Arylsulfonamides as orexin receptor agonists

Abstract

The present disclosure provides novel arylsulfonamide compounds as embodiments of the present disclosure. These compounds are believed to be orexin receptor agonists and are useful in treating diseases and conditions caused by decreased orexin activity.

Description

Technical Field

[0001] The present disclosure provides novel arylsulfonamide compounds as embodiments of the present disclosure. These compounds are believed to be orexin receptor agonists and are useful in treating diseases and conditions caused by decreased orexin activity. Background Art

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

[0003] For 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 neurotransmitters that promote alertness, such as dopamine, serotonin, and norepinephrine. Without sufficient orexin, the body has a hard time staying awake and alert. People diagnosed with narcolepsy type 1 have an 85% to 95% reduction in the number of orexin-producing neurons. This loss of orexin-producing neurons leads to the symptoms of narcolepsy, including excessive daytime sleepiness, sleep paralysis, hallucinations, and cataplexy. This loss of orexin-producing neurons can lead to narcolepsy and cataplexy, an incurable, chronic neurological disease that severely impacts the daily lives of those affected. While weight gain is not a symptom of narcolepsy, people with the condition are also more likely to be overweight. Research suggests that the link between narcolepsy and weight gain may be related to the role of orexin in regulating physical activity.

[0004] Orexin is important for the body's stress response. Orexin-producing neurons receive signals from the environment and respond to stress by firing other neurons that increase heart rate and blood pressure, helping the body transition from a resting state to one ready to react and move. Because there are fewer chemical signals to stimulate the response, orexin deficiency is associated with physical inactivity and obesity. Animal studies have shown that mice without orexin-producing neurons are less physically active, have decreased energy metabolism, and are more likely to develop obesity and diabetes, even when they consume fewer calories.

[0005] Orexin also stimulates neurons important for regulating mood. Too much or too little orexin activity has been linked to depression and other mental health conditions, such as 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 creation of new neurons in the hippocampus, which is important for learning, memory, and spatial abilities. Without enough orexin, people can develop learning and memory problems.

[0006] Consistent with the multifaceted effects of orexin, orexin deficiency is also associated with age-related diseases. Loss of orexin neurons and / or orexin peptides has been found in patients with Alzheimer's and Parkinson's diseases, as well as in elderly people and mice. Several studies have demonstrated that exogenous orexin-A successfully restored normal orexin function and improved learning and memory in animals with narcolepsy. Furthermore, using orexin / spinocerebellar ataxia-3 (O / A3) transgenic mice (a mouse model similar to human narcolepsy), both acute and chronic OXA treatment reversed memory impairment. See, e.g., Hara, J.; Beuckmann, CT; Nambu, T.; Willie, JT; Chemelli, RM; Sinton, CM; Sugiyama, F.; Yagami, K.; Goto, K.; Yanagisawa, M.; Sakurai, T., Genetic ablation oforexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 2001, 30(2), 345-5 and Mavanji, V.; Butterick, TA; Duffy, CM; Nixon, JP; Billington, CJ; Kotz, CM, Orexin / hypocretin treatment restores post-opaque-dependent memory in orexin-deficient mice. Neurobiol. Learn. Mem. 2017, 146, 21-30, each of which is incorporated by reference for such background.

[0007] Among all orexin replacement therapies, orexin agonists suitable for systemic administration would be a promising strategy for orexin deficiency-related disorders.

[0008] To date, drugs targeting the orexin system have initially focused on antagonists due to the role of orexin in regulating sleep and wakefulness. Dual orexin receptor antagonists (DORAs) are a class of prescription sleep aids that target the body's orexin system. These drugs work by acting as orexin receptor antagonists, meaning they block the effects of orexin in the body. They include OX1 / 2R dual antagonists and subtype-selective antagonists to reduce the drive to stay awake and promote sleep. The U.S. Food and Drug Administration (FDA) currently approves two types of DORAs for the treatment of insomnia in adults: suvorexant and lemborexant.

[0009] In contrast, activation of the orexin receptor is primarily accomplished using orexin peptides, in particular 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:

[0011]

[0012] ECs at both OX1R and OX2R 50 >3.2uM

[0013] However, Yan7874 was later found to be a weak agonist of two orexin receptors (EC50>3.2μM) and, unfortunately, exhibited cytotoxicity independent of orexin receptors. See, for example, Turku, A.; Rinne, MK; Boije AfGennas, G.; Xhaard, H.; Lindholm, D.; Kukkonen, JP, Orexin receptor agonist Yan7874 is a weak agonist of orexin / hypocretin receptors and shows orexinreceptor-independent cytotoxicity. PloS one 2017, 12(6), e0178526.

[0014] Recently, several series of small molecules have been reported, represented by YNT-185 and TAK-925. These agonists appear to be selective, activating OX2Rs with good potency while showing little or no activity at OX1Rs. WO2020 / 167706 reports additional OX2R agonists. These compounds, 5-alkylpyrrolidine analogs, are represented by compound 37.

[0015]

[0016] OX1 R EC 50 =2750nM; OX2R EC 50 =28nM

[0017]

[0018] OX1 R EC 50 >30uM; OX2R EC 50 =5.5nM

[0019]

[0020] OX2R IC50=0.23nM; Emax 102%

[0021] In more detail, YNT-185 showed good OX2R potency and selectivity (EC 50=28 nM, compared to 2750 nM at OX1R). Intraperitoneal (ip) administration of YNT-185 (40 mg / kg, salt form) promoted wakefulness in wild-type mice without affecting body temperature, whereas YNT-185 suppressed cataplexy-like episodes in orexin KO and orexin neuron-ablated mice. 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 agonistameliorates 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 measures including motor activity and startle response latency, but did not affect the analgesic effects of morphine. See, Toyama, S.; Shimoyama, N.; Tagaito, Y.; Nagase, H.; Saitoh, T.; Yanagisawa, M.; Shimoyama, M., Nonpeptide Orexin-2 Receptor Agonist AttenuatesMorphine-induced Sedative Effects in Rats. Anesthesiology 2018, 128(5), 992-1003.

[0022] However, the present inventors sought a pharmacological profile for dual orexin agonism.The compounds of the present disclosure exhibit unique structural attributes that contribute to their therapeutic efficacy as dual orexin A / B (alternatively characterized as dual OX1R / OX2R) agonists. Summary of the Invention

[0023] One embodiment of the present disclosure includes a compound of formula (I):

[0024]

[0025] or a pharmaceutically acceptable salt thereof,

[0026] in

[0027] A 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;

[0028] 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;

[0029] X is O or NH;

[0030] R 1 Yes (CH2) m -heteroaryl;

[0031] m is 0, 1, 2, 3, 4, 5, or 6;

[0032] R 2 is hydrogen or C 1-6 alkyl;

[0033] X is a bond, O, C(O), NH, NHC(O), or C(O)NH;

[0034] 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;

[0035] Z is a bond, O, C(O), NH, NHC(O), or C(O)NH;

[0036] R 3 It 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), wherein such 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,

[0037] Each R 3 May be substituted with one or more substituents selected from the group consisting of: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Halogenated alkyl, C 2-6 Halogenated alkenyl, 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 alkyl) and =0; and

[0038] Each n is independently 0, 1, 2 or 3.

[0039] In one aspect, R 1 Yes (CH2) m -pyridinyl. In one aspect, m is 1. In one aspect, R 2 It is C 1-6 In one aspect, R 2 In one aspect, A is phenylene. In one aspect, B is phenylene. In one aspect, B is a divalent pyridyl. In one aspect, X is NH. In one aspect, X is O. In one aspect, Y is C 2-6 In one aspect, Y is CH2CH2. In one aspect, Y is 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. In one aspect, the heterocyclyl ring contains at least one N atom. In one aspect, Z is NHC(O). In one aspect, Z is C(O). In one aspect, each of X, Y, and Z is a bond. In one aspect, R 3 It is C 1-10 Alkyl, (CH2) n -C 3-6 Cycloalkyl or (CH2) n -phenyl, wherein each n is independently 0, 1, 2 or 3. In one aspect, R 3 is C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, CH2CH3 or CH3. In one aspect, R 3 is C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl or C5 alkyl. In one aspect, R 3 Yes (CH2) n -C 3-6 In one aspect, R 3 Yes (CH2) n -C5-6 In one aspect, R 3 is (CH2)1-C6 cycloalkyl, (CH2)2-C6 cycloalkyl or (CH2)3-C6 cycloalkyl. In one aspect, R 3 Yes (CH2) n -phenyl. In one aspect, n is 0. In one aspect, R 3 Substituted with one or more substituents selected from the group consisting of: C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Halogenated alkyl, C 2-6 Halogenated alkenyl, 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 alkyl) and =0. In one aspect, R 3 Through one or more C 1-6 Alkyl substitution.

[0040] One embodiment of the present disclosure includes a compound selected from the group consisting of one or more of the examples.

[0041] One embodiment of the present disclosure includes a pharmaceutical composition comprising a compound of the present disclosure and one or more pharmaceutically acceptable excipients.

[0042] One embodiment of the present disclosure includes a method for treating a disease or condition caused by decreased orexin activity in a subject, comprising administering an effective amount of a compound of the present disclosure. In one aspect, the disease or condition is one or more of the following: sleep disorders, narcolepsy, cataplexy, sleep state regulation, apnea, wake state regulation, sleep-wake cycle, accelerated recovery after anesthesia, jet lag, appetite regulation, feeding regulation, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, mental 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.

[0043] One embodiment of the present disclosure includes the use of a compound of the present disclosure for preparing a medicament for treating a disease or condition caused by decreased orexin activity in a subject, comprising administering an effective amount of the compound. In one aspect, the disease or condition is one or more of the following: sleep disorder, narcolepsy, cataplexy, insomnia, sleep state regulation, apnea, wake state regulation, sleep-wake cycle, accelerated recovery after anesthesia, jet lag, appetite regulation, feeding regulation, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, mental 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.

[0044] One embodiment of the present disclosure includes a compound of the present disclosure for use as an active therapeutic substance.

[0045] One embodiment of the present disclosure includes a compound of the present disclosure for use in treating a disease or condition caused by decreased orexin activity in a subject. In one embodiment, the disease or condition is one or more of the following: sleep disorders, narcolepsy, cataplexy, insomnia, sleep state regulation, apnea, wake state regulation, sleep-wake cycle, accelerated recovery after anesthesia, jet lag, appetite regulation, feeding regulation, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, mental 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.

[0046] One embodiment of the present disclosure comprises a method of treating one or more of: sleep disorders, narcolepsy, cataplexy, insomnia, sleep state regulation, apnea, wake state regulation, sleep-wake cycle, accelerated recovery from anesthesia, jet lag, appetite regulation, feeding regulation, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, mental 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.

[0047] One embodiment of the present disclosure includes the use of a compound of the present disclosure for the preparation of a medicament for the treatment of one or more of: sleep disorders, narcolepsy, cataplexy, insomnia, sleep state regulation, apnea, wake state regulation, sleep-wake cycle, accelerated recovery from anesthesia, jet lag, appetite regulation, feeding regulation, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, mental 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.

[0048] One embodiment of the present disclosure includes a compound of the present disclosure for use in treating one or more of: sleep disorders, narcolepsy, cataplexy, insomnia, sleep state regulation, apnea, wake state regulation, sleep-wake cycle, accelerated recovery from anesthesia, jet lag, appetite regulation, feeding regulation, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, mental 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.

[0049] The scope of the present disclosure includes all different combinations of aspects, embodiments and preferences described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0050] Figure 1 graphically illustrates cognitive improvements in TWAA (left panel) and CORT (right panel) tasks in 12-month-old mice following peripheral injection of RTIOXA-47 (40 mg / kg, ip) or saline (n=8 / group, **p<0.01 ***p<0.005). DETAILED DESCRIPTION

[0051] The present disclosure includes novel arylsulfonamides that are useful as dual orexin receptor agonists.

[0052] The following definitions are intended to clarify but not limit the terms defined herein. If a particular term is not explicitly defined herein, it should not be considered as undefined. Instead, the term is used within its accepted meaning.

[0053] As used throughout this specification, preferred numbers of atoms, such as carbon atoms, will be indicated by, for example, the phrase "C x-y "alkyl" means an alkyl group as defined herein containing the indicated number of carbon atoms. Similar terminology will also apply to other preferred terms and ranges. Thus, for example, C 1-4 Alkyl represents a straight or branched chain hydrocarbon containing one to four carbon atoms.

[0054] As used herein, the term "alkyl" alone or in combination with any other term refers to a straight or branched chain hydrocarbon. As used herein, examples of "alkyl" include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, sec-butyl, isopentyl, n-pentyl, n-hexyl, and the like.

[0055] As used herein, the term "alkenyl" refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-carbon double bonds, which may be optionally substituted, with multiple degrees of substitution being allowed. Examples of "alkenyl" as used herein include, but are not limited to, vinyl and allyl.

[0056] As used herein, the term "alkylene" refers to an optionally substituted linear divalent hydrocarbon group. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.

[0057] As used herein, the term "alkynyl" refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-carbon triple bonds, which may be optionally substituted, with multiple degrees of substitution being allowed. Examples of "alkynyl" as used herein include, but are not limited to, ethynyl.

[0058] As used herein, the term "cycloalkyl" refers to a fully saturated, optionally substituted monocyclic, bicyclic, or bridged hydrocarbon ring, wherein multiple degrees of substitution are allowed. As used herein, exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0059] As used herein, the term "aryl" refers to a single benzene ring or a fused benzene ring system that may be optionally substituted, wherein multiple degrees of substitution are allowed. As used herein, examples of "aryl" groups include, but are not limited to, phenyl, 2-naphthyl, 1-naphthyl, anthracene, and phenanthrene. Preferred aryl rings have five to ten members.

[0060] As used herein, fused benzene ring systems encompassed within the term "aryl" include fused polycyclic hydrocarbons, i.e., cyclic hydrocarbons having less than a maximum number of non-cumulative double bonds, for example, wherein a saturated hydrocarbon ring (a cycloalkyl group, such as a cyclopentyl ring) is fused to an aromatic ring (an aryl group, such as a benzene ring) to form, for example, groups such as indanyl and acenaphthalenyl, and also include, as non-limiting examples, groups such as dihydronaphthalene and tetrahydronaphthalene.

[0061] As used herein, the term "heterocyclyl" refers to a monocyclic five- to seven-membered partially or fully saturated ring, or a fused bicyclic ring system comprising two such rings, which may be optionally substituted, with multiple degrees of substitution being allowed. Preferably, such rings contain five to ten members. These heterocyclyl rings contain one or more nitrogen, sulfur, and / or oxygen atoms, with N-oxides, sulfur oxides, and dioxides being permissible heteroatom substituents. As used herein, examples of "heterocyclyl" groups include, but are not limited to, ethylene oxide, tetrahydrofuran, tetrahydropyran, dioxane, ethyleneimine, pyrrolidine, piperidine, thioethane, tetrahydrothiophene, tetrahydrothiopyran, and morpholine.

[0062] As used herein, the term "heteroaryl" refers to a monocyclic five- to seven-membered aromatic ring, or a fused bicyclic aromatic ring system comprising two such aromatic rings, which may be optionally substituted, with multiple degrees of substitution permitted. Preferably, such rings contain five to ten members. These heteroaryl rings contain one or more nitrogen, sulfur, and / or oxygen atoms, with N-oxides, sulfur oxides, and dioxides being permissible heteroatom substituents. As used herein, examples of "heteroaryl" groups 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.

[0063] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0064] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein that is substituted with at least one halogen. As used herein, examples of branched or straight-chain "haloalkyl" groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and tert-butyl groups that are independently substituted with one or more halogens (e.g., fluorine, chlorine, bromine, and iodine). The term "haloalkyl" should be interpreted as including substituents such as perfluoroalkyl groups, such as -CF3.

[0065] Typically, but not absolutely, the salts of the present disclosure are pharmaceutically acceptable salts. The salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of the present disclosure. Salts of the compounds of the present disclosure may include acid addition salts. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camphorsulfonate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycolylaminophenylarsonic acid salt (glycollylarsanilate), hexylresorcinate, hydrabamine (hydrabamine), hydrobromide, hydrochloride, hydroxynaphthoate, benzoic acid salt ... The present invention also provides the present invention with the compound of the present invention.The present invention also provides the compound of the present invention with the compound of the present invention.

[0066] The compounds of formula (I) may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms ("polymorphs") are within the scope of formula (I). Polymorphism can generally occur as a response to changes in temperature, pressure, or both. Polymorphism 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.

[0067] As used herein, the term "effective amount" means the amount of a drug or pharmaceutical agent that will elicit the biological or medical response being sought by, for example, a researcher or clinician. The term "therapeutically effective amount" means any amount that results in improved treatment, cure, prevention, or amelioration of a disease, condition, or side effect, or results in a reduced rate of progression of a disease or condition, compared to a corresponding subject not receiving that amount. The term also includes within its scope amounts that are effective to enhance normal physiological function.

[0068] For use in therapy, a therapeutically effective amount of a compound of formula (I) and its salts or solvates may be administered as the raw chemical. Alternatively, the active ingredient may be presented as a pharmaceutical composition.

[0069] Therefore, the present disclosure further provides pharmaceutical compositions 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 carrier, diluent or excipient must be acceptable in the sense that it is compatible with the other ingredients of the formulation and is not harmful to the recipient of the pharmaceutical composition.

[0070] The compounds of the present disclosure can be prepared by a variety of methods, including well-known standard synthetic methods. Illustrative general synthetic methods are listed below, and then specific compounds of the present disclosure are prepared in the working examples.

[0071] In all examples described below, according to the general principles of synthetic chemistry, the protecting group for sensitive groups or reactive groups is adopted if necessary. According to the standard method of organic synthesis, protecting group is operated (TW Green and PGM Wuts (1999) Protecting Groups in Organic Synthesis, the 3rd edition, John Wiley & Sons, incorporated by reference about protecting group). These groups are removed using the obvious method of those skilled in the art at the convenient stage of compound synthesis. The selection of process and reaction conditions and its execution order should be consistent with the preparation of compound of the present disclosure.

[0072] The present disclosure also provides a method for synthesizing the compound of formula (I) and novel compounds useful as synthetic intermediates in preparing the compounds of the present disclosure.

[0073] These compounds can be prepared according to the methods described below using readily available starting materials and reagents. In these reactions, variations known to those of ordinary skill in the art may be used but are not mentioned in greater detail.

[0074] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. 13 C or 14Compounds having the structure of the present invention other than C-enriched carbon substitution are within the scope of the present disclosure. For example, deuterium has been widely used to examine the pharmacokinetics and metabolism of biologically active compounds. Although deuterium behaves similarly to hydrogen from a chemical point of view, there are significant differences in the bond energy and bond length between deuterium-carbon bonds and hydrogen-carbon bonds. Therefore, replacing hydrogen with deuterium in a biologically active compound may produce a compound that generally retains its biochemical potency and selectivity, but exhibits significantly different absorption, distribution, metabolism and / or excretion (ADME) properties compared to its isotope-free counterpart. Therefore, deuterium substitution can lead to improved drug efficacy, safety and / or tolerability of some biologically active compounds.

[0075] According to another aspect of the present disclosure, there is also provided a method for preparing a pharmaceutical formulation, which comprises mixing a compound of formula (I) or its salts, solvates and physiologically functional derivatives with one or more pharmaceutically acceptable carriers, diluents or excipients.

[0076] The compounds of the present invention can be used as dual agonists of orexin receptor activity in subjects in need thereof, such as mammals. In addition to primates, especially humans, a variety of other mammals can also be treated according to the methods of the present invention. The present disclosure relates to a compound of the present invention or a pharmaceutically acceptable salt thereof for use in medicine. The present disclosure further relates to the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for antagonizing orexin receptor activity in humans and animals or for treating the conditions and diseases indicated herein. The subjects treated in the methods and uses of the present invention are typically mammals, such as humans, male or female. The term "therapeutically effective amount" means the amount of the subject compound that a researcher, veterinarian, doctor or other clinician is seeking to elicit a biological or medical response in a tissue, system, animal or human. It should be recognized that those skilled in the art can affect these neurological and psychiatric disorders by treating patients currently suffering from neurological and psychiatric disorders or by prophylactically treating patients suffering from neurological and psychiatric disorders with an effective amount of a compound of the present invention. As used herein, the term "treatment" or "treating" refers to all methods by which the progression of the neurological and psychiatric disorders described herein can be slowed, interrupted, prevented, controlled, or stopped, but does not necessarily mean complete elimination of all symptoms of the disorder, as well as prophylactic treatment of the aforementioned disorders, particularly in patients susceptible to such diseases or disorders. The terms "administration" and or "administering" a compound should be understood to mean providing a compound of the present disclosure or a prodrug of a compound of the present disclosure to an individual in need thereof.

[0077] As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The term, in relation to a pharmaceutical composition, is intended to encompass a product comprising the active ingredients and inert ingredients which constitute the carrier, as well as any product that results, directly or indirectly, from the combination, complexation, or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from some other type of reaction or interaction of one or more ingredients.

[0078] Thus, the pharmaceutical compositions of the present disclosure encompass any composition prepared by admixing a compound of the present disclosure and a pharmaceutically acceptable carrier."Pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0079] The selected dosage depends on the desired therapeutic effect, the route of administration, and the 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 is following, concurrent medications, and other factors that will be recognized by those skilled in the art.

[0080] Generally speaking, a dosage level of between 0.0001 and 10 mg / kg body weight is administered to patients (e.g., humans and the elderly) daily to achieve effective antagonism of the orexin receptor. The dosage range will generally be about 0.5 mg to 1.0 g per patient per day, which can be administered in single or multiple doses. In one embodiment, the dosage range will be 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.

[0081] Pharmaceutical composition of the present disclosure can provide in the form of solid dose formulation, and this formulation is such as comprising about 0.5mg to 500mg active ingredient, or comprises about 1mg to 250mg active ingredient.Pharmaceutical composition can provide in the form of solid dose formulation, and this formulation comprises about 1mg, 5mg, 10mg, 25mg, 30mg, 50mg, 80mg, 100mg, 200mg or 250mg active ingredient.For oral administration, composition can provide in the form of tablet, and these tablets contain 1.0 to 1000 milligrams of active ingredient, such as 1,5,10,15,20,25,50,75,100,150,200,250,300,400,500,600,750,800,900 and 1000 milligrams of active ingredient, for the symptomatic adjustment of dosage of patient to be treated.

[0082] The compound can be administered on a schedule of 1 to 4 times per day, such as once or twice per day. The compound can be administered before bedtime. For example, the compound can be administered about 1 hour before bedtime, about 30 minutes before bedtime, about 15 minutes before bedtime, or immediately before bedtime.

[0083] As noted, the therapeutically effective amount of the compounds of the present invention will depend on many factors. For example, the species, age and weight of the recipient, the exact condition to be treated and its severity, the nature of the formulation and the route of administration are all factors to be considered. The therapeutically effective amount should ultimately be determined by the attending physician or veterinarian. The amount can be given in the form of a single dose per day or multiple (such as two, three, four, five or more) sub-doses per day so that the total daily dose is the same. The effective amount of a salt or a solvate thereof can be determined as the ratio of the effective amount of the compound of formula (I) itself. Similar dosages should be suitable for treating other conditions mentioned herein. Pharmaceutical formulations can exist in unit dose form, with each unit dose containing a predetermined amount of active ingredient. Preferred unit dose formulations are those containing a daily dose or sub-dose or an appropriate fraction thereof of the active ingredient as described above. Such pharmaceutical formulations can be prepared by any method well known in the pharmaceutical field.

[0084] The pharmaceutical formulations may be suitable for administration by any appropriate 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) administration. Such formulations may be prepared by any method known in the pharmaceutical art, such as by combining the active ingredient with a carrier or excipient. By way of example, but not intended to limit the present disclosure, certain routes may be preferred over other routes for certain conditions and disorders for which the compounds of the present disclosure are considered useful. In addition, pharmaceutical formulations may be used to allow for delayed or prolonged exposure to compounds of formula (I) where such delayed or prolonged exposure would improve therapy.

[0085] Pharmaceutical formulations suitable for oral administration can be in the form of discrete units such as capsules or tablets; powders or granules; solutions or suspensions, each containing an aqueous or non-aqueous liquid; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. For example, for oral administration in the form of tablets or capsules, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, etc. Generally speaking, powders are prepared by pulverizing the compound to a suitable fine size and mixing it with an appropriate pharmaceutical carrier such as an edible carbohydrate (e.g., starch or mannitol). Flavoring agents, preservatives, dispersants, and colorants may also be present.

[0086] Capsules are prepared by preparing a powder, liquid or suspension mixture and encapsulating with gelatin or some other appropriate shell materials. Before encapsulation, glidants and lubricants (such as colloidal silicon dioxide, talc, magnesium stearate, calcium stearate or solid polyethylene glycol) can be added to the mixture. Disintegrants or solubilizers, such as agar, calcium carbonate or sodium carbonate, can also be added to improve the availability of the drug when the capsule is taken. In addition, when needed or necessary, suitable binders, lubricants, disintegrants and colorants can also be mixed into the mixture. The example of suitable binder includes starch, gelatin, natural sugars (such as glucose or beta-lactose), corn sweeteners, natural gums and synthetic gums (such as gum arabic, tragacanth or sodium alginate), carboxymethyl cellulose, polyethylene glycol, wax etc. The lubricants that can be used in these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride etc. Disintegrants include but are not limited to starch, methyl cellulose, agar, bentonite, xanthan gum etc.

[0087] For example, tablets are formulated by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture can be prepared by mixing a suitably crushed compound with a diluent or base as described above. Optional ingredients include a binder such as carboxymethyl cellulose, alginate, gelatin, or polyvinyl pyrrolidone; a solution retardant such as paraffin; a resorption promoter such as a quaternary salt, and / or an absorbent such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be wet granulated with a binder such as syrup, starch paste, acacia mucilage, or a solution of a cellulose or polymeric material and forced through a screen. As an alternative to granulation, the powder mixture can be passed through a tablet press, and the result is that imperfectly formed lumps are broken into granules. The granules can be lubricated by adding stearic acid, stearate, talc, or mineral oil to prevent adhesion to the tablet forming die. The lubricated mixture is then pressed into tablets. The compounds of the present disclosure can also be combined with a free-flowing inert carrier and compressed directly into tablets without granulation or crushing steps. A transparent or opaque protective coating consisting of a shellac seal coat, a sugar or polymeric material coating, and a wax polish coat can be provided. Dyes can be added to these coatings to distinguish different unit doses.

[0088] Oral liquids, such as solutions, syrups, and elixirs, can be prepared in dosage unit form so that a given amount contains a predetermined amount of the compound. For example, syrups can be prepared by dissolving the compound in an appropriately flavored aqueous solution, while elixirs can be prepared using a non-toxic alcoholic vehicle. Suspensions can generally be prepared by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers, such as ethoxylated isostearyl alcohol and polyoxyethylene sorbitol ethers; preservatives; flavor additives, such as peppermint oil; or natural sweeteners, saccharin or other artificial sweeteners; etc., can also be added.

[0089] Where appropriate, dosage unit formulations for oral administration can be microencapsulated.The formulations can also be prepared to prolong or sustain the release, such as by coating or embedding particulate material in polymers, wax, etc.

[0090] Pharmaceutical formulations adapted for topical administration in the oral cavity include lozenges, pastilles and mouthwashes.

[0091] The present disclosure includes compounds that are active as orexin-1 receptor and / or orexin-2 receptor agonists within the general scope of the present disclosure. Relative to other orexin modulators, the compounds of the present invention exhibit unexpected properties, such as dual agonism, improved oral bioavailability, metabolic stability, reduced inhibition of metabolic enzymes (such as reduced inhibition of cytochrome P450 3A4 (CYP3A4)), reduced inhibition of transporters (such as reduced inhibition of p-glycoprotein / PGP), and / or selectivity relative to other receptors.

[0092] Orexin receptors are associated with a wide range of biological functions. This suggests that these receptors have a potential role in a variety of disease processes in humans or other species. The compounds disclosed herein can be used to treat, prevent, improve, control or reduce the risk of a variety of 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 alertness; reducing daytime sleepiness; treating or reducing excessive daytime sleepiness, narcolepsy, sleep disruption, sleep apnea, arousals, nocturnal myoclonus, REM sleep disruption, jet lag, shift worker sleep disorders, parasomnias, night terrors, insomnia associated with depression, affective / emotional disorders, Alzheimer's disease or cognitive impairment, as well as sleepwalking and enuresis, and sleep disorders associated with aging; Alzheimer's disease sundowning; conditions related to circadian rhythms, and mental and physical conditions associated with travel across time zones and shift work arrangements, conditions caused by medications that result in reduced REM sleep as a side effect; fibrosis Myalgia; syndromes characterized by non-restorative sleep and muscle pain or sleep apnea (associated with breathing disorders during sleep); conditions caused by decreased sleep quality; enhanced learning; enhanced memory; enhanced memory retention; eating disorders associated with excessive food intake and their related complications, compulsive eating disorders, obesity (due to any cause, whether genetic or environmental), obesity-related conditions (including binge eating and bulimia nervosa), hypertension, diabetes, elevated plasma insulin concentrations 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 artery disease, sudden death, stroke, polycystic ovary disease, craniopharyngioma, Prader-Willi syndrome, Frohlich syndrome, GH-deficient subject), normal variant short stature, Turner syndrome and other pathological conditions manifesting reduced metabolic activity or decreased resting energy expenditure as a percentage of total lean mass, such as childhood acute lymphoblastic leukemia, metabolic syndrome (also known as syndrome X), insulin resistance syndrome, reproductive hormone abnormalities, sexual and reproductive dysfunction, such as impaired fertility, infertility, male hypogonadism and female hirsutism, fetal defects associated with maternal obesity, gastrointestinal motility disorders, intestinal motility disorders, obesity-related gastroesophageal reflux, hypothalamic diseases, pituitary diseases, respiratory disorders, such as obesity hypoventilation syndrome (Pickwick syndrome), dyspnea, cardiovascular disease, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricemia, low back pain, gallbladder disease, gout, renal cancer, increased risk of anesthesia, reducing the risk of secondary consequences of obesity, such as reducing the risk of left ventricular hypertrophy;Diseases or conditions in which abnormal oscillatory activity occurs in the brain, including depression, migraine, neuropathic pain, Parkinson's disease, psychosis, and schizophrenia, as well as diseases or conditions in which activity is abnormally coupled, particularly through the thalamus; enhancing cognitive function, including cognitive dysfunction, which includes all types of attention, learning, and memory deficits occurring transiently or chronically in normal, healthy, young, adult, or elderly populations, as well as those occurring transiently or chronically in psychiatric, neurological, cardiovascular, and immune disorders; enhancing memory; improving memory retention; enhancing immune response; enhancing immune function; hot flashes; night sweats; extending lifespan; schizophrenia; and conditions controlled by the excitation / relaxation rhythm imposed by the nervous system. Muscle-related disorders, such as heart rhythm and other disorders of the cardiovascular system; disorders related to cell proliferation, such as vasodilation or vasoconstriction and blood pressure; cancer; cardiac arrhythmias; hypertension; congestive heart failure; reproductive / urinary system disorders; sexual function and fertility disorders; renal adequacy; reaction to anesthetics; mood disorders, such as depression or more specifically melancholic disorders, such as single or recurrent major depressive disorder and dysthymic disorder, or bipolar disorder, such as bipolar I disorder, bipolar II disorder and cyclothymic disorder, mood disorders due to 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 phobia, substance-induced anxiety disorders, and anxiety due to general medical conditions; acute neurological and psychiatric conditions, such as brain damage following heart bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemia, neuronal damage; Huntington's disease; amyotrophic lateral sclerosis; multiple sclerosis; eye injuries; retinopathy; cognitive impairment; idiopathic and drug-induced Parkinson's disease; muscle spasticity and conditions related to muscle spasticity, including tremors, epilepsy, convulsions, epilepsy, absence seizures, complex partial seizures, and generalized seizures Raynaud-Gastehot syndrome; cognitive impairment, including dementia (related to 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 general medical conditions, or substance abuse); delirium, amnesia, or age-related cognitive decline; schizophrenia or psychotic disorder, including schizophrenia (paranoid, disorganized, catatonic, or undifferentiated types), schizophrenia-like disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, and substance-induced psychotic disorder; dissociative disorder, including multiple personality syndrome and psychogenic amnesia;Substance-related disorders, substance use, substance abuse, substance seeking, substance recovery, 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, addictive intake, dependence, withdrawal, or relapse to substances including alcohol, amphetamines, marijuana, cocaine, hallucinogens, inhalants, morphine, nicotine, opioids, phencyclidine, sedatives, hypnotics, or anxiolytics); movement disorders, including akinesia and akinesia-rigidity syndrome (including Parkinson's disease, drug-induced Parkinson's disease, encephalitis, postencephalitis Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, corticobasal degeneration, Parkinson's disease-ALS dementia syndrome, and basal ganglia calcifications), chronic fatigue syndrome, fatigue, including Parkinson's disease fatigue, multiple sclerosis fatigue, fatigue caused by sleep disorders or circadian rhythm disorders, drug-induced Parkinson's disease (such as neuroleptic-induced Parkinson's disease, neuroleptic malignant syndrome, neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia, neuroleptic-induced tardive dyskinesia, and drug-induced postural tremor), Gilles de Ia Tourette syndrome, epilepsy and movement disorders [including tremor (such as rest tremor, essential tremor, postural tremor and intention tremor), chorea (such as Sydenham's chorea, Huntington's disease, benign hereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-induced chorea and hemishashes), myoclonus (including generalized myoclonus and focal myoclonus), tics (including simple tics, complex tics and symptomatic tics), restless legs syndrome and dystonia (including generalized dystonia such as essential dystonia, drug-induced dystonia, symptomatic dystonia and paroxysmal dystonia, and focal dystonia such as blepharospasm, oromandibular dystonia, spasmodic dystonia, spasmodic torticollis, axial dystonia, dystonic writer's cramp and hemiplegic dystonia); attention-deficit / hyperactivity disorder (ADHD); conduct disorder; migraine (including migraine headache); headache; hyperalgesia; pain; increased or exaggerated sensitivity to pain, such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritis pain; sports injury pain; pain associated with infections, such as HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; emesis, nausea, vomiting; gastric motility disorders; gastric ulcer; Kallmann's syndrome (anosmia); conditions associated with visceral pain, such as irritable bowel syndrome and angina; eating disorders; urinary incontinence;Substance tolerance, substance withdrawal (including substances such as opioids, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, sleeping pills, etc.); psychosis; schizophrenia; anxiety (including generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder); mood disorders (including depression, mania, bipolar disorder); trigeminal neuralgia; hearing loss; tinnitus; neuronal damage, including eye damage; retinopathy; macular degeneration of the eye; vomiting; cerebral edema; pain, including acute and chronic pain states, severe pain, intractable pain, inflammatory pain, neuropathic pain, post-traumatic pain, bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscle injuries, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain, neuropathic pain, post-traumatic pain, trigeminal neuralgia, migraine, and migraine headaches. Thus, in specific embodiments, the present disclosure provides methods for: improving sleep quality; enhancing sleep maintenance; increasing REM sleep; increasing stage 2 sleep; reducing fragmentation of sleep patterns; treating insomnia and all types of sleep disorders; treating or controlling sleep disorders associated with diseases such as neurological diseases (including neuropathic pain and restless legs syndrome); treating or controlling addictive 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, eating or alcohol disorders; treating or controlling hypothalamic diseases; treating or controlling depression; treating, controlling, ameliorating 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, psychosis and anxiety disorders; treating or controlling depression, including major depression and major depressive disorder; treating or controlling bipolar disorder; or treating, controlling, ameliorating or reducing the risk of schizophrenia in a mammalian patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of the present disclosure. The subject compounds are further useful in methods for preventing, treating, controlling, ameliorating, or reducing the risk of the diseases, disorders, and conditions identified herein. The dosage of the active ingredient in the compositions of the present disclosure may vary; however, the amount of active ingredient must be such that a suitable dosage form is obtained. The active ingredient may be administered to a patient (animal or human) in need of such treatment in an amount that will provide optimal efficacy.

[0093] The compounds of the present invention can be used in combination with one or more other drugs to treat, prevent, control, improve diseases or conditions, or reduce their risks. For these diseases or conditions, the compounds of the present invention or other drugs may have utility, wherein the drug combination is safer or more effective than using any one drug alone. Such other drugs can be administered simultaneously or sequentially with the compounds of the present invention by their common routes and amounts. When the compounds of the present invention are used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs and compounds of the present invention in unit dosage form is contemplated. Combination therapy can also include the therapy of the compounds of the present invention and one or more other drugs administered with different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and other active ingredients can be used in lower doses than when each is used alone.

[0094] Therefore, the pharmaceutical compositions of the present disclosure include those containing one or more other active ingredients in addition to the compounds of the present disclosure.The above combinations include combinations of the compounds of the present disclosure not only with one other active compound, but also with two or more other active compounds.

[0095] Likewise, the compounds of the present invention can be used in combination with other drugs for preventing, treating, controlling, improving diseases or conditions, or reducing their risks, and for these diseases or conditions, the compounds of the present invention may be useful. Such other drugs can be administered simultaneously or sequentially with the compounds of the present invention by their common routes and amounts. When the compounds of the present invention are used simultaneously with one or more other drugs, pharmaceutical compositions containing such other drugs are considered in addition to the compounds of the present invention. Therefore, pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to the compounds of the present invention.

[0096] The compounds of the present 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, for example, sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytics, antihistamines, benzodiazepines, barbiturates, ciclopirox, GABA agonists, 5HT-2 antagonists (including 5HT-2A antagonists and 5HT-2A / 2C antagonists), histamine antagonists (including histamine H3 antagonists, histamine H3 inverse agonists, imidazopyridines, mild tranquilizers, melatonin agonists and antagonists, melatonergic agents, other orexin antagonists, orexin agonists, prokineticin agonists and antagonists, pyrazolopyridines, T-type calcium channel antagonists, triazolopyridines, and the like, such as adinazolam, diallylbarbital, and the like. amobarbital, amoxapine, armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, capromorelin, capuride, carbocloral, chloral betaine betaine), chloral hydrate, chlordiazepoxide, clomipramine, clonazepam, cloperidone, clorazepate, clorethate, clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014, eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,Flunitrazepam, flurazepam, fluvoxamine, fluoxetine, fosazepam, gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren, imipramine, indiplon, lithium, lorazepam, lormetazepam, LY-156735, maprotiline, MDL-10 0907, mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone, methyprylon, midaflur, midazolam, modafinil, nefazodone, NGD-2-73, nisobamate, nitrazepam, nortriptyline, ornortriptyline e), oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, ramelteon, reclazepam, roletamide , secobarbital, sertraline, suproclone, TAK-375, temazepani, thioridazine, tiagabine, tracazolate, tranylcypromaine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine,Trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam, zopiclone, zolpidem, and salts thereof, and combinations thereof, or the compounds of the present disclosure may be administered in combination with physical methods such as light therapy or electrical stimulation.

[0097] In another embodiment, the subject compounds can be used in combination with other compounds known in the art, either administered alone or in the same pharmaceutical composition, including but not limited to: insulin sensitizers, including (i) PPARγ antagonists, such as the glitazones (e.g., ciglitazone; darglitazone; englitazone; isaglitazone (MCC-555); pioglitazone; rosiglitazone; rosiglitazone); (ii) biguanides such as metformin and phenformin; (iii) insulin or insulin mimetics such as biota, LP-100, novarapid, detemir, lispro, glargine, insulin zinc suspension (slow-acting and ultra-slow-acting); Lys-Pro insulin, GLP-1(73-7) (insulintropin); and GLP-1(7-36)-NH2; (c) sulfonylureas, such as acetohexamide; chlorpropamide; diabinese; glibenclamide; glipizide; glyburide; glimepiride; gliclazide ; glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide; (d) α-glucosidase inhibitors, such as acarbose, lipolytamide; camiglibose; emiglitate; miglitol; voglibose; pranamicin-Q; sabastatin; CKD-71; MDL-25,637; MDL-73,945; and MOR 14, etc.;(e) Cholesterol-lowering agents, such as (i) HMG-CoA reductase inhibitors (atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, simvastatin and other statins), (ii) bile acid absorbers / chelators, such as cholestyramine, colestipol, dialkylaminoalkyl derivatives of cross-linked dextran; etc., (ii) nicotinic acid, nicotinic acid or its salts, (iii) proliferator-activated receptor α agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate), (iv) cholesterol absorption inhibitors such as stanol esters, β-sitosterol, sterol glycosides such as tiqueside; and azetidinones such as ezetimibe, etc., and (acyl CoAx (f) PPARα agonists such as beclofibrate, bezafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil; and other fibric acid derivatives such as and etc., and PPARα agonists; (h) PPARα / δ agonists, such as muraglitazar; (i) anti-obesity agents, such as (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 serotonergic agents; (5) β3-adrenergic receptor agonists; (6) pancreatic lipase inhibitors; (7) Neuropeptide Y1 antagonists; (8) Neuropeptide Y5 antagonists; (9) Melanin-concentrating hormone (MCH) receptor antagonists; (10) Melanin-concentrating hormone 1 receptor (MCH1R) antagonists; (11) Melanin-concentrating hormone 2 receptor (MCH2R) agonists / antagonists; (12) Orexin receptor antagonists; (13) Serotonin reuptake inhibitors, such as fluoxetine, paroxetine, and sertraline; (14) Melanocortin agonists, such as Melanotan II; (15) Mc4r (melanocortin 4 receptor) agonists; (16) 5HT-2 agonists; (17) 5HT2C (5-hydroxytryptamine 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; (2 4) histamine receptor-3 (H3) antagonists / inverse agonists; (25) β-hydroxysteroid dehydrogenase-1 inhibitors (β-HSD-1); (26) PDE (phosphodiesterase) inhibitors; (27) phosphodiesterase-3B (PDE3B) inhibitors; (28) NE (norepinephrine) transporter inhibitors; (29) ghrelin receptor antagonists; (30) leptin, including recombinant human leptin (PEG-OB, Hoffman Labs, Inc. Roche) and recombinant methionyl human leptin (Amgen); (31) leptin derivatives; (32) BRS3 (bombesin receptor subtype 3) agonists; (33) CNTF (ciliary neurotrophic factor); (34) CNTF derivatives, such as axokine (Regeneron); (35) monoamine reuptake inhibitors; (36) UCP-1 (uncoupling protein-1, 2, or 3 activators); (37) thyroid hormone beta agonists; (38 )FAS (fatty acid synthase) inhibitors; (39) DGAT1 (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) dicarboxylate transporter inhibitors; (46) glucose transporter inhibitors;(47) Phosphate transporter inhibitors; (48) Metformin; (49) Topiramate (50) Peptide 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 Yl (NPYl) antagonists; (55) opioid antagonists; (56) 11βHSD-I (11-β hydroxysteroid dehydrogenase type 1) inhibitors; (57) aminorex; (58) 8) Amphetamine; (59) Amphetamine; (60) Benzphetamine; (61) Chlorphentermine; (62) Chlorbenzylrex; (63) Chlorforex; (64) Chloramine; (65) Chlortermine; (66) Cyclohexylmethylamine; (67) Dextroamphetamine; (68) Diphenylpiperidin ethanol, (69) N-ethylamphetamine; (70) Fenbutrazate; (71) fenisorex; (72) fenproporex; (73) fludorex; (74) fluminorex; (75) furfurylmethamphetamine; (76) levoamphetamine; (77) levofloxacin; (78) mefenorex; (79) methamphetamine; (80) methamphetamine; (81) norpseudoephedrine; (82) pentorex; (83) phendimetrazine; (84) phendimetrazine; (85) picirex; (86) phytopharm; and (87) zonisamide, (88) neuromodulators; (89) oxyntomodulin; and (90) neurokinin-1 receptor antagonists (NK-1 antagonists).

[0098] In another embodiment, the subject compounds can be used in combination with antidepressants or antianxiety agents, 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, alpha-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HTIA agonists or antagonists (particularly 5-HTIA partial agonists), and corticotropin-releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine, and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline, and protriptyline; citalopram, duloxetine, fluoxetine, fluvoxamine, paroxetine, and sertraline; isocarboxazid, phenelzine, tranylcypromine, and selegiline. giline); moclobemide: venlafaxine; aprepitant; bupropion, lithium, nefazodone, trazodone, and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam, and prazepam; buspirone, flesinoxan, gepirone, and ipsapirone, and pharmaceutically acceptable salts thereof.

[0099] In another embodiment, the subject compounds can be used in combination with: an anti-Alzheimer's disease agent; a β-secretase inhibitor; a γ-secretase inhibitor; a growth hormone secretagogue; a recombinant growth hormone; an HMG-CoA reductase inhibitor; an NSAID, including ibuprofen; vitamin E; an anti-amyloid antibody; a CB-I receptor antagonist or CB-I receptor inverse agonist; an antibiotic, such as doxycycline and rifampicin; an N-methyl-D-aspartate (NMDA) receptor antagonist, such as memantine; a cholinesterase inhibitor, such as galantamine, rivastigmine, donepezil, and tacrine; a growth hormone secretagogue, such as ibumoren, ibumoren mesylate, and capromorelin; a histamine H3 antagonist; an AMPA agonist; a PDE IV inhibitor; a GABAA inverse agonist; or a neuronal nicotinic agonist.

[0100] In another embodiment, the subject compounds can be used in combination with sedatives, hypnotics, anxiolytics, antipsychotics, anxiolytics, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, mild tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as adizalam, diallylbarbital, psoridomide, alprazolam, amitriptyline, amobarbital, alobarbital, Moxapine, Benazepam, Benzotamine, Brotizolam, Bupropion, Butaproxil, Butalbital, Carpronil, Carbochloral, Chloral Betaine, Chloral Hydrate, Chlordiazepoxide, Clomipramine, Clonazepam, Chlorpiperazine, Chlornithine, Chlordiazepoxide, Clozapine, Ciprozepam, Desipramine, Declamol, Diazepam, Chloral Antipyrine, Divalproex, Diphenhydramine, Doxepin, Estazolam, Ethchlorvinox, Etomidate, Fenobane, Flunitrazepam, Fluoride Diazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloquine, melatonin, mephobarbital, meprobamate, methaqualone, midaflutol, midazolam, nefazodone, nisolbamate, nitrazepam, nortriptyline, oxazepam, paraldehyde, paroxetine, pentobarbital, perazepam, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline , quazepam, resclozepam, lolimide, secobarbital, sertraline, suprolone, temazepam, thioridazine, tracarbazolate, tranylcyprozine, trazodone, triazolam, tripipam, trimethoprim-amide, triclofos, trifluoperazine, trimetozin, trimipramine, udazepam, venlafaxine, zaleplon, zolazepam, zolpidem and salts thereof and combinations thereof, etc., or the subject compounds can be administered in combination with physical methods such as light therapy or electrical stimulation.

[0101] In another embodiment, the subject compounds can be used in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide); anticholinergics such as biperiden (optionally as its hydrochloride or lactate) and benzhexol hydrochloride (benzhexol); 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 alectin, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide, and pramipexole.

[0102] In another embodiment, the subject compounds can be used in combination with acetophenazine, alentemol, antan, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa and benserazide, levodopa and carbidopa, lisuride, loxapine, mesoridazine, molindolone, nagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene, or trifluoperazine.

[0103] In another embodiment, the subject compounds can be used in combination with compounds from the following categories: phenothiazines, thioxanthenes, heterocyclic dibenzazepines, butyrophenones, diphenylbutylpiperidines, and indolone neuroleptics. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine, and trifluoperazine. Suitable 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 molindolone. Other neuroleptics include loxapine, sulpiride, and risperidone. In another embodiment, the subject compounds can be used in combination with nicotine agonists or nicotine receptor partial agonists, such as varenicline; opioid antagonists (e.g., naltrexone); dopaminergic agents (e.g., apomorphine); ADD / ADHD agents (e.g., methylphenidate hydrochloride); and ), atomoxetine (e.g. ), monoamine oxidase inhibitors (MAOIs), amphetamines (e.g. )) and anti-obesity agents such as apo-B / MTP inhibitors, 11β-hydroxysteroid dehydrogenase-1 (11Beta-HSD type 1) inhibitors, peptide YY3-36 or its analogs, MCR agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetics, 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 Y5 receptor antagonist), thyromimetic agent, dehydroepiandrosterone or its analogue, glucocorticoid receptor antagonist, other orexin receptor antagonist, glucagon-like peptide-1 receptor agonist, ciliary neurotrophic factor, human agouti-related protein antagonist, ghrelin receptor antagonist, histamine 3 receptor antagonist or inverse agonist and neuromodulatory peptide U receptor agonist and pharmaceutically acceptable salts thereof.

[0104] In another embodiment, the subject compounds can be used in combination with appetite suppressants such as aminorex, amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex, cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine, dextroamphetamine, diethylaminophenone, diphemethoxidine, N-ethylamphetamine, fenbutrazate, fenfluramine, fenisorex, fenproporex, fluoroquinolone, fenfluramine, fenproporex, fenproporex, fenfluramine ...fluramine, fenfluramine, fenproporex, fenproporex, fenflu fludorex, fluminorex, furfurylmethamphetamine, levamfetamine, levophacetoperane, mazindol, mefenorex, metamfepramone, methamphetamine, norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine, phentermine, phenylpropanolamine, picilorex, and sibutramine; selective serotonin reuptake inhibitors (SSRIs); halogenated amphetamine derivatives including chlorphentermine, cloforex, clortermine, dexfenfluramine, fenfluramine, picilorex, and sibutramine; and pharmaceutically acceptable salts thereof.

[0105] In another embodiment, the subject compounds can 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 nitric oxide synthesis inhibitors, nonsteroidal anti-inflammatory drugs or cytokine-inhibiting anti-inflammatory drugs, for example, in combination with compounds such as acetaminophen, aspirin, clofazodone, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, steroid analgesics, sufentanil, sulindac, tinidacil, and the like. Similarly, the subject compounds can be administered with analgesics; synergists such as caffeine, H2 antagonists, simethicone, aluminum hydroxide, or magnesium hydroxide; decongestants such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, cypromine, or levomethorphan; antitussives such as codeine, hydrocodone, carmiphene, pentoxyverine, or dextromethorphan; diuretics; and sedating or non-sedating antihistamines.

[0106] The compounds of the present disclosure can be administered orally, parenterally (e.g., intramuscularly, intraperitoneally, intravenously, ICV, intracisternal injection or infusion, subcutaneous injection or implant), by inhalation spray, nasal, vaginal, rectal, sublingual or topical administration, and can be formulated, alone or together, into suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles suitable for each administration route. In addition to treating warm-blooded animals (such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc.), the compounds of the present disclosure may also be effective for use in humans.

[0107] Several methods for preparing compounds of the present disclosure are illustrated in the following Schemes and Examples. Starting materials were prepared according to procedures known in the art or as described herein.

[0108] The compounds of the present disclosure or their salts or solvates can be used alone or in combination with other therapeutic agents. The compound of formula (I) and the other pharmaceutically active agent can be administered together or separately, and when administered separately, administration can occur simultaneously or sequentially in any order. The amount of the compound of formula (I) and the other pharmaceutically active agent and the relative administration sequence are selected to achieve the desired combined therapeutic effect. The combined administration of the compound of formula (I) or its salt or solvate and other therapeutic agents can be administered simultaneously in combination as follows: (1) a single pharmaceutical composition comprising the combination of compounds; or (2) a separate pharmaceutical composition each comprising a compound of the present disclosure. Alternatively, the combination can be administered separately in a sequential manner, wherein one therapeutic agent is administered first and another is administered secondarily, or vice versa. Such sequential administration can be close in time or distant in time.

[0109] Those skilled in the art of organic synthesis will appreciate that there are a variety of methods for producing compounds of the present disclosure labeled with radioactive isotopes suitable for various uses.

[0110] Experimental part

[0111] abbreviation:

[0112] As used herein, the symbols and conventions used in these processes, schemes, and examples are consistent with those used in contemporary scientific literature (e.g., the Journal of the American Chemical Society or the Journal of Biological Chemistry). Specifically, the following abbreviations may be used in the examples and throughout the specification:

[0113] g (gram); mg (milligram);

[0114] L (liter); mL (milliliter);

[0115] μL (microliter); psi (pounds per square inch);

[0116] M (mole); mM (millimolar);

[0117] Hz (Hertz); MHz (Megahertz);

[0118] mol (mole); mmol (millimole);

[0119] RT or rt (room temperature); hr (hours);

[0120] min (minute); TLC (thin layer chromatography);

[0121] mp (melting point); RP (reverse phase);

[0122] T r (retention time); TFA (trifluoroacetic acid);

[0123] TEA (triethylamine); THF (tetrahydrofuran);

[0124] TFAA (trifluoroacetic anhydride); CD3OD (deuterated methanol);

[0125] CDCl3 (deuterated chloroform); DMSO (dimethyl sulfoxide);

[0126] SiO2 (silica gel); atm (atmosphere);

[0127] EtOAc (ethyl acetate); CHCl3 (chloroform);

[0128] HCl (hydrochloric acid); Ac (acetyl);

[0129] DMF (N,N-dimethylformamide); Me (methyl);

[0130] Cs2CO3 (cesium carbonate); EtOH (ethanol);

[0131] Et (ethyl); t-Bu (tert-butyl);

[0132] MeOH (methanol) p-TsOH (p-toluenesulfonic acid);

[0133] DCM (dichloromethane) DCE (dichloroethane)

[0134] Et2O (diethyl ether) K2CO3 (potassium carbonate);

[0135] Na2CO3 (sodium carbonate); i-PrOH (isopropyl alcohol)

[0136] NaHCO3 (sodium bicarbonate); ACN (acetonitrile);

[0137] Pr(propyl); i-Pr(isopropyl);

[0138] PE (petroleum ether); Hex (hexane);

[0139] H2SO4 (sulfuric acid); HCl (hydrochloric acid);

[0140] Et3N (triethylamine); Na2SO4 (sodium sulfate);

[0141] MTBE (methyl tert-butyl ether); Boc (tert-butoxycarbonyl);

[0142] DIPEA (diisopropylethylamine); IPA (isopropyl alcohol);

[0143] HMDS (hexamethyldisilazane) NH4Cl (ammonium chloride)

[0144] NH4CO3 (ammonium carbonate) MgSO4 (magnesium sulfate)

[0145] NH4OH (ammonium hydroxide)

[0146] Unless otherwise indicated, all temperatures are expressed in °C (degrees Celsius). Unless otherwise indicated, all reactions were carried out at room temperature.

[0147] The synthesis of all target compounds is shown in Schemes 1-11. 1 The product was characterized by H NMR and LC-MS and had a purity >95% as assessed by HPLC.

[0148] Scheme 1. Synthetic routes of the compounds in Table 1

[0149]

[0150] The compounds of the present disclosure can be synthesized according to the procedures described by Nagahara and colleagues. As shown above, commercially available 1-fluoro-3-nitrobenzene is reacted with excess ethylenediamine at 120°C for 12 hours to obtain a substituted aniline, which is immediately reacted with Boc2O to obtain compound 1-1. After flash chromatography, compound 1-1 is treated with BnBr in DMF in the presence of potassium carbonate to obtain the key intermediate 1-2. Intermediate 1-2 is reduced using iron to obtain compound 1-3. 5-Bromo-2-methoxybenzenesulfonyl chloride in THF is slowly added to compound 1-3 in DCM in the presence of triethylamine and catalytic DMAP to obtain compound 1-4, which is subjected to Susuki coupling with different boronic acids, followed by acid auxiliary Boc deprotection and amide coupling to obtain intermediate 1-6. The benzyl group in intermediate 1-6 is subsequently deprotected to obtain the desired product.

[0151] Scheme 2-1. Synthesis routes of compounds in Table 2

[0152]

[0153] The compounds of the present disclosure can be synthesized according to procedures similar to those described herein. Commercially available 1-fluoro-3-nitrobenzene is reacted with an excess of diamines with different alkyl chain lengths at 120 ° C for 12 hours to obtain a substituted aniline, which is immediately reacted with Boc2O to obtain compound 2-1. After flash chromatography, compound 2-1 is treated with BnBr in DMF in the presence of potassium carbonate to obtain the key intermediate 2-2. Intermediate 2-2 is reduced using iron to obtain compound 2-3. In the presence of triethylamine and catalytic DMAP, 5-bromo-2-methoxybenzenesulfonyl chloride in THF is slowly added to compound 2-3 in DCM to obtain compound 2-4, which is subjected to Susuki coupling with different boronic acids, followed by acid auxiliary Boc deprotection and amide coupling to obtain intermediate 2-6. The benzyl group in intermediate 2-6 is subsequently deprotected to obtain the desired product.

[0154] Scheme 2-2. Synthesis routes of compounds in Table 2

[0155]

[0156] The compounds of the present disclosure can be synthesized as follows: Commercially available 1-fluoro-3-nitrobenzene is reacted with an excess of diamine and 1,4-piperazine at 120°C for 12 hours to give a substituted aniline, which is immediately reacted with Boc2O to give compound 2-1-3. After flash chromatography, compound 2-1-3 is treated with iron and ammonium chloride in EtOH at reflux to give compound 2-3-3. 5-Bromo-2-methoxybenzenesulfonyl chloride in THF is slowly added to compound 2-3-3 in DCM in the presence of triethylamine and catalytic DMAP to give compound 2-4-3, which is subjected to Susuki coupling with N,N-dimethylbenzamide-3-boronic acid, followed by acid auxiliary Boc deprotection and amide coupling to give intermediate 2-5-3. The benzyl group in intermediate 2-5-3 is subsequently deprotected to give the desired product.

[0157] The synthesis of these compounds largely followed the synthetic procedure for compound 1 (YNT-185) as outlined by Nagahara and co-workers. See, 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, which is incorporated by reference for helpful teachings of such synthesis.

[0158] Scheme 3. Synthesis route of the compounds in Table 3 and compound 12 in Table 2:

[0159]

[0160] The compounds of the present disclosure can be synthesized according to a modified procedure as indicated for compound 1 (YNT-185). Thus, commercially available 1-fluoro-3-nitrobenzene is reacted with excess ethylenediamine at 120°C for 12 hours to give a substituted aniline, which is immediately reacted with Boc2O to give compound 3-1. After flash chromatography, compound 3-1 is treated with 4N HCl in dioxane to give the key intermediate 3-2. Amide coupling is performed between compound 3-2 and 3-methylbenzoic acid, followed by reduction using iron to give compound 3-4. 5-Bromo-2-methoxybenzenesulfonyl chloride in THF is slowly added to compound 3-4 in DCM in the presence of DIPEA to give compound 3-5, in which selective acylation of the less hindered aniline is obtained in moderate yield. Subsequent Miyaura borylation gives the boronic acid pinacol ester 3-6, which readily reacts with different halogenated aromatic compounds to provide the final product.

[0161] Scheme 4. Synthetic routes of the compounds in Table 4:

[0162]

[0163] The compounds of the present disclosure can be synthesized according to procedures similar to those in Table 3. Fluorinated aminopyridines were reacted with ethylenediamine in a sealed tube at 150°C overnight to give intermediate 4-1, which was amide coupled with 3-methylbenzoic acid to give key intermediate 4-2. 5-Bromo-2-methoxybenzenesulfonyl chloride was reacted with 4-2 in a mixture of DMF and THF in the presence of triethylamine and DMAP to afford compound 4-3 in reasonable yields. Subsequent Miyaura borylation and Suzuki reactions produced the desired final products 28, 29, and 30. Notably, the Miyaura borylation and Suzuki reactions can be accomplished in one pot using different palladium catalysts and reaction times (see SI for more details). This general sequence with necessary modifications was followed in the subsequent synthesis of the remaining target compounds.

[0164] Scheme 5. Synthesis of compounds in Table 5

[0165]

[0166] The compounds of the present disclosure can be synthesized according to the procedures in Table 2. Compound 2-4 undergoes Miyaura borylation, followed by Suzuki reaction with the corresponding halogenated aromatic amide to afford the desired compound.

[0167] Scheme 6-1. Synthesis of compounds 41 and 42 in Table 6:

[0168]

[0169] The synthesis of compounds 41 and 42 can be accomplished via amide coupling between compound 3-4 and 5-bromo-2-methoxybenzoic acid chloride, followed by Miyaura borylation and Suzuki reaction.

[0170] Scheme 6-2. Synthesis of 43 and 44 in Table 6:

[0171]

[0172] Intermediate 6-A is obtained by reacting 3-boron-5-fluoropyridine with excess ethylenediamine, which is then coupled with 3-methylbenzoic acid to obtain intermediate 6-B. To synthesize 6-C, a Mitsunobu reaction is performed between 5-bromo-3-pyridinol and N-Boc-ethanolamine, followed by subsequent acidic deprotection and amide coupling. 1,3,4-thiadiazole 6-3 is obtained by reacting hydrazinecarboxythioamide and 5-bromo-o-anisic acid in refluxing POCl3. 6-3 is subjected to a Miyaura borylation reaction, followed by a Suzuki reaction with 3-bromo-N-methyl-N-(4-pyridylmethyl)-benzamide to obtain 6-5. Compound 43 can be easily obtained in reasonable yields via Buchwald coupling between 6-5 and 6-B. Similarly, 6-5 reacts with 6-E to produce compound 44.

[0173] Scheme 7-1. Synthesis routes of 47, 48, 49, 50, 53, and 54 in Table 7:

[0174]

[0175] The synthesis of the compounds in Table 7-1 was performed using a different route from the previous one. For compounds 47, 48, 49, 50, 53, and 54, intermediate 7-A was obtained by reacting 5-bromo-2-methoxybenzenesulfonyl chloride with ammonium hydroxide in the presence of saturated sodium bicarbonate. Compound 7-A was refluxed in benzene with various substituted methylmalonyl chlorides to give compound 7-1, which was then subjected to hydrolysis and amide coupling to give intermediate 7-3. Acidic deprotection of the Boc residue in compound 6-4 was followed by amide coupling with 3-methylbenzoic acid to give compound 7-5. Finally, 7-5 was converted to the final product via Miyaura borylation and Suzuki reaction.

[0176] Scheme 7-2. Synthesis routes of compounds 45, 46, 51, and 52 in Table 7:

[0177]

[0178] Compounds 51, 52, 45, and 46 were synthesized using a similar procedure, with intermediate 7-E or 7-F being prepared in a one-pot sequential reaction: an amide coupling between 3-methylbenzoic acid and N-Boc-ethylenediamine, followed by acidic workup, afforded intermediate 7-C. A second amide coupling between compound 7-C and a different N-Boc amino acid gave compound 7-D, which underwent acidic deprotection to afford 7-E or 7-F. Sulfonamide formation between 7-E or 7-F and 5-bromo-2-methoxybenzenesulfonyl chloride yielded 7-7, which was successfully converted to the final product via subsequent Miyaura borylation and Suzuki reaction.

[0179] Scheme 8. Synthesis of compounds 55, 56, 57 and 58 in Table 8:

[0180]

[0181] To improve efficiency, a modified synthetic method was used in the preparation of the compounds in Table 8, in which the scaffold was split into two parts at the sulfonamide functional group. For the right-hand part, the alcohol was first coupled with 3-methylbenzoic acid using CDI in dichloromethane to give 8-A, which was then subjected to S N Ar reaction to give 8-B. For the left part, 7-A undergoes Miyaura borylation reaction, followed by Suzuki reaction to give intermediate 8-2. Then, using tBuXphos as a catalyst, compound 8-2 is reacted with 8-B or 6-C via Buchwald cross coupling to give the final product.

[0182] Scheme 9-1. Synthesis of 38 and 59 in Table 9:

[0183]

[0184] The synthesis of compounds 38 and 59 can be readily accomplished by the procedures described for the compounds in Table 3. Miyaura borylation of intermediate 3-6 followed by Suzuki reaction yielded compounds 38 and 59.

[0185] Scheme 9-2. Synthesis of 60 and 61 in Table 9:

[0186]

[0187] Compounds 60 and 61 were obtained by reacting 7-A and 6-B under Buchwald cross-coupling conditions, followed by Miyaura borylation and Suzuki reaction.

[0188] Examples

[0189] Synthesis. All solvents and chemicals are reagent grade. Unless otherwise stated, all reagents and solvents are purchased from commercial suppliers and used as is. Flash column chromatography is performed on a Teledyne ISCO CombiFlash Rf system using pre-packed columns. The solvents used include hexane, ethyl acetate (EtOAc), dichloromethane, methanol, and chloroform / methanol / ammonium hydroxide (80:18:2) (CMA-80). The purity and characterization of the compound are determined by a combination of HPLC, TLC, mass spectrometry, and NMR analysis. Melting points are recorded by a Mel-Temp II instrument (Laboratory Devices Inc., US). 1 H and 13 C NMR spectra were recorded on a Bruker Avance DPX-300 (300 MHz) spectrometer and measured using tetramethylsilane (TMS) (0.00 ppm) or the solvent peak as an internal reference in chloroform-d, DMSO-d6, or methanol-d4. Chemical shifts are reported in ppm relative to the reference signal, and coupling constant (J) values ​​are reported in Hertz (Hz). Thin layer chromatography (TLC) was performed on EMD pre-coated silica gel 60F254 plates and the spots were visualized using UV light or iodine staining. Low-resolution mass spectra were obtained using a Waters Alliance HT / Micromass ZQ system (ESI). The purity of all tested compounds was greater than 95% as determined by HPLC on an Agilent 1100 system using an Agilent Zorbax SB-Phenyl (2.1 mm x 150 mm, 5 μm) column with a 15-minute gradient of 5-95% solvent B at 1 mL / min, followed by 10 minutes of 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).

[0190] General procedure for the synthesis of compound 1-1:

[0191] 3-Nitrofluorobenzene (5.0mmol, 35.4mmol) and ethylenediamine (11.8mL, 177.2mmol) are mixed in a sealed tube and the reactant is heated to 120°C overnight. After cooling, the volatiles are evaporated at 60°C under reduced pressure. The residue is then redissolved in a mixture of THF (30mL) and water (30mL), followed by the addition of potassium carbonate (14.7g, 106.2mmol) and Boc anhydride (19.3g, 88.5mmol). The reactant is then stirred overnight and diluted with brine (150mL). Ethyl acetate (150mL) is then added, and the organic layer is separated and dried. The solvent is removed under reduced pressure, and the residue is purified by ISCO to obtain the pure desired product. 6.28g of brown oil, yield: 63%. 1 H 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).

[0192] General procedure for the synthesis of compound 1-2:

[0193] 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 was then heated to 60° C. overnight. 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).

[0194] General procedure for the synthesis of compounds 1-3:

[0195] 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 was then heated at 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 H 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).

[0196] General procedure for the synthesis of compounds 1-4:

[0197] 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 reactants were allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated NaHCO (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%. 1 H NMR (300 MHz, chloroform-d) 7.87(d,J=2.45Hz,1H),7.55(dd,J=2.45,8.85Hz,1H),7.18-7.35(m,4H),7.1 0(d,J=6.59Hz,2H),7.00(t,J=8.38Hz,1H),6.90(br.s.,1H),6.78(d,J=8.85H z,1H),6.49(d,J=8.48Hz,1H),6.39(d,J=4.71Hz,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).

[0198] Table 1 General procedures for the synthesis of the final compounds:

[0199] Compound 1-4 (1.0 equivalent), boric acid (1.2 equivalents), Pd(PPh 3 ) 4 (0.1 equivalent) and potassium carbonate (2.0 equivalents) are placed in a round-bottom flask with an efficient condenser. The system is then flushed with nitrogen and a mixture of 1,4-dioxane / water (4 / 1, 0.1M) is added. The reactants are refluxed for 2 hours. After cooling, DCM (50ml) is added, and the organic layer is separated and dried. The solvent is then removed and the residue is dissolved in 4N HCl (10 equivalents) in 1,4-dioxane. The reactants are stirred at room temperature for 2 hours, and the solvent is then removed under reduced pressure. The residue is then dissolved in DMF (0.1M), followed by addition of 2-dimethylaminobenzoic acid (1.1 equivalents), HATU (1.2 equivalents) and DIPEA (1.5 equivalents). The reactants are stirred at room temperature overnight and quenched by saturated NaHCO 3 . DCM (50mL) is added, and the organic layer is separated and dried. The solvent was removed under reduced pressure to give a crude product which was then mixed with Pd / C (0.1 equivalent) in MeOH (0.1 M) under a hydrogen atmosphere (40 psi) for 12 hours. The reaction mixture was filtered and the solvent in the filtrate was removed under reduced pressure. The residue was purified by ISCO to give the pure desired final product.

[0200] Compound 1: Four-step yield: 45%. 1 H NMR (300 MHz, chloroform-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=8.01Hz,1H),6.45(br.s.,1H),6.34(dd,J=8.01,14.79Hz,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).

[0201] Compound 2: Four-step yield: 36%. 1H NMR (300MHz, chloroform-d)d 9.67-9.90(m,1H),8.03(d,J=2.07Hz,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),6.79-6.87(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).

[0202] Compound 3: Four-step yield: 39%. 1 H NMR (300 MHz, chloroform-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=6.50Hz,2H),3.29(t,J= 5.65Hz, 2H), 2.82 (d, J = 8.10Hz, 2H), 2.56 (s, 6H), 1.94-2.03 (m, 2H), 1.85-1.91 (m, 2H).

[0203] Compound 4: Four-step yield: 32%. 1H NMR (300 MHz, chloroform-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=6.59Hz,2H),4.30(br.s.,1H),4.05(s,3H),3.60(q,J=5.78Hz,2H),3.43( q,J=6.47Hz,2H),3.26(br.s.,2H),2.76-2.83(m,6H),1.60-1.71(m,2H),0.98(t,J=7.44Hz,3H).

[0204] Compound 5: Four-step yield: 29%. 1 H NMR (300MHz, chloroform-d)d 9.90(br.s.,1H),8.07-8.16(m,1H),7.97-8.06(m,2H),7.65(dd,J=2.26,8.67Hz,1H),7.46-7.54(m,2 H),7.41(t,J=7.54Hz,2H),7.30(d,J=7.35Hz,1H),7.12-7.22(m,2H),7.03(d,J=8.67Hz,1H),6.95(t, J=8.01Hz,1H),6.44(s,1H),6.34(d,J=5.09Hz,2H),4.31(t,J=5.27Hz,1H),4.07(s,3H),3.65(q,J=5. 84Hz,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).

[0205] Compound 6: Four-step yield: 41%. 1H NMR (300MHz, chloroform-d)d 9.91(br.s.,1H),8.11(dd,J=1.70,7.91Hz,1H),8.05(d,J=2.26Hz,1H),7.65(dd,J=2.35,8.57Hz,1H),7.37- 7.45(m,1H),7.28-7.36(m,3H),7.20(d,J=7.35Hz,2H),7.08-7.16(m,1H),7.02(d,J=8.67Hz,1H),6.94(t,J=8 .10Hz,1H),6.89(s,1H),6.45(t,J=2.07Hz,1H),6.33(td,J=2.28,8.05Hz,2H),4.17-4.54(m,1H),4.05-4.09( m, 3H), 3.64 (q, J = 5.97Hz, 2H), 3.29 (t, J = 5.75Hz, 2H), 2.87-2.99 (m, 1H), 2.54 (s, 6H), 1.27 (d, J = 6.97Hz, 6H).

[0206] Compound 7: Four-step yield: 35%. 1 H NMR (300 MHz, CDCl3)d 9.92(br.s.,1H),8.11(d,J=7.72Hz,1H),8.05(d,J=2.26Hz,1H),7.66(dd,J=2 .26,8.48Hz,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=10.17Hz,1H),6.45(s,1H),6.31(d,J=7.91Hz,2H),3. 97-4.09(m,3H),3.53-3.69(m,2H),3.29(t,J=5.75Hz,2H),2.29-3.06(m,12H).

[0207] Compound 8: Four-step yield: 32%. 1H NMR (300 MHz, chloroform-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=8.10Hz,1H),6.45(d,J=2.07Hz,1H),6.27-6.38(m,2H),4.05(s,3H),3.64(q,J=5.9 7Hz, 2H), 3.38 (q, J = 7.16Hz, 3H), 3.29 (t, J = 5.75Hz, 2H), 2.43-2.60 (m, 6H), 1.17 (t, J = 7.06Hz, 6H).

[0208] Compound 9: Four-step yield: 33%. 1 H NMR (300MHz, chloroform-d)d 9.93(br.s.,1H),8.11(dd,J=1.70,7.72Hz,1H),8.03(d,J=2.45Hz,1H),7.63(dd,J=2.35,8.57Hz,1H),7. 40(dt,J=1.70,7.72Hz,1H),7.10-7.24(m,3H),7.01(d,J=8.67Hz,1H),6.93(t,J=8.01Hz,1H),6.88(s,1H ),6.65-6.73(m,2H),6.61(dd,J=2.26,8.29Hz,1H),6.44(t,J=2.07Hz,1H),6.27-6.36(m,2H),4.05(s,3H ),3.64(q,J=5.84Hz,1H),3.16-3.33(m,4H),2.49-2.58(m,6H),1.57-1.64(m,4H),0.93(t,J=7.44Hz,6H).

[0209] Compound 10: Four-step yield: 39%. 1H NMR (300 MHz, chloroform-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=8.10Hz,1H),7.03(d,J=8.67Hz,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=5.84Hz,2H),2.42-2.60(m,6H),1.29-1.38(m,9H).

[0210] Compound 11: Four-step yield: 31%. 1 H NMR (300MHz, chloroform-d)d 9.91(br.s.,1H),8.11(dd,J=1.70,7.91Hz,1H),8.04(d,J=2.45Hz,1H),7.70(s,1H),7.61-7.68(m,2H) ,7.55-7.60(m,1H),7.52(d,J=7.54Hz,1H),7.42(dt,J=1.79,7.68Hz,1H),7.20(d,J=7.72Hz,1H),7.14( d,J=8.10Hz,1H),7.06(d,J=8.67Hz,1H),6.89-6.99(m,2H),6.39-6.49(m,1H),6.34(d,J=8.10Hz,2H), 4.21-4.57(m,1H),4.06-4.13(m,3H),3.65(q,J=5.97Hz,2H),3.29(t,J=5.75Hz,2H),2.48-2.62(m,6H).

[0211] General procedure for the synthesis of compound 2-1:

[0212] 3-Nitrofluorobenzene (1 equivalent) and ethylenediamine (5 equivalents) are mixed in a sealed tube, and the reactant is heated to 120°C overnight. After cooling, the volatiles are evaporated at 60°C under reduced pressure. The residue is then redissolved in a mixture of THF (30mL) and water (30mL), followed by addition of potassium carbonate (3.0 equivalents) and Boc anhydride (2.5 equivalents). The reactant is then stirred overnight and diluted by saline (150mL). Ethyl acetate (150mL) is then added, and the organic layer is separated and dried. The solvent is removed under reduced pressure, and the pure desired product is obtained by ISCO purification of the residue.

[0213] Compound 2-1-1: Yield: 72%. 1 H NMR (300MHz, chloroform-d)d 7.50(dd,J=1.60,8.01Hz,1H),7.39(t,J=2.26Hz,1H),7.25-7.30(m,1H),6.88(dd,J=2.07,8.10Hz,1H),4. 56-4.69(m,1H),3.25(dq,J=3.58,6.34Hz,4H),2.72(d,J=7.16Hz,1H),1.79(t,J=6.50Hz,2H),1.45(s,9H).

[0214] Compound 2-1-2: Yield: 30%. 1 H NMR (300 MHz, CHLOROFORM-d) d 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).

[0215] General procedure for the synthesis of compound 2-2:

[0216] 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). The reaction was then heated to 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 give the pure desired product.

[0217] Compound 2-2-1: Yield: 84%. 1H NMR (300 MHz, CHLOROFORM-d) d 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).

[0218] Compound 2-2-2: Yield: 81%. 1 H NMR (300MHz, chloroform-d)d 7.58(br.s.,1H),7.48(dd,J=1.51,7.91Hz,1H),7.37(d,J=4.33Hz,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=6.97Hz,1H),3.21-3.82(m,2H),1.31-1.46(m,9H).

[0219] General procedure for the synthesis of compound 2-3:

[0220] 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 was then heated at 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 give the pure desired product.

[0221] 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).

[0222] Compound 2-3-2: Yield: 92%. 1H NMR (300 MHz, chloroform-d) 7.37(d,J=4.33Hz,1H),7.26-7.32(m,2H),7.18(t,J=6.69Hz,2H),6.96(t,J= 8.10Hz,1H),6.23(dd,J=2.45,8.29Hz,1H),6.12-6.19(m,1H),6.06(dd,J=1. 51,7.72Hz,1H),4.49-4.73(m,2H),4.35-4.48(m,1H),3.95-4.09(m,1H),3.4 5-3.69(m,2H),3.08-3.22(m,1H),1.29-1.48(m,9H),1.18(d,J=6.78Hz,3H).

[0223] General procedure for the synthesis of compounds 2-4:

[0224] 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 was allowed to warm to room temperature and stirred overnight. The reaction was quenched by saturated NaHCO (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 give the pure desired product.

[0225] Compound 2-4-1: Yield: 85%. 1 H NMR (300MHz, chloroform-d)d 7.88(d,J=2.64Hz,1H),7.55(dd,J=2.64,8.85Hz,1H),7.28(d,J=7.54Hz,2H),7.23( s,1H),7.11(d,J=6.59Hz,2H),6.97(d,J=8.10Hz,1H),6.92(s,1H),6.79(d,J=8.85H z,1H),6.37-6.46(m,2H),6.33(d,J=8.67Hz,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=6.22Hz,2H),1.70-1.83(m,2H),1.44(s,9H).

[0226] Compound 2-4-2: Yield: 83%. 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=12.06Hz,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=6.59Hz,2H).

[0227] General procedure for the synthesis of the final compounds in Table 2 (Compounds 13, 14, 15 and 16):

[0228] Compound 2-4 (1.0 equivalent), boronic acid (1.2 equivalents), Pd(PPh 3 ) 4 (0.1 equivalent) and potassium carbonate (2.0 equivalents) are placed in a round-bottom flask with an efficient condenser. The system is then flushed with nitrogen and a mixture of 1,4-dioxane / water (4 / 1, 0.1M) is added. The reactants are refluxed for 2 hours. After cooling, DCM (50ml) is added, and the organic layer is separated and dried. The solvent is then removed and the residue is dissolved in 4N HCl (10 equivalents) in 1,4-dioxane. The reactants are stirred at room temperature for 2 hours, and the solvent is then removed under reduced pressure. The residue is then dissolved in DMF (0.1M), followed by the addition of the corresponding benzoic acid (1.1 equivalents), HATU (1.2 equivalents) and DIPEA (1.5 equivalents). The reactants are stirred at room temperature overnight and quenched by saturated NaHCO 3 . DCM (50mL) is added, and the organic layer is separated and dried. The solvent was removed under reduced pressure to give a crude product which was then mixed with Pd / C (0.1 equivalent) in MeOH (0.1 M) under a hydrogen atmosphere (40 psi) for 12 hours. The reaction mixture was filtered and the solvent in the filtrate was removed under reduced pressure. The residue was purified by ISCO to give the pure desired final product.

[0229] Compound 12: 1H NMR (300 MHz, chloroform-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=8.01Hz,1H),6.45(br.s.,1H),6.34(dd,J=8.01,14.79Hz,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).

[0230] Compound 13: Four-step yield: 29%. 1 H NMR(300MHz, chloroform-d)δ9.71(br.s.,1H),7.97-8.15(m,2H),7.62-7.80(m,2H), 7.50-7.57(m,2H),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).

[0231] Compound 14: Four-step yield: 22%. 1 H NMR (300 MHz, chloroform-d) δ 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=8.01Hz,1H),6.42(t,J=1.98Hz,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 = 6.78Hz, 3H).

[0232] Compound 15: Four-step yield: 32%. 1 H NMR (300 MHz, chloroform-d) δ 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=1.88Hz,1H),6.25-6.35(m,2H),4.13(s,1H),4.02-4 .08(m,4H),3.36(q,J=6.22Hz,2H),2.76-3.23(m,14H),2.35(s,3H),1.69-1.74(m,3H).

[0233] Compound 16: Four-step yield: 19%. 1 H NMR (300MHz, chloroform-d)d 8.09(d,J=2.45Hz,1H),8.01(s,1H),7.65(dd,J=2.45,8.67Hz,1H),7.48-7.59(m,4H),7.41(t ,J=7.72Hz,1H),7.30-7.35(m,1H),7.24(s,1H),7.11(s,1H),7.01(d,J=8.67Hz,1H),6.90(t, J=8.01Hz,1H),6.72(d,J=8.10Hz,1H),6.46(t,J=1.98Hz,1H),6.29(dt,J=1.79,7.86Hz,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=6.78Hz,3H).

[0234] General procedure for the synthesis of compound 2-1-3:

[0235] 3-Nitrofluorobenzene (5.0mmol, 35.4mmol) and piperazine (9.16g, 106.31mmol) are mixed in a sealed tube, and the reactant is heated to 120°C overnight. After cooling, volatiles are evaporated at 60°C under reduced pressure. The residue is then redissolved in a mixture of THF (30mL) and water (30mL), followed by addition of potassium carbonate (14.7g, 106.2mmol) and Boc anhydride (19.3g, 88.5mmol). The reactant is then stirred overnight and diluted by saline (150mL). Ethyl acetate (150mL) is then added, and the organic layer is separated and dried. The solvent is removed under reduced pressure, and the residue is purified by ISCO to obtain pure desired product. 5.30g yellow solid, yield: 49%. Compound 2-1-3: 1 H 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).

[0236] General procedure for the synthesis of compound 2-3-3:

[0237] 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 addition of ammonium chloride (9.31 g, 174.1 mmol) and iron powder (6.81 g, 121.8 mmol). The reactants were then heated at reflux for 3 hours. After cooling, DCM (100 mL) was added and the mixture was filtered through diatomaceous earth. 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 H 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).

[0238] General procedure for the synthesis of compound 2-4-3:

[0239] Under nitrogen protection, compound 2-3-3 (3.04g, 10.96mmol) is dissolved in anhydrous DCM (55mL) at 0°C, pyridine (1.06mL, 13.15mmol) is added, followed by 2-methoxy-5-bromobenzenesulfonyl chloride (3.44g, 12.06mmol). The reactant is allowed to warm to room temperature and stirred overnight. The reaction is quenched with saturated NaHCO (30mL) and DCM (100mL) is added. The organic layer is separated and dried. The solvent is removed under reduced pressure, and the residue is purified by ISCO to obtain the pure desired product. 4.61g brown solid, yield: 80%. Compound 2-4-3: 1 H NMR (300MHz, chloroform-d)d 7.94(d,J=2.45Hz,1H),7.58(dd,J=2.54,8.76Hz,1H),7.26(s,3H),7.07(t,J=8.10Hz,1H),6.82-6.93(m,2H),6.69-6.7 6(m,1H),6.64(d,J=8.29Hz,1H),6.41(d,J=7.91Hz,1H),4.01(s,3H),3.48-3.62(m,4H),3.00-3.16(m,4H),1.48(s,9H).

[0240] General procedure for the synthesis of the final compounds (Compounds 17 and 18) in Table 2:

[0241] Compound 2-4-3 (1.0 equivalent), boric acid (1.2 equivalents), Pd(PPh 3 ) 4 (0.1 equivalent) and potassium carbonate (2.0 equivalents) are placed in a round-bottom flask with an efficient condenser. The system is then flushed with nitrogen and a mixture of 1,4-dioxane / water (4 / 1, 0.1M) is added. The reactants are refluxed for 2 hours. After cooling, DCM (50ml) is added, and the organic layer is separated and dried. The solvent is then removed and the residue is dissolved in 4N HCl (10 equivalents) in 1,4-dioxane. The reactants are stirred at room temperature for 2 hours, and the solvent is then removed under reduced pressure. The residue is then dissolved in DMF (0.1M), followed by the addition of the corresponding benzoic acid (1.1 equivalents), HATU (1.2 equivalents) and DIPEA (1.5 equivalents). The reactants are stirred at room temperature overnight and quenched by saturated NaHCO 3 . DCM (50mL) is added, and the organic layer is separated and dried. The solvent was removed under reduced pressure to afford the crude product which was purified by ISCO to afford the pure desired product.

[0242] Compound 17: Four-step yield: 36%. 1H NMR (300MHz, CDCl3) δ8.04(d,J=2.07Hz,1H),8.03(d,J1=9.0Hz,J2=177Hz,1H),7.72(d,J=8.67 Hz,1H),7.52(d,J=12.06Hz,2H),7.42(t,J=7.54Hz,1H),7.30-7.37(m,2H),7.22(d,J=7.16Hz, 1H),7.02-7.12(m,2H),6.89-6.99(m,3H),6.77(s,1H),6.62(d,J=8.10Hz,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).

[0243] Compound 18: Four-step yield: 41%. 1 H NMR (300 MHz, chloroform-d) δ 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=8.85Hz,2H),6.97-7.04(m,1H),6.78(s,1H),6.62(d,J=8.29Hz,1H),6.49(d,J=7.7 2Hz,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).

[0244] Synthesis of compound 3-2.

[0245] 1-fluoro-3-nitrobenzene (14.10g, 100mmol) is mixed with ethylenediamine (75mL), and the mixture is heated to 120 ℃ and spends the night.Then the reactant is cooled to room temperature and toluene (100mL) is added.Then volatile matter is removed under reduced pressure, and the residue is redissolved in a mixture of ethyl acetate (100mL) and saturated sodium bicarbonate (100mL).Di-tert-butyl dicarbonate (32.7g, 150mmol) is added, and the reactant is stirred and spent the night.The organic layer is separated and dried over anhydrous MgSO4.Then the solvent is removed under reduced pressure and the residue is purified by ISCO to obtain 3-1, which is dissolved in a minimum amount of ethyl acetate and added into the 4N HCl (50mL) in the dioxane.Then the mixture is stirred for 2 hours until no bubble is released. Hexane (100mL) is added to precipitate any solid and filter the suspension. The collected solid is rinsed with diethyl ether and dried overnight in a vacuum to obtain pure desired product. 17g tan solid, yield: 78%. 1 H NMR (300MHz, DMSO-d6)d 8.12 (br.s., 4H), 7.29-7.50 (m, 3H), 6.91-7.17 (m, 1H), 3.38 (t, J = 6.40Hz, 2H), 2.87-3.06 (m, 2H).

[0246] Synthesis of compound 3-4.

[0247] 3-Methylbenzoic acid (2.73g, 20mmol) and 1,1'-carbonyldiimidazole (3.25g, 20mmol) are mixed and stirred in DCM for 15 minutes. Then compound 3-2 (2.62g, 10mmol) is added once, followed by DIPEA (10.5mL, 60mmol). The reaction is then monitored by TLC. After completion, saturated NaHCO is added to quench the reaction. The organic layer is then separated and dried over anhydrous MgSO. The solvent is removed under reduced pressure, and the residue is then redissolved in a mixture of EtOH (80mL) and water (30mL), followed by addition of ammonium chloride (10.7g, 0.2mol) and iron powder (7.84g, 0.14mol). The reactant is then refluxed for 2 hours. After cooling to room temperature, the reaction mixture is filtered and the filtrate is concentrated. Ethyl acetate (200mL) and brine (200mL) are added to the residue, and the organic layer is separated and dried. The solvent was removed under reduced pressure and the residue was subjected to ISCO to afford the pure desired compound. 3.33 g of brown oil, yield: 62%. 1H NMR(300MHz,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).

[0248] Synthesis of compound 3-5.

[0249] Compound 3-4 (3.33 g, 12.4 mmol) is dissolved in DCM (100 mL) and triethylamine (3.5 mL, 24.7 mmol) is added, followed by catalytic DMAP (302 mg, 2.47 mmol). The mixture is then cooled to 0 ° C, and 5-bromo-2-methoxybenzenesulfonyl chloride (3.86 g, 13.0 mmol) is slowly added over a 20-minute time period in THF (10 mL). The reactant is allowed to warm to room temperature and stirred overnight. The reactant is quenched with saturated NaHCO (50 mL) and ethyl acetate (100 mL) is added. The organic layer is separated and dried. The solvent is removed under reduced pressure and the residue is subjected to ISCO to obtain pure desired compound. 4.84 g light yellow foam, yield: 76%. 1 H NMR (300MHz, chloroform-d)d 7.94(d,J=2.45Hz,1H),7.47-7.60(m,3H),7.29-7.36(m,2H),6.97(t,J=8.01Hz,1H),6.80-6.92(m,2H),6.45(d,J=2.07Hz,2H),6. 33-6.40(m,1H),6.29(d,J=9.23Hz,1H),4.21(br.s.,1H),4.00(s,3H),3.66(q,J=5.90Hz,2H),3.32(t,J=5.65Hz,2H),2.39(s,3H).

[0250] General procedure for Miyaura borylation reaction:

[0251] The halogenated aromatic compound (1.0 eq) was dissolved in 1,4-dioxane (0.1 M) and bis(pinacolato)diboron (1.5 eq) was added, followed by PdCl2(dppf) (0.1 eq) and KOAc (2 eq). The reaction was then heated to 90°C overnight. 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 give the desired product.

[0252] General procedure for Suzuki coupling reaction:

[0253] Boronic acid pinacol ester (1.0 equivalent), compound 2 (1.0 equivalent) and K2CO3 (2.0 equivalent) are dissolved in a mixture of 1,4-dioxane and water (v / v=4:1, 0.04M). The mixture is degassed and purged with nitrogen three times. Pd(PPh3)4 (0.1 equivalent) is then added, and the reactants are stirred at 90°C for 1 hour. The reactants are then cooled and quenched with brine. Ethyl acetate is then added, and the organic layer is separated and dried. The solvent is removed under reduced pressure and the residue is subjected to ISCO to obtain the pure desired product.

[0254] General procedure for sequential Miyaura borylation and Suzuki coupling reactions:

[0255] The halogenated aromatic compound (1.0 equiv) was dissolved in 1,4-dioxane (0.1 M) and bis(pinacolato)diboron (1.5 equiv) was added, followed by PdCl2(dppf) (0.1 equiv) and KOAc (2 equiv). The reaction was then heated to 90°C for 6 hours. Degassed water (1,4-dioxane / water: v / v = 4:1) was added, followed by K2CO3 (2.0 equiv) and Pd(PPh3)4 (0.1 equiv). The reaction was then stirred at 90°C for 1 hour. The reaction was then cooled and quenched with brine. Ethyl acetate was then 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.

[0256] Synthesis of Compound 3-6: Compound 3-5 was used as the starting material and prepared according to the general procedure of Miyaura borylation reaction with a yield of 87%. 1 H NMR (300 MHz, CHLOROFORM-d) d 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).

[0257] Compounds 3-6 and the corresponding halogenated aromatic amides were used as starting materials and the compounds 12 in Table 2, 19-27 in Table 3 and 31-40 in Table 5 were prepared according to the general procedure of Suzuki coupling reaction:

[0258] Compound 12, yield: 78%.1 H NMR (300MHz, chloroform-d)d 8.12(d,J=2.26Hz,1H),7.69(dd,J=2.45,8.67Hz,1H),7.57(br.s.,3H),7.46-7.54(m,2H),7.42(t,J =7.54Hz,1H),7.30-7.35(m,1H),7.23(s,1H),7.14(br.s.,1H),7.04(d,J=8.85Hz,1H),6.93(t,J=8. 01Hz,1H),6.85(s,1H),6.42-6.49(m,1H),6.32(d,J=8.10Hz,1H),6.23(d,J=7.72Hz,1H),4.37-4.50 (m,1H),4.04(s,3H),3.61(q,J=5.97Hz,2H),3.21(t,J=5.56Hz,2H),2.99-3.16(m,6H),2.34(s,3H).

[0259] Compound 19, yield: 78%. 1 H NMR (300MHz, chloroform-d)d 8.64(d,J=4.90Hz,1H),8.43(d,J=2.45Hz,1H),8.25(dd,J=2.35,8.76Hz,1H),7.67(s,1H),7.55(s,1H),7 .47(d,J=6.59Hz,1H),7.33-7.20(m,2H),7.15(dd,J=1.41,4.99Hz,1H),7.08(d,J=8.85Hz,1H),6.91-6.98 (m,2H),6.84-6.90(m,1H),6.46-6.52(m,1H),6.31(d,J=8.10Hz,1H),6.23(d,J=9.04Hz,1H),4.27-4.44( m,1H),4.07(s,3H),3.61(d,J=5.46Hz,2H),3.25(t,J=5.56Hz,2H),3.15(s,3H),2.98(s,3H),2.35(s,3H).

[0260] Compound 20, yield: 80%. 1H NMR (300 MHz, chloroform-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=8.10Hz,1H),6.25(d,J=7.72Hz,1H ), 4.07 (s, 3H), 3.60-3.70 (m, 2H), 3.26 (t, J = 5.75Hz, 2H), 3.15 (s, 3H), 3.06 (s, 3H), 2.35 (s, 3H).

[0261] Compound 21, yield: 83%. 1 H NMR (300 MHz, chloroform-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 = 8.01Hz,1H),6.86(s,1H),6.48(s,1H),6.32(d,J=8.29Hz,1H),6.20(d,J=9.23Hz,1H),4.43-4.59( m,1H),4.07(s,3H),3.61-3.71(m,2H),3.24(t,J=5.56Hz,2H),3.15(d,J=3.58Hz,6H),2.34(s,3H).

[0262] Compound 22, yield: 85%. 1H NMR (300 MHz, chloroform-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=5.65Hz,2H),3.22(d,J=5.46Hz,2H),3.17(s,3H),3.11(s,3H),2.37(s,3H).

[0263] Compound 23, yield: 68%. 1 H NMR (chloroform-d, 300 MHz): d = 8.01-8.04 (m, 1H), 7.62-7.68 (m, 1H), 7.55 (d, J = 1.5 Hz, 2H), 7.47-7.52 (m, 1H), 7.45 (s, 1H), 7.30 (s, 2H), 7.00-7.05 (m, 1H), 6.91-6.99 (m, 1H), 6.79-6 .83(m,1H),6.58-6.66(m,1H),6.46-6.50(m,1H),6.31-6.37(m,1H),6.24-6.30(m,1H) ,4.21-4.34(m,1H),4.05(s,3H),3.25-3.33(m,2H),3.10-3.24(m,2H),2.38ppm(s,3H).

[0264] Compound 24, yield: 88%. 1H NMR (300 MHz, chloroform-d) d 8.08 (d, J = 2.26 Hz, 1H), 7.64 (dd, J1 = 2.35 Hz, J2 = 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=5.84Hz,2H),3.26(s,2H),3.11(br.s.,6H),2.37(s,3H).

[0265] Compound 25, yield: 70%. 1 H NMR (300MHz, chloroform-d)d 8.31(d,J=2.26Hz,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. 67Hz,1H),6.95(m,1H),6.84(s,1H),6.48(s,1H),6.37-6.43(m,1H),4.0 8(s,3H),3.57-3.67(m,5H),3.24-3.33(m,2H),3.17(s,3H),2.38(s,3H).

[0266] Compound 26, yield: 63%. 1 H NMR (300MHz, chloroform-d)d 8.03(d,J=2.26Hz,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=5.84Hz,2H),3.29(s,2H),3.14(s,3H),3.04(s,3H),2.39(s,3H).

[0267] Compound 27, yield: 67%. 1H NMR (300 MHz, chloroform-d) 7.64(d,J=2.26Hz,1H),7.58(s,1H),7.52(br.s.,1H),7.28-7.36(m,3H),6.95 (t,J=8.01Hz,1H),6.89(d,J=8.29Hz,1H),6.83(s,1H),6.67-6.75(m,1H),6.4 3(s,1H),6.35(s,1H),6.28(d,J=7.54Hz,1H),3.98(s,3H),3.64(d,J=5.65Hz, 2H), 3.30 (t, J = 5.75Hz, 2H), 2.81-2.92 (m, 8H), 2.49-2.57 (m, 2H), 2.39 (s, 3H).

[0268] Compound 31, yield: 72%. 1 H NMR (300MHz, chloroform-d)d 8.12(d,J=2.26Hz,1H),7.69(dd,J1=2.35Hz,J2=8.57Hz,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=8.67Hz,1H),6.93(t,J=8.01Hz,2H),6.46(s,1H),6.32(d,J=7.91 Hz,1H),6.23(d,J=9.23Hz,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),3.11(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).

[0269] Compound 32, yield: 75%. 1H NMR (300MHz, chloroform-d)d 8.14(d,J=2.45Hz,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=3.20Hz,2H),7.20(br.s.,2H),7.04(d,J=8.67Hz,1H),6.93(t,J=7.91Hz,2H),6.55( s,1H),6.31(d,J=8.10Hz,1H),6.23(d,J=6.22Hz,1H),4.03(s,3H),3.65(d,J=5.65Hz,2H),3.47-3.5 8(m,2H),3.26(br.s.,2H),2.57(t,J=5.75Hz,1H),2.52(d,J=6.03Hz,1H),2.31(s,6H),2.25(s,3H).

[0270] Compound 33, yield: 78%. 1 H NMR (300 MHz, chloroform-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).

[0271] Compound 34, 3-step yield: 56%. 1H NMR (300MHz, chloroform-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=7.91Hz,1H),6.85(s,1H),6.45(s,1H),6.32(d,J=8. 10Hz,1H),6.23(d,J=7.72Hz,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).

[0272] Compound 35, yield: 84%. 1 H NMR (300 MHz, chloroform-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=8.10Hz,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 = 15.82Hz, 3H), 2.34 (br.s., 3H).

[0273] Compound 36, yield: 62%. 1 H NMR (300 MHz, chloroform-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=4.90Hz,2H),4. 25-4.48(m,1H),4.00(s,3H),3.65(d,J=5.46Hz,2H),3.29(br.s.,2H),2.30(s,3H).

[0274] Compound 37, yield: 68%.1 H NMR (300 MHz, Methanol-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).

[0275] Compound 38 (RTIOX-43), yield: 80%. 1 H NMR (300 MHz, methanol-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)

[0276] Compound 39, yield: 85%. 1 H NMR (300MHz, methanol-d4)d 8.25(dd,J1=159.0Hz,J2=3.0Hz,1H),7.95(d,J=33.0Hz,1H),7.73–7.84(m,1H),7.58(dd, J1=63.0Hz, J2=9.0Hz,1H),7.18–7.62(m,9H),7.03(t,J=6.0Hz,1H),6.91(t,J=6.0Hz,1H) ,6.48-6.83(m,2H),6.42(t,J=9.0Hz,1H),6.26-6.36(m,1H),4.03(d,J=12.0Hz,3H),3.91 (t,J=6.0Hz,1H),3.71(t,J=6.0Hz,1H),3.35-3.58(m,2H),3.08-3025(m,7H),2.37(s,3H).

[0277] Compound 40, yield: 70%. 1H NMR (300MHz, chloroform-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).

[0278] General procedure for the synthesis of compounds 28, 29 and 30:

[0279] Fluorinated aminopyridine (1.0 equivalent) is mixed with ethylenediamine (10.0 equivalent) and heated to 150 ° C in a sealed tube overnight. Volatiles are then removed under reduced pressure. The residue is then suspended in DCM and DIPEA (5 equivalents) is added. 3-Methylbenzoic acid (1.0 equivalent) in DCM (1.0 M) is loaded into another round-bottom flask, followed by 1,1'-carbonyldiimidazole (CDI) (1.0 equivalent). The mixture is stirred for 15 minutes and then added to the above-mentioned suspension. The reaction is continued overnight, and the solvent is removed under reduced pressure to obtain a viscous oil, which is directly subjected to ISCO to obtain intermediate 4-2.

[0280] 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).

[0281] Intermediate 4-2-2 of compound 29 was used in the next step without further purification.

[0282] Intermediate 4-2-3 of compound 30. 1 H 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).

[0283] Intermediate 4-2 (1.0 equivalents) is dissolved in a mixture of DMF / THF (v / v=1:2, 0.5M), followed by triethylamine (4.0 equivalents) and catalysis DMAP (0.4 equivalents). The mixture is cooled to 0°C, and 5-bromo-2-methoxybenzenesulfonyl chloride (1.2 equivalents) in THF (0.5M) is slowly added, and the reactant is then warmed to room temperature and stirred overnight. Saturated NaHCO is added to quench the reaction and aqueous phase is extracted with DCM. The organic layer is separated and dried over anhydrous magnesium sulfate. The solvent is then removed under reduced pressure and ISCO is performed on residue to give intermediate 4-3.

[0284] Intermediate 4-3-1 of compound 28. 1 H NMR (300MHz, methanol-d4)d 8.02(d,J=2.45Hz,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).

[0285] Intermediate 4-3-2 of compound 29 was used in the next step without further purification.

[0286] Intermediate 4-3-3 of compound 30. 1 H NMR (300MHz, methanol-d4)d 8.08(d,J=2.45Hz,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=5.84Hz,2H),3.46(d,J=5.65Hz,2H),2.36(s,3H).

[0287] Intermediate 4-3 was then subjected to the general procedure of sequential Miyaura borylation and Suzuki coupling reactions using the corresponding halogenated aromatic amides to afford compounds 28, 29, and 30.

[0288] Compound 28, two-step yield: 64%. 1H NMR (300MHz, chloroform-d)d 8.19(d,J=2.26Hz,1H),7.93(br.s.,1H),7.73(d,J=2.26Hz,2H),7.70(d,J=2.26Hz,1H ),7.60(br.s.,2H),7.56(s,2H),7.52(br.s.,1H),7.46(t,J=7.63Hz,1H),7.34-7.38( m,1H),7.19-7.24(m,2H),7.02(d,J=8.67Hz,1H),6.30(d,J=6.03Hz,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).

[0289] Compound 29, two-step yield: 61%. 1 H NMR (300MHz, chloroform-d)d 8.10(d,J=2.45Hz,1H),7.69(d,J=2.64Hz,3H),7.51-7.62(m,6H),7.45(d,J=2.26Hz,2H),7.31-7.38(m,1H),7.04(d,J=8.6 7Hz, 2H), 6.82 (s, 1H), 4.87-5.01 (m, 1H), 4.04 (s, 3H), 3.65 (d, J = 5.09Hz, 2H), 3.14 (m, 5H), 2.96-3.09 (m, 5H), 2.32 (s, 3H).

[0290] Compound 30, two-step yield: 70%. 1 H NMR (300MHz, chloroform-d)d 8.21(d,J=2.26Hz,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=7.72Hz,1H),6.79(d,J=7 .91Hz,2H),6.64(d,J=8.85Hz,1H),5.98(d,J=8.29Hz,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).

[0291] General procedure for the synthesis of compounds 41 and 42:

[0292] Intermediate 3-4 (539 mg, 2.0 mmol) was dissolved in DCM (20 mL) and triethylamine (0.56 mL, 4.0 mmol) was added. Catalytic DMAP (25 mg, 0.4 mmol) was then introduced and the reaction mixture was cooled to 0°C. At this temperature, 5-bromo-2-methoxybenzoyl chloride (499 mg, 2.0 mmol) in THF (10 mL) was slowly added. The reactants were then stirred at this temperature for 1 hour and allowed to warm to room temperature overnight. Saturated sodium bicarbonate (50 mL) was added to quench the reaction and the reactants were 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 give the desired product 6-1. (579 mg, 60%)

[0293] Compound 6-1. 1 H NMR (300MHz, chloroform-d)d 9.61(s,1H),8.35(d,J=2.64Hz,1H),7.47-7.62(m,3H),7.21-7.35(m,4H),7.12(t,J=8.01Hz,1H),6.90(d,J=8.85Hz,1H),6.75(d,J=7.91Hz, 1H), 6.65 (br.s., 1H), 6.43 (dd, J=1.70, 8.10Hz, 1H), 4.15-4.27 (m, 1H), 4.02 (s, 3H), 3.69 (q, J=5.97Hz, 2H), 3.32-3.50 (m, 2H), 2.36 (s, 3H).

[0294] Using compound 6-1 as the starting material, compound 6-2 was synthesized according to the general procedure of Miyaura borylation reaction:

[0295] DZ14171-190 (Compound 5-2), yield: >99%. 1 H NMR (300 MHz, chloroform-d) 9.57(s,1H),8.70(d,J=1.51Hz,1H),7.91(dd,J=1.60,8.19Hz,1H),7.51-7.66 (m,2H),7.42(s,1H),7.22-7.35(m,3H),7.12(t,J=8.01Hz,1H),7.01(d,J=8.2 9Hz,1H),6.73(d,J=7.91Hz,1H),6.63(br.s.,1H),6.44(d,J=7.91Hz,1H),4.0 5(s,3H),3.72(q,J=5.65Hz,2H),3.37-3.52(m,2H),2.37(s,3H),1.33(s,12H).

[0296] Using compound 6-2 as the starting material, compounds 41 and 42 were synthesized according to the general procedure of Suzuki coupling reaction:

[0297] Compound 41, yield: 78%. 1 H 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=8.48Hz,1H),6.46(d,J=8.10Hz,2H),4.13-4.22(m,1H), 4.10(s,3H),3.68-3.78(m,2H),3.47(t,J=5.75Hz,3H),2.93-3.19(m,7H),2.38(s,3H).

[0298] Compound 42, yield: 72%. 1 H NMR (300MHz, chloroform-d)d 9.75(br.s.,1H),8.62(d,J=6.03Hz,2H),8.40-8.57(m,1H),7.69(d,J=7 .72Hz,3H),7.36-7.60(m,5H),7.28-7.34(m,3H),7.06-7.22(m,3H),6.7 2-6.83(m,1H),6.46(d,J=7.91Hz,1H),4.78(br.s.,2H),4.10(s,3H),3. 74(q,J=5.84Hz,2H),3.41-3.53(m,2H),2.90-3.16(m,3H),2.37(s,3H).

[0299] General procedure for the synthesis of compounds 43 and 44:

[0300] 3-Bromo-5-fluoropyridine (1 equivalent) was dissolved in ethylenediamine (20 equivalents) and the reaction was heated to 150° C. in a sealed tube overnight. After cooling to room temperature, the volatiles 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 give a viscous oil, which was redissolved in DCM (0.25 M).

[0301] 3-Methylbenzoic acid (1 equivalent) and 1,1'-carbonyldiimidazole (1 equivalent) were mixed in DCM (0.1M) and stirred for 15 minutes. The mixture was added dropwise to the above solution and the reaction was stirred overnight. Salt water was added to quench the reaction and the reactant 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 in the form of an off-white solid.

[0302] Intermediate 6-B, yield: 59%. 1 H NMR (300MHz, chloroform-d)d 7.98(d,J=1.70Hz,1H),7.94(d,J=2.26Hz,1H),7.59(s,1H),7.53(br.s.,1H),7.33(d,J=5.09Hz,2H),7.04(t,J =2.17Hz,1H),6.36-6.50(m,1H),4.57-4.74(m,1H),3.75(q,J=5.97Hz,2H),3.38(d,J=5.65Hz,2H),2.40(s,3H).

[0303] Synthesis of compound 6-D.

[0304] N-Boc-ethanolamine (1.3 eq) was dissolved in THF (0.5 M) and diisopropyl azodicarboxylate (1.03 eq) was added. The reaction mixture was stirred at room temperature for 30 minutes and 3-bromo-5-hydroxypyridine (1.0 eq) was added followed by triphenylphosphine (1.5 eq). The reaction was then stirred overnight. The reaction was then cooled to 0°C and concentrated HCl (V) was added. 反应混合物 / V 浓HCl =2:1). The reaction was warmed to room temperature and stirred for 30 minutes until bubbling ceased. The acidic aqueous solution was then washed three times with DCM. The aqueous solution was made alkaline with potassium carbonate (pH>10.0) and ethyl acetate was introduced. Boc2O (1.2 equiv) was then added and the reaction 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.

[0305] Compound 6-C, white solid, yield: 82%. 1 H NMR (300MHz, chloroform-d)d 8.30(d,J=1.88Hz,1H),8.24(d,J=2.45Hz,1H),7.37(t,J=2.17Hz,1H),4.8 8-5.08(m,1H),4.06(t,J=5.09Hz,2H),3.55(q,J=5.27Hz,2H),1.46(s,9H).

[0306] Compound 6-C (1 equivalent) was treated with 4N HCl to yield 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 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 to yield compound 6-E, which was used in the next step without further purification.

[0307] Commercially available thiosemicarbazide (1.0 eq) and 5-bromo-2-methoxybenzoic acid (1.0 eq) were mixed in POCl3 (14.0 eq) and the reaction was heated at 75°C for half an hour. After cooling to room temperature, water (V H2O / V POCl3 =4:1) and the reaction was refluxed for 4 hours. After cooling to room temperature, the mixture was basified to pH 8.0 by dropwise addition of 50% NaOH solution with stirring. The precipitate was collected by filtration to give pure compound 6-3 as a white solid.

[0308] Compound 6-3, yield: 76%. 1 H NMR (300MHz, DMSO-d6)d 8.18 (d, J = 2.64Hz, 1H), 7.55-7.63 (m, 1H), 7.30 (s, 2H), 7.20 (s, 1H), 3.93 (s, 3H).

[0309] Using compound 6-3 as the starting material, compound 6-5 was synthesized according to the general procedure of sequential Miyaura borylation and Suzuki coupling reactions:

[0310] Compound 6-5, two-step yield: 56%. 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).

[0311] General procedure for the synthesis of compounds 43 and 44:

[0312] Under nitrogen, compound 6-5 (1.0 equivalent), t-BuBrettphos (0.132 equivalent), Pd2(dba)3 (0.03 equivalent) and potassium carbonate (1.4 equivalent) are mixed in a sealed tube. Compound 6-B or compound 6-E (1.0 equivalent) is then introduced, followed by anhydrous t-BuOH (0.1M). The reaction mixture is then degassed and refilled three times with nitrogen. The reactant is then sealed and heated to 100°C overnight. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and filtered. The filtrate is then washed with water and brine. The organic layer is dried and the solvent is removed under reduced pressure. The residue is then purified by ISCO to obtain the desired product.

[0313] Compound 43, off-white solid, yield: 71%. 1 H NMR (300MHz, chloroform-d)d 8.60(d,J=5.27Hz,3H),8.18(s,1H),8.10(s,1H),7.93(d,J=2.26Hz,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=5.18Hz,2H),4.01(br.s.,3H),3.88(t,J=5.18Hz,2H),2.94-3.18(m,3H),2.39(s,3H).

[0314] 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).

[0315] Synthesis of compound 7-A:

[0316] 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 was then warmed to room temperature and stirred for 2 hours. Water (50 mL) was added and the white precipitate was collected by filtration and air-dried overnight.

[0317] 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).

[0318] General procedure for the synthesis of intermediate 7-5:

[0319] 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.

[0320] Compound 7-1 (1.0 equivalent) was dissolved in a mixture of MeOH / THF / water (v / v / v=15:5:3, 0.2M) and LiOH HO (6.0 equivalents) was added. The reaction was then stirred at room temperature for 2 hours. 2N HCl (10 equivalents) 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 to give a generally white solid (compound 7-2), which was used in the next step without further purification.

[0321] Compound 7-2 (1.0 equivalent) was suspended in DCM (0.1 M) and 1,1'-carbonyldiimidazole (1.0 equivalent) was added. The reaction was stirred at room temperature for 1 hour until the mixture became homogeneous. N-Boc-ethylenediamine (1.2 equivalents) was then added in one go and the reaction was stirred overnight. 1N HCl (10 equivalents) 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 to give intermediate 7-3, which was treated with 4N HCl (20 equivalents) in dioxane for 30 minutes. The solvent was then removed to give intermediate 7-4, which was used in the next step without further purification.

[0322] 3-Methylbenzoic acid (1 equivalent) and 1,1'-carbonyldiimidazole (1 equivalent) were mixed in DCM (0.1M) and stirred for 15 minutes. Intermediate 7-4 from the previous step was suspended in DCM (0.1M) and the above reaction mixture was added dropwise thereto. The reaction was then stirred at room temperature overnight. 1N HCl (10 equivalents) 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 to obtain compound 7-5.

[0323] Intermediate 7-5-1 of compounds 47 and 48, yield in 5 steps: 21%. 1 H NMR (300MHz, methanol-d4)d 8.00(d,J=2.45Hz,1H),7.73(dd,J=2.54,8.95Hz,1H),7.51-7.64(m,2H),7.25-7.39(m,2H),7.12(d,J=8.8 5Hz, 1H), 3.87-3.98 (m, 3H), 3.45 (d, J = 5.84Hz, 2H), 3.39 (d, J = 5.46Hz, 2H), 3.20-3.27 (m, 2H), 2.39 (s, 3H).

[0324] Intermediate 7-5-2 of compounds 49 and 50: Yield in 5 steps: 19%. 1 H NMR (300MHz, methanol-d4)d 7.93-8.02(m,1H),7.74(dd,J=2.54,8.95Hz,1H),7.51-7.66(m,2H),7.34(d,J=5.65Hz,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 = 5.65Hz, 2H), 2.29-2.43 (m, 3H), 1.38-1.54 (m, 4H).

[0325] Intermediate 7-5-3 of compounds 53 and 54: Yield in 5 steps: 25%. 1 H NMR (300MHz, methanol-d4)d 7.82(d,J=2.64Hz,1H),7.56-7.75(m,3H),7.27-7.40(m,2H),7.16(d,J=8.85Hz,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=17.52Hz,4H),1.17(br.s.,2H).

[0326] Using compound 7-5 as the starting material, compounds 47, 48, 49, 50, 53 and 54 were synthesized according to the general procedure of sequential Miyaura borylation and Suzuki coupling reactions:

[0327] Compound 47, two-step yield: 70%. 1H NMR (300MHz, chloroform-d)d 8.19(m,1H),7.72(d,J=7.54Hz,2H),7.50-7.67(m,6H),7.42(m,1H),7.34(m,1H),7.20(m,1H),7.01(d,J=8.67Hz ,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).

[0328] Compound 48, two-step yield: 61%. 1 H NMR (300 MHz, methanol-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).

[0329] Compound 49, two-step yield: 65%. 1 H NMR (300MHz, methanol-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).

[0330] Compound 50, two-step yield: 58%. 1H NMR (300MHz, methanol-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=6.59Hz,4H).

[0331] Compound 53, two-step yield: 76%. 1 H NMR (300 MHz, chloroform-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(br.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).

[0332] Compound 54, two-step yield: 69%. 1 H NMR (300 MHz, chloroform-d) 8.62(d,J=5.46Hz,2H),7.90-8.11(m,1H),7.52-7.87(m,5H),7.30-7.52(m,3 H),7.28-7.30(m,1H),7.25(br.s.,2H),7.10(d,J=16.58Hz,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).

[0333] General procedure for the synthesis of compounds 45, 46, 51 and 52:

[0334] 3-Methylbenzoic acid (1 equivalent) was dissolved in DCM (0.1 M) and 1,1'-carbonyldiimidazole (1.0 equivalent) was added. The reaction was then stirred at room temperature for 15 minutes, after which N-Boc-ethylenediamine (1.2 equivalents) was added. The reaction was stirred overnight. 1N HCl (10 equivalents) 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 to give intermediate 7-B, which was treated with 4N HCl (20 equivalents) in dioxane to give intermediate 7-C.

[0335] N-Boc-amino acids with different alkyl chain lengths (1.0 equivalents) were dissolved in DCM (0.1 M) and 1,1'-carbonyldiimidazole (1.0 equivalents) was added. The reaction was then stirred at room temperature for 15 minutes, followed by the addition of intermediate 7-C from the previous step, followed by DIPEA (3.0 equivalents). The reaction was stirred overnight. 1N HCl (10 equivalents) was added to quench the reaction and the reactants were extracted with ethyl acetate. The organic layer was then separated and dried. The solvent was removed under reduced pressure to give intermediate 7-D, which was treated with 4N HCl (20 equivalents) in dioxane to give intermediate 7-E or 7-F.

[0336] At 0 ° C, intermediate 7-E or 7-F (1 equivalent) is suspended in DCM (0.1M) and triethylamine (4.0 equivalents) is added. Then catalytic DMAP (0.4 equivalents) is introduced. At this temperature, 5-bromo-2-methoxybenzenesulfonyl chloride (1.0 equivalents) in THF (10mL) is slowly added. The reactants are then stirred at this temperature for 1 hour and allowed to warm to room temperature overnight. Saturated sodium bicarbonate (50mL) is added to quench the reaction and the reactants are extracted with ethyl acetate (50mL). The organic layer is separated and dried. The solvent is removed under reduced pressure, and the residue is subjected to ISCO to obtain the desired product 7-7.

[0337] Intermediate 7-7-1 of compounds 51 and 52: Yield in 5 steps: 25%. 1 H NMR (300MHz, methanol-d4)d 7.93-8.02(m,1H),7.74(dd,J=2.54,8.95Hz,1H),7.51-7.66(m,2H),7.34(d,J=5.65Hz,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 = 5.65Hz, 2H), 2.29-2.43 (m, 3H), 1.38-1.54 (m, 4H).

[0338] Intermediate 7-7-2 of compounds 45 and 46: Yield in 5 steps: 28%.1 H NMR (300MHz, methanol-d4)d 7.82(d,J=2.64Hz,1H),7.56-7.75(m,3H),7.27-7.40(m,2H),7.16(d,J=8.85Hz,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=17.52Hz,4H),1.17(br.s.,2H).

[0339] Using intermediate 7-7 as the starting material, compounds 45, 46, 51 and 52 were synthesized according to the general procedure of sequential Miyaura borylation and Suzuki coupling reactions:

[0340] Compound 45, two-step yield: 60%. 1 H NMR (300MHz, chloroform-d)d 8.10(d,J=2.26Hz,1H),7.75(dd,J=2.35,8.57Hz,1H),7.50-7.65(m,4H),7 .40-7.50(m,1H),7.37(d,J=7.54Hz,1H),7.29(d,J=4.33Hz,2H),7.00-7.1 4(m,2H),6.61(br.s.,1H),5.91(t,J=6.40Hz,1H),3.95-4.03(m,3H),3.57 (br.s.,2H),3.46(d,J=5.09Hz,2H),2.95-3.26(m,8H),2.32-2.47(m,5H).

[0341] Compound 46, two-step yield: 70%. 1 H NMR (300MHz, chloroform-d)d 8.61(br.s.,2H),8.12(br.s.,1H),7.36-7.85(m,7H),7.29(d,J=4.71Hz,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 = 5.65Hz, 2H), 2.37 (s, 3H).

[0342] Compound 51, two-step yield: 62%. 1H NMR (300MHz, chloroform-d)d 8.07(d,J=2.26Hz,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=8.67Hz,3H),5.78(s,1H),4.02(s,3H),3.57(d,J=5.84Hz,4H),3.45(br.s.,2H),2.95-3.18(m,6H),2.37(s,3H).

[0343] Compound 52, two-step yield: 68%. 1 H NMR (300MHz, 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).

[0344] General procedure for the synthesis of compounds 33, 34, 35 and 36:

[0345] 3-Methylbenzoic acid (1 equivalent) and 1,1'-carbonyldiimidazole (1 equivalent) were mixed in DCM (0.1 M) and stirred for 15 minutes. Cycloaminol (1 equivalent) of varying sizes was added and the reaction was stirred overnight. 1N HCl (10 equivalents) 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 to provide Intermediate 8-A, which was used in the next step without further purification.

[0346] Intermediate 8-A (1 equivalent) was dissolved in DMF (0.25 M) and the solution was cooled to 0 ° C. NaH (60% in oil, 1.2 equivalents) was added several times at a rate such that the internal temperature did not exceed 10 ° C. 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 reactants were warmed to room temperature and stirred overnight. The reaction 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 give a viscous oil, which was purified by ISCO to give the desired product.

[0347] Intermediate 8-B-1 of compound 56, two-step yield: 53%. 1H NMR (300MHz, chloroform-d)d 8.35(d,J=1.88Hz,1H),8.12(d,J=2.45Hz,1H),7.47(s,1H),7.40(d,J=3.96Hz,1H),7.28-7.35(m,2H),7 .23(t,J=2.17Hz,1H),4.95-5.08(m,1H),4.63(dd,J=6.50,10.08Hz,2H),4.31(br.s.,2H),2.39(s,3H).

[0348] Intermediate 8-B-2 of compound 57, two-step yield: 52%. 1 H 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).

[0349] Intermediate 8-B-3 of compound 58, two-step yield: 60%. 1 H NMR (300MHz, 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).

[0350] Using compound 7-A as the starting material, compound 8-2 was synthesized according to the general procedure of sequential Miyaura borylation and Suzuki coupling reactions:

[0351] Compound 8-2, off-white solid, two-step yield: 93%. 1 H 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).

[0352] General procedure for the synthesis of compounds 55, 56, 57 and 58:

[0353] Compound 8-2 (1 equivalent) is placed in a sealed tube. tBuXphos (0.1 equivalent) is placed, followed by the introduction of compound 6-C or compound 8-B (1 equivalent). Cesium carbonate (2.4 equivalents) is then added, followed by injection of 1,4-dioxane (0.1M). The mixture is then degassed and refilled three times with nitrogen. Pd2(dba)3 (0.05 equivalent) is then added. The tube is then sealed and heated to 100°C overnight. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and filtered. The filtrate is then washed with water and brine. The organic layer is dried and the solvent is removed under reduced pressure. The residue is purified by ISCO to obtain the desired product.

[0354] Compound 55, yield: 62%. 1 H NMR (300 MHz, chloroform-d) 8.62(d,J=6.03Hz,2H),8.04(d,J=2.64Hz,2H),7.85(d,J=2.07Hz,1H),7.78 (s,1H),7.49-7.63(m,4H),7.35-7.48(m,2H),7.29(br.s.,2H),6.99-7.22(m ,3H),6.75-6.91(m,1H),4.49-4.80(m,2H),4.13(t,J=6.0Hz,2H),4.07(br. s.,3H),3.83(dd,J1=6.0Hz,J2=3.0Hz,2H),2.91-.3.15(m,3H),2.37(s,3H).

[0355] Compound 56, yield: 78%. 1 H NMR (300MHz, 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).

[0356] Compound 57, yield: 59%.

[0357] 1H 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).

[0358] Compound 58, yield: 69%. 1 H NMR (300MHz, chloroform-d)d 8.62(d,J=5.09Hz,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).

[0359] Compound 59 was synthesized using compound 3-6 as the starting material according to the general procedure of sequential Miyaura borylation and Suzuki coupling reactions (compound 38 can also be obtained by this procedure):

[0360] Compound 59 (RTIOX-45), two-step yield: 58%. 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=8.85Hz,1H),6.49(d,J=13.37Hz,1H),6.33(d,J=8.48Hz,1H),6.24-6.30(m,1H),4.77(d,J=18.08Hz,2H),4.05(d,J=19 .78Hz,3H),3.59(dd,J=5.75,11.77Hz,2H),3.25(dd,J=5.56,10.46Hz,2H),3.12(d,J=7.35Hz,3H),2.36(d,J=2.07Hz,3H)

[0361] General procedure for the synthesis of 60 and 61:

[0362] Compound 7-A (1 equivalent) and compound 6-B (1 equivalent) are mixed in a sealed tube. tBuXphos (0.1 equivalent) and cesium carbonate (2.4 equivalents) are then added, followed by injection of 1,4-dioxane (0.1M). The mixture is then degassed and refilled three times with nitrogen. Pd2(dba)3 (0.05 equivalent) is then added. The tube is then sealed and heated to 110°C overnight. After cooling to room temperature, the reaction mixture is diluted with ethyl acetate and filtered. The filtrate is then washed with water and brine. The organic layer is dried and the solvent is removed under reduced pressure. The residue is redissolved in DCM, and the solution is passed through short silica gel to obtain a clear solution. The solvent is then removed under reduced pressure to obtain crude intermediate 9-1, which can be used in the next step without further purification.

[0363] Using compound 9-1 as the starting material, the synthesis of 60 and 61 was achieved according to the general procedure of sequential Miyaura borylation and Suzuki coupling reactions:

[0364] Compound 60 (RTIOX-46), 3-step yield: 48%. 1H NMR (300MHz, chloroform-d)d 8.57(d,J=6.0Hz,1H),8.500(dd,J1=129.0Hz,J2=3.0Hz,1H),8.495(dd,J1=129.0Hz,J2=3.0Hz,1H),8.05(d dd, J1=141.0Hz, J2=9.0Hz, J3=3.0Hz,1H),7.98-7.89(m,1H),7.89-7.83(m,1H),7.63-7.53(m,5H),7.47(d,J =3.0Hz,1H),7.40(d,J=3.0Hz,1H),7.37-7.29(m,2H),7.17(dd,J1=69.0Hz,J2=9.0Hz,1H),6.89(dd,J1=12.0 Hz,J2=3.0Hz,1H),4.00(d,J=14.13Hz,3H),3.42(br,2H),3.21(br,2H),3.12(d,J=2.64Hz,3H),2.37(s,3H).

[0365] Compound 61 (RTIOX-47), 3-step yield: 52%. 1 H NMR (300MHz, methanol-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).

[0366] Biological Examples

[0367] OX1R and OX2R calcium mobilization assays.

[0368] The activity of target compounds at human OX1 and OX2 receptors was determined using CHO RD-HGA16 cells (Molecular Devices) engineered to stably express human OX1 or human OX2 receptors. Cells were maintained in a medium supplemented with 10% fetal bovine serum, 100 units of penicillin and streptomycin, and 100 μg / mL normocin. TMHam's F12. For the assay, cells were plated at 25,000 cells / well and incubated overnight at 37°C, 5% CO2. The next day, the cells were washed with assay buffer and loaded with Calcium 5 dye (Molecular Devices). After 45 minutes, the cells were pretreated with a 9% DMSO solution for 15 minutes. Our group has found that this pretreatment incubation period greatly reduces the DMSO-mediated increase in fluorescence. The test compound (8-point concentration response curve) was then added to the 1% DMSO solution and fluorescence was measured using a FlexStation II. In this assay platform, receptor activation is measured by an increase in fluorescence, which is proportional to the increase in internal calcium. The test compound EC 50 The values ​​were determined by nonlinear regression analysis and are the means ± SEM of at least three independent experiments run in duplicate.

[0369] Potency of OX1R and OX2R in calcium mobilization assays.

[0370] All synthesized compounds were characterized for their agonist potency in a calcium mobilization assay using CHO cells overexpressing OX1R or OX2R. See 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, incorporated herein for information on such assays. 50 Listed in Table 1-12.

[0371] Structure-activity elucidation was performed to determine if the model for the terminal aromatic ring on the left side of the compound shown was applicable. Several other alkylamides were substituted for the dimethylaminoamide, but no improvement in potency was observed. When the carbonyl functional group was removed, a complete loss of activity was observed, confirming its importance for orexin receptor activation.

[0372] Table 1.

[0373]

[0374]

[0375] Aromatic amides and ethyl groups on the rightmost moiety were explored. A methyl substituent on the ethyl group slightly reduced potency at both receptors. Extension of the ethyl group to the 3-carbon propyl group resulted in little change in potency. The 3-methylphenyl group appeared to provide improved potency at both the OX1R and OX2R and was therefore used in subsequent SAR studies. When the ethyl group was converted to a rigid piperazine group, all activity was lost.

[0376] Table 2.

[0377]

[0378]

[0379] The first phenyl ring on the left side is replaced with a series of aromatic rings. As an example, 2,6-substituted pyridyl groups improve potency at both OX1R and OX2R. Two 5-membered rings, thiazole and oxazole, were examined and found to be significantly less potent. Ethyl and ethyl analogs were inactive at both receptors.

[0380] SAR Table 3:

[0381]

[0382]

[0383]

[0384] The central phenyl ring was explored and replaced with a pyridyl group. Although the 3,5-pyridyl group was less potent at the OX2R, it was equally potent at both receptors. This suggests that the nitrogen in the 3,5-pyridyl group may have interactions that favor the OX1R. Furthermore, the introduction of nitrogen reduces the electron density of the aromatic ring, potentially making it less susceptible to oxidation and resulting in better PK properties.

[0385] SAR Table 4:

[0386]

[0387]

[0388] Given the importance of the carbonyl group at the amide functional group on the left, the amide was retained and further substitutions at this position were explored. The methyl group on the amide was replaced with a dimethylaminoethyl group, which provided a site for salt formation with the dimethylamino group to improve solubility. However, a slight decrease in efficacy was observed. Notably, removing the other methyl group on the nitrogen caused a sharp decrease in efficacy at OX2R (31 vs. 32), and a complete loss of efficacy at OX1R. Introducing a pyridyl or benzyl group instead of the methyl group on the dimethylamino group resulted in a significant decrease in efficacy at both receptors, with most being inactive at OX1R. However, when a 2-pyridylmethyl group was introduced, the efficacy was completely reversed, showing efficacy similar to compound 1 (YNT-185) at both OX1R and OX2R. This suggests that hydrogen bonding or polar interactions may exist between the pyridyl group and the OX receptor. Similarly, removing the other methyl group on the dimethylamino group again resulted in a complete loss of efficacy at OX1R (35 vs. 36). Next, different pyridylmethyl groups were examined. While the 3-pyridylmethyl group showed a slight decrease in potency, it is exciting that compound 38 with a 4-pyridylmethyl group showed higher and equivalent potency at both OX1R and OX2R, significantly more potent than compound 1 (YNT-185). Replacing the pyridylmethyl group with a longer pyridylethyl group did not improve potency (compounds 39 and 40).

[0389] SAR Table 5:

[0390]

[0391]

[0392]

[0393] The sulfonamide functionality proved to be important for activity, and this was confirmed by 41, which was inactive at the OX1R and had micromolar potency at the OX2R. A pyridylmethyl group at the amide significantly increased both OX1R and OX2R but did not restore potency. We then considered replacing it with 1,3,4-thiadiazole, which can be considered a bioisostere of either the amide or the sulfonamide. However, both compounds (43 and 44) ​​were inactive. This further confirmed the importance of the sulfonamide for achieving activity at the orexin receptor.

[0394] SAR Table 6:

[0395]

[0396]

[0397]

[0398] They then replaced the central phenyl group attached to the sulfonamide nitrogen with alkyl or dicarbonyl groups to investigate whether flexibility could be introduced into this region. However, these compounds were mostly inactive.

[0399] SAR Table 7:

[0400]

[0401]

[0402]

[0403] The ethyl linker proved to be important for activity (Table 2). Due to the presence of a favorable pyridylmethyl group, we re-examined this region. We first replaced the nitrogen with an oxygen atom, which resulted in a ~20-fold decrease in potency at both OX1R and OX2R. When an aliphatic ring was introduced to provide more flexible strain, these analogs did not result in an increase in potency, but 56 showed potency similar to 38 at OX2R.

[0404] SAR Table 8:

[0405]

[0406]

[0407] Finally, several analogs were synthesized that incorporate unexpected key structural elements that result in improved potency at orexin receptors, particularly OX1R (Table 9). These key elements include, but are not limited to: (1) a 4-pyridyl group at Ar1, which is essential for OX1 activity; (2) a 2,6-pyridyl group at Ar2, which facilitates increased potency at both OX1R and OX2R; and (3) a 3,5-pyridyl group at Ar3, which may contribute to increased metabolic stability by reducing electron density. Of all the analogs, one example, compound 61 (RTIOX-47), demonstrated superior overall properties.

[0408] SAR Table 9:

[0409]

[0410]

[0411] The ADME properties of the three most potent compounds were evaluated. All compounds were in salt form and had excellent water solubility at pH 2. While compound 1 (YNT-185), RTIOXA-43, and RTIOXA-45 had moderate metabolic stability in rat liver microsomes (RLM), RTIOXA-47 showed a significantly prolonged half-life (t 1 / 2Compared to the other three compounds, the main structural difference is that in RTIOXA-47, the pyridyl group is linked to the sulfonamide. Replacing the phenyl group with a pyridyl group reduces the electron density of the aromatic ring. The inventors hypothesize that this may lead to a reduced susceptibility to metabolic oxidation.

[0412] Table 10. ADME properties of examples of orexin agonists

[0413]

[0414]

[0415] SAR Table 11:

[0416]

[0417]

[0418] SAR Table 12:

[0419]

[0420]

[0421] analyze

[0422] YNT-185 is one of the earliest reported small molecule orexin agonists. YNT-185 primarily activates OX2R, with minimal agonist activity at OX1R. Through extensive SAR studies at multiple sites, the present 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 having excellent agonist efficacy at both orexin receptors, RTIOXA-47 also exhibits significantly improved metabolic stability when compared to YNT-185.

[0423] The specific pharmacological response observed may vary depending on or upon the particular active compound selected or the presence or absence of a pharmaceutical carrier, as well as the type of formulation and mode of administration employed, and such expected variations or differences in results are contemplated from the practice of the present disclosure.

[0424] Although specific embodiments of the present disclosure are described and illustrated in detail herein, the present disclosure is not limited thereto. The above detailed description is provided as an example of the present disclosure and should not be construed as constituting any limitation of the present disclosure. Modifications will be apparent to those skilled in the art, and all modifications that do not depart from the spirit of the present disclosure are intended to be included within the scope of the appended claims.

Claims

1. A compound, which is a compound of formula (I): or a pharmaceutically acceptable salt thereof, in A is a phenylene group or a divalent pyridyl group; B is a phenylene group or a divalent pyridyl group; R 1 Yes (CH2) m -pyridyl; 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; 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 It is C 1-10 Alkyl, (CH2) n -C 3-6 Cycloalkyl or (CH2) n -phenyl, Each R 3 Optionally substituted with one or more substituents selected from: C 1-6 Alkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 alkyl)2; and Each n is independently 0, 1, 2 or 3.

2. The compound according to claim 1, wherein m is 1.

3. The compound according to claim 1, wherein R 2 It is C 1-6 alkyl.

4. The compound according to claim 3, wherein R 2 It is CH3. The compound according to claim 1 , wherein A is phenylene. The compound according to claim 1 , wherein A is a divalent pyridyl group. The compound according to claim 1 , wherein B is phenylene. The compound according to claim 1 , wherein B is a divalent pyridyl group.

9. The compound of claim 1, wherein X is NH or NHC(O).

10. The compound of claim 1, wherein X is O.

11. The compound according to claim 1, wherein Y is a bond or C 2-6 Alkylene.

12. The compound according to claim 11, wherein Y is CH2CH2.

13. The compound of claim 1, wherein Y is 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. The compound according to claim 13 , wherein for Y, the heterocyclyl ring contains at least one N atom.

15. The compound of claim 1, wherein Z is C(O) or NHC(O).

16. The compound of claim 1, wherein Z is C(O).

17. The compound of claim 1, wherein each of X, Y, and Z is a bond.

18. The compound according to claim 1, wherein R 3 It is C9 alkyl, C8 alkyl, C7 alkyl, C6 alkyl, C5 alkyl, C4 alkyl, C3 alkyl, CH2CH3 or CH3.

19. The compound according to claim 18, wherein R 3 It is a C9 alkyl group, a C8 alkyl group, a C7 alkyl group, a C6 alkyl group or a C5 alkyl group.

20. The compound according to claim 1, wherein R 3 Yes (CH2) n -C 3-6 Cycloalkyl.

21. The compound according to claim 20, wherein R 3 Yes (CH2) n -C 5-6 Cycloalkyl.

22. The compound according to claim 21, wherein R 3 It is (CH2)1-C6 cycloalkyl, (CH2)2-C6 cycloalkyl or (CH2)3-C6 cycloalkyl.

23. The compound according to claim 1, wherein R 3 Yes (CH2) n -phenyl.

24. The compound of claim 23, wherein n is 0.

25. The compound according to claim 1, wherein R 3 Substituted with one or more substituents selected from the group consisting of: C 1-6 Alkyl, NH2, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2.

26. The compound according to claim 25, wherein R 3 Through one or more C 1-6 Alkyl substitution.

27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 26 and one or more pharmaceutically acceptable excipients.

28. Use of a compound according to any one of claims 1 to 26 or a pharmaceutical composition according to claim 27 for the preparation of a medicament for treating a disease or condition caused by decreased orexin activity in a subject, wherein when the medicament is used, an effective amount of the compound is administered to the subject.

29. The use according to claim 28, wherein the disease or condition is one or more of the following: a sleep disorder, a cognitive disorder or an addiction.

30. The use of claim 28, wherein the disease or condition is one or more of narcolepsy, cataplexy, insomnia, sleep state regulation, apnea, wake state regulation, sleep-wake cycle, accelerated recovery from anesthesia, jet lag, appetite regulation, feeding regulation, eating disorders, gastrointestinal motility, energy balance, metabolic disorders, obesity, memory, mental clarity, Alzheimer's disease, attention deficit, dementia, mild cognitive impairment, Parkinson's disease, cognitive dysfunction, brain injury, drug addiction, blood pressure regulation, ischemic events, oxidative stress events, and cancer.

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