CD206 modulator, its use, and preparation method

Abstract

To provide a CD206 modulator, its use, and a method for preparing it. [Solution] Compounds of formulas I, II, and III, as well as pharmaceutically acceptable salts thereof, are disclosed. Variables X, a, b, c, d, R 1~4 , R 10~15 , and R 17~22 The compounds are disclosed herein. The compounds are useful for treating cancer disorders, particularly those related to the M2 phenotype of macrophages. Pharmaceutical compositions containing compounds of formula I, formula II, or formula III, and methods of treatment comprising administering compounds of formula I, formula II, and formula III are also disclosed. TIFF2026053706000094.tif2397

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 62 / 950,488, filed on 19 December 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 project number ZIA-BC011267. The government has certain rights in this invention. [Background technology]

[0002] Background of the Invention 1. Field of Invention This invention relates to immunotherapeutic drugs, and more specifically to compounds that modulate CD206, as well as methods for their use and preparation. 2. Brief explanation of related technologies Pancreatic cancer is a disease in which malignant (cancerous) cells form in the tissue of the pancreas. Pancreatic cancer often has a poor prognosis, even when diagnosed early. Pancreatic cancer typically spreads rapidly and is often undetectable in its early stages, which is the main reason why it 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 each year. By 2030, pancreatic cancer is projected to rank second as the second leading cause of cancer-related death in the United States. Furthermore, the five-year survival rate for pancreatic cancer in the United States ranks low among solid organ tumors. There are no reliable screening tests for the early detection of pancreatic cancer. Signs and symptoms are thought to not appear until pancreatic cancer is quite advanced, and complete surgical removal is not possible. Standard treatments for pancreatic cancer, including surgery, radiotherapy, and chemotherapy, largely demonstrate limited efficacy. In fact, approved treatments, including gemcitabine, FOLFIRINOX, gemcitabine and Abraxane combinations, and gemcitabine and erlotinib combinations, improve survival rates by at best two to three months to several months. Newer treatments have not demonstrated further success, perhaps due to the thick stroma, unique immune infiltration 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, and its five-year survival rate is 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, while the potential of T-cell activation-mediated immunotherapy has so far been largely out of reach for patients in a much larger number of solid organ cancers, such as pancreatic cancer, which are classified as immunologically "cold." These tumors create an immune environment that eliminates cytotoxic T cells or induces exhausted T-cell phenotypes through abundant immune evasion cues that frequently involve innate immune cells. Strategies to reactivate innate immune cells are undervalued within the current scope of immuno-oncological therapy.

[0004] Tumor cells attract and reprogram innate immune cells, including tumor-associated macrophages (TAMs), to support tumor growth and metastatic spread. While the dichotomous M1 vs. M2 classification fails to capture the ontogenetic and tissue-specific cues of TAMs, it is generally proposed that M1-like TAMs are a more common phenotype in the early tumor stage, while M2 TAMs are more prominent in more advanced cancers. CD206 high M2 TAM is Tumor growth is utilized through the elimination of cancer-promoting factors, or through the promotion of angiogenesis, the development of cancer stem cells, or the creation of an immune-evading microenvironment.

[0005] CD206 is a member of the large C-type lectin receptor family that can modulate M2 macrophages. CD206 is involved in the recognition and binding of mannan and fucose carbohydrate residues from microorganisms via its eight carbohydrate-recognizing domains, or, as a scavenger receptor, in the phagocytosis of collagen fragments generated during tissue injury and wound healing via its fibronectin domain II. Ligand binding or low pH induces both a "rolling-in" (via numerous Ca+-dependent intramolecular interactions between carbohydrate-recognizing domains) and a closed ("active") form of the receptor, triggering NF-κB signaling activation, as well as 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 the EMT-like phenotype in cancer cells, and metastasis. high Expression was 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 outcomes. Using a synthetic host defense peptide design known to modulate innate immune function through binding to the C-type lectin receptor (RP-182), binding to the amino acid carbohydrate recognition domain 5 (CRD5) sequence NFGDLVSIQSESEKK of the CD206 receptor: (1) activates the phagocytosis and autophagy programs in M2 macrophages, resulting in reprogramming of the metabolism of these cells and an M1-like phenotype, as well as (2) CD206 highIt has been previously shown that activation of intracellular NF-κB signaling, leading to selective death of M2 macrophages via autocrine TNF-alpha-mediated caspase 8 and 3 activation, is possible (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, a small molecule modulator of CD206 is highly desirable. [Prior art documents] [Patent Documents]

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

[0008] Summary of the Invention This specification describes small molecule modulators that target the CD206 receptor, methods for producing the same, compositions containing the described compounds, and methods for using the described compounds.

[0009] In the first embodiment, compounds of formula I and pharmaceutically acceptable salts of compounds of formula I are provided. [ka]

[0010] In equation I, the following conditions are met.

[0011] Each connection is shown as a combined solid and dashed line, [ka] These can be single bonds, double bonds, or aromatic bonds.

[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 is 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, each time they appear, 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 selected from.

[0014] a, b, c, d, and X are each independently, each time they appear, selected from N, C, and CH.

[0015] R 5 and R 6Each of these terms appears independently as follows: hydrogen, halogen, hydroxyl, 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 The selection is made from -C(O)(C0~C6 alkyl)aryl, -C(O)(C0~C6 alkyl) heteroaryl, and 4 to 7-membered heterocycloalkyl rings 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 These may together form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, the heterocycloalkyl ring containing 0, 1, or 2 additional heteroatoms selected from N, O, S, S(O), and SO2, and this heterocycloalkyl ring The halogens, hydroxyl, cyano, oxo, dioxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl) cycloalkyl, -(C0-C6 alkyl) phenyl, -(C0-C6 alkyl) aryl, and -(C0-C6 alkyl) CO2R are used as needed, with any carbon or heterocyclic atom. 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 It has been replaced with.

[0017] R 7These are 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 That is the case.

[0018] R 8 and R 9 Each of these elements appears independently, and each time it appears, it is 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 Selected from -C(O)C1~C6 alkyl and -(C0~C6 alkyl)cycloalkyl.

[0019] In a second embodiment, compounds of formula II and pharmaceutically acceptable salts of compounds of formula II are provided. [ka]

[0020] In equation II, the following conditions are met.

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

[0022] R 10 , R 11 , and R 13 Each of these independently, as it appears, is hydrogen, hydroxyl, -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)heteroaryl, and -CO2R 16 Selected from.

[0023] R 12 , R 14 , and R 15 Each of these elements is independently selected from hydrogen, halogen, hydroxyl, and cyano as it appears.

[0024] X is either O or S.

[0025] R 16 This refers to a monocyclic or bicyclic heterocycle having 4 to 10 ring atoms, having 1, 2, or 3 ring atoms independently selected from N, S, and O, such as hydrogen, halogen, hydroxyl, amino group, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C0-C6 alkyl)cycloalkyl, -C(O)C1-C6 alkyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -(C0-C6 alkyl)phenyl, or N, S, and O.

[0026] In a third embodiment, compounds of formula III and pharmaceutically acceptable salts of compounds of formula III are provided. [ka]

[0027] In Equation III, the following conditions are met.

[0028] R 17 , R 18 , and R 21 Each of these groups appears independently, and each time it appears, it represents a hydrogen, halogen, hydroxyl, cyano, amidino group, and -NR. 23 R 24 , sulfonic acid group or its salt, phosphate group or its salt, -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 , as well as selected from monocyclic or bicyclic heterocycles of 4 to 10 ring atoms, each having 1, 2, or 3 ring atoms independently selected from N, S, and O.

[0029] Each time X appears, it is selected from O and S.

[0030] R 19 , R 20 , and R 22 Each of these groups is independently selected from hydrogen, halogen, hydroxyl, cyano, and amino groups each time it appears.

[0031] R23 and R 24 Each of these, independently, appears as follows: 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, -SO2phenyl, -SO2aryl, -SO2 heteroaryl, -(C0-C6 alkyl) cycloalkyl, and -CO2R 25 Selected from.

[0032] R 25 This refers to a monocyclic or bicyclic heterocycle having 4 to 10 ring atoms, having 1, 2, or 3 ring atoms independently selected from N, S, and O, such as hydrogen, halogen, hydroxyl, amino group, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C0-C6 alkyl)cycloalkyl, -C(O)C1-C6 alkyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -(C0-C6 alkyl)phenyl, or N, S, and O.

[0033] Pharmaceutical compositions comprising a compound or salt of formula I, formula II, or formula III together with a pharmaceutically acceptable carrier are also disclosed.

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

[0035] In some embodiments, CD206 is represented by a compound or salt of formula I, formula II, or formula III. Targeting M2 macrophages may have a dual effect: CD206 M2 macrophages may be reprogrammed into M1 macrophages, or M2 macrophages may be directly killed.

[0036] Also disclosed is a method 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, hepatocyte, breast, prostate, stomach, renal, endometrial, or pancreatic cancer, comprising administering a therapeutically effective dose of a compound or salt of formula I, formula II, or formula III to a patient in need of such treatment.

[0037] The following detailed description is given merely as an example and is not intended to limit the invention to the specific embodiments described herein, and should be understood in conjunction with the accompanying drawings. [Brief explanation of the drawing]

[0038] [Figure 1A] Figure 1A shows a graph of relative cell viability percentage versus logarithmic molar concentration, illustrating the anti-cell viability screening for compound 1.

[0039] [Figure 1B] Figure 1B shows a graph of relative cell viability percentage versus logarithmic molar concentration, illustrating the anti-cell viability screening for compound 2.

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

[0041] [Figure 2A]Figure 2A is a graph of relative cell viability percentage versus logarithmic 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 logarithmic 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 2 is CD206-dependent.

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

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

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

[0046] [Figure 3C] Figure 3C shows a graph of tumor volume versus treatment days in cubic millimeters (mm3), illustrating the change in tumor volume during in vivo testing of compound 1 in a syngeneic immune function B16.F10 allograft model (mouse melanoma model).

[0047] [Figure 4] Figure 4 shows a graph of relative cell viability percentage versus logarithmic molar concentration, illustrating the macrophage activity of compound 4, which has an IC50 of 8.95 micromolars (μM).

[0048] [Figure 5] Figure 5 shows a graph of relative cell viability percentage versus logarithmic molar concentration, illustrating the macrophage activity of compound 5, which has an IC50 of 7.36 μM.

[0049] [Figure 6] Figure 6 shows a graph of relative cell viability percentage versus logarithmic molar concentration, illustrating the macrophage activity of compound 6, which has an IC50 of 3.85 μM.

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

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

[0052] [Figure 9A]Figure 9A shows a graph of relative cell viability percentage versus logarithmic molar concentration in a panel of CD206-negative control cell lines, illustrating the activity of compound 1 against CD206-high M2 macrophages.

[0053] [Figure 9B] Figure 9B shows a graph of relative cell viability percentage versus logarithmic molar concentration for a panel of dendritic cells DC2.4 for compound 1, illustrating the selectivity of compound 1 for CD206high M2 macrophages.

[0054] [Figure 9C] Figure 9C shows a graph of relative cell viability percentage versus logarithmic molar concentration in a panel of fibroblast HTT for compound 1, illustrating the selectivity of compound 1 for CD206high M2 macrophages.

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

[0056] [Figure 9E] Figure 9E shows a graph of relative cell viability percentage versus logarithmic molar concentration in a panel of KPC cancer cells (mouse pancreatic cancer cells) for compound 1, illustrating the selectivity of compound 1 for CD206high M2 macrophages.

[0057] [Figure 10A] Figure 10A shows a graph of time (hr) versus concentration (ng / mL) of compound 1, illustrating the pharmacokinetic (PK) profile of compound 1 at various concentrations when administered via intravenous (IV) injection.

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

[0059] [Figure 10C] Figure 10C shows a graph of time (hr) versus concentration of compound 1 (ng / mL), illustrating the pharmacokinetic (PK) profile of compound 1 at various concentrations when administered orally.

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

[0061] [Figure 11B] Figure 11B shows a representative series of scanning electron microscopy images of recombinant CD206 incubated with compound 1 and the vehicle for 30 minutes at 1 μM, scored as closed versus open. The number of CD206 particles in the series, scored as closed versus open as shown at the bottom, shows that 48% of the CD206 particles are in the closed state (squares enclosed by thick borders) and 52% are in the open state (squares without borders), indicating that compound 1 binds to CD206 and induces a switching of the receptor's stereoconformation.

[0062] [Figure 12A]Figure 12A shows a graph of quantitative relative fluorescence obtained in mouse M1 and M2 macrophages to demonstrate the induction of early phagocytosis, showing that compound 1 induces early phagocytosis in M2 macrophages rather than in M1 macrophages.

[0063] [Figure 12B] Figure 12B shows a graph of quantitative relative fluorescence obtained in mouse M1 and M2 macrophages to demonstrate the induction of phagocytosis, showing that compound 1 induces phagocytosis in M2 macrophages rather than in M1 macrophages.

[0064] [Figure 12C] Figure 12C shows a graph of quantitative relative fluorescence obtained in mouse M1 and M2 macrophages to demonstrate the induction of phagolysosome formation, showing that compound 1 induces phagolysosome formation in M2 macrophages rather than in M1 macrophages.

[0065] [Figure 12D] Figure 12D shows a graph of quantitative relative fluorescence obtained in mouse M1 and M2 macrophages to demonstrate the induction of autophagy, showing that compound 1 induces autophagy in M2 macrophages rather than M1 macrophages.

[0066] [Figure 12E] Figure 12E shows a graph of quantitative relative fluorescence obtained in mouse M1 and M2 macrophages to demonstrate the induction of apoptosis, showing that compound 1 induces apoptosis in M2 macrophages rather than M1 macrophages.

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

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

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

[0070] [Figure 14A] Figure 14A shows a relative quantitative fluorescence graph to demonstrate the selective induction of cancer cell phagocytosis in M2 macrophages induced by compound 1, showing that compound 1 increases cancer cell phagocytosis within M2 macrophages rather than within M1 macrophages.

[0071] [Figure 14B]Figure 14B shows a graph of relative quantitative fluorescence to show the selective induction of cancer cell phagocytosis in M2 macrophages induced by compound 28, indicating that compound 28 increases cancer cell phagocytosis in M2 rather than in M1 macrophages.

[0072] [Figure 15] Figure 15 shows a graph of relative cell survival percentage versus logarithmic molar concentration, showing the macrophage activity of compound 1 with an IC50 of 2.86 μM.

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

[0074] [Figure 17] Figure 17 shows a graph of the percentage of positive cell fraction for the M1 marker, measured by quantitative flow cytometry of murine M2 macrophages treated with vehicle, 20 μM of compound 1, and 20 μM of compound 2 for 2 hours, showing the induction of the M1 marker 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 the reduction of CD206 macrophages, the shift from CD206high M2 to CD86-positive M1 macrophages, and the increase of intratumoral CD8 cells in KPC tumors treated with Compound 1 compared to vehicle, a graph of the percentage of positive cell fractions in all cells within the tumor measured by quantitative flow cytometry in KPC tumors treated with Compound 1 (CD206 = M2 macrophages; CD86 = M1 macrophages; CD8a = CD8-positive T cells; CD4 = CD4-positive T cells). Figure 18B shows the reduction of CD206-positive cells within the tumor-associated macrophage population measured by CD11b+F4 / 80+Gr-1 negative cells. Figure 18C shows the reduction of signal regulatory protein α (SIRPα), a regulatory membrane glycoprotein from the SIRP family, and shows the inhibition of cancer cell phagocytosis by tumor-associated macrophages 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 percentage of positive cell fractions of intratumoral M1 and M2 macrophage populations measured by quantitative flow cytometry in KPC tumors to show the shift in cytokine profiles after treatment with Compound 1 in KPC for 3 weeks compared to vehicle, showing that Compound 1 induced M1 markers in both intratumoral M1 and intratumoral M2 macrophage populations compared to vehicle. [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. It indicates that after adoptive transfer of M2 macrophages via intratumoral injection, treatment with compound 1 limited tumor growth as much as equivalent injections of M1 macrophages when intratumoral injection frequency was three times per week and measurement frequency was twice per week, compared to the vehicle. Treatment with compound 1 reduced tumor growth with M2 macrophages pretreated with compound 1, except when pretreated with the vehicle, indicating that M2 macrophages treated with compound 1 and injected intratumor exert a tumor-limiting effect.

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

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

[0080] [Figure 22] Figure 22 shows a graph of relative cell viability percentage versus logarithmic molar concentration, illustrating the macrophage activity of compound 10, which has an IC50 of 5.45 μM. [Modes for carrying out 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 those commonly understood by those skilled in the art to which this invention pertains.

[0082] The terms "a" and "an" do not indicate a limit on quantity, but rather indicate the presence of at least one of the items being referred to. The term "or" means "and / or". "comprising", "having", "including", and "containing" The term "to do" shall be interpreted as a non-restrictive term (i.e., meaning "to include but not to limit").

[0083] Unless otherwise specified herein, the enumeration of value ranges serves simply as a means of individually referring to each separate value contained within that range, and each separate value is incorporated herein as if they were individually cited herein. The endpoints of all ranges are contained within that range and can be combined independently.

[0084] All methods described herein may be performed in any suitable order, unless otherwise indicated herein or otherwise clearly contradicted by the context. The use of any and all examples or exemplary language (e.g., "etc.") is illustrative and, unless otherwise asserted, does not impose any limitation on the scope of this disclosure. No language herein should be construed as indicating that any unasserted element is essential for carrying out the invention. Unless otherwise defined, technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art of this disclosure.

[0085] Furthermore, this disclosure encompasses all modifications, 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 dependent on another claim may be modified to include one or more limitations found in any other claim dependent on the same base claim. Where elements are presented enumerated, for example in the Markush group format, each subgroup of elements is also disclosed, and any element(s) may be removed from the group.

[0086] All compounds are understood to include all possible isotopes of the atoms that appear in the compound. Isotopes include atoms that have the same atomic number but different mass numbers. By way of general example, without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include 11 C, 13 C, and 14 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 non-limiting term “comprising” includes the intermediate and limiting terms “consisting essentially of” and “consisting of”.

[0091] The term “substituted” means that one or more hydrogens of any one of the designated atoms or groups are replaced with a selection from the indicated groups, 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 by the corresponding partially unsaturated ring. For example, a pyridyl group substituted with oxo is pyridone. Combinations of substituents and / or variables are permitted only if such combinations result in a stable compound or a useful synthetic intermediate. A stable compound or stable structure is meant to suggest 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 "substituted as needed" positions include, but are not limited to, halogens, cyano, hydroxyl, amino, nitro, oxo, azide, alkanoyl (acyl or similar (-(C=O)alkyl) C2-C6 alkanoyl groups, etc.); carboxamides; alkylcarboxamides; alkyl groups, alkoxy groups, alkylthio groups including those having one or more thioether bonds, alkylsulfinyl groups including those having one or more sulfinyl bonds, alkylsulfonyl groups including those having one or more sulfonyl bonds, mono- and di-aminoalkyl groups including groups having one or more N atoms, all of the aforementioned optional alkyl substituents may have one or more methylene groups substituted by oxygen or -NH-, and about 1 to about 8, about 1 to about 6, or 1 to about 4 carbon atoms, cycloalkyl; phenyl; phenylalkyl with benzyl, which is an exemplary phenylalkyl group, and phenylalkoxy with benzyloxy, which is an exemplary phenylalkoxy group. Alkylthio and alkoxy groups are bonded to positions where they are substituted with sulfur or oxygen atoms, respectively.

[0093] A dashed line ("-") and a (" [ka] The symbol ) is used to indicate bonding points for substituents.

[0094] "Alkyl" includes both branched and linear saturated aliphatic hydrocarbon groups having a specified number of carbon atoms, generally 1 to about 8 carbon atoms. As used herein, the term C1-C6 alkyl refers to alkyl groups 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 alkyls, C1-C4 alkyls, and C1-C2 alkyls. nWhen an alkyl group is used herein in conjunction with another group, e.g., a -C0-C2 alkyl (phenyl), the indicated group, in this case phenyl, is directly bonded by a monocovalent bond (C0 alkyl) or by an alkyl chain having a specified number of carbon atoms, in this case 1, 2, 3, or 4 carbon atoms. Alkyl groups can also be bonded via other groups, such as heteroatoms, as in -O-C0-C4 alkyls (C3-C7 cycloalkyls). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, and sec-pentyl.

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

[0096] "Alkynnyl" is a branched or linear aliphatic hydrocarbon group having one or more double carbon-carbon triple bonds that can occur at any stable point along the chain, having a specified number of carbon atoms.

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

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

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

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

[0101] A "heteroaryl" is a stable monocyclic aromatic ring having the indicated number of ring atoms, containing 1 to 3 heteroatoms selected from N, O, and S, or in some embodiments, 1 to 2 heteroatoms, with the remaining ring atoms being carbon; or a stable bicyclic or tricyclic system containing at least one 5 to 7-membered aromatic ring containing 1 to 3 heteroatoms selected from N, O, and S, or in some embodiments, 1 to 2 heteroatoms, with the remaining ring atoms being carbon. Monocyclic heteroaryl groups typically have 5 to 7 ring atoms. In some embodiments, a bicyclic heteroaryl group is a 9 to 10-membered heteroaryl group, i.e., a group 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 a heteroaryl group is greater than 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in a heteroaryl group is 2 or less. Particularly preferable is that the total number of S and O atoms in an aromatic heterocycle is 1 or less. Heteroaryl groups include, but are not limited to, oxazolyl, piperazinyl, pyranyl, pyrazinyl, pyrazolopyrimidinyl, pyrazolyl, pyrididinyl, pyryryl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienylpyrazolyl, thiophenyl, triazolyl, benzo[d]oxazolyl, benzofuranil, benzothiazolyl, benzothiophenyl, benzoxadiazolyl, dihydrobenzodioxynyl, furanil, imidazolyl, indolyl, isothiazolyl, and isoxazolyl.

[0102] A "heterocyclic" group is a saturated, unsaturated, or aromatic ring group containing 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] A "heterocycloalkyl" is a saturated cyclic group having the indicated number of ring atoms, containing one to about three 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 linear alkyl groups having a specified number of carbon atoms, substituted with one or more halogen atoms, generally the maximum possible number of halogen atoms. Examples of haloalkyls include, but are not limited to, truffles. This includes ruoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

[0105] A "haloalkoxy" is a haloalkyl group defined above, which is bonded via an oxygen bridge (the oxygen of an alcohol radical).

[0106] "Pharmaceutical composition" means a composition comprising at least one activator, such as a compound or salt of formula (I), and at least one other substance, such as a carrier. Pharmaceutical compositions meet the USFDA's GMP (Good Manufacturing Practice) standards for human or non-human drugs.

[0107] "Carrier" means a diluent, excipient, or vehicle with which an active compound is administered. "Pharmacologically acceptable carrier" means a substance useful for preparing a pharmaceutical composition that is generally safe, non-toxic, and not undesirable from a biological or other standpoint, such as an excipient, diluent, or vehicle, and includes carriers acceptable for veterinary use as well as for human medicinal use. "Pharmacologically acceptable carrier" includes both one and more such carriers.

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

[0109] "To provide" means to give, administer, sell, distribute, transport (for commercial or not), manufacture, formulate, or distribute.

[0110] "Treatment" or "to treat" means providing a patient with an active compound in an amount sufficient to measurably reduce any cancer symptoms, slow the progression of cancer, or induce cancer regression. In certain embodiments, cancer treatment may be initiated before the patient presents with symptoms of the disease.

[0111] The "therapeutic dose" of a pharmaceutical composition means the amount that, when administered to a patient, is effective in providing a therapeutic benefit, such as improving symptoms, slowing 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 the Student's T-test, where p < 0.05. chemical description

[0113] Compounds of formula I, II, or III may contain one or more asymmetric elements, such as a chiral center, chiral axis, and the like, e.g., a chiral carbon atom, and thus the compounds can exist in various stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In the case of compounds with two or more asymmetric elements, these compounds can further be mixtures of diastereomers. In the case of compounds with a chiral center, all optical isomers in the pure form and mixtures thereof are included. In these situations, a single enantiomer, i.e., an optically active form, can be obtained by asymmetric synthesis, synthesis from an optically pure precursor, or by racemic resolution. Racemic resolution can also be achieved, for example, by crystallization in the presence of a resolving agent, or by conventional methods such as chromatography, e.g., using a chiral HPLC column. All forms are intended herein, regardless of the methods used to obtain them.

[0114] All forms of activators (e.g., solvates, optical isomers, enantiomers, tautomers) The compounds (forms, polymorphs, free compounds, and salts) may be used individually or in combination.

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

[0116] "Stereoisomers" are compounds that have the same chemical structure but differ in the arrangement of atoms or groups in space.

[0117] Diastereomers are stereoisomers that have two or more chiral centers, and their molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. Mixtures of diastereomers can be separated under high-resolution analytical procedures such as electrophoresis, crystallization in the presence of a resolving agent, or chromatography, such as using a chiral HPLC column.

[0118] An "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0119] The stereochemical definitions and conventions used herein generally follow SP. 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. Compounds exist in an optically active form, that is, 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 rotation of plane-polarized light by the compound, with (-) or l meaning the compound is levorotatory. Compounds prefixed with (+) or d are dextrorotatory.

[0120] A "racemic mixture" or "racemate" is an equimorlar (or 50:50) mixture of two enantiomer species lacking optical activity. Racemic mixtures can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.

[0121] "Tautomers" or "tautomer forms" are structural isomers that are readily interconverted by the transfer of hydrogen atoms, generally in combination with the switching of single and double bonds.

[0122] "Pharmacologically acceptable salts" include derivatives of disclosed compounds in which the parent compound is modified by producing 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 basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as a hydroxide, carbonate, or bicarbonate of Na, Ca, Mg, or K) or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water or in an organic solvent or in a mixture of these two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used where feasible. Salts of the compounds of the present invention further include solvates of the compounds and compound salts.

[0123] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral acids or organic salts of basic residues such as amines; alkalis or organic salts of acidic residues such as carboxylic acids; and the same This includes various types of salts. Pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of parent compounds formed from, for example, non-toxic inorganic or organic acids. For example, conventional non-toxic salts are those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and similar; 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, ecylic acid, besylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH2) n This includes salts prepared from organic acids such as -COOH (where n is 0-4). A list 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. It can be released. chemical description

[0124] Molecules that modulate CD206 are disclosed herein.

[0125] In addition to the compounds of formulas I, II, and III shown in the summary section, this disclosure also includes variables such as X and R. 1 From R 25also includes compounds having the following definitions. The present disclosure includes all combinations of these definitions as long as stable compounds are obtained.

[0126] The present disclosure relates to formula I

Chemical formula

[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 is 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 are 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 That is the case.

[0130] a, b, c, and d are each independently selected from N, C, and CH each time they appear.

[0131] X is N.

[0132] R 5 and R 6 Each of these terms appears independently as follows: hydrogen, halogen, hydroxyl, 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 The selection is made from -C(O)(C0~C6 alkyl)aryl, -C(O)(C0~C6 alkyl) heteroaryl, and 4 to 7-membered heterocycloalkyl rings 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 These may together form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, the heterocycloalkyl ring containing 0, 1, or 2 additional heteroatoms selected from N, O, S, S(O), and SO2, and the heterocycloalkyl ring may optionally contain halogen, hydroxyl, cyano, oxo, dioxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl) cycloalkyl, -(C0-C6 alkyl) phenyl, -(C0-C6 alkyl) aryl, or -(C0-C6 alkyl) CO2R 8 -(C0~C6 alkyl)C(O)NR 8 R9 , -(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 It has been replaced with.

[0134] R 7 These are 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 That is the case.

[0135] R 8 and R 9 Each of these elements appears independently, and each time it appears, it is 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 , -CO2R6 Selected from -C(O)C1~C6 alkyl and -(C0~C6 alkyl)cycloalkyl.

[0136] (B) Embodiment, R 1 is -C6H4-R 7 That is the case.

[0137] R 2 and R 4 H is H.

[0138] R 3 These are -(C0~C6 alkyl)phenyl, -(C0~C6 alkyl)aryl, and It is a -(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 That is the case.

[0143] R 5 and R 6 Each of these independently, upon appearance, is 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 , as well as selected from 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 5and R 6 These may together form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, the heterocycloalkyl ring containing 0, 1, or 2 additional heteroatoms selected from N, O, S, S(O), and SO2, the heterocycloalkyl ring may optionally contain halogen, hydroxyl, cyano, oxo, dioxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl) cycloalkyl, -(C0-C6 alkyl) phenyl, -(C0-C6 alkyl) aryl, -(C0-C6 alkyl) CO2R 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 It has been replaced with.

[0145] R 8 and R 9 Each of these elements appears independently, and each time it appears, it is 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 Selected from -C(O)C1~C6 alkyl and -(C0~C6 alkyl)cycloalkyl.

[0146] (C) In this embodiment, the compounds of formula I are compounds 1 and 4 through 29: [ka] [ka] [ka] A compound represented by at least one of the following, or a pharmaceutically acceptable salt thereof.

[0147] (D) Embodiment, R 1 is -C6H4-R 7 That is the case.

[0148] R 2 and R 4 It is hydrogen.

[0149] R 3 These are -(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 That is the case.

[0153] R bonded to the same nitrogen atom 5 and R 6 They may combine to form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring. The heterocycloalkyl ring contains 0, 1, or 2 additional heteroatoms selected from N, O, S, S(O), and SO2, and the heterocycloalkyl ring is optionally substituted with any carbon or heteroring with halogen, hydroxyl, cyano, oxo, dioxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl)cycloalkyl, -(C0-C6 alkyl)phenyl, or -(C0-C6 alkyl)aryl.

[0154] R 8 It is hydrogen.

[0155] (E) In the embodiment, the compounds of formula I are compound 30 and compound 31: [ka] A compound represented by at least one of the following, or a pharmaceutically acceptable salt thereof.

[0156] (F) Embodiment, R 1 is -C6H4-R 7 That is the case.

[0157] R 2 and R 4 It is hydrogen.

[0158] R 3 These are -(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 That is the case.

[0163] R bonded to the same nitrogen atom 5 and R 6These combine to form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, which contains 0, 1, or 2 additional heteroatoms selected from N, O, S, S(O), and SO2, which may be substituted with any carbon or heterocyclic atom as needed with halogens, hydroxyl, cyano, oxo, dioxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl)cycloalkyl, -(C0-C6 alkyl)phenyl, or -(C0-C6 alkyl)aryl.

[0164] R 8 It is hydrogen.

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

[0166] (H) Embodiment, R 1 is -C6H4-R 7 That is the case.

[0167] R 2 and R 4 It is hydrogen.

[0168] R 3 These are -(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)-NR8 -(C0~C6 alkyl)NR 5 R 6 That is the case.

[0173] R bonded to the same nitrogen atom 5 and R 6 These combine to form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, which contains 0, 1, or 2 additional heteroatoms selected from N, O, S, S(O), and SO2, which may be substituted with any carbon or heterocyclic atom as needed with halogens, hydroxyl, cyano, oxo, dioxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl)cycloalkyl, -(C0-C6 alkyl)phenyl, or -(C0-C6 alkyl)aryl.

[0174] R 8 It is hydrogen.

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

[0176] This disclosure relates to the following formula II [ka] This includes specific embodiments of the.

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

[0178] (A) Embodiment, R 10 and R 11Each of these is independently selected from -(C0-C6 alkyl)phenyl, -(C0-C6 alkyl)aryl, and -(C0-C6 alkyl) heteroaryl as it appears.

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

[0180] R 13 It is a -C(O) heteroaryl compound.

[0181] (B) Embodiment, R 10 It is a -(C0~C6 alkyl)phenyl compound.

[0182] R 11 It is a -(C0~C6 alkyl) heteroaryl compound.

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

[0184] R 13 It is a -C(O) heteroaryl compound.

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

[0186] This disclosure is based on the following formula III [ka] This includes specific embodiments of the.

[0187] (A) Embodiment, R 17These are -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 These are 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 It is hydrogen.

[0190] R 21 -NR 23 R 24 That is the case.

[0191] Each time X appears, it is selected from O and S.

[0192] R 23 and R 24 Each of these independently, as they appear, is -S(O)phenyl, -S(O)aryl, -S(O)heteroaryl, -SO2phenyl, -SO2aryl, -SO2heteroaryl, -(C0~C6alkyl)cycloalkyl, and -CO2R 25 Selected from.

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

[0194] (B) Embodiment, R 17 It is a -C(O)C1~C6 alkyl group.

[0195] R 18These are C1-C6 alkyl groups.

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

[0197] R 21 -NR 23 R 24 That is the case.

[0198] X is oxygen.

[0199] R 23 and R 24 Each of these independently, each instance of a substituted or unsubstituted arylsulfonyl, -CO2R 25 -SO2phenyl, -SO2aryl, and -SO2R 25 Selected from.

[0200] R 25 It is phenyl.

[0201] In this embodiment, 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 comprising these compounds are useful for treating cancer, including achieving tumor regression in vivo. Methods for treating cancer or achieving tumor regression include providing a patient with an effective amount of a compound of formula I, formula II, or formula III. In embodiments, the patient is a mammal, more particularly a human. The disclosure also provides methods for treating non-human patients, such as companion animals, e.g., cats, dogs, and domestic animals. An effective amount of a pharmaceutical composition may be sufficient to inhibit the progression of cancer or a cancerous tumor; or to induce regression of cancer or a cancerous tumor.

[0203] The effective amount of the compound or pharmaceutical composition described herein will also provide a sufficient concentration of the compound of formula I, formula II, or formula III when administered to a patient. A sufficient concentration is the concentration of the compound in the patient's body necessary 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 its bioavailability.

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

[0205] Compounds of formula I, formula II, or formula III may be used to treat cancer, including malignant tumors, to achieve tumor regression. In certain embodiments, the patient suffers from a cytoproliferative disorder or disease. The cytoproliferative disorder may 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, kidney, pancreas, brain, skin including malignant melanoma and Kaposi's sarcoma, testicular or ovarian, carcinoma, renal cancer (renal cell carcinoma), and sarcoma.

[0206] Cancers that can be treated with compounds of Formula I, Formula II, or Formula III include bladder cancer, breast cancer, colon cancer, endometrial cancer, lung cancer, bronchial cancer, melanoma, non-Hodgkin lymphoma, blood cancers, 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 lymphoma. In particular, this specification includes methods of treating cancer by providing a compound of Formula I, Formula II, or Formula III to a patient whose cancer is a solid tumor or a disseminated cancer.

[0207] Furthermore, cancer can be classified as glioma (glioblastoma), acute myelogenous leukemia, acute myeloid leukemia, myelodysplastic / myeloproliferative neoplasm, The invention includes a method of treating cancer in a patient selected from sarcoma, chronic myelomonocytic leukemia, non-Hodgkin lymphoma, astrocytoma, melanoma, non-small cell lung cancer, cholangiocarcinoma, chondrosarcoma, or colon cancer by providing a compound of formula I, formula II, or formula III.

[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 specific compound used, age, weight, overall health, sex, diet, time of administration, route of administration, and excretion rate, drug combinations, and the severity of the specific disease being treated.

[0209] Compounds of formula I, formula II, or formula III may be administered alone (i.e., as a monotherapy regime) or in combination with other activators to treat diseases and conditions such as undesirable 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 regimes of one or more other chemotherapeutic agents, such as antineoplastic agents, e.g., alkylating agents (e.g., mechloroetamine, chlorambucil, cyclophosamide, melphalan, or ifosphamide), antimetabolites, e.g., folate antagonists (e.g., methotrexate), purine antagonists (e.g., 6-mercaptopurine), or pyrimidine antagonists (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. Furthermore, other non-limiting examples of active therapeutic substances include bioagents, such as monoclonal antibodies or IgG chimeric molecules, that achieve their therapeutic effects by specifically binding to receptors or ligands in cancer-related signaling pathways (e.g., therapeutic antibodies against CD20 (e.g., rituximab) or VEGF (e.g., bevacizumab)).

[0210] The treatment methods provided herein are also useful for treating non-human mammals, including veterinary applications such as treating horses and livestock, such as cattle, sheep, dairy cows, goats, pigs, and similar animals, as well as pets (companion animals), such as dogs and cats.

[0211] In diagnostic or research applications, a wide variety of mammals are suitable subjects, including rodents (e.g., mice, rats, hamsters), rabbits, primates, and pigs, such as inbred pigs, and similar species. Furthermore, in vitro diagnostic and research applications are also applicable. In vitro applications, the body fluids mentioned above (e.g., blood, plasma, serum, interstitial fluid, saliva, feces, and urine) as well as cell and tissue samples are suitable for use.

[0212] In embodiments, the present invention provides a method for treating cancerous disorders in patients who have been identified as requiring such treatment, comprising providing the patient with 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 activators.

[0213] In this embodiment, the cancer being treated is characterized by selectively targeting M2 macrophages in the patient and reprogramming the M2 macrophages toward an M1 phenotype.

[0214] As shown in Figure 19, compound 1, compared to the vehicle, demonstrated tumor reduction by M2 macrophages in an M2 macrophage adoptive transfer study in a KPC allograft model of the C57BL / 6 maul model. In this case, intratumoral injections were administered three times a week, and measurements were taken twice a week.

[0215] Tumor growth was suppressed during the in vivo study of compound 1 in fully immune transgenic Kras(G12D) / Trp53(R172H) / Pdx-1-Cre(KPC) mice (a mouse pancreatic cancer model) compared to the vehicle, as shown in Figure 3B. This is further illustrated in Figures 3A and 3C, which show a comparison of tumor volume between 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 the vehicle showed that treatment with compound 1 reduced CD206 macrophages. high This demonstrates 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 comparing cytokine and immune checkpoint profiles in KPC mice treated with compound 1 for two weeks with those of the vehicle, compound 1 showed selective infiltration of tumors by M2 macrophages compared to M1 macrophages. [Examples]

[0218] abbreviation ACN Acetonitrile

[0219] Acetic acid (ACOH)

[0220] DCM Dichloromethane

[0221] DCE 1,2-Dichloroethane

[0222] DIPEA Diisopropylethylamine

[0223] DMF Dimethylformamide

[0224] DMSO (Dimethyl Sulfoxide)

[0225] EDC Ethylene Dichloride

[0226] HCl 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] LC-MS (Liquid Chromatography / Mass Spectroscopy)

[0234] MHz (megahertz)

[0235] μL (microliter)

[0236] mL (milliliter)

[0237] mg milligrams

[0238] mmol millimol

[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 glass containers under positive nitrogen pressure. Anhydrous solvents, such as dichloromethane, N,N-dimethylformamide (DMF), acetonitrile (ACN), methanol (MeOH), and triethylamine (Et3N), were purchased from Sigma-Aldrich (St. Louis, MO). Preparative purification was performed using a Waters half-part 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 minutes was used during purification. Fraction collection was triggered by UV detection at 220 nm. Analytical analysis was performed using 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 for 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 for 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 determination was performed using an Agilent diode array detector for both Method 1 and Method 2. Mass determination was performed using an Agilent 6130 mass spectrometer by electrospray ionization in positive mode. 1¹H NMR spectra were recorded using a Varian 400 MHz spectrophotometer (Agilent Technologies, Santa Clara, CA). Chemical shifts are reported in ppm using non-deuterated solvents (2.50 ppm DMSO and 7.26 ppm CHCl3) as internal standards for DMSO-d6 and CDCl3 solutions, respectively. All analogs tested in biological assays have a purity of higher than 95% based on both analytical methods. High-resolution mass spectrometry was recorded using an Agilent 6210 time-of-flight (TOF) LC-MS system. Formula confirmation 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 in their as-received condition 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-chloropyrazine-2-yl)methanol (500 mg, 3.46 mmol) and catalyst DMF dissolved in DCM (20.0 mL). The resulting reaction mixture was stirred at room temperature for 1 hour (h), after which LC-MS and TLC (in 20% ethyl acetate, hex) analysis was completed. The reaction mixture was concentrated to dryness, absorbed into DCM, and concentrated again to dryness. The residue was absorbed into DMF (10.0 mL), 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 was completed. The reaction mixture was absorbed into H2O, extracted twice with siRNA, washed twice with brine, dried over anhydrous MgSO4, filtered, and concentrated to obtain 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-chloropyrazine-2-yl)methanamine,HCl [ka]

[0243] Triphenylphosphine (1.36 g, 5.19 mmol) was added to a solution of 2-(azidomethyl)-5-chloropyrazine (587 mg, 3.46 mmol) dissolved in MeOH (40.0 mL). A condenser was attached to the resulting reaction mixture and stirred at 80°C for 1.5 hours. Subsequently, LC-MS and TLC (20% siRNA, in Hex) analysis showed completion. The reaction mixture was concentrated to dryness, and the residue was absorbed in toluene (25.0 mL). The mixture was treated with 4.0 molar (M) HCl in dioxane (2.00 mL, 8.00 mmol), and the product precipitated as an HCl salt. The solid was filtered, rinsed with toluene, and air-dried to obtain crude (5-chloropyrazine-2-yl)methaneamine,HCl (550 mg, 3.05 mmol, yield 88%) as a yellowish-brown 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-chloropyrazine-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) added to DMF (10.0 mL) was stirred for 10 minutes. (5-chloropyrazine-2-yl)methaneamine,HCl (550 mg, 3.05 mmol) was added, and the mixture was stirred for 5 minutes. Then DIPEA (1.87 mL, 10.7 mmol) was added, and the resulting reaction mixture was stirred overnight. LC-MS analysis then showed completion. The reaction mixture was diluted with H2O and extracted twice with RINKAN. The combined organic layers were washed twice with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography: silica gel (with a gradient of 20-60% siRNA in hex) to obtain methyl 4-(((5-chloropyrazine-2-yl)methyl)carbamoyl)benzoic acid (897 mg, 2.93 mmol, yield 96%) 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]pyrazine-3-yl)benzoate [ka]

[0245] 1 molar (M) of trifluic anhydride (3.52 mL, 3.52 mmol) in DCM solution was slowly added to a solution of methyl 4-(((5-chloropyrazine-2-yl)methyl)carbamoyl)benzoate (897 mg, 2.93 mmol) and 2-methoxypyridine (339 μL, 3.23 mmol) dissolved in DCE (10.0 mL). The resulting reaction mixture was then placed in a preheated reaction block at 45°C and stirred for 2 hours, after which LC-MS analysis was completed. The reaction mixture was cooled to room temperature, quenched by adding saturated sodium carbonate solution, stirred for 5 minutes, diluted with DCM and H2O, the layers were separated, the organic phase was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue is triturated in EtOH containing 10% hexane, filtered, rinsed with hexane, and air-dried to obtain methyl 4-(6-chloroimidazo[1,5-a]pyrazine-3 -Iyl)benzoate (671 mg, 2.33 mmol, 79% yield) was obtained as a pale yellowish-brown 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]pyrazine-3-yl)benzoic acid [ka]

[0246] A mixture of methyl 4-(6-chloroimidazo[1,5-a]pyrazine-3-yl)benzoate (100 mg, 0.348 mmol), (3-fluorophenyl)boronic acid (58.4 mg, 0.417 mmol), XPhosPd(clotyl)Cl (11.71 mg, 0.017 mmol), and K3PO4 (148 mg, 0.695 mmol) was placed in a vial and purged with N2 for 2 minutes. 2.50 mL of 4:1 dioxane-H2O was added, degassing was continued for 2 minutes, and then the reaction vessel was placed in a block preheated to 90°C. After stirring at 90°C for 30 minutes, LC-MS analysis showed completion. The reaction mixture was allowed to cool to room temperature, diluted with siRNA and H2O, 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 triturated with EtOH containing 10% hexane, filtered, rinsed with hexane, and air-dried to obtain the intermediate methyl ester compound, which was absorbed in 1:1 EtOH-THF (5.00 mL) and treated with 2M sodium hydroxide (2.00 mL, 4.00 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, after which LC-MS analysis showed completion. The reaction mixture was concentrated into a slurry, the residue was absorbed with H2O, and the pH was adjusted to approximately 5 with AcOH to allow the product to precipitate. The product was then collected by filtration, rinsed thoroughly with H2O, and air-dried to obtain 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazine-3-yl)benzoic acid (96.0 mg, 0.289 mmol, yield 83%) 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]pyrazine-3-yl)-N-(3-(2-oxopyrrolidine-1-yl)propyl)benzamide [ka]

[0247] A solution of LiOH (125 mg, 5.21 mmol) dissolved in H2O (1.00 mL) was added to a solution of methyl 4-(6-chloroimidazo[1,5-a]pyrazine-3-yl)benzoate (300 mg, 1.043 mmol) dissolved in THF (4.00 mL). The resulting reaction mixture was stirred at room temperature for 1 hour, after which LC-MS analysis was completed. The reaction mixture was concentrated into a slurry, the residue was absorbed with H2O, and the pH was adjusted to approximately 5 with AcOH to precipitate the product. The product was then collected by filtration, rinsed thoroughly with H2O, and air-dried to obtain an intermediate acid, which was used without further purification.

[0248] The intermediates 4-(6-chloroimidazo[1,5-a]pyrazine-3-yl)benzoic acid (203 mg, 0.742 mmol) and HATU (310 mg, 0.816 mmol) were added to DMF (5.00 mL), the mixture was stirred for 10 minutes, and then 1-(3-aminopropyl)pyrrolidine-2-one (105 mg, 0.742 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, then DIPEA (259 μL, 1.48 mmol) was added, the reaction mixture was stirred for 2 hours, and then LCMS analysis showed completion. The reaction mixture was diluted with SiO2, washed with H2O and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography using silica gel with a gradient of 0-30% MeOH in  to obtain 4-(6-chloroimidazo[1,5-a]pyrazine-3-yl)-N-(3-(2-oxopyrrolidine-1-yl)propyl)benzamide (207 mg, 0.520 mmol, yield 70.1%) 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-oxopyrrolidine-1-yl)propyl)-4-(6-(pyridine-3-yl)imidazo[1,5-a]pyrazine-3-yl)benzamide (compound 26) [ka]

[0249] A mixture of 4-(6-chloroimidazo[1,5-a]pyrazine-3-yl)-N-(3-(2-oxopyrrolidine-1-yl)propyl)benzamide (10.0 mg, 0.025 mmol), pyridine-3-ylboronic acid (3.71 mg, 0.030 mmol), XPhosPd(clotyl)Cl (0.847 mg, 1.26 μmol), and K3PO4 (10.7 mg, 0.050 mmol) was placed in a vial and purged with N2 for 2 minutes. Dioxane-H2O (2.50 mL) in a 4:1 ratio was added, degassing was continued for 2 minutes, and then the reaction vessel was placed in a block preheated to 90°C. After stirring at 90°C for 30 minutes, LC-MS analysis showed completion. The reaction mixture was cooled to room temperature, directly added to a silica gel column, and purified by flash column chromatography using silica gel with a gradient of 5-50% MeOH in  to obtain N-(3-(2-oxopyrrolidine-1-yl)propyl)-4-(6-(pyridine-3-yl)imidazo[1,5-a]pyrazine-3-yl)benzamide (9.3 mg, 0.021 mmol, yield 84%) as an off-white crystalline 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, LCMS RT (Method 1) = 3.232 min, m / z 441.9[M+H + ]. (Example 8) Synthesis of N-(3-(2-oxopyrrolidine-1-yl)propyl)-4-(6-(3-(trifluoromethyl)phenyl)imidazo[1,5-a]pyrazine-3-yl)benzamide (compound 27) [ka]

[0250] 4-(6-chloroimidazo[1,5-a]pyrazine-3-yl)-N-(3-(2-oxopyrrolidine-1-yl)propyl)benzamide (10.0 mg, 0.025 mmol) A mixture of (3-(trifluoromethyl)phenyl)boronic acid (5.73 mg, 0.030 mmol), XPhosPd(clotyl)Cl (0.847 mg, 1.26 μmol), and K3PO4 (10.7 mg, 0.050 mmol) was placed in a vial and purged with N2 for 2 minutes. Dioxane-H2O (2.50 mL) in a 4:1 ratio was added, degassing was continued for 2 minutes, and then the reaction vessel was placed in a block preheated to 90°C. After stirring at 90°C for 30 minutes, LC-MS analysis showed completion. The reaction mixture was cooled to room temperature, directly added to a silica gel column, and purified by flash column chromatography using silica gel with a gradient of 0-30% MeOH in  to obtain N-(3-(2-oxopyrrolidine-1-yl)propyl)-4-(6-(3-(trifluoromethyl)phenyl)imidazo[1,5-a]pyrazine-3-yl)benzamide (10.2 mg, 0.020 mmol, yield 80%) as an off-white crystalline solid. 1 H 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]pyrazine-3-yl)benzamide (compound 4) [ka]

[0251] 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (50.0 mg, 0.159 mmol) and HATU (72.3 mg, 0.190 mmol) were added to DMF (2.00 mL) and the mixture was stirred for 10 minutes. Then, 2-morpholinoethane-1-amine (22.7 mg, 0.174 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, then DIPEA (69.2 μL, 0.396 mmol) was added, and the reaction was stirred overnight. LC-MS analysis then showed completion. The reaction mixture was diluted with ethyl acetate, washed with H2O and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was triturated with EtOH, filtered, and air-dried to obtain N-(2-morpholinoethyl)-4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzamide (49.3 mg, 0.115 mmol, yield 72.7%) as a pale golden solid. 1H 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] Figure 4 shows the IC50 for compound 4 at 8.95 μM. (Example 10) Synthesis of N-(2-acetamidoethyl)-4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzamide (compound 14) [ka]

[0253] A mixture of 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (50.0 mg, 0.159 mmol) and HATU (72.3 mg, 0.190 mmol) was added to DMF (2.00 mL) and stirred for 10 minutes. Then, N-(2-aminoethyl)acetamide (17.8 mg, 0.174 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, then DIPEA (69.2 μL, 0.396 mmol) was added, and the reaction was stirred overnight. LCMS analysis then showed completion. The reaction mixture was diluted with SiO2, washed with H2O and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography: Â with a gradient of 0-20% MeOH on silica gel to obtain N-(2-acetamidoethyl)-4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzamide (41.3 mg, 0.103 mmol, yield 65.2%) 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 Law 1)=3.515 min, m / z 400.1[M+H + ]. (Example 11) Synthesis of (1,1-dioxide thiomorpholino)(4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)phenyl)methanone (compound 15) [ka]

[0254] 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (50.0 mg, 0.159 mmol) and HATU (72.3 mg, 0.190 mmol) are added to D The mixture was added to MF (2.00 mL) and 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 LC-MS analysis showed completion. The reaction mixture was diluted with RINKAN, washed with H2O and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was triturated with EtOH, filtered, and air-dried to obtain (1,1-dioxidethiomorpholino)(4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)phenyl)methanone (54.6 mg, 0.126 mmol, yield 80%) as a pale golden 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)=3.8 45 minutes, m / z 433.1[M+H + ]. (Example 12) Synthesis of N-(3-hydroxypropyl)-4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzamide (compound 16) [ka]

[0255] 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (50.0 mg, 0.159 mmol) and HATU (72.3 mg, 0.190 mmol) were added to DMF (2.00 mL) and the mixture 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 LC-MS analysis showed completion. The reaction mixture was diluted with RINKAN, washed with H2O and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography using silica gel under a gradient of 0-20% MeOH in ELISA to obtain N-(3-hydroxypropyl)-4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzamide (41.3 mg, 0.111 mmol, yield 69.9%) 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]pyrazine-3-yl)benzamide [ka]

[0256] 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (50.0 mg, 0.159 mmol) and HATU (72.3 mg, 0.190 mmol) were added to DMF (2.00 mL) and the mixture was stirred for 10 minutes, after which 7 N (N) 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 LC-MS analysis showed completion. The reaction mixture was diluted with ethyl acetate, washed with H2O and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was triturated with EtOH, filtered, and air-dried to obtain 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzamide (25.0 mg, 0.080 mmol, yield 50.2%) 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) dissolved in EtOH (20.0 mL). The resulting reaction mixture was stirred at 80°C for 2 hours, after which LC-MS analysis was completed. The reaction mixture was cooled to room temperature, and the product was precipitated. The mixture was poured over ice with H2O, stirred vigorously for 5 minutes, filtered, rinsed with H2O, and air-dried to obtain 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-chloropyrazine-2-yl)hydrazine-1-carbonyl)benzoate [ka]

[0258] A 50% solution of propylphosphonic anhydride (T3P) dissolved in DMF (1.58 mL, 2.70 mmol) was added 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) dissolved in DMF (5.00 mL). The resulting reaction mixture was stirred at room temperature for 1 hour, after which LC-MS analysis was completed. The reaction mixture was poured over ice H2O and stirred for 10 minutes. The product was collected by filtration, rinsed thoroughly with H2O, and air-dried to obtain methyl 4-(2-(5-chloropyrazine-2-yl)hydrazin-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]pyrazine-3-yl)benzoate [ka]

[0259] Perchloroethane (232 mg, 0.978 mmol) was added to a suspension of methyl 4-(2-(5-chloropyrazine-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) suspended in ACN (5.00 mL) by molecular sieving (MS) at 4 Å. The resulting reaction mixture was stirred at 80°C for 2 hours, after which LC-MS analysis was completed. The reaction mixture was cooled to room temperature, filtered through Celite, and the filter cake was thoroughly rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography: 20-60% HCl gradient in hexacrystalline solution using silica gel to obtain methyl 4-(6-chloro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzoate (105 mg, 0.364 mmol, yield 74.4%). 1 H 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]pyrazine-3-yl)benzoate [ka]

[0260] A mixture of methyl 4-(6-chloro-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzoate (40.0 mg, 0.139 mmol), phenylboronic acid (21.1 mg, 0.173 mmol), XPhosPd(clotyl)Cl (4.67 mg, 6.93 μmol), and K3PO4 (58.8 mg, 0.277 mmol) was placed in a vial and purged with N2 for 2 minutes. Dioxane:H2O (2.50 mL) in a 4:1 ratio was added, degassing was continued for 2 minutes, and then the reaction vessel was placed in a block preheated to 100°C. After stirring at 100°C for 30 minutes, LCMS analysis showed completion. The reaction mixture was cooled to room temperature, partitioned between brine and ethyl acetate, filtered through Celite, and the layers were separated. The organic phase was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to obtain crude methyl 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzoate (38.0 mg, 0.115 mmol, yield 83%), 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]pyrazine-3-yl)benzoic acid [ka]

[0261] 2M 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]pyrazine-3-yl)benzoate (46.0 mg, 0.139 mmol) dissolved in EtOH (5.00 mL). The resulting reaction mixture was stirred at room temperature for 1 hour, after which LC-MS analysis was performed. The reaction mixture was concentrated into a slurry, and the residue was separated between 1M HCl and ELISA. The layers were separated, the organic phase was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to obtain crude 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzoic acid (44.0 mg, 0.139 mmol, 100% yield), which was used without further purification. LCMS RT (Method 2) = 2.893 mins, m / z 317.0 [M+H] + ]. (Example 19) Synthesis of N-(3-(2-oxopyrrolidine-1-yl)propyl)-4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzamide (compound 30) [ka]

[0262] A mixture of 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzoic acid (44.0 mg, 0.139 mmol) and HATU (63.5 mg, 0.167 mmol) was added to DMF (1.50 mL) and stirred for 10 minutes. Then, 1-(3-aminopropyl)pyrrolidine-2-one (21.5 μL, 0.153 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, then DIPEA (60.7 μL, 0.348 mmol) was added, and the reaction was stirred overnight. LC-MS analysis then showed completion. The reaction mixture was diluted with ethyl acetate, washed with H2O and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography: a 0-20% MeOH gradient in siRNA using silica gel to obtain N-(3-(2-oxopyrrolidine-1-yl)propyl)-4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyrazine-3-yl)benzamide (24.0 mg, 0.054 mmol, yield 39.2%) as a pale yellow solid. 1 1H 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)=4.13 0 min, m / z 882.3[2M+H + ], 441.1[M+H + ]. (Example 20) Synthesis of 5-bromo-2-hydrazinylpyridine [ka]

[0263] 5-Bromo-2-fluoropyridine (1.00 mL, 9.72 mmol) and hydra A solution of din (1.52 mL, 48.6 mmol) dissolved in EtOH (10.0 mL) was stirred at 100°C for 1 hour, after which LC-MS analysis was completed. The reaction volume was reduced by half, and the mixture was cooled to room temperature to precipitate the product. The slurry was poured over ice with H2O and stirred for 5 minutes. The product was filtered, rinsed with H2O, and air-dried to obtain 5-bromo-2-hydrazinylpyridine (1.60 g, 8.51 mmol, yield 88%), an off-white, cottony, off-white 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-bromopyridine-2-yl)hydrazine-1-carbonyl)benzoate [ka]

[0264] A 50% solution of propylphosphonic anhydride (T3P) dissolved in DMF (2.33 mL, 3.99 mmol) was added 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) dissolved in DMF (5.00 mL). The resulting reaction mixture was stirred at room temperature for 1 hour, after which LC-MS analysis was completed. The reaction mixture was poured over ice H2O and stirred for 10 minutes. The product was collected by filtration, rinsed thoroughly with H2O, and air-dried to obtain methyl 4-(2-(5-bromopyridine-2-yl)hydrazine-1-carbonyl)benzoate (906 mg, 2.59 mmol, yield 97%) as a yellowish-brown 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]pyridine-3-yl)benzoate [ka]

[0265] Perchloroethane (946 mg, 4.00 mmol) was added by 4 Å MS to a suspension of methyl 4-(2-(5-bromopyridine-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) suspended in ACN (10.0 mL). The resulting reaction mixture was stirred at 80°C for 2 hours, after which LC-MS analysis was completed. The reaction mixture was cooled to room temperature, filtered through Celite, and the filter cake was thoroughly rinsed with ELISA. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography: 20-80% siRNA gradient in hex in silica gel to obtain methyl 4-(6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-yl)benzoate (604 mg, 1.818 mmol, yield 91%). 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]pyridine-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(clotyl)Cl (30.4 mg, 0.045 mmol), and K3PO4 (383 mg, 1.81 mmol) was placed in a vial and purged with N2 for 2 minutes. 10.0 mL of 4:1 dioxane:H2O was added, degassing was continued for 2 minutes, and then the reaction vessel was placed in a block preheated to 100°C. After stirring at 100°C for 30 minutes, LC-MS analysis showed completion. The reaction mixture was allowed to cool to room temperature, partitioned between brine and RINKAN, 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: 40-100% siRNA gradient in Hex, using silica gel to obtain methyl 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridine-3-yl)benzoate (290 mg, 0.880 mmol, yield 97%) 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]pyridine-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 stirred at room temperature for 30 minutes, after which the solution became clear, and LC-MS analysis indicated completion. The reaction mixture was concentrated into a slurry, poured into a 1 M HCl solution at low temperature, and vigorously stirred for 10 minutes. The insoluble product was filtered, rinsed with H2O, and air-dried to obtain 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)benzoic acid (248 mg, 0.786 mmol, yield 89%) 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-oxopyrrolidine-1-yl)propyl)-4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridine-3-yl)benzamide (compound 31) [ka]

[0268] A mixture of 4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridine-3-yl)benzoic acid (100 mg, 0.317 mmol) and HATU (145 mg, 0.381 mmol) was added to DMF (2.00 mL) and stirred for 10 minutes. Then, 1-(3-aminopropyl)pyrrolidine-2-one (0.049 mL, 0.349 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, then DIPEA (0.138 mL, 0.793 mmol) was added, and the reaction was stirred overnight. LCMS analysis then showed completion. The reaction mixture was diluted with ethyl acetate, washed with H2O and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography using silica gel with a 0-30% MeOH gradient in siRNA to obtain N-(3-(2-oxopyrrolidine-1-yl)propyl)-4-(6-phenyl-[1,2,4]triazolo[4,3-a]pyridine-3-yl)benzamide (33.0 mg, 0.075 mmol, yield 23.68%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.6 8 - 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-nitropyridine-4-yl)aminobenzoate [ka]

[0269] A mixture of 2-chloro-5-nitropyridine-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 N2 for 3 minutes. DMF (4.00 mL) was added, and the reaction mixture was purged by bubbling N2 through the mixture for 3 minutes. The resulting reaction mixture was placed in a reaction block preheated to 120°C and stirred for 16 hours, after which LC-MS analysis showed product formation. The reaction mixture was partitioned between RINKAN and H2O, filtered through Celite, the layers were separated, the organic phase was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography: 10-30% siRNA gradient in hexadecimal with silica gel to obtain methyl 4-((2-chloro-5-nitropyridine-4-yl)amino)benzoate (84.0 mg, 0.273 mmol, yield 23.69%). 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-chloropyridine-4-yl)aminobenzoate [ka]

[0270] Methyl 4-((2-chloro-5-nitropyridine-4-yl)aminobenzoate (80.0 mg, 0.260 mmol), iron powder (72.6 mg, 1.30 mmol), and ammonium chloride (278 mg, 5.20 mmol) in a 1:1 EtOH-H2O(1 The mixture added to 0.0 mL was stirred at 70°C for 1 hour, after which LC-MS analysis was completed. The reaction mixture was cooled to room temperature, partitioned between brine and siRNA, filtered through Celite, and the layers were separated. The organic phase was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to obtain crude methyl 4-((5-amino-2-chloropyridine-4-yl)amino)benzoate (70.0 mg, 0.252 mmol, yield 97%) as a yellowish-brown solid, which was used without further purification. LC-MS 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]pyridine-1-yl)benzoate [ka]

[0271] A solution of methyl 4-((5-amino-2-chloropyridine-4-yl)amino)benzoate (65.0 mg, 0.234 mmol), triethyl orthoformate (0.100 mL, 0.601 mmol), and catalyst p-toluenesulfonic acid (p-TsOH) (6.68 mg, 0.035 mmol) dissolved in THF (5.00 mL) was stirred overnight at 60°C, and then LC-MS analysis was performed. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography: a 20-80% ethyl acetate gradient in HEX with silica gel to obtain methyl 4-(6-chloro-1H-imidazo[4,5-c]pyridine-1-yl)benzoate (41.0 mg, 0.143 mmol, yield 60.9%) 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]pyridine-1-yl)benzoic acid [ka]

[0272] A mixture of methyl 4-(6-chloro-1H-imidazo[4,5-c]pyridine-1-yl)benzoate (35.0 mg, 0.122 mmol), phenylboronic acid (18.54 mg, 0.152 mmol), XPhos Pd(clotyl)Cl (4.10 mg, 6.08 μmol), and K3PO4 (51.6 mg, 0.243 mmol) was placed in a vial and purged with N2 for 2 minutes. Dioxane:H2O (2.50 mL) in a 4:1 ratio was added, degassing was continued for 2 minutes, and then the reaction vessel was placed in a block preheated to 100°C. After stirring at 100°C for 30 minutes, LC-MS analysis showed completion. The reaction mixture was then treated with 2M sodium hydroxide (0.500 mL, 1.00 mmol), stirred at 100°C for 30 minutes, and LC-MS analysis showed complete saponification of the ester. The reaction mixture was cooled to room temperature and diluted with siRNA and H2O. The pH was adjusted to approximately 4-5 with AcOH, the two-phase mixture was filtered through Celite, the layers were separated, the organic phase was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated to obtain crude 4-(6-phenyl-1H-imidazo[4,5-c]pyridine-1-yl)benzoic acid (35.0 mg, 0.111 mmol, yield 91%), which was used without further purification. LC-MS RT (Method 2) = 2.601 min, m / z 315.8 [M] + ]. (Example 30) Synthesis of N-(3-(2-oxopyrrolidine-1-yl)propyl)-4-(6-phenyl-1H-imidazo[4,5-c]pyridine-1-yl)benzamide (compound 32) [ka]

[0273] A mixture of 4-(6-phenyl-1H-imidazo[4,5-c]pyridine-1-yl)benzoic acid (40.0 mg, 0.127 mmol) and HATU (57.9 mg, 0.152 mmol) was added to DMF (1.50 mL) and stirred for 10 minutes. Then, 1-(3-aminopropyl)pyrrolidine-2-one (19.57 μL, 0.140 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, then DIPEA (55.4 μL, 0.317 mmol) was added, and the reaction was stirred overnight. LCMS analysis then showed completion. The reaction mixture was diluted with ethyl acetate, washed with H2O and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography: a 0-20% MeOH gradient in siRNA using silica gel to obtain N-(3-(2-oxopyrrolidine-1-yl)propyl)-4-(6-phenyl-1H-imidazo[4,5-c]pyridine-1-yl)benzamide (32.0 mg, 0.073 mmol, yield 57.4%) as an off-white solid. 1 H 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) Methyl 4-(6-chloro-1H-pyrrolo[3,2-c]pyridine-1-yl)benzoate Synthesis of [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 N2 for 3 minutes. DMF (4.00 mL) was added, and the reaction mixture was purged by bubbling N2 through the mixture for 3 minutes. The resulting reaction mixture was placed in a reaction block preheated to 120°C and stirred for 16 hours, after which LC-MS analysis showed product formation. The reaction mixture was partitioned between HCl and H2O, filtered through Celite, the layers were separated, the organic phase was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated. The crude residue was purified by flash column chromatography: 5-35% siRNA gradient in hex in silica gel to obtain methyl 4-(6-chloro-1H-pyrrolo[3,2-c]pyridine-1-yl)benzoate (213 mg, 0.743 mmol, yield 56.7%). 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]pyridine-1-yl)benzoate [ka]

[0275] A mixture of methyl 4-(6-chloro-1H-pyrrolo[3,2-c]pyridine-1-yl)benzoate (100 mg, 0.349 mmol), phenylboronic acid (53.2 mg, 0.436 mmol), XPhosPd(clotyl)Cl (11.75 mg, 0.017 mmol), and K3PO4 (148 mg, 0.698 mmol) was placed in a vial and purged with N2 for 2 minutes. 2.50 mL of 4:1 dioxane:H2O was added, degassing was continued for 2 minutes, and then the reaction vessel was placed in a block preheated to 100°C. After stirring at 100°C for 30 minutes, LC-MS analysis showed completion. The reaction mixture was allowed to cool to room temperature, partitioned between brine and ethyl acetate, 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 then processed. LC-MS RT (Method 2) = 2.795 min, m / z 329.1[M+H] + ]. (Example 33) Synthesis of 4-(6-phenyl-1H-pyrrolo[3,2-c]pyridine-1-yl)benzoic acid [ka]

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

[0277] A mixture of 4-(6-phenyl-1H-pyrrolo[3,2-c]pyridine-1-yl)benzoic acid (25.0 mg, 0.080 mmol) and HATU (36.3 mg, 0.095 mmol) was added to DMF (1.50 mL) and stirred for 10 minutes. Then, 1-(3-aminopropyl)pyrrolidine-2-one (12.3 μL, 0.087 mmol) was added. The resulting reaction mixture was stirred for 20 minutes, then DIPEA (34.7 μL, 0.199 mmol) was added, and the reaction was stirred overnight. LCMS analysis then showed completion. The reaction mixture was diluted with ethyl acetate, washed with H2O and brine, dried over anhydrous MgSO4, filtered, and concentrated. The residue was analyzed by flash column chromatography: 0 in ethyl acetate. The compound was purified using silica gel under a ~20% MeOH gradient to obtain N-(3-(2-oxopyrrolidine-1-yl)propyl)-4-(6-phenyl-1H-pyrrolo[3,2-c]pyridine-1-yl)benzamide (17.0 mg, 0.039 mmol, yield 48.7%) 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-phenylpyrazine-2-yl)methyl)carbamoyl)benzoate [ka]

[0278] A heterogeneous solution consisting of (5-phenylpyrazine-2-yl)methaneamine (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) dissolved in DMF (100 ml) was stirred at 65°C for 1 minute under N2. EDC (4.10 g, 21.38 mmol) was added to the solution. The solution was stirred at 65°C for 2.5 hours under N2. The solution was cooled to room temperature. Water (500 ml) was added to the solution. The solution was cooled for 18 hours. The solution was filtered. The solid was washed with water (3 times) and dried in air, then under vacuum, to obtain the desired compound (5.4 g, 87%). (LCMS, ESI pos.)C 20 H 17 Calculated value for N3O3: 348.4(M+H), measured value: 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]pyrazine-3-yl)benzoate [ka]

[0279] Methyl 4-(((5-phenylpyrazine-2-yl)methyl)carbamoyl)benzoate (2.5g, 7.20 mmol) and pyridine (3.49 ml, 43.2 mmol) A heterogeneous solution prepared by dissolving ) in DCE (72.0 ml) was treated by adding POCl3 (2.68 ml, 28.8 mmol) dropwise over 1 minute. 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% HCl to 100% HCl in hexane over 20 minutes). The desired fraction was pooled, concentrated, and vacuum-dried to obtain the desired compound (1.8 g, 76%). (LCMS, ESI pos.) 20 H 15 Calculated value for N3O2: 330.4(M+H), measured value: 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]pyrazine-3-yl)benzoic acid [ka]

[0280] Methyl 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoate (1.8 g, 5.47 mmol) was dissolved in MeOH / THF 1:1 (40 ml), to which sodium hydroxide (10.93 ml, 10.93 mmol) was added. 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 (slowly added). The solution was left 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 obtain the desired product (1.0 g, 58%). (LCMS, ESI pos.) 19 H 13 Calculated value for N3O2: 316.3(M+H), measured value: 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-imidazole-5-yl)ethyl)-4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzamide (compound 1) [ka]

[0281] A solution of 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (1 g, 3.17 mmol) dissolved in DMF (10.57 ml) was treated with DIPEA (1.108 ml, 6.34 mmol). HATU (1.326 g, 3.49 ml) was added to the solution. (mol) was added. 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. 1N NaOH (1.9 mmol) was added to the reaction solution. After 30 minutes, the solution was concentrated to a small volume. The solution was partitioned between RINKAN and water. The RINKAN layer was separated and washed sequentially with water (x2) and brine (x1), dried over anhydrous MgSO4, filtered, and concentrated. The residue was subjected to chromatography using C18 reverse-phase chromatography to obtain the desired compound (0.7 g, 54%). (LCMS, ESI pos.) 24 H 20 Calculated value for N6O: 409.5(M+H), measured value: 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 a superior PK profile at various concentrations in plasma, liver, and pancreas when administered via both oral and IP injection. [Table 1] (Example 39) Synthesis of N-(3-(2-oxopyrrolidine-1-yl)propyl)-4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzamide (compound 28) [ka]

[0284] A solution of 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.255 g, 0.809 mmol) and HATU (0.369 g, 0.970 mmol) dissolved 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 minutes, a solution of 1-(3-aminopropyl)pyrrolidine-2-one (0.126 g, 0.890 mmol) dissolved in DMF (0.1 ml) was added to this solution. The reaction solution was stirred at room temperature under N2. After 8 hours, the reaction solution was introduced into a C18 column (15.5 g, equilibrium with water) and purified using a gradient (0-30% CH3CN, 20 minutes) to obtain the desired compound (0.142 g, 40%). (LCMS, ESI pos.) 26 H 25 Calculated value for N5O2: 440.5 (M+H), measured value: 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-hydroxyazetidine-1-yl)(4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)phenyl)methanone (compound 17) [ka]

[0285] A solution of 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) dissolved in DMF (0.317 ml) was treated with DIPEA (0.033 ml, 0.190 mmol). After 10 minutes, azetidine-3-ol (0.012 g, 0.159 mmol) was added to the solution. The solution was stirred overnight at room temperature. The solution was introduced into a 24 g silica gel column equilibrated with HCl. Elution was performed by gradient (HCl to 10% MeOH / HCl). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.04 g, 68%). (LCMS, ESI pos.) 22 H 18 Calculated value for N4O2: 371.4(M+H), measured value: 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-hydroxypiperidine-1-yl)(4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)phenyl)methanone (compound 18) [ka]

[0286] A solution of 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) dissolved in DMF (0.5 ml) was then mixed with DIPEA (0.033 ml, 0.190 mmol). The solution was treated with ) and stirred at room temperature for 10 minutes. Piperidine-4-ol (0.016 g, 0.159 mmol) was added to the solution. The solution was stirred at room temperature overnight. The solution was introduced into a 24 g silica gel column equilibrated with HCl. Elution was performed by gradient (HCl to 10% MeOH / HCl). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.03 g, 48%). (LCMS, ESI pos.) 24 H 22 Calculated value for N4O2: 399.5(M+H), measured value: 399.2. 1 1H 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]pyrazine-3-yl)benzamide (compound 19) [ka]

[0287] A solution of 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) dissolved 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 introduced into a 24 g silica gel column equilibrated with ethyl acetate. Elution was performed by gradient (ethyl acetate to 10% MeOH / ethyl acetate). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.03 g, 47%). (LCMS, ESI pos.) 24 H 25 Calculated value for N5O: 400.5(M+H), measured value: 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]pyrazine-3-yl)benzamide (compound 5) [ka]

[0288] 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) are DM A solution dissolved in F (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 introduced into a 24 g silica gel column equilibrated with ethyl acetate. Elution was performed by gradient (ethyl acetate to 10% MeOH / ethyl acetate). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.04 g, 56%). (LCMS, ESI pos.) 27 H 21 Calculated value for N5O2: 448.5 (M+H), measured value: 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-imidazole-1-yl)propyl)-4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzamide (compound 6) [ka]

[0290] A solution of 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) dissolved in DMF (0.5 ml) was treated with DIPEA (0.033 ml, 0.190 mmol). The solution was stirred for 15 minutes. 3-(1H-imidazole-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 introduced into a 24 g silica gel column equilibrated with ethyl acetate. Elution was performed by gradient (ethyl acetate to 10% MeOH / ethyl acetate). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.03 g, 45%). (LCMS, ESI pos.) 25 H 22 Calculated value for N6O: 423.5(M+H), measured value: 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]pyrazine-3-yl)benzamide (compound 7) [ka]

[0292] A solution of 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) dissolved 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 overnight at room temperature. The solution was introduced into a 24 g silica gel column equilibrated with HCl. Elution was performed by gradient (HCl to 10% MeOH / HCl). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.045 g, 74%). (LCMS, ESI pos.) 23 H 23 Calculated value for N5O: 386.5(M+H), measured value: 385.9. 1 1H 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]pyrazine-3-yl)-N-(pyrazine-2-ylmethyl)benzamide (compound 20) [ka]

[0294] A solution of 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) dissolved in DMF (0.5 ml) was treated with DIPEA (0.033 ml, 0.190 mmol). Pyrazine-2-ylmethaneamine (0.017 g, 0.159 mmol) was added to the solution. The solution was stirred at room temperature for 18 hours. The solution was introduced into a 24 g silica gel column equilibrated with HCl. Elution was performed by gradient (HCl to 10% MeOH / HCl). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.045 g, 74%). (LCMS, ESI pos.) 24 H 18 Calculated value for N6O: 407.5(M+H), measured value: 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]pyrazine-3-yl)benzoyl)piperazine-1-yl)ethane-1-one (compound 21) [ka]

[0295] A solution of 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) dissolved in DMF (0.5 ml) was treated with 1-(piperazin-1-yl)ethane-1-one (0.020 g, 0.159 mmol). The solution was stirred at room temperature for 18 hours. The solution was introduced into a 24 g silica gel column equilibrated with ethyl acetate. Elution was performed by gradient (ethyl acetate to 10% MeOH / ethyl acetate). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.045 g, 74%). (LCMS, ESI pos.) 25 H 23 Calculated value for N5O2: 426.5(M+H), measured value: 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]pyrazine-3-yl)benzamide (compound 22) [ka]

[0296] A solution of 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) dissolved in DMF (0.5 ml) was treated with DIPEA (0.033 ml, 0.190 mmol). The solution was stirred for 15 minutes. 2-methoxyethane-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 introduced into a 24 g silica gel column equilibrated with ethyl acetate. Elution was performed by gradient (ethyl acetate to 10% MeOH / ethyl acetate). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.040 g, 68%). (LCMS, ESI pos.) 22 H 20 Calculated value for N4O2: 373.4(M+H), measured value: 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]pyrazine-3-yl)benzoyl)piperidine-4-carboxamide (compound 23) [ka]

[0297] A solution of 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) dissolved 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 solution was stirred at room temperature for 18 hours. The solution was introduced into a 24 g silica gel column equilibrated with ethyl acetate. Elution was performed by gradient (ethyl acetate to 10% MeOH / ethyl acetate). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.033 g, 47%). (LCMS, ESI pos.) 26 H 25 Calculated value for N5O2: 440.5 (M+H), measured value: 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]pyrazine-3-yl)benzamide (compound 24) [ka]

[0298] A solution of 4-(6-phenylimidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.05 g, 0.159 mmol) and HATU (0.066 g, 0.174 mmol) dissolved 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-aminocyclohexane-1-ol (0.018 g, 0.159 mmol) was added. The solution was stirred at room temperature for 18 hours. The solution was introduced into a 24 g silica gel column equilibrated with SiO2. Elution was performed using a gradient ( The analysis was carried out using Depositphotos (10% MeOH / Depositphotos). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.032 g, 49%). (LCMS, ESI) pos.)C 25 H 24 Calculated value for N4O2: 413.5 (M+H), measured value: 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]pyrazine-3-yl)-N-(3-(2-oxopyrrolidine-1-yl)propyl)benzamide (compound 29) [ka]

[0299] A mixture of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.022 g, 0.066 mmol) and HATU (0.028 g, 0.073 mmol) added to 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)pyrrolidine-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 introduced into a 24 g silica gel column equilibrated with ethyl acetate. Elution was performed by gradient (ethyl acetate to 10% MeOH / ethyl acetate). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.007 g, 23%). (LCMS, ESI pos.) 26 H 24 Calculated value for FN5O2: 458.5 (M+H), measured value: 458.1. 1 1H 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]pyrazine-3-yl)benzamide (compound 8) [ka]

[0300] A mixture of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.02 g, 0.060 mmol) and HATU (0.025 g, 0.066 mmol) added to DMF (0.200 ml) was treated with DIPEA (0.013 ml, 0.072 mmol). The solution was stirred at room temperature for 10 minutes. Ammonia (8.57 μl, 0.060 mmol) was added to the solution. The solution was stirred at room temperature for 18 hours. The solution was filtered. The solid was triturated with siRNA / MeOH 1:1. The solution was decanted. The solid was vacuum-dried to obtain the desired compound (7.7 mg, 39%). (LCMS, ESI pos.) 19 H 13 Calculated value for FN4O: 333.3(M+H), measured value: 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-imidazole-1-yl)propyl)-4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazine-3-yl)benzamide (compound 25) [ka]

[0302] A solution of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.02 g, 0.060 mmol) and HATU (0.025 g, 0.066 mmol) dissolved 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-(1H-imidazole-1-yl)propan-1-amine (7.51 mg, 0.060 mmol) was added to the solution. The solution was stirred at room temperature for 18 hours. The solution was introduced into a 24 g silica gel column equilibrated with ethyl acetate. Elution was performed by gradient (ethyl acetate to 10% MeOH / ethyl acetate). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.005 g, 19%). (LCMS, ESI pos.) 25 H 21 Calculated value for FN6O: 441.5(M+H), measured value: 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]pyrazine-3-yl)-N-(2-methoxyethyl)benzamide (compound 13) [ka]

[0303] A solution of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.02 g, 0.060 mmol) and HATU (0.025 g, 0.066 mmol) dissolved 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-methoxyethane-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 introduced into a 24 g silica gel column equilibrated with ethyl acetate. Elution was performed by gradient (ethyl acetate to 10% MeOH / ethyl acetate). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.009 g, 39%). (LCMS, ESI pos.) 22 H 19 Calculated value for FN4O2: 391.4(M+H), measured value: 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]pyrazine-3-yl)-N-(3-hydroxypropyl)benzamide (compound 9) [ka]

[0304] A mixture of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.02 g, 0.060 mmol) and HATU (0.025 g, 0.066 mmol) added to 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 introduced into a 24 g silica gel column equilibrated with siRNA. Elution was performed by gradient (siRNA to 10% MeOH / siRNA). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.002 g, 9%). (LCMS, ESI pos.) 22 H 19 Calculated value for FN4O2: 391.4(M+H), measured value: 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]pyrazine-3-yl)benzamide)propyl)carbamate (compound 12) [ka]

[0306] A mixture of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.02 g, 0.060 mmol) and HATU (0.025 g, 0.066 mmol) added to DMF (0.200 ml) was treated with DIPEA (0.013 ml, 0.072 mmol). The solution was stirred at room temperature for 10 minutes. Tert-butyl(3-aminopropyl)carbamate (10.45 mg, 0.060 mmol) was added to the solution. The solution was stirred at room temperature for 18 hours. The solution was introduced into a 24 g silica gel column equilibrated with ethyl acetate. Elution was performed by gradient (ethyl acetate to 10% MeOH / ethyl acetate). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.002 g, 7%). (LCMS, ESI pos.) 27 H 28 Calculated value for FN5O3: 490.6 (M+H), measured value: 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]pyrazine-3-yl)benzamide (compound 10) [ka]

[0307] A solution of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.02 g, 0.060 mmol) and HATU (0.025 g, 0.066 mmol) dissolved 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 siRNA / MeOH 1:1. The solution was decanted. The solid was vacuum-dried to obtain the desired compound (2. 4 mg, 10%) was obtained. (LCMS, ESI pos.) 23 H 20 Calculated value for FN5O2: 418.4(M+H), measured value: 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-imidazole-5-yl)ethyl)-4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazine-3-yl)benzamide (compound 11) [ka]

[0309] A mixture of 4-(6-(3-fluorophenyl)imidazo[1,5-a]pyrazine-3-yl)benzoic acid (0.04 g, 0.120 mmol) and HATU (0.050 g, 0.132 mmol) added to 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-imidazole-5-yl)ethane-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 introduced into a 24 g silica gel column equilibrated with HCl. Elution was performed by gradient (HCl to 10% MeOH / HCl). The desired fractions were combined, concentrated, and vacuum-dried to obtain the desired compound (0.005 g, 10%). (LCMS, ESI pos.) 24 H 19 Calculated value for FN6O: 427.5(M+H), measured value: 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 activated CD206 and exhibited IC50 values ​​that selectively targeted M2 macrophages. [Table 2]

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

[0312] When recombinant CD206 was incubated with compound 1, electron microscopy studies showed that compound 1 bound to CD206 and induced a switching of the receptor's conformation. Figures 11A and 11B show the conformational changes of CD206 when incubated 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 also CD206-dependent. Figures 2A-2C show the compounds, respectively. The graphs show relative cell viability percentage versus logarithmic molar concentration, indicating that macrophage activity of substances 1-3 is CD206-dependent. (Example 60) Cell-based assays

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

[0315] The induction of phagocytosis, autophagy, and apoptosis was studied in two in vitro models using M1 and M2 macrophages. First, in a bone marrow-derived macrophage (BMDM) in vitro model, compound 1 showed superior selectivity to induce phagocytosis, autophagy, and apoptosis in M2 macrophages rather than M1 macrophages. Figures 12A–12E illustrate this selectivity. In a RAW264.7 cell in vitro model, compound 1 similarly showed superior selectivity to induce phagocytosis, autophagy, and apoptosis in M2 macrophages rather than M1 macrophages. Figures 13A–13C illustrate this selectivity.

[0316] Compound 1 selectively increases cancer cell phagocytosis in M2 macrophages rather than M1 macrophages. Figures 14A to 14B demonstrate this selectivity for M2 macrophages. As shown again in Figure 16, compound 1 showed a full dose response in inducing phagocytosis.

[0317] As shown in Figure 8, Compound 1 compared to M1-like macrophages with human CD206 derived from healthy volunteers. high It is active in M2 macrophages. Screening in a panel of CD206-negative control cell lines showed that compound 1 is active in CD206 high This demonstrates selectivity with respect to M2 macrophages (Figure 9A). Similar selectivity is observed in dendritic cell DC2.4 survival (Figure 9B), fibroblast HTT survival (Figure 9C), RAW cell survival (Figure 9D), and KPC survival (Figure 9E).

[0318] Figure 14A shows a relative quantitative fluorescence graph demonstrating 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 rather than M1 macrophages.

[0319] Figure 14B shows a relative quantitative fluorescence graph demonstrating 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 rather than M1 macrophages.

[0320] Figure 17 shows a graph of the percentage of positive cell fractions for the M1 marker, measured by quantitative flow cytometry of mouse M2 macrophages treated for 2 hours with vehicle, 20 μM compound 1, and 20 μM compound 2, demonstrating the induction of the M1 marker in M2 macrophages. The present invention provides, for example, the following items: (Item 1) Formula I: [ka] A compound thereof, or a pharmaceutically acceptable salt thereof, Each connection is shown as a combined solid and dashed line, [ka] These can be single, double, or aromatic bonds. R 1 These include 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, and -C(O)NR 8 R 9 ,-(C0~C6 alkyl)NR 5 R 6 , -CO2R 6 -C6H4-R 7 , as well as monocyclic or bicyclic heterocyclic rings of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently selected from N, S, and O, R 2 , R3 , and R 4 Each of these terms appears independently as follows: 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 Selected from, a, b, c, d, and X are each independently selected from N, C, and CH each time they appear. R 5 and R 6 Each of these terms appears independently as follows: hydrogen, halogen, hydroxyl, 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 Selected from -C(O)(C0~C6 alkyl)aryl, -C(O)(C0~C6 alkyl) heteroaryl, and 4 to 7 membered heterocycloalkyl rings 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 6These may together form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, the heterocycloalkyl ring containing 0, 1, or 2 additional heteroatoms selected from N, O, S, S(O), and SO2, and the heterocycloalkyl ring may optionally contain halogen, hydroxyl, cyano, oxo, dioxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl) cycloalkyl, -(C0-C6 alkyl) phenyl, -(C0-C6 alkyl) aryl, -(C0-C6 alkyl) CO2R 8 ,-(C0~C 6 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 It has been replaced with, R 7 These are 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 And, R 8 and R 9 Each of these elements appears independently, and each time it appears, it is 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 Selected from -C(O)C1~C6 alkyl and -(C0~C6 alkyl)cycloalkyl, A compound or a pharmaceutically acceptable salt thereof. (Item 2) R 1 However, -C6H4-R 7 And, R 2 and R 4 However, it is hydrogen, R 3 However, it is -(C0~C6 alkyl)phenyl, -(C0~C6 alkyl)aryl, or -(C0~C6 alkyl) heteroaryl, a, c, and X are N, b is C, d is CH, R 7 However, -C(O)NR 5 R 6 or -C(O)-NR 8 -(C0~C6 alkyl)NR 5 R 6 And, R 5 and R 6 Each of these independently appears as follows: 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, as well as selected from 4 to 7-membered heterocycloalkyl rings 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 However, they may combine to form a 4- to 7-membered monocyclic heterocycloalkyl ring or a 6- to 11-membered bridged bicyclic heterocycloalkyl ring, the heterocycloalkyl ring containing 0, 1, or 2 additional heteroatoms selected from N, O, S, S(O), and SO2, and the heterocycloalkyl ring may optionally contain halogen, hydroxyl, cyano, oxo, dioxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl) cycloalkyl, -(C0-C6 alkyl) phenyl, -(C0-C6 alkyl) aryl, -(C0-C6 alkyl) CO2R 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 It has been replaced with, R 8 and R 9 Each of these elements appears independently, and each time it appears, it is 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)cyclo Selected by Lukil, The compound or salt listed in item 1. (Item 3) The compounds of formula I are compound 1, and compounds 4 through 29: [ka] [ka] [ka] [ka] A compound described in item 2, or a pharmaceutically acceptable salt thereof, which is represented by at least one of the following. (Item 4) R 1 However, -C6H4-R 7 And, R 2 and R 4 However, it is hydrogen, R 3 However, it is -(C0~C6 alkyl)phenyl, -(C0~C6 alkyl)aryl, or -(C0~C6 alkyl) heteroaryl, a, c, d, and X are N, b is C, R 7 However, -C(O)-NR 8 -(C0~C6 alkyl)NR 5 R 6 And, R bonded to the same nitrogen atom 5 and R 6However, together they may 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 SO2, and the heterocycloalkyl ring is optionally substituted with any carbon or heterocyclic atom with halogen, hydroxyl, cyano, oxo, dioxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl)cycloalkyl, -(C0-C6 alkyl)phenyl, or -(C0-C6 alkyl)aryl. R 8 However, it is hydrogen. The compound or salt listed in item 1. (Item 5) The compounds of formula I are compound 30 and compound 31: [ka] A compound represented by at least one of the compounds listed in item 4, or a pharmaceutically acceptable salt thereof. (Item 6) R 1 However, -C6H4-R 7 And, R 2 and R 4 However, it is hydrogen, R 3 However, it is -(C0~C6 alkyl)phenyl, -(C0~C6 alkyl)aryl, or -(C0~C6 alkyl) heteroaryl, a is C, b, d, and X are N, c is CH, R 7 However, -C(O)-NR 8 -(C0~C6 alkyl)NR 5 R 6 And, R bonded to the same nitrogen atom 5 and R 6However, together they may 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 SO2, and the heterocycloalkyl ring is optionally substituted with any carbon or heterocyclic atom with halogen, hydroxyl, cyano, oxo, dioxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl)cycloalkyl, -(C0-C6 alkyl)phenyl, or -(C0-C6 alkyl)aryl. R 8 However, it is hydrogen. The compound or salt listed in item 1. (Item 7) The compound of formula I is compound 32: [ka] A compound represented by, one of the compounds listed in item 6, or a pharmaceutically acceptable salt thereof. (Item 8) R 1 However, -C6H4-R 7 And, R 2 and R 4 However, it is hydrogen, R 3 However, it is -(C0~C6 alkyl)phenyl, -(C0~C6 alkyl)aryl, or -(C0~C6 alkyl) heteroaryl, a is C, b and X are N, c and d are CH, R 7 However, -C(O)-NR 8 -(C0~C6 alkyl)NR 5 R 6 And, R bonded to the same nitrogen atom 5 and R 6However, together they may 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 SO2, and the heterocycloalkyl ring is optionally substituted with any carbon or heterocyclic atom with halogen, hydroxyl, cyano, oxo, dioxo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, -(C0-C6 alkyl)cycloalkyl, -(C0-C6 alkyl)phenyl, or -(C0-C6 alkyl)aryl. R 8 However, it is hydrogen. The compound or salt listed in item 1. (Item 9) The compound of formula I is compound 33: [ka] A compound represented by, one of the compounds listed in item 8, or a pharmaceutically acceptable salt thereof. (Item 10) Formula II: [ka] A compound thereof, or a pharmaceutically acceptable salt thereof, Each connection is shown as a combined solid and dashed line, [ka] These can be single, double, or aromatic bonds. R 10 , R 11 , and R 13Each of these independently, as it appears, is hydrogen, hydroxyl, -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)heteroaryl, and -CO2R 16 Selected from, R 12 , R 14 , and R 15 Each of these is independently selected from hydrogen, halogen, hydroxyl, and cyano as it appears. X is either O or S, R 16 This refers to a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently selected from hydrogen, halogen, hydroxyl, amino group, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C0-C6 alkyl)cycloalkyl, -C(O)C1-C6 alkyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -(C0-C6 alkyl)phenyl, or N, S, and O. A compound or a pharmaceutically acceptable salt thereof. (Item 11) Formula IIA [ka] The compounds or salts listed in item 10. (Item 12) R 10 and R 11 However, each of these is independently selected from -(C0~C6 alkyl)phenyl, -(C0~C6 alkyl)aryl, and -(C0~C6 alkyl) heteroaryl as they appear. R 12 , R 14 , and R 15 However, it is hydrogen, R 13However, it is a -C(O) heteroaryl. The compounds or salts listed in item 11. (Item 13) R 10 However, it is a -(C0~C6 alkyl)phenyl, R 11 However, it is a -(C0~C6 alkyl) heteroaryl compound, R 12 , R 14 , and R 15 However, it is hydrogen, R 13 However, it is a -C(O) heteroaryl. The compounds or salts listed in item 12. (Item 14) The compound of formula IIA is compound 2: [ka] The compounds or salts described in item 13, or pharmaceutically acceptable salts thereof. (Item 15) Formula III: [ka] A compound thereof, or a pharmaceutically acceptable salt thereof, R 17 , R 18 , and R 21 Each of these groups appears independently, and each time it appears, it represents a hydrogen, halogen, hydroxyl, cyano, amidino group, and -NR. 23 R 24 , sulfonic acid group or its salt, phosphate group or its salt, -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~C6alkyl)phenyl, -C(O)(C0~C6alkyl)aryl, -C(O)(C0~C6alkyl)heteroaryl, -C(O)NR 23 R24 ,-(C0~C6 alkyl)NR 23 R 24 , -CO2R 23 , as well as selected from monocyclic or bicyclic heterocycles of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently selected from N, S, and O, Each time X appears, it is selected from O and S. R 19 , R 20 , and R 22 Each of these groups is independently selected from hydrogen, halogen, hydroxyl, cyano, and amino groups as it appears. R 23 and R 24 Each of these, independently, appears as follows: 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, -SO2phenyl, -SO2aryl, -SO2 heteroaryl, -(C0-C6 alkyl) cycloalkyl, and -CO2R 25 Selected from, R 25 This refers to a monocyclic or bicyclic heterocycle of 4 to 10 ring atoms having 1, 2, or 3 ring atoms independently selected from hydrogen, halogen, hydroxyl, amino group, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, -(C0-C6 alkyl)cycloalkyl, -C(O)C1-C6 alkyl, -(C0-C6 alkyl)aryl, -(C0-C6 alkyl)heteroaryl, -(C0-C6 alkyl)phenyl, or N, S, and O. A compound or a pharmaceutically acceptable salt thereof. (Item 16) R 17However, these are -C(O)C1~C6 alkyl, -C(O)(C0~C6 alkyl) phenyl, -C(O)(C0~C6 alkyl) aryl, or -C(O)(C0~C6 alkyl) heteroaryl. R 18 However, these are 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. R 19 , R 20 , and R 22 However, it is hydrogen, R 21 However, -NR 23 R 24 And, Each time X appears, a selection is made from O and S. R 23 and R 24 However, each of these independently appears as -S(O)phenyl, -S(O)aryl, -S(O)heteroaryl, -SO2phenyl, -SO2aryl, -SO2heteroaryl, -(C0~C6alkyl)cycloalkyl, and -CO2R 25 Selected from, and R 25 However, it is a C1-C6 alkyl, -(C0-C6 alkyl)cycloalkyl, -(C0-C6 alkyl)aryl, or -(C0-C6 alkyl)phenyl. The compounds or salts listed in item 15. (Item 17) R 17 However, it is a -C(O)C1~C6 alkyl group, R 18 However, it is a C1-C6 alkyl group, R 19 , R 20 , and R 22 However, it is hydrogen, R 21 However, -NR 23 R 24 And, X is oxygen, R23 and R 24 However, each instance appears independently of the substituted or unsubstituted arylsulfonyl, -CO2R 25 -SO2phenyl, -SO2aryl, and -SO2R 25 Selected from, and R 25 is phenyl, The compounds or salts listed in item 16. (Item 18) The compound of formula III is compound 3: [ka] The compound or salt described in item 17, or a pharmaceutically acceptable salt thereof. (Item 19) A pharmaceutical composition comprising a compound or salt described in any one of items 1 to 18, together with a pharmaceutically acceptable carrier. (Item 20) A method for treating cancer, characterized by selectively targeting M2 macrophages in a patient and reprogramming the M2 macrophages toward an M1 phenotype, comprising the step of providing a therapeutic agent to a patient in need of treatment for cancer, wherein the therapeutic agent is a compound or salt thereof as described in any one of items 1 to 18. (Item 21) The method according to item 20, wherein the large C-type lectin receptor CD206 targets and modulates the M2 macrophage, inducing cell death. (Item 22) The method according to item 20, wherein the cancer is selected from glioma, acute myeloid leukemia, acute myelodysplastic / myeloproliferative neoplasm, sarcoma, chronic myelomonocytic leukemia, non-Hodgkin lymphoma, astrocytoma, melanoma, non-small cell lung cancer, cholangiocarcinoma, chondrosarcoma, colon cancer, or pancreatic cancer. (Item 23) The method according to any one of items 20 to 22, further comprising administering at least one additional therapeutic agent to a patient in need thereof.

Claims

[Claim 1] The invention described in the specification.

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