Pyridoimidazolone compounds, their preparations and their therapeutic use

Abstract

Compounds capable of inhibiting ERK5 are provided. Pharmaceutical compositions and their medical uses are also provided, including for use in treating or preventing conditions such as cancer.

Description

[Technical Field]

[0001] Compounds capable of inhibiting ERK5 are provided. Pharmaceutical compositions and their medical uses are also provided, including for use in treating or preventing conditions such as cancer. [Background technology]

[0002] The mitogen-activated protein kinase (MAPK) cascade is a highly conserved cellular pathway that transmits signals from the cell surface to the nucleus. This pathway plays a crucial role in cell proliferation, differentiation, and migration, and is well known to be involved in cancer development. The proteins in this pathway include extracellular signal-regulated kinase (ERK) proteins, among which ERK5 (expressed from the MAPK7 gene) plays a vital role in cell proliferation, as well as in epithelial development and neural differentiation (see, e.g., Nishimoto et al., EMBO Reports (2006) 7(8):782-786). ERK5 is unique among ERK proteins in that it has a transcriptional activation domain (TAD), a nuclear localization signal, and a large C-terminal domain containing two proline-rich regions (see, e.g., Guo et al., Exp Ther Med. (2020) 19:1997-2007). Autophosphorylation of TAD is required for transcriptional activation (e.g., Morimoto et al., J Biol Chem. (2007) 282(49):35449-35456).

[0003] ERK5 plays a crucial role in regulating cell proliferation and cell cycle progression, for example, through the direct or indirect phosphorylation of MEF2C, cMYC, SGK1, RSK, FOS, and FRA1 (see, e.g., Paudel et al., Int J Mol Sci. (2021) 22:7594-7614; Terasawa et al., Genes to Cells (2003) 8(3):263-273). The involvement of ERK5 in numerous biological pathways suggests that its activity is associated with many aspects of cancer progression, including tumor angiogenesis, metastasis, inflammation, persistent proliferation, and evasion of growth inhibition. Therefore, it presents an attractive target for modulating disease pathology and treatment under a wide range of conditions. Previous studies have shown that ERK5 inhibition or downregulation is necessary, in particular, to block tumorigenesis in mouse leukemia cells, reduce the proliferation of chronic myeloid leukemia cells, inhibit the proliferation of breast cancer and multiple myeloma cells, suppress colon cancer cell proliferation, and affect the proliferation or survival of renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, and hepatocellular carcinoma cells (e.g., Stecca et al., Int J Mol Sci. (2019) 20:1426-1446).

[0004] Therefore, ERK5 inhibition represents a promising approach to address a wide range of cancers. Several ERK5 inhibitors have been developed, and some are currently undergoing clinical review. For example, International Publication No. 2019 / 170543 (Bayer AG and Bayer Pharma AG) discloses compounds that are said to be active as ERK5 inhibitors in the μM to nM concentration range. [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] Despite recent advances in cancer treatment through the development of targeted chemotherapy and immunotherapy, it is not possible to provide an efficient treatment solution for all cancer patients. Therefore, there is a need to identify and develop new drugs. The present disclosure aims to address this need by providing novel compounds for use as ERK5 inhibitors and novel compounds for the treatment of ERK5-related diseases and conditions.

Means for Solving the Problems

[0006] Therefore, a first aspect is the formula (N-I)

Chemical formula

[0007] In this embodiment, R 1 teeth, [ka] Selected from, R 1 As defined earlier, R A It is optionally replaced by one or two occurrences of R. In the embodiment, each R A The alkyl group is independently selected from -F, -OH, oxo, =N-OH, -OCH3, and -(C1~C2)alkyl groups that are optionally substituted with one or more substituents selected from -F and -OH.

[0008] In this embodiment, L 1 It is -O- or -CH2-.

[0009] In this embodiment, R 2 teeth, [ka] Selected from.

[0010] Further aspects are shown in equation (N-II) [ka] [In the formula, R 1 R is selected from halo (e.g., -Br), -(C1~C6)alkyl, -(C3~C7)cycloalkyl, and 4~10 member heterocycloalkyl, 1 is, R AIt is optionally replaced by one or more occurrences of Each R A This is independently selected from halo (e.g., -F), -OH, oxo, -O(C1~C3)alkyl, and -(C1~C3)alkyl which are optionally substituted with one or more groups independently selected from halo (e.g., -F) and -OH. And / or R A The two appearances, together with the atom to which they are bonded, can form a (C3-C6) cycloalkyl group or a 3-6 member heterocycloalkyl group, and the cycloalkyl group is optionally substituted with -F. L 1 It is selected from direct bonds, -O-, and -CH2-. R B1 It is selected from -H, -OH, -NH2, and -NHC(O)OC(CH3)3, R B2 The option is selected from -SF5 and -OCF3. R 3 The present invention provides compounds that are selected from -H and -(C1~C3)alkyl (e.g., -CH3), or pharmaceutically acceptable salts thereof.

[0011] In this embodiment, R 1 teeth, [ka] Selected from, R 1 As defined earlier, R A It is optionally replaced by one or more occurrences of .

[0012] Further embodiments are shown in formula (III) or formula (IV). [ka] [In the formula, R 1 and L 1 The present invention provides a compound that is [as previously defined], or a pharmaceutically acceptable salt thereof.

[0013] Further embodiments are given by formula (V), formula (VI), or formula (VII). [ka] [In the formula, R 1 R is selected from -(C3~C7) cycloalkyl and 4~10 member heterocycloalkyl groups. 1 is, R A It is arbitrarily substituted by one or more occurrences of each R A The present invention provides compounds that are independently -(C1~C3)alkyl groups that are optionally substituted with -OH groups, or pharmaceutically acceptable salts thereof.

[0014] Further aspects include: - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-N-morpholino-3H-imidazo[4,5-b]pyridine-2-one, - 6-Tetrohydropyran-4-yloxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[(1-methyl-4-piperidyl)oxy]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methylpyrrolidine-3-yl)oxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(1-methyl-4-piperidyl)oxy]-3H-imidazo[4,5-b]pyridine-2-one, - 6-N-morpholino-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-(1-methylpyrrolidine-3-yl)oxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[2-(hydroxymethyl)morpholin-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(pentafluoro-λ 6 -Sulfanil)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 6-tetrahydrofuran-3-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-2-one, - 6-Cyclopentyl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-hydroxy-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[4-(pentafluoro-λ 6 -Sulfanil)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-5-methyl-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-fluorospiro[3,3]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-oxo-4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(tetrahydrofuran-3-ylmethyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-2-yl-3H-imidazo[4,5-b]pyridine-2-one, - Trans-6-(4-methoxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - cis-6-(4-methoxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3-azabicyclo[4.1.0]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-cyclobutyl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3-oxabicyclo[4.1.0]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-bicyclo[2.1.1]hexanyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-norcalan-1-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4,4-difluorocyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-cyclohexyl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-norbornan-2-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-2-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(tetrohydropyran-4-ylmethyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-3-yl-3H-imidazo[4,5-b]pyridine-2-one, - 6-Tetrohydropyran-4-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-(oxetane-3-ylmethyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[tetrahydrofuran-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, - trans-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - cis-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[1-methylpyrrolidine-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(pentafluoro-λ 6 -Sulfanil)benzoyl]pyrroridine-3-yl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[4-(pentafluoro-λ 6 -Sulfanil)benzoyl]pyrroridine-3-yl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - trans-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - cis-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methyl-4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-3-yloxy-3H-imidazo[4,5-b]pyridine-2-one, - 6-tetrahydrofuran-3-yloxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - Trans-6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - cis-6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - tert-butyl N-[2-[4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate, - 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - Trans-6-(4-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - cis-6-(4-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-(4-oxocycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[4-hydroxyiminocycloheptyl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - Trans-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - cis-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, The present invention provides compounds selected from the group consisting of and pharmaceutically acceptable salts thereof.

[0015] A further embodiment provides a pharmaceutical composition comprising a compound as defined above and at least one pharmaceutically acceptable excipient or carrier.

[0016] Further embodiments provide compounds or pharmaceutical compositions as defined above for use in therapeutic purposes.

[0017] Further embodiments provide compounds or pharmaceutical compositions as defined above for use in the treatment or prevention of cancer.

[0018] In this embodiment, the cancer is characterized by increased MAPK7 expression and / or increased ERK5 activity.

[0019] In this embodiment, the cancer is selected from leukemia (e.g., chronic myeloid leukemia), breast cancer, multiple myeloma, colon cancer, colorectal cancer, lung cancer, pancreatic cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, melanoma, and hepatocellular carcinoma. [Modes for carrying out the invention]

[0020] Herein, specific embodiments of the present disclosure will be described with reference to the description and examples, but it should be understood that such embodiments are for illustrative purposes only and are merely a few examples of many possible specific embodiments that can represent the application of the principles of the present disclosure. Various changes and modifications will be apparent to those skilled in the art in consideration of the interests of the present disclosure and will be deemed to be within the spirit and scope of the present disclosure as further defined in the appended claims.

[0021] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which this disclosure belongs. Any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, but exemplary methods, apparatus and materials are described herein. All technical and patent publications referenced herein are incorporated herein by reference in their entirety.

[0022] The implementation of this disclosure will utilize conventional techniques, such as chemical synthesis, tissue culture, immunology, molecular biology, microbiology, cell biology, and recombinant DNA, which are within the scope of the art of those skilled in the art, unless otherwise specified. For example, Michael R. Green and Joseph Sambrook, Molecular Cloning (4 th ed., Cold Spring Harbor Laboratory Press 2012); the series Ausubel et al. eds. (2007) Current Protocols in Molecular Biology; the series Methods in Enzymology (Academic Press, Inc., NY); MacPherson et al. (1991) PCR 1:A Practical Approach (IRL Press at Oxford University Press); Practical Approach;Harlow and Lane eds.(1999)Antibodies,A Laboratory Manual;Freshney(2005)Culture of Animal Cells:A Manual of Basic Technique,5 thedition; Gait ed. (1984) Oligonucleotide Synthesis; U.S. Patent No. 4,683,195; Hames and Higgins eds. (1984) Nucleic Acid Hybridization; Anderson (1999) Nucleic Acid Hybridization; Hames and Higgins eds. (1984) Transcription and Translation; Immobilized Cells and Enzymes (IRL Press (1986)); Perbal (1984) A Practical Guide to Molecular Cloning; Miller and Calos eds. (1987) Gene Transfer Vectors for Mammalian Cells (Cold Spring Harbor Laboratory); Makrides ed. (2003) Gene Transfer and Expression in Mammalian Cells; Mayer and Walker eds. (1987) Immunochemical Methods in Cell and Molecular Biology (Academic Press, London); Herzenberg et al. eds (1996) Weir’s Handbook of Experimental Immunology; Manipulating the Mouse Embryo: A Laboratory Manual, 3 rd edition (Cold Spring Harbor Laboratory Press (2002)); See Sohail (ed.) (2004) Gene Silencing by RNA Interference: Technology and Application (CRC Press).

[0023] All numerical specifications (e.g., pH, temperature, time, concentration, molecular weight, including ranges) are approximations that, where appropriate, vary by (+) or (-) in increments of, for example, 0.1 or 1.0. It should be understood that, although not necessarily explicitly stated, the term “approximately” is used before every numerical specification to indicate a conventional level of variability. For example, a numerical specification that is “approximately” given a value may vary by ±10% of the above value, or conversely, this variation may be ±5%, ±2%, or ±1% of this value. It should also be understood that, although not necessarily explicitly stated, the reagents described herein are merely illustrative, and their equivalents are known in the art.

[0024] As used herein and in the claims, the singular forms “a,” “an,” and “the” include multiple referents unless otherwise clearly indicated by the context. For example, the term “cell” includes multiple cells (including mixtures thereof). Unless otherwise specified or made clear by the context, the term “or” as used herein is understood to be inclusive. The term “including” is used herein to mean “including, but not limited to,” and is used interchangeably with this phrase.

[0025] Where used herein, the terms “comprising” or “comprises” are intended to mean that a composition and method includes the elements listed without excluding other elements. “Essentially consisting of” when used to define a composition and method means excluding any other elements that are essentially important to the purposes described. Thus, a composition essentially consisting of the elements defined herein would not exclude trace impurities from isolation and purification methods and pharmaceutically acceptable carriers, such as phosphate-buffered saline, preservatives, etc. “Consists of” means excluding other components beyond trace amounts, and substantial method steps for administering the compositions of this disclosure, or process steps for producing the compositions or achieving the intended results. Embodiments defined by each of these transitional terms are within the scope of this disclosure. The use of the term “comprising” herein is intended to encompass and disclose corresponding statements in which the term “comprising” is replaced by “consisting essentially of” or “consisting of.”

[0026] The terms "subject," "individual," or "patient" are used interchangeably herein and refer to vertebrates such as mammals. Mammals include, but are not limited to, rodents, livestock, sports animals, pets, and primates, such as mice, rats, rabbits, monkeys, cattle, sheep, pigs, dogs, cats, horses, and humans. In certain embodiments, the mammal is a human.

[0027] "Administering" is defined herein as a means of providing a drug or a composition containing a drug to a target in a manner that brings the drug into contact with (e.g., internally) the body of the target. Such administration may be by any route, including but not limited to oral, transdermal (e.g., by vagina, rectal, or oral mucosa), injection (e.g., subcutaneous, intravenous, parenteral, intraperitoneal, or intracentral nervous system), or inhalation (e.g., oral or nasal). Administration may also include providing a substance or composition to a portion of the surface of the body of the target, for example, by topical administration to the skin. Pharmaceutical formulations are, of course, administered in a form appropriate to each route of administration.

[0028] Treating or treating a disease includes: (1) preventing the disease, i.e., preventing the development of clinical symptoms of the disease in patients who are susceptible to the disease but have not yet experienced or manifested symptoms of the disease; (2) inhibiting the disease, i.e., stopping or reducing the onset of the disease or its clinical symptoms; and / or (3) alleviating the disease, i.e., causing regression of the disease or its clinical symptoms.

[0029] The term "affected" refers, when used in conjunction with the term "treatment," to a patient or individual who has been diagnosed with or is susceptible to the disease. A patient may also be referred to as "at risk of developing" the disease due to a family history of the disease or the presence of disease-related genetic mutations. A patient at risk of developing the disease has not yet developed all or some of the characteristic pathological features of the disease.

[0030] An effective dose or therapeutically effective dose is the amount sufficient to produce a beneficial or desired result. An effective dose may be administered in one or more doses, applications, or dosages. Such delivery depends on many variables, including the duration of use of individual dose units, the bioavailability of the therapeutic agent, and the route of administration. However, the specific dose level of the therapeutic agent of this disclosure for any particular subject depends on various factors, including, for example, the activity of the specific compound used, the subject's age, weight, overall health, sex, and diet, administration time, excretion rate, drug combination, severity of the specific disorder being treated, and the form of administration. Therapeutic doses can generally be titrated to optimize safety and efficacy. Typically, dose-response relationships from in vitro and / or in vivo studies can first provide useful guidance on an appropriate dose for patient administration. Generally, it would be desirable to administer an amount of the compound effective in achieving a serum level corresponding to the concentration found to be effective in vitro. Determining these parameters is well within the scope of the art of the art. These considerations, as well as effective formulations and administration procedures, are well known in the art and described in standard texts. As used herein in accordance with this definition, the term “therapeutic dose” is a quantity sufficient to treat (e.g., improve) one or more symptoms associated with a condition. The total daily dose may be administered as a single dose or in divided doses and may, at the physician’s discretion, deviate from the typical range shown herein.

[0031] As used herein, the terms “increase” and “rise” are interchangeable and encompass any measurable increase in biological function and / or biological activity and / or concentration. For example, an increase could be at least about 10%, for example at least about 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, for example at least about 95%, 96%, 97%, 98%, 99%, or 100%. Thus, an increase could be at least about 2, 3, 4, 5, 6, 7, 8, 9, or 10 times the amount or function, or activity or concentration of the control or baseline, for example at least about 20, 25, 50, 100, or more.

[0032] As used herein, the terms “increased expression” and / or “increased activity” of a substance such as ERK5 in a sample or cancer or patient typically refer to an increase in the amount of the substance (e.g., MAPK7 gene product or ERK5 protein), but may also mean an increase in the biological activity of the substance (e.g., constitutive activation of phosphorylation and / or decreased recognition of phosphorylation sites of ERK5). For example, the increase may be in amounts of about 5%, e.g., about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, e.g., about 96%, 97%, 98%, 99%, or 100%. Therefore, the increase may be about 2, 3, 4, 5, 6, 7, 8, 9, or 10 times, for example, about 20, 25, 50, 100 times or more, compared to the amount (or activity) of a substance such as ERK5 in a control sample or multiple control samples, for example, individuals or populations without disease or disorder (e.g., cancer), or in internal controls, as determined by techniques known in the art. If the expression and / or activity of ERK5 increases by 1, 2, 3, 4, 5, or more standard deviations compared to the mean (value) or median of ERK5 in the control group of the sample, the baseline group of the sample, or retrospective analysis of patient samples, the subject may also be determined to have "increased expression" or "increased activity" of ERK5. As practiced in the art, such control or baseline expression levels can be determined or measured in advance of measurements in the sample or cancer or subject, or can be obtained from a database of such control samples.

[0033] As used herein, the term “pharmaceutically acceptable excipients” encompasses any of the standard pharmaceutically acceptable excipients, such as those listed in, for example, Remington's Pharmaceutical Sciences (20th ed., Mack Publishing Co., 2000). Such excipients include carriers such as phosphate-buffered saline and water, and emulsions such as oil / water or water / oil emulsions, as well as various types of wetting agents. Pharmaceutical compositions may also include stabilizers, preservatives, adjuvants, fillers, binders, lubricants, and the like.

[0034] As used herein, the term “alkyl” means a saturated linear or branched free radical essentially consisting of carbon atoms and a corresponding number of hydrogen atoms. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and the like. Other alkyl groups will be readily apparent to those skilled in the art, given the interests of this disclosure. Terms such as “(C1-C3) alkyl” and “(C1-C6) alkyl” have an equivalent meaning, i.e., a saturated linear or branched free radical essentially consisting of 1-3 (or 1-6) carbon atoms and a corresponding number of hydrogen atoms. The definition of “alkyl” also applies in the context of other groups containing alkyl groups, e.g., “O(C1-C3) alkyl”. The term “haloalkyl” means an alkyl group substituted with one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, trifluoroethyl, difluoroethyl, pentafluoroethyl, chloromethyl, and the like. One or more carbon atoms in the alkyl group skeleton may be substituted (or bonded) by heteroatoms via multiple bonds (e.g., double bonds). For example, the carbon atoms of an alkyl group may be bonded to oxygen via double bonds (i.e., substituted with oxos to provide carbonyl functionality). The presence of such substituents does not prevent the carbon skeleton of a free radical from being considered an alkyl group.

[0035] As used herein, the term “cyclic group” means a saturated, partially or fully unsaturated, or aromatic group having at least 3 to 10 atoms (i.e., ring atoms) that form a ring. Where a cyclic group is defined as having a certain number of members, terms such as “membered,” “membered,” etc., are used to indicate the number of ring atoms in the above cyclic group. For example, a five-membered cyclic group (e.g., a five-membered heterocyclic group) contains five ring atoms. It will be understood that a cyclic group may be part of a larger cyclic system. For example, bicyclo[4.3.0]nonane contains two carboncyclic groups, namely a cyclohexane group and a cyclopentane group, fused to form a carbocyclic system that constitutes the molecule. The term “cyclic group” is intended to encompass both carboncyclic and heterocyclic groups. The term “carboncyclic” refers to a group having at least 3 to 9 carbon atoms that form a ring. The term "heterocyclic" refers to a group having at least 3 to 10 atoms forming a ring, where at least 1 to 9 of the ring atoms are carbon, and the remaining at least 1 to 9 ring atoms (i.e., heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen.

[0036] As used herein with respect to cyclic groups, the terms “spiro” or “spirocyclic” indicate that a first cyclic group in a polycyclic system is bonded to a second cyclic group in the same polycyclic system, and the ring atoms of the first and second cyclic groups share only one common atom, i.e., the first and second cyclic groups share only one common ring atom. For example, the spiro[5.5]undecanyl group contains two cyclohexane rings sharing a single carbocyclic atom.

[0037] As used herein with respect to cyclic groups, the term “fusion” means that a first cyclic group in a polycyclic system is bonded to a second cyclic group in the same polycyclic system, and the ring atoms of the first cyclic group and the ring atoms of the second cyclic group have two adjacent atoms in common, i.e., the first and second cyclic groups share two common ring atoms. For example, the bicyclo[4.4.0]decanyl group contains two cyclohexane rings that have two adjacent carbocyclic atoms in common.

[0038] As used herein with respect to cyclic groups, the term “bridged” means that a first cyclic group in a polycyclic system is bonded to a second cyclic group in the same polycyclic system, and the ring atoms of the first cyclic group and the ring atoms of the second cyclic group have more than two adjacent atoms in common, i.e., the first and second cyclic groups share three or more common ring atoms. For example, the bicyclo[3.3.1]nonanyl group contains two cyclohexane rings that have three adjacent carbocyclic atoms in common.

[0039] Within the structural formulas described herein, any ring system (including any spiro, fusion, or bridging ring systems) may be connected to other parts of the molecule via any atom having the appropriate valency. For example, a bicyclic ring may be connected to another part of the molecule via a ring atom (e.g., a second carbon atom or a heteroatom such as N) or a bridgehead (e.g., a third carbon atom). Spiro, fusion, and bridging rings may be fully unsaturated, partially unsaturated, or fully saturated, and one or more of the rings constituting them may have aromatic properties.

[0040] As used herein, the term “cycloalkyl” means a saturated free radical having at least 3 to 9 carbon atoms (i.e., ring atoms) forming a ring. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. It should be understood that cycloalkyl groups can be monocyclic or polycyclic (e.g., fused, cross-linked, or spirocyclic). In the case of polycyclic cycloalkyl groups, there may be further rings, e.g., one or more additional rings, all containing 3 to 7 carbon atoms (i.e., ring atoms). An example of a cycloalkyl group having such additional rings is bicyclo[1.1.1]pentanyl. The term “(C3-C7) cycloalkyl” indicates that the cycloalkyl group contains 3 to 7 carbon atoms in the ring portion of the group, which may be monocyclic or polycyclic (e.g., fused, cross-linked, or spirocyclic), e.g., cyclopropanyl (having 3 ring carbon atoms) or bicyclo[1.1.1]pentanyl (having 5 ring carbon atoms). One or more ring atoms of a cycloalkyl group can be substituted (i.e., bonded) by a heteroatom via a double bond (e.g., an oxo-substituted cycloalkyl group). The presence of such substituents does not prevent the carbon skeleton of the free radical from being considered a cycloalkyl group.

[0041] As used herein, the term “aryl” means an aromatic free radical having at least six carbon atoms (i.e., ring atoms) forming a ring. It will be understood that aryl groups can be monocyclic or polycyclic (e.g., fusion). In the case of polycyclic aryl groups, there are further rings, e.g., one or more further rings, all containing at least three carbon atoms (i.e., ring atoms). The further rings may also contain one or more heteroatoms, which may be saturated, unsaturated, or aromatic. Polycyclic aryl groups are typically bonded to the rest of the molecule via an aromatic ring and not typically via a ring containing heteroatoms. In embodiments, polycyclic aryl groups do not contain ring heteroatoms. Examples of aryl groups include the phenyl and naphthalenyl groups, as well as the indenyl and indanyl groups. Other aryl groups include, for example, tetrahydroisoquinolinyl, which is bonded to the rest of the molecule via its phenyl ring. (C6~C 10 The term "aryl" indicates that the aryl group contains 6 to 10 carbon atoms in the ring portion of the group, which can be monocyclic or polycyclic (e.g., fusion), and can be, for example, phenyl (having 6 ring carbon atoms) or indanyl (having 9 ring carbon atoms). In embodiments, (C6~C 10 ) Aryl is phenyl.

[0042] As used herein, the term “heterocycloalkyl” means a saturated free radical having at least 3 to 10 atoms (i.e., ring atoms) forming a ring, where at least 1 to 9 of the ring atoms are carbon, and the remaining at least 1 to 9 ring atoms (i.e., heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen. In embodiments, the heterocyclic atoms are independently selected from the group consisting of nitrogen and oxygen. For example, the term “4-10 membered heterocycloalkyl” means a saturated free radical containing 4 to 10 ring atoms, one or more of which are heterocyclic atoms. Heterocycloalkyl rings typically have oxo substituents adjacent to the heteroatoms (e.g., 2-oxopyrrolidinyl), but oxygen atoms do not form part of the ring and are excluded from the number of ring atoms. The presence of such substituents does not prevent the ring (or more rings) of the free radical from being considered a heterocycloalkyl group. Exemplary heterocycloalkyl groups include tetrahydrofuranil, piperidinyl, morpholinil, and piperazinyl. Any ring sulfur atom can optionally support one or more pendant (i.e., non-ring) oxygen atoms, as seen, for example, in sulforanyl groups. In the case of polycyclic heterocyclic groups, there are further rings, e.g., one or more rings, all containing 3 to 7 ring atoms selected from carbon, nitrogen, sulfur, and oxygen. The further rings may be saturated or partially or completely unsaturated (e.g., having aromatic properties). Examples of polycyclic heterocyclic groups include fusion, bridging, and spirocyclic ring systems. When a polycyclic heterocycloalkyl group contains an unsaturated fusion ring, the group typically does not bond to the rest of the molecule via its fusion ring. Exemplary polycyclic heterocyclic groups include 2-oxa-6-azaspiro[3.3]heptane, 3,6-diazabicyclo[3.2.0]heptane, 2,6-diazabicyclo[3.2.0]heptane, and octahydropyrrolo[1,2-a]pyrazine. When a heterocycloalkyl group is described as having "X~Y members" (where X and Y are integers), this means that the heterocycloalkyl group contains a total number of ring atoms from X to Y.Therefore, for example, a "4- to 7-membered heterocycloalkyl group" contains a total of 4, 5, 6, or 7 ring atoms, such as tetrahydropyranyl (6 ring atoms).

[0043] As used herein, the term “heteroaryl” typically refers to an aromatic (i.e., aromatic) free radical containing 5 to 10 ring atoms, where 1 to 9 of the ring atoms are carbon, and the remaining 1 to 9 ring atoms (i.e., heterocyclic atoms) are independently selected from the group consisting of nitrogen, sulfur, and oxygen. In embodiments, the heterocyclic atoms are selected from nitrogen and sulfur. It should be understood that heteroaryl groups can be monocyclic or polycyclic (e.g., fusion). In the case of polycyclic heteroaryl groups, there may be further rings, e.g., one or more further rings, all of which contain at least three atoms (i.e., ring atoms), and the further rings may optionally be aromatic. Examples of heteroaryl groups include monocyclic groups such as pyridyl, and polycyclic groups such as 2-oxopyridinyl and indolyl. When a heteroaryl group is described as “X-Y member,” this means that the heteroaryl group contains a total of X to Y ring atoms. Therefore, for example, a "5- to 10-membered heteroaryl group" contains a total of 5, 6, 7, 8, 9, or 10 ring atoms, such as indolyl (9 ring atoms). In embodiments, the 5- to 10-membered heteroaryl is 4,5,6,7-tetrahydrothieno[3,2-c]pyridine.

[0044] As used herein, the terms “halo” and “halogen” mean fluorine, chlorine, bromine, or iodine. These terms are used interchangeably and may refer to a halogen-free radical group or such halogen atom. Those skilled in the art will be able to readily confirm their distinction by considering the context in which these terms are used in this disclosure. In embodiments, halogens are selected from fluorine and bromine, for example, fluorine.

[0045] As used herein, the term "oxo" refers to a free radical in which an oxygen atom is connected to the atom having this radical via a double bond. For example, when a carbon atom supports an oxo radical, it forms a carbon-oxygen double bond. It will be understood that not all atoms in a given structure can be substituted with an oxo, and this depends on the free valence of the atom being substituted.

[0046] The compounds of this disclosure are described in particular by their structural formulas. These formulas typically represent only one form of the compound (e.g., a resonance form, a tautomer form, etc.), but it will be understood that certain compounds may exist in multiple such forms. This will be readily apparent to an experienced reader. This disclosure includes all possible tautomers of the compounds characterized by the preceding and following structural formulas, either as a single tautomer or as any mixture of tautomers in any ratio. For example, the pyridoimidazolon moiety (which may be called 3H-imidazo[4,5-b]pyridine-2-one or 3H-imidazo[4,5-b]pyridine-2-ol, as shown in formula (I)) may be represented by any of the following tautomer forms, which are used interchangeably throughout this specification: [ka]

[0047] It should be understood that certain compounds may exist in one or more isomeric (e.g., stereoisomeric) forms. This disclosure includes all possible stereoisomers, enantiomers, diastereomers, etc., of the compounds described above and below, as well as their cis and trans forms and conformations. Purification and separation of isomers can be achieved by the methods described below and by techniques known in the art. For example, optical isomers of a compound can be obtained by degrading a racemic mixture of its diastereoisomer salts (e.g., by using optically active acids or bases, or by forming covalent diastereomers). Different processes for the separation of optical isomers include the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatization. Enzymatic separation may also be useful, with or without derivatization, and the optically active compounds of this disclosure can similarly be obtained by chiral synthesis utilizing optically active starting materials. This disclosure includes all possible stereoisomers of the compounds described herein, either as single stereoisomers or in any mixture of the stereoisomers, for example, as (R)- or (S)-isomers, in any proportion.

[0048] The compounds of this disclosure may exist in the form of free acids or bases, or as addition salts having a suitable acid or base. For example, the basic compound of formula (I) may be provided as a pharmaceutically acceptable acid addition salt having an acid such as HCl, TFA, or formic acid (e.g., TFA). Methods for forming the salts are described below and are known in the art (e.g., Berge et al., J Pharm Sci. (1977) 66:1-19).

[0049] As used herein, the term “pharmaceutically acceptable” in relation to salts means salts of the compounds of this disclosure that can be administered without causing any substantially undesirable biological effects or consequently harmful interactions with any other components of a pharmaceutical composition in which they may be included.

[0050] A group defined as "optionally substituted" may be unsubstituted or substituted with one or more substituents, e.g., one, two, three, four, five, six or more substituents. In embodiments, the substituent has one to four substituents, e.g., one, two, or three substituents. In embodiments, the substituent has one or two substituents. In embodiments, the substituent has three substituents.

[0051] Any reference to a list of chemical groups in any definition of a variable herein includes the definition of that variable as any single group or as a combination of the listed groups. Any enumeration of embodiments relating to a variable or aspect herein includes this embodiment as any single embodiment or in combination with any other embodiment or part thereof.

[0052] The compositions and methods provided herein can be combined with one or more of the other compositions and methods provided herein.

[0053] The following abbreviations and experimentally based formulas are used herein. ABC Ammonium Bicarbonate Acetyl ACN (Acetonitrile (MeCN)) ATP (Adenosine Triphosphate) Boc tert-butyloxycarbonyl CDI 1,1'-Carbonyldiimidazole DAD Diode Array Detection DCM Dichloromethane DHP (Dihydropyran) DIPEA Diisopropylethylamine DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) 4EBP1 Eukaryotic translation initiation factor 4E binding protein 1 ERK extracellular signal-regulating kinase ELISA / AcOEt Ethyl acetate (also known as EA) FRET Forster Resonance Energy Transfer HATU Hexafluorophosphorate azabenzotriazole tetramethyluronium HPLC (High-Performance Liquid Chromatography) Ir[dF(CF3)ppy]2(dtbpy))PF6[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate LC / MS Liquid Chromatography / Mass Spectrometry LED Light Emitting Diode LiHMDS (Lithium Bis(Trimethylsilyl)amide) min MS mass spectrometry OBD Optimal floor density Pd / C Palladium Carbon PdG2SPhos Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (also known as SPhosPdG2) Pd(OAc)2 Palladium(II) Diacetate Pin = Pinacol (for example, B2Pin2 = Bis(pinacolate)diboron) PPTS Pyridinium p-toluenesulfonate rac racemic mixture RPMI Roswell Park Memorial Laboratory Culture Media RuPhos 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl TAD transcriptional activation domain TATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium Tetrafluoroborate TBAF Tetrabutylammonium Fluoride TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminiumtetrafluoroborate TEA (Triethylamine) TFA (Trifluoroacetic Acid) THF (Tetrahydrofuran) UPLC Ultra-High-Speed ​​Liquid Chromatography UV ultraviolet light Xphos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl XPhosPdG4 Methanesulfonate (2-dicyclohexylphosphinol-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II); CAS Registry Number 1599466-81-5

[0054] compound In a first embodiment, this disclosure relates to formula (NI) [ka] [In the formula, R 1 R is selected from halo, -(C1~C6)alkyl, -(C3~C7)cycloalkyl, 4~10-membered heterocycloalkyl, and 5~10-membered heteroaryl. 1 is, R A It is optionally replaced by one or more occurrences of Each R A The group is independently selected from halo, -OH, oxo, =N-OH, -(C1~C3)alkyl, and -O(C1~C3)alkyl, and each occurrence of -(C1~C3)alkyl is optionally substituted with one or more groups independently selected from halo and -OH. And / or R A The two appearances, together with the atom to which they are bonded, can form a (C3-C6) cycloalkyl group or a 3-6 membered heterocyclic group, and the cycloalkyl or heterocyclic group can be optionally substituted with one or more halos. L 1 It is selected from direct bonds, -O-, and -CH2-. R 2 is, -(C6~C 10) is aryl, R 2 is, R B It is optionally substituted by one or two occurrences. Each R B The elements are independently selected from -OH, -NH2, -SF5, -NHC(O)OC(CH3)3, and -O(C1~C3)alkyl, and each occurrence of -O(C1~C3)alkyl is optionally substituted with one or more halos. R 3 These are selected from -H, -OH, and -(C1~C3)alkyl groups. The present invention provides a compound or a pharmaceutically acceptable salt thereof in which n is 0 or 1.

[0055] In the embodiment, the compound is a compound of formula (NI) or a pharmaceutically acceptable salt thereof, where, R 1 R is selected from halo, -(C1~C6)alkyl, -(C3~C7)cycloalkyl, and 4~10 member heterocycloalkyl. 1 is, R A It is optionally replaced by one or more occurrences of Each R A The group is independently selected from halo, -OH, oxo, =N-OH, -(C1~C3)alkyl, and -O(C1~C3)alkyl, and each occurrence of -(C1~C3)alkyl is optionally substituted with one or more groups independently selected from halo and -OH. And / or R A The two appearances, together with the atom to which they are bonded, can form a (C3-C6) cycloalkyl group or a 3-6 membered heterocyclic group, and the cycloalkyl or heterocyclic group can be optionally substituted with one or more halos. L 1 It is selected from direct bonds, -O-, and -CH2-. R 2 is, -(C6~C 10 ) is aryl, R 2 is, R B It is optionally substituted by one or two occurrences. Each R Bis independently selected from -OH, -NH2, -SF5, -NHC(O)OC(CH3)3, and -O(C1-C3)alkyl, and each occurrence of -O(C1-C3)alkyl is optionally substituted with one or more halos, R 3 is selected from -H and -(C1-C3)alkyl, n is 0 or 1.

[0056] In another aspect, the present disclosure provides a compound of formula (I) [Chemical formula] [wherein, R 1 is selected from -(C1-C6)alkyl, -(C3-C7)cycloalkyl, 4-10 member heterocycloalkyl, and 5-10 member heteroaryl, and R 1 is optionally substituted at one or more occurrences of R A , each R A is independently selected from halo, -OH, -(C1-C3)alkyl, and -O(C1-C3)alkyl, and each occurrence of -(C1-C3)alkyl is optionally substituted with one or more groups independently selected from halo and -OH, and / or two occurrences of R A may combine with the atoms to which they are attached to form a (C3-C6)cycloalkyl group or a 3-6 member heterocyclic group, L 1 is selected from a direct bond and -O-, R 2 is -(C6-C 10 )aryl, and R 2 is optionally substituted at one or two occurrences of R B , each R B is independently selected from -OH, -NH2, -SF5, and -O(C1-C3)alkyl, and each occurrence of -O(C1-C3)alkyl is optionally substituted with one or more halos, n is 0 or 1], or a pharmaceutically acceptable salt thereof.

[0057] In an embodiment, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from -(C1-C6)alkyl, -(C3-C7)cycloalkyl, and 4-10 member heterocycloalkyl, and R 1 is optionally substituted at one or more occurrences of R A ; each R A is independently selected from halo, -OH, -(C1-C3)alkyl, and -O(C1-C3)alkyl, and each occurrence of -(C1-C3)alkyl is optionally substituted with one or more groups independently selected from halo and -OH; and / or two occurrences of R A may together with the atoms to which they are attached form a (C3-C6)cycloalkyl group or a 3-6 member heterocyclic group; L 1 is selected from a direct bond and -O-; R 2 is -(C6-C 10 )aryl, and R 2 is optionally substituted at one or two occurrences of R B ; each R B is independently selected from -OH, -NH2, -SF5, and -O(C1-C3)alkyl, and each occurrence of -O(C1-C3)alkyl is optionally substituted with one or more halos; n is 0 or 1.

[0058] In an embodiment, R 1 is selected from -(C1-C6)alkyl, -(C3-C7)cycloalkyl, and 4-10 member heterocycloalkyl, and R 1 is optionally substituted at one or more occurrences of R A as defined herein.

[0059] In an embodiment, R 1is selected from halo (e.g., -Br), -(C1-C3)alkyl, -(C3-C7)cycloalkyl, and 4-7 member heterocycloalkyl, R 1 is optionally substituted in one or more occurrences of R as defined herein, and in embodiments, R A is optionally substituted in one or more occurrences of R, and in embodiments, R 1 is optionally substituted in one or more occurrences of R, and in embodiments, R A is optionally substituted in one or more occurrences of R, and each R A is independently selected from halo (e.g., -F), -OH, -(C1-C2)alkyl, and -OCH3, and each occurrence of -(C1-C2)alkyl is optionally substituted with one or more (e.g., one, two, or three) groups independently selected from -F and -OH; and / or two occurrences of R A may together with the atoms to which they are attached form a (C3-C6)cycloalkyl group (e.g., cyclopropyl or cyclohexyl) or a six-membered heterocycloalkyl group containing one nitrogen or oxygen ring atom (e.g., tetrahydropyran or piperidine). In embodiments, the (C3-C6)cycloalkyl group or six-membered heterocyclic group formed by two occurrences of R A and the atoms to which they are attached are fused or bridged and attached to R 1 . In embodiments, the six-membered heterocyclic group is a six-membered heterocycloalkyl group.

[0060] In embodiments, R 1 is selected from -(C1-C3)alkyl, -(C4-C6)cycloalkyl, 5-9 member heterocycloalkyl (e.g., 5-7 member heterocycloalkyl, or 5-6 member heterocycloalkyl), and 5-9 member heteroaryl (e.g., 5-member heteroaryl, or 9-member heteroaryl), and R 1 is optionally substituted in one or more occurrences of R as defined herein. In embodiments, R A is optionally substituted in one or more occurrences of R, and in embodiments, R 1 is optionally substituted in one or more occurrences of R, and in embodiments, R A is optionally substituted in one or more occurrences of R, and each R Ais independently selected from halo (e.g., -F), -OH, -(C1~C2)alkyl, and -OCH3, and each occurrence of -(C1~C2)alkyl is optionally substituted with one or more (e.g., one or three) groups independently selected from -F and -OH; and / or R A The two appearances, together with the atom to which they are bonded, can form a 4- to 6-membered heterocycloalkyl group containing a cyclopentanyl group or one nitrogen or oxygen ring atom (e.g., oxetane, azetidine, pyrrolidine, or tetrahydropyridine).

[0061] In this embodiment, R 1 This is a non-substitution.

[0062] In other embodiments, R 1 R as defined herein A It is replaced by one or two occurrences of R. In the embodiment, R 1 is, R A It is replaced by one occurrence of R. In the embodiment, R 1 is, R A It is replaced by two occurrences. In the embodiment, each R A The group is independently selected from halo (e.g., -F), -OH, -(C1~C3)alkyl, and -OCH3, and each occurrence of -(C1~C3)alkyl is optionally substituted with one or more groups independently selected from halo (e.g., -F) and -OH.

[0063] In this embodiment, R 1 R as defined herein A It is replaced by one, two, or three occurrences of R. In the embodiment, R 1 is, R A It is replaced by two or three occurrences of R. In the embodiment, R 1 is, R A It is replaced by these three occurrences.

[0064] In this embodiment, R AThe two appearances, together with the atom to which they are bonded, form a (C3-C6) cycloalkyl group or a 3-6 member heterocyclic group, and the cycloalkyl or heterocyclic group is optionally substituted with one or more halos. In the embodiment, the 3-6 member heterocyclic group is a 3-6 member heterocycloalkyl group.

[0065] In this embodiment, R 1 teeth, [ka] Selected from, R 1 R as defined herein A It is optionally replaced by one or more occurrences of . In the embodiment, each R A R is independently selected from the group consisting of a halo (e.g., -F), -OH, -(C1-C3)alkyl (e.g., methyl or ethyl), and -OCH3, and each appearance of -(C1-C3)alkyl may be optionally substituted with one or more substituents selected from a halo (e.g., -F) and -OH. In embodiments, R 1 is, R A It is optionally substituted by one or two occurrences, and each R A The substituent is independently selected from the group consisting of a halo (e.g., -F), -OH, -(C1-C3)alkyl (e.g., methyl or ethyl), and -OCH3, and each occurrence of the -(C1-C3)alkyl molecule may be optionally substituted with one or more substituents selected from the halo (e.g., -F) and -OH.

[0066] In this embodiment, R 1 teeth, [ka] Selected from, R 1 R as defined herein A It is optionally replaced by one or more occurrences of . In the embodiment, each R Ais independently selected from the group consisting of halo (e.g., -F), -OH, -(C1-C3) alkyl (e.g., methyl or ethyl), and -OCH3, and each occurrence of -(C1-C3) alkyl may be optionally substituted with one or more substituents selected from halo and -OH.

[0067] In an embodiment, R 1 is

Chemical Formula

[0068] In an embodiment, R 1 is

Chemical Formula

[0069] In an embodiment, R 1 is

Chemical Formula

[0070] In an embodiment, R 1 is

Chemical Formula

[0071] In this embodiment, R 1 The heterocycloalkyl group is a 5-6 member heterocycloalkyl group, and the heterocycloalkyl group comprises one or two atoms independently selected from O and N, and the heterocycloalkyl group is R as defined herein. A It is optionally and independently replaced by one or more occurrences of R. In the embodiment, each R A The group is selected independently from -CH2OH and -CH3.

[0072] In this embodiment, R 1 teeth, [ka] Selected from.

[0073] In this embodiment, R 1 teeth, [ka] Selected from.

[0074] In this embodiment, R 1 It is a polycyclic (e.g., bicyclic)-(C5~C7) cycloalkyl, and R 1 is, R A It is optionally replaced by one or more occurrences of R. In the embodiment, R 1 R is a spiro, crosslinked, or fusion-(C5~C7) cycloalkyl, 1 is, R A It is optionally replaced by one or more occurrences of .

[0075] In this embodiment, R 1 R is a 6-10 membered polycyclic (e.g., bicyclic) heterocycloalkyl or a 7-10 membered polycyclic (e.g., bicyclic) heteroaryl, 1 R as defined herein A It is optionally replaced by one or more occurrences of .

[0076] In this embodiment, R 1 R as defined hereinA It is a 6-10 member polycyclic (e.g., bicyclic) heterocycloalkyl that is optionally substituted with one or more occurrences of . In embodiments, R 1 is, R A It is a 7- to 9-membered polycyclic (e.g., bicyclic) heterocycloalkyl that is optionally substituted with one or more of the occurrences of . In embodiments, R 1 R is a 7-9 membered bicyclic heterocycloalkyl containing one or two (e.g., two) heterocyclic atoms selected from nitrogen and oxygen, 1 is R A It is optionally replaced by one or more occurrences of R. In the embodiment, R 1 It is a 7-9 membered bicyclic heterocycloalkyl containing two nitrogen ring atoms, and R 1 is, R A It is optionally replaced by one or more occurrences of .

[0077] In this embodiment, R 1 R as defined herein A It is a 7-10 member polycyclic (e.g., bicyclic) heteroaryl that is optionally substituted by one or more occurrences of . In embodiments, R 1 is, R A It is an 8- to 9-member (e.g., 9-member) polycyclic (e.g., bicyclic) heteroaryl which is optionally substituted by one or more occurrences of . In embodiments, R 1 It is an unsubstituted 9-membered bicyclic heteroaryl.

[0078] In this embodiment, R 2 is, R B It is a phenyl substituted with the appearance of one or two of the following. In embodiments, R 2 is, R B It is replaced by one occurrence of -(C6~C 10 ) is an arrow. In this embodiment, R 2 is, R B It is a phenyl that is substituted with one appearance of R. In an embodiment, R 2 is, R B It is replaced by the two occurrences of -(C6~C 10 ) These are aryl (for example, phenyl).

[0079] Control mechanism, each R B R is independently selected from -OH, -NH2, -NHC(O)OC(CH3)3, -SF5, and -OCF3. In the embodiment, each R B R is independently selected from -OH, -NH2, -SF5, and -OCF3. In the embodiment, R 2 is, R B It is replaced by two occurrences, and each R B It is selected independently from -OH, -NH2, -SF5, and -OCF3.

[0080] In this embodiment, R B At least one occurrence of is -SF5. In an embodiment, R B One occurrence of is -SF5. In the embodiment, R 2 is, R B It is replaced by one occurrence of R B is -SF5. In this embodiment, R 2 is, R B It is replaced by two occurrences, R B One occurrence of is -SF5, and R B Other occurrences are selected from -OH and -NH2.

[0081] In this embodiment, R 2 is, R B A phenyl substituted with one or two of the following, each R B R is independently selected from -OH, -NH2, -SF5, and -OCF3. In the embodiment, R 2 is, R B Phenyl is substituted with two appearances of each R B R is independently selected from -OH, -NH2, -SF5, and -OCF3. In the embodiment, R 2 is, R B It is a phenyl substituted with one appearance of R B This is selected from -SF5 and -OCF3. In the embodiment, R 2 is, R B It is a phenyl substituted with two appearances of and one RB It is selected independently from -SF5 and -OCF3, R B Other occurrences are selected from -OH and -NH2.

[0082] In this embodiment, R 2 is, R B A phenyl substituted with one or two occurrences of R B At least one occurrence of is -SF5. In an embodiment, R 2 is, R B A phenyl substituted with one or two occurrences of R B One occurrence of is -SF5. In the embodiment, R 2 is, R B A phenyl substituted with one or two occurrences of R B One occurrence of is -SF5, R B Other occurrences (if any) are selected from -OH and -NH2. In the embodiment, R 2 is, R B It is a phenyl substituted with two appearances of R B One occurrence of is -SF5, R B Other occurrences are selected from -OH and -NH2. In the embodiment, R 2 is, R B It is a phenyl substituted with one appearance of R B It is -SF5.

[0083] In this embodiment, R 2 teeth, [ka] Selected from. In this embodiment, R 2 teeth, [ka] Selected from.

[0084] In this embodiment, R 3 is -CH3 or -H. In the embodiment, R 3 is -CH3. In the embodiment, R 3It is -H.

[0085] In this embodiment, L 1 In other embodiments, L 1 is -O-. In other embodiments, L 1 is -CH2-. In this embodiment, the present disclosure relates to formula (N-IA), formula (N-IB), or formula (N-IC) [ka] [In the formula, R 1 , R 2 , R 3 The present invention provides compounds of formula (N-IA) or pharmaceutically acceptable salts thereof, where n is as defined herein. In one embodiment, the compound is a compound of formula (N-IA) or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is a compound of formula (N-IB) or a pharmaceutically acceptable salt thereof. In yet another embodiment, the compound is a compound of formula (N-IC) or a pharmaceutically acceptable salt thereof.

[0086] In the embodiment of formula (I), L 1 This is a direct bond. In other embodiments of formula (I), L 1 is -O-. In this aspect, the present disclosure is formula (IA) or formula (IB) [ka] [In the formula, R 1 , R 2 The present invention provides compounds of formula (IA) or pharmaceutically acceptable salts thereof, where n is as defined herein. In some embodiments, the compound is a compound of formula (IA) or a pharmaceutically acceptable salt thereof. In other embodiments, the compound is a compound of formula (IB) or a pharmaceutically acceptable salt thereof.

[0087] In other embodiments of formula (I), L 1 is -CH2-. In this aspect, the present disclosure is based on formula (IC) [ka] [In the formula, R 1 , R 2 The present invention provides compounds of [, and n as defined herein] or pharmaceutically acceptable salts thereof.

[0088] In this embodiment, n is 1.

[0089] In other embodiments, n is 0. In this embodiment, the present disclosure is based on the formula (N-ID) [ka] [In the formula, R 1 , R 2 , R 3 , and L 1 This provides compounds of [as defined herein] or pharmaceutically acceptable salts thereof.

[0090] In the embodiment of formula (I), n is 0. In this embodiment, the present disclosure is equivalent to formula (ID) [ka] [In the formula, R 1 , R 2 , and L 1 This provides compounds of [as defined herein] or pharmaceutically acceptable salts thereof.

[0091] In another embodiment, the compound is of formula (N-II) [ka] [In the formula, R 1 , R 3 , and L 1 R is defined herein as follows: B1 and R B2 R as defined herein B The present invention provides compounds of [independently selected from] or pharmaceutically acceptable salts thereof.

[0092] In the embodiment, the compound is a compound of formula (N-II) or a pharmaceutically acceptable salt thereof, where, R 1 R is selected from halo (e.g., -Br), -(C1~C6)alkyl, -(C3~C7)cycloalkyl, and 4~10 member heterocycloalkyl, 1 is, R A It is optionally replaced by one or more occurrences of Each R A This is independently selected from halo (e.g., -F), -OH, oxo, =N-OH, -O(C1~C3)alkyl, and -(C1~C3)alkyl groups that are optionally substituted with one or more groups independently selected from halo (e.g., -F) and -OH. And / or R A The two appearances, together with the atom to which they are bonded, can form a (C3-C6) cycloalkyl group or a 3-6 member heterocycloalkyl group, and the cycloalkyl group is optionally substituted with -F. L 1 It is selected from direct bonds, -O-, and -CH2-. R B1 It is selected from -H, -OH, -NH2, and -NHC(O)OC(CH3)3, R B2 The option is selected from -SF5 and -OCF3. R 3 The group is selected from -H and -(C1~C3)alkyl groups (e.g., -CH3).

[0093] In another embodiment, the compound is given by formula (II) [ka] [In the formula, R 1 R is selected from halo (e.g., -Br), -(C1~C6)alkyl, -(C3~C7)cycloalkyl, and 4~10 member heterocycloalkyl, 1 is, R A It is optionally replaced by one or more occurrences of Each R AThis is independently selected from halo (e.g., -F), -OH, oxo, =N-OH, -O(C1~C3)alkyl, and -(C1~C3)alkyl groups that are optionally substituted with one or more groups independently selected from halo (e.g., -F) and -OH. And / or R A The two appearances, together with the atom to which they are bonded, can form a (C3-C6) cycloalkyl group or a 3-6 member heterocycloalkyl group, and the cycloalkyl group is optionally substituted with -F. L 1 It is selected from direct bonds, -O-, and -CH2-. R B1 It is selected from -H, -OH, -NH2, and -NHC(O)OC(CH3)3, R B2 [is selected from -SF5 and -OCF3] or a pharmaceutically acceptable salt thereof.

[0094] In this embodiment, the compound is of formula (II) [wherein, R 1 R is selected from -(C3~C7) cycloalkyl and 4~10 member heterocycloalkyl groups. 1 is, R A It is optionally replaced by one or more occurrences of Each R A These are independently -(C1~C3)alkyl groups that are optionally substituted with -OH groups. L 1 It is selected from direct bonding and -O-, R B1 It is selected from -H, -OH, and -NH2. R B2 [is selected from -SF5 and -OCF3] or a pharmaceutically acceptable salt thereof.

[0095] In this embodiment, R 1 is a -(C4~C7) cycloalkyl or a 4~7 member heterocycloalkyl (e.g., a 4~6 member heterocycloalkyl), and R 1 is, R AIt is optionally replaced by one or more occurrences of . In the embodiment, each R A It is independently selected from -F, -OH, oxo, =N-OH, -CH3, -CHF2, -CF3, -CH2OH, -CH2CF3, and -OCH3.

[0096] In this embodiment, R 1 It is a polycyclic (e.g., bicyclic)-(C5~C7) cycloalkyl, and R 1 is, R A It is optionally replaced by one or more occurrences of R. In the embodiment, R 1 These are spiro, crosslinked, or fusion-(C5~C7)cycloalkyl groups.

[0097] In this embodiment, R 1 R is a 6-10 member polycyclic (e.g., bicyclic) heterocycloalkyl, 1 R as defined herein A It is optionally replaced by one or more occurrences of R. In the embodiment, R 1 is a 6-8 membered polycyclic (e.g., bicyclic) heterocycloalkyl. In the embodiment, R 1 It is a 7-membered polycyclic (e.g., bicyclic) heterocycloalkyl.

[0098] In this embodiment, R 1 is a 4-7 membered heterocycloalkyl (e.g., a 4-6 membered heterocycloalkyl), where the heterocycloalkyl contains one or two ring heteroatoms independently selected from O and N, and the heterocycloalkyl is R A It is optionally and independently substituted by one or more occurrences of R. In the embodiment, each R A The group is independently selected from oxo, -CH3, -CH2OH, and -CH2CF3.

[0099] In this embodiment, R 1 The heterocycloalkyl group is a 5-6 member heterocycloalkyl group, and the heterocycloalkyl group contains one or two ring heteroatoms independently selected from O and N, and the heterocycloalkyl group is R AIt is optionally and independently substituted by one or more occurrences of R. In the embodiment, each R A The group is selected independently from -CH2OH and -CH3.

[0100] In this embodiment, R 1 teeth, [ka] Selected from, R 1 is, R A It is arbitrarily substituted by one occurrence of R A This is a methyl group that is optionally substituted with an -OH group.

[0101] In this embodiment, R 1 teeth, [ka] Selected from.

[0102] In this embodiment, R B1 is -H. In this embodiment, R B1 R is selected from -OH and -NH2. In the embodiment, R B1 is -OH. In the embodiment, R B1 It is -NH2.

[0103] In this embodiment, R B2 is -SF5. In this embodiment, R B2 It is -OCF3.

[0104] In this embodiment, R B1 is -H, and R B2 is -SF5. In this embodiment, R B1 is -NH2, and R B2 is -SF5. In this embodiment, R B1 is -H, and R B2 is -OCF3. In the embodiment, R B1 is -OH, and R B2 is -OCF3. In the embodiment, R B1 is -NH2, and R B2is -OCF3. In the embodiment, R B1 It is -NHC(O)OC(CH3)3, and R B2 It is -OCF3.

[0105] In this embodiment, L 1 In other embodiments, L 1 is -O-. In another embodiment, L 1 is -CH2-. In this aspect, the present disclosure relates to formula (N-IIA), formula (N-IIB), or formula (N-IIC) [ka] [In the formula, R 1 , R 3 , R B1 , and R B2 The present invention provides compounds of formula (N-IIA) or pharmaceutically acceptable salts thereof, as defined herein. In one embodiment, the compound is a compound of formula (N-IIB) or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is a compound of formula (N-IIC) or a pharmaceutically acceptable salt thereof.

[0106] In the embodiment of formula (II), L 1 This is a direct bond. In other embodiments of formula (II), L 1 is -O-. In this aspect, the present disclosure is formula (II-A) or formula (II-B) [ka] [In the formula, R 1 , R B1 , and R B2 This provides compounds of [as defined herein] or pharmaceutically acceptable salts thereof.

[0107] In the embodiment, the compound is of formula (II-A) or formula (II-B) [wherein, R 1R is selected from -(C3~C7) cycloalkyl and 4~10 member heterocycloalkyl groups. 1 is, R A It is optionally replaced by one or more occurrences of Each R A These are independently -(C1~C3)alkyl groups that are optionally substituted with -OH groups. R B1 It is selected from -H, -OH, and -NH2. R B2 [is selected from -SF5 and -OCF3] or a pharmaceutically acceptable salt thereof.

[0108] In one embodiment, the compound is the compound of formula (II-A) or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is the compound of formula (II-B) or a pharmaceutically acceptable salt thereof.

[0109] In other embodiments of formula (II), L 1 is -CH2-. In this embodiment, the present disclosure is formula (II-C) [ka] [In the formula, R 1 , R B1 , and R B2 This provides compounds of [as defined herein] or pharmaceutically acceptable salts thereof.

[0110] In the embodiment, the compound is of formula (III) or formula (IV) [ka] [In the formula, R 1 and L 1 This provides compounds of [as defined herein] or pharmaceutically acceptable salts thereof.

[0111] In the embodiment, the compound is a compound of formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein, R 1R is selected from halo (e.g., -Br), -(C1~C6)alkyl, -(C3~C7)cycloalkyl, and 4~10 member heterocycloalkyl, 1 is, R A It is optionally replaced by one or more occurrences of Each R A These are independently selected from halo (e.g., -F), -OH, oxo, -O(C1~C3)alkyl, and -(C1~C3)alkyl groups optionally substituted with -OH. L 1 The bond is selected from direct bonds, -O-, and -CH2-.

[0112] In the embodiment, the compound is a compound of formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein, R 1 R is selected from -(C3~C7) cycloalkyl and 4~10 member heterocycloalkyl groups. 1 is, R A It is optionally replaced by one or more occurrences of Each R A These are independently -(C1~C3)alkyl groups that are optionally substituted with -OH groups. L 1 The choice is made between direct bonding and -O-bonding.

[0113] In one embodiment, the compound is the compound of formula (III) or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is the compound of formula (IV) or a pharmaceutically acceptable salt thereof.

[0114] In the embodiment, the compound is the compound of formula (III) or a pharmaceutically acceptable salt thereof, L 1 In other embodiments, the compound is the compound of formula (III) or a pharmaceutically acceptable salt thereof, L 1 is -O-. In this aspect, the present disclosure is formula (III-A) or formula (III-B) [ka] [In the formula, R1 This provides compounds of [as defined herein] or pharmaceutically acceptable salts thereof.

[0115] In the embodiment, the compound is a compound of formula (III-A) or formula (III-B) or a pharmaceutically acceptable salt thereof, R 1 R is selected from -(C3~C7) cycloalkyl and 4~10 member heterocycloalkyl groups. 1 is, R A It is arbitrarily substituted by one or more occurrences of each R A These are independently -(C1~C3)alkyl groups that are optionally substituted with -OH groups.

[0116] In one embodiment, the compound is the compound of formula (III-A) or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is the compound of formula (III-B) or a pharmaceutically acceptable salt thereof.

[0117] In this embodiment, the compound is of formula (N-IV) [ka] [In the formula, R 1 , R 3 , and L 1 [is defined herein] a compound of or a pharmaceutically acceptable salt thereof.

[0118] In the embodiment, the compound is a compound of formula (N-IV) or a pharmaceutically acceptable salt thereof, where, R 1 R is selected from -(C1~C6)alkyl, -(C3~C7)cycloalkyl, and 4~10 member heterocycloalkyl, 1 is, R A It is optionally replaced by one or more occurrences of Each R A This is independently selected from halo(e.g., -F)-OH, oxo, -O(C1~C3)alkyl, and -(C1~C3)alkyl groups optionally substituted with one, two, or three groups independently selected from -F and -OH. R 3 is -H or -(C1~C3)alkyl, L 1 The bond is selected from direct bonds, -O-, and -CH2-.

[0119] In this embodiment, L 1 This is a direct bond.

[0120] In the embodiment, the compound is the compound of formula (IV) or a pharmaceutically acceptable salt thereof, L 1 In other embodiments, the compound is the compound of formula (IV) or a pharmaceutically acceptable salt thereof, L 1 is -O-. In this aspect, the present disclosure is formula (IV-A) or formula (IV-B) [ka] [In the formula, R 1 This provides compounds of [as defined herein] or pharmaceutically acceptable salts thereof.

[0121] In the embodiment, the compound is a compound of formula (IV-A) or formula (IV-B) or a pharmaceutically acceptable salt thereof, R 1 R is selected from -(C3~C7) cycloalkyl and 4~10 member heterocycloalkyl groups. 1 is, R A It is arbitrarily substituted by one or more occurrences of each R A These are independently -(C1~C3)alkyl groups that are optionally substituted with -OH groups.

[0122] In other embodiments, the compound is the compound of formula (IV) or a pharmaceutically acceptable salt thereof, L 1 is -CH2-. In this aspect, the present disclosure is formula (IV-C) [ka] [In the formula, R 1This provides compounds of [as defined herein] or pharmaceutically acceptable salts thereof.

[0123] In the embodiment, the compound is the compound of formula (IV-C) or a pharmaceutically acceptable salt thereof, R 1 R is selected from -(C1~C3)alkyl and 4~6 member heterocycloalkyl groups. 1 is, R A It is optionally replaced by one or more occurrences of . In the embodiment, each R A These are independently -O(C1~C3) alkyl groups.

[0124] In one embodiment, the compound is the compound of formula (IV-A) or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is the compound of formula (IV-B) or a pharmaceutically acceptable salt thereof.

[0125] In this embodiment, the compound is of formula (V), formula (VI), or formula (VII) [ka] [In the formula, R 1 R is selected from -(C3~C7) cycloalkyl and 4~10 member heterocycloalkyl groups. 1 is, R A It is arbitrarily substituted by one or more occurrences of each R A [is independently a compound of a -(C1~C3) alkyl group that is optionally substituted with an -OH group] or a pharmaceutically acceptable salt thereof.

[0126] In one embodiment, the compound is the compound of formula (V) or a pharmaceutically acceptable salt thereof. In another embodiment, the compound is the compound of formula (VI) or a pharmaceutically acceptable salt thereof. In yet another embodiment, the compound is the compound of formula (VII) or a pharmaceutically acceptable salt thereof.

[0127] In this embodiment, the compound is - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-N-morpholino-3H-imidazo[4,5-b]pyridine-2-one, - 6-Tetrohydropyran-4-yloxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[(1-methyl-4-piperidyl)oxy]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methylpyrrolidine-3-yl)oxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(1-methyl-4-piperidyl)oxy]-3H-imidazo[4,5-b]pyridine-2-one, - 6-N-morpholino-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-(1-methylpyrrolidine-3-yl)oxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[2-(hydroxymethyl)morpholin-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(pentafluoro-λ 6 -Sulfanil)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 6-tetrahydrofuran-3-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-2-one, - 6-Cyclopentyl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-hydroxy-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[4-(pentafluoro-λ 6 -Sulfanil)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-5-methyl-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-fluorospiro[3,3]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-oxo-4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(tetrahydrofuran-3-ylmethyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-2-yl-3H-imidazo[4,5-b]pyridine-2-one, - Trans-6-(4-methoxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - cis-6-(4-methoxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3-azabicyclo[4.1.0]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-cyclobutyl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3-oxabicyclo[4.1.0]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-bicyclo[2.1.1]hexanyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-norcalan-1-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4,4-difluorocyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-cyclohexyl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-norbornan-2-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-2-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(tetrohydropyran-4-ylmethyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-3-yl-3H-imidazo[4,5-b]pyridine-2-one, - 6-Tetrohydropyran-4-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-(oxetane-3-ylmethyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[tetrahydrofuran-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, - trans-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - cis-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[1-methylpyrrolidine-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(pentafluoro-λ 6 -Sulfanil)benzoyl]pyrroridine-3-yl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[4-(pentafluoro-λ 6 -Sulfanil)benzoyl]pyrroridine-3-yl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - trans-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - cis-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methyl-4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-3-yloxy-3H-imidazo[4,5-b]pyridine-2-one, - 6-tetrahydrofuran-3-yloxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - Trans-6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - cis-6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - tert-butyl N-[2-[4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate, - 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - Trans-6-(4-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - cis-6-(4-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-(4-oxocycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[4-hydroxyiminocycloheptyl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - Trans-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - cis-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, Selected from the group consisting of and pharmaceutically acceptable salts thereof.

[0128] In this embodiment, the compound is - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-N-morpholino-3H-imidazo[4,5-b]pyridine-2-one, - 6-Tetrohydropyran-4-yloxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[(1-methyl-4-piperidyl)oxy]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methylpyrrolidine-3-yl)oxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(1-methyl-4-piperidyl)oxy]-3H-imidazo[4,5-b]pyridine-2-one, - 6-N-morpholino-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-(1-methylpyrrolidine-3-yl)oxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[2-(hydroxymethyl)morpholin-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(pentafluoro-λ 6 -Sulfanil)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 6-tetrahydrofuran-3-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-2-one, - 6-Cyclopentyl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-hydroxy-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[4-(pentafluoro-λ 6 -Sulfanil)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, The group is selected from the group consisting of these and their pharmaceutically acceptable salts.

[0129] In embodiments where the compound has an enantiomer form (for example, where the compound has a chiral center, e.g., a chiral carbon atom), the compound exists as a racemic mixture of enantiomers. In embodiments where the compound has a chiral center (e.g., a chiral carbon atom), the compound exists as an (R) isomer. In other embodiments where the compound has a chiral center (e.g., a chiral carbon atom), the compound exists as an (S) isomer.

[0130] Therefore, in the embodiment, the compound is - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methylpyrrolidine-3-yl)oxy-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-6-(1-methylpyrrolidine-3-yl)oxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[(2R)-2-(hydroxymethyl)morpholine-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[(2S)-2-(hydroxymethyl)morpholine-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-6-tetrahydrofuran-3-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-2-one, Selected from the group consisting of and pharmaceutically acceptable salts thereof.

[0131] In this embodiment, the compound is - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methylpyrrolidine-3-yl)oxy-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-6-(1-methylpyrrolidine-3-yl)oxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[(2R)-2-(hydroxymethyl)morpholine-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[(2S)-2-(hydroxymethyl)morpholine-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-6-tetrahydrofuran-3-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-oxo-4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(tetrahydrofuran-3-ylmethyl)-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-2-yl-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3-azabicyclo[4.1.0]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3-oxabicyclo[4.1.0]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-norcalan-1-yl-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-2-yl-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-3-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(3R)-tetrahydrofuran-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(3S)-tetrahydrofuran-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(3R)-1-methylpyrrolidine-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(3S)-1-methylpyrrolidine-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[2-amino-4-(pentafluoro-λ 6 -Sulfanil)benzoyl]pyrroridine-3-yl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[4-(pentafluoro-λ) 6 -Sulfanil)benzoyl]pyrroridine-3-yl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-3-yloxy-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-6-tetrahydrofuran-3-yloxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-trans-6-(4-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-cis-6-(4-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-6-(4-oxocycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-6-[(4E)-4-hydroxyiminocycloheptyl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-6-[(4Z)-4-hydroxyiminocycloheptyl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-trans-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-cis-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, Selected from the group consisting of and pharmaceutically acceptable salts thereof.

[0132] In some embodiments, the compound is selected from the compounds produced in Examples 1 to 67 (i.e., selected from the group consisting of compounds 1 to 67) and their pharmaceutically acceptable salts. In other embodiments, the compound is selected from the compounds that can be obtained by the synthesis method described in any one of Examples 1 to 67 (i.e., the method for synthesizing compounds 1 to 67) and their pharmaceutically acceptable salts.

[0133] In some embodiments, the compound is selected from the compounds produced in Examples 1 to 19 (i.e., from the group consisting of compounds 1 to 19) and their pharmaceutically acceptable salts. In other embodiments, the compound is selected from the compounds that can be obtained by the synthesis method described in any one of Examples 1 to 19 (i.e., the method for synthesizing compounds 1 to 19) and their pharmaceutically acceptable salts. In some embodiments, the compound is - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-N-morpholino-3H-imidazo[4,5-b]pyridine-2-one, - 6-Tetrohydropyran-4-yloxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[(1-methyl-4-piperidyl)oxy]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methylpyrrolidine-3-yl)oxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(1-methyl-4-piperidyl)oxy]-3H-imidazo[4,5-b]pyridine-2-one, - 6-N-morpholino-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-6-(1-methylpyrrolidine-3-yl)oxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[(2R)-2-(hydroxymethyl)morpholine-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[(2S)-2-(hydroxymethyl)morpholine-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(pentafluoro-λ 6-Sulfanil)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-6-tetrahydrofuran-3-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-2-one, - 6-Cyclopentyl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-hydroxy-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[4-(pentafluoro-λ 6 -Sulfanil)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, Selected from the group consisting of and pharmaceutically acceptable salts thereof.

[0134] In embodiments, the compounds of the present disclosure are characterized according to their inhibitory activity against ERK5, as measured, for example, according to a cell-based assay or cell-free assay described in the following examples. In embodiments, the compounds have an IC50 of less than about 10 μM against ERK5 (when measured, for example, according to a cell-free assay described below). 50 It has a value. In embodiments, the compound has an IC50 of less than approximately 5 μM against ERK5 (for example, when measured according to the cell-free assay described below). 50 The compound has a value of less than about 2 μM relative to ERK5, e.g., about 1 μM, 0.5 μM, 0.2 μM, 100 nM, or less than 50 nM IC5 (when measured according to the cell-free assay described below, for example). 50It has a value. In embodiments, when the compound is measured according to the cell-free assay described below, it has an IC50 of less than 10 μM relative to ERK5. 50 The compound has a value of less than about 5 μM relative to ERK5, for example, about 2 μM, 1 μM, 0.5 μM, 0.2 μM, 100 nM, or less than 50 nM, when measured according to the cell-free assay described below. 50 It has a value. In embodiments, when the compound is measured according to the cell-based assay described below, it has an IC50 of less than approximately 10 μM against ERK5. 50 The compound has a value of less than about 5 μM relative to ERK5, for example, about 2 μM, 1 μM, 0.5 μM, 0.2 μM, 100 nM, or less than 50 nM, when measured according to the cell-based assay described below. 50 It has a value.

[0135] In one embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 16, 17, and 19. In another embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 14, 15, 16, 17, and 19. In yet another embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 6, 14, 16, 17, and 19. In yet another embodiment, the compound is selected from the compounds of Examples 1, 2, and 3. In yet another embodiment, the compound is the compound of Example 1.

[0136] In one embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, and 19. In another embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 14, 15, 16, 17, 18, and 19. In another embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 10, 14, 16, 17, and 18. In another embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 6, 7, 16, and 18. In yet another embodiment, the compound is selected from the compounds of Examples 1 and 2.

[0137] In this embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, and 67. In this embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 60, 61, 62, 63, 64, 65, 66, and 67. In other embodiments, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 29, 30, 31, 32, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 61, 62, 63, 64, and 67. In other embodiments, the compound is selected from the compounds of Examples 1, 2, 3, 4, 6, 14, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 31, 33, 37, 39, 40, 41, 42, 43, 44, 45, 46, 48, 53, 54, 55, and 56. In other embodiments, the compound is selected from the compounds of Examples 1, 2, 3, 18, 21, 24, 25, 39, 43, 45, 55, and 56. In other embodiments, the compound is selected from the compounds of Examples 1, 21, and 45.

[0138] In this embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, and 60. In this embodiment, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 24, 25, 26, 28, 29, 31, 33, 34, 35, 36, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 51, 52, 53, 54, 55, 56, 57, and 58. In other embodiments, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 21, 23, 25, 26, 29, 31, 33, 39, 40, 42, 43, 44, 45, 47, 48, 51, 52, 53, 54, 55, 56, 57, and 58. In other embodiments, the compound is selected from the compounds of Examples 1, 2, 3, 4, 5, 6, 7, 10, 14, 16, 17, 18, 23, 39, 43, 45, 48, 51, 52, 54, 55, and 57. In other embodiments, the compound is selected from the compounds of Examples 1, 2, 3, 6, 7, 16, 18, 23, 48, 51, 52, 54, and 55.

[0139] Pharmaceutical composition This disclosure provides pharmaceutical compositions comprising a compound described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) and at least one pharmaceutically acceptable excipient or carrier.

[0140] In the embodiments, the pharmaceutical composition comprises a compound of formula (NI) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (N-IA) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (N-IB) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (N-IC) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (N-ID) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IA) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IB) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IC) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (ID) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition contains a compound of formula (N-II) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition contains a compound of formula (N-IIA) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition contains a compound of formula (N-IIB) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition contains a compound of formula (N-IIC) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition contains a compound of formula (II) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition contains a compound of formula (II-A) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition contains a compound of formula (II-B) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition contains a compound of formula (II-C) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition contains a compound of formula (III) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition contains a compound of formula (III-A) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (III-B) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (N-IV) or a pharmaceutically acceptable salt thereof. In the embodiments, the pharmaceutical composition comprises a compound of formula (IV) or a pharmaceutically acceptable salt thereof.In the embodiment, the pharmaceutical composition contains the compound of formula (IV-A) or a pharmaceutically acceptable salt thereof. In the embodiment, the pharmaceutical composition contains the compound of formula (IV-B) or a pharmaceutically acceptable salt thereof. In the embodiment, the pharmaceutical composition contains the compound of formula (IV-C) or a pharmaceutically acceptable salt thereof. In the embodiment, the pharmaceutical composition contains the compound of formula (V) or a pharmaceutically acceptable salt thereof. In the embodiment, the pharmaceutical composition contains the compound of formula (VI) or a pharmaceutically acceptable salt thereof. In the embodiment, the pharmaceutical composition contains the compound of formula (VII) or a pharmaceutically acceptable salt thereof.

[0141] The pharmaceutical compositions of this disclosure can be formulated for administration in solid or liquid form, for example, using conventional carriers or excipients. The compositions can be adapted, for example, using techniques known in the art, for oral administration (e.g., as a solution, suspension, tablet, or capsule), parenteral administration (e.g., as a solution, dispersion, suspension, or emulsion, or as a dry powder for reconstitution), or topical application (e.g., as a cream, ointment, patch, or spray applied to the skin).

[0142] Medical use The compounds disclosed herein act as ERK5 inhibitors and are useful in treating ERK5-related disorders and conditions. In particular, the compounds disclosed herein are useful in the treatment of cancer.

[0143] In this embodiment, the Disclosure provides a method of treatment comprising administering a therapeutically effective amount of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) to a subject in need of treatment. In a related embodiment, the Disclosure provides the use of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical product. In a further related embodiment, the Disclosure provides the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) for therapeutic use.

[0144] The compounds of this disclosure are useful for treating or preventing diseases or adverse conditions in which ERK5 or its variants or variants are known to play a role; diseases or disorders associated with increased MAPK7 (i.e., ERK5 gene) expression and / or increased ERK5 activity; and diseases or disorders in which inhibition or antagonism of ERK5 activity is beneficial.

[0145] In one aspect, the Disclosure provides a method for treating or preventing a disease or disorder mediated by ERK5, or a disease or disorder involving ERK5, in a subject requiring such treatment, comprising administering an effective amount of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) to the subject. In a related aspect, the Disclosure provides the use of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical product for treating or preventing a disease or disorder mediated by ERK5, or a disease or disorder involving ERK5. In a further related aspect, the Disclosure provides the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in treating or preventing a disease or disorder mediated by ERK5, or a disease or disorder involving ERK5.

[0146] In another aspect, the Disclosure provides a method for treating or preventing an ERK5-related disease or disorder (e.g., cancer) in a subject requiring treatment or prevention of the disease or disorder, comprising administering an effective amount of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) to the subject. In a related aspect, the Disclosure provides the use of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical product for treating or preventing an ERK5-related disease or disorder (e.g., cancer). In a further related aspect, the Disclosure provides the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in the treatment or prevention of an ERK5-related disease or disorder (e.g., cancer).

[0147] In another aspect, the Disclosure provides a method for treating or preventing cancer in a subject requiring treatment or prevention of cancer, comprising administering an effective amount of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) to the subject. In a related aspect, the Disclosure provides the use of the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) in the manufacture of a pharmaceutical product for treating or preventing cancer. In a further related aspect, the Disclosure provides the Compound of the Disclosure (e.g., the Compound of Formula (I) or a pharmaceutically acceptable salt thereof) for use in treating or preventing cancer.

[0148] In the embodiments, the compound reduces angiogenesis, reduces or prevents metastasis, reduces inflammation, blocks tumorigenesis (e.g., partially or completely), reduces evasion of growth inhibition, reduces or inhibits the growth of cancerous or precancerous cells, suppresses the proliferation of cancerous or precancerous cells, and / or reduces the survival of cancerous or precancerous cells.

[0149] In one embodiment, cancer is characterized by increased MAPK7 (i.e., ERK5 gene) expression and / or increased ERK5 activity. In another embodiment, cancer has elevated ERK5 activity. In yet another embodiment, cancer overexpresses ERK5. In yet another embodiment, cancer is characterized by MAPK7 genomic amplification and / or constitutively active ERK5 signaling. In yet another embodiment, cancer has genomically amplified ERK5. In yet another embodiment, cancer has constitutively active ERK5 signaling.

[0150] In some embodiments, the cancer is a solid tumor (e.g., melanoma, carcinoma, or blastoma). In other embodiments, the cancer is a leukemia (e.g., chronic lymphocytic leukemia, CLL; acute myeloid leukemia, AML; or chronic myeloid leukemia, CML).

[0151] In one embodiment, the cancer is a primary tumor. In another embodiment, the cancer is a secondary tumor (e.g., a metastatic tumor).

[0152] In the embodiment, cancer is selected from breast cancer (e.g., ductal carcinoma or mammary gland carcinoma), liver cancer, kidney cancer (e.g., hepatocellular carcinoma), prostate cancer, colorectal cancer (CRC), lung cancer (e.g., non-small cell lung cancer, NSCLC; lung adenocarcinoma; or lung squamous cell carcinoma), pancreatic cancer (e.g., adenocarcinoma), ovarian cancer, brain cancer (e.g., glioblastoma), cervical cancer (e.g., adenocarcinoma), gastric cancer, skin cancer (e.g., melanoma), bile duct cancer (e.g., cholangiocarcinoma), nervous system cancer (e.g., neuroblastoma), and melanoma.

[0153] In the embodiment, cancer is selected from leukemia (e.g., acute leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, or chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenström macroglobulinemia, and multiple myeloma.

[0154] In the embodiment, the cancer is selected from leukemia (e.g., chronic myeloid leukemia), breast cancer, multiple myeloma, colon cancer, colorectal cancer, lung cancer, pancreatic cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, melanoma, and hepatocellular carcinoma.

[0155] In this embodiment, the cancer is selected from leukemia (e.g., chronic myeloid leukemia), breast cancer, multiple myeloma, colon cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, and hepatocellular carcinoma.

[0156] In another embodiment, the Disclosure provides a method for inhibiting ERK5 activity, comprising contacting ERK5 (e.g., cells containing ERK5) with a compound of the Disclosure (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof). In embodiments, the method is in vitro or ex vivo. In other embodiments, the method is in vivo. In relevant embodiments, the Disclosure provides an in vitro method for inhibiting ERK5 activity in cells, comprising contacting cells with a compound of the Disclosure (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof).

[0157] The compounds of this disclosure (e.g., compounds of formula (I)) and pharmaceutically acceptable salts thereof may be administered as pharmaceutical compositions that may optionally contain one or more pharmaceutically acceptable excipients.

[0158] It will be understood that various aspects of the methods and treatments of the present disclosure can be achieved by administering an effective amount of the compound of the present disclosure (e.g., the compound of formula (I) or a pharmaceutically acceptable salt thereof) to a subject in the form of a pharmaceutical composition which may optionally contain one or more pharmaceutically acceptable excipients, as described herein.

[0159] The compounds of this disclosure may be used alone (for example, as monotherapy) or in combination with one or more cancer treatments.

[0160] As generally described herein, non-limiting embodiments are provided below to further illustrate the present disclosure. [Examples]

[0161] General synthesis scheme The following scheme, Scheme 1A, illustrates an exemplary method for preparing compounds in accordance with the present disclosure and examples. [ka] Scheme 1A

[0162] Scheme 1A (wherein R 1 , R 2 , L 1Compound 1C can be obtained in step 1 by nucleophilic aromatic substitution between compound 1A (wherein X=I, Br, Cl, F) and compound 1B, according to the above (wherein X=I, Br, Cl, F). Compound 1E can be prepared by reacting compound 1C with alcohol compound 1D by nucleophilic aromatic substitution using a base such as sodium hydride. Alternatively, compound 1E can be obtained by reacting compound 1C with compound 1D' (wherein R) by Buchwald coupling using a palladium catalyst such as Pd(OAc)2 in the presence of bases such as RuPhos and LiHMDS. 1 Compound 1E can be prepared by reacting it with (-H represents the hydrogen atom of a secondary amine). Compound 1E can be reduced to compound 1F in step 3 by hydrogenation using a catalyst such as Pd / C under a hydrogen pressure of about 5 bar (H2) at 40°C. Compound 1F can then be converted to compound 1G in step 4 by condensation with CDI, for example. Compound 1G can be deprotected with N using HCl or TFA to obtain compound 1H. Compound 1J can then be prepared from compound 1H in step 6 using carboxylic acid compound 1I under conditions known to those skilled in the art, such as HATU in a solvent such as DMF in the presence of a base such as DIPEA.

[0163] Another method for converting compound 1C to compound 1F is shown in the following scheme, scheme 1B. [ka] Scheme 1B

[0164] Scheme 1B (wherein R 1 And n are, for example, as described above, and L 1 According to the formula (where R is a direct bond), compound 1E' is converted to compound 1C by Suzuki coupling using a palladium catalyst such as XPhosPdG4 in the presence of XPhos and a base, thereby converting compound 1C to compound 1D'' (RY[where R is R 1Compound 1E' can be prepared in step 1 by reacting it with an oxidation precursor of [Y=BPin]. Compound 1E' can be reduced to compound 1F in step 2 by hydrogenation using a catalyst such as Pd / C at approximately 5 bar hydrogen pressure (H2) at 40°C; this reduces not only the nitro group of pyridine but also the precursor R. 1 A group is formed.

[0165] Another method for converting compound 1C to compound 1G is shown in the following scheme, scheme 1C. [ka] Scheme 1C

[0166] Scheme 1C (where R 1 , L 1 Compound 1K can be obtained in step 1 by reduction of compound 1C (wherein X may be I, Br, Cl, or F) using B2Pin2 and t-BuOK, for example, according to the above (wherein n may be I, Br, Cl, or F). Compound 1L can be prepared from compound 1K in step 2 by condensation with CDI. Compound 1G can be prepared in step 3, similar to compound 1E in scheme 1A. For example, compound 1L can be reacted with alcohol compound 1D by nucleophilic aromatic substitution using a base such as sodium hydride. Alternatively, compound 1L can be reacted with compound 1D by Buchwald coupling using a palladium catalyst such as Pd(OAc)2 in the presence of a base such as RuPhos and LiHMDS.

[0167] Another method for converting 1 L of compound to 1 G of compound is shown in the following scheme, Scheme 1D (similar to Scheme 1B above): [ka] Scheme 1D

[0168] Scheme 1D (where R 1 And n are, for example, as described above, and L 1According to the formula (where R is a direct bond), compound 1G' is converted to compound 1L by Suzuki coupling using a palladium catalyst such as XPhosPdG4 in the presence of XPhos and a base, thereby converting compound 1L to compound 1D'' (RY[where R is R 1 Compound 1G' can be prepared in step 1 by reacting it with an oxidation precursor of [Y=BPin]. Compound 1G' can be reduced to compound 1G in step 2 by hydrogenation using a catalyst such as Pd / C at a hydrogen pressure of approximately 5 bar (H2) at 40°C.

[0169] Another method for converting 1 L of compound to 1 J of compound is shown in the following scheme, Scheme 1E (similar to Scheme 1C above): [ka] Scheme 1E

[0170] Scheme 1E (wherein R 1 , R 2 , L 1 Compound 1L (wherein X=I, Br, Cl, F) can be deprotected by using HCl or TFA, according to the above (wherein n may be, for example, as described above), to obtain compound 1M in step 1. Compound 1N can then be prepared from compound 1M in step 2 using carboxylic acid compound 1I under conditions known to those skilled in the art, such as HATU in a solvent such as DMF in the presence of a base such as DIPEA. Compound 1J can be prepared in step 3 by reacting compound 1L with either alcohol compound 1D by nucleophilic aromatic substitution using a base such as sodium hydride, or with compound 1D' by Buchwald coupling using a palladium catalyst such as Pd(OAc)2 in the presence of a base such as RuPhos and LiHMDS.

[0171] Another method for converting compound 1N to compound 1J is shown in the following scheme, scheme 1F (similar to schemes 1B and 1D above): [ka] Scheme 1F

[0172] Scheme 1F (where R 1 , R 2 , and n are, for example, as described above, L 1 According to the formula (where R is a direct bond), compound 1J' is converted to compound 1N by Suzuki coupling using a palladium catalyst such as XPhosPdG4 in the presence of XPhos and a base, thereby converting compound 1N to compound 1D'' (RY[where R is R 1 It is an oxidation precursor of and can be prepared in step 1 by reacting it with Y=BPin. Compound 1J' can be reduced to compound 1J in step 2 by hydrogenation using a catalyst such as Pd / C under a hydrogen pressure of approximately 5 bar (H2) at 40°C.

[0173] For example, R 1 Compounds in which R is directly bonded to the pyridoimidazolon core via a tertiary carbon atom (for example, in formula R 1 (where is a bicyclo[1.1.1]pentanyl group), where heteroaryl halides such as compound 1C, compound 1L, or compound 1N can be obtained in the form of redox-active esters, as described, for example, Polites et al., Org. Lett. (2021) 23(12):4828-4833. 1 It reacts directly to R. 1 However, compounds that are directly bonded to the pyridoimidazolon core via a tertiary carbon atom having one oxygen substituent (for example, in formula R AThe -OH group (which is -OH or -O(C1~C3) alkyl) can be obtained, for example, by alkylating the carbonyl group directly bonded to that position on the pyridoimidazolon core (which can be prepared, for example, by palladium-assisted carbonylation from a heteroaryl halide), using, for example, an alkyllithium or alkyl Grignard reagent (for example, according to the procedure described in International Publication No. 2021 / 195781), and optionally, the obtained -OH group is further alkylated with an alkylating agent such as MeI in the presence of a base such as NaH. If necessary in the above conversion, a protecting group may be used, for example, on the -NH- group of the pyridoimidazolon core. Preferred protection strategies will be apparent to those skilled in the art in consideration of this disclosure.

[0174] In the formula, L 1 Is -CH2-, or in the formula, L 1 This is a direct bond, R 1 The preparation of the compounds of this disclosure, in which the remaining part of the molecule is bonded via an aliphatic carbon atom (e.g., a quaternary carbon), can be carried out according to the following scheme, scheme 1G. [ka] Scheme 1G

[0175] Scheme 1G (where R 1 , R 2 X and n can be, for example, as described above, and L 1 Compound 1R is obtained by a photochemical reaction with compound 1Q (wherein Y=BPin) using [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 and nickel(II) chloride in the presence of, for example, 4,4'-di-tert-butyl-2,2'-bipyridine and morpholine or 4-acetamidopiperidine, to obtain compound 1P (wherein A is R as defined herein). 2 , R 2 Precursors of (for example, having an -NO2 group instead of an -NH2 group), and R 2It can be prepared from a protected version of (e.g., containing the -NHBoc group) or from a protected group (e.g., Boc where A is -O-tBu, or Cbz where A is -OBn) that it is bound to the carbonyl. Compound 1P may be prepared, for example, in the same manner as compound 1L or compound 1N. Compound 1R can be converted to compound 1J in step 2, for example, by Boc deprotection using TFA or HCl, or according to steps 5 and 6 of scheme 1A.

[0176] The compounds of this disclosure (e.g., compounds of formula (NI)) [wherein R 3 The compound [is -(C1~C3)alkyl or -OH] can be synthesized in the same manner as described above, for example, using a modified version of Scheme 1A. Scheme 2A below shows a method for preparing such a compound in the same manner as Scheme 1A. [ka] Scheme 2A

[0177] Scheme 2A (wherein R 1 , R 2 , L 1 , and n can be, for example, as described above, and W is R 3 For example, -(C1~C3) alkyl, or R 3 According to a protected version of (e.g., one of -OCH3), compound 2C can be obtained in step 1 by nucleophilic aromatic substitution between compound 2A (wherein X=I, Br, Cl, F) and compound 1B. Compound 2E can be prepared by reacting compound 2C with alcohol compound 1D by nucleophilic aromatic substitution using a base such as sodium hydride. Alternatively, compound 2E can be obtained by reacting compound 2C with compound 1D'[wherein R] by Buchwald coupling using a palladium catalyst such as Pd(OAc)2 in the presence of bases such as RuPhos and LiHMDS. 1Compound 2E can be prepared by reacting it with [H represents the hydrogen atom of the secondary amine]. Compound 2E can be reduced to compound 2F in step 3 by hydrogenation using a catalyst such as Pd / C under a hydrogen pressure of about 5 bar (H2) at 40°C. Compound 2F can then be converted to compound 2G in step 4 by condensation with CDI, for example. Compound 2G can be deprotected with N using HCl or TFA to obtain compound 2H. Compound 2J can then be prepared from compound 2H in step 6 using carboxylic acid compound 1I under conditions known to those skilled in the art, such as HATU in a solvent such as DMF in the presence of a base such as DIPEA. 3 If it is a protected version, step 6 is further R 3 This may include deprotection to clarify the compound, for example, if W is -OCH3, compound 2J can be obtained by using demethylation conditions such as BBr3 or HBr in water, or TMSCl after NaI.

[0178] Another method for converting compound 2C to compound 2G is shown in the following schemes, scheme 2B. [ka] Scheme 2B

[0179] Scheme 2B (wherein R 1 , L 1 Compound 2C can be reduced to compound 2K in step 1 using pinacolborane in the presence of t-BuOK in a solvent such as iPrOH, according to the above (wherein n, X, and W are, for example, as described above). Compound 2L can then be obtained in step 2 by reacting compound 2K with CDI in dioxane, for example. Compound 2L can then be converted to compound 1D'' (RY[wherein R is R) by Suzuki coupling in step 3 using a palladium catalyst such as XPhosPdG4 in the presence of XPhos and a base). 1It is an oxidation precursor of [Y=BPin] and can react with [Y=BPin]. Step 3 optionally involves hydrogenation of R using a catalyst such as Pd / C at a hydrogen pressure of approximately 5 bar (H2) at 40°C, for example, to R 1 This may further include reducing it to...

[0180] If not commercially available, compound 2A can be prepared, for example, by the following schemes, scheme 2C. [ka] Scheme 2C

[0181] According to Scheme 2C, compound 2N can be obtained in step 1 by halogenating compound 2M (wherein W=H or -(C1~C3)alkyl) using a halogenating reagent such as NXS (wherein X=I, Br, Cl, F). Compound 2A can be obtained in step 2, for example, by oxidizing compound 2N with H2O2 and sulfuric acid.

[0182] Experimental Techniques At 400MHz and 500MHz 1 ¹H NMR spectra were obtained using Bruker Avance DRX-400 and Bruker Avance DPX-500 spectrometers, respectively, and the chemical shift (δ(ppm)) in the solvent dimethyl sulfoxide-d6 (DMSO-d6) was referenced at 2.5 ppm at the cited temperature. The coupling constant (J) is given in Hertz units.

[0183] Liquid chromatography / mass spectrometry (LC / MS) was obtained using a UPLC Acquity Waters instrument, a Sedere light scattering detector, and a SQD Waters mass spectrometer. UV (210 < l < 400 nm) was detected using a DAD. The column Acquity UPLC CSH C18 (1.7 μm, dimensions 2.1 × 30 mm) was used with mobile phase H2O + 0.1% HCO2H / CH3CN + 0.1% HCO2H, or the column Acquity BEH C18 (1.7 μm, dimensions 2.1 × 50 mm) was used with mobile phase H2O + 0.05% formic acid / CH3CN + 0.035% formic acid.

[0184] All synthetic reactions were carried out under an inert atmosphere unless otherwise specified. In the following examples, when the source of the starting product is not specified, the product should be understood to be a known compound (e.g., a compound commercially available from suppliers such as Sigma-Aldrich).

[0185] Examples 1 - 67 - Compounds Table 1 below lists the compounds synthesized in the following synthetic examples.

[0186] [Table 1]

[0187] [Table 2]

[0188] [Table 3]

[0189] [Table 4]

[0190] [Table 5]

[0191] [Table 6]

[0192] [Table 7]

[0193] [Table 8]

[0194] [Table 9]

[0195] [Table 10]

[0196] [Table 11]

[0197] Example 1: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: tert-butyl 4-[(5-fluoro-2-nitro-3-pyridyl)amino]piperidine-1-carboxylate [ka] A solution of tert-butyl 4-aminopiperidine-1-carboxylate (1845 mg, 8.93 mmol) in DMF (30 mL) was added dropwise to a solution of 3,5-difluoro-2-nitropyridine (1300 mg, 8.12 mmol) in DMF (20 mL) at 0°C. The reaction mixture was heated to room temperature and stirred overnight. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The organic layers were combined, dried over Na₂SO₄, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography (SiO₂ 120 g) using silica gel eluted with DCM / MeOH / NH₄OH (30% aqueous solution) (99 / 1 / 0.1) to obtain 2.355 g (85% yield) of tert-butyl 4-[(5-fluoro-2-nitro-3-pyridyl)amino]piperidine-1-carboxylate as a yellow solid. LC / MS (m / z, M+): Calculated value 340.2, Measured value 340.0

[0198] Step 2: tert-butyl 4-[(2-nitro-5-tetrohydropyran-4-yloxy-3-pyridyl)amino]piperidine-1-carboxylate [ka] Under an argon atmosphere, 86 mg of sodium hydride (60% dispersion in oil, 2.16 mmol) was added to a solution of tetrohydropyran-4-ol (210 mg, 2.06 mmol) in DMF (3 mL) at 0°C. The reaction mixture was stirred for 20 minutes, and then a solution of tert-butyl 4-[(5-fluoro-2-nitro-3-pyridyl)amino]piperidine-1-carboxylate (350 mg, 1.03 mmol) in DMF (3 mL) was added. The reaction mixture was then warmed to room temperature and stirred for 1.5 hours. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (2 × 100 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to obtain 434 mg (100% yield) of crude tert-butyl 4-[(2-nitro-5-tetrohydropyran-4-yloxy-3-pyridyl)amino]piperidine-1-carboxylate as a yellow solid, which was used in the next step without further purification. LC / MS (m / z, M+): Calculated value 422.2, Measured value 422.0

[0199] Step 3: tert-butyl 4-[(2-amino-5-tetrohydropyran-4-yloxy-3-pyridyl)amino]piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-[(2-nitro-5-tetrohydropyran-4-yloxy-3-pyridyl)amino]piperidine-1-carboxylate (434 mg, 1.03 mmol) in MeOH (10 mL), ammonium formate (1297 mg, 20.57 mmol) and Pd / C 10% (100 mg) were added. The reaction mixture was then stirred at 65°C for 1 hour, cooled to room temperature, filtered through Celite, and washed with MeOH. The filtrate was concentrated under vacuum. The resulting residue was diluted with ethyl acetate (50 mL), washed with 1N NaOH, dried over Na2SO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash chromatography (SiO2 24g) of silica gel eluted with DCM / MeOH / aqueous 30% NH4OH (95 / 5 / 0.5) to obtain 294 mg (69% yield) of tert-butyl 4-[(2-amino-5-tetrohydropyran-4-yloxy-3-pyridyl)amino]piperidine-1-carboxylate as a brown foam. LC / MS (m / z, M+H): Calculated value 393.2, Measured value 393.2

[0200] Step 4: tert-butyl 4-(2-oxo-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-[(2-amino-5-tetrohydropyran-4-yloxy-3-pyridyl)amino]piperidine-1-carboxylate (290 mg, 0.71 mmol) in THF (8 mL), CDI (345 mg, 2.13 mmol) was added. The resulting reaction mixture was refluxed for 1.5 hours, then cooled to room temperature and concentrated. The resulting residue was diluted with a saturated aqueous solution of NaHCO3 (100 mL) and extracted twice with ethyl acetate (2 × 50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash chromatography (SiO2 12g) of silica gel eluted with DCM / MeOH / aqueous 30% NH4OH (95 / 5 / 0.5) to obtain 267 mg (85% yield) of tert-butyl 4-(2-oxo-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate as a green foam. LC / MS (m / z, M+H): Calculated value 419.2, Measured value 419.2

[0201] Step 5: 1-(4-piperidyl)-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-2-one, hydrochloride [ka] To a solution of tert-butyl 4-(2-oxo-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate (264 mg, 0.6 mmol) in MeOH (4 mL), 2.25 mL of HCl 4N solution (8.99 mmol) in dioxane was added. The reaction mixture was stirred at 40°C for 1 hour, then concentrated under vacuum to obtain 234 mg (100% yield) of crude 1-(4-piperidyl)-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-2-one hydrochloride as a yellow foam, which was used in the next step without further purification. LC / MS (m / z, M+H): Calculated value 319.2, Measured value 319.2 (free base)

[0202] Step 6: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-2-one [ka] To a solution of 1-(4-piperidyl)-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-2-one, hydrochloride (234 mg, 0.6 mmol) in DMF (4 mL), DIPEA (387 mg, 0.52 mL, 3 mmol) was added, and the resulting mixture was stirred for 5 minutes. Then, 2-amino-4-(trifluoromethoxy)benzoic acid (132 mg, 0.6 mmol), followed by HATU (251 mg, 0.66 mmol), was added, and the resulting solution was stirred at room temperature for 1 hour, then diluted with ethyl acetate (50 mL), and washed with a 1N solution of NaOH, water, and brine. The organic layer was then dried over Na2SO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash chromatography (12 g) of Puriflash® interchim PF-15SiHP-F0012 eluted with DCM / MeOH / aqueous 30% NH4OH (96 / 4 / 0.4) to obtain 188 mg (57% yield) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 522.2, measured value 522.3; 1H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.64(dtd,J=13,9,9,4Hz,2H),1.74-1.86(m,2H),1.90-2.02(m,2H),2.28(qd,J=13,4H z,2H),3.05(td,J=13,3Hz,2H),3.48(ddd,J=12,9,3Hz,2H),3.81-3.98(m,2H),4.17(br d,J=13Hz,2H),4.33-4.52(m,2H),5.31(s,2H),6.44-6.55(m,1H),6.66-6.73(m,1H ),7.13(d,J=8Hz,1H),7.22(d,J=2Hz,1H),7.63(d,J=2Hz,1H),10.53-11.18(m,1H)

[0203] Example 2: [1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: tert-butyl 4-[(5-bromo-2-nitro-3-pyridyl)amino]piperidine-1-carboxylate [ka] To a solution of 5-bromo-3-fluoro-2-nitropyridine (500 mg, 2.26 mmol) in ethanol (15 mL), triethylamine (950 μL, 6.82 mmol) was added, followed by 4-amino-1-Boc-piperidine (545 mg, 2.72 mmol). The resulting reaction mixture was then stirred at 90°C for 75 minutes, cooled to room temperature, and concentrated under vacuum. The resulting residue was then diluted with 50 mL of ethyl acetate and washed with a saturated aqueous solution of NH4Cl. The aqueous layer was then extracted twice with ethyl acetate (2 × 25 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under vacuum to obtain 908 mg (100% yield) of tert-butyl 4-[(5-bromo-2-nitro-3-pyridyl)amino]piperidine-1-carboxylate as a yellow solid. LC / MS (m / z, M+H): Calculated value 401.1, Measured value 401.3

[0204] Step 2: tert-butyl 4-[[5-(3,6-dihydro-2H-pyran-4-yl)-2-nitro-3-pyridyl]amino]piperidine-1-carboxylate [ka] A solution of tert-butyl 4-[(5-bromo-2-nitro-3-pyridyl)amino]piperidine-1-carboxylate (500 mg, 1.25 mmol) in THF (8 mL) and water (2 mL) was bubbling with argon for 5 minutes, and then tribasic potassium phosphate (650 mg, 3.06 mmol), XPhos (30 mg, 0.063 mmol), 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (315 mg, 1.5 mmol), and XPhosPdG4 (30 mg, 0.035 mmol) were added. The resulting mixture was stirred at 80°C for 1 hour, then cooled to room temperature and diluted with ethyl acetate (50 mL) and water (50 mL). The organic layer was discarded, and the aqueous layer was extracted twice with ethyl acetate (2 × 50 mL). The combined organic layers were then dried over Na₂SO₄, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography (SiO240g) of silica gel eluted with cyclohexane / AcOEt(6 / 4) to obtain 453 mg (90% yield) of tert-butyl 4-[[5-(3,6-dihydro-2H-pyran-4-yl)-2-nitro-3-pyridyl]amino]piperidine-1-carboxylate as a yellow solid. LC / MS (m / z, M+H): Calculated value 405.2, Measured value 405.4

[0205] Step 3: tert-butyl 4-[(2-amino-5-tetrohydropyran-4-yl-3-pyridyl)amino]piperidine-1-carboxylate [ka] A solution of tert-butyl 4-[[5-(3,6-dihydro-2H-pyran-4-yl)-2-nitro-3-pyridyl]amino]piperidine-1-carboxylate (450 mg, 1.11 mmol) in ethanol (6 mL) and ethyl acetate (6 mL) was bubbling with argon for 5 minutes, and then Pd / C 10% (50% wet) (250 mg, 2.35 mmol) was added. The resulting reaction mixture was then hydrogenated at 50°C under 4 bar of hydrogen for 1.5 hours. The resulting mixture was cooled to room temperature, filtered through a GF / F filter, and washed with EtOH / AcOEt. The resulting filtrate was concentrated under vacuum to obtain 405 mg (97% yield) of tert-butyl 4-[(2-amino-5-tetrohydropyran-4-yl-3-pyridyl)amino]piperidine-1-carboxylate as a red solid. LC / MS (m / z, M+H): Calculated value 377.2, Measured value 377.4

[0206] Step 4: tert-butyl 4-(2-oxo-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-[(2-amino-5-tetrohydropyran-4-yl-3-pyridyl)amino]piperidine-1-carboxylate (400 mg, 1.06 mmol) in acetonitrile (5 mL), CDI (350 mg, 2.16 mmol) was added. The resulting mixture was stirred at 80°C for 2 hours, then cooled to room temperature. The resulting precipitate was filtered to obtain 260 mg (61% yield) of tert-butyl 4-(2-oxo-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate as a gray powder. LC / MS (m / z, M+H): Calculated value 403.2, Measured value 403.0

[0207] Step 5: 1-(4-piperidyl)-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, dihydrochloride [ka] To a solution of 4-(2-oxo-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate (255 mg, 0.63 mmol) in methanol (6 mL), 1.8 mL of a 4N solution of HCl in dioxane (7.2 mmol) was added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was then concentrated under vacuum, and the resulting residue was triturated in diethyl ether. The resulting solid was filtered to obtain 245 mg (65% yield) of 1-(4-piperidyl)-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, dihydrochloride, as a gray powder. LC / MS (m / z, M+H): Calculated value 303.2, Measured value 303.3 (free base)

[0208] Step 6: [1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] To a solution of 1-(4-piperidyl)-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, hydrochloride (150 mg, 0.4 mmol) in DMF (3 mL), N,N-diisopropylethylamine (350 μL, 2.01 mmol), followed by 2-amino-4-(trifluoromethoxy)benzoic acid (110 mg, 0.5 mmol) and HATU (190 mg, 0.5 mmol) were added. The resulting reaction mixture was stirred at room temperature for 75 minutes and then concentrated under vacuum. The resulting residue was diluted with ethyl acetate (20 mL) and water (20 mL). The mixture was basicized to pH 11-12 with 1N aqueous NaOH while stirring, and the organic layer was discarded. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The obtained residue was purified by flash chromatography (SiO2 12g) of silica gel eluted with DCM / MeOH 95 / 5~0 / 100 to obtain an orange wax, which was tritulated in acetonitrile. The resulting white precipitate was filtered to obtain 53 mg (26% yield) of [1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 506.5, measured value 506.2; 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.65-1.88(m,6H),2.30(qd,J=13,4Hz,2H),2.82(tt,J=10,5Hz,1H),3.06(td,J=13,3Hz,2H),3.40-3.56(m,2H),3.91-4.03(m,2H),4.17(br d,J=13Hz,2H),4.43(tt,J=12,4Hz,1H),5.41(s,2H),6.39-6.55(m,1H),6.62-6. 74(m,1H),7.14(d,J=8Hz,1H),7.41(d,J=2Hz,1H),7.78(d,J=2Hz,1H),11.03(br s,1H)

[0209] Example 3: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-morpholino-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: tert-butyl 4-[(2-amino-5-bromo-3-pyridyl)amino]piperidine-1-carboxylate [ka] In a sealed tube, tert-butyl 4-[(5-bromo-2-nitro-3-pyridyl)amino]piperidine-1-carboxylate (7.61 g, 19 mmol) was dissolved in i-PrOH (75 mL), to which bis(pinacorato)diborone (14.9 g, 58.8 mmol), followed by t-BuOK (2.55 g, 22.8 mmol). The tube was sealed and heated at 110°C for 2.5 hours with stirring. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The resulting residue was then diluted with saturated aqueous solutions of ethyl acetate and NaCl. The organic layer was discarded, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was diluted in ethyl acetate and washed twice with 2N aqueous solution of NaOH. The organic layer was discarded, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (SiO2 220g) using silica gel eluted with heptane / (AcOEt / EtOH3 / 1)7 / 3 to obtain 5.47 g (78% yield) of tert-butyl 4-[(2-amino-5-bromo-3-pyridyl)amino]piperidine-1-carboxylate as a light brown solid. LC / MS (m / z, M+): Calculated value 370.1, Measured value 370.0

[0210] Step 2: tert-butyl 4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-[(2-amino-5-bromo-3-pyridyl)amino]piperidine-1-carboxylate (5370 mg, 14.5 mmol) in THF (145 mL), CDI (7040 mg, 43.4 mmol) was added, and the resulting reaction mixture was refluxed for 2.5 hours. The reaction mixture was then cooled to room temperature and concentrated under vacuum. The resulting residue was diluted with a saturated aqueous solution of NaHCO3 and extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography (SiO2 120 g) using silica gel eluted with DCM / MeOH96 / 4 to obtain 5.34 g (93% yield) of tert-butyl 4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate as a light brown solid. LC / MS (m / z, M+): Calculated value 396.1, Measured value 396.0

[0211] Step 3: Tert-butyl 4-(6-morpholino-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate [ka] In a sealed tube, a solution of tert-butyl 4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate (266 mg, 0.67 mmol), morpholine (70 mg, 0.80 mmol), and RuPhos (25 mg, 0.054 mmol) in THF (0.45 mL) was bubbling with argon for 5 minutes. Then, Pd(OAc)2 (6 mg, 0.027 mmol) and LiHMDS (1.61 mL, 1.61 mmol, 1 M solution in THF) were added, the tube was sealed, and the reaction mixture was stirred overnight at 75°C. The reaction mixture was then cooled to room temperature, diluted with water, and extracted four times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash chromatography (SiO2 12g) of silica gel eluted with DCM / MeOH / aqueous 30% NH4OH (94.5:5.5:0.55) to obtain 29 mg of a white solid. This was then triturated in i-Pr2O and filtered to obtain 216 mg (80% yield) of tert-butyl 4-(6-morpholino-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate as a white solid. LC / MS (m / z, M+): Calculated value 403.2, Measured value 403.0

[0212] Step 4: 6-Molfolino-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, trihydrochloride [ka] To a solution of tert-butyl 4-(6-morpholino-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate (212 mg, 0.52 mmol) in MeOH (30 mL), HCl (4N solution in dioxane, 1.05 mL, 4.2 mmol) was added at 45°C, and the reaction mixture was stirred at 45°C for 3 hours. The reaction mixture was then concentrated under vacuum. The resulting residue was triturated overnight in ethyl acetate (20 mL) and filtered to obtain 196 mg (90% yield) of 6-morpholino-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one trihydrochloride as a pale yellow solid. LC / MS (m / z, M+H): Calculated value 304.2, measured value 304.0 (free base)

[0213] Step 5: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-morpholino-3H-imidazo[4,5-b]pyridine-2-one [ka] To a solution of 6-morpholino-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, trihydrochloride (95 mg, 0.23 mmol) in DMF (1.5 mL), N,N-diisopropylethylamine (281 μL, 1.61 mmol), followed by 2-amino-4-(trifluoromethoxy)benzoic acid (53 mg, 0.23 mmol), and HATU (96 mg, 0.25 mmol) were added. The resulting reaction mixture was stirred at room temperature for 3 hours and then concentrated under vacuum. The resulting residue was diluted with ethyl acetate (20 mL) and water (20 mL). The mixture was basicized to pH 11-12 with 1N aqueous NaOH while stirring, and the organic layer was discarded. The aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under vacuum. The obtained residue was purified by flash chromatography (12 g) using a Puriflash® interchim PF-15SiHP-F0012 column eluted with AcOEt / MeOH / NH4OH (94 / 6 / 0.6) to obtain wax, which was tritulated in acetonitrile. The resulting white precipitate was filtered to obtain 78 mg (67% yield) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-morpholino-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 507.2, Measured value 507.2; 1 H NMR(400MHz,DMSO-d6,30℃)δ ppm 1.63-1.79(m,2H),2.20-2.40(m,2H),2.85-3.42(m,2H),3.04-3.13(m,4H),3.62-4.89(m,2H) ,3.72-3.80(m,4H),4.44(ddd,J=12,9,4Hz,1H),5.68(s,2H),6.50(dd,J=8,1Hz,1H),6.67(br d,J=1Hz,1H),7.13(d,J=8Hz,1H),7.32(d,J=2Hz,1H),7.57(d,J=2Hz,1H),11.21(br s,1H)

[0214] Example 4: 6-Tetrohydropyran-4-yloxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] To a solution of 1-(4-piperidyl)-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-2-one, dihydrochloride (60.0 mg, 0.15 mmol) in DMF (1 mL), DIPEA (99 mg, 0.13 mL, 0.767 mmol) was added, and the reaction mixture was stirred at room temperature for 5 minutes. 4-(trifluoromethoxy)benzoic acid (32 mg, 0.15 mmol) and HATU (64 mg, 0.17 mmol) were added, and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with 1N aqueous solution of NaOH and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (SiO2 12g) of silica gel eluted with DCM / MeOH / 30% aqueous NH4OH (95 / 5 / 0.5) to obtain 63 mg (81% yield) of 6-tetrohydropyran-4-yloxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a light brown solid. LC / MS (m / z, M+H): Calculated value 507.2, measured value 507.3; 1 H NMR(400MHz,DMSO-d6,101℃)δ ppm 1.64(dtd,J=13,9,9,4Hz,2H),1.80(br d,J=11Hz,2H),1.90-2.04(m,2H),2.29(qd,J=12,4Hz,2H),3.08(br t,J=13Hz,2H),3.47(ddd,J=12,9,3Hz,2H),3.81-3.93(m,2H),4.07-4.28(m,2H),4.33-4.53(m,2H),7.27(d,J=2Hz,1H),7.39(br d,J=8Hz,2H),7.57(d,J=8Hz,2H),7.64(d,J=2Hz,1H),10.44-11.38(m,1H)

[0215] Example 5: 6-[(1-methyl-4-piperidyl)oxy]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: tert-butyl 4-[[5-[(1-methyl-4-piperidyl)oxy]-2-nitro-3-pyridyl]amino]piperidine-1-carboxylate [ka] Under an argon atmosphere, 148 mg of sodium hydride (60% dispersion in oil, 3.70 mmol) was added to a solution of 1-methylpiperidine-4-ol (414 mg, 3.52 mmol) in DMF (5 mL) at 0°C, and the resulting reaction mixture was stirred for 20 minutes. Then, a solution of tert-butyl 4-[(5-fluoro-2-nitro-3-pyridyl)amino]piperidine-1-carboxylate (600 mg, 1.76 mmol) in DMF (4 mL) was added dropwise. The resulting mixture was warmed to room temperature, stirred for 1.5 hours, then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 768 mg (100% yield) of tert-butyl 4-[[5-[(1-methyl-4-piperidyl)oxy]-2-nitro-3-pyridyl]amino]piperidine-1-carboxylate as an orange rubber, which was used in the next step without further purification. LC / MS (m / z, M+): Calculated value 435.2, Measured value 435.0

[0216] Step 2: tert-butyl 4-[[2-amino-5-[(1-methyl-4-piperidyl)oxy]-3-pyridyl]amino]piperidine-1-carboxylate [ka] To a solution of 4-[[5-[(1-methyl-4-piperidyl)oxy]-2-nitro-3-pyridyl]amino]piperidine-1-carboxylate (768 mg, 1.76 mmol) in MeOH (20 mL), ammonium formate (2223 mg, 35.26 mmol) and Pd / C (10%) (150 mg) were successively added, and the resulting mixture was stirred at 65°C for 1 hour. After 1 hour, 556 mg of ammonium formate (8.81 mmol) was added, and the reaction mixture was stirred at 65°C for a further 30 minutes. Then, the mixture was filtered through Celite, washed with MeOH, and the filtrate was concentrated under vacuum. The resulting residue was diluted with ethyl acetate, washed with 1N aqueous NaOH, dried over Na2SO4, filtered, and concentrated under vacuum. The obtained dark oil was purified by flash chromatography (SiO2 24g) of silica gel eluted with DCM / MeOH / 30% aqueous NH4OH (92 / 8 / 0.8) to obtain 448 mg (57% yield) of tert-butyl 4-[[2-amino-5-[(1-methyl-4-piperidyl)oxy]-3-pyridyl]amino]piperidine-1-carboxylate as a brown foam. LC / MS (m / z, M+H): Calculated value 406.2, Measured value 406.3

[0217] Step 3: tert-butyl 4-[6-[(1-methyl-4-piperidyl)oxy]-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-[[2-amino-5-[(1-methyl-4-piperidyl)oxy]-3-pyridyl]amino]piperidine-1-carboxylate (445 mg, 1 mmol) in THF (10 mL), CDI (485 mg, 3 mmol) was added, and the resulting mixture was refluxed for 1 hour. The reaction mixture was then cooled to room temperature, diluted with a saturated aqueous solution of NaHCO3, and extracted with ethyl acetate. The organic layer was then dried over Na2SO4, filtered, and concentrated under vacuum. The obtained dark oil was purified by flash chromatography (SiO2 24 g) of silica gel eluted with DCM / MeOH / 30% aqueous NH4OH (92 / 8 / 0.8) to obtain 431 mg (100% yield) of tert-butyl 4-[6-[(1-methyl-4-piperidyl)oxy]-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate as a brown foam. LC / MS (m / z, M+H): Calculated value 432.2, measured value 432.3

[0218] Step 4: 6-[(1-methyl-4-piperidyl)oxy]-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, trihydrochloride [ka] To a solution of tert-butyl 4-[6-[(1-methyl-4-piperidyl)oxy]-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate (431 mg, 1 mmol) in MeOH (8 mL), 3.74 mL of 4N HCl solution (15 mmol) in dioxane was added, and the resulting mixture was stirred at 40°C for 1 hour. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure to obtain 440 mg (100% yield) of 6-[(1-methyl-4-piperidyl)oxy]-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one trihydrochloride as a brown solid, which was used in the next step without further purification. LC / MS (m / z, M+H): Calculated value 332.2, Measured value 332.2 (free base)

[0219] Step 5: 6-[(1-methyl-4-piperidyl)oxy]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] To a solution of 6-[(1-methyl-4-piperidyl)oxy]-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, trihydrochloride (220 mg, 0.5 mmol) in DMF (3.3 mL), DIPEA (323 mg, 0.44 mL, 2.5 mmol) was added, and the resulting mixture was stirred for 5 minutes. Then, 4-(trifluoromethoxy)benzoic acid (103 mg, 0.5 mmol) and HATU (209 mg, 0.55 mmol) were added successively, and the reaction mixture was stirred at room temperature for 1.5 hours, then diluted with ethyl acetate, and washed with 1N aqueous solution of NaOH, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (SiO2 12g) of silica gel eluted with DCM / MeOH / 30% aqueous NH4OH (92 / 8 / 0.8) to obtain 14 mg (5% yield) of 6-[(1-methyl-4-piperidyl)oxy]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a pale yellow solid. LC / MS (m / z, M+H): Calculated value 520.2, Measured value 520.2; 1 H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.64-1.78(m,2H),1.84(br d,J=11Hz,2H),1.90-2.01(m,2H),2.15-2.26(m,2H),2.23(s,3H),2.32(qd,J=12,4Hz,2H),2.62-2.71(m,2H),3.06-3.17(m,2H),4.20(br d,J=12Hz,2H),4.28(tt,J=8,4Hz,1H),4.42(tt,J=12,4Hz,1H),7.24(d,J=2Hz,1H),7.41(br d,J=9Hz,2H),7.60(d,J=9Hz,2H),7.64(d,J=2Hz,1H),10.43-11.42(m,1H)

[0220] Example 6. (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methylpyrrolidine-3-yl)oxy-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: (rac)-tert-butyl 4-[[5-(1-methylpyrrolidine-3-yl)oxy-2-nitro-3-pyridyl]amino]piperidine-1-carboxylate [ka] Under an argon atmosphere, sodium hydride (60% dispersion in oil, 197 mg, 4.94 mmol) was added at 0°C to a solution of 1-methylpyrrolidine-3-ol (476 mg, 4.7 mmol) in DMF (6 mL), and the reaction mixture was stirred for 20 minutes. Then, a solution of tert-butyl 4-[(5-fluoro-2-nitro-3-pyridyl)amino]piperidine-1-carboxylate (800 mg, 2.35 mmol) in DMF (6 mL) was added dropwise, and the resulting reaction mixture was warmed to room temperature and stirred for 1.5 hours. The mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting orange oil was purified by flash chromatography (SiO2 24 g) using silica gel eluted with DCM / MeOH / 30% aqueous NH4OH (95 / 5 / 0.5) to obtain 931 mg (85% yield) of (rac)-tert-butyl 4-[[5-(1-methylpyrrolidine-3-yl)oxy-2-nitro-3-pyridyl]amino]piperidine-1-carboxylate as a yellow solid. LC / MS (m / z, M+): Calculated value 421.2, Measured value 421.0

[0221] Step 2: (rac)-tert-butyl 4-[[2-amino-5-(1-methylpyrrolidine-3-yl)oxy-3-pyridyl]amino]piperidine-1-carboxylate [ka] To a solution of (rac)-tert-butyl 4-[[5-(1-methylpyrrolidine-3-yl)oxy-2-nitro-3-pyridyl]amino]piperidine-1-carboxylate (928 mg, 2.00 mmol) in MeOH (20 mL), ammonium formate (2527 mg, 40.1 mmol) and Pd / C (10%) (200 mg) were added, and the resulting reaction mixture was stirred at 65°C for 1 hour. The reaction mixture was then cooled to room temperature, filtered through Celite, washed with MeOH, and the filtrate was concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate and washed with 1N aqueous NaOH. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The obtained dark oil was purified by flash chromatography (SiO224g) of silica gel eluted with DCM / MeOH / 30% aqueous NH4OH (90 / 10 / 1) to obtain 458 mg of (rac)-tert-butyl 4-[[2-amino-5-(1-methylpyrrolidine-3-yl)oxy-3-pyridyl]amino]piperidine-1-carboxylate as a brown foam. LC / MS (m / z, M+): Calculated value 391.2, Measured value 391.0

[0222] Step 3: (rac)-tert-butyl4-[6-(1-methylpyrrolidine-3-yl)oxy-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate [ka] To a solution of (rac)-tert-butyl 4-[[2-amino-5-(1-methylpyrrolidine-3-yl)oxy-3-pyridyl]amino]piperidine-1-carboxylate (455 mg, 1.09 mmol) in THF (10 mL), CDI (531 mg, 3.28 mmol) was added. The resulting reaction mixture was refluxed for 1.5 hours, then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with ethyl acetate and washed twice with saturated aqueous solution of NaHCO3. The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash chromatography (SiO2 24g) of silica gel eluted with DCM / MeOH / 30% aqueous NH4OH (90 / 10 / 1) to obtain a purple powder. This was tritulated in acetonitrile and filtered to obtain 305 mg (66% yield) of (rac)-tert-butyl 4-[6-(1-methylpyrrolidine-3-yl)oxy-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate as a pink powder. LC / MS (m / z, M+): Calculated value 417.2, Measured value 417.0

[0223] Step 4: (rac)-6-(1-methylpyrrolidine-3-yl)oxy-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, trihydrochloride [ka] (rac)-tert-butyl4-[6-(1-methylpyrrolidine-3-yl)oxy-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate (300 mg, 0.72 mmol) was dissolved in MeOH (4 mL), to which 2.7 mL of 4N HCl solution (10.8 mmol) in dioxane was added. The resulting mixture was stirred at room temperature for 4 hours and then concentrated under vacuum to obtain 307 mg (100% yield) of (rac)-6-(1-methylpyrrolidine-3-yl)oxy-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one trihydrochloride as a brown foam. LC / MS (m / z, M+H): Calculated value 318.2, Measured value 318.2 (free base)

[0224] Step 5: (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methylpyrrolidine-3-yl)oxy-3H-imidazo[4,5-b]pyridine-2-one [ka] (rac)-6-(1-methylpyrrolidine-3-yl)oxy-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, trihydrochloride (153 mg, 0.36 mmol) in DMF (2.4 mL) was mixed with DIPEA (232 mg, 0.31 mL, 1.8 mmol) and the resulting mixture was stirred at room temperature for 5 minutes. Then, 2-amino-4-(trifluoromethoxy)benzoic acid (79 mg, 0.36 mmol) was added, followed by HATU (150 mg, 0.39 mmol). The resulting reaction mixture was stirred at room temperature for 2 hours, then diluted with ethyl acetate, washed with saturated aqueous solution of NaHCO3, water, and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash chromatography (12 g) of silica gel eluted with DCM / MeOH / 30% aqueous NH4OH (90 / 10 / 1) to obtain a yellow foam, which was then tritulate in i-PrOH. The resulting white precipitate was filtered off to obtain 131 mg (70% yield) of (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methylpyrrolidine-3-yl)oxy-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 521.2, measured value 521.2; 1H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.75-1.91(m,3H),2.12-2.33(m,3H),2.29(s,3H),2.40-2.52(m partially hidden,1H),2.59-2.72(m,2H),2.76-2.87(m Partially hidden, 1H), 3.05 (td, J=13, 3Hz, 2H), 4.16 (br d,J=14Hz,2H),4.39(tt,J=12,4Hz,1H),4.82-4.91(m,1H),5.33(s,2H),6.44-6.54(m,1H),6.6 7-6.73(m,1H),7.14(d,J=8Hz,1H),7.17(d,J=2Hz,1H),7.54(d,J=2Hz,1H),10.71-11.00(m,1H)

[0225] Example 7: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(1-methyl-4-piperidyl)oxy]-3H-imidazo[4,5-b]pyridine-2-one [ka] To a solution of 6-[(1-methyl-4-piperidyl)oxy]-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, hydrochloride (220 mg, 0.5 mmol) in DMF (3.3 mL), DIPEA (323 mg, 0.44 mL, 2.5 mmol) was added, and the resulting mixture was stirred at room temperature for 5 minutes. Then, 2-amino-4-(trifluoromethoxy)benzoic acid (110 mg, 0.5 mmol), followed by HATU (209 mg, 0.55 mmol), was added, and the resulting reaction mixture was stirred at room temperature for 1.5 hours, then diluted with ethyl acetate and washed with 1N aqueous solution of NaOH, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (SiO2 12g) of silica gel eluted with DCM / MeOH / 30% aqueous NH4OH (90 / 10 / 1) to obtain yellow rubber, which was tritulated in acetonitrile. The resulting precipitate was filtered to obtain 19 mg (7% yield) of -[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(1-methyl-4-piperidyl)oxy]-3H-imidazo[4,5-b]pyridine-2-one as a light brown solid. LC / MS (m / z, M+H): Calculated value 535.2, measured value 535.3; 1 H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.62-1.75(m,2H),1.80(br d,J=12Hz,2H),1.87-1.97(m,2H),2.13-2.35(m,4H),2.19(s,3H),2.58-2.67(m,2H),3.05(br t,J=12Hz,2H),4.16(br d,J=13Hz,2H),4.24(tt,J=8,4Hz,1H),4.33-4.45(m,1H),5.31(br s,2H),6.48(br d,J=8Hz,1H),6.69(br s,1H),7.14(d,J=8Hz,1H),7.19(d,J=2Hz,1H),7.60(d,J=2Hz,1H),10.61-11.06(m,1H)

[0226] Example 8: 6-Molfolino-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] To a solution of 6-morpholino-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, trihydrochloride (95 mg, 0.23 mmol) in DMF (1.5 mL), DIPEA (208 mg, 0.28 mL, 1.61 mmol) was added, and the resulting mixture was stirred at room temperature for 5 minutes. Then, 4-(trifluoromethoxy)benzoic acid (47 mg, 0.23 mmol) and HATU (96 mg, 0.25 mmol) were added sequentially, and the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with 1N aqueous solution of NaOH (5 mL). The aqueous layer was extracted four times with ethyl acetate. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography (12 g) of Puriflash® interchim PF-15SiHP-F0012 eluted with AcOEt / MeOH / 30% aqueous NH4OH (94 / 6 / 0.6) to obtain a solid. This solid was tritulated in acetonitrile and filtered to obtain 64 mg (56% yield) of 6-morpholino-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 492.2, Measured value 492.2; 1 H NMR(400MHz,DMSO-d6,30℃)δ ppm 1.52-1.91(m,2H),2.15-2.40(m,2H),2.75-3.40(m Partially hidden,2H),3.03-3.12(m,4H),3.55-3.80(m,1H),3.73-3.83(m,4H),4.44(tt,J=12,4Hz,1H),4.53-4.83(m,1H),7.35(d,J=2Hz,1H),7.46(br d,J=8Hz,2H),7.58(d,J=2Hz,1H),7.60(d,J=9Hz,2H),11.17-11.34(m,1H)

[0227] Example 9: (rac)-6-(1-methylpyrrolidine-3-yl)oxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] To a solution of 6-(1-methylpyrrolidine-3-yl)oxy-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, trihydrochloride (153 mg, 0.36 mmol) in DMF (2.4 mL), DIPEA (232 mg, 0.31 mL, 1.8 mmol) was added, and the resulting reaction mixture was stirred at room temperature for 5 minutes. Then, 4-(trifluoromethoxy)benzoic acid (74 mg, 0.36 mmol), followed by HATU (150 mg, 0.39 mmol), was added, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with ethyl acetate, washed with saturated aqueous solution of NaHCO3, water, and brine, dried over Na2SO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash chromatography (SiO2 12g) of silica gel eluted with DCM / MeOH / 30% aqueous NH4OH (90 / 10 / 1) to obtain 143 mg (78% yield) of (rac)-6-(1-methylpyrrolidine-3-yl)oxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a light brown solid. LC / MS (m / z, M+H): Calculated value 506.2, Measured value 506.2; 1H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.75-1.93(m,3H),2.16-2.36(m,3H),2.29(s,3H),2.41-2.50(m partially hidden,1H),2.61-2.72(m,2H),2.78-2.87(m Partially hidden, 1H), 3.08(td,J=13,3Hz,2H),4.11-4.25(m,2H),4.40(tt,J=12,4Hz,1H),4.83-4.89(m,1H),7.18(d,J=2Hz,1H),7.38(br d,J=8Hz,2H),7.55(d,J=2Hz,1H),7.57(d,J=8Hz,2H),10.58-11.11(m,1H)

[0228] Example 10: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: (2S)-2-(tetrohydropyran-2-yloxymethyl)morpholine [ka] Under an argon atmosphere, DHP (2.48 mL, 2290 mg, 27.3 mmol) and PPTS (343 mg, 1.36 mmol) were successively added to a suspension of [(2S)-morpholine-2-yl]methanol hydrochloride (2.16 g, 13.6 mmol) in DCM (140 mL), and the resulting reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was then diluted with 100 mL of saturated aqueous solution of NaHCO3 and extracted with DCM. The organic layer was then dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography (SiO2 40 g) using silica gel eluted with DCM / MeOH / aqueous 30% NH4OH (95 / 5 / 0.5) to obtain 1.13 g (41% yield) of (2S)-2-(tetrohydropyran-2-yloxymethyl)morpholine as a yellow oil. LC / MS (m / z, M+): Calculated value 201.2, Measured value 201.1

[0229] Step 2: tert-butyl4-[2-oxo-6-[(2S)-2-(tetrohydropyran-2-yloxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate [ka] In a sealed tube, (2S)-2-(tetrohydropyran-2-yloxymethyl)morpholine (319 mg, 1.58 mmol), tert-butyl 4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate (525 mg, 1.32 mmol), and RuPhos (49 mg, 0.11 mmol) were dissolved in THF (0.45 mL). LiHMDS (1 M THF solution, 3.17 mL, 3.17 mmol) was added, and the resulting mixture was bubbling with argon for 5 minutes. Then, Pd(OAc)2 (12 mg, 0.053 mmol) was added, the tube was sealed, and the mixture was heated at 75°C overnight with stirring. After overnight, the reaction mixture was cooled to room temperature, diluted with saturated ammonium chloride aqueous solution, and extracted with DCM. Next, the organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography (SiO2 40g) using silica gel eluted with DCM / MeOH / 30% aqueous NH4OH (94.5 / 5.5 / 0.55) to obtain a solid, which was tritulated in 15 mL of i-Pr2O. The resulting precipitate was filtered off to obtain 544 mg (79% yield) of tert-butyl4-[2-oxo-6-[(2S)-2-(tetrohydropyran-2-yloxymethyl)morpholine-4-yl]-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate as a white solid. LC / MS (m / z, M+): Calculated value 517.3, Measured value 517.0

[0230] Step 3: 6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, hydrochloride [ka] To a solution of tert-butyl 4-[2-oxo-6-[(2S)-2-(tetrohydropyran-2-yloxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate (541 mg, 1.05 mmol) in MeOH (5 mL), 3.13 mL of 4N HCl solution (12.5 mmol) in dioxane was added. The resulting reaction mixture was stirred overnight at room temperature and then concentrated under vacuum. The resulting residue was diluted in MeOH, concentrated three times under vacuum, and the resulting residue was triturated in i-PrOH (20 mL). The precipitate was filtered and washed with ethyl acetate to obtain 367 mg (94% yield) of 6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one hydrochloride as a light brown solid. LC / MS (m / z, M+H): Calculated value 334.2, measured value 334 (free base).

[0231] Step 4: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one [ka] To a suspension of 6-[(2S)-2-(hydroxymethyl)morpholine-4-yl]-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, hydrochloride (180 mg, 0.49 mmol) in DMF (3.2 mL), DIPEA (0.59 mL, 440 mg, 3.41 mmol) was added, and the resulting mixture was stirred at room temperature for 5 minutes. Then, 2-amino-4-(trifluoromethoxy)benzoic acid (108 mg, 0.49 mmol), followed by HATU (185 mg, 0.49 mmol), was added, and the resulting solution was stirred at room temperature overnight. After overnight, the reaction mixture was diluted with 1N aqueous solution of NaOH (5 mL), MeOH (5 mL), and toluene (5 mL), and concentrated under vacuum. The resulting residue was diluted with MeOH and toluene, concentrated three times, and dried. Next, the obtained residue was purified by flash chromatography (12 g) of Puriflash® interchim PF-15SiHP-F0012 eluted with DCM / MeOH / 30% aqueous NH4OH (91.5 / 8.5 / 0.85) to obtain a solid, which was tritulated in i-Pr2O. The precipitate was filtered off to obtain 148 mg (56% yield) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(2S)-2-(hydroxymethyl)morpholine-4-yl]-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 537.2, measured value 537.2; 1H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.75-1.84(m,2H),2.24-2.36(m,2H),2.56(dd,J=12,10Hz,1H),2.74-2.84(m Partially hidden, 1H), 3.01-3.11 (m, 2H), 3.32 (br dd,J=12,2Hz,1H),3.40-3.51(m,2H),3.51-3.59(m,1H),3.59-3.66(m,1H),3.69(td,J=11,3Hz,1H),3.90-3.97(m,1H),4.16(br d,J=13Hz,2H),4.20-4.27(m,1H),4.41(tt,J=12,4Hz,1H),5.32(s,2H),6.45-6.55(m,1H) ,6.66-6.70(m,1H),7.12(d,J=8Hz,1H),7.15(d,J=2Hz,1H),7.57(d,J=2Hz,1H),10.74(br s,1H)

[0232] Example 11: 6-[(2R)-2-(hydroxymethyl)morpholine-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: (2R)-2-(tetrohydropyran-2-yloxymethyl)morpholine [ka] Under an argon atmosphere, DHP (1.28 mL, 1180 mg, 14.1 mmol) and PPTS (177 mg, 0.7 mmol) were successively added to a suspension of [(2R)-morpholine-2-yl]methanol hydrochloride (1.08 g, 7.03 mmol) in DCM (70 mL), and the resulting reaction mixture was stirred at room temperature for 40 hours. The reaction mixture was then concentrated to a volume of approximately 20 mL and slowly poured into a solution of KOH (585 mg, 10.4 mmol) in MeOH (100 mL). The entire mixture was then concentrated to dryness, diluted with DCM, filtered, and the filtrate was concentrated under vacuum. The obtained residue was purified by flash chromatography (SiO240g) of silica gel eluted with DCM / MeOH / aqueous 30% NH4OH (95 / 5 / 0.5) to obtain 1.22 g (86% yield) of (2R)-2-(tetrohydropyran-2-yloxymethyl)morpholine as brown oil. LC / MS (m / z, M+H): Calculated value 202.1, Measured value 202.0

[0233] Step 2: 6-bromo-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, dihydrochloride [ka] To a solution of tert-butyl 4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate (2.01 g, 5.06 mmol) in MeOH (60 mL) and DCM (20 mL) at 45°C, 10.1 mL of 4N HCl solution in dioxane (40.5 mmol) was added, and the resulting mixture was stirred at 45°C for 3 hours. The reaction mixture was then concentrated, and the resulting residue was triturated in ethyl acetate (50 mL). The precipitate was filtered off and washed with ethyl acetate to obtain 1.87 g (100% yield) of 6-bromo-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, dihydrochloride, as a light brown solid. LC / MS (m / z, M+): Calculated value 296.0, Measured value 296.0 (free base)

[0234] Step 3: 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (Example 60) [ka] To a suspension of 6-bromo-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, dihydrochloride (918 mg, 2.48 mmol) in DMF (17 mL), DIPEA (2244 mg, 3.02 mL, 17.4 mmol) was added, and the resulting mixture was stirred at room temperature for 5 minutes. Then, 4-(trifluoromethoxy)benzoic acid (511 mg, 2.48 mmol), followed by HATU (1037 mg, 2.73 mmol), was added, and the resulting mixture was stirred at room temperature overnight. After overnight, the reaction mixture was concentrated under vacuum, diluted with ethyl acetate, and washed with 1N aqueous solution of NaOH (50 mL). The aqueous layer was then extracted twice with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash chromatography (40 g) using a Puriflash® interchim PF-15SiHP / 40G column eluted with DCM / MeOH / 30% aqueous NH4OH (96 / 4 / 0.4) to obtain a solid. This solid was tritulated in i-PrOH (20 mL) to obtain 1.04 g (86% yield) of 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a light brown solid. LC / MS (m / z, M+H): Calculated value 484.0, Measured value 484.0; 1 H NMR(400MHz,DMSO-d6,100℃)d ppm 1.81(br d,J=12.7Hz,2H),2.22-2.33(m,2H),3.01-3.12(m,2H),4.09-4.26(m,2H),4.38-4.47(m,1H),7.39(br d,J=8.4Hz,2H),7.58(br d,J=8.4Hz,2H),7.83(d,J=1.8Hz,1H),7.96(d,J=1.8Hz,1H),11.39-11.49(m,1H)

[0235] Step 4: 6-[(2R)-2-(tetrohydropyran-2-yloxymethyl)morpholin-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] In a sealed tube, (2R)-2-(tetrohydropyran-2-yloxymethyl)morpholine (151 mg, 0.75 mmol), 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (305 mg, 0.63 mmol), and RuPhos (25 mg, 0.05 mmol) were dissolved in THF (0.42 mL). LiHMDS (1 M solution in THF, 1.51 mL, 1.51 mmol) was added, and the resulting mixture was bubbling with argon for 5 minutes. Then, Pd(OAc)2 (6 mg, 0.03 mmol) was added, the tube was sealed, and the mixture was heated overnight at 70°C with stirring. After overnight, the reaction mixture was cooled to room temperature, diluted with saturated ammonium chloride aqueous solution, and extracted with DCM. Next, the organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography (SiO2 40g) using silica gel eluted with DCM / MeOH / 30% aqueous NH4OH (95 / 5 / 0.5) to obtain a solid, which was tritulated in 10 mL of i-Pr2O. The resulting precipitate was filtered to obtain 210 mg (55% yield) of 6-[(2R)-2-(tetrohydropyran-2-yloxymethyl)morpholin-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+): Calculated value 605.2, Measured value 605.0

[0236] Step 5: 6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] 6-[(2R)-2-(tetrohydropyran-2-yloxymethyl)morpholin-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (205 mg, 0.34 mmol) was dissolved in MeOH (15 mL) and DCM (5 mL). 1.02 mL of 4N HCl solution in dioxane (4.06 mmol) was added, and the resulting mixture was stirred overnight at 45°C. After overnight, the entire mixture was concentrated under vacuum, and the resulting residue was diluted with MeOH, basicized with a 15% aqueous solution of NH4OH, and concentrated to dryness. The resulting residue was diluted with MeOH and toluene, concentrated to dryness, and then purified by flash chromatography (SiO2 12 g) of silica gel eluted with DCM / MeOH (94 / 6) to obtain a solid, which was tritulated in i-Pr2O. The precipitate was filtered to obtain 131 mg (74% yield) of 6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a white powder. LC / MS (m / z, M+H): Calculated value 522.2, Measured value 522.2; 1 H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.77-1.85(m,2H),2.31(qd,J=12,4Hz,2H),2.57(dd,J=12,10Hz,1H),2.74-2.84(m,1H),3.0 3-3.15(m,2H),3.27-3.36(m,1H),3.41-3.50(m,2H),3.51-3.58(m,1H),3.58-3.66(m,1H),3. 69(td,J=11,3Hz,1H),3.90-3.99(m,1H),4.11-4.28(m,3H),4.40(tt,J=12,4Hz,1H),7.17(d ,J=2Hz,1H),7.38(d,J=9Hz,2H),7.55(d,J=9Hz,2H),7.57(d,J=2Hz,1H),10.64-10.91(m,1H)

[0237] Example 12: (6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: 6-[(2S)-2-(tetrohydropyran-2-yloxymethyl)morpholin-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] In a sealed tube, (2S)-2-(tetrohydropyran-2-yloxymethyl)morpholine (158 mg, 0.79 mmol), 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (3018 mg, 0.66 mmol), and RuPhos (26 mg, 0.056 mmol) were dissolved in THF (1.6 mL). LiHMDS (1 M solution in THF, 1.57 mL, 1.57 mmol) was added, and the resulting mixture was bubbling with argon for 5 minutes. Then, Pd(OAc)2 (6 mg, 0.03 mmol) was added. The tube was sealed and heated overnight at 70°C with stirring. After overnight, the reaction mixture was cooled to room temperature, diluted with saturated ammonium chloride aqueous solution, and extracted with DCM. Next, the organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography (SiO2 40g) of silica gel eluted with DCM / MeOH / 30% aqueous NH4OH (94.5 / 5.5 / 0.55) to obtain a solid, which was tritulated in 10 mL of i-Pr2O. The resulting precipitate was filtered to obtain 247 mg (62% yield) of 6-[(2S)-2-(tetrohydropyran-2-yloxymethyl)morpholine-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+): Calculated value 605.2, Measured value 605.0

[0238] Step 2: (6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] 6-[(2S)-2-(tetrohydropyran-2-yloxymethyl)morpholin-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (243 mg, 0.40 mmol) was dissolved in MeOH (10 mL) and DCM (5 mL). 1.2 mL of 4N HCl solution in dioxane (4.82 mmol) was added, and the resulting mixture was stirred at 45°C for 4 hours. After 4 hours, the entire mixture was concentrated under vacuum, and the resulting residue was diluted with MeOH, basicized with a 15% aqueous solution of NH4OH, and concentrated to dryness. The resulting residue was diluted with MeOH and toluene, concentrated to dryness, and then purified by flash chromatography (SiO2 12 g) of silica gel eluted with DCM / MeOH (94 / 6) to obtain a solid, which was tritulated in i-Pr2O. The precipitate was filtered to obtain 142 mg (68% yield) of 6-[(2S)-2-(hydroxymethyl)morpholin-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a white powder. LC / MS (m / z, M+H): Calculated value 522.2, measured value 522.2; 1 H NMR(400MHz,DMSO-d6,120℃)δ ppm 1.81(br d,J=11Hz,2H),2.31(qd,J=12,4Hz,2H),2.57(br dd,J=12,10Hz,1H),2.71-2.84(m Partially hidden, 1H), 3.03-3.18 (m, 2H), 3.27-3.36 (m, 1H), 3.40-3.81 (m, 5H), 3.88-4.01 (m, 1H), 4.17 (br d,J=12Hz,3H),4.40(tt,J=12,4Hz,1H),7.17(d,J=2Hz,1H),7.38(br d,J=8Hz,2H),7.55(br d,J=9Hz,2H),7.57(d,J=2Hz,1H),10.62-10.93(m,1H)

[0239] Example 13: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: tert-butyl4-[2-oxo-6-[(2R)-2-(tetrohydropyran-2-yloxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate [ka] In a sealed tube, (2R)-2-(tetrohydropyran-2-yloxymethyl)morpholine (232 mg, 1.15 mmol), tert-butyl 4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate (382 mg, 0.96 mmol), and RuPhos (36 mg, 0.08 mmol) were dissolved in THF (0.64 mL). LiHMDS (1 M solution in THF, 2.31 mL, 2.31 mmol) was added, and the resulting mixture was bubbling with argon for 5 minutes. Then, Pd(OAc)2 (9 mg, 0.04 mmol) was added, the tube was sealed, and the mixture was heated overnight at 75°C with stirring. After overnight, the reaction mixture was cooled to room temperature, diluted with saturated ammonium chloride aqueous solution, and extracted with DCM. Next, the organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography (SiO2 40g) of silica gel eluted with DCM / MeOH / 30% aqueous NH4OH (95 / 5 / 0.5) to obtain a solid, which was tritulated in 15 mL of i-Pr2O. The resulting precipitate was filtered off to obtain 396 mg (79% yield) of tert-butyl4-[2-oxo-6-[(2R)-2-(tetrohydropyran-2-yloxymethyl)morpholine-4-yl]-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate as a white solid. LC / MS (m / z, M+): Calculated value 517.3, Measured value 517.0

[0240] Step 2: 6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, hydrochloride [ka] To a solution of tert-butyl 4-[2-oxo-6-[(2R)-2-(tetrohydropyran-2-yloxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate (390 mg, 0.75 mmol) in MeOH (30 mL) and DCM (5 mL), 2.82 mL of 4N HCl solution (11.3 mmol) in dioxane was added. The resulting reaction mixture was stirred overnight at room temperature and then concentrated under vacuum. The resulting residue was diluted in MeOH, concentrated three times under vacuum, and the resulting residue was triturated in i-PrOH (20 mL). The precipitate was filtered and washed with ethyl acetate to obtain 284 mg (92% yield) of 6-[(2R)-2-(hydroxymethyl)morpholine-4-yl]-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one hydrochloride as a light brown solid. LC / MS (m / z, M+): Calculated value 333.2, measured value 333.0 (free base).

[0241] Step 3: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one [ka] To a solution of 6-[(2R)-2-(hydroxymethyl)morpholine-4-yl]-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, hydrochloride (180 mg, 0.44 mmol) in DMF (3 mL), DIPEA (0.54 mL, 400 mg, 3.1 mmol) was added, and the resulting mixture was stirred at room temperature for 5 minutes. Then, 2-amino-4-(trifluoromethoxy)benzoic acid (98 mg, 0.44 mmol), followed by HATU (185 mg, 0.49 mmol), was added, and the resulting solution was stirred at room temperature for 48 hours. After 48 hours, the reaction mixture was diluted with 1N aqueous solution of NaOH (5 mL), MeOH (5 mL), and toluene (5 mL), and concentrated under vacuum. The obtained residue was diluted with MeOH and toluene, concentrated three times to dryness, and then purified by flash chromatography (12 g) on ​​a Puriflash® interchim PF-15SiHP-F0012 column eluted with DCM / MeOH / 30% aqueous NH4OH (91.5 / 8.5 / 0.85) to obtain a solid, which was tritulated in i-Pr2O. The precipitate was filtered off to obtain 164 mg (69% yield) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(2R)-2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 537.2, measured value 537.2; 1H NMR(400MHz,DMSO-d6,30℃)δ ppm 1.73(br d,J=11Hz,2H),2.21-2.40(m,2H),2.40-2.52(m Partially hidden,1H),2.63-2.77(m,1H),2.88-3.15(m,2H),3.29-3.56(m,4H),3.56-3.64(m,1H),3.60-4.70(m,2H),3.67(td,J=11,2Hz,1H),3.95(br dd,J=11,1Hz,1H),4.37-4.55(m,1H),4.84(t,J=6Hz,1H),5.67(s,2H),6.51(br d,J=8Hz,1H),6.66(br s,1H),7.12(d,J=8Hz,1H),7.33(d,J=2Hz,1H),7.56(d,J=2Hz,1H),11.26(br s,1H)

[0242] Example 14: 1-[1-[2-amino-4-(pentafluoro-λ 6 [-Sulfanil)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] DMF (1 mL) contains 1-(4-piperidyl)-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one; hydrochloride (90 mg, 0.26 mmol), triethylamine (204 μL, 1.46 mmol), 2-amino-4-(pentafluoro-λ6-sulfanyl)benzoic acid; hydrochloride (81 mg, 0.27 mmol), TATU ( Using 103 mg (0.32 mmol), Example 14 was prepared according to the procedure described in step 6 of Example 2, and stirred for 0.5 hours to obtain 55 mg (38% yield) of 1-[1-[2-amino-4-(pentafluoro-λ6-sulfanyl)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 548.2, measured value 548.3; 1H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.70-1.84(m,6H),2.31(m,2H),2.76-2.87(m,1H),3.02-3.13(m,2H),3.39-3 .53(m,2H),3.94-4.00(m,2H),4.09-4.20(m,2H),4.37-4.51(m,1H),5.53(br s,2H),7.01(dd,J=8.4,2.3Hz,1H),7.23(br d,J=8.4Hz,1H),7.28(d,J=2.3Hz,1H),7.42(d,J=1.8Hz,1H),7.79(d,J=1.8Hz,1H),11.00-11.09(m,1H)

[0243] Example 15: (rac)-6-tetrahydrofuran-3-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: (rac)-tert-butyl4-[6-(2,5-dihydrofuran-3-yl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate (400 mg, 1.01 mmol) and 2-(2,5-dihydrofuran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (237 mg, 1.21 mmol) in a dioxane / water mixture (8 mL / 2 mL), K3PO4 (470 mg, 2.21 mmol) was added, and the resulting reaction mixture was bubbling with argon for 5 minutes. Next, chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (73 mg, 0.10 mmol) was added, and the resulting mixture was refluxed for 6 hours, cooled to room temperature, diluted with ethyl acetate, transferred to a separatory funnel, and washed with 1N aqueous NaOH. The aqueous layer was then extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography (SiO2 12 g) eluting with DCM / MeOH97 / 3 to obtain 273 mg (64% yield) of (rac)-tert-butyl4-[6-(2,5-dihydrofuran-3-yl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate as a white solid. LC / MS (m / z, M+H): Calculated value 387.4, measured value 387.3.

[0244] Step 2: (rac)-tert-butyl4-(2-oxo-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate [ka] (rac)-tert-butyl 4-[6-(2,5-dihydrofuran-3-yl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate (270 mg, 0.64 mmol) was dissolved in a mixture of MeOH (10 mL) and DCM (10 mL), to which Pd / C (10%)-50% wet (40 mg) was added. The entire mixture was then hydrogenated with 4 bar H2 at room temperature for 18 hours. The reaction mixture was then filtered and concentrated under vacuum. The obtained residue was purified by flash chromatography (SiO2 12g) eluting with DCM / MeOH / NH4OH (95 / 5 / 0.5) to obtain 240 mg (91% yield) of (rac)-tert-butyl4-(2-oxo-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate as a white solid. LC / MS (m / z, M+H): Calculated value 389.5, measured value 389.3.

[0245] Step 3: (rac)-1-(4-piperidyl)-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-2-one; hydrochloride [ka] (rac)-tert-butyl 4-(2-oxo-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate (235 mg, 0.57 mmol) was dissolved in MeOH (4 mL), to which 2.15 mL of 4N HCl solution (8.62 mmol) in dioxane was added. The resulting mixture was stirred at room temperature for 1 hour and then concentrated under vacuum to obtain 208 mg (100% yield) of (rac)-1-(4-piperidyl)-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-2-one hydrochloride as a white solid. LC / MS (m / z, M+H-HCl): Calculated value 289.2, measured value 289.3.

[0246] Step 4: (rac)-6-tetrahydrofuran-3-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] (rac)-1-(4-piperidyl)-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-2-one;hydrochloride (103 mg, 0.28 mmol) was dissolved in DMF (1.9 mL), to which DIPEA (148 mg, 0.20 mL, 1.14 mmol) was added, and the resulting mixture was stirred for 5 minutes. Then, 4-(trifluoromethoxy)benzoic acid (65 mg, 0.31 mmol) and TBTU (110 mg, 0.34 mmol) were added sequentially. The resulting mixture was then stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of NaHCO3, then with water and brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash chromatography (SiO2 12g) eluting with DCM / MeOH (95 / 5) to obtain 89 mg (65% yield) of (rac)-6-tetrahydrofuran-3-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 477.2, Measured value 477.2; 1 H NMR(400MHz,DMSO-d6,30℃)δ ppm 1.64-1.90(m,2H),1.92-2.04(m,1H),2.16-2.36(m,3H),2,7-3,8(m,3H),3.35-3.49(m,1H),3.59(t ,J=8.0Hz,1H),3.77-3.87(m,1H),3.95-4.07(m,2H),4.41-4.54(m,1H),4.59-4.73(m,1H),7.47(br d,J=8.8Hz,2H),7.57(d,J=1.8Hz,1H),7.61(br d,J=8.8Hz,2H),7.84(d,J=1.8Hz,1H),11.48(br s,1H)

[0247] Example 16: (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] Example 16 was prepared using (rac)-1-(4-piperidyl)-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-2-one;hydrochloride (103 mg, 0.28 mmol), DIPEA (148 mg, 0.2 mL, 1.14 mmol), and 2-amino-4-(trifluoromethoxy)benzoic acid (69 mg, 0.31 mmol), and TBTU (110 mg, 0.34 mmol) in DMF (1.9 mL), following the procedure described in step 4 of Example 15, to obtain 92 mg (65% yield) of (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-2-one as a light brown solid. LC / MS (m / z, M+H): Calculated value 492.2, measured value 492.3; 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.77-1.88(m,2H),1.94-2.05(m,1H),2.22-2.44(m,3H),3.09(br td,J=13.0,1.5Hz,2H),3.40-3.51(m,1H),3.61-3.67(m,1H),3.81-3.89(m,1H),3.97-4.10(m,2H),4.19(br d,J=13,0Hz,2H),4.40-4.59(m,1H),5.43(br s,2H),6.47-6.59(m,1H),6.72(m,1H),7.16(br d,J=8.4Hz,1H),7.43(d,J=1.8Hz,1H),7.83(br d,J=1.8Hz,1H),11.05-11.19(m,1H)

[0248] Example 17: 6-Cyclopentyl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: 6-(cyclopenten-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] A solution of 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (100 mg, 0.21 mmol) and cyclopenta-1-en-1-ylboronic acid (28 mg, 0.25 mmol) in dioxane (2 mL) and water (0.5 mL) was bubbling with argon for 5 minutes. Then, tribasic potassium phosphate (109 mg, 0.51 mmol) and chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (15 mg, 0.021 mmol) were added, and the resulting mixture was refluxed for 2 hours. Next, chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (5 mg, 0.007 mmol) was added, and the resulting solution was refluxed for a further 1 hour. Then, it was cooled to room temperature, diluted with ethyl acetate and water, and transferred to a separatory funnel. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography (SiO2 12 g) eluting with DCM / MeOH95 / 5 to obtain 120 mg (62% yield) of 6-(cyclopenten-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 473.4, measured value 473.3.

[0249] Step 2: 6-Cyclopentyl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Solutions of 6-(cyclopenten-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (120 mg, 0.25 mmol) in MeOH (4 mL) and DCM (4 mL) were bubbling with argon for 5 minutes. Then, 10% Pd / C wet (27 mg, 0.025 mmol) was added, and the resulting mixture was hydrogenated under 3 bar H2 at room temperature for 18 hours. Next, Pd / C 10% wet (10 mg, 0.009 mmol) was added, and the resulting solution was hydrogenated under 3 bar H2 for 48 hours. The solution was filtered, washed with MeOH and DCM, and concentrated under vacuum to obtain 106 mg (88% yield) of 6-cyclopentyl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 475.5, measured value 475.2; 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.51-1.89(m,8H),1.98-2.14(m,2H),2.19-2.40(m,2H),2.99-3.19(m,3 H),4.08-4.28(m,2H),4.38-4.49(m,1H),7.36(d,J=1.8Hz,1H),7.40(br d,J=8.6Hz,2H),7.57(br d,J=8.6Hz,2H),7.78(d,J=1.8Hz,1H),10.88-11.16(m,1H)

[0250] Example 18: 1-[1-[2-hydroxy-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] Under an argon atmosphere, TBTU (148 mg, 0.46 mmol) was added to a solution of 2-hydroxy-4-(trifluoromethoxy)benzoic acid (94 mg, 0.42 mmol) in DMF (3 mL), and the resulting solution was stirred at room temperature for 2 hours. This solution was then added to a solution of 1-(4-piperidyl)-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one hydrochloride (130 mg, 0.38 mmol) in DMF (2 mL), and the resulting reaction mixture was stirred at room temperature for 4 hours. The mixture was then diluted with ethyl acetate and water and transferred to a separatory funnel. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with water and saturated aqueous solutions of NaHCO3, dried over MgSO4, filtered, and concentrated under vacuum. The obtained residue was purified by flash chromatography (SiO2 24g) eluting with DCM / isopropanol 85 / 15 to obtain 55 mg (28% yield) of 1-[1-[2-hydroxy-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 507.2, Measured value 507.2; 1 H NMR(400MHz,DMSO-d6,100℃)δ ppm 1.70-1.84(m,6H),2.22-2.36(m,2H),2.77-2.87(m,1H),2.98-3.10( m,2H),3.41-3.53(m,2H),3.93-4.01(m,2H),4.07-4.20(m,2H),4.37- 4.47(m,1H),6.78-6.84(m,2H),7.28(d,J=8.1Hz,1H),7.36(d,J=1.8Hz,1H),7.79(d,J=1.8Hz,1H),9,98-10.32(m,1H),10.88-11.23(m,1H)

[0251] Example 19: 1-[1-[4-(pentafluoro-λ 6 [-Sulfanil)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] DMF (1 mL) contains 1-(4-piperidyl)-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one; hydrochloride (100 mg, 0.29 mmol), triethylamine (206 μL, 1.47 mmol), and 4-(pentafluoro-λ) 6 Example 19 was prepared using sulfanyl)benzoic acid (75 mg, 0.3 mmol) and TATU (114 mg, 0.35 mmol) according to the procedure described in step 6 of Example 2. The mixture was stirred for 0.5 hours to obtain 57 mg (36% yield) of 1-[1-[4-(pentafluoro-λ6-sulfanyl)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 533.2, measured value 533.2; 1 H NMR(400MHz,DMSO-d6,30℃)δ ppm 1.64-1.90(m,6H),2.19-2.41(partially hidden m,2H),2.78-2.86(m,1H),2.89-2.98(m,1H),3.18-3.27(partially hidden m,1H),3.44(br td,J=11.5,11.5,2.0Hz,2H),3.53-3.71(m,1H),3.91-4.03(m,2H),4.40-4,60(m,1H),4.59-4.74(m,1H),7.59(d,J=1.8Hz,1H),7.70(br d,J=8.5Hz,2H),7.81(br d,J=1.8Hz,1H),8.02(br d,J=8.5Hz,2H),11.41-11.47(m,1H)

[0252] Example 20: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-5-methyl-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: 5-bromo-3-fluoro-6-methylpyridine-2-amine [ka] 3-Fluoro-6-methylpyridine-2-amine (3 g, 23.8 mmol) was stirred in acetonitrile (90 mL) and 1-bromopyrrolidine-2,5-dione (4.23 g, 23.8 mmol) was added at 0°C. The reaction mixture was stirred at room temperature under an argon atmosphere for 1 hour. After 1 hour, the reaction mixture was diluted with ice water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to obtain 3 g (62% yield) of 5-bromo-3-fluoro-6-methylpyridine-2-amine as an off-white solid. LC / MS (m / z, M+H): Calculated value 206.0, measured value 206.7.

[0253] Step 2: 3-Bromo-5-fluoro-2-methyl-6-nitropyridine [ka] Sulfuric acid (60 mL) was added to a stirred solution of hydrogen peroxide (2.49 g, 73.2 mmol) at 0°C. The reaction mixture was then stirred at room temperature under an argon atmosphere for 1.5 hours. After 1.5 hours, 5-bromo-3-fluoro-6-methylpyridine-2-amine (3 g, 14.6 mmol) was added at 0°C, and the reaction mixture was stirred at room temperature for 2 hours. The mixture was then diluted with ice water (500 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to obtain 1.5 g (44% yield) of 3-bromo-5-fluoro-2-methyl-6-nitropyridine as a yellow solid.

[0254] Step 3: tert-butyl 4-[(5-bromo-6-methyl-2-nitro-3-pyridyl)amino]piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-aminopiperidine-1-carboxylate (1.5 g, 7.49 mmol) and 3-bromo-5-fluoro-2-methyl-6-nitropyridine (1.5 g, 6.38 mmol) in tetrahydrofuran (30 mL), potassium carbonate (3.11 g, 22.5 mmol) was added at room temperature. The reaction mixture was stirred at 90 °C for 16 hours. After 16 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with ice water (30 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to obtain 1.5 g (56% yield) of tert-butyl 4-[(5-bromo-6-methyl-2-nitro-3-pyridyl)amino]piperidine-1-carboxylate as a yellow solid. LC / MS (m / z, M+H): Calculated value 416.3, measured value 416.8.

[0255] Step 4: tert-butyl 4-[(2-amino-5-bromo-6-methyl-3-pyridyl)amino]piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-[(5-bromo-6-methyl-2-nitro-3-pyridyl)amino]piperidine-1-carboxylate (1.50 g, 3.61 mmol) in propan-2-ol (60 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (4.59 g, 18.1 mmol), followed by potassium 2-methylpropane-2-oleate (1.22 g, 10.8 mmol), was added at 0°C. The reaction mixture was then stirred at 110°C for 2 hours. After 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with ice water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to obtain 1.39 g (100% yield) of tert-butyl 4-[(2-amino-5-bromo-6-methyl-3-pyridyl)amino]piperidine-1-carboxylate as a blue solid. LC / MS (m / z, M+H): Calculated value 386.3, measured value 387.0.

[0256] Step 5: tert-butyl 4-(6-bromo-5-methyl-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate [ka] A mixture of tert-butyl 4-[(2-amino-5-bromo-3-pyridyl)amino]piperidine-1-carboxylate (1.50 g, 3.88 mmol) and di(imidazole-1-yl)methanone (3.28 g, 20.2 mmol) in 1,4-dioxane (20 mL) was stirred at 90°C for 2 hours. After 2 hours, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with ice water (100 mL) and extracted with ethyl acetate (200 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to obtain 1.5 g (94% yield) of tert-butyl 4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate as an off-white solid. LC / MS (m / z, M+H): Calculated value 411.1, measured value 410.9.

[0257] Step 6: tert-butyl4-[6-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate [ka] 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (750 mg, 3.57 mmol) and tert-butyl 4-(6-bromo-5-methyl-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate (750 mg, 1.82 mmol) were stirred in 1,4-dioxane (10 mL) and water (2 mL). Disodium carbonate (378 mg, 3.57 mmol) was added to the mixture, and the resulting mixture was degassed under an argon stream for 15 minutes. Then, PdCl2 (dppf) (261 mg, 0.357 mmol) was added, and the reaction mixture was stirred at 90°C for 16 hours. After 16 hours, the reaction mixture was cooled to room temperature and then filtered through a Celite bed. The filtrate was diluted with ethyl acetate (50 mL), washed with water (50 mL), and the combined organic layers were dried on anhydrous sodium 2SO4 and concentrated under reduced pressure. The crude compound (30 g) was adsorbed onto silica gel and purified by flash chromatography to obtain 350 mg (46% yield) of tert-butyl 4-[6-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate as an off-white solid. LC / MS (m / z, M+H): Calculated value 415.2, measured value 415.3.

[0258] Step 7: 6-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, dihydrochloride [ka] To a stirred solution of tert-butyl 4-[6-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate (300 mg, 0.72 mmol) in dichloromethane (5 mL), a 4 M hydrogen chloride solution (4.00 mol / L, 1.81 mL, 7.24 mmol) in dioxane was added under an argon atmosphere, and the reaction mixture was then stirred at room temperature for 1 hour. After 1 hour, the reaction mixture was concentrated under reduced pressure. The resulting residue was triturated with diethyl ether (50 mL) and filtered to obtain 300 mg (quantitative yield) of 6-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one dihydrochloride as an off-white solid. LC / MS (m / z, M+H-2HCl): Calculated value 315.2, measured value 315.0.

[0259] Step 8: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-3H-imidazo[4,5-b]pyridine-2-one [ka] 2-amino-4-(trifluoromethoxy)benzoic acid (200 mg, 0.90 mmol) and 6-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, dihydrochloride (0.284 g, 0.73 mmol) were stirred in N,N-dimethylformamide (5 mL). N,N-diethylethanamine (275 mg, 2.71 mmol) and [benzotriazole-1-yloxy(dimethylamino)methylene]-dimethylammonium;tetrafluoroborate (348 mg, 1.09 mmol) were added at 0°C. The reaction mixture was stirred at room temperature under an argon atmosphere for 1 hour. After 1 hour, the reaction mixture was concentrated under reduced pressure, and the resulting residue was diluted with ice water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography to obtain 200 mg (53% yield) of (1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-3H-imidazo[4,5-b]pyridine-2-one as a yellow solid. LC / MS (m / z, M+H): Calculated value 518.2, measured value 518.4.

[0260] Step 9: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-5-methyl-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] To a stirred solution of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3,6-dihydro-2H-pyran-4-yl)-5-methyl-3H-imidazo[4,5-b]pyridine-2-one (200 mg, 0.39 mmol) in methanol (10 mL), Pd / C (206 mg, 1.93 mmol) and a catalytic amount of acetic acid (2.3 mg, 0.039 mmol) were added under an inert atmosphere, and the reaction mixture was stirred at room temperature for 16 hours under 1 atm of hydrogen. After 16 hours, the reaction mixture was filtered through a Celite bed, washed with ethanol, and concentrated to dryness. The resulting residue was purified by preparative HPLC to obtain 67 mg (33% yield) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-5-methyl-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one as an off-white solid. LC / MS (m / z, M+H): Calculated value 520.2, measured value 520.1. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.25-11.34(m,1H)7.37-7.52(m,1H)7.07-7.18(m,1H)6.63-6.73(m,1H)6.42-6.57(m,1H)5.64-5.79(m,2H)4.37-4.55(m,1H)3.89-4. 05(m,2H)3.40-3.56(m,2H)2.86-3.12(m,3H)2.42-2.46(m,3H)2.30-2.35(m,1H)1.76-1.87(m,2H)1.69-1.76(m,2H)1.54-1.63(m,2H).

[0261] Example 21: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-fluorospiro[3,3]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 2-(2-fluorospiro[3.3]heptan-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (60 mg, 0.25 mmol in step 1), Example 21 was prepared according to the procedure described for the preparation of Example 40, yielding 51 mg (38% yield, 2 steps total) of (1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-fluorospiro[3.3]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 534.2, measured value 534.3; 1 H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.75(br d,J=11.1Hz,2H)2.09-2.43(m,10H)2.60-2.69(m,1H)2.95-3.13(m,2H)3.40-3.43(m Partially hidden, 2H)4.41-4.51(m,1H)5.00(dquin,J=55.9,6.7,6.7,6.7,6.7Hz,1H)6.51(dd,J=8.4,1.2Hz ,1H)6.69(d,J=1.2Hz,1H)7.14(d,J=8.4Hz,1H)7.48(d,J=1.5Hz,1H)7.76(d,J=1.5Hz,1H)11.44(br s,1H).

[0262] Example 22: (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-oxo-4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)piperidine-2-one (56 mg, 0.25 mmol in step 1), Example 22 was prepared according to the procedure described for the preparation of Example 40, yielding 51 mg (39% yield, 2 steps total) of (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-oxo-4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 519.2, measured value 519.3; 1 H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.75(br d,J=11.1Hz,2H)1.86-1.96(m,2H)2.20-2.37(m,2H)2.37-2.45(m,2H)2.94-3.13(m,3H)3.23-3.28(m,2H)3.39-3.43(m Hidden,2H)4.41-4.51(m,1H)6.51(br d,J=8.4Hz,1H)6.67(br s,1H)7.14(d,J=8.4Hz,1H)7.56-7.59(m,1H)7.60(d,J=1.5Hz,1H)7.83(d,J=1.5Hz,1H)11.49(br s,1H).

[0263] Example 23: (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(tetrahydrofuran-3-ylmethyl)-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 4,4,5,5-tetramethyl-2-(tetrahydrofuran-3-ylmethyl)-1,3,2-dioxaborolane (53 mg, 0.25 mmol in step 1), Example 23 was prepared according to the procedure described for the preparation of Example 40, yielding 50 mg (40% yield, 2 steps total) of (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(tetrahydrofuran-3-ylmethyl)-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 506.2, measured value 506.3; 1 H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.50-1.61(m,1H)1.75(br d,J=11.1Hz,2H)1.85-1.94(m,1H)2.19-2.34(m,2H)2.42-2.48(m,1H)2.60-2.70(m,2H)2.93-3.12(m,2H)3.32-3.38(m Partially hidden, 3H)3.63-3.67(m,1H)3.68-3.74(m,1H)3.74-3.81(m,1H)4.38-4.52(m,1H)6.51(br d,J=8.4Hz,1H)6.67(br s,1H)7.15(d,J=8.4Hz,1H)7.58(d,J=1.6Hz,1H)7.76(d,J=1.6Hz,1H)11.46(br s,1H).

[0264] Example 24: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 2-(2-methoxyethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (46 mg, 0.25 mmol in step 1), Example 24 was prepared according to the procedure described for the preparation of Example 40, yielding 60 mg (50% yield, 2 steps total) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 480.2, measured value 480.2; 1 H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.75(br d,J=11.1Hz,2H)2.19-2.34(m,2H)2.82(t,J=6.8Hz,2H)2.94-3.13(m,2H)3.26(s,3H)3.40-3.43(m Hidden, 2H)3.55-3.56(m Partially hidden, 2H)4.41-4.51(m,1H)6.51(br d,J=8.4Hz,1H)6.67(br s,1H)7.15(d,J=8.4Hz,1H)7.60(d,J=1.5Hz,1H)7.78(d,J=1.5Hz,1H)11.45(br s,1H).

[0265] Example 25: (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-2-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 4,4,5,5-tetramethyl-2-tetrahydrofuran-2-yl-1,3,2-dioxaborolane (50 mg, 0.25 mmol in step 1), Example 25 was prepared according to the procedure described for the preparation of Example 40, yielding 56 mg (45% yield, 2 steps total) of (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-2-yl-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 492.2, measured value 492.2; 1H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.68-1.85(m,3H)1.90-2.06(m,2H)2.16-2.37(m,3H)2.95-3.15(m,2H)3.40-3.46(m Hidden,2H)3.78-3.83(m,1H)3.99-4.05(m,1H)4.42-4.52(m,1H)4.81(t,J=7.2Hz,1H)6.51(br d,J=8.4Hz,1H)6.67(br s,1H)7.14(d,J=8.4Hz,1H)7.54(d,J=1.5Hz,1H)7.88(d,J=1.5Hz,1H)11.53(br s,1H).

[0266] Examples 26 and 27: trans-6-(4-methoxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one and cis-6-(4-methoxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: 6-(4-methoxycyclohexen-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (200 mg, 0.41 mmol, Example 60) and 2-(4-methoxycyclohexa-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (118 mg, 0.49 mmol), Step 1 of Examples 26 and 27 was carried out according to the protocol described in Step 1 of Example 17, yielding 166 mg (78% yield) of 6-(4-methoxycyclohexen-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H-TFA): Calculated value 517.2, measured value 517.2.

[0267] Step 2: cis-6-(4-methoxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one and trans-6-(4-methoxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 6-(4-methoxycyclohexen-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (164 mg, 0.32 mmol), step 2 of Examples 26 and 27 was carried out according to the protocol described in step 2 of Example 17. 9 mg (5% yield) of trans-6-(4-methoxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one was obtained as a white solid. LC / MS (m / z, M+H-TFA): Calculated value 519.2, measured value 519.5 1H NMR(400MHz,DMSO-d6,100℃)d ppm 1.25-1.36(m,2H),1.51-1.63(m,2H),1.82(br d,J=12.7Hz,2H),1.90(br d,J=12.7Hz,2H),2.13(br d,J=12.7Hz,2H),2.26-2.36(m,2H),2.54-2.63(m,1H),3.07-3.15(m,2H),3.18-3.28(m ,1H),3.30(s,3H),4.13-4.30(m,2H),4.39-4.48(m,1H),7.39(d,J=1.8Hz,1H),7.42(br d,J=8.4Hz,2H),7.59(d,J=8.4Hz,2H),7.79(d,J=1.8Hz,1H),10.99-11.08(m,1H); and 43 mg (26% yield) of cis-6-(4-methoxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one was obtained as a white solid. LC / MS (m / z, M+H-TFA): Calculated value 519.2, measured value 519.5; 1 H NMR(400MHz,DMSO-d6,100℃)d ppm 1.51-1.65(m,4H),1.70-1.86(m,4H),1.99(br d,J=12.7Hz,2H),2.25-2.35(m,2H),2.59-2.67(m,1H),3.06-3.17(m,2H),3.28(s,3H), 3.46-3.52(m,1H),4.09-4.30(m,2H),4.41-4.51(m,1H),7.34(d,J=1.8Hz,1H),7.41(br d,J=8.4Hz,2H),7.58(br d,J=8.4Hz,2H),7.77(d,J=1.8Hz,1H),10.92-11.13(m,1H).

[0268] Example 28: (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3-azabicyclo[4.1.0]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one, 2,2,2-trifluoroacetic acid [ka] Example 28 was prepared using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-azabicyclo[4.1.0]heptane, hydrochloride (65 mg, 0.25 mmol in step 1) following the procedure described for the preparation of Example 34, yielding 3 mg (2% yield, 2 steps total) of (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3-azabicyclo[4.1.0]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one, 2,2,2-trifluoroacetic acid as a solid. LC / MS (m / z, M+H-TFA): Calculated value 517.2, Measured value 517.3; 1 H NMR(400.23MHz,DMSO-d6)d ppm 8.36(br s,2H),7.14(br d,J=8.44Hz,2H),6.68(s,2H),6.52(br d,J=9.78Hz,1H),3.67(br d,J=7.70Hz,4H),3.62(br d,J=4.16Hz,1H),3.15(m,2H),2.50(u),2.33(s,1H),2.25(br d,J=11.74Hz,2H),2.18(s,1H),1.79(br d,J=14.06Hz,3H),1.25(m,5H),1.16(br d,J=3.18Hz,1H),1.11(br (dd, J=17.24, 11.49Hz, 2H)

[0269] Example 29: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-cyclobutyl-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 2-cyclobutyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (45 mg, 0.25 mmol in step 1), Example 29 was prepared according to the procedure described for the preparation of Example 34, yielding 56 mg (47% yield, 2 steps total) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-cyclobutyl-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 476.2, measured value 476.2; 1 H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.75(br d,J=11.1Hz,2H)1.80-1.88(m,1H)1.91-2.02(m,1H)2.10-2.22(m,2H)2.23-2.36(m,4H)2.97-3.13(m,2H)3.50-3.58(m Partially hidden, 3H)4.42-4.53(m,1H)6.51(dd,J=8.4,1.2Hz,1H)6.68(d,J=1.2Hz, 1H)7.14(d,J=8.4Hz,1H)7.54(d,J=1.5Hz,1H)7.79(d,J=1.5Hz,1H)11.44(br s,1H).

[0270] Example 30: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 4,4,5,5-tetramethyl-2-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-1,3,2-dioxaborolane (65 mg, 0.25 mmol in step 1), Example 30 was prepared according to the procedure described for the preparation of Example 34, yielding 12 mg (9% yield, 2 steps total) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 556.2, Measured value 556.2; 1 H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.75(br d,J=11.1Hz,2H)2.24-2.39(m,2H)2.32(s,6H)2.95-3.10(m,2H)3.39-3.39(m Hidden, 2H)4.40-4.51(m,1H)6.51(br d,J=8.4Hz,1H)6.68(br s,1H)7.12(d,J=8.4Hz,1H)7.50(d,J=1.5Hz,1H)7.81(d,J=1.5Hz,1H)11.58(br s,1H).

[0271] Example 31: (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3-oxabicyclo[4.1.0]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 4,4,5,5-tetramethyl-2-(3-oxabicyclo[4.1.0]heptan-6-yl)-1,3,2-dioxaborolane (56 mg, 0.25 mmol in step 1), Example 31 was prepared according to the procedure described for the preparation of Example 34, yielding 10 mg (8% yield, 2 steps total) of (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3-oxabicyclo[4.1.0]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 518.2, Measured value 518.3; 1 H NMR(400MHz,DMSO-d6,27℃)δ ppm 0.84-0.89(m,1H)1.03(dd,J=9.1,4.5Hz,1H)1.35-1.40(m,1H)1.75(br d,J=11.1Hz,2H)1.87-1.94(m,1H)2.05-2.14(m,1H)2.22-2.39(m,2H)2.97-3.10(m,2H)3.47-3.50(m Partially hidden, 4H)3.82(d,J=11.3Hz,1H)4.03(dd,J=11.3,4.6Hz,1H)4.40-4.52(m,1H)6.51(br d,J=8.4Hz,1H)6.68(br s,1H)7.13(d,J=8.3Hz,1H)7.49(d,J=1.8Hz,1H)7.86(d,J=1.8Hz,1H)11.45(br s,1H).

[0272] Example 32: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-bicyclo[2.1.1]hexanyl)-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 2-(1-bicyclo[2.1.1]hexanyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (52 mg, 0.25 mmol in step 1), Example 32 was prepared according to the procedure described for the preparation of Example 34, yielding 6 mg (5% yield, 2 steps total) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-bicyclo[2.1.1]hexanyl)-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 502.2, measured value 502.3; 1 H NMR(400.23MHz,DMSO-d6)d ppm 11.45(br s,1H),7.79(d,J=1.71Hz,1H),7.46(d,J=1.71Hz,1H),7.12(d,J=8.31Hz,1H),6.68(s,1H),6.51(br d,J=8.56Hz,1H),4.46(br s,1H),3.05(br s,2H),2.89(br s,1H),2.67(s,1H),2.50(u),2.45(br s,1H),2.33(br d,J=1.83Hz,2H),2.09(m,1H),1.80(m,7H),1.55(br d,J=8.07Hz,3H),1.45(dd,J=3.73,1.77Hz,1H),1.41(br d,J=4.16Hz,1H),1.26(m,1H),0.81(dd,J=4.03,1.96Hz,1H).

[0273] Example 33: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 2-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (61 mg, 0.25 mmol in step 1), Example 33 was prepared according to the procedure described for the preparation of Example 34, yielding 12 mg (9% yield, 2 steps total) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 538.2, measured value 538.2; 1 H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.75(br d,J=11.1Hz,2H)2.15(s,6H)2.22-2.40(m,2H)2.94-3.11(m,2H)3.41-3.41(m Hidden, 2H)4.40-4.51(m,1H)6.15(t,J=56.4Hz,1H)6.51(br d,J=8.4Hz,1H)6.68(br s,1H)7.12(d,J=8.4Hz,1H)7.48(d,J=1.7Hz,1H)7.79(d,J=1.7Hz,1H)11.55(br s,1H).

[0274] Example 34: (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-norcalan-1-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: (rac)-tert-butyl N-[2-[4-(6-norcalan-1-yl-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate [ka] (rac)-4,4,5,5-tetramethyl-2-norcalan-1-yl-1,3,2-dioxaborolane (55 mg, 0.25 mmol) was weighed into a 4 mL glass vial equipped with a magnetic stirring rod and a screw cap. Subsequently, 1 mL of stock solution A (prepared according to Example 40, Step 1), 0.5 mL of stock solution B (prepared according to Example 40, Step 1), and 4-acetamidopiperidine (27 mg, 0.19 mmol) were added. The vial was closed with a septum-type screw cap. The mixture was degassed for 2 minutes using an argon-connected needle and a second needle (pressure compensation) (argon stream). The reaction mixture was then stirred for 6 hours while being irradiated with a blue LED (445 nm, 190 mW). After 6 hours, the reaction mixture was filtered over a 0.45 μm syringe filter, the vial / filter was rinsed with 0.5 mL of DMF, and the filtrate was subjected to preparative reverse-phase HPLC purification (column: Waters Sunfire C18 OBD 5 μm, 50 × 50 mm, eluted with water + 0.1% TFA / acetonitrile, flow rate 2 mL / min) to obtain 80 mg (52% yield) of (rac)-tert-butyl N-[2-[4-(6-norcalan-1-yl-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate as a solid, which was used in the next step. LC / MS (m / z, M+): calculated value 615.3, measured value 614.2.

[0275] Step 2: (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-norcalan-1-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-norcalan-1-yl-3H-imidazo[4,5-b]pyridine-2-one (80 mg, 0.13 mmol) was placed in an RG24 tube (24 mL thick-walled test tube) and dissolved in 3 mL of dichloromethane. 1 mL of trifluoroacetic acid was added, the vial was screw-capped and shaken overnight at room temperature. After a night, 3 mL of fluorobenzene was added as an azeotrope, and the reaction mixture was evaporated to obtain 5 mg (7% yield) of ((rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-norcalan-1-yl-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 516.2, measured value 516.3; 1 H NMR(400MHz,DMSO-d6,27℃)δ ppm 0.66(t,J=5.0Hz,1H)0.93(dd,J=9.5,5.0Hz,1H)1.18-1.24(m,2H)1.30-1.40(m,2H)1.42-1.51(m,1H)1.59-1.69(m,1H)1.75(br d,J=11.1Hz,2H)1.80-1.88(m,1H)2.01-2.12(m,2H)2.19-2.37(m,2H)2.97-3.11(m,2H)3.43-3.44(m hidden,2H)4.40-4.50(m,1H)6.51(br d,J=8.4Hz,1H)6.69(br s,1H)7.13(d,J=8.4Hz,1H)7.44(d,J=1.8Hz,1H)7.83(d,J=1.8Hz,1H)11.41(br s,1H).

[0276] Example 35: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4,4-difluorocyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 2-(4,4-difluorocyclohexyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (62 mg, 0.25 mmol in step 1), Example 35 was prepared according to the procedure described for the preparation of Example 40, yielding 34 mg (25% yield, 2 steps total) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4,4-difluorocyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 540.2, measured value 540.2; 1 H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.67-1.82(m,4H)1.84-2.05(m,4H)2.10-2.19(m,2H)2.23-2.40(m,2H)2.66-2.80(m,1H)3.04(s,2H)3.21-3.43(m Partially hidden, 2H)4.42-4.52(m,1H)6.51(dd,J=8.4,1.2Hz,1H)6.69(d,J=1.2Hz, 1H)7.14(d,J=8.4Hz,1H)7.54(d,J=1.7Hz,1H)7.80(d,J=1.7Hz,1H)11.45(br s,1H).

[0277] Example 36: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-cyclohexyl-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 2-cyclohexyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (52 mg, 0.25 mmol in step 1), Example 36 was prepared according to the procedure described for the preparation of Example 40, yielding 29 mg (23% yield, 2 steps total) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-cyclohexyl-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 504.2, measured value 504.3; 1H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.24-1.55(m,5H)1.67-1.85(m,7H)2.22-2.38(m,2H)2.52-2.58(m,1H)2.95-3.14(m,2H)3.44-3.46(m Hidden, 2H)4.40-4.51(m,1H)6.51(dd,J=8.3,1.2Hz,1H)6.68(d,J=1.2Hz,1H)7.14(d,J=8.3Hz,1H)7.52(d,J=1.7Hz,1H)7.77(d,J=1.7Hz,1H)11.41(br s,1H).

[0278] Example 37: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-norbornan-2-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 4,4,5,5-tetramethyl-2-norbornan-2-yl-1,3,2-dioxaborolane (55 mg, 0.25 mmol in step 1), Example 37 was prepared according to the procedure described for the preparation of Example 40, yielding 32 mg (25% yield, 2 steps total) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-norbornan-2-yl-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 516.2, measured value 516.3; 1 H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.15-1.20(m,1H)1.24-1.29(m,1H)1.35-1.42(m,1H)1.50-1.61(m,3H)1.61-1.68(m,1 H)1.71-1.81(m,3H)2.20-2.38(m,4H)2.73-2.80(m,1H)2.97-3.14(m,2H)3.31-3.42(m Hidden,2H)4.42-4.53(m,1H)6.51(br d,J=8.3Hz,1H)6.69(br s,1H)7.13(d,J=8.3Hz,1H)7.44(d,J=1.7Hz,1H)7.78(d,J=1.7Hz,1H)11.41(br s,1H).

[0279] Example 38: (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-2-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 4,4,5,5-tetramethyl-2-tetrohydropyran-2-yl-1,3,2-dioxaborolane (53 mg, 0.25 mmol in step 1), Example 38 was prepared according to the procedure described for the preparation of Example 40, yielding 48 mg (38% yield, 2 steps total) of (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-2-yl-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 506.2, Measured value 506.2; 1 H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.52-1.67(m,4H)1.70-1.92(m,4H)2.16-2.36(m,2H)2.98-3.16(m,2H)3.52-3.58(m partially hidden,3H)4.03(br d,J=10.8Hz,1H)4.35(br d,J=10.8Hz,1H)4.40-4.54(m,1H)6.51(dd,J=8.4,1.2Hz,1H)6.68(d,J=1.2Hz ,1H)7.14(d,J=8.4Hz,1H)7.56(d,J=1.7Hz,1H)7.88(d,J=1.7Hz,1H)11.52(br s,1H).

[0280] Example 39: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(tetrohydropyran-4-ylmethyl)-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 4,4,5,5-tetramethyl-2-(tetrohydropyran-4-ylmethyl)-1,3,2-dioxaborolane (56 mg, 0.25 mmol in step 1), Example 39 was prepared according to the procedure described for the preparation of Example 40, yielding 46 mg (35% yield, 2 steps total) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(tetrohydropyran-4-ylmethyl)-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 520.2, measured value 520.3; 1 H NMR(400.23MHz,DMSO-d6)d ppm 11.45(br s,1H),7.72(d,J=1.47Hz,1H),7.53(d,J=1.47Hz,1H),7.15(d,J=8.31Hz,1H),6.68(d,J=1.10Hz,1H),6.50(d,J=7.81Hz,1H),4.45(br t,J=12.04,12.04Hz,2H),3.83(br dd,J=11.13,3.06Hz,5H),3.76(br s,1H),3.54(br s,101H),3.24(br t,J=10.88,10.88Hz,4H),3.15(u),3.03(br s,2H),2.50(u),2.33(br s,1H),2.25(br s,2H),1.75(m,4H),1.49(br d,J=12.72Hz,2H),1.21(m,4H).

[0281] Example 40: (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-3-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: (rac)-tert-butyl N-[2-[4-(2-oxo-6-tetrohydropyran-3-yl-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate [ka] Stock solution A was prepared as follows: In a glass stoppered Erlenmeyer flask, tert-butyl N-[2-[4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate (1651 mg, 2.75 mmol) and [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 (31 mg, 0.028 mmol) were dissolved in dry DMF to a total volume of 22 mL.

[0282] Stock solution B was prepared as follows: Nickel(II) chloride ethylene glycol dimethyl ether complex (30.2 mg, 0.138 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (36.9 mg, 0.138 mmol) were weighed into an Erlenmeyer flask equipped with a septum. Then, 11 mL of DMF was added, and the resulting mixture was heated to 70-100°C using a heat gun until the solution became clear and green.

[0283] Next, 4,4,5,5-tetramethyl-2-tetrohydropyran-3-yl-1,3,2-dioxaborolane (53 mg, 0.25 mmol) was weighed into a 4 mL glass vial equipped with a magnetic stirring rod and a screw cap. Subsequently, 1 mL of stock solution A, 0.5 mL of stock solution B, and morpholine (16 μL, 0.19 mmol) were added. The vial was closed with a septum-type screw cap. The reaction mixture was stirred for 4 hours while being irradiated with a blue LED (445 nm, 190 mW). After 4 hours, the reaction mixture was filtered over a 0.45 μm syringe filter, the vial / filter was rinsed with 0.5 mL of DMF, and the filtrate was separated and subjected to RP-HPLC purification (column: Waters Sunfire C18 OBD 5 μm, 50 × 50 mm, eluted with water + 0.1% TFA / acetonitrile, flow rate 2 mL / min) to obtain 75 mg (50% yield) of (rac)-tert-butyl N-[2-[4-(2-oxo-6-tetrohydropyran-3-yl-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate as a white solid, which was used in the next step. LC / MS (m / z, M+H-BOC): Calculated value 505.2, Measured value 505.2

[0284] Step 2: (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-3-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] (rac)-tert-butylN-[2-[4-(2-oxo-6-tetrohydropyran-3-yl-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate (75 mg, 0.12 mmol) was placed in an RG24 tube (24 mL thick-walled test tube) and dissolved in 3 mL of dichloromethane. 1 mL of trifluoroacetic acid was added, the vial was screw-capped, and the mixture was shaken overnight at room temperature. After overnight, 3 mL of fluorobenzene was added as an azeotrope, and the reaction mixture was evaporated to obtain 18 mg (29% yield) of (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-3-yl-3H-imidazo[4,5-b]pyridin-2-one as a solid. LC / MS (m / z, M+H): Calculated value 506.2, measured value 506.3; 1 H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.58-1.98(m,6H)2.17-2.38(m,2H)2.78-2.87(m,1H)2.95-3.11(m,2H)3.35-3.37(m Partially hidden, 4H)3.80-3.92(m,2H)4.46(br t,J=12.1Hz,1H)6.51(br d,J=8.4Hz,1H)6.68(br s,1H)7.14(d,J=8.4Hz,1H)7.57(d,J=1.7Hz,1H)7.82(d,J=1.7Hz,1H)11.47(br s,1H).

[0285] Example 41: 6-Tetrohydropyran-4-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Example 41 was prepared using 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (61 mg, 0.13 mmol) and 4,4,5,5-tetramethyl-2-tetrohydropyran-4-yl-1,3,2-dioxaborolane (53 mg, 0.25 mmol) according to the protocol described for the preparation of Example 42, yielding 31 mg (50% yield) of 6-tetrohydropyran-4-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 491.2, Measured value 491.2; 1 H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.66-1.88(m,6H)2.18-2.40(m,2H)2.78-2.87(m,1H)2.88-3.06(m,1H)3.12-3.27(m,1H)3.44(br td,J=11.6,2.1Hz,2H)3.59-3.80(m,1H)3.97(br dd,J=11.1,3.5Hz,2H)4.43-4.53(m,1H)4.59-4.75(m,1H)7.47(br d,J=8.4Hz,2H)7.58(d,J=1.7Hz,1H)7.62(br d,J=8.4Hz,2H)7.81(d,J=1.7Hz,1H)11.44(br s,1H).

[0286] Example 42: 6-(oxetan-3-ylmethyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] (Ir[dF(CF3)ppy]2(dtbpy))PF6 (1.42 mg, 0.0013 mmol), 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (61 mg, 0.13 mmol, Example 60), and 4,4,5,5-tetramethyl-2-(oxetan-3-ylmethyl)-1,3,2-dioxaborolane (50 mg, 0.25 mmol) were dissolved in 0.75 mL of DMF in a 4 mL glass vial. In a second vial, nickel(II) chloride ethylene glycol dimethyl ether complex (1.4 mg, 0.0063 mmol) and 4,4'-di-tert-butyl-2,2'-bipyridine (1.7 mg, 0.0063 mmol) were dissolved in 0.5 mL of DMF. The mixture was sonicated for 1 minute, and then heated to 100°C until the complex was completely formed (a clear green solution). Both mixtures were combined, morpholine (16 mg, 0.189 mmol) was added, and the mixture was irradiated with a blue LED (Lumidox96 LED array; 445 nm (indigo); 180 mW, 5 cm distance) for 5 hours. After 5 hours, the reaction mixture was purified by preparative HPLC (conditions: mobile phase A: water + 0.1% TFA; mobile phase B: acetonitrile; column: Waters Sunfire C18 OBD 5 μm, 50 × 50 mm; gradient: time (min) %B, 0 min 5%, 2.5 min 25%, 10.5 min 65%, 11 min 99%, 13.5 min 5%; flow rate: 2 mL / min). Subsequently, 20 mL of 10% NaHCO3 (aqueous solution) was added to the collected fraction, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phase was dried over MgSO4. After filtration, the solvent was removed under reduced pressure to obtain 27 mg (45% yield) of 6-(oxetan-3-ylmethyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a colorless oil. LC / MS (m / z, M+H): Calculated value 477.2, measured value 477.2; 1H NMR(400MHz,DMSO-d6,27℃)δ ppm 1.64-1.88(m,2H)2.13-2.36(m,2H)2.85-3.02(m,1H)2.97(d,J=7.7Hz,2H)3.15-3.29(m,2H)3.57-3. 76(m,1H)4.36(t,J=5.9Hz,2H)4.40-4.52(m,1H)4.57-4.77(m,1H)4.62(dd,J=7.7,5.9Hz,2H)7.47(br d,J=8.4Hz,2H)7.57(d,J=1.5Hz,1H)7.63(br d,J=8.4Hz,2H)7.75(d,J=1.5Hz,1H)11.46(br s,1H).

[0287] Examples 55, 43, and 44: (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[tetrahydrofuran-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, and 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[tetrahydrofuran-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, isomers 1 and 2 [ka]

[0288] Step 1 (Example 55): (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[tetrahydrofuran-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one [ka] Using (rac)-1-(4-piperidyl)-6-tetrahydrofuran-3-yloxy-3H-imidazo[4,5-b]pyridine-2-one, dihydrochloride (113 mg, 0.3 mmol, prepared in step 4 of Example 56), and 2-amino-4-(trifluoromethoxy)benzoic acid (73 mg, 0.33 mmol), step 1 of Examples 43 and 44 was carried out according to the protocol described in step 4 of Example 15 to obtain 98 mg (64% yield) of (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[tetrahydrofuran-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one as a pale yellow solid. LC / MS (m / z, M+H): Calculated value 508.2, measured value 508.1; 1 H NMR(400MHz,DMSO-d6,100℃)d ppm 1.81(br d,J=12.7Hz,2H),1.99-2.07(m,1H),2.16-2.25(m,1H),2.25-2.35(m,2H),3.01-3.11(m,2H),3.76-3.93(m,4H),4.18(br d,J=12.7Hz,2H),4.37-4.47(m,1H),5.04(ddt,J=2.2 and 4.4 and 6.4Hz,1H),5.43(br s,2H),6.50(br d,J=8.4Hz,1H),6.70(br s,1H),7.16(d,J=8.4Hz,1H),7.28(d,J=2.4Hz,1H),7.61(d,J=2.4Hz,1H),11.03(br s,1H).

[0289] Step 2 (Examples 43 and 44): 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[tetrahydrofuran-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, isomers 1 and 2 [ka] Chiral separation of (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[tetrahydrofuran-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one (85 mg, 0.17 mmol) was performed using a Chiralpak AD column (20 μm, 250 × 4.6 mm) eluted with (heptane 50 / EtOH 50) + 0.1% TEA (flow rate 1 mL / min, UV detection at 254 nm), yielding 46 mg (54% yield) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[tetrahydrofuran-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, isomer 1. LC / MS (m / z, M+H): Calculated value 508.2, measured value 508.1; 1 H NMR(400MHz,DMSO-d6,100℃)d ppm 1.78(br d,J=12.7Hz,2H),1.97-2.06(m,1H),2.15-2.24(m,1H),2.24-2.33(m,2H),3.03-3.08(m Partially hidden,2H),3.74-3.90(m,4H),4.16(br d,J=12.7Hz,2H),4.36-4.45(m,1H),5.01(ddt,J=2.2 and 4.4 and 6.4Hz,1H),5.41(br s,2H),6.48(br d,J=8.4Hz,1H),6.68(br s,1H), 7.14(d,J=8.4Hz,1H), 7.26(d,J=2.4Hz,1H), 7.59(d,J=2.4Hz,1H), 10.87-11.13(m,1H); and 32 mg (38% yield) of 11-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[tetrahydrofuran-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, isomer 2 was obtained. LC / MS (m / z,M+H): Calculated value 508.2, measured value 508.1; 1H NMR(400MHz,DMSO-d6,100℃)d ppm 1.78(br d,J=12.7Hz,2H),1.97-2.05(m,1H),2.14-2.23(m,1H),2.23-2.34(m,2H),3.00-3.09(m,2H),3.74-3.91(m,4H),4.16(br d,J=12.7Hz,2H),4.36-4.45(m,1H),5.01(ddt,J=2.2 and 4.4 and 6.4Hz,1H),5.41(br s,2H),6.48(br d,J=8.4Hz,1H),6.68(br s,1H),7.14(d,J=8.4Hz,1H),7.25(d,J=2.4Hz,1H),7.59(d,J=2.4Hz,1H),10.70-11.20(m,1H).

[0290] Examples 45 and 46: trans-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one and cis-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: (rac)-tert-butyl N-[2-[4-[6-(4-methoxycyclohexen-1-yl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate [ka] tert-butyl N-[2-[4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate (300 mg, 0.5 mmol, Example 59) and 2-(4-methoxycyclohexa-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (142 mg, 0.6 mmol) Using the method described in Step 1 of Example 15, Step 1 of Examples 45 and 46 was carried out to obtain 217 mg (69% yield) of (rac)-tert-butyl N-[2-[4-[6-(4-methoxycyclohexen-1-yl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate as a white solid. LC / MS (m / z, M+H): Calculated value 632.3, measured value 632.3.

[0291] Step 2: cis / trans mixture of tert-butyl N-[2-[4-[6-(4-methoxycyclohexyl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate [ka] Using (rac)-tert-butyl N-[2-[4-[6-(4-methoxycyclohexen-1-yl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate (214 mg, 0.34 mmol) in DCM / MeOH (8 mL / 8 mL) as a solvent, Step 2 of Examples 45 and 46 was carried out according to the protocol described in Step 2 of Examples 57 and 58, yielding 215 mg (100% yield) of a cis / trans mixture of tert-butyl N-[2-[4-[6-(4-methoxycyclohexyl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate as a colorless oil. LC / MS (m / z, M+H): Calculated value 634.3, Measured value 634.3.

[0292] Step 3: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, cis / trans mixture of hydrochloride [ka] Using a cis / trans mixture of tert-butyl N-[2-[4-[6-(4-methoxycyclohexyl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate (290 mg, 0.46 mmol), step 3 of Examples 45 and 46 was carried out according to the protocol described in step 5 of Example 1, yielding 235 mg (85% yield) of a cis / trans mixture of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one and hydrochloride as a white solid. LC / MS (m / z, M+H-HCl): Calculated value 534.2, measured value 534.2.

[0293] Step 4: Trans-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one and cis-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one [ka] The cis / trans mixture of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one;hydrochloride (161 mg, 0.26 mmol) was separated using a Chiralcel OD-I column (20 μm, 350 × 76.5 mm) eluted with (heptane 80 / EtOH20) + 0.1% TEA (flow rate 400 mL / min, UV detection at 280 nm), yielding 20 mg (12% yield) of trans-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one. LC / MS (m / z, M+H): Calculated value 534.2, measured value 534.2; 1 H NMR(400MHz,DMSO-d6,100℃)d ppm 1.29-1.36(m,2H),1.50-1.62(m,2H),1.80(br d,J=12.7Hz,2H),1.89(br d,J=12.7Hz,2H),2.13(br d,J=12.7Hz,2H),2.23-2.37(m,2H),2.52-2.62(m,1H),3.03-3.13(m,2H),3.17-3.28(m,1H),3.30(s,3H),4.19(br d,J=12.7Hz,2H),4.39-4.49(m,1H),5.44(br s,2H),6.51(br d,J=8.4Hz,1H),6.72(br s,1H),7.16(d,J=8.4Hz,1H),7.39(d,J=1.8Hz,1H),7.78(d,J=1.8Hz,1H),10.97-11.12(m,1H); and 99 mg (61% yield) of cis-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one was obtained. LC / MS (m / z, M+H): Calculated value 534.2, measured value 534.2; 1 H NMR(400MHz,DMSO-d6,100℃)d ppm 1.51-1.64(m,4H),1.71-1.84(m,4H),2.00(br d,J=12.7Hz,2H),2.24-2.35(m,2H),2.58-2.67(m,1H),3.05-3.14(m,2H),3.29(s,3H),3.48-3.52(m,1H),4.18(br d,J=12.7Hz,2H),4.42-4.51(m,1H),5.41(br s,2H),6.52(br d,J=8.4Hz,1H),6.71(br s,1H),7.16(d,J=8.4Hz,1H),7.35(d,J=1.8Hz,1H),7.77(d,J=1.8Hz,1H),11.03(br s,1H).

[0294] Examples 47 and 48: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[1-methylpyrrolidine-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, isomers 1 and 2 [ka] Chiral separation of (rac)-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methylpyrrolidine-3-yl)oxy-3H-imidazo[4,5-b]pyridine-2-one (Example 6; 111 mg, 0.21 mmol) was performed using a ChiralpakIE column (5 μm, 30 × 250 mm) eluted with (heptane 30 / EtOH 70) + 0.1% TEA (flow rate 400 mL / min, UV detection at 254 nm), yielding 40 mg (36% yield) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methylpyrrolidine-3-yl)oxy-3H-imidazo[4,5-b]pyridine-2-one, isomer 1. LC / MS (m / z, M+H): Calculated value 521.2, measured value 521.1; 1 H NMR(400MHz,DMSO-d6,100℃)d ppm 1.78(br d,J=12.7Hz,2H),1.81-1.89(m,1H),2.17-2.34(m,3H),2.28(s,3H),2.40-2.45(m ,1H),2.60-2.70(m,2H),2.81(dd,J=6.0 and 10.3Hz,1H),2.99-3.09(m,2H),4.16(br d,J=12.7Hz,2H),4.35-4.45(m,1H),4.84-4.90(m,1H),5.41(br s,2H),6.48(br d,J=8.4Hz,1H),6.68(br s,1H), 7.14(d,J=8.4Hz,1H), 7.21(d,J=2.4Hz,1H), 7.54(d,J=2.4Hz,1H), 10.89-11.06(m,1H); and 46 mg (41% yield) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methylpyrrolidine-3-yl)oxy-3H-imidazo[4,5-b]pyridine-2-one, isomer 2 was obtained. LC / MS (m / z,M+H): Calculated value 521.2, measured value 521.1; 1H NMR(400MHz,DMSO-d6,100℃)d ppm 1.78(br d,J=12.7Hz,2H),1.81-1.87(m,1H),2.18-2.33(m,3H),2.28(s,3H),2.40-2.45(m ,1H),2.59-2.70(m,2H),2.81(dd,J=6.0 and 10.3Hz,1H),2.99-3.10(m,2H),4.16(br d,J=12.7Hz,2H),4.35-4.44(m,1H),4.84-4.90(m,1H),5.41(br s,2H),6.48(br d,J=8.4Hz,1H),6.68(br s,1H),7.14(d,J=8.4Hz,1H),7.21(d,J=2.4Hz,1H),7.54(d,J=2.4Hz,1H),10.90-11.03(m,1H).

[0295] Example 49: (rac)-1-[1-[2-amino-4-(pentafluoro-λ 6 [-Sulfanyl)benzoyl]pyrroridine-3-yl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] (rac)-1-pyrroridine-3-yl-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one; dihydrochloride (112 mg, 0.31 mmol) and 2-amino-4-(pentafluoro-λ) 6 Using (rac)-1-[1-[2-amino-4-(pentafluoro-λ)-122 mg (74% yield) of 6 -Sulfanyl)benzoyl]pyrrolidine-3-yl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one was obtained as a light brown solid. LC / MS (m / z, M+H): Calculated value 534.2, measured value 534.1; 1H NMR(400MHz,DMSO-d6,100℃)d ppm 1.69-1.82(m,4H),2.22-2.33(m,1H),2.51-2.56(m Partially hidden,1H),2.77-2.90(m,1H),3.43-3.51(m,2H),3.55-3.63(m,1H),3.74-3.86(m,2H),3.90-4.01(m,3H),5.02(quin,J=7.7Hz,1H),5.70(br s,2H),6.99(dd,J=2.3 and 8.4Hz,1H),7.28(d,J=2.3Hz,1H),7.32(br d,J=8.4Hz,1H),7.37(d,J=1.8Hz,1H),7.83(d,J=1.8Hz,1H),11.16(br s,1H).

[0296] Example 50: (rac)-1-[1-[4-(pentafluoro-λ 6 [-Sulfanyl)benzoyl]pyrroridine-3-yl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: (rac)-tert-butyl 3-[(5-bromo-2-nitro-3-pyridyl)amino]pyrrolidine-1-carboxylate [ka] To a solution of 5-bromo-3-fluoro-2-nitropyridine (3 g, 13.6 mmol) in EtOH (91 mL), triethylamine (5.68 mL, 40.7 mmol) and (rac)-tert-butyl 3-aminopyrrolidine-1-carboxylate (3.03 g, 16.3 mmol) were added. The resulting reaction mixture was refluxed for 1.5 hours, cooled to room temperature, concentrated under vacuum, diluted with ethyl acetate, and washed with saturated aqueous solution of NH4Cl. The organic layer was dried over sodium sulfate, filtered, and concentrated to obtain 5.284 g (89% yield) of (rac)-tert-butyl 3-[(5-bromo-2-nitro-3-pyridyl)amino]pyrrolidine-1-carboxylate as a yellow solid. LC / MS (m / z, M+H-tBu): Calculated value 331.0, Measured value 331.1.

[0297] Step 2: (rac)-tert-butyl 3-[(2-amino-5-bromo-3-pyridyl)amino]pyrrolidine-1-carboxylate [ka] (rac)-tert-butyl 3-[(5-bromo-2-nitro-3-pyridyl)amino]pyrrolidine-1-carboxylate (5 g, 11.5 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (9.05 g, 35.6 mmol) were dissolved in isopropanol (50 mL) at room temperature. Potassium tert-butoxide (1.55 g, 13.8 mmol) was added, and the resulting reaction mixture was refluxed for 1.5 hours, then cooled to room temperature, concentrated under vacuum, diluted with ethyl acetate, and washed twice with a 1N solution of NaOH. The organic layer was then dried over sodium sulfate, filtered, and concentrated under vacuum. The obtained residue was triturated in diisopropyl ether, filtered, washed with diisopropyl ether, and dried under vacuum to obtain 3.505 g (82% yield) of (rac)-tert-butyl 3-[(2-amino-5-bromo-3-pyridyl)amino]pyrrolidine-1-carboxylate as a brown solid. LC / MS (m / z, M+H-tBu): calculated value 302.1, measured value 303.0.

[0298] Step 3: (rac)-tert-butyl3-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyrrolidine-1-yl)pyrrolidine-1-carboxylate [ka] Using (rac)-tert-butyl 3-[(2-amino-5-bromo-3-pyridyl)amino]pyrrolidine-1-carboxylate (3.5 g, 9.41 mmol), step 3 of Example 50 was carried out according to the protocol described in step 4 of Example 1, yielding 3.733 g (97% yield) of (rac)-tert-butyl 3-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyrrolidine-1-yl)pyrrolidine-1-carboxylate as a yellow solid. LC / MS (m / z, M+H): calculated value 383.1, measured value 383.0.

[0299] Step 4: (rac)-tert-butyl3-[6-(3,6-dihydro-2H-pyran-4-yl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]pyrrolidine-1-carboxylate [ka] Using tert-butyl(rac)-3-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyrrolidine-1-yl)pyrrolidine-1-carboxylate (400 mg, 0.98 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (247 mg, 1.18 mmol), step 4 of Example 50 was carried out according to the protocol described in step 1 of Examples 57 and 58, yielding 264 mg (70% yield) of (rac)-tert-butyl3-[6-(3,6-dihydro-2H-pyran-4-yl)-2-oxo-3H-imidazo[4,5-b]pyrrolidine-1-yl]pyrrolidine-1-carboxylate as a light brown solid. LC / MS (m / z, M+H): Calculated value 387.2, measured value 387.2.

[0300] Step 5: (rac)-tert-butyl3-(2-oxo-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-1-yl)pyrrolidine-1-carboxylate [ka] Using (rac)-tert-butyl 3-[6-(3,6-dihydro-2H-pyran-4-yl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]pyrrolidine-1-carboxylate (261 mg, 0.67 mmol), step 5 of Example 50 was carried out according to the protocol described in step 2 of Examples 57 and 58, yielding 246 mg (94% yield) of (rac)-tert-butyl 3-(2-oxo-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-1-yl)pyrrolidine-1-carboxylate as a white solid. LC / MS (m / z, M+H): Calculated value 389.2, measured value 389.2.

[0301] Step 6: (rac)-1-pyrrolin-3-yl-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, dihydrochloride [ka] Using (rac)-tert-butyl3-(2-oxo-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-1-yl)pyrrolidine-1-carboxylate (245 mg, 0.63 mmol), step 6 of Example 50 was carried out according to the protocol described in step 5 of Example 1, yielding 227 mg (99% yield) of (rac)-1-pyrrolidine-3-yl-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one dihydrochloride as a yellow solid. LC / MS (m / z, M+H-2HCl): calculated value 289.2, measured value 289.1.

[0302] Step 7: (rac)-1-[1-[4-(pentafluoro-λ 6 [-Sulfanyl)benzoyl]pyrroridine-3-yl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one [ka] (rac)-1-pyrroridine-3-yl-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, dihydrochloride (112 mg, 0.31 mmol) and 4-(pentafluoro-λ 6 Using (rac)-1-[1-[4-(pentafluoro-λ)-112 mg (70% yield) of (rac)-1-[1-[4-(pentafluoro-λ)-112 mg (70% yield) 6[-sulfanyl)benzoyl]pyrrolidine-3-yl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one was obtained as a light brown solid. LC / MS (m / z, M+H): Calculated value 519.1, Measured value 519.1; 1 H NMR(400MHz,DMSO-d6,100℃)d ppm 1.70-1.81(m,4H),2.25-2.34(m,1H),2.52-2.60(m Partially hidden, 1H), 2.78-2.88 (m, 1H), 3.43-3.52 (m, 2H), 3.57-3.67 (m, 1H), 3.76-3. 89(m,2H),3.91-4.02(m,3H),4.98-5.07(m,1H),7.37(d,J=1.8Hz,1H),7.76(br d,J=8.5Hz,2H),7.82(d,J=1.8Hz,1H),7.95(br d,J=8.5Hz,2H),11.14(br s,1H).

[0303] Examples 51 and 52: trans-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one and cis-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: tert-butyl N-[2-[4-[6-(4-hydroxycyclohexen-1-yl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate [ka] Using tert-butyl N-[2-[4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate (185 mg, 0.31 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-en-1-ol (83 mg, 0.37 mmol) Then, following the protocol described in Step 1 of Examples 57 and 58, Step 1 of Examples 51 and 52 was carried out to obtain 135 mg (71% yield) of tert-butyl N-[2-[4-[6-(4-hydroxycyclohexen-1-yl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate as a light brown solid. LC / MS (m / z, M+H): Calculated value 618.2, measured value 618.2.

[0304] Step 2: cis / trans mixture of tert-butyl N-[2-[4-[6-(4-hydroxycyclohexyl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate [ka] Using tert-butyl N-[2-[4-[6-(4-hydroxycyclohexen-1-yl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate (132 mg, 0.21 mmol), step 2 of Examples 51 and 52 was carried out according to the protocol described in step 2 of Examples 57 and 58, to obtain 88 mg (66% yield) of a cis / trans mixture of tert-butyl N-[2-[4-[6-(4-hydroxycyclohexyl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate as a white solid. LC / MS (m / z, M+H): Calculated value 620.3, Measured value 620.3.

[0305] Step 3: Cis / trans mixture of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one [ka] A cis / trans mixture of tert-butyl N-[2-[4-[6-(4-hydroxycyclohexyl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate (85 mg, 0.14 mmol) was dissolved in MeOH (2 mL), to which a solution of 4N HCl in dioxane (0.51 mL, 2.06 mmol) was added. The resulting mixture was stirred at room temperature for 1.5 hours, followed by 1.5 hours at 40°C. The reaction mixture was then concentrated to dryness, diluted with 4 mL of 7N ammonia solution in MeOH, and concentrated again to dryness. The obtained residue was purified by flash chromatography (SiO2 12g) using silica gel eluted with DCM / MeOH / NH4OH95 / 5 / 0.5 to obtain 68 mg (95% yield) of a cis / trans mixture of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 520.2, Measured value 520.2.

[0306] Step 4: Trans-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one and cis-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one [ka] The cis / trans mixture of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one (68 mg, 0.13 mmol) was separated using a Chiralpak IC column (5 μm, 250 × 30 mm) eluted with (heptane 50 / EtOH 50) + 0.1% TEA (flow rate 40 mL / min, UV detection at 265 nm), yielding 12 mg (18% yield) of trans-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one. LC / MS (m / z, M+H): Calculated value 520.2, Measured value 520.1 1 H NMR(400MHz,DMSO-d6,100℃)dppm 1.28-1.37(m,2H),1.47-1.59(m,2H),1.73-1.86(m,4H),1.91-2.01(m,2H),2.2 1-2.34(m,2H),2.52-2.57(m,1H),3.00-3.10(m,2H),3.42-3.58(m,1H),4.12(br d,J=4.6Hz,1H),4.13-4.20(m,2H),4.37-4.46(m,1H),5.41(br s,2H),6.49(br d,J=8.4Hz,1H),6.69(br s,1H), 7.13(d,J=8.4Hz,1H), 7.36(d,J=1.8Hz,1H), 7.75(d,J=1.8Hz,1H), 10.84-11.14(m,1H); and 36 mg (53% yield) of cis-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one was obtained. LC / MS (m / z, M+H): Calculated value 520.2, measured value 520.1; 1H NMR(400MHz,DMSO-d6,100℃)d ppm 1.50-1.63(m,4H),1.79(br d,J=12.7Hz,4H),1.84-1.96(m,2H),2.21-2.32(m,2H),2.52-2.60(m,1H),3.02-3.12(m,2H),3.91-3.95(m,1H),4.07(br d,J=3.9Hz,1H),4.16(br d,J=12.7Hz,2H),4.39-4.50(m,1H),5.41(br s,2H),6.50(br d,J=8.4Hz,1H),6.70(br s,1H),7.14(d,J=8.4Hz,1H),7.35(d,J=1.8Hz,1H),7.76(d,J=1.8Hz,1H),10.89-11.10(m,1H).

[0307] Example 53: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: tert-butyl4-[2-oxo-6-[1-(2,2,2-trifluoroethyl)-3,6-dihydro-2H-pyridine-4-yl]-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate [ka] tert-butyl 4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate (400 mg, 1.007 mmol, prepared in step 2 of Example 3) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1,2,3,6-tetrahydropyridine (322 mg) Using 1.11 mmol of tert-butyl 4-[2-oxo-6-[1-(2,2,2-trifluoroethyl)-3,6-dihydro-2H-pyridine-4-yl]-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate as a solid, 250 mg (52% yield) of tert-butyl 4-[2-oxo-6-[1-(2,2,2-trifluoroethyl)-3,6-dihydro-2H-pyridine-4-yl]-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate was obtained.

[0308] Step 2: tert-butyl4-[2-oxo-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate [ka] Using tert-butyl 4-[2-oxo-6-[1-(2,2,2-trifluoroethyl)-3,6-dihydro-2H-pyridine-4-yl]-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate (250 mg, 0.52 mmol), step 2 of Example 53 was carried out according to the protocol described in step 2 of Examples 57 and 58, yielding 240 mg (95% yield) of tert-butyl 4-[2-oxo-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate as a white solid. LC / MS (m / z, M+H): Calculated value 484.2, measured value 484.2

[0309] Step 3: 1-(4-piperidyl)-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, hydrochloride [ka] Using tert-butyl 4-[2-oxo-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate (230 mg, 0.44 mmol), step 3 of Example 53 was carried out according to the protocol described in step 5 of Example 1, yielding 185 mg (100% yield) of 1-(4-piperidyl)-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one hydrochloride as a solid. LC / MS (m / z, M+H-HCl): Calculated value 384.2, measured value 384.2

[0310] Step 4: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Using 1-(4-piperidyl)-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, hydrochloride (120 mg, 0.28 mmol), 2-amino-4-(trifluoromethoxy)benzoic acid (69 mg, 0.31 mmol), and triethylamine (0.16 mL, 1.14 mmol) as a substitute for DIPEA, step 4 of Example 53 was carried out according to the protocol described in step 4 of Example 15, to obtain 61 mg (37% yield) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 587.2, measured value 587.1; 1H NMR(400MHz,DMSO-d6,100℃)d ppm 1.71-1.82(m,6H),2.24-2.36(m,2H),2.49-2.59(m Partially hidden,3H),3.00-3.11(m,4H),3.16(q,J=10.2Hz,2H),4.16(br d,J=12.7Hz,2H),4.39-4.48(m,1H),5.40(br s,2H),6.49(br d,J=8.4Hz,1H),6.69(br s,1H),7.14(d,J=8.4Hz,1H),7.42(d,J=1.8Hz,1H),7.77(d,J=1.8Hz,1H),11.03(br s,1H).

[0311] Example 54: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methyl-4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: tert-butyl 4-[6-(1-methyl-3,6-dihydro-2H-pyridine-4-yl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate [ka] Using tert-butyl 4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate (400 mg, 1.007 mmol, prepared in step 2 of Example 3) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (247 mg, 1.11 mmol), step 1 of Example 54 was carried out according to the protocol described in step 1 of Example 15, to obtain 138 mg (33% yield) of tert-butyl 4-[6-(1-methyl-3,6-dihydro-2H-pyridine-4-yl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate as a solid.

[0312] Step 2: tert-butyl4-[6-(1-methyl-4-piperidyl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate [ka] Using tert-butyl 4-[6-(1-methyl-3,6-dihydro-2H-pyridine-4-yl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate (130 mg, 0.27 mmol), step 2 of Example 54 was carried out according to the protocol described in step 2 of Examples 57 and 58, yielding 112 mg (100% yield) of tert-butyl 4-[6-(1-methyl-4-piperidyl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate as a white solid. LC / MS (m / z, M+H): Calculated value 416.2, measured value 416.2

[0313] Step 3: 6-(1-methyl-4-piperidyl)-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, hydrochloride [ka] Using tert-butyl 4-[6-(1-methyl-4-piperidyl)-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl]piperidine-1-carboxylate (140 mg, 0.29 mmol), step 3 of Example 54 was carried out according to the protocol described in step 5 of Example 1, to obtain 100 mg (96% yield) of 6-(1-methyl-4-piperidyl)-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one hydrochloride as a solid. LC / MS (m / z, M+H-HCl): Calculated value 316.2, measured value 316.2

[0314] Step 4: 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methyl-4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 4 of Example 54 was carried out according to the protocol described in Step 4 of Example 15, using 6-(1-methyl-4-piperidyl)-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, hydrochloride (100 mg, 0.28 mmol), 2-amino-4-(trifluoromethoxy)benzoic acid (69 mg, 0.31 mmol), and triethylamine (0.16 mL, 1.14 mmol) instead of DIPEA, to obtain 47 mg (32% yield) of 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methyl-4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one as a solid. LC / MS (m / z, M+H): Calculated value 519.2, measured value 519.2; 1 H NMR(400MHz,DMSO-d6,100℃)d ppm 1.70-1.82(m,6H),1.96-2.06(m,2H),2.22(s,3H),2.29(qd,J=4.6 and 12.7Hz,2H),2.50-2.55(m Partially hidden,1H),2.85-2.90(m Partially hidden,2H),3.01-3.10(m,2H),4.16(br d,J=12.7Hz,2H),4.39-4.47(m,1H),5.42(br s,2H),6.49(br d,J=8.4Hz,1H),6.69(br s,1H),7.14(d,J=8.4Hz,1H),7.40(d,J=1.8Hz,1H),7.77(d,J=1.8Hz,1H),11.03(br s,1H).

[0315] Example 56: (rac)-6-tetrahydrofuran-3-yloxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: (rac)-tert-butyl 4-[(2-nitro-5-tetrahydrofuran-3-yloxy-3-pyridyl)amino]piperidine-1-carboxylate [ka] Using tert-butyl 4-[(5-fluoro-2-nitro-3-pyridyl)amino]piperidine-1-carboxylate (400 mg, 1.17 mmol) and (rac)-tetrahydrofuran-3-ol (207 mg, 2.35 mmol), Step 1 of Example 56 was carried out according to the protocol described in Step 2 of Example 1, yielding 466 mg (97% yield) of (rac)-tert-butyl 4-[(2-nitro-5-tetrahydrofuran-3-yloxy-3-pyridyl)amino]piperidine-1-carboxylate as a yellow solid. LC / MS (m / z, M+H-BOC): Calculated value 309.2, measured value 309.1 (M+H).

[0316] Step 2: (rac)-tert-butyl 4-[(2-amino-5-tetrahydrofuran-3-yloxy-3-pyridyl)amino]piperidine-1-carboxylate [ka] Step 2 of Example 56 was carried out according to the protocol described in Step 3 of Example 1, in which the reaction mixture was heated at 80°C instead of 65°C using (rac)-tert-butyl 4-[(2-nitro-5-tetrahydrofuran-3-yloxy-3-pyridyl)amino]piperidine-1-carboxylate (463 mg, 1.13 mmol), yielding 325 mg (76% yield) of (rac)-tert-butyl 4-[(2-amino-5-tetrahydrofuran-3-yloxy-3-pyridyl)amino]piperidine-1-carboxylate as a brown solid. LC / MS (m / z, M+H): Calculated value 379.2, measured value 379.2.

[0317] Step 3: (rac)-tert-butyl4-(2-oxo-6-tetrahydrofuran-3-yloxy-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate [ka] Using (rac)-tert-butyl 4-[(2-amino-5-tetrahydrofuran-3-yloxy-3-pyridyl)amino]piperidine-1-carboxylate (322 mg, 0.85 mmol), step 3 of Example 56 was carried out according to the protocol described in step 4 of Example 1, yielding 246 mg (71% yield) of (rac)-tert-butyl 4-(2-oxo-6-tetrahydrofuran-3-yloxy-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate as a white solid. LC / MS (m / z, M+H): Calculated value 405.2, measured value 405.2.

[0318] Step 4: (rac)-1-(4-piperidyl)-6-tetrahydrofuran-3-yloxy-3H-imidazo[4,5-b]pyridine-2-one, dihydrochloride [ka] Using (rac)-tert-butyl 4-(2-oxo-6-tetrahydrofuran-3-yloxy-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carboxylate (243 mg, 0.6 mmol), step 4 of Example 56 was carried out according to the protocol described in step 5 of Example 1, yielding 226 mg (100% yield) of (rac)-1-(4-piperidyl)-6-tetrahydrofuran-3-yloxy-3H-imidazo[4,5-b]pyridine-2-one, dihydrochloride, as a gray solid. LC / MS (m / z, M+H-2HCl): calculated value 305.2, measured value 305.1.

[0319] Step 5: (rac)-6-tetrahydrofuran-3-yloxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Using (rac)-1-(4-piperidyl)-6-tetrahydrofuran-3-yloxy-3H-imidazo[4,5-b]pyridine-2-one, dihydrochloride (113 mg, 0.30 mmol), and 4-(trifluoromethoxy)benzoic acid (68 mg, 0.33 mmol), step 5 of Example 56 was carried out according to the protocol described in step 4 of Example 15, yielding 114 mg (77% yield) of (rac)-6-tetrahydrofuran-3-yloxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a white solid. LC / MS (m / z, M+H): Calculated value 493.2, measured value 493.1; 1 H NMR(400MHz,DMSO-d6,100℃)d ppm 1.82(br d,J=12.7Hz,2H),2.00-2.08(m,1H),2.17-2.24(m,1H),2.24-2.36(m,2H),3.04-3.14(m,2H),3.76-3.93(m,4 H),4.12-4.27(m,2H),4.38-4.47(m,1H),5.04(ddt,J=2.2 and 4.4 and 6.4Hz,1H),7.29(d,J=2.4Hz,1H),7.41(br d,J=8.4Hz,2H),7.58-7.63(m,3H),11.03(br s,1H).

[0320] Examples 57 and 58: trans-6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one and cis-6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: (rac)-6-(4-hydroxycyclohexen-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (160 mg, 0.33 mmol, Example 60) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohexa-3-en-1-ol (89 mg, 0.39 mmol) were dissolved in dioxane (8 mL) and water (2 mL). K3PO4 (154 mg, 0.72 mmol) was added to the solution, and the resulting mixture was bubbling with argon for 5 minutes. Then, PdG2SPhos (24 mg, 0.033 mmol) was added, and the resulting mixture was refluxed for 12 hours. After 12 hours, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with a 1N solution of NaOH and brine. The combined aqueous layer was extracted with ethyl acetate, the combined organic layer was dried over sodium sulfate, filtered, and concentrated under vacuum. The resulting residue was purified by flash chromatography (SiO2 10g) using silica gel eluted with DCM / MeOH95 / 5 to obtain 146 mg (88% yield) of (rac)-6-(4-hydroxycyclohexen-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a yellow solid. LC / MS (m / z, M+H): Calculated value 503.2, Measured value 503.2.

[0321] Step 2: Cis / trans mixture of 6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] (rac)-6-(4-hydroxycyclohexen-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (143 mg, 0.28 mmol) was dissolved in MeOH (4 mL) and DCM (4 mL), to which Pd / C (10%)-50% wet (20 mg) was added. The entire mixture was hydrogenated at room temperature for 22 hours using 4 bar of hydrogen. After 22 hours, the reaction mixture was filtered, and Pd / C (10%)-50% wet (80 mg) was added. The resulting mixture was further hydrogenated at room temperature for 48 hours using 4 bar of hydrogen. After 48 hours, the reaction mixture was filtered and concentrated to dryness. The obtained residue was purified by flash chromatography (SiO225g) of silica gel eluted with siRNA / MeOH92 / 8 to obtain 100 mg (69% yield) of a cis / trans mixture of 6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a light brown solid. LC / MS (m / z, M+H): Calculated value 505.2, Measured value 505.2.

[0322] Step 3: Trans-6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one and cis-6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] The cis / trans mixture (100 mg, 0.2 mmol) of 6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one was separated using a Chiralpak IC column (20 μm, 350 × 76.5 mm) eluted with (heptane 50 / EtOH 50) + 0.1% TEA (flow rate 400 mL / min, UV detection at 265 nm), yielding 14 mg (14% yield) of trans-6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one. LC / MS (m / z, M+H): Calculated value 505.2, Measured value 505.1; 1 H NMR(400MHz,DMSO-d6,100℃)dppm 1.28-1.38(m,2H),1.47-1.60(m,2H),1.76-1.86(m,4H),1.91-2.00(m,2H),2.24-2.34(m ,2H),2.51-2.56(m,1H),3.03-3.15(m,2H),3.45-3.54(m,1H),4.07-4.26(m,2H),4.14(br d,J=4.6Hz,1H),4.37-4.46(m,1H),7.36(d,J=1.8Hz,1H),7.40(br d,J=8.4Hz,2H),7.57(d,J=8.4Hz,2H),7.76(d,J=1.8Hz,1H),10.78-11.14(m,1H); and 66 mg (66% yield) of cis-6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one was obtained. LC / MS (m / z, M+H): Calculated value 505.2, measured value 505.1; 1H NMR(400MHz,DMSO-d6,100℃)dppm 1.51-1.64(m,4H),1.73-1.84(m,4H),1.85-1.96(m,2H),2.21-2.31(m ,2H),2.54-2.61(m,1H),3.06-3.15(m,2H),3.90-3.94(m,1H),3.99(br d,J=3.9Hz,1H),4.09-4.25(m,2H),4.36-4.50(m,1H),7.34(br s,1H),7.40(br d,J=8.4Hz,2H),7.57(br d,J=8.4Hz,2H),7.77(br s,1H), 10.86-11.13(m,1H).

[0323] Example 59: tert-butyl N-[2-[4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate [ka] At room temperature, triethylamine (23.4 mL, 8.04 mmol), 2-(tert-butoxycarbonylamino)-4-(trifluoromethoxy)benzoic acid (7.703 g, 23.98 mmol), and TBTU (8.469 g, 26.38 mmol) were successively added to a solution of 6-bromo-1-(4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, hydrochloride (8 g, 23.98 mmol, prepared in step 2 of Examples 60 and 11) in DMF (80 mL). The resulting mixture was stirred for 3 hours, then poured into water (800 mL), extracted twice with AcOEt (2 × 300 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated under vacuum. The obtained residue was purified by flash chromatography (SiO2 400g) of silica gel eluted with DCM / [DCM / MeOH95 / 5]90 / 10 to obtain 4.83 g (34% yield) of tert-butyl N-[2-[4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate as a white solid. LC / MS (m / z, M+H): Calculated value 600.1, Measured value 600.1; 1 H NMR(400MHz,DMSO-d6,100℃)d ppm 1.50(s,9H),1.84(br d,J=12.7Hz,2H),2.27-2.38(m,2H),3.02-3.13(m,2H),4.10-4.27(m,2H),4.39-4.49(m,1H),7.09(br d,J=8.4Hz,1H),7.48(d,J=8.4Hz,1H),7.72(br s,1H),7.83(d,J=1.8Hz,1H),7.98(d,J=1.8Hz,1H),8.66(br s,1H),11.28-11.65(m,1H).

[0324] Examples 63, 61, and 62: (rac)-6-(4-oxocycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, (rac)-trans-6-(4-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, and (rac)-cis-6-(4-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-2-one [ka] To a stirred solution of 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (1.80 g, 3.71 mmol, Example 60) in N,N-dimethylformamide (10 mL) at 0°C, sodium hydride (60% dispersion in oil, 356 mg, 14.8 mmol) was added. The reaction mixture was then stirred at room temperature under an argon atmosphere for 15 minutes. After 15 minutes, 2-(chloromethoxy)ethyl-trimethyl-silane (1.86 g, 11.1 mmol) was added at 0°C. The resulting reaction mixture was stirred at room temperature for 2 hours. After 2 hours, the reaction mixture was diluted with ice water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography using elution with 30% ethyl acetate in hexane to obtain 1.7 g (66% yield) of 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-2-one as a brown solid. LC / MS (m / z, M+H): Calculated value 615.1, measured value 615.2.

[0325] Step 2: [2-Oxo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-6-yl]boronic acid [ka] 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-2-one (1.70 g, 2.76 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.05 g, 4.14 mmol) were stirred in 1,4-dioxane (20 mL), to which KOAc (542 mg, 5.52 mmol) was added, and the resulting mixture was degassed with argon for 15 minutes. Then, PdCl2(dppf).DCM complex (226 mg, 0.28 mmol) was added, and the reaction mixture was stirred at 80°C for 12 hours. After 12 hours, the reaction mixture was cooled to room temperature and then filtered through a Celite bed. The filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with 40% toluene in hexane to obtain 1.5 g (83% yield) of [2-oxo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-6-yl]boronic acid as an off-white solid. LC / MS (m / z, M+H): Calculated value 581.2, measured value 581.1.

[0326] Step 3: 1,4-Dioxaspiro[4,6]undeca-7-en-8-yltrifluoromethanesulfonate [ka] To a stirred solution of 1,4-dioxaspiro[4.6]undecane-8-one (1 g, 5.88 mmol) in tetrahydrofuran (50 mL), lithium bis(trimethylsilyl)azanide (1.00 mol / L, 12.9 mL, 12.9 mmol) at -78°C was added, and the resulting mixture was stirred for 30 minutes. After 30 minutes, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (2.10 g, 5.88 mmol) at -78°C was added, and the resulting reaction mixture was stirred at room temperature for 16 hours. After 16 hours, the reaction mixture was concentrated under reduced pressure, quenched with ice water (100 mL), and extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Next, the resulting residue was purified on silica gel to obtain 1 g (56% yield) of 1,4-dioxaspiro[4.6]undeca-7-en-8-yltrifluoromethanesulfonate as a yellow liquid.

[0327] Step 4: 6-(1,4-dioxaspiro[4,6]undeca-7-en-8-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-2-one [ka] [2-oxo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-6-yl]boronic acid (800 mg, 1.38 mmol) and 1,4-dioxapiro[4.6]undeca-7-en-8-yltrifluoromethanesulfonate (500 mg, 1.65 mmol) were stirred in 1,4-dioxane (10 mL). Potassium carbonate (381 mg, 2.76 mmol) in water (1 mL) was added, and the resulting mixture was purged with argon for 10 minutes. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (56 mg, 0.07 mmol) was added, and the resulting reaction mixture was stirred at 100 °C for 6 hours. After 6 hours, the reaction mixture was poured into ice water (20 mL) and then extracted with RINKAN (150 mL). The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with 30% RINKAN in hexane to obtain 500 mg (53% yield) of 6-(1,4-dioxaspiro[4.6]undeca-7-en-8-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-2-one. LC / MS (m / z, M+H): Calculated value 689.3, measured value 689.5.

[0328] Step 5: 6-(1,4-dioxaspiro[4,6]undeca-7-en-8-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] To a stirred solution of 6-(1,4-dioxaspiro[4.6]undeca-7-en-8-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-2-one (949 mg, 1.38 mmol) in THF (5 mL) at 0°C, tetrabutylammonium fluoride trihydrate (870 mg, 2.76 mmol) was added, and the resulting reaction mixture was stirred at 80°C for 2 hours. After 2 hours, the reaction mixture was quenched with water (30 mL), extracted with ethyl acetate (50 mL), washed with brine, and concentrated under reduced pressure to obtain 500 mg (65% yield) of crude 6-(1,4-dioxaspiro[4.6]undeca-7-en-8-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a yellow solid. LC / MS (m / z, M+H): Calculated value 559.2, measured value 559.4.

[0329] Step 6: 6-(4-oxocyclohepten-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] A 300 mg, 0.54 mmol solution of 6-(1,4-dioxaspiro[4,6]undeca-7-en-8-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (0°C) was stirred in 10 mL of DCM, to which a 4 M HCl solution (4 mol / L, 1.34 mL, 5.4 mmol) in dioxane was added. The reaction mixture was then stirred at room temperature for 2 hours. After 2 hours, the reaction mixture was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether (30 mL) to obtain 250 mg (90% yield) of 6-(4-oxocyclohepten-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a yellow solid. LC / MS (m / z, M+H): Calculated value 515.2, measured value 515.1.

[0330] Step 7 (Example 63): (rac)-6-(4-oxocycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] 6-(4-oxocyclohepten-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (250 mg, 0.49 mmol) was stirred in MeOH (10 mL), to which 10% Pd / C (517 mg, 4.86 mmol) was added at room temperature. The reaction mixture was then stirred under 1 atm of H2 at room temperature for 48 hours. After 48 hours, the reaction mixture was filtered through a Celite bed and washed with ethanol. The resulting filtrate was concentrated under reduced pressure. The obtained residue was purified by flash chromatography eluting with 5% MeOH in DCM to obtain 250 mg (99% yield) of (rac)-6-(4-oxocycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as a yellow solid. LC / MS (m / z, M+H): Calculated value 517.2, Measured value 517.2.

[0331] Step 8 (Examples 61 and 62): (rac)-trans-6-(4-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one and (rac)-cis-6-(4-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] (rac)-6-(4-oxocycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (100 mg, 0.19 mmol) was stirred in MeOH (5 mL) and NaBH4 (37 mg, 0.97 mmol) was added at room temperature. The resulting reaction mixture was stirred at room temperature for 2 hours. After 2 hours, the reaction mixture was diluted with water and extracted with ELISA (30 mL). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The obtained residue was purified by preparative HPLC (conditions: mobile phase A: 10 mm ABC in water, mobile phase B: acetonitrile, column conditions: XSELECT (19 × 150 mm) 10 μm, gradient: time (min) %B, 0 min 25%, 2 min 35%, 8 min 55%, flow rate: 18 mL / min) to obtain 10 mg (10% yield) of (rac)-trans-6-[(4R)-4-hydroxycycloheptyl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one. LC / MS (m / z, M+H): calculated value 519.2, measured value 519.2. 1H NMR(400MHz,DMSO-d6)δ ppm 11.33-11.46(m,1H)7.71-7.81(m,1H)7.55-7.65(m,2H)7.41-7.51(m,3H)4.56-4.77(m,1H)4.39-4.5 6(m,2H)3.62-3.85(m,2H)2.83-3.01(m,1H)2.66-2.78(m,2H)2.21-2.37(m,3H)1.39-2.05(m,12H); and 9 mg (9% yield) of (rac)-cis-6-[(4R)-4-hydroxycycloheptyl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one was obtained as an off-white solid. LC / MS (m / z, M+H): Calculated value 519.2, Measured value 519.2. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.24-11.51(m,1H)4.57-4.72(m,1H)4.39-4.52(m,2H)3.78-3.91(m,1H)3.61-3. 72(m,1H)2.88-2.99(m,1H)1.90-2.04(m,3H)1.66-1.87(m,7H)1.28-1.66(m,6H).

[0332] Examples 64 and 65: (rac)-6-[(4E / Z)-4-hydroxyiminocycloheptyl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, isomers 1 and 2 [ka] (rac)-6-(4-oxocycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one (120 mg, 0.23 mmol) was stirred in EtOH (5 mL), to which NaHCO3 (59 mg, 0.7 mmol) and NH2OH.HCl (48 mg, 0.7 mmol) were added at room temperature, and the resulting reaction mixture was stirred at room temperature for 2 hours. After 2 hours, the reaction mixture was diluted with water (10 mL) and extracted with ELISA (30 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by preparative HPLC (conditions: A line: 10 mM ammonium bicarbonate in water; B line: ACN, column: X-Select (C18, 21.2 mm × 250 mm), gradient program: flow rate 18 mL / min, time (min) (0, 2, 6), %B (34, 45, 60)) to obtain 5 mg (4% yield) of (rac)-6-[(4E / Z)-4-hydroxyiminocycloheptyl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, isomer 1: LC / MS (m / z, M+H): calculated value 532.2, measured value 532.2. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.33-11.53(m,1H)10.22(s,1H)7.78(s,1H)7.61(d,J=8.51Hz,2H)7.46-7.53(m,3H)4.60-4.76(m,1H)4.46(br s,1H)3.60-3.78(m,1H)3.18-3.28(m,1H)2.84-3.05(m,2H)2.63-2.78(m,3H)1.91-2.06(m,3H)1.76-1.89(m,2H)1.56-1.73(m,2H)1.33-1.51(m,4H); and 9 mg (7% yield) of (rac)-6-[(4E / Z)-4-hydroxyiminocycloheptyl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, isomer 2, were obtained as off-white solids. LC / MS (m / z, M+H): Calculated value 532.2, measured value 532.2. 1H NMR(400MHz,DMSO-d6)δ ppm 11.30-11.52(m,1H)10.24(s,1H)7.73-7.81(m,1H)7.57-7.66(m,2H)7.44-7.57(m,3H)4.58-4.78(m,1H)4.38-4.53(m,1H)3.60-3.7 5(m,1H)3.18-3.28(m,1H)2.84-2.96(m,1H)2.63-2.78(m,3H)2.21-2.33(m,2H)1.80-2.01(m,4H)1.60-1.76(m,3H)1.48-1.60(m,1H)

[0333] Examples 66 and 67: (rac)-trans-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one and (rac)-cis-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] Step 1: (3-Oxocyclohepten-1-yl)trifluoromethanesulfonate [ka] To a stirred solution of cycloheptan-1,3-dione (2 g, 15.9 mmol) in DCM (10 mL), Na2CO3 (1.68 g, 15.9 mmol) was added at 0°C. Subsequently, a solution of trifluoromethylsulfonyltrifluoromethanesulfonate (5.37 g, 19 mmol) in DCM (40 mL) was added dropwise over 1 hour at room temperature under an argon atmosphere. The resulting reaction mixture was stirred at room temperature for 2 hours. After 2 hours, the reaction mixture was diluted with ethyl acetate, filtered through a Celite bed, and the resulting filtrate was concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with 5% siRNA in hexane to obtain 700 mg (12% yield) of (3-oxocyclohepten-1-yl)trifluoromethanesulfonate as a brown, sticky solid.

[0334] Step 2: 6-(3-oxocyclohepten-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-2-one [ka] [2-oxo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-6-yl]boronic acid (800 mg, 1.38 mmol, prepared in step 2 of Examples 63, 61, and 62) and (3-oxocyclohepten-1-yl)trifluoromethanesulfonate (356 mg, 1.38 mmol) were stirred in 1,4-dioxane (10 mL) and water (2 mL). Potassium carbonate (571 mg, 4.13 mmol) was added, and the resulting reaction mixture was degassed with argon for 15 minutes. Then, PdCl2(dppf).DCM complex (113 mg, 0.14 mmol) was added, and the resulting reaction mixture was stirred at 100°C for 16 hours. After 16 hours, the reaction mixture was cooled to room temperature and then filtered through a Celite bed. The filtrate was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography eluting with 50% ethyl acetate in hexane to obtain 400 mg (40% yield) of 6-(3-oxocyclohepten-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-2-one as a brown solid. LC / MS (m / z, M+H): Calculated value 645.3, measured value 645.1.

[0335] Step 3: (rac)-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-2-one cis / trans mixture [ka] To a stirred solution of 6-(3-oxocyclohepten-1-yl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-2-one (300 mg, 0.46 mmol) in methanol (10 mL), palladium (10% on carbon) (149 mg, 1.40 mmol), followed by acetic acid (2.3 mg, 0.04 mmol), was added under an argon atmosphere. The reaction mixture was hydrogenated at room temperature under 4 atm of H2 for 48 hours. After 48 hours, the reaction mixture was filtered through a Celite bed and washed with ethanol. The obtained filtrate was concentrated under reduced pressure to obtain 290 mg (74% yield) of a cis / trans mixture of (rac)-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-2-one as a brown solid. LC / MS (m / z, M+H): Calculated value 647.3, measured value 647.0.

[0336] Step 4: (Examples 66 and 67): (rac)-trans-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one and (rac)-cis-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one [ka] A cis / trans mixture of (rac)-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridine-2-one (270 mg, 0.42 mmol) was stirred in tetrahydrofuran (5 mL) at 0 °C. TBAF (263 mg, 0.84 mmol) was added, and the resulting reaction mixture was stirred at 80 °C for 16 hours. After 16 hours, the reaction mixture was quenched with saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were concentrated under reduced pressure. The obtained residue was purified by preparative HPLC (conditions: mobile phase A: 0.1% HCOOH in water, mobile phase B: ACN, flow rate: 16 mL / min; column: X-SELECT-C18 (19 × 250 mm) 5 μm, gradient: time (min) (0, 2, 8) %B (20, 25, 55) to obtain 2 mg (0.9% yield) of (rac)-trans-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one as an off-white solid. LC / MS (m / z, MH): calculated value 517.2, measured value 517.0. 1 H NMR(400MHz,DMSO-d6)δ ppm 11.31(s,1H)7.71-7.86(m,1H)7.55-7.63(m,2H)7.39-7.50(m,3H)4.58-4.72(m,1H)4.40-4.49(m ,2H)3.90-4.00(m,1H)3.58-3.74(m,1H)2.95-3.09(m,3H)1.99-2.12(m,2H)1.45-1.90(m,12H); and 10 mg (4% yield) of (rac)-cis-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one was obtained as an off-white solid. LC / MS (m / z, M+H): Calculated value 519.2, measured value 519.0. 1H NMR(400MHz,DMSO-d6)δ ppm 11.37-11.43(m,1H)7.73-7.81(m,1H)7.57-7.64(m,2H)7.44-7.52(m,3H)4.60-4.72(m,1H)4.42-4.50(m,2H) )3.68-3.80(m,1H)2.88-3.02(m,2H)1.81-1.99(m,4H)1.64-1.81(m,5H)1.45-1.62(m,5H)0.78-0.94(m,2H).

[0337] Example 68 - ERK5 inhibitory activity of the compound Two assays were performed to evaluate the ERK5 inhibitory activity of the compound in the example, using cell-based assays and cell-free biochemical assays. The assay results are shown in Table 2 below. When repeated measurements were performed, the reported values ​​are mean values.

[0338] Inhibition of cellular ERK5 activity Renal cancer cell line SN12C was transduced by lentivirus pGreenFire1 MEF2 EF1 Neo (see TR030VA-N) from SBI using a standard infection protocol. pGreenFire1 MEF2 EF1 Neo enables the expression of the luciferase gene under the control of a minimal promoter with an MEF2 transcriptional response element. Cells containing the reporter construct were selected by genethecin treatment. The selected cells were then transposed with the piggyback-based plasmid pCM4007, enabling the expression of constitutively activated MEK5DD under the control of the doxycycline-regulating promoter, TREG3. Metastatic cells were selected by puromycin treatment. MEK5DD was expressed after doxycycline treatment (1 μg / ml). MEK5DD activates ERK5, which phosphorylates the MEF2C protein. The activated MEF2C protein can then bind to its transcriptional response element. Luciferase is then expressed. 50,000 cells were inoculated into 142.5 μl of RPMI medium containing 10% fetal bovine serum, 1% glutamine, and 1 μg / ml doxycycline in a 96-well plate (96F nuncleon ref137101 thermofisher). After 24 hours, 0.1% of the compound was added to 7.5 μl of culture medium (containing 2% DMSO) to obtain the desired concentration (0.3–10000 nM). Luciferase activity was measured using Kit Bright Glo Luminescent Cell Assay Cat E2610 (Promega) according to the manufacturer's protocol. Luminescence was determined using Tecan SPARK with a reading of 0.2 seconds / well. IC was extracted using XLFIT5 in Microsoft Excel using Method 205. 50 The value was calculated. IC 50 The value represents the concentration of the compound that inhibits measurable luminescence signals by 50% compared to DMSO-treated control cells.

[0339] Cell-free assay for ERK5 inhibition Assays were performed to measure the ability of each compound to inhibit ERK5 enzyme activity. The potency of the compounds was evaluated by time-resolved Forster resonance energy transfer (FRET system). The activation catalytic domain of the protein ERK5 (CarnaBiosciences#04-146) was mixed with various concentrations of the compounds at 4 nM and incubated at room temperature for 30 minutes. A mixture of 1 mM ATP and 1 μM biotinylated synthetic peptide was added (Biosyntan GmbH). This synthetic peptide represents amino acids 30-52 of eukaryotic translation initiation factor 4E-binding protein 1 (see, for example, the sequence of accession number NP_004086.1) biotinylated at the N-terminus. After 30 minutes at 37°C, peptide phosphorylation by ERK5 was measured by adding a FRET reagent consisting of 12.5 μg / ml streptavidin-XL665, 1 nM anti-P-4EBP1 antibody, and 300 ng / ml anti-rabbit K antibody. After 90 minutes at room temperature, the fluorescence signal was read using a BMG Labtech (Exc° 340nm, Em1 620nm, Em2 665nm) Pherastar FSX multimod detector. 50 The value represents the concentration of the compound that inhibits the measurable fluorescence signal by 50% compared to a control with DMSO alone.

[0340] [Table 12]

[0341] [Table 13]

[0342] [Table 14]

[0343] The data in Table 2 show that the synthesized compounds are active in the micromolar or nanomolar concentration range in cell systems and / or cell-free systems. All of the synthesized compounds exhibited IC50 at less than 10 μM in at least one of the cell-based and cell-free assays. 50 It has a value.

[0344] While this disclosure has been described in conjunction with the embodiments described above, it should be understood that the above description and examples are intended to illustrate, and not limit, the scope of this disclosure. Other aspects, advantages, and variations within the scope of this disclosure will be apparent to those skilled in the art in which this disclosure relates.

[0345] In addition, if a feature or aspect is described in terms of the Markush group, a person skilled in the art will recognize that such feature or aspect is also described in terms of any individual member or subgroup of a member of the Markush group.

[0346] All publications, patent applications, patents, and other references referred to herein are expressly incorporated by reference to the same extent as each would be incorporated individually by reference. In case of any conflict, this specification, including its definitions, shall prevail.

Claims

1. Equation (N-I) 【Chemistry 1】 [In the formula, R １ Ha, -(C １ ~C ６ ) alkyl, -(C ３ ~C ７ ) Selected from cycloalkyl, 4-10 member heterocycloalkyl, and 5-10 member heteroaryl, R １ R Ａ It is optionally replaced by one or more occurrences of Each R Ａ is independently selected from halo, -OH, oxo, =N-OH, -(C １ ~C ３ )alkyl, and -O(C １ ~C ３ )alkyl, each occurrence of -(C １ ~C ３ )alkyl is optionally substituted with one or more groups independently selected from halo and -OH, And / or R Ａ The two appearances of these, together with the atom to which they are bonded, (C ３ ~C ６ ) A cycloalkyl group or a 3-6 membered heterocyclic group may be formed, and the cycloalkyl or heterocyclic group may be optionally substituted with one or more halos. L １ These are direct bonds, -O-, and -CH ２ - Selected from, R ２ is, -(C ６ ~C １０ ) is aryl, R ２ R Ｂ It is optionally substituted by one or two occurrences. Each R Ｂ is -OH, -NH ２ , -SF ５ , -NHC(O)OC(CH ３ ) ３ , and -O(C １ ~C ３ ) independently selected from alkyl, -O(C １ ~C ３ Each alkyl group is optionally substituted with one or more halos. R ３ These are -H, -OH, and -(C １ ~C ３ ) Selected from alkyl groups, n is either 0 or 1. A compound that is of the same nature, or a pharmaceutically acceptable salt thereof.

2. R １ teeth, 【Chemistry 2】 Selected from, R １ R as defined in claim 1 Ａ The compound according to claim 1, wherein one or two of the elements are optionally substituted.

3. Each R Ａ -F, -OH, oxo, =N-OH, -OCH ３ , and -(C) which is optionally substituted with one or more substituents selected from -F and -OH. １ ~C ２ The compound according to claim 2, independently selected from alkyl groups.

4. L １ is -O- or -CH ２ - The compound according to any one of claims 1 to 3.

5. R ２ teeth, 【Transformation 3】 A compound selected from any one of claims 1 to 4.

6. Formula (N-II) 【Chemistry 4】 [In the formula, R １ is a halo (for example, -Br), -(C １ ~C ６ ) alkyl, -(C ３ ~C ７ ) Selected from cycloalkyl and 4-10 member heterocycloalkyl, R １ R Ａ It is optionally replaced by one or more occurrences of Each R Ａ These are halo (e.g., -F), -OH, oxo, -O(C) １ ~C ３ -(C) is optionally substituted with one or more groups independently selected from alkyl, halo (e.g., -F), and -OH. １ ~C ３ ) Selected independently from alkyl, And / or R Ａ The two appearances of these, together with the atom to which they are bonded, (C ３ ~C ６ ) may form a cycloalkyl group or a 3-6 member heterocycloalkyl group, and the cycloalkyl group is optionally substituted with -F. L １ These are direct bonds, -O-, and -CH ２ - Selected from, R Ｂ１ -H, -OH, -NH ２ , and -NHC(O)OC(CH ３ ) ３ Selected from, R Ｂ２ is, -SF ５ and -OCF ３ Selected from, R ３ is -H and -(C １ ~C ３ ) Alkyl (e.g., -CH ３ ) Selected from A compound that is of the same nature, or a pharmaceutically acceptable salt thereof.

7. R １ teeth, 【Transformation 5】 Selected from, R １ R is defined in any one of claims 1 to 6. Ａ It is arbitrarily replaced by one occurrence of The compound according to claim 6.

8. Formula (III) or Formula (IV) 【Transformation 6】 [In the formula, R １ and L １ A compound that is as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. Formula (V), Formula (VI), or Formula (VII) 【Transformation 7】 [In the formula, R １ is, -(C ３ ~C ７ ) Selected from cycloalkyl and 4-10 member heterocycloalkyl, R １ R Ａ It is arbitrarily substituted by one or more occurrences of each R Ａ -(C) is independently and optionally substituted with -OH. １ ~C ３ A compound that is alkyl, or a pharmaceutically acceptable salt thereof.

10. - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yloxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-N-morpholino-3H-imidazo[4,5-b]pyridine-2-one, - 6-Tetrohydropyran-4-yloxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[(1-methyl-4-piperidyl)oxy]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methylpyrrolidine-3-yl)oxy-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[(1-methyl-4-piperidyl)oxy]-3H-imidazo[4,5-b]pyridine-2-one, - 6-N-morpholino-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-(1-methylpyrrolidine-3-yl)oxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[2-(hydroxymethyl)morpholin-4-yl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[2-(hydroxymethyl)morpholin-4-yl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(pentafluoro-λ ６ [-Sulfanyl)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 6-tetrahydrofuran-3-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-3-yl-3H-imidazo[4,5-b]pyridine-2-one, - 6-cyclopentyl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-hydroxy-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[4-(pentafluoro-λ ６ [-Sulfanyl)benzoyl]-4-piperidyl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-5-methyl-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-fluorospiro[3,3]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-oxo-4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(tetrahydrofuran-3-ylmethyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(2-methoxyethyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-2-yl-3H-imidazo[4,5-b]pyridine-2-one, - Trans-6-(4-methoxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - cis-6-(4-methoxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3-azabicyclo[4.1.0]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-cyclobutyl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[3-(trifluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(3-oxabicyclo[4.1.0]heptan-6-yl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-bicyclo[2.1.1]hexanyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[3-(difluoromethyl)-1-bicyclo[1.1.1]pentanyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-norcalan-1-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4,4-difluorocyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-cyclohexyl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-norbornan-2-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-2-yl-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(tetrohydropyran-4-ylmethyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrohydropyran-3-yl-3H-imidazo[4,5-b]pyridine-2-one, - 6-Tetrohydropyran-4-yl-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-(oxetane-3-ylmethyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[tetrahydrofuran-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, - trans-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - cis-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-methoxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[1-methylpyrrolidine-3-yl]oxy-3H-imidazo[4,5-b]pyridine-2-one, -1-[1-[2-Amino-4-(pentafluoro-λ ６ -sulfanyl)benzoyl]pyrrolidin-3-yl]-6-tetrahydropyran-4-yl-3H-imidazo[4,5-b]pyridin-2-one, - 1-[1-[4-(pentafluoro-λ ６ -Sulfanyl)benzoyl]pyrroridine-3-yl]-6-tetrohydropyran-4-yl-3H-imidazo[4,5-b]pyridine-2-one, - trans-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - cis-1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(4-hydroxycyclohexyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-[1-(2,2,2-trifluoroethyl)-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-(1-methyl-4-piperidyl)-3H-imidazo[4,5-b]pyridine-2-one, - 1-[1-[2-amino-4-(trifluoromethoxy)benzoyl]-4-piperidyl]-6-tetrahydrofuran-3-yloxy-3H-imidazo[4,5-b]pyridine-2-one, - 6-tetrahydrofuran-3-yloxy-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - Trans-6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - cis-6-(4-hydroxycyclohexyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - tert-butyl N-[2-[4-(6-bromo-2-oxo-3H-imidazo[4,5-b]pyridine-1-yl)piperidine-1-carbonyl]-5-(trifluoromethoxy)phenyl]carbamate, - 6-bromo-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - trans-6-(4-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - cis-6-(4-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-(4-oxocycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - 6-[4-hydroxyiminocycloheptyl]-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - trans-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, - cis-6-(3-hydroxycycloheptyl)-1-[1-[4-(trifluoromethoxy)benzoyl]-4-piperidyl]-3H-imidazo[4,5-b]pyridine-2-one, Compounds selected from the group consisting of and pharmaceutically acceptable salts thereof.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10 and at least one pharmaceutically acceptable excipient or carrier.

12. A compound according to any one of claims 1 to 10, or a pharmaceutical composition according to claim 11, for use in treatment.

13. A compound according to any one of claims 1 to 10, or a pharmaceutical composition according to claim 11, for use in the treatment or prevention of cancer.

14. The compound or pharmaceutical composition for use according to claim 13, wherein the cancer is characterized by increased MAPK7 expression and / or increased ERK5 activity.

15. The compound or pharmaceutical composition for use according to claim 13 or claim 14, wherein the cancer is selected from leukemia (e.g., chronic myeloid leukemia), breast cancer, multiple myeloma, colon cancer, colorectal cancer, lung cancer, pancreatic cancer, renal cell carcinoma, mesothelioma, adenocarcinoma, neuroblastoma, melanoma, and hepatocellular carcinoma.

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