Indazole and pyrazolopyridine compounds as inhibitors of the NLRP3 inflammasome

Abstract

The present disclosure relates to compounds that act as inhibitors of the NLRP3 inflammasome, pharmaceutical compositions containing the compounds, and methods for treating inflammation and inflammation-aging-related disorders, including neurosensory disorders and other diseases associated with aging.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 376,359, filed September 20, 2022, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Age-related frailty is characterized as a syndrome of multisystem physiological dysregulation, causing significant concerns regarding an individual's overall health and well-being. Age-related frailty is a geriatric syndrome characterized by frailty, low physical activity, delayed motor skills, wasting, and unintentional weight loss (Yao, X. et al., Clinics in Geriatric Medicine 27(1):79-87(2011)). Furthermore, numerous studies have demonstrated a direct correlation between age-related frailty and inflammation (Hubbard, RE, et al., Biogerontology 11(5):635-641(2010)). Immunosenescence is characterized by a low-grade chronic systemic inflammatory state known as inflammasenesis (Franceshi, C. et al., Annals of the New York Academy of Sciences 908:244-254(2000)). The increased inflammatory state or chronic inflammation seen in aging and age-related frailty leads to immune dysregulation and complex remodeling of both innate and adaptive immunity.

[0003] Inhibition of the NLRP3 inflammasome, an oligomeric protein complex containing ASC and caspase-1, mediates inflammation in numerous preclinical models (Schwaid, AG, J. Med. Chem. 2021, 64(1), 101-122). At the same time, the NLRP3 inflammasome is part of a larger proinflammatory pathway, and its regulation is also being investigated. NLRP3 is a well-studied inflammasome sensor protein in the context of numerous diseases. A wide variety of indications are linked to the NLRP3 inflammasome, including age-related diseases, cryopyrin-associated periodic syndromes (CAPS), nonalcoholic steatohepatitis (NASH), gout, coronary artery disease, Crohn's disease, osteoarthritis, rheumatoid arthritis, Alzheimer's disease, Parkinson's disease, intestinal disorders, acute respiratory distress syndrome (ARDS), amyotrophic lateral sclerosis (ALS), cancer, and skin diseases.

[0004] Inflammation and activation of the NLRP3 inflammasome have also been shown to cause hearing loss (Nakanishi, H., et al., Frontiers in Neurology, 2020, 11, 1-7; Nakanishi, H., et al., PNAS, 2017, E7766-E7775). Inflammation-related hearing loss can be age-dependent (Fischer, N., et al., Gerontology, 2019, 1-7), noise-induced (Le Prell, C.G., et al., Current Opinion in Physiology, 2020, 18, 32-36), and the result of viral infections, such as Zika virus and coronavirus (Yee, KT, et al., Hearing Research, 2020, 395, 1-15).

[0005] Therefore, the NLRP3 inflammasome is a promising drug target, and the wide range of indications in which it is involved highlights the need for therapeutic agents that target the NLRP3 inflammasome. Summary of the Invention [Problem to be solved by the invention]

[0006] The present invention provides compounds that inhibit the NLRP3 inflammasome. These compounds are therefore useful in treating a variety of indications, including inflammatory aging and neurosensory disorders. The present invention also provides pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another aspect, the present invention provides a method for inhibiting the NLRP3 inflammasome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein. DETAILED DESCRIPTION OF THE INVENTION

[0007] The present invention provides compounds that inhibit the NLRP3 inflammasome, and thus these compounds and pharmaceutical compositions containing these compounds are useful in the treatment of various indications, including inflammation, aging, and other age-related diseases, such as Alzheimer's disease.

[0008] definition Listed below are definitions of various terms used to describe the compounds and compositions disclosed herein. These definitions apply to the terms as they are used throughout the specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0009] Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art. Generally, the nomenclature used herein and the laboratory procedures in cell culture, molecular genetics, organic chemistry, and peptide chemistry are well known and commonly employed in the art.

[0010] As used herein, the articles "a" and "an" refer to more than one (i.e., at least one) of the grammatical object. By way of example, "an element" means one element or more than one element. Furthermore, use of the term "including," as well as other forms such as "include," "includes," and "included," is not limiting.

[0011] As used herein, the term "about" will be understood by those of ordinary skill in the art and will vary to some extent depending on the context in which "about" is used. As used herein, when referring to a measurable value, e.g., an amount, a duration, etc., the term "about" is intended to include a variation of ±20% or ±10% (including ±5%, ±1%, and ±0.1%) from the specified value, and indeed such variations are appropriate for practicing the disclosed methods.

[0012] The term "administration" and the like, as used herein, refers to providing a therapeutic agent to a subject. There are multiple techniques in the art for administering therapeutic agents, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, intraocular administration, pulmonary administration, and topical administration.

[0013] The terms "treat," "treated," "treating," or "treatment" include the alleviation or alleviation of at least one symptom associated with or caused by the condition, disorder, or disease being treated. In certain embodiments, the treatment includes alleviating or preventing symptoms of inflammation, aging, and age-related disorders.

[0014] As used herein, the term "prevent" or "prevention" means the absence of onset of a disorder or disease if none has occurred, or the absence of further onset of a disorder or disease if onset of the disorder or disease has already occurred. Also considered is the ability to prevent some or all of the symptoms associated with the disorder or disease.

[0015] As used herein, the terms "patient," "individual," or "subject" refer to a human or non-human mammal. Non-human mammals include, for example, farm animals and pets, such as sheep, cattle, pigs, dogs, cats, and marine mammals. Preferably, the patient, subject, or individual is human.

[0016] As used herein, the terms "effective amount," "pharmaceutically effective amount," and "therapeutically effective amount" refer to a nontoxic but sufficient amount of an agent to produce a desired biological result. That result may be reduction or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. The appropriate therapeutic amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

[0017] As used herein, the term "pharmaceutically acceptable" refers to a substance, e.g., a carrier or diluent, that does not interfere with the biological activity or properties of the compound and is relatively non-toxic, i.e., the substance may be administered to an individual without causing undesired biological effects or interacting in a deleterious way with any of the components of the composition in which it is included.

[0018] As used herein, the term "pharmaceutically acceptable salt" refers to derivatives of the disclosed compounds in which the parent compound has been modified by converting an acidic or basic moiety present therein into its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues, such as amines, alkali or organic salts of acidic residues, carboxylic acids, and the like. Pharmaceutically acceptable salts of the present disclosure include conventional non-toxic salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present disclosure can be synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two; non-aqueous media such as ether, EtOAc, ethanol, isopropanol, or acetonitrile are usually preferred. The phrase "pharmaceutically acceptable salt" is not limited to monosalts, i.e., 1:1 salts. For example, "pharmaceutically acceptable salts" also includes bis-salts, such as bis-hydrochlorides. Lists of suitable salts can be found in Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated herein by reference in its entirety.

[0019] As used herein, the term "composition" or "pharmaceutical composition" refers to a mixture of at least one compound useful within the present disclosure and a pharmaceutically acceptable carrier. The pharmaceutical composition facilitates administration of the compound to a patient or subject. Multiple techniques for administering compounds exist in the art, including, but not limited to, intravenous administration, oral administration, aerosol administration, parenteral administration, intraocular administration, pulmonary administration, and topical administration.

[0020] As used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable substance, composition, or carrier, such as a liquid or solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating substance, that is involved in carrying or transporting a compound useful within the disclosure in or to a patient so that the compound can perform its intended function. Typically, such constructs carry or transport from one organ or part of the body to another. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a formulation containing a compound useful within the disclosure and not harmful to the patient. Some examples of substances which can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose, starches such as corn starch and potato starch, cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients such as cocoa butter and suppository waxes, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, glycols such as propylene glycol, polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol, esters such as ethyl oleate and ethyl laurate, agar, buffers such as magnesium hydroxide and aluminum hydroxide, surfactants, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate-buffered saline, and other non-toxic compatible substances used in pharmaceutical formulations.

[0021] As used herein, "pharmaceutically acceptable carriers" includes any and all coatings, antibacterial and antifungal agents, absorption delaying agents, and the like, that are compatible with the activity of the compounds useful within the present disclosure and are physiologically acceptable to the patient. Supplementary active compounds may also be incorporated into the compositions of the present invention. "Pharmaceutically acceptable carriers" may further include pharmaceutically acceptable salts of the compounds disclosed herein. Other additional ingredients that may be included in pharmaceutical compositions are known in the art and are described, for example, in Remington's Pharmaceutical Sciences (Genaro, Ed., Mack Publishing Co., 1985, Easton, PA), which is incorporated herein by reference.

[0022] As used herein, "inflammaging" is defined as chronic sterile inflammation associated with many age-related diseases.

[0023] As used herein, "age-related disorder" refers to a disorder associated with the aging process. In other words, an age-related disorder is a disease associated with elderly people. Non-limiting examples of age-related diseases include atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension, and Alzheimer's disease. The incidence of all of these diseases increases exponentially with age.

[0024] As used herein, "neurosensory disease" refers to a disorder affecting the brain and nerves found throughout the human body and spinal cord. In some embodiments, the neurosensory disease is associated with aging. In certain embodiments, the neurosensory disease is the result of a traumatic brain injury.

[0025] compound Provided herein are compounds that are inhibitors of the NLRP3 inflammasome and are therefore useful in the treatment of inflammatory disorders, including cancer and other proliferative diseases.

[0026] In one aspect, the present invention provides a compound selected from the group consisting of the compounds in Table 1: [Table 1-1] [Table 1-2] [Table 1-3] or a pharmaceutically acceptable salt thereof.

[0027] In another aspect, the present invention provides a compound selected from the group consisting of the compounds in Table 2: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12]

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

[0028] In one embodiment, the compound of Table 2 is [Table 3] or a pharmaceutically acceptable salt thereof.

[0029] In yet another aspect, the present invention provides a compound selected from the group consisting of the compounds in Table 3: [Table 4] or a pharmaceutically acceptable salt thereof.

[0030] In one embodiment, the compound is a compound of Table 4: [Table 5-1] [Table 5-2] or a pharmaceutically acceptable salt thereof.

[0031] In another embodiment, the compound is a compound of Table 5, [Table 6] or a pharmaceutically acceptable salt thereof.

[0032] In another aspect, the present invention provides a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0033] The compounds disclosed herein may exist as tautomers and optical isomers (e.g., enantiomers, diastereomers, diastereomeric mixtures, racemic mixtures, etc.). Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. Chiral centers of known absolute configuration are labeled with the prefixes R and S and assigned by standard sequencing procedures, preceded, when necessary, by the appropriate locant (Pure & Appl. Chem. 45, 1976, 11-30). Specific examples include chemical structures depicted or labeled as (R*) or (S*). When (R*) or (S*) is used in a compound name or chemical description of a compound, it is intended to convey that the compound is a pure single isomer at that stereocenter, but the absolute configuration of that stereocenter has not been established. Thus, a compound designated as (R*) refers to a compound that is a single isomer at that stereocenter having either the (R) or (S) absolute configuration, and a compound designated as (S*) refers to a compound that is a pure single isomer at that stereocenter having either the (R) or (S) absolute configuration.

[0034] It is generally well known in the art that any compound that is converted in vivo to provide a compound disclosed herein is a prodrug within the scope of this disclosure.

[0035] The methods provided herein can include all isotopes of atoms present in the intermediates or final compounds of the present invention. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more atoms constituting the compounds of the present invention can be replaced or substituted with an isotope of that atom at natural or non-natural abundance. In some embodiments, the compounds contain at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure can be replaced or substituted with deuterium. In some embodiments, the compounds contain two or more deuterium atoms. In some embodiments, the compounds contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton-Century-Crofts, 1971); The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labelling by James R. Hanson, Royal Society of Chemistry, 2011). Isotopically labeled compounds can be used in a variety of studies, e.g., NMR spectroscopy, metabolic experiments and / or assays.

[0036] In embodiments, compounds provided herein have an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0037] Treatment method In one aspect, the present invention provides a method for inhibiting the NLRP3 inflammasome in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0038] In another aspect, the present invention provides a method of treating inflammation in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0039] In another aspect, the present invention provides a method of treating inflammaging in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0040] In another aspect, the present invention provides a method of treating cryopyrin-associated periodic syndromes (CAPS) in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0041] In one embodiment, the CAPS is selected from the group consisting of familial cold autoinflammatory syndrome, MacAl-Wells syndrome, and neonatal-onset multisystem inflammatory disease.

[0042] In another aspect, the present invention provides a method of treating a skin disorder in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0043] In one embodiment, the skin disorder is selected from the group consisting of psoriasis, urticaria, skin photoaging, and eczema.

[0044] In yet another aspect, the present invention provides a method of treating a neurosensory disorder in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0045] In one embodiment, the neurosensory disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), traumatic brain injury, Parkinson's disease, and Alzheimer's disease.

[0046] In another aspect, the present invention provides a method of treating inflammation in a subject in need thereof, comprising administering to the subject a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 But, Hello, OH, OC 1-3 Alkyl, NH2, N(H)C 1-3 Alkyl, N(C 1-6 alkyl)2, C(O)C 1-3 Alkyl and C 3-6 C optionally substituted with a substituent selected from cycloalkyl 1-6 is alkyl, Each R 2 independently, Halo, C 1-3 Haloalkyl, OH, OC 1-3 Alkyl, OC 3-6 Cycloalkyl and C 3-6 cycloalkyl; R3 But, H, Halo, C 1-3 Haloalkyl, OH, OC 1-3 Alkyl, OC 3-6 Cycloalkyl, CN and C 3-6 cycloalkyl; n is 0, 1 or 2.

[0047] In one embodiment, R 1 is C optionally substituted with OH 1-6 is alkyl, Each R 2 are independently halo and C 3-6 cycloalkyl; R 3 is the halo, n is 1 or 2. In another aspect, the present invention provides a method of treating inflammation-aging and neurosensory disorders in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I and at least one pharmaceutically acceptable carrier.

[0048] In one embodiment, the neurosensory disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), traumatic brain injury, Parkinson's disease, and Alzheimer's disease.

[0049] In yet another aspect, the present invention provides a method for inhibiting the NLRP3 inflammasome in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of formula I and at least one pharmaceutically acceptable carrier.

[0050] In another embodiment, the compound of formula I is [Table 7-1] [Table 7-2] [Table 7-3] or a pharmaceutically acceptable salt thereof.

[0051] In yet another embodiment, the compound of formula I is [Table 8] or a pharmaceutically acceptable salt thereof.

[0052] The present invention provides methods of using the compounds provided herein to treat or ameliorate aging or age-related conditions that adversely affect lifespan or quality of life, including conditions associated with inflammation, anemia, hyperglycemia, dyslipidemia, hyperinsulinemia, insulin resistance, immunosuppression, liver disease, iron overload, hypertriglyceridemia, impaired skin integrity, wound healing, scarring, pain, allergies, sleep disorders and problems, gastrointestinal disorders and problems, Th1-type inflammation, Th2-type inflammation, and T-cell-dependent B-cell proliferation. Inflammatory diseases, T cell-dependent B cell proliferation, allergy, asthma, atherosclerosis, autoimmunity, hypercholesterolemia, chronic inflammation, chronic obstructive pulmonary disease (COPD), Crohn's disease, skin response to tissue injury, fibrosis, hematologic cancers, metabolic diseases, cardiovascular diseases, organ transplantation, psoriasis, liver fibrosis, dermatitis, pulmonary fibrosis, pulmonary response to respiratory infection, restenosis, rheumatoid arthritis, sarcoidosis, stromal biology in tumors, systemic lupus erythematosus (SLE), ulcerative colitis, vascular inflammation, and alpha-smooth muscle actin (αSMA), C D40, CD69, collagen I, collagen III, decorin, e-selectin, eosinophil 3 (CCL26), fibroblast proliferation, human leukocyte antigen-DR isotype (HLA-DR), immunoglobulin G, interferon gamma-inducible protein 10 (IP-10 / CXCL10), interferon-induced T cell alpha chemoattractant (I-TAC / CXCL11), interleukin (IL)-1, IL-1 alpha, IL-2, IL-6, IL-8 (CXCL8), IL-10, IL-17A, IL-17F, keratin 8 / 81, macrophage colony-stimulating factor (M-CSF), matrix metalloproteinase (MMP)-1, MMP-9, monocyte chemoattractant protein 1 (MCP-1), monokine induced by gamma interferon (MIG / CXCL9), plasminogen activator inhibitor 1 (PAI-1), prostaglandin E2 (PGE2), serum amyloid A, T-cell or B-cell proliferation, tissue plasminogen activator (tPA), tumor necrosis factor alpha (TNF-alpha), vascular cell adhesion molecule (VCAM-1),and vascular endothelial growth factor 2 (VEGFR2), and a disease induced or exacerbated by one or more factors selected from the group consisting of, comprising administering a compound provided herein to a subject in need thereof.

[0053] In one aspect, the present invention provides a method of reversing the normal aging process in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0054] In another aspect, provided herein is a method of reversing the normal aging process in a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0055] In yet another aspect, provided herein is a method of extending the lifespan of a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0056] In yet another aspect, the present invention provides a method of extending the lifespan of a subject, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0057] In another aspect, the present invention provides a method of slowing and mitigating the aging process in a subject, comprising administering to the subject a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0058] In another aspect, the present invention provides a method for inhibiting or modulating a proinflammatory pathway in a cell, the method comprising contacting the cell with a compound provided herein, or a pharmaceutically acceptable salt thereof. In yet another aspect, the present invention provides a method for inhibiting or modulating NLRP3 in a cell, the method comprising contacting the cell with a compound provided herein, or a pharmaceutically acceptable salt thereof.

[0059] Treating cells (in vitro or in vivo) expressing the NLRP3 inflammasome with compounds provided herein can result in the inhibition of the pro-inflammatory pathway as well as the inhibition of downstream events associated with that signaling pathway, such as inflammation or inflamed senescence.

[0060] In another aspect, the present invention provides a method of treating a neurosensory disorder in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0061] In one embodiment, the neurosensory disorder is selected from the group consisting of hearing loss, hearing damage, and eye disease, hi one embodiment, the eye disease is retinal nerve damage and optic nerve damage.

[0062] In yet another aspect, the present invention provides a method of treating an inflammatory disorder in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0063] In one embodiment, the inflammatory disorder is selected from the group consisting of allergy, asthma, atopic dermatitis, atherosclerosis, autoimmune disease, celiac disease, chronic inflammation, glomerulonephritis, hepatitis, inflammatory bowel disease, reperfusion injury, SARS-CoV-2 infection, transplant rejection, heart disease, diabetes, arthritis, Crohn's disease, ulcerative colitis, non-alcoholic steatohepatitis (NASH), gout, coronary artery disease, rheumatoid arthritis, intestinal disorders, and acute respiratory distress syndrome (ARDS).

[0064] In another embodiment, the inflammatory disorder is a neuroinflammatory disease, hi yet another embodiment, the inflammatory disorder is labyrinthitis.

[0065] In one embodiment, chronic inflammation includes tissue inflammation, which is chronic inflammation limited to a particular tissue or organ, ie, tissue inflammation includes, for example, skin inflammation, eye inflammation, muscle inflammation, tendon inflammation, ligament inflammation, bone inflammation, cartilage inflammation, lung inflammation, heart inflammation, liver inflammation, pancreas inflammation, kidney inflammation, bladder inflammation, stomach inflammation, intestinal inflammation, neuronal inflammation, and brain inflammation.

[0066] In another embodiment, chronic inflammation includes systemic inflammation. Although the processes involved are the same as tissue inflammation, systemic inflammation is not limited to a particular tissue, but actually inflicts pain throughout the body, including the endothelium and other organ systems. When the inflammation is due to an infection, the term sepsis applies, with the term bacteremia specifically applying to bacterial sepsis and viremia specifically applying to viral sepsis. Vasodilation and organ dysfunction are significant problems associated with a wide range of infections that can lead to septic shock and death.

[0067] In yet another embodiment, the chronic inflammation includes arthritis. Arthritis includes a group of conditions involving damage to the body's joints due to inflammation of the synovial membrane, including, but not limited to, osteoarthritis, rheumatoid arthritis, juvenile idiopathic arthritis, spondyloarthropathies-like ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthritis, enteropathic arthritis associated with inflammatory bowel disease, Whipple's disease and Behçet's disease, septic arthritis, gout (also known as gouty arthritis, crystalline synovitis, and metabolic arthritis), pseudogout (calcium pyrophosphate deposition disease), and Still's disease. Arthritis can affect one infected joint (monoarthritis), two to four joints (oligoarthritis), or five or more joints (polyarthritis), and can be either an autoimmune or non-autoimmune disease.

[0068] In yet another aspect, the present invention provides a method of treating an age-related disorder in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0069] In one embodiment, the age-related disorder is selected from the group consisting of neurodegeneration, cardiovascular disease, insulin resistance, diabetes, osteoporosis, osteoarthritis, cognitive decline, dementia, frailty, cataracts, arthritis, obesity, hypertension, angina pectoris, congestive heart failure, dyslipidemia, myocardial infarction, vascular disease, respiratory disease, kidney disease, cerebrovascular disease, peripheral vascular disease, Alzheimer's disease, diastolic dysfunction, benign prostatic hyperplasia, aortic aneurysm, and emphysema.

[0070] In another aspect, the present invention provides a method of treating a metabolic condition in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0071] In one embodiment, the metabolic condition is selected from the group consisting of diabetes, obesity, cystic fibrosis, and hyperthyroidism.

[0072] In yet another aspect, the present invention provides a method of treating a neurodegenerative disease in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0073] In one embodiment, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Batten disease.

[0074] In one aspect, the present invention provides a method of treating a disease or disorder of the inner ear in a subject in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed herein.

[0075] In one embodiment, the inner ear disease or disorder is selected from the group consisting of hearing loss, hearing impairment, vertigo, Meniere's disease, and tinnitus. In another embodiment, the inner ear disease is hearing loss. In yet another embodiment, the inner ear disease is hearing impairment.

[0076] In another embodiment, the hearing loss is age-related, noise-induced, or the result of a viral infection, hi yet another embodiment, the viral infection is Zika virus or coronavirus.

[0077] The potency of the inhibitors of the present invention is measured by IC 50 It can also be determined by the value of IC 50 Compounds with lower IC values ​​have lower IC values ​​when determined under substantially similar conditions. 50 are more potent inhibitors than compounds with higher values.

[0078] In embodiments of the methods of the present invention, the subject is a human.

[0079] In another aspect, the present disclosure provides a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for treating or preventing a disease in which the NLRP3 inflammasome plays a role.

[0080] In one aspect, the present invention provides a method of treating a condition selected from the group consisting of autoimmune diseases, inflammatory diseases, proliferative and hyperproliferative diseases, immune-mediated diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cardiovascular diseases, hormone-related diseases, allergies, asthma, and Alzheimer's disease. In another embodiment, the condition is selected from a proliferative disorder and a neurodegenerative disorder.

[0081] One aspect of the present disclosure provides compounds useful for treating diseases, disorders, and conditions characterized by excessive or abnormal cell proliferation. Such diseases include, but are not limited to, proliferative or hyperproliferative diseases and neurodegenerative diseases. Examples of proliferative and hyperproliferative diseases include, but are not limited to, cancer.

[0082] Thus, in one aspect, the present invention provides a method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof.

[0083] In one embodiment, the cancer is selected from the group consisting of breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, colorectal, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder cancer, liver and biliary tract, kidney cancer, bone marrow disorders, lymphatic system disorders, Hodgkin's, hairy cell, mouth cavity and pharynx (oral), lip, tongue, mouth cavity, pharynx, small intestine, colon, rectum, large intestine, rectum, brain and central nervous system, chronic myeloid leukemia (CML), and leukemia.

[0084] In another embodiment, the cancer is selected from the group consisting of myeloma, lymphoma, or a cancer selected from gastric cancer, renal cancer, head and neck cancer, oropharyngeal cancer, non-small cell lung cancer (NSCLC), endometrial cancer, hepatocellular carcinoma, non-Hodgkin's lymphoma, and lung.

[0085] In one embodiment, the cancer is selected from the group consisting of prostate cancer, colon cancer, lung cancer, squamous cell carcinoma of the head and neck, esophageal cancer, hepatocellular carcinoma, melanoma, sarcoma, gastric cancer, pancreatic cancer, ovarian cancer, and breast cancer.

[0086] In one embodiment, the cancer is selected from the group consisting of tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas, etc. For example, cancers include, but are not limited to, mesothelioma, leukemias and lymphomas, e.g., cutaneous T-cell lymphoma (CTCL), non-cutaneous peripheral T-cell lymphoma, human T-lymphotropic virus (HTLV)-associated lymphomas, e.g., adult T-cell leukemia / lymphoma (ATLL), B-cell lymphoma, acute non-lymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphoma and multiple myeloma, non-Hodgkin's lymphoma, acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, Burkitt's lymphoma, adult T-cell leukemia lymphoma, acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), or hepatocellular carcinoma. Further examples include myelodysplastic syndromes, pediatric solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone tumors and soft tissue sarcomas, common adult solid tumors such as head and neck cancer (e.g., oral cavity, larynx, nasopharynx and esophagus), genitourinary cancer (e.g., prostate, bladder, kidney, uterus, ovaries, testes), lung cancer (e.g., small cell and non-small cell), breast cancer, pancreatic cancer, melanoma and other skin cancers, gastric cancer, brain tumors, tumors associated with Gorlin syndrome (e.g., medulloblastoma, meningioma, etc.), and liver cancer. Additional exemplary forms of cancer that may be treated by the compounds include, but are not limited to, skeletal or smooth muscle cancer, gastric cancer, cancer of the small intestine, rectal cancer, salivary gland cancer, uterine cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

[0087] Additional cancers that the compounds described herein may be useful in treating are, for example, colon cancer, familial adenomatous polyposis cancer and hereditary nonpolyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, lip cancer, laryngeal cancer, hypopharyngeal cancer, tongue cancer, salivary gland cancer, gastric cancer, adenocarcinoma, thyroid cancer (medullary thyroid cancer and papillary thyroid cancer), kidney cancer, renal parenchymal cancer, cervical cancer, uterine cancer, endometrial cancer, choriocarcinoma, testicular cancer, urinary tract cancer, melanoma, brain tumors such as glioblastoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumor, gallbladder cancer, bronchial carcinoma, multiple myeloma, basal cell tumor, teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, and plasmacytoma.

[0088] In another aspect, the present invention provides the use of one or more compounds of the present disclosure in the manufacture of a medicament for the treatment of cancer, including, but not limited to, the various types of cancer disclosed herein.

[0089] In some embodiments, compounds of the present disclosure are useful for treating cancer, such as colorectal cancer, thyroid cancer, breast cancer, and lung cancer, and myeloproliferative disorders, such as polycythemia vera, thrombocythemia, myeloid metaplasia with myelofibrosis, chronic myelogenous leukemia, chronic myelomonocytic leukemia, hypereosinophilic syndrome, juvenile myelomonocytic leukemia, and systemic mastocytosis. In some embodiments, compounds of the present disclosure are useful for treating hematopoietic disorders, particularly acute myeloid leukemia (AML), chronic myelogenous leukemia (CML), acute promyelocytic leukemia, and acute lymphoblastic leukemia (ALL).

[0090] Administration / Dosage / Formulation Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, EtOAc, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents and aromatics, may also be added to the oral compositions.

[0091] Injectable preparations (e.g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be injectable sterile solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any bland fixed oil can be used, including synthetic monoglycerides or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0092] In order to prolong the effect of drug, it is often desirable to delay the absorption of drug from subcutaneous injection or intramuscular injection.This can be achieved by using liquid suspension of crystalline or amorphous substance with poor water solubility.In addition, the absorption rate of the drug depends on its dissolution rate, which in turn depends on crystal size and crystalline form.Alternatively, the absorption delay of parenterally administered drug form can be achieved by dissolving or suspending the drug in oil vehicle.

[0093] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of the present disclosure with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0094] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled capsules using such excipients as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like.

[0095] The active compound of the present invention can also be in microencapsulated form with one or more of the excipients described above. Solid dosage forms such as tablets, sugar-coated tablets, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms may also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose, as is customary. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents.

[0096] Dosage forms for topical or transdermal administration of the compounds of the present disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier, and any needed preservatives or buffers, as needed. Ophthalmic formulations, ear drops, eye ointments, powders, and solutions are also contemplated as being within the scope of the present disclosure.

[0097] The ointments, pastes, creams and gels may contain, in addition to the active compounds of the present disclosure, excipients such as animal fats and oils, vegetable fats and oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0098] Powders and sprays can contain, in addition to the compounds of this disclosure, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain custom-made propellants, such as chlorofluorohydrocarbons.

[0099] Transdermal patches have the additional advantage of allowing controlled delivery of compounds to the body. Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the amount of the compound that penetrates the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0100] The compounds of the present disclosure can be administered intratympanically, where a long, thin bore needle is passed through the ear canal and tympanic membrane to administer the agent into the middle ear cavity, where it is absorbed by the inner ear.

[0101] According to the therapeutic method of the present disclosure, a disorder is treated or prevented in a subject, for example, a human or other animal, by administering to the subject a therapeutically effective amount of a compound of the present disclosure, in such an amount and for such a time as is necessary to achieve the desired result. As used herein, the term "therapeutically effective amount" of a compound of the present disclosure means an amount of the compound sufficient to alleviate the symptoms of the disorder in the subject. As is well understood in the medical field, a therapeutically effective amount of a compound of the present disclosure will have a reasonable benefit / risk ratio applicable to any medical treatment.

[0102] Typically, the compounds of the present disclosure will be administered in a therapeutically effective amount, either alone or in combination with one or more other therapeutic agents, by any of the conventional and accepted methods known in the art. Therapeutically effective amounts can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. Satisfactory results have generally been obtained with a daily dosage of about 0.03 to 2.5 mg per kg of body weight, systemically. Indicated daily dosages for larger mammals, such as humans, range from about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to four times daily or in delayed form. Suitable unit dosage forms for oral administration contain about 1 to 50 mg of the active ingredient.

[0103] In certain embodiments, the therapeutic amount or dose of a compound of the present disclosure may range from about 0.1 mg / kg to about 500 mg / kg, or from about 1 to about 50 mg / kg. Typically, a treatment regimen according to the present disclosure involves administering to a patient in need of such treatment about 10 mg to about 1000 mg of a compound(s) of the present disclosure per day, in single or multiple doses. The therapeutic amount or dose will also vary depending on the route of administration and the possibility of co-administration with other drugs.

[0104] Once the condition of the subject is improved, the compound, composition or combination of the present disclosure can be administered at a maintenance dose as needed.Then, dosage or administration frequency, or both, can be reduced according to symptoms to maintain the improved condition, and when the condition is alleviated to desired level, treatment should be stopped.However, if the symptom of the disease recurs even slightly, the subject may need to be intermittently treated for a long period of time.

[0105] It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific inhibitory dose for any particular patient will depend on a variety of factors, including the disorder being treated and the severity of the disorder, the activity of the specific compound employed, the specific composition employed, the patient's age, weight, general health, age and diet, the time of administration, route of administration and rate of excretion of the specific compound employed, the duration of treatment, drugs used in combination or concomitantly with the specific compound employed, and similar factors well known in the medical arts.

[0106] The present disclosure also provides pharmaceutical combinations, e.g., kits, comprising: a) a first agent that is a compound of the present disclosure, as disclosed herein, in free form or in pharmaceutically acceptable salt form; and b) at least one concomitant agent. The kit may include instructions for administration thereof.

[0107] Some examples of substances which can function as pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose, starches such as corn starch and butter. Examples of suitable additives include, but are not limited to, starch, cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate, powdered tragacanth, malt, gelatin, talc, excipients, such as cocoa butter and suppository wax, oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil, glycols, such as propylene glycol or polyethylene glycol, esters, such as ethyl oleate and ethyl laurate, agar, buffers, such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and phosphate-buffered saline. In addition, the compositions may contain non-toxic, compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings, and perfuming agents, preservatives, and antioxidants, according to the discretion of the pharmaceutical practitioner. The protein kinase inhibitors of the present invention, or pharmaceutical salts thereof, may be formulated into pharmaceutical compositions for administration to animals or humans. These pharmaceutical compositions, which comprise the protein inhibitor in an amount effective to treat or prevent a protein kinase-mediated condition and a pharmaceutically acceptable carrier, are another embodiment of the present disclosure.

[0108] kit In one aspect, the present invention provides a kit comprising a compound capable of inhibiting NLRP3 inflammasome activity, selected from one or more of the compounds disclosed herein, or a pharmaceutically acceptable salt thereof, and instructions for use in treating an NLRP3 inflammasome-associated disorder.

[0109] In another aspect, the present disclosure provides a kit comprising a compound capable of inhibiting NLRP3 inflammasome activity selected from the compounds disclosed herein, or a pharmaceutically acceptable salt thereof.

[0110] In yet another aspect, the present invention provides a kit comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for treating any of the indications disclosed herein.

[0111] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents are considered to be within the scope of this disclosure and are encompassed by the claims appended hereto. For example, it should be understood that varying reaction conditions (including, but not limited to, reaction times, reaction sizes / volumes, and experimental reagents, e.g., solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing / oxidizing agents) using no more than routine experimentation with art-recognized substitutes is within the scope of this application.

[0112] Whenever values ​​and ranges are given herein, it should be understood that all values ​​and ranges that fall within those values ​​and ranges are intended to be included within the scope of the disclosure. Furthermore, all values ​​that fall within those ranges, as well as the upper or lower limits of a range of values, are also contemplated by the application.

[0113] The following examples further illustrate aspects of the present disclosure, but are not intended to limit the teachings of the disclosure as set forth in any way. [Example]

[0114] The compounds and methods disclosed herein are further illustrated by the following examples, which should not be construed as further limiting. The practice of the present disclosure employs, unless otherwise indicated, conventional techniques of organic synthesis, cell biology, cell culture, and molecular biology, which are within the skill of the art.

[0115] Example 1: Synthetic Procedure [ka]

[0116] To a solution of compound 1 (1 g, 3.66 mmol, 1 eq) and compound 2 (506.30 mg, 3.66 mmol, 1 eq) in DMF (10 mL) in a 40 mL glass vial, TBAF (1 M, 4.03 mL, 1.1 eq), TEA (740.98 mg, 7.32 mmol, 1.02 mL, 2 eq), CuI (139.46 mg, 732.27 μmol, 0.2 eq), and Pd(PPh3)2Cl2 (256.99 mg, 366.14 μmol, 0.1 eq) were added. The mixture was stirred at 100 °C for 12 h under a N2 atmosphere. The reaction mixture was poured into water (60 mL) and extracted with EtOAc (50 mL × 5). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 1 / 0 → 5 / 1), and the purified solution was concentrated in vacuo to give compound 3 (280 mg, 1.08 mmol, 29.61% yield) as a brown oil. LCMS: Retention time = 0.530 min, m / z = 259.1 (M+H) +

[0117] To a solution of compound 3 (280 mg, 1.08 mmol, 1 eq) in EtOH (3 mL) and HO (1 mL) in a round-bottom flask (50 mL) was added LiOH·HO (136.46 mg, 3.25 mmol, 3 eq). The mixture was stirred at 20 °C for 1 h. The organic solvent was evaporated under vacuum, and the resulting mixture was acidified to pH 4 with 1 N HCl, filtered, and the filter cake was washed with water (20 mL), then dissolved in EtOH (20 mL) and concentrated in vacuo to give compound 4 (240 mg, 1.04 mmol, 96.16% yield) as a yellow solid, which was used in the next step. LCMS: retention time = 0.307 min, m / z = 229.1 (M−H). +

[0118] To a solution of compound 4 (131.39 mg, 570.63 μmol, 1 eq) and compound 5 (200 mg, 570.63 μmol, 1 eq) in DCM (10 mL) in a round-bottom flask (50 mL) was added EDCI (164.09 mg, 855.95 μmol, 1.5 eq) and DMAP (6.97 mg, 57.06 μmol, 0.1 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 5 / 1 → 0 / 1), and the purified solution was concentrated in vacuo to give compound 6 (285 mg, 506.46 μmol, 88.75% yield) as a yellow oil. LCMS: retention time = 0.549 min, m / z = 563.3 (M+H). +

[0119] To a solution of compound 6 (285 mg, 506.46 μmol, 1 eq) in MeOH (5 mL) was added LiBH (33.10 mg, 1.52 mmol, 3 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into saturated aqueous NH Cl (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were dried and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, EtOAc:methanol = 1 / 0 → 10 / 1), and the purified solution was concentrated in vacuo to give compound 7 (150 mg, 280.52 μmol, 55.39% yield) as a yellow oil. LCMS: retention time = 0.452 min, m / z = 535.3 (M+H). +

[0120] To a solution of compound 7 (150 mg, 280.52 μmol, 1 eq) in DCM (10 mL) in a glass bottle (40 mL) was added BAST (124.13 mg, 561.04 μmol, 122.90 μL, 2 eq) at 0 °C. The mixture was stirred at 20 °C for 10 min. The reaction mixture was cooled in an ice bath and then poured into saturated aqueous NaHCO (20 mL) and extracted with DCM (30 mL × 3). The combined organic phases were dried and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO, PE: EtOAc = 0:1), and the purified solution was concentrated in vacuo to give compound 8 (40 mg, 74.53 μmol, 26.57% yield) as a colorless oil. LCMS: retention time = 0.530 min, m / z = 537.3 (M+H). +

[0121] To a solution of compound 8 (35 mg, 65.21 μmol, 1 eq) in DMF (1 mL) in a glass vial (8 mL) was added CsF (99.06 mg, 652.12 μmol, 24.04 μL, 10 eq). The mixture was stirred at 100°C for 12 hours. The mixture was stirred at 100°C for 60 hours. The mixture was stirred at 120°C for 24 hours. The reaction mixture was filtered. The filtrate was purified by preparative HPLC (column: Water xbridge (150 × 25 mm, 10 μm), mobile phase: [water (NH4HCO3)-ACN], B (%): 34% → 64%, 8 min). The purified solution was lyophilized to give 001 (5.9 mg, 14.52 μmol, yield 22.26%, purity 100%) as a white solid. LCMS: Retention time = 0.379 min, m / z = 407.0 (M+H) + 1H NMR (400 MHz, chloroform-d) δ = 12.28 - 12.15 (m, 1H), 8.45 - 8.39 (m, 1H), 8.26 - 8.21 (m, 1H), 7.39 - 7.34 (m, 1H), 6.95 - 6.90 (m, 2H), 5.93 - 5.69 (m, 2H), 4.95 - 4.86 (m, 2H), 4.15 - 4.04 (m, 2H), 3.01 - 2.92 (m, 3H), 1.49 (br s, 1H), 1.49 - 1.44 (m, 3H), 0.93 - 0.87 (m, 2H), 0.87 (br s, 2H).

[0122] Compound 012 was prepared in the same manner as in Scheme 1, using TFA instead of CsF, and obtained as an off-white solid (57 mg, 123.90 μmol, 72.57% yield and 99% purity). LCMS: Retention time = 0.423 min, m / z = 456.4 (M+H + ) 1H NMR: (400 MHz, chloroform-d) δ = 12.09 - 11.81 (m, 1H), 8.44 (d, J = 2.6 Hz, 1H), 8.29 (s, 1H), 7.50 (d, J = 8.9 Hz, 1H), 7.45 - 7.40 (m, 1H), 7.38 - 7.33 (m, 2H), 7.16 - 7.09 (m, 1H), 5.93 - 5.77 (m, 2H), 5.01 (s, 2H), 4.44 - 4.35 (m, 2H), 3.05 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).

[0123] Compound 013 was prepared in the same manner as in Scheme 1, using DAST instead of BAST, and obtained as a white solid (2.3 mg, 5.83 μmol, 11.77% yield, 100% purity). LCMS: Retention time =0.351 min, m / z= 395.2 (M+H+). 1H NMR: (Chloroform-d): δ 12.20 (1H, br s), 8.41 (1H, d, J=2.5 Hz), 8.24 (1H, s), 7.39 (1H, d, J=8.3 Hz), 6.88-6.98 (2H, m), 5.69-5.91 (2H, m), 4.91 (2H, s), 4.10 (2H, q, J=7.0 Hz), 2.97 (3H, s), 2.49 (2H, q, J=7.5 Hz), 1.47 (3H, t, J=7.0 Hz), 1.23-1.28 (3H, m).

[0124] Compound 014 was prepared similarly to Scheme 1 and obtained as a white solid (6.8 mg, 17.83 μmol, 22.67% yield, 99.2% purity). LCMS: Retention time = 0.472 min, m / z = 379.0 (M+H). +1H NMR (400 MHz, chloroform-d) δ = 12.29 - 12.14 (m, 1H), 8.28 - 8.18 (m, 2H), 7.39 (d, J = 7.9 Hz, 1H), 6.99 - 6.87 (m, 2H), 5.15 - 5.07 (m, 2H), 4.95 - 4.86 (m, 2H), 4.11 (q, J = 6.9 Hz, 2H), 3.01 - 2.94 (m, 3H), 2.12 (s, 3H), 1.50 - 1.44 (m, 3H).

[0125] Compound 018 was prepared similarly to Scheme 1 and obtained as a white solid (10.01 mg, 20.37 μmol, 35.18% yield and 100% purity). LCMS: Retention time =0.385 min, m / z=492.1(M+H+). HNMR: (400 MHz, chloroform-d) δ = 8.51 (br s, 1H), 8.33 (s, 1H), 7.47 (s, 1H), 7.41 - 7.28 (m, 3H), 6.92 (d, J = 9.3 Hz, 1H), 6.03 - 5.86 (m, 2H), 4.98 (s, 2H), 3.86 - 3.72 (m, 1H), 3.09 (s, 3H), 0.84 (br d, J = 5.9 Hz, 2H), 0.72 (br s, 2H).

[0126] Compound 019 was prepared in a similar manner to Scheme 1 and obtained as a white solid (6.5 mg, 13.66 μmol, 14.99% yield, 99.5% purity). LCMS: Retention time = 0.390 min, m / z = 474.0 (M+H). +1H NMR (400 MHz, chloroform-d) δ ppm 12.13 - 12.39 (m, 1 H) 8.46 - 8.52 (m, 1 H) 8.27 - 8.35 (m, 1 H) 7.64 - 7.68 (m, 2 H) 7.57 - 7.61 (m, 1 H) 7.50 - 7.55 (m, 1 H) 7.25 - 7.26 (m, 1 H) 6.90 - 6.93 (m, 1 H) 5.83 - 6.02 (m, 2 H) 4.95 - 5.01 (m, 2 H) 3.72 - 3.81 (m, 1 H) 3.06 - 3.12 (m, 3H) 0.79 - 0.84 (m, 2 H) 0.68 - 0.74 (m, 2 H).

[0127] Compound 020 was prepared similarly to Scheme 1 and obtained as a white solid (7 mg, 14.45 μmol, 12.69% yield). 1 H-NMR: (400 MHz, chloroform-d) δ = 12.64 - 11.79 (m, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.28 (s, 1H), 7.23 (s, 1H), 6.91 - 6.81 (m, 4H), 5.91 - 5.77 (m, 2H), 4.96 (s, 2H), 3.76 (tt, J = 2.9, 5.8 Hz, 1H), 3.07 (s, 3H), 0.83 - 0.79 (m, 2H), 0.75 - 0.70 (m, 2H). LCMS: Retention time = 0.419 min, m / z = 484.9 (M+H + ).

[0128] Compound 022 was prepared similarly to Scheme 1 and obtained as a white solid (6.5 mg, 13.41 μmol, 32.88% yield, 99.6% purity). LCMS: Retention time = 0.435 min, m / z = 483.2 (M+H). +1H NMR (400 MHz, chloroform-d) δ = 12.62 - 11.60 (m, 1H), 8.44 (d, J = 2.3 Hz, 1H), 8.31 - 8.25 (m, 1H), 7.36 - 7.32 (m, 3H), 7.25 - 7.20 (m, 2H), 6.91 - 6.86 (m, 1H), 5.94 - 5.76 (m, 2H), 4.99 - 4.92 (m, 2H), 3.80 - 3.71 (m, 1H), 3.10 - 3.04 (m, 3H), 0.83 - 0.76 (m, 2H), 0.75 - 0.68 (m, 2H).

[0129] Compound 027 was prepared similarly to Scheme 1 and obtained as a white solid (15.5 mg, 32.76 μmol, 48.88% yield, 98.6% purity). LCMS: Retention time = 0.424 min, m / z = 467.1 (M+H). + 1H NMR (400 MHz, chloroform-d) δ = 8.45 (d, J = 2.5 Hz, 1H), 8.28 (s, 1H), 7.43 - 7.32 (m, 1H), 7.24 (s, 1H), 7.12 (br d, J = 7.4 Hz, 1H), 7.09 - 7.04 (m, 2H), 6.89 (d, J = 8.9 Hz, 1H), 5.95 - 5.79 (m, 2H), 4.96 (s, 2H), 3.76 (br d, J = 3.0 Hz, 1H), 3.08 (s, 3H), 0.91 - 0.86 (m, 2H), 0.80 (br d, J = 5.5 Hz, 2H).

[0130] Compound 046 was prepared in a similar manner to Scheme 1 and obtained as a white solid (45 mg, 92.32 μmol, 38.02% yield, 100% purity). LCMS: Retention time = 0.445 min, m / z = 488.1 (M+H). +1H NMR (400 MHz, chloroform-d) δ ppm 12.11 - 12.36 (m, 1 H) 8.40 - 8.45 (m, 1 H) 8.26 - 8.31 (m, 1 H) 7.87 - 7.92 (m, 1 H) 7.74 - 7.80 (m, 2 H) 7.62 - 7.67 (m, 1 H) 7.54 - 7.59 (m, 1 H) 7.51 (d, J=7.63 Hz, 1 H) 5.75 - 5.92 (m, 2 H) 4.93 - 5.01 (m, 2 H) 4.42 (q, J=7.13 Hz, 2 H) 3.22 (s, 3H) 1.33 - 1.41 (m, 3 H).

[0131] Compound 071 was prepared in the same manner as in Scheme 1, using TFA instead of CsF, to give a white solid (5.4 mg, 11.08 μmol, 22.65% yield, 99.1% purity). LCMS: Retention time = 0.432 min, m / z = 483.2 (M+H). + 1H NMR (400 MHz, chloroform-d) δ = 1 8.44 (d, J = 2.8 Hz, 1H), 8.28 (s, 1H), 7.38 - 7.31 (m, 3H), 7.23 (s, 2H), 6.89 (d, J = 9.0 Hz, 1H), 5.93 - 5.76 (m, 2H), 4.96 (s, 2H), 3.75 (td, J = 3.0, 5.8 Hz, 1H), 3.07 (s, 3H), 0.84 - 0.77 (m, 2H), 0.75 - 0.69 (m, 2H).

[0132] Compound 082 was prepared in the same manner as in Scheme 1, using TFA instead of CsF, and obtained as a white solid (10.38 mg, 21.98 μmol, 43.80% yield, 99% purity). LCMS: Retention time = 0.370 min, m / z = 478.1 (M+Na + ) 1H NMR: (400 MHz, chloroform-d) δ = 12.35 (br d, J = 5.4 Hz, 1H), 8.48 - 8.19 (m, 2H), 7.77 (s, 1H), 7.69 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 7.8 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.41 (d, J = 1.0 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.09 (dd, J = 1.3, 7.7 Hz, 1H), 5.18 (s, 2H), 5.01 (s, 2H), 3.77 (td, J = 2.9, 5.9 Hz, 1H), 3.34 (q, J = 7.0 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H), 0.85 - 0.79 (m, 2H), 0.78 - 0.72 (m, 2H).

[0133] Compound 092 was prepared in the same manner as in Scheme 1, using TFA instead of CsF, and obtained as a white solid (20.4 mg, 41.22 μmol, 36.81% yield, 100% purity). LCMS: Retention time = 0.416 min, m / z = 495.1 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ = 12.97 - 11.80 (m, 1H), 8.37 - 8.28 (m, 2H), 7.38 - 7.32 (m, 3H), 7.23 (br s, 1H), 7.17 (s, 1H), 6.84 (br d, J = 8.9 Hz, 1H), 5.25 - 5.15 (m, 2H), 4.99 (s, 2H), 3.73 (br d, J = 2.6 Hz, 1H), 3.35 (q, J = 6.6 Hz, 2H), 1.33 (br t, J = 6.8 Hz, 3H), 0.82 - 0.76 (m, 2H), 0.72 (br s, 2H).

[0134] Compound 093 was prepared similarly to Scheme 1 and obtained as a white solid (4.2 mg, 8.98 μmol, 26.43% yield, 98% purity). LCMS: Retention time = 0.383 min, m / z = 459.0 (M+H). + 1H NMR (400 MHz, chloroform-d) δ = 12.48 - 11.84 (m, 1H), 8.26 (br d, J = 4.6 Hz, 2H), 7.49 - 7.38 (m, 1H), 6.91 - 6.77 (m, 3H), 5.13 (s, 2H), 4.98 - 4.82 (m, 2H), 4.19 (q, J = 7.0 Hz, 2H), 3.03 (s, 3H), 1.54 (t, J = 7.0 Hz, 3H).

[0135] Compound 105 was prepared analogously to Scheme 1 and obtained as a white solid (5.8 mg, 12.16 μmol, 23.71% yield and 95.3% purity). LCMS: Retention time = 0.384 min, m / z = 454.13 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.37 - 12.07 (m, 1H), 8.45 (d, J = 2.5 Hz, 1H), 8.27 (s, 1H), 7.59 (br s, 1H), 7.45 (d, J = 4.9 Hz, 1H), 7.27 - 7.25 (m, 1H), 7.19 - 7.08 (m, 1H), 6.98 - 6.86 (m, 1H), 5.94 - 5.78 (m, 2H), 4.95 (s, 2H), 3.91 - 3.83 (m, 1H), 3.07 (s, 3H), 0.91 - 0.85 (m, 4H).

[0136] Compound 110 was prepared analogously to Scheme 1 and obtained as a white solid (3.7 mg, 8.06 μmol, 15.71% yield, 99% purity). LCMS: Retention time = 0.372 min, m / z = 455.1 (M+H +). HNMR: (400 MHz, chloroform-d) δ = 12.53 - 12.11 (m, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 7.56 (d, J = 1.3 Hz, 1H), 7.37 - 7.31 (m, 2H), 7.25 ( s, 1H), 6.90 (d, J = 10.0 Hz, 1H), 6.07 - 5.80 (m, 2H), 4.96 (s, 2H), 3.80 (d, J = 3.4 Hz, 1H), 3.08 (s, 3H), 0.83 (t, J = 5.0 Hz, 2H), 0.81 - 0.77 (m, 2H).

[0137] Compound 173 was prepared in the same manner as in Scheme 1, using TFA instead of CsF, and obtained as a white solid (14.2 mg, 31.05 μmol, 36.06% yield, 98.5% purity). LCMS: Retention time = 0.373 min, m / z = 451.3 (M+H + ) 1 H NMR (400 MHz, chloroform-d) δ = 12.24 (br s, 1H), 8.35 (d, J = 2.1 Hz, 1H), 7.40 - 7.28 (m, 4H), 7.09 - 7.00 (m, 3H), 5.86 (s, 1H), 5.89 - 5.70 (m, 1H), 5.74 (s, 1H), 5.11 (s, 2H), 4.07 (q, J = 7.0 Hz, 2H), 3.04 (s, 3H), 2.81 (s, 3H), 1.38 (t, J = 6.9 Hz, 3H).

[0138] Compound 183 was prepared in the same manner as in Scheme 1, using TFA instead of CsF, and obtained as a white solid (29.0 mg, 60.80 μmol, 25.33% yield, 99.5% purity). LCMS: Retention time = 0.393 min, m / z = 477.0 (M+H + ) 1 H NMR: 1H NMR (400 MHz, chloroform-d) δ = 12.64 - 12.08 (m, 1H), 8.30 (br d, J = 13.6 Hz, 2H), 7.45 (s, 1H), 7.38 (s, 1H), 7.36 - 7.30 (m, 4H), 7.08 - 7.04 (m, 1H), 5.17 (s, 2H), 5.03 - 4.98 (m, 2H), 3.75 (tt, J = 3.0, 5.8 Hz, 1H), 3.38 - 3.31 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H), 0.84 - 0.73 (m, 4H).

[0139] [ka]

[0140] To a solution of compound 1 (200 mg, 768.46 μmol, 1 eq) and compound 2 (323.20 mg, 922.16 μmol, 1.2 eq) in DCM (4 mL) was added EDCI (220.97 mg, 1.15 mmol, 1.5 eq) and DMAP (9.39 mg, 76.85 μmol, 0.1 eq). The mixture was stirred at 20° C. for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, PE:EtOAc=0:1). Compound 3 (450 mg, 607.36 μmol, 79.04% yield, 80% purity) was obtained as a yellow oil. LCMS: retention time = 0.525 min, m / z = 593.9 (M+H + )

[0141] To a solution of compound 3 (150 mg, 253.07 μmol, 1 eq) in DCM (2 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 106.74 eq). The mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna (C18, 150×25 mm, 10 μm), mobile phase: [water (FA)-ACN], B (%): 40% to 70%, 10 min). The purified solution was then lyophilized to give the product. 002 (24.6 mg, 52.98 μmol, 20.94% yield, 99.6% purity) was obtained as a white solid. LCMS: retention time = 0.455 min, m / z = 462.17 (M+H + ) 1 H NMR: (400 MHz, DMSO-d6) δ = 14.10 - 13.56 (m, 1H), 8.60 (br s, 1H), 8.44 (br s, 1H), 7.43 (br d, J = 6.3 Hz, 2H), 7.40 - 7.30 (m, 2H), 7.25 - 7.08 (m, 3H), 5.07 (br s, 2H), 4.13 (br s, 2H), 3.99 (s, 3H), 3.07 (br s, 3H), 1.37 - 1.19 (m, 3H).

[0142] Compound 021 was prepared similarly to Scheme 2, using CsF instead of TFA, and obtained as a green solid (10.2 mg, 21.75 μmol, 26.07% yield, 100% purity). LCMS: Retention time = 0.361 min, m / z = 469.0 (M+H). +1H NMR (400 MHz, chloroform-d) δ ppm 12.20 - 12.70 (m, 1 H) 8.26 - 8.38 (m, 2 H) 7.60 - 7.64 (m, 1 H) 7.43 - 7.46 (m, 1 H) 7.29 (d, J=4.00 Hz, 1 H) 7.09 (dd, J=8.07, 1.06 Hz, 1 H) 6.89 - 6.93 (m, 1 H) 5.17 - 5.23 (m, 2 H) 4.97 (s, 2 H) 3.86 - 3.95 (m, 1 H) 3.05 - 3.09 (m, 3 H) 0.88 - 0.93 (m, 4 H).

[0143] Compound 028 was prepared similarly to Scheme 2 and obtained as a white solid (17.3 mg, 37.15 μmol, 36.72% yield, 99.4% purity). LCMS: Retention time = 0.401 min, m / z = 463.4 (M+H). + 1H NMR (400 MHz, chloroform-d) δ = 8.42 - 8.32 (m, 2H), 7.46 - 7.43 (m, 2H), 7.37 - 7.29 (m, 4H), 7.11 (d, J = 7.8 Hz, 1H), 5.23 (s, 2H), 4.98 (s, 2H), 3.80 - 3.75 (m, 1H), 3.09 (s, 3H), 0.85 - 0.79 (m, 2H), 0.78 - 0.72 (m, 2H).

[0144] Compound 032 was prepared similarly to Scheme 2 and obtained as a white solid (3.5 mg, 7.31 μmol, 7.42% yield, 100% purity). LCMS: Retention time = 0.408 min, m / z = 478.16 (M+H + ) 1 H NMR: 1H NMR (400 MHz, chloroform-d) δ = 12.46 - 12.28 (m, 1H), 8.34 - 8.34 (m, 1H), 8.40 - 8.33 (m, 1H), 8.27 (s, 1H), 7.36 - 7.33 (m, 3H), 7.23 (br d, J = 4.0 Hz, 1H), 7.18 (s, 1H), 6.85 (d, J = 8.9 Hz, 1H), 4.97 (s, 2H), 3.77 - 3.71 (m, 1H), 3.34 (q, J = 7.0 Hz, 2H), 3.02 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H), 0.81 - 0.71 (m, 4H).

[0145] Compound 033 was prepared analogously to Scheme 2 and obtained as a white solid (10.2 mg, 23.46 μmol, 43.85% yield and 99% purity). LCMS: Retention time = 0.452 min, m / z = 450.9 (M+H + ). 1H NMR: 1H NMR (chloroform-d): δ 12.05-12.27 (1H, m), 9.05 (1H, s), 8.22 (1H, s), 7.33-7.44 (5H, m), 7.23 (1H, s), 6.86-6.91 (1H, m), 5.12 (2H, s), 3.67-3.81 (1H, m), 3.08 (3H, s), 2.87 (3H, s), 0.75-0.81 (2H, m), 0.68-0.74 (2H, m).

[0146] Compound 038 was prepared similarly to Scheme 2 and obtained as a white solid (53.1 mg, 118.40 μmol, 42.83% yield, 100% purity). LCMS: Retention time = 0.388 min, m / z = 449.4 (M+H). +1H NMR (400 MHz, chloroform-d) δ = 8.57 (s, 1H), 8.50 (s, 1H), 7.42–7.34 (m, 1H), 7.24 (s, 1H), 7.15–7.04 (m, 3H), 6.93–6.88 (m, 1H), 4.98 (s, 2H), 3.80–3.72 (m, 1H), 3.13 (s, 6H), 0.85–0.78 (m, 2H), 0.76–0.70 (m, 2H).

[0147] Compound 048 was prepared similarly to Scheme 2 and obtained as a white solid (15.4 mg, 32.86 μmol, 27.94% yield, 99.2% purity). LCMS: Retention time = 0.391 min, m / z = 465.3 (M+H). + 1H NMR (400 MHz, chloroform-d) δ = 12.27 - 11.83 (m, 1H), 8.31 - 8.13 (m, 2H), 7.38 - 7.32 (m, 3H), 7.23 (s, 2H), 6.88 (dd, J = 1.1, 9.0 Hz, 1H), 4.92 (s, 2H), 3.75 (tt, J = 2.9, 5.9 Hz, 1H), 3.10 - 3.03 (m, 3H), 2.92 - 2.85 (m, 3H), 0.83 - 0.76 (m, 2H), 0.76 - 0.68 (m, 2H).

[0148] Compound 055 was prepared analogously to Scheme 2 and obtained as a white solid (3.8 mg, 8.18 μmol, 23.76% yield and 97% purity). LCMS: Retention time =0.452 min, m / z= 450.9 (M+H+). 1H NMR: (chloroform-d): δ 12.22 (1H, br s), 8.33-8.43 (2H, m), 7.28-7.41 (4H, m), 7.00-7.11 (3H, m), 6.49 (1H, q, J=7.0 Hz), 5.71-5.93 (2H, m), 3.99-4.15 (2H, m), 2.81 (3H, s), 1.88 (3H, d, J=7.3 Hz), 1.37 (3H, t, J=7.0 Hz).

[0149] Compound 062 was prepared in a similar manner to Scheme 2 and obtained as a colorless oil (11.5 mg, 25.54 μmol, 38.90% yield, 99.6% purity). LCMS: Retention time = 0.382 min, m / z = 449.1 (M+H + ).

[0150] Compound 064 was prepared similarly to Scheme 2 and obtained as a white solid (53.6 mg, 123.14 μmol, 57.54% yield, 98.9% purity). LCMS: Retention time = 0.372 min, m / z = 431.2 (M+H+). 1 H NMR (400 MHz, chloroform-d) δ ppm 0.69 - 0.75 (m, 2 H) 0.76 - 0.82 (m, 2 H) 3.09 - 3.18 (m, 6 H) 3.70 - 3.80 (m, 1 H) 4.96 - 5.02 (m, 2 H) 6.91 (dd, J=9.01, 1.38 Hz, 1 H) 7.24 (s, 1 H) 7.32 - 7.36 (m, 2 H) 7.36 - 7.39 (m, 1 H) 7.39 - 7.45 (m, 2 H) 8.51 (s, 1 H) 8.62 (s, 1 H).

[0151] Compound 065 was prepared similarly to Scheme 2 and obtained as a white solid (16.7 mg, 35.23 μmol, 22.93% yield, 96.1% purity). LCMS: Retention time = 0.356 min, m / z = 456.4 (M+H+). 1 H NMR (400 MHz, chloroform-d) δ = 12.66 - 12.38 (m, 1H), 8.50 - 8.45 (m, 1H), 8.42 (s, 1H), 7.68 - 7.64 (m, 2H), 7.61 - 7.57 (m, 1H), 7.56 - 7.51 (m, 1H), 7.25 (s, 1H), 6.91 (s, 1H), 5.01 - 4.89 (m, 2H), 3.80 - 3.73 (m, 1H), 3.13 - 3.08 (m, 3H), 3.07 - 3.02 (m, 3H), 0.85 - 0.78 (m, 2H), 0.75 - 0.68 (m, 2H).

[0152] Compound 068 was prepared similarly to Scheme 2 and obtained as a yellow oil (13.6 mg, 28.14 μmol, 23.93% yield, 96.2% purity). LCMS: Retention time = 0.407 min, m / z = 465.3 (M+H+). 1 H NMR: (400 MHz, chloroform-d) δ = 13.01 - 12.56 (m, 1H), 9.41 (s, 1H), 8.46 (s, 1H), 7.35 (t, J = 4.3 Hz, 3H), 7.23 (s, 2H), 6.90 (d, J = 9.0 Hz, 1H), 5.14 (s, 2H), 3.75 (tt, J = 2.9, 5.8 Hz, 1H), 3.12 (s, 3H), 3.01 (s, 3H), 1.25 (t, J = 7.0 Hz, 1H), 0.85 - 0.76 (m, 2H), 0.75 - 0.70 (m, 2H).

[0153] Compound 078 was prepared similarly to Scheme 2 and obtained as a white solid (10.5 mg, 22.46 μmol, 29.08% yield, 100% purity). LCMS: Retention time = 0.338 min, m / z = 468.3 (M+H + ) 1 H NMR (400 MHz, chloroform-d) δ = 12.33 (br s, J = 0.8 Hz, 1H), 8.22 (s, 1H), 7.77 (s, 1H), 7.69 (td, J = 1.4, 7.9 Hz, 1H), 7.63 (td, J = 1.3, 7.8 Hz, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.45 (d, J = 1.5 Hz, 1H), 7.32 (d, J = 7.4 Hz, 1H), 7.12 (dd, J = 1.5, 7.8 Hz, 1H), 5.12 - 5.10 (m, 4H), 3.78 (td, J = 3.0, 5.8 Hz, 1H), 3.07 (s, 3H), 2.87 (s, 3H), 1.92 - 1.67 (m, 4H), 0.87 - 0.69 (m, 4H).

[0154] Compound 097 was prepared analogously to Scheme 2 and obtained as a brown solid (19 mg, 42.36 μmol, 49.04% yield and 100% purity). LCMS: Retention time = 0.783 min, m / z = 449.3 (M+H + ) 1 H-NMR: (400 MHz, chloroform-d) δ = 12.42 - 12.13 (m, 1H), 8.28 (d, J = 7.4 Hz, 2H), 7.42 - 7.35 (m, 2H), 7.34 - 7.29 (m, 2H), 7.09 - 6.99 (m, 3H), 5.16 (s, 2H), 5.00 (s, 2H), 4.07 (q, J = 6.9 Hz, 2H), 3.34 (br d, J = 7.1 Hz, 2H), 1.39 (t, J = 7.0 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H).

[0155] Compound 100 was prepared analogously to Scheme 2 and obtained as a white solid (21.1 mg, 43.90 μmol, 34.58% yield and 95.8% purity). LCMS: Retention time = 0.394 min, m / z = 461.1 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.25 (br s, 1H), 8.26 (s, 2H), 7.39 (d, J = 1.3 Hz, 1H), 7.37 - 7.30 (m, 2H), 7.25 - 7.17 (m, 2H), 7.08 - 7.00 (m, 2H), 5.14 (br s, 2H), 4.99 (s, 2H), 3.83 - 3.67 (m, 1H), 3.42 - 3.25 (m, 2H), 1.31 (br t, J = 6.9 Hz, 3H), 0.84 - 0.78 (m, 2H), 0.78 - 0.72 (m, 2H).

[0156] Compound 103 was prepared analogously to Scheme 2 and obtained as a white solid (17.3 mg, 37.71 μmol, 44.18% yield, 99.3% purity). LCMS: Retention time = 0.376 min, m / z = 456.5 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ = 8.44 - 8.33 (m, 2H), 7.85 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.55 - 7.49 (m, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 7.00 (s, 1H), 5.23 (s, 2H), 5.01 (s, 2H), 4.06 (q, J = 6.9 Hz, 2H), 3.35 (q, J = 6.7 Hz, 2H), 1.36 (t, J = 6.9 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H).

[0157] Compound 170 was prepared analogously to Scheme 2 and obtained as a white solid (34.3 mg, 82.69 μmol, 27.45% yield, 98% purity). LCMS: Retention time = 0.357 min, m / z = 407.0 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 8.27 (s, 1H), 8.23 ​​(s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.60 (dd, J = 1.1, 3.7 Hz, 1H), 7.38 (dd, J = 1.1, 5.1 Hz, 1H), 7.11 (dd, J = 3.8, 5.1 Hz, 1H), 7.09 - 7.04 (m, 2H), 4.91 (s, 2H), 4.19 (q, J = 6.9 Hz, 2H), 3.03 (s, 3H), 2.89 (s, 3H), 1.55 (t, J = 6.9 Hz, 3H).

[0158] Compound 177 was prepared analogously to Scheme 2 and obtained as a white solid (20.7 mg, 44.52 μmol, 40.77% yield). H-NMR: (400 MHz, chloroform-d) δ = 8.34 (s, 1H), 8.26 (s, 1H), 7.49 (s, 1H), 7.39 - 7.34 (m, 1H), 7.31 - 7.28 (m, 2H), 7.21 (s, 1H), 7.00 - 6.95 (m, 1H), 6.93 (s, 1H), 5.16 (s, 2H), 4.94 (s, 2H), 4.04 - 3.94 (m, 3H), 3.28 (q, J = 7.0 Hz, 2H), 1.31 (t, J = 6.9 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H).

[0159] [ka]

[0160] In a 100 ml round-bottom flask (100 mL), LiBH (184.03 mg, 8.45 mmol, 10 eq) was added to a solution of compound 1 (500 mg, 844.96 μmol, 1 eq) in MeOH (10 mL). The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into saturated aqueous NH Cl (100 mL) and extracted with EtOAc (100 mL × 3). The combined organic phase was dried and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 0:0 → 1:1). Compound 2 (87 mg, 154.33 μmol, 18.26% yield) was obtained as a white solid. LCMS: retention time = 0.633 min, m / z = 564.1 (M+H + ).

[0161] To a solution of compound 2 (87 mg, 154.33 μmol, 1 eq) in DCM (2 mL) was added MnO (268.34 mg, 3.09 mmol, 20 eq), and the mixture was stirred at 30 °C for 2 h.

[0162] After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to obtain the crude product. The residue was purified by preparative TLC (PE: EtOAc = 1: 1). Compound 3 (57 mg, 101.47 μmol, yield 65.75%) was obtained as a white solid. 1H NMR: (chloroform-d): δ 10.10 (1H, br s), 8.21 (2H, br d, J=13.5 Hz), 7.78-8.03 (1H, m), 7.29-7.46 (3H, m), 6.89-7.22 (4H, m), 5.63-5.99 (2H, m), 5.16-5.44 (2H, m), 3.93-4.34 (2H, m), 3.38-3.70 (2H, m), 3.04-3.28 (3H, m), 1.22-1.41 (3H, m), 0.61-1.02 (2H, m), -0.07 (9H, br s)

[0163] To compound 3 (57 mg, 101.47 μmol, 1 eq) dissolved in MeOH (2 mL) in a 100 mL bottle, HOAc (304.69 μg, 5.07 μmol, 0.29 μL, 0.05 eq) in THF (2 M, 152.21 μL, 3 eq) and MeNH were added, and the reaction mixture was stirred magnetically at 20 °C for 2 h. Subsequently, NaBH (7.68 mg, 202.95 μmol, 2 eq) was added at 0 °C, and the mixture was stirred magnetically at 20 °C for 1 h. After the reaction was complete, the reaction mixture was poured into NH Cl (10 mL), filtered, and the filtrate was concentrated under reduced pressure to give a residue. The solution was then triturated with EtOAc and THF (10 mL), filtered, and the filtrate was concentrated under reduced pressure to give a residue. Compound 4 (57 mg, 98.83 μmol, 97.39% yield) was obtained as a yellow oil, which was used in the next step without further purification. LCMS: Retention time = 0.678 min, m / z = 577.2 (M+H + ).

[0164] To a solution of compound 4 (57 mg, 98.83 μmol, 1 eq) in DCM (2 mL) was added TFA (1.26 g, 11.04 mmol, 817.15 μL, 111.68 eq) in an 8 mL vial. The mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters xbridge (150×25 mm, 10 μm), mobile phase: [water (NH4HCO3)-ACN], B (%): 34% to 64%, 8 min), and the purified product was lyophilized. Compound 003 (8.6 mg, 19.26 μmol, 19.49% yield and 100% purity) was obtained as a white solid. LCMS: retention time = 0.379 min, m / z = 447.4 (M+H +). 1H NMR: (chloroform-d): δ 11.57-12.23 (1H, m), 8.08 (1H, s), 7.68 (1H, s), 7.28-7.40 (5H, m), 7.00-7.09 (3H, m), 4.96 (2H, s), 4.06 (2H, q, J=7.0 Hz), 3.89 (2H, s), 3.01 (3H, s), 2.51 (3H, s), 1.36 (3H, t, J=6.9 Hz).

[0165] Compound 005 was prepared similarly to Scheme 3 and obtained as a white solid (16.3 mg, 35.15 μmol, 50.55% yield, 99.3% purity). LCMS: Retention time = 0.387 min, m / z = 461.4 (M+H). + 1H NMR (400 MHz, chloroform-d) δ ppm 8.43 - 8.52 (m, 1H), 8.21 - 8.25 (m, 1H), 7.26 - 7.38 (m, 4H), 7.25 (s, 1H), 7.16 - 7.20 (m, 1H), 6.98 - 7.07 (m, 3H), 4.94 (s, 2H), 4.00 - 4.08 (m, 4H), 2.96 - 3.02 (m, 3H), 2.45 - 2.52 (m, 6H), 1.31 - 1.38 (m, 3H).

[0166] Compound 006 was prepared analogously to Scheme 3 using dimethylamine instead of methylamine and obtained as a white solid (8.3 mg, 17.66 μmol, 14.91% yield and 98% purity). LCMS: Retention time =0.346 min, m / z= 461.4 (M+H+). 1H NMR: (Chloroform-d): δ 11.94 (1H, br s), 8.07 (1H, s), 7.63 (1H, s), 7.28-7.40 (5H, m), 7.00-7.09 (3H, m), 4.96 (2H, s), 4.07 (2H, q, J=6.9 Hz), 3.57 (2H, s), 3.01 (3H, s), 2.30 (6H, s), 1.37 (3H, t, J=7.0 Hz).

[0167] Compound 024 was prepared in the same manner as in Scheme 3, using methyl Grignard instead of methylamine, and obtained as a white solid (13.8 mg, 28.48 μmol, 36.48% yield). LCMS: Retention time = 0.399 min, m / z = 485.1 (M+H + ) 1 H-NMR: (400 MHz, chloroform-d) δ = 12.17 (br s, 1H), 8.33 (s, 1H), 8.27 (s, 1H), 7.00 - 6.94 (m, 2H), 6.90 - 6.81 (m, 3H), 5.34 (d, J = 6.6 Hz, 1H), 4.95 (s, 2H), 4.07 (q, J = 7.0 Hz, 2H), 3.07 (s, 3H), 1.70 (d, J = 6.6 Hz, 3H), 1.35 (t, J = 6.9 Hz, 3H).

[0168] Compound 025 was prepared in the same manner as in Scheme 3, using ethyl Grignard instead of methylamine, and obtained as a white solid (4.1 mg, 8.76 μmol, 17.31% yield and 98.8% purity). LCMS: Retention time = 0.389 min, m / z = 463.5 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.36 (br d, J = 1.8 Hz, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 7.41 - 7.28 (m, 4H), 7.11 - 7.07 (m, 2H), 7.07 - 7.02 (m, 1H), 5.20 - 5.13 (m, 1H), 5.02 - 4.88 (m, 2H), 4.11 - 4.05 (m, 2H), 3.06 (s, 3H), 1.97 - 1.82 (m, 2H), 1.38 (t, J = 6.9 Hz, 3H), 1.02 (t, J = 7.4 Hz, 3H).

[0169] Compound 026 was prepared in the same manner as in Scheme 3, using methyl Grignard instead of methylamine, and obtained as a white solid (8.8 mg, 18.86 μmol, 29.62% yield). LCMS: Retention time = 0.392 min, m / z = 466.9 (M+H + ) 1 H-NMR: (400 MHz, chloroform-d) δ = 12.41 (br s, 1H), 8.35 (s, 1H), 8.29 (s, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.15 - 7.06 (m, 4H), 6.81 (s, 1H), 5.37 (br d, J = 6.6 Hz, 1H), 4.97 (s, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.07 (s, 3H), 1.71 (d, J = 6.6 Hz, 3H), 1.40 (t, J = 7.0 Hz, 3H).

[0170] Compound 029 was prepared in the same manner as in Scheme 3, using methyl Grignard instead of methylamine, and obtained as a white solid (6.7 mg, 14.71 μmol, 21.54% yield, 100% purity). LCMS: Retention time = 0.366 min, m / z = 456.4 (M+H). + 1H NMR (400 MHz, chloroform-d) δ ppm 12.31 - 12.57 (m, 1 H) 8.37 (s, 1 H) 8.26 - 8.31 (m, 1 H) 7.84 - 7.87 (m, 1 H) 7.74 - 7.80 (m, 1 H) 7.61 - 7.66 (m, 1 H) 7.50 - 7.55 (m, 1 H) 7.32 - 7.36 (m, 1 H) 7.09 (s, 2 H) 5.35 - 5.43 (m, 1 H) 4.94 - 4.99 (m, 2 H) 4.05 - 4.12 (m, 2 H) 3.06 - 3.09 (m, 3H) 1.72 (br d, J=6.63 Hz, 3 H) 1.37 (t, J=7.00 Hz, 3 H).

[0171] Compound 030 was prepared similarly to Scheme 3 using methyl Grignard instead of methylamine and obtained as a white solid (purity 98.5%). LCMS: Retention time = 0.393 min, m / z = 464.16 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.47 - 12.21 (m, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 7.59 - 7.58 (m, 1H), 7.55 (s, 1H), 7.42 (br d, J = 6.1 Hz, 1H), 7.38 - 7.30 (m, 3H), 7.12 - 7.05 (m, 2H), 5.37 - 5.31 (m, 1H), 4.95 (s, 2H), 4.07 (q, J = 6.8 Hz, 2H), 3.06 (s, 3H), 1.69 (br d, J = 6.6 Hz, 3H), 1.38 (t, J = 6.9 Hz, 3H).

[0172] Compound 031 was prepared similarly to Scheme 3 using methyl Grignard instead of methylamine and obtained as a white solid (16.7 mg, 38.79 μmol, 21.75% yield, 100% purity). LCMS: Retention time = 0.377 min, m / z = 431.4 (M+H). + 1H NMR (400 MHz, chloroform-d) δ = 13.07 - 12.39 (m, 1H), 8.47 (s, 1H), 8.40 - 8.34 (m, 1H), 7.59 - 7.51 (m, 2H), 7.46 - 7.32 (m, 4H), 7.13 - 7.05 (m, 2H), 5.54 - 5.45 (m, 1H), 5.03 - 4.93 (m, 2H), 4.06 (q, J = 6.9 Hz, 2H), 3.12 - 3.08 (m, 3H), 1.76 (br d, J = 6.5 Hz, 3H), 1.37 (t, J = 6.9 Hz, 3H).

[0173] Compound 070 was prepared in the same manner as in Scheme 3, using methyl Grignard instead of methylamine, and obtained as a white solid (7 mg, 15.23 μmol, 44.22% yield, 98.01% purity). LCMS: Retention time = 0.438 min, m / z = 451.2 (M+H). + 1H NMR (400 MHz, chloroform-d) δ ppm 12.14 - 12.36 (m, 1 H) 8.45 (d, J=3.00 Hz, 1 H) 8.25 (s, 1 H) 7.35 (d, J=7.50 Hz, 2 H) 7.28 - 7.33 (m, 2 H) 7.01 - 7.11 (m, 3 H) 5.90 - 6.11 (m, 1 H) 4.88 - 5.01 (m, 2 H) 4.02 - 4.12 (m, 2 H) 3.05 (s, 3 H) 1.80 - 1.90 (m, 3 H) 1.38 (t, J=6.94 Hz, 3H).

[0174] [ka]

[0175] To a solution of compound 1 (5 g, 14.70 mmol, 1 eq) in MeOH (60 mL) was added Pd(OAc) (329.95 mg, 1.47 mmol, 0.1 eq), DPPF (1.63 g, 2.94 mmol, 0.2 eq), and TEA (4.46 g, 44.09 mmol, 6.14 mL, 3 eq). The mixture was stirred at 80 °C for 12 h under CO (50 psi). The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, EtOAc / methanol = 100 / 1 → 5 / 1). The purified solution was concentrated in vacuo to give a residue. Compound 2 (570 mg, 1.78 mmol, 12.11% yield) was obtained as a yellow solid. LCMS: retention time = 0.504 min, m / z = 319.9 (M+H). +

[0176] To a solution of compound 2 (570 mg, 1.78 mmol, 1 eq) in 2-MeTHF (10 mL) in a 100 mL three-neck flask, LAH (101.61 mg, 2.68 mmol, 1.5 eq) was added at 0 °C. The mixture was stirred at 0 °C for 12 h. After the reaction was completed, NaSO·10H0 (3 g) was added to the resulting mixture. Then, the mixture was filtered, and the filtrate was concentrated to obtain the crude product. The residue was purified by column chromatography (SiO, PE / EtOAc = 10 / 1 → 1 / 2). The purified solution was concentrated under vacuum to obtain the residue. Compound 3 (200 mg, 686.47 μmol, 38.46% yield) was obtained as a colorless oil. LCMS: retention time = 0.367 min, m / z = 292.1 (M+H). +

[0177] To a solution of compound 3 (200 mg, 686.47 μmol, 1 eq) in EtOAc (2 mL) in a 100 mL round-bottom flask was added HCl / dioxane (4 M, 2 mL, 11.65 eq). The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated in vacuo to give a residue. Compound 4 (130 mg, crude, HCl) was obtained as a white solid, which was used in the next step. LCMS: Retention time = 0.122 min, m / z = 161.1 (M-30). +

[0178] To a solution of compound 4 (130 mg, 570.95 μmol, 1 eq, HCl), compound 5 (148.60 mg, 570.95 μmol, 1 eq) in DCM (5 mL) was added EDCI (164.18 mg, 856.43 μmol, 1.5 eq), DMAP (6.98 mg, 57.10 μmol, 0.1 eq), and DIPEA (221.37 mg, 1.71 mmol, 298.35 μL, 3 eq). The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into water (15 mL) and extracted with EtOAc (10 mL × 3). The combined organic phase was dried and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 10 / 1 → 1 / 4). The purified solution was concentrated in vacuo to give a residue. Compound 6 (160 mg, 369.11 μmol, 64.65% yield) was obtained as a colorless oil. LCMS: Retention time = 0.451 min, m / z = 434.3 (M+H) +

[0179] To a solution of compound 6 (160 mg, 369.11 μmol, 1 eq) in DCM (3 mL) in an 8 mL glass bottle, MnO2 (481.34 mg, 5.54 mmol, 15 eq) was added. The mixture was stirred at 20 °C for 2 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to give the crude product. The residue was purified by preparative TLC (PE / EtOAc = 1:1, RF = 0.3), and the purified solution was concentrated under vacuum to give a residue. Compound 7 (120 mg, 278.13 μmol, 75.35% yield) was obtained as a colorless oil. LCMS: Retention time = 0.480 min, m / z = 432.3 (M+H) +

[0180] To a solution of compound 7 (30 mg, 69.53 μmol, 1 eq) in MeOH (2 mL) in a 50 mL round-bottom flask, MeNH (2 M, 104.30 μL, 3 eq) and AcOH (208.78 μg, 3.48 μmol, 1.99 e-1 μL, 0.05 eq) were added at 20 °C. The mixture was stirred at 20 °C for 2 h, and then NaBH (5.26 mg, 139.06 μmol, 2 eq) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 2 h. After the reaction was completed, the reaction mixture was poured into NHCl (5 mL). The temperature was controlled at 10–20 °C. NaCO (1 g) was added to the mixture. The solution was filtered, and the filtrate was concentrated under reduced pressure to give a residue. Subsequently, the solution was triturated with DCM and MeOH, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Welch MLtimate (C18, 150×25 mm, 5 μm), mobile phase: [water (FA)-ACN], B (%): 18%→48%, 10 min), and the purified solution was lyophilized to give a white solid. 004 (21.6 mg, 46.58 μmol, yield 67.00%, purity 96.3%) was obtained as a white solid. LCMS: retention time = 0.381 min, m / z = 447.4 (M+H) + 1H NMR (400 MHz, chloroform-d) δ ppm 8.39 - 8.48 (m, 1 H) 8.22 - 8.28 (m, 1 H) 7.22 - 7.36 (m, 5 H) 7.16 - 7.20 (m, 1 H) 6.97 - 7.04 (m, 3 H) 4.82 - 4.90 (m, 2 H) 4.21 - 4.32 (m, 2 H) 4.02 (q, J=6.84 Hz, 2 H) 2.92 - 3.01 (m, 3 H) 2.48 - 2.59 (m, 3 H) 1.28 - 1.38 (m, 3 H).

[0181] [ka]

[0182] To an 8 mL glass bottle, a solution of compound 9 (50 mg, 90.96 μmol, 1 eq) in DCM (2 mL) was added. Subsequently, EtN (18.41 mg, 181.92 μmol, 25.32 μL, 2 eq) and acetyl chloride (8.57 mg, 109.15 μmol, 7.79 μL, 1.2 eq) were added to the above mixture. The mixture was stirred at 20 °C for 12 h. The mixture was poured into H O (20 mL). The aqueous phase was extracted with EtOAc (20 mL × 2). The combined organic phase was dried over Na SO and concentrated in vacuo. The residue was used directly in the next step without any purification. Compound 11 (53 mg, 89.57 μmol, 98.47% yield, purity not available) was obtained as an off-white solid. LCMS: Retention time =0.690 min, m / z= 474.3 (M+H + ).

[0183] To a solution of compound 11 (73 mg, 123.36 μmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 109.48 eq) in a 100 mL round-bottom flask. The mixture was stirred at 20° C. for 2 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex (C18, 150×25 mm, 10 μm), mobile phase: [water (NH4HCO3)-ACN], B (%): 36% to 66%, 8 min). Compound 007 (7.7 mg, 16.02 μmol, 12.98% yield, 96% purity) was obtained as a white solid. LCMS: retention time = 0.590 min, m / z = 462.2 (M+H + ). 1H NMR: (chloroform-d): δ 12.02 (1H, br s), 8.10 (1H, s), 7.48 (1H, d, J=1.8 Hz), 7.29-7.40 (4H, m), 7.00-7.09 (4H, m), 4.94 (2H, s), 4.06 (2H, q, J=6.9 Hz), 3.03 (3H, s), 2.36 (3H, s), 1.37 (3H, t, J=6.9 Hz).

[0184] Compound 009 was prepared similarly to Scheme 5 and isolated as a white solid (31 mg, 62.33 μmol, 37.82% yield, 95.8% purity). LCMS: Retention time = 0.393 min, m / z = 477.4 (M+H). + 1H NMR (400 MHz, chloroform-d) δ = 12.51 - 11.86 (m, 1H), 8.28 (s, 1H), 8.23 ​​(s, 1H), 7.33 - 7.26 (m, 2H), 7.25 - 7.22 (m, 1H), 7.21 - 7.19 (m, 1H), 7.02 (br d, J = 1.5 Hz, 2H), 6.97 - 6.94 (m, 1H), 5.51 - 5.48 (m, 2H), 4.87 (s, 2H), 4.03 - 3.96 (m, 2H), 2.98 (s, 3H), 2.17 - 2.14 (m, 3H), 1.33 - 1.27 (m, 3H).

[0185] [ka]

[0186] To a solution of compound 1 (2.85 g, 7.68 mmol, 1 eq) and compound 2 (2 g, 7.68 mmol, 1 eq) in DCM (20 mL) in a 40 mL vial, EDCI (2.21 g, 11.53 mmol, 1.5 eq) and DMAP (93.88 mg, 768.46 μmol, 0.1 eq) were added, and the mixture was stirred at 20 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE: EtOAc = 2:1). Compound 3 (3.8 g, 6.20 mmol, 80.72% yield) was obtained as a white solid. LCMS: retention time = 0.610 min, m / z = 612.6 (M+H + ).

[0187] To a solution of compound 3 (3.7 g, 6.04 mmol, 1 eq) in MeOH (40 mL) in a 250 mL hydrogenation bottle, Pd(OAc) (271.20 mg, 1.21 mmol, 0.2 eq), TEA (1.83 g, 18.12 mmol, 2.52 mL, 3 eq), and DPPF (669.67 mg, 1.21 mmol, 0.2 eq) were added, and the mixture was stirred at 80 °C for 12 h under CO (50 psi). The reaction mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 0:0 → 2:1). Compound 4 was obtained as a yellow solid. LCMS: retention time = 0.605 min, m / z = 592.3 (M+H + ).

[0188] To a solution of compound 4 (200 mg, 337.98 μmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 39.96 eq), and the mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral condition, column: Welch Xtimate (C18, 150×25 mm, 5 μm), mobile phase: [water (NH4HCO3)-ACN], B (%): 44% to 74%, 2 min), and the purified product was lyophilized to give 008 (140 mg, 302.46 μmol, 89.49% yield, 99.7% purity) as a white solid. LCMS: retention time = 0.531 min, m / z = 462.2 (M+H + ). 1 H NMR: 1H NMR (400 MHz, chloroform-d) δ = 12.35 - 12.10 (m, 1H), 8.56 (d, J = 1.1 Hz, 1H), 8.23 ​​(s, 1H), 7.99 (s, 1H), 7.41 - 7.29 (m, 4H), 7.11 - 7.02 (m, 3H), 5.00 (s, 2H), 4.07 (q, J = 6.8 Hz, 2H), 3.98 (s, 3H), 3.04 (s, 3H), 1.37 (t, J = 7.0 Hz, 3H).

[0189] [ka]

[0190] To a solution of compound 1 (5 g, 14.70 mmol, 1 eq) in MeOH (60 mL) was added Pd(OAc) (329.95 mg, 1.47 mmol, 0.1 eq), DPPF (1.63 g, 2.94 mmol, 0.2 eq), and TEA (4.46 g, 44.09 mmol, 6.14 mL, 3 eq). The mixture was stirred at 80 °C for 12 h under CO (50 psi). The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 100 / 1 → 5 / 1). The purified solution was concentrated in vacuo to give a residue. Compound 2 (1 g, 3.13 mmol, 21.30% yield) was obtained as a yellow solid. LCMS: retention time = 0.485 min, m / z = 219.7 (M-100). + 1H NMR (400 MHz, chloroform-d) δ ppm 11.59 - 12.41 (m, 1H) 8.56 (s, 1H) 7.85 - 7.90 (m, 1H) 7.23 - 7.26 (m, 1H) 4.65 - 4.69 (m, 2H) 4.03 (s, 3H) 2.81 (s, 3H) 1.49 - 1.54 (m, 9H)

[0191] To a solution of compound 2 (500 mg, 1.57 mmol, 1 eq) in EtOAc (3 mL) in a 100 mL round-bottom flask was added HCl / dioxane (4 M, 6 mL, 15.33 eq). The mixture was stirred at 20° C. for 2 h. The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated in vacuo to give a residue. Compound 3 (450 mg, crude, HCl) was obtained as a white solid, which was used in the next step. LCMS: Retention time = 0.225 min, m / z = 220.2 (M+H) +

[0192] To a solution of compound 3 (450 mg, 1.76 mmol, 1 eq, HCl), compound 4 (458.02 mg, 1.76 mmol, 1 eq) in DCM (8 mL) in a 100 mL round-bottom flask, EDCI (506.06 mg, 2.64 mmol, 1.5 eq), DMAP (21.50 mg, 175.99 μmol, 0.1 eq) and DIPEA (1.14 g, 8.80 mmol, 1.53 mL, 5 eq) were added. The mixture was stirred at 20 °C for 12 h. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic phase was dried and concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna (C18, 150 x 25 mm, 10 um), mobile phase: [water (FA)-ACN], B (%): 51% → 81%, 10 min), and the purified solution was lyophilized to give a white solid. 010 (500 mg, 1.07 mmol, yield 60.83%, purity 98.8%) was obtained as a white solid. LCMS: retention time = 0.502 min, m / z = 462.3 (M+H) + 1H NMR (400 MHz, chloroform-d) δ ppm 8.59 - 8.64 (m, 1 H) 7.92 (d, J=7.25 Hz, 1 H) 7.40 (s, 1 H) 7.33 - 7.36 (m, 2 H) 7.28 - 7.32 (m, 2 H) 7.01 - 7.09 (m, 3 H) 5.03 (s, 2 H) 4.06 - 4.10 (m, 2 H) 4.05 (s, 3 H) 2.99 - 3.04 (m, 3 H) 1.37 (t, J=6.94 Hz, 3 H).

[0193] Compound 066 was prepared in the same manner as in Scheme 7, except for the additional step of reducing the ester by dissolving the esterified compound in 2-MeTHF (5 mL) and adding LAH (16.45 mg, 433.38 μmol, 2 eq) at 0 °C. After the reaction was complete, NaSO·10H0 (5 g) was added to the resulting mixture. The mixture was then filtered, and the filtrate was concentrated to give the crude product. The residue was purified by preparative HPLC (column: Phenomenex Luna (C18, 150 × 25 mm, 10 μm), mobile phase: [water (FA)-ACN], B (%): 49% → 79%, 10 min), and the purified solution was lyophilized to give a white solid. 066 (6.1 mg, 13.92 μmol, yield 6.42%, purity 98.9%) was obtained as a white solid. LCMS: Retention time =0.458 min, m / z =434.3 (M+H) + 1H NMR (400 MHz, chloroform-d) δ ppm 8.25 - 8.29 (m, 1 H) 7.29 - 7.40 (m, 4 H) 7.24 - 7.26 (m, 1 H) 7.12 - 7.15 (m, 1 H) 7.00 - 7.08 (m, 3 H) 5.05 - 5.10 (m, 2 H) 4.95 - 4.98 (m, 2 H) 4.03 - 4.10 (m, 2 H) 2.99 - 3.02 (m, 3 H) 1.37 (t, J=7.00 Hz, 3 H).

[0194] Compound 069 was prepared similarly to Scheme 7, with the additional step of reducing the ester by dissolving the esterified compound in MeOH (2 mL) and adding LiBH (18.41 mg, 844.96 μmol, 5 eq) at 0 °C. The reaction mixture was poured into saturated aqueous NH Cl (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were dried and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (PE: EtOAc = 1:1). Compound 2 (30 mg, 53.22 μmol, 31.49% yield) was obtained as a white oil. LCMS: retention time = 0.553 min, m / z = 446.2 (M+H+).

[0195] [ka]

[0196] Compound 1 (200.00 mg, 645.44 μmol, 1 eq) and compound 2 (166.32 mg, 1.94 mmol, 3 eq) were dissolved in dioxane (5 mL) and HO (0.5 mL) in a 40 mL bottle. CsCO (630.89 mg, 1.94 mmol, 3 eq) and Pd(dppf)Cl CHCl (52.71 mg, 64.54 μmol, 0.1 eq) were added, and the reaction mixture was stirred at 100 °C for 12 h under N. After the reaction was completed and cooled to room temperature, the reaction mixture was filtered with EtOAc (50 mL), and the filtrate was concentrated on a rotary evaporator to give the crude product. The crude product was purified by preparative TLC (PE:EtOAc = 1:1, Rf = 0.7). The purified solution was concentrated in vacuo to give compound 3 (68 mg, 215.54 μmol, 33.39% yield) as a yellow oil. LCMS: Retention time = 0.405 min, m / z = 316.2 (M+H). +

[0197] A solution of compound 3 (74.00 mg, 234.56 μmol, 1 eq) in MeOH (8 mL) and DCM (8 mL) in a three-neck flask (100 mL) was bubbled with ozone (11.26 mg, 234.56 μmol, 1 eq) at 15 psi and −78° C. for 20 min. The mixture was then purged with nitrogen for 10 min. PPh3 (123.04 mg, 469.12 μmol, 2 eq) dissolved in DCM (8 mL) was added to the reaction mixture at −78° C. over 10 min. The mixture was stirred at 20° C. for 1 h. After the reaction was complete, the mixture was concentrated to give a residue. The residue was purified by preparative TLC (SiO2, PE / EtOAc = 1:1). The purified solution was concentrated in vacuo to give compound 4 (35 mg, 110.25 μmol, 47.00% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ = 11.07 (s, 1H), 9.23 (s, 1H), 8.39 (s, 1H), 5.81 (s, 2H), 3.73 - 3.67 (m, 2H), 3.30 - 3.23 (m, 1H), 1.40 - 1.35 (m, 2H), 1.20 - 1.14 (m, 2H), 1.01 - 0.95 (m, 2H), 0.00 -0.01 (m, 9H).

[0198] To a solution of compound 4 (35.00 mg, 110.25 μmol, 1 eq) in MeOH (2 mL) in a round-bottom flask (50 mL) was added AcOH (662.08 μg, 11.03 μmol, 6.31 e-1 μL, 0.1 eq) in THF (2 M, 330.75 μL, 6 eq) and MeNH. The mixture was stirred at 20 °C for 2 h. Subsequently, NaBHCN (10.39 mg, 165.38 μmol, 1.5 eq) was added to the reaction mixture at 0 °C. The mixture was stirred at 20 °C for 3 h. After the reaction was complete, the reaction mixture was poured into NH Cl (0.1 mL), filtered, and the filtrate was concentrated under reduced pressure to give a residue. The solution was then triturated with dichloromethane (10 mL), filtered, and the filtrate was concentrated under reduced pressure to give compound 5 (60 mg, crude) as a yellow oil, which was used in the next step. LCMS: Retention time = 0.573 min, m / z = 333.0 (M+H). +

[0199] To a solution of compound 5 (60 mg, 180.44 μmol, 1 eq) and compound 6 (46.96 mg, 180.44 μmol, 1 eq) in DCM (3 mL) in a round-bottom flask (50 mL) was added EDCI (51.89 mg, 270.66 μmol, 1.5 eq) and DMAP (2.20 mg, 18.04 μmol, 0.1 eq). The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO, PE / EtOAc = 1:1). The purified solution was concentrated in vacuo to give compound 7 (30 mg, 52.20 μmol, 28.93% yield) as a colorless oil. LCMS: retention time = 0.482 min, m / z = 575.6 (M+H). +

[0200] To a solution of compound 7 (30.00 mg, 52.20 μmol, 1 eq) in DCM (0.5 mL) in a round-bottom flask (100 mL) was added TFA (770.00 mg, 6.75 mmol, 500.00 μL, 129.38 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give a residue. The residue was basified with EtN to pH 8. The residue was purified by preparative HPLC (column: Phenomenex luna (C18, 150 × 25 mm, 10 μm), mobile phase: [water (FA)-ACN], B (%): 26% → 56%, 9 min). The purified solution was lyophilized to give 011 (7 mg, 15.24 μmol, 29.21% yield, 96.8% purity) as a white solid. LCMS: Retention time = 0.402 min, m / z = 445.1 (M+H) + 1H NMR (400 MHz, chloroform-d) δ = 9.03 (br s, 1H), 8.20 (br s, 1H), 7.41 - 7.34 (m, 2H), 7.33 - 7.30 (m, 2H), 7.09 - 7.00 (m, 3H), 5.29 - 5.23 (m, 2H), 4.07 (q, J = 6.9 Hz, 2H), 3.11 (s, 3H), 2.46 - 2.37 (m, 1H), 1.40 - 1.35 (m, 3H), 1.33 - 1.26 (m, 4H).

[0201] Compound 016 was prepared similarly to Scheme 8 and obtained as a white solid (45.2 mg, 99.11 μmol, 95.34% yield and 98% purity). LCMS: Retention time = 0.404 min, m / z = 447.2 (M+H + ) 1H NMR: (400 MHz, chloroform-d) δ = 12.15 (br s, 1H), 9.01 (s, 1H), 8.19 (s, 1H), 7.47 - 7.42 (m, 2H), 7.36 - 7.30 (m, 4H), 7.11 - 7.07 (m, 1H), 5.12 (s, 2H), 3.87 - 3.68 (m, 1H), 3.06 (s, 3H), 2.84 (s, 3H), 0.85 - 0.79 (m, 2H), 0.78 - 0.72 (m, 2H).

[0202] [ka]

[0203] To a solution of compound 1 (5 g, 29.91 mmol, 1 eq) and compound 2 (3.62 g, 29.91 mmol, 1 eq) in acetone (50 mL), K2CO3 (8.27 g, 59.82 mmol, 2 eq) and KI (496.53 mg, 2.99 mmol, 0.1 eq) were added in a 250 mL three-necked bottle. The mixture was stirred at 60 °C for 12 h. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (200 mL × 3). The combined organic phase was dried and concentrated in vacuo to give a residue. Compound 1-allyloxy-2,3-dimethyl-4-nitro-benzene (6.02 g, 29.05 mmol, 97.12% yield) was obtained as a yellow oil, which was used in the next step without further purification. LCMS: Retention time = 0.475 min, m / z = 208.4 (M+H + )

[0204] Then, a solution of compound 3 (6.02 g, 29.05 mmol, 1 eq) in EtOH (60 mL) and HO (12 mL) was added to a 500 mL three-neck bottle. To the mixture, Fe (8.11 g, 145.25 mmol, 5 eq) and NHCl (15.54 g, 290.51 mmol, 10 eq) were added in portions at 20 °C. The mixture was stirred at 70 °C for 2 h. The reaction mixture was filtered through a Celite pad, and the filtrate was poured into saturated water (500 mL) at 0 °C and extracted with EtOAc (500 mL × 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous NaSO, and concentrated to give the crude product. The residue was purified by silica gel chromatography (PE: EtOAc = 10:1). Compound 4 (4.42 g, 24.93 mmol, 85.82% yield, purity not available) was obtained as a brown solid. LCMS: Retention time = 0.207 min, m / z = 178.4 (M+H + ) 1 H NMR (400 MHz, chloroform-d) δ = 6.63 (d, J = 8.5 Hz, 1H), 6.55 (d, J = 8.5 Hz, 1H), 6.07 (ddt, 1H), 5.41 (qd, J = 1.7, 17.3 Hz, 1H), 5.25 (qd, J = 1.5, 10.5 Hz, 1H), 4.45 (td, J = 1.5, 5.2 Hz, 2H), 3.62 (br. s, 2H), 2.21 (s, 3H), 2.12 (s, 3H).

[0205] A solution of compound 4 (3.3 g, 18.62 mmol, 1 eq) in DCM (30 mL) and HOAc (3 mL) was added to a 100 mL three-necked round-bottom flask. Subsequently, Br2 (2.98 g, 18.62 mmol, 959.82 μL, 1 eq) in DCM (5 mL) was added dropwise to the above mixture at 0 °C. The mixture was stirred at 0 °C for 3 h. The reaction mixture was poured into saturated aqueous NaHCO3 solution (300 mL) in portions. The aqueous phase was extracted with EtOAc (200 mL × 2). The combined organic phase was washed with HO (200 mL × 3), brine (200 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE: EtOAc = 90:1). Compound 5 (1.26 g, 3.89 mmol, 20.87% yield, 79% purity) was obtained as a brown solid. LCMS: Retention time = 0.422 min, m / z = 256.3, 258.3 (M+H + ). 1 H NMR (400 MHz, chloroform-d) δ = 6.88 (s, 1H), 6.11 - 6.00 (m, 1H), 5.41 (dd, J = 1.0, 17.3 Hz, 1H), 5.27 (dd, J = 0.8, 10.5 Hz, 1H), 4.43 (d, J = 5.1 Hz, 2H), 3.81 (br s, 2H), 2.17 (d, J = 4.6 Hz, 6H).

[0206] To a solution of compound 5 (1 g, 3.90 mmol, 1 eq) in HOAc (20 mL) and HO (2 mL) in a 100 mL single-neck round-bottom flask, NaNO (538.77 mg, 7.81 mmol, 2 eq) was added at 5 °C, and the mixture was stirred at 20 °C for 12 h. The mixture was poured into water (100 mL), adjusted to pH 8 with saturated NaHCO solution, extracted with EtOAc (100 mL × 2), and the combined organic phase was washed with brine (100 mL), dried over anhydrous NaSO, and concentrated to give the crude product. The residue was purified by silica gel column chromatography (PE: EtOAc = 10:1). Compound 6 (389 mg, 1.46 mmol, 37.30% yield, purity not available) was obtained as a light brown solid. LCMS: Retention time = 0.434 min, m / z = 267.0, 269.0 (M+H + ). 1 H NMR (400 MHz, chloroform-d) δ = 8.14 (br s, 1H), 7.28 (s, 1H), 6.14–6.04 (m, 1H), 5.47–5.40 (m, 1H), 5.30 (dd, J = 1.3, 10.5 Hz, 1H), 4.61–4.52 (m, 2H), 2.47 (s, 3H).

[0207] To a solution of compound 6 (276 mg, 1.03 mmol, 1 eq) in 2-MeTHF (5 mL) in a 20 mL one-neck round-bottom flask, NaH (82.65 mg, 2.07 mmol, 60% purity, 2 eq) was added at 0 °C. The mixture was stirred at 0 °C for 0.5 h, and then SEM-Cl (258.39 mg, 1.55 mmol, 274.30 μL, 1.5 eq) was added dropwise. The mixture was warmed to 20 °C and stirred at 20 °C for 2 h. After the reaction was completed, the mixture was poured into saturated NH Cl (50 mL) solution at 0 °C and extracted with EtOAc (50 mL × 2). The combined organic phase was washed with brine (80 mL), dried over anhydrous Na SO , and concentrated to give the crude product. The residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1). Compound 7 (267 mg, 671.90 μmol, 65.03% yield, purity not available) was obtained as a brown oil. LCMS: Retention time = 0.600 min, m / z = 396.8, 398.8 (MH + )

[0208] A solution of compound 7 (206 mg, 518.39 μmol, 1 eq) in 2-MeTHF (5 mL) was added to a 25 mL convoluted tube. Subsequently, n-BμLi in hexane (2.5 M, 414.72 μL, 2 eq) was added to the above mixture at −70 °C under N atmosphere, and the mixture was stirred at −70 °C for 1 h. Subsequently, DMF (41.68 mg, 570.23 μmol, 43.87 μL, 1.1 eq) was added to the above mixture, and the mixture was stirred at −70 °C for 1 h under N atmosphere. The mixture was poured into ice-NH Cl (saturated, 50 mL) and stirred for 1 min. The aqueous phase was extracted with EtOAc (40 mL × 2). The combined organic phase was washed with brine (60 mL), dried over anhydrous Na SO , filtered, and concentrated in vacuo. The residue was purified by preparative TLC (PE: EtOAc = 10:1). Compound 8 (30 mg, 86.58 μmol, 16.70% yield, purity not available) was obtained as a light brown solid. 1H NMR (400 MHz, chloroform-d) δ = 10.39 (s, 1H), 8.10 (s, 1H), 7.69 (s, 1H), 6.15 - 6.08 (m, 1H), 6.03 (s, 2H), 5.47 (dd, J = 1.5, 17.1 Hz, 1H), 5.32 (dd, J = 1.3, 10.5 Hz, 1H), 4.67 (d, J = 5.1 Hz, 2H), 3.54 - 3.48 (m, 3H), 2.59 (s, 3H), 0.90 - 0.80 (m, 2H), -0.08 (s, 9H).

[0209] Compound 8 (45 mg, 129.87 μmol, 1 eq) in MeOH (1 mL) was added to MeNH in THF (2 M, 194.81 μL, 3 eq) and HOAc (779.91 μg, 12.99 μmol, 7.43 e-1 μL, 0.1 eq) in a 100 mL single-bottom flask at 20 °C. The mixture was stirred at 20 °C for 3 h. Then, NaBH (9.83 mg, 259.74 μmol, 2 eq) was added to the mixture at 0 °C. The mixture was stirred at 0 °C for 1 h. After the reaction was complete, the reaction mixture was poured into NH Cl (0.1 mL), filtered, and the filtrate was concentrated under reduced pressure to give a residue. The solution was then triturated with EtOAc and THF (50 mL), filtered, and the filtrate was concentrated under reduced pressure to give a residue. No purification was required and the product was used in the next step. Compound 9 (53 mg, 127.09 μmol, 97.86% yield, 86.7% purity) was obtained as a light brown solid. LCMS: Retention time = 0.359 min, m / z = 362.4 (MH + ) 1H NMR (400 MHz, chloroform-d) δ = 8.01 (s, 1H), 7.12 (s, 1H), 6.21 - 6.11 (m, 1H), 5.99 (s, 2H), 5.49 (dd, J = 1.5, 17.3 Hz, 1H), 5.34 (dd, J = 1.4, 10.5 Hz, 1H), 4.68 - 4.60 (m, 2H), 4.20 - 4.16 (m, 2H), 3.64 - 3.54 (m, 2H), 2.58 (s, 1H), 2.54 (s, 3H), 1.03 - 0.84 (m, 2H), 0.00 (s, 9H).

[0210] A solution of compound 9 (53 mg, 127.09 μmol, 86.7% purity, 1 eq) in DCM (2 mL) was added to a 50 mL single-neck round-bottom flask, and compound 10 (33.08 mg, 127.09 μmol, 1 eq), EDCI (36.55 mg, 190.64 μmol, 1.5 eq), and DMAP (1.55 mg, 12.71 μmol, 0.1 eq) were added. The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (PE: EtOAc = 2:1). Compound 11 (40 mg, 66.25 μmol, 52.12% yield, purity not available) was obtained as a light brown solid. LCMS: retention time = 0.645 min, mass spectrometry of fragment: m / z = 486.8 (M+H + )

[0211] To a solution of compound 11 (40 mg, 66.25 μmol, 1 eq) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 203.87 eq) in a 100 mL single bottle. The mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove residues. The residue was basified with EtN to a pH of approximately 8. The residue was purified by preparative HPLC (column: Phenomenex luna (C18, 150×25 mm, 10 μm), mobile phase: [water (FA)-ACN], B (%): 60% to 90%, 10 min) and lyophilized. Compound 12 (20 mg, 42.24 μmol, 63.75% yield, purity not available) was obtained as a white solid. LCMS: retention time = 0.551 min, m / z = 474.5 (M+H + )

[0212] To a solution of compound 12 (15 mg, 31.68 μmol, 1 eq) in DCM (1 mL) was added Pd(PPh3)4 (7.32 mg, 6.34 μmol, 0.2 eq) and 1,3-dimethylhexahydropyrimidine-2,4,6-trione (14.84 mg, 95.03 μmol, 3 eq) in an 8 mL bottle under N2. The mixture was stirred at 20 °C for 5 h under N2. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The residue was purified by preparative HPLC (column: Phenomenex Luna (C18, 150 × 25 mm, 10 μm), mobile phase: [water (NH4HCO3)-ACN], B (%): 34% → 64%, 8 min) and lyophilized. 015 (4.6 mg, 10.52 μmol, 33.20% yield, 99.1% purity) was obtained as a white solid. LCMS: Retention time = 0.463 min, m / z = 434.3 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ = 8.04 (s, 1H), 7.40 - 7.28 (m, 4H), 7.10 - 7.01 (m, 3H), 6.93 (s, 1H), 4.89 (s, 2H), 4.06 (q, J = 7.0 Hz, 2H), 3.01 (s, 3H), 2.50 (s, 3H), 1.37 (br t, J = 6.8 Hz, 3H).

[0213] Compound 036 was prepared similarly to Scheme 9 and obtained as a white solid (15.1 mg, 36.00 μmol, 27.20% yield, 100% purity). LCMS: Retention time = 0.482 min, m / z = 420.3 (M+H). + 1H NMR (400 MHz, chloroform-d) δ = 8.02 (s, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.39 - 7.28 (m, 4H), 7.09 - 7.00 (m, 3H), 6.87 - 6.81 (m, 1H), 5.02 (s, 2H), 4.03 (q, J = 6.9 Hz, 2H), 3.14 (s, 3H), 1.34 (t, J = 6.9 Hz, 3H).

[0214] [ka]

[0215] To a solution of compound 1 (1.8 g, 8.14 mmol, 1 eq) in DMSO (20 mL) was added NH2NH2.HO (1.43 g, 28.51 mmol, 1.39 mL, 3.5 eq) in a 100 mL three-neck flask. The mixture was stirred at 120 °C for 12 h. The reaction mixture was poured into water (200 mL) and extracted with EtOAc (200 mL × 2). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to give a residue. The combined aqueous phase was acidified with 1 N aqueous HCl to pH 4 and discarded in a waste container. The residue was purified by silica gel chromatography (PE: EtOAc = 0:0 → 1:1). Compound 2 (695 mg, 3.23 mmol, 39.68% yield) was obtained as a white solid. LCMS: Retention time =0.361 min, m / z=216.8(M+H + ).

[0216] To a solution of compound 1 (695 mg, 3.23 mmol, 1 eq) in THF (10 mL) was added NaH (193.91 mg, 4.85 mmol, 60% purity, 1.5 eq) in a 100 mL three-neck flask at 0 °C, and the mixture was stirred at 0 °C for 1 h. Subsequently, SEM-Cl (808.32 mg, 4.85 mmol, 858.09 μL, 1.5 eq) was added to the reaction at 0 °C, and the reaction mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into saturated aqueous NH4Cl (100 mL), and the mixture was extracted with EtOAc (500 mL x 3). The combined organic phases were dried and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 0:0 → 1:1). Compound 3 (787 mg, 2.28 mmol, 70.52% yield) was obtained as a yellow oil. LCMS: Retention time =0.556 min, m / z=344.04 (M+H + ).

[0217] To a solution of compound 3 (787 mg, 2.28 mmol, 1 eq) and compound 4 (1.23 g, 3.42 mmol, 1.15 mL, 1.5 eq) in dioxane (10 mL) and HO (1 mL) in a 50 mL one-neck round-bottom flask was added KCO (630.02 mg, 4.56 mmol, 2 eq) and Pd(PPh)Cl (239.97 mg, 341.89 μmol, 0.15 eq). The mixture was stirred at 100 °C for 12 h.

[0218] After the reaction was completed and cooled to room temperature, the reaction mixture was diluted with saturated potassium fluoride solution (100 mL) and stirred at 20 °C for 2 hours. Subsequently, the mixture was filtered, and the filtrate was extracted with EtOAc (100 mL × 3). The combined organic phase was washed with brine (150 mL × 3), dried over anhydrous Na SO , and concentrated to obtain the crude product. The residue was purified by silica gel chromatography (PE: EtOAc = 0:0 → 10:1). Compound 5 (680 mg, 2.02 mmol, 88.67% yield) was obtained as a yellow oil. 1 H NMR: 1 H NMR (chloroform-d): δ 8.00 (1H, s), 7.65 (1H, dd, J=4.9 and 8.8 Hz), 6.99 (1H, t, J=9.1 Hz), 5.74 (2H, s), 4.42-4.72 (2H, m), 4.13 (2H, q, J=7.1 Hz), 3.49-3.58 (2H, m), 1.40 (3H, t, J=7.0 Hz), 0.84 (3H, s), -0.06 (9H, s)

[0219] To a solution of compound 5 (500 mg, 1.49 mmol, 1 eq) in DCM (5 mL) was added TFA (7.70 g, 67.53 mmol, 5 mL, 45.44 eq) in a 100 mL one-neck round-bottom flask. The mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by silica gel chromatography (PE: EtOAc = 0:0 → 2:1). Compound 6 (250 mg, 1.40 mmol, 94.43% yield) was obtained as a yellow oil. LCMS: Retention time = 0.307 min, m / z = 179.1 (M+H + ).

[0220] To compound 6 dissolved in MeOH (2 mL) in a 100 mL vial, HOAc (471.87 μg, 7.86 μmol, 4.49 e-1 μL, 0.01 eq) and MeNH in THF (2 M, 1.18 mL, 3 eq) were added, and the reaction mixture was stirred magnetically at 20 °C for 2 h. Subsequently, NaBH (59.45 mg, 1.57 mmol, 2 eq) was added at 0 °C, and the mixture was stirred magnetically at 20 °C for 1 h. After the reaction was complete, the reaction mixture was poured into NH Cl (10 mL), filtered, and the filtrate was concentrated under reduced pressure to give a residue. Subsequently, the solution was triturated with EtOAc and THF (10 mL), filtered, and the filtrate was concentrated under reduced pressure to give a residue. Compound 7 was obtained as a yellow oil. LCMS: retention time = 0.412 min, m / z = 194.0 (M+H + ).

[0221] To a solution of compound 7 (133 mg, 688.33 μmol, 1 eq) and compound 8 (179.15 mg, 688.33 μmol, 1 eq) in DCM (5 mL) in a 40 mL vial, EDCI (197.93 mg, 1.03 mmol, 1.5 eq) and DMAP (8.41 mg, 68.83 μmol, 0.1 eq) were added, and the mixture was stirred at 20 °C for 12 h. The mixture was neutralized with Na2CO3 at 20 °C, filtered, and the filtrate was concentrated to give the crude product. The residue was purified by preparative TLC (SiO2, PE:EtOAc = 3:1) to give 017 (7.4 mg, 16.48 μmol, 2.39% yield, 97% purity) as a colorless oil. LCMS: retention time = 0.543 min, m / z = 436.4 (M+H) + ). HNMR: (400 MHz, chloroform-d) δ = 12.27 - 11.82 (m, 1H), 8.07 (s, 1H), 7.67 (dd, J = 4.5, 8.8 Hz, 1H), 7.39 - 7.28 (m, 4H), 7.08 - 6.99 (m, 3H), 6.98 - 6.89 (m, 1H), 6.41 (br d, J = 7.0 Hz, 1H), 4.26 - 3.85 (m, 2H), 3.28 - 2.76 (m, 3H), 1.95 (dd, J = 4.1, 7.3 Hz, 3H), 1.36 (t, J = 6.9 Hz, 3H).

[0222] Compound 116 was prepared similarly to Scheme 10 and obtained as a white solid (11.0 mg, 25.26 μmol, 24.40% yield, 100% purity). LCMS: Retention time = 0.735 min, m / z = 435.9 (M+H +) 1H NMR (400 MHz, chloroform-d) δ = 8.18 (s, 1H), 7.41 - 7.33 (m, 2H), 7.33 - 7.28 (m, 3H), 7.08 - 7.00 (m, 3H), 6.79 (dd, J = 8.1, 9.4 Hz, 1H), 6.48 (d, J = 6.6 Hz, 1H), 4.14 - 3.99 (m, 2H), 2.76 (s, 3H), 1.84 - 1.78 (m, 3H), 1.37 (t, J = 6.9 Hz, 3H).

[0223] [ka]

[0224] To a solution of compound 1 (152.57 mg, 525.64 μmol, 1 eq) and compound 2 (100 mg, 525.64 μmol, 1 eq) in DCM (5 mL) in a round-bottom flask (50 mL) was added EDCI (151.15 mg, 788.46 μmol, 1.5 eq) and DMAP (6.42 mg, 52.56 μmol, 0.1 eq). The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna (C18, 150 × 25 mm, 10 μm), mobile phase: [water (FA)-ACN], B (%): 22% → 52%, 9 min). The purified solution was lyophilized to give compound 3 (85 mg, 173.13 μmol, yield 32.94%, purity 94.2%) as a white solid. LCMS: Retention time = 0.415 min, m / z = 462.9 (M+H) +

[0225] Compound 3 (85 mg, 183.79 μmol, 1 eq) was purified by SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 μm), mobile phase: [ACN / IPA (0.1% NH3HO)], B (%): 45% → 45%, A 2.8, 22 min). The solution was concentrated to remove the organic solvent. The remaining aqueous solution was lyophilized to give 034 (31.6 mg, 68.33 μmol, 37.18% yield, 100% purity) as a white solid, and 035 (32.5 mg, 69.78 μmol, 37.97% yield, 99.3% purity) as a white solid.

[0226] Data for 034: LCMS: Retention time = 0.730 min, m / z = 463.2 (M+H) + SFC: Retention time = 0.591 min 1H NMR (400 MHz, chloroform-d) δ = (400 MHz, chloroform-d) δ = 12.18 - 11.92 (m, 1H), 8.31 (s, 1H), 8.25 (s, 1H), 7.41 - 7.34 (m, 1H), 7.22 - 7.19 (m, 1H), 7.14 - 7.09 (m, 1H), 7.09 - 7.02 (m, 2H), 6.90 - 6.84 (m, 1H), 6.48 - 6.39 (m, 1H), 3.78 - 3.72 (m, 1H), 2.92 - 2.87 (m, 3H), 2.86 - 2.79 (m, 3H), 1.87 (d, J = 7.3 Hz, 3H), 0.84 - 0.76 (m, 2H), 0.75 - 0.65 (m, 2H).

[0227] Data for 035: LCMS: Retention time = 0.731 min, m / z = 463.2 (M+H) +SFC: Retention time = 0.851 min 1H NMR (400 MHz, chloroform-d) δ = (400 MHz, chloroform-d) δ = 8.32 (s, 1H), 8.26 (s, 1H), 7.41 - 7.34 (m, 1H), 7.21 (s, 1H), 7.12 (d, J = 8.1 Hz, 1H), 7.09 - 7.02 (m, 2H), 6.90 - 6.84 (m, 1H), 6.47 - 6.39 (m, 1H), 3.80 - 3.71 (m, 1H), 2.90 (s, 3H), 2.85 - 2.80 (m, 3H), 1.89 - 1.85 (m, 3H), 0.83 - 0.77 (m, 2H), 0.74 - 0.64 (m, 2H).

[0228] Compounds 042 and 043 were prepared similarly to Scheme 11. Data for 042: (17 mg, 39.04 μmol, 34.00% yield), LCMS: retention time = 0.522 min, m / z = 435.9 (M+H + ), 1 H NMR: H NMR (400 MHz, chloroform-d) δ = 11.84 (br s, 1H), 8.00 (s, 1H), 7.33 - 7.21 (m, 5H), 7.11 (dd, J = 1.4, 9.8 Hz, 1H), 7.01 - 6.93 (m, 3H), 6.44 (br d, J = 6.9 Hz, 1H), 4.06 - 3.92 (m, 2H), 2.70 (s, 3H), 1.72 (d, J = 7.1 Hz, 3H), 1.29 (t, J = 6.9 Hz, 3H). Data regarding 043: (15.5mg, 35.59μmol, yield 31.00%), LCMS: Retention time = 0.519 min, m / z = 435.9 (M+H + ) 1H NMR: (400 MHz, chloroform-d) δ = 8.10 (s, 1H), 7.42 - 7.30 (m, 5H), 7.21 (br d, J = 9.4 Hz, 1H), 7.09 - 7.02 (m, 3H), 6.61 - 6.46 (m, 1H), 4.15 - 4.01 (m, 2H), 2.80 (s, 3H), 1.82 (d, J = 7.1 Hz, 3H), 1.38 (t, J = 6.9 Hz, 3H).

[0229] Compounds 044 and 045 were prepared analogously to Scheme 11. Data for 044: (8.2 mg, 18.20 μmol, yield 39.36% and purity 96%), LCMS: retention time =0.689 min, m / z= 433.2 (M+H+). 1H NMR: (chloroform-d): δ 12.18-12.47 (1H, m), 8.99 (1H, s), 8.20 (1H, s), 7.29-7.41 (4H, m), 7.02-7.12 (3H, m), 5.68 (1H, q, J=7.2 Hz), 4.00-4.15 (2H, m), 2.95 (3H, s), 2.83 (3H, s), 2.01 (3H, d, J=7.3 Hz), 1.38 (3H, t, J=6.9 Hz). Data for 045: (9.8 mg, 21.53 μmol, yield 46.55% and purity 95%), LCMS: Retention time =0.619 min, m / z= 433.2 (M+H+). 1H NMR: (Chloroform-d): δ 12.07-12.66 (1H, m), 8.99 (1H, s), 8.20 (1H, s), 7.28-7.39 (4H, m), 6.97-7.12 (3H, m), 5.68 (1H, q, J=7.0 Hz), 4.02-4.14 (2H, m), 2.95 (3H, s), 2.83 (3H, s), 2.01 (3H, br d, J=7.3 Hz), 1.38 (3H, br t, J=7.0 Hz).

[0230] Compounds 049 and 050 were prepared similarly to Scheme 11. Data for 049: (13.1 mg, 28.84 μmol, 34.64% yield, 95% purity), LCMS: retention time = 0.409 min, m / z = 433.4 (M+H + ). 1 H NMR: (400 MHz, chloroform-d) δ = 12.09 (br s, 1H), 8.31 (s, 1H), 8.24 (s, 1H), 7.43 - 7.30 (m, 4H), 7.11 - 7.02 (m, 3H), 6.51 - 6.41 (m, 050 data: (13.8mg, 31.17μmol, 37.45% yield, 97% purity), LCMS: Retention time = 0.406 min, m / z = 433.6 (M+H + ). 1 H NMR: (400 MHz, chloroform-d) δ = 12.00 (br s, 1H), 8.22 (s, 1H), 8.14 (s, 1H), 7.33 - 7.20 (m, 4H), 7.01 - 6.93 (m, 3H), 6.36 (q, J = 7.1 Hz, 1H), 4.07 - 3.91 (m, 2H), 2.77 (s, 3H), 2.73 (s, 3H), 1.78 (d, J = 7.1 Hz, 3H), 1.29 (t, J = 6.9 Hz, 3H).

[0231] Compounds 051 and 052 were prepared analogously to Scheme 11. Data for 051: (11.1mg, 25.79μmol, yield 22.20%), LCMS: retention time =0.613min, m / z= 431.3 (M+H+). 1H NMR: (chloroform-d): δ 12.01-12.32 (1H, m), 9.07-9.18 (1H, m), 8.42-8.50 (1H, m), 8.27 (1H, s), 7.32-7.46 (2H, m), 7.01-7.25 (5H, m), 6.51 (1H, br d, J=6.5 Hz), 3.78 (1H, br s), 2.84 (3H, s), 1.90 (3H, br d, J=7.1 Hz), 0.74-0.88 (4H, m). Data for 051: (12.8mg, 29.73μmol, 25.60% yield), LCMS: Retention time = 0.613 min, m / z= 431.3 (M+H+). 1H NMR: (Chloroform-d): δ 12.05-12.31 (1H, m), 8.96-9.32 (1H, m), 8.22-8.57 (2H, m), 7.44 (1H, s), 7.31-7.40 (2H, m), 7.18-7.25 (2H, m), 7.01-7.12 (2H, m), 6.39-6.62 (1H, m), 3.78 (1H, br d, J=3.0 Hz), 2.84 (3H, s), 1.90 (3H, br d, J=7.1 Hz), 0.80-0.88 (4H, m).

[0232] Compounds 056 and 057 were prepared similarly to Scheme 11. Data for 056: LCMS: Retention time = 0.586 min, m / z = 420.3 (M+H + ). 1H NMR: (400 MHz, chloroform-d) δ = 12.11 - 11.98 (m, 1H), 9.12 (s, 1H), 8.45 (br s, 1H), 8.25 (s, 1H), 7.78 - 7.72 (m, 1H), 7.49 - 7.30 (m, Data regarding 057: LCMS: retention time = 0.586 min, m / z = 420.3 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.09 - 11.94 (m, 1H), 9.05 (s, 1H), 8.40 - 8.34 (m, 1H), 8.18 (s, 1H), 7.67 (br d, J = 6.3 Hz, 1H), 7.42 - 7.22 (m, 5H), 7.04 - 6.97 (m, 1H), 4.46 - 4.20 (m, 2H), 2.86 (br s, 3H), 1.82 (br d, J = 6.3 Hz, 3H), 1.34 - 1.27 (m, 3H).

[0233] Compounds 058 and 059 were prepared similarly to Scheme 11. Data for 058: LCMS: Retention time = 0.696 min, m / z = 418.2 (M+H +). H-NMR: (400 MHz, chloroform-d) δ = 12.00 - 11.76 (m, 1H), 8.13 (s, 1H), 7.78 - 7.73 (m, 1H), 7.42 - 7.28 (m, 5H), 7.21 - 7.15 (m, 1H), 7.07 - 7.00 (m, 3H), 6.58 - 6.50 (m, 1H), 4.14 - 3.99 (m, 2H), 2.76 (s, 3H), 1.84 - 1.80 (m, 3H), 1.37 (t, J = 7.0 Hz, 3H). Data regarding 059: LCMS: retention time = 0.692 min, m / z = 418.1 (M+H + H-NMR: (400 MHz, chloroform-d) δ = 11.85–11.78 (m, 1H), 8.04 (s, 1H), 7.70–7.65 (m, 1H), 7.33–7.21 (m, 5H), 7.13–7.07 (m, 1H), 6.99–6.92 (m, 3H), 6.46 (q, J = 6.9 Hz, 1H), 4.06–3.91 (m, 2H), 2.68 (s, 3H), 1.74 (d, J = 7.1 Hz, 3H), 1.29 (t, J = 7.0 Hz, 3H).

[0234] Compounds 123 and 124 were prepared similarly to Scheme 11. Data for 123: LCMS: Retention time = 0.615 min, m / z = 434.3 (M+H + ) 1H NMR: (400 MHz, chloroform-d) δ = 13.04 - 11.60 (m, 1H), 8.39 - 8.10 (m, 2H), 7.90 - 7.66 (m, 1H), 7.51 - 7.28 (m, 4H), 7.14 - 7.01 (m, 1H), 6.43 (br d, J = 6.6 Hz, 1H), 4.72 - 4.18 (m, 2H), 2.99 - 2.63 (m, 6H), 1.80 - 1.61 (m, 3H), 1.35 - 1.17 (m, 3H) Data for 124: LCMS: Retention time = 0.614 min, m / z = 434.3 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.95–11.89 (m, 1H), 8.33–8.18 (m, 2H), 7.85–7.71 (m, 1H), 7.48–7.31 (m, 4H), 7.12–7.05 (m, 1H), 6.54–6.17 (m, 1H), 4.66–4.23 (m, 2H), 2.93–2.66 (m, 6H), 1.90–1.72 (m, 3H), 1.33 (br s, 3H).

[0235] Compounds 094 and 095 were prepared similarly to Scheme 11. Data for 094: LCMS: Retention time = 0.129 min, m / z = 449.2 (M+H + ). 1H NMR: (chloroform-d) δ: ppm 1.38 (t, J=6.94 Hz, 3 H), 1.68 (d, J=6.63 Hz, 3 H), 3.06 (s, 3 H), 4.07 (q, J=7.13 Hz, 2 H), 4.95 (s, 2 H), 5.32 (q, J=6.59 Hz, 1 H), 7.01 - 7.12 (m, 3 H), 7.31 (d, J=7.38 Hz, 2 H), 7.33 - 7.41 (m, 2 H), 8.20 - 8.33 (m, 2 H), 12.22 - 12.42 (m, 1 H). Data for 095: LCMS: retention time =0.134 min, m / z= 449.2 (M+H + ). 1 H NMR: (chloroform-d) δ: ppm 1.38 (t, J=7.00 Hz, 3 H) 1.51 - 1.60 (m, 5 H) 1.66 - 1.81 (m, 2 H) 3.52 (s, 3 H) 3.57 - 3.63 (m, 1 H) 3.83 - 3.92 (m, 1 H) 4.11 - 4.16 (m, 1 H) 4.94 (s, 1 H) 7.00 - 7.08 (m, 1 H) 7.25 - 7.29 (m, 2 H) 7.30 (d, J=1.13 Hz, 1 H) 7.32 - 7.37 (m, 3 H).

[0236] Compounds 123 and 124 were prepared analogously to Scheme 11. Data for 123 (34.09 mg, 76.44 μmol, 36.82% yield and 97.2% purity): LCMS: retention time = 0.615 min, m / z = 434.3 (M+H + ) 1H NMR: (400 MHz, chloroform-d) δ = 13.04 - 11.60 (m, 1H), 8.39 - 8.10 (m, 2H), 7.90 - 7.66 (m, 1H), 7.51 - 7.28 (m, 4H), 7.14 - 7.01 (m, 1H), 6.43 (br d, J = 6.6 Hz, 1H), 4.72 - 4.18 (m, 2H), 2.99 - 2.63 (m, 6H), 1.80 - 1.61 (m, 3H), 1.35 - 1.17 (m, 3H). Data for 124 (30.89 mg, 69.62 μmol, 33.53% yield and 97.7% purity): LCMS: Retention time = 0.614 min, m / z = 434.3 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.95–11.89 (m, 1H), 8.33–8.18 (m, 2H), 7.85–7.71 (m, 1H), 7.48–7.31 (m, 4H), 7.12–7.05 (m, 1H), 6.54–6.17 (m, 1H), 4.66–4.23 (m, 2H), 2.93–2.66 (m, 6H), 1.90–1.72 (m, 3H), 1.33 (br s, 3H).

[0237] Compounds 159 and 160 were prepared similarly to Scheme 11. Data for 159 (7.4 mg, 16.50 μmol, 37.00% yield): LCMS: retention time = 0.648 min, m / z = 449.1 (M+H + ) 11H NMR: (400 MHz, chloroform-d) δ = 12.19 (s, 1H), 8.35 - 8.25 (m, 1H), 8.18 (s, 1H), 7.45 - 7.20 (m, 5H), 6.99 - 6.96 (m, 2H), 6.40 (q, J = 6.8 Hz, 1H), 5.06 (s, 2H), 4.07 - 3.92 (m, 2H), 2.74 (s, 3H), 1.81 (d, J = 7.1 Hz, 3H), 1.30 (t, J = 7.0 Hz, 3H). Data for 160 (8.4 mg, 18.73 μmol, yield 42.00%): LCMS: retention time = 0.646 min, m / z = 449.1 (M+H + ) 1 1H NMR: (400 MHz, chloroform-d) δ = 12.46 - 11.91 (m, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 7.40 (s, 5H), 6.98 (s, 2H), 6.39 (d, J = 7.0 Hz, 1H), 5.05 (s, 2H), 4.07 - 3.92 (m, 2H), 2.74 (s, 3H), 1.81 (d, J = 7.1 Hz, 3H), 1.29 (t, J = 6.9 Hz, 3H).

[0238]

Chemical Structure

[0239] To a solution of compound 1 (350 mg, 982.23 μmol, 1 eq) in dioxane (5 mL) in a 40 mL vial, SeO2 (544.94 mg, 4.91 mmol, 534.26 μL, 5 eq) was added, and the mixture was stirred at 60 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated to give the crude product. The residue was purified by silica gel chromatography (PE: EtOAc = 10:1). Compound 2 (360 mg, 972.14 μmol, 98.97% yield, purity not available) was obtained as a light brown solid. LCMS: retention time = 0.559 min, m / z = 369.8, 371.8 (M+H + ). 1 H NMR (400 MHz, chloroform-d) δ = 10.20 (s, 1H), 8.73 (s, 1H), 6.11 (s, 2H), 3.63–3.58 (m, 2H), 2.92 (s, 3H), 0.94–0.86 (m, 2H), –0.05 (s, 9H).

[0240] To a solution of compound 2 (325 mg, 877.63 μmol, 1 eq) in MeOH (7 mL) in a 100 mL single-neck round-bottom flask, LiBH (115 mg, 5.28 mmol, 6.02 eq) was added at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. After the reaction was completed, the reaction mixture was quenched with saturated aqueous NH Cl (50 mL) at 0 °C. The mixture was extracted with EtOAc (50 mL × 2), and the combined organic phases were dried over Na SO and concentrated in vacuo to give the crude product. The residue was purified by silica gel chromatography (PE: EtOAc = 1:1). Compound 3 (257 mg, 676.44 μmol, 77.08% yield, 98% purity) was obtained as a white solid. LCMS: retention time = 0.131 min, m / z = 226.0, 228.0 (M+H + ).

[0241] To a solution of compound 3 (257 mg, 690.24 μmol, 1 eq) in DCM (5 mL) in a 50 mL single-neck round-bottom flask, imidazole (117.47 mg, 1.73 mmol, 2.5 eq) and TBSCl (208.07 mg, 1.38 mmol, 169.16 μL, 2 eq) were added at 0 °C, and the mixture was stirred at 20 °C for 12 h. TLC (PE: EtOAc = 10:1, Plate 1) showed that the desired spot (Rf = 0.21) was detected. The mixture was filtered, and the filtrate was concentrated to give the crude product. The residue was purified by silica gel column chromatography (PE: EtOAc = 10:1). Compound 4 (320 mg, 657.63 μmol, 95.28% yield, purity not available) was obtained as a colorless oil. 1 H NMR (400 MHz, chloroform-d) δ = 8.44 (s, 1H), 6.07 (s, 2H), 5.07 (s, 2H), 3.66 - 3.54 (m, 2H), 2.77 (s, 3H), 0.97 (s, 9H), 0.91 - 0.87 (m, 2H), 0.16 (s, 6H), -0.05 (s, 9H)

[0242] To a solution of compound 4 (320 mg, 657.63 μmol, 1 eq) and compound 5 (176.18 mg, 1.32 mmol, 2 eq) in dioxane (4 mL) and HO (0.4 mL) was added KCO (181.78 mg, 1.32 mmol, 2 eq) and Pd(dppf)Cl CHCl (53.70 mg, 65.76 μmol, 0.1 eq) under N. The mixture was stirred at 100 °C for 16 h under N. The reaction mixture was filtered through a Celite pad. The combined filter cake was washed with 10:1 EtOAc / methanol (10 mL × 5). The combined filtrate was concentrated to give the crude product. The crude product was purified by silica gel chromatography (PE: EtOAc = 10:1). Compound 6 (190 mg, 438.06 μmol, 66.61% yield, purity not applicable) was obtained as a colorless oil.

[0243] A solution of compound 6 (190 mg, 438.06 μmol, 1 eq) in DCM (12 mL) and MeOH (12 mL) was treated with ozone (21.03 mg, 438.06 μmol, 1 eq) for 30 min (15 psi) at −78 °C in a 100 mL three-necked round-bottom flask. The mixture was then purged with nitrogen for 0.5 h, and PPh3 (229.79 mg, 876.11 μmol, 2 eq) dissolved in DCM (12 mL) was added dropwise to the mixture at −78 °C. The mixture was warmed to 20 °C and stirred at 20 °C for 1 h. After the reaction was complete, the mixture was concentrated to give the crude product. The residue was purified by silica gel chromatography (PE: EtOAc = 10:1). Compound 7 (140 mg, 321.32 μmol, 73.35% yield, purity not available) was obtained as a light brown solid. 1 H NMR (400 MHz, chloroform-d) δ = 10.81 (s, 1H), 8.64 (s, 1H), 6.07 (s, 2H), 5.24 (br s, 2H), 3.56 - 3.49 (m, 2H), 3.02 (s, 3H), 1.06 (s, 9H), 0.96 - 0.87 (m, 2H), 0.26 (s, 6H), 0.17 (d, J = 12.6 Hz, 1H), 0.00 (s, 9H).

[0244] Compound 7 (140 mg, 321.32 μmol, 1 eq) in MeOH (2 mL) was added to MeNH in THF (2 M, 481.98 μL, 3 eq) and HOAc (1.93 mg, 32.13 μmol, 1.84 μL, 0.1 eq) in a 50 mL round-bottom flask at 20 °C. The mixture was stirred at 20 °C for 3 h. Subsequently, NaBH (24.31 mg, 642.63 μmol, 2 eq) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 1 h. After the reaction was complete, the reaction mixture was poured into NH Cl (0.1 mL), filtered, and the filtrate was concentrated under reduced pressure to give a residue. The solution was then triturated with EtOAc and THF (80 mL), filtered, and the filtrate was concentrated under reduced pressure to give compound 8 (150 mg, crude) as a light brown oil. LCMS: Retention time = 0.446 min, m / z = 452.1 (M+H + )

[0245] In an 8 mL vial, to a solution of compound 8 (50 mg, 94.28 μmol, 85% purity, 1 eq) in DCM (1 mL) was added compound 9 (24.54 mg, 94.28 μmol, 1 eq), EDCI (27.11 mg, 141.43 μmol, 1.5 eq), and DMAP (1.15 mg, 9.43 μmol, 0.1 eq). The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated in vacuo. The residue was purified by preparative TLC (PE: EtOAc = 2:1). Compound 10 (47 mg, 67.82 μmol, 71.93% yield, purity not available) was obtained as an off-white solid. LCMS: retention time = 0.559 min, m / z = 694.0 (M+H + )

[0246] To a solution of compound 10 (42 mg, 60.61 μmol, 1 eq) in HCl / dioxane (4 M, 2 mL, 132.00 eq) in a 50 mL single-neck round-bottom flask was added. The mixture was stirred at 20 °C for 2 h. The reaction mixture was concentrated to give the crude product. The crude product was basified with EtN to a pH of about 8-9. The residue was purified by preparative HPLC (column: Waters xbridge (150 × 25 mm, 10 μm), mobile phase: [water (NH4HCO3)-ACN], B (%): 27% → 57%, 11 min) and lyophilized. 037 (5.2 mg, 11.43 μmol, 18.86% yield and 98.6% purity) was obtained as a white solid. LCMS: retention time = 0.389 min, m / z = 449.5 (M+H + ) 1 H NMR (400 MHz, chloroform-d) δ = 13.15 (br s, 1H), 8.59 (s, 1H), 7.41 - 7.37 (m, 2H), 7.33 - 7.30 (m, 2H), 7.11 - 7.05 (m, 3H), 7.01 (s, 1H), 5.88 (br s, 1H), 5.38 (br s, 2H), 5.11 (s, 2H), 4.08 (q, J = 6.9 Hz, 2H), 3.14 (s, 1H), 3.12 (s, 3H), 1.39 (t, J = 6.9 Hz, 3H).

[0247] Compound 040 was prepared similarly to Scheme 12 and isolated as a white solid (6.8 mg, 13.68 μmol, 25.30% yield and 99.6% purity). LCMS: Retention time = 0.416 min, m / z = 495.5 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ = 12.09 (br s, 1H), 8.11 (s, 1H), 7.30 - 7.28 (m, 1H), 7.20 (s, 2H), 7.15 (br s, 2H), 6.80 (br d, J = 8.4 Hz, 1H), 5.03 (s, 2H), 5.01 (s, 2H), 4.39 (br s, 1H), 3.68 (br d, J = 3.1 Hz, 1H), 2.99 (s, 3H), 2.77 (s, 3H), 0.77 - 0.68 (m, 2H), 0.65 (br s, 2H).

[0248] Compound 041 was prepared similarly to Scheme 12 and isolated as a white solid (13 mg, 27.26 μmol, 35.75% yield and 100% purity). LCMS: Retention time = 0.375 min, m / z = 477.4 (M+H + ) 1 H NMR (400 MHz, chloroform-d) δ = 12.29 (br s, 1H), 8.18 (s, 1H), 7.44 (br d, J = 7.4 Hz, 2H), 7.37 - 7.29 (m, 4H), 7.12 - 7.06 (m, 1H), 5.10 - 5.08 (m, 4H), 4.52 (br s, 1H), 3.81 - 3.74 (m, 1H), 3.06 (s, 3H), 2.84 (s, 3H), 0.85 - 0.72 (m, 4H).

[0249] Compound 053 was prepared similarly to Scheme 12 and isolated as a white solid (30.9 mg, 70.95 μmol, 39.93% yield and 99.3% purity). LCMS: Retention time = 0.388 min, m / z = 433.4 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ = 12.09 (br s, 1H), 8.15 (s, 1H), 7.41 - 7.27 (m, 4H), 7.09 - 7.01 (m, 3H), 5.07 (s, 2H), 4.07 (q, J = 7.0 Hz, 2H), 3.02 (s, 3H), 2.82 (s, 3H), 2.79 (s, 3H), 1.37 (t, J = 6.9 Hz, 3H).

[0250] Compound 054 was prepared similarly to Scheme 12 and isolated as a white solid (7.3 mg, 16.70 μmol, 20.56% yield and 99.4% purity). LCMS: Retention time = 0.443 min, m / z = 435.3 (M+H + ) 1 H NMR (400 MHz, chloroform-d) δ = 12.27 (br s, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.40 - 7.34 (m, 2H), 7.33 - 7.28 (m, 2H), 7.09 - 7.02 (m, 3H), 5.43 (s, 2H), 4.07 (q, J = 6.9 Hz, 2H), 3.31 (s, 3H), 2.56 (s, 3H), 1.39 - 1.35 (m, 3H).

[0251] Compound 079 was prepared similarly to Scheme 12 and isolated as a white solid (6 mg, 12.97 μmol, 18.34% yield and 100% purity). LCMS: Retention time = 0.390 min, m / z = 463.1 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ = 12.46 (s, 1H), 8.31 - 8.23 ​​(m, 1H), 7.41 - 7.34 (m, 2H), 7.33 - 7.28 (m, 2H), 7.13 - 7.00 (m, 3H), 5.39 - 5.24 (m, 1H), 5.10 (s, 2H), 4.08 (q, J = 7.1 Hz, 2H), 3.06 (s, 3H), 2.89 (s, 3H), 1.72 (br s, 3H), 1.38 (t, J = 6.9 Hz, 3H).

[0252] Compound 117 was prepared similarly to Scheme 12 and isolated as a white solid (15 mg, 34.68 μmol, 18.05% yield). LCMS: Retention time = 0.743 min, m / z = 433.2 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.33 - 11.81 (m, 1H), 9.04 (br s, 1H), 8.34 (br s, 1H), 8.19 (s, 1H), 7.36 - 7.21 (m, 4H), 7.04 - 6.90 (m, 3H), 6.19 - 5.97 (m, 1H), 3.99 (br dd, J = 7.2, 17.4 Hz, 2H), 2.76 - 2.66 (m, 3H), 2.41 - 2.10 (m, 2H), 1.33 - 1.26 (m, 3H), 1.17 - 1.11 (m, 3H).

[0253] [ka]

[0254] Compound 2 (200 mg, 652.58 μmol, 1 eq), EDCI (187.65 mg, 978.86 μmol, 1.5 eq), and DMAP (7.97 mg, 65.26 μmol, 0.1 eq) were added to compound 1 (169.84 mg, 652.58 μmol, 1 eq) dissolved in DCM (5 mL) in a 40 mL flask. The reaction mixture was stirred at 20 °C for 16 h using a magnetic stirrer. The reaction mixture was concentrated in vacuo to give a residue. The crude product was purified by silica gel column chromatography eluting with PE: EtOAc = 0:1 (desired compound = 0.5), and the purified solution was concentrated in vacuo to give a colorless oil. Compound 3 (348 mg, 615.17 μmol, 94.27% yield, 97% purity) was obtained as a colorless oil. LCMS: Retention time = 0.484 min, m / z = 549.4 (M+H + )

[0255] To a solution of 3 (100 mg, 182.24 μmol, 1 eq) in DCM (2 mL) in a 50 mL single-neck round-bottom flask, m-CPBA (111.00 mg, 546.72 μmol, 85% purity, 3 eq) was slowly added at 0 °C, and the mixture was stirred at 20 °C with a magnetic stirrer for 1 h. After the reaction was completed, the reaction mixture was quenched with NaSO (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was dried and concentrated under vacuum to give a residue. The crude product was purified by preparative HPLC (column: Waters xbridge (150 × 25 mm, 10 μm), mobile phase: [water (NHHCO)-CAN], B (%): 45% → 75%, 8 min). After preparative HPLC purification, the eluate was concentrated to remove the organic solvent. The remaining aqueous solution was lyophilized to give a white solid. Compound 4 (42 mg, 73.63 μmol, 40.40% yield, 99% purity) was obtained as a white solid. LCMS: Retention time = 0.699 min, m / z = 565.1 (M+H + )

[0256] A solution of compound 4 (50 mg, 88.54 μmol, 1 eq) in 40 mL of AcO (5.45 g, 53.38 mmol, 5 mL, 602.95 eq) was stirred at 100 °C for 16 h under N. The reaction mixture was partitioned between EtOAc (40 mL) and water (40 mL). The separated organic layer was dried over (NaSO) and evaporated to dryness to give the crude product. The crude product was purified by preparative HPLC (column: Phenomenex Luna (C18, 150 × 25 mm, 10 μm), mobile phase: [water (FA)-ACN], B (%): 62% → 92%, 8 min). After preparative HPLC purification, the eluate was concentrated to remove the organic solvent. The remaining aqueous solution was lyophilized to give a white solid. Compound 5 (10 mg, 16.48 μmol, 18.61% yield) was obtained as a white solid. 1 H-NMR: (400 MHz, chloroform-d) δ = 9.15 (s, 1H), 8.24 (s, 1H), 7.44 (s, 2H), 7.38 - 7.34 (m, 2H), 7.20 - 7.13 (m, 2H), 7.08 (br t, J = 8.4 Hz, 1H), 5.99 - 5.98 (m, 2H), 5.52 - 5.38 (m, 4H), 3.65 - 3.60 (m, 2H), 2.91 (s, 3H), 2.19 (s, 3H), 2.06 (s, 2H), 1.45 - 1.41 (m, 3H), 0.95 - 0.91 (m, 3H), 0.00 (s, 9H).

[0257] To compound 5 (7 mg, 11.54 μmol, 1 eq) dissolved in HO (1 mL), THF (1 mL), and EtOH (1 mL) in a 100 mL single-neck round-bottom flask, LiOH.HO (2.42 mg, 57.68 μmol, 5 eq) was added, and the reaction mixture was stirred by magnetic stirring at 20 °C for 1 h. After the reaction was completed, the mixture was extracted with EtOAc (25 mL × 3), and the combined organic phase was washed with brine (50 ml), dried over anhydrous NaSO, and concentrated to give the crude product. The crude product was used in the next step without purification. Compound 6 (30 mg, crude) was obtained as a white solid. LCMS: Retention time = 0.471 min, m / z = 565.5 (M+H + )

[0258] Compound 6 (30 mg, 53.12 μmol, 1 eq) was dissolved in DCM (2 mL) in a 100 mL one-neck round-bottom flask, and TFA (1.54 g, 13.51 mmol, 1 mL, 254.24 eq) was added at 0 °C. The reaction mixture was stirred at 20 °C for 1 h using a magnetic stirrer. After the reaction was complete, the solvent was removed under reduced pressure using a rotary evaporator to obtain the crude product. The crude product was purified by preparative HPLC (column: Phenomenex (C18, 150 × 25 mm, 10 μm), mobile phase: [water (NH4HCO3)-ACN], B (%): 28% → 58%, 8 min). After preparative HPLC purification, the eluate was concentrated to remove the organic solvent. The remaining aqueous solution was lyophilized to obtain a brown solid. 039 (2.8 mg, 6.44 μmol, 12.13% yield) was obtained as a brown solid. LCMS: Retention time = 0.574 min, m / z = 435.3 (M+H + ) 1H-NMR: (400 MHz, chloroform-d) δ = 12.87 - 12.67 (m, 1H), 9.21 (br s, 1H), 8.43 (s, 1H), 7.40 - 7.36 (m, 2H), 7.33 - 7.31 (m, 2H), 7.11 - 7.04 (m, 3H), 5.23 - 5.16 (m, 2H), 5.13 (s, 2H), 4.09 (q, J = 7.0 Hz, 2H), 3.11 (s, 3H), 1.38 (s, 3H).

[0259] [ka]

[0260] To a solution of compound 1 (370 mg, 746.66 μmol, 1 eq) in 2-MeTHF (30 mL) in a 250 mL three-necked bottle, NaH (44.80 mg, 1.12 mmol, 60% purity, 1.5 eq) was added at 0 °C under N 2 , and the mixture was stirred at 0 °C for 1 h under N 2 . Subsequently, SEM-Cl (149.38 mg, 895.99 μmol, 158.58 μL, 1.2 eq) was added dropwise at 0 °C under N 2 , and the mixture was stirred at 20 °C for 12 h under N 2 using a magnetic stirrer. After the reaction was completed, the reaction mixture was poured into saturated NH 4 Cl (100 mL) solution at room temperature and extracted with EtOAc (100 mL × 3). The combined organic phase was washed with brine (100 mL), dried over anhydrous Na 2 SO 4 , and concentrated to give the crude product. The residue was purified by flash silica gel chromatography (ISCO®, 4 g SepaFlash® Silica Flash Column, eluent: 0 to 28% EtOAc / PE gradient (40 mL / min)). Compound 2 (430 mg, 687.12 μmol, 92.03% yield) was obtained as a colorless oil. LCMS: Retention time = 0.637 min, m / z = 626.3 (M+Na + )

[0261] To a solution of compound 2 (200 mg, 319.59 μmol, 1 eq) in MeOH (20 mL) was added Pd / C (200 mg, 31.96 μmol, 10% purity, 0.1 eq) under N2, and the mixture was stirred at 20 °C for 1 h under H2 (644.23 μg, 319.59 μmol, 1 eq) (15 Psi). After the reaction was completed, the mixture was filtered under N2 atmosphere, and the filtrate was concentrated to give the crude product. The residue was purified by preparative TLC (SiO2, PE / EtOAc = 1 / 1). Compound 3 (102 mg, 190.41 μmol, 59.58% yield) was obtained as a yellow oil. LCMS: retention time = 0.590 min, m / z = 536.3 (M+H + )

[0262] To a solution of compound 3 (80 mg, 149.34 μmol, 1 eq) in DMF (2 mL) in an 8 mL vial, KCO (41.28 mg, 298.69 μmol, 2 eq) and MeI (63.59 mg, 448.03 μmol, 27.89 μL, 3 eq) were added. The mixture was stirred at 50 °C for 12 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was dried and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO, PE / EtOAc = 5 / 1). Compound 4 (45 mg, 81.86 μmol, 54.81% yield) was obtained as a colorless oil. LCMS: retention time = 0.625 min, m / z = 550.3 (M+H + )

[0263] To a solution of compound 4 (45 mg, 81.86 μmol, 1 eq) in DCM (2 mL) in a 100 ml round-bottom flask, TFA (3.08 g, 27.01 mmol, 2 mL, 329.97 eq) was added at 20° C. The mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters xbridge (150×25 mm, 10 μm), mobile phase: [water (NH4HCO3)-ACN], B (%): 45% to 75%, 8 min). The purified solution was then lyophilized to give the product. 060 (15.4 mg, 36.71 μmol, 44.85% yield, 100% purity) was obtained as a white solid. LCMS: retention time = 0.491 min, m / z = 420.3 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 11.60 (br s, 1H), 8.06 (s, 1H), 7.77 - 7.66 (m, 1H), 7.44 - 7.39 (m, 1H), 7.35 (d, J = 1.4 Hz, 1H), 7.33 - 7.27 (m, 3H), 7.27 - 7.18 (m, 2H), 7.11 - 7.05 (m, 1H), 7.01 - 6.93 (m, 1H), 5.19 (s, 2H), 4.06 - 3.98 (m, 2H), 3.32 (s, 3H), 1.31 (t, J = 7.0 Hz, 3H).

[0264] [ka]

[0265] To a solution of compound 1 (5 g, 39.95 mmol, 4.55 mL, 1 eq) in DCM (50 mL) was added NBS (7.11 g, 39.95 mmol, 1 eq), and the mixture was stirred at 20 °C for 2 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was dried and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 10 / 1), and the purified solution was concentrated in vacuo to give compound 2 (6 g, 29.41 mmol, 73.60% yield) as an orange oil. LCMS: retention time = 0.386 min, m / z = 204.1 (M+H). + 1H NMR: (400 MHz, chloroform-d) δ = 7.17 - 7.11 (m, 1H), 6.40 - 6.36 (m, 1H), 3.83 - 3.59 (m, 2H), 2.12 - 2.07 (m, 3H)

[0266] To a solution of compound 2 (6 g, 29.41 mmol, 1 eq) in MeCN (60 mL) was added NIS (6.62 g, 29.41 mmol, 1 eq) at 0 °C, and the mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was dried and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 10 / 1), and the purified solution was concentrated in vacuo to give compound 3 (6 g, 18.19 mmol, 61.84% yield) as a brown oil. LCMS: retention time = 0.515 min, m / z = 329.8 (M+H). + 1H NMR: (400 MHz, chloroform-d) δ = 7.69 - 7.65 (m, 1H), 4.21 (br s, 2H), 2.19 - 2.17 (m, 3H)

[0267] To a solution of compound 3 (6 g, 18.19 mmol, 1 eq) in AcOH (60 mL) and HO (6 mL) was added NaNO (1.25 g, 18.19 mmol, 1 eq) at 5 °C, and the mixture was stirred at 20 °C for 2 h. The mixture was poured into water (100 mL), adjusted to pH 8 with saturated NaCO brine (100 mL), dried over anhydrous NaSO, and concentrated to give the crude product. The residue was purified by column chromatography (SiO, PE / EtOAc = 10 / 1 to 5 / 1), and the purified solution was concentrated in vacuo to give compound 4 (4.65 g, 13.64 mmol, 75.00% yield) as a brown solid. 1H NMR: (400 MHz, chloroform-d) δ = 8.35 - 8.28 (m, 1H), 7.84 (br d, J = 5.8 Hz, 1H)

[0268] To a solution of compound 4 (4.65 g, 13.64 mmol, 1 eq) in 2-MeTHF (100 mL) was added NaH (818.30 mg, 20.46 mmol, 60% purity, 1.5 eq) at 0 °C, and the mixture was stirred at 0 °C for 1 h. Subsequently, SEM-Cl (3.41 g, 20.46 mmol, 3.62 mL, 1.5 eq) was added to the reaction at 0 °C, and the reaction mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into saturated aqueous NH Cl (500 mL), and the mixture was extracted with EtOAc (500 mL × 3). The combined organic phases were dried and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 5 / 1), and the purified solution was concentrated in vacuo to give compound 5 (6.2 g, crude) as a brown oil. LCMS: Retention time = 0.662 min, m / z = 354.8 (M+H) +

[0269] To a solution of compound 5 (960 mg, 2.04 mmol, 1 eq) in MeOH (20 mL) in a glass vial (75 mL) was added Pd(OAc) (45.74 mg, 203.74 μmol, 0.1 eq), DPPF (225.90 mg, 407.49 μmol, 0.2 eq), and TEA (412.33 mg, 4.07 mmol, 567.17 μL, 2 eq). The mixture was stirred at 40 °C for 12 h under CO (30 psi). LCMS (5-95 AB / 0.8 min) showed that 70% of compound 5 remained. The reaction mixture was filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 10 / 1 → 5 / 1), and the purified solution was concentrated in vacuo to give compound 6 (190 mg, 471.09 μmol, 23.12% yield) as a yellow oil. LCMS: retention time = 0.545 min, m / z = 285.0 (M+H). +

[0270] To a solution of compound 6 (850 mg, 2.11 mmol, 1 eq) in dioxane (10 mL) in a 40 mL glass bottle, compound 7 (535.18 mg, 2.11 mmol, 1 eq), KOAc (413.67 mg, 4.22 mmol, 2 eq), and Pd(dppf)Cl.CHCl (172.11 mg, 210.75 μmol, 0.1 eq) were added, and the mixture was stirred at 100 °C for 12 h under N. The reaction mixture was filtered under vacuum to obtain a filtrate, which was then concentrated under vacuum to obtain a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 10 / 1 → 5 / 1), and the purified solution was concentrated under vacuum to obtain compound 8 (600 mg, 1.33 mmol, 63.21% yield) as a yellow oil. LCMS: Retention time = 0.623 min, m / z = 333.1 (M+H) +

[0271] To a solution of compound 8 (600 mg, 1.33 mmol, 1 eq) in AcOH (6 mL) in a round-neck flask (100 mL) was slowly added HO (7.08 g, 62.44 mmol, 6 mL, 30% purity, 46.87 eq) at 20 °C. Subsequently, the mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched with NaSO (60 mL), extracted with DCM (60 mL × 3), and the combined organic phases were dried and concentrated at 20 °C to give compound 9 (430 mg, 1.26 mmol, 94.82% yield) as a yellow oil, which was used directly in the next step. LCMS: retention time = 0.492 min, m / z = 223.2 (M+H). +

[0272] To a solution of methyl compound 9 (330 mg, 969.39 μmol, 1 eq) in acetone (4 mL) in a glass bottle (40 mL) was added KCO (267.95 mg, 1.94 mmol, 2 eq), KI (16.09 mg, 96.94 μmol, 0.1 eq), and compound 10 (140.73 mg, 1.16 mmol, 1.2 eq), and the mixture was stirred at 60 °C for 12 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were dried and concentrated in vacuo to give compound 11 (360 mg, 946.16 μmol, 97.60% yield) as a yellow oil, which was used directly in the next step. LCMS: retention time = 0.553 min, m / z = 263.1 (M+H). +

[0273] To a solution of methyl compound 11 (360 mg, 946.16 μmol, 1 eq) in 2-MeTHF (5 mL) in a Schlenk tube (20 mL) was slowly added LAH (53.87 mg, 1.42 mmol, 1.5 eq) at 0 °C, and the mixture was stirred at 0 °C for 1 h. After the reaction was completed, NaSO·10H O (200 mg) was added to the resulting mixture, and the mixture was filtered. The filtrate was concentrated to give compound 12 (230 mg, 736.21 μmol, 77.81% yield) as a white solid, which was used directly in the next step. LCMS: retention time = 0.421 min, m / z = 195.2 (M+H). +

[0274] To a solution of compound 12 (230 mg, 736.21 μmol, 1 eq) in acetone (3 mL) in a glass bottle (40 mL) was added KCO (203.50 mg, 1.47 mmol, 2 eq), KI (12.22 mg, 73.62 μmol, 0.1 eq), and compound 13 (89.06 mg, 736.21 μmol, 1 eq), and the mixture was stirred at 60 °C for 12 h. The reaction mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was dried and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 5 / 1), and the purified solution was concentrated in vacuo to give compound 14 (220 mg, 624.16 μmol, 84.78% yield) as a colorless oil. LCMS: Retention time = 0.495 min, m / z = 235.2 (M+H) +

[0275] To a solution of compound 14 (220 mg, 624.16 μmol, 1 eq) in DCM (3 mL) was added MnO (1.09 g, 12.48 mmol, 20 eq) in a glass bottle (40 mL), and the mixture was stirred at 20° C. for 12 hours. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated to give compound 15 (190 mg, 542.15 μmol, 86.86% yield) as a colorless oil, which was used directly in the next step. LCMS: retention time = 0.540 min, m / z = 233.2 (M+H).+

[0276] To a solution of compound 15 (190 mg, 542.15 μmol, 1 eq) in MeOH (2 mL) in a 100 mL three-neck flask, AcOH (3.26 mg, 54.21 μmol, 3.10 μL, 0.1 eq) and MeNH in THF (2 M, 813.22 μL, 3 eq) were added at 20 °C, and the mixture was stirred at 20 °C for 1 h. Subsequently, NaBH (41.02 mg, 1.08 mmol, 2 eq) was added to the mixture at 0 °C, and the mixture was stirred at 20 °C for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO (20 mL), extracted with dichloromethane (20 mL × 3), and the combined organic phases were dried and concentrated in vacuo to give compound 16 (120 mg, 328.30 μmol, 60.56% yield) as a colorless oil, which was used directly in the next step. LCMS: Retention time = 0.394 min, m / z = 366.3 (M+H) +

[0277] To a solution of compound 17 (37.24 mg, 136.79 μmol, 1 eq) in DCM (1 mL) in a glass bottle (8 mL) was added EDCI (39.34 mg, 205.19 μmol, 1.5 eq), DMAP (1.67 mg, 13.68 μmol, 0.1 eq), and compound 16 (50 mg, 136.79 μmol, 1 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO, PE / EtOAc = 1 / 1), and the purified solution was concentrated in vacuo to give compound 18 (60 mg, 96.81 μmol, 70.77% yield) as a colorless oil. LCMS: retention time = 0.598 min, m / z = 502.3 (M+H). +

[0278] To a solution of compound 18 (60 mg, 96.81 μmol, 1 eq) in THF (1 mL) in a Schlenk tube (20 mL) was added Pd(PPh3)4 (11.19 mg, 9.68 μmol, 0.1 eq). NaBH4 (36.63 mg, 968.10 μmol, 10 eq) was then added to the mixture at 0 °C, and the mixture was stirred at 20 °C for 1 h under N2. The reaction mixture was poured into saturated NH4Cl (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phases were dried and concentrated in vacuo to give compound 19 (40 mg, 69.00 μmol, 71.27% yield) as a brown oil, which was used directly in the next step. LCMS: retention time = 0.550 min, m / z = 462.3 (M+H). +

[0279] To a solution of compound 19 (40 mg, 69.00 μmol, 1 eq) in a round-bottom flask (100 mL) were added TFA (1.54 g, 13.51 mmol, 1 mL, 195.74 eq) and DCM (0.5 mL), and the mixture was stirred at 20 °C for 1 h. The reaction mixture was basified with saturated aqueous NaHCO (10 mL), and the reaction mixture was diluted with HO (10 mL) and extracted with EA (10 mL × 3). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna (C18, 150 × 25 mm, 10 μm), mobile phase: [water (FA)-ACN], B (%): 44% → 74%, 9 min), and the purified solution was lyophilized to give compound 061 (13.7 mg, 29.51 μmol, yield 42.76%, purity 96.8%) as a brown solid. LCMS: retention time = 0.456 min, m / z = 450.2 (M+H) +1H NMR (400 MHz, chloroform-d) δ = 8.12 - 8.09 (m, 1H), 7.44 (d, J = 1.1 Hz, 1H), 7.38 - 7.34 (m, 1H), 7.32 (d, J = 7.6 Hz, 1H), 7.23 (br d, J = 7.8 Hz, 1H), 7.19 (dd, J = 2.3, 10.2 Hz, 1H), 7.09 (d, J = 7.3 Hz, 2H), 7.03 (dt, J = 1.7, 8.5 Hz, 1H), 4.89 (s, 2H), 3.80 - 3.73 (m, 1H), 3.05 - 3.01 (m, 3H), 0.83 - 0.78 (m, 2H), 0.77 - 0.72 (m, 2H).

[0280] Compound 063 was prepared similarly to Scheme 15 and isolated as a yellow solid (26 mg, 58.60 μmol, 55.45% yield, 98.6% purity). LCMS: Retention time = 0.447 min, m / z = 438.2 (M+H). + 1H NMR (400 MHz, chloroform-d) δ = 8.04–8.01 (m, 1H), 7.31–7.26 (m, 2H), 7.25 (s, 1H), 7.24–7.21 (m, 2H), 7.01–6.99 (m, 1H), 6.99–6.97 (m, 2H), 6.97–6.93 (m, 1H), 4.81–4.79 (m, 2H), 4.02–3.96 (m, 2H), 2.94 (s, 3H), 1.31–1.27 (m, 3H).

[0281] Compound 148 was prepared similarly to Scheme 15 and isolated as a white solid (9.7 mg, 21.51 μmol, 12.21% yield, 97% purity). LCMS: Retention time = 0.488 min, m / z = 438.1 (M+H +) 1H NMR (400 MHz, chloroform-d) δ = 8.03 (s, 1H), 7.41 - 7.30 (m, 5H), 7.09 (s, 3H), 5.09 (s, 2H), 4.08 (q, J = 7.0 Hz, 2H), 3.10 - 3.08 (m, 3H), 1.40 - 1.36 (m, 3H).

[0282] Compound 178 was prepared similarly to Scheme 15 and isolated as a white solid (21.8 mg, 48.03 μmol, 31.17% yield). H-NMR: (400 MHz, chloroform-d) δ = 8.00 (s, 1H), 7.41 (s, 1H), 7.36 - 7.33 (m, 2H), 7.32 - 7.28 (m, 1H), 7.11 (d, J = 1.3 Hz, 1H), 6.98 (s, 1H), 6.86 - 6.83 (m, 2H), 4.91 (s, 2H), 4.03 (q, J = 7.0 Hz, 2H), 3.02 (s, 3H), 1.30 (t, J = 6.9 Hz, 3H). LCMS: Retention time = 0.486 min, m / z = 454.0 (M+H + ).

[0283] [ka]

[0284] To a solution of compound 1 (400 mg, 1.44 mmol, 1 eq) and compound 2 (455.92 mg, 2.89 mmol, 2 eq) in dioxane (10 mL) in a glass vial (40 mL) was added Pd(dppf)Cl CHCl (117.89 mg, 144.36 μmol, 0.1 eq) and KCO (399.03 mg, 2.89 mmol, 2 eq). The mixture was stirred at 100 °C for 12 h under a N atmosphere. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 0 / 1 → 5 / 1), and the purified solution was concentrated in vacuo to give compound 3 (340 mg, 1.10 mmol, 75.91% yield) as a white solid. LCMS: Retention time = 0.495 min, m / z = 311.2 (M+H) +

[0285] To a solution of compound 3 (340 mg, 1.10 mmol, 1 eq) in MeOH (5 mL) and HO (1.7 mL) in a round-bottom flask (100 mL) was added LiOH·HO (137.95 mg, 3.29 mmol, 3 eq). The mixture was stirred at 20 °C for 1 h. THF (5 mL) and NaOH (131.49 mg, 3.29 mmol, 3 eq) were added to the reaction mixture, and the reaction mixture was stirred at 20 °C for an additional 1 h. The organic solvent was evaporated in vacuo, and the resulting mixture was acidified to pH 4 with 1 N HCl, filtered, and the filter cake was washed with water (20 mL). It was then dissolved in MeOH (20 mL) and concentrated in vacuo to give compound 4 (300 mg, 1.01 mmol, 92.41% yield) as a white solid, which was used in the next step without further purification. LCMS: Retention time = 0.398 min, m / z = 295.0 (MH) +

[0286] To a solution of compound 4 (300 mg, 1.01 mmol, 1 eq) and compound 5 (354.93 mg, 1.01 mmol, 1 eq) in DCM (10 mL) in a round-bottom flask (50 mL) was added EDCI (291.20 mg, 1.52 mmol, 1.5 eq) and DMAP (12.37 mg, 101.27 μmol, 0.1 eq). The mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 1 / 0 → 0 / 1), and the purified solution was concentrated in vacuo to give compound 6 (380 mg, 604.41 μmol, 59.68% yield) as a green oil. LCMS: retention time = 0.572 min, m / z = 629.3 (M+H). +

[0287] To a solution of compound 6 (380 mg, 604.41 μmol, 1 eq) in MeOH (5 mL) in a round-bottom flask (50 mL) was added LiBH4 in THF (2 M, 906.61 μL, 3 eq) at 0 °C. The mixture was stirred at 20 °C for 2 h. The reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (30 mL × 3). The combined organic phases were dried and concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO2, dichloromethane:methanol = 10:1), and the purified solution was concentrated in vacuo to give compound 7 (210 mg, 349.59 μmol, 57.84% yield) as a colorless oil. LCMS: retention time = 0.458 min, m / z = 601.8 (M+H). +

[0288] To a solution of compound 7 (30 mg, 49.94 μmol, 1 eq) in DCM (1 mL) in a round-bottom flask (50 mL) was added TFA (3.08 g, 27.01 mmol, 2 mL, 540.87 eq). The mixture was stirred at 20° C. for 3 h. The reaction mixture was concentrated under reduced pressure at 20° C. to give a residue. The residue was dissolved in dichloromethane (2 mL) and basified with NaHCO (5 mg) to pH 7 at 20° C., then filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna (C18, 150 × 25 mm, 10 μm), mobile phase: [water (FA)-ACN], B (%): 20% → 50%, 9 min), and the purified solution was lyophilized to give 131 (8.5 mg, 18.07 μmol, 36.18% yield, 100% purity) as a white solid. LCMS: retention time = 0.363 min, m / z = 471.3 (M+H). + 1H NMR (400 MHz, chloroform-d) δ = 8.35 - 8.28 (m, 2H), 6.95 (br d, J = 7.3 Hz, 2H), 6.90 - 6.80 (m, 3H), 5.21 - 5.16 (m, 2H), 4.98 - 4.91 (m, 2H), 4.11 - 4.01 (m, 2H), 3.10 - 3.03 (m, 3H), 1.37 - 1.30 (m, 3H).

[0289] Compound 084 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 084 was obtained as a white solid (41.0 mg, 85.96 μmol, 52.20% yield, 100% purity). LCMS: Retention time = 0.422 min, m / z = 476.16 (M+H + ) 1H NMR: (400 MHz, chloroform-d) δ = 12.43 - 12.15 (m, 1H), 8.28 (d, J = 5.6 Hz, 2H), 7.55 (s, 1H), 7.48 - 7.40 (m, 1H), 7.39 - 7.29 (m, 3H), 7.07 (dd, J = 1.4, 7.8 Hz, 1H), 6.90 (d, J = 1.1 Hz, 1H), 5.15 (s, 2H), 4.95 (s, 2H), 4.67 (quintet, J = 7.0 Hz, 1H), 3.05 (s, 3H), 2.49 - 2.36 (m, 2H), 2.20 - 2.06 (m, 2H), 1.91 - 1.77 (m, 2H).

[0290] Compound 085 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 085 was obtained as a white solid (11.3 mg, 24.84 μmol, 20.04% yield and 95.5% purity). LCMS: Retention time = 0.384 min, m / z = 454.13 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.33 (br s, 1H), 8.27 (s, 2H), 7.68 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 3.6 Hz, 1H), 7.46 (s, 1H), 7.37 (d, J = 5.0 Hz, 1H), 7.15 - 7.05 (m, 2H), 5.14 (s, 2H), 4.95 (s, 2H), 3.96 - 3.80 (m, 1H), 3.06 (s, 3H), 0.92 - 0.86 (m, 4H).

[0291] Compound 087 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 087 was obtained as a white solid (10.7 mg, 22.04 μmol, 38.77% yield, 100% purity). LCMS: Retention time = 0.389 min, m / z = 486.3 (M+H +) 1H NMR (400 MHz, chloroform-d) δ = 8.49 (s, 1H), 8.41 - 8.33 (m, 1H), 7.69 - 7.64 (m, 2H), 7.62 - 7.57 (m, 1H), 7.56 - 7.50 (m, 1H), 7.22 - 7.18 (m, 1H), 6.91 - 6.84 (m, 1H), 5.30 (s, 2H), 5.05 - 4.98 (m, 2H), 3.78 - 3.71 (m, 1H), 3.42 - 3.33 (m, 2H), 1.38 - 1.34 (m, 3H), 0.84 - 0.78 (m, 2H), 0.75 - 0.68 (m, 2H).

[0292] Compound 098 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 087 was obtained as a white solid (15 mg, 34.29 μmol, 29.95% yield). 1 H NMR: (400 MHz, DMSO-d6) δ = 12.87 - 12.73 (m, 1H), 9.15 (br s, 1H), 8.02 - 7.76 (m, 1H), 7.54 - 7.38 (m, 1H), 7.28 - 6.84 (m, 7H), 4.93 - 4.72 (m, 2H), 3.82 - 3.56 (m, 2H), 3.09 - 2.97 (m, 3H), 1.25 - 1.00 (m, 3H). LCMS: Retention time = 0.449 min, m / z = 438.1 (M+H + ).

[0293] Compound 104 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 104 was obtained as a white solid (14.28 mg, 29.91 μmol, 30.29% yield, 100% purity). LCMS: Retention time = 0.368 min, m / z = 478.1 (M+H +). HNMR: (400 MHz, chloroform-d) δ = 12.46 - 11.85 (m, 1H), 8.29 (d, J = 3.6 Hz, 2H), 7.54 (s, 1H), 7.46 - 7.34 (m, 2H), 6.91 - 6.84 (m, 2H), 5.15 (s, 2H), 4.95 (s, 2H), 4.07 (q, J = 6.8 Hz, 2H), 3.05 (s, 3H), 1.34 (t, J = 6.8 Hz, 3H).

[0294] Compound 106 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 106 was obtained as a white solid (11.2 mg, 25.17 μmol, 27.11% yield, 99% purity). LCMS: Retention time = 0.390 min, m / z = 441.5 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ =12.57 - 11.76 (m, 1H), 8.26 (d, J = 6.5 Hz, 2H), 7.66 (br s, 1H), 7.46 (d, J = 5.1 Hz, 1H), 7.14 (t, J = 4.4 Hz, 1H), 6.92 - 6.85 (m, 2H), 5.13 (s, 2H), 4.92 (s, 2H), 4.17 (q, J = 6.9 Hz, 2H), 3.04 (s, 3H), 1.51 (t, J = 6.9 Hz, 3H).

[0295] Compound 107 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 107 was obtained as a white solid (10.3 mg, 21.75 μmol, 24.82% yield, 93% purity). LCMS: Retention time = 0.376 min, m / z = 441.2 (M+H +) 1H NMR (400 MHz, chloroform-d) δ = 12.49 - 11.88 (m, 1H), 8.31 - 8.21 (m, 2H), 7.66 - 7.62 (m, 1H), 7.44 - 7.33 (m, 2H), 6.91 - 6.81 (m, 2H), 5.13 (s, 2H), 4.93 (s, 2H), 4.08 (q, J = 6.9 Hz, 2H), 3.05 (s, 3H), 1.41 (t, J = 6.9 Hz, 3H).

[0296] Compound 109 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 109 was obtained as a white solid (18 mg, 40.09 μmol, 21.83% yield and 99% purity). LCMS: Retention time = 0.748 min, m / z = 445.3 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.18 (s, 1H), 9.13 (s, 1H), 8.51 - 8.21 (m, 2H), 7.54 - 7.33 (m, 3H), 7.27 - 7.17 (m, 2H), 7.15 - 6.98 (m, 2H), 6.18 (s, 1H), 3.78 (s, 1H), 2.82 (s, 3H), 2.46 - 2.22 (m, 2H), 1.29 - 1.16 (m, 3H), 0.88 - 0.72 (m, 4H).

[0297] Compound 111 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 111 was obtained as a white solid (6.5 mg, 14.24 μmol, 20.89% yield, 100% purity). LCMS: Retention time = 0.420 min, m / z = 457.2 (M+H +). HNMR: (400 MHz, chloroform-d) δ = 11.94 - 11.43 (m, 1H), 7.98 (s, 1H), 7.64 (br d, J = 5.9 Hz, 2H), 7.60 - 7.48 (m, 1H), 7.48 - 7.48 (m, 1H), 7.24 (s, 1H), 7.13 (s, 1H), 7.01 (s, 1H), 6.88 (br d, J = 8.9 Hz, 1H), 4.92 (s, 2H), 3.72 (br d, J = 2.4 Hz, 1H), 3.04 (s, 3H), 0.82 - 0.72 (m, 2H), 0.67 (br s, 2H).

[0298] Compound 112 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 112 was obtained as a white solid (10.2 mg, 23.83 μmol, 29.11% yield, 98% purity). LCMS: Retention time = 0.451 min, m / z = 420.0 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ = 8.01 (s, 1H), 7.44 - 7.34 (m, 5H), 7.14 - 7.09 (m, 1H), 7.01 - 6.97 (m, 1H), 6.89 - 6.82 (m, 2H), 4.91 (s, 2H), 4.08 - 3.97 (m, 2H), 3.04 (s, 3H), 1.32 - 1.29 (m, 3H).

[0299] Compound 113 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 113 was obtained as a white solid (5.3 mg, 11.38 μmol, 13.56% yield, 100% purity). LCMS: Retention time = 0.499 min, m / z = 466.2 (M+H +) 1H NMR (400 MHz, chloroform-d) δ = 7.99 (s, 1H), 7.33 (s, 3H), 7.23 ( s, 2H), 7.12 (s, 1H), 6.98 (s, 1H), 6.87 (d, J = 8.8 Hz, 1H), 4.92 (s, 2H), 3.73 (s, 1H), 3.04 (s, 3H), 0.78 (d, J = 4.9 Hz, 2H), 0.70 (s, 2H).

[0300] Compound 114 was prepared similarly to Scheme 16 using LiOH instead of NaOH and isolated as a yellow solid (16.5 mg, 38.24 μmol, 10.74% yield, 100% purity). LCMS: Retention time = 0.451 min, m / z = 431.16 (M+H + ) 1 H NMR: (400 MHz, DMSO-d6) δ = 12.78 (br d, J = 17.1 Hz, 1H), 9.16 (br s, 1H), 7.89 (br s, 1H), 7.40 (br dd, J = 1.1, 5.6 Hz, 1H), 7.33 (br s, 3H), 7.26 - 7.19 (m, 1H), 7.12 - 6.98 (m, 1H), 6.97 - 6.85 (m, 2H), 4.99 - 4.74 (m, 2H), 3.12 - 2.99 (m, 3H), 2.05 (s, 1H), 0.85 - 0.55 (m, 2H), 0.50 - 0.26 (m, 2H)

[0301] Compound 131 was prepared similarly to Scheme 16 and isolated as a white solid (8.5 mg, 18.07 μmol, 36.18% yield, 100% purity). LCMS: Retention time = 0.363 min, m / z = 471.3 (M+H). +1H NMR (400 MHz, chloroform-d) δ = 8.35 - 8.28 (m, 2H), 6.95 (br d, J = 7.3 Hz, 2H), 6.90 - 6.80 (m, 3H), 5.21 - 5.16 (m, 2H), 4.98 - 4.91 (m, 2H), 4.11 - 4.01 (m, 2H), 3.10 - 3.03 (m, 3H), 1.37 - 1.30 (m, 3H).

[0302] Compound 151 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 151 was obtained as a white solid (12.82 mg, 27.72 μmol, 18.26% yield, 100% purity). LCMS: Retention time = 0.322 min, m / z = 463.1 (M+H + ) 1 H NMR: (400 MHz, DMSO-d6) δ ppm 13.38 - 13.67 (m, 1 H) 8.43 - 8.64 (m, 1 H) 8.11 - 8.25 (m, 1 H) 7.38 - 7.52 (m, 4 H) 7.13 - 7.24 (m, 2 H) 6.71 - 6.85 (m, 1 H) 5.61 - 5.82 (m, 1 H) 5.49 (s, 1 H) 4.90 - 5.00 (m, 4 H) 4.64 - 4.88 (m, 2 H) 4.29 - 4.55 (m, 2 H) 2.98 (br d, J=2.00 Hz, 3H).

[0303] Compound 155 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 155 was obtained as a white solid (12.7 mg, 19.83 μmol, 22.65% yield, 98.2% purity). LCMS: Retention time = 0.326 min, m / z = 481.1 (M+H). +1H NMR (400 MHz, chloroform-d) δ = 8.37 (s, 1H), 8.33 (s, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.13 (dd, J = 1.3, 7.8 Hz, 1H), 7.09 (dd, J = 2.1, 8.3 Hz, 2H), 6.87 - 6.80 (m, 1H), 6.61 (d, J = 1.0 Hz, 1H), 5.28 - 5.23 (m, 1H), 5.22 (br s, 2H), 5.00 - 4.97 (m, 2H), 4.96 - 4.94 (m, 2H), 4.72 (dd, J = 5.2, 7.4 Hz, 2H), 3.05 (s, 3H).

[0304] Compound 161 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 161 was obtained as a white solid (23.8 mg, 46.13 μmol, 52.64% yield and 96.4% purity). LCMS: Retention time = 0.419 min, m / z = 497.1 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.34 - 11.99 (m, 1H), 8.28 (s, 2H), 7.35 (d, J = 5.3 Hz, 2H), 7.31 (d, J = 1.3 Hz, 1H), 7.20 (d, J = 0.9 Hz, 1H), 7.17 (d, J = 1.3 Hz, 1H), 7.12 - 7.07 (m, 1H), 5.15 (s, 2H), 4.96 (s, 2H), 3.76 - 3.65 (m, 1H), 3.08 (s, 3H), 0.79 - 0.74 (m, 2H), 0.68 - 0.62 (m, 2H).

[0305] Compound 162 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 162 was obtained as a white solid (37 mg, 76.94 μmol, 39.18% yield and 100% purity). LCMS: Retention time = 0.404 min, m / z = 481.1 (M+H + )1 H NMR: 1 H NMR (400 MHz, chloroform-d) δ = 12.17 (s, 1H), 8.28 (s, 2H), 7.42 - 7.34 (m, 1H), 7.31 (d, J = 1.1 Hz, 1H), 7.17 (d, J = 1.0 Hz, 1H), 7.11 - 7.03 (m, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 9.4 Hz, 1H), 5.14 (s, 2H), 4.95 (s, 2H), 3.75 - 3.67 (m, 1H), 3.08 (s, 3H), 0.82 - 0.72 (m, 2H), 0.69 - 0.60 (m, 2H).

[0306] Compound 165 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 165 was obtained as a white solid (7 mg, 14.07 μmol, 12.60% yield, 99.8% purity). LCMS: Retention time = 0.481 min, m / z = 486.2 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 8.31 (s, 1H), 8.28 (s, 1H), 7.18 (s, 1H), 6.88 (br d, J = 7.2 Hz, 2H), 6.87 - 6.79 (m, 2H), 5.16 (s, 2H), 4.99 (s, 2H), 3.74 (tt, J = 2.8, 6.0 Hz, 1H), 3.34 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H), 0.84 - 0.76 (m, 2H), 0.76 - 0.70 (m, 2H).

[0307] Compound 175 was prepared similarly to Scheme 16, using LiOH instead of NaOH. Compound 175 was obtained as a white solid (9.2 mg, 19.52 μmol, 23.39% yield, 99.5% purity). LCMS: Retention time = 0.366 min, m / z = 468.14 (M+H). +1H NMR (400 MHz, クロロホルム-d) δ = 12.59 - 12.17 (m, 1H), 8.38 - 8.31 (m, 2H), 7.43 - 7.36 (m, 1H), 7.16 - 7.13 (m, 1H), 7.11 - 7.07 (m, 1H), 7.07 - 7.03 (m, 1H), 7.02 - 6.97 (m, 1H), 6.93 (s, 1H), 5.21 (s, 2H), 4.96 (s, 2H), 3.99 (q, J = 7.0 Hz, 2H), 3.09 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H).

[0308]

change

[0309] To a solution of compound 1 (500 mg, 1.56 mmol, 1 eq) and compound 2 (512.27 mg, 3.12 mmol, 281.47 μL, 2 eq) in dioxane (5 mL) and HO (0.5 mL) was added KCO (431.64 mg, 3.12 mmol, 2 eq) and Pd(dppf)Cl CHCl (127.52 mg, 156.16 μmol, 0.1 eq). The mixture was stirred at 100 °C for 12 h under a N atmosphere. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phases were dried and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO 2 , PE / EtOAc=1 / 0→10 / 1), and the purified solution was concentrated in vacuo to give compound 3 (200 mg, 721.14 μmol, yield 46.18%) as a white solid. 1H NMR (400 MHz, chloroform-d) δ = 8.51 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 3.3 Hz, 1H), 7.76 (dd, J = 1.5, 8.3 Hz, 1H), 7.70 (d, J = 1.4 Hz, 1H), 7.49 - 7.45 (m, 1H), 4.45 - 4.39 (m, 2H), 4.39 - 4.34 (m, 2H), 1.65 (t, J = 7.0 Hz, 3H), 1.45 - 1.41 (m, 3H)

[0310] To a solution of compound 3 (200 mg, 721.14 μmol, 1 eq) in EtOH (3 mL), HO (1 mL), and THF (3 mL) was added LiOH·HO (90.79 mg, 2.16 mmol, 3 eq). The mixture was stirred at 20 °C for 12 h. After the solvent was removed by evaporation under reduced pressure, the mixture was acidified to pH 4 with 1 N HCl, and the suspension was then filtered to give compound 4 (130 mg, 521.49 μmol, 72.31% yield) as a white solid, which was used in the next step. LCMS: retention time = 0.355 min, m / z = 247.9 (MH + )

[0311] To a solution of compound 4 (130 mg, 521.49 μmol, 1 eq) and compound 5 (182.78 mg, 521.49 μmol, 1 eq) in DCM (3 mL) was added EDCI (149.96 mg, 782.24 μmol, 1.5 eq) and DMAP (6.37 mg, 52.15 μmol, 0.1 eq). The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 3 / 1 → 0 / 1), and the purified solution was concentrated in vacuo to give compound 6 (180 mg, 309.41 μmol, 59.33% yield) as a yellow oil. LCMS: retention time = 0.561 min, m / z = 582.2 (M+H + )

[0312] To a solution of compound 6 (180 mg, 309.41 μmol, 1 eq) in MeOH (3 mL) was added LiBH (2 M, 773.52 μL, 5 eq) at 0 °C. The mixture was stirred at 30 °C for 12 h. The reaction mixture was poured into saturated aqueous NH Cl (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic phase was dried over anhydrous Na SO and concentrated to give a residue. The residue was purified by preparative TLC (SiO, PE / EtOAc = 0:1). The purified solution was concentrated in vacuo to give compound 7 (95 mg, 171.56 μmol, 55.45% yield) as a yellow oil. LCMS: retention time = 0.400 min, m / z = 554.2 (M+H + )

[0313] To a solution of compound 7 (95 mg, 171.56 μmol, 1 eq) in DCM (3 mL) was added MnO (298.29 mg, 3.43 mmol, 20 eq). The mixture was stirred at 30 °C for 12 h. After the reaction was completed, the mixture was filtered, and the filtrate was concentrated to give a residue. The residue was purified by preparative TLC (SiO, PE / EtOAc = 1:1). The purified solution was concentrated in vacuo to give compound 8 (45 mg, 81.56 μmol, 47.54% yield) as a yellow oil.

[0314] To a solution of compound 8 (45 mg, 81.56 μmol, 1 eq) in THF (2 mL) in a Schlenk tube (40 mL) was added MeMgBr (3 M, 81.56 μL, 3 eq) at −70° C. The mixture was stirred at −70° C. for 1 h. The reaction mixture was poured into saturated NH4Cl (5 mL). The solvent was extracted with EtOAc (5 mL × 3), and the combined organic phases were dried and concentrated in vacuo to give (30 mg, 52.84 μmol, 64.78% yield) as a yellow solid, which was used in the next step. LCMS: Retention time = 0.401 min, m / z = 568.4 (M+H + )

[0315] To a solution of compound 9 (30 mg, 52.84 μmol, 1 eq) in DMF (1 mL) was added CsF (80.26 mg, 528.38 μmol, 19.48 μL, 10 eq). The mixture was stirred at 100° C. for 12 hours. The reaction mixture was filtered to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex (C18, 150×25 mm, 10 μm), mobile phase: [water (NH4HCO3)-ACN], B (%): 18% to 48%, 14 min). The purified solution was lyophilized to obtain 149 (5 mg, 11.43 μmol, 21.63% yield, 100% purity) as a white solid. LCMS: retention time = 0.571 min, m / z = 438.0 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ = 12.41 - 12.31 (m, 1H), 8.48 (d, J = 8.5 Hz, 1H), 8.33 (s, 1H), 8.26 (s, 1H), 7.95 (d, J = 3.1 Hz, 1H), 7.46 (d, J = 3.3 Hz, 1H), 7.18 - 7.13 (m, 2H), 5.39 - 5.29 (m, 1H), 4.95 (s, 2H), 4.80 - 4.68 (m, 1H), 4.31 (q, J = 6.9 Hz, 2H), 3.08 - 3.01 (m, 3H), 1.70 (d, J = 6.6 Hz, 3H), 1.61 (s, 3H).

[0316] Compound 067 was prepared similarly to Scheme 17 and obtained as a brown solid (32.3 mg, 66.83 μmol, 39.62% yield and 95.7% purity). LCMS: Retention time = 0.700 min, m / z = 463.2 (M+H + ) 1 H-NMR: (400 MHz, chloroform-d) δ = 12.31 (br s, 1H), 8.32 (s, 1H), 8.25 (s, 1H), 7.42 - 7.35 (m, 2H), 7.34 - 7.29 (m, 2H), 7.09 - 7.01 (m, 3H), 5.33 (d, J = 6.6 Hz, 1H), 4.99 (s, 2H), 4.07 (q, J = 6.9 Hz, 2H), 3.34 (br d, J = 7.0 Hz, 2H), 1.70 (d, J = 6.6 Hz, 3H), 1.39 (t, J = 6.9 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H).

[0317] Compound 076 was prepared similarly to Scheme 17 and obtained as a white solid (12.09 mg, 24.60 μmol, 25.49% yield, 100% purity). LCMS: Retention time = 0.345 min, m / z = 492.18 (M+H + ). 1 H NMR: (400 MHz, chloroform-d) δ = 12.16 (br s, 1H), 8.46 - 8.16 (m, 2H), 7.54 (d, J = 1.3 Hz, 1H), 7.45 - 7.33 (m, 2H), 6.94 - 6.84 (m, 2H), 5.32 (q, J = 6.6 Hz, 1H), 4.94 (s, 2H), 4.07 (q, J = 6.9 Hz, 2H), 3.05 (s, 3H), 1.68 (d, J = 6.6 Hz, 3H), 1.33 (t, J = 7.0 Hz, 3H).

[0318] Compound 080 was prepared similarly to Scheme 17 and obtained as a white solid. LCMS: retention time =0.369 min, m / z=468.1 (M+H+). HNMR: (400 MHz, chloroform-d) δ = 12.49 - 12.28 (m, 1H), 8.37 - 8.23 ​​(m, 2H), 7.77 (s, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.63 (d, J = 7.9 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.50 - 7.46 (m, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.16 - 7.12 (m, 1H), 5.46 - 5.30 (m, 1H), 4.97 (s, 2H), 3.83 - 3.74 (m, 1H), 3.09 (s, 3H), 1.71 (br d, J = 6.1 Hz, 3H), 0.86 - 0.81 (m, 2H), 0.77 - 0.73 (m, 2H).

[0319] Compound 081 was prepared similarly to Scheme 17 and obtained as a white solid (2.6 mg, 5.49 μmol, 16.53% yield, 99.7% purity). LCMS: Retention time = 0.370 min, m / z = 473.0 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ = 12.47–12.15 (m, 1H), 8.36 (s, 1H), 8.28 (s, 1H), 7.47–7.43 (m, 1H), 6.88 (s, 2H), 6.82 (s, 1H), 5.42–5.32 (m, 1H), 4.96–4.90 (m, 2H), 4.20 (q, J = 7.0 Hz, 2H), 3.05 (s, 3H), 1.71–1.70 (m, 3H), 1.55–1.53 (m, 3H).

[0320] Compound 083 was prepared similarly to Scheme 17 and obtained as a yellow solid (7.1 mg, 15.83 μmol, 9.16% yield and 100% purity). LCMS: Retention time = 0.380 min, m / z = 448.16 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.50 - 12.18 (m, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 2.8 Hz, 1H), 7.47 (d, J = 1.1 Hz, 1H), 7.37 (d, J = 4.5 Hz, 1H), 7.14 - 7.02 (m, 2H), 5.30 (q, J = 6.5 Hz, 1H), 4.94 (s, 2H), 3.95 - 3.85 (m, 1H), 3.06 (s, 3H), 1.67 (s, 3H), 0.93 - 0.85 (m, 4H).

[0321] Compound 088 was prepared similarly to Scheme 17 and obtained as a yellow solid (4.6 mg, 10.12 μmol, 9.86% yield, 100% purity). LCMS: Retention time = 0.388 min, m / z = 455.2 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ = 8.40 (s, 1H), 8.30 (s, 1H), 7.64 (s, 1H), 7.43 - 7.40 (m, 1H), 7.38 - 7.34 (m, 1H), 6.90 - 6.85 (m, 2H), 5.45 - 5.35 (m, 1H), 4.95 (s, 2H), 4.09 (q, J = 7.0 Hz, 2H), 3.08 (s, 3H), 1.73 (d, J = 6.6 Hz, 3H), 1.43 - 1.40 (m, 3H).

[0322] Compound 089 was prepared similarly to Scheme 17 and obtained as a yellow solid (6.3 mg, 13.26 μmol, 19.88% yield, 98.8% purity). LCMS: Retention time = 0.348 min, m / z = 470.3 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ = 8.43 (s, 1H), 8.30 (s, 1H), 7.88 - 7.83 (m, 1H), 7.79 - 7.74 (m, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.36 - 7.32 (m, 1H), 7.09 - 7.05 (m, 1H), 7.01 (s, 1H), 5.47 - 5.41 (m, 1H), 5.00 (d, J = 4.5 Hz, 2H), 4.07 (q, J = 6.8 Hz, 2H), 3.39 - 3.28 (m, 2H), 2.28 - 2.18 (m, 1H), 1.75 ( d, J = 6.6 Hz, 3H), 1.40 - 1.35 (m, 3H), 1.34 - 1.30 (m, 3H).

[0323] Compound 090 was prepared similarly to Scheme 17 and obtained as a yellow solid (2.6 mg, 5.38 μmol, 8.12% yield and 98% purity). LCMS: Retention time = 0.352 min, m / z = 474.2 (M+H + ). 1H NMR: (chloroform-d): δ 12.07-12.26 (1H, m), 8.23-8.33 (2H, m), 7.61-7.76 (3H, m), 7.51-7.57 (1H, m), 6.84-6.91 (2H, m), 5.31 (1H, q, J=6.5 Hz), 4.94 (2H, s), 4.06 (2H, q, J=7.0 Hz), 3.06 (3H, s), 1.68 (3H, d, J=6.6 Hz), 1.32 (3H, t, J=6.9 Hz).

[0324] Compound 091 was prepared similarly to Scheme 17 and obtained as a yellow solid (9.6 mg, 19.58 μmol, 24.11% yield and 99% purity). LCMS: Retention time = 0.380 min, m / z = 486.3 (M+H + ). 1H NMR: (chloroform-d): δ 12.27 (1H, s), 8.36 (1H, s), 8.29 (1H, s), 7.63-7.69 (2H, m), 7.57-7.61 (1H, m), 7.50-7.56 (1H, m), 7.25-7.26 (1H, m), 6.88-6.95 (1H, m), 5.37 (1H, q, J=6.5 Hz), 4.96 (2H, s), 3.77 (1H, td, J=2.9 and 5.9 Hz), 3.10 (3H, s), 1.71 (3H, d, J=6.6 Hz), 0.78-0.86 (2H, m), 0.68-0.75 (2H, m).

[0325] Compound 101 was prepared similarly to Scheme 17 and obtained as a white solid (24.6 mg, 50.85 μmol, 68.62% yield, 98.594% purity). LCMS: Retention time = 0.370 min, m / z = 477.4 (M+H + ) 1H NMR: (400 MHz, chloroform-d) δ ppm 8.41 (s, 1 H) 8.33 (s, 1 H) 7.45 (d, J=1.13 Hz, 2 H) 7.30 - 7.36 (m, 4 H) 7.11 (dd, J=7.75, 1.38 Hz, 1 H) 5.42 (q, J=6.55 Hz, 1 H) 4.98 (d, J=1.25 Hz, 2 H) 3.75 - 3.80 (m, 1 H) 3.09 (s, 3 H) 2.63 (s, 1 H) 1.72 (d, J=6.75 Hz, 3 H) 0.79 - 0.85 (m, 2 H) 0.73 - 0.78 (m, 2 H).

[0326] Compound 102 was prepared similarly to Scheme 17 and obtained as a white solid (22 mg, 44.00 μmol, 39.30% yield, 99% purity). LCMS: Retention time = 0.424 min, m / z = 459.2 (M+H + ). 1 H NMR: (chloroform-d): δ ppm 0.75 - 0.79 (m, 2 H) 0.81 - 0.85 (m, 2 H) 1.69 (d, J=6.63 Hz, 3 H) 3.07 (s, 3 H) 3.78 (tt, J=5.88, 2.94 Hz, 1 H) 4.52 - 4.83 (m, 1 H) 4.96 (s, 2 H) 5.32 (q, J=6.09 Hz, 1 H) 7.05 - 7.13 (m, 3 H) 7.24 (s, 1 H) 7.32 (d, J=7.75 Hz, 1 H) 7.45 (d, J=1.38 Hz, 1 H) 8.26 (s, 1H) 8.31 (s, 1 H) 12.30 (br s, 1 H).

[0327] Compound 115 was prepared similarly to Scheme 17 and obtained as a white solid (4.6 mg, 9.29 μmol, 38.74% yield, 100% purity). LCMS: Retention time = 0.418 min, m / z = 495.4 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ = 12.46 - 12.00 (m, 1H), 8.33 - 8.21 (m, 2H), 7.38 - 7.31 (m, 3H), 7.25 - 7.20 (m, 2H), 6.91 - 6.86 (m, 1H), 5.32 (q, J = 6.5 Hz, 1H), 4.95 (s, 2H), 3.75 (td, J = 3.0, 5.7 Hz, 1H), 3.08 (s, 3H), 1.69 (d, J = 6.5 Hz, 3H), 0.83 - 0.76 (m, 2H), 0.75 - 0.69 (m, 2H).

[0328] Compound 118 was prepared similarly to Scheme 17 and obtained as a white solid (8.3 mg, 17.74 μmol, 35.29% yield, 99.7% purity). LCMS: Retention time = 0.384 min, m / z = 466.9 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 8.43 - 8.41 (m, 1H), 8.35 - 8.31 (m, 1H), 7.43 - 7.36 (m, 1H), 7.21 - 7.12 (m, 2H), 7.11 - 7.05 (m, 1H), 6.90 - 6.84 (m, 2H), 5.44 (q, J = 6.6 Hz, 1H), 4.96 (s, 2H), 4.08 - 4.01 (m, 2H), 3.09 (s, 3H), 1.76 - 1.72 (m, 3H), 1.35 - 1.30 (m, 3H)

[0329] Compound 152 was prepared similarly to Scheme 17 and obtained as a white solid (11.83 mg, 23.81 μmol, 49.77% yield, 100% purity). LCMS: Retention time = 0.379 min, m / z = 497.3 (M+H + ) 1H NMR: (400 MHz, chloroform-d) δ = 12.72–12.19 (m, 1H), 8.41–8.39 (m, 1H), 8.34 (s, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.33 (s, 1H), 7.22–7.17 (m, 1H), 7.15–7.10 (m, 2H), 6.62–6.60 (m, 1H), 5.28–5.24 (m, 1H), 5.23 (s, 2H), 4.99–4.95 (m, 4H), 4.74–4.69 (m, 2H), 3.06 (s, 3H).

[0330] Compound 156 was prepared similarly to Scheme 17, using TFA instead of CsF, to give a colorless solid (18.7 mg, 38.26 μmol, 52.13% yield, 98.8% purity). LCMS: Retention time = 0.363 min, m / z = 483.2 (M+H). + 1H NMR (400 MHz, chloroform-d) δ = 8.38 (s, 1H), 8.32 (s, 1H), 7.43 - 7.36 (m, 1H), 7.15 (d, J = 1.3 Hz, 1H), 7.11 - 7.06 (m, 1H), 7.04 (d, J = 7.6 Hz, 1H), 6.99 (td, J = 1.8, 9.7 Hz, 1H), 6.94 (d, J = 1.1 Hz, 1H), 5.39 (q, J = 6.4 Hz, 1H), 4.95 (s, 2H), 3.99 (q, J = 7.0 Hz, 2H), 3.08 (s, 3H), 1.70 (d, J = 6.6 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H).

[0331] Compound 157 was prepared similarly to Scheme 17 and obtained as a white solid (10.2 mg, 21.29 μmol, 25.05% yield and 95.6% purity). LCMS: Retention time = 0.356 min, m / z = 457.1 (M+H + ) 1 H NMR: 1 H NMR (400 MHz, chloroform-d) δ = 12.36 (d, J = 4.1 Hz, 1H), 8.46 (d, J = 8.5 Hz, 1H), 8.39 - 8.20 (m, 2H), 7.19 (s, 1H), 7.16 - 7.09 (m, 2H), 5.17 (s, 2H), 4.96 (s, 2H), 4.30 (q, J = 6.9 Hz, 2H), 3.03 (s, 3H), 1.62 (s, 3H).

[0332] Compound 158 was prepared similarly to Scheme 17 and obtained as a white solid (1.9 mg, 3.73 μmol, 4.49% yield, 92.7% purity). LCMS: Retention time = 0.372 min, m / z = 471.11 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 12.41 - 12.04 (m, 1H), 8.45 (d, J = 8.4 Hz, 1H), 8.29 (s, 1H), 8.24 (s, 1H), 7.19 (s, 1H), 7.16 - 7.09 (m, 2H), 5.30 (q, J = 6.7 Hz, 1H), 4.93 (s, 2H), 4.30 (q, J = 7.0 Hz, 2H), 3.02 (s, 3H), 1.67 (d, J = 6.6 Hz, 3H), 1.62 (s, 3H).

[0333] Compound 163 was prepared similarly to Scheme 17 and obtained as a white solid (5.3 mg, 11.21 μmol, 26.96% yield, 99.6% purity). LCMS: Retention time = 0.411 min, m / z = 471.2 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ = 12.45 - 12.15 (m, 1H), 8.31 - 8.20 (m, 2H), 7.64 (d, J = 7.9 Hz, 1H), 7.35 - 7.32 (m, 1H), 7.09 - 7.04 (m, 2H), 6.94 - 6.90 (m, 1H), 5.35 - 5.26 (m, 1H), 4.92 (s, 2H), 4.20 (q, J = 6.9 Hz, 2H), 3.07 - 2.99 (m, 3H), 1.71 - 1.64 (m, 3H), 1.59 - 1.54 (m, 3H).

[0334] Compound 164 was prepared similarly to Scheme 17 and obtained as a white solid (3.4 mg, 7.35 μmol, 8.63% yield, 98.8% purity). LCMS: Retention time = 0.409 min, m / z = 457.2 (M+H +) 1H NMR (400 MHz, chloroform-d) δ = 12.36 - 12.19 (m, 1H), 8.32 - 8.21 (m, 2H), 7.67 - 7.61 (m, 1H), 7.34 (d, J = 4.0 Hz, 1H), 7.10 - 7.02 (m, 2H), 6.92 (d, J = 4.1 Hz, 1H), 5.14 (br s, 2H), 4.97 - 4.89 (m, 2H), 4.25 - 4.15 (m, 2H), 3.03 (s, 3H), 1.56 (t, J = 6.9 Hz, 3H).

[0335] Compound 166 was prepared similarly to Scheme 17 and obtained as a white solid (7.8 mg, 15.42 μmol, 38.83% yield, 98.7% purity). LCMS: Retention time = 0.384 min, m / z = 499.1 (M+H). + 1H NMR (400 MHz, chloroform-d) δ = 12.30 - 12.00 (m, 1H), 8.24 (s, 1H), 8.18 (br s, 1H), 7.32 - 7.25 (m, 2H), 7.21 - 7.20 (m, 1H), 7.11 - 7.03 (m, 2H), 6.86 (s, 1H), 5.25 (br d, J = 5.0 Hz, 1H), 4.86 (br s, 2H), 3.92 (q, J = 7.0 Hz, 2H), 2.99 (s, 3H), 1.61 (br d, J = 6.5 Hz, 3H), 1.17 (t, J = 6.9 Hz, 3H).

[0336] Compound 168 was prepared similarly to Scheme 17 and obtained as a white solid (8.5 mg, 17.44 μmol, 35.65% yield, 99.1% purity). LCMS: Retention time = 0.397 min, m / z = 483.2 (M+H). +1H NMR (400 MHz, chloroform-d) δ ppm 12.14 - 12.46 (m, 1 H) 8.18 - 8.33 (m, 2 H) 7.58 - 7.64 (m, 1 H) 7.42 - 7.48 (m, 1 H) 7.28 - 7.31 (m, 1 H) 7.06 - 7.12 (m, 1 H) 6.88 - 6.92 (m, 1 H) 5.24 - 5.35 (m, 1 H) 4.90 - 4.99 (m, 2 H) 3.84 - 3.94 (m, 1 H) 3.02 - 3.09 (m, 3 H) 1.67 (br d, J=6.38Hz, 3H) 0.86 - 0.94 (m, 4 H).

[0337] Compound 172 was prepared similarly to Scheme 17 and obtained as a white solid (4.5 mg, 8.48 μmol, 21.29% yield, 93.7% purity). LCMS: Retention time = 0.410 min, m / z = 497.1 (M+H + ) 1H NMR (400 MHz, chloroform-d) δ = 8.35 (s, 1H), 8.28 - 8.25 (m, 1H), 7.42 (s, 1H), 7.37 - 7.34 (m, 2H), 7.32 - 7.28 (m, 1H), 6.84 - 6.80 (m, 1H), 6.78 (s, 1H), 5.39 - 5.33 (m, 1H), 5.01 - 4.92 (m, 2H), 4.07 - 3.99 (m, 2H), 3.37 - 3.29 (m, 2H), 1.71 (d, J = 6.6 Hz, 3H), 1.34 - 1.29 (m, 6H).

[0338] Compound 176 was prepared similarly to Scheme 17 and obtained as a white solid (6 mg, 12.53 μmol, 9.54% yield). H-NMR: (400 MHz, chloroform-d) δ = 8.30 (s, 1H), 8.23 ​​(s, 1H), 7.55 (d, J = 1.5 Hz, 1H), 7.42 (td, J = 1.8, 6.7 Hz, 1H), 7.35 - 7.32 (m, 3H), 7.04 (dd, J = 1.4, 7.8 Hz, 1H), 7.00 (s, 1H), 5.31 (q, J = 6.5 Hz, 1H), 4.97 (s, 2H), 4.05 (q, J = 6.9 Hz, 2H), 3.31 (q, J = 7.1 Hz, 2H), 1.68 (d, J = 6.6 Hz, 3H), 1.37 (t, J = 7.0 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H).

[0339] [ka]

[0340] To a solution of compound 1 (500 mg, 1.25 mmol, 1 eq) in DMF (5 mL) in an 8 mL vial, compound 2 (325.61 mg, 1.50 mmol, 1.2 eq) and K2CO3 (345.22 mg, 2.50 mmol, 2 eq) were added, and the mixture was stirred at 20 °C for 12 h. After the reaction was completed, the mixture was poured into water (20 mL) and extracted with EtOAc (20 mL × 3). The combined organic phase was washed with brine (20 mL × 3), dried over anhydrous Na2SO4, and concentrated to give the crude product. The crude product was purified by column chromatography (SiO2, PE:EtOAc = 2:1 → 1:1, Rf = 0.4 for the desired product). Compound 3 (550 mg, 1.02 mmol, 82.05% yield) was obtained as a yellow oil. LCMS: Retention time = 0.554 min, m / z = 537.6 (M+H + ) 1H NMR: (400 MHz, chloroform-d) δ = 8.67 (s, 1H), 8.43–8.40 (m, 1H), 5.92 (s, 2H), 5.44 (s, 2H), 4.11–4.09 (m, 3H), 3.56–3.49 (m, 2H), 1.46 (s, 18H), 0.93–0.87 (m, 2H), –0.05 (s, 9H).

[0341] To a solution of compound 3 (500 mg, 931.63 μmol, 1 eq) in MeOH (5 mL) in a 100 mL three-neck flask, LiBH4 in THF (2 M, 2.33 mL, 5 eq) was added at 0 °C, and the mixture was stirred at 20 °C for 2 h. After the reaction was completed, the reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) at room temperature. The mixture was extracted with EtOAc (50 mL × 3), and the combined organic phase was dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude product was purified by column chromatography (SiO2, PE:EtOAc = 5:1 → 1:1, Rf of the desired product = 0.4). Compound 4 (200 mg, 393.17 μmol, 42.20% yield) was obtained as a white solid. LCMS: retention time = 0.441 min, m / z = 509.5 (M+H + )

[0342] To a solution of compound 4 (50 mg, 98.29 μmol, 1 eq) in THF (1 mL) in an 8 mL vial, HCl (1.02 g, 27.98 mmol, 1 mL, 284.61 eq) in HO was added, and the mixture was stirred at 20 °C for 48 h. The reaction mixture was adjusted to pH 7 with NaCO at 20 °C. The mixture was extracted with EtOAc (5 mL × 3), and the combined organic phase was washed with brine (5 mL), dried over anhydrous NaSO, and concentrated to give the crude product. The compound was used in the next step without further purification. Compound 5 (30 mg, 97.26 μmol, 98.95% yield) was obtained as a colorless oil. LCMS: Retention time = 0.235 min, m / z = 309.1 (M+Na + )

[0343] To a solution of compound 5 (30 mg, 97.26 μmol, 1 eq) and compound 6 (25.31 mg, 97.26 μmol, 1 eq) in DCM (1 mL) in a 100 mL round-bottom flask, EDCI (27.97 mg, 145.89 μmol, 1.5 eq) and DMAP (1.19 mg, 9.73 μmol, 0.1 eq) were added, and the mixture was stirred at 20° C. for 12 h. After the reaction was completed, the mixture was concentrated to give the crude product. The crude product was purified by preparative TLC (PE: EtOAc = 0:1). Compound 7 (16 mg, 29.05 μmol, 29.87% yield) was obtained as a colorless oil. LCMS: retention time = 0.450 min, m / z = 551.1 (M+H + )

[0344] To a solution of compound 7 (16 mg, 29.05 μmol, 1 eq) in DCM (0.5 mL) in a 50 mL round-bottom flask, TFA (770.00 mg, 6.75 mmol, 0.5 mL, 232.43 eq) was added, and the mixture was stirred at 20 °C for 2 h. The mixture was concentrated to give a crude product, which was dissolved in ACN (5 mL). 1 g of Na2CO3 was added to the mixture, and the mixture was stirred at 20 °C for 0.5 h. The mixture was then filtered, and the filtrate was concentrated to give a crude product. The crude product was purified by preparative HPLC (FA, column: Phenomenex Luna (C18, 150 × 25 mm, 10 μm), mobile phase: [water (FA)-ACN], B (%): 15% → 45%, 10 min), and the purified solution was lyophilized to give a white solid. Compound 150 (4.9 mg, 11.62 μmol, 39.99% yield, 99.7% purity) was obtained as a white solid. LCMS: Retention time = 0.329 min, m / z = 421.1 (M+H + ). 1H NMR: (400 MHz, chloroform-d) δ = 8.24 - 8.21 (m, 2H), 7.55 (s, 1H), 7.41 - 7.28 (m, 5H), 7.08 - 6.92 (m, 2H), 5.10 (s, 2H), 4.93 (br d, J = 6.0 Hz, 2H), 4.15 (q, J = 6.9 Hz, 2H), 1.40 (br t, J = 6.8 Hz, 3H).

[0345] [ka]

[0346] To a solution of compound 1 (2 g, 7.32 mmol, 1 eq) in EtOH (20 mL) and HO (20 mL) was added LiOH·HO (921.86 mg, 21.97 mmol, 3 eq) in a 250 mL one-neck round-bottom flask, and the mixture was stirred at 25 °C for 1 h. The solvent was removed by evaporation under reduced pressure, and the mixture was acidified to pH 4 with 1 N HCl. The mixture was filtered, and the filter cake was washed with 20 mL of MeOH and dried in vacuo to give compound 2 (1.7 g, 6.94 mmol, 94.73% yield), which was obtained as a white solid. LCMS: retention time = 0.336 min, m / z = 244.8 (MH + )

[0347] To a solution of compound 3 (430 mg, 1.40 mmol, 1 eq) in DCM (8 mL), compound 2 (343.10 mg, 1.40 mmol, 1 eq), EDCI (402.57 mg, 2.10 mmol, 1.5 eq), and DMAP (17.10 mg, 140.00 μmol, 0.1 eq) were added in a 40 mL vial, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 1 / 0 → 0 / 1, Rf = 0.46 for the desired product), and the purified solution was concentrated under vacuum to give the product. Compound 4 (590 mg, 1.11 mmol, 78.99% yield) was obtained as a white solid. LCMS: retention time = 0.419 min, m / z = 535.0 (M+H + )

[0348] To a solution of compound 4 (450 mg, 843.44 μmol, 1 eq) in dioxane (10 mL), compound 5 (428.36 mg, 1.69 mmol, 2 eq), AcOK (165.55 mg, 1.69 mmol, 2 eq), and Pd(dppf)Cl CHCl (68.88 mg, 84.34 μmol, 0.1 eq) were added in a 40 mL vial, and the mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by adding HO (30 mL) and extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with brine (100 mL × 1), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, PE / EtOAc = 1 / 0 → 0 / 1, Rf = 0.30 for the desired product). Compound 6 (190 mg, 289.99 μmol, 62.39% yield) was obtained as a yellow oil. LCMS: Retention time = 0.439 min, m / z = 581.2 (M+H + )

[0349] To a solution of compound 6 (150 mg, 258.35 μmol, 1 eq) in dioxane (5 mL), compound 7 (48.58 mg, 258.35 μmol, 1 eq), K2CO3 (71.41 mg, 516.71 μmol, 2 eq), and Pd(dppf)Cl2·CHCl2 (21.10 mg, 25.84 μmol, 0.1 eq) were added in a 40 mL vial. The mixture was stirred at 100 °C for 12 h under a N2 atmosphere. The reaction mixture was quenched by adding HO (30 mL) and extracted with dichloromethane (30 mL × 3). The combined organic layers were washed with brine (60 mL × 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was then purified by preparative TLC (SiO2, PE:EtOAc = 0:1) to give the product. Compound 8 (100 mg, 178.01 μmol, 68.90% yield) was obtained as a yellow oil. LCMS: Retention time = 0.448 min, m / z = 562.5 (M+H + )

[0350] To a solution of compound 8 (100 mg, 178.01 μmol, 1 eq) in DMF (2 mL) was added CsF (270.40 mg, 1.78 mmol, 65.63 μL, 10 eq) in an 8 mL vial. The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by adding HO (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic layers were washed with brine (50 mL × 1), dried over NaSO, filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (FA, column: Phenomenex luna (C18, 150 × 25 mm, 10 μm), mobile phase: [water (FA)-ACN], B (%): 14% → 44%, 8 min), and the purified product was lyophilized. 153 (20.2 mg, 46.30 μmol, 26.01% yield, 98.9% purity) was obtained as a yellow solid. LCMS: Retention time = 0.356 min, m / z = 432.3 (M+H +) 1H NMR: (400 MHz, chloroform-d) δ = 12.15 - 12.00 (m, 1H), 8.27 - 8.17 (m, 2H), 7.94 (s, 1H), 7.71 - 7.64 (m, 2H), 7.12 - 7.05 (m, 2H), 4.90 (s, 2H), 4.22 (q, J = 7.0 Hz, 2H), 3.01 (s, 3H), 2.90 - 2.84 (m, 3H), 1.57 - 1.53 (m, 3H).

[0351] Compound 099 was prepared similarly to Scheme 19 and obtained as a white solid (7.2 mg, 16.02 μmol, 13.27% yield). 1 H NMR: (400 MHz, chloroform-d) δ = 7.99 (s, 1H), 7.37 (dd, J = 2.2, 8.2 Hz, 1H), 7.23 (s, 1H), 7.13 - 7.11 (m, 2H), 7.08 - 7.03 (m, 3H), 6.97 (d, J = 2.1 Hz, 1H), 6.89 - 6.86 (m, 1H), 4.92 (s, 2H), 3.75 - 3.72 (m, 1H), 3.05 (s, 3H), 0.80 - 0.77 (m, 2H), 0.72 - 0.69 (m, 2H). LCMS: Retention time = 0.449 min, m / z = 449.8 (M+H + ).

[0352] [ka]

[0353] To a solution of compound 1 in THF (1.5 mL) was added CsF (30.37 mg, 199.93 μmol, 7.37 μL, 1.5 eq) and compound 2 (28.43 mg, 199.93 μmol, 1.5 eq) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into H2O (70 mL) and extracted with DCM (50 mL × 3). The combined organics were washed with saturated aqueous NaCl (40 mL × 3), dried over Na2SO4, and concentrated to give a residue. The residue was purified by preparative TLC (SiO2, PE / EtOAc = 1 / 1). Compound 3 (62 mg, 97.99 μmol, 73.52% yield) as a colorless oil. LCMS: Retention time = 0.539 min, m / z = 633.4 (M+H + ).

[0354] To a solution of compound 3 in TFA (1 mL) and DCM (1 mL) in a 50 mL round-bottom flask. The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under vacuum to give a residue. The crude product was purified by preparative RP (column: Waters xbridge (150×25 mm, 10 μm), mobile phase: [water (NH4HCO3)-ACN], B (%): 40% to 70%, 8 min). After purification by preparative HPLC, the eluate was concentrated to remove the organic solvent. The remaining aqueous solution was lyophilized to give a white solid. Compound 171 (22 mg, 43.78 μmol, 36.94% yield, 100% purity) as a white solid. LCMS: retention time = 0.413 min, m / z = 503.1 (M+H + ). 1H NMR: (400 MHz, chloroform-d) δ ppm 1.38 (t, J=6.94 Hz, 3 H) 3.10 (s, 3 H) 4.08 (q, J=6.88 Hz, 2 H) 4.91 - 4.98 (m, 1 H) 5.02 - 5.10 (m, 1 H) 5.57 (br d, J=6.13 Hz, 1 H) 7.02 - 7.13 (m, 3 H) 7.27 - 7.29 (m, 1 H) 7.31 (br d, J=7.50 Hz, 1 H) 7.35 - 7.40 (m, 2 H) 8.38 (s, 2 H) 12.43 - 12.74 (m, 1 H).

[0355] [ka]

[0356] To a solution of compound 1 (1.5 g, 4.84 mmol, 1 eq) in MeOH (10 mL) in a 75 mL hydrogenation bottle, Pd(OAc) (217.36 mg, 968.16 μmol, 0.2 eq), DPPF (536.73 mg, 968.16 μmol, 0.2 eq), and TEA (1.47 g, 14.52 mmol, 2.02 mL, 3 eq) were added, and the mixture was stirred at 80 °C for 48 h under CO (50 psi). After the reaction was completed, it was cooled to room temperature, filtered under N, and the filtrate was concentrated to give the crude product. The crude product was purified by column chromatography (SiO, PE:EtOAc = 20:1 → 5:1, Rf = 0.5 for the desired product). Compound 2 (1.6 g, 4.80 mmol, 99.12% yield) was obtained as a colorless oil. LCMS: Retention time = 0.463 min, m / z = 334.2 (M+H + ) 1 H NMR: (400 MHz, chloroform-d) δ = 9.06 - 9.03 (m, 1H), 8.20 (s, 1H), 7.42 - 7.33 (m, 1H), 5.84 (s, 2H), 5.73 - 5.68 (m, 1H), 5.57 - 5.49 (m, 1H), 3.99 - 3.96 (m, 3H), 3.55 - 3.49 (m, 2H), 1.26 (br t, J = 7.1 Hz, 2H), -0.05 (s, 9H).

[0357] To a solution of compound 2 (700 mg, 2.10 mmol, 1 eq) in THF (5 mL) in a three-necked round bottle, DIBAL-H (1 M, 6.30 mL, 3 eq) was added at −78 °C, and the mixture was stirred at −78 °C for 1 h under N2. The mixture was poured into saturated NH4Cl (80 mL) solution and extracted with EtOAc (50 mL × 3). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated to give the crude product. The crude product was purified by column chromatography (SiO2, PE / EtOAc = 10 / 1 → 0 / 1, Rf = 0.6 for the desired product). Compound 3 (63 mg, 206.26 μmol, 9.83% yield) was obtained as a yellow oil. LCMS: retention time = 0.371 min, m / z = 306.0 (M+H + )

[0358] To a solution of compound 3 (95 mg, 311.02 μmol, 1 eq) in THF (5 mL) in a 100 mL three-neck flask, NaH (18.66 mg, 466.53 μmol, 60% purity, 1.5 eq) was added at 0 °C, and the mixture was stirred at 0 °C for 1 h. Subsequently, MeI (88.29 mg, 622.04 μmol, 38.72 μL, 2 eq) was added, and the mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into saturated NH Cl solution (50 mL) at 0 °C and extracted with EtOAc (50 mL × 2). The combined organic phase was washed with brine (80 mL), dried over anhydrous Na SO , and concentrated to give the crude product. The residue was purified by preparative TLC (SiO , PE: EtOAc = 0:1). Compound 4 (69 mg, 215.98 μmol, 69.44% yield, purity not available) was obtained as a yellow oil. LCMS: Retention time = 0.367 min, m / z = 319.9 (M+Na + )

[0359] A solution of compound 4 (65 mg, 203.46 μmol, 1 eq) in DCM (10 mL) and MeOH (10 mL) in a 100 mL three-neck flask was treated with ozone (9.77 mg, 203.46 μmol, 1 eq) for 30 min (15 psi) at −78 °C. The mixture was then purged with nitrogen for 0.5 h, and PPh3 (106.73 mg, 406.92 μmol, 2 eq) dissolved in DCM (10 mL) was added dropwise to the mixture. The mixture was warmed to 20 °C and stirred at 20 °C for 1 h. After the reaction was complete, the mixture was concentrated to give the crude product. The residue was purified by preparative TLC (SiO2, PE:EtOAc = 0:1). Compound 5 (49 mg, 152.44 μmol, 74.92% yield) was obtained as a yellow oil.

[0360] To a solution of compound 5 (49 mg, 152.44 μmol, 1 eq) in MeOH (4 mL) in a 100 mL round-bottom flask, MeNH2 in THF (2 M, 381.09 μL, 5 eq) and AcOH (915.41 μg, 15.24 μmol, 8.72 e-1 μL, 0.1 eq) was added, and the mixture was stirred at 20 °C for 2 h. Subsequently, NaBH4 (17.30 mg, 457.31 μmol, 3 eq) was added at 0 °C, and the mixture was stirred at 20 °C for 1 h. After the reaction was completed, the reaction mixture was poured into NHCl (10 mL), and the temperature was controlled at 10–20 °C. Then, NaCO3 (1 g) was added to the mixture. The solution was filtered, and the filtrate was concentrated under reduced pressure to give a residue. Subsequently, the solution was triturated with DCM and MeOH, filtered, and the filtrate was concentrated under reduced pressure to give a residue. LCMS: Retention time = 0.722 min, m / z = 377.3 (M+H + )

[0361] To a solution of compound 6 (30 mg, 89.15 μmol, 1 eq) and compound 7 (23.20 mg, 89.15 μmol, 1 eq) in DCM (2 mL) in a 50 mL round-bottom flask, EDCI (25.64 mg, 133.73 μmol, 1.5 eq) and DMAP (1.09 mg, 8.92 μmol, 0.1 eq) were added, and the mixture was stirred at 20 °C for 12 h. The solution was evaporated under reduced pressure in a water bath using a rotary evaporator. The residue was purified by preparative TLC (SiO, PE: EtOAc = 0:1). Compound 8 (50 mg, 69.11 μmol, 77.52% yield, 80% purity) was obtained as a colorless oil. LCMS: retention time = 0.474 min, m / z = 579.3 (M+H + )

[0362] To a solution of compound 8 (50 mg, 69.11 μmol, 80% purity, 1 eq) in DCM (1 mL) in a 100 mL round-bottom flask, TFA (1.54 g, 13.51 mmol, 1 mL, 195.41 eq) was added, and the mixture was stirred at 20 °C for 2 h. The mixture was concentrated to give the crude product, which was dissolved in MeOH (5 mL), 1 g of Na2CO3 was added, and the mixture was stirred at 20 °C for 0.5 h. The mixture was then filtered, and the filtrate was concentrated to give the crude product. The crude product was purified by preparative HPLC (FA, column: Phenomenex luna (C18, 150 × 25 mm, 10 μm), mobile phase: [water (FA)-ACN], B (%): 20% → 50%, 10 min), and the purified solution was lyophilized to give a white solid. Compound 077 (16.6 mg, 36.90 μmol, 53.39% yield, 99.7% purity) was obtained as a white solid. LCMS: Retention time = 0.384 min, m / z = 449.2 (M+H + ) 1H NMR: (400 MHz, chloroform-d) δ = 12.42 - 12.26 (m, 1H), 9.10 - 9.03 (m, 1H), 8.24 (s, 1H), 7.40 - 7.28 (m, 4H), 7.10 - 7.01 (m, 3H), 5.22 (s, 2H), 4.91 - 4.87 (m, 2H), 4.07 (q, J = 7.0 Hz, 2H), 3.54 - 3.47 (m, 3H), 3.05 (s, 3H), 1.37 (t, J = 6.9 Hz, 3H).

[0363] [ka]

[0364] To a solution of compound 1 (50 mg, 142.66 μmol, 1 eq) in THF (1 mL) was added lithium tetradeuterioarmanuide (19.69 mg, 427.98 μmol, 26.75 μL, 3 eq) at 0 °C. The mixture was stirred at 0 °C for 1 h. After the reaction was completed, NaSO·10H O (20 mg) was added to the resulting mixture. Subsequently, the mixture was filtered, and the filtrate was concentrated in vacuo to give compound 2 (46 mg, 141.76 μmol, 99.37% yield) as a yellow oil, which was used in the next step. LCMS: retention time = 0.646 min, m / z = 325.2 (M+H + )

[0365] To a solution of compound 2 (46 mg, 141.76 μmol, 1 eq) and compound 3 (36.89 mg, 141.76 μmol, 1 eq) in DCM (3 mL) in a round-bottom flask (50 mL) was added EDCI (40.76 mg, 212.64 μmol, 1.5 eq) and DMAP (1.73 mg, 14.18 μmol, 0.1 eq). The mixture was stirred at 20° C. for 1 h. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by preparative TLC (SiO, DCM:MeOH=10:1). The purified solution was concentrated in vacuo to give compound 4 (20 mg, 35.29 μmol, 24.89% yield) as a colorless oil. LCMS: retention time = 0.711 min, m / z = 567.2 (M+H + ) D%=94.6%

[0366] To a solution of compound 4 (20 mg, 35.29 μmol, 1 eq) in DCM (0.5 mL) in a round-bottom flask (50 mL) was added TFA (770.00 mg, 6.75 mmol, 0.5 mL, 191.36 eq). The mixture was stirred at 20 °C for 1 h. The reaction mixture was concentrated to give the crude product. The residue was basified with EtN to pH 8. The residue was purified by preparative HPLC (column: Welch Xtimate (C18, 150 × 25 mm, 5 μm), mobile phase: [water (NH3HO)-ACN], B (%): 27% → 57%, 8 min). The purified solution was lyophilized to give 086 (2.6 mg, 5.80 μmol, 16.44% yield, 97.4% purity) as a white solid. LCMS: Retention time = 0.651 min, m / z = 437.1 (M+H + ) D%=94.6% 1H NMR (400 MHz, chloroform-d) δ = 8.41 (s, 1H), 8.32 (s, 1H), 7.40 - 7.35 (m, 2H), 7.33 - 7.29 (m, 2H), 7.11 - 7.04 (m, 3H), 4.98 (s, 2H), 4.11 - 4.04 (m, 2H), 3.08 (s, 3H), 1.38 (t, J = 7.0 Hz, 3H).

[0367] [ka]

[0368] To a solution of compound 1 (437.56 mg, 1.43 mmol, 1 eq) and compound 2 (500 mg, 1.43 mmol, 1 eq) in DCM (15 mL) was added EDCI (410.21 mg, 2.14 mmol, 1.5 eq) and DMAP (17.43 mg, 142.66 μmol, 0.1 eq). The mixture was stirred at 20 °C for 12 h. LCMS (5-95 AB / 0.8 min) showed that 68% of the desired mass was detected. The reaction mixture was concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 5 / 1 → 2 / 1), and the purified solution was concentrated in vacuo to give compound 3 (1.1 g, 1.38 mmol, 96.51% yield, 80% purity) as a yellow oil. LCMS: Retention time = 0.640 min, m / z = 639.3 (M+H) +

[0369] To a solution of compound 3 (1.1 g, 1.38 mmol, 80% purity, 1 eq) in MeOH (15 mL) in a round-bottom flask (100 mL) was added LiBH (149.95 mg, 6.88 mmol, 5 eq) at 0 °C. The mixture was stirred at 20 °C for 12 h. LCMS (5-95AB / 0.8 min) showed that 50% of the desired mass was detected and 33% of compound 3 remained. The reaction mixture was poured into saturated aqueous NH Cl (30 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were dried and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 1 → ethyl acetate:methanol = 10 / 1), and the purified solution was concentrated in vacuo to give compound 4 (330 mg, 539.94 μmol, 39.22% yield) as a yellow oil. LCMS: Retention time = 0.495 min, m / z = 611.8 (M+H) +

[0370] To a solution of compound 4 (50 mg, 81.81 μmol, 1 eq) in DCM (1 mL) in a round-bottom flask (50 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 165.09 eq). The mixture was stirred at 20 °C for 5 h. LCMS (5-95AB / 0.8 min) showed that 86% of the desired mass was detected. The reaction mixture was concentrated under reduced pressure at 20 °C to give a residue. The residue was dissolved in DCM (5 mL), basified with NaHCO (5 mg) to pH 7, filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna (C18, 150 × 25 mm, 10 μm), mobile phase: [water (FA)-ACN], B (%): 22% → 52%, 9 min). The purified solution was lyophilized to give 047 (12.4 mg, 25.50 μmol, 31.17% yield, 98.9% purity) as a white solid. LCMS: Retention time = 0.400 min, m / z = 481.1 (M+H) + 1H NMR (400 MHz, chloroform-d) δ =8.34 (d, J = 14.8 Hz, 2H), 7.38 - 7.31 (m, 3H), 7.23 (s, 2H), 6.89 (dd, J = 1.0, 9.0 Hz, 1H), 5.20 (s, 2H), 4.97 (s, 2H), 3.75 (td, J = 3.0, 5.8 Hz, 1H), 3.09 (s, 3H), 0.83 - 0.77 (m, 2H), 0.76 - 0.68 (m, 2H).

[0371] Example 2: THP-1 cell-based NLRP3 activation assay THP-1 cells were cultured in complete medium (CM) until they reached logarithmic growth and viability exceeded 90%. CM consisted of RPMI-1640 (+Glutamax) / 10% fetal bovine serum / 55 μM β-mercaptoethanol / pen / strep. Cells were spun down and resuspended in CM containing either 20 nM or 500 nM PMA to 1,000,000 cells / mL. 150,000 cells (150 μL) were then added to each well of a 96-well TC plate and incubated for either 24 or 3 hours in a standard cell culture incubator (37°C, 5% CO2). After this incubation, the plate was tilted and the medium was carefully removed. 200 μL of CM containing 100 ng / mL LPS was then added to the well, and the cells were incubated for an additional 3 hours. The medium was again removed and replaced with Opti-Mem medium containing the test compound at a predetermined dilution in replicate wells. After 30 minutes of preincubation with the test compound, 10 μM nigericin (final concentration) in Opti-Mem medium containing the corresponding compound concentration was added to the wells for an additional hour. Positive control wells contained 10 μM nigericin in Opti-Mem in the absence of test compound, while negative control wells contained Opti-Mem alone. Supernatants were then transferred to a new 96-well plate for storage and assayed for IL-1β (human, DuoSet, R&D) and TNFα (human, DuoSet, R&D) levels, as well as relative pyroptosis, using a CytoTox 96 Kit (do not freeze before testing, Promega). After removing the supernatant, the relative viability of adherent cells in the 96-well TC plates is determined using the CellTiter-Glo® Luminescent Cell Viability Assay (Promega).

[0372] Table 6 below shows the IC of the compounds disclosed herein. 50 The data are shown in the table. In the table, "+" indicates IC 50 "++" indicates IC values ​​less than 50uM 50"+++" indicates an IC value less than 10uM. 50 indicates that the value is less than 1 uM. [Table 9-1] [Table 9-2]

[0373] The disclosed subject matter is not limited in scope by the specific embodiments and examples described herein. Indeed, various modifications of the present disclosure, in addition to those described, will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims. All references (e.g., publications, patents, or patent applications) cited herein are incorporated by reference in their entirety for all purposes to the same extent as if each individual reference (e.g., publication, patent, or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes. Other embodiments are within the scope of the following claims.

Claims

1. A compound selected from the group consisting of: 【Table 1-1】 【Table 1-2】 【Table 1-3】 or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 selected from: 【Table 2】 or a pharmaceutically acceptable salt thereof.

3. 10. A pharmaceutical composition comprising a compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. A method for inhibiting the NLRP3 inflammasome in a subject in need of NLRP3 inflammasome inhibition, the method comprising administering to the subject a therapeutically effective amount of a compound described in claim 1 or 2, or a pharmaceutical composition described in claim 3.

5. A method for treating inflammation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or 2, or a pharmaceutical composition of claim 3.

6. 10. A method for treating inflammaging in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or 2, or a pharmaceutical composition of claim 3.

7. A method for treating a neurosensory disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or 2, or a pharmaceutical composition of claim 3.

8. 8. The method of claim 7, wherein the neurosensory disorder is selected from the group consisting of amyotrophic lateral sclerosis (ALS), traumatic brain injury, Parkinson's disease, and Alzheimer's disease.

9. 9. The method of claim 7 or 8, wherein the neurosensory disease is ALS.

10. 9. The method of claim 7 or 8, wherein the neurosensory disorder is traumatic brain injury.

11. The method of claim 7 or 8, wherein the neurosensory disorder is Parkinson's disease.

12. The method of claim 7 or 8, wherein the neurosensory disease is Alzheimer's disease.

13. 1. A method of treating inflammation in a subject in need thereof, comprising administering to said subject a compound of formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ But, Hello, OH, OC １－３ Alkyl, NH ２ , N(H)C １－３ Alkyl, N(C １－６ alkyl) ２ , C(O)C １－３ Alkyl and C ３－６ C optionally substituted with a substituent selected from cycloalkyl １－６ is alkyl, Each R ２ became independent, Halo, C １－３ Haloalkyl, OH, OC １－３ Alkyl, OC ３－６ Cycloalkyl and C ３－６ cycloalkyl; R ３ But, H, halo, C １－３ Haloalkyl, OH, OC １－３ Alkyl, OC ３－６ Cycloalkyl, CN and C ３－６ cycloalkyl; n is 0, 1 or 2; The method.

14. During the ceremony, R １ C optionally substituted with OH １－６ is alkyl, Each R ２ are independently halo and C ３－６ cycloalkyl; R ３ is the halo, n is 1 or 2; The method of claim 13.

15. The compound of formula I is 【Table 3-1】 【Table 3-2】 【Table 3-3】 or a pharmaceutically acceptable salt thereof.

16. The compound of formula I is 【Table 4】 The method according to any one of claims 13 to 15, wherein the compound is selected from the group consisting of benzodiazepine, benzodiazepine, benzophenone, ...

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