Novel substituted benzimidazole derivatives as D-amino acid oxidase (DAAO) inhibitors

Abstract

To provide novel substituted benzimidazole derivatives used as DAAO inhibitors for treatment and / or prevention of neurological disorders.SOLUTION: The present invention provides a compound having the following structural formula.SELECTED DRAWING: None

Description

[Technical Field]

[0001] References to related applications This application claims priority to U.S. Provisional Application No. 62 / 394,479, filed on 14 September 2016, which is incorporated by reference in its entirety.

[0002] The present invention relates to D-amino acid oxidase (DAAO) inhibitors. More specifically, the present invention provides novel substituted benzimidazole derivatives used as DAAO inhibitors for the treatment and / or prevention of neurological disorders. [Background technology]

[0003] Abnormalities in the regulatory mechanisms of glutamatergic neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors have been reported in neuropathology as a contributing factor to schizophrenia. The receptor is a heterotetramer composed of two subunits: NMDA receptor 1 (NR1) and NMDA receptor 1 (NR2). Modulation of the glycine-binding site of the NMDA receptor may improve cognitive function and the negative symptoms of schizophrenia. DAAOs are known to be involved in the activation process of the NMDA receptor. DAAO substrates, particularly D-serine, can bind to the glycine site of the NMDA receptor as co-agonists, thereby regulating the opening of calcium channels in the NMDA receptor. D-serine is known to inhibit α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated currents in rat hippocampal neurons. Therefore, DAAOs were hypothesized to be involved in the pathogenesis of schizophrenia. Furthermore, since NMDA receptors are also involved in emotional disorders, inhibiting DAAO may enhance the function of NMDA receptors and potentially improve symptoms of schizophrenia and other emotional disorders such as depression.

[0004] Well-known DAAO inhibitors include benzoic acid, pyrrole-2-carboxylic acid, and indole-2-carboxylic acid. Indole derivatives, in particular certain indole-2-carboxylates, have been documented in the literature for the treatment of neurodegenerative diseases and neurotoxic injury. Patent Document 1 discloses indole-2-carboxylates and derivatives for the treatment or management of neurotoxic injury caused by central nervous system disorders or traumatic events, or for the treatment or management of neurodegenerative diseases. Patent Documents 2-6 disclose the treatment of neurotoxic injury and neurodegenerative diseases using indole derivatives. Patent Document 7 discloses DAAO inhibitors containing indole-2-carboxylic acid, and methods for treating neurodegenerative diseases, as well as methods for improving learning, memory, and cognition. Patent Document 8 discloses benzoisoxazole analogs and methods for treating mental disorders such as schizophrenia. Patent Document 9 discloses a list of well-known compounds as DAAO inhibitors.

[0005] There is a need to develop candidate drugs with DAAO inhibitory effects to treat various neurological and physical diseases. [Prior art documents] [Patent Documents]

[0006] [Patent Document 1] European Patent No. 396124 [Patent Document 2] U.S. Patent No. 5,373,018 [Patent Document 3] U.S. Patent No. 5,374,649 [Patent Document 4] U.S. Patent No. 5,686,461 [Patent Document 5] U.S. Patent No. 5,962,496 [Patent Document 6] U.S. Patent No. 6,100,289 [Patent Document 7] International Public Gazette No. 03 / 039540 [Patent Document 8] International Public Gazette No. 2005 / 089753 [Patent Document 9] International Public Gazette No. 2015 / 168346 [Overview of the project]

[0007] The present invention provides a list of substituted benzimidazole derivatives used as DAAO inhibitors for the treatment and / or prevention of neurological disorders.

[0008] The present invention provides a compound having formula (I) as described below. Each substituent is described in this specification.

[0009] The present invention also provides pharmaceutical compositions comprising the compounds of the present invention.

[0010] The present invention also provides a method for inhibiting DAAO. The method involves contacting cells with the compound of the present invention.

[0011] The present invention also provides a method for treating or preventing DAAO-related diseases in a subject. The method comprises administering an effective amount of the compound of the present invention to the subject.

[0012] In some embodiments, the disorder is the symptomatic area of ​​schizophrenia and schizoaffective disorder, depression, Tourette syndrome, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), congenital insensitivity to pain, memory and / or cognitive loss associated with neurodegenerative diseases, or loss of neurological function that is characteristic of neurodegenerative diseases. Specific embodiments include mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease, and schizophrenia. [Brief explanation of the drawing]

[0013] [Figure 1] This figure shows that the enhancement of MK-801-induced spontaneous movement can be overcome by using RS-D7, drug 12083, and prodrug 28095 at different doses compared to the MK801 group. [Figure 2]This figure shows that different doses of RS-D7, drug 12083, and prodrug 28095 overcome anesthesia after acute injection of MK-801. [Figure 3] This figure shows that prepulse suppression (PPI) was significantly reduced after acute injection of MK-801. [Modes for carrying out the invention]

[0014] In this specification and the scope of the attached claims, singular articles mean both singular and plural unless otherwise specified. Where ranges are used for physical properties such as molecular weight or chemical properties such as chemical formulas, they are intended to include combinations of those ranges, subcombinations, and all of the particular embodiments. The term "or" means "and / or" unless it is specifically stated that it refers only to substitutes or that the substitutes exclude each other. The term "about" used when referring to a range of numbers or numerical values ​​is used to represent an approximation of the number or numerical range within the range of experimental variability (or within the range of statistical experimental error). The term "contains" (and related term "has") is not intended to exclude the fact that, in other particular embodiments, for example, a compound, composition, method, or process described in this specification "consists of" or "essentially constitutes" the described features.

[0015] definition "Alkyl" refers to a group that does not contain unsaturated carbon atoms and has 1 to 15 carbon atoms (for example, C1-C1). 15 This refers to a linear or branched hydrocarbon chain radical consisting only of carbon atoms and hydrogen atoms, having an alkyl group. In certain embodiments, alkyl may be 1 to 13 carbon atoms (e.g., C1-C1). 10It contains alkyl. In certain embodiments, the alkyl contains 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl contains 1 to 5 carbon atoms (e.g., C1-C6 alkyl). In other embodiments, the alkyl contains 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl contains 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl contains 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl contains 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl contains 5 to 15 carbon atoms (e.g., C5-C 15 In other embodiments, the alkyl group comprises 5 to 8 carbon atoms (e.g., C5-C8 alkyl). In other embodiments, the alkyl group comprises 2 to 5 carbon atoms (e.g., C2-C5 alkyl). In other embodiments, the alkyl group comprises 3 to 5 carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (isopropyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl (n-pentyl). The alkyl group is attached to the remainder of the molecule by a single bond. Unless otherwise specified in the specification, the alkyl group may be optionally substituted with one or more substituents.

[0016] An "alkoxy" is a radical in which an alkyl group is bonded via the oxygen atom of the O-alkyl group, which is the alkyl chain described above.

[0017] An "alkenyl" refers to a linear or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having 2 to 12 carbon atoms. In certain embodiments, the alkenyl contains 2 to 8 carbon atoms. In other embodiments, the alkenyl contains 2 to 4 carbon atoms. The alkenyl is attached to the remainder of the molecule by a single bond. Examples include ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), bute-1-enyl, pento-1-enyl, penta-1,4-dienyl, etc. Unless otherwise specified, the alkenyl group may be optionally substituted with one or more substituents.

[0018] "Alkynyl" refers to a linear or branched hydrocarbon chain radical group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond and having 2 to 12 carbon atoms. In certain embodiments, the alkynyl contains 2 to 8 carbon atoms. In other embodiments, the alkynyl contains 2 to 4 carbon atoms. The alkynyl is attached to the remainder of the molecule by a single bond. Examples include ethynyl, propynyl, butynyl, pentynyl, and hexynyl. Unless otherwise specified, the alkynyl group may be optionally substituted with one or more substituents.

[0019] "Aryl" refers to a radical obtained by removing a hydrogen atom from an aromatic monocyclic or polycyclic hydrocarbon ring system. The aromatic monocyclic or polycyclic hydrocarbon ring system contains only hydrogen and carbon atoms of 5 to 18 carbon atoms, and at least one of the rings in this ring system is completely unsaturated, that is, it contains a cyclic, delocalized (4n + 2)π - electron system according to Hückel's theory. The ring system from which the aryl group is obtained is not particularly limited, but includes groups such as benzene, fluorene, indane, indene, tetralin, and naphthalene. Unless specifically defined otherwise in the specification of this application, the term "aryl" or the prefix "ar-" (e.g., ar of "alkyl") means including an aryl radical optionally substituted by one or more substituents independently selected from the following: alkyl, alkenyl, alkynyl, halogen, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, -R b --OR a 、-R b -OC(O)-R a 、-R b -OC(O)-OR a 、-R b -OC(O)-N(R a )2、-R b --N(R a )2、-R b -C(O)R a 、-R b -C(O)OR a 、-R b -C(O)N(R a )2、-R b -O-R-C(O)N(R a )2、-R b --N(R a )C(O)OR a 、-R b -N(R a )C(O)R a,-R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t Ure a (t is 1 or 2), -R b --S(O) t R a (t is 1 or 2), and -R b -S(O) t N(R a )2(t is 1 or 2). R a Each is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and R b These are, each independently and directly bonded, or linear or branched alkylene or alkenylene chains, and R c These are linear or branched alkylene or alkenylene chains, and each of the substituents is not substituted unless otherwise specified.

[0020] "Heteroaryl" refers to a radical obtained from an aromatic ring radical of 3 to 18 members, containing 2 to 17 carbon atoms selected from nitrogen, oxygen, and sulfur, and 1 to 6 heteroatoms. As used in this specification, heteroaryl radicals may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, where at least one of the rings in the ring system is completely unsaturated, i.e., contains a delocalized (4n+2)π-electron system of the ring system according to Hückel's theory. Heteroaryls include condensed or bridged ring systems. Heteroatoms in heteroaryl radicals are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heteroaryls attach to the remainder of the molecule via any atom of the ring. Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranil, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinil, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyrimidinil Dinyl, Carbazolyl, Synnolinyl, Cyclopenta[d]pyrimidinyl, 6,7-Dihydro-5H-Cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-Dihydrobenzo[h]quinazolinyl, 5,6-Dihydrobenzo[h]sinnolinyl, 6,7-Dihydro-5H-Benzo[6,7]cyclohepta[1,2-c]pyridazinyl, Dibenzofuranyl, Dibenzothiophenyl, Furanyl, Furanolyl, Flo[3,2-c]pyridinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-Hexahydrocycloocta[d]pyridinyl,Isothiazolyl, imidazolyl, indazolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolidinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthilidinyl, 1,6-naphthilidinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxyranil, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4 -d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridadinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyrimidinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyrimidinyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically provided in this specification, the term “heteroaryl” means a heteroaryl radical as defined above, optionally substituted with one or more substituents selected from the following: alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R, b -OR a,-R b -OC(O)-R a ,-R b -OC(O)-OR a ,-R b -OC(O)-N(R a )2, -R b -N(R a )2, -R b -C(O)R a ,-R b -C(O)OR a ,-R b -C(O)N(R a )2, -R b -ORC(O)N(R a )2, -R b -N(R a )C(O)OR a ,-R b -N(R a )C(O)R a ,-R b -N(R a )S(O) t R a (t is 1 or 2), -R b -S(O) t Ure a (t is 1 or 2), -R b -S(O) t R a (t is 1 or 2), and -R b -S(O) t N(R a )2(t is 1 or 2). R a Each of these is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, and R b Each of these is independently a directly linked, or linear or branched alkylene or alkenylene chain, and R c These are linear or branched alkylene or alkenylene chains, and each of the substituents is not substituted unless otherwise specified.

[0021] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds included in the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of the present invention, and are generally prepared by reacting a free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of the present invention are not limited to these, but include acetate, ascorbate, adipine, alginate, aspirate, benzenesulfonate, benzoate, bicarbonate, bisulfate, tartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, cansilate, carbonate, chloride, clavulanate, citrate, cyclopentanepropionate, diethyl acetate, digluconate, dihydrochloride, dodecyl sulfate, edetate, edisylate, estrate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptanate, gluconate, glutamate, glycerophosphate, glycolylarsanylate, hemisulfate, heptaneate, hexanoate, hexylresorcinate, hydravamin, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, This includes hydroxynaphthoates, iodide, isonicotinates, isothionates, lactates, lactobionates, laurates, malates, maleates, mandelates, mesylates, methylbromide, methylnitrates, methylsulfates, methanesulfons, mucinates, 2-naphthalenesulfons, napsilates, nicotinates, nitrates, N-methylglucamine ammonium salts, oleates, oxalates, pamoates (embonates), palmitates, pantothenates, pectins, persulfates, phosphates / diphosphates, pimephosphates, phenylpropionates, polygalacturonates, propions, salicylates, stearates, sulfates, basic acetates, succinates, tannates, tartrates, theoclates, thiocyans, tosylates, triethiozides, trifluoroacetates, undeconeates, valersates, and more.Furthermore, if the compound of the present invention contains an acidic portion, suitable pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic bases, including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are also included. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, cyclic amines, dicyclohexylamines, and salts of basic ion exchange resins such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and tromethamine. Furthermore, the included basic nitrogen-containing groups can be quaternized by, for example, lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl, dibutyl, and diamyl sulfates; long-chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and aralkyl halides such as benzyl and phenethyl bromides.

[0022] The term "subject" includes living organisms such as humans, monkeys, cattle, sheep, horses, pigs, goats, dogs, cats, mice, rats, cultured cells, and their transgenic species. In preferred embodiments, the subject is a human.

[0023] The term "administration" includes the route of administration through which the active ingredient of the present invention can exert its intended function.

[0024] The term "to treat" or "to cure" refers to a method of reducing the effects of a disease or symptom. Treatment also refers to a method of alleviating the underlying cause of the disease or symptom, rather than the symptom itself. Treatment may reduce the disease to any level, but is not limited to completely eliminating the symptoms or symptoms of the disease.

[0025] The term "prevention" or "to prevent" means to prevent symptoms associated with a target disease.

[0026] "A therapeutically effective amount" means an amount of a compound, material, or composition containing the compound of the present invention that can exert a desired therapeutic effect with a reasonable risk / benefit ratio applicable to drug therapy.

[0027] The term "neuropathic disorder" refers to an undesirable condition of the central or peripheral nervous system in mammals. Neuropathic disorders include neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis) and neuropsychiatric disorders (such as schizophrenia and anxiety disorders, including common anxiety disorders). Examples of neuropathic disorders include MLS (cerebellar ataxia), Huntington's disease, Down syndrome, vascular dementia, status epilepticus, contusions (such as spinal cord injury and head trauma), neurodegeneration due to viral infections (such as AIDS and encephalopathy), epilepsy, benign amnesia, closed head injury, sleep disorders, depression (such as bipolar disorder), dementia, motor disorders, psychosis, alcoholism, and post-traumatic stress disorder (PTSD). Neuropathic disorders also include any undesirable conditions associated with the disorder. For example, treatment for neurodegenerative diseases includes treatment for memory loss and / or cognitive impairment associated with the neurodegenerative disease. Such methods would also include treating or preventing the loss of neurological function that is characteristic of neurodegenerative diseases.

[0028] The compound of the present invention One aspect of the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof. [ka] n is 0 or 1, X is -S-, -S(=O)-, or -NR n -. R n is H, or [Chemical formula] and A is -CH, -CR c , or N, R a is -C(=O)OR a1 , -OR a2 , -O-C(=O)R a3 , or -O-C(=O)-T-OR a4 and R a1 is H, or a linear or branched C1-C 15 alkyl, R a2 is H, a linear or branched C1-C 15 alkyl, a phosphonate, a diarylphosphonate, or an O-protecting group, R a3 and R a4 are each independently a protecting group, a linear or branched C1-C 15 alkyl, a linear or branched C2-C 15 alkenyl, -T-C 3-10 cycloalkyl, -T-NHR a3p , -T-C 3-10 cycloalkenyl, -T-C 6-10 aryl, -T-C 5-10 heteroaryl, -T-NH-C(=O)-O-C 1-10 alkyl, -T-adamantyl, or -C 1-3 alkylene-C 6-10 aryl, alkylene is substituted with -T-NHR a3p and R a3p is H, or an N-protecting group, R b is H, a linear or branched C1-C 15Alkyl, linear, or branched C2-C 15 Alkenil, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 Cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Ariel, or -T'-C 5-10 It is a heteroaryl, R c Each of these is independently a linear or branched C1-C chain. 15 Alkyl, linear, or branched C 1-15 Alkoxyl, unprotected or protected hydroxyl group, or -C 1-10 Alkilen-YC 6-10 It is a heteroaryl, -Y- is -CH2-, -NH-, -O-, or -S-. The symbol * indicates the joining position. m is an integer between 0 and 4. -T- does not exist, or C 1-3 Alkylene, or C 2-3 It is alkenylene, -T'- is C 1-3 Alkylene, or C 2-3 It is alkenylene, Each heteroaryl molecule independently contains at least one heteroatom that is either S, N, or O. Alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene, and alkenylene are each independently either unsubstituted or substituted with at least one substituent. The substituents are, independently, halogens, protecting groups, protected or unprotected amino groups, nitros, nitroso groups, and linear or branched C1-C groups. 15 Alkyl, or linear or branched C1-C 15 Alkoxy or C 3-10 It is a cycloalkyl, R b If H is present, tautomers are included. X is -S- or -S(=O)-, and R a ga-OR a2 And R a2 is H, or C in a straight or branched chain. 1-15 If it is an alkyl group, A is either -CH or -CR c And, X is -S- or -S(=O)-, and R a -C(=O)OR a1 If R b C is a linear or branched chain. 6-15 Alkyl, linear, or branched C 6-15 Alkenil, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 Cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Ariel, or -T'-C 5-10 It is a heteroaryl compound.

[0029] In one embodiment, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt thereof. [ka] n is either 0 or 1. X is -S-, -S(=O)-, or -NR n -and, R n is H, or [ka] And, A is -CH, -CR c , or N, R a is -C(=O)OR a1 , -OR a2 -OC(=O)R a3 , or -OC(=O)-T-OR a4 And, R a1 H, or C1-C in a straight or branched chain. 15It is alkyl, R a2 H, linear or branched C1-C 15 Alkyl, diarylphosphonate, or O-protecting group, R a3 and R a4 Each of these is independently a protecting group, a linear or branched C1-C 15 Alkyl, linear, or branched C2-C 15 Alkenyl, -TC 3-10 Cycloalkyl, -T-NHR a3p , -TC 3-10 Cycloalkenyl, -TC 6-10 Ariel, -TC 5-10 Heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl or -T-adamantyl, R a3p is an H or N-protecting group, R b H, linear or branched C1-C 15 Alkyl, linear, or branched C2-C 15 Alkenil, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 Cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Ariel, or -T'-C 5-10 It is a heteroaryl, R c Each of these is independently a linear or branched C1-C chain. 15 Alkyl, linear, or branched C 1-15 Alkoxyl, unprotected or protected hydroxyl group, or -C 1-10 Alkilen-YC 6-10 It is a heteroaryl, -Y- is -CH2-, -NH-, O-, or -S-. The symbol * indicates the joining position. m is an integer between 0 and 4. -T- does not exist, or C 1-3 Alkylene, or C2-3 It is alkenylene, -T'- is C 1-3 Alkylene, or C 2-3 It is an alkenylene; Each heteroaryl molecule independently contains at least one heteroatom that is either S, N, or O. The alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene, and alkenylene are each independently either unsubstituted or substituted with at least one substituent. Each substituent is independently a halogen, a protecting group, a protected or unprotected amino group, a nitro, a nitroso, or a linear or branched C1-C1 group. 15 Alkyl, linear, or branched C1-C 15 Alkoxy, or C 3-10 It is a cycloalkyl, R b If H is present, tautomers are included. X is -S- or -S(=O)-, and R a ga-OR a2 And R a2 is H, or C in a straight or branched chain. 1-15 If it is an alkyl group, A is either -CH or -CR c And, X is -S- or -S(=O)-, and R a -C(=O)OR a1 If R b C is a linear or branched chain. 6-15 Alkyl, linear, or branched C 6-15 Alkenil, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 Cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Ariel, or -T'-C 5-10 It is a heteroaryl compound.

[0030] In one embodiment, the present invention provides a compound of formula (Ib), or a pharmaceutically acceptable salt thereof. [ka] n is either 0 or 1. X is -S-, -S(=O)-, or -NR n -and, R n is H, or [ka] And, A is -CH, -CR c , or N, R a is -C(=O)OR a1 , -OR a2 , or -OC(=O)R a3 And, R a1 H, or C1-C in a straight or branched chain. 15 It is alkyl, R a2 H, linear or branched C1-C 15 Alkyl, phosphonate, diarylphosphonate, or O-protecting group, R a3 is, -T-NHR a3p -T-NH-C(=O)-OC 1-10 Alkyl, or -C 1-3 Alkylene-C 6-10 It is Ariel, The alkylene is -T-NHR a3p It is replaced with, R a3p is an H or N-protecting group, R b H, linear or branched C1-C 15 Alkyl, C 1-3 Alkoxy-C 1-10 Alkyl-, -T'-C 3-10 Cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Ariel, or -T'-C 5-10 It is a heteroaryl, Rc Each of these is independently a linear or branched C1-C chain. 15 Alkyl, linear, or branched C 1-15 Alkoxyl, unprotected or protected hydroxyl group, or -C 1-10 Alkilen-YC 6-10 It is a heteroaryl, -Y- is -CH2-, -NH-, O-, or -S-. The symbol * indicates the joining position. m is an integer between 0 and 4. -T- does not exist, or C 1-3 Alkylene, or C 2-3 It is alkenylene, -T'- is C 1-3 It is alkylene, Each heteroaryl molecule independently contains at least one heteroatom that is either S, N, or O. Alkyl, alkenyl, alkoxy, cycloalkyl, aryl, and heteroaryl compounds are each independently either unsubstituted or substituted with at least one substituent. The substituents are, independently, halogens, protected or unprotected amino groups, nitros, nitroso groups, and linear or branched C1-C groups. 15 Alkyl, linear, or branched C1-C 15 Alkoxy or C 3-10 It is a cycloalkyl, R b If H is present, tautomers are included. X is -S- or -S(=O)-, and R a ga-OR a2 And R a2 is H or linear or branched C 1-15 If it is an alkyl group, A is -CH or -CR c And, X is -S- or -S(=O)-, and R a -C(=O)OR a1 If R b C is a linear or branched chain. 6-15 Alkyl, linear, or branched C6-15 Alkenil, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 Cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Ariel, or -T'-C 5-10 It is a heteroaryl compound.

[0031] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof. n is either 0 or 1. X is -S-, -S(=O)-, or -NR n -and, R n Is it H, or [ka] And, A is -CH, -CR c , or N, R a is -OR a2 -OC(=O)R a3 , or -OC(=O)-T-OR a4 And, R a2 H, linear or branched C1-C 15 Alkyl, phosphonate, diarylphosphonate, or O-protecting group, R a3 and R a4 Each of these is independently a protecting group, a linear or branched C1-C 15 Alkyl, linear, or branched C2-C 15 Alkenyl, -TC 3-10 Cycloalkyl, -T-NHR a3p , -TC 3-10 Cycloalkenyl, -TC 6-10 Ariel, -TC 5-10 Heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl, -T-adamantyl, or -C 1-3 Alkylene-C6-10 It is Ariel, Alkilen is -T-NHR a3p It is replaced with, R a3p is an H or N-protecting group, R b H, linear or branched C1-C 15 Alkyl, linear, or branched C2-C 15 Alkenil, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 Cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Ariel, or -T'-C 5-10 It is a heteroaryl, R c Each of these is independently a linear or branched C1-C chain. 15 Alkyl, linear, or branched C 1-15 Alkoxyl, unprotected or protected hydroxyl group, or -C 1-10 Alkilen-YC 6-10 It is a heteroaryl, -Y- is -CH2-, -NH-, -O-, or -S-. The symbol * indicates the joining position. m is an integer between 0 and 4. -T- does not exist, or C 1-3 Alkylene, or C 2-3 It is alkenylene, -T'- is C 1-3 Alkylene, or C 2-3 It is alkenylene, Each heteroaryl molecule independently contains at least one heteroatom that is either S, N, or O. Alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene, and alkenylene are each independently either unsubstituted or substituted with at least one substituent. The substituents are each independently halogen, a protecting group, a protected or unprotected amino group, nitro, nitroso, linear or branched C1-C 15 alkyl, or linear or branched C1-C 15 alkoxy or C 3-10 cycloalkyl, and R b when is H, tautomers are included, X is -S- or -S(=O)-, and R a is -OR a2 and R a2 is H, or linear or branched C 1-15 alkyl, then A is -CH or -CR c is.

[0032] In a further embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof. n is 0, X is -S(=O)-, A is N, R a is -OR a2 , -O-C(=O)R a3 , or -O-C(=O)-T-OR a4 is, R a2 is H, linear or branched C_{1}-C 15 alkyl, phosphonate, diarylphosphonate, or an O-protecting group, R a3 and R a4 are each independently a protecting group, linear or branched C_{1}-C 15 alkyl, linear or branched C_{2}-C 15 alkenyl, -T-C 3-10 cycloalkyl, -T-NHR a3p , -T-C 3-10 cycloalkenyl, -T-C 6-10 aryl, -T-C 5-10 heteroaryl, -T-NH-C(=O)-O-C 1-10 alkyl, -T-adamantyl, or -C 1-3Alkylene-C 6-10 is aryl, and the alkylene is -T-NHR a3p and is substituted with R a3p is H or an N-protecting group, R b is H, m is 3, R c are each independently a straight-chain or branched C1-C 15 alkyl, straight-chain or branched C 1-15 alkoxyl.

[0033] In one embodiment, n is 0.

[0034] In one embodiment, m is an integer from 0 to 3.

[0035] In some embodiments, R a is -C(=O)OH, -C(=O)OC 1-4 alkyl, H, -OR a2 and R a2 is H, straight-chain or branched C 1-10 alkyl, or an O-protecting group, -O-C(=O)R a3 where R a3 is independently a tert-butyl protecting group; a straight-chain or branched C 1-10 alkyl unsubstituted or substituted by a halogen, tert-butyl protecting group, or protected amino group; straight-chain or branched C 2-10 alkenyl; C 1-4 alkoxy; C 3-10 cycloalkyl; -C 1-3 alkylene-C 3-10 cycloalkyl; -C 3-10 cycloalkenyl; C 1-10 alkyl, nitro, C 1-15 alkoxy, or -C 6-10 aryl unsubstituted or substituted by a halogen, tert-butyl protecting group, or protected amino group; -C 1-10 alkoxy unsubstituted or substituted by a C5-10 Heteroaryl; C 2-3 Alkenylene-C 6-10 Ariel;-C 1-3 Alkylene-NH-C(=O)-OC 1-10 Alkyl; adamantyl, or -OC(=O)-OC 1-10 It is alkyl, C 6-10 Aryls are either not substituted by halogens or are substituted by halogens.

[0036] In some embodiments, R a is, -OC 1-10 Alkyl, -O- protecting group, or -OC(=O)R a3 And R a3 C is a tert-butyl protecting group; adamantyl; a halogen or a linear or branched C that is either substituted or substituted with a tert-butyl protecting group. 1-10 Alkyl; C 1-4 Alkoxy; C 1-10 Alkyl, nitro, C 1-15 -C that is either unsubstituted or substituted with alkoxy or halogen. 6-10 Ariel; C 3-10 Cycloalkyl;-C 3-10 Cycloalkenyls; straight-chain or branched C 2-10 Alkenyl;-C 5-10 Heteroaryl;-C 1-3 Alkylene-C 3-10 Cycloalkyl; C 2-3 Alkenylene-C 6-10 Ariel;-OC(=O)-OC 1-10 It is alkyl, -C 6-10 The aryl is either not substituted with a halogen or is substituted. In some embodiments, R a is, -OC 1-4 Alkyl, -O-tert-butyloxycarbonyl protecting group, or -OC(=O)R a3 And R a3 C is a tert-butyl protecting group; adamantyl; a halogen or a linear or branched C that is either substituted or substituted with a tert-butyl protecting group. 1-8 Alkyl; C 1-4Alkoxy; C 1-6 Alkyl, nitro, C 1-4 Alkoxy, or unsubstituted or substituted halogen-substituted phenyl; C 3-6 Cycloalkyl;-C 3-6 Cycloalkenyls; straight-chain or branched C 2-6 Alkenyl;-C 5-6 Heteroaryl;-C 1-3 Alkylene-C 3-6 Cycloalkyl; C 2-3 Alkenylene-phenyl, -OC(=O)-OC 1-4 Alkyl, where phenyl is either unsubstituted with a halogen or substituted. In some further embodiments, C 3-6 The cycloalkyl is cyclopropyl or cyclohexyl. In some further embodiments, -C 3-10 Cycloalkenyl is cyclohexenyl.

[0037] In some further embodiments, the heteroaryl is pyrrolidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, pyrazolinyl, imidazolinyl, pyrazolyl, imidazolyl, tetrahydrofuranil, furanil, dioxolanil, tetrahydrothiophenyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, oxathiolanil, piperidinyl, pyridinyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrahydropyranil, pyranil, dioxanil, thianil, thiopyranil, morpholinyl, oxazinyl, or thiadinyl. In further embodiments, the heteroaryl is furanil, isoxazolyl, or thiophenyl.

[0038] In some embodiments, R a These are -OH, -COOH, -O-phosphate, -OC 1-6 Alkyl or -OC(=O)-C 1-6 Alkyl, -OC(=O)-C 1-4 Alkylene-NH(Fmoc or Boc protecting group), or -OC(=O)-NH-C(=O)-OC 1-10 It is alkyl.

[0039] In some embodiments, R c Each of these is an independent linear or branched C 1-6 Alkyl, or linear or branched C 1-6 It is an alkoxyl. In some embodiments, R c These are, independently, halogens, linear or branched C atoms. 1-6 Alkyl, linear, or branched C 1-6 Alkoxyl, or -C 1-10 Alkenirene-YC 6-10 It is a heteroaryl. Y is S and C 6-10 Heteroaryls are C 1-15 Alkyl (preferably C) 1-4 Alkyl), C 1-15 Alkenyl (preferably C 2-4 Alkenil), C 1-15 Alkoxy (preferably C) 1-4 Unsubstituted or substituted with alkoxy, -OH, -NH2, -NO2, or halogen. In further embodiments, -C 1-10 Alkenirene-YC 6-10 Heteoraryls are expressed by the following formula: [ka]

[0040] In some embodiments, the compound of the present invention is a compound selected from the group consisting of the following, or a pharmaceutically acceptable salt thereof. [Table 1] JPEG0007836534000010.jpg222167JPEG0007836534000011.jpg237165JPEG0007836534000012.jpg239164JPEG0007836534000013.jpg240168JPEG0007836534000014.jpg226164JPEG0007836534000015.jpg225163JPEG0007836534000016.jpg240167JPEG0007836534000017.jpg209168JPEG0007836534000018.jpg226165JPEG0007836534000019.jpg240168JPEG0007836534000020.jpg232166JPEG0007836534000021.jpg234166JPEG0007836534000022.jpg235165JPEG0007836534000023.jpg235164JPEG0007836534000024.jpg222164JPEG0007836534000025.jpg214164JPEG0007836534000026.jpg235165JPEG0007836534000027.jpg235161JPEG0007836534000028.jpg236167JPEG0007836534000029.jpg231163JPEG0007836534000030.jpg220163

[0041] This invention encompasses all stereoisomers of the compounds of formulas I, Ia, and Ib. The chiral centers present in the compounds of formulas I, Ia, and Ib can all independently have either the (R) or (S) configuration. In the structural formulas of this invention, when the bond to the chiral carbon is depicted as a straight line, it is understood that both the (R) and (S) configurations of the chiral carbon, and therefore both enantiomers and mixtures thereof, are included in that formula. When a specific structure is described, its enantiomers (either (R) or (S) at the center) are intended. Similarly, when a compound name is given without a chiral designation of the chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and therefore individual enantiomers and mixtures thereof, are included by that name.

[0042] The present invention includes all possible enantiomers and diastereomers, and mixtures of two or more stereoisomers, for example, mixtures of enantiomers and / or diastereomers in any ratio. Thus, the enantiomers of the subject matter of the present invention are in enantiomerically pure form as both levorotatory and dextrorotatory antipalmates, in racemic form, and in the form of mixtures of two enantiomers in any ratio. In the case of cis / trans isomerism, the present invention includes both cis and trans forms, and mixtures of these forms in all ratios. Preparation of individual stereoisomers can be carried out as needed by separation of mixtures by general methods, for example by chromatography or crystallization, by the use of stereochemically homogeneous starting materials for synthesis, or by stereoselective synthesis. Optionally, derivatization can be performed before separation of stereoisomers. Separation of mixtures of stereoisomers can be carried out at an intermediate stage in the synthesis of the compounds of formulas I, Ia, and Ib, or at the final racemic product. The absolute stereochemistry may, if necessary, be determined by X-ray crystallography of the crystalline product or crystalline intermediate derivatized with a reagent containing a stereocenter of a known configuration. If the compounds of the present invention are tautomerizable, all individual tautomers and mixtures thereof are included in the scope of the present invention. The present invention includes salts, solvates (such as hydrates), and solvated salts of all such isomers, as well as such racemates, enantiomers, diastereomers, and mixtures thereof.

[0043] Basic preparation procedure for the compound according to the present invention

[0044] The compounds of formula (I) of the present invention are prepared by general chemical synthesis methods. The preparation of compounds according to some embodiments of the present invention is shown below.

[0045] Synthesis scheme and procedure for preparing the compound of the present invention from RS-D7 [ka] R is -R a3 , or -T-ORa4 It is.

[0046] Synthesis schemes and procedures for the adjustment of the NCTU-SUN-26065 series [Chem.]

[0047] Synthesis schemes and procedures for the preparation of the NCTU-SUN-26070 series [Chem.]

[0048] Synthesis schemes and procedures for the preparation of the NCTU-SUN-26079 series [Chem.]

[0049] Synthesis schemes and procedures for the preparation of the NCTU-SUN-26089 series [Chem.]

[0050] <000​​​​​​​​​​​​​​​​​​​​​​​​​​

[0053] Synthesis scheme and procedure for the preparation of the NCTU-SUN-12092 series [ka]

[0054] Synthesis scheme and procedure for the preparation of the NCTU-SUN-22138 series [ka]

[0055] Synthesis scheme and procedure for the preparation of the NCTU-SUN-22139 series [ka]

[0056] Service The compounds of the present invention are beneficial for treating or preventing diseases and / or symptoms, and the regulation of D-serine levels and / or their oxidation products is effective in alleviating symptoms. By inhibiting enzymes, D-serine levels are increased and the formation of toxic D-serine oxidation products is suppressed. Therefore, the present invention provides methods for treating or preventing neurological disorders and methods for enhancing learning, memory, and / or cognition. The present invention also provides methods for treating or preventing diseases caused by DAAO, preferably the symptom domains of schizophrenia and schizoaffective disorder, depression, Tourette syndrome, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), congenital insensitivity to pain, memory and / or cognition loss associated with neurodegenerative diseases, or loss of neurological function characteristic of neurodegenerative diseases. In some embodiments, the symptom domains of schizophrenia and schizoaffective disorder include negative, cognitive, depressive, positive, and systemic psychopathological symptom domains. In other embodiments, the disorders associated with DAAO are mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease, or schizophrenia. In some embodiments, the disorders associated with DAAO are pain, ataxia, or seizures. In some embodiments, the compounds of the present invention can be used to treat or prevent memory and / or cognitive loss associated with neurodegenerative diseases (e.g., Alzheimer's disease and schizophrenia), and to prevent the loss of neuronal function that is characteristic of neurodegenerative diseases. Furthermore, methods for treating or preventing pain, ataxia, and seizures are also provided.

[0057] In some embodiments, the effective amount of the compound described herein is approximately 0.5 mg / kg to approximately 20 g / kg per body weight, approximately 1 mg / kg to approximately 20 g / kg, approximately 2 mg / kg to approximately 20 g / kg, approximately 4 mg / kg to approximately 20 g / kg, approximately 6 mg / kg to approximately 20 g / kg, approximately 8 mg / kg to approximately 20 g / kg, approximately 10 mg / kg to approximately 20 g / kg, approximately 12 mg / kg to approximately 20 g / kg, approximately 14 mg / kg to approximately 20 g / kg, approximately 16 mg / kg to approximately 20 g / kg, The dosage ranges are approximately 0.5 mg / kg to 15 g / kg, 0.5 mg / kg to 12 g / kg, 0.5 mg / kg to 10 g / kg, 0.5 mg / kg to 8 g / kg, 0.5 mg / kg to 6 g / kg, 2 mg / kg to 15 g / kg, 2 mg / kg to 12 g / kg, 2 mg / kg to 10 g / kg, 2 mg / kg to 7 g / kg, 2 mg / kg to 5 g / kg, 5 mg / kg to 15 g / kg, or 5 mg / kg to 10 g / kg.

[0058] Pharmaceutical composition Another aspect of the present invention provides pharmaceutical compositions comprising a compound of formula I (or a pharmaceutically acceptable salt or solvated compound thereof) and a pharmaceutically acceptable carrier. The term “composition” as a pharmaceutical composition is intended to encompass products comprising the active ingredient and inactive ingredients (pharmaceutically acceptable excipients) constituting the carrier, as well as any products obtained directly or indirectly from any combination, complexation, or aggregation of any two or more components, or from the dissociation of one or more components, or from other types of reactions or interactions of one or more components. Accordingly, the pharmaceutical compositions of the present invention encompass any compositions prepared by mixing a compound of formula I with an additional active ingredient and a pharmaceutically acceptable excipient.

[0059] The pharmaceutical compositions of the present invention comprise an active ingredient, a compound represented by formula I (or a pharmaceutically acceptable salt or solvated compound thereof), a pharmaceutically acceptable carrier, and optionally, other therapeutic components or adjuvants. Examples of compositions include those suitable for oral, rectal, topical, and parenteral administration (including subcutaneous, intramuscular, and intravenous administration), but in any case, the most appropriate route of administration shall depend on the specific host and the characteristics and severity of the symptoms to which the active ingredient is intended. The pharmaceutical compositions may exist in unit dose form and can be prepared using any well-known pharmaceutical techniques.

[0060] The active ingredient may be administered orally in solid dosage forms such as capsules, tablets, lozenges, sugar-coated tablets, granules, and powders, or in liquid dosage forms such as elixirs, syrups, emulsions, dispersions, and suspensions. The active ingredient may also be administered parenterally in sterile solution forms such as dispersions, suspensions, or solutions. Other dosage forms may also be used to administer the active ingredient: as ointments, creams, drops, transdermal patches, or powders for topical administration; as eye drops or suspensions, i.e., eye drops; as aerosol sprays or powder formulations for inhalation or intranasal administration; or as creams, ointments, sprays, or suppositories for rectal or vaginal administration.

[0061] The active ingredient or its pharmaceutical composition may be prepared as a suitable ointment for topical application, containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of the active ingredient or its pharmaceutical composition include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, sugars such as lactose, and water. Alternatively, the pharmaceutical composition may be prepared as a suitable lotion or cream containing the active ingredient or its pharmaceutical composition suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0062] Depending on the specific symptoms, disorders, or diseases being treated, additional therapeutic agents may be administered along with the active ingredient or its pharmaceutical composition. These additional agents may be administered in any order (sequential or intermittent) as part of a multiple dosing regimen, or mixed with the active ingredient or its pharmaceutical composition and administered as part of a single dosage form (simultaneous or concomitant administration).

[0063] Pharmaceutical compositions beneficial to the present invention may take the form of solutions, suspensions, tablets, pills, capsules, powders, granules, semi-solids, sustained-release formulations, elixirs, aerosols, etc., for oral administration. Tablets containing various excipients such as sodium citrate, calcium carbonate, and calcium phosphate are preferably used with starches such as potato starch or tapioca starch, various disintegrants such as certain complex silicates, and further with binders such as polyvinylpyrrolidone, sucrose, gelatin, and gum arabic. Smoothing agents such as magnesium stearate, sodium lauryl sulfate, and talc are also often very beneficial for tablet formation. Similar types of solid compositions are also used as fillers for soft and hard gelatin capsules. Preferred materials for solid compositions include high molecular weight polyethylene glycol, as well as lactose or milk sugar. For oral administration, if an aqueous suspension and / or elixir is preferred, the active ingredient or a pharmaceutically acceptable composition thereof of the present invention may be combined with various sweeteners, flavorings, colorings, emulsifiers, and / or suspending agents, as well as diluents such as water, ethanol, propylene glycol, glycerin, and combinations thereof.

[0064] As used in this specification, the term "parenteral" refers to dosage forms including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intramedullary, and intra-articular injections and infusions. Pharmaceutical compositions for parenteral injection include pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders that are returned to a sterile injection solution or dispersion immediately before use. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal injections. In this regard, the sterile aqueous media that can be used are readily apparent to those skilled in the art by standard, well-known techniques. Examples of suitable aqueous and non-aqueous media, diluents, solvents, or excipients include, for example, water, ethanol, polyols (such as glycerol, propylene glycol, and polyethylene glycol), carboxymethylcellulose, and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by using coating materials such as lecithin, maintaining the required particle size in the case of dispersions, and using surfactants.

[0065] Pharmaceutical compositions beneficial to the present invention may include, but are not limited to, adjuncts such as preservatives, humectants, emulsifiers, and dispersants. Microbial activity can be inhibited by encapsulating various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbic acid. It is also desirable to encapsulate isotonic agents such as sugars and sodium chloride. Sustained absorption of injectable pharmaceutical forms can be achieved by encapsulating absorption-delaying agents such as aluminum monostearate and gelatin.

[0066] Slowing the infusion rate during administration is particularly beneficial when using intrathecal or epidural routes. Many implantable or wearable pumps are known in the art that are useful for delivering compounds at a specified rate.

[0067] In addition to the active ingredient, the suspension may contain suspending agents such as ethoxyisostearyl alcohol, polyoxyethylene sorbitol, sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, as well as mixtures thereof.

[0068] For transdermal (e.g., topical) administration, a diluted sterile aqueous or partially aqueous solution (usually at a concentration of about 0.1–5%) is prepared, otherwise similar to the parenteral solution described above.

[0069] Pharmaceutical compositions beneficial to the present invention can also be administered by nasal aerosol or inhalation. Such compositions can be prepared by techniques well known in the field of pharmaceutical formulation, and may also be prepared as saline solutions with benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, carbon fluoride and / or other conventional solubilizers or dispersants.

[0070] Compositions for rectal or vaginal administration can preferably be prepared by mixing the active ingredient or its pharmaceutical composition with a non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or suppository wax, which is solid at room temperature but becomes liquid at body temperature, and therefore dissolves in the rectal or vaginal cavity to release the drug.

[0071] Other pharmaceutically acceptable carriers include, but are not limited to, non-toxic solid, semi-solid, or liquid fillers, diluents, encapsulating materials, or any type of formulation aid, which include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, phosphates, buffers such as glycine, sorbic acid, and potassium sorbate, partially glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, and lanolin.

[0072] Solid pharmaceutical excipients include, but are not limited to, starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, and dried skim milk. Liquid and semi-solid excipients can be selected from a variety of oils, including glycerol, propylene glycol, water, ethanol, petroleum, animal oils, and vegetable or synthetic oils such as peanut oil, soybean oil, mineral oil, and sesame oil. Preferred liquid carriers, especially for injectable preparations, include water, saline solution, aqueous dextrose, and glycol.

[0073] Methods for preparing various pharmaceutical compositions having a certain amount of active ingredient are well known or will be apparent to those skilled in the art in light of this disclosure. Other suitable pharmaceutical excipients and their dosage forms are described in Remington's Pharmacology (edited by EW Martin, Mark Publishing, 19th edition, 1995).

[0074] Even without further details, those skilled in the art will likely be able to make the most of the disclosure of the present invention using the above description. Accordingly, the following examples are to be interpreted as merely illustrative and not to be construed as limiting the scope of the present invention.

[0075] Examples Example 1-1 NCTU-SUN-21122:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl acetate) [ka]

[0076] A solution of RS-D7 (0.1 g, 0.30 mmol) was dissolved in DCM (10 mL), to which NaOH (0.90 mmol) was added. The reaction mixture was stirred under nitrogen for 5-10 minutes. Acetyl chloride (0.60 mmol) was added at 0°C (under an ice bath). After stirring for 5-10 minutes, the mixture was warmed to room temperature by the reaction and stirred for a further 1 hour. The reaction products were extracted using ethyl acetate and pure water. The organic layer was dried over MgSO4, filtered, and concentrated to obtain the reaction mixture. The reaction mixture was purified by silica gel column chromatography to obtain the pure product.

[0077] 1 ¹H NMR (400 MHz, acetone-d6): δ 8.17 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.44 (s, 1H), 7.09 (d, J = 8.7 Hz, 1H), 4.71 (s, 2H), 3.75 (s, 3H), 2.29 (s, 3H), 2.24 (s, 6H).

[0078] LRMS(ESI + )m / z:374.1(M+H) + .

[0079] Examples 1-2 NCTU-SUN-21124: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl benzoate) [ka]

[0080] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with benzyl chloride.

[0081] 1 H NMR (400 MHz, acetone-d6) δ 8.24 (s, 1H), 8.22 (d, J = 1.4 H z, 1H), 8.18 (s, 1H), 7.78 - 7.71 (m, 2H), 7.65 - 7.59 (m, 3H), 7.27 (dd, J= 8.8, 2.2 Hz, 1H), 4.74 (s, 2H), 3.76 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H).

[0082] LRMS(ESI + )m / z:436.2(M+H) + .

[0083] Examples 1-3 NCTU-SUN-26096:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl butyrate) [ka]

[0084] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with butyryl chloride.

[0085] 1H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 2.0 Hz, 1H), 7.08 (dd, J = 8.7, 2.1 Hz, 1H), 4.72 (s, 1H), 3.74 (s, 3H), 2.60 (t, J = 7.3 Hz, 2H), 2.24 (s, 6H), 1.77 (h, J = 7.3 Hz, 3H), 1.04 (t, J= 7.4 Hz, 3H).

[0086] LRMS(ESI + )m / z:402.1(M+H) + .

[0087] Examples 1-4 NCTU-SUN-26097:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-ylcyclohexanecarboxylate) [ka]

[0088] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with hexahydrobenzoyl chloride.

[0089] 1 H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.42 (s, 1H), 7.07 (d, J= 8.7 Hz, 1H), 4.72 (s, 2H), 3.75 (s, 3H), 2.64 (t, J = 11.1 Hz, 1H), 2.24 (s, 7H), 1.88 - 1.76 (m, 2H), 1.69 (d, J = 12.1 Hz, 1H), 1.65 - 1.52 (m, 3H), 1.42 (q, J = 11.8 Hz, 2H).

[0090] LRMS(ESI + )m / z:442.2(M+H) + .

[0091] Examples 1-5 NCTU-SUN-26098:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 4-butylbenzoate) [ka]

[0092] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 4-butylbenzoyl chloride.

[0093] 1 H NMR (400 MHz, acetone-d6) δ 8.18 (s, 1H), 8.13 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.45 (d, J= 8.2 Hz, 2H), 7.25 (d, J = 8.7 Hz, 1H), 4.74 (s, 2H), 3.76 (s, 3H), 2.25 (d, J = 6.2 Hz, 6H), 1.66 (q, J= 7.7 Hz, 3H), 1.47 - 1.28 (m, 3H),0.95(t,J=7.3Hz,3H).

[0094] LRMS(ESI + )m / z:492.1(M+H) + .

[0095] Examples 1-6 NCTU-SUN-21127: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 3-methylbenzoate) [ka]

[0096] The title compound was obtained using the same reaction products and preparation steps as in Example 1-1, except that acetyl chloride was replaced with m-toluyl chloride.

[0097] 1 H NMR (400 MHz, acetone-d6) δ 8.18 (s, 1H), 8.06 - 7.99 (m, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.61 (d, J= 2.2 Hz, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.25 (dd, J = 8.7, 2.2 Hz, 1H), 4.76 (d, J = 3.2 Hz, 2H), 3.74 (s, 3H), 2.47 (s, 3H), 2.25 (s, 3H), 2.23 (s, 3H).

[0098] LRMS(ESI + )m / z:450.1(M+H) + .

[0099] Examples 1-7 NCTU-SUN-27076:2-(((4-Methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl hexanoate [ka]

[0100] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with hexanoyl chloride.

[0101] 1H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.44 (s, 1H), 7.09 (d, J= 8.8 Hz, 1H), 4.72 (s, 2H), 3.74 (s, 3H), 2.62 (t, J = 7.4 Hz, 2H), 2.24 (s, 6H), 1.75 (p, J = 7.3 Hz, 2H), 1.41 (h, J= 7.9, 7.5 Hz, 6H), 0.94 (t, J= 6.7 Hz, 3H).

[0102] LRMS(ESI + )m / z:430.2(M+H) + .

[0103] Examples 1-8 NCTU-SUN-27077:2-(((4-Methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl isobutyrate [ka]

[0104] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with isobutyryl chloride.

[0105] 1 H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.44 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.7, 2.1 Hz, 1H), 4.71 (s, 2H), 3.75 (s, 3H), 2.89 - 2.84 (m, 1H), 2.24 (d, J = 2.4 Hz, 6H), 1.31 (d, J = 7.0 Hz, 6H).

[0106] LRMS(ESI + )m / z:402.2(M+H)+ .

[0107] Examples 1-9 NCTU-SUN-27078:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-ylcyclohex-3-ene-1-carboxylate) [ka]

[0108] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with cyclohex-3-encarbonyl chloride.

[0109] 1 H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.66 (d, J = 8.2 Hz, 1H), 7.42 (s, 1H), 7.07 (dd, J= 8.7, 1.8 Hz, 1H), 5.74 (s, 2H), 4.78 (d, J = 13.6 Hz, 1H), 4.73 (d, J = 13.7 Hz, 1H), 3.70 (s, 3H), 2.96 - 2.80 (m, 2H), 2.54 - 2.30 (m, 3H), 2.22 (d, J = 2.6 Hz, 6H), 1.95 - 1.72 (m, 2H).

[0110] LRMS(ESI + )m / z:440.1(M+H) + .

[0111] Examples 1-10 NCTU-SUN-27079:2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-ylcyclohex-3-encarboxylate [ka]

[0112] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 2-methylbenzoyl chloride.

[0113] 1 H NMR (400 MHz, acetone-d6) δ 8.20 - 8.17 (m, 2H), 7.76 (d, J= 8.7 Hz, 1H), 7.63 (d, J = 2.2 Hz, 1H), 7.57 (td, J = 7.5, 1.5 Hz, 1H), 7.42 (dt, J = 7.4, 3.4 Hz, 2H), 7.27 (dd, J = 8.7, 2.2 Hz, 1H), 4.74 (s, 2H), 3.77 (s, 3H), 2.67 (s, 3H), 2.26 (s, 4H), 2.25 (s, 4H).

[0114] LRMS(ESI + )m / z:450.1(M+H) + .

[0115] Example 1-11 NCTU-SUN-28087:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 4-methylbenzoate) [ka]

[0116] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 4-methylbenzoyl chloride.

[0117] 1H NMR (400 MHz, acetone-d6) δ 8.18 (s, 1H), 8.10 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.7 Hz, 1H), 7.60 (s, 1H), 7.42 (d, J= 7.9 Hz, 2H), 7.24 (d, J = 7.1 Hz, 1H), 4.82 - 4.69 (m, 2H), 3.73 (s, 3H), 2.47 (s, 3H), 2.24 (s, 3H), 2.23 (s, 3H).

[0118] LRMS(ESI + )m / z: 450.1(M+H) + .

[0119] Examples 1-12 NCTU-SUN-28091: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 2-nitrobenzoate) [ka]

[0120] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 2-nitrobenzoyl chloride.

[0121] 1 H NMR (400 MHz, acetone-d6) δ 8.16 (d, J = 5.9Hz, 2H), 8.10 (d, J = 7.3 Hz, 1H), 7.96 (td, J = 7.5, 1.8 Hz, 1H), 7.91 (td, J = 7.8, 1.8 Hz, 1H), 7.74 (dd, J = 8.7, 1.5 Hz, 1H), 7.61 (s, 1H), 7.24 (d, J = 8.4 Hz, 1H), 4.75 (dd, J = 13.7, 5.7 Hz, 2H), 3.69 (s, 3H), 2.20 (s, 6H).

[0122] LRMS(ESI + )m / z:481.2(M+H) + .

[0123] Examples 1-13 NCTU-SUN-28092: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-ylcyclopropanecarboxylate) [ka]

[0124] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with cyclopropanecarbonyl chloride.

[0125] 1 H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.67 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 2.2 Hz, 1H), 7.09 (dd, J = 8.8, 2.2 Hz, 1H), 4.73 (dd, J = 13.7, 2.5 Hz, 2H), 3.73 (s, 3H), 2.23 (s, 6H), 1.92 (dt, J = 12.5, 6.3 Hz, 1H), 1.08 (s, 2H), 1.06 (s, 2H).

[0126] LRMS(ESI + )m / z:400.2(M+H) + .

[0127] Examples 1-14 NCTU-SUN-28093:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 2-ethylbutanoate) [ka]

[0128] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 2-ethylbutanoyl chloride.

[0129] 1 H NMR (400 MHz, acetone-d6) δ 8.15 (s, 1H), 7.64 (d, J = 8.7 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.05 (dd, J = 8.8, 2.2 Hz, 1H), 4.81 (dd, J = 28.8, 13.7 Hz, 2H), 3.65 (s, 3H),2.51 (tt, J= 8.6, 5.5 Hz, 1H), 2.19 (s, 3H), 2.18 (s, 3H), 1.74 (m, 4H), 1.04 (t, 7.5Hz, 6H).

[0130] LRMS(ESI + )m / z:430.2(M+H) + .

[0131] Examples 1-15 NCTU-SUN-28094:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 2-phenylacetate) [ka]

[0132] The title compound was obtained using the same reaction mixture and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 2-phenylacetyl chloride.

[0133] 1H NMR (400 MHz, acetone-d6) δ 8.16 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.41 (m, 5H), 7.30 (m, 1H), 7.06(dd, J = 8.8, 2.2 Hz, 1H), 4.74 (dd, J = 13.7, 19.2 Hz, 2H), 3.98 (s, 2H), 3.70 (s, 3H), 2.21 (s, 6H).

[0134] LRMS(ESI + )m / z:450.2(M+H) + .

[0135] Examples 1-16 NCTU-SUN-28095:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 3,5,5-trimethylhexanoate [ka]

[0136] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 3,5,5-trimethylhexanoyl chloride.

[0137] 1H NMR (400 MHz, acetone-d6) δ 8.15 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.40 (s,1H), 7.09 (dd, J= 8.8, 2.2 Hz, 1H), 4.80 (dd, J= 29.0, 13.7 Hz, 2H), 3.65 (s, 3H), 2.61 (dd, J = 15.0, 6.2 Hz, 1H), 2.44 (dd, J = 15.0, 7.9 Hz, 1H), 2.19 (m, 1H), 2.19 (s, 3H), 2.18 (s, 3H), 1.43 (dd, J = 14.1, 4.0 Hz, 1H), 1.23 (dd, J = 14.1, 6.5 Hz, 1H), 1.12 (d, J = 6.7 Hz, 3H), 0.97 (s, 9H).

[0138] LRMS(ESI + )m / z:472.1(M+H) + .

[0139] Example 1-17 NCTU-SUN-28096:(2-(((5-methoxy-4,6-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 2-ethoxybenzoate) [ka]

[0140] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 2-ethoxybenzoyl chloride.

[0141] 1H NMR (400 MHz, acetone-d6) δ 8.18 (s, 1H), 7.92 (dd, J = 7.8, 1.8 Hz, 1H), 7.71 (d, J = 8.8, 1H), 7.58 (m, 2H), 7.22 (dd, J= 8.8, 2.3 Hz, 1H), 7.18 (d, J= 8.5, 1H), 4.80 (dd, J = 23.0, 13.7 Hz, 2H), 4.19 (q, J = 7.0 Hz, 2H), 3.69 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 1.44 (t, J = 7.1 Hz, 3H).

[0142] LRMS(ESI + )m / z:480.1(M+H) + .

[0143] Examples 1-18 NCTU-SUN-21123:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-ylpropionate) [ka]

[0144] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with propionyl chloride.

[0145] 1 H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.44 (s, 1H), 7.09 (d, J = 8.7 Hz, 1H), 4.73 (s, 2H), 3.74 (s, 3H), 2.64 (d, J = 7.6 Hz, 2H), 2.24 (s, 6H), 1.22 (t, J = 7.6 Hz, 3H).

[0146] LRMS(ESI +)m / z:388.2(M+H) + .

[0147] Example 1-19 NCTU-SUN-21125: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 4-chlorobenzoate) [ka]

[0148] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 4-chlorobenzoyl chloride.

[0149] 1 H NMR (400 MHz, acetone-d6) δ 8.33 - 8.12 (m, 1H), 7.76 (d, J= 8.7 Hz, 0H), 7.72 - 7.61 (m, 1H), 7.27 (dd, J = 8.7, 2.2 Hz, 0H), 4.74 (s, 1H), 3.76 (s, 1H), 2.25 (d, J = 6.00Hz, 2H).

[0150] LRMS(ESI + )m / z:470.2(M+H) + .

[0151] Examples 1-20 NCTU-SUN-21126: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 3-nitrobenzoate) [ka]

[0152] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 3-nitrobenzoyl chloride.

[0153] 1 H NMR (400 MHz, acetone-d6) δ 8.95 (t, J = 2.0 Hz, 1H), 8.64 - 8.56 (m, 2H), 8.18 (s, 1H), 7.95 (t, J = 8.0 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 7.69 (d, J = 2.2 Hz, 1H), 7.32 (dd, J = 8.8, 2.2 Hz, 1H), 4.76 (s, 2H), 3.74 (s, 3H), 2.24 (d, J = 7.0 Hz, 6H).

[0154] LRMS(ESI + )m / z:481.2(M+H) + .

[0155] Examples 1-21 NCTU-SUN-21128: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl heptanoate [ka]

[0156] The title compound was obtained using the same reaction mixture and preparation steps as in Example 1-1, except that acetyl chloride was replaced with heptanyl chloride.

[0157] 1 H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.67 (s, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.08 (dd, J = 8.8, 2.1 Hz, 1H), 4.72 (s, 2H), 3.74 (s, 3H), 2.62 (s, 2H), 2.24 (s, 6H), 1.81 - 1.68 (m, 3H), 1.53 - 1.25 (m, 8H).

[0158] LRMS(ESI +)m / z:444.3(M+H) + .

[0159] Examples 1-22 NCTU-SUN-21129: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 4-fluorobenzoate) [ka]

[0160] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 4-fluorobenzoyl chloride.

[0161] 1 H NMR (400 MHz, acetone-d6) δ 8.30 (dd, J = 8.6, 5.6 Hz, 1H), 7.75 (d, J = 8.7 Hz, 1H), 7.38 (t, J = 8.8 Hz, 1H), 7.26 (d, J = 8.7 Hz, 1H), 2.24 (d, J = 6.5 Hz, 3H).

[0162] LRMS(ESI + )m / z:454.1(M+H) + .

[0163] Examples 1-23 NCTU-SUN-21130:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl (Z)-2-methylbuta-2-enoate) [ka]

[0164] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with (Z)-2-methylbuta-2-enoyl chloride.

[0165] 1 H NMR (400 MHz, acetone-d6) δ 8.18 (s, 1H), 7.68 (s, 1H), 7.46 (d, J = 2.2 Hz, 1H), 7.19 - 7.01 (m, 2H), 4.72 (s, 2H), 3.75 (s, 3H), 2.24 (d, J = 2.6 Hz, 6H), 1.95 (s, 3H), 1.91 (d, J = 7.2 Hz, 3H).

[0166] LRMS(ESI + )m / z:414.2(M+H) + .

[0167] Examples 1-24 NCTU-SUN-21131:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 2-chloropropanoate) [ka]

[0168] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 2-chloropropanoyl chloride.

[0169] 1 H NMR (400 MHz, acetone-d6) δ 8.16 (s, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.54 - 7.40 (m, 1H), 7.13 (dd, J = 8.7, 2.0 Hz, 1H), 4.91 (d, J = 6.8 Hz, 1H), 4.75 (d, J = 4.1 Hz, 2H), 3.71 (s, 4H), 2.22 (s, 6H), 1.83 (d, J = 6.8 Hz, 4H).

[0170] LRMS(ESI + )m / z:422.1(M+H) + .

[0171] Examples 1-25 NCTU-SUN-21132:tert-butyl(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl)carbonate [ka]

[0172] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with tert-butylcarbonochloride.

[0173] 1 H NMR (400 MHz, Acetone-d6) δ 8.17 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 7.15 (d, J = 8.9, 1H), 4.72 (s, 2H), 3.74 (s, 3H), 2.24 (s, 6H), 1.54 (s, 9H).

[0174] LRMS(ESI + )m / z:432.2(M+H) + .

[0175] Examples 1-26 NCTU-SUN-12124:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl(Z)-buta-2-enoate) [ka]

[0176] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with (Z)-buta-2-enoyl chloride.

[0177] 1H NMR (400 MHz, acetone-d6) δ 8.18 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 2.2, 0.4 Hz, 1H), 7.19 (dq, J = 15.5, 6.9 Hz, 1H), 7.11 (dd, J = 8.8, 2.2 Hz, 1H), 6.13 (dq, J = 15.5, 1.7 Hz, 1H), 4.76 - 4.67 (q, J = 13.6, 2H), 3.74 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H), 1.99 (dd, J = 6.9, 1.7 Hz, 3H).

[0178] LRMS(ESI + )m / z:400.2(M+H) + .

[0179] Example 1-27 NCTU-SUN-12125:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 3-methylbuta-2-enoate) [ka]

[0180] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 3-methylbuta-2-enoyl chloride.

[0181] 1H NMR (400 MHz, acetone-d6) δ 8.18 (s, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.45 (d, J = 2.0 Hz, 1H), 7.09 (dd, J = 8.7, 2.1 Hz, 1H), 5.98 (dt, J = 2.6, 1.3 Hz, 1H), 4.71 (dd, J = 13.6 Hz, 2H), 3.74 (s, 3H), 2.24 (s, 3H), 2.24 (s, 3H), 2.22 (d, J = 1.2 Hz, 3H), 2.02 (d, J = 1.3 Hz, 3H).

[0182] LRMS(ESI + )m / z:414.2(M+H) + .

[0183] Examples 1-28 NCTU-SUN-12122:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-ylfuran-2-carboxylate) [ka]

[0184] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with furan-2-carbonyl chloride.

[0185] 1H NMR (400 MHz, acetone-d6) δ 8.18 (s, 1H), 7.96 (dd, J = 1.8, 0.8 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.60 (d, J = 2.1 Hz, 1H), 7.51 (dd, J = 3.5, 0.8 Hz, 1H), 7.24 (dd, J = 8.8, 2.1 Hz, 1H), 6.77 (dd, J = 3.5, 1.8 Hz, 1H), 4.74 (q, J = 13.6 Hz, 2H), 3.75 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H).

[0186] LRMS(ESI + )m / z:426.1(M+H) + .

[0187] Examples 1-29 NCTU-SUN-12123:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl acrylate) [ka]

[0188] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with acryloyl chloride.

[0189] 1H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 8.8, 2.2 Hz, 1H), 6.59 (dd, J = 17.3, 1.5 Hz, 1H), 6.42 (dd, J = 17.3, 10.4 Hz, 1H), 6.11 (dd, J = 10.4, 1.5 Hz, 1H), 4.73 (q, J = 13.6, 2H), 3.74 (s, 3H), 2.24 (s, 3H), 2.24 (s, 3H).

[0190] LRMS(ESI + )m / z:386.1(M+H) + .

[0191] Examples 1-30 NCTU-SUN-12127:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 2-methylbutanoate) [ka]

[0192] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 2-methylbutanoyl chloride.

[0193] 1H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.07 (dd, J = 8.7, 1.9 Hz, 1H), 4.80 - 4.68 (q, J = 13.6 Hz, 2H), 3.72 (s, 3H), 2.75 - 2.63 (m, 1H), 2.23 (s, 6H), 1.89 - 1.77 (m, 1H), 1.71 - 1.60 (m, 1H), 1.29 (d, J = 7.0 Hz, 4H), 1.04 (t, J= 7.4 Hz, 3H).

[0194] LRMS(ESI + )m / z:416.1(M+H) + .

[0195] Examples 1-31 NCTU-SUN-12128: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 3-cyclopentylpropanoate) [ka]

[0196] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with cyclopentane carbonyl chloride.

[0197] 1H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.08 (dd, J = 8.8, 2.2 Hz, 1H), 4.78 - 4.66 (q, J = 13.6, 2H), 3.74 (s, 3H), 2.66 - 2.61 (m, 2H), 2.24 (s, 6H), 1.94 - 1.81 (m, 3H), 1.77 (dd, J = 14.9, 7.4 Hz, 2H), 1.69 - 1.51 (m, 5H), 1.23 - 1.13 (m, 2H).

[0198] LRMS(ESI + )m / z:456.1(M+H) + .

[0199] Examples 1-32 NCTU-SUN-12129: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl (E)-3-(2-chlorophenyl)acrylate) [ka]

[0200] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 2-chlorobenzoyl chloride.

[0201] 1H NMR (400 MHz, acetone-d6) δ 8.26 (d, J = 16.0 Hz, 1H), 8.18 (s, 1H), 8.02 (dd, J = 7.6, 2.0 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.58 - 7.54 (m, 2H), 7.48 (m, 2H), 7.20 (dd, J= 8.7, 2.0 Hz, 1H), 6.88 (d, J= 16.0 Hz, 1H), 4.81 - 4.70 (q, J = 13.6, 2H), 3.73 (s, 3H), 2.24 (s, 3H), 2.23 (s, 3H).

[0202] LRMS(ESI + )m / z:496.0(M+H) + .

[0203] Examples 1-33 NCTU-SUN-12130:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 6-bromohexanoate) [ka]

[0204] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 6-bromohexanoyl chloride.

[0205] 1H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 7.09 (dd, J = 8.8, 2.2 Hz, 0H), 4.77 - 4.68 (q, J = 13.6, 2H), 3.74 (s, 3H), 3.55 (t, J= 6.7 Hz, 2H), 2.66 (t, J = 7.4 Hz, 2H), 2.35 (s, 6H) 1.99 - 1.91 (m, 2H), 1.84-1.76 (m, 2H), 1.66 - 1.56 (m, 2H).

[0206] LRMS(ESI + )m / z:508.1(M+H) + .

[0207] Examples 1-34 NCTU-SUN-11021: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 2-fluorobenzoate) [ka]

[0208] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 2-fluorobenzoyl chloride.

[0209] 1 H NMR (400 MHz, acetone-d6) δ 8.24 - 8.13 (m, 2H), 7.78 (dddd, J = 8.4, 7.4, 4.9, 1.8 Hz, 2H), 7.64 (d, J = 2.3 Hz, 1H), 7.48 - 7.32 (m, 2H), 7.28 (dd, J = 8.8, 2.2 Hz, 1H), 4.74 (s, 3H), 3.76 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H).

[0210] LRMS(ESI + )m / z:454.1(M+H) + .

[0211] Examples 1-35 NCTU-SUN-11020: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 4-methoxybenzoate) [ka]

[0212] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 4-methoxybenzoyl chloride.

[0213] 1 H NMR (400 MHz, acetone-d6) δ 8.76-7.84 (m, 3H), 7.74 (dd, J= 8.8, 0.6 Hz, 1H), 7.59 (dd, J= 2.2, 0.5 Hz, 1H), 7.23 (dd, J= 8.7, 2.2 Hz, 1H), 7.13 (d, J= 8.9 Hz, 2H), 4.74 (s, 2H), 3.94 (s, 3H), 3.75 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H).

[0214] LRMS(ESI + )m / z:466.2(M+H) + .

[0215] Example 1-36 NCTU-SUN-11022:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl(3r,5r,7r)-adamantane-1-carboxylate) [ka]

[0216] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with adamantane-1-carbonyl chloride.

[0217] 1 H NMR (400 MHz, acetone-d6) δ 8.16 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.02 (dd, J = 8.8, 2.2 Hz, 1H), 4.83 - 4.71 (m, 2H), 3.69 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H), 2.20-1.80 (m, 15H).

[0218] LRMS(ESI + )m / z:494.2(M+H) + .

[0219] Example 1-37 NCTU-SUN-11023:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl isoxazole-5-carboxylate) [ka]

[0220] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with isoxazole-5-carbonyl chloride.

[0221] 1H NMR (400 MHz, acetone-d6) δ 8.76 (d, J = 1.8 Hz, 1H), 8.17 (s, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.39 (d, J = 1.8 Hz, 1H), 7.30 (dd, J = 8.8, 2.2 Hz, 1H), 4.86 - 4.72 (m, 2H), 3.70 (s, 3H), 2.22 (s, 3H), 2.21 (s, 3H).

[0222] LRMS(ESI + )m / z:427.0(M+H) + .

[0223] Example 1-38 NCTU-SUN-11030: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 4-(tert-butyl)benzoate) [ka]

[0224] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 4-(tert-butyl)benzoyl chloride.

[0225] 1 H NMR (400 MHz, methanol-d4) δ 8.14 (d, J = 8.5 Hz, 2H), 8.11 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.5 Hz, 2H) 7.51 (d, J = 2.2 Hz, 1H), 7.21 (dd, J = 8.8, 2.2 Hz, 1H), 4.78 (d, J = 9.4 Hz, 2H), 3.69 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H), 1.39 (s, 9H).

[0226] LRMS(ESI + )m / z:492.1(M+H) + .

[0227] Example 1-39 NCTU-SUN-11031:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 3-chloro-4-fluorobenzoate) [ka]

[0228] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 4-chloro-3-fluorobenzoyl chloride.

[0229] 1 H NMR (400 MHz, acetone-d6) δ 8.34 (dd, J = 7.2, 2.2 Hz, 1H), 8.24 (ddd, J = 8.7, 4.7, 2.2 Hz, 1H), 8.18 (t, J = 0.8 Hz, 1H), 7.76 (dd, J = 8.8, 0.6 Hz, 1H), 7.65 (dd, J = 2.3, 0.6 Hz, 1H), 7.58 (t, J = 8.8 Hz, 1H), 7.28 (dd, J = 8.8, 2.2 Hz, 1H), 4.74 (s, 2H), 3.76 (s, 2H), 2.26 (s, 3H), 2.24 (s, 3H).

[0230] LRMS(ESI + )m / z:488.0(M+H) + .

[0231] Examples 1-40 NCTU-SUN-25015: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl pivalate) [ka]

[0232] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with pivaloyl chloride.

[0233] 1 H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.07 (dd, J = 8.7, 2.1 Hz, 1H), 5.62 (s, 1H), 4.71 (s, 2H), 3.75 (s, 3H), 2.24 (d, J = 2.6 Hz, 6H), 1.37 (s, 9H).

[0234] LRMS(ESI + )m / z:416.1(M+H) + .

[0235] Example 1-41 NCTU-SUN-25016:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-ylpentanoate) [ka]

[0236] The title compound was obtained using the same reaction mixture and preparation steps as in Example 1-1, except that acetyl chloride was replaced with pentanoyl chloride.

[0237] 1H NMR (400 MHz, acetone-d6) δ 8.16 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 2.1 Hz, 1H), 7.07 (dd, J = 8.9, 2.1 Hz, 1H), 5.62 (s, 1H), 4.96 - 4.55 (m, 2H), 3.69 (s, 3H), 2.62 (t, J = 7.5 Hz, 2H), 2.21 (d, J = 3.3 Hz, 6H), 1.83 - 1.64 (m, 2H), 1.46 (q, J = 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H).

[0238] LRMS(ESI + )m / z:416.1(M+H) + .

[0239] Examples 1-42 NCTU-SUN-25017: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 4-nitrobenzoate) [ka]

[0240] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 4-nitrobenzoyl chloride.

[0241] 1 H NMR (400 MHz, acetone-d6) δ 8.48 (d, J = 2.3 Hz, 4H), 8.18 (s, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.33 (dd, J = 8.8, 2.3 Hz, 1H), 4.74 (s, 2H), 3.76 (s, 3H), 2.25 (d, J = 7.2 Hz, 6H).

[0242] LRMS(ESI + )m / z:481.2(M+H) + .

[0243] Examples 1-43 NCTU-SUN-25027: (2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-ylcyclobutanecarboxylate) [ka]

[0244] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with cyclobutane carbonyl chloride.

[0245] 1 H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.09 (dd, J = 8.8, 2.2 Hz, 1H), 4.71 (s, 2H), 3.75 (s, 3H), 3.48 (t, J = 8.6 Hz, 1H), 2.39 (dt, J = 29.5, 9.1 Hz, 4H), 2.24 (d, J = 2.9 Hz, 5H), 2.05 (m, J= 2.4 Hz, 2H).

[0246] LRMS(ESI + )m / z:414.2(M+H) + .

[0247] Example 1-44 NCTU-SUN-25028:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-ylthiophene-2-carboxylate) [ka]

[0248] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with thiophene-2-carbonyl chloride.

[0249] 1 H NMR (400 MHz, acetone-d6) δ 8.18 (s, 1H), 8.04 (dd, J = 3.8, 1.4 Hz, 1H), 7.99 (dd, J = 5.0, 1.4 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 2.1 Hz, 1H), 7.32 (dd, J = 5.1, 3.7 Hz, 1H), 7.25 (dd, J = 8.8, 2.2 Hz, 1H), 4.75 (d, J = 2.1 Hz, 2H), 3.74 (d, J = 1.7 Hz, 3H), 2.24 (d, J = 5.4 Hz, 6H).

[0250] LRMS(ESI + )m / z:442.2(M+H) + .

[0251] Example 1-45 NCTU-SUN-25029:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 2-methylbutanoate) [ka]

[0252] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with -2-methylbutanoyl chloride.

[0253] 1H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.49 - 7.32 (m, 1H), 7.07 (ddd, J = 8.7, 2.3, 1.0 Hz, 1H), 4.76 - 4.52 (m, 2H), 3.74 (d, J = 1.0 Hz, 3H), 2.69 (q, J = 7.1 Hz, 1H), 2.24 (s, 6H), 1.92 - 1.75 (m, 1H), 1.65 (dddd, J = 13.7, 7.4, 6.3, 1.1 Hz, 1H), 1.29 (dd, J= 7.0, 1.0 Hz, 3H), 1.04 (td, J= 7.4, 1.0 Hz, 3H).

[0254] LRMS(ESI + )m / z:416.1(M+H) + .

[0255] Example 1-46 NCTU-SUN-25030:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl3,3-dimethylbutanoate) [ka]

[0256] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 3,3-dimethylbutanoyl chloride.

[0257] 1H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.69 (dd, J = 8.7, 0.6 Hz, 1H), 7.43 (dd, J = 2.2, 0.6 Hz, 1H), 7.08 (dd, J = 8.7, 2.2 Hz, 1H), 4.72 (d, J = 1.6 Hz, 2H), 3.74 (s, 3H), 2.50 (s, 2H), 2.24 (d, J = 1.3 Hz, 6H), 1.15 (s, 9H).

[0258] LRMS(ESI + )m / z:430.1(M+H) + .

[0259] Example 1-47 NCTU-SUN-25031:(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl 2-methoxyacetate) [ka]

[0260] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with 2-methoxyacetyl chloride.

[0261] 1 H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.50 (s, 1H), 7.14 (d, J= 8.8 Hz, 1H), 4.72 (s, 2H), 4.36 (s, 2H), 3.75 (s, 3H), 3.49 (d, J = 1.2 Hz, 2H), 2.24 (d, J = 2.5 Hz, 6H).

[0262] LRMS(ESI + )m / z:404.0(M+H) + .

[0263] Example 1-48 NCTU-SUN-25032:(Ethyl(2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-yl)carbonate) [ka]

[0264] The title compound was obtained using the same reaction and preparation steps as in Example 1-1, except that acetyl chloride was replaced with ethyl carbonochloride.

[0265] 1 H NMR (400 MHz, acetone-d6) δ 8.17 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 8.8, 2.2 Hz, 1H), 4.74 (d, J = 2.6 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.73 (s, 3H), 2.23 (s, 7H), 1.35 (t, J= 7.1 Hz, 4H).

[0266] LRMS(ESI + )m / z:404.0(M+H) + .

[0267] Example 2-1 26065: Methyl 1-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylate [ka]

[0268] A solution of 4-fluoro-3-nitrobenzoic acid 1 (5.0 g, 27.0 mmol) was dissolved in dry MeOH (30 mL), to which H2SO4 (5 mL, 0.3 M) was added. The reaction mixture was heated and refluxed for 12 hours. The solvent was removed under reduced pressure, and the unpurified reaction mixture was dissolved in HCl (150 mL) and washed with saturated NaHCO3 (20 mL x 2), water (10 mL x 2), and brine (10 mL). The HCl layer was dried over anhydrous MgSO4 and evaporated to obtain methyl 4-fluoro-3-nitrobenzoate 2 (95%) as a white solid.

[0269] Compound 2 (2.0 g, 10.2 mmol) dissolved in dry CH2Cl2 (50 mL) and 2-aminomethylfuran (3 equivalents) were stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed, and the unpurified product was purified by flash column chromatography to obtain nitrobenzoate 3 (90%).

[0270] Compound 3 (2.0 g, 4.8 mmol) was dissolved in dry MeOH (100 mL), and zinc powder (15 equivalents, 71.4 mmol) and ammonium formate (7.5 equivalents, 35.7 mmol) were added to the solution. The resulting reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the zinc powder was filtered through a Celite bed, the filtrate was evaporated, and the product was dissolved in CH2Cl2 (100 mL). The precipitated ammonium formate was removed by filtration, and compound 4 (92%) was obtained by evaporating the solvent.

[0271] Compound 4 (1.0 g, 4.0 mmol) was dissolved using DCM, and 1.2 equivalents of CNBr were added and the mixture was reacted at room temperature. After 8 hours, the mixture was extracted with DCM and water. After removing the solvent, the unpurified product was purified by flash column chromatography to obtain compound 5 (60%).

[0272] A solution of methyl 2-amino-1-(furan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate 5 (0.05 g, 0.18 mmol) was dissolved in acetonitrile (10 mL). K2CO3 (0.0497 g, 0.36 mmol) and KI (0.0089 g, 0.054 mmol) were added, followed by 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 (0.041 g, 0.22 mmol). The reaction mixture was refluxed for 6 hours. After 6 hours, the solvent was evaporated, the reaction mixture was diluted with saturated NaHCO3 aqueous solution (10 mL), and extracted with siRNA (3 × 10 mL).

[0273] The bound organic phase was washed with saturated brine (30 mL). The unpurified product was purified by silica gel column chromatography using 8% methanol / Âxy to obtain the pure product NCTU-SUN-26065 as a white solid of 0.053 g (71%).

[0274] 1 H NMR (400 MHz, chloroform-d) δ 8.34 (s, 1H), 7.83 (dd, J = 8.3, 1.4 Hz, 1H), 7.73 (d, J = 1.2 Hz, 1H), 7.34 (dd, J = 1.8, 0.7 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.37 (d, J = 3.3 Hz, 1H), 6.32 (dd, J = 3.2, 1.9 Hz, 1H), 5.42 (s, 2H), 5.10 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H); 13¹³C NMR (10¹ MHz, chloroform-d): δ 166.75, 153.88, 142.73, 133.38, 128.36, 124.86, 124.00, 110.60, 109.61, 109.04, 108.26, 77.22, 61.46, 52.24, 38.50, 31.90, 29.67, 29.33, 22.66, 14.64, 14.09, 11.39; LRMS (ESI+): m / z 422.3 (M+H) + .

[0275] Example 2-2 21098: Methyl 2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1-propyl-1H-benzo[d]imidazole-5-carboxylate [ka]

[0276] The title compound was obtained using the same reaction and preparation steps as in Example 2-1, except that the amine was replaced with propan-1-amine.

[0277] 1 H NMR (400 MHz, methanol-d4) δ 7.96 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.42 (d, J= 8.4 Hz, 1H), 5.41 (s, 2H), 4.09 (t, J= 7.4 Hz, 2H), 3.81 (d, J = 13.8 Hz, 6H), 2.34 (s, 3H), 2.20 (s, 3H), 1.85 (d, J = 7.9 Hz, 2H), 1.02 (t, J= 7.4 Hz, 3H); 13C NMR (101 MHz, methanol-d4) δ 164.54 , 148.32 , 134.44 , 126.25 , 124.69 , 124.43 , 109.95 , 108.43 , 59.29 , 51.27 , 45.10 , 43.91, 29.31, 20.86, 11.90, 9.78, 9.16; LRMS(ESI+):m / z 383.3(M+H) + .

[0278] Example 2-3 21103: Methyl 2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-5-carboxylate [ka]

[0279] The title compound was obtained using the same reaction and preparation steps as in Example 2-1, except that the amine was replaced with 3-methoxypropan-1-amine.

[0280] 1 H NMR (400 MHz, methanol-d4) δ 8.10 (s, 1H), 7.90 (t, J = 1.8 Hz, 1H), 7.67 (dt, J = 8.4, 1.9 Hz, 1H), 7.11 (dd, J = 8.4, 2.1 Hz, 1H), 4.58 (d, 2.19 (dd, J = 10.1, 2.1 Hz, 6H), 1.96 (p, J = 6.2 Hz, 2H); 13C NMR (101 MHz, methanol-d4) δ 167.93 , 164.20 , 155.50 , 153.88 , 147.84 , 141.23 , 138.15 , 125.49 , 124.19 , 122.68 , 121.59 , 116.14, 106.85, 68.04, 59.16, 57.48, 50.95, 45.26, 38.49, 28.17, 11.97, 9.08; LRMS (ESI+): m / z 413.3 (M+H) + .

[0281] Example 2-4 26070:1-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylic acid [ka]

[0282] A solution of 4-fluoro-3-nitrobenzoic acid 1 (5.0 g, 27.0 mmol) was dissolved in dry MeOH (30 mL), to which H2SO4 (5 mL, 0.3 M) was added. The reaction mixture was heated and refluxed for 12 hours. The solvent was removed under reduced pressure, and the unpurified reaction mixture was dissolved in HCl (150 mL) and washed with saturated NaHCO3 (20 mL x 2), water (10 mL x 2), and brine (10 mL). The HCl layer was dried over anhydrous MgSO4 and evaporated to obtain methyl 4-fluoro-3-nitrobenzoate 2 (95%) as a white solid.

[0283] Compound 2 (2.0 g, 10.2 mmol) dissolved in dry CH2Cl2 (50 mL) and furan-2-ylmethaneamine (3 equivalents) were stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed, and the unpurified product was purified by flash column chromatography to obtain nitrobenzoate 3 (90%).

[0284] Compound 3 (2.0 g, 4.8 mmol) was dissolved in dry MeOH (100 mL), and zinc powder (15 equivalents, 71.4 mmol) and ammonium formate (7.5 equivalents, 35.7 mmol) were added to the solution. The resulting reaction mixture was stirred at room temperature for 30 minutes. After the reaction was complete, the zinc powder was filtered through a Celite bed, the filtrate was evaporated, and the product was dissolved in CH2Cl2 (100 mL). The precipitated ammonium formate was removed by filtration, and compound 4 (92%) was obtained by evaporating the solvent.

[0285] Compound 4 (1.0 g, 4.0 mmol) was dissolved using DCM, and 1.2 equivalents of CNBr were added and the mixture was reacted at room temperature. After 8 hours, the mixture was extracted with DCM and water. After removing the solvent, the unpurified product was purified by flash column chromatography to obtain compound 5 (60%).

[0286] To a solution of methyl 2-amino-1-(furan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylate 5 (0.05 g, 0.18 mmol) dissolved in acetonitrile (10 mL), K2CO3 (0.0497 g, 0.36 mmol) and KI (0.0089 g, 0.054 mmol), followed by 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 (0.041 g, 0.22 mmol) were added, and the reaction mixture was refluxed for 6 hours. After 6 hours, the solvent was evaporated, and the reaction mixture was diluted with saturated NaHCO3 aqueous solution (10 mL) and extracted with siRNA (3 × 10 mL). The bound organic phase was washed with saturated brine (30 mL). The unpurified product was purified by silica gel column chromatography using 8% methanol / siRNA to obtain methyl 1-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylate 7.

[0287] Under reflux conditions, methyl 1-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylate (0.053 g, 0.126 mmol) was dissolved in EtOH / H2O (1 / 1, 3 mL), to which NaOH (0.0251 g, 0.63 mmol) was added. After 1 hour, the solvent was evaporated, and the reaction mixture was diluted with saturated aqueous HCl (10 mL) and extracted with siRNA (3 × 10 mL). The bound organic phase was washed with saturated brine (10 mL). The unpurified product was purified by silica gel column chromatography using 20% ​​methanol / siRNA to obtain 0.030 g (65%) of the pure product as a white solid.

[0288] LRMS(ESI+):m / z407.2(M+H) + .

[0289] Example 2-5 26066: Methyl 2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1-pentyl-1H-benzo[d]imidazole-5-carboxylate [ka]

[0290] The title compound was obtained using the same reaction and preparation steps as in Example 2-1, except that the amine was replaced with pentane-1-amine.

[0291] 1H NMR (400 MHz, chloroform-d) δ 8.08 (s, 1H), 8.01 (dd, J = 8.4, 1.2 Hz, 1H), 7.72 (s, 1H), 7.29 (d, J = 8.5 Hz, 1H), 5.92 (s, 2H), 4.49 (t, J = 7.2 Hz, 2H), 3.89 (s, 6H), 2.47 (s, 3H), 2.26 (s, 3H), 1.96 - 1.83 (m, 2H), 1.54 - 1.41 (m, 2H), 1.44 - 1.29 (m, 2H), 0.88 (t, J= 7.2 Hz, 3H); LRMS (ESI+): m / z 411.2 (M+H) + .

[0292] Example 2-6 21102:2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid [ka]

[0293] The title compound was obtained using the same reaction and preparation steps as in Examples 2-4 above, except that the amine was replaced with propan-1-amine.

[0294] 1 H NMR (400 MHz, methanol-d4) δ 8.04 (d, J = 8.3 Hz, 1H), 7.95 (s, 1H), 7.89 (s, 1H), 7.64 (d, J= 8.1 Hz, 1H), 5.57 (s, 2H), 4.25 (t, J= 7.3 Hz, 2H), 3.83 (s, 3H), 2.41 (s, 3H), 2.21 (s, 3H), 1.92 (d, J = 7.3 Hz, 2H), 1.07 (t, J = 7.3 Hz, 3H); 13C NMR (101 MHz, methanol-d4) δ 150.03 , 148.40 , 130.63 , 126.40 , 125.74 , 111.55 , 109.87 , 59.38 , 45.34 , 44.56 , 20.95 , 11.93, 9.68, 9.17; LRMS (ESI+): m / z 369.2 (M+H) + .

[0295] Example 2-7 26071: Methyl 2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1-(4-methoxybenzyl)-1H-benzo[d]imidazole-5-carboxylate [ka]

[0296] The title compound was obtained using the same reaction and preparation steps as in Example 2-1, except that the amine was replaced with (4-methoxyphenyl)methaneamine.

[0297] 1 H NMR (400 MHz, methanol-d4) δ 8.02 (s, 1H), 7.83 (dd, J=8.4, 1.5 Hz, 1H), 7.68 (d, J = 1.6 Hz, 1H), 7.29 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 5.43 (s, 2H), 5.29 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 2.36 (s, 3H), 2.24 (s, 3H); LRMS (ESI+): m / z 461.2 (M+H) + .

[0298] Example 2-8 21105:2-(bis((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1-(2-(cyclohex-1-en-1-yl)ethyl)-1H-benzo[d]imidazole-5-carboxylic acid [ka]

[0299] The title compound was obtained using the same reaction and preparation steps as in Examples 2-4 above, except that the amine was replaced with 2-(cyclohex-1-en-1-yl)ethaneamine.

[0300] 1 H NMR (400 MHz, methanol-d4) δ 8.17 (s, 2H), 8.07 (s, 1H), 7.82 (d, J= 8.2 Hz, 1H), 7.26 (d, J = 8.3 Hz, 1H), 5.13 (s, 1H), 4.77 (s, 4H), 4.11 (t, J = 7.8 Hz, 2H), 3.80 - 3.69 (m, 6H), 2.29 (t, J = 8.4 Hz, 2H), 2.18 (d, J = 21.8 Hz, 12H), 1.76 (s, 4H), 1.49 - 1.36 (m, 4H); 13 C NMR (101 MHz, methanol-d4) δ 156.95 , 145.93 , 139.17 , 131.88 , 130.28 , 125.53 , 118.06 , 117.75 , 117.05 , 115.18 , 114.79 , 110.01, 100.70, 51.25, 46.58, 35.22, 28.52, 19.80, 16.65, 14.33, 13.64, 3.99, 1.48; LRMS (ESI+): m / z 584.3 (M+H)+.

[0301] Example 2-9 21104:2-(bis(4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-5-carboxylic acid [ka]

[0302] The title compound was obtained using the same reaction and preparation steps as in Examples 2-4 above, except that the amine was replaced with 3-methoxypropan-1-amine.

[0303] 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 2H), 7.88 (d, J = 1.6 Hz, 1H), 7.68 (dd, J = 8.4, 1.6 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 4.65 (s, 4H), 4.17 (t, J = 7.6 Hz, 2H), 3.62 (s, 6H), 3.20 (t, J= 5.9 Hz, 2H), 3.09 (s, 3H), 2.10 (s, 6H), 2.05 (s, 6H), 1.94 - 1.88 (m, 2H); 13 C NMR (101 MHz, DMSO-d6) δ 168.52 , 163.68 , 158.90 , 155.26 , 148.49 , 141.33 , 125.19 , 125.04 , 124.05 , 122.18 , 118.11 , 109.15, 69.30, 60.07, 58.30, 54.87, 41.74, 29.10, 13.24, 10.68; LRMS (ESI+): m / z 548.3 (M+H) + .

[0304] Example 2-10 26076:2-(((4-Methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1-pentyl-1H-benzo[d]imidazole-5-carboxylic acid [ka]

[0305] The title compound was obtained using the same reaction and preparation steps as in Examples 2-4 above, except that the amine was replaced with pentane-1-amine.

[0306] 1 H NMR (400 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.81 (dd, J = 8.2, 1.3 Hz, 1H), 7.70 (d, J = 1.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 5.59 (s, 2H), 4.23 (t, J= 6.9 Hz, 2H), 3.72 (s, 3H), 2.30 (s, 3H), 2.11 (s, 3H), 1.83 (s, 2H), 1.30 (dq, J = 6.7, 3.3 Hz, 4H), 0.90 - 0.73 (m, 3H); LRMS (ESI+): m / z 397.2 (M+H) + .

[0307] Example 2-11 26077:2-(((4-Methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1-(4-methoxybenzyl)-1H-benzo[d]imidazole-5-carboxylic acid [ka]

[0308] The title compound was obtained using the same reaction and preparation steps as in Examples 2-4 above, except that the amine was replaced with (4-methoxyphenyl)methaneamine.

[0309] LRMS(ESI+):m / z447.2(M+H) + .

[0310] Example 2-12 21115:2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-5-carboxylic acid [ka]

[0311] The title compound was obtained using the same reaction and preparation steps as in Examples 2-4 above, except that the amine was replaced with 3-methoxypropan-1-amine.

[0312] 1 H NMR (400 MHz, methanol-d4) δ 8.20 (s, 1H), 7.98 - 7.92 (m, 2H), 7.50 (d, J = 8.7 Hz, 1H), 4.86 (s, 2H), 4.34 (t, J = 6.7 Hz, 2H), 3.87 (s, 3H), 3.44 (t, J = 5.6 Hz, 2H), 3.27 (s, 3H), 2.35 (s, 3H), 2.28 (s, 3H), 2.17 - 2.10 (m, 2H); 13 C NMR (101 MHz, methanol-d4) δ 169.05 , 152.95 , 147.73 , 136.45 , 132.73 , 127.94 , 127.04 , 126.46 , 125.88 , 114.80 , 110.19 , 69.41, 60.81, 58.69, 46.10, 41.07, 28.74, 13.36, 10.48; LRMS (ESI+): m / z 399.2 (M+H) + .

[0313] Example 2-13 21116: Methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylate [ka]

[0314] The title compound was obtained using the same reaction and preparation steps as in Example 2-1, except that the amine was replaced with 2-(cyclohex-1-en-1-yl)ethaneamine.

[0315] 1 H NMR (400 MHz, acetone-d6) δ 8.20 (s, 1H), 7.94 (d, J = 1.4 Hz, 1H), 7.70 (dt, J = 8.2, 1.4 Hz, 1H), 7.22 (dd, J = 8.3, 1.2 Hz, 1H), 6.71 (s, 1H), 5.33 (dt, J= 4.8, 2.3 Hz, 1H), 4.68 (d, J= 3.7 Hz, 2H), 4.17 (td, J = 7.2, 1.2 Hz, 2H), 3.84 (d, J = 1.2 Hz, 3H), 3.79 (d, J = 1.2 Hz, 3H), 2.41 (t, J = 7.2 Hz, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 2.04 (h, J = 1.8 Hz, 2H), 2.02 - 1.97 (m, 2H), 1.82 - 1.76 (m, 2H), 1.51 (t, J = 5.9 Hz, 2H), 1.42 - 1.37 (m, 2H); 13 ¹³C NMR (10¹ MHz, acetone-d6) δ 167.29, 163.89, 155.45, 154.37, 148.06, 142.70, 138.71, 133.89, 125.06, 124.16, 123.65, 122.50, 120.86, 116.95, 107.03, 59.48, 50.95, 45.16, 41.27, 36.41, 29.18, 8.99, 28.79, 28.11, 24.91, 22.61, 21.81 , 12.36 , 9.35.

[0316] Example 2-14 21117:1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1H-benzo[d]imidazole-5-carboxylic acid [ka]

[0317] The title compound was obtained using the same reaction and preparation steps as in Examples 2-4 above, except that the amine was replaced with 2-(cyclohex-1-en-1-yl)ethaneamine.

[0318] 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.70 (s, 1H), 7.56 (d, J= 8.2 Hz, 1H), 7.15 (d, J = 8.3 Hz, 1H), 7.08 (t, J = 5.3 Hz, 1H), 5.23 (s, 1H), 4.61 (d, J = 4.2 Hz, 2H), 4.12 (t, J = 7.1 Hz, 2H), 3.69 (s, 3H), 2.28 - 2.13 (m, 8H), 1.90 (s, 2H), 1.72 (s, 2H), 1.38 (dq, J = 31.9, 5.4 Hz, 4H); 13 C NMR (101 MHz, DMSO-d6) δ 168.24 , 155.18 , 155.12 , 147.74 , 141.57 , 137.88 , 133.55 , 124.39 , 123.56 , 123.09 , 123.01 , 120.32 , 115.84 , 106.77 , 59.43 , 45.42 , 40.30 , 35.64 , 27.52 , 24.33 , 21.97 , 21.29 , 12.55 , 9.85 .

[0319] Example 2-15 21118: Methyl 2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1-phenethyl-1H-benzo[d]imidazole-5-carboxylate [ka]

[0320] The title compound was obtained using the same reaction and preparation steps as in Example 2-1, except that the amine was replaced with 2-phenylethaneamine.

[0321] 1 H NMR (400 MHz, methanol-d4) δ 8.16 (s, 1H), 7.89 (s, 1H), 7.63 (d, J= 8.2 Hz, 1H), 7.10 (dt, J = 16.2, 7.1 Hz, 5H), 6.99 (d, J = 8.2 Hz, 1H), 4.57 (s, 3H), 4.30 (t, J= 7.0 Hz, 2H), 3.82 (d, J = 25.8 Hz, 6H), 3.05 (t, J = 7.0 Hz, 2H), 2.29 - 2.20 (m, 6H); 13 ¹³C NMR (101 MHz, methanol-d4) δ 169.48, 165.74, 156.92, 155.57, 149.24, 142.52, 139.50, 139.30, 130.05, 129.59, 127.73, 127.01, 125.84, 123.98, 122.90, 117.45, 108.52, 60.62, 52.38, 49.85, 46.69, 44.97, 40.00, 39.79, 39.58, 39.37 39.16, 35.62, 13.36, 10.56; LRMS (ESI+): m / z 445.4 (M+H) + .

[0322] Example 2-16 21119:2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1-phenethyl-1H-benzo[d]imidazole-5-carboxylic acid [ka]

[0323] The title compound was obtained using the same reaction and preparation steps as in Examples 2-4 above, except that the amine was replaced with 2-phenylethaneamine.

[0324] 1 H NMR (400 MHz, methanol-d4) δ 8.19 (s, 1H), 7.89 (d, J = 1.5 Hz, 1H), 7.79 (dd, J = 8.5, 1.7 Hz, 1H), 7.19 - 7.07 (m, 6H), 4.73 (s, 2H), 4.48 (t, J = 6.8 Hz, 2H), 3.87 (s, 3H), 3.16 (t, J = 6.8 Hz, 2H), 2.29 (d, J = 14.6 Hz, 6H); 13 ¹³C NMR (101 MHz, methanol-d4) δ values: 169.15, 167.25, 153.40, 153.06, 148.02, 138.56, 136.34, 130.16, 129.70, 128.21, 128.04, 127.16, 126.66, 126.02, 114.72, 110.61, 61.03, 46.15, 45.80, 34.84, 13.58, 10.68.

[0325] Example 2-17 21120:2-(bis((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1-propyl-1H-benzo[d]imidazole-5-carboxylic acid [ka]

[0326] The title compound was obtained using the same reaction and preparation steps as in Examples 2-4 above, except that the amine was replaced with propan-1-amine.

[0327] 1 H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 2H), 7.88 (d, J = 1.6 Hz, 1H), 7.68 (dd, J = 8.3, 1.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 4.63 (s, 4H), 4.11 (t, J = 7.9 Hz, 2H), 3.62 (s, 6H), 2.08 (d, J= 17.4 Hz, 12H), 1.66 (d, J = 7.7 Hz, 2H), 0.73 (t, J = 7.3 Hz, 3H).

[0328] Example 2-18 21121:2-(bis((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-1-phenethyl-1H-benzo[d]imidazole-5-carboxylic acid [ka]

[0329] The title compound was obtained using the same reaction and preparation steps as in Examples 2-4 above, except that the amine was replaced with 2-phenylethaneamine.

[0330] 1 H NMR (400 MHz, DMSO-d6) δ 8.07 (s, 2H), 7.89 (d, J = 1.5 Hz, 1H), 7.67 (dd, J = 8.4, 1.7 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.19 - 7.13 (m, 3H), 7.10 - 7.05 (m, 2H), 4.64 (s, 4H), 4.39 (t, J = 8.0 Hz, 2H), 3.59 (s, 6H), 2.97 (t, J = 8.1 Hz, 2H), 2.07 (d, J = 11.5 Hz, 12H); 13C NMR (101 MHz, DMSO-d6) δ 168.15 , 163.34 , 154.81 , 148.03 , 140.97 , 138.79 , 138.04 , 128.79 , 128.39 , 126.52 , 124.88 , 124.76, 123.79, 122.04, 117.97, 109.35, 59.74, 55.15, 45.31, 34.51, 12.91, 10.42.

[0331] Example 3-1 NCTU-SUN-26079: Methyl 3-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-3,4-dihydroquinazoline-7-carboxylate [ka]

[0332] To a solution prepared by dissolving 4-(bromomethyl)-3-nitrobenzoic acid 1 (5.0 g, 27.0 mmol) in dry MeOH / CH2Cl2 (3 mL:30 mL), DCC (1.2 equivalents) and DMAP (0.005 equivalents) were added, and the reaction mixture was stirred at room temperature for 16 hours. The byproduct DCU was removed by filtration, and the unpurified material was purified by flash column chromatography to obtain methyl-4-(bromomethyl)-3-nitrobenzoate 2 (76%) as a grayish-white solid.

[0333] Compound 2 (4.0 g, 14.5 mmol) dissolved in dry CH2Cl2 (50 mL) and 2-aminomethylfuran (3 equivalents) were stirred at room temperature for 48 hours. After the reaction was complete, the solvent was removed, and the unpurified product was purified by flash column chromatography to obtain nitrobenzoate 3 (82%).

[0334] Compound 3 (3.65 g, 11.9 mmol) was dissolved in dry MeOH (100 mL), and SnCl2.2H2O (3.5 equivalents) was added to the solution. The resulting reaction mixture was refluxed for 10 minutes. As soon as the reaction was complete, the byproduct was filtered through a Celite bed, and the filtrate was evaporated. The unpurified product was separated into 1N NaOH and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3 × 20 mL), the bound layer was dried over MgSO4, and compound 4 (87%) was obtained by concentration under reduced pressure.

[0335] Compound 4 (1.0 g, 3.8 mmol) was dissolved using DCM, and 1.2 equivalents of CNBr were added and the mixture was reacted at room temperature. After 8 hours, the mixture was extracted with DCM and water. After removing the solvent, the unpurified product was purified by flash column chromatography to obtain compound 5 (60%).

[0336] To a solution prepared by dissolving methyl 2-amino-3-(furan-2-ylmethyl)-3,4-dihydroquinazoline-7-carboxylate 5 (0.3 g, 1.05 mmol) in acetonitrile (20 mL), K2CO3 (0.29 g, 2.1 mmol) and KI (0.005 g, 0.03 mmol) were added, followed by 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 (0.722 g, 3.89 mmol). The reaction mixture was refluxed for 6 hours. After 24 hours, the solvent was evaporated, the reaction mixture was diluted with saturated NaHCO3 aqueous solution (30 mL), and extracted with siRNA (3 × 30 mL).

[0337] The bound organic phase was washed with saturated brine (30 mL). The unpurified product was purified by silica gel column chromatography using 8% methanol / siRNA to obtain the pure product NCTU-SUN-26079 as a white solid of 0.43 g (70%).

[0338] 1H NMR (400 MHz, methanol-d4) δ 8.16 (s, 1H), 7.81 (dd, J = 7.9, 1.4 Hz, 1H), 7.56 (dd, J = 1.8, 0.8 Hz, 1H), 7.37 (d, J = 1.4 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 6.60 (d, J = 3.3 Hz, 1H), 6.47 (dd, J = 3.3, 1.9 Hz, 1H), 5.28 (s, 2H), 4.88 (s, 2H), 4.61 (s, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 2.45 (s, 3H), 2.28 (s, 3H); LRMS (ESI+): m / z 435.3 (M+H) + .

[0339] Example 3-2 21106: Methyl 3-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-3,4-dihydroquinazoline-7-carboxylate [ka]

[0340] The title compound was obtained using the same reaction and preparation steps as in Example 3-1, except that the amine was replaced with 2-(cyclohex-1-en-1-yl)ethaneamine.

[0341] 1H NMR (400 MHz, methanol-d4) δ 8.17 (s, 1H), 7.83 (dd, J = 7.9, 1.5 Hz, 1H), 7.40 - 7.33 (m, 2H), 5.24 (s, 2H), 5.16 (s, 1H), 4.61 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.76 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H), 2.12 (d, J = 8.1 Hz, 2H), 1.99 (s, 2H), 1.63 - 1.55 (m, 4H), 1.43 - 1.36 (m, 2H); LRMS (ESI+): m / z 314.2 (M+H) + .

[0342] Example 3-3 26072: Methyl 2-(bis((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-3-(furan-2-ylmethyl)-3,4-dihydroquinazoline-7-carboxylate [ka]

[0343] The compound described in the title was obtained using the same reaction products and preparation steps as in Example 3-1 described above.

[0344] 1H NMR (400 MHz, methanol-d4) δ 8.21 - 8.19 (m, 1H), 8.07 (d, J= 0.8 Hz, 1H), 7.83 (dd, J = 7.9, 1.5 Hz, 1H), 7.57 (d, J = 1.5 Hz, 1H), 7.43 (dd, J = 1.9, 0.8 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 6.57 (dd, J = 3.4, 0.8 Hz, 1H), 6.41 (dd, J = 3.3, 1.9 Hz, 1H), 5.48 (d, J = 1.9 Hz, 2H), 4.93 (s, 2H), 4.81 (s, LRMS (ESI+) : m / z 584.31 (M+H) + .

[0345] Example 3-4 26091: Methyl 2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-3-pentyl-3,4-dihydroquinazoline-7-carboxylate [ka]

[0346] The title compound was obtained using the same reaction and preparation steps as in Example 3-1, except that the amine was replaced with pentane-1-amine.

[0347] 1H NMR (400 MHz, methanol-d4) δ 8.14 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.32 (s, 1H), 5.24 (s, 2H), 4.70 (s, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 3.64 (t, J = 7.8 Hz, 2H), 2.44 (s, 3H), 2.25 (s, 3H), 1.76 (p, J= 7.9 Hz, 2H), 1.37 (dp, J = 11.3, 7.1, 6.2 Hz, 4H), 0.96 - 0.83 (m, 3H); 13 C NMR (101 MHz, methanol-d4) δ 165.84 , 165.03 , 155.04 , 152.00 , 148.85 , 137.27 , 130.52 , 128.00 , 126.46 , 125.87 , 125.64 , 124.60, 116.16, 59.47, 51.56, 50.90, 50.56, 47.94, 28.23, 26.36, 22.07, 12.93, 12.02, 9.51; LRMS (ESI+): m / z 425.3 (M+H) + .

[0348] Example 3-5 26092: Methyl 2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-3-(4-methoxybenzyl)-3,4-dihydroquinazoline-7-carboxylate [ka]

[0349] The title compound was obtained using the same reaction and preparation steps as in Example 3-1, except that the amine was replaced with (4-methoxyphenyl)methaneamine.

[0350] 1H NMR (400 MHz, methanol-d4) δ 8.09 (s, 1H), 7.71 (dd, J = 7.8, 1.4 Hz, 1H), 7.57 (d, J = 1.4 Hz, 1H), 7.39 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 7.8 Hz, 1H), 6.92 - 6.83 (m, 2H), 5.65 (s, 2H), 5.18 (s, 2H), 4.68 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.74 (s, 3H), 2.43 (s, 3H), 2.18 (s, 3H); LRMS (ESI+) : m / z 475.3 (M+H) + .

[0351] Example 3-6 21110:2-(((4-Methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-3-(3-methoxypropyl)-3,4-dihydroquinazoline-7-carboxylic acid [ka]

[0352] The title compound was obtained using the same reaction and preparation steps as in Example 3-1, except that the amine was replaced with 3-methoxypropan-1-amine.

[0353] 1 H NMR (400 MHz, methanol-d4) δ 7.84 (dd, J = 7.9, 1.4 Hz, 1H), 7.64 (s, 1H), 7.46 (d, J = 1.4 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 5.26 (s, 2H), 4.69 (s, 2H), 3.85 (s, 3H), 3.75 (t, J = 6.9 Hz, 2H), 3.51 (t, J = 5.7 Hz, 2H), 2.27 (s, 3H), 2.04 (d, J = 4.9 Hz, 6H), 1.29 (d, J = 3.5 Hz, 2H); LRMS (ESI+): m / z 413.3 (M+H)+ .

[0354] Example 3-7 26089:3-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-3,4-dihydroquinazoline-7-carboxylic acid [ka]

[0355] To a solution prepared by dissolving 4-(bromomethyl)-3-nitrobenzoic acid 1 (5.0 g, 27.0 mmol) in dry MeOH / CH2Cl2 (3 mL:30 mL), DCC (1.2 equivalents) and DMAP (0.005 equivalents) were added, and the reaction mixture was stirred at room temperature for 16 hours. The byproduct DCU was removed by filtration, and the unpurified material was purified by flash column chromatography to obtain methyl-4-(bromomethyl)-3-nitrobenzoate 2 (76%) as a grayish-white solid.

[0356] Compound 2 (4.0 g, 14.5 mmol) dissolved in dry CH2Cl2 (50 mL) and 2-aminomethylfuran (3 equivalents) were stirred at room temperature for 48 hours. After the reaction was complete, the solvent was removed, and the unpurified product was purified by flash column chromatography to obtain nitrobenzoate 3 (82%).

[0357] Compound 3 (3.65 g, 11.9 mmol) was dissolved in dry MeOH (100 mL), and SnCl2.2H2O (3.5 equivalents) was added to the solution. The resulting reaction mixture was refluxed for 10 minutes. As soon as the reaction was complete, the byproduct was filtered through a Celite bed, and the filtrate was evaporated. The unpurified product was separated into 1N NaOH and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3 × 20 mL), the bound layer was dried over MgSO4, and compound 4 (87%) was obtained by concentration under reduced pressure.

[0358] Compound 4 (1.0 g, 3.8 mmol) was dissolved using DCM, and 1.2 equivalents of CNBr were added and the mixture was reacted at room temperature. After 8 hours, the mixture was extracted with DCM and water. After removing the solvent, the unpurified product was purified by flash column chromatography to obtain compound 5 (60%).

[0359] To a solution prepared by dissolving methyl 2-amino-3-(furan-2-ylmethyl)-3,4-dihydroquinazoline-7-carboxylate 5 (0.3 g, 1.05 mmol) in acetonitrile (20 mL), K2CO3 (0.29 g, 2.1 mmol) and KI (0.005 g, 0.03 mmol) were added, followed by 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 (0.722 g, 3.89 mmol). The reaction mixture was refluxed for 6 hours. After 24 hours, the solvent was evaporated, the reaction mixture was diluted with saturated NaHCO3 aqueous solution (30 mL), and extracted with siRNA (3 × 30 mL).

[0360] The bonded organic phase was washed with saturated brine (30 mL). The unpurified product was purified by silica gel column chromatography using 8% methanol / siRNA to obtain 0.43 g (70%) of methyl 3-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-3,4-dihydroquinazoline-7-carboxylate 7.

[0361] Under reflux conditions, methyl 3-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-3,4-dihydroquinazoline-7-carboxylate 7 (0.43 g, 0.99 mmol) was dissolved in EtOH / H2O (1 / 1, 10 mL), to which NaOH (0.198 g, 4.95 mmol) was added. After 1 hour, the solvent was evaporated, and the reaction mixture was diluted with saturated aqueous HCl (30 mL) and extracted with siRNA (3 × 10 mL). The bound organic phase was washed with saturated brine (30 mL). The unpurified product was purified by silica gel column chromatography using 20% ​​methanol / siRNA to obtain 0.27 g (65%) of the pure product as a white solid.

[0362] 1 H NMR (400 MHz, methanol-d4) δ 8.07 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.53 (d, J = 1.8 Hz, 1H), 7.35 (s, 1H), 7.14 (d, J= 7.8 Hz, 1H), 6.57 (d, J = 3.2 Hz, 1H), 6.43 (dd, J = 3.2, 1.8 Hz, 1H), 5.22 (s, 2H), 4.84 (s, 2H), 4.53 (s, 2H), 3.82 (s, 3H), 2.40 (s, 3H), 2.22 (s, 3H); 13 C NMR (101 MHz, methanol-d4) δ 171.74 , 164.87 , 155.39 , 151.73 , 148.52 , 147.49 , 143.54 , 138.56 , 136.13 , 126.27 , 125.93 , 124.64 , 124.63 , 116.56 , 110.30 , 109.86 , 59.40 , 50.46 , 47.46 , 46.94 , 46.47 , 11.97 , 9.33; LRMS (ESI+) : m / z 421.2 (M+H) + .

[0363] Example 3-8 26090:2-(((4-Methoxy-3,5-dimethylpyridine-2-yl)methyl)amino)-3-pentyl-3,4-dihydroquinazoline-7-carboxylic acid [ka]

[0364] The title compound was obtained using the same reaction and preparation steps as in Examples 3-7 above, except that the amine was replaced with pentane-1-amine.

[0365] 1 H NMR (400 MHz, methanol-d4) δ 8.03 (dd, J = 8.4, 1.4 Hz, 1H), 7.96 (s, 1H), 7.84 (d, J = 1.3 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 3.83 (s, 3H), 2.41 (s, 3H), 2.22 (s, 3H), 1.92 - 1.83 (m, 2H), 1.43 (tt, J = 5.7, 2.8 Hz, 4H), 1.29 (d, J = 4.0 Hz, 2H), 0.97 - 0.92 (m, 3H); (ESI+): m / z 411.3 (M+H) + .

[0366] Example 4-1 NCTU-SUN-12082: Methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylate [ka]

[0367] H2SO4 (5 mL, 0.3 M) was added to a solution of 4-fluoro-3-nitrobenzoic acid 1, and the reaction mixture was heated and refluxed. The solvent was removed under reduced pressure, and the unpurified reaction mixture was dissolved in alkylammonium

[0368] Compound 2 and 2-(cyclohex-1-en-1-yl)ethaneamine were stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed and the unpurified product was purified to obtain nitrobenzoate 3.

[0369] Zinc powder and ammonium formate were added to a solution of compound 3, and the resulting reaction mixture was stirred at room temperature. Once the reaction was complete, the zinc powder was filtered, the filtrate was evaporated, and the product was dissolved in CH2Cl2. Compound 4 was obtained by filtering off the precipitated ammonium formate and evaporating the solvent.

[0370] A solution of compound 4 dissolved in ethanol was mixed with carbon disulfide and KOH, and the mixture was stirred at 50°C for 8 hours. The mixture was neutralized with acetic acid and extracted with ÃA and water. After removing the solvent, the unpurified product was purified to obtain compound 5.

[0371] To a solution of methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate 5, K2CO3 and KI were added, followed by 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6, and the reaction mixture was refluxed. The solvent was evaporated, and the reaction mixture was diluted and extracted with ELISA.

[0372] The bonded organic phase was washed with saturated brine. The unpurified product was purified to obtain the pure product NCTU-SUN-12082 as a white solid of 0.053 g (71%).

[0373] 1H NMR (300 MHz, acetone-d6) δ 8.24 (d, J = 1.2 Hz, 1H), 8.20 (s, 1H), 7.91 (dd, J = 8.5, 1.4 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 5.22 (s, 1H), 4.83 (s, 2H), 4.28 (t, J = 7.0 Hz, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 2.47 - 2.35 (m, 5H), 2.25 (s, 3H), 1.99 (m, 2H), 1.80 (m, 2H), 1.62 - 1.38 (m, 4H).

[0374] Example 4-2 12083:1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylic acid [ka]

[0375] H2SO4 (5 mL, 0.3 M) was added to a solution of 4-fluoro-3-nitrobenzoic acid 1, and the reaction mixture was heated and refluxed. The solvent was removed under reduced pressure, and the unpurified reaction mixture was dissolved in ethyl acetate. The ethyl acetate layer was dried over anhydrous MgSO4 and evaporated to obtain methyl 4-fluoro-3-nitrobenzoate 2 as a white solid. Compound 2 and 2-(cyclohex-1-en-1-yl)ethaneamine were stirred at room temperature for 2 hours. As soon as the reaction was complete, the solvent was removed, and the unpurified product was purified to obtain nitrobenzoate 3.

[0376] Zinc powder and ammonium formate were added to a solution of compound 3, and the resulting reaction mixture was stirred at room temperature. Once the reaction was complete, the zinc powder was filtered, the filtrate was evaporated, and the product was dissolved in CH2Cl2. Compound 4 was obtained by filtering off the precipitated ammonium formate and evaporating the solvent.

[0377] A solution of compound 4 dissolved in ethanol was mixed with carbon disulfide and KOH, and the mixture was stirred at 50°C for 8 hours. The mixture was neutralized with acetic acid and extracted with ÃA and water. After removing the solvent, the unpurified product was purified to obtain compound 5.

[0378] To a solution of methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate 5, K2CO3 and KI were added, followed by 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6, and the reaction mixture was refluxed. The solvent was evaporated, and the reaction mixture was diluted and extracted with ELISA.

[0379] The bonded organic phase was washed with saturated brine. Purification of the unpurified product yielded 0.053 g (71%) of methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylate 7.

[0380] Under reflux conditions, methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylate 7 (0.53 g, 0.126 mmol) was dissolved in EtOH / H2O (1 / 1, 3 mL), to which NaOH (0.0251 g, 0.63 mmol) was added. After 1 hour, the solvent was evaporated, the reaction mixture was diluted with saturated aqueous HCl (10 mL), and extracted with siRNA (3 × 10 mL). The bound organic phase was washed with saturated brine (30 mL). The unpurified product was purified by silica gel column chromatography using 20% ​​methanol / siRNA to obtain the pure product NCTU-SUN-12083 as a white solid of 0.030 g (65%).

[0381] 1H NMR (300 MHz, CD3OD) δ 8.30 (d, J= 1.4 Hz, 1H), 8.14 (s, 1H), 7.98 (dd, J= 8.5, 1.5 Hz, 1H), 7.49 (d, J= 8.5 Hz, 1H), 5.51 (s, 2H), 5.08 (s, 1H), 4.71 (s, 2H), 4.24 (t, J = 6.8 Hz, 2H), 3.79 (s, 3H), 2.44 - 2.31 (m, 5H), 2.27 (s, 3H), 2.04 - 1.89 (m, 2H), 1.88 - 1.70 (m, 2H), 1.62 - 1.39 (m, 4H).

[0382] Example 4-3 12084: Methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole-5-carboxylate [ka]

[0383] H2SO4 (5 mL, 0.3 M) was added to a solution of 4-fluoro-3-nitrobenzoic acid 1, and the reaction mixture was heated and refluxed. The solvent was removed under reduced pressure, and the unpurified reaction mixture was dissolved in alkylammonium

[0384] Compound 2 and 2-(cyclohex-1-en-1-yl)ethaneamine were stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed and the unpurified product was purified to obtain nitrobenzoate 3.

[0385] Zinc powder and ammonium formate were added to a solution of compound 3, and the resulting reaction mixture was stirred at room temperature. Once the reaction was complete, the zinc powder was filtered, the filtrate was evaporated, and the product was dissolved in CH2Cl2. Compound 4 was obtained by filtering off the precipitated ammonium formate and evaporating the solvent.

[0386] A solution of compound 4 dissolved in ethanol was mixed with carbon disulfide and KOH, and the mixture was stirred at 50°C for 8 hours. The mixture was neutralized with acetic acid and extracted with ÃA and water. After removing the solvent, the unpurified product was purified to obtain compound 5.

[0387] To a solution of methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate 5, K2CO3 and KI were added, followed by 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6, and the reaction mixture was refluxed. The solvent was evaporated, and the reaction mixture was diluted and extracted with ELISA.

[0388] The bonded organic phase was washed with saturated brine. Purification of the unpurified product yielded 0.053 g (71%) of methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylate 7.

[0389] Under ice bath conditions, mCPBA (0.0058 g, 0.034 mmol) was added to a solution of methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-carboxylate 7 (0.053 g, 0.0126 mmol) dissolved in DCM / MeOH (9 / 1, 4.5 mL). Then, NaHCO3 (0.0007 g, 0.0088 mmol) was added, and the ice bath was removed. The unpurified mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with DCM (5 mL). By evaporating the solvent, the pure product NCTU-SUN-12084 was obtained as 0.030 g (65%) of a white solid.

[0390] 1 H NMR (300 MHz, CDCl3) δ 8.55 (s, 1H), 8.13 (s, 1H), 8.10 (dd, J = 8.7, 1.5 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 5.03 (q, J = 12.9 Hz, 3H), 4.59 - 4.35 (t, J= 8.3 Hz, 2H), 4.58 - 4.36 (m, 2H), 3.97 (s, 3H), 3.71 (s, 3H), 2.49 (t, J = 8.3 Hz, 2H), 2.30 (s, 3H), 2.22 (s, 3H), 2.03 - 1.78 (m, 4H), 1.51 (m, 4H).

[0391] Example 5-1 12092:2-(((4-Methoxy-3,5-dimethylpyridine-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-yl(((9H-fluoren-9-yl)methoxy)carbonyl)glycinate [ka]

[0392] To a solution of 2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)acetate 1 (0.08 g, 0.18 mmol) dissolved in ethanol (9 mL), NaOH (0.079 g, 0.198 mmol) was added, followed by 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 2 (0.367 g, 0.198 mmol), and the reaction mixture was refluxed for 1 hour. After the reaction was complete, the solvent was evaporated, and the unpurified product was purified by silica gel column chromatography using 2% MeOH / DCM to obtain the pure product NCTU-SUN-12092 as a white solid of 0.31 g (54.5%).

[0393] 1 H NMR (300 MHz, acetone-d6) δ 8.26 (s, 1H), 7.87 (d, J = 7.4 Hz, 2H), 7.74 (d, J= 7.4 Hz, 2H), 7.51 (d, J = 8.6 Hz, 1H), 7.41 (t, J = 7.3 Hz, 2H), 7.32 (t, J = 7.4 Hz, 3H), 7.14 (t, J = 6.6 Hz, 1H), 6.95 (dd, J = 8.7, 2.1 Hz, 1H), 4.67 (s, 2H), 4.40 (d, J = 7.3 Hz, 2H), 4.36 - 4.21 (m, 3H), 3.80 (s, 3H), 2.36 (s, 3H), 2.25 (s, 3H).

[0394] Example 5-2 12093: 2-(((4-Methoxy-3,5-dimethylpyridine-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-yl(tert-butoxycarbonyl)glycinate [ka]

[0395] The title compound was obtained using the same reaction and preparation steps as in Example 5-1, except that imidazole was replaced with 2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl 2-((tert-butoxycarbonyl)amino)acetate.

[0396] 1 H NMR (300 MHz, acetone) δ 8.27 (s, 1H), 7.50 (s, 1H), 7.29 (d, J = 2.1 Hz, 1H), 6.93 (dd, J = 8.6, 2.1 Hz, 1H), 6.50 (s, 1H), 4.67 (s, 2H), 4.12 (d, J = 6.2 Hz, 2H), 3.81 (s, 3H), 2.38 (s, 3H), 2.26 (s, 3H), 1.45 (s, 9H).

[0397] Example 5-3 12094:2-(((4-Methoxy-3,5-dimethylpyridine-2-yl)methyl)thio)-1Hbenzo[d]-imidazole-5-yl(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-phenylacetate [ka]

[0398] The title compound was obtained by the same reaction and preparation steps as in Example 5-1, except that imidazole was replaced with (S)-2-thioxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl 2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-phenylacetate.

[0399] 1H NMR (300 MHz, acetone-d6) δ 8.24 (s, 1H), 7.85 (d, J = 7.5 Hz, 2H), 7.75 (d, J = 7.4 Hz, 2H), 7.65 (d, J = 7.2 Hz, 2H), 7.52 - 7.39 (m, 6H), 7.32 (m, 2H), 7.22 (d, J = 1.6 Hz, 1H), 6.83 (dd, J = 9.1, 1.5 Hz, 1H), 5.67 (s, 1H), 4.66 (s, 2H), 4.48 - 4.25 (m, 3H), 2.35 (s, 3H), 2.25 (s, 3H).

[0400] Example 6-1 NCTU-SUN-22138:5-Methoxy-2-((2-Methoxy-3,6-dimethylbenzyl)thio)-1H-benzo[d]imidazole [ka]

[0401] To a solution of 2-methoxy-1,3,4-trimethylbenzene 1 (0.3 g, 2.00 mmol) dissolved in chloroform (30 mL), NBS (0.177 g, 1.00 mmol) was added. During the photo-induced reaction, two Philips IR lamps (250 W) were placed away from the reaction flask to maintain reflux. After the reaction was complete, the solvent was evaporated, and the unpurified product was purified by silica gel column chromatography using hexane to obtain 0.092 g (20%) of brominated product 2.

[0402] To a solution of bromination product 2 (0.1 g, 0.43 mmol) dissolved in ethanol (2 mL), NaOH (0.017 g, 0.43 mmol) was added, followed by 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 3 (0.071 g, 0.39 mmol). The reaction mixture was refluxed for 1 hour. After the reaction was complete, the solvent was evaporated, and the unpurified product was purified by silica gel column chromatography using 2% MeOH / DCM to obtain 0.077 g (60%) of NCTU-SUN-22138.

[0403] LRMS(ESI+):m / z329.2(M+H) + .

[0404] Example 6-2 22141:2-((2-methoxy-3,6-dimethylbenzyl)thio)-1H-benzo[d]imidazole-5-ol [ka]

[0405] To a solution of 2-methoxy-1,3,4-trimethylbenzene 1 (0.3 g, 2.00 mmol) dissolved in chloroform (30 mL), NBS (0.177 g, 1.00 mmol) was added. During the photo-induced reaction, two Philips IR lamps (250 W) were placed away from the reaction flask to maintain reflux. After the reaction was complete, the solvent was evaporated, and the unpurified product was purified by silica gel column chromatography using hexane to obtain 0.092 g (20%) of brominated product 2.

[0406] To a solution of bromination product 2 (0.1 g, 0.43 mmol) dissolved in ethanol (2 mL), NaOH (0.017 g, 0.43 mmol) was added, followed by 2-(chloromethyl)-4-hydrotoxy-3,5-dimethylpyridine 3 (0.071 g, 0.39 mmol). The reaction mixture was refluxed for 1 hour. After the reaction was complete, the solvent was evaporated, and the unpurified product was purified by silica gel column chromatography using 2% MeOH / DCM to obtain 0.077 g (60%) of NCTU-SUN-22138.

[0407] LRMS(ESI+):m / z315.1(M+H) + .

[0408] Example 6-3 21133:2-((3-(bromomethyl)-2-((tert-butyldimethylsilyl)oxy)-6-methylbenzyl)thio)-5-methoxy-1H-benzo[d]imidazole [ka]

[0409] To a solution of tert-butyldimethyl(2,3,6-trimethylphenoxy)silane 1 (1.2 g, 4.7 mmol) dissolved in chloroform (50 mL), NBS (1.7 g, 9.5 mmol) was added. During the photo-induced reaction, two Philips IR lamps (250 W) were placed away from the reaction flask to maintain reflux. After the reaction was complete, the solvent was evaporated, and the unpurified product was purified by silica gel column chromatography using hexane to obtain 0.31 g (20%) of brominated product 2.

[0410] To a solution of bromination product 2 (0.3 g, 0.90 mmol) dissolved in ethanol (9 mL), NaOH (0.036 g, 0.90 mmol) was added, followed by 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 3 (0.148 g, 0.82 mmol). The reaction mixture was refluxed for 1 hour. After the reaction was complete, the solvent was evaporated, and the unpurified product was purified by silica gel column chromatography using 2% MeOH / DCM to obtain 0.23 g (60%) of NCTU-SUN-21133.

[0411] 1 H NMR (400 MHz, chloroform-d) δ 7.43 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 4.69 (s, 2H), 3.78 (s, 4H), 2.22 (s, 3H), 2.13 (s, 4H), 0.98 (s, 9H), 0.09 (s, 6H).

[0412] LRMS(ESI+):m / z507.1(M+H) + .

[0413] Example 6-4 22139:5-Methoxy-2-((2-Methoxy-3,6-dimethylbenzyl)sulfinyl)-1H-benzo[d]imidazole [ka]

[0414] To a solution of 2-methoxy-1,3,4-trimethylbenzene 1 (0.3 g, 2.00 mmol) dissolved in chloroform (30 mL), NBS (0.177 g, 1.00 mmol) was added. During the photo-induced reaction, two Philips IR lamps (250 W) were placed away from the reaction flask to maintain reflux. After the reaction was complete, the solvent was evaporated, and the unpurified product was purified by silica gel column chromatography using hexane to obtain 0.092 g (20%) of brominated product 2.

[0415] To a solution of bromination product 2 (0.1 g, 0.43 mmol) dissolved in ethanol (2 mL), NaOH (0.017 g, 0.43 mmol) was added, followed by 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 3 (0.071 g, 0.39 mmol), and the reaction mixture was refluxed for 1 hour. After the reaction was complete, the solvent was evaporated, and the unpurified product was purified by silica gel column chromatography using 2% MeOH / DCM to obtain 0.077 g (60%) of 5-methoxy-2-((2-methoxy-3,6-dimethylbenzyl)thio)-1H-benzo[d]imidazole 3.

[0416] Under ice bath conditions, mCPBA (0.069 g, 0.40 mmol) was added to a solution of 5-methoxy-2-((2-methoxy-3,6-dimethylbenzyl)thio)-1H-benzo[d]imidazole 3 dissolved in DCM / MeOH (9 / 1, 10 mL). Then, NaHCO3 (0.013 g, 0.16 mmol) was added, and the ice bath was removed. The unpurified mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with DCM (10 mL). By evaporating the solvent, the pure product was obtained as 0.047 g (65%) of a white solid.

[0417] LRMS (ESI+): m / z 345.1 (M+H) + .

[0418] Example 7 DAAO Enzyme Assay

[0419] The DAAO enzyme activity assay was modified according to the report by Oguri et al. (Oguri, S., Screening of d-amino acid oxidase inhibitors by a novel multi-assay method; Food Chemistry, 2007, 100(2), 616).

[0420] DAAO activity was measured by generating hydrogen peroxide (H2O2) using the reaction of the substrate D-alanine, and then reacting it with 3-(4-hydroxyphenyl)propionic acid (HPPA). HPPA was oxidized with H2O2 and peroxidase to form a fluorescent dimer, which was then used to measure DAAO activity.

[0421] For the DAO IC50 assay of porcine kidneys, DAO substrates were prepared in 50 mM D-alanine (dissolved in 0.2 M Tris-HCl buffer, pH 8.3). 100 μl of the D-alanine solution was mixed with 4 μl of candidate compounds of different concentrations (dissolved in 100% dimethyl sulfoxide (DMSO)) as shown in the table below. The concentrations were 48.83 μM, 97.66 μM, 195.31 μM, 390.63 μM, 781.25 μM, 1.56 mM, 3.13 mM, 6.25 mM, 12.50 mM, 25.00 mM, and 50.00 mM, with a final DMSO concentration of 0.167% at each reaction concentration. A mixture of 10 μl of D-alanine and the candidate compound was incubated in a Black 96-well plate with 220 μl of reaction master mix at 37°C for 5 minutes. The reaction master mix contained 110 μl of 5 U / mL porcine kidney DAO (Sigma-Aldrich, USA) solution (dissolved in 0.2 M tris-HCl buffer, pH 8.3), 1.1 mL of 15 U / mL peroxidase solution (dissolved in 0.2 M tris-HCl buffer, pH 8.3), 1.1 mL of 20 mM HPPA solution (dissolved in 0.2 M tris-HCl buffer, pH 8.3), and 22 mL of 2 M tris-HCl buffer (pH 8.3) for 110 reaction assays.

[0422] The fluorescence intensity (Fs) at a fluorescence wavelength of 405 nm was measured after irradiation excitation at a wavelength of 320 nm. Higher DAO enzyme activity was associated with higher fluorescence intensity. The fluorescence quantification inhibition index (Fi) was obtained from the following formula. Fi = (Fs - F Drug ) / (F DMSO )

[0423] Fluorescent drug blank (F Drug ) was measured using a drug mixture solution (using 0.2 M tris-HCl buffer (pH 8.3) without D-alanine). DMSO blank (F DMSO The values ​​were measured under 100% DMSO solution.

[0424] Since FAD readily dissociates from the holoenzyme, it is generally included in the reaction mixture in D-amino acid oxidase assays; however, this method was performed without using FAD. The inhibitory effect of the DAO inhibitor was determined by the inhibitory concentration (IC) that reduces DAAO activity by 50%. 50 The comparison was performed using the following method. The IC50 values ​​were calculated using a nonlinear regression model with GraphPad Prism, version 5 software (GraphPad Software, Inc., La Jolla, California). The results of the DAO IC50 assay of the candidate compounds of the present invention are shown in the table below. [Table 2]

[0425] Example 8: Cell-based DAO assay

[0426] Nerve cell culture

[0427] SK-N-SH neuroblastoma cells were purchased from the American Type Culture Collection (ATCC). They were cultured in MEM medium (Invitrogen / GIBCO) supplemented with 10% fetal bovine serum and 1X NEAA (Invitrogen / GIBCO, Rockville, Maryland) at 37°C under a humidified atmosphere of 5% CO2. Prior to cell-based DAO assays, the cells were trypsin-treated and seeded at a concentration of 125,000 cells / well in 50 μl of medium in Black 96-well plates (NUNC No. 237108).

[0428] Cell-based DAO assay

[0429] A DAO activity assay in cells was performed using a modified method according to Brandish et al. (Brandish, PE et al., Cell-based ultra-high-throughput screening assay for identifying D-amino acid oxidase inhibitors; J Biomol Screen, 2006, 11(5):p481~7). SK-N-SH cells were suspended in Hanks buffer (Invitrogen / GIBCO No.14025-092), an assay buffer, with 20 mM HEPES. D-serine (final concentration 50 mM) was added to each well as a substrate for the DAO enzyme. The production of H2O2 that diffused across the cell membrane into the assay medium after the DAO reaction was measured using the Amplex Red hydrogen peroxide / peroxidase assay kit (molecular probe / Invtrogen, catalog number A22188). After seeding cells into a Black 96-well plate (Nunc No. 237108, Denmark), 50 μl of SK-N-SH cells (125,000 cells / well) were mixed with 50 μl of drug solution (2.5 times the final concentration) and incubated at 37°C for 30 minutes under a humidified atmosphere of 5% CO2. After 30 minutes, 25 μl of a 5x mixture containing D-serine, horseradish peroxidase (HRP), and Amplex Red was added to the well containing 100 μl of the cell-drug mixture and incubated at 37°C for 3 hours under a humidified atmosphere of 5% CO2. The final concentration of DMSO was less than 1%. Fluorescence signals were detected using a SpectraMax M2e microplate reader (Molecular Devices, USA) with an excitation wavelength of 544 nm and an emission wavelength of 590 nm. The optimized assay buffer contained 50 mM D-serine, 0.625 units of HRP, and 50 μM Amplex Red in an assay volume of 125 μl. The results of cell-based DAO assays of the candidate compounds of the present invention are shown in the table below. [Table 3]

[0430] Example 9: Animal experiment on the potential of treating symptoms of schizophrenia.

[0431] Drug efficacy screening Negative or cognitive impairment in C57BL / 6 mice induced by the NMDA receptor antagonist MK-801 is recognized as a mouse model of drug-induced schizophrenia and is known as a useful pharmacological animal model for identifying whether RS-D7, its analogues, and its prodrugs improve NMDA receptor-mediated symptoms.

[0432] animal Wild-type (WT) mice used in this experiment were backcrossed with C57BL / 6J background mice obtained from the Animal Experiment Center of National Taiwan University Hospital, and all behavioral tests were performed on wild-type mice. To allow the mice to acclimate to laboratory conditions, they were given free access to food and water and were housed in groups in the psychology department laboratory at National Taiwan University. The room temperature and humidity were controlled, and the light-dark cycle was set to 12 hours each. For one week prior to the tests, all mice under 3 months of age were housed individually and given free access to food and water. First, the weight of the mice was measured by hand daily for at least one week prior to the behavioral tests. The entire animal experiment was conducted in accordance with the experimental protocol approved by the Animal Experiment Committee established by National Taiwan University.

[0433] Preparation of drugs for treating animals MK-801 was suspended in physiological saline and administered at a dose of 0.01 mg / g per body weight. Before use, RS-D7 and drug 12083 (an analogue of RS-D7) were freshly dissolved in 1% CMC to a concentration of 2 mg / ml. Before use, prodrug 28095 was freshly dissolved in NMP:HP-β-CD:H2O (5:25:70) to a concentration of 2 mg / ml. Before the behavioral test, all mice were given either a control (physiological saline) or MK-801 (0.2 mg / kg, intraperitoneal) for 25 minutes. Both the control group (1% CMC or NMP:HP-β-CD:H2O) and the experimental group were treated 5 minutes after oral administration of an appropriate amount of MK-801 (0.01 ml / g per body weight).

[0434] Behavioral testing procedures To investigate the therapeutic effects of RS-D7 on negative cognitive impairment and cognitive impairment, a series of behavioral tests (from week 1 to week 3) were conducted, including an open-field test, a sucrose preference test, and a prepulse suppression test. A one-week interval was observed between each test.

[0435] Open field testing To assess spontaneous activity, each subject was placed in an open-field apparatus (25.40 × 25.40 × 40.64 cm) under dim lighting conditions (60 lx). 3 It was located in the center of Coulbourn Instruments (Whitehall, Pennsylvania, USA).

[0436] Spontaneous movement parameters (including total distance traveled and distance traveled every 10 minutes) were monitored and recorded for 60 minutes using smart video tracking software (Panlab Harvard apparatus, USA). To compare the therapeutic effects of different treatment groups, the percentage change in the inhibitory effect on the enhancement of MK-801-induced spontaneous movement was calculated using the following formula. % = (Inhibitory effect due to drugs - Effect of MK-801) × 100% / Effect of MK-801

[0437] Compared to a control group receiving physiological saline, mice that underwent acute injection of MK-801 showed increased spontaneous movement in an open field. Injection of 200 mg / kg and 400 mg / kg of RS-D7 suppressed the increased spontaneous movement in mice. However, no therapeutic effect was observed with 100 mg / kg of RS-D7. The results of this open field test suggest that acute injection of RS-D7 normalized the MK-801-induced increase in spontaneous movement, a positive symptom of schizophrenia. Drug 12083 suppressed the increase in MK-801-induced spontaneous movement at doses of 20 mg / kg and 40 mg / kg. Prodrug 28095 suppressed the increase in MK-801-induced spontaneous movement at a dose of 100 mg. In conclusion, RS-D7, drug 12083, and prodrug 28095 can suppress the enhancement of MK-801-induced spontaneous movement in the MK-801 group at different doses. The inhibitory effects of these drugs on the enhancement of MK-801-induced spontaneous movement are shown in Figure 1.

[0438] Sucrose Preference Test To evaluate anemia, one of the negative symptoms of schizophrenia, all mice were tested for 4 days.

[0439] First, all mice were deprived of water for 23 hours starting one day before the first day of the sucrose preference test. On the first day, each mouse was allowed to freely consume from two identical bottles containing water for one hour. On the second day, one of the two identical bottles was filled with a 1% (weight / volume) sucrose solution, and the other with water. On the third and fourth days, each mouse was treated with MK-801 and RS-D7 before the experiment, and then allowed to freely consume from the bottles for one hour. After the experiment, the weight of the two bottles was measured to determine the hourly consumption of sucrose solution and water. The percentage of sucrose preference (SPP) was calculated using the following formula. %SPP = Amount of sucrose solution consumed (g) × 100% / [Amount of water consumed (g) + Amount of sucrose solution consumed (g)]

[0440] Compared to the control group administered physiological saline, mice after acute injection of MK801 showed a significant decrease in sucrose intake in the sucrose preference test. Injection of RS-D7 at 100 mg / kg, 200 mg / kg, and 400 mg / kg restored MK-801-induced anesthesia in mice. Similarly, drug 12083 at 20 mg / kg and prodrug 28095 at 200 mg / kg also restored MK-801-induced anesthesia to normal. In conclusion, different doses of RS-7, drug 12083, and prodrug 28095 restored anesthesia after acute injection of MK-801. The therapeutic effects of these drugs on MK-801-induced anesthesia are shown in Figure 2.

[0441] Prepulse suppression test To evaluate sensorimotor gating function, each mouse was tested using the SR-LAB startle response device (San Diego Instruments, San Diego, California, USA). Background noise during testing was set at 72 dB. Each session began with a 5-minute habituation period, followed by 64 tests including pulse-only trials, pre-pulse + pulse trials, and no-stimulation trials. Pulse-only trials were performed with a 40-millisecond white noise burst (120 dB). Pre-pulse + pulse trials involved a 20-millisecond white noise burst pre-pulse (78 dB: PP6), (82 dB: PP10), or (90 dB: PP18) preceding the 120 dB pulse by 100 milliseconds. No-stimulation trials consisted of background noise only. Each session began and ended with a block of six pulses alone. The remaining 52 trials were performed in a pseudo-random manner between two blocks, with an average interval of 15 seconds (10-20 seconds). Prepulse suppression, as a percentage of the startle response, was calculated using the following formula. %PPI = 100 × [(Score of pulse alone) - (Score of pre-pulse + pulse)] / (Score of pulse alone) The score for pulse alone is the average of the pulse alone values ​​from 52 trials between the two blocks.

[0442] Auditory prepulse suppression was significantly attenuated in mice that received acute injection of MK-801. However, injection of 100 mg / kg, 200 mg / kg, and 400 mg / kg of RS-D7, 20 mg / kg and 40 mg / kg of drug 12083, and 100 mg / kg and 200 mg / kg of prodrug significantly improved the MK-801-induced prepulse suppression impairment in these mice. In other words, although the mice showed a significant attenuation of prepulse suppression after acute injection of MK-801, it returned to normal with any dose of RS-D7, drug 12083, and prodrug 28095. The recovery rate of MK-801-induced prepulse suppression impairment is shown in Figure 3.

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 In formula (I), n is either 0 or 1, X is -S-, A is N, R a is -O-C(=O)R a3 , or -O-C(=O)-T-OR a4 And, R a3 and R a4 are each independently a straight-chain or branched-chain C 1-15 alkyl, a straight-chain or branched-chain C 2-15 alkenyl, -T-C 3-10 cycloalkyl, -T-NHR a3p 、-T-C 3-10 cycloalkenyl, -T-C 6-10 aryl, -T-C 5-10 heteroaryl, -T-NH-C(=O)-O-C 1-10 alkyl, -T-adamantyl, or -C 1-3 alkylene-C 6-10 aryl, and The alkylene is -T-NHR a3p Replaced by, R a3p is an N-protecting group selected from H, Fmoc, or Boc. R b H, and C in a linear or branched chain. 1-15 Alkyl, linear, or branched C 2-15 Alkenil, C 1-3 Alkoxy-C 1-15 Alkyl-,-T'-C 3-10 Cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Arial, or -T'-C 5-10 It is a heteroaryl, R c Each of these is an independent linear or branched C 1-15 Alkyl, or linear or branched C 1-15 It is an alkoxyl, m is 3, and the three R c groups are individually located at positions 3, 4, and 5 of the ring containing A in formula (I). -T- does not exist, or C 1-3 Alkylene, or C 2-3 It is alkenylene, -T'- is C 1-3 Alkylene, or C 2-3 It is alkenylene, Each of the heteroaryls independently comprises at least one heteroatom that is S, N, or O. The alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene, and alkenylene are each independently either unsubstituted or substituted with at least one substituent. Each of the substituents is independently a halogen, amino, nitro, nitroso, linear or branched carbon. 1-15 Alkyl, or linear or branched C 1-15 Alkoxy or C 3-10 It is a cycloalkyl, R b If H is present, tautomers are included. The aforementioned compound is not 6-phenylcarbonyloxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thio]-1H-benzimidazole.

2. The aforementioned compound is a compound of formula (I-a), 【Chemistry 2】 n is either 0 or 1, X is -S-, A is N, R a is -O-C(=O)R a3 , or -O-C(=O)-T-OR a4 And, R a3 and R a4 Each of these is independently a linear or branched C 1-15 Alkyl, linear, or branched C 2-15 Alkenyl, -T-C 3-10 Cycloalkyl, -T-NHR a3p , -T-C 3-10 Cycloalkenyl, -T-C 6-10 Ariel, -T-C 5-10 Heteroaryl, -T-NH-C(=O)-O-C 1-10 Alkyl or -T-adamantyl, R a3p is an N-protecting group selected from H, Fmoc, or Boc. R b H, and C in a linear or branched chain. 1-15 Alkyl, linear or branched C alkenyl, C 1-3 Alkoxy-C 1-15 Alkyl-,-T'-C 3-10 Cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Arial, or -T'-C 5-10 It is a heteroaryl, R c Each of these is an independent linear or branched C 1-15 Alkyl, or linear or branched C 1-15 It is an alkoxyl, m is 3, and the three R c groups are individually located at positions 3, 4, and 5 of the ring containing A in formula (I). -T- does not exist, or C 1-3 Alkylene, or C 2-3 It is alkenylene, -T'- is C 1-3 Alkylene, or C 2-3 It is alkenylene, Each of the heteroaryls independently comprises at least one heteroatom that is S, N, or O. The alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene, and alkenylene are each independently either unsubstituted or substituted with at least one substituent. Each of the substituents is independently a halogen, amino, nitro, nitroso, linear or branched carbon. 1-15 Alkyl, linear, or branched C 1-15 Alkoxy, or C 3-10 It is a cycloalkyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The aforementioned compound is a compound of formula (I-b), 【Transformation 3】 n is either 0 or 1, X is -S-, A is N, R a is -O-C(=O)R a3 And, R a3 is -T-NHR a3p , -T-NH-C(=O)-OC 1-10 Alkyl, or -C 1-3 Alkylene-C 6-10 It is Ariel, The alkylene is -T-NHR a3p Replaced by, R a3p is an N-protecting group selected from H, Fmoc, or Boc. R b H, and C in a linear or branched chain. 1-15 Alkyl, C 1-3 Alkoxy-C 1-15 Alkyl-,-T'-C 3-10 Cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Arial, or -T'-C 5-10 It is a heteroaryl, R c Each of these is an independent linear or branched C 1-15 Alkyl, or linear or branched C 1-15 It is an alkoxyl, m is 3, and the three R c groups are individually located at positions 3, 4, and 5 of the ring containing A in formula (I). -T- does not exist, or C 1-3 Alkylene, or C 2-3 It is alkenylene, -T'- is C 1-3 It is alkylene, Each of the heteroaryls independently comprises at least one heteroatom that is S, N, or O. The alkyl, alkenyl, alkoxy, cycloalkyl, aryl, and heteroaryl compounds are each independently either unsubstituted or substituted with at least one substituent. Each of the substituents is independently halogen, amino, nitro, nitroso, linear or branched C 1-15 alkyl, linear or branched C 1-15 alkoxy, or C 3-10 cycloalkyl, R b If H is present, tautomers are included. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The compound according to any one of claims 1 to 3, wherein n is 0.

5. R a is -O-C(=O)R a3 And, R a3 is tert-butyl; adamantyl; unsubstituted or substituted linear or branched C 1-10 alkyl; C 1-4 alkoxy; C 1-10 alkyl, nitro, C 1-15 alkoxy, or unsubstituted or substituted -C 6-10 aryl; C 3-10 cycloalkyl; -C 3-10 cycloalkenyl; linear or branched C 2-10 alkenyl; -C 5-10 heteroaryl; -C 1-3 alkylene-C 3-10 cycloalkyl; C 6-10 aryl unsubstituted or substituted by halogen C 2-3 alkenylene-C 6-10 aryl; -O-C(=O)-O-C 1-10 alkyl, The compound according to any one of claims 1 to 3.

6. R a is -O-C(=O)R a3 And, R a3 This refers to tert-butyl; adamantyl; and linear or branched C that is unsubstituted or substituted with halogens. 1-8 Alkyl; C 1-4 Alkoxy; C 1-6 Alkyl, nitro, C 1-4 Alkoxy, or unsubstituted or substituted halogen-substituted phenyl; C 3-6 Cycloalkyl; -C 3-6 Cycloalkenyls; linear or branched C 2-6 Alkenyl; -C 5-6 Heteroaryl; -C 1-3 Alkylene-C 3-6 Cycloalkyl; phenyl is either unsubstituted or substituted with a halogen. 2-3 Alkenylene-phenyl,-O-C(=O)-O-C 1-4 It is alkyl. The compound according to any one of claims 1 to 3.

7. R a is -O-C(=O)-C 1-6 Alkyl, -O-C(=O)-C 1-4 Alkylene-NHFmoc or -O-C(=O)-C 1-4 Alkylene-NHBoc, or -O-C(=O)-NH-C(=O)-O-C 1-10 It is alkyl. The compound according to any one of claims 1 to 3.

8. R c Each of these is independently a linear or branched C 1-6 Alkyl, or linear or branched C 1-6 It is an alkoxyl. The compound according to any one of claims 1 to 3.

9. The group consists of the following: 12092: 2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-yl(((9H-fluoren-9-yl)methoxy)carbonyl)glycinate, 12093: 2-(((4-methoxy-3,5-dimethylpyridine-2-yl)methyl)thio)-1H-benzo[d]imidazole-5-yl(tert-butoxycarbonyl)glycinate, and, 12094: 2-(((4-Methoxy-3,5-dimethylpyridine-2-yl)methyl)thio)-1Hbenzo[d]-imidazole-5-yl(S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-2-phenylacetate A compound according to claim 1, selected from the above, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound described in any one of claims 1 to 9.

11. A drug for inhibiting D-amino acid oxidase (DAAO), wherein the inhibition comprises contacting cells with a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

12. A drug for treating or preventing a D-amino acid oxidase (DAAO)-related disease in a subject, wherein the treatment or prevention comprises administering to the subject an effective amount of a compound described in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

13. The agent according to claim 12, wherein the disease is the symptomatic area of ​​schizophrenia and schizoaffective disorder, depression, Tourette syndrome, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), congenital insensitivity to pain, loss of memory and / or cognition associated with neurodegenerative diseases, or loss of neuronal function that is characteristic of neurodegenerative diseases.

14. The agent according to claim 13, wherein the symptom areas of schizophrenia and schizoaffective disorder include negative, cognitive, depressive, positive, and systemic psychopathological symptom areas.

15. The agent according to claim 12, wherein the disease is mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease, or schizophrenia.

16. The agent according to claim 12, wherein the disease associated with the D-amino acid oxidase (DAAO) is pain, ataxia, or convulsions.

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