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

Abstract

This application relates to novel substituted benzimidazole derivatives as D-amino acid oxidase (DAAO) inhibitors. The present invention provides novel substituted benzimidazole derivatives for use as DAAO inhibitors and for the treatment and / or prevention of neurological disorders.

Description

[0001] This application is a divisional application of the invention patent application filed on September 14, 2017, with application number 201780056602.0 and entitled "Novel substituted benzimidazole derivative as an inhibitor of D-amino acid oxidase (DAAO)".

[0002] Cross-referencing of related applications

[0003] This application claims priority to U.S. Provisional Application No. 62 / 394,497, filed on September 14, 2016, the entire contents of which are incorporated herein by reference. Technical Field

[0004] This invention relates to D-amino acid oxidase (DAAO) inhibitors. Specifically, this invention provides novel substituted benzimidazole derivatives that can be used as DAAO inhibitors and for the treatment and / or prevention of neurological disorders. Background Technology

[0005] Aberrant regulation of glutamate transmission through the N-methyl-D-aspartic acid (NMDA) receptor has been reported as a neuropathological aspect of schizophrenia. This receptor is a heterotetramer composed of two structural subunits of NMDA receptor 1 (NR1) and NR2. Regulation of the glycine binding site of the NMDA receptor can improve cognitive function and negative symptoms in schizophrenia. D-amino acid oxidase (DAAO) has been found to participate in the activation of the NMDA receptor. DAAO receptors, particularly D-serine, can act as co-agonists binding to the glycine site of the NMDA receptor. This, in turn, regulates the receptor by opening calcium channels. D-serine has been found to inhibit AMPA-mediated electrical currents in rat hippocampal neurons. Therefore, it is hypothesized that DAAO is related to the pathogenesis of schizophrenia. Since NMDA receptors are also involved in affective disorders, inhibiting DAAO may improve NMDA function and alleviate symptoms of schizophrenia and depressive disorder.

[0006] Known DAAO inhibitors include benzoic acid, pyrrole-2-carboxylic acid, and indole-2-carboxylic acid. Indole derivatives, and specifically certain indole-2-carboxylic esters, have been described in the literature for the treatment of neurodegenerative diseases and neurotoxic injuries. EP396124 discloses indole-2-carboxylic esters and their derivatives for the treatment or management of neurotoxic injuries caused by CNS conditions or traumatic events, or for the treatment or management of neurodegenerative diseases. US Patents 5,373,018, 5,374,649, 5,686,461, 5,962,496, and 6,100,289 disclose the use of indole derivatives to treat neurotoxic injuries and neurodegenerative diseases. WO 03 / 039540 discloses DAAO inhibitors (including indole-2-carboxylic acid) and methods for enhancing learning, memory, and cognition, as well as methods for treating neurodegenerative diseases. Patent application No. WO / 2005 / 089753 discloses benzisoxazole analogues and methods for treating mental illnesses (e.g., schizophrenia). WO / 2015 / 168346 discloses a list of known compounds as DAAO inhibitors.

[0007] The industry needs to develop candidate drugs with DAAO inhibitory effects to treat various neurological and physical ailments. Summary of the Invention

[0008] This invention relates to a list of substituted benzimidazole derivatives used as DAAO inhibitors and for the treatment and / or prevention of neurological disorders.

[0009] The present invention provides compounds having the following formula (I), wherein each substitution is based on that set forth herein.

[0010] The present invention also provides pharmaceutical compositions comprising the compounds of the present invention.

[0011] The present invention also provides a method for inhibiting DAAO, which includes contacting cells with the compounds of the present invention.

[0012] The present invention also provides a method for treating or preventing diseases associated with DAAO suppression in an individual, comprising administering an effective amount of the compound of the present invention to the individual.

[0013] In some embodiments, the disease is a symptom domain of schizophrenia and affective schizophrenia, depression, Tourette syndrome, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), analgesia, memory and / or cognitive loss associated with neurodegenerative diseases, or loss of neuronal function characteristic of neurodegenerative diseases. Some embodiments include mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease, and schizophrenia. Attached Figure Description

[0014] Figure 1 The results showed that, compared with the MK-801 group, different doses of RS-D7, drug 12083 and prodrug 28095 could salvage MK-801-induced excessive kinetic activity.

[0015] Figure 2 The results showed that different doses of RS-D7, drug 12083, and prodrug 28095 rescued patients with alexia after acute MK-801 injection.

[0016] Figure 3 The results showed that PPI decreased significantly after acute MK-801 injection. Detailed Implementation

[0017] Unless the context clearly indicates otherwise, as used herein and in the claims of the appended patent applications, the singular forms “a (a, an)” and “described” include a plurality of indicators. When the scope is used herein in reference to physical properties (e.g., molecular weight) or chemical properties (e.g., chemical formula), it is intended to include all combinations and sub-combinations of the scope and specific embodiments. Unless explicitly indicated as a substitution only or unless substitutions are mutually exclusive, the term “or” means “and / or”. The term “about” when referring to numbers or ranges of numbers means that the numbers or ranges referred to are approximate values ​​within experimental variability (or within statistical experimental error). The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude situations where, for example, in some other embodiments, any composition, composition, method, or process or such embodiment described herein may “consist of” or “substantially consist of” the described features.

[0018] definition

[0019] "alkyl" refers to a straight-chain or branched hydrocarbon chain group that consists only of carbon and hydrogen atoms, contains no unsaturated groups, and has 1 to 15 carbon atoms (e.g., C1-C1). 15 Alkyl group). In some embodiments, the alkyl group comprises 1 to 13 carbon atoms (e.g., C1-C1). 13Alkyl group. In some embodiments, the alkyl group comprises 1 to 8 carbon atoms (e.g., C1-C8 alkyl). In other embodiments, the alkyl group comprises 1 to 5 carbon atoms (e.g., C1-C5 alkyl). In other embodiments, the alkyl group comprises 1 to 4 carbon atoms (e.g., C1-C4 alkyl). In other embodiments, the alkyl group comprises 1 to 3 carbon atoms (e.g., C1-C3 alkyl). In other embodiments, the alkyl group comprises 1 to 2 carbon atoms (e.g., C1-C2 alkyl). In other embodiments, the alkyl group comprises 1 carbon atom (e.g., C1 alkyl). In other embodiments, the alkyl group comprises 5 to 15 carbon atoms (e.g., C5-C6 alkyl). 15 Alkyl group. 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 (dibutyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tertiary butyl), and 1-pentyl (n-pentyl). The alkyl group is attached to other parts of the molecule by a single bond. Unless otherwise expressly stated in this specification, the alkyl group is substituted with one or more substituents as appropriate.

[0020] "Alkoxy" refers to a group bonded by an oxygen atom of the formula -O-alkyl, where the alkyl is an alkyl chain as defined above.

[0021] "Alkenyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon double bond and having 2 to 12 carbon atoms. In some embodiments, the alkenyl group contains 2 to 8 carbon atoms. In other embodiments, the alkenyl group contains 2 to 4 carbon atoms. The alkenyl group is attached to other parts of the molecule by single bonds, such as ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentenyl, 1,4-dienyl, and the like. Unless otherwise expressly stated in this specification, the alkenyl group may be substituted with one or more substituents as appropriate.

[0022] "Alynyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having 2 to 12 carbon atoms. In some embodiments, the alkynyl group contains 2 to 8 carbon atoms. In other embodiments, the alkynyl group has 2 to 4 carbon atoms. The alkynyl group is attached to other parts of the molecule by single bonds, such as ethynyl, propynyl, butynyl, pentyynyl, hexynyl, and the like. Unless otherwise expressly stated in this specification, the alkynyl group is substituted with one or more substituents as appropriate.

[0023] "Aryl" refers to a group derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. Aromatic monocyclic or polycyclic hydrocarbon ring systems contain only hydrogen and carbon atoms from 5 to 18 carbon atoms, wherein at least one ring in the system is completely unsaturated, meaning it contains a cyclic, non-localized (4n+2) π-electron system according to Huckel's theory. Ring systems derived into aryl groups include (but are not limited to) groups such as benzene, benzo[a], dihydroindene, indene, tetrahydronaphthalene, and naphthalene. Unless otherwise expressly stated in this specification, the term "aryl" or the prefix "ar-" (e.g., in "aralkyl") is intended to include aryl groups that are substituted, as appropriate, by one or more substituents independently selected from: alkyl, alkenyl, ynyl, haloyl, fluoroalkyl, cyano, nitro, aryl groups that are substituted, aralkyl groups that are substituted, aralkyl groups that are substituted, aralkyl-alkenyl groups that are substituted, aralkylynyl groups that are substituted, carbocyclic groups that are substituted, carbocyclic alkyl groups that are substituted, heterocyclic groups that are substituted, heterocyclic alkyl groups that are substituted, heteroaryl groups that are substituted, heteroarylalkyl groups that are substituted, -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 (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b --S(O).sub t R a(where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Independently, each of the following is a hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (substituted with one or more halogen groups as appropriate), aralkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl group, each R.sup.b being independently a direct bond or a straight chain or a branched alkyl or alkenyl chain, and R.sup.c being a straight chain or a branched alkyl or alkenyl chain, wherein, unless otherwise indicated, each of the above substituents is unsubstituted.

[0024] "Heteroaryl" refers to a group derived from a 3- to 18-membered aromatic ring group, comprising 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, wherein at least one ring in the ring system is completely unsaturated, i.e., it contains a cyclic, nonlocal (4n+2) π-electron system according to Heckel's theory. Heteroaryl includes fused or bridging ring systems. One or more heteroatoms in the heteroaryl are oxidized, if applicable. One or more nitrogen atoms (if present) are quaternized, if applicable. The heteroaryl is attached to other parts of the molecule by means of any atom of the ring. Examples of heteroaryl groups include (but are not limited to) aziryl, acridine, benzimidazolyl, benzoindolyl, 1,3-benzodioxacyclopentenyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxazinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxacyclohexyl, benzonaphthofuranyl, benzoxazolyl, and benzo[b][1,4]oxazinyl. Dioxacyclopentenyl, benzodioxacyclohexenyl, benzopyranyl, benzopyranone, benzofuranyl, benzofuranone, benzothienyl (benzothienyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazoleyl, Linyl, cyclopentan[d]pyrimidinyl, 6,7-dihydro-5H-cyclopentan[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h] Linyl, 6,7-dihydro-5H-benzo[6,7]cycloheptane[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiopheneyl, furanyl, furanoneyl, furano[3,2-c]pyridyl, 5,6,7,8,9,10-hexahydrocyclooct[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooct[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooct[d]pyridyl, isothiazolyl, imidazole, indazole Indole, isoindole, dihydroindole, isodihydroindole, isoquinolinyl, indazinyl, isoxazolyl, 5,8-bridged methylene-5,6,7,8-tetrahydroquinazolinyl, naphridinyl, 1,6-naphridinoneyl, oxadiazolyl, 2-side-oxy-nitro-pyrrolyl, oxazolyl, ethylene oxide, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenthiazinyl, phen... Oxazinyl, tarazinyl, pteridinyl, purineyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, 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-cycloheptane[4,5]thiophene[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thiophene[2,3-d]pyrimidinyl, thiophene[3,2-d]pyrimidinyl, thiophene[2,3-c]pyridinyl and thiophenyl (also known as thienyl)). Unless otherwise expressly stated in this specification, the term "heteroaryl" is intended to include heteroaryl groups as defined above, which are optionally substituted with one or more substituents selected from the following: alkyl, alkenyl, alkynyl, haloyl, fluoroalkyl, haloalkenyl, haloalkynyl, syloxy, thionyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkylenyl, optionally substituted arynyl, optionally substituted carbocyclic, optionally substituted carbocyclic alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, 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(Ra )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 (where t is 1 or 2), -R b -S(O) t OR a (where t is 1 or 2), -R b --S(O).sub t R a (where t is 1 or 2) and -R b -S(O) t N(R a )2 (where t is 1 or 2), where each R a Each of the above substituents is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclic, heterocyclic alkyl, heteroaryl, or heteroarylalkyl, each R.sup.b is independently a direct bond or a straight chain or a branched alkyl or alkenyl chain, and R.sup.c is a straight chain or a branched alkyl or alkenyl chain, and wherein, unless otherwise indicated, each of the above substituents is unsubstituted.

[0025] 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 encompassed in the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention, which are typically prepared by reacting a free base with a suitable organic or inorganic acid. Representative salts of the basic compounds of the present invention include (but are not limited to) the following: acetates, ascorbic acid salts, adipic acid salts, alginates, aspartate salts, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, borates, bromides, butyrates, camphorates, camphor sulfonates, dextrorotatory camphor sulfonates, carbonates, chlorides, clavulanates, citrates, cyclopentanepropionates, diethylacetate, digluconate, dihydrochloride, dodecyl sulfate, edetate, ethanedisulfonate, estolate, esylate, ethanesulfonate, formate, fumarate, glucono-heptahydrate, glucono-heptahydrate, gluconate, glutamate, glyceryl phosphates, glycolyl larsanilate, hemisulfates, heptahydrates, hexanoates, and hexylresorcinol. ate), hydrabamine, hydrobromide, hydrochloride, 2-hydroxyethanesulfonate, hydroxynaphthylcarboxylate, iodide, isonicotinate, isethionate, lactate, lacturonate, laurate, malate, maleate, mandelate, methanesulfonate, methyl bromide, methyl nitrate, methyl sulfate, methanesulfonate, mucilage, 2-naphthalenesulfonate, naphthalenesulfonate, nicotinate, nitrate, N-methylglucosamine ammonium salt, oleate, Oxalate, embonate, palmitate, pantothenate, pectinate, persulfate, phosphate / hydrogen phosphate, pimecrolate, phenylpropionate, polygalacturonate, propionate, salicylate, stearate, sulfate, hypoacetate, succinate, tannate, tartrate, teoclate, thiocyanate, toluenesulfonate, triethyliodide, trifluoroacetate, undecanoate, valerate, and the like. Furthermore, in cases where the compounds of the present invention carry an acidic moiety, suitable pharmaceutically acceptable salts include (but are not limited to) salts derived from inorganic bases, including aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, divalent manganese salts, potassium salts, sodium salts, zinc salts, and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts are also included.Salts derived from pharmaceutically acceptable organic non-toxic alkaloids include the following: primary, secondary, and tertiary amines, cyclic amines, dicyclohexylamine, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N-ethylmorpholine, N-ethylhexahydropyridine, reduced glucosamine, glucosamine, histidine, halamine, isopropylamine, lysine, methyl reduced glucosamine, morpholine, hexahydropyrazine, hexahydropyridine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, glycerol, and the like. It also includes basic nitrogen-containing groups that can be quaternarily ammonized with reagents such as: low-carbon alkyl halides, such as chlorides, bromides, and iodides of methyl, ethyl, propyl, and butyl; dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and dipentyl sulfate; long-chain halides, such as chlorides, bromides, and iodides of decyl, lauryl, myristyl, and stearyl; aralkyl halides, such as benzyl bromide and phenethyl bromide, and others.

[0026] The term "individual" includes living organisms such as humans, monkeys, cows, sheep, horses, pigs, cattle, goats, dogs, cats, mice, rats, cultured cells, and their transgenic species. In a preferred embodiment, the individual is a human.

[0027] The term "addition" includes the administration route that allows the active ingredient of the present invention to perform its intended function.

[0028] The term "treatment" refers to a method of reducing the effect of a disease or symptom. Treatment can also refer to a method of reducing the underlying cause of a disease or symptom itself, not just the symptoms. Treatment can be any reduction from the natural degree and can be (but is not limited to) the complete elimination of the disease, symptom, or symptoms of a disease or symptom.

[0029] The term “prevent, prevention, or preventing” refers to suppressing or avoiding symptoms associated with a target disease.

[0030] The phrase “therapeutic effective amount” refers to the amount of a compound, material, or composition comprising the compound of the present invention that produces the desired therapeutic effect in a way that is reasonably beneficial / risk-free for any medical treatment.

[0031] The term "neuropathy" refers to any undesirable symptom of the central or peripheral nervous system in mammals. The term "neuropathy" includes neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis), and neuropsychiatric disorders (e.g., schizophrenia and anxiety, such as generalized anxiety disorder). Exemplary neuropathies include MLS (cerebellar motor ataxia), Huntington's disease, Down syndrome, multiple infarction dementia, status epilepticus, contusionary injuries (e.g., spinal cord injury and head injury), viral infection-induced neurodegeneration (e.g., AIDS, encephalopathy), epilepsy, benign amnesia, closed head injury, sleep disorders, depression (e.g., bipolar disorder), dementia, motor disorders, psychosis, alcoholism, post-traumatic stress disorder, and the like. "Neuropathy" also includes any undesirable symptom associated with the aforementioned conditions. For example, methods of treating neurodegenerative diseases include methods of treating memory loss and / or cognitive loss associated with neurodegenerative diseases. This approach will also include the treatment or prevention of neuronal function loss characteristic of neurodegenerative diseases.

[0032] The compounds of the present invention

[0033] In one state, the present invention provides a compound of formula (I):

[0034]

[0035] Where n is 0 or 1,

[0036] X is -S-, -S(=O)-, or -NR n -;in

[0037] R n Is it H or

[0038] A is -CH, -CR c Or N;

[0039] R a It is -C(=O)OR a1 -OR a2 -OC(=O)R a3 Or -OC(=O)-T-OR a4 ;in

[0040] R a1 It is H or straight chain or branched chain C 1-15 alkyl;

[0041] R a2 It is H, straight chain or branched chain C 1-15Alkyl, phosphonate, diarylphosphonate or O-protecting group;

[0042] R a3 and R a4 Independently, it is a protecting group, a straight chain, or a branched C. 1-15 Alkyl, straight-chain or branched C 2-15 alkenyl, -TC 3-10 cycloalkyl, -T-NHR a3p -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC 5-10 heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl, -T-adamantyl or -C 1-3 alkyl-C 6-10 aryl, wherein the alkylene group is via -T-NHR a3p replace;

[0043] R a3p It is an H or N-protecting group;

[0044] R b It is H, straight chain or branched chain C 1-15 Alkyl, straight-chain or branched C 2-15 alkenyl, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Aryl or -T'-C 5-10 Mixed aromatics;

[0045] R c Each is independently either a straight chain or a branched chain C. 1-15 Alkyl, straight-chain or branched C 1-15 Alkyl groups, unprotected or protected hydroxyl groups, or -C 1-10 alkyl-YC 6-10 Heteroaryl groups, wherein -Y- is -CH2-, -NH-, -O-, or -S-;

[0046] The symbol * indicates the location of the bond;

[0047] m is an integer from 0 to 4;

[0048] -T- means non-existent, C 1-3 alkyl or C 2-3 Enylene;

[0049] -T'- is C 1-3 alkyl or C 2-3 enylene; and

[0050] The heteroaryl group contains at least one heteroatom, each heteroatom being independently S, N, or O;

[0051] Wherein, alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene and alkenyl are each independently unsubstituted or substituted by at least one substituent;

[0052] Each substituent can be independently a halogen, a protecting group, a protected or unprotected amino group, a nitro group, a nitroso group, or a straight-chain or branched C group. 1-15 Alkyl, straight-chain, or branched C 1-15 Alkoxy or C 3-10 cycloalkyl; and

[0053] When R b When it is H, it includes tautomers.

[0054] The condition is

[0055] When X is -S- or -S(=O)-, R a Yes - OR a2 And R a2 It is H or straight chain or branched chain C 1-15 When alkyl, A is -CH or -CR. c ;

[0056] When X is -S- or -S(=O)- and R a It is -C(=O)OR a1 At that time, R b Is it a straight chain or a branched chain? 6-15 Alkyl, straight-chain or branched C 6-15 alkenyl, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Aryl or -T'-C 5-10 Mixed aromatics;

[0057] Or its medicinally acceptable salt.

[0058] In one embodiment, the present invention provides a compound of formula (Ia):

[0059]

[0060] Where n is 0 or 1,

[0061] X is -S-, -S(=O)-, or -NR n -;in

[0062] R n Is it H or

[0063] A is -CH, -CR c Or N;

[0064] R a It is -C(=O)OR a1 -OR a2 -OC(=O)R a3 Or -OC(=O)-T-OR a4 ;in

[0065] R a1 It is H or straight chain or branched chain C 1-15 alkyl;

[0066] R a2 It is H, straight chain or branched chain C 1-15 Alkyl, diarylphosphonate or O-protecting groups;

[0067] R a3 and R a4 Independently, it is a protecting group, a straight chain, or a branched C. 1-15 Alkyl, straight-chain or branched C 2-15 alkenyl, -TC 3-10 cycloalkyl, -T-NHR a3p -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC 5-10 heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl or -T-adamantyl;

[0068] R a3p It is an H or N-protecting group;

[0069] R b It is H, straight chain or branched chain C 1-15 Alkyl, straight-chain or branched C 2-15 alkenyl, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Aryl or -T'-C 5-10 Mixed aromatics;

[0070] R c Each is independently either a straight chain or a branched chain C. 1-15 Alkyl, straight-chain or branched C 1-15 Alkyl groups, unprotected or protected hydroxyl groups, or -C 1-10 alkyl-YC 6-10Heteroaryl groups, wherein -Y- is -CH2-, -NH-, -O-, or -S-;

[0071] The symbol * indicates the location of the bond;

[0072] m is an integer from 0 to 4;

[0073] -T- means non-existent, C 1-3 alkyl or C 2-3 Enylene;

[0074] -T'- is C 1-3 alkyl or C 2-3 enylene; and

[0075] The heteroaryl group contains at least one heteroatom, each heteroatom being independently S, N, or O;

[0076] Wherein, alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene and alkenyl are each independently unsubstituted or substituted by at least one substituent;

[0077] Each substituent can be independently a halogen, a protecting group, a protected or unprotected amino group, a nitro group, a nitroso group, or a straight-chain or branched C group. 1-15 Alkyl, straight-chain or branched C 1-15 Alkoxy or C 3-10 cycloalkyl and

[0078] When R b When it is H, it includes tautomers.

[0079] The condition is

[0080] When X is -S- or -S(=O)-, R a Yes - OR a2 And R a2 It is H or straight chain or branched chain C 1-15 When alkyl, A is -CH or -CR. c ;

[0081] When X is -S- or -S(=O)- and R a It is -C(=O)OR a1 At that time, R b Is it a straight chain or a branched chain? 6-15 Alkyl, straight-chain or branched C 6-15 alkenyl, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Aryl or -T'-C 5-10 Mixed aromatics;

[0082] Or its medicinally acceptable salt.

[0083] In one embodiment, the present invention provides a compound of formula (Ib),

[0084]

[0085] Where n is 0 or 1,

[0086] X is -S-, -S(=O)-, or -NR n -;

[0087] R n Is it H or

[0088] A is -CH, -CR c Or N;

[0089] R a It is -C(=O)OR a1 -OR a2 or -OC(=O)R a3 ;in

[0090] R a1 It is H or straight chain or branched chain C 1-15 alkyl;

[0091] R a2 It is H, straight chain or branched chain C 1-15 Alkyl, phosphonate, diarylphosphonate or O-protecting group;

[0092] R a3 It is -T-NHR a3p -T-NH-C(=O)-OC 1-10 Alkyl or -C 1-3 alkyl-C 6-10 aryl, wherein the alkyl group is via -T-NHR a3p replace;

[0093] R a3p It is an H or N-protecting group;

[0094] R b It is H, straight chain or branched chain C 1-15 Alkyl, C 1-3 Alkoxy-C 1-10 Alkyl-, -T'-C 3-10 cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Aryl or -T'-C 5-10 Mixed aromatics;

[0095] R cEach is independently either a straight chain or a branched chain C. 1-15 Alkyl, straight-chain or branched C 1-15 Alkyl groups, unprotected or protected hydroxyl groups, or -C 1-10 alkyl-YC 6-10 Heteroaryl groups, wherein -Y- is -CH2-, -NH-, -O-, or -S-;

[0096] The symbol * indicates the location of the bond;

[0097] m is an integer from 0 to 4;

[0098] -T- means non-existent, C 1-3 alkyl or C 2-3 Enylene;

[0099] -T'- is C 1-3 alkyl groups; and

[0100] The heteroaryl group contains at least one heteroatom, each heteroatom being independently S, N, or O;

[0101] Wherein, alkyl, alkenyl, alkoxy, cycloalkyl, aryl and heteroaryl groups are each independently unsubstituted or substituted by at least one substituent;

[0102] Each substituent is independently a halogen, a protected or unprotected amino group, a nitro group, a nitroso group, or a straight-chain or branched C group. 1-15 Alkyl, straight-chain or branched C 1-15 Alkoxy or C 3-10 cycloalkyl; and

[0103] When R b When it is H, it includes tautomers.

[0104] The condition is

[0105] When X is -S- or -S(=O)-, R a Yes - OR a2 And R a2 It is H or straight chain or branched chain C 1-15 When alkyl, A is -CH or -CR. c ;

[0106] When X is -S- or -S(=O)- and R a It is -C(=O)OR a1 At that time, R b Is it a straight chain or a branched chain? 6-15 Alkyl, straight-chain or branched C 6-15 alkenyl, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 cycloalkyl, -T'-C3-10 Cycloalkenyl, -T'-C 6-10 Aryl or -T'-C 5-10 Mixed aromatics;

[0107] Or its medicinally acceptable salt.

[0108] In one embodiment, the present invention provides a compound of formula (I),

[0109] Where n is 0 or 1;

[0110] X is -S-, -S(=O)-, or -NR n -;in

[0111] R n Is it H or

[0112] A is -CH, -CR c Or N;

[0113] R a Yes - OR a2 -OC(=O)R a3 Or -OC(=O)-T-OR a4 ;in

[0114] R a2 It is H, straight chain or branched chain C 1-15 Alkyl, phosphonate, diarylphosphonate or O-protecting group;

[0115] R a3 and R a4 Independently, it is a protecting group, a straight chain, or a branched C. 1-15 Alkyl, straight-chain or branched C 2-15 alkenyl, -TC 3-10 cycloalkyl, -T-NHR a3p -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC 5-10 heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl, -T-adamantyl or -C 1-3 alkyl-C 6-10 aryl, wherein the alkyl group is via -T-NHR a3p replace;

[0116] R a3p It is an H or N-protecting group;

[0117] R b It is H, straight chain or branched chain C 1-15 Alkyl, straight-chain or branched C 2-15 alkenyl, C1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Aryl or -T'-C 5-10 Mixed aromatics;

[0118] R c Each is independently either a straight chain or a branched chain C. 1-15 Alkyl, straight-chain or branched C 1-15 Alkyl groups, unprotected or protected hydroxyl groups, or -C 1-10 alkyl-YC 6-10 Heteroaryl groups, wherein -Y- is -CH2-, -NH-, -O-, or -S-;

[0119] The symbol * indicates the location of the bond;

[0120] m is an integer from 0 to 4;

[0121] -T- means non-existent, C 1-3 alkyl or C 2-3 Enylene;

[0122] -T'- is C 1-3 alkyl or C 2-3 enylene; and

[0123] The heteroaryl group contains at least one heteroatom, each heteroatom being independently S, N, or O;

[0124] Wherein, alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene and alkenyl are each independently unsubstituted or substituted by at least one substituent;

[0125] Each substituent can be independently a halogen, a protecting group, a protected or unprotected amino group, a nitro group, a nitroso group, or a straight-chain or branched C group. 1-15 Alkyl, straight-chain, or branched C 1-15 Alkoxy or C 3-10 cycloalkyl; and

[0126] When R b When it is H, it includes tautomers.

[0127] The condition is

[0128] When X is -S- or -S(=O)-, R a Yes - OR a2 And R a2 It is H or straight chain or branched chain C 1-15 When alkyl, A is -CH or -CR. c ;

[0129] Or its medicinally acceptable salt.

[0130] In another embodiment, the present invention provides a compound of formula (I), wherein

[0131] n is 0;

[0132] X is -S(=O)-;

[0133] A is N;

[0134] R a Yes - OR a2 -OC(=O)R a3 Or -OC(=O)-T-OR a4 , where R a2 It is H, straight chain or branched chain C 1-15 Alkyl, phosphonate, diarylphosphonate or O-protecting group;

[0135] R a3 and R a4 Independently, it is a protecting group, a straight chain, or a branched C. 1-15 Alkyl, straight-chain or branched C 2-15 alkenyl, -TC 3-10 cycloalkyl, -T-NHR a3p -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC 5-10 heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl, -T-adamantyl or -C 1-3 alkyl-C 6-10 aryl, wherein the alkyl group is via -T-NHR a3p Replace; R a3p It is an H or N-protecting group;

[0136] R b It is H;

[0137] m is 3; and

[0138] R c Each is independently either a straight chain or a branched chain C. 1-15 Alkyl, straight-chain or branched C 1-15 Alkoxy;

[0139] Or its medicinally acceptable salt.

[0140] In one embodiment, n is 0.

[0141] In one embodiment, m is an integer from 0 to 3.

[0142] In some embodiments, Ra It is -C(=O)OH; -C(=O)OC 1-4 Alkyl; H; -OR a2 , where R a2 It is H, straight chain or branched chain C 1-10 Alkyl or O-protecting group; -OC(=O)R a3 , where R a3 Independently a third butyl protecting group; a straight-chain or branched C-chain that is unsubstituted or substituted by a halogen, a third butyl protecting group, or a protected amino group. 1-10 Alkyl; straight-chain or branched C 2-10 alkenyl; C 1-4 Alkoxy; C 3-10 cycloalkyl; -C 1-3 alkyl-C 3-10 cycloalkyl; -C 3-10 Cycloalkenyl; unsubstituted or derived from C 1-10 Alkyl, nitro, C 1-15 Alkoxy or halogen-substituted -C 6-10 Aryl; unsubstituted or derived from C 1-10 Alkoxy-substituted -C 5-10 heteroaryl; C 2-3 Entenyl-C 6-10 Aryl, of which C 6-10 Aryl groups are either unsubstituted or substituted by halogens; -C 1-3 alkyl-NH--C(=O)-OC 1-10 Alkyl; or adamantyl; or -OC(=O)-OC 1-10 alkyl.

[0143] In some embodiments, R a Yes - OC 1-10 Alkyl group; -O- protecting group or -OC(=O)R a3 , where R a3 It is a third butyl protecting group; adamantyl; a straight-chain or branched C-chain that is unsubstituted or substituted by a halogen or a third butyl protecting group. 1-10 Alkyl; C 1-4 Alkyl group; unsubstituted or derived from C 1-10 Alkyl, nitro, C 1-15 Alkoxy or halogen-substituted -C 6-10 Aryl; C 3-10 cycloalkyl; -C 3-10 Cycloalkenyl; straight-chain or branched C 2-10 alkenyl; -C 5-10 heteroaryl; -C 1-3 alkyl-C 3-10 cycloalkyl; C 2-3 Entenyl-C 6-10 Aryl, of which C6-10 The aryl group is either unsubstituted or substituted by a halogen; -OC (=O)-OC 1-10 Alkyl group. In some embodiments, R a Yes - OC 1-4 Alkyl, -O-tert-butyloxycarbonyl protecting group or -OC(=O)R a3 , where R a3 It is a third butyl protecting group; adamantyl; a straight-chain or branched C-chain that is unsubstituted or substituted by a halogen or a third butyl protecting group. 1-8 Alkyl; C 1-4 Alkyl group; unsubstituted or derived from C 1-6 Alkyl, nitro, C 1-4 Alkoxy or halogen-substituted -phenyl; C 3-6 cycloalkyl; -C 3-6 Cycloalkenyl; straight-chain or branched C 2-6 alkenyl; -C 5-6 heteroaryl; -C 1-3 alkyl-C 3-6 cycloalkyl; C 2-3 enyl-phenyl, wherein the phenyl group is unsubstituted or substituted by a halogen; -OC(=O)-OC 1-4 Alkyl group. In some other embodiments, C 3-6 The cycloalkyl group is cyclopropyl or cyclohexyl. In some other embodiments, -C 3-10 The cycloalkenyl group is the cyclohexenyl group.

[0144] In some other embodiments, the heteroaryl group is pyrrolidyl, pyrrololinyl, pyrazolidyl, imidazolidinyl, pyrazolinyl, imidazolinyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, furanyl, dioxopentyl, tetrahydrophenylthio, phenylthio, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxothiocyclopentyl, hexahydropyridyl, pyridyl, hexahydropyrazinyl, pyrazinyl, pyrimidyl, pyrazinyl, tetrahydropyranyl, pyranyl, dioxalkyl, thiaalkyl, thiaranyl, morpholinyl, oxazinyl, or thiazolyl. In other embodiments, the heteroaryl group is furanyl, isoxazolyl, or phenylthio.

[0145] In some embodiments, R a It is -OH, -COOH, -O-phosphate, -OC 1-6 Alkyl or -OC(=O)-C 1-6 Alkyl group, -OC(=O)-C 1-4 alkyl-NH (Fmoc or Boc protecting group) or -OC (=O)-NH-C (=O)-OC 1-10 alkyl.

[0146] In some embodiments, R c Each is independently either a straight chain or a branched chain C.1-6 Alkyl, straight-chain, or branched C 1-6 Alkyl group. In some embodiments, R c Each is independently halogenated, straight-chain or branched C 1-6 Alkyl, straight-chain or branched C 1-6 alkoxy or -C 1-10 Enylene-YC 6-10 Heteroaryl; wherein Y is S and C 6-10 Unsubstituted heteroaryl groups or those derived from C 1-15 Alkyl (preferably C) 1-4 Alkyl), C 1-15 alkenyl (preferably C) 2-4 Alkyl), C 1-15 Alkoxy (preferably C) 1-4 Alkyl group), -OH, -NH2, -NO2, or halogen substitution. In another embodiment, -C 1-10 Enylene-YC 6-10 heteroaryl is

[0147] In some embodiments, the compounds of the present invention are selected from the group consisting of:

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167] Or its medicinally acceptable salt.

[0168] This invention covers all stereoisomers of compounds of formulas I, Ia, and Ib. The asymmetric centers present in the compounds of formulas I, Ia, and Ib can each independently have either an (R) configuration or an (S) configuration. When the bond to the chiral carbon is drawn as a straight line in the structural formula of this invention, it should be understood that both the (R) and (S) configurations of the chiral carbon, and thus their two mirror-image isomers and mixtures, are encompassed within the formula. When a specific configuration is drawn, it refers to the mirror-image isomer (the (R) or (S) at the center). Similarly, when a compound name is stated where no chirality is specified for the chiral carbon, it should be understood that the name encompasses both the (R) and (S) configurations of the chiral carbon, and thus their individual mirror-image isomers and mixtures.

[0169] The compounds of this invention comprise all possible mirror-image isomers and non-mirror-image isomers, as well as mixtures of two or more stereoisomers (e.g., mixtures of mirror-image isomers and / or non-mirror-image isomers in all ratios). Thus, mirror-image isomers are a target of this invention, existing in pure mirror-image isomeric forms (both levorotatory and dextrorotatory mirror-images), racemic forms, and mixtures of the two mirror-image isomers in all ratios. In the case of cis / trans isomerism, this invention comprises both cis and trans forms, as well as mixtures of these forms in all ratios. Individual stereoisomers can be prepared by separating mixtures using conventional methods (e.g., by chromatography or crystallization), by using stereochemically consistent starting materials for synthesis, or by stereoselective synthesis, if desired. Derivatization may be performed prior to the separation of stereoisomers, depending on the circumstances. The separation of mixtures of stereoisomers may be carried out as an intermediate step during the synthesis of compounds of formulas I, Ia, and Ib, or may be performed on the final racemic product. Absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate (if necessary, derived with a reagent containing a stereocenter of known configuration). If the compounds of the present invention are tautomerizable, all individual tautomers and mixtures thereof are included within the scope of the present invention. The present invention includes all such isomers, as well as salts, solvates (including hydrates), and solvate salts of these racemic, mirror-image, non-mirror-image, and tautomers, and mixtures thereof.

[0170] General preparation procedure of the compounds of the present invention

[0171] The compounds of formula (I) of the present invention are prepared according to a general chemical synthesis procedure. Examples of the preparation of the compounds of the present invention are illustrated below.

[0172] Synthetic scheme and procedure for preparing the compounds of the present invention from RS-D7

[0173]

[0174] Synthetic schemes and procedures for the preparation of NCTU-SUN-26065 series

[0175]

[0176] Synthetic schemes and procedures for the preparation of NCTU-SUN-26070 series

[0177]

[0178] Synthetic schemes and procedures for the preparation of NCTU-SUN-26079 series

[0179]

[0180] Synthetic schemes and procedures for the preparation of NCTU-SUN-26089 series

[0181]

[0182] Synthetic schemes and procedures for the preparation of NCTU-SUN-12082 series

[0183]

[0184] Synthetic schemes and procedures for the preparation of NCTU-SUN-12083 series

[0185]

[0186] Synthetic scheme and procedure for the preparation of NCTU-SUN-12084

[0187]

[0188] Synthetic schemes and procedures for the preparation of NCTU-SUN-12092 series

[0189]

[0190] Synthetic schemes and procedures for the preparation of NCTU-SUN-22138 series

[0191]

[0192] Synthetic scheme and procedure for the preparation of NCTU-SUN-22139

[0193]

[0194] application

[0195] The compounds of this invention can be used to treat or prevent any disease and / or symptom, wherein regulating the levels of D-serine and / or its oxidation products is effective in improving symptoms. Inhibiting the enzyme can increase D-serine levels and reduce the formation of toxic D-serine oxidation products. Therefore, this invention provides methods for treating or preventing neurological disorders and methods for enhancing learning, memory, and / or cognition. This invention also provides methods for treating or preventing diseases mediated by DAAO inhibition; said diseases are preferably symptom domains of schizophrenia and affective schizophrenia, depression, Tourette syndrome, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), analgesia, memory and / or cognitive loss associated with neurodegenerative diseases, or neuronal function loss characteristic of neurodegenerative diseases. In some embodiments, symptom domains of schizophrenia and affective schizophrenia include negative, cognitive, depressive, positive, and general psychopathological symptom domains. In another embodiment, diseases associated with DAAO inhibition are mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease, or schizophrenia. In some embodiments, the diseases associated with DAAO inhibition are pain, ataxia, or tic disorders. 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 loss of neuronal function characteristic of neurodegenerative diseases. Additionally, methods for treating or preventing pain, ataxia, and tic disorders are provided.

[0196] In some embodiments, the effective amount of the compounds described herein is in the following ranges: about 0.5 mg / kg body weight to about 20 g / kg, about 1 mg / kg body weight to about 20 g / kg, about 2 mg / kg body weight to about 20 g / kg, about 4 mg / kg body weight to about 20 g / kg, about 6 mg / kg body weight to about 20 g / kg, about 8 mg / kg body weight to about 20 g / kg, about 10 mg / kg body weight to about 20 g / kg, about 12 mg / kg body weight to about 20 g / kg, about 14 mg / kg body weight to about 20 g / kg, about 16 mg / kg body weight to about 20 g / kg, about 0.5 ... mg / kg body weight to about 15g / kg, about 0.5mg / kg body weight to about 12g / kg, about 0.5mg / kg body weight to about 10g / kg, about 0.5mg / kg body weight to about 8g / kg, about 0.5mg / kg body weight to about 6g / kg, about 2mg / kg body weight to about 15g / kg, about 2mg / kg body weight to about 12g / kg, about 2mg / kg body weight to about 10g / kg, about 2mg / kg body weight to about 7g / kg, about 2mg / kg body weight to about 5g / kg, about 5mg / kg body weight to about 15g / kg, or about 5mg / kg body weight to about 10g / kg body weight.

[0197] Pharmaceutical Composition

[0198] Another aspect of the invention provides a pharmaceutical composition comprising a compound of formula I (or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable carrier. The term "composition" (as in pharmaceutical compositions) is intended to encompass products comprising one or more active ingredients and one or more inert components (pharmaceutically acceptable excipients) constituting a carrier, as well as any product obtained directly or indirectly from: combinations, complexes, or aggregates of any two or more components, or dissociation of one or more components, or other types of reactions or interactions of one or more components. Therefore, the pharmaceutical compositions of the invention encompass any composition prepared by mixing a compound of formula I, other active ingredients, and pharmaceutically acceptable excipients.

[0199] The pharmaceutical compositions of the present invention comprise a compound of formula I (or a pharmaceutically acceptable salt or solvate thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, where appropriate, other therapeutic ingredients or adjuvants. These compositions include those suitable for oral, rectal, topical, and non-intestinal (including subcutaneous, intramuscular, and intravenous) administration; however, in any given case, the most suitable route will depend on the specific host and the nature and severity of the condition for which the active ingredient is administered. The pharmaceutical compositions are preferably in unit dosage forms and can be prepared by any method well known in the pharmaceutical industry.

[0200] The active ingredient may be administered orally in solid dosage forms (e.g., capsules, tablets, sugar tablets, sugar-coated tablets, granules, and powders) or in liquid dosage forms (e.g., elixirs, syrups, emulsions, dispersions, and suspensions). The active ingredient may also be administered non-enterally in sterile liquid dosage forms (e.g., dispersions, suspensions, or solutions). Other dosage forms may also be used to administer the active ingredient, such as ointments, creams, drops, transdermal patches, or powders for topical administration; ophthalmic solutions or suspensions for administration to the eye (i.e., eye drops); aerosol sprays or powder compositions for inhalation or intranasal administration; or creams, ointments, sprays, or suppositories for rectal or vaginal administration.

[0201] For topical application, the active ingredient or its pharmaceutical composition may be formulated into a suitable ointment containing the active component 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 paraffin, white paraffin, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified wax, sugar (e.g., lactose), and water. Alternatively, the pharmaceutical composition may be formulated into 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, cetyl alcohol, 2-octyldodecyl alcohol, benzyl alcohol, and water.

[0202] Depending on the specific symptoms, condition, or disease to be treated, the active ingredient or its pharmaceutical composition may be administered together with other therapeutic agents. These other agents may be administered as part of a multi-dosing regimen, sequentially (continuously or intermittently) by the active ingredient or its pharmaceutical composition. Alternatively, these agents may be part of a single dosage form, mixed with the active ingredient or its pharmaceutical composition (administered simultaneously or concurrently).

[0203] For oral administration, the pharmaceutical compositions used in this invention can take the following forms: solutions, suspensions, tablets, pills, capsules, powders, granules, semi-solids, sustained-release formulations, elixirs, aerosols, and the like. Tablets containing various excipients (e.g., sodium citrate, calcium carbonate, and calcium phosphate) can be used together with various disintegrants (e.g., starch (preferably potato or cassava starch) and certain complex silicates) and binders (e.g., polyvinylpyrrolidone, sucrose, gelatin, and gum arabic). Additionally, lubricants (e.g., magnesium stearate, sodium lauryl sulfate, and talc) are generally well-suited for tablet compression. Similar types of solid compositions are also used as fillers in soft-filled and hard-filled gelatin capsules; in this regard, preferred materials also include lactose or tartrate and high molecular weight polyethylene glycol. When it is desired to administer the active ingredient of the present invention or its pharmaceutical composition thereof orally, it may be combined with various sweeteners, flavoring agents, coloring agents, emulsifiers and / or suspending agents and diluents (e.g., water, ethanol, propylene glycol, glycerin and various combinations thereof).

[0204] As used herein, the term "non-enteric" refers to administration methods including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intramedullary, and intra-articular injection and infusion. Non-enteric injection pharmaceutical compositions may comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders reconstituted into sterile injectable solutions or dispersions prior to use. Aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous, and intraperitoneal injection purposes. In this regard, the sterile aqueous media used can be readily obtained using standard techniques familiar to those skilled in the art. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or mediators include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate). For example, appropriate flowability can be maintained by using coating materials such as lecithin, by maintaining the desired particle size (in the case of dispersions), and by using surfactants.

[0205] Pharmaceutical compositions used in this invention may also contain adjuvants, such as (but not limited to) preservatives, wetting agents, emulsifiers, and dispersants. Prevention of microbial action can be ensured by incorporating various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenolic sorbic acid, and the like. Isotonic agents, such as sugars, sodium chloride, and the like, may also be desired. Prolonged absorption in injectable pharmaceutical forms can be achieved by incorporating agents that delay absorption (e.g., aluminum monostearate and gelatin).

[0206] When using intrathecal or epidural routes, administration via slow infusion is particularly useful. A variety of implantable or in vivo pumps are known in the industry for delivering compounds at specified rates.

[0207] In addition to active compounds, suspensions may also contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and dehydrated sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and tragacanth gum and mixtures thereof.

[0208] For transdermal (e.g., local) administration purposes, dilute, sterile aqueous or partially aqueous solutions (typically at a concentration of about 0.1% to 5%) similar in other respects to the above-described non-enteric solutions are prepared.

[0209] The pharmaceutical compositions used in this invention can also be administered via nasal aerosol or inhalation. These compositions can be prepared according to techniques well known in the pharmaceutical formulation field and can be prepared as saline solutions, using benzyl alcohol or other suitable preservatives, absorption enhancers (for enhancing bioavailability), fluorocarbons and / or other conventional solubilizers or dispersants.

[0210] Compositions for rectal or vaginal administration are preferably suppositories, which can be prepared by mixing an active ingredient or its pharmaceutical composition with a suitable non-irritating excipient or carrier (e.g., cocoa butter, polyethylene glycol, or suppository wax) that is solid at room temperature but liquid at body temperature, and thus melts and releases the drug within the rectal or vaginal cavity.

[0211] 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 aids, including (but not limited to) ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffers (e.g., phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acids in the form of glycerides, water, salts, or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, polyethylene glycol, and lanolin.

[0212] Solid pharmaceutical excipients include (but are not limited to) starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice flour, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, skim milk powder, and the like. Liquid and semi-solid excipients may be selected from glycerol, propylene glycol, water, ethanol, and various oils, including petroleum, animal, vegetable, or synthetically derived oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Liquid carriers are preferred, especially injectable solutions including water, saline, dextran aqueous solution, and glycols.

[0213] Those skilled in the art will know, or will understand from the content of this disclosure, methods for preparing various pharmaceutical compositions having a certain amount of active ingredient. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by EW Martin, Mack Publishing Company, 19th edition, mid-1995.

[0214] It is believed that those skilled in the art will be able to utilize the invention to the fullest extent based on the foregoing description without further detailed explanation. Therefore, the following examples should be interpreted as illustrative only and not as limiting the scope of the invention in any way.

[0215] Example

[0216] Example 1-1 NCTU-SUN-21122: (acetic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0217]

[0218] Add 0.90 mmol of NaOH to a solution of RS-D7 (0.1 g, 0.30 mmol) in DCM (10 mL), and stir the reaction mixture in nitrogen for 5–10 minutes. Then add 0.60 mmol of acetyl chloride at 0 °C (in an ice bath). After stirring for 5–10 minutes, allow the reaction mixture to reach room temperature and stir for another hour. Extract the reaction mixture with ethyl acetate and pure water. Dry the organic layer with MgSO4, filter, and concentrate to obtain the reaction mixture. Purify the reaction mixture by silica gel column chromatography to obtain the pure product.

[0219] 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).

[0220] LRMS(ESI + m / z: 374.1 (M+H) + .

[0221] Example 1-2 NCTU-SUN-21124: (benzoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0222]

[0223] Except for the substitution of acetyl chloride with benzyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0224] 1 ¹H NMR (400 MHz, acetone-d6) δ 8.24 (s, 1H), 8.22 (d, J = 1.4 Hz, 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).

[0225] LRMS(ESI + m / z: 436.2 (M+H) + .

[0226] Example 1-3 NCTU-SUN-26096: (Butyric acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0227]

[0228] Except for the substitution of acetyl chloride with butyryl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0229] 1 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).

[0230] LRMS(ESI + m / z: 402.1 (M+H) + .

[0231] Example 1-4 NCTU-SUN-26097: (cyclohexanecarboxylic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0232]

[0233] Except for the substitution of acetyl chloride with hexahydrobenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0234] 1 ¹H 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).

[0235] LRMS(ESI + m / z: 442.2 (M+H) + .

[0236] Example 1-5 NCTU-SUN-26098: (4-Butylbenzoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0237]

[0238] Except for the substitution of acetyl chloride with 4-butylbenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0239] 1 ¹H 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 = 7.3 Hz, 3H).

[0240] LRMS(ESI + m / z: 492.1 (M+H) + .

[0241] Example 1-6 NCTU-SUN-21127: (3-Methylbenzoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0242]

[0243] Except for the substitution of acetyl chloride with m-methylbenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0244] 1 ¹H 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).

[0245] LRMS(ESI + m / z: 450.1 (M+H) + .

[0246] Example 1-7 NCTU-SUN-27076: Hexanoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester

[0247]

[0248] Except for the substitution of acetyl chloride with hexanoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0249] 1 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).

[0250] LRMS(ESI+ m / z: 430.2 (M+H) + .

[0251] Example 1-8 NCTU-SUN-27077: Isobutyric acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester

[0252]

[0253] Except for the substitution of acetyl chloride with isobutyryl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0254] 1 ¹H 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).

[0255] LRMS(ESI + m / z: 402.2(M+H) + .

[0256] Example 1-9 NCTU-SUN-27078: (cyclohexyl-3-en-1-carboxylic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0257]

[0258] Except for acetyl chloride being replaced by cyclohexyl-3-encarboxyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0259] 1H NMR (400MHz, acetone-d6) δ 8.17 (s, 1H), 7.66 (d, J = 8.2Hz, 1H), 7.42 (s, 1H), 7.07 (dd, J = 8.7, 1.8Hz, 1H), 5.74 (s, 2H), 4.78 (d, J = 13. 6Hz, 1H), 4.73 (d, J=13.7Hz, 1H), 3.70 (s, 3H), 2.96-2.80 (m, 2H), 2.54-2.30 (m, 3H), 2.22 (d, J=2.6Hz, 6H), 1.95-1.72 (m, 2H).

[0260] LRMS(ESI + m / z: 440.1 (M+H) + .

[0261] Example 1-10 NCTU-SUN-27079: Cyclohexyl-3-carboxylic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester

[0262]

[0263] Except for the substitution of acetyl chloride with 2-methylbenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0264] 1 ¹H 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).

[0265] LRMS(ESI + m / z: 450.1 (M+H) + .

[0266] Example 1-11 NCTU-SUN-28087: (4-methylbenzoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0267]

[0268] Except for the substitution of acetyl chloride with 4-methylbenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0269] 1 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).

[0270] LRMS(ESI + m / z: 450.1 (M+H) + .

[0271] Example 1-12 NCTU-SUN-28091: (2-Nitrobenzoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0272]

[0273] Except for the substitution of acetyl chloride with 2-nitrobenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0274] 1 H NMR (400MHz, acetone-d6) δ8.16 (d, J=5.9Hz, 2H), 8.10 (d, J=7.3Hz, 1H), 7.96 (td, J=7.5, 1.8Hz, 1H), 7.91 (td, J=7.8, 1.8Hz, 1H ), 7.74 (dd, J=8.7, 1.5Hz, 1H), 7.61 (s, 1H), 7.24 (d, J=8.4Hz, 1H), 4.75 (dd, J=13.7, 5.7Hz, 2H), 3.69 (s, 3H), 2.20 (s, 6H).

[0275] LRMS(ESI + m / z: 481.2 (M+H) + .

[0276] Example 1-13 NCTU-SUN-28092: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester of cyclopropanecarboxylic acid)

[0277]

[0278] Except for acetyl chloride being replaced by cyclopropaneformyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0279] 1 ¹H 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).

[0280] LRMS(ESI + m / z: 400.2(M+H) + .

[0281] Example 1-14 NCTU-SUN-28093: (2-Ethylbutyric acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0282]

[0283] Except for 2-ethylbutyryl chloride, which was substituted for acetyl chloride, the other reactants and preparation steps were similar to those described in Example 1, yielding the title compound.

[0284] 1 H NMR (400MHz, acetone-d6) δ 8.15 (s, 1H), 7.64 (d, J = 8.7Hz, 1H), 7.39 (d, J = 2.2Hz, 1H), 7.05 (dd, J = 8.8, 2.2Hz, 1H), 4.81 (dd, J = 28.8, 13.7Hz, 2H), 3.65 (s, 3H), 2.51 (tt, J=8.6, 5.5Hz, 1H), 2.19 (s, 3H), 2.18 (s, 3H), 1.74 (m, 4H), 1.04 (t, 7.5Hz, 6H).

[0285] LRMS(ESI + m / z: 430.2 (M+H) + .

[0286] Example 1-15 NCTU-SUN-28094: (2-Phenylacetic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0287]

[0288] Except for the substitution of acetyl chloride with 2-phenylacetyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0289] 1 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).

[0290] LRMS(ESI + m / z: 450.2 (M+H) + .

[0291] Example 1-16 NCTU-SUN-28095: (3,5,5-trimethylhexanoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0292]

[0293] Except for the substitution of acetyl chloride with 3,5,5-trimethylhexanoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0294] 1¹H 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, 7.9Hz, 1H), 2.19 (m, 1H), 2.19 (s, 3H), 2.18 (s, 3H), 1.43 (dd, J =14.1, 4.0Hz, 1H), 1.23 (dd, J=14.1, 6.5Hz, 1H), 1.12 (d, J=6.7Hz, 3H), 0.97 (s, 9H).

[0295] LRMS(ESI + m / z: 472.1 (M+H) + .

[0296] Example 1-17 NCTU-SUN-28096: (2-ethoxybenzoic acid 2-(((5-methoxy-4,6-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0297]

[0298] Except for the substitution of acetyl chloride with 2-ethoxybenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0299] 1 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)

[0300] LRMS(ESI + m / z: 480.1 (M+H) + .

[0301] Example 1-18 NCTU-SUN-21123: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0302]

[0303] Except for the substitution of acetyl chloride with propionyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0304] 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), 4.73 (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).

[0305] LRMS(ESI + m / z: 388.2 (M+H) + .

[0306] Example 1-19 NCTU-SUN-21125: (4-chlorobenzoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0307]

[0308] Except for the substitution of acetyl chloride with 4-chlorobenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0309] 1 ¹H NMR (400 MHz, acetone-d6) δ 8.33–8.12 (m, 1H), 7.76 (d, J = 8.7 Hz, OH), 7.72–7.61 (m, 1H), 7.27 (dd, J = 8.7, 2.2 Hz, OH), 4.74 (s, 1H), 3.76 (s, 1H), 2.25 (d, J = 6.00 Hz, 2H).

[0310] LRMS(ESI + m / z: 470.2 (M+H) + .

[0311] Example 1-20 NCTU-SUN-21126: (3-Nitrobenzoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0312]

[0313] Except for the substitution of acetyl chloride with 3-nitrobenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0314] 1 ¹H 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).

[0315] LRMS(ESI + m / z: 481.2 (M+H) + .

[0316] Example 1-21 NCTU-SUN-21128: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester of heptanoic acid

[0317]

[0318] Except for the substitution of acetyl chloride with heptanyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0319] 1 ¹H 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).

[0320] LRMS(ESI + m / z: 444.3 (M+H) + .

[0321] Example 1-22 NCTU-SUN-21129: (4-Fluorobenzoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0322]

[0323] Except for the substitution of acetyl chloride with 4-fluorobenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0324] 1 ¹H 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).

[0325] LRMS(ESI + m / z: 454.1 (M+H) + .

[0326] Example 1-23 NCTU-SUN-21130: ((Z)-2-methylbut-2-enoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0327]

[0328] Except for acetyl chloride being replaced by (Z)-2-methylbut-2-enoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0329] 1 ¹H 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).

[0330] LRMS(ESI + m / z: 414.2 (M+H) + .

[0331] Example 1-24 NCTU-SUN-21131: (2-chloropropionic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0332]

[0333] Except for the substitution of acetyl chloride with 2-chloropropionyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0334] 1 H NMR (400MHz, acetone-d6) δ8.16 (s, 1H), 7.71 (d, J=8.7Hz, 1H), 7.54-7.40 (m, 1H), 7.13 (dd, J=8.7, 2.0Hz , 1H), 4.91 (d, J=6.8Hz, 1H), 4.75 (d, J=4.1Hz, 2H), 3.71 (s, 4H), 2.22 (s, 6H), 1.83 (d, J=6.8Hz, 4H).

[0335] LRMS(ESI + m / z: 422.1 (M+H) + .

[0336] Example 1-25 NCTU-SUN-21132: Tertiary butyl ester of (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl) carbonate.

[0337]

[0338] Except for acetyl chloride being replaced by tert-butyl chloroformate, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0339] 1 ¹H 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).

[0340] LRMS(ESI + m / z: 432.2 (M+H) + .

[0341] Example 1-26 NCTU-SUN-12124: ((Z)-but-2-enoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0342]

[0343] Except for the substitution of acetyl chloride with (Z)-but-2-enoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0344] 1 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).

[0345] LRMS(ESI + m / z: 400.2(M+H) + .

[0346] Example 1-27 NCTU-SUN-12125: (3-methylbut-2-enoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0347]

[0348] Except for the substitution of acetyl chloride with 3-methylbut-2-enoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0349] 1¹H 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).

[0350] LRMS(ESI + m / z: 414.2 (M+H) + .

[0351] Example 1-28 NCTU-SUN-12122: (furan-2-carboxylic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0352]

[0353] Except for replacing acetyl chloride with furan-2-formyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0354] 1 H NMR (400MHz, acetone-d6) δ8.18 (s, 1H), 7.96 (dd, J=1.8, 0.8Hz, 1H), 7.74 (d, J=8.8Hz, 1H), 7.60 (d, J=2.1Hz, 1H), 7.51 (dd, J=3.5, 0.8 Hz, 1H), 7.24 (dd, J=8.8, 2.1Hz, 1H), 6.77 (dd, J=3.5, 1.8Hz, 1H), 4.74 (q, J=13.6Hz, 2H), 3.75 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H).

[0355] LRMS(ESI + m / z: 426.1 (M+H) + .

[0356] Example 1-29 NCTU-SUN-12123: (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0357]

[0358] Except for the substitution of acetyl chloride with acryloyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0359] 1 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).

[0360] LRMS(ESI + m / z: 386.1 (M+H) + .

[0361] Example 1-30 NCTU-SUN-12127: (2-methylbutyric acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0362]

[0363] Except for the substitution of acetyl chloride with 2-methylbutyryl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0364] 1 H NMR (400MHz, acetone-d6) δ8.17 (s, 1H), 7.68 (d, J = 8.0Hz, 1H), 7.42 (s, 1H), 7.07 (dd, J = 8.7, 1.9Hz, 1H), 4.80-4.68 (q, J = 13.6Hz, 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=7.0Hz, 4H), 1.04 (t, J=7.4Hz, 3H).

[0365] LRMS(ESI + m / z: 416.1 (M+H) + .

[0366] Example 1-31 NCTU-SUN-12128: (3-Cyclopentylpropionic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0367]

[0368] Except for the substitution of acetyl chloride with cyclopentaneformyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0369] 1 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).

[0370] LRMS(ESI + m / z: 456.1 (M+H) + .

[0371] Example 1-32 NCTU-SUN-12129: ((E)-3-(2-chlorophenyl)acrylate 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0372]

[0373] Except for the substitution of acetyl chloride with 2-chlorobenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0374] 1¹H 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).

[0375] LRMS(ESI + m / z: 496.0 (M+H) + .

[0376] Example 1-33 NCTU-SUN-12130: (6-bromohexanoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0377]

[0378] Except for the substitution of acetyl chloride with 6-bromohexanoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0379] 1 H NMR (400MHz, acetone-d6) δ8.17 (s, 1H), 7.68 (d, J=8.5Hz, 1H), 7.44 (d, J=2.3Hz, 1H), 7.09 (dd, J=8.8, 2.2Hz, 0H), 4.77-4.68 (q, J=13.6, 2H), 3.74 (s, 3H), 3.55 (t, J=6.7Hz, 2H), 2.66 (t, J=7.4Hz, 2H), 2.35 (s, 6H) 1.99-1.91 (m, 2H), 1.84-1.76 (m, 2H), 1.66-1.56 (m, 2H).

[0380] LRMS(ESI + m / z: 508.1 (M+H) + .

[0381] Example 1-34 NCTU-SUN-11021: (2-fluorobenzoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0382]

[0383] Except for the substitution of acetyl chloride with 2-fluorobenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0384] 1 ¹H 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).

[0385] LRMS(ESI + m / z: 454.1 (M+H) + .

[0386] Example 1-35 NCTU-SUN-11020: (4-methoxybenzoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0387]

[0388] Except for the substitution of acetyl chloride with 4-methoxybenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0389] 1 ¹H 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).

[0390] LRMS(ESI + m / z: 466.2 (M+H) + .

[0391] Example 1-36 NCTU-SUN-11022: ((3r, 5r, 7r)-adamantane-1-carboxylic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0392]

[0393] Except for replacing acetyl chloride with adamantane-1-formyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0394] 1 ¹H 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)

[0395] LRMS(ESI + m / z: 494.2 (M+H) + .

[0396] Example 1-37 NCTU-SUN-11023: (isoxazole-5-carboxylic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0397]

[0398] Except for the substitution of acetyl chloride with isoxazole-5-formyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0399] 1 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).

[0400] LRMS(ESI + m / z: 427.0 (M+H) + .

[0401] Example 1-38 NCTU-SUN-11030: (4-(tertiary butyl)benzoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0402]

[0403] Except for the substitution of acetyl chloride with 4-(tert-butyl)benzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0404] 1 ¹H 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).

[0405] LRMS(ESI + m / z: 492.1 (M+H) + .

[0406] Example 1-39 NCTU-SUN-11031: (3-chloro-4-fluorobenzoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0407]

[0408] Except for acetyl chloride being replaced by 4-chloro-3-fluorobenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0409] 1H NMR (400MHz, acetone-d6) δ8.34 (dd, J=7.2, 2.2Hz, 1H), 8.24 (ddd, J=8.7, 4.7, 2.2Hz, 1H), 8.18 (t, J=0.8Hz, 1H), 7.76 (dd, J=8.8, 0.6Hz, 1H ), 7.65 (dd, J=2.3, 0.6Hz, 1H), 7.58 (t, J=8.8Hz, 1H), 7.28 (dd, J=8.8, 2.2Hz, 1H), 4.74 (s, 2H), 3.76 (s, 2H), 2.26 (s, 3H), 2.24 (s, 3H).

[0410] LRMS(ESI + m / z: 488.0 (M+H) + .

[0411] Example 1-40 NCTU-SUN-25015: (Neovaleic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0412]

[0413] Except for the substitution of acetyl chloride with neopentanoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0414] 1 ¹H 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).

[0415] LRMS(ESI + m / z: 416.1 (M+H) + .

[0416] Example 1-41 NCTU-SUN-25016: (Valentanoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0417]

[0418] Except for the substitution of acetyl chloride with valeryl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0419] 1 H NMR (400MHz, acetone-d6) δ8.16 (s, 1H), 7.65 (d, J=8.7Hz, 1H), 7.41 (d, J=2.1Hz, 1H), 7.07 (dd, J=8.9, 2.1Hz, 1H), 5.62 (s, 1H), 4.96-4.5 5 (m, 2H), 3.69 (s, 3H), 2.62 (t, J=7.5Hz, 2H), 2.21 (d, J=3.3Hz, 6H), 1.83-1.64 (m, 2H), 1.46 (q, J=7.4Hz, 2H), 0.97 (t, J=7.4Hz, 3H).

[0420] LRMS(ESI + m / z: 416.1 (M+H) + .

[0421] Example 1-42 NCTU-SUN-25017: (4-Nitrobenzoic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0422]

[0423] Except for the substitution of acetyl chloride with 4-nitrobenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0424] 1 ¹H 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).

[0425] LRMS(ESI + m / z: 481.2 (M+H) + .

[0426] Example 1-43 NCTU-SUN-25027: (Cyclobutanecarboxylic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0427]

[0428] Except for the substitution of acetyl chloride with cyclobutaneformyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0429] 1 H NMR (400MHz, acetone-d6) δ 8.17 (s, 1H), 7.69 (d, J = 8.8Hz, 1H), 7.44 (d, J = 2.2Hz, 1H), 7.09 (dd, J = 8.8, 2.2Hz, 1H), 4.71 (s , 2H), 3.75 (s, 3H), 3.48 (t, J=8.6Hz, 1H), 2.39 (dt, J=29.5, 9.1Hz, 4H), 2.24 (d, J=2.9Hz, 5H), 2.05 (m, J=2.4Hz, 2H).

[0430] LRMS(ESI + m / z: 414.2 (M+H) + .

[0431] Example 1-44 NCTU-SUN-25028: (Thiophene-2-carboxylic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0432]

[0433] Except for the substitution of acetyl chloride with thiophene-2-formyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0434] 1 H NMR (400MHz, acetone-d6) δ8.18 (s, 1H), 8.04 (dd, J=3.8, 1.4Hz, 1H), 7.99 (dd, J=5.0, 1.4Hz, 1H), 7.74 (d, J=8.8Hz, 1H), 7.62 (d, J=2.1Hz , 1H), 7.32 (dd, J=5.1, 3.7Hz, 1H), 7.25 (dd, J=8.8, 2.2Hz, 1H), 4.75 (d, J=2.1Hz, 2H), 3.74 (d, J=1.7Hz, 3H), 2.24 (d, J=5.4Hz, 6H).

[0435] LRMS(ESI + m / z: 442.2 (M+H) + .

[0436] Example 1-45 NCTU-SUN-25029: (2-methylbutyric acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0437]

[0438] Except for the substitution of acetyl chloride with 2-methylbutyryl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0439] 1 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).

[0440] LRMS(ESI + m / z: 416.1 (M+H) + .

[0441] Example 1-46 NCTU-SUN-25030: (3,3-Dimethylbutyric acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0442]

[0443] Except for the substitution of acetyl chloride with 3,3-dimethylbutyryl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0444] 1H NMR (400MHz, acetone-d6) δ8.17 (s, 1H), 7.69 (dd, J=8.7, 0.6Hz, 1H), 7.43 (dd, J=2.2, 0.6Hz, 1H), 7.08 (dd, J =8.7, 2.2Hz, 1H), 4.72 (d, J = 1.6Hz, 2H), 3.74 (s, 3H), 2.50 (s, 2H), 2.24 (d, J = 1.3Hz, 6H), 1.15 (s, 9H).

[0445] LRMS(ESI + m / z: 430.1 (M+H) + .

[0446] Example 1-47 NCTU-SUN-25031: (2-methoxyacetic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl ester)

[0447]

[0448] Except for the substitution of acetyl chloride with 2-methoxyacetyl chloride, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0449] 1 ¹H 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).

[0450] LRMS(ESI + m / z: 404.0 (M+H) + .

[0451] Example 1-48 NCTU-SUN-25032 (ethyl ester of (2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazol-5-yl) ester)

[0452]

[0453] Except for acetyl chloride being replaced by ethyl chloroformate, the other reactants and preparation steps are similar to those described in Example 1, yielding the title compound.

[0454] 1¹H 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).

[0455] LRMS(ESI + m / z: 404.0 (M+H) + .

[0456] Example 2-1 26065: 1-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester

[0457]

[0458] H₂SO₄ (5 mL, 0.3 M) was added to a solution of 4-fluoro-3-nitrobenzoic acid 1 (5.0 g, 27.0 mmol) in anhydrous MeOH (30 mL), and the reaction mixture was heated to reflux for 12 h. The solvent was removed under reduced pressure, and the crude reaction mixture was dissolved in EtOAc (150 mL) and washed with saturated NaHCO₃ (20 mL × 2), water (10 mL × 2), and brine (10 mL). The EtOAc layer was dried over anhydrous MgSO₄ and evaporated to obtain methyl 4-fluoro-3-nitrobenzoic acid 2 (95%) as a white solid.

[0459] Compound 2 (2.0 g, 10.2 mmol) and 2-aminomethylfuran (3 equivalents) were stirred in anhydrous CH2Cl2 (50 mL) at room temperature for 2 h. After the reaction was complete, the solvent was removed and the crude product was purified by rapid column chromatography to give nitrobenzene ester 3 (90%).

[0460] Zinc dust (15 equivalents, 71.4 mmol) and ammonium formate (7.5 equivalents, 35.7 mmol) were added to a solution of compound 3 (2.0 g, 4.8 mmol) in anhydrous MeOH (100 mL), and the resulting reaction mixture was stirred at room temperature for 30 min. After the reaction was complete, the Zn dust was filtered through a diatomaceous earth bed, the filtrate was evaporated, and the product was dissolved in CH2Cl2 (100 mL). The precipitated ammonium formate was filtered off, and the solvent was evaporated to provide compound 4 (92%).

[0461] Compound 4 (1.0 g, 4.0 mmol) was dissolved in DCM, and then 1.2 equivalents of CNBr were added to react at room temperature. After 8 hours, the mixture was extracted with DCM and water. The solvent was removed and the crude product was purified by rapid column chromatography to give compound 5 (60%).

[0462] K₂CO₃ (0.0497 g, 0.36 mmol) and KI (0.0089 g, 0.054 mmol) were added to a solution of methyl 1H-benzo[d]imidazolium-5-carboxylate 5 (0.05 g, 0.18 mmol) in acetonitrile (10 mL), followed by the addition of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 (0.041 g, 0.22 mmol), and the reaction mixture was refluxed for 6 h. After 6 h, the solvent was evaporated, and the reaction mixture was diluted with saturated aqueous NaHCO₃ solution (10 mL) and extracted with EtOAc (3 x 10 mL).

[0463] The combined organic phases were washed with saturated brine (30 mL). The crude product was purified by silica gel column chromatography using 8% methanol / EtOAc to give 0.053 g of pure product NCTU-SUN-26065 (71%) as a white solid.

[0464] 1 H NMR (400MHz, chloroform-d) δ8.34 (s, 1H), 7.83 (dd, J=8.3, 1.4Hz, 1H), 7.73 (d, J=1.2Hz, 1H), 7.34 (dd, J=1.8, 0.7Hz, 1H), 7.13 (d, J=8.3Hz, 1 H), 6.37 (d, J=3.3Hz, 1H), 6.32 (dd, J=3.2, 1.9Hz, 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); 13 C 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) + .

[0465] Example 2-2 21098: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-propyl-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester

[0466]

[0467] Except for the substitution of amine with propan-1-amine, the other reactants and preparation steps are similar to those described in Example 2-1, yielding the title compound.

[0468] 1 H NMR (400MHz, methanol-d4) δ7.96 (s, 1H), 7.91 (d, J = 8.4Hz, 1H), 7.68 (s, 1H), 7.42 (d, J = 8.4Hz, 1H), 5.41 (s, 2H), 4.09 ( t, J=7.4Hz, 2H), 3.81 (d, J=13.8Hz, 6H), 2.34 (s, 3H), 2.20 (s, 3H), 1.85 (d, J=7.9Hz, 2H), 1.02 (t, J=7.4Hz, 3H); 13 C 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) + .

[0469] Example 2-3 21103: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(3-methoxypropyl)-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester

[0470]

[0471] Except for the substitution of the amine with 3-methoxypropyl-1-amine, the other reactants and preparation steps are similar to those described in Example 2-1, yielding the title compound.

[0472] 1H NMR (400MHz, methanol-d4) δ8.10 (s, 1H), 7.90 (t, J=1.8Hz, 1H), 7.67 (dt, J=8.4, 1.9Hz, 1H), 7.11 (dd, J=8.4, 2.1Hz, 1H), 4.58 (d, J=2.1Hz, 2H), 4 .09-4.01 (m, 2H), 3.82 (d, J=2.1Hz, 3H), 3.73 (d, J=2.1Hz, 3H), 3.19 (d, J=2.1Hz, 3H), 2.19 (dd, J=10.1, 2.1Hz, 6H), 1.96 (p, J=6.2Hz, 2H); 13 C 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) + .

[0473] Example 2-4 26070: 1-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazol-5-carboxylic acid

[0474]

[0475] H₂SO₄ (5 mL, 0.3 M) was added to a solution of 4-fluoro-3-nitrobenzoic acid 1 (5.0 g, 27.0 mmol) in anhydrous MeOH (30 mL), and the reaction mixture was heated to reflux for 12 h. The solvent was removed under reduced pressure, and the crude reaction mixture was dissolved in EtOAc (150 mL) and washed with saturated NaHCO₃ (20 mL × 2), water (10 mL × 2), and brine (10 mL). The EtOAc layer was dried over anhydrous MgSO₄ and evaporated to obtain methyl 4-fluoro-3-nitrobenzoic acid 2 (95%) as a white solid.

[0476] Compound 2 (2.0 g, 10.2 mmol) and furan-2-ylmethylamine (3 equivalents) in anhydrous CH2Cl2 (50 mL) were stirred at room temperature for 2 h. After the reaction was complete, the solvent was removed and the crude product was purified by rapid column chromatography to give nitrobenzene ester 3 (90%).

[0477] Zinc dust (15 equivalents, 71.4 mmol) and ammonium formate (7.5 equivalents, 35.7 mmol) were added to a solution of compound 3 (2.0 g, 4.8 mmol) in anhydrous MeOH (100 mL), and the resulting reaction mixture was stirred at room temperature for 30 min. After the reaction was complete, the Zn dust was filtered through a diatomaceous earth bed, the filtrate was evaporated, and the product was dissolved in CH2Cl2 (100 mL). The precipitated ammonium formate was filtered off, and the solvent was evaporated to provide compound 4 (92%).

[0478] Compound 4 (1.0 g, 4.0 mmol) was dissolved in DCM, and then 1.2 equivalents of CNBr were added to react at room temperature. After 8 hours, the mixture was extracted with DCM and water. The solvent was removed and the crude product was purified by rapid column chromatography to give compound 5 (60%).

[0479] K₂CO₃ (0.0497 g, 0.36 mmol) and KI (0.0089 g, 0.054 mmol) were added to a solution of methyl 1H-benzo[d]imidazolium-5-carboxylate 5 (0.05 g, 0.18 mmol) in acetonitrile (10 mL), followed by the addition of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 (0.041 g, 0.22 mmol), and the reaction mixture was refluxed for 6 h. After 6 h, the solvent was evaporated, and the reaction mixture was diluted with saturated aqueous NaHCO₃ solution (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with saturated brine (30 mL). The crude product was purified by silica gel column chromatography using 8% methanol / EtOAc to obtain 1-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester 7.

[0480] NaOH (0.0251 g, 0.63 mmol) was added to a solution of 1-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester 7 (0.053 g, 0.126 mmol) in EtOH / H2O (1 / 1, 3 mL) under reflux conditions. After 1 h, the solvent was evaporated, and the reaction mixture was diluted with saturated aqueous HCl (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with saturated brine (10 mL). The crude product was purified by silica gel column chromatography using 20% ​​methanol / EtOAc to give 0.030 g of pure product (65%) as a white solid.

[0481] LRMS(ESI+): m / z 407.2(M+H)+ .

[0482] Example 2-5 26066: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-pentyl-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester

[0483]

[0484] Except for the substitution of pentyl-1-amine for the amine, the other reactants and preparation steps are similar to those described in Example 2-1, yielding the title compound.

[0485] 1 ¹H NMR (400MHz, chloroform-d): δ 8.08 (s, 1H), 8.01 (dd, J = 8.4, 1.2Hz, 1H), 7.72 (s, 1H), 7.29 (d, J = 8.5Hz, 1H), 5.92 (s, 2H), 4.49 (t, J = 7.2Hz, 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 = 7.2Hz, 3H); LRMS (ESI+): m / z 411.2 (M+H) + .

[0486] Example 2-6 21102: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-propyl-1H-benzo[d]imidazol-5-carboxylic acid

[0487]

[0488] Except for the substitution of amine with propan-1-amine, the other reactants and preparation steps are similar to those described in Examples 2-4, yielding the title compound.

[0489] 1 H NMR (400MHz, methanol-d4) δ8.04 (d, J=8.3Hz, 1H), 7.95 (s, 1H), 7.89 (s, 1H), 7.64 (d, J=8.1Hz, 1H), 5.57 (s, 2H), 4.25 (t, J=7.3Hz, 2H), 3.83 (s, 3H), 2.41 (s, 3H), 2.21 (s, 3H), 1.92 (d, J=7.3Hz, 2H), 1.07 (t, J=7.3Hz, 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) + .

[0490] Example 2-7 26071: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-5-carboxylic acid methyl ester

[0491]

[0492] Except for the substitution of the amine with (4-methoxyphenyl)methylamine, the other reactants and preparation steps are similar to those described in Example 2-1, yielding the title compound.

[0493] 1 H NMR (400MHz, methanol-d4) δ8.02 (s, 1H), 7.83 (dd, J=8.4, 1.5Hz, 1H), 7.68 (d, J=1.6Hz, 1H), 7.29 (d, J=8.7Hz, 2H), 7.23 (d, J=8.4Hz, 1H), 6.92 (d, J=8.7Hz, 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) + .

[0494] Example 2-8 21105: 2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(2-(cyclohex-1-en-1-yl)ethyl)-1H-benzo[d]imidazol-5-carboxylic acid

[0495]

[0496] Except for the amine being replaced by 2-(cyclohex-1-en-1-yl)ethylamine, the other reactants and preparation steps are similar to those described in Examples 2-4, yielding the title compound.

[0497] 1H NMR (400MHz, methanol-d4) δ8.17 (s, 2H), 8.07 (s, 1H), 7.82 (d, J = 8.2Hz, 1H), 7.26 (d, J = 8.3Hz, 1H), 5.13 (s, 1H), 4.77 (s, 4H), 4 .11 (t, J=7.8Hz, 2H), 3.80-3.69 (m, 6H), 2.29 (t, J=8.4Hz, 2H), 2.18 (d, J=21.8Hz, 12H), 1.76 (s, 4H), 1.49-1.36 (m, 4H); 13 C NMR (101MHz, 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)+.

[0498] Example 2-9 21104: 2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(3-methoxypropyl)-1H-benzo[d]imidazol-5-carboxylic acid

[0499]

[0500] Except for the substitution of the amine with 3-methoxypropyl-1-amine, the other reactants and preparation steps are similar to those described in Examples 2-4, yielding the title compound.

[0501] 1 H NMR (400MHz, DMSO-d6) δ8.06 (s, 2H), 7.88 (d, J=1.6Hz, 1H), 7.68 (dd, J=8.4, 1.6Hz, 1H), 7.32 (d, J=8.4Hz, 1H), 4.65 (s, 4 H), 4.17 (t, J=7.6Hz, 2H), 3.62 (s, 6H), 3.20 (t, J=5.9Hz, 2H), 3.09 (s, 3H), 2.10 (s, 6H), 2.05 (s, 6H), 1.94-1.88 (m, 2H); 13C NMR (101MHz, DMSO-d6) δ168.52, 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) + .

[0502] Example 2-10 26076: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-pentyl-1H-benzo[d]imidazol-5-carboxylic acid

[0503]

[0504] Except for the substitution of pentyl-1-amine for the amine, the other reactants and preparation steps are similar to those described in Examples 2-4, yielding the title compound.

[0505] 1 H NMR (400MHz, DMSO-d6) δ7.88 (s, 1H), 7.81 (dd, J=8.2, 1.3Hz, 1H), 7.70 (d, J=1.6Hz, 1H), 7.39 (d, J=8.4Hz, 2H), 5.59 (s, 2H), 4.23 (t , J=6.9Hz, 2H), 3.72 (s, 3H), 2.30 (s, 3H), 2.11 (s, 3H), 1.83 (s, 2H), 1.30 (dq, J=6.7, 3.3Hz, 4H), 0.90-0.73 (m, 3H); LRMS (ESI+): m / z 397.2(M+H) + .

[0506] Example 2-11 26077: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-5-carboxylic acid

[0507]

[0508] Except for the substitution of the amine with (4-methoxyphenyl)methylamine, the other reactants and preparation steps are similar to those described in Examples 2-4, yielding the title compound.

[0509] LRMS(ESI+): m / z 447.2(M+H) + .

[0510] Example 2-12 21115: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-(3-methoxypropyl)-1H-benzo[d]imidazol-5-carboxylic acid

[0511]

[0512] Except for the substitution of the amine with 3-methoxypropyl-1-amine, the other reactants and preparation steps are similar to those described in Examples 2-4, yielding the title compound.

[0513] 1 ¹H 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) + .

[0514] Example 2-13 21116: 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester

[0515]

[0516] Except for the amine being replaced by 2-(cyclohex-1-en-1-yl)ethylamine, the other reactants and preparation steps are similar to those described in Example 2-1, yielding the title compound.

[0517] 1¹H 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=1.2Hz, 3H), 3.79 (d, J=1.2Hz, 3H), 2.41 (t, J=7.2Hz, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 2 .04(h, J=1.8Hz, 2H), 2.02-1.97(m, 2H), 1.82-1.76(m, 2H), 1.51(t, J=5.9Hz, 2H), 1.42-1.37(m, 2H); 13 C 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.

[0518] Example 2-14 21117: 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1H-benzo[d]imidazol-5-carboxylic acid

[0519]

[0520] Except for the amine being replaced by 2-(cyclohex-1-en-1-yl)ethylamine, the other reactants and preparation steps are similar to those described in Examples 2-4, yielding the title compound.

[0521] 1H NMR (400MHz, DMSO-d6) δ8.15 (s, 1H), 7.70 (s, 1H), 7.56 (d, J = 8.2Hz, 1H), 7.15 (d, J = 8.3Hz, 1H), 7.08 (t, J = 5.3Hz, 1H), 5.23 (s, 1H), 4 .61 (d, J=4.2Hz, 2H), 4.12 (t, J=7.1Hz, 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, 5.4Hz, 4H); 13 C NMR (101MHz, DMSO-d6) δ168.24, 155.18, 155.12, 147.74, 141.57, 137.88, 133.55, 124.39, 123.56, 123.0 9, 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.

[0522] Example 2-15 21118: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-phenethyl-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester

[0523]

[0524] Except for the substitution of amine with 2-phenylethylamine, the other reactants and preparation steps are similar to those described in Example 2-1, yielding the title compound.

[0525] 1 H NMR (400MHz, methanol-d4) δ8.16 (s, 1H), 7.89 (s, 1H), 7.63 (d, J=8.2Hz, 1H), 7.10 (dt, J=16.2, 7.1Hz, 5H), 6.99 (d, J=8 .2Hz, 1H), 4.57 (s, 3H), 4.30 (t, J=7.0Hz, 2H), 3.82 (d, J=25.8Hz, 6H), 3.05 (t, J=7.0Hz, 2H), 2.29-2.20 (m, 6H); 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) + .

[0526] Example 2-16 21119: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-phenethyl-1H-benzo[d]imidazol-5-carboxylic acid

[0527]

[0528] Except for the substitution of amine with 2-phenylethylamine, the other reactants and preparation steps are similar to those described in Examples 2-4, yielding the title compound.

[0529] 1 H NMR (400MHz, methanol-d4) δ8.19 (s, 1H), 7.89 (d, J=1.5Hz, 1H), 7.79 (dd, J=8.5, 1.7Hz, 1H), 7.19-7.07 (m, 6H), 4.73 (s, 2H), 4.48 (t, J=6.8Hz, 2H), 3.87 (s, 3H), 3.16 (t, J=6.8Hz, 2H), 2.29 (d, J=14.6Hz, 6H); 13 C NMR (101 MHz, methanol-d4) δ 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.

[0530] Example 2-17 21120: 2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-propyl-1H-benzo[d]imidazol-5-carboxylic acid

[0531]

[0532] Except for the substitution of amine with propan-1-amine, the other reactants and preparation steps are similar to those described in Examples 2-4, yielding the title compound.

[0533] 1 H NMR (400MHz, DMSO-d6) δ8.09 (s, 2H), 7.88 (d, J=1.6Hz, 1H), 7.68 (dd, J=8.3, 1.6Hz, 1H), 7.39 (d, J=8.4Hz, 1H), 4.6 3(s, 4H), 4.1] (t, J=7.9Hz, 2H), 3.62 (s, 6H), 2.08 (d, J=17.4Hz, 12H), 1.66 (d, J=7.7Hz, 2H), 0.73 (t, J=7.3Hz, 3H).

[0534] Example 2-18 21121: 2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-1-phenethyl-1H-benzo[d]imidazol-5-carboxylic acid

[0535]

[0536] Except for the substitution of amine with 2-phenylethylamine, the other reactants and preparation steps are similar to those described in Examples 2-4, yielding the title compound.

[0537] 1 H NMR (400MHz, DMSO-d6) δ8.07 (s, 2H), 7.89 (d, J=1.5Hz, 1H), 7.67 (dd, J=8.4, 1.7Hz, 1H), 7.40 (d, J=8.4Hz, 1H), 7.19-7.13 ( m, 3H), 7.10-7.05 (m, 2H), 4.64 (s, 4H), 4.39 (t, J=8.0Hz, 2H), 3.59 (s, 6H), 2.97 (t, J=8.1Hz, 2H), 2.07 (d, J=11.5Hz, 12H); 13 C NMR (101MHz, DMSO-d6) δ168.15, 163.34, 154.81, 148.03, 140.97, 138.79, 138.04, 128.79, 128.39, 1 26.52, 124.88, 124.76, 123.79, 122.04, 117.97, 109.35, 59.74, 55.15, 45.31, 34.51, 12.91, 10.42.

[0538] Example 3-1 NCTU-SUN-26079: 3-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3,4-dihydroquinazolin-7-carboxylic acid methyl ester

[0539]

[0540] DCC (1.2 equivalents) and DMAP (0.005 equivalents) were added to a solution of 4-(bromomethyl)-3-nitrobenzoic acid 1 (5.0 g, 27.0 mmol) in anhydrous MeOH / CH2Cl2 (3 mL: 30 mL), and the reaction mixture was stirred at room temperature for 16 hours. The byproduct DCU was filtered off and the crude product was purified by rapid column chromatography to obtain methyl 4-(bromomethyl)-3-nitrobenzoic acid ester 2 (76%) as a grayish-white solid.

[0541] Compound 2 (4.0 g, 14.5 mmol) and 2-aminomethylfuran (3 equivalents) were stirred in anhydrous CH2Cl2 (50 mL) at room temperature for 48 hours. After the reaction was complete, the solvent was removed and the crude product was purified by rapid column chromatography to give nitrobenzene ester 3 (82%).

[0542] SnCl₂·2H₂O (3.5 equivalents) was added to a solution of compound 3 (3.65 g, 11.9 mmol) in anhydrous MeOH (100 mL), and the resulting reaction mixture was refluxed for 10 min. After the reaction was complete, the byproducts were filtered through a diatomaceous earth bed and the filtrate was evaporated. The crude product was partitioned between 1 N NaOH and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3 × 20 mL), and the combined layers were dried over MgSO₄ and concentrated under reduced pressure to provide compound 4 (87%).

[0543] Compound 4 (1.0 g, 3.8 mmol) was dissolved in DCM, and then 1.2 equivalents of CNBr were added to react at room temperature. After 8 hours, the mixture was extracted with DCM and water. The solvent was removed and the crude product was purified by rapid column chromatography to give compound 5 (60%).

[0544] A solution of methyl 2-amino-3-(furan-2-ylmethyl)-3,4-dihydroquinazoline-7-carboxylic acid ester 5 (0.3 g, 1.05 mmol) in acetonitrile (20 mL) was treated with K₂CO₃ (0.29 g, 2.1 mmol) and KI (0.005 g, 0.03 mmol), followed by the addition of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 (0.722 g, 3.89 mmol), and the reaction mixture was refluxed for 6 hours. After 24 hours, the solvent was evaporated, and the reaction mixture was diluted with saturated aqueous NaHCO₃ solution (30 mL) and extracted with EtOAc (3 x 30 mL).

[0545] The combined organic phases were washed with saturated brine (30 mL). The crude product was purified by silica gel column chromatography using 8% methanol / EtOAc to give 0.43 g of pure product NCTU-SUN-26079 (70%) as a white solid.

[0546] 1 H NMR (400MHz, methanol-d4) δ8.16 (s, 1H), 7.81 (dd, J=7.9, 1.4Hz, 1H), 7.56 (dd, J=1.8, 0.8Hz, 1H), 7.37 (d, J=1.4Hz, 1H), 7.32 (d, J=7.9Hz, 1H), 6.60 (d, J= 3.3Hz, 1H), 6.47(dd, J=3.3, 1.9Hz, 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) + .

[0547] Example 3-2 21106: 3-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3,4-dihydroquinazolin-7-carboxylic acid methyl ester

[0548]

[0549] Except for the amine being replaced by 2-(cyclohex-1-en-1-yl)ethylamine, the other reactants and preparation steps are similar to those described in Example 3-1, yielding the title compound.

[0550] 1H NMR (400MHz, methanol-d4) δ8.17 (s, 1H), 7.83 (dd, J=7.9, 1.5Hz, 1H), 7.40-7.33 (m, 2H), 5.24 (s, 2H), 5.16 (s, 1H), 4.61 (s, 2H), 3.88 (s, 3H), 3.8 4 (s, 3H), 3.76 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H), 2.12 (d, J=8.1Hz, 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) + .

[0551] Example 3-3 26072: 2-(bis((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-(furan-2-ylmethyl)-3,4-dihydroquinazolin-7-carboxylic acid methyl ester

[0552]

[0553] As described in Example 3-1, the title compound was obtained.

[0554] 1 H NMR (400MHz, methanol-d4) δ8.21-8.19 (m, 1H), 8.07 (d, J=0.8Hz, 1H), 7.83 (dd, J=7.9, 1.5Hz, 1H), 7.57 ( d, J=1.5Hz, 1H), 7.43 (dd, J=1.9, 0.8Hz, 1H), 7.29 (d, J=7.9Hz, 1H), 6.57 (dd, J=3.4, 0.8Hz, 1H), 6. 41 (dd, J=3.3, 1.9Hz, 1H), 5.48 (d, J=1.9Hz, 2H), 4.93 (s, 2H), 4.81 (s, 2H), 4.62 (s, 2H), 3.86 (s, 3 H), 3.85 (s, 3H), 3.77 (s, 3H), 2.44 (s, 3H), 2.26 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H); LRMS (ESI+): m / z 584.31(M+H) + .

[0555] Example 3-4 26091: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-pentyl-3,4-dihydroquinazolin-7-carboxylic acid methyl ester

[0556]

[0557] Except for the substitution of pentyl-1-amine for the amine, the other reactants and preparation steps are similar to those described in Example 3-1, yielding the title compound.

[0558] 1 H NMR (400MHz, methanol-d4) δ 8.14 (s, 1H), 7.79 (d, J = 7.9Hz, 1H), 7.39 (d, J = 7.9Hz, 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=7.8Hz, 2H), 2.44 (s, 3H), 2.25 (s, 3H), 1.76 (p, J=7.9Hz, 2H), 1.37 (dp, J=11.3, 7.1, 6.2Hz, 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) + .

[0559] Example 3-5 26092: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-7-carboxylic acid methyl ester

[0560]

[0561] Except for the substitution of the amine with (4-methoxyphenyl)methylamine, the other reactants and preparation steps are similar to those described in Example 3-1, yielding the title compound.

[0562] 1H NMR (400MHz, methanol-d4) δ8.09 (s, 1H), 7.71 (dd, J=7.8, 1.4Hz, 1H), 7.57 (d, J=1.4Hz, 1H), 7.39 (d, J=8.5Hz, 2H), 7.31 (d, J=7.8Hz, 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) + .

[0563] Example 3-6 21110: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-(3-methoxypropyl)-3,4-dihydroquinazolin-7-carboxylic acid

[0564]

[0565] Except for the substitution of the amine with 3-methoxypropyl-1-amine, the other reactants and preparation steps are similar to those described in Examples 3-7, yielding the title compound.

[0566] 1 H NMR (400MHz, methanol-d4) δ7.84 (dd, J=7.9, 1.4Hz, 1H), 7.64 (s, 1H), 7.46 (d, J=1.4Hz, 1H), 7.40 (d, J=7.9Hz, 1H), 5.26 (s, 2H), 4.69 (s, 2H) , 3.85 (s, 3H), 3.75 (t, J = 6.9Hz, 2H), 3.51 (t, J = 5.7Hz, 2H), 2.27 (s, 3H), 2.04 (d, J = 4.9Hz, 6H), 1.29 (d, J = 3.5Hz, 2H); LRMS (ESI+): m / z 413.3(M+H) + .

[0567] Example 3-7 26089: 3-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3,4-dihydroquinazolin-7-carboxylic acid

[0568]

[0569] DCC (1.2 equivalents) and DMAP (0.005 equivalents) were added to a solution of 4-(bromomethyl)-3-nitrobenzoic acid 1 (5.0 g, 27.0 mmol) in anhydrous MeOH / CH2Cl2 (3 mL: 30 mL), and the reaction mixture was stirred at room temperature for 16 h. The byproduct DCC was filtered off and the crude product was purified by rapid column chromatography to obtain methyl 4-(bromomethyl)-3-nitrobenzoic acid ester 2 (76%) as a grayish-white solid.

[0570] Compound 2 (4.0 g, 14.5 mmol) and 2-aminomethylfuran (3 equivalents) were stirred in anhydrous CH2Cl2 (50 mL) at room temperature for 48 hours. After the reaction was complete, the solvent was removed and the crude product was purified by rapid column chromatography to give nitrobenzene ester 3 (82%).

[0571] SnCl₂·2H₂O (3.5 equivalents) was added to a solution of compound 3 (3.65 g, 11.9 mmol) in anhydrous MeOH (100 mL), and the resulting reaction mixture was refluxed for 10 min. After the reaction was complete, the byproducts were filtered through a diatomaceous earth bed, and the filtrate was evaporated. The crude product was partitioned between 1 N NaOH and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3 × 20 mL), and the combined layers were dried over MgSO₄ and concentrated under reduced pressure to provide compound 4 (87%).

[0572] Compound 4 (1.0 g, 3.8 mmol) was dissolved in DCM, and then 1.2 equivalents of CNBr were added to react at room temperature. After 8 hours, the mixture was extracted with DCM and water. The solvent was removed and the crude product was purified by rapid column chromatography to give compound 5 (60%).

[0573] A solution of methyl 2-amino-3-(furan-2-ylmethyl)-3,4-dihydroquinazoline-7-carboxylic acid ester 5 (0.3 g, 1.05 mmol) in acetonitrile (20 mL) was treated with K₂CO₃ (0.29 g, 2.1 mmol) and KI (0.005 g, 0.03 mmol), followed by the addition of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 6 (0.722 g, 3.89 mmol), and the reaction mixture was refluxed for 6 hours. After 24 hours, the solvent was evaporated, and the reaction mixture was diluted with saturated aqueous NaHCO₃ solution (30 mL) and extracted with EtOAc (3 x 30 mL).

[0574] The combined organic phases were washed with saturated brine (30 mL). The crude product was purified by silica gel column chromatography using 8% methanol / EtOAc to obtain 70.43 g (70%) of methyl 3-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3,4-dihydroquinazoline-7-carboxylic acid.

[0575] NaOH (0.198 g, 4.95 mmol) was added to a solution of methyl 3-(furan-2-ylmethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3,4-dihydroquinazolin-7-carboxylic acid ester 7 (0.43 g, 0.99 mmol) in EtOH / H2O (1 / 1, 10 mL) under reflux conditions. After 1 hour, the solvent was evaporated, and the reaction mixture was diluted with saturated aqueous HCl (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phases were washed with saturated brine (30 mL). The crude product was purified by silica gel column chromatography using 20% ​​methanol / EtOAc to give 0.27 g of pure product (65%) as a white solid.

[0576] 1 H NMR (400MHz, methanol-d4) δ 8.07 (s, 1H), 7.70 (d, J = 7.9Hz, 1H), 7.53 (d, J = 1.8Hz, 1H), 7.35 (s, 1H), 7.14 (d, J = 7.8Hz, 1H), 6.57 (d , J=3.2Hz, 1H), 6.43 (dd, J=3.2, 1.8Hz, 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) + .

[0577] Example 3-8 26090: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)amino)-3-pentyl-3,4-dihydroquinazoline-7-carboxylic acid

[0578]

[0579] Except for the substitution of pentyl-1-amine for the amine, the other reactants and preparation steps are similar to those described in Examples 3-7, yielding the title compound.

[0580] 1 H NMR (400MHz, methanol-d4) δ8.03 (dd, J=8.4, 1.4Hz, 1H), 7.96 (s, 1H), 7.84 (d, J=1.3Hz, 1H), 7.55 (d, J=8.4Hz, 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, 2.8Hz, 4H), 1.29 (d, J=4.0Hz, 2H), 0.97-0.92 (m, 3H);; LRMS (ESI+): m / z 411.3(M+H) + .

[0581] Example 4-1 NCTU-SUN-12082: 1-(2-(cyclohexyl-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester

[0582]

[0583] H₂SO₄ (5 mL, 0.3 M) was added to a solution of 4-fluoro-3-nitrobenzoic acid 1, and the reaction mixture was heated to reflux. The solvent was removed under reduced pressure, and the crude reaction mixture was dissolved in EtOAc. The EtOAc layer was dried over anhydrous MgSO₄ and evaporated to obtain methyl 4-fluoro-3-nitrobenzoic acid 2 as a white solid.

[0584] Compound 2 and 2-(cyclohexyl-1-en-1-yl)ethylamine were stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed and the crude product was purified to give nitrobenzene ester 3.

[0585] Zinc dust and ammonium formate were added to a solution of compound 3, and the resulting reaction mixture was stirred at room temperature. After the reaction was complete, the Zn dust was filtered off, the filtrate was evaporated, and the product was dissolved in CH₂Cl₂. The precipitated ammonium formate was filtered off, and the solvent was evaporated to provide compound 4.

[0586] Carbon disulfide and KOH were added to a stirred solution of compound 4 in ethanol for 8 hours at 50°C. The mixture was neutralized with acetic acid and extracted with EtOAc and water. The solvent was evaporated and the crude product was purified to give compound 5.

[0587] K₂CO₃ and KI were added to a solution of methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-thionone-2,3-dihydro-1H-benzo[d]imidazolium-5-carboxylate 5, followed by the addition of 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 EtOAc.

[0588] The combined organic phases were washed with saturated brine. The crude product was purified to give 0.053 g of pure product NCTU-SUN-12082 (71%) as a white solid.

[0589] 1 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).

[0590] Example 4-2 12083: 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazol-5-carboxylic acid

[0591]

[0592] H₂SO₄ (5 mL, 0.3 M) was added to a solution of 4-fluoro-3-nitrobenzoic acid 1, and the reaction mixture was heated to reflux. The solvent was removed under reduced pressure, and the crude reaction mixture was dissolved in EtOAc. The EtOAc layer was dried over anhydrous MgSO₄ and evaporated to obtain methyl 4-fluoro-3-nitrobenzoic acid 2 as a white solid.

[0593] Compound 2 and 2-(cyclohexyl-1-en-1-yl)ethylamine were stirred at room temperature for 2 h. After the reaction was complete, the solvent was removed and the crude product was purified to give nitrobenzene ester 3.

[0594] Zinc dust and ammonium formate were added to a solution of compound 3, and the resulting reaction mixture was stirred at room temperature. After the reaction was complete, the Zn dust was filtered off, the filtrate was evaporated, and the product was dissolved in CH₂Cl₂. The precipitated ammonium formate was filtered off, and the solvent was evaporated to provide compound 4.

[0595] Carbon disulfide and KOH were added to a stirred solution of compound 4 in ethanol for 8 hours at 50°C. The mixture was neutralized with acetic acid and extracted with EtOAc and water. The solvent was evaporated and the crude product was purified to give compound 5.

[0596] K₂CO₃ and KI were added to a solution of methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-thionone-2,3-dihydro-1H-benzo[d]imidazolium-5-carboxylate 5, followed by the addition of 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 EtOAc.

[0597] The combined organic phases were washed with saturated brine. The crude product was purified to give 0.053 g of 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester 7 (71%).

[0598] NaOH (0.0251 g, 0.63 mmol) was added to a solution of 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester 7 (0.053 g, 0.126 mmol) in EtOH / H2O (1 / 1, 3 mL) under reflux conditions. After 1 hour, the solvent was evaporated, and the reaction mixture was diluted with saturated aqueous HCl (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with saturated brine (30 mL). The crude product was purified by silica gel column chromatography using 20% ​​methanol / EtOAc to give 0.030 g of pure product NCTU-SUN-12083 (65%) as a white solid.

[0599] 1 H NMR (300MHz, CD3OD) δ8.30 (d, J=1.4Hz, 1H), 8.14 (s, 1H), 7.98 (dd, J=8.5, 1.5Hz, 1H), 7.49 (d, J=8.5Hz, 1H), 5.51 (s, 2H), 5.08 (s, 1H), 4 .71 (s, 2H), 4.24 (t, J=6.8Hz, 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).

[0600] Example 4-3 12084: 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)sulfinyl)-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester

[0601]

[0602] H₂SO₄ (5 mL, 0.3 M) was added to a solution of 4-fluoro-3-nitrobenzoic acid 1, and the reaction mixture was heated to reflux. The solvent was removed under reduced pressure, and the crude reaction mixture was dissolved in EtOAc. The EtOAc layer was dried over anhydrous MgSO₄ and evaporated to obtain methyl 4-fluoro-3-nitrobenzoic acid 2 as a white solid.

[0603] Compound 2 and 2-(cyclohexyl-1-en-1-yl)ethylamine were stirred at room temperature for 2 hours. After the reaction was complete, the solvent was removed and the crude product was purified to give nitrobenzene ester 3.

[0604] Zinc dust and ammonium formate were added to a solution of compound 3, and the resulting reaction mixture was stirred at room temperature. After the reaction was complete, the Zn dust was filtered off, the filtrate was evaporated, and the product was dissolved in CH₂Cl₂. The precipitated ammonium formate was filtered off, and the solvent was evaporated to provide compound 4.

[0605] Carbon disulfide and KOH were added to a stirred solution of compound 4 in ethanol for 8 hours at 50°C. The mixture was neutralized with acetic acid and extracted with EtOAc and water. The solvent was evaporated and the crude product was purified to give compound 5.

[0606] K₂CO₃ and KI were added to a solution of methyl 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-thionone-2,3-dihydro-1H-benzo[d]imidazolium-5-carboxylate 5, followed by the addition of 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 EtOAc.

[0607] The combined organic phases were washed with saturated brine. The crude product was purified to give 0.053 g of 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester 7 (71%).

[0608] mCPBA (0.0058 g, 0.034 mmol) was added to a solution of 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester 7 (0.053 g, 0.0126 mmol) in DCM / MeOH (9 / 1, 4.5 mL) in an ice bath. Then, NaHCO3 (0.0007 g, 0.0088 mmol) was added and the ice bath was removed. The crude product was stirred at room temperature for 1 hour. The reaction mixture was washed with DCM (5 mL). The solvent was evaporated, and 0.030 g of the pure product NCTU-SUN-12084 (65%) as a white solid was obtained.

[0609] 1 H NMR (300MHz, CDCl3) δ8.55 (s, 1H), 8.13 (s, 1H), 8.10 (dd, J=8.7, 1.5Hz, 1H), 7.43 (d, J=8.8Hz, 1H), 5.03 (q, J=12.9Hz, 3H), 4.59-4.35 (t, J =8.3Hz, 2H), 4.58-4.36 (m, 2H), 3.97 (s, 3H), 3.71 (s, 3H), 2.49 (t, J = 8.3Hz, 2H), 2.30 (s, 3H), 2.22 (s, 3H), 2.03-1.78 (m, 4H), 1.51 (m, 4H).

[0610] Example 5-1 12092: (((9H-furo-9-yl)methoxy)carbonyl)glycine 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazol-5-yl ester

[0611]

[0612] To a solution of 2-((((9H-en-9-yl)methoxy)carbonyl)amino)acetic acid 2-thione-2,3-dihydro-1H-benzo[d]imidazol-5-yl ester 1 (0.08 g, 0.18 mmol) in ethanol (9 mL), NaOH (0.079 g, 0.198 mmol) was added, followed by the addition of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 2 (0.367 g, 0.198 mmol), and the reaction mixture was refluxed for 1 hour. Once the reaction was complete, the solvent was evaporated, and the crude product was purified by silica gel column chromatography using 2% MeOH / DCM to give the pure product NCTU-SUN-12092 (0.31 g, 54.5%) as a white solid.

[0613] 1H NMR (300MHz, acetone-d6) δ8.26 (s, 1H), 7.87 (d, J = 7.4Hz, 2H), 7.74 (d, J = 7.4Hz, 2H), 7.51 (d, J = 8.6Hz, 1H), 7.41 (t, J = 7.3Hz, 2H), 7.32 (t, J = 7.4Hz, 3H) , 7.14 (t, J=6.6Hz, 1H), 6.95 (dd, J=8.7, 2.1Hz, 1H), 4.67 (s, 2H), 4.40 (d , J=7.3Hz, 2H), 4.36-4.21 (m, 3H), 3.80 (s, 3H), 2.36 (s, 3H), 2.25 (s, 3H).

[0614] Example 5-2 12093: (tert-butoxycarbonyl)glycine 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazol-5-yl ester

[0615]

[0616] Except that the imidazole is replaced by 2-((tert-butoxycarbonyl)amino)acetic acid 2-thione-2,3-dihydro-1H-benzo[d]imidazol-5-yl ester, the other reactants and preparation steps are similar to those described in Example 5-1, to obtain the title compound.

[0617] 1 ¹H 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).

[0618] Example 5-3 12094: (S)-2-((((9H-furo-9-yl)methoxy)carbonyl)amino)-2-phenylacetic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H benzo[d]-imidazol-5-yl ester

[0619]

[0620] Except for the imidazole being replaced by (S)-2-((((9H-furo-9-yl)methoxy)carbonyl)amino)-2-phenylacetic acid 2-thione-2,3-dihydro-1H-benzo[d]imidazol-5-yl ester, the other reactants and preparation steps are similar to those described in Example 5-1, to obtain the title compound.

[0621] 1 H NMR (300MHz, acetone-d6) δ8.24 (s, 1H), 7.85 (d, J = 7.5Hz, 2H), 7.75 (d, J = 7.4Hz, 2H), 7.65 (d, J = 7.2Hz, 2H), 7.52-7.39 (m, 6H), 7.32 (m , 2H), 7.22 (d, J=1.6Hz, 1H), 6.83 (dd, J=9.1, 1.5Hz, 1H), 5.67 (s, 1H), 4.66 (s, 2H), 4.48-4.25 (m, 3H), 2.35 (s, 3H), 2.25 (s, 3H).

[0622] Example 6-1 NCTU-SUN-22138: 5-methoxy-2-((2-methoxy-3,6-dimethylbenzyl)thio)-1H-benzo[d]imidazole

[0623]

[0624] NBS (0.177 g, 1.00 mmol) was added to a solution of 2-methoxy-1,3,4-trimethylbenzene 1 (0.3 g, 2.00 mmol) in chloroform (30 mL), and in the photoinduced reaction, the distance between the two Philips″IR 250W lamps placed from the reaction flask was such that reflux was maintained. Once the reaction was complete, the solvent was evaporated and the crude product was purified by hexane using silica gel column chromatography to obtain bromide product 2 (0.092 g, 20%).

[0625] NaOH (0.017 g, 0.43 mmol) was added to a solution of bromide product 2 (0.1 g, 0.43 mmol) in ethanol (2 mL), followed by the addition of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 3 (0.071 g, 0.39 mmol), and the reaction mixture was refluxed for 1 hour. Once the reaction was complete, the solvent was evaporated, and the crude product was purified by silica gel column chromatography using 2% MeOH / DCM to obtain NCTU-SUN-22138 (0.077 g, 60%).

[0626] LRMS(ESI+): m / z 329.2(M+H) +

[0627] Example 6-2 22141: 2-((2-methoxy-3,6-dimethylbenzyl)thio)-1H-benzo[d]imidazol-5-ol

[0628]

[0629] NBS (0.177 g, 1.00 mmol) was added to a solution of 2-methoxy-1,3,4-trimethylbenzene 1 (0.3 g, 2.00 mmol) in chloroform (30 mL), and in the photoinduced reaction, the distance between the two Philips″IR 250W lamps placed from the reaction flask was such that reflux was maintained. Once the reaction was complete, the solvent was evaporated and the crude product was purified by hexane using silica gel column chromatography to obtain bromide product 2 (0.092 g, 20%).

[0630] NaOH (0.017 g, 0.43 mmol) was added to a solution of bromide product 2 (0.1 g, 0.43 mmol) in ethanol (2 mL), followed by the addition of 2-(chloromethyl)-4-hydroxy-3,5-dimethylpyridine 3 (0.071 g, 0.39 mmol), and the reaction mixture was refluxed for 1 hour. Once the reaction was complete, the solvent was evaporated, and the crude product was purified by silica gel column chromatography using 2% MeOH / DCM to obtain NCTU-SUN-22138 (0.077 g, 60%).

[0631] LRMS(ESI+): m / z 315.1(M+H) +

[0632] Example 6-3 21133: 2-((3-(bromomethyl)-2-((tert-butyldimethylsilyl)oxy)-6-methylbenzyl)thio)-5-methoxy-1H-benzo[d]imidazole

[0633]

[0634] NBS (1.7 g, 9.5 mmol) was added to a solution of tert-butyldimethyl(2,3,6-trimethylphenoxy)silane 1 (1.2 g, 4.7 mmol) in chloroform (50 mL), and in the photoinduced reaction, the distance between the two Philips″IR 250W lamps placed from the reaction flask was such that reflux was maintained. Once the reaction was complete, the solvent was evaporated and the crude product was purified by hexane using silica gel column chromatography to obtain dibromide product 2 (0.31 g, 20%).

[0635] NaOH (0.036 g, 0.90 mmol) was added to a solution of dibromide product 2 (0.3 g, 0.90 mmol) in ethanol (9 mL), followed by the addition of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 3 (0.148 g, 0.82 mmol), and the reaction mixture was refluxed for 1 hour. Once the reaction was complete, the solvent was evaporated, and the crude product was purified by silica gel column chromatography using 2% MeOH / DCM to obtain NCTU-SUN-21133 (0.23 g, 60%).

[0636] 1 H NMR (400MHz, chloroform-d) δ7.43 (d, J=8.8Hz, 1H), 7.16 (s, 1H), 7.04 (d, J=2.3Hz, 1H), 6.82 (d, J= 2.3Hz, 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).

[0637] LRMS(ESI+): m / z 507.1(M+H) +

[0638] Example 6-4 22139: 5-methoxy-2-((2-methoxy-3,6-dimethylbenzyl)sulfinyl)-1H-benzo[d]imidazole

[0639]

[0640] NBS (0.177 g, 1.00 mmol) was added to a solution of 2-methoxy-1,3,4-trimethylbenzene 1 (0.3 g, 2.00 mmol) in chloroform (30 mL), and in the photoinduced reaction, the distance between the two Philips″IR 250W lamps placed from the reaction flask was such that reflux was maintained. Once the reaction was complete, the solvent was evaporated and the crude product was purified by hexane using silica gel column chromatography to obtain bromide product 2 (0.092 g, 20%).

[0641] NaOH (0.017 g, 0.43 mmol) was added to a solution of bromide product 2 (0.1 g, 0.43 mmol) in ethanol (2 mL), followed by the addition of 2-(chloromethyl)-4-methoxy-3,5-dimethylpyridine 3 (0.071 g, 0.39 mmol), and the reaction mixture was refluxed for 1 hour. Once the reaction was complete, the solvent was evaporated, and the crude product was purified by silica gel column chromatography using 2% MeOH / DCM to obtain 5-methoxy-2-((2-methoxy-3,6-dimethylbenzyl)thio)-1H-benzo[d]imidazole 3 (0.077 g, 60%).

[0642] 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 (0.077 g, 0.23 mmol) in DCM / MeOH (9 / 1, 10 mL) in an ice bath. Then, NaHCO3 (0.013 g, 0.16 mmol) was added, and the ice bath was removed. The crude product was stirred at room temperature for 1 h. The reaction mixture was washed with DCM (10 mL). The solvent was evaporated, and 0.047 g of the pure product (65%) as a white solid was obtained.

[0643] LRMS(ESI+): m / z 345.1(M+H) +

[0644] Example 11 DAAO Enzyme Analysis

[0645] The DAAO enzyme activity assay was modified based on the report by Oguri et al. (Oguri, S., Screening of d-amino acid oxidase inhibitor by a new multi-assay method. Food Chemistry 2007, 100(2), 616). DAAO activity was measured by further reacting 3-(4-hydroxyphenyl)propionic acid (HPPA) with hydrogen peroxide (H2O2) generated from the reaction of reactant D-alanine. HPPA was oxidized by H2O2 and peroxidase to form a fluorescent dimer, which was measured to represent DAAO activity.

[0646] For porcine kidney DAO IC50 analysis, DAO acceptors 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 (in 100% dimethyl sulfoxide (DMSO)) at different concentrations shown in the table below (ranges of 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% in each reaction concentration. 10 μl of the D-alanine and candidate compound mixture was incubated with 220 μl of reaction master mix in a black 96-well plate at 37 °C for 5 min. The reaction mixture stock solution 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 analysis of 110 reactions.

[0647] Fluorescence intensity (Fs) is measured at 405 nm after irradiation at 320 nm. Higher DAO enzyme activity results in higher fluorescence intensity. The fluorescence inhibition index (Fi) is obtained from the following equation: Fi = (Fs - F 药物 ) / (F DMSO ), including fluorescent drug blank (F 药物 The measurement was performed in a drug mixture solution (using 0.2M Tris HCl buffer, pH 8.3, D-alanine-free). DMSO blank (F DMSO The value was measured in a 100% DMSO solution.

[0648] Although FAD is typically included in the reaction mixture in D-amino acid oxidase assays due to its easy dissociation from the holoenzyme, the method of this invention is carried out in the absence of FAD. This is achieved by using an inhibitory concentration (IC50) that inhibits DAAO activity by 50%. 50 To compare the inhibitory effects of DAO inhibitors. IC 50The values ​​were calculated using a nonlinear regression model with GraphPadPrism, version 5 (GraphPad Software, Inc., La Jolla, CA). The DAOIC50 analysis results of the candidate compounds of this invention are shown in the table below.

[0649]

[0650]

[0651] Example 12: Cell-based DAO Analysis

[0652] Neuron cell culture

[0653] The SK-N-SH neuroblastoma cell line was purchased from the American Type Culture Collection (ATCC). The cell line was cultured in MEM medium (Invitrogen / GIBCO, Rockville, MD) supplemented with 10% fetal bovine serum and 1×NEAA (Invitrogen / GIBCO) at 37°C and 5% CO2 under a humidified atmosphere. Cells were trypsinized and seeded at a density of 125,000 cells / well in 50 μl samples into black 96-well plates (NUNC number 237108), followed by cell-based DAO analysis.

[0654] Cell-based DAO analysis

[0655] Cellular DAO activity assays were performed using a modified method reported by Brandish et al. (Brandish, PE, et al., A cell-based ultra-high-throughput screening assay for identifying inhibitors of D-aminoacid oxidase. J Biomol Screen, 2006, 11(5): 481-7). SK-N-SH cells were suspended in an assay buffer containing 20 mM HEPES in HANKS buffer (Invitrogen / GIBCO No. 14025-092). D-serine (final concentration 50 mM) was added to each well as the acceptor for the DAO enzyme. The H2O2 produced after the DAO reaction, diffusing across the cell membrane into the assay medium, was measured using an Amplex Red hydrogen peroxide / peroxidase assay kit (Molecular Probes / Invitrogen, catalog No. A22188). After seeding cells into black 96-well plates (Nunc number 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 of interest) and incubated at 37°C and 5% CO2 for 30 min under humidified conditions. After 30 min, 25 μl of a 5-fold mixture containing D-serine, horseradish peroxidase (HRP), and Amplex Red was added to wells containing 100 μl of the cell-drug mixture and incubated at 37°C and 5% CO2 for 3 h under humidified conditions. The final concentration of DMSO was less than 1%. Fluorescence signals were then detected using a SpectraMax M2e microplate reader (Molecular Devices, USA), showing excitation at 544 nm and emission at 590 nm. The optimized analysis buffer contained a final concentration of 50 mM M-serine, 0.625 units of HRP, and 50 μM Amplex Red in a 125 μl analysis volume. Cell-based DAO analysis results of the candidate compounds of this invention are shown in the table below.

[0656]

[0657]

[0658] Example 13: Animal studies on the efficacy of treating symptoms of schizophrenia

[0659] Drug efficacy screening

[0660] The negative or cognitive deficits induced by the NMDA receptor antagonist MK-801 in C57BL / 6 mice are well-established drug-induced mouse models of schizophrenia and serve as useful pharmacological animal models to identify whether RS-D7, its analogues, and its prodrugs improve symptoms by means of NMDA receptors.

[0661] animal

[0662] All wild-type (WT) mice used in this study were reintroduced to the C57BL / 6J background from the Laboratory Animal Center of National Taiwan University Hospital, and all behavioral examinations were conducted on WT mice. To adapt to laboratory conditions, mice were allowed free access to food and water and were housed in groups in a temperature- and humidity-controlled room at the Department of Psychology, National Taiwan University, using a 12-hour light-dark cycle. All animals under 3 months of age were individually housed one week prior to the experiment to test their availability of food and water. At the start of the experiment, mice were handled and weighed daily for at least one week prior to the behavioral experiments. The entire animal procedure was conducted according to a protocol approved by the Animal Care and Use Committee established by National Taiwan University.

[0663] Preparation of drugs for treating animals

[0664] Dissolve MK-801 in saline and administer at 0.01 ml / g body weight. Before use, freshly dissolve RS-D7 and drug 12083 (an analogue of RS-D7) in 1% CMC to a concentration of 2 mg / ml. Before use, freshly dissolve prodrug 28095 in NMP:HP-β-CD:H2O (5:25:70) to a concentration of 2 mg / ml. Administer either the mediator (saline) or MK-801 (0.2 mg / kg, ip) to all animals 25 minutes before the behavioral experiment. Five minutes after MK-801 administration, treat both the mediator group (1% CMC or NMP:HP-β-CD:H2O) and the experimental group (RS-D7, drug 12083, or prodrug 28095) via PO injection at an appropriate dose (0.01 ml / g body weight).

[0665] Behavioral Experiment Procedure

[0666] To investigate the therapeutic effects of RS-D7 on negative and cognitive symptoms, a series of three behavioral tests, including the open field test, the sucrose preference test, and the pre-pulse inhibition test, were conducted sequentially (from week one to week three), with a one-week interval between each test.

[0667] open field

[0668] To evaluate spontaneous activity, each individual was placed in an open field apparatus (25.40*25.40*40.64cm) under dim lighting conditions (60 lx).3 The study was conducted at Coulburn Instruments, Whitehall, PA, USA. Motion activity parameters (including total distance traveled and distance traveled every 10 minutes) were monitored and recorded over a 60-minute period using Smart video tracking software (Panlab, Harvard apparatus, US). To compare the treatment effects across different treatment groups, the percentage change in the rescue effect against MK-801-induced excessive movement was calculated using the following formula: % = (Rescue effect of the drug - MK-801 effect) × 100% / MK-801 effect.

[0669] Compared to the saline control, mice exhibited hyperkinesis in the open field following acute MK-801 injection. Injections of 200 mg / kg and 400 mg / kg RS-D7 rescued MK-801-induced hyperkinesis in mice. However, 100 mg / kg RS-D7 did not show a therapeutic effect. These results indicate that acute RS-D7 injection in the open field test normalizes MK-801-induced hyperkinesis as a positive symptom of schizophrenia. Drug 12083 at doses of 20 and 40 mg / kg alleviated the MK-801-induced hyperkinesis defect. Prodrug 28095 at 100 mg / kg alleviated MK-801-induced hyperkinesis. In conclusion, different doses of RS-D7, drug 12083, and prodrug 28095 rescued MK-801-induced hyperkinesis compared to the MK-801 group. The rescue effect of these drugs on MK-801-induced hyperkinesis indicates… Figure 1 middle.

[0670] Sugar Preference Test

[0671] To evaluate schizophrenia (one of the negative symptoms of schizophrenia), all mice underwent a 4-day test. At the start of sucrose preference, all mice were deprived of water for 23 hours prior to day one in all experiments. On day one, each mouse was given free access to two identical bottles containing water for one hour. Then, on day two, the two identical bottles were replaced, one filled with a 1% (wt / vol) sucrose solution and the other with water. On days three and four, each mouse received MK-801 and RS-D7 treatment prior to the experiment and also had free access to the bottles for one hour. After the experiment, the two bottles were weighed to measure the one-hour consumption of sucrose solution and water. The percentage of sucrose preference (SPP) was calculated using the following formula: %SPP = sucrose solution consumption (g) × 100% / [water consumption (g) + sucrose solution consumption (g)].

[0672] Compared to the saline control, a significant reduction in sucrose intake was observed in test mice following acute MK-801 injection in the sucrose preference test. Injections of 100 mg / kg, 200 mg / kg, and 400 mg / kg RS-D7 rescued MK-801-induced alexia in mice. 20 mg / kg of drug 12083 and 200 mg / kg of prodrug 28095 also regularized MK-801-induced alexia. As a result, different doses of RS-D7, drug 12083, and prodrug 28095 rescued alexia after acute MK-801 injection. The rescue effect of these drugs on MK-801-induced alexia indicates… Figure 2 middle.

[0673] Prepulse suppression

[0674] To evaluate sensorimotor gating function, each mouse was tested using the SR-LAB startle device (San Diego Instruments, San Diego, CA, USA). Background noise during testing was 72 dB. Each working phase began with a 5-minute adaptation period, followed by 64 trials consisting of a single-pulse (single P) test, a pre-pulse-pulse (pp+P) test, and a nostim test. The single P test consisted of a 40-msec 120 dB white burst noise. In the pp+P test, a 20-msec pre-pulse of white burst noise of 78 dB (PP6), 82 dB (PP10), or 90 dB (PP18) was preceding the 120 dB pulse (100 msec). The nostim test consisted of only background noise. Working phases began and ended with a block of six presentations from the single P test. Between the two blocks, the remaining 52 trials were pseudo-randomized and separated by an intertrial interval of 15 seconds (varying between 10 and 20 seconds). The PPI was calculated as a percentage of the startle response using the formula: %PPI = 100 × [(single P score) - (pp + P score)] / (single pulse score), where the single pulse score is the average of the single pulse values ​​from the middle block of the 52 trials.

[0675] Mice receiving acute MK-801 injections exhibited a significant decrease in auditory PPI. However, injections of 100 mg / kg, 200 mg / kg, and 400 mg / kg RS-D7, 20 mg / kg and 40 mg / kg drug 12083, and 100 mg / kg and 200 mg / kg prodrug 28095 significantly alleviated MK-801-induced PPI deficiency in these mice. In other words, mice exhibited a significant decrease in PPI following acute MK-801 injection, which could be normalized by all doses of RS-D7, drug 12083, and prodrug 28095. The rate of recovery from MK-801-induced PPI deficiency indicated... Figure 3 middle.

Claims

1. A compound of formula (I), (I) Where n is 0, X is -S-; where A is N; R a It is -C(=O)OR a1 ;in R a1 It is H or straight chain or branched chain C 1-15 alkyl; R b Is it a straight chain or a branched chain? 6-15 Alkyl, straight-chain or branched C 6-15 alkenyl, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Aryl or -T'-C 5-10 Mixed aromatics; R c Each is independently either a straight chain or a branched chain C. 1-15 Alkyl, straight-chain or branched C 1-15 alkoxy, hydroxyl or -C 1-10 alkyl-YC 6-10 Heteroaryl groups, wherein -Y- is -CH2-, -NH-, -O-, or -S-; m is an integer from 0 to 4; -T'- is C 1-3 alkyl or C 2-3 enylene; and The heteroaryl group contains at least one heteroatom, each heteroatom being independently S, N, or O; In these alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylyl and alkenyl groups, each is independently unsubstituted or substituted by at least one substituent; The substituents therein are each independently a halogen, amino, nitro, nitroso, straight-chain or branched C. 1-15 Alkyl, straight-chain, or branched C 1-15 Alkoxy or C 3-10 cycloalkyl; and When R b When it is H, it includes tautomers. Or its medicinally acceptable salt.

2. The compound according to claim 1, wherein R a It is -C(=O)OH; -C(=O)OC 1-4 alkyl.

3. The compound according to claim 1, wherein it is selected from the group consisting of: 12082: 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazolium-5-carboxylic acid methyl ester; 12083: 1-(2-(cyclohex-1-en-1-yl)ethyl)-2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazol-5-carboxylic acid; and 12088: 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1-octyl-1H-benzo[d]imidazol-5-carboxylic acid methyl ester.

4. A compound of formula (I): (I) Where n is 0, X is -S-; A is N; R a It is -OC(=O)R a3 or -OC(=O)-T-OR a4 ;in R a3 and R a4 Independently, it is a protecting group, a straight chain, or a branched C. 1-15 Alkyl, straight-chain or branched C 2-15 alkenyl, -TC 3-10 cycloalkyl, -T-NHR a3p -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC 5-10 heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl, -T-adamantyl or -C 1-3 alkyl-C 6-10 aryl, wherein the alkylene group is via -T-NHR a3p replace; R a3p It is an H or N-protecting group; R b It is H, straight chain or branched chain C 1-15 Alkyl, straight-chain or branched C 2-15 alkenyl, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Aryl or -T'-C 5-10 Mixed aromatics; R c Each is independently either a straight chain or a branched chain C. 1-15 Alkyl, straight-chain or branched C 1-15 Alkyl groups, unprotected or protected hydroxyl groups, or -C 1-10 alkyl-YC 6-10 Heteroaryl groups, wherein -Y- is -CH2-, -NH-, -O-, or -S-; m is an integer from 0 to 4; -T- means non-existent, C 1-3 alkyl or C 2-3 Enylene; -T'- is C 1-3 alkyl or C 2-3 enylene; and The heteroaryl group contains at least one heteroatom, each heteroatom being independently S, N, or O; In these alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylyl and alkenyl groups, each is independently unsubstituted or substituted by at least one substituent; The substituents therein are each independently a halogen, a protecting group, a protected or unprotected amino group, a nitro group, a nitroso group, or a straight-chain or branched C group. 1-15 Alkyl, straight-chain or branched C 1-15 Alkoxy or C 3-10 cycloalkyl, and When R b When it is H, it includes tautomers. Or its medicinally acceptable salt.

5. The compound according to claim 4, wherein it is a compound of formula (Ia): (I-a) Where n is 0, X is -S-; A is N; R a It is -OC(=O)R a3 or -OC(=O)-T-OR a4 ;in R a3 and R a4 Independently, it is a protecting group, a straight chain, or a branched C. 1-15 Alkyl, straight-chain or branched C 2-15 alkenyl, -TC 3-10 cycloalkyl, -T-NHR a3p -TC 3-10 Cycloalkenyl, -TC 6-10 Aryl, -TC 5-10 heteroaryl, -T-NH-C(=O)-OC 1-10 Alkyl or -T-adamantyl; R a3p It is an H or N-protecting group; R b It is H, straight chain or branched chain C 1-15 Alkyl, straight-chain or branched C 2-15 alkenyl, C 1-3 Alkoxy-C 1-15 Alkyl-, -T'-C 3-10 cycloalkyl, -T'-C 3-10 Cycloalkenyl, -T'-C 6-10 Aryl or -T'-C 5-10 Mixed aromatics; R c Each is independently either a straight chain or a branched chain C. 1-15 Alkyl, straight-chain or branched C 1-15 Alkyl groups, unprotected or protected hydroxyl groups, or -C 1-10 alkyl-YC 6-10 Heteroaryl groups, wherein -Y- is -CH2-, -NH-, -O-, or -S-; m is an integer from 0 to 4; -T- means non-existent, C 1-3 alkyl or C 2-3 Enylene; -T'- is C 1-3 alkyl or C 2-3 enylene; and The heteroaryl group contains at least one heteroatom, each heteroatom being independently S, N, or O; In these alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylyl and alkenyl groups, each is independently unsubstituted or substituted by at least one substituent; The substituents therein are each independently a halogen, a protecting group, a protected or unprotected amino group, a nitro group, a nitroso group, or a straight-chain or branched C group. 1-15 Alkyl, straight-chain or branched C 1-15 Alkoxy or C 3-10 cycloalkyl, and Or its medicinally acceptable salt.

6. The compound according to claim 4, wherein it is a compound of formula (Ib): (I-b) Where n is 0, X is -S-; A is N; R a It is -OC(=O)R a3 ;in R a3 It is -T-NHR a3p -T-NH-C(=O)-OC 1-10 Alkyl or -C 1-3 alkyl-C 6-10 aryl, wherein the alkylene group is via -T-NHR a3p replace; R a3p It is an H or N-protecting group; R b It is H, straight chain or branched chain C 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 Aryl or -T'-C 5-10 Mixed aromatics; R c Each is independently either a straight chain or a branched chain C. 1-15 Alkyl, straight-chain or branched C 1-15 Alkyl groups, unprotected or protected hydroxyl groups, or -C 1-10 alkyl-YC 6-10 Heteroaryl groups, wherein -Y- is -CH2-, -NH-, -O-, or -S-; m is an integer from 0 to 4; -T- means non-existent, C 1-3 alkyl or C 2-3 Enylene; -T'- is C 1-3 alkyl groups; and The heteroaryl group contains at least one heteroatom, each heteroatom being independently S, N, or O; These alkyl, alkenyl, alkoxy, cycloalkyl, aryl, and heteroaryl groups are each independently unsubstituted or substituted by at least one substituent; The substituents therein are each independently a halogen, a protected or unprotected amino group, a nitro group, a nitroso group, a straight-chain or branched C group. 1-15 Alkyl, straight-chain or branched C 1-15 Alkoxy or C 3-10 cycloalkyl; and When R b When it is H, it includes tautomers. Or its medicinally acceptable salt.

7. The compound according to any one of claims 1 to 6, wherein m is an integer from 0 to 3.

8. The compound according to claim 4 or 5, wherein R a It is -OC(=O)R a3 , where R a3 It is a third butyl protecting group; adamantyl; a straight-chain or branched C-chain that is unsubstituted or substituted by a halogen or a third butyl protecting group. 1-10 Alkyl; unsubstituted or composed of C 1-10 Alkyl, nitro, C 1-15 Alkoxy or halogen-substituted -C 6-10 Aryl; C 3-10 cycloalkyl; -C 3-10 Cycloalkenyl; straight-chain or branched C 2-10 alkenyl; -C 5-10 heteroaryl; -C 1-3 alkyl-C 3-10 cycloalkyl; C 2-3 Entenyl-C 6-10 Aryl, of which C 6-10 The aryl group is either unsubstituted or substituted by a halogen.

9. The compound according to claim 4 or 5, wherein R a It is -OC(=O)R a3 , where R a3 It is a third butyl protecting group; adamantyl; a straight-chain or branched C-chain that is unsubstituted or substituted by a halogen or a third butyl protecting group. 1-8 Alkyl; unsubstituted or composed of C 1-6 Alkyl, nitro, C 1-4 Alkoxy or halogen-substituted -phenyl; C 3-6 cycloalkyl; -C 3-6 Cycloalkenyl; straight-chain or branched C 2-6 alkenyl; -C 5-6 heteroaryl; -C 1-3 alkyl-C 3-6 cycloalkyl; C 2-3 Enenyl-phenyl, wherein the phenyl group is unsubstituted or substituted with a halogen.

10. The compound according to claim 4 or 5, wherein R a It is -OC(=O)-C 1-6 Alkyl, -OC(=O)-C 1-4 alkyl-NH (Fmoc or Boc protecting group) or -OC (=O)-NH-C (=O)-OC 1-10 alkyl.

11. The compound according to any one of claims 1 to 2, wherein R c Each is independently either a straight chain or a branched chain C. 1-6 Alkyl, straight-chain or branched C 1-6 alkoxy or -C 1-10 alkyl-YC 6-10 Heteroaryl; wherein Y is S and C 6-10 Unsubstituted heteroaryl groups or those derived from C 1-15 Alkyl, C 1-15 Alkyl, -NH2, -NO2 or halogen substitution.

12. The compound according to claim 4, wherein it is selected from the group consisting of: 12092: (((9H-furo-9-yl)methoxy)carbonyl)glycine 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazol-5-yl ester 12093: (tert-butoxycarbonyl)glycine 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1H-benzo[d]imidazol-5-yl ester 12094: (S)-2-((((9H-furo-9-yl)methoxy)carbonyl)amino)-2-phenylacetic acid 2-(((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)thio)-1Hbenzi[d]-imidazol-5-yl ester Or its medicinally acceptable salt.

13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12.

14. Use of a compound according to any one of claims 1 to 12, for the preparation of a medicament for treating or preventing diseases associated with DAAO inhibition in an individual.

15. The use according to claim 14, wherein the disease is a symptom domain of schizophrenia and affective schizophrenia, depression, Tourette syndrome, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD), analgesia, memory and / or cognitive loss associated with neurodegenerative diseases, or loss of neuronal function characteristic of neurodegenerative diseases.

16. The use according to claim 15, wherein these symptom domains of schizophrenia and affective schizophrenia include negative, cognitive, depressive, positive, and general psychopathological symptom domains.

17. The use according to claim 14, wherein the disease is mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease, or schizophrenia.

18. The use according to claim 14, wherein the disease associated with DAAO inhibition is pain, ataxia, or tic.

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