Novel aminopyridines and their use in cancer treatment

Abstract

The present invention provides substituted imidazo[4,5 - c]pyridine - 2 - The compounds of formula I inhibit DNA-dependent protein kinase (DNA) - It selectively inhibits the activity of PK, - It is useful in treating diseases in which inhibition of PK is beneficial. TIFF2023542548000315.tif3548

Description

[Technical Field]

[0001] 1. Field of Invention The present invention generally relates to substituted imidazo[4,5-c]pyridine-2-one compounds, prodrugs, and pharmaceutically acceptable salts thereof. These compounds selectively inhibit the activity of DNA-dependent protein kinases (DNA-PKs). The present invention also relates to the use of these compounds, prodrugs, their salts, and solvates for the treatment of diseases regulated by DNA-PKs (including cancer). The present invention also relates to pharmaceutical formulations of substituted imidazo[4,5-c]pyridine-2-one compounds. [Background technology]

[0002] 2. Background technology Cancer treatment still primarily uses cytotoxic agents, including therapies such as ionizing radiation and topoisomerase inhibitors, which produce DNA double-strand breaks (DSBs) as the primary cytotoxic damage. All cells possess a highly organized DNA damage response (DDR) that includes DNA damage repair. Two major repair mechanisms handle DNA DSBs: homologous recombination repair (HRR) achieves high fidelity repair in the S and G2 phases of the cell cycle using sister chromatids, and non-homologous end joining (NHEJ) leads to erroneous chromosomal rejoining throughout the cell cycle. These repair mechanisms give rise to resistance to cytotoxic chemotherapy and radiotherapy. Conversely, loss of function of specific DDR pathways can make cancer cells sensitive to certain cytotoxic agents through persistent DNA damage. Therapeutic targeting of DDR has been widely employed to enhance the activity of conventional chemotherapy and overcome drug resistance.

[0003] Inactivation of elements in the NHEJ pathway leads to a highly radiosensitive phenotype, making NHEJ the primary repair pathway for radioinducible double-stranded bones (DSBs). At the heart of NHEJ is the DNA-dependent protein kinase (DNA-PK) complex. This complex contains proteins Ku70 and Ku80, which bind to the free DNA ends of DSBs and recruit the DNA-PK catalytic subunit (DNA-PKcs). The resulting complex autophosphorylates DNA-PKcs (Ser2056) and several other targets, thereby isolating them from DNA and recruiting Artemis, the XRCC4 complex, specialized DNA polymerase, and DNA ligase 4 to rejoin the broken DSBs. Loss of DNA-PK function increases sensitivity to DSBs, and DNA-PK has been identified as a reliable drug target in DDR.

[0004] However, the selectivity of DNA-PKs over other protein kinases has been a challenge. DNA-PKcs, rapamycin telangiectatic ataxia (ATM) variants, ATM-related variants (ATR), and mammalian target (mTOR) are members of the PI3K-related kinase (PIKK) family. These are homologous to the Pi3K enzyme but are proteins (Ser / Thr) rather than lipid kinases. For them to be clinically useful, novel DNA-PK inhibitors must be demonstrated to have at least some selectivity for DNA-PKs compared to PI3K isoforms and other PIKK family members.

[0005] DNA-PKs also have functions beyond their typical role in DSB repair. They have been reported to act on glucose deficiency, hypoxia tolerance, myogenic differentiation, endothelial cell function, vascular smooth muscle proliferation, neuroprotection, mitosis, telomere protection, and the regulation of inflammation and immune responses. Therefore, the normal tissue toxicity of DNA-PK inhibitors is not unexpected.

[0006] The combination of DDR inhibitors and DNA-damaging chemotherapy suffers from enhanced normal tissue toxicity, necessitating reduced chemotherapy doses and impairing therapeutic efficacy. This suggests that the combination of DNA-PK inhibition and radiotherapy presents a promising opportunity. Concerns about enhanced normal tissue toxicity in the radiation field have been mitigated to some extent by the emergence of advanced conformal radiotherapy techniques such as intensity-modulated radiotherapy (IMRT), image-guided radiotherapy (IGRT), and stereotactic radiotherapy (SBRT).

[0007] Tumor-selective drug delivery to hypoxic regions within solid tumors may offer alternative layer selectivity to minimize normal tissue toxicity. Hypoxia is a major component of the tumor microenvironment and plays a dynamic role in determining tumor progression and treatment response. Hypoxia has also been shown to reduce RAD51 and BRCA1, limit HRR repair in hypoxic cells, and increase NHEJ dependence. Hypoxic cells lead to resistance to treatment, particularly radiotherapy, and targeting these cells offers clinical benefits. Hypoxia-activated prodrugs are activated by enzymatic reduction in hypoxic tissue, releasing activators that may diffuse into adjacent tumor tissue (local bystander effect).

[0008] Therefore, while targeting DDR holds considerable potential for cancer treatment, novel DNA-PK inhibitors and / or effective hypoxia-activated prodrugs are needed to deliver these compounds to tumors. Thus, one object of the present invention is to satisfy such needs in at least some way, or at least to provide a useful alternative to the public.

[0009] This specification typically refers to external sources, including patent specifications and other documents, to provide background for describing the features of the invention. Unless otherwise stated, in no country or region shall any reference to such sources be construed as acknowledging that such sources constitute part of the state of the art or the prior art in that field. [Overview of the project]

[0010] 3. Outline of the Invention The inventors unexpectedly discovered that certain imidazo[4,5-c]pyridine-2-one compounds exhibit high selectivity for DNA-PK and show activity as DNA-PK inhibitors in vivo. Therefore, these compounds are useful in treating diseases that would benefit from the inhibition of such enzymes, such as cancer. The present invention also relates to such novel nitroheteroaryl prodrugs that are active in vivo against radiation-induced (hypoxic) tumor cells.

[0011] Therefore, a compound or salt thereof of any of the following formulas I, II, III, IV, V, VI, VII, or XII is provided.

[0012] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I, II, III, IV, V, VI, or VII, or a salt or solvate thereof, in combination with one or more pharmaceutically acceptable excipients.

[0013] In another embodiment, the present invention provides a method for treating a disease in which DNA-PK inhibition is beneficial for a subject requiring DNA-PK inhibition, comprising administering to the subject a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, or VII or a pharmaceutically acceptable salt or solvate thereof.

[0014] In another aspect, the present invention provides the use of compounds of formula I, II, III, IV, V, VI, or VII or pharmaceutically acceptable salts or solvates thereof in the manufacture of pharmaceuticals for the treatment of diseases in which inhibition of DNA-PK is beneficial.

[0015] In another embodiment, the present invention provides compounds of formula I, II, III, IV, V, VI, or VII, or pharmaceutically acceptable salts or solvates thereof, for the treatment of diseases in which inhibition of DNA-PK is beneficial.

[0016] In one embodiment, cancer is a disease in which inhibition of DNA-PK is beneficial.

[0017] In another embodiment, the present invention provides a method for inhibiting sub-phosphorylation of DNA-PK-mediated peptides, comprising contacting a peptide substrate with an effective amount of any compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt or solvate thereof.

[0018] In another embodiment, the present invention provides a method for radiosensitizing tumor cells, comprising contacting the tumor cells with an effective amount of any compound of formula I, II, III, IV, V, VI, or VII or a pharmaceutically acceptable salt or solvate thereof.

[0019] In another embodiment, the present invention provides a method for inhibiting tumor growth, comprising contacting a tumor with an effective amount of any compound of formula I, II, III, IV, V, VI, or VII or a pharmaceutically acceptable salt or solvate thereof.

[0020] In another embodiment, the present invention provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of any compound of formula I, II, III, IV, V, VI, or VII or a pharmaceutically acceptable salt or solvate thereof in combination with radiotherapy, wherein the compound of formula I, II, III, IV, V, VI, or VII or a pharmaceutically acceptable salt or solvate thereof is administered concurrently with radiotherapy, alone, or sequentially.

[0021] In one embodiment, radiotherapy is selected from the group consisting of IMRT, FRT, SBRT, SABR, and IORT.

[0022] In one embodiment, the cancer is squamous cell carcinoma of the head and neck.

[0023] While the present invention is generally defined above, it is not limited thereto, and it will be understood by those skilled in the art that the present invention further includes embodiments described below. [Brief explanation of the drawing]

[0024] 4. Brief explanation of the drawing The present invention will be described below with reference to the attached drawings. [Figure 1] Figure 1 shows the kinase inhibition histogram of compound 48, indicating that the kinase inhibitory effect of compound 48 at 1 μM (repeated mean, 10 μM ATP) is in descending order. Shading represents kinase families, and DNA-PK is indicated. Kinase activity inhibition was evaluated for a panel of 397 protein kinases and 20 lipid kinases using the HotSpot assay platform by Reaction Biology Corporation (Malvern, PA). [Figure 2] Figure 2 is a kinase inhibition histogram of compound 121, showing that the kinase inhibitory effect of compound 121 at 1 μM (repeated mean, 10 μM ATP) is in descending order. Shading represents kinase families, and DNA-PK is indicated. Kinase activity inhibition was evaluated for a panel of 397 protein kinases and 20 lipid kinases using the HotSpot assay platform by Reaction Biology Corporation (Malvern, PA). [Figure 3A] Figure 3 is a series of graphs showing the radiosensitizing effect of the compounds of the present invention on UT-SCC-54C head and neck squamous cell carcinoma cells under aerobic conditions, as measured by a regrowth test. UT-SCC-54C cells were inoculated into 96-well plates (0.2 mL / well) with 200 and 800 cells (unirradiated and 3 Gy plates, respectively), exposed to the compounds before (3 Gy) irradiation, during irradiation, and for 18 hours after irradiation, then regrowed in fresh medium for 5 days and stained with sulforhodamine B. Controls were treated similarly without irradiation (0 Gy). Regrowth fractions were normalized to drug-free values. Values ​​are the mean of two biological replications. [Figure 3B]Figure 3 is a series of graphs showing the radiosensitizing effect of the compounds of the present invention on UT-SCC-54C head and neck squamous cell carcinoma cells under aerobic conditions, as measured by a regrowth test. UT-SCC-54C cells were inoculated into 96-well plates (0.2 mL / well) with 200 and 800 cells (unirradiated and 3 Gy plates, respectively), exposed to the compounds before (3 Gy) irradiation, during irradiation, and for 18 hours after irradiation, then regrowed in fresh medium for 5 days and stained with sulforhodamine B. Controls were treated similarly without irradiation (0 Gy). Regrowth fractions were normalized to drug-free values. Values ​​are the mean of two biological replications. [Figure 3C] Figure 3 is a series of graphs showing the radiosensitizing effect of the compounds of the present invention on UT-SCC-54C head and neck squamous cell carcinoma cells under aerobic conditions, as measured by a regrowth test. UT-SCC-54C cells were inoculated into 96-well plates (0.2 mL / well) with 200 and 800 cells (unirradiated and 3 Gy plates, respectively), exposed to the compounds before (3 Gy) irradiation, during irradiation, and for 18 hours after irradiation, then regrowed in fresh medium for 5 days and stained with sulforhodamine B. Controls were treated similarly without irradiation (0 Gy). Regrowth fractions were normalized to drug-free values. Values ​​are the mean of two biological replications. [Figure 4] Figure 4 is a series of graphs showing the radiosensitizing effect of the compounds of the present invention on HAP1 and HAP1 / PRKDC- / - cells under aerobic conditions, as measured by a regrowth test. Cells were inoculated into 96-well plates, exposed to the compounds for 1 hour before irradiation (3 Gy), during irradiation, and for 18 hours after irradiation, then regrowed in fresh medium for 5 days and stained with sulforhodamine B. Controls were treated similarly without irradiation (0 Gy). Regrowth fractions were normalized to drug-free values. [Figure 5]Figure 5 shows immunoblots of cellular DNA-PK autophosphorylation inhibitors, measured by Western immunoblotting of Ser2056 of DNA-PKcs under aerobic conditions. Degradation products were prepared from mid-irradiation to 30 minutes later. UT-SCC-54C cells were exposed to 20 μM 48 or 88 (DNA-PK inhibitor) or 234 (prodrug) and irradiated 3 hours later. Inhibition rates compared to controls are shown above each lane. [Figure 6] Figure 6 shows immunoblots demonstrating inhibition of cellular DNA-PK autophosphorylation, measured by Western immunoblotting of Ser2056 of DNA-PKcs under oxygen-deficient conditions. Degradation products were prepared from mid-irradiation to 30 minutes later. UT-SCC-54C cells were exposed to 20 μM 48 or 88 (DNA-PK inhibitor) or 234 (prodrug) and irradiated 3 hours later. Inhibition rates compared to controls are shown above each lane. [Figure 7] Figure 7 shows immunoblots in UT-SCC-54C cells showing inhibition of cellular autophosphorylation of DNA-PKcs Ser2056 or the ataxia telangiectasia mutation (ATM) Ser1981, measured by Western immunoblotting from mid-irradiation to 30 minutes later. UT-SCC-54C cells were exposed to 10 μM AZD1390 (ATM inhibitor), 48 (DNA-PK inhibitor), 234 (prodrug), 195 (DNA-PK inhibitor), 121 (DNA-PK inhibitor), M3814 (DNA-PK inhibitor), or IC87361 (DNA-PK inhibitor) under aerobic conditions and irradiated 3 hours later. [Figure 8]Figure 8 shows a series of graphs illustrating the radiosensitization of UT-SCC-54C tumor cells. Monolayer radiation survival curves are shown for cells exposed to compounds 48, 121, 125, 135, and 195. UT-SCC-54C cells were exposed to the compounds for 3 hours before and during irradiation under oxygen, followed by a further 18 hours of retention under aerobic conditions, after which trypsinization, counting, and clonality assays were performed for colony formation. Scores represent the average of two biological replications in a single experiment. Survival rate (SF) is calculated as the colony formation rate (PE) of the compound plus irradiation divided by the colony formation rate alone: ​​(SF = PE(compound + RAD) / PE(compound only) (see Table 18 for complete data). The straight line fits a linear quadratic model. [Figure 9A] Figure 9 shows a series of graphs illustrating the radiosensitization effects of UT-SCC-54C tumor cells under aerobic and oxygen-deficient conditions. UT-SCC-54C cells were exposed to the compound for 3 hours before and during irradiation under aerobic or oxygen-deficient conditions, then held under low-acid conditions for 18 hours, followed by trypsinization, counting, and clonality assays for colony formation. SF = PE(compound + RAD) / PE(compound only) (see Table 18 for complete data). The score represents the mean of two biological replications in a single experiment. The straight line fits a linear quadratic model. [Figure 9B] Figure 9 shows a series of graphs illustrating the radiosensitization effects of UT-SCC-54C tumor cells under aerobic and oxygen-deficient conditions. UT-SCC-54C cells were exposed to the compound for 3 hours before and during irradiation under aerobic or oxygen-deficient conditions, then held under low-acid conditions for 18 hours, followed by trypsinization, counting, and clonality assays for colony formation. SF = PE(compound + RAD) / PE(compound only) (see Table 18 for complete data). The score represents the mean of two biological replications in a single experiment. The straight line fits a linear quadratic model. [Figure 10]Figure 10 shows a series of graphs illustrating the radiosensitization effect on UT-SCC-54C tumor cells under oxygen deficiency. Under oxygen deficiency conditions, three clonal survival tests were performed in UT-SCC-54C cells for compounds 88, 121, and 135, and their respective prodrugs 234, 248, and 236, to determine the 10% survival rate (SER10) and the sensitization enhancement rate at 10% radiation dose (D10). Under hypoxic conditions, the SER of the clonal survival test was also measured in UT-SCC-54C cells for compounds 121, 135, and 121, and their prodrugs 251, 238, and 250. [Figure 11] Figure 11 shows the radiosensitization of UT-SCC-54C HNSCC tumors. The survival of tumor clonens after 18 hours following administration of compound 121 or compound 248 alone, or in combination with 13 Gy total body radiation (RAD), to female NIH-III mice with subcutaneous UT-SCC-54C tumors. The compounds (50 mg / kg) were administered intraperitoneally (IP) to mice 15 minutes before irradiation and 6 hours after irradiation. Tumors were excised and dissected 18 hours later to form colonies for clonality assay. The dots represent clonens of tumor tissue per gram of mouse, and the horizontal bars are the mean values ​​of the logarithmic transformation. Using bidirectional ANOVA with radiotherapy and drug therapy as factors, the effects of individual radiation were very significant (P<0.001), and the effects of combined radiation with compound 121 and prodrug 248 were more significant compared to individual radiation (P=0.005 and P=0.018, respectively). [Figure 12]Figure 12 shows a pair of graphs illustrating radiosensitization of UT-SCC-54C HNSCC tumors. Tumor growth in female NIH-III mice with subcutaneous UT-SCC-54C tumors was inhibited by administering compound 121 alone or in combination with 10 Gy targeted radiation (RAD). Mice (8 per group) were orally administered (PO)121 (100 or 400 mg / kg) 15 minutes before irradiation and 3 hours after irradiation. Tumor volume was measured until it exceeded four times the treatment volume. Differences in endpoint arrival time between groups were evaluated by log-rank tests using Holm-Sidak multiple comparison analysis. The combination of the DNA-PK inhibitor 121 and radiation provided a significant expansion of tumor volume over time, four times the original, compared to 121 or radiation alone. [Figure 13] Figure 13 is a series of graphs showing comparative selection data for 121 and AZD7648. Each pair represents an independent comparison. PIC50 values ​​(-log IC50) were measured by biochemical analysis of DNA-PK against mTOR and related PI3K isoforms by Reaction Biology Corp (Malvern, PA). The multiple selectivity of DNA-PK is expressed as IC50(enzyme) / IC50(DNA-PK) and is displayed above each bar for the enzyme. [Figure 14] Figure 14 shows the metabolism of prodrug 248 by UT-SCC-54C cells under oxygen-deficient conditions, rather than aerobic conditions. Selective metabolism of 248 releases the DNA-PK inhibitor 121. The concentrations of 121 and 248 were quantified by LC-MS as the mean ± standard deviation of three biological replicates. [Modes for carrying out the invention]

[0025] 5. Modes for Carrying Out the Invention Details of the present invention are described in the attached description below.

[0026] However, methods and materials similar to or equivalent to those described herein are not permitted. The present invention may be used in the implementation or testing of the present invention, but hereby exemplary methods and The materials are described. Other features, purposes, and advantages of the present invention are apparent from the specification and claims. In the specification and appended claims, singular nouns also include plural nouns, unless otherwise explicitly stated in the context. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art. All patents and publications referenced herein are incorporated herein by reference.

[0027] 5.1 Definition As used herein, the following words, phrases, and symbols shall generally have the meanings set forth below, insofar as they indicate different contexts of their use.

[0028] The term “comprising” as used herein means “to constitute at least part of.” When interpreting the term “comprising” in this specification and each claim, there may be other features besides those preceding the paragraph or item. Related terms such as “comprise” and “comprises” are interpreted in the same way.

[0029] As used herein, the term “and / or” means “and” or “or” or both.

[0030] When the term "optionally" is used, the intent is the possibility or non-possibility of the subsequent feature occurring. Therefore, the use of the term "optionally" includes instances in which the feature exists and instances in which the feature does not exist. For example, a group that "may be optionally substituted with one hydroxyl group" includes groups with or without a hydroxyl substituent.

[0031] As used herein, the term “substituted” means that one or more hydrogens on a given group are substituted by a given substituent, provided that any of the substituted atoms maintain an acceptable valency. The substituent combinations include only stabilized compounds and stabilized synthetic intermediates. As used herein, the term “stabilized” means that the compound or intermediate in question is robust enough to be isolated and has utility as a synthetic intermediate or as a drug with potential therapeutic utility. Unless a group is described as “substituted” or “optionally substituted,” that group is considered unsubstituted (i.e., the hydrogens of a particular group are not substituted).

[0032] The term "therapeutic dose" means the amount of the compound of the present invention that is effective in providing "therapy" in a subject or in "treating" a disease or disorder in a subject.

[0033] As used herein, the terms “therapy” and “treatment” mean addressing a disease in order to completely or partially alleviate one, some or all of its symptoms, or to modify or compensate for an underlying condition. Unless otherwise specified, the terms “therapy” and “treatment” also include “prevention.” The terms “therapeutic” and “therapeutically” should be interpreted appropriately. Similarly, the term “treat” can also be understood as “applied therapy.”

[0034] The term "prevention" includes primary prevention, which aims to prevent the onset of a disease, and secondary prevention, which involves protecting a subject temporarily or permanently from disease exacerbation or the onset of new disease-related symptoms once the disease has developed.

[0035] As used herein in relation to treatments, the term “subject” means the warm-blooded animal to which the treatment is applied. Examples of warm-blooded animals include, but are not limited to, primates, domestic animals (e.g., sheep, cattle, pigs, goats, horses), and companion animals (e.g., cats, dogs). In one embodiment, the warm-blooded animal is a human.

[0036] Chiral centers may be present in the compounds described herein. Chiral centers can be designated as (R) or (S) depending on the arrangement of substituents in three-dimensional space at the chiral carbon atom. All stereochemical isomeric forms of compounds, including diastereomers, enantiomers, and epimers, as well as d-isomers and l-isomers, and mixtures thereof, including enantiomer enrichments and diastereomer enrichments of stereoisomers, are within the scope of the present invention.

[0037] Individual enantiomers can be prepared by synthesis from commercially available pure enantiomer starting materials, or by preparing an enantiomer mixture and then separating the mixture into individual enantiomers. Separation methods include converting the enantiomer mixture into a diastereomer mixture and isolating the diastereomers by, for example, recrystallization or chromatography, and any other suitable methods known in the art. The starting materials for the defined stereochemistry are commercially available or manufactured and can be separated by techniques known in the art as needed.

[0038] The compounds described herein may also exist as conformational or geometric isomers, including cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers. All of these isomers and any mixture thereof are within the scope of the present invention.

[0039] Tautomers of compounds or mixtures thereof are also within the scope of the present invention. As those skilled in the art will understand, various functional groups and other structures can exhibit tautomerism. Examples include, but are not limited to, ketone / enol, imine / enamine, and thion / enthiol tautomers.

[0040] The compounds described herein may also exist as isotopologes and isotopomers in which one or more atoms in the compound are substituted with different isotopes. Suitable isotopes include, for example, 1 H, 2 H (D), 3 H (T), 12 C, 13 C, 14 C, 16 O, and 18 It contains O. Methods for incorporating such isotopes into the compounds described herein will be obvious to those skilled in the art, and isotopologues and isotopomers of the compounds described herein are also within the scope of the present invention.

[0041] The scope of the present invention includes pharmaceutically acceptable salts, including salts of the compounds described herein. These salts include acid addition salts, base addition salts, and basic nitrogen-containing quaternary salts. Acid addition salts can be produced by reacting a compound in the form of a free base with an inorganic or organic acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, stearic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, isethionic acid, sulfonic acid, adipic acid, butyric acid, and pivalic acid. Base addition salts can be produced by reacting a compound in the form of a free acid with an inorganic or organic base. Examples of inorganic base addition salts include alkali metal salts, alkaline earth metal salts, and other physiologically acceptable metal salts such as aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc salts. Examples of organic base addition salts include amine salts such as trimethylamine, diethylamine, ethanolamine, diethanolamine, and ethylenediamine salts. Quaternary salts of basic nitrogen-containing groups in compounds can be produced, for example, by reacting the compound with alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides, or dialkyl sulfates such as dimethyl, diethyl, dibutyl, and diamyl sulfates.

[0042] The term "pharmaceutically acceptable" is used to identify specific articles (e.g., salts, dosage forms, diluents, or carriers) that are suitable for administration to subjects, particularly human subjects. A list of examples of pharmacopoeialy acceptable salts can be found in H and the book of Pharmaceutical Salts: Properties, Selection and Use, edited by PH Stahl and CG Wermuth, Weinheim / Zurich: Wiley-VCH / VHCA, 2002.

[0043] A suitable pharmaceutically acceptable salt of the compound of formula (I) is, for example, an acid addition salt. An acid addition salt of the compound of formula (I) can be formed by contacting the compound with a suitable inorganic or organic acid under conditions known to those skilled in the art. An acid addition salt can be formed using, for example, an inorganic acid selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. An acid addition salt can also be formed using an organic acid selected from the group consisting of trifluoroacetic acid, citric acid, maleic acid, oxalic acid, acetic acid, formic acid, benzoic acid, fumaric acid, succinic acid, tartaric acid, lactic acid, pyruvic acid, mesylic acid, benzenesulfonic acid, and p-toluenesulfonic acid.

[0044] The compounds described herein may be formed or exist as solvates in various solvents. When the solvent is water, the solvates may be called hydrates, such as monohydrates, dihydrates, and trihydrates. All dissolved and undissolved forms of the compounds described in this section are within the scope of the invention. The common chemical terms used herein have their usual meanings. Standard abbreviations for chemical groups are known to those skilled in the art, for example, Me=methyl, Et=ethyl, iPr=isopropyl, Bu=butyl, t-Bu=t-butyl, Ph=phenyl, Bn=benzyl, Ac=acetyl, Boc=t-butoxycarbonyl, Fmoc=9-fluorenylmethoxycarbonyl, Tf=triflate, OMOM=methoxymethyl ether, OMEM=methoxyethoxymethyl ether, OTBDMS=t-butyldimethylsilyl ether, DPPA=diphenylphosphoryl azide, NBS=N-bromosuccinimide, NIS=N -Iodosuccinimide, OPMB=4-methoxybenzyl ether, EDCI=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, HOBt=hydroxybenzotriazole, OSEM=[2-(trimethylsilyl))ethoxy]methyl ether, Alloc=allyloxycarbonyl, Cbz=benzyloxycarbonyl, Teoc=(2-(trimethylsilyl)ethoxycarbonyl), TEMPO=2,2,6,6-tetramethyl-1-piperidinoxy, Troc=2,2,2-trichloroethylcarbonyl, etc.

[0045] As used herein, the terms "halo", "halide", or "halogen group" mean a fluorine, chlorine, bromine or iodine group.

[0046] As used herein, the term "amino" means -NH2.

[0047] As used herein, the term "alkyl" means a saturated straight-chain or branched acyclic hydrocarbon group, for example a straight-chain or branched group having 1 to 20, 1 to 8 or 1 to 6 carbon atoms, and in this specification, they are respectively called (C1-C 20 )alkyl, (C1-C8)alkyl, and (C1-C6)alkyl. Exemplary alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, heptyl, octyl, etc.

[0048] As used herein, the term "alkenyl" means an unsaturated straight-chain or branched acyclic hydrocarbon group having at least one carbon-carbon double bond, for example a straight-chain or branched group having 2 to 20, 2 to 8 or 2 to 6 carbon atoms, and in this specification, they are respectively called (C2-C 20 )alkenyl, (C2-C8)alkenyl and (C2-C6)alkenyl. Exemplary alkenyls include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl, and 4-(2-methyl-3-butenyl)-pentenyl.

[0049] As used herein, the term "cycloalkyl" means a saturated hydrocarbon cyclic group. The prefix "C" x ~C y When used in combination with the term "cycloalkyl," (where x and y are integers) refers to the number of ring carbon atoms in a cycloalkyl group. Examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexanyl, as well as crosslinked and caged saturated ring groups such as adamantane.

[0050] The term "heterocycloalkyl" means a single aliphatic ring containing at least two carbon atoms in addition to one to three heteroatoms independently selected from oxygen, sulfur, and nitrogen, and a combination containing at least one of the said heteroatoms. x ~C y When used in combination with the term "heterocycloalkyl," (where x and y are integers) refers to the number of cyclic carbon atoms in the heterocycloalkyl. Suitable heterocycloalkyls include, for example, 2-pyrrolinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, and 2,5-piperidinyl (numbered from the linking position with priority 1). Morpholinyl may also include 2-morpholinyl and 3-morpholinyl (oxygen has priority 1). Substituted heterocycloalkyls further include cyclic systems partially substituted with one or more oxos, such as piperidinyl N-oxide, morpholinyl N-oxide, 1-oxo-l-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

[0051] As used herein, the term “aryl” means a cyclic aromatic hydrocarbon group that does not contain a cyclic heteroatom. Aryls include monocyclic and bicyclic systems. Examples of aryls include, but are not limited to, phenyl, azlenyl, heptenyl, indenyl, indenyl, pentenyl, and naphthyl. In some embodiments, aryls have 6 to 20, 6 to 14, 6 to 12, or 6 to 10 carbon atoms in the ring. In some embodiments, the aryl is phenyl or naphthyl. Aryls include aromatic carbocyclic condensed ring systems. Examples include, but are not limited to, indanyl and tetrahydronaphylyl. Prefix “C x ~C y When used in combination with the term “aryl”, “x” (where x and y are both integers) means the number of cyclic carbon atoms in the aryl group. In some embodiments, “aryl” may be substituted with one or more substituents as described herein.

[0052] As used herein, the term “heteroaryl” means an aromatic ring system comprising five or more ring atoms, one or more of which are heteroatoms. In some embodiments, the heteroatoms are nitrogen, oxygen, or sulfur. Heteroaryls are various heterocyclic groups having an aromatic electronic structure. In some embodiments, heteroaryls include monocyclic, dicyclic, and tricyclic systems having 5-20, 5-16, 5-14, 5-12, 5-10, 5-8, or 5-6 ring atoms. Heteroaryls include, but are not limited to, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridadinyl, pyrimidinyl, pyrazinyl, thiophenyl, benzothiophenyl, furanil, benzofuranil, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimimidazolyl, pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, imidazopyridinyl, imidazyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl. Heteroaryls include fused ring systems in which all rings are aromatic, such as indolyl, and fused ring systems in which only one ring is aromatic, such as 2,3-dihydroindolyl. The prefix "xy-member" (where x and y are integers), when used in combination with the term "heteroaryl," refers to the number of ring atoms in the heteroaryl. In some embodiments, "heteroaryl" may be substituted with one or more of the substituents described herein.

[0053] The references to numerical ranges disclosed herein (e.g., 1 to 10) also include all rational numbers within that range (e.g., 1, 1.1, 2, 3, 3.9, 4, 5, 6, 6.5, 7, 8, 9, and 10) and any range of rational numbers within that range (e.g., 2 to 8, 1.5 to 5.5, and 3.1 to 4.7). Therefore, all subranges of all ranges expressly disclosed herein are expressly disclosed herein. These are merely examples of a particular intent, and all possible combinations of numerical values ​​between the listed minimum and maximum values ​​should be considered expressly described herein in a similar manner.

[0054] 5.2 DNA-PK Inhibitor Compounds of the Present Invention The present invention relates to imidazo[4,5-c]pyridine-2-one compounds that inhibit DNA-PK, and selected prodrug forms of these compounds.

[0055] In a first aspect, the present invention provides a compound of formula I or a salt thereof. [ka] (Here, X is selected from the group consisting of (a), (b), and (c) below. (a) -H; (b) -OH, -HALO, -OR 1 -OC(O)H, -OC(O)R 1 -OC(O)NH2, -OC(O)NHR 1 , -O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 ,-NHC(O)H, -NHC(O)R 1 ,-NRC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 , -NR 1 C(O)NH2, -NHC(O)NR 1 R 1 , -NR 1 C(O)NHR 1 , -NR 1 C(O)NR 1 R 1 -SH, -SR 1 -S(O)H, -S(O)R 1 , -SO2R 1 -SO2NH2, -SO2NHR 1 -SO2NR 1 R 1, -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 -CHO, -C(O)R 1 -C(O)NH2, -C(O)NHR 1 -C(O)NR 1 R 1 -CONHSO2H, -CONHSO2R 1 ,-CONR 1 SO2R 1 ,-Ph, -(C3-C7)cycloalkylamino, imidazolyl, piperazinyl, -(C1-C6)-alkylpiperazinyl, and morpholinyl may optionally be substituted with one or more groups independently selected from -(C 1- C6) alkyl; (c) -OH, -HALO, -OR 1 -OC(O)H, -OC(O)R 1 -OC(O)NH2, -OC(O)NHR 1 , -O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 ,-NHC(O)H, -NHC(O)R 1 ,-NRC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 , -NR 1 C(O)NH2, -NHC(O)NR 1 R 1 , -NR 1 C(O)NHR 1 ,-NRC(O)NR 1 R 1 -SH, -SR 1 -S(O)H, -S(O)R 1 , -SO2R 1 -SO2NH2, -SO2NHR 1 , -SO2NR 1 R 1, -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 , -CHO, -C(O)R 1 , -C(O)NH2, -C(O)NHR 1 , -C(O)NR 1 R 1 , -CONHSO2H, -CONHSO2R 1 , -CONR 1 SO2R 1 , -Ph, -(C3-C7) cycloalkylamino, imidazolyl, piperazinyl, -(C1-C6)-alkylpiperazinyl and morpholinyl, optionally substituted with one or more groups independently selected from (C 2- C6) alkenyl; Each R 1 is -halo, -OH, -OR 2 , -NO2, -NH2, -NHR 2 , -NR 2 R 2 , -SH, -SR 2 , -SO2R 2 , -SO2NH2, -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 , -CHO, -C(O)R 2 , -C(O)NH2, -C(O)NHR 2 or -C(O)NR 2 R 2 which may be optionally substituted with -(C 1- C6) alkyl, independently selected from 2 where R 1- is -(C -Ph is, -(C 1- C6) alkyl, -halo, -OH, -OR 2 , -NO2, -NH2, -NHR 2 , -NR 2 R 2 , -SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2-CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 and -C(O)NR 2 R 2 R may be optionally substituted with one or more elements independently selected from R. 2 ha-(C 1- C6) alkyl, Y is selected from the group consisting of (a) to (f) below, (a) -OH, -HALO, -OR 1 -OC(O)H, -C(O)R 1 -OC(O)NH2, -OC(O)NHR 1 ,-O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 , -NHC(O)H, -NHC(O)R 1 ,-NRC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 , -NR 1 C(O)NH2, -NHC(O)NR 1 R 1 , -NR 1 C(O)NHR 1 , -NR 1 C(O)NR 1 R 1 -SH, -SR 1 -S(O)H, -S(O)R 1 , -SO2R 1 , -SO2NH2, -SO2NHR 1 -SO2NR 1 R 1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 -CHO, -C(O)R 1 , -C(O)NH2, -C(O)NHR 1 -C(O)NR 1 R 1-CONHSO2H, -CONHSO2R 1 ,-CONR 1 SO2R 1 , -Ph; -OH, -OR 1 -NH2, -NHR 1 or -NR 1 R 1 (C3-C7)cycloalkyl, which may be optionally substituted; and containing one oxygen atom or one nitrogen atom on the ring, -OH, -OR 1 -NH2, -NHR 1 , -NR 1 R 1 , or -(C 1- C6) May be optionally substituted with alkyl - (C3-C7) May be optionally substituted with one or more groups independently selected from heterocycloalkyl groups - (C 1- C6) alkyl; Each R 1 -HALO, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH2, -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 -CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 or -C(O)NR 2 R 2 It may be arbitrarily replaced with -(C 1- C6) Selected independently from alkyl, R 2 ha-(C 1- C6) alkyl, -Ph is -(C 1- C6) alkyl, -halo, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2, -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 , -CHO, -C(O)R2, -C(O)NH2, -C(O)NHR 2 and -C(O)NR 2 R 2 R may be optionally substituted with one or more elements independently selected from R. 2 ha-(C 1- C6) alkyl, (b) -OH, -HALO, -OR 1 -OC(O)H, -C(O)R 1 -OC(O)NH2, -OC(O)NHR 1 ,-O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 , -NHC(O)H, -NHC(O)R 1 ,-NRC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 , -NR 1 C(O)NH2, -NHC(O)NR 1 R 1 , -NR 1 C(O)NHR 1 , -NR 1 C(O)NR 1 R 1 -SH, -SR 1 -S(O)H, -S(O)R 1 , -SO2R 1 , -SO2NH2, -SO2NHR 1 -SO2NR 1 R 1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 -CHO, -C(O)R 1 , -C(O)NH2, -C(O)NHR 1 -C(O)NR1 R 1 -CONHSO2H, -CONHSO2R 1 ,-CONR 1 SO2R 1 , -Ph; -OH, -OR 1 -NH2, -NHR 1 or -NR 1 R 1 (C3-C7)cycloalkyl, which may be optionally substituted; and containing one oxygen atom or one nitrogen atom on the ring, -OH, -OR 1 -NH2, -NHR 1 , -NR 1 R 1 , or -(C 1- C6) May be substituted with alkyl - (C3-C7) May be substituted with one or more groups independently selected from heterocycloalkyl groups - (C 2- C6) Alkenyl; Each R 1 -HALO, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH2, -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 -CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 or -C(O)NR 2 R 2 It may be arbitrarily replaced with -(C 1- C6) Selected independently from alkyl, R 2 ha-(C 1- C6) alkyl, -Ph is -(C 1- C6) alkyl, -halo, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 , -CHO, -C(O)R2, -C(O)NH2, -C(O)NHR 2 and -C(O)NR 2 R 2 R may be optionally substituted with one or more elements independently selected from R. 2 ha-(C 1- C6) alkyl, (c)-R 1 -OH, -halo, -OR 1 -OC(O)H,OC(O)R 1 -OC(O)NH2, -OC(O)NHR 1 ,-O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 , -NHC(O)H, -NHC(O)R 1 ,-NRC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 , -NR 1 C(O)NH2, -NHC(O)NR 1 R 1 , -NR 1 C(O)NHR 1 , -NR 1 C(O)NR 1 R 1 -SH, -SR 1 -S(O)H, -S(O)R 1 , -SO2R 1 , -SO2NH2, -SO2NHR 1 -SO2NR 1 R 1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 -CHO, -C(O)R1 -C(O)NH2, -C(O)NHR 1 -C(O)NR 1 R 1 -CONHSO2H, -CONHSO2R 1 , and -CONR 1 SO2R 1 -(C 3- C7) Cycloalkyl; Each R 1 -HALO, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 ,- CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 and -C(O)NR 2 R 2 R is independently selected from (C1-C6) alkyl groups, which may be optionally substituted. 2 ha-(C 1- C6) alkyl, (D)-R 1 -OH, -halo, -OR 1 -OC(O)H, -C(O)R 1 -OC(O)NH2, -OC(O)NHR 1 ,-O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 , -NHC(O)H, -NHC(O)R 1 ,-NRC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 , -NR1 C(O)NH2, -NHC(O)NR 1 R 1 , -NR 1 C(O)NHR 1 , -NR 1 C(O)NR 1 R 1 -SH, -SR 1 -S(O)H, -S(O)R 1 , -SO2R 1 , -SO2NH2, -SO2NHR 1 -SO2NR 1 R 1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 -CHO, -C(O)R 1 -C(O)NH2, -C(O)NHR 1 -C(O)NR 1 R 1 -CONHSO2H, -CONHSO2R 1 , and -CONR 1 SO2R 1 It may be optionally replaced by one or more elements selected independently of (C 3- C7) Heterocycloalkyl; Each R 1 -HALO, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 ,- CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 and -C(O)NR 2 R 2 R is independently selected from (C1-C6) alkyl groups, which may be optionally substituted. 2 ha-(C 1- C6) alkyl, (e) -R 1 -OH, -halo, -OR 1 -OC(O)H,OC(O)R 1 -OC(O)NH2, -OC(O)NHR 1 ,-O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 , -NHC(O)H, -NHC(O)R 1 ,-NRC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 ,-NHC(O)NR 1 R 1 , -NR 1 C(O)NH2, -NR 1 C(O)NHR 1 , -NR 1 C(O)NH2, -NR 1 C(O)NR 1 R 1 -SH, -SR 1 ,-S(O)H, -S(O)R 1 , -SO2R 1 -SO2NH2, -SO2NHR 1 -SO2NR 1 R 1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 -CHO, -C(O)R 1 -C(O)NH2, -C(O)NHR 1 -C(O)NR 1 R 1 ,-CONHSO2H, -CONHSO2R 1 and -CONR 1 SO2R 1 -(C 4- C8) Ariel; Each R 1-HALO, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -O2R 2 -CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 and -C(O)NR 2 R 2 It may be arbitrarily replaced with -(C 1- C6) Selected independently from alkyl, R 2 ha-(C 1- C6) alkyl, (F) -R 1 -OH, -halo, -OR 1 -OC(O)H, -OC(O)R 1 -OC(O)NH2, -OC(O)NHR 1 ,-O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 -NHC(O)H, -NHC(O)R 1 ,-NRC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 , -NR 1 C(O)NH2, -NHC(O)NR 1 R 1 , -NR 1 C(O)NHR 1 , -NRC(O)NR 1 R 1 -SH, -SR 1 -S(O)H, -S(O)R 1 , -SO2R 1 -SO2NH2, -SO2NHR 1 -SO2NR 1 R1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 -CHO, -C(O)R 1 -C(O)NH2, -C(O)NHR 1 -C(O)NR 1 R 1 -CONHSO2H, -CONHSO2R 1 , and -CONR 1 SO2R 1 It may be optionally replaced by one or more elements selected independently of (C 5- C 12 ) Heteroaryl; Each R 1 -HALO, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 -CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 and -C(O)NR 2 R 2 It may be arbitrarily replaced with -(C 1- C6) Selected independently from alkyl, R 2 ha-(C 1- C6) alkyl, Z is selected from the group consisting of (a) and (b) below, (A) -R 1 -OH, -halo, -OR 1 -OC(O)H, -OC(O)R 1 -OC(O)NH2, -OC(O)NHR 1 , -O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1,-NHC(O)H, -NHC(O)R 1 ,-NRC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 , -NR 1 C(O)NH2, -NHC(O)NR 1 R 1 , -NR 1 C(O)NHR 1 , -NR 1 C(O)NR 1 R 1 -SH, -SR 1 -S(O)H, -S(O)R 1 , -SO2R 1 -SO2NH2, -SO2NHR 1 -SO2NR 1 R 1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 -CHO, -C(O)R 1 , -C(O)NH2, -C(O)NHR 1 -C(O)NR 1 R 1 -CONHSO2H, -CONHSO2R 1 ,-CONR 1 SO2R 1 , may optionally be substituted with one or more groups independently selected from morpholinyl, piperazinyl, pyridinyl and pyrimidinyl - (C 4- C8) Ariel; Each R 1 is, -(C 1- The groups are independently selected from C6)alkyl and -(C4-C8)aryl, and each of these groups is -halo, -OH, or -OR. 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 ,-SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2-CHO, -C(O)R 2 , -C(O)NH2, -C(O)NHR 2 or -C(O)NR 2 R 2 It may be arbitrarily substituted with R 2 ha-(C 1- C6) alkyl, Morpholinil, piperazinil, pyridinil, and pyrimidinil each have -(C 1- C6) alkyl, -halo, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, CH2F, -CN, -CO2H, -CO2R 2 -CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 and -C(O)NR 2 R 2 R may be optionally substituted with one or more elements independently selected from R. 2 ha-(C 1- C6) alkyl, (b) -R 1 -OH, -halo, -OR 1 -OC(O)H, -OC(O)R 1 -OC(O)NH2, -OC(O)NHR 1 , -O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 ,-NHC(O)H, -NHC(O)R 1 ,-NRC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 , -NR 1 C(O)NH2, -NHC(O)NR1 R 1 , -NR 1 C(O)NHR 1 , -NR 1 C(O)NR 1 R 1 -SH, -SR 1 -S(O)H, -S(O)R 1 , -SO2R 1 -SO2NH2, -SO2NHR 1 -SO2NR 1 R 1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 -CHO, -C(O)R 1 , -C(O)NH2, -C(O)NHR 1 -C(O)NR 1 R 1 -CONHSO2H, -CONHSO2R 1 ,-CONR 1 SO2R 1 It may be optionally substituted with one or more groups independently selected from morpholinyl and piperazinyl - (C 5- C 12 ) Heteroaryl; Each R 1 ha-(C 1- The groups are independently selected from C6)alkyl and -(C4-C8)aryl, and each of these groups is -halo, -OH, or -OR. 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 ,-SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 -CHO, -C(O)R2, -C(O)NH2, -C(O)NHR 2 or -C(O)NR 2 R 2 It may be arbitrarily replaced with R 2 ha-(C 1-C6) alkyl, Morpholinil and piperazinil, respectively, are -(C 1- C6) alkyl, -halo, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 ,-SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 -CHO, -C(O)R 2 , -C(O)NH2, -C(O)NHR 2 and -C(O)NR 2 R 2 R may be optionally substituted with one or more elements independently selected from R. 2 ha-(C 1- C6) It is an alkyl group. In one embodiment, X is (b) below, (b) -OH, -HALO, -OR 1 -OC(O)H, -OC(O)R 1 -OC(O)NH2, -OC(O)NHR 1 , -O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 ,-NHC(O)H, -NHC(O)R 1 ,-NRC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 , -NR 1 C(O)NH2, -NHC(O)NR 1 R 1 , -NR 1 C(O)NHR 1 , -NR 1 C(O)NR 1 R 1 -SH, -SR1 -S(O)H, -S(O)R 1 , -SO2R 1 -SO2NH2, -SO2NHR 1 -SO2NR 1 R 1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 -CHO, -C(O)R 1 -C(O)NH2, -C(O)NHR 1 -C(O)NR 1 R 1 -CONHSO2H, -CONHSO2R 1 ,-CONR 1 SO2R 1 ,-Ph, -(C3-C7)cycloalkylamino, imidazolyl, piperazinyl, -(C1-C6)-alkylpiperazinyl, and morpholinyl may optionally be substituted with one or more groups independently selected from -(C 1- C6) alkyl; Each R 1 -HALO, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH2, -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 -CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 or -C(O)NR 2 R 2 It may be arbitrarily replaced with -(C 1- C6) Selected independently from alkyl, R 2 ha-(C 1- C6) alkyl, -Ph is -(C 1- C6) alkyl, -halo, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R2 -SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 , -CHO, -C(O)R2, -C(O)NH2, -C(O)NHR 2 and bC(O)NR 2 R 2 It may be optionally substituted with one or more elements independently selected from R 2 ha-(C 1- C6) It is an alkyl group.

[0056] In one embodiment, X is -(C 1- C6) It is an alkyl group. In one embodiment, X is Me.

[0057] In one embodiment, X may be optionally substituted with OH or NH2 - (C 1-6 ) It is alkylalkyl.

[0058] In one embodiment, Y is selected from the group consisting of (c), (d), and (e) above.

[0059] In one embodiment, Y is -(C 3- C7) Selected from the group consisting of cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, cyclohexanyl, pyrrolidinyl, and phenyl, each of these groups is -R 1 -OH, -halo, -OR 1 -OC(O)H, -C(O)R 1 -OC(O)NH2, -OC(O)NHR 1 ,-O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 , -NHC(O)H, -NHC(O)R 1,-NRC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 , -NR 1 C(O)NH2, -NHC(O)NR 1 R 1 , -NR 1 C(O)NHR 1 , -NR 1 C(O)NR 1 R 1 -SH, -SR 1 -S(O)H, -S(O)R 1 , -SO2R 1 , -SO2NH2, -SO2NHR 1 -SO2NR 1 R 1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 -CHO, -C(O)R 1 -C(O)NH2, -C(O)NHR 1 -C(O)NR 1 R 1 -CONHSO2H, -CONHSO2R 1 and -CONR 1 SO2R 1 It may be optionally replaced by one or more elements selected independently of it, Each R 1 -HALO, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 ,- CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 and -C(O)NR 2 R 2 R is independently selected from (C1-C6) alkyl groups, which may be optionally substituted. 2ha-(C 1- C6) alkyl, In one embodiment, Y is -(C 3- C7) Selected from the group consisting of cycloalkyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, methoxycyclohexanil, hydroxycyclohexanil, aminocyclohexanil, N-methylaminocyclohexanil, N,N-dimethylcyclohexanil, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, furanil, pyrrolyl, pyridinyl, hydroxyphenyl, and methoxyphenyl.

[0060] In one embodiment, Y is selected from the group consisting of tetrahydropyranil, aminocyclohexanil, hydroxycyclohexanil, methoxycyclohexanil, and piperidinil.

[0061] In one embodiment, Y is 4-tetrahydropyranyl or 4-piperidinyl.

[0062] In one embodiment, Y is selected from the group consisting of furanil, pyrrolyl, and pyridinil.

[0063] In one embodiment, Y is selected from the group consisting of 4-methoxycyclohexanyl, 4-hydroxycyclohexanyl, or 4-aminocyclohexanyl.

[0064] In one embodiment, Y is 4-hydroxyphenyl or 4-methoxyphenyl.

[0065] In one embodiment, Z is selected from the group consisting of furanyl, thiophenyl, pyrrolyl, pyridinyl, imidazolyl, thiazolyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, purinyl, benzodioxolyl, quinoxalinyl, benzothiadinyl, triazolopyridinyl, benzothiazolyl, benzoxazolyl, benzodioxolyl and imidazopyridinyl - (C 5- C 12 ) are heteroaryls, and each of these groups is -R1 -OH, -halo, -OR 1 -OC(O)H, -C(O)R 1 -OC(O)NH2, -OC(O)NHR 1 ,-O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 , -NHC(O)H, -NHC(O)R 1 ,-NRC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 , -NR 1 C(O)NH2, -NHC(O)NR 1 R 1 , -NR 1 C(O)NHR 1 , -NR 1 C(O)NR 1 R 1 -SH, -SR 1 -S(O)H, -S(O)R 1 , -SO2R 1 , -SO2NH2, -SO2NHR 1 -SO2NR 1 R 1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 -CHO, -C(O)R 1 -C(O)NH2, -C(O)NHR 1 -C(O)NR 1 R 1 -CONHSO2H, -CONHSO2R 1 and -CONR 1 SO2R 1 It may be optionally replaced by one or more elements selected independently of it, Each R 1 ha-(C 1- C6) Alkyl and -(C 4- C8) Selected independently from aryl groups, each of these groups is -halo, -OH, -OR2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 ,- CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 and -C(O)NR 2 R 2 It may be arbitrarily replaced with R 2 ha-(C 1- C6) alkyl, In one embodiment, Z is selected from the group consisting of pyrimidinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, isoquinolinyl, purinyl, benzodioxolyl, quinoxalinyl, benzothiadinyl, triazolopyridinyl, benzothiazolyl, benzoxazolyl, benzodioxolyl and imidazopyridinyl - (C 5- C 12 ) is a heteroaryl, and each group is -(C 1- C6) Aryl, -OH, -HALO, -OR 1 -OC(O)H, -C(O)R 1 -OC(O)NH2, -OC(O)NHR 1 -O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 -NHC(O)H, -NHC(O)R 1 , -NRC(O)R 1 -NHC(O)NH2, -NHC(O)NHR 1 ,-NHC(O)NR 1 R 1 ,-NRC(O)NHR 1 ,-NRC(O)NR 1 R1 ,-SH, -SR 1 -S(O)H, -S(O)R 1 , -SO2R 1 -SO2NH2, -SO2NHR 1 -SO2NR 1 R 1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 -CHO, -C(O)R 1 -C(O)NH2, -C(O)NHR 1 -C(O)NR 1 R 1 -CONHSO2H, -CONHSO2R 1 , and -CONR 1 SO2R 1 And, Each R 1 is, -(C 1- C6) Alkyl and -(C 4- C8) Selected independently from the aryl group, each of these groups is a halo, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH2, -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 -CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 , -C(O)NR 2 R 2 It may be arbitrarily substituted with R 2 ha-(C 1- C6) It is an alkyl group.

[0066] In one embodiment, Z is (C 1- C6) alkyl, preferably substituted with Me-(C 5- C 12 It is a heteroaryl compound.

[0067] In one embodiment, Z is (C 1- C6) alkyl, preferably substituted with Me-(C 4- C8) It is an arrow.

[0068] In one embodiment, Z is R 1 -OH, -OR 1 -HALO, -NO2, -NH2, -NHR 1 , -NR 1 R 1 , -SO2R 1 A phenyl which may be optionally substituted with one or more of -Bn, and -R 1 is (C 1- C6) Alkyl, preferably Me

[0069] In one embodiment, Z has -OMe, -Cl, and It is a phenyl molecule substituted with either -OH group.

[0070] In one embodiment, Z is -SO2R at position 5. 1 A phenyl substituted with either NO2, where -R 1 is (C 1- C6) It is an alkyl group, preferably Me.

[0071] In one embodiment, Z is selected from the group consisting of 4-methoxy-2-methylphenyl, 4-chloro-2-methylphenyl, 5-(methylsulfonyl)-2-methylphenyl, and 4-hydroxy-2-methylphenyl.

[0072] In one embodiment, Z is 4-methoxy-2-methylphenyl.

[0073] In a second aspect, the present invention provides a compound of formula II or a salt thereof. [ka] Here, X and Y are defined as in equation I, A 1、 A2 and A3 are selected independently of CH or N. B1 is -OH, -OR 1 , Halo, -NO2, -NH2, NHR 1 , -SO2R 1 Selected from -OBn, Each R 1 -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH2, -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 , -CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 or -C(O)NR 2 R 2 It may be arbitrarily replaced with -(C 1- C6) alkyl, R 2 ha-(C 1- C6) It is an alkyl group.

[0074] In one embodiment, X is Me.

[0075] In one embodiment, Y is -(C 3- C7) Selected from the group consisting of cycloalkyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, methoxycyclohexanil, hydroxycyclohexanil, aminocyclohexanil, N-methylaminocyclohexanil, N,N-dimethylcyclohexanil, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, furanil, pyrrolyl, pyridinyl, hydroxyphenyl, and methoxyphenyl.

[0076] In one embodiment, Y is selected from the group consisting of tetrahydropyranil, aminocyclohexanil, hydroxycyclohexanil, methoxycyclohexanil, and piperidinil.

[0077] In one embodiment, Y is 4-tetrahydropyranyl or 4-piperidinyl.

[0078] In one embodiment, Y is selected from the group consisting of furanil, pyrrolyl, and pyridinil.

[0079] In one embodiment, Y is selected from the group consisting of 4-methoxycyclohexanyl, 4-hydroxycyclohexanyl, or 4-aminocyclohexanyl.

[0080] In one embodiment, Y is 4-hydroxyphenyl or 4-methoxyphenyl.

[0081] In one embodiment, A1 is N, A2 and A3 are C, and B1 is OMe.

[0082] In a third aspect, the present invention provides a compound of formula III or a salt thereof. [ka] Here, X and Y are defined as in equation I, A1 is either N or C.

[0083] D is selected from N, O, and S. [ka] This represents a single bond or a double bond. [ka] It is a single bond unless D is N, R 3 H, -(C 1- C6) Alkyl, -CO2R 1 -CONHR 1 and CON HR 1 R 1 Selected from the group consisting of R 1 ha-(C 1- C6) It is an alkyl group.

[0084] In one embodiment, X is Me.

[0085] In one embodiment, Y is -(C 3- C7) Selected from the group consisting of cycloaryl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, methoxycyclohexanil, hydroxycyclohexanil, aminocyclohexanil, N-methylaminocyclohexanil, N,N-dimethylcyclohexanil, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, furanil, pyrrolyl, pyridinyl, hydroxyphenyl, and methoxyphenyl.

[0086] In one embodiment, Y is selected from the group consisting of tetrahydropyranil, aminocyclohexanil, hydroxycyclohexanil, methoxycyclohexanil, and piperidinil.

[0087] In one embodiment, Y is 4-tetrahydropyranyl or 4-piperidinyl.

[0088] In one embodiment, Y is selected from the group consisting of furanil, pyrrolyl, and pyridinil.

[0089] In one embodiment, Y is selected from the group consisting of 4-methoxycyclohexanyl, 4-hydroxycyclohexanyl, or 4-aminocyclohexanyl.

[0090] In one embodiment, Y is 4-hydroxyphenyl or 4-methoxyphenyl.

[0091] In one embodiment, R 3 These are H, Me, OMe, or CO2Me.

[0092] In one embodiment, A1 is N, D is CH, and R 3 H is H.

[0093] In one embodiment, A1 is N, D is N, and R 3 H is H.

[0094] In one embodiment, A1 is N, D is CH, and R 3 It is CO2Me.

[0095] In a fourth aspect, the present invention provides a compound of formula IV. [ka] Here, X and Y are defined as in equation I, B2 and D are selected independently from N, O, and S. [ka] Represents a single bond or a double bond, [ka] It is a single bond unless D is N, R 3 H, -(C 1- C6) Alkyl, -CO2R 1 -CONHR 1 and CONHR 1 R 1 Selected from the group consisting of R 1 ha-(C 1- C6) It is an alkyl group.

[0096] In one embodiment, X is Me.

[0097] In one embodiment, Y is -(C 3- C7) Selected from the group consisting of cycloalkyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, methoxycyclohexanil, hydroxycyclohexanil, aminocyclohexanil, N-methylaminocyclohexanil, N,N-dimethylcyclohexanil, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, furanil, pyrrolyl, pyridinyl, hydroxyphenyl, and methoxyphenyl.

[0098] In one embodiment, Y is selected from the group consisting of tetrahydropyranil, aminocyclohexanil, hydroxycyclohexanil, methoxycyclohexanil, and piperidinil.

[0099] In one embodiment, Y is 4-tetrahydropyranyl or 4-piperidinyl.

[0100] In one embodiment, Y is selected from the group consisting of furanil, pyrrolyl, and pyridinil.

[0101] In one embodiment, Y is selected from the group consisting of 4-methoxycyclohexanyl, 4-hydroxycyclohexanyl, or 4-aminocyclohexanyl.

[0102] In one embodiment, Y is 4-hydroxyphenyl or 4-methoxyphenyl.

[0103] In one embodiment, R 3 is H, Me, or OMe.

[0104] In one embodiment, B2 is N, D is O or S, and R3 is Me.

[0105] In one embodiment, B2 is N and D is O.

[0106] In addition to the DNA-PK inhibitor described above, the present invention also includes a prodrug compound (reducible prodrug trigger) comprising the DNA-PK inhibitor of the present invention and an aromatic nitroheterocycle or nitrocarbon ring that is broken upon reduction.

[0107] Therefore, in a fifth aspect, the present invention provides a compound of formula V or a salt thereof. [ka] Here, X, Y, and Z are defined by equation I, Pro is [ka] selected from, where * represents the connection point with the N atom of formula V.

[0108] R 11 is -OH, -halo, -OR 1 , -OC(O)H, -OC(O)R 1 , -OC(O)NH2, -OC(O)NHR 1 , -O(CO)NR 1 R 1 , -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 , -NHC(O)H, -NHC(O)R 1 , -NRC(O)R 1 , -NHC(O)NH2, -NHC(O)NHR 1 , -NR 1 C(O)NH2, -NHC(O)NR 1 R 1 , -NR 1 C(O)NHR 1 , -NR 1 C(O)NR 1 R 1 , -SH, -SR 1 , -S(O)H, -S(O)R 1 , -SO2R 1 , -SO2NH2, -SO2NHR 1 , -SO2NR 1 R 1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 , -CHO, -C(O)R 1 , -C(O)NH2, -C(O)NHR 1 , -C(O)NR 1 R 1 , -CONHSO2H, -CONHSO2R 1 , -CONR 1 SO2R 1 , -Ph, -(C3-C7)cycloalkylamino, imidazolyl, piperazinyl, -(C1-C6)-alkylpiperazinyl, and morpholinyl may be optionally substituted. 1- C6) alkyl, Each R 1 -HALO, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 -SO2NH2, -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 -CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 and -C(O)NR 2 R 2 It may be arbitrarily replaced with -(C 1- C6) Selected independently from alkyl, R 2 ha-(C 1- C6) alkyl, -Ph is -(C 1- C6) alkyl, -halo, -OH, -OR 2 , -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 , -CHO, -C(O)R2, -C(O)NH2, -C(O)NHR 2 -C(O)NR 2 R 2 It may be arbitrarily replaced with one or more of the following: R 2 ha-(C 1- C6) alkyl, R 12 and R 13 This is independently selected from the group consisting of -H, -Me, and -Et.

[0109] In one embodiment, X is Me.

[0110] In one embodiment, Y is -(C 3- C7) Selected from the group consisting of cycloalkyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, methoxycyclohexanil, hydroxycyclohexanil, aminocyclohexanil, N-methylaminocyclohexanil, N,N-dimethylcyclohexanil, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, furanil, pyrrolyl, pyridinyl, hydroxyphenyl, and methoxyphenyl.

[0111] In one embodiment, Y is selected from the group consisting of tetrahydropyranil, aminocyclohexanil, hydroxycyclohexanil, methoxycyclohexanil, and piperidinil.

[0112] In one embodiment, Y is 4-tetrahydropyranyl or 4-piperidinyl.

[0113] In one embodiment, Y is selected from the group consisting of furanil, pyrrolyl, and pyridinil.

[0114] In one embodiment, Y is selected from the group consisting of 4-methoxycyclohexanyl, 4-hydroxycyclohexanyl, or 4-aminocyclohexanyl.

[0115] In one embodiment, Y is 4-hydroxyphenyl or 4-methoxyphenyl.

[0116] In one embodiment, Z is (C 1- C6) alkyl, preferably substituted with Me-(C 5- C 12 It is a heteroaryl compound.

[0117] In one embodiment, Z is [ka] A1 is N or C, and D is selected from the group consisting of N, O, S, and . [ka] This represents a single bond or a double bond. [ka] It is a single bond unless D is N, R 3 H, -(C 1- C6) Alkyl, -CO2R 1 -CONHR 1 and CONHR 1 R 1 Selected from the group consisting of R 1 ha-(C 1- C6) It is an alkyl group.

[0118] In one embodiment, R 3 These are H, Me, OMe, or CO2Me.

[0119] In one embodiment, A1 is N, D is CH, and R 3 H is H.

[0120] In one embodiment, A1 is N, D is N, and R 3 H is H.

[0121] In one embodiment, A1 is N, D is CH, and R 3 It is CO2Me.

[0122] In one embodiment, Z is [ka] B2 and D are independently selected from the group consisting of N, O, and S. [ka] represents a single bond or a double bond, [Chemical formula] is a single bond unless D is N, and R 3 is H, -(C 1- C6) alkyl, -CO2R 1 , -CONHR 1 and CONHR 1 R 1 is selected from the group consisting of, and R 1 is -(C 1- C6) alkyl.

[0123] In one embodiment, R 3 is H, Me or OMe.

[0124] In one embodiment, B2 is N, D is O or S, and R3 is Me.

[0125] In one embodiment, B2 is N and D is O.

[0126] In one embodiment, Z is (C 1- C6) alkyl, preferably -(C 4- C8) aryl substituted with Me.

[0127] In one embodiment, Z is phenyl optionally substituted with one or more of R 1 , -OH, -OR 1 , -halo, -NO2, -NH2, -NHR 1 , -NR 1 R 1 , -SO2R 1 and -Bn, and -R 1 is (C 1- C6) alkyl, preferably Me.

[0128] In one embodiment, Z is phenyl substituted at the 4-position with either -OMe, -Cl, or -OH.

[0129] In one embodiment, Z is phenyl substituted at the 5-position with -SO2R 1A phenyl substituted with either NO2, where -R 1 is (C 1- C6) It is an alkyl group, preferably Me.

[0130] In one embodiment, Z is selected from the group consisting of 4-methoxy-2-methylphenyl, 4-chloro-2-methylphenyl, 5-(methylsulfonyl)-2-methylphenyl, and 4-hydroxy-2-methylphenyl.

[0131] In one embodiment, Z is 4-methoxy-2-methylphenyl.

[0132] In one embodiment, Pro is [ka] And here, R 12 and R 13 It is defined as described above.

[0133] In one embodiment, Pro is [ka] It is selected from the group consisting of the following.

[0134] In one embodiment, X is Me, Y is tetrahydropyranyl, Z is 4-methoxy-2-methylphenyl, and Pro is [ka] That is the case.

[0135] In a sixth aspect, the present invention provides a compound of formula VI or a salt thereof. [ka] Here, X and Y are defined as in equation I, E is -O-, -NHCO2-, -N(Me)CO2-, -COO-, -NH(C 1- C6) Alkyl , -O-(C1-C6)alkyl-N-dimethylamino-,-NH(C 1- C6) Alkyl-N-dimethylamino-, -NHCO(C 1- C6) Selected from alkyl-N-dimethylamino- and -NHCOCH=CHCH2-N-dimethylamino-, Pro is [ka] Selected from the group consisting of , Here, * represents the connection point with E in equation VI, Each R 11 -OH, -halo, -OR 1 -OC(O)H, -OC(O)R 1 -OC(O)NH2, -OC(O)NHR 1 ,-O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 -NHC(O)H, -NHC(O)R 1 ,-NRC(O)R 1 , -NHC(O)NH2, -NHC(O)NHR 1 , -NR 1 C(O)NH2, -NHC(O)NR 1 R 1 , -NR 1 C(O)NHR 1 , -NR 1 C(O)NR 1 R 1 -SH, -SR 1 -S(O)H, -S(O)R 1 , -SO2R 1 -SO2NH2, -SO2NHR 1 -SO2NR 1 R 1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1-CHO, -C(O)R 1 -C(O)NH2, -C(O)NHR 1 -C(O)NR 1 R 1 ,-CONHSO2H, -CONHSO2R 1 ,-CONR 1 SO2R 1 ,-Ph,-(C3-C7)cycloalkylamino, imidazolyl, piperazinyl, -(C1-C6)-alkylpiperazinyl and morpholinyl may be optionally substituted -(C 1- C6) alkyl, Each R 1 -HALO, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH2, -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 -CHO, -C(O)R 2 -C(O)NH2, -C(O)NHR 2 or -C(O)NR 2 R 2 It may be arbitrarily replaced with -(C 1- C6) Independently selected from alkyl groups, R 2 It is a C1-6 alkyl group, -Ph is -(C 1- C6) alkyl, -halo, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 , -CHO, -C(O)R2, -C(O)NH2, -C(O)NHR 2 and -C(O)NR 2 R 2R may be optionally substituted with one or more elements independently selected from R. 2 ha-(C 1- C6) alkyl, R 12 and R 13 It is independently selected from the group consisting of -H, -Me, and -Et, R 14 The group is selected from -H, -Me, -Et, -OMe, -CF3, -CN, and ethynyl.

[0136] However, E is -O-(C1-C6)alkyl-N-dimethylamino-,-NH(C 1- C6) Alkyl-N-dimethylamino-, -NHCO(C 1- If C6) is selected from alkyl-N-dimethylamino- or -NHCOCH=CHCH2-N-dimethylamino-, Pro is [ka] That is the case.

[0137] In one embodiment, Pro is [ka] And here, R 12 and R 13 is defined above, and E is -O-.

[0138] In one embodiment, Pro is [ka] Selected from the group consisting of, where E is -O- or NHCO2.

[0139] In one embodiment, Pro is [ka] And R 14 is defined above, and E is O-(C1-C6)alkyl-N-dimethylamino, preferably -OCH2CH2NMe2 or -OCH2CH2CH2NMe2.

[0140] In one embodiment, X is Me.

[0141] In one embodiment, Y is -(C 3- C7) Selected from the group consisting of cycloalkyl, oxetanyl, tetrahydrofuranil, tetrahydropyranil, methoxycyclohexanil, hydroxycyclohexanil, aminocyclohexanil, N-methylaminocyclohexanil, N,N-dimethylcyclohexanil, pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, furanil, pyrrolyl, pyridinyl, hydroxyphenyl, and methoxyphenyl.

[0142] In one embodiment, Y is selected from the group consisting of tetrahydropyranil, aminocyclohexanil, hydroxycyclohexanil, methoxycyclohexanil, and piperidinil.

[0143] In one embodiment, Y is 4-tetrahydropyranyl or 4-piperidinyl.

[0144] In one embodiment, Y is selected from the group consisting of furanil, pyrrolyl, and pyridinil.

[0145] In one embodiment, Y is selected from the group consisting of 4-methoxycyclohexanyl, 4-hydroxycyclohexanyl, or 4-aminocyclohexanyl.

[0146] In one embodiment, Y is 4-hydroxyphenyl or 4-methoxyphenyl.

[0147] In one embodiment, Pro is [ka] E is selected from the options, and E is O.

[0148] In one embodiment, X is Me, Y is tetrahydropyranyl, and Pro is [ka] That is the case.

[0149] In one embodiment, X is Me, Y is 4-methoxycyclohexanyl, and Pro is [ka] That is the case.

[0150] In one embodiment, X is Me, Y is 4-methoxyphenyl, and Pro is [ka] That is the case.

[0151] In a seventh aspect, the present invention provides a compound of formula VII. [ka] Here, X and Z are defined as in equation I, Here, J is either CH2 or does not exist. [ka] It is either a saturated ring or an unsaturated ring, B3 is either C or N. G is -O-, -NHCO2-, -N(Me)CO2-, -COO-, -NH(C 1- C6) Alkyl , -O-(C1-C6)alkyl-N-dimethylamino-, -NH(C 1- C6)alkyl-N-dimethylamino-, -NHCO(C1-C6)alkyl-N-dimethylamino, and Selected from the group consisting of -NHCOCH=CHCH2-N-dimethylamino, and Pro is [ka] Selected from the group consisting of , Here, * represents the connection point with G in equation VII, Each R 11 -OH, -halo, -OR 1 -OC(O)H, -OC(O)R 1 -OC(O)NH2, -OC(O)NHR 1 ,-O(CO)NR 1 R 1 -OP(O)(OH)2, -OP(O)(OR 1 )2, -NH2, -NHR 1 , -NR 1 R 1 -NHC(O)H, -NHC(O)R 1 ,-NRC(O)R 1 , -NHC(O)NH2, -NHC(O)NHR 1 , -NR 1 C(O)NH2, -NHC(O)NR 1 R 1 , -NR 1 C(O)NHR 1 , -NR 1 C(O)NR 1 R 1 -SH, -SR 1 -S(O)H, -S(O)R 1 , -SO2R 1 -SO2NH2, -SO2NHR 1 -SO2NR 1 R 1 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 1 -CHO, -C(O)R 1 -C(O)NH2, -C(O)NHR 1 -C(O)NR 1 R 1 ,-CONHSO2H, -CONHSO2R 1 ,-CONR 1 SO2R 1,-Ph,-(C3-C7)cycloalkylamino, imidazolyl, piperazinyl, -(C1-C6)-alkylpiperazinyl and morpholinyl may be optionally substituted -(C 1- C6) alkyl, Each R 1 -HALO, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH2, -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 , -CHO, -C(O)R2, -C(O)NH2, -C(O)NHR 2 or -C(O)NR 2 R 2 It may be arbitrarily replaced with -(C 1- C6) Selected independently from alkyl, each R 2 It is a C1-6 alkyl group, -Ph is, -(C 1- C6) alkyl, -halo, -OH, -OR 2 -NO2, -NH2, -NHR 2 , -NR 2 R 2 -SH, -SR 2 , -SO2R 2 , -SO2NH 2 , -CF3, -CHF2, -CH2F, -CN, -CO2H, -CO2R 2 , -CHO, -C(O)R2, -C(O)NH2, -C(O)NHR 2 and -C(O)NR 2 R 2 It may be substituted with one or more groups independently selected from each R 2 It is a C1-6 alkyl group.

[0152] R 12 and R 13 It is selected independently from -H, -Me, and -Et. R 14 The group is selected from -H, -Me, -Et, -OMe, -CF3, -CN, and ethynyl.

[0153] However, G is -O-(C1-C6)alkyl-N-dimethylamino-, -NH(C 1- C6) Alkyl-N-dimethylamino-, -NHCO(C 1- If selected from C6) alkyl-N-dimethylamino- or -NHCOCH=CHCH2-N-dimethylamino, Pro is [ka] That is the case.

[0154] [ka] B3 is N only if it is a saturated ring. G is -COO- only if B3 is N, and G is -O- only if B3 is C.

[0155] In one embodiment, Z is (C 1- C6) alkyl, preferably substituted with Me-(C 5- C 12 It is a heteroaryl compound.

[0156] In one embodiment, Z is (C 1- C6) alkyl, preferably substituted with Me-(C 4- C8) It is an arrow.

[0157] In one embodiment, Z is R 1 -OH, -OR 1 -HALO, -NO2, -NH2, -NHR 1 , -NR 1 R 1 , -SO2R 1 A phenyl which may be optionally substituted with one or more of -Bn, and -R 1 is (C 1-C6) Alkyl, preferably Me

[0158] In one embodiment, Z has -OMe, -Cl, and It is a phenyl molecule substituted with either -OH group.

[0159] In one embodiment, Z is -SO2R at position 5. 1 A phenyl substituted with either NO2, where -R 1 is (C 1- C6) It is an alkyl group, preferably Me.

[0160] In one embodiment, Z is selected from the group consisting of 4-methoxy-2-methylphenyl, 4-chloro-2-methylphenyl, 5-(methylsulfonyl)-2-methylphenyl, and 4-hydroxy-2-methylphenyl.

[0161] In one embodiment, Z is 4-methoxy-2-methylphenyl.

[0162] In one embodiment, Pro is [ka] And here, R 12 and R 13 The above definition is given, and G is -NHCO2-.

[0163] In one embodiment, Pro is [ka] And G is -NHCO2-.

[0164] In one embodiment, J is absent, the ring is saturated, B3 is N, G is CO2, and Pro is [ka] That is the case.

[0165] In one embodiment, J is absent, the ring is saturated, B3 is CH, G is NHCO2, and Pro is [ka] That is the case.

[0166] The prodrug compound of formula V-VII comprises the DNA-PK inhibitor of the present invention and a reducing "trigger." The reducing trigger is an aromatic nitroheterocyclic or nitrocarbon ring that undergoes fragmentation upon reduction. This nitroheterocyclic or nitrocarbon ring unit is preferably bound to the DNA-PK inhibitor effector via a carbamate bond, ether bond, or quaternary ammonium bond.

[0167] The prodrug compound of the present invention is reduced in vivo by an enzyme, a radiation-induced radical, and / or a chemical reducing agent. Under reducing conditions, the fragmentation of the trigger releases the active DNA-PK inhibitor, and the oxygen or nitrogen atom bound to the trigger becomes the remaining portion of the released DNA-PK inhibitor.

[0168] The prodrug compounds of the present invention selectively release DNA-PK inhibitors in tumors, more specifically in hypoxic regions within tumors. One characteristic common to most tumors is that the tissue regions of the tumor are at hypoxic levels (hypoxia). Related terms such as "hypoxia" and "hypoxia" mean that the oxygen concentration in the tissue is significantly lower than the normal physiological concentration of oxygen in healthy, well-perfused tissue, and in particular, that the partial pressure of oxygen is about 1% (10,000 parts per million oxygen; 7.6 mmHg) or less. The terms "oxygen deficiency" and "oxygen deficiency state" mean a state of oxygen deficiency or near-oxygen deficiency.

[0169] Under hypoxic or oxygen-deficient conditions, endogenous one-electron enzymes such as cytochrome P450 oxidoreductase (POR) reduce nitro to nitro anions.

[0170] This process for compounds of formula V is shown in general formula 1 below.

[0171] [ka] The nitroradical anion functions as an oxygen sensor because it is reoxidated to an initiating prodrug while forming superoxide.

[0172] This type of reduction by one-electron reductase effectively targets the release of DNA-PK inhibitors into hypoxic regions within tumors. The presence of oxygen inhibits reduction in normal oxidative tissue.

[0173] While theoretical constraints are undesirable, oxidative regions that limit the release of DNA-PK inhibitors into hypoxic tissues and subsequent diffusion of the inhibitors into tumors are considered a major basis for endogenous enzyme-mediated tumor selectivity. This targeting of DNA-PK inhibitors to tumors is also advantageous in expanding the therapeutic opportunities for such inhibitors.

[0174] In general, the prodrugs of the present invention, formed by the combination of a fragmentation-reduction activation trigger and a DNA-PK inhibitor, are determined by the applicant to possess many remarkable properties, making them particularly suitable as targeted anticancer agents. Of these properties, the most important is their targeting effect. Many reducing triggers are widely known.

[0175] However, there is no guarantee that each combination of trigger and specific effector will be effective, and each combination needs to be optimized empirically. The inventors have demonstrated that the specific triggers defined above bind to specific DNA-PK inhibitors to inactivate effectors, which are stable and enable delivery of prodrugs to tumors. The prodrugs are also effectively fragmented to release cytotoxic effectors under hypoxic conditions and possess therapeutic antitumor effects.

[0176] In the eighth aspect, the present invention provides a compound of formula XII. [ka] Here, X, Y, and Z are defined by equation I.

[0177] The anilinoimidazopyridinones exemplified by compounds of formulas I, II, III, and IV offer an opportunity to prepare hypoxia-activated prodrugs of these compounds, which are not available in compounds similar to 2-anilino-7,9-dihydropurin-8-one described in formula XIII. The preparation of carbamate prodrugs of these DNA-PK inhibitors (e.g., 247, 248, 250, 251, 254-259) is made possible by the high stability of the intermediate carbamoyl chloride (e.g., 249, scheme 33). Such a stable intermediate offers advantages, including isolation and purification, which allow for improved synthetic conditions and rapid purification from the starting material before subsequent reactions and the installation of nitroaryl triggers. Repeating this procedure using the corresponding 2-anilino-7,9-dihydropurin-8-one core of formula XIII (e.g., AZD7648) yielded no results, indicating the instability of the carbamoyl chloride intermediate.

[0178] [ka] 5.3 DNA-PK Inhibition by the Compounds of the Present Invention 5.3.1 Inhibition of DNA-PKcs and Related Kinases The compounds of the present invention are evaluated as DNA-PK-mediated phosphorylation inhibitors of peptide substrates (Table 12). The compounds are also evaluated against the related PI3-K and PIKK members, mTOR kinases. Compared to PI-3K and mTOR, these compounds inhibit DNA-PK in the nM to μM range and exhibit selectivity for DNA-PK.

[0179] 5.3.2 Comparative Inhibition of 397 Kinases and 20 Lipid Kinases The selectivity of a particular embodiment of the present invention is evaluated at a concentration of 1 μM for 397 kinases and 20 lipid kinases. Compounds 48 (Table 13, Figure 1) and 121 (Table 14, Figure 2) showed significant selectivity for DNA-PK compared to other kinases.

[0180] 5.3.3. Selectivity for DNA-PKcs compared to other PIKK kinases The selectivity of the compounds of the present invention for DNA-PKcs compared to other members of the phosphatidylinositol 3-kinase-related kinase family (ATM, ATR, mTOR) and related phosphatidylinositol 3-kinase isoforms (PI3Kα, β, γ, δ) is confirmed in Table 15 and Figure 13. An example of the present invention shows increased selectivity of DNA-PK for PIKK kinase compared to another known kinase inhibitor (AZD7648).

[0181] 5.3.4 Radiosensitizing Effect on Human Head and Neck Cancer Cells The radiosensitizing ability of the compounds of the present invention to human tumor cells is evaluated using proliferation endpoints under aerobic conditions. UT-SCC-54C cells are cultured in a certain concentration of the compound for 1 hour and then incubated for 24 hours before treatment with 0 or 3 Gy of radiation. After washing off the drug and allowing the cells to regrow for 5 days, they are fixed and stained with sulfohodamine B. The compounds of the present invention exhibit a concentration-dependent radiosensitizing effect on UT-SCC-54C cells and show little cytotoxicity in the absence of radiation (Figure 3). Cytotoxicity is defined as the drug concentration required to inhibit culture regrowth by 50% during the assay: IC50 value. Radiosensitization is defined as the drug concentration required to inhibit culture regrowth by 50% during the assay when used in combination with 3 Gy radiation: S50 value (Table 16). Examples of prodrugs of the compound (e.g., 234, 236, 238, 240, 246, 247, 248, 250, 251, 257, 258, and 259) do not exhibit different growth inhibition, demonstrating the effective inactivation of the drug.

[0182] 5.3.5. DNA-PKcs-dependent radiosensitization of cells: HAP1 wild-type cell line and PRKDC (HAP1 / PRKDC - / -The present invention was evaluated in a proliferation inhibition test using a DNA-PK-inactive HAP1 cell line with a CRISPR-induced shift mutation. As shown in Figure 4 and Table 18, compounds 48, 88, 121, 125, 126, 127, 129, 132, and 135 induced concentration-dependent radiosensitization of HAP1 cells, significantly inhibiting regrowth of cultures after 3 Gy cobalt-60γ irradiation compared to irradiation with radiation alone, and had little effect on HAP1 cells that were not irradiated. On the other hand, compounds 48, 88, 121, 125, 126, 127, 129, 132, and 135 did not show radiosensitization of HAP1 cell lines that invalidated DNA-PK-dependent radiosensitization of HAP cells. Furthermore, prodrugs 135, 234, 236, and 248 induced radiosensitization of HAP1 cells or PRKDCs. - / - In the presence of radiation in cells, this drug shows inactivation without exhibiting different growth inhibition.

[0183] 5.3.6 Inhibition of Ser2056 autophosphorylation of DNA-PKcs in cells. Further evidence of the cellular mechanism of action of the compounds of the present invention was confirmed by inhibiting the autophosphorylation of DNA-PKcs by Ser2056. Irradiation of UT-SCC-54C hypoxic cells with 10 Gy induced autophosphorylation of Ser2056 on DNA-PKcs and compounds 48 and 88, confirming inhibition of Ser2056 autophosphorylation under hypoxic conditions (Figure 5). Similarly, compounds 48 and 88 showed inhibition of radiation-induced Ser2056 autophosphorylation under hypoxic conditions (Figure 6). Prodrug 234 did not inhibit Ser2056 autophosphorylation much under hypoxic conditions, but when experiments were conducted under hypoxic conditions, prodrug 234 was able to inhibit Ser2056 phosphorylation (Figure 6).

[0184] UT-SCC-54 C cells irradiated with 10 Gy under aerobic conditions induced autophosphorylation of Ser 2056 on DNA-PKcs and phosphorylation of Ser 1981 on ATM (Figure 7). Compounds 48, 121, 195, and the published DNA-PK inhibitors M3814 and IC87361 demonstrated inhibitory effects on Ser 2056 on DNA-PKcs, but did not show inhibitory effects on Ser 1981 on ATM. On the other hand, the ATM inhibitor AZD1393 inhibited radiation-induced phosphorylation of Ser 1981 on ATM, but did not affect autophosphorylation of Ser 2056 on DNA-PKcs. Prodrug 234 did not inhibit the phosphorylation of either enzyme under aerobic conditions.

[0185] 5.3.7. Hypoxia-selective metabolism of prodrugs releases DNA-PK inhibitors. UT-SCC-54C cells selectively metabolize prodrug 248 under oxygen-deficient conditions but do not metabolize it under aerobic conditions, thus confirming the hypoxia-selective release of DNA-PK inhibitor 121 (Figure 13).

[0186] 5.3.8 Radiosensitizing effect on human head and neck cancer cells. When evaluated using the clonal survival endpoint, the compounds of the present invention provide radiosensitizing effects on human head and neck squamous cell carcinoma cells. For example, 48, 121, 135, and 195 show a concentration-dependent increase in radiosensitization (Figure 8, Table 18).

[0187] Compound 88 provides radiosensitization to UT-SCC-54 C cells under aerobic conditions, but does not provide prodrug 234 (Figure 9 and Table 18). On the other hand, under oxygen-deficient conditions, prodrug 234 is activated, and radiosensitization is obtained (SER=1.37, Figure 10). Similarly, compound 121 provides radiosensitization to UT-SCC-54 C cells under aerobic conditions, but does not provide prodrug 248. Under oxygen-deficient conditions, prodrug 248 is activated, and radiosensitization is obtained (SER=1.82, Figure 10). Similarly, the prodrugs of compounds 236 and 135 selectively provide sensitization to UT-SCC-54 C cells under oxygen-deficient conditions (SER 1.51, Figure 10). Similarly, the prodrugs of compounds 236, 238, 250, and 251, and compounds 88, 135, 121, and 122 selectively provide sensitization to UT-SCC-54 C cells under oxygen deprivation conditions, respectively (Figures 9 and 10).

[0188] 5.3.9. Radiosensitizing Effect of UT-SCC-54C on HNSCC Tumors When administered to mice carrying UT-SCC-54C tumor xenografts, compounds 121 and 248 alone did not reduce the amount of klonogen / g in tumor tissue compared to the DMSO control (Figure 11). Approximately 1.5 logarithmic reduction occurred with radiation (13 Gy) alone. Combining compound 121 with radiation (13 Gy) resulted in a significant additional reduction in klonogen / gram tumor (p=0.005) compared to radiation alone. Combination radiation with prodrug 248 showed a small but significant effect (p=0.018) compared to radiation alone. These studies demonstrate the efficacy of combined radiotherapy with DNA-PK inhibitors and their prodrugs in a xenograft model of human head and neck tumors.

[0189] 5.3.10. When compound 121, an inhibitor of UT-SCC-54C HNSCC tumor growth, was administered to mice carrying UT-SCC-54C tumor xenografts, it inhibited tumor growth less significantly compared to the individual vectors (Figure 12A). A single dose of radiation (10 Gy) moderately slowed tumor growth, while compound 121, when administered in combination with radiation, significantly inhibited tumor growth (Figure 12B). These studies further demonstrated the therapeutic effect of combining DNA-PK inhibitors with radiotherapy in a xenograft model of human head and neck tumors.

[0190] As described above, the compounds of formulas I, II, III, IV, V, VI, and VII exhibit selectivity for DNA-PK. In one embodiment, the present invention provides IC for DNA-PK as measured by the embodiments enumerated in Example 171. 50 The present invention provides compounds of formulas I, II, III, IV, V, VI, and VII with a concentration of less than 500 nM.

[0191] In one embodiment, the present invention provides a compound having one or more of the following properties, which is any of formulas I, II, III, IV, V, VI, and VII.

[0192] (a) IC for DNA-PK, measured by quantifying the phosphorylation of peptide substrates by human DNA-PK in the presence of DNA and ATP. 50 The value must be less than 500 nM. (b) The selectivity ratio for one or more PI3K isoforms is greater than 100×. (c) The selectivity ratio for one or more PIKK kinases selected from the group consisting of mTOR, ATM, and ATR is greater than 100×. In one embodiment, the compound of the present invention is used in IC for DNA-PK. 50The value is less than 400, 300, 200, or 100 nM. In one embodiment, the compound of the present invention has a selectivity ratio of 200, 300, or 400 × for one or more π3K isoforms. In one embodiment, the compound of the present invention has a selectivity ratio of 200, 300, or 400 × for one or more PIKK kinases selected from the group consisting of mTOR, ATM, and ATR.

[0193] In one embodiment, the present invention provides a compound having one or more of the following properties, which is any of formulas I, II, III, or IV.

[0194] (a) The S50 value when combined with 3 Gy radiation to UT-SCC-54C HNSCC cells, as determined by the scheme described in Example 175, is less than 1 μM. (b) The ability to increase the concentration of the compound to restrict tumor cell proliferation was measured in a cell proliferation test, and the S50 value was less than 1 μM when combined with 3 Gy radiation to UT-SCC-54C HNSCC cells. (c) SER at 1 μM when combined with radiation to UT-SCC-54c HNSCC cells as determined by the scheme described in Example 178. 10 The value of exceeds 1.5, and (d) When measuring the ability of a compound to make tumor cells sensitive to increased radiation doses by inhibiting clonal survival, when used in combination with radiation on UT-SCC-54C HNSCC cells at a concentration of 1 μM, SER 10 The value must exceed 1.5. In one embodiment, the present invention relates to SER under oxygen-deficient conditions, as determined by the scheme enumerated in Example 178. 10 The present invention provides compounds whose value is greater than 1.5 and whose formula is one of formulas V, VI, and VII.

[0195] In one embodiment, the present invention relates to compounds 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 35, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54 , 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 94, 95, 96, 97, 98, 99, 104, 105, 110, 115, 116, 121 ,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,141,146,147,152,153,157,162,163,167,172,173,178,179,184,185,190,195,196,197,198,199 The present invention provides compounds selected from the group consisting of 200, 205, 206, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 230, 234, 236, 238, 240, 242, 246, 247, 248, 250, 251, 252, 253, 254, 255, 256, 258, and 260.

[0196] In one embodiment of the present invention, the present invention provides a compound selected from the group consisting of 121, 125, 127, 135, 172, 225, 230, 238, 248, and 260.

[0197] The compounds of the present invention can be prepared using the methods and processes described herein or similar methods and processes. Methods for obtaining the compounds described herein will be obvious to those skilled in the art; for example, suitable methods are described in the reaction schemes and references cited below. It should be understood that, where typical or preferred process conditions (e.g., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are indicated, other process conditions may also be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants used.

[0198] Conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be easily determined by those skilled in the art, as can be seen as suitable protecting groups for various functional groups and appropriate conditions for the protection and deprotection of specific functional groups (see, for example, TW Greene and GMWuts, Protecting Groups in Organic Synthesis, 3rd edition, Wiley, New York, 1999).

[0199] The starting materials useful for these methods and reactions are commercially available or can be prepared by known methods or modifications thereof, as described in standard references such as Fischer and Fischer's Organic Synthesis Reagents, Volumes 1-15 (John Wiley and Sons, 1991), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (John Wiley and Sons, 4th edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0200] Where appropriate, various starting materials, intermediates, and compounds can be isolated and purified using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Characterization of compounds can be carried out using conventional methods such as melting point, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses.

[0201] For example, a compound of formula I or a pharmacoposly acceptable salt thereof is [ka] It can be created following the general scheme below.

[0202] First, 2,4-dichloro-5-nitropyridine is reacted with an amine to produce the compound of formula VIII. [ka] The amine may be an alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, or heteroarylamine, and may be substituted. Other functional groups present in the amine can be protected according to standard protection strategies.

[0203] Next, the compound of formula VIII is reduced using a reducing agent such as tin chloride dihydrate, zinc powder, or ammonium chloride to form the compound of formula IX. However, Y is defined as described above. [ka] Next, compound IX of formula is reacted with carbonyldiimidazole or a similar reagent to form compound X of formula, where Y is defined as described above. [ka] A compound of formula X is reacted with an optionally substituted alkyl, cycloalkyl, alkenylaryl, or benzyl halide under basic conditions to form a compound of formula XI, where X and Y are defined as described above. [ka] Next, the compound of formula XI is reacted with an optionally substituted arylamine or heteroarylamine using an acid catalyst or palladium-mediated catalyst to form the compound of formula I.

[0204] The compound of formula V can be stably used to produce the carbamoyl chloride of formula XII by reacting it with the compound of formula I and a carbamoylating agent such as phosgene, bisphosgene, or triphosgene. This can then be purified, isolated, and reacted with various nitroaromatic alcohols to form the carbamate of formula V. [ka] Compounds of formula VI can be prepared from compounds of formulas I-IV by reacting phenol with a nitroheteroarylalkyl halide under basic conditions. Further examples of compounds of formula VI can be prepared by quaternizing a suitable tertiary amine side chain on compounds of formulas I-VI with a nitroheteroarylalkyl halide.

[0205] It should be understood that some of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated before or immediately after the above method by conventional functional group modification. For example, the compound of formula I can be further converted to the compound of formula I by standard aromatic substitution reactions or conventional functional group modification. Such reactions and modifications include, for example, the introduction of substituents by aromatic substitution reactions, the reduction of substituents, the alkylation of substituents, and the oxidation of substituents. The reagents and reaction conditions for such methods are known in the chemical field. Specific examples of aromatic substitution reactions include the introduction of nitro using concentrated nitric acid, the introduction of acyls using, for example, acyl halides and Lewis acids (e.g., aluminum trichloride) under Friedel-Crafts conditions, and the introduction of halogen groups. Specific examples of modifications include, for example, the reduction of nitro to amino by catalytic hydrogenation with a nickel catalyst or by iron treatment by heating in the presence of hydrochloric acid. Alkylthios are oxidized to alkylsulfinyls or alkylsulfonyls.

[0206] Referring to (1) below, 4-chloro-5-nitropyridine-2-ol (1) is treated with phosphorus oxychloride and tetramethylammonium chloride to obtain dichloride 2. Chloride 2 is substituted with cyclopentaamine to obtain nitroamine 3, and tin chloride dihydrate 3 is reduced to obtain diamine 4. 4 is reacted with carbonyldiimidazole to obtain pyridoimidazolone 5, and this pyridoimidazolone is alkylated with sodium hydride and methyl iodide to obtain chloride 6. The chloride of 6 is substituted with aniline using Buchwald conditions to obtain compound 7.

[0207] [ka] Similarly, compounds 8-81 can be obtained by reacting chloride 6 with various anilines and heteroarylamines under Buchwald conditions (Scheme 2).

[0208] [ka] [Table 1-1] [Table 1-2] [Table 1-3] Nitro-substituted compounds 14-16 were reduced with Pd / C under hydrogen gas to obtain the corresponding anilines 82-84 (Scheme 3).

[0209] [ka] [Table 2] Benzyl ethers 34-36 are reduced by Pd / C under hydrogen gas to obtain the corresponding phenols 85-87 (Scheme 4). Similarly, phenol 88 is obtained by reducing benzyl ether 51.

[0210] [ka] [Table 3] Imidazolone 5 is alkylated with NaH and various alkyl halides to obtain chlorides 89-93 (Scheme 5). Under Buchwald conditions, chlorides 89-93 are substituted to obtain the corresponding imidazopyridinones 94-98. Benzyl ether is reduced to 98 to obtain alcohol 99.

[0211] [ka] [Table 4] Chloride 2 is substituted with 2-methoxyethylamine to obtain nitroamine 100, and 100 is reduced with tin chloride dihydrate to obtain diamine 101 (Scheme 6). 101 is reacted with carbonyldiimidazole to obtain pyridinoimidazolone 102, and this pyridinoimidazolone is alkylated with sodium hydride and methyl iodine to obtain chloride 103. Chloride 103 is substituted with 4-methoxy-2-methylaniline or 4-chloro-2-methylaniline using Buchwald conditions to obtain the corresponding compounds 104 (SN39478) and 105 (SN39551).

[0212] [ka] Chloride 2 is substituted with oxetane-3-amine to obtain nitroamine 106, and 106 is reduced with tin chloride dihydrate to obtain diamine 107 (Scheme 7). 107 is reacted with carbonyldiimidazole to obtain pyridinoimidazolone 108, and this pyridinoimidazolone is alkylated with sodium hydride and methyl iodine to obtain chloride 109. The chloride of 109 is substituted with 4-methoxy-2-methylaniline using Buchwald conditions to obtain compound 110.

[0213] [ka] Chloride 2 is substituted with tetrahydrofuran-3-amine to obtain nitroamine 111, and 111 is reduced with tin chloride dihydrate to obtain diamine 112 (Scheme 8). 112 is reacted with carbonyldiimidazole to obtain pyridinoimidazolone 113, and this pyridinoimidazolone is alkylated with sodium hydride and methyl iodine to obtain chloride 114. Chloride 114 is substituted with 4-methoxy-2-methylaniline or 4-chloro-2-methylaniline using Buchwald conditions to obtain the corresponding compounds 115 (SN39878) and 116 (SN39881).

[0214] [ka] Chloride 2 is substituted with tetrahydro-2H-pyran-4-amine to obtain nitroamine 117, and 117 is reduced with tin chloride dihydrate to obtain diamine 118 (Scheme 9). 118 is reacted with carbonyldiimidazole to obtain pyridinoimidazolone 119, and this pyridinoimidazolone is alkylated with sodium hydride and methyl iodine to obtain chloride 120. The chloride of 120 is substituted with various amines using Buchwald conditions to obtain compounds 121-132.

[0215] [ka] [Table 5] Imidazopyridinones 121 and 122 were reacted with benzylchloroformic acid and iPr2NEt to obtain the corresponding carbamates 133 (SN39689) and 134 (SN39690) (Scheme 10).

[0216] [ka] Benzyl ether 124 is reduced with Pd / C under hydrogen gas to obtain the corresponding phenol 135 (SN39872) (Scheme 11).

[0217] [ka] Ester 129 is hydrolyzed under basic conditions to obtain acid 136 (SN40071) (Scheme 12).

[0218] [ka]

[0219] Chloride 2 is substituted with (tetrahydro-2H-pyran-4-yl)methylamine to obtain nitroamine 137, and 137 is reduced with zinc powder and ammonium chloride to obtain diamine 138 (Scheme 13). 138 is reacted with carbonyldiimidazole to obtain pyridinoimidazolone 139, and this pyridinoimidazolone is alkylated with sodium hydride and methyl iodine to obtain chloride 140. The chloride of 140 is substituted with 4-methoxy-2-methylaniline using Buchwald conditions to obtain compound 141 (SN39667).

[0220] [ka] Chloride 2 is substituted with 2-(tetrahydro-2H-pyran-4-yl)ethane-1-amine to obtain nitroamine 142, and 142 is reduced with zinc powder and ammonium chloride to obtain diamine 143 (Scheme 14). 143 is reacted with carbonyldiimidazole to obtain pyridinoimidazolone 144, and this pyridinoimidazolone is alkylated with sodium hydride and methyl iodine to obtain chloride 145. The chloride of 145 is substituted with 4-methoxy-2-methylaniline or 4-chloro-2-methylaniline, and the corresponding compounds 146 (SN39550) and 147 (SN39552) are obtained using Buchwald conditions.

[0221] [ka] Substitution of 4-aminopiperidine-1-carboxylic acid with t-butyl chloride 2 yields nitroamine 148, and reduction of 148 with zinc powder and ammonium chloride yields diamine 149 (Scheme 15). Reaction of 149 with carbonyldiimidazole yields pyridinoimidazolone 150, and alkylation of this pyridinoimidazolone with sodium hydride and methyl iodine yields chloride 151. Substitution of the chloride of 151 with 4-methoxy-2-methylaniline under Buchwald conditions yields carbamate 152 (SN39598). Hydrolysis of carbamate 152 under acidic conditions yields compound 153 (SN39600) as the hydrochloride salt.

[0222] [ka] Imidazopyridinone 152 is reacted with benzoylchloroformic acid to obtain carbamate 154 (Scheme 16). Acid hydrolysis of 154 yields amine 155. 155 is reduced and aminated with formaldehyde and sodium triacetoxyborohyde to obtain amine 156, which is converted to compound 157 (SN39686) under reducing conditions.

[0223] [ka]

[0224] Chloride 2 is substituted with 4-(aminomethyl)piperidine-1-carboxylate t-butyl to obtain nitroamine 158, and 158 is reduced with zinc powder and ammonium chloride to obtain diamine 159 (Scheme 17). 159 is reacted with carbonyldiimidazole to obtain pyridinoimidazolone 160, and this pyridinoimidazolone is alkylated with sodium hydride and methyl iodine to obtain chloride 161. The chloride of 161 is substituted with 4-methoxy-2-methylaniline using Buchwald conditions to obtain carbamate 162 (SN39627). Carbamate 162 is hydrolyzed to obtain amine 163 (SN39628) as the hydrochloride salt.

[0225] [ka] Imidazopyridinone 162 is reacted with benzoylchloroformic acid to obtain carbamate 164 (Scheme 18). Acid hydrolysis of 164 yields amine 165. 165 is reduced and aminated with formaldehyde and sodium triacetoxyborohydride to obtain amine 166, which is converted to compound 167 (SN39687) under reducing conditions.

[0226] [ka] Chloride 2 is substituted with 4-methoxycyclohexane-1-amine to obtain nitroamine 168, and 168 is reduced with tin chloride dihydrate to obtain diamine 169 (Scheme 19). 169 is reacted with carbonyldiimidazole to obtain pyridinoimidazolone 170, and this pyridinoimidazolone is alkylated with sodium hydride and methyl iodine to obtain chloride 171. The chloride of 171 is substituted with 4-methoxy-2-methylaniline or 4-chloro-2-methylaniline, and the corresponding compounds 172 (SN39540) and 173 (SN39539) are obtained using Buchwald conditions.

[0227] [ka] Chloride 2 is substituted with 4-(benzyloxy)cyclohexane-1-amine to obtain nitroamine 174, and 174 is reduced with tin chloride dihydrate to obtain diamine 175 (Scheme 20). 175 is reacted with carbonyldiimidazole to obtain pyridinoimidazolone 176, and this pyridinoimidazolone is alkylated with sodium hydride and methyl iodine to obtain chloride 177. The chloride of 177 is substituted with 4-methoxy-2-methylaniline using Buchwald conditions to obtain compound 178 (SN39581). Benzyl ether 178 is hydrolyzed to obtain alcohol 179 (SN39584).

[0228] [ka] Chloride 2 is substituted with t-butyl (4-aminocyclohexyl)carbamate to obtain nitroamine 180, and 180 is reduced with zinc powder and ammonium formate to obtain diamine 181 (Scheme 21). 181 is reacted with carbonyldiimidazole to obtain pyridinoimidazolone 182, and this pyridinoimidazolone is alkylated with sodium hydride and methyl iodine to obtain chloride 183. The chloride of 183 is substituted with 4-methoxy-2-methylaniline using Buchwald conditions to obtain compound 184. Carbamate 184 (SN40297) is acid hydrolyzed to obtain amine 185 (SN39695).

[0229] [ka] Chloride 2 is substituted with aniline to obtain nitroamine 186, and tin chloride dihydrate 186 is reduced to obtain diamine 187 (Scheme 22). 187 is reacted with carbonyldiimidazole to obtain pyridinoimidazolone 188, and this pyridinoimidazolone is alkylated with sodium hydride and methyl iodine to obtain chloride 189. Chloride 189 is substituted with 4-methoxy-2-methylaniline using Buchwald conditions to obtain 190 (SN39623).

[0230] [ka] Chloride 2 is substituted with an anisoamine to obtain nitroamine 191, and tin chloride dihydrate 191 is reduced to obtain diamine 192 (Scheme 23). 192 is reacted with carbonyl diimidazole to obtain pyridinoimidazolone 193, and this pyridinoimidazolone is alkylated with sodium hydride and methyl iodine to obtain chloride 194. The chloride of 194 is substituted with various anilines using Buchwald conditions to obtain compounds 195-199.

[0231] [ka] [Table 6] Benzyl ether 199 is reduced by Pd / C under hydrogen to obtain the corresponding phenol 200 (SN39530) (Scheme 24).

[0232] [ka] Chloride 2 is substituted with 4-(benzyloxy)aniline to obtain nitroamine 201, and 201 is reduced with tin chloride dihydrate to obtain diamine 202 (Scheme 25). 202 is reacted with carbonyldiimidazole to obtain pyridinoimidazolone 203, and this pyridinoimidazolone is alkylated with sodium hydride and methyl iodine to obtain chloride 204. The chloride of 204 is substituted with 4-methoxy-2-methylaniline under Buchwald conditions to obtain compound 205 (SN39525). Benzyl ether 205 is reduced by Pd / C under hydrogen to obtain the corresponding phenol 206 (SN39528).

[0233] [ka] Chloride 2 is substituted with 2-(4-aminophenyl)-2-methylpropanenitrile to obtain nitroamine 207, and tin chloride dihydrate 207 is reduced to obtain diamine 208 (Scheme 26). 208 is reacted with carbonyldiimidazole to obtain pyridinoimidazolone 209, and this pyridinoimidazolone is alkylated with sodium hydride and methyl iodine to obtain chloride 210. Using Buchwald conditions, the chloride of 210 is substituted with various anilines to obtain compounds 211-214.

[0234] [ka] [Table 7] Using improved Buchwald conditions, chloride 120 was substituted with another aniline (Scheme 9) to obtain compounds 215-226 (Scheme 27).

[0235] [ka] [Table 8] Imidazopyridinone 124 is reacted with di-t-butyl dicarbonate to obtain carbamate 227 (Scheme 28). 227 is hydrolyzed to obtain phenol 228. Under basic conditions, 228 is alkylated with 2-chloro-N,N-dimethylethyl-1-aminochloride to obtain ether 229, and this ether is protected under acidic conditions to obtain imidazopyridinone 230 (SN40558).

[0236] [ka] Imidazopyridinone 51 is reacted with di-t-butyl dicarbonate to obtain carbamate 231 (Scheme 29). 231 is hydrolyzed to obtain phenol 232. 232 is alkylated with 5-(bromomethyl)-1-methyl-2-nitro-1H-imidazole under basic conditions to obtain ether 233, and this ether is protected under acidic conditions to obtain prodrug 234 (SN39586).

[0237] [ka] Phenol 228 (Scheme 28) is alkylated with 5-(chloromethyl)-1-methyl-2-nitro-1H-imidazole, 5-(1-chloroethyl)-1-methyl-2-nitro-1H-imidazole, or (1-methyl-5-nitro-1H-imidazole-2-yl)methanol under basic conditions to obtain ethers 235, 237, and 238. Phenol 228 is also alkylated with (5-nitrothiophenol-2-yl)methanol under Mitsunobu conditions to obtain ether 241. Esters 235, 237, 239, and 241 are protected under acidic conditions to obtain prodrugs 236, 238, and 240 (Scheme 30).

[0238] [ka] [Table 9] Imidazopyridinone 199 is reacted with di-t-butyl dicarbonate to obtain carbamate 243 (Scheme 31). 243 is hydrolyzed to obtain phenol 244. 244 is alkylated with 5-(chloromethyl)-1-methyl-2-nitro-1Himidazole under basic conditions to obtain ether 245, and this ether is protected under acidic conditions to obtain prodrug 246 (SN39591).

[0239] [ka] Imidazopyridinone 48 is reacted with triphosgene and NaHCO3 to form the intermediate carbamoyl chloride, which is then reacted with 5-(hydroxymethyl)-1-methyl-2-nitro-1H-imidazole to obtain prodrug 247 (SN39725) (Scheme 32).

[0240] [ka] Imidazopyridinone 121 is reacted with triphosgene and NaHCO3 to form an intermediate carbamoyl chloride, which is then reacted with 5-(hydroxymethyl)-1-methyl-2-nitro-1H-imidazole, DMAP and K2CO3 to obtain prodrug 248 (SN39884) (Scheme 33). Process optimization involves isolating intermediate carbamoyl chloride 249 before reacting it with 1-(1-methyl-2-nitro-1H-imidazole-5-yl)ethane-1-ol or (1-methyl-5-nitro-1H-imidazole-2-yl)methanol to form prodrugs 250 (SN40425) and 251 (SN40353).

[0241] [ka] Imidazopyridinone 153 is reacted with (1-methyl-2-nitro-1H-imidazole-5-yl)methyl(4-nitrophenyl)carbonate to obtain prodrug 252 (SN40275) (Scheme 34).

[0242] [ka] Imidazopyridinone 185 is reacted with (1-methyl-2-nitro-1H-imidazole-5-yl)methyl(4-nitrophenyl)carbonate to obtain prodrug 253 (SN40302) (Scheme 35).

[0243] [ka] Imidazopyridinones 129, 225, and 130 were reacted with triphosgene and NaHCO3 to form carbamoyl chloride intermediates, which were then reacted with 5-(hydroxymethyl)-1-methyl-2-nitro-1Himidazole and Cs2CO3 to obtain prodrugs 254-256 (Scheme 36).

[0244] [ka] [Table 10] Imidazopyridinones 122, 172, and 195 were reacted with triphosgene and NaHCO3 to form carbamoyl chloride intermediates, which were then reacted with 5-(hydroxymethyl)-1-methyl-2-nitro-1Himidazole and Cs2CO3 to obtain prodrugs 257-259 (Scheme 37).

[0245] [ka] [Table 11] After converting imidazopyridinedione 230 to a free base, it is reacted with 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole to obtain the quaternary ammonium salt (SN40564) 260 (Scheme 38).

[0246] [ka] 5.4 Use of the Compounds of the Present Invention in Cancer Treatment The demonstrated DNA-PK inhibitory activity of the compounds of the present invention makes them useful therapeutic agents for a range of diseases, including cancer. In particular, the compounds of the present invention are useful as antitumor agents. Although theoretical limitations are undesirable, the inventors believe that the DNA-PK inhibitor compounds described herein are useful as antiproliferative agents, apoptotic agents, and / or anti-invasive agents in the treatment or prevention of solid and liquid tumors that are sensitive to DNA-PK inhibition, or at least partially mediated by DNA-PK.

[0247] Accordingly, in one embodiment, the present invention provides a method for treating a disease in which inhibition of DNA-PK is a necessary benefit in a subject, comprising administering to the subject a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, or VII or a pharmaceutically acceptable salt thereof.

[0248] In another aspect, the present invention provides the use of compounds of formula I, II, III, IV, V, VI, or VII or pharmaceutically acceptable salts thereof in the manufacture of pharmaceuticals for the treatment of diseases in which inhibition of DNA-PK is beneficial.

[0249] In another embodiment, the present invention provides compounds of formula I, II, III, IV, V, VI, or VII or pharmaceutically acceptable salts thereof for treating diseases in which inhibition of DNA-PK is beneficial.

[0250] In one embodiment, the disease is cancer.

[0251] In one embodiment, cancer is a solid tumor that includes, but is not limited to, carcinoma, sarcoma, leukemia, and lymphoid malignancy.

[0252] In one embodiment, cancer includes leukemia (including chronic lymphocytic leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and multiple myeloma); lymphomas such as Hodgkin's disease and non-Hodgkin lymphoma (including mantle cell lymphoma); and myelodysplastic syndromes; as well as solid tumors and their metastatic cancers, such as breast cancer, lung cancer (non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), squamous cell carcinoma), endometrial cancer; glioma, germ cell dysplastic neuroepithelial tumor, glioblastoma multiforme, mixed glioma, medulloblastoma, retinoblastoma, neuroblastoma, germ cell tumor and paradoxical tumor. The group is selected from central nervous system tumors such as cystoma, gastrointestinal cancers such as stomach cancer, esophageal cancer, hepatocellular (liver) cancer, bile duct cancer, colon and rectal cancer, small intestine cancer, and pancreatic cancer; skin cancers such as melanoma (especially metastatic melanoma), thyroid cancer, head and neck cancer, and salivary gland cancers, bile duct, bone, prostate, testes, ovaries, cervix, uterus, vulva, bladder, kidney (including renal cell carcinoma, clear cell carcinoma, and renal tumor cell tumor), squamous cell carcinoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, Ewing's sarcoma (a soft tissue sarcoma), gastrointestinal stromal tumors (GIST), Kaposi's sarcoma, and childhood cancers such as rhabdomyosarcoma and neuroblastoma.

[0253] In one embodiment, the cancer is a tumor containing a significantly hypoxic fraction.

[0254] In one embodiment, the cancer is selected from the group consisting of squamous cell carcinoma (including head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC)), pancreatic ductal adenocarcinoma, cervical cancer, and prostate cancer.

[0255] The method of the present invention involves administering a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt or solvate thereof, to a subject requiring such an amount.

[0256] A therapeutically effective dose is capable of inducing any observable or measurable change in the subject, as defined above in the definitions of "therapy," "treatment," and "prophylaxis."

[0257] For example, in the treatment of cancer, a therapeutically effective amount of the compound of the present invention can reduce the number of cancer or tumor cells, reduce the overall size of the tumor, inhibit or block the invasion of tumor cells into peripheral organs, such as soft tissues and bone, inhibit or block tumor metastasis, inhibit and block tumor growth, alleviate one or more cancer-related symptoms to some extent, reduce the incidence and mortality rates, improve quality of life, or achieve a combination of these effects.

[0258] The effectiveness of treatment can be measured by evaluating survival time, time to disease progression (TTP), remission rate (RR), duration of remission, and / or quality of life.

[0259] The therapeutically effective dose may vary depending on the route of administration, the use of excipients, and concomitant use with other drugs. For example, when used in combination therapy, the amount of the compound or pharmaceutically acceptable salt of the present invention described herein, and the amount of other pharmaceutically active drugs, when combined, can effectively treat the target disease of the subject.

[0260] Therefore, the anti-cancer effects useful for treating cancer in a subject include, but are not limited to, antitumor effects, response rates, time to disease progression, and survival rates. The antitumor effects of the therapeutic method of the present invention include, but are not limited to, inhibition of tumor growth, delay of tumor growth, tumor regression, tumor reduction, increased time to tumor regrowth after discontinuation of treatment, and delay of disease progression. The anti-cancer effects include not only preventive treatment but also treatment of existing diseases.

[0261] The therapeutic method of the present invention may include, but is not limited to, other treatments including, radiotherapy and / or chemotherapy, in addition to the administration of the compound of the present invention.

[0262] Radiation therapy may include one or more of the following treatment categories:

[0263] (a) External radiation therapy using electromagnetic radiation and intraoperative radiation therapy using electromagnetic radiation, (b) Internal radiotherapy or short-range radiotherapy, intratissue radiotherapy or intraluminal radiotherapy, and (c) Whole-body radiotherapy including, but not limited to, iodine-131 and strontium-89.

[0264] Modern radiotherapy is generally delivered by linear accelerators that generate high-energy X-rays that can be collimated to form a treatment field. Intensity-modulated radiotherapy (IMRT) uses a heterogeneous, computer-controlled radiation field to optimize delivery to tumor tissue rather than surrounding normal tissue. Standard fractionated radiotherapy (FRT) is typically performed in small doses (1.8–2.0 Gy) totaling 30–70 Gy over 4–7 weeks. Improvements in treatment planning and implementation have made low-fractionated radiotherapy possible, allowing for small, high doses (15–20 Gy) to be delivered to the tumor. This is called stereotactic radiotherapy (SBRT) or stereotactic ablation of brain radiation (SABR). High-energy charged particles such as protons and carbon ions are also useful in treating tumors, having the advantage of delivering most of the particle energy within the tumor. Brachytherapy, which delivers radiotherapy inside the patient using radioactive implants, is sometimes called intraoperative radiotherapy (IORT).

[0265] Chemotherapy may include one or more of the following types of antitumor substances:

[0266] (a) Antitumor agents and combinations thereof, e.g., DNA alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, isophosphamide, bendamostine, melphalan, chlorambucil, busulfan, temozolomide, and nitrogen mustards such as nitrosoureas); antimetabolites (e.g., gemcitabine and antifolic acid agents, e.g., fluoropyrimidines such as 5-fluorouracil and tegafur, larcitrexed, methotrexate, cytosine arabinoside and hydroxyurea); antitumor antibiotics (e.g., adriamycin, bleomycin, doxorubicin, liposomal doxorubicin) Anthracycline antibiotics such as cin, pirarubicin, daunomycin, barurubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, amrubicin, and mitramycin); antimitotic agents (e.g., vincristine alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine; paclitaxel-type drugs such as taxol and taxotere, and po kinase inhibitors); and topoisomerase inhibitors (epipodophyllotoxins such as etoposide, teniposide, amsacrin, irinotecan, topotecan, and camptothecin); DNA repair mechanism inhibitors such as CHK kinase; ATM inhibitors (AZD 0156 and AZD 1390, etc.); poly(ADP-ribose) polymerase inhibitors (PARP inhibitors including olaparib); Hsp90 inhibitors such as tanespimycin and letaspimycin; ATR kinase inhibitors (e.g., AZD6738) and WEE1 kinase inhibitors (AZD1775 / MK-1775, etc.); and (b) Immunotherapy, including both in vivo and in vivo methods, to increase the immunogenicity of a patient's tumor cells, such as transfection with cytokines like interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor; methods to reduce T cell inactivity or modulate T cell function; methods to enhance the T cell response to tumors, such as blocking antibodies against CTLA4 (e.g., ipilimumab and tremelimumab), B7H1, PD-1 (e.g., BMS-936558 or AMP-514), PD-L-1 (e.g., MEDI4736 (durvalumab)), and agonist antibodies against CD137; Methods using transfected immune cells such as dendritic cells into which tokines have been introduced; methods using tumor cell lines transfected with cytokines; methods using antibodies against tumor-associated antigens and antibodies that deplete target cell types (e.g., unbound anti-CD20 antibodies such as rituximab, radiolabeled anti-CD20 antibodies Bexxar and Zevalin, and anti-CD54 antibody Campath); methods using anti-idiotype antibodies; methods for enhancing the function of natural killer cells; methods utilizing antibody-toxin conjugates (e.g., anti-CD33 antibody Mylotarg); immunotoxins such as mosetumomab-pasdotox; agonists of Toll-like permeator 7 or Toll-like permeator 9. In one embodiment, the present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, or VII or a pharmaceutically acceptable salt or solvate thereof to a subject in combination with radiotherapy, and administering the compound of formula I, II, III, IV, V, VI, or VII or a pharmaceutically acceptable salt or solvate thereof simultaneously with, alone, or sequentially with radiotherapy.

[0267] In one embodiment, radiotherapy is administered to the subject before, during, or after administration of a compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt or solvate thereof.

[0268] In one embodiment, the present invention provides the use of a compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical for treating cancer.

[0269] In one embodiment, the drug of the present invention is used to be administered simultaneously with, alone, or sequentially with, radiotherapy.

[0270] In one embodiment, radiotherapy is selected from the group consisting of IMRT, FRT, SBRT, SABR, and IORT.

[0271] One embodiment provides a method for treating cancer, comprising administering a therapeutically effective amount of a compound of formula I, II, III, IV, V, VI, or VII or a pharmaceutically acceptable salt or solvate thereof in combination with chemotherapy, wherein the compound of formula I, II, III, IV, V, VI, or VII or a pharmaceutically acceptable salt or solvate thereof is administered simultaneously with, alone, or sequentially with chemotherapy.

[0272] In one embodiment, chemotherapy is administered to the subject before, during, or after administration of a compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt or solvate thereof.

[0273] In one embodiment, the present invention provides the use of a compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt or solvate thereof, in the manufacture of a pharmaceutical for treating cancer.

[0274] In one embodiment, the drug of the present invention is used to be administered simultaneously with chemotherapy, alone, or sequentially.

[0275] Generally, compounds of formulas I, II, III, IV, V, VI, or VII, or their pharmaceutically acceptable salts or solvates, are permitted in concentrations of 2.5 to 5000 mg / m². 2The drug is administered to the subject at a unit dose within the range of the animal's body area, or approximately 0.05 to 100 mg / kg. Unit dose forms, such as tablets or capsules, generally contain, for example, 0.1 to 250 mg of the active ingredient. The dosage should be adjusted depending on the subject to be treated, the specific route of administration, any concomitant therapies, and the severity of the disease being treated. The optimal dosage is determined by the physician treating the subject.

[0276] The compounds of the present invention can be administered by any of several routes of administration, which include, for example, oral administration (e.g., aqueous or non-aqueous solution, or suspension, tablets, pills, powders, granules, pastes for tongue administration); sublingual; transanal, transrectal, or transvaginal (e.g., pessaries, creams, or foams); extra-gastrointestinal administration (e.g., intramuscular, intravenous, subcutaneous, or intra-shelter administration as a sterile solution or suspension); nasal; intraperitoneal; subcutaneous; transdermal (e.g., as a patch applied to the skin) or topical (e.g., as a cream, ointment, or spray applied to the skin). At least one compound and / or salt described herein can also be formulated for inhalation.

[0277] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula I, II, III, IV, V, VI, or VII, or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable excipients.

[0278] The pharmaceutical compositions of the present invention can be incorporated into dose-unit formulations for oral, topical, parenteral, inhalation, spray, or rectal administration. The term "injection" includes intravenous, intramuscular, subcutaneous, and extra-gastrointestinal injections, as well as the use of infusion techniques. One or more compounds may be present in combination with one or more non-toxic, pharmaceutically acceptable carriers, and may also be present in combination with other active ingredients as needed.

[0279] A "pharmaceutically acceptable carrier" is a pharmaceutically acceptable material, composition, or vehicle, such as a liquid, diluent, excipient, filler, solvent, or encapsulating material involved in the in vivo transport of the compound of interest. Each carrier is considered "acceptable" because it is compatible with the other components of the formulation and harmless to the subject. The pharmaceutically acceptable compositions of the present invention may further contain other activators that provide additional therapeutic functions.

[0280] Examples of substances that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose, cellulose acetate); (4) sawdust; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) propylene (11) Ethylene glycols such as glycols; (12) Polyhydric alcohols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (13) Esters such as ethyl oleate and ethyl laurate; (14) Agar; (15) Buffers such as magnesium hydroxide and aluminum hydroxide; (16) Alginic acid; (17) Water free of pyrogens; (18) Isotonic saline; (19) Ringer's solution; (10) Ethanol; (11) Phosphate buffer; (22) Other non-toxic compatible substances used in pharmaceutical formulations, but not limited to these. See Remington: The Science and Practice of Pharmacy, 20th edition, (edited by Alfonso R. Gennaro), 2000.

[0281] Pharmaceutical compositions intended for oral administration can be prepared according to any suitable method known in the art, and such compositions may contain one or more agents selected from the group consisting of diluents, sweeteners, flavoring agents, coloring agents, and preservatives to provide a flavorful formulation. Tablets contain an active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; and binders such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and provide a longer-lasting effect. For example, delaying materials such as glyceride monostearate or glyceride distearate can be used. These compounds can also be manufactured in a solid, rapidly released form.

[0282] The oral formulation may be a hard gelatin capsule containing the active ingredient mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, kaolin), or a soft gelatin capsule containing the active ingredient mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, olive oil).

[0283] The aqueous suspension comprises a mixture of the active substance and excipients suitable for producing the aqueous suspension. These excipients may be suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, granoco gum, and gum arabic; or dispersing or wetting agents which may be naturally occurring phospholipids such as lecithin, condensates with fatty acids, or alkylene oxides such as polyoxyethylene stearate, condensates of ethylene oxide and long-chain fatty alcohols such as hexadecinoloxycetyl alcohol, or condensates of ethylene oxide and partial esters derived from fatty acids and hexanol, such as polyoxyethylene sorbitol monooleate, or condensates of ethylene oxide and partial esters derived from fatty acids and hexanolic anhydride, such as polyethylene sorbitol monooleate. The aqueous suspension may further contain one or more preservatives such as ethyl p-hydroxybenzoate or n-propyl, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0284] Dispersible powders and particles suitable for preparing aqueous suspensions by adding water provide active ingredients mixed with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are, for example, those described above. Additional excipients such as sweeteners, flavorings, and colorants may also be present.

[0285] The pharmaceutical composition of the present invention may also be in the form of a non-aqueous liquid formulation, such as an oily suspension, in which the active ingredient can be suspended in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or peanut oil) or mineral oil (e.g., liquid paraffin). The oily suspension may contain thickeners such as beeswax, hard paraffin, or cetyl alcohol. By adding sweeteners and flavorings as described above, an oral formulation with a pleasant taste can be provided. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0286] The pharmaceutical composition of the present invention may also be in the form of an oil-in-water emulsion.

[0287] The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be natural gums such as gum arabic or gum furanoco, natural phospholipids such as soybeans and lecithin, and esters or partial esters derived from fatty acids and hexanolic anhydrides, such as dehydrated sorbitol monooleate and condensates of partial esters with ethylene oxide, such as polyoxyethylene dehydrated sorbitol monooleate. The emulsion may contain sweeteners and flavorings.

[0288] The pharmaceutical compositions for rectal, vaginal, or urethral administration described herein may be provided as suppositories, which are prepared by mixing one or more compounds or salts with one or more suitable non-irritating excipients or carriers, such as cocoa butter, polyethylene glycol, suppository wax, or salicylates, and are solid at room temperature but liquid at body temperature, thereby allowing the active compound to melt and be released in the rectal or vaginal cavity.

[0289] The pharmaceutical compositions described herein may be formulated for delivery via catheters, stents, wires, or other intraluminal devices. Delivery by such devices may be particularly useful for delivery to the bladder, urethra, ureters, rectum, or intestines.

[0290] Drug formulations administered topically or transdermally include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound can be mixed with pharmaceutically acceptable carriers under sterile conditions and with any necessary preservatives, buffers, or propellants. Ointments, pastes, creams, and gels may contain excipients or mixtures thereof, such as animal and vegetable fats, oils, waxes, paraffin, starch, xanthocomb, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide.

[0291] The powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof, in addition to the compounds described herein. The sprays may also contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0292] Transdermal patches have the additional advantage of providing controlled delivery to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to increase the flux that passes through the skin. The rate of such flux can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel. The ophthalmic preparations, ophthalmic ointments, powders, solutions, etc. of the present invention may also contain at least one of the compounds or salts described herein.

[0293] The pharmaceutical composition suitable for extra-gastrointestinal administration described in the present invention contains at least one compound of the present invention or a pharmaceutically acceptable salt thereof in combination with one or more pharmaceutically acceptable sterile or other permeable or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders, and can be reconstituted as a sterile injectable solution or dispersion before use, and may contain antioxidants, buffers, bacteriostatic agents, solutes or suspensions that are isotonic with the blood of the target subject to which the formulation is intended, or thickeners.

[0294] Suitable aqueous and non-aqueous carriers useful for pharmaceutical compositions include water, ethanol, polyhydric alcohols (e.g., glycerin, propylene glycol, polyethylene glycol, etc.) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by using a coating material such as lecithin, maintaining the desired particle size in the case of a dispersion, or by using a surfactant.

[0295] These compositions may further contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. By including various antibacterial and antifungal agents such as p-hydroxybenzoic acid esters, chlorobutanol, phenolsorbic acid, and chelating agents, control effects against microorganisms can be ensured.

[0296] In some embodiments, the composition may include isotonic agents, such as sugars or sodium chloride. Furthermore, by including delayed absorption agents such as aluminum monostearate or gelatin, extended absorption in the form of an injectable drug can be achieved.

[0297] 6. Example The following examples illustrate the present invention and detailed methods for producing these compounds. However, the scope of the present invention is not limited to these examples.

[0298] All final products were analyzed using an Achilen 1260 Infinity reversed-phase HPLC (ZORBAX Eclipse XDB C 8 5 μm column, 4.6 × 150 mm; Agilent Technologies) equipped with a diode array detector. The mobile phase was a gradient of 80% acetonitrile / 20% H2O (v / v) in 45 mM ammonium formate at pH 3.5 and 0.8 mL / min. The purity of the final compound was determined by monitoring at 330 ± 50 nM, and was >95%. The melting point was measured using an electrothermal 2300 melting point spectrometer. A Bruker Avance 400 spectrometer was used at 400 MHz. 1NMR spectra of the H spectrum were acquired. Chemical shifts were recorded in ppm and coupling constants in Hz. Low-resolution mass spectra were collected by directly injecting a methanol solution into an Agilent 6120 mass spectrometer using atmospheric pressure chemical ionization (APCI) mode with a fragmenter voltage of 50 V and a dry gas temperature of 250 °C. High-resolution mass spectra (HRMS) were measured on an Agilent Technologies 6530 Accurate-Mass Quadrupole Time of Flight (Q-TOF) LC / MS connected to an Agilent Jet Stream electrospray ionization (ESI) source, enabling detection of positive or negative ions. Organic solutions were dried with MgSO4 or Na2SO4, and the solvent was evaporated under reduced pressure using a rotary evaporator. Thin-layer chromatography was performed on an aluminum-backed silica gel plate (Merck 60 F). 254 The analysis was performed using ), and the components were visualized by exposure to UV light (254 nm) or I2. Column chromatography was performed on silica gel (Merck 230-400 mesh). BrettPhos G3 is [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, CDI is carbonyldiimidazole, Cs2CO3 is cesium carbonate, DCM is dichloromethane, DIPEA is diisopropylethylamine, DMAP is 4-dimethylaminopyridine, DMF is dimethylformamide, and DMSO is dimethylaminopyridine. In the formula, toluenesulfoxide, siRNA refers to ethyl acetate, EtOH to ethanol, MeOH to methanol, MeCN to acetonitrile, MgSO4 to magnesium sulfate, NMP to N-methylpyrrolidone, Pd2dba3 to tris(dibenzylideneacetone)dipalladium(0), pet.ether to petroleum ether boiling fraction at 40-60°C, THF to tetrahydrofuran, and XPhos to 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0299] Example 1: SN39228 1-Cyclopentyl-3-methyl-6-(phenylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(7) [ka] A mixture of 2,4-dichloro-5-nitropyridine(2):4-chloro-5-nitropyridine-2-ol(1) (5.38 g, 30.8 mmol), POCl3, and tetramethylammonium chloride (10.1 g, 32.5 mmol) was stirred at 120°C for 3 hours. The mixture was cooled and poured into ice / water (500 mL), and stirred at 0-10°C for 1 hour. The mixture was extracted with DCM (3 × 100 mL), and the mixed organic extract was dried with (MgSO4). The solution was filtered through a neutral alumina column and washed with DCM (50 mL). The solvent was evaporated to obtain nitropyridine 2 (5.43 g, 91%) as a clarified oil. 1 H NMR (CDCl3) δ 8.97 (s,1 H,H-6),7.59 (s,1 H,H-3); MS m / z 192.9 (MH + ,100%),194.9 (MH + 70%). 2-Chloro-N-cyclopentyl-5-nitropyridine-4-amine(3): To a solution of nitropyridine 2 (1.76 g, 9.12 mmol) and 2NEt (1.87 mL, 10.94 mmol) stirred in dry DCM (5 mL) at 5°C, cyclopentaamine (0.95 mL, 9.6 mmol) was added dropwise. This mixture was stirred at 20°C for 16 hours, then diluted with DCM (100 mL), washed with water (3 × 50 mL), dried (MgSO4), and the solvent was evaporated. The residue was purified by chromatography to obtain amine 3 (2.25 g, 100%) as a yellow oil eluted with 10% siRNA / petroleum ether. 1H NMR (CDCl3) δ 9.01 (s,1 H,H-6),8.17 (br s,1 H,4-NH),6.76 (s,1 H,H-3),3.93 (br dpent,J = 6.7,5.3 Hz,1 H,NCH),2.10-2.18 (m,2 H,CH2),1.70-1.88 (m,4 H,2 × CH2),1.59-1.69 (m,2 H,CH2); MS m / z 242.1 (MH + ,100%),244.1 (MH + 35%). 6-Chloro-N 4 -Cyclopentylpyridine-3,4-diamine(4): To a suspension of SnCl2·2H2O (7.16 g, 31.7 mmol) in HCl (100 ml), a solution of nitropyridine 3 (1.92 g, 7.93 mmol) in HCl (20 ml) was added dropwise at a temperature below 60°C. The mixture was stirred at 60°C for 2 hours, then cooled to 5°C and concentrated (solution). NH3 solution was added until the solution became basic (pH 9). The precipitate was filtered and washed with HCl (100 mL). The combined organic fraction was dried (MgSO4), filtered, and the solvent was evaporated to obtain diamine 4 as a white powder. mp 103-105 °C; 1 H NMR [(CD3)2SO] δ 7.35 (s,1 H,H-2),6.29 (s,1 H,H-5),5.48 (d,J = 6.2 Hz,1 H,4-NH),4.78 (br s,2 H,3-NH2),3.75 (br dpent,J = 6.7,5.3 Hz,1 MS m / z 212.2 (MH + ,100%),214.2 (MH + 35%). Anal calcd for C 10 H 14 ClN3·0.1 EtOAc: C,56.65; H,6.77; N,19.06. Found: C,56.66; H,6.84; N,19.20%. 6-Chloro-1-cyclopentyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(5): To a solution of diamine 4 (1.69 g, 7.98 mmol) in 80 ml of dry MeCN, CDI (1.36 g, 8.38 mmol) was added at 20°C. The mixture was stirred at 20°C for 96 hours. The solvent was evaporated, and the residue was partitioned between 150 ml of CHCl3 and 100 ml of water. The organic fraction was washed with water (2 × 50 ml), then with brine (50 ml), dried (MgSO4), filtered, and the solvent was evaporated. The residue was precipitated from 50% siRNA / petroleum ether to obtain pyridinone 5 (1.80 g, 95%) as a white powder. mp 222-224 °C; 1 H NMR (CDCl3) δ 9.76 (br s,1 H,3-NH),8.13 (s,1 H,H-4),7.01 (s,1 H,H-7),4.79 (pent,J = 8.7 Hz,1 H,1-CH),1.94-2.12 (m,6 H,3 × CH2),1.72-1.81 (m,2 H,CH2); MS m / z 238.2 (MH + ,100%),240.2 (MH + 35%). Anal calcd for C 11 H 12 ClN3O: C,55.59; H,5.09; N,17.68. Found: C,55.31; H,5.16; N,17.61%. 6-Chloro-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (6): A solution of pyridinone 5 (1.68 g, 7.1 mmol) and MeI (0.57 ml, 9.2 mmol) in dry DMF (20 ml), stirred at 5°C, was mixed with NaH (60% dispersion, 312 mg, 7.8 mmol). The mixture was stirred at 20°C for 16 hours, then quenched with ice / water (5 mL). The solvent was evaporated, and the residue was partitioned between ethyl acetate (100 ml) and water (50 ml). The organic fraction was washed with water (2 × 50 ml), then with brine (50 ml), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using ethyl acetate / petroleum ether on a gradient (40-50%) to obtain chloride 6 as white crystals. mp 141-142 °C; 1 H NMR (CDCl3) δ 7.98 (s,1 H,H-4),6.98 (s,1 H,H-7),4.81 (pent,J = 8.8 Hz,1 H,1-CH),3.44 (s,3 H,3-CH3),1.92-2.07 (m,6 H,3 × CH2),1.69-1.79 (m,2 H,CH2); MS m / z 252.2 (MH + ,100%),254.2 (MH + 35%). Anal calcd for C 12 H 14 ClN3O: C,56.26; H,5.61; N,16.69. Found: C,57.26; H,5.68; N,16.86%. A degassed mixture of 1-cyclopentyl-3-methyl-6-(phenylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(7):chloride 6 (120 mg, 0.48 mmol), aniline (53 mg, 0.57 mmol), Pd2dba3 (22 mg, 24 μmol), XPhos (46 mg, 96 μmol)Cs2CO3 (313 mg, 0.96 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with ethyl acetate (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (40-60%) of siRNA / petroleum ether to obtain imidazopyridinone 7 (84 mg, 57%) as a yellowish-brown powder. (mp (siRNA / pet ether) 168-170 °C) 1 H NMR (CDCl3) δ 7.83 (s,1 H,H-4),7.33 (br dd,J = 8.6,7.2 Hz,2 H,H-3',H-5'),7.26 (br d,J = 8.6 Hz,2 H,H-2',H-6'),7.01 (tt,J = 7.2,1.2 Hz,1 H,H-4'),6.64 (s,1 H,H-7),6.48 (s,1 H,6-NH),4.77 (pent,J = 8.8 Hz,1 H,1-CH),3.40 (s,3 H,3-CH3),1.95-2.05 (m,4 H,2 × CH2),1.81-1.90 (m,2 H,CH2),1.63-1.72 (m,2 H,CH2); MS m / z 309.2 (MH + ,100%). Anal calcd for C 18 H 20 N4O: C,70.11; H,6.54; N,18.17. Found: C,70.06; H,6.64; N,18.23%. HPLC purity 100.0%.

[0300] Example 2: SN39229 1-Cyclopentyl-3-methyl-6-(4-methylphenylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(8) [ka] A degassed mixture of chloride 6 (120 mg, 0.48 mmol), 4-methylaniline (61 mg, 0.57 mmol), Pd2dba3 (22 mg, 24 μmol), XPhos (46 mg, 96 μmol), and Cs2CO3 (313 mg, 0.96 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using elution with a gradient (40-60%) of HCl / petroleum ether to obtain imidazopyridinone 8 (99 mg, 64%) as a yellowish-brown powder. mp (EtOAc / pet ether) 153-154 °C; 1 H NMR (CDCl3) δ 7.80 (s,1 H,H-4),7.12-7.17 (m,4 H,H-2',H-3',H-5',H-6'),6.58 (d,J = 0.6 Hz,1 H,H-7),6.39 (s,1 H,6-NH),4.75 (pent,J = 8.8 Anal calcd for C 19 H 22 N4O: C,70.78; H,6.88; N,17.38. Found: C,70.39; H,7.21; N,17.43%. HPLC purity 98.5%.

[0301] Example 3: SN39231 1-Cyclopentyl-3-methyl-6-(3-methylphenylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(9) [ka] A degassed mixture of chloride 6 (120 mg, 0.48 mmol), 3-methylaniline (61 mg, 0.57 mmol), Pd2dba3 (22 mg, 24 μmol), XPhos (46 mg, 96 μmol), and Cs2CO3 (311 mg, 0.96 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using HCl / petroleum ether with a gradient (50-70%) to obtain imidazopyridinone 9 (131 mg, 85%) as a yellowish-brown powder. mp (EtOAc / pet ether) 124-126 °C; 1 H NMR (CDCl3) δ 7.82 (d,J = 0.6 Hz,1 H,H-4),7.21 (br t,J = 7.7 Hz,1 H,H-5'),7.03-7.10 (m,2 H,H-2',H-6'),6.85 (d,J = 7.5 Hz,1 H,H-4'),6.68 (d,J = 0.6 Hz,1 H,H-7),6.44 (s,1 H,6-NH),4.80 (pent,J = 8.8 Hz,1 H,1-CH),3.97 (s,3 H,3-CH3),2.34 (s,3 H,3'-CH3),1.94-2.05 (m,4 H,2 × CH2),1.82-1.90 (m,2 H,CH2),1.66-1.74 (m,2 H,CH2). Anal calcd for C 19 H 22 N4O: C,70.78; H,6.88; N,17.38. Found: C,70.50; H,6.99; N,17.56%. HPLC purity 99.7%.

[0302] Example 4: SN39232 1-Cyclopentyl-3-methyl-6-(2-methylphenylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (10) [ka] A degassed mixture of chloride 6 (120 mg, 0.48 mmol), 2-methylaniline (61 mg, 0.57 mmol), Pd2dba3 (22 mg, 24 μmol), XPhos (46 mg, 96 μmol), and Cs2CO3 (311 mg, 0.96 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (50-70%) of butyl / petroleum ether to obtain imidazopyridinone 10 (131 mg, 85%) as a yellowish-brown foam. 1 H NMR (CDCl3) δ 7.81 (d,J = 0.6 Hz,1 H,H-4),7.39 (d,J = 7.6 Hz,1 H,H-3'),7.24 (d,J = 7.4 Hz,1 H,H-6'),7.20 (br t,J = 7.7 Hz,1 H,H-4'),7.02 (dt,J = 7.4,1.1 Hz,1 H,H-5'),6.45 (d,J = 0.6 Hz,1 H,H-7),6.13 (s,1 H,6-NH),4.73 (pent,J = 8.8 Hz,1 H,1-CH),3.39 (s,3 H,3-CH3),2.29 (s,3 H,3'-CH3),1.92-2.02 (m,4 H,2 × MS m / z 323.2 (MH + ,100%). Anal calcd for C 19 H 22N4O·1 / 4EtOAc: C,70.35; H,6.94; N,16.92. Found: C,70.34; H,7.10; N,16.77%. HPLC purity 97.7%.

[0303] Example 5: SN39236 1-Cyclopentyl-6-((4-methoxyphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(11) [ka] A degassed mixture of chloride 6 (128 mg, 0.51 mmol), 4-methoxyaniline (75 mg, 0.61 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 102 μmol), and Cs2CO3 (331 mg, 1.02 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using a gradient (50-100%) of HCl / petroleum ether to obtain imidazopyridinone 11 (72 mg, 42%) as a brown powder. mp (EtOAc / pet ether) 159-161 °C; 1 H NMR (CDCl3) δ 7.77 (s,1 H,H-4),7.21 (ddd,J = 8.9,3.5,2.2 Hz,2 H,H-2',H-6'),6.91 (ddd,J = 8.9,3.5,2.2 Hz,2 H,H-3',H-5'),6.42 (s,1 H,H-7),6.27 (br s,1 H,6-NH),4.72 (pent,J = 8.8 Hz,1 H,1-CH),3.82 (s,3 H,4'-OCH3),3.38 (s,3 H,3-CH3),1.93-2.02 (m,4 H,2 × CH2),1.78-1.88 (m,2 H,CH2),1.63-1.72 (m,2 H,CH2); MS m / z 339.2 (MH+ ,100%). Anal calcd for C 19 H 22 N4O2·1 / 4EtOAc: C,66.65; H,6.71; N,15.54. Found: C,66.29; H,6.57; N,15.90%. HPLC purity 98.1%.

[0304] Example 6: SN39239 1-Cyclopentyl-6-((3-methoxyphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(12) [ka] A degassed mixture of chloride 6 (126 mg, 0.50 mmol), 3-methoxyaniline (74 mg, 0.60 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (47 mg, 102 μmol), and Cs2CO3 (326 mg, 1.02 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography to obtain imidazopyridinone 12 (136 mg, 80%) as a yellowish-brown powder eluted with HCl. mp (EtOAc / pet ether) 66-69 °C; 1H NMR (CDCl3) δ 7.83 (d,J = 0.4 Hz,1 H,H-4),7.22 (t,J = 8.1 Hz,1 H,H-5'),6.89 (t,J = 2.3 Hz,1 H,H-2'),6.82 (dd,J = 8.0,1.4 Hz,1 H,H-6'),6.68 (d,J = 0.6 Hz,1 H,H-7),6.57 (ddd,J = 8.2,2.4,0.7 Hz,1 H,H-4'),6.49 (s,1 H,6-NH),4.79 (pent,J = 8.8 Hz,1 H,1-CH),3.80 (s,3 H,3'-OCH3),3.40 (s,3 H,3-CH3),1.95-2.06 (m,4 H,2 × CH2),1.80-1.92 (m,2 H,CH2),1.62-1.72 (m,2 H,CH2); MS m / z 339.2 (MH + ,100%). Anal calcd for C 19 H 22 N4O·1 / 2H2O: C,65.69; H,6.67; N,16.13. Found: C,65.42; H,6.36; N,15.92%. HPLC purity 99.7%.

[0305] Example 7: SN39240 1-Cyclopentyl-6-(2-methoxyphenylamino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(13) [ka] A degassed mixture of chloride 6 (110 mg, 0.44 mmol), 2-methoxyaniline (65 mg, 0.52 mmol), Pd2dba3 (20 mg, 22 μmol), XPhos (42 mg, 88 μmol), and Cs2CO3 (285 mg, 0.88 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (60-100%) of acetone / petroleum ether to obtain imidazopyridinone 13 (135 mg, 91%) as a yellowish-brown powder. 1 H NMR (CDCl3) δ 7.83-7.90 (m,2 H,H-4,H-6'),7.89-6.98 (m,3 H,H-3',H-4',H-5'),6.83 (s,1 H,6-NH),6.61 (s,1 H,H-7),4.78 (pent,J = 8.8 Hz,1 MS m / z 338.4 (MH + ,100%); HRMS calcd for C 19 H 23 N4O2(MH + ) m / z 339.1816,found 339. 1819 (-1.0 ppm). HPLC purity 99.9%.

[0306] Example 8: SN39241 6-((4-chlorophenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(14) [ka] A degassed mixture of chloride 6 (119 mg, 0.47 mmol), 4-chloroaniline (72 mg, 0.57 mmol), Pd2dba3 (22 mg, 24 μmol), XPhos (45 mg, 95 μmol), and Cs2CO3 (308 mg, 0.95 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The solvent was evaporated after filtration. The residue was purified by chromatography using a gradient (40-60%) of HCl / petroleum ether to obtain imidazopyridinone 14 (80 mg, 49%) as a brown powder. mp (HCl / pet ether) 179-181 °C; 1 H NMR (CDCl3) δ 7.83 (s,1 H,H-4),7.22-7.18 (m,4 H,H-2',H-3',H-5',H-6'),6.54 (s,1 H,H-7),6.43 (s,1 H,6-NH),4.76 (pent,J = 8.8 Hz,1 MS m / z 343.2 (MH + ,100%),345.2 (MH + 35%). Anal calcd for C 18 H 19 ClN4O·0.1EtOAc: C,62.65; H,5.76; N,15.54. Found: C,62.56; H,5.62; N,15.84%. HPLC purity 99.0%.

[0307] Example 9: SN39242 6-((3-chlorophenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(15) [ka] A degassed mixture of chloride 6 (132 mg, 0.52 mmol), 3-chloroaniline (80 mg, 0.63 mmol), Pd2dba3 (24 mg, 26 μmol), XPhos (50 mg, 104 μmol), and Cs2CO3 (339 mg, 1.04 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using HCl / petroleum ether with a gradient (50-75%) to obtain imidazopyridinone 15 (110 mg, 62%) as a yellowish-brown powder. mp (EtOAc / pet ether) 145-147 °C; 1 H NMR (CDCl3) δ 7.86 (d,J = 0.6 Hz,1 H,H-4),7.40 (t,J = 2.1 Hz,1 H,H-2'),7.22 (t,J = 8.0 Hz,1 H,H-5'),7.11 (ddd,J = 8.2,2.1,0.9 Hz,1 H,H-6'),6.95 (ddd,J = 7.9,2.0,1.0 Hz,1 H,H-4'),6.62 (d,J = 0.6 Hz,1 H,H-7),6.51 (s,1 H,6-NH),4.81 (pent,J = 8.8 Hz,1 H,1-CH),3.41 (s,3 H,3-CH3),1.97-2.08 (m,4 H,2 × MS m / z 343.2 (MH + ,100%),345.2 (MH + 35%). Anal calcd for C 18 H 19 ClN4O·0.1EtOAc: C,62.85; H,5.68; N,15.93. Found: C,62.73; H,5.54; N,15.94%. HPLC purity 99.9%.

[0308] Example 10: SN39245 6-((2-chlorophenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(16). [ka] A degassed mixture of chloride 6 (130 mg, 0.52 mmol), 2-chloroaniline (80 mg, 0.62 mmol), Pd2dba3 (24 mg, 26 μmol), XPhos (50 mg, 104 μmol), and Cs2CO3 (339 mg, 1.04 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography eluting with a gradient (5-10%) of HCl / DCM to obtain imidazopyridinone 16 (79 mg, 45%) as a brown foam. 1 H NMR (CDCl3) δ 7.90 (dd,J = 8.3,1.5 Hz,1 H,H-6'),7.87 (s,1 H,H-4),7.39 (dd,J = 8.0,1.5 Hz,1 H,H-3'),7.23 (dt,J = 8.5,1.5 Hz,1 H,H-5'),6.90 (dt,J = 7.9,1.5 Hz,1 H,H-4'),6.74 (br s,1 H,6-NH),6.61 (s,1 H,H-7),4.77 (pent,J = 8.8 Hz,1 H,1-CH),3.41 (s,3 H,3-CH3),1.98-2.08 (m,4 H,2 × CH2),1.86-1.96 (m,2 H,CH2),1.68-1.77 (m,2 H,CH2); MS m / z 343.2 (MH + ,100%),345.2 (MH + ,35%); HRMS calcd for C 18 H 20 ClN4O (MH+ ) m / z 343.1320,found 343.1318 (0.5 ppm). HPLC purity 98.4%.

[0309] Example 11: SN39246 1-Cyclopentyl-3-methyl-6-(4-nitrophenylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (17). [ka] A degassed mixture of chloride 6 (131 mg, 0.52 mmol), 4-nitroaniline (86 mg, 0.63 mmol), Pd2dba3 (24 mg, 26 μmol), XPhos (50 mg, 104 μmol), and Cs2CO3 (339 mg, 1.04 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using a gradient (50-100%) of HCl / petroleum ether to obtain imidazopyridinone 17 (127 mg, 69%) as red crystals. mp (siRNA / petroleum ether) 270-272 °C; 1 H NMR (CDCl3) δ 8.18 (ddd,J = 9.2,3.1,2.1 Hz,2 H,H-3',H-5'),7.94 (s,1 H,H-4),7.46 (ddd,J = 9.2,3.1,2.1 Hz,2 H,H-2',H-6'),6.94 (br s,1 H,6-NH),6.64 (d,J = 0.5 Hz,1 H,H-7),4.82 (pent,J = 8.8 Hz,1 H,1-CH),3.44 (s,3 H,3-CH3),2.02-2.10 (m,4 H,2 × CH2),1.88-1.98 (m,2 H,CH2),1.70-1.80 (m,2 H,CH2); MS m / z 354.2 (MH +,100%). Anal calcd for C 18 H 19 N5O3: C,61.18; H,5.42; N,19.82. Found: C,61.29; H,5.29; N,19.94%. HPLC purity 100.0%.

[0310] Example 12: SN39247 1-Cyclopentyl-3-methyl-6-(3-nitropheniramino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (18) [ka] A degassed mixture of chloride 6 (131 mg, 0.52 mmol), 3-nitroaniline (86 mg, 0.63 mmol), Pd2dba3 (24 mg, 26 μmol), XPhos (50 mg, 104 μmol), and Cs2CO3 (339 mg, 1.04 mmol) in dioxane (6 mL) was stirred in a sealed tube at 0.120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using HCl / petroleum ether on a gradient (50-80%) to obtain imidazopyridinone 18 (147 mg, 80%) as a yellow powder. mp (EtOAc / pet ether) 184-186 °C; 1H NMR (CDCl3) δ 8.36 (t,J = 2.2 Hz,1 H,H-2'),7.91 (s,1 H,H-4),7.78 (ddd,J = 8.1,2.1,0.8 Hz,1 H,H-6'),7.59 (ddd,J = 8.1,2.0,0.8 Hz,1 H,H-4'),7.43 (t,J = 8.1 Hz,1 H,H-5'),6.75 (s,1 H,6-NH),6.61 (d,J = 0.4 Hz,1 H,H-7),4.83 (pent,J = 8.8 Hz,1 H,1-CH),3.43 (s,3 H,3-CH3),2.00-2.08 (m,4 H,2 × CH2),1.87-1.97 (m,2 H,CH2),1.70-1.78 (m,2 H,CH2); MS m / z 354.2 (MH + ,100%). Anal. calcd for C 18 H 19 N5O3: C,61.18; H,5.42; N,19.82. Found: C,60.98; H,5.29; N,19.82%. HPLC purity 99.9%.

[0311] Example 13: SN39263 1-Cyclopentyl-3-methyl-6-(2-nitrophenylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (19) [ka] A degassed mixture of chloride 6 (131 mg, 0.52 mmol), 2-nitroaniline (86 mg, 0.63 mmol), Pd2dba3 (24 mg, 26 μmol), XPhos (50 mg, 104 μmol), and Cs2CO3 (339 mg, 1.04 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography and eluted with 40% HCl / petroleum ether to obtain red crystalline imidazopyridinone 19 (161 mg, 88%). 1 H NMR (CDCl3) δ 10.10 (br s,1 H,6-NH),8.42 (dd,J = 8.8,1.2 Hz,1 H,H-3'),8.32 (dd,J = 8.6,1.6 Hz,1 H,H-6'),7.97 (s,1 H,H-4),7.51 (ddd,J = 8.4,7.1,1.4 Hz,1 H,H-5'),6.90 (ddd,J = 8.4,7.1,1.4 Hz,1 H,H-4'),6.68 (s,1 H,H-7),4.81 (pent,J = 8.8 Hz,1 H,1-CH),3.45 (s,3 H,3-CH3),1.92-2.10 (m,6 H,3 × CH2),1.70-1.80 (m,2 H,CH2); MS m / z 354.2 (MH + ,100%). Anal calcd for C 18 H 19 N5O3: C,61.18; H,5.42; N,19.82. Found: C,60.89; H,5.34; N,19.61%. HPLC purity 99.9%.

[0312] Example 14: SN39273 N-(4-((1-cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-yl)amino)phenyl)acetamide(20) [ka] A degassed mixture of chloride 6 (118 mg, 0.47 mmol), N-(4-aminophenyl)acetamide (85 mg, 0.56 mmol), Pd2dba3 (22 mg, 24 μmol), XPhos (45 mg, 94 μmol), and Cs2CO3 (306 mg, 0.94 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (0-10%) of MeOH / Âde to obtain imidazopyridinone 20 (136 mg, 75%) as a milky white powder. mp (Âde / pet ether) 152-155 °C; 1 H NMR (CDCl3) δ 7.80 (s,1 H,H-4''),7.45 (br d,J = 8.8 Hz,2 H,H-2',H-6'),7.20-7.30 (m,3 H,CONH,H-3',H-5'),6.55 (s,1 H,H-7''),6.43 (s,1 H,4'-NH),4.74 (pent,J = 8.8 Hz,1 H,1''-CH),3.39 (s,3 H,3''-CH3),2.17 (s,3 H,COCH3),1.95-2.04 (m,4 H,2 × CH2),1.82-1.92 (m,2 H,CH2),1.63-1.73 (m,2 H,CH2); MS m / z 366.2 (MH + ,100%). Anal calcd for C 20 H 23 N5O2: C,65.73; H,6.34; N,19.16. Found: C,65.88; H,6.44; N,18.81%. HPLC purity 100.0%.

[0313] Example 15: SN39280N-(3-((1-cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-yl)amino)phenyl)acetamide(21) [ka] A degassed mixture of chloride 6 (110 mg, 0.44 mmol), N-(3-aminophenyl)acetamide (80 mg, 0.53 mmol), Pd2dba3 (20 mg, 22 μmol), XPhos (42 mg, 88 μmol), and Cs2CO3 (289 mg, 0.88 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography (0-10% MeOH / HCl) to obtain imidazopyridinone 21 (130 mg, 81%) as yellowish-brown crystals. mp (SiO) 215-217 °C; 1 H NMR (CDCl3) δ 7.83 (s,1 H,H-4'),7.78 (br s,1 H,H-2),7.38 (br s,1 H,CONH),7.22 (t,J = 8.0 Hz,1 H,H-5),7.04 (br dd,J = 8.0,1.3 Hz,1 H,H-6),6.93 (d,J = 7.9 Hz,1 H,H-4),6.66 (s,1 H,H-7'),6.62 (s,1 H,3-NH),4.78 (pent,J = 8.8 Hz,1 H,1'-CH),3.39 (s,3 H,3'-CH3),2.16 (s,3 H,COCH3),1.98-2.07 (m,4 H,2 × CH2),1.84-1.92 (m,2 H,CH2),1.65-1.74 (m,2 H,CH2); MS m / z 366.2 (MH + ,100%); HRMS calcd for C 20 H 24 N5O2(MH +) m / z 366.1925,found 366.1920 (1.3 ppm). HPLC purity 99.3%.

[0314] Example 16: SN39301N-(2-((1-cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-yl)amino)phenyl)acetamide(22) [ka] A degassed mixture of chloride 6 (133 mg, 0.53 mmol), N-(2-aminophenyl)acetamide (95 mg, 0.63 mmol), Pd2dba3 (24 mg, 27 μmol), XPhos (50 mg, 106 μmol), and Cs2CO3 (345 mg, 1.06 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (0-5%) of MeOH / Â, yielding imidazopyridinone 22 (185 mg, 96%) as a yellowish-brown powder. mp (MeOH / Â) 181-183 °C; 1H NMR (CDCl3) δ 8.11 (br s,1 H,CONH),7.95 (d,J = 7.4 Hz,1 H,H-6),7.78 (s,1 H,H-4'),7.30 (d,J = 7.2 Hz,1 H,H-3),7.18 (br dd,J = 7.6,6.6 Hz,1 H,H-5),7.13 (br dd,J = 7.7,6.4 Hz,1 H,H-4),6.39 (br s,1 H,6'-NH),6.18 (s,1 H,H-7'),4.68 (pent,J = 8.7 Hz,1 H,1-CH),3.38 (s,3 H,3-CH3),2.12 (s,3 H,COCH3),1.89-2.00 (m,4 H,2 × MS m / z 366.2 (MH + ,100%); HRMS calcd for C 20 H 24 N5O2(MH + ) m / z 365.1852,found 365.1872 (-5.4 ppm). HPLC purity 98.9%.

[0315] Example 17: SN39275 4-((1-cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-yl)amino)benzylnitrile(23) [ka] A degassed mixture of chloride 6 (122 mg, 0.49 mmol), 4-aminobenzonitrile (69 mg, 0.58 mmol), Pd2dba3 (22 mg, 25 μmol), XPhos (47 mg, 98 μmol), and Cs2CO3 (319 mg, 0.98 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120°C for 16 hours. The mixture was cooled, diluted with RINKAN (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between RINKAN (50 mL) and water (50 mL). The organic fraction was separated into water 39278. The solution was washed with (mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography (60-80% alkyl / petroleum ether) to obtain 23 (131 mg, 81%) as a milky white powder. mp (alkyl / petroleum ether) 236-238 °C; 1 H NMR (CDCl3) δ 7.91 (s,1 H,H-4'),7.45 (ddd,J = 8.8,2.3,2.0 Hz,2 H,H-3,H-5),7.43 (ddd,J = 8.8,2.3,2.0 Hz,2 H,H-2,H-6),6.77 (s,1 MS m / z 351.2 (MH + ,100%). Anal calcd for C 19 H 19 N5O: C,68.45; H,5.74; N,21.01. Found: C,68.24; H,5.84; N,20.86%. HPLC purity 100.0%.

[0316] Example 18: SN39291 3-((1-cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-yl)amino)benzylnitrile(24) [ka] A degassed mixture of chloride 6 (122 mg, 0.49 mmol), 3-aminobenzonitrile (69 mg, 0.58 mmol), Pd2dba3 (22 mg, 25 μmol), XPhos (47 mg, 98 μmol), and Cs2CO3 (319 mg, 0.98 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120°C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using elution with a gradient (50-60%) of HCl / petroleum ether to obtain imidazopyridinone 24 (120 mg, 74%) as a milky white powder. mp (EtOAc / pet ether) 233-235 °C; 1 H NMR (CDCl3) δ 7.88 (s,1 H,H-4),7.85 (t,J = 1.8 Hz,1 H,H-2'),7.50 (ddd,J = 8.3,2.3,1.0 Hz,1 H,H-6'),7.36 (t,J = 8.0 Hz,1 H,H-5'),7.22 (dt,J = 7.6,1.2 Hz,1 H,H-4'),6.61 (br s,1 H,6-NH),6.53 (s,1 H,H-7),4.81 (pent,J = 8.8 Hz,1 H,1-CH),3.42 (s,3 H,3-CH3),1.98-2.08 (m,4 H,2 × CH2),1.87-1.97 (m,2 H,CH2),1.69-1.79 (m,2 H,CH2); MS m / z 334.2 (MH + ,100%). Anal calcd for C 19 H 19 N5O·0.1EtOAc: C,68.09; H,5.83; N,20.47. Found: C,67.93; H,6.05; N,20.47%. HPLC purity 100.0%.

[0317] Example 19: SN39297 2-((1-cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-yl)amino)benzylnitrile(25) [ka] A degassed mixture of chloride 6 (120 mg, 0.48 mmol), 2-aminobenzonitrile (68 mg, 0.57 mmol), Pd2dba3 (22 mg, 24 μmol), XPhos (46 mg, 96 μmol), and Cs2CO3 (313 mg, 0.96 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography to obtain imidazopyridinone 25 (101 mg, 64%) as orange crystals eluted with HCl. mp (MeOH / HCl) 171-173 °C; 1 H NMR (CDCl3) δ 8.83 (s,1 H,H-4),8.13 (br s,1 H,6-NH),7.90 (dd,J = 8.2,1.0 Hz,1 H,H-6'),7.63 (ddd,J = 8.3,6.9,1.3 Hz,1 H,H-4'),7.55 (dd,J = 8.3,1.0 Hz,1 H,H-3'),7.30 (ddd,J = 8.2,6.9,1.2 Hz,1 H,H-5'),6.76 (s,1 H,H-7),4.82 (pent,J = 8.8 Hz,1 H,1-CH),3.49 (s,3 H,3-CH3),1.95-2.15 (m,6 H,3 × CH2),1.68-1.80 (m,2 H,CH2); MS m / z 334.2 (MH + ,100%). Anal. calcd for C 19 H 19N5O·1.3CH3OH: C, 65.01; H, 6.50; N, 18.67. Found C,64.71; H,6.41; N,18.99%. HPLC purity 98.8%.

[0318] Example 20: SN39278 1-Cyclopentyl-3-methyl-6-((4-(trifluoromethyl)phenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(26). [ka] A degassed mixture of chloride 6 (111 mg, 0.44 mmol), 4-(trifluoromethyl)aniline (85 mg, 0.53 mmol), Pd2dba3 (20 mg, 22 μmol), XPhos (42 mg, 88 μmol), and Cs2CO3 (289 mg, 0.88 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography (50-70% HCl / petroleum ether) to obtain 26 (125 mg, 75%) as a milky white powder. mp (EtOAc / pet ether) 196-199 °C; 1 H NMR (CDCl3) δ 7.88 (d,J = 0.4 Hz,1 H,H-4),7.53 (d,J = 8.6 Hz,2 H,H-3',H-5'),7.39 (d,J = 8.5 Hz,2 H,H-2',H-6'),6.66 (br s,1 H,6-NH),6.63 (s,1 H,H-7),4.80 (pent,J = 8.8 Hz,1 H,1-CH),3.42 (s,3 H,3-CH3),1.99-2.07 (m,4 H,2 × CH2),1.87-1.95 (m,2 H,CH2),1.68-1.78 (m,2 H,CH2); 13C NMR (CDCl3) δ 154.2,149.4,145.0,137.0,126.8 (q,J = 3.8 Hz),125.9 (2),124.7 (q,J = 233.6 Hz),123.7,123.0 (q,J = 32.8 Hz),117.1 (2),91.2,53.9,29.1 (2),27.6,25.3 (2); MS m / z 377.2 (MH + ,100%). Anal. calcd for C 19 H 19 F3N4O: C,60.63; H,5.09; N,14.89. Found: C,60.68; H,5.30; N,15.02%. HPLC purity 99.7%.

[0319] Example 21: SN39290 1-Cyclopentyl-3-methyl-6-((3-(trifluoromethyl)phenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(27) [ka] A degassed mixture of chloride 6 (125 mg, 0.50 mmol), 3-(trifluoromethyl)aniline (96 mg, 0.60 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol), and Cs2CO3 (326 mg, 1.00 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography (40-50% HCl / petroleum ether) to obtain imidazopyridinone 27 (146 mg, 78%) as a milky white needle. mp (HCl) 162-163 °C; 1H NMR (CDCl3) δ 7.87 (s,1 H,H-4),7.78 (s,1 H,H-2'),7.40-7.43 (m,2 H,H-5',H-6'),7.21-7.23 (m,1 H,H-4'),6.68 (br s,1 H,6-NH),6.63 (d,J = 0.4 Hz,1 H,H-7),4.83 (pent,J = 8.8 Hz,1 H,1-CH),3.42 (s,3 H,3-CH3),1.96-2.07 (m,4 H,2 × CH2),1.83-1.92 (m,2 H,CH2),1.68-1.76 (m,2 H,CH2); 13 C NMR (CDCl3) δ 154.3,149.8,142.4,136.9,131.8 (q,J = 32.1 Hz),130.0,126.1,124.3 (q,J = 272.3),123.5,121.6,118.2 (q,J = 3.8 Hz),114.5 (q,J = 3.9 Hz),90.4,53.7,29.2 (2),27.6,25.3 (2); + ,100%); HRMS calcd for C 19 H 20 F3N4O (MH + ) m / z 377.1584,found 377.1585 (-0.4 ppm). HPLC purity 99.3%.

[0320] Example 22: SN39283 1-Cyclopentyl-3-methyl-6-((2-(trifluoromethyl)phenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(28) [ka] A degassed mixture of chloride 6 (114 mg, 0.45 mmol), 2-trifluoroaniline (88 mg, 0.54 mmol), Pd2dba3 (21 mg, 23 μmol), XPhos (43 mg, 90 μmol), and Cs2CO3 (293 mg, 0.90 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography eluting with HCl / petroleum ether on a gradient (10-50%) to obtain imidazopyridinone 28 (110 mg, 65%) as a gray foam. 1 H NMR (CDCl3) δ 7.87 (s,1 H,H-4),7.76 (d,J = 8.3 Hz,1 H,H-3'),7.62 (dd,J = 7.8,0.7 Hz,1 H,H-6'),7.47 (br dd,J = 8.0,7.6 Hz,1 H,H-4'),7.07 (br dd,J = 7.7,765 Hz,1 H,H-5'),6.63 (br s,1 H,6-NH),6.58 (d,J = 0.5 Hz,1 H,H-7),4.76 (pent,J = 8.8 Hz,1 H,1-CH),3.41 (s,3 H,3-CH3),1.97-2.06 (m,4 H,2 × CH2),1.83-1.93 (m,2 H,CH2),1.62-1.74 (m,2 H,CH2); MS m / z 377.2 (MH + ,100%); HRMS calcd for C 19 H 19 F3N4O (MH + ) m / z 376.1511,found 376.1535 (6.3 ppm). HPLC purity 99.7%.

[0321] Example 23: SN39274 6-((4-acetylphenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (29) [ka] A degassed mixture of chloride 6 (117 mg, 0.47 mmol), 1-(4-aminophenyl)ethane-1-one (75 mg, 0.56 mmol), Pd2dba3 (22 mg, 24 μmol), XPhos (45 mg, 94 μmol), and Cs2CO3 (326 mg, 0.94 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography (60-100% HCl / petroleum ether) to obtain imidazopyridinone 29 (131 mg, 80%):mp (HCl / petroleum ether) as lemon powder. mp (HCl / pet ether) 181-183 °C; 1 H NMR (CDCl3) δ 7.89-7.95 (m,3 H,H-4,H-3',H-5'),7.36 (ddd,J = 8.8,2.6,1.9 Hz,2 H,H-2',H-6'),6.82 (s,1 H,6-NH),6.69 (d,J = 0.5 Hz,1 H,H-7''),4.81 (pent,J = 8.8 Hz,1 H,1-CH),3.43 (s,3 H,3-CH3),2.56 (s,3 H,COCH3),2.00-2.08 (m,4 H,2 × CH2),1.87-1.97 (m,2 H,CH2),1.70-1.78 (m,2 H,CH2); MS m / z 351.2 (MH + ,100%). Anal calcd for C 20 H 22 N4O2·0.1EtOAc: C,68.21; H,6.40; N,15.60. Found: C,68.09; H,6.52; N,15.37%. HPLC purity 97.9%.

[0322] Example 24: SN39279 6-((3-acetylphenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(30) [ka] A degassed mixture of chloride 6 (110 mg, 0.44 mmol), 1-(3-aminophenyl)ethane-1-one (71 mg, 0.53 mmol), Pd2dba3 (22 mg, 20 μmol), XPhos (42 mg, 88 μmol), and Cs2CO3 (287 mg, 0.88 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with SiO2 (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between SiO2 (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography (50-100% HCl / petroleum ether) to obtain imidazopyridinone 30 (147 mg, 80%) as a milky white powder. mp (HCl / pet ether) 125-127 °C; 1 H NMR (CDCl3) δ 7.93 (t,J = 1.9 Hz,1 H,H-2'),7.86 (s,1 H,H-4),7.56 (ddd,J = 7.6,1.4,1.1 Hz,1 H,H-6'),7.53 (ddd,J = 8.1,2.3,0.9 Hz,1 H,H-4'),7.40 (t,J = 7.8 Hz,1 H,H-5'),6.63 (s,1 H,H-7),6.61 (br s,1 H,6-NH),4.81 (pent,J = 8.8 Hz,1 H,1-CH),3.41 (s,3 H,3-CH3),2.60 (s,3 H,COCH3),1.98-2.07 (m,4 H,2 × MS m / z 351.2 (MH + ,100%). Anal. calcd for C 20 H 22N4O2: C,68.55; H,6.33; N,15.99. Found: C,68.54; H,6.52; N,16.03%. HPLC purity 99.6%.

[0323] Example 25: SN39304 1-Cyclopentyl-3-methyl-6-((4-(methylsulfonyl)phenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(31) [ka] A degassed mixture of chloride 6 (125 mg, 0.50 mmol), 4-(methylsulfonyl)aniline (102 mg, 0.60 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol), and Cs2CO3 (326 mg, 1.00 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (60-100%) of acetaldehyde / petroleum ether to obtain imidazopyridinone 31 (154 mg, 80%) as a milky white needle. mp (acetaldehyde / petroleum ether) 161-164 °C; 1H NMR (CDCl3) δ 7.92 (s,1 H,H-4),7.82 (ddd,J = 8.8,2.6,1.9 Hz,2 H,H-2',H-6'),7.51 (ddd,J = 8.8,2.6,1.9 Hz,2 H,H-3',H-5'),6.86 (s,1 H,6-NH),6.63 (d,J = 0.3 Hz,1 H,H-7),4.81 (pent,J = 8.8 Hz,1 H,1-CH),3.43 (s,3 H,3-CH3),3.04 (s,3 H,SO2CH3),2.00-2.08 (m,4 H,2 × CH2),1.88-1.98 (m,2 H,CH2),1.88-1.98 (m,2 H,CH2); MS m / z 387.2 (MH + ,100%). Anal. calcd for C 19 H 22 N4O3S·1 / 2EtOAc: C, 58.59; H, 6.09; N, 13.01. Found: C,58.86; H,6.30; N,13.20%. HPLC purity 99.9%.

[0324] Example 26: SN39308 1-Cyclopentyl-3-methyl-6-((3-(methylsulfonyl)phenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(32) [ka] A degassed mixture of chloride 6 (112 mg, 0.45 mmol), 3-(methylsulfonyl)aniline, HCl (111 mg, 0.53 mmol), Pd2dba3 (21 mg, 23 μmol), XPhos (43 mg, 90 μmol), and Cs2CO3 (484 mg, 1.49 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using elution with a gradient (80-100%) of acetate / petroleum ether to obtain imidazopyridinone 32 (154 mg, 90%) as a white powder. (mp (acetate / pet ether) 208-211 °C;) 1 H NMR (CDCl3) δ 8.00 (d,J = 2.8 Hz,1 H,H-2'),7.89 (s,1 H,H-4),7.61-7.66 (m,1 H,H-5'),7.44-7.49 (m,2 H,H-4',H-6'),6.84 (s,1 H,6-NH),6.60 (d,J = 0.5 Hz,1 H,H-7),4.82 (pent,J = 8.8 Hz,1 H,1-CH),3.42 (s,3 H,3-CH3),3.07 (s,3 H,SO2CH3),2.00-2.08 (m,4 H,2 × CH2),1.87-1.97 (m,2 H,CH2),1.68-1.77 (m,2 H,CH2); MS m / z 387.2 (MH + ,100%). Anal. calcd for C 19 H 22 N4O3S·1 / 2EtOAc: C,58.59; H,6.09; N,13.01. Found: C,58.73; H,6.25; N,13.28%. HPLC purity 99.8%.

[0325] Example 27: SN39330 1-Cyclopentyl-3-methyl-6-((2-(methylsulfonyl)phenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(33) [ka] A degassed mixture of chloride 6 (126 mg, 0.50 mmol), 2-(methylsulfonyl)aniline (103 mg, 0.60 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol), and Cs2CO3 (358 mg, 1.10 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (60-80%) of HCl / petroleum ether to obtain imidazopyridinone 33 (168 mg, 87%) as a white powder. mp (HCl / pet. ether) 178-181 °C; 1 H NMR (CDCl3) δ 8.42 (br s,1 H,6-NH),8.11 (dd,J = 8.4,0.7 Hz,1 H,H-3'),7.87-7.92 (m,2 H,H-4,H-6'),7.53 (ddd,J = 8.6,7.1,1.6 Hz,1 H,H-5'),7.04 (ddd,J = 8.2,7.1,1.0 Hz,1 H,H-4'),6.55 (d,J = 0.5 Hz,1 H,H-7),4.78 (pent,J = 8.8 Hz,1 H,1-CH),3.43 (s,3 H,3-CH3),3.12 (s,3 H,2'-SO2CH3),1.93-2.10 (m,6 H,3 × CH2),1.70-1.80 (m,2 H,CH2); MS m / z 387.2 (MH + ,100%); HRMS calcd for C 19 H 23 N4O3(MH +) m / z 387.1485,found 387.1493 (-1.9 ppm). HPLC purity 100.0%.

[0326] Example 28: SN39302 6-((4-(benzyloxy)phenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(34) [ka] A degassed mixture of chloride 6 (200 mg, 0.80 mmol), 4-(benzyloxy)aniline, HCl (225 mg, 0.95 mmol), PPd2dba3 (37 mg, 40 μmol), XPhos (76 mg, 160 μmol), and Cs2CO3 (860 mg, 2.64 mmol) in dioxane (8 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (50-80%) of siRNA / petroleum ether to obtain imidazopyridinone 34 (215 mg, 65%) as yellowish-brown crystals. mp (siRNA / petroleum ether) 144-147 °C; 1H NMR (CDCl3) δ 7.77 (s,1 H,H-4),7.45 (br d,J = 7.2 Hz,2 H,H-2'',H-6''),7.39 (br dd,J = 7.6,7.1 Hz,2 H,H-3'',H-5''),7.33 (br t,J = 7.1 Hz,1 H,H-4''),7.20 (ddd,J = 8.9,3.5,2.2 Hz,2 H,H-2',H-6'),6.97 (ddd,J = 8.9,3.5,2.2 Hz,2 H,H-3',H-5'),6.42 (d,J = 0.5 Hz,1 H,H-7),6.29 (s,1 H,6-NH),5.07 (s,2 H,CH2O),4.73 MS m / z 415.2 (MH + ,100%). Anal calcd for C 25 H 26 N4O2·1 / 4EtOAc: C,71.54; H,6.47; N,12.83. Found: C,71.26; H,6.44; N,12.72%. HPLC purity 99.9%.

[0327] Example 29: SN39303 6-(3(benzyloxy)phenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(35) [ka] A degassed mixture of chloride 6 (203 mg, 0.81 mmol), 3-(benzyloxy)aniline (193 mg, 0.97 mmol), Pd2dba3 (37 mg, 40 μmol), XPhos (77 mg, 162 μmol), and Cs2CO3 (528 mg, 1.62 mmol) in dioxane (8 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (50-80%) of siRNA / petroleum ether to obtain imidazopyridinone 35 (246 mg, 74%) as a white needle. mp (siRNA / petroleum ether) 110-112 °C; 1 H NMR (CDCl3) δ 7.85 (d,J = 0.4 Hz,1 H,H-4),7.38-7.46 (m,4 H,H-2'',H-3'',H-5'',H-6''),7.36 (br tt,J = 7.0,1.5 Hz,1 H,H-4''),7.24 (t,J = 8.1 Hz,1 H,H-5'),7.01 (t,J = 2.2 Hz,1 H,H-2'),6.86 (dd,J = 8.0,1.0 Hz,1 H,H-6'),6.71 (d,J = 0.6 Hz,1 H,H-7),6.65 (ddd,J = 8.2,2.4,0.7 Hz,1 H,H-4'),6.51 (br s,1 H,6-NH),5.08 (s,2 H,CH2O),4.81 (pent,J = 8.8 Hz,1 H,1-CH),3.42 (s,3 H,3-CH3),1.99-2.08 (m,4 H,2 × CH2),1.85-1.96 (m,2 H,CH2),1.67-1.77 (m,2 H,CH2); MS m / z 415.2 (MH + ,100%). Anal calcd for C 25 H 26N4O2: C,72.44; H,6.32; N,13.52. Found: C,71.16; H,6.36; N,13.19%. HPLC purity 100.0%.

[0328] Example 30: SN39328 6-((2-(benzyloxy)phenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(36) [ka] A degassed mixture of chloride 6 (164 mg, 0.65 mmol), 2-(benzyloxy)aniline (156 mg, 0.78 mmol), Pd2dba3 (30 mg, 33 μmol), XPhos (63 mg, 130 μmol), and Cs2CO3 (466 mg, 1.43 mmol) in dioxane (10 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (40-50%) of acetate / petroleum ether to obtain imidazopyridinone 36 (166 mg, 61%) as a white powder. (mp (acetate / pet. ether) 170-173 °C;) 1H NMR (CDCl3) δ 7.84-7.88 (m,2 H,H-4,H-6'),7.42-7.46 (m,2 H,H-2'',H-6''),7.32-7.40 (m,3 H,H-3'',H-4'',H-5''),6.94-6.99 (m,2 H,H-3',H-4'),6.87-6.89 (m,1 H,H-5'),6.85 (br s,1 H,6-NH),6.61 (d,J = 0.5 Hz,1 H,H-7),5.15 (s,2 H,CH2O),4.77 (pent,J = 8.8 Hz,1 H,1-CH),3.39 (s,3 H,3-CH3),1.97-2.05 (m,4 H,2 × MS m / z 415.2 (MH + ,100%); HRMS calcd for C 25 H 27 N4O2(MH + ) m / z 415.2129,found 415.2135 (-1.7 ppm). HPLC purity 99.6%.

[0329] Example 31: SN39309 2-(4-((1-cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-yl)amino)phenyl)-2-methylpropanenitrile(37) [ka] A degassed mixture of chloride 6 (126 mg, 0.50 mmol), 2-(4-aminophenyl)-2-methylpropanenitrile (96 mg, 0.60 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol), and Cs2CO3 (358 mg, 1.10 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with RINKAN (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between RINKAN (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (60-100%) of HCl / petroleum ether to obtain imidazopyridinone 37 (160 mg, 85%) as a yellowish-brown powder. mp (MeOH / HCl) 144-146 °C; 1 H NMR (CDCl3) δ 7.84 (d,J = 0.5 Hz,1 H,H-4''),7.41 (ddd,J = 8.8,2.7,2.1 Hz,2 H,H-3',H-5'),7.32 (ddd,J = 8.8,2.7,2.1 Hz,2 H,H-2',H-6'),6.58 (d,J = 0.6 Hz,1 H,H-7''),6.50 (s,1 H,6''-NH),4.78 (pent,J = 8.8 Hz,1 H,1-CH),3.40 (s,3 H,3''-CH3),1.99-2.07 (m,4 H,2 × CH2),1.86-1.95 (m,2 H,CH2),1.68-1.77 (m,8 H,2-CH3,H-3,CH2) MS m / z 376.2 (MH + ,100%). Anal. calcd for C 19 H 25 N5O·1 / 4CH3OH: C,69.69; H,6.83; N,18.26. Found: C,69.37; H,6.37; N,18.20%. HPLC purity 99.4%.

[0330] Example 32: SN39385 1-Cyclopentyl-6-((2,4-dimethylphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (38) [ka] A degassed mixture of chloride 6 (128 mg, 0.51 mmol), 2,4-dimethylaniline (74 mg, 0.61 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (49 mg, 102 μmol), and Cs2CO3 (366 mg, 1.12 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (60-100%) of  / petroleum ether to obtain imidazopyridinone 38 (58 mg, 34%) as a white powder. mp ( / petroleum ether) 173-175 °C; 1 H NMR (CDCl3) δ 7.78 (d,J = 0.6 Hz,1 H,H-4),7.24 (d,J = 8.0 Hz,1 H,H-6'),7.08 (s,1 H,H-3'),7.01 (d,J = 8.0 Hz,1 H,H-5'),6.34 (d,J = 0.6 Hz,1 H,H-7),6.06 (br s,1 H,6-NH),4.70 (pent,J = 8.8 Hz,1 H,1-CH),3.38 (s,3 H,3-CH3),2.34 (s,3 H,4'-CH3),2.24 (s,3 H,2'-CH3),1.92-1.98 (m,4 H,2 × CH2),1.75-1.85 (m,2 H,CH2),1.58-1.68 (m,2 H,CH2); MS m / z 337.2 (MH + ,100%); HRMS calcd for C 20 H 25 N4O (MH +) m / z 337.2010,found 337.2008 (0.4 ppm). HPLC purity 99.6%.

[0331] Example 33: SN39390 1-Cyclopentyl-6-((2,3-dimethylphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (39) [ka] A degassed mixture of chloride 6 (126 mg, 0.50 mmol), 2,3-dimethylaniline (73 mg, 0.60 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol), and Cs2CO3 (358 mg, 1.10 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with pharmaceutically acceptable solution (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between pharmaceutically acceptable solution (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (60-100%) of acetone / petroleum ether to obtain imidazopyridinone 39 (47 mg, 28%) as a yellowish-brown foam. 1 H NMR (CDCl3) δ 7.79 (s,1 H,H-4),7.20 (d,J = 7.9 Hz,1 H,H-6'),7.10 (dd,J = 7.8,7.6 Hz,1 H,H-5'),6.98 (d,J = 7.4 Hz,1 H,H-4'),6.31 (d,J = 0.4 Hz,1 H,H-7),6.20 (br s,1 H,6-NH),4.71 (pent,J = 8.8 Hz,1 H,1-CH),3.38 (s,3 H,3-CH3),2.34 (s,3 H,3'-CH3),2.19 (s,3 H,2'-CH3),1.89-1.98 (m,4 H,2 × CH2),1.70-1.80 (m,2 H,CH2),1.58-1.67 (m,2 H,CH2); MS m / z 337.2 (MH +,100%). HRMS calcd for C 20 H 25 N4O (MH + ) m / z 337.2023,found 337.2017 (1.7 ppm). HPLC purity 99.1%.

[0332] Example 34: SN39393 1-Cyclopentyl-6-(3,4-dimethylphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (40). [ka] A degassed mixture of chloride 6 (129 mg, 0.51 mmol), 3,4-dimethylaniline (75 mg, 0.61 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (49 mg, 102 μmol), and Cs2CO3 (366 mg, 1.12 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (60-100%) of acetate / petroleum ether to obtain imidazopyridinone 40 (99 mg, 57%) as a brown cube. (mp (acetate / petroleum ether) 150-151 °C) 1H NMR (CDCl3) δ 7.80 (d,J = 0.5 Hz,1 H,H-4),7.08 (d,J = 8.0 Hz,1 H,H-5'),7.04 (d,J = 2.3 Hz,1 H,H-2'),6.99 (dd,J = 8.0,2.3 Hz,1 H,H-6'),6.64 (d,J = 0.7 Hz,1 H,H-7),6.40 (br s,1 H,6-NH),4.78 (pent,J = 8.8 Hz,1 H,1-CH),3.39 (s,3 H,3-CH3),2.25 (s,3 H,3'-CH3),2.24 (s,3 H,2'-CH3),1.96-2.04 (m,4 H,2 × MS m / z 337.2 (MH + ,100%);. HRMS calcd for C 20 H 25 N4O (MH + ) m / z 337.2023,found 337.2017 (1.7 ppm). HPLC purity 99.9%.

[0333] Example 35: SN39378 6-((3-chloro-2-methylphenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(41) [ka] A degassed mixture of chloride 6 (127 mg, 0.50 mmol), 3-chloro-2-methylaniline (86 mg, 0.61 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol), and Cs2CO3 (358 mg, 1.10 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with RINKAN (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between RINKAN (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (60-80%) of siRNA / petroleum ether to obtain imidazopyridinone 41 (42 mg, 23%) as a milky white needle. mp (siRNA / petroleum ether) 173-175 °C; 1 H NMR (CDCl3) δ 7.81 (d,J = 0.4 Hz,1 H,H-4),7.31 (dd,J = 7.5,1.6 Hz,1 H,H-4'),7.09-7.16 (m,2 H,H-5',H-4'),6.38 (s,1 H,H-7),6.19 (br s,1 H,6-NH),4.74 (pent,J = 8.7 Hz,1 H,1-CH),3.39 (s,3 H,3-CH3),2.34 (s,3 H,2'-CH3),1.90-2.02 (m,4 H,2 × CH2),1.75-1.83 (m,2 H,CH2),1.63-1.70 (m,2 H,CH2); MS m / z 357.2 (MH + ,100%),359.2 (MH + ,35%); HRMS calcd for C 19 H 22 ClN4O (MH + ) m / z 357.1477,found 357.1480 (-1.0 ppm). HPLC purity 98.0%.

[0334] Example 36: SN39376 6-((4-chloro-2-methylphenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (42) [ka] A degassed mixture of chloride 6 (126 mg, 0.50 mmol), 4-chloro-2-methylaniline (85 mg, 0.60 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol), and Cs2CO3 (358 mg, 1.10 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with RINKAN (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between RINKAN (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (60-100%) of acetone / petroleum ether to obtain imidazopyridinone 42 (85 mg, 48%) as a yellowish-brown foam. 1 H NMR (CDCl3) δ 7.81 (s,1 H,H-4),7.36 (d,J = 8.6 Hz,1 H,H-6'),7.23 (d,J = 2.4 Hz,1 H,H-3'),7.15 (dd,J = 8.6,2.5 Hz,1 H,H-5'),6.40 (s,1 H,H-7),6.06 (br s,1 H,6-NH),4.73 (pent,J = 8.8 Hz,1 H,1-CH),3.39 (s,3 H,3-CH3),2.26 (s,3 H,2'-CH3),1.93-2.02 (m,4 H,2 × CH2),1.78-1.88 (m,2 H,CH2),1.63-1.72 (m,2 H,CH2); MS m / z 357.2 (MH + ,100%),359.2 (MH + ,35%); HRMS calcd for C 19 H 22 ClN4O (MH +) m / z 357.1477,found 357.1476 (0.1 ppm). HPLC purity 97.5%.

[0335] Example 37: SN39379 6-((5-chloro-2-methylphenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(43) [ka] A degassed mixture of chloride 6 (131 mg, 0.52 mmol), 5-chloro-2-methylaniline (88 mg, 0.62 mmol), Pd2dba3 (24 mg, 26 μmol), XPhos (50 mg, 104 μmol), and Cs2CO3 (373 mg, 1.14 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using ethyl acetate / petroleum ether at a gradient (60-80%) to obtain imidazopyridinone 43 (73 mg, 39%) as a yellowish-brown foam. 1 H NMR (CDCl3) δ 7.84 (s,1 H,H-4),7.50 (d,J = 2.1 Hz,1 H,H-6'),7.14 (d,J = 8.1 Hz,1 H,H-3'),6.94 (dd,J = 8.1,2.1 Hz,1 H,H-4'),6.58 (s,1 H,H-7),6.15 (br s,1 H,6-NH),4.81 (pent,J = 8.8 Hz,1 H,1-CH),3.39 (s,3 H,3-CH3),2.54 (s,3 H,2'-CH3),1.83-2.08 (m,6 H,3 × CH2),1.66-1.75 (m,2 H,CH2); MS m / z 357.2 (MH + ,100%),359.2 (MH + ,35%); HRMS calcd for C 19H 22 ClN4O (MH + ) m / z 357.1477,found 357.147180 (1.6 ppm). HPLC purity 98.0%.

[0336] Example 38: SN39396 1-Cyclopentyl-3-methyl-6-((2-methyl-4-(methylsulfonyl)phenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(44) [ka] A degassed mixture of chloride 6 (126 mg, 0.50 mmol), 2-methyl-4-(methylsulfonyl)aniline (110 mg, 0.60 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol), and Cs2CO3 (358 mg, 1.10 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using acetaldehyde / petroleum ether with a gradient (70-100%) to obtain imidazopyridinone 44 (134 mg, 67%) as a yellowish-brown powder. (mp (acetaldehyde / pet ether) 201-203 °C) 1H NMR (CDCl3) δ 7.92 (d,J = 0.6 Hz,1 H,H-4),7.78 (d,J = 8.5 Hz,1 H,H-6'),7.69-7.75 (m,2 H,H-3',H-5'),6.70 (d,J = 0.6 Hz,1 H,H-7),6.40 (br s,1 H,6-NH),4.79 (pent,J = 8.8 Hz,1 H,1-CH),3.44 (s,3 H,3-CH3),3.04 (s,3 H,4'-SO2CH3),2.37 (s,3 H,2'-CH3),2.00-2.08 (m,4 H,2 × CH2),1.87-1.96 (m,2 H,CH2),1.70-1.78 (m,2 H,CH2); MS m / z 401.2 (MH + ,100%); HRMS calcd for C 20 H 25 N4O3S (MH + ) m / z 401.1642,found 401.1635 (1.8 ppm). HPLC purity 98.7%.

[0337] Example 39: SN39397 1-Cyclopentyl-3-methyl-6-((2-methyl-5-(methylsulfonyl)phenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(45). [ka] A degassed mixture of chloride 6 (126 mg, 0.50 mmol), 2-methyl-5-(methylsulfonyl)aniline (111 mg, 0.60 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol), and Cs2CO3 (358 mg, 1.10 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with butyl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between butyl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgS4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (70-100%) of siRNA / petroleum ether to obtain imidazopyridinone 45 (156 mg, 78%) as a yellowish-brown powder. (mp (siRNA / pet ether) 170-172 °C) 1 H NMR (CDCl3) δ 8.15 (d,J = 1.8 Hz,1 H,H-6'),7.88 (s,1 H,H-4),7.46 (dd,J = 7.8,1.8 Hz,1 H,H-4'),7.38 (d,J = 7.8 Hz,1 H,H-3'),6.66 (d,J = 0.6 Hz,1 H,H-7),6.26 (br s,1 H,6-NH),4.82 (pent,J = 8.8 Hz,1 H,1-CH),3.42 (s,3 H,3-CH3),3.02 (s,3 H,5'-SO2CH3),2.38 (s,3 H,2'-CH3),1.98-2.07 (m,4 H,2 × CH2),1.84-1.94 (m,2 H,CH2),1.65-1.75 (m,2 H,CH2); MS m / z 401.2 (MH + ,100%); HRMS calcd for C 20 H 25 N4O3S (MH + ) m / z 401.1642,found 401.1638 (1.0 ppm). HPLC purity 99.7%.

[0338] Example 40: SN39398 4-((1-cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-yl)amino)-3-methylbenzylnitrile(46) [ka] A degassed mixture of chloride 6 (129 mg, 0.51 mmol), 4-amino-3-methylbenzonitrile (81 mg, 0.61 mmol), Pd2dba3 (23 mg, 26 μmol), XPhos (49 mg, 102 μmol), and Cs2CO3 (366 mg, 1.12 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography (50-100% HCl / petroleum ether) to obtain nitrile 50 (43 mg, 24%) as yellowish-brown crystals. 1 H NMR (CDCl3) δ 7.91 (d,J = 0.4 Hz,1 H,H-4'),7.70 (d,J = 8.7 Hz,1 H,H-5),7.43-7.47 (m,2 H,H-2,H-6),6.67 (d,J = 0.4 Hz,1 H,H-7'),6.36 (br s,1 H,4-NH),4.80 (pent,J = 8.8 Hz,1 H,1'-CH),3.43 (s,3 H,3'-CH3),2.32 (s,3 H,3-CH3),1.99-2.08 (m,4 H,2 × CH2),1.86-1.96 (m,2 H,CH2),1.70-1.79 (m,2 H,CH2); MS m / z 348.2 (MH + ,100%); HRMS calcd for C 20 H 22 N5O (MH + ) m / z 348.1819,found 348.1812 (2.0 ppm). HPLC purity 99.9%.

[0339] Example 41: SN39401 4-((1-cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-yl)amino)-2-methylbenzylnitrile (47) [ka] A degassed mixture of chloride 6 (129 mg, 0.51 mmol), 4-amino-2-methylbenzonitrile (81 mg, 0.62 mmol), Pd2dba3 (26 mg, 23 μmol), XPhos (49 mg, 102 μmol), and Cs2CO3 (366 mg, 1.12 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography (50-60% HCl / petroleum ether) to obtain nitrile 47 (66 mg, 37%) as milky white crystals. 1 H NMR (CDCl3) δ 7.91 (s,1 H,H-4'),7.49 (d,J = 8.5 Hz,1 H,H-6),7.29 (d,J = 2.2 Hz,1 H,H-3),7.20 (dd,J = 8.5,2.2 Hz,1 H,H-5),6.71 (br s,1 H,4-NH),6.63 (s,1 H,H-7'),4.83 (pent,J = 8.7 Hz,1 H,1'-CH),3.42 (s,3 H,3'-CH3),2.50 (s,3 H,2-CH3),1.99-2.09 (m,4 H,2 × CH2),1.86-1.95 (m,2 H,CH2),1.70-1.78 (m,2 H,CH2); MS m / z 348.2 (MH + ,100%); HRMS calcd for C 20 H 22 N5O (MH + ) m / z 348.1819,found 348.1812 (2.0 ppm). HPLC purity 100.0%.

[0340] Example 42: SN39369 1-Cyclopentyl-6-((4-methoxy-2-methylphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (48) [ka] A degassed mixture of chloride 6 (128 mg, 0.51 mmol), 4-methoxy-2-methylaniline (84 mg, 0.61 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (49 mg, 102 μmol), and Cs2CO3 (366 mg, 1.12 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using elution with a gradient (70-100%) of HCl / petroleum ether to obtain imidazopyridinone 48 (84 mg, 47%) as a yellowish-brown gum. 1 H NMR (CDCl3) δ 7.75 (d,J = 0.4 Hz,1 H,H-4),7.23 (d,J = 8.6 Hz,1 H,H-6'),6.84 (d,J = 2.9 Hz,1 H,H-3'),6.77 (d,J = 8.6,2.9 Hz,1 H,H-5'),6.10 (s,1 H,H-7),5.99 (br s,1 H,6-NH),4.67 (pent,J = 8.7 Hz,1 H,1-CH),3.82 (s,3 H,4'-OCH3),3.37 (s,3 H,3-CH3),2.50 (s,3 H,2'-CH3),1.87-1.97 (m,4 H,2 × CH2),1.70-1.80 (m,2 H,CH2),1.57-1.67 (m,2 H,CH2); MS m / z 353.2 (MH + ,100%); HRMS HRMS calcd for C 20 H 25 N4O2(MH+ ) m / z 353.1972,found 353.1979 (-2.0 ppm). HPLC purity 99.4%.

[0341] Example 43: SN39382 1-Cyclopentyl-6-((5-methoxy-2-methylphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (49) [ka] A degassed mixture of chloride 6 (128 mg, 0.51 mmol), 5-methoxy-2-methylaniline (84 mg, 0.61 mmol), Pd2dba3 (23 mg, 26 μmol), XPhos (41 mg, 102 μmol), and Cs2CO3 (366 mg, 1.12 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (50-100%) of acetone / petroleum ether to obtain imidazopyridinone 49 (93 mg, 52%) as a brown foam. 1 H NMR (CDCl3) δ 7.82 (s,1 H,H-4),7.13 (d,J = 8.3 Hz,1 H,H-3'),7.03 (d,J = 2.6 Hz,1 H,H-6'),6.57 (dd,J = 8.3,2.6 Hz,1 H,H-4'),6.54 (d,J = 0.6 Hz,1 H,H-7),6.15 (br s,1 H,6-NH),4.76 (pent,J = 8.8 Hz,1 H,1-CH),3.76 (s,3 H,5'-OCH3),3.40 (s,3 H,3-CH3),2.21 (s,3 H,2'-CH3),1.96-2.04 (m,4 H,2 × CH2),1.78-1.88 (m,2 H,CH2),1.62-1.72 (m,2 H,CH2); MS m / z 353.2 (MH+ ,100%); HRMS calcd for C 20 H 25 N4O2(MH + ) m / z 353.1972,found 352.1964 (2.2 ppm). HPLC purity 99.0%.

[0342] Example 44: SN39474 1-Cyclopentyl-6-((4-methoxy-2-methylphenyl)(methyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(50) [ka] A solution of imidazopyridinone 44 (105 mg, 0.30 mmol) and MeI (28 μL, 0.45 mmol) at 5°C was stirred in dry DMF (5 mL) and NaH (60% dispersion, 13 mg, 0.33 mmol) was added. The mixture was stirred at 20°C for 16 hours and then rapidly cooled with ice / water (2 mL). The mixture was partitioned between RINKAN (50 mL) and HCl (30 mL). The organic fraction was washed with HCl (2 × 30 mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using a gradient (50-80%) of HCl / petroleum ether to obtain imidazopyridinone 50 (69 mg, 66%) as a clear gel. 1 H NMR (CDCl3) δ 7.81 (s,1 H,H-4),7.09 (d,J = 8.5 Hz,1 H,H-6'),6.86 (d,J = 2.9 Hz,1 H,H-3'),6.82 (d,J = 8.5,2.9 Hz,1 H,H-5'),5.69 (s,1 H,H-7),4.62 (pent,J = 8.6 Hz,1 H,1-CH),3.83 (s,3 H,4'-OCH3),3.36 (s,3 H,6-NCH3),3.34 (s,3 H,3-CH3),2.05 (s,3 H,2'-CH3),1.76-1.90 (m,4 H,2 × CH2),1.50-1.60 (m,4 H,2 × CH2); MS m / z 367.2 (MH +,100%); HRMS calcd for C 21 H 27 N4O2(MH + ) m / z 367.2129,found 367.2124 (1.2 ppm). HPLC purity 97.2%.

[0343] Example 45: SN39370 6-((4-(benzyloxy)-2-methylphenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(51) [ka] A degassed mixture of chloride 6 (281 mg, 1.12 mmol), 4-phenoxy-2-methylaniline (286 mg, 1.34 mmol), Pd2dba3 (51 mg, 56 μmol), XPhos (107 mg, 224 μmol), and Cs2CO3 (803 mg, 2.46 mmol) in dioxane (10 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using ethyl acetate / petroleum ether at a gradient (60-100%) to obtain imidazopyridinone 51 (219 mg, 46%) as a yellowish-brown foam. 1H NMR (CDCl3) δ 7.76 (s,1 H,H-4),7.45 (br d,J = 8.9 Hz,2 H,H-2'',H-6''),7.36-7.43 (m,2 H,H-3'',H-5''),7.33 (br t,J = 7.2 Hz,1 H,H-4''),7.23 (d,J = 8.6 Hz,1 H,H-6'),6.92 (d,J = 2.9 Hz,1 H,H-3'),6.83 (dd,J = 8.6,2.9 Hz,1 H,H-5'),6.12 (d,J = 0.5 Hz,1 H,H-7),5.98 (br s,1 H,6-NH),5.07 (s,2 H,CH2O),4.67 (pent,J = MS m / z 429.2 (MH + ,100%); HRMS calcd for C 26 H 29 N4O2(MH + ) m / z 429.2285,found 429.2292 (-1.6 ppm). HPLC purity 99.0%.

[0344] Example 46: SN39642 1-Cyclopentyl-6-((4-fluoro-2-methylphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (52) [ka] A degassed mixture of chloride 6 (404 mg, 1.61 mmol), 4-fluoro-2-methylaniline (241 mg, 1.93 mmol), Pd2dba3 (74 mg, 81 μmol), XPhos (154 mg, 154 μmol), and Cs2CO3 (1.154 mg, 3.54 mmol) in dioxane (20 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (80 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (80 mL) and water (80 mL). The organic fraction was washed with water (50 mL), washed with brine (50 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (50-100%) of acetone / petroleum ether to obtain imidazopyridinone 52 (368 mg, 67%) as a yellowish-brown gum. 1 H NMR (CDCl3) δ 7.77 (d,J = 0.5 Hz,1 H,H-4),7.31 (dd,J = 8.7,5.3 Hz,1 H,H-6'),6.98 (dd,J = 9.2,2.9 Hz,1 H,H-3'),6.92 (dt,J = 8.4,2.9 Hz,1 H,H-5'),6.19 (d,J = 0.6 Hz,1 H,H-7),6.15 (br s,1 H,6-NH),4.70 (pent,J = 8.7 Hz,1 H,1-CH),3.38 (s,3 H,3-CH3),2.27 (s,3 H,2'-CH3),1.88-2.00 (m,4 H,2 × CH2),1.73-1.82 (m,2 H,CH2),1.60-1.70 (m,2 H,CH2); MS m / z 341.2 (MH + ,100%). HRMS calcd for C 19 H 22 FN4O (MH + ) m / z 341.1772,found 341.1776 (-1.1 ppm). HPLC purity 97.9%.

[0345] Example 47: SN39748 1-Cyclopentyl-3-methyl-6-((2-methyl-4-(trifluoromethoxy)phenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(53). [ka] A degassed mixture of chloride 6 (136 mg, 0.54 mmol), 2-methyl-4-(trifluoromethoxy)aniline (124 mg, 0.65 mmol), Pd2dba3 (25 mg, 27 μmol), XPhos (51 mg, 108 μmol), and Cs2CO3 (387 mg, 1.19 mmol) in MeCN (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with RINKAN (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between RINKAN (50 mL) and RINKAN (50 mL). The organic fraction was washed with RINKAN (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (70-100%) of  / petroleum ether to obtain imidazopyridinone 53 (96 mg, 44%) as a yellowish-brown gum. 1 H NMR (CDCl3) δ 7.84 (s,1 H,H-4),7.46 (d,J = 8.7 Hz,1 H,H-6'),7.13 (br s,1 H,H-3'),7.08 (br d,J = 8.6 Hz,1 H,H-5'),6.40 (d,J = 0.3 Hz,1 H,H-7),6.10 (br s,1 H,6-NH),4.77 (pent,J = 8.8 Hz,1 H,1-CH),3.41 (s,3 H,3-CH3),2.31 (s,3 H,2'-CH3),1.94-2.04 (m,4 H,2 × CH2),1.78-1.87 (m,2 H,CH2),1.66-1.76 (m,2 H,CH2); MS m / z 407.2 (MH + ,100%). HRMS calcd for C 20 H 22 F3N4O2(MH +) m / z 407.1689,found 407.1692 (-0.5 ppm). HPLC purity 98.2%.

[0346] Example 48: SN3976 1-Cyclopentyl-6-((4-(difluoromethoxy)-2-methylphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(54) [ka] A degassed mixture of chloride 6 (136 mg, 0.54 mmol), 4-(difluoromethoxy)-2-methylaniline, HCl (136 mg, 0.65 mmol), Pd2dba3 (25 mg, 27 μmol), XPhos (52 mg, 108 μmol), and Cs2CO3 (563 mg, 1.73 mmol) in MeCN (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (70-100%) of acetone / petroleum ether to obtain imidazopyridinone 54 (105 mg, 50%) as a yellowish-brown gum. 1H NMR (CDCl3) δ 7.80 (s,1 H,H-4),7.39 (d,J = 8.7 Hz,1 H,H-6'),7.03 (d,J = 2.7 Hz,1 H,H-3'),6.98 (dd,J = 8.7,2.7 Hz,1 H,H-5'),6.48 (t,J = 74.2 Hz,1 H,4'-OCHF2),6.33 (d,J = 0.6 Hz,1 H,H-7),6.07 (br s,1 H,6-NH),4.73 (pent,J = 8.7 Hz,1 H,1-CH),3.39 (s,3 H,3-CH3),2.28 (s,3 H,2'-CH3),1.98-2.04 (m,4 H,2 × MS m / z 389.2 (MH + ,100%). HRMS calcd for C 20 H 23 F2N4O2(MH + ) m / z 389.1784,found 389.1783 (0.1 ppm). HPLC purity 99.9%.

[0347] Example 49: SN39764 1-Cyclopentyl-6-((4-ethoxy-2-methylphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (55) [ka] 4-Ethoxy-2-methyl-1-nitrobenzene: To a stirred suspension of 3-methyl-4-nitrophenol (1.00 g, 6.5 mmol) and K2CO3 (2.26 g, 16.3 mmol) in methyl ethyl ketone (50 ml), diethyl sulfate (0.94 mL, 7.2 mmol) was added and the mixture was stirred at 70 °C for 4 hours. The mixture was cooled to 20 °C, cNH4OHOH solution (2 mL) was added, and the mixture was stirred at 20 °C for 16 hours. The mixture was partitioned between siRNA (100 ml) and water (100 ml). The organic fraction was washed with water (2 × 50 mL), washed with brine (50 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography eluting with a gradient (5-10%) siRNA / petroleum ether, and nitrobenzene (1.14 g, 96%) was obtained as a white solid: mp 50-51 °C (lit. 1 mp 50-52 °C); 1 H NMR (CDCl3) δ 8.08 (d,J = 8.6 Hz,1 H,H-6),6.76-6.80 (m,2 H,H-3,H-5),4.10 (q,J = 7.0 Hz,2 H,CH2O),2.63 (s,3 H,2-CH3),1.45 (t,J = 7.0 Hz,3 H,CH3); MS m / z 182.2 (MH + 100%). A mixture of 4-ethoxy-2-methylaniline:nitrobenzene (413 mg, 2.3 mmol) and Pd / C (5%, 50 mg) in EtOH (100 mL) was vigorously stirred with H2 for 6 hours. The mixture was filtered through a washing mat with diatomaceous earth and EtOH (10 mL). The solvent was evaporated to obtain aniline (329 mg, 95%) as a clarified oil. 1 H NMR (CDCl3) δ 6.35-6.68 (m,1 H,H-6),6.60-6.62 (m,2 H,H-3,H-5),3.95 (q,J = 7.0 Hz,2 H,CH2O),3.34 (br s,2 H,NH2),2.16 (s,3 H,2-CH3),1.36 (t,J = 7.0 Hz,3 H,CH3); MS m / z 152.2 (MH + 100%). A degassed mixture of 1-cyclopentyl-6-((4-ethoxy-2-methylphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(55):chloride 6 (127 mg, 0.50 mmol), 4-ethoxy-2-methylaniline (92 mg, 0.61 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol), and Cs2CO3 (358 mg, 1.10 mmol) in MeCN (8 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with ethyl acetate (50 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic fraction was washed with water (30 mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using ethyl elution with a gradient (60-100%) of siRNA / petroleum ether, yielding imidazopyridinone 55 (123 mg, 67%) as a yellowish-brown foam. (mp 192-194 °C) 1 H NMR (CDCl3) δ 7.75 (d,J = 0.3 Hz,1 H,H-4),7.21 (d,J = 8.6 Hz,1 H,H-6'),6.83 (d,J = 2.9 Hz,1 H,H-3'),6.76 (dd,J = 8.6,2.9 Hz,1 H,H-5'),6.10 (d,J = 0.5 Hz,1 H,H-7),5.99 (br s,1 H,6-NH),4.67 (p,J = 8.7 Hz,1 H,1-CH),4.04 (q,J = 7.0 Hz,2 H,4'-OCH2),3.37 (s,3 H,3-CH3),2.24 (s,3 H,2'-CH3),1.90-1.96 (m,4 H,2 × MS m / z 367.2 (MH + ,100%). HRMS calcd for C 21 H 27 N4O2(MH +) m / z 367.2129,found 367.2141 (-3.5 ppm). HPLC purity 98.2%.

[0348] Example 50: SN39673 1-Cyclopentyl-6-((4-((2-(dimethylamino)ethyl)amino)-2-methylphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (56) [ka] A mixture of N,N-dimethyl-2-(3-methyl-4-nitrophenoxy)ethane-1-amine, 4-fluoro-2-methyl-1-nitrobenzene (2.00 g, 12.9 mmol), K2CO3 (5.35 g, 38.7 mmol), and 2-(dimethylamino)ethane-1-ol (1.61 g, 18.1 mmol) in DMF (30 ml) was stirred at 60°C for 16 hours. The mixture was partitioned between ELISA (200 mL) and water (100 mL). The organic fraction was washed with water (3 × 100 mL) and brine (50 mL), dried (MgSO4), and the solvent was evaporated. The residue was purified by chromatography using a gradient (0-5%) MeOH / DCM to obtain the amine (0.58 g, 20%) as a red oil. 1 H NMR (CDCl3) δ 8.07 (dd,J = 7.8,1.7 Hz,1 H,H-6'),6.79-6.83 (m,2 H,H-2',H-5'),4.13 (br t,J = 5.6 Hz,2 H,H-2),2.76 (br t,J = 5.6 Hz,2 H,H-1),2.62 (s,3 H,3'-CH3),2.36 [s,6 H,N(CH3)2]; MS m / z 225.1 (MH + 100%). 4-(2-(dimethylamino)ethoxy)-2-methylaniline:nitroaniline (0.58 g, 2.59 mmol) and Pd / C (100 mg) were mixed in EtOH (100 mL) and ELISA (100 mL) and stirred with H2 (60 psi) for 4 hours. The mixture was filtered through a diatomaceous earth mat, washed with EtOH (50 mL), and the solvent was evaporated to obtain aniline (0.44 g, 87%) as a beige solid. 1 H NMR [(CD3)2SO] δ 6.56 (d,J = 1.2 Hz,1 H,H-3),6.48-6.53 (m,2 H,H-5,H-6),4.35 (br s,2 H,1-NH2),3.84 (br t,J = 6.0 Hz,2 H,H-1'),2.53 (br t,J = 6.0 Hz,2 H,H-2'),2.18 [s,6 H,N(CH3)2],2.02 (s,3 H,2-CH3); MS m / z 195.1 (MH + 100%). A degassed mixture of 1-cyclopentyl-6-((4-((2-(dimethylamino)ethyl)amino)-2-methylphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(56):chloride 6 (148 mg, 0.59 mmol), 4-(2-(dimethylamino)ethoxy)-2-methylaniline (91 mg, 0.47 mmol), Pd2dba3 (27 mg, 30 μmol), XPhos (56 mg, 118 μmol), and Cs2CO3 (432 mg, 1.30 mmol) in MeCN (8 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with SiO (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between SiO (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using a gradient (0-10%) MeOH / DCM to obtain imidazopyridinone 56 (80 mg, 33%) as a yellowish-brown powder. 1H NMR (CDCl3) δ 7.74 (s,1 H,H-4),7.23 (d,J = 8.6 Hz,1 H,H-6'),6.86 (d,J = 2.9 Hz,1 H,H-3'),6.78 (d,J = 8.6,2.9 Hz,1 H,H-5'),6.16 (br s,1 H,6-NH),6.10 (s,1 H,H-7),4.67 (pent,J = 8.7 Hz,1 H,1-CH),4.10 (br t,J = 5.6 Hz,2 H,CH2O),3.37 (s,3 H,3-CH3),2.80 (br t,J = 5.6,2 H,CH2N),2.40 [s,6 H,N(CH3)2],2.14 (s,3 MS m / z 410.2 (MH + ,100%). HRMS calcd for C 23 H 32 N5O2(MH + ) m / z 410.2551,found 410.2557 (-1.7 ppm). HPLC purity 97.4%.

[0349] Example 51: SN39663 1-Cyclopentyl-3-methyl-6-((2-methyl-4-morpholinophenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (57) [ka] A mixture of 4-(3-methyl-4-nitrophenyl)morpholine, 4-fluoro-2-methyl-1-nitrobenzene (1.92 g, 12.4 mmol)K2CO3 (2.05 g, 14.9 mmol), and morpholine (2.16 g, 24.8 mmol) was stirred in DMF (20 ml) at 60°C for 72 hours. The mixture was partitioned between siRNA (200 mL) and water (100 mL). The organic fraction was washed with water (3 × 100 mL) and brine (50 mL), dried (MgSO4), and the solvent was evaporated. The residue was purified by chromatography to obtain morpholide (2.40 g, 87%) as a yellow needle eluted with 20% siRNA / petroleum ether. mp 140-142 °C; 1 H NMR (CDCl3) δ 8.09 (d,J = 9.2 Hz,1 H,H-5'),6.71 (dd,J = 9.2,2.9 Hz,1 H,H-6'),6.65 (d,J = 2.9 Hz,1 H,H-2'),3.86 (br dd,J = 5.0,4.9 Hz,4 MS m / z 223.1 (MH + 100%). 2-Methyl-4-morpholinoaniline: Nitroaniline (1.30 g, 5.85 mmol) and Pd / C (100 mg) were mixed in EtOH (100 mL) and siRNA (100 mL) and stirred with H2 for 4 hours. The mixture was filtered through a diatomaceous earth mat, washed with EtOH (50 mL), and the solvent was evaporated to obtain aniline (1.12 g, 99%) as a beige solid. mp 84-86 °C; 1H NMR (CDCl3) δ 6.71 (d,J = 2.6 Hz,1 H,H-3),6.67 (dd,J = 8.4,2.6 Hz,1 H,H-5),6.63 (d,J = 8.4 Hz,1 H,H-6),3.84 (br dd,J = 4.8,4.7 Hz,4 MS m / z 223.1 (MH + 100%). A degassed mixture of 1-cyclopentyl-3-methyl-6-((2-methyl-4-morpholinophenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(57):chloride 6 (133 mg, 0.53 mmol), 2-methyl-4-morpholinoaniline (122 mg, 0.63 mmol), Pd2dba3 (24 mg, 27 μmol), XPhos (51 mg, 106 μmol), and Cs2CO3 in MeCN (6 mL) was stirred in a sealed tube at 120°C for 16 hours. The mixture was cooled, diluted with ethyl acetate (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using a gradient (70-100%) of  / petroleum ether to obtain imidazopyridinone 57 (110 mg, 51%) as a yellowish-brown powder. 1H NMR (CDCl3) δ 7.75 (d,J = 0.5 Hz,1 H,H-4),7.23 (d,J = 8.6 Hz,1 H,H-6'),6.84 (d,J = 2.8 Hz,1 H,H-3'),6.78 (d,J = 8.6,2.9 Hz,1 H,H-5'),6.15 (d,J = 0.6 Hz,1 H,H-7),6.07 (br s,1 H,6-NH),4.66 (pent,J = 8.7 Hz,1 H,1-CH),3.88 (br dd,J = 4.9,4.7 Hz,4 H,H-2'',H-6''),3.47 (s,3 H,3-CH3),3.14 (br dd,J = 4.9,4.7 Hz,4 MS m / z 408.2 (MH + ,100%). HRMS HRMS calcd for C 23 H 30 N5O2(MH + ) m / z 408.2394,found 408.2396 (-0.4 ppm). HPLC purity 98.1%.

[0350] Example 52: SN39637 1-Cyclopentyl-3-methyl-6-((2-methyl-4-(4-methylpiperazine-1-yl)phenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (58). [ka] A mixture of 1-methyl-4-(3-methyl-4-nitrophenyl)piperazine:4-fluoro-2-methyl-1-nitrobenzene (2.28 g, 14.7 mmol), K2CO3 (4.06 g, 29.4 mmol), and 1-methylpiperazine (2.20 g, 22.1 mmol) was stirred in DMF (50 ml) at 80°C for 16 hours. The mixture was partitioned between ELISA (200 mL) and water (100 mL). The organic fraction was washed with water (3 × 100 mL), then with brine (50 mL), dried (MgSO4), and the solvent was evaporated. The residue was purified by chromatography using a gradient (0-5%) MeH / DCM to obtain piperazine (3.22 g, 93%) as yellow flakes. mp 63-65 °C; 1 H NMR (CDCl3) δ 8.08 (d,J = 9.3 Hz,1 H,H-5'),6.70 (dd,J = 9.3,2.8 Hz,1 H,H-6'),6.64 (d,J = 2.8 Hz,1 H,H-2'),3.04 (br dd,J = 5.2,5.1 Hz,4 MS m / z 236.1 (MH + 100%). 2-Methyl-4-(4-methylpiperazin-1-yl)aniline:nitroaniline (0.42 g, 1.79 mmol) and Pd / C (50 mg) were mixed in EtOH (50 mL) and siRNA (50 mL) and stirred at H2 (50 psi) for 4 hours. The mixture was filtered through a diatomaceous earth mat, washed with EtOH (50 mL), and the solvent was evaporated to obtain aniline (0.35 g, 96%) as a white solid. mp 100-102 °C; 1H NMR (CDCl3) δ 6.73 (d,J = 2.7 Hz,1 H,H-3),6.69 (dd,J = 8.4,2.7 Hz,1 H,H-5),6.62 (d,J = 8.4 Hz,1 H,H-6),3.37 (br s,2 H,NH2),3.07 (br dd,J = MS m / z 206.1 (MH + 100%). A degassed mixture of 1-cyclopentyl-3-methyl-6-((2-methyl-4-(4-methylpiperazin-1-yl)phenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(58):chloride 6 (136 mg, 0.54 mmol), 2-methyl-4-(4-methylpiperazin-1-yl)aniline (133 mg, 0.65 mmol), Pd2dba3 (25 mg, 27 μmol), XPhos (51 mg, 108 μmol), and Cs2CO3 (387 mg, 1.19 mmol) in MeCN (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with ELISA (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between ELISA (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using a gradient (0-5%) MeOH / DCM to obtain imidazopyridinone 58 (167 mg, 67%) as a yellowish-brown gum. 1H NMR (CDCl3) δ 7.75 (s,1 H,H-4),7.21 (d,J = 8.6 Hz,1 H,H-6'),6.86 (d,J = 2.7 Hz,1 H,H-3'),6.80 (d,J = 8.6,2.7 Hz,1 H,H-5'),6.13 (d,J = 0.5 Hz,1 H,H-7),6.02 (br s,1 H,6-NH),4.65 (pent,J = 8.7 Hz,1 H,1-CH),3.37 (s,3 H,3-CH3),3.21 (br dd,J = 5.1,4.9 Hz,4 H,H-3'',H-5''),2.61 (br dd,J = 5.1,4.9 Hz,4 MS m / z 421.2 (MH + ,100%); HRMS calcd for C 24 H 33 N6O (MH + ) m / z 421.2710,found 421.2718 (-1.7 ppm). HPLC purity 99.2%.

[0351] Example 53: SN39758 1-Cyclopentyl-6-((4-Methoxy-2-(trifluoromethyl)phenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (59) [ka] A degassed mixture of chloride 6 (137 mg, 0.54 mmol), 4-methoxy-2-(trifluoromethyl)aniline (124 mg, 0.65 mmol), Pd2dba3 (25 mg, 27 μmol), XPhos (51 mg, 108 μmol), and Cs2CO3 (387 mg, 1.19 mmol) in MeCN (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (50-100%) of acetone / petroleum ether to obtain imidazopyridinone 59 (101 mg, 46%) as a yellowish-brown gum. 1 H NMR (CDCl3) δ 7.80 (s,1 H,H-4),7.58 (d,J = 8.9 Hz,1 H,H-6'),7.18 (d,J = 2.9 Hz,1 H,H-3'),7.06 (dd,J = 8.9,2.9 Hz,1 H,H-5'),6.34 (s,1 H,H-7),6.31 (br s,1 H,6-NH),4.71 (pent,J = 8.8 Hz,1 H,1-CH),3.85 (s,3 H,4'-OCH3),3.38 (s,3 H,3-CH3),1.94-2.02 (m,4 H,2 × CH2),1.78-1.88 (m,2 H,CH2),1.63-1.72 (m,2 H,CH2); MS m / z 407.2 (MH + ,100%). HRMS calcd for C 20 H 22 F3N4O2(MH + ) m / z 407.1689,found 407.1689 (0.1 ppm). HPLC purity 99.6%.

[0352] Example 54: SN39762 2-((1-cyclopentyl-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-6-yl)amino)-5-methoxybenzylnitrile(60) [ka] A degassed mixture of chloride 6 (128 mg, 0.51 mmol), 2-amino-5-methoxybenzonitrile (90 mg, 0.61 mmol), Pd2dba3 (23 mg, 26 μmol), XPhos (49 mg, 102 μmol), and Cs2CO3 (366 mg, 1.12 mmol) in MeCN (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with RINKAN (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between RINKAN (50 mL) and HCl (50 mL). The organic fraction was washed with RINKAN (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (50-100%) of acetate / petroleum ether to obtain imidazopyridinone 60 (85 mg, 46%) as a yellow powder. (mp (acetate / pet ether) 197-200 °C;) 1 H NMR [(CD3)2SO] δ 9.16 (br s,1 H,6'-NH),8.81 (s,1 H,H-4'),7.92 (d,J = 2.8 Hz,1 H,H-3),7.38 (d,J = 8.9 Hz,1 H,H-6),7.25 (dd,J = 8.9,2.8 Hz,1 H,H-5),6.75 (s,1 H,H-7'),4.72 (pent,J = 8.5 Hz,1 H,1'-CH),3.87 (s,3 H,4-OCH3),3.30 (s,3 H,3'-CH3),2.00-2.08 (m,4 H,2 × CH2),1.86-1.95 (m,2 H,CH2),1.60-1.70 (m,2 H,CH2); MS m / z 364.2 (MH + ,100%). HRMS calcd for C 20 H 22 N5O2(MH + ) m / z 364.1768,found 364.1766 (0.5 ppm). HPLC purity 98.8%.

[0353] Example 55: SN39759 6-((2-chloro-4-methoxyphenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (61) [ka] A degassed mixture of chloride 6 (130 mg, 0.52 mmol), 2-chloro-4-methoxyaniline (98 mg, 0.62 mmol), Pd2dba3 (24 mg, 26 μmol), XPhos (50 mg, 104 μmol), and Cs2CO3 (373 mg, 1.14 mmol) in MeCN (8 mL) was stirred in a sealed tube at 120°C for 16 hours. The mixture was cooled, diluted with HCl (50 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (100 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography to obtain imidazopyridinone 61 (108 mg, 56%) as a gray foam eluted with 50% HCl / petroleum ether. 1 H NMR (CDCl3) δ 7.82 (d,J = 0.3 Hz,1 H,H-4),7.67 (d,J = 9.0 Hz,1 H,H-6'),7.00 (d,J = 2.9 Hz,1 H,H-3'),6.83 (dd,J = 9.0,2.9 Hz,1 H,H-5'),6.40 (br s,2 H,6-NH,H-7),4.75 (p,J = 8.8 Hz,1 H,1-CH),3.81 (s,3 H,4'-OCH3),3.39 (s,3 H,3-CH3),1.95-2.05 (m,4 H,2 × CH2),1.81-1.91 (m,2 H,CH2),1.64-1.72 (m,2 H,CH2); MS m / z 373.2 (MH + ,100%). HRMS calcd for C 19 H 22 35 ClN4O2(MH + ) m / z 373.1426,found 373.1426 (-0.5 ppm); calcd for C19 H 22 37 ClN4O2(MH + ) m / z 375.1403,found 375.1407 (-1.0 ppm). HPLC purity 99.3%.

[0354] Example 56: SN39717 1-Cyclopentyl-6-((2,4-dimethoxyphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(62) [ka] A degassed mixture of chloride 6 (1330 mg, 0.532 mmol), 2,4-dimethoxyaniline (97 mg, 0.63 mmol), Pd2dba3 (24 mg, 27 μmol), XPhos (51 mg, 106 μmol), and Cs2CO3 (380 mg, 1.17 mmol) in MeCN (8 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (50 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (100 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using elution with a gradient (80-100%) of acetone / petroleum ether to obtain imidazopyridinone 62 (162 mg, 83%) as a pink foam. 1H NMR (CDCl3) δ 7.80 (d,J = 0.5 Hz,1 H,H-4),7.64 (d,J = 8.7 Hz,1 H,H-6'),6.55 (d,J = 2.7 Hz,1 H,H-3'),6.50 (dd,J = 8.7,2.7 Hz,1 H,H-5'),6.46 (br s,1 H,6-NH),6.43 (d,J = 0.6 Hz,1 H,H-7),4.76 (p,J = 8.8 Hz,1 H,1-CH),3.85 (s,3 H,2'-OCH3),3.82 (s,3 H,4'-OCH3),3.54 (s,3 H,3-CH3),1.96-2.03 (m,4 H,2 × MS m / z 369.2 (MH + ,100%). HRMS calcd for C 20 H 25 N4O3(MH + ) m / z 369.1921,found 369.1926 (-0.2 ppm). HPLC purity 99.6%.

[0355] Example 57: SN39313 1-Cyclopentyl-3-methyl-6-(quinoline-6-ylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (63) [ka] A degassed mixture of chloride 6 (121 mg, 0.48 mmol), quinoline-6-amine (83 mg, 0.58 mmol), Pd2dba3 (22 mg, 24 μmol), XPhos (46 mg, 96 μmol), and Cs2CO3 (344 mg, 1.06 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (50-100%) of acetate / petroleum ether to obtain imidazopyridinone 63 (126 mg, 73%) as a yellow powder. (mp (acetate / pet ether) 260-263 °C) 1 H NMR (CDCl3) δ 8.76 (dd,J = 4.2,1.6 Hz,1 H,H-2'),7.98-8.05 (m,2 H,H-4',H-8'),7.92 (s,1 H,H-4),7.87 (d,J = 2.5 Hz,1 H,H-5'),7.56 (dd,J = 9.1,2.5 Hz,1 H,H-7'),7.34 (dd,J = 8.3,4.2 Hz,1 H,H-3'),6.81 (br s,1 H,6-NH),6.72 (s,1 H,H-7),4.82 (pent,J = 8.8 Hz,1 H,1-CH),3.43 (s,3 H,3-CH3),1.97-2.08 (m,4 H,2 × MS m / z 360.2 (MH + ,100%). Anal calcd for C 21 H 21 N5O·1 / 4H2O: C,69.31; H,5.95; N,19.24. Found: C,69.06; H,5.62; N,19.38%. HPLC purity 100.0%.

[0356] Example 58: SN39316 1-Cyclopentyl-3-methyl-6-(quinoline-3-ylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (64) [ka] A degassed mixture of chloride 6 (126 mg, 0.50 mmol), quinoline-3-amine (87 mg, 0.60 mmol), Pd2dba3 (24 mg, 25 μmol), XPhos (47 mg, 100 μmol), and Cs2CO3 (358 mg, 1.10 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography to obtain imidazopyridinone 64 (143 mg, 79%) as a yellowish-brown powder eluted with HCl. mp (EtOAc / pet ether) 207-210 °C; 1 H NMR (CDCl3) δ 8.80 (d,J = 2.7 Hz,1 H,H-2'),8.40 (d,J = 2.6 Hz,1 H,H-4'),8.02 (d,J = 8.2 Hz,1 H,H-5'),7.92 (s,1 H,H-4),7.72 (dd,J = 8.3,1.5 Hz,1 H,H-8'),7.56 (dd,J = 8.3,1.5 Hz,1 H,H-7'),7.50 (ddd,J = 8.2,6.9,1.3 Hz,1 H,H-6'),6.83 (br s,1 H,6-NH),6.62 (d,J = 0.5 Hz,1 H,H-7),4.80 (pent,J = 8.8 Hz,1 MS m / z 360.2 (MH + ,100%); HRMS calcd for C 21 H22 N5O (MH + ) m / z 360.1819,found 360.1822 (-0.9 ppm). HPLC purity 99.9%.

[0357] Example 59: SN39322 1-Cyclopentyl-3-methyl-6-(quinoline-5-ylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (65) [ka] A degassed mixture of chloride 6 (120 mg, 0.48 mmol), quinoline-5-amine (83 mg, 0.57 mmol), Pd2dba3 (22 mg, 24 μmol), XPhos (46 mg, 96 μmol), and Cs2CO3 (344 mg, 1.06 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography to obtain imidazopyridinone 65 (94 mg, 55%) as yellowish-brown crystals eluted with HCl. mp (EtOAc / pet ether) 150-152 °C; 1H NMR (CDCl3) δ 8.95 (dd,J = 4.2,1.6 Hz,1 H,H-2'),8.40 (ddd,J = 8.5,1.4,0.8 Hz,1 H,H-4'),7.94 (d,J = 8.5 Hz,1 H,H-6'),7.82 (s,1 H,H-4),7.71 (dd,J = 8.4,7.6 Hz,1 H,H-7'),7.57 (d,J = 7.4 Hz,1 H,H-8'),7.40 (dd,J = 8.5,4.2 Hz,1 H,H-3'),6.85 (br s,1 H,6-NH),6.36 (s,1 H,H-7),4.68 (pent,J = 8.8 Hz,1 MS m / z 360.2 (MH + ,100%); HRMS calcd for C 21 H 22 N5O (MH + ) m / z 360.1819,found 360.1824 (-1.3 ppm). HPLC purity 99.8%.

[0358] Example 60: SN39323 1-Cyclopentyl-6-(isoquinoline-5-ylamino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (66) [ka] A degassed mixture of chloride 6 (120 mg, 0.48 mmol), isoquinoline-5-amine (83 mg, 0.57 mmol), Pd2dba3 (22 mg, 24 μmol), XPhos (46 mg, 96 μmol), and Cs2CO3 (344 mg, 1.06 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography to obtain imidazopyridinone 66 (73 mg, 43%) as a milky white powder eluted with HCl. mp (Â / MeOH) 234-237 °C; 1 H NMR (CDCl3) δ 9.28 (d,J = 0.6 Hz,1 H,H-1'),8.53 (d,J = 6.0 Hz,1 H,H-3'),7.86 (s,1 H,H-4),7.73-7.82 (m,3 H,H-4',H-6',H-8'),7.58 (dd,J = 7.9,7.8 Hz,1 H,H-7'),6.83 (br s,1 H,6-NH),6.44 (d,J = 0.6 Hz,1 H,H-7),4.74 (pent,J = 8.8 Hz,1 H,1-CH),3.41 (s,3 H,3-CH3),1.83-1.99 (m,4 H,2 × CH2),1.54-1.67 (m,4 H,2 × CH2); MS m / z 360.2 (MH + ,100%); HRMS calcd for C 21 H 22 N5O (MH + ) m / z 360.1819,found 360.1822 (-0.9 ppm). HPLC purity 93.6%.

[0359] Example 61: SN39325 1-Cyclopentyl-3-methyl-6-((2-methylquinoline-4-yl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (67) [ka] A degassed mixture of chloride 6 (128 mg, 0.51 mmol), 2-methylquinoline-4-amine (97 mg, 0.61 mmol), Pd2dba3 (23 mg, 26 μmol), XPhos (48 mg, 102 μmol), and Cs2CO3 (366 mg, 1.12 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with butyl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between butyl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (0-10%) of MeOH / siRNA to obtain imidazopyridinone 67 (134 mg, 71%) as yellowish-brown crystals. mp (siRNA / MeOH) 233-236 °C; 1 H NMR (CDCl3) δ 8.01 (dd,J = 8.4,0.6 Hz,1 H,H-5'),7.98 (s,1 H,H-3'),7.94 (dd,J = 8.3,0.6 Hz,1 H,H-8'),7.68 (ddd,J = 8.3,7.0,1.2 Hz,1 H,H-7'),7.44-7.50 (m,2 H,H-4,H-6'),7.27 (br s,1 H,6-NH),6.92 (s,1 H,H-7),4.87 (pent,J = 8.8 Hz,1 H,1-CH),3.46 (s,3 H,3-CH3),2.65 (s,3 H,2'-CH3),1.95-2.10 (m,4 H,2 × MS m / z 374.2 (MH + ,100%); HRMS calcd for C 22 H 24 N5O (MH + ) m / z 374.1975,found 374.1986 (-2.8 ppm). HPLC purity 100.0%.

[0360] Example 62: SN39326 1-Cyclopentyl-3-methyl-6-(quinoxaline-6-ylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (68) [ka] A degassed mixture of chloride 6 (121 mg, 0.48 mmol), quinoxaline-6-amine (83 mg, 0.58 mmol), Pd2dba3 (22 mg, 24 μmol), XPhos (46 mg, 96 μmol), and Cs2CO3 (344 mg, 1.06 mmol) in dioxane (8 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography to obtain imidazopyridinone 68 (146 mg, 84%) as a yellow powder eluted with HCl. mp (EtOAc / pet. ether) 230-232 °C; 1 H NMR (CDCl3) δ 8.74 (d,J = 1.9 Hz,1 H,H-2'),8.65 (d,J = 1.9 Hz,1 H,H-3'),8.13 (d,J = 2.5 Hz,1 H,H-5'),8.00 (d,J = 9.1 Hz,1 H,H-8'),7.93 (s,1 H,H-4),7.67 (dd,J = 9.1,2.5 Hz,1 H,H-7'),6.99 (br s,1 H,6-NH),6.77 (s,1 H,H-7),4.81 (pent,J = 8.8 Hz,1 H,1-CH),3.44 (s,3 H,3-CH3),2.01-2.10 (m,4 H,2 × CH2),1.86-1.96 (m,2 H,CH2),1.66-1.76 (m,2 H,CH2); MS m / z 361.2 (MH + ,100%); HRMS calcd for C 20 H 21 N6O (MH +) m / z 361.1761,found 361.1778 (-1.8 ppm). HPLC purity 100.0%.

[0361] Example 63: SN39402 6-(benzo[d][1,3]dioxol-5-ylamino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (69) [ka] A degassed mixture of chloride 6 (133 mg, 0.53 mmol), benzo[d][1,3]dioxol-5-amine (87 mg, 0.63 mmol), Pd2dba3 (24 mg, 24 μmol), XPhos (51 mg, 106 μmol), and Cs2CO3 (380 mg, 1.17 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with RINKAN (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between RINKAN (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography (50-70% alkyl / petroleum ether) to obtain imidazopyridinone 69 (130 mg, 70%) as a yellowish-brown powder. 1 H NMR (CDCl3) δ 7.78 (s,1 H,H-4),6.88 (d,J = 2.1 Hz,1 H,H-4'),6.78 (d,J = 8.2 Hz,1 H,H-7'),6.69 (dd,J = 8.2,2.2 Hz,1 H,H-6'),6.45 (d,J = 0.4 Hz,1 H,H-7),6.31 (br s,1 H,6-NH),5.96 (s,2 H,H-2'),4.73 (pent,J = 8.8 Hz,1 H,1-CH),3.38 (s,3 H,3-CH3),1.95-2.04 (m,4 H,2 × CH2),1.80-1.90 (m,2 H,CH2),1.62-1.70 (m,2 H,CH2); MS m / z 353.2 (MH + ,100%). HPLC purity 99.8%.

[0362] Example 64: SN39441 6-(benzo[d]thiazole-6-ylamino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (70) [ka] A degassed mixture of chloride 6 (126 mg, 0.50 mmol), benzo[d]thiazole-6-amine (90 mg, 0.60 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol), and Cs2CO3 (358 mg, 1.10 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography (50-100% HCl / petroleum ether) to obtain imidazopyridinone 70 (12 mg, 7%) as gum. 1 H NMR (CDCl3) δ 8.84 (s,1 H,H-2'),8.12 (d,J = 2.2 Hz,1 H,H-7'),8.03 (d,J = 8.8 Hz,1 H,H-4'),7.87 (s,1 H,H-4),7.33 (dd,J = 8.8,2.2 Hz,1 H,H-5'),6.65 (br s,1 H,6-NH),6.61 (s,1 H,H-7),4.79 (pent,J = 8.7 Hz,1 H,1-CH),3.41 (s,3 H,3-CH3),1.98-2.04 (m,4 H,2 × CH2),1.82-1.90 (m,2 H,CH2),1.65-1.74 (m,2 H,CH2); MS m / z 366.2 (MH + ,100%); HRMS calcd for C 19 H 20 N5OS (MH +) m / z 366.1370,found 366.1374 (-1.2 ppm). HPLC purity 96.3%.

[0363] Example 65: SN39333 1-Cyclopentyl-3-methyl-6-(pyridine-4-ylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (71) [ka] A degassed mixture of chloride 6 (124 mg, 0.49 mmol), 4-aminopyridine (56 mg, 0.59 mmol), Pd2dba3 (22 mg, 25 μmol), XPhos (47 mg, 98 μmol), and Cs2CO3 (351 mg, 1.08 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography eluting with a gradient (0-20%) MeOH / HCl to obtain imidazopyridinone 71 (54 mg, 35%) as a white powder. mp (ï) 250-252 °C; 1 H NMR (CDCl3) δ 8.37 (dd,J = 4.9,1.4 Hz,2 H,H-2',H-6'),7.93 (s,1 H,H-4),7.28 (dd,J = 4.9,1.5 Hz,2 H,H-3',H-5'),7.00 (br s,1 H,6-NH),6.67 (d,J = 0.4 Hz,1 H,H-7),4.81 (pent,J = 8.8 Hz,1 H,1-CH),3.43 (s,3 H,3-CH3),1.99-2.09 (m,4 H,2 × CH2),1.87-1.97 (m,2 H,CH2),1.68-1.78 (m,2 H,CH2); MS m / z 310.2 (MH + ,100%); HRMS calcd for C 17 H 20 N5O (MH+ ) m / z 310.1662,found 310.1668 (-1.8 ppm). HPLC purity 98.0%.

[0364] Example 66: SN39334 1-Cyclopentyl-3-methyl-6-(pyridine-3-ylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (72) [ka] A degassed mixture of chloride 6 (117 mg, 0.47 mmol), 3-aminopyridine (53 mg, 0.56 mmol), Pd2dba3 (22 mg, 25 μmol), XPhos (45 mg, 94 μmol), and Cs2CO3 (337 mg, 1.03 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120°C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue eluted with MeOH / HCl on a gradient (0-10%) was purified by chromatography to obtain imidazopyridinone 72 (121 mg, 84%) as a white powder. mp (ï) 203-206 °C; 1 H NMR (CDCl3) δ 8.57 (d,J = 2.5 Hz,1 H,H-2'),8.23 (dd,J = 4.7,1.4 Hz,1 H,H-6'),7.88 (ddd,J = 8.3,2.7,1.4 Hz,1 H,H-5'),7.84 (s,1 H,H-4),7.23 (dd,J = 8.3,4.7 Hz,1 H,H-4'),6.50-6.55 (m,2 H,6-NH,H-7),4.79 (pent,J = 8.8 Hz,1 H,1-CH),3.40 (s,3 H,3-CH3),1.97-2.07 (m,4 H,2 × CH2),1.83-1.95 (m,2 H,CH2),1.65-1.68 (m,2 H,CH2); MS m / z 310.2 (MH +,100%); HRMS calcd for C 17 H 20 N5O (MH + ) m / z 310.1662,found 310.1668 (-1.9 ppm). HPLC purity 98.5%.

[0365] Example 67: SN39341 1-Cyclopentyl-3-methyl-6-(pyridine-2-ylamino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (73) [ka] A degassed mixture of chloride 6 (122 mg, 0.49 mmol), 2-aminopyridine (55 mg, 0.58 mmol), Pd2dba3 (22 mg, 25 μmol), XPhos (47 mg, 98 μmol), and Cs2CO3 (351 mg, 1.08 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography eluting with a gradient (0-5%) MeOH / HCl to obtain imidazopyridinone 73 (112 mg, 75%) as a yellowish-brown powder. mp (æ) 151-153 °C; 1H NMR (CDCl3) δ 8.25 (ddd,J = 5.0,1.8,0.7 Hz,1 H,H-6'),7.93 (s,1 H,H-4),7.86 (s,1 H,H-7),7.56 (ddd,J = 8.4,7.2,1.9 Hz,1 H,H-4'),7.49 (br s,1 H,6-NH),7.10 (d,J = 8.4 Hz,1 H,H-3'),6.81 (ddd,J = 7.2,5.0,0.8 Hz,1 H,H-5'),4.87 (pent,J = 8.4 Hz,1 H,1-CH),3.41 (s,3 H,3-CH3),1.98-2.13 (m,6 H,3 × CH2),1.70-1.80 (m,2 H,CH2); MS m / z 310.2 (MH + ,100%); HRMS calcd for C 17 H 20 N5O (MH + ) m / z 310.1662,found 310.1665 (-0.8 ppm). HPLC purity 99.9%.

[0366] Example 68: SN39344 1-Cyclopentyl-3-methyl-6-((3-methylpyridine-4-yl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(74) [ka] A degassed mixture of chloride 6 (137 mg, 0.54 mmol), 3-methylpyridine-4-amine (71 mg, 0.65 mmol), Pd2dba3 (25 mg, 27 μmol), XPhos (51 mg, 108 μmol), and Cs2CO3 (387 mg, 1.19 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with pharmaceutically acceptable solution (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between pharmaceutically acceptable solution (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (0-20%) of MeOH / siRNA to obtain imidazopyridinone 74 (150 mg, 85%) as a brown cube. mp (siRNA) 217-220 °C; 1 H NMR (CDCl3) δ 8.27-8.31 (m,2 H,H-2',H-6'),7.93 (s,1 H,H-4),7.52 (d,J = 5.7 Hz,1 H,H-5'),6.76 (d,J = 0.4 Hz,1 H,H-7),6.40 (br s,1 H,6-NH),4.81 (pent,J = 8.8 Hz,1 H,1-CH),3.44 (s,3 H,3-CH3),2.74 (s,3 H,3'-CH3),2.00-2.09 (m,4 H,2 × CH2),1.78-1.85 (m,2 H,CH2),1.70-1.78 (m,2 H,CH2); MS m / z 324.2 (MH + ,100%); HRMS calcd for C 18 H 22 N5O (MH + ) m / z 324.1819,found 324.1825 (-1.9 ppm). HPLC purity 99.5%.

[0367] Example 69: SN39361 1-Cyclopentyl-3-methyl-6-((2-methylpyridine-4-yl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(75) [ka] A degassed mixture of chloride 6 (129 mg, 0.51 mmol), 2-methylpyridine-4-amine (67 mg, 0.61 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (49 mg, 102 μmol), and Cs2CO3 (366 mg, 1.12 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (0-10%) of MeOH / siRNA to obtain imidazopyridinone 75 (127 mg, 77%) as a milky white powder. mp (siRNA) 214-216 °C; 1 H NMR (CDCl3) δ 8.25 (d,J = 5.8 Hz,1 H,H-6'),7.93 (s,1 H,H-4),7.16 (d,J = 2.1 Hz,1 H,H-3'),7.06 (dd,J = 5.8,2.2 Hz,1 H,H-5'),7.03 (br s,1 H,6-NH),6.70 (s,1 H,H-7),4.83 (pent,J = 8.7 Hz,1 H,1-CH),3.43 (s,3 H,3-CH3),2.49 (s,3 H,2'-CH3),2.00-2.10 (m,4 H,2 × CH2),1.87-1.96 (m,2 H,CH2),1.70-1.78 (m,2 H,CH2); MS m / z 324.2 (MH + ,100%); HRMS calcd for C 18 H 22 N5O (MH + ) m / z 324.1819,found 324.1820 (-0.2 ppm). HPLC purity 99.0%.

[0368] Example 70: SN39346 1-Cyclopentyl-3-methyl-6-((2-methylpyridine-3-yl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (76) [ka] A degassed mixture of chloride 6 (125 mg, 0.50 mmol), 2-methylpyridine-3-amine (64 mg, 0.60 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol), and Cs2CO3 (358 mg, 1.10 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography to obtain imidazopyridinone 76 (103 mg, 64%) as yellowish-brown crystals eluted with HCl. mp (HCl) 144-146 °C; 1 H NMR (CDCl3) δ 8.22 (dd,J = 4.8,1.4 Hz,1 H,H-6'),7.82-7.86 (m,2 H,H-4,H-4'),7.14 (dd,J = 8.1,4.8 Hz,1 H,H-5'),6.41 (d,J = 0.6 Hz,1 H,H-7),6.14 (br s,1 H,6-NH),4.75 (pent,J = 8.8 Hz,1 H,1-CH),3.41 (s,3 H,3-CH3),2.55 (s,3 H,2'-CH3),1.95-2.05 (m,4 H,2 × CH2),1.80-1.88 (m,2 H,CH2),1.64-1.72 (m,2 H,CH2); MS m / z 324.2 (MH + ,100%); HRMS calcd for C 18 H 22 N5O (MH + ) m / z 324.1819,found 324.1819 (-0.1 ppm). HPLC purity 99.7%.

[0369] Example 71: SN39362 1-Cyclopentyl-3-methyl-6-((5-methylpyridine-3-yl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (77) [ka] A degassed mixture of chloride 6 (118 mg, 0.47 mmol), 5-methylpyridine-3-amine (61 mg, 0.56 mmol), Pd2dba3 (22 mg, 24 μmol), XPhos (45 mg, 94 μmol), and Cs2CO3 (337 mg, 1.03 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (0-10%) of MeOH / SiO2 to obtain imidazopyridinone 77 (129 mg, 78%) as a milky white powder. mp (SiO2) 182-185 °C; 1 H NMR (CDCl3) δ 8.37 (d,J = 2.5 Hz,1 H,H-6'),8.07 (d,J = 1.2 Hz,1 H,H-2'),7.85 (s,1 H,H-4),7.69 (br s,1 H,H-4'),6.62 (br s,1 H,6-NH),6.55 (d,J = 0.5 Hz,1 H,H-7),4.79 (pent,J = 8.8 Hz,1 H,1-CH),3.40 (s,3 H,3-CH3),2.33 (s,3 H,5'-CH3),1.96-2.07 (m,4 H,2 × CH2),1.84-1.92 (m,2 H,CH2),1.68-1.75 (m,2 H,CH2); MS m / z 324.2 (MH + ,100%); HRMS calcd for C 18 H 22 N5O (MH +) m / z 324.1819,found 324.1821 (-0.6 ppm). HPLC purity 94.3%.

[0370] Example 72: SN39342 1-Cyclopentyl-3-methyl-6-((4-methylpyridine-3-yl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (78) [ka] A degassed mixture of chloride 6 (127 mg, 0.51 mmol), 4-methylpyridine-3-amine (66 mg, 0.61 mmol), Pd2dba3 (23 mg, 26 μmol), XPhos (49 mg, 102 μmol), and Cs2CO3 (366 mg, 1.12 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (0-10%) of MeOH / ¼ to obtain imidazopyridinone 78 (99 mg, 61%) as a brown foam. 1 H NMR (CDCl3) δ 8.69 (s,1 H,H-2'),8.25 (d,J = 4.8 Hz,1 H,H-6'),7.81 (s,1 H,H-4),7.17 (d,J = 4.8 Hz,1 H,H-5'),6.39 (d,J = 0.5 Hz,1 H,H-7),6.14 (br s,1 H,6-NH),4.70 (pent,J = 8.8 Hz,1 H,1-CH),3.40 (s,3 H,3-CH3),2.30 (s,3 H,4'-CH3),1.95-2.02 (m,4 H,2 × CH2),1.80-1.90 (m,2 H,CH2),1.63-1.72 (m,2 H,CH2); MS m / z 324.2 (MH + ,100%); HRMS calcd for C 18 H 22N5O (MH + ) m / z 324.1819,found 324.1816 (1.0 ppm). HPLC purity 98.6%.

[0371] Example 73: SN39360 1-Cyclopentyl-3-methyl-6-((3-methylpyridine-2-yl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (79) [ka] A degassed mixture of chloride 6 (125 mg, 0.50 mmol), 3-methylpyridine-2-amine (64 mg, 0.60 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (48 mg, 100 μmol)Cs2CO3 (358 mg, 1.10 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with ethyl acetate (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography (70-100% EA / petroleum ether) to obtain imidazopyridinone 79 (149 mg, 93%) as a yellowish-brown powder. mp (EtOAc / pet ether) 169-172 °C; 1 H NMR (CDCl3) δ 8.04 (d,J = 0.5 Hz,1 H,H-4),7.85 (s,1 H,H-7),7.45 (dd,J = 8.2,7.4 Hz,1 H,H-5'),7.28 (s,1 H,6-NH),6.79 (d,J = 8.2 Hz,1 H,H-6'),6.67 (d,J = 7.4 Hz,1 H,H-4'),4.92 (pent,J = 8.7 Hz,1 H,1-CH),3.41 (s,3 H,3-CH3),2.48 (s,3 H,3'-CH3),1.98-2.16 (m,6 H,3 × CH2),1.72-1.80 (m,2 H,CH2); MS m / z 324.2 (MH +,100%); HRMS calcd for C 18 H 22 N5O (MH + ) m / z 324.1819,found 324.1818 (0.4 ppm). HPLC purity 99.6%.

[0372] Example 74: SN39405 1-Cyclopentyl-6-((6-methoxy-4-methylpyridine-3-yl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(80) [ka] A degassed mixture of chloride 6 (129 mg, 0.51 mmol), 5-methoxy-3-methylpyridine-2-amine (85 mg, 0.61 mmol), Pd2dba3 (23 mg, 26 μmol), XPhos (49 mg, 102 μmol), and Cs2CO3 (366 mg, 1.12 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with RINKAN (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between RINKAN (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography (70-100% HCl / petroleum ether) to obtain imidazopyridinone 80 (4 mg, 2%) as a clarified oil. 1 H NMR (CDCl3) δ 8.11 (s,1 H,H-2'),7.45 (s,1 H,H-4),6.69 (s,1 H,H-5'),6.03 (s,1 H,H-7),5.97 (br s,1 H,6-NH),4.64 (pent,J = 8.7 Hz,1 MS m / z 354.2 (MH +,100%); HRMS calcd for C 19 H 24 N5O2(MH + ) m / z 354.1925,found 354.1922 (0.6 ppm).

[0373] Example 75: SN39395 1-Cyclopentyl-6-((6-methoxypyrimidine-4-yl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(81) [ka] A degassed mixture of chloride 6 (128 mg, 0.51 mmol), 6-methoxypyrimidine-4-amine (76 mg, 0.61 mmol), Pd2dba3 (23 mg, 25 μmol), XPhos (49 mg, 102 μmol), and Cs2CO3 (366 mg, 1.12 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (60-100%) of acetate / petroleum ether to obtain imidazopyridinone 81 (88 mg, 51%) as white crystals. (mp (acetate / pet ether) 180-182 °C) 1 H NMR (CDCl3) δ 8.44 (d,J = 0.8 Hz,1 H,H-2'),7.90 (d,J = 0.4 Hz,1 H,H-4),7.82 (br s,1 H,6-NH),7.43 (s,1 H,H-5'),6.76 (d,J = 0.7 Hz,1 HRMS calcd for C17 H 21 N6O2(MH + ) m / z 341.1721,found 371.1711 (2.7 ppm). HPLC purity 99.8%.

[0374] Example 76: SN39258 6-((4-aminophenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (82) [ka] A mixture of nitroaniline 17 (66 mg, 0.19 mol) and Pd / C (10 mg) in EtOH / siRNA (1:1, 30 mL) was stirred at H2 (50 psi) for 3 hours. The mixture was filtered through diatomaceous earth, the mat was washed with EtOH (20 mL), and the combined filtrate was evaporated. The residue was crystallized to obtain imidazopyridinone 82 (40 mg, 66%) as a brown powder. mp (siRNA / PET ether) 171-173 °C; 1 H NMR (CDCl3) δ 7.74 (d,J = 0.4 Hz,1 H,H-4),7.08 (ddd,J = 8.6,3.1,2.1 Hz,2 H,H-2',H-6'),6.71 (ddd,J = 8.6,3.1,2.1 Hz,2 H,H-3',H-5'),6.37 (d,J = 0.6 Hz,1 H,H-7),6.21 (s,1 H,6-NH),4.70 (pent,J = 8.7 Hz,1 H,1-CH),3.62 (br s,2 H,4'-NH2),3.37 (s,3 H,3-CH3),1.92-1.98 (m,4 H,2 × CH2),1.76-1.86 (m,2 H,CH2),1.59-1.60 (m,2 H,CH2); MS m / z 324.2 (MH + ,100%). Anal calcd for C 18 H 21 N5O·1 / 4H2O: C,65.93; H,6.61; N,21.36. Found: C,65.90; H,6.37; N,21.47%. HPLC purity 99.3%.

[0375] Example 77: SN39259 6-((3-aminophenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (83) [ka] A mixture of nitroaniline 18 (80 mg, 0.23 mmol) and Pd / C (10 mg) in EtOH / Â (1:1, 30 mL) was stirred at H2 (50 psi) for 3 hours. The mixture was filtered through diatomaceous earth, the mat was washed with EtOH (20 mL), and the combined filtrate was evaporated. The residue was crystallized to obtain imidazopyridinone 83 (40 mg, 54%) as a yellowish-brown powder. mp (Â / pet ether) 151-153 °C; 1 H NMR (CDCl3) δ 7.81 (s,1 H,H-4),7.10 (d,J = 7.9 Hz,1 H,H-5'),6.67 (d,J = 0.6 Hz,1 H,H-7),6.61-6.65 (m,2 H,H-2',H-6'),6.39 (br s,1 H,6-NH2 CH2),1.83-1.93 (m,2 H,CH2),1.64-1.74 (m,2 H,CH2); MS m / z 324.2 (MH + ,100%). Anal calcd for C 18 H 21 N5O: C,66.85; H,6.55; N,21.66. Found: C,66.93; H,6.56; N,21.57%. HPLC purity 97.9%.

[0376] Example 78: SN39272 6-((2-aminophenyl)amino)-1-cyclopentyl-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (84) [ka] A mixture of nitroaniline 19 (100 mg, 0.28 mmol) and Pd / C (10 mg) in EtOH / siRNA (1:1, 30 mL) was stirred with H2 (50 psi) for 3 hours. The mixture was filtered through diatomaceous earth, the mat was washed with EtOH (20 mL), and the combined filtrate was evaporated. The residue was crystallized to obtain imidazopyridinone 84 (56 mg, 62%) as a pink needle. mp (siRNA / PET ether) 150-151 °C; 1 H NMR (CDCl3) δ 7.77 (s,1 H,H-4),7.18 (dd,J = 7.8,1.3 Hz,1 H,H-6'),7.07 (ddd,J = 7.7,7.6,1.4 Hz,1 H,H-4'),6.83 (dd,J = 7.9,1.4 Hz,1 H,H-3'),6.78 (dt,J = 7.6,1.4 Hz,1 H,H-5'),6.14 (d,J = 0.6 Hz,1 H,H-7),6.03 (br s,1 H,6-NH),4.68 (pent,J = 8.7 Hz,1 H,1-CH),3.86 (br s,2 H,2'-NH2),3.39 (s,3 MS m / z 324.2 (MH + ,100%). Anal calcd for C 18 H 21 N5O: C,66.85; H,6.55; N,21.66. Found: C,66.97; H,6.57; N,21.44%. HPLC purity 99.6%.

[0377] Example 79: SN39305 1-Cyclopentyl-6-((4-hydroxyphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (85) [ka] A mixture of benzyl ether 34 (130 mg, 0.31 mmol) and Pd / C (25 mg) in  (25 ml) and EtOH (25 ml) was stirred at H2 (50 psi) at 20°C for 16 hours. The mixture was filtered through diatomaceous earth, and the filtrate was evaporated. The residue was purified by chromatography using a gradient (80-100%) of  / petroleum ether to obtain imidazopyridinone 85 (73 mg, 72%) as milky white crystals. mp ( / Petroleum ether) 257-260 °C; 1 H NMR [(CD3)2SO] δ 8.84 (s,1 H,4'-OH),8.34 (s,1 H,6-NH),7.83 (s,1 H,H-4),7.36 (ddd,J = 8.9,3.4,2.1 Hz,2 H,H-2',H-6'),6.65 (ddd,J = 8.9,3.4,2.1 Hz,2 H,H-3',H-5'),6.50 (s,1 H,H-7),4.70 (pent,J = 8.4 Hz,1 H,1-CH),3.27 (s,3 H,3-CH3),1.85-1.96 (m,6 H,3 × CH2),1.63-1.70 (m,2 H,CH2); MS m / z 325.2 (MH + ,100%). Anal. calcd for C 18 H 20 N4O2·0.2EtOAc: C,66.02; H,6.38; N,16.38. Found: C,66.10; H,6.61; N,16.73%. HPLC purity 99.9%.

[0378] Example 80: SN39306 1-Cyclopentyl-6-((3-hydroxyphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (86) [ka] A mixture of benzyl ether 35 (198 mg, 0.31 mol) and Pd / C (25 mg) in ethyl (25 ml) and ethyl (25 ml) was stirred at 20°C for 16 hours under H2 (50 psi). The mixture was filtered through diatomaceous earth, and the filtrate was evaporated. The residue was purified by chromatography using a gradient (80-100%) of ethyl / petroleum ether to obtain imidazopyridinone 86 (97 mg, 63%) as white crystals. mp (ethyl / petroleum ether) 216-218 °C; 1 H NMR [(CD3)2SO] δ 9.11 (s,1 H,4'-OH),8.64 (s,1 H,6-NH),7.92 (s,1 H,H-4),7.20 (d,J = 2.0 Hz,1 H,H-2'),7.93-7.01 (m,2 H,H-5',H-6'),6.64 (s,1 H,H-7),6.24 (dt,J = 6.9,2.2 Hz,1 H,H-4'),4.72 (pent,J = 8.8 Hz,1 H,1-CH),3.30 (s,3 H,3-CH3),1.87-1.97 (m,6 H,3 × CH2),1.65-1.72 (m,2 H,CH2); MS m / z 325.2 (MH + ,100%). Anal. calcd for C 18 H 20 N4O2·0.2EtOAc: C,66.02; H,6.37; N,16.38. Found: C,65.91; H,6.50; N,16.38%. HPLC purity 99.2%.

[0379] Example 81: SN39329 1-Cyclopentyl-6-((2-hydroxyphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (87) [ka] Benzyl ether 36 (108 mg, 0.26 mmol) and Pd / C (20 mg) were mixed in a mixture of alkyl (25 mL) and EtOH (25 mL). The mixture was stirred at 20°C for 16 hours under H2 (50 psi). The mixture was filtered through diatomaceous earth, and the filtrate was evaporated. The residue was purified by chromatography using a gradient (50-100%) of alkyl / petroleum ether to obtain imidazopyridinone 87 (46 mg, 55%) as a white powder. mp (alkyl / petroleum ether) 160-163 °C; 1 H NMR [(CD3)2SO] δ 10.53 (s,1 H,OH),8.14 (br s,1 H,6-NH),7.88 (s,1 H,H-4),7.78 (dd,J = 7.7,1.8 Hz,1 H,H-6'),6.88 (s,1 H,H-7),6.82 (dd,J = 7.7,1.8 Hz,1 H,H-3'),6.77 (ddd,J = 7.7,7.2,1.8 Hz,1 H,H-4'),6.72 (ddd,J = 7.7,7.2,1.8 Hz,1 H,H-5'),4.70 (pent,J = 8.6 Hz,1 H,1-CH),3.29 (s,3 H,3-CH3),1.89-1.99 (m,6 H,3 × CH2),1.60-1.70 (m,2 H,CH2); MS m / z 325.2 (MH + ,100%); HRMS calcd for C 18 H 21 N4O2(MH + ) m / z 325.1659,found 325.1666 (-2.2 ppm). HPLC purity 99.0%.

[0380] Example 82: SN39375 1-Cyclopentyl-6-((4-hydroxy-2-methylphenyl)amino)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (88) [ka] A mixture of benzyl ether 51 (172 mg, 0.40 mol) and Pd / C (20 mg) in HCl (25 ml) and EtOH (25 ml) was stirred at 20°C for 16 hours at hH2 (50 psi). The mixture was filtered through diatomaceous earth, and the filtrate was evaporated. The residue was purified by chromatography using a gradient (50-100%) of HCl / petroleum ether to obtain imidazopyridinone 88 (44 mg, 32%) as a pink powder. mp (HCl / pet. ether) 244-246 °C; 1 H NMR [(CD3)2SO] δ 9.03 (s,1 H,4'-OH),7.76 (br s,1 H,6-NH),7.57 (s,1 H,H-4),7.14 (d,J = 8.5 Hz,1 H,H-6'),6.54 (dd,J = 8.5,2.8 Hz,1 H,H-5'),6.62 (d,J = 2.7 Hz,1 H,H-3'),6.25 (s,1 H,H-7),4.64 (pent,J = 8.7 Hz,1 H,1-CH),3.25 (s,3 H,3-CH3),2.09 (s,3 H,2'-CH3),1.82-1.89 (m,4 H,2 × CH2),1.72-1.82 (m,2 H,CH2),1.58-1.68 (m,2 H,CH2); MS m / z 339.2 (MH + ,100%); HRMS calcd for C 19 H 23 N4O2(MH + ) m / z 339.1816,found 339.1811 (1.3 ppm). HPLC purity 99.2%.

[0381] Example 83: SN39777 3-benzyl-1-cyclopentyl-6-((4-methoxy-2-methylphenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(94) [ka] 3-benzyl-6-chloro-1-cyclopentyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(89): To a stirred mixture of imidazopyridinone 5 (321 mg, 1.35 mol) and benzyl bromine (0.24 mL, 2.03 mol) in dry DMF (5 mL), NaH (60% dispersion, 65 mg, 1.62 mol) was added at 5 °C. The mixture was stirred at 20 °C for 16 hours, then quenched with ice / water (5 mL) and partitioned between ethyl acetate (100 mL) and water (50 mL). The organic fraction was washed with water (2 × 50 mL), then with brine (50 mL), dried (MgSO₄), filtered, and the solvent evaporated. The residue was purified by chromatography using ammonium ether / petroleum ether with a gradient (10-20%) to obtain chloride 89 (352 mg, 80%) as a yellowish-brown oil. 1 H NMR (CDCl3) δ 7.83 (d,J = 0.5 Hz,1 H,H-4),7.27-7.38 (m,5 H,aryl-H),6.98 (d,J = 0.5 Hz,1 H,H-7),5.05 (s,2 H,3-CH2),4.82 (pent,J = 8.7 Hz,1 MS m / z 328.2 (MH + ,100%),330.2 (MH + ,35%). HRMS calcd for C 18 H 19 35 ClN3O (MH + ) m / z 328.1211,found 328.1223 (-3.7 ppm). A degassed mixture of 3-benzyl-1-cyclopentyl-6-((4-methoxy-2-methylphenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(94):chloride 89 (170 mg, 0.52 mmol), 4-methoxy-2-methylaniline (85 mg, 0.62 mmol), Pd2dba3 (24 mg, 26 μmol), XPhos (50 mg, 104 μmol), and Cs2CO3 (373 mg, 1.14 mmol) in MeCN (8 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with ELISA (50 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between ELISA (100 mL) and water (50 mL). The organic fraction was washed with water (30 mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using a gradient (40-50%) of alkyl ethyl acetate / petroleum ether to obtain imidazopyridinone 94 (70 mg, 31%) as a yellowish-brown foam. 1 H NMR (CDCl3) δ 7.62 (d,J = 0.4 Hz,1 H,H-4),7.27-7.34 (m,5 H,aryl-H),7.20 (d,J = 8.6 Hz,1 H,H-6'),6.82 (d,J = 2.9 Hz,1 H,H-3'),6.75 (dd,J = 8.6,2.9 Hz,1 H,H-5'),6.10 (d,J = 0.5 Hz,1 H,H-7),5.94 (br s,1 H,6-NH),4.98 (s,2 H,3-CH2),4.70 (pent,J = 8.7 Hz,1 H,1-CH),3.81 (s,3 H,4'-OCH3),2.23 (s,3 MS m / z 429.2 (MH + ,100%). HRMS calcd for C 26 H 29 N4O2(MH + ) m / z 429.2285,found 429.2298 (-3.0 ppm). HPLC purity 98.7%.

[0382] Example 84: SN39778 1,3-dicyclopentyl-6-((4-methoxy-2-methylphenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(95) [ka] 6-Chloro-1,3-dicyclopentyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(90):pyridinone 5 (300 mg, 1.26 mmol) and iodocyclopentane (0.22 mL, 1.89 mmol) were stirred in dry DMF (5 mL), to which NaH (60% dispersion, 61 mg, 1.51 mmol) was added at 5 °C. The mixture was stirred at 20 °C for 16 hours, then quenched with ice / water (5 mL), and partitioned between ethyl acetate (100 mL) and water (50 mL). The organic fraction was washed with water (2 × 50 mL), washed with brine (50 mL), dried (MgSO₄), filtered, and the solvent was evaporated. The residue was purified by chromatography using acetone / petroleum ether with a gradient (10-20%) to obtain chloride 90 (215 mg, 56%) as a yellowish-brown oil. 1 H NMR (CDCl3) δ 8.04 (d,J = 0.4 Hz,1 H,H-4),6.98 (d,J = 0.4 Hz,1 H,H-7),4.75-4.87 (m,2 H,1-CH,3-CH),1.91-2.08 (m,12 H,6 × CH2),1.70-1.78 (m,4 H,2 × CH2); MS m / z 306.2 (MH + ,100%),308.2 (MH + ,35%). HRMS calcd for C 16 H 21 35 ClN3O (MH + ) m / z 306.1368,found 306.1374 (-2.2 ppm). A degassed mixture of 1,3-dicyclopentyl-6-((4-methoxy-2-methylphenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(95):chloride 90 (190 mg, 0.62 mmol), 4-methoxy-2-methylaniline (103 mg, 0.75 mmol), Pd2dba3 (28 mg, 31 μmol), XPhos (59 mg, 124 μmol), and Cs2CO3 (444 mg, 1.36 mmol) in MeCN (8 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with ethyl acetate (50 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic fraction was washed with water (30 mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using a gradient (25-30%) of  / petroleum ether to obtain imidazopyridinone 95 (51 mg, 20%) as a yellowish-brown powder. mp 163-165 °C; 1 H NMR (CDCl3) δ 7.84 (d,J = 0.5 Hz,1 H,H-4),7.23 (d,J = 8.6 Hz,1 H,H-6'),6.84 (d,J = 2.9 Hz,1 H,H-3'),6.77 (dd,J = 8.6,2.9 Hz,1 H,H-5'),6.12 (d,J = 0.5 Hz,1 H,H-7),5.96 (br s,1 H,6-NH),4.81 (pent,J = 8.8 Hz,1 H,3-CH),4.68 (pent,J = 8.8 Hz,1 H,1-CH),3.82 (s,3 H,4'-OCH3),2.25 (s,3 H,2'-CH3),2.00-2.07 (m,4 H,2 × MS m / z 407.2 (MH + ,100%). HRMS calcd for C 24 H 31 N4O2(MH +) m / z 407.2441,found 407.2437 (-1.2 ppm). HPLC purity 99.4%.

[0383] Example 85: SN39790 1-Cyclopentyl-3-isopropyl-6-((4-methoxy-2-methylphenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (96) [ka] 6-Chloro-1-cyclopentyl-3-isopropyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(91): To a stirred solution of pyridinone 5 (0.30 g, 1.3 mmol) and isopropyl bromide (0.18 mL, 1.9 mmol) in dry DMF (5 mL), NaH (60% dispersion, 61 mg, 1.5 mmol) was added at 5 °C. The mixture was stirred at 20 °C for 16 hours, then quenched with ice / water (5 mL) and partitioned between ethyl acetate (100 mL) and water (50 mL). The organic fraction was washed with water (2 × 50 mL), then with brine (50 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography to obtain chloride 91 (235 mg, 67%) as a white solid eluted with 20% ethyl acetate / petroleum ether. mp 129-131 °C; 1 H NMR (CDCl3) δ 8.12 (d,J = 0.4 Hz,1 H,H-4),6.98 (d,J = 0.4 Hz,1 H,H-7),4.78 (pent,J = 8.7 Hz,1 H,1-CH),4.72 (sept,J = 7.0 Hz,1 MS m / z 280.2 (MH + ,100%),282.2 (MH + ,35%). HRMS calcd for C 14 H 19 35 ClN3O (MH +) m / z 280.1211,found 280.1217 (-2.1 ppm). A degassed mixture of 1-cyclopentyl-3-isopropyl-6-((4-methoxy-2-methylphenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(96):chloride 91 (123 mg, 0.44 mmol), 4-methoxy-2-methylaniline (72 mg, 0.53 mmol), Pd2dba3 (20 mg, 22 μmol), XPhos (42 mg, 88 μmol), and Cs2CO3 (315 mg, 0.97 mmol) in MeCN (8 mL) was stirred in a sealed tube at 120°C for 16 hours. The mixture was cooled, diluted with ethyl acetate (50 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between ethyl acetate (100 mL) and water (50 mL). The organic fraction was washed with water (30 mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography to obtain imidazopyridinone 96 (46 mg, 12%) as a red solid eluted with 50% siRNA / petroleum ether. (mp 140-142 °C;) 1 H NMR (CDCl3) δ 7.93 (d,J = 0.5 Hz,1 H,H-4),7.22 (d,J = 8.6 Hz,1 H,H-6'),6.84 (d,J = 2.9 Hz,1 H,H-3'),6.77 (dd,J = 8.6,2.9 Hz,1 H,H-5'),6.11 (d,J = 0.5 Hz,1 H,H-7),5.98 (br s,1 H,6-NH),4.63-4.70 (m,2 H,1-CH,3-CH),3.82 (s,3 H,4'-OCH3),2.26 (s,3 H,2'-CH3),1.88-1.96 (m,4 H,2 × CH2),1.70-1.78 (m,2 H,CH2),1.57-1.66 (m,2 H,CH2),1.51 (d,J = 7.0 Hz,6 H,2 × CH3); MS m / z 381.2 (MH + ,100%). HRMS calcd for C 22 H 28 N4O2(MH +) m / z 381.2285,found 381.2295 (-2.7 ppm). HPLC purity 97.7%.

[0384] Example 86:SN39789 1-Cyclopentyl-6-((4-methoxy-2-methylphenyl)amino)-3-(2-methoxyethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(97) [ka] 6-Chloro-1-cyclopentyl-3-(2-methoxyethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(92):pyridinone 5 (0.32 g, 1.4 mmol) and 1-bromo-2-methoxyethane (0.19 mL, 2.0 mmol) were stirred in dry DMF (5 mL), to which NaH (60% dispersion, 65 mg, 1.6 mmol) was added at 5 °C. The mixture was stirred at 20 °C for 16 hours, then quenched with ice / water (5 mL), and partitioned between ethyl acetate (100 mL) and water (50 mL). The organic fraction was washed with water (2 × 50 mL), washed with brine (50 mL), dried (MgSO₄), filtered, and the solvent was evaporated. The residue was purified by chromatography using elution with a gradient (40-50%) of Â1 / petroleum ether to obtain chloride 92 (301 mg, 75%) as a white solid. (mp 80-83 °C) 1 H NMR (CDCl3) δ 8.14 (s,1 H,H-4),6.97 (d,J = 0.4 Hz,1 H,H-7),4.80 (pent,J = 8.7 Hz,1 H,1-CH),4.05 (dd,J = 5.3,5.0 Hz,2 H,CH2O),3.66 (dd,J = MS m / z 296.2 (MH + ,100%),298.2 (MH + ,35%). HRMS calcd for C 14 H 19 35ClN3O2(MH + ) m / z 296.1160, found 296.1166 (-1.9 ppm). A degassed mixture of 1-cyclopentyl-6-((4-methoxy-2-methylphenyl)amino)-3-(2-methoxyethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(97):chloride 92 (217 mg, 0.73 mmol), 4-methoxy-2-methylaniline (120 mg, 0.88 mmol), Pd2dba3 (33 mg, 37 μmol), XPhos (70 mg, 146 μmol), and Cs2CO3 (523 mg, 1.61 mmol) in MeCN (8 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with ELISA (50 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between ELISA (100 mL) and water (50 mL). The organic fraction was washed with water (30 mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using a gradient (60-100%) of siRNA / petroleum ether to obtain imidazopyridinone 97 (122 mg, 42%) as a red foam. 1 H NMR (CDCl3) δ 7.90 (d,J = 0.5 Hz,1 H,H-4),7.22 (d,J = 8.6 Hz,1 H,H-6'),6.83 (d,J = 2.9 Hz,1 H,H-3'),6.76 (dd,J = 8.6,3.0 Hz,1 H,H-5'),6.10 (d,J = 0.5 Hz,1 H,H-7),5.98 (br s,1 H,6-NH),4.67 (pent,J = 8.7 Hz,1 H,1-CH),3.99 (dd,J = 5.4,5.3 Hz,2 H,CH2O),3.82 (s,3 H,4'-OCH3),3.66 (dd,J = 5.4,5.3 Hz,2 MS m / z 397.2 (MH +,100%); HRMS calcd for C 22 H 29 N4O3(MH + ) m / z 397.2234,found 397.2244 (-2.5 ppm). HPLC purity 96.8%.

[0385] Example 87: SN39793 3-(2-(benzyloxy)ethyl)-1-cyclopentyl-6-((4-methoxy-2-methylphenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one (98) [ka] 3-(2-(benzyloxy)ethyl)-6-chloro-1-cyclopentyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(93):pyridinone 5 (0.45 g, 1.9 mmol) and benzyl 2-bromodiethyl ether (0.45 mL, 2.8 mmol) were stirred in dry DMF (5 ml), to which NaH (60% dispersion, 90 mg, 2.3 mmol) was added at 5 °C. The mixture was stirred at 20 °C for 16 hours, then quenched with ice / water (5 ml), and partitioned between ethyl acetate (100 ml) and water (50 ml). The organic fraction was washed with water (2 × 50 mL), washed with brine (50 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (20-50%) of  / petroleum ether to obtain chloride 93 (656 mg, 94%) as white crystals. (mp 133-135 °C) 1H NMR (CDCl3) δ 8.14 (d,J = 0.5 Hz,1 H,H-4),7.24-7.31 (m,3 H,aryl-H),7.17-7.20 (m,2 H,aryl-H),6.97 (d,J = 0.5 Hz,1 H,H-7),4.78 (pent,J = 8.7 Hz,1 H,1-CH),4.49 (s,3 H,CH2O),4.07 (dd,J = 5.3,5.0 Hz,2 H,CH2O),3.75 (dd,J = 5.3,5.0 Hz,2 H,3-CH2),1.92-2.07 (m,6 H,3 × CH2),1.70-1.78 (m,2 H,CH2); MS m / z 372.2 (MH + ,100%),374.2 (MH + ,35%). HRMS calcd for C 20 H 23 35 ClN3O2(MH + ) m / z 372.1473,found 372.1477 (-1.0 ppm). A degassed mixture of 3-(2-(benzyloxy)ethyl)-1-cyclopentyl-6-((4-methoxy-2-methylphenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(98):chloride 93 (614 mg, 1.65 mmol), 4-methoxy-2-methylaniline (272 mg, 1.98 mmol), Pd2dba3 (75 mg, 82 μmol), XPhos (157 mg, 330 μmol), and Cs2CO3 (1.18 g, 3.63 mmol) in MeCN (12 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with SiO2 (50 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between SiO2 (100 mL) and water (50 mL). The organic fraction was washed with water (30 mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using a gradient (40-60%) of siRNA / petroleum ether to obtain imidazopyridinone 98 (308 mg, 39%) as a yellowish-brown powder. mp (siRNA / petroleum ether) 126-127 °C; 1H NMR (CDCl3) δ 7.90 (d,J = 0.5 Hz,1 H,H-4),7.21-7.35 (m,6 H,H-6',5 × Aryl-H),6.84 (d,J = 2.9 Hz,1 H,H-3'),6.77 (dd,J = 8.6,3.0 Hz,1 H,H-5'),6.10 (d,J = 0.6 Hz,1 H,H-7),5.98 (br s,1 H,6-NH),4.67 (pent,J = 8.7 Hz,1 H,1-CH),4.52 (s,2 H,CH2O),4.02 (t,J = 5.5 Hz,2 H,CH2O),3.81 (s,3 H,4'-OCH3),3.74 (t,J = 5.5 Hz,2 MS m / z 473.2 (MH + ,100%). HRMS calcd for C 28 H 33 N4O3(MH + ) m / z 473.2547,found 473.2557 (-2.0 ppm). HPLC purity 99.7%.

[0386] Example 88:SN39794 1-Cyclopentyl-3-(2-hydroxyethyl)-6-((4-methoxy-2-methylphenyl)amino)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(99) [ka] A mixture of benzyl ether 98 (255 mg, 0.54 mmol) and Pd / C (30 mg) in HOAc (50 ml) was vigorously stirred at H2 (60 psi) for 24 hours. The mixture was filtered through diatomaceous earth and washed with ethyl acetate (20 ml). The solvent was evaporated, and the residue was dissolved in ethyl acetate (80 ml) and washed sequentially with NaHCONaHCO3 (50 ml), water (50 ml), and brine (30 ml). The organic fraction was dried (MgSO4), and the solvent was evaporated. The residue was purified by chromatography to obtain alcohol 99 (179 mg, 87%) as a white powder eluted with ethyl acetate. mp 159-161 °C 1 H NMR (CDCl3) δ 7.85 (d,J = 0.5 Hz,1 H,H-4),7.12 (d,J = 8.6 Hz,1 H,H-6'),6.84 (d,J = 2.9 Hz,1 H,H-3'),6.77 (d,J = 8.6,2.9 Hz,1 H,H-5'),6.09 (d,J = 0.6 Hz,1 H,H-7),6.04 (br s,1 H,6-NH),4.67 (pent,J = 8.7 Hz,1 H,1-CH),3.95-4.00 (m,4 H,3-CH2,CH2O),3.82 (s,3 H,4'-OCH3),2.24 (s,3 H,2'-CH3),1.88-1.98 (m,4 H,2 × MS m / z 383.2 (MH + ,100%). HRMS calcd for C 21 H 27 N4O3(MH + ) m / z 383.2078,found 383.2082 (-1.7 ppm). HPLC purity 99.4%.

[0387] Example 89: SN39478 6-((4-methoxy-2-methylphenyl)amino)-1-(2-methoxyethyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(104) [ka] 2-Chloro-N-(2-methoxyethyl)-5-nitropyridine-4-amine(100): To a stirred solution of nitropyridine 2 (1.04 g, 5.39 mmol) and iPr2NEt (1.00 mL, 5.93 mmol) in dry DCM (5 mL), a solution of 2-methoxyethylamine (0.49 mL, 5.66 mmol) in dry DCM (5 mL) was added dropwise at 5°C. The mixture was stirred at 20°C for 16 hours, then diluted with DCM (100 mL), washed with water (3 × 50 mL), dried (MgSO4), and the solvent was evaporated. The residue was purified by chromatography with elution using a gradient (10-20%) Âx / petroleum ether to obtain chloride 100 (1.19 g, 95%) as a yellow needle. mp 84-86 °C; 1 H NMR (CDCl3) δ 9.02 (s, 1 H, H-6), 8.36 (br s, 1 H, 4-NH), 6.77 (s, 1 H, H-3), 3.67 (dd, J = 5.4, 5.0 Hz, 2 H, H-2'), 3.49 (dt, J = 5.3, 5.1 Hz, 2 H, H-1'), 3.44 (s, 3 H, 2'-OCH3); MS m / z 232.2 (MH + , 100%), 234.2 (MH) + , 35%). Analysis calcd for C8H 10 ClN3O3: C, 41.48; H, 4.35; N, 18.18. Found: C, 41.65; H, 4.24; N, 18.18%. 6-Chloro-N 4 -(2-methoxyethyl)pyridine-3,4-diamine(101): A solution of nitropyridine 100 (1.14 g, 4.95 mmol) in ethyl acetate (50 mL) was added dropwise to a stirred suspension of SnCl2·2H2O (4.47 g, 19.8 mmol) in ethyl acetate (100 mL) at a temperature below 60°C. The mixture was stirred at 60°C for 2 hours, then cooled to 5°C and concentrated (solution). NH3 solution was added until the solution became basic (pH 9). The resulting precipitate was filtered and washed with ethyl acetate (100 mL). The combined organic fraction was dried (MgSO4), filtered, and the solvent was evaporated to obtain diamine 101 as a white powder. mp 130-131 °C;1 H NMR (CDCl3) δ 7.65 (s,1 H,H-2),6.45 (s,1 H,H-5),4.60 (br s,1 H,4-NH),3.64 (dd,J = 5.3,5.0 Hz,2 H,H-2'),3.40 (s,3 H,2'-OCH3),3.31 (dt,J = 5.3,5.1 Hz,2 H,H-1'),3.06 (br s,2 H,3-NH2); MS m / z 202.2 (MH + ,100%),204.1 (MH + 35%). Analysis calcd for C8H 12 ClN3O: C,47.65; H,6.00; N,20.84. Found: C,47.42; H,6.03; N,21.10%. 6-Chloro-1-(2-methoxyethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(102):diamine 101 (0.99 g, 4.90 mmol) was mixed in a stirred solution in dry MeCN (50 ml) with CDI (0.96 g, 5.89 mmol) at 20°C. The mixture was stirred at 20°C for 48 hours. The solvent was evaporated, and the residue was partitioned between CHCl3 (100 mL) and water (100 mL). The organic fraction was washed with water (2 × 50 mL), then with brine (50 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was precipitated from 50% siRNA / petroleum ether to obtain pyridinone 102 (0.75 g, 67%) as a white powder. mp 170-171 °C; 1 H NMR (CDCl3) δ 9.52 (br s,1 H,3-H),8.10 (d,J = 0.5 Hz,1 H,H-4),7.12 (d,J = 0.5 Hz,1 H,H-7),4.03 (dd,J = 5.2,4.9 Hz,2 H,H-2'),3.68 (dd,J = 5.2,4.9 Hz,2 H,H-1'),3.34 (s,3 H,2'-OCH3); MS m / z 228.1 (MH + ,100%),230.1 (MH + 35%). Anal calcd for C9H 10ClN3O2: C,47.49; H,4.43; N,18.46. Found: C,47.54; H,4.28; N,18.57%. 6-Chloro-1-(2-methoxyethyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(103):pyridinone 102 (0.72 g, 3.16 mmol) and MeI (0.30 ml, 4.74 mmol) were stirred in dry DMF (20 ml) to which NaH (60% dispersion, 152 mg, 3.80 mmol) was added at 5°C. The mixture was stirred at 20°C for 16 hours, and then quenched with ice / water (5 mL). The solvent was evaporated, and the residue was partitioned between ELISA (100 ml) and water (50 ml). The organic fraction was washed with water (2 × 50 ml), washed with brine (50 ml), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using ethyl acetate / petroleum ether with a gradient (50-100%) to obtain chloride 103 (0.43 g, 56%) as a white powder. mp (DCM) 80-82 °C; 1 H NMR (CDCl3) δ 7.96 (s,1 H,H-4),7.09 (d,J = 0.5 Hz,1 H,H-7),4.02 (dd,J = 5.3,4.9 Hz,1 H,H-2'),3.65 (dd,J = 5.2,4.9 Hz,2 H,H-1'),3.45 (s,3 H,3-CH3),3.34 (s,3 H,2'-OCH3); MS m / z 242.2 (MH + ,100%),244.1 (MH + 35%). Anal calcd for C 10 H 12 ClN3O2·0.1CH2Cl2: C,48.49; H,4.92; N,116.80 Found: C,48.66; H,4.95; N,16.89%. A degassed mixture of 6-((4-methoxy-2-methylphenyl)amino)-1-(2-methoxyethyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(104):chloride 103 (117 mg, 0.48 mmol), aniline (80 mg, 0.58 mmol), Pd2dba3 (22 mg, 24 μmol), XPhos (46 mg, 96 μmol), and Cs2CO3 (344 mg, 1.06 mmol) in MeCN (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography to obtain imidazopyridinone 104 (84 mg, 51%) as a white needle eluted with HCl / petroleum ether. mp (HCl / pet ether) 133-135 °C; 1 H NMR (CDCl3) δ 7.74 (d,J = 0.4 Hz,1 H,H-4),7.22 (d,J = 8.6 Hz,1 H,H-6''),6.83 (d,J = 2.9 Hz,1 H,H-3''),6.76 (dd,J = 8.6,2.9 Hz,1 H,H-5''),6.15 (d,J = 0.4 Hz,1 H,H-7),5.98 (s,1 H,6-NH),3.88 (t,J = 5.3 Hz,1 H,H-2'),3.82 (s,3 H,4''-OCH3),3.57 (t,J = 5.3 Hz,2 H,H-1'),3.39 (s,3 H,3-CH3),3.26 (s,3 H,2'-OCH3),2.24 (s,3 H,2''-CH3); MS m / z 343.2 (MH + ,100%). Anal calcd for C 18 H 22 N4O3: C,63.14; H,6.48; N,16.36. Found: C,63.25; H,6.38; N,16.45%. HPLC purity 99.8%.

[0388] Example 90: SN39551 6-((4-chloro-2-methylphenyl)amino)-1-(2-methoxyethyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(105) [ka] A degassed mixture of chloride 103 (110 mg, 0.46 mmol), 4-chloro-2-methylaniline (77 mg, 0.55 mmol), Pd2dba3 (21 mg, 23 μmol), XPhos (44 mg, 92 μmol), and Cs2CO3 (330 mg, 1.01 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography (80-100% HCl / petroleum ether) to obtain imidazopyridinone 105 (107 mg, 68%) as a milky white powder. mp (HCl / pet ether) 92-95 °C; 1 H NMR (CDCl3) δ 7.79 (d,J = 0.6 Hz,1 H,H-4),7.36 (d,J = 8.5 Hz,1 H,H-6''),7.22 (d,J = 2.5 Hz,1 H,H-3''),7.15 (dd,J = 8.5,2.5 Hz,1 H,H-5''),6.47 (d,J = 0.6 Hz,1 H,H-7),6.08 (s,1 H,6-NH),3.94 (dd,J = 5.3,5.0 Hz,2 H,H-2'),3.61 (dd,J = 5.3,5.0 Hz,2 H,H-1'),3.41 (s,3 H,2'-OCH3),3.30 (s,3 H,3-CH3),2.26 (s,3 H,2''-CH3); MS m / z 347.1 (MH + ,100%),349.2 (MH + ,35%). HRMS calcd for C 17 H 20 35ClN4O2(MH + ) m / z 347.1269,found 347.1276 (-1.9 ppm); calcd for C 17 H 20 37 ClN4O2(MH + ) m / z 349.1246,found 349.1249 (-1.0 ppm). HPLC purity 96.9%.

[0389] Example 91: SN39887 6-((4-methoxy-2-methylphenyl)amino)-3-methyl-1-(oxetan-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(110) [ka] 2-Chloro-5-nitro-N-(oxetan-3-yl)pyridine-4-amine (106): To a stirred solution of nitropyridine 2 (0.87 g, 4.50 mmol) and iPr2NEt (1.18 mL, 6.75 mmol) in dry DCM (5 mL), a solution of oxetan-3-amine (0.36 g, 5.0 mmol) in dry DCM (5 mL) was added dropwise at 5°C. The mixture was stirred at 20°C for 16 hours, then diluted with DCM (100 ml), washed with water (3 × 50 ml), dried (MgSO4), and the solvent was evaporated. The residue was purified by chromatography using elution with a gradient (20-40%) siRNA / petroleum ether to obtain chloride 106 (1.17 g, 90%) as a yellow powder. mp 139-141 °C; 1 H NMR (CDCl3) δ 9.06 (s,1 H,H-6),8.52 (br s,1 H,4-NH),6.42 (s,1 H,H-3),5.08 (dd,J = 7.2,6.7 Hz,2 H,H-2',H-4'),4.73-4.78 (m,1 H,H-3'),4.67 (dd,J = 6.4,6.2 Hz,2 H,H-2',H-4'); MS m / z 230.1 (MH + ,100%),232.0 (MH + ,35%); HRMS calcd for C8H9 35ClN3O3(MH + ) m / z 230.0327,found 230.0321 (2.5 ppm). 6-Chloro-N 4 A solution of -(oxetan-3-yl)pyridine-3,4-diamine (107):SnCl2·2H2O (4.60 g, 20.4 mmol) in HCl (100 ml) was prepared by adding a solution of nitropyridine 106 (1.17 g, 5.10 mmol) in HCl (50 ml) dropwise at a temperature below 60°C. The mixture was stirred at 60°C for 2 hours, then cooled to 5°C and concentrated (solution). NH3 solution was added until the solution became basic (pH 9). The resulting precipitate was filtered and washed with HCl (100 ml). The combined organic fraction was dried (MgSO4), filtered, and the solvent was evaporated to obtain diamine 107 (1.01 g, 99%) as a white powder. mp 183-186 °C; 1 H NMR [(CD3)2SO] δ 7.25 (s,1 H,H-2),6.71 (br s,1 H,3-NH2),6.34 (s,1 H,H-5),5.57 (br s,1 H,3-NH2),3.33-3.40 (m,4 MS m / z 200.1 (MH + ,100%),202.1 (MH + ,35%); HRMS calcd for C8H 11 35 ClN3O (MH + ) m / z 200.0585,found 200.0589 (-2.1 ppm). 6-Chloro-1-(oxetan-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(108):diamine 107 (1.00 g, 5.01 mmol) was stirred in dry MeCN (50 ml), to which CDI (0.97 g, 6.00 mmol) was added at 20°C. The mixture was stirred at 20°C for 96 hours. The solvent was evaporated, and the residue was partitioned between CHCl3 (150 mL) and water (100 mL). The organic fraction was washed with water (2 × 50 ml), then with brine (50 ml), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using elution with a gradient (80-100%) of siRNA / petroleum ether to obtain pyridinone 108 (0.24 g, 22%) as white crystals. mp 234 °C (decomp); 1 H NMR [(CD3)2SO] δ 7.74 (s,1 H,H-4),7.69 (s,1 H,H-7),6.55 (br d,J = 4.0 Hz,1 H,3-NH),4.60-4.67 (m,1 H,H-3'),4.12-4.22 (m,2 MS m / z 226.1 (MH + ,100%),228.1 (MH + ,35%); HRMS calcd for C9H9 35 ClN3O2(MH + ) m / z 226.0378,found 226.0374 (1.8 ppm). 6-Chloro-3-methyl-1-(oxetan-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(109):pyridinone 108 (0.30 g, 1.33 mol) and MeI (0.12 ml, 2.00 mol) were stirred in dry DMF (10 ml) to which NaH (60% dispersion, 64 mg, 1.60 mol) was added at 5°C. The mixture was stirred at 20°C for 16 hours, and then quenched with ice / water (5 mL). The solvent was evaporated, and the residue was partitioned between ELISA (100 ml) and water (50 ml). The organic fraction was washed with water (2 × 50 ml), washed with brine (50 ml), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using sorbent / petroleum ether with a gradient (50-100%) to obtain chloride 109 (0.16 g, 49%) as a white powder. (mp 192-194 °C) 1 H NMR (CDCl3) δ 7.98 (s,1 H,H-4),7.75 (s,1 H,H-7),4.66 (t,J = 8.6 Hz,1 H,H-2'),4.34-4.43 (m,1 H,H-3''),4.12 (t,J = 8.6 Hz,1 H,H-4'),3.47 (dd,J = 11.1,3.3 Hz,1 H,H-2'),3.15 (dd,J = 11.1,9.7 Hz,1 H,H-4'),3.00 (s,3 H,3-CH3); MS m / z 240.0 (MH + ,100%),242.0 (MH + ,35%); HRMS calcd for C 10 H 11 35 ClN3O2(MH + ) m / z 240.0534,found 240.0543 (-3.7 ppm). A degassed mixture of 6-((4-methoxy-2-methylphenyl)amino)-3-methyl-1-(oxetan-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(110):chloride 109 (148 mg, 0.62 mmol), 4-methoxy-2-methylaniline (102 mg, 0.74 mmol), Pd2dba3 (28 mg, 31 μmol), XPhos (59 mg, 124 μmol), and Cs2CO3 (444 mg, 1.36 mmol) in MeCN (10 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with ELISA (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between ELISA (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography, and imidazopyridinone 110 (101 mg, 48%) was obtained as a pink foam eluted with HCl. mp (HCl / pet ether) 77-80 °C; 1 H NMR (CDCl3) δ 7.63 (s,1 H,H-4),7.31 (s,1 H,H-7),7.30 (d,J = 8.6 Hz,1 H,H-6''),6.78 (d,J = 2.9 Hz,1 H,H-3''),6.74 (dd,J = 8.6,2.9 Hz,1 H,H-5''),5.81 (s,1 H,6-NH),4.58 (t,J = 8.6 Hz,1 H,H-2' or H-4'),4.38 (dq,J = 8.5,3.1 Hz,1 H,1-CH),4.05 (t,J = 8.6 Hz,1 H,H-2' or H-4'),3.81 (s,3 H,4''-OCH3),3.33 (dd,J = 10.9, 3.2 Hz, 1 H, H-2' or H-4'), 3.00 (dd, J = 10.8, 10.0 Hz, 1 H, H-2' or H-4'), 2.90 (s, 3 H, 3-CH3), 2.24 (s, 3 H, 2''-CH3); MS m / z 341.2 (MH + ,100%); HRMS calcd for C 18 H 21 N4O3(MH +) m / z 341.1608,found 341.1612 (-1.0 ppm). HPLC purity 98.0%.

[0390] Example 92: SN39878 6-((4-methoxy-2-methylphenyl)amino)-3-methyl-1-(tetrahydrofuran-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(115) [ka] 2-Chloro-5-nitro-N-(tetrahydrofuran-3-yl)pyridine-4-amine (111): To a stirred solution of nitropyridine 2 (1.17 g, 6.02 mmol), tetrahydrofuran-3-amine, and HCl (0.78 g, 6.3 mmol) in dry DCM (80 ml), iPr2NEt (2.62 mL, 15.1 mmol) was added dropwise at 5°C. The mixture was stirred at 20°C for 16 hours, then diluted with DCM (100 ml), washed with water (3 × 50 ml), dried (MgSO4), and the solvent was evaporated. The residue was purified by chromatography using elution with a gradient (40-50%) siRNA / petroleum ether to obtain chloride 111 (1.37 g, 93%) as yellow crystals. mp 132-134 °C; 1 H NMR (CDCl3) δ 9.03 (s,1 H,H-6),8.27 (br s,1 H,4-NH),6.73 (s,1 H,H-3),4.18-4.25 (m,1 H,H-3'),4.00-4.08 (m,2 H,H-2'),3.93 (ddd,J = MS m / z 244.1 (MH + ,100%),246.1 (MH + ,35%); HRMS calcd for C9H 11 35 ClN3O3(MH + ) m / z 244.0484,found 244.04387(-1.3 ppm). A solution of 6-chloro-N4-(tetrahydrofuran-3-yl)pyridine-3,4-diamine (112):SnCl2·2H2O (5.05 g, 22.4 mmol) in 100 ml of ethyl acetate was added dropwise to a stirred solution of nitropyridine 111 (1.36 g, 5.80 mmol) in 50 ml of ethyl acetate at a temperature below 60°C. The mixture was stirred at 60°C for 2 hours, then cooled to 5°C and concentrated (solution). NH3 solution was added until the solution became basic (pH 9). The resulting precipitate was filtered and washed with ethyl acetate (100 ml). The combined organic fraction was dried (MgSO4), filtered, and the solvent was evaporated to obtain diamine 112 (1.17 g, 94%) as a white powder. 1 H NMR [(CD3)2SO] δ 7.66 (s,1 H,H-2),6.43 (s,1 H,H-5),4.46 (br d,J = 5.3 Hz,1 H,3-NH),4.04-4.10 (m,1 H,H-3'),3.94-4.02 (m,2 H,H-2'),3.88 MS m / z 214.1 (MH + ,100%),216.1 (MH + ,35%); HRMS calcd for C9H 13 35 ClN3O (MH + ) m / z 214.0742,found 214.0739 (1.2 ppm). 6-Chloro-1-(tetrahydrofuran-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(113):diamine 112 (0.48 g, 2.25 mmol) was stirred in dry MeCN (50 ml) to which CDI (0.44 g, 2.71 mmol) was added at 20°C. The mixture was stirred at 20°C for 96 hours. The solvent was evaporated, and the residue was partitioned between CHCl3 (150 mL) and water (100 mL). The organic fraction was washed with water (2 × 50 ml), washed with brine (50 ml), dried (MgSO4), filtered, and the solvent was evaporated. The residue was precipitated from 50% siRNA / petroleum ether to obtain pyridinone 113 (0.45 g, 83%) as a white powder. mp 254-256 °C; 1 H NMR [(CD3)2SO] δ 11.42 (br s,1 H,3-H),7.97 (s,1 H,H-4),7.28 (s,1 H,H-7),5.02-5.10 (m,1 H,H-3'),4.18 (dt,J = 8.5,4.3 Hz,1 H,H-5'),3.98 (dd,J = 9.9,3.6 Hz,1 H,H-2'),3.82 (dd,J = 9.9,7.5 Hz,1 H,H-2'),3.66 (q,J = 8.3 Hz,1 H,H-5'),2.27-2.40 (m,1 H,H-4'),2.00-2.10 (m,1 H,H-4'); MS m / z 240.1 (MH + ,100%),242.1 (MH + ,35%); HRMS calcd for C 10 H 11 35 ClN3O2(MH + ) m / z 240.0534,found 240.0535 (-0.3 ppm). 6-Chloro-3-methyl-1-(tetrahydrofuran-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(114):pyridinone 113 (0.76 g, 3.15 mmol) and MeI (0.29 mL, 4.73 mmol) were stirred in dry DMF (10 mL), to which NaH (60% dispersion, 151 mg, 3.78 mmol) was added at 5°C. The mixture was stirred at 20°C for 16 hours, then rapidly cooled with ice / water (5 mL). The solvent was evaporated, and the residue was partitioned between SiO (100 mL) and water (50 mL). The organic fraction was washed with water (2 × 50 mL), washed with brine (50 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography, and chloride 114 (0.54 g, 68%) was obtained as a white powder eluted with dimethyl. (mp 154-156 °C) 1 H NMR (CDCl3) δ 8.00 (s,1 H,H-4),7.32 (d,J = 0.4 Hz,1 H,H-7),5.23-5.29 (m,1 H,H-3'),4.33 (dt,J = 8.8,3.5 Hz,1 H,H-5'),4.09 (dd,J = 10.4,3.0 Hz,1 H,H-2'),3.92 (dd,J = 10.4,7.5 Hz,1 H,H-2'),3.76 (dt,J = 9.2,7.4 Hz,1 H,H-5'),3.45 (s,3 H,3-CH3),2.42-2.52 (m,1 H,H-4'),2.03-2.14 (m,1 H,H-4'); MS m / z 254.0 (MH + ,100%),256.0 (MH + ,35%); HRMS calcd for C 11 H 13 35 ClN3O2(MH + ) m / z 254.0691,found 254.0686 (1.9 ppm). A degassed mixture of 6-((4-methoxy-2-methylphenyl)amino)-3-methyl-1-(tetrahydrofuran-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(115):chloride 114 (112 mg, 0.41 mmol), 4-methoxy-2-methylaniline (73 mg, 0.53 mmol), Pd2dba3 (19 mg, 21 μmol), XPhos (39 mg, 82 μmol), and Cs2CO3 (294 mg, 0.90 mmol) in MeCN (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with ELISA (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between ELISA (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography, yielding imidazopyridinone 115 (104 mg, 66%) as a yellowish-brown foam eluted with ethyl acetate. (mp 113-116 °C) 1 H NMR [(CD3)2SO] δ 7.78 (s,1 H,H-4),7.73 (s,1 H,6-NH),7.27 (d,J = 8.7 Hz,1 H,H-6''),6.79 (d,J = 2.9 Hz,1 H,H-3''),6.70 (dd,J = 8.7,2.9 Hz,1 H,H-5''),6.51 (s,1 H,H-7),5.00-5.07 (m,1 H,H-3'),4.04 (dt,J = 8.5,4.4 Hz,1 H,H-5'),3.88 (dd,J = 9.7,4.0 Hz,1 H,H-2'),3.80 (dd,J = 9.7,7.6 Hz,1 H,H-2'),3.72 (s,3 MS m / z 355.2 (MH + ,100%); HRMS calcd for C 19 H 23 N4O3(MH +) m / z 355.1765,found 355.1785 (-5.7 ppm). HPLC purity 99.4%.

[0391] Example 93: SN39881 6-((4-chloro-2-methylphenyl)amino)-3-methyl-1-(tetrahydrofuran-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(116) [ka] A degassed mixture of chloride 114 (118 mg, 0.47 mmol), 4-chloro-2-methylaniline (79 mg, 0.56 mmol), Pd2dba3 (21 mg, 23 μmol), XPhos (44 mg, 93 μmol), and Cs2CO3 (333 mg, 1.02 mmol) in MeCN (8 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography to obtain imidazopyridinone 116 (134 mg, 80%) as a white powder eluted with HCl. mp (EtOAc / pet ether) 153-156 °C; 1H NMR [(CD3)2SO] δ 7.94 (s,1 H,H-4),7.87 (s,1 H,6-NH),7.65 (d,J = 8.7 Hz,1 H,H-6''),7.21 (d,J = 2.6 Hz,1 H,H-3''),7.13 (dd,J = 8.7,2.6 Hz,1 H,H-5''),6.79 (s,1 H,H-7),5.03-5.10 (m,1 H,H-3'),4.13 (dt,J = 8.5,4.3 Hz,1 H,H-5'),3.92 (dd,J = 9.7,4.1 Hz,1 H,H-2'),3.84 (dd,J = 9.7,7.7 Hz,1 H,H-2'),3.69 (q,J = MS m / z 359.2 (MH + ,100%),MS m / z 361.2 (MH + ,35%); HRMS calcd for C 18 H 20 35 ClN4O 2 (MH + ) m / z 359.1269,found 359.1290 (-5.7 ppm). HPLC purity 94.4%.

[0392] Example 94: SN39536 6-((4-methoxy-2-methylphenyl)amino)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(121) [ka] (2) 2,4-dichloro-5-nitropyridine (2):<!--13960-->A mixture of 4-chloro-5-nitropyridine-2-ol (5.38 g, 30.8 mmol), POCl3 (60 ml), and tetramethylammonium chloride (10.1 g, 32.5 mmol) was stirred at 120°C for 3 hours. The mixture was cooled and poured into ice / water (500 ml), and mixed at 0-10°C for 1 hour. The mixture was extracted with DCM (3 × 100 mL), and the mixed organic extract was dried with (MgSO4). The solution was filtered through a neutral alumina column and washed with DCM (50 mL). The solvent was evaporated to obtain nitropyridine 2 (5.43 g, 91%) as a clarified oil. 1 H NMR (CDCl3) δ 8.97 (s, 1 H, H-6), 7.59 (s, 1 H, H-3); MS m / z 192.9 (MH + , 100%), 194.9 (MH) + 70%). 2-Chloro-5-nitro-N-(tetrahydro-2H-pyran-4-yl)pyridine-4-amine (117): To a stirred solution of nitropyridine 2 (1.00 g, 5.18 mmol) and iPr2NEt (1.15 mL, 6.22 mmol) in dry DCM (5 mL), a solution of tetrahydro-2H-pyran-4-amine (0.55 g, 5.4 mmol) in dry DCM (5 mL) was added dropwise at 5°C. The mixture was stirred at 20°C for 16 hours, then diluted with DCM (100 ml), washed with water (3 × 50 ml), dried (MgSO4), and the solvent was evaporated. The residue was purified by chromatography with elution using a gradient (30-50%) Âx / petroleum ether to obtain chloride 117 (1.12 g, 84%) as a yellow needle. mp 169-171 °C; 1H NMR (CDCl3) δ 9.04 (s,1 H,H-6),8.19 (br s,1 H,4-NH),6.75 (s,1 H,H-3),4.04 (ddd,J = 12.0,3.8,3.6 Hz,2 H,H-2',H-6'),3.65-3.76 (m,1 MS m / z 256.0 (MH + ,100%),258.0 (MH + ,35%); HRMS calcd for C 10 H 13 35 ClN3O3(MH + ) m / z 256.0640,found 256.0638 (0.8 ppm). 6-Chloro-N 4 -(tetrahydro-2H-pyran-4-yl)pyridine-3,4-diamine (118): To a stirred solution of SnCl2·2H2O (3.78 g, 16.8 mmol) in 100 ml of siRNA, a solution of nitropyridine 117 (1.08 g, 4.19 mmol) in 30 ml of siRNA was added dropwise while maintaining the temperature below 60°C. The mixture was stirred at 60°C for 2 hours, then cooled to 5°C and concentrated (solution). NH3 solution was added until the solution became basic (pH 9). The resulting precipitate was filtered and washed with siRNA (100 ml). The combined organic fraction was dried (MgSO4), filtered, and the solvent evaporated to obtain diamine 118 as a white powder. mp 139-141 °C; 1H NMR [(CD3)2SO] δ 7.67 (s,1 H,H-2),6.46 (s,1 H,H-5),4.27 (br d,J = 6.8 Hz,1 H,4-NH),4.03 (ddd,J = 11.7,3.6,3.3 Hz,2 H,H-2',H-6'),3.46-3.57 (m,3 H,H-2',H-4',H-6'),2.99 (br s,2 H,3-NH2),2.02 (br d,J = 12.4 Hz,2 H,H-3',H-5'),1.50-1.61 (m,2 H,H-3',H-5'); MS m / z 228.1 (MH + ,100%),230.1 (MH + ,35%); HRMS calcd for C 10 H 15 35 ClN3O (MH + ) m / z 228.0898,found 258.0896 (1.1 ppm). Anal. calcd for C 10 H 14 ClN3O·1 / 4EtOAc: C,52.91; H,6.46; N,16.83. Found: C,52.91; H,6.58; N,16.90%. 6-Chloro-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(119):Diamine 118 (0.94 g, 4.13 mmol) was stirred in dry MeCN (50 ml) to which CDI (0.74 g, 4.54 mmol) was added at 20°C. The mixture was stirred at 20°C for 96 hours. The solvent was evaporated, and the residue was partitioned between CHCl3 (150 mL) and water (100 mL). The organic fraction was washed with water (2 × 50 ml), washed with brine (50 ml), dried (MgSO4), filtered, and the solvent was evaporated. The residue was precipitated from 50% siRNA / petroleum ether to obtain pyridinone 119 (0.83 g, 84%) as a white powder. mp 281-283 °C; 1H NMR (CDCl3) δ 9.13 (br s,1 H,3-H),8.13 (s,1 H,H-4),7.19 (s,1 H,H-7),4.54 (tt,J = 12.5,4.4 Hz,1 H,H-4'),4.17 (dd,J = 11.7,4.6 Hz,2 H,H-2',H-6'),3.56 (dt,J = 12.0,1.8 Hz,2 H,H-2',H-6'),2.40 (dq,J = 12.6,4.6 Hz,2 H,H-3',H-5'),1.86 (ddd,J = 12.6,3.9,1.3 Hz,2 H,H-3',H-5'); MS m / z 254.1 (MH + ,100%),256.1 (MH + 35%). Anal calcd for C 11 H 12 ClN3O2: C,52.08; H,4.77; N,16.56. Found: C,52.16; H,4.77; N,16.23%. 6-Chloro-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(120):pyridinone 119 (0.86 g, 3.39 mmol) and MeI (0.32 mL, 5.09 mmol) were stirred in dry DMF (20 mL), to which NaH (60% dispersion, 163 mg, 4.07 mmol) was added at 5°C. The mixture was stirred at 20°C for 16 hours, then quenched with ice / water (5 mL). The solvent was evaporated, and the residue was partitioned between siRNA (100 mL) and water (50 mL). The organic fraction was washed with water (2 × 50 mL), washed with brine (50 mL), dried (MgSO₄), filtered, and the solvent was evaporated. The residue was purified by chromatography using acetaldehyde / petroleum ether with a gradient (50-100%) to obtain chloride 120 (0.43 g, 47%) as white crystals. (mp 190-192 °C) 1H NMR (CDCl3) δ 7.99 (s,1 H,H-4),7.15 (d,J = 0.5 Hz,1 H,H-7),4.54 (tt,J = 12.5,4.4 Hz,1 H,H-4'),4.15 (dd,J = 11.7,4.7 Hz,2 H,H-2',H-6'),3.55 (dt,J = 12.0,1.9 Hz,2 H,H-2',H-6'),3.45 (s,3 H,3-CH3),2.38 (dq,J = 12.5,4.7 Hz,2 H,H-3',H-5'),1.77 (ddd,J = 12.4,4.0,1.5 Hz,2 H,H-3',H-5'); MS m / z 268.0 (MH + ,100%),270.0 (MH + ,35%); HRMS calcd for C 12 H 15 35 ClN3O2(MH + ) m / z 268.0847,found 268.0854 (-2.6 ppm). A degassed mixture of 6-((4-methoxy-2-methylphenyl)amino)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(121):chloride 120 (125 mg, 0.47 mmol), aniline (77 mg, 0.56 mmol), Pd2dba3 (21 mg, 24 μmol), XPhos (45 mg, 94 μmol), and Cs2CO3 (337 mg, 1.03 mmol) in MeCN (6 mL) was stirred in a sealed tube at 120°C for 16 hours. The mixture was cooled, diluted with ethyl acetate (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), then with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography using elution with a gradient (80-100%) of siRNA / petroleum ether to obtain imidazopyridinone 121 (122 mg, 70%) as pink crystals. mp (siRNA / petroleum ether) 176-178 °C; 1H NMR (CDCl3) δ 7.77 (s,1 H,H-4),7.25 (d,J = 8.6 Hz,1 H,H-6''),6.85 (d,J = 2.9 Hz,1 H,H-3''),6.78 (dd,J = 8.6,2.9 Hz,1 H,H-5''),6.24 (d,J = 0.5 Hz,1 H,H-7),5.95 (s,1 H,6-NH),4.41 (tt,J = 12.4,4.2 Hz,1 H,H-4'),4.07 (dd,J = 11.6,4.4 Hz,2 H,H-2',H-6'),3.83 (s,3 H,4''-OCH3),3.50 (dt,J = 12.0,1.6 Hz,2 MS m / z 369.2 (MH + ,100%). Anal calcd for C 20 H 24 N4O3·1 / 4EtOAc: C,64.60; H,6.71; N,14.35. Found: C,64.76; H,6.74; N,14.48%. HPLC purity 99.4%.

[0393] Example 95: SN39537 6-((4-chloro-2-methylphenyl)amino)-3-methyl-1-(tetrahydro-2-pyran-4-yl)-1,3-dihydro-2-imidazo[4,5-c]pyridine-2-one(122) [ka] A degassed mixture of chloride 120 (107 mg, 0.40 mmol), 4-chloro-2-methylaniline (68 mg, 0.48 mmol), Pd2dba3 (18 mg, 20 μmol), XPhos (38 mg, 80 μmol), and Cs2CO3 (287 mg, 0.88 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), and the solvent was filtered and evaporated. The residue was purified by chromatography (80-100% siRNA / petroleum ether) to obtain imidazopyridinone 122 (111 mg, 74%) as gray crystals. mp (siRNA / petroleum ether) 203-205 °C; 1 H NMR (CDCl3) δ 7.83 (s,1 H,H-4),7.43 (d,J = 8.5 Hz,1 H,H-6''),7.22 (d,J = 2.5 Hz,1 H,H-3''),7.17 (dd,J = 8.5,2.5 Hz,1 H,H-5''),6.52 (d,J = 0.6 Hz,1 H,H-7),6.02 (s,1 H,6-NH),4.48 (tt,J = 12.4,4.3 Hz,1 H,H-4'),4.10 (dd,J = 11.8,4.4 Hz,2 H,H-2',H-6'),3.52 (dt,J = 12.0,1.7 Hz,2 H,H-2',H-6'),3.40 (s,3 MS m / z 373.2 (MH + ,100%). Anal calcd for C 19 H 21 ClN4O2: C,61.21; H,5.68; N,15.03. Found: C,61.24; H,5.84; N,15.01%. HPLC purity 98.4%.

[0394] Example 96: SN39538 3-methyl-6-((2-methyl-5-(methylsulfonyl)phenyl)amino)-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(123) [ka] A degassed mixture of chloride 120 (104 mg, 0.39 mmol), 2-methyl-5-(methylsulfonyl)aniline (86 mg, 0.47 mmol), Pd2dba3 (18 mg, 20 μmol), XPhos (37 mg, 78 μmol), and Cs2CO3 (280 mg, 0.86 mmol) in dioxane (6 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent evaporated. The residue was purified by chromatography (HCl / petroleum ether) to obtain imidazopyridinone 123 (8 mg, 5%) as a yellowish-brown powder. mp (EtOAc / pet ether) 302-305 °C; 1H NMR (CDCl3) δ 8.23 ​​(d,J = 1.8 Hz,1 H,H-6''),7.90 (s,1 H,H-4),7.51 (dd,J = 7.9,1.8 Hz,1 H,H-5''),7.39 (d,J = 7.9 Hz,1 H,H-3''),6.83 (s,1 H,H-7),6.30 (s,1 H,6-NH),4.58 (tt,J = 12.5,4.4 Hz,1 H,H-4'),4.11 (dd,J = 11.6,4.4 Hz,2 H,H-2',H-6'),3.53 (dt,J = 12.0,1.6 Hz,2 H,H-2',H-6'),3.44 (s,3 MS m / z 417.2 (MH + ,100%). HRMS calcd for C 20 H 25 N4O4S (MH + ) m / z 417.1591,found 417.1589 (0.5 ppm). HPLC purity 89.0%.

[0395] Example 97: SN39871 6-((4-(benzyloxy)-2-methylphenyl)amino)-3-methyl-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(124) [ka] A degassed mixture of chloride 120 (415 mg, 1.55 mmol), 4-(benzyloxy)-2-methylaniline (397 mg, 1.86 mmol), Pd2dba3 (71 mg, 78 μmol), XPhos (148 mg, 310 μmol), and Cs2CO3 (1.10 g, 3.41 mmol) in MeCN (8 mL) was stirred in a sealed tube at 120 °C for 16 hours. The mixture was cooled, diluted with HCl (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between HCl (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography, and imidazopyridinone 124 (538 mg, 78%) was obtained as a white needle eluted with HCl. mp (HCl / PET ether) 179-181 °C; 1 H NMR (CDCl3) δ 7.78 (s,1 H,H-4),7.47 (br d,J = 7.0 Hz,2 H,H-2''',H-6'''),7.40 (br dd,J = 7.5,7.1 Hz,2 H,H-3''',H-5'''),7.34 (br t,J = 7.2 Hz,1 H,H-4'''),7.26 (d,J = 8.6 Hz,1 H,H-6''),6.93 (d,J = 2.9 Hz,1 H,H-3''),6.84 (dd,J = 8.6,2.9 Hz,1 H,H-5''),6.26 (d,J = 0.5 Hz,1 H,H-7),5.94 (s,1 H,6-NH),5.08 (s,2 H CH2O),4.41 (tt,J = 12.4,4.2 Hz,1 H,H-4'),4.07 (dd,J = 11.6,4.4 Hz,2 H,H-2',H-6'),3.50 (dt,J = 11.9,1.6 Hz,2 H,H-2',H-6'),3.33 (s,3 MS m / z 445.2 (MH + ,100%); HRMS calcd for C 26 H29 N4O3(MH + ) m / z 445.2234,found 445.2250 (-3.6 ppm). HPLC purity 98.9%.

[0396] Example 98: SN40019 3-methyl-6-((7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)amino)-1-(tetrahydro-2H-pyran-4-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2-one(125) [ka] A degassed mixture of chloride 120 (133 mg, 0.50 mmol), 7-methyl-[1,2,4]triazolo[1,5-a]pyridine-6-amine (74 mg, 0.50 mmol), BrettPhos G3 (27 mg, 50 mol), and Cs2CO3 (358 mg, 1.10 mmol) in dioxane (8 mL) was stirred in a sealed tube at 120 °C for 4 hours. The mixture was cooled, diluted with pharmaceutically acceptable solution (30 mL), filtered through diatomaceous earth, and the filtrate was evaporated. The residue was partitioned between pharmaceutically acceptable solution (50 mL) and water (50 mL). The organic fraction was washed with water (30 mL), washed with brine (30 mL), dried (MgSO4), filtered, and the solvent was evaporated. The residue was purified by chromatography using a gradient (0-10%) of MeOH / Âde to obtain imidazopyridinone 125 (88 mg, 46%) as a yellowish-brown solid. (mp 260-263 °C) 1H NMR (CDCl3) δ 9.40 (s,1 H,H-5''),8.26 (s,1 H,H-2''),7.87 (s,1 H,H-4),7.59 (s,1 H,H-8''),6.53 (s,1 H,H-7),6.10 (s,1 H,6-NH),4.53 (tt,J = 12.4,4.4 Hz,1 H,H-4'),4.12 (dd,J = 11.7,4.5 Hz,2 H,H-2',H-6'),3.55 (dt,J = 12.0,1.7 Hz,2 H,H-2',H-6'),3.43 (s,3 H,3-CH3),2.47 (s,3 H,7''-CH3),2.39 (dq,J =12.6,4.7 Hz,2 H,H-3',H-5'),1....

Claims

1. Compound of formula I: 【Chemistry 1】 or a pharmaceutically acceptable salt or solvate thereof (Here, X is selected from the group consisting of (a), (b), and (c) below. (a) -H; (b) -OH、-ハロ、-OR １ 、-OC(O)H、-OC(O)R １ 、-OC(O )NH ２ 、-OC(O)NHR １ 、 -OOOOOOO １ R １ 、---------- ２ 、-O?(O)(OR １ ) ２ 、-NH ２ 、-NHR １ 、-NR １ R １ 、-NHC(O)H、 -NHC(O)R １ 、-NRC(O)R １ 、-NHC(O)NH ２ 、-NHC(O)NH R １ 、-NR １ C(O)NH ２ 、-NHC(O)NR １ R １ 、 -NR １ C(O)NHR １ 、-NR １ C(O)NR １ R １ ,-EH,-ER １ ,-S(O )H、-S(O)R １ 、-SO ２ R １ 、-SO ２ NH ２ 、-SO ２ NHR １ 、-SO ２ N R １ R １ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-CO ２ R １ 、- CHO, -C(O)R １ 、-C(O)NH ２ 、 -C(O)NHR １ 、-C(O)NR １ R １ 、-CONHSO ２ H, -CONHSO ２ R １ 、-CONR １ SO ２ R １ 、-Ph、 - (C ３ -C ７ ) Cycloalkylamino, imidazolyl, piperazinyl, -(C １ -C ６ ) - Optionally one or more groups independently selected from alkylpiperazinyl and morpholinyl. It may be replaced with - (C １－ C ６ ) alkyl; (c) -OH、-ハロ、-OR １ 、-OC(O)H、-OC(O)R １ 、-OC( O)NH ２ 、-OC(O)NHR １ 、 -OOOOOOO １ R １ 、---------- ２ 、-O?(O)(OR １ ) ２ 、-NH ２ 、-NHR １ 、-NR １ R １ 、-NHC(O)H、 -NHC(O)R １ 、-NRC(O)R １ 、-NHC(O)NH ２ 、-NHC(O)NH R １ 、-NR １ C(O)NH ２ 、-NHC(O)NR １ R １ 、 -NR １ C(O)EER １ 、-NAC(O)NR １ R １ 、-SH、-SR １ 、-S(O) H、-S(O)R １ 、-SO ２ R １ 、-SO ２ NH ２ 、-SO ２ NHR １ 、 -SO ２ NR １ R １ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-CO ２ R １ 、-CHO、-C(O)R １ 、-C(O)NH ２ 、 -C(O)NHR １ 、-C(O)NR １ R １ 、-CONHSO ２ H, -CONHSO ２ R １ 、-CONR １ SO ２ R １ 、-Ph、 - (C ３ -C ７ ) Cycloalkylamino, imidazolyl, piperazinyl, -(C １ -C ６ ) - Optionally one or more groups independently selected from alkylpiperazinyl and morpholinyl. It may be replaced with (C ２－ C ６ ) Alkenil; Each of the aforementioned R １ -HALO, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ , -NR ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ 、 -SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-CO ２ R ２ 、 -CHO, -C(O)R ２ 、 -C(O)NH ２ 、 -C(O)NHR ２ or -C(O) NR ２ R ２ It may be arbitrarily replaced with (C １－ C ６ ) Selected independently from alkyl, The aforementioned R ２ Ha- (C １－ C ６ ) is alkyl, The aforementioned -Ph is -(C １－ C ６ ) alkyl, -halo, -OH, -OR ２ , -NO ２ , - NH ２ 、-NHR ２ 、-NR ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ 、 -SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-CO ２ R ２ , -CHO, -C(O)R ２ , -C(O)NH ２ , -C(O)NHR ２ and -C(O) NR ２ R ２ R may be optionally substituted with one or more groups independently selected from the above, ２ teeth - (C １－ C ６ ) is alkyl, The aforementioned Y is selected from the group consisting of (c) to (e) below, (c)-R １ 、-OH、-ハロ、-OR １ 、-OC(O)H,OC(O)R １ 、-OC (O)NH ２ 、 -OCOOOOO １ 、-O(A)NR １ R １ 、---------- ２ 、-O@(O )(OR １ ) ２ 、-NH ２ 、-NHR １ 、-NR １ R １ 、 -NHC(O)H、-NHC(O)R １ 、-NRC(O)R １ 、-NHC(O)NH ２ 、 -NHC(O)NHR １ 、-NR １ C(O)NH ２ 、 -NHC(O)NR １ R １ ,-NR １ C(O)NHR １ ,-NR １ C(O)NR １ R １ 、 - SH, - SR １ 、-S(O)H、-S(O)R １ 、-SO ２ R １ 、 -SO ２ NH ２ 、-SO ２ NHR １ 、-SO ２ NR １ R １ 、-CF ３ 、-CHF ２ 、-C H ２ F, -CN, -CO ２ H,-CO ２ R １ 、-CHO、 -C(O)R １ 、-C(O)NH ２ 、-C(O)NHR １ 、-C(O)NR １ R １ ,-C ONHSO ２ H, -CONHSO ２ R １ , and -CONR １ SO ２ R １ It may be optionally replaced by one or more elements selected independently of it. - (C ３－ C ７ ) Cycloalkyl; Each of the aforementioned R １ -HALO, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ , -NR ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ 、 -SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-CO ２ R ２ ,- CHO,!-C(O)R ２ 、-C(O)NH ２ 、 -C(O)NHR ２ and -C(O)NR ２ R ２ It may be arbitrarily replaced with - (C1-C 6) Selected independently from alkyl, the R ２ Ha- (C １－ C ６ ) is alkyl, (d)-R １ 、-OH、-ハロ、-OR １ 、-OC(O)H、-C(O)R １ 、-OC (O)NH ２ 、 -OCOOOOO １ 、-O(A)NR １ R １ 、---------- ２ 、-O@(O )(OR １ ) ２ 、-NH ２ 、-NHR １ 、-NR １ R １ 、 -NHC(O)H、-NHC(O)R １ 、-NRC(O)R １ 、-NHC(O)NH ２ 、 -NHC(O)NHR １ 、-NR １ C(O)NH ２ 、 -NHC(O)NR １ R １ ,-NR １ C(O)NHR １ ,-NR １ C(O)NR １ R １ 、 - SH, - SR １ 、-S(O)H、-S(O)R １ 、-SO ２ R １ 、 -SO ２ NH ２ 、-SO ２ NHR １ 、-SO ２ NR １ R １ 、-CF ３ 、-CHF ２ 、-C H ２ F, -CN, -CO ２ H,-CO ２ R １ 、-CHO、 -C(O)R １ 、-C(O)NH ２ 、-C(O)NHR １ 、-C(O)NR １ R １ ,-C ONHSO ２ H, -CONHSO ２ R １ , and -CONR １ SO ２ R １ Select independently It may be optionally substituted with one or more of the groups being replaced - (C ３－ C ７ ) Heterocycloalkyl; Each of the aforementioned R １ -HALO, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ , -NR ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ 、 -SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-CO ２ R ２ ,- CHO,!-C(O)R ２ 、-C(O)NH ２ 、 -C(O)NHR ２ and -C(O)NR ２ R ２ It may be arbitrarily replaced with - (C1-C 6) Selected independently from alkyl, the R ２ Ha- (C １－ C ６ ) is alkyl, (e) -R １ -OH, -HALO, -OR １ , -OC(O)H,OC(O)R １ , -OC (O)NH ２ 、 -OCOOOOO １ 、-O(A)NR １ R １ 、---------- ２ 、-O@(O )(OR １ ) ２ 、-NH ２ 、-NHR １ 、-NR １ R １ 、 -NHC(O)H、-NHC(O)R １ 、-NRC(O)R １ 、-NHC(O)NH ２ 、 -NHC(O)NHR １ 、-NHC(O)NR １ R １ 、 -NR １ C(O)NH ２ 、-NR １ C(O)NHR １ 、-NR １ C(O)NH ２ 、-NR １ C(O)NR １ R １ ,-EH,-ER １ ,-S(O)H, -S(O)R １ 、-SO ２ R １ 、-SO ２ NH ２ 、-SO ２ NHR １ 、-SO ２ NR １ R １ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、 -CO ２ R １ 、-CHO、-C(O)R １ 、-C(O)NH ２ 、-C(O)NHR １ - C(O)NR １ R １ 、-CONHSO ２ H、 - CONHSO ２ R １ and -CONR １ SO ２ R １ One or more bases selected independently from It may be arbitrarily replaced with - (C ４－ C ８ ) Aryl; Each of the aforementioned R １ -HALO, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ , -NR ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ 、 -SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-O ２ R ２ 、-CHO、-C(O)R ２ 、-C(O)NH ２ 、 -C(O)NHR ２ and -C(O)NR ２ R ２ It may be arbitrarily replaced with (C １－ C ６ ) independently selected from alkyl, and the R ２ Ha- (C １－ C ６ ) is alkyl, The aforementioned Z is selected from the group consisting of (a) and (b) below, (a) -R １ 、-OH、-ハロ、-OR １ 、-OC(O)H、-OC(O)R １ 、- OC(O)NH ２ 、-OC(O)NHR １ 、 -OOOOOOO １ R １ 、---------- ２ 、-O?(O)(OR １ ) ２ 、-NH ２ 、-NHR １ 、-NR １ R １ 、-NHC(O)H、 -NHC(O)R １ 、-NRC(O)R １ 、-NHC(O)NH ２ 、-NHC(O)NH R １ 、-NR １ C(O)NH ２ 、-NHC(O)NR １ R １ 、 -NR １ C(O)NHR １ 、-NR １ C(O)NR １ R １ ,-EH,-ER １ ,-S(O )H、-S(O)R １ 、-SO ２ R １ 、-SO ２ NH ２ 、 -SO ２ NHR １ ,-SO ２ NR １ R １ ,-CF ３ ,-CHF ２ ,--H ２ F、-CN、 -CC ２ H、-CO ２ R １ 、-CHOO、-C(O)R １ 、 -C(O)NH ２ 、-C(O)NHR １ 、-C(O)NR １ R １ 、-CONHSO ２ H, - CONHSO ２ R １ , -CONR １ SO ２ R １ Morpholinil, piperazinil, pyrid It may be optionally substituted with one or more groups independently selected from yl and pyrimidinyl groups. (C ４－ C ８ ) Aryl; Each of the aforementioned R １ is, -(C １－ C ６ ) Alkyl and -(C ４ -C ８ ) Independent from the army Selected, each of the above groups is -halo, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ ,-NR ２ R ２ ,-SH, -SR ２ 、-SO ２ R ２ 、-SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN ,-CO ２ H、-CO ２ R ２ 、-CHOO、-C(O)R ２ , -C(O)NH ２ , -C(O)NHR ２ or -C(O)NR ２ R ２ Even if it is arbitrarily replaced Often, the aforementioned R ２ Ha- (C １－ C ６ ) is alkyl, Each of the aforementioned morpholinil, piperazinil, pyridinil, and pyrimidinil is -(C １－ C ６ ) alkyl, -halo, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ , -NR ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ 、-SO ２ NH ２ 、-CF ３ 、-CHF ２ CH ２ F, -CN, -CO ２ H,-CO ２ R ２ 、-CHO、 -C(O)R ２ , -C(O)NH ２ , -C(O)NHR ２ and -C(O)NR ２ R ２ from The R may be optionally substituted with one or more independently selected groups. ２ Ha- (C １－ C ６ ) is alkyl, (b) -R １ 、-OH、-ハロ、-OR １ 、-OC(O)H、-OC(O)R １ 、- OC(O)NH ２ 、-OC(O)NHR １ 、 -OOOOOOO １ R １ 、---------- ２ 、-O?(O)(OR １ ) ２ 、-NH ２ 、-NHR １ 、-NR １ R １ 、-NHC(O)H、 -NHC(O)R １ 、-NRC(O)R １ 、-NHC(O)NH ２ 、-NHC(O)NH R １ 、-NR １ C(O)NH ２ 、-NHC(O)NR １ R １ 、 -NR １ C(O)NHR １ 、-NR １ C(O)NR １ R １ ,-EH,-ER １ ,-S(O )H、-S(O)R １ 、-SO ２ R １ 、-SO ２ NH ２ 、 -SO ２ NHR １ ,-SO ２ NR １ R １ ,-CF ３ ,-CHF ２ ,--H ２ F、-CN、 -CC ２ H、-CO ２ R １ 、-CHOO、-C(O)R １ 、 -C(O)NH ２ 、-C(O)NHR １ 、-C(O)NR １ R １ 、-CONHSO ２ H, - CONHSO ２ R １ , -CONR １ SO ２ R １ From morpholinil and piperazinil It may be optionally substituted with one or more independently selected groups - (C ５－ C １２ ) Hetero reel; Each of the aforementioned R １ Ha- (C １－ C ６ ) Alkyl and -(C ４ -C ８ ) Selected independently from the arrow And each of these groups is -halo, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ , -NR ２ R ２ ,-SH, -SR ２ 、-SO ２ R ２ 、-SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN ,-CO ２ H、-CO ２ R ２ 、-CHOO、-C(O)R ２ 、 -C(O)NH ２ , -C(O)NHR ２ or -C(O)NR ２ R ２ Even if it is arbitrarily replaced Often, the aforementioned R ２ Ha- (C １－ C ６ ) is alkyl 、 Each of the aforementioned morpholinil and piperazinil is -(C １－ C ６ ) alkyl, -halo, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ , -NR ２ R ２ ,-SH, -SR ２ 、-SO ２ R ２ 、-SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN ,-CO ２ H、-CO ２ R ２ 、-CHOO、-C(O)R ２ 、 -C(O)NH ２ , -C(O)NHR ２ and -C(O)NR ２ R ２ Selected independently from The R may be optionally substituted with one or more groups, ２ Ha- (C １－ C ６ ) is alkyl 。）。

2. The aforementioned X is the compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is (b) below. is a solvate ((b) -OH、-ハロ、-OR １ 、-OC(O)H、-OC(O)R １ 、-OC( O)NH ２ 、-OC(O)NHR １ 、 -OOOOOOO １ R １ 、---------- ２ 、-O?(O)(OR １ ) ２ 、-NH ２ 、-NHR １ 、-NR １ R １ 、-NHC(O)H、 -NHC(O)R １ 、-NRC(O)R １ 、-NHC(O)NH ２ 、-NHC(O)NH R １ 、-NR １ C(O)NH ２ 、-NHC(O)NR １ R １ 、 -NR １ C(O)NHR １ 、-NR １ C(O)NR １ R １ ,-EH,-ER １ ,-S(O )H、-S(O)R １ 、-SO ２ R １ 、-SO ２ NH ２ 、-SO ２ NHR １ 、-SO ２ N R １ R １ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-CO ２ R １ 、- CHO, -C(O)R １ 、-C(O)NH ２ 、 -C(O)NHR １ 、-C(O)NR １ R １ 、-CONHSO ２ H, -CONHSO ２ R １ 、-CONR １ SO ２ R １ 、-Ph、 - (C ３ -C ７ ) Cycloalkylamino, imidazolyl, piperazinyl, -(C １ -C ６ ) - Optionally one or more groups independently selected from alkylpiperazinyl and morpholinyl. It may be replaced with - (C １－ C ６ ) alkyl; Each of the aforementioned R １ -HALO, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ , -NR ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ 、 -SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-CO ２ R ２ 、-CHO、-C(O)R ２ 、-C(O)NH ２ 、 -C(O)NHR ２ or -C(O)NR ２ R ２ It may be arbitrarily replaced with (C １－ C ６ ) independently selected from alkyl, and the R ２ Ha- (C １－ C ６ ) is alkyl, The aforementioned -Ph is -(C １－ C ６ ) alkyl, -halo, -OH, -OR ２ , -NO ２ , -NH ２ 、-NHR ２ 、-NR ２ R ２ 、-SH、-SR ２ 、 -SO ２ R ２ 、-SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H,-CO ２ R ２ 、-CHO、-C(O)R ２ 、-C(O)NH ２ 、 -C(O)NHR ２ and b-C(O)NR ２ R ２ One or more selected independently from The base can be arbitrarily substituted, R ２ Ha- (C １－ C ６ )It is alkyl.

3. The compound described in claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein X is OH or NH ２ It may be arbitrarily replaced with - (C １－ C ６ ) It is alkyl, Compounds or pharmaceutically acceptable salts or solvates thereof.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt or solvation thereof. It is an object, and Y is -(C ３－ C ７ ) Cycloalkyl, oxetanyl, tetrahydro Furanil, tetrahydropyranil, cyclohexanil, pyrrolidinil, piperidinil, and Selected from the group consisting of biphenyl, each of the above groups is -R １ -OH, -HALO, -OR １ 、-OC(O)H、-C(O)R １ 、-OC(O)NH ２ 、 -OCOOOOO １ 、-O(A)NR １ R １ 、---------- ２ 、-O@(O )(OR １ ) ２ 、-NH ２ 、-NHR １ 、-NR １ R １ 、 -NHC(O)H、-NHC(O)R １ 、-NRC(O)R １ 、-NHC(O)NH ２ 、 -NHC(O)NHR １ 、-NR １ C(O)NH ２ 、 -NHC(O)NR １ R １ ,-NR １ C(O)NHR １ ,-NR １ C(O)NR １ R １ 、 - SH, - SR １ 、-S(O)H、-S(O)R １ 、-SO ２ R １ 、 -SO ２ NH ２ 、-SO ２ NHR １ 、-SO ２ NR １ R １ 、-CF ３ 、-CHF ２ 、-C H ２ F, -CN, -CO ２ H,-CO ２ R １ 、-CHO、 -C(O)R １ 、-C(O)NH ２ 、-C(O)NHR １ 、-C(O)NR １ R １ ,-C ONHSO ２ H, -CONHSO ２ R １ and -CONR １ SO ２ R １ Selected independently It may be optionally substituted with one or more of the groups, Each of the aforementioned R １ -HALO, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ , -NR ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ 、 -SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-CO ２ R ２ ,- CHO,!-C(O)R ２ 、-C(O)NH ２ 、 -C(O)NHR ２ and -C(O)NR ２ R ２ It may be arbitrarily replaced with (C １－ C ６ ) independently selected from alkyl, and the R ２ Ha- (C １－ C ６ ) is alkyl, A compound or a pharmaceutically acceptable salt or solvate thereof.

5. The compound according to claim 4 or a pharmaceutically acceptable salt or solvate thereof, wherein Y is, -(C ３－ C ７ ) Cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydro Dropyranil, methoxycyclohexanil, hydroxycyclohexanil, aminocyclo Hexanyl, N-methylaminocyclohexanyl, N,N-dimethylcyclohexanyl, Pyrrolidinyl, N-methylpyrrolidinyl, piperidinyl, N-methylpiperidinyl, fura The group consisting of nyl, pyrrolyl, pyridinyl, hydroxyphenyl, and methoxyphenyl A compound or a pharmaceutically acceptable salt or solvate thereof, selected from among them.

6. The compound described in claim 5 or a pharmaceutically acceptable salt or solvate thereof, wherein Y These are 4-methoxycyclohexanyl, 4-hydroxycyclohexanyl, or 4-aminocy A compound selected from the group consisting of chlorhexanil, or a pharmaceutically acceptable salt or solution thereof. medium.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt or solvation thereof. A substance in which Z is furanyl, thiophenyl, pyrrolyl, pyridinyl, or imidazolyl , thiazolyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, quinolinyl, Isoquinolinyl, prinyl, benzodioxolyl, quinoxalinyl, benzothiadinyl, Triazolopyridinyl, benzothiazolyl, benzoxazolyl, benzodioxolyl and Selected from the group consisting of bi and imidazopyridinyl - (C ５－ C １２ ) Heteroaryl Each of the above units is -R １ -OH, -HALO, -OR １ , -OC(O)H, -C(O)R １ 、-OC(O)NH ２ 、 -OCOOOOO １ 、-O(A)NR １ R １ 、---------- ２ 、-O@(O )(OR １ ) ２ 、-NH ２ 、-NHR １ 、-NR １ R １ 、 -NHC(O)H、-NHC(O)R １ 、-NRC(O)R １ 、-NHC(O)NH ２ 、 -NHC(O)NHR １ 、-NR １ C(O)NH ２ 、 -NHC(O)NR １ R １ ,-NR １ C(O)NHR １ ,-NR １ C(O)NR １ R １ 、 - SH, - SR １ 、-S(O)H、-S(O)R １ 、-SO ２ R １ 、 -SO ２ NH ２ 、-SO ２ NHR １ 、-SO ２ NR １ R １ 、-CF ３ 、-CHF ２ 、-C H ２ F, -CN, -CO ２ H,-CO ２ R １ 、-CHO、 -C(O)R １ 、-C(O)NH ２ 、-C(O)NHR １ 、-C(O)NR １ R １ ,-C ONHSO ２ H, -CONHSO ２ R １ and -CONR １ SO ２ R １ Selected independently It may be optionally substituted with one or more of the groups, Each of the aforementioned R １ is, -(C １－ C ６ ) Alkyl and -(C ４－ C ８ ) Selected independently from the army Selected, each of the above groups is -halo, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ , - NR ２ R ２ ,-EH,-ER ２ 、 -SO ２ R ２ 、-SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H,-CO ２ R ２ ,- CHO,!-C(O)R ２ 、-C(O)NH ２ 、 -C(O)NHR ２ and -C(O)NR ２ R ２ 、 It may be arbitrarily replaced with the above R ２ Ha- (C １－ C ６ ) A compound that is alkyl, or a pharmaceutically acceptable salt or solvate thereof. 。

8. The compound according to claim 7 or a pharmaceutically acceptable salt or solvate thereof, wherein Z is, (C １－ C ６ ) alkyl-substituted - (C ５－ C １２ ) It is a heteroaryl compound. Compounds or pharmaceutically acceptable salts or solvates thereof.

9. The compound according to claim 8 or a pharmaceutically acceptable salt or solvate thereof, wherein Z is replaced by Me - (C ５－ C １２ ) A compound or its pharmaceutical A salt or solvate that is permissible.

10. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or solvation thereof. It is an object, and the aforementioned Z is (C １－ C ６ ) alkyl-substituted - (C ４－ C ８ ) Aryl A compound or a pharmaceutically acceptable salt or solvate thereof.

11. The compound according to claim 10 or a pharmaceutically acceptable salt or solvate thereof, wherein Z is replaced by Me - (C ４－ C ８ ) Compounds that are aryl or their pharmaceutically acceptable A salt or solvate that is produced.

12. The compound according to claim 10 or a pharmaceutically acceptable salt or solvate thereof, wherein Z is R １ -OH, -OR １ , -Hello, -NO ２ , -NH ２ , - NHR １ , -NR １ R １ 、 -SO ２ R １ and phenyl which may be optionally substituted with one or more of -Bn , the R １ is (C １－ C ６ ) A compound that is alkyl or a pharmaceutically acceptable salt thereof or Solvate.

13. The compound according to claim 12 or a pharmaceutically acceptable salt or solvate thereof, the R １ A compound or a pharmaceutically acceptable salt or solvate thereof, in which is Me.

14. The compound according to claim 12 or a pharmaceutically acceptable salt or solvate thereof, the Z is a phenyl compound in which the 4-position is substituted with -OMe, -Cl, or -OH, or the above Z's 5th place is -SO ２ R １ and - NO ２ A phenyl substituted with any of the -R １ is (C １－ C ６ ) Al A kill compound or a pharmaceutically acceptable salt or solvate thereof.

15. The compound according to claim 14 or a pharmaceutically acceptable salt or solvate thereof, the -R １ A compound or a pharmaceutically acceptable salt or solvate thereof, in which is Me.

16. Compounds of formula II: 【Chemistry 2】 or a pharmaceutically acceptable salt or solvate thereof (Here, X and Y are as defined in claim 1, A １、 A ２ and A ３ It is selected independently of CH or N, B １ -OH, -OR １ Hello, -NO ２ , -NH ２ NHR １ , -SO ２ R １ Reach Selected from B-OBn, Each R １ is halo, -OH, -OR ２ , -NO ２ , -NH ２ , -NHR ２ 、-NR ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ 、-SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-CO ２ R ２ 、 -CHO, -C(O)R ２ , -C(O)NH ２ , -C(O)NHR ２ or -C(O)NR ２ R ２ It may be arbitrarily replaced with (C １－ C ６ ) is alkyl, R ２ Ha- (C １－ C ６ )It is alkyl.

17. Compounds of formula III: 【Transformation 3】 or a pharmaceutically acceptable salt or solvate thereof (Here, X and Y are as defined in claim 1, A １ is N or C. D is selected from N, O, and S. 【Chemistry 4】 This represents a single bond or a double bond. 【Transformation 5】 It is a single bond unless D is N, R ３ H, -(C １－ C ６ ) Alkyl, -CO ２ R １ , -CONHR １ and CON HR １ R １ Selected from the group consisting of R １ Ha- (C １－ C ６ )It is alkyl.

18. Compounds of formula IV: 【Transformation 6】 or a pharmaceutically acceptable salt or solvate thereof (Here, X and Y are as defined in claim 1, B ２ And D is selected independently from N, O, and S. 【Transformation 7】 This represents a single bond or a double bond. 【Transformation 8】 It is a single bond unless D is N, R ３ H, -(C １－ C ６ ) Alkyl, -CO ２ R １ , -CONHR １ and CON HR １ R １ Selected from the group consisting of R １ Ha- (C １－ C ６ )It is alkyl.

19. Compound of formula V: 【Chemistry 9】 or a pharmaceutically acceptable salt or solvate thereof (Here, X, Y and Z are as defined in claim 1, Pro is, 【Chemistry 10】 Selected from, where * represents the connection point with the N atom in formula V. Each of the aforementioned R １１ is -OH, -HALO, -OR １ , -OC(O)H, -OC(O)R １ ,-OC(O)NH ２ 、-OC(O)NHR １ ,-O(CO)NR １ R １ 、-OP(O)(OH) ２ 、-OP(O)(OR １ ) ２ 、-NH ２ 、 -NHR １ 、-NR １ R １ 、-NHC(O)H、-NHC(O)R １ 、-NRC(O)R １ 、-NHC(O)NH ２ 、-NHC(O)NHR １ 、-NR １ C(O)NH ２ 、-NH C(O)NR １ R １ ,-NR １ C(O)NHR １ ,-NR １ C(O)NR １ R １ ,-EH 、-SR １ 、 -S(O)H、-S(O)R １ 、-SO ２ R １ 、-SO ２ NH ２ 、-SO ２ NHR １ 、- SO ２ NR １ R １ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、 -CO ２ R １ 、-CHO、-C(O)R １ 、-C(O)NH ２ 、-C(O)NHR １ - C(O)NR １ R １ 、-CONHSO ２ H、-CONHSO ２ R １ 、 -CONR １ SO ２ R １ 、-Ph、 - (C ３ -C ７ ) Cycloalkylamino, imidazolyl, piperazinyl, -(C １ -C ６ ) - May optionally be substituted with alkylpiperazinyl and morpholinyl - (C １－ C ６ ) It is alkyl, Each of the aforementioned R １ -HALO, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ , -NR ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ 、-SO ２ NH ２ 、-CF ３ 、-CHF ２ 、 --H ２ F、-CNN、-CO ２ H、-CO ２ R ２ 、-CHO、-C(O)R ２ 、-C(O ) NH ２ , -C(O)NHR ２ and -C(O)NR ２ R ２ It may be arbitrarily replaced with (C １－ C ６ ) independently selected from alkyl, and the R ２ teeth - (C １－ C ６ ) is alkyl, The aforementioned -Ph is -(C １－ C ６ ) alkyl, -halo, -OH, -OR ２ , -NO ２ , -NH ２ 、-NHR ２ 、-NR ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ 、-SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-CO ２ R ２ 、 -CHO,!C(O)R ２ 、-C(O)NH ２ 、-C(O)NHR ２ 、-C(O)NR ２ R ２ It may be arbitrarily replaced with one or more of the above, and the R ２ Ha- (C １－ C ６ ) alkyl And, The aforementioned R １２ and R １３ It is independently selected from the group consisting of -H, -Me, and -Et. (It can be done.)

20. Compounds of formula VI: 【Chemistry 11】 or a pharmaceutically acceptable salt or solvate thereof (Here, X and Y are as defined in claim 1, ----、-NHCO ２ -、-N(Me)CO ２ -、-COO-、-NH(C １－ C ６ ) alkyl, -O-(C １ -C ６ ) Alkyl-N-dimethylamino-,-NH(C １－ C ６ ) alkyl -N-dimethylamino-, - NHCO (C １－ C ６ ) Alkyl-N-dimethylamino- and -NHCOCH=CHC H ２ Selected from -N-dimethylamino-, Pro is, 【Chemistry 12】 Selected from the group consisting of, Here, * represents the connection point with E in equation VI, Each of the aforementioned R １１ is -OH, -HALO, -OR １ , -OC(O)H, -OC(O)R １ ,-OC(O)NH ２ 、-OC(O)NHR １ ,-O(CO)NR １ R １ 、-OP(O)(OH) ２ 、-OP(O)(OR １ ) ２ 、-NH ２ 、 -NHR １ 、-NR １ R １ 、-NHC(O)H、-NHC(O)R １ 、-NRC(O)R １ 、-NHC(O)NH ２ 、 -NHC(O)NHR １ 、-NR １ C(O)NH ２ 、-NHC(O)NR １ R １ 、-NR １ C(O)EER １ 、-NR １ C(O)NR １ R １ 、-SH、-SR １ 、-S(O)H、 -S(O)R １ 、-SO ２ R １ 、-SO ２ NH ２ 、-SO ２ NHR １ 、-SO ２ NR １ R １ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、 -. ２ H-. ２ R １ 、-CHO、-C(O)R １ 、-C(O)NH ２ 、-C(O) NHR １ 、-C(O)NR １ R １ 、-CONHSO ２ H, - CONHSO ２ R １ , -CONR １ SO ２ R １ , -Ph, -(C ３ -C ７ ) Cycloal Killamino, imidazolyl, piperazinil, - (C １ -C ６ ) -Optionally substituted with alkylpiperazinyl and morpholinyl- (C １－ C ６ ) is alkyl, Each of the aforementioned R １ -HALO, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ , -N R ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ 、 -SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-CO ２ R ２ 、 -CHO, -C(O)R ２ 、 -C(O)NH ２ 、 -C(O)NHR ２ or -C(O ) NR ２ R ２ It may be arbitrarily replaced with (C １－ C ６ ) Selected independently from alkyl , R ２ Ha-C １ - ６ It is alkyl, The aforementioned -Ph is -(C １－ C ６ ) alkyl, -halo, -OH, -OR ２ , -NO ２ , - NH ２ 、-NHR ２ 、-NR ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ , -SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-CO ２ R ２ 、 -CHO, -C(O)R ２ 、 -C(O)NH ２ 、 -C(O)NHR ２ and -C(O) NR ２ R ２ R may be optionally substituted with one or more groups independently selected from the above, ２ teeth - (C １－ C ６ ) is alkyl, The aforementioned R １２ and R １３ It is independently selected from the group consisting of -H, -Me, and -Et. R １４ -H, -Me, -Et, -OMe, -CF ３ , -CN and ethynyl Selected from the following group. However, if E is -O-(C １ -C ６ ) Alkyl-N-dimethylamino-,-NH(C １－ C ６ ) alkyl -N-dimethylamino-, - NHCO (C １－ C ６ ) Alkyl-N-dimethylamino- or -NHCOCH=CH CH ２ When selected from -N-dimethylamino-, the Pro is, 【Chemistry 13】 (That is the case.)

21. Compounds of formula VII: 【Chemistry 14】 or a pharmaceutically acceptable salt or solvate thereof (Here, X and Z are as defined in claim 1, Here, J is CH ２ or not exist, 【Chemistry 15】 It is either a saturated ring or an unsaturated ring, B ３ is either C or N, G is, -O-、-NHCO ２ -、-N(Me)CO ２ -、-COO-、-NH(C １－ C ６ ) Alkyl, -O-(C １ -C ６ ) alkyl-N-dimethylamino-, -NH(C) １－ C ６ ) Alkyl-N-dimethylamino-,-NHCO(C １ -C ６ ) Al Kill-N-dimethylamino, and -NHCOCH=CHCH ２ Selected from the group consisting of -N-dimethylamino, The aforementioned Pro is, 【Chemistry 16】 Selected from the group consisting of, Here, * represents the connection point with G in equation VII, Each R １１ is -OH, -HALO, -OR １ , -OC(O)H, -OC(O)R １ ,-OC(O)NH ２ 、-OC(O)NHR １ ,-O(CO)NR １ R １ 、-OP(O)(OH) ２ 、-OP(O)(OR １ ) ２ 、-NH ２ 、 -NHR １ 、-NR １ R １ 、-NHC(O)H、-NHC(O)R １ 、-NRC(O)R １ 、-NHC(O)NH ２ 、 -NHC(O)NHR １ 、-NR １ C(O)NH ２ 、-NHC(O)NR １ R １ 、-NR １ C(O)EER １ 、-NR １ C(O)NR １ R １ 、-SH、-SR １ 、-S(O)H、 -S(O)R １ 、-SO ２ R １ 、-SO ２ NH ２ 、-SO ２ NHR １ 、-SO ２ NR １ R １ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、 -. ２ H-. ２ R １ 、-CHO、-C(O)R １ 、-C(O)NH ２ 、-C(O) NHR １ 、-C(O)NR １ R １ 、-CONHSO ２ H, - CONHSO ２ R １ , -CONR １ SO ２ R １ , -Ph, -(C ３ -C ７ ) Cycloal Killamino, imidazolyl, piperazinil, - (C １ -C ６ ) -Optionally substituted with alkylpiperazinyl and morpholinyl- (C １－ C ６ ) is alkyl, Each of the above R １ -HALO, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ , -N R ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ 、 -SO ２ NH ２ 、-CF ３ 、-CHF ２ 、-CH ２ F、-CN、-CO ２ H、-CO ２ R ２ , -CHO, -C(O)R ２ , -C(O)NH ２ , -C(O)NHR ２ or -C(O ) NR ２ R ２ It may be arbitrarily replaced with (C １－ C ６ ) Selected independently from alkyl , each of the above R ２ is -C １ - ６ It is alkyl, The aforementioned -Ph is, - (C １－ C ６ ) alkyl, -halo, -OH, -OR ２ , -NO ２ , -NH ２ , - NHR ２ 、-NR ２ R ２ 、-SH、-SR ２ 、-SO ２ R ２ 、-SO ２ NH ２ 、-CF ３ 、-C HF ２ ,-EH ２ F、-CNN、-CO ２ H、-CO ２ R ２ 、-CHO、-C(O)R ２ 、 -C(O)NH ２ , -C(O)NHR ２ and -C(O)NR ２ R ２ It may be replaced by one or more groups independently selected from each of the above. R ２ Ha-C １ - ６ It is alkyl. The aforementioned R １２ and R １３ It is selected independently from -H, -Me, and -Et. The aforementioned R １４ -H, -Me, -Et, -OMe, -CF ３ From -CN and ethynyl It is selected from the following group. However, if G is -O-(C １ -C ６ ) Alkyl-N-dimethylamino-,-NH(C １－ C ６ ) alkyl-N-dimethylamino-, - NHCO (C １－ C ６ ) Alkyl-N-dimethylamino-, or -NHCOCH=CH CH ２ -N － When selected from dimethylamino-, the Pro is, 【Chemistry 17】 And, [Chemistry 18] Only if is a saturated ring, the above B ３ is N, B ３ G is -COO- and B only when N is true. ３ Only if C, G is -O-.

22. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvent thereof. A pharmaceutical composition comprising a Japanese compound in combination with one or more pharmaceutically acceptable excipients.

23. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt or solvent thereof. A pharmaceutical composition containing a compound, wherein the inhibition of DNA-PK is beneficial in subjects requiring it. A pharmaceutical composition for treating a certain disease.

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