NZ792401A - Novel substituted benzimidazole derivatives as D-amino acid oxidase (DAAO) inhibitors - Google Patents

Abstract

The present invention provides novel substituted benzimidazole derivatives used as DAAO inhibitors and for treatment and/or prevention of neurological disorders.

Description

NOVEL TUTED BENZIMIDAZOLE DERIVATIVES AS D-AMINO ACID OXIDASE (DAAO) INHIBITORS Cross-Reference to Related Applications This application is a divisional of New Zealand Patent Application No. 779170, itself a divisional of New Zealand Patent No. , being a national entry of International Patent Application No which claims the benefit of U.S. ional Application Ser. No. 62/394,479, filed on ber 14, 2016, each of which are incorporated herein by reference in its entirety.

Field of the Invention The invention relates to D-amino acid e (DAAO) inhibitors. Particularly, the present invention provides novel substituted benzimidazole derivatives used as DAAO inhibitors and for treatment and/or prevention of neurological disorders.

Background of the Invention The aberrant regulatory mechanism of ate transmission on N-methyl-D- aspartic acid (NMDA) receptor has been reported as one of the athology in phrenia. The receptor is a heterotetramer composed of two structure subunits of NMDA receptor 1 (NR1) and NR2. Modulation of the e binding site of NMDA receptor may improve the cognitive function and negative symptoms in schizophrenia. D-amino acid oxidase (DAAO) was found to be involved in the activation process of the NMDA receptor.

The ates of DAAO, especially the ne, may bind to the glycine site of the NMDA receptor as a co-agonist. This in turn may te the NMDA receptor in opening its calcium channel. D-serine has been found to inhibit the α-aminohydroxymethylisoxazole propionic acid (AMPA) receptor-mediated current in rat hippocampus neurons.

Accordingly, there is a need to develop candidate drugs having DAAO inhibitory effect to treat various neurological and physical disorder.

Summary of the ion The present invention pertains to a list of substituted benzimidazole derivatives used as DAAO inhibitors and for treatment and/or prevention of neurological disorders.

The present invention provides a nd having the following formula (I), wherein each substituent is described herein.

The present invention also provides a pharmaceutical composition comprising a compound of the present invention.

The present invention also provides a method of ting a DAAO comprising contacting a cell with a compound of the present invention.

The present invention also provides a method of ng or preventing the e ated with DAAO dysregulation in a subject comprising administrating an effective amount of a compound of the present invention to the subject.

In some embodiments, the disease is symptom domains of schizophrenia and schizoaffective disorder, depression, Tourette Syndrome, Post—traumatic stress disorder (PTSD), Obsessive-compulsive disorder (OCD), analgesics, loss of memory and/or cognition associated with neurodegenerative diseases or loss of neuronal function characteristic of neurodegenerative diseases. n embodiments include mild ive impairment (MCI), Alzheimer's disease, Parkinson's disease and schizophrenia.

Brief ption of the Drawing Figure 1 shows that compared to the MK—801 group, different dosages of RS-D7, Drug 12083 and Prodrug 28095 can rescue the MK—801—induced hyperlocomotion.

Figure 2 shows that different dosages of RS—D7, Drug 12083 and Prodrug 28095 rescue the anhedonia after acute MK—801 injection.

Figure 3 shows a significant ion of PPI after acute MK-801 ions. ed Description of the Invention ingly, DAAO was hypothesized to be implicated in the pathogenesis of schizophrenia. As the NMDA receptor also involved in affective disorder, it is likely that inhibiting the DAAO may elevate the function of NIVIDA and improve both the symptoms of schizophrenia and depression affective disorder.

Known inhibitors ofDAAO include benzoic acid, pyrrolecarboxylic acids, and indolecarboxylic acids. Indole derivatives and particularly certain indolecarboxylates have been described in the literature for treatment of neurodegenerative disease and neurotoxic injury. EP 396124 discloses indolecarboxylates and derivatives for treatment or ment of neurotoxic injury ing from a CNS disorder or traumatic event or in treatment or management of a neurodegenerative disease. US. Pat. Nos. 5,373,018; ,374,649; 461; 5,962,496 and 6,100,289 disclose treatment of neurotoxic injury and neurodegenerative disease using indole derivatives. W0 03/039540 disclose DAAO inhibitors, including indolecarboxylic acids, and methods of enhancing learning, memory and cognition as well as methods for treating neurodegenerative disorders. Patent Application No. WO/2005/O89753 discloses benzisoxazole analogs and methods of treating mental disorders, such as phrenia. WO/2015/168346 discloses a list of known known compounds as DAAO inhibitors.

As used herein and in the appended claims, the singular forms "a, and," and "the" include plural referents unless the context clearly dictates otherwise. When ranges are used herein for physical properties, such as molecular weight, or chemical ties, such as chemical formulae, all combinations and subcombinations of ranges and specific ments therein are intended to be included. The term "or" refers to "and/or" unless explicitly indicated to refer to alternatives only or unless the alternatives are mutually exclusive. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation 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 that in other certain embodiments, for e, an ment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of" or ”consist essentially of" the described features.

"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain ments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C1o . In n embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C6 alkyl). In other embodiments, an alkyl ses one to four carbon atoms (e.g., C1-C4 alkyl). In other ments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., C1 alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e. g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (e.g., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1- ethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropy1 (sec-butyl), 2-methy1propy1 (iso- butyl), 1,1-dimethylethyl (tert—butyl), 1—pentyl (n—pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless specifically stated otherwise in the specification, an alkyl group is optionally substituted by one or more of substituents, "Alkoxy" refers to a radical bonded through an oxygen atom of the a alkyl, where alkyl is an alkyl chain as defined above.

"Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and en atoms, ning at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain ments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl ses two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., , but-l-enyl, -enyl, penta-1,4- dienyl, and the like. Unless specifically stated otherwise in the specification, an alkenyl group is optionally substituted by one or more of substituents.

"Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, ning at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain ments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless specifically stated otherwise in the specification, an alkynyl group is optionally substituted by one or more of substituents.

"Aryl" refers to a radical derived from an aromatic monocyclic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) pi-electron system in accordance with the Huckel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as e, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally tuted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, ally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, ally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb--0Ra, -Rb-OC(O)-Ra, —Rb-OC(O)-0Ra, -Rb-OC(O)-N(Ra)2, -Rb--N(Ra)2, - Rb-C(O)Ra, -Rb-C(O)0Ra, -Rb-C(O)N(Ra)2, -Rb-O-R-C(O)N(Ra)2, -Rb--N(Ra)C(O)ORa, -Rb- N(Ra) C(O)Ra, -Rb-N(R‘1‘)S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is l or 2), -Rb-- S(O).subtRa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl (optionally tuted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each Risupb is ndently a direct bond or a straight or branched alkylene or alkenylene chain, and R.sup.c is a straight or branched ne or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

"Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring , wherein at least one of the rings in the ring system is fully rated, i.e., it ns a cyclic, lized (4n+2) pi-electron system in ance with the Huckel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally ized. The heteroaryl is ed to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), hieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6- dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]py1idazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10— hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyc1oocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, olyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, thano—5,6,7,8—tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2—oxoazepinyl, oxazolyl, oxiranyl, ,6,6a,7,8,9,10, 10a-octahydrobenzo[h]quinazolinyl, l—phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, azinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, nyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidiny1, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, alinyl, quinolinyl, nolinyl, tetrahydroquinolinyl, 5,6,7,8—tetrahydroquinazolinyl, 5,6,7,8- tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H- cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3—d]pyrimidinyl, thieno[3,2- d]pyrimidiny1, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents ed from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally tuted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, ally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally tuted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, Ra, -Rb- OC(O)—Ra, -Rb-OC(O)-0Ra, -Rb-OC(O)-N(Ra)2, -Rb--N(Ra)2, -Rb-C(O)Ra, O)0Ra, -Rb- C(O)N(Ra)2, -Rb-O-R-C(O)N(Ra)2, -Rb--N(Ra)C(O)ORa, -Rb-N(Ra) C(O)Ra, -Rb- N(Ra)S(O)tRa (where t is 1 or 2), -Rb-S(O)tORa (where t is l or 2), -Rb--S(O).subtRa (where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2), where each Ra is independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R.sup.b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R.sup.c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless ise indicated.

The term aceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable xic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds encompassed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid. entative salts of basic compounds of the present invention e, but are not limited to, the following: acetate, ascorbate, e, te, aspirate, benzenesulfonate, te, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentane propionate, diethylacetic, digluconate, dihydrochloride, dodecylsulfanate, edetate, edisylate, estolate, esylate, ethanesulfonate, formic, fumarate, gluceptate, glucoheptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, oxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic, onate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N- methylglucamine ammonium salt, oleate, oxalate, pamoate ate), palmitate, pantothenate, pectinate, fate, phosphate/diphosphate, pimelic, phenylpropionic, polygalacturonate, propionate, salicylate, stearate, sulfate, tate, ate, tannate, tartrate, teoclate, thiocyanate, tosylate, triethiodide, trifluoroacetate, undeconate, valerate and the like. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof include, but are not limited to, salts derived from inorganic bases including aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, ous, potassium, sodium, zinc, and the like. Also included are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of y, secondary, and tertiary amines, cyclic , dicyclohexyl amines and basic ion-exchange , such as arginine, betaine, caffeine, e, N,N—dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, mine, ethylenediamine, lmorpholine, N—ethylpiperidine, glucamine, amine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, dine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Also, ed are the basic nitrogen-containing groups that may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, l, dibutyl; and diamyl sulfates, long chain halides such as decyl, , myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

The term "subject" includes living organisms such as humans, monkeys, cows, sheep, horses, pigs, cattle, goats, dogs, cats, mice, rats, cultured cells, and transgenic s thereof. In a preferred embodiment, the subject is a human.

The term "administering" includes routes of administration which allow the active ingredient of the invention to perform their intended function.

The term "treat" or "treatment" refers to a method of reducing the effects of a disease or condition. ent can also refer to a method of reducing the ying cause of the disease or condition itself rather than just the symptoms. The ent can be any reduction from native levels and can be, but is not limited to, the complete ablation of the disease, condition, or the symptoms of the e or condition.

The term "prevent," "prevention" or "preventing" means inhibition or ng of symptoms associated with the target disease.

The phrase "therapeutically effective " refers to that amount of a compound, material, or composition comprising a compound of the t invention which is effective for producing a desired therapeutic effect, at a reasonable benefit/risk ratio applicable to any medical treatment.

The term "neurological disorder" refers to any rable condition of the central or peripheral s system of a mammal. The term "neurological disorder" includes neurodegenerative diseases (e. g., Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis), neuropsychiatric diseases (e.g. schizophrenia and anxieties, such as general anxiety disorder). Exemplary neurological disorders include MLS (cerebellar ataxia), Huntington's disease, Down syndrome, multi-infarct dementia, status epilecticus, contusive injuries (e. g. spinal cord injury and head injury), viral infection induced neurodegeneration, (e. g. AIDS, encephalopathies), epilepsy, benign forgetfulness, closed head injury, sleep disorders, depression (e.g., bipolar disorder), dementias, movement disorders, psychoses, lism, post-traumatic stress disorder and the like. "Neurological disorder" also es any rable condition associated with the disorder. For instance, a method of treating a neurodegenerative er includes methods of treating loss of memory and/or loss of cognition associated with a neurodegenerative disorder. Such method would also include treating or preventing loss of neuronal function characteristic of neurodegenerative disorder.

Compounds ofthepresent invention In one aspect, the present invention provides a compound of formula (I): . 35}m wherein n is O or 1, X is —S—, —S(=O)— or —NRn—; wherein Rn is H or A is —CH, —CRC or N; Ra is ORa1, —ORa2, —O—C(=O)Ra3 or —O—C(=O)-T-0Ra4; n Ral is H or linear or branched C1-15alkyl, Raz is H, linear or branched C1-15alkyl, phosphonate, phosphonate or an O- protecting group; Ra3 and Ra4 are independently a protecting group, linear or branched C1-15alkyl, linear or ed C2-15alkenyl, —T—C3-1ocycloalkyl, -T-NHRa3p, -T-C3. iocycloalkenyl, -T-C6-1oaryl, -T—C5-10heteroaryl, -T-NH-C(=O)-O-C1-1oalkyl, -T- adamantyl or -C1.3all<ylene-C6-1oaryl where the alkylene is substituted with -T- NHRa3p; Ragp is H or an N-protecting group; Rb is H, linear or branched C1-1salkyl, linear or branched C2-15alkenyl, C1-3alkoxy-C1- 15alkyl-, -T'-C3.10cycloalkyl, -T'—C3.1ocycloalkenyl, -T‘—C6.10 aryl or -T'—C5.1oheteroaryl; RC each is independently linear or branched C1.1salkyl, linear or branched C1.15alkoxyl, unprotected or protected hydroxyl group, or —C1.10a]kylene-Y-C6.1oheteroaryl wherein - Y- is -CH2-, —NH—, —O— or —S—; symbol * represents the g position; m is an integer from O to 4; -T- is , C1.3alkylene or C2-3alkenylene; -T'— is C1-3alkylene or C2-3alkenylene; and wherein the aryl contains at least one heteroatom, each heteroatom being independently S, N or 0; wherein the alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene and alkenylene are each independently unsubstituted or substituted with at least one sub stituent; wherein the substituent is each independently a halogen, a protecting group, protected or unprotected amino group, nitro, nitroso, linear or ed C1.15 alkyl,or linear or branched C145 alkoxy or C3.1ocycloalkyl; and when Rb is H, the tautomers are ed, with the o that when X is —S— or —S(=O)—, Ra is —0Ra2 and Raz is H or linear or branched C1-15alkyl, then A is —CH or —CRC; when X is —S— or — and Ra is —C(=O)ORa1, Rb is linear or branched C6-15alkyl, linear or branched lkenyl, C1-3alkoxy-C1-15alkyl-, -T'-C3-1ocycloalkyl, -T'-C3- iocycloalkenyl, -T'-C6.10 aryl or -T‘-C5-10heteroaryl; or a aceutically acceptable salt thereof.

In one embodiment, the present invention provides a compound of formula (I-a): wherein n is 0 or 1, X is —S—, —S(=O)— or —NRn—; wherein Rn is H or “ A is —CH, —CRc or N, Ra is —C(=O)0Ra1, —ORa2, —O—C(=O)Ra3 or —O—C(=O)—T-0Ra4; wherein Ral is H or linear or branched C1-15alkyl; Raz is H, linear or branched C1-15alkyl, diarylphosphonate or an O-protecting group, Ra3 and Ra4 are independently a protecting group, linear or branched C1-15alkyl, linear or branched lkenyl, —T—C3-1ocycloalkyl, -T-NHRa3p, -T-C3. oalkenyl, -T-C6-1oaryl, —T—C5-1oheteroaryl, -T-NH-C(=O)-O-C1.1oalkyl or -T- adamantyl; Ragp is H or an N—protecting group; Rb is H, linear or branched C1-15alkyl, linear or branched lkenyl, C1-3alkoxy-C1- 15alkyl-, -T'-C3-1ocycloalkyl, -T'—C3-1ocycloalkenyl, -T'-C6.1o aryl or -T'—C5.1oheteroaryl; RC each is independently linear or ed C1.15alkyl, linear or branched C1.15alkoxy1, unprotected or protected hydroxyl group, or —C1.ioalkylene-Y—C6.1oheteroaryl n - Y- is -CH2-, -NH-, -O- or -S-; symbol * represents the bonding position; m is an integer from 0 to 4; -T- is absent, C1.3alkylene or C2-3alkenylene; -T'— is C1-3alkylene or C2-3alkenylene; and wherein the heteroaryl contains at least one heteroatom, each heteroatom being independently S, N or 0; n the alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene and alkenylene are each independently unsubstituted or substituted with at least one sub stituent, wherein the substituent is each independently a halogen, a protecting group, protected or unprotected amino group, nitro, nitroso, linear or branched €1.15 alkyl, linear or branched C145 alkoxy or C3-1ocycloalkyl and when Rb is H, the tautomers are included, with the proviso that when X is —S— or —S(=O)—, R21 is —OR32 and R32 is H or linear or branched C1-15alkyl, then A is —CH or —CRC; when X is —S— or —S(=O)— and Ra is —C(=O)OR31, R], is linear or branched C6-15alkyl, linear or branched C6.15alkenyl, C1.3alkoxy-C1.1salkyl-, -T'-C3.1ocycloalkyl, -T'-C3. oalkenyl, -T'-C6.10 aryl or -T'-Cs.10heteroaryl; or a phannaceutically acceptable salt f.

In one ment, the present invention provides a compound of formula (I-b), (1-b) wherein n is 0 or 1, X is —S—, —S(=O)— or —NRn-; Rn is H or A is —CH; —CRC or N; Ra is —C(=O)ORa1; —ORa2 or —O—C(=O)Ra3; wherein Ral is H or linear or branched C1-15alkyl; Raz is H; linear or branched C1-15alkyl; onate, diarylphosphonate or an O- ting group; Ra3 is -T-NHRa3p, -T-NH-C(=O)—O-C1-1oalkyl or -C1.3alkylene-C6-1oaryl where the alkylene is substituted with -T-NHRa3p; Ragp is H or an N—protecting group; Rb is H; linear or branched C1-15alkyl, C1-3alkoxy-C1-1oalkyl-, -T'-C3.1o cycloalkyl; -T'-C3- iocycloalkenyl; -T'-C6.1o aryl or -T'-C5-10 heteroaryl; RC each is independently linear or ed C1-15alkyl; linear or branched C1-15alkoxyl; unprotected or protected yl group or —C1-1oalkylene-Y-C6-1oheteroaryl wherein -Y- is -CH2-, -NH-, -O- or -S-; symbol * represents the bonding position; In is an integer from O to 4; -T- is absent, C1.3alkylene or C2.3alkenylene; -T'- is C1-3alkylene; and n the aryl contains at least one heteroatom; each heteroatom being independently S; N or 0; wherein the alkyl; alkenyl; alkoxy; cycloalkyl, aryl and heteroaryl are each independently unsubstituted or substituted with at least one substituent; wherein the substituent is each independently a halogen, protected or unprotected amino group, nitro, nitroso, linear or branched €1-15 alkyl, linear or branched C145 alkoxy or C3- iocycloalkyl, and when Rb is H, the tautomers are included, with the proviso that when X is —S— or —S(=O)—, R21 is -OR32 and R32 is H or linear or branched C1-15alkyl, then A is—CH or —CRc; when X is —S— or —S(=O)— and Ra is ORa1, Rb is linear or branched C6.15alkyl, linear or branched lkenyl, C1.3alkoxy-C1.1salkyl-, -T'-C3.10cycloalkyl, -T'-C3. iocycloalkenyl, -T'-C6.10 aryl or -T'-Cs.10heteroaryl; or a pharmaceutically acceptable salt thereof.

In one embodiment, the present invention provides the compound of formula (I), wherein n is O or 1; X is —S—, —S(=O)— or —NRn—; wherein Rn is H or A A is —CH, —CRc or N, Ra is —ORa2, —O—C(=O)Ra3 or —O—C(=O)-T—0Ra4; n Raz is H, linear or branched C1-15alkyl, phosphonate, phosphonate or an O-protecting group; R23 and Ra4 are independently a protecting group, linear or branched lkyl, linear or branched C2-15alkenyl, -T-C3.1ocycloalkyl, -T-NHR33p, -T-C3-1ocycloalkenyl, -T-C6-10aryl, -T- eteroaryl, -T-NH-C(=O)-O-C1.1oalkyl, -T-adamantyl or -C1.3alkylene-C6.1oaryl where the alkylene is substituted with -T-NHRa3p; Ra3p is H or an N—protecting group; Rb is H, linear or branched C1.15alkyl, linear or branched C2.15alkenyl, koxy-C1.1salkyl-, -T'-C3.1ocycloalkyl, -T'-C3.1ocycloalkenyl, -T'-C6.10 aryl or -T'-C5.10heteroaryl; RC each is independently linear or branched C1.15alkyl, linear or branched C1.15alkoxyl, unprotected or protected hydroxyl group, or —C1-10a]kylene—Y-C6-1oheteroaryl n -Y- is - CH2-, -NH-, -O- or -S-; symbol * represents the bonding position; m is an integer from O to 4; -T- is absent, C1-3alkylene or C2-3alkenylene; -T'- is Ci-3alkylene or C2-3alkenylene; and wherein the heteroaryl contains at least one heteroatom, each heteroatom being independently S, N or 0, wherein the alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene and alkenylene are each independently unsubstituted or substituted with at least one substituent; wherein the substituent is each independently a halogen, a protecting group, protected or unprotected amino group, nitro, nitroso, linear or branched €1-15 alkyl, or linear or branched C1.15 alkoxy or C3.iocycloalkyl; and when Rb is H, the tautomers are included, with the proviso that when X is —S— or —S(=O)—, Ra is —ORa2 and Ra; is H or linear or branched Ci-15alkyl, then A is —CH or —CRC; or a pharrnaceutically acceptable salt thereof.

In a further embodiment, the present invention provides the compound of a (I), wherein n is O, X is —S(=O)—, A is N, Ra is —ORa2, —O—C(=O)Ra3 or —O—C(=O)—T—0Ra4, wherein Raz is H, linear or branched C1- l, phosphonate, diarylphosphonate or an O-protecting group; R23 and Ra4 are independently a ting group, linear or branched Ci-15alkyl, linear or ed C2-15alkenyl, -T—C3-iocycloalkyl, -T-NHRa3p, -T-C3-1ocycloalkenyl, -T—C6.10aryl, -T- C5-ioheteroaryl, -T—NH-C(=O)-O-Ci-ioalkyl, -T-adamantyl or -C1.3alkylene-C6.ioaryl where the alkylene is substituted with a3p; R33], is H or an N—protecting group; Rb is H; m is 3; and RC each is independently linear or branched C1.1salkyl, linear or ed C1.isalkoxyl; or a ceutically acceptable salt thereof.

In one embodiment, n is 0.

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

In some embodiments, Ra is —C(=O)OH, —C(=O)OC1.4alkyl, H, —ORa2 wherein Raz is H, linear or ed C1-1oall<yl or an O—protecting group; —O—C(=O)Ra3 wherein Ra3 is independently tert-butyl protecting group; linear or branched lkyl unsubstituted or tuted by halogen, tert-butyl protecting group or protected amino group; linear or branched C2-10alkenyl; C1-4alkoxy; ycloalkyl; -C1-3alkylene-C3.iocycloalkyl; -C3. 1ocycloalkenyl; -C6.1oaryl unsubstituted or substituted by C1-10 alkyl, nitro, C1.15alkoxy or halogen; -C5.1oheteroaryl unsubstituted or substituted by C1-10alkoxy; C2-3alkenylene-C6.1oaryl wherein C6.1oaryl is unsubstituted or substituted by halogen; —C1.3alkylene-NH--C(=O)—O-C1. loalkyl; or adamantly; or —O—C(=O)—O-C1-1oalkyl.

In some embodiments, Ra is —O-C1.1oalkyl; —O-protecting group or —O—C(=O)Ra3 wherein Rag is a tert-butyl protecting group; tly; linear or branched C1.1oalkyl unsubstituted or substituted by halogen or a utyl protecting group; C1.4alkoxy; -C6.10aryl unsubstituted or substituted by C140 alkyl, nitro, C1-15alkoxy or halogen; C3-10cycloalkyl; -C3. iocycloalkenyl; linear or branched C2-10alkenyl; —C5-1oheteroaryl; -C1.3alkylene-C3. iocycloalkyl; C2-3alkenylene-C6.1oaryl wherein C6-1oaryl is unsubstituted or substituted by halogen; —O—C(=O)-O-C1-1oalkyl. In some embodiments, Ra is —O-C1-4alkyl, tbutyloxycarbonyl protecting group or —O—C(=O)R33 wherein Ra3 is a tert-butyl protecting group; adamantly; linear or branched C1-salkyl unsubstituted or substituted by halogen or a tert-butyl protecting group; C1.4alkoxy; -phenyl unsubstituted or substituted by C1-6 alkyl, nitro, C1.4alkoxy or halogen; C3.6cycloalkyl; -C3-6cycloalkenyl; linear or branched C2- 6alkenyl; -C5-6heteroaryl; -C1-3alkylene—C3-6cycloalkyl; C2-3alkenylene-phenyl wherein phenyl is tituted or substituted by halogen; —O—C(=O)—O-C1-4alkyl. In some further embodiments, C3-6cycloalkyl is ropyl or cyclohexyl. In some further embodiments, - C3-1ocycloalkenyl is cyclohexenyl.

In some r embodiments, aryl is pyrrolidinyl, inyl, pyrazolidinyl, imidazolidinyl, pyrazolinyl, imidazolinyl, pyrazolyl, imidazolyl, tetrahydrofuranyl, furanyl, dioxolanyl, tetrahydrothiophenyl, thiophenyl, oxazolyl, isoxazolyl, azolyl, thiazolyl, oxathiolanyl, piperidinyl, nyl, piperazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetrahydropyranyl, pyranyl, dioxanyl; thianyl, thiopyranyl, morpholinyl, oxazinyl or thiazinyl.

In further embodiments, heteroaryl is furanyl, isoxazolyl or thiophenyl.

In some embodiments, Ra is -OH, -COOH, -O-phosphate, 6alkyl or —O— C(=O)-C1-6alkyl, O)—C1.4alkylene—NH(Fmoc or tecting group), or —O—C(=O)- NH-C(=O)-O-C1.10alkyl.

In some embodiments, RC each is independently linear or branched C1.6alkyl or linear or branched C1-6alkoxyl. In some embodiments, RC each is independently halogen, linear or branched C1-6alkyl, linear or branched C1-6alkoxyl, or —C1-1oalkenylene-Y-C6- ioheteroaryl; wherein Y is S and C6-1oheteroaryl is unsubstituted or substituted by C1-15alkyl (preferably C1-4alkyl), C1-15alkenyl (preferably C2-4alkyl), C1.15alkoxy (preferably C1- 4alkoxy), -OH, -NH2, -N02 or halogen. In a further embodiment, —C1-1oalkenylene-Y-C6- ioheteroaryl is Ma: In some embodiments, the compound of the present invention is selected from the group consisting of: NCTU-SUN- M.W. al ure 2-(((4-methoxy-3,5-dimethylpyridin yl)methyl)sulfinyl)— zo[d]imidazolyl 2-((tert- butoxycarbonyl)amino)acetate 26090 410.52 2-(((4-methoxy-3,5-dimethylpyridin hyl)amino)pentyl-3,4-dihydroquinazoline carboxylic acid NCTU-SUN- M.W. al Structure 21115 398 46 2-(((4-methoxy-3,5-dimethy1pyridin yl)methyl)amino) (3-methoxypropy1)-1H— benzo[d]imidazole—S—carboxylic acid 25030 429 17 (2-(((4-methoxy—3,5—dimethy1pyn'din yl)methyl)sulfinyl)—1H—benzo[d]imidazoly1 3,3- dimethylbutanoate) €271 (Ir 1; 28096 479.55 (2-(((5—methoxy-4,6—dimethy1pyridin y1)methyl)sulfinyl)—lH—benzo[d]imidazoly1 2- ethoxybenzoate) 12093 472.56 2-(((4-methoxy-3,5-dimethy1pyridiny1)methy1)thio)- 1H—benzo[d]imidazol—5—yl (tertbutoxycarbonyl )glycinate NCTU-SUN- M.W. Chemical Structure /\/\g/ \©:H\N>i \bN [bi 25016 (2-(((4-methoxy-3,5-dimethy1pyridin yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl pentanoate) 1213 0 5 08 43 (2—(((4—methoxy—3,5—dimethy1pyridin yl)methy1)sulfinyl)—1H—benzo[d]imidazolyl 6- bromohexanoate) O N\ {—67 27077 40148 2-(((4-methoxy-3,5-d1methylpyr1d1n, . . yl)methy1)sulfinyl)—1H—benzo[d]imidazoly1 isobutyrate qoUp)N\ [5* 27079 449 52 -methoxy-3,5-dimethy1pyridin yl)methyl)sulfinyl)-1H-benzo[d]imidazolyl cyclohexenecarboxylate 26089 420.47 NCTU-SUNChemical Structure anylmethyl)(((4-methoxy-3,5- dimethylpyridinyl)methy1)amino)-3 ,4- oquinazoline-7—carb0xylic acid (Excuwg (2-(((4-methoxy-3,5-dimethy1pyn'din yl)methyl)sulfinyl)—1H—benzo[d]imidazoly1 4- fluorobenzoate) “1%:wa 25032 (ethyl (2-(((4—methoxy—3,5-dimethy1pyridin y1)methyl)sulfinyl)—1H-benzo[d]imidazoly1) carbonate) WOU;\>—\b3?\ / 26098 (2-(((4—methoxy-3,5—dimethy1pyridin y1)methyl)sulfinyl)—1H—benzo[d]imidazoly1 4- butylbenzoate) H _ E OCEEHCQ 21127 (2-(((4-methoxy-3,5-dimethy1pyn'din yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl 3 - methylbenzoate) NCTU-SUNChemical Structure OZN \O E l O N % 25017 (2-(((4-methoxy-3,5-dimethy1pyridin yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl 4- nitrobenzoate) 12128 (2—(((4—methoxy—3,5—dimethy1pyridin hyl)sulfinyl)—1H—benzo[d]imidazolyl 3 - cyclopentylpropanoate) 26071 Methyl 2—(((4-methoxy-3,5-dimethylpyridin yl)methyl)amino)— 1 —(4-methoxybenzy1)-1H- benzo[d]imidazolecarboxy1ate 11021 (2-(((4-methoxy-3,S-dimethylpyridin yl)methyl)sulfinyl)-1H-benzo[d]imidazolyl 2- fluorobenzoate) NCTU-SUN- 21 1 18 93' Methyl 2-(((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)amino) phenethyl-1H-benzo[d]imidazole- -carboxylate 26070 1-(furanylmethyl)—2—(((4-methoxy-3,5- dimethylpyridin—2—yl)methyl)amino)- 1H- d]imidazole—5—carboxylic acid 25029 (2-(((4—methoxy-3,5—dimethy1pyridin yl)methyl)sulfinyl)— 1 H—benzo[d]imidazoly1 2- methylbutanoate) 12129 (2-(((4-methoxy-3,5-dimethy1pyn'din yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl (E)-3 -(2- chlorophenyl)acrylate) NCTU-SUN- . . Chemical Structure 11023 (2-(((4-methoxy-3,5-dimethy1pyridin yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl isoxazole-S-carboxylate) WOW?\b 26096 H (2-(((4—methoxy—3,5—dimethy1pyridin yl)methy1)sulfinyl)—1H—benzo[d]imidazolyl te) 6% CE? bO N $57 25027 (2-(((4-methoxy-3,5-dimethy1pyridin yl)methy1)sulfinyl)—1H—benzo[d]imidazoly1 cyclobutanecarboxylate) %O [ifN\ {—57‘b 28092 (2-(((4-methoxy-3,5-dimethy1pyridin yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl cyclopropanecarboxylate) NCTU-SUN- M.W. Chemical Structure methyl 2-(((4-methoxy-3,S-dimethylpyridin-Z- y1)methyl)thio)—l-octyl—1H—benzo[d]imidazole-5 - carboxylate (2-(((4-methoxy-3,S-dimethylpyridin yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl 2- methylbutanoate) 21117 . 1-(2-(cyclohex—1-enyl)ethy1)(((4-methoxy-3 , 5 - ylpyridin-Z- yl)methyl)amino)-1H- benzo[d]imidazole-S-carboxylic acid Methyl 1 -(2-(cycloheXen-1 -y1)ethy1)(((4-methoxy- 3,5-dimethylpyridiny1)methy1)su1f1ny1)-1H- benzo[d]imidazole—S—carboxylate 21126 NCTU-SUN- M.W. Chemical Structure (2-(((4—methoxy-3,5—dimethy1pyridin y1)methy1)sulfinyl)—1H—benzo[d]imidazoly1 3- enzoate) 26097 441 .5 5 (2-(((4-methoxy-3,5-dimethy1py11'din yl)methyl)sulfinyl)—1H—benzo[d]imidazoly1 cyclohexanecarboxylate) Rf: N I‘,»"V‘4 21110 412.49 2-(((4-methoxy-3,5—dimethy1pyridin yl)methyl)amino)—3- (3-methoxypropy1)-3,4- dihydroquinazolinecarboxylic acid 21116 448457 Methyl 1-(2—(cycloheXeny1)ethyl)-2—(((4-methoxy- 3,5- dimethylpyfidinyl)methy1)amino)-1H- benzo[d]imidazole-S-carboxylate NCTU-SUN- M.W. Chemical Structure 21120 2-(bis((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)amino)propy1- 1H-benzo[d]imidazole carboxylic acid 21121 1; 2-(bis((4-methoxy—3,S-dimethylpyridin-Z- hyl)amino)—1-phenethyl- 1H-benzo[d]imidazole- -carboxylic acid 22138 -methoxy—2—((2-meth0xy-3,6-dimethylbenzyl)thio)- 1H—benzo[d]imidazole 2501 5 (2—(((4—methoxy—3,5—dimethylpyridin y1)methyl)sulfinyl)—1H—benzo[d]imidazolyl pivalate) NCTU-SUNChemical Structure mUrbN fl; 28094 (2-(((4-methoxy-3,5-dimethy1pyridin yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl 2- acetate) GWEN W 28091 (2-(((4—methoxy—3,5—dimethy1pyridin yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl 2- nitrobenzoate) W015? 21130 (2-(((4-methoxy-3,5-dimethy1pyridin yl)methy1)sulfinyl)—1H—benzo[d]imidazoly1 (Z) methylbut—2—enoate) 21103 Methyl 2-(((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)amino) (3-methoxypropy1)-1H— benzo[d]imidazole—S—carboxylate NCTU-SUN- . . al Structure 7; (Ir 1,N [U 21 122 H (2-(((4-meth0xy-3,5-dimethy1pyridin yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl acetate) ”(Exfd% 1 1022 (2—(((4—methoxy—3,5—dimethylpyridin hyl)sulfinyl)—1H—benzo[d]imidazolyl (3 r, 5r,7r)—adamantane— 1 —carboxylate) kg; " 1 103 O (2-(((4-methoxy-3,S-dimethylpyridin-Z- yl)methy1)sulfinyl)— 1H-benzo[d]imidazoly1 4-(tertbutyl )benzoate) 2-(((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)amino)propy1- 1H-benzo[d]imidazole carboxylic acid 21132 NCTU-SUN- M.W. Chemical Structure .'y1)methyl)sulfinyl)—1H—benzo[d]imidazoly1)tert-butyl (2-(((4-meth0xy-3 , 5 -dimethylpyridincarbonate 12123 3 8 5 44 (2-(((4-methoxy-3,5-dimethy1pyn'din yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl acrylate) 13 084 563 56 2-(((4-methoxy—3,5—dimethylpyridin hyl)sulfinyl)—1H—benzo[d]imidazoly1 diphenyl phosphate 12094 670.78 2-(((4—methoxy-3,5—dimethylpyridinyl)methy1)thio)- 1H benzo[d]—imidazoley1 (S)((((9H-fluoren yl)methoxy)carbonyl)amino)—2-pheny1acetate 21105 583.73 ‘ NCTU-SUN- M.W. Chemical Structure 2-(bis((4-methoxy-3,5—dimethylpyridin hyl)amino) (2-(cycloheXeny1)ethy1)-1H- benzo[d]imidazole-S-carboxylic acid 12124 3 99.46 (2-(((4-methoxy-3,5-dimethy1pyn'din yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl (Z)-but- 12122 425 .46 (2-(((4-methoxy—3,5—dimethy1pyridin yl)methyl)sulfinyl)— 1H-benzo[d]imidazoly1 furan carboxylate) Methyl 2-(bis((4-meth0xy-3,5-dimethylpyridin yl)methyl)amino)—3-(furan-2—y1methyl)-3 ,4- dihydroquinazolinecarboxy1ate NCTU-SUN- 22140 2,2'-(((2-methoxymethy1-1,3- phenylene)bis(methylene))bis(su1fanediy1))bis(5- methoxy- 1 H-benzo[d]imidazol e) 21 13 3 2-((3 -(bromomethyl)—2-((tert-butyldimethylsi1y1)oxy) methylbenzy1)thio)—5-methoxy-1H-benzo[d]imidazole 21 125 2-(((4-methoxy-3,5—dimethy1pyridin y1)methy1)sulfinyl)—1H—benzo[d]imidazoly1 4- chlorobenzoate 27078 4-methoxy-3,5-dimethy1pyn'din yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl cyclohex—3—ene—1—carboxylate) NCTU-SUN- M.W. Chemical Structure O N {—67 1 1020 (2-(((4-methoxy-3,5-dimethy1pyridin yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl 4- methoxybenzoate) 396.49 2-(((4-methoxy—3,5—dimethylpyridin y1)methyl)amino)— 1 —pentyl-1H-benzo[d]imidazole carboxylic acid Wm»???‘b 25031 403. 12 (2-(((4—methoxy-3,5—dimethy1pyridin yl)methyl)sulfinyl)—1H—benzo[d]imidazoly1 2- methoxyacetate) wU?N 2%?\ / ‘23 21128 443.19 -methoxy-3,5-dimethy1pyridin yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl heptanoate NCTU-SUN- M.W. Chemical Structure 27076 429153 -methoxy-3,5-dimethy1pyridin yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl hexanoate 12083 . ix? 1-(2-(cyclohex—1—en—1—yl)ethy1)(((4-methoxy-3 , 5 - dimethylpyridin—2—yl)methyl)thio)- 1H- benzo[d]imidazole—5—carboxylic acid 21119 km? 2-(((4—methoxy-3,5—dimethylpyridin yl)methyl)amino)— 1 -phenethy1- 1H-benzo[d]imidazole- -carboxylic acid 21 104 NCTU-SUN- M.W. Chemical Structure 2-(bis((4-methoxy-3,S—dimethylpyridin-Z- y1)methyl)amino) (3-methoxypropyl)- 1H- benzo[d]imidazole-S-carboxylic acid Methyl 3 —(2—(cycloheX—1—eny1)ethyl)(((4-methoxy- 3,5— dimethylpyfidin—Z—yl)methyl)amino)-3,4- oquinazoline—7—carboxylate 26077 2-(((4-methoxy-3,S-dimethylpyridin-Z- y1)methyl)amino)(4-methoxybenzy1)-1H- benzo[d]imidazole-S-carboxylic acid Methyl 2-(((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)amino)penty1-1H-benzo[d]imidazole carboxylate 12125 NCTU-SUNChemical (2-(((4—methoxy-3,5—dimethy1pyridin y1)methyl)sulfinyl)—lH—benzo[d]imidazoly1 3 - methylbut—2—enoate) Methyl 1—(furan—2—ylmethyl)(((4-methoxy-3 ,5 - dimethylpyridin—2—yl)methyl)amino)- 1H- benzo[d]imidazole—S—carboxylate 26079 Methyl 3 -(furanylmethyl)(((4-methoxy-3 , 5 - dimethylpyridinyl)methy1)amino)-3 ,4- dihydroquinazolinecarboxy1ate 25028 (2-(((4-methoxy-3,5-dimethy1pyridin yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl thiophene-Z-carboxylate) 26092 NCTU-SUN- . . Chemical Structure Methyl 2—(((4-meth0xy—3,S-dimethylpyridin-Z- yl)methyl)amino)—3-(4—methoxybenzy1)-3,4- dihydroquinazolinecarb0xy1ate 3figgxffi? 21124 (2-(((4-methoxy-3,S-dimethylpyn'din-z- yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl benzoate) O N {—57 28093 (2-(((4-methoxy—3,5—dimethy1pyn'din yl)methyl)sulfinyl)—1H—benzo[d]imidazoly1 2- ethylbutanoate) 26091 Methyl -meth0xy—3,S-dimethylpyridin-Z- yl)methyl)amino)—3-penty1-3,4-dihydroquinazoline carboxylate 22139 —methoxy—2—((2—methoxy—3,6- dimethylbenzyl)sulfinyl)—1H—benzo[d]imidazole NCTU-SUN- . . Chemical Structure 22141 ~ 2-((2-methoxy—3,6-dimethy1benzyl)thio)-1H- benzo[d]imidazolol 28087 (2—(((4—methoxy—3,5—dimethylpyridin hyl)sulfinyl)—1H—benzo[d]imidazolyl 4- methylbenzoate) 21 123 (2-(((4-methoxy-3,5-dimethylpyridin yl)methyl)sulfinyl)—1H—benzo[d]imidazoly1 propionate) 12092 2-(((4—methoxy-3,5—dimethy1pyridin—2—y1)methyl)thio)- 1H-benzo[d]imidazoly1 (((9H—fluoren yl)methoxy)carbonyl)glycinate 21098 NCTU-SUN- . . Chemical ure Methyl 2—(((4-meth0xy—3,S-dimethylpyridin-Z- y1)methyl)amino)- 1—propy1-1H-benzo[d]imidazole carboxylate (2-(((4-methoxy-3,S-dimethylpyridin yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl 2- chloropropanoate) 11 1‘ 1:11.; a "a f \ 12082 Methyl 1 -(2-(cycloheXeny1)ethy1)(((4-methoxy- , 5-dimethylpyridiny1)methy1)thio)-1H- benzo[d]imidazolecarboxylate (2-(((4-meth0xy-3,5-dimethy1pyridin yl)methyl)sulfiny1)—1H-benzo[d]imidazolyl 3,5,5- trimethylhexanoate 11031 NCTU-SUN- M.W. Chemical Structure (2-(((4—methoxy-3,5—dimethy1pyridin hyl)sulfinyl)— 1 H—benzo[d]imidazolyl 3 -chloro- 4-fluorobenzoate) or a pharmaceutically acceptable salt thereof.

The present ion encompasses all stereoisomeric forms of the compounds of Formula I, Formula I-a and Formula I-b. Centers of asymmetry that are present in the compounds of Formula I, Formula La and Formula I—b can all independently of one another have (R) configuration or (S) configuration. When bonds to the chiral carbon are depicted as straight lines in the structural Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formula. When a particular configuration is depicted, that entantiomer (either (R) or (S), at that center) is intended. rly, when a compound name is recited without a chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence individual enantiomers and mixtures f, are embraced by the name.

The invention es all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of omers and/or diastereomers, in all ratios. Thus, omers are a subject of the invention in enantiomerically pure form, both as tatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios. In the case of a cis/trans isomerism the invention includes both the cis form and the trans form as well as mixtures of these forms in all ratios. The preparation of individual stereoisomers can be carried out, if d, by separation of a mixture by customary s, for example by chromatography or crystallization, by the use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis. Optionally a derivatization can be carried out before a separation of stereoisomers. The tion of a e of stereoisomers can be carried out at an intermediate step during the synthesis of a nd of Formula 1, Formula La and Formula I—b or it can be done on a final racemic product. Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration. Where compounds of this invention are capable of tautomerization, all individual tautomers as well as mixtures thereof are included in the scope of this invention.

The present invention es all such isomers, as well as salts, solvates (including hydrates) and solvated salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof.

Generalpreparation procedures ofthe compounds ofthe present invention The compounds of a (I) of the present invention are prepared ing to general chemical synthetic procedures. The preparation of the embodiments of the compounds of the present ion is rated below.

Synthetic Scheme and Procedurefor the Preparation of the compounds of the inventionfrom RS—D7 Ur / R Cl EtOH,rt,1h RIO>—\©:21 ft; ‘b z\ RS-D7 R is —Ra3 or —T-ORa4. tic Scheme and Procedurefor the Preparation ofNCTU—SUN-26065 series o o Rb—NH2 N02 ConC' H2804 (0'3 M) N02 (3 equiv) Ho \0 MeOH' reflux' 12h DCM’ rt’ 2 h F F Zn (15 eqUiV) O HCOONH4 (75 eqUiV) NH2 CNBr (1'2eq) MeOH' r1'30 min ,Rb DCM' n r't' em 3 a :4) 2 eq) KI<O3 eq) \0 N Rn \3 :E—NHz + Cl — ACN N\>—N reflux 6h Rb / a mmkuwkxxxxx Rb — H ”near or branched (51:15_a|ky| linear or branched 02 15a|keny| Rn H' / /N C1 Salkoxy C1 1:5alkyl’ T C3 1OCyC|°a|ky|‘ T C3 1OCyC|°a|keny| I T C6 10 aryl or T C5 1Oheter03ryl Synthetic Scheme and Procedurefor the Preparation ofNCTU—SUN-260 70 series 0 O Rb—NHZ N02 conc‘ H2804 (0'3 M) HO \0 N02 (3 equiv) MeOH‘ refIUX‘ 12h F DCM’ r11 2 h 1 2 o 2n (15 equiv) 0 HCOONH4 (7'5 eqUiV) \OJUNW CNBr(1‘2eQ) —> —> MeOH' '1' 30 min‘ Rb DCM’ H H a 4 0 o 0 K CO;3Q);2 e \$ 2 q) \ Kl \ N Rn \O N a e Rn O ::_NH2 (03‘! N OH(5)5 q HO + Cl rJ: \>_N _ \>_N _ ACN NR \ / EtOH/HZO (1:1) NR \ / reflux 6h b RefIUX’ 1h b '"= 7 rItTIfsuw‘xxxxxx Rb =H "near or branched C1 | "near or branched 02 15a|keny|v Rrl H' )5. [N _I<OXyc1 1'_5aI_I<yI_I T "cs1oconaIkyI "T ca 100y0|03|kenyr l "T"ce1o aryI or T cs 1oneteroaryI \ Synthetic Scheme and Procedurefor the Preparation ofNCTU—SUN—260 79 series 0 0 DCC 1'2 eqUiV) . . Rb—NH2 3 equlv.

No2 DMA (o 005 equIv) N02 ( ) HO \0 DCM’ rt’ 48 h Br MeOH/DCM (119)’ gr rt’ 16h I 2 O o N02 SnCIZ' 2H20 (3'5 eqUiV) CN Br ) \0 NH \ 2 H —> —> MeOH' reflux) 10 mIn' DCM’ ‘Rb ‘Rb W 3hr 0 <5 \ K20032 eq 0 \ NI: K[(0 3 eq) reflux 24h ncru‘sum‘xxxxxx RLa—_'H linear Ol‘ branched C1 153|ky| linear Ol‘ branched C2 153|kenyl' Rn H' a J“ c1"3aI_I<c>Xyc1 1saI_I<yI , T c3 10°y°|°alkyl‘ T c3'1OCyCIoaIkenyI- | T CS 10 aryl 0" T CS 10heter°aryl Synthetic Scheme and Procedurefor the Preparation ofNCTU—SUN-26089 series 0 D00 12 eqUiv 0 DMA . . Rb_NH2 No2 ) (3 equiv HO (0 005 eqUIV) N02 Br MeOH/DCM (1 9) Br DCM' rt’ 48 h n11eh 1 2 O o \0 N02 SnCI2' 2H2O (3'5 eqUiV) NH2 cNBr (1'2eq) H‘ —.

MeOH1 1 10 mm‘ H DCM, Rb ‘Rb W em 3 4 0 (g o Rn / N NH chosé2:01) 5% N N | N\ / EtOH/H20(1 1) N R“ ACN Reflux 1h ‘Rb reflux 24h s a 7 nea‘u‘suw‘xxxxxx Rb H1 ”near or branched c1'1§a|ky|1 ”near or ed c2'15aIkenyI1 Rn H' 3,1 /N 01'33Ik0Xy'c1'153Ikyl'1 'T'C3'1OCyCI03IkyI’ 'T'C3'1ocycloalkenyl' I 'T'06'10 aWyl or 'T 'c5'10heteroary1 Synthetic Scheme and Procedurefor the Preparation ofNCTU—SUN-]2082 series 0 o Rb—NH2 N02 conC' H2804 (03 M) HO N02 \0 (3 equiv) Meow refIUX1 12h F DCM’ rt1 2 h 0 Zn (15 eqUiV) O \0 HCOONH4 (7'5 eqUiV) NH2 \o CS2 (12%) —> —’ R Me0H1 rt1 30 min' R 1 b b N} N, KOI: EtOH H H 50 0 SH 3 4 o o \o N A) b \O N S + Cl \ K200312 eq) we Kl(0 3. [\l e N 1.21) N / —> Rb / Rb ACN reflux 6h s ficTu'suN”xxxxxx Rb: H linear or bran0hed c1 1salkyl1 linear or bran0hed 02,'_1sa_lkenyl c1"3alk0Xy01"15a1ky1 1 T "c3 1OCyC|03|ky|’ T c3 1OCyCIoaIkenyI T "ce1oaryl or T "cs10heteroaryl Synthetic Scheme and Procedurefor the ation ofNCTU—SUN-]2083 series o o Rb—NH2 HOXCENOZ conC' H2304 (0'3 M) N02 \0 (3 eqUiV) MeOH' reflux: 12h F DcM’ rt, 2 n 1 2 0 2n (15 equiv) 0 \0 N02 HCOONH4 (7'5 eqUiV) NH2 032 (1 2eq) N’Rb MeOH' r1'30 min' MRb KOH' EtOH H H 50°C am 3 A: 0 O H \3 \o N $ chog‘g32qeq N + K|(03% Na0H(55eq HO )=s 0' \ ,J / _ ACN \)—s N N\>_s EtOH/HZO (1 1) N Rb reflux 6h Reflux) 1h Rb / 6 7 NCTU‘SUN‘XXXXXX Rb H' linear or branChed C1_1Sa|ky|’ linear or braHChed lkenylv 01'salkOXy'c1'1saIkyIV 'T"cs‘100yCIoaIkyIv 'T"c3'1OCyCIoaIkenyIv 'T"ce'1o aryl or 'T"cs' 1oheteroary| Synthetic Scheme and Procedurefor the Preparation ofNCTU—SUN-]2084 o o Rb—NHZ U NO2 HO : conC' H2504 (0'3 M) (3 equiv) MeOH’ reflux: 12h F \O)K©[NOZ DCM’ rt: 2 h 1 2 o zn (15 equiv) \0 N02 (7Hc00NH4 5 eqUiV) \o 052 (1 260!) N’Rb MeOH rt 30 min KOH EtOH H 50°C em a 4 o K2c03£32qeq) \3 mCPBA1o7 eq) N 0 \3 \ H 4; Kl 03g NH , o + ( \>—§ >=S CI \ _ ,J / N N N\>b_s\_ DCM/MeOH=9/1 \ R / kn reflux 6h b rt' 1h 5 7 Ham'suw‘xxxxxx Rb H’ linear or branChed C1_1salkyl’ linear or ed 02‘1salkenylv 01‘33Ik0Xy‘c1‘153IkyI‘v ‘T"03‘100yCI°aIkyI' ’T"c3’106yCI°aIkenyI' 'T"cs'1o aryl or 'T"cs' 1oheteroary| Synthetic Scheme and Procedurefor the Preparation ofNCTU—SUN-]2092 series Ra N NaOH (2‘5 eq) )=s + /O \ Ra N \ / M | EtOH’ Reflux N/ CI \CE'P— 1'0 eq 11 eq 1 :2 ascm'suw'xxxxx _ o o o Ra _ ’ ’ FmocH N$03!; PhO\ BocHN$031; FmocHN 032; PhdfiLOx‘ tic Scheme and Procedurefor the Preparation ofNCTU—SUN-22138 series Ra N RC1 Rex R R H °1 C1 NBS (1'2 eq) NaOH (1'1 eq) Ra N —> R —> CHCI3’hV’refIUX \©:Bfix EtOH’ reflux NI)— 1 2 weru'suw'xxxxx = = = R8 OH’ 0M6 RC1 OMe’ OTBS RCX H’ Br Synthetic Scheme and Procedurefor the Preparation ofNCTU—SUN-22139 RC1 RC1 NBS (1 2 eq). NaOH (1 1 9(1) —> Rex—> CHCIS' hv: reflux \©:cx EtOH reflux \l 1 2 4 R\©:§—RC1 R“ R°X mCPBA (1 7 eq) Ncho3 Ra N DCM/MeOH=9/1 U \>— N ‘23 Ft’ 1h H 4 Nerueuwxxxxx = = = R8 OH' OMe RC1 OMe' OTBS RCX H' Br! /0CEWNN .

Utilities The compounds of the invention are useful for treating or preventing any disease and/or condition, n modulation of D-serine levels, and/or its oxidative ts, is effective in ameliorating symptoms. Inhibition of the enzyme can lead to increases in D- serine levels and a reduction in the ion of toxic D-serine oxidation products. Thus, the invention provides methods for the ent or prevention of neurological disorders and methods of enhancing learning, memory and/or cognition. The invention also provides s for the treatment or tion of the disease ed by DAAO inhibition, preferably, symptom domains of schizophrenia and schizoaffective disorder, depression, Tourette Syndrome, raumatic stress disorder (PTSD), Obsessive-compulsive disorder (OCD), analgesics, loss of memory and/or cognition associated with neurodegenerative diseases or loss of neuronal function characteristic of neurodegenerative diseases. In some embodiments, the symptom domains of schizophrenia and affective disorder include negative, cognitive, depressive, positive and general psychopathology symptom domains. In another embodiment, the disease associated with DAAO inhibition is mild cognitive impairment (MCI), mer's disease, Parkinson’s disease or schizophrenia. In some embodiments, the disease ated with DAAO inhibition is pain, ataxia or convulsion. In some embodiments, the compounds of the invention can be used for treating or preventing loss of memory and/or cognition associated with neurodegenerative diseases (e.g., Alzheimer's disease and schizophrenia) and for preventing loss of neuronal function characteristic of neurodegenerative diseases. r, methods are provided for the treatment or prevention of pain, ataxia and convulsion.

In some embodiment, the effective amount of the compound described herein ranges from 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 15 g/kg, about 0.5 mg/kg body weight to about 12 g/kg, about 0.5 mg/kg body weight to about 10 g/kg, about 05 mg/kg body weight to about 8 g/kg, about 0.5 mg/kg body weight to about 6 g/kg, about 2 mg/kg body weight to about 15 g/kg, about 2 mg/kg body weight to about 12 g/kg, about 2 mg/kg body weight to about 10 g/kg, about 2 mg/kg body weight to about 7 g/kg, about 2 mg/kg body weight to about 5 g/kg, about 5 mg/kg body weight to about 15 g/kg or about 5 mg/kg body weight to about 10 g/kg body weight.

Pharmaceutical Composition r aspect of the present invention provides pharmaceutical compositions which comprises a compound of a I (or a pharmaceutically acceptable salt or solvate thereof) and a ceutically acceptable carrier. The term sition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the ceutical compositions of the present invention encompass any composition made by admixing a compound of Formula 1, additional active ient(s), and pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present invention compiise a compound represented by Formula I (or a pharmaceutically acceptable salt or solvate thereof) as an active ingredient, a pharmaceutically acceptable earlier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions le for oral, rectal, l, and parenteral (including aneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be iently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, troches, dragees, granules and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions. The active ingredient can also be administered parenterally, in sterile liquid dosage forms, such as dispersions, suspensions or solutions. Other dosages forms that can also be used to administer the active ingredient as an ointment, cream, drops, transdermal patch or powder for topical administration, as an ophthalmic solution or suspension formation, i.e., eye drops, for ocular administration, as an aerosol spray or powder composition for inhalation or intranasal administration, or as a cream, ointment, spray or suppository for rectal or vaginal administration.

For topical ations, the active ingredient or a pharmaceutical composition thereof can be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the active ingredient or a pharmaceutical ition thereof include, but are not limited to, mineral oil, liquid atum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax, sugars such as lactose and water. atively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active ingredient or a pharmaceutical composition thereof suspended or dissolved in one or more pharmaceutically acceptable carriers. le rs include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

Depending on the particular condition, disorder or disease to be d, additional therapeutic agents can be administered together with the active ient or a pharmaceutical composition thereof. Those onal agents can be stered sequentially in any order, as part of a multiple dosage regimen, from the active ingredient or a pharmaceutical composition thereof (consecutive or intermittent administration). Alternatively, those agents can be part of a single dosage form, mixed together with the active ingredient or a pharmaceutical composition f (simultaneous or concurrent administration).

For oral administration, a pharmaceutical ition useful in the invention can take the form of solutions, suspensions, tablets, pills, capsules, powders, granules, semisolids, sustained release formulations, elixirs, aerosols, and the like. Tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate are employed along with various disintegrants such as starch, preferably potato or tapioca starch, and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia, Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type are also employed as fillers in soft and hard-filled gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral stration, t the active ingredient or a ceutical composition thereof of this invention can be ed with various sweetening agents, ng agents, ng agents, emulsifying agents and/or suspending agents, as well as such diluents as water, ethanol, ene glycol, glycerin and various like combinations thereof.

The term "parenteral" as used herein refers to modes of administration which include intravenous, uscular, intraperitoneal, intrasternal, subcutaneous, intramedullary and intraarticular injection and infusion. A pharmaceutical composition for parenteral injection can comprise pharrnaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Aqueous solutions are especially suitable for enous, intramuscular, subcutaneous and eritoneal injection purposes. In this connection, the sterile aqueous media employed are all readily obtainable by standard techniques well-known to those skilled in the art. Examples of suitable s and nonaqueous carriers, ts, solvents or vehicles include water, l, polyols (such as glycerol, propylene glycol, hylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable c esters such as ethyl oleate. Proper fluidity can be maintained, for e, by the use of coating materials such as in, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

The pharmaceutical compositions useful in the present invention can also contain adjuvants such as, but not limited to, preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, such as for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be t about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin.

Administration by slow infusion is particularly useful when intrathecal or epidural routes are employed. A number of implantable or body-mountable pumps useful in delivering compound at a regulated rate are known in the art.

Suspensions, in addition to the active compounds, can contain suspending agents as, for example, ethoxylated isostearyl alcohols, yethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and es thereof.

For es of transdermal (e.g., l) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise r to the above parenteral solutions, are prepared.

The pharmaceutical compositions useful in the invention can also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well- known in the art of ceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents. itions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the active ingredient or a pharmaceutical composition thereof with suitable non-irritating excipients or rs such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the drugs.

Other pharmaceutically able carriers include, but are not limited to, a non- toxic solid, semisolid or liquid filler, t, encapsulating al or formulation auxiliary of any type, including but not limited to ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride es of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, dal silica, ium trisilicate, polyvinyl idone, cellulose—based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block rs, hylene glycol and wool fat.

Solid pharmaceutical excipients e, but are not limited to, starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients can be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e. g., peanut oil, n oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

Methods of preparing s pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W. Martin, Mack Publishing Company, 19th ed. 1995.

Without further elaboration, it is believed that one skilled in the art can utilize the present invention to its fullest extent on the basis of the preceding ption. The following examples are, therefore, to be ued as merely illustrative and not a limitation of the scope of the t invention in any way.

Examples Example 1-1 NCTU-SUN-21122: _(2-(((4-methoxy—3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S—yl acetate) O N \ / To a solution of RS-D7 (0.1 g, 0.30 mmol) in DCM (10 mL) was added NaOH (0.90 mmol) and the reaction mixture was stirred for 5-10 minutes in the nitrogen. Then acetyl chloride (0.60 mmol) was added at 0 °C (in the ice bath). After stirring for 5-10 minutes, the reaction was allowed to warm to room ature and d further for 1 hour.

The reaction was extracted with ethyl acetate and pure water. The organic layer was dried over MgSO4, d and concentrated to give the reaction mixture. The reaction mixture was purified by silica-gel column tography to obtain the pure product. 1H NMR (400 MHz, Acetone-d6) 8 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).

LRMS (ESE) m/z : 374.1 (M+H)+.

Example 1-2 NCTU-SUN-21124: 4-methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl benzoate) Except that acetyl chloride is replaced by benzyl chloride, the other reactants and ation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 6 8.24 (s, 1H), 8.22 (d, J = 1.4 H z, 1H), 8.18 (s 1H), 7.78 — 7.71 (m, 2H), 7.65 — 7.59 (m, 3H), 7.27 (dd, J: 8.8, 2.2 Hz, 1H), 4.74 (s, 2H), 3.76 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H).

LRMS (ESP) m/Z : 436.2 (M+H)+.

Example 1-3 NCTU-SUN-26096: (2—(((4—meth0xy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S-yl butyrate) mug—b / Except that acetyl chloride is replaced by butyryl chloride, the other reactants and preparation steps are similar to those bed in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d6) 8 8.17 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.43 (d, J: 2.0 Hz, 1H), 7.08 (dd, J: 8.7,2.1Hz, 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).

LRMS (ESF) m/z : 402.1 (M+H)+.

Example 1-4 UN-26097: (2-(((4-methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)-1H-benzo[d]imidazol-S-yl cyclohexanecarboxylate) 03011?ng Except that acetyl chloride is replaced by drobenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 8 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).

LRMS (ESE) m/z : 442.2 (M+H)+.

Example 1-5 NCTU-SUN-26098: (2-(((4-methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)-lH-benzo[d]imidazol-S-yl 4-butylbenzoate) mougyé—bi Except that acetyl de is replaced by 4—Butylbenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title 1H NMR (400 MHz, Acetone-d6) 5 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),O.95(t,J=7.3Hz,3H).

LRMS (ESF) m/z ; 492.1 (M+H)+.

Example 1-6 NCTU-SUN-21127: (2—(((4—methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl 3-methylbenzoate) Except that acetyl chloride is replaced by m-Toluoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 6 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).

LRMS (ESE) m/z : 450.1 (M+H)+.

Example 1-7 NCTU-SUN-27076: 2—(((4—methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl hexanoate Except that acetyl chloride is replaced by hexanoyl de, the other nts and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 5 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).

LRMS (ESE) m/z : 430.2 (M+H)+.

Example 1-8 NCTU-SUN-27077: 2—(((4—meth0xy—3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl yrate *tfilrfm Except that acetyl chloride is replaced by isobutyryl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d6) 8 8.17 (s, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.44 (d, J: 2.1 Hz, 1H), 7.08 (dd, J: 8.7,2.1Hz,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).

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

Example 1-9 UN-27078: (2—(((4—methoxy-3,5—dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl cyclohexenecarb0xylate) UN/>_‘b \ / Except that acetyl de is ed by cyclohexenecarbonyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, e—d6) 8 8.17 (s, 1H), 7.66 (d, J: 8.2 Hz, 1H), 7.42 (s, 1H), 7.07 (dd, J= 8.7, 1.8 Hz, 1H), 5.74 (s, 2H), 4.78 (d, J= 13.6 Hz, 1H), 4.73 (d, J= 13.7 Hz, 1H), 3.70 (s, 3H), 2.96 — 2.80 (m, 2H), 2.54 — 2.30 (m, 3H), 2.22 (d, J= 2.6 Hz, 6H), 1.95 — 1.72 (m, 2H).

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

Example 1-10 NCTU-SUN-27079: 2—(((4—meth0xy-3,5-dimethylpyridin yl)methyl)sulfinyl)—1H-benzo[d]imidaz0lyl cyclohexenecarboxylate Crowd} Except that acetyl chloride is replaced by 2-methylbenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. ] 1H NMR (400 MHz, Acetone—d6) 8 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).

LRMS (ESF) m/z : 450.1 (M+H)+.

Example 1-11 NCTU-SUN-28087: (2—(((4—methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH—benzo[d]imidazol-S—yl 4-methylbenzoate) @013wa Except that acetyl chloride is replaced by 4-methylbenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 8 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).

LRMS (ESF) m/z : 450.1 (M+H)+.

Example 1-12 UN-2809l: (2—(((4—methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)-1H-benzo[d]imidazol-S-yl 0benzoate) NO2 \o 9:7UQ—way‘b Except that acetyl chloride is replaced by 2—nitrobenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d6) 6 8.16 (d, J : 5.9Hz, 2H), 8.10 (d, J: 7.3 Hz, 1H), 7.96 (td, J: 7.5, 1.8 Hz, 1H), 7.91 (td, J: 7.8, 1.8 Hz, 1H), 7.74 (dd, J: 8.7, 1.5 Hz, 1H), 7.61 (s, 1H), 7.24 (d, J: 8.4 Hz, 1H), 4.75 (dd, J: 13.7, 5.7 Hz, 2H), 3.69 (s, 3H), 2.20 (s, 6H).

LRMS (ESF) m/Z ; 481.2 (M+H)+.

Example 1-13 NCTU-SUN-28092: (2-(((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S—yl cyclopropanecarboxylate) “@1860‘b Except that acetyl chloride is replaced by cyclopropanecarbonyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, e—d6) 6 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, 25 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).

] LRMS (ESP) m/Z : 400.2 (M+H)+.

Example 1-14 NCTU-SUN-28093: 4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S—yl 2—ethylbutanoate) grow)? Except that acetyl chloride is replaced by 2-ethy1butanoy1 chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d6) 6 8.15 (s, 1H), 7.64 (d, J= 8.7 Hz, 1H), 7.39 (d, J: 2.2 Hz, 1H), 7.05 (dd, J: 8.8, 2.2 Hz, 1H), 4.81 (dd, J: 28.8, 13.7 Hz, 2H), 3.65 (s, 3H),2.51 (tt, J = 8.6, 5.5 Hz, 1H), 2.19 (s, 3H), 2.18 (s, 3H), 1.74 (m, 4H), 1.04 (t, 7.5Hz, LRMS (ESP) m/z : 430.2 (M+H)+.

Example 1-15 NCTU-SUN-28094: (2—(((4—methoxy-3,S-dimethylpyridin-Z- hyl)sulfinyl)—1H-benzo[d]imidazol-S—yl 2—phenylacetate) mocrHC/r ] Except that acetyl chloride is replaced by 2-pheny1acety1 chloride, the other reactants and preparation steps are similar to those bed in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 5 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).

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

Example 1-16 NCTU-SUN-28095: (2-(((4-methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)-1H-benz0[d] imidazol-S-yl 3,5,5-trimethylhexanoate Except that acetyl de is replaced by 3,5,5-trimethylhexanoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title nd. 1H NMR (400 MHz, Acetone—d6) 8 8.15 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.40 (s,1H), 7.09 (dd, J: 8.8, 2.2 Hz, 1H), 4.80 (dd, J: 29.0, 13.7 Hz, 2H), 3.65 (s, 3H), 2.61 (dd, J: 15.0, 6.2 Hz, 1H), 2.44 (dd, J: 15.0, 7.9 Hz, 1H), 2.19 (m, 1H), 2.19 (s, 3H), 2.18 (s, 3H), 1.43 (dd, J: 14.1, 4.0 Hz, 1H), 1.23 (dd, J=14.1, 6.5 Hz, 1H), 1.12 (d, J: 6.7 Hz, 3H), 0.97 (s, 9H).

LRMS (ESF) m/z : 472.1 (M+H)+.

Example 1-17 NCTU-SUN-28096: (2-(((5-methoxy-4,6-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl 2—eth0xybenz0ate) $003? ] Except that acetyl chloride is replaced by 2—ethoxybenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d6) 5 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) LRMS (ESF) m/z ; 480.1 (M+H)+.

Example 1-18NCTU-SUN-21123: (2-(((4-methoxy-3,5-dimethylpyridin-Z- hyl)sulfinyl)—1H-benz0[d]imidazol-S—yl propionate) 960385} Except that acetyl chloride is replaced by propionyl chlonde, the other nts and preparation steps are similar to those described in Example 1 to afford the title compound. ] 1H NMR (400 MHz, Acetone-d6) 8 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).

LRMS (ESE) m/z : 388.2 (M+H)+.

Example 1-19NCTU-SUN-21125: (2-(((4-methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S—yl robenzoate) CI 0— O N\ 5767 Except that acetyl chloride is replaced by 4—chlorobenzoyl chloride, the other nts and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 6 8.33 — 8.12 (m, 1H), 7.76 (d, J = 8.7 Hz, 0H), 7.72 — 7.61 (m, 1H), 7.27 (dd, J: 8.7, 2.2 Hz, 0H), 4.74 (s, 1H), 3.76 (s, 1H), 2.25 (d, J: 6.00Hz, 2H).

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

Example 1-20 NCTU-SUN-21126: 4—methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S-yl 3-nitrobenz0ate) H _ UQ— ‘b / Except that acetyl chloride is replaced by 3—nitrobenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d6) 5 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).

LRMS (ESF) m/z : 481.2 .

Example 1-21 NCTU-SUN-21128: 2—(((4—meth0xy-3,5-dimethylpyridin yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl heptanoate Wm». / Except that acetyl chloride is replaced by heptanoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d6) 5 8.1? (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).

LRMS (ESF) m/z : 444.3 (M+H)+.

Example 1-22 NCTU-SUN-21129: (2—(((4—methoxy-3,5—dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl 4-flu0r0benz0ate) F o— \OE UNy— \b0 N {—m Except that acetyl chloride is replaced by 4-fluorobenzoyl de, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, e-d6) 5 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).

LRMS (ESE) m/z ; 454.1 (M+H)+.

Example 1-23 NCTU-SUN-21130: 4—methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S—yl (Z)—2—methylbut-Z-enoate) draw? Except that acetyl chloride is replaced by methy1butenoyl chloride, the other reactants and preparation steps are similar to those bed in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d6) 8 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).

] LRMS (ESE) m/z : 414.2 (M+H)+.

Example 1-24 NCTU-SUN-21131: 4-methoxy-3,5-dimethylpyridin-Z- hyl)sulfinyl)—1H-benz0[d]imidazol-S—yl 2-chloropropanoate) 266585?CI _ Except that acetyl chloride is replaced by 2—chloropropanoyl chlon'de, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 6 8.16 (s, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.54 — 7.40 (m, 1H), 7.13 (dd, J: 8.7, 2.0 Hz, 1H), 4.91 (d, J: 6.8 Hz, 1H), 4.75 (d, J: 4.1 Hz, 2H), 3.71 (s, 4H), 2.22 (s, 6H), 1.83 (d, J = 6.8 Hz, 4H).

LRMS (ESP) m/Z : 422.1 (M+H)+.

Example 1-25 NCTU-SUN-21132: utyl (2—(((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl) carbonate [300/ Ur \ \ / Except that acetyl chloride is replaced by tert-butyl carbonochloridate, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d5) 8 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).

LRMS (ESF) m/z : 432.2 (M+H)+.

Example 1-26 NCTU-SUN-12124: (2—(((4—methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl (Z)—but—2-en0ate) We _O.

Except that acetyl de is replaced by (Z)-butenoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d6) 5 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).

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

Example 1-27 NCTU-SUN-12125: (2—(((4—meth0xy-3,5-dimethylpyridin yl)methyl)sulfinyl)—1H—benzo[d]imidazol-S—yl 3—methylbutenoate) O O— (ZrN \ \ / Except that acetyl chloride is replaced by 3-methylbutenoyl de, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. ] 1H NMR (400 MHz, Acetone—d5) 8 8.18 (s, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.45 (d, J: 2.0 Hz, 1H), 7.09 (dd, J: 87,21 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).

LRMS (ESF) m/z : 414.2 (M+H)+.

Example 1-28 UN-12122: (2—(((4—methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)-1H-benzo[d] imidazol-S-yl furan-Z-carboxylate) / i O O— \ / N ‘b Except that acetyl chloride is replaced by furancarbonyl chloride, the other reactants and ation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d5) 8 8.18 (s, 1H), 7.96 (dd, J = 1.8, 0.8 Hz, 1H), 7.74 (d, J: 8.8 Hz, 1H), 7.60 (d, J: 2.1Hz, 1H), 7.51 (dd, J: 3.5, 0.8 Hz, 1H), 7.24 (dd, J: 8.8, 2.1 Hz, 1H), 6.77 (dd, J: 3.5, 1.8 Hz, 1H), 4.74 (q, J: 13.6 Hz, 2H), 3.75 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H).

LRMS (ESE) m/z : 426.1 (M+H)+.

Example 1-29 NCTU-SUN-12123: (2-(((4-methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)-1H-benzo[d]imidazolyl acrylate) O 0— flf — U”>— \b Except that acetyl chloride is replaced by acryloyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title nd. 1H NMR (400 MHz, Acetone-d6) d 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).

LRMS (ESF) m/Z ; 386.1 (M+H)+.

Example 1-30 NCTU-SUN-12127: (2-(((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S—yl ylbutanoate) Quid 0— Except that acetyl chloride is ed by 2-methylbutanoyl chlon'de, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. ] 1H NMR (400 MHz, Acetone—d6) 6 8.17 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.07 (dd, J: 8.7, 1.9 Hz, 1H), 4.80 — 4.68 (q, J: 13.6 Hz, 2H), 3.72 (s, 3H), 2.75 — 2.63 (m, 1H), 2.23 (s, 6H), 1.89 — 1.77 (m, 1H), 1.71 — 1.60 (m, 1H), 1.29 (d, J: 7.0 Hz, 4H), 1.04 (t, J: 7.4 Hz, 3H).

LRMS (ESE) m/z : 416.1 (M+H)+.

Example 1-31 NCTU-SUN-12128: (2-(((4-methoxy-3,5-dimethylpyridin yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl 3-cyclopentylpropanoate) Except that acetyl chloride is replaced by cyclopentanecarbonyl chloride, the other reactants and preparation steps are r to those described in e 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 6 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).

LRMS (ESP) m/Z : 456.1 (M+H)+.

Example 1-32 UN-12129: (2-(((4—methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-5—yl (E)(2-chlor0phenyl)acrylate) (1:? O— O N / \©:N>— \b\ f0 Except that acetyl chloride is replaced by 2-chlorobenzoyl chloride, the other nts and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d5) 5 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).

LRMS (ESP) m/z : 496.0 (M+H)+.

Example 1-33 NCTU-SUN-12130: (2—(((4—meth0xy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H—benzo[d]imidazol-S—yl 6—br0m0hexan0ate) Br/\/\/\g/ Org—biN Except that acetyl chloride is replaced by 6-bromohexanoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. ] 1H NMR (400 MHz, Acetone-d6) 5 8.17 (s, 1H), 7.68 (d, J: 8.5 Hz, 1H), 7.44 (d, J= 2.3 Hz, 1H), 7.09 (dd, J= 8.8, 2.2 Hz, 0H), 4.77 — 4.68 (q, J= 13.6, 2H), 3.74 (s, 3H), 3.55 (t, J= 6.7 Hz, 2H), 2.66 (t, J= 7.4 Hz, 2H), 2.35 (s, 6H) 1.99 — 1.91 (m, 2H), 1.84-1.76 (m, 2H), 1.66 — 1.56 (m, 2H).

LRMS (ESP) m/z : 508.1 (M+H)+.

Example 1-34 NCTU-SUN-11021: (2—(((4—meth0xy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H—benzo[d]imidazol-S—yl Z-fluorobenzoate) F \0 Gray??? Except that acetyl chloride is replaced by 2-fluorobenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d5) 8 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).

LRMS (ESF) m/z : 454.1 (M+H)+.

Example 1-35 NCTU-SUN-11020: (2—(((4—methoxy-3,5-dimethylpyridin yl)methyl)sulfinyl)—lH—benzo[d]imidazol-S—yl 4-methoxybenzoate) O N f6, ] Except that acetyl chloride is ed by 4—methoxybenzoyl chloride, the other nts and preparation steps are similar to those bed in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d6) 8 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).

LRMS (ESE) m/z : 466.2 .

Example 1-36 NCTU-SUN-11022: (2—(((4-methoxy-3,5-dimethylpyridin yl)methyl)sulfinyl)—1H-benz0[d]imidazol-S—yl (3r,5r,’7r)-adamantane—l-carboxylate) @OHHU\o Except that acetyl chloride is replaced by adamantane-l-carbonyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title nd. 1H NMR (400 MHz, Acetone—d6) 6 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) LRMS (ESP) m/Z : 494.2 (M+H)+.

Example 1-37 NCTU-SUN-11023: (2-(((4—methoxy-3,S-dimethylpyridin-Z- hyl)sulfinyl)—1H—benzo[d]imidazol-S-yl isoxazole—S-carboxylate) ‘0 N\ IE}\ / Except that acetyl chloride is replaced by isoxazole-S-carbonyl chloride, the other reactants and preparation steps are similar to those bed in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 8 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).

LRMS (ESI+) m/z : 427 .0 (M+H)+.

Example 1-38 NCTU-SUN-11030: (2—(((4—meth0xy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H—benzo[d]imidazol-S—yl 4—(tert—butyl)benzoate) Except that acetyl chloride is replaced by 4-(tert-butyl)benzoyl de, the other reactants and preparation steps are similar to those bed in Example 1 to afford the title compound. 1H NMR (400 MHz, Methanol—d4) 8 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).

LRMS (1381+) m/z : 492.1 (M+H)+. e 1-39 NCTU-SUN-11031: (2—(((4—meth0xy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S—yl 3-chl0r0fluorobenzoate) 803380283? Except that acetyl chloride is replaced by 4-chlorofluorobenzoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 8 8.34 (dd, J = 7.2, 2.2 Hz, 1H), 8.24 (ddd, J = 8.7, 4.7, 2.2 Hz, 1H), 8.18 (t, J: 0.8 Hz, 1H), 7.76 (dd, J: 8.8, 0.6 Hz, 1H), 7.65 (dd, J: 2.3, 0.6 Hz, 1H), 7.58 (t, J: 8.8 Hz, 1H), 7.28 (dd, J: 8.8, 2.2 Hz, 1H), 4.74 (s, 2H), 3.76 (s, 2H), 2.26 (s, 3H), 2.24 (s, 3H).

LRMS (ESF) m/z : 488.0 (M+H)+.

Example 1-40 NCTU-SUN-25015: (2—(((4—methoxy-3,5-dimethylpyridin-Z- hyl)sulfinyl)—lH-benzo[d]imidazol-S—yl pivalate) $803833“ Except that acetyl chloride is replaced by pivaloyl chlon'de, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d6) 8 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).

LRMS (ESE) m/z : 416.1 (M+H)+.

Example 1-41 NCTU-SUN-25016: (2—(((4-methoxy-3,5-dimethylpyridin hyl)sulfinyl)—1H-benz0[d]imidazol-S—yl pentanoate) WOUE>—f©¥‘23 Except that acetyl de is replaced by pentanoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. ] 1H NMR (400 MHz, Acetone—d6) 6 8.16 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.41 (d, J: 2.1 Hz, 1H), 7.07 (dd, J: 8.9, 2.1 Hz, 1H), 5.62 (s, 1H), 4.96 — 4.55 (m, 2H), 3.69 (s, 3H), 2.62 (t, J: 7.5 Hz, 2H), 2.21 (d, J: 3.3 Hz, 6H), 1.83 — 1.64 (m, 2H), 1.46 (q, J: 7.4 Hz, 2H), 0.97 (t, J: 7.4 Hz, 3H). [0019s] LRMS (ESE) m/z : 416.1 (M+H)+.

Example 1-42 NCTU-SUN-25017: (2-(((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl 4-nitrobenzoate) 2 @6616)? Except that acetyl chloride is replaced by 4-nitrobenzoy1 chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, e-d6) 8 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).

LRMS (ESE) m/z : 481.2 (M+H)+.

Example 1-43 NCTU-SUN-25027: (2—(((4—meth0xy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H—benzo[d]imidazol-S—yl cyclobutanecarboxylate) SWIM?‘b Except that acetyl chloride is replaced by cyclobutanecarbonyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. ] 1H NMR (400 MHz, Acetone—d6) 8 8.17 (s, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.44 (d, J= 2.2 Hz, 1H), 7.09 (dd, J= 8.8, 2.2 Hz, 1H), 4.71 (s, 2H), 3.75 (s, 3H), 3.48 (t, J= 8.6 Hz, 1H), 2.39 (dt, J= 29.5, 9.1 Hz, 4H), 2.24 (d, J= 2.9 Hz, 5H), 2.05 (m, J= 2.4 Hz, 2H).

LRMS (ESF) m/z : 414.2 (M+H)+.

Example 1-44 NCTU-SUN-25028: (2—(((4—meth0xy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H—benzo[d]imidazol-S—yl thiophene-Z-carboxylate) (jjl/Umy‘bQ 0 N sci? Except that acetyl chloride is replaced by enecarbonyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. ] 1H NMR (400 MHz, Acetone—d6) 8 8.18 (s, 1H), 8.04 (dd, J = 3.8, 1.4 Hz, 1H), 7.99 (dd, J: 5.0, 1.4 Hz, 1H), 7.74 (d, J: 8.8 Hz, 1H), 7.62 (d, J: 2.1 Hz, 1H), 7.32 (dd, J: .1, 3.7 Hz, 1H), 7.25 (dd, J: 8,8, 2.2 Hz, 1H), 4.75 (d,J= 2.1 Hz, 2H), 3.74 (d, J: 1.7 Hz, 3H), 2.24 (d, J: 5.4 Hz, 6H), LRMS (ESF) m/z : 442.2 (M+H)+.

Example 1-45 NCTU-SUN-25029: (2-(((4-methoxy-3,5-dimethylpyridin yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl 2-methylbutanoate) Except that acetyl chloride is replaced by 2-methylbutanoyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 8 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).

LRMS (ESE) m/z : 416.1 (M+H)+. e 1-46 NCTU-SUN-25030: (2-(((4-methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)-lH-benzo[d]imidazol-S-yl 3,3-dimethylbutanoate) $33075? Except that acetyl chloride is replaced by methylbutanoyl chloride, the other reactants and ation steps are similar to those bed in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d6) 5 8.17 (s, 1H), 7.69 (dd, J = 8.7, 0.6 Hz, 1H), 7.43 (dd, J: 2.2, 0.6 Hz, 1H), 7.08 (dd, J: 8.7, 2.2 Hz, 1H), 4.72 (d, J: 1.6 Hz, 2H), 3.74 (s, 3H), 2.50 (s, 2H), 2.24 (d, J = 1.3 Hz, 6H), 1.15 (s, 9H).

LRMS (ESF) m/Z ; 430.1 (M+H)+.

Example 1-47 UN-2503l: (2—(((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl 2-methoxyacetate) \ “Kb 070,». / Except that acetyl chloride is replaced by 2-methoxyacetyl chloride, the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 6 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).

] LRMS (ESF) m/Z : 404.0 (M+H)+.

Example 1-48 NCTU-SUN-25032 (ethyl (2-(((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-5—yl) carbonate) \/0 O N\ {—67 Except that acetyl chloride is replaced by ethyl carbonochloridate the other reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 6 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).

LRMS (ESP) m/Z : 404.0 (M+H)+.

Example 2-1 26065: Methyl 1-(furan-2—ylmethyl)—2—(((4-methoxy-3,5-dimethylpyridin-Z- yl)methyl)amino)—1H-benzo[d]imidazole—S-carboxylate \O*ElrN\ A?\ / To a solution of 4-fluoronitrobenzoic acid 1 (5.0 g, 27.0 mmol) in dry MeOH (30 mL), H2804 (5 mL, 0.3 M) was added and the reaction mixture was heated to reflux for 12 h. The solvent was removed under reduced pressure, crude on mixture was dissolved in EtOAc (150 mL), washed with saturated NaHCO3 (20 mL X 2), water (10 mL X 2) and brine (10 mL). The EtOAc layer was dried over anhydrous MgSO4 and evaporated to get methyl 4-fluoronitrobenzoate 2 (95%) as a white solid.

Compound 2 (2.0 g, 10.2 mmol) and omethy1furan (3 equiv.) in dry CH2C12 (50 mL) were stirred at room temperature for 2 h. Upon completion of reaction the solvent was removed and the crude t was purified by flash column chromatography to afford nitro benzoates 3 ( 90%).

To a on of nd 3 (2.0 g, 4.8 mmol) in dry MeOH (100 mL), zinc dust (15 equiv, 71.4 mmol) and ammonium formate (7.5 equiv, 35.7 mmol) were added and the resulting reaction mixture was stirred at room temperature for 30 min. Upon completion of on, Zn dust was filtered through a bed of celite, filtrate was evaporated and the product was dissolved in CH2C12 (100 mL). The precipitated ammonium formate was filtered off and the solvent was evaporated to furnish compound 4 (92 %).

] Use DCM to dissolve compound 4 (1.0 g, 4.0 mmol) then add 1.2 equiv. CNBr to react at room ature. After 8 hours the mixture can be extracted with DCM and water.

The solvent was removed and the crude product was purified by flash column chromatography to afford 5 ( 60%) To a solution of methyl 2-amino(furanylmethyl)-1H-benzo[d]imidazole carboxylate 5 (0.05 g, 0.18 mmol) in iritle (10 mL) was added K2CO3 (0.0497 g, 0.36 mmol) and KI (0.0089 g, 0.054 mmol) ed by 2—(chloromethyl)methoxy-3,5- dimethylpyridine 6 (0.041 g, 0.22 mmol) and the reaction mixture was allowed to reflux for six hours. After 6 h, the solvent was evaporated and the reaction mixture was diluted with saturated aq. NaHCO3 (10 mL) and ted with EtOAc (3* 10 mL).

The combined organic phase was washed with saturated brine (30 mL). The crude product was purified by silica-gel column chromatography using 8 % methanol/ EtOAc to obtain the pure product NCTU-SUN-26065 as a white solid 0.053 g (71 %). 1H NMR (400 MHz, Chloroform-d) 5 8.34 (s, 1H), 7.83 (dd, J = 8.3, 1.4 Hz, 1H), 7.73 (d, J: 1.2 Hz, 1H), 7.34 (dd, J: 1.8, 0.7 Hz, 1H), 7.13 (d, J: 8.3 Hz, 1H), 6.37 (d, J: 3.3 Hz, 1H), 6.32 (dd, J: 3.2, 1.9 Hz, 1H), 5.42 (s, 2H), 5.10 (s, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H), 13C NMR (101 MHz, Chloroform-d) 5 166.75 , 153.88, 142.73 109.61 , 133.38, , 124.86, 124.00, 110.60, , 109.04, , 77.22, 61.46, 52.24, 38.50, 31.90, 29.67, 29.33 LRMS (ESI+) : m/z 422.3 , 22.66, 14.64, 14.09, 11.39, (M+H)+.

Example 2-2 21098: Methyl 2-(((4-methoxy-3,5-dimethylpyridin yl)methyl)amin0)— l-propyl-IH-benzo[d]imidazole—S-carboxylate \O)K©:E>—r\d-l—©i Except that amine is ed by propan—l—amine, the other reactants and preparation steps are similar to those described in Example 2-1 to afford the title compound. 1H NMR (400 MHz, Methanol-d4) 8 7.96 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.42 (d, J: 8.4 Hz, 1H), 5.41 (s, 2H), 4.09 (t, J: 7.4 Hz, 2H), 3.81 (d, J: 13.8 Hz, 6H), 2.34 (s, 3H), 2.20 (s, 3H), 1.85 (d, J: 7.9 Hz, 2H), 1.02 (t, J: 7.4 Hz, 3H), 13C NMR (101 MHz, Methanol-d4) 6 164.54, 14832, 134.44 126.25 124.43 109.95 108.43 , , 124.69, , , , 59.29 51.27 45.10 43.91 29.31 20.86 ,11.90 9.78 9.16 : m/z 383.3 , , , , , , , ; LRMS (ESI+) (M+H)+.

Example 2-3 21103: Methyl 2-(((4-methoxy-3,5—dimethylpyridinyl)methyl)amino)—1- (3-meth0xypr0pyl)—lH-benzo[d]imidazole—S-carboxylate Except that amine is replaced by 3—methoxypropanamine, the other reactants and preparation steps are r to those described in Example 2-1 to afford the title compound. ] 1H NMR (400 MHz, Methanol-d4) 6 8.10 (s, 1H), 7.90 (t, J: 1.8 Hz, 1H), 7.67 (dt, J: 8.4, 1.9 Hz, 1H), 7.11 (dd, J: 8.4, 2.1 Hz, 1H), 4.58 (d, J: 2.1 Hz, 2H), 4.09 — 4.01 (m, 2H), 3.82 (d, J: 2.1 Hz, 3H), 3.73 (d, J: 2.1 Hz, 3H), 3.19 (d, J: 2.1 Hz, 3H), 2.19 (dd, J: 10.1, 2.1 Hz, 6H), 1.96 (p, J: 6.2 Hz, 2H); 13C NMR (101 MHz, Methanol-d4) 5 167.93 164.20,155.50,153.88,147.84,141.23 ,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)+, Example 2-4 26070: 1-(furanylmethyl)—2—(((4—methoxy-3,5-dimethylpyridin yl)methyl)amino)—1H-benzo[d]imidazole—S-carboxylic acid 0 N *Cmflk/_\ HO N\ To a solution of o—3—nitrobenzoic acid 1 (5.0 g, 27.0 mmol) in dry MeOH (30 mL), H2804 (5 mL, 0.3 M) was added and the reaction mixture was heated to reflux for 12 h. The solvent was removed under reduced re, crude on e was dissolved in EtOAc (150 mL), washed with saturated NaHCO3 (20 mL X 2), water (10 mL X 2) and brine (10 mL). The EtOAc layer was dried over anhydrous MgSO4 and evaporated to get methyl onitrobenzoate 2 (95%) as a white solid.

Compound 2 (2.0 g, 10.2 mmol) and furanylmethanamine (3 ) in dry CH2C12 (50 mL) were stirred at room temperature for 2 h. Upon completion of reaction the solvent was removed and the crude product was purified by flash column chromatography to afford nitro benzoates 3 (90%).

To a solution of compound 3 (2.0 g, 4.8 mmol) in dry MeOH (100 mL), zinc dust (15 equiv, 71.4 mmol) and ammonium formate (7.5 equiv, 35.7 mmol) were added and the resulting reaction mixture was stirred at room temperature for 30 min. Upon completion of reaction, Zn dust was filtered through a bed of celite, filtrate was evaporated and the product was dissolved in CH2C12 (100 mL). The precipitated ammonium formate was filtered off and the solvent was evaporated to h compound 4 (92 %).

Use DCM to dissolve compound 4 (1.0 g, 4.0 mmol) then add 1.2 equiv. CNBr to react at room temperature. After 8 hours the mixture can be extracted with DCM and water.

The solvent was removed and the crude product was purified by flash column tography to afford 5 ( 60%) ] To a solution of methyl 2-amino—1-(furanylmethyl)-1H-benzo[d]imidazole carboxylate 5 (0.05 g, 0.18 mmol) in acetoniritle (10 mL) was added K2C03 (0.0497 g, 0.36 mmol) and K1 (0.0089 g, 0.054 mmol) followed by 2-(chloromethyl)methoxy-3,5- dimethylpyridine 6 (0.041 g, 0.22 mmol) and the reaction mixture was allowed to reflux for six hours. After 6 h, the solvent was evaporated and the reaction mixture was diluted with saturated aq. NaHC03 (10 mL) and extracted with EtOAc (3* 10 mL). The combined c phase was washed with saturated brine (30 mL). The crude product was purified by silica-gel column chromatography using 8 % methanol/ EtOAc to obtain Methyl 1—(furanylmethyl)- 2-(((4-methoxy-3,5-dimethylpyridin—2—yl)methyl)amino)—1H—benzo[d]imidazole carboxylate 7.

And add NaOH (0.0251 g, 0.63 mmol) to a solution of Methyl an ylmethyl)(((4—methoxy—3,5—dimethylpyridin—2—yl)methyl)amino)-1H-benzo[d]imidazole carboxylate 7 (0.053 g, 0.126 mmol) in the EtOH/HzO (1/ 1, 3mL) in the reflux condition.

After 1 h, the solvent was ated and the reaction mixture was diluted with saturated aq.

HCl (10 mL) and extracted with EtOAc (3* 10 mL). The combined organic phase was washed with saturated brine (10 mL). The crude product was purified by silica-gel column chromatography using 20 % methanol/ EtOAc to obtain the pure product as a white solid 0.030 g (65%).

LRMS (ESI+) ; m/z 407.2 (M+H)+.

Example 2-5 26066: Methyl 2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)amin0)—1- pentyl-lH-benzo [d]imidazole—S-carboxylate Except that amine is replaced by pentan—l—amine, the other reactants and preparation steps are similar to those described in Example 2-1 to afford the title compound. 1H NMR (400 MHz, Chloroform—d) 5 8.08 (s, 1H), 8.01 (dd, J = 8.4, 1.2 Hz, 1H), 7.72 (s, 1H), 7.29 (d, J = 8.5 Hz, 1H), 5.92 (s, 2H), 4.49 (t, J = 7.2 Hz, 2H), 3.89 (s, 6H), 2.47 (s, 3H), 2.26 (s, 3H), 1.96 — 1.83 (m, 2H), 1.54 — 1.41 (m, 2H), 1.44 — 1.29 (m, 2H), 0.88 (t, J = 7.2 Hz, 3H), LRMS (ESI+): m/z 411.2 .

Example 2-6 21102: 2-(((4-meth0xy-3,5—dimethylpyridinyl)methyl)amin0)—1-pr0pyl- 1H-benzo[d]imidazole-S-carboxylic acid Except that amine is replaced by propan-l-amine, the other nts and preparation steps are similar to those described in Example 2-4 to afford the title compound. 1H NMR (400 MHz, Methanol-6106 8.04 (d, J= 8.3 Hz, 1H), 7.95 (s, 1H), 7.89 (s, 1H), 7.64 (d, J= 8.1 Hz, 1H), 5.57 (s, 2H), 4.25 (t, J= 7.3 Hz, 2H), 3.83 (s, 3H), 2.41 (s, 3H), 2.21 (s, 3H), 1.92 (d, J: 7.3 Hz, 2H), 1.07 (t, J: 7.3 Hz, 3H); 13C NMR (101 MHz, Methanol-d4) 5 150.03, 148.40, 130.63, , , 111.55, 109.87, 59.38, 45.34, 44.56, .95, 11.93, 9.68, 9.17, LRMS (ESI+): m/z 369.2 (M+H)+.

Example 2-7 26071: Methyl 2-(((4-methoxy-3,5—dimethylpyridin-Z-yl)methyl)amin0)—1- (4-methoxybenzyl)—1H-benzo[d]imidazole—S-carboxylate Except that amine is replaced by (4-methoxyphenyl)methanamine, the other reactants and preparation steps are r to those described in Example 2-1 to afford the title compound. 1H NMR (400 MHz, Methanol—d4) 6 8.02 (s, 1H), 7.83 (dd, J =84, 1.5 Hz, 1H), 7.68 (d, J: 1.6 Hz, 1H), 7.29 (d, J: 8.7 Hz, 2H), 7.23 (d, J: 84 Hz, 1H), 6.92 (d, J: 8.7 Hz, 2H), 5.43 (s, 2H), 5.29 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 2.36 (s, 3H), 2.24 (s, 3H), LRMS (ESI+) : m/z 461.2 (M+H)+.

Example 2-8 21105: 2-(bis((4-meth0xy-3,5—dimethylpyridin-Z-yl)methyl)amin0)—1- (2- (cyclohex-l-enyl)ethyl)-1H-benzo[d]imidazole—S-carboxylic acid o / \ / Except that amine is replaced by 2—(cyclohexeny1)ethanamine, the other reactants and ation steps are similar to those described in Example 2-4 to afford the title compound. 1H NMR (400 MHz, Methanol-d4) 5 8.17 (s, 2H), 8.07 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.26 (d, J: 8.3 Hz, 1H), 5.13 (s, 1H), 4.77 (s, 4H), 4.11 (t, J: 7.8 Hz, 2H), 3.80 — 3.69 (m, 6H), 2.29 (t, J: 8.4 Hz, 2H), 2.18 (d, J: 21.8 Hz, 12H), 1.76 (s, 4H), 149 — 1.36 (m, 4H), 13C NMR (101 MHz, Methanol—d4) 8 156.95, 145.93, 139.17, 131.88, , 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)+. e 2-9 21104: 2-(bis((4-methoxy-3,5-dimethylpyridin-Z-yl)methyl)amin0)—1- (3- methoxypropyl)—1H-benzo[d]imidazole—S—carboxylic acid o / ”W118N N— Except that amine is replaced by 3—methoxypropanamine, the other reactants and preparation steps are r to those bed in Example 2-4 to afford the title compound. ] 1H NMR (400 MHz, DMSO-ds) 6 8.06 (s, 2H), 7.88 (d, J = 1.6 Hz, 1H), 7.68 (dd, J: 8.4, 1.6 Hz, 1H), 7.32 (d, J: 8.4 Hz, 1H), 4.65 (s, 4H), 4.17 (t, J: 7.6 Hz, 2H), 3.62 (s, 6H), 3.20 (t, J = 5.9 Hz, 2H), 3.09 (s, 3H), 2.10 (s, 6H), 2.05 (s, 6H), 1.94 — 1.88 (m, 2H), 13C NMR(101 MHz, DMSO-ds) 5 168.52, 163.68, 158.90, 155.26, 148.49, 141.33, 125.19, 125.04, 124.05, 122.18, 118.11, 109.15, 69.30, 60.07, 58.30, 54.87, 41.74, 29.10, 13.24, .68, LRMS (ESI+): m/z 548.3 (M+H)+.

Example 2-10 26076: 2-(((4-methoxy-3,5—dimethylpyridin-Z-yl)methyl)amin0)—1- pentyl-lH-benzo[d]imidazole—S-carboxylic acid HOJ\©:N\>_N{‘I—507N \ / Except that amine is replaced by pentan-l-amine, the other nts and preparation steps are similar to those described in Example 2-4 to afford the title compound. 1H NMR (400 MHz, DMSO—ds) 6 7.88 (s, 1H), 7.81 (dd, J = 8,2, 1.3 Hz, 1H), 7.70 (d, J: 1.6 Hz, 1H), 7.39 (d, J: 8.4 Hz, 2H), 5.59 (s, 2H), 4.23 (t, J: 6.9 Hz, 2H), 3.72 (s, 3H), 2.30 (s, 3H), 2.11 (s, 3H), 1.83 (s, 2H), 1.30 (dq, J: 6.7, 3.3 Hz, 4H), 0.90 — 0.73 (m, 3H) , LRMS (ESI+) : m/z 397.2 .

Example 2-11 26077: 2-(((4-methoxy-3,5—dimethylpyridin-Z-yl)methyl)amin0)—1- (4-methoxybenzyl)—1H-benzo[d]imidazole—S-carboxylic acid HOJUN \ \off?/H Except that amine is replaced by (4-methoxyphenyl)methanamine, the other reactants and preparation steps are similar to those described in Example 2-4 to afford the title compound.

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

Example 2-12 21 1 15: 2-(((4-meth0xy-3,5—dimethylpyridin-Z-yl)methyl)amin0)—1- (3-methoxypropyl)—1H-benzo[d]imidazole—S-carboxylic acid Except that amine is replaced by 3-methoxypropan—1-amine, the other reactants and preparation steps are r to those bed in Example 2-4 to afford the title compound. 1H NMR (400 MHz, Methanol—d4) 5 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); 13C NMR (101 MHz, Methanol-d4) 6 169.05,152.95,147.73, 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 10.48 , , , , , 28.74, 13.36, , LRMS (ESI+) ; m/z , 399.2 (M+H)+.

Example 2-13 21116: Methyl 1-(2-(cyclohexenyl)ethyl)—2-(((4-methoxy-3,5- dimethylpyridinyl)methyl)amino)—1H-benzo[d]imidazole-S-carboxylate Except that amine is replaced by 2-(cyclohexeny1)ethanamine, the other reactants and preparation steps are similar to those described in Example 2-1 to afford the title compound. 1H NMR (400 MHz, Acetone—d6) 6 8.20 (s, 1H), 7.94 (d, J = 1.4 Hz, 1H), 7.70 (dt, J: 8.2, 1.4 Hz, 1H), 7.22 (dd, J: 8.3, 1.2 Hz, 1H),6.71(s, 1H), 5.33 (dt, J: 4.8, 2.3 Hz, 1H), 4.68 (d, J: 3.7 Hz, 2H), 4.17 (td, J: 7.2, 1.2 Hz, 2H), 3.84 (d, J: 1.2 Hz, 3H), 3.79 (d, J = 1.2 Hz, 3H), 2.41 (t, J = 7.2 Hz, 2H), 2.28 (s, 3H), 2.23 (s, 3H), 2.04 (h, J = 1.8 Hz, 2H), 2.02 — 1.97 (m, 2H), 1.82 — 1.76 (m, 2H), 1.51 (t, J: 5.9 Hz, 2H), 1.42 — 1.37 (m, 2H), 13C NMR(101MHz,Acetone-d6)8167.29,163.89,155.45,154.37,148.O6,142.70,138.71, 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 28.11 ,24.91 22.61 21.81 9.35 , , 8.99, 28.79, , , , 12.36, . e 2-14 21117: 1-(2-(cyclohex-l-enyl)ethyl)—2-(((4-methoxy-3,5- dimethylpyridin-Z- yl)methyl)amino)—1H-benzo[d]imidazole-S-carboxylic acid Except that amine is replaced by loheX—1—eny1)ethanamine, the other reactants and ation steps are similar to those described in Example 2-4 to afford the title compound. 1H NMR (400 MHz, DMSO—d6) 6 8.15 (s, 1H), 7.70 (s, 1H), 7.56 (d, J = 8.2 Hz, 1H), 7.15 (d, J: 8.3 Hz, 1H), 7.08 (t, J: 5.3 Hz, 1H), 5.23 (s, 1H), 4.61 (d, J: 4.2 Hz, 2H), 4.12 (t, J: 7.1 Hz, 2H), 3.69 (s, 3H), 2.28 — 2.13 (m, 8H), 1.90 (s, 2H), 1.72 (s, 2H), 1.38 (dq, J: 31.9, 5.4 Hz, 4H), 13C NMR (101 MHz, DMSO-ds) 6 168.24 155.18 155.12 , , , 147.74,141.57,137.88,133.55,124.39,123.56,123.09,123.01,120.32,115.84, 106.77 59.43 45.42 40.30 35.64 27.52 24.33 12.55 9.85 , , , , , , , 21.97,21.29, , .

Example 2-15 21118: Methyl 2-(((4-methoxy-3,5-dimethylpyridin-Z- yl)methyl)amino)—1- phenethyl-1H-benzo[d]imidazole-S-carboxylate ] Except that amine is replaced by 2—phenylethanamine, the other reactants and preparation steps are similar to those described in Example 2-1 to afford the title compound. 1H NMR (400 MHz, Methanol—d4) 6 8.16 (s, 1H), 7.89 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.10 (dt, J: 16.2, 7.1 Hz, 5H), 6.99 (d, J: 8.2 Hz, 1H), 4.57 (s, 3H), 4.30 (t, J: 7.0 Hz, 2H), 3.82 (d, J: 25.8 Hz, 6H), 3.05 (t, J: 7.0 Hz, 2H), 2.29 — 2.20 (m, 6H), 13C NMR (101 MHz, Methanol-d4) 5 169.48, 165.74, 156.92, 155.57, 149.24, , 139.50, 139.30, 130.05, 129.59, 127.73 127.01 108.52 60.62 , , 125.84, 123.98, 122.90, 117.45, , , 52.38, 49.85 46.69 44.97 40.00 39.79 39.58 39.16 10.56 , , , , , , 39.37, , 35.62, 13.36, , LRMS (ESI+) : m/z 445.4 (M+H)+.

Example 2-16 21 1 19: 2-(((4-methoxy-3,5—dimethylpyridin-Z-yl)methyl)amin0)—1- phenethyl- 1H-benzo[d]imidazole—S-carboxylic acid HOJK©::\>7 \ / Except that amine is replaced by 2—phenylethanamine, the other nts and ation steps are similar to those described in Example 2-4 to afford the title compound. 1H NMR (400 MHz, ol—d4) 6 8.19 (s, 1H), 7.89 (d, J = 1.5 Hz, 1H), 7.79 (dd, J: 8.5, 1.7 Hz, 1H), 7.19 — 7.07 (m, 6H), 4.73 (s, 2H), 4.48 (t, J: 6.8 Hz, 2H), 3.87 (s, 3H), 3.16 (t, J: 6.8 Hz, 2H), 2.29 (d, J = 14.6 Hz, 6H); 13C NMR (101 MHz, Methanol-d4) 5 ,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, .68 .

Example 2-17 21120: 2-(bis((4-meth0xy-3,5—dimethylpyridin-Z-yl)methyl)amin0)— l-propyl- 1H-benzo[d]imidazole—S-carboxylic acid “Cirfi Except that amine is replaced by propan—l—amine, the other nts and preparation steps are similar to those bed in Example 2-4 to afford the title compound. 1H NMR (400 MHz, DMSO-ds) 6 8.09 (s, 2H), 7.88 (d, J = 1.6 Hz, 1H), 7.68 (dd, J: 8.3, 1.6 Hz, 1H), 7.39 (d, J: 8.4 Hz, 1H), 4.63 (s, 4H), 4.11 (t, J: 7.9 Hz, 2H), 3.62 (s, 6H), 2.08 (d, J: 17.4 Hz, 12H), 1.66 (d, J: 7.7 Hz, 2H), 0.73 (t, J: 7.3 Hz, 3H).

Example 2-18 21121: 2-(bis((4-methoxy—3,5-dimethylpyridin-Z-yl)methyl)amin0)— 1-phenethyl- 1H-benzo[d]imidazole—S-carboxylic acid Except that amine is replaced by 2-phenylethanamine, the other reactants and preparation steps are similar to those described in Example 2-4 to afford the title compound. 1H NMR (400 MHz, DMso—d6) 5 8.07 (s, 2H), 7.89 (d, J: 1.5 Hz, 1H), 7.67 (dd, J: 8.4, 1.7 Hz, 1H), 7.40 (d, J: 8.4 Hz, 1H), 7.19 — 7.13 (m, 3H), 7.10 — 7,05 (m, 2H), 4.64 (s, 4H), 4.39 (t, J: 8.0 Hz, 2H), 3.59 (s, 6H), 2.97 (t, J: 8.1 Hz, 2H), 2.07 (d, J: 11.5 Hz, 12H),13CNMR(101MHz,DMSO—d6)6168.15,163.34,154,81,148.03,140.97,138.79, ,128.79,128.39,126.52,124.88 124.76 109.35 59.74 , , 123.79, 122.04, 117.97, , 55.15 45.31 34.51 12.91 10.42 , , , , , .

Example 3-1 NCTU-SUN-26079 : Methyl anylmethyl)(((4-meth0xy-3,5- dimethylpyridinyl)methyl)amin0)-3,4-dihydroquinazolinecarboxylate O / N H I \O \I \N To a solution of 4—(bromomethyl)—3—nitrobenzoic acid 1 (5.0 g, 27.0 mmol) in dry MeOH/CHzClz (3 mL: 30 mL), was added DCC (1.2 equiv) and DMAP (0,005 equiv) and the reaction mixture was stirred at room temperature for 16 hours. The byproduct DCU was filtered off and crude was purified by flash column chromatography to get methyl 4- methyl)-3 -nitrobenzoate 2 (76%) as an off—white solid.

Compound 2 (4.0 g, 14.5 mmol) and 2—aminomethylfuran (3 equiv) in dry CH2C12 (50 mL) were stirred at room temperature for 48 hours. Upon completion of reaction the solvent was d and the crude product was purified by flash column chromatography to afford nitro benzoate 3 (82%).

To a solution of compound 3 (3.65 g, 11.9 mmol) in dry MeOH (100 mL), SnC12.2HzO (3.5 equiv) was added and the resulting reaction mixture was refluxed for 10 minutes. Upon completion of reaction, the byproduct was filtered through a bed of celite and e was evaporated. The crude product was portioned n 1 N NaOH and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3 x 20 mL) and the combined layers were dried over MgSO4 and concentrated under reduced re to furnish compound 4 (87%).

Use DCM to dissolve compound 4 (1.0 g, 3.8 mmol) then add 1.2 equiv. CNBr to react at room temperature. After 8 hours the mixture can be extracted with DCM and water.

The solvent was removed and the crude product was purified by flash column tography to afford 5 (60%).

To a solution of methyl 2—amino—3—(furan—2—ylmethyl)-3,4-dihydroquinazoline carboxylate 5 (0.3 g, 1.05mmol) in acetoniritle (20 mL) was added K2CO3 (0.29g, 2.1 mmol) and K1 (0.005 g, 0.03 mmol) followed by 2—(chloromethyl)methoxy-3,5-dimethylpyridine 6 (0.722 g, 3.89 mmol) and the reaction mixture was allowed to reflux for six hours. After 24 hours, the t was evaporated and the reaction e was diluted with saturated aq.

NaHC03 (30 mL) and extracted with EtOAc (3* 30 mL).

The combined organic phase was washed with saturated brine (30 mL). The crude t was purified by silica-gel column chromatography using 8 % methanol/ EtOAc to obtain the pure product NCTU-SUN-26079 as a white solid 0.43 g (70 %). ] 1H NMR (400 MHz, Methanol-d4) 8 8.16 (s, 1H), 7.81 (dd, J= 7.9, 1.4 Hz, 1H), 7.56 (dd, J= 1.8, 0.8 Hz, 1H), 7.37 (d, J=1.4 Hz,1H), 7.32 (d, J= 7.9 Hz, 1H), 6.60 (d, J: 3.3 Hz, 1H), 6.47 (dd, J= 3.3, 1.9 Hz, 1H), 5.28 (s, 2H), 4.88 (s, 2H), 4.61 (s, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 2.45 (s, 3H), 2.28 (s, 3H) ; LRMS (ESI+) : m/z 435.3 (M+H)+.

Example 3-2 21106: Methyl 3-(2-(cycl0hex-l-enyl)ethyl)(((4-meth0xy-3,5- dimethylpyridinyl)methyl)amino)—3,4—dihydroquinazolinecarb0xylate Except that amine is replaced by 2-(cyclohex-l-en-l-yl)ethanamine, the other reactants and preparation steps are similar to those described in Example 3-1 to afford the title compound. 1H NMR (400 MHz, Methanol-d4) 8 8.17 (s, 1H), 7.83 (dd, J = 7.9, 1.5 Hz, 1H), 7.40 — 7.33 (m, 2H), 5.24 (s, 2H), 5.16 (s, 1H), 4.61 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 3.76 (s, 2H), 2.46 (s, 3H), 2.28 (s, 3H), 2.12 (d, J = 8.1 Hz, 2H), 1.99 (s, 2H), 1.63 — 1.55 (m, 4H), 1.43 — 1.36 (m, 2H); LRMS (ESI+) : m/z 314.2 (M+H)+.

Example 3-3 26072: Methyl 2-(bis((4-methoxy-3,5—dimethylpyridinyl)methyl)amino)— 3-(furanylmethyl)-3,4-dihydroquinazoline—7—carboxylate o N/ fl Same as described in Example 3-1 to afford the title compound. 1H NMR (400 MHz, Methanol—d4) 8 8.21 — 8.19 (m, 1H), 8.07 (d, J: 0.8 Hz, 1H), 7.83 (dd, J: 7.9, 1.5 Hz, 1H), 7.57 (d,J= 1.5 Hz, 1H), 7.43 (dd, J: 1.9, 0.8 Hz, 1H), 7.29 (d, J: 7.9 Hz, 1H), 6.57 (dd, J: 3.4, 0.8 Hz,1H), 6.41 (dd, J: 3.3,1.9 Hz, 1H), 5.48 (d, J: 1.9 Hz, 2H), 4.93 (s, 2H), 4.81 (s, 2H), 4.62 (s, 2H), 3.86 (s, 3H), 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)+.

Example 3-4 26091: Methyl 2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)amino)—3- pentyl-3,4-dihydr0quinazoline—7—carb0xylate Except that amine is replaced by pentan—l—amine, the other reactants and preparation steps are similar to those described in Example 3-1 to afford the title nd. 1H NMR (400 MHz, Methanol—d4) 6 8.14 (s, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.32 (s, 1H), 5.24 (s, 2H), 4.70 (s, 2H), 3.86 (s, 3H), 3.81 (s, 3H), 3.64 (t, J: 7.8 Hz, 2H), 2.44 (s, 3H), 2.25 (s, 3H), 1.76 (p, J: 7.9 Hz, 2H), 1.37 (dp, J: 11.3, 7.1, 6.2 Hz, 4H), 0.96 — 0.83 (m, 3H), 13C NMR (101 MHz, Methanol-d4) 5 165.84, 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 12.93 12.02 , , , , , , , , 22.07, , , 9.51, LRMS (ESI+) : m/z 425.3 (M+H)+.

Example 3-5 26092: Methyl 2-(((4-methoxy-3,5—dimethylpyridinyl)methyl)amin0)—3- hoxybenzyl)—3,4-dihydroquinazoline—7—carboxylate o \N N NH O \O \ \ Except that amine is ed by (4-methoxyphenyl)methanamine, the other reactants and preparation steps are similar to those described in Example 3-1 to afford the title nd. 1H NMR (400 MHz, Methanol—d4) 6 8.09 (s, 1H), 7.71 (dd, J = 7.8, 1.4 Hz, 1H), 7.57 (d, J: 1.4 Hz, 1H), 7.39 (d, J: 8.5 Hz, 2H), 7.31 (d, J: 7.8 Hz, 1H), 6.92 — 6.83 (m, 2H), 5.65 (s, 2H), 5.18 (s, 2H), 4.68 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.74 (s, 3H), 2.43 (s, 3H), 2.18 (s, 3H), LRMS (ESI+) : m/z 475.3 (M+H)+.

Example 3-6 21110: -methoxy-3,5—dimethylpyridin-Z-yl)methyl)amin0)—3- (3- methoxypropyl)—3,4-dihydroquinazoline—7—carboxylic acid 0 N/ *CUN N HO \ 0 ] Except that amine is replaced by 3-methoxypropanamine, the other reactants and preparation steps are similar to those described in Example 3-7 to afford the title compound. 1H NMR (400 MHz, Methanol—d4) 6 7.84 (dd, J = 7.9, 1.4 Hz, 1H), 7.64 (s, 1H), 7.46 (d, J = 1.4 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 5.26 (s, 2H), 4.69 (s, 2H), 3.85 (s, 3H), 3.75 (t, J: 6.9 Hz, 2H), 3.51 (t, J: 5.7 Hz, 2H), 2.27 (s, 3H), 2.04 (d, J: 4.9 Hz, 6H), 1.29 (d, J = 3.5 Hz, 2H), LRMS (ESI+) : m/z 413.3 (M+H)+.

Example 3-7 26089: 3-(furan-2—ylmethyl)-2—(((4—methoxy-3,5-dimethylpyridin-Z- yl)methyl)amino)—3,4-dihydroquinazoline—7—carboxylic acid o \N HO NYNH\ To a solution of 4-(bromomethyl)nitrobenzoic acid 1 (5.0 g, 27.0 mmol) in dry MeOH/CH2C12 (3 mL: 30 mL), was added DCC (1.2 equiv) and DMAP (0.005 equiv) and the reaction e was stirred at room temperature for 16 h. The byproduct DCU was filtered off and crude was purified by flash column chromatography to get methyl 4-(bromomethyl)- 3-nitrobenzoate 2 (76%) as an off—white solid.

Compound 2 (4.0 g, 14.5 mmol) and 2—Aminomethylfuran (3 equiv) in dry CH2C12 (50 mL) were stirred at room temperature for 48 hours. Upon completion of reaction the solvent was removed and the crude product was purified by flash column chromatography to afford nitro benzoate 3 (82%).

To a solution of compound 3 (3.65 g, 11.9 mmol) in dry MeOH (100 mL), SnClz.2HzO (3.5 equiv) was added and the resulting reaction mixture was refluxed for 10 min. Upon completion of on, the byproduct was filtered through a bed of celite and filtrate was evaporated. The crude product was portioned n 1 N NaOH and ethyl acetate. The aqueous layer was ted with ethyl acetate (3 x 20 mL) and the combined layers were dried over MgSO4 and concentrated under reduced pressure to furnish compound 4 (87%).

Use DCM to dissolve compound 4 (1.0 g, 3.8 mmol) then add 1.2 equiv. CNBr to react at room temperature. After 8 hours the mixture can be extracted with DCM and water.

The solvent was removed and the crude product was purified by flash column chromatography to afford 5 (60%).

To a on of methyl 2—amino—3—(furan—2—ylmethyl)-3,4-dihydroquinazoline carboxylate 5 (0.3 g, 1.05mmol) in iritle (20 mL) was added K2CO3 (0.29g, 2.1 mmol) and K1 (0.005 g, 0.03 mmol) followed by 2-(chloromethyl)methoxy-3,5-dimethylpyridine 6 (0.722 g, 3.89 mmol) and the reaction mixture was allowed to reflux for six hours. After 24 hours, the solvent was evaporated and the reaction mixture was diluted with ted aq.

NaHC03 (30 mL) and extracted with EtOAc (3* 30 mL).

The combined c phase was washed with saturated brine (30 mL). The crude product was d by silica-gel column chromatography using 8 % methanol/ EtOAc to obtain Methyl 3-(furanylmethyl)(((4-methoxy-3,5-dimethylpyridin yl)methyl)amino)-3,4-dihydroquinazoline-7—carboxylate 7 0.43 g (70 %).

And add NaOH (0.198 g, 4.95 mmol) to a on of methyl 3-(furan ylmethyl)(((4-methoxy-3,5-dimethylpyridin—2—yl)methyl)amino)—3,4-dihydroquinazoline- 7-carboxylate 7 (0.43 g, 0.99 mmol) in the EtOH/HzO (l/l, lOmL) in the reflux condition.

After 1 hour, the solvent was evaporated and the reaction mixture was d with saturated aq. HCl (30 mL) and extracted with EtOAc (3* 30 mL). The combined organic phase was washed with saturated brine (30 mL). The crude product was purified by silica-gel column chromatography using 20 % methanol/ EtOAc to obtain the pure product as a white solid 0.27 g (65%). 1H NMR (400 MHz, Methanol—d4) 6 8.07 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.53 (d, J: 1.8 Hz, 1H), 7.35 (s, 1H), 7.14 (d, J: 7.8 Hz, 1H), 6.57 (d, J: 3.2 Hz, 1H), 6.43 (dd, J: 3.2, 1.8 Hz, 1H), 5.22 (s, 2H), 4.84 (s, 2H), 4.53 (s, 2H), 3.82 (s, 3H), 2.40 (s, 3H), 2.22 (s,3H),13C N1V1R(1011VIHz,Methanol-d4)5171.74 151.73 , 164.87, 155.39, , 148.52, 147.49,143.54,138.56,136.13,126.27,125.93 ,124.64,124.63,116.56,110.30, , 59.40, 50.46, 47.46, 46.94, 46.47 11.97 LRMS (ESI+) : m/z 421.2 , , 9.33; (M+H)+.

Example 3-8 26090: 2-(((4-methoxy-3,5—dimethylpyridinyl)methyl)amino)—3-pentyl- 3,4-dihydr0quinazoline—7-carboxylic acid Except that amine is replaced by pentan—l—amine, the other reactants and preparation steps are similar to those described in Example 3-7 to afford the title compound. 1H NMR (400 MHz, ol—d4) 6 8.03 (dd, J = 8,4, 1.4 Hz, 1H), 7.96 (s, 1H), 7.84 (d, J: 1.3 Hz, 1H), 7.55 (d, J: 8.4 Hz, 1H), 3.83 (s, 3H), 2.41 (s, 3H), 2.22 (s, 3H), 1.92 — 1.83 (m, 2H), 1.43 (tt, J: 5.7, 2.8 Hz, 4H), 1.29 (d, J: 4.0 Hz, 2H), 0.97 — 0.92 (m, 3H), LRMS (ESI+) : m/z 411.3 (M+H)+.

Example 4-1 NCTU-SUN-12082: Methyl 1-(2-(cyclohexenyl)ethyl)—2-(((4- y-3,5-dimethylpyridin-Z-yl)methyl)thio)—1H—benzo[d]imidazole—S-carboxylate To a solution of 4-fluoronitrobenzoic acid 1, H2SO4 (5 mL, 0.3 M) is added and the reaction mixture is heated to reflux. The solvent is removed under reduced pressure; crude reaction mixture is dissolved in EtOAc. The EtOAc layer was dried over ous MgSO4 and evaporated to get methyl 4—fluoro—3—nitrobenzoate 2 as a White solid.

Compound 2 and 2-(cyclohex-1—enyl)ethanamine were stirred at room ature for 2 hours. Upon completion of reaction the solvent was removed and the crude product was d to afford nitro benzoates 3.

To a solution of compound 3, zinc dust and ammonium formate are added and the ing reaction mixture is d at room temperature. Upon completion of reaction, Zn dust is filtered and the filtrate is evaporated and the t is dissolved in CH2Clz. The precipitated ammonium formate was filtered off and the solvent was ated to furnish compound 4.

To the stirred on of compound 4 is added carbon disulfide and KOH at 50 °C in the ethanol for 8 hours. The mixture can be neutralized by acetic acid and extracted with EtOAc and water. The solvent was removed and the crude product was purified to afford 5.

To a solution of methyl l—(2—(cyclohex—1—en—l—yl)ethyl)thioxo-2,3-dihydro-1H- d]imidazolecarboxylate 5 is added K2CO3 and K1 followed by 2-(chloromethyl)—4- methoxy-3,5-dimethylpyridine 6 and the reaction mixture was allowed to reflux. The solvent is evaporated and the reaction mixture is diluted and extracted with EtOAc.

The combined organic phase was washed with saturated brine. The crude product was purified to obtain the pure product NCTU-SUN—12082 as a white solid 0.053 g (71 %). 1H NMR (300 MHz, Acetone-d6) 6 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).

Example 4-2 12083: 1-(2-(cyclohexenyl)ethyl)(((4-methoxy-3,5- dimethylpyridinyl)methyl)thio)—1H-benzo[d]imidazole-S-carboxylic acid To a solution of 4—fluoro—3—nitrobenzoic acid 1, H2804 (5 mL, 0.3 M) is added and the reaction mixture is heated to reflux. The solvent is removed under reduced pressure; crude reaction mixture is dissolved in EtOAc. The EtOAc layer was dried over anhydrous MgSO4 and evaporated to get methyl 4-fluoronitrobenzoate 2 as a white solid.

Compound 2 and 2-(cyclohexen-l-yl)ethanamine were stirred at room temperature for 2 h. Upon completion of on the solvent was removed and the crude product was purified to afford nitro tes 3.

To a solution of compound 3, zinc dust and ammonium formate are added and the resulting reaction mixture is stirred at room temperature. Upon completion of reaction, Zn dust is filtered and the filtrate is evaporated and the product is dissolved in CH2C12. The precipitated ammonium formate was filtered off and the solvent was evaporated to furnish compound 4.

To the d solution of compound 4 is added carbon disulfide and KOH at 50 °C in the ethanol for 8 hours. The mixture can be neutralized by acetic acid and ted with EtOAc and water. The solvent was removed and the crude product was purified to afford 5.

To a solution of methyl l—(2—(cyclohex—l—en—l—yl)ethyl)thioxo-2,3-dihydro-lH- benzo[d]imidazolecarboxylate 5 is added K2CO3 and K1 followed by 2-(chloromethyl) methoxy-3,5-dimethylpyridine 6 and the reaction mixture was allowed to reflux. The solvent is evaporated and the reaction mixture is diluted and extracted with EtOAc.

The ed organic phase was washed with saturated brine. The crude product was purified to obtain Methyl l-(2-(cyclohex—1-en-l-yl)ethyl)(((4-methoxy-3,5- dimethylpyridinyl)methyl)thio)-lH-benzo[d]imidazolecarboxylate 7 0.053 g (71 %).

And add NaOH (0.0251 g, 0.63 mmol) to a solution of Methyl l-(2-(cyclohex-l- enyl)ethyl)(((4-methoxy-3 5 -dimethylpyridinyl)methyl)thio)- zo[d]imidazole- -carboxylate 7 (0.053 g, 0.126 mmol) in the EtOH/HzO (l/l, 3mL) in the reflux condition.

After 1 hour, the solvent was ated and the reaction mixture was diluted with saturated aq. HCl (10 mL) and extracted with EtOAc (3* 10 mL). The ed c phase was washed with saturated brine (30 mL). The crude product was purified by silica-gel column tography using 20 % methanol/ EtOAc to obtain the pure product NCTU-SUN-12083 as a white solid 0.030 g (65%). 1H NMR (300 MHz, CD3OD) 6 8.30 (d, J= 1.4 Hz, 1H), 8.14 (s, 1H), 7.98 (dd, J = 8.5, 1.5 Hz, 1H), 7.49 (d, J: 8.5 Hz, 1H), 5.51 (s, 2H), 5.08 (s, 1H), 4.71 (s, 2H), 4.24 (t, J = 6.8 Hz, 2H), 3.79 (s, 3H), 2.44 — 2.31 (m, 5H), 2.27 (s, 3H), 2.04 — 1.89 (m, 2H), 1.88 — 1.70 (m, 2H), 1.62 — 1.39 (m, 4H).

Example 4-3 12084: Methyl 1-(2-(cyclohexenyl)ethyl)—2-(((4-methoxy-3,5- dimethylpyridin-Z-yl)methyl yl)-1H-benzo[d]imidazole-S-carboxylate \0*EIN»N\ ft?\ / To a solution of 4-fluoronitrobenzoic acid 1, H2804 (5 mL, 0.3 M) is added and the reaction mixture is heated to reflux. The t is removed under reduced pressure; crude reaction e is dissolved in EtOAc. The EtOAc layer was dried over anhydrous MgSO4 and evaporated to get methyl 4—fiuoro—3—nitrobenzoate 2 as a white solid.

Compound 2 and 2—(cyclohexen—1—yl)ethanamine were d at room temperature for 2 hours. Upon completion of reaction the solvent was removed and the crude product was purified to afford nitro benzoates 3.

To a solution of compound 3, zinc dust and ammonium e are added and the resulting reaction mixture is stirred at room temperature. Upon completion of reaction, Zn dust is filtered and the filtrate is evaporated and the product is dissolved in CH2C12. The precipitated ammonium formate was filtered off and the solvent was evaporated to furnish compound 4.

] To the stirred solution of compound 4 is added carbon disulfide and KOH at 50 0C in the ethanol for 8 hours. The mixture can be neutralized by acetic acid and extracted with EtOAc and water. The solvent was removed and the crude product was purified to afford 5.

To a solution of methyl 1-(2-(cyclohexen-l-yl)ethyl)thioxo-2,3-dihydro-1H- benzo[d]imidazolecarboxylate 5 is added K2C03 and K1 followed by 2-(chloromethyl) methoxy-3,5-dimethylpyridine 6 and the reaction mixture was allowed to reflux. The solvent is ated and the reaction mixture is d and extracted with EtOAc.

The ed organic phase was washed with saturated brine. The crude product was purified to obtain Methyl 1-(2-(cyclohexenyl)ethy1)(((4-methoxy-3,5- dimethylpyridin—2—yl)methyl)thio)—lH—benzo[d]imidazole—5-carboxylate 7 0.053 g (71 %).

And add mCPBA (0.0058 g, 0.034 mmol) to a solution of Methyl l-(2-(cyclohex- l-enyl)ethyl)(((4-methoxy—3,5—dimethylpyridin—2—yl)methyl)thio)-1H- benzo[d]imidazolecarboxylate 7 (0.053 g, 0.0126 mmol) in the DCM/ MeOH (9/1, 4.5 mL) in the ice bath. Then, add NaHC03 (0.0007 g, 0.0088 mmol) and remove the ice bath. Let the crude stir at room temperature in 1 hour. The on e was washed with DCM (5 mL). The solvent was evaporated and the to obtain the pure product NCTU-SUN-12084 as a white solid 0.030 g (65%). 1H NMR (300 MHz, CDC13) 6 8.55 (s, 1H), 8.13 (s, 1H), 8.10 (dd, J: 8.7, 1.5 Hz, 1H), 7.43 (d, J: 8.8 Hz, 1H), 5.03 (q, J: 12.9 Hz, 3H), 4.59 — 4.35 (t, J: 8.3 Hz, 2H), 4.58 — 4.36 (m, 2H), 3.97 (s, 3H), 3.71 (s, 3H), 2.49 (t, J: 8.3 Hz, 2H), 2.30 (s, 3H), 2.22 (s, 3H), 2.03 — 1.78 (m, 4H), 1.51 (m, 4H).

Example 5-1 12092: 2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)thio)-1H- benzo[d]imidazolyl (((9H-fluorenyl)methoxy)carbonyl)glycinate FmOCHN/\g/ UNN \ / To a solution of 2-thioxo-2,3—dihydro—lH—benzo[d]imidazolyl 2-((((9H-fluoren- 9-yl)methoxy)carbonyl)amino)acetate 1 (0.08 g, 0.18 mmol) in ethanol (9 mL) was added NaOH (0.079 g, 0.198 mmol) followed by 2-(chloromethyl)methoxy-3,5- ylpyridine 2 (0.367 g, 0.198 mmol) and the reaction mixture was allowed to reflux for one hour. Once the reaction was completed, the solvent was evaporated and the crude product was purified by silica-gel column chromatography using 2 % MeOH/DCM to obtain the pure product NCTU-SUN-12092 as a white solid. 0.31 g, 54.5 %. 1H NMR (300 MHz, e-d6) 5 8.26 (s, 1H), 7.87 (d, J = 7.4 Hz, 2H), 7.74 (d, J: 7.4 Hz, 2H), 7.51 (d, J: 8.6 Hz, 1H), 7.41 (t, J: 7.3 Hz, 2H), 7.32 (t, J: 7.4 Hz, 3H), 7.14 (t, J: 6.6 Hz, 1H), 6.95 (dd, J: 8.7, 2.1 Hz, 1H), 4.67 (s, 2H), 4.40 (d, J: 7.3 Hz, 2H), 4.36 — 4.21 (m, 3H), 3.80 (s, 3H), 2.36 (s, 3H), 2.25 (s, 3H).

Example 5-2 12093: 2-(((4-meth0xy-3,5—dimethylpyridinyl)methyl)thio)—1H- benzo[d]imidazolyl (tert-butoxycarbonyl)glycinate Except that imidazole is ed by 2-thioxo-2,3-dihydro-1H-benzo[d]imidazol- -yl 2-((tert-butoxycarbonyl)amino)acetate, the other reactants and preparation steps are similar to those described in Example 5-1 to afford the title compound. 1H NMR (300 MHz, Acetone) 8 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).

Example 5-3 12094: 2-(((4-meth0xy-3,5—dimethylpyridinyl)methyl)thio)—1H benz0[d]- imidazole—S-yl (S)((((9H-flu0ren-9—yl)methoxy)carbonyl)amino)—2-phenylacetate NHFmoc o \o (INN \ / Except that imidazole is replaced by (S)—2—thioxo-2,3-dihydro-1H- benzo[d]imidazolyl 2-((((9H-fluorenyl)methoxy)carbonyl)amino)—2-phenylacetate, the other reactants and preparation steps are similar to those described in Example 5-1 to afford the title compound. 1H NMR (300 MHz, Acetone-d6) 6 8.24 (s, 1H), 7.85 (d, J: 7.5 Hz, 2H), 7.75 (d, J: 7.4 Hz, 2H), 7.65 (d, J: 7.2 Hz, 2H), 7.52 — 7.39 (m, 6H), 7.32 (m, 2H), 7.22 (d, J: 1.6 Hz, 1H), 6.83 (dd, J: 9.1, 1.5 Hz, 1H), 5.67 (s, 1H), 4.66 (s, 2H), 4.48 — 4.25 (m, 3H), 2.35 (s, 3H), 2.25 (s, 3H).

Example 6-1 UN-22138: S-methoxy((2-methoxy-3,6-dimethylbenzyl)thi0)— 1H-benzo[d]imidazole UrN\ M.

To a solution of oxy-1,3,4-trimethylbenzene 1 (0.3 g, 2.00 mmol) in chloroform (30 mL) was added NBS (0.177 g, 1.00 mmol) and in the light-induced ons, two Philips "IR 250 W lamps were placed at such a ce from the reaction flask that reflux was maintained. Once the reaction was completed, the solvent was evaporated and the crude product was purified by silica—gel column chromatography using hexane to obtain brominated product 2 0.092 g, 20 %.

To a solution of t brominated product 2 (0.1 g, 0.43 mmol) in ethanol (2 mL) was added NaOH (0.017 g, 0.43 mmol) followed by 2-(chloromethyl)methoxy-3,5- dimethylpyridine 3 (0.071 g, 0.39 mmol) and the reaction mixture was d to reflux for one hour. Once the reaction was completed, the solvent was evaporated and the crude product was purified by silica-gel column tography using 2 % MeOH/DCM to obtain NCTU- SUN-22138 0.077 g, 60 %.

LRMS (ESI+): m/z 329.2 (M+H)+ Example 6-2 22141: methoxy-3,6-dimethylbenzyl)thio)—1H-benzo[d]imidazolol UrN\ M, To a on of oxy—1,3,4—trimethylbenzene 1 (0.3 g, 2.00 mmol) in chloroform (30 mL) was added NBS (0.177 g, 1.00 mmol) and in the light-induced reactions, two Philips "IR 250 W lamps were placed at such a distance from the reaction flask that reflux was ined. Once the reaction was completed, the solvent was evaporated and the crude product was purified by -gel column chromatography using hexane to obtain brominated product 2 0.092 g, 20 %.

To a solution of t brominated product 2 (0.1 g, 0.43 mmol) in ethanol (2 mL) was added NaOH (0.017 g, 0.43 mmol) followed by 2-(chloromethyl)hydroxy-3,5- dimethylpyridine 3 (0.071 g, 0.39 mmol) and the reaction mixture was allowed to reflux for one hour. Once the reaction was completed, the solvent was evaporated and the crude product was purified by silica-gel column chromatography using 2 % CM to obtain NCTU- SUN-22138 0.077 g, 60 %.

LRMS (ESI+): m/z 315.1 (M+H)+ Example 6-3 21133: 2-((3-(br0m0methyl)((tert-butyldimethylsilyl)oxy)—6- methylbenzyl)thi0)—5-methoxy-1H-benzo[d] imidazole To a solution of tert—butyldimethyl(2,3,6—t1imethylphenoxy)silane 1 (1.2 g, 4.7 mmol) in chloroform (50 mL) was added NBS (1.7 g, 9.5 mmol) and in the light-induced reactions, two Philips "IR 250 W lamps were placed at such a distance from the reaction flask that reflux was maintained. Once the on was ted, the solvent was evaporated and the crude product was purified by silica-gel column chromatography using hexane to obtain dibrominated product 2 0.31 g, 20 %.

To a on of dibrominated product 2 (0.3 g, 0.90 mmol) in ethanol (9 mL) was added NaOH (0.036 g, 0.90 mmol) followed by 2-(chloromethyl) methoxy-3,5- dimethylpyridine 3 (0.148 g, 0.82 mmol) and the reaction mixture was allowed to reflux for one hour. Once the reaction was ted, 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 %. 1H NMR (400 MHz, Chloroform-d) 6 7.43 (d, J = 8.8 Hz, 1H), 7.16 (s, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.82 (d, J = 2.3 Hz, 1H), 4.69 (s, 2H), 3.78 (s, 4H), 2.22 (s, 3H), 2.13 (s, 4H), 0.98 (s, 9H), 0.09 (s, 6H).

LRMS (ESI+): m/z 507.1 (M+H)+ Example 6-4 S-meth0xy((2-meth0xy-3,6-dimethylbenzyl)sulfinyl)—1H- benz0[d]imidazole M30 OrN o \ 3” To a solution of 2-methoxy-1,3,4—trimethylbenzene 1 (0.3 g, 2.00 mmol) in chloroform (30 mL) was added NBS (0.177 g, 1.00 mmol) and in the light-induced reactions, two Philips "IR 250 W lamps were placed at such a distance from the reaction flask that reflux was maintained. Once the on was completed, the solvent was evaporated and the crude product was purified by silica-gel column chromatography using hexane to obtain brominated product 2 0.092 g, 20 %.

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

] And add mCPBA (0.069g, 0.40 mmol) to a solution of 5-methoxy((2-methoxy- 3,6-dimethylbenzyl)thio)-1H-benzo[d]imidazole 3 (0.077g, 0.23 mmol) in the DCM/ MeOH (9/1, 10 mL) in the ice bath. Then, add NaHCO3 (0.013g, 0.16 mmol) and remove the ice bath. Let the crude stir at room temperature in 1 h. The reaction mixture was washed with DCM (10 mL). The t was evaporated and the to obtain the pure product as a white solid 0.047 g (65%).

LRMS (ESI+) ; m/z 345.1 (M+H)+ Example 7 DAAO enzymatic assay The DAAO tic activity assay was modified according to the report of Oguri el al (Oguri, 5., Screening ofd-ctmino acid oxidase inhibitor by a new mulii-assay method. Food chemistry 2007, 100 (2), 616). The DAAO activity was measured by using ate D-alanine reaction produced en peroxide (H202) to further react with 3-(4- hydroxyphenyl) propionic acid (HPPA). The HPPA were oxidized by H202 and peroxidase to become the fluorogenic dimer which was measured to represent the activity of DAAO.

] For porcine kidney DAO IC50 assay, the DA0 substrate was prepared in 50 mM D-alanine (dissolved in 0.2 M Cl buffer, pH 8.3). A 100 pl ofD-alanine solution was mixed with 4 ul (in 100% dimethyl sulfoxide, DMSO) of different concentrations of candidate compounds shown in tables below ranging from 48.83 uM, 97.66 uM, 195.31 uM, 390.63 “M, 781.25 “M, 1.56 mM, 3.13 mM, 625 mM, 12.50 mM, 25.00 mM, and 50.00 mM, with a final DMSO concentration of 0.167% in each reaction concentration. 10 ul ofD- alanine and candidate compound mixture was incubated with 220 pl of Reaction Master Mix in black 96 well plate at 37°C for 5 minutes. The Reaction Master Mix contained 110 pl of 5 U/mL porcine kidney DAO (Sigma-Aldrich, USA) solution (dissolved with 0.2 M Tris—HCl buffer, pH 8.3), 1.1 mL of 15 U/mL peroxidase on lved with 0.2 M Tris—HCl buffer, pH 8.3), 1.1 mL of 20 mM HPPA solution (dissolved with 0.2 M Tris—HCl buffer, pH 8.3), and 22 ml of 2 M Tris—HCl buffer (pH 8.3) for 110 reaction assays.

Fluorescence intensity (Fs) was measured at 405 nm by irradiation excitation at 320 nm. The higher the DA0 tic activity was, the higher the cence intensity.

The fluorometric inhibition indicator (Fi) was obtained from the following equation: Fi = (Fs- FDrug)/ (FDMso), where the fluorescent drug blank (FDrug) was ed in the drug mixture solution (using 0.2 M Tris HCl buffer, pH 8.3, without D-alanine). A DMSO blank (FDMso) was measured under a 100% DMSO solution.

Although FAD is generally included in the reaction mixture in the D-amino acid oxidase assay since it easily iates from the holoenzyme, the present method was performed without FAD. The inhibitory effect of DAO inhibitors was compared by using inhibitory concentrations leading to 50% tion ofDAAO activity (IC50). The IC50 values were calculated by nonlinear regression model using GraphPad Prism, n 5 (GraphPad Software, Inc., La Jolla, CA). The results ofDAO IC50 assay of the candidate compounds of the invention are shown in the table below.

Example 8 Cel-lbased DAO Assay al cell culture The H neuroblastoma cell line was purchased from American Type Culture Collection (ATCC). It was cultured in MEM media (Invitrogen/GBCO, Rockville, MD) supplemented with 10% fetal bovine serum, 1X NEAA (Invitrogen/GBCO) at 37 °C with 5% C02 in a humidified atmosphere. Cells were trypsinized and plated into a black 96- well plate (NUNC No. 237108) at a density of 125,000 cells/well in 50 ul before cell-based DAO assay.

Cell-basedDAO Assay The cellular DAO activity assay was using a method d according to the report of Brandish el‘ al. (Brandish, P.E., et al., A cell-based ultra-high-throughpui screening assayfor idenZiJj/ing inhibitors ofD-amino acid oxidase. l Screen, 2006. 11(5): p. 481-7.). SK-N—SH cells were ded in assay buffers ofHANKS buffer solution (Invitrogen/GIBCO No. 14025-092) with 20 mM HEPES. D—serine of (final concentration 50 mM) was added in each well as the substrate for DAO enzyme. The Amplex Red Hydrogen Peroxide/Proxidase Assay Kit (Molecular Probes/Invitrogen, cat. A22188) was used to e H202 production which diffused across the cell ne into the assay medium after DAO reaction. After seeding cells into black 96-well plate (Nunc No. 237108, Denmark), 50 ul of SK—N—SH cells (125,000 cells/well) was mixed with 50 111 drug solution (2.5 fold of interesting final concentration) and te at 37 °C with 5% CO2 in a humidified here for 30 s. After 30 minutes later, 25 ul of a 5 fold mixture containing ne, horseradish peroxidase (HRP), and Amplex Red was added into wells containing 100 pl of cell-drugs mixture and incubated at 37 °C with 5% CO2 in a humidified atmosphere for 3 hours. The final concentration ofDMSO is below 1%. The fluorescence signal was then detected in SpectraMax M2e microplate reader (Molecular Devices, USA) with excitation at 544 nm and emission at 590 nm. The optimized assay buffer contained a final concentration of 50 mM D-serine, 0.625 units HRP, and 50 uM Amplex Red in a 125 pl assay volume. The results of the cell-base DAO assay of the candidate compounds of the invention are shown in the table below. reated for 3.5 hr) DAG activity Final Cone.

IC50 95% Confidence (11M) Range (11M) CBIO 2814 to 547.0 RS-D7 “_-81.07to245.1 12083 451.5811 __7415 27.04t0203.4 21105 583.73 __218.80 98.89to4843 Example 9 Animal Studies of Potency in Treating Schizophrenia Symptoms Drug cy Screening The NMDA-receptor antagonist MK—801—induced negative or cognitive s in C57BL/6 mice were in a well-established drug-induced schizophrenia mouse model and as a useful pharmacological animal model to fy if the RS-D7, its analog and its prodrug improve the symptoms through the NMDA or.

Animals ] All wild-type (WT) mice used in this study were ossed onto a C57BL/6J background from the Laboratory Animal Center of National Taiwan University Hospital, and all behavioral examinations were conducted in WT mice. For acclimatizing to laboratory conditions, the mice were allowed free access to food and water and were housed in groups with a 12 hours light-dark cycle in a temperature and humidity controlled room of the Psychology Department, National Taiwan sity. All animals within the age of 3 months were housed individually one week before experiment testing with food and water available ad libitum. In the beginning of the experiments, the mice were handled and weighted daily at least 1 week before the behavioral experiments. The entire animal procedures were performed according to protocols approved by the Animal Care and Use Committee established by the National Taiwan University.

Drugpreparationfor treating animals MK-801 was dissolved in saline and administered at a volume of 0.01 ml/g body weight. RS-D7, Drug 12083 (analog ofRS-D7) and was y dissolved in 1% CMC to the concentration of 2 mg/ml before usage. g 28095 was freshly dissolved in NMPzHP- beta-CDszO (5:25:70) to the concentration of 2 mg/ml before usage. All s were given vehicle (saline) or MK-801 (0.2 mg/kg, ip.) 25 minutes before the behavioral ments.

Both vehicle (1% CMC or NMP:HP-beta—CD:H20) and experimental groups (RS-D7, Drug 12083 or Prodrug 28095) were treated after 5 minutes MK-801 administration with the appropriate dose via P. 0. injections (at a volume of 0.01 ml/g body weight).

Behavioral experiment procedure For investigating the treatment effect of RS—D7 for negative and ive symptoms, a series of three behavioral tests (run from the first to the third week), which included open field, sucrose preference test and prepulse inhibition were performed in sequence with a 1-week interval between tests.

Openfield To assess neous locomotor activity, each subject was placed into the center of an open-field apparatus (25.40*25.40*40.64 cm3, Coulboum Instruments, all, PA, USA) under dim lighting condition (60 1x). Motor activity parameters (including total travel distance and travel distance per 10 s) were red and recorded over a 60 minutes period by using Smart video tracking software (Panlab, Harvard apparatus, US). For comparing the treatment effects of different treatment groups, the percentage change of rescue effect on MKinduced hyperlocomotion was calculated using the ing formula: % = (rescue effect of drug — MK-801 effect) X 100 % / MK-801 effect.

Compared with the saline controls, mice exhibit the hyperlocomotion in the open field after acute MK-801 inj ection. The injection of 200 and 400 mg/kg RS-D7 rescued the MK-801 induced hyperlocomotion in mice. However, the 100 mg/kg RS—D7 did not display the treatment effect. This result suggests that acute RS-D? injection normalized MK induced hyperlocomotion as a positive symptom of schizophrenia in the open field test. Drug 12083 alleviated MK-801 induced hyperlocomotion deficits at 20 and 40 mg/kg dose. 100 mg/kg Prodrug 28095 alleviated MK-801 induced ocomotion. In conclusion, compared to the MK-801 group, ent dosages of RS-D7, Drug 12083 and Prodrug 28095 can rescue the MKinduced hyperlocomotion. The rescue effects of these drugs on MK-801 induced hyperlocomotion were indicated in Figure l.

Sucrosepreference test To assess the anhedonia, one of the negative symptoms of schizophrenia, all mice underwent 4-day testing. In the beginning of the sucrose preference, all mice were ed of water for 23 hours in all the experiment from one day before the first day. On the first day, each mouse was given free access to 2 identical bottles with water for 1 hour. Then, the 2 indentical bottles were replaced that one filled with 1 % (wt/vol) sucrose solution and the other with water on the second day. On the third and fourth day, each mouse was received MK-801 and RS-D7 treatment before the experiment, and also free accessed to bottles for 1 hour. After the experiment, the 2 bottles were weighted to measure the l-hour ption of sucrose solution and water. The sucrose preference tage (SPP) was calculated using the ing formula: %SPP = sucrose solution consumption (g) X 100 %/ [water consumption (g) + sucrose solution consumption (g)].

Compared with the saline controls, a significant reduction of sucrose intake in the sucrose preference test was ed in g mice after acute MK-801 injection. The injection of 100, 200 and 400 mg/kg RS-D7 rescued the MK-801 induced anhedonia deficit in mice. 20 mg/kg Drug 12083 and 200 mg/kg g 28095 also normalized MK-801 induced anhedonia. As a result, different dosages of RS-D7, Drug 12083 and Prodrug 28095 rescued the anhedonia after acute MK-801 injection. The rescue effects of these drugs on MK-801 induced anhedonia were indicated in Figure 2.

Prepulse inhibition To assess the sensorimotor gating function, each mouse was tested with the SR- LAB startle apparatus (San Diego Instruments, San Diego, CA, USA). The background noise was 72 dB during testing. Each session was initiated with a 5 minutes acclimatization period followed by 64 trials, consisting of pulse-alone ne) trials, prepulse pulse (pp + P) trials, and no stimulation m) trials. A P-alone trial was a 120 dB white noise burst of 40 msec.

In the pp + P , the 120 dB pulse was ed (by 100 msec) by a 20 msec of white noise prepulse burst of 78 dB (PP6), 82 dB (PP10), or 90 dB . The nostim trials consisted of background noise only. The session began and ended with a block of six presentations of the P-alone trial. Between these two blocks, the rest of the 52 trials were performed pseudorandomly and separated by intertrial intervals of 15 sec on average (varying n 10 and 20 sec). PPI was calculated as a percentage of the startle response using the formula: %PPI = 100 x [(P-alone score)—(pp + P score)]/(pulse-alone score), where the pulse-alone score was the average of the pulse—alone values from the in-between block of 52 trials.

Mice with acute MK-80l injection exhibited a profound reduction of ic PPI.

However, the injection of 100, 200, and 400 mg/kg RS—D7, 20 and 40 mg/kg Drug 12083, and 100 and 200 mg/kg Prodrug 28095 significantly alleviated MK-801 induced PPI deficit in these mice. In other words, Mice displayed a significant ion of PPI after acute MK- 801 injections and they can be normalized by all dosages of RS-D7, Drug 12083 and Prodrug 280954 The recovery rates of MK-801 induced PPI deficit were indicated in Figure 3.

Claims

Claims (21)

What is claimed is:

1. l. A compound of formula (I), wherein n is 0 or 1, X is —S—, —S(=O)— or —NRn—; wherein Rn is H or A is —CH, —CRc or N; Ra is —C(=O)ORa1, —ORa2, —O—C(=O)Ra3 or —O—C(=O)-T-0Ra4; wherein Ral is H or linear or branched C1-15alkyl; Raz is H, linear or branched lkyl, phosphonate, diarylphosphonate or an O- protecting group; Ra3 and Ra4 are independently a protecting group, linear or branched C1-15alkyl, linear or branched C2-15alkenyl, —T-C3-1ocycloalkyl, -T-NHRa3p, -T-C3. iocycloalkenyl, -T-C6-1oaryl, -T-C5-10heteroaryl, C(=O)-O-C1-1oalkyl, -T- tyl or -C1.3alkylene-C6-1oaryl where the alkylene is substituted with -T- NHRa3p; Ra3p is H or an N—protecting group; Rb is H, linear or branched C1.15alkyl, linear or branched C2.15alkeny1, C1.3alkoxy-C1. 15alkyl-, -T'-C3.10cycloalkyl, -T'-C3.1ocycloalkenyl, -T'-C6.10 aryl or -T'-C5.1oheteroaryl; RC each is independently linear or branched C1.1salkyl, linear or branched C1.1salkoxyl, unprotected or protected yl group, or alkylene-Y-C6-10heteroaryl wherein - Y- is -CH2-, -NH-, -O— or —S—; symbol * represents the bonding position; m is an integer from O to 4; -T- is absent, C1.3alkylene or kenylene; -T'— is C1-3alkylene or C2-3alkenylene; and wherein the heteroaryl contains at least one heteroatom, each heteroatom being independently S, N or 0; wherein the alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene and alkenylene are each independently unsubstituted or substituted with at least one sub stituent; wherein the substituent is each independently a halogen, a protecting group, protected or unprotected amino group, nitro, nitroso, linear or branched C145 alkyl, or linear or ed C1.15 alkoxy or C3.1ocycloalkyl; and when Rb is H, the ers are included, with the proviso that when X is —S— or —, Ra is —OR32 and Ra; is H or linear or branched C1-15alkyl, then A is —CH or —CRC, when X is —S— or —S(=O)— and Ra is —C(=O)ORa1, Rb is linear or branched lkyl, linear or branched C6-15alkenyl, C1-3alkoxy-C1-15alkyl-, -T'-C3-1ocycloalkyl, -T'—C3- iocycloalkenyl, -T'-C6.10 aryl or -T'-C5-10heteroaryl; or a pharrnaceutically acceptable salt thereof.

2. The compound of Claim 1, which is a compound of a (I-a): (I-a) wherein n is 0 or 1, X is —S—, —S(=O)— or —NRn—; wherein ‘ 83):» Rn is H or ; A is —CH, —CRc or N, Ra is —C(=O)0Ra1, —ORa2, —O—C(=O)Ra3 or —O—C(=O)—T-0Ra4; wherein Rai is H or linear or branched C1-15alkyl; Raz is H, linear or branched C1-15alkyl, diarylphosphonate or an O-protecting group; Ra3 and Ra4 are independently a protecting group, linear or branched C1-15alkyl, linear or branched C2-15alkenyl, -T-C3-1ocycloalkyl, -T-NHRa3p, -T-C3. iocycloalkenyl, -T-C6-1oaryl, -T—C5-1oheteroaryl, -T-NH-C(=O)-O-C1-1oalkyl or -T- adamantyl, Ra3p is H or an N—protecting group; Rb is H, linear or branched C1.15alkyl, linear or branched C2.15alkeny1, C1.3alkoxy-C1. 15alkyl-, -T'-C3.10cycloalkyl, .1ocycloalkenyl, -T'-C6.10 aryl or -T'-C5.1oheteroaryl; RC each is independently linear or branched C1.1salkyl, linear or branched C1.1salkoxyl, unprotected or protected hydroxyl group, or —C1-1oalkylene-Y-C6-10heteroaryl wherein - Y- is -CH2-, -NH—, -O— or —S—; symbol * represents the bonding position; m is an integer from O to 4; -T- is absent, C1.3alkylene or C2-3alkenylene; -T'— is kylene or C2-3alkenylene; and wherein the heteroaryl contains at least one heteroatom, each heteroatom being independently S, N or 0, wherein the alkyl, alkenyl, , cycloalkyl, aryl, aryl, ne and alkenylene are each independently tituted or tuted with at least one sub stituent, wherein the substituent is each independently a halogen, a protecting group, protected or unprotected amino group, nitro, nitroso, linear or branched C145 alkyl, linear or branched C145 alkoxy or C3-1ocycloalkyl and when Rb is H, the tautomers are included, with the proviso that when X is —S— or —S(=O)—, Ra is —ORa2 and Raz is H or linear or branched C1-15alkyl, then A is —CH or —CRC; when X is —S— or —S(=O)— and Ra is —C(=O)OR31, Rb is linear or branched C6.15alkyl, linear or branched C6.15alkenyl, C1.3alkoxy-C1.1salkyl-, -T'-C3.1ocycloalkyl, -T'-C3. iocycloalkenyl, —T'—C6.10 aryl or -T‘—C5-10heteroaryl; or a pharrnaceutically acceptable salt thereof.

3. The compound of Claim 1, which is a nd of formula (I-b): (I-b) wherein n is 0 or 1, X is —S—, — or —NRn-; Rn is H or A is —CH; —CRC or N; Ra is —C(=O)ORa1; —ORa2 or —O—C(=O)Ra3; wherein Ral is H or linear or ed C1-15alkyl; Raz is H; linear or branched C1-15alkyl; phosphonate, diarylphosphonate or an O- protecting group; Ra3 is -T-NHRa3p, -T-NH-C(=O)—O-C1-1oalkyl or -C1.3alkylene-C6-1oaryl where the alkylene is tuted with -T-NHRa3p; Ragp is H or an N—protecting group; Rb is H; linear or branched C1-15alkyl, C1-3alkoxy-C1-15alkyl-, -10cycloalkyl; -T'—C3- iocycloalkenyl; -T'-C6.1o aryl or -10 heteroaryl; RC each is independently linear or branched C1-15alkyl; linear or branched C1-15alkoxyl; unprotected or protected hydroxyl group or —C1-1oalkylene-Y-C6-1oheteroaryl wherein -Y- is -CH2-, -NH-, -O- or -S-; symbol * ents the bonding position; In is an integer from O to 4; -T- is absent, C1.3alkylene or C2.3alkenylene; -T'- is C1-3alkylene; and wherein the heteroaryl contains at least one heteroatom; each heteroatom being independently S; N or 0; wherein the alkyl; alkenyl; alkoxy; cycloalkyl, aryl and heteroaryl are each independently unsubstituted or substituted with at least one substituent; wherein the substituent is each independently a halogen, ted or unprotected amino group, nitro, nitroso, linear or branched C1-15 alkyl, linear or branched C1.15 alkoxy or C3- oalkyl, and when Rb is H, the tautomers are included, with the proviso that when X is —S— or —S(=O)—, R21 is -OR32 and R32 is H or linear or branched C1-15alkyl, then A is—CH or —CRc; when X is —S— or —S(=O)— and Ra is OR31, Rb is linear or branched C6.1oa1kyl, linear or branched C6.15alkenyl, C1.3alkoxy-C1.1salkyl-, -T'-C3.10cycloalkyl, -T'-C3. iocycloalkenyl, -T'-C6.10 aryl or -T'-Cs.10heteroaryl; or a pharmaceutically acceptable salt thereof.

4. The compound of any one of Claim 1, wherein n is O or 1; X is —S—, —S(=O)— or —NRn—; Rn is H or A is —CH, —CRc or N, Ra is —ORa2, —O—C(=O)Ra3 or —O—C(=O)—T-0Ra4; Raz is H, linear or branched C1-15alkyl, phosphonate, diarylphosphonate or an O- protecting group, R23 and Ra4 are independently a protecting group, linear or branched C1-15alkyl, linear or branched lkenyl, 1ocycloalkyl, -T-NHRa3p, -T-C3. iocycloalkenyl, -T-C6-1oaryl, -T-C5-10heteroaryl, -T-NH-C(=O)-O-C1-1oalkyl, -T- adamantyl or -C1.3alkylene-C6-1oaryl where the alkylene is substituted with -T- Ragp is H or an N-protecting group; Rb is H, linear or branched C1.15alkyl, linear or branched C2.15alkenyl, C1.3alkoxy-C1. 15alkyl-, -T'-C3.10cycloalkyl, -T'-C3.1ocycloalkenyl, -T'-C6.10 aryl or -T'-C5.1oheteroaryl; RC each is independently linear or ed lkyl, linear or branched C1-15alkoxyl, unprotected or protected hydroxyl group, or —C1-1oalkylene-Y-C6-10heteroaryl wherein - Y- is -CH2-, -NH-, -O- or -S-; symbol * represents the bonding position; n1 is an integer from O to 4, -T- is absent, C1.3alkylene or C2-3alkenylene; -T'— is C1-3alkylene or C2-3alkenylene; and wherein the heteroaryl contains at least one heteroatom, each heteroatom being independently S, N or 0; wherein the alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene and alkenylene are each independently unsubstituted or tuted with at least one sub stituent; wherein the substituent is each independently a halogen, a ting group, protected or unprotected amino group, nitro, nitroso, linear or branched €1.15 alkyl, or linear or branched C145 alkoxy or C3.1ocycloalkyl; and when Rb is H, the ers are included, with the o that when X is —S— or —S(=O)—, Ra is —OR32 and Ra; is H or linear or branched C1-15alkyl, then A is —CH or —CRC, or a pharrnaceutically acceptable salt.

5. The compound of Claim 1, wherein: n is O, X is —S(=O)—, A is N, Ra is —ORa2, O)Ra3 or —O—C(=O)—T—ORa4, wherein Raz is H, linear or branched C1-15alkyl, phosphonate, diarylphosphonate or an O-protecting group; R313 and Ra4 are each independently a protecting group, linear or branched C1-15alkyl, linear or branched C2-15alkenyl, -T-C3-1ocycloalkyl, -T-NHRa3p, -T-C3.1ocycloalkenyl, -T- C6.1oaryl, -T—C5.1oheteroaryl, -T-NH—C(=O)-O-C1-1oalkyl, —T—adamantyl or -C1-3alkylene- C6.1oaryl where the alkylene is substituted with -T-NHRa3p; Ra3p is H or an N—protecting group; Rb is H; mis 3; and RC each is independently linear or branched C1-15alkyl, linear or branched C1.15alkoxyl; or a pharrnaceutically acceptable salt.

6. The compound of any one of Claims 1 to 5, wherein n is 0.

7. The compound of any one of Claims 1 to 4, wherein m is an r from O to 3.

8. The compound of any one of Claims 1 to 3, n Ra is —C(=O)OH, —C(=O)OC1- 4alkyl, H, —ORa2 wherein Raz is H, linear or branched C1-1oalkyl or an 0-protecting group; — O—C(=O)Ra3 wherein Rag is independently tert-butyl ting group; linear or branched C1- ioalkyl unsubstituted or substituted by halogen, tert-butyl protecting group or protected amino group; linear or branched C2.10alkenyl; C1.4alkoxy; ycloalkyl; -C1.3alkylene-C3. 10cycloalkyl; -C3.1ocycloalkenyl; —C6-1oaryl unsubstituted or substituted by C140 alkyl, nitro, C1.15alkoxy or halogen; —C5-10heteroaryl unsubstituted or tuted by C1-10alkoxy; C2- 3alkenylene-C6-1oaryl wherein C6-1oaryl is unsubstituted or substituted by halogen; -C1. 3alkylene-NH--C(=O)-O-C1-1oalkyl; or adamantly; or —O—C(=O)-O-C1-10alkyl.

9. The compound of any one of Claims 1 to 3, wherein Ra is —O-C1-1oalkyl; —O- protecting group or —O—C(=O)Ra3 wherein Ra3 is a tert—butyl protecting group; adamantly; linear or branched C1-1oalkyl unsubstituted or substituted by halogen or a tert-butyl protecting group; C1-4alkoxy; -C6.1oaryl unsubstituted or substituted by C140 alkyl, nitro, lkoxy or halogen; C3-1ocycloalkyl; -C3.1ocycloalkenyl; linear or ed C2-10alkenyl; heteroaryl‘7 -C1.3alkylene-C3-1ocycloalkyl; C2-3alkenylene—C6-1oaryl n C6-1oaryl is unsubstituted or substituted by halogen; —O—C(=O)-O-C1-1oalkyl.

10. The compound of any one of Claims 1 to 3, wherein Ra is —O-C1-4alkyl, -O-tert- butyloxycarbonyl ting group or —O—C(=O)Ra3 n Ra3 is a utyl protecting group; adamantly; linear or branched C1-8alkyl unsubstituted or substituted by halogen or a tert-butyl protecting group; C1.4alkoxy; -phenyl unsubstituted or substituted by C14) alkyl, nitro, C1.4alkoxy or n; C3.6cycloalkyl; —C3-6cycloalkenyl; linear or branched C2- salkenyl; -C5-6heteroaryl; -C1-3alkylene—C3-6cycloalkyl; C2-3alkenylene-phenyl wherein phenyl is unsubstituted or substituted by halogen; —O—C(=O)-O-C1.4alkyl. In some further embodiments, cloalkyl is cyclopropyl or cyclohexyl. In some further embodiments, - C3-10cycloalkenyl is cyclohexenyl.

11. The compound of any one of Claims 1 to 3, wherein Ra is -OH, -COOH, phosphate; -O-C1-6alkyl or —O—C(=O)—C1-6alkyl, —O—C(=O)-C1.4alkylene-NH(Fmoc or Bocprotecting group); or —O—C(=O)—NH—C(=O)—O—C1-10alkyl,

12. The compound of any one of Claims 1 to 3, wherein R; each is independently halogen, linear or branched kyl, linear or branched C1.6alkoxyl, or —C1.1oalkenylene-YC6.1oheteroaryl ; wherein Y is S and C6-1oheteroaryl is unsubstituted or substituted by C1- 15alkyl (preferably C1-4alkyl), C1-15alkenyl (preferably C2-4alkyl), C1.15alkoxy (preferably C1- 4alkoxy), -OH, -NH2, -N02 or halogen.

13. The compound of Claim 1 or 2, which is selected from the group consisting of: 21122: (2-(((4-methoxy-3,5-dimethylpyridin—2—yl)methyl)sulf1nyl)-1H- benzo[d]imidazolyl acetate) 21124: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulf1nyl)-1H- benzo[d]imidazolyl benzoate) 26096: 4—methoxy—3,5—dimethylpyridin—2—yl)methyl)sulf1nyl)-1H- benzo[d]imidazolyl butyrate) 26097: (2-(((4-methoxy—3,5—dimethylpyridin—2—yl)methyl)sulf1nyl)-1H- benzo[d]imidazolyl cyclohexanecarboxylate) 26098: (2-(((4-methoxy-3,5-dimethylpyridin—2—yl)methyl)sulf1nyl)-1H- benzo[d]imidazolyl 4-butylbenzoate) 21 127: 4-methoxy-3 1H- , 5-dimethylpyridin—2—yl)methyl)sulf1nyl)- benzo[d]imidazolyl 3-methylbenzoate) 27076: 2-(((4-methoxy-3 ,5-dimethylpyridinyl)methyl)sulf1nyl)-1H- benzo[d]imidazolyl hexanoate 27077: 2-(((4-methoxy-3 ethylpyridinyl)methyl)sulf1nyl)-1H- benzo[d]imidazolyl isobutyrate 27078: (2-(((4-methoxy-3 1H- , 5-dimethylpyridin-2—yl)methyl)sulf1nyl)- benzo[d]imidazolyl cycloheX-3 -ene— 1 —carboxyl ate) 27079: -methoxy-3,5-dimethylpyridinyl)methyl)sulf1nyl)-1H- benzo[d]imidazolyl exenecarboxylate 28087: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulf1nyl)-1H- benzo[d]imidazolyl ylbenzoate) 28091: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulf1nyl)-1H- benzo[d]imidazol—5—yl 2—nitrobenzoate) 28092: (2-(((4-methoxy—3,5—dimethylpyridin—2—yl)methyl)sulf1nyl)-1H- benzo[d]imidazolyl cyclopropanecarboxylate) 28093: (2-(((4-methoxy-3 1H- , 5-dimethylpyridiny1)methy1)sulfiny1)- benzo[d]imidazoly1 2-ethylbutanoate) 28094: 4-methoxy-3 1H- , 5-dimethylpyridiny1)methy1)sulfiny1)- benzo[d]imidazoly1 2-phenylacetate) 28095: (2-(((4-methoxy-3 , 5-dimethylpyridin-2—y1)methy1)sulfiny1)-1H- benzo[d]imidazolyl 3,5,5-tfimethylhexanoate 28096: (2-(((5 -methoxy-4,6-dimethylpyridin—2—y1)methy1)sulfinyl)- 1H- benzo[d]imidazolyl 2-ethoxybenzoate) 21 123: (2-(((4-methoxy-3,5-dimethylpyridiny1)methy1)su1f1ny1)-1H- benzo[d]imidazolyl nate) 21 125: (2—(((4—methoxy—3 1H- , 5—dimethylpyridin—2—yl)methyl)sulfinyl)- benzo[d]imidazoly1 4—chlorobenzoate) 21 126: (2-(((4-methoxy—3 1H- , 5—dimethylpyridin—2—yl)methy1)sulfiny1)- benzo[d]imidazoly1 3-nitrobenzoate) 21 128: 2-(((4-methoxy-3 ,5-dimethylpyridin—2—yl)methyl)sulfiny1)- 1H- benzo[d]imidazoly1 heptanoate 21 129: (2-(((4-methoxy-3 5 -dimethylpyridin—2—yl)methyl)sulfiny1)- 1H- benzo[d]imidazoly1 4-fluorobenzoate) 21 13 0: (2-(((4-methoxy-3 5 -dimethylpyridinyl)methy1)sulfiny1)-1H- benzo[d]imidazolyl (Z)methy1butenoate) 21 13 1 : (2-(((4-methoxy-3 1H- , 5-dimethylpyridiny1)methy1)sulfiny1)- benzo[d]imidazoly1 2-chloropropanoate) 21 13 2: tert-butyl (2-(((4-methoxy-3 1 H- , 5—dimethylpyridiny1)methyl)sulfiny1)- benzo[d]imidazoly1) carbonate 12124: (2-(((4-methoxy-3 , 5-dimethylpyridin-2—y1)methy1)sulfiny1)-1H- benzo[d]imidazolyl tenoate) 12125: (2-(((4-methoxy-3 1H- , 5-dimethylpyridiny1)methy1)su1finyl)- d]imidazolyl ylbutenoate) 12122: (2-(((4-methoxy-3,5-dimethylpyridiny1)methy1)su1f1ny1)-1H- benzo[d]imidazol—5—y1 furan—2—carboxylate) 12123: (2-(((4-methoxy—3 1H- , 5—dimethylpyridin—2—yl)methy1)sulfiny1)- benzo[d]imidazoly1 acrylate) 12127: (2-(((4-methoxy-3 , 5-dimethylpyridiny1)methy1)sulfiny1)-1H- benzo[d]imidazoly1 2-methy1butanoate) 12128: (2-(((4-methoxy-3 , 5-dimethylpyridiny1)methy1)su1finy1)-1H- d]imidazoly1 3-cyclopenty1propanoate) 12129: (2-(((4-methoxy-3 , 5-dimethylpyridin-2—y1)methy1)su1finy1)-1H- d]imidazoly1 (E)(2-ch1orophenyl)acrylate) 1213 0: (2-(((4-methoxy-3,5-dimethylpyridin—2—y1)methy1)sulfinyl)- 1H- benzo[d]imidazolyl 6-bromohexanoate) 1 1021: 4-methoxy-3,5-dimethylpyridiny1)methy1)su1f1ny1)-1H- benzo[d]imidazolyl 2-fluorobenzoate) 1 1020: (2—(((4—methoxy—3 1H- , thylpyridin—2—yl)methyl)sulfinyl)- benzo[d]imidazoly1 4—methoxybenzoate) 1 1022: (2-(((4-methoxy—3 1H- , 5—dimethylpyridin—2—yl)methy1)sulfiny1)- d]imidazoly1 (3r,5r,7r)-adamantane—1—carboxylate) 1 1023: (2-(((4-methoxy-3 1H- , 5-dimethylpyridin—2—yl)methy1)sulfiny1)- benzo[d]imidazoly1 isoxazole-S-carboxylate) 1 103 0: (2-(((4-methoxy-3 5 hylpyridin—2—yl)methy1)sulfiny1)- 1H- benzo[d]imidazoly1 4-(tert-buty1)benzoate) 1 103 1 : (2-(((4-methoxy-3 , 5-dimethylpyridinyl)methy1)sulfiny1)-1H- benzo[d]imidazoly1 3-chlorofluorobenzoate) 25015: (2-(((4-methoxy-3 , 5-dimethylpyridiny1)methy1)su1finy1)-1H- benzo[d]imidazoly1 pivalate) 25016: (2-(((4-methoxy-3 , 5-dimethylpyridin-2—y1)methy1)su1finy1)-1H- benzo[d]imidazoly1 pentanoate) 25017: (2-(((4-methoxy-3 , 5-dimethylpyridin-2—y1)methy1)su1finy1)-1H- benzo[d]imidazolyl 4-nitrobenzoate) 25027: (2-(((4-methoxy-3 1H- , 5-dimethylpyridiny1)methy1)su1finyl)- benzo[d]imidazolyl cyclobutanecarboxylate) 25028: (2-(((4-methoxy-3,5-dimethylpyridiny1)methy1)su1f1ny1)-1H- benzo[d]imidazol—5—y1 thiophene—2—carboxylate) 25029: (2-(((4-methoxy—3 1H- , 5—dimethylpyridin—2—yl)methy1)sulfiny1)- benzo[d]imidazoly1 2-methy1butanoate) 2503 0: (2-(((4-methoxy-3 1H- , 5-dimethylpyridinyl)methyl)sulfinyl)- benzo[d]imidazolyl 3,3-dimethylbutanoate) 25031: (2-(((4-methoxy-3 1H- , 5-dimethylpyridinyl)methyl)sulfinyl)- benzo[d]imidazolyl 2-methoxyacetate) and 25032: (ethyl (2-(((4-methoxy—3,5—dimethylpyridin-2—yl)methyl)sulfinyl)- 1H- benzo[d]imidazolyl) carbonate) or a ceutically acceptable salt thereof.

14. The compound of Claim 1 or 3, which is selected from the group consisting of: 12082: Methyl 1-(2-(cyclohexenyl)ethyl)(((4-methoxy-3,5-dimethylpyridin- 2-yl)methyl)thio)-1H-benzo[d]imidazole-S-carboxylate 12083: 1-(2—(cyclohex—1—en—1—yl)ethyl)—2—(((4—methoxy-3 ,5 -dimethylpyridin yl)methyl)thio)-1H-benzo[d]imidazole—S—carboxylic acid 12084: Methyl 1-(2-(cyclohex—1—en—1—yl)ethyl)—2—(((4-methoxy-3 , 5-dimethylpy1idin- 2-yl)methyl)sulfinyl)-1H-benzo[d]imidazole—5—carboxylate 12088: methyl 2-(((4-methoxy-3,5—dimethylpyridinyl)methyl)thio)octyl-1H- benzo[d]imidazolecarboxylate 21098: Methyl 2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)amino)- 1-propyl- 1H-benzo[d]imidazolecarboxylate 26065: Methyl 1-(furanylmethyl)—2-(((4-methoxy-3,5-dimethylpyridin yl)methyl)amino)-1H-benzo[d]imidazole-5—carboxylate 21 102: 2-(((4-methoxy-3 ,5-dimethylpyridinyl)methyl)amino)propyl- 1H- benzo[d]imidazolecarboxylic acid 21 103: Methyl 2-(((4-methoxy-3,5—dimethylpyridinyl)methyl)amino) (3 - methoxypropyl)-1H-benzo[d]imidazole—5—carboxylate 21 104: 2-(bis((4-methoxy-3 1 - (3 - , 5—dimethylpyridinyl)methyl)amino)- methoxypropyl)-1H—benzo[d]imidazolecarboxylic acid 26066: Methyl 2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)amino)pentyl-1H- benzo[d]imidazolecarboxylate 21 105: 2-(bis((4-methoxy-3 1 - (2-(cyclohex- , 5-dimethylpy1idinyl)methyl)amino)- -yl)ethyl)-1H—benzo[d]imidazole—S—carboxylic acid 26070: an-2—ylmethyl)—2—(((4—methoxy—3,5—dimethylpyridin yl)methyl)amino)-1H-benzo[d]imidazole—S—carboxylic acid 26071 : Methyl 2-(((4-methoxy-3,5—dimethylpyridinyl)methyl)amino)(4- methoxybenzyl)-1H-benzo[d]imidazole-S-carboxylate 26072: Methyl 2-(bis((4-methoxy—3,5—dimethylpyridinyl)methyl)amino)-3 n- 2-ylmethyl)-3 ,4-dihydroquinazoline—7-carb0xylate 21 106: Methyl 3 -(2-(cycloheX—1—enyl)ethyl)—2-(((4-methoxy-3 5- ylpyridin- 2-yl)methyl)amino)-3 ,4-dihydroquinazolinecarb0xylate 12092: 2-(((4-methoxy-3,5-dimethylpyiidinyl)methyl)thi0)-1H—benzo[d]imidazol- 5-yl (((9H-fluorenyl)methoxy)carbonyl)glycinate 12093: 2-(((4-methoxy-3,5-dimethylpyiidinyl)methyl)thio)-1H-benzo[d]imidazol- 5-yl butoxycarbonyl)glycinate 21 1 10: 2-(((4—methoxy—3 ,5—dimethylpyiidin—2—yl)methyl)amino)-3 - (3 - methoxypropyl)-3,4-dihydroquinazoline-7—carboxylic acid 26076: 2-(((4-methoxy—3 ,5—dimethylpyridin—2—yl)methyl)amino)pentyl- 1H- benzo[d]imidazolecarboxylic acid 26077: 2-(((4-methoxy-3 ,5-dimethylpyridin—2—yl)methyl)amino)(4- methoxybenzyl)-1H-benzo[d]imidazole-S-carboxylic acid 12094: 2-(((4-methoxy-3 ethylpyridin—2—yl)methyl)thio)- 1H benzo[d]— imidazole-S-yl (S)((((9H-fluoreny1)methoxy)carbonyl)amino)phenylacetate 13 001 : 2-(((4-methoxy-3 ,5-dimethylpy1idinyl)methyl)sulfinyl)- 1H- benzo[d]imidazolyl 2-((tert-butoxycarbonyl)amino)acetate 13 084: 2-(((4-methoxy-3 ,5-dimethylpyridinyl)methyl)sulfinyl)- 1H- benzo[d]imidazolyl diphenyl phosphate 26079: Methyl 3-(furanylmethyl)—2—(((4-methoxy-3,5-dimethylpyridin yl)methyl)amino)-3 ,4-dihydroquinazolinecarboxylate 26089: 3-(furanylmethyl)(((4—methoxy-3,5-dimethylpyridin yl)methyl)amino)-3,4-dihydroquinazoline-7—carboxylic acid 26090: 2-(((4-methoxy-3 ,5-dimethylpyridinyl)methyl)amin0)-3 -pentyl-3 ,4- dihydroquinazolinecarboxylic acid 26091: Methyl -methoxy-3,S-dimethylpyridinyl)methyl)amino)pentyl-3,4- dihydroquinazoline—7—carboxylate 26092: Methyl 2-(((4—methoxy—3,5—dimethylpyridin—2-yl)methyl)amino)-3 -(4- methoxybenzyl)-3 ,4-dihydroquinazoline—7—carboxylate 21 1 15: 2-(((4-methoxy-3 ,5-dimethylpyridinyl)methyl)amino) (3- methoxypropyl)-1H-benzo[d]imidazole—5-carboxylic acid 21 1 16: Methyl 1-(2-(cycloheX-1—en—1—yl)ethyl)—2-(((4-methoxy-3 5- dimethylpyridin- 2-yl)methyl)amino)- zo[d]imidazole—5-carboxylate 21 1 17: 1-(2-(cycloheXen-1—yl)ethyl)—2—(((4—methoxy-3 ,5 -dimethylpyridin hyl)amino)-1H-benzo[d]imidazole—5-carboxylic acid 21 1 18: Methyl 2-(((4-methoxy—3,5-dimethylpyridinyl)methy1)amino) phenethyl- 1H—benzo[d]imidazolecarboxylate 21 1 19: 2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)amino)phenethyl- 1H- benzo[d]imidazolecarboxylic acid 21 120: 2-(bis((4—methoxy—3 1H- , 5—dimethylpy1idin—2—yl)methyl)amino)propyl- benzo[d]imidazolecarboxylic acid 21 121: 2-(bis((4-methoxy—3 1H- , 5—dimethylpyridin—2—yl)methyl)amino)phenethyl- benzo[d]imidazolecarboxylic acid 2213 8: 5-methoxy((2-methoxy—3,6—dimethylbenzyl)thio)-1H-benzo[d]imidazole 2213 9: 5-methoxy((2-methoxy-3,6—dimethylbenzyl)sulf1nyl)-1H- benzo[d]imidazole 22140: 2,2'-(((2-methoxymethyl-1,3- phenylene)bis(methylene))bis(sulfanediyl))bis(5-methoxy-1H-benzo[d]imidazole) 21 13 3 : 2-((3 -(bromomethyl)((tert—butyldimethylsilyl)oxy)methylbenzyl)thio) methoxy-1H-benzo[d]imidazole and 22141: 2-((2-methoxy-3 ,6-dimethylbenzyl)thio)—1H-benzo[d]imidazolol or a pharrnaceutically acceptable salt thereof.

15. A pharmaceutical composition, sing a compound of any one of Claims 1 to

16. A method of inhibiting a DAAO, comprising contacting a cell with a compound of any one of Claims 1 to 14.

17. A method of treating or preventing the disease associated with DAAO inhibition in a subject, which comprises administrating an effective amount of a compound of any one of Claims 1 to 14 to the subject.

18. The method of Claim 17, wherein the disease is symptom domains of schizophrenia and schizoaffective disorder, depression, Tourette me, raumatic stress disorder , Obsessive-compulsive disorder (OCD), analgesics, loss of memory and/or cognition associated with neurodegenerative diseases or loss of neuronal on characteristic of neurodegenerative diseases.

19. The method of Claim 18, wherein the symptom domains of schizophrenia and schizoaffective disorder include negative, ive, depressive, positive and general pathology symptom domains.

20. The method of Claim 17, wherein the disease is mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease or schizophrenia.

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