5-cyano-1H-imidazole-2-carboxamide compounds as CSF1R inhibitors

Abstract

The present invention relates to a compound of formula (I) or its prodrug or salt (wherein R 1 , R x , R y The present invention provides a composition comprising a compound of formula (I) in addition to (where X has any of the values ​​described herein). This compound is useful as a kinase inhibitor. The present invention also provides a pharmaceutical composition comprising a compound of formula I or its prodrug or pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition provides blood-brain barrier (BBB) ​​permeability. JPEG2026519814000191.jpg58165

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority from U.S. Provisional Patent Application No. 63 / 472,202 filed on 9 June 2023 and U.S. Provisional Patent Application No. 63 / 540,141 filed on 25 September 2023. The entire contents of each of these U.S. Provisional Patent Applications are incorporated herein by reference. [Background technology]

[0002] The colony-stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR) and CD115 (differentiation antigen group 115), is a cell surface protein encoded by the human CSF1R gene (also known as c-FMS). CSF1R is a receptor that can be activated by two ligands: colony-stimulating factor 1 (CSF-1) and interleukin-34 (IL-34). CSF1R is highly expressed in myeloid cells. CSF1R signaling is required for the survival, proliferation, and differentiation of many myeloid cell types in vivo and in vitro. CSF1R signaling is involved in many diseases and is a therapeutic target for cancer, neurodegenerative diseases, and inflammatory bone diseases.

[0003] WO2009 / 052237 describes compounds that inhibit protein kinases, particularly c-fms kinase. These compounds have been reported to be useful in the treatment of certain cancers, metastases of certain cancers, pain, and certain autoimmune diseases. One compound, 4-cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethylcyclohexa-1-enyl)-6-(2,2,6,6-tetramethyl-tetrahydropyran-4-yl)-pyridine-3-yl]amide (Example 15, page 83 of this specification), is a selective inhibitor of colony-stimulating factor-1 (CSF-1, c-fms) receptor kinase and acts to inhibit macrophage survival, proliferation, and differentiation in patients with active rheumatoid arthritis, and advanced to a Phase II clinical trial as JNJ-40346527 (Genovese, MC, et al (2015) Journal of Rheumatology, 42:10). Currently, there is a need for therapeutic agents that function as kinase inhibitors to treat diseases and mitigate or delay the progression of many disease states. In particular, there is a need for c-fms kinase inhibitors with higher potency, better selectivity than off-target agents that cause side effects and limit dosage, and therefore increased exposure of the active molecule in the brain, increased free fraction in the brain due to decreased brain homogenate binding, enhanced pharmacodynamic effects through extended off-rate from CSF1R, as well as tissue-related methods facilitated by differentiated metabolism that deliver high levels of active drugs (and / or active metabolites). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Genovese,MC,et al(2015)Journal of Rheumatology,42:10 [Overview of the project] [Means for solving the problem]

[0005] In one embodiment, the present invention provides a compound of formula (I):

Chemical formula

Chemical formula

Chemical formula

[0006] The present invention also provides a pharmaceutical composition comprising a compound of formula I or its prodrug or pharmaceutically acceptable salt, and a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical composition provides blood-brain barrier (BBB) ​​permeability.

[0007] The present invention also provides a method for treating a disease selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, bone-destructive tumors, myeloma, and tumor metastases to bone in animals, the method comprising administering a compound of formula (I) or its prodrug or pharmaceutically acceptable salt to an animal.

[0008] The present invention also provides a method for treating diseases that are initiated or progressed by immune activation of myeloid cells, including but not limited to monocytes, macrophages, and microglia.

[0009] The present invention also addresses glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), neurocognitive disorders, chemobrain cognitive impairment or cognitive impairment, psoriasis, diabetes, tumor-associated angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson's disease, Alzheimer's disease, chronic traumatic encephalopathy, Huntington's disease, progressive bulbar palsy, progressive supranuclear palsy, Lewy body dementia, myotonic dystrophy, telangiectatic ataxia, bovine spongiform encephalopathy, kuru disease, and scrutiny. The present invention also provides a method for treating a disease or disorder selected from the group consisting of leupie, anti-N-methyl-D-aspartate receptor encephalitis, myasthenia gravis, progressive multifocal leukoencephalopathy, central nervous system disorders, lupus vasculitis / neuropsychiatric systemic lupus erythematosus, bacterial and viral meningitis, corticobasal degeneration, primary age-related tauopathy, argyrophilic granulopathy, stroke, traumatic brain injury, ALSP, sarcopenia, age-related loss of motor units, muscular dystrophy, and Alzheimer's disease, the method comprising administering a compound of formula (I) or its prodrug or pharmaceutically acceptable salt to an animal.

[0010] The present invention also provides a method for treating pain in animals, the method comprising administering a compound of formula (I) or its prodrug or pharmaceutically acceptable salt to an animal. In one embodiment, the pain is skeletal pain caused by tumor metastasis or osteoarthritis, or visceral pain, inflammatory pain, or neurogenic pain.

[0011] The present invention also provides a method for treating cancer in animals, the method comprising administering a compound of formula (I) or its prodrug or pharmaceutically acceptable salt to an animal. In one embodiment, the cancer is selected from the group consisting of ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, gastric cancer, and hairy cell leukemia.

[0012] The present invention also provides a method for treating or preventing cancer metastasis in animals, the method comprising administering a compound of formula (I) or its prodrug or pharmaceutically acceptable salt to an animal. In one embodiment, the cancer is selected from the group consisting of ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, gastric cancer, and hairy cell leukemia.

[0013] The present invention also provides a method for treating autoimmune diseases in animals, the method comprising administering a compound of formula (I) or its prodrug or pharmaceutically acceptable salt to an animal. In one embodiment, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis and other forms of inflammatory arthritis, psoriasis, Sjögren's syndrome, multiple sclerosis, and uveitis.

[0014] The present invention also provides a method for inhibiting the activity of c-fms kinase, the method comprising contacting c-fms kinase with a compound of formula (I) or its prodrug or pharmaceutically acceptable salt. In one embodiment, c-fms kinase is contacted with the compound or salt in vitro. In one embodiment, c-fms kinase is contacted with a compound of formula (I) or its pharmaceutically acceptable salt in vivo. In one embodiment, the present invention provides an inhibitor of c-fms kinase that is not converted to a biologically active metabolite in vivo.

[0015] The present invention also provides a method for treating atherosclerosis in animals, the method comprising administering a compound of formula (I) or its prodrug or pharmaceutically acceptable salt to an animal.

[0016] The present invention also provides a method for treating a disease selected from the group consisting of ALS, FTD, C9-related disease, Alzheimer's disease, Parkinson's disease, MS, Huntington's disease, Giant Tenosynovial Carcinoma, and epilepsy in animals, the method comprising administering a compound of formula (I) or its prodrug or pharmaceutically acceptable salt to an animal.

[0017] The present invention also provides a method for treating ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, gastric cancer, bladder cancer, pancreatic cancer, glioblastoma, melanoma, lymphoma, leukemia, or hairy cell leukemia in animals, the method comprising administering a compound of formula (I) or its prodrug or pharmaceutically acceptable salt to an animal.

[0018] The present invention also provides a method for treating diseases selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, bone-destructive tumors, myeloma, tenosynovial giant cell tumor, brain cancer, and tumor metastases to the brain or bone, any progressive solid tumors and cancerous tumor metastases in animals (particularly metastases to the brain, CNS, bone, or lymph nodes), the method comprising administering a compound of formula (I) or its prodrug or pharmaceutically acceptable salt to an animal.

[0019] The present invention also addresses glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), hepatitis, neurocognitive disorders, chemobrain cognitive impairment or cognitive impairment, psoriasis, diabetes, tumor-associated angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson's disease, Alzheimer's disease, chronic traumatic encephalopathy, Huntington's disease, progressive bulbar palsy, progressive supranuclear palsy, Lewy body disease, myotonic dystrophy, telangiectatic ataxia, bovine spongiform encephalopathy, kuru disease, scrapie, anti-N-methyl-D-aspartate receptor encephalitis, myasthenia gravis, progressive The present invention also provides a method for treating diseases selected from the group consisting of multifocal leukoencephalopathy, central nervous system disorders, lupus vasculitis / neuropsychiatric systemic lupus erythematosus, bacterial and viral meningitis, corticobasal degeneration, primary age-related tauopathy, tauopathy, argyrophilic granulopathy, stroke, traumatic brain injury, ALSP, sarcopenia, amyotrophic lateral sclerosis, frontotemporal dementia, frontotemporal lobe dementia, epilepsy, any disorder resulting from C9ORF72 mutation, age-related loss of motor units, muscular dystrophy and any other form of dementia, radiation-induced cognitive impairment, and Crohn's disease, the method comprising administering a compound of formula (I) or its prodrug or pharmaceutically acceptable salt to an animal.

[0020] The present invention also provides compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for use in pharmacotherapy.

[0021] The present invention also provides compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for the prophylactic or therapeutic treatment of diseases selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, bone-destructive tumors, myeloma, and tumor metastases to bone.

[0022] The present invention also addresses glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), neurocognitive disorders, chemobrain cognitive impairment or cognitive impairment, psoriasis, diabetes, tumor-associated angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson's disease, Alzheimer's disease, chronic traumatic encephalopathy, Huntington's disease, progressive bulbar palsy, progressive supranuclear palsy, Lewy body dementia, myotonic dystrophy, telangiectatic ataxia, bovine spongiform encephalopathy, and Kuru disease. The invention also provides compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for the prophylactic or therapeutic treatment of diseases selected from the group consisting of scrapie, anti-N-methyl-D-aspartate receptor encephalitis, myasthenia gravis, progressive multifocal leukoencephalopathy, central nervous system disorders, lupus vasculitis / neuropsychiatric systemic lupus erythematosus, bacterial and viral meningitis, corticobasal degeneration, primary age-related tauopathy, argyrophilic granulopathy, stroke, traumatic brain injury, ALSP, sarcopenia, age-related loss of motor units, muscular dystrophy, and Alzheimer's disease.

[0023] The present invention also provides compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for the prophylactic or therapeutic treatment of pain. In one embodiment, the pain is skeletal pain caused by tumor metastasis or osteoarthritis, or visceral pain, inflammatory pain, or neurogenic pain. In one embodiment, the cancer is selected from the group consisting of ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, gastric cancer, and hairy cell leukemia.

[0024] The present invention also provides compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for the treatment or prevention of cancer metastasis. In one embodiment, the cancer is selected from the group consisting of ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, gastric cancer, and hairy cell leukemia.

[0025] The present invention also provides compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for the prophylactic or therapeutic treatment of autoimmune diseases. In one embodiment, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis and other forms of inflammatory arthritis, psoriasis, Sjögren's syndrome, multiple sclerosis, and uveitis.

[0026] The present invention also provides compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for inhibiting the activity of c-fms kinase.

[0027] The present invention also provides compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for the treatment of atherosclerosis.

[0028] The present invention also provides compounds of formula (I) or prodrugs or pharmaceutically acceptable salts thereof for treating diseases selected from the group consisting of ALS, FTD, C9-related diseases, Alzheimer's disease, Parkinson's disease, MS, Huntington's disease, tenosynovial giant cell tumor, and epilepsy.

[0029] The present invention also provides compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for treating ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, gastric cancer, bladder cancer, pancreatic cancer, glioblastoma, melanoma, lymphoma, leukemia, or hairy cell leukemia.

[0030] The present invention also provides compounds of formula (I) or its prodrugs or pharmaceutically acceptable salts for treating diseases selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, bone-destructive tumors, myeloma, tenosynovial giant cell tumor, brain cancer, and tumor metastases to the brain or bone, any progressive solid tumors and cancerous tumor metastases (particularly to the brain, CNS, bone, or lymph nodes).

[0031] The present invention also addresses glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), hepatitis, neurocognitive disorders, chemobrain cognitive impairment or cognitive dysfunction, psoriasis, diabetes, tumor-associated angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson's disease, Alzheimer's disease, chronic traumatic encephalopathy, Huntington's disease, progressive bulbar palsy, progressive supranuclear palsy, Lewy body dementia, myotonic dystrophy, telangiectatic ataxia, bovine spongiform encephalopathy, kuru disease, scrapie, anti-N-methyl-D-aspartate receptor encephalitis, and myasthenia gravis. The present invention also provides compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for treating diseases selected from the group consisting of: dysphagia, progressive multifocal leukoencephalopathy, central nervous system disorders, lupus vasculitis / neuropsychiatric systemic lupus erythematosus, bacterial and viral meningitis, corticobasal degeneration, primary age-related tauopathy, tauopathy, argyrophilic granulopathy, stroke, traumatic brain injury, ALSP, sarcopenia, amyotrophic lateral sclerosis, frontotemporal dementia, frontotemporal lobar dementia, epilepsy, any disorder resulting from C9ORF72 mutation, age-related loss of motor units, muscular dystrophy and any other form of dementia, radiation-induced cognitive impairment, and Crohn's disease.

[0032] The present invention also provides the use of compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for preparing pharmaceuticals useful for the treatment of diseases selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, bone-destructive tumors, myeloma, and tumor metastases to bone in animals.

[0033] The present invention also addresses glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), neurocognitive disorders, chemobrain cognitive impairment or cognitive dysfunction, psoriasis, diabetes, tumor-associated angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson's disease, Alzheimer's disease, chronic traumatic encephalopathy, Huntington's disease, progressive bulbar palsy, progressive supranuclear palsy, Lewy body dementia, myotonic dystrophy, telangiectatic ataxia, bovine spongiform encephalopathy, and kuru in animals. The use of compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for preparing pharmaceuticals useful for the treatment of diseases selected from the group consisting of diseases, scrapie, anti-N-methyl-D-aspartate receptor encephalitis, myasthenia gravis, progressive multifocal leukoencephalopathy, central nervous system diseases, lupus vasculitis / neuropsychiatric systemic lupus erythematosus, bacterial and viral meningitis, corticobasal degeneration, primary age-related tauopathy, argyrophilic granulopathy, stroke, traumatic brain injury, ALSP, sarcopenia, age-related loss of motor units, muscular dystrophy, and Alzheimer's disease is also provided.

[0034] The present invention also provides the use of a compound of formula (I) or its prodrug or pharmaceutically acceptable salt for preparing a medicament useful for the treatment of pain in animals. In one embodiment, the pain is skeletal pain caused by tumor metastasis or osteoarthritis, or visceral pain, inflammatory pain, or neurogenic pain.

[0035] The present invention also provides the use of a compound of formula (I) or its prodrug or pharmaceutically acceptable salt for preparing a pharmaceutical useful for the treatment of cancer in animals. In one embodiment, the cancer is ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, gastric cancer, or hairy cell leukemia.

[0036] The present invention also provides the use of a compound of formula (I) or its prodrug or pharmaceutically acceptable salt for preparing a pharmacopoeia useful for the treatment or prevention of cancer metastasis in animals. In one embodiment, the cancer is ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, gastric cancer, or hairy cell leukemia.

[0037] The present invention also provides the use of a compound of formula (I) or its prodrug or pharmaceutically acceptable salt for preparing formulations that optimize the exposure level and other pharmacodynamic properties of the compound.

[0038] The present invention also provides the use of compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for preparing pharmaceuticals useful for the treatment of autoimmune diseases in animals. In one embodiment, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis and other forms of inflammatory arthritis, psoriasis, Sjögren's syndrome, multiple sclerosis, and uveitis.

[0039] The present invention also provides the use of a compound of formula (I) or its prodrug or pharmaceutically acceptable salt for preparing a pharmaceutical useful for inhibiting the activity of c-fms kinase in animals.

[0040] The present invention also provides the use of a compound of formula (I) or its prodrug or pharmaceutically acceptable salt for preparing a pharmaceutical useful for the treatment of atherosclerosis in animals.

[0041] The present invention also provides the use of a compound of formula (I) or its prodrug or pharmaceutically acceptable salt for preparing a pharmacopoeia useful for the treatment of a disease selected from the group consisting of ALS, FTD, C9-related disease, Alzheimer's disease, Parkinson's disease, MS, Huntington's disease, tenosynovial giant cell tumor, and epilepsy in animals.

[0042] The present invention also provides the use of a compound of formula (I) or its prodrug or pharmaceutically acceptable salt for preparing a medicament useful for the treatment of ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, gastric cancer, bladder cancer, pancreatic cancer, glioblastoma, melanoma, lymphoma, leukemia, or hairy cell leukemia in animals.

[0043] The present invention also provides the use of compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for preparing pharmaceuticals useful for the treatment of diseases selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, bone-destructive tumors, myeloma, tenosynovial giant cell tumor, brain cancer, and tumor metastases to the brain or bone, and any progressive solid tumors and cancerous tumor metastases in animals (particularly metastases to the brain, CNS, bone, or lymph nodes).

[0044] The present invention also addresses glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), hepatitis, neurocognitive disorders, chemobrain cognitive impairment or cognitive impairment, psoriasis, diabetes, tumor-associated angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson's disease, Alzheimer's disease, chronic traumatic encephalopathy, Huntington's disease, progressive bulbar palsy, progressive supranuclear palsy, Lewy body disease, myotonic dystrophy, telangiectatic ataxia, bovine spongiform encephalopathy, kuru disease, scrapie, anti-N-methyl-D-aspartate receptor encephalitis, myasthenia gravis, and other conditions in animals. The use of compounds of formula (I) or their prodrugs or pharmaceutically acceptable salts for preparing pharmaceuticals useful for the treatment of diseases selected from the group consisting of: multifocal leukoencephalopathy, central nervous system disorders, lupus vasculitis / neuropsychiatric systemic lupus erythematosus, bacterial and viral meningitis, corticobasal degeneration, primary age-related tauopathy, tauopathy, argyrophilic granulopathy, stroke, traumatic brain injury, ALSP, sarcopenia, amyotrophic lateral sclerosis, frontotemporal dementia, frontotemporal lobe dementia, epilepsy, any disorder resulting from C9ORF72 mutation, age-related loss of motor units, muscular dystrophy and any other form of dementia, radiation-induced cognitive impairment, and Crohn's disease.

[0045] The present invention also provides processes and intermediates disclosed herein that are useful for the preparation of compounds of formula I or salts thereof.

[0046] A certain compound has the group R 1 It is deuterated, chlorinated, or fluorinated in [location]. Group R 1 Deuteration, chlorination, or fluorination in different R 1 Compared to similar compounds with substituents, it may improve metabolic stability, potency, and / or in vivo efficacy.

[0047] Certain compounds exhibit higher metabolic stability than their corresponding non-deuterated compounds.

[0048] Certain compounds exhibit superior in vivo pharmacokinetics compared to their corresponding non-deuterated compounds.

[0049] Certain compounds exhibit superior in vitro efficacy compared to their corresponding non-deuterated compounds.

[0050] Certain compounds exhibit higher metabolic stability than their corresponding non-fluorinated compounds.

[0051] Certain compounds exhibit superior in vivo pharmacokinetics compared to their corresponding non-fluorinated compounds.

[0052] Certain compounds exhibit superior in vitro efficacy compared to their corresponding non-fluorinated compounds.

[0053] Certain compounds exhibit higher metabolic stability than their corresponding non-chlorinated compounds.

[0054] Certain compounds exhibit superior in vivo pharmacokinetics compared to their corresponding non-chlorinated compounds.

[0055] Certain compounds exhibit superior in vitro efficacy compared to their corresponding non-chlorinated compounds. [Modes for carrying out the invention]

[0056] The present invention will now be described in detail in part, with examples of which are illustrated in the attached structures and formulas. While the present invention will be described in conjunction with the listed embodiments, it should be understood that these are not intended to limit the invention to those embodiments. Conversely, the present invention is intended to encompass all alternative forms, modifications, and equivalents, which may fall within the scope of the invention as defined by the claims.

[0057] Those skilled in the art will understand that there are many methods and materials similar to or equivalent to those described herein that can be used in carrying out the present invention. The present invention is by no means limited to the methods and materials described herein.

[0058] definition Unless otherwise specified, the following definitions are used: Halo or halogen is fluoro, chloro, bromo, or iodine. Alkyl, alkoxy, etc., refer to both linear and branched groups, but references to individual radicals such as propyl include only linear radicals, while branched isomers such as isopropyl are specifically mentioned.

[0059] The term "alkyl" means, unless otherwise specified, a molecule having a specified number of carbon atoms, either by itself or as part of another substituent (i.e., C 1~6 A alkyl group refers to a linear or branched hydrocarbon radical (meaning 1 to 6 carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, and n-hexyl.

[0060] In particular, the (C1-C6) alkyl group may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, or hexyl.

[0061] The term "alkoxy" refers to an alkyl group that is bonded to the rest of a molecule via an oxygen atom ("oxy").

[0062] The term "alkoxycarbonyl," as used herein, refers to the group (alkyl)-OC(=O)-, where the term alkyl has the meaning defined herein. The term (C1-C6)alkoxycarbonyl may be methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, pentoxycarbonyl, or hexyloxycarbonyl.

[0063] As used herein, the term "alkanoyl" refers to the group (alkyl)-C(=O)-, where the term alkyl has the meaning defined herein.

[0064] As used herein, the term “protecting group” refers to a substituent commonly used to block or protect a particular functional group on a compound. For example, an “amino protecting group” is a substituent attached to an amino group that blocks or protects an amino functional group in a compound. Preferred amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, a “hydroxy protecting group” refers to a substituent of a hydroxyl group that blocks or protects a hydroxyl functional group. Preferred protecting groups include acetyl and silyl. A “carboxy protecting group” refers to a substituent of a carboxyl group that blocks or protects a carboxyl functional group. Common carboxy protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphinol)ethyl, and nitroethyl. For an overview of protecting groups and their uses, see PGMWuts and TWGreene, Greene's Protective Groups in Organic Synthesis 4. th See edition, Wiley-Interscience, New York, 2006.

[0065] Where used herein, a wavy line intersecting a bond in a chemical structure is used. [ka] This indicates the bonding point to the molecular residue of the bond where the wavy bond intersects in the chemical structure.

[0066] The terms “treat,” “treatment,” or “treating” include, to the extent that they relate to a disease or condition, inhibiting a disease or condition, eliminating a disease or condition, and / or reducing one or more symptoms of a disease or condition. The terms “treat,” “treatment,” or “treating” also refer to both therapeutic measures and / or preventive measures or preventive actions, the purpose of which is to prevent or slow (mitigate) undesirable physiological changes or impairments, such as the onset or spread of cancer. Beneficial or desired clinical outcomes, for example, include, but are not limited to, symptom reduction, attenuation of the degree of disease or impairment, stabilization of the disease or impairment (i.e., no worsening), delay or slowing of disease progression, relief or temporary relief of the disease state or impairment, and remission (partial or complete), whether detectable or undetectable. “Treat,” “treatment,” or “treating” may also mean an extension of survival compared to the survival expected if no treatment were received. Those requiring treatment include those who already have a disease or disability, those who are prone to developing a disease or disability, or those for whom a disease or disability should be prevented. In one embodiment, “to treat,” “treatment,” or “treating” does not include prevention or prevention.

[0067] The terms “therapeutic dose” or “effective dose” include, but are not limited to, an amount of a compound that (i) treats or prevents a particular disease, condition or disorder; (ii) reduces, improves or eliminates one or more symptoms of a particular disease, condition or disorder; or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition or disorder as described herein.

[0068] As used herein, the term “mammal” refers to humans, higher non-human primates, rodents, domestic animals, cattle, horses, pigs, sheep, dogs, and cats. In one embodiment, the mammal is a human. As used herein, the term “patient” refers to any animal, including mammals. In one embodiment, the patient is a mammalian patient. In one embodiment, the patient is a human patient.

[0069] This disclosure also includes “deuterated analogues” of the compounds described herein, in which 1 to n hydrogens bonded to carbon atoms are replaced by deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are therefore useful for extending the half-life of any compound when administered to mammals, particularly humans. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens are replaced by deuterium. Therapeutic compounds of the present invention labeled or substituted with deuterium may have improved DMPK (drug metabolism and pharmacokinetic) properties with respect to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may result in certain therapeutic benefits derived from higher metabolic stability, such as extension of in vivo half-life, reduction of required dose, and / or improvement of therapeutic index. 18 F, 3 H, or 1114C-labeled compounds may be useful for PET, SPECT, or other imaging studies. The isotope-labeled compounds and their prodrugs of this disclosure can generally be prepared by performing the procedures disclosed in the schemes or examples and preparations described below, using readily available isotope-labeling reagents in place of non-isotope-labeling reagents. In this context, deuterium is understood to be considered a substituent in the compounds described herein. The concentration of such heavier isotopes, specifically deuterium, may be defined by the isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, where a position is specifically designated as "H" or "hydrogen," that position is understood to have hydrogen in its naturally occurring isotopic composition. Thus, in the compounds of this disclosure, any atom specifically designated as deuterium (D) is meant to represent deuterium.

[0070] When a compound is substituted with one or more deuterium atoms, it is understood that the compound is enriched with deuterium at a given position in a quantity exceeding the natural abundance of deuterium. In one embodiment, the compound may be enriched with deuterium at least twice the natural abundance. In one embodiment, the compound may be enriched with deuterium at least 10 times the natural abundance. In one embodiment, the compound may be enriched with deuterium at least 100 times the natural abundance. In one embodiment, the compound may be enriched with deuterium at least 1000 times the natural abundance.

[0071] The compounds disclosed herein may also exist as tautomers in certain cases. Although only one delocalized resonance structure may be shown, all such forms are intended within the scope of the present invention.

[0072] Those skilled in the art will know that the present invention is not limited thereto, but deuterium ( 2It is understood to include any claimed compound that may be enriched with any atom or all atoms above the naturally occurring isotopic ratio, including one or more isotopes such as H or D). As a non-limiting example, a -CH3 group may be replaced with -CD3.

[0073] The pharmaceutical compositions of the present invention may contain one or more excipients. When used in combination with the pharmaceutical compositions of the present invention, the term "excipient" generally refers to additional ingredients that are combined with a compound of formula (I) or a pharmaceutically acceptable salt thereof to provide the corresponding composition. For example, when used in combination with the pharmaceutical compositions of the present invention, the term "excipient" includes, but is not limited to: carriers, binders, disintegrants, lubricants, sweeteners, flavors, coatings, preservatives and dyes.

[0074] The stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Since the compounds of the present invention can contain asymmetric or chiral centers, they exist in various stereoisomers. All stereoisomers of the compounds of the present invention (including, but not limited to, diastereomers, enantiomers and atropisomers), as well as mixtures thereof (such as racemic mixtures), are intended to form part of the present invention. Many organic compounds exist as optically active forms, i.e., these compounds have the ability to rotate the plane of plane-polarized light. When describing optically active compounds, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecule around its chiral center(s). The prefixes d and l, or (+) and (-), are used to indicate the sign of rotation of plane-polarized light by the compound, and (-) or l means that the compound is levorotatory. A compound with the prefix (+) or d is dextrorotatory. In a given chemical structure, these stereoisomers are identical except when they are mirror images of each other. Special stereoisomers can also be referred to as enantiomers, and mixtures of such isomers are often called enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate and can be found in chemical reactions or processes that do not have stereoselectivity or stereospecificity. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species that is optically inactive.

[0075] It will be apparent to those skilled in the art that the compounds of the present invention having a chiral center can exist as optically active and racemic forms, and can be isolated as optically active and racemic forms. Some compounds may exhibit polymorphism. It should be understood that the present invention includes any racemic, optically active, crystalline polymorph, or stereoisomer of the compounds of the present invention, or mixtures thereof, that have the useful properties described herein, and methods for preparing optically active compounds (e.g., by recrystallization techniques, by resolution of racemic forms, by synthesis from optically active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase) are well known in the art.

[0076] In the compound formulas herein, if a bond is depicted in a non-stereochemical form (e.g., planar), the atom to which the bond is attached includes all stereochemical possibilities. In the compound formulas herein, if a bond is depicted in a defined stereochemical form (e.g., thick line, thick wedge, dashed line, or dashed wedge), the atom to which the stereochemical bond is attached should be understood to be concentrated in the illustrated diastereomer unless otherwise noted. In one embodiment, the compound may be at least 51% of the shown absolute stereoisomers. In another embodiment, the compound may be at least 60% of the shown absolute stereoisomers. In another embodiment, the compound may be at least 80% of the shown absolute stereoisomers. In another embodiment, the compound may be at least 90% of the shown absolute stereoisomers. In another embodiment, the compound may be at least 95% of the shown absolute stereoisomers. In another embodiment, the compound may be at least 99% of the shown absolute stereoisomers.

[0077] The specific values ​​listed below for radicals, substituents, and ranges are for illustrative purposes only; they do not exclude other defined values ​​or other values ​​within the defined ranges for radicals and substituents. It should be understood that two or more values ​​can be combined. It should also be understood that the values ​​(or subsets thereof) listed below herein may be excluded.

[0078] In one embodiment, the compound of formula (III): [ka] or a salt thereof is provided, in the formula: R 1 teeth, [ka] Selected from the group consisting of, R 1 R is optionally substituted with one or more groups independently selected from (C1-C6) alkyl and OH groups, 1 It is substituted with one or more groups independently selected from deuterium, chloro, and fluoro. R a is H, (C1-C6) alkyl, (C1-C6) alkanoyl, or (C1-C6) alkoxycarbonyl, R b is H, (C1-C6) alkyl, (C1-C6) alkanoyl, or (C1-C6) alkoxycarbonyl, R c The elements are H, (C1-C6) alkyl, (C1-C6) alkanoyl, or (C1-C6) alkoxycarbonyl.

[0079] R 1 The specific value of the structure is: [ka] Selected from, R 1 is optionally substituted with one or more OH groups, R 1is substituted with one or more groups independently selected from deuterium, chloro, and fluoro.

[0080] R 1 The specific value of

Chemical formula

[0081] R 1 The specific value of

Chemical formula

[0082] R 1 The specific value of

Chemical formula

[0083] R 1 The specific value of

Chemical formula

[0084] R 1 The specific value of [ka] Selected from, R 1 It is substituted with one or more groups independently selected from deuterium, chloro, and fluoro.

[0085] R 1 The specific value of the structure is: [ka] Selected from, R 1 It is replaced by one or more deuterium atoms.

[0086] R 1 The specific value of the structure is: [ka] Selected from, R 1 It is replaced by one or more deuterium atoms.

[0087] R 1 The specific value of the structure is: [ka] Selected from, R 1 It is replaced by one or more deuterium atoms.

[0088] R 1 The specific value of the structure is: [ka] Selected from, R 1 It is substituted with one or more groups independently selected from chloro and fluoro.

[0089] R 1 The specific value of the structure is: [ka] Selected from, R 1 It is substituted with one or more groups independently selected from chloro and fluoro.

[0090] R 1 The specific value of the structure is: [ka] Selected from, R 1 It is substituted with one or more groups independently selected from chloro and fluoro.

[0091] R 1 The specific value of the structure is: [ka] It has, R 1 It is replaced by two or more deuterium atoms.

[0092] R 1 The specific value of the structure is: [ka] It has, R 1 It is replaced by three or more deuterium atoms.

[0093] R 1 The specific value of the structure is: [ka] It has, R 1 It is replaced by six or more deuterium atoms.

[0094] R 1 The specific value of the structure is: [ka] It has, R 1 It is replaced by 12 or more deuterium atoms.

[0095] R 1 The specific value of is [ka] It is selected from the group consisting of the following.

[0096] R 1 The specific value of is [ka] [ka] It is selected from the group consisting of the following.

[0097] Certain compounds, prodrugs, or salts are [ka] or its prodrug or salt.

[0098] Certain compounds, prodrugs, or salts are compounds of formula (III): [ka] or its prodrug or salt, in the formula: R 1 teeth, [ka] Selected from the group consisting of, R 1 It is optionally substituted with one or more groups independently selected from OH, deuterium, chloro, and fluoro. R a is H, (C1-C6) alkyl, (C1-C6) alkanoyl, or (C1-C6) alkoxycarbonyl, R b is H, (C1-C6) alkyl, (C1-C6) alkanoyl, or (C1-C6) alkoxycarbonyl, Rc The elements are H, (C1-C6) alkyl, (C1-C6) alkanoyl, or (C1-C6) alkoxycarbonyl.

[0099] Certain compounds, prodrugs, or salts are compounds of formula (I): [ka] or its prodrug or salt, in the formula: R 1 teeth, [ka] Selected from the group consisting of, R 1 R is optionally substituted with one or more groups independently selected from (C1-C6) alkyl and OH groups, 1 It is substituted with one or more groups independently selected from deuterium, chloro, and fluoro. R a is H, (C1-C6) alkyl, (C1-C6) alkanoyl, or (C1-C6) alkoxycarbonyl, R b is H, (C1-C6) alkyl, (C1-C6) alkanoyl, or (C1-C6) alkoxycarbonyl, R c The elements are H, (C1-C6) alkyl, (C1-C6) alkanoyl, or (C1-C6) alkoxycarbonyl.

[0100] In one embodiment, R a It is a methoxycarbonyl compound.

[0101] In one embodiment, R a H is H.

[0102] In one embodiment, R b It is either H or methyl.

[0103] In one embodiment, R c It is H, methyl, or ethyl.

[0104] In one embodiment, X is N.

[0105] In one embodiment, X is CH.

[0106] In one aspect, a compound of formula (II):

Chem.

Chem.

Chem.

[0107] R 2 The specific values of

Chem.

[0108] R b and R c The specific values of are independently selected from CH3, CH2F, and CH2OH.

[0109] In one embodiment, the present invention provides a compound of formula (III):

Chemical formula

Chemical formula

[0110] In one embodiment, the present invention provides a compound of formula (II):

Chemical formula

[0111] A certain compound (for example, R 1 Certain compounds of formula (I) or formula (II) containing a cross-linked bicyclic ring have improved kinase selectivity, potency, stability, pharmacokinetics, pharmacodynamics, blood-brain barrier permeability, chirality, and / or metabolite activity. Certain compounds may also induce beneficial intrinsic microglial transcriptome states.

[0112] Prepare all the exemplary compounds listed in Table 1 and use LC-MS [M+H] detection with parent ion detection. + The compounds were characterized by liquid chromatography-mass spectrometry and tested according to the assay described in Example 24. Exemplary Formula I compounds exhibit the following assay activity IC2 ranges: 50 Compounds with a value greater than 7 have an IC50 of less than 10 nM. 50 It contains more than 11 compounds with ICs of 10 nM to 100 nM. 50 Certain exemplary compounds exhibit blood-brain barrier (BBB) ​​permeability. Exemplary compounds of formula I are shown in Table 1.

[0113] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10]

[0114] Processes and intermediates useful for preparing the compound of formula (I) are provided as further embodiments of the present invention and are illustrated by the following procedure, in which, unless otherwise limited, the general meaning of radical is as set forth above.

[0115] [ka] Compound of formula (Ia) (wherein R x A compound of formula (Ia) (where R is a protecting group) can be converted to a compound of formula (I) by deprotecting the compound of formula (Ia) to provide a compound of the corresponding formula (I). Therefore, the present invention provides a method for preparing a compound of formula (I), the corresponding compound of formula (Ia) (where R is a protecting group). xThe present invention includes providing a compound of formula (I) by deprotecting a protecting group (where R is a protecting group). The present invention also provides a compound of formula (Ia), where R is a protecting group. x is a suitable protecting group. In one embodiment, R x This is a trimethylsilylethoxymethyl (SEM) group. In one embodiment, the present invention provides a method for preparing a compound of formula (I), the method for preparing the corresponding compound of formula (Ia) (wherein R x The present invention involves treating a trimethylsilylethoxymethyl (SEM) protecting group with a fluoride source (e.g., tetrabutylammonium fluoride) to provide a compound of formula (I).

[0116] If the compound is sufficiently basic or acidic, salts of the compound of formula I may be useful as intermediates for isolating or purifying the compound of formula I. Furthermore, it may be appropriate to administer the compound of formula I as a pharmaceutically acceptable acidic or basic salt. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylates, methanesulfonates, acetates, citrates, malons, tartrates, succinates, benzoates, ascorbicates, α-ketoglutarates, and α-glycerophosphates. Suitable inorganic salts, including hydrochlorides, sulfates, nitrates, bicarbonates, and carbonates, may also be formed.

[0117] Salts can be obtained by reacting a sufficiently basic compound, such as an amine, with a suitable acid that yields a physiologically acceptable anion, using standard procedures well known in the art. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be prepared.

[0118] In addition to salt forms, the present invention provides compounds in prodrug forms. As used herein, the term “prodrug” refers to those compounds that readily undergo chemical transformation under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, a prodrug can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir together with a suitable enzyme or chemical reagent.

[0119] The prodrugs of the present invention include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues, is covalently bonded to a free amino, hydroxy, or carboxylic acid group of the compound of the present invention via an amide or ester bond.

[0120] Additional types of prodrugs are also included. For example, the free carboxyl group of the compounds of the present invention may be derivatized as an amide or alkyl ester. As another example, compounds of the present invention containing a free hydroxyl group may be derivatized as prodrugs by converting the hydroxyl group to a group, for example, but not limited to, phosphate esters, hemisuccinic acid, dimethylaminoacetic acid, or phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamate prodrugs of hydroxyl and amino groups are also included, as are carbonate prodrugs, sulfonic acid esters, and sulfate esters of hydroxyl groups. Derivatization of the hydroxyl group as (acyloxy)methyl and (acyloxy)ethyl ethers is also included, where the acyl group may be an alkyl ester optionally substituted with a group including, but not limited to, ethers, amines, and carboxylic acid functional groups, or the acyl group may be an amino acid ester as described above. This type of prodrug is described in J.Med.Chem., (1996), 39:10. A more specific example is a group in which the hydrogen atoms of an alcohol group are replaced, for example, (C 1~6 ) Alkanoyloxymethyl, 1-((C 1~6 )Alkanoyloxy)ethyl, 1-methyl-1-((C 1~6 )Alkanoyloxy)ethyl, (C 1~6 ) Alkoxycarbonyloxymethyl, N-(C 1~6 ) Alkoxycarbonylaminomethyl, succinoyl, (C 1~6 ) Alkanoyl, alpha-amino(C 1~4 ) Includes substitution with alkanoyl, arylacyl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where each alpha-aminoacyl group is a naturally occurring L-amino acid, P(O)(OH)2, -P(O)(O(C) 1~6A radical independently selected from alkyl-2 or glycosyl (a radical obtained by removing the hydroxyl group from the hemiacetal form of a carbohydrate).

[0121] For examples of the addition of prodrug derivatives, see, for instance, a) Design of Prodrugs (edited by H. Bundgaard) (Elsevier, 1985) and Methods in Enzymology, Vol. 42, pp. 309-396 (edited by K. Widder, et al.) (Academic Press, 1985), b) A Textbook of Drug Design and Development (edited by Krogsgaard-Larsen and H. Bundgaard), Chapter 5 “Design and Application of Prodrugs,” (by H. Bundgaard) pp. 113-191 (1991), c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992), d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988), and e) N. Kakeya, et al. See al., Chem. Pharm. Bull., 32:692 (1984), each of which is specifically incorporated herein by reference.

[0122] The compound of formula I may be formulated as a pharmaceutical composition and administered to a mammalian host, such as a human patient, in various forms suitable for a selected route of administration, i.e., orally or parenterally, intravenously, intramuscularly, topically or subcutaneously.

[0123] In other words, the compounds of the present invention can be administered systemically, for example, orally, in combination with an inert diluent or a pharmaceutically acceptable vehicle such as an assimilated food carrier. They may be encapsulated in hard or soft-shelled gelatin capsules, compressed into tablets, or directly incorporated into the patient's prescribed diet. For oral therapeutic administration, the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers, etc. Such compositions and preparations should contain at least 0.1% of the active compound. The percentage of such compositions and preparations may, of course, vary and, for convenience, may be about 2 to about 60% of the weight of a given unit dosage form. The amount of the active compound in such therapeutically useful compositions is such that an effective dose level is obtained.

[0124] Tablets, lozenges, pills, capsules, etc., may contain binders such as tragacanth gum, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, fructose, lactose, or aspartame, or flavorings such as peppermint, wintergreen oil, or cherry flavoring. When the unit dosage form is a capsule, in addition to the above types of substances, it may also contain a liquid carrier such as vegetable oil or polyethylene glycol. Various other substances may be present as a coating or separately to modify the physical form of the solid unit dosage form. For example, tablets, pills, or capsules may be coated with gelatin, wax, shellac, or sugar. The syrup or elixir may contain the active compound, sucrose or fructose as a sweetener, methylparaben and propylparaben as preservatives, colorants, and flavorings such as cherry or orange flavor. Naturally, all substances used to prepare any unit dosage form must be pharmaceutically acceptable and substantially nontoxic in the amounts used. In addition, the active compound may be incorporated into sustained-release preparations and devices.

[0125] The active compound may also be administered intravenously or intraperitoneally by injection or infusion. Solutions of the active compound or its salts may be prepared in water and optionally mixed with a non-toxic surfactant. Dispersions may also be prepared in glycerol, liquid polyethylene glycol, triacetin and mixtures thereof, as well as in oil. These preparations contain preservatives to prevent microbial growth under normal storage and use conditions.

[0126] Suitable pharmaceutical dosage forms for injection or infusion include sterile aqueous solutions or sterile dispersions containing the active ingredient, or sterile powders containing the active ingredient, adapted for immediate preparation of sterile solutions or sterile dispersions for injection or infusion, which are optionally encapsulated in liposomes. In any case, the final dosage form must be sterile, fluid, and stable under manufacturing and storage conditions. The liquid carrier or liquid vehicle may be a solvent or liquid dispersion medium containing, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and suitable mixtures thereof. Adequate fluidity can be maintained, for example, by forming liposomes, by maintaining the required particle size in the case of dispersions, or by using surfactants. Microbial activity can be inhibited by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc. In many cases, it would be preferable to include isotonic agents, such as sugars, buffers, or sodium chloride. The absorption of an injectable composition can be prolonged by using an absorption retarder in the composition, such as aluminum monostearate and gelatin.

[0127] Sterile injectable solutions are prepared by incorporating the required amount of the active compound, along with the various other components listed above as needed, into a suitable solvent, followed by filtration sterilization. In the case of sterile powders for preparing sterile injectable solutions, preferred preparation methods are vacuum drying and freeze-drying techniques, which yield powders of the active components and any desired additional components present in the pre-sterilized filtered solution.

[0128] For topical administration, the compounds of the present invention may be applied in their pure form, i.e., in liquid form. However, it is generally preferable to administer them to the skin as a composition or formulation in combination with a dermatologically acceptable carrier (which may be solid or liquid).

[0129] Useful solid carriers include pulverized solids (talc, clay, microcrystalline cellulose, silica, alumina, etc.). Useful liquid carriers include water, alcohol or glycol, or water-alcohol / glycol mixtures, and the compound can be dissolved or dispersed at an effective level, optionally with the aid of non-toxic surfactants. The properties can be optimized to suit the intended use by adding adjuvants such as fragrances and additional antimicrobial agents. The resulting liquid composition can be applied from an absorbent pad, used to impregnate bandages and other dressings, or sprayed onto the affected area using a pump-type or aerosol spray.

[0130] Thickening agents, such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty acid alcohols, modified cellulose, or modified mineral materials, can also be used with the liquid carrier to form spreadable pastes, gels, ointments, soaps, etc., for direct application to the user's skin.

[0131] Examples of useful dermatological compounds that can be used to deliver compounds of formula I to the skin are known in the art; see, for example, Jacquet et al. (U.S. Patent No. 4,608,392), Geria (U.S. Patent No. 4,992,478), Smith et al. (U.S. Patent No. 4,559,157), and Wortzman (U.S. Patent No. 4,820,508).

[0132] The effective dosage of the compounds of formula I can be determined by comparing their in vitro activity with their in vivo activity in animal models. Methods for extrapolating effective dosages in mice and other animals to humans are known in the art; see, for example, U.S. Patent No. 4,938,949.

[0133] The amount of the compound of the present invention, or its active salt or derivative, required for therapeutic use will vary not only depending on the specific salt selected, but also on the route of administration, the nature of the condition being treated, and the patient's age and condition, and will ultimately be left to the discretion of the attending physician or clinician.

[0134] The desired dose may, for convenience, be provided as a single dose or as divided doses administered at appropriate intervals, for example, two, three, four, or more times a day as sub-dose doses. The sub-dose itself may be further divided into multiple separate doses at staggered intervals, for example, by multiple inhalations from an inhaler or multiple eye drops.

[0135] The compounds of the present invention may also be administered in combination with other therapeutic agents, such as checkpoint inhibitors, cholinesterase inhibitors, antibodies targeting disease RNA and protein species including but not limited to amyloid beta, gene therapies including but not limited to ASO, siRNA, shRNA, and AAV-based approaches, cell therapies including but not limited to CRISPR, TALEN, and ZFN, and compounds that modulate autophagy, ferroptosis, DNA damage repair, misfolded proteins, protein aggregation, apoptosis, mitochondrial function, biogenesis, fusion / fission, or inflammasomes.

[0136] The present invention will be illustrated by the following non-limiting embodiments. [Examples]

[0137] As used herein, the following abbreviations have the meanings indicated. ACN: Acetonitrile AIBN: Azobisisobutyronitrile Boc:tert-butoxycarbonyl CDCl3:Chloroform-d C Phos Pd G3:[(2-dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate DAPI: 4',6-Diamidino-2-phenylindole DCM: Dichloromethane DIEA: N,N-diisopropylethylamine DIPEA: Diisopropylethylamine DMA: N,N-dimethylacetamide DMAP: 4-dimethylaminopyridine DMF: Dimethylformamide DMSO: Dimethyl sulfoxide DMSO-d6: Dimethyl sulfoxide-d6 Dppf: Diphenylphosphine Dtbbpy: 4,4'-di-tert-butyl-2,2'-dipyridyl Eq.: Equivalent (multiple) æ:ethyl acetate EtOH: Ethanol Glyme: Dimethoxyethane HPLC: High-Performance Liquid Chromatography IPA: Isopropyl alcohol iPrOAc: Isopropyl acetate i-Pr: Isopropyl KOAc: Potassium acetate LC / MS: Liquid Chromatography / Mass Spectrometry LDA: Lithium diisopropylamide LED: Light-emitting diode LiHMDS: Lithium bis(trimethylsilyl)amide m / z: mass-to-charge ratio. m-CPBA: Meth-chloroperbenzoic acid MeCN: Acetonitrile MeOD: Methanol-d1 MeOH: methanol MeOH-d4: Methanol-d4 MS: Mass spectrometry MTBE: tert-butyl methyl ether NBS: N-bromosuccinimide NFSI: N-Fluorobenzenesulfonimide NHC-1:5,7-di-tert-butyl-3-phenylbenzo[d]oxazole-3-iumtetrafluoroborate Pet.Et.: Petroleum ether Pin2B2:4,4,5,5-Tetramethyl-2-(4,4,5,5-Tetramethyl-1,3,2-Dioxaborolane-2-yl)-1,3,2-Dioxaborolane PPTS: Pyridinium p-toluenesulfonate PyBroP: Bromotris-pyrrolidino-phosphonium hexafluorophosphate R t :Holding time SEM: 2-(trimethylsilyl)ethoxymethyl SPhos Pd G3: (2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate TEA: Triethylamine TEBAC: Benzyltriethylammonium chloride TFA: Trifluoroacetic acid THF: Tetrahydrofuran TLC: Thin-layer chromatography

[0138] General method LC / MS was performed on each compound tested using the Shimadzu LC-20ADXR system under appropriate conditions. 1 ¹H NMR was performed using a Bruker 400MHz Avance system. Selected purifications were carried out using either a) an ISCO® SEPAFLASH® silica column system or b) a suitable preparative HPLC system, under conditions appropriate for each compound. Those skilled in the art will readily understand that other systems for analyzing and / or purifying compounds and intermediates can achieve similar results.

[0139] synthetic intermediate The following is a description of synthetic intermediates (INT-1 to INT-6) that are useful for preparing representative compounds of the present invention.

[0140] Intermediate INT-1 [ka] 2-(4,4-dimethylcyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(INT-1) A solution of 4,4-dimethylcyclohexanone (1, 50 g, 396.21 mmol, 1 eq) in THF (300 mL) was added dropwise at -70°C to a solution of LiHMDS (1 M, 475.45 mL, 1.2 eq) in THF (900 mL). The mixture was stirred at -70°C for 2 hours. Then, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (2, 148.62 g, 416.0 mmol, 1.05 eq) was added at -70°C. The mixture was stirred under N2 at 20°C for 10 hours. The reaction was monitored by TLC (Pet.Et.: siRNA = 10:1) until completion was indicated. The reaction mixture was quenched with NH4Cl (aqueous solution, 1000 mL) and extracted with siRNA (1000 mL x 3). The organic layers were combined, washed with brine (1000 mL), dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA=1 / 0~10 / 1, gradient) to obtain (4,4-dimethylcyclohexen-1-yl)trifluoromethanesulfonate (3, 79 g, 305.9 mmol, yield 77.2%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3) δ = 5.68-5.66 (m, 1H), 2.35 - 2.32 (m, 2H), 1.99-1.97 (m, 2H), 1.54 (t, J = 6.4 Hz, 2H), 0.97 (s, 6H).

[0141] To a solution of (4,4-dimethylcyclohexen-1-yl)trifluoromethanesulfonate (3, 79 g, 305.90 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (4, 85.45 g, 336.49 mmol, 1.1 eq) in 1000 mL of dioxane, a solution of KOAc (90.06 g, 917.7 mmol, 3 eq) and Pd(dppf)Cl2.CH2Cl2 (7.49 g, 9.18 mmol, 0.03 eq) was added dropwise. The mixture was stirred at 90°C for 12 hours under N2. The reaction was monitored using TLC (Pet.Et.: siRNA=10:1) until completion was indicated. The reaction mixture was quenched with H2O (1000 mL) and extracted with siRNA (1000 mL x 3). The organic layers were combined, washed with brine (1000 mL), dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 10 / 1 to 1 / 1 gradient) to obtain 2-(4,4-dimethylcyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (INT-1, 38 g, 160.9 mmol, yield 52.6%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3) δ = 6.51-6.46 (m, 1H), 2.13 - 2.10 (m, 2H), 1.85-1.84 (m, 2H), 1.32 (t, J = 6.4 Hz, 2H), 1.20 (s, 12H), 0.86 (s, 6H).

[0142] Intermediate INT-2 [ka] [4-Cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]oxypotassium (INT-2) To a solution of 1H-imidazole-5-carbonitrile (5, 45 g, 483.42 mmol, 1 ep) in THF (500 mL), 2-(chloromethoxy)ethyl-trimethyl-silane (96.72 g, 580.10 mmol, 102.67 mL, 1.2 eq) and K2CO3 (133.62 g, 966.8 mmol, 2 eq) were added. The mixture was stirred at 25°C for 12 hours. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 10 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with water (300 mL) and extracted with Depositphotos (200 mL x 2). The organic layers were combined, washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 330 g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 80 mL / min). 1-(2-trimethylsilylethoxymethyl)imidazole-4-carbonitrile (6, 92 g, 411.9 mmol, yield 85.2%) was obtained as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3, 294 K) δ (ppm) = 7.79 - 7.59 (m, 2H), 5.44 - 5.30 (m, 2H), 3.64 - 3.43 (m, 2H), 0.99 - 0.86 (m, 2H), -0.01 (s, 9H).

[0143] To a solution of 1-(2-trimethylsilylethoxymethyl)imidazole-4-carbonitrile (6, 92 g, 411.92 mmol, 1 eq) in isopropyl acetate (900 mL), NBS (80.65 g, 453.11 mmol, 1.1 eq) and AIBN (6.76 g, 41.19 mmol, 0.1 eq) were added. The mixture was stirred under N2 at 60°C for 12 hours. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 1 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with water (100 mL) and extracted with Depositphotos (80 mL x 2). The organic layers were combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 330g SEPAFLASH® silica flash column, eluent: 0-50% Pet.Et.: siRNA gradient, flow rate 80 mL / min). 2-Bromo-1-(2-trimethylsilylethoxymethyl)imidazole-4-carbonitrile (7, 90g, 297.77 mmol, yield 72.3%) was obtained as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3) δ (ppm) = 7.65 (s, 1H), 5.32 (s, 2H), 3.61 - 3.52 (m, 2H), 1.00 - 0.90 (m, 2H), 0.02 (s, 9H).

[0144] To a solution of 2-bromo-1-(2-trimethylsilylethoxymethyl)imidazole-4-carbonitrile (7, 90 g, 297.77 mmol, 1 eq) in THF (200 mL), i-PrMgCl (2 M, 163.78 mL, 1.1 eq) was added dropwise at -40°C. The mixture was stirred at -40°C for 0.5 hours. Then, ethyl cyanoformate (8, 59.01 g, 595.6 mmol, 58.37 mL, 2 eq) was added at -78°C. The mixture was warmed and stirred at 25°C for a further 2.5 hours. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 3:1) until the starting materials were completely consumed. The reaction mixture was diluted with water (300 mL) and extracted with Depositphotos (200 mL x 2). The organic layers were combined, washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 330 g SEPAFLASH® silica flash column, eluent: 0-50% Pet.Et.: siRNA gradient, flow rate 80 mL / min). Ethyl 4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylate (9, 60 g, 203.1 mmol, yield 68.2%) was obtained as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3, 295 K) δ (ppm) = 7.79 (s, 1H), 5.80 (s, 2H), 4.46 (q, J = 7.1 Hz, 2H), 3.61 (dd, J = 7.9, 8.7 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H), 0.98 - 0.93 (m, 2H), 0.00 (s, 9H).

[0145] To a solution of ethyl 4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylate (9, 5.00 g, 16.93 mmol, 1 eq) in EtOH (40 mL), KOH (949.63 mg, 16.93 mmol, 1 eq) was added. The mixture was stirred at 25°C for 10 minutes. The reaction was monitored by TLC (Pet.Et.:Â=3:1) until the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the residue of [4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]oxypotassium (INT-2, 5 g, 16.4 mmol, yield 96.7%), which was then used as is. 1 H NMR (400 MHz, MeOH-d4, 298 K) δ (ppm) = 7.96 (s, 1H), 5.88 (s, 2H), 3.62 - 3.58 (m, 2H), 0.94 - 0.88 (m, 2H), -0.01 (s, 9H).

[0146] Intermediate INT-3 [ka] N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl(INT-3) To a solution of 6-bromopyridine-3-amine (10, 20 g, 115.60 mmol, 1 eq) in EtOH (300 mL), Ag2SO4 (36.04 g, 115.60 mmol, 19.59 mL, 1 eq) and I2 (29.34 g, 115.60 mmol, 23.29 mL, 1 eq) were added. The mixture was stirred at 25°C for 12 hours. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 3 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with water (100 mL) and extracted with Depositphotos (100 mL x 2). The organic layers were combined, washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 120g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 80 mL / min) to obtain 6-bromo-2-iodopyridine-3-amine (11, 22 g, 73.60 mmol, yield 63.7%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3, 300 K) δ (ppm) = 7.19 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 4.29 - 3.01 (m, 2H).

[0147] To a solution of 6-bromo-2-iodopyridine-3-amine (11, 10 g, 33.46 mmol, 1 eq) in toluene (500 mL) and EtOH (250 mL), 2-(4,4-dimethylcyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (INT-1, 10.27 g, 43.49 mmol, 1.3 eq), Na2CO3 (2 M, 133.82 mL, 8 eq), and Pd(PPh3)4 (1.93 g, 1.67 mmol, 0.05 eq) were added. The mixture was stirred at 80°C for 12 hours under N2. The reaction was monitored by TLC (Pet.Et.: siRNA = 5:1) until completion was indicated. The reaction mixture was quenched with H2O (500 mL) and extracted with siRNA (500 mL x 3). The organic layers were combined, washed with brine (500 mL), dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 10 / 1 to 1 / 1 gradient) to obtain 6-bromo-2-(4,4-dimethylcyclohexen-1-yl)pyridine-3-amine (12, 25 g, 88.91 mmol, yield 88.6%) as a yellow solid, which was then used as is.

[0148] To a solution of 6-bromo-2-(4,4-dimethylcyclohexen-1-yl)pyridine-3-amine (12, 25 g, 88.91 mmol, 1 eq) in DCM (250 mL), Boc2O (58.21 g, 266.72 mmol, 61.28 mL, 3 eq), TEA (26.99 g, 266.72 mmol, 37.12 mL, 3 eq), and DMAP (2.17 g, 17.8 mmol, 0.2 eq) were added. The mixture was stirred under N2 at 20°C for 12 hours. The reaction was monitored by TLC (Pet.Et.: siRNA=5:1) until completion was indicated. The reaction mixture was quenched with H2O (250 mL) and extracted with DCM (250 mL x 3). The organic layers were combined, washed with brine (250 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 10 / 1 to 1 / 1 gradient) to obtain N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-N-tert-butoxycarbonylcarbamate tert-butyl (13, 29 g, 60.24 mmol, yield 67.8%) as a yellow solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0149] To a solution of N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-N-tert-butoxycarbonylcarbamate tert-butyl (13, 29 g, 60.24 mmol, 1 eq) in MeOH (290 mL), K2CO3 (24.98 g, 180.7 mmol, 3 eq) was added. The mixture was stirred under N2 at 50°C for 12 hours. The reaction was monitored by TLC (Pet.Et.: siRNA=5:1) until completion was indicated. The reaction mixture was quenched with H2O (190 mL) and extracted with siRNA (190 mL x 3). The organic layers were combined, washed with brine (190 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 10 / 1 to 1 / 1) to obtain N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (INT-3, 19 g, 49.83 mmol, yield 82.7%) as a yellow solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used directly. MS (LC / MS) m / z: Measured value 381.1, predicted value 381.1 [M+H].

[0150] Intermediate INT-4 [ka] tert-butyl-[[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-oxabicyclo[3.2.1]octa-2,6-dien-1-yl]methoxy]-dimethyl-silane(INT-4) To a solution of [5-(hydroxymethyl)-2-furyl]methanol (14, 50 g, 390.24 mmol, 1 eq) in DMF (500 mL), TBSCl (147.04 g, 975.61 mmol, 119.55 mL, 2.5 eq) and imidazole (79.70 g, 1.17 mol, 3 eq) were added. The mixture was stirred at 25°C for 12 hours. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 10 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with water (500 mL) and extracted with Depositphotos (200 mL x 2). The organic layers were combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. Without further purification, tert-butyl-[[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-furyl]methoxy]dimethyl-silane (15, 110 g, 308.43 mmol, yield 79.0%) was obtained as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 6.16 (s, 2H), 4.62 (s, 4H), 0.91 (s, 18H), 0.09 (s, 12H).

[0151] To a solution of tert-butyl-[[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2-furyl]methoxy]dimethyl-silane (15, 30 g, 84.12 mmol, 1 eq) in CF3CH2OH (300 mL), N,N-diethylethanamine (34.05 g, 336.47 mmol, 46.83 mL, 4 eq) and 1,1,3-trichloropropan-2-one (16, 40.73 g, 252.35 mmol, 3 eq) were added under N2 at 25°C. The mixture was stirred at 25°C for 12 hours. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 10 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with water (20 mL) and extracted with Depositphotos (20 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue without further purification. 1,5-Bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,4-dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-one (17, 60 g, 49.83 mmol, yield 59.2%, purity 40%) was obtained as crude yellow oil without further characterization and was used as is.

[0152] A mixture of CuCl (6.17 g, 62.29 mmol, 1.49 mL, 0.5 eq), NH4Cl (46.65 g, 872.09 mmol, 7 eq), and zinc (40.73 g, 622.92 mmol, 5 eq) in MeOH (600 mL) was mixed with a solution of 1,5-bis[[tertbutyl(dimethyl)silyl]oxymethyl]-2,4-dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-one (17, 60 g, 124.58 mmol, 1 eq) in MeOH (30 mL) at 25°C, and the mixture was stirred at 25°C for 16 hours. The reaction was monitored by TLC (Pet.Et. / siRNA=10 / 1) until the starting materials were completely consumed. The reaction mixture was filtered through a CELITE® pad. The filtrate was diluted with water (200 mL) and extracted with siRNA (150 mL x 2). The precipitate was dissolved by adding HCl (2N). The organic layers were combined, washed with brine, dried on MgSO4, and evaporated to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 330 g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 50 mL / min) to obtain 1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octa-6-en-3-one (18, 12 g, 29.08 mmol, yield 23.3%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 6.10 (s, 2H), 3.80 (d, J = 1.4 Hz, 4H), 2.64 - 2.55 (m, 2H), 2.46 - 2.37 (m, 2H), 0.90 (s, 17H), 0.08 (s, 12H).

[0153] To a solution of 1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octa-6-en-3-one (18, 10 g, 24.23 mmol, 1 eq) in THF (100 mL), LDA (2 M, 24.23 mL, 2 eq) was added dropwise at -78 °C. After 0.5 hours, a solution of 1,1,1-trifluoro-N-(2-pyridyl)-N-(trifluoromethylsulfonyl)methanesulfonamide (13.02 g, 36.35 mmol, 1.5 eq) in THF (20 mL) was added dropwise at -78 °C. The mixture was warmed and stirred for a further 2.5 hours at 25 °C. The reaction was monitored by TLC (Pet.Et. / siRNA=10 / 1) until the starting materials were completely consumed. The reaction mixture was quenched with NH4Cl (saturated aqueous solution, 20 mL) and extracted with siRNA (10 mL x 2). The organic layers were combined, washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 80 mL / min) to obtain [1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]trifluoromethanesulfonate (19, 10 g, 18.36 mmol, yield 75.8%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 6.42 (d, J = 5.9 Hz, 1H), 6.29 (s, 1H), 5.92 (d, J = 5.8 Hz, 1H), 3.81 (s, 4H), 2.82 (dd, J = 1.8, 17.6 Hz, 1H), 2.13 (dd, J = 1.1, 17.6 Hz, 1H), 0.91 (s, 18H), 0.12 - 0.06 (m, 12H).

[0154] To a solution of [1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]trifluoromethanesulfonate (19, 5 g, 9.18 mmol, 1 eq) in dioxane (60 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (4, 4.66 g, 18.36 mmol, 2 eq), KOAc (2.70 g, 27.53 mmol, 3 eq), and Pd(dppf)Cl2 (671.57 mg, 917.82 μmol, 0.1 eq) were added. The mixture was stirred at 100°C for 12 hours under N2. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 10 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with water (50 mL) and extracted with Depositphotos (50 mL x 2). The organic layers were combined, washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using an 80g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 60 mL / min) to obtain tert-butyl-[[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-oxabicyclo[3.2.1]octa-2,6-dien-1-yl]methoxy]dimethyl-silane (INT-4, 4.6g, 8.80 mmol, yield 95.9%) as a yellow solid, which was then used as is. 1H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 6.96 (t, J = 2.0 Hz, 1H), 6.34 (d, J = 5.8 Hz, 1H), 5.84 (d, J = 5.8 Hz, 1H), 3.80 - 3.75 (m, 4H), 2.47 (dd, J = 2.3, 18.7 Hz, 1H), 1.92 (dd, J = 1.9, 18.6 Hz, 1H), 1.24 (s, 12H), 0.91 (s, 12H), 0.09 - 0.06 (m, 18H).

[0155] intermediate INT-5 [ka] N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide(INT-5) To a solution of 6-bromo-2-(4,4-dimethylcyclohexen-1-yl)pyridine-3-amine (20 g, 7.11 mmol, 1 eq) in DMF (20 mL), [5-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]oxypotassium (INT-2, 3.91 g, 12.80 mmol, 1.8 eq), PyBroP (4.97 g, 10.67 mmol, 1.5 eq), and DIEA (2.76 g, 21.34 mmol, 3.72 mL, 3 eq) were added. The mixture was stirred at 25°C for 12 hours. The reaction was analyzed by LC / MS (R tThe reaction mixture was monitored for 1.438 minutes (M+H=530.2) until it indicated that the reaction product had been completely consumed. The reaction mixture was diluted with water (30 mL) and extracted with siRNA (30 mL x 2). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 60 mL / min) to obtain N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (INT-5, 3.4 g, 6.41 mmol, yield 90.1%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 9.91 (s, 1H), 8.64 (d, J = 8.7 Hz, 1H), 7.78 (s, 1H), 7.37 (d, J = 8.7 Hz, 1H), 6.00 (td, J = 2.0, 3.5 Hz, 1H), 5.92 (s, 2H), 3.70 - 3.62 (m, 2H), 2.51 - 2.42 (m, 2H), 2.13 (br d, J = 3.4 Hz, 2H), 1.63 - 1.60 (m, 3H), 1.12 (s, 6H), 1.01 - 0.95 (m, 2H), 0.01 (s, 8H), MS (LC / MS) m / z: Measured value 530.2, Predicted value 530.2 [M+H].

[0156] Intermediate INT-6 [ka] 6,7-Diduterio-1,5-dimethyl-3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]octa-2-ene-8-carboxylate methyl(INT-6) To a solution of 2,5-dimethyl-1H-pyrrole (21, 45 g, 472.98 mmol, 48.13 mL, 1 eq) in THF (500 mL), n-BuLi (2.5 M, 227.03 mL, 1.2 eq) was added at -78°C. The mixture was further stirred under N2 at -78°C for 0.5 hours. Then, methyl carbonochloride (53.63 g, 567.57 mmol, 43.85 mL, 1.2 eq) was added at -78°C. The mixture was warmed and further stirred under N2 at 20°C for 11.5 hours. The reaction was monitored by TLC (Pet.Et.: siRNA = 10:1) until completion was indicated. The two separate reactants were combined for workup. The reaction mixture was quenched by adding NH4Cl (saturated aqueous solution, 1000 mL) and extracted with siRNA (1000 mL x 3). The organic layers were combined, washed with brine (1500 mL), dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 1 / 0~1 / 1 gradient) to obtain methyl 2,5-dimethylpyrrole-1-carboxylate (22, 115 g, 750.76 mmol, yield 79.37%) as a white solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0157] To a solution of methyl 2,5-dimethylpyrrole-1-carboxylate (22, 20 g, 130.57 mmol, 1 eq) and 1,1,3-trichloropropan-2-one (63.23 g, 391.70 mmol, 3 eq) in CF3CH2OH (40 mL), TEA (39.64 g, 391.70 mmol, 54.52 mL, 3 eq) was added. The mixture was stirred under N2 at 20°C for 12 hours. The reaction was monitored by TLC (Pet.Et.: siRNA = 10:1) until completion was indicated. The reaction mixture was diluted with H2O (100 mL) and extracted with siRNA (100 L x 3). The organic layers were combined, washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Without further purification, the residue was obtained as a white solid: 2,4-dichloro-1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octa-6-ene-8-carboxylate methyl (23, 30 g, 107.86 mmol, yield 82.6%). This solid was used as is without further characterization.

[0158] To a solution of CuCl (5.34 g, 53.93 mmol, 1.29 mL, 0.5 eq), NH4Cl (40.39 g, 755.04 mmol, 7 eq), and Zn (35.27 g, 539.31 mmol, 5 eq) in MeOH (300 mL), a solution of 2,4-dichloro-1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octa-6-ene-8-carboxylate methyl (23, 30 g, 107.86 mmol, 1 eq) in MeOH (50 mL) was added. The mixture was stirred under N2 at 20°C for 12 hours. The reaction was monitored by TLC (Pet.Et.: Â=10:1) until completion was indicated. The reaction mixture was passed through a CELITE® pad and filtered. The filtrate was diluted with water (400 mL) and extracted with siRNA (200 mL x 3). The organic layers were combined, washed with brine (300 mL), dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 250 × 70 mm, 10 μm, mobile phase: [H2O (10 mM NH4HCO3)-ACN], gradient: 20%~50% B over 18.0 mins) to obtain methyl 1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octa-6-ene-8-carboxylate (24, 6 g, 28.68 mmol, yield 26.6%) as a yellow oil. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0159] To a solution of methyl 1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octa-6-ene-8-carboxylate (24, 4.9 g, 23.42 mmol, 1 eq) in siRNA (30 mL), Pd / C (1.96 g, 1.84 mmol, 10% purity, 0.079 eq) was added. The mixture was stirred at 20°C for 3 hours under a D2 (15 psi) atmosphere. The reaction was monitored by TLC (Pet.Et.: siRNA = 5:1) until completion was indicated. The reaction mixture was filtered and concentrated under reduced pressure. Without further purification by removing MeOD, methyl 6,7-dijuterio-1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (25, 4.5 g, 21.10 mmol, 90.1% yield) was obtained as a yellow oil. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0160] To a 10 mL solution of LiHMDS (1 M, 23.21 mL, 1.1 eq) in THF (10 mL), a 50 mL solution of methyl 6,7-diduterio-1,5-dimethyl-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (25 g, 4.5 g, 21.10 mmol, 1 eq) in THF (50 mL) was added dropwise at -70°C. The mixture was heated and stirred at 20°C for 0.5 hours. Next, a 10 mL solution of 1,1,1-trifluoro-N-(2-pyridyl)-N-(trifluoromethylsulfonyl)methanesulfonamide (8.31 g, 23.21 mmol, 1.1 eq) in THF (10 mL) was added at -70°C. The reaction mixture was heated and stirred at 20°C for 2.5 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et.: ÂTED=5 / 1) until completion was indicated. The reaction mixture was quenched with NH4Cl (saturated aqueous solution, 40 mL) and extracted with ÂTED (40 mL x 3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / ÂTED=1 / 0~5 / 1) to obtain 6,7-diduterio-1,5-dimethyl-3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]octa-2-ene-8-carboxylate methyl (INT-6, 4 g, 11.58 mmol, yield 54.9%) as a yellow oil. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0161] The following is a description of the preparation of representative compounds of the present invention.

[0162] Example 1 4-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)tetrahydropyran-4-yl]-3-pyridyl]-1H-imidazole-2-carboxamide A-1 [ka] [ka] To a solution of 4-methoxybenzaldehyde (26, 15 g, 110.17 mmol, 13.39 mL, 1 eq) in ethyl 3-oxobutanoate (43.01 g, 330.52 mmol, 41.76 mL, 3 eq), piperidine (1.29 g, 15.19 mmol, 1.50 mL, 0.14 eq) was added. The mixture was stirred at 25°C for 48 hours. The reaction was monitored by TLC (Pet.Et.: siRNA = 10:1) until completion was indicated. The reaction mixture was filtered and concentrated under reduced pressure to obtain 2,4-diacetyl-3-(4-methoxyphenyl)pentanedioate diethyl (27, 30 g, 79.3 mmol, yield 72.0%) as a white solid without further purification. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0163] A mixture of diethyl 2,4-diacetyl-3-(4-methoxyphenyl)pentanedioate (27, 30 g, 79.28 mmol, 1 eq) and KOH (20 M, 150.00 mL, 37.8 eq) was stirred at 80°C for 2 hours. The reaction was monitored by TLC (Pet.Et.: siRNA = 10:1) until completion was indicated. The reaction mixture was diluted with ice water (100 mL) and extracted with siRNA (100 mL x 3). The aqueous phase was adjusted to pH 6 with concentrated HCl and extracted with siRNA (100 mL x 3). The organic layers were combined, washed with brine (100 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 3-(4-methoxyphenyl)pentanedioic acid (28, 15 g, 63.0 mmol, yield 79.4%) as a white solid without further purification or characterization, which was then used as is.

[0164] To a solution of 3-(4-methoxyphenyl)pentanedioic acid (28, 15 g, 63.0 mmol, 1 eq) in EtOH (60 mL), H2SO4 (3.68 g, 37.52 mmol, 2 mL, 0.6 eq) was added. The mixture was stirred at 90°C for 5 hours. The reaction was monitored by TLC (Pet.Et.: Depositphotos = 3:1) until the reaction was complete. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / Depositphotos = 10 / 1 to 1 / 1) to obtain diethyl 3-(4-methoxyphenyl)pentanedioic acid (29, 15 g, 51.0 mmol, yield 80.9%) as a yellow oil. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0165] To a solution of diethyl 3-(4-methoxyphenyl)pentanedioate (29, 5 g, 16.99 mmol, 1 eq), a solution of magnesium iod(triduteriomethyl) (1 M, 108.72 mL, 6.40 eq) in THF (10 mL) was added at 0°C. The mixture was heated and then stirred under N2 at 20°C for 12 hours. The reaction was monitored by TLC (Pet.Et.: siRNA=1:1) until completion was indicated. The reaction mixture was quenched by the addition of NH4Cl (saturated aqueous solution, 50 mL) and extracted with siRNA (50 mL x 3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / SiO7 = 10 / 1 to 1 / 1) to obtain 1,1,1,7,7,7-hexaduterio-4-(4-methoxyphenyl)-2,6-bis(triduteriomethyl)heptane-2,6-diol (30, 3g, 10.77 mmol, yield 63.4%) as a white solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0166] To a solution of 1,1,1,7,7,7-hexaduterio-4-(4-methoxyphenyl)-2,6-bis(triduteriomethyl)heptane-2,6-diol (30, 3g, 10.77 mmol, 1eq) in DCM (30 mL), TFA (4.62 g, 40.52 mmol, 3.00 mL, 3.76 eq) was added. The mixture was stirred at 20°C for 12 hours. The reaction was monitored by TLC (Pet.Et.: siRNA=10:1) until completion was indicated. The reaction mixture was diluted with NaHCO3 (saturated aqueous solution, 10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, Pet.Et.: SiO7 = 1:0 to 1:1) to obtain 4-(4-methoxyphenyl)-2,2,6,6-tetrakis(triduteriomethyl)tetrahydropyran (31, 1.8 g, 6.91 mmol, yield 64.2%) as a white solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0167] To a solution of 4-(4-methoxyphenyl)-2,2,6,6-tetrakis(triduteriomethyl)tetrahydropyran (31, 1.8 g, 6.91 mmol, 1 eq) in DCM (10 mL), MeCN (10 mL), and H2O (15 mL), NaHCO3 (290.32 mg, 3.46 mmol, 134.41 μL, 0.5 eq), NaIO4 (14.78 g, 69.12 mmol, 3.83 mL, 10 eq), and RuCl3 (143.37 mg, 691.15 μmol, 46.10 μL, 0.1 eq) were added at 0°C. The mixture was stirred at 0°C for 2 hours. The reaction was monitored by TLC (Pet.Et.: SiO=1:1) until the reaction was complete. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (30 mL x 3). The organic layers were combined, washed with brine (50 mL), dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et.: Depositphotos = 1:0 to 1:1) to obtain 2,2,6,6-tetrakis(triduteriomethyl)tetrahydropyran-4-carboxylic acid (32, 0.7 g, 3.53 mmol, yield 51.1%) as a white solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0168] Dichloronickel; 1,2-dimethylcyclohexenyl-1-yl)-3-pyridyl]carbamate tert-butyl (INT-3, 0.35 g, 917.90 μmol, 1 eq) and 2,2,6,6-tetrakis(triduteriomethyl)tetrahydropyran-4-carboxylic acid (233.01 mg, 1.17 mmol, 1.28 eq) are dissolved in DMF (10 mL) and 1,2-dimethylcyclohexenyl The following compounds were added: cyethane (20.17 mg, 91.8 μmol, 0.1 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (32 mg, 36.95 mg, 137.68 μmol, 0.15 eq), Cs2CO3 (598.14 mg, 1.84 mmol, 2 eq), and (IR(dF(CH3)ppy)2(dtbbpy))PF6 (9.31 mg, 9.18 μmol, 0.01 eq). The mixture was stirred at 20°C for 12 hours under N2 atmosphere and 34 W blue LED illumination. The reaction was monitored by TLC (Pet.Et.: SiO=10:1) until completion was indicated. The reaction mixture was quenched with H2O (20 mL) and extracted with SiO (10 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA=1 / 0~10 / 1) to obtain N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)tetrahydropyran-4-yl]-3-pyridyl]carbamate tert-butyl (33, 0.4 g, 879.69 μmol, yield 31.95%) as a yellow oil. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0169] To a solution of N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)tetrahydropyran-4-yl]-3-pyridyl]carbamate tert-butyl (33, 0.4 g, 879.7 μmol, 1 eq) in DCM (5 mL), TFA (2.40 g, 21.04 mmol, 1.56 mL, 23.9 eq) was added. The mixture was stirred at 20°C for 1 hour. The reaction was analyzed by HPLC (R t The reaction was monitored until it was clear that it was complete (3.076 mins). The reaction mixture was concentrated under reduced pressure and DCM was removed. The resulting residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×30mm×10μm, mobile phase: [water(NH4HCO3)-ACN], B%: gradient 50%~90%, 8 mins) to obtain 2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)tetrahydropyran-4-yl]pyridine-3-amine (34, 0.2 g, 564.03 μmol, yield 64.12%) as a white solid, which was then used as is.

[0170] To a solution of 2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)tetrahydropyran-4-yl]pyridine-3-amine (34 mg, 0.2 g, 564.03 μmol, 1 eq) and 4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylic acid (INT-2, 345.70 mg, 1.13 mmol, 2 eq) in DMF (5 mL), PyBroP (394.41 mg, 846.04 μmol, 1.5 eq) and DIEA (218.69 mg, 1.69 mmol, 294.72 μL, 3 eq) were added. The mixture was stirred under N2 at 20°C for 12 hours. The reaction was monitored by TLC (Pet.Et.: Depositphotos = 5:1) until completion was indicated. The reaction mixture was quenched with H2O (20 mL) and extracted with Depositphotos (10 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / ethyl acetate = 1 / 0~10 / 1) to obtain 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)tetrahydropyran-4-yl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (35, 0.25 g, 413.95 μmol, yield 73.4%) as a yellow oil, which was then used as is. MS (LC / MS) m / z measured value 604.7, predicted value 604.5 [M+H].

[0171] To a solution of 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)tetrahydropyran-4-yl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (35, 0.25 g, 413.95 μmol, 1 eq) in DCM (1 mL), TFA (7.33 g, 64.28 mmol, 4.77 mL, 155.28 eq) was added. The mixture was stirred at 20°C for 2 hours under an N2 atmosphere. The reaction was monitored by LC / MS until completion was indicated. The reaction mixture was concentrated under reduced pressure and the DCM was removed. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5μm, mobile phase: [water (TFA)-ACN], gradient: 40%~70%B over 8 minutes) to obtain the title compound 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)tetrahydropyran-4-yl]-3-pyridyl]-1H-imidazole-2-carboxamide (A-1) as a white solid (112.9 mg, 238.4 μmol, yield 57.6%). 1 H NMR (400 MHz, MeOH-d4) δ = 9.03 - 8.94 (m, 1H), 8.07 (s, 1H), 7.80 - 7.66 (m, 1H), 6.22 (br s, 1H), 3.67 - 3.51 (m, 1H), 2.53 - 2.42 (m, 2H), 2.17 (br d, J = 3.5 Hz, 2H), 1.89 (br d, J = 12.9 Hz, 2H), 1.71 - 1.61 (m, 4H), 1.13 (s, 6H), MS (LC / MS) m / z Actual value 474.5, Predicted value 474.4 [M+H].

[0172] Example 2 N-[6-(8-azabicyclo[3.2.1]octan-3-yl)-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-5-cyano-1H-imidazole-2-carboxamide A-3 [ka] Dichloronickel; 1,2-dimethoxyethyl ester (INT-3, 0.5 g, 1.31 mmol, 1 eq) and 8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]octane-3-carboxylic acid (42, 334.78 mg, 1.31 mmol, 1 eq) are dissolved in DMF (5 mL) and 1,2-dimethoxyethyl ester (INT-3, 0.5 g, 1.31 mmol, 1 eq) Tan (28.81 mg, 131.13 μmol, 0.1 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (52.79 mg, 196.69 μmol, 0.15 eq), Cs2CO3 (854.48 mg, 2.62 mmol, 2 eq), and (Ir(dF(CH3)ppy)2(dtbbpy))PF6 (13.30 mg, 13.11 μmol, 0.01 eq) were added. The mixture was stirred at 20°C for 12 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et.: SiO=10:1) until completion was indicated. The reaction mixture was quenched with H2O (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA=1 / 0~10 / 1) to obtain 3-[5-(tert-butoxycarbonylamino)-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl (43, 0.8 g, 1.56 mmol, yield 39.7%) as a yellow oil, which was used as is without further characterization.

[0173] To a solution of 3-[5-(tert-butoxycarbonylamino)-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl (43, 0.8 g, 1.56 mmol, 1 eq) in dioxane (4 mL), HCl / dioxane (4 M, 4 mL, 10.23 eq) was added. The mixture was stirred at 20°C for 2 hours under an N2 atmosphere. The reaction was analyzed by LC / MS (R t The reaction was monitored for 0.444 minutes (M+H = 312.4) until completion was indicated. The reaction mixture was concentrated under reduced pressure to remove dioxane, and without further purification, 6-(8-azabicyclo[3.2.1]octan-3-yl)-2-(4,4-dimethylcyclohexen-1-yl)pyridine-3-amine (44, 0.5 g, 1.44 mmol, yield 91.9%) was obtained as an HCl salt, a yellow oil, which was then used as is. MS (LC / MS) m / z measured value 312.4, predicted value 312.2 [M+H].

[0174] To a solution of 6-(8-azabicyclo[3.2.1]octan-3-yl)-2-(4,4-dimethylcyclohexen-1-yl)pyridine-3-amine hydrochloride (44, 0.5 g, 1.44 mmol, 1 eq) in DCM (1 mL), Boc2O (313.65 mg, 1.44 mmol, 330.15 uL, 1 eq) and TEA (159.96 mg, 1.58 mmol, 220.03 uL, 1.1 eq) were added. The mixture was stirred at 20°C for 1 hour under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et.: Â=10:1) until completion was indicated. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (10 mL x 3), dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et.: siRNA=1 / 0~10 / 1 gradient) to obtain 3-[5-amino-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl (45, 0.35 g, 850.4 μmol, yield 59.2%) as a white solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used directly. MS (LC / MS) m / z: Measured value 412.3, predicted value 412.3 [M+H].

[0175] To a solution of tert-butyl 3-[5-amino-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid (45, 0.3 g, 728.90 μmol, 1 eq) and 4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylic acid (INT-2, 379.74 mg, 1.24 mmol, 1.7 eq) in DMF (2 mL), DIEA (282.61 mg, 2.19 mmol, 380.9 μL, 3 eq) and PyBroP (509.70 mg, 1.09 mmol, 1.5 eq) were added. The mixture was stirred at 20°C for 12 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et. / siRNA=10:0) until completion was indicated. The reaction mixture was quenched with H2O (1 mL) and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA=1 / 0 to 10 / 1 gradient) to obtain 3-[5-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl (46, 0.2 g, 302.6 μmol, yield 41.5%) as a white solid, which was used directly without further characterization.

[0176] To a solution of 3-[5-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl (46, 0.05 g, 75.65 μmol, 1 eq) in DCM (1 mL), TFA (770.00 mg, 6.75 mmol, 500.00 μL, 89.27 eq) was added. The mixture was stirred at 0°C for 2 hours under an N2 atmosphere. The reaction was analyzed by HPLC (R tThe reaction was monitored for 1.12 minutes ([M+H]=431.4) until it indicated completion. The reaction mixture was concentrated under reduced pressure and DCM was removed. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×30mm×10μm, mobile phase: [water(NH4HCO3)-ACN], B%: 15%~55% gradient, 8 min) to obtain the title compound N-[6-(8-azabicyclo[3.2.1]octan-3-yl)-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-5-cyano-1H-imidazole-2-carboxamide (A-3, 19.60 mg, 45.52 μmol, yield 60.2%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ = 10.01 (s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 5.87 (br s, 1H), 4.03 (br s, 2H), 3.21 - 3.17 (m, 1H), 2.38 (br s, 2H), 2.13 - 1.95 (m, 8H), 1.91 - 1.82 (m, 2H), 1.50 (br t, J = 6.3 Hz, 2H), 1.09 - 1.01 (m, 6H), MS (LC / MS) m / z actual value 431.4, Predicted value: 431.3

[0177] Example 3 4-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-3-pyridyl]-1H-imidazole-2-carboxamide A-4 [ka] 3-[5-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl (46, 0.15 g, 226.96 μmol, 1 eq) was dissolved in DCM (5 mL) and ZnBr2 (408.89 mg, 1.82 mmol, 90.86 μL, 8 eq) was added. The mixture was stirred at 20°C for 12 hours under an N2 atmosphere. The reaction was analyzed by LCMS (R t The reaction was monitored for 1.196 minutes ([M+H]=561.4) until completion was indicated. The reaction mixture was quenched with H2O (5 mL) and extracted with DCM (5 mL x 3). The organic layers were combined, washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex C18 80×40mm×3μm, mobile phase: [water (NH4HCO3)-ACN], B%: 25%~55% gradient, 8 min) to obtain N-[6-(8-azabicyclo[3.2.1]octan-3-yl)-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (47, 0.02 g, 35.66 μmol, yield 15.7%) as a white solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used directly. MS (LC / MS) m / z: measured value 561.4, predicted value 561.3 [M+H].

[0178] To a solution of N-[6-(8-azabicyclo[3.2.1]octan-3-yl)-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (47 mg, 0.02 g, 35.66 μmol, 1 eq) in MeOH (2 mL), formaldehyde (14.47 mg, 178.32 μmol, 13.28 μL, purity 37%, 5 eq) was added. The mixture was stirred at 0°C for 0.5 hours under an N2 atmosphere, and then NaBH3CN (5.60 mg, 89.16 μmol, 2.5 eq) was added. The mixture was stirred further at 20°C for 11.5 hours under an N2 atmosphere. The reaction was analyzed by LC / MS (R t The reaction was monitored for 0.892 minutes (M+H = 575.5) until completion was indicated. The reaction mixture was diluted with H2O (5 mL) and extracted with siRNA (5 mL x 3). The organic layers were combined, washed with brine (5 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (48, 0.015 g, 26.09 μmol, yield 73.2%) as a white solid without further purification, which was then used as is. MS (LC / MS) m / z: measured value 575.5, predicted value 575.4 [M+H].

[0179] To a solution of 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (48, 0.015 g, 26.09 μmol, 1 eq) in DCM (1 mL), TFA (462.00 mg, 4.05 mmol, 0.3 mL, 155.28 eq) was added. The mixture was stirred at 20°C for 2 hours under an N2 atmosphere. The reaction was analyzed by LC / MS (R tThe reaction was monitored for 0.709 minutes ([M+H]=445.3) until completion was indicated. The reaction mixture was diluted with H2O (5 mL) and extracted with pharmaceutically acceptable toluene (5 mL x 3). The organic layers were combined, washed with brine (5 mL x 3), dried over anhydrous sodium 2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×30mm×10μm, mobile phase: [water (NH4HCO3)-ACN], B%: 20%~55% gradient, 8 min) to obtain the title compound 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(8-methyl-8-azabicyclo[3.2.1]octan-3-yl)-3-pyridyl]-1H-imidazole-2-carboxamide (A-4, 0.0032 g, 7.2 μmol, yield 27.6%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 10.04 (s, 1H), 8.38 - 8.25 (m, 1H), 8.13 - 7.92 (m, 1H), 7.32 - 7.15 (m, 1H), 5.99 - 5.81 (m, 1H), 3.88 (br d, J = 1.6 Hz, 2H), 2.67 (s, 3H), 2.45 - 2.40 (m, 2H), 2.34 - 2.11 (m, 5H), 2.10 - 2.00 (m, 2H), 1.99 - 1.86 (m, 4H), 1.52 - 1.44 (m, 2H), 1.00 (s, 6H), MS (LC / MS) m / z Measured value 445.4, Predicted value 445.3 [M+H].

[0180] Example 4 5-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2-(fluoromethyl)-2,6,6-trimethyltetrahydropyran-4-yl]-3-pyridyl]-1H-imidazole-2-carboxamide A-5 [ka] [ka] Diethyl oxalate (49, 50 g, 342.14 mmol, 46.73 mL, 1 eq) was added to a solution of EtOH (400 mL) with 4-methylpenta-3-en-2-one (50, 33.58 g, 342.14 mmol, 39.50 mL, 1 eq) at 0°C. The mixture was added to a solution of EtONa (151.34 g, 444.78 mmol, 20% purity, 1.3 eq). The mixture was stirred at 20°C for 16 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et. / HCl=5 / 1) until the starting materials were completely consumed. H2SO4 (300 mL) was added to the reaction mixture at 25°C and stirred for 16 hours. The organic layers were combined and washed with H2O (400 mL x 3), extracted with siRNA (500 mL x 3), and washed with brine (300 mL). The organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 5 / 1~3 / 1 gradient) to obtain 2,2-dimethyl-4-oxo-3H-pyran-6-carboxylate ethyl (51, 30 g, 151.35 mmol, yield 44.2%) as a yellow solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0181] Ethylene glycol (71.39 g, 1.15 mol, 64.32 mL, 10 eq) and PPTS (2.89 g, 11.50 mmol, 0.1 eq) were added to a solution of ethyl 2,2-dimethyl-4-oxo-3H-pyran-6-carboxylate (51, 22.8 g, 115.03 mmol, 1 eq) in toluene (230 mL). The mixture was stirred at 135 °C for 16 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et.: HCl = 5:1) until the starting materials were completely consumed. The reaction mixture was diluted with H2O (180 mL), extracted with HCl (350 mL x 3), and washed with brine (400 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 5 / 1~3 / 1 gradient) to obtain ethyl 9,9-dimethyl-1,4,8-trioxaspiro[4.5]deca-6-ene-7-carboxylate (52, 10 g, 41.28 mmol, yield 35.9%) as a yellow solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0182] To a solution of ethyl 9,9-dimethyl-1,4,8-trioxaspiro[4.5]decane-6-ene-7-carboxylate (52, 20 g, 82.55 mmol, 1 eq) in THF (200 mL), Pd / C (10 g, purity 5%) was added. The mixture was stirred at 25°C for 2 hours under H2 (50 psi). The reaction was monitored by TLC (Pet.Et.: Â=5:1) until the starting materials were completely consumed. The mixture was filtered and concentrated under reduced pressure, and the residue was obtained without further purification to obtain ethyl 7,7-dimethyl-1,4,8-trioxaspiro[4.5]decane-9-carboxylate (53, 20 g, 81.87 mmol, yield 99.2%) as a yellow oil, which was then used as is. 1H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 4.38 (dd, J = 2.4, 12.3 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 4.05 - 3.99 (m, 2H), 3.97 - 3.90 (m, 2H), 1.99 (td, J = 2.4, 13.0 Hz, 1H), 1.74 - 1.63 (m, 3H), 1.34 (s, 6H), 1.29 (t, J = 7.2 Hz, 3H).

[0183] To a solution of ethyl 7,7-dimethyl-1,4,8-trioxaspiro[4.5]decane-9-carboxylate (53, 7 g, 28.66 mmol, 1 eq) in THF (100 mL), LDA (2 M, 15.76 mL, 1.1 eq) was added at -78 °C. After 2 hours, MeI (6.10 g, 42.98 mmol, 2.68 mL, 1.5 eq) was added. The mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC (Pet.Et.: Depositphotos = 5:1) until the starting materials were completely consumed. The reaction mixture was diluted with NH4Cl (aqueous solution, 100 mL) and extracted with Depositphotos (100 mL x 2). The organic layers were combined, washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 220g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 80 mL / min) to obtain ethyl 7,9,9-trimethyl-1,4,8-trioxaspiro[4.5]decane-7-carboxylate (54, 5.7g, 22.1 mmol, yield 77%) as a yellow solid, which was then used as is without further characterization.

[0184] To a solution of ethyl 7,9,9-trimethyl-1,4,8-trioxaspiro[4.5]decane-7-carboxylate (54, 5.7 g, 22.07 mmol, 1 eq) in THF (60 mL), LAH (1.00 g, 26.48 mmol, 1.2 eq) was added at 0°C. The mixture was stirred at 25°C for 4 hours. The reaction was monitored by TLC (Pet.Et.: Â=5:1) until the starting materials were completely consumed. The reaction mixture was quenched with water (1.0 mL) and NaOH (1.0 mL, 15%). The reaction mixture was filtered and concentrated under reduced pressure to obtain (7,9,9-trimethyl-1,4,8-trioxaspiro[4.5]decane-7-yl)methanol (55, 4 g, 18.5 mmol, yield 83.8%) as a yellow oil without further purification, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 4.04 - 3.97 (m, 2H), 3.97 - 3.88 (m, 2H), 3.41 - 3.33 (m, 1H), 3.32 - 3.25 (m, 1H), 1.96 (d, J = 13.8 Hz, 1H), 1.76 (dd, J = 1.8, 13.7 Hz, 1H), 1.66 - 1.58 (m, 1H), 1.54 (dd, J = 1.8, 13.8 Hz, 1H), 1.38 (s, 3H), 1.29 (s, 3H), 1.27 (s, 3H).

[0185] To a solution of (7,9,9-trimethyl-1,4,8-trioxaspiro[4.5]decane-7-yl)methanol (55, 4 g, 18.50 mmol, 1 eq) in DCM (50 mL), DAST (5.96 g, 36.99 mmol, 4.89 mL, 2 eqs) was added at 0°C. The mixture was stirred at 25°C for 12 hours. The reaction was monitored by TLC (Pet.Et.: Â=5:1) until the starting material was completely consumed. The reaction mixture was diluted with NaHCO3 (30 mL) and extracted with DCM (30 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 40g SEPAFLASH® silica flash column, eluent: 0-5% Pet.Et.: siRNA gradient, flow rate 80 mL / min) to obtain 7-(fluoromethyl)-7,9,9-trimethyl-1,4,8-trioxaspiro[4.5]decane (56, 4g, 18.33 mmol, yield 99.1%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, DMSO-d6, 298 K) δ (ppm) = 3.90 - 3.75 (m, 4H), 3.66 - 3.53 (m, 2H), 2.21 (dd, J = 13.7, 16.9, Hz, 1H), 2.02 - 1.92 (m, 1H), 1.91 - 1.82 (m, 2H), 1.34 - 1.25 (m, 3H), 1.19 (s, 3H), 1.15 (s, 3H).

[0186] To a solution of 7-(fluoromethyl)-7,9,9-trimethyl-1,4,8-trioxaspiro[4.5]decane (56, 4 g, 18.33 mmol, 1 eq) in H2O (30 mL) and ACN (30 mL), TFA (4.18 g, 36.65 mmol, 2.71 mL, 2 eq) was added. The mixture was stirred at 25 °C for 12 hours. The reaction was monitored by TLC (Pet.Et.: siRNA=5:1) until the starting material was completely consumed. The reaction mixture was diluted with NaHCO3 (30 mL) and extracted with DCM (30 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 20g SEPAFLASH® silica flash column, eluent: 0-5% Pet.Et.: siRNA gradient, flow rate 80 mL / min) to obtain 2-(fluoromethyl)-2,6,6-trimethyltetrahydropyran-4-one (57, 2.3g, 13.20 mmol, yield 72.0%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, DMSO-d6, 298 K) δ (ppm) = 3.90 - 3.75 (m, 4H), 3.66 - 3.53 (m, 2H), 2.21 (dd, J = 13.7, 16.9 Hz, 1H), 2.02 - 1.92 (m, 1H), 1.91 - 1.82 (m, 2H), 1.34 - 1.25 (m, 3H), 1.19 (s, 3H), 1.15 (s, 3H).

[0187] 2-(fluoromethyl)-2,6,6-trimethyltetrahydropyran-4-one (57 mg, 2.3 g, 13.20 mmol, 1 eq) was added to a solution of MeOH (30 mL) with NaBH4 (499.47 mg, 13.20 mmol, 1 eq) at 0°C. The mixture was stirred at 25°C for 1 hour. The reaction was monitored by TLC (Pet.Et.: siRNA=3:1) until the starting material was completely consumed. The reaction mixture was diluted with NH4Cl (50 mL) and extracted with siRNA (30 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 20g SEPAFLASH® silica flash column, eluent: 0-20% siRNA / Pet.Et. gradient, flow rate 60 mL / min) to obtain 2-(fluoromethyl)-2,6,6-trimethyltetrahydropyran-4-ol (58 g, 1.8 g, 10.21 mmol, yield 77.4%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, DMSO-d6, 297 K) δ (ppm) = 4.63 (d, J = 4.4 Hz, 1H), 4.53 (d, J = 4.4 Hz, 1H), 3.94 - 3.83 (m, 1H), 3.17 (ddd, J = 2.3, 7.4, 12.2 Hz, 1H), 2.11 - 2.00 (m, 2H), 1.84 (dd, J = 10.3, 14.3 Hz, 1H), 1.73 (br dd, J = 2.3, 4.9 Hz, 2H), 1.37 - 1.29 (m, 3H), 1.10 (d, J = 5.6 Hz, 5H).

[0188] To a 2 mL MTBE solution of 2-(fluoromethyl)-2,6,6-trimethyltetrahydropyran-4-ol (58 mg, 202.20 mg, 1.15 mmol, 1.75 eq) and NHC-1 (414.62 mg, 1.05 mmol, 1.6 eq), a 1 mL MTBE solution of pyridine (82.98 mg, 1.05 mmol, 84.67 μL, 1.6 eq) was added dropwise over 5 minutes at 25°C. After 10 minutes, the mixture was filtered, and the filtrate was used to obtain N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (INT-3, 250 mg). The following substances were added under N2 conditions to a DMA (3 mL) solution containing 655.64 μmol, 1 eq) of bis[2-(2-pyridyl)phenyl]iridium(1+); 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine; hexafluorophosphate (8.99 mg, 9.83 μmol, 0.015 eq), dibromonickel; 1,2-dimethoxyethane (10.12 mg, 32.78 μmol, 0.05 eq), dtbbpy (13.20 mg, 49.17 μmol, 0.075 eq), and quinuclidine (127.57 mg, 1.15 mmol, 1.75 eq). The mixture was stirred at 25°C for 3 hours under blue LED illumination. The reaction was analyzed by LC / MS (R t The mixture was monitored for 0.971 minutes ([M+H]=461.4) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with SiO2 (10 mL x 2). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×30mm×5μm, mobile phase: [water (TFA)-ACN], B%: 45%~70% gradient, 8 min) to obtain N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2-(fluoromethyl)-2,6,6-trimethyl-tetrahydropyran-4-yl]-3-pyridyl]carbamate tert-butyl (59, 100 mg, 217.10 μmol, yield 33.1%) as a yellow solid, which was then used as is. 1H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 8.79 (br d, J = 8.9 Hz, 1H), 7.33 (d, J = 8.9 Hz, 1H), 6.81 (s, 1H), 6.03 (br s, 1H), 3.74 (br dd, J = 3.4, 12.6 Hz, 2H), 3.51 - 3.45 (m, 3H), 2.37 (br s, 3H), 2.25 - 2.12 (m, 2H), 2.11 - 2.07 (m, 3H), 2.05 - 1.91 (m, 2H), 1.84 (br d, J = 14.1 Hz, 1H), 1.59 (br t, J = 6.3 Hz, 3H), 1.50 (d, J = 4.8 Hz, 3H), 1.27 (s, 3H), 1.24 (s, 3H), 1.08 - 1.00 (m, 9H), MS (LC / MS) m / z actual value 461.4, predicted value 461.3 [M+H].

[0189] A solution of N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2-(fluoromethyl)-2,6,6-trimethyltetrahydropyran-4-yl]-3-pyridyl]carbamate tert-butyl (59, 100 mg, 217.10 μmol, 1 eq) in HCl / dioxane (5 mL) was stirred at 25°C for 2 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 0.778 minutes ([M+H]=361.4) until the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100×30mm×10μm, mobile phase: [water(NH4HCO3)-ACN], B%: 60%~90% gradient, 8 min) to obtain 2-(4,4-dimethylcyclohexen-1-yl)-6-[2-(fluoromethyl)-2,6,6-trimethyltetrahydropyran-4-yl]pyridine-3-amine (60, 80 mg, 210.81 μmol, yield 97.1%, purity 95%) as a yellow solid, which was then used as is. 1H NMR (400 MHz, DMSO-d6, 298 K) δ (ppm) = 6.96 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 5.88 (br s, 1H), 4.71 (s, 2H), 3.73 (d, J = 12.4 Hz, 1H), 3.29 - 3.19 (m, 1H), 2.76 - 2.65 (m, 1H), 2.40 - 2.30 (m, 2H), 2.05 - 1.89 (m, 5H), 1.66 (d, J = 14.8 Hz, 1H), 1.48 - 1.37 (m, 5H), 1.15 (d, J = 5.6 Hz, 6H), 0.97 (s, 6H), MS (LC / MS) m / z. Measured value 361.4, predicted value 361.3 [M+H].

[0190] To a solution of 2-(4,4-dimethylcyclohexen-1-yl)-6-[2-(fluoromethyl)-2,6,6-trimethyltetrahydropyran-4-yl]pyridine-3-amine (60, 70 mg, 194.17 μmol, 1 eq) in DMF (1 mL), [4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]oxypotassium (INT-2, 118.62 mg, 388.34 μmol, 2 eq), PyBroP (135.78 mg, 291.26 μmol, 1.5 eq), and DIEA (75.28 mg, 582.51 μmol, 101.46 μL, 3 eq) were added. The mixture was stirred at 25°C for 12 hours. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 1.119 minutes (M+H=610.4) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with dimethyl phosphate (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×30mm×5μm, mobile phase: [water (TFA)-ACN], B%: 60%~100% gradient, 8 min) to obtain 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2-(fluoromethyl)-2,6,6-trimethyl-tetrahydropyran-4-yl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (61, 60 mg, 98.39 μmol, yield 50.7%) as a yellow solid, which was then used as is. MS (LC / MS) m / z measured value 610.4, predicted value 610.4 [M+H].

[0191] 4-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2-(fluoromethyl)-2,6,6-trimethyl-tetrahydropyran-4-yl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (61, 60 mg, 98.39 μmol, 1 eq) was dissolved in DCM (5 mL) and TFA (1 mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 0.951 minutes ([M+H]=480.3) until the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×30mm×5μm, mobile phase: [water(TFA)-ACN], B%: 70%~100% gradient, 8 min) to obtain the title compound 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2-(fluoromethyl)-2,6,6-trimethyl-tetrahydropyran-4-yl]-3-pyridyl]-1H-imidazole-2-carboxamide (A-5, 19.2 mg, 40.0 μmol, yield 40.7%) (yellow solid). 1 H NMR (400 MHz, DMSO-d6, 295 K) δ (ppm) = 14.27 (br s, 1H), 10.09 (s, 1H), 8.33 (s, 1H), 8.11 (br d, J = 8.0 Hz, 1H), 7.26 (br d, J = 8.4 Hz, 1H), 5.90 (br s, 1H), 3.78 (br d, J = 12.0 Hz, 1H), 3.28 (br dd, J = 6.4, 11.6 Hz, 1H), 2.94 (br t, J = 10.4 Hz, 1H), 2.40 (br s, 2H), 2.17 - 1.97 (m, 3H), 1.91 (br s, 2H), 1.73 (br d, J = 14.8 Hz, 1H), 1.51 - 1.40 (m, 5H), 1.18 (br d, J = 8.0 Hz, 6H), 0.96 (s, 6H), MS (LC / MS) m / z: Measured value 480.3, Predicted value 480.3 [M+H].

[0192] Example 5 5-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2-(fluoromethyl)-2,6,6-trimethyltetrahydropyran-4-yl]-3-pyridyl]-1H-imidazole-2-carboxamide A-6 [ka] To a solution of furan (62, 15 g, 220.35 mmol, 16.03 mL, 1 eq) in CF3CH2OH (150 mL), N,N-diethylethanamine (89.19 g, 881.40 mmol, 122.68 mL, 4 eq) and 1,1,3-trichloropropan-2-one (16, 106.70 g, 661.05 mmol, 3 eq) were added under N2 at 25°C. The mixture was stirred at 25°C for 12 hours. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 10 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with water (20 mL) and extracted with Depositphotos (20 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 2,4-dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-one (63, 40 g, 207.22 mmol, yield 94.0%) as a yellow oil without further purification, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 6.53 (s, 2H), 5.15 (d, J = 4.8 Hz, 2H), 4.72 (d, J = 4.6 Hz, 2H).

[0193] A mixture of CuCl (15.39 g, 155.42 mmol, 3.72 mL, 0.5 eq), NH4Cl (116.39 g, 2.18 mol, 7 eq), and zinc (101.63 g, 1.55 mol, 5 eq) in MeOH (600 mL) was mixed with a solution of 2,4-dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-one (63, 60 g, 310.84 mmol, 1 eq) in MeOH (30 mL) and added dropwise at 25°C. The mixture was stirred at 25°C for a further 16 hours. The reaction was monitored by TLC (Pet.Et. / Â=10 / 1) until the starting materials were completely consumed. The reaction mixture was filtered through a CELITE® pad. The filtrate was diluted with water (200 mL) and extracted with  (150 mL x 2). The precipitate was dissolved by adding HCl(2N). The organic layers were combined, washed with brine, dried on anhydrous MgSO4, and evaporated to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 330 g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 50 mL / min) to obtain 8-oxabicyclo[3.2.1]octa-6-en-3-one (64, 20 g, 112.78 mmol, yield 36.3%, purity 70%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3) δ (ppm) = 6.28 (s, 2H), 5.05 (d, J = 5.0 Hz, 2H), 2.77 (dd, J = 5.1, 16.9 Hz, 2H), 2.35 (d, J = 16.4 Hz, 2H).

[0194] To a solution of 8-oxabicyclo[3.2.1]octa-6-en-3-one (64, 18 g, 145.00 mmol, 1 eq) in THF (150 mL), LDA (2 M, 290.00 mL, 4 eq) was added at -78 °C. After 2 hours, a solution of NFSI (182.90 g, 580.00 mmol, 4 eq) in THF (150 mL) was added. The mixture was stirred at -78 °C for 3 hours. The reaction was monitored by TLC (Pet.Et.: siRNA=3:1) until the starting material was completely consumed. The reaction mixture was diluted with NH4Cl (aqueous solution, 300 mL) and extracted with siRNA (200 mL x 2). The organic layers were combined, washed with brine (500 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 330g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 80 mL / min) to obtain 2-fluoro-8-oxabicyclo[3.2.1]octa-6-en-3-one (65, 5g, 35.2 mmol, yield 24.3%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 6.51 (br d, J = 6.1 Hz, 1H), 6.18 (dd, J = 1.7, 5.9 Hz, 1H), 5.09 (d, J = 4.8 Hz, 2H), 4.39 - 4.21 (m, 1H), 3.08 (dd, J = 5.0, 16.5 Hz, 1H), 2.44 (d, J = 16.5 Hz, 1H).

[0195] 2-Fluoro-8-oxabicyclo[3.2.1]octa-6-en-3-one (65, 5 g, 35.18 mmol, 1 eq) was dissolved in MeOH (60 mL) and NaBH4 (2.00 g, 52.77 mmol, 1.5 eq) was added at 0°C. The mixture was stirred at 25°C for 2 hours. The reaction was monitored by TLC (Pet.Et.: HCl=3:1) until the starting material was completely consumed. The reaction mixture was diluted with NH4Cl (aqueous solution, 50 mL) and extracted with HCl (30 mL x 2). The organic layers were combined, washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 40g SEPAFLASH® silica flash column, eluent: 0-20% siRNA / Pet.Et. gradient, flow rate 60 mL / min) to obtain 2-fluoro-8-oxabicyclo[3.2.1]octa-6-en-3-ol (66, 1.5g, 10.4 mmol, yield 29.6%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3, 295 K) δ (ppm) = 6.28 (td, J = 1.6, 6.1 Hz, 1H), 6.20 (dd, J = 1.9, 6.1 Hz, 1H), 4.99 - 4.91 (m, 1H), 4.90 - 4.85 (m, 1H), 4.66 - 4.50 (m, 1H), 4.06 - 3.88 (m, 1H), 2.03 - 1.94 (m, 2H), 1.87 - 1.80 (m, 1H).

[0196] To a 4 mL MTBE solution of 2-fluoro-8-oxabicyclo[3.2.1]octa-6-en-3-ol (66 mg, 198.46 mg, 1.38 mmol, 1.75 eq) and NHC-1 (497.54 mg, 1.26 mmol, 1.6 eq), a 1 mL MTBE solution of pyridine (99.57 mg, 1.26 mmol, 101.61 μL, 1.6 eq) was added dropwise over 5 minutes at 25°C. After another 10 minutes, the mixture was filtered, and the filtrate contained N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (INT-3, 300 mg, 786.77 μmol, 1 eq), bis[2-(2-pyridyl)phenyl]yl Dium(1+); 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine; hexafluorophosphate (10.79 mg, 11.80 μmol, 0.015 eq), dibromonickel; 1,2-dimethoxyethane (12.14 mg, 39.34 μmol, 0.05 eq), quinuclidine (153.08 mg, 1.38 mmol, 1.75 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (15.84 mg, 59.01 μmol, 0.075 eq), and isoindoline-1,3-dione (26.05 mg, 177.02 μmol, 0.225 eq) were added to a DMA (4 mL) solution under N2 conditions. The mixture was stirred at 25°C for 12 hours under blue LED illumination. The reaction is analyzed by LC / MS(R tThe mixture was monitored for 1.144 minutes ([M+H]=429.3) until the starting material was completely consumed. The reaction mixture was diluted with water (30 mL) and extracted with SiO2 (20 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 4g, SEPAFLASH® silica flash column, eluent: 0-20% siRNA / Pet.Et. gradient, flow rate 60 mL / min) to obtain N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2-fluoro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]-3-pyridyl]carbamate tert-butyl (67 mg, 130 mg, 151.7 μmol, yield 19.3%, purity 50%) as a yellow solid, which was then used as is. MS (LC / MS) m / z measured value 429.3, predicted value 429.3 [M+H].

[0197] To a solution of N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2-fluoro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]-3-pyridyl]carbamate tert-butyl (67, 230 mg, 536.71 μmol, 1 eq) in DCM (5 mL), TFA (2 mL) was added. The mixture was stirred at 25 °C for 3 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 0.393 minutes ([M+H]=329.3) until the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain a residue, and without further purification, 2-(4,4-dimethylcyclohexen-1-yl)-6-[2-fluoro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]pyridine-3-amine (68, 230 mg, 389.88 μmol, yield 72.6%, purity 75%) was obtained as the TFA salt, as a yellow solid, which was then used as is. 1H NMR (400 MHz, MeOH-d4, 299 K) δ (ppm) = 7.72 - 7.67 (m, 1H), 7.64 - 7.59 (m, 1H), 6.48 - 6.45 (m, 1H), 6.44 - 6.39 (m, 1H), 6.14 (td, J = 1.9, 3.7 Hz, 1H), 4.97 - 4.94 (m, 1H), 4.62 - 4.46 (m, 1H), 3.92 - 3.75 (m, 1H), 2.44 - 2.38 (m, 1H), 2.37 - 2.33 (m, 2H), 2.15 - 2.08 (m, 2H), 2.02 (s, 1H), 1.71 - 1.65 (m, 1H), 1.62 (t, J = 6.2 Hz, 2H), 1.07 (s, 6H), MS (LC / MS) m / z: Measured value 329.3, Predicted value 329.3 [M+H].

[0198] To a solution of 2-(4,4-dimethylcyclohexen-1-yl)-6-[2-fluoro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]pyridine-3-amine (68, 230 mg, 700.32 μmol, 1 eq) in DMF (5 mL), [4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]oxypotassium (INT-2, 427.82 mg, 1.40 mmol, 2 eqs), DIEA (271.53 mg, 2.10 mmol, 365.94 μL, 3 eqs) and PyBroP (489.71 mg, 1.05 mmol, 1.5 eq) were added. The mixture was stirred at 25°C for 12 hours. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 2.853 minutes ([M+H]=578.3) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with dimethyl phosphate (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 12g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 60 mL / min) to obtain 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2-fluoro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (69, 260 mg, 315.01 μmol, yield 45.0%, purity 70%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3) δ (ppm) = 9.88 (s, 1H), 8.71 (br d, J = 8.7 Hz, 1H), 7.77 (s, 1H), 7.30 (br s, 1H), 6.42 - 6.31 (m, 2H), 6.00 - 5.91 (m, 3H), 5.02 (br s, 1H), 4.93 (br d, J = 8.0 Hz, 1H), 4.87 - 4.66 (m, 1H), 3.72 - 3.62 (m, 3H), 2.52 - 2.39 (m, 3H), 2.18 (s, 2H), 2.14 (br d, J = 1.9 Hz, 2H), 1.71 (br dd, J = 5.9, 13.2 Hz, 1H), 1.36 (br dd, J = 5.3, 7.6 Hz, 2H), 1.12 (d, J = 4.1 Hz, 6H), 0.01 (s, 9H), MS (LC / MS) m / z: Measured value 578.3, Predicted value 578.3 [M+H].

[0199] 4-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2-fluoro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (69, 260 mg, 450.01 μmol, 1 eq) was dissolved in DCM (5 mL) and TFA (2 mL) was added. The mixture was stirred at 25 °C for 2 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 2.164 minutes ([M+H]=448.3) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5μm, mobile phase: [H2O(0.1%TFA)-ACN], 35%~65% B gradient over 8.0 minutes) to obtain the title compound 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2-fluoro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]-3-pyridyl]-1H-imidazole-2-carboxamide (A-6, 49.8 mg, 111.3 μmol, yield 24.7%) as a yellow oil. 1H NMR (400 MHz, MeOH-d4, 298 K) δ (ppm) = 8.82 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.61 (d, J = 8.4 Hz, 1H), 6.49 - 6.46 (m, 1H), 6.44 - 6.40 (m, 1H), 6.09, (td, J = 2.0, 3.5 Hz, 1H), 4.99 - 4.96 (m, 1H), 4.88 (br d, J = 2.4 Hz, 1H), 4.76 - 4.61 (m, 1H), 3.85 - 3.67 (m, 1H), 2.52 - 2.47 (m, 1H), 2.47 - 2.41 (m, 2H), 2.13 (br d, J = 3.6 Hz, 2H), 1.76 - 1.69 (m, 1H), 1.63 (t, J = 6.4 Hz, 2H), 1.11 (s, 6H), MS (LC / MS) m / z actual value 448.3, Predicted value 448.2 [M+H].

[0200] Example 6 5-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3-pyridyl]-1H-imidazole-2-carboxamide A-7 [ka] To a 5 mL solution of MTBE (70, 558.31 mg, 2.29 mmol, 1.75 eq) and NHC-1 (829.23 mg, 2.10 mmol, 1.6 eq), a 1 mL solution of MTBE (165.96 mg, 2.10 mmol, 169.34 μL, 1.6 eq) was added dropwise over 5 minutes at 25°C. After stirring for another 10 minutes, the mixture was filtered, and the filtrate contained N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (INT-3, 500 mg, 1.31 mmol, 1 eq), bis[2-(2-pyridyl)phenyl]iridium(1+); 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine; hexaful Olophosphate (17.98 mg, 19.67 μmol, 0.015 eq), dibromonickel; 1,2-dimethoxyethane (20.23 mg, 65.56 μmol, 0.05 eq), quinuclidine (255.15 mg, 2.29 mmol, 1.75 eq), and dtbbpy (26.40 mg, 98.35 μmol, 0.075 eq) were added to a DMA (5 mL) solution under N2. The mixture was stirred at 25°C for 3 hours under blue LED illumination. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 0.935 minutes ([M+H]=528.4) until the starting material was completely consumed. The reaction mixture was diluted with water (30 mL) and extracted with pharmaceutically acceptable phosphate (20 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 20g SEPAFLASH® silica flash column, eluent: 0-30% Pet.Et.: siRNA gradient, flow rate 60 mL / min) to obtain 7-[5-(tert-butoxycarbonylamino)-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl (71, 580 mg, 1.10 mmol, yield 83.8%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 8.26 - 8.17 (m, 1H), 7.02 - 6.96 (m, 1H), 6.90 (s, 1H), 5.82 (br s, 1H), 4.17 - 4.11 (m, 1H), 4.02 (br s, 1H), 3.95 (br t, J = 12.3 Hz, 2H), 3.86 - 3.77 (m, 2H), 2.49 - 2.29 (m, 2H), 2.19 - 1.88 (m, 7H), 1.50 (d, J = 1.9 Hz, 18H), 1.03 (s, 6H), MS (LC / MS) m / z actual value 528.4, predicted value 528.3 [M+H].

[0201] A solution of 7-[5-(tert-butoxycarbonylamino)-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl (71, 580 mg, 1.10 mmol, 1 eq) in HCl / dioxane (10 mL) was stirred at 25°C for 3 hours. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 0.603 minutes ([M+H]=328.3) until the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was obtained without further purification. 2-(4,4-dimethylcyclohexen-1-yl)-6-(3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)pyridine-3-amine (72, 350 mg, 1.07 mmol, yield 97.2%) was obtained as a yellow solid and used as is. MS (LC / MS) m / z measured value 328.3, predicted value 328.2 [M+H].

[0202] To a 10 mL solution of 2-(4,4-dimethylcyclohexen-1-yl)-6-(3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)pyridine-3-amine (72, 350 mg, 1.07 mmol, 1 eq) in DCM, Boc2O (233.27 mg, 1.07 mmol, 245.54 μL, 1 eq) and TEA (324.46 mg, 3.21 mmol, 446.30 μL, 3 eq) were added, and the mixture was stirred at 25°C for 3 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 0.776 minutes ([M+H]=428.3) until the starting material was completely consumed. The reaction mixture was diluted with water (20 mL) and extracted with DCM (20 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 60 mL / min) to obtain 7-[5-amino-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl (73, 200 mg, 467.75 μmol, yield 43.8%) as a yellow solid, which was then used as is. MS (LC / MS) m / z: Measured value 428.3, Predicted value 428.3 [M+H].

[0203] To a solution of 7-[5-amino-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl (73, 180 mg, 420.98 μmol, 1 eq) in DMF (3 mL), 4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylic acid (INT-2, 258.02 mg, 841.95 μmol, 2 eq), DIEA (108.82 mg, 841.95 μmol, 146.65 μL, 2 eq), and PyBroP (294.38 mg, 631.46 μmol, 1.5 eq) were added, and the mixture was stirred at 25°C for 12 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 1.078 minutes ([M+H]=667.4) until the starting material was completely consumed. The reaction mixture was diluted with H2O (5 mL) and extracted with siRNA (8 mL × 3). The organic layers were combined, washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA=2 / 1~1 / 1 gradient) to obtain 7-[5-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl (74, 280 mg, 413.64 μmol, yield 98.3%) as a yellow solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used directly. MS (LC / MS) m / z: Measured value 677.4, predicted value 677.4 [M+H].

[0204] To a solution of 7-[5-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate tert-butyl (74, 120 mg, 177.3 μmol, 1 eq) in DCM (1 mL), TFA (687.25 mg, 6.03 mmol, 446.3 μL, 34 eq) was added. The mixture was stirred at 25°C for 2 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 2.501 minutes (M+H+=447.2) until the starting material was completely consumed. The reaction mixture was diluted with H2O (5 mL) and extracted with HCl (8 mL x 3). The organic layers were combined, washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×30mm×5μm, mobile phase: [water (TFA)-ACN], B%: 15%~45% gradient, 8 min) to obtain 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)-3-pyridyl]-1H-imidazole-2-carboxamide (A-7, 15.5 mg, 27.65 μmol, yield 15.6%) of the title compound as a TFA salt, as a white solid. 1H NMR (400 MHz, MeOH-d4) δ = 8.61 (d, J = 8.5 Hz, 1H), 8.03 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 5.99 (td, J = 1.9, 3.5 Hz, 1H), 4.32 - 4.21 (m, 1H), 4.21 - 4.14 (m, 2H), 4.09 (s, 1H), 4.07 - 4.04 (m, 1H), 3.63 (br s, 2H), 2.52 - 2.47 (m, 2H), 2.46 - 2.39 (m, 2H), 2.37 - 2.28 (m, 2H), 2.10 (br d, J = 3.4 Hz, 2H), 1.60 (t, J = 6.4 Hz, 2H), 1.10 (s, 6H), MS (LC / MS) m / z actual value 447.2, predicted value 447.3 [M+H].

[0205] Example 7 4-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)-3-pyridyl]-1H-imidazole-2-carboxamide A-8 [ka] Dichloronickel; 1,2-dimethoxyethyl ester (75 mg, 334.78 mg, 1.31 mmol, 1 eq) and 8-tert-butoxycarbonyl-8-azabicyclo[3.2.1]octane-3-carboxylic acid (75 mg, 334.78 mg, 1.31 mmol, 1 eq) are dissolved in DMF (5 mL) and 1,2-dimethoxyethyl ester (1,2-dimethoxyethyl ester). Tan (28.81 mg, 131.13 μmol, 0.1 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (52.79 mg, 196.69 μmol, 0.15 eq), Cs2CO3 (854.48 mg, 2.62 mmol, 2 eq), and (Ir(dF(CH3)ppy)2(dtbbpy))PF6 (13.30 mg, 13.11 μmol, 0.01 eq) were added. The mixture was stirred at 20°C for 12 hours under 34W blue LED illumination. The reaction was monitored by TLC (Pet.Et.: SiO=10:1) until completion was indicated. The reaction mixture was quenched with H2O (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 1 / 0 to 10 / 1 gradient) to obtain 3-[5-(tert-butoxycarbonylamino)-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl (76, 0.8 g, 1.56 mmol, yield 39.7%) as a yellow oil, which was used as is without further characterization.

[0206] To a solution of tert-butyl 3-[5-(tert-butoxycarbonylamino)-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-8-azabicyclo[3.2.1]octane-8-carboxylate (76, 1 g, 1.95 mmol, 1 eq) in dioxane (4 mL), HCl / dioxane (4 M, 5.00 mL, 10.23 eq) was added. The mixture was stirred at 20°C for 2 hours under an N2 atmosphere. The reaction was analyzed by LC / MS (R t The reaction was monitored for 0.436 minutes (M+H = 312.2) until completion was indicated. The reaction mixture was concentrated under reduced pressure to remove dioxane, and without further purification, 6-(8-azabicyclo[3.2.1]octan-3-yl)-2-(4,4-dimethylcyclohexen-1-yl)pyridine-3-amine hydrochloride (77, 0.65 g, 1.87 mmol, yield 95.6%) was obtained as a yellow oil and used as is. MS (LC / MS) m / z measured value 312.2, predicted value 312.2 [M+H].

[0207] To a solution of 6-(8-azabicyclo[3.2.1]octan-3-yl)-2-(4,4-dimethylcyclohexen-1-yl)pyridine-3-amine hydrochloride (77, 0.65 g, 1.87 mmol, 1 eq) in DCM (1 mL), Boc2O (407.74 mg, 1.87 mmol, 429.20 μL, 1 eq) and TEA (207.95 mg, 2.06 mmol, 286.04 μL, 1.1 eq) were added. The mixture was stirred at 20°C for 1 hour under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et.: siRNA=10:1) until completion was indicated. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL × 3). The organic layers were combined, washed with brine (10 mL x 3), dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et.: siRNA=1 / 0~10 / 1) to obtain 3-[5-amino-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl (78, 0.3 g, 728.90 μmol, yield 39.0%) as a white solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used directly. MS (LC / MS) m / z: Measured value 312.1 [M-Boc], Predicted value 412.2 [M+H].

[0208] To a solution of tert-butyl 3-[5-amino-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-8-azabicyclo[3.2.1]octane-8-carboxylic acid (78 mg, 0.3 g, 728.90 μmol, 1 eq) and 4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylic acid (INT-2, 446.75 mg, 1.46 mmol, 2 eq) in DMF (3 mL), DIEA (282.61 mg, 2.19 mmol, 380.88 μL, 3 eq) and PyBroP (509.70 mg, 1.09 mmol, 1.5 eq) were added. The mixture was stirred at 20°C for 12 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et.: siRNA = 10:1) until completion was indicated. The reaction mixture was quenched with H2O (1 mL) and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 × 30 mm × 5 μm, mobile phase: [water (TFA)-ACN], B%: 65%~100% gradient, 8 min) to obtain 3-[5-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl (79, 0.2 g, 302.61 μmol, yield 41.52%) as a white solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used directly. MS (LC / MS) m / z: measured value 661.5, predicted value 661.4 [M+H].

[0209] 3-[5-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-8-azabicyclo[3.2.1]octane-8-carboxylate tert-butyl (79, 0.2 g, 302.61 μmol, 1 eq) was dissolved in DCM (5 mL) and ZnBr2 (545.18 mg, 2.42 mmol, 121.15 μL, 8 eq) was added. The mixture was stirred at 20 °C for 12 hours under an N2 atmosphere. The reaction was analyzed by LC / MS (R t The reaction was monitored for 0.886 minutes ([M+H]=561.3) until completion was indicated. The reaction mixture was quenched with H2O (3 mL) and extracted with DCM (5 mL x 3). The organic layers were combined, washed with brine (5 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. Without further purification, N-[6-(8-azabicyclo[3.2.1]octan-3-yl)-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (80, 0.1 g, 178.32 μmol, yield 58.9%) was obtained as a white solid and used as is. MS (LC / MS) m / z: Measured value 561.3, Predicted value 561.3 [M+H].

[0210] Acetaldehyde (98.19 mg, 891.58 μmol, 125.08 μL, 5 eq) was added to a solution of N-[6-(8-azabicyclo[3.2.1]octan-3-yl)-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (80, 0.1 g, 178.32 μmol, 1 eq) in MeOH (2 mL). The mixture was stirred at 0°C for 0.5 hours under an N2 atmosphere. Then, NaBH3CN (28.01 mg, 445.79 μmol, 2.5 eq) was added. The mixture was stirred at 20°C for 11.5 hours under an N2 atmosphere. The reaction was analyzed by LC / MS (R tThe reaction was monitored for 0.897 minutes (M+H = 589.4) until completion was indicated. The reaction mixture was diluted with H2O (5 mL) and extracted with siRNA (5 mL x 3). The organic layers were combined, washed with brine (5 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. Without further purification, the residue was obtained as a white solid: 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (81, 0.04 g, 67.93 μmol, yield 38.1%), which was used as is. MS (LC / MS) m / z: measured value 589.4, predicted value 589.4 [M+H].

[0211] To a solution of 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (81, 0.04 g, 67.93 μmol, 1 eq) in DCM (1 mL), TFA (1.20 g, 10.55 mmol, 780.94 μL, 155.3 eq) was added. The mixture was stirred at 20°C for 2 hours under an N2 atmosphere. The reaction was analyzed by LC / MS (R tThe reaction was monitored for 0.766 minutes (M+H = 459.3) until completion was indicated. The reaction mixture was diluted with H2O (5 mL) and extracted with ₹ (5 mL × 3). The organic layers were combined, washed with brine (5 mL × 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10μm, mobile phase: [water (NH4HCO3)-ACN], B%: 20%~50% gradient, 8 min) to obtain the title compound 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(8-ethyl-8-azabicyclo[3.2.1]octan-3-yl)-3-pyridyl]-1H-imidazole-2-carboxamide (A-8, 0.017 g, 37.07 μmol, yield 54.6%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ = 10.01 (s, 1H), 8.50 (br d, J = 8.1 Hz, 1H), 7.70 (br s, 1H), 7.20 (d, J = 8.6 Hz, 1H), 5.86 (br s, 1H), 3.88 (br s, 2H), 3.19 (br d, J = 5.1 Hz, 1H), 2.87 (br d, J = 5.6 Hz, 2H), 2.38 (br s, 2H), 2.18 - 2.05 (m, 4H), 2.04 - 1.93 (m, 4H), 1.86 (br d, J = 12.9 Hz, 2H), 1.50 (br t, J = 6.2 Hz, 2H), 1.20 (br t, J = 7.1 Hz, 3H), 1.03 (s, 6H), MS (LC / MS) m / z actual value 459.3, predicted value 459.3 [M+H].

[0212] Example 8 N-[6-(1-acetyl-2,2,6,6-tetramethyl-4-piperidyl)-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-5-cyano-1H-imidazole-2-carboxamide A-9 [ka] A solution of 2,2,6,6-tetramethylpiperidine-4-one (82, 3 g, 19.33 mmol, 1 eq) in Ac2O (15 mL) was heated and stirred at 100°C for 12 hours under N2. The reaction was monitored by TLC (Pet.Et.: siRNA=3:1) until one main new spot with lower polarity was detected. The reaction mixture was basicized to pH=7-8 with NaOH (aqueous solution, 10%) and extracted with DCM (50 mL x 3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 10 / 0~1 / 1) to obtain 1-acetyl-2,2,6,6-tetramethyl-piperidine-4-one (83, 3.6 g, 18.25 mmol, yield 94.4%) as a yellow oil, which was then used as is. ¹H NMR was analyzed.

[0213] To a solution of 1-acetyl-2,2,6,6-tetramethylpiperidine-4-one (83 mg, 2.6 g, 13.18 mmol, 1 eq) in MeOH (26 mL), NaBH4 (747.88 mg, 19.77 mmol, 1.5 eq) was added at 0°C, and the mixture was stirred at 20°C for 2 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et. / siRNA=1 / 1) until the starting material was completely consumed. The reaction mixture was quenched with NH4Cl (aqueous solution, 35 mL) and extracted with DCM (25 mL x 3). The organic layers were combined and dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 10 / 1 to 1 / 1) to obtain 1-(4-hydroxy-2,2,6,6-tetramethyl-1-piperidyl)ethanone (84, 1.5 g, 7.53 mmol, yield 57.1%) as a yellow solid, which was then used as is. 11H NMR (400 MHz, CDCl3-d) δ = 4.26 - 4.15 (m, 1H), 2.21 - 2.13 (m, 5H), 1.85 (dd, J = 5.9, 14.7 Hz, 2H), 1.56 (s, 6H), 1.45 (s, 6H).

[0214] N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (INT-3, 800 mg, 2.10 mmol, 1 eq) and 1-(4-hydroxy-2,2,6,6-tetramethyl-1-piperidyl)ethanone (84 mg, 731.71 mg, 3.67 mmol, 1.75 eq) are dissolved in MTBE (7 mL) with bis[2-(2-pyridyl)phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine;hexafluorophosphate (28.76 mg, 31.47 μmol, 0.015 eq), dibro Monickel; 1,2-dimethoxyethane (32.38 mg, 104.90 μmol, 0.05 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (42.23 mg, 157.35 μmol, 0.075 eq), isoindoline-1,3-dione (69.45 mg, 472.06 μmol, 0.225 eq), pyridine (265.53 mg, 3.36 mmol, 270.95 μL, 1.6 eq), NHC-1 (1.33 g, 3.36 mmol, 1.6 eq), quinuclidine (408.24 mg, 3.67 mmol, 1.75 eq), and DMA (7 mL) were added at 25°C. The mixture was further stirred at 25°C for 2 hours under 34 W blue LED illumination. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 5 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with H2O (15 mL), extracted with Depositphotos (10 mL x 3), and washed with brine (30 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / Depositphotos = 100 / 1~3 / 1) to obtain N-[6-(1-acetyl-2,2,6,6-tetramethyl-4-piperidyl)-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (85, 900 mg, 1.86 mmol, yield 88.7%) as a yellow oil, which was then used as is. 1H NMR (400 MHz, CDCl3) δ = 8.27 (br d, J = 8.0 Hz, 1H), 7.92 - 7.74 (m, 1H), 7.04 (br d, J = 8.5 Hz, 1H), 6.93 (s, 1H), 5.83 (br s, 1H), 3.25 (quintet, J = 7.9 Hz, 1H), 2.42 (br s, 2H), 2.24 (s, 3H), 2.16 (br dd, J = 9.3, 14.0 Hz, 2H), 2.08 - 1.97 (m, 4H), 1.55 (d, J = 7.8 Hz, 12H), 1.51 (s, 9H), 1.04 (s, 6H), MS (LC / MS) m / z: Measured value 484.3, Predicted value 484.4 [M+H].

[0215] To a solution of N-[6-(1-acetyl-2,2,6,6-tetramethyl-4-piperidyl)-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (85, 350 mg, 723.61 μmol, 1 eq) in DCM (4 mL), TMSOTf (643.32 mg, 2.89 mmol, 523.02 μL, 4 eq) and 2,6-dimethylpyridine (465.21 mg, 4.34 mmol, 505.66 μL, 6 eq) were added at 0°C. The mixture was heated and then stirred at 20°C for 16 hours under an N2 atmosphere. The reaction was analyzed by LC / MS (R t The mixture was monitored for 0.729 minutes ([M+H]=384.4) until the starting material was completely consumed and the desired product mass was observed. The reaction mixture was poured into water (6 mL) and extracted with DCM (5 mL x 3). The organic layers were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (Pet.Et. / siRNA=1 / 1) to obtain 1-[4-[5-amino-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-2,2,6,6-tetramethyl-1-piperidyl]ethanone (86, 190 mg, 495.35 μmol, yield 68.5%) as a yellow oil, which was then used as is. 1H NMR (400 MHz, MeOH-d4) δ = 7.17 - 6.94 (m, 2H), 5.86 (br s, 1H), 3.26 - 3.15 (m, 1H), 2.43 - 2.36 (m, 2H), 2.25 (s, 3H), 2.07 - 2.01 (m, 4H), 1.57 (s, 8H), 1.54 (s, 6H), 1.29 (br d, J = 3.5 Hz, 2H), 1.05 (s, 6H), MS (LC / MS) m / z actual value 384.4, predicted value 384.3 [M+H].

[0216] To a solution of 1-[4-[5-amino-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-2,2,6,6-tetramethyl-1-piperidyl]ethenone (86, 190 mg, 495.35 μmol, 1 eq) and 4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylate (INT-2, 302.60 mg, 990.70 μmol, 2 eq) in DMF (3 mL), DIEA (192.06 mg, 1.49 mmol, 258.84 μL, 3 eq) and PyBroP (346.38 mg, 743.02 μmol, 1.5 eq) were added at 0°C. The mixture was heated and then stirred at 20°C for 16 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et. / Â=1 / 1) until the starting material was completely consumed. The reaction mixture was diluted with H2O (7 mL) and extracted with  (5 mL x 3). The organic layers were combined and dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, Pet.Et. / Â=1 / 1) to obtain N-[6-(1-acetyl-2,2,6,6-tetramethyl-4-piperidyl)-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (87, 100 mg, 158.00 μmol, yield 31.9%) as a yellow solid, which was then used as is. 1H NMR (400 MHz, MeOH-d4) δ = 8.57 (d, J = 8.6 Hz, 1H), 8.22 (s, 1H), 7.28 (d, J = 8.4 Hz, 1H), 5.97 - 5.89 (m, 3H), 3.70 - 3.64 (m, 2H), 2.47 (br d, J = 1.8 Hz, 2H), 2.27 - 2.24 (m, 3H), 2.21 (br d, J = 4.6 Hz, 2H), 2.18 (d, J = 4.3 Hz, 1H), 2.11 (br s, 3H), 2.10 - 2.06 (m, 3H), 1.59 (s, 6H), 1.57 (s, 6H), 1.11 (s, 6H), 0.96 - 0.92 (m, 2H), -0.01 - -0.04 (m, 9H), MS (LC / MS) m / z: Measured value 633.5, Predicted value 633.4 [M+H].

[0217] To a solution of N-[6-(1-acetyl-2,2,6,6-tetramethyl-4-piperidyl)-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (87,90 mg, 142.20 μmol, 1 eq) in THF (3 mL), TBAF (1 M, 284.40 μL, 2 eqs) was added at 0°C. The mixture was heated and then stirred at 20°C for 16 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et. / siRNA=0 / 1) until the starting material was completely consumed. The reaction product was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10μm, mobile phase: [water (NH4HCO3)-ACN], B%: 35%~85% gradient, 8 min) to obtain the title compound N-[6-(1-acetyl-2,2,6,6-tetramethyl-4-piperidyl)-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-5-cyano-1H-imidazole-2-carboxamide (A-9, 18.3 mg, 36.41 μmol, yield 25.6%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 10.02 (s, 1H), 8.30 (s, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 5.89 (br s, 1H), 3.28 (br s, 1H), 2.42 (br s, 2H), 2.13 (s, 3H), 2.10 - 2.03 (m, 2H), 2.01 - 1.95 (m, 2H), 1.92 (br s, 2H), 1.49 (s, 6H), 1.47 (s, 6H), 1.23 (br s, 2H), 0.97 (s, 6H), MS (LC / MS) m / z Measured value 503.5, Predicted value 503.3 [M+H].

[0218] Example 9 5-Cyano-N-[6-[2,4-Dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-1H-imidazole-2-carboxamide A-10 [ka] 2,4-Dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-one (63, 20 g, 103.61 mmol, 1 eq) was dissolved in MeOH (200 mL) and NaBH4 (5.88 g, 155.42 mmol, 1.5 eq) was added at 0°C. The mixture was heated and further heated at 25°C for 2 hours. The reaction was monitored by TLC (Pet.Et.: siRNA=3:1) until the starting material was completely consumed. The reaction mixture was diluted with NH4Cl (aqueous solution, 80 mL) and extracted with siRNA (70 mL x 2). The organic layers were combined, washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 120g SEPAFLASH® silica flash column, eluent: 0-20% siRNA / Pet.Et. gradient, flow rate 60 mL / min) to obtain 2,4-dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-ol (88, 2.7g, 13.84 mmol, yield 13.4%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 6.55 (s, 2H), 4.76 (d, J = 3.5 Hz, 2H), 4.35 (dd, J = 3.8, 4.6 Hz, 2H), 4.27 - 4.21 (m, 1H), 2.32 (d, J = 5.4 Hz, 1H).

[0219] To a 5 mL MTBE solution of 2,4-dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-ol (88, 268.54 mg, 1.38 mmol, 1.75 eq) and NHC-1 (497.54 mg, 1.26 mmol, 1.6 eq), a 1 mL MTBE solution of pyridine (99.57 mg, 1.26 mmol, 101.61 μL, 1.6 eq) was added dropwise over 5 minutes at 25°C. After stirring for another 10 minutes, the mixture was filtered, and the filtrate contained N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (INT-3, 300 mg, 786.77 μmol, 1 eq), bis[2-(2-pyridyl)phenyl]iridium(1+); 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine; hexafluorophosphate (10.79 mg, 11.80 μmol, 0.015 eq), Dibromonickel; 1,2-dimethoxyethane (12.14 mg, 39.34 μmol, 0.05 eq), quinuclidine (153.09 mg, 1.38 mmol, 1.75 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (15.84 mg, 59.01 μmol, 0.075 eq), and isoindoline-1,3-dione (26.05 mg, 177.02 μmol, 0.225 eq) were added to a DMA (5 mL) solution under N2 conditions. The mixture was stirred at 25°C for 3 hours under blue LED illumination. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 2.786 minutes ([M+H]=479.2) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with dimethyl phosphate (10 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 20g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 60 mL / min) to obtain N-[6-[2,4-dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (89, 150 mg, 312.87 μmol, yield 4.4%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 8.32 (br d, J = 7.9 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 7.01 (s, 1H), 6.56 (s, 2H), 5.88 (br s, 1H), 4.91 (d, J = 3.9 Hz, 2H), 4.38 (dd, J = 3.9, 9.5 Hz, 2H), 3.10 (t, J = 9.4 Hz, 1H), 2.45 (br d, J = 1.9 Hz, 2H), 2.06 (br d, J = 3.1 Hz, 2H), 1.58 (t, J = 6.4 Hz, 2H), 1.51 (s, 9H), 1.05 (s, 6H), MS (LC / MS) m / z: Measured value 479.2, Predicted value 479.2 [M+H].

[0220] To a solution of N-[6-[2,4-dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (89, 150 mg, 312.87 μmol, 1 eq) in DCM (5 mL), TFA (2 mL) was added. The mixture was stirred at 25 °C for 3 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 0.523 minutes ([M+H]=379.1) until the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was obtained without further purification to obtain 6-[2,4-dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)pyridine-3-amine (90, 110 mg, 289.99 μmol, yield 92.7%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, MeOH-d4, 298 K) δ (ppm) = 7.86 - 7.82 (m, 1H), 7.79 - 7.76 (m, 1H), 6.64 (s, 2H), 6.14 (td, J = 2.0, 3.7 Hz, 1H), 4.98 (d, J = 3.9 Hz, 2H), 4.33 (dd, J = 3.9, 10.1 Hz, 2H), 3.64 (t, J = 10.1 Hz, 1H), 2.37 - 2.30 (m, 2H), 2.15 - 2.08 (m, 2H), 1.63 (t, J = 6.3 Hz, 2H), 1.07 (s, 6H), MS (LC / MS) m / z Measured value 379.1, Predicted value 379.1 [M+H].

[0221] To a solution of 6-[2,4-dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)pyridine-3-amine (90, 110 mg, 289.99 μmol, 1 eq) in DMF (5 mL), [4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]oxypotassium (INT-2, 177.15 mg, 579.98 μmol, 2 eqs), DIEA (112.44 mg, 869.97 μmol, 151.53 μL, 3 eqs) and PyBroP (202.78 mg, 434.99 μmol, 1.5 eq) were added. The mixture was stirred at 25°C for 12 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 1.216 minutes ([M+H]=628.3) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with dimethyl phosphate (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 12g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 60 mL / min) to obtain 4-cyano-N-[6-[2,4-dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (91, 130 mg, 206.79 μmol, yield 71.3%) as a yellow oil, which was then used as is. 1H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 10.02 (s, 1H), 8.68 (d, J = 8.3 Hz, 1H), 7.78 (s, 1H), 7.11 (d, J = 8.3 Hz, 1H), 6.58 (s, 2H), 6.01 (br s, 1H), 5.94 (s, 2H), 4.93 (d, J = 3.8 Hz, 2H), 4.42 (dd, J = 3.9, 9.5 Hz, 2H), 3.72 - 3.60 (m, 2H), 3.16 (t, J = 9.5 Hz, 1H), 2.52 (br d, J = 1.6 Hz, 2H), 2.17 (br d, J = 3.1 Hz, 2H), 1.63 (t, J = 6.4 Hz, 2H), 1.13 (s, 6H), 1.01 - 0.95 (m, 2H), 0.01 (s, 9H), MS (LC / MS) m / z Actual value 628.3, Predicted value 628.3 [M+H].

[0222] 4-Cyano-N-[6-[2,4-Dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (91, 130 mg, 206.79 μmol, 1 eq) was dissolved in DCM (5 mL) and TFA (2 mL) was added. The mixture was stirred at 25 °C for 2 hours. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 2.486 minutes ([M+H]=498.2) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5μm, mobile phase: [H2O(0.1%TFA)-ACN], 60%~90% B gradient over 8.0 minutes) to obtain the title compound 5-cyano-N-[6-[2,4-dichloro-8-oxabicyclo[3.2.1]octa-6-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-1H-imidazole-2-carboxamide (A-10, 42.8 mg, 85.87 μmol, yield 41.5%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6, 298 K) δ (ppm) = 14.29 (br s, 1H), 10.09 (s, 1H), 8.34 (s, 1H), 8.17 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 6.65 (s, 2H), 5.98 (br s, 1H), 4.98 (d, J = 4.0 Hz, 2H), 4.34 (br dd, J = 4.0, 9.6 Hz, 4H), 3.13 (t, J = 9.6 Hz, 1H), 1.94 (br s, 2H), 1.50 (br t, J = 6.4 Hz, 2H), 0.99 (s, 6H), MS (LC / MS) m / z: Measured value 498.2, Predicted value 498.2 [M+H].

[0223] Example 10 5-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]-1H-imidazole-2-carboxamide A-11 [ka] To a solution of MgO (1.57 g, 38.99 mmol, 438.93 μL, 0.5 eq), Na2CO3 (1.65 g, 15.60 mmol, 0.2 eq), and NH4Cl (1.67 g, 31.19 mmol, 0.4 eq), 1,1,1,3,3,3-hexaduteriopropan-2-one (88.5 g, 77.98 mmol, 5.73 mL, 1 eq) was added at 20°C. The mixture was heated and then stirred at 50°C for 12 hours under an N2 atmosphere. The reaction was monitored by TLC (SiO2 / MeOH = 5 / 1) until the starting materials were completely consumed. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 100 / 1~0 / 1) to obtain 3,3,5,5-tetraduterio-2,2,6,6-tetrakis(triduteriomethyl)piperidine-4-one (89, 500 mg, 2.92 mmol, yield 3.7%) as a yellow solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used directly. MS (LC / MS) m / z: measured value 172.3, predicted value 172.2 [M+H].

[0224] To a solution of 3,3,5,5-tetraduterio-2,2,6,6-tetrakis(triduteriomethyl)piperidine-4-one (89, 100 mg, 583.65 μmol, 1 eq) in THF (3 mL), LDA (2 M, 1.46 mL, 5 eq) was added at -60°C. The mixture was heated and then stirred at 20°C for 16 hours under an N2 atmosphere. The reaction was analyzed by LC / MS (R t The mixture was monitored for 0.133 minutes ([M+H]=168.2) until the starting material was completely consumed. The reaction mixture was quenched with NH4Cl (aqueous solution, 5 mL) and extracted with DCM (5 mL x 3). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, Pet.Et. / Âi=3 / 1~0 / 1) to obtain 2,2,6,6-tetrakis(triduteriomethyl)piperidine-4-one (90 mg, 119.54 μmol, yield 20.48%) as a yellow solid. 1¹H NMR (400 MHz, CDCl3) δ = 2.37 (s, 4H), MS (LC / MS) m / z: Measured value 168.2, Predicted value 168.2 [M+H].

[0225] To a solution of 2,2,6,6-tetrakis(triduteriomethyl)piperidine-4-one (90 mg, 1 g, 5.98 mmol, 1 eq) in MeOH (20 mL), NaBH4 (339.18 mg, 8.97 mmol, 1.5 eq) was added at 0°C. The mixture was heated and then stirred at 25°C for 2 hours under an N2 atmosphere. The reaction was monitored by TLC (siRNA / MeOH = 5 / 1) until the starting material was completely consumed. The reaction mixture was quenched with NH4Cl (aqueous solution, 30 mL) and extracted with siRNA (20 mL x 3). The organic layers were combined and dried over Na2SO4, filtered, and concentrated under reduced pressure. Without further purification, the residue was obtained as a yellow solid: 2,2,6,6-tetrakis(triduteriomethyl)piperidine-4-ol (91 mg, 1 g, 5.91 mmol, yield 98.8%), which was then used as is. 1 H NMR (400 MHz, MeOH-d4) δ (ppm) = 4.01 - 3.93 (m, 1H), 1.89 - 1.79 (m, 1H), 1.14 (br dd, J = 7.6, 14.0 Hz, 2H), 1.05 (t, J = 12.0 Hz, 1H).

[0226] To a 10 mL solution of MTBE (MTBE) containing 2,2,6,6-tetrakis(triduteriomethyl)piperidine-4-ol (91, 412.99 mg, 2.44 mmol, 1.55 eq) and NHC-1 (995.08 mg, 2.52 mmol, 1.6 eq), a 1 mL solution of MTBE (MTBE) containing pyridine (199.15 mg, 2.52 mmol, 203.21 μL, 1.6 eq) was added dropwise over 5 minutes at 25°C. After stirring for another 10 minutes, the mixture was filtered, and the filtrate contained tert-butyl N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate (INT-3, 600 mg, 1.57 mmol, 1 eq), bis[2-(2-pyridyl)phenyl]iridium(1+); 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine; hexafluorophosphate (21.57 mg, 23.60 μmol, 0.015 eq), dibro Monickel; 1,2-dimethoxyethane (24.28 mg, 78.68 μmol, 0.05 eq), quinuclidine (306.17 mg, 2.75 mmol, 1.75 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (31.67 mg, 118.02 μmol, 0.075 eq), and isoindoline-1,3-dione (52.09 mg, 354.05 μmol, 0.225 eq) were added to a DMA (10 mL) solution under N2 conditions. The mixture was stirred at 25°C for 12 hours under blue LED illumination. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 0.451 minutes ([M+H]=454.5) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with HCl (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5μm, mobile phase: [H2O(0.1%TFA)-ACN], 25%~55% B gradient over 8.0 minutes) to obtain N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]carbamate tert-butyl (92,160 mg, 352.64 μmol, yield 22.4%) as a yellow solid, which was then used directly. MS (LC / MS) m / z measured value 454.4, predicted value 454.4 [M+H].

[0227] To a solution of N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]carbamate tert-butyl (92,160 mg, 352.6 μmol, 1 eq) in DCM (3 mL), TFA (2 mL) was added. The mixture was stirred at 25 °C for 2 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 0.330 minutes ([M+H]=354.3) until the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure, and the residue was obtained without further purification. 2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]pyridine-3-amine (93,160 mg, 339.36 μmol, yield 96.2%, purity 75%) was obtained as a yellow oil, which was then used as is. 1H NMR (400 MHz, MeOH-d4, 298 K) δ (ppm) = 7.73 (d, J = 8.9 Hz, 1H), 7.57 (d, J = 8.9 Hz, 1H), 6.19 (td, J = 1.9, 3.7 Hz, 1H), 3.74 - 3.62 (m, 1H), 2.45 - 2.36 (m, 2H), 2.13 (br d, J = 3.5 Hz, 2H), 2.09 - 2.03 (m, 1H), 2.02 (s, 1H), 1.64 (t, J = 6.3 Hz, 2H), 1.58 - 1.46 (m, 2H), 1.08 (s, 6H), MS (LC / MS) Measured value (m / z): 354.3, predicted value: 354.4 [M+H].

[0228] To a solution of 2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]pyridine-3-amine (93 mg, 220 mg, 622.16 μmol, 1 eq) in DMF (5 mL), [4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]oxypotassium (INT-2, 380.07 mg, 1.24 mmol, 2 eqs), DIEA (241.23 mg, 1.87 mmol, 325.11 μL, 3 eqs), and PyBroP (435.06 mg, 933.24 μmol, 1.5 eqs) were added. The mixture was stirred at 25°C for 12 hours. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 2.508 minutes ([M+H]=603.5) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with dimethyl phosphate (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5μm, mobile phase: [H2O(0.1%TFA)-ACN], 35%~65% B gradient over 8.0 minutes) to obtain 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (94,200 mg, 331.70 μmol, yield 53.3%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, MeOH-d4, 298 K) δ (ppm) = 8.72 (d, J = 8.5 Hz, 1H), 8.24 (s, 1H), 7.41 (d, J = 8.6 Hz, 1H), 6.03 (br s, 1H), 5.91 (s, 2H), 3.70 - 3.64 (m, 2H), 3.52 - 3.44 (m, 1H), 2.47 (br d, J = 2.0 Hz, 2H), 2.13 (br d, J = 3.4 Hz, 2H), 2.10 - 2.01 (m, 2H), 1.88 (t, J = 13.5 Hz, 2H), 1.62 (t, J = 6.3 Hz, 2H), 1.58 -1.53 ​​(m, 1H), 1.48 - 1.43 (m, 1H), 1.11 (s, 6H), -0.02 (s, 9H), MS (LC / MS) m / z: Measured value 603.5, Predicted value 603.5 [M+H].

[0229] To a solution of 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (94,200 mg, 331.70 μmol, 1 eq) in DCM (5 mL), TFA (2 mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction was analyzed by LC / MS (R t The reaction mixture was monitored for 1.899 minutes ([M+H]=473.4) until it indicated that the reactants were completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5μm, mobile phase: [H2O(0.1%TFA)-ACN], 20%~50% B gradient over 8.0 minutes) to obtain the title compound 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]-1H-imidazole-2-carboxamide (A-11, 52.6 mg, 111.28 μmol, yield 33.6%) as a yellow oil. 1 H NMR (400 MHz, MeOH-d4, 295 K) δ (ppm) = 8.59 (d, J = 8.5 Hz, 1H), 8.03 (s, 1H), 7.30 (d, J = 8.4 Hz, 1H), 5.99 - 5.93 (m, 1H), 3.47 - 3.38 (m, 1H), 2.47 (br d, J = 2.0 Hz, 2H), 2.11 (br d, J = 3.1 Hz, 2H), 2.06 - 1.82 (m, 3H), 1.61 (t, J = 6.3 Hz, 2H), 1.57 - 1.44 (m, 1H), 1.10 (s, 6H), MS (LC / MS) m / z Actual value: 473.4, Predicted value: 473.4 [M+H].

[0230] Example 11 5-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1-methyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]-1H-imidazole-2-carboxamide A-12 [ka] NaBH3CN (72.71 mg, 1.16 mmol, 2.5 eq) was added at 0°C to a solution of N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]carbamate tert-butyl (92, 210 mg, 462.84 μmol, 1 eq) and formaldehyde (187.80 mg, 2.31 mmol, 172.29 μL, 5 eq) in MeOH (5 mL). The mixture was heated and then stirred at 20°C for 16 hours under an N2 atmosphere. The reaction was analyzed by LC / MS (R t The mixture was monitored for 0.816 minutes ([M+H]=468.5) until the starting material was completely consumed and the desired product mass was observed. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (6 mL x 3). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the residue. Without further purification, N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1-methyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]carbamate tert-butyl (95, 200 mg) was obtained as a crude yellow solid and used as is. 1H NMR (400 MHz, MeOH-d4) δ = 7.88 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 5.81 (td, J = 2.0, 3.5 Hz, 1H), 3.28 - 3.21 (m, 1H), 2.55 (br s, 3H), 2.44 - 2.35 (m, 2H), 2.02 (br d, J = 3.4 Hz, 2H), 1.87 (br s, 2H), 1.55 (t, J = 6.4 Hz, 2H), 1.48 (s, 9H), 1.30 (br d, J = 5.9 Hz, 2H), 1.04 (s, 6H), MS (LC / MS) m / z Measured value 468.5, Predicted value 468.4 [M+H].

[0231] To a solution of N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1-methyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]carbamate tert-butyl (95, 200 mg, 427.58 μmol, 1 eq) in DCM (1.5 mL), TFA (0.5 mL) was added at 0°C. The mixture was heated and then stirred at 20°C for 16 hours under an N2 atmosphere. The reaction was analyzed by LC / MS (R t The reaction was monitored for 0.314 minutes ([M+H]=368.4) until the starting material was completely consumed and the desired product mass was observed. The reaction mixture was adjusted to pH 8-9 with NaHCO3 (aqueous solution) and extracted with siRNA (5 mL x 3). The organic layers were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue without further purification. 2-(4,4-dimethylcyclohexen-1-yl)-6-[1-methyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]pyridine-3-amine (96, 120 mg, 326.41 μmol, yield 76.3%) was obtained as a yellow solid and used as is. MS (LC / MS) m / z: measured value 368.4, predicted value 368.4 [M+H].

[0232] To a solution of 2-(4,4-dimethylcyclohexen-1-yl)-6-[1-methyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]pyridine-3-amine (96, 120 mg, 326.41 μmol, 1 eq) and [4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]oxypotassium (INT-2, 224.93 mg, 736.39 μmol, 2.26 eq) in DMF (2 mL), DIEA (126.56 mg, 979.24 μmol, 170.56 μL, 3 eq) and PyBroP (228.25 mg, 489.62 μmol, 1.5 eq) were added at 0°C. The mixture was heated and stirred for a further 16 hours at 20°C under an N2 atmosphere. The reaction is analyzed by LC / MS(R t The mixture was monitored for 0.927 minutes ([M+H]=617.6) until the starting material was completely consumed and the desired product mass was observed. The reaction mixture was diluted with H2O (7 mL) and extracted with siRNA (5 mL × 3). The organic layers were combined and dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5μm, mobile phase: [H2O(0.1%TFA)-ACN], 40%~70% B gradient over 8.0 minutes) to obtain 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1-methyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (97, 110 mg, 150.48 μmol, yield 46.1%) as the TFA salt, which was then used as is as a white solid. 1H NMR (400 MHz, MeOH-d4) δ = 8.77 (d, J = 8.5 Hz, 1H), 8.24 (s, 1H), 7.46 (d, J = 8.6 Hz, 1H), 6.07 (br s, 1H), 5.91 (s, 2H), 3.70 - 3.64 (m, 2H), 3.52 (qdd, J = 4.0, 8.2, 12.2 Hz, 1H), 2.90 (s, 3H), 2.47 (br d, J = 1.9 Hz, 2H), 2.18 - 2.12 (m, 4H), 1.62 (t, J = 6.3 Hz, 2H), 1.56 - 1.48 (m, 2H), 1.11 (s, 6H), 0.97 - 0.91 (m, 2H), -0.02 (s, 9H), MS (LC / MS) m / z: Measured value 617.6, Predicted value 617.5 [M+H].

[0233] To a 1.5 mL solution of 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1-methyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (97, 110 mg, 178.29 μmol, 1 eq) in DCM (1.5 mL), TFA (0.5 mL) was added at 0°C and the mixture was heated, then stirred at 20°C for 2 hours under an N2 atmosphere. The reaction was analyzed by LC / MS (R tThe reaction was monitored for 0.415 minutes ([M+H]=486.5) until the starting material was completely consumed and the desired product mass was observed. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5μm, mobile phase: [H2O(0.1%TFA)-ACN], 25%~55%B gradient over 8.0 minutes) to obtain the title compound 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1-methyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]-1H-imidazole-2-carboxamide (A-12, 84.2 mg, 140.16 μmol, yield 78.6%) as the TFA salt, as a white solid. 1 H NMR (400 MHz, MeOH-d4) δ = 8.68 - 8.60 (m, 1H), 8.03 (s, 1H), 7.40 - 7.32 (m, 1H), 5.99 (br s, 1H), 3.53 - 3.41 (m, 1H), 2.89 (s, 3H), 2.51 - 2.44 (m, 2H), 2.13 (br d, J = 9.0 Hz, 4H), 1.61 (t, J = 6.3 Hz, 2H), 1.56 - 1.47 (m, 2H), 1.10 (s, 6H), MS (LC / MS) m / z actual value 486.5, Predicted value 487.4 [M+H].

[0234] Example 12 N-[6-[1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-5-cyano-1H-imidazole-2-carboxamide A-13 [ka] In a solution of tert-butyl-[[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-oxabicyclo[3.2.1]octa-2,6-dien-1-yl]methoxy]dimethylsilane (INT-4, 3.4g, 6.51 mmol, 1eq) in dioxane (40mL) and H2O (4mL), N-[6 Bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (INT-5, 3.28 g, 6.18 mmol, 0.95 eq), K2CO3 (2.70 g, 19.52 mmol, 3 eq), and Pd(dppf)Cl2 (475.98 mg, 650.51 μmol, 0.1 eq) were added. The mixture was stirred at 100°C for 12 hours. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 5 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with water (50 mL) and extracted with Depositphotos (50 mL x 2). The organic layers were combined, washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 40g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 60 mL / min) to obtain N-[6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (98, 4.2g, 4.96 mmol, yield 76.3%) as a yellow oil, which was then used as is. 1H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 10.00 (s, 1H), 8.68 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.29 (s, 1H), 7.17 (s, 1H), 6.42 (d, J = 5.8 Hz, 1H), 5.97 (br d, J = 3.8 Hz, 1H), 5.95 - 5.92 (m, 4H), 3.91 - 3.86 (m, 4H), 3.69 - 3.63 (m, 3H), 2.82 (dd, J = 1.9, 18.1 Hz, 1H), 2.52 (br d, J = 1.1 Hz, 2H), 2.45 (br dd, J = 1.4, 18.1 Hz, 2H), 2.14 (br s, 3H), 1.64 - 1.58 (m, 4H), 1.11 (s, 9H), 0.99 - 0.97 (m, 2H), 0.94 (d, J = 2.4 Hz, 18H), 0.01 (s, 12H).

[0235] N-[6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (98 g, 4.2 g, 4.96 mmol, 1 eq) was dissolved in THF (50 mL) and TBAF·3H2O (4.70 g, 14.89 mmol, 3 eq) was added. The mixture was stirred at 25°C for 3 hours. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 2.676 minutes ([M+H]=618.3) until the starting material was completely consumed. The reaction mixture was diluted with water (50 mL) and extracted with pharmaceutically acceptable phosphate (40 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Welch Xtimate C18 180×70mm×10μm, mobile phase: [water (10mM NH4HCO3)-ACN], 50%~80% B gradient over 20.0 minutes) to obtain N-[6-[1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (99, 1.1g, 1.78 mmol, yield 35.9%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 10.01 (s, 1H), 8.68 (d, J = 8.6 Hz, 1H), 7.77 (s, 1H), 7.29 (s, 1H), 6.95 (s, 1H), 6.38 (d, J = 5.8 Hz, 1H), 5.98 - 5.91 (m, 4H), 4.05 - 3.87 (m, 4H), 3.72 - 3.61 (m, 2H), 2.89 (dd, J = 1.6, 18.0 Hz, 1H), 2.49 (br d, J = 1.5 Hz, 2H), 2.40 - 2.23 (m, 3H), 2.14 (br d, J = 2.5 Hz, 2H), 1.67 - 1.54 (m, 4H), 1.25 (s, 1H), 1.13 (s, 6H), 1.02 - 0.95 (m, 2H), 0.01 (s, 8H), MS (LC / MS) m / z actual value 618.3, Predicted value 618.3 [M+H].

[0236] To a 10 mL solution of N-[6-[1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (99, 300 mg, 485.6 μmol, 1 eq) in DCM (10 mL), pyridine (192.05 mg, 2.43 mmol, 195.97 μL, 5 eq) and trifluoromethylsulfonyl trifluoromethanesulfonate (411.01 mg, 1.46 mmol, 240.36 μL, 3 eq) were added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was monitored by TLC (Pet.Et. / Â=3 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 12g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 60 mL / min) to obtain 3-[5-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-5-(trifluoromethylsulfonyloxymethyl)-8-oxabicyclo[3.2.1]octa-3,6-dien-1-yl]methyltrifluoromethanesulfonate (100, 400 mg, 453.55 μmol, yield 93.4%) as a yellow solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0237] [3-[5-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-5-(trifluoromethylsulfonyloxymethyl)-8-oxabicyclo[3.2.1]octa-3,6-dien-1-yl]methyltrifluoromethanesulfonate (100, 400 mg, 453.55 μmol, 1 eq) was dissolved in THF (10 mL) and TBAF (1 M, 2.27 mL, 5 eq) was added. The mixture was stirred at 40 °C for 4 hours. The reaction was monitored by LC / MS (Rt = 0.721 min, [M + H] = 622.4) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with ELISA (10 mL × 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 60 mL / min) to obtain N-[6-[1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (101, 210 mg, 337.73 μmol, yield 74.5%) as a yellow solid, which was then used as is. 1H NMR (400 MHz, CDCl3) δ (ppm) = 10.02 (s, 1H), 8.69 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 7.30 (d, J = 8.8 Hz, 1H), 7.02 (s, 1H), 6.46 (d, J = 5.8 Hz, 1H), 6.00 - 5.95 (m, 2H), 5.93 (s, 2H), 4.85 - 4.73 (m, 2H), 4.72 - 4.61 (m, 2H), 3.70 - 3.63 (m, 2H), 2.93 (dd, J = 1.7, 18.0 Hz, 1H), 2.53 - 2.40 (m, 3H), 2.15 (br d, J = 2.9 Hz, 2H), 1.63 (t, J = 6.3 Hz, 2H), 1.13 (s, 6H), 1.04 - 0.94 (m, 2H), 0.01 (s, 9H), MS (LC / MS) m / z actual value 622.4, Predicted value 622.3 [M+H].

[0238] To a solution of N-[6-[1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (101, 210 mg, 337.7 μmol, 1 eq) in DCM (5 mL), TFA (3 mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction was analyzed by LC / MS (R tThe reaction mixture was monitored for 0.591 minutes ([M+H]=492.2) until it indicated that the reactants were completely consumed. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×30mm×5μm, mobile phase: [water (TFA)-ACN], B%: 40%~75% gradient, 8 min) to obtain the title compound N-[6-[1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-5-cyano-1H-imidazole-2-carboxamide (A-13, 105.9 mg, 215.45 μmol, yield 63.8%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6, 298 K) δ (ppm) = 14.29 (br s, 1H), 10.01 (s, 1H), 8.34 (s, 1H), 8.24 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.04 (s, 1H), 6.50 (d, J = 5.6 Hz, 1H), 6.03 (dd, J = 1.2, 5.7 Hz, 1H), 5.90 (br s, 1H), 4.88 - 4.61 (m, 4H), 2.74 (dd, J = 1.6, 18.2 Hz, 1H), 2.41 (br s, 2H), 2.31 (br d, J = 17.8 Hz, 1H), 1.94 (br s, 2H), 1.49 (t, J = 6.4 Hz, 2H), 0.99 (s, 6H), MS (LC / MS) m / z: Measured value 492.2, Predicted value 492.2 [M+H].

[0239] Example 13 5-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(1-ethyl-2,2,6,6-tetramethyl-4-piperidyl)-3-pyridyl]-1H-imidazole-2-carboxamide A-14 [ka] To a solution of 2,2,6,6-tetramethylpiperidine-4-ol (102, 2.5 g, 15.90 mmol, 1 eq) in MeOH (25 mL), CH3CH2I (18.85 g, 120.82 mmol, 9.66 mL, 7.6 eq) and Na2CO3 (960.47 mg, 9.06 mmol, 0.57 eq) were added at 20°C. The mixture was heated and stirred at 65°C for 120 hours under an N2 atmosphere. The reaction was then carried out. 1 The mixture was monitored by 1H NMR until the starting material was completely consumed. The reaction mixture was quenched with water (40 mL) and extracted with siRNA (30 mL x 3). The organic layers were combined and dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain the residue without further purification. 1-ethyl-2,2,6,6-tetramethyl-piperidine-4-ol (103, 2 g, 6.48 mmol, yield 40.7%, purity 60%) was obtained as a white solid and used as is. 1 H NMR (400 MHz, MeOH-d4) δ = 3.91 (tt, J = 4.1, 11.6 Hz, 1H), 2.59 (q, J = 6.6 Hz, 2H), 1.76 (dd, J = 4.1, 12.3 Hz, 2H), 1.34 (br t, J = 11.9 Hz, 2H), 1.15 (s, 6H), 1.08 (s, 6H), 1.06 - 1.02 (m, 3H), MS (LC / MS) m / z Actual value 186.2, Predicted value 186.2 [M+H].

[0240] N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (INT-3, 350 mg, 917.90 μmol, 1 eq) and 1-ethyl-2,2,6,6-tetramethylpiperidine-4-ol (103, 510.27 mg, 2.75 mmol, 3 eq) are dissolved in MTBE (5 mL) and bis[2-(2-pyridyl)phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine;hexafluorophosphate (12.58 mg, 13.77 μmol, 0.015 eq), dibromon The following were added at 25°C: 1,2-dimethoxyethane (14.16 mg, 45.89 μmol, 0.05 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (18.48 mg, 68.84 μmol, 0.075 eq), NHC-1 (1.16 g, 2.94 mmol, 3.2 eq), pyridine (232.34 mg, 2.94 mmol, 237.08 μL, 3.2 eq), quinuclidine (178.61 mg, 1.61 mmol, 1.75 eq), isoindoline-1,3-dione (30.39 mg, 206.53 μmol, 0.225 eq), and DMA (3 mL). The mixture was further stirred at 25°C for 16 hours under 34 W blue LED lighting. The reaction is analyzed by LC / MS(R t The mixture was monitored for 0.487 minutes ([M+H]=470.4) until the starting material was completely consumed and the desired product mass was observed. The reaction mixture was quenched with NH4Cl (aqueous solution, 8 mL) and extracted with DCM (6 mL x 3). The organic layers were combined and dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250 × 70 mm, 15 μm), mobile phase: [H2O (0.1% TFA)-ACN], 30% to 60% B gradient over 20.0 minutes) to obtain N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(1-ethyl-2,2,6,6-tetramethyl-4-piperidyl)-3-pyridyl]carbamate tert-butyl (104 mg, 250 mg, 342.63 μmol, yield 187.6%, purity 80%) as the TFA salt, which was obtained as a white solid.1 H NMR (400 MHz, MeOH-d4) δ = 8.33 (d, J = 8.5 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 6.03 (td, J = 2.0, 3.6 Hz, 1H), 3.66 (tt, J = 3.4, 12.6 Hz, 1H), 3.41 (q, J = 7.4 Hz, 2H), 2.43 - 2.37 (m, 2H), 2.25 - 2.18 (m, 2H), 2.12 (br d, J = 3.5 Hz, 2H), 2.10 - 2.04 (m, 3H), 1.60 (br s, 1H), 1.55 (d, J = 2.6 Hz, 12H), 1.51 (s, 9H), 1.47 (t, J = 7.4 Hz, 3H), 1.04 (s, 6H), MS (LC / MS) m / z: Measured value 470.4, Predicted value 470.4 [M+H].

[0241] To a solution of tert-butyl N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(1-ethyl-2,2,6,6-tetramethyl-4-piperidyl)-3-pyridyl]carbamate (104, 250 mg, 425.80 μmol, 1 eq) in DCM (3 mL), TFA (1 mL) was added at 0°C. The mixture was heated and then stirred at 20°C for 1 hour under an N2 atmosphere. The reaction was analyzed by LC / MS (R t The reaction was monitored for 0.326 minutes ([M+H]=370.4) until the starting material was completely consumed and the desired product mass was observed. The reaction mixture was adjusted to pH 8-9 with NaHCO3 (aqueous solution) and extracted with DCM (5 mL x 3). The organic layers were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue without further purification. 2-(4,4-dimethylcyclohexen-1-yl)-6-(1-ethyl-2,2,6,6-tetramethyl-4-piperidyl)pyridine-3-amine (105, 150 mg) was obtained as crude yellow oil and used as is. MS (LC / MS) m / z: measured value 370.4, predicted value 370.3 [M+H].

[0242] To a solution of 2-(4,4-dimethylcyclohexen-1-yl)-6-(1-ethyl-2,2,6,6-tetramethyl-4-piperidyl)pyridine-3-amine (105 mg, 150 mg, 324.69 μmol, 1 eq) and [4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]oxypotassium (INT-2, 198.35 mg, 649.38 μmol, 2 eq) in DMF (2 mL), DIEA (125.89 mg, 974.07 μmol, 169.66 μL, 3 eq) and PyBroP (227.04 mg, 487.03 μmol, 1.5 eq) were added at 20°C. The mixture was further stirred at 20°C for 16 hours under an N2 atmosphere. Continue LC / MS(R) until the starting material is completely consumed and the desired product mass is observed. t The reaction mixture was subjected to preparative HPLC ([M+H]=619.5) for 0.941 minutes. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5μm, mobile phase: [H2O(0.1%TFA)-ACN], 35%~65%B gradient over 8.0 minutes) to obtain 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(1-ethyl-2,2,6,6-tetramethyl-4-piperidyl)-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (106, 150 mg, 204.65 μmol, yield 63.0%) as the TFA salt, which was obtained as a white solid and used as is. 1H NMR (400 MHz, MeOH-d4) δ = 8.65 (d, J = 8.4 Hz, 1H), 8.23 ​​(s, 1H), 7.34 (d, J = 8.5 Hz, 1H), 5.99 (br s, 1H), 5.92 (s, 2H), 3.67 (t, J = 7.9 Hz, 2H), 3.42 (br d, J = 7.4 Hz, 2H), 2.47 (br s, 2H), 2.22 - 2.16 (m, 2H), 2.15 - 2.04 (m, 5H), 1.63 - 1.60 (m, 2H), 1.57 (s, 6H), 1.54 (s, 6H), 1.46 (br t, J = 7.4 Hz, 3H), 1.11 (s, 6H), 0.94 (t, J = 8.0 Hz, 2H), -0.02 (s, 9H), MS (LC / MS) m / z actual value 619.5, predicted value 619.4 [M+H].

[0243] To a solution of 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(1-ethyl-2,2,6,6-tetramethyl-4-piperidyl)-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (106, 150 mg, 204.65 μmol, 1 eq) as the TFA salt in DCM (1.5 mL), TFA (0.5 mL) was added at 0°C. The mixture was heated and then stirred at 20°C for 1 hour under an N2 atmosphere. The reaction was analyzed by LC / MS (R tThe reaction was monitored for 0.422 minutes ([M+H]=489.4) until the starting material was completely consumed and the desired product mass was observed. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×3μm, mobile phase: [H2O(0.1%TFA)-ACN], 35%~65%B gradient over 8.0 minutes) to obtain the title compound 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(1-ethyl-2,2,6,6-tetramethyl-4-piperidyl)-3-pyridyl]-1H-imidazole-2-carboxamide (A-14, 81.6 mg, 133.70 μmol, yield 65.3%, purity 98.8%) as the TFA salt, as a white solid. 1 H NMR (400 MHz, MeOH-d4) δ = 8.65 (br d, J = 8.5 Hz, 1H), 8.03 (s, 1H), 7.37 (br d, J = 8.5 Hz, 1H), 6.00 (br s, 1H), 3.51 (br t, J = 12.7 Hz, 1H), 3.42 (q, J = 7.3 Hz, 2H), 2.47 (br d, J = 1.8 Hz, 2H), 2.25 - 2.16 (m, 2H), 2.13 - 2.03 (m, 4H), 1.61 (t, J = 6.4 Hz, 2H), 1.57 (s, 6H), 1.54 (s, 6H), 1.46 (t, J = 7.4 Hz, 3H), 1.10 (s, 6H), MS (LC / MS) m / z. Measured value 489.4, predicted value 489.3 [M+H].

[0244] Example 14 5-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1-ethyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]-1H-imidazole-2-carboxamide A-15 [ka] To a solution of MgO (1.57 g, 38.99 mmol, 438.93 μL, 0.5 eq), Na2CO3 (1.65 g, 15.60 mmol, 0.2 eq), and NH4Cl (1.67 g, 31.19 mmol, 0.4 eq), 1,1,1,3,3,3-hexaduteriopropan-2-one (107 g, 77.98 mmol, 5.73 mL, 1 eq) was added at 20°C. The mixture was heated and then stirred at 50°C for 48 hours under an N2 atmosphere. The reaction was monitored by TLC (SiO2 / MeOH = 5 / 1) until a single new product spot was observed. The reaction mixture was filtered and concentrated under vacuum. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 100 / 1 to 0 / 1) to obtain 2,2,6,6-tetrakis(triduteriomethyl)piperidine-4-one (10⁸, 1.5 g, 8.97 mmol, yield 3.8%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, MeOH-d4) δ = 2.30 (s, 4H).

[0245] To a solution of 2,2,6,6-tetrakis(triduteriomethyl)piperidine-4-one (108 mg, 1.5 g, 8.97 mmol, 1 eq) in MeOH (15 mL), NaBH4 (678.32 mg, 17.93 mmol, 2 eqs) was added at 0°C. The mixture was heated and then stirred at 20°C for 16 hours under an N2 atmosphere. The reaction was monitored by TLC (siRNA / MeOH = 5 / 1) until the starting material was completely consumed. The reaction mixture was quenched with NH4Cl (aqueous solution, 20 mL) and extracted with DCM (15 mL x 3). The organic layers were combined and dried over Na2SO4, filtered, and concentrated under reduced pressure. Without further purification, the residue was obtained as a yellow solid: 2,2,6,6-tetrakis(triduteriomethyl)piperidine-4-ol (10⁹, 1.2 g, 7.09 mmol, yield 79.1%), which was then used as is. 1 MS (LC / MS) m / z: Measured value 170.2, predicted value 170.2 [M+H].

[0246] 2,2,6,6-tetrakis(triduteriomethyl)piperidine-4-ol (109, 600 mg, 3.54 mmol, 1 eq) was dissolved in MeOH (5 mL) and CH3CH2I (3 mL), to which Na2CO3 (214.07 mg, 2.02 mmol, 0.57 eq) was added at 20°C. The mixture was then heated to 65°C and stirred for a further 120 hours under an N2 atmosphere. The reaction was then carried out, 1 The reaction mixture was monitored by 1H NMR until it indicated that the starting material had been completely consumed. The reaction mixture was quenched with water (10 mL) and extracted with siRNA (10 mL x 3). The organic layers were combined and dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain 1-ethyl-2,2,6,6-tetrakis(triduteriomethyl)piperidine-4-ol (110, 700 mg, 2.48 mmol, yield 70.1%, purity 70%) as a yellow solid without further purification, which was then used as is. 1 H NMR (400 MHz, MeOH-d4) δ = 3.95 (br s, 1H), 2.72 (br s, 2H), 1.82 (br d, J = 11.1 Hz, 2H), 1.40 (br s, 2H), 1.11 (br s, 3H), MS (LC / MS) m / z actual measurement 198.3, predicted value 198.3 [M+H].

[0247] N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (110, 350 mg, 917.90 μmol, 1 eq) and 1-ethyl-2,2,6,6-tetrakis(triduteriomethyl)piperidine-4-ol (543.52 mg, 2.75 mmol, 3 eq) are dissolved in MTBE (2 mL) with bis[2-(2-pyridyl)phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine;hexafluorophosphate (12.58 mg, 13.77 μmol, 0.015 eq), dibro Monickel; 1,2-dimethoxyethane (14.16 mg, 45.89 μmol, 0.05 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (18.48 mg, 68.84 μmol, 0.075 eq), NHC-1 (1.16 g, 2.94 mmol, 3.2 eq), pyridine (232.34 mg, 2.94 mmol, 237.08 μL, 3.2 eq), quinuclidine (178.61 mg, 1.61 mmol, 1.75 eq), isoindoline-1,3-dione (30.39 mg, 206.53 μmol, 0.225 eq), and DMA (1 mL) were added at 25°C. The mixture was further stirred at 25°C for 16 hours under 34 W blue LED illumination. The reaction is analyzed by LC / MS(R tThe mixture was monitored for 0.809 minutes ([M+H]=482.5) until the starting material was completely consumed and the desired product mass was observed. The reaction mixture was diluted with H2O (5 mL) and extracted with siRNA (4 mL × 3). The organic layers were combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250 × 70 mm, 15 μm), mobile phase: [H2O (0.1% TFA)-ACN], 30% to 60% B gradient over 20.0 minutes) to obtain N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1-ethyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]carbamate tert-butyl (111, 150 mg, 249.08 μmol, yield 27.1%, purity 80%) as a white solid, which was then used as is. 1 H NMR (400 MHz, MeOH-d4) δ = 8.30 (d, J = 8.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 6.02 (br s, 1H), 3.69 - 3.58 (m, 1H), 3.42 (q, J = 7.4 Hz, 2H), 2.42 (br d, J = 1.8 Hz, 3H), 2.25 - 2.17 (m, 2H), 2.13 (br d, J = 3.5 Hz, 2H), 2.08 (br d, J = 3.3 Hz, 3H), 1.52 (s, 9H), 1.48 (t, J = 7.4 Hz, 3H), 1.06 (s, 6H), MS (LC / MS) m / z: Measured value 482.5, predicted value 482.5 [M+H].

[0248] To a solution of N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1-ethyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]carbamate tert-butyl (111, 150 mg, 249.08 μmol, 1 eq) in DCM (3 mL), TFA (1 mL) was added at 0°C, and the mixture was heated and then stirred at 20°C for 1 hour under an N2 atmosphere. The reaction was analyzed by LC / MS (Rt The mixture was monitored for 0.313 minutes ([M+H]=381.4) until the starting material was completely consumed and the desired product mass was observed. The reaction mixture was adjusted to pH 8-9 with NaHCO3 (aqueous solution) and extracted with SiO4 (5 mL x 3). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure, and the residue was obtained without further purification to obtain 2-(4,4-dimethylcyclohexen-1-yl)-6-[1-ethyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]pyridine-3-amine (112, 110 mg, TFA salt) as a crude yellow oil, which was then used as is. 1 H NMR (400 MHz, MeOH-d4) δ = 7.10 (d, J = 8.3 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 5.85 (br d, J = 1.4 Hz, 1H), 3.28 - 3.23 (m, 1H), 2.41 - 2.32 (m, 3H), 2.03 (br d, J = 3.5 Hz, 2H), 1.96 - 1.87 (m, 2H), 1.56 (t, J = 6.4 Hz, 3H), 1.40 (br d, J = 7.0 Hz, 5H), 1.04 (s, 6H), MS (LC / MS) m / z Actual value 381.4, Predicted value 382.4 [M+H].

[0249] DIEA (89.40 mg, 691.72 μmol, 120.48 μL, 3 eq) and PyBroP (161.23 mg, 345.86 μmol, 1.5 eq) were added at 0°C to a solution of 2-(4,4-dimethylcyclohexen-1-yl)-6-[1-ethyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]pyridine-3-amine (112, 110.00 mg, 230.57 μmol, 1 eq) and [4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]oxypotassium (INT-2, 140.85 mg, 461.14 μmol, 2 eq) in DMF (2 mL). The mixture was stirred at 0°C under an N2 atmosphere at 20°C for 16 hours. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 0.937 minutes ([M+H]=631.6) until the starting material was completely consumed and the desired product mass was observed. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×3μm, mobile phase: [H2O(0.1%TFA)-ACN], 35%~65% B gradient over 8.0 minutes) to obtain 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1-ethyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (113, 110 mg, 147.65 μmol, yield 64.0%, TFA salt) as a white solid, which was then used as is. 1 H NMR (400 MHz, MeOH-d4) δ = 8.65 (d, J = 8.4 Hz, 1H), 8.23 ​​(s, 1H), 7.35 (br d, J = 8.4 Hz, 1H), 5.98 (br s, 1H), 5.91 (s, 2H), 3.67 (t, J = 7.9 Hz, 2H), 3.48 (br d, J = 3.5 Hz, 1H), 3.41 (q, J = 7.4 Hz, 2H), 2.46 (br d, J = 1.5 Hz, 2H), 2.23 - 2.14 (m, 2H), 2.14 - 2.02 (m, 4H), 1.61 (t, J = 6.3 Hz, 2H), 1.56 - 1.49 (m, 2H), 1.45 (t, J = 7.4 Hz, 3H), 1.11 (s, 6H), 0.94 (t, J = 8.0 Hz, 2H), -0.02 (s, 9H), MS (LC / MS) m / z actual value 631.6, predicted value 631.5 [M+H].

[0250] To a 1.5 mL solution of DCM (113, 120 mg, 161.07 μmol, 1 eq) of the TFA salt of 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1-ethyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide, TFA (0.5 mL) was added at 0°C. The mixture was stirred at 20°C for 1 hour under an N2 atmosphere. The reaction was analyzed by LC / MS (R t The reaction was monitored for 0.428 minutes ([M+H]=501.5) until the starting materials were completely consumed and the desired product mass was observed. The reactants were concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×3μm, mobile phase: [H2O(0.1%TFA)-ACN], 30%~60% B gradient over 8.0 minutes) to obtain the title compound 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1-ethyl-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]-1H-imidazole-2-carboxamide (A-15, 62.8 mg, 100.0 μmol, yield 62.1%, purity 97.9%, TFA salt) as a white solid. 1 H NMR (400 MHz, MeOH-d4) δ = 8.61 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 6.00 - 5.95 (m, 1H), 3.53 - 3.44 (m, 1H), 3.41 (q, J = 7.5 Hz, 2H), 2.47 (br d, J = 1.9 Hz, 2H), 2.23 - 2.14 (m, 2H), 2.13 - 2.02 (m, 4H), 1.60 (t, J = 6.4 Hz, 2H), 1.45 (t, J = 7.4 Hz, 3H), 1.10 (s, 6H), MS (LC / MS) m / z Measured value 501.5, Predicted value 501.4 [M+H].

[0251] Example 15 5-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,3,6,7-tetraduterio-1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octan-3-yl]-3-pyridyl]-1H-pyrrole-2-carboxamide A-16 [ka] To a solution of 1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octa-6-en-3-one (18, 2 g, 4.85 mmol, 1 eq) in siRNA (30 mL), Pd / C (1.03 g, 969.21 μmol, 10% purity, 0.2 eq) was added at 25°C. The mixture was stirred for a further 2 hours at 25°C under D2 (15 psi). The reaction was monitored by TLC (Pet.Et. / siRNA = 10 / 1) until the starting material was completely consumed. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 12g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 80 mL / min) to obtain 1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-6,7-diduterio-8-oxabicyclo[3.2.1]octan-3-one (114, 1.9g, 4.56 mmol, yield 94.1%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 3.75 - 3.60 (m, 4H), 2.62 (d, J = 15.6 Hz, 2H), 2.32 (d, J = 15.5 Hz, 2H), 1.82 - 1.72 (m, 1H), 1.70 (s, 1H), 0.90 (s, 17H), 0.07 (s, 11H).

[0252] To a solution of 1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-6,7-diduterio-8-oxabicyclo[3.2.1]octan-3-one (114, 1.9 g, 4.56 mmol, 1 eq) in THF (30 mL), LDA (2 M, 2.74 mL, 1.2 eq) was added at -78 °C. After 1 hour, D2O (4.57 g, 227.96 mmol, 50 eq) was added. The mixture was heated and stirred at 25 °C for a further 1 hour. The reaction was monitored by TLC (Pet.Et. / siRNA=10 / 1) until the starting material was completely consumed. The reaction mixture was quenched with D2O (2 mL) and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 20g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 80 mL / min) to obtain 1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,6,7-triduterio-8-oxabicyclo[3.2.1]octan-3-one (115, 1.6g, 3.83 mmol, yield 84%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 3.74 - 3.60 (m, 4H), 2.62 (d, J = 15.5 Hz, 1H), 2.37 - 2.27 (m, 2H), 1.81 - 1.69 (m, 2H), 0.90 (s, 18H), 0.08 (s, 11H).

[0253] Sodium tetraduterioboranide (173.88 mg, 4.60 mmol, 1.2 eq) was added at 0°C to a solution of 1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,6,7-triduterio-8-oxabicyclo[3.2.1]octan-3-one (115, 1.6 g, 3.83 mmol, 1 eq) in THF (15 mL) and CD3OD (1 mL). The mixture was heated and stirred at 25°C for 2 hours. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 10 / 1) until the starting material was completely consumed. The reaction mixture was quenched with H2O (20 mL) and extracted with Depositphotos (20 mL x 2). The organic layers were combined, washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 20g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 80 mL / min) to obtain tert-butyl-[[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-3-duteriooxy-8-oxabicyclo[3.2.1]octane-1-yl]methoxy]dimethyl-silane (116, 1.6g, 3.79 mmol, yield 99.0%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 3.60 (q, J = 10.3 Hz, 4H), 2.06 - 1.98 (m, 2H), 1.70 - 1.67 (m, 1H), 1.65 (s, 1H), 1.32 (s, 1H), 0.90 (s, 18H), 0.06 (d, J = 1.0 Hz, 12H).

[0254] To a solution of tert-butyl-[[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-3-duteriooxy-8-oxabicyclo[3.2.1]octane-1-yl]methoxy]dimethyl-silane (116, 707.92 mg, 1.68 mmol, 1.6 eq) and NHC-1 (663.39 mg, 1.68 mmol, 1.6 eq) in MTBE (8 mL), a solution of pyridine (132.76 mg, 1.68 mmol, 135.47 μL, 1.6 eq) in MTBE (1 mL) was added dropwise over 5 minutes at 25°C. After another 10 minutes, the mixture was filtered, and the filtrate contained N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (INT-3, 400 mg, 1.05 mmol, 1 eq), bis[2-(2-pyridyl)phenyl]iridium(1+); 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine; hexafluorophosphate (14.38 mg, 15.74 μmol, 0.015 eq), dibro Monickel; 1,2-dimethoxyethane (16.19 mg, 52.45 μmol, 0.05 eq), quinuclidine (204.12 mg, 1.84 mmol, 1.75 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (21.12 mg, 78.68 μmol, 0.075 eq), and isoindoline-1,3-dione (34.73 mg, 236.03 μmol, 0.225 eq) were added to a DMA (8 mL) solution under N2 conditions. The mixture was stirred at 25°C for 3 hours under blue LED illumination. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 3.054 minutes ([M+H]=705.5) until the starting material was completely consumed. The reaction mixture was diluted with water (20 mL) and extracted with pharmaceutically acceptable phosphate (20 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC using a Welch Xltimate C4 100×30×10μm column, mobile phase [H2O (10mM NH4HCO3)-ACN], and gradient over 10.0 minutes to 70%~100% (B), yielding N-[6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-8-oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (117, 300 mg, 425.43 μmol, yield 20.28%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 8.24 (br d, J = 8.4 Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.88 (s, 1H), 5.81 (br s, 1H), 3.68 - 3.58 (m, 4H), 2.40 (br d, J = 1.9 Hz, 2H), 2.06 - 2.02 (m, 2H), 1.89 - 1.81 (m, 4H), 1.69 (br d, J = 13.1 Hz, 1H), 1.58 (br t, J = 6.4 Hz, 2H), 1.50 (s, 9H), 1.04 (s, 6H), 0.88 (s, 18H), 0.04 (s, 12H), MS (LC / MS) m / z: Measured value 705.5, Predicted value 705.5 [M+H].

[0255] To a 15 mL solution of N-[6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-8-oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate tert-butyl (117, 300 mg, 425.43 μmol, 1 eq) in DCM (15 mL), ZnBr2 (958.07 mg, 4.25 mmol, 212.90 μL, 10 eq) was added. The mixture was stirred at 25 °C for 12 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 2.938 minutes ([M+H]=605.5) until the starting material was completely consumed. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue without further purification. 6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-8-oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)pyridine-3-amine (118, 250 mg, 413.19 μmol, yield 97.1%) was obtained as a yellow solid and used as is. MS (LC / MS) m / z measured value 605.5, predicted value 605.5 [M+H].

[0256] To a 10 mL solution of 6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-8-oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)pyridine-3-amine (118, 250 mg, 413.19 μmol, 1 eq) in DMF (10 mL), [4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]oxypotassium (INT-2, 252.42 mg, 826.38 μmol, 2 eq), DIEA (160.21 mg, 1.24 mmol, 215.91 μL, 3 eq), and PyBroP (288.93 mg, 619.79 μmol, 1.5 eq) were added. The mixture was stirred at 25°C for 12 hours. The reaction was analyzed by LC / MS(R tThe mixture was monitored for 4.359 minutes ([M+H]=854.6) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with dimethyl phosphate (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 12g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 80 mL / min) to obtain N-[6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-8-oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (119, 240 mg, 280.9 μmol, yield 68.0%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 9.90 (s, 1H), 8.63 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.12 (d, J = 8.6 Hz, 1H), 5.94 (s, 3H), 3.72 - 3.56 (m, 7H), 2.49 (br d, J = 1.6 Hz, 2H), 2.14 (br d, J = 3.0 Hz, 2H), 1.91 - 1.85 (m, 4H), 1.79 (br dd, J = 6.4, 10.2 Hz, 1H), 1.73 (br d, J = 13.0 Hz, 1H), 1.62 (t, J = 6.4 Hz, 2H), 1.27 (t, J = 7.1 Hz, 1H), 1.12 (s, 6H), 1.00 - 0.96 (m, 2H), 0.89 (s, 18H), 0.05 (s, 12H), 0.03 - -0.01 (m, 9H), MS (LC / MS) m / z actual value 854.6, predicted value 854.5 [M+H].

[0257] To a solution of N-[6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-8-oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)pyrrole-2-carboxamide (119, 140 mg, 164.05 μmol, 1 eq) in DCM (3 mL), TFA (2 mL) was added. The mixture was stirred at 25 °C for 2 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 0.375 minutes ([M+H]=496.4) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5μm, mobile phase: [H2O(0.1%TFA)-ACN], 15%~50% B gradient over 7.0 minutes) to obtain the title compound 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,3,6,7-tetraduterio-1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octan-3-yl]-3-pyridyl]-1H-pyrrole-2-carboxamide (A-16, 37.9 mg, 76.62 μmol, yield 46.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6, 298 K) δ (ppm) = 14.29 (br s, 1H), 10.10 (s, 1H), 8.33 (s, 1H), 8.21 (br d, J = 8.4 Hz, 1H), 7.36 (br d, J = 8.0 Hz, 1H), 5.92 (br s, 1H), 3.45 - 3.36 (m, 4H), 2.39 (br s, 2H), 1.93 (br s, 2H), 1.83 - 1.75 (m, 2H), 1.68 (d, J = 7.6 Hz, 3H), 1.48 (t, J = 6.4 Hz, 2H), 0.97 (s, 6H), MS (LC / MS) m / z: Measured value 496.4, Predicted value 496.3 [M+H].

[0258] Example 16 5-Cyano-N-[6-[6,7-diduterio-1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octa-2-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-1H-imidazole-2-carboxamide A-17 [ka] To a solution of tert-butyl-[[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-oxabicyclo[3.2.1]octa-2,6-dien-1-yl]methoxy]dimethyl-silane (INT-4, 5g, 9.57 mmol, 1eq) in dioxane (50 mL) and H2O (5 mL), 6-bromo-2-chloropyridine-3-amine (120, 1.98g, 9.57 mmol, 1eq), K2CO3 (3.97g, 28.70 mmol, 3eq), and Pd(dppf)Cl2 (699.97 mg, 956.63 μmol, 0.1eq) were added. The mixture was heated and stirred at 100°C for 12 hours under N2. The reaction is analyzed by LC / MS(R tThe mixture was monitored for 3.093 minutes ([M+H]=523.3) until the starting material was completely consumed. The reaction mixture was diluted with water (50 mL) and extracted with pharmaceutically acceptable ammonium compounds (50 mL x 2). The organic layers were combined, washed with brine (80 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150×50mm, 10μm, mobile phase: [H2O (10mM NH4HCO3)-ACN], 70%~98% B gradient over 8.0 minutes) to obtain 6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-chloropyridine-3-amine (121, 1.6g, 3.06 mmol, yield 32.0%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 7.15 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.91 (s, 1H), 6.40 (d, J = 5.8 Hz, 1H), 5.90 (d, J = 5.8 Hz, 1H), 4.04 (s, 2H), 3.94 - 3.82 (m, 4H), 2.73 (dd, J = 1.6, 18.0 Hz, 1H), 2.34 (d, J = 18.0 Hz, 1H), 0.93 (d, J = 2.3 Hz, 18H), 0.13 - 0.08 (m, 12H), MS (LC / MS) m / z Measured value 523.3, Predicted value 523.3 [M+H].

[0259] 6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-chloropyridine-3-amine (121, 500 mg, 955.56 μmol, 1 eq) was added to a CD3OD (5 mL) solution with Rh / Al2O3 (98.34 mg, 955.56 μmol, 1 eq) at 25°C. The mixture was stirred under D2 at 25°C for 2 hours. The reaction was analyzed by LC / MS (Rt The mixture was monitored for 3.383 minutes ([M+H]=527.3) until the starting material was completely consumed. The reaction mixture was filtered and concentrated under reduced pressure. Without further purification, the residue was obtained as a yellow solid: 6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-6,7-diduterio-8-oxabicyclo[3.2.1]octa-2-en-3-yl]-2-chloropyridine-3-amine (122, 400 mg, 758.61 μmol, yield 79.4%), which was used as is. MS (LC / MS) m / z measured value 527.3, predicted value 527.3 [M+H].

[0260] To a solution of 6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-6,7-diduterio-8-oxabicyclo[3.2.1]octa-2-en-3-yl]-2-chloropyridine-3-amine (122, 400 mg, 758.61 μmol, 1 eq) in dioxane (5 mL) and H2O (0.5 mL), 2-(4,4-dimethylcyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (INT-1, 358.30 mg, 1.52 mmol, 2 eq), K2CO3 (314.53 mg, 2.28 mmol, 3 eq), and Pd(dppf)Cl2 (55.51 mg, 75.86 μmol, 0.1 eq) were added. The mixture was stirred at 100°C for 12 hours under N2. The reaction was analyzed by LC / MS(R tThe mixture was monitored for 1.082 minutes ([M+H]=601.5) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with dimethyl phosphate (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 12 g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 60 mL / min) to obtain 6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-6,7-diduterio-8-oxabicyclo[3.2.1]octa-2-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)pyridine-3-amine (123, 400 mg, 665.54 μmol, yield 87.7%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 7.06 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.79 (s, 1H), 6.04 - 5.98 (m, 1H), 3.88 (br s, 2H), 3.81 - 3.73 (m, 4H), 2.77 - 2.65 (m, 2H), 2.53 (br d, J = 1.6 Hz, 2H), 2.46 (d, J = 17.8 Hz, 1H), 1.73 (d, J = 9.1 Hz, 1H), 1.59 - 1.51 (m, 4H), 1.02 (s, 6H), 0.93 (s, 18H), 0.10 (s, 12H), MS (LC / MS) m / z: Measured value 601.5, Predicted value 601.4 [M+H].

[0261] To a 10 mL solution of 6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-6,7-diduterio-8-oxabicyclo[3.2.1]octa-2-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)pyridine-3-amine (123 mg, 400 mg, 665.54 μmol, 1 eq) in DMF (10 mL), potassium 4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylate (INT-2, 406.57 mg, 1.33 mmol, 2 eqs), DIEA (258.05 mg, 2.00 mmol, 347.77 μL, 3 eqs), and PyBroP (465.39 mg, 998.31 μmol, 1.5 eqs) were added. The mixture was stirred at 25°C for 12 hours. The reaction is analyzed by LC / MS(R t The mixture was monitored for 0.802 minutes ([M+H]=850.5) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with dimethyl phosphate (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 12g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA, flow rate 60 mL / min) to obtain N-[6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-6,7-diduterio-8-oxabicyclo[3.2.1]octa-2-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (124, 260 mg, 305.75 μmol, yield 45.9%) as a yellow solid, which was then used as is. 1H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 10.02 (s, 1H), 8.67 (d, J = 8.6 Hz, 1H), 7.77 (s, 1H), 7.28 (s, 1H), 6.99 (s, 1H), 5.99 (br s, 1H), 5.96 - 5.92 (m, 2H), 3.83 (d, J = 10.4 Hz, 2H), 3.78 (s, 2H), 3.70 - 3.64 (m, 2H), 2.82 - 2.74 (m, 1H), 2.54 (br s, 2H), 2.47 (br d, J = 17.0 Hz, 1H), 2.15 (br d, J = 2.5 Hz, 2H), 2.07 (d, J = 9.3 Hz, 1H), 1.74 (d, J = 9.3 Hz, 1H), 1.61 (br t, J = 6.3 Hz, 2H), 1.12 (s, 6H), 0.99 (br d, J = 8.4 Hz, 2H), 0.93 (s, 18H), 0.12 - 0.09 (m, 12H), 0.01 (s, 9H), MS (LC / MS) m / z actual value 850.5, predicted value 850.5 [M+H].

[0262] To a solution of N-[6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-6,7-diduterio-8-oxabicyclo[3.2.1]octa-2-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (124, 260 mg, 305.75 μmol, 1 eq) in DCM (5 mL), TFA (2 mL) was added. The mixture was stirred at 25 °C for 2 hours. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 2.202 minutes ([M+H]=429.3) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5μm, mobile phase: [H2O(0.1%TFA)-ACN], 25%~60% B gradient over 8.0 minutes) to obtain the title compound 5-cyano-N-[6-[6,7-diduterio-1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octa-2-en-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-1H-imidazole-2-carboxamide (A-17, 51.5 mg, 104.76 μmol, yield 34.3%) as a white solid. 1 H NMR (400 MHz, DMSO-d6, 298 K) δ (ppm) = 14.29 (br s, 1H), 10.02 (s, 1H), 8.33 (s, 1H), 8.23 ​​(d, J = 8.6 Hz, 1H), 7.45 - 7.38 (m, 1H), 6.93 (s, 1H), 5.90 (br s, 1H), 3.65 - 3.48 (m, 4H), 2.70 (br d, J = 17.9 Hz, 1H), 2.43 (br s, 2H), 2.34 (br d, J = 16.6 Hz, 1H), 1.94 (br s, 2H), 1.88 (d, J = 9.4 Hz, 1H), 1.61 (d, J = 9.3 Hz, 1H), 1.50 (br t, J = 6.2 Hz, 2H), 0.99 (s, 6H), MS (LC / MS) m / z: Measured value 491.6, Predicted value 491.6 [M+H].

[0263] Example 17 5-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,3,6,7-tetraduterio-1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octan-3-yl]-3-pyridyl]-1H-imidazole-2-carboxamide A-18 [ka] N-[6-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-8-oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (124, 400 mg, 468.17 μmol, 1 eq) was dissolved in THF (10 mL) and TBAF (1 M, 1.17 mL, 2.5 eq) was added. The mixture was stirred at 25 °C for 2 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 2.615 minutes ([M+H]=626.4) until the starting material was completely consumed. The reaction mixture was diluted with water (20 mL) and extracted with butyl (20 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5μm, mobile phase: [H2O(0.1%TFA)-ACN], 30%~80% B gradient over 8.0 minutes) to obtain 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,3,6,7-tetraduterio-1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octan-3-yl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (125, 200 mg, 319.56 μmol, yield 68.3%) as a yellow solid, which was then used as is. 1H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 9.82 (s, 1H), 9.19 (d, J = 8.9 Hz, 1H), 7.82 (s, 1H), 7.57 (d, J = 8.9 Hz, 1H), 6.18 (br s, 1H), 5.90 (s, 2H), 3.72 - 3.61 (m, 6H), 2.44 (br d, J = 1.4 Hz, 2H), 2.17 (br d, J = 3.0 Hz, 2H), 1.92 - 1.87 (m, 4H), 1.85 (s, 1H), 1.64 (t, J = 6.2 Hz, 2H), 1.13 (s, 6H), 1.04 - 0.95 (m, 2H), 0.05 - -0.02 (m, 9H), MS (LC / MS) m / z: Measured value 626.4, Predicted value 626.4 [M+H].

[0264] To a 5 mL solution of 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,3,6,7-tetraduterio-1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octan-3-yl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (125, 200 mg, 319.56 μmol, 1 eq) in DCM, pyridine (126.38 mg, 1.60 mmol, 128.96 μL, 5 eq) and Tf2O (270.48 mg, 958.67 μmol, 158.17 μL, 3 eq) were added. The mixture was stirred at 25°C for 2 hours. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 1.111 minutes ([M+H]=890.3) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with dimethyl phosphate (15 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 4g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 40 mL / min) to obtain [3-[5-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-3,4,6,7-tetraduterio-5-(trifluoromethylsulfonyloxymethyl)-8-oxabicyclo[3.2.1]octan-1-yl]methyltrifluoromethane-sulfonate (126, 200 mg, 224.72 μmol, yield 70.3%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 9.93 (s, 1H), 8.79 - 8.58 (m, 1H), 7.78 (s, 1H), 7.10 (br d, J = 8.6 Hz, 1H), 6.04 - 5.85 (m, 3H), 4.60 - 4.51 (m, 2H), 4.50 - 4.43 (m, 1H), 4.35 - 4.28 (m, 1H), 3.70 - 3.64 (m, 2H), 2.47 (br s, 2H), 2.15 (br s, 2H), 2.04 - 1.95 (m, 2H), 1.94 - 1.87 (m, 1H), 1.86 - 1.80 (m, 2H), 1.64 (br t, J = 6.2 Hz, 2H), 1.13 (s, 6H), 1.04 - 0.94 (m, 2H), 0.01 (s, 9H), MS (LC / MS) m / z Actual value 890.3, Predicted value 890.3 [M+H].

[0265] [3-[5-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-6-(4,4-dimethylcyclohexen-1-yl)-2-pyridyl]-3,4,6,7-tetraduterio-5-(trifluoromethylsulfonyloxymethyl)-8-oxabicyclo[3.2.1]octan-1-yl]methyltrifluoromethanesulfonate (126, 200 mg, 224.72 μmol, 1 eq) was dissolved in THF (3 mL) and TBAF (1 M, 1.12 mL, 5 eq) was added. The mixture was stirred at 40 °C for 2 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 1.046 minutes ([M+H]=630.5) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with dimethyl phosphate (15 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 4g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 40 mL / min) to obtain 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,3,6,7-tetraduterio-1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octan-3-yl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (127 mg, 100 mg, 158.77 μmol, yield 70.7%) as a yellow solid, which was then used directly. MS (LC / MS) m / z measured value 630.5, predicted value 630.4 [M+H].

[0266] 4-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,3,6,7-tetraduterio-1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octan-3-yl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (127, 100 mg, 158.77 μmol, 1 eq) was dissolved in DCM (3 mL) and TFA (1 mL) was added. The mixture was stirred at 25°C for 2 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 0.505 minutes ([M+H]=500.4) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5μm, mobile phase: [H2O(0.1%TFA)-ACN], 35%~60% B gradient over 8.0 minutes) to obtain the title compound 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[2,3,6,7-tetraduterio-1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octan-3-yl]-3-pyridyl]-1H-imidazole-2-carboxamide (A-18, 32.5 mg, 65.05 μmol, yield 41.0%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, 298 K) δ (ppm) = 14.28 (br s, 1H), 10.06 (s, 1H), 8.33 (s, 1H), 8.16 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.4 Hz, 1H), 5.89 (br s, 1H), 4.53 - 4.42 (m, 2H), 4.41 - 4.29 (m, 2H), 2.40 (br s, 2H), 1.91 (br d, J = 9.2 Hz, 4H), 1.82 - 1.75 (m, 1H), 1.72 - 1.66 (m, 2H), 1.48 (br t, J = 6.4 Hz, 2H), 0.97 (s, 6H), MS (LC / MS) m / z. Measured value 500.4, predicted value 500.3 [M+H].

[0267] Example 18 N-[4-[1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-5-cyano-1H-imidazole-2-carboxamide B-1 [ka] 4-Bromo-2-iodoaniline (128 g, 20 g, 67.13 mmol, 1 eq) and 2-(4,4-dimethylcyclohexen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (INT-1, 23.78 g, 100.70 mmol, 1.5 eq) were dissolved in toluene (200 mL) and EtOH (100 mL). Na2CO3 (2 M, 268.53 mL, 8 eq) and Pd(PPh3)4 (3.88 g, 3.36 mmol, 0.05 eq) were added to these solutions. The mixture was heated and stirred at 80°C for 12 hours under N2. The reaction was monitored by TLC (Pet.Et.: siRNA = 1:1) until completion was indicated. The reaction mixture was diluted with H2O (100 mL) and extracted with siRNA (100 mL x 3). The organic layers were combined, washed with brine (100 mL), dried on anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 250 × 70 mm × 10 μm, mobile phase: [water (NH4HCO3)-ACN], B%: 60%~90% gradient, 18 min) to obtain 4-bromo-2-(4,4-dimethylcyclohexen-1-yl)aniline (129, 10 g, 35.69 mmol, yield 53.2%) as a white solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0268] To a solution of 4-bromo-2-(4,4-dimethylcyclohexen-1-yl)aniline (129 g, 10.71 mmol, 1 eq) in DMF (15 mL), [4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]oxypotassium (INT-2, 5.89 g, 19.27 mmol, 1.8 eq), PyBroP (7.49 g, 16.06 mmol, 1.5 eq), and DIEA (4.15 g, 32.12 mmol, 5.59 mL, 3 eq) were added. The mixture was stirred at 25°C for 12 hours. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 5 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with water (50 mL) and extracted with Depositphotos (50 mL x 2). The organic layers were combined, washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, 40 g SEPAFLASH® silica flash column, eluent: 0-50% Pet.Et.: siRNA gradient, flow rate 80 mL / min) to obtain N-[4-bromo-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (130, 3.7 g, 6.99 mmol, yield 65.3%) as a yellow oil, which was then used as is. 1 H NMR (400 MHz, CDCl3) δ (ppm) = 9.73 (s, 1H), 8.30 (d, J = 8.9 Hz, 1H), 7.77 (s, 1H), 7.40 (dd, J = 2.4, 8.8 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1H), 5.94 (s, 2H), 5.79 (td, J = 1.9, 3.6 Hz, 1H), 3.70 - 3.62 (m, 2H), 2.30 - 2.25 (m, 2H), 2.14 - 2.08 (m, 2H), 1.59 (t, J = 6.3 Hz, 2H), 1.11 (s, 6H), 0.98 (s, 2H), 0.03 - 0.00 (m, 9H).

[0269] tert-butyl-[[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-oxabicyclo[3.2.1]octa-2,6-dien-1-yl]methoxy]dimethylsilane (INT-4, 2.96g, 5.67 mmol, 1eq) in a solution of dioxane (40mL) and H2O (4mL). N-[4-bromo-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (130 mg, 3 g, 5.67 mmol, 1 eq), K2CO3 (2.35 g, 17.00 mmol, 3 eq), and Pd(dppf)Cl2 (414.53 mg, 566.53 μmol, 0.1 eq) were added. The mixture was heated and stirred at 100°C for 12 hours. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 5 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with water (20 mL) and extracted with Depositphotos (30 mL x 2). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 40g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 60 mL / min) to obtain N-[4-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (131, 1.7g, 2.01 mmol, yield 35.5%) as a yellow oil, which was then used as is. 1H NMR (400 MHz, CDCl3) δ (ppm) = 9.77 (s, 1H), 8.33 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 1.0 Hz, 1H), 7.18 (s, 1H), 6.60 (s, 1H), 6.43 (d, J = 5.8 Hz, 1H), 5.96 (s, 2H), 5.92 (d, J = 5.8 Hz, 1H), 5.76 (br s, 1H), 5.33 - 5.28 (m, 1H), 3.91 - 3.83 (m, 4H), 3.69 - 3.64 (m, 2H), 2.75 (br d, J = 17.1 Hz, 1H), 2.28 (br s, 2H), 2.22 - 2.18 (m, 1H), 2.10 (br s, 2H), 1.44 (s, 5H), 1.11 (s, 6H), 0.95 - 0.92 (m, 18H), 0.11 (s, 11H), 0.02 - -0.01 (m, 9H).

[0270] N-[4-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (131, 1.7g, 2.01 mmol, 1 eq) was dissolved in THF (30 mL) and TBAF·3H2O (3.17 g, 10.06 mmol, 5 eq) was added. The mixture was stirred at 25°C for 3 hours. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 1.287 minutes ([M+H]=617.3) until the starting material was completely consumed. The reaction mixture was diluted with water (30 mL) and extracted with dimethyl phosphate (20 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (neutral conditions) using a Waters Xbridge C18 column (150 × 50 mm × 10 μm), mobile phase [H2O (10 mM NH4HCO3)-ACN], over 8.0 minutes (70% to 98% B gradient), to obtain N-[4-[1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (132, 400 mg, 648.49 μmol, yield 32.3%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 9.77 (s, 1H), 8.34 (d, J = 8.6 Hz, 1H), 7.76 (s, 1H), 7.29 (dd, J = 2.3, 8.8 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H), 6.44 (s, 1H), 6.40 (d, J = 5.9 Hz, 1H), 5.95 (s, 2H), 5.94 (d, J = 5.9 Hz, 1H), 5.76 (br s, 1H), 4.03 - 3.85 (m, 4H), 3.70 - 3.62 (m, 2H), 2.88 (dd, J = 1.8, 17.5 Hz, 1H), 2.28 (br d, J = 1.9 Hz, 2H), 2.15 (dd, J = 1.4, 17.4 Hz, 1H), 2.10 (br d, J = 3.0 Hz, 2H), 1.60 (t, J = 6.3 Hz, 2H), 1.12 (s, 6H), 1.01 - 0.94 (m, 2H), 0.01 (s, 9H), MS (LC / MS) m / z actual value 617.3, predicted value 617.3 [M+H].

[0271] To a 5 mL solution of N-[4-[1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (132, 200 mg, 324.24 μmol, 1 eq) in DCM, pyridine (128.24 mg, 1.62 mmol, 130.86 μL, 5 eq) and trifluoromethylsulfonyl trifluoromethanesulfonate (274.45 mg, 972.73 μmol, 160.49 μL, 3 eq) were added. The mixture was stirred at 25°C for 4 hours. The reaction was monitored by TLC (Pet.Et. / siRNA=3 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with dimethyl (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 4g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 60 mL / min) to obtain [3-[4-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-3-(4,4-dimethylcyclohexen-1-yl)phenyl]-5-(trifluoromethylsulfonyloxymethyl)-8-oxabicyclo[3.2.1]octa-3,6-dien-1-yl]methyltrifluoromethanesulfonate (133, 200 mg, 227.03 μmol, yield 70.0%) as a yellow solid, which was then used as is. 1H NMR (400 MHz, CDCl3) δ (ppm) = 9.79 (s, 1H), 8.38 (d, J = 8.7 Hz, 1H), 7.77 (s, 1H), 7.25 (dd, J = 2.1, 8.7 Hz, 1H), 7.12 (d, J = 1.9 Hz, 1H), 6.49 (d, J = 5.8 Hz, 1H), 6.39 (s, 1H), 6.00 (d, J = 5.9 Hz, 1H), 5.95 (s, 2H), 5.77 (br s, 1H), 4.84 - 4.78 (m, 1H), 4.77 - 4.71 (m, 3H), 3.71 - 3.63 (m, 2H), 2.90 - 2.81 (m, 1H), 2.32 - 2.21 (m, 3H), 2.11 (br s, 2H), 1.61 (t, J = 6.3 Hz, 2H), 1.13 (s, 6H), 1.03 - 0.94 (m, 2H), 0.01 (s, 9H).

[0272] [3-[4-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-3-(4,4-dimethylcyclohexen-1-yl)phenyl]-5-(trifluoromethylsulfonyloxymethyl)-8-oxabicyclo[3.2.1]octa-3,6-dien-1-yl]methyltrifluoromethanesulfonate (133, 200 mg, 227.03 μmol, 1 eq) was dissolved in THF (8 mL) and TBAF (1 M, 1.14 mL, 5 eq) was added. The mixture was stirred at 40 °C for 4 hours. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 0.741 minutes ([M+H]=621.3) until the starting material was completely consumed. The reaction mixture was diluted with water (30 mL) and extracted with dimethyl phosphate (30 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 4g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 60 mL / min) to obtain N-[4-[1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (134 mg, 100 mg, 161.08 μmol, yield 71.0%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 9.78 (s, 1H), 8.35 (d, J = 8.5 Hz, 1H), 7.76 (s, 1H), 7.30 (br d, J = 1.8 Hz, 1H), 7.18 (d, J = 1.9 Hz, 1H), 6.51 (s, 1H), 6.47 (d, J = 5.8 Hz, 1H), 6.00 - 5.94 (m, 3H), 5.76 (br s, 1H), 4.82 - 4.60 (m, 4H), 3.70 - 3.63 (m, 2H), 2.91 (d, J = 17.0 Hz, 1H), 2.28 (br s, 2H), 2.21 (d, J = 17.5 Hz, 1H), 2.11 (br d, J = 2.3 Hz, 2H), 1.60 (t, J = 6.3 Hz, 2H), 1.12 (s, 7H), 1.02 - 0.94 (m, 2H), 0.01 (s, 9H), MS (LC / MS) m / z actual value 621.3, predicted value 621.3 [M+H].

[0273] To a solution of N-[4-[1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (134, 100 mg, 161.08 μmol, 1 eq) in DCM (5 mL), TFA (3 mL) was added. The mixture was stirred at 25 °C for 1 hour. The reaction was analyzed by LC / MS (R t The reaction mixture was monitored for 0.615 minutes ([M+H]=491.3) until it indicated that the reaction was completely consumed. The reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×30mm×5μm, mobile phase: [water (TFA)-ACN], B%: 40%~75% gradient, 8 min) to obtain the title compound N-[4-[1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-5-cyano-1H-imidazole-2-carboxamide (B-1, 35.2 mg, 71.76 μmol, yield 44.6%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6, 298 K) δ (ppm) = 14.29 (br s, 1H), 9.71 (s, 1H), 8.33 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 2.0, 8.5 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.63 (s, 1H), 6.49 (d, J = 5.6 Hz, 1H), 6.00 (dd, J = 1.2, 5.7 Hz, 1H), 5.69 (br s, 1H), 4.85 - 4.58 (m, 4H), 2.72 (dd, J m / z Actual value 491.3, predicted value 491.2 [M+H].

[0274] Example 19 5-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-4-[2,3,6,7-tetraduterio-1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octan-3-yl]phenyl]-1H-imidazole-2-carboxamide B-2 [ka] To a solution of 4-bromo-2-(4,4-dimethylcyclohexen-1-yl)aniline (129, 16 g, 57.10 mmol, 1 eq) in dioxane (160 mL) and H2O (40 mL), Boc2O (16.20 g, 74.23 mmol, 17.05 mL, 1.3 eq) and K2CO3 (15.78 g, 114.20 mmol, 2 eq) were added under N2 at 20°C. The resulting mixture was heated and stirred at 60°C for 12 hours. The reaction was monitored by TLC (Pet.Et.: SiO=10:1) until the starting materials were completely consumed. The reaction mixture was poured into water (50 mL) and extracted with SiO (100 mL × 3). The organic layers were combined, washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / HCl = 50 / 1 to 10 / 1 gradient) to obtain N-[4-bromo-2-(4,4-dimethylcyclohexen-1-yl)phenyl]carbamate tert-butyl (135, 18 g, 47.33 mmol, yield 82.9%) as a white solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0275] To a 10 mL solution of MTBE (1 mL) of tert-butyl-[[5-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-3-duteriooxy-8-oxabicyclo[3.2.1]octan-1-yl]methoxy]dimethyl-silane (116, 582.22 mg, 1.38 mmol, 1.75 eq) and NHC-1 (498.83 mg, 1.26 mmol, 1.6 eq), a 1 mL solution of MTBE (1 mL) of pyridine (99.83 mg, 1.26 mmol, 101.87 μL, 1.6 eq) was added dropwise over 5 minutes at 25°C. After 10 minutes, the mixture was filtered, and the filtrate contained N-[4-bromo-2-(4,4-dimethylcyclohexen-1-yl)phenyl]carbamate tert-butyl (135, 300 mg, 788.81 μmol, 1 eq), bis[2-(2-pyridyl)phenyl]iridium(1+); 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine; hexafluorophosphate (10.81 mg, 11.83 μmol, 0.015 eq), dibromonyl Kell; 1,2-dimethoxyethane (12.17 mg, 39.44 μmol, 0.05 eq), quinuclidine (153.49 mg, 1.38 mmol, 1.75 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (15.88 mg, 59.16 μmol, 0.075 eq), and isoindoline-1,3-dione (26.11 mg, 177.48 μmol, 0.225 eq) were added to a DMA (10 mL) solution under N2. The mixture was stirred at 25°C for 3 hours under blue LED illumination. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 5 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue.The residue was purified by preparative HPLC (column: Welch Xltimate C4 100×30×10 μm, mobile phase: [H2O (10 mM NH4HCO3)-ACN], 90%~100% B gradient over 10.0 minutes) to obtain N-[4-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-8-oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)phenyl]carbamate tert-butyl (136, 1.3 g, 1.85 mmol, yield 33.4%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 7.88 (br d, J = 8.8 Hz, 1H), 7.12 (dd, J = 2.0, 8.5 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.69 (s, 1H), 5.68 - 5.55 (m, 1H), 3.65 - 3.58 (m, 4H), 2.22 (br d, J = 2.0 Hz, 2H), 2.01 - 1.97 (m, 2H), 1.83 - 1.76 (m, 3H), 1.74 - 1.73 (m, 1H), 1.62 (br d, J = 13.3 Hz, 1H), 1.55 (br d, J = 2.0 Hz, 2H), 1.50 (s, 9H), 1.03 (s, 6H), 0.88 (s, 18H), 0.04 (d, J = 1.5 Hz, 12H).

[0276] To a 15 mL solution of N-[4-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-8-oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)phenyl]carbamate tert-butyl (136, 1.3 g, 1.85 mmol, 1 eq) in DCM (15 mL), ZnBr2 (4.16 g, 18.46 mmol, 923.89 μL, 10 eq) was added. The mixture was stirred at 25 °C for 12 hours. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 3.860 minutes ([M+H]=604.5) until the starting material was completely consumed. The reaction mixture was filtered and concentrated under reduced pressure, and without further purification, the residue was obtained as a yellow solid: 4-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-8-oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)aniline (137, 1.3g, 1.72 mmol, yield 93.3%, purity 80%), which was used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 6.95 (dd, J = 2.1, 8.1 Hz, 1H), 6.89 (d, J = 2.0 Hz, 1H), 6.73 - 6.66 (m, 1H), 5.70 (br s, 1H), 3.65 - 3.58 (m, 4H), 2.33 - 2.22 (m, 2H), 1.98 (br d, J = 3.3 Hz, 2H), 1.54 - 1.51 (m, 2H), 1.01 (s, 6H), 0.90 - 0.88 (m, 18H), 0.06 - 0.03 (m, 12H), MS (LC / MS) m / z actual value 604.5, predicted value 604.5 [M+H].

[0277] To a 20 mL solution of 4-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-8-oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)aniline (137 mg, 1.3 g, 2.15 mmol, 1 eq) in DMF (20 mL), [4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]oxypotassium (INT-2, 1.31 g, 4.30 mmol, 2 eq), DIEA (834.42 mg, 6.46 mmol, 1.12 mL, 3 eq), and PyBroP (1.50 g, 3.23 mmol, 1.5 eq) were added. The mixture was stirred at 25°C for 12 hours. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 5 / 1) until the starting materials were completely consumed. The reaction mixture was diluted with water (20 mL) and extracted with Depositphotos (20 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 12g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 80 mL / min) to obtain N-[4-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-8-oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (138, 1.1g, 1.29 mmol, yield 59.9%) as a yellow solid, which was then used as is. 1H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 9.73 (s, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.18 (dd, J = 1.9, 8.5 Hz, 1H), 7.08 (d, J = 1.9 Hz, 1H), 5.96 (s, 2H), 5.76 (br s, 1H), 3.69 - 3.61 (m, 6H), 2.30 (br d, J = 1.3 Hz, 2H), 2.10 (br s, 2H), 1.82 (s, 2H), 1.77 (s, 2H), 1.65 (br d, J = 12.9 Hz, 1H), 1.59 (t, J = 6.3 Hz, 2H), 1.11 (s, 6H), 1.00 - 0.95 (m, 2H), 0.89 (s, 18H), 0.05 (d, J = 1.1 Hz, 12H), 0.01 (s, 9H).

[0278] To a solution of N-[4-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-8-oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (138, 200 mg, 234.36 μmol, 1 eq) in DCM (3 mL), TFA (2 mL) was added. The mixture was stirred at 25 °C for 2 hours. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 1.959 minutes ([M+H]=495.3) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with DCM (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5μm, mobile phase: [H2O(0.1%TFA)-ACN], 15%~50% B gradient over 7.0 minutes) to obtain the title compound 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-4-[2,3,6,7-tetraduterio-1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octan-3-yl]phenyl]phenyl]-1H-imidazole-2-carboxamide (B-2, 35.3 mg, 71.37 μmol, yield 30.5%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6, 298 K) δ (ppm) = 14.24 (s, 1H), 9.71 (s, 1H), 8.31 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 2.0, 8.3 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 5.65 (br s, 1H), 4.59 (t, J = 5.8 Hz, 2H), 3.44 - 3.34 (m, 4H), 2.24 (br s, 2H), 1.95 (br s, 2H), 1.81 - 1.71 (m, 2H), 1.69 - 1.60 (m, 2H), 1.53 (br d, J = 12.9 Hz, 1H), 1.48 (t, J = 6.4 Hz, 2H), 1.00 (s, 6H), MS (LC / MS) m / z actual value 495.3, predicted value 495.3 [M+H].

[0279] Example 20 5-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-4-[2,3,6,7-tetraduterio-1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octan-3-yl]phenyl]-1H-imidazole-2-carboxamide B-3 [ka] N-[4-[1,5-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3,6,7-tetraduterio-8-oxabicyclo[3.2.1]octan-3-yl]-2-(4,4-dimethylcyclohexen-1-yl)phenyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (138, 900 mg, 1.05 mmol, 1 eq) was dissolved in THF (15 mL) and TBAF·3H2O (998.22 mg, 3.16 mmol, 3 eq) was added. The mixture was stirred at 25°C for 2 hours. The reaction was analyzed by LC / MS (R t The mixture was monitored for 0.641 minutes ([M+Na]=647.6) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with butyl (10 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 4g SEPAFLASH® silica flash column, eluent: 0-100% Pet.Et.: HCl, flow rate 80 mL / min) to obtain 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-4-[2,3,6,7-tetraduterio-1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octan-3-yl]phenyl]phenyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (139, 440 mg, 704.14 μmol, yield 66.8%) as a yellow solid, which was then used as is. 1H NMR (400 MHz, CDCl3, 297 K) δ (ppm) = 9.72 (s, 1H), 8.30 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.17 (dd, J = 2.2, 8.5 Hz, 1H), 7.07 (d, J = 2.1 Hz, 1H), 5.96 (s, 2H), 5.75 (br s, 1H), 4.13 (q, J = 7.1 Hz, 4H), 2.32 - 2.24 (m, 2H), 2.10 (br d, J = 2.9 Hz, 2H), 1.85 - 1.80 (m, 2H), 1.80 - 1.75 (m, 2H), 1.69 - 1.64 (m, 3H), 1.59 (t, J = 6.3 Hz, 2H), 1.11 (s, 6H), 1.00 - 0.95 (m, 2H), 0.04 - -0.02 (m, 9H), MS (LC / MS) m / z actual value 647.6, predicted value 647.4 [M+Na].

[0280] To a 15 mL solution of 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-4-[2,3,6,7-tetraduterio-1,5-bis(hydroxymethyl)-8-oxabicyclo[3.2.1]octan-3-yl]phenyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (139, 440 mg, 704.14 μmol, 1 eq) in DCM (15 mL), pyridine (556.97 mg, 7.04 mmol, 568.34 μL, 10 eqs) and Tf2O (993.33 mg, 3.52 mmol, 580.89 μL, 5 eqs) were added. The mixture was stirred at 25°C for 2 hours. The reaction was analyzed by LC / MS (R tThe mixture was monitored for 0.774 minutes ([M+Na]=911.4) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with SiO2 (15 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by flash silica gel chromatography (ISCO®, using a 4g SEPAFLASH® silica flash column, eluent: 0-20% Pet.Et.: siRNA gradient, flow rate 40 mL / min) to obtain [3-[4-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-3-(4,4-dimethylcyclohexen-1-yl)phenyl]-3,4,6,7-tetraduterio-5-(trifluoromethylsulfonyloxymethyl)-8-oxabicyclo[3.2.1]octan-1-yl]methyltrifluoromethanesulfonate (140, 380 mg, 427.45 μmol, yield 60.7%) as a yellow solid, which was then used as is. 1 H NMR (400 MHz, CDCl3, 298 K) δ (ppm) = 9.74 (s, 1H), 8.34 (d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.15 (dd, J = 1.9, 8.6 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 5.96 (s, 2H), 5.77 (br s, 1H), 4.57 - 4.53 (m, 2H), 4.48 - 4.44 (m, 2H), 3.71 - 3.61 (m, 2H), 2.29 (br s, 2H), 2.11 (br d, J = 2.5 Hz, 2H), 2.02 (s, 2H), 1.87 - 1.78 (m, 2H), 1.76 (s, 1H), 1.60 (t, J = 6.2 Hz, 2H), 1.12 (s, 6H), 1.02 - 0.95 (m, 2H), 0.01 (s, 9H), MS (LC / MS) m / z actual measurement 911.4, predicted value 911.3 [M+Na].

[0281] [3-[4-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-3-(4,4-dimethylcyclohexen-1-yl)phenyl]-3,4,6,7-tetraduterio-5-(trifluoromethylsulfonyloxymethyl)-8-oxabicyclo[3.2.1]octan-1-yl]methyltrifluoromethanesulfonate (140, 380 mg, 427.45 μmol, 1 eq) was dissolved in THF (10 mL) and TBAF (1 M, 2.14 mL, 5 eq) was added. The mixture was heated and stirred at 40 °C for 12 hours. The reaction was monitored by LC / MS (Rt = 2.462 min, [M + H] = 499.3) until the starting material was completely consumed. The reaction mixture was diluted with water (10 mL) and extracted with DCM (15 mL x 2). The organic layers were combined, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100 × 40 mm × 5 μm, mobile phase: [H2O (0.1% TFA)-ACN], 50%~100% B gradient over 7.0 minutes) to obtain the title compound 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-4-[2,3,6,7-tetraduterio-1,5-bis(fluoromethyl)-8-oxabicyclo[3.2.1]octan-3-yl]phenyl]phenyl]-1H-imidazole-2-carboxamide (B-3, 75.5 mg, 123.24 μmol, yield 28.8%) as the TFA salt, as a yellow solid. 1H NMR (400 MHz, DMSO-d6, 298 K) δ (ppm) = 14.25 (s, 1H), 9.72 (s, 1H), 8.32 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.21 (dd, J = 2.0, 8.4 Hz, 1H), 7.15 (d, J = 2.0 Hz, 1H), 5.66 (br s, 1H), 4.52 - 4.40 (m, 2H), 4.40 - 4.28 (m, 2H), 2.25 (br s, 2H), 1.95 (br d, J = 1.6 Hz, 2H), 1.92 - 1.87 (m, 2H), 1.70 - 1.60 (m, 3H), 1.48 (t, J = 6.4 Hz, 2H), 1.00 (s, 6H), MS (LC / MS) m / z actual value 499.3, predicted value 499.3 [M+H].

[0282] Example 21 3-[4-[(5-cyano-1H-imidazole-2-carbonyl)amino]-3-(1,2-diduterio-4,4-dimethylcyclohexyl)phenyl]-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-ene-8-carboxylate methyl B-4 [ka] To a solution of tert-butyl N-[4-bromo-2-(4,4-dimethylcyclohexen-1-yl)phenyl]carbamate (135, 0.5 g, 1.31 mmol, 1 eq) and Pin2B2 (4, 400.62 mg, 1.58 mmol, 1.2 eq) in dioxane (10 mL), KOAc (322.56 mg, 3.29 mmol, 2.5 eq) and Pd(dppf)Cl2 (96.20 mg, 131.47 μmol, 0.1 eq) were added. The mixture was heated and stirred at 90°C for 12 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et.: SiO=5:1) until completion was indicated. The reaction mixture was quenched with H2O (10 mL) and extracted with SiO (10 mL × 3). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 1 / 0~1 / 1 gradient) to obtain N-[2-(4,4-dimethylcyclohexen-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate tert-butyl (141, 0.4 g, 935.93 μmol, yield 71.2%) as a yellow solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0283] To a solution of N-[2-(4,4-dimethylcyclohexen-1-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate tert-butyl (141 mg, 2 g, 4.68 mmol, 1 eq) in MeOD (3 mL), Pd / C (400.00 mg, 375.87 μmol, 10% purity, 0.08 eq) was added. The mixture was stirred at 30°C for 12 hours under a D2 (15 psi) atmosphere. The reaction was monitored by TLC (Pet.Et.: Â=5:1) until completion was indicated. The reaction mixture was filtered and concentrated under reduced pressure, and phenyl was removed to obtain the residue. Without further purification, N-[2-(1,2-diduterio-4,4-dimethylcyclohexyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate tert-butyl (142, 1.8g, 4.17 mmol, yield 89.2%) was obtained as a yellow oil. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0284] N-[2-(1,2-diduterio-4,4-dimethyl-cyclohexyloxy)-8-azabicyclo[3.2.1]octa-2-ene-8-carboxylate methyl (INT-6, 1.3g, 3.76 mmol, 1eq) is dissolved in H2O (2mL) and 1,4-dioxane (20mL) and N-[2-(1,2-diduterio-4,4-dimethyl-cyclohexyl The tert-butyl (142, 1.79 g, 4.14 mmol, 1.1 eq) sil-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate, K2CO3 (1.30 g, 9.41 mmol, 2.5 eq), and Pd(dppf)Cl2 (275.45 mg, 376.45 μmol, 0.1 eq) were added at 20°C. The mixture was then heated and stirred at 80°C for 12 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et.: SiO=1:1) until completion was indicated. The reaction mixture was quenched with H2O (10 mL) and extracted with SiO (10 mL x 3). The organic layers were combined, washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, Pet.Et.: HCl=1 / 0~0 / 1) to obtain 3-[4-(tert-butoxycarbonylamino)-3-(1,2-diduterio-4,4-dimethylcyclohexyl)phenyl]-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-ene-8-carboxylate methyl (143, 1.4g, 2.80 mmol, yield 74.3%) as a white solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0285] ZnBr2 (5.04 g, 22.37 mmol, 1.12 mL, 8 eq) was added to a solution of 3-[4-(tert-butoxycarbonylamino)-3-(1,2-diduterio-4,4-dimethylcyclohexyl)phenyl]-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-ene-8-carboxylate methyl (143, 1.4 g, 2.80 mmol, 1 eq) in DCM (15 mL). The mixture was stirred at 20°C for 12 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et.: siRNA = 1:1) until completion was indicated. The reaction mixture was quenched with H2O (15 mL) and extracted with DCM (15 mL x 3). The organic layers were combined, washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. Without further purification, 3-[4-amino-3-(1,2-diduterio-4,4-dimethylcyclohexyl)phenyl]-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-ene-8-carboxylate methyl (144, 1 g, 2.50 mmol, yield 89.3%) was obtained as a white solid. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0286] To a solution of 3-[4-amino-3-(1,2-diduterio-4,4-dimethylcyclohexyl)phenyl]-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-ene-8-carboxylate methyl (144, 1g, 2.50 mmol, 1eq) and 4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxylic acid (INT-2, 1.53g, 4.99 mmol, 2eq) in DMF (5 mL), PyBroP (1.75 g, 3.74 mmol, 1.5eq) and DIEA (967.88 mg, 7.49 mmol, 1.30 mL, 3eq) were added. The mixture was stirred under N2 at 20°C for 12 hours. The reaction was monitored by TLC (Pet.Et.: Depositphotos = 5:1) until completion was indicated. The reaction mixture was quenched with H2O (20 mL) and extracted with Depositphotos (10 mL x 3). The organic layers were combined, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 1 / 0~10 / 1 gradient) to obtain 3-[4-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-3-(1,2-diduterio-4,4-dimethyl-cyclohexyl)phenyl]-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-ene-8-carboxylate methyl (145, 1.2g, 1.85 mmol, yield 74.0%) as a yellow oil. 1 The 1H NMR spectrum matched the predicted structure, and the product was used as is.

[0287] 3-[4-[[4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]amino]-3-(1,2-diduterio-4,4-dimethylcyclohexyl)phenyl]-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-ene-8-carboxylate methyl (145, 1.2 g, 1.85 mmol, 1 eq) was dissolved in THF (10 mL) and TBAF (1 M, 2.77 mL, 1.5 eq) was added. The mixture was stirred at 70 °C for 12 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et.: siRNA = 3:1) until completion was indicated. The reaction mixture was quenched with H2O (5 mL) and extracted with DCM (5 mL x 3). The organic layers were combined, washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 250 × 50 mm × 10 μm, mobile phase: [H2O (10 mM NH4HCO3)-ACN], 50%~80% B gradient over 10.0 min) to obtain the title compound 3-[4-[(5-cyano-1H-imidazole-2-carbonyl)amino]-3-(1,2-diduterio-4,4-dimethylcyclohexyl)phenyl]-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-ene-8-carboxylate (B-4, 0.58 g, 1.12 mmol, yield 60.5%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ = 14.37 - 13.99 (m, 1H), 10.26 (s, 1H), 8.32 (s, 1H), 7.35 (s, 1H), 7.26 (s, 2H), 6.42 (s, 1H), 3.52 (s, 3H), 2.90 (br d, J = 17.0 Hz, 1H), 2.33 (br d, J = 17.0 Hz, 1H), 1.93 - 1.76 (m, 3H), 1.63 (s, 6H), 1.60 - 1.50 (m, 3H), 1.47 - 1.15 (m, 3H), 1.00 (s, 3H), 0.91 (s, 3H), MS (LC / MS) m / z: Measured value 520.3, Predicted value 520.3 [M+H].

[0288] Examples 22 and 23 3-[4-[(5-cyano-1H-imidazole-2-carbonyl)amino]-3-(1,2-diduterio-4,4-dimethylcyclohexyl)phenyl]-6,7-diduterio-(s)-3-hydroxy-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate methyl isomer 1 B-5A, 3-[4-[(5-cyano-1H-imidazole-2-carbonyl)amino]-3-(1,2-diduterio-4,4-dimethylcyclohexyl)phenyl]-6,7-diduterio-(s)-3-hydroxy-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate methyl isomer 2 B-5B (Absolute stereochemistry is shown to distinguish the isomers, but is not definitive) [ka] To a solution of 3-[4-[(5-cyano-1H-imidazole-2-carbonyl)amino]-3-(1,2-diduterio-4,4-dimethylcyclohexyl)phenyl]-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-ene-8-carboxylate methyl (B-4, 570 mg, 1.10 mmol, 1 eq) in DCM (4 mL) and i-PrOH (40 mL), tris[(Z)-1-tert-butyl-4,4-dimethyl-3-oxo-penta-1-enoxy]manganese (66.33 mg, 109.69 μmol, 0.1 eq) and phenylsilane (237.38 mg, 2.19 mmol, 270.67 μL, 2 eq) was added at 20°C. The mixture was stirred at 20°C for 12 hours under an O2 atmosphere (15 psi). The reaction was monitored by LC / MS until completion was indicated. The reaction mixture was quenched with H2O (10 mL) and extracted with RINKAN (10 mL x 3). The organic layers were combined, washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by (SiO2, Pet.Et.: SiO2 = 1 / 0 to 0 / 1 gradient), then further purified by preparative HPLC (column: Waters Xbridge C18 150 × 50 mm × 10 μm, mobile phase: [H2O (10 mM NH4HCO3)-ACN], 40% to 70% B gradient over 8.0 minutes), and the title compound 3-[4-[(5-cyano-1H-imidazole-2-carbonyl)amino]-3-(1,2-diduterio-4,4-dimethylcyclohexyl)phenyl]-6,7-diduterio-3-hydroxy-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate methyl (B-5A, 58.3 mg, 108.43 μmol, yield 9.9%) was obtained as a white solid ( 1H NMR (400 MHz, DMSO-d6) δ = 14.15 (br d, J = 4.5 Hz, 1H), 10.25 (s, 1H), 8.30 (s, 1H), 7.26 (s, 1H), 7.21 - 7.10 (m, 2H), 5.07 (s, 1H), 3.64 (s, 3H), 2.36 - 2.25 (m, 2H), 2.15 (br d, J = 14.4 Hz, 2H), 1.66 (br d, J = 14.4 Hz, 2H), 1.61 - 1.50 (m, 3H), 1.43 (s, 8H), 1.31 - 1.13 (m, 2H), 0.98 (s, (3H), 0.90 (s, 3H), MS (LC / MS) m / z Measured value 531.4, Predicted value 538.3 [M+H].) and 3-[4-[(5-cyano-1H-imidazole-2-carbonyl)amino]-3-(1,2-diduterio-4,4-dimethylcyclohexyl)phenyl]-6,7-diduterio-3-hydroxy-1,5-dimethyl-8-azabicyclo[3.2.1]octane-8-carboxylate methyl (B-5B, 10.1 mg, 18.78 μmol, yield 1.7%) as a white solid ( 1 H NMR (400 MHz, DMSO-d6) δ = 14.39 - 13.74 (m, 1H), 10.21 (s, 1H), 8.31 (s, 1H), 7.55 (s, 1H), 7.45 (br d, J = 8.8 Hz, 1H), 7.27 (d, J = 8.3 Hz, 1H), 4.91 (s, 1H), 3.59 (s, 3H), 2.42 (br d, J = 14.4 Hz, 2H), 2.02 (br d, J = 14.4 Hz, 2H), 1.63 - 1.52 (m, 3H), 1.48 (s, 6H), 1.44 - 1.34 (m, 4H), 1.30 - 1.14 (m, 2H), 0.99 (s, 3H), 0.91 (s, 3H), MS (LC / MS) m / z measured value 531.4, predicted value 538.3 [M+H]).

[0289] Example 24 5-Cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethylcyclohexa-1-enyl)-6-(1,5-dimethyl-8-oxa-bicyclo[3.2.1]octa-2,6-dien-3-yl)-pyridine-3-yl]amide A-19 [ka] To a solution of 2,5-dimethylfuran (146, 5g, 52.01 mmol, 5.52 mL, 1 eq) and 1,1,3-trichloropropan-2-one (16, 25.19g, 156.04 mmol, 3 eq) in 2,2,2-trifluoroethanol (100 mL), TEA (21.05 g, 208.06 mmol, 28.96 mL, 4 eq) was added at 0°C, and the resulting mixture was stirred at 20°C for 12 hours. The reaction was monitored by TLC (Pet.Et.: Â=5:1) until the main desired spot was observed. The reaction mixture was diluted with H2O (150 mL) and extracted with Â(100 mL × 3). The organic layers were combined and dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. Without further purification, 2,4-dichloro-1,5-dimethyl-8-oxabicyclo[3.2.1]octa-6-en-3-one (147, 16 g) was obtained as a crude yellow solid. 1 ¹H NMR (400 MHz, CDCl3) δ = NMR spectrum is not integrated or assigned. MS (LC / MS) m / z. Measured mass is not immediately observable in the provided spectrum; predicted value 221.1 [M+H].

[0290] To a solution of 2,4-dichloro-1,5-dimethyl-8-oxabicyclo[3.2.1]octa-6-en-3-one (147, 16 g, 72.37 mmol, 1 eq) in MeOH (250 mL), CuCl (3.58 g, 36.19 mmol, 865.31 μL, 0.5 eq) and NH4Cl (27.10 g, 506.60 mmol, 7 eq) were added at 0°C, followed by Zn (28.39 g, 434.23 mmol, 6 eq) in several portions. The resulting mixture was heated and stirred at 25°C for 12 hours. The reaction was monitored by TLC (Pet.Et. / siRNA=5 / 1) until the starting materials were completely consumed. The reaction mixture was filtered through a CELITE® pad. The filtrate was diluted with water (200 mL) and extracted with ethyl acetate (150 mL x 3). The organic layers were combined, washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / ethyl acetate = 50 / 1 to 20 / 1) to obtain 1,5-dimethyl-8-oxabicyclo[3.2.1]octa-6-en-3-one (148, 7.5 g, 49.28 mmol, yield 68.1%) as a yellow oil. 1 H NMR (400 MHz, CDCl3, 299 K) δ (ppm) = 5.96 (s, 2H), 2.49 - 2.44 (m, 2H), 2.39 - 2.33 (m, 2H), 1.50 (s, 6H).

[0291] To a 10 mL solution of THF containing 1,5-dimethyl-8-oxabicyclo[3.2.1]octa-6-en-3-one (148, 3 g, 19.71 mmol, 1 eq), the mixture was added at -70°C to a 10 mL solution of THF containing LiHMDS (1 M, 23.65 mL, 1.2 eq). The mixture was heated to 20°C and stirred for a further 0.5 hours. The mixture was cooled again to -78°C, and a 12 mL solution of THF containing 1,1,1-trifluoro-N-(2-pyridyl)-N-(trifluoromethylsulfonyl)methanesulfonamide (8.47 g, 23.65 mmol, 1.2 eq) was added dropwise. The resulting mixture was heated to 25°C and stirred for a further 2 hours. The reaction was monitored by TLC (Pet.Et. / siRNA=5 / 1) until the starting materials were completely consumed. The reaction mixture was poured into NH4Cl (50 mL, aqueous solution) and extracted with siRNA (50 mL x 3). The organic layers were combined, washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 50 / 1~20 / 1) to obtain [1,5-dimethyl-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]trifluoromethanesulfonate (149 g, 5.6 g, 19.70 mmol, yield 99.9%) as a yellow oil. 1 ¹H NMR (400 MHz, CDCl3) δ (ppm) = 6.25 (d, J = 5.6 Hz, 1H), 6.11 (s, 1H), 5.77 (d, J = 5.6 Hz, 1H), 2.63 (dd, J = 1.6, 17.5 Hz, 1H), 2.12 (d, J = 17.5 Hz, 1H), 1.52 (s, 6H). MS (LC / MS) m / z: Measured value 283.2, Predicted value 283.0 [MH].

[0292] To a solution of [1,5-dimethyl-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]trifluoromethanesulfonate (149, 5.6 g, 19.70 mmol, 1 eq) and Pin2B2 (4, 6.00 g, 23.64 mmol, 1.2 eq) in 1,4-dioxane (60 mL), KOAc (4.83 g, 49.25 mmol, 2.5 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (6.00 g, 23.64 mmol, 1.2 eq) and Pd(dppf)Cl2 (720.76 mg, 985.04 μmol, 0.05 eq) were added. The resulting mixture was stirred at 100°C for 12 hours under N2. The reaction was monitored by TLC (Pet.Et. / Depositphotos = 5 / 1) until the starting materials were completely consumed. The reaction mixture was poured into NH4Cl (50 mL, aqueous solution) and extracted with Depositphotos (50 mL x 3). The organic layers were combined, washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / Depositphotos = 50 / 1 to 30 / 1) to obtain 2-[1,5-dimethyl-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (150, 4.5 g, 17.17 mmol, yield 87.1%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ = 6.82 (t, J = 1.9 Hz, 1H), 6.16 (d, J = 5.6 Hz, 1H), 5.67 (d, J = 5.6 Hz, 1H), 2.41 (dd, J = 2.3, 18.6 Hz, 1H), 1.90 (dd, J = 2.0, 18.5 Hz, 1H), 1.43 (s, 6H), 1.25 (s, 12H).

[0293] 2-[1,5-dimethyl-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (150, 148.24 mg, 565.47 μmol, 1.5 eq) and N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilyl eth To a solution of xymethyl)imidazole-2-carboxamide (INT-5, 0.2 g, 376.98 μmol, 1 eq) in 1,4-dioxane (10 mL) and H2O (1 mL), K2CO3 (156.30 mg, 1.13 mmol, 3 eq) and cyclopentyl(diphenyl)phosphan; dichloropalladium; iron (27.58 mg, 37.70 μmol, 0.1 eq) were added. The resulting mixture was stirred at 100°C for 12 hours under N2. The reaction was monitored by TLC (Pet.Et. / HCl=5 / 1) until the starting materials were completely consumed. The reaction mixture was poured into NH4Cl (20 mL, aqueous solution) and extracted with HCl (20 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et. / siRNA = 50 / 1 to 10 / 1) to obtain 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1,5-dimethyl-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)-imidazole-2-carboxamide (151, 0.18 g, 307.27 μmol, yield 81.5%) as a crude yellow solid. 1H NMR (400 MHz, CDCl3) δ = 9.99 (s, 1H), 8.64 (d, J = 8.8 Hz, 1H), 7.76 (s, 1H), 7.26 (s, 2H), 6.94 (s, 1H), 6.22 (d, J = 5.5 Hz, 1H), 5.96 - 5.93 (m, 1H), 5.93 (s, 2H), 5.75 (d, J = 5.6 Hz, 1H), 3.68 - 3.62 (m, 2H), 2.69 (dd, J = 1.8, 18.1 Hz, 1H), 2.49 (br d, J = 1.5 Hz, 2H), 2.39 (dd, J = 1.4, 18.1 Hz, 1H), 2.13 (br d, J = 3.1 Hz, 2H), 1.56 (s, 6H), 1.12 (s, 6H), 1.00 - 0.95 (m, 2H), 0.01 - -0.01 (m, 9H), MS (LC / MS) m / z: Measured value 586.4, Predicted value 586.3 [M+H].

[0294] To a solution of 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1,5-dimethyl-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)-imidazole-2-carboxamide (151 mg, 0.18 g, 307.27 μmol, 1 eq) in DCM (3 mL), TFA (35.04 mg, 307.27 μmol, 22.82 μL, 1 eq) was added. The resulting mixture was stirred at 20°C for 5 hours. The reaction was analyzed by LC-MS (R tThe reaction mixture was monitored for 0.593 min (M+H=456.2) until the starting material was completely consumed and the main desired product was detected. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 100×40mm×5um, mobile phase: [H2O(0.1%TFA)-ACN], 55%~85% B gradient over 8.0 min) to obtain the title compound 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[1,5-dimethyl-8-oxabicyclo[3.2.1]octa-2,6-dien-3-yl]-3-pyridyl]-1H-imidazole-2-carboxamide (A-19, 0.0485 g, 106.46 μmol, yield 34.7%) as a yellow solid. 1 H NMR (400 MHz, MeOH-d4) δ = 8.78 (d, J = 8.9 Hz, 1H), 8.03 (s, 1H), 7.59 (d, J = 8.8 Hz, 1H), 6.97 (s, 1H), 6.30 (d, J = 5.6 Hz, 1H), 6.08 (br s, 1H), 5.85 (d, J = 5.5 Hz, 1H), 2.69 (dd, J = 1.6, 18.1 Hz, 1H), 2.47 (br s, 2H), 2.41 (br d, J = 18.0 Hz, 1H), 2.14 (br s, 2H), 1.64 (t, J = 6.4 Hz, 2H), 1.53 (s, 6H), 1.11 (s, 6H), MS (LC / MS) m / z. Measured value 456.3, predicted value 456.2 [M+H].

[0295] Example 25 5-Cyano-1H-imidazole-2-carboxylic acid [2-(4,4-dimethylcyclohexa-1-enyl)-6-(8-isopropyl-8-aza-bicyclo[3.2.1]octa-3-yl)-pyridine-3-yl]amide A-20 [ka] To a solution of N-[6-(8-azabicyclo[3.2.1]octan-3-yl)-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (80, 0.5 g, 891.58 μmol, 1 eq) in MeOH (5 mL), acetone (1.04 g, 17.83 mmol, 1.31 mL, 20 eq) and NaBH3CN (196.10 mg, 3.12 mmol, 3.5 eq) were added at 20°C for 20 minutes. The mixture was adjusted to pH=7 with acetic acid and stirred. The mixture was further stirred at 20°C for 12 hours under an N2 atmosphere and analyzed by LC / MS (R t The reaction was monitored for 0.543 minutes until [M+H]=603.3) indicated completion. The reaction mixture was quenched with H2O (5 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250 × 70 mm × 15 μm), mobile phase: [H2O (0.1% TFA)-ACN], 45% to 75% B gradient over 20.0 minutes) to obtain 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide hydrochloride (152, 0.25 g, 414.67 μmol, yield 46.5%) as a crude yellow solid. 1H NMR (400 MHz, CDCl3) δ = 9.80 (s, 1H), 9.14 (d, J = 8.8 Hz, 1H), 7.90 (d, J = 8.9 Hz, 1H), 7.81 (s, 2H), 6.12 (br s, 1H), 5.91 (s, 2H), 4.22 (br s, 3H), 3.67 (s, 2H), 3.03 (br d, J = 7.3 Hz, 1H), 2.77 (br s, 2H), 2.42 (br s, 4H), 2.20 (br s, 3H), 2.22 - 2.19 (m, 1H), 1.65 (s, 2H), 1.54 - 1.52 (m, 6H), 1.13 (s, 6H), 0.99 (s, 2H), 0.02 (s, 9H), MS (LC / MS) m / z: Measured value 603.3, Predicted value 603.3 [M+H].

[0296] To a 3 mL solution of 4-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)-3-pyridyl]-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (152, 0.25 g, 391.03 μmol, 1 eq, HCl salt) in DCM, 1 mL of TFA was added. The mixture was stirred at 20°C for 2 hours under an N2 atmosphere and analyzed by LC / MS (R t The reaction was monitored for 0.407 minutes ([M+H]=473.4) until it was clear that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150×50mm×10um, mobile phase: [H2O(10mM NH4HCO3)-ACN], 30%~70% B gradient over 6.0 minutes) to obtain the title compound 5-cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-(8-isopropyl-8-azabicyclo[3.2.1]octan-3-yl)-3-pyridyl]-1H-imidazole-2-carboxamide (A-20, 83.28 mg, 176.21 μmol, yield 45.1%) as a white solid. 1H NMR (400 MHz, CD3OD) δ = 8.55 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.22 (d, J = 8.5 Hz, 1H), 5.91 (br s, 1H), 4.17 (br s, 2H), 3.44 - 3.32 (m, 2H), 2.42 (br d, J = 1.9 Hz, 2H), 2.30 - 2.19 (m, 4H), 2.16 - 2.06 (m, 4H), 1.96 (br d, J = 13.5 Hz, 2H), 1.59 (t, J = 6.3 Hz, 2H), 1.37 (d, J = 6.4 Hz, 6H), 1.08 (s, 6H), MS (LC / MS) m / z: Measured value 473.4, Predicted value 473.3 [M+H].

[0297] Example 26 N-[6-[8-acetyl-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-en-3-yl]-2-(1,2-diduterio-4,4-dimethylcyclohexyl)-3-pyridyl]-5-cyano-1H-imidazole-2-carboxamide A-21 [ka] [ka] To a solution of acetamide (5 g, 84.65 mmol, 1 eq) and hexane-2,5-dione (153 g, 12.56 g, 110.04 mmol, 12.91 mL, 1.3 eq) in toluene (150 mL), TsOH (728.84 mg, 4.23 mmol, 0.05 eq) was added at 20 °C. The mixture was stirred at 140 °C for 12 hours under an N2 atmosphere using a Dean-Stark trap. The reaction was monitored by TLC (Pet.Et.: HCl=10:1, Rf=0.7) until completion was indicated. The reaction mixture was quenched with H2O (20 mL) and extracted with HCl (30 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et.: Â1 / 0~0 / 1) to obtain 1-(2,5-dimethylpyrrole-1-yl)ethanone (154, 3.2 g, 23.33 mmol, yield 27.6%) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ = 5.84 (s, 2H), 2.54 (s, 3H), 2.42 (s, 6H).

[0298] TEA (7.08 g, 69.98 mmol, 9.74 mL, 3 eq) was added at 20°C to a solution of 1-(2,5-dimethylpyrrole-1-yl)ethanone (154 g, 3.2 g, 23.33 mmol, 1 eq) and 1,1,3-trichloropropan-2-one (16 g, 11.30 g, 69.98 mmol, 3 eq) in CF3CH2OH (30 mL). The mixture was stirred at 20°C for 12 hours under an N2 atmosphere. The reaction was analyzed by LC / MS (R tThe reaction was monitored for 0.435 minutes ([M+H]=262.1) until it was clear that the reaction was complete. The reaction mixture was quenched with H2O (50 mL) and extracted with siRNA (100 mL x 3). The organic layers were combined, washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. Without further purification, 8-acetyl-2,4-dichloro-1,5-dimethyl-8-azabicyclo[3.2.1]octa-6-en-3-one (155, 6 g, 11.44 mmol, yield 49.1%, purity 50%) was obtained as a crude brown solid and used as is. 1 H NMR (400 MHz, CDCl3) δ = 5.83 (s, 2H), 4.59 - 4.53 (m, 1H), 3.99 - 3.92 (m, 1H), 2.54 (s, 3H), 2.41 (s, 5H), 2.42 - 2.39 (m, 1H), MS (LC / MS) m / z actual value 262.1, predicted value 262.0 [M+H].

[0299] To a solution of 8-acetyl-2,4-dichloro-1,5-dimethyl-8-azabicyclo[3.2.1]octa-6-en-3-one (155, 6 g, 22.89 mmol, 1 eq) in MeOH (60 mL), CuCl (1.13 g, 11.44 mmol, 273.67 μL, 0.5 eq), NH4Cl (8.57 g, 160.22 mmol, 7 eq), and Zn (7.48 g, 114.45 mmol, 5 eq) were added. The mixture was stirred under N2 at 20°C for 12 hours and monitored by TLC (Pet.Et.: siRNA=1:1, Rf=0.5) until the reaction was complete. The reaction mixture was quenched with H2O (20 mL) and extracted with siRNA (30 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et.: siRNA=1 / 0~0 / 1) to obtain 8-acetyl-1,5-dimethyl-8-azabicyclo[3.2.1]octa-6-en-3-one (156, 1.7 g, 8.80 mmol, yield 38.4%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ = 5.78 (s, 2H), 2.78 (br d, J = 16.8 Hz, 2H), 2.36 (d, J = 17.1 Hz, 2H), 2.17 (s, 3H), 1.74 (s, 6H), MS (LC / MS) m / z actual measurement 194.2, predicted value 194.1 [M+H].

[0300] To a solution of 8-acetyl-1,5-dimethyl-8-azabicyclo[3.2.1]octa-6-en-3-one (156 mg, 1.7 g, 8.80 mmol, 1 eq) in CD3OD (20 mL), Pd / C (468.10 mg, 439.86 μmol, 10% purity, 0.05 eq) was added. The mixture was stirred at 200 °C for 12 hours under D2 (15 psi), and LC / MS (R) was performed. t The reaction was monitored for 0.34 minutes ([M+H]=198.2) until completion was indicated. The suspension was filtered through a CELITE® or silica gel pad, and the pad or filtration cake was washed with CD3OD (5 mL x 3). The filtrates were combined, concentrated to dryness, and 8-acetyl-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one (157, 1.5 g, 7.60 mmol, yield 86.4%) was obtained as a brown solid without further purification and was used as is. 1 H NMR (400 MHz, CDCl3) δ = 2.75 (br d, J = 15.6 Hz, 2H), 2.30 (br d, J = 15.8 Hz, 2H), 2.22 (br s, 3H), 1.69 (br s, 2H), 1.65 (s, 6H), MS (LC / MS) m / z actual value 198.2, predicted value 198.2 [M+H].

[0301] To a solution of LiHMDS (1M, 7.60mL, 1eq) in THF (3mL), a solution of 8-acetyl-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-one (157, 1.5g, 7.60 mmol, 1eq) in THF (15mL) was added dropwise at -70°C. The mixture was heated and stirred at 20°C for 0.5 hours. Next, a solution of 1,1,1-trifluoro-N-(2-pyridyl)-N-(trifluoromethyl-sulfonyl)methanesulfonamide (3.00g, 8.36 mmol, 1.1eq) in THF (3mL) was added at -70°C. The reaction mixture was heated and stirred at 20°C for 2.5 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et.: siRNA = 1:1, Rf = 0.7) until completion was indicated. The reaction mixture was quenched with NH4Cl (20 mL) and extracted with siRNA (30 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et.: siRNA = 1 / 0~0 / 1) to obtain [8-acetyl-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-en-3-yl]trifluoromethanesulfonate (158, 0.96 g, 2.91 mmol, yield 38.34%) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ = 6.00 - 5.93 (m, 1H), 3.12 (dd, J = 1.6, 17.0 Hz, 1H), 2.17 - 2.11 (m, 4H), 2.02 - 1.96 (m, 1H), 1.90 - 1.86 (m, 1H), 1.73 (s, 3H), 1.70 (s, 3H), MS (LC / MS) m / z Actual value 330.1, Predicted value 330.1 [M+H].

[0302] To a 10 mL solution of dioxane containing [8-acetyl-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-en-3-yl]trifluoromethanesulfonate (158, 960.00 mg, 2.91 mmol, 1 eq) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (888.27 mg, 3.50 mmol, 1.2 eq), KOAc (715.21 mg, 7.29 mmol, 2.5 eq) and Pd(dppf)Cl2 (213.29 mg, 291.50 μmol, 0.1 eq) were added. The mixture was stirred at 90°C for 12 hours under an N2 atmosphere. The reaction was monitored by TLC (Pet.Et.: siRNA = 10:1, Rf = 0.7) until completion was indicated. The reaction mixture was quenched with NH4Cl (20 mL) and extracted with siRNA (30 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et.: siRNA = 1 / 0~0 / 1) to obtain 1-[6,7-diduterio-1,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]octa-2-en-8-yl]ethanone (159, 0.79 g, 2.57 mmol, yield 88.2%) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ = 6.60 (t, J = 2.0 Hz, 1H), 2.82 (dd, J = 1.8, 17.8 Hz, 1H), 2.11 (s, 3H), 1.98 (dd, J = 1.7, 17.6 Hz, 1H), 1.88 - 1.75 (m, 2H), 1.64 (d, J = 1.9 Hz, 6H), 1.25 (d, J = 0.8 Hz, 12H), MS (LC / MS) m / z actual value 308.3, predicted value 308.2 [M+H].

[0303] To a solution of tert-butyl N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate (INT-3, 0.5 g, 1.31 mmol, 1 eq) in CD3OD (10 mL), chlorodium;triphenylphosphan (606.61 mg, 655.64 μmol, 0.5 eq) was added. The mixture was stirred at 50°C for 12 hours under D2 (50 psi). The reaction was monitored by TLC (Pet.Et.: Â=10:1) until completion was indicated. The suspension was filtered through a CELITE® or silica gel pad, and the pad or filter cake was washed with CD3OD (10 mL x 3). The filtrates were combined and concentrated to dryness. The residue was purified by column chromatography (SiO2, Pet.Et.: siRNA=1 / 0~0 / 1) to obtain N-[6-bromo-2-(1,2-diduterio-4,4-dimethylcyclohexyl)-3-pyridyl]carbamate tert-butyl (160, 1.85 g, 2.40 mmol, yield 36.6%, purity 50%) as a brown solid. 1 H NMR (400 MHz, CDCl3) δ = 8.21 (br d, J = 8.5 Hz, 1H), 7.92 (br d, J = 6.5 Hz, 1H), 6.81 (br s, 1H), 2.34 - 2.27 (m, 2H), 1.95 (br d, J = 3.3 Hz, 2H), 1.81 (br s, 1H), 1.46 (s, 9H), 1.30 - 1.26 (m, 2H), 0.95 (s, 6H), MS (LC / MS) m / z actual value 385.1, predicted value 385.2 [M+H].

[0304] 1-[6,7-diduterio-1,5-dimethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]octa-2-en-8-yl]ethanone (159, 0.59 g, 1.92 mmol, 1 eq) and N-[6-bromo-2-(1,2-diduterio-4,4-dimethyl-sili] To a solution of tert-butyl chlorohexyl)-3-pyridyl]carbamate (160 mg, 887.98 mg, 2.30 mmol, 1.2 eq) in dioxane (5 mL) and H2O (1 mL), K2CO3 (796.22 mg, 5.76 mmol, 3 eq) and Pd(dppf)Cl2 (140.51 mg, 192.04 μmol, 0.1 eq) were added. The mixture was stirred at 90°C for 12 hours under an N2 atmosphere and analyzed by LC / MS (R t The reaction was monitored for 0.664 minutes ([M+H]=486.4) until completion was indicated. The reaction mixture was quenched with NH4Cl (20 mL) and extracted with HCl (30 mL x 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 (250 × 70 mm × 15 μm), mobile phase: [H2O (0.1% TFA)-ACN], 68%~88% B gradient over 20.0 minutes) to obtain N-[6-[8-acetyl-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-en-3-yl]-2-(1,2-diduterio-4,4-dimethyl-cyclohexyl)-3-pyridyl]carbamate tert-butyl (161, 0.43 g, 885.33 μmol, yield 46.1%) as a brown solid. 1H NMR (400 MHz, CDCl3) δ = 8.21 - 8.03 (m, 1H), 7.21 (d, J = 8.5 Hz, 1H), 6.78 (s, 1H), 6.38 (br s, 1H), 3.17 (br d, J = 17.1 Hz, 1H), 2.45 (d, J = 17.4 Hz, 1H), 2.16 (s, 3H), 2.00 - 1.86 (m, 4H), 1.78 (d, J = 11.6 Hz, 6H), 1.64 - 1.52 (m, 12 H), 1.42 - 1.31 (m, 2H), 1.01 (d, J = 14.3 Hz, 6H), MS (LC / MS) Measured value (m / z): 486.3, predicted value: 486.4 [M+H].

[0305] To a 5 mL solution of N-[6-[8-acetyl-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-en-3-yl]-2-(1,2-diduterio-4,4-dimethylcyclohexyl)-3-pyridyl]carbamate tert-butyl (161, 0.33 g, 679.44 μmol, 1 eq) in DCM (5 mL), ZnBr2 (1.53 g, 6.79 mmol, 340.02 μL, 10 eq) was added at 20 °C. The mixture was stirred at 20 °C for 12 hours under an N2 atmosphere and analyzed by LC / MS (R t The reaction was monitored for 0.434 minutes ([M+H]=386.4) until completion was indicated. The reaction mixture was quenched with H2O (5 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. Without further purification, 1-[3-[5-amino-6-(1,2-diduterio-4,4-dimethylcyclohexyl)-2-pyridyl]-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-en-8-yl]etanone (162, 0.25 g, 648.38 μmol, yield 95.4%) was obtained as a yellow solid and used as is. 1H NMR (400 MHz, CD3OD) δ = 7.21 - 7.06 (m, 1H), 6.59 (s, 1H), 3.11 (br d, J = 17.1 Hz, 1H), 2.48 (d, J = 17.1 Hz, 1H), 2.15 (s, 3H), 1.96 - 1.83 (m, 4H), 1.75 (d, J = 6.8 Hz, 6H), 1.66 - 1.53 (m, 2H), 1.51 - 1.34 (m, 4H), 1.04 - 0.97 (m, 6H)), MS (LC / MS) m / z actual value 386.3, predicted value 386.4 [M+H].

[0306] PyBroP (453.39 mg, 972.57 μmol, 1.5 eq) and DIEA (251.39 mg, 1.95 mmol, 338.81 μL, 3 eq) were added to a 5 mL DMF solution of 1-[3-[5-amino-6-(1,2-diduterio-4,4-dimethylcyclohexyl)-2-pyridyl]-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-en-8-yl]etanone (162, 0.25 g, 648.38 μmol, 1 eq) and [4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carbonyl]oxypotassium (INT-2, 237.65 mg, 778.05 μmol, 1.2 eq) and DIEA (251.39 mg, 1.95 mmol, 338.81 μL, 3 eq). The mixture was stirred in an N2 atmosphere at 20°C for 2 hours and then measured by LC / MS(R tThe reaction was monitored for 0.768 minutes ([M+H]=635.4) until completion was indicated. The reaction mixture was quenched with H2O (5 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, Pet.Et.: siRNA=1 / 0~0 / 1) to obtain N-[6-[8-acetyl-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-en-3-yl]-2-(1,2-diduterio-4,4-dimethyl-cyclohexyl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (163, 0.25 g, 393.75 μmol, yield 60.7%) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ = 9.19 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H), 7.82 (s, 1H), 7.23 (d, J = 8.5 Hz, 1H), 6.86 (s, 1H), 5.95 (s, 2H), 3.70 -3.64 (m, 2H), 3.18 (br d, J = 17.5 Hz, 1H), 2.47 (d, J = 17.4 Hz, 1H), 2.15 (s, 3H), 1.98 - 1.94 (m, 2H), 1.79 (d, J = 11.4 Hz, 4H), 1.56 (s, 6H), 1.47 - 1.42 (m, 2H), 1.03 (d, J = 12.0 Hz, 6H), 0.98 (d, J = 8.3 Hz, 2H), 0.01 (s, 9H), MS (LC / MS) m / z actual value 635.4, predicted value 635.4 [M+H].

[0307] To a solution of N-[6-[8-acetyl-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-en-3-yl]-2-(1,2-diduterio-4,4-dimethyl-cyclohexyl)-3-pyridyl]-4-cyano-1-(2-trimethylsilylethoxymethyl)imidazole-2-carboxamide (163, 0.22 g, 346.50 μmol, 1 eq) in THF (2 mL), TBAF (1 M, 693.00 μL, 2 eq) was added. The mixture was stirred at 20 °C for 12 hours under an N2 atmosphere, and the reaction was analyzed by LC / MS (R tThe reaction was monitored for 0.613 minutes until [M+H]=505.3) indicated completion. The reaction mixture was quenched with H2O (5 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150×40mm×10um, mobile phase: [H2O (10mM NH4HCO3)-ACN], 50%~80% B gradient over 6.0 minutes) to obtain the title compound N-[6-[8-acetyl-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-en-3-yl]-2-(1,2-diduterio-4,4-dimethyl-cyclohexyl)-3-pyridyl]-5-cyano-1H-imidazole-2-carboxamide (A-21, 0.13g, 257.60μmol, yield 74.3%) as a white solid. 1H NMR (400 MHz, CD3OD) δ = 8.01 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 6.88 (s, 1H), 3.17 (br d, J = 17.2 Hz, 1H), 2.57 (d, J = 17.6 Hz, 1H), 2.16 (s, 3H), 2.03 - 1.97 (m, 1H), 1.95 - 1.87 (m, 3H), 1.78 (d, J = 4.6 Hz, 6H), 1.67 - 1.59 (m, 1H), 1.54 - 1.47 (m, 2H), 1.41 - 1.34 (m, 2H), 1.03 (s, 3H), 0.96 (s, 3H), MS (LC / MS) m / z actual value 505.3, predicted value 505.3 [M+H].

[0308] Examples 27 and 28 N-[6-[8-acetyl-6,7-diduterio-3-hydroxy-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl]-2-(1,2-diduterio-4,4-dimethylcyclohexyl)-3-pyridyl]-5-cyano-1H-imidazole-2-carboxamide A-22 and N-[6-[8-acetyl-6,7-diduterio-3-hydroxy-1,5-dimethyl-8-azabicyclo[3.2.1]octane-3-yl]-2-(1,2-diduterio-4,4-dimethylcyclohexyl)-3-pyridyl]-5-cyano-1H-imidazole-2-carboxamide A-23 (Stereochemistry is shown to distinguish isomers, but is not definitive) [ka] Phenylsilane (85.77 mg, 792.62 μmol, 97.80 μL, 4 eq) and tris[(Z)-1-tert-butyl-4,4-dimethyl-3-oxopenta-1-enoxy]manganese (35.95 mg, 59.45 μmol, 0.3 eq) were added to a solution of N-[6-[8-acetyl-6,7-diduterio-1,5-dimethyl-8-azabicyclo[3.2.1]octa-2-en-3-yl]-2-(1,2-diduterio-4,4-dimethyl-cyclohexyl)-3-pyridyl]-5-cyano-1H-imidazole-2-carboxamide (A-21, 0.1 g, 198.15 μmol, 1 eq) in DCM (0.5 mL) and i-PrOH (5 mL). The mixture was stirred at 25°C for 12 hours under an O2 (15 psi) atmosphere, and then LC / MS(R t =0.528 minutes, [M+H]=523.4) and LC / MS(R tThe reaction was monitored for 0.572 minutes ([M+H]=523.4) until completion was indicated. The reaction mixture was quenched with H2O (5 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (5 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was preparatively HPLC (column: Phenomenex Luna C18). The sample was purified by a 100×40mm×5um mobile phase (H2O(0.1%TFA)-ACN) over 8.0 minutes using a 45%~70% B gradient) to obtain the title compound N-[6-[8-acetyl-6,7-diduterio-3-hydroxy-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl]-2-(1,2-diduterio-4,4-dimethyl-cyclohexyl)-3-pyridyl]-5-cyano-1H-imidazole-2-carboxamide isomer 1(A-2 A-23, 4.6 mg, 8.80 μmol, yield 4.4%, Example 27) and N-[6-[8-acetyl-6,7-diduterio-3-hydroxy-1,5-dimethyl-8-azabicyclo[3.2.1]octan-3-yl]-2-(1,2-diduterio-4,4-dimethyl-cyclohexyl)-3-pyridyl]-5-cyano-1H-imidazole-2-carboxamide isomer 2 (A-23, 2.3 mg, 4.40 μmol, yield 2.2%, Example 28) were obtained as white solids. A-22: 1 H NMR (400 MHz, CD3OD) δ = 8.05 (t, J = 4.2 Hz, 2H), 7.66 (d, J = 8.5 Hz, 1H), 3.63 (d, J = 15.3 Hz, 2H), 2.32 (d, J = 15.3 Hz, 2H), 1.98 (s, 2H), 1.94 (br d, J = 3.1 Hz, 1H), 1.89 (s, 3H), 1.71 - 1.65 (m, 1H), 1.64 - 1.59 (m, 1H), 1.55 (s, 6H), 1.51 (br s, 2H), 1.47 - 1.37 (m, 2H), 1.03 (s, 3H), 1.00 - 0.96 (m, 3H), MS (LC / MS) m / z Measured value 523.4, Predicted value 523.4 [M+H], and A-23:1 H NMR (400 MHz, CD3OD) δ = 8.03 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 2.71 (d, J = 14.4 Hz, 2H), 2.41 - 2.37 (m, 2H), 2.22 (s, 3H), 1.95 - 1.84 (m, 2H), 1.64 (br d, J = 14.4 Hz, 3H), 1.59 (s, 6H), 1.53 - 1.46 (m, 2H), 1.40 - 1.31 (m, 2H), 1.06 - 0.95 (m, 6H), MS (LC / MS) m / z actual value 523.4, predicted value 523.4 [M+H].

[0309] Example 29 5-Cyano-N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[3,3,5,5-tetraduterio-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]-1H-imidazole-2-carboxamide A-24 [ka] To a solution of 3,3,5,5-tetraduterio-2,2,6,6-tetrakis(triduteriomethyl)piperidine-4-one (89 mg, 1 g, 5.84 mmol, 1 eq) in CD3OD (10 mL), NaBH4 (287.03 mg, 7.59 mmol, 1.3 eq) was added at 0°C. The mixture was stirred at 25°C for 2 hours and monitored by TLC (siRNA:MeOH=3:1, Rf=0.3) until the starting material was completely consumed. The reaction mixture was diluted with D2O (2 mL) and concentrated under reduced pressure to obtain the residue, and without purification, 3,3,5,5-tetraduterio-2,2,6,6-tetrakis(triduteriomethyl)-piperidine-4-ol (164 mg, 1 g, 5.77 mmol, yield 98.8%) was obtained as a yellow oil. 1 H NMR (400 MHz, CD3OD, 301 K) δ (ppm) = 3.96 (s, 1H).

[0310] To a 15 mL solution of MTBE containing 3,3,5,5-tetraduterio-2,2,6,6-tetrakis(triduteriomethyl)piperidine-4-ol (164 mg, 477.36 mg, 2.75 mmol, 1.75 eq) and NHC-1 (995.08 mg, 2.52 mmol, 1.6 eq), a 1 mL solution of MTBE containing pyridine (199.15 mg, 2.52 mmol, 203.21 μL, 1.6 eq) was added dropwise within 5 minutes at 25°C. After 10 minutes, the mixture was filtered, and the filtrate contained tert-butyl N-[6-bromo-2-(4,4-dimethylcyclohexen-1-yl)-3-pyridyl]carbamate (INT-3, 0.6 g, 1.57 mmol, 1 eq), and bis[2-(2-pyridyl) [phenyl]iridium(1+);4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine;hexafluorophosphate (21.57 mg, 23.60 μmol, 0.015 eq), dibromonickel;1,2-dimethoxyethane (24.28 mg, 78.68 μmol, 0.05 eq), quinuclidine (306.18 mg, 2.75 mmol, 1.75 eq), 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (31.68 mg, 118.02 μmol, 0.075 eq), and isoindoline-1,3-dione (52.09 mg, 354.05 μmol, 0.225 eq) were added to a DMA (15 mL) solution under N2 conditions. The mixture was stirred under blue LED light at 25°C for 3 hours and then measured by LC / MS(R tThe mixture was monitored for 0.447 minutes ([M+H]=458.5) until the starting material was completely consumed. The reaction mixture was diluted with water (20 mL) and extracted with pharmaceutically acceptable phosphate (20 mL x 2). The organic layers were combined, washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (Phenomenex Luna C18 100×40mm×5um, mobile phase: [H2O(0.1%TFA)-ACN], 50%~90% B gradient over 8.0 minutes) to obtain N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[3,3,5,5-tetraduterio-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]-carbamate tert-butyl (165, 150 mg, 327.69 μmol, yield 10.4%) as a yellow solid. 1 H NMR (400 MHz, CD3OD, 298 K) δ (ppm) = 8.11 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 5.93 (br t, J = 3.7 Hz, 1H), 3.48 - 3.43 (m, 1H), 2.44 - 2.34 (m, 2H), 2.05 (br d, J = 3.4 Hz, 2H), 1.57 (t, J = 6.3 Hz, 2H), 1.50 (s, 9H), 1.04 (s, 6H), MS (LC / MS) m / z actual value 458.4, predicted value 458.5 [M+H].

[0311] To a 3 mL solution of N-[2-(4,4-dimethylcyclohexen-1-yl)-6-[3,3,5,5-tetraduterio-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]-3-pyridyl]carbamate tert-butyl (165, 150 mg, 327.69 μmol, 1 eq) in DCM, 1 mL of TFA was added at 25°C. The mixture was stirred at 25°C for 2 hours and analyzed by LC / MS (R tThe mixture was monitored for 0.323 minutes ([M+H]=358.4) until the starting material was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the residue, and without further purification, 2-(4,4-dimethylcyclohexen-1-yl)-6-[3,3,5,5-tetraduterio-2,2,6,6-tetrakis(triduteriomethyl)-4-piperidyl]pyridine-3-amine (166, 150 mg, 318.03 μmol, yield 97.05%, TFA salt) was obtained as a yellow solid. 1 H NMR (400 MHz, CD3OD, 298 K) δ (ppm) = 7.71 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H), 6.18 (td, J = 2.0, 3.6 Hz, 1H), 3.62 (s, 1H), 2.44 - 2.32 (m, 2H), 2.12 (br d, J = 3.4 Hz, 2H), 1.63 (t, J = 6.3 Hz, 2H), 1.07 (s, 6H), MS (LC / MS) m / z actual value 358.4, predicted value 358.4 [M+H].

[0312] To a solution of 2-(4,4-dimethylcyc...

Claims

1. Compound of formula (I): 【Chemistry 113】 or its prodrug or salt, in the formula: X is N, NR ｅ , or CH, R １ but, 【Chemical 114】 Selected from the group consisting of, R １ is optionally substituted with one or more groups independently selected from (C １ ~C ６ )alkyl and OH, and R １ is substituted with one or more groups independently selected from deuterium, chloro, and fluoro, or R １ is R ２ or R ３ and R ２ but, 【Chemical 115】 And, D, Cl, F, OH, and (C １ ~C ８ ) optionally substituted with one or more groups independently selected from alkyl, (C １ ~C ８ ) The alkyl group is optionally substituted with one or more groups independently selected from D, Cl, F, and OH. X １ However, NR ａ or S, R ａ However, H, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkanoyl, and C １ ~C ６ ) Selected from alkoxycarbonyls, R ｂ However, H, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkanoyl, or (C １ ~C ６ ) It is an alkoxycarbonyl, R ｃ However, H, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkanoyl, or (C １ ~C ６ ) It is an alkoxycarbonyl, R ３ but, 【Chemistry 116】 And, R ｘ and R ｙ However, it is selected independently from H and D, or R ｘ and R ｙ Together they form a double bond, R ｅ However, it forms ammonium oxide with the nitrogen it is bonded to, each 【Chemistry 117】 However, they are independently single or double bonds, However, R ２ but, 【Chemistry 118】 Provided that it is not the case, In the formula, R ａ However, C １ ~C ６ A compound of formula (I) or its prodrug or salt, which is an alkoxycarbonyl compound.

2. Compound of formula (III): 【Chemical 119】 or its prodrug or salt, in the formula: X is N or CH, R １ but, 【Chemical 120】 Selected from the group consisting of, R １ However, (C １ ~C ６ ) optionally substituted with one or more groups independently selected from alkyl and OH, R １ However, it is substituted with one or more groups independently selected from deuterium, chloro, and fluoro. R ａ However, H, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkanoyl, or (C １ ~C ６ ) It is an alkoxycarbonyl, R ｂ However, H, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkanoyl, or (C １ ~C ６ ) It is an alkoxycarbonyl, R ｃ However, H, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkanoyl, or (C １ ~C ６ The compound according to claim 1, wherein it is an alkoxycarbonyl.

3. R １ but, 【Chemistry 121】 And, R １ However, it is arbitrarily substituted with one or more OH groups, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with one or more groups independently selected from deuterium, chloro, and fluoro.

4. R １ but, 【Chemistry 122】 And, R １ However, it is arbitrarily substituted with one or more OH groups, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with one or more groups independently selected from deuterium, chloro, and fluoro.

5. R １ but, 【Chemical 123】 And, R １ However, it is arbitrarily substituted with one or more OH groups, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with one or more groups independently selected from deuterium, chloro, and fluoro.

6. R １ but, 【Chemistry 124】 And, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with one or more groups independently selected from deuterium, chloro, and fluoro.

7. R １ but, 【Chemistry 125】 And, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with one or more groups independently selected from deuterium, chloro, and fluoro.

8. R １ but, 【Chemistry 126】 And, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with one or more groups independently selected from deuterium, chloro, and fluoro.

9. R １ but, 【Chemistry 127】 And, R １ The compound, prodrug, or salt according to claim 2, wherein R is substituted with one or more deuteriums.

10. R １ but, 【Chemistry 128】 And, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with one or more deuterium atoms.

11. R １ but, 【Chemistry 129】 And, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with one or more deuterium atoms.

12. R １ but, 【Chemistry 130】 And, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with one or more groups independently selected from chloro and fluoro.

13. R １ is 【Chemistry 131】 And, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with one or more groups independently selected from chloro and fluoro.

14. R １ but, 【Chemistry 132】 And, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with one or more groups independently selected from chloro and fluoro.

15. R １ but, 【Chemistry 133】 And, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with two or more deuterium atoms.

16. R １ but, 【Chemistry 134】 And, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with three or more deuterium atoms.

17. R １ but, 【Chemistry 135】 And, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with six or more deuterium atoms.

18. R １ but, 【Transformation 136】 And, R １ The compound, prodrug, or salt according to claim 2, wherein the compound is substituted with 12 or more deuterium atoms.

19. R １ but, 【Chemistry 137】 A compound, prodrug, or salt according to claim 2, selected from the group consisting of the following.

20. R １ but, 【Chemistry 138-1】 【Chemistry 138-2】 A compound, prodrug, or salt according to claim 1, selected from the group consisting of the following.

21. A compound, prodrug, or salt according to any one of claims 1 to 20, wherein X is N.

22. A compound, prodrug, or salt according to any one of claims 1 to 20, wherein X is CH. 【Request Item 23】 【Chemistry 139】 The compound, prodrug, or salt according to claim 2, or a prodrug or salt thereof.

24. R １ but, [Chemical 140] Selected from the group consisting of, R １ However, it is optionally substituted with one or more groups independently selected from OH, R １ However, it is substituted with one or more groups independently selected from deuterium, chloro, and fluoro. R ａ However, H, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkanoyl, or (C １ ~C ６ ) It is an alkoxycarbonyl, R ｂ However, H, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkanoyl, or (C １ ~C ６ ) It is an alkoxycarbonyl, R ｃ However, H, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkanoyl, or (C １ ~C ６ The compound or its prodrug or salt according to claim 1, wherein it is an alkoxycarbonyl.

25. R １ but, 【Chemistry 141】 Selected from the group consisting of, R １ However, (C １ ~C ６ ) optionally substituted with one or more groups independently selected from alkyl and OH, R １ However, it is substituted with one or more groups independently selected from deuterium, chloro, and fluoro. R ａ However, H, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkanoyl, or (C １ ~C ６ The compound or its prodrug or salt according to claim 1, wherein it is an alkoxycarbonyl.

26. Compound of formula (II): 【Chemistry 142】 or its prodrug or salt, in the formula: X is N or CH, R ２ but, 【Chemistry 143】 And, X １ However, NR ａ or S, R ａ However, H, (C １ ~C ６ ) alkyl, (C １ ~C ６ ) Alkanoyl, and (C １ ~C ６ ) Selected from alkoxycarbonyls, 【Chemistry 144】 However, it is either a single bond or a double bond. R ２ However, D, Cl, F, OH, and (C １ ~C ６ ) optionally substituted with one or more groups independently selected from alkyl, (C １ ~C ６ The compound according to claim 1, wherein the alkyl group is optionally substituted with one or more groups independently selected from D, Cl, F, and OH.

27. R ２ but, 【Chemistry 145】 And, In the formula, R ｂ and R ｃ However, D, Cl, F, OH, and (C １ ~C ６ ) independently selected from alkyl, (C １ ~C ６ The compound, prodrug, or salt according to claim 26, wherein the alkyl group is optionally substituted with one or more groups independently selected from D, Cl, F, and OH.

28. R ｂ and R ｃ However, CH ３ ,CH ２ F, and CH ２ A compound, prodrug, or salt according to claim 27, independently selected from OH. 【Request Item 29】 【Chemistry 146-1】 【Chemistry 146-2】 【Chemistry 146-3】 【Chemistry 146-4】 【Chemistry 146-5】 【Chemistry 146-6】 The compound, prodrug, or salt according to claim 1, selected from the group consisting of the prodrug and salt thereof.

30. A pharmaceutical composition comprising a compound or prodrug as described in any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

31. A method for treating a disease selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, bone-destructive tumors, myeloma, tenosynovial giant cell tumor, brain cancer, and tumor metastases to the brain or bone, the method comprising administering to the animal a compound or prodrug as described in any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

32. Glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), hepatitis, neurocognitive disorders, chemobrain cognitive impairment or cognitive impairment, psoriasis, diabetes, tumor-associated angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson's disease, Alzheimer's disease, chronic traumatic encephalopathy, Huntington's disease, progressive bulbar palsy, progressive supranuclear palsy, Lewy body dementia, myotonic dystrophy, telangiectatic ataxia, bovine spongiform encephalopathy, kuru disease, scrapie, anti-N-methyl-D-aspartate receptor encephalitis, myasthenia gravis, progressive multifocal leukoencephalopathy, central nervous system A method for treating a disease selected from the group consisting of disorders, lupus vasculitis / neuropsychiatric systemic lupus erythematosus, bacterial and viral meningitis, corticobasal degeneration, primary age-related tauopathy, tauopathy, argyrophilic granulopathy, stroke, traumatic brain injury, ALSP, sarcopenia, amyotrophic lateral sclerosis, frontotemporal dementia, frontotemporal lobe dementia, epilepsy, any disorder resulting from C9ORF72 mutation, age-related loss of motor units, muscular dystrophy and any other form of dementia, radiation-induced cognitive impairment, and Crohn's disease, the method comprising administering to the animal a compound or prodrug as described in any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

33. A method for treating pain in an animal, comprising administering to the animal a compound or prodrug as described in any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

34. The method according to claim 33, wherein the pain is skeletal pain caused by tumor metastasis or osteoarthritis, or visceral pain, inflammatory pain, or neurogenic pain.

35. A method for treating cancer in an animal, comprising administering to the animal a compound or prodrug as described in any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

36. A method for treating or preventing cancer metastasis in an animal, comprising administering to the animal a compound or prodrug as described in any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

37. The method according to claim 35 or 36, wherein the cancer is selected from the group consisting of ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, bladder cancer, pancreatic cancer, glioblastoma, melanoma, lymphoma, leukemia, and hairy cell leukemia.

38. A method for treating an autoimmune disease in an animal, comprising administering to the animal a compound or prodrug as described in any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

39. The method according to claim 38, wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis and other forms of inflammatory arthritis, psoriasis, Sjögren's syndrome, multiple sclerosis, and uveitis.

40. A method for inhibiting c-fms kinase activity, comprising contacting the c-fms kinase with a compound or prodrug as described in any one of claims 1 to 29, or a salt thereof.

41. The method according to claim 40, wherein the c-fms kinase is contacted in vitro with the compound or prodrug or the salt.

42. The method according to claim 40, wherein the c-fms kinase is contacted in vivo with a compound or prodrug as described in any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.

43. A method for treating atherosclerosis in an animal, comprising administering to the animal a compound of formula (I) as described in any one of claims 1 to 29, or a prodrug or pharmaceutically acceptable salt thereof.

44. A method for treating a disease selected from the group consisting of ALS, FTD, C9-related disease, Alzheimer's disease, Parkinson's disease, MS, Huntington's disease, Giant Tenosynovial Carcinoma, and epilepsy in an animal, the method comprising administering to the animal a compound of formula (I) as described in any one of claims 1 to 29, or a prodrug or pharmaceutically acceptable salt thereof.

45. A compound or prodrug as described in any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

46. Compounds or prodrugs as described in any one of claims 1 to 29 or pharmaceutically acceptable salts thereof for the prophylactic or therapeutic treatment of diseases selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, bone-destructive tumors, myeloma, tenosynovial giant cell tumor, brain cancer, and tumor metastases to the brain or bone, any progressive solid tumors and cancerous tumor metastases (especially the aforementioned metastases to the brain, CNS, bone, or lymph nodes) in animals.

47. Glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), hepatitis, neurocognitive disorder, chemobrain cognitive impairment or cognitive impairment, psoriasis, diabetes, tumor-associated angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson's disease, Alzheimer's disease, chronic traumatic encephalopathy, Huntington's disease, progressive bulbar palsy, progressive supranuclear palsy, Lewy body dementia, myotonic dystrophy, telangiectatic ataxia, bovine spongiform encephalopathy, kuru disease, scrapie, anti-N-methyl-D-aspartate receptor encephalitis, myasthenia gravis, progressive multifocal leukoencephalopathy, Compounds or prodrugs or pharmaceutically acceptable salts thereof as described in any one of claims 1 to 29 for the prophylactic or therapeutic treatment of diseases selected from the group consisting of central nervous system disorders, lupus vasculitis / neuropsychiatric systemic lupus erythematosus, bacterial and viral meningitis, corticobasal degeneration, primary age-related tauopathy, tauopathy, argyrophilic granulopathy, stroke, traumatic brain injury, ALSP, sarcopenia, amyotrophic lateral sclerosis, frontotemporal dementia, frontotemporal lobe dementia, epilepsy, any disorder resulting from C9ORF72 mutation, age-related loss of motor units, muscular dystrophy and any other form of dementia, radiation-induced cognitive impairment, and Crohn's disease.

48. A compound or prodrug as described in any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of pain.

49. The compound, prodrug, or pharmaceutically acceptable salt according to claim 48, wherein the pain is skeletal pain caused by tumor metastasis or osteoarthritis, or visceral pain, inflammatory pain, or neurogenic pain.

50. A compound or prodrug as described in any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of cancer.

51. A compound or prodrug as described in any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for treating or preventing cancer metastasis.

52. The compound, prodrug, or pharmaceutically acceptable salt according to claim 50 or 51, wherein the cancer is selected from the group consisting of ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, gastric cancer, bladder cancer, pancreatic cancer, glioblastoma, melanoma, lymphoma, leukemia, and hairy cell leukemia.

53. A compound or prodrug as described in any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for the treatment of atherosclerosis.

54. A compound or prodrug or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 29, for the treatment of a disease selected from the group consisting of ALS, FTD, C9-related disease, Alzheimer's disease, Parkinson's disease, MS, Huntington's disease, tenosynovial giant cell tumor, and epilepsy.

55. A compound or prodrug as described in any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for the prophylactic or therapeutic treatment of an autoimmune disease.

56. The compound, prodrug, or pharmaceutically acceptable salt according to claim 55, wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis and other forms of inflammatory arthritis, psoriasis, Sjögren's syndrome, multiple sclerosis, and uveitis.

57. A compound or prodrug or salt thereof, as described in any one of claims 1 to 29, for inhibiting the activity of c-fms kinase.

58. Use of compounds or prodrugs or pharmaceutically acceptable salts thereof as described in any one of claims 1 to 29 for preparing a medicament useful for the treatment of diseases selected from the group consisting of osteoporosis, Paget's disease, rheumatoid arthritis and other forms of inflammatory arthritis, osteoarthritis, prosthesis failure, bone-destructive tumors, myeloma, tenosynovial giant cell tumor, brain cancer, and tumor metastases to the brain or bone, any progressive solid tumors and cancerous tumor metastases in animals (especially metastases to the brain, CNS, bone, or lymph nodes).

59. In animals, glomerulonephritis, inflammatory bowel disease, prosthesis failure, sarcoidosis, congestive obstructive pulmonary disease, idiopathic pulmonary fibrosis, asthma, pancreatitis, HIV infection, COVID-19 (SARS-CoV-2), hepatitis, neurocognitive disorders, chemobrain cognitive impairment or cognitive impairment, psoriasis, diabetes, tumor-associated angiogenesis, age-related macular degeneration, diabetic retinopathy, restenosis, schizophrenia, Parkinson's disease, Alzheimer's disease, chronic traumatic encephalopathy, Huntington's disease, progressive bulbar palsy, progressive supranuclear palsy, Lewy body dementia, myotonic dystrophy, telangiectatic ataxia, bovine spongiform encephalopathy, kuru disease, scrapie, anti-N-methyl-D-aspartate receptor encephalitis, myasthenia gravis, progressive multifocal leukoencephalopathy, Use of compounds or prodrugs or pharmaceutically acceptable salts thereof as described in any one of claims 1 to 29 for preparing a medicament useful for the treatment of a disease selected from the group consisting of central nervous system disorders, lupus vasculitis / neuropsychiatric systemic lupus erythematosus, bacterial and viral meningitis, corticobasal degeneration, primary age-related tauopathy, tauopathy, argyrophilic granulopathy, stroke, traumatic brain injury, ALSP, sarcopenia, amyotrophic lateral sclerosis, frontotemporal dementia, frontotemporal lobe dementia, epilepsy, any disorder resulting from C9ORF72 mutation, age-related loss of motor units, muscular dystrophy and any other form of dementia, radiation-induced cognitive impairment, and Crohn's disease.

60. Use of a compound or prodrug or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 29 for preparing a medicament useful for the treatment of pain in animals.

61. The use according to claim 60, wherein the pain is skeletal pain caused by tumor metastasis or osteoarthritis, or visceral pain, inflammatory pain, or neurogenic pain.

62. Use of a compound or prodrug or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 29 for preparing a pharmaceutical useful for the treatment of cancer in animals.

63. Use of a compound or prodrug or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 29 for preparing a pharmacopoeia useful for the treatment or prevention of cancer metastasis in animals.

64. The use according to claim 62 or 63, wherein the cancer is ovarian cancer, uterine cancer, breast cancer, prostate cancer, lung cancer, colon cancer, stomach cancer, bladder cancer, pancreatic cancer, glioblastoma, melanoma, lymphoma, leukemia, or hairy cell leukemia.

65. Use of a compound or prodrug or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 29 for preparing a pharmaceutical useful for treating autoimmune diseases in animals.

66. The use according to claim 65, wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis and other forms of inflammatory arthritis, psoriasis, Sjögren's syndrome, multiple sclerosis, and uveitis.

67. Use of a compound or prodrug or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 29 for preparing a pharmaceutical useful for inhibiting c-fms kinase activity in animals.

68. Use of a compound or prodrug or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 29 for preparing a medicament useful for the treatment of atherosclerosis in animals.

69. Use of a compound or prodrug or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 29 for preparing a medicament useful for the treatment of a disease selected from the group consisting of ALS, FTD, C9-related disease, Alzheimer's disease, Parkinson's disease, MS, Huntington's disease, tenosynovial giant cell tumor, and epilepsy in animals.

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