Polymorphic carbazole derivatives and their uses

Abstract

The present invention relates to a free base and salt form, a composition, and a method useful for treating various pathological conditions associated with AHR by administering a small molecule therapeutic agent acting as an inhibitor of aryl hydrocarbon receptor (AHR).

Description

Technology Field

[0001] Cross-reference of related patents

[0002] This application claims the benefit of 35 USC § 119(e) of U.S. Provisional Patent Application No. 62 / 940,481 filed November 26, 2019, the entire contents of which are incorporated herein by reference.

[0003] Technology field

[0004] The present application relates to various forms and compositions and methods useful for treating various pathological conditions associated with aryl hydrocarbon receptors (AHR) by administering small molecule therapeutic agents that act as inhibitors of AHR. Background Technology

[0005] The aryl hydrocarbon receptor (AHR) is a transcription factor that exists in an inactive, ligand-free state in the cytoplasm bound to HSP90. Upon ligand binding, AHR translocates to the nucleus, where it is dimerized by ARNT to form a functional transcription factor. AHR / ARNT binds the dioxin response element (DRE) to the promoters of numerous genes that regulate gene transcription. The best-known genes regulated by AHR are the cytochrome P450 genes Cyp1b1 and Cyp1a1, and AHR activation significantly increases the expression of these genes. Therefore, Cyp1b1 and Cyp1a1 mRNA levels are selective readouts of AHR activation (Reference: Murray). et al. , 2014).

[0006] There are numerous exogenous and endogenous agonists of AHR that activate the receptor. The most well-identified class of exogenous ligands is dioxins. One of the primary endogenous ligands that needs to be identified is kynurenine, which is produced by TDO (Opitz 2011) or IDO (Mezrich 2010). Kynurenine is a stable metabolite in the IDO / TDO pathway and a product of tryptophan degradation. Like other DRE-driven genes, kynurenine has been shown to activate AHR, as measured by increased Cyp1a1 and / or Cyp1b1 mRNA levels in many cell types.

[0007] AHR activation exerts a pro-tumor effect by acting directly on tumor cells and indirectly inducing immunosuppression, thereby preventing the body's own immune system from attacking the tumor. For example, AHR activation via multiple ligands increases FoxP3 expression and leads to the polarization of CD4+ T-cells toward a repressive subset called FoxP3+ T-regulatory cells (Tregs). These T-reg cells inhibit the proliferation of activated T cells (Funatake 2005, other refs). Interestingly, kynurenine has been shown to induce immunosuppressive Tregs via AHR. Kynurenine does not affect T-reg development in AHR-null T cells or when AHR antagonists are added (Mezrich). In addition to T-regs, AHR activation also leads to the expansion of repressive Tr1 T cells (Gandhi 2010). Furthermore, it has been shown that IDO expression is regulated by AHR activation in both tumor cells and T cells, thereby increasing immunosuppression (Vogel). There may also be a role for AHR in immunosuppressed myeloid cells (Nguyen 2013). Immunosuppression is often associated with high concentrations of anti-inflammatory cytokines, and there is evidence that AHR is involved in the activation of several of these cytokines, such as IL-10 (Gandhi 2010, Wagage 2014).

[0008] There remains an unmet need to develop AHR inhibitors to treat related diseases, disorders, and pathological conditions.

[0009] In the present invention, the compounds and compositions thereof have been found to be useful for the treatment, prevention, and / or reduction of diseases, disorders, or conditions associated with the onset of aldehyde toxicity. In general, salt forms or free base forms and pharmaceutically acceptable compositions thereof are useful for the treatment or alleviation of various severe diseases or disorders, as disclosed herein in detail. These compounds are represented by the following chemical formulas, which are compounds A It is said:

[0010]

[0011] The compounds of the present invention and pharmaceutically acceptable compositions thereof are useful for the treatment of various diseases, disorders, or conditions associated with AHR. Such diseases, disorders, or conditions include those disclosed herein.

[0012] The compounds provided in the present invention are also useful for the study of AHR in biological and pathological phenomena; the study of intracellular signaling pathways; and the comparative evaluation of novel AHR inhibitors in vitro or in vivo. Brief explanation of the drawing

[0013] do 1 silver compounds A , illustrates the XRPD pattern of type B. do 2 is a compound A , illustrates the TG / DTA trace of type B. do 3 silver compounds A , illustrates the XRPD pattern of type C. do 4 is a compound A , illustrates the TG / DTA trace of type C. do 5 is a compound 1 , illustrates the XRPD pattern of type A. do 6 silver compounds 1 , plots the TG / DTA trace of Type A. do7 silver compounds 1 , illustrates the XRPD pattern of type B. do 8 silver compounds 2 , illustrates the XRPD pattern of type A. do 9 is a compound 2 , plots the TG / DTA trace of Type A. do 10 silver compounds 3 , illustrates the XRPD pattern of type A. do 11 silver compounds 3 , plots the TG / DTA trace of Type A. do 12 is a compound 3 , illustrates the XRPD pattern of type B. do 13 silver compounds 3 , plots the TG / DTA trace of type B. do 14 is a compound 4 , illustrates the XRPD pattern of type A. do 15 is a compound 4 , plots the TG / DTA trace of Type A. do 16 silver compounds 5 , illustrates the XRPD pattern of type A. do 17 silver compounds 5 , plots the TG / DTA trace of Type A. do 18 silver compounds 6 , illustrates the XRPD pattern of type A. do 19 is a compound 6 , plots the TG / DTA trace of Type A. do 20 silver compounds 6 , illustrates the XRPD pattern of type B. do 21 silver compounds 6 , plots the TG / DTA trace of type B. do 22is a compound 7 , illustrates the XRPD pattern of type A. do 23 silver compounds 7 , plots the TG / DTA trace of Type A. do 24 is a compound A The XRPD pattern of a mixture of type A and type B is illustrated. do 25 is a compound A Figures the TG / DTA traces of a mixture of type A and type B. Specific details for implementing the invention

[0014] General description of specific aspects of the present invention

[0015] U.S. Patent Application 15 / 958,586 filed on April 20, 2018, i.e., U.S. Published Patent Application 2018-0327411, disclosed on November 15, 2018 ("'411", the full contents of which are incorporated herein by reference), discloses specific AHR inhibitory compounds. These compounds are compounds A Includes:

[0016]

[0017] compound A (3R)-N-[2-(5-fluoro-3-pyridyl)-8-isopyridyl-pyrazolo[1,5-a][1,3,5]triazine-4-yl]-2,3,4,9-tetrahydro-1H-carbazole-3-amine is described 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 re-prepared herein for convenience of reference.

[0018] compound A It is desirable to provide a solid form of (e.g., as its free base or its salt), which imparts properties such as improved water solubility, stability, and ease of formulation. Accordingly, the present invention relates to a compound A It provides both the free base and salt forms of:

[0019]

[0020] compound A free base form of

[0021] compound A It is considered to be able to exist in various physical forms. For example, compounds A It may be in a liquid or suspension, or in solid form. In certain embodiments, the compound A It is in solid form. Compound A If is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in detail below.

[0022] In some embodiments, the present invention relates to a specific type of compound that is substantially free of impurities. A Provides. As used herein, the term "substantially free of impurities" means that said compound contains an insignificant amount of external substance. Such external substance is a compound of different forms. A , residual solvent, or compound A It may contain any other impurities that may be generated from the manufacture and / or isolation of. In certain embodiments, at least about 95 weight percent of the compound A The form exists. In another aspect of the present invention, at least about 99 weight percent of the compound A The form of exists.

[0023] Depending on one mode, compound A The form is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8% by weight based on the total weight of the composition. According to another embodiment, the compound AThe form contains, with respect to the total area of ​​the HPLC chromatogram, about 3.0 area% or less of total organic impurities in the HPLC, and in certain embodiments, about 1.5 area% or less of total organic impurities in the HPLC. In other embodiments, the compound A The form contains any single impurity of HPLC at about 1.0 area% or less, any single impurity of HPLC at about 0.6 area% or less, and in a specific embodiment, any single impurity of HPLC at about 0.5 area% or less, with respect to the total area of ​​the HPLC chromatogram.

[0024] compound A The structure depicted for the form of is a compound A It also means that it includes all tautomeric forms of. Furthermore, the structures described herein also mean that they include different compounds only in the presence of one or more isotope-enriched atoms. For example, hydrogen is replaced by deuterium or tritium, or carbon 13 C- or 14 Compounds having the structure of the present invention are within the scope of the present invention, except that they are replaced with C-rich carbon.

[0025] compound A It has been found that it can exist in various solid forms. Examples of these forms include polymorphs as described herein.

[0026] As used herein, the term "polymorph" refers to a different crystal structure in which a compound, or its salt or solvate, can be crystallized.

[0027] In a specific mode, a compound A is a crystalline solid. In another embodiment, a compound A is an amorphous compound A It is a crystalline solid that substantially does not contain. The term "amorphous compound" as used herein A "Substantially not containing" refers to an insignificant amount of the above compound, an amorphous compound AIt means containing. In certain embodiments, at least about 95 weight percent of a crystalline compound A is present. In another aspect of the present invention, at least about 99 weight percent of a crystalline compound A There exists.

[0028] compound A It has been found that it can exist in at least three distinct polymorphic forms. In certain embodiments, the present invention relates to a compound referred herein as Type A. A The present invention provides a polymorphic form of. In certain embodiments, the present invention provides a compound referred herein as type B. A The present invention provides a polymorphic form of. In certain embodiments, the present invention provides a compound A The present invention provides a mixture of types A and B of the compound. In certain embodiments, the present invention provides a compound referred herein as type C. A It provides polymorphic forms of.

[0029] In some embodiments, compounds A is amorphous. In some embodiments, the compound A is amorphous, and a crystalline compound A It does not substantially contain.

[0030] compound A Type B

[0031] In some embodiments, compounds A Type B of has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from those listed in Table B.

[0032]

[0033] In some embodiments, compounds A The B form of is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 9.5, about 9.8, and about 14.7 degrees 2-theta. In some embodiments, the compound AType B of is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 9.5, about 9.8, and about 14.7 degrees 2-theta. In some embodiments, the compound A Type B is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at about 9.5, about 9.8, and about 14.7 degrees 2-theta.

[0034] In a specific mode, a compound A The X-ray powder diffraction pattern of type B is substantially similar to the XRPD provided in Fig. 1.

[0035] compound A The manufacturing method of Type B is described later.

[0036] compound A Type C

[0037] In some embodiments, compounds A Type C of has at least 1, 2, 3, 4, or 5 spectral peaks selected from those listed in Table C.

[0038]

[0039]

[0040] In some embodiments, compounds A The C-type of is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.02, about 8.61, and about 10.29 degrees 2-theta. In some embodiments, the compound A The C-type of is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.02, about 8.61, and about 10.29 degrees 2-theta. In some embodiments, the compound AType C is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at approximately 6.02, approximately 8.61, and approximately 10.29 degrees 2-theta.

[0041] In a specific mode, a compound A The X-ray powder diffraction pattern of type C is substantially similar to the XRPD provided in Fig. 3.

[0042] compound A The manufacturing method of Type C is described later.

[0043] compound A A mixture of Type A and Type B of

[0044] In some embodiments, the present invention relates to a compound A A mixture of type A and type B is provided, which has an X-ray powder diffraction pattern similar to the XRPD provided in Fig. 24.

[0045] In some embodiments, compounds A A mixture of types A and B of has a TGA similar to the TGA provided in FIG. 25. In some embodiments, the compound A A mixture of type A and type B has a DSC similar to the DSC provided in Fig. 25.

[0046] compound A A method for preparing a mixture of Type A and Type B is described below.

[0047] In some embodiments, the present invention relates to a compound A It provides, and the above compound is crystalline.

[0048]

[0049] In some embodiments, the present invention relates to a compound A It provides, and the compound is an amorphous compound A It does not substantially contain.

[0050] In some embodiments, the present invention relates to a compound A It provides, and the compound substantially contains no impurities.

[0051] In some embodiments, the present invention relates to a compound A It provides, and the compound has an XRPD substantially similar to that shown in FIG. 1.

[0052] In some embodiments, the present invention relates to a compound A It provides, and the compound has an XRPD substantially similar to that shown in FIG. 3.

[0053] In some embodiments, the present invention relates to a compound A It provides, and the compound has an XRPD substantially similar to that shown in FIG. 24.

[0054] In some embodiments, the present invention relates to a compound A A composition comprising a pharmaceutically acceptable carrier or excipient is provided.

[0055] In some embodiments, the present invention provides a compound to a patient. A The present invention provides a method for inhibiting AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to a patient. A The present invention provides a method for inhibiting the AHR of said patient, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to the patient. A A method for treating one or more disorders related to the activity of AHR is provided, comprising administering a composition thereof.

[0056] In some embodiments, the present invention provides a compound to a patient requiring treatment for an AHR-mediated disorder. A The present invention provides a method for treating an AHR-mediated disorder, comprising the step of administering a composition thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease such as cancer or an inflammatory disorder.

[0057] Salt form of compound A

[0058] In some embodiments, acids and compounds A ionically bonded, the compound described below 1inside 7 Forms one of the compounds. 1 inside 7 It is considered to be able to exist in various physical forms. For example, compounds 1 inside 7 silver It may be in a liquid or suspension, or in solid form. In certain embodiments, a compound 1 inside 7 It is in solid form. Compound 1 inside 7 If this is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Compound 1 inside 7 Examples of such solid forms are disclosed in more detail below.

[0059] compound 1 (compound A esylate salts)

[0060] According to one embodiment, the present invention relates to a compound A It provides an esylate salt of, which is a compound 1 Represented as:

[0061]

[0062] Those skilled in the art, ethanesulfonic acid and compounds A A compound formed by ionic bonding 1 You will know that it forms a compound 1 It is considered to be able to exist in various physical forms. For example, compounds 1 It may be in a liquid or suspension, or in solid form. In certain embodiments, the compound 1 It is in solid form. Compound 1 In this solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in detail below.

[0063] In some embodiments, the present invention relates to a compound that is substantially free of impurities.1 Provides. As used herein, the term "substantially free of impurities" means that said compound contains an insignificant amount of external substance. Such external substance is an excess of methanesulfonic acid, an excess of compound A , residual solvent, or compound 1 It may contain any other impurities that may be generated from the manufacture and / or isolation of. In certain embodiments, at least about 95 weight percent of the compound 1 This exists. In another aspect of the present invention, at least about 99 weight percent of the compound 1 This exists.

[0064] Depending on one mode, compound 1 Silver is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8% by weight based on the total weight of the composition. According to another embodiment, the compound 1 It contains, with respect to the total area of ​​the HPLC chromatogram, about 3.0 area% or less of total organic impurities in the HPLC, and in certain embodiments, about 1.5 area% or less of total organic impurities in the HPLC. In other embodiments, the compound 1 It contains any single impurity of HPLC at about 1.0 area% or less with respect to the total area of ​​the HPLC chromatogram, any single impurity of HPLC at about 0.6 area% or less, and in certain embodiments, any single impurity of HPLC at about 0.5 area% or less.

[0065] compound 1 The structure described for is a compound 1 It also means that it includes all tautomeric forms of. Furthermore, the structures described herein also mean that they include different compounds only in the presence of one or more isotope-enriched atoms. For example, hydrogen is replaced by deuterium or tritium, or carbon 13 C- or 14Compounds having the structure of the present invention are within the scope of the present invention, except that they are replaced with C-rich carbon.

[0066] compound 1 It has been found that it can exist in various solid forms. Examples of these forms include polymorphs as described herein.

[0067] In a specific mode, a compound 1 It is a crystalline solid. In other embodiments, the compound 1 amorphous compounds 1 It is a crystalline solid that substantially does not contain. The term "amorphous compound" as used herein 1 "Substantially not containing" refers to an insignificant amount of the above compound, an amorphous compound 1 It means containing. In certain embodiments, at least about 95 weight percent of a crystalline compound 1 This exists. In another aspect of the present invention, at least about 99 weight percent of a crystalline compound 1 This exists.

[0068] compound 1 It has been found that it may exist in at least one distinct polymorphic form. In some embodiments, the present invention relates to a compound referred herein as type A. 1 The present invention provides a polymorphic form of. In some embodiments, the present invention provides a compound referred herein as type B. 1 It provides polymorphic forms of.

[0069] In some embodiments, compounds 1 It is amorphous. In some embodiments, the compound 1 It is amorphous, and a crystalline compound 1 It does not substantially contain.

[0070] compound 1 Type A

[0071] In some embodiments, compounds 1Type A of has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from those listed in Table 1.

[0072]

[0073] In some embodiments, compounds 1 Type A of is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.8, about 11.6, and about 18.8 degrees 2-theta. In some embodiments, the compound 1 Type A of is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.8, about 11.6, and about 18.8 degrees 2-theta. In some embodiments, the compound 1 Type A is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at approximately 5.8, approximately 11.6, and approximately 18.8 degrees 2-theta.

[0074] In a specific embodiment, the X-ray powder diffraction pattern is 5 It is substantially similar to the XRPD provided.

[0075] compound 1 The manufacturing method of Type A is described later.

[0076] compound 1 Type B

[0077] In some embodiments, compounds 1 Type B of has at least 1, 2, 3, 4, or 5 spectral peaks selected from those listed in Table 2.

[0078]

[0079] In some embodiments, compounds 1 The B form of is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.6, about 11.2, and about 16.9 degrees 2-theta. In some embodiments, the compound1 The B form of is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.6, about 11.2, and about 16.9 degrees 2-theta. In some embodiments, the compound 1 Type B is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at approximately 5.6, approximately 11.2, and approximately 16.9 degrees 2-theta.

[0080] In a specific embodiment, the X-ray powder diffraction pattern is 7 It is substantially similar to the XRPD provided.

[0081] compound 1 The manufacturing method of Type B is described later.

[0082] In some embodiments, the present invention relates to a compound 1 provides:

[0083]

[0084] In some embodiments, the present invention relates to a compound 1 It provides, and the above compound is crystalline.

[0085] In some embodiments, the present invention relates to a compound 1 It provides, and the compound is an amorphous compound 1 It is a crystalline solid that substantially does not contain.

[0086] In some embodiments, the present invention relates to a compound 1 It provides, and the compound substantially contains no impurities.

[0087] In some embodiments, the present invention relates to a compound 1 The present invention provides, wherein the compound has one or more peaks in its XRPD selected from those at 5.8, about 11.6, and about 18.8 degrees at 2-theta. In some such embodiments, the present invention provides a compound 1The present invention provides, wherein the compound has at least two peaks in its XRPD selected from those at about 5.8, about 11.6, and about 18.8 degrees at 2-theta. In some such embodiments, the present invention provides a compound 1 It provides, and the above compound is of type A.

[0088] In some embodiments, the present invention relates to a compound 1 It provides, and the above compound also 5 It has an XRPD substantially similar to that described in.

[0089] In some embodiments, the present invention relates to a compound 1 The present invention provides, wherein the compound has one or more peaks in its XRPD selected from those at 5.6, about 11.2, and about 16.9 degrees at 2-theta. In some such embodiments, the present invention provides a compound 1 The invention provides, wherein the imaginary compound has at least two peaks in its XRPD selected from those at about 5.6, about 11.2, and about 16.9 degrees at 2-theta. In some such embodiments, the present invention provides a compound 1 It provides, and the above compound is of type B.

[0090] In some embodiments, the present invention relates to a compound 1 It provides, and the above compound also 7 It has an XRPD substantially similar to that described in.

[0091] In some embodiments, the present invention relates to a compound 1 A composition comprising a pharmaceutically acceptable carrier or excipient is provided.

[0092] In some embodiments, the present invention provides a compound to a patient. 1 The present invention provides a method for inhibiting AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to a patient. 1 The present invention provides a method for inhibiting a patient's AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to the patient.1 A method for treating one or more disorders related to AHR activity is provided, comprising administering a composition thereof.

[0093] In some embodiments, the present invention provides a compound to a patient requiring treatment for an AHR-mediated disorder. 1 The present invention provides a method for treating an AHR-mediated disorder, comprising the step of administering a composition thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease such as cancer or an inflammatory disorder.

[0094] compound 2 (compound A maleate salt)

[0095] According to one embodiment, the present invention relates to a compound A It provides the maleate salt of, which is a compound 2 Represented as:

[0096]

[0097] Here, approximately 1 ≤ x ≤ approximately 2.

[0098] Those skilled in the art, maleic acid and compounds A A compound formed by ionic bonding 2 You will know that it forms. In some embodiments, the compound A and maleic acid are in a ratio of about 1:1. In some embodiments, the compound A and maleic acid are in a ratio of approximately 2:1. Compound 2 It is considered to be able to exist in various physical forms. For example, compounds 2 It may be in a liquid or suspension, or in solid form. In certain embodiments, the compound 2 It is in solid form. Compound 2 If is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in detail below.

[0099] In some embodiments, the present invention relates to a compound that is substantially free of impurities. 2 Provides. As used herein, the term "substantially free of impurities" means that the compound contains an insignificant amount of external substance. Such external substance is an excess of benzenesulfonic acid, an excess of the compound A , residual solvent, or compound 2 It may contain any other impurities that may be generated from the manufacture and / or isolation of. In certain embodiments, at least about 95 weight percent of the compound 2 is present. In another aspect of the present invention, at least about 99 weight percent of the compound 2 There exists.

[0100] Depending on one mode, compound 2 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight% based on the total weight of the composition. According to another embodiment, the compound 2 It contains about 3.0 area% or less of total organic impurities in the HPLC with respect to the total area of ​​the HPLC chromatogram, and in certain embodiments, about 1.5 area% or less of total organic impurities in the HPLC. In other embodiments, the compound 2 It contains any single impurity of HPLC at about 1.0 area% or less with respect to the total area of ​​the HPLC chromatogram, any single impurity of HPLC at about 0.6 area% or less, and in certain embodiments, any single impurity of HPLC at about 0.5 area% or less.

[0101] compound 2 The structure described for is a compound 2 It also means that it includes all tautomeric forms of. Furthermore, the structures described herein also mean that they include different compounds only in the presence of one or more isotope-enriched atoms. For example, hydrogen is replaced by deuterium or tritium, or carbon 13 C- or 14Compounds having the structure of the present invention are within the scope of the present invention, except that they are replaced with C-rich carbon.

[0102] compound 2 It has been found that it may exist in at least one distinct polymorphic form. In some embodiments, the present invention relates to a compound referred herein as type A. 2 It provides polymorphic forms of. In some embodiments, the compound 2 Type A is a compound A It contains maleic acid in a ratio of about 2:1.

[0103] In a specific mode, a compound 2 is a crystalline solid. In another embodiment, a compound 2 is an amorphous compound 2 It is a crystalline solid that substantially does not contain. The term "amorphous compound" as used herein 2 "Substantially not containing" refers to an insignificant amount of the above compound, an amorphous compound 2 It means containing. In certain embodiments, at least about 95 weight percent of a crystalline compound 2 is present. In another aspect of the present invention, at least about 99 weight percent of a crystalline compound 2 There exists.

[0104] compound 2 It has been found that it may exist in at least one distinct polymorphic form. In some embodiments, the present invention relates to a compound referred herein as type A. 2 It provides polymorphic forms of.

[0105] In some embodiments, compounds 2 is amorphous. In some embodiments, the compound 2 is amorphous, and a crystalline compound 2 It does not substantially contain.

[0106] compound 2 Type A

[0107] In some embodiments, compounds2 Type A of has at least 1, 2, 3, 4, or 5 spectral peaks selected from those listed in Table 3.

[0108]

[0109] In some embodiments, compounds 2 Type A of is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.3, about 11.3, and about 16.0 degrees 2-theta. In some embodiments, the compound 2 Type A of is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.3, about 11.3, and about 16.0 degrees 2-theta. In some embodiments, the compound 2 Type A is characterized by having all three peaks in its X-ray powder diffraction pattern, selected from those at approximately 5.3, approximately 11.3, and approximately 16.0 degrees 2-theta.

[0110] In a specific embodiment, the X-ray powder diffraction pattern is 9 It is substantially similar to the XRPD provided.

[0111] compound 2 The manufacturing method of Type A is described later.

[0112] In some embodiments, the present invention relates to a compound 2 It provides.

[0113]

[0114] Here, approximately 1 ≤ x ≤ approximately 2.

[0115] In some embodiments, the present invention relates to a compound 2 It provides, and the above compound is crystalline.

[0116] In some embodiments, the present invention relates to a compound 2 It provides, and the compound is an amorphous compound 2 It is a crystalline solid that substantially does not contain.

[0117] In some embodiments, the present invention relates to a compound 2 It provides, and the compound substantially contains no impurities.

[0118] In some embodiments, the present invention relates to a compound 2 The present invention provides, wherein the compound has one or more peaks in its XRPD selected from those at about 5.3, about 11.3, and about 16.0 degrees 2-theta. In some such embodiments, the present invention provides a compound 2 The present invention provides, wherein the compound has at least two peaks in its XRPD selected from those at about 5.3, about 11.3, and about 16.0 degrees at 2-theta. In some such embodiments, the present invention provides a compound 2 It provides, said compound is of type A. In some embodiments, the compound 2 Type A is a compound A It contains maleic acid in a ratio of about 2:1.

[0119] In some embodiments, the present invention relates to a compound 2 It provides, and the above compound also 9 It has an XRPD substantially similar to that described in.

[0120] In some embodiments, the present invention relates to a compound 2 A composition comprising a pharmaceutically acceptable carrier or excipient is provided.

[0121] In some embodiments, the present invention provides a compound to a patient. 2 The present invention provides a method for inhibiting AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to a patient. 2 The present invention provides a method for inhibiting a patient's AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to the patient. 2 A method for treating one or more disorders related to the activity of AHR is provided, comprising administering a composition thereof.

[0122] In some embodiments, the present invention provides a compound to a patient requiring treatment for an AHR-mediated disorder. 2 The present invention provides a method for treating an AHR-mediated disorder, comprising the step of administering a composition thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease such as cancer or an inflammatory disorder.

[0123] compound 3 (compound A (Mesylate salt)

[0124] According to one embodiment, the present invention relates to a compound A It provides the mesylate salt of, which is a compound 3 Represented as:

[0125]

[0126] Those skilled in the art, methanesulfonic acid and compounds A A compound formed by ionic bonding 3 You will know that it forms a compound 3 It is considered to be able to exist in various physical forms. For example, compounds 3 It may be in a liquid or suspension, or in solid form. In certain embodiments, the compound 3 It is in solid form. Compound 3 If is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in detail below.

[0127] In some embodiments, the present invention relates to a compound that is substantially free of impurities. 3 Provides. As used herein, the term "substantially free of impurities" means that said compound contains an insignificant amount of external substance. Such external substance is an excess of sulfuric acid, an excess of compound A , residual solvent, or compound 3It may contain any other impurities that may be generated from the manufacture and / or isolation of. In certain embodiments, at least about 95 weight percent of the compound 3 This exists. In another aspect of the present invention, at least about 99 weight percent of the compound 3 This exists.

[0128] Depending on one mode, compound 3 Silver is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8% by weight based on the total weight of the composition. According to another embodiment, the compound 3 It contains about 3.0 area% or less of total organic impurities in the HPLC with respect to the total area of ​​the HPLC chromatogram, and in certain embodiments, about 1.5 area% or less of total organic impurities in the HPLC. In other embodiments, the compound 3 It contains any single impurity of HPLC at about 1.0 area% or less with respect to the total area of ​​the HPLC chromatogram, any single impurity of HPLC at about 0.6 area% or less, and in certain embodiments, any single impurity of HPLC at about 0.5 area% or less.

[0129] compound 3 The structure described for is a compound 3 It also means that it includes all tautomeric forms of. Furthermore, the structures described herein also mean that they include different compounds only in the presence of one or more isotope-enriched atoms. For example, hydrogen is replaced by deuterium or tritium, or carbon 13 C- or 14 Compounds having the structure of the present invention are within the scope of the present invention, except that they are replaced with C-rich carbon.

[0130] compound 3 It has been found that it can exist in at least two distinct polymorphic forms. In some embodiments, the present invention relates to a compound referred herein as type A. 3The present invention provides a polymorphic form of. In some embodiments, the present invention provides a compound referred herein as type B. 3 It provides polymorphic forms of.

[0131] In a specific mode, a compound 3 It is a crystalline solid. In other embodiments, the compound 3 amorphous compounds 3 It is a crystalline solid that substantially does not contain. The term "amorphous compound" as used herein 3 "Substantially not containing" refers to an insignificant amount of the above compound, an amorphous compound 3 It means containing. In certain embodiments, at least about 95 weight percent of a crystalline compound 3 This exists. In another aspect of the present invention, at least about 99 weight percent of a crystalline compound 3 This exists.

[0132] In some embodiments, compounds 3 It is amorphous. In some embodiments, the compound 3 It is amorphous, and a crystalline compound 3 It does not substantially contain.

[0133] compound 3 Type A

[0134] In some embodiments, compounds 3 Type A of has at least 1, 2, 3, 4, or 5 spectral peaks selected from those listed in Table 4.

[0135]

[0136] In some embodiments, compounds 3 Type A of is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.6, about 11.2, and about 16.9 degrees 2-theta. In some embodiments, the compound 3Type A of is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.6, about 11.2, and about 16.9 degrees 2-theta. In some embodiments, the compound 3 Type A is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at approximately 5.6, approximately 11.2, and approximately 16.9 degrees 2-theta.

[0137] In a specific embodiment, the X-ray powder diffraction pattern is 11 It is substantially similar to the XRPD provided.

[0138] compound 3 The manufacturing method of Type A is described later.

[0139] compound 3 Type B

[0140] In some embodiments, compounds 3 Type B of has at least 1, 2, 3, 4, or 5 spectral peaks selected from those listed in Table 5.

[0141]

[0142] In some embodiments, compounds 3 The B form of is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 12.1, and about 18.1 degrees 2-theta. In some embodiments, the compound 3 Type B is It is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.0, about 12.1, and about 18.1 degrees at 2-theta. In some embodiments, the compound 3 Type B is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at approximately 6.0, approximately 12.1, and approximately 18.1 degrees at 2-theta.

[0143] In a specific embodiment, the X-ray powder diffraction pattern is 13 It is substantially similar to the XRPD provided.

[0144] compound 3 The manufacturing method of Type B is described later.

[0145] In some embodiments, the present invention relates to a compound 3 provides:

[0146]

[0147] In some embodiments, the present invention relates to a compound 3 It provides, and the above compound is crystalline.

[0148] In some embodiments, the present invention relates to a compound 3 It provides, and the compound is an amorphous compound 3 It is a crystalline solid that substantially does not contain.

[0149] In some embodiments, the present invention relates to a compound 3 It provides, and the compound substantially contains no impurities.

[0150] In some embodiments, the present invention relates to a compound 3 The present invention provides, wherein the compound has one or more peaks in its XRPD selected from those at about 5.6, about 11.2, and about 16.9 degrees at 2-theta. In some such embodiments, the present invention provides a compound 3 The present invention provides, wherein the compound has at least two peaks in its XRPD selected from those at about 5.6, about 11.2, and about 16.9 degrees at 2-theta. In some such embodiments, the present invention provides a compound 3 It provides, and the above compound is of type A.

[0151] In some embodiments, the present invention relates to a compound 3 It provides, and the above compound also 11 It has an XRPD substantially similar to that described in.

[0152] In some embodiments, the present invention relates to a compound3 The compound provides, wherein the compound has one or more peaks in its XRPD selected from those at about 6.0, about 12.1, and about 18.1 degrees at 2-theta. In some of these embodiments, the present invention provides a compound 3 The present invention provides a compound having at least two peaks in its XRPD selected from those at about 6.0, about 12.1, and about 18.1 degrees at 2-theta. In some of these embodiments, the present invention provides a compound 3 It provides, and the above compound is of type B.

[0153] In some embodiments, the present invention relates to a compound 3 It provides, and the above compound also 13 It has an XRPD substantially similar to that described in.

[0154] In some embodiments, the present invention relates to a compound 3 A composition comprising a pharmaceutically acceptable carrier or excipient is provided.

[0155] In some embodiments, the present invention provides a compound to a patient. 3 The present invention provides a method for inhibiting AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to a patient. 3 The present invention provides a method for inhibiting a patient's AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to the patient. 3 A method for treating one or more disorders related to the activity of AHR is provided, comprising administering a composition thereof.

[0156] In some embodiments, the present invention provides a compound to a patient requiring treatment for an AHR-mediated disorder. 3 The present invention provides a method for treating an AHR-mediated disorder, comprising the step of administering a composition thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease such as cancer or an inflammatory disorder.

[0157] compound 4 (compound A (Lead silate salt)

[0158] According to one embodiment, the present invention relates to a compound A It provides a lead silate salt of, which is a compound 4 Represented as:

[0159]

[0160] Those skilled in the art, naphthalenesulfonic acid and compounds A A compound formed by ionic bonding 4 You will know that it forms a compound 4 It is considered to be able to exist in various physical forms. For example, compounds 4 It may be in a liquid or suspension, or in solid form. In certain embodiments, the compound 4 It is in solid form. Compound 4 If is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in detail below.

[0161] In some embodiments, the present invention relates to a compound that is substantially free of impurities. 4 It provides. As used herein, the term "substantially free of impurities" means that said compound contains an insignificant amount of external substance. Such external substance is an excess of p - Toluenesulfonic acid, excess compound A , residual solvent, or compound 4 It may contain any other impurities that may be generated from the manufacture and / or isolation of. In certain embodiments, at least about 95 weight percent of the compound 4 is present. In another aspect of the present invention, at least about 99 weight percent of the compound 4 There exists.

[0162] Depending on one mode, compound 4is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight% based on the total weight of the composition. According to another embodiment, the compound 4 It contains, with respect to the total area of ​​the HPLC chromatogram, about 3.0 area% or less of total organic impurities in the HPLC, and in certain embodiments, about 1.5 area% or less of total organic impurities in the HPLC. In other embodiments, the compound 4 It contains any single impurity of HPLC at about 1.0 area% or less, any single impurity of HPLC at about 0.6 area% or less, and in certain embodiments, any single impurity of HPLC at about 0.5 area% or less, with respect to the total area of ​​the HPLC chromatogram.

[0163] compound 4 The structure described for is a compound 4 It also means that it includes all tautomeric forms of. Furthermore, the structures described herein also mean that they include different compounds only in the presence of one or more isotope-enriched atoms. For example, hydrogen is replaced by deuterium or tritium, or carbon 13 C- or 14 Compounds having the structure of the present invention are within the scope of the present invention, except that they are replaced with C-rich carbon.

[0164] compound 4 It has been found that it can exist in at least one solid form. Examples of such forms include polymorphs as described herein.

[0165] compound 4 It has been found that it may exist in at least one distinct polymorphic form. In some embodiments, the present invention relates to a compound referred herein as type A. 4 It provides polymorphic forms of.

[0166] In a specific mode, a compound 4 is a crystalline solid. In another embodiment, a compound4 is an amorphous compound 4 It is a crystalline solid that substantially does not contain. The term "amorphous compound" as used herein 4 "Substantially not containing" refers to an insignificant amount of the above compound, an amorphous compound 4 It means containing. In certain embodiments, at least about 95 weight percent of a crystalline compound 4 is present. In another aspect of the present invention, at least about 99 weight percent of a crystalline compound 4 There exists.

[0167] In some embodiments, compounds 4 is amorphous. In some embodiments, the compound 4 is amorphous, and a crystalline compound 4 It does not substantially contain.

[0168] compound 4 Type A

[0169] In some embodiments, compounds 4 Type A of has at least 1, 2, 3, 4, or 5 spectral peaks selected from those listed in Table 6.

[0170]

[0171] In some embodiments, compounds 4 Type A of is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 7.5, about 8.4, and about 20.1 degrees 2-theta. In some embodiments, the compound 4 Type A of is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 7.5, about 8.4, and about 20.1 degrees 2-theta. In some embodiments, the compound 4 Type A is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at about 7.5, about 8.4, and about 20.1 degrees 2-theta.

[0172] In a specific embodiment, the X-ray powder diffraction pattern is 15 It is substantially similar to the XRPD provided.

[0173] compound 4 The manufacturing method of Type A is described later.

[0174] In some embodiments, the present invention relates to a compound 4 provides:

[0175]

[0176] In some embodiments, the present invention relates to a compound 4 It provides, and the above compound is crystalline.

[0177] In some embodiments, the present invention relates to a compound 4 It provides, and the compound is an amorphous compound 4 It is a crystalline solid that substantially does not contain.

[0178] In some embodiments, the present invention relates to a compound 4 It provides, and the compound substantially contains no impurities.

[0179] In some embodiments, the present invention relates to a compound 4 The present invention provides, wherein the compound has one or more peaks in its XRPD selected from those at about 7.5, about 8.4, and about 20.1 degrees at 2-theta. In some such embodiments, the present invention provides a compound 4 The present invention provides, wherein the compound has at least two peaks in its XRPD selected from those at about 7.5, about 8.4, and about 20.1 degrees at 2-theta. In some such embodiments, the present invention provides a compound 4 It provides, and the above compound is of type A.

[0180] In some embodiments, the present invention relates to a compound 4 It provides, and the compound also 15 It has an XRPD substantially similar to that described in.

[0181] In some embodiments, the present invention relates to a compound 4 A composition comprising a pharmaceutically acceptable carrier or excipient is provided.

[0182] In some embodiments, the present invention provides a compound to a patient. 4 The present invention provides a method for inhibiting AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to a patient. 4 The present invention provides a method for inhibiting a patient's AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to the patient. 4 A method for treating one or more disorders related to the activity of AHR is provided, comprising administering a composition thereof.

[0183] In some embodiments, the present invention provides a compound to a patient requiring treatment for an AHR-mediated disorder. 4 The present invention provides a method for treating an AHR-mediated disorder, comprising the step of administering a composition thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease such as cancer or an inflammatory disorder.

[0184] compound 5 (compound A oxalate salts)

[0185] According to one embodiment, the present invention relates to a compound A It provides the oxalate salt of, which is a compound 5 Represented as:

[0186]

[0187] Those skilled in the art, oxalic acid and compounds A A compound formed by ionic bonding 5 You will know that it forms a compound 5 It is considered to be able to exist in various physical forms. For example, compounds 5 It may be in a liquid or suspension, or in solid form. In certain embodiments, the compound 5It is in solid form. Compound 5 If is in a solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in detail below.

[0188] In some embodiments, the present invention relates to a compound that is substantially free of impurities. 5 Provides. As used herein, the term "substantially free of impurities" means that said compound contains an insignificant amount of external substance. Such external substance is an excess of hydrochloric acid, an excess of compound A , residual solvent, or compound 5 It may contain any other impurities that may be generated from the manufacture and / or isolation of. In certain embodiments, at least about 95 weight percent of the compound 5 is present. In another aspect of the present invention, at least about 99 weight percent of the compound 5 There exists.

[0189] Depending on one mode, compound 5 is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8 weight% based on the total weight of the composition. According to another embodiment, the compound 5 It contains, with respect to the total area of ​​the HPLC chromatogram, about 3.0 area% or less of total organic impurities in the HPLC, and in certain embodiments, about 1.5 area% or less of total organic impurities in the HPLC. In other embodiments, the compound 5 It contains any single impurity of HPLC at about 1.0 area% or less, any single impurity of HPLC at about 0.6 area% or less, and in certain embodiments, any single impurity of HPLC at about 0.5 area% or less, with respect to the total area of ​​the HPLC chromatogram.

[0190] compound 5 The structure described for is a compound 5It also means that it includes all tautomeric forms of. Furthermore, the structures described herein also mean that they include different compounds only in the presence of one or more isotope-enriched atoms. For example, hydrogen is replaced by deuterium or tritium, or carbon 13 C- or 14 Compounds having the structure of the present invention are within the scope of the present invention, except that they are replaced with C-rich carbon.

[0191] compound 5 It has been found that it may exist in at least one distinct polymorphic form. In some embodiments, the present invention relates to a compound referred herein as type A. 5 It provides polymorphic forms of.

[0192] In a specific mode, a compound 5 is a crystalline solid. In another embodiment, a compound 5 is an amorphous compound 5 It is a crystalline solid that substantially does not contain. The term "amorphous compound" as used herein 5 "Substantially not containing" refers to an insignificant amount of the above compound, an amorphous compound 5 It means containing. In certain embodiments, at least about 95 weight percent of a crystalline compound 5 is present. In another aspect of the present invention, at least about 99 weight percent of a crystalline compound 5 There exists.

[0193] In some embodiments, compounds 5 is amorphous. In some embodiments, the compound 5 is amorphous, and a crystalline compound 5 It does not substantially contain.

[0194] compound 5 Type A

[0195] In some embodiments, compounds 5Type A of has at least 1, 2, 3, 4, or 5 spectral peaks selected from those listed in Table 7.

[0196]

[0197] In some embodiments, compounds 5 Type A of is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.4, about 7.1, and about 12.7 degrees 2-theta. In some embodiments, the compound 5 Type A of is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.4, about 7.1, and about 12.7 degrees 2-theta. In some embodiments, the compound 5 Type A is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at approximately 6.4, approximately 7.1, and approximately 12.7 degrees 2-theta.

[0198] In a specific embodiment, the X-ray powder diffraction pattern is 17 It is substantially similar to the XRPD provided.

[0199] compound 5 The manufacturing method of Type A is described later.

[0200] In some embodiments, the present invention relates to a compound 5 provides:

[0201]

[0202] In some embodiments, the present invention relates to a compound 5 It provides, and the above compound is crystalline.

[0203] In some embodiments, the present invention relates to a compound 5 It provides, and the compound is an amorphous compound 5 It is a crystalline solid that substantially does not contain.

[0204] In some embodiments, the present invention relates to a compound 5It provides, and the compound substantially contains no impurities.

[0205] In some embodiments, the present invention relates to a compound 5 The present invention provides, wherein the compound has one or more peaks in its XRPD selected from those at about 6.4, about 7.1, and about 12.7 degrees at 2-theta. In some such embodiments, the present invention provides a compound 5 The present invention provides, wherein the compound has at least two peaks in its XRPD selected from those at about 6.4, about 7.1, and about 12.7 degrees at 2-theta. In some such embodiments, the present invention provides a compound 5 It provides, and the above compound is of type A.

[0206] In some embodiments, the present invention relates to a compound 5 It provides, and the compound also 17 It has an XRPD substantially similar to that described in.

[0207] In some embodiments, the present invention relates to a compound 5 A composition comprising a pharmaceutically acceptable carrier or excipient is provided.

[0208] In some embodiments, the present invention provides a compound to a patient. 5 The present invention provides a method for inhibiting AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to a patient. 5 The present invention provides a method for inhibiting a patient's AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to the patient. 5 A method for treating one or more disorders related to the activity of AHR is provided, comprising administering a composition thereof.

[0209] In some embodiments, the present invention provides a compound to a patient requiring treatment for an AHR-mediated disorder. 5The present invention provides a method for treating an AHR-mediated disorder, comprising the step of administering a composition thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease such as cancer or an inflammatory disorder.

[0210] compound 6 (compound A (Tartrate salt)

[0211] According to one embodiment, the present invention relates to a compound A It provides the tartrate salt of, which is a compound 6 Represented as:

[0212]

[0213] Here, approximately 1 ≤ x ≤ approximately 2.

[0214] Those skilled in the art, tartaric acid and compounds A A compound formed by ionic bonding 6 You will know that it forms. In some embodiments, the compound A and tartaric acid are in a ratio of about 1:1. In some embodiments, the compound A and tartaric acid are in a ratio of approximately 2:1. Compound 6 It is considered to be able to exist in various physical forms. For example, compounds 6 It may be in a liquid or suspension, or in solid form. In certain embodiments, the compound 6 It is in solid form. Compound 6 In this solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in detail below.

[0215] In some embodiments, the present invention relates to a compound that is substantially free of impurities. 6 Provides. As used herein, the term "substantially free of impurities" means that said compound contains an insignificant amount of external substance. Such external substance is an excess of oxalic acid, an excess of compound A, residual solvent, or compound 6 It may contain any other impurities that may be generated from the manufacture and / or isolation of. In certain embodiments, at least about 95 weight percent of the compound 6 This exists. In another aspect of the present invention, at least about 99 weight percent of the compound 6 This exists.

[0216] Depending on one mode, compound 6 Silver is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8% by weight based on the total weight of the composition. According to another embodiment, the compound 6 It contains, with respect to the total area of ​​the HPLC chromatogram, about 3.0 area% or less of total organic impurities in the HPLC, and in certain embodiments, about 1.5 area% or less of total organic impurities in the HPLC. In other embodiments, the compound 6 It contains any single impurity of HPLC at about 1.0 area% or less, any single impurity of HPLC at about 0.6 area% or less, and in certain embodiments, any single impurity of HPLC at about 0.5 area% or less, with respect to the total area of ​​the HPLC chromatogram.

[0217] compound 6 The structure described for is a compound 6 It also means that it includes all tautomeric forms of. Furthermore, the structures described herein also mean that they include different compounds only in the presence of one or more isotope-enriched atoms. For example, hydrogen is replaced by deuterium or tritium, or carbon 13 C- or 14 Compounds having the structure of the present invention are within the scope of the present invention, except that they are replaced with C-rich carbon.

[0218] compound 6 It has been found that it can exist in at least two distinct polymorphic forms. In some embodiments, the present invention relates to a compound referred herein as type A.6 The present invention provides a polymorphic form of. In some embodiments, the present invention provides a compound referred herein as type B. 6 It provides polymorphic forms of. In some embodiments, the compound 6 Type A is a compound A and contains tartaric acid in a ratio of about 1:1. In some embodiments, the compound 6 Type B is a compound A It contains tartaric acid in a ratio of about 2:1.

[0219] In a specific mode, a compound 6 It is a crystalline solid. In other embodiments, the compound 6 amorphous compounds 6 It is a crystalline solid that substantially does not contain. The term "amorphous compound" as used herein 6 "Substantially not containing" refers to an insignificant amount of the above compound, an amorphous compound 6 It means containing. In certain embodiments, at least about 95 weight percent of a crystalline compound 6 This exists. In another aspect of the present invention, at least about 99 weight percent of a crystalline compound 6 This exists.

[0220] In some embodiments, compounds 6 It is amorphous. In some embodiments, the compound 6 It is amorphous, and a crystalline compound 6 It does not substantially contain.

[0221] compound 6 Type A

[0222] In some embodiments, compounds 6 Type A of has at least 1, 2, 3, 4, or 5 spectral peaks selected from those listed in Table 8.

[0223]

[0224] In some embodiments, compounds 6Type A of is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 5.5, about 11.1, and about 18.9 degrees 2-theta. In some embodiments, the compound 6 Type A of is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 5.5, about 11.1, and about 18.9 degrees 2-theta. In some embodiments, the compound 6 Type A is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at approximately 5.5, approximately 11.1, and approximately 18.9 degrees 2-theta.

[0225] In a specific embodiment, the X-ray powder diffraction pattern is 19 It is substantially similar to the XRPD provided.

[0226] compound 6 The manufacturing method of Type A is described later.

[0227] compound 6 Type B

[0228] In some embodiments, compounds 6 Type B of has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from those listed in Table 9.

[0229]

[0230] In some embodiments, compounds 6 The B form of is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.2, about 6.8, and about 13.5 degrees 2-theta. In some embodiments, the compound 6 The B form of is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.2, about 6.8, and about 13.5 degrees 2-theta. In some embodiments, the compound 6Type B is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at approximately 6.2, approximately 6.8, and approximately 13.5 degrees 2-theta.

[0231] In a specific embodiment, the X-ray powder diffraction pattern is 21 It is substantially similar to the XRPD provided.

[0232] compound 6 The manufacturing method of Type B is described later.

[0233] In some embodiments, the present invention relates to a compound 6 provides:

[0234]

[0235] Here, approximately 1 ≤ x ≤ approximately 2.

[0236] In some embodiments, the present invention relates to a compound 6 It provides, and the above compound is crystalline.

[0237] In some embodiments, the present invention relates to a compound 6 It provides, and the compound is an amorphous compound 6 It is a crystalline solid that substantially does not contain.

[0238] In some embodiments, the present invention relates to a compound 6 It provides, and the compound substantially contains no impurities.

[0239] In some embodiments, the present invention relates to a compound 6 The present invention provides, wherein the compound has one or more peaks in its XRPD selected from those at about 5.5, about 11.1, and about 18.9 degrees at 2-theta. In some such embodiments, the present invention provides a compound 6 The present invention provides, wherein the compound has at least two peaks in its XRPD selected from those at about 5.5, about 11.1, and about 18.9 degrees at 2-theta. In some such embodiments, the present invention provides a compound 6It provides, said compound is of type A. In some embodiments, the compound 6 Type A is a compound A It contains tartaric acid in a ratio of about 1:1.

[0240] In some embodiments, the present invention relates to a compound 6 It provides, and the above compound also 19 It has an XRPD substantially similar to that described in.

[0241] In some embodiments, the present invention relates to a compound 6 The present invention provides, wherein the compound has one or more peaks in its XRPD selected from those at about 6.2, about 6.8, and about 13.5 degrees 2-theta. In some such embodiments, the present invention provides a compound 6 The present invention provides, wherein the compound has at least two peaks in its XRPD selected from those at about 6.2, about 6.8, and about 13.5 degrees at 2-theta. In some such embodiments, the present invention provides a compound 6 It provides, said compound is of type B. In some embodiments, the compound 6 Type B is a compound A It contains tartaric acid in a ratio of about 2:1.

[0242] In some embodiments, the present invention relates to a compound 6 It provides, and the compound is Fig. 2 1 It has an XRPD substantially similar to that described in.

[0243] In some embodiments, the present invention relates to a compound 6 A composition comprising a pharmaceutically acceptable carrier or excipient is provided.

[0244] In some embodiments, the present invention provides a compound to a patient. 6 The present invention provides a method for inhibiting AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to a patient. 6The present invention provides a method for inhibiting a patient's AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to the patient. 6 A method for treating one or more disorders related to the activity of AHR is provided, comprising administering a composition thereof.

[0245] In some embodiments, the present invention provides a compound to a patient requiring treatment for an AHR-mediated disorder. 6 The present invention provides a method for treating an AHR-mediated disorder, comprising the step of administering a composition thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease such as cancer or an inflammatory disorder.

[0246] compound 7 (compound A (of edicilate salt)

[0247] According to one embodiment, the present invention relates to a compound A It provides an edicilate salt of, which is a compound 7 Represented as:

[0248]

[0249] Here, approximately 1 ≤ x ≤ approximately 2.

[0250] Those skilled in the art, ethanedisulfonic acid and compounds A A compound formed by ionic bonding 7 You will know that it forms. In some embodiments, the compound A and ethanedisulfonic acid are in a ratio of about 1:1. In some embodiments, the compound A and ethanedisulfonic acid are in a ratio of approximately 2:1. Compound 7 It is considered to be able to exist in various physical forms. For example, compounds 7 It may be in a liquid or suspension, or in solid form. In certain embodiments, the compound 7 It is in solid form. Compound 7In this solid form, the compound may be amorphous, crystalline, or a mixture thereof. Exemplary solid forms are described in detail below.

[0251] In some embodiments, the present invention relates to a compound that is substantially free of impurities. 7 Provides. As used herein, the term "substantially free of impurities" means that said compound contains an insignificant amount of external substance. Such external substance is an excess of phosphoric acid, an excess of compound A , residual solvent, or compound 7 It may contain any other impurities that may be generated from the manufacture and / or isolation of. In certain embodiments, at least about 95 weight percent of the compound 7 This exists. In another aspect of the present invention, at least about 99 weight percent of the compound 7 This exists.

[0252] Depending on one mode, compound 7 Silver is present in an amount of at least about 97, 97.5, 98.0, 98.5, 99, 99.5, 99.8% by weight based on the total weight of the composition. According to another embodiment, the compound 7 It contains, with respect to the total area of ​​the HPLC chromatogram, about 3.0 area% or less of total organic impurities in the HPLC, and in certain embodiments, about 1.5 area% or less of total organic impurities in the HPLC. In other embodiments, the compound 7 It contains any single impurity of HPLC at about 1.0 area% or less, any single impurity of HPLC at about 0.6 area% or less, and in certain embodiments, any single impurity of HPLC at about 0.5 area% or less, with respect to the total area of ​​the HPLC chromatogram.

[0253] compound 7 The structure described for is a compound 7It also means that it includes all tautomeric forms of. Furthermore, the structures described herein also mean that they include different compounds only in the presence of one or more isotope-enriched atoms. For example, hydrogen is replaced by deuterium or tritium, or carbon 13 C- or 14 Compounds having the structure of the present invention are within the scope of the present invention, except that they are replaced with C-rich carbon.

[0254] compound 7 It has been found that it may exist in at least one distinct polymorphic form. In some embodiments, the present invention relates to a compound referred herein as type A. 7 It provides polymorphic forms of. In some embodiments, the compound 7 Type A is a compound A It contains ethanedisulfonic acid in a ratio of about 2:1.

[0255] In a specific mode, a compound 7 It is a crystalline solid. In other embodiments, the compound 7 amorphous compounds 7 It is a crystalline solid that substantially does not contain. The term "amorphous compound" as used herein 7 "Substantially not containing" refers to an insignificant amount of the above compound, an amorphous compound 7 It means containing. In certain embodiments, at least about 95 weight percent of a crystalline compound 7 This exists. In another aspect of the present invention, at least about 99 weight percent of a crystalline compound 7 This exists.

[0256] In some embodiments, compounds 7 It is amorphous. In some embodiments, the compound 7 It is amorphous, and a crystalline compound 7 It does not substantially contain.

[0257] compound 7 Type A

[0258] In some embodiments, compounds 7 Type A of has at least 1, 2, 3, 4, or 5 spectral peak(s) selected from those listed in Table 10.

[0259]

[0260] In some embodiments, compounds 7 Type A of is characterized by having one or more peaks in its X-ray powder diffraction pattern selected from those at about 6.6, about 10.4, and about 13.2 degrees at 2-theta. In some embodiments, the compound 7 Type A of is characterized by having two or more peaks in its X-ray powder diffraction pattern selected from those at about 6.6, about 10.4, and about 13.2 degrees at 2-theta. In some embodiments, the compound 7 Type A is characterized by having all three peaks in its X-ray powder diffraction pattern selected from those at approximately 6.6, approximately 10.4, and approximately 13.2 degrees at 2-theta.

[0261] In a specific embodiment, the X-ray powder diffraction pattern is 23 It is substantially similar to the XRPD provided.

[0262] compound 7 The manufacturing method of Type A is described later.

[0263] In some embodiments, the present invention relates to a compound 7 provides:

[0264]

[0265] Here, approximately 1 ≤ x ≤ approximately 2.

[0266] In some embodiments, the present invention relates to a compound 7 It provides, and the above compound is crystalline.

[0267] In some embodiments, the present invention relates to a compound 7 It provides, and the compound is an amorphous compound 7It is a crystalline solid that substantially does not contain.

[0268] In some embodiments, the present invention relates to a compound 7 It provides, and the compound substantially contains no impurities.

[0269] In some embodiments, the present invention relates to a compound 7 The present invention provides, wherein the compound has one or more peaks in its XRPD selected from those at about 6.6, about 10.4, and about 13.2 degrees at 2-theta. In some such embodiments, the present invention provides a compound 7 The present invention provides, wherein the compound has at least two peaks in its XRPD selected from those at about 6.6, about 10.4, and about 13.2 degrees at 2-theta. In some such embodiments, the present invention provides a compound 7 It provides, said compound is of type A. In some embodiments, the compound 7 Type A is a compound A It contains ethanedisulfonic acid in a ratio of about 2:1.

[0270] In some embodiments, the present invention relates to a compound 7 It provides, and the above compound also 23 It has an XRPD substantially similar to that described in.

[0271] In some embodiments, the present invention relates to a compound 7 A composition comprising a pharmaceutically acceptable carrier or excipient is provided.

[0272] In some embodiments, the present invention provides a compound to a patient. 7 The present invention provides a method for inhibiting AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to a patient. 7 The present invention provides a method for inhibiting a patient's AHR, comprising administering a composition thereof. In some embodiments, the present invention provides a compound to the patient. 7A method for treating one or more disorders related to the activity of AHR is provided, comprising administering a composition thereof.

[0273] In some embodiments, the present invention provides a compound to a patient requiring treatment for an AHR-mediated disorder. 7 The present invention provides a method for treating an AHR-mediated disorder, comprising the step of administering a composition thereof. In some embodiments, the AHR-mediated disorder is a proliferative disease such as cancer or an inflammatory disorder.

[0274] In some embodiments, the present invention relates to a compound A , type B; compound A , type C; compound 1 , type A; compound 1 , type B; compound 2 , type A; compound 3 , type A; compound 3 , type B; compound 4 , type A; compound 5 , type A; compound 6 , type A; compound 6 , type B; and compound 7 , provides a compound selected from type A. In some such embodiments, the present invention provides a composition comprising one of the said compound forms and a pharmaceutically acceptable carrier or excipient.

[0275] In some of these embodiments, the present invention provides a method for inhibiting AHR, comprising administering a compound of the present invention or a composition thereof to a patient. In some of these embodiments, the present invention provides a method for inhibiting AHR in a patient, comprising administering a compound of the present invention or a composition thereof to a patient. In some of these embodiments, the present invention provides a method for treating one or more disorders related to AHR activity, comprising administering a compound of the present invention or a composition thereof to a patient.

[0276] In some of these embodiments, the present invention provides a method for treating an AHR-mediated disorder, comprising administering a compound of the present invention or a composition thereof to a patient requiring treatment for the AHR-mediated disorder. In some of these embodiments, the AHR-mediated disorder is a proliferative disease such as cancer or an inflammatory disorder.

[0277] General method for providing salt compounds

[0278] compound A It is prepared according to the method disclosed in detail in Publication 411, the entire contents of which are incorporated herein by reference. Among these, the salt compound 1 inside 7 Chemical formula containing X Salt compounds of, and / or specific forms thereof, compounds according to the following reaction scheme A It is manufactured from.

[0279]

[0280] For example, each compound 1 inside 7 , and their forms are compounds A By combining with a suitable acid to form a salt of the said acid, a compound A It is manufactured from. Therefore, another aspect of the present invention is a compound 1 inside 7 , and a method for manufacturing the forms thereof is provided.

[0281] As generally disclosed above, in some embodiments, the present invention comprises: a formula X As a method for preparing a salt compound of

[0282]

[0283] chemical formula X Compound under conditions suitable for the formation of salt compounds A A method is provided comprising the step of combining with a suitable acid and optionally a suitable solvent.

[0284]

[0285] In some embodiments, the suitable acid is ethanesulfonic acid. In some embodiments, the present invention relates to a compound A A method for preparing an esylate salt of is provided. In a specific embodiment, a compound A The esylate salt of is a compound 1 is. In a specific embodiment, a compound A The esylate salt of is a compound 1 It is type A of. In a specific embodiment, the compound A The esylate salt of is a compound 1 It is type B.

[0286] In some embodiments, the suitable acid is maleic acid. In some embodiments, the present invention relates to a compound A A method for preparing a maleate salt of is provided. In a specific embodiment, the compound A The maleate salt of is a compound 2 is. In a specific embodiment, a compound A The maleate salt of is a compound 2 It is type A.

[0287] In some embodiments, the suitable acid is methanesulfonic acid. In some embodiments, the present invention relates to a compound A A method for preparing a mesylate salt of is provided. In a specific embodiment, the compound A The mesylate salt of is a compound 3 is. In a specific embodiment, a compound A The mesylate salt of is a compound 3 It is type A of. In a specific embodiment, the compound A The mesylate salt of is a compound 3 It is type B.

[0288] In some embodiments, the suitable acid is naphthalenesulfonic acid. In some embodiments, the present invention relates to a compound A A method for preparing a lead silate salt of is provided. In a specific embodiment, the compound A The lead silate salt of is a compound 4 is. In a specific embodiment, a compound A The lead silate salt of is a compound 4 It is type A.

[0289] In some embodiments, the suitable acid is oxalic acid. In some embodiments, the present invention relates to a compound A A method for preparing an oxalate salt of is provided. In a specific embodiment, the compound A The oxalate salt of is a compound 5 is. In a specific embodiment, a compound A The oxalate salt of is a compound 5 It is type A.

[0290] In some embodiments, the suitable acid is tartaric acid. In some embodiments, the present invention relates to a compound A A method for preparing a tartrate salt of is provided. In a specific embodiment, the compound A The tartrate salt of is a compound 6 is. In a specific embodiment, a compound A The tartrate salt of is a compound 6 It is type A of. In a specific embodiment, the compound A The tartrate salt of is a compound 6 It is type B.

[0291] In some embodiments, the suitable acid is ethanedisulfonic acid. In some embodiments, the present invention relates to a compound A A method for preparing an edicilate salt of is provided. In a specific embodiment, a compound A The edicilate salt of is a compound 7 is. In a specific embodiment, a compound A The edicilate salt of is a compound 7 It is type A.

[0292] A suitable solvent is the compound A and / or it may be any solvent system (e.g., a single solvent or a mixture of solvents) in which the acid is soluble or at least partially soluble.

[0293] Examples of suitable solvents useful in the present invention include, but are not limited to, protic solvents, aprotic solvents, polar aprotic solvents, or mixtures thereof. In certain embodiments, suitable solvents include ethers, esters, alcohols, ketones, or mixtures thereof. In some embodiments, the solvent is one or more organic alcohols. In some embodiments, the solvent is chlorinated. In some embodiments, the solvent is an aromatic solvent.

[0294] In certain embodiments, a suitable solvent is methanol, ethanol, isopropanol, or acetone, said solvent being anhydrous or combined with water or heptane. In some embodiments, a suitable solvent includes tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, glym, diglym, methyl t-butyl ether, t-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.

[0295] In some embodiments, the suitable solvent is ethyl acetate. In some embodiments, the suitable solvent is a mixture of methanol and methylene chloride. In some embodiments, the suitable solvent is a mixture of acetonitrile and water. In certain embodiments, the suitable solvent is methyl acetate, isopyridyl acetate, acetone, or tetrahydrofuran. In certain embodiments, the suitable solvent is diethyl ether. In certain embodiments, the suitable solvent is water. In certain embodiments, the suitable solvent is methyl ethyl ketone. In certain embodiments, the suitable solvent is toluene.

[0296] In some embodiments, the present invention comprises a chemical formula including the steps of removing a solvent and adding a solvent. XA method for preparing a salt compound is provided. 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. The meaning of solvent removal is known in the field of synthesis and chemistry and includes, but is not limited to, any one of those described in this invention and examples.

[0297] In some embodiments, chemical formula X A method for preparing a salt compound includes one or more steps of heating and cooling the preparation.

[0298] In some embodiments, chemical formula X A method for preparing a salt compound includes one or more steps of shaking and stirring the preparation.

[0299] In some embodiments, chemical formula X The method for preparing the salt compound of the compound A It includes the step of adding a suitable acid to the solution or slurry.

[0300] In some embodiments, chemical formula X The method for preparing the salt compound includes a heating step.

[0301] In a specific embodiment, chemical formula X The salt compound of precipitates from the mixture. In another embodiment, the chemical formula X The salt compound of is crystallized from the mixture. In another embodiment, the chemical formula X The salt compound of crystallizes from the solution after inoculation (i.e., chemical formula X Adding crystals of the salt compound to the solution).

[0302] chemical formula X The salt compound of can be produced by precipitating from the reaction mixture, or by removing part or all of the solvent through methods such as evaporation, distillation, filtration (e.g., nanofiltration, ultrafiltration), reverse osmosis, absorption and reaction, by adding an anti-solvent such as heptane, by cooling, or by other combinations of these methods.

[0303] As generally disclosed above, the chemical formula X The salt compound of is optionally isolated. Chemical formula X It is recognized that the salt compound of can be isolated by any suitable physical means known to those skilled in the art. In certain embodiments, the precipitated chemical formula X The solid salt compound is separated from the supernatant by filtration. In another embodiment, the precipitated chemical formula X The solid salt compound is separated from the supernatant by gradient filtration of the supernatant.

[0304] In a specific embodiment, chemical formula X The salt compounds are separated from the supernatant by filtration.

[0305] In a specific embodiment, chemical formula X The isolated salt compound of is dried in air. In another embodiment, the chemical formula X The isolated salt compound is dried under reduced pressure at an optionally elevated temperature.

[0306] Uses, formulations and administration, and pharmaceutically acceptable compositions

[0307] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable salt, ester, or salt of an ester thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The amount of the compound in the composition of the present invention is an amount effective for measurably inhibiting AHR in a biological sample or patient. In a specific embodiment, the amount of the compound in the composition of the present invention is an amount effective for measurably inhibiting AHR in a biological sample or patient. In a specific embodiment, the composition of the present invention is formulated for administration to a patient who requires such composition. In some embodiments, the composition of the present invention is formulated for oral administration to a patient.

[0308] The term "patient" as used herein means an animal, preferably a mammal, and most preferably a person.

[0309] The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that does not impair the pharmacological activity of the compound being formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that may be used in the composition of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffering substances, such as phosphate, glycine, sorbic acid, potassium sorbate, mixtures of partial glycerides of saturated vegetable fatty acids, water, salts, or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0310] "Pharmaceuticalally acceptable derivatives" means any non-toxic salt, ester, salt of ester, or other derivative of the compound of the present invention that, when administered to a subject, can directly or indirectly provide the compound of the present invention, an inhibitory active metabolite, or a residue thereof.

[0311] The compositions of the present invention may be administered orally, parenterally, or by inhalation spray, or topically, rectally, nasally, buccally, vaginally, or through implanted reservoirs. As used herein, the term "parenterally" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. The sterile injectable form of the compositions of the present invention may be an aqueous or oily suspension. Such suspensions may be formulated according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. Additionally, the sterile injectable formulation may be a sterile injectable solution or suspension in a non-toxic diluent or solvent that is acceptable for parenteral use, and may be provided, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oil is commonly used as a solvent or suspension medium.

[0312] For this purpose, any non-irritating bland fixed oil containing synthetic monoglycerides or diglycerides may be used. Fatty acids such as oleic acid and their glyceride derivatives are useful for the preparation of injectables, as are pharmaceutically acceptable natural oils such as olive oil or castor oil, particularly in their polyoxyethylated forms. Additionally, these oil solutions or suspensions may contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifying agents or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.

[0313] The pharmaceutically acceptable compositions of the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. For oral tablets, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. When administered orally in capsule form, useful diluents include lactose and dried corn starch. If an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifying agent and a suspending agent. If desired, specific sweeteners, flavoring agents, or coloring agents may also be added.

[0314] Otherwise, the pharmaceutically acceptable composition of the present invention may be administered in the form of a suppository for rectal administration. This may be prepared by mixing the formulation with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, so that it melts at the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0315] The pharmaceutically acceptable compositions of the present invention may also be administered topically, particularly when the subject of treatment includes areas or organs that are easily accessible by topical administration, such as diseases of the eyes, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0316] Topical application to the lower intestine may be performed in rectal suppository formulations (see above) or suitable enema formulations. Topical transdermal patches may also be used.

[0317] For topical application, the provided pharmaceutically acceptable composition may be formulated into a suitable ointment containing an active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the provided pharmaceutically acceptable composition may be formulated into a suitable lotion or cream containing an active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldocecanol, benzyl alcohol, and water.

[0318] For ophthalmic use, the provided pharmaceutically acceptable composition may be formulated as a finely divided suspension in pH-controlled isotonic sterile saline, or preferably as a solution in pH-controlled isotonic sterile saline with or without a preservative such as benzyl alcoholonium chloride. Otherwise, for ophthalmic use, the pharmaceutically acceptable composition may be formulated as an ointment such as petrolatum.

[0319] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulations and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption promoters to improve bioavailability, fluorocarbons and / or other conventional solubilizers or dispersants.

[0320] Most preferably, the pharmaceutically acceptable composition of the present invention is formulated for oral administration. Such formulation may be administered with or without food. In some embodiments, the pharmaceutically acceptable composition of the present invention is administered without food. In other embodiments, the pharmaceutically acceptable composition of the present invention is administered with food.

[0321] The amount of the compound of the present invention that can be combined with a carrier material to produce a composition as a single-dose form will vary depending on the target of treatment and the specific method of administration. Preferably, the provided composition should be formulated so that a dose of inhibitor ranging from 0.01 to 100 mg / day per kg of body weight can be administered to a patient receiving such composition.

[0322] In addition, it should be understood that the specific dosage and treatment regimen for any specific patient will depend on various factors including the activity of the specific compound used, age, body weight, overall health, gender, diet, time of administration, elimination rate, concomitant use of drugs, and 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.

[0323] Uses of compounds and pharmaceutically acceptable compositions

[0324] The activity of the compound used in the present invention as an inhibitor of AHR can be evaluated in vitro or in vivo. In vivo evaluation of the efficacy of the compound of the present invention may be performed using animal models of obesity or metabolic syndrome, such as rodent or primate models. Cell-based assays may be performed, for example, using cell lines isolated from tissues expressing AHR. Additionally, biochemical or mechanism-based assays, such as transcription assays using purified proteins, Northern blot, RT-PCR, etc., may be performed. In vitro assays include assays determining cell morphology, protein expression and / or cytotoxicity, enzyme inhibitory activity, and / or subsequent functional results of treating cells with the compound of the present invention. Another in vitro assay quantifies the ability of the inhibitor to bind to protein or nucleic acid molecules within the cell. Inhibitor binding may be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / target molecule complex, and determining the amount of radiolabeled binding. Otherwise, binding may be determined by performing a competitive experiment in which the novel inhibitor is incubated with a purified protein or nucleic acid bound to a known radioligand. Detailed conditions for testing the compounds used in the present invention as inhibitors of AHR are described in the following examples. The aforementioned testing is exemplary and is not intended to limit the scope of the invention. Those skilled in the art will understand that conventional analytical methods can be modified to develop equivalent analytical methods to obtain the same results.

[0325] As used herein, the terms “treatment,” “to treat,” and “treating” refer to the reversal, alleviation, delayed onset, or inhibition of progression of a disease or disorder, or one or more of its symptoms, as described herein. In some embodiments, treatment may be administered after one or more symptoms have occurred. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before symptoms begin (e.g., taking into account a history of symptoms and / or genetic or other susceptibility factors). For example, treatment may be continued after symptoms have resolved to prevent or delay recurrence.

[0326] Compounds and compositions according to the method of the present invention may be administered in any amount and via any route of administration effective to treat metabolic disorders or conditions, cancer, bacterial infections, fungal infections, parasitic infections (e.g., malaria), autoimmune disorders, neurodegenerative or nervous system disorders, schizophrenia, bone-related disorders, liver disease, or heart disorders, or to reduce the severity thereof.

[0327] In some embodiments, compounds and compositions according to the method of the present invention may be administered using any amount and any route of administration effective in treating diseases associated with AHR or reducing their severity.

[0328] The exact amount required will vary from subject to subject depending on the subject's species, age and general condition, severity of infection, specific formulation, and mode of administration. The compounds of the present invention are preferably formulated in unit doses for ease of administration and uniformity of administration. As used herein, the term "unit dose" refers to a physically individual unit of formulation suitable for the patient being treated. However, it will be understood that the total daily dose of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend on various factors including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, overall health, sex, and diet; the time of administration, route of administration, and elimination rate of the specific compound used; the duration of treatment; drugs used in combination or simultaneously with the specific compound used; and similar factors well known in the medical field. As used herein, the term "patient" means an animal, preferably a mammal, and most preferably a human.

[0329] The pharmaceutically acceptable composition of the present invention may be administered orally, rectally, parenterally, intravaginally, vaginally, intraperitoneally, topically (by powder, ointment, or drops), or orally to humans or other animals, depending on the severity of the infection being treated, or by oral or nasal spray, etc. In certain embodiments, the compound of the present invention may be administered orally or parenterally at a dose level of about 0.01 mg to about 50 mg, preferably about 1 mg to about 25 mg per day per kg of body weight of a subject at least once a day to obtain the desired therapeutic effect.

[0330] Liquid formulations for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid formulation may contain inert diluents commonly used in the art, e.g., water or other solvents, solubilizers and emulsifying agents, e.g., ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), fatty acid esters of glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan, and mixtures thereof. In addition to the inert diluent, the oral composition may also include adjuvants such as humectants, emulsifying and suspending agents, sweeteners, flavoring agents, and fragrances.

[0331] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions, or emulsions in non-toxic diluents or solvents acceptable for parenteral administration, and may be provided, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP, and isotonic sodium chloride. Additionally, sterile fixatives are commonly used as solvents or suspension media. For this purpose, any non-irritating fixative containing synthetic monoglycerides or diglycerides may be used. Additionally, fatty acids such as oleic acid are used in the preparation of injectable preparations.

[0332] The injectable formulation may be sterilized, for example, by filtration through a bacterial retention filter or by incorporating a sterile agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0333] To prolong the effect of the compound of the present invention, it is often desirable to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. Subsequently, the absorption rate of the compound varies depending on its dissolution rate, which may also vary depending on crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound form is achieved by dissolving or suspending the compound in an oil vehicle. The injectable depot form is prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. 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. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). The injectable depot formulation is also prepared by entrapping the compound in liposomes or microemulsions that are miscible with body tissues.

[0334] A composition for rectal or vaginal administration is a suppository that can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at ambient temperature but liquid at body temperature and thus melts in the rectal or vaginal cavity to release the active compound.

[0335] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound comprises at least one pharmaceutically acceptable inert excipient or carrier, e.g., sodium citrate or dicalcium phosphate, and / or a) fillers or extenders, e.g., starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) wetting agents, e.g., glycerol; d) disintegrants, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) dissolution retardants, e.g., paraffin; f) absorption promoters, e.g., quaternary ammonium compounds; g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; h) absorbents, e.g., kaolin and bentonite clay; and i) lubricants, For example, it is mixed with talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffer.

[0336] Similar types of solid compositions may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose, as well as high molecular weight polyethylene glycol, etc. Solid dosage forms, such as tablets, coated tablets, capsules, pills, and granules, may be manufactured with coatings and shells such as enteric coatings and other coatings well known in the field of pharmaceutical formulations. This may optionally contain an opacifying agent and may also be a composition that releases the active ingredient(s) only in specific parts of the intestinal tract or preferentially, optionally, and in a delayed manner in specific parts. Examples of embedding compositions that may be used include polymeric materials and waxes. Similar types of solid compositions may also be used as fillers in soft and hard filled gelatin capsules using excipients such as lactose or lactose, as well as high molecular weight polyethylene glycol, etc.

[0337] The active compound may also be in a micro-encapsulated form with one or more excipients as described above. Solid dosage forms, such as tablets, coated tablets, capsules, pills, and granules, may be manufactured with coatings and shells such as enteric coatings, controlled-release coatings, and other coatings well known in the field of pharmaceutical formulation. In these solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. These dosage forms may also include additional substances other than the inert diluent, such as tablet lubricants and other tablet aids, such as magnesium stearate and microcrystalline cellulose, as in conventional practice. In the case of capsules, tablets, and pills, the dosage forms may also include a buffer. They may optionally contain an opacifying agent and may also be compositions that release the active ingredient(s) only in specific parts of the intestinal tract or preferentially, optionally, in a delayed manner in specific parts. Examples of embedding compositions that may be used include polymeric materials and waxes.

[0338] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required under sterile conditions. Ophthalmic formulations, ear drops, and ophthalmic preparations are also considered to be within the scope of the present invention. Additionally, the present invention considers the use of transdermal patches, which have the additional advantage of controlling the delivery of the compounds to the body. Such dosage forms may be prepared by dissolving or dispensing the compounds in a suitable medium. Absorption enhancers may also be used to increase the flux of the compounds through the skin. The rate may be controlled by providing a rate-controlling membrane or by dispersing the compounds in a polymer matrix or gel.

[0339] Therapeutic Uses and Treatment Methods

[0340] 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 said compound.

[0341] 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 body fluids or extracts thereof.

[0342] Inhibition of enzymes in biological samples is useful for various purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, biological analysis, gene expression studies, and identification of biological targets.

[0343] Another aspect of the present invention relates to a method for inhibiting AHR in a patient, comprising the step of administering a compound of the present invention or a composition containing said compound to the patient.

[0344] Since the provided compound is an inhibitor of AHR, it is useful for treating one or more disorders associated with AHR activity. Accordingly, in certain embodiments, the present invention provides a method for treating an AHR-mediated disorder in a patient requiring treatment of an AHR-mediated disorder, comprising administering the compound of the present invention or a pharmaceutically acceptable composition thereof to the patient requiring treatment of the AHR-mediated disorder. In some embodiments, the present invention provides the use of the compound of the present invention, in solid form, or a pharmaceutically acceptable composition thereof for treating the disease, disorder, or pathological condition disclosed herein.

[0345] As used herein, the term "AHR-mediated" disorder, disease, and / or condition refers to any disease or other harmful condition known to be in which AHR or a mutant thereof plays a role. Accordingly, another aspect of the present invention relates to treating or reducing the severity of one or more diseases known to be in which AHR or a mutant thereof plays a role.

[0346] AHR-mediated disorders are well established in the art. The linkage between the AHR and AHR-mediated disorders, diseases, and / or pathological conditions mentioned herein is well established in the relevant technical field. For example, the literature [Uyttenhove et al ., "Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase" Nature Medicine , 2003 vol. 9(10), 1038; Murray et al., "AH RECEPTOR LIGANDS IN CANCER: FRIEND AND FOE" Nat. Rev. Cancer December 2014, vol. 14(12), pages 801-814; Moon et al ., "Targeting the indoleamine 2,3-dioxygenase pathway in cancer" J. ImmunoTherapy of Cancer , 2015 vol 3, page 51; Ishida et al ., "Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke" Int. J. Cancer July 2015 vol. 15, no. 137(2), pages 299-310; Ishida et al ., "Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer" Carcinogenesis February 2010 vol. 31(2), pages 287-295. Su et al ., "Prognostic value of nuclear translocation of aryl hydrocarbon receptor for non-small cell lung cancer" Anticancer Res . September 2013, vol. 33(9), pages 3953-3961; Peng et al., "Aryl hydrocarbon receptor pathway activation enhances gastric cancer cell invasiveness likely through a c-Jun-dependent induction of matrix metalloproteinase-9" BMC Cell Biol . April 2009 vol. 16; pages 10-27; Jin et al ., "Aryl Hydrocarbon Receptor Activation Reduces Dendritic Cell Function during Influenza Virus Infection" Toxicol Sci. August 2010, vol. 116(2), pages 514-522; Head et al ., "The aryl hydrocarbon receptor is a modulator of anti-viral immunity" Biochem. Pharmacol . February 2009 vol. 15; no. 77(4), pages 642-53; Jin et al ., "New insights into the role of the aryl hydrocarbon receptor in the function of CD11c + cells during respiratory viral infection" Eur. J. Immunol. June 2014, vol. 44(6), pages 1685-98; Nguyen et al ., "Aryl hydrocarbon receptor and kynurenine: recent advances in autoimmune disease research" Front Immunol . October 2014, vol. 29, no. 5, page 551; Esser et al ., "The aryl hydrocarbon receptor in immunity" Trends in ImmunologyRefer to [ , Vol.30, No. 9].

[0347] In some embodiments, the present invention provides a method for treating one or more disorders, diseases and / or conditions, wherein the disorder, disease or condition is a proliferative disease such as cancer, an inflammatory disorder or a viral infection.

[0348] In a specific embodiment, the present invention provides a method for treating cancer or another proliferative disorder, comprising administering a compound or composition of the present invention to a patient with cancer or another proliferative disorder. In a specific embodiment, the method for treating cancer or another proliferative disorder comprises administering a compound and composition of the present invention to a mammal. In a specific embodiment, the mammal is a human.

[0349] As used herein, the terms "inhibition of cancer" and "inhibition of cancer cell proliferation" refer to the inhibition of the growth, division, maturation, or viability of cancer cells, and / or the death of cancer cells, either individually or together with other cancer cells, by cytotoxicity, nutrient depletion, or the induction of apoptosis.

[0350] Examples of tissues containing cancerous cells whose proliferation is inhibited by the compounds and compositions described herein and for which the method described herein is useful include, but are not limited to, breast, prostate, brain, blood, bone marrow, liver, pancreas, skin, kidney, colon, ovary, lung, testis, penis, thyroid, parathyroid, pituitary gland, thymus, retina, uvea, conjunctiva, spleen, head, neck, trachea, gallbladder, rectum, salivary gland, adrenal gland, throat, esophagus, lymph nodes, sweat glands, sebaceous glands, muscle, heart, and stomach.

[0351] In some embodiments, the cancer treated by the compound or composition of the present invention is melanoma, liposarcoma, lung cancer, breast cancer, prostate cancer, leukemia, kidney cancer, esophageal cancer, brain cancer, lymphoma, or colon cancer. In certain embodiments, the cancer is primary exudative lymphoma (PEL).

[0352] The compounds of the present invention are used for benign or malignant tumors, brain carcinoma, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervical, testis, genitourinary system, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma or gastrointestinal cancer, particularly colon carcinoma or colorectal adenoma or tumors of the neck and head, epidermal hyperplasia, psoriasis, prostatic hypertrophy, neoplasm formation, epithelial neoplasm formation, adenoma, adenocarcinoma, corneal carcinoma, epidermal carcinoma, giant cell carcinoma, non-small cell lung carcinoma, lymphoma, Hodgkin's disease and non-Hodgkin's disease, Waldenström macroglobulinemia, mammary carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, melanoma, MYD88-driving disorder, DLBCL, ABC It is useful for the treatment of DLBCL, IL-1-driven disorders, smoldering of painless multiple myeloma, or proliferative disorders selected from leukemia.

[0353] In some modalities, cancer is leukemia (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute premyeloid leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphoblastic 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, myosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chondroma, angiosarcoma, endothelial sarcoma, lymphangisarcoma, lymphangiendothelial sarcoma, synovoma, mesothelioma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, It includes, without limitation, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic carcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, liver cancer, cholangiocarcinoma, cholangiocarcinoma, seminoma, embryonic carcinoma, Wilms tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, glioblastoma pleomorphic (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

[0354] In some modalities, the cancer is a glioma, astrocytoma, glioblastoma pleomorphic (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0355] In some embodiments, the cancer is an acoustic neuroma, astrocytoma (e.g., Grade I - morphic astrocytoma, Grade II - low-grade astrocytoma, Grade III - malignant astrocytoma, or Grade IV - glioblastoma (GBM)), chordoma, CNS lymphoma, craniopharyngioma, brainstem glioma, ependymoma, mixed glioma, optic glioma, subependymoma, medulloblastoma, meningioma, metastatic brain tumor, oligodendroglioma, pituitary tumor, primitive neuroectodermal (PNET) tumor, or schwannoma. In some embodiments, the cancer is a type found more commonly in children than in adults, e.g., brainstem glioma, craniopharyngioma, ependymoma, juvenile morphic astrocytoma (JPA), medulloblastoma, optic glioma, pineal tumor, primitive neuroectodermal (PNET) tumor, or rod tumor. In some embodiments, the patient is an adult. In some modalities, the patient is a child or a pediatric patient.

[0356] In other modalities, cancer is mesothelioma, hepatobiliary (liver and bile ducts), bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, melanoma of the skin or eye, ovarian cancer, colon cancer, rectal cancer, cancer of the anal area, gastric cancer, gastrointestinal (stomach, colorectal and duodenum), uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal gland carcinoma, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, testicular cancer, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvic carcinoma, non-Hodgkin lymphoma, vertebral axis tumor, brainstem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder cancer, multiple myeloma, cholangiocarcinoma, fibrosis It includes, without limitation, sarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the aforementioned cancers.

[0357] 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 carcinoma; soft tissue and bone synovial sarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; malignant thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; head and neck squamous cell carcinoma (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1-associated malignant peripheral nerve cis tumor (MPNST); Waldenström macroglobulinemia; or medulloblastoma.

[0358] 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), hepatobiliary carcinoma, soft tissue and bone myxosarcoma, rhabdomyosarcoma, osteosarcoma, malignant thyroid cancer, adrenal cortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0359] In some embodiments, cancer is a solid tumor such as a sarcoma, carcinoma, or lymphoma. Generally, a solid tumor contains an abnormal mass of tissue that does not typically contain cysts or fluid regions. In some embodiments, cancer is renal cell carcinoma, or renal cancer; hepatocellular carcinoma (HCC) or hepatoblastoma, or liver cancer; melanoma; breast cancer; colorectal carcinoma, 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 carcinoma, ovarian carcinoma, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; hepatobiliary carcinoma; soft tissue and bone myxosarcoma; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; malignant thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; It is selected from gastrointestinal / gastric (GIST) cancer; lymphoma; head and neck squamous cell carcinoma (SCCHN); salivary gland cancer; glioma, or brain cancer; neurofibromatosis-1 related malignant peripheral nerve cis tumor (MPNST); Waldenström macroglobulinemia; or medulloblastoma.

[0360] In some embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal carcinoma, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial carcinoma, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatobiliary carcinoma, soft tissue and bone myxosarcoma, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, malignant thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1-associated malignant peripheral nerve cis tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0361] In some embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, ovarian epithelial carcinoma, ovarian carcinoma, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatobiliary carcinoma, soft tissue and bone myxosarcoma, rhabdomyosarcoma, osteosarcoma, malignant thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST), Waldenström macroglobulinemia, or medulloblastoma.

[0362] In some modalities, it is hepatocellular carcinoma (HCC). In some modalities, the cancer is hepatoblastoma. In some modalities, the cancer is colon cancer. In some modalities, the cancer is rectal cancer. In some modalities, the cancer is ovarian cancer or ovarian carcinoma. In some modalities, the cancer is ovarian epithelial carcinoma. In some modalities, the cancer is fallopian tube cancer. In some modalities, the cancer is papillary serous cystadenocarcinoma. In some modalities, the cancer is uterine papillary serous carcinoma (UPSC). In some modalities, the cancer is hepatobiliary carcinoma. In some modalities, the cancer is soft tissue and bone synovial sarcoma. In some modalities, the cancer is rhabdomyosarcoma. In some modalities, the cancer is osteosarcoma. In some modalities, the cancer is malignant thyroid cancer. In some modalities, the cancer is adrenocortical carcinoma. In some modalities, the cancer is pancreatic cancer or pancreatic duct carcinoma. In some embodiments, the cancer is pancreatic adenocarcinoma. In some embodiments, the cancer is glioma. In some embodiments, the cancer is malignant peripheral nerve sheath tumor (MPNST). In some embodiments, the cancer is neurofibromatosis-1 related MPNST. In some embodiments, the cancer is Waldenström macroglobulinemia. In some embodiments, the cancer is medulloblastoma.

[0363] In some modalities, cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendicitis, atypical organic / rod-body tumor, basal cell carcinoma, cholangiocarcinoma, bladder cancer, bone cancer, brain tumor, astrocytoma, brain and spinal cord tumor, brainstem glioma, central nervous system atypical organic / rod-body tumor, central nervous system embryonic tumor, breast cancer, bronchial tumor, Burkitt lymphoma, carcinoid tumor, unknown primary carcinoma, central nervous system cancer, cervical cancer, pediatric cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorder, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, intraductal carcinoma of cerebrospinal fluid (DCIS), embryonic tumor, endometrial cancer, cerebrospinal cell tumor, ependymoma, esophageal cancer, Sensory neuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic cholangiocarcinoma, ocular cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, gestational choriocarcinoma, glioma, gallocyte leukemia, head and neck cancer, heart cancer, hepatocellular carcinoma, histiocytoma, Langerhans cell carcinoma, Hodgkin lymphoma, hypothalamic cancer, intraocular melanoma, islet cell tumor, Kaposi sarcoma, kidney cancer, Langerhans cell histiocytoma, laryngeal cancer, leukemia, lip and oral cancer, liver cancer, intraductal lobular carcinoma (LCIS), lung cancer, lymphoma, AIDS-associated lymphoma, macroglobulinemia, male breast cancer, medulloblastoma, medullomatosis, melanoma, Merkel cell carcinoma, malignant mesothelioma, latent primary metastatic squamous cell tumor Cervical cancer, NUT gene-associated midline-track carcinoma, oral cancer, multiple endocrine neoplasm syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), myeloma, multiple myeloma, chronic myeloproliferative disorder, nasal cavity cancer, paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, stomatal cancer, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma,Ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, sinus cancer, nasal cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, intermediately differentiated pineal parenchymal tumor, pineal blastoma, pituitary tumor, plasma cell neoplasm, pleural-pulmonary blastoma, breast cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, clear cell renal cell carcinoma, renal bone cancer, urinary cancer, metastatic cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sizzari syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, latent primary squamous cell cervical cancer, high squamous cell carcinoma of the head and neck (HNSCC), gastric cancer, supratentorial primitive neuroectodermal tumor, T-cell lymphoma, testicular cancer, throat cancer, thymoma, thymic carcinoma, thyroid cancer, renal, pelvic, and ureteral It is metastatic cell carcinoma, triple-negative breast cancer (TNBC), gestational trophoblastic tumor, unknown primary cancer, specific pediatric cancer, urethral cancer, uterine cancer, uterine sarcoma, Waldenström macroglobulinemia, or Wilms tumor.

[0364] The compound according to the present invention is useful for the treatment of inflammatory or obstructive airway diseases, for example, by reducing tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression. Inflammatory or obstructive airway diseases to which the present invention is applicable include asthma of all types or origins, including intolerance (non-allergic) asthma and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchial asthma, exercise-induced asthma, occupational asthma, and asthma induced after bacterial infection. Additionally, asthma treatment should also be understood to include the treatment of subjects under the age of 4 or 5 who exhibit wheezing symptoms and are or may be diagnosed as "wheezing infants" (often classified as patients with onset or early-stage asthma, a patient category established as a major medical concern).

[0365] The preventive efficacy in asthma treatment will be demonstrated, for example, by a reduction in the frequency or severity of symptomatic attacks of acute asthma or bronchoconstrictor attacks, improvement in lung function, or improvement in airway hyperresponsiveness. Additionally, this may be demonstrated by a reduction in the need for other symptomatic therapies, such as anti-inflammatory drugs or bronchodilators, which are used to limit or stop symptomatic attacks when they occur. The preventive benefits in asthma may be particularly evident in subjects with a tendency toward "morning dipping." "Morning dipping" is an asthma syndrome recognized as common in a significant number of asthma cases, characterized, for example, between approximately 4 a.m. and 6 a.m., that is, at a time significantly different from when the previously administered symptomatic asthma therapy was administered.

[0366] The compounds of the present invention may be used for other inflammatory or obstructive airway diseases and conditions to which the present invention is applicable, including acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive lung, airway or lung disease (COPD, COAD, or COLD), which include chronic bronchitis or associated dyspnea, emphysema, as well as exacerbation of airway hyperresponsiveness due to other drug therapies, particularly other inhaled drug therapies. The present invention may also be applied to the treatment of bronchitis of any type or origin, including but not limited to acute, arachnid, catarrhal, croupic, chronic, or tuberculous bronchitis. Additional inflammatory or obstructive airway diseases to which the present invention may be applied include pneumoconiosis of any type or origin (an inflammatory lung disease associated with ordinary occupation that often involves chronic or acute airway obstruction and is caused by repeated dust inhalation), which includes, for example, aluminatesitism, carbonaceous effluvium, asbestosis, pycnidiasis, pycnidiasis, iron deposition, silicosis, tobacco poisoning, and cotton pneumoconiosis.

[0367] In particular with respect to anti-inflammatory activity related to the inhibition of eosinophil activation, the compounds of the present invention are also useful for the treatment of eosinophil-related disorders, e.g., eosinophil-related disorders of the airway (e.g., related to pathological eosinophil infiltration of lung tissue), including eosinophilia, particularly eosinophilia affecting the airway and / or lungs; and, e.g., eosinophil-related disorders of the airway causing or accompanying Loeffler syndrome, eosinophilic pneumonia, parasitic (particularly metazoan) infection (including tropical eosinophilia), bronchopulmonary aspergillosis, nodular polyarteritis (including Chug-Strauss syndrome), eosinophilic granuloma, and eosinophil-related disorders affecting the airway caused by drug-response.

[0368] The compounds of the present invention are also useful for the treatment of inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigus, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, pemphigus associated with tumors, acquired epidermal bullous disease, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0369] The compounds of the present invention may also be used to treat other diseases or conditions, such as diseases or pathologies having inflammatory components, for example, ocular diseases and pathologies such as ocular allergies, conjunctivitis, dry keratoconjunctivitis, and vernal conjunctivitis; diseases affecting the nose, including allergic rhinitis; inflammatory diseases having autoimmune components or etiologies, including autoimmune reactions or autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red blood cell anemia, and idiopathic thrombocytopenia); systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatitis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease. Multiple sclerosis, endocrine ocular disease, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjögren's syndrome, dry keratoconjunctivitis and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-related periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephropathy, e.g., idiopathic nephrotic syndrome or nephropathy with minor changes), chronic granulomatous disease, endometriosis, leptospirotic renal disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiomegaly, muscle wasting, catabolic disorder, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, hypoxic subcutaneous dysplasia, Behcet's disease, dyschromatosis, Paget's disease, pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchial and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, rhinosinusitis,It may be used for the treatment of ocular allergies, silica-induced diseases, COPD (reduction in damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression), lung diseases, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, myositis associated with systemic sclerosis, dermatomyositis, polymyositis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 diabetes, or type 2 diabetes.

[0370] In some embodiments, the inflammatory disease that can be treated according to the method of the present invention is selected from acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryopyrin-associated periodic syndrome (CAPS), or osteoarthritis.

[0371] In some embodiments, the inflammatory disease that can be treated according to the method of the present invention is selected from TH17-mediated diseases. In some embodiments, the TH17-mediated disease is selected from inflammatory bowel diseases including systemic lupus erythematosus; multiple sclerosis; Crohn's disease or ulcerative colitis.

[0372] In some embodiments, inflammatory diseases that can be treated according to the method of the present invention are selected from Sjögren's syndrome, allergic disorders, and osteoarthritis. Pathological conditions of the eye, such as ocular allergies, conjunctivitis, dry keratoconjunctivitis, and vernal conjunctivitis, affect the nose, including allergic rhinitis.

[0373] In some embodiments, inflammatory diseases that can be treated according to the method of the present invention are selected from contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, herpetic dermatitis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigus-like disease, pemphigus vulgaris, pemphigus foliaceus, tumor-associated pemphigus, acquired epidermal bullous disease, and other inflammatory or allergic conditions of the skin.

[0374] In certain embodiments, the provided compound is useful for treating viral infections, diseases, or pathological conditions. In some embodiments, the present invention relates to HIV-1, HIV-2, human T-cell leukemia virus-I (HTLV-I), HTLV-II, HTLV-III, primate immunodeficiency virus (SIV), lymphadenitis-associated virus (LAV-2), primate T-lymphotrophic virus-I (STLV-I), STLV-II, STLV-III, primate B-lymphotrophic (SBL) virus, gibbon leukemia virus (GALV), bovine leukemia virus (BLV), equine infectious anemia virus (EIAV), feline leukemia virus (FELV), murine leukemia virus (MuLV), avian leukemia virus (ALV); and other viral infections such as hepadnavirus (hepatitis B); The present invention provides a method for treating viral diseases selected from herpes viruses (herpes simplex type I, herpes simplex type II, varicella zoster, Epstein-Barr virus and cytomegalovirus); parvoviruses (human parvovirus B-19); papovavirus group (human papillomavirus types 1 to 60, JC and BK viruses); poxviruses (smallpox, mild smallpox, smallpox, monkeypox, cowpox, pseudocox, or milker's nodular virus, parapox or ORF virus, molluscum contagiosum) and retroviral diseases such as cancer, lymphoma and other leukemias.

[0375] Combination therapy

[0376] Depending on the specific condition or disease being treated, additional therapeutic agents typically administered to treat such condition may be administered in combination with the compounds and compositions of the present invention. The additional therapeutic agents typically administered to treat a specific disease or condition used herein are known to be "suitable for the disease or condition being treated."

[0377] In a specific embodiment, the provided compound or composition thereof is administered to a patient who requires it in combination with other anticancer agents, cytotoxins, or chemotherapy agents.

[0378] In certain embodiments, anticancer agents or chemotherapy agents used in combination with the compounds or compositions of the present invention include metformin, phenformin, buformin, imatinib, nilotinib, gefitinib, sunitinib, carfilzomib, salinosporamide A, retinoic acid, cisplatin, carboplatin, oxaliplatin, mechloretamine, cyclophosphamide, chlorambucil, ifosfamide, azathioprine, mercaptopurine, doxifluridine, fluorouracil, gemcitabine, methotrexate, thioguanine, vincristine, vinblastine, vinorelbine, vindecin, podophyllotoxin, etoposide, tenifoside, taflufoside, paclitaxel, docetaxel, irinotecan, topotecan, amsacrin, actinomycin, doxorubicin, daunorubicin, and valubicin. Idarubicin, Epirubicin, Placamycin, Mitomycin, Mithoxantrone, Melphalan, Busulfan, Capecitabine, Pemetrexid, Epotillon, 13-Cis-Retinoic Acid, 2-CdA, 2-Chlorodeoxyadenosine, 5-Azacitidine, 5-Fluorouracil, 5-FU, 6-Mercaptopurine, 6-MP, 6-TG, 6-Thioguanine, Abraxane, Accutane®, Actinomycin-D, Adrimycin®, Adrusil®, Afinitor®, Agrilin®, Ala-Cort®, Aldesleukin, Alemtuzumab, ALIMTA, Alitretinoin, Alcapan-AQ®, Alkelan®, All-Transretinoic Acid, Alpha Interferon, Altretamine, Ametophterin, Amifostine, Aminoglutechimide, Anagrelide, Anandron®, Anastrozole, Arabinosylcytosine, Ara-C, Aranesp®, Aredia®, Arimidex®, Aromasin®, Aranon®, Arsenic Trioxide, Argera™, Asparaginase, ATRA, Avastin®, Azacitidine, BCG, BCNU, Bendamustine, Bevacizumab, Bexarotene, BEXXAR®, Bicalutamide, BiCNU, Blenoxan®, Bleomycin, Bortezomib, Busulfan, Busulpex® C225, Calcium Leucovorin, Campart®, Camptosar®, Camptothecin-11, Capecitabine, Karac™, Carboplatin, Camustine, Camustine Wafer, Casodex®, CC-5013, CCI-779, CCNU, CDDP, CeeNU, Ceruvidin®, cetuximab,Chlorambucil, Citroborum Factor, Cladribine, Cortisone, Cosmegen®, CPT-11, Citadren®, Cytosar-U®, Cytoxan®, Dacarbazine, Dacogen, Dactinomycin, Derbepoetin Alpha, Dasatinib, Daunomycin, Daunorubicin Hydrochloride, Daunorubicin Liposomal, Daunosome®, Decadron, Decitabine, Delta-Cortef®, Deltason®, Denileukin, Diptitox, DepoCyt™, Dexamethasone, Dexamethasone Acetate, Dexamethasone Sodium Phosphate, Dexasone, Texrazoxane, DHAD, DIC, Diodex, Docetaxel, Doxil®, Doxorubicin, Doxorubicin Liposomal, Droxia™, DTIC, DTIC-Dom®, Duralon®, Efudex®, Eligard™, Ellens™, Eloxatin™, Elspar®, Emcyt®, Epirubicin, Epoetin Alpha, Erbitux, Erlotinib, Erwinia L-Asparaginase, Estramustine, Etiol, Etopofos®, Etoposide, Etoposide Phosphate, Urexin®, Everolimus, Evista®, Exemestane, Pareston®, Faslodex®, Femara®, Filgrastim, Floxuridine, Fludara®, Fludarabine, Fluoroflex®, Fluorouracil, Fluorouracil (Cream), Fluoxymesterone, Flutamide, Folic Acid, FUDR®, Fulvestrant, G-CSF, Gefitinib, Gemcitabine, Gemtuzumab, Ozogamicin, Gemzar, Gleevec™, Gliadel® Wafer, GM-CSF, Goserelin, Granulocyte-Colony-Stimulating Factor, Granulocyte-Macrophage Colony-Stimulating Factor, Halotestin®, Herceptin®, Hexadrol, Hexalen®, Hexamethylmelamine, HMM, Hycamtin®, Hydrea®, Hydrocort Acetate®, Hydrocortisone, Hydrocortisone Sodium Phosphate, Hydrocortisone Sodium Succinate, Hydrocortone Phosphate, Hydroxyurea, Ibritumomab, Ibritumomab, Tiuxetane, Idamycin®, Idarubicin Ephex®, IFN-Alpha, Ifosfamide, IL-11, IL-2, Imatinib Mesylate, Imidazole Carboxamide, Interferon Alpha, Interferon alpha-2b (PEG conjugate), interleukin-2, interleukin-11,Intron A® (Interferon Alpha-2b), Iressa®, Irinotecan, Isotretinoin, Ixabepilone, Ixempra™, Kidrolase®, Lanacort®, Lapatinib, L-Asparaginase, LCR, Lenalidomide, Letrozole, Leucovorin, Leukelan, Leukin™, Leuprolide, Leurocristin, Rhyustatin™, Liposomal Ara-C, Liquid Pred®, Lomustine, L-PAM, L-Sarcolysine, Lupron®, Lupron Depot®, Matulan®, Maxidex, Mechloretamine, Mechloretamine Hydrochloride, Medralon®, Medrol®, Megase®, Megestrol, Megestrol Acetate, Melphalan, Mercaptopurine, Mesna, Mesnex™, Methotrexate, Methotrexate sodium, methylprednisolone, Meticorten®, mitomycin, mitomycin-C, mitoxantrone, M-prednisol®, MTC, MTX, Mustargen®, Mustin, Mutamicin®, Maileran®, Mylocell™, Mylotarg®, Navelbin®, Nelarabine, Neosar®, Neulasta™, Neumega®, Neupogen®, Nexavar®, Nylandron®, Nilotinib, Nilutamide, Nifent®, Nitrogen Mustard, Novaldex®, Novantron®, N-Plate, Octreotide, Octreotide Acetate, Ofatumumab, Oncospar®, Oncobin®, Ontax®, Onsal™, Ofrelbekin, Orapred®, Orason®, Oxaliplatin, Paclitaxel, Paclitaxel protein-binding, Famidronate, panitumumab, Panretin®, Paraplatin®, Pazopanib, Pediapred®, PEG Interferon, Pegaspargase, Pegfilgrastim, PEG-Intron™, PEG-L-Asparaginase, PEMETREXED, Pentostatin, Phenylalanine Mustard, Platinol®, Platinol-AQ®, Prednisolone, Prednisone, Prelon®, Procarbazine, PROCRIT®, Proleukin®, Prolipeprospan 20 with Carmustine Implant, Purintol®, Raloxifene, Revlimid®, Leumatrex®, Rituxan®, Rituximab, Loferon-A® (Interferon Alpha-2a), Romiplastim, Luvex®, Rubidomycin Hydrochloride, Sandostatin®, Sandostatin LAR®, Sargramostim, Solu-Cortef®, Solu-Medrol®,Sorafenib, SPRYCEL™, STI-571, Streptozosin, SU11248, Sunitinib, Sutent®, Tamoxifen, Tarceva®, Targretin®, Tasigna®, Taxol®, Taxotere®, Temozolomide, Temsirolimus, Tenifoside, TESPA, Thalidomide, Talomide®, Therasys®, Thioguanine, Thioguanine Tabloid®, Thiophosphamide, Tioflex®, Tiotepa, TICE®, Toposar®, Topotecan, Toremifene, Torisel®, Tocitumomab, Trastuzumab, Treanda®, Tretinoin, Trexal™, Trisenox®, TSPA, TYKERB®, VCR, Vectibix™, Velban®, Velcade®, It includes, but is not limited to, Bepecid®, Besanoid®, Viadur™, Vidaza®, Vinblastine, Vinblastine Sulfate, Vincazar Pfs®, Vincristine, Vinorelbine, Vinorelbine Tartrate, VLB, VM-26, Vorinostat, Votrient, VP-16, Vumon®, Celoda®, Zanosarr®, Zebalin™, Zinecard®, Zoladex®, Zolidronic Acid, Zolinza, Zometa®, or a combination of any of these.

[0379] In certain embodiments, the tumor-oncology agent may be administered together with the compounds described herein for the treatment of proliferative disorders as described herein. As used herein, the term "immuno-oncology agent" refers to an agent effective in enhancing, stimulating, and / or upregulating the immune response of a subject. In some embodiments, the administration of the tumor-oncology agent together with the compounds described herein has a synergistic effect in the treatment of cancer.

[0380] In some embodiments, a compound as described herein is administered sequentially before the administration of a tumor-immunotherapy agent. In some embodiments, a compound as described herein is administered simultaneously with the tumor-immunotherapy agent. In some embodiments, a compound as described herein is administered sequentially after the administration of the tumor-immunotherapy agent.

[0381] In some embodiments, compounds as described herein may be formulated together with tumor-immunotherapy agents.

[0382] Tumor-immunotherapy agents may be, for example, small molecule drugs, antibodies, biological molecules, or small molecules. Examples of biological tumor-immunotherapy 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.

[0383] In some embodiments, the tumor-immunotherapy agent is (i) an agonist of a stimulating (including co-stimulating) receptor or (ii) an antagonist of a signal inhibiting (including co-inhibiting) T cell, both of which amplify antigen-specific T cell responses.

[0384] Specific stimulatory and inhibitory molecules are members of the immunoglobulin superfamily (IgSF). One important group of membrane-bound ligands that bind to co-stimulatory or co-inhibitory receptors is the B7 group, 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 group of membrane-bound ligands that binds to co-stimulatory or co-inhibitory receptors is the TNF family of molecules that bind to members of the homologous TNF receptor family, which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137(4-1BB), TRAIL / Apo2-L, TRAILR1 / DR4, TRAILR2 / DR5, TRAILR3, TRAILR4, OPG, RANK, RANKL, TWEAKR / Fn14, TWEAK, BAFFR, EDAR, XEDAR, TACI, APRIL, BCMA, LTβR, LIGHT, DcR3, HVEM, VEGI / TL1A, TRAMP / DR3, EDAR, EDA1, XEDAR, EDA2, TNFR1, limbotoxin α / TNFβ, Includes TNFR2, TNFα, LTβR, lymphotoxin α1β2, FAS, FASL, RELT, DR6, TROY, and NGFR.

[0385] In some embodiments, the tumor-immunotherapy agent is a cytokine that inhibits T cell activation (e.g., IL-6, IL-10, TGF-β, VEGF and other immunosuppressive cytokines) or a cytokine that stimulates T cell activation to stimulate an immune response.

[0386] In some embodiments, a combination of a compound and a tumor-immunotherapy agent as described herein may stimulate a T cell response. In some embodiments, the tumor-immunotherapy agent is (i) an antagonist of a protein that inhibits T cell activation (e.g., an immune checkpoint inhibitor), e.g., CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) agonists of proteins that stimulate T cell activation, e.g., B7-1, B7-2, CD28, 4-1BB(CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H.

[0387] In some embodiments, the tumor-immunotherapy agent is an antagonist of the inhibitory receptor for NK cells or an agonist of the activating receptor for NK cells. In some embodiments, the tumor-immunotherapy agent is an antagonist of KIR, for example, rililumab.

[0388] In some embodiments, the tumor-immunotherapy agent is a agent that inhibits or depletes macrophages or monocytes, and includes, but is not limited to, CSF-1R antagonists such as CSF-1R antagonist antibodies including RG7155 (WO 11 / 70024, WO 11 / 107553, WO 11 / 131407, WO 13 / 87699, WO 13 / 119716, WO 13 / 132044) or FPA-008 (WO 11 / 140249, WO 13169264, WO 14 / 036357).

[0389] In some embodiments, the tumor-immunotherapy agent is selected from agonists that ligate positive co-stimulatory receptors, blockers that attenuate signal transduction through inhibitory receptors, antagonists, and one or more agents that systemically increase the frequency of anti-tumor T cells, agents that overcome distinct immunosuppressive pathways within the tumor microenvironment (e.g., blocking inhibitory receptor engagement (e.g., PD-L1 / PD-1 interaction), depleting or inhibiting Tregs (e.g., by using an anti-CD25 monoclonal antibody (e.g., daclizumab) or by in vitro anti-CD25 bead depletion), inhibiting metabolic enzymes such as IDO, or reversing / preventing T cell energy or depletion), and agents that induce innate immune activation and / or inflammation at the tumor site.

[0390] In some embodiments, the tumor-immunotherapy 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.

[0391] In some embodiments, the tumor-immunotherapy agent is a PD-1 antagonist. In some embodiments, the PD-1 antagonist is administered by infusion. In some embodiments, the tumor-immunotherapy agent is an antibody or its antigen-binding site that specifically binds to the Programmed Death-1 (PD-1) receptor to inhibit PD-1 activity. In some embodiments, the PD-1 antagonist is an antagonistic PD-1 antibody. In some embodiments, the antagonistic PD-1 antibody is OPDIVO (nivolumab), KEYTRUDA (pembrolizumab), or MEDI-0680 (AMP-514; WO 2012 / 145493). In some embodiments, the tumor-immunotherapy agent may be pidilizumab (CT-011). In some embodiments, the tumor-immunotherapy agent is a recombinant protein consisting of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1 called AMP-224.

[0392] In some embodiments, the tumor-immunotherapy 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 antibodies are MPDL3280A (RG7446; WO 2010 / 077634), durvalumab (MEDI4736), BMS-936559 (WO 2007 / 005874), and MSB0010718C (WO 2013 / 79174).

[0393] In some embodiments, the tumor-immunotherapy agent is a LAG-3 antagonist. In some embodiments, the LAG-3 antagonist is an antagonistic LAG-3 antibody. In some embodiments, the LAG3 antibody is BMS-986016 (WO 10 / 19570, WO 14 / 08218), or IMP-731 or IMP-321 (WO 08 / 132601, WO 009 / 44273).

[0394] In some embodiments, the tumor-immunotherapy agent is a CD137(4-1BB) agonist. In some embodiments, the CD137(4-1BB) agonist is an active CD137 antibody. In some embodiments, the CD137 antibody is urelumab or PF-05082566 (WO 12 / 32433).

[0395] In some embodiments, the tumor-immunotherapy agent is a GITR agonist. In some embodiments, the GITR agonist is an active GITR antibody. In some embodiments, the GITR antibody is BMS-986153, BMS-986156, TRX-518 (WO 006 / 105021, WO 009 / 009116) or MK-4166 (WO 11 / 028683).

[0396] In some embodiments, the tumor-immunotherapy agent is an IDO antagonist. In some embodiments, the IDO antagonist is INCB-024360 (WO 2006 / 122150, WO 07 / 75598, WO 08 / 36653, WO 08 / 36642), indoxymod, or NLG-919 (WO 09 / 73620, WO 009 / 1156652, WO 11 / 56652, WO 12 / 142237).

[0397] In some embodiments, the tumor-immunotherapy agent is an OX40 agonist. In some embodiments, the OX40 agonist is an active OX40 antibody. In some embodiments, the OX40 antibody is MEDI-6383 or MEDI-6469.

[0398] In some embodiments, the tumor-immunotherapy agent is an OX40L antagonist. In some embodiments, the OX40L antagonist is an antagonistic OX40 antibody. In some embodiments, the OX40L antagonist is RG-7888 (WO 06 / 029879).

[0399] In some embodiments, the tumor-immunotherapy agent is a CD40 agonist. In some embodiments, the CD40 agonist is an agonist CD40 antibody. In some embodiments, the tumor-immunotherapy agent is a CD40 antagonist. In some embodiments, the CD40 antagonist is an antagonist CD40 antibody. In some embodiments, the CD40 antibody is rucatumumab or dasetuzumab.

[0400] In some embodiments, the tumor-immunotherapy agent is a CD27 agonist. In some embodiments, the CD27 agonist is an activating CD27 antibody. In some embodiments, the CD27 antibody is varilumab.

[0401] In some embodiments, the tumor-immunotherapy agent is MGA271 (for B7H3) (WO 11 / 109400).

[0402] In some embodiments, the tumor-immunotherapy agent is avagovomab, adecaturumab, afutuzumab, alemtuzumab, anatumomab, mapenatox, apolizumab, atezolimab, avelumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, efacadostat, efratuzumab, indoximod, innotuzumab, ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumomab, olatutumab, pembrolizumab, fidilizumab, rituximab, ticilimumab, samallizumab, or tremelimumab.

[0403] In some aspects, tumor-immunotherapy agents are immunostimulants. For example, antibodies blocking the PD-1 and PD-L1 inhibition axes can trigger activated tumor-responsive T cells and have been shown in clinical trials to induce sustained anti-tumor responses in an increasing number of tumor histologies, including some tumor types that were not previously considered sensitive to immunotherapy. For example, the literature [Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. Refer to [(2016) Sci. Transl. Med. 8]. Anti-PD-1 antibody nivolumab (Opdivo ® , also known as Bristol-Myers Squibb, ONO-4538, MDX1106, and BMS-936558) has shown potential to improve overall survival in RCC patients who have experienced disease progression during or after a previous course of angiogenic therapy.

[0404] In some embodiments, immunomodulatory therapeutics specifically induce apoptosis in tumor cells. Approved immunomodulatory therapeutics that may be used in the present invention include pomalidomide (Pomalyst®, Celgene); lenalidomide (Revlimid®, Celgene); and genol mebutate (Picato®, LEO Pharma).

[0405] In some embodiments, the tumor-immunotherapy agent is a cancer vaccine. In some embodiments, the cancer vaccine is selected from Cipulcel-T (Provenge®, Dendreon / Valeant Pharmaceuticals), approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-resistant) prostate cancer; and Talimogen Laherparefvec (Imlygic®, BioVex / Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable cutaneous, subcutaneous, and nodular lesions in melanoma.In some embodiments, the tumor-immunotherapy agent is a tumor-lytic viral therapy such as Pexastimogen Devaxirefvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-) deficient vaccinia virus engineered to express GM-CSF, for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); Pelareorep (Reolysin®, Oncolytics Biotech), a variant of respiratory enterovirus (reovirus) that does not replicate in RAS-inactivated cells in a number of cancers including colorectal cancer (NCT01622543), prostate cancer (NCT01619813), head and neck squamous cell carcinoma (NCT01166542), pancreatic adenocarcinoma (NCT00998322), and non-small cell lung cancer (NSCLC) (NCT 00861627); In ovarian cancer (NCT02028117) and in metastatic or advanced epithelial tumors such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma and salivary gland cancer (NCT02636036), N-AdenothuSirev (NG-348, psiOxus, formerly known as ColoAd1), an adenovirus engineered to express full-length CD80 and an antibody fragment specific to the T-cell receptor CD3 protein; in melanoma (NCT03003676), and in peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831), ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF; It is selected from GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), a vaccinia virus engineered to express beta-galactosidase (beta-gal) / beta-glucoronidase or beta-gal / human sodium iodide isotransporter (hNIS), which is studied in peritoneal carcinomatosis (NCT01443260), fallopian tube cancer, and ovarian cancer (NCT 02759588), respectively; or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF in bladder cancer (NCT02365818).

[0406] In some embodiments, the tumor-immunotherapy agents are JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase capable of converting proprog 5-fluorocytosine into the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), peptide immunotherapies targeting refractory RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated as Ad5 / 3-E2F-delta24-hTNFα-IRES-hIL20; and antigen-specific CD8 + It is selected from VSV-GP (ViraTherapeutics), a vesicular stomatitis virus (VSV) that can be further engineered to express antigens designed to induce a T cell response.

[0407] In some embodiments, tumor-immunotherapy agents are T-cells engineered to express a chimeric antigen receptor or CAR. T-cells engineered to express such a chimeric antigen receptor are referred to as CAR-T cells.

[0408] A CAR is constructed comprising a binding domain that can be derived from a single chain variable fragment (scFv) derived from a monoclonal antibody specific to a cell-surface antigen, fused to a natural ligand or an endodomain, which is the functional terminal of a T-cell receptor (TCR), for example, a CD3-zeta signaling domain from a TCR capable of generating an activation signal in T lymphocytes. Upon antigen binding, this CAR connects to an endogenous signaling pathway in effector cells and generates an activation signal similar to that initiated by the TCR complex.

[0409] For example, in some embodiments, CAR-T cells are one of those described in U.S. Patent 8,906,682 (June; the full text thereof is incorporated herein by reference), which discloses CAR-T cells engineered to include an extracellular domain having an antigen-binding domain (e.g., a domain binding to CD19) fused to an intracellular signaling domain of the T cell antigen receptor complex zeta chain (e.g., CD3 zeta). When expressed in T cells, the CAR can redirect antigen recognition based on antigen-binding specificity. In the case of CD19, the antigen is expressed in malignant B cells. More than 200 clinical trials using CAR-T as a broad indication are currently underway [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0410] In some embodiments, the immunostimulator is an activator of retinoic acid receptor-associated orphan receptor γ (RORγt). RORγt is a transcription factor that plays a major 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 subpopulations 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).

[0411] In some embodiments, the immunostimulator is an agonist or activator of a Toll-like receptor (TLR). Suitable activators of TLRs include agonists or activators of TLR9, such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG being studied for B-cell, follicular lymphoma, and other lymphomas (NCT02254772). A agonist or activator of TLR8 that may be used in the present invention includes motolimod (VTX-2337, VentiRx Pharmaceuticals), which is being studied for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0412] Other tumor-immunotherapy agents that may be used in the present invention include urelumab (BMS-663513, Bristol-Myers Squibb), anti-CD137 monoclonal antibody; valilumab (CDX-1127, Celldex Therapeutics), anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), anti-OX40 monoclonal antibody; lirilumab (IPH2102 / BMS-986015, Innate Pharma, Bristol-Myers Squibb), anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), anti-NKG2A monoclonal antibody; andecaliximab (GS-5745, Gilead Sciences), anti-MMP9 antibody; and MK-4166 (Merck & Co.), anti-GITR monoclonal antibody.

[0413] In some embodiments, the immunostimulator is selected from elotuzumab, mifamurtide, agonists or activators of Toll-like receptors, and activators of RORγt.

[0414] In some embodiments, the immunostimulatory agent is recombinant human interleukin 15 (rhIL-15). rhIL-15 has been tested in clinical trials 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 immunotherapeutic agent is a fusion complex composed of a heteromeric IL-15 (hetIL-15, Novartis / Admune) and a synthetic form of endogenous IL-15 complexed to the soluble IL-15 binding protein IL-15 receptor alpha chain (IL15: sIL-15RA), which was tested in Phase 1 clinical trials for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). In some embodiments, the recombinant human interleukin 12 (rhIL-12) is NM-IL-12 (Neumedicines, Inc.), NCT02544724, or NCT02542124.

[0415] In some embodiments, the tumor-immunotherapy agent is selected from those described in the literature [Jerry L. Adams et al., "Big opportunities for small molecules in immuno-oncology", Cancer Therapy 2015, Vol. 14, pages 603-622], the full text of which is incorporated herein by reference. In some embodiments, the tumor-immunotherapy agent is selected from the examples described in Table 1 of the literature [Jerry L. Adams et al.]. In some embodiments, the tumor-immunotherapy agent is a small molecule targeting a tumor-immunotherapy target selected from those listed in Table 2 of the literature [Jerry L. Adams et al.]. In some embodiments, the tumor-immunotherapy agent is a small molecule preparation selected from those listed in Table 2 of the literature [Jerry L. Adams et al.].

[0416] In some embodiments, the tumor-immunotherapy agent is selected from small molecule tumor-immunotherapy agents described in the literature [Peter L. Toogood, "Small molecule immuno-oncology therapeutic agents", Bioorganic & Medicinal Chemistry Letters 2018, Vol. 28, pages 319-329], the full text of which is incorporated herein by reference. In some embodiments, the tumor-immunotherapy agent is an agent targeting the pathway described in the literature [Peter L. Toogood].

[0417] In some embodiments, the tumor-immunotherapy agent is selected from those disclosed in the literature [Sandra L. Ross et al., "Bispecific T cell engager (BiTE®) antibody constructs can mediate bystander tumor cell killing", PLoS ONE 12(8): e0183390], the full text of which is incorporated herein by reference. In some embodiments, the tumor-immunotherapy agent is a bispecific T cell engager (BiTE®) antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is a CD19 / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct is an EGFR / CD3 bispecific antibody construct. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells, which release cytokines that induce the upregulation of intercellular adhesion molecule 1 (ICAM-1) and FAS in bystander cells. In some embodiments, the bispecific T cell engager (BiTE®) antibody construct activates T cells that induce bystander cell lysis. In some embodiments, the bystander cells are located within a solid tumor. In some embodiments, the bystander cells being lysed are in proximity to the BiTE® activated T cells. In some embodiments, the bystander cells include tumor-associated antigen (TAA) negative cancer cells. In some embodiments, the bystander cells include EGFR-negative cancer cells. In some embodiments, the tumor-immunotherapy agent is an antibody that blocks the PD-L1 / PD1 axis and / or CTLA4. In some embodiments, the tumor-immunotherapy agent is an ex vivo expanded tumor-infiltrating T cell. In some embodiments, the tumor-immunotherapy agent is a bispecific antibody construct or chimeric antigen receptor (CAR) that directly links T cells to tumor-associated surface antigens (TAAs).

[0418] In certain embodiments, a combination of two or more therapeutic agents may be administered together with the compound of the present invention. In certain embodiments, a combination of three or more therapeutic agents may be administered together with the compound of the present invention.

[0419] Other examples of formulations that may be combined with the inhibitor of the present invention also include, without limitation, the following formulations: vitamins and nutritional supplements, cancer vaccines, treatments for neutropenia (e.g., G-CSF, filgrastim, lenograstim), treatments for thrombocytopenia (e.g., blood transfusion, erythropoietin), PI3 kinase (PI3K) inhibitors, MEK inhibitors, mTOR inhibitors, CPT1 inhibitors, AMPK activators, PCSK9 inhibitors, SREBP site 1 protease inhibitors, HMG CoA reductase inhibitors, antiemetics (e.g., 5-HT3 receptor antagonists, dopamine antagonists, NK1 receptor antagonists, histamine receptor antagonists, cannabinoids, benzodiazepines, or anticholinergics), treatments for Alzheimer's disease, e.g., Aricept ® and Exelon ® ; Treatments for Parkinson's disease, e.g., L-DOPA / carbidopa, entacapone, lopinrol, pramipexole, bromocriptine, pergolide, trihexaphendyl, and amantadine; treatments for multiple sclerosis (MS), e.g., beta interferon (e.g., Avonex ® and Levip ® ), Copaxone ® and mitoxantrone; asthma medications, e.g., albuterol and Singulair ®; Antipsychotics, e.g., Zaprexa, Risperdal, Serokel, and Haloperidol; anti-inflammatory agents, e.g., corticosteroids, TNF blockers, IL-1 RAs, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants, e.g., cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors, e.g., acetylcholinesterase inhibitors, MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole, and anti-parkinsonian agents; antipsychotics, e.g., beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins, fibrin, cholesterol absorption inhibitors, bile acid sequestrants, and niacin; Treatments for liver diseases, e.g., corticosteroids, cholestyramine, interferon, and antiviral agents; treatments for blood disorders, e.g., corticosteroids, anti-leukemia agents, and growth factors; treatments for immunodeficiency disorders, e.g., gamma globulin; and anti-diabetic agents, e.g., biguanides (metformin, phenformin, buformin), thiazolidinediones (rosiglitazone, pioglitazone, troglitazone), sulfonylureas (tolbutamide, acetohexaamide, tolazamide, chlorpropamide, glipizide, gliburide, glimepiride, gliclazide), meglitinides (repaglinide, nateglinide), alpha-glucosidase inhibitors (miglitol, acarbose), incretin mimics (exenatanide, liraglutide, taspoglutide), gastric inhibitory peptide analogs, DPP-4 inhibitors (vildagliptin, sitagliptin, saxagliptin, linagliptin, alogliptin), amylin analogs (pramlintide), and insulin and insulin analogs.

[0420] In certain embodiments, the compound of the present invention or a pharmaceutically acceptable composition thereof is administered in combination with an antisensitizer, a monoclonal or polyclonal antibody, or a siRNA therapeutic.

[0421] In another aspect, the present invention provides a method for treating an inflammatory disease, disorder, or pathological condition by administering a compound of the present invention and one or more additional therapeutic agents to a patient requiring treatment for the inflammatory disease, disorder, or pathological condition. These additional therapeutic agents may be small molecule or recombinant biological agents, e.g., acetaminophen; non-steroidal anti-inflammatory drugs (NSAIDs), e.g., aspirin, ibuprofen, natroxen, etodolac (Lodin®) and celecoxib, colchicine (Colcris®); corticosteroids, e.g., prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.; probenecid, allopurinol, febuxostat (Uloric®); sulfasalazine (azulpidine®); antimalarials, e.g., hydroxychloroquine (Plaquenil®) and chloroquine (Aralen®); methotrexate (Leumatrex®); gold salts, e.g., gold thioglucose (Solgaral®), gold thiomaleate (Myocrysin®) and auranofin (Lidaura®); D-penicillamine (Defen® or Cuprimin®), azathioprine (Imuran®), cyclophosphamide (Cytoxan®), chlorambucil (Leukeran®), cyclosporine (Sandimune®), leflunomide (Arava®), and "anti-TNF" agents, e.g., etanercept (Enbrel®), infliximab (Remicade®), golimumab (Symponi®), sertolizumab pegol (Simzia®), and adalimumab (Humira®), "anti-IL-1" agents, e.g., anakinra (Kineret®) and rilonacept (Arcalist®), canakinumab (Ilaris®), anti-Jak inhibitors, e.g., tofacitinib, antibodies, e.g., rituximab (Rituxan®), "anti-T-cell" agents, e.g., abatacept (Orencia®), and "anti-IL-6" agents, e.g. Tocilizumab (Actemra®), diclofenac, cortisone, hyaluronic acid (Synvisc® or Hyalgan®), monoclonal antibodies, e.g., tanezumab, anticoagulants, e.g., heparin (calsinfarin® or liquaemin®) and warfarin (Coumadin®), laxatives, e.g., diphenoxylate (Lomotil®) and loperamide (Imodium®), bile acid binders,For example, cholestyramine, alosetron (Rotronex®), rubiprostone (Amitiza®), laxatives, for example, milk of magnesia, polyethylene glycol (Miralax®), Dulcolax®, Correctol®, and Cenocort®, anticholinergics or antispasmodics, for example, dicyclomin (Ventil®), Singulair®, beta-2 agonists, for example, albuterol (Ventolin® HFA, Proventil® HFA), levalbuterol (Sokfenex®), metaproterenol (Alufent®), pirbuterol acetate (Maxair®), terbutaline sulfate (Bretaire®), salmeterol cinapoate (Cerevent®), and formoterol (Foradil®), anticholinergics, for example, ipratropium bromide (Atrovent®) and tiotropium (Spiriva®), inhalation Corticosteroids, e.g., beclomethasone dipropionate (Beclovent®, Qvar®, and Banseryl®), triamcinolone acetonide (Azmacort®), mometasone (Astmanex®), budesonide (Pulmocort®), and flunisolide (Aerovid®), Afviar®, Symbicort®, Dulera®, cromolin sodium (Intal®), methylxanthines, e.g., theophylline (Theo-Dur®, Theoleir®, Slo-Vid®, Unifil®, Theo-24®) and aminophylline, IgE antibodies, e.g., omalizumab (Xolair®), nucleoside reverse transcriptase inhibitors, e.g., zidovudine (Letrovir®), abacavir (Ziagen®), abacavir / lamivudine (FGCOM®), Abacavir / lamivudine / zidovudine (Trizivir®), didanosine (Videx®), emtricitabine (Emtriva®), lamivudine (Ampivir®), lamivudine / zidovudine (Combivir®), stavudine (Zerith®), and zalcitabine (Hivid®), non-nucleoside reverse transcriptase inhibitors, e.g., delavirdine (Rescriptor®), efavirenz (Sustiva®), nevirapine (Viramun®), and etravirine (Intellense®), nucleotide reverse transcriptase inhibitors, e.g., tenofovir (Vired®), protease inhibitors, e.g., amprenavir (Agenerase®), atazanavir (Reyataz®), darunavir (Prezista®), fosamprenavir (Lexiva®),It comprises indinavir (Crixivan®), lopinavir and ritonavir (Kaletra®), nelfinavir (Viracept®), ritonavir (Norvir®), saquinavir (Portobase® or Invirase®), and tipranavir (Aptivur®), entry inhibitors, e.g., enfuvirtide (Fugeon®) and maraviroc (Selgentri®), integrase inhibitors, e.g., lactegravir (Isentress®), dosolubicin (Hydrodaunorubicin®), vincristine (Oncovin®), bortezomib (Belcade®), and dexamethasone (Decadron®) combined with lenalidomide (Revlimid®), or any combination(s) thereof.

[0422] In some embodiments, the provided compounds are, for example, acyclovir, penciclovir, cidofovir, idoxuridine, zidovudine, ribavarin, amantadine, foscarnet, didanosine, acyclovir, ganciclovir, cidofovir, zalcitabine, rimantadine, calacyclovir, famicyclovir, abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, zidovudine, zidovudine-lamivudine, TRIZIVIR (zidovudine, lamivudine, abacavir), EPZICOM (abacavir-lamivudine), TRUVADA (tenofovir-emtricitabine), efavirenz, nevirapine, and delavirdine, amprenavir, atazanavir, fosamprenavir, indinavir, It is administered in combination with antiviral agents including lopinavir-ritonavir, nelfinavir, ritonavir, saquinavir, and tipranavir. In some embodiments, the antiviral agent is an anti-inflammator agent including, for example, rimantadine, amantadine, oseltamivir, and zanamivir.

[0423] These additional agents may be administered separately from the composition containing the compound of the present invention as part of a multiple-dose regimen. Otherwise, these agents may be part of a single-dose formulation mixed with the compound of the present invention in a single composition. When administered as part of a multiple-dose regimen, the two active agents may be provided simultaneously, sequentially, or from each other within a certain period of time, generally within 5 hours from each other.

[0424] As used herein, the terms “concurrent,” “concurrently used,” and related terms refer to the simultaneous or sequential administration of the therapeutic agent according to the present invention. For example, the compound of the present invention may be administered simultaneously or sequentially with another therapeutic agent in a separate unit dosage form, or together in a single unit dosage form. Accordingly, the present invention provides a single unit dosage form comprising the compound of the present invention, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0425] The amounts of both the provided compound and additional therapeutic agents (in a composition containing additional therapeutic agents as described above) that can be combined with a carrier material to produce a single dose will vary depending on the subject being treated and the specific mode of administration. Preferably, the composition of the present invention should be formulated so that a dose of 0.01 to 100 mg / day of the compound of the present invention can be administered per kg of body weight.

[0426] In a composition containing additional therapeutic agents, the additional therapeutic agents and the compound of the present invention may act synergistically. Therefore, in such a composition, the amount of additional therapeutic agents will be less than that required in a monotherapy using only the therapeutic agents. In such a composition, a dose of 0.01 to 100 μg / day of additional therapeutic agents per kg of body weight may be administered.

[0427] The amount of additional therapeutic agent present in the composition of the present invention will be less than or equal to the amount typically administered to a composition containing said therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the composition disclosed herein will be in the range of about 50% to 100% of the amount typically present in a composition containing said agent as the sole therapeutic active agent.

[0428] In one embodiment, the present invention provides a composition comprising a compound of the present invention and one or more additional therapeutic agents. The therapeutic agent may be administered together with the compound of the present invention, or may be administered before or after administration of the compound of the present invention. Suitable therapeutic agents are described in further detail below. In a specific embodiment, 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 another embodiment, 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.

[0429] In some embodiments, the present invention provides a pharmaceutical agent comprising at least one compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0430] All features of each aspect of the present invention are applied to all other aspects with necessary modifications.

[0431] The following examples are provided to help to more fully understand the invention described herein. It should be understood that these examples are for illustrative purposes only and should not be construed as limiting the invention in any way.

[0432] example

[0433] As described in the examples below, in certain exemplary embodiments, the compounds are prepared according to the following general procedure. While the general method describes the synthesis of specific compounds of the present invention, it will be understood that the following general method and other methods known to those skilled in the art are applicable to all compounds as described herein and to each of the subclasses and chemical species of these compounds.

[0434] General Procedure

[0435] X-ray powder diffraction (XRPD)

[0436] The X-ray diffraction system is configured for reflective Bragg-Brentano geometry using a line source X-ray beam. This source provides an incident beam profile to the sample that changes from a narrow line at a high angle to a wide rectangle at a low angle. A beam conditioning slit is used with the line X-ray source to ensure that the maximum beam size is less than 10 mm both along the line and perpendicular to it. Bragg-Brentano geometry is a para-focal geometry controlled by a receiving slit containing the sample itself, which acts as the passive divergence and optical focusing component. The inherent resolution of Bragg-Brentano geometry is determined in part by the diffractometer radius and the width of the receiving slit used. Typically, the X-ray diffraction system is operated to provide 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.

[0437] Powder samples are prepared in a low-background Si holder using light manual pressure to keep the sample surface flat and level with the reference surface of the sample holder. Each sample is analyzed from 2 to 40°2θ using a continuous scan of 6°2θ per minute with an effective step size of 0.02°2θ.

[0438] Differential Scanning Calorimetry (DSC)

[0439] DSC analysis is performed using a TA instrument. Instrument temperature calibration is performed using indium. The DSC cell is maintained under a nitrogen purge of ~50 mL per minute during each analysis. The sample is placed in a corrugated standard aluminum pan and heated from 25°C to 350°C at a rate of 10°C per minute.

[0440] Thermogravimetric (TG) analysis

[0441] TG analysis is performed using a TA instrument. The instrument balance is calibrated using Class M weights, and temperature calibration is performed using an Alumel. Nitrogen purging is approximately 40 mL per minute on the balance and 60 mL per minute in the furnace. Each sample is placed in a pre-weighed platinum pan and heated from 25°C to 350°C at a rate of 10°C per minute.

[0442] Nuclear Magnetic Resonance (NMR) Spectroscopy

[0443] Prepare a sample by dissolving the material in a solvent. Filter the solution and place it into individual 5mm NMR tubes for subsequent spectrum collection.

[0444] Primary inflammation screening

[0445] Salt screening experiments were performed using 12 acid salt-forming agents utilizing various crystallization techniques (cooling, slurrying, evaporation, and vapor diffusion). Experimental details for each salt-forming attempt are described in Table 11.

[0446]

[0447]

[0448] Secondary infection screening

[0449] compound 1 , Type A, compound 2 , Type A, compound 3 , type B, and compound 4 , expanded to Type A, and experimental details are described in Table 12.

[0450]

[0451] Example A - Preparation of Compound A

[0452]

[0453] The title compound was prepared according to the steps and intermediates described below and disclosed in Publication 411 (the full text thereof is incorporated herein by reference) (e.g., Reaction Scheme 1).

[0454] Reaction Equation 1 - compound A Synthesis of

[0455]

[0456] Step 1 : (3 R )- N -[2-(5-fluoro-3-pyridyl)-8-isopyridyl-pyrazolo[1,5-a][1,3,5]triazine-4-yl]-2,3,4,9-tetrahydro-1 H -Carbazole-3-amine (Compound A)

[0457]

[0458] i 4-chloro-2-(5-fluoro-3-pyridyl)-8-isopyridyl-pyrazolo[1,5-a][1,3,5]triazine (60.00 mg, 205.68 νmol, 1 oz) in -PrOH (4 mL) eq ), (3 R )-2,3,4,9-tetrahydro-1 H -Carbazole-3-amine (42.14 mg, 226.25 νmol, 1.1 eq ), DIEA (79.75 mg, 617.05 νmol, 107.48 νL, 3 eq The mixture of ) was degassed and purged three times with N2. The mixture was stirred at 55°C for 3 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to provide a residue, which was purified using a preparatory HPLC (Column: Phenomenex Gemini 150*25mm*10um; Mobile phase: [Water(0.05%HCl)-ACN]; B%: 70%-100%, 10 min) and subsequently freeze-dried, (3 R )- N -[2-(5-fluoro-3-pyridyl)-8-isopyridyl-pyrazolo[1,5-a][1,3,5]triazine-4-yl]-2,3,4,9-tetrahydro-1 H -Carbazole-3-amine (42.07 mg, 75.45 νmol, 36.7% yield, 98.8% purity, 3HCl) is obtained as a yellow solid. 1 H NMR (400MHz, CD3OD) δ ppm 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-LCMS m / z 442.2 [M+H] + .

[0459] Example 1 - Preparation of Free Bases A, B, and C of Compound A

[0460]

[0461] compound A Type B

[0462] compound AType B of was manufactured as described above.

[0463] Table B above is reproduced below, and the compound A The X-ray diffraction peaks observed for type B are presented.

[0464]

[0465] Fig. 1 silver compounds A The XRPD pattern of type B is illustrated.

[0466] Fig. 2 is a compound A Figure B's TG / DTA trace.

[0467] compound A Type C

[0468] compound A Type C of was manufactured as described above.

[0469] Table C above is reproduced below, and the compound A The X-ray diffraction peaks observed for the C type are presented.

[0470]

[0471]

[0472] Fig. 3 silver compounds A The XRPD pattern of type C is illustrated.

[0473] Fig. 4 is a compound A Figure C's TG / DTA trace.

[0474] compound A A mixture of Type A and Type B of

[0475] 7.0 g of the hydrochloride salt of Compound A was dissolved in a mixture of 150 mL of EtOAc and 200 mL of a saturated solution of NaHCO3 and stirred at 28°C for 30 minutes. The mixture was extracted with EtOAc (150 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried with Na2SO4, and concentrated to obtain the residue, which was added to 150 mL of MeOH and stirred for 30 minutes. The mixture was filtered, and the filter cake was concentrated to obtain the desired product, which was freeze-dried to obtain the compound A A mixture of type A and type B (6.7g) was obtained as a solid.

[0476] Fig. 24 is a compound A The XRPD pattern of a mixture of type A and type B is illustrated.

[0477] Fig. 25 is a compound A TGA / DSC of a mixture of Type A and Type B is shown.

[0478] Example 2 - Preparation of Type A of Compound 1

[0479]

[0480] compound 1 Type A

[0481] compound 1 Type A of was manufactured as described above.

[0482] Table 1 above is reproduced below, and the compound 1 The X-ray diffraction peaks observed for type A are presented.

[0483]

[0484] Fig. 5 is a compound 1 The XRPD pattern of type A is illustrated.

[0485] Fig. 6 silver compounds 1 It illustrates the TG / DTA trace of Type A.

[0486] compound 1 Type B

[0487] compound 1 Type B of was manufactured as described above.

[0488] Table 2 above is reproduced below, and the compound 1 The X-ray diffraction peaks observed for type B are presented.

[0489]

[0490] Fig. 7 silver compounds 1 The XRPD pattern of type B is illustrated.

[0491] Example 3 - Preparation of Type A of Compound 2

[0492]

[0493] compound 2 Type A

[0494] compound 2 Type A of was manufactured as described above.

[0495] Table 3 above is reproduced below, and the compound 2 The X-ray diffraction peaks observed for type A are presented.

[0496]

[0497] Fig. 8 silver compounds 2 The XRPD pattern of type A is illustrated.

[0498] Fig. 9 is a compound 2 It illustrates the TG / DTA trace of Type A.

[0499] Example 4 - Preparation of Type A of Compound 3

[0500]

[0501] compound 3 Type A

[0502] compound 3 Type A of was manufactured as described above.

[0503] Table 4 above is reproduced below, and the compound 3 The X-ray diffraction peaks observed for type A are presented.

[0504]

[0505] Fig. 10 silver compounds 3 The XRPD pattern of type A is illustrated.

[0506] Fig. 11 silver compounds 3 It illustrates the TG / DTA trace of Type A.

[0507] compound 3 Type B

[0508] compound 3 Type B of was manufactured as described above.

[0509] Table 5 above is reproduced below, and the compound 3 The X-ray diffraction peaks observed for type B are presented.

[0510]

[0511] Fig. 12 is a compound 3 The XRPD pattern of type B is illustrated.

[0512] Fig. 13 silver compounds 3 Figure B's TG / DTA trace.

[0513] Example 5 - Preparation of Type A of Compound 4

[0514]

[0515] compound 4 Type A

[0516] compound 4 Type A of was manufactured as described above.

[0517] Table 6 above is reproduced below, and the compound 4 The X-ray diffraction peaks observed for type A are presented.

[0518]

[0519] Fig. 14 is a compound 4 The XRPD pattern of type A is illustrated.

[0520] Fig. 15 is a compound 4 It illustrates the TG / DTA trace of Type A.

[0521] Example 6 - Preparation of Type A of Compound 5

[0522]

[0523] compound 5 of Type A

[0524] compound 5 of Type A was manufactured as described above.

[0525] Table 7 above is reproduced below, and the compound 5 of The X-ray diffraction peaks observed for Type A are presented.

[0526]

[0527] Fig. 16 silver compounds 5 of The XRPD pattern of type A is illustrated.

[0528] Fig. 17 silver compound 5 of Illuminates the TG / DTA trace of Type A.

[0529] Example 7 - Preparation of Type A and B of Compound 6

[0530]

[0531] Here, X is approximately 1 or 2.

[0532] compound 6 of Type A

[0533] compound 6 Type A of the compound was prepared as described above. 6 Type A is a compound A It was determined that it contains ethanedisulfonic acid in a ratio of about 1:1.

[0534] Table 8 above is reproduced below, and the compound 6 The X-ray diffraction peaks observed for type A are presented.

[0535]

[0536] Fig. 18 silver compounds 6 The XRPD pattern of type A is illustrated.

[0537] Fig. 19 is a compound 6 It illustrates the TG / DTA trace of Type A.

[0538] compound 6 of Type B

[0539] compound 6 Type B of was prepared as previously described. Compound 6 Type B is a compound A It was determined that it contains ethanedisulfonic acid in a ratio of about 2:1.

[0540] Table 9 above is reproduced below, and the compound 6 The X-ray diffraction peaks observed for type B are presented.

[0541]

[0542] Fig. 20 silver compounds 6 The XRPD pattern of type B is illustrated.

[0543] Fig. 21 silver compounds 6Figure B's TG / DTA trace.

[0544] Example 8 - Preparation of Type A of Compound 7

[0545]

[0546] compound 7 Type A

[0547] compound 7 Type A of was manufactured as described above.

[0548] Table 10 above is reproduced below, and the compound 7 The X-ray diffraction peaks observed for type A are presented.

[0549]

[0550] Fig. 22 is a compound 7 The XRPD pattern of type A is illustrated.

[0551] Fig. 23 silver compounds 7 It illustrates the TG / DTA trace of Type A.

[0552] Example 9 - Solubility Study

[0553] compound A , type B, compound 1 , type B, compound 2 , Type A, compound 3 , type B, and compound 4The solubility of type A was evaluated in water, fasted-state simulated intestinal fluid (FaSSIF), fed-state simulated intestinal fluid (FeSSIF), and fasted-state simulated gastric fluid (FaSSGF). The simulated fluids were prepared by supplying FaSSIF / FeSSIF / FaSSGF powder (v1, known as SIF powder) according to biorelevant.com. Samples were prepared by adding an excess of solid to 5 mL of medium at 37°C. Samples were drawn at 30 minutes, 120 minutes, and 24 hours, filtered, and tested for solution concentration using the HPLC parameters listed in Table 13.

[0554]

[0555] The pH of the samples was also measured at each time point; due to the small sample size, pH paper was used at 30 and 120 minutes, while a pH meter was used at 24 hours. The material remaining from all experiments was analyzed by XRD after 24 hours to determine whether changes in polymorphic forms had occurred. The material remaining from the water test was analyzed by NMR after 24 hours to determine whether dissociation had occurred. Compounds 1 Type B was not analyzed by NMR at 24 hours due to low material availability. The results are shown in Table 14.

[0556]

[0557]

[0558] As can be seen, compounds 2 , type A and compounds 3 , type B showed the highest solubility in FeSSIF at 24 hours.

[0559] Example 10 - Stability Study

[0560] compound A , type B, compound 1 , type B, compound 2 , Type A, compound 3 , type B, and compound 4 Stability studies of type A were performed at 40°C / 75% RH. Samples were stored in loosely capped vials in a chamber containing a saturated NaCl solution to achieve approximately 75% RH within the chamber. The chamber was stored in a 40°C oven. Samples were analyzed at time = 0, 1 week, 2 weeks, and 4 weeks using the HPLC parameters listed in Table 13. The results are shown in Table 15.

[0561]

[0562] Overall, compounds 3 Significant decomposition over time was observed for Type B. At the end of the study, the solid was confirmed to have lost all crystallinity and become X-ray amorphous. Compound A Type B and compounds 1 Form B appears to be equally stable at 40°C / 75% RH. Compound 4 Type A exhibited decomposition at weeks 1 and 2, but the decomposition peak was no longer present at week 4, resulting in an improvement in the area percentage of the main peak. 2 Type A is quite stable under these accelerated conditions, losing only ~1.5% of its area over 4 weeks.

[0563] Although many aspects of the present invention have been described, it is evident that the basic embodiments of the present invention may be modified to provide other aspects utilizing the compounds and methods of the present invention. Accordingly, it will be understood that the scope of the present invention is limited by the present application and claims, rather than by the specific aspects shown as examples.

Claims

Claim 1 compound 2 As a solid form of, A solid form that is a crystalline type A, characterized in that, where x = 2, the solid form has one or more peaks in its XRPD selected from those at 5.3, 11.3 and 16.0, ±0.2 degrees at 2-theta. Claim 2 A solid form having at least two peaks in its XRPD selected from those at 5.3, 11.3 and 16.0, ±0.2 degrees at 2-theta. Claim 3 In claim 1, solid form having peaks in its XRPD at 5.3, 6.6, 8.0, 9.6, 10.6, 11.3, 13.3, 14.1, 14.7, 16.0, 16.8, 17.4, 17.8, 18.7, 19.2, 19.9, 20.7, 21.3, 22.7, 24.0, 24.5, 26.3, 26.7, 27.1, 27.6, 28.1, 28.8, 29.3, 31.8, and 32.2, ±0.2 degrees, with peaks in its XRPD at 2-theta. Claim 4 In any one of claims 1 to 3, the solid form is an amorphous compound 2 Solid form that substantially does not contain. Claim 5 In any one of claims 1 to 3, the solid form is a solid form that substantially does not contain impurities. Claim 6 In claim 1, a solid form having an XRPD substantially similar to the following. Claim 7 An in vitro method for inhibiting AHR in a biological sample, comprising contacting the biological sample with a solid form according to any one of claims 1 to 3. Claim 8 A pharmaceutical composition used to treat an AHR-mediated disorder in a patient requiring treatment for an AHR-mediated disorder, comprising a solid form and a pharmaceutically acceptable carrier, adjuvant, or vehicle according to any one of claims 1 to 3, wherein the AHR-mediated disorder is a cancer or inflammatory disorder. Claim 9 In claim 8, the above AHR-mediated disorder is a cancer, a pharmaceutical composition. Claim 10 In claim 8, the above AHR-mediated disorder is an inflammatory disorder, pharmaceutical composition. Claim 11 In claim 8, the above pharmaceutical composition is a pharmaceutical composition administered orally. Claim 12 In claim 8, the pharmaceutical composition is administered in a range of 0.01 to 100 mg / day per 1 kg of body weight of the patient. Claim 13 In claim 8, the above composition is a pharmaceutical composition administered to the patient in combination with an additional therapeutic agent. Claim 14 A method for manufacturing a solid form according to any one of paragraphs 1 to 3, wherein the compound A A method comprising the steps of combining with maleic acid, dissolving in acetone at 50°C to form a mixture, cooling the mixture to room temperature, adding heptane to the mixture, and refrigerating the mixture overnight. Claim 15 delete Claim 16 delete Claim 17 delete Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete Claim 23 delete Claim 24 delete Claim 25 delete Claim 26 delete

Images