Aryl sulfonamides as orexin receptor agonists

Abstract

To provide aryl sulfonamides as orexin receptor agonists. [Solution] This disclosure provides, as embodiments of this disclosure, novel arylsulfonamide compounds. The compounds are considered to be orexin receptor agonists useful for treating diseases and conditions caused by reduced orexin activity. The compounds of this disclosure exhibit unique structural attributes for therapeutic effects as agonists, characterized as dual orexin A / B or dual OX1R / OX2R.

Description

[Technical Field]

[0001] This disclosure provides, as embodiments thereof, novel arylsulfonamide compounds. The compounds are considered to be orexin receptor agonists useful for treating diseases and conditions caused by reduced orexin activity. [Background technology]

[0002] Orexin is a neuropeptide produced in the hypothalamus. There are two types, orexin-A and B, which can also be referred to as hypocretin 1 and 2, respectively. Orexin-expressing neurons are limited in number and are mainly located in a small region of the lateral hypothalamus. However, the nerve fibers of orexin neurons protrude throughout the central nervous system (CNS), and their afferent nerves are sent to brain regions in the cortex, limbic system, and brainstem circuits. The orexin system has been shown to regulate a variety of important biological processes, including sleep / wakefulness, feeding, spontaneous motor activity, stress hormone secretion, energy homeostasis, and learning and memory.

[0003] As an example, one role of orexin is to control sleep and wakefulness. Neurons that release orexin are most active during the day. To keep us awake, these neuropeptides stimulate other neurons to release wakefulness-promoting neurotransmitters such as dopamine, serotonin, and norepinephrine. Without enough orexin, the body has difficulty staying awake and alert. People diagnosed with type 1 narcolepsy have an 85% to 95% reduction in the number of orexin-producing neurons. This loss of orexin-producing neurons leads to symptoms of narcolepsy, including excessive daytime sleepiness, sleep paralysis, hallucinations, and cataplexy. The loss of orexin-producing neurons results in narcolepsy with cataplexy, an incurable chronic neurological disorder that severely impacts the daily life of affected individuals. While weight gain is not a symptom of narcolepsy, people with this condition are also likely to be overweight. The study suggests that the link between narcolepsy and weight gain may be related to the role of orexin in regulating physical activity.

[0004] Orexin plays a crucial role in the body's response to stress. Upon receiving signals from the environment, orexin-producing neurons respond to pressure by exciting other neurons that increase heart rate and blood pressure, helping to transition the body from a resting state to one ready to respond and move. With fewer chemical signals to trigger the response, orexin deficiency is associated with sedentary lifestyles and obesity. Animal studies have shown that mice that lose those orexin-producing neurons are more likely to develop obesity and diabetes, even when they have less physical activity, a reduced energy metabolism, and burn fewer calories.

[0005] Orexin also excites neurons that are important in regulating mood. Having excessive or insufficient orexin activity is associated with depression and other mental health conditions, including anxiety, panic disorder, addiction, and post-traumatic stress disorder. These neuropeptides also influence mood through their function in a part of the brain called the hippocampus. Orexin promotes the generation of new neurons in the hippocampus, which is important in learning, memory, and spatial abilities. Without sufficient orexin, people may experience problems with learning and memory.

[0006] Consistent with the multifaceted role of orexin, orexin deficiency has also been associated with age-related disorders. Loss of orexin neurons and / or orexin peptides has been found in patients with Alzheimer's disease and Parkinson's disease, as well as in aged humans and mice. Several studies have demonstrated that exogenous orexin-A successfully restored normal orexin function and improved learning and memory in narcolepsy animals. Furthermore, using orexin / ataxin-3 (O / A3) transgenic mice, a mouse model similar to human narcolepsy, both acute and chronic OXA treatment restored memory deficits. For example, Hara, J.; Beuckmann, CT; Nambu, T.; Willie, JT; Chemelli, RM; Sinton, CM; Sugiyama, F.; Yagami, K.; Goto, K.; Yanagisawa, M.; Sakurai, T., Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. 2001, 30(2), 345-5 and Mavanji, V.; Butterick, TA; Duffy, CM; Nixon, JP; Billington, CJ; Kotz, CM, Orexin / hypocretin treatment restores hippocampal-dependent memory in orexin-deficient Please refer to mice.Neurobiol.Learn.Mem.2017,146,21-30, as each of these references incorporates such background information.

[0007] Orexin agonists suitable for systemic administration may be the most promising strategy among all orexin replacement therapies for orexin deficiency-related conditions.

[0008] To date, drugs targeting the orexin system have initially focused on antagonists due to orexin's role in regulating sleep and wakefulness. Dual orexin receptor antagonists (DORAs) are a type of prescription sleep aid that targets the body's orexin system. These drugs work by acting as orexin receptor antagonists, meaning they block the effects of orexin in the body, including OX1 / 2R dual and subtype-selective antagonists, thereby reducing the drive to stay awake and promoting sleep. For the treatment of insomnia in adults, two types of DORAs, suvorexant and lemborexant, are currently approved by the Food and Drug Administration (FDA).

[0009] In contrast, activation of the orexin receptor is primarily achieved using orexin peptides, particularly orexin A(33AA). Only a limited number of small molecule orexin agonists have been disclosed to date.

[0010] For example, Yan7874 is a small molecule reported in US2010 / 0150840: [ka] However, Yan7874 was later found to be a weak agonist of both orexin receptors (EC50 > 3.2 μM) and unfortunately exhibited orexin receptor-independent cytotoxicity. See, for example, Turku, A.; Rinne, MK; Boije Af Gennas, G.; Xhaard, H.; Lindholm, D.; Kukkonen, JP, Orexin receptor agonist Yan 7874 is a weak agonist of orexin / hypocretin receptors and shows orexin receptor-independent cytotoxicity. PloS one 2017, 12(6), e0178526.

[0011] More recently, several series of small molecules have been reported, represented by YNT-185 and TAK-925, respectively. These agonists appear to exhibit selectivity, i.e., little to no activity at OX1R but activation of OX2R with good potency. Additional OX2R agonists were reported in WO2020 / 167706. The compound, a 5-alkylpyrrolidine analog, is represented by compound 37 within it. [ka] [ka] [ka] More specifically, YNT-185 showed good OX2R efficacy and selectivity (EC 50(28 nM vs. 2750 nM for OX1R). Intraperitoneal (ip) administration of YNT-185 (40 mg / kg, salt form) promoted wakefulness in wild-type mice without affecting body temperature, but in orexin KO and orexin neuron ablation mice, YNT-185 suppressed cataplexy-like episodes. See Irukayama-Tomobe, Y.; Ogawa, Y.; Tominaga, H.; Ishikawa, Y.; Hosokawa, N.; Ambai, S.; Kawabe, Y.; Uchida, S.; Nakajima, R.; Saitoh, T.; Kanda, T.; Vogt, K.; Sakurai, T.; Nagase, H.; Yanagisawa, M., Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. Proc. Natl. Acad. Sci. USA 2017, 114(22), 5731-5736. In another study, YNT-185 attenuated morphine-induced sedation in rats, as assessed by EEG changes and behavioral scales including spontaneous motor activity and startle response latency, without affecting the analgesic effect of morphine. Toyama, S.; Shimoyama, N.; Tagaito, Y.; Nagase, H.; Saitoh, T.; Yanagisawa, M.; Shimoyama, M., Nonpeptide Orexin-2 Receptor See Agonist Attenuates Morphine-induced Sedative Effects in Rats. Anesthesiology 2018, 128(5), 992-1003. However, the inventors seek a pharmacological profile for biorexin agonism. The compounds of this disclosure exhibit unique structural attributes for therapeutic efficacy as agonists, characterized as biorexin A / B or biorexin OX1R / OX2R. [Prior art documents] [Patent Documents]

[0012] [License 1] U.S. Patent and Trademark Office Publication No. 2010 / 0150840 [License 2] International Publication No. 2020 / 167706 [Non-licensed literature]

[0013] [Non-licensed Document 1] Hara,J.;Beuckmann,CT;Nambu,T.;Willie,JT;Chemelli,RM;Sinton,CM;Sugiyama,F.;Yagami,K.;Goto,K.;Yanagisawa,M.;Sakurai,T., Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 2001,30(2),345-5 [Non-licensed Document 2] Mavanji,V.;Butterick,TA;Duffy,CM;Nixon,JP;Billington,CJ;Kotz,CM,Orexin / hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice.Neurobiol.Learn.Mem.2017,146,21-30 [Non-licensed Document 3] Turku, A.; Rinne, MK; Boije Af Gennas, G.; [Non-Patent Document 4] Irukayama-Tomobe, Y.; Ogawa, Y.; Tominaga, H.; Ishikawa, Y.; Hosokawa, N.; Ambai, S.; Kawabe, Y.; Uchida, S.; Nakajima, R.; Saitoh, T.; Kanda, T.; Vogt, K.; Sakurai, T.; Nagase, H.; type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models.Proc.Natl.Acad.Sci.USA2017,114(22),5731-5736 [Non-Patent Document 5] Toyama, S.; Shimoyama, N.; Tagaito, Y.; Nagase, H.; Saitoh, T.; Yanagisawa, M.; Shimoyama, M., Nonpeptide Orexin-2 Receptor Agonist Attenuates Morphine-induced Sedative Effects in Rats.Anesthesiology 2018,128(5),992-1003 [Overview of the project] [Means for solving the problem]

[0014] One embodiment of the present disclosure is a compound of formula (I), [ka] or containing a pharmaceutically acceptable salt thereof, During the ceremony, A is C 2-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkynylene, phenylene, or a divalent 4-7 membered cycloalkyl or heterocyclyl ring having one or more degrees of unsaturation and containing 1-3 heteroatoms selected from the group consisting of O, N, or S, B is C 2-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, phenylene, or a divalent 4- to 7-membered cycloalkyl or heterocyclyl ring optionally having one or more degrees of unsaturation and containing 1 to 3 heteroatoms selected from the group consisting of O, N, or S X is O or NH R 1 is (CH2) m -heteroaryl m is 0, 1, 2, 3, 4, 5, or 6 R 2 is hydrogen or C 1-6 alkyl X is a bond, O, C(O), NH, NHC(O), or C(O)NH When Y is a bond, C 2-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, a divalent 4- to 7-membered cycloalkyl ring optionally having one or more degrees of unsaturation, or a divalent 4- to 7-membered heterocyclyl ring optionally having one or more degrees of unsaturation and containing 1 to 3 heteroatoms selected from the group consisting of O, N, or S Z is a bond, O, C(O), NH, NHC(O), or C(O)NH R 3 is C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, (CH2) n -C 3-6 cycloalkyl, (CH2) n -phenyl, (CH2) n -naphthyl, or (CH2) n -(4- to 7-membered heterocyclyl ring) (where such a ring optionally has one or more degrees of unsaturation and contains 1 to 3 heteroatoms selected from the group consisting of O, N, or S) Each R 3 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6Alkynyl, halogen, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2,CN,NO2,OH,O(C 1-6 Alkyl), SH, S(C 1-6 It may be substituted with one or more substituents selected from alkyl and =O. Each n is independently 0, 1, 2, or 3.

[0015] In one embodiment, R 1 (CH2) m -It is pyridyl. In one embodiment, m is 1. In one embodiment, R 2 C 1-6 It is alkyl. In one embodiment, R 2 is CH3. In one embodiment, A is phenylene. In one embodiment, B is phenylene. In one embodiment, B is divalent pyridyl. In one embodiment, X is NH. In one embodiment, X is O. In one embodiment, Y is C 2-6 It is an alkylene. In one embodiment, Y is CH2CH2. In one embodiment, Y is a divalent 4-7 membered heterocyclyl ring having one or more degrees of unsaturation and containing 1-3 heteroatoms selected from the group consisting of O, N, or S. In one embodiment, the heterocyclyl ring contains at least one N atom. In one embodiment, Z is NHC(O). In one embodiment, Z is C(O). In one embodiment, each of X, Y, and Z is a bond. In one embodiment, R 3 C 1-10 Alkyl, (CH2) n -C 3-6 Cycloalkyl, or (CH2) n -phenyl, where each n is independently 0, 1, 2, or 3. In one embodiment, R 3 is C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, CH2CH3, or CH3. In one embodiment, R 3is a C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, or C5 alkyl. In one embodiment, R 3 (CH2) n -C 3-6 It is a cycloalkyl. In one embodiment, R 3 (CH2) n -C 5-6 It is a cycloalkyl. In one embodiment, R 3 is (CH2)1-C6 cycloalkyl, (CH2)2-C6 cycloalkyl, or (CH2)3-C6 cycloalkyl. In one embodiment, R 3 (CH2) n - is phenyl. In one embodiment, n is 0. In one embodiment, R 3 C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2,CN,NO2,OH,O(C 1-6 Alkyl), SH, S(C 1-6 It is substituted with one or more substituents selected from alkyl and =O. In one embodiment, R 3 is one or more C 1-6 It is substituted with alkyl.

[0016] One embodiment of the present disclosure includes a compound selected from the group consisting of one or more examples.

[0017] One embodiment of the present disclosure includes a pharmaceutical composition comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients.

[0018] One embodiment of the present disclosure includes a method for treating a disease or disorder in a subject caused by reduced orexin activity, comprising administering an effective amount of a compound of the present disclosure. In one embodiment, the disease or disorder is one or more of the following: sleep disorders, narcolepsy, cataplexy, sleep state regulation, apnea, wake state regulation, sleep-wake cycling, enhanced recovery from anesthesia, jet lag, appetite regulation, feeding regulation, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, clarity, cognitive impairment, Alzheimer's disease, attention deficit, dementia, mild cognitive impairment, Parkinson's disease, cognitive dysfunction, brain injury, cognitive impairment, blood pressure regulation, ischemic events, oxidative stress events, and cancer.

[0019] One embodiment of the present disclosure involves the use of the compound of the present disclosure for the preparation of a pharmaceutical for the treatment of a disease or disorder in a subject caused by reduced orexin activity, including the administration of an effective amount of the compound. In one embodiment, the disease or disorder is one or more of the following: sleep disorders, narcolepsy, cataplexy, insomnia, regulation of sleep states, apnea, regulation of wakefulness, sleep-wake cycling, enhanced recovery from anesthesia, jet lag, regulation of appetite, regulation of eating, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, clarity, cognitive impairment, Alzheimer's disease, attention deficit, dementia, mild cognitive impairment, Parkinson's disease, cognitive dysfunction, brain injury, cognitive impairment, addiction, drug addiction, blood pressure regulation, ischemic events, oxidative stress events, and cancer.

[0020] One embodiment of the present disclosure includes a compound of the present disclosure for use as an active therapeutic agent.

[0021] One embodiment of the present disclosure comprises a compound of the present disclosure for use in the treatment of a disease or disorder in a subject caused by reduced orexin activity. In one embodiment, the disease or disorder is one or more of the following: sleep disorders, narcolepsy, cataplexy, insomnia, regulation of sleep states, apnea, regulation of wakefulness, sleep-wake cycling, enhanced recovery from anesthesia, jet lag, regulation of appetite, regulation of eating, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, clarity, cognitive impairment, Alzheimer's disease, attention deficit, dementia, mild cognitive impairment, Parkinson's disease, cognitive dysfunction, brain injury, cognitive impairment, addiction, drug addiction, blood pressure regulation, ischemic events, oxidative stress events, and cancer.

[0022] One embodiment of the present disclosure includes a method for treating one or more of the following conditions: sleep disorders, narcolepsy, cataplexy, insomnia, regulation of sleep states, apnea, regulation of wakefulness, sleep-wake cycling, enhanced recovery from anesthesia, jet lag, regulation of appetite, regulation of eating, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, clarity, cognitive impairment, Alzheimer's disease, attention deficit, dementia, mild cognitive impairment, Parkinson's disease, cognitive dysfunction, brain injury, cognitive impairment, addiction, drug addiction, blood pressure regulation, ischemic events, oxidative stress events, and cancer, comprising administering a compound of the present disclosure.

[0023] One embodiment of the present disclosure includes the use of the compounds of the present disclosure for the preparation of pharmaceuticals for the treatment of one or more of the following: sleep disorders, narcolepsy, cataplexy, insomnia, regulation of sleep states, apnea, regulation of wakefulness, sleep-wake cycling, enhanced recovery from anesthesia, jet lag, regulation of appetite, regulation of eating, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, clarity, cognitive impairment, Alzheimer's disease, attention deficit, dementia, mild cognitive impairment, Parkinson's disease, cognitive dysfunction, brain injury, cognitive impairment, addiction, drug addiction, blood pressure regulation, ischemic events, oxidative stress events, and cancer.

[0024] One embodiment of the present disclosure includes compounds of the present disclosure for use in the treatment of one or more of the following: sleep disorders, narcolepsy, cataplexy, insomnia, regulation of sleep states, apnea, regulation of wakefulness, sleep-wake cycling, enhanced recovery from anesthesia, jet lag, regulation of appetite, regulation of eating, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, clarity, cognitive impairment, Alzheimer's disease, attention deficit, dementia, mild cognitive impairment, Parkinson's disease, cognitive dysfunction, brain injury, cognitive impairment, addiction, drug addiction, blood pressure regulation, ischemic events, oxidative stress events, and cancer.

[0025] The scope of this disclosure includes all different combinations of the embodiments, models, and preferences described herein. [Brief explanation of the drawing]

[0026] [Figure 1] The improved cognitive function in 12-month-old mice on the TWAA (left panel) and CORT (right panel) tasks after peripheral injection of RTIOXA-47 (40 mg / kg, ip) or physiological saline is illustrated (n=8 / group, **p<0.01 ***p<0.005). [Modes for carrying out the invention]

[0027] This disclosure includes novel arylsulfonamides useful as dual orexin receptor agonists.

[0028] The following definitions are intended to clarify, rather than limit, the defined terms. Where a particular term used herein is not specifically defined, such term should not be considered uncertain. Rather, the term should be used within the scope of its accepted meaning.

[0029] As used throughout this specification, a preferred number of atoms, such as carbon atoms, is, for example, "C x-yThe term "alkyl" refers to an alkyl group as defined herein, containing a specified number of carbon atoms. Similar terminology applies to other preferred terms and ranges. For example, C 1-4 Alkyl refers to a straight-chain or branched-chain hydrocarbon containing 1 to 4 carbon atoms.

[0030] As used herein, the term “alkyl” refers, alone or in combination with any other term, to a linear or branched hydrocarbon. Examples of “alkyl” as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, sec-butyl, isopentyl, n-pentyl, and n-hexyl.

[0031] As used herein, the term “alkenyl” refers to a linear or branched aliphatic hydrocarbon containing one or more carbon-carbon double bonds, which may be optionally substituted, with multiple degrees of substitution permitted. Examples of “alkenyl” as used herein include, but are not limited to, vinyl and allyl.

[0032] As used herein, the term "alkylene" refers to a linear divalent hydrocarbon radical that is optionally substituted. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, and n-butylene.

[0033] As used herein, the term "alkynyl" refers to a linear or branched aliphatic hydrocarbon containing one or more carbon-carbon triple bonds that can be optionally substituted, with multiple degrees of substitution permitted. Examples of "alkynyl" as used herein include, but are not limited to, ethynyl.

[0034] As used herein, the term “cycloalkyl” refers to a fully saturated, optionally substituted monocyclic, bicyclic, or crosslinked hydrocarbon ring, allowing for multiple degrees of substitution. Examples of “cycloalkyl” groups as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0035] As used herein, the term “aryl” refers to a monobenzene ring or fused benzene ring system that can be optionally substituted, with multiple degrees of substitution permitted. Examples of “aryl” groups used include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, anthracene, and phenanthrene. Preferred aryl rings have 5 to 10 members.

[0036] As used herein, the condensed benzene ring system encompassed within the term "aryl" includes condensed polycyclic hydrocarbons, i.e., cyclic hydrocarbons having fewer than the maximum number of non-cumulative double bonds, for example, a saturated hydrocarbon ring (cycloalkyl, e.g., a cyclopentyl ring) condensed with an aromatic ring (aryl, e.g., a benzene ring) to form groups such as indanyl and acenaphthalenyl, and also, as non-limiting examples, groups such as dihydronaphthalene and tetrahydronaphthalene.

[0037] As used herein, the term “heterocyclyl” refers to a monocyclic 5- to 7-membered moiety or a fully saturated ring, or a fused bicyclic ring system containing two such rings, which may be optionally substituted, with multiple degrees of substitution permitted. Preferably, such rings contain 5- to 10 members. These heterocyclyl rings contain one or more nitrogen, sulfur, and / or oxygen atoms, and N-oxides, sulfur oxides, and dioxides are permitted heteroatom substitutions. Examples of “heterocyclyl” groups as used herein include, but are not limited to, ethylene oxide, tetrahydrofuran, tetrahydropyran, dioxane, ethyleneimine, pyrrolidine, piperidine, ethylene sulfide, tetrahydrothiophene, tetrahydrothiopyran, and morpholine.

[0038] As used herein, the term “heteroaryl” refers to a monocyclic 5- to 7-membered aromatic ring, or a condensed bicyclic aromatic ring system containing two such aromatic rings, which may be optionally substituted, with multiple degrees of substitution permitted. Preferably, such rings contain 5- to 10 members. These heteroaryl rings contain one or more nitrogen, sulfur, and / or oxygen atoms, and N-oxides, sulfur oxides, and dioxides are permitted heteroatom substitutions. Examples of “heteroaryl” groups as used herein include, but are not limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzoxazole, benzothiophene, indole, indazole, benzimidazole, imidazopyridine, pyrazolopyridine, and pyrazolopyrimidine.

[0039] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0040] As used herein, the term “haloalkyl” refers to an alkyl group as defined herein, which is substituted with at least one halogen. Examples of branched or linear “haloalkyl” groups as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl, independently substituted with one or more halogens, e.g., fluoro, chloro, bromo, and iodo. The term “haloalkyl” should be interpreted to include substituents such as perfluoroalkyl groups, such as -CF3.

[0041] While not absolute, typically the salts of the present disclosure are pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” encompasses non-toxic salts of the compounds of the present disclosure. Salts of the compounds of the present disclosure may include acid addition salts. Typical salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, calcium edetate, cansylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estrate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, and laurate. Examples include malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucoate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate / diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, acetate, succinate, sulfate, tannate, tartrate, theoclate, tosylate, triethiozide, trimethylammonium, and valerate. Other pharmaceutically unacceptable salts may be useful in the preparation of the compounds of this disclosure and should be considered to form further embodiments of this disclosure.

[0042] Compounds of formula (I) may crystallize in two or more forms, which are characteristics known as polymorphisms, and such polymorphic forms ("polymorphs") are within the range of formula (I). Polymorphisms can generally arise in response to changes in temperature, pressure, or both. Polymorphisms can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art, such as X-ray diffraction patterns, solubility, and melting points.

[0043] As used herein, the term “effective dose” means, for example, the amount of a drug or agent that would elicit a desired biological or medical response in a tissue, system, animal, or human being, as determined by a researcher or clinician. The term “therapeutic effective dose” means any amount that results in an improved treatment, cure, prevention, or enhancement of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder, compared to a corresponding subject that has not received such a dose. The term also includes, within its scope, amounts that are effective in enhancing normal physiological function.

[0044] For therapeutic use, a therapeutically effective amount of the compound of formula (I), and its salts or solvates, may be administered as raw material chemicals. In addition, the active ingredient may be presented as a pharmaceutical composition.

[0045] Accordingly, this disclosure further provides a pharmaceutical composition comprising an effective amount of one or more compounds of formula (I), or salts or solvates thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of formula (I), or salts or solvates thereof, are as described herein. The carriers, diluents, or excipients must be acceptable in the sense that they are compatible with the other components of the formulation and are not harmful to the recipient of the pharmaceutical composition.

[0046] The compounds of this disclosure can be prepared by a variety of methods, including well-known standard synthetic methods. Exemplary general synthetic methods are described below, followed by the preparation of specific compounds of this disclosure in working examples.

[0047] In all the examples described below, protecting groups for sensitive or reactive groups are used as needed, in accordance with the general principles of synthetic chemistry. Protecting groups are incorporated by reference to standard methods of organic synthesis (TW Green and PGMWuts (1999) Protecting Groups in Organic Synthesis, 3). rd The procedure is carried out according to (Edition, John Wiley & Son). These groups are removed at a convenient stage in the compound synthesis using methods readily apparent to those skilled in the art. The selection of processes, as well as the reaction conditions and the order in which they are carried out, shall be consistent with the preparation of the compounds of this disclosure.

[0048] This disclosure also provides methods for synthesizing compounds of formula (I) and novel compounds useful as synthetic intermediates in the preparation of the compounds of this disclosure.

[0049] The compounds can be prepared using readily available starting materials and reagents according to the methods described below. These reactions may utilize variants that are known to those skilled in the art but are not described in more detail.

[0050] Unless otherwise stated, the structures shown herein also include compounds that differ only in the presence of one or more isotopically enriched atoms, such as the substitution of a hydrogen atom with deuterium or tritium, or 13 C or 14Apart from the substitution of carbon atoms with carbon-enriched carbon, compounds having this structure are within the scope of this disclosure. For example, deuterium is widely used to study the pharmacokinetics and metabolism of biologically active compounds. Although deuterium behaves similarly to hydrogen from a chemical standpoint, there are significant differences in bond energy and bond length between deuterium-carbon bonds and hydrogen-carbon bonds. As a result, hydrogen substitution with deuterium in biologically active compounds can generally result in compounds that retain their biochemical potency and selectivity but exhibit significantly different absorption, distribution, metabolism, and / or excretion (ADME) characteristics compared to their isotopic counterparts. Thus, deuterium substitution can result in improved pharmacokinetics, safety, and / or tolerability for some biologically active compounds.

[0051] Another aspect of the present disclosure also provides a method for preparing a pharmaceutical formulation, comprising mixing a compound of formula (I) or a salt, solvate, or physiologically functional derivative thereof with one or more pharmaceutically acceptable carriers, diluents, or excipients.

[0052] The compounds of this disclosure are useful as dual agonists of orexin receptor activity in subjects such as mammals that require orexin receptor activity. Primates, particularly humans, and various other mammals can be treated according to the methods of this disclosure. This disclosure covers the compounds of this disclosure or pharmaceutically acceptable salts thereof for use in medicine. This disclosure further covers the use of the compounds of this disclosure or pharmaceutically acceptable salts thereof for antagonistizing orexin receptor activity or for the manufacture of medicinal products for treating the disorders and diseases described herein in humans and animals. The subjects treated by the methods and uses are generally mammals, such as humans, males or females. The term "therapeutic dose" means the amount of the compound that will induce a biological or medical response in a tissue, system, animal, or human, as determined by researchers, veterinarians, physicians, or other clinicians. Those skilled in the art will recognize that neurological and psychiatric disorders can be affected by treating patients currently suffering from a disorder or by prophylactically treating patients suffering from a disorder with an effective dose of the compound of this disclosure. As used herein, the terms “treatment” and “to treat” refer to all processes that may delay, interrupt, block, control, or halt the progression of the neurological and psychiatric disorders described herein, but not necessarily indicate the complete elimination of all disorder symptoms, and also refer to prophylactic treatment of the conditions mentioned, particularly in patients susceptible to such diseases or disorders. “Administration of” and / or “administration of” a compound should be understood to mean providing the compound or a prodrug of a compound herein to an individual in need.

[0053] As used herein, the term “composition” is intended to encompass any product containing a specified component in a specified amount, and any product obtained directly or indirectly from a combination of a specified component in a specified amount. Such terminology relating to a pharmaceutical composition is intended to encompass any product containing an active component and an inactive component constituting a support, and any product arising directly or indirectly from any combination, complexation, or aggregation of any two or more components, or from the dissociation of one or more components, or from other types of reactions or interactions of one or more components.

[0054] Accordingly, the pharmaceutical compositions of this disclosure encompass any composition prepared by mixing the compounds of this disclosure with a pharmaceutically acceptable carrier. "pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other components of the formulation and must not be harmful to its recipient.

[0055] The selected dosage depends on the desired therapeutic effect, route of administration, and duration of treatment. The dosage will vary from patient to patient depending on the nature and severity of the disease, the patient's weight, any special diet the patient follows, concomitant medications, and other factors that a person skilled in the art would recognize.

[0056] Generally, a dose level of 0.0001 to 10 mg / kg of body weight per day is administered to patients, e.g., humans and elderly individuals, to obtain effective antagonistism of the orexin receptor. The dose range is generally about 0.5 mg to 1.0 g per patient per day, which can be administered as a single or multiple doses. In one embodiment, the dose range is about 0.5 mg to 500 mg per patient per day; in another embodiment, about 0.5 mg to 200 mg per patient per day; and in yet another embodiment, about 5 mg to 50 mg per patient per day.

[0057] The pharmaceutical compositions of this disclosure may be provided in solid-state formulations containing about 0.5 mg to 500 mg of the active ingredient, or about 1 mg to 250 mg of the active ingredient. The pharmaceutical compositions may be provided in solid-state formulations containing about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 200 mg, or 250 mg of the active ingredient. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, for example, 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750, 800, 900, and 1000 milligrams of the active ingredient, for symptomatic adjustment of the dosage for patients being treated.

[0058] The compound may be administered in regimens of 1 to 4 times per day, such as once or twice per day. The compound may be administered before bedtime. For example, the compound may be administered about 1 hour before bedtime, about 30 minutes before bedtime, about 15 minutes before bedtime, or immediately before bedtime.

[0059] As stated above, the therapeutically effective dose of the compounds disclosed herein will depend on several factors. For example, the recipient's species, age, and weight, the exact condition requiring treatment and its severity, the nature of the formulation, and the route of administration are all factors to be considered. The therapeutically effective dose should ultimately be at the discretion of the attending physician or veterinarian. This amount may be given as a single daily dose or as multiple partial doses per day (e.g., two, three, four, five or more times) such that the total daily dose is the same. The effective amount of the salt or its solvate may be determined as the proportion of the compound of formula (I) itself in the effective amount. Similar doses should be appropriate for the treatment of other conditions mentioned herein. Pharmaceutical formulations may be presented in unit dose form containing a predetermined amount of the active ingredient per unit dose. Preferred unit dose formulations are those containing the active ingredient in a daily dose, a partial dose, or an appropriate fraction thereof, as listed above herein. Such pharmaceutical formulations may be prepared by any method well known in the pharmaceutical field.

[0060] Pharmaceutical formulations may be adapted for administration via any suitable route, such as oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous, or intradermal) routes. Such formulations may be prepared by any method known in the field of pharmacy, for example, by associating the active ingredient with a carrier or excipient. For example, without meaning to limit the disclosure, certain routes may be preferred over others for certain conditions and disorders for which the compounds of the disclosure are considered useful. In addition, pharmaceutical formulations may be used to enable delayed or prolonged exposure to the compound of formula (I) in situations where delayed or prolonged exposure would improve therapy.

[0061] Pharmaceutical formulations suitable for oral administration may be presented as individual units, such as capsules or tablets; powders or granules; solutions or suspensions, each containing aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water or water-in-oil liquid emulsions. For example, for administration in tablet or capsule form, the active drug component can be combined with an orally acceptable, non-toxic, and pharmaceutically acceptable inert carrier such as ethanol, glycerol, or water. Generally, powders are prepared by grinding the compound to a suitable fine size and mixing it with a suitable pharmaceutical carrier, such as starch or edible carbohydrates such as mannitol. Flavoring agents, preservatives, dispersants, and colorants may also be present.

[0062] Capsules are prepared by preparing a powder, liquid, or suspension mixture and encapsulating it in gelatin or other suitable shell material. Flow enhancers and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol may be added to the mixture before encapsulation. Disintegrants or solubilizers such as agar, calcium carbonate, or sodium carbonate may also be added to improve the availability of the drug when the capsule is ingested. Additionally, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the mixture as desired or as needed. Examples of suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, and waxes. Useful lubricants in these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Examples of disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum.

[0063] Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging it, adding lubricants and disintegrants, and pressing it into tablets. The powder mixture can be prepared by mixing preferably ground compounds with the diluents or bases described above. Optional components include binders such as carboxymethylcellulose, alligator, gelatin, or polyvinylpyrrolidone; solution retarders such as paraffin; absorption enhancers such as quaternary salts; and / or absorbents such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be wet-granulated with a binder such as syrup, starch paste, Acadia mucus, or a solution of cellulose or polymer material and forced through a screen. As an alternative to granulation, the powder mixture can be passed through a tablet machine, resulting in an incompletely formed slag that is divided into granules. The granules can be lubricated by adding stearic acid, stearate, talc, or mineral oil to prevent them from adhering to the tablet-forming die. The lubricated mixture is then compressed into tablets. The compounds of this disclosure can also be combined with a free-flowing inert carrier and compressed directly into tablets without granulation or slugging steps. Transparent or opaque protective coatings can be provided, consisting of a shellac sealing coat, a sugar or polymer material coating, and a wax polishing coating. Dyes can be added to these coatings to distinguish between different unit doses.

[0064] Oral fluids such as solutions, syrups, and elixirs can be prepared in dose-unit form so that a given amount contains a predetermined amount of the compound. Syrups can be prepared, for example, by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can generally be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ether, preservatives, flavoring additives such as peppermint oil, or natural sweeteners, saccharin, or other artificial sweeteners may also be added.

[0065] If necessary, dosage units for oral administration can be microencapsulated. The formulations can also be prepared to extend or maintain release by, for example, coating or embedding particulate materials in polymers, waxes, etc.

[0066] Pharmaceutical formulations suitable for topical administration by mouth include lozenges, troches, and mouthwashes.

[0067] This disclosure includes compounds within the general scope of this disclosure that have activity as agonists of the orexin-1 receptor and / or orexin-2 receptor. With respect to other orexin modulators, these compounds exhibit unexpected properties such as dual agonism, increased oral bioavailability, metabolic stability, reduced inhibition of metabolic enzymes (e.g., reduced cytochrome P450 3A4 (CYP3A4) inhibition), reduced inhibition of transporters (e.g., reduced p-glycoprotein / PGP inhibition), and / or selectivity for other receptors.

[0068] Orexin receptors are involved in a wide range of biological functions. This indicates the potential role of these receptors in various disease processes in humans or other species. The compounds of this disclosure treat, prevent, improve, control or reduce the risk of various neurological and psychiatric disorders associated with orexin receptors, including one or more of the following conditions or diseases: sleep disorders, reducing nighttime awakenings, especially early morning awakenings, increasing daytime awakenings; reducing daytime sleepiness; excessive daytime sleepiness, narcolepsy, intermittent sleep, sleep apnea, wakefulness, nocturnal myoclonus, intermittent REM sleep, jet lag, sleep disorders of shift workers, sleep disturbances, night terrors, insomnia associated with depression, affective / mood disorders, Alzheimer's disease or This includes cognitive impairment, as well as sleepwalking and enuresis, and age-related sleep disorders; evening syndrome of Alzheimer's disease; conditions related to circadian rhythms, as well as mental and physical disorders associated with inter-time zone travel and shift work schedule rotations, conditions caused by drugs that reduce REM sleep as a side effect; fibromyalgia; sleep disturbances and syndromes manifested by muscle pain or sleep apnea associated with sleep breathing disorders; conditions resulting from reduced sleep quality; increasing learning; enhancing memory; increasing memory retention;Eating disorders and related complications associated with excessive food intake, compulsive eating disorder, obesity (of any cause, whether genetic or environmental), obesity-related disorders including bulimia and bulimia nervosa, hypertension, diabetes, elevated plasma insulin levels and insulin resistance, dyslipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrhythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovary disease, craniopharyngioma, Prader- Willi syndrome, Fröhlich syndrome, GH deficiency, normal variant short stature, Turner syndrome, and other pathological conditions showing reduced metabolic activity or reduced resting energy expenditure as a percentage of total lean body mass, such as children with acute lymphoblastic leukemia, also known as syndrome X, metabolic syndromes, insulin resistance syndromes, reproductive hormone abnormalities, sexual dysfunction and reproductive dysfunction, such as reproductive dysfunction, infertility, hypogonadism in males, and hirsutism in females, fetal defects associated with maternal obesity, gastrointestinal motility disorders, bowel motility disorders Reduce the risk of secondary outcomes of obesity, such as skeletal dyspnea, obesity-related gastroesophageal reflux, hypothalamic disorders, pituitary disorders, respiratory disorders, e.g., obesity hypoventilation syndrome (Pickwick's syndrome), dyspnea, cardiovascular disorders, inflammation, e.g., systemic inflammation of the blood vessels, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, increased anesthesia risk, and secondary outcomes of obesity, e.g., reduced risk of left ventricular hypertrophy; diseases or disorders in which abnormal oscillatory activity occurs in the brain, including depression, migraines, neuropathic pain, Parkinson's disease, psychosis, and schizophrenia. Diseases or disorders involving harm, and especially abnormal coupling of activity through the thalamus; enhancing cognitive function, including cognitive impairment, including all types of deficits in attention, learning, and memory, occurring transiently or chronically in normal, healthy, young, adult, or older populations, and also transiently or chronically in mental, neurological, cardiovascular, and immune disorders; enhancing memory; increasing memory retention; increasing immune response; increasing immune function; hot flashes; night sweats; extending lifespan; schizophrenia;Muscle-related disorders controlled by excitation / relaxation rhythms imposed by the nervous system, such as heart rhythm, and other cardiovascular disorders; conditions related to cell proliferation, such as vasodilation or vasoconstriction and blood pressure; cancer; cardiac arrhythmias; hypertension; congestive heart failure; conditions of the reproductive / urinary system; impairments of sexual function and fertility; appropriateness of renal function; responsiveness to anesthetics; mood disorders, e.g., depression or more particularly depressive disorders, e.g., solitary or recurrent major depressive disorder, and dysthymic disorder, or bipolar disorders, e.g., type I bipolar disorder, type II bipolar disorder, and Cyclothymic disorders, mood disorders resulting from general medical conditions, and substance-induced mood disorders; anxiety disorders, including acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, specific phobias, substance-induced anxiety disorders, and anxiety resulting from general medical conditions; acute neurological and psychiatric disorders such as cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head injury, periperitoneal hypoxia, cardiac arrest, and brain defects after hypoglycemic neuropathy; Huntington's disease; muscle atrophy Lateral sclerosis; multiple sclerosis; eye injury; retinopathy; cognitive impairment; idiopathic and drug-induced Parkinson's disease; muscle spasms and disorders associated with muscle spasms, including tremors, epilepsy, convulsions, seizure disorders, absence seizures, complex partial and generalized seizures; Lennox-Gastaut syndrome; cognitive impairment including dementia (associated with Alzheimer's disease, ischemia, trauma, vascular problems or stroke, HTV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, perinatal hypoxia, other common medical conditions or substance abuse); delirium, amnesia, or age-related cognitive decline; Psychosis, including psychotic disorders resulting from schizophrenia or schizophrenia (paranoid, disorganized, catatonic, or undifferentiated), schizotypal disorders, schizoaffective disorder, delusional disorder, short-term psychotic disorder, shared psychotic disorder, general medical conditions, and substance-induced psychotic disorders; dissociative disorders, including multiple personality disorder and psychogenic amnesia; substance-related disorders, substance use, substance abuse, substance seeking, substance relapse, all types of psychological and physical addictions and addictive behaviors, reward-related behaviors (including substance-induced delirium, persistent dementia, persistent amnesia, psychotic disorders, or anxiety disorders);Tolerance, dependence, addiction, withdrawal, or relapse from substances including alcohol, amphetamines, cannabis, cocaine, hallucinogens, inhalants, morphine, nicotine, opioids, phencyclidine, sedatives, hypnotics, or anti-anxiety agents; akinesia and akinesia-rigidity syndrome (Parkinson's disease, drug-induced Parkinson's disease, post-encephalitis Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, Parkinson's disease-ALS dementia complex and Fatigue, including fatigue caused by sleep disorders or circadian rhythm disorders (including basal ganglia calcification), chronic fatigue syndrome, motor disorders, Parkinson's disease fatigue, multiple sclerosis fatigue, drug-induced Parkinson's disease (including neuroleptic-induced Parkinson's disease, neuroleptic-induced malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia, and drug-induced postural tremor), Le de la Tourette syndrome, epilepsy, and dyskinesia [tremors (resting tremor, postural tremor, and intentional tremor, etc.), chorea (Sydenham chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea, and hemivalism, etc.), myoclonus (including generalized myoclonus and focal myoclonus), tics (including simple tics, complex tics, and symptomatic tics), rest tics] Leslegg syndrome and dystonia (including generalized dystonia such as idiopathic dystonia, drug-induced dystonia, symptomatic dystonia, and paroxysmal dystonia, and focal dystonia such as blepharospasm, maxillofacial dystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp, and hemiplegic dystonia); attention deficit / hyperactivity disorder (ADHD); conduct disorder; migraine (migraine Headache (including headache); headache; hyperalgesia; pain; increased or exaggerated sensitivity to pain such as hyperalgesia, burning pain, and allodenitis; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritis pain; sports injury pain; pain from infections, e.g., pain associated with HIV, pain after chemotherapy; pain after stroke; pain after surgery; neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcer; Kallmann syndrome (smell disorder); irritable bowel syndrome, and conditions associated with visceral pain such as angina pectoris; eating disorders;It is useful in urinary incontinence; substance tolerance, substance withdrawal (including substances such as opioids, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, and hypnotics); psychosis; schizophrenia; anxiety (including generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder); mood disorders (including depression, mania, and bipolar disorder); trigeminal neuralgia; hearing loss; tinnitus; nerve damage including eye damage; retinopathy; macular degeneration of the eye; vomiting (emesis); cerebral edema; and pain, severe pain, intractable pain, inflammatory pain, neuropathic pain, post-traumatic pain, bone and joint pain (osteoarthritis), repetitive movement pain, toothache, cancer pain, myofascial pain (muscle injury, fibromyalgia), postoperative pain (general surgery, gynecology), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine, and migraine headache. Therefore, in certain embodiments, the Disclosure provides for the following purposes in mammalian patients requiring treatment: improving sleep quality; enhancing sleep maintenance; increasing REM sleep; increasing stage 2 sleep; reducing sleep pattern fragmentation; treating insomnia and all types of sleep disorders; treating or controlling sleep disorders associated with diseases such as neuropathic pain and restless legs syndrome; treating or controlling addiction disorders; treating or controlling psychoactive substance use and abuse; enhancing cognition; increasing memory retention; treating or controlling obesity; treating or controlling diabetes and appetite, taste, and eating disorders; treating or controlling hypothalamic disorders; treating or controlling depression; treating, controlling, improving or reducing the risk of epilepsy, including absence epilepsy; treating or controlling pain, including neuropathic pain; treating or controlling Parkinson's disease; treating or controlling psychosis; treating or controlling dysthymia, mood, psychotic, and anxiety disorders; treating or controlling depression, including major depression and major depressive disorder; treating or controlling bipolar disorder;The present invention provides a method for treating, controlling, improving, or reducing the risk thereof of schizophrenia, comprising administering a therapeutically effective amount of the compound of this disclosure to a patient. The compound is further useful in methods for preventing, treating, controlling, improving, or reducing the risk thereof of the diseases, disorders, and conditions described herein. The dosage of the active ingredient in the composition of this disclosure may vary, but the amount of the active ingredient must be such that a suitable dosage form is obtained. The active ingredient may be administered in a dose that will provide optimal pharmaceutically effective results to patients (animals and humans) requiring such treatment.

[0069] The compounds of this disclosure may be used in combination with one or more other drugs in the treatment, prevention, control, improvement, or reduction of the risk thereof of diseases or conditions in which the compounds of this disclosure or other drugs may be useful, and the combination of drugs may be safer or more effective than either drug alone. Such other drugs may be administered concurrently with or consecutively with the compounds of this disclosure in the routes and amounts commonly used for such purposes. When the compounds of this disclosure are used concurrently with one or more other drugs, a pharmaceutical composition in unit dosage forms containing such other drugs and the compounds of this disclosure is intended. Combination therapy may also include therapies in which the compounds of this disclosure and one or more other drugs are administered in different overlapping schedules. When used in combination with one or more other active ingredients, the compounds of this disclosure and the other active ingredients may also be used at lower doses than when each is used alone.

[0070] Accordingly, the pharmaceutical compositions of this disclosure include those containing one or more other active ingredients in addition to the compounds of this disclosure. The above combinations include not only combinations of one other active compound with the compounds of this disclosure, but also combinations of two or more other active compounds.

[0071] Similarly, the compounds of the Disclosure may be used in combination with other drugs used in the prevention, treatment, control, improvement, or reduction of the risk thereof of diseases or conditions for which the compounds of the Disclosure are useful. Such other drugs may be administered simultaneously with or following the compounds of the Disclosure in the routes and amounts commonly used for that purpose. When the compounds of the Disclosure are used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compounds of the Disclosure is contemplated. Accordingly, the pharmaceutical compositions of the Disclosure include those containing one or more other active ingredients in addition to the compounds of the Disclosure.

[0072] The compounds disclosed herein include, for example, sedatives, hypnotics, anxiety relievers, antipsychotics, anxiolytics, antihistamines, benzodiazepines, barbiturates, cyclopyrrolone, GABA agonists, 5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A / 2C antagonists, histamine antagonists including histamine H3 antagonists, histamine H3 reverse agonists, imidazopyridine, minor tranquilizers, melatonin agonists and antagonists, melatonin agonists, other orexin antagonists, orexin agonists, and p Lokinethicin agonists and antagonists, pyrazolopyrilundines, T-type calcium channel antagonists, triazolopyridines, etc., such as azinazolam, arobarbital, aronimide, alprazolam, amitriptyline, amobarbital, amoxapine, almodafinil, APD-125, bentazepam, benzoctamin, brotizolam, bupropion, busprion, butabarbital, butarbital, capromolene, capride, carbochloral, chloral betaine, chloral hydroxide, chlordiazepoxide, clomiphene Lamin, clonazepam, cloperidone, chlorazepate, chlorate, clozapine, conazepam, siprazepam, desipramine, dexcramol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, eprivanserin, estazolam, eszopiclone, eschlorinol, etomidate, phenobam, flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, glutethimid, harazepam, hydroxyzine, ibutamoren, imipramine, i Dipron, Lithium, Lorazepam, Lormetazepam, LY-156735, Maprotiline, MDL-100907, Mecloquan, Melatonin, Mefobarbital, Meprobamate, Metaquan, Metiprilone, Midaflul, Midazolam, Modafinil, Nefazodone, NGD-2-73, Nisobamate, Nitrazepam, Nortriptyline, Ornortriptyline, Oxazepam, Paraldide, Paroxetine, Pentobarbital, Perlapine, Perphenazine, Phenelzine, Phenobarbital, Prazepam, Promethazine, Propofol,The compounds of this disclosure may be administered in combination with other compounds known in the art to be useful for treating or preventing sleep disorders, including narcolepsy, including protriptyline, quazepam, ramelteon, leclazepam, loretamide, secobarbital, sertraline, suproclon, TAK-375, temazepani, thioridazine, thiagabine, tracazolate, tranylcypromine, trazodone, triazolam, trepipam, tricetamide, triclophos, trifluoperazine, trimethodine, trimipramine, urdazepam, venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem, and their salts, and combinations thereof, or the compounds of this disclosure may be administered in combination with the use of physical methods such as phototherapy or electrical stimulation.

[0073] In another embodiment, the compound may be administered separately or in the same pharmaceutical composition, such as (i) a PPARγ antagonist, e.g., glitazone (e.g., siglitazone; dalglitazone; englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone; troglitazone; turalic; BRL49653; CLX-0921; 5-BTZD), GW-0207, LG-100641, and LY-300512); (iii) a biguanide, e.g., metformin and phenfornin; (b) insulin or insulin Imitators, e.g., Biota, LP-100, Novalapid, Insulin Detemir, Insulin Lispro, Insulin Glargine, Insulin Zinc Suspension (Lente and Ultralente); Lys-Pro Insulin, GLP-1(73-7)(Insulin Tropin); and GLP-I(7-36)-NH2); (c) Sulfonylureas, e.g., Acetohexamide; Chlorpropamide; Diabinese; Glibenclamide; Glipizide; Glibrid; Glimepiride; Gliclazide; Glypentide; Glycidone; Glisoramide; Trazamide; and Tolbutamide; ( d) α-glucosidase inhibitors, e.g., acarbose, adiposin; camiglibose; emiglitate; miglitol; voglibose; prazimycin-Q; salvostatin; CKD-71; MDL-25,637; MDL-73,945; and MOR14, etc.; (e) cholesterol lowering agents, e.g., (i) HMG-CoA reductase inhibitors (atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin, and other statins), (ii) bile acid absorbers / chelating agents, e.g. (ii) cholestyramine, colestipol, dialkylaminoalkyl derivatives of cross-linked dextran; Colestid®; LoCholest®, etc.; (iii) nicotinyl alcohol, nicotinic acid, or salts thereof; (iv) growth factor activator receptor α-agonists, e.g., fenofibrate derivatives (gemfibrozil, clofibrate, fenofibrate, and benzafibrate); (iv) cholesterol absorption inhibitors, e.g., sterol glycosides such as stanol esters, beta-sitosterol, and tikeside;(v) Antioxidants such as azetimibe, and acyl-CoA cholesterol acyltransferase (ACAT) inhibitors such as abasimibe and melinamide; (v) Antioxidants such as probucol; (vi) Vitamin E; and (vii) Thyroid hormone mimetic; (f) PPARa agonists such as beclofibrate, benzafibrate, cyprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; and other fibrinic acid derivatives such as Atromid®, Lopid®, and Tricor®, as well as PPARα agonists; (h) PPAR α / δ agonists, e.g., mulagritazal; (i) anti-obesity agents, e.g., (1) growth hormone secretagogues or growth hormone secretagogue receptor agonists / antagonists; (2) protein tyrosine phosphatase-IB (PTP-IB) inhibitors; (3) cannabinoid receptor ligands; (4) anti-obesity serotonin agonists; (5) β3-adrenergic receptor agonists; (6) pancreatic lipase inhibitors; (7) neuropeptide Y1 antagonists; (8) neuropeptides (9) Melanin-concentrating hormone (MCH) receptor antagonists; (10) Melanin-concentrating hormone 1 receptor (MCH1R) antagonists; (11) Melanin-concentrating hormone 2 receptor (MCH2R) agonist / antagonist; (12) Orexin receptor antagonists; (13) Serotonin reuptake inhibitors, e.g., fluoxetine, paroxetine, and sertraline; (14) Melanocortin agonists, e.g., Melanotan II; (15) Mc4r (melanocortin 4 receptor) agonists; (16) 5HT-2 agonists; (17) 5HT2C (serotonin receptor 2C) agonists; (18) galanin antagonists; (19) CCK agonists; (20) CCK-A (cholecystokinin A) agonists; (21) GLP-1 agonists; (22) corticotropin-releasing hormone agonists; (23) histamine receptor-3 (H3) modulators; (24) histamine receptor-3 (H3) antagonists / reverse agonists; (25) β-hydroxysteroid dehydrogenase-1 inhibitors (β-HSD-1); (26) PDE (phosphodiesterase) inhibitors;(27) Phosphodiesterase-3B (PDE3B) inhibitors; (28) Norepinephrine (NE) transport inhibitors; (29) Ghrelin receptor antagonists; (30) Leptins, including recombinant human leptin (PEG-OB, Hoffman La Roche) and recombinant methionyl human leptin (Amgen); (31) Leptin derivatives; (32) BRS3 (Bombesin receptor subtype 3) agonists; (33) Ciliary neurotrophic factor (CNTF); (34) CNTF derivatives, e.g., axokine (Regeneron); (35) Monoamine reuptake inhibitors; (36) UCP-I (Uncoupling protein-1, 2, or 3 activator); (37) Thyroid hormone β-agonists; (38) Fat 30 acid synthase (FAS) inhibitors; (39) DGATL (Diacylglycerol acyltransferase) 1) Inhibitors; (40) DGAT2 (diacylglycerol acyltransferase 2) inhibitors; (41) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (42) Glucocorticoid antagonists; (43) Acyl estrogens; (44) Dipeptidyl peptidase IV (DPP-IV) inhibitors; (45) Dicarboxylic acid transporter inhibitors; (46) Glucose transporter inhibitors; (47) Phosphate transporter inhibitors; (48) Metformin (Glucophage®); (49) Topiramate (Topimax®); (50) Peptides YY, PYY 3-36, Peptide YY analogs, derivatives, and fragments; (51) Neuropeptide Y2 (NPY2) receptor agonists; (52) Neuropeptide Y4 (NPY4); (53) Cyclooxygenase-2; (54) Neuropeptide Y1 (NPY1) antagonists; (55) Opioid antagonists; (56) 11 β HSD-I (11-beta-hydroxysteroid dehydrogenase type 1) inhibitors; (57) Aminorex; (58) Amfechloral; (59) Amphetamine; (60) Benzfetamine; (61) Chlorphentermine; (62) Clobenzorex; (63) Cloforex; (64) Clominorex; (65) Chlortermine; (66) Ciclexedrine; (67) Dextroamphetamine; (68) Difemethoxyzine; (69) N-Ethylamphetamine; (70) Fenbutrazate; (71) Phenisolex;(72) Fenproporex; (73) Fludrex; (74) Fluminorex; (75) Flufurylmethylamphetamine; (76) Levanfetamine; (77) Levofacetoperan; (78) Mefenorex; (79) Methamphepramon; (80) Methamphetamine; (81) Norpsoidephedrine; (82) Pentrex; (83) Fendimethrazine; (84) Fenmethrazine; (85) Pisilorex; (86) Phytofarm; and (87) Zonisamide, (88) Neuromedin; (89) Oxintomodulin; and (90) Neurokinin-1 receptor antagonists (NK-I antagonists), which may be used in combination with other compounds known in the art, including but not limited to these insulin sensitizers.

[0074] In another embodiment, the compound may be used in combination with antidepressants or anxiolytics, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible monoamine oxidase inhibitors (RIMAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), corticotropin-releasing factor (CRF) antagonists, α-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HTI A agonists or antagonists, particularly 5-HTI A partial agonists, and corticotropin-releasing factor (CRF) antagonists. Specific examples of drugs include amitriptyline, clomipramine, doxepin, imipramine, and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline, and protriptyline; citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine, and sertraline; isocarboxazide, phenelzine, tranylcypromine, and selegiline; moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone, trazodone, and piroxazine; alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, harazepam, lorazepam, oxazepam, and prazepam; buspirone, fresinoxane, gepirone, and ipsapirone, as well as their pharmaceutically acceptable salts.

[0075] In another embodiment, the compound may be used in combination with anti-Alzheimer's disease agents, beta-secretase inhibitors, gamma-secretase inhibitors; growth hormone secretagogues; recombinant growth hormone; HMG-CoA reductase inhibitors; NSAIDs including ibuprofen; vitamin E; anti-amyloid antibodies; CB-I receptor antagonists or reverse CB-I receptor agonists; antibiotics such as doxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptor antagonists such as memantine; cholinesterase inhibitors such as galantamine, rivastigmine, donepezil, and tacrine; growth hormone secretagogues such as ibutamorene, ibutamorene mesylate, and capromolelin; histamine H3 antagonists; AMPA agonists; PDE IV inhibitors; GABAA reverse agonists; or neuronal nicotinic agonists.

[0076] In another embodiment, the compound is used as a sedative, hypnotic, anxiety reliever, antipsychotic, anxiolytic, cyclopyrrolone, imidazopyridine, pyrazolopyrimidine, minor tranquilizer, melatonin agonist and antagonist, melatonin agonist, benzodiazepine, barbiturate, 5HT-2 antagonist, etc., such as azinazolam, arobarbital, aronimide, alprazolam, amitriptyline, amobarbital, amoxapine, bentazepam, benzoctaamine, brotizolam, bupropion, busprion, Butabarbital, Butarbital, Capride, Carbochloral, Chloral Betaine, Chloral Hydroxide, Chlordiazepoxide, Clomipramine, Clonazepam, Cloperidone, Chlorazepate, Chloretate, Clozapine, Ciprazepam, Desipramine, Dexcramol, Diazepam, Dichloral Phenazone, Divalproex, Diphenhydramine, Doxepin, Estazolam, Etochlorbinol, Etomidate, Phenobam, Flunitrazepam, Flurazepam, Fluvoxamine, Fluoxetine, Phosazepam Glutethimide, Harazepam, Hydroxyzine, Imipramine, Lithium, Lorazepam, Lormetazepam, Maprotiline, Mecloquan, Melatonin, Mefobarbital, Meprobamate, Metaquan, Midaflul, Midazolam, Nefazodone, Nisobamate, Nitrazepam, Nortriptyline, Oxazepam, Paraldide, Paroxetine, Pentobarbital, Perlapine, Perphenazine, Phenelzine, Phenobarbital, Prazepam, Promethazine, Propofol, Protriptyline, Quazepam, Leclar This compound may be used in combination with zepam, loretamide, secobarbital, sertraline, sproclone, temazepam, thioridazine, tracazolate, tranylcypromine, trazodone, triazolam, trepipam, tricetamide, triclophos, trifluoperazine, trimethodine, trimipramine, urdazepam, venlafaxine, zaleplon, zolazepam, zolpidem, and their salts, as well as combinations thereof, or the compound may be administered in conjunction with the use of physical methods such as phototherapy or electrical stimulation.

[0077] In another embodiment, the compound may be used in combination with anticholinergic agents such as levodopa (with or without selective extraneurocarbon decarboxylase inhibitors such as carbidopa or benserazide), biperiden (optionally as its hydrochloride or lactate), and trihexyphenidyl (benzexol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists, and dopamine receptor agonists such as allentemol, bromocriptine, phenoldopam, rislide, naxagolide, pergolide, and pramipexole.

[0078] In another embodiment, the compound may be used in combination with acetophenazine, allentemol, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixen, clozapine, diazepam, phenoldopam, fluphenazine, haloperidol, levodopa, levodopa and benserazide, levodopa and carbidopa, rislid, roxapine, mesolidazine, morindron, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixen, or trifluoperazine.

[0079] In another embodiment, the compound may be used in combination with compounds derived from phenothiazines, thioxanthenes, heterocyclic dibenzazepines, butyrophenones, diphenylbutylpiperidines, and indolone class neuroleptics. Preferred examples of phenothiazines include chlorpromazine, mesolidazine, thioridazine, acetophenazine, fluphenazine, perphenazine, and trifluoperazine. Preferred examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is morindron. Other neuroleptics include roxapine, sulpiride, and risperidone.In another embodiment, the compound is a nicotine agonist or nicotine receptor partial agonist, e.g., varenicline; an opioid antagonist (e.g., naltrexone); a dopamine agonist (e.g., apomorphine); an ADD / ADHD agent (e.g., methylphenidate hydrochloride (e.g., Ritalin® and Concerta®)); atomoxetine (e.g., Strattera®); a monoamine oxidase inhibitor (MAOI); an amphetamine (e.g., Adderall®); and an anti-obesity agent, e.g., an apo-B / MTP inhibitor; a 1L beta-hydro Xysteroid dehydrogenase-1 (1I-beta-HSD1 type) inhibitors, peptide YY3-36 or analogs thereof, MCR agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, β3 adrenergic receptor agonists, dopamine receptor agonists, melanocyte-stimulating hormone receptor analogs, 5-HT2c receptor agonists, melanin-concentrating hormone receptor antagonists, leptin, leptin analogs, leptin receptor agonists, galanin receptor antagonists, lipase inhibitors, bombesin receptor agonists, neuropeptide-Y receptor antagonists (e.g., NPY These may be used in combination with Y5 receptor antagonists, thyroid hormone-like agents, dehydroepiandrosterone or its analogues, glucocorticoid receptor antagonists, other orexin receptor antagonists, glucagon-like peptide-1 receptor agonists, pilosinic neurotrophic factor, human agouti-related protein antagonists, ghrelin receptor antagonists, histamine 3 receptor antagonists or inverse agonists, and neuromedin U receptor agonists, as well as pharmaceutically acceptable salts thereof.

[0080] In another embodiment, the compound is aminorex, amphetoral, amphetamine, benzfetamine, chlorphentermine, clobenzorex, cloforex, clominorex, chlortermine, ciclexedrin, dexfenfluramine, dextroamphetamine, diethylpropion, difemethoxyzine, N-ethylamphetamine, fenbutrazet, fenfluramine, phenisorex, fenproporex, fludrex, fluminorex, furfurylmethylamphetamine, levanfetamine, levofacetoperan, maji Appetite stimulants such as Ndol, Mephenorex, Methamphepramon, Methamphetamine, Norpsoidephedrine, Pentrex, Fendimetrazine, Fenmetrazine, Phentermine, Phenpropanolamine, Pisirolex, and Sibutramine; Selective serotonin reuptake inhibitors (SSRIs); Halogenated amphetamine derivatives including Chlorphentermine, Cloforex, Chlortermine, Dexfenfluramine, Fenfluramine, Pisirolex, and Sibutramine; and may be used in combination with pharmaceutically acceptable salts thereof.

[0081] In another embodiment, the compound may be used in combination with opioid agonists, lipoxygenase inhibitors such as 5-lipoxygenase inhibitors, cyclooxygenase inhibitors such as cyclooxygenase-2 inhibitors, interleukin inhibitors such as interleukin-1 inhibitors, NMDA antagonists, nitric oxide inhibitors or inhibitors of nitric oxide synthesis, nonsteroidal anti-inflammatory agents, or cytokine-suppressing anti-inflammatory agents, including, for example, compounds such as acetaminophen, aspurine, codiene, fentanyl, ibuprofen, indomethacin, ketrolac, morphine, naproxen, phenacetin, piroxicam, steroidal analgesics, sufentanyl, sunrindac, and tenidap. Similarly, this compound may be administered with analgesics; enhancers such as caffeine, H2 antagonists, simethicone, aluminum hydroxide, or magnesium; decongestants such as phenylephrine, phenylpropanolamine, pseudofedrine, oxymetazoline, efinephrine, naphazoline, xylometazoline, propylhexedrine, or levodesoxyephedrine; antitussives such as codeine, hydrocodone, calamiphene, carbetapentane, or dextramethorphan; diuretics; and sedatives or non-sedative antihistamines.

[0082] The compounds of this disclosure may be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisional injection or infusion, subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical administration routes, and may be formulated alone or together in suitable dose units containing conventional, non-toxic, and pharmaceutically acceptable carriers, adjuvants, and vehicles appropriate for each administration route. In addition to the treatment of warm-blooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, and monkeys, the compounds of this disclosure are also effective for use in humans.

[0083] Several methods for preparing the compounds of this disclosure are shown in the following schemes and examples. Starting materials are prepared according to procedures known in the art or as shown herein.

[0084] The compounds of this disclosure, or their salts or solvates, may be used alone or in combination with other therapeutic agents. The compound of formula (I) and other pharmaceutically active agents may be administered together or separately, and when administered separately, the administration may be simultaneous or sequential in any order. The amounts of the compound of formula (I) and other pharmaceutically active agents, as well as the relative timing of administration, will be selected to achieve the desired combined therapeutic effect. The administration of the compound of formula (I) or its salt or solvate and other therapeutic agents may be a combination by simultaneous administration as follows: (1) a single pharmaceutical composition comprising the combination of compounds, or (2) separate pharmaceutical compositions each comprising the compound of this disclosure. Alternatively, the combination may be administered separately in a sequential manner, with one therapeutic agent administered first and the other second, or vice versa. Such sequential administrations may be close in time or far apart in time.

[0085] Those skilled in organic synthesis will understand that there are multiple means of producing the compounds of this disclosure labeled with radioisotopes suitable for various uses.

[0086] Experiment Section Abbreviation: Where used herein, the symbols and conventions used in these processes, schemes, and examples are based on modern scientific literature, e.g., the Journal of the American Chemical Society or Journal of Biological This is consistent with the abbreviations used in Chemistry. Specifically, the following abbreviations may be used in the examples and throughout the specification. [Table 1]

[0087] Unless otherwise specified, all temperatures are expressed in degrees Celsius (°C). Unless otherwise stated, all reactions were carried out at room temperature.

[0088] The synthesis of all target compounds is shown in schemes 1 to 11. All compounds are 1 The purity was >95%, as characterized by 1H NMR and LC-MS and evaluated by HPLC. [ka]

[0089] The compounds of this disclosure can be synthesized according to the procedure described by Nagahara et al. As shown above, commercially available 1-fluoro-3-nitrobenzase was reacted with excess ethylenediamine at 120°C for 12 hours to yield a substituted aniline, which was immediately reacted with Boc2O to obtain compound 1-1. After flash chromatography, compound 1-1 was treated with BnBr in the presence of potassium carbonate in DMF to obtain the important intermediate 1-2. Reduction of intermediate 1-2 with iron yielded compound 1-3. Slow addition of 5-bromo-2-methoxybenzenesulfonyl chloride in THF to compound 1-3 in DCM in the presence of triethylamine and catalyst DMAP yielded compound 1-4, which underwent Suzuki coupling with different boronic acids, followed by acid-assisted Boc deprotection and amide coupling, to yield intermediate 1-6. Subsequent deprotection of the benzyl group of intermediate 1-6 yielded the desired product. [ka]

[0090] The compounds of this disclosure can be synthesized by procedures similar to those described herein. Commercially available 1-fluoro-3-nitrobenzase was reacted with excess diamines having alkyl chains of different lengths at 120°C for 12 hours to obtain substituted anilines, which were immediately reacted with Boc2O to obtain compound 2-1. After flash chromatography, compound 2-1 was treated with BnBr in the presence of potassium carbonate in DMF to obtain the important intermediate 2-2. Reduction of intermediate 2-2 with iron yielded compound 2-3. Slow addition of 5-bromo-2-methoxybenzenesulfonyl chloride in THF to compound 2-3 in DCM in the presence of triethylamine and catalyst DMAP yielded compound 2-4, which underwent Suzuki coupling with different boronic acids, followed by acid-assisted Boc deprotection and amide coupling, to yield intermediate 2-6. Subsequent deprotection of the benzyl group of intermediate 2-6 yielded the desired product. [ka]

[0091] The compounds of this disclosure can be synthesized as follows: Commercially available 1-fluoro-3-nitrobenzase was reacted with an excess diamine containing 1,4-piperazine at 120°C for 12 hours to obtain substituted aniline, which was immediately reacted with Boc2O to obtain compound 2-1-3. After flash chromatography, compound 2-1-3 was refluxed with iron chloride and ammonia in EtOH to obtain compound 2-3-3. Slow addition of 5-bromo-2-methoxybenzenesulfonyl chloride in THF to compound 2-3-3 in DCM in the presence of triethylamine and catalyst DMAP yielded compound 2-4-3, which underwent Suzuki coupling with N,N-dimethylbenzamido-3-boronic acid, followed by acid-assisted Boc deprotection and amide coupling to yield intermediate 2-5-3. Subsequent deprotection of the benzyl group of intermediate 2-5-3 yielded the desired product.

[0092] The synthesis of these compounds followed primarily the procedure for the synthesis of compound 1 (YNT-185), outlined by Nagahara and colleagues. For such synthetic instructions, see the useful reference incorporated by reference: Nagahara, T.; Saitoh, T.; Kutsumura, N.; Irukayama-Tomobe, Y.; Ogawa, Y.; Kuroda, D.; Gouda, H.; Kumagai, H.; Fujii, H.; Yanagisawa, M.; Nagase, H., Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists. J. Med. Chem. 2015, 58(20), 7931-7. [ka]

[0093] The compounds of this disclosure can be synthesized by a modified procedure, as described for compound 1 (YNT-185). Thus, commercially available 1-fluoro-3-nitrobenzase was reacted with excess ethylenediamine at 120°C for 12 hours to yield a substituted aniline, which was immediately reacted with Boc2O to obtain compound 3-1. After flash chromatography, compound 3-1 was treated with 4N HCl in dioxane to obtain the important intermediate 3-2. Amide coupling between compound 3-2 and 3-methylbenzoic acid, followed by reduction with iron, yielded compound 3-4. Slow addition of 5-bromo-2-methoxybenzenesulfonyl chloride in THF to compound 3-4 in DCM in the presence of DIPEA yielded compound 3-5, with selective acylation of aniline in moderate yield and with little interference. Subsequent Miyaura boration reaction yielded pinacol boronic acid 3-6, which readily reacted with different halogenated aromatic compounds to obtain the final product. [ka]

[0094] The compounds of this disclosure can be synthesized by a procedure similar to that of Table 3. Fluorinated aminopyridine was reacted with ethylenediamine overnight in a sealed tube at 150°C to obtain intermediate 4-1, which underwent amide coupling with 3-methylbenzoic acid to yield the main intermediate 4-2. Reaction of a mixture of 5-bromo-2-methoxybenzenesulfonyl chloride and 4-2 in DMF and THF in the presence of triethylamine and DMAP yielded compound 4-3 in reasonable yield. Subsequent Miyaura borylation, followed by the Suzuki reaction, yielded the desired final products 28, 29, and 30. Note that the Miyaura borylation and Suzuki reactions can be carried out in one pot using different palladium catalysts and reaction times (see SI for more details). This general sequence with the necessary modifications followed in the subsequent synthesis of the remainder of the target compounds. [ka]

[0095] The compounds of this disclosure can be synthesized according to the procedures for those in Table 2. Compounds 2-4 underwent Miyaura boration followed by Suzuki reaction with the corresponding halogenated aromatic amides to obtain the desired compounds. [ka]

[0096] The synthesis of compounds 41 and 42 can be achieved via amide coupling between compounds 3-4 and 5-bromo-2-methoxybenzoate, followed by Miyaura boration and the Suzuki reaction. [ka]

[0097] Intermediate 6-B was obtained by the reaction of 3-bromo-5-fluoropyridine with excess ethylenediamine to provide intermediate 6-A, which was then coupled with 3-methylbenzoic acid. For the synthesis of 6-C, the Mitsunobu reaction was carried out between 5-bromo-3-pyridinol and N-Boc-ethanolamine, followed by subsequent acidic deprotection and amide coupling. 1,3,4-thiadiazole 6-3 was obtained via the reaction of hydrazinecarbothioamide and 5-bromo-anisic acid in refluxed POCl3. The Miyaura borylation reaction of 6-3, followed by the Suzuki reaction with 3-bromo-N-methyl-N-(4-pyridinylmethyl)-benzamide, yielded 6-5. Compound 43 can be readily obtained in moderate yield via the Buchwald coupling between 6-5 and 6-B. Similarly, the reaction of 6-5 with 6-E yielded compound 44. [ka]

[0098] The synthesis of the compounds in Table 7-1 was carried out according to a different route than previously described. For compounds 47, 48, 49, 50, 53, and 54, intermediate 7-A was obtained by the reaction of 5-bromo-2-methoxybenzenesulfonyl chloride with ammonium hydroxide in the presence of saturated sodium bicarbonate. Refluxing compound 7-A in benzene with various substituted methylmalonyl chloride yielded compound 7-1, which subsequently underwent hydrolysis and amide coupling to obtain intermediate 7-3. Acidic deprotection of Boc of compound 6-4, followed by amide coupling with 3-methylbenzoic acid, yielded compound 7-5. Finally, 7-5 was converted to the final product via the Miyaura borylation and Suzuki reaction. [ka]

[0099] Compounds 51, 52, 45, and 46 were synthesized by a similar procedure to which intermediates 7-E or 7-F were prepared by a one-pot sequence reaction: amide coupling between 3-methylbenzoic acid and N-Boc-ethylenediamine, followed by acid treatment, yielded intermediate 7-C. A second amide coupling between compound 7-C and a different N-Boc amino acid yielded compound 7-D, which underwent acidic deprotection to yield compound 7-E or 7-F. Formation of a sulfonylamide between 7-E or 7-F and 5-bromo-2-methoxybenzenesulfonyl chloride yielded 7-7, which was smoothly converted to the final product by subsequent Miyaura borylation and Suzuki reactions. [ka]

[0100] In efforts to improve efficiency, a modified synthetic approach was used for the preparation of the compounds in Table 8, and the scaffold was divided into two parts with sulfonylamide functionality. For the right-hand part, the alcohol was first coupled with 3-methylbenzoic acid using CDI in dichloromethane to obtain 8-A, which is S N The compound underwent an Ar reaction to yield 8-B. Regarding the left-hand portion, 7-A underwent a Miyaura boration reaction followed by a Suzuki reaction to obtain intermediate 8-2. Compound 8-2 then reacted with 8-B or 6-C via a Buchwald cross-coupling reaction catalyzed with tBuXphos to provide the final product. [ka]

[0101] The synthesis of compounds 38 and 59 can be easily achieved by the procedures described for the compounds in Table 3. Intermediates 3-6 were subjected to Miyaura borylation, followed by the Suzuki reaction, to yield compounds 38 and 59. [ka]

[0102] Compounds 60 and 61 were obtained from the reaction between 7-A and 6-B under Buchwald cross-coupling conditions, followed by the Miyaura borylation reaction and the Suzuki reaction. [Examples]

[0103] Synthesis. All solvents and chemicals were reagent grade. Unless otherwise noted, all reagents and solvents were purchased from commercial vendors and used as received. Flash column chromatography was performed using a Teledyne ISCO CombiFlash® Rf system with pre-packed columns. Solvents used included hexane, ethyl acetate (Â), dichloromethane, methanol, and chloroform / methanol / ammonium hydroxide (80:18:2) (CMA-80). The purity and characterization of the compounds were established by a combination of HPLC, TLC, mass spectrometry, and NMR analysis. Melting points were recorded using a Mel-Temp II instrument (Laboratory Devices Inc., US). 1 H and 13¹³C NMR spectra were recorded using a Bruker Avance DPX-300 (300 MHz) spectrometer and determined using tetramethylsilane (TMS) (0.00 ppm) or chloroform-d, DMSO-d6, or methanol-d4 with a solvent peak as an internal reference. Chemical shifts were reported in ppm compared to the reference signal, and coupling constant (J) values ​​were reported in Hertz (Hz). Thin-layer chromatography (TLC) was performed on EMD pre-coated silica gel 60 F254 plates, and spots were visualized by UV light or iodine staining. Low-resolution mass spectra were obtained using a Waters Alliance HT / Micromass ZQ system (ESI). All test compounds were found to be of greater than 95% purity, as determined by HPLC on an Agilent 1100 system, using an Agilent Zorbax SB-Phenyl, 2.1 mm × 150 mm, 5 μm column, with a 15-minute gradient elution of 5–95% solvent B at 1 mL / min, followed by 10 minutes in 95% solvent B (solvent A, water containing 0.1% TFA; solvent B, acetonitrile containing 0.1% TFA and 5% water; absorbance monitored at 220 and 280 nm).

[0104] General procedure for the synthesis of compound 1-1: 3-Nitrofluorobenzene (5.0 mmol, 35.4 mmol) and ethylenediamine (11.8 mL, 177.2 mmol) were mixed in a sealed tube, and the reaction mixture was heated overnight at 120°C. After cooling, the volatiles were evaporated under reduced pressure at 60°C. The residue was then redissolved in a mixture of THF (30 mL) and water (30 mL), followed by the addition of potassium carbonate (14.7 g, 106.2 mmol) and anhydrous Boc (19.3 g, 88.5 mmol). The reaction mixture was then stirred overnight and diluted with brine (150 mL). Ethyl acetate (150 mL) was then added, the organic layer was separated, and dried. The solvent was removed under reduced pressure, and the residue was purified by ISCO to obtain the pure desired product. 6.28 g of brown oil, yield: 63%. 1¹H NMR (300 MHz, chloroform-d) d 7.51 (dd, J=1.60, 8.01 Hz, 1H), 7.37 (t, J=2.26 Hz, 1H), 7.22-7.31 (m, 1H), 6.87 (dd, J=2.07, 8.10 Hz,1H),4.78-4.94(m,1H),4.56-4.73(m,1H),3.36-3.50(m,2H),3.21-3.34(m,2H),1.38-1.50(m,9H).

[0105] General procedure for the synthesis of compounds 1-2: Compound 1-1 (6.28 g, 22.30 mmol) was dissolved in DMF (110 mL), followed by the addition of potassium carbonate (6.17 g, 44.65 mmol) and benzyl bromide (3.2 mL, 26.79 mmol). The reaction mixture was then heated overnight at 60°C. Water (500 mL) and ethyl acetate (200 mL) were added, and the organic layer was separated and dried. The solvent was removed under reduced pressure, and the residue was purified by ISCO to obtain the pure desired product: 5.11 g of orange syrup, yield: 62%. 1 H NMR(300 MHz,chloroform-d)d 7.46-7.59(m,2H),7.34-7.40(m,1H),7.26-7.34(m,3H),7.17(d,J=7.16 Hz,2H),7.02(d,J=6.22 Hz,1H),4.58-4.76(m,3H),3.57-3.72(m,2H),3.37(q,J=6.47 Hz,2H),1.35-1.48(m,9H).

[0106] General procedure for the synthesis of compounds 1-3: Compound 1-2 (5.11 g, 13.76 mmol) was dissolved in a mixture of ethanol and water (55 mL / 22 mL), followed by the addition of ammonium chloride (7.36 g, 137.6 mmol) and iron powder (5.38 g, 96.3 mmol). The reaction mixture was then heated under reflux for 3 hours. After cooling, DCM (100 mL) was added, and the mixture was filtered through Celite. The organic layer was then separated and dried. The solvent was then removed under reduced pressure, and the residue was purified by ISCO to obtain the pure desired product: 4.61 g of brown oil, yield: 98%. 1 ¹H NMR (300 MHz, chloroform-d) d: 7.08-7.46 (m, 6H), 6.98 (t, J=8.19 Hz, 1H), 6.02-6.26 (m, 2H), 4.62-4.77 (m, 1H), 4.40-4.60 (m, 2H), 3.41-3.58 (m, 2H), 3.22-3.39 (m, 2H), 1.55-2.23 (m, 2H), 1.32-1.53 ​​(m, 9H).

[0107] General procedure for the synthesis of compounds 1-4: Under nitrogen protection, compound 1-3 (3.52 g, 10.31 mmol) was dissolved in anhydrous DCM (50 mL) at 0°C, pyridine (1 mL, 12.37 mmol) was added, followed by 2-methoxy-5-bromobenzenesulfonyl chloride (3.24 g, 11.34 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NaHCO3 (30 mL) and DCM (100 mL) was added. The organic layer was separated and dried. The solvent was removed under reduced pressure, and the residue was purified by ISCO to obtain the pure desired product: 5.46 g of off-white solid, yield: 90%. 1H NMR(300 MHz,chloroform-d)d 7.87(d,J=2.45 Hz,1H),7.55(dd,J=2.45,8.85 Hz,1H),7.18-7.35(m,4H),7.10(d,J=6.59 Hz,2H),7.00(t,J=8.38 Hz,1H),6.90(br.s.,1H),6.78(d,J=8.85 Hz,1H),6.49(d,J=8.48 Hz,1H),6.39(d,J=4.71 Hz,2H),4.59-4.73(m,1H),4.48(s,2H),3.84(s,3H),3.41-3.53(m,2H),3.19-3.34(m,2H),1.36-1.47(m,9H).

[0108] General procedure for the synthesis of the final compound in Table 1: Compounds 1-4 (1.0 equivalent), boronic acid (1.2 equivalents), Pd(PPh3)4 (0.1 equivalent), and potassium carbonate (2.0 equivalents) were placed in a round-bottom flask equipped with an efficient condenser. The system was then flushed with nitrogen, and a mixture of 1,4-dioxane / water (4 / 1, 0.1 M) was added. The reaction mixture was refluxed for 2 hours. After cooling, DCM (50 mL) was added, the organic layer was separated, and dried. The solvent was then removed, and the residue was dissolved in 4N HCl in 1,4-dioxane (10 equivalents). The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure. The residue was then dissolved in DMF (0.1 M), followed by the addition of 2-dimethylaminobenzoic acid (1.1 equivalents), HATU (1.2 equivalents), and DIPEA (1.5 equivalents). The reaction mixture was stirred at room temperature overnight and quenched with saturated NaHCO3. DCM (50 mL) was added, and the organic layer was separated and dried. The solvent was removed under reduced pressure to obtain the crude product, which was then mixed with Pd / C (0.1 equivalent) in MeOH (0.1 M) under a hydrogen (40 psi) atmosphere for 12 hours. The reaction mixture was filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by ISCO to obtain the pure desired final product.

[0109] Compound 1: Yield: 45% in 4 steps. 1H NMR(300 MHz,クロロホルム-d)□ 9.89(br.s.,1H),8.00-8.17(m,2H),7.64(dd,J=1.88,8.67 Hz,1H),7.48-7.58(m,2H),7.25-7.46(m,3H),7.10-7.23(m,3H),7.01(d,J=8.67 Hz,1H),6.94(t,J=8.01 Hz,1H),6.45(br.s.,1H),6.34(dd,J=8.01,14.79 Hz,2H),4.33(br.s.,1H),3.94-4.09(m,3H),3.54-3.73(m,2H),3.28(br.s.,2H),2.86-3.20(m,6H),2.42-2.66(m,6H).

[0110] Compound 2: Yield: 4 ステップで36%. 1 H NMR(300 MHz,クロロホルム-d)d 9.67-9.90(m,1H),8.03(d,J=2.07 Hz,2H),7.65-7.74(m,1H),7.56-7.65(m,1H),7.36-7.56(m,6H),7.31(s,2H),7.07(s,2H),6.92(br.s.,2H),6.7 9-6.87(m,1H),4.04(s,3H),3.79(br.s.,4H),3.44(br.s.,4H),3.14(s,6H),1.69(br.s.,4H),1.44-1.59(m,2H).

[0111] Compound 3: Yield: 4ステップで39%. 1H NMR(300 MHz,クロロホルム-d)d 9.90(br.s.,1H),7.99-8.15(m,2H),7.59-7.71(m,2H),7.49-7.55(m,1H),7.35-7. 47(m,3H),7.10-7.22(m,2H),6.86-7.07(m,3H),6.44(s,1H),6.34(dd,J=4.71,7.54 Hz,2H),4.23-4.39(m,1H),4.06(s,3H),3.56-3.72(m,8H),3.42(t,J=6.50 Hz,2H),3.29(t,J=5.65 Hz,2H),2.82(d,J=8.10 Hz,2H),2.56(s,6H),1.94-2.03(m,2H),1.85-1.91(m,2H).

[0112] Compound 4: Yield: 4ステップで32%. 1 H NMR(300 MHz,クロロホルム-d)d 9.87(br.s.,1H),7.97-8.17(m,3H),7.90(s,1H),7.63-7.75(m,2H),7.57(d,J=7.72 Hz,1H),7.33-7.49(m,2H),7.10-7.23(m,2H),7.02(d,J=4.33 Hz,1H),6.88-6.98(m,1H),6.51(br.s.,1H),6.44(s,1H),6.32(t,J=6.59 Hz,2H),4.30(br.s.,1H),4.05(s,3H),3.60(q,J=5.78 Hz,2H),3.43(q,J=6.47 Hz,2H),3.26(br.s.,2H),2.76-2.83(m,6H),1.60-1.71(m,2H),0.98(t,J=7.44 Hz,3H).

[0113] Compound 5: Yield: 4 ステップで29%. 1H NMR(300 MHz,クロロホルム-d)d 9.90(br.s.,1H),8.07-8.16(m,1H),7.97-8.06(m,2H),7.65(dd,J=2.26,8.67 Hz,1H),7.46-7.54(m,2H),7.41(t,J=7.54 Hz,2H),7.30(d,J=7.35 Hz,1H),7.12-7.22(m,2H),7.03(d,J=8.67 Hz,1H),6.95(t,J=8.01 Hz,1H),6.44(s,1H),6.34(d,J=5.09 Hz,2H),4.31(t,J=5.27 Hz,1H),4.07(s,3H),3.65(q,J=5.84 Hz,2H),3.55(br.s.,2H),3.17-3.36(m,4H),2.75-2.99(m,6H),1.26(br.s.,3H),1.11(br.s.,3H).

[0114] Compound 6: Yield: 41%. 1 H NMR(300 MHz,クロロホルム-d)d 9.91(br.s.,1H),8.11(dd,J=1.70,7.91 Hz,1H),8.05(d,J=2.26 Hz,1H),7.65(dd,J=2.35,8.57 Hz,1H),7.37-7.45(m,1H),7.28-7.36(m,3H),7.20(d,J=7.35 Hz,2H),7.08-7.16(m,1H),7.02(d,J=8.67 Hz,1H),6.94(t,J=8.10 Hz,1H),6.89(s,1H),6.45(t,J=2.07 Hz,1H),6.33(td,J=2.28,8.05 Hz,2H),4.17-4.54(m,1H),4.05-4.09(m,3H),3.64(q,J=5.97 Hz,2H),3.29(t,J=5.75 Hz,2H),2.87-2.99(m,1H),2.54(s,6H),1.27(d,J=6.97 Hz,6H).

[0115] Compound 7: Yield: 4 ステップで35%. 1H NMR(300 MHz, CDCl3)d 9.92(br.s.,1H),8.11(d,J=7.72 Hz,1H),8.05(d,J=2.26 Hz,1H),7.66(dd,J=2.26,8.48 Hz,1H),7.31-7.51(m,1H),7.06-7.24(m,3H),6.84-7.05(m,3H),6.73-6.84(m,2H),6.70(d,J=10.17 Hz,1H),6.45(s,1H),6.31(d,J=7.91 Hz,2H),3.97-4.09(m,3H),3.53-3.69(m,2H),3.29(t,J=5.75 Hz, 2H), 2.29-3.06 (m, 12H).

[0116] Compound 8: Yield: 4 ステップで32%. 1 H NMR(300 MHz,クロロホルム-d)d 9.93(br.s.,1H),8.11(dd,J=1.70,7.91 Hz,1H),8.04(d,J=2.26 Hz,1H),7.64(dd,J=2.26,8.67 Hz,1H),7.36-7.46(m,1H),7.07-7.24(m,3H),7.00(d,J=8.67 Hz,1H),6.87-6.96(m,2H),6.69-6.77(m,2H),6.65(d,J=8.10 Hz,1H),6.45(d,J=2.07 Hz,1H),6.27-6.38(m,2H),4.05(s,3H),3.64(q,J=5.97 Hz,2H),3.38(q,J=7.16 Hz,3H),3.29(t,J=5.75 Hz,2H),2.43-2.60(m,6H),1.17(t,J=7.06 Hz,6H).

[0117] Compound 9: Yield: 4 ステップで33%. 1H NMR(300 MHz,クロロホルム-d)d 9.93(br.s.,1H),8.11(dd,J=1.70,7.72 Hz,1H),8.03(d,J=2.45 Hz,1H),7.63(dd,J=2.35,8.57 Hz,1H),7.40(dt,J=1.70,7.72 Hz,1H),7.10-7.24(m,3H),7.01(d,J=8.67 Hz,1H),6.93(t,J=8.01 Hz,1H),6.88(s,1H),6.65-6.73(m,2H),6.61(dd,J=2.26,8.29 Hz,1H),6.44(t,J=2.07 Hz,1H),6.27-6.36(m,2H),4.05(s,3H),3.64(q,J=5.84 Hz,1H),3.16-3.33(m,4H),2.49-2.58(m,6H),1.57-1.64(m,4H),0.93(t,J=7.44 Hz,6H).

[0118] Compound 10: Yield: 4 ステップで39%. 1 H NMR(300 MHz,クロロホルム-d)d 9.77-10.00(m,1H),8.11(dd,J=1.60,7.82 Hz,1H),8.04(d,J=2.26 Hz,1H),7.65(dd,J=2.35,8.57 Hz,1H),7.47(s,1H),7.39(dd,J=1.70,7.54 Hz,1H),7.32-7.37(m,1H),7.28-7.31(m,1H),7.26(s,1H),7.15-7.22(m,1H),7.12(d,J=8.10 Hz,1H),7.03(d,J=8.67 Hz,1H),6.88-6.99(m,2H),6.43-6.49(m,1H),6.27-6.38(m,2H),4.06(s,3H),3.57-3.70(m,2H),3.29(t,J=5.84 Hz,2H),2.42-2.60(m,6H),1.29-1.38(m,9H).

[0119] Compound 11: Yield: 4 ステップで31%. 1 H NMR(300 MHz,クロロホルム-d)d 9.91(br.s.,1H),8.11(dd,J=1.70,7.91 Hz,1H),8.04(d,J=2.45 Hz,1H),7.70(s,1H),7.61-7.68(m,2H),7.55-7.60(m,1H),7.52(d,J=7.54 Hz,1H),7.42(dt,J=1.79,7.68 Hz,1H),7.20(d,J=7.72 Hz,1H),7.14(d,J=8.10 Hz,1H),7.06(d,J=8.67 Hz,1H),6.89-6.99(m,2H),6.39-6.49(m,1H),6.34(d,J=8.10 Hz,2H),4.21-4.57(m,1H),4.06-4.13(m,3H),3.65(q,J=5.97 Hz,2H),3.29(t,J=5.75 Hz,2H),2.48-2.62(m,6H).

[0120] General procedure for the synthesis of compound 2-1: 3-nitrofluorobenzene (1 equivalent) and ethylenediamine (5 equivalents) were mixed in a sealed tube, and the reaction mixture was heated overnight at 120°C. After cooling, the volatiles were evaporated under reduced pressure at 60°C. The residue was then redissolved in a mixture of THF (30 mL) and water (30 mL), followed by the addition of potassium carbonate (3.0 equivalents) and anhydrous Boc (2.5 equivalents). The reaction mixture was then stirred overnight and diluted with brine (150 mL). Ethyl acetate (150 mL) was then added, the organic layer was separated, and dried. The solvent was removed under reduced pressure, and the residue was purified by ISCO to obtain the pure desired product.

[0121] Compound 2-1-1: Yield: 72%. 1 H NMR(300 MHz,chloroform-d)d 7.50(dd,J=1.60,8.01 Hz,1H),7.39(t,J=2.26 Hz,1H),7.25-7.30(m,1H),6.88(dd,J=2.07,8.10 Hz,1H),4.56-4.69(m,1H),3.25(dq,J=3.58,6.34 Hz,4H),2.72(d,J=7.16 Hz,1H),1.79(t,J=6.50 Hz,2H),1.45(s,9H).

[0122] Compound 2-1-2: Yield: 30%.1 1H NMR (300 MHz, chloroform-d) δ 7.47 - 7.52 (m, 2H), 7.35 (t, J = 2.26 Hz, 2H), 7.24 - 7.29 (m, 1H), 6.87 (dd, J = 1.88, 8.10 Hz, 1H), 4.78 - 4.87 (m, 1H), 4.46 - 4.59 (m, 1H), 3.92 - 4.03 (m, 1H), 3.21 (s, 2H), 3.06 - 3.15 (m, 1H), 2.74 - 2.92 (m, 1H), 1.40 - 1.47 (m, 9H), 1.24 - 1.28 (m, 3H).

[0123] General procedure for the synthesis of compound 2-2: Compound 2-1 (1 equivalent) was dissolved in DMF (0.2 M), followed by the addition of potassium carbonate (2 equivalents) and benzyl bromide (1.2 equivalents). Then, the reaction mixture was heated at 60 °C overnight. Water and ethyl acetate were added, and the organic layer was separated and dried. The solvent was removed under reduced pressure, and the residue was purified by ISCO to obtain the pure desired product.

[0124] Compound 2-2-1: Yield: 84%. 1 1H NMR (300 MHz, chloroform-d) δ 7.46 - 7.54 (m, 2H), 7.28 - 7.39 (m, 3H), 7.25 - 7.27 (m, 1H), 7.18 (d, J = 6.78 Hz, 2H), 6.86 - 6.96 (m, 1H), 4.60 (s, 2H), 3.45 - 3.58 (m, 1H), 3.21 (d, J = 6.40 Hz, 1H), 1.82 - 1.94 (m, 2H), 1.44 (s, 9H).

[0125] Compound 2-2-2: Yield: 81%. 1 1H NMR (300 MHz, chloroform-d) δ 7.58 (br.s., 1H), 7.48 (dd, J = 1.51, 7.91 Hz, 1H), 7.37 (d, J = 4.33 Hz, 1H), 7.25 - 7.32 (m, 4H), 7.17 (s, 1H), 6.97 - 7.12 (m, 1H), 4.59 - 4.77 (m, 3H), 4.27 - 4.50 (m, 1H), 4.09 (d, J = 6.97 Hz, 1H), 3.21 - 3.82 (m, 2H), 1.31 - 1.46 (m, 9H).

[0126] General procedure for the synthesis of compounds 2-3: Compound 2-2 (1 equivalent) was dissolved in a mixture of ethanol and water (5:2, 0.2 M), followed by the addition of ammonium chloride (10 equivalents) and iron powder (7 equivalents). The reaction mixture was then heated under reflux for 3 hours. After cooling, DCM (100 mL) was added, and the mixture was filtered through Celite. The organic layer was then separated and dried. The solvent was then removed under reduced pressure, and the residue was purified by ISCO to obtain the pure desired product.

[0127] Compound 2-3-1: Yield: 92%. 1 H NMR(300 MHz,chloroform-d)d 7.27-7.40(m,2H),7.18-7.25(m,3H),6.97(t,J=8.01 Hz,1H),5.98-6.21(m,3H),4.49(m,3H),3.29-3.45(m,2H),3.15(d,J=6.22 Hz,2H),1.74-1.88(m,2H),1.43(s,9H).

[0128] Compound 2-3-2: Yield: 92%. 1 ¹H NMR (300 MHz, chloroform-d) d 7.37 (d, J=4.33 Hz, 1H), 7.26-7.32 (m, 2H), 7.18 (t, J=6.69 Hz, 2H), 6.96 (t, J=8.10 Hz, 1H), 6.23 (dd, J=2.45, 8.29 Hz, 1H), 6.12-6.19 (m, 1H), 6.06 (dd, J=1.51, 7.72 Hz,1H),4.49-4.73(m,2H),4.35-4.48(m,1H),3.95-4.09(m,1H),3.45-3.69(m,2H),3.08-3.22(m,1H),1.29-1.48(m,9H),1.18(d,J=6.78 Hz,3H).

[0129] General procedure for the synthesis of compounds 2-4: Under nitrogen protection, compound 2-3 (1 equivalent) was dissolved in anhydrous DCM (0.2 equivalents) at 0°C, pyridine (1.2 equivalents) was added, followed by 2-methoxy-5-bromobenzenesulfonyl chloride (1.1 equivalents). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NaHCO3 (10 mL) and DCM (30 mL) was added. The organic layer was separated and dried. The solvent was removed under reduced pressure, and the residue was purified by ISCO to obtain the pure desired product.

[0130] Compound 2-4-1: Yield: 85%. 1 H NMR(300 MHz,chloroform-d)d 7.88(d,J=2.64 Hz,1H),7.55(dd,J=2.64,8.85 Hz,1H),7.28(d,J=7.54 Hz,2H),7.23(s,1H),7.11(d,J=6.59 Hz,2H),6.97(d,J=8.10 Hz,1H),6.92(s,1H),6.79(d,J=8.85 Hz,1H),6.37-6.46(m,2H),6.33(d,J=8.67 Hz,1H),4.54-4.64(m,1H),4.44(s,2H),3.85(s,3H),3.30-3.42(m,2H),3.15(d,J=6.22 Hz,2H),1.70-1.83(m,2H),1.44(s,9H).

[0131] Compound 2-4-2: Yield: 83%. 1 ¹H NMR (300 MHz, chloroform-d) d 7.86 (d, J=2.64 Hz, 1H), 7.54 (dd, J=2.45, 8.85 Hz, 1H), 7.25-7.30 (m, 3H), 7.07 (d, J=6.59 Hz,2H),6.99(t,J=8.10 Hz,1H),6.90(br.s.,1H),6.70-6.83(m,1H),6.52(d,J=8.48 Hz,1H),6.34-6.46(m,2H),4.42-4.64(m,2H),4.33(d,J=12.06 Hz,1H),3.90-4.05(m,1H),3.79-3.88(m,3H),3.58(br.s.,1H),3.18(br.s.,1H),1.37(s,9H),1.16(d,J=6.59 Hz,2H).

[0132] General procedure for the synthesis of the final compounds (compounds 13, 14, 15, and 16) in Table 2: Compounds 2-4 (1.0 equivalent), boronic acid (1.2 equivalents), Pd(PPh3)4 (0.1 equivalent), and potassium carbonate (2.0 equivalents) were placed in a round-bottom flask equipped with an efficient condenser. The system was then flushed with nitrogen, and a mixture of 1,4-dioxane / water (4 / 1, 0.1 M) was added. The reaction mixture was refluxed for 2 hours. After cooling, DCM (50 mL) was added, the organic layer was separated, and dried. The solvent was then removed, and the residue was dissolved in 4N HCl in 1,4-dioxane (10 equivalents). The reaction mixture was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure. The residue was then dissolved in DMF (0.1 M), followed by the addition of the corresponding benzoic acid (1.1 equivalents), HATU (1.2 equivalents), and DIPEA (1.5 equivalents). The reaction mixture was stirred at room temperature overnight and quenched with saturated NaHCO3. DCM (50 mL) was added, and the organic layer was separated and dried. The solvent was removed under reduced pressure to obtain the crude product, which was then mixed with Pd / C (0.1 equivalent) in MeOH (0.1 M) under a hydrogen (40 psi) atmosphere for 12 hours. The reaction mixture was filtered, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by ISCO to obtain the pure desired final product.

[0133] Compound 12: 1H NMR(300 MHz,クロロホルム-d)δ 9.89(br.s.,1H),8.00-8.17(m,2H),7.64(dd,J=1.88,8.67 Hz,1H),7.48-7.58(m,2H),7.25-7.46(m,3H),7.10-7.23(m,3H),7.01(d,J=8.67 Hz,1H),6.94(t,J=8.01 Hz,1H),6.45(br.s.,1H),6.34(dd,J=8.01,14.79 Hz,2H),4.33(br.s.,1H),3.94-4.09(m,3H),3.54-3.73(m,2H),3.28(br.s.,2H),2.86-3.20(m,6H),2.42-2.66(m,6H).

[0134] Compound 13: Yield: 4 ステップで29%. 1 H NMR(300 MHz,クロロホルム-d)□ 9.71(br.s.,1H),7.97-8.15(m,2H),7.62-7.80(m,2H),7.50-7.57(m,2 H),7.30-7.48(m,4H),7.14-7.22(m,2H),7.02-7.10(m,1H),6.88-6.97 (m,2H),6.39-6.53(m,1H),6.20-6.37(m,2H),4.03-4.10(m,3H),3.31- 3.54(m,2H),2.78-3.21(m,12H),2.38-2.64(m,2H),1.74-1.90(m,2H).

[0135] Compound 14: Yield: 4 ステップで22%. 1H NMR(300 MHz,クロロホルム-d)□ 9.70-9.79(m,1H),8.01-8.11(m,2H),7.64(dd,J=2.45,8.67 Hz,1H),7.49-7.56(m,2H),7.38-7.47(m,2H),7.30-7.37(m,1H),7.11-7.23(m,2H),6.97-7.06(m,2H),6.93(t,J=8.01 Hz,1H),6.42(t,J=1.98 Hz,1H),6.25-6.38(m,2H),4.35-4.46(m,1H),4.06(s,3H),3.13-3.20(m,2H),2.85-3.06(m,7H),2.80(s,6H),1.28(d,J=6.78 Hz,3H).

[0136] Compound 15: Yield: 4 ステップで32%. 1 H NMR(300 MHz,クロロホルム-d)□ 8.08(d,J=2.45 Hz,1H),7.71-8.04(m,1H),7.67(dd,J=2.35,8.57 Hz,1H),7.57(s,1H),7.52(td,J=1.53,3.53 Hz,3H),7.29-7.45(m,3H),7.04(d,J=8.85 Hz,2H),6.85-6.98(m,2H),6.48(d,J=1.88 Hz,1H),6.25-6.35(m,2H),4.13(s,1H),4.02-4.08(m,4H),3.36(q,J=6.22 Hz,2H),2.76-3.23(m,14H),2.35(s,3H),1.69-1.74(m,3H).

[0137] Compound 16: Yield: 4 ステップで19%. 1H NMR(300 MHz,chloroform-d)d 8.09(d,J=2.45 Hz,1H),8.01(s,1H),7.65(dd,J=2.45,8.67 Hz,1H),7.48-7.59(m,4H),7.41(t,J=7.72 Hz,1H),7.30-7.35(m,1H),7.24(s,1H),7.11(s,1H),7.01(d,J=8.67 Hz,1H),6.90(t,J=8.01 Hz,1H),6.72(d,J=8.10 Hz,1H),6.46(t,J=1.98 Hz,1H),6.29(dt,J=1.79,7.86 Hz,2H),4.39-4.47(m,1H),4.02(s,3H),3.00(s,2H),2.80(s,6H),2.32(s,3H),1.25(d,J=6.78 Hz,3H).

[0138] General procedure for the synthesis of compound 2-1-3: 3-Nitrofluorobenzene (5.0 mmol, 35.4 mmol) and piperazine (9.16 g, 106.31 mmol) were mixed in a sealed tube, and the reaction mixture was heated overnight at 120°C. After cooling, the volatiles were evaporated under reduced pressure at 60°C. The residue was then redissolved in a mixture of THF (30 mL) and water (30 mL), followed by the addition of potassium carbonate (14.7 g, 106.2 mmol) and anhydrous Boc (19.3 g, 88.5 mmol). The reaction mixture was then stirred overnight and diluted with brine (150 mL). Ethyl acetate (150 mL) was then added, the organic layer was separated, and dried. The solvent was removed under reduced pressure, and the residue was purified by ISCO to obtain the pure desired product. 5.30 g of yellow solid, yield: 49%. Compound 2-1-3: 1 ¹H NMR (300 MHz, chloroform-d) d: 7.64-7.76 (m, 2H), 7.40 (t, J=8.10 Hz, 1H), 7.16-7.24 (m, 1H), 3.54-3.67 (m, 2H), 3.19-3.30 (m, 4H), 1.49 (s, 9H).

[0139] General procedure for the synthesis of compound 2-3-3: Compound 2-1-3 (5.35 g, 17.41 mmol) was dissolved in a mixture of ethanol and water (70 mL / 30 mL), followed by the addition of ammonium chloride (9.31 g, 174.1 mmol) and iron powder (6.81 g, 121.8 mmol). The reaction mixture was then heated under reflux for 3 hours. After cooling, DCM (100 mL) was added, and the mixture was filtered through Celite. The organic layer was then separated and dried. The solvent was then removed under reduced pressure, and the residue was purified by ISCO to obtain the pure desired product: 4.15 g of brown oil, yield: 86%. Compound 2-3-3: 1 ¹H NMR (300 MHz, chloroform-d) d: 6.98-7.11 (m,1H), 6.32-6.39 (m,1H), 6.20-6.30 (m,2H), 3.58-3.85 (m,2H), 3.49-3.58 (m,4H), 3.07-3.14 (m,4H), 1.47-1.50 (m,9H).

[0140] General procedure for the synthesis of compound 2-4-3: Under nitrogen protection, compound 2-3-3 (3.04 g, 10.96 mmol) was dissolved in anhydrous DCM (55 mL) at 0°C, pyridine (1.06 mL, 13.15 mmol) was added, followed by 2-methoxy-5-bromobenzenesulfonyl chloride (3.44 g, 12.06 mmol). The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NaHCO3 (30 mL) and DCM (100 mL) was added. The organic layer was separated and dried. The solvent was removed under reduced pressure, and the residue was purified by ISCO to obtain the pure desired product. 4.61 g of brown solid, yield: 80%. Compound 2-4-3: 1 H NMR(300 MHz,chloroform-d)d 7.94(d,J=2.45 Hz,1H),7.58(dd,J=2.54,8.76 Hz,1H),7.26(s,3H),7.07(t,J=8.10 Hz,1H),6.82-6.93(m,2H),6.69-6.76(m,1H),6.64(d,J=8.29 Hz,1H),6.41(d,J=7.91 Hz,1H),4.01(s,3H),3.48-3.62(m,4H),3.00-3.16(m,4H),1.48(s,9H).

[0141] General procedure for the synthesis of the final compounds (compounds 17 and 18) in Table 2: Compound 2-4-3 (1.0 equivalent), boronic acid (1.2 equivalents), Pd(PPh3)4 (0.1 equivalent), and potassium carbonate (2.0 equivalents) were placed in a round-bottom flask equipped with an efficient condenser. The system was then flushed with nitrogen, and a mixture of 1,4-dioxane / water (4 / 1, 0.1 M) was added. The reaction was refluxed for 2 hours. After cooling, DCM (50 mL) was added, the organic layer was separated, and dried. The solvent was then removed, and the residue was dissolved in 4N HCl in 1,4-dioxane (10 equivalents). The reaction was stirred at room temperature for 2 hours, and then the solvent was removed under reduced pressure. The residue was then dissolved in DMF (0.1 M), followed by the addition of the corresponding benzoic acid (1.1 equivalents), HATU (1.2 equivalents), and DIPEA (1.5 equivalents). The reaction was stirred at room temperature overnight and quenched with saturated NaHCO3. DCM (50 mL) was added, the organic layer was separated and dried. The solvent was removed under reduced pressure to obtain the crude product, which was purified by ISCO to obtain the pure desired product.

[0142] Compound 17: Yield: 36% in 4 steps. 1 H NMR(300 MHz,CDCl3)□ 8.04(d,J=2.07 Hz,1H),8.03(d,J 1= 9.0 Hz, J 2= 177 Hz,1H),7.72(d,J=8.67 Hz,1H),7.52(d,J=12.06 Hz,2H),7.42(t,J=7.54 Hz,1H),7.30-7.37(m,2H),7.22(d,J=7.16 Hz,1H),7.02-7.12(m,2H),6.89-6.99(m,3H),6.77(s,1H),6.62(d,J=8.10 Hz,1H),6.48(d,J=7.54 Hz,1H),4.08(s,3H),3.93(br.s.,1H),3.84(br.s.,1H),2.94-3.22(m,10H),2.73-2.86(m,8H).

[0143] Compound 18: Yield: 41% in 4 steps. 1 H NMR (300 MHz, chloroform-d)□ 8.04(d,J=2.26 Hz,1H),7.71(dd,J=2.35,8.57 Hz,1H),7.48-7.60(m,2H),7.42(t,J=7.54 Hz,1H),7.31-7.37(m,1H),7.21-7.30(m,4H),7.17(d,J=7.16 Hz,1H),7.08(d,J=8.85 Hz,2H),6.97-7.04(m,1H),6.78(s,1H),6.62(d,J=8.29 Hz,1H),6.49(d,J=7.72 Hz,1H),4.07(s,3H),3.83(br.s.,2H),3.54(br.s.,2H),2.90-3.25(m,10H),2.38(s,3H).

[0144] Synthesis of compound 3-2. 1-Fluoro-3-nitrobenzene (14.10 g, 100 mmol) was mixed with ethylenediamine (75 mL), and the mixture was heated overnight at 120°C. The reaction mixture was then cooled to room temperature, and toluene (100 mL) was added. Volatile substances were then removed under reduced pressure, and the residue was redissolved in a mixture of ethyl acetate (100 mL) and saturated sodium bicarbonate (100 mL). Decarboxylated di-tert-butyl (32.7 g, 150 mmol) was added, and the reaction mixture was stirred overnight. The organic layer was separated and dried over anhydrous MgSO4. The solvent was then removed under reduced pressure, and the residue was purified by ISCO to obtain 3-1, which was dissolved in a small amount of ethyl acetate, and 4N HCl in dioxane (50 mL) was added. The mixture was then stirred for 2 hours until no more bubbles were released. Hexane (100 mL) was added to precipitate any solids, and the suspension was filtered. The collected solid was rinsed with diethyl ether and dried overnight in vacuum to obtain the pure desired product. 17 g of yellowish-brown solid, yield: 78%. 1 H NMR(300 MHz,DMSO-d6)d 8.12(br.s.,4H),7.29-7.50(m,3H),6.91-7.17(m,1H),3.38(t,J=6.40 Hz,2H),2.87-3.06(m,2H).

[0145] Synthesis of compounds 3-4. 3-Methylbenzoic acid (2.73 g, 20 mmol) and 1,1'-carbonyldiimidazole (3.25 g, 20 mmol) were mixed in DCM and stirred for 15 minutes. Compound 3-2 (2.62 g, 10 mmol) was then added all at once, followed by the addition of DIPEA (10.5 mL, 60 mmol). The reaction was then monitored by TLC. After completion, saturated NaHCO3 was added to quench the reaction. The organic layer was then separated and dried over anhydrous MgSO4. The solvent was removed under reduced pressure, and the residue was redissolved in a mixture of EtOH (80 mL) and water (30 mL), followed by the addition of ammonium chloride (10.7 g, 0.2 mol) and iron powder (7.84 g, 0.14 mol). The reaction was then refluxed for 2 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated. Ethyl acetate (200 mL) and brine (200 mL) were added to the residue, and the organic layer was separated and dried. The solvent was removed under reduced pressure, and the residue was subjected to ISCO to obtain the pure desired compound. 3.33 g of brown oil, yield: 62%. 1 H NMR(300 MHz,d6-DMSO)d 8.56(m,2H),7.54-8.22(m,3H),7.10-7.50(m,2H),7.02(br.s,2H),3.60-3.20(m,4H),2.35(s,3H).

[0146] Synthesis of compounds 3-5. Compound 3-4 (3.33 g, 12.4 mmol) was dissolved in DCM (100 mL), triethylamine (3.5 mL, 24.7 mmol) was added, followed by the addition of catalyst DMAP (302 mg, 2.47 mmol). The mixture was then cooled to 0°C, and 5-bromo-2-methoxybenzenesulfonyl chloride (3.86 g, 13.0 mmol) in THF (10 mL) was slowly added over 20 minutes. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NaHCO3 (50 mL), and ethyl acetate (100 mL) was added. The organic layer was separated and dried. The solvent was removed under reduced pressure, and the residue was subjected to ISCO to obtain the pure desired compound. 4.84 g of pale yellow foam, yield: 76%.1 H NMR(300 MHz,chloroform-d)d 7.94(d,J=2.45 Hz,1H),7.47-7.60(m,3H),7.29-7.36(m,2H),6.97(t,J=8.01 Hz,1H),6.80-6.92(m,2H),6.45(d,J=2.07 Hz,2H),6.33-6.40(m,1H),6.29(d,J=9.23 Hz,1H),4.21(br.s.,1H),4.00(s,3H),3.66(q,J=5.90 Hz,2H),3.32(t,J=5.65 Hz,2H),2.39(s,3H).

[0147] General procedure for the Miyaura boration reaction: A halogenated aromatic compound (1.0 equivalent) was dissolved in 1,4-dioxane (0.1 M), and bis(pinacolate)diborone (1.5 equivalents), followed by PdCl2 (dppf) (0.1 equivalent) and KOAc (2 equivalents). The reaction mixture was then heated overnight at 90°C. After cooling to room temperature, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to ISCO to obtain the desired product.

[0148] General procedure for the Suzuki coupling reaction: 1.0 equivalent of pinacol boronic acid, 1.0 equivalent of compound 2, and 2.0 equivalents of K2CO3 were dissolved in a mixture of 1,4-dioxane and water (v / v=4:1, 0.04M). The mixture was degassed and purged three times with nitrogen. Then, 0.1 equivalent of Pd(PPh3)4 was added, and the reaction was stirred at 90°C for 1 hour. The reaction was then cooled and quenched with brine. Ethyl acetate was then added, the organic layer was separated, and dried. The solvent was removed under reduced pressure, and the residue was subjected to ISCO to obtain the pure desired product.

[0149] General procedure for sequential Miyaura borylation and Suzuki coupling reactions: The halogenated aromatic compound (1.0 eq) was dissolved in 1,4-dioxane (0.1 M), and bis(pinacolato)diboron (1.5 eq), followed by PdCl2(dppf) (0.1 eq) and KOAc (2 eq) were added. Then, the reaction mixture was heated to 90 °C over 6 h. Degassed water (1,4-dioxane / water: v / v = 4:1), followed by K2CO3 (2.0 eq) and Pd(PPh3)4 (0.1 eq) were added. Then, the reaction mixture was stirred at 90 °C for 1 h. Then, the reaction mixture was cooled and quenched with brine. Then, ethyl acetate was added, and the organic layer was separated and dried. The solvent was removed under reduced pressure, and the residue was subjected to ISCO to obtain the pure desired product.

[0150] Synthesis of compounds 3-6. Prepared according to the general procedure for the Miyaura borylation reaction using compounds 3-5 as starting materials. Yield: 87%. 1 H NMR (300 MHz, chloroform-d) δ 8.29 (d, J = 1.51 Hz, 1H), 8.15 - 8.27 (m, 1H), 7.85 - 7.95 (m, 1H), 7.45 - 7.65 (m, 2H), 7.28 - 7.34 (m, 2H), 6.89 - 7.00 (m, 3H), 6.84 (s, 1H), 6.20 - 6.53 (m, 3H), 4.10 - 4.22 (m, 1H), 4.03 (s, 3H), 3.64 (d, J = 6.03 Hz, 2H), 3.33 (br.s., 2H), 2.34 - 2.41 (m, 3H), 1.26 - 1.31 (m, 12H).

[0151] Compounds 12 in Table 2, 19 - 27 in Table 3, and 31 - 40 in Table 5 were prepared according to the general procedure for the Suzuki coupling reaction using compounds 3-6 and the corresponding halogenated aromatic amides as starting materials.

[0152] Compound 12, Yield: 78%. 1 H NMR (300 MHz, chloroform-d) δ 8.12 (d, J = 2.26 Hz, 1H), 7.69 (dd, J = 2.45, 8.67 Hz,1H),7.57(br.s.,3H),7.46-7.54(m,2H),7.42(t,J=7.54 Hz,1H),7.30-7.35(m,1H),7.23(s,1H),7.14(br.s.,1H),7.04(d,J=8.85 Hz,1H),6.93(t,J=8.01 Hz,1H),6.85(s,1H),6.42-6.49(m,1H),6.32(d,J=8.10 Hz,1H),6.23(d,J=7.72 Hz,1H),4.37-4.50(m,1H),4.04(s,3H),3.61(q,J=5.97 Hz,2H),3.21(t,J=5.56 Hz,2H),2.99-3.16(m,6H),2.34(s,3H).

[0153] Compound 19, yield: 78%. 1 H NMR(300 MHz,クロロホルム-d)d 8.64(d,J=4.90 Hz,1H),8.43(d,J=2.45 Hz,1H),8.25(dd,J=2.35,8.76 Hz,1H),7.67(s,1H),7.55(s,1H),7.47(d,J=6.59 Hz,1H),7.33-7.20(m,2H),7.15(dd,J=1.41,4.99 Hz,1H),7.08(d,J=8.85 Hz,1H),6.91-6.98(m,2H),6.84-6.90(m,1H),6.46-6.52(m,1H),6.31(d,J=8.10 Hz,1H),6.23(d,J=9.04 Hz,1H),4.27-4.44(m,1H),4.07(s,3H),3.61(d,J=5.46 Hz,2H),3.25(t,J=5.56 Hz,2H),3.15(s,3H),2.98(s,3H),2.35(s,3H).

[0154] Compound 20, yield: 80%. 1H NMR(300 MHz,クロロホルム-d)d 8.78(d,J=2.26 Hz,1H),8.60(d,J=1.88 Hz,1H),8.08(d,J=2.45 Hz,1H),7.89(t,J=2.17 Hz,1H),7.70(dd,J=2.45,8.67 Hz,1H),7.57(s,1H),7.50(d,J=6.41 Hz,1H),7.09(d,J=8.67 Hz,1H),6.95-7.03(m,1H),6.86-6.95(m,1H),6.46-6.51(m,1H),6.34(d,J=8.10 Hz,1H),6.25(d,J=7.72 Hz,1H),4.07(s,3H),3.60-3.70(m,2H),3.26(t,J=5.75 Hz,2H),3.15(s,3H),3.06(s,3H),2.35(s,3H).

[0155] Compound 21, yield: 83%. 1 H NMR(300 MHz,クロロホルム-d)d 8.59(d,J=5.27 Hz,1H),8.19(d,J=2.26 Hz,1H),7.77(d,J=2.07 Hz,1H),7.74(d,J=2.45 Hz,1H),7.58(s,1H),7.51(d,J=6.41 Hz,1H),7.47(dd,J=1.88,5.27 Hz,1H),7.08(d,J=8.67 Hz,1H),6.92(t,J=8.01 Hz,1H),6.86(s,1H),6.48(s,1H),6.32(d,J=8.29 Hz,1H),6.20(d,J=9.23 Hz,1H),4.43-4.59(m,1H),4.07(s,3H),3.61-3.71(m,2H),3.24(t,J=5.56 Hz,2H),3.15(d,J=3.58 Hz,6H),2.34(s,3H).

[0156] Compound 22, yield: 85%. 1H NMR(300 MHz,クロロホルム-d)d 8.58(d,J=2.45 Hz,1H),8.15(d,J=8.67 Hz,1H),7.77(d,J=7.72 Hz,1H),7.70(s,1H),7.56(s,1H),7.48(d,J=6.41 Hz,2H),7.06(d,J=8.85 Hz,1H),6.86-6.98(m,1H),6.82(s,2H),6.46(s,1H),6.21-6.35(m,2H),4.28-4.44(m,1H),4.06(s,3H),3.57(d,J=5.65 Hz,2H),3.22(d,J=5.46 Hz,2H),3.17(s,3H),3.11(s,3H),2.37(s,3H).

[0157] Compound 23, yield: 68%. 1 H NMR(クロロホルム-d,300MHz): d=8.01-8.04(m,1 H),7.62-7.68(m,1 H),7.55(d,J=1.5 Hz,2 H),7.47-7.52(m,1 H),7.45(s,1 H),7.30(s,2 H),7.00-7.05(m,1 H),6.91-6.99(m,1 H),6.79-6.83(m,1 H),6.58-6.66(m,1 H),6.46-6.50(m,1 H),6.31-6.37(m,1 H),6.24-6.30(m,1 H),4.21-4.34(m,1 H),4.05(s,3 H),3.25-3.33(m,2 H),3.10-3.24(m,2 H),2.38 ppm(s,3 H).

[0158] Compound 24, yield: 88%. 1 H NMR(300 MHz,クロロホルム-d)d 8.08(d,J=2.26 Hz,1H),7.64(dd,J 1= 2.35 Hz, J 2=8.57 Hz,1H),7.56(s,1H),7.46-7.52(m,1H),7.35(s,1H),7.33-7.34(m,1H),6.99(d,J=8.67 Hz,1H),6.92(d,J=8.29 Hz,1H),6.83-6.88(m,1H),6.81(s,1H),6.48(s,1H),6.30-6.37(m,1H),6.21-6.27(m,1H),4.34-4.47(m,1H),4.04(s,3H),3.64(d,J=5.84 Hz,2H),3.26(s,2H),3.11(br.s.,6H),2.37(s,3H).

[0159] Compound 25, yield: 70%. 1 H NMR(300 MHz,クロロホルム-d)d 8.31(d,J=2.26 Hz,1H),7.99-8.07(m,1H),7.63-7.73(m,1H),7.57(s,1H),7.51-7.56(m,1H),7.45-7.50(m,2H),7.28-7.33(m,2H),7.06(d,J=8.67 Hz,1H),6.95(m,1H),6.84(s,1H),6.48(s,1H),6.37-6.43(m,1H),4.08 (s,3H),3.57-3.67(m,5H),3.24-3.33(m,2H),3.17(s,3H),2.38(s,3H).

[0160] Compound 26, yield: 63%. 1 H NMR(300 MHz,クロロホルム-d)d 8.03(d,J=2.26 Hz,1H),7.46-7.59(m,5H),7.28-7.34(m,2H),6.91-7.01(m,2H),6.73-6.85(m,2H),6.50-6 .58(m,1H),6.44(s,1H),6.24-6.38(m,2H),4.13-4.32(m,1H),4.04(s,3H),3.65(d,J=5.84 Hz,2H),3.29(s,2H),3.14(s,3H),3.04(s,3H),2.39(s,3H).

[0161] Compound 27, yield: 67%. 1H NMR(300 MHz,クロロホルム-d)d 7.64(d,J=2.26 Hz,1H),7.58(s,1H),7.52(br.s.,1H),7.28-7.36(m,3H),6.95(t,J=8.01 Hz,1H),6.89(d,J=8.29 Hz,1H),6.83(s,1H),6.67-6.75(m,1H),6.43(s,1H),6.35(s,1H),6.28(d,J=7.54 Hz,1H),3.98(s,3H),3.64(d,J=5.65 Hz,2H),3.30(t,J=5.75 Hz,2H),2.81-2.92(m,8H),2.49-2.57(m,2H),2.39(s,3H).

[0162] Compound 31, yield: 72%. 1 H NMR(300 MHz,クロロホルム-d)d 8.12(d,J=2.26 Hz,1H),7.69(dd,J 1= 2.35 Hz, J 2= 8.57 Hz,1H),7.58(br.s.,3H),7.53(s,2H),7.38-7.47(m,2H),7.30-7.37(m,2H),7.15(br.s.,2H),7.04(d,J=8.67 Hz,1H),6.93(t,J=8.01 Hz,2H),6.46(s,1H),6.32(d,J=7.91 Hz,1H),6.23(d,J=9.23 Hz,1H),4.04(s,3H),3.65-3.74(m,1H),3.55-3.64(m,2H),3.31-3.42(m,1H),3.17-3.26(m,2H),3.1 1(br.s.,1H),3.04(br.s.,2H),2.61-2.71(m,1H),2.41-2.50(m,1H),2.34(s,6H),2.08(br.s.,3H).

[0163] Compound 32, yield: 75%. 1H NMR(300 MHz,クロロホルム-d)d 8.14(d,J=2.45 Hz,1H),8.02(s,1H),7.78-7.84(m,1H),7.66-7.73(m,2H),7.63(s,1H),7.55(br.s.,2H),7.49(d,J=3.20 Hz,2H),7.20(br.s.,2H),7.04(d,J=8.67 Hz,1H),6.93(t,J=7.91 Hz,2H),6.55(s,1H),6.31(d,J=8.10 Hz,1H),6.23(d,J=6.22 Hz,1H),4.03(s,3H),3.65(d,J=5.65 Hz,2H),3.47-3.58(m,2H),3.26(br.s.,2H),2.57(t,J=5.75 Hz,1H),2.52(d,J=6.03 Hz,1H),2.31(s,6H),2.25(s,3H).

[0164] Compound 33, yield: 78%. 1 H NMR(300 MHz,クロロホルム-d)d 8.36-8.40(m,1H),8.24-8.33(m,2H),8.18-8.22(m,1H),7.70-7.76(m,1H),7.59-7.62(m,1H),7.56-7.59 (m,1H),7.53-7.56(m,1H),7.50-7.52(m,1H),7.47-7.50(m,1H),7.44-7.47(m,1H),7.30-7.39(m,2H),7.2 1(s,1H),7.18(s,1H),7.02-7.07(m,1H),6.89-6.96(m,1H),6.79-6.83(m,1H),6.49-6.58(m,2H),6.27-6. 33(m,1H),6.14-6.22(m,1H),4.04(s,3H),3.90(s,3H),3.63-3.73(m,2H),3.23-3.35(m,2H),2.28(s,3H).

[0165] Compound 34. Yield: 3ステップで56%. 1H NMR(300 MHz,クロロホルム-d)d 8.13(br.s.,1H),7.48-7.75(m,5H),7.30-7.46(m,6H),6.99-7.21(m,3H),6.93(t,J=7.91 Hz,1H),6.85(s,1H),6.45(s,1H),6.32(d,J=8.10 Hz,1H),6.23(d,J=7.72 Hz,1H),4.49-4.82(m,2H),4.04(s,3H),3.58(br.s.,2H),3.21(br.s.,2H),2.76-3.11(m,3H),2.33(br.s.,3H).

[0166] Compound 35, yield: 84%. 1 H NMR(300 MHz,クロロホルム-d)d 8.56-8.69(m,1H),8.00-8.17(m,1H),7.67-7.77(m,2H),7.47-7.66(m,5H),7.42(br.s.,3H),7.01-7.13(m,2H),6.93(t,J=8.01 Hz,1H),6.84(br.s.,1H),6.46(s,1H),6.32(d,J=8.10 Hz,1H),6.17-6.27(m,1H),4.88(s,1H),4.62(s,1H),4.04(br.s.,3H),3.59(br.s.,2H),3.21(br.s.,2H),3.09(d,J=15.82 Hz,3H),2.34(br.s.,3H).

[0167] Compound 36, yield: 62%. 1H NMR(300 MHz,クロロホルム-d)d 8.52-8.60(m,1H),8.14(d,J=2.45 Hz,1H),8.04(s,1H),7.78(d,J=7.72 Hz,2H),7.61-7.72(m,3H),7.44-7.56(m,3H),7.06-7.14(m,1H),6.98-7.05(m,2H), 6.88-6.98(m,1H),6.55(s,1H),6.27-6.36(m,1H),6.19-6.26(m,1H),4.72(d,J=4.90 Hz,2H),4.25-4.48(m,1H),4.00(s,3H),3.65(d,J=5.46 Hz,2H),3.29(br.s.,2H),2.30(s,3H).

[0168] Compound 37, yield: 68%. 1 H NMR(300 MHz,メタノール-d4)d 8.40-8.62(m,1H),7.86-8.07(m,1H),7.31(s,12H),7.10-7.23(m,1H),6.84-6.92(m,1H),6.45-6.51(m,1H),6. 35-6.42(m,1H),6.24-6.35(m,1H),3.99(s,3H),3.40-3.48(m,2H),3.21(m,2H),2.94-3.08(m,3H),2.36(s,3H).

[0169] Compound 38 (RTIOX-43), yield: 80%. 1 H NMR(300 MHz,メタノール-d4)d 8.43-8.57(m,2H),7.91-8.09(m,1H),7.62-7.86(m,2H),7.49-7.60(m,3H ),7.37-7.47(m,2H),7.23-7.37(m,3H),7.10-7.23(m,1H),6.83-6.94(m,1 H),6.43-6.52(m,1H),6.35-6.42(m,1H),6.26-6.35(m,1H),3.92-4.02(m ,3H),3.36-3.49(m,2H),3.15-3.24(m,3H),2.88-3.13(m,4H),2.36(s,3H)

[0170] Compound 39, yield: 85%.1 H NMR(300 MHz,メタノール-d4)d 8.25(dd,J 1= 159.0 Hz, J 2= 3.0 Hz,1H),7.95(d,J=33.0 Hz,1H),7.73-7.84(m,1H),7.58(dd,J 1= 63.0 Hz, J 2= 9.0 Hz,1H),7.18-7.62(m,9H),7.03(t,J=6.0 Hz,1H),6.91(t,J=6.0 Hz,1H),6.48-6.83(m,2H),6.42(t,J=9.0 Hz,1H),6.26-6.36(m,1H),4.03(d,J=12.0 Hz,3H),3.91(t,J=6.0 Hz,1H),3.71(t,J=6.0 Hz,1H),3.35-3.58(m,2H),3.08-3025(m,7H),2.37(s,3H).

[0171] Compound 40, yield: 70%. 1 H NMR(300 MHz,クロロホルム-d)d 8.55(br.s.,1H),8.25-8.36(m,1H),7.95-8.11(m,1H),7.30-7.75(m,6H),6.68-7.22(m,8H),6.49(br.s.,1H),6.31(br.s .,2H),4.04(s,3H),3.83(br.s.,1H),3.59(br.s.,4H),3.12-3.29(m,3H),3.03(br.s.,1H),2.90(br.s.,3H),2.34(s,3H).

[0172] General instructions for the synthesis of compounds 28, 29, and 30: Fluorinated aminopyridine (1.0 equivalent) was mixed with ethylenediamine (10.0 equivalent) and heated overnight in a sealed tube at 150°C. The volatile substances were then removed under reduced pressure. The residue was then suspended in DCM and DIPEA (5 equivalents) was added. In another round-bottom flask, 3-methylbenzoic acid (1.0 equivalent) in DCM (1.0 M) was packed in, followed by the addition of 1,1'-carbonyldiimidazole (CDI) (1.0 equivalent). The mixture was stirred for 15 minutes and then added to the suspension. The reaction was continued overnight, and the solvent was removed under reduced pressure to obtain a viscous oil, which was then directly subjected to ISCO to obtain intermediate 4-2.

[0173] Intermediate 4-2-1 of compound 28. 1 H NMR(300 MHz,chloroform-d)d 7.62-7.71(m,2H),7.24-7.34(m,3H),6.07(dd,J=2.07,7.16 Hz,1H),6.00(d,J=2.07 Hz,1H),3.75(br.s.,4H),3.54-3.62(m,2H),3.40-3.47(m,2H),2.40(s,3H).

[0174] Intermediate 4-2-2 of compound 29 was used in the next step without further purification.

[0175] Intermediate 4-2-3 of compound 30. 1 ¹H NMR (300 MHz, methanol-d4): d 7.93-8.01 (m, 1H), 7.90 (s, 1H), 7.55-7.66 (m, 3H), 7.27-7.33 (m, 2H), 3.45-3.55 (m, 3H), 2.86 (s, 3H).

[0176] Intermediate 4-2 (1.0 equivalent) was dissolved in a mixture of DMF / THF (v / v=1:2, 0.5M), followed by the addition of triethylamine (4.0 equivalents) and catalyst DMAP (0.4 equivalents). The mixture was cooled to 0°C, and 5-bromo-2-methoxybenzenesulfonyl chloride (1.2 equivalents) in THF (0.5M) was slowly added. The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was quenched with saturated NaHCO3, and the aqueous phase was extracted with DCM. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was then removed under reduced pressure, and the residue was subjected to ISCO to obtain intermediate 4-3.

[0177] Intermediate 4-3-1 of compound 28. 1 H NMR(300 MHz, methanol-d4)d 8.02(d,J=2.45 Hz,1H),7.61-7.67(m,1H),7.59(br.s.,4H),7.34(s,2H),7.01-7.07(m,1H),6.29- 6.36(m,1H),6.26(s,1H),3.86(s,3H),3.46-3.55(m,2H),3.41(s,3H),2.38(s,3H).

[0178] Intermediate 4-3-2 of compound 29 was used in the next step without further purification.

[0179] Intermediate 4-3-3 of compound 30. 1 H NMR(300 MHz, methanol-d4)d 8.08(d,J=2.45 Hz,1H),7.59-7.65(m,1H),7.47-7.53(m,1H),7.39-7.44(m,1H),7.30(s,3H),6.95(s,1H),6.03-6.19(m,2H),3.81(s,3H),3.52(d,J=5.84 Hz,2H),3.46(d,J=5.65 Hz,2H),2.36(s,3H).

[0180] Next, intermediates 4-3 were subjected to the general procedure for a sequential Miyaura borylation and Suzuki coupling reaction, and compounds 28, 29, and 30 were obtained using the corresponding halogenated aromatic amides.

[0181] Compound 28, yield: 2ステップで64%. 1 H NMR(300 MHz,クロロホルム-d)d 8.19(d,J=2.26 Hz,1H),7.93(br.s.,1H),7.73(d,J=2.26 Hz,2H),7.70(d,J=2.26 Hz,1H),7.60(br.s.,2H),7.56(s,2H),7.52(br.s.,1H),7.46(t,J=7.63 Hz,1H),7.34-7.38(m,1H),7.19-7.24(m,2H),7.02(d,J=8.67 Hz,1H),6.30(d,J=6.03 Hz,1H),6.24(s,1H),3.93(s,3H),3.54(br.s.,2H),3.45(br.s.,2H),3.14(s,3H),3.02(s,3H),2.32(s,3H).

[0182] Compound 29, yield: 2ステップで61%. 1 H NMR(300 MHz,クロロホルム-d)d 8.10(d,J=2.45 Hz,1H),7.69(d,J=2.64 Hz,3H),7.51-7.62(m,6H),7.45(d,J=2.26 Hz,2H),7.31-7.38(m,1H),7.04(d,J=8.67 Hz,2H),6.82(s,1H),4.87-5.01(m,1H),4.04(s,3H),3.65(d,J=5.09 Hz,2H),3.14(m,5H),2.96-3.09(m,5H),2.32(s,3H).

[0183] Compound 30, yield: 2ステップで70%. 1H NMR(300 MHz,chloroform-d)d 8.21(d,J=2.26 Hz,1H),7.57-7.68(m,3H),7.53(s,1H),7.44-7.51(m,2H),7.35-7.41(m,2H),7.11-7.18(m,1H),7.06(d,J=7.72 Hz,1H),6.79(d,J=7.91 Hz,2H),6.64(d,J=8.85 Hz,1H),5.98(d,J=8.29 Hz,1H),3.61(s.,3H),3.38(br.s.,2H),3.23(br.s.,2H),3.16(s,3H),3.04(s,3H),2.20(s,3H).

[0184] General procedure for the synthesis of compounds 41 and 42: Intermediate 3-4 (539 mg, 2.0 mmol) was dissolved in DCM (20 mL), and triethylamine (0.56 mL, 4.0 mmol) was added. Then, catalyst DMAP (25 mg, 0.4 mmol) was introduced, and the reaction mixture was cooled to 0°C. At this temperature, 5-bromo-2-methoxybenzene carboxylic acid chloride (499 mg, 2.0 mmol) in THF (10 mL) was slowly added. The reaction mixture was then stirred at this temperature for 1 hour and warmed to room temperature overnight. The reaction mixture was quenched with saturated sodium bicarbonate (50 mL), and extracted with ethyl acetate (50 mL). The organic layer was separated and dried. The solvent was removed under reduced pressure, and the residue was subjected to ISCO to obtain the desired product 6-1 (579 mg, 60%).

[0185] Compound 6-1. 1H NMR(300 MHz,chloroform-d)d 9.61(s,1H),8.35(d,J=2.64 Hz,1H),7.47-7.62(m,3H),7.21-7.35(m,4H),7.12(t,J=8.01 Hz,1H),6.90(d,J=8.85 Hz,1H),6.75(d,J=7.91 Hz,1H),6.65(br.s.,1H),6.43(dd,J=1.70,8.10 Hz,1H),4.15-4.27(m,1H),4.02(s,3H),3.69(q,J=5.97 Hz,2H),3.32-3.50(m,2H),2.36(s,3H).

[0186] Compound 6-2 was synthesized according to the general procedure for the Miyaura borylation reaction using compound 6-1 as the starting material: DZ14171-190 (Compound 5-2), Yield: >99%. 1 H NMR(300 MHz,chloroform-d)d 9.57(s,1H),8.70(d,J=1.51 Hz,1H),7.91(dd,J=1.60,8.19 Hz,1H),7.51-7.66(m,2H),7.42(s,1H),7.22-7.35(m,3H),7.12(t,J=8.01 Hz,1H),7.01(d,J=8.29 Hz,1H),6.73(d,J=7.91 Hz,1H),6.63(br.s.,1H),6.44(d,J=7.91 Hz,1H),4.05(s,3H),3.72(q,J=5.65 Hz,2H),3.37-3.52(m,2H),2.37(s,3H),1.33(s,12H).

[0187] Compounds 41 and 42 were synthesized according to the general procedure for the Suzuki coupling reaction using compound 6-2 as the starting material: Compound 41, yield: 78%. 1H NMR(300 MHz,chloroform-d)d 9.77(s,1H),8.53(d,J=2.26 Hz,1H),7.73(dd,J=2.45,8.48 Hz,1H),7.66(s,2H),7.58(s,1H),7.54(br.s.,1H),7.47(t,J=7.91 Hz,1H),7.34-7.42(m,3H),7.29(d,J=4.71 Hz,2H),7.09-7.21(m,3H),6.79(d,J=8.48 Hz,1H),6.46(d,J=8.10 Hz,2H),4.13-4.22(m,1H),4.10(s,3H),3.68-3.78(m,2H),3.47(t,J=5.75 Hz,3H),2.93-3.19(m,7H),2.38(s,3H).

[0188] Compound 42, yield: 72%. 1 H NMR(300 MHz,chloroform-d)d 9.75(br.s.,1H),8.62(d,J=6.03 Hz,2H),8.40-8.57(m,1H),7.69(d,J=7.72 Hz,3H),7.36-7.60(m,5H),7.28-7.34(m,3H),7.06-7.22(m,3H),6.72-6.83(m,1H),6.46(d,J=7.91 Hz,1H),4.78(br.s.,2H),4.10(s,3H),3.74(q,J=5.84 Hz,2H),3.41-3.53(m,2H),2.90-3.16(m,3H),2.37(s,3H).

[0189] General procedure for the synthesis of compounds 43 and 44: 3-Bromo-5-fluropyridine (1 equivalent) was dissolved in ethylenediamine (20 equivalents), and the reaction mixture was heated overnight in a sealed tube at 150°C. After cooling to room temperature, volatile substances were removed under reduced pressure at 80°C. The residue was then redissolved in ethyl acetate, and potassium carbonate was added. The solution was stirred for 1 hour and filtered. The solvent was removed under reduced pressure to obtain a viscous oil, which was then redissolved in DCM (0.25 M).

[0190] 3-methylbenzoic acid (1 equivalent) and 1,1'-carbonyldiimidazole (1 equivalent) were mixed in DCM (0.1 M) and stirred for 15 minutes. The mixture was added dropwise to the above solution and the reaction was stirred overnight. Brine was added to quench the reaction, and the reaction was extracted with ethyl acetate. The organic layer was then separated and dried. The solvent was removed under reduced pressure, and the residue was purified by ISCO to obtain compound 6-B as an off-white solid.

[0191] Intermediate 6-B, yield: 59%. 1 H NMR (300 MHz, chloroform-d) 7.98(d,J=1.70 Hz,1H),7.94(d,J=2.26 Hz,1H),7.59(s,1H),7.53(br.s.,1H),7.33(d,J=5.09 Hz,2H),7.04(t,J=2.17 Hz,1H),6.36-6.50(m,1H),4.57-4.74(m,1H),3.75(q,J=5.97 Hz,2H),3.38(d,J=5.65 Hz,2H),2.40(s,3H).

[0192] Synthesis of compound 6-D. N-Boc-ethanolamine (1.3 equivalents) was dissolved in THF (0.5 M), and diisopropyl azodicarboxylic acid (1.03 equivalents) was added. The reaction mixture was stirred at room temperature for 30 minutes, and 3-bromo-5-hydroxypyridine (1.0 equivalent) was added, followed by triphenylphosphine (1.5 equivalents). The reaction mixture was then stirred overnight. The reaction mixture was then cooled to 0°C and concentrated with HCl (V 反応混合物 / V 濃縮HCl A 2:1 ratio of ethyl acetate was added. The reaction mixture was heated to room temperature and stirred for 30 minutes until bubbling was complete. The acidic aqueous solution was then washed three times with DCM. The aqueous solution was made basic with potassium carbonate (pH > 10.0) and ethyl acetate was introduced. Boc2O (1.2 equivalents) was then added and the reaction mixture was stirred for 2 hours. The organic layer was then separated and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed under reduced pressure, and the residue was purified by ISCO to obtain compound 6-C.

[0193] Compound 6-C, white solid, yield: 82%. 1 ¹H NMR (300 MHz, chloroform-d) d 8.30 (d, J=1.88 Hz, 1H), 8.24 (d, J=2.45 Hz, 1H), 7.37 (t, J=2.17 Hz, 1H), 4.88-5.08 (m, 1H), 4.06 (t, J=5.09 Hz, 2H), 3.55 (q, J=5.27 Hz, 2H), 1.46(s, 9H).

[0194] Compound 6-C (1 equivalent) was treated with 4N HCl to obtain compound 6-D. 3-methylbenzoic acid (1 equivalent) and 1,1'-carbonyldiimidazole (1 equivalent) were mixed in DCM (0.1 M) and stirred for 15 minutes. Intermediate 6-D (1 equivalent) was added, and the reaction mixture was stirred overnight. Brine was added to quench the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The organic layer was then separated and dried. The solvent was removed under reduced pressure to obtain compound 6-E, which was used in the next step without further purification.

[0195] Commercially available thiosemicarbazide (1.0 equivalent) and 5-bromo-2-methoxybenzoic acid (1.0 equivalent) were mixed in POCl3 (14.0 equivalents), and the reaction mixture was heated at 75°C for 30 minutes. After cooling to room temperature, water (V) was added. H2O / V POCl3 The reaction mixture was slowly added (4:1) and refluxed for 4 hours. After cooling to room temperature, the mixture was basicized to pH 8.0 by dropwise addition of 50% NaOH solution under stirring. The precipitate was collected by filtration to obtain pure compound 6-3 as a white solid.

[0196] Compound 6-3, yield: 76%. 1 H NMR(300 MHz,DMSO-d6)d 8.18(d,J=2.64 Hz,1H),7.55-7.63(m,1H),7.30(s,2H),7.20(s,1H),3.93(s,3H).

[0197] Compound 6-5 was synthesized according to the general procedure for a sequential Miyaura borylation and Suzuki coupling reaction using compound 6-3 as the starting material: Compound 6-5, yield: 56% in 2 steps. 1 H NMR(300MHz,DMSO)d 8.50-8.63(m,2H),8.26-8.47(m,1H),7.74-7.84(m,2H),7.47-7.64(m,2 H),7.16-7.42(m,5H),4.51-4.86(m,2H),3.99(s,3H),2.92-2.99(m,3H).

[0198] General procedure for the synthesis of compounds 43 and 44: Under nitrogen, compound 6-5 (1.0 equivalent), t-BuBrettphos (0.132 equivalents), Pd2(dba)3 (0.03 equivalents), and potassium carbonate (1.4 equivalents) were mixed in a sealed tube. Then, compound 6-B or compound 6-E (1.0 equivalent), followed by anhydrous t-BuOH (0.1 M), was introduced. The reaction mixture was then degassed and refilled three times with nitrogen. The reaction mixture was then sealed and heated overnight at 100°C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was then washed with water and brine. The organic layer was dried and the solvent was removed under reduced pressure. The residue was then purified by ISCO to obtain the desired product.

[0199] Compound 43, off-white solid, yield: 71%. 1 H NMR(300 MHz,chloroform-d)d 8.60(d,J=5.27 Hz,3H),8.18(s,1H),8.10(s,1H),7.93(d,J=2.26 Hz,1H),7.56-7.80(m,5H),7.35-7.55(m,3H),7.32(br.s.,2H),7.06(s,3H),4.80(br.s.,2H),4.26(t,J=5.18 Hz,2H),4.01(br.s.,3H),3.88(t,J=5.18 Hz,2H),2.94-3.18(m,3H),2.39(s,3H).

[0200] Compound 44, off-white solid, yield: 68%. 1 H NMR(300MHz,CDCl3)d 10.42(br.s.,1H),8.47-8.74(m,2H),7.75-8.43(m,1H),7.29-7.74(m,8H),6.78-7.26(m,8H),4.30- 5.09(m,3H),3.62-4.03(m,3H),3.45-3.62(m,2H),3.37(br.s.,2H),2.86-3.19(m,3H),2.31(s,3H).

[0201] Synthesis of compound 7-A: 5-bromo-2-methoxybenzenesulfonyl chloride (2.85 g, 10.0 mmol) was dissolved in acetonitrile (25 mL), and ammonium hydroxide solution (4 mL) was added at 0°C. The reaction mixture was then heated to room temperature and stirred for 2 hours. Water (50 mL) was added, and the white precipitate was collected by filtration and dried in the air overnight.

[0202] Compound 7-A, 2.66 g, white solid, yield: 100%. 1 H NMR(300 MHz, methanol-d4)d 7.91(d,J=2.45 Hz,1H),7.69(dd,J=2.64,8.85 Hz,4H),7.14(d,J=8.85 Hz,2H),3.87-4.03(m,6H).

[0203] General procedure for the synthesis of compound 7-5: Compound 7-A (1.0 equivalent) was suspended in anhydrous benzene (0.8 M), and the corresponding substituted methylmalonyl chloride (1.0 equivalent) was added. The mixture was then refluxed overnight. The solvent was then removed, and the residue (compound 6-2) was used in the next step without further purification.

[0204] Compound 7-1 (1.0 equivalent) was dissolved in a mixture of MeOH / THF / water (v / v / v = 15:5:3, 0.2 M), and LiOH·H2O (6.0 equivalents) was added. The reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was quenched with 2N HCl (10 equivalents), and the reaction mixture was extracted with ethyl acetate. The organic layer was then separated and dried. The solvent was removed under reduced pressure to obtain a typically white solid (compound 7-2), which was used in the next step without further purification.

[0205] Compound 7-2 (1.0 equivalent) was suspended in DCM (0.1 M), and 1,1'-carbonyldiimidazole (1.0 equivalent) was added. The reaction mixture was stirred at room temperature for 1 hour until homogeneous. Then, N-Boc-ethylenediamine (1.2 equivalents) was added all at once, and the reaction mixture was stirred overnight. The reaction mixture was quenched with 1N HCl (10 equivalents), and the reaction mixture was extracted with ethyl acetate. The organic layer was then separated and dried. The solvent was removed under reduced pressure to obtain intermediate 7-3, which was treated with 4N HCl in dioxane (20 equivalents) for 30 minutes. Then, the solvent was removed to obtain intermediate 7-4, which was used in the next step without further purification.

[0206] 3-Methylbenzoic acid (1 equivalent) and 1,1'-carbonyldiimidazole (1 equivalent) were mixed in DCM (0.1 M) and stirred for 15 minutes. Intermediate 7-4 from the last step was suspended in DCM (0.1 M) and the reaction mixture described above was added dropwise. The reaction mixture was then stirred overnight at room temperature. The reaction mixture was quenched by adding 1N HCl (10 equivalents) and extracted with ethyl acetate. The organic layer was then separated and dried. The solvent was removed under reduced pressure to obtain compound 7-5.

[0207] Intermediate 7-5-1 of compounds 47 and 48, yield: 21% in 5 steps. 1H NMR(300 MHz, methanol-d4)d 8.00(d,J=2.45 Hz,1H),7.73(dd,J=2.54,8.95 Hz,1H),7.51-7.64(m,2H),7.25-7.39(m,2H),7.12(d,J=8.85 Hz,1H),3.87-3.98(m,3H),3.45(d,J=5.84 Hz,2H),3.39(d,J=5.46 Hz,2H),3.20-3.27(m,2H),2.39(s,3H).

[0208] Intermediate 7-5-2 of compounds 49 and 50: Yield: 19% in 5 steps. 1 H NMR(300 MHz, methanol-d4)d 7.93-8.02(m,1H),7.74(dd,J=2.54,8.95 Hz,1H),7.51-7.66(m,2H),7.34(d,J=5.65 Hz,2H),7.11(d,J=9.04 Hz,1H),3.85-3.97(m,3H),3.45-3.56(m,2H),3.43(d,J=5.65 Hz,2H),2.29-2.43(m,3H),1.38-1.54(m,4H).

[0209] Intermediate 7-5-3 of compounds 53 and 54: Yield: 25% in 5 steps. 1 H NMR(300 MHz, methanol-d4)d 7.82(d,J=2.64 Hz,1H),7.56-7.75(m,3H),7.27-7.40(m,2H),7.16(d,J=8.85 Hz,1H),4.01(s,3H),3.51-3.60(m,2H),3.33-3.41(m,2H),2.38(s,3H),1.80(br.s.,4H),1.32(d,J=17.52 Hz,4H),1.17(br.s.,2H).

[0210] Compounds 47, 48, 49, 50, 53, and 54 were synthesized according to the general procedure for sequential Miyaura borylation and Suzuki coupling reactions using compounds 7-5 as starting materials: Compound 47, yield: 70% in 2 steps. 1H NMR(300 MHz,クロロホルム-d)d 8.19(m,1H),7.72(d,J=7.54 Hz,2H),7.50-7.67(m,6H),7.42(m,1H),7.34(m,1H),7.20(m,1H),7.01(d,J=8.67 Hz,2H),3.91(s,3H),3.51(br.s.,2H),3.41(br.s.,2H),3.23(m,2H),3.07-3.14(m,3H),2.98(m,3H),2.33(m,3H).

[0211] Compound 48. Yield: 2ステップで61%. 1 H NMR(300 MHz,メタノール-d4)d 8.49-8.60(m,2H),8.10-8.28(m,1H),7.84-7.96(m,1H),7.61(s,10H),7.27(s,4H ),4.42-4.79(m,2H),3.99(s,3H),3.65-3.78(m,1H),3.43(s,2H),3.39(d,J=5.46 Hz,2H),3.17-3.26(m,1H),3.03(br.s.,3H),2.34(s,3H).

[0212] Compound 49, yield: 2 ステップで65%. 1 H NMR(300 MHz,メタノール-d4)d 8.13-8.21(m,1H),7.82-7.93(m,1H),7.69-7.76(m,2H),7.62-7.68(m,2H),7.56-7.61(m,1H),7.51-7.55(m,1H),7.36-7.44 (m,1H),7.33(s,1H),7.20-7.29(m,1H),3.93(s,3H),3.40-3.55(m,4H),3.13(s,3H),3.03(s,3H),2.37(s,3H),1.43(s,4H).

[0213] Compound 50, yield: 2ステップで58%. 1H NMR(300 MHz,メタノール-d4)d 8.46-8.61(m,2H),8.10-8.25(m,1H),7.69-7.94(m,3H),7.54-7.67(m,3H),7.41-7.53(m,2H),7.27-7.40(m,3H),7 .06-7.27(m,1H),4.52-4.80(m,2H),3.91(s,3H),3.42-3.56(m,4H),3.02-3.14(m,3H),2.35(s,3H),1.31(d,J=6.59 Hz,4H).

[0214] Compound 53. Yield: 2ステップで76%. 1 H NMR(300 MHz,クロロホルム-d)d 8.04(d,J=2.26 Hz,1H),7.74-7.82(m,1H),7.62-7.72(m,3H),7.53-7.60(m,2H),7.46-7.51(m,1H),7.43(s,1H),7.34(d,J=7.72 Hz,2H),7.13(d,J=8.85 Hz,1H),7.04-7.10(m,1H),5.50(s,1H),4.09(s,3H),3.63(br.s.,2H),3.40(br.s.,2H),3.14(b r.s.,3H),3.02(br.s.,3H),2.34(s,3H),1.84(br.s.,4H),1.46(br.s.,4H),0.83-0.93(m,2H).

[0215] Compound 54. Yield: 2ステップで69%. 1 H NMR(300 MHz,クロロホルム-d)d 8.62(d,J=5.46 Hz,2H),7.90-8.11(m,1H),7.52-7.87(m,5H),7.30-7.52(m,3H),7.28-7.30(m,1H),7.25(br.s.,2H),7.10(d,J=16.58 Hz,3H),5.52(s,1H),4.47-4.85(m,2H),4.09(s,3H),3.64(br.s.,2H),3.43(br.s.,2H ),2.98(br.s.,3H),2.34(s,3H),1.72-1.99(m,4H),1.45(br.s.,4H),1.05(br.s.,2H).

[0216] General procedure for the synthesis of compounds 45, 46, 51, and 52: 3-Methylbenzoic acid (1 equivalent) was dissolved in DCM (0.1 M), and 1,1'-carbonyldiimidazole (1.0 equivalent) was added. The reaction mixture was then stirred at room temperature for 15 minutes, after which N-Boc-ethylenediamine (1.2 equivalents) was added. The reaction mixture was stirred overnight. The reaction mixture was quenched with 1N HCl (10 equivalents), and the reaction mixture was extracted with ethyl acetate. The organic layer was then separated and dried. The solvent was removed under reduced pressure to obtain intermediate 7-B, which was treated with 4N HCl in dioxane (20 equivalents) to obtain intermediate 7-C.

[0217] N-Boc-amino acids with alkyl chains of different lengths (1.0 equivalent) were dissolved in DCM (0.1 M), and 1,1'-carbonyldiimidazole (1.0 equivalent) was added. The reaction mixture was then stirred at room temperature for 15 minutes, after which intermediate 7-C from the last step, followed by DIPEA (3.0 equivalents), was added. The reaction mixture was stirred overnight. The reaction mixture was quenched with 1N HCl (10 equivalents), and the reaction mixture was extracted with ethyl acetate. The organic layer was then separated and dried. The solvent was removed under reduced pressure to obtain intermediate 7-D, which was treated with 4N HCl (20 equivalents) in dioxane to obtain intermediate 7-E or 7-F.

[0218] At 0°C, intermediate 7-E or 7-F (1 equivalent) was suspended in DCM (0.1 M), and triethylamine (4.0 equivalents) was added. Then, catalyst DMAP (0.4 equivalents) was introduced. At this temperature, 5-bromo-2-methoxybenzenesulfonyl chloride (1.0 equivalent) in THF (10 mL) was slowly added. The reaction mixture was then stirred at this temperature for 1 hour and warmed to room temperature overnight. The reaction mixture was quenched by adding saturated sodium bicarbonate (50 mL), and the reaction mixture was extracted with ethyl acetate (50 mL). The organic layer was separated and dried. The solvent was removed under reduced pressure, and the residue was subjected to ISCO to obtain the desired product 7-7.

[0219] Intermediate 7-7-1 of compounds 51 and 52: Yield: 25% in 5 steps.1 H NMR(300 MHz, methanol-d4)d 7.93-8.02(m,1H),7.74(dd,J=2.54,8.95 Hz,1H),7.51-7.66(m,2H),7.34(d,J=5.65 Hz,2H),7.11(d,J=9.04 Hz,1H),3.85-3.97(m,3H),3.45-3.56(m,2H),3.43(d,J=5.65 Hz,2H),2.29-2.43(m,3H),1.38-1.54(m,4H).

[0220] Intermediate 7-7-2 of compounds 45 and 46: Yield: 28% in 5 steps. 1 H NMR(300 MHz, methanol-d4)d 7.82(d,J=2.64 Hz,1H),7.56-7.75(m,3H),7.27-7.40(m,2H),7.16(d,J=8.85 Hz,1H),4.01(s,3H),3.51-3.60(m,2H),3.33-3.41(m,2H),2.38(s,3H),1.80(br.s.,4H),1.32(d,J=17.52 Hz,4H),1.17(br.s.,2H).

[0221] Compounds 45, 46, 51, and 52 were synthesized according to the general procedure for sequential Miyaura borylation and Suzuki coupling reactions using intermediates 7-7 as starting materials: Compound 45, yield: 60% in 2 steps. 1 ¹H NMR (300 MHz, chloroform-d) d 8.10 (d, J=2.26 Hz, 1H), 7.75 (dd, J=2.35, 8.57 Hz, 1H), 7.50-7.65 (m, 4H), 7.40-7.50 (m, 1H), 7.37 (d, J=7.54 Hz, 1H), 7.29 (d, J=4.33 Hz,2H),7.00-7.14(m,2H),6.61(br.s.,1H),5.91(t,J=6.40 Hz,1H),3.95-4.03(m,3H),3.57(br.s.,2H),3.46(d,J=5.09 Hz,2H),2.95-3.26(m,8H),2.32-2.47(m,5H).

[0222] Compound 46, yield: 70% in 2 steps. 1 H NMR(300 MHz,chloroform-d)d 8.61(br.s.,2H),8.12(br.s.,1H),7.36-7.85(m,7H),7.29(d,J=4.71 Hz,3H),6.94-7.20(m,3H),6.56(br.s.,1H),5.91(br.s.,1H),4.49-4.86(m,2H), 4.00(s,3H),3.59(br.s.,2H),3.49(br.s.,2H),2.93-3.25(m,5H),2.42(t,J=5.65 Hz,2H),2.37(s,3H).

[0223] Compound 51, yield: 62% in 2 steps. 1 H NMR(300 MHz,chloroform-d)d 8.07(d,J=2.26 Hz,1H),7.73-7.82(m,1H),7.62(s,1H),7.50-7.59(m,3H),7.44(s,1H),7.36(s,1H),7.29(br.s.,1H),7.14-7.23(m,1H),7.10(d,J=8.67 Hz,3H),5.78(s,1H),4.02(s,3H),3.57(d,J=5.84 Hz,4H),3.45(br.s.,2H),2.95-3.18(m,6H),2.37(s,3H).

[0224] Compound 52, yield: 68% in 2 steps. 1 H NMR(300 MHz,chloroform-d)d 8.61(br.s.,2H),7.70-8.18(m,2H),7.52-7.68(m,4H),7.42(br.s.,3H),7.17(br.s.,4H),5.81 (s,1H),4.51-4.84(m,2H),4.01(br.s.,3H),3.40-3.65(m,6H),2.91-3.20(m,3H),2.37(s,3H).

[0225] General procedure for the synthesis of compounds 33, 34, 35, and 36: 3-Methylbenzoic acid (1 equivalent) and 1,1'-carbonyldiimidazole (1 equivalent) were mixed in DCM (0.1 M) and stirred for 15 minutes. Cycloamine alcohols of different sizes (1 equivalent) were added, and the reaction mixture was stirred overnight. The reaction mixture was quenched with 1N HCl (10 equivalents), and the reaction mixture was extracted with ethyl acetate. The organic layer was then separated and dried. The solvent was removed under reduced pressure to obtain intermediate 8-A, which was used in the next step without further purification.

[0226] Intermediate 8-A (1 equivalent) was dissolved in DMF (0.25 M), and the solution was cooled to 0°C. NaH (60% of the oil, 1.2 equivalents) was added in several portions at a rate that did not exceed 10°C internally. After stirring at 0°C for 30 minutes, 3-bromo-5-fluoropyridine (1.0 equivalent) in DMF (0.5 M) was added dropwise, and the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with water, and ethyl acetate was added. The organic layer was then separated and dried. The solvent was removed under reduced pressure to obtain a viscous oil, which was purified by ISCO to obtain the desired product.

[0227] Intermediate 8-B-1 of compound 56, yield: 53% in 2 steps. 1 H NMR(300 MHz,chloroform-d)d 8.35(d,J=1.88 Hz,1H),8.12(d,J=2.45 Hz,1H),7.47(s,1H),7.40(d,J=3.96 Hz,1H),7.28-7.35(m,2H),7.23(t,J=2.17 Hz,1H),4.95-5.08(m,1H),4.63(dd,J=6.50,10.08 Hz,2H),4.31(br.s.,2H),2.39(s,3H).

[0228] Intermediate 8-B-2 of compound 57, yield: 52% in 2 steps. 1¹H NMR (300 MHz, chloroform-d) d: 8.28-8.37 (m,1H), 8.12-8.28 (m,1H), 7.27-7.42 (m,4H), 7.19-7.26 (m,1H), 4.86-5.08 (m,1H), 3.55-4.09 (m,4H), 2.33-2.43 (m,3H), 2.06-2.31 (m,2H).

[0229] Intermediate 8-B-3 of compound 58, yield: 60% in 2 steps. 1 H NMR(300 MHz,CDCl3)d 8.03-8.36(m,2H),7.20(br.s.,5H),4.32(br.s.,2H),3.59(br.s.,3H),2.32(br.s.,3H),1.98(br.s.,4H).

[0230] Compound 8-2 was synthesized according to a general procedure for sequential Miyaura borylation and Suzuki coupling reactions using compound 7-A as the starting material: Compound 8-2, off-white solid, yield: 93% in 2 steps. 1 1H NMR (300 MHz, chloroform-d)d 8.46-8.63 (m, 2H), 7.87-8.10 (m, 2H), 7.64-7.81 (m, 2H), 7.42-7.61 (m, 2H), 7.24-7.41 (m, 3H), 7.03-7.22 (m, 2H), 4.64-4.79 (m, 1H), 4.45-4.63 (m, 1H), 3.95 (s, 3H), 2.83-3.02 (m, 3H).

[0231] General procedure for the synthesis of compounds 55, 56, 57, and 58: Compound 8-2 (1 equivalent) was placed in a sealed tube. tBuXphos (0.1 equivalent), followed by compound 6-C or compound 8-B (1 equivalent), was introduced. Cesium carbonate (2.4 equivalents) was then added, followed by injection of 1,4-dixoane (0.1 M). The mixture was then degassed and refilled three times with nitrogen. Pd2(dba)3 (0.05 equivalents) was then added. The tube was then sealed and heated to 100°C overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was then washed with water and brine. The organic layer was dried, and the solvent was removed under reduced pressure. The residue was purified by ISCO to obtain the desired product: Compound 55, yield: 62%. 1 ¹H NMR (300 MHz, chloroform-d) d 8.62 (d, J=6.03 Hz, 2H), 8.04 (d, J=2.64 Hz,2H),7.85(d,J=2.07 Hz,1H),7.78(s,1H),7.49-7.63(m,4H),7.35-7.48(m,2H),7.29(br.s.,2 H),6.99-7.22(m,3H),6.75-6.91(m,1H),4.49-4.80(m,2H),4.13(t,J=6.0 Hz,2H),4.07(br.s.,3H),3.83(dd,J1=6.0 Hz,J2=3.0 Hz,2H),2.91-.3.15(m,3H),2.37(s,3H).

[0232] Compound 56, yield: 78%. 1 H NMR(300 MHz,chloroform-d)d 8.64(m,2H),7.66-8.15(m,4H),7.29-7.65(m,7H),7.01-7.26(m,6H),4.69-5.04(m,2H),4.53(br.s.,1H),4.0 1-4.18(m,3H),3.83-3.99(m,1H),3.51-3.80(m,4H),2.88-3.20(m,3H),2.28-2.40(m,3H),2.07-2.24(m,2H).

[0233] Compound 57, yield: 59%.

[0234] 1¹H NMR (300 MHz, chloroform-d) d 8.62 (d, J=5.65) Hz,2H),7.65-8.15(m,4H),7.30-7.64(m,5H),6.90-7.25(m,8H),4.50-4.85(m,2H),4.25 -4.40(m,1H),4.09(br.s.,3H),3.30-3.70(m,3H),2.88-3.15(m,3H),2.05-2.45(m,7H).

[0235] Compound 58, yield: 69%. 1 H NMR(300 MHz,chloroform-d)d 8.62(d,J=5.09 Hz,2H),7.94-8.09(m,1H),7.90(s,2H),7.33-7.82(m,9H),7.28-7.32(m,2H),6.68-7.20(m,3H),4.98(br.s.,1H),4. 77(br.s.,1H),4.57(br.s.,3H),4.30(br.s.,1H),4.19(br.s.,1H),4.07(br.s.,3H),2.91-3.20(m,3H),2.37(s,3H).

[0236] Compound 59 was synthesized according to a general procedure for a sequential Miyaura borylation and Suzuki coupling reaction using compounds 3-6 as starting materials (compound 38 can also be obtained by this procedure): Compound 59 (RTIOX-45), yield: 58% in 2 steps. 1 1H NMR (300 MHz,Chloroform-d)d 8.61(d,J=6.41 Hz,1H),8.56(d,J=6.03 Hz,1H),8.33(d,J=2.26 Hz,1H),8.13-8.19(m,0H),7.64-7.87(m,3H),7.61(d,J=6.59 Hz,1H),7.56(br.s.,1H),7.50(br.s.,1H),7.31(d,J=6.03 Hz,1H),7.09(d,J=8.85 Hz,0H),6.89-7.00(m,2H),6.84(d,J=8.85 Hz,1H),6.49(d,J=13.37 Hz,1H),6.33(d,J=8.48 Hz,1H),6.24-6.30(m,1H),4.77(d,J=18.08 Hz,2H),4.05(d,J=19.78 Hz,3H),3.59(dd,J=5.75,11.77 Hz,2H),3.25(dd,J=5.56,10.46 Hz,2H),3.12(d,J=7.35 Hz,3H),2.36(d,J=2.07 Hz,3H)

[0237] General procedure for the synthesis of 60 and 61: Compound 7-A (1 equivalent) and compound 6-B (1 equivalent) were mixed in a sealed tube. Then, tBuXphos (0.1 equivalent) and cesium carbonate (2.4 equivalents) were added, followed by injection of 1,4-dioxane (0.1 M). The mixture was then degassed and refilled three times with nitrogen. Then, Pd2(dba)3 (0.05 equivalent) was added. The tube was then sealed and heated to 110°C overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was then washed with water and brine. The organic layer was dried and the solvent was removed under reduced pressure. The residue was redissolved in DCM, and the solution was passed through a short silica gel to obtain a clear solution. The solvent was then removed under reduced pressure to obtain crude intermediate 9-1, which was used in the next step without further purification.

[0238] The synthesis of compounds 60 and 61 was achieved by following a general procedure for sequential Miyaura borylation and Suzuki coupling reactions using compound 9-1 as the starting material: Compound 60 (RTIOX-46), yield: 48% in 3 steps.1 H NMR (300) MHz,クロロホルム-d)d 8.57(d,J=6.0 Hz,1H),8.500(dd,J 1= 129.0 Hz, J 2= 3.0 Hz, 1H), 8.495 (dd, J) 1= 129.0 Hz, J 2= 3.0 Hz, 1H), 8.05 (ddd, J) 1= 141.0 Hz, J 2= 9.0 Hz, J 3= 3.0 Hz,1H),7.98-7.89(m,1H),7.89-7.83(m,1H),7.63-7.53(m,5H),7.47(d,J=3.0 Hz,1H),7.40(d,J=3.0 Hz,1H),7.37-7.29(m,2H),7.17(dd,J 1= 69.0 Hz, J 2= 9.0 Hz, 1H), 6.89 (dd, J) 1= 12.0 Hz, J 2= 3.0 Hz,1H),4.00(d,J=14.13 Hz,3H),3.42(br,2H),3.21(br,2H),3.12(d,J=2.64 Hz,3H),2.37(s,3H).

[0239] Compound 61 (RTIOX-47), yield: 3ステップで52%. 1 H NMR (300) MHz,メタノール-d4)d 8.50-8.58(m,2H),7.99-8.15(m,1H),7.79-7.90(m,1H),7.77(s,1H) ,7.65-7.70(m,1H),7.60(br.s.,5H),7.38-7.49(m,2H),7.32(s,3H), 7.12-7.24(m,1H),6.83-6.94(m,1H),4.25-4.75(m,2H),4.00(s,3H), 3.44-3.52(m,2H),3.18-3.29(m,2H),2.95-3.15(m,4H),2.38(s,3H).

[0240] examples of biology OX1R and OX2R カルシウムmobilization アッセイ. The activity of target compounds in human OX1 and OX2 receptors was determined using CHO RD-HGA16 cells (Molecular Devices) engineered to stably express either human OX1 or human OX2 receptor. Cells were maintained in Ham's F12 supplemented with 10% fetal bovine serum, 100 units of penicillin and streptomycin, and 100 μg / mL normocin®. For the assay, cells were seeded at 25,000 cells / well and incubated overnight at 37°C and 5% CO2. The following day, cells were washed with assay buffer and loaded with Calcium 5 dye (Molecular Devices). After 45 minutes, cells were pre-treated with 9% DMSO solution for 15 minutes. Our group found that this pre-treatment incubation period significantly reduced the DMSO-mediated increase in fluorescence. The test compounds (8-point concentration response curves) were then added to 1% DMSO solution while measuring fluorescence using FlexStation II. In this assay platform, receptor activation is measured by an increase in fluorescence, which is directly proportional to the increase in internal calcium. Test compound EC 50 The values ​​are determined by nonlinear regression analysis, and the values ​​are the mean ± SEM of at least three independent experiments that were performed overlappingly.

[0241] Efficacy in OX1R and OX2R calcium mobilization assays. All synthesized compounds were characterized for their agonist efficacy in a calcium mobilization assay using CHO cells overexpressing either OX1R or OX2R. For details of such assays, refer to German, NA; Decker, AM; Gilmour, BP; Thomas, BF; Zhang, Y., Truncated Orexin Peptides: Structure-Activity Relationship Studies. ACS medicinal chemistry letters 2013, 4(12), 1224-1227. EC 50 These are listed in Tables 1-12.

[0242] Structural-activity analysis was performed to determine if a pattern was available in the left-hand terminal aromatic ring of the compound being described. Substitution of dimethylaminoamide with several other alkylamides did not result in any improvement in potency. Removal of the carbonyl functional group resulted in complete loss of activity, confirming its importance for orexin receptor activation. Table 1. [ka] [Table 2]

[0243] The aromatic amide and ethyl group at the rightmost end were examined. Methyl substituents on the ethyl group slightly reduced potency in both acceptors. Extension of the ethyl group to a 3-carbon propyl group resulted in little change in potency. 3-methylphenyl appeared to provide better potency in both OX1R and OX2R and was therefore used in subsequent SAR studies. All activity was lost when the ethyl group was converted to a rigid piperazine group. Table 2. [ka] [Table 3]

[0244] The first phenyl ring on the left was replaced with a series of aromatic rings. In one embodiment, 2,6-substituted pyridyl improved potency in both OX1R and OX2R. Two five-membered rings, thiazole and oxazole, were examined and showed significantly lower potency. Ethylene and ethyl analogs were inactive in both acceptors. SAR table 3: [ka] [Table 4]

[0245] The central phenyl ring was examined and replaced with a pyridyl group. 3,5-pyridyl showed low potency with OX2R but equal potency with both acceptors. This suggests that the nitrogen on this 3,5-pyridyl may have a favorable interaction with OX1R. Additionally, the introduction of nitrogen reduces the electron density of the aromatic ring, which may make it less susceptible to oxidation and thus result in better PK properties. SAR table 4: [ka] [Table 5]

[0246] Considering the importance of the carbonyl group in the amide functional group on the left, we retained the amide and explored further substitutions at this position. Replacing the methyl group on the amide with a dimethylaminoethyl group improved solubility by providing a site for salt formation with the dimethylamino group. However, a slight reduction in potency was observed. In particular, the removal of other methyl groups on the nitrogen resulted in a sharp decrease in potency in OX2R (31 vs. 32) and complete loss of potency in OX1R. The introduction of a pyridyl or benzyl group in place of the methyl group on the dimethylamino group led to a significant decrease in potency in both receptors, with little activity in OX1R. However, when a 2-pyridylmethyl group was introduced, a reversal of potency was achieved, exhibiting similar potency to compound 1 (YNT-185) in both OX1R and OX2R. This suggests that this may be due to hydrogen bonding or polarity interactions between pyridyl and the OX receptor. Similarly, the removal of other methyl groups on the dimethylamino group again led to complete loss of potency in OX1R (35 vs. 36). Next, we investigated different pyridylmethyl groups. While 3-pyridylmethyl showed a slight decrease in potency, interestingly, compound 38, containing 4-pyridylmethyl, exhibited significantly stronger, higher, and equal potency than compound 1 (YNT-185) in both OX1R and OX2R. Substitution of pyridylmethyl with a longer pyridylethyl group proved to have no improvement in potency (compounds 39 and 40). SAR table 5: [ka] [Table 6]

[0247] Sulfonamide functionality was shown to be important for activity, as confirmed by 41, which was inactive with OX1R and had micromolar potency with OX2R. The pyridylmethyl group in the amide significantly increased OX1R and OX2R, but did not restore potency. We then considered substituting with 1,3,4-thiadiazole, which can be considered a bioequivalent of the amide or sulfonamide. However, both compounds (43 and 44) ​​were inactive. This further confirms the importance of sulfonamide for obtaining activity at the orexin receptor. SAR table 6: [ka] [Table 7]

[0248] Next, we investigated whether flexibility could be introduced to this region by replacing the central phenyl group connected to the sulfonamide nitrogen with an alkyl or dicarbonyl group. However, these compounds were mostly inert. SAR table 7: [ka] [Table 8]

[0249] The ethyl linker was shown to be important for activity (Table 2). Since a preferred pyridylmethyl group is present, we re-examined this region. We first replaced the nitrogen with an oxygen atom, which resulted in an approximately 20-fold reduction in potency in both OX1R and OX2R. When an aliphatic ring was introduced for greater flexibility, these analogues did not result in improved potency, although 56 had similar potency to 38 in OX2R. SAR table 8: [ka] [Table 9]

[0250] Finally, we synthesized several analogues combining unexpected key structural elements that resulted in improved potency at the orexin receptor, particularly OX1R (Table 9). These key elements include, but are not limited to, (1) 4-pyridyl at Ar1, which is essential for OX1 activity; (2) 2,6-pyridyl at Ar2, which is preferred for improved potency at both OX1R and OX2R; and (3) 3,5-pyridyl at Ar3, which may help improve metabolic stability by reducing electron density. Of all the analogues, in one embodiment, compound 61 (RTIOX-47) was demonstrated to have preferred overall properties. SAR table 9: [ka] [Table 10]

[0251] Three of the most potent compounds were evaluated for their ADME properties. At pH 2, all compounds were in salt form and exhibited excellent aqueous solubility. Compounds 1 (YNT-185), RTIOXA-43, and RTIOXA-45 showed moderate metabolic stability in rat liver microsomes (RLMs), while RTIOXA-47 showed a significantly improved half-life (t 1 / 2 The results showed that the main structural difference in RTIOXA-47, compared to the other three compounds, is the pyridyl group attached to the sulfonamide. The pyridyl substitution of the phenyl group reduced the electron density of this aromatic ring. One hypothesis from the inventors is that this may have resulted in reduced susceptibility to metabolic oxidation. [Table 11] SAR Table 11: [ka] [Table 12] SAR Table 12: [ka] [Table 13]

[0252] analysis YNT-185 was one of the first small molecule orexin agonists reported. YNT-185 primarily activates OX2R with minimal agonist activity at OX1R. Through extensive SAR studies across multiple sites, this disclosure demonstrates several OX1R / OX2R dual agonists, including RTIOX-47. These are the first and only small molecule dual orexin agonists discovered to date. In addition to superior agonist potency at both orexin receptors, RTIOX-47 also demonstrated significantly improved metabolic stability when compared to YNT-185.

[0253] The specific pharmacological responses observed may vary depending on and in accordance with the presence of a particular active compound or pharmaceutical carrier selected, as well as the type of formulation and method of administration used, and such expected variations or differences in the results are contingent upon implementation of this disclosure.

[0254] Specific embodiments of the Disclosure are illustrated and described in detail herein, but the Disclosure is not limited thereto. The above detailed descriptions are provided as examples of the Disclosure and should not be construed as constituting any limitation of the Disclosure. Modifications will be obvious to those skilled in the art, and all modifications that do not deviate from the spirit of the Disclosure are intended to be included in the appended claims. The present invention provides, for example, the following items: (Item 1) Compound of formula (I), [ka] or a pharmaceutically acceptable salt thereof During the ceremony, A, C 2-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkynylene, phenylene, or a divalent 4-7 membered cycloalkyl or heterocyclyl ring having one or more degrees of unsaturation and containing 1-3 heteroatoms selected from the group consisting of O, N, or S, B is C 2-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkynylene, phenylene, or a divalent 4-7 membered cycloalkyl or heterocyclyl ring having one or more degrees of unsaturation and containing 1-3 heteroatoms selected from the group consisting of O, N, or S, X is either O or NH, R 1 However, (CH2) m -It is a heteroaryl compound, m is 0, 1, 2, 3, 4, 5, or 6. R 2 However, hydrogen or C 1-6 It is alkyl, X is a bond, O, C(O), NH, NHC(O), or C(O)NH. Y is bonded, C 2-6 Alkilen, C 2-6 Alkenylene, C 2-6 Alkynylene, a divalent 4-7 membered cycloalkyl ring having one or more degrees of unsaturation, or a divalent 4-7 membered heterocyclyl ring having one or more degrees of unsaturation and containing 1-3 heteroatoms selected from the group consisting of O, N, or S, Z is a bond, O, C(O), NH, NHC(O), or C(O)NH. R 3 However, C 1-10 Alkyl, C 2-10 Alkenil, C 2-10 Alkinyl, (CH2) n -C 3-6 Cycloalkyl, (CH2) n - Phenyl, (CH2) n - Naphthyl, or (CH2) n -(4-7 membered heterocyclyl ring) (where such a ring optionally has one or more degrees of unsaturation and contains 1 to 3 heteroatoms selected from the group consisting of O, N, or S), Each R 3 However, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2,CN,NO2,OH,O(C 1-6 Alkyl), SH, S(C 1-6 It may be substituted with one or more substituents selected from alkyl and =O. A compound, or a pharmaceutically acceptable salt thereof, in which each n is independently 0, 1, 2, or 3. (Item 2) R 1 However, (CH2) m - A compound that is pyridyl, as listed in item 1. (Item 3) The compound listed in item 2, where m is 1. (Item 4) R 2 However, C 1-6 A compound that is alkyl, as described in item 1 or 2. (Item 5) R 2 However, it is a compound listed in item 4, which is CH3. (Item 6) A compound listed in any one of items 1 to 5, wherein A is phenylene. (Item 7) A compound listed in any one of items 1 to 6, wherein B is phenylene. (Item 8) A compound listed in any one of items 1 to 6, wherein B is divalent pyridyl. (Item 9) A compound listed in any one of items 1 to 8, wherein X is NH. (Item 10) A compound listed in any one of items 1 to 8, wherein X is O. (Item 11) Y, C 2-6 A compound that is alkylene, as described in any one of items 1 to 10. (Item 12) A compound listed in item 11, wherein Y is CH2CH2. (Item 13) A compound according to any one of items 1 to 10, wherein Y is a divalent 4-7 membered heterocyclyl ring having one or more degrees of unsaturation and containing 1 to 3 heteroatoms selected from the group consisting of O, N, or S. (Item 14) The compound according to item 13, wherein the heterocyclyl ring contains at least one N atom. (Item 15) A compound listed in any one of items 1 to 14, wherein Z is NHC(O). (Item 16) A compound listed in any one of items 1 to 14, wherein Z is C(O). (Item 17) A compound described in any one of items 1 to 8, wherein X, Y, and Z are each bonds. (Item 18) R 3 However, C 1-10 Alkyl, (CH2) n -C 3-6 Cycloalkyl, or (CH2) n A compound according to any one of items 1 to 17, wherein each n is independently 0, 1, 2, or 3. (Item 19) R 3The compounds listed in item 18, which are C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, CH2CH3, or CH3. (Item 20) R 3 The compounds listed in item 19, which are C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, or C5 alkyl. (Item 21) R 3 However, (CH2) n -C 3-6 A cycloalkyl compound, as described in item 18. (Item 22) R 3 However, (CH2) n -C 5-6 A cycloalkyl compound, as described in item 21. (Item 23) R 3 The compounds listed in item 22, which are (CH2)1-C6 cycloalkyl, (CH2)2-C6 cycloalkyl, or (CH2)3-C6 cycloalkyl. (Item 24) R 3 However, (CH2) n -The compound listed in item 18, which is phenyl. (Item 25) The compounds listed in item 24, where n is 0. (Item 26) R 3 However, C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 2-6 Haloalkenil, C 2-6 Haloalkynyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2,CN,NO2,OH,O(C 1-6 Alkyl), SH, S(C 1-6 A compound according to any one of items 1 to 25, substituted with one or more substituents selected from alkyl and =O. (Item 27) R 3 However, one or more C 1-6 Compounds listed in item 26 that are substituted with alkyl. (Item 28) A compound selected from a group consisting of one or more examples. (Item 29) A pharmaceutical composition comprising a compound described in any one of items 1 to 28 and one or more pharmaceutically acceptable excipients. (Item 30) A method for treating a disease or disorder in a subject caused by reduced orexin activity, comprising administering an effective amount of any one of items 1 to 28. (Item 31) The method according to item 30, wherein the disease or disorder is one or more of the following: sleep disorders, narcolepsy, cataplexy, regulation of sleep states, apnea, regulation of wakefulness, sleep-wake cycling, enhanced recovery from anesthesia, jet lag, regulation of appetite, regulation of eating, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, clarity, cognitive impairment, Alzheimer's disease, attention deficit, dementia, mild cognitive impairment, Parkinson's disease, cognitive dysfunction, brain injury, cognitive impairment, blood pressure regulation, ischemic events, oxidative stress events, and cancer. (Item 32) Use of any one of items 1 to 28 for the preparation of a pharmaceutical product for the treatment of a disease or disorder in a subject caused by reduced orexin activity, including administration of an effective amount of the compound. (Item 33) Use as described in item 32, where the disease or disorder is one or more of the following: sleep disorders, narcolepsy, cataplexy, insomnia, regulation of sleep states, apnea, regulation of wakefulness, sleep-wake cycling, enhanced recovery from anesthesia, jet lag, regulation of appetite, regulation of eating, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, clarity, cognitive impairment, Alzheimer's disease, attention deficit, dementia, mild cognitive impairment, Parkinson's disease, cognitive dysfunction, brain injury, cognitive impairment, addiction, drug addiction, blood pressure regulation, ischemic events, oxidative stress events, and cancer. (Item 34) A compound described in any one of items 1 to 28 for use as an active therapeutic agent. (Item 35) A compound described in any one of items 1 to 28 for use in the treatment of a disease or disorder in a subject caused by reduced orexin activity. (Item 36) Compounds described in item 35, wherein the disease or disorder is one or more of the following: sleep disorders, narcolepsy, cataplexy, insomnia, regulation of sleep states, apnea, regulation of wakefulness, sleep-wake cycling, enhanced recovery from anesthesia, jet lag, regulation of appetite, regulation of eating, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, clarity, cognitive impairment, Alzheimer's disease, attention deficit, dementia, mild cognitive impairment, Parkinson's disease, cognitive dysfunction, brain injury, cognitive impairment, addiction, drug addiction, blood pressure regulation, ischemic events, oxidative stress events, and cancer. (Item 37) A method for treating one or more of the following conditions: sleep disorders, narcolepsy, cataplexy, insomnia, regulation of sleep states, apnea, regulation of wakefulness, sleep-wake cycling, enhanced recovery from anesthesia, jet lag, regulation of appetite, regulation of eating, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, clarity, cognitive impairment, Alzheimer's disease, attention deficit, dementia, mild cognitive impairment, Parkinson's disease, cognitive dysfunction, brain injury, cognitive impairment, addiction, drug addiction, regulation of blood pressure, ischemic events, oxidative stress events, and cancer, comprising administering a compound described in any one of items 1 to 28. (Item 38) Use of any one of the compounds described in items 1 to 28 for the preparation of pharmaceuticals for the treatment of one or more of the following: sleep disorders, narcolepsy, cataplexy, insomnia, regulation of sleep states, apnea, regulation of wakefulness, sleep-wake cycling, enhanced recovery from anesthesia, jet lag, regulation of appetite, regulation of eating, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, clarity, cognitive impairment, Alzheimer's disease, attention deficit, dementia, mild cognitive impairment, Parkinson's disease, cognitive dysfunction, brain injury, cognitive impairment, addiction, drug addiction, regulation of blood pressure, ischemic events, oxidative stress events, and cancer. (Item 39) Compounds described in any one of items 1 to 28 for use in the treatment of one or more of the following: sleep disorders, narcolepsy, cataplexy, insomnia, regulation of sleep states, apnea, regulation of wakefulness, sleep-wake cycling, enhanced recovery from anesthesia, jet lag, regulation of appetite, regulation of eating, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, clarity, cognitive impairment, Alzheimer's disease, attention deficit, dementia, mild cognitive impairment, Parkinson's disease, cognitive dysfunction, brain injury, cognitive impairment, addiction, drug addiction, regulation of blood pressure, ischemic events, oxidative stress events, and cancer.

Claims

[Claim 1] The invention described in the present specification.

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