Biomarkers related to immune checkpoint inhibitor therapy and methods of using the same

Abstract

To provide biomarkers related to immune checkpoint inhibitor therapy and methods of using the same.SOLUTION: The disclosure relates to biomarkers predictive of a patient's cancer responsiveness to an immune checkpoint inhibitor therapy. The disclosure provides, in some embodiments, diagnostic and / or prognostic methods of using such biomarkers for determining whether a cancer patient could benefit from being treated with an aryl hydrocarbon receptor antagonist. In some embodiments, the biomarkers described herein may be used to inform and provide effective therapeutic methods for treating cancer comprising administering an aryl hydrocarbon receptor antagonist, optionally in combination with an immune checkpoint inhibitor therapy.SELECTED DRAWING: None

Description

[Technical field]

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 091,192, filed October 13, 2020, and U.S. Provisional Patent Application No. 63 / 107,309, filed October 29, 2020, the contents of each of which are incorporated by reference in their entirety herein.

[0002] The present disclosure relates to biomarkers that are predictive of a patient's cancer responsiveness to immune checkpoint inhibitor (ICI) therapy. In some embodiments, the present disclosure provides a diagnostic and / or prognostic method using such biomarkers, comprising: (a) measuring or having measured the amount of at least one biomarker from a serum, plasma, or stool sample obtained from a cancer patient; (b) comparing or having compared the amount of at least one biomarker with a threshold score; and (c) determining whether the cancer patient is likely to respond to treatment with an aryl hydrocarbon receptor (AhR) antagonist if the amount of at least one biomarker is above the threshold score. Aspects of the present disclosure further provide a method of treating cancer, comprising administering an AhR antagonist, optionally in combination with ICI therapy. [Background technology]

[0003] ICI therapy has become standard of care in the first-line setting for several tumors (Gandhi et al.,N Engl J Med.,2018,378(22),2078-2092; Socinski et al.N Engl J Med.,2018,378(24),2288-2301; Antonia et al.,N Engl J Med.,2017,377(20),1919-1929; Wolchok et al.,N Engl J Med.,2017,377(14),1345-1356; Cella et al.,Lancet Oncol.,2019,20(2),297-310). Treatment with this class of therapeutic agents aims to enhance the host immune response to various stages of tumor progression with fewer off-target outcomes compared to chemotherapy drugs (Tsai et al., Journal of biomedical science, 2017, 24(1), 35). Major ICI targets include programmed death 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), lymphocyte activation gene 3 (LAG-3), T-cell immunoglobulin and mucin domain-containing-3 (TIM-3), T-cell immunoglobulin and ITIM domain (TIGIT), and V-domain Ig suppressor of T-cell activation (VISTA).

[0004] Although ICI therapy has demonstrated significant clinical benefit in the treatment of multiple solid tumors, lack of response and / or development of resistance to this therapy has been observed in many patients (Horsman et al. al.,Int J Mol Sci.,2020,21(13),4778). Moreover, ICI therapy is generally expensive and may induce inflammatory toxicity in these patients (Das et al.,J Immunother Cancer.,2019,7(1),306). Therefore, it is important to define the likelihood of response to ICI therapy in order to design therapeutic strategies that can overcome primary or secondary resistance to such treatments.

[0005] Microbial metabolites play a role in patient response to ICI therapy. The gut microbiome is a diverse group of microorganisms that normally reside within specific regions of the gastrointestinal tract (Dieterich et al., Med Sci (Basel), 2018, 6(4): 116; Donaldson et al., Nat Rev Microbiol., 2016, 14(1): 20-32). In recent years, the relationship between the gut microbiome and overall host health has become a hot area of ​​medical research (Lin et al., BMC Immunol., 2017, 18(1): 2). In addition to playing a role in gut barrier homeostasis, the gut microbiota also plays a role in regulating immune function, and correlations between gut microbiota dysbiosis and certain inflammatory and malignant disease states of the gastrointestinal system have been established. The gut microbiota regulates immune responses at multiple levels, influencing neutrophil migration, shaping T cell differentiation at Th1, Th2, and Th17 or regulatory T cells (Tregs), and modulating immune homeostasis and inflammation (Rossi et al., Int Rev Immunol., 2013, 32(5-6):471-474; Pandiyan et al., Front Immunol., 2019, 10:426). Responses to ICI therapy are impaired in response to microbiome modifications. Germ-free and antibiotic-treated mice bearing solid tumors often exhibit a suppressed response to ICI therapy, associated with a diminished cellular immune response and reduced cytokine production (Gopalakrishnan et al., Science, 2018, 359(6371):97-103). Administration of a probiotic cocktail of Bifidobacterium was able to restore a more efficient response to ICI therapy in a mouse cancer model (Matson et al., Science, 2018, 359(6371):104-108). Stool metagenomic analysis performed in melanoma patients revealed different microbiome compositions in responders versus non-responders to ICI therapy, with responders exhibiting higher abundance of Bifidobacterium longum, Collinsella aerofaciens, and Enterococcus faecium (Matson et al., Science, 2018, 359(6371):104-108). Similarly, microbiota composition analysis in humans, particularly enrichment of Akkermansia muciniphila and Alistipes, has been used to predict response to anti-PD-1 / PD-L1 therapy in solid epithelial tumors such as non-small cell lung cancer (Routy et al., Science, 2018, 359(6371):91-97). A significant number of Clostridiales, Ruminococcaceae, or Faecalibacterium bacteroidales strains were identified in melanoma patients with CD4 + and CD8 +It has been associated with better responses to anti-PD-1 through T cell activation and modulation of Tregs and myeloid-derived suppressor cells (Gopalakrishnan et al., Science, 2018, 359(6371):97-103). Fecal microbiota transfer from responder patients to germ-free (GF) mice improved ICI efficacy. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Gandhi et al.,N Engl J Med.,2018,378(22),2078-2092 [Non-Patent Document 2] Socinski et al.N Engl J Med.,2018,378(24),2288-2301 [Non-Patent Document 3] Antonia et al.,N Engl J Med.,2017,377(20),1919-1929 [Non-Patent Document 4] Wolchok et al.,N Engl J Med.,2017,377(14),1345-1356 [Non-Patent Document 5] Cella et al.,Lancet Oncol.,2019,20(2),297-310 [Non-Patent Document 6] Tsai et al.,Journal of biomedical science,2017,24(1),35 [Non-Patent Document 7] Horsman et al.,Int J Mol Sci.,2020,21(13),4778 [Non-Patent Document 8] Das et al.,J Immunother Cancer.,2019,7(1),306 [Non-Patent Document 9] Dieterich et al.,Med Sci(Basel),2018,6(4):116 [Non-Patent Document 10] Donaldson et al., Nat Rev Microbiol.,2016,14(1):20-32 [Non-Patent Document 11] Lin et al.,BMC Immunol.,2017,18(1):2 [Non-Patent Document 12] Rossi et al.,Int Rev Immunol.,2013,32(5-6):471-474 [Non-Patent Document 13] Pandiyan et al.,Front Immunol.,2019,10:426 [Non-Patent Document 14] Gopalakrishnan et al.,Science,2018,359(6371):97-103 [Non-Patent Document 15] Matson et al.,Science,2018,359(6371):104-108 [Non-Patent Document 16] Routy et al.,Science,2018,359(6371):91-97 Summary of the Invention [Problem to be solved by the invention]

[0007] Thus, preclinical studies in mice and even early observation human cohorts suggest a complex interplay between bacteria and immune host response in antitumor activity. There is still a need to identify biomarkers, such as microbial metabolites, that are predictive of cancer patient responsiveness to ICI therapy. Such biomarkers may provide valuable information for determining the efficacy of ICI therapy and incorporating such determination into improved therapeutic strategies for cancer treatment. [Means for solving the problem]

[0008] The present disclosure relates to biomarkers that are predictive of a patient's cancer responsiveness to ICI therapy. In some embodiments, the present disclosure provides a method for determining whether a cancer patient is likely to respond to treatment with an AhR antagonist. In some embodiments, the present disclosure provides a method for predicting a patient's cancer responsiveness to ICI therapy. Aspects of the present disclosure further provide an improved method for treating a cancer patient, comprising administering an AhR antagonist to a cancer patient, optionally in combination with ICI therapy. In some embodiments, the patient has been previously treated with ICI therapy, but has not responded to ICI therapy. In some embodiments, the patient has been previously treated with ICI therapy, and has developed resistance to ICI therapy.

[0009] Particular embodiments of the present disclosure are summarized in the following paragraphs: This list is exemplary only and is not intended to be exhaustive of all embodiments provided by the present disclosure.

[0010] Embodiment 1. A method of treating cancer in a patient in need thereof, comprising: (a) measuring or having measured an amount of at least one aryl hydrocarbon receptor (AhR) ligand from a serum, plasma, or fecal sample obtained from the patient; (b) comparing or having compared the amount of the at least one AhR ligand to a threshold score; (c) determining or having determined that the patient is likely to respond to treatment with an AhR antagonist if the amount of the at least one AhR ligand is above the threshold score; and (d) treating the patient determined to be responsive in (c) with an effective amount of an AhR antagonist.

[0011] Embodiment 2. The patient is having non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, adenocarcinoma of the stomach, nasopharyngeal neoplasms, urothelial carcinoma, colorectal cancer, pleural mesothelioma, triple negative breast cancer, esophageal neoplasms, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung cancer, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma, diffuse large B cell neoplasms. 2. The method of embodiment 1, wherein the patient is suffering from alveolar lymphoma, renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignancies, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer, gastric cancer, colon cancer, or liver cancer.

[0012] Embodiment 3. The method of embodiment 1 or embodiment 2, wherein the patient has been treated with immune checkpoint inhibitor (ICI) therapy but has not responded to the ICI therapy.

[0013] Embodiment 4. The method of embodiment 1 or embodiment 2, wherein the patient has been treated with ICI therapy and has developed resistance to ICI therapy.

[0014] Embodiment 5. The method of any one of embodiments 1-4, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indole lactate, or a combination thereof.

[0015] Embodiment 6 The method of embodiment 5, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, and indole lactate.

[0016] Embodiment 7. The method of any one of embodiments 1 to 6, wherein the amount of at least one AhR ligand in the sample is measured by liquid chromatography-mass spectrometry or gas phase chromatography-mass spectrometry.

[0017] Embodiment 8. The method of any one of embodiments 1 to 7, wherein the threshold score is determined by measuring the amount of corresponding at least one AhR ligand in a control serum, plasma, or fecal sample obtained from a patient responding to ICI therapy.

[0018] Embodiment 9. The AhR antagonist has Formula I: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: R 1 and R 2 are each independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3 is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H.

[0019] Embodiment 10. The AhR antagonist has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and The method of any one of embodiments 1-9, wherein R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H.

[0020] Embodiment 11. The method of any one of embodiments 1-9, wherein the AhR antagonist is any one of those listed in Table 2, or a pharma- ceutically acceptable salt thereof.

[0021] Embodiment 12. An in vitro method for determining whether a patient is likely to benefit from treatment with an aryl hydrocarbon receptor (AhR) antagonist, comprising: (a) measuring or having measured an amount of at least one AhR ligand from a serum, plasma, or stool sample obtained from the patient; (b) comparing or having compared the amount of the at least one AhR ligand with a threshold score; and (c) determining that the patient is likely to benefit from treatment with an AhR antagonist if the amount of the at least one AhR ligand is above the threshold score.

[0022] Embodiment 13. The patient is having non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, adenocarcinoma of the stomach, nasopharyngeal neoplasms, urothelial carcinoma, colorectal carcinoma, pleural mesothelioma, triple negative breast cancer, esophageal neoplasms, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung carcinoma, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma, diffuse large B cell neoplasms. 13. The method of embodiment 12, wherein the patient is suffering from alveolar lymphoma, renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignant tumor, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer, gastric cancer, colon cancer, or liver cancer.

[0023] Embodiment 14. The method of embodiment 12 or embodiment 13, wherein the patient has been treated with immune checkpoint inhibitor (ICI) therapy but has not responded to ICI therapy.

[0024] Embodiment 15. The method of embodiment 12 or embodiment 13, wherein the patient has been treated with ICI therapy and has developed resistance to ICI therapy.

[0025] Embodiment 16 The method of any one of embodiments 12-15, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indole lactate, or a combination thereof.

[0026] Embodiment 17 The method of embodiment 16, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, and indole lactate.

[0027] Embodiment 18. The method according to any one of embodiments 12 to 17, wherein the amount of at least one AhR ligand in the sample is measured by liquid chromatography-mass spectrometry or gas phase chromatography-mass spectrometry.

[0028] Embodiment 19. The method according to any one of embodiments 12 to 18, wherein the threshold score is determined by measuring the amount of corresponding at least one AhR ligand in a control serum, plasma, or fecal sample obtained from a patient responding to ICI therapy.

[0029] Embodiment 20. The AhR antagonist has Formula I: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: R 1 and R 2 are each independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3 is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H.

[0030] Embodiment 21. The AhR antagonist has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and 21. The method of any one of embodiments 12-20, wherein R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H.

[0031] Embodiment 22 The method of any one of embodiments 12-20, wherein the AhR antagonist is any one of those listed in Table 2, or a pharma- ceutically acceptable salt thereof.

[0032] Embodiment 23. A method of treating cancer with a combination therapy comprising an immune checkpoint inhibitor (ICI) and an aryl hydrocarbon receptor (AhR) antagonist in a patient in need thereof, comprising: (a) measuring or having measured an amount of at least one AhR ligand from a serum, plasma, or stool sample obtained from the patient; (b) comparing or having compared the amount of the at least one AhR ligand with a threshold score; (c) determining or having determined that the patient is likely to respond to the combination therapy if the amount of the at least one AhR ligand is above the threshold score; and (d) treating a patient determined to respond in (c) with the combination therapy.

[0033] Embodiment 24. The patient is having non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, adenocarcinoma of the stomach, nasopharyngeal neoplasms, urothelial carcinoma, colorectal carcinoma, pleural mesothelioma, triple negative breast cancer, esophageal neoplasms, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung carcinoma, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma, diffuse large B cell neoplasms. 24. The method of embodiment 23, wherein the patient is suffering from alveolar lymphoma, renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignant tumor, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer, gastric cancer, colon cancer, or liver cancer.

[0034] Embodiment 25 The method of embodiment 23 or embodiment 24, wherein the patient has been treated with ICI therapy but has not responded to ICI therapy.

[0035] Embodiment 26 The method of embodiment 23 or embodiment 24, wherein the patient has been treated with ICI therapy and has developed resistance to ICI therapy.

[0036] Embodiment 27. The method of any one of embodiments 23-26, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indole lactate, or a combination thereof.

[0037] Embodiment 28 The method of embodiment 27, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, and indole lactate.

[0038] Embodiment 29. The method of any one of embodiments 23 to 28, wherein the amount of at least one AhR ligand in the sample is measured by liquid chromatography-mass spectrometry or gas phase chromatography-mass spectrometry.

[0039] Embodiment 30. The method of any one of embodiments 23-29, wherein the ICI therapy comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-TIGIT antibody, an anti-VISTA antibody, or a combination thereof.

[0040] Embodiment 31. The method according to any one of embodiments 23 to 30, wherein the threshold score is determined by measuring the amount of corresponding at least one AhR ligand in a control serum, plasma, or fecal sample obtained from a patient responding to ICI therapy.

[0041] Embodiment 32. The AhR antagonist has Formula I: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: R 1 and R 2are each independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3 is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H.

[0042] Embodiment 33. The AhR antagonist has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and The method of any one of embodiments 23-32, wherein R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H.

[0043] Embodiment 34 The method of any one of embodiments 23-33, wherein the AhR antagonist is any one of those listed in Table 2, or a pharma- ceutically acceptable salt thereof.

[0044] Embodiment 35. An in vitro method for predicting a patient's cancer responsiveness to immune checkpoint inhibitor (ICI) therapy, comprising: (a) measuring or having measured an amount of at least one aryl hydrocarbon receptor (AhR) ligand from a serum, plasma, or stool sample obtained from the patient; (b) comparing or having compared the amount of the at least one AhR ligand to a threshold score; and (c) determining that the patient's cancer is likely to respond to ICI therapy if the amount of the at least one AhR ligand is equal to or less than the threshold score.

[0045] Embodiment 36. The patient is having non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, adenocarcinoma of the stomach, nasopharyngeal neoplasms, urothelial carcinoma, colorectal carcinoma, pleural mesothelioma, triple negative breast cancer, esophageal neoplasms, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung carcinoma, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma, diffuse large B cell neoplasms. 36. The method of embodiment 35, wherein the patient is suffering from alveolar lymphoma, renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignant tumor, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer, gastric cancer, colon cancer, or liver cancer.

[0046] Embodiment 37 The method of embodiment 35 or embodiment 36, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indole lactate, or a combination thereof.

[0047] Embodiment 38 The method of embodiment 37, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, and indole lactate.

[0048] Embodiment 39. The method according to any one of embodiments 35 to 38, wherein the amount of at least one AhR ligand in the sample is measured by liquid chromatography-mass spectrometry or gas phase chromatography-mass spectrometry.

[0049] Embodiment 40. The method of any one of embodiments 35-39, wherein the ICI therapy comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-TIGIT antibody, an anti-VISTA antibody, or a combination thereof.

[0050] Embodiment 41. The method according to any one of embodiments 35 to 40, wherein the threshold score is determined by measuring the amount of corresponding at least one AhR ligand in a control serum, plasma, or fecal sample obtained from a patient responding to ICI therapy.

[0051] Embodiment 42. The method of any one of embodiments 35 to 41, further comprising determining that the patient's cancer is likely to respond to ICI therapy in combination with an AhR antagonist if the amount of at least one AhR ligand is above a threshold score.

[0052] Embodiment 43. The AhR antagonist has Formula I: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: R 1 and R 2 are each independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3 is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H.

[0053] Embodiment 44. The AhR antagonist has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and The method of embodiment 42 or embodiment 43, wherein R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H.

[0054] Embodiment 45 The method of any one of embodiments 42-44, wherein the AhR antagonist is any one of those listed in Table 2, or a pharma- ceutically acceptable salt thereof.

[0055] Embodiment 46. A method of treating cancer in a patient in need thereof comprising treating the patient with an effective amount of an aryl hydrocarbon receptor (AhR) antagonist, wherein a serum, plasma, or fecal sample obtained from the patient has an amount of at least one AhR ligand above a threshold score.

[0056] Embodiment 47. The patient is having non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, adenocarcinoma of the stomach, nasopharyngeal neoplasms, urothelial carcinoma, colorectal carcinoma, pleural mesothelioma, triple negative breast cancer, esophageal neoplasms, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung carcinoma, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma, diffuse large B cell neoplasms. 47. The method of embodiment 46, wherein the patient is suffering from alveolar lymphoma, renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignant tumor, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer, gastric cancer, colon cancer, or liver cancer.

[0057] Embodiment 48. The method of embodiment 46 or embodiment 47, wherein the patient has been treated with immune checkpoint inhibitor (ICI) therapy but has not responded to ICI therapy.

[0058] Embodiment 49. The method of embodiment 46 or embodiment 47, wherein the patient has been treated with ICI therapy and has developed resistance to ICI therapy.

[0059] Embodiment 50. The method of any one of embodiments 46-49, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indole lactate, or a combination thereof.

[0060] Embodiment 51 The method of embodiment 50, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, and indole lactate.

[0061] Embodiment 52. The method of any one of embodiments 46 to 51, wherein the amount of at least one AhR ligand in the sample is measured by liquid chromatography-mass spectrometry or gas phase chromatography-mass spectrometry.

[0062] Embodiment 53. The method according to any one of embodiments 46 to 52, wherein the threshold score is determined by measuring the amount of at least one corresponding AhR ligand in a control serum, plasma, or fecal sample obtained from a patient responding to ICI therapy.

[0063] Embodiment 54. The AhR antagonist has Formula I: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: R 1 and R 2 are each independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3 is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H.

[0064] Embodiment 55. The AhR antagonist has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and 54. The method of any one of embodiments 46-53, wherein R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H.

[0065] Embodiment 56 The method of any one of embodiments 46-55, wherein the AhR antagonist is any one of those listed in Table 2, or a pharma- ceutically acceptable salt thereof.

[0066] Embodiment 57. A method of treating cancer in a patient in need thereof comprising treating the patient with a combination therapy comprising an immune checkpoint inhibitor (ICI) and an aryl hydrocarbon receptor (AhR) antagonist, wherein a serum, plasma, or fecal sample obtained from the patient has an amount of at least one AhR ligand above a threshold score.

[0067] Embodiment 58. The patient is having non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, adenocarcinoma of the stomach, nasopharyngeal neoplasm, urothelial carcinoma, colorectal carcinoma, pleural mesothelioma, triple negative breast cancer, esophageal neoplasm, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung carcinoma, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma, diffuse large B cell neoplasm. 58. The method of embodiment 57, wherein the patient is suffering from alveolar lymphoma, renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignant tumor, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer, gastric cancer, colon cancer, or liver cancer.

[0068] Embodiment 59. The method of embodiment 57 or embodiment 58, wherein the patient has been treated with immune checkpoint inhibitor (ICI) therapy but has not responded to ICI therapy.

[0069] Embodiment 60. The method of embodiment 57 or embodiment 58, wherein the patient has been treated with ICI therapy and has developed resistance to ICI therapy.

[0070] Embodiment 61. The method of any one of embodiments 57-60, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indole lactate, or a combination thereof.

[0071] Embodiment 62. The method of embodiment 61, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, and indole lactate.

[0072] Embodiment 63. The method of any one of embodiments 57 to 62, wherein the amount of at least one AhR ligand in the sample is measured by liquid chromatography-mass spectrometry or gas phase chromatography-mass spectrometry.

[0073] Embodiment 64. The method of any one of embodiments 57-63, wherein the ICI therapy comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-TIGIT antibody, an anti-VISTA antibody, or a combination thereof.

[0074] Embodiment 65. The method according to any one of embodiments 57 to 64, wherein the threshold score is determined by measuring the amount of at least one corresponding AhR ligand in a control serum, plasma, or fecal sample obtained from a patient responding to ICI therapy.

[0075] Embodiment 66. The AhR antagonist has Formula I: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: R 1 and R 2 are each independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H.

[0076] Embodiment 67. The AhR antagonist has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and The method of any one of embodiments 57-66, wherein R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H.

[0077] Embodiment 68. The method of any one of embodiments 57-66, wherein the AhR antagonist is any one listed in Table 2, or a pharma- ceutically acceptable salt thereof.

[0078] Embodiment 69. An arylhydrocarbon receptor (AhR) antagonist for use in a method for treating cancer in a patient in need thereof, wherein a serum, plasma or stool sample obtained from the patient has an amount of at least one AhR ligand above a threshold score.

[0079] Embodiment 70. The patient is diagnosed with non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, adenocarcinoma of the stomach, nasopharyngeal neoplasms, urothelial carcinoma, colorectal carcinoma, pleural mesothelioma, triple negative breast cancer, esophageal neoplasms, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell type lung carcinoma, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma, diffuse large B cell lymphoma, renal 70. The AhR antagonist for use according to embodiment 69, in which the patient is suffering from: carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignant tumors, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer, gastric cancer, colon cancer, or liver cancer.

[0080] Embodiment 71. The AhR antagonist for use according to embodiment 69 or embodiment 70, wherein the patient is being treated with immune checkpoint inhibitor (ICI) therapy but is not responding to ICI therapy.

[0081] Embodiment 72. The AhR antagonist for use according to embodiment 69 or embodiment 70, wherein the patient is being treated with ICI therapy and has developed resistance to ICI therapy.

[0082] Embodiment 73. The AhR antagonist for use according to any one of embodiments 69 to 72, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indole lactate, or a combination thereof.

[0083] Embodiment 74. The AhR antagonist for use according to embodiment 73, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, and indole lactate.

[0084] Embodiment 75. The AhR antagonist for use according to any one of embodiments 69 to 74, wherein the amount of at least one AhR ligand in the sample is measured by liquid chromatography-mass spectrometry or gas phase chromatography-mass spectrometry.

[0085] Embodiment 76. An AhR antagonist for use according to any one of embodiments 69 to 75, wherein the threshold score is determined by measuring the amount of at least one corresponding AhR ligand in a control serum, plasma or fecal sample obtained from a patient responding to ICI therapy.

[0086] Embodiment 77. The AhR antagonist has formula I: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: R 1 and R 2 are each independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3 is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H.

[0087] Embodiment 78. The AhR antagonist has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and The AhR antagonist for use according to any one of embodiments 69 to 77, wherein R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H.

[0088] Embodiment 79. The AhR antagonist for use according to any one of embodiments 69 to 77, wherein the AhR antagonist is any one listed in Table 2, or a pharma- ceutically acceptable salt thereof.

[0089] Embodiment 80. A combination therapy for use in a method of treating cancer in a patient in need thereof, the combination therapy comprising an immune checkpoint inhibitor (ICI) and an aryl hydrocarbon receptor (AhR) antagonist, and further wherein a serum, plasma, or stool sample obtained from the patient has an amount of at least one AhR ligand above a threshold score.

[0090] Embodiment 81. The patient is diagnosed with non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, adenocarcinoma of the stomach, nasopharyngeal neoplasms, urothelial carcinoma, colorectal carcinoma, pleural mesothelioma, triple-negative breast cancer, esophageal neoplasms, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung carcinoma, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma, diffuse large B-cell lymphoma. , renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignant tumors, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer, gastric cancer, colon cancer, or liver cancer.

[0091] Embodiment 82. The combination therapy for use according to embodiment 80 or embodiment 81, wherein the patient has been treated with immune checkpoint inhibitor (ICI) therapy but has not responded to ICI therapy.

[0092] Embodiment 83. The combination therapy for use according to embodiment 80 or embodiment 81, wherein the patient has been treated with ICI therapy and has developed resistance to ICI therapy.

[0093] Embodiment 84. The combination therapy for use according to any one of embodiments 80 to 83, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indole lactate, or a combination thereof.

[0094] Embodiment 85. The combination therapy for use according to embodiment 84, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, and indole lactate.

[0095] Embodiment 86. A combination therapy for use according to any one of embodiments 80 to 85, wherein the amount of at least one AhR ligand in the sample is measured by liquid chromatography-mass spectrometry or gas phase chromatography-mass spectrometry.

[0096] Embodiment 87. The combination therapy for use according to any one of embodiments 80 to 86, wherein the ICI therapy comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-TIGIT antibody, an anti-VISTA antibody, or a combination thereof.

[0097] Embodiment 88. A combination therapy for use according to any one of embodiments 80 to 87, wherein the threshold score is determined by measuring the amount of corresponding at least one AhR ligand in a control serum, plasma or fecal sample obtained from a patient responding to ICI therapy.

[0098] Embodiment 89. The AhR antagonist has Formula I: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: R 1 and R 2are each independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3 is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H.

[0099] Embodiment 90. The AhR antagonist has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and The combination therapy for use according to any one of embodiments 80 to 89, wherein R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H.

[0100] Embodiment 91. The combination therapy for use according to any one of embodiments 80 to 89, wherein the AhR antagonist is any one listed in Table 2, or a pharma- ceutically acceptable salt thereof.

[0101] Embodiment 92. Use of an aryl hydrocarbon receptor (AhR) antagonist in the manufacture of a pharmaceutical agent for treating cancer in a patient in need thereof, wherein a serum, plasma or stool sample obtained from the patient has an amount of at least one AhR ligand above a threshold score.

[0102] Embodiment 93. The patient is having non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, adenocarcinoma of the stomach, nasopharyngeal neoplasms, urothelial carcinoma, colorectal carcinoma, pleural mesothelioma, triple negative breast cancer, esophageal neoplasms, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung carcinoma, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma, diffuse large B cell neoplasms. The use according to embodiment 92, wherein the patient is suffering from alveolar lymphoma, renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignant tumor, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer, gastric cancer, colon cancer, or liver cancer.

[0103] Embodiment 94. The use of embodiment 92 or embodiment 93, wherein the patient has been treated with immune checkpoint inhibitor (ICI) therapy but has not responded to ICI therapy.

[0104] Embodiment 95. The use according to embodiment 92 or embodiment 93, wherein the patient has been treated with ICI therapy and has developed resistance to ICI therapy.

[0105] Embodiment 96. The use according to any one of embodiments 92 to 95, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indole lactate, or a combination thereof.

[0106] Embodiment 97. The use according to embodiment 96, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, and indole lactate.

[0107] Embodiment 98. The use according to any one of embodiments 92 to 97, wherein the amount of at least one AhR ligand in the sample is measured by liquid chromatography-mass spectrometry or gas phase chromatography-mass spectrometry.

[0108] Embodiment 99. The use according to any one of embodiments 92 to 98, wherein the threshold score is determined by measuring the amount of at least one corresponding AhR ligand in a control serum, plasma or fecal sample obtained from a patient responding to ICI therapy.

[0109] Embodiment 100. The AhR antagonist has Formula I: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: R 1 and R 2are each independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3 The use according to any one of embodiments 92 to 99, wherein is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H.

[0110] Embodiment 101. The AhR antagonist has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and The use according to any one of embodiments 92 to 100, wherein R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H.

[0111] Embodiment 102. The use according to any one of embodiments 92 to 100, wherein the AhR antagonist is any one listed in Table 2, or a pharma- ceutically acceptable salt thereof.

[0112] Embodiment 103. Use of an immune checkpoint inhibitor (ICI) and an aryl hydrocarbon receptor (AhR) antagonist in the manufacture of a pharmaceutical agent for treating cancer in a patient in need thereof, wherein a serum, plasma or stool sample obtained from the patient has an amount of at least one AhR ligand above a threshold score.

[0113] Embodiment 104. The patient is having non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, adenocarcinoma of the stomach, nasopharyngeal neoplasms, urothelial carcinoma, colorectal carcinoma, pleural mesothelioma, triple negative breast cancer, esophageal neoplasms, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung carcinoma, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma, diffuse large B cell neoplasms. The use according to embodiment 103, wherein the patient is suffering from alveolar lymphoma, renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignant tumor, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer, gastric cancer, colon cancer, or liver cancer.

[0114] Embodiment 105. The use according to embodiment 103 or embodiment 104, wherein the patient has been treated with immune checkpoint inhibitor (ICI) therapy but has not responded to ICI therapy.

[0115] Embodiment 106. The use according to embodiment 103 or embodiment 104, wherein the patient has been treated with ICI therapy and has developed resistance to ICI therapy.

[0116] Embodiment 107. The use according to any one of embodiments 103 to 106, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indole lactate, or a combination thereof.

[0117] Embodiment 108. The use according to embodiment 107, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, and indole lactate.

[0118] Embodiment 109. The use according to any one of embodiments 103 to 108, wherein the amount of at least one AhR ligand in the sample is measured by liquid chromatography-mass spectrometry or gas phase chromatography-mass spectrometry.

[0119] Embodiment 110. The use according to any one of embodiments 103 to 109, wherein the ICI therapy comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-TIGIT antibody, an anti-VISTA antibody, or a combination thereof.

[0120] Embodiment 111. The use according to any one of embodiments 103 to 110, wherein the threshold score is determined by measuring the amount of at least one corresponding AhR ligand in a control serum, plasma or fecal sample obtained from a patient responding to ICI therapy.

[0121] Embodiment 112. The AhR antagonist has formula I: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: R 1 and R 2 are each independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H.

[0122] Embodiment 113. The AhR antagonist has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, and wherein: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and The use according to any one of embodiments 103 to 112, wherein R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H.

[0123] Embodiment 114. The use according to any one of embodiments 103 to 112, wherein the AhR antagonist is any one of those listed in Table 2, or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0124] [Figure 1A] 1A-1B show levels of kynurenine, tryptophan, phenylpyruvate, and indolactate (collectively, the associated ligands) from fecal samples (FIG. 1A) and plasma samples (FIG. 1B) obtained from the 73 patients from Example 1 who were ultimately further characterized as either responders or non-responders. [Figure 1B] 1A-1B show levels of kynurenine, tryptophan, phenylpyruvate, and indolactate (collectively, the associated ligands) from fecal samples (FIG. 1A) and plasma samples (FIG. 1B) obtained from the 73 patients from Example 1 who were ultimately further characterized as either responders or non-responders. [Diagram 2] FIG. 2 shows elevated levels of related ligands from fecal samples obtained from 19 patients who received ICI therapy alone (no concomitant therapy) who were eventually further characterized as either responders or non-responders. [Diagram 3] Figure 3 shows a principal component analysis for dimensionality reduction of the signal from the full panel of 29 AhR ligands compared to the associated ligands: Left panel: 73 patients-29 AhR ligands; Middle panel: 73 patients-associated ligands; Right panel: 19 patients receiving ICI therapy only-associated ligands. [Figure 4A-4B] Figures 4A-4B show tumor growth curves (Figure 4A) and tumor weights (Figure 4B) measured after administration of an isotype control antibody, an anti-PD-L1 antibody, and compound #30 from Table 2 in combination with an anti-PD-L1 antibody (BioXcell anti-mouse PD-L1, B7-H1 clone 10F.9G2) in a mouse model of colon cancer resistant to anti-PD-L1 therapy. [Diagram 5]FIG. 5 shows the levels of AhR ligands listed in Table 1 in patients who received ICI therapy alone (no concomitant therapy) who were eventually further characterized as either responders or non-responders. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0125] The present disclosure is based in part on the discovery that certain AhR ligands, such as kynurenine, tryptophan, phenylpyruvate, and indole lactate, are useful biomarkers that are predictive of a patient's cancer responsiveness to ICI therapy. In some embodiments, the present disclosure provides a method for predicting a patient's cancer responsiveness to ICI therapy based on determining the amount of at least one biomarker compared to a threshold score. In some embodiments, the biomarkers described herein may allow for the identification and / or stratification of cancer patients who may benefit from treatment with AhR antagonists. In some embodiments, the biomarkers described herein may be used to inform and provide effective treatment methods for cancer patients receiving one or more ICI therapies.

[0126] References herein to methods of treatment (e.g., methods of treating cancer) using aryl hydrocarbon receptor (AhR) antagonists or combination therapies include the following: - an AhR antagonist or combination therapy, for example for use in a method for treating cancer; and / or - Use of an AhR antagonist or a combination therapy in the manufacture of a pharmaceutical agent for treating, for example, cancer. It should be understood that this should also be construed as a reference to

[0127] The following detailed description and examples illustrate specific embodiments of the present disclosure. Those skilled in the art will recognize that there are many variations and modifications of the present disclosure that fall within its scope. Therefore, the description of a specific embodiment should not be considered as limiting the scope of the present disclosure.

[0128] definition In order that the present disclosure may be more readily understood, certain terms are defined throughout the detailed description. Unless otherwise defined herein, all technical and scientific terms used in connection with the present disclosure have the same meaning as commonly understood by one of ordinary skill in the art.

[0129] As used herein, the singular forms of words also include the plural unless the context clearly dictates otherwise; by way of example, the terms "a," "an," and "the" are understood to be either singular or plural. The word "or" is intended to mean "and / or" unless the specific context dictates otherwise.

[0130] As used herein, the term "biomarker" refers to a biological compound present in a biological sample, which can be isolated from or measured in a biological sample. Such biomarkers include, but are not limited to, nucleic acids, proteins, carbohydrates, lipids, organic or inorganic chemicals, natural polymers, and metabolites. In some embodiments, the biomarkers include one or more AhR ligands, such as kynurenine, tryptophan, phenylpyruvate, and indole lactate, as shown in Example 1. In some embodiments, the biomarkers disclosed herein can be predictors of the responsiveness of cancer patients to ICI therapy.

[0131] As used herein, the terms "measuring" or "detecting" refer to assessing the presence, absence, or amount of a biomarker disclosed herein in a biological sample, including derivation of a quantitative level of such a biomarker. In some embodiments, the amount of at least one biomarker in a biological sample is measured or detected using methods known in the art, such as liquid chromatography mass spectrometry or gas phase chromatography mass spectrometry.

[0132] As used herein, the term "threshold score" refers to the amount of a reference biomarker, suitable for providing a comparison with the amount of that biomarker in a test sample. In some embodiments, the threshold score is the amount of the biomarker in serum, plasma, or fecal samples from cancer patients responding to ICI therapy. In some embodiments, the threshold score can be generated from a population or cohort of two or more cancer patients responding to ICI therapy. The population or cohort can include, for example, at least 2, 3, 4, 5, 10, 15, 18, 20, 30, 40, 50, 75, 100, or more cancer patients. In such embodiments, the threshold score for each biomarker can be the average amount of that biomarker in serum, plasma, or fecal samples from a population or cohort of cancer patients responding to ICI therapy.

[0133] The terms "biological sample" and "sample" are used interchangeably and refer to a specimen obtained from a patient, including bodily fluids, biological tissues (e.g., tumor tissue), cells, or other sources. In some embodiments, the biological sample comprises feces obtained from a cancer patient undergoing ICI therapy. In some embodiments, the biological sample comprises plasma obtained from a cancer patient undergoing ICI therapy. In some embodiments, the biological sample comprises feces obtained from a cancer patient not undergoing ICI therapy. In some embodiments, the biological sample comprises plasma obtained from a cancer patient not undergoing ICI therapy. Methods for obtaining such biological samples from cancer patients are known in the art.

[0134] As used herein, the term "AhR ligand" refers to a compound that binds to and activates the aromatic hydrocarbon receptor (i.e., AhR), which is expressed on many cells of the immune system, and upon binding causes the translocation of AhR to the nucleus, where it interacts with and regulates the transcription of dioxin response elements (DREs) of AhR-responsive genes. AhR ligands are known in the art and include classical xenobiotics such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 3-methylcholanthrene. Other examples of AhR ligands include kynurenine, tryptophan, phenylpyruvate, indolactate, beta-naphthoflavone (BNF), 6-formylindolo(3,2-b)carbazole (FICZ), and 2-(1H-indol-3-ylcarbonyl)-4-thiazole carboxylic acid methyl ester (ITE). Additionally, Table 1 lists the 29 AhR ligands examined in Example 1, including kynurenine, tryptophan, phenylpyruvate, and indole lactate.

[0135] As used herein, the term "AhR antagonist" refers to any agent capable of inhibiting or reducing the biological activity of the AhR to which it is bound. In some embodiments, the AhR antagonist reduces the activity of AhR by at least about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 99% compared to the activity of AhR in the absence of the AhR antagonist. Certain AhR antagonists, such as α-naphthoflavone and resveratrol, are known in the art. Other AhR antagonists are described in this disclosure. See, for example, Table 2.

[0136] The terms "comprise," "contain," "have," and "include" are open-ended linking verbs. Any form or tense of one or more of these verbs, such as "comprises," "comprising," "contains," "containing," "has," "having," "includes," and "including," are also open-ended. For example, any method that "comprises," "contains," "has," or "includes" one or more steps is not limited to only that one or more steps, but may also cover other unlisted steps. The use of any examples or exemplary language (e.g., "such as") provided for specific embodiments herein is intended merely to facilitate a better understanding of the disclosure and is not intended to impose limitations on the scope of the disclosure as otherwise claimed.

[0137] The terms "patient" and "subject" are used interchangeably herein and refer to a human or non-human animal (e.g., a mammal). As used herein, the term "cancer patient" refers to a patient who has been diagnosed with cancer or a tumor by a certified professional (e.g., a doctor or nurse practitioner).

[0138] The terms "cancer" or "tumor" are used interchangeably herein and refer to the presence of cells that have characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. In some embodiments, such cells exhibit some or all of these characteristics due to the expression and activity of immune checkpoint inhibitors, such as PD-1, PD-L1, and / or CTLA-4. Cancers include, but are not limited to, non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, gastric adenocarcinoma, nasopharyngeal neoplasms, urothelial carcinoma, colorectal cancer, pleural mesothelioma, triple-negative breast cancer, esophageal neoplasms, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung cancer, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma , diffuse large B-cell lymphoma, renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasms, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasms, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignancies, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasms, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer, stomach cancer, colon cancer, and liver cancer.

[0139] As used herein, the term "immune checkpoint" refers to a group of molecules on the cell surface of CD4+ and / or CD8+ T cells that downregulate or inhibit the immune response to minimize associated tissue damage, maintaining self-tolerance, preventing autoimmunity, and controlling the duration and magnitude of the immune response. Immune checkpoint proteins are known in the art and include, but are not limited to, CTLA-4, PD-1, PD-L1, VISTA, B7-H2, B7-H3, B7-H4, B7-H6, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, GITR, 4-IBB, OX-40, BTLA, SIRP, CD47, CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, HHLA2, butyrophilin, IDO, CD39, CD73, and A2aR.

[0140] As used herein, the term "immune checkpoint inhibitor" (ICI) refers to any therapeutic agent that inhibits one or more immune checkpoint proteins, including any small molecule chemical compound, nucleic acid molecule, or polypeptide (e.g., antibody), or any fragment thereof. Inhibition of one or more immune checkpoint proteins can upregulate immune responses by blocking or otherwise neutralizing inhibitory signaling, for example, to more effectively treat cancer. Exemplary immune checkpoint inhibitors include antibodies against one or more immune checkpoint proteins that directly block the interaction of the protein with its native receptor, inactive forms of one or more immune checkpoint proteins, small molecules or peptides that block the interaction of one or more immune checkpoint proteins with their native receptors, nucleic acid molecules that block the transcription or translation of immune checkpoint protein nucleic acids, and the like.

[0141] As used herein, the term "treating" or "treatment" refers to alleviating a condition, slowing the onset or onset rate of a condition, reducing the risk of the onset of a condition, preventing or delaying the onset of symptoms associated with a condition, reducing or terminating symptoms associated with a condition, causing complete or partial regression of a condition, curing a condition, or some combination thereof. In some embodiments, the condition is cancer. With respect to treating cancer, the term "treating" or "treatment" can refer to providing ICI therapy, optionally in combination with an AhR antagonist, to a cancer patient so that at least one or more symptoms of cancer are ameliorated.

[0142] As used herein, the term "effective amount" refers to an amount of a therapeutic agent or a pharma- ceutically acceptable salt thereof sufficient to reduce at least one or more symptoms of a condition disclosed herein or to provide a desired effect. With respect to treating cancer, an "effective amount" may vary depending on factors such as the stage of the cancer and / or the age, sex, and weight of the cancer patient.

[0143] As used herein, the term "administering" refers to the placement of a therapeutic agent (e.g., an AhR antagonist or an ICI) into a mammalian tissue or subject by a method or route that results in at least partial localization of the therapeutic agent to a desired site or tissue location. In some embodiments, a therapeutic agent may be administered to a subject using routes known in the art, such as intramuscular injection, subcutaneous injection, and intravenous injection or infusion.

[0144] As used herein, the term "resistance" refers to acquired or natural resistance (i.e., non-responsiveness or reduced or limited response to a therapeutic treatment) of a cancer sample or mammal to a cancer therapy, for example, having a reduced response to the therapeutic treatment by 25% or more, for example, a reduced response of 30%, 40%, 50%, 60%, 70%, 80% or more. The reduced response can be measured by comparing to the same cancer sample or mammal before it acquired resistance, or by comparing to a different cancer sample or mammal that is known not to have resistance to the therapeutic treatment. Determining resistance to a therapeutic treatment is routine in the art and is within the skill of a clinician of ordinary skill.

[0145] The term "respond", "response" or "responsiveness" refers to an anti-cancer response, for example, in the sense of a reduction in tumor size or inhibition of tumor growth. The term may also refer to an improved prognosis, for example, as reflected by an increase in time to recurrence or an increase in overall survival, which is the time from treatment to death from any cause. Responding or having a response means that there is a beneficial endpoint that is achieved upon exposure to a stimulus. Alternatively, responding or having a response means that a negative or adverse symptom is minimized, reduced, or attenuated by exposure to a stimulus. Determining response or responsiveness to a therapeutic treatment is routine in the art and within the skill of a clinician of ordinary skill. For example, whether a patient responds to ICI therapy can be determined based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. See Example 1.

[0146] As used herein, the term "combination therapy" refers to administering two or more different therapies to a patient during the patient's illness, disorder, or condition (e.g., cancer). For example, in some embodiments, two therapies, such as an ICI therapy and an AhR antagonist, are administered after the patient is diagnosed with cancer and before the cancer is cured or eliminated. In some embodiments, the administration of one treatment is still present when the administration of the second treatment begins, and there is an overlap between the two. In some embodiments, the first and second treatments are started at the same time. In other embodiments, the first and second treatments are started at different times. In some embodiments, one treatment is terminated before the second treatment begins. In some embodiments, the ICI therapy and the AhR antagonist are administered simultaneously. In some embodiments, the ICI therapy and the AhR antagonist are administered sequentially. In some embodiments, the two therapies are administered close enough in time to provide the desired therapeutic effect.

[0147] AhR ligands as biomarkers of ICI responsiveness According to the present disclosure, certain AhR ligands, such as kynurenine, tryptophan, phenylpyruvate, and indole lactate, are useful as biomarkers for predicting a patient's cancer responsiveness to ICI therapy.

[0148] AhR is a ligand-activated transcription factor that belongs to the basic helix-loop-helix / Per-Arnt-Sim (bHLH / PAS) protein family located in the cytosol. Upon ligand binding, AhR translocates to the nucleus where it heterodimerizes with the AhR nuclear translocator (ARNT) to interact with and regulate the transcription of dioxin response elements (DREs) of AhR-responsive genes. Representative target genes include cytochrome P450 family-1 subfamily-A polypeptide-1 (CYP1A1), cytochrome P450 family-1 subfamily-A polypeptide-2 (CYP1A2), cytochrome P450 family-1 subfamily-B polypeptide-1 (CYP1B1), and microsomal cytochrome P450-dependent monooxygenases, including NAD(P)H-quinone oxidoreductase. AhR can also affect chromatin remodeling, acting on deacetylases to proofread its gene regulatory activity and direct gene repression (Rothhammer et al., Nat Rev Immunol., 2019, 19(3):184-197). Additionally, AhR interacts with transcription factors such as NF-κB, c-Maf, and a series of other gene regulators to affect the activity of these regulators (Hankinson et al., Arch Biochem Biophys., 2005, 433(2):379-386). A feedback loop for NF-κB activation has also been described.

[0149] AhR is expressed in many cells of the immune system, including dendritic cells (DCs), macrophages, T cells, and NK cells, and plays a role in immunoregulation (Nguyen et al., Front. Immunol., 2014, 5:551). There are multiple reports that AhR mediates CD4(+) T cell polarization, specifically Th17 and Th22 differentiation, in mice, exacerbating autoimmunity (Funatake et al., J Immunol., 2005, 175(7):4184-4188; Quintana et al., Nature, 2008, 453(7191):65-71; Veldhoen et al., Nature, 2008, 453(7191):106-109; Xiong et al., Exp Cell Res., 2020, 112288). AhR also regulates the tone of adaptive immune responses and modulates T cell differentiation towards a regulatory phenotype. Furthermore, Quintana et al. reported a role for AhR in regulating Th17 biology and controlling IL-22 production (Quintana et al., Nature, 2008, 453(7191):65-71; Quintana et al., Eur J Immunol., 2009, 39(3):655-657; Yeste et al., Nat Commun., 2014, 5:3753).

[0150] In the context of immune suppression, AhR activation promotes regulatory T cell generation, directly and indirectly inhibits Th1 and Th17 differentiation, and reduces dendritic cell (DC) activation and maturation (Wang et al., Clin. Exp. Immunol., 2014, 177(2):521-30; Mezrich et al., J. Immunol., 2010, 185(6):3190-8; Wei et al., Lab. Invest., 2014, 94(5):528-35; Nguyen et al., PNAS, 2010, 107(46):19961-6). The classical exogenous AhR ligands TCDD and 3-methylcholanthrene are known to induce severe immunosuppression, promote carcinogenesis, and even induce tumor growth (Gramatzki et al., Oncogene, 2009, 28(28):2593-605; Bui et al., Oncogene, 2009, 28(41):3642-51; Esser et al., Trends Immunol., 2009, 30:447-454).

[0151] AhR activation also regulates innate immune responses, and constitutive AhR expression has been shown to downregulate type 1 interferon responses to viral infection (Yamada et al., Nat. Immunol., 2016, 17(6):687-94).

[0152] Mice with constitutively active AhR spontaneously develop tumors (Andersson et al., PNAS, 2002, 99(15):9990-5). There is evidence that AhR activity is dysregulated within the tumor environment and affects immune cells, causing impaired immune surveillance. For example, AhR can directly affect tumorigenesis, disrupting cell proliferation, tissue invasion, angiogenesis, tumor-associated inflammation, and metastasis (Xiong et al., Exp Cell Res., 2020, 112288; Veldhoen et al. al., Nature, 2008, 453(7191): 106-109; Dietrich et al., Carcinogenesis, 2010, 31(8): 1319-1328; Opitz et al., Nature, 2011, 478(7368): 197-203).

[0153] AhR signaling can be activated by one or more AhR ligands known in the art. For example, AhR can be activated by environmental toxins such as TCDD, and by natural ligands provided directly by the diet or dietary substances further converted by enzyme activity of the gut microbiome. These ligands then modulate the transcriptional activity of AhR in the host immune system to affect immune responses to the microbiome. Tryptophan metabolites such as kynurenine and kynurenic acid have been reported to activate AhR (DiNatale et al., Toxicol. Sci., 2010, 115(1):89-97; Mezrich et al., J. Immunol., 2010, 185(6):3190-8; Opitz et al., Nature, 2011, 478(7368):197-203). Other endogenous ligands are known to bind to the AHR, but their physiological roles are currently unknown (Nguyen & Bradfield, Chem. Res. Toxicol., 2008, 21(1): 102-116).

[0154] The essential amino acid tryptophan has been suggested to be catabolized in tumor tissues by the rate-limiting enzymes indoleamine-2,3-dioxygenase 1 and 2 (IDO1 / IDO2) and by tryptophan-2,3-dioxygenase 2 (TDO2), which are expressed in tumor cells, bone marrow or antigen-presenting cells (Platten et al., Front Immunol., 2015, 5:673). IDO1 / 2-mediated metabolic pathways create an immune-tolerant microenvironment in tumors and tumor-draining lymph nodes by inducing T cell anergy and apoptosis through tryptophan depletion and accumulation of immunosuppressive tryptophan catabolites (Fallarino et al., Cell Death Differ., 2002, 9(10):1069-1077; Uyttenhove et al., Nat. Med., 2003, 9(10):1269-74; Liu et al., Blood, 2005, 115(17):3520-30; Muller et al., Nat. Med., 11(3):312-9; Metz, Cancer Res., 2007, 67(15):7082-7). Competitive inhibitors of IDO are currently being tested in clinical trials in patients with solid tumors, aiming to enhance the efficacy of conventional chemotherapy.

[0155] TDO2 is highly expressed in cancers and can lead to the production of immunosuppressive kynurenine. In gliomas, AHR activation by kynurenine downstream of TDO-mediated tryptophan degradation increases tumor growth as a result of inhibiting antitumor immune responses and directly promoting tumor cell survival and motility (Opitz et al., Nature, 2011, 478(7368):197-203). Thus, AHR ligands produced by tumor cells act in both autocrine and paracrine ways on tumor cells and lymphocytes, respectively, to promote tumor growth.

[0156] Constitutive activation of the IDO1 / TDO2 / AhR pathway and accumulation of nuclear AhR protein are associated with non-response to immune checkpoint inhibitors and poor overall survival (Chen et al., Medicine (Baltimore), 2020, 99(21); Ferns et al., Oncoimmunology, 2015, 4(2); Suzuki et al., Lung Cancer, 2010, 67(3):361-365). Inhibition of IDO1 with epacadostat improved the antitumor efficacy of the anti-PD-1 checkpoint inhibitor Keytruda in a phase II trial in melanoma, but development was terminated at phase III (ECHO-301) due to lack of durable efficacy (Muller et al., Semin Immunopathol., 2019, 41(1):41-48). One possible explanation is that tumors switched to other sources of AhR ligands that are not susceptible to epacadostat inhibition.

[0157] Table 1 lists the 29 AhR ligands investigated in this disclosure as potential biomarkers predictive of patient cancer responsiveness to ICI therapy.

[0158] [Table 1]

[0159] Example 1 shows that of these 29 AhR ligands, kynurenine, tryptophan, phenylpyruvate, and indole lactate are differentially secreted in fecal samples at baseline, with FDR-corrected p-values ​​of less than 0.05 when comparing patients who became responsive to ICI therapy (responders) with those who did not respond to any ICI therapy (non-responders).All four of these AhR ligands are elevated in fecal samples from non-responders compared to responders.Furthermore, these four AhR ligands do not show statistical differences in plasma samples from non-responders compared to responders.

[0160] In some embodiments, the biomarkers disclosed herein include one or more of kynurenine, tryptophan, phenylpyruvate, and indolelactate. For example, in some embodiments, the biomarkers disclosed herein include kynurenine. In some embodiments, the biomarkers disclosed herein include tryptophan. In some embodiments, the biomarkers disclosed herein include phenylpyruvate. In some embodiments, the biomarkers disclosed herein include indolelactate.

[0161] In some embodiments, the biomarkers disclosed herein include kynurenine and tryptophan. In some embodiments, the biomarkers disclosed herein include kynurenine and phenylpyruvate. In some embodiments, the biomarkers disclosed herein include kynurenine and indolelactate. In some embodiments, the biomarkers disclosed herein include tryptophan and phenylpyruvate. In some embodiments, the biomarkers disclosed herein include tryptophan and indolelactate. In some embodiments, the biomarkers disclosed herein include phenylpyruvate and indolelactate.

[0162] In some embodiments, the biomarkers disclosed herein include kynurenine, tryptophan, and phenylpyruvate. In some embodiments, the biomarkers disclosed herein include kynurenine, tryptophan, and indolelactate. In some embodiments, the biomarkers disclosed herein include tryptophan, phenylpyruvate, and indolelactate.

[0163] In some embodiments, biomarkers according to the present disclosure include kynurenine, tryptophan, phenylpyruvate, and indole lactate.

[0164] The biomarkers of the present disclosure are predictors of a patient's cancer response to ICI therapy. Several ICI therapies have been approved by the Food and Drug Administration for the treatment of melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck squamous cell carcinoma, Hodgkin's lymphoma, urothelial carcinoma, small cell lung cancer, esophageal squamous cell carcinoma, cervical cancer, primary mediastinal large B-cell lymphoma, MSI-H / dMMR colorectal cancer, hepatocellular carcinoma, Merkel cell carcinoma, triple-negative breast cancer, and cutaneous squamous cell carcinoma, among others.

[0165] In some embodiments, the ICI therapy includes an agent that inhibits one or more of CTLA-4, PD-1, PD-L1, VISTA, B7-H2, B7-H3, B7-H4, B7-H6, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, GITR, 4-IBB, OX-40, BTLA, SIRP, CD47, CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, HHLA2, butyrophilin, IDO, CD39, CD73, and A2aR.

[0166] CTLA-4 and PD-1 are negative regulators of T cell immune function and act at different stages of the immune response: CTLA-4 regulates the early activation of naive and memory T cells, typically in lymph nodes, whereas the PD-1 pathway regulates pre-activated T cells in response to inflammatory signals at later stages of the immune response, primarily in peripheral tissues and within the cancer itself (Fife et al., Immunol Rev., 2008, 224:166-182).

[0167] PD-1 is highly expressed by activated T cells, B cells, dendritic cells (DCs), and natural killer cells (NKs), whereas PD-L1 can be expressed on some types of tumor cells. PD-1 is regulated by two ligands, programmed death ligand 1 (PD-L1; B7-H1, CD274) and PD-L2 (B7-DC), leading to inhibition of T cell activation. PD-1 binding inhibits T cell proliferation and production of pro-inflammatory cytokines such as interferon-γ (IFN-γ), tumor necrosis factor-α, and IL-2 (Chamoto et al., Curr Top Microbiol Immunol., 2017, 410:75-97). Ligation of PD-L1 by PD-1 in normal tissues maintains immune system homeostasis and prevents autoimmunity during infection or inflammation. Their interactions in the tumor microenvironment provide tumor cells with an immune evasion mechanism by switching off cytotoxic T cells that would block these interactions.

[0168] CTLA-4, PD-1, and PD-L1 are well-validated targets of ICI therapy. Approved ICI therapies targeting these checkpoint proteins include pembrolizumab (Keytruda), nivolumab (Opdivo), ipilimumab (Yervoy), avelumab (Bavencio), atezolizumab (Tecentriq), durvalumab (Imfinzi), cemiplimab (LBTAYO), sintilimab (Tyvyt), toripalimab (Tuoyi), and camrelizumab (AiRuiKa).

[0169] Ongoing clinical trials include therapeutics targeting LAG-3, TIM-3 TIGIT, and VISTA (Qin et al. Molecular Cancer, 2019, 18:155). Non-limiting examples of ICI therapies targeting LAG-3 include IMP321 (Eftilagimod alpha), leratolimab (BMS-986016), LAG525, MK-4280, REGN3767, TSR-033, BI754111, Sym022, FS118, and MGD013. Non-limiting examples of ICI therapies targeting TIM-3 include TSR-022, MBG453, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, and RO7121661. Non-limiting examples of ICI therapies targeting TIGIT include MK-7684, etigilimab (OMP 313), tiragolumab (MTIG7192A, RG-6058), BMS-986207, AB-154, and ASP-8374. Non-limiting examples of ICI therapies targeting VISTA include JNJ-61610588 and CA-170.

[0170] In some embodiments, the ICI therapy according to the present disclosure comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-TIGIT antibody, an anti-VISTA antibody, or a combination thereof.

[0171] In some embodiments, the ICI therapy according to the present disclosure is selected from the group consisting of pembrolizumab (Keytruda), nivolumab (Opdivo), ipilimumab (Yervoy), avelumab (Bavencio), atezolizumab (Tecentriq), durvalumab (Imfinzi), cemiplimab (LBTAYO), sintilimab (Tyvyt), toripalimab (Tuoyi), camrelizumab (AiRuiKa), IMP321 (Eftilagimod alfa), leratolimab (BMS-986016), LAG525, MK-4280, REGN3767, TSR-033, BI754111, Sym022, FS118, MGD013, TSR-022, MBG453, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, RO7121661, MK-7684, etigilimab (OMP-313), tiragolumab (MTIG7192A, RG-6058), BMS-986207, AB-154, ASP-8374, JNJ-61610588, CA-170, or combinations thereof.

[0172] According to the present disclosure, the amount of biomarkers in a biological sample is measured using one or more applicable methods known in the art. In some embodiments, the biological sample comprises a plasma sample taken from a cancer patient. In some embodiments, the biological sample comprises a serum, plasma, or fecal sample (e.g., an intestinal luminal sample) taken from a cancer patient.

[0173] Diagnostic / prognostic and therapeutic uses of biomarkers The biomarkers of the present disclosure can be used in a variety of diagnostic / prognostic and therapeutic applications, or a combination thereof.

[0174] The biomarkers of the present disclosure can be used in an in vitro method for predicting a patient's cancer responsiveness to ICI therapy. In some embodiments, the method includes: (a) measuring or having measured the amount of at least one biomarker from a serum, plasma, or stool sample obtained from the patient; (b) comparing or having compared the amount of the at least one biomarker to a threshold score; and (c) determining that the patient's cancer is likely to respond to ICI therapy if the amount of the at least one biomarker is equal to or less than the threshold score.

[0175] The biomarkers of the present disclosure can be used in an in vitro method for determining whether a patient is likely to benefit from treatment with an AhR antagonist. In some embodiments, the method includes: (a) measuring or has been measuring the amount of at least one biomarker from a serum, plasma, or fecal sample obtained from the patient; (b) comparing or has compared the amount of the at least one biomarker to a threshold score; and (c) determining that the patient is likely to benefit from treatment with an AhR antagonist if the amount of the at least one biomarker is above the threshold score.

[0176] The biomarkers of the present disclosure may be used to stratify cancer patients based on the amount of at least one biomarker present in their serum, plasma, or fecal samples, in some embodiments, such stratification may be used to inform and provide effective therapeutic regimens for treating cancer patients.

[0177] In some embodiments, if the amount of at least one biomarker in a patient's serum, plasma, or fecal sample is equal to or less than the threshold score for that biomarker, the patient is likely to respond to ICI therapy, even if ICI therapy is not administered in combination with an AhR antagonist. In such embodiments, the patient may be treated with an ICI therapy as disclosed herein. Thus, in some embodiments, the present disclosure provides a method of treating cancer in a patient in need thereof, comprising: (a) measuring or having measured the amount of at least one biomarker from a serum, plasma, or fecal sample obtained from the patient; (b) comparing or having compared the amount of at least one AhR ligand with a threshold score; and (c) treating the patient with ICI therapy if the amount of at least one biomarker is equal to or less than the threshold score. In some embodiments, the ICI therapy may be optionally combined with a different cancer therapy known in the art, such as surgery, chemotherapy, or radiation therapy to remove cancerous tissue. In some embodiments, the different cancer therapy is not an AhR antagonist. In some embodiments, the different cancer therapy is an AhR antagonist.In some embodiments, at least one AhR ligand is selected from piperine, nicotinamide, 4-hydroxyphenylacetate, urolithin A, berberine, quinolinate, bilirubin, phenylacetate, citrulline, phenylpyruvate, xanthurenate, spermidine, indolepropionate, pyridoxine (vitamin B6), indole, indolelactate, kynurenate, curcumin, biliverdin, indoleacetate, picolinate, kynurenine, tryptophan, 3-indoxyl sulfate, serotonin, phenyllactate (PLA), tryptamine, benzoate, and 4-hydroxyphenylpyruvate.In some embodiments, the at least one AhR ligand comprises two or more of piperine, nicotinamide, 4-hydroxyphenylacetate, urolithin A, berberine, quinolinate, bilirubin, phenylacetate, citrulline, phenylpyruvate, xanthurenate, spermidine, indolepropionate, pyridoxine (vitamin B6), indole, indolelactate, kynurenate, curcumin, biliverdin, indoleacetate, picolinate, kynurenine, tryptophan, 3-indoxyl sulfate, serotonin, phenyllactate (PLA), tryptamine, benzoate, and 4-hydroxyphenylpyruvate. In some embodiments, the at least one AhR ligand comprises three or more of piperine, nicotinamide, 4-hydroxyphenylacetate, urolithin A, berberine, quinolinate, bilirubin, phenylacetate, citrulline, phenylpyruvate, xanthurenate, spermidine, indolepropionate, pyridoxine (vitamin B6), indole, indolelactate, kynurenate, curcumin, biliverdin, indoleacetate, picolinate, kynurenine, tryptophan, 3-indoxyl sulfate, serotonin, phenyllactate (PLA), tryptamine, benzoate, and 4-hydroxyphenylpyruvate. In some embodiments, the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indolelactate, or a combination thereof.

[0178] In some embodiments, if the amount of at least one biomarker in a patient's serum, plasma, or fecal sample is above a threshold score for that biomarker, the patient is unlikely to respond to ICI therapy in the absence of an AhR antagonist (e.g., ICI therapy alone or in combination with a different (non-AhR antagonist) cancer therapy, such as surgery, chemotherapy, and / or radiation therapy). In such embodiments, the patient may be treated with a combination of ICI therapy and an AhR antagonist. Thus, in some embodiments, the present disclosure provides a method of treating cancer in a patient in need thereof, comprising: (a) measuring or having measured the amount of at least one biomarker from a serum, plasma, or stool sample obtained from the patient; (b) comparing or having compared the amount of at least one AhR ligand with a threshold score; (c) determining or having determined that the patient is likely to respond to treatment with an AhR antagonist if the amount of the at least one biomarker is above the threshold score; and (d) treating the patient determined to be responsive in (d) with an effective amount of an AhR antagonist.

[0179] In some embodiments, the disclosure provides a method of treating cancer with a combination therapy comprising an ICI therapy and an AhR antagonist in a patient in need thereof, comprising: (a) measuring or having measured an amount of at least one biomarker from a serum, plasma, or stool sample obtained from the patient; (b) comparing or having compared the amount of the at least one biomarker to a threshold score; (c) determining or having determined that the patient is likely to respond to the combination therapy if the amount of the at least one biomarker is above the threshold score; and (d) treating the patient determined to be successful in (c) with the combination therapy.

[0180] In some embodiments of the diagnostic / prognostic and treatment methods disclosed herein, the biomarker is selected from piperine, nicotinamide, 4-hydroxyphenylacetate, urolithin A, berberine, quinolinate, bilirubin, phenylacetate, citrulline, phenylpyruvate, xanthurenate, spermidine, indolepropionate, pyridoxine (vitamin B6), indole, indolelactate, kynurenate, curcumin, biliverdin, indoleacetate, picolinate, kynurenine, tryptophan, 3-indoxyl sulfate, serotonin, phenyllactate (PLA) tryptamine, benzoate, and 4-hydroxyphenylpyruvate. For example, in some embodiments, the biomarkers include two or more of piperine, nicotinamide, 4-hydroxyphenylacetate, urolithin A, berberine, quinolinate, bilirubin, phenylacetate, citrulline, phenylpyruvate, xanthurenate, spermidine, indolepropionate, pyridoxine (vitamin B6), indole, indolelactate, kynurenate, curcumin, biliverdin, indoleacetate, picolinate, kynurenine, tryptophan, 3-indoxyl sulfate, serotonin, phenyllactate (PLA), tryptamine, benzoate, and 4-hydroxyphenylpyruvate. In some embodiments, the biomarkers include three or more of piperine, nicotinamide, 4-hydroxyphenylacetate, urolithin A, berberine, quinolinate, bilirubin, phenylacetate, citrulline, phenylpyruvate, xanthurenate, spermidine, indolepropionate, pyridoxine (vitamin B6), indole, indolelactate, kynurenate, curcumin, biliverdin, indoleacetate, picolinate, kynurenine, tryptophan, 3-indoxyl sulfate, serotonin, phenyllactate (PLA), tryptamine, benzoate, and 4-hydroxyphenylpyruvate.

[0181] In some embodiments of the diagnostic / prognostic and treatment methods disclosed herein, the biomarkers include kynurenine, tryptophan, phenylpyruvate, indolelactate, or combinations thereof. For example, in some embodiments, the biomarkers include kynurenine. In some embodiments, the biomarkers include tryptophan. In some embodiments, the biomarkers include phenylpyruvate. In some embodiments, the biomarkers include indolelactate. In some embodiments, the biomarkers include kynurenine and tryptophan. In some embodiments, the biomarkers include kynurenine and phenylpyruvate. In some embodiments, the biomarkers include kynurenine and indolelactate. In some embodiments, the biomarkers include tryptophan and phenylpyruvate. In some embodiments, the biomarkers include tryptophan and indolelactate. In some embodiments, the biomarkers include phenylpyruvate and indolelactate. In some embodiments, the biomarkers include kynurenine, tryptophan, and phenylpyruvate. In some embodiments, the biomarkers include kynurenine, tryptophan, and indolelactate. In some embodiments, the biomarkers include tryptophan, phenylpyruvate, and indolelactate. In some embodiments, the biomarkers include kynurenine, tryptophan, phenylpyruvate, and indolelactate.

[0182] In some embodiments of the diagnostic / prognostic and treatment methods disclosed herein, the cancer patient is a patient with non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, gastric adenocarcinoma, nasopharyngeal neoplasm, urothelial carcinoma, colorectal cancer, pleural mesothelioma, triple negative breast cancer, esophageal neoplasm, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung cancer, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic non-Hodgkin's lymphoma, The patient is suffering from melanoma, urothelial carcinoma, diffuse large B-cell lymphoma, renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignant tumor, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer, stomach cancer, colon cancer, or liver cancer.

[0183] In some embodiments of the diagnostic / prognostic and treatment methods disclosed herein, the cancer patient has been previously treated with ICI therapy but has not responded to ICI therapy. In some embodiments, the patient has been previously treated with ICI therapy and has developed resistance to ICI therapy. In some embodiments, the ICI therapy of the present disclosure comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-TIGIT antibody, an anti-VISTA antibody, or a combination thereof. In some embodiments, the ICI therapy is selected from the group consisting of pembrolizumab (Keytruda), nivolumab (Opdivo), ipilimumab (Yervoy), avelumab (Bavencio), atezolizumab (Tecentriq), durvalumab (Imfinzi), cemiplimab (LBTAYO), sintilimab (Tyvyt), toripalimab (Tuoyi), camrelizumab (AiRuiKa), IMP321 (Eftilagimod alfa), lelatolimab (BMS-986016), LAG525, MK- 4280, REGN3767, TSR-033, BI754111, Sym022, FS118, MGD013, TSR-022, MBG453, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, RO7121661, MK-7684, etigilimab (OMP-313), tiragolumab (MTIG7192A, RG-6058), BMS-986207, AB-154, ASP-8374, JNJ-61610588, CA-170, or combinations thereof.

[0184] In some embodiments of the diagnostic / prognostic and treatment methods disclosed herein, the cancer patient may have been previously treated with or is currently undergoing a different (non-ICI and non-AhR antagonist) cancer therapy, such as surgery, chemotherapy, or radiation therapy to remove cancerous tissue.

[0185] In some embodiments of the diagnostic / prognostic and therapeutic methods disclosed herein, the amount of a biomarker disclosed herein is measured in a serum, plasma, or fecal sample taken from a cancer patient at an appropriate time. In some embodiments, the sample is taken approximately 1 week after the initiation of ICI therapy. In some embodiments, the sample is taken approximately 2 weeks after the initiation of ICI therapy. In some embodiments, the sample is taken approximately 3 weeks after the initiation of ICI therapy. In some embodiments, the sample is taken approximately 4 weeks after the initiation of ICI therapy. In some embodiments, the sample is taken approximately 5 weeks after the initiation of ICI therapy. In some embodiments, the sample is taken approximately 6 weeks after the initiation of ICI therapy. In some embodiments, the sample is taken approximately 7 weeks after the initiation of ICI therapy. In some embodiments, the sample is taken approximately 8 weeks after the initiation of ICI therapy. In some embodiments, the sample is taken approximately 9 weeks after the initiation of ICI therapy. In some embodiments, the sample is taken approximately 10 weeks after the initiation of ICI therapy. In some embodiments, samples are taken 10 weeks, 3 months, 5 months, 7 months, 10 months, 1 year, 2 years, 3 years, 4 years, 5 years after initiation of ICI therapy.

[0186] Sample preparation may include any procedure known in the art, including, by way of example only, concentration, dilution, pH adjustment, removal of high abundance polypeptides (such as, for example, albumin, gamma globulin, and transferrin), addition of preservatives and calibrants, addition of protease inhibitors, addition of denaturants, desalting of the sample, concentration of sample proteins, and lipid extraction and purification.

[0187] After sample preparation, the amount of biomarkers in serum, plasma, or fecal samples is measured using one or more applicable methods known in the art. Suitable measurement / detection methods may include mass spectrometry methods such as liquid chromatography mass spectrometry (LC-MS), gas phase chromatography mass spectrometry (GC-MS), or tandem mass spectrometry (MS-MS). Other suitable methods include reversed phase chromatography (e.g., in positive and / or negative ionization mode) and hydrophobic interaction liquid ion chromatography (HILIC) (e.g., in positive and / or negative ionization mode), or combinations thereof. In some embodiments, the amount of biomarkers is measured by LC-MS. In some embodiments, the amount of biomarkers is analyzed using ultra-performance liquid chromatography-tandem mass spectrometry. See Example 1.

[0188] In some embodiments, fecal samples can be fractionated before applying the measurement / detection method. In some embodiments, the amount of biomarkers can be measured by methods that do not require physical separation of the biomarkers themselves. For example, nuclear magnetic resonance (NMR) spectroscopy can be used to elucidate the amount of biomarkers from a complex mixture of metabolites, including various AhR ligands.

[0189] In some embodiments of the diagnostic / prognostic and therapeutic methods disclosed herein, the amount of each biomarker is compared to a predetermined threshold score for that biomarker. In some embodiments, the threshold score is the amount of the biomarker in serum, plasma, or fecal samples from control cancer patients who are responding to ICI therapy. In some embodiments, the threshold score can be generated from a population or cohort of two or more control cancer patients who are responding to ICI therapy. The population or cohort can include, for example, at least 2, 3, 4, 5, 10, 15, 18, 20, 30, 40, 50, 75, 100, or more cancer patients. In such embodiments, the threshold score for each biomarker can be the average amount of that biomarker in serum, plasma, or fecal samples from a population or cohort of control cancer patients who are responding to ICI therapy.

[0190] To determine the threshold score for each biomarker, serum, plasma, or fecal samples may be collected at appropriate times from control cancer patients responding to ICI therapy as disclosed herein. The control cancer patients may be those responding to ICI therapy, including any agent that inhibits one or more of CTLA-4, PD-1, PD-L1, VISTA, B7-H2, B7-H3, B7-H4, B7-H6, ICOS, HVEM, PD-L2, CD160, gp49B, PIR-B, KIR family receptors, TIM-1, TIM-3, TIM-4, LAG-3, GITR, 4-IBB, OX-40, BTLA, SIRP, CD47, CD48, 2B4 (CD244), B7.1, B7.2, ILT-2, ILT-4, TIGIT, HHLA2, butyrophilin, IDO, CD39, CD73, and A2aR. In some embodiments, the ICI therapy includes an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-TIGIT antibody, an anti-VISTA antibody, or a combination thereof. ...LAG-4 antibody, an anti-LAG-5 antibody, an anti-LAG-6 antibody, an anti-LAG-7 antibody, an anti-LAG-8 antibody, an anti-LAG-9 antibody, an anti-LAG-1 antibody, an anti-LAG-1 antibody, an anti-LAG-2 antibody, an anti-LAG-3 antibody, an anti-LAG-4 antibody, an anti-LAG-5 antibody, an anti-LAG-6 antibody, an anti-LAG-7 antibody, an anti-LAG-8 antibody, an anti-LAG-1 antibody, an anti-LAG-1 antibody, an anti-LAG-2 antibody, an anti-LAG-3 antibody, an anti-LAG-4 antibody, an anti-LAG-5 antibody, an anti-LAG-1 antibody, an anti-LAG-2 antibody, an anti-LAG-3 antibody, an anti-LAG-4 antibody, an anti-LAG-5 antibody, an anti-LAG-1 antibody, an anti-LAG 4280, REGN3767, TSR-033, BI754111, Sym022, FS118, MGD013, TSR-022, MBG453, Sym023, INCAGN2390, LY3321367, BMS-986258, SHR-1702, RO7121661, MK-7684, etigilimab (OMP-313), tiragolumab (MTIG7192A, RG-6058), BMS-986207, AB-154, ASP-8374, JNJ-61610588, CA-170, or combinations thereof.

[0191] The amount of a biomarker in a serum, plasma, or fecal sample from a cancer patient can be "above" a threshold score for that biomarker, e.g., at least 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 350%, 400% higher, 500%, 600%, 700%, 800%, 900%, 1000% or more higher than the threshold score. In some embodiments, the amount of a biomarker in a serum, plasma, or fecal sample from a test cancer patient can be "below" a threshold score for that biomarker, e.g., at least about 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more lower than the threshold score.

[0192] In some embodiments of the therapeutic methods disclosed herein, when the amount of biomarker in the serum, plasma, or fecal sample of a cancer patient is above the threshold score, the patient may be administered an AhR antagonist in combination with ICI therapy. In these embodiments, the AhR antagonist may be administered simultaneously with ICI therapy. In some embodiments, the AhR antagonist is administered sequentially with ICI therapy. In some embodiments, the combination therapy results in an increased or synergistic anti-tumor response compared to treatment with the corresponding ICI therapy alone.

[0193] Pyridopyrimidinone derivatives as AhR antagonists Disclosed herein are novel 6,8-trisubstituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds of Formula (I), Formula (Ia), or Formula (Ib), or pharma- ceutically acceptable salts thereof, that effectively inhibit AhR and thus can be used in the methods of treatment disclosed herein like known AhR antagonists.

[0194] Unless otherwise specified, the nomenclature used to describe chemical groups or moieties used herein follows the convention of reading the name from left to right with the point of attachment to the remainder of the molecule on the right hand side of the name. For example, the group "(C 1~3Alkoxy)C 1~3 The "alkyl" is attached to the remainder of the molecule at the alkyl terminus. Further examples include methoxyethyl, where the point of attachment is at the ethyl terminus, and methylamino, where the point of attachment is at the amine terminus.

[0195] Unless otherwise indicated, when a chemical group is depicted by its formula or structure having a terminal attachment portion represented by a "-", it will be understood that the "-" represents the point of attachment. [ka] ) represents a connection point.

[0196] As used herein, the term "pharmaceutical acceptable salt" refers to a salt that is pharmaceutically acceptable as defined herein and has the desired pharmacological activity of the parent compound.Non-limiting examples of pharmaceutically acceptable salts include those derived from inorganic acids, including but not limited to hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and those derived from organic acids, including but not limited to acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, stearic acid, malic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, and lactic acid. Additional non-limiting examples of pharmaceutically acceptable salts include those formed when an acidic proton in a parent compound is replaced by a metal ion, including but not limited to alkali metal ions and alkaline earth metal ions, and those formed when an acidic proton present in a parent compound is replaced by an ammonium ion, a primary ammonium ion, a secondary ammonium ion, a tertiary ammonium ion, or a quaternary ammonium ion. Non-limiting examples of alkali metals and alkaline earth metals include sodium, potassium, lithium, calcium, aluminum, magnesium, copper, zinc, iron, and manganese. Additional non-limiting examples of pharmaceutically acceptable salts include those that include one or more counterions and zwitterions.

[0197] As used herein, "acyl" or "alkanoyl" is a functional group having the formula RCO-, where R is attached by a single bond to the carbon atom of a carbonyl functional group and the "-" indicates the point of attachment to the rest of the molecule. Non-limiting examples of acyls include formyl (HC(O)-, also known as methanoyl), acetyl (CHC(O)-, also known as ethanoyl), and benzoyl (PhC(O)-).

[0198] The term "alkyl" or "aliphatic" as used herein means a straight (i.e. unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated and has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an alkyl group is a hydrocarbon chain of 1 to 20 alkyl carbon atoms. In some embodiments, an alkyl group contains 1 to 12 carbon atoms (C1 to C6). 12 ). In some embodiments, an alkyl group contains 1-8 carbon atoms (C1-C8). In some embodiments, an alkyl group contains 1-6 carbon atoms (C1-C6). In some embodiments, an alkyl group contains 1-4 carbon atoms (C1-C4). In some embodiments, a cyclic alkyl group contains 3-6 carbon atoms (C3-C6). Non-limiting examples of substituted and unsubstituted straight chain, branched chain, and cyclic alkyl groups include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, cyclobutyl, cyclopentyl, cyclohexyl, hydroxymethyl, chloromethyl, fluoromethyl, trifluoromethyl, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, dimethylaminomethyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 4-dimethylaminobutyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, trifluoroethyl, and trifluoropropyl.

[0199] As used herein, "alkoxy" refers to an alkyl group, as defined above, attached to the main carbon chain by an oxygen ("alkoxy") atom.

[0200] As used herein, "halo" and "halogen" are interchangeable and refer to halogen atoms such as fluoro (F), chloro (Cl), bromo (Br), and iodo (I).

[0201] "Haloalkyl" refers to an alkyl group substituted with one or more halo atoms (F, Cl, Br, I). For example, "fluoromethyl" refers to a methyl group substituted with one or more fluoro atoms (e.g., monofluoromethyl, difluoromethyl, or trifluoromethyl).

[0202] "Haloalkoxy" refers to an alkoxy group substituted with one or more halo atoms (F, Cl, Br, I). For example, "fluoromethoxy" refers to a methoxy group substituted with one or more fluoro atoms (e.g., monofluoromethoxy, difluoromethoxy, or trifluoromethoxy).

[0203] "Hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups (-OH).

[0204] The terms "cycloalkyl" and "cycloalkyl group," used interchangeably herein, refer to a cyclic saturated monovalent hydrocarbon group of three to twelve carbon atoms having a single point of attachment to the remainder of the molecule. Cycloalkyl groups can be unsubstituted or substituted. In some embodiments, cycloalkyl groups contain three to eight carbon atoms (C3-C8). In some embodiments, cycloalkyl groups contain three to six carbon atoms (C3-C6). Non-limiting examples of substituted and unsubstituted cycloalkyls include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0205] The terms "alkylene" and "alkylene group," as used interchangeably herein, refer to alkylene groups having 1 to 12 carbon atoms (C 12 ) refers to a saturated divalent (i.e., having two points of attachment to the rest of the molecule) hydrocarbon group containing an alkylene group. An alkylene group can be straight chain, branched chain, or cyclic. An alkylene group can be unsubstituted or substituted. In some embodiments, an alkylene group contains 1 to 8 carbon atoms (C1-C8). In some embodiments, an alkylene group contains 1 to 6 carbon atoms (C1-C6). In some embodiments, an alkylene group contains 1 to 4 carbon atoms (C1-C4). Non-limiting examples of alkylene groups include methylene and ethylene.

[0206] The terms "alkenyl" and "alkenyl group", as used interchangeably herein, refer to a monovalent (i.e., having one point of attachment to the remainder of the molecule) hydrocarbon group containing from 2 to 8 carbon atoms (C2-C8) and having at least one site of unsaturation (i.e., an sp2 carbon-carbon double bond). Alkenyl groups can be straight chain, branched chain, or cyclic. Alkenyl groups can be unsubstituted or substituted. In some embodiments, alkenyl groups contain from 2 to 6 carbon atoms (C2-C6). In some embodiments, alkenyl groups contain from 2 to 4 carbon atoms (C2-C4). Alkenyl groups can have either the E or Z configuration. Non-limiting examples of alkenyl groups include ethenyl (also known as vinyl), 1-propenyl, iso-propenyl, and 2-chloroethenyl.

[0207] The terms "alkenylene" and "alkenylene group", as used interchangeably herein, refer to a divalent (i.e., having two points of attachment to the remainder of the molecule) hydrocarbon group of 2 to 8 carbon atoms (C2-C8) with at least one site of unsaturation (e.g., an sp2 carbon-carbon double bond). Alkenylene groups can be straight chain, branched chain, or cyclic. Alkenylene groups can be unsubstituted or substituted. In some embodiments, alkylene groups contain 2 to 6 carbon atoms (C2-C6). In some embodiments, alkylene groups contain 2 to 4 carbon atoms (C2-C4). Alkylene groups can have either the E or Z configuration. A non-limiting example of an alkenyl group is ethenylene (also called vinylene).

[0208] The terms "alkynyl" and "alkynyl group," used interchangeably herein, refer to a monovalent (i.e., having one point of attachment to the remainder of the molecule) hydrocarbon group of two to eight carbon atoms (C2-C8) with at least one site of unsaturation (i.e., a sp carbon-carbon triple bond). Alkynyl groups can be straight or branched chain. Alkynyl groups can be unsubstituted or substituted. In some embodiments, alkynyl groups contain two to six carbon atoms (C2-C6). In some embodiments, alkynyl groups contain two to four carbon atoms (C2-C4). A non-limiting example of an alkynyl group is ethynyl.

[0209] The terms "alkynylene" and "alkynylene group," as used interchangeably herein, refer to a divalent (i.e., having two points of attachment to the remainder of the molecule) hydrocarbon group of 2 to 8 carbon atoms (C2-C8) with at least one site of unsaturation (i.e., a sp carbon-carbon triple bond). Alkynylene groups can be straight or branched chain. Alkynylene groups can be unsubstituted or substituted. In some embodiments, alkynylene groups contain 2 to 6 carbon atoms (C2-C6). In some embodiments, alkynylene groups contain 2 to 4 carbon atoms (C2-C4). A non-limiting example of an alkynylene group is ethynylene.

[0210] As used herein, an "aromatic group" or "aromatic ring" refers to a chemical group that contains a conjugated planar ring system having a delocalized π orbital made up of [4n+2] p orbitals, where n is an integer from 0 to 6. Non-limiting examples of aromatic groups include aryl and heteroaryl groups.

[0211] The terms "aryl" and "aryl group", as used interchangeably herein, refer to aryl groups having 6 to 20 carbon atoms (C 20 Aryl groups refer to a monovalent (i.e., having one point of attachment to the remainder of the molecule) aromatic hydrocarbon group. Aryl groups can be unsubstituted or substituted. Non-limiting examples of unsubstituted and substituted aryl groups include phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, Examples of aryl include aryl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-dimethylaminophenyl, 3-dimethylaminophenyl, 4-dimethylaminophenyl, 3-methylsulfonylphenyl, 4-methylsulfonylphenyl, 3-aminophenyl, 3-methylaminophenyl, 3-(2-hydroxyethoxy)phenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 1-naphthyl, and 2-naphthyl.

[0212] As used herein, the term "heteroalkyl" refers to an alkyl group in which at least one of the carbon atoms in the chain is replaced with a heteroatom, such as nitrogen, oxygen, phosphorus, and sulfur. Heteroalkyl groups can be unsubstituted or substituted.

[0213] The terms "heterocycloalkyl", "heterocycle", "heterocyclyl", and "heterocyclic group", used interchangeably herein, refer to a saturated or partially unsaturated ring system of 3 to 20 atoms in which at least one of the ring atoms is a heteroatom, such as nitrogen, oxygen, phosphorus, and sulfur. Heterocycloalkyl groups can be unsubstituted or substituted. In some embodiments, heterocycloalkyl groups contain 3 to 10 atoms. In some embodiments, heterocycloalkyl groups contain 3 to 7 atoms. In some embodiments, heterocycloalkyl groups are monocyclic. In some embodiments, heterocycloalkyl groups are bicyclic. In some embodiments, heterocycloalkyl groups contain fused rings. Non-limiting examples of unsubstituted and substituted heterocycloalkyl groups include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, 3-methoxypyrrolidinyl, and benzodioxolyl.

[0214] The terms "heteroaryl" and "heteroaryl group", used interchangeably herein, refer to an aromatic ring system of 3 to 20 atoms in which at least one of the ring atoms is a heteroatom, such as nitrogen, oxygen, phosphorus, and sulfur. Heteroaryl groups can be unsubstituted or substituted. In some embodiments, heteroaryl groups contain 5 to 20 atoms. In some embodiments, heteroaryl groups contain 5 to 9 atoms. In some embodiments, heteroaryl groups contain 5 atoms. In some embodiments, heteroaryl groups contain 6 atoms. In some embodiments, heteroaryl groups contain 7 atoms. In some embodiments, heteroaryl groups are monocyclic. In some embodiments, heteroaryl groups are bicyclic. In some embodiments, heteroaryl groups contain fused rings. Non-limiting examples of heteroaryl groups include pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl-1,2,4-oxadiazolyl, 3-phenyl-1,2,4-oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoaryl, ... Non-limiting examples of heteroaryl groups include isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, and 1H-pyrrolo[2,3-b]pyridinyl. [ka] There is.

[0215] As used herein, the phrase "optionally substituted" means that the specified moiety may or may not be "substituted". As used herein, the term "substituted" refers to the replacement of one or more hydrogen atoms on a group (such as on an alkyl group, an alkylene group, an alkenyl group, an alkenylene group, an alkynyl group, an alkynylene group, an aryl group, a heterocycloalkyl group, or a heteroaryl group) with one or more substituents. Non-limiting examples of substituents that replace one hydrogen atom include halogen, hydroxyl, and amino. Non-limiting examples of substituents that replace two hydrogen atoms include oxo and methene. Non-limiting examples of substituents that replace three hydrogen atoms include nitrile.

[0216] Additional non-limiting examples of substituents include C1-C6 straight chain, branched chain, and cyclic alkyl groups, non-limiting examples of which include methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl sec-butyl, iso-butyl, tert-butyl, cyclobutyl, cyclopentyl, and cyclohexyl; C2-C8 straight chain, branched chain, and cyclic alkenyl groups, non-limiting examples of which include ethenyl (also called vinyl), 1-propenyl, and iso-propenyl; C2-C8 straight and branched chain alkynyl groups, non-limiting examples of which include ethynyl; Substituted and unsubstituted aryl groups, non-limiting examples of which include phenyl, 2-fluorophenyl, 3-methylphenyl, 4-chlorophenyl, 2,6-dichlorophenyl, 3,4-difluorophenyl, 3-hydroxyphenyl, 4-cyanophenyl, 2-dimethylaminophenyl, 3-methylsulfonylphenyl, 4-trifluoromethylphenyl, 3-isopropylphenyl, 1-naphthyl, and 2-naphthyl; Substituted and unsubstituted heterocyclic groups, non-limiting examples of which include pyrrolidinyl, N-methylpyrrolidinyl, azetidinyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, 3-hydroxypyrrolidinyl, and 3-methoxypyrrolidinyl; Substituted and unsubstituted heteroaryl groups, non-limiting examples of which include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, furyl, 2-thienyl, 3-thienyl, isoxazolyl, thiazolyl, oxadiazolyl, 3-methyl-1,2,4-oxadiazolyl, 3-phenyl-1,2,4-oxadiazolyl, indolyl, benzothiazolyl, and 1H-pyrrolo[2,3-b]pyridinyl; -(CR a R b ) z OR c , non-limiting examples of which include -OH, -OCH3, -OCH2OH, and -OCH2CH3; -(CR a R b )zN(R c )(R d ), non-limiting examples of which include -NH2, -NHCH3, -N(CH3)2, -CH2NH2, -CH2NHCH3; halogen atoms, non-limiting examples of which include fluorine atoms (-F) and chlorine atoms (-Cl); -(CR a R b ) z CN; -(CR a R b ) z NO2; -CH x X y (wherein X is a halogen atom and x+y sums to 3), non-limiting examples of which include -CH2F, -CHF2, and -CF3; -(CR a R b ) z C(O)R c , non-limiting examples of which include -COCH3, -COCH2CH3, and -CH2COCH3; -(CR a R b ) z C(O)OR c , non-limiting examples include CO2H, -CO2CH3, -CO2CH2CH3, and -CH2CO2CH3; -(CR aR b ) z C(O)N(R c )(R d ), non-limiting examples of which are -CONH2, -CONHCH3, -CON(CH3)2, -CH2CONH2, -CH2CONHCH3, -CH2CON(CH3)2; -(CR a R b ) z SO2R c non-limiting examples of which include -SO2H, -SO2CH3, -CH2SO2H, -CH2SO2CH3, -SO2C6H5, and -CH2SO2C6H5; and -(CR a R b ) z SO3R c non-limiting examples of which include -SO3H, -SO3CH3, -CH2SO3H, -CH2SO3CH3, -SO3C6H5, and -CH2SO3C6H5; There are In the formula, R a and R b each is independently selected from hydrogen and substituted or unsubstituted C1-C6 straight chain, branched chain, or cyclic alkyl; R c and R d each is selected from hydrogen, substituted or unsubstituted C1-C6 straight chain, branched chain, or cyclic alkyl, and aryl, or R c and R d together form a ring system containing 3 to 7 atoms, and z is selected from 0, 1, 2, 3, and 4.

[0217] In some embodiments, the AhR antagonist according to the present disclosure is a compound of formula (I): [ka] or a pharma- ceutically acceptable salt thereof. (In the formula: R 1 and R 2are independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H.

[0218] In some embodiments, R 2 is a dialkylamine. In some embodiments, R 2 is diethylamine.

[0219] In some embodiments, the AhR antagonist according to the present disclosure is a compound of formula Ia: [ka] or a pharma- ceutically acceptable salt thereof. (In the formula: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H.

[0220] In some embodiments, Ring A is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, wherein each of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is selected from 1 to 5 instances of R A is optionally substituted independently by:

[0221] In some embodiments, Ring B is selected from 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, wherein each of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is selected from 1-5 instances of R B is optionally substituted independently by:

[0222] In some embodiments, R is hydrogen, C1-C 10 Alkyl, 6-10 membered aryl, -C(O)R', -C(O)NR'R', 3-10 membered cycloalkyl, -C(O)OR', C1-C 10 is selected from heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H, where each C1-C 10 Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C1-C 10 Heteroalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl are each independently selected from 1 to 5 instances of R Cis optionally substituted independently by:

[0223] In some embodiments, each R' is hydrogen, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Hydroxyalkyl and C1-C 10 heteroalkyl.

[0224] In some embodiments, each R A Halo, hydroxy, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy, C1-C 10 is independently selected from hydroxyalkyl, and NR″R″.

[0225] In some embodiments, each R B Halo, hydroxy, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy, C1-C 10 is independently selected from hydroxyalkyl, and NR″R″.

[0226] In some embodiments, each R C are halo, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 and independently selected from haloalkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl.

[0227] In some embodiments, each R″ is hydrogen, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Hydroxyalkyl and C1-C 10heteroalkyl.

[0228] In some embodiments, Ring A is selected from 6-10 membered aryl, 5-8 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl, wherein each of 6-10 membered aryl, 5-10 membered heteroaryl, 3-10 membered cycloalkyl, and 3-10 membered heterocycloalkyl is selected from 1-5 instances of R A and Ring B is selected from 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocycloalkyl, wherein each of the 6- to 10-membered aryl, 5- to 10-membered heteroaryl, 3- to 10-membered cycloalkyl, and 3- to 10-membered heterocycloalkyl is selected from 1 to 5 instances of R B and R is hydrogen, C1-C 10 Alkyl, 6-10 membered aryl, -C(O)R', -C(O)NR'R', 3-10 membered cycloalkyl, -C(O)OR', C1-C 10 is selected from heteroalkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H, where each C1-C 10 Alkyl, 6-10 membered aryl, 3-10 membered cycloalkyl, C1-C 10 Heteroalkyl, 5- to 10-membered heteroaryl, and 3- to 10-membered heterocycloalkyl are each independently selected from 1 to 5 instances of R C and Each R' is hydrogen, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Hydroxyalkyl and C1-C 10 heteroalkyl; Each R A Halo, hydroxy, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy, C1-C10 is independently selected from hydroxyalkyl, and NR"R"; Each R B Halo, hydroxy, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Alkoxy, C1-C 10 Haloalkoxy, C1-C 10 is independently selected from hydroxyalkyl, and NR"R"; Each R C are halo, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 independently selected from haloalkyl, 3- to 10-membered cycloalkyl, 3- to 10-membered heterocycloalkyl, 6- to 10-membered aryl, and 5- to 10-membered heteroaryl; and Each R'' is hydrogen, C1-C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Hydroxyalkyl and C1-C 10 heteroalkyl.

[0229] In some embodiments, ring A is selected from 1 to 5 instances of R A In some embodiments, ring A is selected from 1 to 5 instances of R A In some embodiments, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, optionally substituted with 1 to 5 instances of R A In some embodiments, ring A is selected from 6-8 membered aryl optionally substituted with 1-3 instances of R A In some embodiments, ring A is phenyl optionally substituted with 1 to 5 instances of R A and wherein the aryl is selected from 5-8 membered heteroaryl optionally substituted by

[0230] In some embodiments, Ring A is selected from pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazoyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl, wherein each of pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl is selected from 1 to 3 instances of R A is optionally substituted independently by:

[0231] In some embodiments, ring A is selected from 1 to 3 instances of R A In some embodiments, ring A is pyridinyl optionally substituted with 1 to 5 instances of R A In some embodiments, Ring A is selected from pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl, wherein each of pyrrolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino, azepinyl, tetrahydropyranyl, and tetrahydrofuranyl is selected from 1 to 3 instances of R A In some embodiments, ring A is optionally substituted independently with 1 to 3 instances of R A or morpholino, optionally substituted by

[0232] In some embodiments, each R A , Halo, C1~C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Alkoxy, C1-C 10 In some embodiments, each R B , Halo, C1~C 10Alkyl and C1-C 10 In some embodiments, each R C are halo, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 In some embodiments, each R" is independently selected from hydrogen and C1-C6. 10 alkyl.

[0233] In some embodiments, each R A , Halo, C1~C 10 Alkyl, C1-C 10 Haloalkyl, C1-C 10 Alkoxy, C1-C 10 independently selected from haloalkoxy, and NR"R"; Each R B , Halo, C1~C 10 Alkyl and C1-C 10 independently selected from haloalkyl; Each R C are halo, hydroxy, cyano, C1-C 10 Alkyl, C1-C 10 independently selected from alkoxy, 3- to 8-membered cycloalkyl, 3- to 8-membered heterocycloalkyl, and 6- to 8-membered aryl; and Each R'' is hydrogen or C1-C 10 alkyl.

[0234] In some embodiments, ring B is selected from 1 to 5 instances of R B In some embodiments, ring B is selected from 6-8 membered aryl optionally substituted with 1-3 instances of R B In some embodiments, ring B is phenyl optionally substituted with 1 to 5 instances of R BIn some embodiments, Ring B is selected from pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyridinonyl, and pyrimidinyl, wherein each of pyrrolyl, furanyl, furazanyl, thiophenyl, imidazolyl, isothiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, tetrazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl is selected from 1 to 3 instances of R B In some embodiments, Ring B is selected from pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl, wherein each of pyrazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyrimidinyl, and thiophenyl is independently selected from 1 to 3 instances of R B is optionally substituted independently by:

[0235] In some embodiments, ring A is [ka] is selected from.

[0236] In some embodiments, ring A is [ka] is selected from.

[0237] In some embodiments, ring A is [ka] is selected from.

[0238] In some embodiments, Ring B is [ka] is selected from.

[0239] In some embodiments, Ring B is [ka] It is from.

[0240] In some embodiments, Ring B is [ka] is selected from.

[0241] In some embodiments, R is methyl, [ka] is selected from.

[0242] In some embodiments, R is methyl, [ka] is selected from.

[0243] In some embodiments, the AhR antagonist according to the present disclosure is a compound of formula (Ib): [ka] or a pharma- ceutically acceptable salt thereof. (In the formula: Ring A is selected from optionally substituted heteroaryl and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted heteroaryl and optionally substituted heterocycloalkyl; and R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H.

[0244] In some embodiments, the AhR antagonist is any one of the compounds listed in Table 2.

[0245] [Table 2-1]

[0246] [Table 2-2]

[0247] [Table 2-3]

[0248] [Table 2-4]

[0249] [Table 2-5]

[0250] [Table 2-6]

[0251] [Table 2-7]

[0252]

Table 2-8

[0253]

Table 2-9

[0254]

Table 2-10

[0255]

Table 2-11

[0256]

Table 2-12

[0257]

Table 2-13

[0258]

Table 2-14

[0259]

Table 2-15

[0260]

Table 2-16

[0261]

Table 2-17

[0262]

Table 2-18

[0263] [Table 2-19]

[0264] [Table 2-20]

[0265] [Table 2-21]

[0266] [Table 2-22]

[0267] [Table 2-23]

[0268] [Table 2-24]

[0269] [Table 2-25]

[0270] In some embodiments, the AhR antagonist is selected from the following compounds and pharma- ceutically acceptable salts thereof: (i) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (ii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (iii) (S)-8-(benzo[d][1,3]dioxol-4-yl)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (iv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (v) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (vi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (vii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (viii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (ix) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (x) 6,8-di(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xi) (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xiii) 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xiv) 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xv) 6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xvi) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xvii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xviii) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xix) 3-(2-hydroxy-2-methylpropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xx) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxi) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxiv) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxv) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyrido[3,4-d]pyrimidin-4(3H)-one; (xxvii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxviii) 3-methyl-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxix) Rac-6-(4-chlorophenyl)-3-((trans)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxx) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxi) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxii) rac-6-(4-chlorophenyl)-3-((cis)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxiii) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxiv) (S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxv) (S)-6,8-bis(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxvi) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxvii) (S)-8-(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxviii) 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxix) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xl) (S)-3-(1-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xli) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xliii) (S)-3-(1-hydroxypropan-2-yl)-6-morpholino-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlv) (S)-3-(1-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlvii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlviii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlix) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (l) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethoxy)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (li) (S)-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lii) Methyl (S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinate (liii) (S)-3-(1-hydroxypropan-2-yl)-6-(isothiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (liv) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lv) (S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lvi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lvii) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lviii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lix) 3-(2-hydroxy-2-methylpropyl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lx) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxi) 6-(4-chloro-2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(2-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxiv) (S)-3-(1-hydroxypropan-2-yl)-8-(4-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxv) (S)-3-(1-hydroxypropan-2-yl)-6-(4-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxvi) (S)-6-(2-cyclopropylthiazol-5-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxvii) (S)-3-(1-hydroxypropan-2-yl)-6-(2-isopropylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxviii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxix) (S)-3-(1-hydroxypropan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxx) 6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxi) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxii) 3-(2-hydroxyethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxiii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxiv) (S)-6-(6-cyclopropylpyridin-3-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxv) (S)-3-(1-hydroxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxvii) (S)-6-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxviii) (S)-6,8-bis(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxix) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxx) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxi) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxii) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxiii) (S)-6-(6-cyclopropylpyridin-3-yl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxiv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxvii) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxviii) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxix) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xc) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xci) (S)-3-(1-hydroxypropan-2-yl)-6-(piperidin-1-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcii) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xciii) (S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xciv) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcv) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvi) (3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvii) 3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcviii) (R)-3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcix) (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (c) (S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ci) (R)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cii) (S)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ciii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (civ) (R)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cv) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvi) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvii) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cviii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cix) (S)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cx) (R)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxi) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxii) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiii) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiv) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxv) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxvi) Methyl (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate (cxvii) 6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxviii) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxix) (R)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxx) (S)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxi) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxii) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiv) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxv) (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvi) (S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvii) (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxviii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxix) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxx) (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxi) (S)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiii) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiv) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxv) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvi) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvii) (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid (cxxxviii) (S)-N-Methyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (cxxxix) (S)-N,N-Dimethyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propenamide (cxl) 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxli) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlii) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxliii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-1,2,4-triazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlvii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlviii) (S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlix) (S)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cl) (S)-3-(1-hydroxypropan-2-yl)-8-(pyrrolidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cli)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-6-Cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-3-(1-hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clv) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvi) (S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvii) (R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (clviii) (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clx) 6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxi) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylpyrimidin-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxii) 3-(2-hydroxy-2-methylpropyl)-8-(1-(trifluoromethyl)-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxiv) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxv) (S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinic acid (clxvi) (S)-3-(1-hydroxypropan-2-yl)-6-(6-methylpyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxvii) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxviii) 3,8-di(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxix) 8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxx) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxi) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxii) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxiii) 3-Cyclopentyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxiv) 3-phenyl-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxv) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxvi) 3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxvii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxviii) (S)-N-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (clxxix) 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxx) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxi) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxiii) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxiv) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxv) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxvi) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxvii) (S)-3-(1-hydroxypropan-2-yl)-8-morpholino-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxviii) 3-(2-hydroxy-2-methylpropyl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clxxxix) (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxc) (S)-3-(1-hydroxypropan-2-yl)-6-(5-methylpyrimidin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxci) (S)-8-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcii) (S)-8-Cyclohexyl-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxciii) (S)-3-(1-hydroxypropan-2-yl)-N,N-dimethyl-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidine-6-carboxamide (cxciv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcv) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methoxyethyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxcvi) (S)-3-(1-hydroxypropan-2-yl)-8-(2-methoxyethyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one.

[0271] In some embodiments, the AhR antagonist is selected from the following compounds and pharma- ceutically acceptable salts thereof: (i) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (ii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (iii) (S)-8-(benzo[d][1,3]dioxol-4-yl)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (iv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (v) (S)-8-(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (vi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (vii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (viii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (ix) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (x) 6,8-di(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xi) (S)-6-chloro-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xiii) 6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xiv) 8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xv) 6-(4-chlorophenyl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xvi) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xvii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xviii) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xix) 3-(2-hydroxy-2-methylpropyl)-6,8-bis(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xx) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxi) 6-(4-chlorophenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(4-(trifluoromethyl)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxiv) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxv) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-phenylpyrido[3,4-d]pyrimidin-4(3H)-one; (xxvii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxviii) 3-methyl-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxix) Rac-6-(4-chlorophenyl)-3-((trans)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxx) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxi) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxii) rac-6-(4-chlorophenyl)-3-((cis)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxiii) (R)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxiv) (S)-3-(3-hydroxy-3-methylbutan-2-yl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxv) (S)-6,8-bis(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxvi) (S)-6-(4-chlorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxvii) (S)-8-(3,5-difluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxviii) 6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(2-hydroxy-2-methylpropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xxxix) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xl) (S)-3-(1-(benzyloxy)propan-2-yl)-8-(3-fluorophenyl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xli) (R)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlii) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xliii) (S)-3-(1-hydroxypropan-2-yl)-6-morpholino-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlv) (S)-3-(1-methoxypropan-2-yl)-8-(pyridin-3-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlvii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlviii) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(p-tolyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (xlix) (S)-8-(3-fluorophenyl)-3-(1-hydroxypropan-2-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one; (l) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethoxy)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (li) (S)-3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lii) Methyl (S)-5-(3-(1-hydroxypropan-2-yl)-4-oxo-8-(pyridin-3-yl)-3,4-dihydropyrido[3,4-d]pyrimidin-6-yl)picolinate (liii) (S)-3-(1-hydroxypropan-2-yl)-6-(isothiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (liv) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lv) (S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lvi) (S)-3-(1-hydroxypropan-2-yl)-6,8-di(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lvii) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lviii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lix) 3-(2-hydroxy-2-methylpropyl)-6,8-di(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lx) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxi) 6-(4-chloro-2-methylphenyl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxiii) (S)-3-(1-hydroxypropan-2-yl)-8-(2-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxiv) (S)-3-(1-hydroxypropan-2-yl)-8-(4-methylpyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxv) (S)-3-(1-hydroxypropan-2-yl)-6-(4-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxvi) (S)-6-(2-cyclopropylthiazol-5-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxvii) (S)-3-(1-hydroxypropan-2-yl)-6-(2-isopropylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxviii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxix) (S)-3-(1-hydroxypropan-2-yl)-6,8-bis(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxx) 6-(4-chlorophenyl)-3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxi) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxii) 3-(2-hydroxyethyl)-8-(pyridin-3-yl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxiii) (S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxiv) (S)-6-(6-cyclopropylpyridin-3-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxv) (S)-3-(1-hydroxypropan-2-yl)-6-(4-methyl-6-(trifluoromethyl)pyridin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxvii) (S)-6-(cyclohex-1-en-1-yl)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxviii) (S)-6,8-bis(5-fluoropyridin-3-yl)-3-(1-hydroxypropan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxix) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxx) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxi) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxii) 6-(6-cyclopropylpyridin-3-yl)-3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxiii) (S)-6-(6-cyclopropylpyridin-3-yl)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxiv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxv) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxvi) (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxvii) 3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxviii) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (lxxxix) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xc) (S)-6-(4-chlorophenyl)-8-(3-fluorophenyl)-3-(1-hydroxy-3-methylbutan-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xci) (S)-3-(1-hydroxypropan-2-yl)-6-(piperidin-1-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcii) 3-(2-hydroxy-2-methylpropyl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xciii) (S)-3-(1-hydroxypropan-2-yl)-8-(isothiazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xciv) 3-(2-hydroxy-2-methylpropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcv) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvi) (3-(2-hydroxy-2-methylpropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcvii) 3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcviii) (R)-3-(1,1-dioxidetetrahydrothiophen-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (xcix) (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (c) (S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ci) (R)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cii) (S)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (ciii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (civ) (R)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cv) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvi) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cvii) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cviii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cix) (S)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cx) (R)-6-(6-cyclopropylpyridin-3-yl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxi) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxii) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiii) (S)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(4-(trifluoromethoxy)phenyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxiv) 6-(4-chlorophenyl)-3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxv) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxvi) Methyl (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoate (cxvii) 6-(4-chlorophenyl)-3-(4-hydroxy-1-methylpyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxviii) 6-(4-chlorophenyl)-3-((3R,4R)-4-hydroxypyrrolidin-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxix) (R)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxx) (S)-6-(6-cyclopropylpyridin-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxi) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxii) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiii) 3-((3S,4R)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxiv) 3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxv) (R)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvi) (S)-3-(2-hydroxypropyl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxvii) (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxviii) (R)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxix) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxx) (S)-3-(2-hydroxypropyl)-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxi) (S)-8-(1-methyl-1H-pyrazol-4-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiii) 3-((3S,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxiv) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxv) 6-(4-chlorophenyl)-3-((3R,4S)-4-hydroxytetrahydrofuran-3-yl)-8-(1-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvi) (R)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxxxvii) (S)-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanoic acid (cxxxviii) (S)-N-Methyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propanamide (cxxxix) (S)-N,N-Dimethyl-2-(4-oxo-8-(pyridin-3-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-3(4H)-yl)propenamide (cxl) 3-(2-hydroxy-2-methylpropyl)-8-(1H-pyrazol-4-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxli) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlii) 3-(2-hydroxy-2-methylpropyl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxliii) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(5-(trifluoromethyl)pyridin-2-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxliv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-imidazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlv) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-1,2,4-triazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlvi) (S)-3-(1-hydroxypropan-2-yl)-8-(1H-pyrazol-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlvii) (S)-3-(1-hydroxypropan-2-yl)-8-(1-methyl-1H-pyrazol-4-yl)-6-(2-(trifluoromethyl)thiazol-5-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlviii) (S)-8-(diethylamino)-3-(1-hydroxypropan-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cxlix) (S)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cl) (S)-3-(1-hydroxypropan-2-yl)-8-(pyrrolidin-1-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (cli)(S)-6-(4-chlorophenyl)-3-(1-hydroxypropan-2-yl)-8-(piperidin-1-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-3-(1-hydroxypropan-2-yl)-8-(pyridin-2-yl)-6-(6-(trifluoromethyl)pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-6-Cyclohexyl-3-(1-hydroxypropan-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (S)-3-(1-hydroxypropan-2-yl)-6-(pyridin-2-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clv) (S)-3-(1-hydroxypropan-2-yl)-6-(2-methylthiazol-4-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvi) (S)-3-(1-hydroxypropan-2-yl)-6-(1-methyl-1H-1,2,3-triazol-5-yl)-8-(pyridin-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (clvii) (R)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one (clviii) (S)-6-(4-chlorophenyl)-8-(pyridin-3-yl)-3-(3,3,3-trifluoro-2-hydroxypropyl)pyrido[3,4-d]pyrimidin-4(3H)-one. EXAMPLES

[0272] The synthesis of the AhR antagonists in Table 2, along with biological data for these compounds, are described in PCT Publication No. WO 2021 / 102288A1, the contents of which are incorporated by reference in their entirety into this specification.

[0273] Example 1: AhR ligands as predictors of ICI responsiveness An experimental cohort of patients (donors) with late stage (III-IV) non-small cell lung cancer was recruited to participate in a study evaluating the role of the microbiome on response to ICI therapy. Therapy types evaluated included either single or combined use of therapies targeting PD-1, PD-L1 and CLTA-4. Samples collected to characterize the impact of the microbiome on patient response consisted of paired stool and plasma and were collected at two time points: (i) before the start of therapy and (ii) 6 weeks after the start of therapy. Patients were monitored up to 3 years after recruitment to establish the response to the immunomodulatory therapy administered based on the adopted RECIST 1.1 criteria. A total of 73 patients were eligible for the study and provided samples.

[0274] Fecal (intestinal luminal) and plasma samples collected from all donors at all time points were processed in parallel to characterize signals from metabolites shared across the microbiome and host. Samples were stored according to best practices in microbiome science.

[0275] Metabolite concentrations were measured by Metabolon, Inc., Durham, North Carolina, USA using targeted GC / MS, LC / MS and LC / MS / MS platforms as described by Zierer et al. (Nat Genet., 2018, 50(6):790-795), including ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS / MS). The following equipment / conditions were used: Waters ACQUITY ultra-performance liquid chromatography (UPLC) and Thermo Scientific Q-Exactive high-resolution / accurate mass spectrometer interfaced with a heated electrospray ionization (HESI-II) source and an Orbitrap mass analyzer operated at a mass resolution of 35,000. Sample extracts were dried and then reconstituted in a solvent compatible with each of the four assay aliquots described below. Each reconstitution solvent contains a series of standards at fixed concentrations to ensure injection and chromatographic consistency.

[0276] The first aliquot was analyzed using acidic cation conditions chromatographically optimized for more hydrophilic compounds. The extract was eluted from a C18 column (Waters UPLC BEH C18-2.1×100 mm, 1.7 μm) using a gradient elution with water and methanol containing 0.05% perfluoroheptanoic acid (PFPA) and 0.1% formic acid (FA). The second aliquot was also analyzed using acidic cation conditions, but chromatographically optimized for more hydrophobic compounds. In this assay, the extract was eluted from the same C18 column using a gradient elution with methanol, acetonitrile, water, 0.05% PFPA, and 0.01% FA, operating at a higher overall organic content. The third aliquot was analyzed using basic anion optimized conditions using a separate dedicated C18 column. The basic extract was eluted from the column using a gradient of methanol and water with 6.5 mM ammonium bicarbonate at pH 8. The fourth aliquot was analyzed using negative ionization after elution from a HILIC column (Waters UPLC BEH Amide 2.1 x 150 mm, 1.7 μm) with a gradient of water and acetonitrile in 10 mM ammonium formate, pH 10.8. MS analysis consisted of alternating MS and data-dependent MSn scans with dynamic exclusion. The scan range covered 70-1000 m / z, although it varied slightly between assays. Raw data files were stored and extracted by Metabolon Inc.

[0277] From the generated small molecule profiling data, we investigated a targeted panel of 29 compounds known to function as AhR ligands (Table 1). Utilizing metadata describing patient outcomes, a binary representation of response to ICI therapy was constructed for each patient. To assess whether such ligands could have a predictive or predetermining effect on the success of ICI therapy by leveraging a baseline time point before the start of actual therapy, AhR ligands were further analyzed using statistical association tests (MannWhitneyU with false discovery rate correction) in both stool and plasma samples. As shown in Figure 1A, four of the ligands, namely kynurenine, tryptophan, phenylpyruvate, and indole lactate, were found to be differentially abundant at baseline with FDR-corrected p-values ​​less than 0.05 when comparing between patients who eventually became either responders or non-responders.

[0278] Of these four AhR ligands that were statistically associated with future response in this clinical trial, all were found to be elevated on average in non-responders compared with responders, suggesting that observation of depletion signals of these AhR ligands may be indicative of a higher likelihood of response to ICI therapy.

[0279] As shown in Figure 1B, the corresponding signals of these ligands in paired plasma samples from these donors showed no statistical difference using the same method, suggesting that in patients who eventually became non-responders, the elevation of these AhR ligands was only observable via direct measurement of stool samples and not plasma samples.

[0280] Although only a minority of the clinical population (19 of 73), patients who received only ICIs and no other concomitant therapies such as chemotherapy also demonstrated this significant upward shift in these four AhR ligands, suggesting future non-response to ICI therapy (Figure 2).The data further demonstrate the relevance of the microbial metabolism of these AhR ligands for predicting successful therapeutic response from ICI therapy.

[0281] The signals from the full panel of 29 AhR ligands compared to the four statistically relevant ligands, as presented via principal component analysis for dimensionality reduction, allowed a visual overview of these signals in future responders or non-responders. As shown in the left and middle panels of Figure 3, the grouping of responders qualitatively increased as one moved from the full panel to the visualized signals of only the four relevant ligands. When comparing this view of the relevant ligands in ICI-only donors, the division between responders and non-responders became more pronounced (right panel), confirming that the observation of these four AhR ligands is either predictive or determinative of the success of ICI therapy.

[0282] Example 2: DRE-luciferase reporter assay AHR binds to dioxin response elements (DREs) upstream of the genes it activates. One measure of AHR activity is the activation of a reporter gene, such as luciferase, downstream of one or more DRE elements. Luciferase activity reflects the activation and inhibition of AHR in cells expressing this reporter. 20,000 human HepG2 hepatocarcinoma-AhR-Lucia reporter cells or human HT29 colon adenocarcinoma-AhR reporter cells or other cell lines stably transfected with DRE-luciferase reporter were seeded in plates (96-well, 384-well, or other plates) in Eagle's Minimum Essential Medium, 10% heat-inactivated FBS, 1X non-essential amino acids, Pen-Strep (10,000U / mL) and Normocin (100ug / mL), incubated overnight at 37°C in a CO2 incubator, and treated with or without AhR antagonists in log dilutions starting at 100uM.

[0283] One hour after seeding the cells, AHR activating ligands such as TCDD, kynurenine, ITE (2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester), VAF347, BNF (β-naphthoflavone), FICZ (6-formylindolo(3,2-b)carbazole), or other AHR ligands were administered at their specific EC 50 Concentrations of 100 mM NaCl, 10 mM MHC class II, 10 mM NaCl, 10 mM MHC class III, 10 mM NaCl, and 10 mM MHC class II were added to cells with or without AHR antagonist.

[0284] Cells were incubated for 24 or 48 hours or other time points and supernatants were analyzed for measurement of luciferase activity as a readout of AHR activation or inhibition. Luciferase was measured by a commercial kit QUANTI-Luc™ Assay Solution Kit from Invivogen according to the manufacturer's instructions.

[0285] The level of luciferase where only agonist ligand was added gave the highest signal, whereas luciferase without antagonist gave the lowest signal. IC 50 The luciferase IC value was determined as the concentration that inhibited half of the luciferase activity. 50 Levels are reported in Table 3. "A" indicates IC<100 nM 50 values, and "B" indicates IC values ​​between 100 and 500 nM. 50 "C" indicates IC > 500 nM 50 "D" stands for IC 50 Indicates that a value could not be generated from the data.

[0286] [Table 3-1]

[0287] [Table 3-2]

[0288] [Table 3-3]

[0289] [Table 3-4]

[0290] [Table 3-5]

[0291] Example 3: Combination Therapy The anti-tumor efficacy of compound #30 was tested in the CT26 mouse model, which is unresponsive to anti-PD-L1 therapy alone. CT26 cells were implanted subcutaneously in Balb / c mice and then randomized to treat with either an isotype control antibody, an anti-PD-L1 antibody, or a combination of compound #30 and an anti-PD-L1 antibody from Table 2. Compound #30 was administered at 10 mg / kg po once daily for 14 days, and anti-PD-L1 antibody was administered at 10 mg / kg ip every 3 days. Tumor growth curves and tumor weights for all treatment groups are shown in Figures 4A and 4B. Anti-PD-L1 antibody alone had no significant effect on tumor growth or tumor weight, whereas co-administration of compound #30 with anti-PD-L1 antibody resulted in a reduction in tumor volume, p=0.039 (Figure 4A, Mann-Whitney nonparametric test). Additionally, coadministration of compound 30 with anti-PD-L1 antibody resulted in a reduction in tumor weight, p = 0.067 (Figure 4B, Mann-Whitney nonparametric test).

[0292] Although the present disclosure has been particularly shown and described with reference to specific embodiments, it should be understood by those skilled in the art that various changes in form and detail can be made therein without departing from the spirit and scope of the disclosure. The present invention provides, for example, the following items. (Item 1) 1. A method of treating cancer in a patient in need thereof, comprising administering to the patient: (a) determining or having determined the amount of at least one aryl hydrocarbon receptor (AhR) ligand in a fecal sample obtained from said patient; (b) comparing or having been compared the amount of the at least one AhR ligand to a threshold score; (c) determining or having determined that the patient is likely to benefit from treatment with an AhR antagonist if the amount of the at least one AhR ligand is above the threshold score; (d) treating said patient determined to be responsive in (c) with an effective amount of said AhR antagonist; A method comprising: (Item 2) The patient is a patient with non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, gastric adenocarcinoma, nasopharyngeal neoplasm, urothelial carcinoma, colorectal cancer, pleural mesothelioma, triple negative breast cancer, esophageal neoplasm, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung cancer, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma, diffuse large B cell The method according to item 1, wherein the patient is suffering from lymphoma, renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignant tumor, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer, gastric cancer, colon cancer, or liver cancer. (Item 3) The method of claim 1 or 2, wherein the patient has been treated with immune checkpoint inhibitor (ICI) therapy but has not responded to the ICI therapy. (Item 4) The method of claim 1 or 2, wherein the patient has been treated with an ICI therapy and has developed resistance to the ICI therapy. (Item 5) 5. The method of any one of items 1 to 4, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indole lactate, or a combination thereof. (Item 6) 6. The method of claim 5, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, and indole lactate. (Item 7) 7. The method according to any one of items 1 to 6, wherein the amount of the at least one AhR ligand in the sample is measured by liquid chromatography-mass spectrometry or gas phase chromatography-mass spectrometry. (Item 8) 8. The method according to any one of items 1 to 7, wherein the threshold score is determined by measuring the amount of the corresponding at least one AhR ligand in a control fecal sample obtained from a patient responding to ICI therapy. (Item 9) The AhR antagonist has formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 and R 2 are each independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H. (Item 10) The AhR antagonist has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, wherein: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and 10. The method according to any one of items 1 to 9, wherein R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H. (Item 11) 11. The method according to any one of items 1 to 10, wherein the AhR antagonist is any one of those listed in Table 2, or a pharma- ceutically acceptable salt thereof. (Item 12) 1. An in vitro method for determining whether a patient is likely to benefit from treatment with an aryl hydrocarbon receptor (AhR) antagonist, comprising: (a) determining or having determined the amount of at least one AhR ligand in a fecal sample obtained from said patient; (b) comparing or having been compared the amount of the at least one AhR ligand to a threshold score; (c) determining that the patient is likely to benefit from treatment with an AhR antagonist if the amount of the at least one AhR ligand is above the threshold score; and A method comprising: (Item 13) The patient is a patient with non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, gastric adenocarcinoma, nasopharyngeal neoplasm, urothelial carcinoma, colorectal cancer, pleural mesothelioma, triple negative breast cancer, esophageal neoplasm, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung cancer, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma, diffuse large B cell lymphoma, or diffuse large B cell lymphoma. 13. The method according to item 12, wherein the patient is suffering from malignant lymphoma, renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignant tumor, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, solid organ cancer, gastric cancer, colon cancer, or liver cancer. (Item 14) The method of claim 12 or 13, wherein the patient has been treated with immune checkpoint inhibitor (ICI) therapy but has not responded to the ICI therapy. (Item 15) The method of claim 12 or 13, wherein the patient has been treated with an ICI therapy and has developed resistance to the ICI therapy. (Item 16) 16. The method of any one of items 12 to 15, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indole lactate, or a combination thereof. (Item 17) 17. The method of claim 16, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, and indole lactate. (Item 18) 18. The method according to any one of items 12 to 17, wherein the amount of the at least one AhR ligand in the sample is measured by liquid chromatography-mass spectrometry or gas phase chromatography-mass spectrometry. (Item 19) 19. The method according to any one of items 12 to 18, wherein the threshold score is determined by measuring the amount of the corresponding at least one AhR ligand in a control fecal sample obtained from a patient responding to ICI therapy. (Item 20) The AhR antagonist has formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 and R 2 are each independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H. (Item 21) The AhR antagonist has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, wherein: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and 21. The method according to any one of items 12 to 20, wherein R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H. (Item 22) 21. The method according to any one of items 12 to 20, wherein the AhR antagonist is any one of those listed in Table 2, or a pharma- ceutically acceptable salt thereof. (Item 23) 1. A method of treating cancer with a combination therapy comprising an immune checkpoint inhibitor (ICI) and an aryl hydrocarbon receptor (AhR) antagonist in a patient in need thereof, comprising: (a) determining or having determined the amount of at least one AhR ligand in a fecal sample obtained from said patient; (b) comparing or having been compared the amount of the at least one AhR ligand to a threshold score; (c) determining or having determined that the patient is likely to respond to the combination therapy if the amount of the at least one AhR ligand is above the threshold score; (d) treating said patient determined to be responsive in (c) with said combination therapy; A method comprising: (Item 24) The patient is a patient with non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, gastric adenocarcinoma, nasopharyngeal neoplasm, urothelial carcinoma, colorectal cancer, pleural mesothelioma, triple negative breast cancer, esophageal neoplasm, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung cancer, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma, diffuse large B cell lymphoma, or diffuse large B cell lymphoma. 24. The method according to item 23, wherein the patient is suffering from malignant lymphoma, renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignant tumor, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, parenchymal organ cancer, gastric cancer, colon cancer, or liver cancer. (Item 25) The method of claim 23 or 24, wherein the patient has been treated with ICI therapy but has not responded to the ICI therapy. (Item 26) The method of claim 23 or 24, wherein the patient has been treated with an ICI therapy and has developed resistance to the ICI therapy. (Item 27) 27. The method of any one of items 23 to 26, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indole lactate, or a combination thereof. (Item 28) 28. The method of claim 27, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, and indole lactate. (Item 29) 29. The method according to any one of items 23 to 28, wherein the amount of the at least one AhR ligand in the sample is measured by liquid chromatography-mass spectrometry or gas phase chromatography-mass spectrometry. (Item 30) 30. The method of any one of items 23 to 29, wherein the ICI therapy comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-TIGIT antibody, an anti-VISTA antibody, or a combination thereof. (Item 31) 31. The method according to any one of items 23 to 30, wherein the threshold score is determined by measuring the amount of the corresponding at least one AhR ligand in a control fecal sample obtained from a patient responding to ICI therapy. (Item 32) The AhR antagonist has formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 and R 2are each independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3 is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H. (Item 33) The AhR antagonist has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, wherein: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and 33. The method according to any one of items 23 to 32, wherein R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H. (Item 34) 34. The method according to any one of items 23 to 33, wherein the AhR antagonist is any one of those listed in Table 2, or a pharma- ceutically acceptable salt thereof. (Item 35) 1. An in vitro method for predicting a patient's cancer responsiveness to immune checkpoint inhibitor (ICI) therapy, comprising: (a) determining or having determined the amount of at least one aryl hydrocarbon receptor (AhR) ligand in a fecal sample obtained from said patient; (b) comparing or having been compared the amount of the at least one AhR ligand to a threshold score; (c) determining that the patient's cancer is likely to respond to ICI therapy if the amount of the at least one AhR ligand is equal to or less than the threshold score; and A method comprising: (Item 36) The patient is a patient with non-small cell lung cancer, small cell lung cancer, squamous cell carcinoma of the head and neck, renal cell carcinoma, gastric adenocarcinoma, nasopharyngeal neoplasm, urothelial carcinoma, colorectal cancer, pleural mesothelioma, triple negative breast cancer, esophageal neoplasm, multiple myeloma, gastric and gastroesophageal junction cancer, melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, lung cancer, head and neck cancer, non-Hodgkin's lymphoma, metastatic clear cell renal carcinoma, squamous cell lung cancer, mesothelioma, gastric cancer, gastroesophageal junction cancer, metastatic melanoma, metastatic noncutaneous melanoma, urothelial carcinoma, diffuse large B cell lymphoma, or diffuse large B cell lymphoma. 36. The method according to item 35, wherein the patient is suffering from malignant lymphoma, renal cell carcinoma, ovarian cancer, fallopian tube cancer, peritoneal neoplasm, extensive small cell lung cancer, bladder cancer, transitional cell carcinoma, prostate neoplasm, recurrent or metastatic PD-L1 positive or negative squamous cell carcinoma of the head and neck, recurrent squamous cell lung cancer, advanced solid malignant tumor, hypopharyngeal squamous cell carcinoma, laryngeal squamous cell carcinoma, unresectable or metastatic melanoma, biliary tract neoplasm, esophageal squamous cell carcinoma, breast cancer, pancreatic cancer, glioblastoma, metastatic cancer, prostate cancer, parenchymal organ cancer, gastric cancer, colon cancer, or liver cancer. (Item 37) 37. The method of claim 35 or 36, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, indole lactate, or a combination thereof. (Item 38) 38. The method of claim 37, wherein the at least one AhR ligand comprises kynurenine, tryptophan, phenylpyruvate, and indole lactate. (Item 39) 39. The method according to any one of items 35 to 38, wherein the amount of the at least one AhR ligand in the sample is measured by liquid chromatography-mass spectrometry or gas phase chromatography-mass spectrometry. (Item 40) 40. The method of any one of items 35 to 39, wherein the ICI therapy comprises an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM-3 antibody, an anti-TIGIT antibody, an anti-VISTA antibody, or a combination thereof. (Item 41) 41. The method according to any one of items 35 to 40, wherein the threshold score is determined by measuring the amount of the corresponding at least one AhR ligand in a control fecal sample obtained from a patient responding to ICI therapy. (Item 42) 42. The method according to any one of items 35 to 41, further comprising determining that the patient's cancer is likely to respond to ICI therapy in combination with an AhR antagonist if the amount of the at least one AhR ligand is above the threshold score. (Item 43) The AhR antagonist has formula I: [ka] or a pharma- ceutically acceptable salt thereof, wherein: R 1 and R 2 are each independently selected from optionally substituted alkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted amine, and optionally substituted heterocycloalkyl; and R 3 is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amide, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amine, cyano, halo, hydroxy, and -C(O)H. (Item 44) The AhR antagonist has formula Ia: [ka] or a pharma- ceutically acceptable salt thereof, wherein: Ring A is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; Ring B is selected from optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl; and 44. The method of claim 42 or 43, wherein R is selected from hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted amido, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted ester, optionally substituted heteroalkyl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, amino, cyano, halo, hydroxy, and -C(O)H. (Item 45) 45. The method according to any one of items 42 to 44, wherein the AhR antagonist is any one of those listed in Table 2, or a pharma- ceutically acceptable salt thereof.

Claims

[Claim 1] The invention described in the specification.

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