NZ751050B2 - Novel substituted benzimidazole derivatives as d-amino acid oxidase (daao) inhibitors - Google Patents

Novel substituted benzimidazole derivatives as d-amino acid oxidase (daao) inhibitors Download PDF

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NZ751050B2
NZ751050B2 NZ751050A NZ75105017A NZ751050B2 NZ 751050 B2 NZ751050 B2 NZ 751050B2 NZ 751050 A NZ751050 A NZ 751050A NZ 75105017 A NZ75105017 A NZ 75105017A NZ 751050 B2 NZ751050 B2 NZ 751050B2
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methyl
methoxy
benzo
sulfinyl
imidazol
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NZ751050A
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NZ751050A (en
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Hai Gwo Hwu
Wen Sung Lai
Chih Min Liu
Yu Li Liu
Chung Ming Sun
Yufeng Jane Tseng
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National Chiao Tung University
National Health Research Institutes
National Taiwan University
Yufeng Jane Tseng
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Priority claimed from PCT/US2017/051610 external-priority patent/WO2018053161A1/en
Publication of NZ751050A publication Critical patent/NZ751050A/en
Publication of NZ751050B2 publication Critical patent/NZ751050B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/28—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Abstract

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

Description

(12) Granted patent specificaon (19) NZ (11) 751050 (13) B2 (47) Publicaon date: 2021.12.24 (54) NOVEL SUBSTITUTED BENZIMIDAZOLE DERIVATIVES AS D-AMINO ACID OXIDASE (DAAO) INHIBITORS (51) Internaonal Patent Classificaon(s): C07D 401/12 C07D 235/04 A61K 31/4439A61K 4 (22) Filing date: (73) Owner(s): 2017.09.14 National Taiwan University National Chiao Tung sity (23) Complete specificaon filing date: National Health Research Institutes 9.14 Yufeng Jane Tseng (30) Internaonal Priority Data: (74) Contact: US 62/394,479 2016.09.14 Spruson & Ferguson Pty Ltd (86) Internaonal Applicaon No.: (72) Inventor(s): SUN, Chung-Ming TSENG, Yufeng Jane (87) Internaonal Publicaon number: LIU, Yu-Li 8/053161 LAI, Wen-Sung LIU, Chih-Min HWU, Hai-Gwo (57) Abstract: The present invenon provides novel substuted benzimidazole derivaves used as DAAO inhibitors and for treatment and/or on of neurological disorders. 751050 B2 NOVEL SUBSTITUTED BENZIMIDAZOLE DERIVATIVES AS O ACID E (DAAO) INHIBITORS Reference to Related Application This ation claims the benefit of U.S. Provisional Application Ser. No. 62/394,479, filed on September 14, 2016, which is incorporated herein by reference in its entirety.
Field of the Invention The ion 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 tion ological disorders.
Background of the Invention The aberrant regulatory ism ofglutamate transmission on N-methyl-D- aspartic acid (NMDA) receptor has been reported as one of the neuropathology in schizophrenia. The receptor is a heterotetramer composed of two structure subunits of NMDA receptor 1 (NRl) and NR2. Modulation of the e binding site ofNMDA receptor may improve the cognitive function and negative symptoms in phrenia. D­ amino acid oxidase (DAAO) was found to be involved in the activation process of the NMDA receptor. The substrates ofDAAO, especially the D-serine, 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 a-aminohydroxy methylisoxazole nic 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 Invention The present invention pertains to a list ofsubstituted benzimidazole derivatives used as DAAO tors and for treatment and/or prevention ofneurological disorders.
The present invention provides a compound 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 inhibiting a DAAO comprising contacting a cell with a compound of the present invention.
The present invention also provides a method of treating or preventing the disease associated 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, sion, 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. Certain embodiments include mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease and schizophrenia.
Brief Description of the Drawing Figure 1 shows that compared to the MK—801 group, different s 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 nia after acute MK—801 injection.
Figure 3 shows a significant reduction of PPI after acute MK-80l injections.
Detailed ption of the Invention Accordingly, 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 phrenia and depression affective disorder.
Known inhibitors ofDAAO include benzoic acid, ecarboxylic acids, and indolecarboxylic acids. Indole derivatives and particularly certain indolecarboxylates have been described in the literature for ent of neurodegenerative disease and neurotoxic injury. EP 396124 discloses carboxylates and tives for treatment or management of neurotoxic injury ing from a CNS disorder or traumatic event or in treatment or management of a neurodegenerative disease. US. Pat. Nos. 018; ,374,649; 5,686,461; 5,962,496 and 6,100,289 disclose treatment of neurotoxic injury and neurodegenerative disease using indole derivatives. W0 03/039540 se DAAO inhibitors, including indolecarboxylic acids, and methods of enhancing learning, memory and cognition as well as s for treating neurodegenerative disorders. Patent Application No. WO/2005/O89753 discloses benzisoxazole analogs and methods of treating mental disorders, such as Schizophrenia. 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 properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be ed. 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 imation within mental variability (or within statistical experimental . The term "comprising" (and related terms such as ise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, may "consist of" or st essentially of" the described features. ions "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, ning no ration, having from one to fifteen carbon atoms (e.g., C1-C15 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C1o alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C1-C8 alkyl). In other ments, an alkyl comprises one to five carbon atoms (e.g., C1-C6 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, 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 . In other ments, 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- methylethyl (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 tuted by one or more of substituents.
"Alkoxy" refers to a radical bonded through an oxygen atom of the formula 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 hydrogen atoms, containing at least one -carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other ments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, l (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-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, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other ments, an alkynyl has two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for e, 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 d from an aromatic clic or multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic arbon ring system ns 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 benzene, 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 ally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally tuted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally tuted carbocyclylalkyl, optionally substituted heterocyclyl, optionally tuted cyclylalkyl, 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) , -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 substituted with one or more halo groups), aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, each R. sup.b is independently a direct bond or a ht 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 otherwise ted.
"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 yclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it ns a cyclic, delocalized (4n+2) pi-electron system in accordance with the Huckel theory. aryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally ed. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the le through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, nyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, yranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[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]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, l, 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, isoindolyl, indolinyl, isoindolinyl, nolyl, indolizinyl, isoxazolyl, 5,8—methano—5,6,7,8—tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, zepinyl, oxazolyl, oxiranyl, ,6,6a,7,8,9,10, tahydrobenzo[h]quinazolinyl, l—phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, [3,4-d]pyrimidiny1, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, 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 ls as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally tuted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted cyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -Rb--0Ra, -Rb- OC(O)—Ra, -Rb-OC(O)-0Ra, -Rb-OC(O)-N(Ra)2, (Ra)2, -Rb-C(O)Ra, -Rb-C(O)0Ra, -Rb- C(O)N(Ra)2, -Rb-O-R-C(O)N(Ra)2, (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 ed 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 otherwise indicated.
The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts of basic compounds assed within the term "pharmaceutically acceptable salt" refer to non-toxic salts of the compounds of this ion which are generally prepared by reacting the free base with a suitable organic or inorganic acid. Representative salts of basic compounds of the present invention include, but are not limited to, the ing: acetate, ascorbate, adipate, te, te, benzenesulfonate, benzoate, onate, bisulfate, bitartrate, borate, bromide, butyrate, rate, rsulfonate, camsylate, carbonate, chloride, clavulanate, citrate, cyclopentane propionate, diethylacetic, onate, dihydrochloride, dodecylsulfanate, edetate, edisylate, estolate, esylate, ethanesulfonate, formic, te, gluceptate, eptanoate, gluconate, glutamate, glycerophosphate, glycollylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, oxyethanesulfonate, hydroxynaphthoate, iodide, isonicotinic, isothionate, lactate, lactobionate, laurate, , maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N- methylglucamine ammonium salt, oleate, oxalate, e (embonate), palmitate, pantothenate, pectinate, persulfate, phosphate/diphosphate, pimelic, phenylpropionic, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, 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 um, ammonium, calcium, , ferric, ferrous, lithium, magnesium, manganic, mangamous, potassium, sodium, zinc, and the like. Also included are the ammonium, calcium, ium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, cyclic amines, dicyclohexyl amines and basic ion-exchange , such as arginine, betaine, caffeine, choline, N,N—dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylamine, ethylenediamine, N—ethylmorpholine, N—ethylpiperidine, glucamine, glucosamine, ine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, pylamine, hamine, and the like. Also, included are the basic nitrogen-containing groups that may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, , and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl es, long chain halides such as decyl, lauryl, myristyl and l chlorides, bromides and iodides, l halides like benzyl and phenethyl bromides and others.
The term "subject" es living organisms such as humans, monkeys, cows, sheep, horses, pigs, cattle, goats, dogs, cats, mice, rats, ed cells, and transgenic species 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. Treatment can also refer to a method of reducing the underlying cause of the disease or condition itself rather than just the symptoms. The treatment can be any reduction from native levels and can be, but is not limited to, the complete ablation of the e, condition, or the symptoms of the disease or condition.
The term "prevent," "prevention" or "preventing" means inhibition or averting of symptoms associated with the target disease.
The phrase "therapeutically effective amount" refers to that amount of a nd, material, or composition comprising a compound of the present 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 undesirable condition of the central or peripheral nervous system of a . The term "neurological disorder" es egenerative diseases (e. g., mer's disease, Parkinson's disease and amyotrophic lateral sis), neuropsychiatric diseases (e.g. phrenia and anxieties, such as general anxiety er). 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, sion (e.g., bipolar disorder), dementias, movement disorders, psychoses, lism, post-traumatic stress disorder and the like. logical disorder" also includes any undesirable condition associated with the disorder. For instance, a method of treating a neurodegenerative disorder 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 on 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—; n Rn is H or A is —CH, —CRC or N; Ra is 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 C1-15alkyl, 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, -T-NH-C(=O)-O-C1-1oalkyl, -T- adamantyl or -C1.3all In one embodiment, the present ion provides a compound of formula (I-a): wherein n is 0 or 1, X is —S—, —S(=O)— or —NRn—; wherein Rfiim 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 ed 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 ed 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; Ragp is H or an N—protecting group; Rb is H, linear or branched C1-15alkyl, linear or branched C2-15alkenyl, C1-3alkoxy-C1- l-, -T'-C3-1ocycloalkyl, -T'—C3-1ocycloalkenyl, -T'-C6.1o aryl or -T'—C5.1oheteroaryl; RC each is independently linear or ed C1.1salkyl, linear or branched C1.15alkoxyl, unprotected or protected hydroxyl group, or —C1.ioalkylene-Y—C6.1oheteroaryl wherein - Y- is -CH2-, -NH-, -O- or -S-; symbol * represents the bonding position; m is an integer from 0 to 4; -T- is , kylene 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 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)—, 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 thereof.
In one embodiment, 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)Ra3; n Ral is H or linear or ed C1-15alkyl; Raz is H; linear or branched C1-15alkyl; phosphonate, phosphonate 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 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'-C3.10 cycloalkyl; -T'-C3- iocycloalkenyl; -T'-C6.1o aryl or -T'-C5-10 heteroaryl; 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 wherein -Y- is -CH2-, -NH-, -O- or -S-; symbol * represents the bonding on; In is an integer from O to 4; -T- is absent, C1.3alkylene or C2.3alkenylene; -T'- is kylene; 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, protected or unprotected amino group, nitro, nitroso, linear or branched €1-15 alkyl, linear or ed C145 alkoxy or C3- iocycloalkyl, and when Rb is H, the ers 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)ORa1, Rb is linear or branched C6.15alkyl, 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.
In one embodiment, the present invention provides the compound of formula (I), n n is O or 1; X is —S—, —S(=O)— or —NRn—; wherein Fish Rn is H or A A is —CH, —CRc or N, Ra is —ORa2, —O—C(=O)Ra3 or —O—C(=O)-T—0Ra4; wherein Raz is H, linear or ed lkyl, phosphonate, diarylphosphonate or an ecting group; R23 and Ra4 are independently a protecting group, linear or branched C1-15alkyl, linear or branched C2-15alkenyl, 1ocycloalkyl, -T-NHR33p, -T-C3-1ocycloalkenyl, -T-C6-10aryl, -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, linear or branched C1.15alkyl, linear or branched C2.15alkenyl, C1.3alkoxy-C1.1salkyl-, .1ocycloalkyl, -T'-C3.iocycloalkenyl, -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-ioalkylene—Y-C6-1oheteroaryl 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 C1-3alkylene or C2-3alkenylene; and wherein the heteroaryl contains at least one atom, 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 C145 alkyl, or linear or branched C1.15 alkoxy or C3.iocycloalkyl; and when Rb is H, the tautomers are included, with the o that when X is —S— or —S(=O)—, Ra is —ORa2 and Ra; is H or linear or ed Ci-15alkyl, then A is —CH or —CRC; or a pharrnaceutically acceptable salt thereof.
In a r embodiment, the present invention provides the compound of formula (I), wherein n is O, X is —, A is N, Ra is —ORa2, —O—C(=O)Ra3 or —O—C(=O)—T—0Ra4, wherein Raz is H, linear or branched C1- isalkyl, phosphonate, diarylphosphonate or an O-protecting group; R23 and Ra4 are independently a protecting group, linear or branched C1-15alkyl, linear or branched lkenyl, -T—C3-iocycloalkyl, -T-NHRa3p, -T-C3-1ocycloalkenyl, -T—C6.10aryl, -T- C5-ioheteroaryl, C(=O)-O-Ci-ioalkyl, -T-adamantyl or -C1.3alkylene-C6.1oaryl 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 branched C1.isalkoxyl; or a phannaceutically able 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 branched C1-1oalkyl or an O—protecting group; —O—C(=O)Ra3 wherein Ra3 is independently utyl protecting group; linear or branched C1-1oalkyl unsubstituted or substituted by halogen, tert-butyl protecting group or protected amino group; linear or branched C2-1oalkenyl; C1-4alkoxy; C3-1ocycloalkyl; -C1-3alkylene-C3.iocycloalkyl; -C3. 1ocycloalkenyl; -C6.1oaryl unsubstituted or tuted by C1-10 alkyl; nitro, C1.15alkoxy or halogen; -C5.1oheteroaryl unsubstituted or substituted by C1-10alkoxy; C2-3alkenylene-C6.10aryl wherein C6.1oaryl is unsubstituted or tuted 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)Ra3 wherein Rag is a tert-butyl protecting group; adamantly; linear or branched C1.1oalkyl unsubstituted or tuted by halogen or a utyl protecting group; C1.4alkoxy; aryl unsubstituted or substituted by C140 alkyl; nitro, C1-15alkoxy or halogen; C3-10cycloalkyl; -C3. iocycloalkenyl; linear or branched lkenyl; —C5-1oheteroaryl; -C1.3alkylene-C3. oalkyl; 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, -O-tertbutyloxycarbonyl 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; koxy; -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 unsubstituted or substituted by halogen; —O—C(=O)—O-C1-4alkyl. In some further embodiments; C3-6cycloalkyl is cyclopropyl or cyclohexyl. In some further embodiments; - ycloalkenyl is cyclohexenyl.
In some further embodiments; heteroaryl is idinyl; pyrrolinyl; pyrazolidinyl; imidazolidinyl; pyrazolinyl; imidazolinyl; pyrazolyl; imidazolyl; tetrahydrofuranyl; furanyl; anyl; tetrahydrothiophenyl; thiophenyl; oxazolyl; isoxazolyl; isothiazolyl; thiazolyl; oxathiolanyl; piperidinyl; pyridinyl; piperazinyl; pyridazinyl; pyrimidinyl; pyrazinyl, tetrahydropyranyl, pyranyl; dioxanyl; thianyl; ranyl; morpholinyl; oxazinyl or thiazinyl.
In further embodiments; heteroaryl is furanyl; isoxazolyl or thiophenyl.
In some ments; Ra is -OH, -COOH; -O-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.
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 rably 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- :x'x N" w '\ I firw;\‘3«} ‘Xwi‘r‘: M245 ioheteroaryl is In some ments, the compound of the t invention is selected from the group ting of: NCTU-SUN- M.W. Chemical Structure 2-(((4-methoxy-3,5-dimethylpyridin yl)methyl)sulfinyl)— lH—benzo[d]imidazolyl 2-((tertbutoxycarbonyl )amino)acetate 26090 410.52 2-(((4-methoxy-3,5-dimethylpyridin yl)methyl)amino)pentyl-3,4-dihydroquinazoline carboxylic acid NCTU-SUN- M.W. Chemical 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) Q71 (Ir 1, 28096 479.55 (2-(((5—methoxy-4,6—dimethy1pyridin y1)methyl)sulfinyl)—1H—benzo[d]imidazoly1 2- ethoxybenzoate) 12093 472.56 2—(((4—methoxy—3,5—dimethylpyridinyl)methyl)thio)- zo[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 hyl)sulfinyl)—1H—benzo[d]imidazolyl 6- bromohexanoate) O N\ {—57 27077 40148 2-(((4-methoxy-3,5-d1methylpyr1d1n_ . . yl)methy1)sulfinyl)—1H—benzo[d]imidazoly1 isobutyrate ©\EOUp)N\ [5* 27079 449 52 2-(((4-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- dihydroquinazoline-7—carb0xylic acid (2-(((4-methoxy-3,5-dimethy1pyn'din yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl 4- fluorobenzoate) "1%:wa 25032 (ethyl (2-(((4—methoxy—3,5-dimethy1pyridin y1)methyl)sulfinyl)—1H-benzo[d]imidazoly1) carbonate) WOU;\>—\b[Ci\ / 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 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 yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl 3 - cyclopentylpropanoate) 26071 Methyl 2—(((4-methoxy-3,5-dimethylpyridin yl)methyl)amino)— 1 —(4-methoxybenzy1)-1H- benzo[d]imidazole-S-carboxylate 11021 (2-(((4-methoxy-3,S-dimethylpyridin yl)methyl)sulfinyl)-1H-benzo[d]imidazolyl 2- fluorobenzoate) NCTU-SUN- 21 1 18 Methyl 2-(((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)amino) phenethyl-1H-benzo[d]imidazole- oxylate 26070 1-(furanylmethyl)—2—(((4-methoxy-3,5- dimethylpyridin—2—yl)methyl)amino)- 1H- benzo[d]imidazole—5—carboxylic acid 25029 (2-(((4—methoxy-3,5—dimethy1pyridin y1)methyl)sulfinyl)—lH—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 4-methoxy-3,5-dimethy1pyridin yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl isoxazole-S-carboxylate) Wme\b 26096 H (2-(((4—methoxy—3,5—dimethy1pyridin yl)methy1)sulfinyl)—1H—benzo[d]imidazolyl butyrate) air my 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)-1—octyl-1H—benzo[d]imidazole carboxylate 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 - dimethylpyridin-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)methyl)sulfinyl)—1H—benzo[d]imidazoly1 3- nitrobenzoate) : O N $5; E Ur \b ‘ / 26097 441 .5 5 4-methoxy-3,5-dimethy1py11'din yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl cyclohexanecarboxylate) :11? Rf: N .3." 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-dimethylpyn'din-Z- hyl)amino)propy1- 1H-benzo[d]imidazole carboxylic acid 21121 . 2; 2-(bis((4-methoxy—3,5-dimethylpyridin yl)methyl)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 % 28094 (2-(((4-methoxy-3,5-dimethy1pyridin yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl 2- acetate) no2 \o @mmfi 28091 (2-(((4—methoxy—3,5—dimethy1pyfidin 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- . . Chemical Structure 7; (Ir 1,N [U 21 122 H 4-meth0xy-3,5-dimethy1pyridin yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl acetate) "(Exfd% 1 1022 (2—(((4—methoxy—3,5—dimethylpyridin yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl (3 r, 5r,7r)—adamantane— 1 —carboxylate) XQX 1’ OUM? 1 103 O (2-(((4-methoxy-3,5-dimethy1pyridin yl)methy1)sulfinyl)—1H—benzo[d]imidazoly1 4-(tert- butyl)benzoate) 2-(((4-methoxy-3,5-dimethy1pyridin yl)methyl)amino)propy1- 1H-benzo[d]imidazole carboxylic acid 21132 NCTU-SUN- M.W. Chemical ure .'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 y1)methyl)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)amin0)—2-pheny1acetate 21105 583.73 ‘ NCTU-SUN- M.W. Chemical Structure 2-(bis((4-methoxy-3,5—dimethylpyridin y1)methyl)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 hyl)amino)—3-(furan-2—y1methyl)-3 ,4- dihydroquinazolinecarboxy1ate NCTU-SUN- 22140 2,2'-(((2-methoxymethy1-1,3 - phenylene)bis(methylene))bis(su1fanediyl))bis(5- methoxy—1H—benzo[d]imidazole) 21 13 3 2-((3 -(bromomethyl)—2-((tert-butyldimethylsi1y1)oxy) benzy1)thio)—5-methoxy-1H-benzo[d]imidazole 21 125 2-(((4-methoxy-3,5—dimethy1pyridin y1)methyl)sulfinyl)—1H—benzo[d]imidazoly1 4- chlorobenzoate 27078 (2-(((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 -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 2-(((4-methoxy-3,5-dimethy1pyridin yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl heptanoate NCTU-SUN- M.W. Chemical Structure 27076 429. 53 2-(((4-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 fixkfi 21119 km? -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- hyl)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- dihydroquinazoline—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 Structure 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 21124 (2-(((4-methoxy-3,S-dimethylpyn'din-z- yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl benzoate) \J:g/ Ug—‘bO N A? \ / 28093 (2-(((4-methoxy—3,5—dimethy1pyn'din yl)methyl)sulfinyl)—1H—benzo[d]imidazoly1 2- ethylbutanoate) 26091 Methyl 2—(((4-meth0xy—3,S-dimethylpyridin-Z- hyl)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 ~ methoxy-3,6-dimethy1benzyl)thi0)-1H- benzo[d]imidazolol 28087 (2—(((4—methoxy—3,5—dimethy1pyridin yl)methyl)sulfinyl)—1H—benzo[d]imidazolyl 4- methylbenzoate) 21 123 (2-(((4-methoxy-3,5-dimethy1pyridin yl)methy1)sulfinyl)—1H—benzo[d]imidazoly1 propionate) 12092 2-(((4—methoxy-3,5—dimethylpyridin—2—y1)methy1)thio)- 1H-benzo[d]imidazoly1 (((9H—fluoren yl)methoxy)carbonyl)glycinate 21098 NCTU-SUN- . . Chemical Structure Methyl 2—(((4-meth0xy—3,S-dimethylpyridin-Z- y1)methyl)amino)— 1—propy1—1H-benzo[d]imidazole carboxylate 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. al 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 invention encompasses all stereoisomeric forms of the nds of Formula I, a I-a and a I-b. Centers of asymmetry that are present in the compounds of Formula I, Formula La and Formula I—b can all ndently 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. Similarly, when a compound name is recited without a chiral ation for a chiral carbon, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence individual enantiomers and mixtures thereof, are embraced by the name.
The invention includes all possible enantiomers and diastereomers and mixtures of two or more isomers, for e mixtures of omers and/or diastereomers, in all ratios. Thus, enantiomers are a subject of the invention in enantiomerically pure form, both as levorotatory 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 d out, if desired, by separation of a mixture by customary methods, 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 separation of a e of stereoisomers can be earned out at an intermediate step during the synthesis of a compound 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 ts 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 f are included in the scope of this ion.
The present invention includes all such isomers, as well as salts, solvates (including hydrates) and ed salts of such racemates, enantiomers, diastereomers and tautomers and mixtures thereof. lpreparation procedures ofthe compounds ofthe present invention The compounds of Formula (I) of the present invention are prepared according to general chemical synthetic ures. The preparation of the embodiments of the compounds of the present ion is illustrated below.
Synthetic Scheme and Procedurefor the Preparation of the compounds of the inventionfrom RS—D7 H — O NaOH HOUri—bi + N RJkCI 21 EtOH, rt, 1 h RIO>—\©:ft;z\ RS-D7 R is —Ra3 or —T-ORa4.
Synthetic Scheme and Procedurefor the Preparation ofNCTU—SUN-26065 series o o Rb—NH2 N02 ConC' H2804 (0'3 M) N02 (3 equi") HO \0 MeOH' reflux' 12h DC'V" 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 4 K2CO3(2 eq) s :E—NHz \0 N R" + KI(O3 eq) Cl :4, N\>—N — ACN \ reflux 6h Rb / a NCWEUNRXXXXX Rb — H "near or branched (51:15_alky| linear or branched 02 15a|keny| Rn H' / /N C1 Salkoxy C1 1:5alkyl’ T C3 °a|kyl T C3 1OCyC|°a|keny| I T C6 10 aryl or T C5 1Oheter03ry| 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’ rt! 2 h 1 2 o 2n (15 equiv) 0 4 (7'5 eqUiV) \OJUNW ‘ZBQ) —> —> MeOH' r1130 mIn‘ Rb DCM’ r1 em H H a 4 0 o 0 Mai-w K CO;3Q);2 e I 2 q) \"cmN Rn \O \O N Kl e Rn _ _.~a IJ: 3 _ \ EtOH/HZO (1:1) \ reflux 5" NR / NR / b RefIUX’ 1h b '"= 7 IICTIISIIN‘XXXXXX Rb =H "near or branched C1 | "near or branched CZ 158|keny|‘ Rn H’ :11?- [N 01 '3'aI_I<0Xyc1 -1‘_53|_ky|-_’ 'T c'3'100yCIoaIkyI -T-CS-100y0|03|kenyl‘ l 'T"cs10 aryI or 'T '05'10heteroaryI \ 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 1 2 O o N02 SnCIZ' 2H20 (3'5 eqUiV) CN Br (1'2eq) \0 NH \ 2 H —> —> MeOH' reflux) 10 min' DCM’ ‘Rb ‘Rb W 3hr 0 <5 \ K20032 eq 0 \ ml: K[(0 3 eq) reflux 24h NCTU‘SUNJXXXXXX Rb-_'H linear Ol‘ branched C1 153|ky| linear Ol‘ branched C2 153|kenyl' Rn H' a J" c1"3aI_IXyc1 1saI_I\O H‘ —.
MeOH' reflux’ 10 mm‘ H DCM, Rb ‘Rb W em 3 4 0 (g o Rn / N NH chosé2qeq) NaOH(s5% N N | N\ / EtOH/HZO(13 1) N R" ACN Reflux 1h ‘Rb reflux 24h s a 7 nm‘u‘suw‘xxxxxx Rb H’ "near or branched c1'1§a|ky|v "near or branched c2'15a|keny|v Rn H' 3,1 /N 01'33Ik0Xy'c1'153IkyI" 'T'C3'1OCyCI03IkyI’ 'T'C3'1ocycloalkenyl' I 'T'06'10 aWyl or 'T'CS'10heter03ryl Synthetic Scheme and Procedurefor the Preparation ofNCTU—SUN-]2082 series 0 o Rb—NH2 NO2 conc‘ sto4 (0'3 M) HO N02 \0 (3 equiv) MeOH’ reflux, 12h F DCM’ rt: 2 h 0 Zn (15 eqUiV) 0 \0 HCOONH4 (7'5 eqUiV) NH2 \o CS2 (12%) —> —’ R MeOH’ rt, 30 min' R , b b N} N, KOHo EtOH H H 50 c 8hr 3 4 o o \o N A) b \O N S + Cl \ @0312 eq) ‘>—8 KI(0 3‘ [\l / e N (1) N —> Rb / Rb ACN reflux 6h s wkxxxxx Rb: H linear or bran0hed c1 | linear or bran0hed 02,'_1sa_lkenyl c1"3alk0Xyc1"15alkyl : T "c3 1OCyC|03|ky|’ T c3 1OCyCIoaIkenyI T "ce1oaryl or T "cs10heteroaryl Synthetic Scheme and Procedurefor the Preparation 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 R reflux 6h Reflux) 1h / b RD 6 7 NCTU‘SUN‘XXXXXX Rb H' linear or ed C1_1Sa|ky|’ linear or braHChed 02'1salkenylv 01'salkOXy'c1'1saIkyIV 'T"c3‘100yCIoaIkyIv 'T"c3'1OCyCIoaIkenyIv 'T"ce'1o aryl or 'T"cs' roary| tic Scheme and Procedurefor the Preparation ofNCTU—SUN-]2084 o o Rh—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 Nflu‘suw‘xxxxxx Rb H’ linear or branCheq C1-153|ky|’ linear or branCheq C2_1salkenyl’C1-Salk0Xy_C1-153|kyl-’-T'_CS_1OCy0|°alkyl' ’T"cs’1OCyCIoaIkenyI' 'T"ce'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— eq 11 eq 1 :2 ascm'suw'xxxxx _ o o o Ra _ ’ ’ FmocH N$03!; PhO\ BocHN$031; FmocHN 032; PhdflLOx‘ Synthetic Scheme and Procedurefor the Preparation —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 N/>— 1 2 weru'suw'xxxxx = = = R8 OH’ 0M6 RC1 OMe’ OTBS RCX H’ Br Synthetic Scheme and Procedurefor the Preparation ofNCTU—SUN-22139 UNZI RC1 RC1 NBS (1 2 eq). NaOH (1 1 9(1) —> Rex—> CHCIS' hv: reflux \©:cx EtOH reflux \l 1 2 4 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 .
The nds of the invention are useful for treating or preventing any disease and/or condition, wherein modulation of D-serine , and/or its oxidative products, is effective in ameliorating symptoms. Inhibition of the enzyme can lead to increases in D- serine levels and a reduction in the formation of toxic D-serine oxidation products. Thus, the invention provides methods for the treatment or tion of neurological disorders and methods of ing learning, memory and/or cognition. The invention also es methods for the treatment or prevention of the disease ed by DAAO inhibition, preferably, 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. In some embodiments, the m domains of schizophrenia and schizoaffective disorder include negative, cognitive, depressive, positive and general psychopathology symptom domains. In another embodiment, the disease associated with DAAO inhibition is mild ive impairment (MCI), Alzheimer's disease, Parkinson’s e or schizophrenia. In some embodiments, the disease associated 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 teristic of neurodegenerative diseases. Further, 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 Another aspect of the present invention provides ceutical compositions which comprises a compound of Formula I (or a pharmaceutically acceptable salt or solvate thereof) and a pharmaceutically acceptable carrier. The term "composition", as in pharmaceutical composition, is intended to ass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from ation, 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 ion encompass any composition made by admixing a compound of Formula 1, onal active ingredient(s), and pharmaceutically able excipients.
The pharmaceutical compositions of the present invention compnse a compound represented by Formula I (or a pharmaceutically acceptable salt or solvate f) as an active ingredient, a pharmaceutically able earlier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, 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 ient is being administered. The pharmaceutical compositions may be conveniently 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 es, 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 l administration, as an ophthalmic solution or suspension formation, i.e., eye drops, for ocular administration, as an aerosol spray or powder ition for inhalation or intranasal administration, or as a cream, ointment, spray or suppository for rectal or l administration.
For topical applications, the active ient or a pharmaceutical composition thereof can be ated 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 composition thereof include, but are not d to, mineral oil, liquid petrolatum, white petrolatum, ene glycol, polyoxyethylene, ypropylene nd, emulsifying wax, sugars such as lactose and water.
Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active ingredient or a pharmaceutical composition f suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
Depending on the particular ion, disorder or disease to be treated, additional therapeutic agents can be stered together with the active ingredient or a pharmaceutical composition thereof. Those additional agents can be administered 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 thereof (simultaneous or concurrent administration).
For oral administration, a pharmaceutical composition useful in the invention can take the form of solutions, suspensions, tablets, pills, capsules, s, 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 a starch, and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, n 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 s. When aqueous suspensions and/or elixirs are desired for oral administration, t the active ingredient or a pharmaceutical composition thereof of this invention can be combined with various sweetening agents, flavoring agents, coloring agents, emulsifying agents and/or suspending agents, as well as such ts as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
The term "parenteral" as used herein refers to modes of administration which e enous, intramuscular, intraperitoneal, ternal, aneous, intramedullary and intraarticular injection and infusion. A pharmaceutical composition for parenteral injection can se pharmaceutically acceptable e aqueous or nonaqueous ons, dispersions, suspensions or ons as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Aqueous ons are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes. In this connection, the sterile aqueous media employed are all readily obtainable by rd techniques well-known to those skilled in the art. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene , polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for e, by the use of coating materials such as lecithin, 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 , 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 e isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption such as um 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 on to the active compounds, can contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and es thereof.
For es of transdermal (e.g., topical) stration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar 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 pharmaceutical ation and can be prepared as solutions in saline, employing benzyl l or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.
Compositions for rectal or vaginal administration are ably itories which can be prepared by mixing the active ingredient or a ceutical composition thereof with suitable ritating excipients or carriers 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 acceptable carriers include, but are not limited to, a non- toxic solid, semisolid or liquid filler, diluent, encapsulating material 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, e, sorbic acid, potassium sorbate, partial glyceride mixtures of ted vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium en phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose—based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
Solid pharmaceutical ents include, 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 ents 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, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, ularly for injectable ons, include water, saline, aqueous se, and glycols.
Methods of preparing various pharmaceutical itions with a certain amount of active ient 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 description. The following examples are, ore, to be ued as merely illustrative and not a limitation of the scope of the present 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 temperature and stirred further for 1 hour.
The reaction was extracted with ethyl acetate and pure water. The c layer was dried over MgSO4, filtered and concentrated to give the reaction mixture. The reaction mixture was purified by silica-gel column chromatography 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: (2-(((4-methoxy-3,5-dimethylpyridin-Z- hyl)sulfinyl)—lH-benzo[d]imidazol-S—yl benzoate) Except that acetyl chloride is replaced by benzyl 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 8.24 (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 r 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), 7.43 (d, J: 2.0 Hz, 1H), 7.08 (dd, J: 87,21 Hz, 1H), 4.72 (s, 1H), 3.74 (s, 3H), 2.60 (t, J: 7.3 Hz, 2H), 2.24 (s, 6H), 1.77 (h, J = 7.3 Hz, 3H), 1.04 (t, J = 7.4 Hz, 3H).
LRMS (ESF) m/z : 402.1 (M+H)+.
Example 1-4 NCTU-SUN-26097: (2-(((4-methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)-1H-benzo[d]imidazol-S-yl cyclohexanecarboxylate) 0301:8332 Except that acetyl chloride is replaced by hexahydrobenzoyl chloride, the other reactants and preparation steps are similar to those described in e 1 to afford the title 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-butylbenz0ate) mougyé—bi Except that acetyl chloride is replaced by 4—Butylbenzoyl 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), 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) firm/mA?W Except that acetyl chloride is replaced by m-Toluoyl chloride, the other reactants and preparation steps are r 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 UN-27076: 2—(((4—methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazolyl hexanoate \/\/\g/ UN\>_N \ / Except that acetyl chloride is ed by hexanoyl 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) 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, 2.1 Hz, 1H), 4.71 (s, 2H), 3.75 (s, 3H), 2.89 — 2.84 (m, 1H), 2.24 (d, J= 2.4 Hz, 6H), 1.31 (d, J= 7.0 Hz, 6H).
LRMS (ESI+) m/z : 402.2 (M+H)+. e 1-9 NCTU-SUN-27078: (2—(((4—methoxy-3,5—dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl cyclohexenecarb0xylate) UN)—‘b \ / Except that acetyl chloride 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, Acetone—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)+. e 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 r 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) @8113»??? 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, e-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 NCTU-SUN-28091: (2-(((4-methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)-1H-benzo[d]imidazol-S-yl 2-nitr0benzoate) NO2 \o 9:7UNVway‘b Except that acetyl de 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) WONG‘b Except that acetyl chloride is replaced by cyclopropanecarbonyl 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) 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: (2-(((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S-yl 2—ethylbutanoate) 4m:ng Except that acetyl chloride is replaced by 2-ethylbutanoyl chloride, the other reactants and preparation steps are r 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, 6H).
LRMS (ESP) m/z : 430.2 (M+H)+.
Example 1-15 NCTU-SUN-28094: 4—methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S—yl 2—phenylacetate) mocrHC/r Except that acetyl de is replaced by 2-phenylacetyl 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 8.16 (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 chloride is replaced by 3,5,5-trimethylhexanoyl 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 8.15 (s, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.40 (s,lH), 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 xybenz0ate) $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 yl)methyl)sulfinyl)—1H-benz0[d]imidazol-S—yl propionate) 2603860 Except that acetyl chloride is replaced by propionyl chlonde, the other reactants and preparation steps are r 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: 4-methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S—yl 4-chlorobenzoate) CI 0— O N\ 5% Except that acetyl chloride is replaced by robenzoyl 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 8.33 — 8.12 (m, 1H), 7.76 (d, J = 8.7 Hz, OH), 7.72 — 7.61 (m, 1H), 7.27 (dd, J: 8.7, 2.2 Hz, 0H), 4.74 (s, 1H), 3.76 (s, 1H), 2.25 (d, J: , 2H).
LRMS (ESE) m/z : 470.2 (M+H)+.
Example 1-20 UN-21126: (2-(((4—methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S-yl 3-nitrobenz0ate) H _ UN’>_ ‘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 (M+H)+.
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 r to those bed in e 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 UN-21129: (2—(((4—methoxy-3,5—dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S—yl 4-flu0r0benz0ate) F o— \OE UNy— \b0 N {—m Except that acetyl chloride is replaced by 4-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-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 (ESF) m/z ; 454.1 (M+H)+.
Example 1-23 NCTU-SUN-21130: (2—(((4—methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S—yl (Z)—2—methylbut-Z-enoate) crow? Except that acetyl chloride is replaced by (Z)methy1butenoy1 chloride, the other reactants and ation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, e-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: (2-(((4-methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benz0[d]imidazol-S—yl 2-chloropropanoate) WUHUCI _ Except that acetyl chloride is replaced by 2—chloropropanoyl de, the other reactants and preparation steps are r 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: tert—butyl (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 r 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), 7.49 (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- hyl)sulfinyl)—lH-benzo[d]imidazol-S—yl (Z)—but—2-en0ate) We _.._ Except that acetyl chloride 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, e—d6) 8 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— W — (ZrN \ \ / ] Except that acetyl chloride is replaced by 3-methylbutenoyl 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 8.18 (s, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.45 (d, J: 2.0 Hz, 1H), 7.09 (dd, J: 8.7, 2.1 Hz, 1H), 5.98 (dt, J: 2.6, 1.3 Hz, 1H), 4.71 (dd, J: 13.6 Hz, 2H), 3.74 (s, 3H), 2.24 (s, 3H), 2.24 (s, 3H), 2.22 (d, J = 1.2 Hz, 3H), 2.02 (d, J = 1.3 Hz, 3H).
LRMS (ESF) m/z : 414.2 (M+H)+. e 1-28 NCTU-SUN-12122: (2—(((4—methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)-1H-benzo[d] imidazol-S-yl furan-Z-carboxylate) / \ O O— \ / N ‘b Except that acetyl chloride is replaced by 2-carbonyl 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 8.18 (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-benz0[d]imidaz0lyl 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- hyl)sulfinyl)—1H-benzo[d]imidazol-S—yl 2—methylbutanoate) Quid 0— Except that acetyl chloride is replaced by 2-methylbutanoyl chlon'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) 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,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl 3-cyclopentylpropanoate) Except that acetyl chloride is replaced by cyclopentanecarbonyl chloride, the other nts 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), 7.68 (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 NCTU-SUN-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 reactants and preparation steps are similar to those described in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d6) 5 8.26 (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: 4—meth0xy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H—benzo[d]imidazol-S—yl Z-fluorobenzoate) F \0 Except that acetyl chloride is replaced by 2-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, 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) E l O UukN f6,\b Except that acetyl chloride is replaced by 4—methoxybenzoyl chloride, the other reactants and preparation steps are r to those bed in Example 1 to afford the title compound. 1H NMR (400 MHz, Acetone-d6) 8 8676-784 (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 (M+H)+.
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 compound. 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 UN-11023: (2-(((4—methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S-yl ole—S-carboxylate) H 0 ‘0 N\ IE}\ / ] Except that acetyl chloride is replaced by isoxazole-S-carbonyl chloride, the other nts and ation steps are similar to those described 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)benz0ate) Except that acetyl chloride is replaced by 4-(tert-butyl)benzoyl chloride, the other reactants and preparation steps are similar to those described 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)+.
Example 1-39 NCTU-SUN-11031: (2—(((4—meth0xy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S—yl 3-chl0r0fluorobenzoate) 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, e—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 UN-25015: (2—(((4—methoxy-3,5-dimethylpyridin-Z- yl)methyl)sulfinyl)-lH-benzo[d]imidazol-S-yl pivalate) 8160383? Except that acetyl chloride is replaced by pivaloyl chlofide, the other nts and preparation steps are similar to those described in e 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 yl)methyl)sulfinyl)—1H-benzo[d]imidazol-S—yl pentanoate) WOUE>—f©¥‘23 Except that acetyl chloride is replaced by oyl chloride, the other reactants and preparation steps are similar to those bed in e 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).
LRMS (ESE) m/z : 416.1 (M+H)+.
Example 1-42 UN-25017: (2-(((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl 4-nitrobenzoate) 2 @8086)? Except that acetyl chloride is replaced by 4-nitrobenzoy1 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 8.48 (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 (ESP) 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) 3&1:wa‘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= 88,22 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‘b9 O 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 UN-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, e-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) Except that acetyl chloride is ed by 3,3-dimethylbutanoyl 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), 7.69 (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 NCTU-SUN-2503l: (2—(((4-methoxy-3,S-dimethylpyridin-Z- yl)methyl)sulfinyl)—lH-benzo[d]imidazol-S—yl 2-methoxyacetate) \ "Kb 070,». / Except that acetyl de is replaced by 2-methoxyacetyl 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), 7.70 (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 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 d pressure, crude reaction 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 2-Aminomethy1furan (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 product was purified by flash column tography 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 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 temperature. After 8 hours the mixture can be extracted with DCM and water.
The solvent was removed and the crude product was d 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 acetoniritle (10 mL) was added K2CO3 (0.0497 g, 0.36 mmol) and KI (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 t was evaporated and the reaction e was diluted with ted aq. NaHCO3 (10 mL) and extracted 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, , , 124.00, 110.60, , 109.04, 108.26, 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)+. e 2-2 21098: Methyl 2-(((4-methoxy-3,5-dimethylpyridin-Z- yl)methyl)amin0)— l-propyl-1H-benzo[d]imidazole—S-carboxylate \OJUEnybi Except that amine is replaced by propan—l—amine, the other reactants and ation 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, 148432 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)—1H-benzo[d]imidazole—S-carboxylate Except that amine is replaced by 3—methoxypropanamine, 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 8.10 (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, ol-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 .
Example 2-4 26070: 1-(furanylmethyl)—2—(((4—methoxy-3,5-dimethylpyridin yl)methyl)amino)—1H-benzo[d]imidazole—S-carboxylic acid 0 N kN\ /_ To a solution of 4-fluoro—3—nitrobenzoic acid 1 (5.0 g, 27.0 mmol) in dry MeOH (30 mL), H2SO4 (5 mL, 0.3 M) was added and the reaction mixture was heated to reflux for 12 h. The solvent was d under d pressure, crude reaction 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 furanylmethanamine (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 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 e was stirred at room temperature for 30 min. Upon completion of reaction, Zn dust was filtered through a bed of , filtrate was evaporated and the product was dissolved in CH2C12 (100 mL). The precipitated ammonium e 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 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 solution of methyl 2-amino—1-(furanylmethyl)-1H-benzo[d]imidazole carboxylate 5 (0.05 g, 0.18 mmol) in iritle (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 on 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 ed organic phase was washed with saturated brine (30 mL). The crude product was purified by -gel column chromatography using 8 % methanol/ EtOAc to obtain Methyl 1—(furanylmethyl)- 2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)amino)-1H-benzo[d]imidazole carboxylate 7.
And add NaOH (0.0251 g, 0.63 mmol) to a solution of Methyl 1-(furan 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 evaporated 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 kgfldg?\o \O N\ Except that amine is replaced by pentan—l—amine, the other reactants and ation 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 (M+H)+.
Example 2-6 21102: 2-(((4-meth0xy-3,5—dimethylpyridinyl)methyl)amin0)—1-pr0pyl- 1H-benzo[d]imidazole-S-carboxylic acid N ft} Except that amine is ed 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, 126.40, , 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 bed 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 preparation steps are similar to those described in Example 2-4 to afford the title compound. 1H NMR (400 MHz, Methanol-d4) 8 8.17 (s, 2H), 8.07 (s, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.26 (d, J: 8.3 Hz, 1H), 5.13 (s, 1H), 4.77 (s, 4H), 4.11 (t, J: 7.8 Hz, 2H), 3.80 — 3.69 (m, 6H), 2.29 (t, J: 8.4 Hz, 2H), 2.18 (d, J: 21.8 Hz, 12H), 1.76 (s, 4H), 1.49 — 1.36 (m, 4H), 13C NMR (101 MHz, ol—d4) 8 156.95, 145.93, 139.17, 131.88, 130.28, 125.53, 118.06, 117.75, 117.05, 115.18, 114.79, 110.01, , 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 / "W18N N— Except that amine is replaced by 3—methoxypropanamine, 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-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, , 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 HQJK©:N\>_N{-I_2:;07N \ / ] Except that amine is replaced by pentan—l—amine, the other reactants and preparation steps are r 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 (M+H)+.
Example 2-11 26077: -methoxy-3,5—dimethylpyridin-Z-yl)methyl)amin0)—1- (4-methoxybenzyl)—1H-benzo[d]imidazole—S-carboxylic acid HOJUN \ \oft}/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 similar to those described in Example 2-4 to afford the title compound. 1H NMR (400 MHz, Methanol-d4) 8 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)—lH-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 1MHz,Acetone-d6)8167.29,163.89,155.45,154.37,148.O6,142.70,138.71, 133.89, 125.06, 124.16, 123.65, , 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, .
Example 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 2-(cycloheX—1—eny1)ethanamine, the other reactants and preparation steps are similar to those bed in Example 2-4 to afford the title compound. 1H NMR (400 MHz, DMSO—ds) 6 8.15 (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 ed 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, , 142.52, 139.50, 139.30, 130.05, , 127.73 127.01 108.52 60.62 , , 125.84, 123.98, 122.90, , , , 52.38, 49.85 46.69 44.97 40.00 39.79 39.58 39.37 39.16 10.56 , , , , , , , , 35.62, 13.36, , LRMS (ESI+) : m/z 445.4 (M+H)+.
Example 2-16 21119: -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 reactants and preparation steps are similar to those described in Example 2-4 to afford the title compound. 1H NMR (400 MHz, Methanol—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) 5 169.15,167.25,153.40,153.06,148.02 138.56 ,136.34,130.16,129.70,128.21, 128.04,127.16,126.66,126.02,114.72 ,110.61, 61.03 46.15 , , 45.80, 34.84, 13.58, .68 .
Example 2-17 21120: 2-(bis((4-meth0xy-3,5—dimethylpyridin-Z-yl)methyl)amin0)— yl- 1H-benzo[d]imidazole—S-carboxylic acid "Cirfi Except that amine is replaced by propan—l—amine, 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-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, 138.04,128.79,128.39,126.52,124.88 124.76 109.35 59.74 , , 123.79, 122.04, , , 55.15 45.31 34.51 12.91 10.42 , , , , , .
Example 3-1 NCTU-SUN-26079 : Methyl anylmethyl)(((4-meth0xy-3,5- dimethylpyridinyl)methyl)amino)-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 d 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 d 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 on, the byproduct was filtered through a bed of celite and filtrate was evaporated. The crude product was portioned between 1 N NaOH and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3 x 20 mL) and the ed 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 solution of methyl 2—amino—3—(furan—2—ylmethyl)-3,4-dihydroquinazoline ylate 5 (0.3 g, ol) 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 solvent was evaporated and the reaction mixture was d with saturated aq.
NaHC03 (30 mL) and ted 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 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- ylpyridinyl)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, ol-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 e 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-dihydroquinazolinecarboxylate Except that amine is ed by pentan—l—amine, 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) 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 , 165.03 155.04,152.00,148.85,137.27,130.52,128.00,126.46,125.87,125.64,124.60, 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- (4-methoxybenzyl)—3,4-dihydroquinazoline—7—carboxylate o \N N NH O \O \ \ Except that amine is replaced by (4-methoxyphenyl)methanamine, 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) 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: 2-(((4-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 1H NMR (400 MHz, ol—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/CHzClz (3 mL: 30 mL), was added DCC (1.2 equiv) and DMAP (0.005 equiv) and the reaction mixture was d at room temperature for 16 h. The byproduct DCU was d 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 t 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 reaction, the byproduct was filtered through a bed of celite and e was evaporated. The crude t was portioned between 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 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 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 solvent was evaporated and the reaction mixture was diluted with saturated aq.
NaHC03 (30 mL) and extracted with EtOAc (3* 30 mL).
The combined organic phase was washed with ted brine (30 mL). The crude product was purified 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 solution of methyl an 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 ion.
After 1 hour, the t was ated and the reaction mixture was diluted 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 t 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 ,13C N1V1R(1011VIHZ,Methanol-d4)5171.74 151.73 , 164.87, , , 148.52, 147.49,143.54,138.56,136.13,126.27,125.93 ,124.64,124.63,116.56,110.30, 109.86 59.40 50.46 47.46 46.94 46.47 11.97 LRMS (ESI+) : m/z 421.2 , , , , , , , 9.33; 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, Methanol—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- methoxy-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 e is dissolved in EtOAc. The EtOAc layer was dried over anhydrous 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 temperature for 2 hours. Upon completion of reaction the solvent was removed and the crude t was purified to afford nitro benzoates 3.
To a solution of nd 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 ved in CH2Clz. 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 °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 cyclohex—1—en—l—yl)ethyl)thioxo-2,3-dihydro-1H- 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 d and extracted with EtOAc.
The ed 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 e is heated to reflux. The t 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-fluoronitrobenzoate 2 as a white solid.
Compound 2 and 2-(cyclohexen-l-yl)ethanamine were d at room temperature for 2 h. 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 resulting reaction mixture is stirred at room ature. Upon completion of on, Zn dust is d 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 °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—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 e 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 t 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)- lH-benzo[d]imidazole- -carboxylate 7 (0.053 g, 0.126 mmol) in the EtOH/HzO (l/l, 3mL) in the reflux ion.
After 1 hour, the solvent was evaporated 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 (30 mL). The crude product was purified by silica-gel column chromatography using 20 % ol/ 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-(cyclohex-l-enyl)ethyl)—2-(((4-methoxy-3,5- dimethylpyridin-Z-yl)methyl sulfinyl)-1H-benzo[d]imidazole-S-carboxylate \0%).»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 solvent is removed under reduced pressure; crude reaction mixture is dissolved in EtOAc. The EtOAc layer was dried over anhydrous MgSO4 and ated to get methyl 4—fiuoro—3—nitrobenzoate 2 as a white solid.
Compound 2 and 2-(cyclohexen—1—yl)ethanamine were stirred 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 formate are added and the resulting reaction mixture is stirred at room temperature. Upon completion of reaction, Zn dust is d and the filtrate is evaporated and the product is dissolved in CH2C12. The precipitated ammonium e 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 d to afford 5.
To a solution of methyl 1-(2-(cyclohexen-l-yl)ethyl)thioxo-2,3-dihydro-1H- 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 t is evaporated and the reaction mixture is diluted and extracted with EtOAc.
The combined organic phase was washed with ted brine. The crude product was d 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 8 g, 0.034 mmol) to a solution of Methyl 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 ature in 1 hour. The reaction mixture 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- benz0[d]imidazolyl (((9H-flu0renyl)methoxy)carbonyl)glycinate FmOCHN/\g/ UNN \ / To a solution of xo-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- dimethylpyridine 2 (0.367 g, 0.198 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 -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, Acetone-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-methoxy-3,5—dimethylpyridinyl)methyl)thio)—1H- benzo[d]imidazolyl (tert-butoxycarbonyl)glycinate Except that imidazole is replaced by 2-thioxo-2,3-dihydro-1H-benzo[d]imidazol- -yl 2-((tert-butoxycarbonyl)amino)acetate, the other nts and preparation steps are similar to those described in e 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). e 5-3 12094: 2-(((4-meth0xy-3,5—dimethylpyridinyl)methyl)thio)—1H d]- imidazole-S-yl (S)((((9H-fluorenyl)methoxy)carbonyl)amino)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 NCTU-SUN-22138: S-methoxy((2-methoxy-3,6-dimethylbenzyl)thi0)— 1H-benzo[d]imidazole UrN\ M.
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 t 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- ylpyridine 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 NCTU- SUN-22138 0.077 g, 60 %.
LRMS (ESI+): m/z 329.2 (M+H)+ Example 6-2 22141: 2-((2-methoxy-3,6-dimethylbenzyl)thio)-lH-benzo[d]imidazolol UrN\ Me To a on of 2—methoxy—1,3,4—trimethylbenzene 1 (0.3 g, 2.00 mmol) in form (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)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 % MeOH/DCM 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 TBSO 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 ons, two Philips "IR 250 W lamps were placed at such a distance from the reaction flask that reflux was maintained. Once the reaction was completed, the t 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 solution 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 d to reflux for one hour. Once the reaction was completed, the solvent was ated 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, form-d) 8 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 22139: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 reaction was completed, the solvent was ated 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) ed by 2—(chloromethyl)methoxy-3,5- dimethylpyridine 3 (0.071 g, 0.39 mmol) and the reaction mixture was allowed to reflux for one hour. Once the on was completed, the t 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 ature in 1 h. The on mixture was washed with DCM (10 mL). The solvent 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 enzymatic activity assay was modified according to the report of Oguri et a] (Oguri, 5., Screening ofd-ctmino acid oxidase tor by a new mulii-assay method. Food chemistry 2007, 100 (2), 616). The DAAO activity was measured by using substrate D-alanine reaction produced hydrogen 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 ty of DAAO.
For porcine kidney DAO IC50 assay, the DA0 substrate was prepared in 50 mM D-alanine (dissolved in 0.2 M Tris—HCl 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 11M, 97.66 uM, 195.31 uM, 390.63 uM, 781.25 uM, 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 nd 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) on (dissolved with 0.2 M Tris—HCl buffer, pH 8.3), 1.1 mL of 15 U/mL peroxidase solution (dissolved with 0.2 M Tris—HCl , pH 8.3), 1.1 mL of 20 mM HPPA on (dissolved with 0.2 M Cl 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 ation excitation at 320 nm. The higher the DA0 enzymatic activity was, the higher the fluorescence intensity.
The fluorometric inhibition indicator (Fi) was obtained from the following equation: Fi = (Fs- FDrug)/ (FDMso), where the fluorescent drug blank (FDrug) was measured in the drug mixture solution (using 0.2 M Tris HCl , 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 dissociates from the holoenzyme, the present method was performed without FAD. The inhibitory effect of DAO inhibitors was compared by using tory concentrations leading to 50% inhibition ofDAAO activity (ICso). The IC50 values were calculated by nonlinear regression model using GraphPad Prism, version 5 (GraphPad Software, Inc., La Jolla, CA). The results ofDAO IC50 assay of the candidate nds of the ion are shown in the table below.
Example 8 ased DAO Assay Neuronal cell culture The SK-N—SH 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 ar DAO activity assay was using a method modified 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 suspended 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 membrane 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 incubate at 37 °C with 5% C02 in a humidified atmosphere for 30 minutes. After 30 minutes later, 25 111 of a 5 fold mixture containing D-serine, horseradish peroxidase (HRP), and Amplex Red was added into wells containing 100 pl of cell-drugs mixture and incubated at 37 °C with 5% C02 in a humidified atmosphere for 3 hours. The final concentration ofDMSO is below 1%. The cence signal was then detected in SpectraMax M2e microplate reader (Molecular Devices, USA) with tion 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 s of the ase DAO assay of the candidate nds of the invention are shown in the table below. reated for 3.5 hr) Ve DAG activity ID nbrmalize to DMSO at Final Cone.
IC50 95% Confidence 100 uM Range (11M) CBIO 392.30 281.4 to 547.0 RS-D7 331.39 W 14100 81.07 to 245.1 12083 451.5811 74.15 27.04 to 203.4 21105 218.80 98.89 to 484.3 Example 9 Animal Studies of Potency in Treating Schizophrenia Symptoms Drug Efi‘icacy Screening The NMDA-receptor antagonist MK-801—induced negative or cognitive s in 6 mice were in a well-established drug-induced schizophrenia mouse model and as a useful pharmacological animal model to identify if the RS-D7, its analog and its prodrug improve the symptoms through the NMDA receptor.
Animals All wild-type (WT) mice used in this study were backcrossed 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 dark cycle in a temperature and humidity lled room of the Psychology Department, al Taiwan University. All animals within the age of 3 months were housed individually one week before experiment g 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 ures 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 g ofRS-D7) and was freshly dissolved in 1% CMC to the concentration of 2 mg/ml before usage. Prodrug 28095 was freshly dissolved in NMPzHP- beta-CDszO (5:25:70) to the concentration of 2 mg/ml before usage. All animals were given e e) or MK-801 (0.2 mg/kg, ip.) 25 minutes before the behavioral experiments.
Both vehicle (1% CMC or NMP:HP-beta—CD:H20) and experimental groups , 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 cognitive symptoms, a series of three behavioral tests (run from the first to the third week), which included open field, sucrose preference test and se inhibition were performed in sequence with a 1-week interval between tests.
Openfield To assess spontaneous locomotor activity, each subject was placed into the center of an eld apparatus (25.40*25.40*40.64 cm3, Coulboum Instruments, Whitehall, PA, USA) under dim lighting condition (60 1x). Motor activity parameters ding total travel ce and travel distance per 10 minutes) were monitored 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 , the percentage change of rescue effect on MKinduced hyperlocomotion was calculated using the following formula: % = e effect of drug — MK-801 effect) X 100 % / MK-801 effect.
] Compared with the saline controls, mice t 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-D7 injection ized 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 hyperlocomotion. In conclusion, compared to the MK-801 group, different s 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 deprived 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 ed MK-801 and RS-D7 treatment before the ment, and also free accessed to bottles for 1 hour. After the experiment, the 2 bottles were weighted to measure the l-hour consumption of sucrose solution and water. The sucrose preference percentage (SPP) was calculated using the following a: %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 observed in testing 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 Prodrug 28095 also ized 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 SRLAB startle apparatus (San Diego Instruments, San Diego, CA, USA). The ound noise was 72 dB during testing. Each session was initiated with a 5 minutes acclimatization period followed by 64 trials, consisting of pulse-alone (P-alone) trials, prepulse pulse (pp + P) trials, and no stimulation (nostim) trials. A P-alone trial was a 120 dB white noise burst of 40 msec.
In the pp + P trials, the 120 dB pulse was preceded (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 n 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 randomly and separated by intertrial intervals of 15 sec on average ng n 10 and 20 sec). PPI was calculated as a percentage of the startle response using the a: %PPI = 100 x one 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 ion of acoustic 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 reduction of PPI after acute MK- 801 injections and they can be normalized by all dosages of RS-D7, Drug 12083 and Prodrug 28095. The ry rates of MK-801 induced PPI deficit were indicated in Figure 3.
I/

Claims (17)

WE CLAIM :
1. A compound of formula (I), wherein n is 0 or 1, X is –; A is –CH, –CRc or N; Ra is –O–C(=O)Ra3 or –O–C(=O)-T-ORa4; n Ra3 is a linear or branched C1-15alkyl, linear or branched C2-15alkenyl, -T-C3- 10cycloalkyl, -T-NHRa3p, -T-C3-10cycloalkenyl, 10aryl, -T-C5-10heteroaryl, -TNH-C (=O)-O-C1-10alkyl, -T-adamantyl or -C1-3alkylene-C6-10aryl where the alkylene is substituted with -T-NHRa3p; Ra4 is a linear or branched C1-15alkyl, linear or branched C2-15alkenyl, -T-C3- 10cycloalkyl, -T-NHRa3p, -T-C3-10cycloalkenyl, -T-C6-10aryl, -T-C5-10heteroaryl, -TNH-C (=O)-O-C1-10alkyl, -T-adamantyl or -C1-3alkylene-C6-10aryl where the alkylene is substituted with -T-NHRa3p; Ra3p is H or an ecting group selected from Fmoc or Boc; Rb is H, linear or branched C1-15alkyl, linear or branched C2-15alkenyl, C1-3alkoxy-C1-15alkyl-, -10cycloalkyl, -T'-C3-10cycloalkenyl, -T'-C6-10 aryl or -T'-C5-10heteroaryl; Rc each is independently linear or branched C1-15alkyl, linear or branched C1-15alkoxyl, hydroxyl group, or –C1-10alkylene-Y-C6-10heteroaryl wherein -Y- is -CH2-, -NH-, -O- or -S-; symbol * ents 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 O; 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, amino, nitro, nitroso, linear or branched C1-15 alkyl, or linear or branched C1-15 alkoxy or C3-10cycloalkyl; and when Rb is H, the tautomers are included, or a pharmaceutically acceptable salt thereof.
2. The compound of Claim 1, wherein n is 0; A is N; Rb is H; m is 3; and Rc each is independently linear or branched C1-15alkyl, linear or branched C1-15alkoxyl; or a pharmaceutically able salt.
3. The compound of Claim 1 or 2, wherein n is 0.
4. The compound of Claim 1, wherein m is an integer from 0 to 3.
5. The compound of Claim 1 or 2, wherein Ra is –O–C(=O)Ra3 wherein Ra3 is tert-butyl; adamantyl; linear or branched C1-10alkyl unsubstituted or substituted by halogen; C1-4alkoxy; -C6- 10aryl unsubstituted or substituted by C1-10 alkyl, nitro, C1-15alkoxy or halogen; C3-10cycloalkyl; - C3-10cycloalkenyl; linear or branched C2-10alkenyl; heteroaryl; -C1-3alkylene-C3- 10cycloalkyl; kenylene-C6-10aryl wherein C6-10aryl is unsubstituted or substituted by halogen; –O–C(=O)-O-C1-10alkyl.
6. The compound of Claim 1 or 2, wherein Ra is O)Ra3 wherein Ra3 is tert-butyl; tyl; linear or ed C1-8alkyl unsubstituted or substituted by halogen; C1-4alkoxy; - phenyl unsubstituted or substituted by C1-6 alkyl, nitro, C1-4alkoxy or halogen; C3-6cycloalkyl; - C3-6cycloalkenyl; linear or branched kenyl; -C5-6heteroaryl; -C1-3alkylene-C3-6cycloalkyl; C2-3alkenylene-phenyl wherein phenyl is unsubstituted or substituted by halogen; –O–C(=O)-OC1-4alkyl.
7. The compound of Claim 1 or 2, wherein Ra is –O–C(=O)-C1-6alkyl, –O–C(=O)-C1- 4alkylene-NHFmoc, O)-C1-4alkylene-NHBoc, or O)-NH-C(=O)-O-C1-10alkyl.
8. The compound of Claim 1 or 2, wherein Rc each is independently halogen, linear or branched kyl, linear or branched C1-6alkoxyl, or –C1-10alkenylene-Y-C6-10heteroaryl; wherein Y is S and C6-10heteroaryl is unsubstituted or substituted by C1-15alkyl, lkenyl, C1- 15alkoxy, -OH, -NH2, -NO2 or halogen.
9. The compound of Claim 1 or 2, which is selected from the group consisting of: 21122: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl acetate) 21124: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl benzoate) 26096: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl te) 26097: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl cyclohexanecarboxylate) 26098: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 4-butylbenzoate) 21127: 4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl ylbenzoate) 27076: 2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl hexanoate 27077: 2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl isobutyrate 27078: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl cyclohexenecarboxylate) 27079: 2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl cyclohexenecarboxylate 28087: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 4-methylbenzoate) 28091: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 2-nitrobenzoate) 28092: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl cyclopropanecarboxylate) 28093: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 2-ethylbutanoate) 28094: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 2-phenylacetate) 28095: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 3,5,5-trimethylhexanoate 28096: 5-methoxy-4,6-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 2-ethoxybenzoate) 21123: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl propionate) 21125: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 4-chlorobenzoate) 21126: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 3-nitrobenzoate) 21128: 2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl heptanoate 21129: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 4-fluorobenzoate) 21130: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl (Z)methylbutenoate) 21131: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 2-chloropropanoate) 21132: tert-butyl 4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H- benzo[d]imidazolyl) carbonate 12124: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl (Z)-butenoate) 12125: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl ylbutenoate) 12122: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl furancarboxylate) 12123: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl acrylate) 12127: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 2-methylbutanoate) 12128: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 3-cyclopentylpropanoate) 12129: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl (E)(2-chlorophenyl)acrylate) 12130: 4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 6-bromohexanoate) 11021: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 2-fluorobenzoate) 11020: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 4-methoxybenzoate) 11022: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl (3r,5r,7r)-adamantanecarboxylate) 11023: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl isoxazolecarboxylate) 11030: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 4-(tert-butyl)benzoate) 11031: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 3-chlorofluorobenzoate) 25015: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl pivalate) 25016: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl pentanoate) 25017: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 4-nitrobenzoate) 25027: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl cyclobutanecarboxylate) 25028: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl thiophenecarboxylate) 25029: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 2-methylbutanoate) 25030: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 3,3-dimethylbutanoate) 25031: (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 5-yl 2-methoxyacetate) and 25032: (ethyl (2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H- benzo[d]imidazolyl) carbonate) or a ceutically able salt thereof.
10. The compound of Claim 1 or 2, which is 13001: 2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)sulfinyl)-1H-benzo[d]imidazol- 6-yl 2-((tert-butoxycarbonyl)amino)acetate or a pharmaceutically acceptable salt thereof.
11. A ceutical composition, comprising a compound of any one of Claims 1 to 10.
12. An in vitro method of inhibiting a DAAO, comprising contacting a cell with a compound of any one of Claims 1 to 10.
13. Use of a compound of any one of Claims 1 to 10 in the manufacture of a medicament for treating or preventing a disease associated with DAAO tion.
14. The use of Claim 13, wherein the e is symptom domains of schizophrenia and schizoaffective disorder, sion, 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 on characteristic of neurodegenerative diseases.
15. The use of Claim 14, wherein the symptom domains of schizophrenia and schizoaffective disorder include negative, cognitive, depressive, positive and general psychopathology m domains.
16. The use of Claim 13, wherein the disease is mild cognitive impairment (MCI), Alzheimer's disease, Parkinson's disease or schizophrenia.
17. The use of Claim 13, wherein the disease associated with DAAO inhibition is pain, ataxia or convulsion. Yufeng Jane Tseng National Taiwan University al Chiao Tung University National Health Research Institutes By the Attorneys for the ant SPRUSON & FERGUSON Per:
NZ751050A 2016-09-14 2017-09-14 Novel substituted benzimidazole derivatives as d-amino acid oxidase (daao) inhibitors NZ751050B2 (en)

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