Compositions for the treatment of cancer

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application Number 62 / 791,591, filed January 11, 2019, U.S. Provisional Application Number 62 / 886,235, filed August 13, 2019, U.S. Provisional Application Number 62 / 936,223, filed November 15, 2019, and U.S. Provisional Application Number 62 / 946,631, filed December 11, 2019.STATEMENT REGARDING SEQUENCE LISTING

[0002] The sequence listing associated with this application is provided in text format in lieu of a paper copy. The name of the text file containing the sequence listing is OG_1_0294_US_Sequence_Listing_20200107_ST25.txt. The file is 11 KB; was created on January 7, 2020; and is being submitted via EFS-Web with the filing of the specification.TECHNICAL FIELD

[0003] This disclosure is directed to compounds for use in treating cancer by administering to a subject a therapeutically effective amount of an inhibitor of G protein-coupled receptor 174 (GPR174)-mediated signaling, or a combination of an inhibitor of GPR174-mediated signaling and an inhibitor of ATP-Adenosine-A2aR-or A2bR-mediated signaling (such as an A2aR antagonist, and / or an A2bR antagonist, or a combination of an inhibitor of GPR174-mediated signaling and an inhibitor of an enzymatic pathway involved in the production of adenosine, such as CD38, CD39 and / or CD73 (such as a CD73 inhibitor and / or a CD38 inhibitor and / or a CD39 inhibitor), or an inhibitor of GPR174-mediated signaling and a regulatory T cell (Treg) attenuating agent, thereby stimulating an immune response in a mammalian subject in need thereof, such as a subject suffering from cancer.BACKGROUND

[0004] Mammalian G protein-coupled receptors (GPCRs) constitute a superfamily of diverse proteins with hundreds of members. GPCRs act as receptors for a multitude of different signals. Sensory GPCRs (spur) are receptors for sensory signals of external origin that are sensed as light of different colors, odors, pheromones, or tastes. Most other GPCRs respond to endogenous signals, such as peptides, lipids, neurotransmitters, or nucleotides. GPCRs falling in the latter group are involved in numerous physiological processes, including the regulation of neuronal excitability, metabolism, reproduction, development, cell division, hormonal homeostasis, and behavior, and are differentially expressed in many cell types in the body.

[0005] Ligands have been identified for some GPCRs. GPCRs that do not yet have an identified endogenous or cognate ligand are known as orphan GPCRs. As of 2019, approximately 120 GPCRs were considered to be orphan GPCRs, including GPR174 (see "Orphan and other 7TM receptors, IUPHAR / BPS Guide to Pharmacology," accessed on 6 / 8 / 2019; Alexander S. et al., Br. J. Pharmacol. 174 Suppl 1:S17-S129, 2017). Of all currently marketed drugs, 30-40% are modulators of specific GPCRs. Of about 240 non-orphan GPCRs, more than half are targeted by drugs on the market or currently in clinical development (see Hauser A.S. et al., Nature Reviews Drug Discovery 16(12):829-842, 2017).

[0006] Development of a drug to target a specific GPCR generally requires knowledge of the endogenous ligand or a surrogate ligand, i.e., a non-endogenous molecule that binds and functionally interacts with the specific GPCR, which can serve as a screening control and / or as the basis for medicinal chemistry to develop synthetic drug molecules that functionally interact with that specific GPCR. Given the potential use of orphan GPCRs as targets for new drugs, identification of ligands or surrogate ligands for orphan GPCRs would hasten the development of new drugs for those receptors. However, despite significant effort to identify such ligands, a large number of orphan receptors remain (see, e.g., Levoye et al., Drug Discov. Today 13(1-2):52-8, 2008). Conventional GPCR screening campaigns typically rely on screening for drug discovery using both biochemical and functional assays, such as assays measuring Ca ++< signaling as a response to GPCR activation. However, these conventional approaches rely on the presence of the endogenous ligand or a surrogate ligand. When used with orphan GPCRs, these assays can only identify agonists to GPCRs. With conventional assay technology, neither inverse agonists nor antagonists can be identified until an agonist is available. Importantly, many of the FDA approved drugs targeting GPCRs are functional inhibitors (e.g., partial agonists, inverse agonists, partial inverse agonists or antagonists). Thus, conventional approaches miss detecting this common and critical class of GPCR ligands.

[0007] GPR174, also known as FKSG79 and GPCR17, is expressed in a relatively small number of tissues including spleen, thymus, bone marrow and lymph node (Regard et al., Cell 135:561-71, 2008; Chu et al., J Med Genet 50:479-85, 2013; Sugita et al., Biochem Biophys Res Commun 430:190-5, 2013. Within the lymphoid tissues, GPR174 is expressed to high levels in naive B and T cells, especially in regulatory T cells (Tregs) (Barnes et al., J Exp Med 212:1011-20, 2015). WO 2009 / 120899 discloses methods and compositions for use in the diagnosis, prognosis, and treatment of human hematopoietic cancers with GPR174 specifically binding antibodies. Vijayan et al., Nature Reviews Cancer 17:709-724, 2017 discloses the role of adenosine signaling in regulating tumor immunity; and Leone et al., J Immunother Cancer, 6:1-9, 2018, discloses adenosine receptor inhibitors in the treatment of primary tumors and metastases and Saitoh et al., BIOCHEMICAL PHARMACOLOGY, vol. 67, no. 10, 1 May 2004 (2004-05-01), pages 2005-2011, discloses adenosine induction of apoptosis in human gastric cancer cells.

[0008] As described herein, GPR174 activity has been associated with cancer. Given the role that GPR174 appears to play in cancer, it is desirable to identify inhibitors of this receptor. There is a need in the art for effective cancer treatments. The compositions provided herein address these and other deficiencies in the art.BRIEF SUMMARY

[0009] The present invention is as set out in the claims. Other disclosures herein not falling within the claims are for the assistance of the skilled person in understanding and practicing the disclosed invention and are not part of the invention. For the avoidance of doubt, it is noted that the present invention does not extend to methods of treatment of the human or animal body. Any references in the description to methods of treatment refer to compounds, pharmaceutical compositions, and medicaments of the present disclosure for use in a method of treatment of the human or animal body by therapy.

[0010] The present inventors have identified chemical compounds that functionally interact with GPR174 and inhibit one or more GPR174-mediated signaling pathways and, additionally, have characterized the GPR174 receptor signaling profile, which includes the Gs signaling pathway. The inventors have demonstrated that representative GPR174 inhibitory compounds are capable of reducing the fraction of highly suppressive regulatory T cells or "TRegs" (FoxP3+Helios+) in human peripheral blood mononuclear cells (PBMCs), as described in Examples 6, 8, and 9. The inventors have further determined that GPR174 inhibition stimulates IL-2 production in a dose-dependent manner in PBMCs, as described in Examples 6-11. The inventors have also determined that GPR174 inhibition reduces immune-cell associated programmed death-ligand 1 (PD-L1) expression, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) expression, T cell immunoreceptor with Ig and ITIM domains (TIGIT) expression and amphiregulin (AREG) expression, as described in Example 13 and 14. Therefore, the GPR174 inhibitory compounds can be used as drugs for use in stimulating an immune response in a mammalian subject and can form the basis for additional therapeutic agents. Based on these discoveries, the present disclosure is related to in vivo and in vitro methods for inhibiting the GPR174 receptor and thereby stimulating an immune response, particularly in a subject suffering from a non-malignant neoplasm or a malignant neoplasm (i.e., cancer).

[0011] As further described herein, the inventors have also demonstrated that the combined inhibition of GPR174 and inhibition of the Adenosine 2a Receptor (A2aR) and / or the inhibition of the Adenosine 2b receptor (A2bR) results in synergistic induction of Th1 cytokine production (e.g., IFN-γ, IL-2, TNF and GM-CSF), in human PBMCs, as described in Examples 15, 18-23, 27, and 29.

[0012] As further described herein, the inventors have also demonstrated that murine colon carcinoma tumor growth and melanoma tumor growth was reduced in GPR174-deficient mice treated with an anti-GITR antibody (i.e., a Treg attenuating agent) as compared to wild-type mice, as described in Examples 24 and 25.

[0013] As further described herein, the inventors have determined that cancer cell-derived exosomes stimulate GPR174 and inhibition of GPR174 in the presence of cancer cell-derived exosomes enhances Th1 cytokine levels, thereby stimulating and / or amplifying the immune system as described in Example 26.

[0014] In summary, as demonstrated herein, GPR174 is an immune system-restricted Gαs-coupled GPCR and PS exposed on liposomes and cellular membranes stimulates GPR174, supporting a model of active GPR174-mediated immune suppression in the tumor microenvironment. Under conditions where both PS / lysoPS and adenosine are present, inhibition of both axes is necessary for effective restoration of T cell function. As further demonstrated herein, GPR174-deficiency enhances anti-tumor immune responses in mice.

[0015] Therefore, in one aspect, the present disclosure provides methods and compositions for stimulating and / or amplifying an immune response (e.g. for treating cancer) by administering to a subject suffering from, or at risk of developing cancer or cancer metastasis, a therapeutically effective amount of an inhibitor of GPR174-mediated signaling as a single agent or optionally in combination with an inhibitor of ATP-Adenosine-A2aR-or A2bR-mediated signaling (such as an A2aR antagonist, an A2bR antagonist and / or a CD73 inhibitor and / or a CD38 inhibitor and / or a CD39 inhibitor, and / or a Treg attenuating agent, or a combination thereof), thereby stimulating and / or amplifying an immune response in a mammalian subject in need thereof. In some cases, the methods comprise administering to a subject suffering from cancer an inhibitor of GPR174 and an A2aR antagonist. In some cases, the methods comprise administering to a subject suffering from cancer an inhibitor of GPR174 and an A2bR antagonist. In some cases, the methods comprise administering to a subject suffering from cancer an inhibitor of GPR174 and an A2aR / A2bR antagonist. In some cases, the methods comprise administering to a subject suffering from cancer an inhibitor of GPR174 and a CD73 inhibitor. In some cases, the methods comprise administering to a subject suffering from cancer an inhibitor of GPR174 and a CD38 inhibitor. In some cases, the methods comprise administering to a subject suffering from cancer an inhibitor of GPR174 and a CD39 inhibitor. In some cases, the methods comprise administering to a subject suffering from cancer an inhibitor of GPR174 and a Treg attenuating agent. In some cases, the methods comprise administering to a subject suffering from cancer an inhibitor of GPR174 and an A2aR antagonist and optionally at least one or more of an A2bR antagonist, a CD73 inhibitor, a CD38 inhibitor, a CD39 inhibitor and a Treg attenuating agent. In some cases, the A2aR antagonist is a small molecule. In some cases, the A2aR antagonist is an antibody. In some cases, the A2aR antagonist is a peptide- or a nucleotide / nucleic acid-based molecule. In some cases, the A2bR antagonist is a small molecule. In some cases, the A2bR antagonist is an antibody. In some cases, the A2bR antagonist is a peptide- or a nucleotide / nucleic acid-based molecule. In some cases, the CD38 inhibitor is a small molecule. In some cases, the CD38 inhibitor is an antibody. In some cases, the CD38 antagonist is a peptide- or a nucleotide / nucleic acid-based molecule. In some cases, the CD39 inhibitor is a small molecule. In some cases, the CD39 inhibitor is an antibody. In some cases, the CD39 antagonist is a peptide- or a nucleotide / nucleic acid-based molecule. In some cases, the CD73 inhibitor is a small molecule. In some cases, the CD73 inhibitor is an antibody. In some cases, the CD73 antagonist is a peptide- or a nucleotide / nucleic acid-based molecule. In some cases, the Treg attenuating agent is a small molecule. In some cases, the Treg attenuating agent is an antibody. In some cases, the Treg attenuating agent is a peptide or a nucleotide / nucleic acid-based molecule. In some cases, the GPR174 inhibitor is a small molecule. In some cases, the GPR174 inhibitor is an antibody. In some cases of the method, the GPR174 inhibitor, and at least one or more of the A2aR antagonist, the A2bR antagonist, the CD38 inhibitor, the CD39 inhibitor, the CD73 inhibitor and the Treg attenuating agent are administered simultaneously (e.g., co-administered separately or together), or sequentially in any order, provided the effects of the first administered inhibitor remain present at the time of the second (and optionally third) administered inhibitor or attenuating agent.

[0016] As further described herein in Examples 16 and 17, the inventors have also discovered that phosphatidylserine (PS) is an agonist for GPR174-mediated Gs signaling. Example 17 provides experimental results demonstrating that apoptotic cells stimulate GPR174 Gs signaling pathway in cells expressing GPR174. As further described in Example 16 and shown in FIGURES 47A-47F, PS-mediated GPR174 Gs signaling is inhibited by representative GPR174 inhibitory compounds 6, 10, 11, 20, 23 and 30 which belong to different chemical classes (i.e., Groups I, II and IV). This data demonstrates that compounds 6, 10, 11, 20, 23, and 30 act as GPR174 antagonists and inhibit PS liposome-mediated cAMP signaling. Thus, PS liposome signaling through GPR174 is inhibited by multiple GPR174 inhibitory small molecule compounds with diverse chemical structures. Accordingly, in one case, the present disclosure provides a method of inhibiting PS-mediated activation of GPR174 Gs signaling in an immune cell expressing GPR174 comprising contacting said immune cell with an inhibitor of GPR174 Gs signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent. In one case, the present disclosure provides a method of stimulating T-cell mediated immunity in a subject suffering from cancer comprising administering a GPR174 inhibitor either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor, and / or a Treg attenuating agent to said subject in an amount effective to stimulate T-cell mediated immunity as described herein.

[0017] In another case, the disclosure provides a method of increasing an anti-tumor immune response in a subject that is currently undergoing, or has undergone treatment with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent, comprising administering an effective amount of a GPR174 inhibitor to stimulate an enhanced anti-tumor immune response in the subject, provided that the use of a CD73 inhibitor is preferably avoided during early tumor formation or in the setting of metastasis due to the fact that it might be preferable to have CD73 remain active in such settings.

[0018] In some cases, provided herein is a method of stimulating an immune response in a mammalian patient in need thereof comprising administering to the mammalian patient a small molecule inhibitor of GPR174 signaling, alone or in combination with an inhibitor of ATP-Adenosine-A2aR-or ATP-Adenosine-A2bR-mediated signaling (such as an A2aR antagonist, an A2bR antagonist, and / or a CD73 inhibitor and / or a CD38 inhibitor and / or a CD39 inhibitor) and / or a Treg attenuating agent. In some cases, the GPR174 inhibitor inhibits GPR174-mediated signaling through the Gs alpha subunit of the heterotrimeric G protein that stimulates the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent pathway. The cAMP-dependent pathway (also referred to as Gs signaling or Gs pathway) involves synthesis of the second messenger cAMP, which in turn activates the cAMP-dependent protein kinase (Protein Kinase A or PKA).

[0019] In one case, the disclosure provides a pharmaceutical composition comprising a combination of an inhibitor of GPR174 signaling and a least one or more of an adenosine A2A receptor antagonist, an adenosine A2B receptor antagonist, a CD73 inhibitor and / or a CD38 inhibitor and / or a CD39 inhibitor and a pharmaceutically acceptable carrier.

[0020] In one case, the disclosure provides a pharmaceutical composition comprising a combination of an inhibitor of GPR174 signaling and a Treg attenuating agent and a pharmaceutically acceptable carrier.

[0021] In some cases, the GPR174 inhibitor is a small molecule inhibitor that is an inverse agonist of GPR174 signaling.

[0022] In some cases, the small molecule inhibitor is an antagonist of GPR174 signaling.

[0023] In some cases, the small molecule inhibitor inhibits phosphatidylserine (PS), or lysophosphatidylserine (LysoPS), or pepducin dependent activation of GPR174 signaling in a cell expressing GPR174 by at least 25%.

[0024] In some cases, the stimulated immune response comprises a T-cell-mediated immune response.

[0025] In some cases, the T-cell mediated immune response comprises suppression of T-Reg activity, differentiation, growth and / or proliferation. In some cases, the T-cell mediated immune response comprises stimulation of Teffector activity, differentiation, growth and / or proliferation. In some cases, the T-cell mediated immune response comprises stimulation of Th1 cell activity, differentiation, growth and / or proliferation. In some cases, the T-cell mediated immune response comprises suppression of Th17 cell activity, differentiation, growth and / or proliferation. In one case, the T-cell mediated immune response comprises preferential growth and activation of Teffector cells over those of Tregulatory cells, resulting in a relative decrease in Tregulatory cell frequency, abundance and / or function.

[0026] In some cases, the stimulated immune response comprises a reduction in immune-cell or cancer-cell associated programmed death-ligand 1 (PD-L1) expression or cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) expression or T cell immunoreceptor with Ig and ITIM domains (TIGIT) expression or amphiregulin (AREG) expression.

[0027] In some cases, the stimulated immune response comprises an NK-cell mediated immune response. In some cases, at least a portion of the T-cells or the NK-cells express GPR174. In some cases, the NK-cell mediated immune response comprises stimulation of NK-cell function, activity, differentiation, growth and / or proliferation.

[0028] In some cases, the stimulated immune response and / or amplified immune response comprises an increase in Th1 cytokine production in the presence of cancer cell-derived exosomes.

[0029] In some cases, the patient is suffering from, or harboring a neoplasm not recognized by the body as self. In some cases, the neoplasm is a non-malignant neoplasm, such as a non-malignant tumor. In some cases, the neoplasm is a malignant tumor. In some cases, the neoplasm (either malignant or non-malignant tumor) comprises a T cell infiltrate. In some cases, tumor cells are destroyed by the immune response stimulated by the GPR174 inhibitory compound either as a single agent, or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent.

[0030] In some cases, the patient is a cancer patient. In some cases, the mammalian patient is a human. In some cases, the cancer is a solid tumor. In some cases, the cancer is a blood cancer. In some cases, the cancer is as disclosed herein. In some cases, at least a portion of the cancer cells express GPR174. In some cases, the GPR174 has 90% or greater sequence identity to SEQ ID NO: 1.

[0031] In some cases, T-cell activity, differentiation, proliferation, and / or growth is stimulated in a population of peripheral blood mononuclear cells (PBMCs) contacted with the GPR174 small molecule inhibitor either as a single agent, or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control population of PBMCs not contacted with the GPR174 small molecule inhibitor.

[0032] In some cases, the fraction of FoxP3 +< Helios+ T-cells (regulatory T-cells) is decreased by at least 20% in a population of PBMCs contacted with the GPR174 small molecule inhibitor either as a single agent, or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor, and / or a Treg attenuating agent as compared to a control population of PBMCs not contacted with the small molecule GPR174 inhibitor.

[0033] In some cases, the cAMP level is decreased by at least 20%, at least 50%, or at least 75% in a cell expressing GPR174 contacted with the small molecule inhibitor of GPR174 signaling either as a single agent, or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the GPR174 small molecule inhibitor.

[0034] In some cases, the activity of protein kinase A (PKA) is decreased by at least 20% in cells expressing GPR174 contacted with the small molecule inhibitor of GPR174 either as a single agent, or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent, as compared to a control cell not contacted with the GPR174 small molecule inhibitor.

[0035] In some cases, the PKA activity is decreased by at least 20%, at least 50%, or at least 75% in a cell expressing GPR174 contacted with the small molecule inhibitor of GPR174 signaling either as a single agent, or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the GPR174 small molecule inhibitor.

[0036] In some cases, the production of one or more of IL-2, IFN-γ, TNF-α, IL-6, and IL-10 is increased by at least 20% in peripheral blood mononuclear cells (PBMCs) contacted with the small molecule inhibitor of GPR174 as compared to control cells not contacted with the small molecule inhibitor.

[0037] In some cases, the production of one or more of IL-2, IFN-γ, TNF-α, and GM-CSF is increased by at least 20% in peripheral blood mononuclear cells (PBMCs) contacted with the small molecule inhibitor of GPR174 in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor, and / or a Treg attenuating agent as compared to control cells not contacted with the small molecule inhibitor of GPR174.

[0038] In some cases, the production of IL-17A is decreased by at least 20% in PBMCs contacted with the small molecule inhibitor as compared to control cells not contacted with the small molecule inhibitor.

[0039] In some cases, the production of one or more cytokines is decreased by at least 20%, at least 50%, or at least 80% in in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the production of IL-17A is decreased by at least 20%, at least 50%, or at least 80% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling.

[0040] In some cases, the production of one or more cytokines is increased by at least 20%, at least 50%, or at least 80% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the cytokine is selected from IL-2, IFN-γ, TNF, IL-6, and IL-10.

[0041] In some cases, the production of one or more cytokines is increased by at least 20%, at least 50%, or at least 80% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to control cells not contacted with the small molecule inhibitor of GPR174. In some cases, the cytokine is a T helper type 1 cell (Th1) cytokine selected from IL-2, IFN-γ, TNF, and GM-CSF.

[0042] In some cases, the production of one or more cytokines is increased by at least 20%, at least 50%, at least 100%, at least 500%, or at least 1000% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the cytokine is selected from IL-2, IFN-γ, TNF, and GM-CSF. In some cases, the production of one or more of IL-2, IFN-γ, TNF, or GM-CSF is increased by at least 20%, at least 50%, at least 100%, at least 500%, or at least 1000% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor, and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling.

[0043] In some cases, the production of IL-2 is increased by at least 100%, at least 500%, or at least 1000% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the production of IFN-γ is increased by at least 50%, at least 100%, or at least 500% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the production of TNF-α is increased by at least 50%, at least 100%, or at least 500% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling.

[0044] In some cases, the production of GM-CSF is increased by at least 50%, at least 100%, or at least 500% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling.

[0045] In some cases, the production of one or more cytokines are not modulated and do not increase or decrease by more than 20% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the cytokine or cytokines is selected from the group consisting of: IL-4, IL-5, IL-9, IL-13, IL-17F, IL-21, and IL-22.

[0046] In some cases, the production of one or more cytokines is decreased by at least 20%, at least 50%, or at least 80% in a cell expressing GPR174 contacted with the small molecule inhibitor as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor. In some cases, the production of IL-17A is decreased by at least 20%, at least 50%, or at least 80% in a cell expressing GPR174 contacted with the small molecule inhibitor as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor.

[0047] In some cases, the production of one or more cytokines is increased by at least 20%, at least 50%, at least 100%, at least 500%, or at least 1000% in a cell expressing GPR174 contacted with the small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174. In some cases, the production of one or more of IL-2, IFN-γ, TNF, or GM-CSF is increased by at least 20%, at least 50%, at least 100%, at least 500%, or at least 1000% in a cell expressing GPR174 contacted with the small molecule inhibitor of GPR174 as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174. In some cases, the production of IL-2 is increased by at least 100%, at least 500%, or at least 1000% in a cell expressing GPR174 contacted with a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174. In some cases, the production of IFN-γ is increased by at least 50%, at least 100%, or at least 500% in a cell expressing GPR174 contacted with a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174. In some cases, the production of TNF-α is increased by at least 50%, at least 100%, or at least 500% in a cell expressing GPR174 contacted with a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174.

[0048] In some cases, the production of one or more or IL-4, IL-5, IL-9, IL-13, IL-17F, IL-21, and IL-22 are not modulated and do not increase or decrease by more than 20% in a cell expressing GPR174 contacted with a small molecule inhibitor of GPR174 signaling as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor. In some cases, the patient has one or more tumor(s) which may or may not comprise infiltrating regulatory T-cells.

[0049] In some cases, provided herein is a method of inhibiting the level of cAMP in a cell that expresses GPR174, the method comprising contacting the cell with a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent.

[0050] In some cases, the cAMP level is decreased by at least 20%, at least 50%, or at least 75% in a cell expressing GPR174 contacted with the small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174.

[0051] In some cases, the contacting is in vivo. In some cases, the contacting is in vitro. In some cases, the contacting is ex vivo.

[0052] In some cases, the cell is an immune cell. In some cases, the cell is a T-cell or NK-cell. In some cases, the NK-cell or T-cell activity, differentiation, growth and / or proliferation is stimulated. In some cases, the cell is a mammalian cell. In some cases, the cell is a human cell. In some cases, the cell is a thymus, lymph node, spleen, bone marrow, or PMBC cell.

[0053] In some cases, the GPR174 has 90% or greater sequence identity, such as 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% to SEQ ID NO:1. In some cases, the GPR174 has a sequence set forth as SEQ ID NO:1.

[0054] In some cases, provided herein is a method of modulating the level of one or more cytokines in PBMCs, the method comprising contacting the PBMCs with a small-molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent.

[0055] In some cases, the contacting is in vivo. In some cases, the contacting is in vitro. In some cases, the contacting is ex vivo.

[0056] In some cases, the PBMCs comprise immune cells. In some cases, the immune cells comprise T-cells or NK-cells. In some cases, the activity, differentiation, growth and / or proliferation of the NK-cells or T-cells is stimulated. In some cases, the PBMCs comprise mammalian cells. In some cases, the PBMCs comprise human cells.

[0057] In some cases, the GPR174 has 90% or greater sequence identity to SEQ ID NO: 1.

[0058] In some cases, the cytokine is selected from IL-2, IFN-γ, TNF, GM-CSF, IL-6, IL-17A, IL-10, IL-4, IL-5, IL-9, IL-12, IL-13, IL-17F, IL-21, and IL-22. In some cases, the level of one or more cytokines is increased. In some cases, the level of one or more of cytokines selected from the group consisting of IL-2, IFN-γ, TNF and GM-CSF is increased. In some cases, the level of one or more cytokines is decreased. In some cases, the level of one or more cytokines is not modulated.

[0059] In some cases, the level of one or more cytokines is decreased by at least 20%, at least 50%, or at least 80% in in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the level of IL-17A is decreased by at least 20%, at least 50%, or at least 80% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling.

[0060] In some cases, the level of one or more cytokines is increased by at least 20%, at least 50%, or at least 80% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the cytokine is selected from IL-2, IFN-γ, TNF, and GM-CSF.

[0061] In some cases, the level of one or more cytokines is increased by at least 20%, at least 50%, at least 100%, at least 500%, or at least 1000% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the cytokine is selected from IL-2, IFN-γ, TNF, and GM-CSF. In some cases, the level of one or more of IL-2, IFN-γ, TNF-α, or GM-CSF is increased by at least 20%, at least 50%, at least 100%, at least 500%, or at least 1000% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling.

[0062] In some cases, the level of IL-2 is increased by at least 100%, at least 500%, or at least 1000% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the level of IFN-γ is increased by at least 50%, at least 100%, or at least 500% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the level of TNF-α is increased by at least 50%, at least 100%, or at least 500% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling.

[0063] In some cases, the level of one or more cytokines are not modulated and do not increase or decrease by more than 20% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the cytokine or cytokines is selected from the group consisting of: IL-4, IL-5, IL-9, IL-13, IL-17F, IL-21, and IL-22.

[0064] In some cases, the level of one or more cytokines is decreased by at least 20%, at least 50%, or at least 80% in a cell expressing GPR174 contacted with the small molecule inhibitor as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor. In some cases, the level of IL-17A is decreased by at least 20%, at least 50%, or at least 80% in a cell expressing GPR174 contacted with the small molecule inhibitor as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor.

[0065] In some cases, the level of one or more cytokines is increased by at least 20%, at least 50%, at least 100%, at least 500%, or at least 1000% in a cell expressing GPR174 contacted with the small molecule inhibitor of GPR174 either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174. In some cases, the level of one or more of IL-2, IFN-γ, TNF, or GM-CSF is increased by at least 20%, at least 50%, at least 100%, at least 500%, or at least 1000% in a cell expressing GPR174 contacted with the small molecule inhibitor of GPR174 either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174.

[0066] In some cases, the level of IL-2 is increased by at least 100%, at least 500%, or at least 1000% in a cell expressing GPR174 contacted with a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174.

[0067] In some cases, the level of IFN-γ is increased by at least 50%, at least 100%, or at least 500% in a cell expressing GPR174 contacted with a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174.

[0068] In some cases, the level of TNF (also referred to as "TNF-α") is increased by at least 50%, at least 100%, or at least 500% in a cell expressing GPR174 contacted with a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174.

[0069] In some cases, the level of one or more or IL-4, IL-5, IL-9, IL-13, IL-17F, IL-21, and IL-22 are not modulated and do not increase or decrease by more than 20% in a cell expressing GPR174 contacted with a small molecule inhibitor of GPR174 signaling as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor.

[0070] In some cases, provided herein is a pharmaceutical composition comprising a small molecule inhibitor of GPR174 signaling and a pharmaceutically acceptable excipient.

[0071] In some cases, provided herein is a pharmaceutical composition comprising a small molecule inhibitor of GPR174 signaling in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor and / or a CD73 inhibitor and a pharmaceutically acceptable excipient.

[0072] In some cases, provided herein is a pharmaceutical composition comprising a small molecule inhibitor of GPR174 signaling in combination with an A2aR antagonist and a pharmaceutically acceptable excipient.

[0073] In some cases, provided herein is a pharmaceutical composition comprising a small molecule inhibitor of GPR174 signaling in combination with an A2bR antagonist and a pharmaceutically acceptable excipient.

[0074] In some cases, provided herein is a pharmaceutical composition comprising a small molecule inhibitor of GPR174 signaling in combination with an A2aR antagonist and an A2bR antagonist and a pharmaceutically acceptable excipient.

[0075] In some cases, provided herein is a pharmaceutical composition comprising a small molecule inhibitor of GPR174 signaling in combination with a Treg attenuating agent and a pharmaceutically acceptable excipient.

[0076] In some cases, provided herein is a pharmaceutical composition comprising a small molecule inhibitor of GPR174 and at least one of (i) an A2aR antagonist and / or an A2bR antagonist; and (ii) at least one of a CD73 inhibitor and / or a CD38 inhibitor and / or a CD39 inhibitor. In some cases, the pharmaceutical composition further comprises a Treg attenuating agent.

[0077] In some cases, the small molecule inhibitor of GPR174 does not comprise an alkyl chain comprising 10 or more C atoms. In some cases, the small molecule inhibitor of GPR174 is not pepducin, LysoPS, PS, or a compound disclosed in US Pub. No. 2015 / 0361119. In some cases, the small molecule inhibitor has a molecular weight from about 50 Da to about 2500 Da. In some cases, the small molecule inhibitor has a molecular weight from about 50 to 800 Da, such as from about 100 Da to about 800 Da.

[0078] In some cases, the small molecule inhibitor alters the cellular distribution of a recombinant GPR174 polypeptide modified to include a nuclear localization signal as compared to the cellular distribution of the recombinant GPR174 polypeptide in the absence of the inhibitor. In some cases, the small molecule inhibitor competitively binds to GPR174 as compared to any one of compounds 1-59. In some cases, the small molecule inhibitor has an EC 50 for GPR174 of less than 15 µM as determined by a cellular redistribution assay (CRA). CRA is described in detail herein under "Screening Methods." In some cases, the small molecule inhibitor binds competitively to GPR174 as compared to any one of compounds 1-59 and results in an altered apparent binding affinity of the compound for GPR174 when a cell expressing GPR174 is contacted with the compound and the small molecule inhibitor at the same time as compared to the binding affinity of compound for GPR174 alone. In some cases, the small molecule inhibitor causes a difference in the inhibitory activity of any one of reference compounds 1-59 in a GPR174-mediated signaling assay when tested in the presence of said reference compound as compared to the inhibitory activity of the reference compound alone. In some cases, the small molecule inhibitor binds allosterically to GPR174 as compared to any one of compounds 1-59. In some cases, the small molecule inhibitor is specific for GPR174 as compared to one or more GPCRs in a reference panel of GPCRs as disclosed herein. In some cases, the small molecule inhibitor is specific for GPR174 relative to P2Y10. In some cases, the small molecule inhibitor is specific for GPR174 relative to GPR34. In some cases, the small molecule inhibitor inhibits the Gs signaling pathway.

[0079] In some cases, T-cell activity, differentiation, proliferation, and / or growth is stimulated in a population of peripheral blood mononuclear cells (PBMCs) contacted with the small molecule inhibitor of GPR174 either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control population of PBMCs not contacted with the small molecule inhibitor of GPR174.

[0080] In some cases, the subpopulation of regulatory T-cells is decreased in a population of PBMCs contacted with the small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control population of PBMCs not contacted with the small molecule inhibitor of GPR174.

[0081] In some cases, the fraction of FoxP3 +< Helios+ T-cells (regulatory T-cells) is decreased by at least 20% in a population of PBMCs contacted with the small molecule inhibitor of GPR174 either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control population of PBMCs not contacted with the small molecule inhibitor of GPR174.

[0082] In some cases, the level of cAMP is decreased by at least 20% in a cell expressing GPR174 contacted with the small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174.

[0083] In some cases, the cAMP level is decreased by at least 20%, at least 50%, or at least 75% in a cell expressing GPR174 contacted with the small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174.

[0084] In some cases, the activity of PKA is decreased by at least 20% in cells expressing GPR174 contacted with the small molecule inhibitor of GPR174 either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell not contacted with the small molecule inhibitor of GPR174.

[0085] In some cases, the PKA activity is decreased by at least 20%, at least 50%, or at least 75% in a cell expressing GPR174 contacted with the small molecule inhibitor of GPR174 either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174.

[0086] In some cases, the level of one or more cytokines is modulated in PBMCs contacted with the small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to control cells not contacted with the small molecule inhibitor of GPR174.

[0087] In some cases, the level of one or more of IL-2, IFN-γ, TNF, and GM-CSF is increased by at least 20% in PBMCs contacted with the small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to control cells not contacted with the small molecule inhibitor of GPR174.

[0088] In some cases, the level of IL-17A is decreased by at least 20% in PBMCs contacted with the small molecule inhibitor as compared to control cells not contacted with the small molecule inhibitor.

[0089] In some cases, the level of one or more cytokines is decreased by at least 20%, at least 50%, or at least 80% in in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the level of IL-17A is decreased by at least 20%, at least 50%, or at least 80% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling.

[0090] In some cases, the level of one or more cytokines is increased by at least 20%, at least 50%, or at least 80% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the cytokine is selected from IL-2, IFN-γ, TNF and GM-CSF.

[0091] In some cases, the level of one or more cytokines is increased by at least 20%, at least 50%, at least 100%, at least 500%, or at least 1000% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the cytokine is selected from IL-2, IFN-γ, TNF, and GM-CSF. In some cases, the level of one or more of IL-2, IFN-γ, TNF, or GM-CSF is increased by at least 20%, at least 50%, at least 100%, at least 500%, or at least 1000% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling.

[0092] In some cases, the level of IL-2 is increased by at least 100%, at least 500%, or at least 1000% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the level of IFN-γ is increased by at least 50%, at least 100%, or at least 500% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the level of TNF-α is increased by at least 50%, at least 100%, or at least 500% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling.

[0093] In some cases, the level of one or more cytokines are not modulated and do not increase or decrease by more than 20% in a population of PBMCs exposed to a small molecule inhibitor of GPR174 signaling as compared to a population of PBMCs not exposed to the small molecule inhibitor of GPR174 signaling. In some cases, the cytokine or cytokines is selected from the group consisting of: IL-4, IL-5, IL-9, IL-13, IL-17F, IL-21, and IL-22.

[0094] In some cases, the level of one or more cytokines is decreased by at least 20%, at least 50%, or at least 80% in an immune cell contacted with the small molecule inhibitor as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor. In some cases, the level of IL-17A is decreased by at least 20%, at least 50%, or at least 80% in an immune cell contacted with the small molecule inhibitor as compared to a control cell not contacted with the small molecule inhibitor

[0095] In some cases, the level of one or more cytokines is increased by at least 20%, at least 50%, at least 100%, at least 500%, or at least 1000% in an immune cell contacted with the small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell not contacted with the small molecule inhibitor of GPR174. In some cases, the level of one or more of IL-2, IFN-γ, TNF, or GM-CSF is increased by at least 20%, at least 50%, at least 100%, at least 500%, or at least 1000% in an immune cell contacted with the small molecule inhibitor of GPR174 either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell not contacted with the small molecule inhibitor of GPR174.

[0096] In some cases, the level of IL-2 is increased by at least 100%, at least 500%, or at least 1000% in an immune cell contacted with a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell not contacted with the small molecule inhibitor of GPR174. In some cases, the level of IFN-γ is increased by at least 50%, at least 100%, or at least 500% in an immune cell contacted with a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell not contacted with the small molecule inhibitor of GPR174. In some cases, the level of TNF-α is increased by at least 50%, at least 100%, or at least 500% in an immune cell contacted with a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell not contacted with the small molecule inhibitor of GPR174.

[0097] In some cases, the level of one or more or IL-4, IL-5, IL-9, IL-13, IL-17F, IL-21, and IL-22 are not modulated and do not increase or decrease by more than 20% in an immune cell contacted with a small molecule inhibitor of GPR174 signaling as compared to a control cell not contacted with the small molecule inhibitor.

[0098] In some cases, the small molecule inhibitor reduces ligand-induced receptor internalization of GPR174 in cells expressing GPR174 as compared to control cells not contacted with the small molecule inhibitor.

[0099] In some cases, the receptor internalization is reduced by at least 10%, at least 20%, at least 50%, or at least 80% in a cell expressing GPR174 contacted with a small molecule inhibitor of GPR174 signaling as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor. In some cases, the receptor internalization is reduced by 1-99% in a cell expressing GPR174 contacted with a small molecule inhibitor of GPR174 signaling as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor. In some cases, the receptor internalization is reduced by 1-20%, 20-40%, 40-60%, 60-80%, or 80-99% in a cell expressing GPR174 contacted with a small molecule inhibitor of GPR174 signaling as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor.

[0100] In some cases, the β-arrestin recruitment is reduced by at least 10%, at least 20%, at least 50%, or at least 80% in a cell expressing GPR174 contacted with a small molecule inhibitor of GPR174 signaling as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor. In some cases, the β-arrestin recruitment is reduced by 1-99% in a cell expressing GPR174 contacted with a small molecule inhibitor of GPR174 signaling as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor. In some cases, the β-arrestin recruitment is reduced by 1-20%, by 20-40%, 40-60%, 60-80%, or by 80-99% in a cell expressing GPR174 contacted with a small molecule inhibitor of GPR174 signaling as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor.

[0101] In some cases, provided herein is a composition comprising a small molecule inhibitor of GPR174 either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent and a cell expressing GPR174.

[0102] In some cases, the cell is a mammalian cell. In some cases, the cell is a human cell. In some case, the cell is an immune cell. In some cases, the cell is a T cell. In some cases, the T cell is a naive T cell. In some cases, the T cell is a regulatory T cell. In some cases, the T cell is an effector T cell. In some cases, the cell is a thymus, lymph node, spleen, bone marrow, or PBMC cell. In some cases, the level of cAMP is decreased by at least 20% in the composition as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174. In some cases, the activity of PKA is decreased by at least 20% in the composition as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174. In some cases, the level of one or more cytokines is modulated in the composition as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174.

[0103] In some cases, the cAMP level is decreased by at least 20%, at least 50%, or at least 75% in a cell expressing GPR174 contacted with the small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174.

[0104] In some cases, the PKA activity is decreased by at least 20%, at least 50%, or at least 75% in a cell expressing GPR174 contacted with the small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent as compared to a control cell expressing GPR174 not contacted with the small molecule inhibitor of GPR174.

[0105] In some cases, provided herein is a composition comprising a small molecule inhibitor of GPR174 signaling either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent and a population of cells, wherein at least a portion of the population of cells express GPR174, and wherein at least a portion of the population of cells expressing GPR174 comprises T-cells.

[0106] In some cases, wherein the population of cells comprise cancer cells. In some cases, the population of T-cells comprises regulatory T cells. In some cases, the population of T-cells comprises effector T cells.

[0107] In another aspect, the disclosure features a method of inhibiting a GPR174-mediated signaling pathway (e.g., a Gs signaling pathway) in a cell. The method includes the step of contacting a cell with an isolated compound predetermined to functionally interact with GPR174 either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent, where the cell includes a GPR174-mediated signaling pathway and expresses GPR174 (e.g., a GPR174 polypeptide) and the isolated compound inhibits the ability of the GPR174 to modulate the GPR174-mediated signaling pathway, thereby inhibiting the GPR174-mediated signaling pathway in the cell. In certain cases, the compound is capable of functionally interacting with human GPR174 having the sequence set forth as SEQ ID NO:1, or a naturally occurring variant of GPR174 having at least 90% identity to SEQ ID NO: 1. In particular cases, the isolated compound is capable of altering the cellular distribution of a recombinant GPR174 polypeptide (e.g., human GPR174 having the sequence of SEQ ID NO: 1) modified to alter cellular distribution as compared to the cellular distribution of the recombinant GPR174 polypeptide in the absence of the compound. In some cases, the cell is contacted in vivo in a subject suffering from a disease such as cancer.

[0108] In a related aspect, the disclosure features a method of inhibiting a GPR174-mediated signaling pathway in a cell by (i) providing an isolated compound predetermined to functionally interact with human GPR174 and to inhibit a GPR174-mediated signaling pathway in cells expressing GPR174; and (ii) contacting a cell expressing GPR174 with said isolated compound either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent, thereby inhibiting a GPR174-mediated signaling pathway in the cell. In some cases, the cell expresses human GPR174 having the sequence set forth as SEQ ID NO:1 or a naturally occurring variant of GPR174 having at least 90% identity to SEQ ID NO:1 (such as at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) identity to SEQ ID NO:1 and to inhibit a GPR174-mediated signaling pathway in cells expressing GPR174. In some cases, the method comprises contacting a cell expressing human GPR174 with an isolated compound predetermined to functionally interact with human GPR174 having the sequence set forth as SEQ ID NO:1 or a naturally occurring variant of GPR174 having at least 90% (such as at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%) identity to SEQ ID NO:1 and to inhibit a GPR174-mediated signaling pathway in cells expressing GPR174. In some cases, step (i) comprises performing at least one assay to measure functional interaction of said compound with GPR174 prior to contacting a cell in accordance with step (ii).

[0109] In either aspect, the compound optionally competitively binds the same region of GPR174 as any one of compounds 1-59, provided below.

[0110] In another aspect, the disclosure features a method of using a small molecule chemical compound for inhibiting a GPR174-mediated signaling pathway in a cell, said method comprising the steps of (a) providing a small molecule chemical compound that functionally interacts with GPR174 and inhibits a GPR174-mediated Gs signaling pathway in cells expressing GPR174, wherein the compound is characterized by at least one of the following criteria: (i) said compound has a structure selected from the group consisting of Formula I, II, III, IV, V and VI (or (I), (II), (III), (IV), (V), (Va), or (VI)); or (ii) said compound changes the binding affinity of any one of reference compounds 1-59 (as set forth in Table 1) to GPR174; or (iii) said compound causes a difference in the inhibitory activity of any one of reference compounds 1-59 (as set forth in Table 1), in a GPR174-mediated signaling pathway assay when tested in the presence of the reference compound as compared to the inhibitory activity of the reference compound alone; and (b) contacting a cell expressing GPR174 that includes a GPR174-mediated Gs signaling pathway with the compound according to step (a) either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent, thereby inhibiting a GPR174-mediated signaling pathway in the cell.

[0111] In another aspect, the disclosure features a method of using a small molecule chemical compound for inhibiting a GPR174-mediated signaling pathway in a cell, said method comprising the steps of (a) providing a small molecule chemical compound that functionally interacts with GPR174 and inhibits a GPR174-mediated Gs signaling pathway in cells expressing GPR174, wherein the compound is characterized by at least one of the following criteria: (i) said compound has a structure selected from the group consisting of Formula I, II, III, IV, V and VI (or (I), (II), (III), (IV), (V), (Va), or (VI)); or (ii) said compound changes the apparent binding affinity of any one of reference compounds 1-59 (as set forth in Table 1) for GPR174; or (iii) said compound causes a difference in the inhibitory activity of any one of reference compounds 1-59 (as set forth in Table 1), in a GPR174-mediated signaling pathway assay when tested in the presence of said reference compound as compared to the inhibitory activity of the reference compound alone; and (b) contacting a cell expressing GPR174 that includes a GPR174-mediated Gs signaling pathway with the compound according to step (a) either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent, thereby inhibiting a GPR174-mediated signaling pathway in the cell.

[0112] In some cases, the compound changes the binding affinity of any one of the compounds described herein (e.g., any one of reference compounds 1-59 of Table 1). In certain cases, the compound decreases (i.e., inhibits) the binding affinity of any one of reference compounds 1-59 to GPR174. In particular cases, the compound competitively decreases (i.e., competitively inhibits) the binding affinity of any one of reference compounds 1-59 to GPR174. In alternate cases, the compound increases the binding affinity of any one of reference compounds 1-59 to GPR174. In one case, said compound has a structure selected from the group consisting of Formula I-VI. In one case, said compound inhibits lysophosphatidylserine (LysoPS)-dependent activation of the GPR174 receptor in said cell. In one case, said compound inhibits lysophosphatidylserine (LysoPS)-dependent activation of the GPR174 receptor in said cell.

[0113] In one case, said compound inhibits phosphatidylserine (PS)-dependent activation of the GPR174 receptor in said cell. As described herein in Examples 16 and 17, the inventors have discovered that phosphatidylserine (PS) is an agonist for GPR174-mediated Gs signaling. Example 17 provides experimental results demonstrating that apoptotic cells stimulate GPR174 Gs signaling pathway in cells expressing GPR174. As further described in Example 16 and shown in FIGURES 47A-47F, PS-mediated GPR174 Gs signaling is inhibited by representative GPR174 inhibitory compounds 6, 10, 11, 20, 23 and 30 which belong to different chemical classes (i.e., Groups I, II and IV). This data demonstrates that compounds 6, 10, 11, 20, 23, and 30 act as GPR174 antagonists and inhibit PS liposome-mediated cAMP signaling. Thus, PS liposome signaling through GPR174 is inhibited by multiple GPR174 inhibitory small molecule compounds with diverse chemical structures.

[0114] As described herein, extracellular PS is highly enriched in the tumor microenvironment and is found on the surface of tumor cells as well as endothelial cells of blood vessels permeating solid tumors. Furthermore, apoptotic neutrophils and activated platelets, both of which expose PS, are also recruited to solid tumors (see A.K and Rao D.A., Blood 120:4667-4668, 2012; Schlesinger, M., Journal of Hematology and Oncology (11) 125, 2018; Treffers L.W. et al., Immunological Reviews vol 273: 312-328, 2016; and Gregory A. D. and Houghton A. M., Cancer Research Vol 71 (7): 2411-6, 2011). Thus, high concentrations of PS are considered a major source of tumor-mediated immunosuppression and may play a role in resistance to cancer immunotherapies such as checkpoint inhibitors.

[0115] Accordingly, the experimental results described in Examples 16 and 17 provide support for a method of stimulating T-cell mediated immunity in a subject suffering from cancer comprising administering a GPR174 inhibitor either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent to said subject in an amount effective to stimulate T-cell mediated immunity as described herein.

[0116] As further described herein, the inventors have determined that cancer cell-derived exosomes stimulate GPR174 and inhibition of GPR174 in the presence of cancer cell-derived exosomes enhances Th1 cytokine levels to a greater extent than in the presence of PS liposomes, as described in Example 26. Accordingly, in one case, a method is provided for stimulating and / or amplifying an immune response in a mammalian subject suffering from, or at risk of developing cancer or cancer metastasis, comprising: (a) determining the presence of cancer cell-derived exosome(s) expressing phosphatidylserine (PS) in a sample obtained from said mammalian subject; and (b) administering a therapeutically effective amount of a GPR174 inhibitor to said subject.

[0117] In some cases, the GPR174 inhibitor is a small molecule that inhibits PS-mediated immune suppression. In some cases, the sample is a tissue, cell or cell extract, or a fluid selected from the group consisting of blood, serum, plasma, sputum, urine, saliva and tears. In some cases, step (a) comprises contacting said sample or exosome extract obtained from said sample with a PS binding agent and thereby determining the presence of said cancer cell-derived exosome. As exosome surface membranes reflect the plasma membrane of their parent cells, exosomes from tumor cells are characterized by having phosphatidylserine (PS) on their surface, as opposed to exosomes from normal cells. Exemplary PS-binding agents include, for example an anti-PS antibody or any other PS-binding agent such as, for example, PKC, protein S, factor VII, factor III and other known PS-binding agents. The PS binding agent may be labeled with a detectable agent, such as a radioactive isotope, a colorimetric label, a fluorescent label, a magnetic resonance label, an enzyme, an affinity ligand or a luminescent label. Exosomes may be extracted from a sample obtained from a subject by various means such as, for example, selective precipitation, affinity purification or by differential centrifugation according to known methods (see, e.g., Zhang Y. et al., Mol Cell 39:133-144, 2010). In some cases, the step (a) comprises determining a quantitative amount of cancer cell-derived exosomes in a sample obtained from a subject. In some cases, the method comprises determining whether or not the subject has an amount of cancer cell-derived exosomes above a threshold indicative of the presence of cancer (i.e. one or more tumors). In general, normal tumor-free individuals have undetectable levels of PS-exosomes in an unconcentrated sample. In contrast, patients with tumors will typically exhibit values above 100 pg / 50 µL of sample in an unconcentrated sample. Thus, values greater than 50 pg / 50 µL plasma (or serum) are indicative of a malignancy (i.e., cancer or one or more tumors).

[0118] It is known that PS-expressing exosomes are released from tumor cells and circulating PS-positive tumor exosomes can be detected in biological fluids such as blood and urine. In some cases, said cancer cell-derived exosome(s) expressing PS is from a lung cancer cell, a pancreatic cancer cell, an ovarian cancer cell, a breast cancer cell, a colon cancer cell, a renal cancer cell, a liver cancer cell, a skin cancer cell, a brain cancer cell, a head and neck cancer cell or a thyroid cancer cell, or any other cancer cell type disclosed herein. In some cases, the method further comprises administering to said subject at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent.

[0119] In some cases, the GPR174 inhibitory compound changes the apparent binding affinity of any one of the compounds described herein (e.g., any one of reference compounds 1-59 of Table 1) for GPR174. In certain cases, the compound decreases the apparent binding affinity of any one of reference compounds 1-59 for GPR174. In particular cases, the compound competitively binds to GPR174 and decreases the apparent binding affinity of any one of reference compounds 1-59 for GPR174. In alternate cases, the compound allosterically binds to GPR174 and decreases the apparent binding affinity of any one of reference compounds 1-59 for GPR174. In alternate cases, the compound increases the apparent binding affinity of any one of reference compounds 1-59 for GPR174. In one case, said compound has a structure selected from the group consisting of Formula I-VI. In one case, said compound inhibits lysophosphatidylserine (LysoPS)-dependent activation of the GPR174 receptor in said cell. In one case, said compound inhibits PS-dependent activation of the GPR174 receptor in said cell.

[0120] The cell expressing GPR174 may be a eukaryotic cell, such as a mammalian cell (e.g., a human cell). The cell may be in a mammal (e.g., a human, non-human primate, rodent, canine, feline, equine, swine or bovine). In some cases, the cell is contacted in vitro. In some cases, the cell is in a mammal and is contacted in vivo. In some cases, the cell expressing GPR174 is an immune cell, such as a T cell. In particular cases, the mammal (e.g., human) may be suffering from, or at risk for developing cancer.

[0121] In another aspect, the disclosure features a compound for use in treating cancer, characterized in that the compound interacts with GPR174 to inhibit a GPR174-mediated signaling pathway (e.g., a Gs signaling pathway) wherein the GPR174 inhibitory compound is used for treating cancer either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent. In certain cases, this GPR174 inhibitory compound is characterized in that it also exhibits the ability to alter the cellular distribution of a recombinant GPR174 polypeptide modified to include a nuclear localization signal as compared to the cellular distribution of the recombinant GPR174 polypeptide in the absence of the compound. In some cases, the method comprises contacting a cancer cell expressing GPR174 and / or an immune cell expressing GPR174 with an isolated compound predetermined to functionally interact with GPR174 and inhibit a GPR174-mediated signaling pathway either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent. In some cases, the method comprises contacting an immune cell expressing GPR174, such as a T cell with a compound that inhibits a GPR174-mediated signaling pathway either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent. In some cases, the method comprises performing at least one assay to measure the functional interaction of said compound with GPR174 prior to administrating said compound to the subject. In another aspect, the disclosure features a compound for use in treating a tumor in a patient suffering from cancer, characterized in that the compound interacts with GPR174 to inhibit a GPR174-mediated signaling pathway (e.g., a Gs signaling pathway) either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent. In certain cases, this GPR174 inhibitory compound is characterized in that it also exhibits the ability to alter the cellular distribution of a recombinant GPR174 polypeptide modified to include a nuclear localization signal as compared to the cellular distribution of the recombinant GPR174 polypeptide in the absence of the compound. In some cases, the tumor comprises regulatory T cell (Treg) infiltration. In some cases, the tumor comprising Treg infiltration is a solid organ tumor. In some cases, the tumor is in a subject suffering from a cancer selected from the group consisting of breast, lung (such as small-cell lung cancer or non-small cell lung cancer), colorectal, cervical, renal, ovarian, melanoma, pancreatic, hepatocellular, gastric, glioblastoma, glioma, bladder, myeloma (such as multiple myeloma), prostate, thyroid, testicular, and esophageal cancer. In some cases, the method comprises performing at least one assay to measure the functional interaction of said compound with GPR174 prior to administrating said compound to the subject

[0122] In another aspect, the disclosure features a method of treating or preventing cancer in a subject in need thereof. The method involves administering to the subject a compound that binds to and inhibits the GPR174 receptor, thereby inhibiting a GPR174-mediated signaling pathway, wherein inhibition of the GPR174-mediated signaling pathway with a GPR174 inhibitory agent, optionally in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent, results in treatment or prevention of the cancer. In some cases, the method comprises administrating to the subject an isolated compound predetermined to functionally interact with GPR174 and to inhibit a GPR174-mediated signaling pathway wherein inhibition of the signaling pathway results in the treatment of the cancer. In some cases, said GPR174 inhibitory compound is characterized by at least one of the following criteria: (i) said compound has a structure selected from the group consisting of Formula I-VI; (ii) said compound changes the binding affinity of any one of reference compounds 1-59 (as set forth in Table 1) to GPR174; and / or (iii) said compound causes a difference in the inhibitory activity of any one of reference compounds 1-59 (as set forth in Table 1), in a GPR174-mediated signaling pathway assay when tested in the presence of said reference compound as compared to the inhibitory activity of the reference compound alone. In some cases, said compound inhibits LysoPS-dependent activation of the GPR174 receptor in said subject. In some cases, said compound inhibits PS-dependent activation of the GPR174 receptor in said subject. In some cases, said GPR174 inhibitory compound is characterized by at least one of the following criteria: (i) said compound has a structure selected from the group consisting of Formula I-VI; (ii) said compound changes the apparent binding affinity of any one of reference compounds 1-59 (as set forth in Table 1) for GPR174; and / or (iii) said compound causes a difference in the inhibitory activity of any one of reference compounds 1-59 (as set forth in Table 1), in a GPR174-mediated signaling pathway assay when tested in the presence of said reference compound as compared to the inhibitory activity of the reference compound alone. In some cases, said compound inhibits LysoPS-dependent or PS-dependent activation of the GPR174 receptor in said subject. In another aspect, the disclosure features a method of stimulating T cell-mediated immunity in a subject suffering from cancer comprising administering to the subject a small molecule compound predetermined to inhibit a GPR174-mediated signaling pathway either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor and / or a CD73 inhibitor. In some cases, the compound inhibits GPR174-mediated signaling in a regulatory T cell, thereby inhibiting the growth and / or proliferation and / or inhibiting the activity of the regulatory T cell. In some cases, the compound inhibits GPR174-mediated signaling in an effector T cell, thereby stimulating the growth and / or proliferation and / or cytotoxic activity of the effector T cell. In some cases, the subject is suffering from a tumor comprising regulatory T cells and inhibition of GPR174 inhibits and / or suppresses growth and / or proliferation of regulatory T cells. In some cases of any of the above aspects, the cell is in a mammal, and said mammal is suffering from, or at risk for developing a cancer.

[0123] In some cases, the subject is suffering from or harboring a neoplasm not recognized by the body as self. In some cases, the neoplasm is a non-malignant neoplasm. In some cases, the neoplasm is a malignant neoplasm.

[0124] In some cases, the subject is suffering from, or is harboring, a malignant neoplasm (i.e., cancer), selected from the group consisting of: acoustic neuroma, anal cancer (including carcinoma in situ), squamous cell carcinoma, adrenal tumor (including adenoma, hyperaldosteronism, adrenalcortical cancer), Cushing's syndrome, benign paraganglioma, appendix cancer (including pseudomyxoma peritonei, carcinoid tumors, non-carcinoid appendix tumors), bile duct cancer (including intrahepatic bile duct cancer, extrahepatic bile duct cancer, perihilar bile duct cancer, distal bile duct cancer), gallbladder cancer, bone cancer (including chondrosarcoma, osteosarcoma, malignant fibrous histiocytoma, fibrosarcoma, chordoma), brain tumor (including craniopharyngioma, dermoid cysts, epidermoid tumors, glioma, astrocytoma, low-grade astrocytoma, anaplastic astrocytoma, ependymoma, glioblastoma, oligodendrogliomas, hemangioblastoma, pineal gland tumors, pituitary tumors, sarcoma, chordoma), breast cancer (including lobular carcinoma, triple negative breast cancer, recurrent breast cancer, brain metastases), bladder cancer (including transitional cell bladder cancer, squamous cell carcinoma, adenocarcinoma), cancers of unknown urimary (CUP), (including adenocarcinoma, poorly differentiated carcinoma, squamous cell carcinoma, poorly differentiated malignant neoplasm, neuroendocrine carcinoma), cervical cancer (including squamous cell carcinoma, adenocarcinoma, mixed carcinoma), carcinoid tumors, childhood germ cell tumors (including yolk sac tumors, teratoma, embryonal carcinoma, polyembryoma, germinoma), childhood brain tumors, (including ependymoma, craniopharyngioma, chordoma, pleomorphic xanthoastrocytoma, meningioma, primitive neuroectodermal tumors, ganglioglioma, pineoblastoma, germ cell tumors, mixed glial and neuronal tumors, astrocytoma, choroid plexus tumors), childhood leukemias (including lymphoblastic leukemia, myeloid leukemia), childhood hematology disorders (including Fanconi anemia, Diamond-Blackfan anemia, aplastic anemia, Shwachman-Diamond syndrome, Kostmann's syndrome, Neutropenia, Thrombocytopenia, Hemoglobinopathies, erythrocytosis, histioctic disorders, iron overload, clotting and bleeding disorders), childhood liver cancers (including hepatoblastoma, hepatocellular carcinoma), childhood lymphomas (including Hodgkin's lymphoma, Non-Hodgkin's lymphoma, Burkitt's lymphoma, lymphoblastic lymphoma, large cell lymphoma), childhood osteosarcomas; childhood melanomas; childhood soft tissue sarcomas, colon cancer (including adenocarcinoma, hereditary nonpolyposis colorectal cancer syndrome, familial adenomatous polyposis), desmoplastic Small Round Cell Tumors (DSRCT); esophageal cancers (including adenocarcinoma, squamous cell carcinoma), Ewing's sarcomas (including Ewing's Sarcoma of the bone, extraosseous Ewing tumor, peripheral primitive neuroectodermal tumors), Eye cancers (including uveal melanoma, basal cell carcinoma, squamous cell carcinoma, melanoma of the eyelid, melanoma of the conjunctiva, sebaceous carcinoma, merkel cell carcinoma, mucosa-associated lymphoid tissue lymphoma, orbital lymphoma, orbital sarcoma, orbital and optic nerve meningioma, metastic orbital tumors, lacrimal gland lymphoma, adenoid cystic carcinoma, pleomorphic adenoma, transitional cell carcinoma, lacrimal sac lymphoma); Fallopian tube cancers (including endometrioid adenocarcinoma, serous adenocarcinoma, leiomyosarcoma, transitional cell fallopian tube cancer); Hodgkin's lymphomas (including classical Hodgkin's lymphoma, nodular sclerosing Hodgkin's lymphoma, lymphocyte-rich classical Hodgkin's lymphoma, mixed cellularity Hodgkin's lymphoma, lymphocyte depletion Hodgkin's lymphoma, lymphocyte-predominant Hodgkin's lymphoma), Implant-Associated Anaplastic Large Cell Lymphomas (ALCL); Inflammatory Breast Cancers (IBC); Kidney cancers (including renal cell carcinoma, urothelial cancer of the kidney, pelvis and ureter); Leukemias, (including acute lymphocyte leukemia, acute myeloid leukemia, chronic lymphoblastic leukemia, chronic myeloid leukemia), Liver cancers (including hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, angiosarcoma, hepatoblastoma, hemangiosarcoma), Lung cancers (including non-small cell lung cancer, adenocarcinoma, squamous cell carcinoma, large cell carcinoma, small cell lung cancer, carcinoid tumor, salivary gland carcinoma, lung metastases, sarcoma); Medulloblastomas; Melanomas (including cutaneous melanoma, superficial spreading melanoma, nodular melanoma, lentigo maligna melanoma, acral lentiginous melanoma, ocular melanoma, mucosal melanoma); Mesotheliomas (including sarcomatoid mesothelioma, biphasic mesothelioma), Multiple Endocrine Neoplasias (MEN), (including multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2); Multiple Myelomas; Myelodysplastic syndromes (MDS) (including refractory anemia, refractory cytopenia with multilineage dysplasia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory cytopenia with multilineage dysplasia and ringed sideroblasts); Myeloproliferative disorders (MPD), (including polycythemia vera, primary myelofibrosis, essential thrombocythemia, systemic mastocytosis, hypereosinophilic syndrome); Neuroblastomas; Neurofibromatosis (including neurofibromatosis type 1, neurofibromatosis type 2, schwannomatosis); Non-Hodgkin's Lymphomas (including b-cell lymphoma, t-cell lymphoma, NK-cell lymphoma, mucosa-associated lymphoid tissue lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large cell lymphoma, primary mediastinal large cell lymphoma, anaplastic large cell lymphoma, burkitt's lymphoma, lymphoblastic lymphoma, marginal zone lymphoma); Oral cancers (including squamous cell carcinoma); Ovarian cancers (including epithelial ovarian cancer, germ cell ovarian cancer, stromal ovarian cancer, primary peritoneal ovarian cancer); Pancreatic cancers (including islet cell carcinoma, sarcoma, lymphoma, pseudopapillary neoplasms, ampullary cancer, pancreatoblastoma, adenocarcinoma); Parathyroid diseases (including hyperparathyroidism, hypoparathyroidism, parathyroid cancer), Penile cancers (including squamous cell carcinoma, kaposi sarcoma, adenocarcinoma, melanoma, basal cell carcinoma); Pituitary tumors (including non-functioning tumors, functioning tumors, pituitary cancer), Prostate cancers (including adenocarcinoma, prostatic intraepithelial neoplasia), Rectal cancers (including adenocarcinoma), Retinoblastomas (including unilateral retinoblastoma, bilateral retinoblastoma, PNET retinoblastoma), Skin cancers (including basal cell carcinoma, squamous cell carcinoma, actinic (solar) keratosis); Skull base tumors (including meningioma, pituitary adenoma, acoustic neuroma, glomus tumors, squamous cell carcinoma, basal cell carcinoma, adenoid cystic carcinoma, adenocarcinoma, chondrosarcoma, rhabdomyosarcoma, osteosarcoma, esthesioblastoma, neuroendocrine carcinoma, mucosal melanoma), Soft tissue sarcomas; Spinal tumors (including intramedullary spinal tumors, intradural extramedullary spinal tumors, extradural spinal tumors, osteoblastoma, enchondroma, aneurysmal bone cysts, giant cell tumors, hangioma, eosinophilic granuloma, osteosarcoma, chordoma, chondrosarcoma, plasmacytoma); Stomach cancers (including lymphoma, gastrointestinal stromal tumors, carcinoid tumors); Testicular cancers (including germ cell tumors, nonseminoma, seminoma, embryonal carcinoma, yolk sac tumors, teratoma, sertoli cell tumors, choriocarcinoma, stromal tumors, leydig cell tumors); Throat cancers (including squamous cell carcinoma); Thyroid cancers (including papillary thyroid cancer, follicular thyroid cancer, hurthle cell carcinoma, medullary thyroid cancer, anaplastic thyroid cancer); Uterine cancers (including endometrioid adenocarcinoma, uterine carcinosarcoma, uterine sarcoma); Vaginal cancers (including squamous cell carcinoma, adenocarcinoma, melanoma, sarcoma); Vulvar cancers (including squamous cell carcinoma, adenocarcinoma, melanoma, sarcoma); von Hippel Lindau Diseases; Waldenstrom's Macroglobulinemias; and Wilms' Tumors.

[0125] In some cases, the subject is suffering from, or is harboring, a malignant or non-malignant neoplasm as set forth in paragraphs 1-10 below: Connective tissue, (including adult fibrous tissue, embryonic (myxomatous) fibrous tissue, fat, cartilage, bone, notochord): 1a. benign neoplasms of the connective tissue include: fibroma, myxoma, lipoma, chondroma, osteoma and fibrous histiocytoma. 1b. malignant neoplasms of the connective tissue include: fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, malignant fibrosis histiocytoma, Endothelium and Mesothelium (including blood vessels, lymph vessels and mesothelium): 2a. benign neoplasms of the endothelium and mesothelium include: hemangioma, hemangiopericytoma and lymphangioma. 2b. malignant neoplasms of the endothelium and mesothelium include: hemangiosarcoma, angiosarcoma, lymphangiosarcoma and mesothelioma. Blood and Lymphoid cells (including hematopoietic cells and lymphoid tissue, 3a. benign neoplasms of the blood and lymphoid cells include: preleukemias, myeloproliferative disorders and plasmacytosis. 3b. malignant neoplasms of the blood and lymphoid cells include: plasmacytoma, multiple myeloma, Hodgkin lymphoma and Non-Hodgkin lymphoma. Muscle (including smooth muscle and striated muscle): 4a. benign neoplasms of the muscle include: leiomyoma and rhabdomyoma. 4b. malignant neoplasms of the muscle include: leiomyosarcoma and rhabdomyosarcoma. Epithelial tissues (including stratified squamouse, glandular epithelium (including liver, kidney and bile duct), transitional epithelium, placenta and testis): 5a. benign neoplasms of epithelial tissues include: papilloma, seborrheic keratosis and skin adnexal tumors, adenoma (including hepatic adenoma, renal tubular adenoma and bile duct adenoma), transitional cell papilloma and hydatidiform mole. 5b. malignant neoplasms of epithelial tissues include: squamous cell carcinoma; epidermoid carcinoma malignant skin adnexal tumors, adenocarcinoma, hepatoma, hepatocellular carcinoma, renal cell carcinoma, hypernephroma, cholangiocarcinoma, transitional cell carcinoma, choriocarcinoma, seminoma and embryonal cell carcinoma. Neural tissues (including glial cells, nerve cells, meninges and nerve sheath): 6a. benign neoplasms of neural tissues include: ganglioneuroma, meningioma, schwannoma, neurilemmoma, and neurofibroma. 6b. malignant neoplasms of neural tissues include: glioma (grades I-III), anaplastic, glioblastoma multiforme (grade IV), neuroblastoma, medulloblastoma, malignant meningioma, malignant schwannoma, neurofibrosarcoma. Amine Precursor Uptake and Decarboxylation (APUD) tissues (including pituitary, parathyroid, thyroid (C cells), bronchial lining (Kultschitzky cells), adrenalmedulla, pheochromocytoma, pancreas, stomach and intestines, carotid body and chemo-receptor system): 7a. benign neoplasms of APUD tissues include: basophilic adenoma, eosinophilic adenoma, chromophobe adenoma, parathyroid adenoma, C cell hyperplasia, pheochromocytoma, Islet celladenoma, insulinoma, gastrinoma, carcinoid, chemodectoma and paraganglioma. 7b. malignant neoplasms of APUD tissues include: parathyroid carcinoma, medullary carcinoma of thyroid, bronchial carcinoid, oat cell carcinoma, malignant pheochromocytoma, Islet cell carcinoma, malignant carcinoid, malignantcarcinoid, and malignant paraganglioma. Other Neural Crest-derived cells (including pigment-producing cells in skin, eyes, and occasional other sites, Schwann cells of peripheral nervous system and Merkel cells in squamous epithelium): 8a. benign neoplasms of neural crest-derived cells include: nevus, schwannoma and neurilemmoma. 8b. malignant neoplasms of neural crest-derived cells include: melanoma, malignant schwannoma and Merkel cell neoplasm. Tumors (including breast tissue and renal anlage tissue) 9a. benign neoplasms of breast tissue include fibroadenoma. 9b. malignant neoplasms of breast tissue include cystosarcoma phylloids; malignant neoplasms of renal anlage include Wilms tumor. Ovary and Testis (including multipotential cells, germ cells, connective tissue stroma and epithelial tissue) 10a. Malignant neoplasms of ovary and testis include: seminoma (dysgerminoma in women), choriocarcinoma, embryonal carcinoma, endodermal sinus tumor, and teratocarcinoma and Sertoli-Leydig cell tumors.

[0126] In some cases, the subject is suffering from, or is harboring a non-malignant tumor selected from the group consisting of adenoma (including liver, adrenal, pituitary, thyroid and colon and gastric polyps), astrocytoma, craniopharyngioma, desmoid tumor, enchondroma, fibromas or fibroids of any organ, such as uterine fibroma, ganglioneuroma, hemagioma, lipoma, lipoblastoma, hibernoma, lymphanglioma, meningioma, myoma (including leiomyomas and rhabdomyomas), nevi or moles, neuroma, neurofibroma, schwannoma, osteochondroma and papilloma (including skin, cervix, breast duct and conjunctiva).

[0127] In some cases, the subject is a cancer patient, wherein the cancer is selected from the group consisting of breast cancer, melanoma, colon cancer, urological cancer, lung cancer, small-cell and non-small-cell lung cancer, relapsed or refractory malignancies, non-Hodgkin and Hodgkin lymphomas, lymphoma, follicular lymphoma, lymphocytic lymphoma, CNS lymphoma, T-cell lymphoma, AIDS-related lymphoma, acute lymphoblastic leukemia, gastrointestinal cancers, liver cancer, hepatocellular carcinoma, ovarian cancer, pancreatic cancer, bile duct cancer, prostate cancer, renal carcinoma, bladder cancer, colorectal cancer, multiple myeloma, mesothelioma, cervical cancer, vaginal cancer, anal cancer, oropharyngeal cancer, myelogenous leukemia, chronic myeloid leukemia, gastric cancer, nasopharyngeal carcinoma, head and neck carcinoma, glioblastoma, gliosarcoma, squamous cell brain cancer, malignant glioma, diffuse pontine gliomas, esophageal cancer, thyroid cancer, astrocytoma, thoracic cancer, endometrial cancer, cutaneous cell carcinoma, leukemia, acinar cell carcinoma, adenocarcinoma, bronchioloalveolar carcinoma, cholangiocarcinoma, chordoma, giant cell carcinoma, intestinal carcinoma, major salivary gland carcinoma, malignant odontogenic neoplasm, malignant peripheral nerve sheath tumor, skin cancer, testicular cancer, germ cell tumor, neuroendocrine carcinoma, parathyroid carcinoma, pituitary gland carcinoma, placental choriocarcinoma, scrotal cancer, tracheal carcinoma, transitional cell carcinoma, cancer of the uterus, vulvar cancer, kidney cancer, rectum cancer, fallopian tube carcinoma, peritoneal carcinoma, epithelial cancer, pleural mesothelioma, sarcomatoid carcinoma, synovial sarcoma, nephroblastoma, neuroblastoma, adult acute myeloid leukemia, myelodysplastic / myeloproliferative neoplasm, embryonal carcinoma, Kaposi sarcoma, bone cancer, uterine cancer, stomach cancer, carcinoma of the endometrium, cancer of the small intestine, cancer of the endocrine system, cancer of the paragland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, cancer of the ureter, carcinoma of the pelvis, neoplasm of the central nervous system, primary tumor angiogenesis, spinal axis tumor, epidermoid cancer, environmentally induced cancers including those induced by asbestos, adenosarcoma, adenosquamous carcinoma, adrenocortical carcinoma, astrocytic tumors, basal cell carcinoma, chondosarcoma, Ewing's sarcoma, gallbladder cancer, hypopharyngeal cancer, intraocular melanoma, laryngeal cancer, leiomyosarcoma, lip and oral cavity cancer, malignant mesothelial tumors, malignant thymoma, medulloblastoma, medulloepithelioma, Merkel cell carcinoma, mucoepidermoid carcinoma, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, osteosarcoma, pulmonary blastoma, pineal and supratentorial primitive neuroectodermal tumors, plasma cell neoplasm, retinoblastoma, rhabdomyosarcoma, sarcoma, neuroectodermal tumors and Wilm's tumor.

[0128] In some cases, the subject is a cancer patient suffering from, or harboring a solid tumor. In some cases, the cancer patient has a solid tumor that is infiltrated with lymphocyte cells that express GPR174.

[0129] In some cases, the subject has one or more tumors infiltrated with regulatory T cells, such as, for example, breast, lung (such as small-cell lung cancer or non-small cell lung cancer), colorectal, cervical, renal, ovarian, melanoma, pancreatic, hepatocellular, gastric, glioblastoma, glioma, bladder, myeloma (such as multiple myeloma), prostate, thyroid, testicular, and esophageal cancer.

[0130] In some cases, the method comprises administering a GPR174 inhibitory compound as a single agent. In some cases, the method comprises administering a GPR174 inhibitory compound in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent. In some cases, the method comprises administering a GPR174 inhibitory compound in combination with an A2aR antagonist. In some cases, the method comprises administering a GPR174 inhibitory compound in combination with an A2bR antagonist. In some cases, the method comprises administering a GPR174 inhibitory compound in combination with a Treg attenuating agent, such as, for example, an agent that binds to one or more of GITR, CTLA-4, CD25, LAG3, TIGIT, NRP1, TGF-β, CCR2, CCR4, CCR8, TNFR2, and / or EZH2 and attenuates, depletes or otherwise impairs the tumor suppressor function of Treg cells. In some cases, the Treg attenuating agent is a small molecule. In some cases, the Treg attenuating agent is selected from the group consisting of an anti-GITR, anti-CTLA-4, anti-CD25, anti-LAG3, anti-TIGIT, anti-NRP1, anti-TGF-β, anti-CCR2, anti-CCR4, anti-CCR8, anti-TNFR2, and / or anti-EZH2 antibody. Exemplary Treg attenuating agents for use in the compositions and methods of the disclosure are provided in Example 25.

[0131] In some cases, the method further includes administering one or more additional therapeutic agents. In certain cases, the cancer cell is further contacted with a chemotherapeutic agent.

[0132] In another aspect, the disclosure features a pharmaceutical composition including a combination of a GPR174 inhibitor selected from any of the compounds described below (e.g., those of Formulas I-VI and the compounds 1-59 of Table 1) and an inhibitor of ATP-Adenosine-A2aR-A2bR-mediated signaling (such as an A2aR antagonist, an A2bR antagonist and / or a CD73 inhibitor and / or a CD38 inhibitor and / or a CD39 inhibitor and / or a Treg attenuating agent) and a pharmaceutically acceptable carrier. The pharmaceutical composition may be in unit dosage form. In particular cases, the compound may be formulated for oral, intravenous, intraperitoneal, intramuscular, topical, rectal, cutaneous, subcutaneous, nasal, skin (e.g., as a transdermal patch), intracerebroventricular, intraparenchymal, intrathecal, inhalational, intracranial or ocular administration. The pharmaceutical compositions may be used to carry out the methods disclosed herein.

[0133] In another aspect, the disclosure features compounds of Formula I that have activity as GPR174 inhibitors. In some cases, the compounds of Formula I have a structure in accordance with Formula IA or Formula IB or Formula IC as described herein. In some cases, the disclosure features pharmaceutical compositions comprising a compound of Formula I, such as a compound in accordance with Formula IA or Formula IB or Formula IC as described herein. Compounds of Formula I are useful in the methods of inhibiting at least one GPR174-mediated signaling pathway either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent for treating or preventing cancer as described herein.

[0134] In another aspect, the disclosure features compounds of Formula II that have activity as GPR174 inhibitors. In some cases, the compounds of Formula II have a structure in accordance with Formula IIA, Formula IIB, Formula IIC, Formula IID or Formula IIE as described herein. In some cases, the disclosure features pharmaceutical compositions comprising a compound of Formula II, such as a compound in accordance with Formula IIA, Formula IIB, Formula IIC, Formula IID or Formula IIE as described herein. Compounds of Formula II are useful in the methods of inhibiting at least one GPR174-mediated signaling pathway either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent for treating or preventing cancer as described herein.

[0135] In another aspect, the disclosure features compounds of Formula III that have activity as GPR174 inhibitors. In some cases, the compounds of Formula III have a structure in accordance with Formula IIIA, Formula IIIB, Formula IIIC, Formula IIID, Formula IIIE, or Formula IIIF as described herein. In some cases, the disclosure features pharmaceutical compositions comprising a compound of Formula III, such as a compound in accordance with Formula IIIA, Formula IIIB, Formula IIIC, Formula IIID, Formula IIIE or Formula IIIF as described herein. Compounds of Formula III are useful in the methods of inhibiting at least one GPR174-mediated signaling pathway either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent for treating or preventing cancer as described herein.

[0136] In another aspect, the disclosure features compounds of Formula IV that have activity as GPR174 inhibitors. In some cases, the compounds of Formula IV have a structure in accordance with Formula IVA, Formula IVB, Formula IVC, Formula IVD, or Formula IVE as described herein. In some cases, the disclosure features pharmaceutical compositions comprising a compound of Formula IV, such as a compound in accordance with Formula IVA, Formula IVB, Formula IVC, Formula IVD or Formula IVE as described herein. Compounds of Formula IV are useful in the methods of inhibiting at least one GPR174-mediated signaling pathway either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent for treating or preventing cancer as described herein.

[0137] In another aspect, the disclosure features compounds of Formula V that have activity as GPR174 inhibitors. In some cases, the disclosure features pharmaceutical compositions comprising a compound of Formula V as described herein. Compounds of Formula V are useful in the methods of inhibiting at least one GPR174-mediated signaling pathway either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent for treating or preventing cancer as described herein.

[0138] In another aspect, the disclosure features compounds of Formula Va that have activity as GPR174 inhibitors. In some cases, the disclosure features pharmaceutical compositions comprising a compound of Formula Va as described herein. Compounds of Formula Va are useful in the methods of inhibiting at least one GPR174-mediated signaling pathway either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor, and / or a Treg attenuating agent for treating or preventing cancer as described herein.

[0139] In another aspect, the disclosure features compounds of Formula VI that have activity as GPR174 inhibitors. In some cases, the disclosure features pharmaceutical compositions comprising a compound of Formula VI as described herein. Compounds of Formula VI are useful in the methods of inhibiting at least one GPR174-mediated signaling pathway either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent for treating or preventing cancer as described herein.

[0140] In another aspect, the disclosure features a method of preparing a pharmaceutical composition including a compound that is an inhibitor of a GPR174-mediated signaling pathway, the compound having been contacted in vitro with a mammalian cell expressing GPR174 and determined to inhibit a GPR174-mediated signaling pathway, wherein the ability of the compound to inhibit said GPR174-mediated signaling pathway is indicative of being a GPR174 inhibitor, the method comprising formulating the GPR174 inhibitory compound with a pharmaceutically acceptable carrier either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent, wherein said GPR174 inhibitory compound is characterized by at least one of the following criteria: (i) said compound has a structure selected from the group consisting of Formula I-VI; (ii) said compound changes the binding affinity of any one of reference compounds 1-59 (as set forth in Table 1) to GPR174; and / or (iii) said compound causes a difference in the inhibitory activity of any one of reference compounds 1-59 (as set forth in Table 1), in a GPR174-mediated signaling pathway assay when tested in the presence of said reference compound as compared to the inhibitory activity of the reference compound alone.

[0141] In another aspect, the disclosure features a method of preparing a pharmaceutical composition including a compound that is an inhibitor of a GPR174-mediated signaling pathway, the compound having been contacted in vitro with a mammalian cell expressing GPR174 and determined to inhibit a GPR174-mediated signaling pathway, wherein the ability of the compound to inhibit said GPR174-mediated signaling pathway is indicative of being a GPR174 inhibitor, the method comprising formulating the GPR174 inhibitory compound with a pharmaceutically acceptable carrier, either as a single agent or in combination with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor and / or a Treg attenuating agent wherein said GPR174 inhibitory compound is characterized by at least one of the following criteria: (i) said compound has a structure selected from the group consisting of Formula I-VI; (ii) said compound changes the apparent binding affinity of any one of reference compounds 1-59 (as set forth in Table 1) to GPR174; and / or (iii) said compound causes a difference in the inhibitory activity of any one of reference compounds 1-59 (as set forth in Table 1), in a GPR174-mediated signaling pathway assay when tested in the presence of said reference compound as compared to the inhibitory activity of the reference compound alone.

[0142] In another case, the disclosure features a GPR174-interacting compound comprising a structure according to any of Formulas I-VI disclosed herein and a detectable moiety. In some cases, the GPR174-interacting compound is characterized by at least one of the following criteria: (i) said compound has a structure selected from the group consisting of Formula I-VI; (ii) said compound changes the binding affinity of any one of reference compounds 1-59 (as set forth in Table 1) to GPR174; and / or (iii) said compound causes a difference in the inhibitory activity of any one of reference compounds 1-59 (as set forth in Table 1), in a GPR174-mediated signaling pathway assay when tested in the presence of said reference compound as compared to the inhibitory activity of the reference compound alone. In one case, the GPR174-interacting compound comprising a detectable moiety comprises a structure according to any of compounds 1-59 disclosed in Table 1. In particular cases, the detectable moiety is at least one of a radioisotope, a bioluminescent tag, a chemiluminescent tag, or a photo-affinity label. In one case, the detectable moiety is a radioisotope.

[0143] In another case, the disclosure features a GPR174-interacting compound comprising a structure according to any of Formulas I-VI disclosed herein and a detectable moiety. In some cases, the GPR174-interacting compound is characterized by at least one of the following criteria: (i) said compound has a structure selected from the group consisting of Formula I-VI; (ii) said compound changes the apparent binding affinity of any one of reference compounds 1-59 (as set forth in Table 1) to GPR174; and / or (iii) said compound causes a difference in the inhibitory activity of any one of reference compounds 1-59 (as set forth in Table 1), in a GPR174-mediated signaling pathway assay when tested in the presence of said reference compound as compared to the inhibitory activity of the reference compound alone. In one case, the GPR174-interacting compound comprising a detectable moiety comprises a structure according to any of compounds 1-59 disclosed in Table 1. In particular cases, the detectable moiety is at least one of a radioisotope, a bioluminescent tag, a chemiluminescent tag, or a photo-affinity label. In one case, the detectable moiety is a radioisotope.

[0144] In any of the above aspects, the GPR174 inhibitory compound may be a synthetic compound, a semi-synthetic compound (e.g., a chemically modified steroid derived from a natural source), or a natural product. In certain cases, the compound is not an endogenous ligand of GPR174 (e.g., is a surrogate ligand). In various cases, the compound is a functional inhibitor of a GPR174-mediated signaling pathway (e.g., an antagonist, partial agonist, inverse agonist, partial inverse agonist, or negative allosteric modulator). In some cases, the compound is an antagonist of GPR174 and inhibits at least one GPR174-mediated signaling pathway in the presence of an agonist or partial agonist. In some cases, the compound is an inverse agonist. In specific cases, the compound decreases GPR174-mediated signaling pathway activation at least 2 / 3, 1 / 2 ,1 / 5, 1 / 10, 1 / 50, or 1 / 100 of the basal activity at a concentration less than 40, 25, 10, 5, 1, 0.5, 0.25, 0.1, or 0.5 µM (e.g., from 0.01 µM to 0.5 µM, from 0.01 µM to 0.5 µM, from 0.01 µM to 5 µM, from 0.01 µM to 10 µM, from 0.01 µM to 25 µM, or from 0.01 µM to 40 µM). In some cases, the compound is an inverse agonist and decreases at least one GPR174-mediated signaling pathway by at least 1 / 2 in comparison to basal activity at a concentration of less than 10 µM (e.g., from 0.01 µM to 10 µM).

[0145] The GPR174 inhibitory compound may be a polypeptide, an antibody, a non-peptide compound, an expression inhibitor (e.g., GPR174 antisense nucleic acid molecules such as antisense RNA, antisense DNA or antisense oligonucleotides, GPR174 ribozymes or GPR174 RNAi molecules) that inhibits GPR174 expression, or a small molecule (e.g., a small organic or organometallic molecule).

[0146] In some cases, the compound was not in development by any entity prior to January 11, 2019. In some cases, the compound is not a regulatory agency-approved compound. In some cases, the compound is a compound that was not approved prior to January 11, 2019 by the United States Food and Drug Administration or other regulatory authority for use in a disease associated with GPR174. In some cases, the compound was not in development by any entity prior to January 11, 2019 for use in a disease associated with GPR174. In some cases, the compound was not approved prior to January 11, 2019 by the United States Food and Drug Administration or equivalent regulatory authority as targeting GPR174. In particular cases, the compound is not an antibody or a receptor-binding fragment thereof. In particular cases, the compound is not a pepducin, a cell-penetrating membrane-tethered peptide (see, e.g., Covic L. et al., PNAS 99(2):643-8 (2002)).

[0147] In particular cases of any aspect, the GPR174 inhibitory isolated compound is not LysoPS or PS.

[0148] In certain cases, the GPR174 inhibitory compound is capable of functionally interacting with human GPR174 having the sequence of SEQ ID NO: 1 and / or altering the cellular distribution of a recombinant GPR174 polypeptide (e.g., human GPR174 having the sequence of SEQ ID NO: 1) modified to include a nuclear localization signal as compared to the cellular distribution of the recombinant GPR174 polypeptide in the absence of the compound.

[0149] The compound may be specific for GPR174, e.g., as compared to a reference panel of GPCRs.

[0150] In particular cases of any aspect, the isolated compound selectively binds to GPR174 and does not bind to P2Y10.

[0151] In particular cases of any aspect, the isolated compound selectively binds to GPR174 and does not bind to GPR34.

[0152] In particular cases of any aspect, the isolated compound functionally interacts with GPR174 and does not bind to P2Y10.

[0153] In particular cases of any aspect, the isolated compound functionally interacts with GPR174 and does not bind to GPR34.

[0154] In particular cases of any aspect, the isolated compound is not disclosed in US2015 / 0361119.

[0155] In addition, the methods and compositions of any of the aspects of the disclosure may employ any compound having a structure according to the formulas described below, such as the exemplary compounds in Table 1, or a pharmaceutically acceptable salt thereof.

[0156] In some cases, the GPR174 inhibitory compound has a structure according to the following formula (I): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, X 1< is N or CR 10< ; X 2< is N or CR 11< ; X 3< is N or CR 12< ; X 4< is N or CR 13< ; X 5< is N or CR 14< ; X 6< is N or CR 15< ; X 7< is N or CR 16< ; each of R 1< , R 2< , R 3< , R 4< , R 5< , R 6< , R 7< , R 8< , and R 9< is, independently, H, hydroxy, thiol, optionally substituted amino, optionally substituted amido, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, hydroxycarbonyl, optionally substituted ester, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 1 -C 6 alkylsulfinyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfinyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfinyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfinyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 4 -C 10 cycloalkenyl, optionally substituted C 8 -C 10 cycloalkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkenyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heterocyclyl, optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkenyl, or optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkynyl; or R 2< and R 3< combine to form =O, =S, or =NR 17< ; or R 4< and R 5< combine to form =O, =S, or =NR 17< ; or R 6< and R 7< combine to form =O, =S, or =NR 17< ; or R 8< and R 9< combine to form =O, =S, or =NR 17< ; each of R 10< , R 11< , R 12< , R 13< , R 14< , R 15< , and R 16< is, independently, H, hydroxy, halogen, thiol, optionally substituted amino, optionally substituted amido, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, hydroxycarbonyl, optionally substituted ester, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 1 -C 6 alkylsulfinyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfinyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfinyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 4 -C 10 cycloalkenyl, optionally substituted C 8 -C 10 cycloalkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkenyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heterocyclyl, optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkenyl, or optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkynyl; or one of: (i) R 12< and R 13< , together with the atoms to which each is attached, combine to form an optionally substituted 5-, 6-, or 7-member ring; (ii) R 13< and R 14< , together with the atoms to which each is attached, combine to form an optionally substituted 5-, 6-, or 7-member ring; (iii) R 14< and R 15< , together with the atoms to which each is attached, combine to form an optionally substituted 5-, 6-, or 7-member ring; and (iv) R 15< and R 16< , together with the atoms to which each is attached, combine to form an optionally substituted 5-, 6-, or 7-member ring; and R 17< is H, hydroxyl, cyano, optionally substituted amino, optionally substituted amido, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 1 -C 6 alkylsulfinyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfinyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfinyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 4 -C 10 cycloalkenyl, optionally substituted C 8 -C 10 cycloalkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkenyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heterocyclyl, optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkenyl, or optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkynyl; wherein three or fewer of X 3< , X 4< , X 5< , X 6< , and X 7< are N; and at least one of X 1< and X 2< is N.

[0157] In some cases of formula (I), X 1< is N. In certain cases of formula (I), X 2< is N. In particular cases of formula (I), X 3< is CR 12< . In other cases of formula (I), X 4< is CR 13< . In yet other cases of formula (I), X 5< is CR 14< . In still other cases of formula (I), X 6< is CR 15< . In certain other cases of formula (I), X 7< is CR 16< .

[0158] In particular cases of formula (I), the isolated compound has the structure according to formula (IA):

[0159] In certain cases of formula (I) or (IA), R 2< is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In some cases of formula (I) or (IA), R 2< is H or optionally substituted C 1 -C 6 alkyl. In other cases of formula (I) or (IA), R 2< is H.

[0160] In yet other cases of formula (I) or (IA), R 3< is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In still other cases of formula (I) or (IA), R 3< is H or optionally substituted C 1 -C 6 alkyl. In particular cases of formula (I) or (IA), R 3< is H.

[0161] In some cases of formula (I) or (IA), R 4< is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In certain cases of formula (I) or (IA), R 4< is H or optionally substituted C 1 -C 6 alkyl. In particular cases of formula (I) or (IA), R 4< is H.

[0162] In other cases of formula (I) or (IA), R 5< is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In yet other cases of formula (I) or (IA), R 5< is H or optionally substituted C 1 -C 6 alkyl. In still other cases of formula (I) or (IA), R 5< is H.

[0163] In particular cases of formula (I) or (IA), R 6< is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In certain cases of formula (I) or (IA), R 6< is H or optionally substituted C 1 -C 6 alkyl. In some cases of formula (I) or (IA), R 6< is H.

[0164] In certain cases of formula (I) or (IA), R 7< is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In other cases of formula (I) or (IA), R 7< is H or optionally substituted C 1 -C 6 alkyl. In still other cases of formula (I) or (IA), R 7< is H.

[0165] In some cases of formula (I) or (IA), R 8< is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In certain cases of formula (I) or (IA), R 8< is H or optionally substituted C 1 -C 6 alkyl. In particular cases of formula (I) or (IA), R 8< is H.

[0166] In other cases of formula (I) or (IA), R 9< is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In yet other cases of formula (I) or (IA), R 9< is H or optionally substituted C 1 -C 6 alkyl. In still other cases of formula (I) or (IA), R 9< is H.

[0167] In particular cases of formula (I) or (IA), R 13< is H, hydroxy, optionally substituted amino, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl. In certain cases of formula (I) or (IA), R 13< is H or optionally substituted C 1 -C 6 alkyl. In other cases of formula (I) or (IA), R 13< is H.

[0168] In certain cases of formula (I) or (IA), R 16< is H, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, hydroxycarbonyl, optionally substituted ester, or optionally substituted C 1 -C 9 heterocyclyl. In other cases of formula (I) or (IA), R 16< is H or optionally substituted C 1 -C 6 alkyl. In yet other cases of formula (I) or (IA), R 16< is H.

[0169] In some cases of formula (I), the compound has the structure according to formula (IB):

[0170] In certain cases of formula (I), (IA), or (IB), R 12< is H, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, hydroxycarbonyl, optionally substituted ester, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl. In particular cases of formula (I), (IA), or (IB), R 12< is H, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkanoyl, optionally substituted C 1 -C 6 alkylsulfonyl, hydroxycarbonyl, optionally substituted ester, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl. In other cases of formula (I), (IA), or (IB), R 12< is H, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted ester, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, or optionally substituted C 1 -C 9 heteroaryl. In yet other cases of formula (I), (IA), or (IB), R 12< is H, halogen, nitro, optionally substituted ester, or optionally substituted C 1 -C 6 alkanoyloxy. In still other cases of formula (I), (IA), or (IB), R 12< is halogen (e.g., R 12< is fluorine). In certain cases of formula (I), (IA), or (IB), R 12< is nitro.

[0171] In particular cases of formula (I), (IA), or (IB), R 14< is H, halogen, cyano, nitro, optionally substituted C 1 -C 6 alkyl, hydroxycarbonyl, optionally substituted ester, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 1 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfinyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl. In some cases of formula (I), (IA), or (IB), R 14< is H, halogen, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted ester, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 1 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfonyl, or optionally substituted C 1 -C 9 heteroaryl. In other cases of formula (I), (IA), or (IB), R 14< is H, halogen, optionally substituted C 1 -C 6 alkyl, optionally substituted ester, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 1 -C 6 alkanoyl. In yet other cases of formula (I), (IA), or (IB), R 14< is halogen, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 alkanoyl. In still other cases of formula (I), (IA), or (IB), R 14< is halogen (e.g., R 14< is fluorine). In some cases of formula (I), (IA), or (IB), R 14< is optionally substituted C 1 -C 6 alkanoyl. In particular cases of formula (I), (IA), or (IB), R 14< is optionally substituted C 2 -C 4 alkanoyl. In certain cases of formula (I), (IA), or (IB), R 14< is unsubstituted C 2 -C 4 alkanoyl.

[0172] In some cases of formula (I), (IA), or (IB), R 15< is H, optionally substituted amino, optionally substituted amido, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In certain cases of formula (I), (IA), or (IB), R 15< is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl. In particular cases of formula (I), (IA), or (IB), R 15< is H or optionally substituted C 1 -C 9 heterocyclyl. In other cases of formula (I), (IA), or (IB), R 15< is H. In yet other cases of formula (I), (IA), or (IB), R 15< is optionally substituted C 1 -C 9 heterocyclyl (e.g., R 15< is piperidinyl, methyl-substituted piperidinyl or benzpiperidinyl).

[0173] In some cases of Formula (IB), R 1< is selected from the group consisting of C 1- C 6 alkanoyl, C 6 -C 10 aryl, C 7 -C 11 aryloyl, C 2 -C 10 heteroaryloyl, C 2 -C 7 alkoxycarbonyl, and C 6 -C 10 arylsulfonyl, wherein R 1< is optionally substituted; R 12< is H, nitro, or halogen; R 14< is C 1 -C 6 alkanoyl or halogen; and R 15< is H or optionally substituted C 1 -C 9 heterocyclyl.

[0174] In some cases of Formula (IB), R 1< is selected from an optionally substituted group consisting of C 1- C 6 -alkanoyl, C 7 -C 11 aryloyl, C 2 -C 10 heteroaryloyl, C 2 -C 7 alkoxycarbonyl, and C 6 -C 10 arylsulfonyl.

[0175] In some cases of formula (IB), R 12< is nitro, and R 14< is fluoro.

[0176] In some cases of formula (IB), R 15< is optionally substituted piperidin-1-yl or optionally substituted azepan-1-yl. In some cases of formula (I), (IA), or (IB), the compound has the structure according to formula (IC): wherein R 16< is H or C 1 -C 6 alkyl.

[0177] In some cases of formula (IC), R 16< is H or methyl.

[0178] In particular cases of formula (I), (IA), (IB), or (IC), R 1< is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, optionally substituted ester, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkylsulfonyl, substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In certain cases of formula (I), (IA), (IB), or (IC), R 1< is optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, optionally substituted ester, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkylsulfonyl, substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In particular cases of formula (I), (IA), (IB), or (IC), R 1< is optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted ester, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkylsulfonyl, substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, or optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl. In some cases of formula (I), (IA), (IB), or (IC), R 1< is optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted ester, optionally substituted C 6 -C 10 arylsulfonyl, or optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl. In other cases of formula (I), (IA), (IB), or (IC), R 1< is optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 6 -C 10 arylsulfonyl, or optionally substituted ester. In yet other cases of formula (I), (IA), (IB), or (IC), R 1< is optionally substituted C 2 -C 7 alkoxycarbonyl (e.g., methyloxycarbonyl or ethyloxycarbonyl). In still other cases of formula (I), (IA), (IB), or (IC), R 1< is optionally substituted C 2 -C 6 alkanoyl (e.g., R 1< is acetyl, propanoyl, n-butanoyl, isobutanoyl, or t-pentanoyl). In some cases of formula (I), (IA), (IB), or (IC), R 1< is optionally substituted C 7 -C 11 aryloyl (e.g., R 1< is 4-fluorobenzoyl or benzoyl). In other cases of formula (I), (IA), (IB), or (IC), R 1< is optionally substituted C 2 -C 10 heteroaryloyl (e.g., R 1< is 2-thiophenecarbonyl). In certain cases of formula (I), (IA), (IB), or (IC), R 1< is optionally substituted C 6 -C 10 arylsulfonyl (e.g., R 1< is p-tolylsulfonyl or phenylsulfonyl). In other cases of formula (I), (IA), (IB), or (IC), R 1< is optionally substituted C 1 -C 6 alkyl, (e.g., R 1< is ethyl or methyl).

[0179] In particular cases of formula (I), (IA), (IB), or (1C), the isolated compound is compound 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, or 53:

[0180] In a particular case of formula (IB), the isolated compound is compound 53:

[0181] In some cases, the GPR174 inhibitory compound has a structure according to formula (II): or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, X 1< is N or CR 2< ; X 2< is N or CR 3< ; R A< and R B< , together with the atoms to which is attached combine to form an optionally substituted 5-membered ring, optionally substituted 6-membered ring, or optionally substituted 7-membered ring; R 1< is H, halo, hydroxy, optionally substituted amino, optionally substituted amido, thiol, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 1 -C 6 thioalkyl, optionally substituted C 1 -C 6 alkylsulfinyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylthio, optionally substituted C 6 -C 10 arylsulfinyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylthio, optionally substituted C 1 -C 9 heteroarylsulfinyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfinyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted sulfamoyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 4 -C 10 cycloalkenyl, optionally substituted C 8 -C 10 cycloalkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkenyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heterocyclyl, optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkenyl, or optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkynyl; and Ar 1< is optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl.

[0182] In some cases of formula (II), R A< and R B< , together with the atoms to which each is attached, combine to form an optionally substituted carbocyclic ring. In certain cases of formula (II), R A< and R B< , together with the atoms to which each is attached, combine to form an optionally substituted heterocyclic ring. In particular cases of formula (II), R A< and R B< , together with the atoms to which each is attached, combine to form an optionally substituted 6-membered ring. In other cases of formula (II), R A< and R B< , together with the atoms to which each is attached, combine to form an optionally substituted non-aromatic ring. In yet other cases of formula (II), R A< and R B< , together with the atoms to which each is attached, combine to form an optionally substituted aromatic ring.

[0183] In still other cases of formula (II), the isolated compound has a structure according to formula (IIA): wherein X 3< is N, CR 4< ; X 4< is N, CR 5< ; X 5< is N, CR 6< ; X 6< is N, CR 7< , or absent; and each of R 4< , R 5< , R 6< , and R 7< is, independently, H, halo, hydroxy, optionally substituted amino, optionally substituted amido, thiol, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 1 -C 6 thioalkyl, optionally substituted C 1 -C 6 alkylsulfinyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylthio, optionally substituted C 6 -C 10 arylsulfinyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylthio, optionally substituted C 1 -C 9 heteroarylsulfinyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfinyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted sulfamoyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 4 -C 10 cycloalkenyl, optionally substituted C 8 -C 10 cycloalkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkenyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heterocyclyl, optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkenyl, or optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkynyl; wherein three or fewer of X 1< , X 2< , X 3< , X 4< , X 5< , and X 6< are N.

[0184] In particular cases of formula (IIA), X 3< is CR 4< .

[0185] In still other cases of formula (IIA), X 4< is CR 5< .

[0186] In other cases of formula (IIA), X 5< is CR 6< . In yet other cases of formula (IIA), X 6< is CR 7< .

[0187] In some cases of formula (II) or (IIA), X 1< is N. In certain cases of formula (II) or (IIA), X 2< is N.

[0188] In still other cases of formula (II), the isolated compound has a structure of formula (IIB):

[0189] In some cases of formula (IIA) or (IIB), R 4< is H, optionally substituted amino, halo, optionally substituted amido, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted sulfamoyl, optionally substituted C 1 -C 6 thioalkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In certain cases of formula (IIA) or (IIB), R 4< is H, optionally substituted amino, halo, optionally substituted amido, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted sulfamoyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl. In particular cases of formula (IIA) or (IIB), R 4< is H, halo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted carboxamide, or optionally substituted sulfamoyl. In other cases of formula (IIA) or (IIB), R 4< is H.

[0190] In yet other cases of formula (IIA) or (IIB), R 5< is H, optionally substituted amino, halo, optionally substituted amido, optionally substituted carboxamide, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted C 1 -C 6 thioalkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In still other cases of formula (IIA) or (IIB), R 5< is H, optionally substituted amino, halo, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl. In some cases of formula (IIA) or (IIB), R 5< is H, optionally substituted amino, halo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, or optionally substituted C 6 -C 10 aryl. In particular cases of formula (IIA) or (IIB), R 5< is H.

[0191] In certain cases of formula (IIA) or (IIB), R 6< is H, optionally substituted amino, halo, optionally substituted amido, optionally substituted carboxamide, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted C 1 -C 6 thioalkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In other cases of formula (IIA) or (IIB), R 6< is H, optionally substituted amino, halo, optionally substituted amido, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl. In yet other cases of formula (IIA) or (IIB), R 6< is H, optionally substituted amino, optionally substituted amido, halo, or optionally substituted C 1 -C 6 alkyl. In still other cases of formula (IIA) or (IIB), R 6< is H.

[0192] In some cases of formula (IIA) or (IIB), R 7< is H, optionally substituted amino, halo, optionally substituted amido, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted sulfamoyl, optionally substituted C 1 -C 6 thioalkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In certain cases of formula (IIA) or (IIB), R 7< is H, optionally substituted amino, halo, optionally substituted amido, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted sulfamoyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl. In particular cases of formula (IIA) or (IIB), R 7< is H, halo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted carboxamide, or optionally substituted sulfamoyl. In other cases of formula (IIA) or (IIB), R 7< is H.

[0193] In yet other cases of formula (II), the isolated compound has the structure according to formula (IIC):

[0194] In some cases of formula (II), (IIA), (IIB), or (IIC), Ar 1< is optionally substituted C 6 -C 10 aryl. In other cases of formula (II), (IIA), (IIB), or (IIC), Ar 1< is optionally substituted C 6 aryl.

[0195] In yet other cases of formula (II), the isolated compound has the structure according to formula (IID): wherein each of R 8< , R 9< , R 10< , R 11< , and R 12< is, independently, H, halo, hydroxy, optionally substituted amino, optionally substituted amido, thiol, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 1 -C 6 thioalkyl, optionally substituted C 1 -C 6 alkylsulfinyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylthio, optionally substituted C 6 -C 10 arylsulfinyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylthio, optionally substituted C 1 -C 9 heteroarylsulfinyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfinyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted sulfamoyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 4 -C 10 cycloalkenyl, optionally substituted C 8 -C 10 cycloalkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkenyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heterocyclyl, optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkenyl, or optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkynyl; or any two of adjacent R 8< , R 9< , R 10< , R 11< , and R 12< , together with the two adjacent carbon atoms to which they are attached, form a 5, 6, or 7-memebered optionally substituted carbocyclic or heterocyclic ring.

[0196] In certain cases of formula (IID), R 8< is H, halo, or optionally substituted C 1 -C 6 alkyl. In other cases of formula (IID), R 8< is H.

[0197] In particular cases of formula (IID), R 11< is H, halo, or optionally substituted C 1 -C 6 alkyl. In other cases of formula (IID), R 11< is H.

[0198] In some cases of formula (IID), R 12< is H, halo, or optionally substituted C 1 -C 6 alkyl. In other cases of formula (IID), R 12< is H.

[0199] In certain cases of formula (IID), R 9< is H, optionally substituted amino, halo, optionally substituted amido, optionally substituted carboxamide, cyano, nitro, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted C 1 -C 6 alkylsulfinyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfinyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfinyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted sulfamoyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In other cases of formula (IID), R 9< is H, optionally substituted amido, halo, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted sulfamoyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl. In yet other cases of formula (IID), R 9< is H, optionally substituted carboxamide, halo, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, or optionally substituted sulfamoyl. In still other cases of formula of formula (IID), R 9< is optionally substituted sulfamoyl (e.g., unsubstituted sulfamoyl).

[0200] In certain cases of formula (IID), R 10< is H, halo, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 2 -C 6 alkanoyl, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted carboxamide, optionally substituted C 1 -C 6 thioalkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In yet other cases of formula (IID), R 10< is H, halo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In still other cases of formula (IID), R 10< is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 10 cycloalkyl. In some cases of formula of formula (IID), R 10< is optionally substituted C 1 -C 6 alkyl (e.g., methyl).

[0201] In particular cases of formula (II), (IIA), (IIB), (IIC), or (IID), R 1< is H, hydroxy, optionally substituted amino, halo, thiol, optionally substituted amido, optionally substituted carboxamide, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 1 -C 6 thioalkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In certain cases of formula (IID), R 10< is H, optionally substituted amino, optionally substituted amido, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In some cases of formula (II), (IIA), (IIB), (IIC), or (IID), R 1< is H, optionally substituted amino, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl. In other cases of formula (II), (IIA), (IIB), (IIC), or (IID), R 1< is optionally substituted amino. In yet other cases of formula (IID), R 10< is substituted amino, wherein at least one substituent is phenyl. In still other cases of formula (II), (IIA), (IIB), (IIC), or (IID), R 1< is substituted amino, wherein at least one substituent is o-tolyl.

[0202] In some cases of formula (II), the compound of formula (II) has a structure of formula (IIE): wherein R A< is an optionally substituted phenyl, and Ar 1< is an optionally substituted phenyl.

[0203] In some cases of formula (IIE), R A< is phenyl or 2-methylphenyl.

[0204] In some cases of formula (IIE), Ar 1< is 3-aminosulfonyl-4-methylphenyl.

[0205] In some cases of formula (II), (IIA), (IIB), or (IIC), the isolated compound is compound 19 or 20:

[0206] In some cases, the GPR174 inhibitory compound has a structure according to formula (III): or a stereoisomer thereof, or a tautomer, or a pharmaceutically acceptable salt thereof, wherein each of R 1< and R 2< is, independently, H, halo, cyano, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 1 -C 6 heteroalkyl; and each of Ar 1< and Ar 2< is, independently, optionally substituted C 6 -C 10 aryl or optionally substituted C 1 -C 9 heteroaryl.

[0207] In certain cases of formula (III), Ar 1< is optionally substituted C 6 -C 10 aryl. In other cases of formula (III), Ar 1< is optionally substituted C 6 aryl, e.g., optionally substituted phenyl.

[0208] In certain cases of formula (III), Ar 2< is optionally substituted C 6 -C 10 aryl. In other cases of formula (III), Ar 2< is optionally substituted C 6 aryl, e.g., optionally substituted phenyl.

[0209] In yet other cases of formula (III), the isolated compound has the structure according to formula (IIIA): wherein each of R 3< , R 4< , R 5< , R 6< , R 7< , R 8< , R 9< , R 10< , R 11< , and R 12< is, independently, H, halo, hydroxy, optionally substituted amino, optionally substituted amido, thiol, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted carboxamide, optionally substituted C 2 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 2 -C 6 alkanoylamino, optionally substituted C 7 -C 11 aryloylamino, optionally substituted C 2 -C 10 heteroaryloylamino, optionally substituted C 2 -C 10 heterocyclyloylamino, optionally substituted C 1 -C 6 thioalkyl, optionally substituted C 1 -C 6 alkylsulfinyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylthio, optionally substituted C 6 -C 10 arylsulfinyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylthio, optionally substituted C 1 -C 9 heteroarylsulfinyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfinyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted sulfamoyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 4 -C 10 cycloalkenyl, optionally substituted C 8 -C 10 cycloalkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkenyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heterocyclyl, optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkenyl, or optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkynyl.

[0210] In particular cases of formula (III) or (IIIA), R 1< is H, halo, or optionally substituted C 1 -C 6 alkyl. In other cases of formula (III) or (IIIA), R 1< is H, halo, or methyl. In yet other cases of formula (III) or (IIIA), R 1< is H.

[0211] In certain cases of formula (III) or (IIIA), R 2< is H, halo, or optionally substituted C 1 -C 6 alkyl. In other cases of formula (III) or (IIIA), R 2< is H, halo, or methyl. In yet other cases of formula (III) or (IIIA), R 2< is H.

[0212] In some cases of formula (III) or (IIIA), the isolated compound has the structure according to formula (IIIB):

[0213] In particular cases of formula (III), (IIIA), or (IIIB), R 3< is H, halo, or optionally substituted C 1 -C 6 alkyl. In other cases of formula (III), (IIIA), or (IIIB), R 3< is H.

[0214] In certain cases of formula (III), (IIIA), or (IIIB), R 4< is H, halo, or optionally substituted C 1 -C 6 alkyl. In other cases of formula (III), (IIIA), or (IIIB), R 4< is H.

[0215] In some cases of formula (III), (IIIA), or (IIIB), R 7< is H, halo, or optionally substituted C 1 -C 6 alkyl. In other cases of formula (III), (IIIA), or (IIIB), R 7< is H.

[0216] In other cases of formula (III), (IIIA), or (IIIB), the isolated compound has the structure according to formula (IIIC):

[0217] In particular cases of formula (III), (IIIA), (IIIB), or (IIIC), R 11< is H, halo, or optionally substituted C 1 -C 6 alkyl. In other cases of formula (III), (IIIA), (IIIB), or (IIIC), R 11< is H.

[0218] In certain cases of formula (III), (IIIA), (IIIB), or (IIIC), R 12< is H, halo, or optionally substituted C 1 -C 6 alkyl. In other cases of formula (III), (IIIA), (IIIB), or (IIIC), R 12< is H.

[0219] In some cases of formula (III), (IIIA), (IIIB), or (IIIC), R 8< is H, halo, or optionally substituted C 1 -C 6 alkyl. In other cases of formula (III), (IIIA), (IIIB), or (IIIC), R 8< is H.

[0220] In other cases of formula (III), (IIIA), (IIIB), or (IIIC), the isolated compound has the structure according to formula (IIID):

[0221] In some cases of formula (III), (IIIA), (IIIB), (IIIC), or (IIID), R 5< is H, halo, cyano, optionally substituted amino, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, optionally substituted C 2 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 2 -C 6 alkanoylamino, optionally substituted C 7 -C 11 aryloylamino, optionally substituted C 2 -C 10 heteroaryloylamino, optionally substituted C 2 -C 10 heterocyclyloylamino, hydroxycarbonyl, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkylsulfonyl, substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In other cases of formula (III), (IIIA), (IIIB), (IIIC), or (IIID), R 5< is optionally substituted amino, optionally substituted C 2 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 2 -C 6 alkanoylamino, optionally substituted C 7 -C 11 aryloylamino, optionally substituted C 2 -C 10 heteroaryloylamino, optionally substituted C 2 -C 10 heterocyclyloylamino, hydroxycarbonyl, or optionally substituted carboxamide. In yet other cases of formula (III), (IIIA), (IIIB), (IIIC), or (IIID), R 5< is optionally substituted amino, optionally substituted C 2 -C 6 alkanoylamino, optionally substituted C 7 -C 11 aryloylamino, optionally substituted C 2 -C 10 heteroaryloylamino, or optionally substituted C 2 -C 10 heterocyclyloylamino.

[0222] In particular cases of formula (III), (IIIA), (IIIB), (IIIC), or (IIID), R 10< is H, halo, cyano, optionally substituted amino, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, optionally substituted C 2 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 2 -C 6 alkanoylamino, optionally substituted C 7 -C 11 aryloylamino, optionally substituted C 2 -C 10 heteroaryloylamino, optionally substituted C 2 -C 10 heterocyclyloylamino, hydroxycarbonyl, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkylsulfonyl, substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In other cases of formula (III), (IIIA), (IIIB), (IIIC), or (IIID), R 10< is optionally substituted amino, optionally substituted C 2 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 2 -C 6 alkanoylamino, optionally substituted C 7 -C 11 aryloylamino, optionally substituted C 2 -C 10 heteroaryloylamino, optionally substituted C 2 -C 10 heterocyclyloylamino, hydroxycarbonyl, or optionally substituted carboxamide. In yet other cases of formula (III), (IIIA), (IIIB), (IIIC), or (IIID), R 10< is optionally substituted amino, optionally substituted C 2 -C 6 alkanoylamino, optionally substituted C 7 -C 11 aryloylamino, optionally substituted C 2 -C 10 heteroaryloylamino, or optionally substituted C 2 -C 10 heterocyclyloylamino.

[0223] In certain cases of formula (III), (IIIA), (IIIB), (IIIC), or (IIID), the isolated compound has the structure according to formula (IIIE): wherein each of R A< and R B< is, independently, H or optionally substituted C 1 -C 6 alkyl; and each of R C< and R D< is, independently, H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl.

[0224] In some cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R A< is H. In other cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R B< is H.

[0225] In certain cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R C< is optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl. In other cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R C< is optionally substituted C 4 heteroaryl, e.g., thiophen-2-yl.

[0226] In other cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R D< is optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl. In still other cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R D< is optionally substituted C 4 heteroaryl, e.g., thiophen-2-yl.

[0227] In particular cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R 6< is H, halo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In other cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R 6< is H, halo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 10 cycloalkyl. In other cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R 6< is H, halo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 10 cycloalkyl. In still other cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R 6< is H or optionally substituted C 1 -C 6 alkyl. In some cases of formula (III), (IIIA), (IIIB), (IIIC), or (IIID), R 6< is H. In other cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R 6< is C 1 -C 6 alkyl, e.g., methyl.

[0228] In certain cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R 9< is H, halo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl, or optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl. In other cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R 9< is H, halo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 10 cycloalkyl. In other cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R 9< is H, halo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted C 3 -C 10 cycloalkyl. In still other cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R 9< is H or optionally substituted C 1 -C 6 alkyl. In some cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R 9< is H. In other cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), R 9< is C 1 -C 6 alkyl, e.g., methyl.

[0229] In some cases, the compound of formula (III) has a structure of formula (IIIF): wherein each of R C< and R D< is independently optionally substituted C 1 -C 9 heteroaryl; and each of R 6< and R 9< is independently optionally substituted C 1 -C 6 alkyl.

[0230] In some cases of formula (IIIF), each of R C< and R D< is independently unsubstituted C 1 -C 9 heteroaryl; and each of R 6< and R 9< is independently unsubstituted C 1 -C 6 alkyl.

[0231] In some cases of formula (IIIF), each of R C< and R D< is thien-2-yl.

[0232] In some cases of formula (IIIF), each of R 6< and R 9< is methyl.

[0233] In some cases of formula (III), (IIIA), (IIIB), (IIIC), (IIID), or (IIIE), the isolated compound is compound 21:

[0234] In some cases, the GPR174 inhibitory compound has a structure according to formula (IV): or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein each of R 1< and R 2< is, independently, H, hydroxy, halo, optionally substituted amino, optionally substituted amido, thiol, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 1 -C 6 thioalkyl, optionally substituted C 1 -C 6 alkylsulfinyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylthio, optionally substituted C 6 -C 10 arylsulfinyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylthio, optionally substituted C 1 -C 9 heteroarylsulfinyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfinyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 4 -C 10 cycloalkenyl, optionally substituted C 8 -C 10 cycloalkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkenyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heterocyclyl, optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkenyl, or optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkynyl; each of R 3< and R 4< is, independently, H, hydroxy, halo, optionally substituted amino, optionally substituted amido, thiol, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted carboxamide, optionally substituted C 1 -C 6 alkanoyloxy, optionally substituted C 7 -C 11 aryloyloxy, optionally substituted C 2 -C 10 heteroaryloyloxy, optionally substituted C 2 -C 10 heterocyclyloyloxy, optionally substituted C 1 -C 6 thioalkyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylthio, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylthio, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 4 -C 10 cycloalkenyl, optionally substituted C 8 -C 10 cycloalkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkenyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heterocyclyl, optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkenyl, or optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkynyl; R 5< is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 6 -C 10 aryloxy, optionally substituted C 1 -C 9 heteroaryloxy, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, optionally substituted C 1 -C 6 alkyloxycarbonyl, optionally substituted C 1 -C 6 alkylsulfinyl, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 6 -C 10 arylsulfinyl, optionally substituted C 6 -C 10 arylsulfonyl, optionally substituted C 1 -C 9 heteroarylsulfinyl, optionally substituted C 1 -C 9 heteroarylsulfonyl, optionally substituted C 1 -C 9 heterocyclylsulfinyl, optionally substituted C 1 -C 9 heterocyclylsulfonyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 4 -C 10 cycloalkenyl, optionally substituted C 8 -C 10 cycloalkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkenyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heterocyclyl, optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkenyl, or optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkynyl. n is 0, 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, or 6.

[0235] In some cases of formula (IV), m is 0.

[0236] In other cases of formula (IV), the isolated compound has a structure according to formula (IVA):

[0237] In particular cases of formula (IV) or (IVA), R 1< is H, halo, optionally substituted amino, optionally substituted amido, thiol, cyano, or optionally substituted C 1 -C 6 alkyl. In other cases of formula (IV) or (IVA), R 1< is H, halo, or optionally substituted C 1 -C 6 alkyl. In yet other cases of formula (IV) or (IVA), R 1< is H.

[0238] In certain cases of formula (IV) or (IVA), the isolated compound has a structure according to formula (IVB):

[0239] In some cases of formula (IV), (IVA), or (IVB), R 5< is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, optionally substituted C 2 -C 10 heteroaryloyl, optionally substituted C 2 -C 10 heterocyclyloyl, optionally substituted C 1 -C 6 alkyloxycarbonyl, optionally substituted C 1 -C 6 alkylsulfonyl, or optionally substituted C 6 -C 10 arylsulfonyl. In other cases of formula (IV), (IVA), or (IVB), R 5< is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkanoyl, optionally substituted C 7 -C 11 aryloyl, or optionally substituted C 1 -C 6 alkyloxycarbonyl. In yet other cases of formula (IV), (IVA), or (IVB), R 5< is H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 2 -C 6 alkanoyl. In still other cases of formula (IV), (IVA), or (IVB), R 5< is H.

[0240] In certain cases of formula (IV), (IVA), or (IVB), the isolated compound has a structure according to formula (IVC):

[0241] In particular cases of formula (IV), (IVA), (IVB), or (IVC), R 2< is H, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 heteroalkenyl, optionally substituted C 2 -C 6 heteroalkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 4 -C 10 cycloalkenyl, optionally substituted C 8 -C 10 cycloalkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 6 -C 10 aryl C 1 -C 6 alkyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heteroaryl, optionally substituted C 1 -C 9 heteroaryl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkenyl, optionally substituted C 1 -C 9 heteroaryl C 2 -C 6 alkynyl, optionally substituted C 1 -C 9 heterocyclyl, optionally substituted C 1 -C 9 heterocyclyl C 1 -C 6 alkyl, optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkenyl, or optionally substituted C 1 -C 9 heterocyclyl C 2 -C 6 alkynyl. In other cases of formula (IV), (IVA), (IVB), or (IVC), R 2< is optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 4 -C 10 cycloalkenyl, optionally substituted C 8 -C 10 cycloalkynyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl. In yet other cases of formula (IV), (IVA), (IVB), or (IVC), R 2< is optionally substituted C 6 -C 10 aryl, optionally substituted C 1 -C 9 heteroaryl, or optionally substituted C 1 -C 9 heterocyclyl. In still other cases of formula (IV), (IVA), (IVB), or (IVC), R 2< is optionally substituted C 6 -C 10 aryl or optionally substituted C 1 -C 9 heteroaryl. In other cases of formula (IV), (IVA), (IVB), or (IVC), R 2< is optionally substituted pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl). In certain cases of formula (IV), (IVA), (IVB), or (IVC), R 2< is optionally substituted phenyl.

[0242] In some cases of formula (IV), (IVA), (IVB), or (IVC), the isolated compound has a structure according to formula (IVD): wherein R 6< at each occurrence is independently, halo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 6 heteroaryl, optionally substituted C 2 -C 6 heterocyclyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted amino, optionally substituted amido, thiol, cyano, nitro, C 1 -C 6 alkylsulfonyl, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted C 6 -C 10 aryloxy, or optionally substituted C 2 -C 6 heteroaryloxy; Z 1< is C or N; Z 2< is C or N; Z 3< is N or C; and p is 0, 1, 2, 3, 4, or 5.

[0243] In some cases of formula (IVD), Z 1< is C, Z 2< is C, and Z 3< is N. In other cases of formula (IVD), Z 1< is C, Z 2< is N, and Z 3< is C. In certain cases of formula (IVD), Z 1< is N, Z 2< is C, and Z 3< is C. In certain other cases of formula (IVD), Z 1< is C, Z 2< is C, and Z 3< is C.

[0244] In some cases of formula (IV), (IVA), (IVB), or (IVC), the isolated compound has a structure according to formula (IVD): wherein R 6< at each occurrence is independently, halo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 2 -C 6 heteroaryl, optionally substituted C 2 -C 6 heterocyclyl, optionally substituted C 2 -C 6 alkynyl,optionally substituted amino, optionally substituted amido, thiol, cyano, nitro, C 1 -C 6 alkylsulfonyl, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, optionally substituted C 2 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenoxy, optionally substituted C 6 -C 10 aryloxy, or optionally substituted C 2 -C 6 heteroaryloxy; Z 1< is CH or N; Z 2< is CH or N; Z 3< is N or CH; and p is 0, 1, 2, 3, 4, or 5.

[0245] In some cases of formula (IVD), Z 1< is C, Z 2< is C, and Z 3< is N. In other cases of formula (IVD), Z 1< is C, Z 2< is N, and Z 3< is CH. In certain cases of formula (IVD), Z 1< is N, Z 2< is CH, and Z 3< is CH. In certain other cases of formula (IVD), Z 1< is CH, Z 2< is CH, and Z 3< is CH.

[0246] In some cases of formula (IVD), p is 0. In other cases of formula (IVD), p is 1. In certain cases of formula (IVD), p is 2. In some cases of formula (IVD), p is 1, and R 6< is in the p- or m-position.

[0247] In certain cases of formula (IVD), R 6< is methoxy, methyl, hydroxyl, ethoxy, ethyl, optionally substituted phenoxy, optionally substituted cyclopentyloxy, t-butoxy, allyoxy, isopropyloxy, n-pentyloxy, trifluoromethyloxy, difluoromethyloxy, fluoro, chloro, nitro, 2-hydroxyethyloxy, optionally substituted 1,3,4-oxadiazolyl, or optionally substituted pyrrolidyl.

[0248] In particular cases of formula (IV), (IVA), (IVB), (IVC), or (IVD), R 3< is H, halo, optionally substituted amino, optionally substituted amido, thiol, cyano, hydroxycarbonyl, optionally substituted C 2 -C 7 alkoxycarbonyl, or optionally substituted C 1 -C 6 alkyl.

[0249] In other cases of formula (IV), (IVA), (IVB), (IVC), or (IVD), n is 0.

[0250] In some cases of formula (IV), the compound has a structure of formula (IVE): wherein each of Z 2< and Z 3< is independently CR 6< or N; and each of R 6< is independently H, halogen, hydroxy, nitro, optionally substituted C 1 -C 6 alkylsulfonyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 4- C 11 cycloalkoxy, optionally substituted C 1 -C 6 haloalkoxy, optionally substituted C 2 -C 6- alkenoxy, optionally substituted C 6- C 10 aryloxy, optionally substituted C 1 -C 9 heterocyclyl, optionally substituted C 6- C 10 aryl, or optionally substituted C 1 -C 9 heteroaryl; or two adjacent R 6< groups, taken together with the carbon atoms to which they are attached, form a C 1 -C 9 heterocyclyl.

[0251] In some cases of formula IV, (IVA), (IVB), or (IVC), the isolated compound is compound 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 54 or 55:

[0252] In some cases, the compound of formula (IVE) is compound 54 or 55.

[0253] In some cases, the GPR174 inhibitory compound has a structure according to the following formula (V): or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1< is phenyl, and R 2< is optionally substituted C 6 -C 10 aryl or optionally substituted C 1 -C 9 heteroaryl.

[0254] In some cases of formula (V), R 2< is optionally substituted phenyl.

[0255] In some cases of formula (V), R 2< is phenyl substituted with para-C 2 -C 6 alkenoxy.

[0256] In some cases of formula (V), R 2< is phenyl substituted with para-(2-methylallyl)oxy. In some cases of formula (V), the compound of formula (V) is compound 56:

[0257] In some cases, the GPR174 inhibitory compound has a structure according to the following formula (Va): or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is O or S; R 1a< is an optionally substituted phenyl; and R 2a< is an optionally substituted C 6 -C 10 aryl, an optionally substituted C 3 -C 9 heteroaryl or an optionally substituted C 3 -C 10 heteroarylalkyl.

[0258] In some cases, R 1a< is a substituted phenyl. In some more specific cases, R 1a< is optionally substituted with halo (e.g., F, Br, Cl, or I). In some cases, R 1a< has the following structure:

[0259] In some cases, R 2a< is an optionally substituted C 3 -C 10 heteroarylalkyl. In some cases, R 2a< is unsubstituted. In some more specific cases, R 2a< has the following structure:

[0260] In some cases, X is O. In certain cases, X is S.

[0261] In some cases, provided herein is a GPR174 inhibitory compound according to formula (VI): or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1< is an optionally substituted C 1 -C 9 heteroaryl, and R 2< is halogen.

[0262] In some cases of formula (VI), the N=C bond has the (E) configuration.

[0263] In some cases of formula (VI), the N=C bond has the (Z) configuration.

[0264] In some cases of formula (VI), R 1< is an optionally substituted pyridinyl or an optionally substituted furanyl.

[0265] In some cases of formula (VI), R 1< is pyridin-4-yl.

[0266] In some cases of formula (VI), R 1< is 2,5-dimethyl-fur-3-yl.

[0267] In some cases of formula (VI), R 2< is halo.

[0268] In some cases of formula (VI), R 2< is chloro or bromo.

[0269] In some cases of formula (VI), the compound of formula (VI) is compound 57 or 58: or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0270] In any of the cases described herein, the compound may be a compound described in Table 1 (e.g., any of compounds 1-59).

[0271] In another aspect, the disclosure features a method of identifying a modulatory agent capable of modulating a GPR174-mediated Gs signaling pathway comprising: (a) contacting a cell with a candidate modulatory agent, wherein said cell expresses GPR174 and includes the GPR174-mediated signaling pathway, and (b) determining whether the candidate modulatory agent modulates a GPR174-mediated Gs signaling pathway in comparison to a cell contacted with a control or in comparison to a reference standard. In some cases, said candidate modulatory agent is a chemical compound comprising a structure according to any of Formulas I-VI disclosed herein. In certain cases, step (b) further involves performing an assay to detect at least one of the following: transcriptional reporter gene expression, GTPase activity, cAMP level, intracellular messenger level, calcium level, downstream kinase activity, transcriptional activation of downstream genes, change in cell morphology, change in cell growth rate, arachidonic acid release, or extracellular acidification rate.

[0272] In some cases, the candidate modulatory agent is selected from the group consisting of a compound, a nucleic acid, a natural extract, and a gas. In certain cases, the compound is a small molecule compound. In particular cases, the chemical compound includes a structure according to any of Formulas I-VI disclosed herein.

[0273] In another aspect, the disclosure features a method of identifying a modulatory agent capable of modulating GPR174-mediated Gs signaling pathway activity, comprising: (a) contacting a cell expressing GPR174 with: (i) at least one candidate modulatory agent; and (ii) a reference chemical compound known to modulate GPR174-mediated Gs signaling pathway activity; (b) determining the GPR174-mediated signaling pathway activity level in the cell contacted in accordance with step (a); and (c) comparing the GPR174-mediated signaling pathway activity level in a cell contacted with the reference chemical compound only with the GPR174-mediated signaling pathway activity determined in step (b); wherein a difference in GPR174-mediated signaling activity between the cell containing the candidate modulatory agent in the presence of the reference compound and the cell contacted with only the reference compound indicates that the candidate modulatory agent is capable of modulating GPR174 activity.

[0274] In some cases, said reference chemical compound known to modulate GPR174-mediated Gs signaling pathway activity comprises a structure according to any of Formulas I-VI disclosed herein. In certain cases, step (b) further involves performing an assay to detect at least one of the following: transcriptional reporter gene expression, GTPase activity, cAMP level, intracellular messenger level, calcium level, downstream kinase activity, transcriptional activation of downstream genes, change in cell morphology, change in cell growth rate, arachidonic acid release, or extracellular acidification rate. In some cases, the candidate modulatory agent is selected from the group consisting of a compound, a nucleic acid, a natural extract, and a gas. In certain cases, the compound is a chemical compound. In particular cases, the small molecule compound includes a structure according to any of Formulas I-VI.

[0275] In another aspect, the disclosure features a method of identifying a modulatory agent capable of modulating GPR174-mediated signaling pathway activity. The method involves: (a) contacting a cell expressing GPR174 with (i) at least one candidate modulatory agent and (ii) a reference chemical compound known to modulate GPR174-mediated signaling pathway activity; (b) determining the GPR174-mediated signaling pathway activity level in the cell contacted in accordance with step (a); and (c) comparing the GPR174-mediated signaling pathway activity level in a cell contacted with the reference chemical compound only with the GPR174-mediated signaling pathway activity determined in step (b); in which a difference in GPR174-mediated signaling activity between the cell containing the candidate modulatory agent in the presence of the reference compound and the cell contacted with only the reference compound indicates that the candidate modulatory agent is capable of modulating GPR174 activity. In some cases, the reference chemical compound includes a structure according to any one of Formulas I-VI (e.g., any of compounds 1-59).

[0276] In certain cases, step (b) further involves performing an assay to detect at least one of the following: transcriptional reporter gene expression, GTPase activity, cAMP level, intracellular messenger level, calcium level, downstream kinase activity, transcriptional activation of downstream genes, change in cell morphology, change in cell growth rate, arachidonic acid release, or extracellular acidification rate.

[0277] In some cases, the candidate modulatory agent is selected from the group consisting of a compound, a nucleic acid, a natural extract, and a gas. In certain cases, the compound is a small molecule chemical compound.

[0278] In another aspect, the disclosure features a method of using a small molecule chemical compound for inhibiting a GPR174-mediated signaling pathway in a cell. The method involves the following steps: (a) providing a small molecule chemical compound that functionally interacts with GPR174 and inhibits a GPR174-mediated Gs signaling pathway in cells expressing GPR174, wherein the compound is characterized by at least one of the following criteria: (i) the compound has a structure selected from the group consisting of Formula I, II, III, IV, V and VI (or (I), (II), (III), (IV), (V), (Va), or (VI)); or (ii) the compound changes the binding affinity of any one of reference compounds 1-59 (as set forth in Table 1) to GPR174; or (iii) the compound causes a difference in the inhibitory activity of any one of reference compounds 1-59 (as set forth in Table 1) in a GPR174-mediated signaling pathway assay when tested in the presence of the reference compound as compared to the inhibitory activity of the reference compound alone; and (b) contacting a cell expressing GPR174 that includes a GPR174-mediated signaling pathway with the compound according to step (a), thereby inhibiting a GPR174-mediated signaling pathway in the cell.

[0279] In another aspect, the disclosure features a method of using a small molecule chemical compound for inhibiting a GPR174-mediated signaling pathway in a cell. The method involves the following steps: (a) providing a small molecule chemical compound that functionally interacts with GPR174 and inhibits a GPR174-mediated Gs signaling pathway in cells expressing GPR174, wherein the compound is characterized by at least one of the following criteria: (i) the compound has a structure selected from the group consisting of Formula I, II, III, IV, V and VI (or (I), (II), (III), (IV), (V), (Va), or (VI)); or (ii) the compound changes the apparent binding affinity of any one of reference compounds 1-59 (as set forth in Table 1) to GPR174; or (iii) said compound causes a difference in the inhibitory activity of any one of reference compounds 1-59 (as set forth in Table 1), in a GPR174-mediated signaling pathway assay when tested in the presence of said reference compound as compared to the inhibitory activity of the reference compound alone; and (b) contacting a cell expressing GPR174 that includes a GPR174-mediated signaling pathway with the compound according to step (a), thereby inhibiting a GPR174-mediated signaling pathway in the cell.

[0280] In some cases, the compound changes the binding affinity of any one of reference compounds 1-59 (as set forth in Table 1) to GPR174. In certain cases, the compound decreases (i.e., inhibits) the binding affinity of any one of reference compounds 1-59 to GPR174. In particular cases, the compound competitively decreases (i.e., competitively inhibits) the binding affinity of any one of reference compounds 1-59 to GPR174. In other cases, the compound increases the binding affinity of any one of reference compounds 1-59 (as set forth in Table 1) to GPR174.

[0281] In some cases, the compound changes the apparent binding affinity of any one of reference compounds 1-59 (as set forth in Table 1) for GPR174. In certain cases, the compound decreases the apparent binding affinity of any one of reference compounds 1-59 for GPR174. In particular cases, the compound competitively binds to GPR174 and decreases the apparent binding affinity of any one of reference compounds 1-59 for GPR174. In alternate cases, the compound allosterically binds to GPR174 and decreases the apparent binding affinity of any one of reference compounds 1-59 for GPR174. In other cases, the compound increases the binding affinity of any one of reference compounds 1-59 (as set forth in Table 1) for GPR174.

[0282] In certain cases of any of the above aspects of the disclosure, the GPR174-mediated signaling pathway is a Gs pathway.

[0283] In some cases of any of the above aspects, the cell is in a mammalian subject in need of treatment for any condition, disease or disorder described herein.

[0284] Inhibition of ATP-Adenosine-A2aR- and / or A2bR-mediated signaling (such as an A2aR antagonist, and / or an A2bR antagonist and / or a CD73 inhibitor and / or a CD38 inhibitor and / or a CD39 inhibitor)

[0285] Adenosine signaling, via the A2A receptor and / or the A2B receptor pathway in particular, has been identified as a promising approach to cancer immunotherapy. Leone et al., "Targeting adenosine for cancer immunotherapy", J. ImmunoTher. Cancer., 2018, 6:57. Allard et al., " The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets", Immunol. Rev., 2017, 276(1), 121-144 (see also Table 15 below). Adenosine is an immunosuppressive metabolite produced at high levels within the tumor microenvironment. Adenosine signaling has emerged as a key metabolic pathway that regulates tumor immunity. In particular, adenosine signaling through the A2A receptor expressed on immune cells potently dampens immune responses in inflamed tissues. Adenosine is produced under hypoxic conditions in inflamed and malignant tissues via conversion of ATP mediated by the enzymes CD73 (NT5E, 5'-nucleotidase (5'-NT) or ecto-5'-nucleotidase) and CD39 (ectonucleoside triphosphate diphosphohydrolase-1, NTPDase1). Adenosine may also be produced from NAD+ by an axis centered on the NAD+-metabolizing CD38 generating adenosine diphosphate ribose (ADPR). Adenosine generated through a CD38-mediated pathway has been shown to correlate with progression of human myeloma (Horenstein et al., Mol Med 22:694-704, 2016). Adenosine generation and signaling, particularly through the A2A receptor, plays a role in resolution of inflammation in response to tissue injury, dampening the immune response. This coupling of wound healing and immunosuppression, however, represents a mechanism of cancer immune evasion. Accordingly, inhibition of the hypoxia-CD38-CD39-CD73-A2AR pathway has been identified as a promising target for cancer immunotherapy.Inhibitors of the ATP-adenosine A2A and / or A2B receptor pathway

[0286] Inhibitors of the ATP-adenosine A2A receptor pathway and / or inhibitors of the ATP-adenosine A2B receptor pathway that can be used in combination with GPR174 inhibitors in the compositions, methods and uses described herein include adenosine A2A receptor antagonists, A2B receptor antagonists and inhibitors of enzymes that degrade ATP to adenosine such as inhibitors of CD73 and inhibitors of CD38 and inhibitors of inhibitors of CD39, and combinations of such agents.Adenosine A2A receptor antagonists

[0287] Adenosine A2A receptor antagonists include the compounds ATL-444, AZD4635, caffeine, ciforadenant (CPI-444; V81444), CPI-445, EOS100850, MK-3814, istradefylline (KW-6002), MSX-3, PBF-509 (NIR178), preladenant (SCH-420,814), SCH-58261, SCH-412,348, SCH-442,416, ST-1535, ST-4206, theophylline, tozadenant (SYN115), VER-6623, VER-6947, VER-7835, vipadenant (BIIB-014) and ZM-241,385, whose structures are given below.

[0288] Further A2A receptor antagonists are described in Preti, et al., "History and Perspectives of A2A Adenosine Receptor Antagonists as Potential Therapeutic Agents", Med. Res. Rev., 2015, 35(4), 790-848, and Congreve et al., "Targeting adenosine A2A receptor antagonism for treatment of cancer", Exp. Opin. Drug Discov., 2018, 13(11), 997-1003.

[0289] Other A2A receptor antagonists are described in the following international patent applications: PCT pub. Nos. WO 2019 / 007140; WO 2018 / 166493; WO 2018 / 161910; WO 2018 / 130184; WO 2018 / 059531; WO 2017 / 136375; WO2 017 / 112917; WO 2017 / 008205; WO 2017 / 011214; WO 2016 / 200717; WO 2016 / 126570; WO 2016 / 087429; WO 2016 / 081290; WO 2015 / 020565; WO 2014 / 105664 ; WO 2014 / 105666; WO 2014 / 101120 ; WO 2014 / 101113; WO 2013 / 156614, WO 2013 / 058681; WO 2012 / 129381; WO 2012 / 112962; WO 2012 / 061787; WO 2012 / 060844; WO 2012 / 038980; WO 2011 / 061527; WO 2011 / 060207; WO 2011 / 053507; WO 2010 / 040003; WO 2010 / 037122; WO 2009 / 055308; WO 2009 / 050198; WO 2008 / 055711; WO 2007 / 047293; WO 2007 / 038212; WO 2006 / 137527; WO 2006 / 129626; WO 2006 / 124770; WO 2006 / 083949; WO 2012 / 03898; WO 2011 / 06152; WO 2011 / 06020; WO 2011 / 05350; WO 2010 / 04000; WO 2010 / 03712; WO 2009 / 055308; WO 2009 / 050198; WO 2008 / 055711; WO 2007 / 047293; WO 2007 / 038212; WO 2006 / 137527; WO 2006 / 129626; WO 2006 / 124770; and WO 2006 / 083949.Adenosine A2B receptor antagonists

[0290] Adenosine A2B receptor antagonists include the compounds MRS-1754, GS-6201, ISAM-140, PSB-0788, PSB-1115 and PSB-603 whose structures are given below:

[0291] Further A2B receptor antagonists include ATL-801, CVT-6883, MRS-1706, OSIP-339,391, PSB-1901, PBF-1129 and additional A2B receptor antagonists as described in Vigano S. et al., Frontiers in Immunology vol 10:925, 2019; Volpini R. et al., Journal of Med Chem 45(15):3271-9, 2002; Volpini R. et al., Current Pharmaceutical Design 8(25):2285-98, 2002; Baraldi P.G. et al., Journal of Med Chem 47(6):1434-47, 2004; Cacciari B. et al., Mini Reviews in Med Chem 5(12):1053-60, 2005; Baraldi P.G. et al., Current Med Chem 13(28):3467-82, 2006; Beukers M.W. et al., Medicinal Research Reviews, 26(5):667-98, 2006; Elzein E. et al., Bioorganic & Medicinal Chemistry Letters 16(2):302-6, 2006; Carotti A. et al., Journal of Med Chem 49(1):282-99, 2006; Tabrizi M.A. et al., Bioorganic & Medicinal Chemistry 16(5):2419-30, 2008; Stefanachi A. et al., Bioorganic & Medicinal Chemistry 16(6):2852-69, 2008 and Jiang et al., Journal of Med Chem 62(8):4032-4055, 2019 as well as compound 38 described in Stefanachi A. et al., Bioorganic & Medicinal Chemistry 16(22):9780-9, 2008.

[0292] Other A2B receptor antagonists are described in the following international patent applications, PCT Pub. Nos WO 1995 / 011681; WO 1999 / 042093; WO 2000 / 049051; WO 2000 / 073307; WO 2009 / 157938; WO 2011 / 005871; WO 2012 / 112964; WO 2007 / 149277; WO 2019 / 123482; WO 2007 / 134958; WO 2005 / 051951; WO 2003 / 042214; WO 2007 / 039297; WO 2005 / 040155; WO 2005 / 042534; WO 2004 / 106337; WO 2001 / 016134; WO 2008 / 027585; WO 2003 / 053366; WO 2003 / 053361; WO 2005 / 070926; WO 2008 / 080461; WO 2016 / 150901; WO 2005 / 051951; WO 2003 / 042214; WO 2003 / 063800; and WO 2016 / 164838. CD73 (NT5E, 5'-nucleotidase (5'-NT) or ecto-5'-nucleotidase) Inhibitors

[0293] CD73 inhibitors can include CD73 antibodies, nucleotides (e.g., inhibitory RNA) that inhibit CD73 expression as well as chemical (e.g., small molecule) inhibitors.

[0294] CD73 antibodies including Oleclumab, are described in the following international patent applications: PCT Pub. Nos. WO 2018 / 237157; WO 2018 / 237173; WO 2018 / 215535; WO 2018 / 187484; WO 2018 / 137598; WO 2018 / 013611; WO 2017 / 152085; WO 2017 / 118613; WO 2017 / 100670; WO 2017 / 064043; WO 2016 / 131950; WO 2016 / 081748; WO 2016 / 075176; WO 2016 / 075099; and WO 2016 / 055609.

[0295] Nucleotides that inhibit CD73 expression are described in the following international patent applications: PCT Pub. No. WO 2018 / 065627.

[0296] CD73 inhibitors include N-benzyl-α,β-methyleneadenosine 5'-diphosphate sodium salt and α,β-methyleneadenosine 5'-diphosphate sodium salt (PSB 12379), BMS-986179, MEDI9447, CPI-006 and NZV930. CD73 inhibitors are also described in the following international patent applications: PCT Pub. Nos WO 2018 / 208727; WO 2018 / 208980; WO 2018 / 187512; WO 2018 / 183635; WO 2018 / 110555; WO 2018 / 094148; WO 2018 / 067424; WO 2017 / 153952; WO 2017 / 120508; WO 2017 / 098421; WO 2015 / 164573; WO 2015 / 049447; and WO 2007 / 135195.

[0297] It is noted that while CD73 inhibitors are useful in the compositions and methods described herein for the treatment of cancer, the use of a CD73 inhibitor is preferably avoided during early tumor formation and in the setting of metastasis due to the fact that CD73-derived adenosine could be helpful in preventing metastasis (may act as a barrier in the vascular endothelium), therefore it might be preferable to have CD73 remain active in such settings.CD38 (cyclic ADP ribose hydrolase) Inhibitors

[0298] CD38 is an ectoenzyme that catalyzes the synthesis and hydrolysis of cyclic ADP-ribose (cADPR) from NAD+ to ADP-ribose in addition to synthesis of NAADP from NADP+. [<

[0299] CD38 inhibitors can include CD38 antibodies, nucleotides (e.g., inhibitory RNA) that inhibit CD38 expression as well as chemical (e.g., small molecule) inhibitors.

[0300] CD38 antibodies, including Daratumumab, and other CD38 inhibitors are described in the following publications and international patent applications; Xia C, et al, Drugs of Today. 52 (10): 551-560, 2016; Escande C. et al., Diabetes 62(4):1084-1093, 2013; US Patent No. 9,840,496; US Pub. Nos 2018 / 85383; 2017 / 0260164; PCT Pub. Nos. WO 2019 / 140410; WO 20190 / 74973; WO 2019 / 0904931; WO 2019 / 087151; WO 2019 / 074973; WO 2019 / 034753; WO 2019 / 034752; WO 2019 / 020643; WO 2018 / 224685; WO 2018 / 224683; WO 2018 / 224682; WO 2016 / 087975; and WO 2013 / 002879CD39 (Ectonucleoside triphosphate diphosphohydrolase-1, NTPDase1) Inhibitors

[0301] CD39 inhibitors can include CD39 antibodies, nucleotides (e.g., inhibitory RNA) that inhibit CD39 expression as well as chemical (e.g., small molecule) inhibitors.

[0302] CD39 antibodies, including TTX-030, are described in the following international patent applications: PCT Pub. Nos. WO 2018 / 167267; WO 2018 / 065552; WO 2017 / 191300; WO 2017 / 157948; WO 2017 / 089334; WO 2017 / 064043; WO 2016 / 073845; WO 2012 / 085132; and WO 2009 / 095478.

[0303] Nucleotides that inhibit CD39 expression are described in the following international patent applications: PCT Pub. No. WO 2018 / 065622.

[0304] CD39 inhibitors include sodium metatungstate (POM 1); 6-N,N-diethyl-D-β,γ-dibromomethylene ATP trisodium salt (ARL-67156); 1-amino-4-(1-naphthyl)aminoanthraquinone-2-sulfonic acid sodium salt (PSB 06126), 1-amino-4-(4-chlorophenyl)aminoanthraquinone-2-sulfonic acid sodium salt (PSB069) and IPH52. CD39 inhibitors are also described in the following international patent applications: PCT Pub. No. WO 2007 / 135195.

[0305] Other features and advantages of the disclosure will be apparent from the following Detailed Description, the drawings, and the claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0306] FIGURE 1A depicts the amino acid sequence of human GPR174 (NP_115942.1), set forth as SEQ ID NO:1. FIGURE 1B depicts the cDNA encoding human GPR174 (NM_032553.1), set forth as SEQ ID NO:2. FIGURE 1C depicts the amino acid sequence of mouse GPR174 (NP_001028423.1), set forth as SEQ ID NO:3. FIGURE 1D depicts the amino acid sequence of rat GPR174 (NP_001100408.1), set forth as SEQ ID NO:4. FIGURE 2 is a graph showing that the rank-ordering of the reported potency of a variety of known agonists to the Muscarinic acetylcholine receptor M1 (CHRM1) receptor is preserved in the cellular redistribution assay (CRA). FIGURE 3 is a schematic diagram showing the algorithm used to determine the G-protein signaling profile for an orphan GPCR. FIGURE 4A is a graph showing the effect of various compounds on signaling of the beta-2 adrenergic receptor (ADBR2). FIGURE 4B is a graph showing the effects of ADBR2 over-expression on the CRE-luc reporter, as determined by transient transfection of increasing amounts (ng) of DNA encoding ADBR2. FIGURE 4C is a graph showing the effects of ADBR2 over-expression on the NFAT-luc reporter, as determined by transient transfection of increasing amounts (ng) of DNA encoding ADBR2. FIGURE 4D is a graph demonstrating that the compound ICI 118551, an inverse agonist of ADBR2, specifically inhibits CRE-luc reporter activity in cells transiently transfected with ADBR2. FIGURE 4E is a graph demonstrating that the compound ICI 118551 does not inhibit the NFAT-luc reporter activity in cells transiently transfected with ADBR2. FIGURE 5A is a graph illustrating the dose-response curves of representative compounds, including compounds 1, 2, 3, 4, and 20 against GPR174 in the Cellular Redistribution Assay (CRA) assay. FIGURE 5B is a graph illustrating the dose-response curve of representative compounds, including compound 1, 2, 3, 4, and 20 against CHRM1 in the CRA assay. Also shown is the dose-response curve of the CHRM1-interacting compound pirenzepine. FIGURES 6A-6B are graphs showing that compound 1 (Group I) inhibited the Gs pathway in the presence of GPR174 (FIGURE 6A), but not in the presence of ADBR2 (FIGURE 6B). FIGURES 7A-7B are graphs showing that compound 2 (Group I) inhibited the Gs pathway in the presence of GPR174 (FIGURE 7A), but not in the presence of ADBR2 (FIGURE 7B). FIGURES 8A-8B are graphs showing that compound 4 (Group I) did not modulate the Gs pathway in the presence of GPR174 (FIGURE 8A) and did not modulate the Gs pathway in the presence of ADBR2 (FIGURE 8B). FIGURES 9A-9B are graphs showing that compound 6 (Group I) inhibited the Gs pathway in the presence of GPR174 (FIGURE 9A), but not in the presence of ADBR2 (FIGURE 9B). FIGURES 10A-10B are graphs showing that compound 7 (Group I) inhibited the Gs pathway in the presence of GPR174 (FIGURE 10A), but not in the presence of ADBR2 (FIGURE 10B). FIGURES 11A-11B are graphs showing that compound 10 (Group I) inhibited the Gs pathway in the presence of GPR174 (FIGURE 11A), but not in the presence of ADBR2 (FIGURE 11B). FIGURES 12A-12B are graphs showing that compound 11 (Group I) inhibited the Gs pathway in the presence of GPR174 (FIGURE 12A), but not in the presence of ADBR2 (FIGURE 12B). FIGURES 13A-13B are graphs showing that compound 19 (Group II) did not modulate the Gs pathway in the presence of GPR174 (FIGURE 13A) and did not modulate the Gs pathway in the presence of ADBR2 (FIGURE 13B). FIGURES 14A-14B are graphs showing that compound 21 (Group III) did not modulate the Gs pathway in the presence of GPR174 (FIGURE 14A) and did not modulate the Gs pathway in the presence of ADBR2 (FIGURE 14B). FIGURES 15A-15B are graphs showing that compound 22 (Group IV) inhibited the Gs pathway in the presence of GPR174 (FIGURE 15A), but not in the presence of ADBR2 (FIGURE 15B). FIGURE 16A-16B are graphs showing that compound 23 (Group IV) inhibited the Gs pathway in the presence of GPR174 (FIGURE 16A), but not in the presence of ADBR2 (FIGURE 16B). FIGURE 17A-17B are graphs showing that compound 31 (Group IV) inhibited the Gs pathway in the presence of GPR174 (FIGURE 17A), but not in the presence of ADBR2 (FIGURE 17B). FIGURES 18A-18B are graphs showing that compound 33 (Group IV) inhibited the Gs pathway in the presence of GPR174 (FIGURE 18A), but not in the presence of ADBR2 (FIGURE 18B). FIGURES 19A-19B are graphs showing that compound 36 (Group IV) inhibited the Gs pathway in the presence of GPR174 (FIGURE 19A), but not in the presence of ADBR2 (FIGURE 19B). FIGURES 20A-20B are graphs showing that compound 42 (Group IV) inhibited the Gs pathway in the presence of GPR174 (FIGURE 20A), but not in the presence of ADBR2 (FIGURE 20B). FIGURES 21A-21B are graphs showing that compound 4 (Group I) does not modulate the Gs pathway in the presence of GPR174 but does compete with the GPR174 agonist LysoPS (FIGURE 21A), and neither compound 4 nor LysoPS modulate Gs signaling in the presence of ADBR (FIGURE 21B). FIGURE 22 graphically illustrates the relative transcript abundance of GPR174 in human tissues, as measured by qPCR, as described in Example 5. FIGURE 23 graphically illustrates the relative transcript abundance of GPR174 in human lymphoid cells, as measured by qPCR, as described in Example 5. FIGURE 24A graphically illustrates the percentage of FoxP3 +< Helios -< cells in the CD4 +< cell population at day 3 post-stimulation in human peripheral blood mononuclear cells (PBMC) cultures treated with vehicle, compound 10, or interleukin-2 (IL-2) (p=0.03 for compound 10 vs vehicle; p=0.003 for IL-2 vs vehicle), as described in Example 6. FIGURE 24B graphically illustrates the percentage of FoxP3 +< Helios +< cells in the CD4 +< cell population at day 7 post-stimulation in PBMC cultures treated with vehicle, compound 10, or IL-2 (p=0.01 for compound 10 vs. vehicle; p=0.01 for IL-2 vs vehicle), as described in Example 6. FIGURE 25 graphically illustrates the amount of IL-2 in culture supernatants (fold over vehicle levels) on day 2 post-stimulation in PBMC cultures treated with vehicle or compound 10 (1 µM, 3 µM or 10 µM), as described in Example 6. FIGURE 26 graphically illustrates the amount of IFN-γ in culture supernatants (fold over vehicle levels) on day 2 post-stimulation in PBMC cultures treated with vehicle or compound 10 (1 µM, 3 µM or 10 µM), as described in Example 6. FIGURE 27 graphically illustrates the amount of IL-2 (pg / mL) in culture supernatants 48 hours after stimulation in splenocyte cultures from WT or GPR174 KO mice treated with vehicle or compound 10 (10 µM), as described in Example 7. FIGURE 28 graphically illustrates the percentage of FoxP3 +< Helios +< cells in the CD4 +< cell population at day 7 post-stimulation in human PBMC cultures from a single donor treated with vehicle or compound 10 (3 µM, 10 µM or 30 µM) (n=3, *p<0.05; **p<0.01), as described in Example 8. FIGURE 29 graphically illustrates the amount of IL-2 (pg / mL) in culture supernatants on day 3 post-stimulation in human PBMC cultures from a single donor treated with vehicle or GPR174 inhibitory compound 10 (3 µM, 10 µM, 30 µM, or 60 µM), as described in Example 8. FIGURE 30 graphically illustrates the fraction of vehicle of FoxP3 +< Helios +< cells in the CD4 +< cell population at day 7 post-stimulation in human PBMC cultures from eight different donors treated with vehicle or compound 10 (30 µM), as described in Example 9. FIGURE 31 graphically illustrates the amount of IL-2 (fold over IL-2 produced by vehicle) in culture supernatants on day 2 post-stimulation in human PBMC cultures from eight different donors treated with vehicle or compound 10 (30 µM), as described in Example 9. FIGURE 32 graphically illustrates the amount of various cytokines (fold over vehicle produced cytokine) in culture supernatants on day 2 post-stimulation from human PBMCs obtained from eight donors treated with vehicle or compound 10 (30 µM), wherein a statistically significant fold increase was observed for interleukin-6 (IL-6) (***p<0.001), interleukin-10 (IL-10) (*p<0.05), interferon gamma (IFN-γ) (*p<0.05) and tumor necrosis factor (TNF-α)(*p<0.05) as compared to vehicle control and wherein a statistically significant fold decrease was observed for interleukin 17 (IL-17A) (***p<0.001) as compared to vehicle control, as described in Example 9. FIGURE 33 graphically illustrates the fold induction by compound 10 (30 µM) on a panel of cytokines in co-cultured mouse C57BL / 6+DBA1 splenocytes at day 6 after mixing, as compared to the cytokine levels measured in co-cultured C57BL / 6+DBA1 splenocytes on day 6 in the absence of compound 10, as described in Example 10. FIGURE 34A shows the CD4 +< (46.2%), CD8 +< (17.1%) and non-T cell (33.9%) populations present in a representative PBMC culture from a single donor, four hours after stimulation with anti-CD3 and anti-CD28 antibodies in the presence of compound 10 (10 µM), as described in Example 11. FIGURE 34B graphically illustrates the fraction of cells with intracellular IL-2 in the CD4 +< T cell population treated with compound 10 (10 µM) shown in FIGURE 34A, as compared to vehicle control, as described in Example 11. FIGURE 34C graphically illustrates the fraction of cells with intracellular IL-2 in the CD8 +< T cell population treated with compound 10 (10 µM) shown in FIGURE 34A, as compared to vehicle control, as described in Example 11. FIGURE 35A shows the CD4 +< (31.8%), CD8 +< (27.5%) and non-T cell (33.1%) populations present in a representative PBMC culture from a single donor, two days after stimulation with anti-CD3 and anti-CD28 antibodies, as described in Example 11. FIGURE 35B graphically illustrates the fraction of cells with intracellular IL-2 staining in the CD4 +< T cell population in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, or 3.0 µM), a representative of which is shown in FIGURE 35A, as described in Example 11. FIGURE 35C graphically illustrates the fraction of cells with intracellular IL-2 staining in the CD8 +< T cell population in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, or 3.0), a representative of which is shown in FIGURE 35A, as described in Example 11. FIGURE 35D graphically illustrates the fraction of cells with intracellular IL-2 staining in non-T cell populations in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, or 3.0 µM), a representative of which is shown in FIGURE 35A, as described in Example 11. FIGURE 35E graphically illustrates the fraction of cells with intracellular IL-10 staining in the CD4 +< T cell population in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, or 3.0 µM), a representative of which is shown in FIGURE 35A, as described in Example 11. FIGURE 35F graphically illustrates the fraction of cells with intracellular IL-10 staining in the CD8 +< T cell population in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, or 3.0 µM), a representative of which is shown in FIGURE 35A, as described in Example 11. FIGURE 35G graphically illustrates the fraction of cells with intracellular IL-10 staining in non-T cell populations in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, or 3.0 µM), a representative of which is shown in FIGURE 35A, as described in Example 11. FIGURE 35H graphically illustrates the fraction of cells with intracellular IFN-γ staining in the CD4 +< T cell population in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, or 3.0 µM), a representative of which is shown in FIGURE 35A, as described in Example 11. FIGURE 35I graphically illustrates the fraction of cells with intracellular IFN-γ staining in the CD8 +< T cell population in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, or 3.0 µM), a representative of which is shown in FIGURE 35A, as described in Example 11. FIGURE 35J graphically illustrates the fraction of cells with intracellular IFN-γ staining in non-T cell populations in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, or 3.0 µM), a representative of which is shown in FIGURE 35A, as described in Example 11. FIGURE 35K graphically illustrates the fraction of cells with intracellular TNF-α staining in the CD4 +< T cell population in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, 3.0, or 10 µM), a representative of which is shown in FIGURE 35A, as described in Example 11. FIGURE 35L graphically illustrates the fraction of cells with intracellular TNF-α staining in the CD8 +< T cell population in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, 3.0, or 10 µM), a representative of which is shown in FIGURE 35A, as described in Example 11. FIGURE 35M graphically illustrates the fraction of cells with intracellular TNF-α staining in the non-T cell populations in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, 3.0, or 10 µM), a representative of which is shown in FIGURE 35A, as described in Example 11. FIGURE 36A shows additional analysis of the non-T cell population from FIGURE 35A sorted into CD56 +< CD16 -< (2.27%), CD56 +< CD16 +< (11.8%) and non-NK (78.5%) populations present in the non-T cell population in a representative PBMC culture 2 days after stimulation with anti-CD3 and anti-CD28 antibodies, as described in Example 11. FIGURE 36B graphically illustrates the fraction of cells with intracellular IFN-γ staining in non-T-CD56 +< CD16 +< cell populations in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, or 3.0 µM), a representative of which is shown in FIGURE 36A, as described in Example 11. FIGURE 36C graphically illustrates the fraction of cells with intracellular IFN-γ staining in non-T-CD56 +< CD16 -< cell populations in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, or 3.0 µM), a representative of which is shown in FIGURE 36A, as described in Example 11. FIGURE 36D graphically illustrates the fraction of cells with intracellular TNF-α staining in non-T-CD56 +< CD16 +< cell populations in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, 3.0, or 10 µM), a representative of which is shown in FIGURE 36A, as described in Example 11. FIGURE 36E graphically illustrates the fraction of cells with intracellular TNF-α staining in non-T-CD56 +< CD16 -< cell populations in PBMC cultures treated with compound 10 (0, 0.1, 0.3, 1.0, 3.0, or 10 µM), a representative of which is shown in FIGURE 36A, as described in Example 11. FIGURE 37 graphically illustrates the amount of dextramer stained cells (antigen-specific T cells) as a percent of total CD8 +< cells in splenocyte cultures obtained from WT and GPR174 KO mice three weeks after immunization with 1000 HAU influenza virus A / PR / 8 / 34, and cultured for 5 days in the presence of NP antigenic peptide, wherein splenocytes obtained from naive WT mice are included as a control, as described in Example 12. FIGURE 38 graphically illustrates the amount of dextramer stained cells (antigen-specific T cells) as a percent of total CD8 +< cells in splenocyte cultures obtained from WT and GPR174 KO mice immunized and boosted three weeks later with 1000 HAU (hemagglutinin units) of influenza virus A / PR / 8 / 34, wherein the splenocytes were analyzed 11 days after boost, and wherein splenoctyes obtained from naive WT mice are included as a control, as described in Example 12. FIGURE 39A graphically illustrates the fraction of naive Regulatory T cells (Treg) with CTLA-4 positive staining (percentage of naive Treg cells (CD45RA+FOXP3+) in PBMC cultures treated with GPR174 inhibitory compound 10 (0, 0.19, 0.38, 0.75, 1.5, 3.0 or 6.0 µM) or equivalent amounts of vehicle control (DMSO), at one day post-stimulation, as described in Example 13; FIGURE 39B graphically illustrates the fraction of non-regulatory T cells (non-Treg) with CTLA4 positive staining (percentage of naive non-Treg cells (CD45RA+FOXP3-) in PBMC cultures treated with GPR174 inhibitory compound 10 (0, 0.19, 0.38, 0.75, 1.5, 3.0 or 6.0 µM) or equivalent amounts of vehicle control (DMSO), at one day post-stimulation, as described in Example 13; FIGURE 40A graphically illustrates the fraction of memory Treg with CTLA4 positive staining (percentage of memory Treg (CD45RA-FOXP3+) in PBMC cultures treated with GPR174 inhibitory compound 10 (0, 0.19, 0.38, 0.75, 1.5, 3.0, or 6.0 µM) or equivalent amounts of vehicle control (DMSO), at one day post-stimulation, as described in Example 13; FIGURE 40B graphically illustrates the fraction of memory non-Treg cells with CTLA4 positive staining (percentage of memory non-Treg (CD45RA-FOXP3-) in PBMC cultures treated with GPR174 inhibitory compound 10 (0, 0.19, 0.38, 0.75, 1.5, 3.0, or 6.0 µM) or equivalent amounts of vehicle control (DMSO), at one day post-stimulation, as described in Example 13; FIGURE 41 graphically illustrates the fraction of human CD4+ T cells with PD-L1 positive staining in PBMC cultures treated with GPR174 inhibitory compound 10 (0, 1.25 or 5µM) at one day post-stimulation, showing that PD-L1 expression is reduced in CD4+ T cells treated with compound 10 in a dose-dependent manner as compared to vehicle control treated cells, as described in Example 14; FIGURE 42 graphically illustrates the fraction of human CD8+ T cells with TGIT positive staining in PBMC cultures treated with GPR174 inhibitory compound 10 (0, 1.25 or 5 µM) at one day post-stimulation, showing that TGIT expression is reduced in CD8+ T cells treated with compound 10 in a dose-dependent manner as compared to vehicle control treated cells, as described in Example 14; and FIGURE 43 graphically illustrates the fraction of human CD4+ T cells with AREG positive staining in PBMC cultures treated with GPR174 inhibitory compound 10 (0, 1.25 or 5 µM) at one day post-stimulation, showing that AREG expression is reduced in CD4+ T cells treated with compound 10 in a dose-dependent manner as compared to vehicle control treated cells, as described in Example 14; FIGURE 44 graphically illustrates the amount of IFN-γ in culture supernatants 24 hours post-stimulation in human PBMC cultures from a single donor cultured in the presence of GPR174 inhibitory compound 10 (3 µM); A2aRinhibitory compound (ZM241385, 1 µM or 10 µM); a combination of compound 10 (3 µM) plus 1 µM ZM241385; a combination of compound 10 (3 µM) plus 10 µM ZM241385; or vehicle control (DMSO), demonstrating that the combined inhibition of GPR174 and A2aR results in synergistic induction of IFN-γ production, as described in Example 15. FIGURE 45A graphically illustrates the fold induction of Gs-signaling activity in HEK293 cells expressing wild-type GPR174 and cAMP biosensor expressing plasmid pGlo22F in the presence of increasing concentrations of phosphatidylserine liposomes (PS) or lysophosphatidylserine (Lyso-PS), as described in Example 16. FIGURE 45B graphically illustrates the fold induction of Gs-signaling activity in HEK293 cells expressing mutant GPR174-v38 and cAMP biosensor expressing plasmid pGlo22F in the presence of increasing concentrations of phosphatidylserine liposomes (PS) or lysophosphatidylserine (Lyso-PS), as described in Example 16. FIGURE 46 graphically illustrates the level of GPR174 Gs signaling activity in HEK293 cells expressing GPR174 and cAMP biosensor expressing plasmid pGlo22F (shown as the ratio of luminescence after phospholipid addition to the pre-read luminescence value) in the presence of PS, phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI) liposomes, as described in Example 16. FIGURE 47A graphically illustrates the inhibition of PS-induced GPR174 Gs signaling by the GPR174 inhibitory compound 10 (Group I) in a dose-responsive manner, with an apparent IC 50 of about 20-40 nM, as described in Example 16. FIGURE 47B graphically illustrates the inhibition of PS-induced GPR174 Gs signaling by the GPR174 inhibitory compound 6 (Group I) in a dose-responsive manner, with an apparent IC 50 of about 0.1 µM, as described in Example 16. FIGURE 47C graphically illustrates the inhibition of PS-induced GPR174 Gs signaling by the GPR174 inhibitory compound 11 (Group I) in a dose-responsive manner, with an apparent IC 50 of about 0.1 µM, as described in Example 16. FIGURE 47D graphically illustrates the inhibition of PS-induced GPR174 Gs signaling by the GPR174 inhibitory compound 20 (Group II) in a dose-responsive manner, with an apparent IC 50 of about 3.0 µM, as described in Example 16. FIGURE 47E graphically illustrates the inhibition of PS-induced GPR174 Gs signaling by the GPR174 inhibitory compound 30 (Group IV) in a dose-responsive manner, with an apparent IC 50 of about 1.3 µM, as described in Example 16. FIGURE 47F graphically illustrates the inhibition of PS-induced GPR174 Gs signaling by the GPR174 inhibitory compound 23 (Group IV) in a dose-responsive manner, with an apparent IC 50 of about 0.15 µM, as described in Example 16. FIGURE 48A graphically illustrates the ratio of post-addition to pre-read luminescence of GPR174 and GloSensor expressing HEK293 cells exposed to culture medium, or untreated (non-apoptotic) K562 cells, or apoptotic K562 cells (treated with H 2 O 2 for 20 hours), as described in Example 17. FIGURE 48B graphically illustrates the ratio of post-addition to pre-read luminescence of GPR174 and GloSensor expressing HEK293 cells exposed to culture medium, or freshly isolated neutrophils, or apoptotic neutrophils (treated with anti-Fas antibodies), as described in Example 17. FIGURE 48C graphically illustrates the ratio of post-addition to pre-read luminescence of GPR174 and GloSensor expressing HEK293 cells exposed to culture supernatant (Sup) or platelets (Pl), as described in Example 17. FIGURE 49A graphically illustrates the amount of IFN-γ (pg / mL) in culture supernatants 24 hours post-stimulation in human PBMC cultures from a single donor (donor 1) cultured in the presence of GPR174 inhibitory compound 10 (2 µM); A2aR inhibitory compound (SCH-58261, 0.2 µM, 0.6 µM or 2 µM); a combination of compound 10 (2 µM) plus 0.2 µM SCH-58261; a combination of compound 10 (2 µM) plus 0.6 µM SCH-58261 or a combination of compound 10 (2 µM) plus 2 µM SCH-58261; or vehicle control (DMSO), as described in Example 18. FIGURE 49B graphically illustrates the amount of IL-2 (pg / mL) in culture supernatants 24 hours post-stimulation in human PBMC cultures from a single donor (donor 1) cultured in the presence of GPR174 inhibitory compound 10 (2 µM); A2aR inhibitory compound (SCH-58261, 0.2 µM, 0.6 µM or 2 µM); a combination of compound 10 (2 µM) plus 0.2 µM SCH-58261; a combination of compound 10 (2 µM) plus 0.6 µM SCH-58261 or a combination of compound 10 (2 µM) plus 2 µM SCH-58261; or vehicle control (DMSO), as described in Example 18. FIGURE 49C graphically illustrates the amount of TNF (pg / mL) in culture supernatants 24 hours post-stimulation in human PBMC cultures from a single donor (donor 1) cultured in the presence of GPR174 inhibitory compound 10 (2 µM); A2aR inhibitory compound (SCH-58261, 0.2 µM, 0.6 µM or 2 µM); a combination of compound 10 (2 µM) plus 0.2 µM SCH-58261; a combination of compound 10 (2 µM) plus 0.6 µM SCH-58261 or a combination of compound 10 (2 µM) plus 2 µM SCH-58261; or vehicle control (DMSO), as described in Example 18. FIGURE 50A graphically illustrates the amount of IFN-γ (pg / mL) in culture supernatants 24 hours post-stimulation in human PBMC cultures from a single donor (donor 2) cultured in the presence of GPR174 inhibitory compound 10 (1 µM); A2aR inhibitory compound (ZM, 0.2 µM); A2aR inhibitory compound (PBF-509 0.1 µM), a combination of compound 10 (1 µM) plus 0.2 µM ZM; a combination of compound 10 (1 µM) plus 0.1 µM PBF-509; or vehicle control (DMSO), as described in Example 18. FIGURE 50B graphically illustrates the amount of IL-2 (pg / mL) in culture supernatants 24 hours post-stimulation in human PBMC cultures from a single donor (donor 2) cultured in the presence of GPR174 inhibitory compound 10 (1 µM); A2aR inhibitory compound (ZM, 0.2 µM); A2aR inhibitory compound (PBF-509 0.1 µM), a combination of compound 10 (1 µM) plus 0.2 µM ZM; a combination of compound 10 (1 µM) plus 0.1 µM PBF-509; or vehicle control (DMSO), as described in Example 18. FIGURE 50C graphically illustrates the amount of TNF (pg / mL) in culture supernatants 24 hours post-stimulation in human PBMC cultures from a single donor (donor 2) cultured in the presence of GPR174 inhibitory compound 10 (1 µM); A2aR inhibitory compound (ZM, 0.2 µM); A2aR inhibitory compound (PBF-509 0.1 µM), a combination of compound 10 (1 µM) plus 0.2 µM ZM; a combination of compound 10 (1 µM) plus 0.1 µM PBF-509; or vehicle control (DMSO), as described in Example 18. FIGURE 51A graphically illustrates the amount of IFN-γ (pg / mL) in culture supernatants 24 hours post-stimulation in human PBMC cultures from a single donor (donor 3) cultured in the presence of GPR174 inhibitory compound 10 (1 µM); A2aR inhibitory compound (ZM, 0.2 µM); A2aR inhibitory compound (PBF-509 0.2 µM), a combination of compound 10 (1 µM) plus 0.2 µM ZM; a combination of compound 10 (1 µM) plus 0.2 µM PBF-509; or vehicle control (DMSO), as described in Example 18. FIGURE 51B graphically illustrates the amount of IL-2 (pg / mL) in culture supernatants 24 hours post-stimulation in human PBMC cultures from a single donor (donor 3) cultured in the presence of GPR174 inhibitory compound 10 (1 µM); A2aR inhibitory compound (ZM, 0.2 µM); A2aR inhibitory compound (PBF-509 0.2 µM), a combination of compound 10 (1 µM) plus 0.2 µM ZM; a combination of compound 10 (1 µM) plus 0.2 µM PBF-509; or vehicle control (DMSO), as described in Example 18. FIGURE 51C graphically illustrates the amount of TNF (pg / mL) in culture supernatants 24 hours post-stimulation in human PBMC cultures from a single donor (donor 3) cultured in the presence of GPR174 inhibitory compound 10 (1 µM); A2aR inhibitory compound (ZM, 0.2 µM); A2aR inhibitory compound (PBF-509 0.2 µM), a combination of compound 10 (1 µM) plus 0.2 µM ZM; a combination of compound 10 (1 µM) plus 0.2 µM PBF-509; or vehicle control (DMSO), as described in Example 18. FIGURE 52A graphically illustrates the fold change from vehicle in the amount of IFN-γ in culture supernatants 24 hours post-stimulation in human PBMC cultures from 12 donors cultured in the presence of GPR174 inhibitory compound 10 (1-2 µM); A2aR inhibitory compound (ZM, 0.2-1 µM); a combination of compound 10 (1-2 µM) plus 0.2-1 µM ZM; or vehicle control (DMSO), as described in Example 19. FIGURE 52B graphically illustrates the fold change from vehicle in the amount of IL-2 in culture supernatants 24 hours post-stimulation in human PBMC cultures from 12 donors cultured in the presence of GPR174 inhibitory compound 10 (1-2 µM); A2aR inhibitory compound (ZM, 0.2-1 µM); a combination of compound 10 (1-2 µM) plus 0.2-1 µM ZM; or vehicle control (DMSO), as described in Example 19. FIGURE 52C graphically illustrates the fold change from vehicle in the amount of TNF in culture supernatants 24 hours post-stimulation in human PBMC cultures from 12 donors cultured in the presence of GPR174 inhibitory compound 10 (1-2 µM); A2aR inhibitory compound (ZM, 0.2-1 µM); a combination of compound 10 (1-2 µM) plus 0.2-1 µM ZM; or vehicle control (DMSO), as described in Example 19. FIGURE 52D graphically illustrates the fold change from vehicle in the amount of GM-CSF in culture supernatants 24 hours post-stimulation in human PBMC cultures from 12 donors cultured in the presence of GPR174 inhibitory compound 10 (1-2 µM); A2aR inhibitory compound (ZM, 0.2-1 µM); a combination of compound 10 (1-2 µM) plus 0.2-1 µM ZM; or vehicle control (DMSO), as described in Example 19. FIGURE 53A graphically illustrates the amount of IFN-γ (pg / mL) in culture supernatants 24 hours post-stimulation of human PBMC cultures from a single donor (donor 3) cultured in the presence of GPR174 inhibitory compound 10 (1 µM); ZM, 0.1 µM); PBF (0.1 µM), SCH (0.2 µM), MRS (1 µM), Adenosine deaminase (ADA, 0.75 µg / mL), alone or in combination with compound 10, or vehicle control, as described in Example 20. FIGURE 53B graphically illustrates the amount of IL-2 (pg / mL) in culture supernatants 24 hours post-stimulation of human PBMC cultures from a single donor (donor 3) cultured in the presence of GPR174 inhibitory compound 10 (1 µM); ZM, 0.1 µM); PBF (0.1 µM), SCH (0.2 µM), MRS (1 µM), Adenosine deaminase (ADA, 0.75 µg / mL), alone or in combination with compound 10, or vehicle control, as described in Example 20. FIGURE 53C graphically illustrates the amount of TNF (pg / mL) in culture supernatants 24 hours post-stimulation of human PBMC cultures from a single donor (donor 3) cultured in the presence of GPR174 inhibitory compound 10 (1 µM); ZM, 0.1 µM); PBF (0.1 µM), SCH (0.2 µM), MRS (1 µM), Adenosine deaminase (ADA, 0.75 µg / mL), alone or in combination with compound 10, or vehicle control, as described in Example 20. FIGURE 54A graphically illustrates the amount of IFN-γ (pg / mL) in culture supernatants 24 hours post-stimulation of human PBMC cultures from a single donor (donor 6) cultured in the presence of GPR174 inhibitory compound 10 (1 µM); ZM, 0.1 µM); PBF (0.1 µM), SCH (0.2 µM), MRS (1 µM), Adenosine deaminase (ADA, 0.75 µg / mL), alone or in combination with compound 10, or vehicle control, as described in Example 20. FIGURE 54B graphically illustrates the amount of IL-2 (pg / mL) in culture supernatants 24 hours post-stimulation of human PBMC cultures from a single donor (donor 6) cultured in the presence of GPR174 inhibitory compound 10 (1 µM); ZM, 0.1 µM); PBF (0.1 µM), SCH (0.2 µM), MRS (1 µM), Adenosine deaminase (ADA, 0.75 µg / mL), alone or in combination with compound 10, or vehicle control, as described in Example 20. FIGURE 54C graphically illustrates the amount of TNF (pg / mL) in culture supernatants 24 hours post-stimulation of human PBMC cultures from a single donor (donor 6) cultured in the presence of GPR174 inhibitory compound 10 (1 µM); ZM, 0.1 µM); PBF (0.1 µM), SCH (0.2 µM), MRS (1 µM), Adenosine deaminase (ADA, 0.75 µg / mL), alone or in combination with compound 10, or vehicle control, as described in Example 20. FIGURE 55A graphically illustrates the amount of IFN-γ (pg / mL) in supernatants 24 hours post-stimulation of human PBMC (donor 7) in the presence of GPR174 inhibitory compounds 6, 10, 11 or 20, each in the presence or absence of ZM, as described in Example 21. FIGURE 55B graphically illustrates the amount of IL-2 (pg / mL) in supernatants 24 hours post-stimulation of human PBMC (donor 7) in the presence of GPR174 inhibitory compounds 6, 10, 11 or 20, each in the presence or absence of ZM, as described in Example 21. FIGURE 55C graphically illustrates the amount of TNF (pg / mL) in supernatants 24 hours post-stimulation of human PBMC (donor 7) in the presence of GPR174 inhibitory compounds 6, 10, 11 or 20, each in the presence or absence of ZM, as described in Example 21. FIGURE 55D graphically illustrates the amount of GM-CSF (pg / mL) in supernatants 24 hours post-stimulation of human PBMC (donor 7) in the presence of GPR174 inhibitory compounds 6, 10, 11 or 20, each in the presence or absence of ZM, as described in Example 21. FIGURE 56A graphically illustrates the fold change from vehicle in the amount of IFN-γ in culture supernatants 24 hours post-stimulation in human PBMC cultures from 5 donors cultured in the presence of GPR174 inhibitory compound 10 (1 µM); A2aR inhibitory compound (ZM, 0.2 µM); A2bR inhibitory compound MRS (2 µM), or a combination of compound 10 (1 µM) plus 0.2 µM ZM plus 2 µM MRS, or vehicle control (DMSO), as described in Example 22. FIGURE 56B graphically illustrates the fold change from vehicle in the amount of IL-2 in culture supernatants 24 hours post-stimulation in human PBMC cultures from 5 donors cultured in the presence of GPR174 inhibitory compound 10 (1 µM); A2aR inhibitory compound (ZM, 0.2 µM); A2bR inhibitory compound MRS (2 µM), or a combination of compound 10 (1 µM) plus 0.2 µM ZM plus 2 µM MRS, or vehicle control (DMSO), as described in Example 22. FIGURE 56C graphically illustrates the fold change from vehicle in the amount of TNF in culture supernatants 24 hours post-stimulation in human PBMC cultures from 5 donors cultured in the presence of GPR174 inhibitory compound 10 (1 µM); A2aR inhibitory compound (ZM, 0.2 µM); A2bR inhibitory compound MRS (2 µM), or a combination of compound 10 (1 µM) plus 0.2 µM ZM plus 2 µM MRS, or vehicle control (DMSO), as described in Example 22. FIGURE 57 graphically illustrates the fold reduction in AREG+ cells in the presence of vehicle; GPR174 inhibitory compound 10 (1 µM); ZM-241385 (0.2 µM); or the combination of compound 10 (1 µM) and ZM (0.2 µM), as described in Example 23. FIGURE 58 is a schematic diagram illustrating how both GPR174 and Adenosine receptors respond to products of cell stress and death, as described in Example 23. FIGURE 59A graphically illustrates the growth of CT26 tumors in individual wild-type (WT) mice inoculated with CT26.cl25 murine colon carcinoma cells on day 0 and treated with anti-GITR antibody on day 7 and 9, as described in Example 24; FIGURE 59B graphically illustrates the growth of CT26 tumors in individual GPR174-KO mice inoculated with CT26.cl25 murine colon carcinoma cells on day 0 and treated with anti-GITR antibody on day 7 and 9; as described in Example 24; FIGURE 60 graphically illustrates the percent survival of tumor-bearing WT and GPR174-KO mice inoculated with CT26.cl25 murine colon carcinoma cells on day 0 and treated with anti-GITR antibody on day 7 and 9, demonstrating that GPR174-KO mice had a higher percent survival (i.e., were euthanized significantly later) than WT mice (p = 0.03, log-rank test), as described in Example 24; FIGURE 61A graphically illustrates the growth of CT26 tumors in individual WT mice inoculated with CT26.cl25 murine colon carcinoma cells on day 0 and treated with anti-GITR antibody on day 7, 9, and 14, as described in Example 24; FIGURE 61B graphically illustrates the growth of tumors in individual GPR174-KO mice inoculated with CT26.cl25 murine colon carcinoma cells on day 0 and treated with anti-GITR antibody on day 7, 9, and 14; as described in Example 24; FIGURE 62 graphically illustrates the percent survival of tumor-bearing WT and GPR174-KO mice inoculated with CT26.cl25 murine colon carcinoma cells on day 0 and treated with anti-GITR antibody on days 7, 9 and 14, demonstrating that GPR174-KO mice had a higher percent survival (i.e., were euthanized significantly later) than WT mice, as described in Example 24; FIGURE 63A graphically illustrates the growth of B16F10-Kb melanoma tumors in individual WT mice inoculated with B16F10-Kb cells on day 0 and treated with anti-GITR antibody on day 4 and 14, as described in Example 25; FIGURE 63B graphically illustrates the growth of B16F10-Kb melanoma tumors in individual GPR174-KO mice inoculated with B16F 10-Kb cells on day 0 and treated with anti-GITR antibody on day 4 and 14, as described in Example 25; FIGURE 63C graphically illustrates the average tumor volume of B16F10-Kb melanoma tumors in WT and GPR174-KO mice inoculated with B16F10-Kb cells on day 0 and treated with anti-GITR antibody on day 4 and 14, demonstrating that average tumor sizes were significantly smaller in GPR174 KO mice on days 14 (wherein "*" indicates p=0.01) and 16 (wherein "***" indicates: p=0.00005), as described in Example 25; FIGURE 64 graphically illustrates the percent survival of B16F10-Kb melanoma tumor-bearing WT and GPR174-KO mice inoculated with B16F10-Bb cells on day 0 and treated with anti-GITR antibody on day 4 and 14, demonstrating that GPR174-KO mice had a higher percent survival (i.e., were euthanized significantly later) than WT mice (p = 0.006, log-rank test), as described in Example 25; FIGURE 65 graphically illustrates IL-2 concentrations in cultures of stimulated human T cells in the presence or absence of PS liposomes (PSL) or a GPR174 inhibitor (compound 10, 3 µM), as described in Example 26; FIGURE 66A graphically illustrates the concentration of IL-2 in cultures of stimulated human T cells in the presence or absence of PS liposomes, tumor exosomes, or a GPR174 inhibitory compound (compound 10, 0.5 µM), as described in Example 26; FIGURE 66B graphically illustrates the concentration of IFN-γ in cultures of stimulated human T cells in the presence or absence of PS liposomes, tumor exosomes, or a GPR174 inhibitory compound (compound 10, 0.5 µM), as described in Example 26; FIGURE 66C graphically illustrates the concentration of TNF in cultures of stimulated human T cells in the presence or absence of PS liposomes, tumor exosomes, or a GPR174 inhibitory compound (compound 10, 0.5 µM), as described in Example 26; FIGURE 67 graphically illustrates the IL-2 levels (fold-change from vehicle) in cultures of stimulated WT or GPR174-KO mouse T cells in the presence or absence of PS liposomes (PSL) or a GPR174 inhibitor (compound 10, 1 µM), as described in Example 26; FIGURE 68A graphically illustrates the effects of A2a / A2b adenosine receptor antagonist ZM-241385 (0.1 µM), GPR174 inhibitory Compound 10 (1 µM), or both compounds (ZN-241385 plus compound 10) on IL-2 levels in supernatants of cultured splenocytes isolated from n=3 WT mice following 2 days of stimulation with anti-CD3 and anti-CD28 antibodies, as described in Example 27; FIGURE 68B graphically illustrates the effects of A2a / A2b adenosine receptor antagonist ZM-241385 (0.1 µM), GPR174 inhibitory Compound 10 (1 µM), or both compounds (ZN-241385 plus compound 10) on IL-2 levels in supernatants of cultured splenocytes isolated from n=3 GPR174-KO mice following 2 days of stimulation with anti-CD3 and anti-CD28 antibodies, as described in Example 27; FIGURE 69 graphically illustrates the effects of A2a / A2b adenosine receptor antagonist ZM-241385 (0.2 µM), GPR174 inhibitory compound 10 (0.3 µM) or GPR174 inhibitory compound 6 (0.3 µM), or ZM-241385 plus compound 10 or ZM-241385 plus compound 6 on IL-2 levels in supernatants of cultured splenocytes isolated from 3 WT mice following 2 days of stimulation with anti-CD3 and anti-CD28 antibodies in the presence of the adenosine receptor agonist NECA (0.1 µM), as described in Example 27; FIGURE 70A graphically illustrates the effects of A2a / A2b adenosine receptor antagonist ZM-241385 (0.2 µM), GPR174 inhibitory compounds 10 (0.3 µM) or compound 6 (0.3 µM), or ZM-241385 alone or combined with either GPR174 inhibitory compound on IL-2 levels in supernatants of cultured splenocytes isolated from 3 WT mice following 2 days of stimulation with anti-CD3 and anti-CD28 antibodies in the presence of the adenosine receptor agonist NECA (0.1 µM), as described in Example 27; FIGURE 70B graphically illustrates the effects of A2a / A2b adenosine receptor antagonist ZM-241385 (0.2 µM), GPR174 inhibitory compounds 10 (0.3 µM) or compound 6 (0.3 µM), or ZM-241385 alone or combined with either GPR174 inhibitory compound on IL-2 levels in supernatants of cultured splenocytes isolated from 3 GPR174-KO mice following 2 days of stimulation with anti-CD3 and anti-CD28 antibodies in the presence of the adenosine receptor agonist NECA (0.1 µM), as described in Example 27; FIGURE 71 graphically illustrates the levels of IL-2 in supernatants of human PBMC stimulated with anti-CD3 and anti-CD28 in the presence or absence of GPR174 inhibitory compound 10 (1µM); A2aR / A2bR inhibitory compound ZM-241385 (0.1 µM), or CD73 inhibitory compound APCP (10 µM) collected at 24 hours post-stimulation, as described in Example 28; FIGURE 72A graphically illustrates the concentration of IL-2 in purified human T cells stimulated with CD3 / CD28 activator in the presence of PS liposomes (PS, 1µM), adenosine receptor agonist NECA (0.1 µM), or a combination of PS (1µM) plus NECA (0.1 µM), as compared to media only, as described in Example 29; FIGURE 72B graphically illustrates the concentration of IFN-γ (FIG 72B) in purified human T cells stimulated with CD3 / CD28 activator in the presence of PS liposomes (PS, 1µM), adenosine receptor agonist NECA (0.1 µM), or a combination of PS (1µM) plus NECA (0.1 µM), as compared to media only, as described in Example 29; and FIGURE 72C graphically illustrates the concentration of IFN-γ (FIG 72C) in purified human T cells stimulated with CD3 / C28 activator in the presence of PS liposomes (PS, 1µM), adenosine receptor agonist NECA (0.05 µM), or a combination of PS (1 µM) plus NECA (0.05 µM), as compared to media only, as described in Example 29. DETAILED DESCRIPTION

[0307] As set forth in detail below, the present inventors have identified compounds that functionally interact with GPR174 and are capable of inhibiting one or more GPR174-mediated signaling pathways. We have further characterized the signaling pathways activated by GPR174 and have determined a signaling profile for this receptor that includes the Gs signaling pathway. The inventors have further determined that the combined inhibition of GPR174 and inhibition of the Adenosine 2a Receptor (A2aR) and / or Adenosine 2b Receptor (A2bR), or a combination of a GPR174 inhibitory and an inhibitor of ATP hydrolysis into adenosine by CD38, CD39 and CD73 (such as a CD73 inhibitor and / or a a CD38 inhibitor and / or a CD39 inhibitor) and / or a Treg attenuating agent results in synergistic induction of IFN-γ, IL-2, TNF and GM-CSF production in human PBMCs. The inventors have further discovered that phosphatidylserine (PS) is an agonist for GPR174-mediated Gs signaling and have demonstrated that PS signaling through GPR174 is inhibited by multiple GPR174 inhibitory small molecule compounds with diverse chemical structures. As further demonstrated herein, GPR174-deficiency enhances anti-tumor immune responses in mice.

[0308] Based on these discoveries, the present disclosure relates to in vivo and in vitro methods of inhibiting the GPR174-mediated signaling pathways, either alone, or in combination with the inhibition of ATP-Adenosine-A2aR and / or A2bR- mediated signaling (such as an A2aR antagonist and / or an A2bR antagonist), or a combination of an inhibitor of GPR174-mediated signaling and an inhibitor of ATP hydrolysis into adenosine by CD38, CD39 and CD73 (such as a CD73 inhibitor or a CD38 inhibitor or a CD39 inhibitor) and / or a Treg attenuating agent, and thereby stimulating an immune response in a mammalian subject, particularly in subjects suffering from conditions such as cancer as described herein.Definitions

[0309] The term "G-protein coupled receptor" or "GPCR," or "GPR" refers to a transmembrane receptor that is capable of transmitting a signal from the outside of a cell to the inside of a cell through a G-protein pathway and / or an arrestin pathway. Hundreds of such receptors are known in the art; see, e.g., Fredriksson et al., Mol. Pharmacol. 63:1256-1272, 2003, and Vassilatis, D.K., Proc Natl Acad Sci USA 100: 4903-4908 (2003). These references have characterized the human and mouse GPCRs based on sequence homology and function. Human GPCRs can be broken down into five classes: secretin, rhodopsin, glutamate, frizzled / Tas2, and adhesion. Alternatively, receptors may be classified by their ligands, e.g., peptide hormones or small molecules (e.g., biogenic amines). Other classification schemes include the A-F classification, where class A represents receptors related to rhodopsin and the adrenergic receptors, class B, receptors related to the calcitonin and parathyroid hormone receptors, class C, receptors related to the metabotropic receptors, and classes D-F represent receptors found in fungi and archaebacteria.

[0310] The terms "G-protein coupled receptor 174," "GPR174," "FKSG79, or "GPCR17" refer to any naturally occurring forms of the GPR174 protein, e.g., SEQ ID NO:1 shown in Figure 1, or naturally occurring variants thereof, such as variants having at least 90% identity (such as at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity) to SEQ ID NO: 1. Preferable forms of GPR174 have the ability to signal through at least one G-protein coupled receptor pathway such as Gs.

[0311] The term "G-protein" refers to a heterotrimeric protein complex that transmits a signal from an activated GPCR to effector molecule(s) inside the cell such as enzymes and ion channels. G-proteins are made up of Gα, Gβ, and Gγ subunits. Families of Gα subunits include Gq, Gi, Gs, and Gα12 / 13. G-protein signaling pathways are named for the activated Gα subunit, i.e., Gαs, Gαi, Gαq, and Gα12 / 13. A heterotrimeric G-protein binds to an activated GPCR protein, that is, a GPCR protein that is bound to a ligand or surrogate ligand. When bound to a GPCR protein, the Gα subunit exchanges bound guanosine diphosphate (GDP) for guanosine-5'-triphosphate (GTP) and dissociates from the Gβ and Gγ subunits, which are typically associated in a heterodimeric complex. Once dissociated, both the Gα-GTP-bound protein and the Gβγ complex can activate signaling pathways. The Gq family includes Gαq, Gα11, Gα14, and Gα15 / 16. The Gi family includes Gαi1-3, Gαo, Gαt, Gαgust, and Gαz. The Gs family includes Gαs and Gαolf. The G12 / 13 includes Gα12 and Gα13.

[0312] The term "signaling pathway" refers to an intracellular response to a signal. For the purposes of this disclosure, a G-protein signaling pathway refers to an intracellular response that occurs after binding of a ligand, surrogate ligand, or any other functional activator or functional inactivator to a G-protein coupled receptor, e.g., GPR174, and activates a G-protein coupled pathway. G-protein signaling pathways include the Gq, Gi, Gs, G12 / 13 and βγ pathways. An arrestin signaling pathway refers to an intracellular response that occurs after binding of a ligand, surrogate ligand, or any other functional activator or functional inactivator to a G-protein coupled receptor, e.g., GPR174, and activation of an arrestin-mediated signaling pathway, such as arrestin 1, arrestin 2, arrestin 3, and arrestin 4 signaling pathways.

[0313] A "Gq signaling pathway" or "Gαq signaling pathway" refers to an intracellular signaling pathway that is activated by an activated Gq alpha protein. The Gαq protein is activated by exchanging GDP for GTP after binding to an activated GPCR protein. Activation of a Gq signaling pathway typically activates phospholipase C β isoforms (PLCβ), which hydrolyze phosphatidylinositol to generate diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP 3 ). IP 3 is soluble and diffuses through the cytoplasm and interacts with IP 3 receptors on the endoplasmic reticulum, causing the release of calcium and raising the level of intracellular calcium. DAG remains tethered to the inner leaflet of the plasma membrane due to its hydrophobic character, where it recruits protein kinase C (PKC), which becomes activated in conjunction with binding calcium ions. PKC then phosphorylates other proteins to control their function. Downstream effects can also be detected, e.g., expression of a reporter gene regulated by an appropriate transcription factor.

[0314] A "Gi signaling pathway" or "Gαi signaling pathway" refers to an intracellular signaling pathway that is activated by an activated Gi alpha protein. The Gαi protein is activated after binding to an activated GPCR protein. Gαi1-3, Gαo, and Gαz inhibit the activity of adenylyl cyclases (AC). The sensory Gi protein, Gαt, activates the cyclic guanosine monophosphate (cGMP)-dependent phosphodiesterase, causing a decrease in intracellular cGMP and Gαgust activates phospholipase C (PLC). All G i family members, except for Gαz, are sensitive to inhibition by pertussis toxin via adenosine diphosphate (ADP) ribosylation of their α subunit (Siehler, Biotechnology 3:471-83, 2008).

[0315] A "Gs signaling pathway" or "Gαs signaling pathway" refers to an intracellular signaling pathway that is activated by an activated Gs alpha protein. The Gαs protein is activated after binding to an activated GPCR protein. The Gs family of G proteins (Gαs and Gαolf) activates AC, which generates the second messenger 3',5'-cyclic adenosine monophosphate (cAMP).

[0316] A "G12 / 13 signaling pathway" or "Gα12 / 13 signaling pathway" refers to an intracellular signaling pathway that is activated by an activated G12 / 13 alpha protein. The Gα12 / 13 protein is activated after binding to a GPCR protein. The G12 / 13 family of G proteins (Gα12 and Gα13) activates Rho guanine exchange factor (Rho-GEF) proteins. Rho-GEF proteins catalyze the exchange of GDP for GTP to activate RhoA. RhoA, in turn, activates Rho kinase, which further leads to the activation of Activating Transcription Factor 2 (ATF2) and results in cellular responses (Liu et al., Methods Mol. Biol. 237:145-9, 2004).

[0317] A "βγ signaling pathway" refers to an intracellular pathway that is activated by a free (i.e., unbound to Gα protein) βγ complex. βγ complexes can, for example, activate phospholipase A2, direct opening of G-protein coupled inward rectifying potassium channels (GIRKs) when bound to muscarinic acetylcholine receptors, activate L-type calcium channels, and initiate the phospholipase C pathway by activating PLC.

[0318] An "arrestin signaling pathway" refers to an intracellular signaling pathway that is activated by arrestin 1, arrestin 2, arrestin 3, or arrestin 4. The arrestins have been implicated in signaling through ERK, JNK, p38, Akt, PI3 kinase, and RhoA (DeWire et al., Annu. Rev. Physiol. 69:483-510, 2007).

[0319] The term "contacting" is used herein interchangeably with the following: combined with, added to, mixed with, introducing to, passed over, incubated with, flowed over, etc. For purposes of clarity, the phrase "contacting a cell" includes introducing a compound into a mammal (e.g., orally, into the plasma, or intramuscularly) such that the compound contacts the cells of the mammal in vivo.

[0320] By the term "GPR174-mediated signaling pathway" is meant a signaling pathway the activity of which is modulated at least in part through GPR174.

[0321] As used herein, the phrase "modulates at least one GPR174-mediated signaling pathway" refers to modulating (activating or inhibiting) at least the Gs signaling pathway that is functional in a cell expressing GPR174 by contacting the cell with a compound that functionally interacts with GPR174.

[0322] A "modulator" is a compound that functionally interacts with a GPCR and affects the GPCR-mediated signaling activity either by itself or by altering the ability of another compound to affect the GPCR-mediated signaling activity. Modulators include activators and inhibitors of the GPCR-mediated signaling pathway.

[0323] An "activator" is a compound that increases GPCR-mediated signaling in a signaling pathway. Activators can activate a receptor directly (e.g., an agonist) or can increase activation of a receptor by another compound (e.g., a positive allosteric modulator). Activators can bind to and increase receptor activity, increase, open, activate, facilitate, enhance activation, sensitize, agonize, drive the conformation of the receptor to the active state, or up-regulate receptor-protein activity. Activators include agonists, partial agonists, and positive allosteric modulators.

[0324] An "agonist," which may be a full agonist or a partial agonist, binds to a GPCR, activates the receptor, and initiates a response, typically through activation of a G-protein. An agonist increases receptor activity as compared to the normal baseline level. A compound is deemed to be a receptor agonist if it increases GPCR-mediated signaling pathway activity by at least 20% over an appropriate control (e.g., background or basal activity) at a concentration of up to 50 µM. A full agonist is always an activator. A partial agonist has a lower intrinsic activity than a full agonist but increases receptor activity as compared to basal activity. A partial agonist may act as a functional inhibitor when in the presence of a full agonist.

[0325] A "positive allosteric modulator" or "PAM" is a compound that binds to the GPCR at a site distinct from the ligand-binding site and increases GPCR-mediated signaling activity in response to agonists.

[0326] An "inhibitor" is a compound that decreases GPCR-mediated signaling in a signaling pathway. Inhibitors are compounds that functionally interact with a GPCR and partially or totally block activity, decrease, prevent, delay activation, inactivate, antagonize, desensitize, drive the conformation of the receptor to the inactive conformation, block the ability of another compound (e.g., an endogenous agonist ligand) to interact with the receptor, or otherwise down-regulate the activity of the receptor. Inhibitors can reduce basal activity of the receptor (e.g., an inverse agonist) or can block or reduce activity of another compound (e.g., a partial agonist or antagonist). Inhibitors include antagonists, inverse agonists, partial agonists, partial inverse agonists, and negative allosteric modulators. Inhibitors do not include compounds that act solely by decreasing expression of the receptor nucleic acid or protein.

[0327] An "antagonist" is an inhibitor that binds to a GPCR, usually at the same site as a ligand or an agonist. On its own, an antagonist does not activate or inhibit signaling activity via the receptor and does not change receptor activity from basal levels. However, an antagonist is able to inhibit or block activation of a receptor in the presence of an agonist or a ligand or inhibit or block inhibition of a receptor in the presence of an inverse agonist. A compound is deemed to be a receptor antagonist or allosteric modulator if, at a concentration of up to 50 µM, it has activity in a CRA assay, and it increases GPCR-receptor mediated signaling pathway activity by less than a 20% increase over an appropriate control (e.g., background or basal), or decreases GPCR-mediated signaling pathway activity by less than 10% inhibition in comparison to an appropriate control (e.g., background or basal). Additionally, a compound that inhibits the effect of an agonist or inverse agonist can be considered an antagonist.

[0328] An "inverse agonist," which may be a full inverse agonist or a partial inverse agonist, is an inhibitor that binds to a receptor and reduces the basal signaling of the GPCR-mediated signaling pathway. A compound is deemed to be an inverse agonist if, at a concentration of up to 50 µM, it reduces the basal signaling of a GPCR-mediated signaling pathway by at least 10%. A partial inverse agonist has less intrinsic inhibitory activity than a full inverse agonist.

[0329] A "negative allosteric modulator" is a compound that binds to a receptor at a site distinct from the ligand binding site and decreases GPCR-mediated signaling activity in response to agonists.

[0330] A "partial agonist" can be a functional activator or a functional inhibitor, depending on the presence or absence of a full agonist in a given biological environment. Partial agonists bind the receptor and increase receptor activity as compared to the basal level of activity but have only partial efficacy relative to a full agonist. For example, in the presence of a full agonist, a partial agonist can decrease receptor activation, thereby acting as a functional inhibitor. In the absence of a full agonist, the partial agonist can increase receptor activation, thereby acting as a functional activator.

[0331] A "partial inverse agonist" can be a functional activator or a functional inhibitor, depending on the presence or absence of a full inverse agonist in a given biological environment. Partial inverse agonists bind the receptor and decrease receptor activity as compared to the basal level of activity but have only partial efficacy relative to a full inverse agonist. For example, in the presence of a full inverse agonist, a partial inverse agonist can increase receptor activation, thereby acting as a functional activator. In the absence of a full inverse agonist, the partial inverse agonist can decrease receptor activation, thereby acting as a functional inhibitor.

[0332] As used herein, the term "basal level of activity" or "basal signaling activity," or baseline activity" refers to the level of GPCR-mediated signaling activity in the absence of a modulator compound. In one case, a basal level of GPR174-mediated signaling pathway activity is established with reference to a specific cell line wherein the cell line is known to have functional GPR174 activity or defective GPR174 activity. In another case, a basal level of GPR174-mediated signaling pathway activity is established with reference to a cell over-expressing GPR174 (e.g., as described in Examples 2, 3, and 4 herein). In some cases, a basal level of GPR174-mediated signaling pathway activity is established with reference to a cell known to interact with an endogenous ligand, or known to contain an endogenous GPR174 ligand, or with reference to a cell known to not contain an endogenous GPR174-ligand, assuming such an endogenous GPR174 ligand is later identified.

[0333] A "ligand" is a compound that binds to a receptor and modulates the activity of the receptor.

[0334] An "endogenous ligand" is an endogenous entity (e.g., molecule, peptide, or ion) that modulates a receptor in a cell, tissue, or organism of origin.

[0335] A "surrogate ligand" is a non-endogenous molecule that binds to and modulates the activity of a receptor. A surrogate ligand may be naturally occurring or may be synthetic. A surrogate ligand can activate or inhibit activity of a receptor. In one case, a surrogate ligand is a small molecule. In a further case, a surrogate ligand is a small organic molecule.

[0336] A "biased ligand" is a compound that binds to a GPCR and selectively modulates (more than 2-fold) the activity of one of the GPCR-mediated signaling pathways (e.g., Gq, Gi, Gs, G12 / 13, βγor an arrestin signaling pathway) as compared to other GPCR-mediated signaling pathway(s).

[0337] As used herein, the term "apparent binding affinity" refers to the observed change in binding affinity of a compound for GPR174 in the presence of an additional compound that binds GPR174 compared to the binding affinity observed for the compound for GPR174 without the presence of the additional compound. In some cases, the compound and the additional compound compete for binding at the same site on GPR174. Although the binding affinities of each compound for GPR174 do not change, determining the binding affinity of one compound for GPR174 in the presence of an additional compound that binds GPR174 may result in the measured binding affinity of the compound for GPR174 to decrease. In some cases, the two compounds do not bind at the same site, and the allosteric binding of one compound to GPR174 may result in the binding affinity for GPR174 of the other compound to decrease or increase. This may be due to conformational changes in GPR174 caused by the binding of one of the compounds to GPR174 that affect the binding site of the other compound.

[0338] A compound is "specific for" GPR174 if it is capable of modulating (e.g., inhibiting) GPR174 activity but does not have similar activity at other proteins such as other G-protein coupled receptors, e.g., as compared to a reference panel of proteins (e.g., including GPCRs other than GPR174, and, optionally, also including ion channels and / or other types of transporters). In one example, the reference panel includes the following receptors: muscarinic M1, CCRL2, CMKOR1, GPR3, GPR4, GPR12, GPR17, GPR18, GPR19, GPR20, GPR21, GPR22, GPR25, GPR26, GPR27, GPR31, GPR32, GPR34, GPR37, GPR37L1, GPR39, GPR43, GPR45, GPR48, GPR50, GPR52, GPR61, GPR62, GPR63, GPR65, GPR68, GPR78, GPR80, GPR83, GPR85, GPR87, GPR88, GPR101, GPR132, GPR135, GPR139, GPR141, GPR146, GPR148, GPR149, GPR150, GPR151, GPR152, GPR153, GPR160, GPR161, GPR162, GPR173, GPR182, GPR183, LGR5, LGR6, MAS1, MRGD, MRGE, MRGF, MRGI4, OPN3, OPN4, OPN5, P2Y8, P2Y10, TAAR6, and TAAR8.

[0339] In another example, the reference panel includes the following receptors: human adenosine A1; human adenosine A2A; rat adrenergic α1A; rat adrenergic α1B; human adrenergic α2A; human adrenergic β1; human adrenergic β2; rat calcium channel L-type dihydropyridine; human dopamine D1; human dopamine D2; and human G protein-coupled receptor, GPR103. In another example, the reference panel includes the following receptors: rat GABA A; rat glutamate NMDA; human histamine H 1 ; human muscarinic M 2 ; human nicotinic acetylcholine α 1 ; human opiate µ (OP3, MOP); human potassium channel [K ATP ]; human potassium channel hERG; human sigma σ 1 ; rat sigma σ 2 ; rat sodium channel, site 2; and human transporter, norepinephrine.

[0340] In certain cases, a compound that is specific for GPR174 has 2-, 5-, 10-, 25-, 50-, 100-, 500-, 1000-, 5000-, or 10,000-fold greater activity at inhibiting GPR174 activity as compared to other G-protein coupled receptors, e.g., the other GPCRs in one or more of the reference panels described above.

[0341] In certain cases, a compound that is specific for GPR174 has 2-, 5-, 10-, 25-, 50-, 100-, 500-, 1000-, 5000-, or 10,000-fold greater activity in a Gs signaling assay that is carried out in in a cell expressing GPR174 as compared to the Gs signaling activity in a cell expressing other GPCRs, e.g. the other GPCRs in each of the reference panels described above.

[0342] An "agency-approved compound" refers to a compound that was approved for clinical use for human or veterinary purposes prior to November 4, 2016 by the United States Food and Drug Administration (FDA) or similar governmental regulatory agency (e.g., European Medicines Agency (EMA), Health Canada, Japanese Ministry of Health and Welfare).

[0343] A compound that is "not approved for use in a disease associated with GPR174" refers to a compound that has not been approved prior to November 4, 2016 for therapeutic use by the FDA or similar governmental regulator agency (e.g., EMA, Health Canada, and Japanese Ministry of Health and Welfare) for an indication that is associated with GPR174 activity (e.g., any of those described herein, such as cancer or a nervous system disease or disorder).

[0344] By a compound that "is not approved as targeting GPR174" is meant a compound that is not indicated in the pharmacology data submitted to the US FDA or similar governmental regulatory agency (e.g., EMA, Health Canada, and Japanese Ministry of Health and Welfare) as targeting GPR174 prior to November 4, 2016. An indication of such targeting is often found in the label of the approved drug.

[0345] The term "compound" or grammatical equivalents as used herein refers to molecules, either naturally occurring or synthetic, e.g., protein; antibody, oligopeptide (e.g., from about 5 to about 25 amino acids in length, such as from about 10 to 20 or 12 to 18 amino acids in length, for example, 12, 15, or 18 amino acids in length); nucleotides (e.g., inhibitory RNA) that inhibits GPR174 expression, small molecule chemical compound, e.g., small organic, organometallic, or inorganic molecule; polysaccharide; oligonucleotides; lipid; and fatty acid. The compound can be included in a library of compounds, such as a combinatorial, synthetic, natural, heterocyclic, drug-like, lead-like, organic, inorganic, unrandomized, or randomized library that provides a sufficient range of diversity or it may be a focused or targeted collection of the above compounds. Compounds are optionally linked to a fusion partner, e.g., targeting compounds, rescue compounds, dimerization compounds, stabilizing compounds, addressable compounds, and other functional moieties. Conventionally, new chemical entities with useful properties are generated by identifying a compound (called a "lead compound") having some desirable property or activity, e.g., inhibitory activity, creating variants of the lead compound, and evaluating the property and activity of those variant compounds. Often, high-throughput screening ("HTS") methods are employed for such an analysis.

[0346] The terms "small molecule," "small organic molecule," and "small inorganic molecule" refer to molecules (either organic, organometallic, or inorganic), organic molecules, and inorganic molecules, respectively, which are either naturally occurring or synthetic and that have a molecular weight of more than about 50 Da and less than about 2500 Da. Small organic (for example) molecules may be less than about 2000 Da, between about 100 Da to about 1000 Da, or between about 100 to about 600 Da, or between about 200 to 500 Da.

[0347] The term "a compound predetermined to functionally interact with GPR174" is a compound that has been determined, prior to contacting a cell expressing GPR174 or administering the compound to the subject, to modulate a GPR174-mediated signaling pathway by functionally interacting with GPR174. This predetermination may be made by either (i) directly acquiring knowledge that the compound functionally interacts with GPR174 by physically demonstrating that the compound functionally interacts with GPR174 by performing an assay measuring functional interaction with GPR174, or by performing an assay measuring GPR174-mediated signaling activity, or (ii) by indirectly acquiring knowledge that the compound functionally interacts with GPR174 by receiving or obtaining such knowledge or information regarding the results from others physically demonstrating such interaction using an assay measuring functional interaction of the compound with GPR174 or measuring GPR174-mediated signaling activity from another party or source (e.g., knowledge or information regarding the results from research carried out by others physically demonstrating such interaction using an assay measuring functional interaction of the compound with GPR174 or measuring GPR174-mediated signaling activity, obtained, for example, from publication in a scientific journal, or in a published patent application, or by reading prescribing information, or obtained through private channels (e.g., personal communication), in each case prior to contacting with the compound a cell expressing GPR174 or administering the compound to the subject. In one case, the compound is predetermined to functionally interact with human GPR174 by directly or indirectly acquiring knowledge that the compound functionally interacts with human GPR174 set forth as SEQ ID NO: 1, or a naturally occurring variant of GPR174 having at least 95% identity to SEQ ID NO: 1.

[0348] By "therapeutically effective amount" is meant an amount that produces a desired effect for which it is administered, e.g., improvement or delay of at least one symptom associated with the disease or condition being treated. The exact dose will depend on the purpose of the treatment and can be ascertained by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); and Pickar, Dosage Calculations (1999)).

[0349] By "substantially pure" or "isolated" is meant a compound (e.g., a polypeptide or conjugate) that has been separated from other chemical components. Typically, the compound is substantially pure when it is at least 30%, by weight, free from other components. In certain cases, the preparation is at least 50%, 60%, 75%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% by weight, free from other components. A purified polypeptide may be obtained, for example, by expression of a recombinant polynucleotide encoding such a polypeptide or by chemically synthesizing the polypeptide. Purity can be measured by any appropriate method, for example, column chromatography, polyacrylamide gel electrophoresis, or by HPLC analysis.

[0350] In the context of a naturally occurring compound, the term "isolated" is one which is altered or removed from the natural state (e.g., through human intervention).

[0351] The term "mammal" includes all mammals, including without limitation humans, non-human primates, dogs, cats, horses, sheep, goats, cows, rabbits, pigs, and rodents.

[0352] As used herein, and as well understood in the art, "to treat" a disease, disorder, or condition, "treatment" of the disease, disorder, or condition (e.g., the conditions described herein, such as inflammatory conditions), or "therapy" is an approach for obtaining beneficial or desired results, such as clinical results, and can be performed either for prophylaxis or during the course of clinical pathology. Beneficial or desired results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; diminishment of extent of the disease, disorder, or condition; reduced likelihood of developing the disease, disorder, or condition; stabilized (i.e., not worsening) state of disease, disorder, or condition; preventing the development of or spread of the disease, disorder, or condition; delay or slowing the progress of the disease, disorder, or condition; amelioration or palliation of the disease, disorder, or condition; and remission (whether partial or total), whether detectable or undetectable. "Palliating" a disease, disorder, or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder, or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment.

[0353] As used herein, the terms "subject" or "patient" refer to any organism to which a compound or composition in accordance with the disclosure may be administered, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. A subject to be treated with a compound or composition described here may be one who has been diagnosed by a medical practitioner as having a disease, disorder, or condition, described herein, or one at risk for developing the disease, disorder, or condition described herein. Diagnosis may be performed by any technique or method known in the art. One skilled in the art will understand that a subject may have been diagnosed as having the disease, disorder, or condition, using a standard test or examination or may have been identified, without examination, as one at high risk due to the presence of one or more risk factors. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans).

[0354] As used herein, the term "neoplasm" refers to any new and abnormal growth of cells, specifically one in which cell multiplication is uncontrolled and progressive. Neoplasms may be non-malignant (i.e. benign) or malignant.

[0355] As used herein, the term "tumors" means neoplasms, including solid and liquid (i.e., blood) neoplasms, and benign and malignant neoplasms, including primary and / or metastatic neoplasms.

[0356] The term "alkanoyl," as used herein, refers to a group having the structure - C(O)-R, in which R is alkyl. Alkanoyl may be unsubstituted or substituted (e.g., optionally substituted alkanoyl) as described for alkyl. The suffix "oyl" may be used to define other groups having the structure -C(O)-R. For example, in alkenoyl group, R is alkenyl; in alknynoyl group, R is alkynyl; in cycloalkanoyl group, R is cycloalkyl; in cycloalkenoyl group, R is cycloalkenyl; and in cycloalkynoyl group, R is cycloalkynyl (all groups are as defined herein). Further, the groups defined with a suffix "oyl" may be further used to define groups having the structure -O-C(O)-R' by adding the suffix "oxy," e.g., when R' is alkyl, this group is "alkanoyloxy." For example, in alkenoyloxy group, R' is alkenyl; in alknynoyloxy group, R' is alkynyl; in cycloalkanoyloxy group, R' is cycloalkanyl; in cycloalkenoyloxy group, R' is cycloalkenyl; and in cycloalkynoyloxy group, R' is cycloalkynyl (all groups are as defined herein). Each of these groups may be unsubstituted or substituted (e.g., optionally substituted) as described for each respective group.

[0357] The term "alkenyl," as used herein, refers to a straight-chain or branched-chain monovalent substituent including one or two carbon-carbon double bonds and containing only C and H when unsubstituted. Alkenyl group may contain, unless otherwise specified, 2, 3, 4, 5, or 6 carbon atoms, excluding the carbon atoms of any substituents, if present. Non-limiting examples of alkenyl groups include ethenyl, prop-1-enyl, prop-2-enyl, 1-methylethenyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methylprop-1-enyl, 2-methylprop-1-enyl, and 1-methylprop-2-enyl. Alkenyl may be unsubstituted or substituted (e.g., optionally substituted alkenyl) as described for alkyl.

[0358] The term "alkenylene," as used herein, refers to a straight-chain or branched-chain divalent substituent including one or two carbon-carbon double bonds and containing only C and H when unsubstituted. Alkenylene group may contain, unless otherwise specified, 2, 3, 4, 5, or 6 carbon atoms, excluding the carbon atoms of any substituents, if present. Non-limiting examples of alkenylene groups include ethen-1,1-diyl; ethen-1,2-diyl; prop-1-en-1,1-diyl, prop-2-en-1,1-diyl; prop-1-en-1,2-diyl, prop-1-en-1,3-diyl; prop-2-en-1,1-diyl; prop-2-en-1,2-diyl; but-1-en-1,1-diyl; but-1-en-1,2-diyl; but-1-en-1,3-diyl; but-1-en-1,4-diyl; but-2-en-1,1-diyl; but-2-en-1,2-diyl; but-2-en-1,3-diyl; but-2-en-1,4-diyl; but-2-en-2,3-diyl; but-3-en-1,1-diyl; but-3-en-1,2-diyl; but-3-en-1,3-diyl; but-3-en-2,3-diyl; buta-1,2-dien-1,1-diyl; buta-1,2-dien-1,3-diyl; buta-1,2-dien-1,4-diyl; buta-1,3-dien-1,1-diyl; buta-1,3-dien-1,2-diyl; buta-1,3-dien-1,3-diyl; buta-1,3-dien-1,4-diyl; buta-1,3-dien-2,3-diyl; buta-2,3-dien-1,1-diyl; and buta-2,3-dien-1,2-diyl. Alkenylene may be unsubstituted or substituted (e.g., optionally substituted alkenylene) as described for alkylene.

[0359] The term "alkoxy" represents a chemical substituent of formula -OR, where R is an optionally substituted alkyl group (e.g., optionally substituted C 1 -C 6 alkyl group). The substituted alkoxy group can have 1, 2, 3, 4, 5, or 6 substituent groups as defined herein. Similarly, the term "arylalkoxy" represents a chemical substituent of formula -OR, where R is an optionally substituted arylalkyl group. The term "cycloalkoxy" represents a substituent of formula -OR', where R' is an optionally substituted cycloalkyl group as described herein. Similarly, the term "alkenoxy" represents a chemical substituent of formula -OR", where R" is an optionally substituted alkenyl group as described herein.

[0360] The term "alkyl," as used herein, refers to a saturated straight-chain or branched-chain monovalent substituent, containing only C and H when unsubstituted. Alkyl group may contain, unless otherwise specified, 1, 2, 3, 4, 5, or 6 carbon atoms, excluding the carbon atoms of any substituents, if present. Non-limiting examples of alkyl group include methyl, ethyl, isobutyl, tert-butyl, and the like. Alkyl group may be unsubstituted or substituted (e.g., optionally substituted alkyl) with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of: halo (e.g., F, Cl, Br, or I), CN, NO 2 , CF 3 , OCF 3 , COOR', CONR' 2 , OR', SR', SOR', SO 2 R', NR' 2 , NR'(CO)R', NR'C(O)OR', NR'C(O)NR' 2 , NR'SO 2 NR' 2 , NR'SO 2 R', oxo (=O), or oximido (=NOR"), where each R' is, independently, H or an optionally substituted group selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, and aryl (all as defined herein); and R" is H or an optionally substituted group selected from alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteralkynyl, heteroaryl, and aryl (all as defined herein). Alternatively, a substituted alkyl group may be a perfluoroalkyl group. In certain cases, when at least one of the substituents on alkyl group is oxo, the oxo group is not bonded to the carbon atom bonded to the parent molecular group.

[0361] The term "alkylene," as used herein, refers to a saturated straight-chain or branched-chain divalent substituent, containing only C and H when unsubstituted. Alkylene group may contain, unless otherwise specified, 1, 2, 3, 4, 5, or 6 carbon atoms, excluding the carbon atoms of any substituents, if present. Non-limiting examples of alkylene group include methylene, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, propane-1,1-diyl, propane-2,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, butane-1,1-diyl, and butane-2,2-diyl, butane-2,3-diyl. Alkylene group may be unsubstituted or substituted (e.g., optionally substituted alkylene) with 1, ...

Claims

1. A combination of a GPR174 inhibitor and at least one additional agent selected from the group consisting of: i. an adenosine-A2A (A2A) receptor antagonist; ii. an adenosine-A2B (A2B) receptor antagonist; iii. a CD73 inhibitor; iv. a CD38 inhibitor; v. a CD39 inhibitor; and vi. one or more agent selected from the group consisting of an anti-GITR antibody, anti-CTLR-4 antibody, anti-LAG3 antibody, anti-TIGIT antibody, anti-NRP1 antibody, anti-TGF-β antibody, anti-CCR2 antibody, anti-CCR4 antibody, anti-CCR8 antibody, anti-TNFR2 antibody, and an anti-EZH2 antibody, for use in the treatment of cancer, wherein the GPR174 inhibitor and the at least one additional agent are administered simultaneously, or sequentially in any order, provided that the effects of the first administered inhibitor or antagonist remain present at the time of the second administered inhibitor or antagonist.

2. The combination for use according to claim 1, wherein the additional agent is an anti-GITR, anti-CTLA-4, anti-CD25, anti-LAG3, anti-TIGIT, anti-NRP1, anti-TGF-β, anti-CCR2, anti-CCR4, anti-CCR8, or anti-TNFR2 antibody, or an EZH2 inhibitor.

3. The combination for use according to any one of claims 1-2, wherein the GPR174 inhibitor inhibits PS-dependent or LysoPS-dependent activation of GPR174 signaling in a cell expressing GPR174 by at least 25%.

4. The combination for use according to any one of claims 1-3, wherein the GPR174 inhibitor stimulates immune response in the patient by inhibiting a GPR174 G-alpha-s signaling, and optionally, wherein the stimulated immune response comprises an NK-cell mediated immune response or an anti-tumor cytotoxic T-cell-mediated immune response.

5. An in vitro_method of increasing the level of Th1 cytokines in human peripheral blood mononuclear cells (PBMCs), the method comprising contacting in vitro human PBMCs with an inhibitor of GPR174 signaling and at least one of an adenosine-A2A (A2A) receptor antagonist, an adenosine-A2B (A2B) receptor antagonist, or a combination thereof.

6. The in vitro method of claim 5, wherein the PBMCs comprise T-cells or NK-cells.

7. The in vitro method of any one of claims 5-6, wherein the level of at least one of Th1 cytokines IFN-γ, IL-2, TNF, or GM-CSF is increased by at least 20%.

8. A pharmaceutical composition comprising a combination of an inhibitor of GPR174 signaling with at least one of an adenosine-A2A (A2A) receptor antagonist, an adenosine-A2B (A2B) receptor antagonist, a CD73 inhibitor, a CD38 inhibitor, and a CD39 inhibitor and optionally a pharmaceutically acceptable excipient.

9. The pharmaceutical composition of claim 8, wherein the GPR174 inhibitor has a structure according to formula (IV): or a stereoisomer thereof, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein each of R1 and R2 is, independently, H, hydroxy, halo, optionally substituted amino, optionally substituted amido, thiol, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryloxy, optionally substituted C1-C9 heteroaryloxy, optionally substituted C2-C6 alkanoyl, optionally substituted C7-C11 aryloyl, optionally substituted C2-C10 heteroaryloyl, optionally substituted C2-C10 heterocyclyloyl, hydroxycarbonyl, optionally substituted ester, optionally substituted carboxamide, optionally substituted C1-C6 alkanoyloxy, optionally substituted C7-C11 aryloyloxy, optionally substituted C2-C10 heteroaryloyloxy, optionally substituted C2-C10 heterocyclyloyloxy, optionally substituted C1-C6 thioalkyl, optionally substituted C1-C6 alkylsulfinyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C6-C10arylthio, optionally substituted C6-C10arylsulfinyl, optionally substituted C6-C10 arylsulfonyl, optionally substituted C1-C9 heteroarylthio, optionally substituted C1-C9 heteroarylsulfinyl, optionally substituted C1-C9 heteroarylsulfonyl, optionally substituted C1-C9 heterocyclylsulfinyl, optionally substituted C1-C9 heterocyclylsulfonyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C6-C10 aryl C2-C6 alkenyl, optionally substituted C6-C10 aryl C2-C6 alkynyl, optionally substituted C1-C9 heteroaryl, optionally substituted C1-C9 heteroaryl C1-C6 alkyl, optionally substituted C1-C9 heteroaryl C2-C6 alkenyl, optionally substituted C1-C9 heteroaryl C2-C6 alkynyl, optionally substituted C1-C9 heterocyclyl, optionally substituted C1-C9 heterocyclyl C1-C6 alkyl, optionally substituted C1-C9 heterocyclyl C2-C6 alkenyl, or optionally substituted C1-C9 heterocyclyl C2-C6 alkynyl; each of R3 and R4 is, independently, H, hydroxy, halo, optionally substituted amino, optionally substituted amido, thiol, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryloxy, optionally substituted C1-C9 heteroaryloxy, optionally substituted C2-C6 alkanoyl, optionally substituted C7-C11 aryloyl, optionally substituted C2-C10 heteroaryloyl, optionally substituted C2-C10 heterocyclyloyl, hydroxycarbonyl, optionally substituted ester, optionally substituted carboxamide, optionally substituted C1-C6 alkanoyloxy, optionally substituted C7-C11 aryloyloxy, optionally substituted C2-C10 heteroaryloyloxy, optionally substituted C2-C10 heterocyclyloyloxy, optionally substituted C1-C6 thioalkyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C6-C10 arylthio, optionally substituted C6-C10 arylsulfonyl, optionally substituted C1-C9 heteroarylthio, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C6-C10 aryl C2-C6 alkenyl, optionally substituted C6-C10 aryl C2-C6 alkynyl, optionally substituted C1-C9 heteroaryl, optionally substituted C1-C9 heteroaryl C1-C6 alkyl, optionally substituted C1-C9 heteroaryl C2-C6 alkenyl, optionally substituted C1-C9 heteroaryl C2-C6 alkynyl, optionally substituted C1-C9 heterocyclyl, optionally substituted C1-C9 heterocyclyl C1-C6 alkyl, optionally substituted C1-C9 heterocyclyl C2-C6 alkenyl, or optionally substituted C1-C9 heterocyclyl C2-C6 alkynyl; R5 is H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryloxy, optionally substituted C1-C9 heteroaryloxy, optionally substituted C2-C6 alkanoyl, optionally substituted C7-C11 aryloyl, optionally substituted C2-C10 heteroaryloyl, optionally substituted C2-C10 heterocyclyloyl, optionally substituted C1-C6 alkyloxycarbonyl, optionally substituted C1-C6 alkylsulfinyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C6-C10 arylsulfinyl, optionally substituted C6-C10 arylsulfonyl, optionally substituted C1-C9 heteroarylsulfinyl, optionally substituted C1-C9 heteroarylsulfonyl, optionally substituted C1-C9 heterocyclylsulfinyl, optionally substituted C1-C9 heterocyclylsulfonyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C6-C10 aryl C2-C6 alkenyl, optionally substituted C6-C10 aryl C2-C6 alkynyl, optionally substituted C1-C9 heteroaryl, optionally substituted C1-C9 heteroaryl C1-C6 alkyl, optionally substituted C1-C9 heteroaryl C2-C6 alkenyl, optionally substituted C1-C9 heteroaryl C2-C6 alkynyl, optionally substituted C1-C9 heterocyclyl, optionally substituted C1-C9 heterocyclyl C1-C6 alkyl, optionally substituted C1-C9 heterocyclyl C2-C6 alkenyl, or optionally substituted C1-C9 heterocyclyl C2-C6 alkynyl. n is 0, 1, 2, 3, or 4; and m is 0, 1, 2, 3, 4, 5, or 6.

10. The composition of claim 8, wherein the GPR174 inhibitor has a structure according to the following formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, X1 is N or CR10; X2 is N or CR11; X3 is N or CR12; X4 is N or CR13; X5 is N or CR14; X6 is N or CR15; X7 is N or CR16; each of R1, R2, R3, R4, R5, R6, R7, R8, and R9 is, independently, H, hydroxy, thiol, optionally substituted amino, optionally substituted amido, cyano, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryloxy, optionally substituted C1-C9 heteroaryloxy, optionally substituted C2-C6 alkanoyl, optionally substituted C7-C11 aryloyl, optionally substituted C2-C10 heteroaryloyl, optionally substituted C2-C10 heterocyclyloyl, hydroxycarbonyl, optionally substituted C2-C7 alkoxycarbonyl, optionally substituted carboxamide, optionally substituted C1-C6 alkanoyloxy, optionally substituted C7-C11 aryloyloxy, optionally substituted C2-C10 heteroaryloyloxy, optionally substituted C2-C10 heterocyclyloyloxy, optionally substituted C1-C6 alkylsulfinyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C6-C10 arylsulfinyl, optionally substituted C6-C10 arylsulfonyl, optionally substituted C1-C9 heteroarylsulfinyl, optionally substituted C1-C9 heteroarylsulfonyl, optionally substituted C1-C9 heterocyclylsulfinyl, optionally substituted C1-C9 heterocyclylsulfonyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C6-C10 aryl C2-C6 alkenyl, optionally substituted C6-C10 aryl C2-C6 alkynyl, optionally substituted C1-C9 heteroaryl, optionally substituted C1-C9 heteroaryl C1-C6 alkyl, optionally substituted C1-C9 heteroaryl C2-C6 alkenyl, optionally substituted C1-C9 heteroaryl C2-C6 alkynyl, optionally substituted C1-C9 heterocyclyl, optionally substituted C1-C9 heterocyclyl C1-C6 alkyl, optionally substituted C1-C9 heterocyclyl C2-C6 alkenyl, or optionally substituted C1-C9 heterocyclyl C2-C6 alkynyl; or R2 and R3 combine to form =O, =S, or =NR17; or R4 and R5 combine to form =O, =S, or =NR17; or R6 and R7 combine to form =O, =S, or =NR17; or R8 and R9 combine to form =O, =S, or =NR17; each of R10, R11, R12, R13, R14, R15, and R16 is, independently, H, hydroxy, halogen, thiol, optionally substituted amino, optionally substituted amido, cyano, nitro, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted C6-C10 aryloxy, optionally substituted C1-C9 heteroaryloxy, optionally substituted C2-C6 alkanoyl, optionally substituted C7-C11 aryloyl, optionally substituted C2-C10 heteroaryloyl, optionally substituted C2-C10 heterocyclyloyl, hydroxycarbonyl, optionally substituted C2-C7 alkoxycarbonyl, optionally substituted carboxamide, optionally substituted C1-C6 alkanoyloxy, optionally substituted C7-C11 aryloyloxy, optionally substituted C2-C10 heteroaryloyloxy, optionally substituted C2-C10 heterocyclyloyloxy, optionally substituted C1-C6 alkylsulfinyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C6-C10 arylsulfinyl, optionally substituted C6-C10 arylsulfonyl, optionally substituted C1-C9 heteroarylsulfinyl, optionally substituted C1-C9 heteroarylsulfonyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C6-C10 aryl C2-C6 alkenyl, optionally substituted C6-C10 aryl C2-C6 alkynyl, optionally substituted C1-C9 heteroaryl, optionally substituted C1-C9 heteroaryl C1-C6 alkyl, optionally substituted C1-C9 heteroaryl C2-C6 alkenyl, optionally substituted C1-C9 heteroaryl C2-C6 alkynyl, optionally substituted C1-C9 heterocyclyl, optionally substituted C1-C9 heterocyclyl C1-C6 alkyl, optionally substituted C1-C9 heterocyclyl C2-C6 alkenyl, or optionally substituted C1-C9 heterocyclyl C2-C6 alkynyl; or one of: (i) R12 and R13, together with the atoms to which each is attached, combine to form an optionally substituted 5-, 6-, or 7-member ring; (ii) R13 and R14, together with the atoms to which each is attached, combine to form an optionally substituted 5-, 6-, or 7-member ring; (iii) R14 and R15, together with the atoms to which each is attached, combine to form an optionally substituted 5-, 6-, or 7-member ring; and (iv) R15 and R16, together with the atoms to which each is attached, combine to form an optionally substituted 5-, 6-, or 7-member ring; and R17 is H, hydroxyl, cyano, optionally substituted amino, optionally substituted amido, optionally substituted carboxamide, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkanoyl, optionally substituted C7-C11 aryloyl, optionally substituted C2-C10 heterocyclyloyl, optionally substituted C2-C10 heteroaryloyl, optionally substituted C1-C6 alkylsulfinyl, optionally substituted C1-C6 alkylsulfonyl, optionally substituted C6-C10 arylsulfinyl, optionally substituted C6-C10 arylsulfonyl, optionally substituted C1-C9 heteroarylsulfinyl, optionally substituted C1-C9 heteroarylsulfonyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted C3-C10 cycloalkyl, optionally substituted C4-C10 cycloalkenyl, optionally substituted C8-C10 cycloalkynyl, optionally substituted C6-C10 aryl, optionally substituted C6-C10 aryl C1-C6 alkyl, optionally substituted C6-C10 aryl C2-C6 alkenyl, optionally substituted C6-C10 aryl C2-C6 alkynyl, optionally substituted C1-C9 heteroaryl, optionally substituted C1-C9 heteroaryl C1-C6 alkyl, optionally substituted C1-C9 heteroaryl C2-C6 alkenyl, optionally substituted C1-C9 heteroaryl C2-C6 alkynyl, optionally substituted C1-C9 heterocyclyl, optionally substituted C1-C9 heterocyclyl C1-C6 alkyl, optionally substituted C1-C9 heterocyclyl C2-C6 alkenyl, or optionally substituted C1-C9 heterocyclyl C2-C6 alkynyl; wherein three or fewer of X3, X4, X5, X6, and X7 are N; and at least one of X1 and X2 is N.

11. The composition of claim 8, wherein the composition further comprises one or more agent selected from the group consisting of an anti-GITR antibody, anti-CTLR-4 antibody, anti-LAG3 antibody, anti-TIGIT antibody, anti-NRP1 antibody, anti-TGF-β antibody, anti-CCR2 antibody, anti-CCR4 antibody, anti-CCR8 antibody, anti-TNFR2 antibody, and an anti-EZH2 antibody.

12. A GPR174 inhibitor for use in a method of enhancing an anti-tumor immune response in a subject that is currently undergoing treatment with at least one of an A2aR antagonist, an A2bR antagonist, a CD38 inhibitor, a CD39 inhibitor, a CD73 inhibitor, and an agent selected from the group consisting of an anti-GITR antibody, anti-CTLR-4 antibody, anti-LAG3 antibody, anti-TIGIT antibody, anti-NRP1 antibody, anti-TGF-β antibody, anti-CCR2 antibody, anti-CCR4 antibody, anti-CCR8 antibody, anti-TNFR2 antibody, and an ant-EZH2 antibody.

13. The GPR174 inhibitor for use according to claim 12, wherein the GPR174 inhibitor inhibits PS-dependent or LysoPS-dependent activation of GPR174 signaling in a cell expressing GPR174 by at least 25%.