CD206 Modulators, Their Uses, and Methods of Preparation - Patent application

Abstract

Disclosed are compounds of Formula I, Formula II, and Formula III, and pharmaceutically acceptable salts thereof. The variables X, a, b, c, d, R 1~4 , R 10~15 , and R 17~22 Disclosed herein are compounds useful for treating cancer disorders, particularly those involving the M2 phenotype of macrophages. Pharmaceutical compositions containing compounds of Formula I or Formula II or Formula III, and methods of treatment comprising administering compounds of Formula I, Formula II, and Formula III, are also disclosed. TIFF2023507610000095.tif2397

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 62 / 950,488, filed December 19, 2019, which is incorporated herein by reference in its entirety. Statement of government support This invention was made in part with government support from the National Institutes of Health under grant number ZIA-BC011267. The government has certain rights in this invention. [Background technology]

[0002] Background of the Invention 1. Field of the Invention The present invention is directed to immunotherapeutic agents, and more particularly to compounds that modulate CD206 and methods of their use and preparation. 2. Brief description of related technologies Pancreatic cancer is a disease in which malignant (cancerous) cells form in the tissues of the pancreas. Pancreatic cancer often has a poor prognosis, even when diagnosed early. Pancreatic cancer typically spreads quickly and is rarely detected in its early stages, which is the primary reason why pancreatic cancer is a leading cause of cancer death. Pancreatic cancer is the fourth leading cause of cancer death in both men and women in the United States, killing more than 44,000 people annually. Pancreatic cancer is predicted to rank second among all cancer-related deaths in the United States by 2030. Furthermore, the 5-year survival rate for pancreatic cancer in the United States ranks lowest among solid organ tumors. There are no reliable screening tests for early detection of pancreatic cancer. Signs and symptoms may not appear until pancreatic cancer is well advanced, and complete surgical removal is not possible. Standard treatments for pancreatic cancer, including surgery, radiation therapy, and chemotherapy, largely demonstrate limited efficacy. In fact, approved treatments, including gemcitabine, forfirinox, the combination of gemcitabine and Abraxane, and the combination of gemcitabine and erlotinib, improve survival rates by only a few months. Newer therapies have not demonstrated further success, likely due to a thick stroma, a unique immune infiltrate characterized by a lack of cytotoxic tumor-infiltrating T cells, numerous immunosuppressive tumor-promoting myeloid cells, and the relative absence of abundant blood vessels in the pancreas. Pancreatic ductal adenocarcinoma (PDA) accounts for >90% of pancreatic cancer cases, with a 5-year survival rate of 6%.

[0003] Recent advances in immunotherapy have transformed the care of many cancer patients. However, these positive findings have been limited to immunologically "hot" cancers; in contrast, for the much larger number of solid organ cancers classified as immunologically "cold," such as pancreatic cancer, the promise of immunotherapy via T cell activation has largely remained remote to patients. These tumors create an immune environment that either excludes cytotoxic T cells or induces an exhausted T cell phenotype through a wealth of immune evasion cues, frequently involving innate immune cells. Strategies to reactivate innate immune cells are underappreciated within the scope of current immuno-oncology therapies.

[0004] Tumor cells attract and reprogram innate immune cells, including tumor-associated macrophages (TAMs), to support tumor growth and metastatic spread. The dichotomous M1 vs. M2 classification misses the ontogeny and tissue-specific cues of TAMs, but generally, M1-like TAMs are proposed to be the more prevalent phenotype in early tumor stages, while M2 TAMs are more prominent in more advanced cancers. CD206 high M2 TAMs exploit tumor growth through the efflux of cancer-promoting factors or by promoting angiogenesis, nurturing cancer stem cells, or generating an immune-evasive microenvironment.

[0005] CD206 is a member of the large C-type lectin receptor family that can target and regulate M2 macrophages. CD206 is involved in the recognition and binding of mannan and fucose carbohydrate residues from microorganisms via its eight carbohydrate-recognition domains, and as a scavenger receptor, via its fibronectin domain II, in the phagocytosis of collagen fragments generated during tissue injury and wound healing. Ligand binding or low pH induces the receptor's "rolling-in" (through multiple Ca+-dependent intramolecular interactions between the carbohydrate-recognition domains) and closed ("active") form, which triggers NF-kB signaling activation, phagocytosis, and autophagy in M2 macrophages via GRB2-mediated activation of small Rho-GTPases, among other signaling cascades.

[0006] TAMs express scavenger receptors such as CD206, which facilitate tumor angiogenesis, tumor cell migration, maintenance of an EMT-like phenotype of cancer cells, and metastasis. high Expression has been associated with poor clinical outcomes in pancreatic cancer and other solid organ cancers. Selective depletion of M2 tumor-associated macrophages may improve antitumor immunity and cancer outcome. Using a synthetic host defense peptide design known to regulate innate immune function through binding to the C-type lectin receptor (RP-182), we demonstrated that binding to the amino acid carbohydrate recognition domain 5 (CRD5) sequence NFGDLVSIQSESEKK of the CD206 receptor: (1) activates phagocytosis and autophagy programs in M2 macrophages, resulting in metabolic reprogramming of these cells and an M1-like phenotype; and (2) CD206 highIt has previously been shown to result in the intracellular signaling activation of NF-kB, leading to selective death of M2 macrophages via autocrine TNF-alpha-mediated caspase 8 and 3 activation (U.S. Patent No. 10,016,480). However, the unfavorable pharmacokinetic (PK) properties of peptide-based innate immune regulators hinder the clinical prospects of synthetic peptides such as RP-182. Therefore, small molecule modulators of CD206 are highly desirable. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] U.S. Patent No. 10,016,480 Summary of the Invention [Means for solving the problem]

[0008] Summary of the Invention Described herein are small molecule modulators that target the CD206 receptor, methods for making the same, compositions containing the described compounds, and methods of using the described compounds.

[0009] In a first aspect, compounds of Formula I and pharmaceutically acceptable salts of compounds of Formula I are provided. [ka]

[0010] In formula I, the following conditions are met:

[0011] Each bond shown as a joined solid and dashed line, [ka] can be a single, double, or aromatic bond.

[0012] R 1is hydrogen, halogen, hydroxyl, cyano, -CO2H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C0-C6 alkyl)cycloalkyl, C1-C6 haloalkyl, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -C(O)C1-C6 alkyl, -C(O)NR 8 R 9 , -(C0-C6 alkyl)NR 5 R 6 , -CO2R 6 , -C6H4-R 7 and a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently selected from N, S, and O.

[0013] R 2 , R 3 , and R 4 are each independently, at each occurrence, hydrogen, halogen, hydroxyl, cyano, -COH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C0-C6 alkyl)cycloalkyl, C1-C6 haloalkyl, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -C(O)C1-C6 alkyl, -C(O)NR 5 R 6 , (C0-C6 alkyl)NR 8 R 9 , -CO2R 6 , and -C6H4-R 7 is selected from.

[0014] a, b, c, d, and X are each independently selected at each occurrence from N, C, and CH.

[0015] R 5 and R 6each independently at each occurrence represents hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, substituted or unsubstituted -(C0-C6 alkyl)cycloalkyl, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -C(O)C1-C6 alkyl, -C(O)(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)NR 8 R 9 , —C(O)(C0-C6 alkyl)aryl, —C(O)(C0-C6 alkyl)heteroaryl, and a 4- to 7-membered heterocycloalkyl ring having 1, 2, or 3 ring atoms independently selected from N, O, and S.

[0016] Any R bonded to the same nitrogen atom 5 and R 6 may be joined to form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms selected from N, O, S, S(O), and SO, and which heterocycloalkyl ring optionally contains at any carbon or hetero ring atom halogen, hydroxyl, cyano, oxo, dioxo, C-C alkyl, C-C alkoxy, C-C haloalkyl, -(C-C alkyl)cycloalkyl, -(C-C alkyl)phenyl, -(C-C alkyl)aryl, -(C-C alkyl)COR 8 , -(C0-C6 alkyl)C(O)NR 8 R 9 , -(C1-C6 alkyl)OR 8 , -C(O)C1-C6 alkyl, -(C0-C6 alkyl)NR 8 R 9 or -C(O)(C0-C6 alkyl)NR 8 R 9 is replaced by .

[0017] R 7is hydrogen, halogen, hydroxyl, cyano, -CO2H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl)cycloalkyl, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -CO2R 8 , -C(O)C1-C6 alkyl, -C(O)C2-C6 alkenyl, -C(O)C2-C6 alkynyl, -C(O)C1-C6 alkoxy, -C(O)C1-C6 hydroxyalkyl, -C(O)-(C0-C6 alkyl)cycloalkyl, -C(O)-(C0-C6 alkyl)phenyl, -C(O)-(C0-C6 alkyl)aryl, -C(O)-(C0-C6 alkyl)heteroaryl, -C(O)NR 8 R 9 , -C(O)NR 5 R 6 , -C(O)-(C0-C6 alkyl)NR 5 R 6 , -C(O)-NR 8 -(C0-C6 alkyl)NR 5 R 6 , or (C0-C6 alkyl)NR 5 R 6 is.

[0018] R 8 and R 9 each occurrence independently represents hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)NR 5 R 6 , -CO2R 6 , —C(O)C1-C6 alkyl, and —(C0-C6 alkyl)cycloalkyl.

[0019] In a second aspect, there are provided compounds of Formula II and pharmaceutically acceptable salts of compounds of Formula II: [ka]

[0020] In formula II, the following conditions are met:

[0021] Each bond shown as a joined solid and dashed line, [ka] can be a single or double bond.

[0022] R 10 , R 11 , and R 13 are each independently selected at each occurrence from hydrogen, hydroxyl, -COH, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C0-C6 alkyl)cycloalkyl, C1-C6 haloalkyl, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -C(O)C1-C6 alkyl, -C(O)heteroaryl, and -COR 16 is selected from.

[0023] R 12 , R 14 , and R 15 is independently selected at each occurrence from hydrogen, halogen, hydroxyl, and cyano.

[0024] X is O or S.

[0025] R 16 is hydrogen, halogen, hydroxy, amino, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, -(C-C alkyl)cycloalkyl, -C(O)C-C alkyl, -(C-C alkyl)aryl, -(C-C alkyl)heteroaryl, -(C-C alkyl)phenyl, or a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently selected from N, S, and O.

[0026] In a third aspect, there are provided compounds of formula III and pharmaceutically acceptable salts of compounds of formula III: [ka]

[0027] In formula III, the following conditions are met:

[0028] R 17 , R 18 , and R 21 each occurrence independently represents hydrogen, halogen, hydroxyl, cyano, amidino group, -NR 23 R 24 , sulfonic acid group or salt thereof, phosphate group or salt thereof, -CO2H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C0-C6 alkyl)cycloalkyl, C1-C6 haloalkyl, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -C(O)C1-C6 alkyl, -C(O)(C0-C6 alkyl)phenyl, -C(O)(C0-C6 alkyl)aryl, -C(O)(C0-C6 alkyl)heteroaryl, -C(O)NR 23 R 24 , -(C0-C6 alkyl)NR 23 R 24 , -CO2R 23 and monocyclic or bicyclic heterocycles of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently selected from N, S, and O.

[0029] Each occurrence of X is selected from O and S.

[0030] R 19 , R 20 , and R 22 is independently selected at each occurrence from hydrogen, halogen, hydroxy, cyano, and amino groups.

[0031] R23 and R 24 are each independently selected at each occurrence from hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -C(O)(C0-C6 alkyl)phenyl, -C(O)(C0-C6 alkyl)aryl, -C(O)(C0-C6 alkyl)heteroaryl, -S(O)phenyl, -S(O)aryl, -S(O)heteroaryl, -S02phenyl, -S02aryl, -S02heteroaryl, -(C0-C6 alkyl)cycloalkyl, and -CO2R 25 is selected from.

[0032] R 25 is hydrogen, halogen, hydroxy, amino, C-C alkyl, C-C alkenyl, C-C alkynyl, C-C alkoxy, -(C-C alkyl)cycloalkyl, -C(O)C-C alkyl, -(C-C alkyl)aryl, -(C-C alkyl)heteroaryl, -(C-C alkyl)phenyl, or a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently selected from N, S, and O.

[0033] Also disclosed are pharmaceutical compositions comprising a compound or salt of Formula I or Formula II or Formula III together with a pharmaceutically acceptable carrier.

[0034] Also disclosed is a method for treating cancer, which can include selectively targeting M2 macrophages and reprogramming M2 macrophages toward an M1 phenotype in a patient, comprising administering a compound of Formula I or Formula II or Formula III, or a salt thereof, to a patient in need of cancer treatment.

[0035] In some embodiments, targeting CD206 M2 macrophages with a compound or salt of Formula I or Formula II or Formula III may exert a dual effect: it may reprogram CD206 M2 macrophages to M1 macrophages and it may directly kill M2 macrophages.

[0036] Also disclosed are methods for treating cancers characterized by the presence of CD206-positive tumor-associated macrophages (TAMs), such as glioma (glioblastoma), sarcoma, astrocytoma, melanoma, non-small cell lung cancer, cholangiocarcinoma, colon cancer, hepatocellular, breast, prostate, gastric, renal cell, endometrial, or pancreatic cancer, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt of Formula I or Formula II or Formula III.

[0037] The following detailed description, given by way of example only and not intended to limit the invention to the particular embodiments described, may be understood in conjunction with the accompanying drawings, in which: [Brief explanation of the drawings]

[0038] [Figure 1A] FIG. 1A shows a graph of relative cell viability percentage versus log molar concentration illustrating the anti-cell viability screen for Compound 1.

[0039] [Figure 1B] FIG. 1B shows a graph of relative cell viability percentage versus log molar concentration illustrating the anti-cell viability screen for Compound 2.

[0040] [Figure 1C] FIG. 1C shows a graph of relative cell viability percentage versus log molar concentration illustrating the anti-cell viability screen for compound 3.

[0041] [Figure 2A]Figure 2A is a graph of relative cell viability percentage versus log molar concentration showing cell viability in M2-polarized macrophages with intact CD206 (wild-type) versus cell viability in isogenic M2-polarized macrophages lacking the CD206 receptor, demonstrating that the macrophage activity of Compound 1 is CD206-dependent.

[0042] [Figure 2B] Figure 2B is a graph of relative cell viability percentage versus log molar concentration showing cell viability in M2-polarized macrophages with intact CD206 (wild-type) versus cell viability in isogenic M2-polarized macrophages lacking the CD206 receptor, indicating that the macrophage activity of Compound 2 is CD206-dependent.

[0043] [Figure 2C] Figure 2C shows a graph of relative cell viability percentage versus log molar concentration showing cell viability in M2-polarized macrophages with intact CD206 (wild-type) versus cell viability in isogenic M2-polarized macrophages lacking the CD206 receptor, indicating that the macrophage activity of compound 3 is CD206-dependent.

[0044] [Figure 3A] Figure 3A shows a graph of tumor volume in cubic millimeters (mm3) versus days of treatment showing the change in tumor volume during in vivo testing of Compound 1 in fully immunocompetent transgenic Kras(G12D) / Trp53(R172H) / Pdx-1-Cre (KPC) mice (a murine pancreatic cancer model).

[0045] [Figure 3B] Figure 3B shows the change in tumor weight during in vivo testing of Compound 1 in fully immunocompetent transgenic Kras(G12D) / Trp53(R172H) / Pdx-1-Cre (KPC) mice (a murine pancreatic cancer model), showing the change in tumor weight in vehicle and Compound 1 at the study endpoint in grams of wet weight.

[0046] [Figure 3C] FIG. 3C shows a graph of tumor volume in cubic millimeters (mm3) versus days of treatment showing the change in tumor volume during in vivo testing of Compound 1 in a syngeneic, immunocompetent B16.F10 allograft model (a murine melanoma model).

[0047] [Figure 4] FIG. 4 shows a graph of relative cell viability percentage versus log molar concentration showing the macrophage activity of Compound 4, which has an IC 50 of 8.95 micromolar (μM).

[0048] [Figure 5] FIG. 5 shows a graph of relative cell viability percentage versus log molar concentration showing the macrophage activity of Compound 5, which has an IC50 of 7.36 μM.

[0049] [Figure 6] FIG. 6 shows a graph of relative cell viability percentage versus log molar concentration showing the macrophage activity of Compound 6, which has an IC50 of 3.85 μM.

[0050] [Figure 7] FIG. 7 shows a graph of relative cell viability percentage versus log molar concentration showing the macrophage activity of compound 7, which has an IC50 of 3.13 μM.

[0051] [Figure 8] FIG. 8 shows a graph of relative cell viability percentage versus log molar concentration in a human macrophage cell viability assay for Compound 1, demonstrating that Compound 1 is active in human CD206-high M2 macrophages isolated from healthy volunteers.

[0052] [Figure 9A]FIG. 9A shows a graph of relative cell viability percentage versus log molar concentration in a panel of CD206-negative control cell lines demonstrating the activity of Compound 1 against CD206high M2 macrophages.

[0053] [Figure 9B] FIG. 9B shows a graph of relative cell viability percentage versus log molar concentration in a panel of dendritic cells DC2.4 for Compound 1, demonstrating the selectivity of Compound 1 for CD206high M2 macrophages.

[0054] [Figure 9C] FIG. 9C shows a graph of relative cell viability percentage versus log molar concentration in a panel of fibroblast HTT cells for Compound 1, demonstrating selectivity of Compound 1 for CD206high M2 macrophages.

[0055] [Figure 9D] FIG. 9D shows a graph of relative cell viability percentage versus log molar concentration in a panel of non-polarized RAW264.7 cells for Compound 1, demonstrating selectivity of Compound 1 for CD206high M2 macrophages.

[0056] [Figure 9E] FIG. 9E shows a graph of relative cell viability percentage versus log molar concentration in a panel of KPC cancer cells (murine pancreatic cancer cells) for Compound 1, demonstrating the selectivity of Compound 1 for CD206high M2 macrophages.

[0057] [Figure 10A] FIG. 10A shows a graph of concentration in nanograms per milliliter (ng / mL) of Compound 1 versus time in hours (hr) showing the pharmacokinetic (PK) profile of Compound 1 at various concentrations when given via intravenous (IV) injection.

[0058] [Figure 10B]FIG. 10B shows a graph of time (hr) versus concentration of Compound 1 (ng / mL) showing the pharmacokinetic (PK) profile of Compound 1 at various concentrations when given via intraperitoneal (IP) injection.

[0059] [Figure 10C] FIG. 10C shows a graph of time (hr) versus concentration of Compound 1 (ng / mL) showing the pharmacokinetic (PK) profile of Compound 1 at various concentrations when given orally.

[0060] [Figure 11A] Figure 11A shows a representative electron microscopy image of recombinant human CD206 protein (UniProt ID P22897-1 NCBI ID: NP_002429.1) incubated with vehicle against Compound 1 at 1 micromolar (μM) for 30 minutes, demonstrating that Example 38 induces a closed conformation of the CD206 receptor (solid arrow indicates the open conformation of the CD206 receptor; dotted arrow indicates the closed conformation).

[0061] [Figure 11B] Figure 11B shows a representative series of sequential scanning electron microscopy images of recombinant CD206 incubated with vehicle versus compound 1 at 1 μM for 30 minutes, scored as closed versus open. The number of CD206 particles in the series was scored as closed versus open as indicated at the bottom, and collectively shows that 48% of the CD206 particles were in the closed state (boxes with dark borders) and 52% were in the open state (boxes without borders), indicating that compound 1 binds to CD206 and induces a conformational switch in the receptor.

[0062] [Figure 12A]FIG. 12A shows a graph of quantitative relative fluorescence obtained in murine M1 and M2 macrophages to demonstrate induction of early phagocytosis, showing that Compound 1 induces early phagocytosis in M2 but not M1 macrophages.

[0063] [Figure 12B] FIG. 12B shows a graph of quantitative relative fluorescence obtained in murine M1 and M2 macrophages to demonstrate induction of phagocytosis, showing that Compound 1 induces phagocytosis in M2 but not M1 macrophages.

[0064] [Figure 12C] FIG. 12C shows a graph of quantitative relative fluorescence obtained in murine M1 and M2 macrophages to demonstrate induction of phagolysosome formation, showing that Compound 1 induces the formation of phagolysosomes in M2 but not M1 macrophages.

[0065] [Figure 12D] FIG. 12D shows a graph of quantitative relative fluorescence obtained in murine M1 and M2 macrophages to demonstrate the induction of autophagy, showing that Compound 1 induces autophagy in M2 but not M1 macrophages.

[0066] [Figure 12E] FIG. 12E shows a graph of quantitative relative fluorescence obtained in murine M1 and M2 macrophages to demonstrate induction of apoptosis, showing that Compound 1 induces apoptosis in M2 but not M1 macrophages.

[0067] [Figure 13A]FIG. 13A shows a graph of quantitative relative fluorescence obtained in a second murine in vitro macrophage model, M1- and M2-polarized RAW264.7 macrophages, to demonstrate the induction of phagocytosis in RAW264.7 macrophages treated with Compound 1 compared to vehicle-only treated RAW264.7 macrophages, demonstrating that Compound 1 induces phagocytosis in M2 macrophages.

[0068] [Figure 13B] Figure 13B shows a graph of quantitative relative fluorescence obtained in a second murine in vitro macrophage model, M1- and M2-polarized RAW264.7 macrophages, to demonstrate the induction of autophagy in RAW264.7 macrophages treated with Compound 1 compared to vehicle-only treated RAW264.7 macrophages, demonstrating that Compound 1 induces autophagy in M2 macrophages.

[0069] [Figure 13C] FIG. 13C shows a graph of quantitative relative fluorescence obtained in a second murine in vitro macrophage model, M1- and M2-polarized RAW264.7 macrophages, to demonstrate the induction of apoptosis in RAW264.7 macrophages treated with Compound 1 compared to vehicle-only treated RAW264.7 macrophages, demonstrating that Compound 1 induces apoptosis in M2 macrophages.

[0070] [Figure 14A] Figure 14A shows a graph of relative quantitative fluorescence to demonstrate the selective induction of cancer cell phagocytosis in M2 macrophages induced by Compound 1, indicating that Compound 1 increases cancer cell phagocytosis in M2 but not M1 macrophages.

[0071] [Figure 14B]Figure 14B shows a graph of relative quantitative fluorescence to demonstrate the selective induction of cancer cell phagocytosis in M2 macrophages induced by compound 28, indicating that compound 28 increases cancer cell phagocytosis in M2 but not M1 macrophages.

[0072] [Figure 15] FIG. 15 shows a graph of relative cell viability percentage versus log molar concentration showing the macrophage activity of Compound 1, which has an IC50 of 2.86 μM.

[0073] [Figure 16] FIG. 16 shows a graph of the relative induced immunofluorescence percentage, measuring induced phagocytosis, versus log molar concentration in murine M2 macrophages treated with Compound 1 for 24 hours, demonstrating the concentration-dependent induction of phagocytosis by Compound 1.

[0074] [Figure 17] FIG. 17 shows a graph of the percent positive cell fraction for M1 markers as measured by quantitative flow cytometry of murine M2 macrophages treated for 2 hours with vehicle, 20 μM Compound 1, and 20 μM Compound 2, demonstrating the induction of M1 markers in M2 macrophages.

[0075] [Figure 18A]Figures 18A to 18C show the reprogramming of the intratumoral immune landscape by Compound 1 in spontaneous KPC tumors. Figure 18A shows that treatment with Compound 1 reduced CD206 macrophages, CD206high Figure 18 shows graphs of the percent positive cell fraction of total cells in tumors measured by quantitative flow cytometry in Compound 1-treated KPC tumors (CD206 = M2 macrophages; CD86 = M1 macrophages; CD8a = CD8-positive T cells; CD4 = CD4-positive T cells) compared to vehicle, demonstrating a shift from M2 to CD86-positive M1 macrophages and an increase in intratumoral CD8 cells. Figure 18B shows a reduction in CD206-positive cells within the tumor-associated macrophage population as measured by CD11b+F4 / 80+Gr-1-negative cells. Figure 18C shows a reduction in innate checkpoint signal-regulatory protein alpha (SIRPα), a regulatory membrane glycoprotein from the SIRP family, inhibiting cancer cell phagocytosis by tumor-associated macrophages as determined by CD11b+F4 / 80+Gr-1-negative cells. [Figure 18B] Same as above. [Figure 18C] Same as above.

[0076] [Figure 18D] Figures 18D to 18I show graphs of the percent positive cell fraction of intratumoral M1 and M2 macrophage populations measured by quantitative flow cytometry within KPC tumors to demonstrate the shift in cytokine profile after 3 weeks of intratumoral treatment with Compound 1 compared to vehicle, demonstrating that Compound 1 demonstrated induction of M1 markers compared to vehicle in both intratumoral M1 and intratumoral M2 macrophage populations. [Figure 18E] Same as above. [Figure 18F] Same as above. [Figure 18G] Same as above. [Figure 18H] Same as above. [Figure 18I] Same as above.

[0077] [Figure 19]Figure 19 shows the relative tumor growth of KPC allograft tumors grown in C57BL / 6 mice, showing that after adoptive transfer of M2 macrophages via intratumoral injection, when treated with Compound 1 compared to vehicle, M2 macrophages restricted tumor growth similarly to injection of an equal amount of M1 macrophages when the intratumoral injection frequency was three times per week and the measurement frequency was twice per week. Treatment with Compound 1 showed that tumor growth was reduced by M2 macrophages pretreated with Compound 1, except when pretreated with vehicle, indicating that M2 macrophages treated with Compound 1 and injected intratumorally exert a tumor-restricting effect.

[0078] [Figure 20] FIG. 20 shows a graph of relative cell viability percentage versus log molar concentration showing the macrophage activity of compound 8, which has an IC50 of 0.45 μM.

[0079] [Figure 21] FIG. 21 shows a graph of relative cell viability percentage versus log molar concentration showing the macrophage activity of compound 9, which has an IC50 of 0.73 μM.

[0080] [Figure 22] FIG. 22 shows a graph of relative cell viability percentage versus log molar concentration showing the macrophage activity of compound 10, which has an IC50 of 5.45 μM. DETAILED DESCRIPTION OF THE INVENTION

[0081] Detailed Description of the Invention term Compounds are described using standard nomenclature. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0082] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term "or" means "and / or." The terms "comprising," "having," "including," and "containing" shall be construed as open-ended terms (i.e., meaning "including, but not limited to").

[0083] The recitation of ranges of values, unless otherwise stated herein, is merely intended to serve as a shorthand method of referring individually to each separate value falling within that range, and each separate value is incorporated herein as if it were individually recited herein. The endpoints of all ranges are included within the ranges and are independently combinable.

[0084] All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") is for illustrative purposes only and does not impose limitations on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention. Unless otherwise defined, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0085] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, phrases, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends from the same base claim. Where elements are presented as enumerations, e.g., in Markush group format, each subgroup of elements is also disclosed, and any element(s) can be removed from the group.

[0086] All compounds are understood to include all possible isotopes of atoms occurring in the compound. Isotopes include atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include fluorine and fluorine. 11 C. 13 C, and 14 Contains C.

[0087] Formula I includes all pharmaceutically acceptable salts of Formula I.

[0088] Formula II includes all pharmaceutically acceptable salts of Formula II.

[0089] Formula III includes all pharmaceutically acceptable salts of Formula III.

[0090] The open-ended term "comprising" includes the intermediate and limiting terms "consisting essentially of" and "consisting of."

[0091] The term "substituted" means that one or more hydrogens on any of the designated atoms or groups are replaced with one selected from the indicated group, provided that the normal valence of the designated atom is not exceeded. When the substituent is oxo (i.e., =O), two hydrogens on the atom are replaced. When an aromatic moiety is substituted with an oxo group, the aromatic ring is replaced with the corresponding partially unsaturated ring. For example, a pyridyl group substituted with oxo is a pyridone. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is intended to indicate a compound that is sufficiently robust to survive isolation from a reaction mixture and subsequent formulation into an effective therapeutic agent.

[0092] Suitable groups that may be present in the "optionally substituted" position include, but are not limited to, halogen, cyano, hydroxyl, amino, nitro, oxo, azido, alkanoyl (including C2-C6 alkanoyl groups such as acyl or the like (-(C=O)alkyl)); carboxamido; alkylcarboxamido; alkyl, alkoxy, alkylthio groups including those with one or more thioether linkages, alkylsulfinyl groups including those with one or more sulfinyl linkages, alkylsulfonyl groups including those with one or more sulfonyl linkages, mono- and di-aminoalkyl groups including groups with one or more N atoms, all of the foregoing optional alkyl substituents may have one or more methylene groups replaced by oxygen or -NH- and may have from about 1 to about 8, from about 1 to about 6, or from 1 to about 4 carbon atoms, cycloalkyl; phenyl; phenylalkyl, with benzyl being an exemplary phenylalkyl group, and phenylalkoxy, with benzyloxy being an exemplary phenylalkoxy group. The alkylthio and alkoxy groups are attached at positions substituted by sulfur or oxygen atoms, respectively.

[0093] A dashed line ("-") and a dashed line (" [ka] ") is used to indicate a point of attachment for a substituent.

[0094] "Alkyl" includes both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, generally from 1 to about 8 carbon atoms. As used herein, the term C1-C6 alkyl refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Other embodiments include alkyl groups having 1 to 8 carbon atoms, 1 to 4 carbon atoms, or 1 or 2 carbon atoms, such as C1-C8 alkyl, C1-C4 alkyl, and C1-C2 alkyl. C0-C nWhen alkyl is used herein in conjunction with another group, such as —C0-C2 alkyl (phenyl), the indicated group, in this case phenyl, is directly linked by a single covalent bond (C0 alkyl) or by an alkyl chain having the specified number of carbon atoms, in this case 1, 2, 3, or 4 carbon atoms. The alkyl can also be linked through other groups, such as heteroatoms, as in —O—C0-C4 alkyl (C3-C7 cycloalkyl). Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, and sec-pentyl.

[0095] "Alkenyl" refers to a branched or straight-chain aliphatic hydrocarbon group having the specified number of carbon atoms and one or more carbon-carbon double bonds that may occur at any stable point along the chain. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.

[0096] "Alkynyl" refers to a branched or straight-chain aliphatic hydrocarbon group having the specified number of carbon atoms and having one or more double carbon-carbon triple bonds which may occur at any stable point along the chain.

[0097] "Alkoxy" refers to an alkyl group, as defined above, having the indicated number of carbon atoms covalently bonded to a group substituted by an oxygen bridge (-O-). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly, an "alkylthio" or "thioalkyl" group refers to an alkyl group, as defined above, having the indicated number of carbon atoms covalently bonded to a group substituted by a sulfur bridge (-S-).

[0098] "Aryl" means a stable substituted monocyclic or polycyclic aromatic ring having from 1 to 60 ring carbon atoms. Aryl groups include, but are not limited to, tolyl, xylyl, naphthyl, phenanthryl, and anthracenyl.

[0099] "Cycloalkyl" is a saturated hydrocarbon ring group having a specified number of carbon atoms, usually from 3 to about 7 carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, as well as bridged or caged saturated ring groups, such as norborane or adamantane. "-(C0-C n An "alkyl)cycloalkyl" is a cycloalkyl group attached to a substituted position by either a single covalent bond (C0) or an alkylene linker having from 1 to n carbon atoms.

[0100] "Halo" or "halogen" means fluoro, chloro, bromo, or iodo.

[0101] "Heteroaryl" refers to a stable monocyclic aromatic ring having the indicated number of ring atoms, containing 1 to 3, or in some embodiments 1 to 2, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, or a stable bicyclic or tricyclic ring system containing at least one 5- to 7-membered aromatic ring containing 1 to 3, or in some embodiments 1 to 2, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Monocyclic heteroaryl groups typically have 5 to 7 ring atoms. In some embodiments, bicyclic heteroaryl groups are 9- to 10-membered heteroaryl groups, i.e., groups containing 9 or 10 ring atoms, with one 5- to 7-membered aromatic ring fused to a second aromatic or non-aromatic ring. If the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. Preferably, the total number of S and O atoms in the heteroaryl group is 2 or less. It is particularly preferred that the total number of S and O atoms in the aromatic heterocycle is 1 or less. Heteroaryl groups include, but are not limited to, oxazolyl, piperazinyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyridizinyl, pyridylyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl, thiophenyl, triazolyl, benzo[d]oxazolyl, benzofuranyl, benzothiazolyl, benzothiophenyl, benzoxadiazolyl, dihydrobenzodioxinyl, furanyl, imidazolyl, indolyl, isothiazolyl, and isoxazolyl.

[0102] A "heterocycle" is a saturated, unsaturated, or aromatic ring group having the indicated number of ring atoms containing from one to about three heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heterocyclic groups include piperazine and thiazole groups.

[0103] "Heterocycloalkyl" is a saturated cyclic group having the indicated number of ring atoms containing from 1 to about 3 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of heterocycloalkyl groups include tetrahydrofuranyl and pyrrolidinyl groups.

[0104] "Haloalkyl" refers to both branched and straight-chain alkyl groups having the specified number of carbon atoms substituted with one or more halogen atoms, generally up to the maximum possible number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.

[0105] "Haloalkoxy" is a haloalkyl group as defined above attached through an oxygen bridge (oxygen of an alcohol radical).

[0106] "Pharmaceutical composition" means a composition comprising at least one active agent, such as a compound or salt of Formula (I), and at least one other substance, such as a carrier. The pharmaceutical composition meets USFDA GMP (Good Manufacturing Practice) specifications for human or non-human drugs.

[0107] "Carrier" refers to a diluent, excipient, or vehicle with which an active compound is administered. "Pharmaceutically acceptable carrier" refers to a substance, e.g., an excipient, diluent, or vehicle, useful in preparing pharmaceutical compositions that are generally safe, non-toxic, and not biologically or otherwise undesirable, and includes carriers acceptable for veterinary use as well as for human pharmaceutical use. "Pharmaceutically acceptable carrier" includes both one and more than one such carrier.

[0108] "Patient" means a human or non-human animal in need of medical treatment. Medical treatment can include treatment of an existing condition, such as a disease or disorder, or diagnostic treatment. In some embodiments, the patient is a human patient.

[0109] "Providing" means giving, administering, selling, distributing, transporting (commercially or not), manufacturing, compounding, or distributing.

[0110] "Treatment" or "treating" means providing an active compound to a patient in an amount sufficient to measurably reduce any cancer symptoms, slow the progression of cancer, or cause regression of cancer. In certain embodiments, cancer treatment may begin before the patient exhibits symptoms of the disease.

[0111] A "therapeutically effective amount" of a pharmaceutical composition means an amount that, when administered to a patient, is effective to provide a therapeutic benefit, such as amelioration of symptoms, slowing of cancer progression, or causing cancer regression.

[0112] A significant change is any detectable change that is statistically significant in a standard parametric test of statistical significance, such as a Student's T test, where p<0.05. chemical description

[0113] The compounds of Formula I, II, or III may contain one or more asymmetric elements, such as asymmetric carbon atoms, including asymmetric centers, asymmetric axes, and the like, and therefore the compounds can exist in various stereoisomeric forms. These compounds can be, for example, racemic or optically active. In the case of compounds with two or more asymmetric elements, these compounds can also be mixtures of diastereomers. In the case of compounds with asymmetric centers, all optical isomers in pure form and mixtures thereof are encompassed. In these situations, single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemate. Resolution of the racemate can also be achieved by conventional methods, such as crystallization in the presence of a resolving agent, or chromatography, e.g., using a chiral HPLC column. All forms are contemplated herein, regardless of the method used to obtain them.

[0114] All forms of the active agent (eg, solvates, optical isomers, enantiomeric forms, tautomers, polymorphs, free compounds and salts) may be used alone or in combination.

[0115] The term "chiral" refers to molecules that possess the property of non-superimposability of their mirror image partners.

[0116] "Stereoisomers" are compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

[0117] "Diastereomers" are stereoisomers with two or more chiral centers whose molecules are not mirror images of one another. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high-resolution analytical procedures such as electrophoresis, crystallization in the presence of a resolving agent, or chromatography, e.g., using a chiral HPLC column.

[0118] "Enantiomers" refer to two stereoisomers of a compound that are non-superimposable mirror images of one another. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, and may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.

[0119] Stereochemical definitions and conventions used herein generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule with respect to its chiral center(s). The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory.

[0120] A "racemic mixture" or "racemate" is an equimolar (or 50:50) mixture of two enantiomeric species, devoid of optical activity. A racemic mixture may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.

[0121] "Tautomers" or "tautomeric forms" are structural isomers that are readily interconvertible by hydrogen atom migration, generally combined with single and double bond switching.

[0122] "Pharmaceutically acceptable salts" include derivatives of the disclosed compounds in which the parent compound is modified by making its inorganic and organic non-toxic acid or base addition salts. Salts of the compounds of the present invention can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of an appropriate base (such as hydroxide, carbonate, bicarbonate, or salt of Na, Ca, Mg, or K), or by reacting the free base forms of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used, where practicable. Salts of the compounds of the present invention also include solvates of the compounds and compound salts.

[0123] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, mesylic acid, esylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) nand salts prepared from organic acids such as —COOH, where n is 0 to 4. Lists of additional suitable salts can be found, for example, in G. Steffen Paulekuhn, et al., Journal of Medicinal Chemistry 2007, 50, 6665 and Handbook of Pharmaceutically Acceptable Salts: Properties, Selection and Use, P. Heinrich Stahl and Camille G. Wermuth Editors, Wiley-VCH, 2002. chemical description

[0124] Disclosed herein are molecules that modulate CD206.

[0125] In addition to the compounds of Formula I, Formula II, and Formula III shown in the Summary section, the present disclosure also provides compounds containing variables such as X and R 1 From R 25 Also included are compounds having the following definitions: The present disclosure includes all combinations of these definitions so long as a stable compound results.

[0126] The present disclosure provides a compound of formula I [ka] The following specific embodiments include:

[0127] (A) In an embodiment, R 1 is hydrogen, halogen, hydroxyl, cyano, -CO2H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C0-C6 alkyl)cycloalkyl, C1-C6 haloalkyl, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -C(O)C1-C6 alkyl, -C(O)NR 8 R 9 , -(C0-C6 alkyl)NR 5 R 6 , -CO2R 6, -C6H4-R 7 and a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently selected from N, S, and O.

[0128] R 2 and R 4 is H.

[0129] R 3 is hydrogen, halogen, hydroxyl, cyano, -CO2H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C0-C6 alkyl)cycloalkyl, C1-C6 haloalkyl, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -C(O)C1-C6 alkyl, -C(O)NR 5 R 6 , (C0-C6 alkyl)NR 8 R 9 , -CO2R 6 , and -C6H4-R 7 is.

[0130] a, b, c, and d are each independently selected at each occurrence from N, C, and CH.

[0131] X is N.

[0132] R 5 and R 6 each independently at each occurrence represents hydrogen, halogen, hydroxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, substituted or unsubstituted -(C0-C6 alkyl)cycloalkyl, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -C(O)C1-C6 alkyl, -C(O)(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)NR 8 R 9, —C(O)(C0-C6 alkyl)aryl, —C(O)(C0-C6 alkyl)heteroaryl, and a 4- to 7-membered heterocycloalkyl ring having 1, 2, or 3 ring atoms independently selected from N, O, and S.

[0133] Any R bonded to the same nitrogen atom 5 and R 6 may be joined to form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, wherein the heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms selected from N, O, S, S(O), and SO, and the heterocycloalkyl ring optionally contains at any carbon or hetero ring atom: halogen, hydroxyl, cyano, oxo, dioxo, C-C alkyl, C-C alkoxy, C-C haloalkyl, -(C-C alkyl)cycloalkyl, -(C-C alkyl)phenyl, -(C-C alkyl)aryl, -(C-C alkyl)COR 8 , -(C0-C6 alkyl)C(O)NR 8 R 9 , -(C1-C6 alkyl)OR 8 , -C(O)C1-C6 alkyl, -(C0-C6 alkyl)NR 8 R 9 or -C(O)(C0-C6 alkyl)NR 8 R 9 is replaced by .

[0134] R 7 is hydrogen, halogen, hydroxyl, cyano, -CO2H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl)cycloalkyl, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -CO2R 8, -C(O)C1-C6 alkyl, -C(O)C2-C6 alkenyl, -C(O)C2-C6 alkynyl, -C(O)C1-C6 alkoxy, -C(O)C1-C6 hydroxyalkyl, -C(O)-(C0-C6 alkyl)cycloalkyl, -C(O)-(C0-C6 alkyl)phenyl, -C(O)-(C0-C6 alkyl)aryl, -C(O)-(C0-C6 alkyl)heteroaryl, -C(O)NR 8 R 9 , -C(O)NR 5 R 6 , -C(O)-(C0-C6 alkyl)NR 5 R 6 , -C(O)-NR 8 -(C0-C6 alkyl)NR 5 R 6 , or (C0-C6 alkyl)NR 5 R 6 is.

[0135] R 8 and R 9 are each independently, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)NR 5 R 6 , -CO2R 6 , —C(O)C1-C6 alkyl, and —(C0-C6 alkyl)cycloalkyl.

[0136] (B) In an embodiment, R 1 is -C6H4-R 7 is.

[0137] R 2 and R 4 is H.

[0138] R 3 is -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, or -(C0-C6 alkyl)heteroaryl.

[0139] a, c, and X are N.

[0140] b is C.

[0141] d is CH.

[0142] R 7 is -C(O)NR 5 R 6 or -C(O)-NR 8 -(C0-C6 alkyl)NR 5 R 6 is.

[0143] R 5 and R 6 each occurrence independently represents hydrogen, substituted or unsubstituted -(C0-C6 alkyl)cycloalkyl, -(C0-C6 alkyl)heteroaryl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, -(C0-C6 alkyl)NR 8 R 9 and 4- to 7-membered heterocycloalkyl rings having 1, 2, or 3 ring atoms independently selected from N, O, and S.

[0144] Any R bonded to the same nitrogen atom 5 and R 6 may be joined to form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms selected from N, O, S, S(O), and SO, and which heterocycloalkyl ring optionally contains at any carbon or hetero ring atom: halogen, hydroxyl, cyano, oxo, dioxo, C-C alkyl, C-C alkoxy, C-C haloalkyl, -(C-C alkyl)cycloalkyl, -(C-C alkyl)phenyl, -(C-C alkyl)aryl, -(C-C alkyl)COR 8 , -(C0-C6 alkyl)C(O)NR 8 R 9 , -(C1-C6 alkyl)OR 8, -CO2R 8 , -C(O)C1-C6 alkyl, -(C0-C6 alkyl)NR 8 R 9 or -C(O)(C0-C6 alkyl)NR 8 R 9 is replaced by .

[0145] R 8 and R 9 are each independently, at each occurrence, hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)NR 5 R 6 , -CO2R 6 , —C(O)C1-C6 alkyl, and —(C0-C6 alkyl)cycloalkyl.

[0146] (C) In embodiments, the compounds of formula I are compounds 1 and 4 through 29: [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0147] (D) In ​​an embodiment, R 1 is -C6H4-R 7 is.

[0148] R 2 and R 4 is hydrogen.

[0149] R 3 is -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, or -(C0-C6 alkyl)heteroaryl.

[0150] a, c, d, and X are N.

[0151] b is C.

[0152] R 7 is -C(O)-NR 8 -(C0-C6 alkyl)NR 5 R 6 is.

[0153] R attached to the same nitrogen atom 5 and R 6 may be joined to form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring containing 0, 1, or 2 additional heteroatoms selected from N, O, S, S(O), and SO, and the heterocycloalkyl ring is optionally substituted at any carbon or heterocycle with halogen, hydroxyl, cyano, oxo, dioxo, C-C alkyl, C-C alkoxy, C-C haloalkyl, -(C-C alkyl)cycloalkyl, -(C-C alkyl)phenyl, or -(C-C alkyl)aryl.

[0154] R 8 is hydrogen.

[0155] (E) In an embodiment, the compound of formula I is selected from Compound 30 and Compound 31: [ka] or a pharmaceutically acceptable salt thereof.

[0156] (F) In an embodiment, R 1 is -C6H4-R 7 is.

[0157] R 2 and R 4 is hydrogen.

[0158] R 3 is -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, or -(C0-C6 alkyl)heteroaryl.

[0159] a is C.

[0160] b, d, and X are N.

[0161] c is CH.

[0162] R 7 is -C(O)-NR 8 -(C0-C6 alkyl)NR 5 R 6 is.

[0163] R attached to the same nitrogen atom 5 and R 6 are taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms selected from N, O, S, S(O), and SO, and which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C-C alkyl, C-C alkoxy, C-C haloalkyl, -(C-C alkyl)cycloalkyl, -(C-C alkyl)phenyl, or -(C-C alkyl)aryl.

[0164] R 8 is hydrogen.

[0165] (G) In an embodiment, the compound of formula I is compound 32: [ka] or a pharmaceutically acceptable salt thereof.

[0166] (H) In an embodiment, R 1 is -C6H4-R 7 is.

[0167] R 2 and R 4 is hydrogen.

[0168] R 3 is -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, or -(C0-C6 alkyl)heteroaryl.

[0169] a is C.

[0170] b and X are N.

[0171] c and d are CH.

[0172] R 7 is -C(O)-NR 8 -(C0-C6 alkyl)NR 5 R 6 is.

[0173] R attached to the same nitrogen atom 5 and R 6 are taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, which heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms selected from N, O, S, S(O), and SO, and which heterocycloalkyl ring is optionally substituted at any carbon or hetero ring atom with halogen, hydroxyl, cyano, oxo, dioxo, C-C alkyl, C-C alkoxy, C-C haloalkyl, -(C-C alkyl)cycloalkyl, -(C-C alkyl)phenyl, or -(C-C alkyl)aryl.

[0174] R 8 is hydrogen.

[0175] (I) In an embodiment, the compound of formula I is compound 33: [ka] or a pharmaceutically acceptable salt thereof.

[0176] The present disclosure provides a compound of formula II [ka] This includes specific embodiments of:

[0177] In some embodiments, the compound of formula II has the formula IIA [ka] is a compound of

[0178] (A) In an embodiment, R 10 and R 11 is independently selected at each occurrence from -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, and -(C0-C6 alkyl)heteroaryl.

[0179] R 12 , R 14 , and R 15 is hydrogen.

[0180] R 13 is —C(O)heteroaryl.

[0181] (B) In an embodiment, R 10 is —(C0-C6 alkyl)phenyl.

[0182] R 11 is —(C0-C6 alkyl)heteroaryl.

[0183] R 12 , R 14 , and R 15 is hydrogen.

[0184] R 13is —C(O)heteroaryl.

[0185] (C) In embodiments, the compound of formula IIA is compound 2: [ka] or a pharmaceutically acceptable salt thereof.

[0186] The present disclosure provides a compound of formula III [ka] This includes specific embodiments of:

[0187] (A) In an embodiment, R 17 is —C(O)C1-C6 alkyl, —C(O)(C0-C6 alkyl)phenyl, —C(O)(C0-C6 alkyl)aryl, or —C(O)(C0-C6 alkyl)heteroaryl.

[0188] R 18 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C0-C6 alkyl)cycloalkyl, C1-C6 haloalkyl, -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, or -(C0-C6 alkyl)heteroaryl.

[0189] R 19 , R 20 , and R 22 is hydrogen.

[0190] R 21 is -NR 23 R 24 is.

[0191] Each occurrence of X is selected from O and S.

[0192] R 23 and R 24are each independently selected from -S(O)phenyl, -S(O)aryl, -S(O)heteroaryl, -SO2phenyl, -SO2aryl, -SO2heteroaryl, -(C0-C6 alkyl)cycloalkyl, and -CO2R 25 is selected from.

[0193] R 25 is C1-C6 alkyl, -(C0-C6 alkyl)cycloalkyl, -(C0-C6 alkyl)aryl, or -(C0-C6 alkyl)phenyl.

[0194] (B) In an embodiment, R 17 is —C(O)C1-C6 alkyl.

[0195] R 18 is a C1-C6 alkyl.

[0196] R 19 , R 20 , and R 22 is hydrogen.

[0197] R 21 is -NR 23 R 24 is.

[0198] X is oxygen.

[0199] R 23 and R 24 is independently selected from each occurrence of substituted or unsubstituted arylsulfonyl, -COR 25 , -SO2phenyl, -SO2aryl, and -SO2R 25 is selected from.

[0200] R 25 is phenyl.

[0201] In embodiments, the compound of formula III is compound 3: [ka] or a pharmaceutically acceptable salt thereof. Treatment method

[0202] Compounds of Formula I, Formula II, or Formula III, or salts thereof, and pharmaceutical compositions containing the compounds are useful for treating cancer, including achieving tumor regression in vivo. A method for treating cancer or achieving tumor regression includes providing an effective amount of a compound of Formula I, Formula II, or Formula III to a patient. In embodiments, the patient is a mammal, more particularly a human. The present disclosure also provides methods for treating non-human patients, such as companion animals, e.g., cats, dogs, and livestock animals. An effective amount of the pharmaceutical composition may be an amount sufficient to inhibit the progression of cancer or cancerous tumors; or to cause regression of cancer or cancerous tumors.

[0203] An effective amount of the compound or pharmaceutical composition described herein, when administered to a patient, will also provide a sufficient concentration of the compound of Formula I, Formula II, or Formula III. A sufficient concentration is the concentration of the compound in the patient's body required to eliminate the disorder. Such an amount can be determined experimentally, for example, by assaying the blood concentration of the compound, or theoretically, by calculating bioavailability.

[0204] The method of treatment comprises providing a patient with a certain dosage of a compound of Formula I, Formula II, or Formula III. A dosage level of about 20 milligrams (mg) or less per kilogram of body weight per day of each compound is useful for treating the above-mentioned conditions. The frequency of administration may vary depending on the compound used and the specific disease being treated.

[0205] The compounds of Formula I, Formula II, or Formula III may be used to treat cancer, including cancerous tumors, and achieve tumor regression. In certain embodiments, the patient suffers from a cell proliferation disorder or disease. The cell proliferation disorder can be cancer, tumor (cancerous or benign), neoplasm, neovascularization, or melanoma. Cancers to be treated include both solid and disseminated cancers. Exemplary solid cancers (tumors) that can be treated by the methods provided herein include, for example, lung, prostate, breast, liver, colon, breast, kidney, pancreas, brain, skin, testicular, or ovarian carcinomas, including malignant melanoma and Kaposi's sarcoma, renal cancer (renal cell), and sarcoma.

[0206] Cancers that can be treated with a compound of Formula I, Formula II, or Formula III include bladder cancer, breast cancer, colon cancer, endometrial cancer, lung cancer, bronchial cancer, melanoma, non-Hodgkin's lymphoma, blood cancer, pancreatic cancer, prostate cancer, thyroid cancer, brain or spinal cancer, and leukemia. Exemplary disseminated cancers include leukemia or lymphoma, including Hodgkin's disease, multiple myeloma and mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), T-cell leukemia, multiple myeloma, and Burkitt's lymphoma. In particular, the present specification includes a method for treating cancer by providing a compound of Formula I, Formula II, or Formula III to a patient whose cancer is a solid tumor or disseminated cancer.

[0207] Further included are methods of treating cancer by providing a compound of Formula I, Formula II, or Formula III to a patient whose cancer is selected from glioma (glioblastoma), acute myelogenous leukemia, acute myeloid leukemia, myelodysplastic / myeloproliferative neoplasm, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin's lymphoma, astrocytoma, melanoma, non-small cell lung cancer, cholangiocarcinoma, chondrosarcoma, or colon cancer.

[0208] However, it will be understood that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration and excretion rate, drug combination, and the severity of the particular disease being treated.

[0209] The compounds of Formula I, Formula II, or Formula III may be administered alone (i.e., in a monotherapeutic regime) or in combination with another active agent to treat diseases and conditions such as unwanted cell proliferation, cancer, and / or tumor growth. One or more compounds of Formula I, Formula II, or Formula III may be administered in conjunction with a regime of one or more other chemotherapeutic agents, such as an anti-neoplastic agent, e.g., an alkylating agent (e.g., mechloroethamine, chlorambucil, cyclophosamide, melphalan, or ifosfamide), an antimetabolite, e.g., a folate antagonist (e.g., methotrexate), a purine antagonist (e.g., 6-mercaptopurine), or a pyrimidine antagonist (e.g., 5-fluorouracil). Other non-limiting examples of chemotherapeutic agents that may be used in conjunction with one or more compounds of Formula I, Formula II, or Formula III include taxanes and topoisomerase inhibitors. Further, other non-limiting examples of active therapeutic substances include biologic agents, such as monoclonal antibodies or IgG chimeric molecules, which achieve their therapeutic effect by specifically binding to a receptor or ligand in a signal transduction pathway associated with cancer (e.g., therapeutic antibodies against CD20 (e.g., rituximab) or VEGF (e.g., bevacizumab)).

[0210] The methods of treatment provided herein are also useful for treating mammals other than humans, including veterinary applications, such as treating horses and livestock, e.g., cattle, sheep, dairy cows, goats, pigs, and the like, as well as pets (companion animals), e.g., dogs and cats.

[0211] For diagnostic or research applications, a wide variety of mammals are suitable subjects, including rodents (e.g., mice, rats, hamsters), rabbits, primates, and pigs, e.g., inbred pigs, and the like. Furthermore, for in vitro applications, such as in vitro diagnostic and research applications, bodily fluids (e.g., blood, plasma, serum, interstitial fluid, saliva, stool, and urine) and cell and tissue samples from the subjects are suitable for use.

[0212] In embodiments, the present invention provides a method of treating a cancer disorder in a patient identified as in need of such treatment, comprising providing to the patient an effective amount of a compound of Formula I, Formula II, or Formula III. The compounds and salts of Formula I, Formula II, or Formula III provided herein may be administered alone or in combination with one or more other active agents.

[0213] In embodiments, the cancer treated is characterized by selective targeting of M2 macrophages in the patient and reprogramming M2 macrophages toward an M1 phenotype.

[0214] As shown in Figure 19, Compound 1 demonstrated tumor reduction by M2 macrophages in an M2 macrophage adoptive transfer study in a KPC allograft model of the C57BL / 6 maul model compared to vehicle, with intratumoral injections at a frequency of three times per week and measurements at a frequency of twice per week.

[0215] Tumor growth was suppressed during in vivo testing of Compound 1 in fully immunocompetent transgenic Kras(G12D) / Trp53(R172H) / Pdx-1-Cre (KPC) mice (a murine pancreatic cancer model) compared to vehicle, as shown in Figure 3B. This point is further illustrated in Figures 3A and 3C, which show a comparison of tumor volumes for mice treated with Compound 1 and untreated mice (vehicle).

[0216] As shown in Figures 18A to 18C, flow cytometry analysis of KPC tumors treated with Compound 1 compared to vehicle demonstrated that treatment with Compound 1 resulted in a reduction of CD206 macrophages, CD206 high demonstrate a shift from M2 to CD86-positive M1 macrophages and an increase in intratumoral CD8 cells;

[0217] As shown in Figures 18D to 18I, when cytokine and immune checkpoint profiles were compared with vehicle after 2 weeks of treatment with Compound 1 in KPC mice, Compound 1 demonstrated preferential infiltration of tumors by M2 macrophages compared with M1 macrophages. [Example]

[0218] Abbreviation ACN Acetonitrile

[0219] AcOH acetic acid

[0220] DCM dichloromethane

[0221] DCE 1,2-dichloroethane

[0222] DIPEA Diisopropylethylamine

[0223] DMF Dimethylformamide

[0224] DMSO dimethyl sulfoxide

[0225] EDC Ethylene dichloride

[0226] EtOAc ethyl acetate

[0227] EtOH ethanol

[0228] ESI electrospray ionization

[0229] HATU Hexafluorophosphate Azabenzotriazole Tetramethyluronium

[0230] HEX / Hex Hexane

[0231] HOBt 1-hydroxybenzotriazole

[0232] HPLC High Performance Liquid Chromatography

[0233] LCMS Liquid Chromatography / Mass Spectroscopy

[0234] MHz Megahertz

[0235] μL microliter

[0236] mL milliliter

[0237] mg milligram

[0238] mmol millimolar

[0239] NMR nuclear magnetic resonance

[0240] TLC thin layer chromatography Schematic method

[0241] All air- or moisture-sensitive reactions were carried out in oven-dried glassware under a positive nitrogen pressure. Anhydrous solvents, such as dichloromethane, N,N-dimethylformamide (DMF), acetonitrile (ACN), methanol (MeOH), and triethylamine (EtN), were purchased from Sigma-Aldrich (St. Louis, MO). Preparative purifications were performed on a Waters semi-preparative HPLC system (Waters Corp., Milford, MA). The column used was a Phenomenex Luna C18 (5 micron, 30 × 75 mm; Phenomenex, Inc., Torrance, CA) with a flow rate of 45.0 mL / min. The mobile phase consisted of acetonitrile and water (each containing 0.1% trifluoroacetic acid). A gradient of 10% to 50% acetonitrile over 8 min was used during purification. Fraction collection was triggered by UV detection at 220 nm. Analytical analysis was performed on an Agilent LCMS (Agilent Technologies, Santa Clara, CA). Method 1: A 7-minute gradient of 4% to 100% acetonitrile (containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) was used at a flow rate of 1.0 mL / min with an 8-minute run time. Method 2: A 3-minute gradient of 4% to 100% acetonitrile (containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) was used at a flow rate of 1.0 mL / min with a 4.5-minute run time. A Phenomenex Luna C18 column (3 microns, 3 × 75 mm) was used at a temperature of 50 °C. Purity determinations were performed using an Agilent diode array detector for both Methods 1 and 2. Mass determinations were performed using an Agilent 6130 mass spectrometer with electrospray ionization in positive mode. 1H NMR spectra were recorded on a Varian 400 MHz spectrophotometer (Agilent Technologies, Santa Clara, CA). Chemical shifts are reported in ppm with non-deuterated solvents (DMSO at 2.50 ppm and CHCl at 7.26 ppm) as internal standards for DMSO-d and CDCl solutions, respectively. All analogs tested in biological assays have purity greater than 95% based on both analytical methods. High-resolution mass spectrometry was recorded on an Agilent 6210 time-of-flight (TOF) LCMS system. Confirmation of molecular formula was achieved using electrospray ionization in positive mode with Agilent Masshunter software (Version B.02). Starting materials were purchased from Combi-Blocks (San Diego, CA) or Sigma-Aldrich (St. Louis, MO) and used as received without further purification. Example 1 Synthesis of 2-(azidomethyl)-5-chloropyrazine [ka]

[0242] Thionyl chloride (505 μL, 6.92 mmol) was added to a solution of (5-chloropyrazin-2-yl)methanol (500 mg, 3.46 mmol) and catalytic DMF in DCM (20 mL). The resulting reaction mixture was stirred at room temperature for 1 hour (h), after which LC-MS and TLC (20% EtOAc in HEX) analysis indicated completion. The reaction mixture was concentrated to dryness, taken up in DCM, and concentrated to dryness again. The residue was taken up in DMF (10 mL), and potassium carbonate (478 mg, 3.46 mmol) was added, followed by sodium azide (270 mg, 4.15 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, after which LC-MS analysis indicated completion. The reaction mixture was taken up in HO and extracted twice with EtOAc, and the combined organic layers were washed twice with brine, dried over anhydrous MgSO, filtered, and concentrated to give 2-(azidomethyl)-5-chloropyrazine (587 mg, 3.46 mmol, 100% yield) as a golden oil, which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 1.4 Hz, 1H), 8.57 (d, J = 1.2 Hz, 1H), 4.64 (s, 2H).LCMS retention time (RT) (method 2) = 2.644 min, m / z 170.6[M+H + ]. Example 2 Synthesis of (5-chloropyrazin-2-yl)methanamine, HCl [ka]

[0243] To a solution of 2-(azidomethyl)-5-chloropyrazine (587 mg, 3.46 mmol) in MeOH (40.0 mL) was added triphenylphosphine (1.36 grams (g), 5.19 mmol). The resulting reaction mixture was fitted with a condenser and stirred at 80° C. for 1.5 hours, after which LCMS and TLC (20% EtOAc in Hex) analysis indicated completion. The reaction mixture was concentrated to dryness, and the residue was taken up in toluene (25.0 mL) and treated with 4.0 molar (M) HCl in dioxane (2.00 mL, 8.00 mmol), precipitating the product as the HCl salt. The solid was filtered, rinsed with toluene, and air-dried to afford crude (5-chloropyrazin-2-yl)methanamine, HCl (550 mg, 3.05 mmol, 88% yield) as a tan solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.88 (d, J = 1.4 Hz, 1H), 8.68 (d, J = 1.4 Hz, 1H), 8.65 (s, 3H), 4.26 (s, 2H). Example 3 Synthesis of methyl 4-(((5-chloropyrazin-2-yl)methyl)carbamoyl)benzoate [ka]

[0244] A mixture of 4-(methoxycarbonyl)benzoic acid (605 mg, 3.36 mmol) and HATU (1394 mg, 3.67 mmol) in DMF (10.0 mL) was stirred for 10 minutes (min). (5-Chloropyrazin-2-yl)methanamine, HCl (550 mg, 3.05 mmol) was added and the mixture was allowed to stir for 5 minutes, after which DIPEA (1.87 mL, 10.7 mmol) was added and the resulting reaction mixture was stirred overnight, after which LCMS analysis indicated completion. The reaction mixture was diluted with HO and extracted twice with EtOAc. The combined organic layers were washed twice with brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by flash column chromatography: silica gel (with a gradient of 20–60% EtOAc in Hex) to afford methyl 4-(((5-chloropyrazin-2-yl)methyl)carbamoyl)benzoate (897 mg, 2.93 mmol, 96% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (t, J = 5.7 Hz, 1H), 8.75 (d, J = 1.4 Hz, 1H), 8.53 (d, J = 1.4 Hz, 1H), 8.07 - 8.04 (m, 2H), 8.03 - 7.99 (m, 2H), 4.63 (d, J = 5.7 Hz, 2H), 3.88 (s, 3H).LCMS RT (Method 2) = 2.886 min, m / z 635.6[2M+Na + ]. Example 4 Synthesis of methyl 4-(6-chloroimidazo[1,5-a]pyrazin-3-yl)benzoate [ka]

[0245] A 1 molar (M) solution of triflic anhydride (3.52 mL, 3.52 mmol) in DCM was slowly added to a solution of methyl 4-(((5-chloropyrazin-2-yl)methyl)carbamoyl)benzoate (897 mg, 2.93 mmol) and 2-methoxypyridine (339 μL, 3.23 mmol) in DCE (10.0 mL). The resulting reaction mixture was then placed in a preheated reaction block at 45 °C and allowed to stir for 2 h, after which LCMS analysis indicated completion. The reaction mixture was cooled to room temperature and quenched by the addition of saturated sodium carbonate solution, stirred for 5 min, diluted with DCM and HO, the layers were separated, and the organic phase was washed with brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was triturated in 10% hexanes in EtOH, filtered, rinsed with hexanes, and air-dried to give methyl 4-(6-chloroimidazo[1,5-a]pyrazin-3-yl)benzoate (671 mg, 2.33 mmol, 79% yield) as a light tan solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 1.4 Hz, 1H), 8.66 (t, J = 1.2 Hz, 1H), 8.17 (d, J = 1.0 Hz, 1H), 8.14 (d, J = 8.8 Hz, 2H), 8.11 (d, J = 8.9 Hz, 2H), 3.91 (s, 3H).LCMS RT(Method 2)=3.071 min, m / z 287.8[M + ]. Example 5 Synthesis of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzoic acid [ka]

[0246] A mixture of methyl 4-(6-chloroimidazo[1,5-a]pyrazin-3-yl)benzoate (100 mg, 0.348 mmol), (3-fluorophenyl)boronic acid (58.4 mg, 0.417 mmol), XPhosPd(crotyl)Cl (11.71 mg, 0.017 mmol), and KPO (148 mg, 0.695 mmol) was placed in a vial and purged with N for 2 minutes. 4:1 dioxane-HO (2.50 mL) was added, degassing continued for 2 minutes, and then the reaction vessel was placed in a preheated block at 90 °C. After stirring at 90 °C for 30 minutes, LCMS analysis indicated completion. The reaction mixture was cooled to room temperature, diluted with EtOAc and HO, filtered through Celite, and the layers were separated. The organic phase was washed with brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was triturated with 10% hexanes in EtOH, filtered, rinsed with hexanes, and air-dried to give the intermediate methyl ester compound, which was taken up in 1:1 EtOH-THF (5.00 mL) and treated with 2 M sodium hydroxide (2.00 mL, 4.00 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, after which LCMS analysis indicated completion. The reaction mixture was concentrated to a slurry, and the residue was taken up in HO and the pH was adjusted to approximately 5 with AcOH to precipitate the product. The product was then collected by filtration, rinsed generously with HO, and air-dried to give 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzoic acid (96.0 mg, 0.289 mmol, 83% yield) as an off-white solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 9.30 (d, J = 1.6 Hz, 1H), 8.89 - 8.84 (m, 1H), 8.15 (s, 4H), 8.10 (d, J = 0.9 Hz, 1H), 7.98 - 7.90 (m, 2H), 7.53 (td, J = 8.2, 6.3 Hz, 1H), 7.30 - 7.20 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ -112.98 (td, J = 9.9, 6.3 Hz).LCMS RT (Method 2)=3.144 min, m / z 334.8[M+H + ]. Example 6 Synthesis of 4-(6-chloroimidazo[1,5-a]pyrazin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)benzamide [ka]

[0247] A solution of LiOH (125 mg, 5.21 mmol) in HO (1.00 mL) was added to a solution of methyl 4-(6-chloroimidazo[1,5-a]pyrazin-3-yl)benzoate (300 mg, 1.043 mmol) in THF (4.00 mL). The resulting reaction mixture was stirred at room temperature for 1 hour, after which LCMS analysis indicated completion. The reaction mixture was concentrated to a slurry, and the residue was taken up in HO and the pH was adjusted to approximately 5 with AcOH to precipitate the product. The product was then collected by filtration, rinsed generously with HO, and air-dried to give the intermediate acid, which was used without further purification.

[0248] A mixture of intermediate 4-(6-chloroimidazo[1,5-a]pyrazin-3-yl)benzoic acid (203 mg, 0.742 mmol) and HATU (310 mg, 0.816 mmol) in DMF (5.00 mL) was stirred for 10 minutes, after which 1-(3-aminopropyl)pyrrolidin-2-one (105 mg, 0.742 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, after which DIPEA (259 μL, 1.48 mmol) was added and the reaction was stirred for 2 hours, after which LCMS analysis indicated completion. The reaction mixture was diluted with EtOAc, washed with HO and brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with a gradient of 0–30% MeOH in EtOAc to afford 4-(6-chloroimidazo[1,5-a]pyrazin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)benzamide (207 mg, 0.520 mmol, 70.1% yield) as an off-white solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.87 (d, J = 1.4 Hz, 1H), 8.21 (t, J = 1.2 Hz, 1H), 8.17 (d, J = 8.4 Hz, 2H), 8.08 (s, 1H), 8.01 (d, J = 1.0 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 3.49 - 3.44 (m, 6H), 2.50 (t, J = 8.1 Hz, 2H), 2.17 - 2.07 (m, 2H), 1.86 - 1.77 (m, 2H).LCMS RT (method 2) = 2.772 min, m / z 398.8[M+H + ]. Example 7 Synthesis of N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(6-(pyridin-3-yl)imidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 26) [ka]

[0249] A mixture of 4-(6-chloroimidazo[1,5-a]pyrazin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)benzamide (10.0 mg, 0.025 mmol), pyridin-3-ylboronic acid (3.71 mg, 0.030 mmol), XPhosPd(crotyl)Cl (0.847 mg, 1.26 μmol), and KPO (10.7 mg, 0.050 mmol) was placed in a vial and purged with N for 2 minutes. 4:1 dioxane-HO (2.50 mL) was added and degassing continued for 2 minutes, after which the reaction vessel was placed in a preheated block at 90 °C. After stirring for 30 minutes at 90 °C, LCMS analysis indicated completion. The reaction mixture was cooled to room temperature, loaded directly onto a silica gel column, and purified by flash column chromatography: silica gel with a gradient of 5–50% MeOH in EtOAc to give N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(6-(pyridin-3-yl)imidazo[1,5-a]pyrazin-3-yl)benzamide (9.3 mg, 0.021 mmol, 84% yield) as an off-white crystallized solid. 1 H NMR (400 MHz, Chloroform-d) δ 9.14 (d, J = 1.6 Hz, 1H), 9.13 (dd, J = 2.4, 0.9 Hz, 1H), 8.66 (dd, J = 4.8, 1.6 Hz, 1H), 8.50 (dd, J = 1.6, 1.0 Hz, 1H), 8.23 ​​(ddd, J = 8.0, 2.4, 1.7 Hz, 1H), 8.20 - 8.16 (m, 2H), 8.08 (t, J = 6.3 Hz, 1H), 8.00 (d, J = 0.9 Hz, 1H), 7.98 - 7.93 (m, 2H), 7.42 (ddd, J = 8.0, 4.8, 0.9 Hz, 1H), 3.46 (tt, J = 7.4, 2.7 Hz, 6H), 2.49 (dd, J = 8.7, 7.6 Hz, 2H), 2.17 - 2.06 (m, 2H), 1.87 - 1.77 (m, 2H).LCMS RT (method 1) = 3.232 min, m / z 441.9[M+H + ]. Example 8 Synthesis of N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(6-(3-(trifluoromethyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 27) [ka]

[0250] A mixture of 4-(6-chloroimidazo[1,5-a]pyrazin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)benzamide (10.0 mg, 0.025 mmol), (3-(trifluoromethyl)phenyl)boronic acid (5.73 mg, 0.030 mmol), XPhosPd(crotyl)Cl (0.847 mg, 1.26 μmol), and KPO (10.7 mg, 0.050 mmol) was placed in a vial and purged with N for 2 minutes. 4:1 dioxane-HO (2.50 mL) was added and degassing continued for 2 minutes, after which the reaction vessel was placed in a preheated block at 90 °C. After stirring for 30 minutes at 90 °C, LCMS analysis indicated completion. The reaction mixture was cooled to room temperature and loaded directly onto a silica gel column and purified by flash column chromatography: silica gel with a gradient of 0–30% MeOH in EtOAc to give N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(6-(3-(trifluoromethyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)benzamide (10.2 mg, 0.020 mmol, 80% yield) as an off-white crystallized solid. 1H NMR (400 MHz, Chloroform-d) δ 9.14 (d, J = 1.6 Hz, 1H), 8.50 (dd, J = 1.7, 1.0 Hz, 1H), 8.23 ​​(dd, J = 2.0, 1.1 Hz, 1H), 8.21 - 8.17 (m, 2H), 8.10 - 8.02 (m, 2H), 7.99 (d, J = 0.9 Hz, 1H), 7.98 - 7.94 (m, 2H), 7.70 - 7.65 (m, 1H), 7.59 (dt, J = 7.8, 0.7 Hz, 1H), 3.46 (tt, J = 7.5, 2.7 Hz, 6H), 2.53 - 2.44 (m, 2H), 2.17 - 2.06 (m, 2H), 1.83 (qd, J = 7.7, 6.9, 5.1 Hz, 2H). 19 F NMR (376 MHz, CDCl3) δ -62.60 (s, 3F).LCMS RT (Method 1)=5.058 min, m / z 508.8[M+H + ]. Example 9 Synthesis of N-(2-morpholinoethyl)-4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 4) [ka]

[0251] A mixture of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (50.0 mg, 0.159 mmol) and HATU (72.3 mg, 0.190 mmol) in DMF (2.00 mL) was stirred for 10 minutes, after which 2-morpholinoethan-1-amine (22.7 mg, 0.174 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, after which DIPEA (69.2 μL, 0.396 mmol) was added and the reaction was stirred overnight, after which LCMS analysis indicated completion. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was triturated with EtOH, filtered, and air-dried to give N-(2-morpholinoethyl)-4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (49.3 mg, 0.115 mmol, 72.7% yield) as a pale gold solid. 1 H NMR (400 MHz, Chloroform-d) δ 9.14 (d, J = 1.6 Hz, 1H), 8.47 (dd, J = 1.6, 1.0 Hz, 1H), 8.03 - 7.92 (m, 5H), 7.92 - 7.85 (m, 2H), 7.52 - 7.46 (m, 2H), 7.45 - 7.40 (m, 1H), 6.87 (s, 1H), 3.79 - 3.72 (m, 4H), 3.66 - 3.57 (m, 2H), 2.65 (t, J = 6.0 Hz, 2H), 2.54 (t, J = 4.6 Hz, 4H).LCMS RT (method 1) = 3.645 min, m / z 428.1[M+H + ].

[0252] FIG. 4 shows an IC50 for compound 4 of 8.95 μM. Example 10 Synthesis of N-(2-acetamidoethyl)-4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 14) [ka]

[0253] A mixture of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (50.0 mg, 0.159 mmol) and HATU (72.3 mg, 0.190 mmol) in DMF (2.00 mL) was stirred for 10 minutes, after which N-(2-aminoethyl)acetamide (17.8 mg, 0.174 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, after which DIPEA (69.2 μL, 0.396 mmol) was added and the reaction was stirred overnight, after which LCMS analysis showed completion. The reaction mixture was diluted with EtOAc, washed with HO and brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with a gradient of 0–20% MeOH in EtOAc to give N-(2-acetamidoethyl)-4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (41.3 mg, 0.103 mmol, 65.2% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J = 1.5 Hz, 1H), 8.74 (dd, J = 1.6, 1.0 Hz, 1H), 8.67 (t, J = 5.6 Hz, 1H), 8.15 - 8.03 (m, 7H), 8.00 (t, LCMS RT (method 1) = 3.515 min, m / z 400.1[M+H + ]. Example 11 Synthesis of (1,1-dioxidethiomorpholino)(4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)phenyl)methanone (Compound 15) [ka]

[0254] A mixture of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (50.0 mg, 0.159 mmol) and HATU (72.3 mg, 0.190 mmol) in DMF (2.00 mL) was stirred for 10 minutes, after which thiomorpholine 1,1-dioxide (21.4 mg, 0.159 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, after which DIPEA (69.2 μL, 0.396 mmol) was added, and the reaction was stirred overnight, after which LCMS analysis indicated completion. The reaction mixture was diluted with EtOAc, washed with HO and brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was triturated with EtOH, filtered, and air-dried to give (1,1-dioxidothiomorpholino)(4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)phenyl)methanone (54.6 mg, 0.126 mmol, 80% yield) as a pale gold solid. 1 H NMR (400 MHz, Chloroform-d) δ 9.15 (d, J = 1.6 Hz, 1H), 8.44 (dd, J = 1.6, 1.0 Hz, 1H), 8.01 - 7.96 (m, 3H), 7.92 - 7.86 (m, 2H), 7.69 - 7.64 (m, 2H), 7.53 - 7.47 (m, 2H), 7.46 - 7.41 (m, 1H), 4.16 (s, 4H), 3.11 (s, 4H).LCMS RT(Method 1)=3.845 min, m / z 433.1[M+H + ]. Example 12 Synthesis of N-(3-hydroxypropyl)-4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 16) [ka]

[0255] A mixture of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (50.0 mg, 0.159 mmol) and HATU (72.3 mg, 0.190 mmol) in DMF (2.00 mL) was stirred for 10 minutes, after which 3-aminopropan-1-ol (13.1 mg, 0.174 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, after which DIPEA (69.2 μL, 0.396 mmol) was added and the reaction was stirred overnight, after which LCMS analysis indicated completion. The reaction mixture was diluted with EtOAc, washed with HO and brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with a gradient of 0 to 20% MeOH in EtOAc to give N-(3-hydroxypropyl)-4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (41.3 mg, 0.111 mmol, 69.9% yield) as an off-white foam. 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J = 1.5 Hz, 1H), 8.74 (dd, J = 1.6, 1.0 Hz, 1H), 8.60 (t, J = 5.6 Hz, 1H), 8.15 - 8.00 (m, 7H), 7.54 - 7.45 (m, 2H), 7.45 - 7.38 (m, 1H), 4.49 (t, J = 5.2 Hz, 1H), 3.49 (td, J = 6.3, 5.2 Hz, 2H), 3.36 (q, J = 6.6 Hz, 2H), 1.71 (dq, J = 7.6, 6.4 Hz, 2H).LCMS RT (method 1) = 3.920 min, m / z 373.1[M+H + ]. Example 13 Synthesis of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide [ka]

[0256] A mixture of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (50.0 mg, 0.159 mmol) and HATU (72.3 mg, 0.190 mmol) in DMF (2.00 mL) was stirred for 10 minutes, after which 7N ammonia in MeOH (0.200 mL, 1.40 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, after which DIPEA (0.069 mL, 0.396 mmol) was added and the reaction was stirred overnight, after which LCMS analysis indicated completion. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was triturated with EtOH, filtered, and air-dried to give 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (25.0 mg, 0.080 mmol, 50.2% yield) as a pale yellow-gold solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.29 (d, J = 1.5 Hz, 1H), 8.75 (dd, J = 1.6, 0.9 Hz, 1H), 8.15 - 8.03 (m, 8H), 7.49 (tq, J = 6.2, 1.4 Hz, 3H), 7.45 - 7.39 (m, 1H).LCMS RT(Method 1)=4.038 min, m / z 651.7[2M+Na + ], 315.9 [M+H + ]. Example 14 Synthesis of 2-chloro-5-hydrazinylpyrazine [ka]

[0257] Hydrazine (0.211 mL, 6.71 mmol) was added to a solution of 2,5-dichloropyrazine (1.00 g, 6.71 mmol) in EtOH (20.0 mL). The resulting reaction mixture was stirred at 80 °C for 2 h, after which LC-MS analysis indicated completion. The reaction mixture was cooled to room temperature, causing the product to precipitate. The mixture was poured into ice-water HO, stirred vigorously for 5 min, filtered, rinsed with HO, and air-dried to afford 2-chloro-5-hydrazinylpyrazine (885 mg, 6.12 mmol, 91% yield) as a white powder, which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 4.32 (s, 2H). Example 15 Synthesis of 4-(2-(5-chloropyrazin-2-yl)hydrazine-1-carbonyl)benzoate [ka]

[0258] To a solution of 2-chloro-5-hydrazinylpyrazine (260 mg, 1.80 mmol), 4-(methoxycarbonyl)benzoic acid (405 mg, 2.25 mmol), and DIPEA (0.942 mL, 5.40 mmol) in DMF (5.00 mL) was added a 50% solution of propylphosphonic anhydride (T3P) in DMF (1.58 mL, 2.70 mmol). The resulting reaction mixture was allowed to stir at room temperature for 1 hour, after which LC-MS analysis indicated completion. The reaction mixture was poured into iced HO, stirred for 10 minutes, and the product was collected by filtration, rinsed generously with HO, and air-dried to afford methyl 4-(2-(5-chloropyrazin-2-yl)hydrazine-1-carbonyl)benzoate as a pale yellow solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 9.33 (s, 1H), 8.21 (d, J = 1.4 Hz, 1H), 8.12 - 8.06 (m, 2H), 8.06 - 7.99 (m, 2H), 7.94 (d, J = 1.4 Hz, 1H), 3.90 (s, 3H).LCMS RT (Method 2)=2.784 min, m / z 306.8[M + ]. Example 16 Synthesis of methyl 4-(6-chloro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzoate [ka]

[0259] Perchloroethane (232 mg, 0.978 mmol) was added to a suspension of methyl 4-(2-(5-chloropyrazin-2-yl)hydrazine-1-carbonyl)benzoate (150 mg, 0.489 mmol), triphenylphosphine (257 mg, 0.978 mmol), and DIPEA (0.342 mL, 1.96 mmol) in ACN (5.00 mL) filtered through 4 Å molecular sieves (MS). The resulting reaction mixture was stirred at 80 °C for 2 h, after which LCMS analysis indicated completion. The reaction mixture was cooled to room temperature and filtered through Celite, and the filter cake was rinsed generously with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel with a 20-60% EtOAc gradient in Hex to give methyl 4-(6-chloro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzoate (105 mg, 0.364 mmol, 74.4% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.46 (d, J = 1.5 Hz, 1H), 8.94 (d, J = 1.5 Hz, 1H), 8.19 (d, J = 2.5 Hz, 2H), 8.17 (d, J = 2.7 Hz, 2H), 3.93 (s, 3H).LCMS RT (Method 2) = 2.972 min, m / z 600.6[2M+Na + ], 289.9[M + ]. Example 17 Synthesis of methyl 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzoate [ka]

[0260] A mixture of methyl 4-(6-chloro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzoate (40.0 mg, 0.139 mmol), phenylboronic acid (21.1 mg, 0.173 mmol), XPhosPd(crotyl)Cl (4.67 mg, 6.93 μmol), and KPO (58.8 mg, 0.277 mmol) was placed in a vial and purged with N for 2 minutes. 4:1 dioxane:HO (2.50 mL) was added and degassing continued for 2 minutes, after which the reaction vessel was placed in a preheated block at 100 °C. After stirring at 100 °C for 30 minutes, LCMS analysis indicated completion. The reaction mixture was cooled to room temperature, partitioned between brine and EtOAc, filtered through Celite, and the layers were separated. The organic phase was washed with brine, dried over anhydrous MgSO, filtered, and concentrated to give crude methyl 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzoate (38.0 mg, 0.115 mmol, 83% yield), which was used without further purification. LCMS RT (Method 2) = 3.319 min, m / z 683.7 [2M+Na + ]. Example 18 Synthesis of 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzoic acid [ka]

[0261] 2 M sodium hydroxide (1.00 mL, 2.00 mmol) was added to a solution of methyl 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzoate (46.0 mg, 0.139 mmol) in EtOH (5.00 mL). The resulting reaction mixture was stirred at room temperature for 1 hour, after which LCMS analysis indicated completion. The reaction mixture was concentrated to a slurry, and the residue was partitioned between 1 M HCl and EtOAc. The layers were separated, and the organic phase was washed with brine, dried over anhydrous MgSO, filtered, and concentrated to give crude 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzoic acid (44.0 mg, 0.139 mmol, 100% yield), which was used without further purification. LCMS RT (method 2) = 2.893 min, m / z 317.0[M+H + ]. Example 19 Synthesis of N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzamide (Compound 30) [ka]

[0262] A mixture of 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzoic acid (44.0 mg, 0.139 mmol) and HATU (63.5 mg, 0.167 mmol) in DMF (1.50 mL) was stirred for 10 minutes, after which 1-(3-aminopropyl)pyrrolidin-2-one (21.5 μL, 0.153 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, after which DIPEA (60.7 μL, 0.348 mmol) was added and the reaction was stirred overnight, after which LCMS analysis showed completion. The reaction mixture was diluted with EtOAc, washed with HO and brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with a gradient of 0 to 20% MeOH in EtOAc to afford N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)benzamide (24.0 mg, 0.054 mmol, 39.2% yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.63 (d, J = 1.6 Hz, 1H), 8.92 (d, J = 1.6 Hz, 1H), 8.68 (t, J = 5.7 Hz, 1H), 8.20 - 8.15 (m, 2H), 8.14 - 8.09 (m, 4H), 7.56 - 7.50 (m, 2H), 7.49 - 7.43 (m, 1H), 3.37 (t, J = 7.1 Hz, 2H), 3.32 - 3.23 (m, 4H), 2.24 (dd, J = 8.3, 7.8 Hz, 2H), 1.98 - 1.89 (m, 2H), 1.75 (p, J = 7.0 Hz, 2H).LCMS RT(Method 1)=4.130 min, m / z 882.3[2M+H + ], 441.1 [M+H + ]. Example 20 Synthesis of 5-bromo-2-hydrazinylpyridine [ka]

[0263] A solution of 5-bromo-2-fluoropyridine (1.00 mL, 9.72 mmol) and hydrazine (1.52 mL, 48.6 mmol) in EtOH (10.0 mL) was stirred at 100 °C for 1 h, after which LCMS analysis indicated completion. The reaction volume was reduced by half, and the mixture was cooled to room temperature to precipitate the product. The slurry was poured into iced HO and stirred for 5 min. The product was filtered, rinsed with HO, and air-dried to give 5-bromo-2-hydrazinylpyridine (1.60 g, 8.51 mmol, 88% yield) as an off-white fluffy solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (dd, J = 2.6, 0.7 Hz, 1H), 7.65 (s, 1H), 7.58 (dd, J = 8.9, 2.5 Hz, 1H), 6.69 (dd, J = 9.0, 0.7 Hz, 1H), 4.15 (s, 2H).LCMS RT(Method 2)=1.150 min, m / z 189.3[M+H + ]. Example 21 Synthesis of methyl 4-(2-(5-bromopyridin-2-yl)hydrazine-1-carbonyl)benzoate [ka]

[0264] To a solution of 5-bromo-2-hydrazinylpyridine (500 mg, 2.66 mmol), 4-(methoxycarbonyl)benzoic acid (599 mg, 3.32 mmol), and DIPEA (1.39 mL, 7.98 mmol) in DMF (5.00 mL) was added a 50% solution of propylphosphonic anhydride (T3P) in DMF (2.33 mL, 3.99 mmol). The resulting reaction mixture was allowed to stir at room temperature for 1 hour, after which LCMS analysis indicated completion. The reaction mixture was poured into ice-cold HO and stirred for 10 minutes. The product was collected by filtration, rinsed generously with HO, and air-dried to afford methyl 4-(2-(5-bromopyridin-2-yl)hydrazine-1-carbonyl)benzoate (906 mg, 2.59 mmol, 97% yield) as a tan solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (d, J = 1.9 Hz, 1H), 8.80 (d, J = 1.9 Hz, 1H), 8.15 (dd, J = 2.5, 0.7 Hz, 1H), 8.10 - 8.05 (m, 2H), 8.05 - 8.00 (m, 2H), 7.71 (dd, J = 8.9, 2.5 Hz, 1H), 6.66 (dd, J = 8.9, 0.7 Hz, 1H), 3.89 (d, J = 2.5 Hz, 3H).LCMS RT(Method 2)=2.863 min, m / z 352.3[M+H + ]. Example 22 Synthesis of methyl 4-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzoate [ka]

[0265] Perchloroethane (946 mg, 4.00 mmol) was added to a suspension of methyl 4-(2-(5-bromopyridin-2-yl)hydrazine-1-carbonyl)benzoate (700 mg, 1.99 mmol), triphenylphosphine (1.05 g, 4.00 mmol), and DIPEA (1.39 mL, 8.00 mmol) in ACN (10.0 mL) with a 4 Å MS. The resulting reaction mixture was stirred at 80 °C for 2 h, after which LCMS analysis indicated completion. The reaction mixture was cooled to room temperature and filtered through Celite, and the filter cake was rinsed generously with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel with a 20-80% EtOAc gradient in Hex to give methyl 4-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzoate (604 mg, 1.818 mmol, 91% yield). LCMS RT (Method 2) = 3.004 min, m / z 333.7 [M+H + ]. Example 23 Synthesis of methyl 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzoate [ka]

[0266] A mixture of methyl 4-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzoate (300 mg, 0.903 mmol), phenylboronic acid (138 mg, 1.13 mmol), XPhos Pd(crotyl)Cl (30.4 mg, 0.045 mmol), and KPO (383 mg, 1.81 mmol) was placed in a vial and purged with N for 2 minutes. 4:1 dioxane:HO (10.0 mL) was added and degassing continued for 2 minutes, after which the reaction vessel was placed in a preheated block at 100 °C. After stirring at 100 °C for 30 minutes, LC-MS analysis indicated completion. The reaction mixture was cooled to room temperature, partitioned between brine and EtOAc, filtered through Celite, and the layers were separated. The organic phase was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with a 40-100% EtOAc gradient in Hex to give methyl 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzoate (290 mg, 0.880 mmol, 97% yield) as an off-white solid. LCMS RT (Method 2) = 3.156 min, m / z 330.1 [M+H + ]. Example 24 Synthesis of 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzoic acid [ka]

[0267] A suspension of methyl 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzoate (290 mg, 0.880 mmol) in EtOH (8.00 mL) was treated with 2 M sodium hydroxide (2.00 mL, 4.00 mmol). The resulting reaction mixture was allowed to stir at room temperature for 30 minutes, after which time the solution became clear and LCMS analysis indicated completion. The reaction mixture was concentrated to a slurry and poured into cold 1 M HCl solution and stirred vigorously for 10 minutes. The insoluble product was filtered, rinsed with HO, and air-dried to afford 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzoic acid (248 mg, 0.786 mmol, 89% yield) as an off-white solid, which was used without further purification. LCMS RT (Method 2) = 2.956 min, m / z 316.8[M+H + ]. Example 25 Synthesis of N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzamide (Compound 31) [ka]

[0268] A mixture of 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzoic acid (100 mg, 0.317 mmol) and HATU (145 mg, 0.381 mmol) in DMF (2.00 mL) was stirred for 10 minutes, after which 1-(3-aminopropyl)pyrrolidin-2-one (0.049 mL, 0.349 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, after which DIPEA (0.138 mL, 0.793 mmol) was added and the reaction was stirred overnight, after which LCMS analysis showed completion. The reaction mixture was diluted with EtOAc, washed with HO and brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with a gradient of 0 to 30% MeOH in EtOAc to afford N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzamide (33.0 mg, 0.075 mmol, 23.68% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.68 - 8.61 (m, 2H), 8.14 - 8.10 (m, 2H), 8.08 (d, J = 8.8 Hz, 2H), 7.99 (dd, J = 9.6, 1.0 Hz, 1H), 7.85 - 7.74 (m, 3H), 7.54 - 7.48 (m, 2H), 7.47 - 7.41 (m, 1H), 3.40 - 3.34 (m, 2H), 3.27 (q, J = 6.9 Hz, 4H), 2.23 (dd, J = 8.6, 7.5 Hz, 2H), 2.01 - 1.87 (m, 2H), 1.74 (p, J = 7.0 Hz, 2H).LCMS RT(Method 1)=4.071 min, m / z 440.1[M+H + ]. Example 26 Synthesis of methyl 4-((2-chloro-5-nitropyridin-4-yl)amino)benzoate [ka]

[0269] A mixture of 2-chloro-5-nitropyridin-4-amine (200 mg, 1.152 mmol), methyl 4-iodobenzoate (302 mg, 1.152 mmol), copper(I) iodide (32.9 mg, 0.173 mmol), and cesium carbonate (563 mg, 1.73 mmol) was placed in a vial, sealed, and purged with N for 3 minutes. DMF (4.00 mL) was added, and the reaction mixture was purged by bubbling N through the mixture for 3 minutes. The resulting reaction mixture was placed in a preheated reaction block at 120 °C and stirred for 16 hours, after which LCMS analysis indicated product formation. The reaction mixture was partitioned between EtOAc and H2O, filtered through Celite, the layers separated, and the organic phase was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography: silica gel with a 10-30% EtOAc gradient in Hex to afford methyl 4-((2-chloro-5-nitropyridin-4-yl)amino)benzoate (84.0 mg, 0.273 mmol, 23.69% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.99 (s, 1H), 8.08 - 8.00 (m, 2H), 7.57 - 7.49 (m, 2H), 7.03 (s, 1H), 3.87 (s, 3H).LCMS RT (method 2) = 3.334 min, m / z 308.0[M+H + ]. Example 27 Synthesis of methyl 4-((5-amino-2-chloropyridin-4-yl)amino)benzoate [ka]

[0270] A mixture of methyl 4-((2-chloro-5-nitropyridin-4-yl)amino)benzoate (80.0 mg, 0.260 mmol), iron powder (72.6 mg, 1.30 mmol), and ammonium chloride (278 mg, 5.20 mmol) in 1:1 EtOH-HO (10.0 mL) was stirred at 70 °C for 1 h, after which LCMS analysis indicated completion. The reaction mixture was cooled to room temperature, partitioned between brine and EtOAc, filtered through Celite, and the layers separated. The organic phase was washed with brine, dried over anhydrous MgSO, filtered, and concentrated to afford crude methyl 4-((5-amino-2-chloropyridin-4-yl)amino)benzoate (70.0 mg, 0.252 mmol, 97% yield) as a tan solid, which was used without further purification. LCMS RT (method 2) = 2.573 min, m / z 278.0[M+H + ]. Example 28 Synthesis of methyl 4-(6-chloro-1H-imidazo[4,5-c]pyridin-1-yl)benzoate [ka]

[0271] A solution of methyl 4-((5-amino-2-chloropyridin-4-yl)amino)benzoate (65.0 mg, 0.234 mmol), triethyl orthoformate (0.100 mL, 0.601 mmol), and catalytic p-toluenesulfonic acid (p-TsOH) (6.68 mg, 0.035 mmol) in THF (5.00 mL) was stirred at 60 °C overnight, after which LCMS analysis indicated completion. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO, brine, dried over anhydrous MgSO, filtered, and concentrated. The crude residue was purified by flash column chromatography on silica gel with a 20–80% EtOAc gradient in HEX to afford methyl 4-(6-chloro-1H-imidazo[4,5-c]pyridin-1-yl)benzoate (41.0 mg, 0.143 mmol, 60.9% yield) as a white powder. 1H NMR (400 MHz, Chloroform-d) δ 8.97 (d, J = 0.9 Hz, 1H), 8.34 - 8.28 (m, 2H), 8.22 (s, 1H), 7.61 - 7.58 (m, 2H), 7.54 (d, J = 0.9 Hz, 1H), 4.00 (s, 3H).LCMS RT(Method 2)=3.034 min, m / z 287.8[M + ]. Example 29 Synthesis of 4-(6-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)benzoic acid [ka]

[0272] A mixture of methyl 4-(6-chloro-1H-imidazo[4,5-c]pyridin-1-yl)benzoate (35.0 mg, 0.122 mmol), phenylboronic acid (18.54 mg, 0.152 mmol), XPhos Pd(crotyl)Cl (4.10 mg, 6.08 μmol), and KPO (51.6 mg, 0.243 mmol) was placed in a vial and purged with N for 2 minutes. 4:1 dioxane:HO (2.50 mL) was added and degassing continued for 2 minutes, after which the reaction vessel was placed in a preheated block at 100 °C. After stirring for 30 minutes at 100 °C, LCMS analysis indicated completion. The reaction mixture was then treated with 2 M sodium hydroxide (0.500 mL, 1.00 mmol) and stirring was continued at 100 °C for 30 min, after which LCMS analysis indicated complete saponification of the ester. The reaction mixture was cooled to room temperature and diluted with EtOAc and HO. The pH was adjusted to approximately 4-5 with AcOH, the biphasic mixture was filtered through Celite, the layers were separated, and the organic phase was washed with brine, dried over anhydrous MgSO, filtered, and concentrated to give crude 4-(6-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)benzoic acid (35.0 mg, 0.111 mmol, 91% yield), which was used without further purification. LCMS RT (Method 2) = 2.601 min, m / z 315.8 [M + ]. Example 30 Synthesis of N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(6-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)benzamide (Compound 32) [ka]

[0273] A mixture of 4-(6-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)benzoic acid (40.0 mg, 0.127 mmol) and HATU (57.9 mg, 0.152 mmol) in DMF (1.50 mL) was stirred for 10 minutes, after which 1-(3-aminopropyl)pyrrolidin-2-one (19.57 μL, 0.140 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, after which DIPEA (55.4 μL, 0.317 mmol) was added and the reaction was stirred overnight, after which LCMS analysis showed completion. The reaction mixture was diluted with EtOAc, washed with HO and brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with a gradient of 0 to 20% MeOH in EtOAc to afford N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(6-phenyl-1H-imidazo[4,5-c]pyridin-1-yl)benzamide (32.0 mg, 0.073 mmol, 57.4% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J = 1.0 Hz, 1H), 8.82 (s, 1H), 8.65 (t, J = 5.7 Hz, 1H), 8.19 - 8.08 (m, 5H), 7.97 - 7.88 (m, 2H), 7.51 - 7.44 (m, 2H), 7.43 - 7.37 (m, 1H), 3.37 (t, J = 7.0 Hz, 2H), 3.28 (dt, J = 15.9, 6.9 Hz, 4H), 2.24 (dd, J = 8.6, 7.4 Hz, 2H), 1.94 (ddd, J = 15.4, 13.1, 6.4 Hz, 2H), 1.75 (p, J = 7.1 Hz, 2H).LCMS RT(Method 1)=3.523 min, m / z 440.8[M+H + ]. Example 31 Synthesis of methyl 4-(6-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)benzoate [ka]

[0274] A mixture of 6-chloro-1H-pyrrolo[3,2-c]pyridine (200 mg, 1.31 mmol), methyl 4-iodobenzoate (343 mg, 1.31 mmol), copper(I) iodide (37.4 mg, 0.197 mmol), and cesium carbonate (641 mg, 1.97 mmol) was placed in a vial, sealed, and purged with N for 3 minutes. DMF (4.00 mL) was added, and the reaction mixture was purged by bubbling N through the mixture for 3 minutes. The resulting reaction mixture was placed in a preheated reaction block at 120 °C and stirred for 16 hours, after which LCMS analysis indicated product formation. The reaction mixture was partitioned between EtOAc and H2O, filtered through Celite, the layers were separated, and the organic phase was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography on silica gel with a 5-35% EtOAc gradient in Hex to give methyl 4-(6-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)benzoate (213 mg, 0.743 mmol, 56.7% yield). LCMS RT (Method 2) = 3.247 min, m / z 287.0 [M+H + ]. Example 32 Synthesis of methyl 4-(6-phenyl-1H-pyrrolo[3,2-c]pyridin-1-yl)benzoate [ka]

[0275] A mixture of methyl 4-(6-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)benzoate (100 mg, 0.349 mmol), phenylboronic acid (53.2 mg, 0.436 mmol), XPhosPd(crotyl)Cl (11.75 mg, 0.017 mmol), and KPO (148 mg, 0.698 mmol) was placed in a vial and purged with N for 2 minutes. 4:1 dioxane:HO (2.50 mL) was added and degassing continued for 2 minutes, after which the reaction vessel was placed in a preheated block at 100 °C. After stirring at 100 °C for 30 minutes, LCMS analysis indicated completion. The reaction mixture was cooled to room temperature, partitioned between brine and EtOAc, filtered through Celite, and the layers were separated. The organic phase was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel with a 10-35% EtOAc gradient in Hex to give methyl 4-(6-phenyl-1H-pyrrolo[3,2-c]pyridin-1-yl)benzoate (110 mg, 0.335 mmol, 96% yield). LCMS RT (Method 2) = 2.795 min, m / z 329.1 [M+H + ]. Example 33 Synthesis of 4-(6-phenyl-1H-pyrrolo[3,2-c]pyridin-1-yl)benzoic acid [ka]

[0276] 2 M sodium hydroxide (2.00 mL, 4.00 mmol) was added to a solution of methyl 4-(6-phenyl-1H-pyrrolo[3,2-c]pyridin-1-yl)benzoate (100 mg, 0.305 mmol) in EtOH (5.00 mL). The resulting reaction mixture was stirred at room temperature for 2 hours, after which LCMS analysis indicated completion. The reaction mixture was concentrated to a slurry, and the residue was partitioned between 1 M HCl and EtOAc. The layers were separated, and the organic phase was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to give crude 4-(6-phenyl-1H-pyrrolo[3,2-c]pyridin-1-yl)benzoic acid (55.0 mg, 0.175 mmol, 57.5% yield), which was used without further purification. LCMS RT (Method 2) = 2.664 min, m / z 314.9 [M + ]. Example 34 Synthesis of N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(6-phenyl-1H-pyrrolo[3,2-c]pyridin-1-yl)benzamide (Compound 33) [ka]

[0277] A mixture of 4-(6-phenyl-1H-pyrrolo[3,2-c]pyridin-1-yl)benzoic acid (25.0 mg, 0.080 mmol) and HATU (36.3 mg, 0.095 mmol) in DMF (1.50 mL) was stirred for 10 minutes, after which 1-(3-aminopropyl)pyrrolidin-2-one (12.3 μL, 0.087 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, after which DIPEA (34.7 μL, 0.199 mmol) was added and the reaction was stirred overnight, after which LCMS analysis showed completion. The reaction mixture was diluted with EtOAc, washed with HO and brine, dried over anhydrous MgSO, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with a gradient of 0 to 20% MeOH in EtOAc to afford N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(6-phenyl-1H-pyrrolo[3,2-c]pyridin-1-yl)benzamide (17.0 mg, 0.039 mmol, 48.7% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (s, 1H), 8.62 (t, J = 5.6 Hz, 1H), 8.10 (t, J = 7.4 Hz, 4H), 8.02 (s, 1H), 7.88 (d, J = 3.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.37 (t, J = 7.2 Hz, 1H), 6.93 (d, J = 3.3 Hz, 1H), 3.37 (t, J = 7.0 Hz, 2H), 3.27 (q, J = 7.1, 6.6 Hz, 4H), 2.23 (t, J = 8.1 Hz, 2H), 1.93 (p, J = 7.5 Hz, 2H), 1.74 (p, J = 7.1 Hz, 2H).LCMS RT(Method 1)=3.521 min, m / z 439.1[M+H + ]. Example 35 Synthesis of methyl 4-(((5-phenylpyrazin-2-yl)methyl)carbamoyl)benzoate [ka]

[0278] A heterogeneous solution of (5-phenylpyrazin-2-yl)methanamine (Key Organics) (3.3 g, 17.82 mmol), 4-(methoxycarbonyl)benzoic acid (3.53 g, 19.60 mmol), HOBt (3.55 g, 23.16 mmol), and DIPEA (9.33 ml, 53.4 mmol) in DMF (100 ml) was stirred at 65 °C for 1 minute under N2. To the solution was added EDC (4.10 g, 21.38 mmol). The solution was stirred at 65 °C for 2.5 hours under N2. The solution was cooled to room temperature. To the solution was added water (500 ml). The solution was cooled for 18 hours. The solution was filtered. The solid was washed with water (x3) and dried in air and then in vacuo to give the desired compound (5.4 g, 87%). (LCMS, ESI pos.)C 20 H 17 Calculated for N3O3: 348.4 (M+H), Found: 348.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.43 (t, J = 5.7 Hz, 1H), 9.23 (d, J = 1.5 Hz, 1H), 8.76 (d, J = 1.5 Hz, 1H), 8.19 - 8.14 (m, 2H), 8.13 - 8.05 (m, 4H), 7.61 - 7.50 (m, 3H), 4.72 (d, J = 5.7 Hz, 2H), 3.93 (s, 3H). Example 36 Synthesis of methyl 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoate [ka]

[0279] A heterogeneous solution of methyl 4-(((5-phenylpyrazin-2-yl)methyl)carbamoyl)benzoate (2.5 g, 7.20 mmol) and pyridine (3.49 mL, 43.2 mmol) in DCE (72.0 mL) was treated dropwise over 1 minute with POCl3 (2.68 mL, 28.8 mmol). The heterogeneous solution was stirred at 70 °C under N2. The solution was stirred at 70 °C for 5 hours. The reaction was cooled to room temperature. The solution was cooled (ice bath). MeOH (10 mL) was slowly added to the solution. The solution was concentrated to a small volume and chromatographed using gradient silica gel chromatography (5% EtOAc in hexanes to 100% EtOAc over 20 minutes). The desired fractions were pooled, concentrated, and dried in vacuo to give the desired compound (1.8 g, 76%). (LCMS, ESI pos.) C 20 H 15 Calculated for N3O2: 330.4 (M+H), Found: 330.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J = 1.5 Hz, 1H), 8.82 (t, J = 1.3 Hz, 1H), 8.21 (d, J = 1.1 Hz, 4H), 8.15 - 8.08 (m, 3H), 7.59 - 7.49 (m, 2H), 7.49 - 7.42 (m, 1H), 3.95 (d, J = 1.2 Hz, 3H). Example 37 Synthesis of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid [ka]

[0280] To a solution of methyl 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoate (1.8 g, 5.47 mmol) in 1:1 MeOH / THF (40 ml) was added sodium hydroxide (10.93 ml, 10.93 mmol). The solution was stirred at room temperature under N2. After 3 hours, the reaction solution was concentrated to a small volume. The solution was cooled using an ice / water bath. The pH was adjusted to 2 (litmus) using 1N HCl (slow addition). The solution was placed in the refrigerator overnight. The solution was filtered. The solid was washed with water (x3). The solid was air-dried and then vacuum-dried to give the desired product (1.0 g, 58%). (LCMS, ESI pos.) C 19 H 13 Calculated for N3O2: 316.3 (M+H), Found: 316.1. 1 H NMR (400 MHz, DMSO-d6) δ 13.23 (s, 1H), 9.27 (s, 1H), 8.75 (s, 1H), 8.07 (m, J = 21.4 Hz, 7H), 7.43 (m, J = 23.8 Hz, 3H). Example 38 Synthesis of N-(2-(1H-imidazol-5-yl)ethyl)-4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 1) [ka]

[0281] A solution of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (1 g, 3.17 mmol) in DMF (10.57 mL) was treated with DIPEA (1.108 mL, 6.34 mmol). To the solution was added HATU (1.326 g, 3.49 mmol). The solution was stirred at room temperature under N2. After 30 minutes, histamine (0.388 g, 3.49 mmol) was added to the solution. The reaction solution was stirred at room temperature under N2 for 18 hours. To the reaction solution was added 1 N NaOH (1.9 mmol). After 30 minutes, the solution was concentrated to a small volume. The solution was partitioned between EtOAc and water. The EtOAc layer was separated, washed successively with water (×2) and brine (×1), dried over anhydrous MgSO4, filtered, and concentrated. The residue was chromatographed using C18 reverse phase chromatography to give the desired compound (0.7 g, 54%). (LCMS, ESI pos.) 24 H 20 Calculated for N6O: 409.5 (M+H), Found: 409.2. 1 H NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 9.33 (d, J = 1.5 Hz, 1H), 8.84 - 8.71 (m, 2H), 8.22 - 8.03 (m, 7H), 7.69 - 7.40 (m, 4H), 6.90 (s, 1H), 3.57 (td, J = 7.5, 5.5 Hz, 2H), 2.83 (s, 2H).

[0282] Figure 15 shows that the IC50 for Compound 1 is 2.86 μM.

[0283] As shown in Figures 10A to 10C and Table 1, Compound 1 exhibited excellent PK profiles at various concentrations in plasma, liver, and pancreas when administered using both the oral route and IP injection. [Table 1] Example 39 Synthesis of N-(3-(2-oxopyrrolidin-1-yl)propyl)-4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 28) [ka]

[0284] A solution of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.255 g, 0.809 mmol) and HATU (0.369 g, 0.970 mmol) in DMF (2.70 mL) was treated with DIPEA (0.282 mL, 1.617 mmol). The solution was stirred at room temperature under N2. After 20 min, a solution of 1-(3-aminopropyl)pyrrolidin-2-one (0.126 g, 0.890 mmol) in DMF (0.1 mL) was added to the solution. The reaction solution was stirred at room temperature under N2. After 18 h, the reaction solution was loaded onto a C18 column (15.5 g, equilibrated with water) and purified using a gradient (0–30% CH3CN over 20 min) to give the desired compound (0.142 g, 40%). (LCMS, ESI pos.)C 26 H 25 Calculated for N5O2: 440.5 (M+H), Found: 440.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.34 (d, J = 1.5 Hz, 1H), 8.79 (t, J = 1.3 Hz, 1H), 8.66 (t, J = 5.7 Hz, 1H), 8.19 - 8.05 (m, 7H), 7.53 (dd, J = 8.3, 6.6 Hz, 2H), 7.49 - 7.43 (m, 1H), 3.41 (t, J = 7.0 Hz, 2H), 3.32 (dt, J = 14.0, 6.9 Hz, 4H), 2.27 (t, J = 8.1 Hz, 2H), 2.05 - 1.91 (m, 2H), 1.78 (p, J = 7.1 Hz, 2H). Example 40 Synthesis of (3-hydroxyazetidin-1-yl)(4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)phenyl)methanone (Compound 17) [ka]

[0285] A solution of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) in DMF (0.317 mL) was treated with DIPEA (0.033 mL, 0.190 mmol). After 10 minutes, azetidin-3-ol (0.012 g, 0.159 mmol) was added to the solution. The solution was stirred at room temperature overnight. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.04 g, 68%). (LCMS, ESI pos.) C 22 H 18 Calculated for N4O2: 371.4 (M+H), Found: 371.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.33 (d, J = 1.5 Hz, 1H), 8.81 - 8.76 (m, 1H), 8.57 (dd, J = 8.4, 1.4 Hz), 8.16 - 8.06 (m, 4H), 7.91 - 7.84 (m, 2H), 7.57 - 7.49 (m, 2H), 7.49 - 7.43 (m, 1H), 5.83 (s, 1H), 4.57 (d, J = 5.1 Hz, 2H), 4.33 (s, 1H), 4.16 (s, 1H), 3.94 - 3.84 (m, 1H), 1.29 (td, J = 7.1, 5.1 Hz, 3H). Example 41 Synthesis of (4-hydroxypiperidin-1-yl)(4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)phenyl)methanone (Compound 18) [ka]

[0286] A solution of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) in DMF (0.5 mL) was treated with DIPEA (0.033 mL, 0.190 mmol). The solution was stirred at room temperature for 10 minutes. To the solution was added piperidin-4-ol (0.016 g, 0.159 mmol). The solution was stirred at room temperature overnight. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (from EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.03 g, 48%). (LCMS, ESI pos.) C 24 H 22 Calculated for N4O2: 399.5 (M+H), Found: 399.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.32 (d, J = 1.5 Hz, 1H), 8.80 (t, J = 1.2 Hz, 1H), 8.16 - 8.05 (m, 5H), 7.70 - 7.58 (m, 2H), 7.58 - 7.42 (m, 3H), 4.86 (s, 1H), 3.86 - 3.76 (m, 1H), 3.63 (s, 1H), 3.28 (s, 3H), 1.82 (s, 2H), 1.44 (s, 3H). Example 42 Synthesis of N-(2-(dimethylamino)ethyl)-N-methyl-4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 19) [ka]

[0287] A solution of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) in DMF (0.5 mL) was treated with DIPEA (0.033 mL, 0.190 mmol). After 10 minutes, N1,N1,N2-trimethylethane-1,2-diamine (0.021 mL, 0.159 mmol) was added. The solution was stirred overnight at room temperature. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.03 g, 47%). (LCMS, ESI pos.) C 24 H 25 Calculated for NO: 400.5 (M+H), Found: 400.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 1.5 Hz, 1H), 8.41 (t, J = 1.2 Hz, 1H), 7.93 (d, J = 1.0 Hz, 1H), 7.87 (td, J = 6.1, 2.8 Hz, 4H), 7.66 - 7.59 (m, 2H), 7.52 - 7.44 (m, 2H), 7.43 - 7.37 (m, 1H), 3.68 (s, 1H), 3.40 (d, J = 10.2 Hz, 1H), 3.09 (d, J = 29.0 Hz, 3H), 2.67 - 2.38 (m, 2H), 2.32 (s, 3H), 2.10 (s, 3H). Example 43 Synthesis of N-(4-acetamidophenyl)-4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 5) [ka]

[0288] A solution of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) in DMF (0.5 mL) was treated with DIPEA (0.033 mL, 0.190 mmol). After 10 minutes, N-(4-aminophenyl)acetamide (0.024 g, 0.159 mmol) was added to the solution. The solution was stirred at room temperature. After 18 hours, the solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.04 g, 56%). (LCMS, ESI pos.) C 27 H 21 Calculated for N5O2: 448.5 (M+H), Found: 448.2. 1 H NMR (400 MHz, Chloroform-d) δ 9.10 (d, J = 1.5 Hz, 1H), 8.41 (t, J = 1.2 Hz, 1H), 7.93 (d, J = 1.0 Hz, 1H), 7.87 (td, J = 6.1, 2.8 Hz, 4H), 7.66 - 7.59 (m, 2H), 7.52 - 7.44 (m, 2H), 7.43 - 7.37 (m, 1H), 3.68 (s, 1H), 3.40 (d, J = 10.2 Hz, 1H), 3.09 (d, J = 29.0 Hz, 3H), 2.67 - 2.38 (m, 2H), 2.32 (s, 3H), 2.10 (s, 3H).

[0289] Figure 5 shows that the IC50 for compound 5 is 7.36 μM. Example 44 Synthesis of N-(3-(1H-imidazol-1-yl)propyl)-4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 6) [ka]

[0290] A solution of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) in DMF (0.5 mL) was treated with DIPEA (0.033 mL, 0.190 mmol). The solution was stirred for 15 minutes. 3-(1H-imidazol-1-yl)propan-1-amine (0.020 g, 0.159 mmol) was added to the solution. The solution was stirred at room temperature. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.03 g, 45%). (LCMS, ESI pos.) C 25 H 22 Calculated for N6O: 423.5 (M+H), Found: 423.1. 1 H NMR (400 MHz , Chloroform-d) δ 9.11 (d, J = 1.6 Hz, 1H), 8.43 (dd, J = 1.6, 0.9 Hz, 1H), 7.93 (s, 5H), 7.89 - 7.83 (m, 2H), 7.51 (t, J = 1.1 Hz, 1H), 7.50 - 7.43 (m, 2H), 7.43 - 7.37 (m, 1H), 7.06 (d, J = 1.1 Hz, 1H), 6.98 (t, J = 1.3 Hz, 1H), 6.60 - 6.49 (m, 1H), 4.09 (dt, J = 11.4, 7.0 Hz, 2H), 3.51 (q, J = 6.5 Hz, 2H), 2.15 (p, J = 6.8 Hz, 2H).

[0291] Figure 6 shows that the IC50 for compound 6 is 3.85 μM. Example 45 Synthesis of N-(2-(dimethylamino)ethyl)-4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 7) [ka]

[0292] A solution of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) in DMF (0.5 mL) was treated with DIPEA (0.033 mL, 0.190 mmol). N1,N1-dimethylethane-1,2-diamine (0.017 mL, 0.159 mmol) was added to the solution. The solution was stirred at room temperature overnight. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (from EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.045 g, 74%). (LCMS, ESI pos.) C 23 H 23 Calculated for NO: 386.5 (M+H), Found: 385.9. 1 H NMR (400 MHz, Chloroform-d) δ 9.11 (d, J = 1.6 Hz, 1H), 8.44 (dd, J = 1.7, 0.9 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.96 - 7.91 (m, 3H), 7.90 - 7.85 (m, 2H), 7.50 - 7.44 (m, 2H), 7.44 - 7.37 (m, 1H), 6.96 (s, 1H), 3.61 - 3.51 (m, 2H), 2.54 (t, J = 5.9 Hz, 2H), 2.28 (s, 6H).

[0293] Figure 7 shows that the IC50 for compound 7 is 3.13 μM. Example 46 Synthesis of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)-N-(pyrazin-2-ylmethyl)benzamide (Compound 20) [ka]

[0294] A solution of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) in DMF (0.5 mL) was treated with DIPEA (0.033 mL, 0.190 mmol). Pyrazin-2-ylmethanamine (0.017 g, 0.159 mmol) was added to the solution. The solution was stirred at room temperature for 18 hours. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (from EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.045 g, 74%). (LCMS, ESI pos.) C 24 H 18 Calculated for N6O: 407.5 (M+H), Found: 407.2. 1 H NMR (400 MHz , Chloroform-d) δ 9.10 (d, J = 1.6 Hz, 1H), 8.68 (d, J = 1.5 Hz, 1H), 8.56 - 8.48 (m, 2H), 8.42 (t, J = 1.3 Hz, 1H), 8.08 - 8.01 (m, 2H), 7.96 - 7.90 (m, 3H), 7.88 - 7.81 (m, 2H), 7.53 (t, J = 5.3 Hz, 1H), 7.48 - 7.34 (m, 3H), 4.84 (d, J = 5.1 Hz, 2H). Example 47 Synthesis of 1-(4-(4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoyl)piperazin-1-yl)ethan-1-one (compound 21) [ka]

[0295] A solution of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) in DMF (0.5 mL) was treated with 1-(piperazin-1-yl)ethan-1-one (0.020 g, 0.159 mmol). The solution was stirred at room temperature for 18 hours. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.045 g, 74%). (LCMS, ESI pos.) C 25 H 23 Calculated for N5O2: 426.5 (M+H), Found: 426.1. 1 H NMR (400 MHz , Chloroform-d) δ 9.12 (d, J = 1.6 Hz, 1H), 8.49 - 8.36 (m, 1H), 7.96 - 7.90 (m, 3H), 7.90 - 7.84 (m, 2H), 7.65 - 7.60 (m, 2H), 7.51 - 7.44 (m, 2H), 7.44 - 7.38 (m, 1H), 3.93 - 3.33 (m, 8H), 2.13 (s, 3H). Example 48 Synthesis of N-(2-methoxyethyl)-4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 22) [ka]

[0296] A solution of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) in DMF (0.5 mL) was treated with DIPEA (0.033 mL, 0.190 mmol). The solution was stirred for 15 minutes. 2-Methoxyethan-1-amine (0.014 mL, 0.159 mmol) was added to the solution. The solution was stirred at room temperature for 18 hours. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.040 g, 68%). (LCMS, ESI pos.) C 22 H 20 Calculated for N4O2: 373.4 (M+H), Found: 372.9. 1 H NMR (400 MHz , Chloroform-d) δ 9.12 (d, J = 1.6 Hz, 1H), 8.44 (t, J = 1.2 Hz, 1H), 8.02 - 7.92 (m, 5H), 7.90 - 7.85 (m, 2H), 7.47 (dd, J = 8.3, 6.5 Hz, 2H), 7.44 - 7.38 (m, 1H), 6.60 (s, 1H), 3.69 (q, J = 5.2 Hz, 2H), 3.59 (t, J = 5.0 Hz, 2H), 3.40 (s, 3H). Example 49 Synthesis of N-methyl-1-(4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoyl)piperidine-4-carboxamide (compound 23) [ka]

[0297] A solution of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) in DMF (0.5 mL) was treated with DIPEA (0.033 mL, 0.190 mmol). The solution was stirred at room temperature for 15 minutes. N-methylpiperidine-4-carboxamide (0.023 g, 0.159 mmol) was added to the solution. The reaction mixture was stirred at room temperature for 18 hours. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (from EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.033 g, 47%). (LCMS, ESI pos.) C 26 H 25 Calculated for N5O2: 440.5 (M+H), Found: 439.9. 1 H NMR (400 MHz, Chloroform-d) δ 9.08 (d, J = 1.5 Hz, 1H), 8.39 (p, J = 0.7 Hz, 1H), 7.90 (d, J = 0.9 Hz, 1H), 7.88 - 7.80 (m, 4H), 7.61 - 7.52 (m, 2H), 7.44 (dd, J = 8.3, 6.5 Hz, 2H), 7.41 - 7.34 (m, 1H), 5.84 (q, J = 4.9 Hz, 1H), 4.67 (s, 1H), 3.84 (s, 1H), 3.17 - 2.81 (m, 2H), 2.78 (d, J = 4.8 Hz, 3H), 2.35 (tt, J = 11.1, 4.1 Hz, 1H), 1.83 (d, J = 51.1 Hz, 4H). Example 50 Synthesis of N-(4-hydroxycyclohexyl)-4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzamide (compound 24) [ka]

[0298] A solution of 4-(6-phenylimidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) in DMF (0.5 mL) was treated with DIPEA (0.033 mL, 0.190 mmol). The solution was stirred at room temperature. After 10 minutes, 4-aminocyclohexan-1-ol (0.018 g, 0.159 mmol) was added. The solution was stirred at room temperature for 18 hours. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.032 g, 49%). (LCMS, ESI pos.) C 25 H 24 Calculated for N4O2: 413.5 (M+H), Found: 412.9. 1 H NMR (400 MHz, Chloroform-d) δ 9.11 (d, J = 1.6 Hz, 1H), 8.42 (t, J = 1.3 Hz, 1H), 7.94 (dd, J = 3.4, 1.1 Hz, 5H), 7.89 - 7.83 (m, 2H), 7.50 - 7.43 (m, 2H), 7.43 - 7.37 (m, 1H), 6.00 (d, J = 7.9 Hz, 1H), 4.00 (tdt, J = 11.5, 8.0, 4.1 Hz, 1H), 3.66 (tt, J = 10.3, 4.1 Hz, 1H), 2.22 - 2.10 (m, 2H), 2.04 (dd, J = 12.0, 3.8 Hz, 2H), 1.58 - 1.41 (m, 2H), 1.34 (qd, J = 12.8, 3.1 Hz, 2H). Example 51 Synthesis of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)-N-(3-(2-oxopyrrolidin-1-yl)propyl)benzamide (Compound 29) [ka]

[0299] A mixture of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.022 g, 0.066 mmol) and HATU (0.028 g, 0.073 mmol) in DMF (0.220 ml) was treated with DIPEA (0.014 ml, 0.079 mmol). The solution was stirred at room temperature. After 10 minutes, 1-(3-aminopropyl)pyrrolidin-2-one (9.39 mg, 0.066 mmol) was added. The solution was stirred at room temperature. The solution was stirred at room temperature for 3 hours. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.007 g, 23%). (LCMS, ESI pos.) C 26 H 24 Calculated for FN5O2: 458.5 (M+H), Found: 458.1. 1 H NMR (400 MHz, Chloroform-d) δ 9.11 (d, J = 1.6 Hz, 1H), 8.46 (t, J = 1.3 Hz, 1H), 8.24 - 8.14 (m, 2H), 8.06 (t, J = 6.4 Hz, 1H), 8.02 - 7.91 (m, 3H), 7.72 - 7.60 (m, 2H), 7.43 (td, J = 8.2, 5.9 Hz, 1H), 7.10 (tdd, J = 8.3, 2.6, 1.0 Hz, 1H), 3.46 (ddt, J = 9.2, 6.1, 2.9 Hz, 6H), 2.57 - 2.42 (m, 2H), 2.23 - 2.05 (m, 2H), 1.90 - 1.77 (m, 2H). Example 52 Synthesis of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 8) [ka]

[0300] A mixture of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.02 g, 0.060 mmol) and HATU (0.025 g, 0.066 mmol) in DMF (0.200 ml) was treated with DIPEA (0.013 ml, 0.072 mmol). The solution was stirred at room temperature for 10 minutes. To the solution was added ammonia (8.57 μl, 0.060 mmol). The solution was stirred at room temperature for 18 hours. The solution was filtered. The solid was triturated with 1:1 EtOAc / MeOH. The solution was decanted. The solid was dried in vacuo to give the desired compound (7.7 mg, 39%). (LCMS, ESI pos.) C 19 H 13 Calculated for FNO: 333.3 (M+H), Found: 333.1. 1 H NMR (400 MHz, Chloroform-d) δ 8.96 (t, J = 1.2 Hz, 1H), 8.38 (d, J = 1.5 Hz, 1H), 7.90 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 1.0 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.70 (d, J = 5.7 Hz), 7.53 - 7.47 (m, 2H), 7.20 (td, J = 7.9, 5.8 Hz, 1H), 6.91 - 6.82 (m, 1H), 6.76 (s, 1H).

[0301] Figure 20 shows that the IC50 of compound 8 is 0.45 μM. Example 53 Synthesis of N-(3-(1H-imidazol-1-yl)propyl)-4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 25) [ka]

[0302] A solution of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.02 g, 0.060 mmol) and HATU (0.025 g, 0.066 mmol) in DMF (0.200 ml) was treated with DIPEA (0.013 ml, 0.072 mmol). The solution was stirred at room temperature for 10 minutes. To the solution was added 3-(1H-imidazol-1-yl)propan-1-amine (7.51 mg, 0.060 mmol). The solution was stirred at room temperature for 18 hours. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.005 g, 19%). (LCMS, ESI pos.) C 25 H 21 Calculated for FNO: 441.5 (M+H), Found: 441.1. 1 H NMR (400 MHz, Chloroform-d) δ 9.08 (t, J = 1.2 Hz, 1H), 8.40 (dt, J = 1.6, 1.0 Hz, 1H), 8.02 (dd, J = 7.5, 1.3 Hz, 2H), 7.99 - 7.85 (m, 4H), 7.78 (s, 1H), 7.61 (dt, J = 8.8, 1.6 Hz, 2H), 7.48 - 7.36 (m, 1H), 7.09 (tdd, J = 6.4, 2.9, 1.5 Hz, 2H), 7.01 (s, 1H), 4.20 - 4.05 (m, 2H), 3.51 (q, J = 6.4 Hz, 2H), 2.18 (p, J = 6.6 Hz, 2H). Example 54 Synthesis of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)-N-(2-methoxyethyl)benzamide (Compound 13) [ka]

[0303] A solution of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.02 g, 0.060 mmol) and HATU (0.025 g, 0.066 mmol) in DMF (0.200 ml) was treated with DIPEA (0.013 ml, 0.072 mmol). The solution was stirred at room temperature for 10 minutes. 2-Methoxyethan-1-amine (5.22 μl, 0.060 mmol) was added to the solution. The solution was stirred at room temperature for 18 hours. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.009 g, 39%). (LCMS, ESI pos.) C 22 H 19 Calculated for FN4O2: 391.4 (M+H), Found: 391.2. 1 H NMR (400 MHz, Chloroform-d) δ 9.12 (d, J = 1.6 Hz, 1H), 8.44 (dd, J = 1.6, 1.0 Hz, 1H), 8.04 - 7.97 (m, 3H), 7.97 - 7.88 (m, 2H), 7.67 - 7.59 (m, 2H), 7.43 (td, J = 8.2, 6.0 Hz, 1H), 7.16 - 7.05 (m, 1H), 6.60 (s, 1H), 3.69 (td, J = 5.6, 4.3 Hz, 2H), 3.63 - 3.55 (m, 2H), 3.40 (d, J = 0.9 Hz, 3H). Example 55 Synthesis of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)-N-(3-hydroxypropyl)benzamide (Compound 9) [ka]

[0304] A mixture of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.02 g, 0.060 mmol) and HATU (0.025 g, 0.066 mmol) in DMF (0.200 ml) was treated with DIPEA (0.013 ml, 0.072 mmol). The solution was stirred at room temperature for 10 minutes. 3-Aminopropan-1-ol (4.56 μl, 0.060 mmol) was added to the solution. The solution was stirred at room temperature for 18 hours. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.002 g, 9%). (LCMS, ESI pos.) C 22 H 19 Calculated for FN4O2: 391.4 (M+H), Found: 391.2. 1 H NMR (400 MHz, Chloroform-d) δ 9.14 (d, J = 1.6 Hz, 1H), 8.43 (t, J = 1.3 Hz, 1H), 8.04 - 7.97 (m, 3H), 7.97 - 7.89 (m, 2H), 7.68 - 7.59 (m, 2H), 7.43 (td, J = 8.2, 5.9 Hz, 1H), 7.15 - 7.06 (m, 1H), 6.96 (d, J = 10.7 Hz, 1H), 3.78 (t, J = 5.5 Hz, 2H), 3.68 (q, J = 6.0 Hz, 2H), 1.85 (p, J = 5.6 Hz, 2H).

[0305] Figure 21 shows that the IC50 for compound 9 is 0.73 μM. Example 56 Synthesis of tert-butyl (3-(4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzamido)propyl)carbamate (Compound 12) [ka]

[0306] A mixture of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.02 g, 0.060 mmol) and HATU (0.025 g, 0.066 mmol) in DMF (0.200 ml) was treated with DIPEA (0.013 ml, 0.072 mmol). The solution was stirred at room temperature for 10 minutes. To the solution was added tert-butyl (3-aminopropyl)carbamate (10.45 mg, 0.060 mmol). The solution was stirred at room temperature for 18 hours. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.002 g, 7%). (LCMS, ESI pos.) C 27 H 28 Calculated for FN5O3: 490.6 (M+H), Found: 490.3. 1 H NMR (400 MHz, Chloroform-d) δ 9.10 (d, J = 1.6 Hz, 1H), 8.45 (t, J = 1.3 Hz, 1H), 8.08 (d, J = 8.1 Hz, 2H), 7.97 - 7.90 (m, 3H), 7.68 - 7.61 (m, 2H), 7.51 (d, J = 12.0 Hz, 1H), 7.42 (td, J = 8.2, 6.0 Hz, 1H), 7.09 (tdd, J = 8.3, 2.5, 1.1 Hz, 1H), 4.86 (s, 1H), 3.54 (q, J = 6.1 Hz, 2H), 3.28 (q, J = 6.4 Hz, 2H), 1.74 (p, J = 6.1 Hz, 2H), 1.45 (s, 9H). Example 57 Synthesis of N-(2-acetamidoethyl)-4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 10) [ka]

[0307] A solution of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.02 g, 0.060 mmol) and HATU (0.025 g, 0.066 mmol) in DMF (0.200 ml) was treated with DIPEA (0.013 ml, 0.072 mmol). The solution was stirred at room temperature. After 10 minutes, the solution was treated with N-(2-aminoethyl)acetamide (6.13 mg, 0.060 mmol). The solution was stirred at room temperature. The solution was filtered. The solid was triturated with 1:1 EtOAc / MeOH. The solution was decanted. The solid was dried in vacuo to give the desired compound (2.4 mg, 10%). (LCMS, ESI pos.) C 23 H 20 Calculated for FN5O2: 418.4 (M+H), Found: 417.8. 1 H NMR (400 MHz, Chloroform-d) δ 9.19 (d, J = 1.5 Hz, 1H), 8.43 - 8.39 (m, 1H), 8.26 (s, 1H), 8.11 - 8.05 (m, 2H), 7.90 (d, J = 8.1 Hz, 2H), 7.64 - 7.52 (m, 3H), 7.40 - 7.33 (m, 1H), 7.04 (td, J = 8.4, 2.2 Hz, 1H), 3.51 (d, J = 5.7 Hz, 2H), 3.39 (d, J = 8.1 Hz, 2H), 1.96 - 1.91 (m, 3H).

[0308] Figure 22 shows that the IC50 for compound 10 is 5.45 μM. Example 58 Synthesis of N-(2-(1H-imidazol-5-yl)ethyl)-4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzamide (Compound 11) [ka]

[0309] A mixture of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)benzoic acid (0.04 g, 0.120 mmol) and HATU (0.050 g, 0.132 mmol) in DMF (0.400 ml) was treated with DIPEA (0.025 ml, 0.144 mmol). The solution was stirred at room temperature for 10 minutes. 2-(1H-imidazol-5-yl)ethan-1-amine (0.013 g, 0.120 mmol) was added to the solution. The solution was stirred at room temperature for 18 hours. The solution was loaded onto a 24 g silica gel column equilibrated with EtOAc. Elution was performed with a gradient (EtOAc to 10% MeOH / EtOAc). The desired fractions were combined, concentrated, and dried under vacuum to give the desired compound (0.005 g, 10%). (LCMS, ESI pos.) C 24 H 19 Calculated for FNO: 427.5 (M+H), Found: 427.1. 1 H NMR (400 MHz, Chloroform-d) δ 9.33 (d, J = 1.5 Hz, 1H), 8.87 (t, J = 1.3 Hz, 1H), 8.78 (t, J = 5.6 Hz, 1H), 8.52 (dd, J = 4.3, 1.4 Hz, 1H), 8.34 (dd, J = 8.4, 1.4 Hz, 1H), 8.18 - 8.06 (m, 4H), 8.01 - 7.93 (m, 1H), 7.66 (d, J = 1.3 Hz, 1H), 7.57 (td, J = 8.2, 6.2 Hz, 1H), 7.34 (dd, J = 8.4, 4.3 Hz, 1H), 7.29 (ddd, J = 10.4, 8.1, 2.6 Hz, 1H), 6.91 (s, 1H), 3.58 (td, J = 7.4, 5.5 Hz, 1H), 2.84 (t, J = 7.4 Hz, 1H). Example 59 Enzyme assay

[0310] The assay was performed in a 96-well black solid-bottom plate with a final assay volume of 100 μL. As shown in Table 2, compounds 1–3 exhibited IC50 values ​​that activated CD206 and selectively targeted M2 macrophages. [Table 2]

[0311] 1A-1C show graphs of relative cell viability percentage versus log molar concentration showing selective anti-M2 macrophage activity as determined by reduction in M2 macrophage cell viability for compounds 1-3, respectively.

[0312] When recombinant CD206 was incubated with Compound 1, electron microscopy studies showed that Compound 1 bound to CD206 and induced a conformational switch in the receptor. Figures 11A and 11B show the conformational change of CD206 upon incubation with Compound 1.

[0313] Similar to the activity of the M2 macrophage-selective synthetic peptide RP-182, the anti-M2 macrophage activity of compounds 1-3 is CD206-dependent. Figures 2A-2C show graphs of relative cell viability percentage versus log molar concentration, demonstrating that the macrophage activity of compounds 1-3, respectively, is CD206-dependent. Example 60 Cell-based assays

[0314] The cell-based 2HG quantification assay was performed in a 96-well clear plate with a final assay volume of 100 μL.

[0315] Induction of phagocytosis, autophagy, and apoptosis was studied in two in vitro models using M1 and M2 macrophages. First, in the bone marrow-derived macrophage (BMDM) in vitro model, compound 1 demonstrated superior selectivity for inducing phagocytosis, autophagy, and apoptosis in M2 macrophages but not in M1 macrophages. Figures 12A to 12E demonstrate this selectivity. In the RAW264.7 cell in vitro model, compound 1 similarly demonstrated superior selectivity for inducing phagocytosis, autophagy, and apoptosis in M2 macrophages but not in M1 macrophages. Figures 13A to 13C demonstrate this selectivity.

[0316] Compound 1 selectively increases cancer cell phagocytosis in M2 macrophages but not in M1 macrophages. Figures 14A-14B demonstrate this selectivity for M2 macrophages. As also shown in Figure 16, Compound 1 exhibited a full dose response in inducing phagocytosis.

[0317] As shown in Figure 8, Compound 1 inhibited the proliferation of human CD206 macrophages derived from healthy volunteers compared to M1-like macrophages. high Compound 1 is active in M2 macrophages. Screening with a panel of CD206 negative control cell lines demonstrated that the activity of Compound 1 is high The results show that the antibody is selective for M2 macrophages (Figure 9A). Similar selectivity is observed for dendritic cell DC2.4 viability (Figure 9B), fibroblast HTT viability (Figure 9C), RAW cell viability (Figure 9D), and KPC viability (Figure 9E).

[0318] FIG. 14A shows a graph of relative quantitative fluorescence showing the selective induction of cancer cell phagocytosis in M2 macrophages induced by Compound 1, indicating that Compound 1 increases cancer cell phagocytosis in M2 macrophages but not in M1 macrophages.

[0319] Figure 14B shows a graph of relative quantitative fluorescence showing the selective induction of cancer cell phagocytosis in M2 macrophages induced by compound 28, indicating that compound 28 increases cancer cell phagocytosis in M2 macrophages but not in M1 macrophages.

[0320] FIG. 17 shows a graph of the percent positive cell fraction for M1 markers as measured by quantitative flow cytometry of murine M2 macrophages treated for 2 hours with vehicle, 20 μM Compound 1, and 20 μM Compound 2, demonstrating the induction of M1 markers in M2 macrophages. The present invention provides, for example, the following items. (Item 1) Formula I: [ka] or a pharmaceutically acceptable salt thereof, Each bond shown as a joined solid and dashed line, [ka] can be a single, double, or aromatic bond; R 1 is hydrogen, halogen, hydroxyl, cyano, -CO 2 H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Alkoxy, -(C 0 ~C 6 alkyl)cycloalkyl, C 1 ~C 6 Haloalkyl, -(C 0 ~C 6 alkyl)phenyl, -(C 0 ~C 6 alkyl)aryl, -(C 0 ~C 6 alkyl)heteroaryl, -C(O)C 1 ~C 6 Alkyl, -C(O)NR 8 R 9 、-(C 0 ~C 6 alkyl)NR 5 R 6 , -CO 2 R 6 、-C 6 H 4 -R 7 and a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently selected from N, S, and O; R 2 、R 3 , and R 4 are each independently represented at each occurrence by hydrogen, halogen, hydroxyl, cyano, -CO 2 H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Alkoxy, -(C 0 ~C 6 alkyl)cycloalkyl, C 1 ~C 6 Haloalkyl, -(C 0 ~C 6 alkyl)phenyl, -(C 0 ~C 6 alkyl)aryl, -(C 0 ~C 6 alkyl)heteroaryl, -C(O)C 1 ~C 6 Alkyl, -C(O)NR 5 R 6 、(C 0 ~C 6 alkyl)NR 8 R 9 , -CO 2 R 6 , and -C 6 H 4 -R 7 is selected from a, b, c, d, and X are each independently selected at each occurrence from N, C, and CH; R 5 and R 6 are independently selected for each occurrence as hydrogen, halogen, hydroxy, or C. 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Alkoxy, substituted or unsubstituted -(C 0~C 6 alkyl)cycloalkyl, -(C 0 ~C 6 alkyl)phenyl, -(C 0 ~C 6 alkyl)aryl, -(C 0 ~C 6 alkyl)heteroaryl, -C(O)C 1 ~C 6 Alkyl, -C(O)(C 0 ~C 6 alkyl)phenyl, -(C 0 ~C 6 alkyl)NR 8 R 9 , -C(O)(C 0 ~C 6 alkyl)aryl, -C(O)(C 0 ~C 6 alkyl)heteroaryl, and a 4- to 7-membered heterocycloalkyl ring having 1, 2, or 3 ring atoms independently selected from N, O, and S; Any R bonded to the same nitrogen atom 5 and R 6 may be taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, said heterocycloalkyl ring being selected from the group consisting of N, O, S, S(O), and SO 2 and the heterocycloalkyl ring optionally contains 0, 1, or 2 additional heteroatoms selected from halogen, hydroxyl, cyano, oxo, dioxo, C at any carbon or hetero ring atom. 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, -(C 0 ~C 6 alkyl)cycloalkyl, -(C 0 ~C 6 alkyl)phenyl, -(C 0 ~C 6 alkyl)aryl, -(C 0 ~C 6 alkyl)CO 2 R 8 、-(C 0 ~C 6 alkyl)C(O)NR 8 R 9 、-(C 1 ~C 6 alkyl) OR 8 , -C(O)C 1 ~C 6 Alkyl, -(C 0 ~C 6 alkyl)NR 8 R 9 , or -C(O)(C 0 ~C 6 alkyl)NR 8 R 9 is replaced by R 7 is hydrogen, halogen, hydroxyl, cyano, -CO2 H, C 1 ~C 6 Alkyl, C 2 ~C 6 Alkenyl, C 2 ~C 6 Alkynyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, -(C 0 ~C 6 alkyl)cycloalkyl, -(C 0 ~C 6 alkyl)phenyl, -(C 0 ~C 6 alkyl)aryl, -(C 0 ~C 6 alkyl)heteroaryl, -CO 2 R 8 , -C(O)C 1 ~C 6 Alkyl, -C(O)C 2 ~C 6 Alkenyl, -C(O)C 2 ~C 6 Alkynyl, -C(O)C 1 ~C 6 Alkoxy, -C(O)C 1 ~C 6 Hydroxyalkyl, -C(O)-(C 0 ~C 6 alkyl)cycloalkyl, -C(O)-(C 0 ~C 6 alkyl)phenyl, -C(O)-(C 0 ~C 6 alkyl)aryl, -C(O)-(C 0 ~C 6 alkyl)heteroaryl, -C(O)NR 8 R 9 , -C(O)NR 5 R 6 , -C(O)-(C 0 ~C 6 alkyl)NR 5 R 6 , -C(O)-NR 8 -(C 0 ~C 6 alkyl)NR 5 R 6 , or (C 0 ~C 6 alkyl)NR 5 R 6 and R 8 and R 9 are independently hydrogen, halogen, or C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, -(C 0 ~C 6 alkyl)phenyl, -(C 0 ~C 6 alkyl)aryl, -(C 0 ~C 6 alkyl)NR 5 R 6 , -CO 2 R 6 , -C(O)C 1 ~C 6 Alkyl, and -(C 0 ~C 6 alkyl)cycloalkyl; A compound or a pharmaceutically acceptable salt thereof. (Item 2) R 1 But -C 6 H 4 -R 7 and R 2 and R 4 is hydrogen, R 3 But -(C 0 ~C 6 alkyl)phenyl, -(C 0 ~C 6 alkyl)aryl, or -(C 0 ~C 6 alkyl)heteroaryl; a, c, and X are N; b is C, d is CH; R 7 But -C(O)NR 5 R 6 or -C(O)-NR 8 -(C 0 ~C 6 alkyl)NR 5 R 6 and R 5 and R 6 each occurrence independently represents hydrogen, substituted or unsubstituted -(C 0 ~C 6 alkyl)cycloalkyl, -(C 0 ~C 6 alkyl)heteroaryl, C 1 ~C 6 Hydroxyalkyl, C 1 ~C 6 Alkoxy, -(C 0 ~C 6 alkyl)NR 8 R 9 and a 4- to 7-membered heterocycloalkyl ring having 1, 2, or 3 ring atoms independently selected from N, O, and S; Any R bonded to the same nitrogen atom 5 and R 6 may be taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, said heterocycloalkyl ring being selected from the group consisting of N, O, S, S(O), and SO 2 and the heterocycloalkyl ring optionally contains 0, 1, or 2 additional heteroatoms selected from halogen, hydroxyl, cyano, oxo, dioxo, C at any carbon or hetero ring atom. 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, -(C 0 ~C 6 alkyl)cycloalkyl, -(C 0 ~C 6 alkyl)phenyl, -(C 0 ~C 6 alkyl)aryl, -(C 0 ~C 6 alkyl)CO 2 R 8 、-(C 0 ~C 6 alkyl)C(O)NR 8 R 9 、-(C 1 ~C 6 alkyl) OR 8 , -CO 2 R 8 , -C(O)C 1 ~C 6 Alkyl, -(C 0 ~C 6 alkyl)NR 8 R 9 , or -C(O)(C 0 ~C 6 alkyl)NR 8 R 9 is replaced by R 8 and R9 Each occurrence of represents a hydrogen, halogen, or C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl, -(C 0 ~C 6 alkyl)phenyl, -(C 0 ~C 6 alkyl)aryl, -(C 0 ~C 6 alkyl)NR 5 R 6 , -CO 2 R 6 , -C(O)C 1 ~C 6 Alkyl, and -(C 0 ~C 6 alkyl)cycloalkyl; Item 1. The compound or salt according to item 1. (Item 3) The compounds of formula I include Compound 1, and Compounds 4 to 29:

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Claims

1. 1. A composition comprising a compound for use in treating a cancer selected from lung cancer, prostate cancer, breast cancer, liver cancer, colon cancer, breast cancer, kidney cancer, pancreatic cancer, brain cancer, skin cancer, testicular cancer, ovarian cancer, carcinoma, sarcoma, bladder cancer, endometrial cancer, blood cancer, thyroid cancer, and spinal cancer, wherein the compound is formula: 【Chemistry 92】 or a pharmaceutically acceptable salt thereof, (a) X is N, a is N, b is C, c is N, d is CH, the bond between the bridgehead carbon marked with an asterisk and d is a double bond, the bond between c and d is a single bond, the bond between b and c is a double bond, and the bond between a and the bridgehead carbon marked with an asterisk is a single bond; or (b) X is N or CH, a is N, b is C, c is N, d is N, the bond between the bridgehead carbon marked with an asterisk and d is a double bond, the bond between c and d is a single bond, the bond between b and c is a double bond, and the bond between a and the bridgehead carbon marked with an asterisk is a single bond; or (c) X is N, a is C, b is N, c is CH, d is N, the bond between the bridgehead carbon marked with an asterisk and d is a single bond, the bond between c and d is a double bond, the bond between b and c is a single bond, and the bond between a and the bridgehead carbon marked with an asterisk is a double bond; or (d) X is N, a is C, b is N, c is CH, d is CH, the bond between the bridgehead carbon marked with an asterisk and d is a single bond, the bond between c and d is a double bond, the bond between b and c is a single bond, and the bond between a and the bridgehead carbon marked with an asterisk is a double bond; R ３ is halo or C １ ~C ６ phenyl or pyridyl optionally substituted with haloalkyl; R ７ is -C(O)NR ５ R ６ or —C(O)—NR ８ -(C ０ ~C ６ alkyl)NR ５ R ６ and R ５ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Alkoxy, unsubstituted -(C ０ ~C ６ alkyl)cycloalkyl, -(C ０ ~C ６ alkyl)phenyl, -(C ０ ~C ６ alkyl)heteroaryl, —C(O)C １ ~C ６ Alkyl, —C(O)(C ０ ~C ６ alkyl)phenyl, -(C ０ ~C ６ alkyl)NR ８ R ９ , -C(O)(C ０ ~C ６ alkyl)aryl, —C(O)(C ０ ~C ６ alkyl)heteroaryl, 4- to 7-membered heterocycloalkyl rings having 1, 2, or 3 ring atoms independently selected from N, O, and S, as well as halogen, cyano, hydroxyl, amino, nitro, oxo, azido, C ２ ~C ６ Alkanoyl, C １ ~C ４ Alkoxy, C １ ~C ４ Alkyl, C １ ~C ４ alkylthio, and -(C ０ ~C ６ alkyl)cycloalkyl, and R ６ are each independently hydrogen or C １ ~C ６ is alkyl, or R ５ and R ６ are taken together to form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, said heterocycloalkyl ring being selected from the group consisting of N, O, S, S(O), and SO ２ and the heterocycloalkyl ring optionally contains 0, 1, or 2 additional heteroatoms selected from halogen, hydroxyl, cyano, oxo, dioxo, C at any carbon or hetero ring atom. １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, -(C ０ ~C ６ alkyl)cycloalkyl, -(C ０ ~C ６ alkyl)phenyl, -(C ０ ~C ６ alkyl)aryl, -(C ０ ~C ６ alkyl)CO ２ R ８ , -(C ０ ~C ６ alkyl)C(O)NR ８ R ９ , -(C １ ~C ６ alkyl) OR ８ , -C(O)C １ ~C ６ Alkyl, -(C ０ ~C ６ alkyl)NR ８ R ９ , or -C(O)(C ０ ~C ６ alkyl)NR ８ R ９ is replaced by, and R ８ and R ９ are independently hydrogen, C １ ~C ６ Alkyl, and —C(O)C １ ~C ６ selected from alkyl, composition.

2. The compound has the formula: 【Chemistry 93】 2. The composition of claim 1, wherein the compound is 3. A composition comprising a compound for use in treating cancer selected from lung cancer, prostate cancer, breast cancer, liver cancer, colon cancer, breast cancer, kidney cancer, pancreatic cancer, brain cancer, skin cancer, testicular cancer, ovarian cancer, carcinoma, sarcoma, bladder cancer, endometrial cancer, blood cancer, thyroid cancer, and spinal cancer, wherein the compound is selected from the group consisting of Compound 1, and Compounds 4 through 29: 【Transformation 79】 【Chemistry 80】 【Chemistry 81】 【Chemistry 82】 or a pharmaceutically acceptable salt thereof.

4. The compound has the formula: 【Chemical 94】 is a compound of X is N or CH; R ７ is —C(O)—NR ８ -(C ０ ~C ６ alkyl)NR ５ R ６ and R attached to the same nitrogen atom ５ and R ６ taken together form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, said heterocycloalkyl ring being selected from the group consisting of N, O, S, S(O), and SO ２ and the heterocycloalkyl ring optionally contains 0, 1, or 2 additional heteroatoms selected from halogen, hydroxyl, cyano, oxo, dioxo, C at any carbon or hetero ring atom. １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, -(C ０ ~C ６ alkyl)cycloalkyl, -(C ０ ~C ６ alkyl)phenyl, or -(C ０ ~C ６ alkyl)aryl; R ８ is hydrogen, The composition of claim 1.

5. The compounds are Compound 30 and Compound 31: 【Chemistry 83】 or a pharmaceutically acceptable salt thereof.

6. The compound has the formula: 【Chemical 95】 is a compound of R ７ is —C(O)—NR ８ -(C ０ ~C ６ alkyl)NR ５ R ６ and R attached to the same nitrogen atom ５ and R ６ taken together form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, said heterocycloalkyl ring being selected from the group consisting of N, O, S, S(O), and SO ２ and the heterocycloalkyl ring optionally contains 0, 1, or 2 additional heteroatoms selected from halogen, hydroxyl, cyano, oxo, dioxo, C at any carbon or hetero ring atom. １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, -(C ０ ~C ６ alkyl)cycloalkyl, -(C ０ ~C ６ alkyl)phenyl, or -(C ０ ~C ６ alkyl)aryl; R ８ is hydrogen, The composition of claim 1.

7. The compound is Compound 32: 【Chemical 84】 7. The composition of claim 6, wherein the compound is a compound represented by:

8. The compound has the formula: 【Chemistry 96】 is a compound of R ７ is —C(O)—NR ８ -(C ０ ~C ６ alkyl)NR ５ R ６ and R attached to the same nitrogen atom ５ and R ６ taken together form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, said heterocycloalkyl ring being selected from the group consisting of N, O, S, S(O), and SO ２ and the heterocycloalkyl ring optionally contains 0, 1, or 2 additional heteroatoms selected from halogen, hydroxyl, cyano, oxo, dioxo, C at any carbon or hetero ring atom. １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl, -(C ０ ~C ６ alkyl)cycloalkyl, -(C ０ ~C ６ alkyl)phenyl, or -(C ０ ~C ６ alkyl)aryl; R ８ is hydrogen, The composition of claim 1.

9. The compound is Compound 33: 【Chemical 85】 or a pharmaceutically acceptable salt thereof.

10. The composition of any one of claims 1 to 9, wherein the cancer is associated with CD206-positive tumor-associated macrophages.

11. The composition of any one of claims 1 to 9, wherein CD206, a large C-type lectin receptor, targets, regulates and induces cell death of the M2 macrophages.

12. 12. The composition of any one of claims 1 to 11, wherein the cancer is selected from glioma, acute myeloid leukemia, acute myelogenous leukemia, chronic myelomonocytic leukemia, non-Hodgkin's lymphoma, astrocytoma, melanoma, non-small cell lung cancer, chondrosarcoma, and Kaposi's sarcoma.

13. The composition according to any one of claims 1 to 11, wherein the cancer is pancreatic cancer.

14. formula: 【Chemistry 97】 or a pharmaceutically acceptable salt thereof, (a) X is N, a is N, b is C, c is N, d is CH, the bond between the bridgehead carbon marked with an asterisk and d is a double bond, the bond between c and d is a single bond, the bond between b and c is a double bond, the bond between a and the bridgehead carbon marked with an asterisk is a single bond, and R ３ is pyridyl, or (b) X is N, a is N, b is C, c is N, d is N, the bond between the bridgehead carbon marked with an asterisk and d is a double bond, the bond between c and d is a single bond, the bond between b and c is a double bond, the bond between a and the bridgehead carbon marked with an asterisk is a single bond, and R ３ is pyridyl, or halo or C １ ~C ６ phenyl optionally substituted with haloalkyl; (c) X is N, a is C, b is N, c is CH, d is N, the bond between the bridgehead carbon marked with an asterisk and d is a single bond, the bond between c and d is a double bond, the bond between b and c is a single bond, the bond between a and the bridgehead carbon marked with an asterisk is a double bond, and R ３ is pyridyl, or halo or C １ ~C ６ phenyl optionally substituted with haloalkyl; (d) X is N, a is C, b is N, c is CH, d is CH, the bond between the bridgehead carbon marked with an asterisk and d is a single bond, the bond between c and d is a double bond, the bond between b and c is a single bond, the bond between a and the bridgehead carbon marked with an asterisk is a double bond, and R ３ is pyridyl, or halo or C １ ~C ６ phenyl optionally substituted with haloalkyl; R ７ is -C(O)NR ５ R ６ or —C(O)—NR ８ -(C ０ ~C ６ alkyl)NR ５ R ６ and R ５ each occurrence independently represents hydrogen, hydroxy, C １ ~C ６ Alkyl, C １ ~C ６ Hydroxyalkyl, C １ ~C ６ Alkoxy, unsubstituted -(C ０ ~C ６ alkyl)cycloalkyl, -(C ０ ~C ６ alkyl)phenyl, -(C ０ ~C ６ alkyl)heteroaryl, —C(O)C １ ~C ６ Alkyl, as well as halogen, cyano, hydroxyl, amino, nitro, oxo, azido, C ２ ~C ６ Alkanoyl, C １ ~C ４ Alkoxy, C １ ~C ４ Alkyl, C １ ~C ４ alkylthio, and -(C ０ ~C ６ alkyl)cycloalkyl, and R ６ are each hydrogen or C １ ~C ６ is alkyl, or R ５ and R ６ taken together form a 4- to 7-membered monocyclic heterocycloalkyl ring, said heterocycloalkyl ring being selected from the group consisting of N, O, S, S(O), and SO ２ and the heterocycloalkyl ring optionally contains 0, 1, or 2 additional heteroatoms selected from oxo, C １ ~C ６ Alkyl, CO ２ C １ ~C ６ Alkyl, —C(O)NR ８ R ９ , or -C(O)C １ ~C ６ is substituted with alkyl, and R ８ and R ９ are independently hydrogen, C １ ~C ６ Alkyl, and —C(O)C １ ~C ６ selected from alkyl, A compound or a pharmaceutically acceptable salt thereof.

15. The compound has the formula: 【Chem.98】 is a compound of R ７ is —C(O)—NR ８ -(C ０ ~C ６ alkyl)NR ５ R ６ and R attached to the same nitrogen atom ５ and R ６ taken together form a 4- to 7-membered monocyclic heterocycloalkyl ring, said heterocycloalkyl ring being selected from the group consisting of N, O, S, S(O), and SO ２ and the heterocycloalkyl ring optionally contains 0, 1, or 2 additional heteroatoms selected from oxo or C at any carbon or hetero ring atom. １ ~C ６ is substituted with alkyl, R ８ is hydrogen, 15. A compound or salt according to claim 14.

16. The compounds are Compound 30 and Compound 31: 【Chem.99】 or a pharmaceutically acceptable salt thereof.

17. The compound has the formula: 【Chemistry 100】 is a compound of R ７ is —C(O)—NR ８ -(C ０ ~C ６ alkyl)NR ５ R ６ and R attached to the same nitrogen atom ５ and R ６ taken together form a 4- to 7-membered monocyclic heterocycloalkyl ring, said heterocycloalkyl ring being selected from the group consisting of N, O, S, S(O), and SO ２ and the heterocycloalkyl ring optionally contains oxo or C at any carbon or hetero ring atom. １ ~C ６ is substituted with alkyl, R ８ is hydrogen, 15. A compound or salt according to claim 14.

18. The compound is Compound 32: 【Chemistry 101】 18. The compound or salt of claim 17, which is a compound represented by: or a pharmaceutically acceptable salt thereof.

19. The compound has the formula: 【Chemical Engineering 102】 is a compound of R ７ is —C(O)—NR ８ -(C ０ ~C ６ alkyl)NR ５ R ６ and R attached to the same nitrogen atom ５ and R ６ taken together form a 4- to 7-membered monocyclic heterocycloalkyl ring, said heterocycloalkyl ring being selected from the group consisting of N, O, S, S(O), and SO ２ and the heterocycloalkyl ring optionally contains 0, 1, or 2 additional heteroatoms selected from oxo, C １ ~C ６ is substituted with alkyl, R ８ is hydrogen, 15. A compound or salt according to claim 14.

20. The compound is Compound 33: 【Chemistry 103】 20. The compound or salt of claim 19, which is a compound represented by: or a pharmaceutically acceptable salt thereof.

21. 21. A pharmaceutical composition comprising a compound or salt according to any one of claims 14 to 20 together with a pharmaceutically acceptable carrier.

22. 21. A composition comprising a compound of any of claims 14 to 20 for use in treating a cancer selected from lung cancer, prostate cancer, breast cancer, liver cancer, colon cancer, breast cancer, kidney cancer, pancreatic cancer, brain cancer, skin cancer, testicular cancer, ovarian cancer, carcinoma, sarcoma, bladder cancer, endometrial cancer, blood cancer, thyroid cancer and spinal cancer in a patient.

23. 23. The composition of claim 22, wherein the cancer is associated with CD206-positive tumor-associated macrophages.

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