Substituted 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-C]quinolin-2-one compounds with blood-brain barrier permeability

Abstract

The present invention discloses substituted 1-(3,3-difluoropiperidin-4-yl)-8-(pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one compounds having the ability to penetrate the blood-brain barrier, the compounds having the structural formula represented by formula (I): [Formula 1] JPEG2023542606000016.jpg3954. The substituted 1-(3,3-difluoropiperidin-4-yl)-8-(pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-d]quinolin-2-one compounds, derivatives thereof and pharmaceutically acceptable salts thereof of the present invention have the ability to penetrate the blood-brain barrier and can act as drug properties of protein kinase inhibitors, particularly against protein expression by ataxia telangiectasia mutated (ATM) kinase, and can be used to treat or prevent disorders associated with abnormal protein kinase activity, such as cancer, cancer with brain metastasis, cancer with meningeal metastasis, glioma, glioblastoma and DIPG, either as monotherapy or in combination with other therapies.

Description

[Technical field]

[0001] The present invention relates to novel 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivatives, salts, hydrates thereof and polymorphs thereof, in particular to substituted 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one compounds having the ability to penetrate the blood-brain barrier and selectively modulate ataxia telangiectasia mutated (ATM) kinase, and thus the present specification also relates to the use of such compounds and salts thereof for treating or preventing ATM kinase mediated diseases including cancer, in particular when combined with radiation therapy or DNA double strand break agents for glioma, glioblastoma, diffuse pontine glioma, and cancers with central nervous system metastases. [Background technology]

[0002] Ataxia telangiectasia mutated (ATM) kinase, a member of the phosphatidylinositol 3-kinase-related kinase (PIKK) family of serine / threonine protein kinases located on human chromosome 11 (11q22.3) and consisting of 69 exons spanning 150 kb of genomic DNA, includes DNA-dependent protein kinase catalytic subunit (DNA-PKcs / PRKDC), mammalian target of rapamycin (MTOR / FRAP), and suppressor of genital morphogenesis (SMG1). The cellular functions of ATM kinase range from regulating DNA damage response (DDR) to cell survival, proliferation, metabolism, differentiation, motility, and nonsense-mediated mRNA decay (SP Jackson, J. Bartek, Nature, 461 (2010), pp. 1071-1078, A. Ciccia, SJ Elledge Mol Cell, 40 (2011), pp. 179-204).

[0003] ATM kinase plays a key role in activating the G1 / S cell cycle checkpoint, preventing cells with damaged DNA from entering the S phase. ATM-deficient cells are sensitive to DNA double-strand break inducers such as ionizing radiation and topoisomerase II inhibitors (doxorubicin, etoposide, teniposide, doxorubicin, idarubicin, epirubicin, mitoxantrone), as well as to the conversion of single-strand breaks to double-strand breaks in replicative agents such as topoisomerase I inhibitors (irinotecan, topotecan, etc.), making ATM an attractive target for anticancer chemosensitization and radiosensitization. As a result, ATM kinase inhibitors are expected to be useful in the treatment of cancer as rational combination partners of existing therapies.

[0004] In its inactive state, ATM forms homodimers or higher-order multimers that dissociate into active monomers following rapid intermolecular autophosphorylation of serine 1981, a direct pharmacodynamic and patient-selective biomarker of tumor pathway dependence on ATM activation. ATM recruitment to sites of DNA DSBs is mediated by the MRE11-RAD50-NBS1 (MRN) complex. The MRN complex rapidly assembles at sites of DNA DSBs, where it functions as a damage sensor that can also form physical bridges spanning the DSB (THStracker, JHJ Petrini, Nat Rev Mol Cell Biol, 12 (2011), pp. 90-103).

[0005] ATM recruitment requires binding to the C-terminus of NBS1, and this interaction has been shown to also enhance ATM kinase activity (Z. You, C. Chahwan, J. Bailis, T. Hunter, P. Russell, Mol Cell Biol, 25 (2005), pp. 5363-5379). Immediately after recruitment to sites of DNA DSBs, ATM contributes to the phosphorylation of the histone variant H2AX on serine 139 (S. Burma, BP Chen, M. Murphy, A. Kurimasa, DJ Chen, Biol Chem, 276 (2001), pp. 42462-42467), which initiates a cascade that assembles DDR components at the break site (TT Paull, EP Rogakou, V. Yamazaki, CU Kirchgessner, M. Gellert, WM Bonner, Curr Biol, 10 (2000), pp. 886-895).

[0006] Downstream targets of ATM include the tumor suppressor protein p53 and checkpoint kinase 2 (CHK2) during the G1 / S cell cycle. ATM also contributes to the activation of the S-phase checkpoint, as ATM-deficient cells do not reduce DNA synthesis after induction of DNA DSBs, a phenotype called radioresistant DNA synthesis. ATM's S-phase checkpoint function in response to IR is mediated in part by phosphorylation of NBS1 and SMC1. Further enforcement of the S-phase checkpoint by ATM is mediated via activation of CHK2, which induces ubiquitination and degradation of the S-phase promoting phosphatase Cdc25A, which promotes S-phase progression via activation of cyclin-dependent kinase 2 (Cdk2), which is required for DNA synthesis. While hundreds of substrates are phosphorylated in an ATM-dependent manner in response to IR, ATM functions in regulating signaling pathways involved in maintaining cellular homeostasis, such as cellular metabolism, response to hypoxia, and oxidative stress through a DDR-independent role.

[0007] Glioblastoma or glioblastoma multiforme (GBM) is an aggressive, malignant WHO grade IV brain tumor. Due to the presence of the blood-brain barrier (BBB), no targeted therapy capable of achieving effective doses in the brain has been approved for the treatment of patients with GBM or diffuse pontine glioma (DIPG). Radiation therapy in combination with temozolomide and surgery remain the main means of treatment, but the therapeutic efficacy is limited. For DIPG patients in particular, radiation is the only treatment option in the event of recurrence within 5.5 months. See, for example, Hamer et al., Neuro-Oncology 12(3):304-316, 2010. GBM is a whole-brain disease, and all GBMs have clinically significant tumor areas with an intact BBB. Failure to effectively treat all areas of GBM will lead to treatment failure and recurrence is inevitable (Sarkaria et al. Neuro-Oncology 20(2):184-191, 2018). The role of ATM in radiation sensitivity and the potential use of brain-penetrant ATM inhibitors as radiosensitizers could be very useful in the treatment of brain tumors or central nervous system metastatic cancers, especially in cases where radiation is the only treatment option, such as DIPG. Summary of the Invention [Problem to be solved by the invention]

[0008] Considering the importance of the above-mentioned brain tumors, especially glioblastoma, DIPG, and cancers that have resistance to central nervous system metastasis by radiation, ATM inhibitors that can penetrate the blood-brain barrier and reach an effective amount intracranially are particularly useful for treating or preventing cancer. The object of the present invention is to provide a substituted 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one compound having the desired blood-brain barrier penetrating ability and the drug properties of ATM protein kinase inhibitors, and its use.

[0009] The present invention discloses a number of compounds that have favorable physical and chemical properties (e.g., high permeability and low efflux rates), and / or favorable toxicity properties (e.g., hERG reduction and low drug-drug interaction tendency), and / or other more favorable metabolic curves (non-aldehyde oxidase substrates). Thus, such compounds have effective amounts to penetrate the blood-brain barrier intracranially for the treatment and / or prevention of central nervous system metastases and brain tumors when combined with radiation therapy or other DNA double-strand breaking agents. [Means for solving the problem]

[0010] The object of the present invention is achieved by the following technical scheme. The present invention relates to compounds comprising structures represented by formulas (I), (II) and (III). [ka]

[0011] In the formula, R1 is independently selected from OC1-3 alkyl, OC3-5 cycloalkyl, OC1-C3 deuterated alkyl, dialkylamine, substituted C4-C6 cycloamine, or diazabicycloamine; R2 is independently selected from hydrogen or fluoro; R3 is independently selected from methyl or deuterated methyl; R4 is independently selected from C1 to C3 alkyl or C1 to C3 deuterated alkyl. Preferably, in the formulas (I), (II) and (III), R1 is independently selected from methoxy, ethoxy, isopropoxy, cyclopropoxy, deuterated methoxy, dimethylamine, N,N-dimethylazetidin-3-amine, or 2-methyl-2,6-diazabicyclo[3.2.0]heptane; R2 is independently selected from hydrogen or fluoro; R3 is independently selected from methyl or deuterated methyl; R4 is independently selected from methyl, ethyl, isopropyl, or deuterated methyl.

[0012] The present invention also relates to a pharmaceutical composition comprising the compound, a salt thereof, a solvate thereof, a hydrate thereof, or a polycrystal thereof, and a pharma- ceutically acceptable excipient or auxiliary ingredient.

[0013] The present invention also relates to an ATM inhibitor which is an active ingredient of the above compound and can permeate the blood-brain barrier.

[0014] The invention also relates to the use of said compound, or said pharmaceutical composition, or said inhibitor in the manufacture of a medicament for the treatment or prevention of a disease mediated by ATM kinase.

[0015] Preferably, the protein is the kinase of activated ATM.

[0016] Preferably, the disease is a central nervous system metastatic disease of cancer, a proliferative disease, a brain tumor, a central nervous system disease, or cancer.

[0017] Preferred central nervous system metastasis of cancer includes brain metastasis of cancer, meningeal metastasis of cancer, glioma, DIPG, and glioblastoma.

[0018] Preferred diseases are brain cancer, lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, membranous adenocarcinoma, kidney cancer, lymphoma, ovarian cancer, gastric cancer, skin cancer, bone cancer, glioma, neuroblastoma, hepatocellular carcinoma, papillary renal cell carcinoma, or squamous cell carcinoma of the head and neck.

[0019] Preferably, the disease is non-small cell lung cancer (NSCLC). Preferably, the disease is non-small cell lung cancer (NSCLC) with brain metastases.

[0020] Preferably, the disease is non-small cell lung cancer (NSCLC) with leptomeningeal metastases. Preferably, the disease is glioma.

[0021] Preferably, the disease is glioblastoma.

[0022] Preferably, the disease is DIPG.

[0023] In another aspect, the present invention relates to a method for treating a disease or disease condition in a subject in need thereof, comprising administering to the subject an effective amount of any compound represented by the general formula herein, or a pharma- ceutically acceptable salt, solvate or hydrate thereof (or a combination thereof). The disease or disease condition may be any disease regulated by ATM protein kinase for DNA damage response pathways, particularly for repair of DNA double strand breaks caused by radiation or other agents. These diseases or disease conditions may be, for example, cancer or proliferative diseases or disorders, including, for example, those described herein. Effect of the Invention

[0024] Compared with the prior art, the present invention has the following beneficial effects: 1) The 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivatives of the present invention and pharma- ceutical acceptable salts thereof have the ability to penetrate the blood-brain barrier, and can act as a drug property of a protein kinase inhibitor, particularly against proteins expressed in ATM, and can be used to treat or prevent disorders associated with abnormal protein kinase activity, such as cancer, cancer with brain metastasis, cancer with meningeal metastasis, glioma, glioblastoma, and DIPG. 2) The 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivatives and their pharma- ceutical acceptable salts of the present invention have a low efflux rate and are not human P-glycoprotein and breast cancer resistance protein efflux substrates, thereby reducing resistance to efflux enzymes. 3) 1-(3,3-Difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivatives and their pharmaceutically acceptable salts have good pharmacokinetics (non-aldehyde oxidase substrates) and high biological activity and selectivity against other PIKKs such as ATR and DNA-PK, which can minimize potential toxicity, reduce tablet burden, and improve tablet compliance. 4) 1-(3,3-difluoropiperidin-4-yl)-imidazo[4,5-c]quinolin-2-one derivatives and pharma- ceutical acceptable salts thereof have a favorable safety profile, good compatibility with other drugs, low risk of potential drug-drug interactions and time-dependent inhibition, and low risk of inhibition of ion channels such as hERG. [Brief description of the drawings]

[0025] [Figure 1A] 1A to 1C show the structures of the following compounds. [Figure 1B] 1A to 1C show the structures of the following compounds. [Figure 1C]1A to 1C show the structures of the following compounds: (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (1); (R / S)-1-(1-ethyl-3,3-difluoropiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (2); (R / S)-1-(3,3-difluoro-1-isopropylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (3); (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (3);(R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-ethoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one ();(R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-7-fluoro-8-(6-methoxypyridin-3-yl )-3-Methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (5);(R / S)-1-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (6);(R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-isopropoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one zo[4,5-c]quinolin-2-one (7);(R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(dimethylamino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (8);(R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-(methyl-d3)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (9);(R / S)-8-(6-cyclopropoxypyridin-3-yl)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (10); (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (11); (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (12); -methylpiperidin-4-yl)-8-(6-(methoxy-d3)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (12); (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(6-((1R,5R / 1S,5S)-(2-methyl-2,6-diazabicyclo[3.2.0]heptan-6-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (13); (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(6-((1R,5R / 1S,5S)-(2-methyl-2,6-diazabicyclo[3.2.0]heptan-6-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (13); Fluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (14); (R)-1-(1-ethyl-3,3-difluoropiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (15); (R)-1-(3,3-difluoro-1-isopropylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3- Methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (16); (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-ethoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (17); (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-7-fluoro-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (18);(R)-1-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (19); (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-isopropoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (20); (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(dimethylamino) )pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (21);(R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-(methyl-d3)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (22);(R)-8-(6-cyclopropoxypyridin-3-yl)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one -one (23);(R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (24);(R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(methoxy-d3)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (25);(R)-1-(3,3-difluoro-1-methylpiperidine-4-yl)-8-(6-(methoxy-d3)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (26);(R)-1-(3,3-difluoro-1-methylpiperidine-4-yl)-8-(6-(methoxy-d3)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (27);(R)-1-(3,3-difluoro-1-methylpiperidine-4-yl)- (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(6-((1S,5S)-(2-methyl-2,6-diazabicyclo[3.2.0]heptan-6-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (26); (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(6-((1S,5S)-(2-methyl-2,6-diazabicyclo[3.2.0]heptan-6-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (27);(S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (28); (S)-1-(1-ethyl-3,3-difluoropiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (29); (S)-1-(3,3-difluoro-1-isopropylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl) -3-Methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (30);(S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-ethoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (31);(S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-7-fluoro-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (32);(S)-1 -(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (33);(S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-isopropoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (34);(S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-dimethylamino)pyridine- 3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (); (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-(methyl-d3)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (36); (S)-8-(6-cyclopropoxypyridin-3-yl)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (37);(S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (38); (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(methoxy-d3)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (39); (S)-1-(3,3-difluoro-1-methylpiperidine- (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(6-((1S,5S)-(2-methyl-2,6-diazabicyclo[3.2.0]heptan-6-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (40); (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(6-((1S,5S)-(2-methyl-2,6-diazabicyclo[3.2.0]heptan-6-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (41); [Diagram 2] 1 shows the chemical structures and synthesis of 3,3-difluoro-1-methylpiperidin-4-amine A6 and 1-benzyl-3,3-difluoropiperidin-4-amine A5′. [Diagram 3] 1 shows the chemical structures and synthesis of 8-bromo-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one B5 and 8-bromo-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-(methyl-d3)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one B5′. [Figure 4] The chemical structure and synthesis of 8-bromo-1-(3,3-difluoro-1-methylpiperidin-4-yl)-7-fluoro-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one C5 are shown. [Diagram 5]1 shows the chemical structure and synthesis of 1-(3,3-difluoropiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one D7. [Figure 6] 1 shows the chemical structure and synthesis of 2-cyclopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine E3. [Figure 7] The chemical structure and synthesis of 2-(methoxy-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine F3 are shown. [Figure 8] 1 shows the chemical structure and synthesis of N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine G2. [Figure 9] The chemical structure and synthesis of N,N-dimethyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)azetidin-3-amine H2. [Figure 10] The chemical structure and synthesis of 2-methyl-6-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2,6-diazabicyclo[3.2.0]heptane I6 are shown. [Figure 11] A general synthetic method for the coupling of boronic acid intermediates with aryl bromides is shown. [Figure 12] A representative example is shown using a general synthetic method for the coupling of a boronic acid intermediate with an aryl bromide. [Figure 13] A general method for the chiral separation of racemic products 1-13 is presented. [Figure 14] A representative example using a general method for chiral separation of racemic products is shown. [Figure 15]FIG. 1 shows the chemical structure and synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (1). [Figure 16] FIG. 1 shows the chemical structure and synthesis of (R / S)-1-(1-ethyl-3,3-difluoropiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (2). [Figure 17] FIG. 1 shows the chemical structure and synthesis of (R / S)-1-(3,3-difluoro-1-isopropylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (3). [Figure 18] FIG. 1 shows the chemical structure and synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-ethoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (4). [Figure 19] FIG. 1 shows the chemical structure and synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-7-fluoro-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (5). [Figure 20] FIG. 1 shows the chemical structure and synthesis of (R / S)-1-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (6). [Figure 21] FIG. 1 shows the chemical structure and synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-isopropoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (7). [Figure 22] FIG. 1 shows the chemical structure and synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(dimethylamino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (8). [Figure 23] FIG. 1 shows the chemical structure and synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-(methyl-d3)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (9). [Figure 24] FIG. 1 shows the chemical structure and synthesis of (R / S)-8-(6-cyclopropoxypyridin-3-yl)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (10). [Diagram 25] FIG. 1 shows the chemical structure and synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (11). [Figure 26] FIG. 1 shows the chemical structure and synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(methoxy-d3)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (12). [Figure 27] FIG. 1 shows the chemical structure and synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(6-((1R,5R / 1S,5S)-(2-methyl-2,6-diazabicyclo[3.2.0]heptan-6-yl]pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (13). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] The terms of the present invention are explained as follows.

[0027] The terms "ameliorating" and "treating" are used interchangeably to mean reducing, inhibiting, preventing, or stabilizing the occurrence or progression of a disease (e.g., a disease or disorder described herein), in addition to, but not limited to, a therapeutic benefit and / or a prophylactic benefit.

[0028] "Disease" refers to any disease or disorder that damages or interferes with the normal function of a cell, organ, or tissue.

[0029] "Marker" refers to any change associated with a disease or disorder, for example, any protein or polynucleic acid that has altered expression levels or activity associated with a disease or disorder.

[0030] As used herein, the terms "comprise," "contain," "have," and similar terms have the meaning given in the patent law, "consisting essentially of" or "essentially of" have the same meaning given in the patent law, and the terms are open-ended, permitting the presence of things other than the referenced subject matter, so long as the presence of things other than the referenced subject matter does not alter the basis or new characteristics of the referenced subject matter, and do not include prior art implementations.

[0031] As used herein, the terms "antagonist" and "inhibitor" are used interchangeably and refer to the ability of a compound or agent to inhibit the biological function of a target protein or polypeptide, for example, by inhibiting the activity or expression of the protein or polypeptide. Some antagonists herein interact with a particular target protein or polypeptide (e.g., bind to ATM), but these compounds also inhibit the biological activity of a target protein or polypeptide by interacting with other members of a signal transduction pathway that targets the protein or polypeptide, members that inhibit the development of tumors that develop, grow, or spread, or members associated with undesirable immune responses exhibited by autoimmune diseases, which are included within the definition.

[0032] As used herein, the terms "anti-cancer agent", "anti-tumor agent" or "chemotherapeutic agent" refer to any agent useful in the treatment of neoplastic disease. The class of anti-cancer agents includes chemotherapeutic agents. "Chemotherapy" refers to treatment with one or more chemotherapeutic and / or other agents administered in a variety of ways, including intravenously, orally, subcutaneously, intramuscularly, intraperitoneally, intravesically, transdermally, bucally, or by inhalation.

[0033] As used herein, the term "cell proliferation" refers to an increase in cell number as a result of cell division, and to cell growth (eg, an increase in size) consistent with proliferation signals due to cell morphology.

[0034] The term "co-administration" as used herein refers to the simultaneous use of two or more drugs and the administration of a co-present composition using two or more agents, as well as the administration alone or at different times of two or more drugs and / or their metabolites.

[0035] The term "effective amount" or "therapeutically effective amount" as used herein means an amount of a compound or pharmaceutical composition described herein that is sufficient to achieve the intended purpose of use, including but not limited to the treatment of a disease. In some embodiments, the amount is detected as effective to kill or inhibit the growth or spread of cancer cells, the size or number of tumors, or the level of severity, stage and progression of cancer. The therapeutically effective amount may vary depending on the intended use, such as in vitro or in vivo, the state and level of severity of the disease, the age, weight, or method of administration of the subject. The term also applies to dosages that induce target cells, for example, to reduce cell migration in response to a particular response. Specific dosages will vary, for example, depending on the particular compound selected, the subject species and their age / existing health or condition, the route of administration, the severity of the disease, combination with other drugs, the time of administration, the tissue to which it is administered, and the administration device.

[0036] The term "therapeutic benefit" as used herein includes therapeutic benefit and / or prophylactic benefit. A prophylactic benefit includes delaying or eliminating the onset of a disease or condition, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, halting or reversing a disease or condition, or a combination thereof.

[0037] The term "signal transduction" as used herein is the process by which a stimulatory or inhibitory signal is delivered to a cell to initiate a response within the cell. A "modulator" of a signal transduction pathway means that a compound regulates the activity of one or more cellular proteins mediated by a particular signal transduction pathway. A "modulator" may either enhance (agonist) or inhibit (antagonist) the activity of a signal transduction molecule.

[0038] The term "selective inhibition" as used herein refers to the ability of a compound to selectively reduce a target signaling activity, by direct or indirect interaction, compared to the target activity against an off-target. For example, the activity of a compound that selectively inhibits ATM is at least about 2-fold, about 3-fold, about 5-fold, about 10-fold, about 20-fold, about 50-fold, about 100-fold or more than the activity of ATR.

[0039] As used herein, the term "radiation therapy" refers to exposing a subject to radiation emitters (including, but not limited to, alpha particle emitting radionuclides (e.g., actinium and thorium radionuclides), (e.g., beta emitters), conversion electron emitters (e.g., strontium-89 and samarium-153-EDTMP), and the like), or high energy radiation (including, but not limited to, x-rays, gamma rays, and neutrons).

[0040] The term "subject" as used herein includes, but is not limited to, humans (e.g., any age group, e.g., male or female (e.g., infant, child, adolescent) or adult subjects (e.g., young adult, middle-aged adult or elderly)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals (including commercially relevant mammals such as cows, sheep, goats, pigs, horses, cats and / or dogs); and / or poultry (including commercially relevant poultry such as chickens, geese, quail, ducks and / or turkeys).

[0041] As used herein, the term "in vivo" refers to events that occur within the body of a subject, including incidents that occur within rodents, such as rats, mice, guinea pigs, etc.

[0042] As used herein, the term "in vitro" refers to events that occur outside the subject's body. For example, in vitro testing includes any detection that occurs outside the body. In vitro assays include cell determinations based on live or dead cells, and cell-free assays used within intact cells.

[0043] The term "compound" as used herein is also intended to include salts of the general formula herein. This term also includes any solvates, hydrates and polymorphs of the foregoing. In certain aspects of the invention described in this application, specific reference to "solvates", "hydrates" or "polymorphs" should not be construed as meaning that such forms are excluded in other aspects of the invention that use the term "compound" without reference to these other forms.

[0044] The salts of the compounds of the present invention are formed between an acid and a basic group of the compound (e.g., an amino functional group). According to another preferred embodiment, the compound is a pharma-ceutically acceptable acid addition salt.

[0045] As used herein, the term "pharmaceutical acceptable" refers to a pharmaceutical composition that is suitable for use in contact with human and other mammalian tissues without reasonable toxicity, irritation, allergic response, etc., and poses reasonable concerns / risks than the ingredients. A "pharmaceutical acceptable salt" refers to any non-toxic salt that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the present invention.

[0046] Acids commonly used to form pharma- ceutically acceptable salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric, hydroiodic, and phosphoric; and trifluoroacetic, citric, maleic, oxalic, picric, acetic, adipic, alginic, aspartic, sulfuric, boric, butyric, valeric, camphoric, camphorsyl thiocyanate, digluconic, dodecyl sulfate, pivalic, formic, fumaric, hydroiodic, benzoic, 2-hydroxyethanesulfonic, fumaric, stearic, lactobionic, propionic, and lauric acids. , organic acids such as oleic acid, nicotinic acid, lactic acid cinnamic acid, succinic acid, mandelic acid, malic acid, tartaric acid, lactic acid, pyruvic acid, pectinic acid, methanesulfonic acid, pamoic acid, benzenesulfonic acid, persulfate, palmitic acid, malonic acid, glycerophosphoric acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, salicylic acid, ascorbic acid, 3-phenylpropionic acid, gluconic acid, glucuronic acid, phosphoric acid, glutamic acid, ethanesulfonic acid, p-bromobenzenesulfonic acid, and carbonic acid; and related inorganic and organic acids.

[0047] The term "hydrate" as used herein refers to a compound that contains a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The term "solvate" as used herein refers to a compound that contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces, such as water, dichloromethane, 2-propanol, acetone, methanol, ethanol, and the like. Pharmaceutically acceptable solvates and hydrates are complexes that may contain, for example, 1 to about 100, or 1 to about 10, or 1 to about 4, about 3, or about 2 solvent or water molecules. It is to be understood that the term "compound" as used herein includes the above compounds and solvates, hydrates, or mixtures thereof of the compounds.

[0048] The term "polymorph" as used herein refers to a solid crystalline form of a compound or a complex thereof. Different polymorphs of the same compound can exhibit different physical, chemical and / or spectral properties. Different physical properties include, but are not limited to, stability (e.g., heat, light or humidity), density, hygroscopicity, solubility, compressibility, and dissolution rate.

[0049] As used herein, the term "isomers" are different compounds that have the same molecular formula. "Stereoisomers" are isomers that differ only in the spatial arrangement of the atoms. As used herein, the term "isomer" includes all geometric and stereoisomers. For example, "isomers" includes cis / trans isomers of geometric double bonds (also known as E / Z isomers), R / S-enantiomers; diastereomers, (D)-isomers and (L)-isomers, racemic mixtures thereof, and other mixtures thereof are disclosed herein.

[0050] Substituents around a carbon-carbon double bond are designated as having the "Z" or "E" configuration, and the terms "Z" and "E" are used in accordance with IUPAC standards. Unless otherwise indicated, the structures show both the "E" and "Z" isomers.

[0051] Substitutable substituents surrounding a carbon-carbon double bond may be referred to as "cis" or "trans", where "cis" refers to the substituents on the same side of the double bond and "trans" refers to the substituents on both sides. The arrangement of the carbon rings around the substituents may also be referred to as "cis" or "trans". The term "cis" refers to the substituents on the same side in the plane of the ring and "trans" refers to the substituents on both sides of the plane of the ring. Here, a mixture of substituents on the same and opposite sides of the plane of the two rings is referred to as "cis / trans".

[0052] The term "enantiomer" as used herein is a pair of non-superimposable mirror image stereoisomers that are superimposed on each other. A mixture of enantiomers in any ratio may be called a "racemate". The term "(±)" is used to identify a racemic mixture where appropriate. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is an enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. The absolute configuration of this compound is unknown and can be specified as (+) or (-) depending on the direction of rotation (right or left) of polarized light at the wavelength of the sodium D line. Some of the materials described herein contain one or more asymmetric centers and can therefore produce enantiomers, diastereomers, and other stereoisomers may be defined, in the absolute configuration about each asymmetric atom (R)- or (S)-, and the pharmaceutical compositions and methods include all of these possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active (R)- and (S)- can also be prepared using chiral synthetic methods or chiral reagents, or by conventional techniques.

[0053] As used herein, the term "enantiomeric excess" can be calculated using the following formula: In the example below, the composition contains 90% of one enantiomer (e.g., the S enantiomer) and 10% of the other enantiomer (e.g., the R enantiomer). ee value=(90-10) / 100=80%。

[0054] Thus, a composition containing 90% of one enantiomer and 10% of the other enantiomer is said to have an enantiomeric excess of 80%. Some compositions described herein contain at least about 50% enantiomeric excess, about 75%, about 90%, about 95%, or about 99% S enantiomer. In other words, the composition contains an enantiomeric excess of S enantiomer in R enantiomer. In other embodiments, some compositions described herein contain at least about 50% enantiomeric excess, about 75%, about 90%, about 95%, or about 99% R enantiomer. In other words, the composition contains an enantiomeric excess of R enantiomer in S enantiomer. For example, an isomer / enantiomer can, in some embodiments, provide the ee value of the corresponding enantiomer and may also be referred to as "optically enriched," "enantiomerically enriched," "enantiomerically pure," and "non-racemic," which are used interchangeably herein. These terms mean that the weight percentage of one enantiomer is greater than the amount of a control mixture of a composition (e.g., greater than 1:1 by weight) than a racemic composition in one enantiomer. For example, the enantiomer of the S enantiomer is present in about 75% by weight of the enantiomer, e.g., greater than about 50% by weight, at least about 80% by weight of the compound. In some embodiments, enrichment can provide greater than about 80% by weight, "substantially enantiomerically enriched," "substantially enantiomerically pure," or "substantially non-racemic," meaning that the weight of an enantiomer comprises at least 85% by weight of the composition, such as at least about 90% by weight of the formulation, and further, such as at least about 95% by weight relative to one of the other enantiomers. In some embodiments, the compounds provided herein may be present in an amount from about 90% by weight of at least one enantiomer. In other embodiments, the compounds may be present in an amount of at least about 95%, about 98%, or about 100% by weight of the enantiomer. In some embodiments, the compounds are (S)- and (R)-racemic mixtures.In other embodiments, methods are provided in which the individual compounds of the mixture (S) are predominantly mixtures of compounds or mixtures of compounds in which (R)- is predominantly present, e.g., the mixture of compounds is about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In other embodiments, the mixture of compounds has an (S) enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 80% to about 99.5%, greater than about 85% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5% or more. In other embodiments, the mixture of compounds has an (R)-enantiomer purity of about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 96%, about 97%, about 98%, about 99%, about 99.5% or more. In other embodiments, the mixture of compounds has an (R)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 70% to about 99.5%, greater than about 75% to about 99.5%, greater than about 95% to about 99.5%, greater than about 85% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5% or more.

[0055] In other embodiments, the mixture of compounds contains the same chemical entity in addition to their stereochemical orientation, i.e., (S)- or (R)-. For example, if there is a -CH(R)- unit in a compound, where R is not hydrogen, then -CH(R)- is the same chemical entity as either the (S)- or (R)-stereochemical orientation. In some embodiments, the (S)-isomer in the mixture of the same chemical entity has an (S)-enantiomeric excess of greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 65% to about 99.5%, greater than about 90% to about 99.5%, greater than about 90% to about 99.5%, greater than about 90% to about 99.5%, greater than about 90% to about 99.5% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5% or more.

[0056] In another embodiment, the (R)-isomer is about 55%, about 60%, about 65, about 90%, about 95%, about 85%, about 90%, about 95%, about 96%, about 97%, about 99%, about 99.5% or more of the same chemical identity (except for its stereochemical orientation) to the (S)-isomer. In some embodiments, the (R)-enantiomeric excess in a mixture of identical chemical entities (except for their stereochemical orientation) is greater than about 55% to about 99.5%, greater than about 60% to about 99.5%, greater than about 75% to about 99.5%, greater than about 75% to about 99.5%, greater than about 75% to about 99.5%, greater than about 90% to about 99.5%, greater than about 95% to about 99.5%, greater than about 96% to about 99.5%, greater than about 97% to about 99.5%, greater than about 98% to about 99.5%, greater than about 99% to about 99.5% or more.

[0057] Enantiomers can be isolated from a racemic mixture by any method known to those skilled in the art, including chiral high performance liquid chromatography (HPLC), formation and crystallization of chiral salts, or asymmetric synthesis.

[0058] The optical isomers can also be obtained by conventionally cleaving the racemic mixture with an optically active acid or base, for example by forming diastereomeric salts. Suitable acids include, but are not limited to, tartaric acid, diacetyl, dibenzoyl, dimethyltartaric acid, camphorsulfonic acid, and the like. Separation of the isomers from the mixture of optically active bases of these salts can be achieved by diastereomeric crystallization. Alternatively, reaction of an open compound with an activated, optically pure acid or an optically pure isocyanate includes synthesis of covalently bonded diastereomeric molecules. The synthesized enantiomers can be isolated by conventional methods such as chromatography, distillation, crystallization, or sublimation, and then hydrolyzed to obtain enantiomerically enriched compounds. Optically active compounds of the present invention can also be obtained using active substances. In some embodiments, these isomers can be in the form of free acids, free bases, esters, or salts.

[0059] In some embodiments, the pharma- ceutically acceptable form is a tautomer. The term "tautomer" as used herein is a type of isomer that includes at least one form of migration and change of two or more interconverting compounds from a hydrogen atom and a covalent bond (e.g., from a single bond to a double bond, from a triple bond to a single bond, or vice versa). "Tautomerism" includes proton or proton-transfer tautomerism, which is considered a subset of acid-base chemistry. "Proton-transfer tautomerism" includes a proton transfer with a change in bond. The exact ratio of tautomers depends on several factors, such as temperature, solvent, and pH. In that tautomerism is possible (e.g., in solution), chemical equilibrium of tautomers can be reached. Tautomerism (i.e., the reaction that produces the tautomeric pair) can be catalyzed by acid or base, or can occur with or without the presence of an exogenous agent. Tautomeric additions include, but are not limited to, ketone to enol, amide to imide, enamine to imine, and one form of enamine to different enamine. A specific example of a ketone to enol tautomer is the tautomer of pentane-2,4-dione and 4-hydroxypent-3-en-2-one. Another example of tautomerism is the tautomer of phenol and ketone. A specific example of a phenol and ketone tautomer is pyridine 4-phenols and pyridin-4-(1H)-one tautomer.

[0060] Unless otherwise stated, structures depicted herein are meant to include compounds that contain only one or more isotopically enriched atoms, for example, compounds having structures where a single hydrogen is replaced with deuterium or tritium, or carbon-13 or carbon-14 enriched structures within the scope of the disclosure.

[0061] The present disclosure also includes "isotopically labeled derivatives," which are pharma- ceutically acceptable forms of those compounds listed herein, except that one or more atoms have a different atomic mass than is typically found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, e.g., 2 H, 3 H,13 C. 14 C. 15 N, 18 O. 17 O. 18 F, and 36 Certain isotopically labeled disclosed compounds (e.g., 3 H and 14 C) are useful for measuring the tissue distribution of compounds and / or substrates. 3 H) and carbon 14 (i.e. 14 C) isotopes can be easily prepared and tested. In addition, deuterium (i.e. 2 Substitution with heavier isotopes such as H or D may provide certain therapeutic advantages due to higher metabolic stability (e.g., increased half-life in vivo or reduced dose required). Isotopically labeled disclosed compounds can generally be prepared by substituting an isotopically labeled reagent with a non-isotopically labeled reagent. In some embodiments, those provided herein may also include one or more non-natural atomic isotopes to form such compounds. All isotopic variants of the disclosed compounds, whether radioactive or not, are used within the scope of the present disclosure. In some embodiments, radiolabeled compounds may be used to study the metabolism and tissue distribution of compounds to alter metabolic pathways, or rates or other biological functions.

[0062] As used herein, the term "stereoisomers" refers to enantiomers and diastereomers.

[0063] The term "halo" or "halogen" as used herein refers to any radical of fluorine, chlorine, bromine or iodine.

[0064] The term "alkyl" as used herein refers to a straight or branched chain of carbon and hydrogen atoms containing no unsaturated atoms, having a hydrocarbon chain of 1 to 10 carbon atoms, preferably 1 to 8 carbon atoms. "Lower alkyl" refers to alkyl groups having 1 to 4 carbon atoms, inclusive.

[0065] The term "arylalkyl" refers to a moiety in which an alkyl hydrogen atom is replaced by an aryl group.

[0066] The term "alkenyl" refers to a straight or branched hydrocarbon chain having at least one double bond and having from 2 to 10 carbon atoms, preferably from 2 to 4 carbon atoms. When an alkenyl group is attached to a nitrogen atom, it is preferred not to attach such group directly through a carbon containing a double bond.

[0067] The term "alkoxy" refers to an -O-alkyl group containing from 1 to 10 carbon atoms from a linear, branched, saturated cyclic structure, and combinations thereof, to the parent molecular structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclohexyloxy, etc. "Lower alkoxy" refers to an alkoxy group containing from 1 to 6 carbon atoms.

[0068] The term "alkynyl" refers to a linear or branched hydrocarbon chain containing at least one triple bond in a linear hydrocarbon group having from 2 to 10 carbon atoms (i.e., C2-C10 alkynyl), preferably from 2 to 4 carbon atoms. When an alkynyl group is bonded to a nitrogen atom, it is preferred not to bond such group directly through a carbon bearing a triple bond.

[0069] The term "alkylene" refers to a divalent linear bridge of 1 to 5 carbon atoms linked by single bonds (e.g., -(CH2) x -, where x is 1-5), which may be substituted with 1-3 alkyl substituents.

[0070] As used herein, the terms "cycloalkyl" and "cycloalkenyl" include saturated and partially saturated cyclic hydrocarbon alkyl groups having 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms.

[0071] The term "Ar" or "aryl" refers to an aromatic ring group having 6 to 14 carbon atoms (e.g., a 6-membered monocyclic or 10-membered bicyclic ring). Exemplary aryl groups include phenyl, naphthyl, and biphenyl.

[0072] The terms "heterocycle", "heterocycloed" and "heterocyclyl" refer to fully saturated or partially unsaturated cyclic groups, such as 3- to 7-membered monocyclic, 7- to 12-membered bicyclic, and 15-membered tricyclic ring systems, having at least one heteroatom in at least one ring, where 0, 1, 2, or 3 atoms of each ring may be substituted with a substituent. Each ring of a heteroatom-containing heterocyclic group may have 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen atoms, oxygen atoms, and / or sulfur atoms, where the nitrogen atoms and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system.

[0073] The term "substituent" refers to a group that is "substituted" with any of the functional groups described herein, such as an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl base, a heterocyclyl group, or a heteroaryl group. Suitable substituents include halogen, CN, NO2, OR, SR, S(O)2OR, NRR', C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy, (NR)NRR', N(NR)NRR', N(NR)NRR', N(NR)NRR', C(O)(O)R", S(0)2R", R', C(0)R', C(O)R", N(R)(CH2) n OH, (CH2) n OR, (CH2) nThese include, but are not limited to, C(O)NRR', NRS(O)2R', where n is independently 0-6, including 0 and 6. Each R is independently hydrogen, C1-C4 alkyl, or C3-C6 cycloalkyl. Each R' is independently hydrogen, alkenyl, alkynyl, C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4 alkyl, or substituted with C3-C5 cycloalkyl, aryl, heterocyclyl, or heteroaryl substituted C-C4 alkyl. Each R" is independently a C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4 alkyl, or substituted with a C3-C6 cycloalkyl, aryl, heterocyclyl, or heteroaryl C1-C4 alkyl. Each C3-C5 cycloalkyl, aryl, heterocyclyl, heteroaryl, and C1-C4 alkyl in each R, R', and R" may be optionally substituted with halogen, CN, C1-C4 alkyl, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino, C1-C4 dialkylamino, C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy, or 1,2-methylenedioxy.

[0074] The term "oxo" refers to an oxygen atom which, when attached to carbon, forms a carboxyl group, when attached to nitrogen, forms an N-oxide, and when attached to sulfur, forms a sulfoxide or sulfone.

[0075] The term "acyl" refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclocarbonyl, or heteroarylcarbonyl substituent, any of which may be further substituted by substituents.

[0076] The term "CDCl3" refers to deuterated chloroform.

[0077] The term "DMSO-d6" refers to deuterated dimethylsulfoxide.

[0078] The term "LC-MS: (ESI)" refers to electrospray ionization liquid chromatography mass spectrometry.

[0079] The term "alteration" as used herein is defined as a change in relative physiological state. Exemplary alterations include mutations, deletions, fusions with other proteins, overexpression or underexpression.

[0080] The recitation of a listing of chemical groups in any definition of a variable herein includes defining the variable as any single group or combination of the groups listed. The recitation of an embodiment for a variable herein includes that embodiment in any single embodiment or in combination with any other embodiment or portion thereof. The recitation of an embodiment of this embodiment includes that embodiment in any single embodiment or in combination with any other embodiment or portion thereof.

[0081] The compounds of the present invention may contain one or more asymmetric centers, and thus appear as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures.All such isomeric forms of these compounds are expressly included in the present invention.The compounds of the present invention may also exist in various tautomeric forms, in which case the present invention expressly includes all tautomeric forms of the compounds described herein.All such isomeric forms of the compounds are included in the present invention.All crystalline forms of the compounds described herein are expressly included in the present invention.

[0082] The compound of the present invention is In one embodiment, the present invention provides a compound of formula (I) or a salt thereof, or a hydrate, solvate or polymorph thereof, wherein In the formula, R1 is independently selected from OC1-3 alkyl, OC3-5 cycloalkyl, OC1-C3 deuterated alkyl, dialkylamine, substituted C4-C6 cycloamine, or diazabicycloamine; R2 is independently selected from hydrogen or fluoro; R3 is independently selected from methyl or deuterated methyl; R4 is independently selected from C1 to C3 alkyl or C1 to C3 deuterated alkyl.

[0083] In another embodiment, the present invention provides a compound of formula (II) or a salt thereof, or a hydrate, solvate or polymorph thereof, wherein R1 is independently selected from OC1-3 alkyl, OC3-5 cycloalkyl, OC1-C3 deuterated alkyl, dialkylamine, substituted C4-C6 cycloamine or diazabicycloamine; R2 is independently selected from hydrogen or fluoro; R3 is independently selected from methyl or deuterated methyl; R4 is independently selected from C1 to C3 alkyl or C1 to C3 deuterated alkyl.

[0084] In another embodiment, the present invention provides a compound of formula (III) or a salt thereof, or a hydrate, solvate or polymorph thereof, wherein R1 is independently selected from OC1-3 alkyl, OC3-5 cycloalkyl, OC1-C3 deuterated alkyl, dialkylamine, substituted C4-C6 cycloamine or diazabicycloamine; R2 is independently selected from hydrogen or fluoro; R3 is independently selected from methyl or deuterated methyl; R4 is independently selected from C1 to C3 alkyl or C1 to C3 deuterated alkyl.

[0085] Representative compounds of the present invention are compounds 1-41 shown in Figures 1A-1C. In these examples, the stereochemistry at the chiral carbon atoms is independently R / S, R or S unless otherwise indicated. The structures described herein include the structures of compounds 1-41 below with reference to Figures 1A-1C, which may have certain NH, NH2 (amino) and OH (hydroxy) groups where the corresponding hydrogen atoms are not explicitly shown, but which are read as NH, NH2 or OH, as appropriate. In some structures, drawing a rod bond denotes a methyl group.

[0086] Representative compounds of the present invention are as follows: (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (1) (R / S)-1-(1-ethyl-3,3-difluoropiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (2) (R / S)-1-(3,3-difluoro-1-isopropylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (3) (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-ethoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (4) (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-7-fluoro-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (5) (R / S)-1-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (6) (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-isopropoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (7) (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(dimethylamino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (8) (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-(methyl-d3)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (9) (R / S)-8-(6-cyclopropoxypyridin-3-yl)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (10) (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (11) (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(methoxy-d3)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (12) (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(6-((1R,5R / 1S,5S)-(2-methyl-2,6-diazabicyclo[3.2.0]heptan-6-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (13) (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (14) (R)-1-(1-ethyl-3,3-difluoropiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (15) (R)-1-(3,3-difluoro-1-isopropylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (16) (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-ethoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (17) (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-7-fluoro-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (18) (R)-1-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (19) (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-isopropoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (20) (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(dimethylamino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (21) (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-(methyl-d3)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (22) (R)-8-(6-cyclopropoxypyridin-3-yl)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (23) (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (24) (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(methoxy-d3)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (25) (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(6-((1R,5R)-(2-methyl-2,6-diazabicyclo[3.2.0]heptan-6-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (26) (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(6-((1S,5S)-(2-methyl-2,6-diazabicyclo[3.2.0]heptan-6-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (27) (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (28) (S)-1-(1-ethyl-3,3-difluoropiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (29) (S)-1-(3,3-difluoro-1-isopropylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (30) (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-ethoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (31) (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-7-fluoro-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (32) (S)-1-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (33) (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-isopropoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (34) (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(dimethylamino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (35) (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-(methyl-d3)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (36) (S)-8-(6-cyclopropoxypyridin-3-yl)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (37) (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (38) (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(methoxy-d3)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (39) (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(6-((1R,5R)-(2-methyl-2,6-diazabicyclo[3.2.0]heptan-6-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (40) (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(6-((1S,5S)-(2-methyl-2,6-diazabicyclo[3.2.0]heptan-6-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (41)

[0087] The synthesis of compounds of the general formula herein can be readily carried out by one of ordinary skill in the art of synthetic chemistry, for example, by the relevant methods and intermediates disclosed herein. Each patent, patent application and publication referred to herein, whether traditional journal or internet only, is hereby incorporated by reference in its entirety.

[0088] Other methods for the synthesis of compounds of the general formula described herein can be readily adapted from the references cited herein. Modification of these procedures and their optimization are within the capabilities of those skilled in the art.

[0089] The specific formats and compounds above are not intended to be limiting. The chemical structures in this scheme show many variables that are used to sterilize the chemical groups (partial, atomic, etc.) defined at the corresponding positions of the compounds of the formula, whether they are represented by the same variable names (e.g., R1, R2, R, R', R'', X, etc.). It is within the ability of the skilled artisan that the chemical groups in the compound structure are suitable for the synthesis of another compound structure. Other methods of synthesis of compounds of the general formula and their synthetic precursors, including those not explicitly shown in this disclosure, are within the chemical means of the skilled artisan. Methods for optimizing reaction conditions to reduce competitive by-products are known in the art. The methods described herein may further include steps of incorporating or removing appropriate protecting groups before or after the steps described herein, thereby allowing for the final synthesis herein. Furthermore, the individual synthetic steps may be performed in variable order or sequence to obtain the desired compounds.

[0090] The methods described herein are intended to convert a compound of formula to another compound of formula. The conversion process refers to one or more chemical transformations that can be carried out in situ or can be separated from an intermediate compound. The conversion can include the use of techniques and protocols known in the art for reacting a starting compound or intermediate with additional reagents, including those described in the references cited herein. The intermediate can be purified (e.g., filtration, distillation, sublimation, crystallization, trituration, solid phase extraction and chromatography) or used without purification.

[0091] Combinations of substituents and variables contemplated by this invention are only those that result in the formation of stable compounds.

[0092] The present invention also provides a composition comprising an effective amount of a compound of any of the general formulas herein, or, if applicable, a pharma- ceutically acceptable salt, solvate, hydrate, or polymorph of said compound, and an acceptable carrier.Preferably, the composition of the present invention is prepared for medicinal use (pharmaceutical composition), and said carrier is a pharma- ceutically acceptable carrier.In terms of compatibility with other components of the formulation, in the case of a pharma- ceutical acceptable carrier, said carrier must be "acceptable" and not impair its receptor in the amount normally used in the drug.

[0093] A "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. A pharmaceutically acceptable carrier or excipient does not interfere with the pharmacological activity of the disclosed compounds and is non-toxic when administered in a dosage of the compound sufficient to deliver. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions disclosed herein is contemplated.Examples of pharma-ceutically acceptable carriers and excipients include, but are not limited to, the following: sugars such as lactose, sucrose, glucose, etc.; starches such as potato starch, corn starch, etc.; cellulose and its derivatives, such as sodium carboxymethylcellulose, cellulose acetate, ethylcellulose, etc.; gelatin; tragacanth powder; talc; malt; cocoa butter and suppository waxes; oils such as peanut oil, safflower oil, cottonseed oil, olive oil, sesame oil, corn oil, soybean oil, etc.; diols such as polyethylene glycol, propylene glycol; esters such as ethyl oleate, ethyl laurate; agar; buffers such as magnesium hydroxide, aluminum hydroxide, etc.; alginic acid; aldehydes; phosphates; phosphate buffers; e.g., non-toxic compatible lubricants such as sodium lauryl sulfate, magnesium stearate; colorants; coatings; release agents (release agents); sweeteners, flavors and fragrances (fragrances); Vitamin E polyethylene glycol 1000 succinate (SEDDS); surfactants for pharmaceutical dosage forms, such as Tween or other similar polymeric delivery matrices; serum proteins such as human serum albumin; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water, salts or electrolytes such as protamine sulfate, potassium hydrogen phosphate, disodium hydrogen phosphate, sodium chloride and zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based materials; polyacrylates; waxes; and polyethylene-polyoxypropylene-block polymers; cyclodextrins, such as α, β and γ-cyclodextrin, or chemically modified derivatives, such as hydroxyalkyl cyclodextrins including 2- and 3-hydroxypropyl cyclodextrin or other solubilizing derivatives to enhance delivery of the compounds.

[0094] The pharmaceutical compositions of the invention can be administered in solid or liquid form, including: oral administration, e.g., irrigation (aqueous or non-aqueous solutions or suspensions), tablets (e.g., for oral, subcutaneous and systemic absorption), hard or soft capsules, pills, syrups, powders, granules, pastes applied to the tongue, duodenal route; intravenous, intraarterial, subcutaneous, intramuscular administration, parenteral administration, including, e.g., creams, ointments, gelling agents, aqueous or oily solutions or suspensions, e.g., creams, ointments, gelling agents, or vaginal suppositories, creams or scaffolds; sublingual administration; topical administration via a catheter or stent; intrathecal or intranasal administration (e.g., as a fine powder), or administration by inhalation (e.g., as a fine powder or liquid aerosol).

[0095] Examples of suitable aqueous and non-aqueous carriers in pharmaceutical compositions include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Proper fluidity is maintained, for example, by using coating materials such as lecithin, by maintaining the desired particle size of the dispersion, and by using surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, lubricants, and / or antioxidants. The action of the compounds described herein to prevent microorganisms can be ensured by including various antibacterial and antifungal agents, for example, p-hydroxybenzoates, chlorobutanol, phenol sorbic acid, and the like. This may also be in a composition containing an isotonic agent, such as sugar, sodium chloride, and the like. In addition, prolonged absorption of the injectable dosage form can be achieved by including an absorption delaying agent, such as aluminum monostearate and gelatin.

[0096] The method of making such formulations or compositions includes steps involving the compounds and / or chemotherapeutic vehicles described herein and, optionally, one or more accessory ingredients. In general, the formulations are formed by uniformly structuring the compounds disclosed herein with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product. Excipients are also contemplated to be within the scope of this disclosure, so long as any conventional excipient vehicle is incompatible with the compounds provided herein (e.g., interacts with any other components of the pharma-ceutically acceptable composition to produce any undesirable biological or deleterious effects).

[0097] In some embodiments, the concentration of one or more disclosed compounds is about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 14%, about 13%, about 12%, about 11%, about 10%, about 10%, about 5%, about 4%, about 3%, about 2%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.05%, about 0.06%, about 0.07%, about 0.08 ... It may be less than 0.02%, about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%, about 0.0002%, or about 0.0001% weight / weight, weight / volume, or volume / volume.

[0098] In some embodiments, the concentration of one or more compounds disclosed herein is about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, about 18.5%, about 18.25%, about 17.5%, about 17.25%, about 17%, about 16.5%, about 16.25%, about 16, about 15.5%, about 15.25%, about 15%, about 14.5%, about 14.25%, about 14%, about 13.5%, about 13.25%, about 13%, or about 15%. ,about 12.5%,about 12.25%,about 12%,about 11.5%,about 11.25%,about 11%,about 10.75%,about 10.5%,about 10%,about 9.75%,about 9.5%,about 9.25%,about 9%,about 8.75%,about 8.5%,about 8.25%,about 8%,about 7.75%,about 7.5%,about 7.25%,about 7%,about 6.75%,about 6.5%,about 6.25%,about 6%,about 5.75%,about 5.5%,about 5.25%,about 5%,about 4.75%,about 4. 5%, about 4.25%, about 4%, about 3.75%, about 3.5%, about 3%, about 2.75%, about 2.50%, about 2.25%, about 2%, about 1.75%, about 1.50%, about 1.25%, about 1%, about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%, about 0.09%, about 0.08%, about 0.07%, about 0.06%, about 0.05%, about 0.04%, about 0.03%, about 0.02%, It may be greater than about 0.01%, about 0.009%, about 0.008%, about 0.007%, about 0.006%, about 0.005%, about 0.004%, about 0.003%, about 0.002%, about 0.001%, about 0.0009%, about 0.0008%, about 0.0007%, about 0.0006%, about 0.0005%, about 0.0004%, about 0.0003%, about 0.0002%, or about 0.0001% weight / weight, weight / volume, or volume / volume.In some embodiments, the concentration of one or more compounds disclosed herein is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 20%, from about 0.09% to about 24%, from about 0.08% to about 23%, from about 0.07% to about 22%, from about 0.06% to about 24%, from about 0.2% The weight / weight ratio, weight / volume ratio, or volume / volume ratio may be about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, or about 1% to about 10%. In some embodiments, the concentration of one or more compounds disclosed herein may be from about 0.001% to about 10%, from about 0.01% to about 5%, from about 0.02% to about 4.5%, from about 0.03% to about 4%, from about 0.04% to about 3.5%, from about 0.05% to about 3%, from about 0.06% to about 2.5%, from about 0.07% to about 2%, from about 0.08% to about 1.5%, from about 0.09% to about 1%, or from about 0.1% to about 0.9% weight / weight, weight / volume, or volume / volume.

[0099] In some embodiments, the amount of one or more compounds disclosed herein is about 10 g, about 9.5 g, about 9.0 g, about 8.5 g, about 8.0 g, about 7.5 g, about 7.0 g, about 6.5 g, about 6 g, about 5.5 g, about 5 g, about 4.5 g, about 4 g, about 3.5 g, about 3 g, about 2.5 g, about 2.0 g, about 1.5 g, about 1.0 g, about 0.95, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75 g, about 0.7 g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g, about 0.45 g, about 0.4 g, about 0.35 g, about 0.3 g, about 0.25 g, about 0. The amount may be less than or equal to 2 g, about 0.15 g, about 0.1 g, about 0.09 g, about 0.08 g, about 0.07 g, about 0.06 g, about 0.05 g, about 0.04 g, about 0.03 g, about 0.02 g, about 0.01 g, about 0.009 g, about 0.008 g, about 0.007 g, about 0.006 g, about 0.005 g, about 0.004 g, about 0.003 g, about 0.002 g, about 0.001 g, about 0.0009 g, about 0.0008 g, about 0.0007 g, about 0.0006 g, about 0.0005 g, about 0.0004 g, about 0.0003 g, about 0.0002 g, or about 0.0001 g.In some embodiments, the amount of one or more compounds disclosed herein is about 0.0001 g, about 0.0002 g, about 0.0003 g, about 0.0004 g, about 0.0005 g, about 0.0006 g, about 0.0007 g, about 0.0008 g, about 0.0009 g, about 0.001 g, about 0.0015 g, about 0.002 g, about 0.0025 g, about 0.003 g, about 0.004 g, about 0.005 g, about 0.006 g, about 0. ...8 g, about 0.009 g, about 0.001 g, about 0.0015 g, about 0.002 g, about 0.003 g, about 0.004 g, about 0.005 g, about 0.006 g, about 0.007 g, about 0.008 g, about 0.009 g, about 0.001 g, about 0.0015 g, about 0.002 g, about 0.003 g, about 0.004 g, about 0.005 g, about 0.006 g, about 0.007 g, about 0.008 g, about 0.009 g, about 0.001 g, about 0.0015 g, about 0.03g, about 0.0035g, about 0.004g, about 0.0045g, about 0.005g, about 0.0055g, about 0.006g, about 0.0065g, about 0.007g, about 0.0075g, about 0.008g, about 0.0085g, about 0.009g, about 0.0095g, about 0.01g, about 0.015g, about 0.02g, about 0.025g, about 0.03g, about 0.03 5g, about 0.04g, about 0.045g, about 0.05g, about 0.055g, about 0.06g, about 0.065g, about 0.07g, about 0.075g, about 0.08g, about 0.085g, Approximately 0.09g, approximately 0.095g, approximately 0.1g, approximately 0.15g, approximately 0.2g, approximately 0.25g, approximately 0.3g, approximately 0.35g, approximately 0.4g, approximately 0.45g, approximately 0.5g, approximately 0.55g , about 0.6 g, about 0.65 g, about 0.7 g, about 0.75 g, about 0.8 g, about 0.85 g, about 0.9 g, about 0.95 g, about 1 g, about 1.5 g, about 2 g, about 2.5 g, about 3 g, about 3.5 g, about 4 g, about 4.5 g, about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, or about 10 g.

[0100] In some embodiments, the amount of one or more compounds disclosed herein may be from about 0.0001 g to about 10 g, from about 0.0005 g to about 9 g, from about 0.001 g to about 0.5 g, from about 0.001 g to about 8 g, from about 0.005 g to about 7 g, from about 0.01 g to about 6 g, from about 0.05 g to about 5 g, from about 0.1 g to about 4 g, from about 0.5 g to about 4 g, or from about 1 g to about 3 g.

[0101] In some preferred embodiments, pharmaceutical compositions for oral administration of the compounds disclosed herein and pharmaceutical excipients suitable for oral administration are provided. In some embodiments, pharmaceutical compositions for oral administration are provided that include: (1) an optionally effective amount of a disclosed compound, (2) an effective amount of one or more second agents, and (3) one or more pharma- ceutically acceptable excipients for oral administration. In some embodiments, the pharmaceutical composition further includes (4) an effective amount of a third agent.

[0102] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration. Pharmaceutical compositions suitable for oral administration may be in the form of individual dosage forms, such as capsules, cachets, tablets, liquids, solutions, aerosol sprays, or suspensions, containing a predetermined amount of active ingredient, in powder or granular form, in water or non-aqueous liquid, liquid emulsion in water, or water in liquid emulsion. Such dosage forms may be prepared by any pharmaceutical method, but all methods include the step of preparing the composition by uniformly and intimately mixing the active ingredient with liquid carriers, liposomes, or finely divided solid carriers, or both. In general, pharmaceutical compositions are formed by uniformly and intimately mixing the active ingredient with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired form. For example, a tablet may be one or more components that can be compressed or molded. Tablets may be formed by mixing a free-flowing form such as powdered or granulated active ingredient with any excipient, such as, but not limited to, a mixture of binders, lubricants, inert diluents and / or surfactants or dispersants, and compressing in a suitable machine. The molded tablets may be prepared by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. The tablets may be uncoated, coated, or nicked, and may be formulated to allow slow or controlled release of the active ingredient therein, such that the effect can be sustained over a longer period, such as, for example, glyceryl monostearate or glyceryl distearate. Oral formulations may also be hard gelatin capsules in which the active ingredient may be mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or soft gelatin capsules in which the active ingredient may be mixed with water or an oil medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0103] The active ingredient can be intimately combined with a pharma- ceutically acceptable carrier by conventional drug mixing techniques. The carrier can take a variety of forms depending on the desired dosage form of the formulation. In preparing pharmaceutical compositions in oral dosage form, any of the usual pharmaceutical media can be used as carriers, such as water, glycols, oils, ethanol, flavoring agents, preservatives, coloring agents, and carriers for oral liquids (e.g., suspensions, solutions, elixirs) or aerosols, or carriers for oral solid formulations, such as starch, sugar, microcrystalline cellulose, diluents, granules, lubricants, binders, disintegrants, etc. In some embodiments, lactose is not used. In some embodiments, the compound can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, calcium phosphate, sodium phosphate, calcium sulfate, sodium sulfate, gelatin, gum arabic, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol for further formulation. For example, carriers suitable for the preparation of oral solid dosage forms further include powders, capsules, and tablets. In some embodiments, tablets may be coated by standard aqueous or nonaqueous techniques.

[0104] Coatings suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch or other starches, gelatin, natural binders and synthetic gums such as gum arabic, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, calcium carboxymethylcellulose, sodium carboxymethylcellulose), polyvinylpyrrolidone, cellulose, pregelatinized starch, hydroxypropyl methylcellulose, microcrystalline cellulose, and mixtures thereof.

[0105] Examples of fillers suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, glucose binder, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

[0106] Disintegrants may be used in the pharmaceutical compositions provided herein to provide tablets that disintegrate when exposed to an aqueous environment. Too much disintegrant may cause the tablet to disintegrate in the bottle. Too little disintegrant may not be enough to disintegrate, which may alter the rate and extent of release of the active ingredient in the dosage form. Thus, the amount of disintegrant should be sufficient, but not too little or too much to impair the release of the active ingredient. The amount of disintegrant varies depending on the formulation and mode of administration, and can be readily implemented by one of ordinary skill in the art. About 0.5 to about 15% by weight of disintegrant, or about 1 to about 5% by weight of disintegrant may be used in the pharmaceutical compositions. Disintegrants that may be used in forming pharmaceutical compositions and dosage forms include, but are not limited to, agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose, crospovidone, sodium acetate, potato or tapioca starch, other starches, preformed starches, clays, other algae, other celluloses, gums, or mixtures thereof.

[0107] Lubricants that can be used to form the pharmaceutical composition include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other diols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil (maize oil), and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Lubricants also include, for example, silica gel, coagulated aerosol, or mixtures thereof. Lubricants may be added, if desired, in an amount of less than about 1% by weight of the pharmaceutical composition.

[0108] When aqueous suspensions and / or elixirs are used for oral administration, the active ingredient may be combined with various sweeteners or flavoring agents, coloring agents or dyes, emulsifying and / or suspending agents, diluents such as water, ethanol, propylene glycol, glycerol, and combinations thereof.

[0109] Surfactants that can be used in forming pharmaceutical compositions and dosage forms include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. Suitable hydrophilic surfactants generally have an HLB value of at least about 10, and suitable lipophilic surfactants may generally have an HLB value of less than about 10. An empirical parameter used to characterize relative hydrophilicity and hydrophobicity is the hydrophilic lipophilic balance value HLB ("HLB" value). The lower the HLB value of a surfactant, the more lipophilic or hydrophobic it is and the more soluble it is in oil, whereas active agents with higher HLB values ​​are more hydrophilic and more soluble in aqueous solutions. Hydrophilic surfactants are generally considered to be those with HLB values ​​greater than about 10, while anionic, cationic, or zwitterionic compounds generally have less of an HLB scale. Similarly, lipophilic (i.e., hydrophobic) surfactants are those with HLB values ​​of about 10 or less. However, surfactant HLB values ​​are only a rough guide for general use in industrial, pharmaceutical, and cosmetic emulsions.

[0110] Hydrophilic surfactants can be ionic or non-ionic.Suitable ionic surfactants include, but are not limited to, alkyl ammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides and polypeptides; glycerol ester derivatives of amino acids, oligopeptides and polypeptides; lecithin and phospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfate salts; fatty acid salts; dodetil sodium; acyl lactate salts; tartaric acid esters of mono / diacetylated mono / diglycerides; succinylated mono / diglycerides; citric acid esters of mono / diglycerides; and mixtures thereof.Ionic surfactants include, but are not limited to, for example, lecithin, lysolecithin, phospholipids, lysophospholipids and their derivatives; carnitine fatty acid ester salts; alkyl sulfate salts; fatty acid salts; acyl lactate salts; diacylated tartaric acid esters of mono / diglycerides; succinylated mono / diglycerides; citric acid esters of mono / diglycerides; and mixtures thereof. Hydrophilic nonionic surfactants include, but are not limited to, alkyl glycosides; alkyl maltose; alkyl thiosides; lauroyl polyglycol glycerides; polyoxyalkylene alkyl ethers (e.g., polyethylene glycol polyoxyalkylene alkylphenols (e.g., polyethylene glycol alkylphenols)); polyoxyalkylene alkylphenol fatty acid esters (e.g., polyethylene glycol fatty acid monoesters, polyethylene glycol fatty acid diesters); diol glycerin fatty acid esters; polyglycerin fatty acid esters; polyoxyalkylene sorbitan fatty acid esters (e.g., polyethylene glycol sorbitol fatty acid esters); glycerol esters, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, polyoxyethylene sterols and derivatives thereof, and the like; polyoxyethylated vitamins and derivatives thereof, and the like; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; hydrophilic transesterification products of polyethylene glycol sorbitan fatty acid esters with at least one polyol selected from the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils.The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a sugar. Other hydrophilic non-ionic surfactants include PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20-oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-40 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate. , PEG-100 Stearate, PEG-20 Dilaurate, PEG-25-Glycerol Trioleate, PEG-32 Dioleate, PEG-20 Glyceryl Lauryl Lactone, PEG-30 Glyceryl Laurate, PEG-20 Glycerate, PEG-20 Glyceryl Oleate, PEG-30 Glycerol, PEG-30 Glycerides, PEG-40 Castor Oil, PEG-40 Castor Oil, PEG-40 Castor Oil, PEG-40 Castor Oil PEG-40 Castor Oil, PEG-40 Castor Oil, PEG-40 Castor Oil, PEG-Hydrogenated Castor Oil, PEG-60 Corn Oil, PEG-6 Glyceryl / Capric Glyceride, PEG-8 Capric / Capic Glyceride, Polyglycerol 1-10 Laurate, PEG-30 Cholesterol, PEG-25 Phytosterols, PEG-30 Soy Sterols, PEG-20 Trioleate, PEG-40 Sorbitol Oleate Examples of suitable glycerols include, but are not limited to, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 dodecyl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearin, PEG-100 tocopherol succinate, PEG-24 cholesterol, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamer.Suitable lipophilic surfactants include, but are not limited to, for example, fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acid esters; propylene glycol fatty acid esters; sorbitol fatty acid esters; diol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylenated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; and lactic acid derivatives of mono / diglycerides.

[0111] The pharmaceutical composition may include a solubilizer to ensure good solubilization and / or dissolution of the compound and minimize precipitation of the compound. Solubilizers may be particularly useful for pharmaceutical compositions for parenteral administration, e.g., injection administration. Solubilizers may also be added to enhance the solubility of other ingredients, such as hydrophilic drugs and / or surfactants, or to enhance the maintenance of the pharmaceutical composition as a stable or homogeneous solution or dispersion. Examples of suitable solubilizing agents include alcohols and polyols (e.g., ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol, and their isomers), glycerol, pentaerythritol, sorbitol, mannitol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycol having a molecular weight of about 200 to about 6000 (e.g., tetrahydrofurfuryl alcohol PEG ether (tetrahydrofuran polyglycol ether) or methoxy PEG); amides and other nitrogen-containing compounds (e.g., 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alanine, α-phenylenediamine ... alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidine, N-alkylcaprolactam, dimethylacetamide, and polyvinylpyrrolidone; esters (e.g., ethyl propionate, esters, acetyl triethyl citrate, tributyl citrate, triethyl citrate, ethyl oleate, ethyl octanoate, ethyl butyrate, glycerol triacetate, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and its isomers), delta-valerolactone and its isomers, butyrolactone and its isomers; other known solubilizing agents (e.g., but not limited to, dimethylacetamide, dimethyl isosorbide, N-methylpyrrolidone, diethylene glycol monoethyl ether, and water. Mixtures of solubilizing agents may also be used.

[0112] The amount of a given solubilizer may be limited to a biologically acceptable amount, which can be easily determined by one skilled in the art. The solubilizer may be present in a mass ratio of about 10% by weight, about 25% by weight, about 50% by weight, about 100% by weight, or up to about 200% by weight, based on the total mass of the drug and other excipients. If necessary, a small amount of solubilizer may be used, for example, about 5%, 2%, 1% or less. Typically, the solubilizer may be present in an amount of about 1% by weight to about 100% by weight, typically about 5% by weight to about 25% by weight.

[0113] The pharmaceutical composition may also include one or more pharma- ceutically acceptable additives and excipients, flavoring agents, coloring agents, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof. Preservatives include, but are not limited to, for example, antioxidants, chelating agents, antibacterial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Antioxidants include, but are not limited to, α-tocopherol, ascorbic acid, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium pyrosulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfate, and sodium sulfite. Chelating agents include, but are not limited to, for example, ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium ethylenediaminetetraacetate, dipotassium ethylenediaminetetraacetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and triethylenediaminetetraethyl citrate. Antimicrobial preservatives include, but are not limited to, for example, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bromonitropyrene glycol, cetrimonium bromide, cetylpyridinium chloride, chlorocresol, cresol, ethanol, glycerol, heptacidine, imidazolidine, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, and propylene glycol. Antifungal agents include, but are not limited to, for example, butyl p-hydroxybenzoate, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, propyl p-hydroxybenzoate, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Preservatives include, but are not limited to, for example, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoates, and phenylethanol. Acidic preservatives include, but are not limited to, for example, vitamin A, vitamin C, vitamin E, β-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.Other preservatives include, but are not limited to, for example, tocopherol acetate, cetrimonium bromide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfate, sodium metabisulfite, potassium sulfite, potassium pyrosulfite, and methyl p-hydroxybenzoate. In some embodiments, the preservative may be an antioxidant. In other embodiments, the preservative may be a chelating agent.

[0114] In some embodiments, a pharmaceutical composition for parenteral administration is provided that comprises: (1) an effective amount of a disclosed compound; (2) optionally, an effective amount of one or more second reagents; (3) one or more pharmaceutical excipients suitable for parenteral administration; and (4) an effective amount of a third reagent.

[0115] Here, the pharmaceutical compositions may be administered in the form of aqueous or oily suspensions or emulsions, sesame oil, corn oil, cottonseed oil, or peanut oil, and elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical carriers. Physiological saline is also commonly used for injections. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, benzyl alcohol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, sodium chloride, tragacanth, buffers, and vegetable oils may also be used. Proper fluidity can be maintained by using a coating agent, such as lecithin, or, in the case of dispersions, by using a surfactant to maintain the desired particle size. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, such as p-hydroxybenzoic acid esters, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. The pharmaceutical compositions may also be injected with suitable carriers including saline, glucose or water, or may be solubilized with cyclodextrins, cosolvents (eg propylene glycol) or micelles (eg Tween 80).

[0116] Sterile injectable solutions can be prepared by filtration and sterilization with a desired amount of the compounds disclosed herein and a suitable solvent for the various other ingredients mentioned above. Typically, this dispersion is prepared by incorporating the various sterilized active ingredients into a sterile carrier containing the basic dispersion medium and the appropriate other ingredients mentioned above. Sterile injectable solutions are prepared using sterile powders, some of the preparation methods are carried out by vacuum drying and freeze-drying techniques to produce the above active ingredients and any other sterile filtered ingredients. Sterile injectable preparations may also be prepared by solutions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol or sterile injectable solutions. Acceptable carriers and solvents that can be used include, but are not limited to, water, Ringer's solution, and isotonic sodium chloride solution. Sterile fixed oils are also commonly used as solvents or suspending media, including, but not limited to, synthetic monoglycerides or diglycerides. In addition, fatty acids, such as oleic acid, can also be used in the preparation of injectables. Injectable formulations may be sterilized, for example, by a bacterial-retaining filter, or by adding sterilizing agents incorporated into sterile solid compositions which may be dissolved or dispersed in sterile water or other sterile injectable medium. The injectable compositions may contain from about 0.1 to about 5% by weight of the compounds disclosed herein.

[0117] In some embodiments, a compound (or transdermal)-containing pharmaceutical formulation is provided that includes one or more pharmaceutical excipients suitable for topical administration, such as those disclosed herein. In some embodiments, a drug-containing composition for topical administration is provided that includes: (1) an effective amount of a disclosed compound, (2) optionally one or more second pharmaceutical agents, (3) one or more pharmaceutical excipients suitable for topical administration, and (4) an effective amount of a third pharmaceutical agent.

[0118] The pharmaceutical compositions provided herein may be formulated in solid, semi-solid or liquid forms suitable for topical or local application, such as gelling agents, water-soluble gels, liniments, creams, lotions, suspensions, foams, powders, ointments, salves, solutions, oils, pastes, suppositories, sprays, emulsions, saline, dimethylsulfoxide (DMSO)-based solutions, etc. Generally, carriers with higher density can provide areas with prolonged exposure to the active ingredient. In contrast, solution formulations can provide more direct contact of selected areas with the active ingredient. For example, ointment formulations can be paraffinic or water-miscible. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water cream base. The aqueous phase of the cream matrix may contain at least about 30% by weight of a polyol (e.g., propylene glycol, butane-1,3-diol, mannitol, sorbitol, glycerol, polyethylene glycol, and mixtures thereof). The pharmaceutical compositions may contain suitable solid or gel phase carriers or excipients, which may increase the penetration or aid in the delivery of the compound through the stratum corneum skin barrier layer, such as urea (e.g., urea), (e.g., menthol), amines, amides, alkanes, alkanols, water, and the like, e.g., isopropyl myristate and sodium sulfate, pyrrolidone, glycerol monolaurate, sulfoxides, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

[0119] Another exemplary formulation used in the disclosed method uses transdermal administration ("patch"). Such transdermal patches can be used to provide a controlled or discontinuous pharmaceutical composition continuously or discontinuously. If the active agent is absorbed through the skin, a controlled amount and a predetermined flow rate of the active agent can be administered to the subject. In the case of microcapsules, the encapsulating agent can also be used as a film. The use of transdermal patches is well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139.

[0120] The pharmaceutical composition of the present invention can be administered in the form of suppositories for rectal administration.These compositions can be prepared by mixing the compound of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and melts in the rectum to release the active ingredient.These materials include, but are not limited to, polyethylene glycol, beeswax, and cocoa butter.

[0121] The pharmaceutical compositions of the present invention may be administered by nasal aerosol or inhalation. Such compositions may be prepared according to techniques known in the pharmaceutical formulation art, and may be prepared as solutions in brine, and may be used with benzyl alcohol or other suitable preservatives to enhance the bioavailability of absorption enhancers, fluorocarbons, and other solubilizing or dispersing agents known in the art.

[0122] The application of the therapeutic agent can be administered locally to the target site. A variety of techniques can be used to provide the host composition at the target site, such as injections, catheters, gels, stents, trocars, propellants, drug releasing polymers or other devices to provide internal access.

[0123] According to another embodiment, the present invention provides an implantable medical device comprising a compound of the present invention or a composition comprising a compound of the present invention, such that the compound is therapeutically active.

[0124] According to another embodiment, the present invention provides a method of injecting an implantable drug delivery device comprising contacting the drug delivery device with a compound or composition of the present invention. Implantable drug delivery devices include, but are not limited to, biodegradable polymer capsules or pills, non-degradable dispersible polymer capsules, and biodegradable polymer flakes.

[0125] In another embodiment, the composition of the present invention further comprises a second therapeutic agent. The second therapeutic agent includes any compound or therapeutic agent known or proven to have favorable properties when administered alone or in combination with any of the compounds of the general formula herein. Drugs that may be usefully combined with these compounds include other kinase inhibitors and / or other chemotherapeutic agents for the treatment of the above diseases and disorders. Such agents are described in detail in the art. Preferably, the second therapeutic agent is an agent that can be used to treat or prevent a disease or condition selected from cancer via a DNA double breaks mechanism.

[0126] In another embodiment, the present invention provides separate dosage forms of a compound of the present invention and a second therapeutic agent associated with each other. As used herein, the term "associated with each other" means that the individual dosage forms are packaged together or otherwise connected to each other such that they are expected to be sold or administered together (within 24 hours, sequentially or simultaneously).

[0127] In the pharmaceutical compositions of the present invention, the compounds of the present invention are present in an effective amount. As used herein, the term "effective amount" refers to an amount that, when administered in an appropriate dosage regimen, is sufficient to reduce or ameliorate the severity, duration or development of the disorder being treated, prevent the progression of the disorder, discontinue the treated disorder, or enhance or improve the prophylactic or therapeutic effects of other therapies.

[0128] An effective amount of the compound of the present invention may range from about 0.001 mg / kg to about 500 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 2.5 mg / kg. As will be appreciated by those skilled in the art, the effective dosage may vary depending on the disease being treated, the severity of the disease, the route of administration, the age, sex, and general health of the patient, the use of excipients, and other treatment methods for routine use (e.g., the use of other drugs), as well as the judgment of the treating physician.

[0129] In the case of a pharmaceutical composition containing a second therapeutic agent, the effective amount of the second therapeutic agent is about 20% to 100% of the usual dose in a monotherapy regimen using only the agent, and preferably, the effective amount is about 70% to 100% of the usual dose in monotherapy.

[0130] Some of the second therapeutic agents mentioned herein are expected to act synergistically with the compounds of the invention. This allows the effective amount of the second therapeutic agent and / or the compounds of the invention to be less than the dosage required for monotherapy. This provides the advantage of minimizing secondary side effects of the second therapeutic agent or the compounds of the invention, improving efficacy, improving ease of administration or use, and / or reducing the overall cost of preparation or formulation of the compounds.

[0131] Treatment methods include: According to another embodiment, the present invention provides a method of treating a subject suffering from or susceptible to a disease or disorder (e.g., as described herein), comprising administering to said subject an effective amount of a compound or composition of the present invention. These diseases are well known in the art and disclosed herein.

[0132] Treatment includes treatment of disorders mediated by protein kinases such as ATM.

[0133] In another aspect, the present invention provides a method of treating a disease in a subject, comprising administering to the subject a composition comprising any of the compounds of the general formulae herein.

[0134] In certain embodiments, the disease is mediated by ATM kinase.

[0135] In another embodiment, the disease is cancer or a proliferative disease.

[0136] In another embodiment, as inhibitors of activated ATM, the compounds of formula (I) and pharma- ceutically acceptable salts are expected to be useful, such as in the treatment of cancer or medical conditions that are present or partially mediated by the activity of ATM. Cancers treatable by the compounds of formula (I) or pharma- ceutically acceptable salts include, but are not limited to, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, thymoma, melanoma, prostate cancer, leukemia, lymphoma, non-Hodgkin's lymphoma, gastric cancer, lung cancer, liver cancer, bone cancer, gastrointestinal stromal tumor (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, brain tumor, membranous adenocarcinoma, diffuse pontine glioma (DIPG), skin cancer, or squamous cell carcinoma of the head and neck.

[0137] In another embodiment, the disease is a cancer that is resistant to treatment with radiation.

[0138] In another embodiment, the disease is a cancer that is resistant to treatment with agents that cause DNA double strand breaks.

[0139] In another embodiment, the disease is cancer with central nervous system metastases.

[0140] In another embodiment, the disease is glioma.

[0141] In another embodiment, the disease is glioblastoma.

[0142] In another embodiment, the disease is diffuse pontine glioma.

[0143] In one embodiment, the method of the present invention is used to treat a subject suffering from or susceptible to a disease or condition. These diseases, disorders or conditions include, for example, those regulated by protein kinases (e.g., ATM protein kinase). The disease or disease condition can be, for example, a cancer or a proliferative disease or disorder. The disease or disease condition can be, for example, ovarian cancer, cervical cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, diffuse pontine glioma, melanoma, prostate cancer, leukemia, lymphoma (GIST), thyroid cancer, cholangiocarcinoma, endometrial cancer, kidney cancer, anaplastic large cell lymphoma, acute myeloid leukemia (GIST), gastric cancer, lung cancer, liver cancer, acute myeloid leukemia (AML), multiple myeloma, melanoma, mesothelioma, brain tumor, membranous adenocarcinoma, skin cancer, or head and neck squamous cell carcinoma. The methods described herein are applied to subjects determined to be in need of the treatment specifically described. The identification of a subject (as to whether or not they are in need of such treatment) requires that the treatment be within the judgment of the subject or a health care professional, and this judgment may be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

[0144] In another embodiment, the compounds of the general formulas herein (and compositions thereof) are useful for treating subjects suffering from a disease or disorder and who have been treated with other therapeutic agents (e.g., anti-cancer agents, neurological agents, psychiatric agents, cardiovascular agents, anti-obesity agents, or anti-diabetic agents) and have developed resistance. In one aspect, the methods herein include administering a compound of the formulas herein (or a composition thereof) to a subject who is resistant to the treatment (or who has been identified as having resistance to treatment with radiation or chemotherapy that induces DNA double-strand breaks). Thus, in another aspect, the subject responds to the treatment such that the disorder is modulated or improved compared to before treatment with the compounds herein.

[0145] In another embodiment, the invention provides a method for modulating the activity of a protein kinase (e.g., a protein kinase, a kinase enumerated herein) in a cell, comprising contacting the cell with one or more compounds of the general formulae herein.

[0146] The above anti-cancer treatments may use the compounds of the present invention as monotherapy or together with conventional compounds for radiotherapy, chemotherapy or immunotherapy. In such chemotherapy, anti-tumor agents may be administered simultaneously, sequentially or separately with the compounds of the present invention, including, but not limited to, one or more of the following categories: anti-proliferative / anti-tumor agents, alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolomide and nitrosoureas), antimetabolites (e.g., 5-fluorouracil and tegafur, etc.), anti-tumor agents (e.g., 5-fluorouracil, ... gemcitabine and antifungal acids, raltitrexed, methotrexate, cytarabine, and hydroxyurea; antitumor antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, adriamycin, daunorubicin, epirubicin, idarubicin, mitomycin C, gentamicin, and grilamycin); antimitotics (e.g., vinca alkaloids such as vincristine, alkaloids such as paclitaxel and tacrolimus, and polo kinase inhibitors); and topoisomerase inhibitors (e.g., cyclosporine ... somerase inhibitors (e.g., epipodophyllotoxin etoposide and dipyridine glycosides, acridine, topotecan and camptothecin); cell proliferation inhibitors such as antihormones (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and difoxifene), antiandrogens (e.g., amylamine, flutamide, nilutamide acetate and cyclopropanone), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide and bromide). choline), progesterone (e.g., megestrol acetate, aromatase inhibitors (e.g., anastrozole, letrozole, buoxazole, and exemestane), and inhibitors of 5-alpha reductase such as finasteride; anti-invasion agents (e.g., c-Src kinase family inhibitors such as cetazonib, dasatinib, postinib, metalloproteinase inhibitors (e.g., equine), inhibitors of urokinase plasminogen activator receptor function or antibody-based heparanase.Inhibitors of growth factor function include, for example, growth factor antibodies and growth factor receptor antibodies (e.g., the anti-erbB2 antibody trastuzumab [Herceptin. TM ], the anti-EGFR antibody panitumumab, the anti-ErbB antibody cetuximab (erbatide, C225) and the growth factor receptors or growth factor receptor antibodies disclosed in Stem et al. Critical reviews in oncology / haematology, 2005, Vol. 54, 11-29. Such inhibitors also include tyrosine kinase inhibitors, such as epidermal growth factor family inhibitors (e.g., EGFR family inhibitors such as gefitinib, erlotinib, icotinib, afatinib, dacomitinib and talisso, erbB2 tyrosine kinase inhibitors such as lapatinib and neratinib); hepatocyte growth factor family inhibitors; platelet-derived growth factor family (e.g., imatinib and / or nilotinib); inhibitors of serine / threonine kinases (e.g., RAS / RAF signal inhibitors (e.g., farnesyltransferase inhibitors, kinase inhibitors (e.g., sorafenib, tipifarnib, lonafarnib), MEK and / or AKT kinase cell signaling inhibitors, c-kit inhibitors, abl fusion kinase inhibitors, PI3 kinase inhibitors, PLT3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; Aurora kinase inhibitors, cyclin-dependent kinase inhibitors (e.g., CDK2 and / or CDK4 inhibitors); angiogenesis inhibitors (e.g., agents that inhibit the action of vascular endothelial growth factor, bevacizumab (Avastin TM), and for example, VEGF receptor tyrosine kinase inhibitors (e.g., vandetanib, vatalanib, sunitinib, axitinib, cabozantinib, pazopanib, and cediranib), compounds acting by other mechanisms (e.g., tricarboxyaminoquinolines, integrin αV3 function inhibitors, and angiogenesis inhibitors); antisense (nucleic acid) therapy (including, for example, replacement of abnormal genes such as the above-mentioned abnormal p53, abnormal BRCA1, or abnormal BRCA2) (e.g., ISIS2503, anti-ras gene antisense (nucleic acid) (e.g., olaparib, niraparib, rucaparib, talazoparib), GDEPT (gene-directed prodrug therapy) methods (e.g., enzymes that use cytosine deaminase, thymidine kinase, or bacterial nitroreductase); multidrug resistance gene therapy immunotherapy, and other methods for improving a patient's resistance to chemotherapy or radiotherapy, such as, for example, These include methods to increase the immunogenicity of tumor cells and decrease T cell unresponsiveness using immunogenicity transfected with cytokines such as interleukin 2, 4 or granulocyte-macrophage stimulating factor, methods using transfected immune cells such as dendritic cells transfected with cytokines, methods using tumor cell lines transfected with cytokines, methods to inhibit the function of immunosuppressive cells (e.g., regulatory T cells, myeloid suppressor cells, IDO, TDO) by using anti-idiotypic antibodies, cancer vaccines derived from proteins or peptides derived from tumor associated antigens such as NY-ES0-1, MAGE-3, WTI or HER2 / neu, any other agent commonly used as a carrier or adjuvant in cancer treatment regimes (e.g., antiemetics, antianemic agents, etc.).

[0147] The term "co-administered" as used herein means that the second therapeutic agent is administered in combination with the compound of the present invention as a single dosage form (e.g., a composition comprising the compound of the present invention and the second therapeutic agent), partially or in separate multiple dosage forms. Alternatively, the additional agent may be administered before, during or after the administration of the compound of the present invention. In such a combination therapy, the compound of the present invention and the second therapeutic agent are administered by conventional methods. The composition of the present invention comprising the compound of the present invention and the second therapeutic agent is administered to a subject, but does not exclude the independent administration of the same therapeutic agent, any other second therapeutic agent or any compound of the present invention to said subject at other times during the course of treatment. Here, in the case of sequential, separate or delayed administration of the second component, the advantage of the effect resulting from the use of the combination should not be lost.

[0148] In one embodiment of the present invention, when a second therapeutic agent is administered to a subject, the effective amount of the compound of the present invention is lower than the effective amount of the second therapeutic agent when the second therapeutic agent is not administered. In another embodiment, the effective amount of the second therapeutic agent is lower than the effective amount of the second therapeutic agent when the compound of the present invention is not administered. In this way, undesirable side effects associated with high doses of either agent can be minimized. Potential advantages (including, but not limited to, improved dosing regimens and / or reduced drug costs) will be apparent to those skilled in the art.

[0149] In another aspect, the present invention provides the use of any of the compounds of the general formulae herein, alone or in combination with one or more second therapeutic agents as described herein, in the manufacture of a medicament, either as a single composition or in a separate dosage form, for the treatment or prevention of a disease, disorder or condition as described herein in a subject. Another aspect of the present invention is the use of a compound of the general formulae herein for the treatment or prevention of a disease, disorder or condition as described herein in a subject.

[0150] In other embodiments, the methods of the invention further comprise monitoring the subject's response to the therapeutic administration. Such monitoring may include periodic sampling of the subject's tissues, bodily fluids, cerebrospinal fluid, samples, cells, proteins, chemical markers, genetic material, etc., as markers or indicators of the therapeutic regimen. In other methods, subjects may be pre-screened or identified as in need of such treatment by assessing the suitability of relevant markers or indicators for such treatment.

[0151] In one embodiment, the present invention provides a method for monitoring the progress of a treatment. The method includes measuring a diagnostic marker (e.g., any target or cell type described herein that is modulated by a compound of the present invention) or a diagnostic measurement (e.g., a screening, assay) in a subject suffering from or susceptible to a disorder or condition described herein, and the subject has been administered a therapeutic amount of a compound of the present invention sufficient to treat the disease or condition. The level of the marker measured by the above method can be compared to known levels in healthy controls or other disease patients to determine the disease status of the subject. In a preferred embodiment, a second level of the marker is measured in the subject at a time later than the time of measuring the first level, and the two levels are compared to monitor the progress of the disease or the effectiveness of the treatment. In a preferred embodiment, a pre-treatment level of the marker is measured in the treated subject before the initiation of treatment according to the present invention, and the efficacy of the treatment can be determined by comparing the pre-treatment level of the marker with the level of the marker in the subject after the initiation of treatment.

[0152] In some method embodiments, the level of the marker or marker activity in the subject is measured at least once. The level of the marker is compared, for example, with other measurements of the level of the marker obtained before and after from the same patient, another patient, or a normal subject, to determine whether the treatment of the present invention has the desired effect and to adjust the dosage level if necessary. The measurement of the level of the marker can be performed by any sampling / expression assay known in the art or described herein. Preferably, a tissue or liquid sample is first removed from the subject. Examples of suitable samples include blood, urine, cerebrospinal fluid, tissue, oral or buccal cells, and hair samples with roots. Other suitable samples are known to those of skill in the art. The measurement of protein levels, ctDNA, cfDNA, and / or mRNA levels (e.g., marker levels) in the sample can utilize any suitable technique known in the art, including, but not limited to, enzyme immunoassay, ELISA, radiolabeling techniques, Western blot / chemiluminescence, real-time PCR, electrochemical signals, etc.

[0153] The present invention also provides kits for treating a disease, disorder, or condition described herein. Such kits include 1) a pharmaceutical composition comprising any of the compounds of the general formula of the present invention, or a salt thereof, or a salt thereof, or a hydrate, solvate, or polymorph thereof, contained in a container, and 2) instructions describing how to use the pharmaceutical composition to treat a disease, disorder, or condition described herein. The container may be any container or other sealed or sealable device capable of containing the pharmaceutical composition. Examples of containers include bottles, compartmented or multi-chambered storage bottles (each compartment or chamber has a single dose of the composition), compartmented foil packaging (each compartment has a single dose of the composition), or dispensers (which dispense a single dose of the composition). The container may be of any conventional shape or form known in the art and is made of a pharma- ceutically acceptable material (e.g., a paper or cardboard box, a glass bottle, a plastic bottle, a can, a resealable bag (e.g., a "refill" containing tablets is used to place into another container), or a blister pack with a single dose, the contents of which can be pushed out of the package according to the treatment regimen). The container used may depend on the dosage form to be contained, e.g., a normal cardboard box is not generally used to contain a liquid suspension. It is possible to use multiple containers together in a single package to sell a single dosage form. For example, tablets are placed in a bolt, which is then placed in a box. Preferably, the container is a blister pack.

[0154] The kit may contain information and / or instructions for the physician, pharmacist, or subject. These memory aids include the number of days of the week printed on each compartment or partition that corresponds to the number of days in the program or capsule dosing regimen, or cards containing the same type of information.

[0155] The biological activity of the compounds of the invention can be evaluated by regimens known in the art, including, for example, the methods described herein. Some of the compounds described herein exhibit surprisingly good properties (e.g., metabolic stability, high selectivity, low efflux rate, high permeability, non-P-glycoprotein and BCRP efflux substrates, non-aldehyde oxidase substrates, low hERG propensity, low drug-drug interaction propensity, etc.), making them excellent candidates for potential therapeutic agents.

[0156] All references cited herein, whether electronic, printed, computer readable or otherwise, including, but not limited to, abstracts, articles, journals, publications, textbooks, technical data sheets, internet sites, databases, patents, patent applications, and patent publications, are hereby expressly incorporated by reference in their entirety.

[0157] The present invention will be described in detail below with reference to examples. The following examples are intended to help those skilled in the art to further understand the present invention, and are not intended to limit the present invention. It should be understood that many modifications and improvements may be made by those skilled in the art without departing from the spirit of the present invention. All of these are included within the scope of the present invention. EXAMPLES

[0158] The intermediates 3,3-difluoro-1-methylpiperidin-4-amine A6 and 1-benzyl-3,3-difluoropiperidin-4-amine A5′ were synthesized as shown in FIG.

[0159] Step 1: To a solution of 2-methylpropane-2-sulfinamide (404 g, 3.33 mol) and Ti(OEt)4 (1003 g, 4.44 mol) in THF (2.5 L) at 25°C, a solution of A1 (500 g, 2.22 mol) was added dropwise. The reaction mixture was stirred at 70°C for 1 h and then cooled to 0°C. The reaction mixture was then charged to NaBH4 (166 g, 2.0 equiv.) in THF (2.5 L) in a separate reactor at 0°C. The reaction mixture was stirred at 0°C for 0.5 h and then slowly warmed to 25°C and continued to stir for 0.5 h. Methanol (2.5 L) was added and then stirred for 0.5 h. The mixture was added to a vessel containing a saturated solution of NaCl (2.5 L) and stirred at 25°C for 1 h. The reaction mixture was extracted twice with DCM (2.5 L). The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give product A2.

[0160] Step 2: To a solution of crude A2 in ethyl acetate (1 L) at 25° C., HCl (5.0 equiv., 4 M in ethyl acetate) was added and stirred at 25° C. for 1 h, then filtered to give A3.

[0161] Step 3: The filter cake A3 was added to water (1.5 L) and then the pH was adjusted to 8-9 with 20% aqueous NaOH at 25 °C. The mixture was extracted with DCM (1.5 L) and the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Triethylamine (267 g, 1.2 equiv.) was added to this crude product followed by (Boc)2O (577 g, 1.2 equiv.) and the mixture was stirred at 25 °C for 1 h. 10% citric acid solution (2 L) was added to this mixture and then the organic layer was separated. The aqueous layer was extracted with DCM (1 L). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give A4 (430 g, 59.4%).

[0162] Step 4: To a solution of A2 (380 g, 1.0 equiv.) in MeOH (3.8 L) was added Pd(OH)2 / C (20%, w / w) and the mixture was stirred at 25° C. under 20 atm for at least 1 h. The mixture was filtered and the filtrate was concentrated to give A5 (250 g, 91%).

[0163] Step 4': A mixture of A4 (4 g, 12.27 mmol) in TFA (20 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo. The residue was further purified by column chromatography (DCM:MeOH=12:1) to give compound A5' (2 g, 74.1%) as a yellow oil.

[0164] Step 5: To a solution of A5 (236 g, 1.0 equiv.) in MeOH (2.4 L) at 5 °C, HCHO (37% in water, w / w) was added. The reaction mixture was stirred at 5 °C for 1 h, then NaBH(OAc)3 was added portionwise until LC-MS showed disappearance of A5. The reaction mixture was added to 10% aqueous NaOH, pH was adjusted to 8-9 at 25 °C, and stirred at 25 °C for 0.5 h. Methanol was evaporated in vacuum, then the residue was extracted with ethyl acetate (1.2 L). The organic layer was separated and concentrated. HCl (5.0 equiv., 4 M in ethyl acetate) was added, then filtered. The filter cake was collected and dried under vacuum at 45 °C to give the HCl salt of A6 (125.1 g, 53.7%).

[0165] As shown in FIG. 3, the intermediates 8-bromo-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one B5 and 8-bromo-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-(methyl-d3)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one B5′ were synthesized.

[0166] Step 1: To a mixture of B1 (25 g, 79.48 mmol) in DMA (500 mL) was added 2 (14.92 g, 99.34 mmol) and DIEA (30 g, 238.744 mmol). The mixture was heated to 60 °C for 5 h. The mixture was cooled to room temperature and poured into a mixture of DCM (500 mL) and H2O (250 mL), the organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give B2 (15 g, 44.09%) as an off-white solid. LC-MS: (ESI) m / z = 404 [M+H] +

[0167] Step 2: To a mixture of B2 (15 g, 33.35 mmol) in MeOH / H2O / THF (300 mL / 150 mL / 150 mL) was added NaOH (8 g, 100 mmol) at room temperature and heated to 50 °C for 2 h. The mixture was cooled to room temperature and concentrated in vacuo to remove the organic layer. The residue was added to H2O (150 mL), adjusted to pH = 4 by addition of 10% HCl, and filtered to give B3 (11 g, 78.57%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 12 - 11.85(m, 1H), 8.80 - 8.65 (m, 1H), 8.01 - 7.67 (m, 2H), 5.35 - 5.01 (m, 1H), 3.68 - 3.51(m, 1H), 3.30 - 3.22 (m, 1H), 3.17 (d, J = 8.0 Hz, 1H), 2.92 (d, J = 12.0 Hz, 1H), 2.63 - 2.53 (m, 1H), 2.47 - 2.29 (m, 4H), 2.07 - 1.92 (m, 1H).

[0168] Step 3: To a solution of B3 (11 g, 27.5 mmol) and DPPA (7.12 mL, 33 mmol) in DMF (350 mL) was added TEA (28.2 mL, 82.5 mmol). The mixture was stirred at 60 °C for 2 h. The reaction was cooled to room temperature and then poured into H2O (500 mL). The precipitate was filtered, washed with H2O (50 mL), and the filter cake was dried to give B4 (10 g, 91.82%) as a brown solid.

[0169] Step 4: To a mixture of B4 (10 g, 25.2 mmol) in DMF (250 mL) was added DMF-DMA (15.15 g, 126 mmol) at room temperature. The mixture was then heated to 80 °C for 2 h, the mixture was cooled to room temperature and filtered. The filtrate was washed with HO and dried to give B5 (9 g, 86.95%) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.05 - 8.95 (m, 1H), 8.75 - 8.36 (m, 1H), 8.04 - 7.71 (m, 2H), 5.37 - 5.16 (m, 1H), 3.67 - 3.55 (m, 1H), 3.50 (s, 2H), 3.30 - 3.23 (m, 1H), 2.93 (d, J = 8.0 Hz, 1H), 2.74 - 2.53 (m, 1H), 2.48 - 2.32 (m, 4H), 2.07 - 1.93 (m, 1H).LC-MS: (ESI) m / z=411, 413 [M+H] +

[0170] Step 4': B4 (400 mg, 1.01 mmol) in THF (20 mL) was cooled to -78 °C, NaHMDS (221 mg, 1.21 mmol, 1M in THF solution) was added to the mixture and stirred at -78 °C for 30 min. Then, CD3I (87 mg, 1.21 mmol) was added dropwise to the mixture. The reaction mixture was stirred at room temperature for 16 h. H2O (10 mL) was added to the mixture and extracted with EtOAc (30 mL x 3), then the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM:MeOH = 30:1) to give compound B5' (380 mg, 91.9%) as a yellow solid. LC-MS: (ESI) m / z = 414, 416 [M + H] +

[0171] The intermediate 8-bromo-1-(3,3-difluoro-1-methylpiperidin-4-yl)-7-fluoro-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one C5 was synthesized as shown in FIG.

[0172] Step 1: To a mixture of C1 (1.48 g, 4.45 mmol) in DMA (20 mL) was added A6 (1.09 g, 9.54 mmol) and DIEA (1.72 g, 13.35 mmol). The mixture was heated to 80 °C for 8 h. The mixture was cooled to room temperature and poured into a mixture of ethyl acetate (200 mL) and H2O (100 mL), the organic layer was separated, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give C2 (2.2 g, 100%) as a brown solid. LC-MS: (ESI) m / z = 448 [M + H] +

[0173] Step 2: To a mixture of C2 (2.2 g, 5 mmol) in MeOH / H2O / THF (60 mL / 20 mL / 20 mL) was added NaOH (1 g, 25 mmol) at room temperature and heated to 60 °C for 2 h. The mixture was cooled to room temperature and concentrated in vacuo to remove the organic layer. The residue was added to H2O (50 mL), adjusted to pH = 4 by addition of 10% HCl, and filtered to give C3 (2 g, 92.4%) as a yellow solid. LC-MS: (ESI) m / z = 420 [M+H] +

[0174] Step 3: To a solution of C3 (1.93 g, 4.62 mmol) and DPPA (1.53 g, 5.55 mmol) in DMF (10 mL) was added TEA (1.4 g, 13.86 mmol). The mixture was stirred at 60 °C for 2 h. The reaction was cooled to room temperature and then poured into H2O (80 mL) and extracted with ethyl acetate (200 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to give C4 (1.19 g, 61.7%) as a brown solid. 1 H NMR (400 MHz, CD3OD_SPE) δ 9.04 - 8.73 (m, 1H), 8.69 (d, J = 2.7 Hz, 1H), 8.54 (d, J = 6.6 Hz,1H), 7.80 (dd, J = 9.7, 2.9 Hz, 1H), 5.20 (dd, J = 23.7, 8.8 Hz, 1H), 3.80 (d, J = 12.1 Hz, 1H), 3.21-2.83(m, 2H), 2.66 (dd, J = 28.4, 12.5 Hz, 1H), 2.54 - 2.41 (m, 4H), 2.07 (s, 1H).LC-MS: (ESI) m / z=417[M+H] +

[0175] Step 4: Methyl iodide (334 mg, 2.42 mmol) was added to a mixture of C4 (500 mg, 1.21 mmol), NaOH (73 mg, 1.82 mmol) and TBAHS (41 mg, 0.12 mmol) in DCM / HO (4 mL / 3 mL). The resulting mixture was stirred at room temperature for 5 h. The cooled mixture was poured into a mixture of DCM (200 mL) and HO (150 mL). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by Pre-TLC to give C5 (533 mg, 100%) as a brown solid. 1 H NMR (400 MHz, DMSO) δ 9.09 - 8.95 (m, 1H), 8.89 - 8.53 (m, 1H), 8.03 - 7.96 (m, 1H), 5.31 (dd, J= 25.6, 11.6 Hz, 1H), 3.73 - 3.60 (m, 1H), 3.54 (d, J = 34.3 Hz, 3H), 3.28 - 3.12 (m, 3H), 2.71 - 2.54 (m,2H), 2.48 - 2.29 (m, 4H), 1.98 (d, J = 12.5 Hz, 1H).LC-MS: (ESI) m / z=431[M+H] +

[0176] The intermediate 1-(3,3-difluoropiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one D7 was synthesized as shown in FIG.

[0177] Step 1: A mixture of B1 (5 g, 15.90 mmol), A5' (4.32 g, 19.07 mmol) and DIEA (3.54 g, 38.14 mmol) in DMA (50 mL) was heated to 100 °C for 12 h. The mixture was poured into H2O (100 mL) and extracted with EtOAc (100 mL × 3), the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (DCM:MeOH = 30:1) to give compound D2 (3 g, 37.42%) as a yellow oil.

[0178] Step 2: To a mixture of D2 (2.3 g, 4.56 mmol) in MeOH / H2O / THF (20 mL / 5 mL / 5 mL) was added NaOH (0.65 g, 16.2 mmol) at room temperature and heated to 50 °C for 2 h. The mixture was cooled to room temperature and concentrated in vacuo to remove the organic layer, then the residue was added to H2O (50 mL), adjusted to pH = 4 by addition of 10% aqueous HCl, and filtered to give D3 (2.0 g, 92.08%) as an off-white solid. LC-MS: (ESI) m / z = 506.0 [M+H].

[0179] Step 3: A solution of D3 (2.0 g, 4.20 mmol), DPPA (1.7 g, 6.18 mmol), TEA (3.74 g, 25.1 mmol) in DMF (35 mL) was stirred at 60 °C for 2 h. The reaction mixture was cooled to room temperature. The mixture was poured into H2O (50 mL) and the precipitate was filtered. The solid was washed once with H2O and the filter cake was dried to give D4 (1.8 g, 90.57%) as a brown solid.

[0180] Step 4: To a mixture of D4 (1.80 g, 3.80 mmol) in DMF (25 mL) was added DMF-DMA (2.30 g, 19.2 mmol) at room temperature. The mixture was then heated to 80 °C for 2 h. The reaction mixture was cooled to room temperature and filtered. The filter cake was washed with HO and dried to give D5 (1.0 g, 53.96%) as an off-white solid. LC-MS: (ESI) m / z=489.2 [M+H].

[0181] Step 5: A mixture of D5 (1.0 g, 2.05 mmol), (6-methoxypyridin-3-yl)boronic acid (377 mg, 2.46 mmol), PdCl2(dtdppf) (240 mg, 0.21 mmol), K2CO3 (1.5 mg, 6.15 mmol) in 1,4-dioxane / HO (15 mL / 4 mL) was degassed twice with N2 and then heated to 80 °C for 3 h. The reaction mixture was poured into a mixture of DCM (50 mL) and HO (50 mL), then the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM:MeOH=30:1) to give compound D6 (1 g, 94.53%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.95 (d, J = 32.8 Hz, 1H), 8.80 (s, 1H), 8.67 (s, J = 43.2, 2.4 Hz, 1H), 8.37 (s, 1H), 8.23 ​​- 8.09 (m, 2H), 8.00 - 7.90 (m, 1H), 7.40 - 7.23 (m, 5H), 7.01 (d, J = 8.6 Hz, 1H), 5.59 - 5.23 (m, 1H), 3.98 - 3.90 (m, 3H), 3.79 (d, J = 13.3 Hz, 1H), 3.73 (m, J = 11.2, 4.4 Hz, 2H), 3.58 (m, J = 32.0, 21.2 Hz, 4H), 3.11 (d, J = 11.0 Hz, 1H), 3.03 - 2.87 (m, 1H), 2.74 - 2.55 (m, 1H), 2.40 (m, J = 32.4, 18.1 Hz, 1H), 2.07 - 1.94 (m, 1H).LC-MS: (ESI) m / z=516.0 [M+H].

[0182] Step 6: To a solution of D6 (400 mg, 0.78 mmol) in MeOH (10 mL) was added Pd(OH)2 / C (100 mg, 10% Pd, water <10%). The reaction mixture was stirred at 30 °C for 5 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give compound D7 (300 mg, 90.89%) as a brown oil. LC-MS: (ESI) m / z=426.0 [M+H].

[0183] The intermediate 2-cyclopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine E3 was synthesized as shown in FIG.

[0184] Step 1: A mixture of E1 (1 g, 5.68 mmol), cyclopropanol (396 mg, 6.82 mmol) and KOtBu (2.1 g, 14.3 mmol) in THF (20 mL) was heated to 80 °C for 3 h. The mixture was added with H2O (40 mL) and extracted with EtOAc (40 mL x 3), then the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether: EtOAc = 4: 1) to give compound E2 (1.1 g, 90.4%) as a yellow oil.

[0185] Step 2: A mixture of E2 (1.1 g, 5.14 mmol), Pin2B2 (1.57 g, 6.17 mmol) and KOAc (1.5 g, 15.42 mmol) in dioxane (20 mL) was heated to 100 °C for 8 h. H2O (40 mL) was added to the mixture and extracted with EtOAc (40 mL × 3), then the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether: EtOAc = 4: 1) to give compound E3 (700 mg, 52.23%) as a yellow oil.

[0186] The intermediate 2-(methoxy-d3)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine F3 was synthesized as shown in FIG.

[0187] Step 1: A mixture of F1 (1 g, 5.75 mmol) and Ag2CO3 (3.17 mg, 11.49 mmol) in CHCl3 (15 mL) was stirred for 3 h at 30 °C. The mixture was poured into a mixture of DCM (30 mL) and H2O (30 mL), and the organic layer was then washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give compound F2 (900 mg, 81.97%) as a colorless oil.

[0188] Step 2: A mixture of F2 (900 mg, 4.71 mmol), Pin2B2 (1.44 g, 5.65 mmol) and KOAc (1.38 g, 14.51 mmol) in dioxane (20 mL) was heated to 100 °C for 8 h. H2O (40 mL) was added to the mixture and extracted with EtOAc (40 mL × 3), then the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (petroleum ether: EtOAc = 4: 1) to give compound F3 (800 mg, 71.3%) as a yellow oil.

[0189] The intermediate N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine G2 was synthesized as shown in FIG.

[0190] To a mixture of G1 (550 mg, 2.74 mmol) and Pin2B2 (835 mg, 3.288 mmol) in dioxane (20 mL), Pd(dppf)Cl2 (201 mg, 0.274 mmol) and KOAc (807 mg, 8.22 mmol) were added and the mixture was stirred at 100 °C for 3 h. The mixture was cooled to room temperature, filtered, concentrated in vacuo, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to give G2 (300 mg, 44.1%). LC-MS: (ESI) m / z = 248, 249 [M + H] +

[0191] The intermediate N,N-dimethyl-1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)azetidin-3-amine H2 was synthesized as shown in FIG.

[0192] Step 1: To a mixture of E1 (550 mg, 3.1 mmol) and N,N-dimethylazetidin-3-amine (805 mg, 4.65 mmol) in DMF (5 mL), DIEA (2003 mg, 15.5 mmol) was added and the mixture was stirred at 90 °C for 12 h. The mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated in vacuum, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to give H1 (438 mg, 55%). LC-MS: (ESI) m / z = 257, 258 [M + H] +

[0193] Step 2: To a mixture of H1 (438 mg, 1.71 mmol) and Pin2B2 (521 mg, 2.05 mmol) in dioxane (20 mL), Pd(dppf)Cl2 (125 mg, 0.171 mmol) and KOAc (503 mg, 5.13 mmol) were added, and the mixture was then stirred at 100 °C for 3 h. The mixture was cooled to room temperature, filtered, concentrated in vacuo, and purified by silica gel column chromatography (DCM:MeOH = 10:1) to give H2 (359 mg, 63.6%). LC-MS: (ESI) m / z = 303, 304 [M + H] +

[0194] The intermediate 2-methyl-6-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-2,6-diazabicyclo[3.2.0]heptane I6 was synthesized as shown in FIG.

[0195] Step 1: To a mixture of I1 (50 mg, 0.174 mmol) in THF (5 mL) was added Pd / C (10 mg, 0.08 mmol). The mixture was heated to 50 °C under H2 for 12 h. The mixture was filtered and the filtrate was concentrated in vacuo to give I2 (30 mg, 90%) as an off-white solid. LC-MS: (ESI) m / z=198.9[M+H] +

[0196] Step 2: To a mixture of I2 (30 mg, 0.152 mmol) in DMSO (3 mL), E1 (40 mg, 0.5 mmol) and DIEA (28 mg, 0.3 mmol) were added at room temperature and heated to 120 °C for 2 h. The reaction was cooled to room temperature and then poured into H2O (50 mL), the organic layer was washed with brine, dried over anhydrous Na2SO4 and purified by column (DCM:MeOH = 30:1) to give I3 (33 mg, 78.57%) as an off-white solid.

[0197] Step 3: To a solution of I3 (33 mg, 0.093 mmol) in DCM (3 mL) was added TFA (19 mg, 0.27 mmol). The mixture was stirred at room temperature for 1 h. The mixture was poured into a mixture of DCM (15 mL) and H2O (15 mL), and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column (DCM:MeOH=30:1) to give I4 (20 mg, 91.82%) as a brown solid.

[0198] Step 4: To a solution of I4 (20 mg, 0.079 mmol), MeCN (2 mL) in AcOH (2 mL) was added NaBH3CN (13 mg, 0.16 mmol) and aqueous CHO under N2. The mixture was stirred at room temperature for 1 h. The mixture was poured into a mixture of DCM (15 mL) and H2O (15 mL), and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by column (DCM:MeOH=30:1) to give I5 (12 mg, 91.82%) as an off-white solid.

[0199] Step 5: A mixture of I5 (12 mg, 0.045 mmol), Pin2B2 (20 mg, 0.13 mmol), PdCl2(dppf) (3 mg, 0.004 mmol) and AcOH (6 mg, 0.08 mmol) in 1,4-dioxane (3 mL) was degassed twice with N2 and then heated to 100 °C for 3 h. The mixture was poured into a mixture of DCM (15 mL) and H2O (15 mL) and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column (DCM:MeOH = 30:1) to give I6 (15 mg, 56.07%) as a white solid.

[0200] FIG. 11 shows a general method for the coupling of boronic acid intermediates with aryl bromides.

[0201] A mixture of starting material (1 equiv.), boronic acid intermediate (1.2 equiv.), PdCl2(dtdppf) (1 equiv.), and K2CO3 (3 equiv.) in 1,4-dioxane / HO (2.5:1, v / v, 0.035M) was degassed twice with N2 and then heated to 80 °C for 3 h. The mixture was poured into a mixture of DCM and HO, and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by column (DCM:MeOH=30:1) to give the desired coupling product.

[0202] FIG. 12 shows a representative example using the general method for coupling of a boronic acid intermediate with an aryl bromide.

[0203] A mixture of B5 (2 g, 4.87 mmol), pyridin-3-ylboronic acid (888 mg, 5.844 mmol), PdCl2(dtdppf) (318 mg, 4.87 mmol), and K2CO3 (2 g, 14.61 mmol) in 1,4-dioxane / HO (100 mL / 40 mL) was degassed twice with N2 and then heated to 80 °C for 3 h. The mixture was poured into a mixture of DCM (500 mL) and HO (500 mL), and the organic layer was washed with brine, dried over anhydrous Na2SO4, and purified by column chromatography (DCM:MeOH=30:1) to give the product (1.22 g, 57.07%) as a white solid. 1 H NMR (400 MHz, DMSO) δ 9.09 (d, J = 42.0, 1.9 Hz, 1H), 8.98 (d, J = 26.8 Hz, 1H), 8.90 (s, 1H), 8.67 - 8.61 (m, 1H), 8.48 (s, 1H), 8.34 - 8.19 (m, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.15-8.05 (m, 1H), 7.68-7.48 (m, 1H), 5.57 - 5.25 (m, 1H), 3.69 (d, J = 4.0 Hz, 1H), 3.56 (d, J = 33.2 Hz, 3H), 3.44 - 3.34 (m, 1H), 3.30 (s, 1H), 3.11 (d, J = 11.2 Hz, 1H), 2.94 (d, J = 12.0 Hz, 1H), 2.73-2.53 (m, 1H), 2.42 (d, J = 32.4, 16.4 Hz, 4H), 2.11 - 1.92 (m, 1H).LC-MS: (ESI) m / z=410.1 [M+H] +

[0204] FIG. 13 shows a general method for the chiral separation of racemic products 1-13.

[0205] The sample was dissolved in approximately 150 mL of EtOH and loaded onto a chiral pre-SFC column. The enantiomers were separated using a JPEG0007669473000002.jpg27163 with 7 mL injections each (55:45 supercritical CO2:EtOH mobile phase monitored at a flow rate of 70 g / min and a wavelength of 214 nm).

[0206] FIG. 14 shows a representative example using the general method for chiral separation of racemic products.

[0207] According to the general method for chiral separation of racemates, (R)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolone-2-one (500 mg, 99% yellow solid) was obtained from 1.22 g of 1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one. 1H NMR (400 MHz, DMSO) δ 9.09 (d, J = 42.0, 1.9 Hz, 1H), 8.98 (d, J = 26.8 Hz, 1H), 8.90 (s, 1H), 8.67 - 8.61 (m, 1H), 8.48 (s, 1H), 8.34 - 8.19 (m, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.15-8.05 (m, 1H), 7.68-7.48 (m, 1H), 5.57 - 5.25 (m, 1H), 3.69 (d, J = 4.0 Hz, 1H), 3.56 (d, J = 33.2 Hz, 3H), 3.44 - 3.34 (m, 1H), 3.30 (s, 1H), 3.11 (d, J = 11.2 Hz, 1H), 2.94 (d, J = 12.0 Hz, 1H), 2.73-2.53 (m, 1H), 2.42 (d, J = 32.4, 16.4 Hz, 4H), 2.11 - 1.92 (m, 1H).LC-MS: (ESI) m / z=410.1 [M+H] SFC: 99% and (S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (504 mg, 99.03% yellow solid). 1H NMR (400 MHz, DMSO) δ 9.09 (d, J = 42.0, 1.9 Hz, 1H), 8.98 (d, J = 26.8 Hz, 1H), 8.90 (s, 1H), 8.67 - 8.60 (m, 1H), 8.48 (s, 1H), 8.34 - 8.19 (m, 1H), 8.18 (d, J = 8.8 Hz, 1H), 8.15-8.05 (m, 1H), 7.68-7.48 (m, 1H), 5.57 - 5.24 (m, 1H), 3.71 - 3.62 (m, 1H), 3.56 (d, J = 33.2 Hz, 3H), 3.44 - 3.34 (m, 1H), 3.30 (s, 1H), 3.10 (d, J = 11.2 Hz, 1H), 2.94 (d, J = 12.0 Hz, 1H), 2.73-2.53 (m, 1H), 2.42 (dd, J = 32.4, 16.4 Hz, 4H), 2.11 - 1.93 (m, 1H).LC-MS: (ESI) m / z=410.1 [M+H] SFC: 99%. EXAMPLES

[0208] Synthesis of Compound 1 shown in FIG. 15: Synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0209] Following the general procedure for the coupling of boronic acid intermediates with aryl bromides, a mixture of B5 (2 g, 4.87 mmol), (6-methoxypyridin-3-yl)boronic acid (888 mg, 5.844 mmol), PdCl(dtdppf) (318 mg, 4.87 mmol) and KCO (2 g, 14.61 mmol) in 1,4-dioxane / HO (100 mL / 40 mL) afforded compound 1 (1.2 g, 56.07%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.94 (d, J = 25.6 Hz, 1H), 8.80 (s, 1H), 8.68 (dd, J = 39.6, 2.0 Hz, 1H), 8.38 (s, 1H), 8.29 - 8.10 (m, 2H), 8.05-7.95 (m, 1H), 7.01 (dd, J = 18.8, 8.8 Hz, 1H), 5.45-5.25 (m, 1H), 3.94 (d, J = 4.8 Hz, 3H), 3.73 - 3.61 (m, 1H), 3.56 (d, J = 33.2 Hz, 3H), 3.44 - 3.35 (m, 1H), 3.15 - 2.87 (m, 1H), 2.72 - 2.53 (m, 1H), 2.48 - 2.39 (m, 2H), 2.35 (s, 2H), 2.10 - 1.91 (m, 1H).LC-MS: (ESI) m / z=440.1 [M+H] + EXAMPLES

[0210] Synthesis of compound 2 shown in FIG. 16: Synthesis of (R / S)-1-(1-ethyl-3,3-difluoropiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0211] To a mixture of D7 (100 mg, 0.24 mmol) in acetaldehyde (10 mL) was added NaBH3CN (18 mg, 0.28 mmol). The mixture was stirred at 30 °C for 5 h. H2O (20 mL) was added to the mixture, extracted with EtOAc (20 mL x 3), and then the organic layer was concentrated in vacuo. The residue was purified by column chromatography (DCM:MeOH = 30:1) to give compound 2 (10 mg, 9.38%) as a white solid. LC-MS: (ESI) m / z = 454.0 [M + H]. 1H NMR (400 MHz, DMSO-d6) δ 8.99 - 8.89 (m, 1H), 8.80 (s, 0.4H), 8.75 - 8.61 (m, 1H), 8.39 (s, 0.5H), 8.25 - 8.11 (m, 2H), 8.04 - 7.91 (m, 1H), 7.05 - 6.90 (m, 1H), 5.55 - 5.24 (m, 1H), 3.93 (d, J = 8.0 Hz, 3H), 3.70 - 3.62 (m, 0.3H), 3.60 (s, 1H), 3.52 (s, 2H), 3.49 - 3.35 (m, 1H), 3.20 (d, J = 8.0 Hz, 0.7H), 3.04 (d, J = 8.0 Hz, 1H), 2.66 - 2.59 (m, 1H), 2.58 - 2.53 (m, 1H), 2.46 - 2.38 (m, 2H), 2.10 - 1.93 (m, 1H), 1.16 - 1.04 (m, 3H). EXAMPLES

[0212] Synthesis of compound 3 shown in FIG. 17: Synthesis of (R / S)-1-(3,3-difluoro-1-isopropylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0213] To a solution of D7 (100 mg, 0.24 mmol) in propan-2-one (10 mL) was added NaBH3CN (22 mg, 0.35 mmol). The reaction mixture was stirred at 30 °C for 5 h. H2O (20 mL) was added to the mixture, extracted with EtOAc (20 mL x 3), and then the organic layer was concentrated. The residue was purified by column chromatography (DCM:MeOH = 30:1) to give compound 3 (10 mg, 9.74%) as a white solid. LC-MS: (ESI) m / z = 468.2 [M + H]. 1H NMR (400 MHz, DMSO-d6) δ 8.99 - 8.89 (m, 1H), 8.80 (s, 0.5H), 8.73 - 8.60 (m, 1H), 8.39 (s, 0.5H), 8.22 - 8.09 (m, 2H), 8.02 - 7.90 (m, 1H), 7.04 - 6.89 (m, 1H), 5.52 - 5.19 (m, 1H), 3.95 - 3.88 (m, 3H), 3.61 - 3.35 (m, 4H), 3.15 - 2.53 (m, 5H), 2.09 - 1.93 (m, 1H), 1.05 (d, J = 8.0 Hz, 6H). EXAMPLES

[0214] Synthesis of compound 4 shown in FIG. 18: Synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-ethoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0215] Following the general procedure for coupling of boronic acid intermediates with aryl bromides, a mixture of B5 (2 g, 4.87 mmol), (6-ethoxypyridin-3-yl)boronic acid (970 mg, 5.844 mmol), PdCl2(dtdppf) (318 mg, 0.49 mmol) and K2CO3 (2 g, 14.61 mmol) in 1,4-dioxane / H2O (100 mL / 40 mL) afforded compound 4 (1.3 g, 59.1%) as a white solid. LC-MS: (ESI) m / z=454.1 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ 9.03 - 8.95 (m, 1H), 8.79 (s, 0.35H), δ 8.74 - 8.53 (m, 1H), δ 8.44 - 8.33 (m, 1H), 8.30 - 8.06 (m, 2H), 8.05 - 7.85 (m, 1H), 7.05 - 6.96 (m, 1H), 5.58 - 5.20 (m, 1H), 4.39 (s, 2H), 3.74 - 3.62 (m, 0.57H), 3.62 - 3.42 (m, 3H), 3.45 - 3.36 (m, 0.47H), 3.17 - 2.93 (m, 2H), 2.74 - 2.56 (m, 1H), 2.49 - 2.29 (m, 4H), 2.13 - 1.96 (m, 1H), 1.36 (s, 3H). EXAMPLES

[0216] Synthesis of compound 5 shown in FIG. 19: Synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-7-fluoro-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0217] Following the general method for coupling of boronic acid intermediates with aryl bromides, C5 (150 mg, 0.35 mmol), (6-methoxypyridin-3-yl)boronic acid (70 mg, 0.46 mmol), PdCl2(dtdppf) (14 mg, 0.02 mmol), K2CO3 (145 mg, 1.05 mmol) in 1,4-dioxane / HO (4 mL / 0.8 mL) was degassed twice with N2 and then heated to 90 °C for 3 h. The mixture was poured into HO (20 mL), extracted with DCM (45 mL), and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Pre-HPLC (FA) to give compound 5 (79.2 mg, 49.4%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.98 (d, J = 27.3 Hz, 1H), 8.72 (d, J = 8.0 Hz, 1H), 8.63 - 8.13 (m, 2H), 8.17 - 7.95 (m, 1H), 7.93 (d, J = 12.2 Hz, 1H), 7.11 - 6.86 (m, 1H), 5.49 - 5.24 (m, 1H), 3.94 (d, J = 5.6 Hz, 3H), 3.68 - 3.35 (m, 4H), 3.08 (d, J = 10.8 Hz, 1H), 2.99 - 2.57 (m, 2H), 2.48 - 2.17 (m, 4H), 2.08 - 1.79 (m, 1H).LC-MS: (ESI) m / z= 458.3 [M+H] + EXAMPLES

[0218] Synthesis of Compound 6 shown in FIG. 20: Synthesis of (R / S)-1-(3,3-difluoro-1-(methyl-d3)piperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0219] A solution of D7 (100 mg, 0.24 mmol) in ACN (20 mL) was stirred at 28 °C, and K2CO3 (71.4 mg, 0.52 mmol) was added to the mixture and stirred at 28 °C for 30 min. Then, CD3I (51 mg, 0.35 mmol) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 16 h. H2O (10 mL) was added to the reaction mixture and extracted with EtOAc (30 mL x 3), then the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuum. The residue was purified by column chromatography (DCM:MeOH = 30:1) to give compound 6 (2.6 mg, 2.5%) as a white solid. LC-MS: (ESI) m / z = 442.2 [M + H]. 1H NMR (400 MHz, DMSO-d6) δ 8.99 - 8.89 (m, 1H), 8.80 (s, 0.3H), 8.75 - 8.61 (m, 1H), 8.38 (s, 0.7H), 8.25 - 8.11 (m, 2H), 8.05 - 7.91 (m, 1H), 7.05 - 6.95 (m, 1H), 5.55 - 5.24 (m, 1H), 3.94 (d, J = 4.0 Hz, 3H), 3.70 - 3.62 (m, 0.6H), 3.60 (s, 1H), 3.51 (s, 2H), 3.43 - 3.38 (m, 0.4H), 3.15 - 3.06 (m, 0.4H), 2.99 - 2.90 (m, 1H), 2.64 - 2.54 (m, 0.6H), 2.45 - 2.38 (m, 1H), 2.08 - 1.93 (m, 1H), 1.23 (s, 1H). EXAMPLES

[0220] Synthesis of compound 7 shown in FIG. 21: Synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-isopropoxypyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0221] Following the general procedure for coupling of boronic acid intermediates with aryl bromides, a mixture of B5 (100 mg, 0.24 mmol), (6-isopropoxypyridin-3-yl)boronic acid (52.8 mg, 0.29 mmol), PdCl2(dtdppf) (16 mg, 0.02 mmol) and K2CO3 (89 mg, 0.73 mmol) in 1,4-dioxane / HO (10 mL / 4 mL) afforded compound 7 (10.6 mg, 9.4%) as a white solid. LC-MS: (ESI) m / z=468.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.99 - 8.89(m, 1H), 8.91 - 8.77(m, 0.35H), 8.73 - 8.57 (m, 1H), 8.36 (s, 1H), 8.27 - 8.07 (m, 2H), 8.05 - 7.90 (m, 1H), 6.99 - 6.94 (m, 1H), 5.52 - 5.26 (m, 2H), 3.66 - 3.62 (m, 0.5H), 3.61 - 3.49 (m, 3H), 3.45 - 3.37 (m, 0.5H), 2.99 - 2.87 (m, 1H), 2.47 - 2.39 (m, 3H), 2.36 - 2.31 (m, 2H), 2.10 - 1.91 (m, 1H), 1.36 - 1.31 (m, 6H). EXAMPLES

[0222] Synthesis of compound 8 shown in FIG. 22: Synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(dimethylamino)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0223] Following the general procedure for coupling of boronic acid intermediates with aryl bromides, to a mixture of B5 (300 mg, 0.73 mmol) and G2 (181 mg, 0.73 mmol) in dioxane / HO (10 mL / 2 mL) was added Pd(dtbpf)Cl (53 mg, 0.073 mmol) and KCO (302 mg, 2.19 mmol) to give compound 8 (321 mg, 97%). 1H NMR (400 MHz, MeOD) δ 8.88 - 8.75 (m, 1H), 8.53 (dd, J = 41.6, 2.4 Hz, 1H), 8.37 (s, 1H), 8.12 (t, J = 8.9 Hz, 1H), 8.02 - 7.87 (m, 2H), 6.83 (dd, J = 19.9, 9.0 Hz, 1H), 5.43 (dd, J = 26.8, 8.8 Hz, 1H), 3.89 - 3.74 (m, 1H), 3.67 (s, 1H), 3.59 (s, 2H), 3.44 (d, J = 29.6 Hz, 1H), 3.17 (d, J = 4.9 Hz, 6H), 3.10 (d, J = 15.9 Hz, 1H), 2.75 - 2.50 (m, 2H), 2.43 (d, J = 18.8 Hz, 3H), 2.08 (d, J = 13.5 Hz, 1H).LC-MS: (ESI) m / z=452, 453 [M+H] + EXAMPLES

[0224] Synthesis of Compound 9 shown in FIG. 23: Synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-methoxypyridin-3-yl)-3-(methyl-d3)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0225] Following the general procedure for coupling of boronic acid intermediates with aryl bromides, a mixture of B5' (100 mg, 0.24 mmol), (6-methoxypyridin-3-yl)boronic acid (44 mg, 0.29 mmol), PdCl2(dtdppf) (31.8 mg, 0.02 mmol) and K2CO3 (200 mg, 1.46 mmol) in 1,4-dioxane / HO (100 mL / 40 mL) afforded compound 9 (10 mg, 9.36%) as a white solid. LC-MS: (ESI) m / z=443.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.99 - 8.89 (m, 1H), 8.80 (s, 0.3H), 8.74 - 8.61 (m, 1H), 8.38 (s, 0.7H), 8.22 - 8.09 (m, 2H), 8.02 - 7.90 (m, 1H), 7.07 - 6.94 (m, 1H), 3.97 - 3.90 (m, 3H), 3.71 - 3.59 (m, 1H), 3.44 - 3.38 (m, 0.6H), 3.15 - 3.06 (m, 0.4H), 3.0 - 2.86 (m, 1H), 2.78 - 2.54 (m, 1H), 2.47 - 2.45 (m, 1H), 2.45 - 2.40 (m, 1H), 2.35 (s, 2H), 2.09 - 1.92 (m, 1H). EXAMPLES

[0226] Synthesis of compound 10 shown in FIG. 24: Synthesis of (R / S)-8-(6-cyclopropoxypyridin-3-yl)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0227] Following the general procedure for coupling of boronic acid intermediates with aryl bromides, a mixture of B5 (200 mg, 0.47 mmol), E3 (152 mg, 0.58 mmol), PdCl2(dtdppf) (32 mg, 0.02 mmol) and K2CO3 (130 mg, 1.2 mmol) in 1,4-dioxane / HO (10 mL / 4 mL) afforded compound 10 (10 mg, 4.42%) as a white solid. LC-MS: (ESI) m / z=466.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.99 - 8.90 (m, 1H), 8.93 - 8.77 (m, 0.35H), 8.76 - 8.62 (m, 1H), 8.45 - 8.33 (m, 1.3H), 8.29 - 8.10 (m, 2H), 8.05 - 7.91 (m, 1H), 7.15 - 6.93 (m, 1H), 5.57 - 5.23 (m, 1H), 4.36 - 4.22 (m, 1H), 3.70 - 3.56 (m, 2H), 3.52 (s, 2H), 3.14 - 3.06 (m, 0.5H), 2.97 -2.89 (m, 1H), 2.72 - 2.54 (m, 0.5H), 2.47 -2.41 (m, 2H), 2.35 (s, 2H), 2.09 - 1.92 (m, 1H), 0.95 - 0.77 (m, 2H), 0.74 - 0.66(m, 2H). EXAMPLES

[0228] Synthesis of compound 11 shown in FIG. 25: Synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(3-(dimethylamino)azetidin-1-yl)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0229] Following the general procedure for coupling of boronic acid intermediates with aryl bromides, a mixture of H2 (359 mg, 1.18 mmol) and B5 (335 mg, 0.815 mmol) in dioxane / HO (10 mL / 2 mL) was added with K2CO3 (337 mg, 2.445 mmol) to give compound 11 (160 mg, 38.7%). 1H NMR (400 MHz, MeOD) δ 8.81 (dd, J = 18.5, 3.4 Hz, 1H), 8.44 (dd, J = 35.7, 33.3 Hz, 2H), 8.18 - 8.07 (m, 1H), 8.02 - 7.83 (m, 2H), 6.67 - 6.53 (m, 1H), 5.41 (dd, J = 25.5, 11.6 Hz, 1H), 4.20 (t, J = 7.1 Hz, 2H), 4.01 - 3.73 (m, 3H), 3.62 (dd, J = 31.4, 2.3 Hz, 3H), 3.42 - 3.33 (m, 2H), 3.09 (d, J = 11.9 Hz, 1H), 2.63 (dd, J = 28.2, 12.3 Hz, 1H), 2.53 - 2.36 (m, 4H), 2.27 (s, 6H), 2.08 (d, J = 13.7 Hz, 1H).LC-MS: (ESI) m / z=507, 508[M+H] + EXAMPLES

[0230] Synthesis of compound 12 shown in FIG. 26: Synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-8-(6-(methoxy-d3)pyridin-3-yl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0231] Following the general procedure for coupling of boronic acid intermediates with aryl bromides, a mixture of F3 (200 mg, 0.84 mmol), B5 (287 mg, 0.70 mmol), PdCl2(dtdppf) (31 mg, 4.87 mmol) and K2CO3 (347 mg, 2.52 mmol) in 1,4-dioxane / HO (10 mL / 4 mL) afforded compound 12 (10 mg, 3.2%) as a white solid. LC-MS: (ESI) m / z=443.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.98 - 8.94 (m, 1H), 8.70 - 8.54 (s, 0.41H), 8.33 - 8.25 (m, 1H), 8.23 ​​(s, 0.56H), 8.14 - 8.06 (m, 1H), 7.97 - 7.85 (m, 2H), 6.64 - 6.52 (m, 1H), 5.50 - 5.22 (m, 1H), 3.66 - 3.62 (m, 1H), 3.59 (s, 1H), 3.51 (s, 2H), 3.16 - 3.06 (m, 0.54H), 2.99 - 2.88 (m, 1H), 2.88 - 2.55 (m, 1.5H), 2.46 (s, 1H), 2.44 - 2.38 (m, 1H), 2.35 (s, 2H), 2.09 - 1.93 (m, 1H), 1.38 (s, 1H). EXAMPLES

[0232] Synthesis of compound 13 shown in FIG. 27: Synthesis of (R / S)-1-(3,3-difluoro-1-methylpiperidin-4-yl)-3-methyl-8-(6-((1R,5R / 1S,5S)-(2-methyl-2,6-diazabicyclo[3.2.0]heptan-6-yl)pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one

[0233] Following the general method for coupling of boronic acid intermediates with aryl bromides, a mixture of I6 (15 mg, 0.038 mmol), B5 (12 mg, 0.058 mmol), PdCl2(dppf) (3 mg, 0.0038 mmol), and Na2CO3 (6 mg, 0.12 mmol) in 1,4-dioxane / HO (3 mL / 0.5 mL) was degassed twice with N2 and heated to 100 °C for 3 h. The mixture was poured into a mixture of DCM (15 mL) and HO (15 mL), and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column (DCM:MeOH=30:1) to give compound 13 (2.8 mg, 47.1%) as a white solid. 1H NMR (400 MHz, DMSO) δ 1 H NMR (400 MHz, MeOD) δ 8.80 (d, J = 18.3 Hz, 1H), 8.46 (m, J = 32.8, 2.4 Hz, 1H), 8.34 (s, 1H), 8.18 - 7.82 (m, 3H), 6.56 (d, J = 18.0, 8.8 Hz, 1H), 5.40 (d, J = 26.0, 10.4 Hz, 1H), 4.97 (t, J = 4.8 Hz, 1H), 4.16 - 4.00 (m, 2H), 3.90 - 3.70 (m, 2H), 3.62 (d, J = 31.2 Hz, 3H), 3.43 - 3.34 (m, 1H), 3.15 - 3.03 (m, 2H), 2.89 (d, J = 10.8, 4.8 Hz, 1H), 2.64 (d, J = 28.0, 12.4 Hz, 1H), 2.51 (s, 1H), 2.48 (s, 3H), 2.43 (d, J = 10.8 Hz, 3H), 2.16 (d, J = 12.8, 3.2 Hz, 1H), 2.11 - 2.00 (m, 1H), 1.98 - 1.85 (m, 1H).LC-MS: (ESI) m / z=520.6 [M+H] + Example 14

[0234] Following the general method for chiral separation of racemic products 1-13, the following enantiopure products 14-41 were obtained: JPEG0007669473000003.jpg76150JPEG0007669473000004.jpg106149JPEG0007669473000005.jpg107150JPEG0007669473000006.jpg11915 0JPEG0007669473000007.jpg94151JPEG0007669473000008.jpg124150JPEG0007669473000009.jpg88150JPEG0007669473000010.jpg113150

[0235] Example 12 Biological Data Phosphorylation of ATM protein using MCF-7 cells was detected using ODYSSEY CLx (LI-COR), about 25 μL of cells were seeded into each blank 384-well plate, after 24 hours, proportionally diluted compounds were added and incubated at 37 °C for 1 hour using a pin tool, then cells were fixed by adding 25 μL of 8% paraformaldehyde for 20 minutes at room temperature. Cells were permeabilized with 1X PBS containing 0.1% Triton X-100 and blocked by adding 50 μL of Odyssey Blocking Buffer and shaking at room temperature for 1.5 hours. Blocking buffer was removed and 20 μL of anti-pKAP1 antibody was added and the anti-pKAP1 antibody was incubated overnight at 4 degrees with gentle shaking. 20 μL of secondary antibody (IRDye 800CW Goat anti-rabbit IgG) solution containing DNA stain DRAQ5 (1 / 4,000) was added to each plate well and diluted in blocking buffer with 0.1% Tween-20 (1 / 5000), and the secondary antibody was incubated for 1 hour. The solution was washed away. The plate was immediately scanned using ODYSSEY CLx (LI-COR) to inhibit the phosphorylation of ATM protein.

[0236] In cell-based inhibition of ATM phosphorylation, the compounds of the present invention are effective in inhibiting pATM signaling on MCF-7 cells and therefore have the potential to overcome radiotherapy or chemotherapy resistance due to DNA damage repair of the ATM protein.

[0237] [Table 1]

[0238] Blood-brain barrier permeability: To examine whether a compound can penetrate the blood-brain barrier (BBB), rats or mice were administered with a test compound. Four hours after administration, the rats or mice were sacrificed, and blood and brain tissue were collected to analyze the concentration of the test compound. Brain permeability is defined as the ratio of the compound concentration in brain tissue to the concentration in plasma. P-glycoprotein and BCRP (breast cancer resistance protein) are blood-brain barrier efflux proteins, and the substrates of P-glycoprotein (efflux ratio>1.5) and / or BCRP substrates (efflux ratio>1.5) are outside the brain.

[0239] [Table 2]

[0240] In the brain permeability assay, the ratio of the compound concentration of the compounds of the present invention (compounds 1-41) in brain tissue to the concentration in plasma exceeded 30%, and the compounds were not P-glycoprotein substrates and BCRP substrates, and penetrated the blood-brain barrier, so that they may achieve effective plasma concentrations in the brain for the treatment and / or prevention of cancer brain metastasis, meningeal metastasis, glioma, glioblastoma, DIPG and other central nervous system diseases.

[0241] Aldehyde oxidase sensitive: Human aldehyde oxidase (hAOX) is a cytosolic drug-metabolizing enzyme expressed in human liver, which, like CYP, contributes to the oxidation of a significant amount of quinoline derivatives, but acts in the absence of NADPH cofactor. Drugs that are substrates of AOX often exhibit high metabolic clearance, resulting in low exposure and reduced drug efficacy in humans (Lepri et al. PNAS, 2017, pp. E3178-E3187). The compounds of the present invention (compounds 1-41) are not substrates of human aldehyde oxidase, which has a long half-life, and therefore may achieve effective efficacy in the brain, where metabolic clearance is low, for the treatment and / or prevention of cancer brain metastasis, meningeal metastasis, glioma, glioblastoma, DIPG and other central nervous system diseases.

[0242] [Table 3]

[0243] While the present invention describes a number of embodiments, the basic embodiment of the invention can be modified to provide other embodiments that utilize the compounds and methods of the invention. Thus, the scope of the invention is defined by the appended claims rather than by the specific embodiments shown by way of example.

[0244] All references cited in this application (including, but not limited to, abstracts, articles, journals, publications, textbooks, treatises, technical data sheets, internet sites, databases, patents, patent applications, and patent publications) are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art.

Claims

1. The following formula 【Chemistry 1】 A compound comprising a structure represented by wherein R1 is independently selected from OC1-3 alkyl, OC3-5 cycloalkyl, OC1-C3 deuterated alkyl, dialkylamine, substituted C3-C6 cycloamine, or substituted diazabicycloamine; R2 is independently selected from hydrogen or fluoro; R3 is independently selected from methyl or deuterated methyl; R4 is independently selected from C1-C3 alkyl or C1-C3 deuterated alkyl; compound.

2. R1 is independently selected from methoxy, ethoxy, isopropoxy, cyclopropoxy, deuterated methoxy, dimethylamine, N,N-dimethylazetidin-3-amine, or 2-methyl-2,6-diazabicyclo[3.2.0]heptane; R2 is independently selected from hydrogen or fluoro; R3 is independently selected from methyl or deuterated methyl; R4 is independently selected from methyl, ethyl, isopropyl or deuterated methyl; The compound according to claim 1 . 【Request 3】 【Chemistry 2】 【change】 【change】 A compound selected from:

4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, a salt thereof, a solvate thereof, or a hydrate thereof, and a pharma- ceutically acceptable excipient or auxiliary ingredient.

5. An ATM inhibitor capable of penetrating the blood-brain barrier, comprising the compound according to any one of claims 1 to 3 as an active ingredient.

6. Use of a compound according to any one of claims 1 to 3, or a pharmaceutical composition according to claim 4, or an ATM inhibitor according to claim 5, in the manufacture of a medicament for treating or preventing ATM-mediated activation of the ATM protein.

7. 7. The use according to claim 6, characterized in that the protein is ataxia telangiectasia mutated kinase.

8. Use of a compound according to any one of claims 1 to 3, or a pharmaceutical composition according to claim 4, or an ATM inhibitor according to claim 5, in the manufacture of a medicament for the treatment or prevention of a disease mediated by ATM kinase.

9. The disease is a central nervous system metastasis disease of cancer, a brain tumor, a proliferative disease, or cancer, The use according to claim 8, characterized in that the compound according to any one of claims 1 to 3 is administered simultaneously, separately or sequentially with radiation therapy.

10. The compound according to any one of claims 1 to 3, wherein the compound is cisplatin, oxaliplatin, carboplatin, valrubicin, idarubicin, doxorubicin, pirarubicin, irinotecan, topotecan, amrubicin, epirubicin, etoposide, mitomycin, bendamustine, chlorambucil, cyclophosphamide, ifosfamide, carmustine, melphalan, bleomycin, olaparib, rucaparib, niraparib, talazoparib, pamiparib, pembrolizumab, or cefotaxime. The use according to claim 8 for use in the treatment of cancer according to claim 9, which is administered simultaneously, separately or sequentially with at least one further antitumor substance capable of inducing DNA cleavage selected from the group consisting of lolizumab, nivolumab, cemiplimab, spartalizumab, sintilimab, tisulizumab, dostarimab, atezolizumab, avelumab, durvalumab, AZD1775, VX-970, BAY1895344, and AZD6738.

11. 10. The use according to claim 9, characterized in that the disease is glioblastoma, diffuse pontine glioma, astrocytoma, oligodendroglioma, ependymoma, meningioma, pituitary adenoma, acoustic neuroma and medulloblastoma.

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