings well known in the pharmaceutical formulation field). They may optionally contain light-blocking agents and may also be compositions in which the active ingredient is optionally released in a delayed manner only or preferably in a portion of the intestine. Examples of encapsulation compositions that can be used include polymeric substances and waxes. Similar solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or toffee and high molecular weight polyethylene.

[0395] The active compound can also be in a microencapsulated form having one or more of the excipients described above. Solid dosage forms such as tablets, sugar-coated pills, capsules, pellets, and granules can be prepared using coatings and shells (e.g., enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation). In these solid dosage forms, the active compound can be mixed with at least one inert diluent (e.g., sucrose, lactose, or starch). As is common practice, such dosage forms may also contain additional substances besides inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pellets, the dosage form may also contain buffers. They may optionally contain light-blocking agents and may also be compositions in which the active ingredient is optionally released in a delayed manner only or preferably in a portion of the intestine. Examples of encapsulation compositions that can be used include polymers and waxes.

[0396] Topical or transdermal formulations of the compounds of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers, or patches. The active ingredient is mixed under aseptic conditions with a pharmaceutically acceptable carrier and any desired preservatives or buffers that may be necessary. Ophthalmic formulations, ear drops, and eye drops are also considered to be within the scope of this invention. Additionally, the invention contemplates the use of transdermal patches, which offer the additional advantage of controlled delivery of the compounds to the body. These dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flux of the compounds across the skin. The rate can be controlled by providing a rate-controlled membrane or by dispersing the compounds in a polymer matrix or gel.

[0397] Uses and methods of treatment

[0398] According to one embodiment, the present invention relates to a method for inhibiting AHR in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0399] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material or extracts thereof obtained from mammals; and blood, saliva, urine, feces, semen, tears or other bodily fluids or extracts thereof.

[0400] Inhibition of enzymes in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of these purposes include, but are not limited to, bioassays, gene expression studies, and biological target identification.

[0401] Another embodiment of the present invention relates to a method for inhibiting AHR in a patient, comprising the step of administering the compound of the present invention or a composition comprising the compound to the patient.

[0402] The provided compounds are inhibitors of AHR and are therefore suitable for treating one or more diseases associated with AHR activity. Accordingly, in some embodiments, the present invention provides a method of treating AHR-mediated conditions comprising administering the compounds of the present invention or pharmaceutically acceptable compositions thereof to a patient in need. In some embodiments, the present invention provides the use of the compounds of the present invention, or in solid form or pharmaceutically acceptable compositions thereof, for treating diseases, conditions, and symptoms as described herein.

[0403] As used herein, the term "AHR-mediated" condition, disease, and / or symptom means any disease or other harmful symptom in which a known AHR or its mutants play a role. Therefore, another embodiment of the invention relates to treating or alleviating the severity of a disease in which one or more known AHRs or their mutants play a role.

[0404] AHR-mediated diseases are well established in this field. The relationship between AHR and AHR-mediated diseases and / or symptoms, as described herein, is well established in the relevant fields. For example, see: Uyttenhove et al., “Evidence for atumoral 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 or foe,” *Nature Review on Cancer*, December 2014, Vol. 14(12), pp. 801-814; Moon et al., “Targeting the indoleamine 2,3-dioxygenase pathway in cancer.” "Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal carcinoma and is associated with poor prognosis and cigarette smoke," *International Journal of Cancer*, Vol. 3, 2015, p. 51; Ishida et al., "Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal carcinoma and is associated with poor prognosis and cigarette smoke," *International Journal of Cancer*.Cancer, July 2015, Vol. 15, No. 137(2), pp. 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), pp. 287-295. Su et al., “Prognostic value of nuclear translocation of arylhydrocarbon receptor for non-small cell lung cancer”, *AnticancerRes*, September 2013, Vol. 33(9), pp. 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 Biology*, April 2009, Vol. 16, pp. 10-27; Jin et al., “Aryl Hydrocarbon Receptor Activation Reduces Dendritic Cell Function during Influenza Virus Infection”. "Infection", British Journal of Toxicology (Toxicol Sci).August 2010, Vol. 116(2), pp. 514-522; Head et al., “The aryl hydrocarbon receptor is a modulator of antiviral immunity”, Biochem.Pharmacol. February 2009, Vol. 15, No. 77(4), pp. 642-53; Jin et al., “On the role of aryl hydrocarbon receptor in CD11c during respiratory viral infection”. + New insights into the role of the aryl hydrocarbon receptor in the function of CD11c + "cells during respiratory viral infection" European Journal of Immunology, June 2014, Vol. 44(6), pp. 1685-98; Nguyen et al., "Aryl hydrocarbon receptor and kynurenine: recent advances in autoimmune disease research" Front Immunol., October 2014, Vol. 29, No. 5, p. 551; Esser et al., "Thearyl hydrocarbon receptor in immunity" Trends in Immunology, Vol. 30, No. 9.

[0405] In some embodiments, the present invention provides a method for treating one or more conditions, diseases, and / or symptoms, wherein the condition, disease, or symptom is a proliferative disease, such as cancer, inflammatory conditions, or viral infections.

[0406] In some embodiments, the present invention provides a method of treating cancer or another proliferative condition, comprising administering a compound or composition of the present invention to a patient suffering from cancer or another proliferative condition. In some embodiments, the method of treating cancer or another proliferative condition comprises administering the compound or composition of the present invention to a mammal. In some embodiments, the mammal is a human.

[0407] As used in this article, the terms “cancer inhibition” and “cancer cell proliferation inhibition” refer to the suppression of the growth, division, maturation, or viability of cancer cells through cytotoxicity, nutrient depletion, or apoptosis, and / or the resulting death of cancer cells, alone or in combination with other cancer cells.

[0408] Examples of tissues containing cancer cells include, but are not limited to, breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, ovary, lung, testis, penis, thyroid gland, parathyroid gland, pituitary gland, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary glands, adrenal glands, pharynx, esophagus, lymph nodes, sweat glands, sebaceous glands, muscles, heart, and stomach, the proliferation of which is inhibited and targeted by the compounds and compositions described herein.

[0409] 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 some embodiments, the cancer is primary exudative lymphoma (PEL).

[0410] The compounds of this invention can be used to treat proliferative disorders selected from benign or malignant tumors, including brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, gastric cancer, gastric tumors, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, urogenital tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer, or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, or gastrointestinal cancer, especially colon cancer or colorectal adenoma or tumors of the neck and head, epidermal hyperplasia, psoriasis, benign prostatic hyperplasia, tumor formation, epithelial-characteristic tumor formation, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's and non-Hodgkin's lymphoma, Wardenström macroglobulinemia, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, MYD88-driven diseases, DLBCL, and ABC. DLBCL, IL-1-driven conditions, smoking indolent multiple myeloma, or leukemia.

[0411] In some embodiments, cancer includes, but is 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, lymphoma (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, endothelial sarcoma, lymphangiosarcoma, lymphangioendothelial sarcoma, synovoma, mesothelioma, Ewing's sarcoma, etc.). 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, cystic adenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, nephroblastoma, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, angioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

[0412] In some embodiments, the cancer is a glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0413] In some embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., grade I - pilocytic astrocytoma, grade II - low-grade astrocytoma, grade III - anaplastic astrocytoma, or grade IV - glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngioma, a brainstem glioma, an ependymoma, a mixed glioma, an optic glioma, a subependymal tumor, a medulloblastoma, a meningioma, a metastatic brain tumor, an oligodendroglioma, a pituitary tumor, a primitive neuroectodermal (PNET) tumor, or a schwannoma. In some embodiments, the cancer is a type more common in children than in adults, such as a brainstem glioma, a craniopharyngioma, an ependymoma, a juvenile pilocytic astrocytoma (JPA), a medulloblastoma, an optic glioma, a pineal tumor, a primitive neuroectodermal tumor (PNET), or a rhabdomyosarcoma. In some embodiments, the patient is an adult. In some embodiments, the patient is a child or a pediatric patient.

[0414] In another embodiment, cancers include, but are not limited to, mesothelioma, hepatobiliary duct (hepatic duct and bile duct), bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma of the skin or eye, ovarian cancer, colon cancer, rectal cancer, anal cancer, stomach cancer, gastrointestinal cancer (gastric cancer, colorectal cancer, and duodenal cancer), uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, esophageal cancer, small bowel cancer, endocrine system cancers, thyroid cancer, parathyroid cancer, and adrenal cancer. Cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis cancer, non-Hodgkin's lymphoma, spinal axis tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, bile duct carcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the aforementioned cancers.

[0415] In some embodiments, the cancer is selected from hepatocellular carcinoma, ovarian cancer, ovarian epithelial carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatobiliary ductal carcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid carcinoma; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / stomach (GIST) cancer; lymphoma; head and neck squamous cell carcinoma (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenström macroglobulinemia; or medulloblastoma.

[0416] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid carcinoma, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic cancer, glioma, neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0417] In some embodiments, the cancer is a solid tumor, such as a sarcoma, carcinoma, or lymphoma. Solid tumors typically comprise an abnormal mass of tissue that does not usually include cysts or fluid-filled areas. In some embodiments, the cancer is selected from renal cell carcinoma or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal cancer, or colorectal cancer; 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 cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; liver cancer. Cholangiocarcinoma; soft tissue and synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid carcinoma; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / stomach (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland carcinoma; glioma, or brain cancer; neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenström macroglobulinemia; or medulloblastoma.

[0418] In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal cancer, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid carcinoma, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0419] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial carcinoma, malignant ovarian tumor, fallopian tube cancer, papillary serous cystadenocarcinoma, papillary serous uterine carcinoma (UPSC), cholangiocarcinoma, soft tissue and bone synovial sarcoma, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid carcinoma, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0420] 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 (ovarian cancer or ovarian carcinoma). In some embodiments, the cancer is ovarian epithelial carcinoma. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is papillary serous cystadenocarcinoma. In some embodiments, the cancer is papillary serous uterine carcinoma (UPSC). In some embodiments, the cancer is 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 anaplastic thyroid carcinoma. In some embodiments, the cancer is adrenocortical carcinoma. In some embodiments, the cancer is pancreatic cancer or pancreatic ductal carcinoma. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral schwannoma (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.

[0421] In some embodiments, cancer includes acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendiceal cancer, atypical teratoid / rhabdoid tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain tumor, astrocytoma, brain and spinal cord tumor, brainstem glioma, atypical teratoid / rhabdoid tumor of the central nervous system, embryonal tumor of the central nervous system, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, primary unknown cancer, 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, and cutaneous T cells. Cystic lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, olfactory neuroblastoma, Ewing sarcoma, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, ocular cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, ovarian germ cell tumors, gestational trophoblastoma, glioma, hairy cell leukemia, head and neck cancer, gastric cardia cancer, hepatocellular carcinoma, histiocytosis, Langerhans cell carcinoma, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, Kaposi's sarcoma, renal cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, lip and oral cancer, liver cancer. Lobular carcinoma in situ (LCIS), lung cancer, lymphoma, AIDS-related lymphoma, macroglobulinemia, male breast cancer, medulloblastoma, medullary epithelioma, melanoma, Merkel cell carcinoma, malignant mesothelioma, occult primary metastatic squamous neck carcinoma, midline carcinoma involving the NUT gene, oral cancer, multiple endocrine adenoma syndrome, multiple myeloma / plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myeloma, multiple myeloma, chronic myeloproliferative disorders, nasal cavity carcinoma, sinus carcinoma, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, oral cavity cancer, lip cancer Oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, sinus cancer, nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, intermediately differentiated pineal parenchymal tumor, pineal blastoma, pituitary adenoma, plasma cell tumor, pleural pulmonary blastoma, breast cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, clear cell renal cell carcinoma, renal pelvis cancer, ureteral cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Cezari syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, occult primary squamous neck cancer, 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 primary, rare childhood cancer, urethral cancer, uterine cancer, uterine sarcoma, Waldenström macroglobulinemia, or nephroblastoma.

[0422] The compounds according to the invention can be used to treat inflammatory or obstructive airway diseases, thereby reducing, for example, tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression. Inflammatory or obstructive airway diseases to which the invention applies include asthma of any type or origin, including intrinsic (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced by bacterial infection. Treatment of asthma should also be understood to include treatment of, for example, subjects younger than 4 or 5 years of age who exhibit wheezing symptoms and are diagnosed or can be diagnosed as “wheezing infants,” a patient category of established major medical concern now commonly identified as having initial or early-stage asthma.

[0423] The preventative efficacy of asthma treatment will be demonstrated by reducing the frequency or severity of symptom attacks (such as acute asthma attacks or bronchoconstrictor attacks), improving lung function, or reducing airway hyperresponsiveness. It can be further demonstrated by reducing the need for other symptomatic treatments, such as therapies used when or designed to limit or stop symptom attacks, like anti-inflammatory or bronchodilator medications. The preventative benefits of asthma are particularly evident in subjects who tend to experience “morning drops.” “Morning drops” is a recognized asthma syndrome common in a significant proportion of asthma patients, characterized by asthma attacks, for example, occurring between approximately 4 and 6 a.m., a time generally detached from any previously administered symptomatic asthma treatments.

[0424] The compounds of this invention can be used for other inflammatory or obstructive airway diseases and symptoms to which this invention applies, including acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, airway or lung disease (COPD, COAD, or COLD), including chronic bronchitis or associated dyspnea, emphysema, and exacerbations of airway hyperresponsiveness due to other drug treatments (particularly other inhaled drug treatments). This invention is also applicable to the treatment of bronchitis of any type or origin, including but not limited to acute, peanut inhalation, catarrhal, gravid, chronic, or tuberculous bronchitis. Other inflammatory or obstructive airway diseases to which this invention applies include pneumoconiosis of any type or origin (inflammatory, often occupational lung disease, frequently accompanied by airway obstruction, whether chronic or acute, and caused by repeated inhalation of dust), including, for example, alumina deposition disease, coal dusting, asbestos deposition disease, stone dusting disease, ostrich feather pneumoconiosis, iron deposition disease, silicosis, tobacco dusting, and cotton dusting disease.

[0425] In terms of its anti-inflammatory activity, particularly in terms of inhibiting eosinophil activation, the compounds of the present invention can also be used to treat eosinophil-related conditions, such as eosinophilia, especially eosinophil-related conditions of the airways (e.g., morbid eosinophilic infiltration involving lung tissue), including eosinophilia because it affects the airways and / or lungs, as well as eosinophilic pneumonia, for example, caused by Loffler syndrome, eosinophilic pneumonia, parasitic (especially metazoan) infections (including tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including allergic granulomatous vasculitis (Churg-strauss) syndrome), eosinophilic granulomas, and eosinophil-related conditions of the airways caused by drug reactions.

[0426] The compounds of this invention can also be used to treat inflammatory or allergic skin conditions, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired bullous epidermolysis bullosa, acne vulgaris, and other inflammatory or allergic skin conditions.

[0427] The compounds of this invention can also be used to treat other diseases or conditions, such as those with inflammatory components, such as eye diseases and conditions, such as eye allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; and inflammatory diseases involving autoimmune reactions or having autoimmune components or causes, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenic purpura), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, and so on. Stevens-Johnson syndrome, idiopathic stomatitis, autoimmune inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic allergic pneumonia, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryomycin-associated periodic syndrome, nephritis, vasculitis, diverticulitis Interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change disease), chronic granulomatous disease, endometriosis, leptospirosis nephropathy, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiomegaly, muscular atrophy, catabolism disorder, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic cortical dysplasia, Behçet's disease, pigment incontinence, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma. (Allergic and non-allergic, mild, moderate, severe, bronchitis and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, allergic reaction, sinusitis, ocular allergy, silica-induced disease, COPD (reduced damage, airway inflammation, bronchial hyperresponsiveness, remodeling or disease progression), lung disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, myositis with systemic sclerosis, dermatomyositis, polymyositis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes.

[0428] In some embodiments, the inflammatory diseases treatable according to the method of the present invention are selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryoprene-associated periodic syndrome (CAPS), or osteoarthritis.

[0429] In some embodiments, the inflammatory diseases treatable according to the method of the present invention are selected from TH17-mediated diseases. In some embodiments, TH17-mediated diseases are selected from systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases including Crohn's disease or ulcerative colitis.

[0430] In some embodiments, the inflammatory diseases treatable according to the method of the invention are selected from Sjögren's syndrome, allergic conditions, osteoarthritis, ocular symptoms such as ocular allergies, conjunctivitis, dry keratoconjunctivitis and vernal conjunctivitis, and diseases affecting the nose, including allergic rhinitis.

[0431] In some embodiments, the inflammatory diseases treatable according to the method of the present invention are selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, allergic vasculitis, urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, acquired epidermolysis bullosa, and other inflammatory or allergic skin conditions.

[0432] In some embodiments, the provided compounds can be used to treat viral infections, diseases, or symptoms. In some embodiments, the present invention provides a method for treating viral diseases selected from retroviral diseases, such as HIV-1, HIV-2, human T-cell leukemia virus-1 (HTLV-1), HTLV-II, HTLV-III, simultaneous immunodeficiency virus (SIV), lymph node disease-associated virus (LAV-2), simultaneous T-lymphocyte virus-1 (STLV-1), STLV-II, STLV-III, simultaneous B-lymphocyte virus (SBL), gibberish leukemia virus (GALV), bovine leukemia virus (BLV), and equine infectious anemia virus (EI). AV), feline leukemia virus (FELV), murine leukemia virus (MuLV), avian leukemia virus (ALV); other viral infections such as hepatophiloviridae (hepatitis B); herpesviruses (herpes simplex I, herpes simplex II, varicella-zoster virus, Epstein-Barr virus and cytomegalovirus); parvoviruses (human parvovirus B-19); papillomaviruses (human papillomavirus types 1 to 60, JC and BK viruses); poxviruses (smallpox, smallpox, cowpox, monkeypox, cowpox, paracoccosis or milker's tubercle virus, parapox or ORF virus, molluscum contagiosum) and cancer, lymphoma and other leukemias.

[0433] Combination therapy

[0434] Depending on the specific symptom or disease to be treated, additional therapeutic agents typically used to treat that symptom may be administered in combination with the compounds and compositions of the present invention. As used herein, additional therapeutic agents typically used to treat a specific disease or symptom are referred to as “the disease or condition to be treated”.

[0435] In some embodiments, the provided compound or a combination thereof is administered to a patient in need in combination with another anticancer agent, cytotoxic agent or chemotherapeutic agent.

[0436] In some embodiments, the anticancer 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, salsalamide A, retinic acid, cisplatin, carboplatin, oxaliplatin, methyl chloroethylamine, cyclophosphamide, chlorambucil, ifosfamide, azathioprine, mercaptopurine, docefluorouracil, fluorouracil, gemcitabine, methotrexate, thioguanine, vincristine, vinorelbine, vindesine, and virucide. Paclitaxel, etoposide, teniposide, tafluposide, paclitaxel, docetaxel, irinotecan, topotecan, acridine, actinomycin, doxorubicin, daunorubicin, vararubicin, idarubicin, epirubicin, procainamide, mitomycin, mitoxantrone, melphalan, busulfan, capecitabine, epromycin, 13-cis-retinoic acid, 2-CdA, 2-chlorodeoxyadenosine, 5-azacitidine, 5-fluorouracil, 5-FU, 6-mercaptopurine, 6-MP, 6-TG, 6-thioguanine, paclitaxel nanoparticles Actinomycin-D, Aldehyde interleukin, alemtuzumab, ALIMTA, retinoic acid Total reversal retinoic acid, alpha interferon, hexamethylmelamine, methotrexate, amifostine, aminoglutethimide, anagrelide hydrochloride, Anatozol, cytarabine, Ara-C Arsenic trioxide, olfamomumab TM Asparaginase, ATRA Azacitidine, BCG, BCNU, Bendamustine, Bevacizumab, Bexarotine Bicalutamide, BiCNU Bleomycin, bortezomib, busulfan C225, calcium formyl tetrahydrofolate, Camptothecin-11, capecitabine, Carac TM Carboplatin, Carmustine, Carmustine tablets CC-5013, CCI-779, CCNU, CDDP, CeeNU, Cetuximab, chlorambucil, citric acid, cladribine, cortisone CPT-11, Aminoglutamate, Dacarbiazine, Dacodone, Dermazomycin, Alfadabeppe, Dasatinib, Dasatinib, Datocin, Danomycin Hydrochloride, Daunorubicin Liposome Dexamethasone, desitabin, DepoCyt interleukin TM Dexamethasone, Dexamethasone Acetate, Dexamethasone Sodium Phosphate, Dexamethasone, Dexamethasone, Dexamethasone, DHAD, DIC, Diodex, Docetaxel Doxorubicin, Doxorubicin liposomes, Hydroxyurea capsules TM DTIC Leuprorelin TM Epirubicin TM Lesha Ding TM , Epirubicin, Ibertin afa, Cetuximab, Erlotinib, Erwinia L-asparaginase, Estrostimine, Amifostine Etoposide, Etoposide phosphate, Everolimus Isimmetan, Filgrastim, fluorouracil, Fludarabine, Fluorouracil, fluorouracil (cream), fluoxymesterone, flutamide, folic acid, Fulvestrant, G-CSF, Gefitinib, Gemcitabine, Giemzamab, Ozomicin, GemzarGleevec TM , Implantable membrane, GM-CSF, goserelin, granulocyte-colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, Dexamethasone, Hexamethylmelamine, HMM Hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone phosphate, hydroxyurea, ibuprofen, tiemoxib, Idabi Star Interferon alpha, ifosfamide, IL-11, IL-2, imatinib mesylate, imidazole carbamide, IFN-α, interferon α-2b (PEG conjugate), interleukin-2, interleukin-11 (interferon α-2b) Irinotecan, Isotretinoin, Ixaspirone, Ixaspirone TM , Lapatinib, L-asparaginase, LCR, Lenalidomide, Letrozole, Leucovorin, Leuconazole, Moraxillin TM Leuprorelin, Vincristine, and Loxetine Injection TM Liposome Ara-C Lomustine, L-PAM, L-sarcomain, Leuprorelin Acetate, Leuprorelin Microspheres for Injection, Carbazine, Ambroxol, Nitrogen Mustard, Nitrogen Mustard Hydrochloride Medrol, medroxyprogesterone acetate, medroxyprogesterone acetate, melphalan, mercaptopurine, mesna, mesna TM Methotrexate, Methotrexate Sodium, Methylprednisolone Mitomycin, Mitomycin-C, Mitoxantrone MTC, MTX nitrogen mustard Mylocel TM , Narabin, Peffersky TM , Nilotinib, Nilumet nitrogen mustard Romistastatin, Octreotide, Octreotide Acetate, Olfamumab Onxal TM Interleukin-1, Oprui Oxaliplatin, paclitaxel, paclitaxel protein binder, pamidronate, panitumumab Pazopanib PEG-interferon, pegaspargase, ethylene glycol-modified filgrastim, PEG-INTRON TM PEG-L-asparaginase, PEMETREXED, pentostatin, phenylalanine mustard Prednisolone, Prednisolone Procarbazine, Polyphenylpropionate 20 contains carmustine implant, purine alcohol, raloxifene, lenalidomide, rhein, rituximab, and more. (Interferon Alfa-2a), Romistatin, Lubimycin hydrochloride, Good attainment of concentration Shagstine, Sorafenib, SPRYCELTM STI-571, streptozotocin, SU11248, sunitinib Tamoxifen, Temozolomide, Sirolimus esters, Teniposide, TESPA, Thalidomide Thioguanine, thioguanine Thiophosphoramide, thiophosphoric acid Theta, Topotecan, toremifene, Tosimomab, Trastuzumab Retinoic acid, methotrexate TM , TSPA, VCR, Panitumumab TM , VePesid, Implants Vincristine, Vincristine Sulfate, Vincristine Sulfate, Vincristine, Vinorelbine, Vinorelbine Tartrate, VLB, VM-26, Vorinostat, Pazopanib, VP-16 Zewaling TM , Zoledronic acid, vorinostat, Or any combination thereof.

[0437] In some embodiments, immunotumor agents may be administered in combination with compounds as described herein to treat proliferative conditions as described herein. As used herein, the term "immunotumor agent" refers to an agent that effectively enhances, stimulates, and / or upregulates the immune response of a subject. In some embodiments, the administration of immunotumor agents in conjunction with compounds as described herein has a synergistic effect in the treatment of cancer.

[0438] In some embodiments, the compounds described herein are administered sequentially before the administration of an immunotumor agent. In some embodiments, the compounds described herein are administered simultaneously with the immunotumor agent. In some embodiments, the compounds described herein are administered sequentially after the administration of an immunotumor agent.

[0439] In some embodiments, the compounds described herein may be formulated in combination with immunotumor agents.

[0440] Immunotumor agents can be, for example, small molecule drugs, antibodies, or biological or small molecule agents. Examples of biological immunotumor agents include, but are not limited to, cancer vaccines, antibodies, and cytokines. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the monoclonal antibody is humanized or human-derived.

[0441] In some embodiments, the immunotumor agent is either (i) an agonist that stimulates (including co-stimulatory) receptors or (ii) an antagonist of inhibitory (including co-inhibitory) signals on T cells, both of which result in amplification of antigen-specific T cell responses.

[0442] Certain stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). An important family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 family, which includes B7-1, B7-2, B7-H1 (PD-L1), B7-DC (PD-L2), B7-H2 (ICOS-L), B7-H3, B7-H4, B7-H5 (VISTA), and B7-H6. Another family of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the TNF molecule family that binds to members of the homologous TNF receptor family, including CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, and TWEAKR. / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1 , XEDAR, EDA2, TNFR1, Lymphotoxinα / TNFβ, TNFR2, TNFα, LTβR, Lymphotoxinα1β2, FAS, FASL, RELT, DR6, TROY, NGFR.

[0443] In some embodiments, the immunotumor 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, used to stimulate an immune response.

[0444] In some embodiments, the combination of the compounds described herein and immunotumor agents can stimulate a T cell response. In some embodiments, the immunotumor agent is: (i) an antagonist of proteins that inhibit T cell activation (e.g., immune checkpoint inhibitors), such as CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, galactoglobulin 9, CEACAM-1, BTLA, CD69, galactoglobulin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of proteins that stimulate 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.

[0445] In some embodiments, the immunotumor agent is an antagonist of inhibitory receptors on NK cells or an agonist of activating receptors on NK cells. In some embodiments, the immunotumor agent is an antagonist of KIR, such as lirilumab.

[0446] In some embodiments, the immunotumor agent is a reagent 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).

[0447] In some embodiments, the immunotumor agent is selected from agonists that link positive co-stimulatory receptors, blockers that attenuate signal transduction via inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome different immunosuppressive pathways in the tumor microenvironment (e.g., blocking inhibitory receptor involvement (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., using anti-CD25 monoclonal antibodies (e.g., dazumab (interactions)) or through in vitro depletion of anti-CD25 beads), inhibiting metabolic enzymes (e.g., IDO), or reversing / preventing T cell energy or depletion), and agents that trigger innate immune activation and / or inflammation at the tumor site.

[0448] In some embodiments, the immuno-oncology agent is a CTLA-4 antagonist. In some embodiments, the CTLA-4 antagonist is an antagonistic CTLA-4 antibody. In some embodiments, the antagonistic CTLA-4 antibody is YERVOY (ipilimumab) or tremelimumab.

[0449] 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 its antigen-binding moiety that specifically binds to the programmed death-1 (PD-1) receptor and inhibits PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, the antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO2012 / 145493). In some embodiments, the immuno-oncology agent may be pidilizumab (CT-011). In some embodiments, the immuno-oncology agent is a recombinant protein, referred to as AMP-224, consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1.

[0450] In some embodiments, the immuno-oncology agent is a PD-L1 antagonist. In some embodiments, the PD-L1 antagonist is an antagonistic PD-L1 antibody. In some embodiments, the PD-L1 antibody is MPDL3280A (RG7446; WO2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO2007 / 005874), and MSB0010718C (WO2013 / 79174).

[0451] In some embodiments, the immunotumor agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, the LAG3 antibody is BMS-986016 (WO10 / 19570, WO14 / 08218), or IMP-731 or IMP-321 (WO08 / 132601, WO009 / 44273).

[0452] In some embodiments, the immunotumor agent is a CD137 (4-1BB) agonist. In some embodiments, the CD137 (4-1BB) agonist is an agonistic CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO12 / 32433).

[0453] In some embodiments, the immunotumor agent is a GITR agonist. In some embodiments, the GITR agonist is an agonistic GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO006 / 105021, WO009 / 009116) or MK-4166 (WO11 / 028683).

[0454] 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).

[0455] In some embodiments, the immunotumor agent is an OX40 agonist. In some embodiments, the OX40 agonist is an agonistic OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0456] In some embodiments, the immunotumor agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO06 / 029879).

[0457] In some embodiments, the immunotumor agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonist CD40 antibody. In some embodiments, the immunotumor 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.

[0458] In some embodiments, the immuno-oncology agent is a CD27 agonist. In some embodiments, the CD27 agonist is an agonistic CD27 antibody. In some embodiments, the CD27 antibody is varlilumab.

[0459] In some embodiments, the immunotumor agent is MGA271 (to B7H3) (WO11 / 109400).

[0460] In some embodiments, the immuno-oncology agents are abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolimusab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indomod, and inotuzumab. (ozogamicin), intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pildizumab, rituximab, CTLA-4 monoclonal antibody, samalizumab, or trimelimumab.

[0461] In some embodiments, immunotumor agents are immunostimulants. For example, antibodies that block the PD-1 and PD-L1 inhibitory axes can deplete activated tumor-reactive T cells and have been shown in clinical trials to induce durable antitumor responses in increased numbers of tumor histology, including some tumor types not conventionally considered sensitive to immunotherapy. See, for example, Okazaki, T. et al. (2013), *Nature Immunology*, 14, 1212–1218; Zou et al. (2016), *Science Translational Medicine*, 8. Anti-PD-1 antibody nivolumab (… Bristol-Myers Squibb (also known as ONO-4538, MDX1106, and BMS-936558) has shown potential to improve overall survival in patients with RCC who have experienced disease progression during or after prior anti-angiogenic therapy.

[0462] In some embodiments, immunomodulatory therapy specifically induces apoptosis in tumor cells. Approved immunomodulatory therapeutic agents that can be used in this invention include pomalidomide (…). Celgene; Lenalidomide Neo-based); Megaphoryl methyl butyl ester ( LEO Pharma).

[0463] In some embodiments, the immunotumor agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from sipuleucel-T (Pulvec). Dendreon / Valeant Pharmaceuticals, Inc., has been approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and oncolytic viruses (…). BioVex / Amgen (formerly known as T-VEC), a genetically modified oncolytic virus therapy, is approved for the treatment of unresectable cutaneous, subcutaneous, and lymph node lesions of melanoma. In some embodiments, the immunotumor agent is selected from oncolytic virus therapies, such as pexastimogene devacirepvec (PexaVec / JX-594, Silla JenBiotherapeutics (formerly Jennerex Biotherapeutics)) for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312), a thymidine kinase-(TK-)-deficient vaccinia virus engineered to express GM-CSF; Pelareorep ( Oncolytic biotechnology), a variant of a respiratory enteric orphan virus (reovirus) that does not replicate in non-RAS-activated cells in a variety of cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell carcinoma (NCT01166542); pancreatic cancer (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT01622543). 00861627); enadenotucirev (NG-348, PsiOxus, formerly ColoAd1), an adenovirus engineered to express full-length CD80 and an antibody fragment specific to the T-cell receptor CD3 protein in ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors, such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax (formerly Oncos)), an adenovirus engineered to express GM-CSF in melanoma (NCT03003676); and peritoneal diseases, colorectal cancer, or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux) studied in peritoneal carcinoma (NCT01443260). GmbH), a vaccinia virus engineered to express β-galactosidase (β-gal) / β-glucuronidase or β-gal / human sodium-iodide transporter (hNIS); fallopian tube cancer, ovarian cancer (NCT 02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818).

[0464] In some embodiments, the immuno-oncology agent is selected from JX-929 (SillaJen Biotherapeutics (formerly Jennerex Biotherapeutics)), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is capable of converting the prodrug 5-fluorocytosine into the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), peptide-based immunotherapeutics targeting refractory RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus named Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20; and VSV-GP (ViraTherapeutics), a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which may be further engineered to express an antigen designed to generate an antigen-specific CD8+ T cell response.

[0465] 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 these chimeric antigen receptors are referred to as CAR-T cells.

[0466] CARs composed of binding domains have been constructed. These binding domains can be derived from natural ligands or from single-chain variable fragments (scFvs) of monoclonal antibodies specifically targeting cell surface antigens. These CARs are fused to internal domains that function as the terminal part of the T cell receptor (TCR), such as the CD3-zeta signaling domain from the TCR, and can generate activation signals in T lymphocytes. Upon antigen binding, these CARs connect to endogenous signaling pathways in effector cells and generate activation signals similar to those initiated by the TCR complex.

[0467] For example, in some embodiments, CAR-T cells are one of the cells described in U.S. Patent 8,906,682 (June; incorporated herein by reference in its entirety), which discloses that CAR-T cells are engineered to include an extracellular domain having an antigen-binding domain (e.g., a domain that binds to CD19), fused to an intracellular signaling domain of the zeta chain of the T cell antigen receptor complex (e.g., CD3 zeta). When expressed in T cells, CARs are able to redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Currently, more than 200 clinical trials are underway using CAR-T in various indications. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0468] In some embodiments, the immunostimulant is an activator of retinoic acid receptor-associated orphan receptor γ (RORγtt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of the type 17 effector subset of CD4+ (Th17) and CD8+ (Tc17) T cells, as well as in the differentiation of IL-17-expressing innate immune cell subsets such as NK cells. In some embodiments, the activator of RORγt is LYC-55716 (Lycera), which is currently being evaluated in a clinical trial for the treatment of solid tumors (NCT02929862).

[0469] In some embodiments, the immunostimulant is an agonist or activator of a toll-like receptor (TLR). Suitable TLR activators include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG being investigated for use in B-cell, follicular, and other lymphomas (NCT02254772). Agonists or activators of TLR8 that can be used in this invention include motolimod (VTX-2337, a clinical-stage biopharmaceutical company (VentiRx Pharmaceuticals)) being investigated for the treatment of head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0470] Other immuno-oncology agents that can be used in this invention include uroselumab (BMS-663513, Bristol-Myers Squibb), anti-CD137 monoclonal antibody; varlilumab (CDX-1127, Celldex therapeutic agent), anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), anti-OX40 monoclonal antibody; lirelumab (IPH2102 / BMS-986015, congenital drug, Bristol-Myers Squibb), anti-KIR monoclonal antibody; monarizumab (IPH2201, congenital drug, AstraZeneca), anti-NKG2A monoclonal antibody; and andecaliximab (GS-5745, Gilead Sciences). Sciences), anti-MMP9 antibody; MK-4166 (Merck & Co.), anti-GITR monoclonal antibody.

[0471] In some embodiments, the immunostimulant is selected from elotuzumab, mifamurtide, agonists or activators of Toll-like receptors, and activators of RORγt.

[0472] In some embodiments, the immunostimulatory 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 immunostimulator is recombinant human interleukin-12 (rhIL-12). In some embodiments, the IL-15-based immunotherapy agent is heterodimeric IL-15 (hetIL-15, Novartis / Admune), which is a fusion complex consisting of a synthetic form of endogenous IL-15 and a soluble IL-15-binding protein IL-15 receptor α chain (IL15:sIL-15RA), and has been tested in phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, recombinant human interleukin-12 (rhIL-12) is NM-IL-12 (Neumedicines), NCT02544724, or NCT02542124.

[0473] In some embodiments, the immuno-oncology agent is selected from those described by Jerry L. Adams et al., “Big opportunities for small molecules in immuno-oncology,” *Cancer Therapy*, 2015, Vol. 14, pp. 603-622, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is selected from the examples described in Table 1 by Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule targeting immuno-oncology targets selected from those listed in Table 2 by Jerry L. Adams et al. In some embodiments, the immuno-oncology agent is a small molecule reagent selected from those listed in Table 2 by Jerry L. Adams et al.

[0474] In some embodiments, the immuno-oncology agent is selected from the small molecule immuno-oncology agents described by Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents," *Bioorganic & medicinal chemistry letters*, 2018, Vol. 28, pp. 319-329, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the immuno-oncology agent is a reagent that targets the pathway described by Peter L. Toogood.

[0475] In some embodiments, the immuno-oncology agent is selected from those described by Sandra L. Ross et al., "bispecific T-cell binding agents". Antibody constructs can mediate bystander tumor cell killing (Bispecific T-cell engager) "Antibody constructs can mediate by stander tumor cell killing," PLoS ONE, 12(8):e0183390, the contents of which are incorporated herein by reference in full. In some embodiments, the immunotumor agent is a bispecific T-cell binding agent. Antibody construct. In some embodiments, a bispecific T-cell conjugate. The antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, a bispecific T-cell binding agent... The antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, a bispecific T-cell binding agent... Antibody constructs activate T cells. In some embodiments, a bispecific T cell conjugate is used. The antibody construct activates T cells, which release cytokines and induce upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS on bystander cells. In some embodiments, a bispecific T cell conjugate... The antibody construct activates T cells, leading to induced bystander cell lysis. In some embodiments, the bystander cells are in solid tumors. In some embodiments, the lysed bystander cells are in... Near activated T cells. In some embodiments, bystander cells comprise tumor-associated antigen (TAA)-negative cancer cells. In some embodiments, bystander cells comprise EGFR-negative cancer cells. In some embodiments, the immunotumor agent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the immunotumor agent is ex vivo expanded tumor-infiltrating T cells. In some embodiments, the immunotumor agent is a bispecific antibody construct or chimeric antigen receptor (CAR) that directly links T cells to tumor-associated surface antigens (TAAs).

[0476] In some embodiments, a combination of two or more therapeutic agents may be administered together with the compounds of the present invention. In some embodiments, a combination of three or more therapeutic agents may be administered together with the compounds of the present invention.

[0477] Other examples of reagents that can be combined with the inhibitors of the present invention include, but are not limited to: vitamins and nutritional supplements, cancer vaccines, treatments for neutropenia (e.g., G-CSF, filgrastim, lenograstim), treatments for thrombocytopenia (e.g., blood transfusions, 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 anticholinergics), and treatments for Alzheimer's disease, such as... and Treatments for Parkinson's disease, such as L-DOPA / carbidopa, entacapone, ropinilol, pramipexole, bromocriptine, pergolide, benztropine, and amantadine; medications for multiple sclerosis (MS), such as beta-interferon (e.g., and ), And mitoxantrone; agents for treating asthma, such as salbutamol and montelukast; agents for treating schizophrenia, such as zyprexa, risperidone, serotonin, and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1RAs, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and anti-Parkinson's drugs; agents for treating cardiovascular diseases, such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, statins, fibrates, cholesterol absorption inhibitors, bile acid sequestrants, and niacin; agents for treating liver diseases, such as corticosteroids. Alcohols, cholestyramine, interferon, and antiviral agents; agents for treating blood disorders, such as corticosteroids, anti-leukemia agents, and growth factors; agents for treating immunodeficiency disorders such as gamma globulin; and antidiabetic agents, such as biguanides (metformin, phenformin, buformin), thiazolidinediones (rosiglitazone, pioglitazone, troglitazone), and sulfonylureas (tolbutamide, acesulfame potassium, tolazoline, chlorpropamide, glipizide, etc.). Glibenclamide, glimepiride, gliclazide, chloropicrin derivatives (repaglinide, nateglinide), alpha-glucosidase inhibitors (miglitol, acarbose), enterohepatic hormone analogs (exenatide, liraglutide, tasglutide), gastric inhibitory peptide analogs, DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, lindagliptin, alogliptin), dextrin analogs (pramlintide), and insulin and insulin analogs.

[0478] In some embodiments, the compounds of the present invention or pharmaceutically acceptable compositions thereof are administered in combination with antisense agents, monoclonal or polyclonal antibodies, or siRNA therapeutic agents.

[0479] In another embodiment, the present invention provides a method for treating an inflammatory disease, condition, or symptom by administering the compound of the invention and one or more other therapeutic agents to a patient in need. Such other therapeutic agents may be small molecule or recombinant biological agents and include, for example, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen, naproxen, and etodoxacin. celecoxib and colchicine Corticosteroids such as prednisone, prednisolone, methylprednisolone, hydrocortisone, probenecid, allopurinol, febuxostat, etc. sulfasalazine Antimalarial drugs such as hydroxychloroquine and chloroquine Methotrexate Gold salts such as glucosamine Gold thiomalate and aureophen (R leflunomide) And "anti-TNF" agents, such as etanercept Infliximab Golimumab Sertolizumab and adalimumab "Anti-IL-1" agents, such as anakinase and Lilonap Cannabidiol Anti-Jaks, such as tofacitinib; antibodies, such as rituximab. Anti-T cell agents, such as abatacept "Anti-IL-6" agents, such as tocilizumab (Actemra), and bile acid binders, such as cholestyramine and alosetron. Lubiprostone Mild laxatives, such as Milmagase, polyethylene glycol and Anticholinergic drugs or antispasmodics, such as bicyclic amine β-2 agonists, such as salbutamol ( HFA, HFA), levosalbutanol Osinarin Pyrboterol acetate tert-butyl sulfate Salmeterol senna and Formotero Anticholinergic drugs, such as ipratropium bromide and tiotropium bromide Inhaled corticosteroids, such as beclomethasone dipropionate ( and ), Triamcinolone Momison Buddyne and flunisulfanil Sodium cromoglycate Methylxanthine drugs, such as theophylline And aminophylline, IgE antibodies such as omalizumab For example, zidovudine Abacave Abacave / Lamivudine Enqutabin Lamivudine Lamivudine / Zidovudine Stavudine (Lopinavir and Litonavir) Nefernavir Litonavir Saquinavir or ) and tepranavir Enter For example, Enfwedi and Malawi Integrase For example, Retgway Dorothy Star Changchun New Alkali Bortezomib and dexamethasone With lenalidomide A combination of, or any combination thereof.

[0480] In some embodiments, the provided compounds are administered in combination with antiviral agents, including, for example, acyclovir, penciclovir, cidofovir, iodouridine, zidovudine, ribavarin, amantadine, phosphonoformic acid, doxorubicin, acyclovir, ganciclovir, cidofovir, zalcitabine, amantadine, carciclovir, famciclovir, abacavir, doxorubicin, emtricitabine, lamivudine, stavudine, tenofovir, etc. Sitabine, zidovudine, zidovudine-lamivudine, TRIZIVIR (zidovudine, lamivudine, abacavir), EPZICOM (abacavir-lamivudine), TRUVADA (tenofovir-emtricitabine), efavirenz and deravir, ampravir, atazanavir, fosanavir, indinavir, lopinavir-ritonavir, nelfinavir, ritonavir, saquinavir, and telanavir. In some embodiments, the antiviral agent is an anti-influenza agent, including, for example, amantadine, oseltamivir, and zanamivir.

[0481] These additional agents can be administered separately from the composition containing the compound of the invention as part of a multiple-dosing regimen. Alternatively, these agents can be part of a single dosage form, mixed together with the compound of the invention in a single composition. If administered as part of a multiple-dosing regimen, the two active agents can be administered simultaneously, sequentially, or over a period of time, typically within 5 hours of each other.

[0482] As used herein, the terms "combination" and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the invention. For example, compounds of the invention may be administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or together in a single unit dosage form. Thus, the invention provides a single unit dosage form comprising compounds of the invention, additional therapeutic agents, and pharmaceutically acceptable carriers, adjuvants, or mediators.

[0483] The amounts of the provided compound and additional therapeutic agents (in those compositions containing additional therapeutic agents as described above) that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific method of administration. Preferably, the compositions of the present invention should be formulated such that the dosage of the present invention can be administered at a rate of 0.01-100 mg / kg body weight / day.

[0484] In those compositions that include an additional therapeutic agent, the additional therapeutic agent and the compound of the present invention can act synergistically. Therefore, the amount of the additional therapeutic agent in these compositions will be less than that required in a single therapy using only the therapeutic agent. In these compositions, the additional therapeutic agent can be administered at a dose between 0.01 and 100 μg / kg body weight / day.

[0485] The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount normally applied in compositions containing the therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the currently disclosed compositions will be in the range of about 50% to 100% of the amount normally present in compositions containing the agent as the sole active agent.

[0486] In one embodiment, the present invention provides a composition comprising the compound of the present invention and one or more other therapeutic agents. The therapeutic agent may be administered together with the compound of the present invention, or may be administered before or after the administration of the compound of the present invention. Suitable therapeutic agents are described in further detail below. In some embodiments, the compound of the present invention may 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 may 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.

[0487] In some embodiments, the present invention provides a medicament comprising at least one compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0488] All features of each aspect of the invention, after necessary modifications, are applicable to all other aspects.

[0489] To better understand the invention described herein, the following examples are presented. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0490] Example

[0491] As described in the following examples, in some exemplary embodiments, compounds are prepared according to the following general procedure. It should be understood that although the general method describes the synthesis of certain compounds of the present invention, the following general method and other methods known to those skilled in the art can be applied to all compounds and subclasses and species of each of these compounds, as described herein.

[0492] General Procedure

[0493] X-ray powder diffraction (XRPD)

[0494] The X-ray diffraction system is configured to use a reflecting Bragg-Brentano geometry for a line-source X-ray beam. This source provides an incident beam profile at the sample that varies from a narrow line at high angles to a wide rectangle at low angles. A beam-tuning slit is used on the line X-ray source to ensure that the maximum beam size along and perpendicular to the line is less than 10 mm. The Bragg-Brentano geometry is an alignment-focusing geometry controlled by passive divergence and receiving slits, where the sample itself acts as the focusing component of the optics. The inherent resolution of the Bragg-Brentano geometry is controlled in part by the diffractometer radius and the width of the receiving slit used. Typically, the X-ray diffraction system is operated to obtain a peak width of 0.1°2θ or less. The axial divergence of the X-ray beam is controlled by a 5.0-degree Soller slit in both the incident and diffracted beam paths.

[0495] Powder samples were prepared using light manual pressure in a low-background Si holder to keep the sample surface flat and level with the reference surface of the sample holder. Each sample was analyzed from 2 to 40°2θ using continuous scans at 6°2θ / min with effective steps of 0.02°2θ.

[0496] Differential scanning calorimetry (DSC)

[0497] DSC analysis was performed using a TA instrument. Instrument temperature calibration was performed using indium. During each analysis, the DSC cell was maintained under nitrogen purging at approximately 50 mL per minute. The sample was placed in a standard rolled aluminum pan and heated from 25°C to 350°C at a rate of 10°C / min.

[0498] Thermogravimetric (TG) analysis

[0499] TG analysis was performed using a TA instrument. The instrument balance was calibrated using M-class weights, and the temperature was calibrated using AlNi alloy. The nitrogen purging rate was approximately 40 mL / min at the balance and approximately 60 mL / min at the furnace. Each sample was placed in a pre-prepared platinum pan and heated from 20 °C to 350 °C at a rate of 10 °C / min.

[0500] Nuclear magnetic resonance (NMR) spectroscopy

[0501] Samples are prepared by dissolving the material in a solvent. The solution is filtered and placed in a separate 5-mm NMR tube for subsequent spectral acquisition.

[0502] Primary salt screening

[0503] Salt screening experiments were conducted using twelve (12) acid salt forming agents and a variety of crystallization techniques (cooling, slurrying, evaporation, and vapor diffusion). Table 11 describes the experimental details of each salt formation attempt.

[0504] Table 11. Salt screening experiment

[0505]

[0506]

[0507] Secondary salt screening

[0508] Compound 1 (Form A), Compound 2 (Form A), Compound 3 (Form B), and Compound 4 (Form A) were scaled up proportionally, and the experimental details are described in Table 12 below.

[0509] Table 12. Secondary Salt Screening Experiment

[0510]

[0511]

[0512] Example A - General preparation of compound A

[0513]

[0514] The title compound was prepared according to the steps and intermediates (e.g., Scheme 1) described below and in publication '411, which are incorporated herein by reference in their entirety.

[0515] Scheme 1 - Synthesis of Compound A

[0516]

[0517] Step 1:(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 (Compound A)

[0518]

[0519] A mixture of 4-chloro-2-(5-fluoro-3-pyridinyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazine (60.00 mg, 205.68 mol, 1 equivalent), (3R)-2,3,4,9-tetrahydro-1H-carbazole-3-amine (42.14 mg, 226.25 mol, 1.1 equivalent), and DIEA (79.75 mg, 617.05 mol, 107.48 L, 3 equivalent) in i-PrOH (4 mL) was degassed and purged three times with N2. The mixture was stirred at 55 °C for 3 hours under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by preparative HPLC (column: Phenomenex Gemini 150*25mm*10um; mobile phase: [water (0.05% HCl)-ACN]; B%: 70% to 100%, 10 min). The residue was then lyophilized to give (3R)-N-[2-(5-fluoro-3-pyridinyl)-8-isopropyl-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-2,3,4,9-tetrahydro-1H-carbazole-3-amine (42.07 mg, 75.45 mol, 36.7% yield, 98.8% purity, 3HCl) as a yellow solid. 1 H NMR(400MHz,CD3OD)δppm 9.46(s,1H),8.81(d,J=9.3Hz,1H),8.76(s,1H),8.12-7.92(m,1H),7.37(d,J=7.7Hz,1H),7.27(d,J=7.9Hz,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=7.1Hz,6H); ES-LCMSm / z 442.2[M+H] + .

[0520] Example 1 - Preparation of free base forms A, B, and C of compound A

[0521]

[0522] Form B of compound A

[0523] Compound A in form B was prepared as described above.

[0524] Table B (same as above) reproduces below and lists the X-ray diffraction peaks observed in form B of compound A.

[0525] Table B - XRPD peak positions of compound A in form B

[0526]

[0527]

[0528] 1 In this table and all subsequent tables,

[0529] Position 2θ is within ±0.2.

[0530] Figure 1 An XRPD plot of compound A in form B is shown.

[0531] Figure 2 The TG / DTA trace of compound A in form B was depicted.

[0532] Form C of compound A

[0533] Compound A was prepared in form C as described above.

[0534] Table C (as above) is reproduced below and lists the X-ray diffraction peaks observed in form C of compound A.

[0535] Table C shows the XRPD peak positions of compound C in form C of compound A.

[0536]

[0537]

[0538] 1 In this table and all subsequent tables,

[0539] Position 2θ is within ±0.2.

[0540] Figure 3 An XRPD plot of compound A in form C is shown.

[0541] Figure 4 The TG / DTA trace of compound A in form C was depicted.

[0542] A mixture of form A and form B of compound A

[0543] Compound A hydrochloride (7.0 g) was dissolved in a mixture of ethyl acetate (150 mL) and saturated NaHCO3 solution (200 mL) and stirred at 28 °C for 30 min. The mixture was extracted with ethyl acetate (150 mL × 3). The combined organic layers were washed with brine (200 mL × 2), dried over Na2SO4, and concentrated to obtain a residue, which was added to methanol (150 mL) and stirred for 30 min. The mixture was filtered and the filter cake was concentrated to obtain the desired product, which was then lyophilized to give a mixture of form A and form B of compound A (6.7 g) as a solid.

[0544] Figure 24 An XRPD plot depicting a mixture of form A and form B of compound A is shown.

[0545] Figure 25 TGA / DSC describes a mixture of form A and form B of compound A.

[0546] Example 2 - Preparation of form A of compound 1

[0547]

[0548] Form A of compound 1

[0549] Compound 1 in form A was prepared as described above.

[0550] Table 1 (as above) reproduces and lists the X-ray diffraction peaks observed in form A of compound 1 below.

[0551] Table 1 - XRPD peak positions of form A of compound 1

[0552]

[0553]

[0554] Figure 5 An XRPD plot of compound 1 in form A is shown.

[0555] Figure 6 The TG / DTA trace of compound 1 in form A was depicted.

[0556] Form B of compound 1

[0557] Compound 1 in form B was prepared as described above.

[0558] Table 2 (as above) reproduces and lists the X-ray diffraction peaks observed in form B of compound 1 below.

[0559] Table 2 - XRPD peak positions of form B of compound 1

[0560]

[0561]

[0562] Figure 7 An XRPD plot of form B of compound 1 was depicted.

[0563] Example 3 - Preparation of form A of compound 2

[0564]

[0565] Form A of compound 2

[0566] Compound 2 was prepared in form A as described above.

[0567] Table 3 (as above) reproduces and lists the X-ray diffraction peaks observed in form A of compound 2 below.

[0568] Table 3 - XRPD peak positions of compound 2, form A

[0569]

[0570]

[0571] Figure 8 An XRPD plot of compound 2 in form A was depicted.

[0572] Figure 9 The TG / DTA trace of compound 2 in form A was depicted.

[0573] Example 4 - Preparation of form A of compound 3

[0574]

[0575] Form A of compound 3

[0576] Compound 3 was prepared in form A as described above.

[0577] Table 4 (as above) reproduces and lists the X-ray diffraction peaks observed in form A of compound 3 below.

[0578] Table 4 - XRPD peak positions of form A of compound 3

[0579]

[0580]

[0581] Figure 10 An XRPD plot of compound 3 in form A was depicted.

[0582] Figure 11The TG / DTA trace of compound 3 in form A was depicted.

[0583] Form B of compound 3

[0584] Compound 3 in form B was prepared as described above.

[0585] Table 5 (as above) reproduces and lists the X-ray diffraction peaks observed in form B of compound 3 below.

[0586] Table 5 - XRPD peak positions of form B of compound 3

[0587] Position [°2θ] d(Angle) strength[%] 6.0 14.7036 100 11.6 7.6195 10 12.1 7.3357 32.3 13.6 6.5115 2.1 14.6 6.0801 3.1 15.6 5.66 2 16.1 5.514 0.6 17.6 5.0376 4.5 18.1 4.8948 12.5 19.8 4.4702 1 20.1 4.4033 3.3 20.8 4.2687 0.2 21.1 4.2034 1.3 21.9 4.0542 2.2 22.2 4.0022 4.2 22.6 3.9386 0.5 23.0 3.8694 0.3 23.5 3.7822 1.2 24.3 3.6649 0.3 25.1 3.5465 1.8 26.9 3.3177 1.9 27.4 3.2583 3 28.3 3.1563 0.9 29.4 3.0401 0.9

[0588] Figure 12 An XRPD plot of form B of compound 3 was depicted.

[0589] Figure 13 The TG / DTA traces of form B of compound 3 were depicted.

[0590] Example 5 - Preparation of form A of compound 4

[0591]

[0592] Form A of compound 4

[0593] Compound 4 was prepared in form A as described above.

[0594] Table 6 (as above) reproduces and lists the X-ray diffraction peaks observed in form A of compound 4 below.

[0595] Table 6 - XRPD peak positions of form A of compound 4

[0596]

[0597]

[0598] Figure 14 An XRPD plot of compound 4 in form A was depicted.

[0599] Figure 15 The TG / DTA trace of compound 4 in form A was depicted.

[0600] Example 6 - Preparation of form A of compound 5

[0601]

[0602] Form A of compound 5

[0603] Compound 5 was prepared in form A as described above.

[0604] Table 7 (as above) reproduces and lists the X-ray diffraction peaks observed in form A of compound 5 below.

[0605] Table 7 - XRPD peak positions of form A of compound 5

[0606]

[0607] Figure 16 An XRPD plot of compound 5 in form A was depicted.

[0608] Figure 17 The TG / DTA trace of form A of compound 5 was depicted.

[0609] Example 7 - Preparation of compounds 6 in forms A and B

[0610]

[0611] Where X is approximately 1 or 2.

[0612] Form A of compound 6

[0613] Compound 6 in form A was prepared as described above. The determination of compound 6 in form A showed that it contained compound A and ethanedisulfonic acid in an approximately 1:1 ratio.

[0614] Table 8 (as above) reproduces and lists the X-ray diffraction peaks observed in form A of compound 6 below.

[0615] Table 8 - XRPD peak positions of form A of compound 6

[0616]

[0617] Figure 18 An XRPD plot of compound 6 in form A was depicted.

[0618] Figure 19 The TG / DTA trace of compound 6 in form A was depicted.

[0619] Form B of compound 6

[0620] Compound 6 in form B was prepared as described above. The determination of compound 6 in form B showed that it contained compound A and ethanedisulfonic acid in a ratio of approximately 2:1.

[0621] Table 9 (as above) reproduces and lists the X-ray diffraction peaks observed in form B of compound 6 below.

[0622] Table 9 - XRPD peak positions of form B of compound 6

[0623]

[0624] Figure 20 An XRPD plot of form B of compound 6 was depicted.

[0625] Figure 21 The TG / DTA trace of form B of compound 6 was depicted.

[0626] Example 8 - Preparation of form A of compound 7

[0627]

[0628] Form A of compound 7

[0629] Compound 7 was prepared in form A as described above.

[0630] Table 10 (as above) reproduces and lists the X-ray diffraction peaks observed in form A of compound 7 below.

[0631] Table 10 - XRPD peak positions of form A of compound 7 (Compound 7)

[0632]

[0633] Figure 22 An XRPD plot of compound 7 in form A was depicted.

[0634] Figure 23 The TG / DTA trace of form A of compound 7 was depicted.

[0635] Example 9 - Solubility Study

[0636] Solubility studies of compounds A (form B), 1 (form B), 2 (form A), 3 (form B), and 4 (form A) were conducted in water, fasting-state simulated intestinal fluid (FaSSIF), fed-state simulated intestinal fluid (FeSSIF), and fasting-state simulated gastric fluid (FaSSGF). The simulated fluids were sourced from biorelevant.com and prepared according to their use of FaSSIF / FeSSIF / FaSSGF powders (v1, formerly known as SIF powder). Samples were prepared by adding excess solids to 5 mL of medium at 37 °C. Samples were extracted and filtered at 30 min, 120 min, and 24 h, and solution concentrations were determined using the HPLC parameters described in Table 13 below.

[0637] Table 13 - HPLC Parameters

[0638]

[0639]

[0640] The pH value of the samples was also measured at each time point; due to the small sample size, pH test strips were used at 30 and 120 minutes, and a pH meter was used at 24 hours. After 24 hours, the remaining material from all tests was analyzed by XRPD to determine if any polymorphic form changes occurred. After 24 hours, the remaining material from the water tests was analyzed by NMR to determine if dissociation occurred. Due to low material availability, compound 1 form B did not pass NMR analysis at 24 hours. The results are shown in Table 14 below.

[0641] Table 14 - Solubility Study

[0642]

[0643] It can be seen that compound form A and compound form B showed the highest solubility in FeSSIF at 24 hours.

[0644] Example 10 - Stability Study

[0645] Stability studies were conducted on compounds A (form B), Compound 1 (form B), Compound 2 (form A), Compound 3 (form B), and Compound 4 (form A) at 40°C and 75% relative humidity. Samples were stored in loosely capped vials in a chamber containing a saturated sodium chloride solution to achieve approximately 75% relative humidity within the chamber. The chamber was then stored in an oven at 40°C. Samples were analyzed using the HPLC parameters described in Table 13 at times 0, 1, 2, and 4 weeks. The results are shown in Table 15 below.

[0646] Table 15 - Stability Study

[0647]

[0648] *1mg / mL

[0649] Overall, significant degradation of compound 3 form B was observed over time. The solid at the end of the study was confirmed to have lost all crystallinity and become X-ray amorphous. Compound A form B and compound 1 form B appeared equally stable at 40 °C / 75% relative humidity. Compound 4 form A showed degradation at 1 and 2 weeks, but the degradation peak was no longer present at 4 weeks, which improved the area percentage of the main peak. Compound 2 form A was fairly stable under these accelerated conditions, losing only about 1.5% of its area over four weeks.

[0650] While we have described many embodiments of the invention, it will be apparent that our basic examples can be modified to provide other embodiments utilizing the compounds and methods of the invention. Therefore, it should be understood that the scope of the invention is defined by this application and the claims, and not by the specific embodiments illustrated by example.

Claims

1. A crystalline form of compound 2, 2 Where x = 2, and the crystalline form is form A, which is characterized by having peaks at the following positions in its XRPD: 。 2. The crystalline form according to claim 1, wherein the crystalline form is substantially free of amorphous compound 2.

3. The crystalline form according to claim 1 or 2, wherein the crystalline form is substantially free of impurities.

4. The crystalline form according to claim 1 or 2, having a substantially similar XRPD as depicted in Figure 8.

5. A composition comprising a crystalline form according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

6. A composition comprising a crystalline form according to any one of claims 1 to 4 and a pharmaceutically acceptable excipient.

7. Use of a crystalline form according to any one of claims 1 to 4 or a composition according to claim 5 or 6 in the preparation of a medicament for inhibiting AHR in patients in need.

8. A method for inhibiting AHR in a biological sample, comprising contacting the biological sample with a crystalline form according to any one of claims 1 to 4 or a composition according to claim 5 or 6.

9. Use of a crystalline form according to any one of claims 1 to 4 or a composition according to claim 5 or 6 in the preparation of a medicament for treating AHR-mediated conditions in patients in need.

10. The use according to claim 9, wherein the AHR-mediated condition is cancer.

11. The use according to claim 9, wherein the AHR-mediated condition is an inflammatory condition.

12. The use according to claim 9, wherein the compound or composition is administered orally.

13. The use according to claim 9, wherein an additional therapeutic agent is further administered to the patient.

14. A method for preparing the crystalline form according to claim 1 or 2, Includes the following steps: Compound A: A Combined with maleic acid and optional solvents.

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