WO2011023812A1 - Microsomal prostaglandin e synthase-1 (mpges1) inhibitors - Google Patents

Microsomal prostaglandin e synthase-1 (mpges1) inhibitors Download PDF

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WO2011023812A1
WO2011023812A1 PCT/EP2010/062596 EP2010062596W WO2011023812A1 WO 2011023812 A1 WO2011023812 A1 WO 2011023812A1 EP 2010062596 W EP2010062596 W EP 2010062596W WO 2011023812 A1 WO2011023812 A1 WO 2011023812A1
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benzo
carboxamide
imidazol
piperidine
tetrahydrofuran
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PCT/EP2010/062596
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French (fr)
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Johan Wannberg
Mathias Alterman
Johan Malm
Patric Stenberg
Jacob Westman
Hans Wallberg
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Novasaid Ab
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory 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
    • A61P25/28—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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D401/14—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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to piperidinyl benzoimidazole derivatives and to the use thereof in disease therapy.
  • the present invention relates to compounds useful in the treatment or prevention of diseases in which inhibition of the activity of microsomal prostaglandin E synthase- 1 (accession number "014684" at http://www.uniprot.org/) is desired and/or required and, more particularly, in the treatment of diseases such as inflammatory diseases, nociceptive pain, auto-immune disease, breathing disorders, fever, cancer, inflammation related anorexia, Alzheimer's disease and cardiovascular disease.
  • diseases such as inflammatory diseases, nociceptive pain, auto-immune disease, breathing disorders, fever, cancer, inflammation related anorexia, Alzheimer's disease and cardiovascular disease.
  • Prostaglandin (PG) E 2 is produced in a sequential action including liberation of arachidonic acid, conversion into PGG2/PGH2 by cyclooxygenase (Cox) -1 or Cox-2, and finally prostaglandin E synthase converts PGH 2 into PGE 2 .
  • mPGEs-1 was regarded as the enzyme predominantly coupled with Cox-2 activity. However; later results demonstrate that mPGEs-1 can also catalyze the conversion of Cox- 1 derived PGH2 into PGE2. mPGEs-1 possesses the highest catalytic efficiency of the known PGE synthases.
  • PGE2 as one of the most potent mediators of inflammation together with many in vitro reports on the presence of mPGEs-1 in different models of inflammation suggested this enzyme to be an attractive drug target for development of new anti inflammatory drugs with fewer side effects than the currently available NSAIDs and selective Cox-2 inhibitors [Samuelsson, B.;
  • examples of treatable diseases of the invention include inflammatory diseases, nociceptive pain, auto-immune disease, breathing disorders, fever, cancer, inflammation related anorexia, Alzheimer's disease and cardiovascular disease. More specifically, non-limiting examples of these diseases include the treatment or prevention of rheumatoid arthritis [Murakami, M.; Nakashima, K.; Kamei, D.; Masuda, S.; Ishikawa, Y.; Ishii, T.; Ohmiya, Y.; Watanabe, K.; Kudo, I. Cellular prostaglandin E2 production by membrane- bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2. J. Biol.
  • osteoarthritis [Kojima, F.; Naraba, H.; Miyamoto, S.; Beppu, M.; Aoki H, and Kawai S (2004) Membraneassociated prostaglandin E synthase- 1 is upregulated by proinflammatory cyto-kines in chondrocytes from patients with osteoarthritis. Arthritis Res. Ther. 2004, R355-R365; Masuko-Hongo, K.; Berenbaum, F.; Humbert, L.; Salvat, C; Goldring, M. B.; Thirion, S.
  • cephalalgia headache
  • PGE2 Prostaglandin E2
  • Cephalalgia 2009, 29, 509-519
  • pain due to gall-stones pain due to metastasis, familial adenomatous polyposis (FAP) condition
  • FAP familial adenomatous polyposis
  • epithelial ovarian cancer [Rask, K.; Zhu, Y.; Wang, W.; Hedin, L.; Sundfeldt, K. Ovarian epithelial cancer: a role for PGE2-synthesis and signalling in malignant transformation and progression. MoI. Cancer, 2006, 16, 62], breast cancer [Mehrotra, S.; Morimiya, A.; Agarwal, B.; Konger, R.; Badve, S. Microsomal prostaglandin E2 synthase- 1 in breast cancer: a potential target for therapy. J. Pathol. 2006, 208, 356-363], gastric
  • Oshima M. Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and prostaglandin E2 pathway. Gastroenterology, 2006, 131, 1086-1095], multiple sclerosis, atherosclerosis such as myocardial infarction and stroke [Ikeda-Matsuo, Y.; Ota, A.; Fukada, T.; Uematsu, S.; Akira, S.; Sasaki, Y. Microsomal prostaglandin E synthase-1 is a critical factor of stroke-reperfusion injury. Proc. Natl. Acad. Sci. USA.
  • Neutrophils CDl Ib and fibroblasts PGE(2) are elevated in Alzheimer's disease. Neurobiol. Aging, 2002, 23, 523-30], as well as the use of the said compounds in the manufacture of medicaments for the treatment of those disorders [For a reviews discussing most of the therapeutic indications mentioned above see: Samuelsson, B.; Morgenstern, R.; Jakobsson, P. -J. Membrane Prostaglandin E Synthase-1 : A Novel Therapeutic Target. Pharmacol. Rev. 2007, 5P,207-224; Murakami M, Kudo I. Prostaglandin E synthase: a novel drug target for
  • mPGES-1 Other examples of medical conditions associated with mPGES-1 are pain in connection to ankylosing spondylitis, gout, or rheumatic fever, tootache, cellular neoplastic transformations and metastatic tumor growth, endometriosis, hemophilic arthropathy, Parkinson's disease, mPGES-1 -mediated proliferative disorders such as may occur in diabetic retinopathy and tumor angiogenesis, symptoms associated with viral infections, and premature labor.
  • WO 2008/084218 discloses benzazole derivatives of the general formula
  • One object of the present invention is to provide compounds having said desired improved properties.
  • the present inventors now have surprisingly found certain piperidinyl benzoimidazoles that are capable of efficiently blocking mPGEs-1.
  • R 1 is selected from branched or unbranched C 1 -C 10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl; C3- Cio cycloalkyl; C4-C10 cycloalkenyl; Cs-Cio cycloalkynyl; C 1 -Cg heterocyclyl; and C 6 -CiO aryl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or cycloalkynyl moiety optionally is substituted with 1, 2 or 3 groups R a ; and any heterocyclyl or aryl moiety optionally is substituted with 1, 2, 3, 4 or 5 groups R b ; R 2 is selected from branched or unbranched C 1 -Cg alkyl, C2-C9 alkenyl, or C2-C9 alkynyl; C3-C6 cycloalkyl; C 4 -C 6
  • R 3 and R 4 are each independently selected from Ci -C 4 alkyl; C 2 -C 4 alkenyl; C 2 -C 4 alkynyl; C 3 -C 4 cycloalkyl; Ci-C 4 alkyloxy; C 2 -C 4 alkenyloxy; C 2 -C 4 alkynyloxy; Ci-C 4 alkylthio; C 2 -C 4 alkenylthio; C 2 -C 4 alkynylthio; halogen; Ci-C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl secondary or tertiary amino; and Ci-C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl carbonyl; wherein any alkyl, alkenyl, alkynyl or cycloalkyl moiety optionally is substituted with 1, 2, or 3 groups R c ; R 5 and R 6 are independently selected
  • X represents a bond or branched or unbranched Ci -C 3 alkyl, C 2 -C 3 alkenyl or C 2 -C 3 alkynyl;
  • Q represents carbonyl, sulfonyl or sulfmyl; m is an integer of 0, 1 or 2; each R a is independently selected from halogen; hydroxy; Ci-C 4 alkyl; C 2 -C 4 alkenyl; C 2 -C 4 alkynyl; Ci-C 4 alkyloxy; C 2 -C 4 alkenyloxy; C 2 -C 4 alkynyloxy; Ci-C 4 alkyl, C 2 -C 4 alkenyl or C 2 - C 4 alkynyl secondary or tertiary amino; Ci-C 4 alkylthio; C 2 -C 4 alkenylthio; C 2 -C 4 alkynylthio; wherein any alkyl, alkenyl or alkynyl moiety optionally is substituted with 1, 2 or 3 groups R c ; each R b is independently selected from halogen; carboxy; hydroxy; cyano; C1-C5 heteroaryl;
  • Another aspect of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable adjuvant, diluent or carrier.
  • Another aspect of the present invention is to provide a method of medical treatment by use of said pharmaceutical compositions.
  • Another aspect of the present invention provides a compound of formula (I) or a
  • Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of a disorder in which inhibition of the activity of microsomal prostaglandin E synthase- 1 is desired and/or required.
  • Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of an inflammatory disease, said disease preferably being selected from rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, psoriasis, eczema, swelling and periodontitis.
  • Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of nociceptive pain, said pain preferably being selected from inflammatory pain, post-operative pain, fibromyalgia, dysmenorrhea, migraine, arthrotic pain, arthritic pain, pain in connection with osteoarthritis, cephalalgia, pain due to gall-stones and pain due to metastasis, ankylosing spondylitis, gout, or rheumatic fever, and tootache.
  • the compound of formula (I) also may be used in preemptive treatment of surgical pain.
  • Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of an autoimmune disease, said autoimmune disease preferably being selected from rheumatoid arthritis and multiple sclerosis.
  • Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of a breathing disorder, said disorder preferably being selected from apnea or other respiratory distress symptoms in adults and children, sudden infant death syndrome (SIDS), asthma and other chronic obstructive lung-diseases and sarcoidosis.
  • a breathing disorder preferably being selected from apnea or other respiratory distress symptoms in adults and children, sudden infant death syndrome (SIDS), asthma and other chronic obstructive lung-diseases and sarcoidosis.
  • Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of cancer, said cancer preferably being selected from familial adenomatous polyposis (FAP) condition, colorectal cancer, breast cancer, gastric tumorigenesis and epithelial ovarian cancer, as well as cellular neoplastic transformations and metastatic tumor growth.
  • FAP familial adenomatous polyposis
  • Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of cardiovascular diseases due to atherosclerosis such as myocardial infarction and stroke.
  • Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of fever- or inflammation-related anorexia.
  • Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of Alzheimer's disease.
  • Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of endometriosis, hemophilic arthropathy, Parkinson's disease, mPGES-1 -mediated proliferative disorders such as may occur in diabetic retinopathy and tumor angiogenesis, symptoms associated with viral infections, and premature labor.
  • Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of an inflammatory disease, said disease preferably being selected from rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, psoriasis, eczema, swelling and periodontitis.
  • Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of nociceptive pain, said pain preferably being selected from inflammatory pain, post-operative pain, fibromyalgia, dysmenorrhea, migraine, arthrotic pain, arthritic pain, pain in connection with osteoarthritis, cephalalgia, pain due to gall-stones and pain due to metastasis, pain due to ankylosing spondylitis, pain due to gout, toothache and pain due to rheumatic fever, or for the preemptive treatment of surgical pain.
  • Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of an autoimmune disease, said autoimmune disease preferably being selected from rheumatoid arthritis and multiple sclerosis.
  • Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of a breathing disorder, said disorder preferably being selected from apnea or other respiratory distress symptoms in adults and children, sudden infant death syndrome (SIDS), asthma and other chronic obstructive lung- diseases and sarcoidosis.
  • a breathing disorder preferably being selected from apnea or other respiratory distress symptoms in adults and children, sudden infant death syndrome (SIDS), asthma and other chronic obstructive lung- diseases and sarcoidosis.
  • Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of cancer, said cancer preferably being selected from familial adenomatous polyposis (FAP) condition, colorectal cancer, breast cancer, gastric tumorigenesis and epithelial ovarian cancer, as well as cellular neoplastic transformations and metastatic tumor growth.
  • FAP familial adenomatous polyposis
  • Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of cardiovascular diseases due to atherosclerosis such as myocardial infarction and stroke.
  • Another aspect of the present invention provides the use of a compound of formula (I), in preparation of a medicament for the treatment and/or prevention of fever- or inflammation- related anorexia.
  • Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of Alzheimer's disease.
  • Another aspect of the present invention provides a method of treatment of a disease in which inhibition of the activity of mPGEs-1 is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, such a condition.
  • Another aspect of the present invention provides a method of treatment of an inflammatory disease, said disease preferably being selected from rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, psoriasis, eczema, swelling and periodontitis, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient in the need of such treatment.
  • Another aspect of the present invention provides a method of treatment of nociceptive pain, said pain preferably being selected from inflammatory pain, post-operative pain, fibromyalgia, dysmenorrhea, migraine, arthrotic pain, arthritic pain, pain in connection with osteoarthritis, cephalalgia, pain due to gall-stones and pain due to metastasis, pain due to ankylosing spondylitis, gout, toothache and pain due to rheumatic fever, as well as preemptive treatment of surgical pain, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient in the need of such treatment.
  • a compound of formula (I) or a pharmaceutically-acceptable salt thereof
  • Another aspect of the present invention provides a method of treatment of an autoimmune disease, said autoimmune disease preferably being selected from rheumatoid arthritis and multiple sclerosis, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient in the need of such treatment.
  • Another aspect of the present invention provides a method of treatment of a breathing disorder, said disorder preferably being selected from apnea or other respiratory distress symptoms in adults and children, sudden infant death syndrome (SIDS), asthma and other chronic obstructive lung-diseases and sarcoidosis, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient in the need of such treatment.
  • SIDS sudden infant death syndrome
  • asthma chronic obstructive lung-diseases and sarcoidosis
  • Another aspect of the present invention provides a method of treatment of cancer, said cancer preferably being selected from familial adenomatous polyposis (FAP) condition, colorectal cancer, breast cancer, gastric tumorigenesis and epithelial ovarian cancer, as well as cellular neoplastic transformations and metastatic tumor growth, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically- acceptable salt thereof, to a patient in the need of such treatment.
  • FAP familial adenomatous polyposis
  • Another aspect of the present invention provides a method of treatment of cardiovascular diseases due to atherosclerosis such as myocardial infarction and stroke, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient in the need of such treatment.
  • Another aspect of the present invention provides a method of treatment of fever- or
  • inflammation-related anorexia which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient in the need of such treatment.
  • Another aspect of the present invention provides a method of treatment of Alzheimer's disease, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient in the need of such treatment.
  • Figure 1 is a bar diagram showing results of a carrageenan- induced paw edema assay in Wistar rats using the compound synthesised in Example 41.
  • the compound at 10, 30 and 100 mg/kg, as well as vehicle was administered intraperitoneally immediately before carrageenan challenge.
  • Hind paw edema a measure of inflammation, was recorded 6 hours after carrageenan administration.
  • Volume increase is paw volume at 6 hours after carrageenan administration minus paw volume before carrageenan administration.
  • Figure 2 is a bar diagram showing inhibition of CFA- induced paw swelling by the compound synthesised in Example 41 compared to vehicle control.
  • any alkyl, alkenyl or alkynyl group as referred to herein may be branched or unbranched. This also applies to said groups when present in moieties such as alkoxy groups, and the like.
  • alkyl refers to an acyclic straight or branched chain radical, unless otherwise specified containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbons in the normal chain, which includes methyl, ethyl, /? -propyl, /? -butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl.
  • Alkyl also includes a straight or branched alkyl group that contains or is interrupted by a carbocyclyl group, exemplified by cyclopropane, as exemplified below: (CH ⁇ -J- ⁇ ( CH ⁇ )z—
  • alkyl portions can be attached at any variable point of attachment to the carbocyclyl, including the same ring carbon, as exemplified below:
  • substituted alkyl when substituted alkyl is present, this refers to a straight or branched alkyl group, substituted with 1, 2, 3 groups of R a , which groups may be the same or different at any available point, as defined with respect to each variable.
  • alkenyl refers to a straight or branched chain radical, unless otherwise specified containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, containing at least one carbon to carbon double bond, which includes in the normal chain vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3- heptenyl, 4-heptenyl, 3-octenyl, and the like.
  • branched chain radicals examples include 2-buten-2-yl, 4-methyl-2-pentenyl, 6-methylene- 2-octenyl, and the like. All possible (E)- and (Z)-isomers is contemplated within the scope of the invention.
  • the straight or branched portion of the alkenyl group may be optionally substituted when a substituted alkenyl group is provided, and the chain may be interrupted by a carbocyclyl group.
  • substituted alkenyl when substituted alkenyl is present, this refers to a straight or branched alkyl group, substituted with 1, 2, 3 groups of R a , which groups may be the same or different at any available point, as defined with respect to each variable.
  • alkynyl refers to a straight or branched chain radical, unless otherwise specified containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbons, which contains at least one carbon to carbon triple bond, which in the normal chain such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2- heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, and the like.
  • Examples of branched chain radicals are 3-methyl-l-butynyl, 2-methyl-4- pentynyl, 6-methyl-4-octynyl, 6-methyl-3-propyl-4-octynyl, and the like.
  • the alkynyl can in addition to carbon to carbon triple bonds also include a to carbon double bond.
  • Examples of such radicals, not excuding any of the possible not mentioned, are 3-buten-l-ynyl, l-buten-3-ynyl, 6- methylene-2-octynyl, 3-allyl-6-methyl-l-octen-4-ynyl, and the like.
  • the straight or branched portion of the alkynyl group may be optionally substituted when a substituted alkynyl group is provided, and the chain may be interrupted by a carbocyclyl group.
  • substituted alkynyl this refers to a straight or branched alkyl group, substituted with 1, 2, 3 groups of R a , which groups may be the same or different at any available point, as defined with respect to each variable.
  • carbocyclyl refers to a cyclic moiety containing only carbon atoms.
  • bicyclic refers to a cyclic moiety containing two rings.
  • a bicyclic group may, for example, be fused or bridged.
  • heterocyclyl mean a mono- or bicyclic, saturated or unsaturated cyclic group, possibly aromatic, containing one or more heteroatom(s) preferably selected from N, O and S, such as, but not limited to, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl, dioxolanyl, dioxanyl, dithianyl, dithiolanyl, imidazolidinyl, imidazolinyl, morpholinyl, oxetanyl, oxiranyl, pyrrolidinyl, pyrrolidinonyl, piperidyl, piperazinyl, piperidinyl, pyrazolidinyl, quinuclidinyl, sulfalonyl, 3-sulfolenyl, tetrahydrofuranyl tetrahydropyranyl,
  • benzobenzoxadiazolyl benzoxazinyl, benzoxazolyl, benzo morpholinyl, benzoselenadiazolyl, benzothienyl, purinyl, pteridinyl, and the like.
  • halogen refers to fluorine, chlorine, bromine and iodine, where the preferred halogen radicals are fluoro and chloro.
  • aryl means an aromatic group, monocyclic or bicyclic such as, but not limited to phenyl or naphthyl, and the like. The aryl group is preferably a monocyclic C 6 aryl (phenyl).
  • cycloalkyl as employed herein alone or as part of another group includes saturated cyclic hydrocarbyl groups, mono- or bicyclic rings(s), having a total of 3, 4, 5, 6, 7, 8, 9 or 10 carbons forming the ring(s), which includes cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclodecane, bicyclo[4.1.0]heptane, bicyclo[4.3.3]dodecane, cyclopentyl, decahydronaphthalene, bicyclo[2.2.2]octane, and the like, optionally substituted with 1, 2 or 3 groups of R a .
  • cycloalkenyl as employed herein alone or as part of another group includes unsaturated cyclic rings(s), mono- or bicyclic, having a total of 4, 5, 6, 7, 8, 9 or 10 carbons forming the ring(s), which includes cyclohexene, cyclobutene, bicyclo[4.2.0]-3-octene, 1,3- cyclodecadiene and the like, optionally substituted with 1, 2 or 3 groups of R a .
  • cycloalkynyl as employed herein alone or as part of another group includes mono- or bicyclic, rings having one carbon to carbon triple bond, and having a total of 8, 9 or 10 carbons forming the ring, which includes cyclooctyne, cyclodecyne, bicyclo[6.2.0]-4-decyne and the like, optionally substituted with 1, 2 or 3 groups of R a .
  • the cycloalkynyl can in addition to carbon to carbon triple bonds also contain a carbon to carbon double bond, which includes l-cyclodecen-5- yne and the like.
  • Carbocyclyl as employed herein alone or as part of another group includes saturated cyclic hydrocarbyl groups or unsaturated (at least one carbon to carbon double bond) cyclic hydrocarbyl groups, containing one ring and a total of 3, 4, 5, 6, 7, 8, 9 or 10 carbons forming the ring, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cycloheptyl, and the like.
  • the cyclic hydrocarbyl may be mono- or bicyclic.
  • tern ⁇ 'unsaturated when referring to a bicyclic system, is meant a ring system
  • both rings may be unsaturated or only one ring may be unsaturated, the other one being saturated.
  • unsaturated bicyclic also is intended to refer to a non- aromatic bicyclic system comprising a ring that is either unsaturated or saturated fused to a ring that by itself would be aromatic, such as in indane or 4,5-dihydro-l -indole.
  • aromatic refers to an unsaturated cyclic moiety that has an aromatic character
  • non-aromatic refers to a cyclic moiety, that may be unsaturated, but that does not have an aromatic character
  • the rings may be both saturated or both unsaturated, e.g. both aromatic.
  • the rings may also be of different degrees of saturation, and one ring may be aromatic whereas the other is non-aromatic.
  • the rings also may comprise different numbers of atoms, e.g. one ring being 5-membered and the other one being 6-membered.
  • a bicyclic heterocyclyl as referred to herein, one or both of the rings may contain one or several heteroatoms.
  • hydroxy (i), carboxy (ii) and aminocarbonyl (iii), refer to radicals of the type:
  • alkyloxy, alkenyloxy, alkynyloxy and cycloalkyloxy refer to a radical of the type:
  • R is an alkyl, alkenyl, alkynyl or cycloalkyl moiety.
  • alkylthio, alkenylthio, and alkynylthio refer to a radical of the type:
  • R is an alkyl, alkenyl or alkynyl moiety.
  • alkyl, alkenyl and alkynyl secondary amino refer to a radical of the type:
  • R is an alkyl, alkenyl or alkynyl moiety.
  • alkyl, alkenyl and alkynyl tertiary amino refer to a radical of the type:
  • R and R' are each an independently selected alkyl, alkenyl or alkynyl moiety.
  • alkyl, alkenyl and alkynyl secondary amido refer to a radical of the type:
  • R is an alkyl, alkenyl or alkynyl moiety.
  • alkyl, alkenyl and alkynyl tertiary amido refer to a radical of the type:
  • R and R' are each an independently selected alkyl, alkenyl or alkynyl moiety.
  • alkyl, alkenyl and alkynyl carbonyl refer to a radical of the type:
  • R is an alkyl, alkenyl or alkynyl moiety.
  • alkyl, alkenyl and alkynyl sulfonyl refer to a radical of the type:
  • R is an alkyl, alkenyl or alkynyl moiety.
  • alkyl, alkenyl and alkynyl secondary sulphonamido refer to a radical of the type:
  • R is an alkyl, alkenyl or alkynyl moiety.
  • alkyl, alkenyl and alkynyl tertiary sulphonamido refer to a radical of the type:
  • R and R' are each independently selected from alkyl, alkenyl or alkynyl moiety.
  • alkyl, alkenyl and alkynyl secondary acylsulphonamido refer to a radical of the type:
  • R is an alkyl, alkenyl or alkynyl moiety.
  • alkyl, alkenyl and alkynyl tertiary acylsulphonamido refer to a radical of the type:
  • each R is independently selected from an alkyl, alkenyl or alkynyl moiety.
  • alkyl, alkenyl and alkynyl alkynyloxy carbonyl refer to a radical of the type: o
  • R is an alkyl, alkenyl or alkynyl moiety.
  • cyclic refers to an atom that is a member of at least one ring in a carbocycle or heterocycle.
  • a cyclyl according to the invention may comprise 1-10 carbons, it being understood that in case the cyclyl comprises less than 3 carbons, it must necessarily also comprise at least one heteroatom. Unless otherwise indicated or apparent from the context, in a bicyclic moiety according to the invention, each constituent monocycle may independently be selected from aromatic or non- aromatic carbo- and heterocycles.
  • R 1 in formula (I) is selected from branched or unbranched C 1 -C 10 alkyl, C 2 -C 10 alkenyl or C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; Cs-Cio cycloalkynyl; C1-C9 heterocyclyl; and C 6 - Cio aryl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or cycloalkynyl moiety optionally is substituted with 1, 2 or 3 groups R a ; and any heterocyclyl or aryl moiety optionally is substituted with 1, 2, 3, 4 or 5 groups R b , as defined herein.
  • R 1 in formula (I) is selected from branched or unbranched C 1 -C 10 alkyl; C3- Cio cycloalkyl; C1-C9 heterocyclyl; and C 6 -CiO aryl; said alkyl and cycloalkyl optionally being substituted with 1 , 2 or 3 groups R a ; and said heterocyclyl and aryl optionally being substituted with 1, 2, 3, 4 or 5 groups R b .
  • R 1 in formula (I) is optionally substituted branched or unbranched C 1 -C 10 alkyl, e.g. Ci-Cs alkyl, i.e. methyl, ethyl and branched or unbranched propyl, butyl, pentyl, hexyl, heptyl, and octyl, such as methyl, ethyl, n-propyl, ⁇ o-propyl, n-butyl, iso- butyl, sec-butyl, n-pentyl, pentan-2-yl, pentan-3-yl, n-hexyl, n-heptyl, and n-octyl.
  • Ci-Cs alkyl i.e. methyl, ethyl and branched or unbranched propyl, butyl, pentyl, hexyl, heptyl, and octyl
  • R 1 in formula (I) may be selected from optionally substituted branched or unbranched Ci-C 6 alkyl, e.g. methyl, ethyl, n-propyl, ⁇ o-propyl, n-butyl, ⁇ o-butyl, sec-butyl, n -pentyl, pentan-2-yl, pentan-3-yl, n-hexyl, or from optionally substituted branched or unbranched Ci -C 4 alkyl.
  • R 1 may be optinally substituted iso- propyl.
  • R 1 in formula (I) when R 1 in formula (I) is selected from optionally substituted branched or unbranched Ci -C 10 alkyl, m is 0. In another embodiment, R 1 in formula (I) is optionally substituted C 3 -C 10 cycloalkyl, in particular C 3 -C 6 cycloalkyl, or C3-C5 cycloalkyl.
  • R 1 in formula (I) also may be optionally substituted C1-C9 heterocyclyl, in particular C1-C5 heterocyclyl, such as a 6-membered C1-C5 heterocyclyl, C2-C5 heterocyclyl, C3-C5 heterocyclyl, C4-C5 heterocyclyl or C5 heterocyclyl, e.g.
  • R 1 in formula (I) also may be optionally substituted C 6 -CiO aryl, preferably phenyl.
  • R 1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, it optionally is substituted with 1, 2 or 3 groups, e.g. 1 or 2 independently selected groups R a , e.g. 1 group R a , as defined herein, i.e.
  • halogen selected from halogen; hydroxy; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amino; C1-C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; wherein any alkyl, alkenyl or alkynyl moiety optionally is substituted with 1, 2 or 3 groups R c .
  • each R a is indpendently selected from hydroxy, C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; and C1-C4 alkyl, C2-C4 alkenyl or C 2 -C 4 alkynyl secondary or tertiary amino, in particular from hydroxy, C 1 -C 4 alkoxy, such as methoxy, or C 1 -C 4 alkyl secondary or tertiary amino, e.g. such as ethyl secondary or tertiary amino, e.g. diethylamino.
  • R 1 is not substituted with any R a .
  • R 1 is heterocyclyl or aryl, it optionally is substituted with 1, 2, 3, 4 or 5 independently selected groups R b , as defined herein, i.e. selected from halogen; carboxy; hydroxy; cyano; C1-C5 heteroaryl; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; Ci-C 4 alkylthio; C 2 -C 4 alkenylthio; C 2 -C 4 alkynylthio; Ci-C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl secondary or tertiary amino; amino carbonyl; Ci-C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl secondary or tertiary amido; Ci-C 4 alky
  • R b is selected from halogen; carboxy; cyano; Ci-C 5 heteroaryl; Ci-C 4 alkyl; C 2 -C 4 alkenyl; C 2 -C 4 alkynyl; amino carbonyl; Ci-C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl secondary or tertiary amido; Ci-C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl secondary or tertiary acylsulphonamido; Ci-C 4 alkyloxy, C 2 -C 4 alkenyloxy, or C 2 -C 4 alkynyloxy carbonyl; and C 1 -C 5 heterocyclyl; wherein any alkyl, alkenyl and alkynyl moiety optionally is substituted with 1, 2 or 3 groups Rc.
  • R b is selected from halogen, i.e. F, Cl and Br, in particular F; carboxy; cyano; 5- or 6-membered C1-C5 heteroaryl, in particular 5- membered Ci-C 4 heteroaryl, such as triazole; Ci-C 4 alkyl, such as methyl; amino carbonyl; Ci-C 4 alkyl secondary or tertiary amido, such as methyl secondary or tertiary amido; Ci-C 4 alkyl secondary or tertiary acylsulphonamido, such as methyl secondary or tertiary acylsulphonamido; C1-C4 alkyloxy carbonyl, such as methoxy carbonyl; and C1-C5 heterocyclyl, such as 5- or 6- membered heterocyclyl, e.g. 5-membered C1-C4 heterocyclyl, e.g. tetrazole.
  • R 1 is substituted with 1-3 groups R b as defined herein, e.g. with 1 or 2 groups, in particular with 1 group R b . In another embodiment, R 1 is not substituted with any R b .
  • R 1 when R 1 is a 6-membered heterocyclyl or aryl, it is substituted with at least one group R b in para -position relative to the linking bond or chain attaching R 1 to the benzimidazol moiety.
  • R 2 in formula (I) is selected from branched or unbranched C1-C9 alkyl, C2-C9 alkenyl or C2-C9 alkynyl; C3-C6 cycloalkyl, C 4 -C 6 cycloalkenyl; Cs-Cio cycloalkynyl; C 1-C9 heterocyclyl; and C 6 - Cio aryl; said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl optionally being substituted with 1 , 2 or 3 groups R a ; and said heterocyclyl or aryl optionally being substituted with 1, 2, 3, 4 or 5 groups R b .
  • R 2 is optionally substituted branched or unbranched C1-C9 alkyl, C2-C9 alkenyl or C2-C9 alkynyl.
  • R 2 more particularly may be Ci-C 6 alkyl, C2-C6 alkenyl or C 2 -C 6 alkynyl, e.g. C 1 -C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl.
  • R 2 may be branched or unbranched C1-C9 alkyl, or Ci-C 6 alkyl, e.g. C1-C4 alkyl, e.g. C2-C4 alkyl.
  • R 2 when R 2 is optionally substituted branched or unbranched C1-C9 alkyl, C2- C 9 alkenyl or C 2 -C 9 alkynyl, X is a bond.
  • R 2 is optionally substituted C 3 -C 6 cycloalkyl or C 4 -C 6 cycloalkenyl, and then more particularly may be C 3 -C 6 cycloalkyl, in particular pentyl.
  • R 2 is optionally substituted C 1 -C 9 heterocyclyl.
  • R 2 may in particular be C1-C5 heterocyclyl, e.g. 5-membered C1-C4 heterocyclyl or 6-membered C1-C5 heterocyclyl, in particular 5-membered C1-C4 heterocyclyl, e.g. 5-membered C3-C4 heterocyclyl.
  • R 2 may be selected from tetrahydrofuryl and thiazolyl.
  • R 2 is optionally substituted C 6 -CiO aryl, and then preferably is phenyl.
  • R 2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or cycloalkynyl, it optionally is substituted with 1, 2 or 3 groups, e.g. 1 or 2 groups, R a , as defined herein, i.e.
  • halogen selected from halogen; hydroxy; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amino; C 1 - C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; wherein any alkyl, alkenyl or alkynyl moiety optionally is substituted with 1 , 2 or 3 groups R c .
  • each R a is independently selected from C 1 - C4 alkyloxy; C2-C4 alkenyloxy; and C2-C4 alkynyloxy, in particular C1-C4 alkyloxy, such as Ci- C3 alkyloxy, more particularly methoxy and iso-propoxy.
  • R 2 is substituted with 1 group R a and in another embodiment, R 2 is not substituted with any group R a .
  • R 2 when R 2 is cycloalkyl, cycloalkenyl, or cycloalkynyl, it is not substituted with any group R a .
  • R 2 When R 2 is heterocyclyl or aryl, it optionally is substituted with 1, 2, 3, 4 or 5 groups R b , as defined herein above. In one embodiment, R 2 is substituted with 1, 2, 3, 4 or 5 groups R b each independently selected from halogen, e.g. F, Cl and Br, in particular F or Br; cyano; and C1-C5 heterocyclyl, e.g. f ⁇ ve-membered C 1-C4 heterocyclyl.
  • halogen e.g. F, Cl and Br, in particular F or Br
  • cyano cyano
  • C1-C5 heterocyclyl e.g. f ⁇ ve-membered C 1-C4 heterocyclyl.
  • R 2 may be 6-membered heterocyclyl or aryl, such as phenyl, substituted with at least one R b in para -position in relation to the bond attaching R 2 to X or - in case X is a bond - in para -position in relation to the bond X.
  • R 2 is substituted with 1-3 groups R b , e.g. 1 or 2 groups R b , in particular 1 group R b .
  • R 3 and R 4 are each independently selected from C1-C4 alkyl; C2-C4 alkenyl; C 2 -C 4 alkynyl; C3-C4 cycloalkyl; C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; Ci-C 4 alkylthio; C 2 -C 4 alkenylthio; C 2 -C 4 alkynylthio; halogen; Ci-C 4 alkyl, C 2 -C 4 alkenyl or C 2 - C 4 alkynyl secondary or tertiary amino; and Ci-C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl carbonyl; wherein any alkyl, alkenyl, alkynyl or cycloalkyl moiety optionally is substituted with 1, 2, or 3 groups R c .
  • R 3 and R 4 are each independently selected from Ci-C 4 alkyl and
  • R 3 and R 4 may be both halogen or both Ci-C 4 alkyl, e.g. both are Cl or both are methyl, or one may be halogen, e.g. Cl, and the other one Ci-C 4 alkyl, e.g. methyl.
  • R 3 is selected from C 1 -C 4 alkyl, e.g. methyl
  • R 4 is selected from halogen and C 1 -C 4 alkyl, e.g. Cl and methyl.
  • R 3 is selected from halogen, e.g. Cl
  • R 4 is selected from halogen and C1-C4 alkyl, e.g. Cl and methyl.
  • R 3 is selected from halogen and C 1 -C 4 alkyl, e.g. Cl and methyl, and R 4 is selected from C 1 -C 4 alkyl, e.g. methyl.
  • R 3 is selected from halogen and C1-C4 alkyl, e.g. Cl and methyl, and R 4 is selected from halogen, e.g. Cl.
  • R 5 and R 6 in formula (I) are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C 2 -C 4 alkynyl and halogen; whereby any alkyl; alkenyl; or alkynyl is optionally substituted with 1, 2, or 3 groups R c .
  • R 5 and R 6 are independently selected from hydrogen and C 1 -C 4 alkyl, more particularly from H and methyl, for example, R 5 and R 6 may both be H; or R 5 may be H and R 6 methyl.
  • X represents a bond (i.e. a single, covalent bond) or branched or unbranched Ci- C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl.
  • X represents a bond or C1-C3 alkyl, more preferably a bond or methylene (-CH2-).
  • Q in formula (I) is selected from carbonyl, sulfonyl and sulf ⁇ nyl and preferably is carbonyl.
  • m is an integer of 0, 1 or 2, preferably 0 or 1. In one particular embodiment, m is 0. In another embodiment, m is 1.
  • Each R a is independently selected from halogen; hydroxy; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; C1-C4 alkyl, C2-C4 alkenyl or C2- C4 alkynyl secondary or tertiary amino; C1-C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; wherein any alkyl, alkenyl or alkynyl moiety optionally is substituted with 1, 2 or 3 groups R c .
  • each R a is independently selected from hydroxy; C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; and C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amino; wherein any alkyl, alkenyl and alkynyl moiety optionally is substituted with 1, 2 or 3 groups R c .
  • each R a is independently selected from hydroxy; C 1 -C 4 alkyloxy, e.g. methoxy and ⁇ o-propoxy; and C1-C4 alkyl secondary or tertiary amino, e.g.diethylamino.
  • Each R b in formula (I) is independently selected from halogen; carboxy; hydroxy; cyano; C 1 -C 5 heteroaryl; Ci-C 4 alkyl; C 2 -C 4 alkenyl; C 2 -C 4 alkynyl; C 3 -C 5 cycloalkyl; Ci-C 4 alkyloxy; C 2 -C 4 alkenyloxy; C 2 -C 4 alkynyloxy; C3-C5 cycloalkyloxy; Ci-C 4 alkylthio; C 2 -C 4 alkenylthio; C 2 -C 4 alkynylthio; C3-C5 cycloalkylthio; Ci-C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl secondary or tertiary amino; amino carbonyl; Ci-C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl secondary
  • acylsulphonamido Ci-C 4 alkyloxy, C 2 -C 4 alkenyloxy, or C 2 -C 4 alkynyloxy carbonyl; C1-C5 heterocyclyl; wherein any alkyl, alkenyl, alkynyl or cycloalkyl moiety optionally is substituted with 1 , 2 or 3 groups R c as defined herein.
  • each R b is independently selected from halogen; carboxy; hydroxy; cyano; Ci -C 5 heteroaryl; Ci-C 4 alkyl; C 3 -C 5 cycloalkyl; Ci-C 4 alkyloxy; C 3 -C 5 cycloalkyloxy; Ci-C 4 alkylthio; Ci-C 4 alkyl secondary or tertiary amino; amino carbonyl; Ci-C 4 alkyl secondary or tertiary amido; Ci-C 4 alkyl carbonyl; Ci-C 4 alkyl sulfonyl; Ci-C 4 alkyl secondary or tertiary sulphonamido; Ci-C 4 alkyl secondary or tertiary acylsulphonamido; Ci-C 4 alkyloxy carbonyl; Ci-C 5 heterocyclyl; wherein any alkyl or cycloalkyl moiety optionally is substituted with 1, 2 or 3 groups R c as defined herein.
  • each R b is independently selected from halogen; carboxy, cyano; Ci-C 5 heteroaryl; Ci-C 4 alkyl; C 2 -C 4 alkenyl; C 3 -C 5 cycloalkyl; Ci-C 4 alkyloxy; C 3 -C 5 cycloalkyloxy; C 2 -C 4 alkynyl; amino carbonyl; Ci-C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl secondary or tertiary amido; Ci-C 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl secondary or tertiary acylsulphonamido; C 1 - C 4 alkyloxy carbonyl; and Ci-C 5 heterocyclyl; wherein any alkyl, alkenyl and alkynyl moiety optionally is substituted with 1 , 2 or 3 groups R c as defined herein.
  • each R b is independently selected from halogen; carboxy; cyano; Ci-C 5 heteroaryl; Ci-C 4 alkyl; C 3 -C 5 cycloalkyl; Ci-C 4 alkyloxy; C 3 -C 5 cycloalkyloxy;
  • Ci-C 4 alkyl secondary or tertiary amido Ci-C 4 alkyl secondary or tertiary acylsulphonamido
  • Ci-C 4 alkyloxy carbonyl Ci-C 5 heterocyclyl; wherein any alkyl, moiety optionally is substituted with 1, 2 or 3 groups R c as defined herein.
  • each R b is independently selected from halogen; carboxy, cyano; C 1-C5 heteroaryl; C1-C4 alkyl; amino carbonyl; C1-C4 alkyl secondary or tertiary amido; C1-C4 alkyl secondary or tertiary acylsulphonamido; C1-C4 alkyloxy carbonyl; and C1-C5 heterocyclyl; wherein any alkyl, moiety optionally is substituted with 1, 2 or 3 groups R c as defined herein.
  • R b When R b is C1-C5 heterocyclyl, it may be C1-C4 heterocyclyl, and preferably is 6-membered Ci- C5 heterocyclyl or 5-membered C1-C4 heterocyclyl, more preferably 5-membered C1-C4 heterocyclyl.
  • R b When R b is C1-C5 heteroaryl, it may be C1-C4 heteroaryl, and prefereably is 6- membered C1-C5 heteroaryl or 5-membered C1-C4 heteroaryl.
  • R c in formula (I) is selected from fluorine and chlorine. In one embodiment, R c is absent. In another embodiment, R c is fluorine.
  • X represents methylene or a bond and R 2 represents C3-C 6 cycloalkyl or heterocyclyl.
  • X represents a bond and R 2 represents cyclopentyl.
  • R 1 is selected from branched or unbranched C 1 -C 10 alkyl; C3-C10 cycloalkyl; C1-C9 heterocyclyl; and C 6 -CiO aryl; wherein any alkyl or cycloalkyl moiety optionally is substituted with 1, 2 or 3 groups R a ; and any heterocyclyl or aryl moiety optionally is substituted with 1, 2, 3, 4 or 5 groups R b ;
  • R 2 is selected from branched or unbranched C1-C9 alkyl; C 3 -C 6 cycloalkyl; C1-C9 heterocyclyl; and C 6 -CiO aryl; wherein any alkyl or cycloalkyl moiety optionally is substituted with 1, 2 or 3 groups R a ; and any heterocyclyl or aryl moiety optionally is substituted with 1, 2, 3, 4 or 5 groups R b ;
  • R 3 and R 4 are each independently selected from C 1 -C 4 alkyl and halogen;
  • R 5 and R 6 are each selected from H and methyl; m is 0 or 1 ;
  • Q is carbonyl;
  • X represents a bond or methylene;
  • each R a is independently selected from hydroxy; C1-C4 alkyloxy; C1-C4 alkyl secondary or tertiary amino;
  • each R b is independently selected from halogen; cyano; C1-C5 heteroaryl, carboxy, C1-C4 alkyl; C 1 -C 4 alkyl secondary or tertiary amido; C 1 -C 4 alkyl carbonyl; C 1 -C 4 alkyloxy carbonyl; C 1 -C 4 alkyl secondary or tertiary acylsulphonamido; and C1-C5 heterocyclyl; and
  • R c is absent.
  • R 1 is selected from branched or unbranched C 1 -C 10 alkyl; C3-C6 cycloalkyl; 5- or 6-membered C 3 -C 5 heterocyclyl; and phenyl; wherein any alkyl or cycloalkyl . moiety optionally is substituted with 1 or 2 groups R a ; and any heterocyclyl or phenyl moiety optionally is substituted with 1 or 2 groups R b ;
  • R 2 is selected from branched or unbranched Ci-C 6 alkyl; C3-C6 cycloalkyl; 5- or 6-membered C3- C 5 heterocyclyl; and phenyl; wherein any alkyl or cycloalkyl moiety optionally is substituted with 1 or 2 groups R a ; and any heterocyclyl or phenyl moiety optionally is substituted with 1 or 2 groups R b ;
  • R 3 and R 4 are each independently selected from methyl and chloro
  • R 5 and R 6 are each selected from H.
  • R 1 represents C 1 -C 10 alkyl, e.g. Ci-Cs alkyl, or C 1 - C 6 alkyl
  • R 2 represents C4-C6 cycloalkyl or C4-C5 heterocyclyl, e.g. C4-C6 cycloalkyl or 5- or 6- membered C4-C5 heterocyclyl
  • R 3 and R 4 are independently selected from methyl and chlorine
  • R 5 and R 6 are hydrogen
  • X represents a bond
  • Q represents carbonyl.
  • the compound of formula (I) may be represented by the formula (Ia):
  • intej ger p is 0-11, e.g. 0-9, or 0-7.
  • R 1 represents C3-C6 cycloalkyl
  • R 2 represents C 4 -C 6 cycloalkyl or C4-C5 heterocyclyl
  • R 3 and R 4 are independently selected from methyl and chlorine
  • X represents a bond
  • Q represents carbonyl
  • R 1 represents phenyl or C 4 -C 5 heterocyclyl
  • R 2 represents C 4 -C 6 cycloalkyl or C4-C5 heterocyclyl
  • R 3 and R 4 are independently selected from methyl and chlorine
  • X represents a bond
  • Q represents carbonyl
  • R 1 represents phenyl or C4-C5 heterocyclyl, e.g. 5- or 6-membered C4-C5 heterocyclyl, optionally substituted with one or more R b ;
  • R 2 represents cyclopentyl;
  • R 3 and R 4 are independently selected from methyl and chlorine; the integer m is equal to 1 or 0 (zero);
  • R 5 and R 6 are hydrogen;
  • X represents a bond; and Q represents carbonyl.
  • the compound of formula (I) may be represented by the formula (Ib):
  • R 1 represents C 1 -C 10 alkyl, e.g. Ci-Cs alkyl, or Ci- C 6 alkyl
  • R 2 represents Ci-C 9 alkyl, e.g. Ci-C 6 alkyl, or Ci-C 4 alkyl
  • R 3 and R 4 are independently selected from methyl and chlorine, R 5 and R 6 are hydrogen
  • Q represents carbonyl.
  • the compound of formula (I) may be represented by the formula (Ic):
  • R 1 represents C4-C5 saturated heterocyclyl, e.g. 5- or 6-membered C4-C5 heterocyclyl
  • R 2 represents cyclopentyl
  • R 3 and R 4 are independently selected from methyl and chlorine
  • the integer m is equal to 1
  • R 5 and R 6 are hydrogen
  • X represents a bond
  • Q represents carbonyl.
  • the compound of formula (I) may be represented by the formula (Id):
  • R 1 represents C 3 -C 5 cycloalkyl
  • R 2 represents cyclopentyl or tetrahydrofuranyl
  • R 3 and R 4 are independently selected from methyl and chlorine
  • the integer m is equal to either 0 (zero) or 1
  • R 5 and R 6 are hydrogen
  • X represents a bond
  • Q represents carbonyl
  • the compounds of formula (I) of the invention can be prepared according to the synthetic routes outlined herein and by following the methods described herein below and illustrated in the Examples. Alternative synthetic routes to these compounds can easily be visualized by any person skilled in the art and the present synthetic routes are not limiting for the invention. With respect to the reaction schemes below, although the various R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Q and X moieties sometimes are specifically defined, unless otherwise indicated, it is to be understood that R 1 , R 2 , R 3 , R 4 and X may be any of the groups encompassed thereby.
  • a compound of formula (I) as defined herein may be formed in a three step procedure wherein, first, a suitable substituted 2-aminobenzoimidazol (i) is diazotizated and subjected to the Sandmeyer reaction, or any suitable modification of this method, the formed chloro intermediate (ii) is coupled with a piperidine-4-carboxamide derivative (iii) to form the product (iv), which subsequently is JV-alkylated or arylated by Y- (CR 5 R 6 ) m -R 1 (v) to yield the final compound of formula (I).
  • the entire synthetic route is depicted below in Reaction Scheme 1.
  • diazonium compounds from aromatic or heteroaromatic amines has been known for more than 150 years and involves an amine that reacts with a nitrite salt such as sodium nitrite to form a diazonium salt at low temperature, a procedure that should be well known for the one skilled in the art.
  • a nitrite salt such as sodium nitrite
  • diazonium compounds are not isolated, but used immediately in further reactions as described below in the Sandmeyer reaction.
  • Diazonium compounds can, however, also be isolated as tetrafluoroborate salts.
  • Conditions suitable for the Sandmeyer reaction are well known to the person skilled in the art and comprise an diazonium salt of an aromatic or heterocyclic kept at low temperature, which is decomposed in the presence of copper(I) salts, such as copper(I) chloride or copper(I) bromide, to form the desired chloro or bromo derivative.
  • copper(I) salts such as copper(I) chloride or copper(I) bromide
  • the chloro intermediate (ii) is reacted with the piperidine-4-carboxamide derivative (iii) to form the coupled product (iv) in the presence of a base, such as as N, ⁇ /-diisopropylethylamine (Hunig's base, DIEA, CAS Registry Number: 7087-68-5), in a suitable solvent, such as 1,4-dioxane.
  • a base such as as N, ⁇ /-diisopropylethylamine (Hunig's base, DIEA, CAS Registry Number: 7087-68-5)
  • a suitable solvent such as 1,4-dioxane.
  • TMP 2,2,6,6- tetramethylpiperidine
  • JV-alkylation or JV-arylation by Y-R 1 is employed.
  • JV-alkylation is treated with a chloro-, bromo or iodoalkyl electrophile in the presence of a base such as caesium carbonate in a solvent such as acetonitrile and/or N, ⁇ /-dimethylformamide.
  • a palladium catalyst such as, but not limited to [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), CAS Registry Number: 72287-26-4) can also be employed in this reaction.
  • (iv) is treated with a haloaryl in the presence of a base such as caesium carbonate, and an agent as 1,10-phenanthroline, 4,7-dimethoxy-l,10- phenanthroline or 8-hydroxyquinoline, polyethylene glycol and copper(I) oxide in a solvent such as dimethylsulfoxide.
  • a base such as caesium carbonate
  • an agent such as 1,10-phenanthroline, 4,7-dimethoxy-l,10- phenanthroline or 8-hydroxyquinoline, polyethylene glycol and copper(I) oxide
  • solvent such as dimethylsulfoxide
  • Alternative reagents include phosphorus pentachloride (CAS Registry Number: 10026-13-8) or phosphorus trichloride (CAS Registry Number: 7719-12-2), the former also, alone or as mixtures in various ratios, or any other chlorination agent, all that exists in abundance in the scientific literature, for the purpose of transforming a hydroxyl group to a chlorine group.
  • the corresponding bromo derivative of (ii) also can be useful as an intermediate in the reaction schemes, leading to the target compounds of the invention, and could be prepared by the action of phosphoryl bromide (CAS Registry Number: 7789-59-5) phosphorus tribromide (CAS
  • the carboxylic acid ester (xi) is saponified with a base such as aqueous sodium hydroxide and a solvent such as ethanol. Acidification of the completed reaction mixture is followed by standard work-up and crystallization or chromatography, to yield the carboxylic acid (xii).
  • a base such as aqueous sodium hydroxide
  • a solvent such as ethanol.
  • Acidification of the completed reaction mixture is followed by standard work-up and crystallization or chromatography, to yield the carboxylic acid (xii).
  • a wide variety of other protecting groups for the carboxylic acid can be employed, and their usage is known to those skilled in the art (references describing protecting group strategy include, for example, "Protecting Groups in Organic Chemistry", J. F. W. McOmie, Plenum Press, London, New York, 1973, and "Protective Groups in Organic Synthesis", T. W. Greene, Wiley, New York, 1984).
  • a suitable amide coupling reagent such as 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU; CAS Registry Number: 148893-10-1) and N,N- diisopropylethylamine in a suitable solvent, such as dichloromethane, or by reacting the acid derivative in the presence of e.g. triethylamine in a suitable solvent, such as chloroform or in the presence of N,7V-diisopropylethylamine in a suitable solvent, such as dichloromethane.
  • a suitable amide coupling reagent such as 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU; CAS Registry Number: 148893-10-1) and N,N- diisopropylethy
  • the present invention also involve the use of microwave irridation for heating purposes, which today is well known for the one skilled in the art, as witnessed by a large number of book chapters and published books [eg. Strauss, C. R., Application of microwaves for environmentally benign organic chemistry, In Handbook of Green Chemistry and Technology, Clark, J.;
  • reaction mixtures are purified by standard purification procedures as extraction, washing, recrystallization, and column chromatography employing silica gel, aluminia or reverse phase and the like, employing the appropriate eluents for the purification of the Examples described herein.
  • the compounds of the invention can also be prepared by the application of combinatorical and/or parallell chemistry techniques eg. methods of making libraries of compounds, techniques well known for the one skilled in the art, which can include solution phase synthesis, and solid phase synthesis including design of resins, linkers and the like.
  • combinatorical and/or parallell chemistry techniques eg. methods of making libraries of compounds, techniques well known for the one skilled in the art, which can include solution phase synthesis, and solid phase synthesis including design of resins, linkers and the like.
  • (x) can be saponif ⁇ cated to give the intermediate (xiv) that can serve as a suitable scaffold for further manipulation.
  • JV-alkylation with (v), followed by amide coupling with (xiii) can be conducted in one pot (in the same reaction vessel) if the two reactions are selective in terms of regioselectivity (a term that is well known for the one skilled in the art), which also includes the reverse reaction order eg. amide coupling followed by N-alkylation, or alternatively both reactions acting at the same time.
  • regioselectivity a term that is well known for the one skilled in the art
  • Outlined in Reaction Scheme 7 is the one of the synthetic strategies of the invention that involves tautomeric forms of the intermediate compounds. Accordingly, the tautomeric mixture of (iia) and (iib) is treated with a nucleophilic agent, as exemplified by (iii), but not restricted to, then yet two tautomeric compounds (iva) and (ivb) are formed. In the final step an N-alkylating agent (v) is employed and a regioisomeric mixture of end products (I) is formed, which might be tested directly in biological assays.
  • a nucleophilic agent as exemplified by (iii)
  • iva tautomeric compounds
  • ivb N-alkylating agent
  • the regioisomers of the mixture can be separated before biological testing, using for instance column chromatography, recrystallization, sublimation or any other methods available for the one skilled in the art of chemical separation.
  • the final purification can only take palace after the final synthetic step, since all previous intermediates are tautomers.
  • N-alkylation or N-arylation can be introduced at an earlier stage in the synthetic procedure, as exemplified shown in Reaction Scheme 7.
  • This will provide the compounds (xia) and (xib), which already at this stage can be separated using any of the techniques mentioned above.
  • this strategy will ultimately lead to the end products (I).
  • This synthetic strategy can, for example, be considered when the final Examples are difficult to separate, or because of any other advantageous reason.
  • the invention at hand also comprises a synthetic method that is strictly
  • N-alkylation when N-alkylation is mentioned in the text or in the Reaction Schemes, then the N-arylation of the available -NH- or -NH 2 group is not excluded, but an important aspect of the present invention. Also, when only N-arylation is mentioned, then should neither N-alkylation be excluded.
  • the present invention also comprises stereoisomers that, for example, are prepared with the available metods described above.
  • a large number of available single enantiomers are available commercially or in the literature.
  • the single enantiomers can be amines that are used in the amide coupling of present invention, such as, but not limited to, (R)-(+)-tetrahydrofuran-3 -amine 4-methylbenzenesulfonate (CAS Registry Number: 111769-27-8), (S)-(-)-tetrahydrofuran-3- amine hydrochloride (CAS Registry Number: 204512-95-8), (lS,2S)-trans-2- aminocyclopentanol hydrochloride (CAS Registry Number: 68327-04-8), (lR,2R)-trans-2- aminocyclopentanol hydrochloride (CAS Registry Number: 68327-11-7).
  • (xxii), which includes a protection group PG, is coupled with an amine (xiii) to give the sulphonamide (xxiii), that can be coupled, after de-protection with a suitable halobenzimidazole (ii), and finally N-alkylated or N-arylated with (v) to the end products (I).
  • a suitable halobenzimidazole ii
  • v N-alkylated or N-arylated with (v)
  • H a and H d correlates as a pair, as H b and H c .
  • the compounds according to formula (I) will be useful for treating various diseases such as inflammatory diseases, nociceptive pain, auto-immune disease, breathing disorders, fever, cancer, inflammation related anorexia, Alzheimer's disease and cardiovascular disease.
  • the treatment may be preventive, palliative or curative.
  • pharmaceutically acceptable addition salts for use in the pharmaceutical compositions of the present invention include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids.
  • the pharmaceutically acceptable excipients described herein for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public.
  • the pharmaceutically acceptable carrier may be one that is chemically inert to the active compounds and that has no detrimental side effects or toxicity under the conditions of use. Pharmaceutical formulations are found e.g. in Remington: The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995).
  • All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form.
  • the compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substitutents. Consequently, compounds of formula (I) can exist in enantiomeric or diasteromeric forms or in mixtures thereof.
  • the processes for preparation can utilize racemates, enantiomers or diasteromers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods, which for example is chromatographic or fractional crystallization.
  • Prodrugs of the compounds of formula (I) may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent.
  • Prodrugs include compounds of formula (I) wherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group in a compound of formula (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively.
  • prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives, JV-Mannich bases.
  • General information on prodrugs may be found in the scientific literature [eg. Bundegaard, H. "Design of Prodrugs” p 1-92, Elesevier, New York- Oxford, 1985; The Practice of Medicinal Chemistry, Camille G. Wermuth et al., chapter 31, Academic Press, 1996; A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. chapter 5, pgs 113 - 191, Harwood Academic Publishers, 1991). Said references are incorporated herein by reference.
  • the compounds of the formula (I) can be administered for any of the uses described herein by any suitable means, for example, orally, such as in the form of tablets, aqueous or oily suspensions or solutions, elexirs, syrups, capsules, granules or powders; sublingually; buccally; ocular; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions). Also, the compounds of the formula (I) may be applied as gargles and mouth washes.
  • a parenterally acceptable aqueous or oily suspension, emulsion or solution is employed, which is pyrogen free and has requisite pH, isotonicity and stability.
  • a parenterally acceptable aqueous or oily suspension, emulsion or solution is employed, which is pyrogen free and has requisite pH, isotonicity and stability.
  • the compounds of the formula (I) can be administered nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a gel, cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents.
  • the present compounds can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps.
  • the present compounds can also be administered liposomally.
  • the precise nature of the carrier or other material will depend on the route of administration and those skilled in the art are well able to prepare suitable solutions and numerous methods are described in the literature.
  • compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art.
  • the compounds of formula (I) can also be delivered through the oral cavity by sublingual and/or buccal administration.
  • Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used.
  • Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG).
  • Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934).
  • HPC hydroxy propyl cellulose
  • HPMC hydroxy propyl methyl cellulose
  • SCMC sodium carboxy methyl cellulose
  • maleic anhydride copolymer e.g., Gantrez
  • agents to control release such as polyacrylic copolymer (e.g. Carbopol 934).
  • Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
  • compositions for nasal aerosol or inhalation administration include solutions in saline which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
  • compositions for parenteral administration include injectable solutions, emulsions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, oil or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.
  • suitable non-toxic, parenterally acceptable diluents or solvents such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, oil or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor.
  • compositions for rectal administration include suppositories which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
  • a suitable non-irritating excipient such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
  • compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
  • a topical carrier such as Plastibase (mineral oil gelled with polyethylene).
  • the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable time frame.
  • dosage will depend upon a variety of factors including the potency of the specific compound, the age, condition and body weight of the patient, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration, as well as the stage and severity of the disease.
  • the dose will also be determined by the route (administration form), timing and frequency of administration.
  • Oral dosages of the present invention when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 mg per kg of body weight per day (mg/kg/day) to 20 mg/kg/day, and most preferably 0.1 to 10 mg/kg/day, for adult humans.
  • the compositions are preferably provided in the form of tablets or other forms of presentation provided in discrete units containing 0.5 to 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated, for example 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 200, 400, 500, 600 and 800 mg..
  • the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during a constant rate infusion.
  • compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be
  • a nasal, sublingual or buccal administration typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from about 1 mg to about 100 mg of active ingredient, per dose.
  • the compounds of the present invention may be also be used or administered in combination with one or more additional drugs useful in the treatment of inflammatory diseases, nociceptive pain, auto-immune diseases, breathing disorders, fever, cancer, inflammation related anorexia, Alzheimer's disease and cardiovascular diseases.
  • the components may be in the same formulation or in separate formulations for administration simultaneously or sequentially.
  • the compounds of the present invention may also be used or administered in combination with other treatment such as irradiation for the treatment of cancer.
  • (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • a pharmaceutically-acceptable adjuvant, diluent or carrier Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent, and a pharmaceutically-acceptable adjuvant, diluent or carrier;
  • cyclooxygenase-2 inhibitors and conventional NSAIDs in preparations wherein they are presently co-administered with other agents or ingredients.
  • agents for the administration in combination with compounds of the invention include suitable anti-inflammatory, anti-pain, anti-autoimmune, anti-fever, anti-cancer and anti- anorexia (inflammatoriy) agents, and agents for the treatment or prevention of breathing disorders, cardiovascular diseases and Alzheimer's disease, a potentiator including caffeine, an H2 antagonist, aluminium or magnesium hydroxide, simethicone, a decongestant, an antitussive, an antihistamine, a diuretic, a proton pump inhibitor, a bradykinin-1 antagonist, a sodium channel blocker, a 5 -HT agonist or a CGRP antagonist.
  • compounds for use in combination with the compounds of the present invention include, but is not limited to, prednisone (CAS Registry Number: 53-03-2);
  • dexamethasone (CAS Registry Number: 50-02-2); any of the selective glucocorticoid receptor agonists (SEGRAs) exemplified by All 6515 (Lin, C. et al. MoL Pharm., 2002, 62, 297-303), and ZK209614 (Schacke, H. et al, Proc. Natl. Acad. Sci.
  • budesonide (CAS Registry Number: 51333-22-3); clofazimine (CAS Registry Number: 2030-63-9); selective thyroid hormone agonists such as GC-I (Johansson, L. et al,Proc. N ⁇ tl. Ac ⁇ d. Sci. USA. 2005, 102, 10297-10302), KB2115 (Berkenstam, A. et al., Proc. N ⁇ tl Ac ⁇ d. Sci. USA. 2008, 105, 663-667); KB-141 (Graver, G. J. et al., Proc. N ⁇ tl. Ac ⁇ d. Sci. USA.
  • FXRs farnesoid X receptor agonists
  • WAY-362450 farnesoid X receptor agonists
  • CD4 antagonists such as priliximab (CAS Registry Number: 147191-91-1); p38 mitogen-activated protein kinase inhibitors such as SB203580 (CAS Registry Number: 152121-47-6); mesalazine (CAS Registry Number: 89-57-6); azathioprine (CAS Registry Number: 446-86-6); sumatriptan (CAS Registry Number: 103628- 46-2); paracetamol (CAS Registry Number: 103-90-2); fast-acting bronchodilators such as salbutamol (CAS Registry Number: 18559-94-9) and ephedrine (CAS Registry Number: 299-42- 3); rituximab; NO-releasing drugs such as nitroglycerine (CAS Registry Number: 55-63-0) and isosorbide dinitrate (CAS Registry Number: 87-33-2); Selective Estrogen Receptor Modulators (SERMs) such as tamoxifen (CAS Registry Number: 147191-91-1);
  • antidepressant drugs and pain-relivers such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) such as desvenlafaxine (CAS Registry Number: 93413-62-8); duloxetine (CAS Registry Number:
  • treating encompasses not only treating a patient to relieve the patient of the signs and symptoms of the disease or condition but also prophylactically treating an asymptomatic patient to prevent the onset or progression of the disease or condition.
  • patients include mammalian (including human) patients.
  • the term "effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient.
  • the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
  • the expression "purified on reverse- phase hplc" will mean utilizing a preparative hplc-system comprising the following conditions and equipment: Shimadzu LC8A, C 18 column (22 x 250 mm, lO ⁇ m), acetonitrile/water gradient (0.1% trifluoroacetic acid), flowrate 15 mL/min.
  • N-cyclopentyl- 1 -(5,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (17.0 mg, 0.05 mmol), 1-iodopropane (17.0 mg, 0.10 mmol), caesium carbonate (48.9 mg, 0.15 mmol) and acetonitrile (2 mL) were mixed and the reaction mixture heated at 100 0 C over night.
  • N-cyclopentyl-l-(l-heptyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide was prepared from ⁇ /-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (17.0 mg, 0.05 mmol), 1-bromo heptane (17.9 mg, 0.10 mmol), caesium carbonate (48.9 mg, 0.15 mmol) and acetonitrile (2 mL), using the method described in Example 2 to give 12.2 mg (56 % yield) of the title compound.
  • N-cyclopentyl- 1 -(5,6-dimethyl- 1 -octyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide was prepared from N-cyclopentyl- 1 -(5,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (17.0 mg, 0.05 mmol), 1-bromooctane (19.3 mg, 0.1 mmol), caesium carbonate (48.9 mg, 0.15 mmol) and acetonitrile (2 mL), using the method described in Example 2. This gave 8.4 mg (37% yield) of the title compound.
  • the reaction mixture was concentrated in vacuo and purified on preparative hplc (performed on a Gilson- Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 ⁇ m, 21.2 x 150 mm) column, using acetonitrile/water (0.05 % formic acid) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection). This gave 0.7 mg (3 % yield) of JV-cyclopentyl-1- (5,6-dimethyl-l-(pyridin-2-ylmethyl)-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC- MS (m/z) 432.3 (M+ 1).
  • N-cyclopentyl- 1 -(5,6-dichloro- 1 -(pyridin-3-ylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide was prepared from sodium hydride (72 mg, 0.30 mmol) in N, ⁇ /-dimethylformamide (2 mL), ⁇ /-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (80 mg, 0.20 mmol) in N, ⁇ /-dimethylformamide (2 mL) and 3 -bromo methyl pyridinium
  • N-cyclopentyl- 1 -(5,6-dichloro- 1 -(pyridin-2-ylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide was prepared from sodium hydride (72 mg, 0.30 mmol) in N, ⁇ /-dimethylformamide (2 mL), ⁇ /-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (80 mg, 0.20 mmol) in N, ⁇ /-dimethylformamide (2 mL) and 2-bromomethyl pyridinium
  • the resulting reaction mixture was subjected to microwave irradiation for 45 min at 12O 0 C.
  • the reaction mixture was concentrated in vacuo, the solid residue filtered off, washed with ethyl acetate and the filtrate extracted with ethyl acetate (2 x 15 mL).
  • the combined organic phases were washed with water (3 x 15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo.
  • the reaction mixture was filtered, cooncentrated in vacuo and subjected to preparative hplc (performed on a Gilson-Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 ⁇ m, 21.2 x 150 mm) column, using acetonitrile/water (0.05 % formaldehyde) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 1.9 mg (18 %) of the title compound.
  • N-cyclopentyl- 1 -(5,6-dichloro- 1 -ethyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide was prepared from ⁇ /-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (10 mg, 0.026 mmol), caesium carbonate (25.6 mg, 0.079 mmol), acetonitrile (2 mL), ⁇ /, ⁇ /-dimethylformamide (0.5 mL), iodoethane (6.1 mg, 0.039 mmol) using the method described in Example 18 to give 5.4 mg (50 % yield) of the title compound.
  • N-cyclopentyl- 1 -(5,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide was prepared from ⁇ /-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (10 mg, 0.026 mmol), caesium carbonate (25.6 mg, 0.079 mmol), acetonitrile (2 mL), ⁇ /, ⁇ /-dimethylformamide (0.5 mL), 2-bromopropane (9.7 mg, 0.079 mmol) using the method described in Example 18 to give 5.0 mg (45 % yield) of the title compound.
  • N-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-fluorobenzyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide was prepared from ⁇ /-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (10 mg, 0.026 mmol), caesium carbonate (25.6 mg, 0.079 mmol), acetonitrile (2 mL), N, ⁇ /-dimethylformamide (0.5 mL), l-(bromomethyl)-4-fluorobenzene (4.96 mg, 0.026 mmol) using the method described in Example 18 to give 4.2 mg (33 % yield) of the title compound.
  • Example 23 methyl 4-((2-(4-(cyclopentylcarbamoyl)piperidin-l-yl)-5,6-dimethyl-lH- benzo[d]imidazol-l-yl)methyl)benzoate
  • N-cyclopropyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (0.09 g, 0.25 mmol) was dissolved in N, ⁇ /-dimethylformamide (1 mL).
  • Caesium carbonate (332 mg, 1 mmol) and isopropyl bromide (56 mg, 0.45 mmol) were added, and the reaction mixture irradiated under microwave conditions at 120 0 C for 60 minutes.
  • the reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (2 x25 mL).
  • N-cyclobutyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide was prepared from 1 -(5,6-dichloro- lH-benzoimidazol-2-yl)-piperidine-4-carboxylic acid (0.05 g, 0.16 mmol), ⁇ /, ⁇ /-dimethylformamide (2 mL), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate ( ⁇ ATU, 91 mg, 0.24 mmol), ⁇ /, ⁇ /-diisopropylethylamine ( ⁇ unig's base,
  • N-cyclo butyl- 1 -(5,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide was prepared from N-cyclobutyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.28g, 0.76mmol), N, ⁇ /-dimethylformamide (3 mL), caesium carbonate (0.99 g, 3 mmol) and isopropyl bromide (168 mg, 1.3 mmol) using the method described in Example 26(d) to give 61 mg (20 % yield) of the title compound as a light yellow solid.
  • l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-propylpiperidine-4-carboxamide was prepared from l-(5,6-dichloro-lH-benzoimidazol-2-yl)-piperidine-4-carboxylic acid (0.07 g, 0.22 mmol), N, ⁇ /-dimethylformamide (4 mL), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate ( ⁇ ATU, 127 mg, 0.33 mmol), JV,JV-diisopropylethylamine ( ⁇ unig's base, DIEA, 0.052 mL, 0.45 mmol) and propan-1 -amine (0.27 mmol), using the method described in Example 26(c) to give 10 mg (13 % yield) of l-(5,6-d
  • N-(cyclohexylmethyl)- 1 -(5,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide was prepared from N-(cyclohexylmethyl)-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.15 g, 0.36 mmol), N, ⁇ /-dimethylformamide (3 mL), caesium carbonate (0.716 g, 2.2 mmol) and isopropyl bromide (0.09 g, 0.72 mmol) using the method described in Example 29(b) to give 20 mg (12 % yield) of the title compound.
  • the title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.29 mmol), N, ⁇ /-dimethylformamide (2 mL), caesium carbonate (0.566 g, 1.7 mmol) and 4-(bromomethyl)benzonitrile (0.103 g, 0.52 mmol), using the method described in Example 36 to give 0.08 g (62 % yield) of l-(l-(4-cyanobenzyl)-5,6- dimethyl-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as a white solid.
  • the title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.29 mmol), N, ⁇ /-dimethylformamide (2 mL), caesium carbonate (0.566 g, 1.7 mmol) and cyclobutylbromide (0.07 g, 0.527 mmol), using the method described in Example 36, to give 9 mg (8 % yield) of l-(l-cyclobutyl-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as an off-white solid.
  • a reaction mixture consisting of l-(l-(4-bromobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)-N-cyclopentylpiperidine-4-carboxamide (0.1 g, 0.19 mmol), £ra/?s-di( ⁇ -acetato)-bis[o-(di-o- tolylphosphino)-benzyl]dipalladium(II) (Hermann palladacycle, 0.089 g, 0.095 mmol), N 5 N- diisopropylethylamine (Hunig's base, DIEA, 0.07 mL, 0.39 mmol), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU, 0.19 mmol), tri tertiarybutyl phosphonium
  • the title compound was prepared from l-(l-(4-bromobenzyl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide (0.1 g, 0.19 mmol), trans-di( ⁇ - acetato)-bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II) (Hermann palladacycle, 0.089 g, 0.095 mmol), N,N-diisopropylethylamine (Hunig's base, 0.07 mL, 0.39 mmol), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU, 0.028 mL, 0.19 mmol), tri tertiarybutyl phosphonium hexafluoborate ([(t-Bu) 3 PH]BF 4 , 0.0055 g,
  • Example 46 7V-cyclopentyl-l-(5,6-dimethyl-l-(4-(methylsulfonylcarbamoyl)benzyl)-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide l-(l-(4-bromobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4- carboxamide (O.lg, 0.19mmol), £rans-di( ⁇ -acetato)-bis[o-(di-o-tolylphosphino)- benzyl]dipalladium(II) (Hermann palladacycle, 0.089 g, 0.095 mmol), N 5 N- diisopropylethylamine (Hunig's base, DIEA, 0.07 niL, 0.39 mmol), 1,8- diazabicyclo
  • reaction mixture was allowed to warm to room temperature and was stirred for 10 hours.
  • the reaction mixture was washed with aqueous hydrochloric acid (3 x15 mL, 2N), saturated aqueous sodium bicarbonate (2 x15 mL), dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo.
  • the residue was recrystallized from dichloro methane/pet ether to give 1.15 g (88%) of tert-butyl 4-(tetrahydrofuran-3-ylcarbamoyl)piperidine-l-carboxylate.
  • Example 49 l-(5-chloro-l-cyclobutyl-6-methyl-lH-benzo[d]imidazol-2-yl)-7V-cyclopentyl- piperidine-4-carboxamide and l-(6-chloro-l-cyclobutyl-5-methyl-lH-benzo[d]imidazol-2- yl)-7V-cyclopentylpiperidine-4-carboxamide
  • aqueous extract was acidified to pH 5 via addition of aqueous hydrochloric acid (1.57V) and the resulting brown precipitate was filtered, washed with water (3 ⁇ 20mL) and dried under high vacuum to obtain 0.28 g (80 % yield) of 5-chloro-6-methyl-lH- benzo[d]imidazol-2(3H)-one.
  • N-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-cyanobenzyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide was prepared from ⁇ /-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (50 mg, 0.13 mmol), N, ⁇ /-dimethylformamide (0.5 mL), caesium carbonate (171 mg, 0.52 mmol) and 4-(bromomethyl)benzonitrile (31 mg, 0.15 mmol), using the method described in Example 52 to give 20 mg (15 % yield) of the title compound.
  • N-cyclopentyl- 1 -(5,6-dichloro- 1 -(cyclopropylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide was prepared from ⁇ /-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (100 mg, 0.26 mmol), N, ⁇ /-dimethylformamide (0.5 mL), caesium carbonate (512 mg, 1.5 mmol) and (bromomethyl)cyclopropane (43 mg, 0.32 mmol), using the method described in Example 52 to give 19 mg (17 % yield) of the title compound.
  • N-cyclopentyl- 1 -(5,6-dichloro- 1 -((tetrahydro-2H-pyran-4-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide was prepared from N-cyclopentyl- 1 -(5 ,6-dichloro- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide (100 mg, 0.26 mmol), N,N-dimethylformamide (0.5 mL), caesium carbonate (512 mg, 1.5 mmol), and 4-(bromomethyl)tetrahydro-2H-pyran (80 mg, 0.47 mmol), using the method described in Example 55 to give 70 mg (57 % yield) of the title compound.
  • a reaction mixture consisting of l-(l-(4-bromobenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)- N-cyclopentylpiperidine-4-carboxamide (Example 51, 100 mg, 0.182 mmol), trans-di( ⁇ - acetato)-bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II) (Hermann palladacycle, 9 mg, 0.009 mmol), ⁇ /, ⁇ /-diisopropylethylamine (Hunig's base, DIEA, 0.06 mL, 0.36 mmol), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU, 0.028 mL, 1.82 mmol), tri tertiarybutyl phosphonium hexafluoborate ([(t-Bu)sPH]BF4,
  • the reaction mixture was filtered, concentrated in vacuo and subjected to preparative hplc (performed on a Gilson-Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 ⁇ m, 21.2 x 150 mm) column, using acetonitrile/water (0.05% HCOOH) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 3.6 mg (15 %) of the title compound.
  • N-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-cyanobenzyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (Example 53, 50 mg, 0.1 mmol), sodium azide (78 mg, 1.2 mmol), ammonium chloride (64 mg, 1.2 mmol), lithium chloride (catalytic amount) was refluxed in N 5 N- dimethylformamide (3 mL) for 2 hours.
  • the title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.1 g, 0.26 mmol), N, ⁇ /-dimethylformamide (2 mL), caesium carbonate (0.508 g, 1.56 mmol) and 1-bromopentane (0.033 mL, 0.31mmol) using the method described in Example 64(b), to give 17 mg (14 % yield) of l-(5,6-dichloro-l-pentyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid.
  • the title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.1 g, 0.26 mmol), N, ⁇ /-dimethylformamide (2 mL), caesium carbonate (0.508 g, 1.56 mmol) and 4-(bromomethyl)benzonitrile (0.062 g, 0.31 mmol) using the method described in Example 64(b), to give 13 mg (10 % yield) of l-(5,6- dichloro- 1 -(4-cyanobenzyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a white solid.
  • Example 72 l-(5,6-dichloro-l-((6-fluoropyridin-3-yl)methyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
  • the title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.1 g, 0.26 mmol), N, ⁇ /-dimethylformamide (2 mL), caesium carbonate (0.508 g, 1.56 mmol) and l-bromo-4-(bromomethyl)benzene (0.078 g, 0.31 mmol) using the method described in Example 74, to give 22 mg (15 % yield) of l-(l-(4- bromobenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a white solid.
  • the title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.30 g, 0.829 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.316 mmol), l-bromo-4-iodobenzene (3.316 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.132 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.044 mmol) using the method described in Example 76.
  • the title compound was prepared from N-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.293 mmol), N, ⁇ /-dimethylformamide (3 mL), caesium carbonate (1.172 mmol), (bromomethyl)cyclo butane (1.172 mmol) and dichlorobis(triphenyl- phosphine)palladium (II) (Pd(PPhS) 2 Cl 2 (0.0293 mmol) using the method described in Example 14.
  • the title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.293 mmol), N, ⁇ /-dimethylformamide (3 mL), caesium carbonate (1.172 mmol), 3-bromoprop-l-yne (1.172 mmol) and dichlorobis(triphenyl- phosphine)palladium (II) (Pd(PPlIs) 2 Cl 2 (0.0293 mmol) using the method described in Example 14.
  • the title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.293 mmol), N, ⁇ /-dimethylformamide (3 mL), caesium carbonate (1.172 mmol), 3-(bromomethyl)pentane (1.172 mmol) and dichlorobis(triphenyl- phosphine)palladium (II) (Pd(PPh 3 ) 2 Cl2 (0.0293 mmol) using the method described in Example 14.
  • the title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.293 mmol), N, ⁇ /-dimethylformamide (3 mL), caesium carbonate (1.172 mmol), l-bromo-2,2-dimethylpropane (1.172 mmol) and dichlorobis(triphenyl- phosphine)palladium (II) (Pd(PPh 3 ) 2 Cl2 (0.0293 mmol) using the method described in Example 14.
  • the title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.293 mmol), N, ⁇ /-dimethylformamide (3 mL), caesium carbonate ( 1.172 mmo 1), bromocyclohexane ( 1.172 mmo 1) and dichlorobis(triphenyl- phosphine)palladium (II) (Pd(PPh 3 ) 2 Cl2 (0.0293 mmol) using the method described in Example 14.
  • the title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.293 mmol), N, ⁇ /-dimethylformamide (3 mL), caesium carbonate (1.172 mmol), 2-bromobutane (1.172 mmol) and dichlorobis(triphenylphosphine)- palladium (II) (Pd(PPlIs) 2 Cl 2 (0.0293 mmol) using the method described in Example 14.
  • N-cyclopentyl- 1 -(5 ,6-dichloro- 1 -(2-methoxyethyl)- lH-benzo [d]imidazol-2-yl)piperidine-4- carboxamide was dissolved in dichloromethane and stirred under nitrogen at O 0 C for 15 minutes, treated with tribromoborane via drop-wise addition and gradually warmed to room temperature.
  • the reaction mixture was stirred at room temperature for 1 hour, quenched with aqueous sodium hydrogencarbonate (10%) to ashive neutral p ⁇ and extracted with dichloromethane (2x 50 mL).
  • reaction mixture was filtered, concentrated in vacuo and purified on preparative hplc (performed on a Gilson- Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 ⁇ m, 21.2 x 150 mm) column, using acetonitrile/water (0.05 % formic acid) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 8.3 mg (19 % yield) of l-(l-benzyl-5,6- dimethyl- lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide.

Abstract

A compound of formula (I): as well as pharmaceutically acceptable salts thereof, and a pharmaceutical composition comprising the compound. The compound is useful for the treatment of disorder selected from inflammatory diseases, nociceptive pain, auto-immune disease, breathing disorders, fever, cancer, inflammation related anorexia, Alzheimer's disease and cardiovascular diseases.

Description

MICROSOMAL PROSTAGLANDIN E SYNTHASE-1 (MPGES1) INHIBITORS
FIELD OF THE INVENTION
The present invention relates to piperidinyl benzoimidazole derivatives and to the use thereof in disease therapy. Particularly, the present invention relates to compounds useful in the treatment or prevention of diseases in which inhibition of the activity of microsomal prostaglandin E synthase- 1 (accession number "014684" at http://www.uniprot.org/) is desired and/or required and, more particularly, in the treatment of diseases such as inflammatory diseases, nociceptive pain, auto-immune disease, breathing disorders, fever, cancer, inflammation related anorexia, Alzheimer's disease and cardiovascular disease.
BACKGROUND OF THE INVENTION
The following is provided as background information only and represents the current state-of-art in the scientific literature. Furthermore, this background information should not be taken as an admission that any subject matter discussed or that any reference mentioned is prior art to the instant invention.
Prostaglandin (PG) E2 is produced in a sequential action including liberation of arachidonic acid, conversion into PGG2/PGH2 by cyclooxygenase (Cox) -1 or Cox-2, and finally prostaglandin E synthase converts PGH2 into PGE2. There exist three known enzymes that catalyze the latter reaction, i.e. microsomal prostaglandin E synthase-1 (mPGEs-1), cytosolic prostaglandin E synthase (cPGEs), and microsomal prostaglandin E synthase-2 (mPGEs-2). The latter two enzymes are constitutively expressed whereas mPGEs-1 is inducible. Initially, mPGEs-1 was regarded as the enzyme predominantly coupled with Cox-2 activity. However; later results demonstrate that mPGEs-1 can also catalyze the conversion of Cox- 1 derived PGH2 into PGE2. mPGEs-1 possesses the highest catalytic efficiency of the known PGE synthases. The role of PGE2 as one of the most potent mediators of inflammation together with many in vitro reports on the presence of mPGEs-1 in different models of inflammation suggested this enzyme to be an attractive drug target for development of new anti inflammatory drugs with fewer side effects than the currently available NSAIDs and selective Cox-2 inhibitors [Samuelsson, B.;
Morgenstern, R.; Jakobsson, P. -J. Membrane Prostaglandin E Synthase-1 : A Novel Therapeutic Target. Pharmacol. Rev. 2007, 5P,207-224; Jachak, S. M. PGE synthase inhibitors as an alternative to COX-2 inhibitors. Curr. Opin. Investig. Drugs, 2007, 8, 411-415]. The rationale is that mPGEs-1 is predominantly expressed during inflammation and that other enzymes exist as mediating "house keeping functions". Furthermore, mPGEs-1 -derived PGE2 has been implicated in a range of diseases, not confined to inflammation, and it is suggested that inhibitors of mPGEs-1 are effective for the treatment or prevention of these diseases also. Consequently, examples of treatable diseases of the invention include inflammatory diseases, nociceptive pain, auto-immune disease, breathing disorders, fever, cancer, inflammation related anorexia, Alzheimer's disease and cardiovascular disease. More specifically, non-limiting examples of these diseases include the treatment or prevention of rheumatoid arthritis [Murakami, M.; Nakashima, K.; Kamei, D.; Masuda, S.; Ishikawa, Y.; Ishii, T.; Ohmiya, Y.; Watanabe, K.; Kudo, I. Cellular prostaglandin E2 production by membrane- bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2. J. Biol. Chem. 2003, 278, 37937-37947; Westman, M.; Korotkova, M.; af Klint, E.; Stark, A.; Audoly, L. P.; Klareskog, L.; Ulfgren, A. K.; Jakobsson, P. J. Expression of microsomal prostaglandin E synthase 1 in rheumatoid arthritis synovium. Arthritis Rheum. 2004, 50, 1774-1780] or other inflammatory diseases related to arthritis [Kojima, F.; Kato, S.; Kawai, S. Prostaglandin E synthase in the pathophysiology of arthritis. Fundam. Clin. Pharmacol. 2005, 19, 255-261; Fahmi, H. mPGEs-1 as a novel target for arthritis. Curr. Opin. Rheumatol. 2004, 16, 623-627] inflammatory bowel disease [Dey, L; Giembycz, M. A.; Chadee, K. Prostaglandin E(2) couples through EP(4) prostanoid receptors to induce IL-8 production in human colonic epithelial cell lines. Br. J. Pharmacol. 2009, 156, 475-85], osteoarthritis [Kojima, F.; Naraba, H.; Miyamoto, S.; Beppu, M.; Aoki H, and Kawai S (2004) Membraneassociated prostaglandin E synthase- 1 is upregulated by proinflammatory cyto-kines in chondrocytes from patients with osteoarthritis. Arthritis Res. Ther. 2004, R355-R365; Masuko-Hongo, K.; Berenbaum, F.; Humbert, L.; Salvat, C; Goldring, M. B.; Thirion, S. Up-regulation of microsomal prostaglandin E synthase 1 in osteoarthritic human cartilage: critical roles of the ERK-1/2 and p38 signaling pathways. Arthritis Rheum. 2004, 50, 2829-2838], dermatitis including psoriasis [Stark, K.; Tόrma, H.; Oliw, E. H. Co- localization of COX-2, CYP4F8, and mPGEs-1 in epidermis with prominent expression of CYP4F8 mRNA in psoriatic lesions. Prostaglandins Other Lipid Mediat. 2006, 79, 114-125] and eczema, swelling, inflammatory pain [Trebino, C. E.; Stock, J. L.; Gibbons, C. P.; Naiman, B. M.; Wachtmann, T. S.; Umland, J. P.; Pandher, K.; Lapointe, J. M.; Saha, S.; Roach, M. L, Carter, D.; Thomas, N. A.; Durtschi, B. A.; McNeish, J. D.; Hambor, J. E.; Jakobsson, P. J.; Carty, T. J.; Perez, J. R.; Audoly, L. P. Impaired inflammatory and pain responses in mice lacking an inducible prostaglandin E synthase. Proc. Natl. Acad. Sci. USA, 2004, 100, 9044- 9049], post-operative pain [Shavit, Y.; Fridel, K.; Beilin, B. Postoperative pain management and proinflammatory cytokines: animal and human studies. J. Neuroimmune Pharmacol. 2006, 443- 451], fibromyalgia, dysmenorrhea [Proctor, M.; Farquhar, C. Dysmenorrhoea. Clin. Evid., 2002, 7,1639-1653], migraine, arthrotic and arthritic pain [Schaible, H. G.; Ebersberger, A.; von Banchet, G. S. Mechanisms of pain in arthritis. Ann. N Y Acad. Sci. 2002, 966, 343-354], pain in connection with osteoarthritis, cephalalgia (headache) [Wienecke, T.; Olesen, J.; Oturai, P. S.; Ashina, M. Prostaglandin E2 (PGE2) induces headache in healthy subjects. Cephalalgia, 2009, 29, 509-519], pain due to gall-stones, pain due to metastasis, familial adenomatous polyposis (FAP) condition [Takeda, H.; Sonoshita, M.; Oshima, H.; Sugihara, K.; Chulada, P. C;
Langenbach, R.; Oshima, M.; Taketo, M. M. Cooperation of cyclooxygenase 1 and
cyclooxygenase 2 in intestinal polyposis. Cancer Res. 2003, 63, 4872-4877], colorectal cancer [Kamei, D.; Murakami, M.; Nakatani, Y.; Ishikawa, Y.; Ishii, T.; Kudo, I. Potential role of microsomal prostaglandin E synthase- 1 in tumorigenesis. J. Biol. Chem., 2003, 278, 19396-
19405; Yoshimatsu, K.; Golijanin, D.; Paty, P. B.; Soslow, R. A.; Jakobsson, P. -J.; DeLellis, R. A.; Subbaramaiah, K.; Dannenberg, A. J. Inducible microsomal prostaglandin E synthase is overexpressed in colorectal adenomas and cancer. Clin. Cancer Res. 2001, 7, 3971-3976;
Elander, N.; Ungerback, J.; Olsson, H.; Uematsu, S.; Akira, S.; Sόderkvist, P. Genetic deletion of mPGEs-1 accelerates intestinal tumorigenesis in APC(Min/+) mice. Biochem. Biophys. Res.
Commun. 2008, 372, 249-253], epithelial ovarian cancer [Rask, K.; Zhu, Y.; Wang, W.; Hedin, L.; Sundfeldt, K. Ovarian epithelial cancer: a role for PGE2-synthesis and signalling in malignant transformation and progression. MoI. Cancer, 2006, 16, 62], breast cancer [Mehrotra, S.; Morimiya, A.; Agarwal, B.; Konger, R.; Badve, S. Microsomal prostaglandin E2 synthase- 1 in breast cancer: a potential target for therapy. J. Pathol. 2006, 208, 356-363], gastric
tumorigenesis [Oshima, H.; Matsunaga, A.; Fujimura, T.; Tsukamoto, T.; Taketo, M. M.;
Oshima, M. Carcinogenesis in mouse stomach by simultaneous activation of the Wnt signaling and prostaglandin E2 pathway. Gastroenterology, 2006, 131, 1086-1095], multiple sclerosis, atherosclerosis such as myocardial infarction and stroke [Ikeda-Matsuo, Y.; Ota, A.; Fukada, T.; Uematsu, S.; Akira, S.; Sasaki, Y. Microsomal prostaglandin E synthase-1 is a critical factor of stroke-reperfusion injury. Proc. Natl. Acad. Sci. USA. 2006, 103, 11790-11795], apnea or other respiratory distress symptoms in adults and children [Hofstetter, A. O.; Saha, S.; Siljehav, V.; Jakobsson, P. J.; Herlenius, E. The induced prostaglandin E2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates. Proc. Natl. Acad. Sci. USA. 2007, 104, 9894-9899], sudden infant death syndrome (SIDS), asthma, fever [Engblom, D.; Saha, S.;
Engstrόm, L.; Westman, M.; Audoly, L. P.; Jakobsson, P. J.; Blomqvist, A. Microsomal prostaglandin E synthase-1 is the central switch during immune-induced pyresis. Nat. Neurosci. 2003, 6, 1137-1138; Saha, S.; Engstrόm, L.; Mackerlova, L.; Jakobsson, P. J.; Blomqvist, A. Impaired febrile responses to immune challenge in mice deficient in microsomal prostaglandin E synthase-1. Am. J. Physiol. 2005, 288, Rl 100-Rl 107], inflammation related anorexia [Samuelsson, B.; Morgenstern, R.; Jakobsson, P. -J. Membrane Prostaglandin E Synthase-1 : A Novel Therapeutic Target. Pharmacol. Rev. 2007, 5P,207-224], Alzheimer's disease [Satoh, K.; Nagano, Y.; Shimomura, C; Suzuki, N.; Saeki, Y.; Yokota, H. Expression of prostaglandin E synthase mRNA is induced in beta-amyloid treated rat astrocytes. Neurosci. Lett. 2000, 283, 221-223; Licastro, F.; Davis, L. J.; Pedrini, S.; Galasko, D.; Masliah, E. Prostaglandin E2 induced polymerization of human alpha- 1-antichymotrypsin and suppressed its protease inhibitory activity: implications for Alzheimer's disease. Biochem. Biophys. Res. Commun. 1998, 249, 182- 186; Chaudhry, U. A.; Zhuang, H.; Crain, B. J.; Dore, S. Elevated microsomal prostaglandin-E synthase-1 in Alzheimer's disease. Akheimers Dement. 2008, 4, 6-13; Hoozemans, J. J.;
Veerhuis, R.; Janssen, L; van Elk, E. J.; Rozemuller, A. J.; Eikelenboom, P. The role of cyclo- oxygenase 1 and 2 activity in prostaglandin E(2) secretion by cultured human adult microglia: implications for Alzheimer's disease. Brain Res. 2002, 951, 218-226; Scali, C; Prosperi, C; Bracco, L.; Piccini, C; Baronti, R.; Ginestroni, A.; Sorbi, S.; Pepeu, G.; Casamenti, F.
Neutrophils CDl Ib and fibroblasts PGE(2) are elevated in Alzheimer's disease. Neurobiol. Aging, 2002, 23, 523-30], as well as the use of the said compounds in the manufacture of medicaments for the treatment of those disorders [For a reviews discussing most of the therapeutic indications mentioned above see: Samuelsson, B.; Morgenstern, R.; Jakobsson, P. -J. Membrane Prostaglandin E Synthase-1 : A Novel Therapeutic Target. Pharmacol. Rev. 2007, 5P,207-224; Murakami M, Kudo I. Prostaglandin E synthase: a novel drug target for
inflammation and cancer. Curr Pharm Des. 2006, 12, 943-954; Kojima, F.; Kato, S.; Kawai, S. Prostaglandin E synthase in the pathophysiology of arthritis. Fundam. Clin. Pharmacol. 2005, 19, 255-261].
Other examples of medical conditions associated with mPGES-1 are pain in connection to ankylosing spondylitis, gout, or rheumatic fever, tootache, cellular neoplastic transformations and metastatic tumor growth, endometriosis, hemophilic arthropathy, Parkinson's disease, mPGES-1 -mediated proliferative disorders such as may occur in diabetic retinopathy and tumor angiogenesis, symptoms associated with viral infections, and premature labor. WO 2008/084218 discloses benzazole derivatives of the general formula
Figure imgf000006_0001
as useful in the treatment of diseases in which it is desired and/or required to inhibit the activity of a member of the MAPEG family, e.g. microsomal prostaglandin £ synthase- 1 (mPGEs- 1). SUMMARY OF THE INVENTION
There still is a large unmet need for drugs that are as effective as NSAID inhibitors but having significantly improved side effect profile, for the treatment of conditions such as inflammatory diseases, nociceptive pain, auto-immune diseases, breathing disorders, fever, cancer, inflammation related anorexia, Alzheimer's disease and cardiovascular diseases. One object of the present invention is to provide compounds having said desired improved properties. The present inventors now have surprisingly found certain piperidinyl benzoimidazoles that are capable of efficiently blocking mPGEs-1.
Consequently, in one aspect the present invention provides a compound of formula (I)
Figure imgf000006_0002
(I)
wherein:
R1 is selected from branched or unbranched C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl; C3- Cio cycloalkyl; C4-C10 cycloalkenyl; Cs-Cio cycloalkynyl; C1-Cg heterocyclyl; and C6-CiO aryl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or cycloalkynyl moiety optionally is substituted with 1, 2 or 3 groups Ra; and any heterocyclyl or aryl moiety optionally is substituted with 1, 2, 3, 4 or 5 groups Rb; R2 is selected from branched or unbranched C1-Cg alkyl, C2-C9 alkenyl, or C2-C9 alkynyl; C3-C6 cycloalkyl; C4-C6 cycloalkenyl; Cs-Cio cycloalkynyl; C 1-C9 heterocyclyl; and C6-CiO aryl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety optionally is substituted with 1 , 2 or 3 groups Ra; and any heterocyclyl or aryl moeiety optionally is substituted with 1, 2, 3, 4 or 5 groups Rb;
R3 and R4 are each independently selected from Ci -C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C3-C4 cycloalkyl; Ci-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; Ci-C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; halogen; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amino; and Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl carbonyl; wherein any alkyl, alkenyl, alkynyl or cycloalkyl moiety optionally is substituted with 1, 2, or 3 groups Rc; R5 and R6 are independently selected from hydrogen; Ci-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; and halogen; wherein any alkyl; alkenyl or alkynyl moiety optionally is substituted with 1, 2, or 3 groups Rc;
X represents a bond or branched or unbranched Ci -C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl;
Q represents carbonyl, sulfonyl or sulfmyl; m is an integer of 0, 1 or 2; each Rais independently selected from halogen; hydroxy; Ci-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; Ci-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; Ci-C4 alkyl, C2-C4 alkenyl or C2- C4 alkynyl secondary or tertiary amino; Ci-C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; wherein any alkyl, alkenyl or alkynyl moiety optionally is substituted with 1, 2 or 3 groups Rc; each Rb is independently selected from halogen; carboxy; hydroxy; cyano; C1-C5 heteroaryl; C1- C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C3-C5 cycloalkyl; Ci-C4 alkyloxy; C2-C4 alkenyloxy; C2- C4 alkynyloxy; C3-C5 cycloalkyloxy; Ci-C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; C1- C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amino; amino carbonyl; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amido; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl carbonyl; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl sulfonyl; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary sulphonamido; Ci-C4 alkyl, C2-C4 alkenyl or C2- C4 alkynyl secondary or tertiary acylsulphonamido; Ci-C4 alkyloxy, C2-C4 alkenyloxy, or C2-C4 alkynyloxy carbonyl; Ci-C5 heterocyclyl; wherein any alkyl, alkenyl, alkynyl or cycloalkyl moiety optionally is substituted with 1, 2 or 3 groups Rc; each Rc is independently selected from fluorine and chlorine; and pharmaceutically acceptable salts thereof. Another aspect of the present invention is to provide a compound of formula (I) for use as a medicament.
Another aspect of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable adjuvant, diluent or carrier.
Another aspect of the present invention is to provide a method of medical treatment by use of said pharmaceutical compositions.
Another aspect of the present invention provides a compound of formula (I) or a
pharmaceutically acceptable salt thereof, as defined herein above, for use in the treatment of a disorder in which inhibition of the activity of microsomal prostaglandin E synthase- 1 is desired and/or required.
Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of a disorder in which inhibition of the activity of microsomal prostaglandin E synthase- 1 is desired and/or required. Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of an inflammatory disease, said disease preferably being selected from rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, psoriasis, eczema, swelling and periodontitis. Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of nociceptive pain, said pain preferably being selected from inflammatory pain, post-operative pain, fibromyalgia, dysmenorrhea, migraine, arthrotic pain, arthritic pain, pain in connection with osteoarthritis, cephalalgia, pain due to gall-stones and pain due to metastasis, ankylosing spondylitis, gout, or rheumatic fever, and tootache. The compound of formula (I) also may be used in preemptive treatment of surgical pain. Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of an autoimmune disease, said autoimmune disease preferably being selected from rheumatoid arthritis and multiple sclerosis.
Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of a breathing disorder, said disorder preferably being selected from apnea or other respiratory distress symptoms in adults and children, sudden infant death syndrome (SIDS), asthma and other chronic obstructive lung-diseases and sarcoidosis.
Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of cancer, said cancer preferably being selected from familial adenomatous polyposis (FAP) condition, colorectal cancer, breast cancer, gastric tumorigenesis and epithelial ovarian cancer, as well as cellular neoplastic transformations and metastatic tumor growth.
Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of cardiovascular diseases due to atherosclerosis such as myocardial infarction and stroke.
Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of fever- or inflammation-related anorexia.
Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of Alzheimer's disease.
Another aspect of the present invention provides a compound of formula (I), for use in the treatment and/or prevention of endometriosis, hemophilic arthropathy, Parkinson's disease, mPGES-1 -mediated proliferative disorders such as may occur in diabetic retinopathy and tumor angiogenesis, symptoms associated with viral infections, and premature labor.
Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of an inflammatory disease, said disease preferably being selected from rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, psoriasis, eczema, swelling and periodontitis. Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of nociceptive pain, said pain preferably being selected from inflammatory pain, post-operative pain, fibromyalgia, dysmenorrhea, migraine, arthrotic pain, arthritic pain, pain in connection with osteoarthritis, cephalalgia, pain due to gall-stones and pain due to metastasis, pain due to ankylosing spondylitis, pain due to gout, toothache and pain due to rheumatic fever, or for the preemptive treatment of surgical pain. Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of an autoimmune disease, said autoimmune disease preferably being selected from rheumatoid arthritis and multiple sclerosis.
Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of a breathing disorder, said disorder preferably being selected from apnea or other respiratory distress symptoms in adults and children, sudden infant death syndrome (SIDS), asthma and other chronic obstructive lung- diseases and sarcoidosis.
Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of cancer, said cancer preferably being selected from familial adenomatous polyposis (FAP) condition, colorectal cancer, breast cancer, gastric tumorigenesis and epithelial ovarian cancer, as well as cellular neoplastic transformations and metastatic tumor growth.
Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of cardiovascular diseases due to atherosclerosis such as myocardial infarction and stroke.
Another aspect of the present invention provides the use of a compound of formula (I), in preparation of a medicament for the treatment and/or prevention of fever- or inflammation- related anorexia.
Another aspect of the present invention provides the use of a compound of formula (I), in the preparation of a medicament for the treatment and/or prevention of Alzheimer's disease. Another aspect of the present invention provides a method of treatment of a disease in which inhibition of the activity of mPGEs-1 is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, such a condition.
Another aspect of the present invention provides a method of treatment of an inflammatory disease, said disease preferably being selected from rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, psoriasis, eczema, swelling and periodontitis, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient in the need of such treatment.
Another aspect of the present invention provides a method of treatment of nociceptive pain, said pain preferably being selected from inflammatory pain, post-operative pain, fibromyalgia, dysmenorrhea, migraine, arthrotic pain, arthritic pain, pain in connection with osteoarthritis, cephalalgia, pain due to gall-stones and pain due to metastasis, pain due to ankylosing spondylitis, gout, toothache and pain due to rheumatic fever, as well as preemptive treatment of surgical pain, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient in the need of such treatment.
Another aspect of the present invention provides a method of treatment of an autoimmune disease, said autoimmune disease preferably being selected from rheumatoid arthritis and multiple sclerosis, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient in the need of such treatment.
Another aspect of the present invention provides a method of treatment of a breathing disorder, said disorder preferably being selected from apnea or other respiratory distress symptoms in adults and children, sudden infant death syndrome (SIDS), asthma and other chronic obstructive lung-diseases and sarcoidosis, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient in the need of such treatment. Another aspect of the present invention provides a method of treatment of cancer, said cancer preferably being selected from familial adenomatous polyposis (FAP) condition, colorectal cancer, breast cancer, gastric tumorigenesis and epithelial ovarian cancer, as well as cellular neoplastic transformations and metastatic tumor growth, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically- acceptable salt thereof, to a patient in the need of such treatment.
Another aspect of the present invention provides a method of treatment of cardiovascular diseases due to atherosclerosis such as myocardial infarction and stroke, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient in the need of such treatment.
Another aspect of the present invention provides a method of treatment of fever- or
inflammation-related anorexia, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient in the need of such treatment.
Another aspect of the present invention provides a method of treatment of Alzheimer's disease, which method comprises administration of a therapeutically effective amount of a compound of formula (I), or a pharmaceutically-acceptable salt thereof, to a patient in the need of such treatment.
In another aspect of the invention, methods for preparing a compound of formula (I) are provided. BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a bar diagram showing results of a carrageenan- induced paw edema assay in Wistar rats using the compound synthesised in Example 41. The compound at 10, 30 and 100 mg/kg, as well as vehicle was administered intraperitoneally immediately before carrageenan challenge. Hind paw edema, a measure of inflammation, was recorded 6 hours after carrageenan administration. Volume increase is paw volume at 6 hours after carrageenan administration minus paw volume before carrageenan administration. The bars represent average ±standard error of the mean (n=8). Figure 2 is a bar diagram showing inhibition of CFA- induced paw swelling by the compound synthesised in Example 41 compared to vehicle control. Data represent average inhibition of paw swelling ±standard error of the mean for acute (A) or delayed (B) phase (n=5). Inhibition of paw swelling = (paw volume (vehicle) - paw volume (treatment))/paw volume (vehicle).
DETAILED DESCRIPTION OF THE INVENTION
Unless otherwise indicated or apparent from the context, any alkyl, alkenyl or alkynyl group as referred to herein may be branched or unbranched. This also applies to said groups when present in moieties such as alkoxy groups, and the like.
The term "alkyl" as employed herein, alone or as part of another group, refers to an acyclic straight or branched chain radical, unless otherwise specified containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbons in the normal chain, which includes methyl, ethyl, /? -propyl, /? -butyl, n-pentyl, n-hexyl, n-heptyl and n-octyl. Examples of branched chain radicals, not excluding any of the possible isomers not mentioned, are ώo-propyl, sec-butyl, ώo-pentyl, 3-methylpentyl, 2,3- dimethylhexyl, 3-ethylhexyl, and the like. Alkyl also includes a straight or branched alkyl group that contains or is interrupted by a carbocyclyl group, exemplified by cyclopropane, as exemplified below: (CH \ -J- \ (CH∑)z—
wherein, w and z are 1 to 8, the sum of w and z is not more than 9. The alkyl portions can be attached at any variable point of attachment to the carbocyclyl, including the same ring carbon, as exemplified below:
Figure imgf000013_0001
(CH2)W
When substituted alkyl is present, this refers to a straight or branched alkyl group, substituted with 1, 2, 3 groups of Ra, which groups may be the same or different at any available point, as defined with respect to each variable.
The term "alkenyl" as used herein, alone or as part of another group, refers to a straight or branched chain radical, unless otherwise specified containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12, containing at least one carbon to carbon double bond, which includes in the normal chain vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3- heptenyl, 4-heptenyl, 3-octenyl, and the like. Examples of branched chain radicals, not excluding any of the possible isomers not mentioned, are 2-buten-2-yl, 4-methyl-2-pentenyl, 6-methylene- 2-octenyl, and the like. All possible (E)- and (Z)-isomers is contemplated within the scope of the invention. As described above with respect to the "alkyl", the straight or branched portion of the alkenyl group may be optionally substituted when a substituted alkenyl group is provided, and the chain may be interrupted by a carbocyclyl group. When substituted alkenyl is present, this refers to a straight or branched alkyl group, substituted with 1, 2, 3 groups of Ra, which groups may be the same or different at any available point, as defined with respect to each variable.
The term "alkynyl" as used herein by itself or as part of another group refers to a straight or branched chain radical, unless otherwise specified containing 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbons, which contains at least one carbon to carbon triple bond, which in the normal chain such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2- heptynyl, 3-heptynyl, 4-heptynyl, 3-octynyl, and the like. Examples of branched chain radicals, not excluding any of the possible isomers not mentioned, are 3-methyl-l-butynyl, 2-methyl-4- pentynyl, 6-methyl-4-octynyl, 6-methyl-3-propyl-4-octynyl, and the like. The alkynyl can in addition to carbon to carbon triple bonds also include a to carbon double bond. Examples of such radicals, not excuding any of the possible not mentioned, are 3-buten-l-ynyl, l-buten-3-ynyl, 6- methylene-2-octynyl, 3-allyl-6-methyl-l-octen-4-ynyl, and the like. As described above with respect to the "alkyl", the straight or branched portion of the alkynyl group may be optionally substituted when a substituted alkynyl group is provided, and the chain may be interrupted by a carbocyclyl group. When substituted alkynyl is present, this refers to a straight or branched alkyl group, substituted with 1, 2, 3 groups of Ra, which groups may be the same or different at any available point, as defined with respect to each variable. As used herein, the term "carbocyclyl" refers to a cyclic moiety containing only carbon atoms.
As used herein with respect to any carbocyclyl, heterocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl the term "monocyclic" refers to a cyclic moiety containing only one ring. The term "bicyclic" refers to a cyclic moiety containing two rings. A bicyclic group may, for example, be fused or bridged.
The concept of fused and bridged rings are well known to the one skilled in the art, and for example is explained in "Fused Ring and Bridged Fused Ring Nomenclature, FR-I from IUPAC Recommendations 1998" As used herein, the terms "(E)- and (Z)-isomers" refer to the terms "Entgegen" and "Zusammen", respectively. Whether a molecular configuration is designated as Entgegen or Zusammen is determined by the "Cahn-Ingold-Prelog" priority rules, which is well known for the one skilled in the art.
As used herein, the terms "heterocyclyl" mean a mono- or bicyclic, saturated or unsaturated cyclic group, possibly aromatic, containing one or more heteroatom(s) preferably selected from N, O and S, such as, but not limited to, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl, dioxolanyl, dioxanyl, dithianyl, dithiolanyl, imidazolidinyl, imidazolinyl, morpholinyl, oxetanyl, oxiranyl, pyrrolidinyl, pyrrolidinonyl, piperidyl, piperazinyl, piperidinyl, pyrazolidinyl, quinuclidinyl, sulfalonyl, 3-sulfolenyl, tetrahydrofuranyl tetrahydropyranyl, tetrahydropyridyl, thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl, tropanyl, IH- indazolyl, monosaccharide, pyridyl, quinolinyl, furanyl, thienyl, oxadiazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, isoquinolinyl, naphthyridinyl, imidazolyl, phenazinyl, phenothiazinyl, phthalazinyl, indolyl, pyridazinyl, quinazolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl, pyrazinyl, indazolyl, indolinyl, pyrimidinyl, thiophenetyl, pyranyl, carbazolyl, chromanyl, cinnolinyl, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl, benzo furanyl, benzothiazolyl,
benzobenzoxadiazolyl, benzoxazinyl, benzoxazolyl, benzo morpholinyl, benzoselenadiazolyl, benzothienyl, purinyl, pteridinyl, and the like.
The term "halogen" refers to fluorine, chlorine, bromine and iodine, where the preferred halogen radicals are fluoro and chloro. As used herein, the term "aryl" means an aromatic group, monocyclic or bicyclic such as, but not limited to phenyl or naphthyl, and the like. The aryl group is preferably a monocyclic C6 aryl (phenyl).
The term "cycloalkyl" as employed herein alone or as part of another group includes saturated cyclic hydrocarbyl groups, mono- or bicyclic rings(s), having a total of 3, 4, 5, 6, 7, 8, 9 or 10 carbons forming the ring(s), which includes cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclodecane, bicyclo[4.1.0]heptane, bicyclo[4.3.3]dodecane, cyclopentyl, decahydronaphthalene, bicyclo[2.2.2]octane, and the like, optionally substituted with 1, 2 or 3 groups of Ra. The term "cycloalkenyl" as employed herein alone or as part of another group includes unsaturated cyclic rings(s), mono- or bicyclic, having a total of 4, 5, 6, 7, 8, 9 or 10 carbons forming the ring(s), which includes cyclohexene, cyclobutene, bicyclo[4.2.0]-3-octene, 1,3- cyclodecadiene and the like, optionally substituted with 1, 2 or 3 groups of Ra.
The term "cycloalkynyl" as employed herein alone or as part of another group includes mono- or bicyclic, rings having one carbon to carbon triple bond, and having a total of 8, 9 or 10 carbons forming the ring, which includes cyclooctyne, cyclodecyne, bicyclo[6.2.0]-4-decyne and the like, optionally substituted with 1, 2 or 3 groups of Ra. The cycloalkynyl can in addition to carbon to carbon triple bonds also contain a carbon to carbon double bond, which includes l-cyclodecen-5- yne and the like.
The term "carbocyclyl" as employed herein alone or as part of another group includes saturated cyclic hydrocarbyl groups or unsaturated (at least one carbon to carbon double bond) cyclic hydrocarbyl groups, containing one ring and a total of 3, 4, 5, 6, 7, 8, 9 or 10 carbons forming the ring, which includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, cycloheptyl, and the like. The cyclic hydrocarbyl may be mono- or bicyclic.
By the ternϊ'unsaturated", when referring to a bicyclic system, is meant a ring system
comprising at least one double or triple bond in at least one ring. Thus, it is contemplated that both rings may be unsaturated or only one ring may be unsaturated, the other one being saturated. Furthermore, the term "unsaturated bicyclic" also is intended to refer to a non- aromatic bicyclic system comprising a ring that is either unsaturated or saturated fused to a ring that by itself would be aromatic, such as in indane or 4,5-dihydro-l -indole.
The term "aromatic", as used herein, refers to an unsaturated cyclic moiety that has an aromatic character, while the term "non-aromatic", as used herein, refers to a cyclic moiety, that may be unsaturated, but that does not have an aromatic character. In a bicyclic ring system, as referred to herein, the rings may be both saturated or both unsaturated, e.g. both aromatic. The rings may also be of different degrees of saturation, and one ring may be aromatic whereas the other is non-aromatic. The rings also may comprise different numbers of atoms, e.g. one ring being 5-membered and the other one being 6-membered. In a bicyclic heterocyclyl, as referred to herein, one or both of the rings may contain one or several heteroatoms.
The terms hydroxy (i), carboxy (ii) and aminocarbonyl (iii), refer to radicals of the type:
Figure imgf000017_0001
(i) (ϋ) (iϋ)
The terms alkyloxy, alkenyloxy, alkynyloxy and cycloalkyloxy refer to a radical of the type:
RCr ^
wherein R is an alkyl, alkenyl, alkynyl or cycloalkyl moiety.
The terms alkylthio, alkenylthio, and alkynylthio refer to a radical of the type:
RS^
wherein R is an alkyl, alkenyl or alkynyl moiety. The terms alkyl, alkenyl and alkynyl secondary amino refer to a radical of the type:
Figure imgf000017_0002
wherein R is an alkyl, alkenyl or alkynyl moiety.
The terms alkyl, alkenyl and alkynyl tertiary amino refer to a radical of the type:
Rγv
R
wherein R and R' are each an independently selected alkyl, alkenyl or alkynyl moiety.
The terms alkyl, alkenyl and alkynyl secondary amido refer to a radical of the type:
Figure imgf000017_0003
wherein R is an alkyl, alkenyl or alkynyl moiety.
The terms alkyl, alkenyl and alkynyl tertiary amido refer to a radical of the type:
R'
N \'
O wherein R and R' are each an independently selected alkyl, alkenyl or alkynyl moiety.
The terms alkyl, alkenyl and alkynyl carbonyl refer to a radical of the type:
Figure imgf000018_0001
wherein R is an alkyl, alkenyl or alkynyl moiety.
The terms alkyl, alkenyl and alkynyl sulfonyl refer to a radical of the type:
1VV
ό'h
wherein R is an alkyl, alkenyl or alkynyl moiety.
The terms alkyl, alkenyl and alkynyl secondary sulphonamido refer to a radical of the type:
Figure imgf000018_0002
wherein R is an alkyl, alkenyl or alkynyl moiety.
The terms alkyl, alkenyl and alkynyl tertiary sulphonamido refer to a radical of the type:
Figure imgf000018_0003
wherein R and R' are each independently selected from alkyl, alkenyl or alkynyl moiety.
The terms alkyl, alkenyl and alkynyl secondary acylsulphonamido refer to a radical of the type:
Figure imgf000018_0004
wherein R is an alkyl, alkenyl or alkynyl moiety.
The terms alkyl, alkenyl and alkynyl tertiary acylsulphonamido refer to a radical of the type:
Figure imgf000018_0005
wherein each R is independently selected from an alkyl, alkenyl or alkynyl moiety.
The terms alkyl, alkenyl and alkynyl alkynyloxy carbonyl refer to a radical of the type: o
wherein R is an alkyl, alkenyl or alkynyl moiety.
The terms carbonyl (i), sulfonyl (ii) and sulfmyl (iii), when used to define the scope of Q, refer to di-radicals of the type:
Figure imgf000019_0001
(i) (ϋ) (iϋ)
The term "cyclic", as used herein in respect of an atom, refers to an atom that is a member of at least one ring in a carbocycle or heterocycle.
A cyclyl according to the invention may comprise 1-10 carbons, it being understood that in case the cyclyl comprises less than 3 carbons, it must necessarily also comprise at least one heteroatom. Unless otherwise indicated or apparent from the context, in a bicyclic moiety according to the invention, each constituent monocycle may independently be selected from aromatic or non- aromatic carbo- and heterocycles.
In a first aspect of the invention, there is provided a compound of formula (I):
Figure imgf000019_0002
(I)
as defined herein above.
R1 in formula (I) is selected from branched or unbranched C1-C10 alkyl, C2-C 10 alkenyl or C2-C10 alkynyl; C3-C10 cycloalkyl; C4-C10 cycloalkenyl; Cs-Cio cycloalkynyl; C1-C9 heterocyclyl; and C6- Cio aryl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or cycloalkynyl moiety optionally is substituted with 1, 2 or 3 groups Ra; and any heterocyclyl or aryl moiety optionally is substituted with 1, 2, 3, 4 or 5 groups Rb, as defined herein. In one embodiment, R1 in formula (I) is selected from branched or unbranched C1-C10 alkyl; C3- Cio cycloalkyl; C1-C9 heterocyclyl; and C6-CiO aryl; said alkyl and cycloalkyl optionally being substituted with 1 , 2 or 3 groups Ra; and said heterocyclyl and aryl optionally being substituted with 1, 2, 3, 4 or 5 groups Rb.
In one embodiment of the invention, R1 in formula (I) is optionally substituted branched or unbranched C1-C10 alkyl, e.g. Ci-Cs alkyl, i.e. methyl, ethyl and branched or unbranched propyl, butyl, pentyl, hexyl, heptyl, and octyl, such as methyl, ethyl, n-propyl, ώo-propyl, n-butyl, iso- butyl, sec-butyl, n-pentyl, pentan-2-yl, pentan-3-yl, n-hexyl, n-heptyl, and n-octyl. More specifically, in this embodiment, R1 in formula (I) may be selected from optionally substituted branched or unbranched Ci-C6 alkyl, e.g. methyl, ethyl, n-propyl, ώo-propyl, n-butyl, ώo-butyl, sec-butyl, n -pentyl, pentan-2-yl, pentan-3-yl, n-hexyl, or from optionally substituted branched or unbranched Ci -C4 alkyl. For example, in this embodiment, R1 may be optinally substituted iso- propyl.
In one embodiment of the invention, when R1 in formula (I) is selected from optionally substituted branched or unbranched Ci -C 10 alkyl, m is 0. In another embodiment, R1 in formula (I) is optionally substituted C3-C10 cycloalkyl, in particular C3-C6 cycloalkyl, or C3-C5 cycloalkyl.
R1 in formula (I) also may be optionally substituted C1-C9 heterocyclyl, in particular C1-C5 heterocyclyl, such as a 6-membered C1-C5 heterocyclyl, C2-C5 heterocyclyl, C3-C5 heterocyclyl, C4-C5 heterocyclyl or C5 heterocyclyl, e.g. tetrahydropyryl or pyridyl, such as pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, or tetrahydropyran-4-yl; or 5-membered Ci -C4 heterocyclyl, C2-C4 heterocyclyl, or C3-C4 heterocyclyl, e.g. thiazolyl or tetrahydrofuryl, such as thiazol-4-yl and tetrahydrofuran-2-yl. R1 in formula (I) also may be optionally substituted C6-CiO aryl, preferably phenyl.
When R1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, it optionally is substituted with 1, 2 or 3 groups, e.g. 1 or 2 independently selected groups Ra, e.g. 1 group Ra, as defined herein, i.e. selected from halogen; hydroxy; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amino; C1-C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; wherein any alkyl, alkenyl or alkynyl moiety optionally is substituted with 1, 2 or 3 groups Rc.
In one embodiment, when R1 is substituted with Ra, each Ra is indpendently selected from hydroxy, C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; and C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amino, in particular from hydroxy, C1-C4 alkoxy, such as methoxy, or C1-C4 alkyl secondary or tertiary amino, e.g. such as ethyl secondary or tertiary amino, e.g. diethylamino. In one embodiment, R1 is not substituted with any Ra.
When R1 is heterocyclyl or aryl, it optionally is substituted with 1, 2, 3, 4 or 5 independently selected groups Rb, as defined herein, i.e. selected from halogen; carboxy; hydroxy; cyano; C1-C5 heteroaryl; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; Ci-C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amino; amino carbonyl; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amido; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl carbonyl; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl sulfonyl; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary sulphonamido; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary acylsulphonamido; Ci-C4 alkyloxy, C2-C4 alkenyloxy, or C2-C4 alkynyloxy carbonyl; Ci- C5 heterocyclyl; wherein any alkyl, alkenyl or alkynyl moiety optionally is substituted with 1, 2 or 3 groups Rc.
In one embodiment, when R1 is substituted with Rb, Rb is selected from halogen; carboxy; cyano; Ci-C5 heteroaryl; Ci-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; amino carbonyl; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amido; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary acylsulphonamido; Ci-C4 alkyloxy, C2-C4 alkenyloxy, or C2-C4 alkynyloxy carbonyl; and C1-C5 heterocyclyl; wherein any alkyl, alkenyl and alkynyl moiety optionally is substituted with 1, 2 or 3 groups Rc.
In one particular embodiment, when R1 is substituted with Rb, Rb is selected from halogen, i.e. F, Cl and Br, in particular F; carboxy; cyano; 5- or 6-membered C1-C5 heteroaryl, in particular 5- membered Ci-C4 heteroaryl, such as triazole; Ci-C4 alkyl, such as methyl; amino carbonyl; Ci-C4 alkyl secondary or tertiary amido, such as methyl secondary or tertiary amido; Ci-C4 alkyl secondary or tertiary acylsulphonamido, such as methyl secondary or tertiary acylsulphonamido; C1-C4 alkyloxy carbonyl, such as methoxy carbonyl; and C1-C5 heterocyclyl, such as 5- or 6- membered heterocyclyl, e.g. 5-membered C1-C4 heterocyclyl, e.g. tetrazole.
In one embodiment, R1 is substituted with 1-3 groups Rb as defined herein, e.g. with 1 or 2 groups, in particular with 1 group Rb. In another embodiment, R1 is not substituted with any Rb.
In one embodiment, when R1 is a 6-membered heterocyclyl or aryl, it is substituted with at least one group Rb in para -position relative to the linking bond or chain attaching R1 to the benzimidazol moiety.
R2 in formula (I) is selected from branched or unbranched C1-C9 alkyl, C2-C9 alkenyl or C2-C9 alkynyl; C3-C6 cycloalkyl, C4-C6 cycloalkenyl; Cs-Cio cycloalkynyl; C 1-C9 heterocyclyl; and C6- Cio aryl; said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl optionally being substituted with 1 , 2 or 3 groups Ra; and said heterocyclyl or aryl optionally being substituted with 1, 2, 3, 4 or 5 groups Rb.
In one embodiment, R2 is optionally substituted branched or unbranched C1-C9 alkyl, C2-C9 alkenyl or C2-C9 alkynyl. In this embodiment, R2 more particularly may be Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, e.g. C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl. In particular, R2 may be branched or unbranched C1-C9 alkyl, or Ci-C6 alkyl, e.g. C1-C4 alkyl, e.g. C2-C4 alkyl.
In one embodiment, when R2 is optionally substituted branched or unbranched C1-C9 alkyl, C2- C9 alkenyl or C2-C9 alkynyl, X is a bond. In another embodiment, R2 is optionally substituted C3-C6 cycloalkyl or C4-C6 cycloalkenyl, and then more particularly may be C3-C6 cycloalkyl, in particular pentyl.
In still another embodiment, R2 is optionally substituted C 1-C9 heterocyclyl. In this embodiment, R2 may in particular be C1-C5 heterocyclyl, e.g. 5-membered C1-C4 heterocyclyl or 6-membered C1-C5 heterocyclyl, in particular 5-membered C1-C4 heterocyclyl, e.g. 5-membered C3-C4 heterocyclyl. For example, R2 may be selected from tetrahydrofuryl and thiazolyl.
In another embodiment, R2 is optionally substituted C6-CiO aryl, and then preferably is phenyl. When R2 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or cycloalkynyl, it optionally is substituted with 1, 2 or 3 groups, e.g. 1 or 2 groups, Ra, as defined herein, i.e. selected from halogen; hydroxy; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amino; C1- C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; wherein any alkyl, alkenyl or alkynyl moiety optionally is substituted with 1 , 2 or 3 groups Rc.
In one embodiment, when R2 is substituted with Ra, each Ra is independently selected from C1- C4 alkyloxy; C2-C4 alkenyloxy; and C2-C4 alkynyloxy, in particular C1-C4 alkyloxy, such as Ci- C3 alkyloxy, more particularly methoxy and iso-propoxy. In one embodiment, R2 is substituted with 1 group Ra and in another embodiment, R2 is not substituted with any group Ra. In one embodiment, when R2 is cycloalkyl, cycloalkenyl, or cycloalkynyl, it is not substituted with any group Ra. When R2 is heterocyclyl or aryl, it optionally is substituted with 1, 2, 3, 4 or 5 groups Rb, as defined herein above. In one embodiment, R2 is substituted with 1, 2, 3, 4 or 5 groups Rb each independently selected from halogen, e.g. F, Cl and Br, in particular F or Br; cyano; and C1-C5 heterocyclyl, e.g. fϊve-membered C 1-C4 heterocyclyl. For example, R2 may be 6-membered heterocyclyl or aryl, such as phenyl, substituted with at least one Rb in para -position in relation to the bond attaching R2 to X or - in case X is a bond - in para -position in relation to the bond X. In one embodiment, R2 is substituted with 1-3 groups Rb, e.g. 1 or 2 groups Rb, in particular 1 group Rb.
In a compound of formula (I), R3 and R4 are each independently selected from C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C3-C4 cycloalkyl; C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; Ci-C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; halogen; Ci-C4 alkyl, C2-C4 alkenyl or C2- C4 alkynyl secondary or tertiary amino; and Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl carbonyl; wherein any alkyl, alkenyl, alkynyl or cycloalkyl moiety optionally is substituted with 1, 2, or 3 groups Rc.
In one embodiment, R3 and R4 are each independently selected from Ci-C4 alkyl and
halogen, in particular from methyl and chloro. For example, R3 and R4 may be both halogen or both Ci-C4 alkyl, e.g. both are Cl or both are methyl, or one may be halogen, e.g. Cl, and the other one Ci-C4 alkyl, e.g. methyl. In one embodiment, R3 is selected from C1-C4 alkyl, e.g. methyl, and R4 is selected from halogen and C1-C4 alkyl, e.g. Cl and methyl. In another embodiment, R3 is selected from halogen, e.g. Cl, and R4 is selected from halogen and C1-C4 alkyl, e.g. Cl and methyl. In still another embodiment, R3 is selected from halogen and C1-C4 alkyl, e.g. Cl and methyl, and R4 is selected from C1-C4 alkyl, e.g. methyl. In still another embodiment, R3 is selected from halogen and C1-C4 alkyl, e.g. Cl and methyl, and R4 is selected from halogen, e.g. Cl.
R5 and R6 in formula (I) are independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl and halogen; whereby any alkyl; alkenyl; or alkynyl is optionally substituted with 1, 2, or 3 groups Rc.
In one embodiment, R5 and R6 are independently selected from hydrogen and C1-C4 alkyl, more particularly from H and methyl, for example, R5 and R6 may both be H; or R5 may be H and R6 methyl.
In formula (I), X represents a bond (i.e. a single, covalent bond) or branched or unbranched Ci- C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl. Preferably X represents a bond or C1-C3 alkyl, more preferably a bond or methylene (-CH2-).
Q in formula (I) is selected from carbonyl, sulfonyl and sulfϊnyl and preferably is carbonyl.
In formula (I), m is an integer of 0, 1 or 2, preferably 0 or 1. In one particular embodiment, m is 0. In another embodiment, m is 1.
Each Rais independently selected from halogen; hydroxy; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; C1-C4 alkyl, C2-C4 alkenyl or C2- C4 alkynyl secondary or tertiary amino; C1-C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; wherein any alkyl, alkenyl or alkynyl moiety optionally is substituted with 1, 2 or 3 groups Rc.
In one embodiment, each Ra is independently selected from hydroxy; C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; and C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amino; wherein any alkyl, alkenyl and alkynyl moiety optionally is substituted with 1, 2 or 3 groups Rc. In another embodiment, each Ra is independently selected from hydroxy; C1-C4 alkyloxy, e.g. methoxy and ώo-propoxy; and C1-C4 alkyl secondary or tertiary amino, e.g.diethylamino.
Each Rb in formula (I) is independently selected from halogen; carboxy; hydroxy; cyano; C1-C5 heteroaryl; Ci-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C3-C5 cycloalkyl; Ci-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; C3-C5 cycloalkyloxy; Ci-C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; C3-C5 cycloalkylthio; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amino; amino carbonyl; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amido; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl carbonyl; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl sulfonyl; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary sulphonamido; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary
acylsulphonamido; Ci-C4 alkyloxy, C2-C4 alkenyloxy, or C2-C4 alkynyloxy carbonyl; C1-C5 heterocyclyl; wherein any alkyl, alkenyl, alkynyl or cycloalkyl moiety optionally is substituted with 1 , 2 or 3 groups Rc as defined herein.
In one embodiment, each Rb is independently selected from halogen; carboxy; hydroxy; cyano; Ci -C5 heteroaryl; Ci-C4 alkyl; C3-C5 cycloalkyl; Ci-C4 alkyloxy; C3-C5 cycloalkyloxy; Ci-C4 alkylthio; Ci-C4 alkyl secondary or tertiary amino; amino carbonyl; Ci-C4 alkyl secondary or tertiary amido; Ci-C4 alkyl carbonyl; Ci-C4 alkyl sulfonyl; Ci-C4 alkyl secondary or tertiary sulphonamido; Ci-C4 alkyl secondary or tertiary acylsulphonamido; Ci-C4 alkyloxy carbonyl; Ci-C5 heterocyclyl; wherein any alkyl or cycloalkyl moiety optionally is substituted with 1, 2 or 3 groups Rc as defined herein.
In another embodiment, each Rb is independently selected from halogen; carboxy, cyano; Ci-C5 heteroaryl; Ci-C4 alkyl; C2-C4 alkenyl; C3-C5 cycloalkyl; Ci-C4 alkyloxy; C3-C5 cycloalkyloxy; C2-C4 alkynyl; amino carbonyl; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amido; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary acylsulphonamido; C1- C4 alkyloxy carbonyl; and Ci-C5 heterocyclyl; wherein any alkyl, alkenyl and alkynyl moiety optionally is substituted with 1 , 2 or 3 groups Rc as defined herein.
In still another embodiment, each Rb is independently selected from halogen; carboxy; cyano; Ci-C5 heteroaryl; Ci-C4 alkyl; C3-C5 cycloalkyl; Ci-C4 alkyloxy; C3-C5 cycloalkyloxy;
aminocarbonyl; Ci-C4 alkyl secondary or tertiary amido; Ci-C4 alkyl secondary or tertiary acylsulphonamido; Ci-C4 alkyloxy carbonyl; and Ci-C5 heterocyclyl; wherein any alkyl, moiety optionally is substituted with 1, 2 or 3 groups Rc as defined herein. In still another embodiment, each Rb is independently selected from halogen; carboxy, cyano; C 1-C5 heteroaryl; C1-C4 alkyl; amino carbonyl; C1-C4 alkyl secondary or tertiary amido; C1-C4 alkyl secondary or tertiary acylsulphonamido; C1-C4 alkyloxy carbonyl; and C1-C5 heterocyclyl; wherein any alkyl, moiety optionally is substituted with 1, 2 or 3 groups Rc as defined herein.
When Rb is C1-C5 heterocyclyl, it may be C1-C4 heterocyclyl, and preferably is 6-membered Ci- C5 heterocyclyl or 5-membered C1-C4 heterocyclyl, more preferably 5-membered C1-C4 heterocyclyl. When Rb is C1-C5 heteroaryl, it may be C1-C4 heteroaryl, and prefereably is 6- membered C1-C5 heteroaryl or 5-membered C1-C4 heteroaryl.
Rc in formula (I) is selected from fluorine and chlorine. In one embodiment, Rc is absent. In another embodiment, Rc is fluorine.
In a particular embodiment of the invention, X represents methylene or a bond and R2 represents C3-C 6 cycloalkyl or heterocyclyl.
In another embodiment of the invention, X represents a bond and R2 represents cyclopentyl.
In one embodiment of the invention, in a compound of formula (I)
R1 is selected from branched or unbranched C1-C10 alkyl; C3-C10 cycloalkyl; C1-C9 heterocyclyl; and C6-CiO aryl; wherein any alkyl or cycloalkyl moiety optionally is substituted with 1, 2 or 3 groups Ra; and any heterocyclyl or aryl moiety optionally is substituted with 1, 2, 3, 4 or 5 groups Rb;
R2 is selected from branched or unbranched C1-C9 alkyl; C3-C6 cycloalkyl; C1-C9 heterocyclyl; and C6-CiO aryl; wherein any alkyl or cycloalkyl moiety optionally is substituted with 1, 2 or 3 groups Ra; and any heterocyclyl or aryl moiety optionally is substituted with 1, 2, 3, 4 or 5 groups Rb;
R3 and R4 are each independently selected from C1-C4 alkyl and halogen;
R5 and R6 are each selected from H and methyl; m is 0 or 1 ;
Q is carbonyl; X represents a bond or methylene; each Rais independently selected from hydroxy; C1-C4 alkyloxy; C1-C4 alkyl secondary or tertiary amino; each Rb is independently selected from halogen; cyano; C1-C5 heteroaryl, carboxy, C1-C4 alkyl; C1-C4 alkyl secondary or tertiary amido; C1-C4 alkyl carbonyl; C1-C4 alkyloxy carbonyl; C1-C4 alkyl secondary or tertiary acylsulphonamido; and C1-C5 heterocyclyl; and
Rc is absent. In one embodiment of the invention, in a compound of formula (I)
R1 is selected from branched or unbranched C1-C10 alkyl; C3-C6 cycloalkyl; 5- or 6-membered C3-C5 heterocyclyl; and phenyl; wherein any alkyl or cycloalkyl. moiety optionally is substituted with 1 or 2 groups Ra; and any heterocyclyl or phenyl moiety optionally is substituted with 1 or 2 groups Rb;
R2 is selected from branched or unbranched Ci-C6 alkyl; C3-C6 cycloalkyl; 5- or 6-membered C3- C5 heterocyclyl; and phenyl; wherein any alkyl or cycloalkyl moiety optionally is substituted with 1 or 2 groups Ra; and any heterocyclyl or phenyl moiety optionally is substituted with 1 or 2 groups Rb;
R3 and R4 are each independently selected from methyl and chloro; and
R5 and R6 are each selected from H. In yet another embodiment of the invention, R1 represents C1-C10 alkyl, e.g. Ci-Cs alkyl, or C1- C6 alkyl; R2 represents C4-C6 cycloalkyl or C4-C5 heterocyclyl, e.g. C4-C6 cycloalkyl or 5- or 6- membered C4-C5 heterocyclyl; R3 and R4 are independently selected from methyl and chlorine; R5 and R6 are hydrogen; X represents a bond; and Q represents carbonyl. Thus, in this embodiment, the compound of formula (I) may be represented by the formula (Ia):
Figure imgf000028_0001
wherein the intej ger p is 0-11, e.g. 0-9, or 0-7.
In yet another embodiment of the invention, R1 represents C3-C6 cycloalkyl; R2 represents C4-C6 cycloalkyl or C4-C5 heterocyclyl; R3 and R4 are independently selected from methyl and chlorine; X represents a bond; and Q represents carbonyl.
In yet another embodiment of the invention, R1 represents phenyl or C4-C5 heterocyclyl; R2 represents C4-C6 cycloalkyl or C4-C5 heterocyclyl; R3 and R4 are independently selected from methyl and chlorine; X represents a bond; and Q represents carbonyl.
In yet another embodiment of the invention, R1 represents phenyl or C4-C5 heterocyclyl, e.g. 5- or 6-membered C4-C5 heterocyclyl, optionally substituted with one or more Rb; R2 represents cyclopentyl; R3 and R4 are independently selected from methyl and chlorine; the integer m is equal to 1 or 0 (zero); R5 and R6 are hydrogen; X represents a bond; and Q represents carbonyl. Thus, in this embodiment, the compound of formula (I) may be represented by the formula (Ib):
Figure imgf000028_0002
In yet another embodiment of the invention, R1 represents C1-C10 alkyl, e.g. Ci-Cs alkyl, or Ci- C6 alkyl; R2 represents Ci-C9 alkyl, e.g. Ci-C6 alkyl, or Ci-C4 alkyl; R3 and R4 are independently selected from methyl and chlorine, R5 and R6 are hydrogen; and Q represents carbonyl. Thus, in this embodiment, the compound of formula (I) may be represented by the formula (Ic):
Figure imgf000028_0003
wherein the integer p is 0-11, e.g. 0-9 , or 0-7; and the integer r is 0-12, e.g. 0-10, or 0-8. In yet another embodiment of the invention, R1 represents C4-C5 saturated heterocyclyl, e.g. 5- or 6-membered C4-C5 heterocyclyl; R2 represents cyclopentyl; R3 and R4 are independently selected from methyl and chlorine; the integer m is equal to 1 ; R5 and R6 are hydrogen; X represents a bond; and Q represents carbonyl. Thus, in this embodiment, the compound of formula (I) may be represented by the formula (Id):
Figure imgf000029_0001
In yet another embodiment of the invention, R1 represents C3-C5 cycloalkyl; R2 represents cyclopentyl or tetrahydrofuranyl; R3 and R4 are independently selected from methyl and chlorine; the integer m is equal to either 0 (zero) or 1; R5 and R6 are hydrogen; X represents a bond and Q represents carbonyl. Thus, in this embodiment, the compound of formula (I) may be represented by the formula (Ie):
Figure imgf000029_0002
wherein the integer t is 0, 1 or 2, and W is oxygen or methylene.
Unless otherwise specified, or apparent from the context, in preferred embodiments of the compounds of formulae (Ia), (Ib), (Ic), (Id), and (Ie), the identity of R1, R2, R3, R4, R5, R6, m, X,
Q, Ra, Rb, and Rc, is as defined herein above in relation to the inventive compound of the general formula (I).
In another embodiment of the invention, there is provided a compound selected from:
Λ/-cyclopentyl-l-(l-ethyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -propyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide; l-(l-butyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4-carboxamide; Λ/-cyclopentyl-l-(l-heptyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -octyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -pentyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide; Λ/-cyclopentyl-l-(l-hexyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -(pyridin-2-ylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -( 1 -isopropyl-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-(2-(diethylamino)ethyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-
4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(pyridin-4-ylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(pyridin-3-ylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(pyridin-2-ylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
l-(l-sec-butyl-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4-carboxamide; Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(pentan-3-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5 ,6-dichloro- 1 -cyclobutyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl-l -(5,6-dichloro- l-(l-phenylethyl)-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -methyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -ethyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5 ,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-fluorobenzyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-(3,5-difluorobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
methyl 4-((2-(4-(cyclopentylcarbamoyl)piperidin- 1 -yl)-5,6-dimethyl- lH-benzo[d]imidazol- 1 - yl)methyl)benzoate;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -((2-methylthiazol-4-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -phenyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopropyl- 1 -(5 ,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclo butyl- 1 -(5,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide; l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-propylpiperidine-4-carboxamide; l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-(2-methoxyethyl)piperidine-4- carboxamide;
l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-(isopropoxymethyl)piperidine-4- carboxamide;
l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
Λ/-(cyclohexylmethyl)-l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-((tetrahydro-2H-pyran-4- yl)methyl)piperidine-4-carboxamide;
Λ/-butyl- 1 -(5,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-(cyclopentylmethyl)- 1 -(5,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -( 1 -((6-fluoropyridin-3-yl)methyl)-5 ,6-dimethyl- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
l-(l-(4-cyanobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-(cyclopropylmethyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -((tetrahydrofuran-2-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
1 -( 1 -(4-( IH- 1 ,2,4-triazol- 1 -yl)benzyl)-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide;
1 -( 1 -cyclobutyl-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
l-(l-(4-bromobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -(4-(methylcarbamoyl)benzyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl-l-(l-(4-(dimethylcarbamoyl)benzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
l-(l-(4-carbamoylbenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide; Λ/-cyclopentyl- 1 -(5 ,6-dimethyl- 1 -(4-(methylsulfonylcarbamoyl)benzyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3-yl)piperidine-4- carboxamide;
1 -( 1 -(4-fluorobenzyl)-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)-JV-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide;
1 -(5-chloro- 1 -cyclobutyl-6-methyl- lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentyl-piperidine-4- carboxamide;
1 -(6-chloro- 1 -cyclobutyl-5 -methyl- lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -cyclopentyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
l-(l-(4-bromobenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -((6-fluoropyridin-3-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-cyanobenzyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(cyclopropylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -((tetrahydrofuran-2-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -((tetrahydro-2H-pyran-4-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5 ,6-dichloro- 1 -(4-(methylcarbamoyl)benzyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-(dimethylcarbamoyl)benzyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
l-(l-(4-carbamoylbenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-cyclopentyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4- carboxamide;
l-(l-(4-chlorobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide; l-(l-(4-(lH-tetrazol-5-yl)benzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5 ,6-dichloro- 1 -(4-(methylsulfonylcarbamoyl)benzyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
TV-butyl- 1 -(5,6-dichloro- 1 -cy clo butyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-butyl- 1 -(5 ,6-dichloro- 1 -pentyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
N-butyl- 1 -(5 ,6-dichloro- 1 -(4-fluorobenzyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
N-butyl- 1 -(5,6-dichloro- 1 -((6-fluoropyridin-3-yl)methyl)- lH-benzo[d]imidazol-2-yl)piperidine- 4-carboxamide;
1 -(5,6-dichloro- 1-cyclo butyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
1 -(5,6-dichloro- l-pentyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
1 -(5,6-dichloro- l-(4-cyanobenzyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -(5,6-dichloro- l-(cyclopropylmethyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -(5,6-dichloro- l-((6-fluoropyridin-3-yl)methyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -((tetrahydro-2H-pyran-4-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
1 -(5,6-dichloro- l-cyclopentyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
l-(l-(4-bromobenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide; l-(l-(4-(lH-tetrazol-5-yl)benzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide;
1 -(5,6-dichloro- 1 -(4-fluorobenzyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1.( 1.(4-( IH- 1 ,2,4-triazol- 1 -yl)benzyl)-5 ,6-dichloro- lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide;
N-cyclopentyl- 1 -(5,6-dichloro- 1 -(2-methoxyethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide; Λ/-cyclopentyl-l-(l-(4-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
l-(l-(cyclobutylmethyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -(prop-2-ynyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-(2-ethylbutyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5 ,6-dimethyl- 1 -neopentyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
l-(l-cyclohexyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
l-(l-sec-butyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentyl-piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(2-hydroxyethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -( 1 ,5 ,6-trimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl-l-(l-isobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide; l-(l-benzyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4-carboxamide; Λ/-cyclopentyl-l-(l-(2-methoxyethyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-(4-fluorobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
1 -(5-chloro- 1 -cyclobutyl-6-fluoro- lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4- carboxamide;
1 -(6-chloro- 1 -cyclobutyl-5-fluoro- lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -(pentan-2-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-butyl- 1 -( 1 -cyclobutyl-5 ,6-dimethyl- lH-benzo [d]imidazo l-2-yl)piperidine-4-carboxamide;
Λ/-butyl-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
N-butyl- 1 -(5,6-dimethyl- 1 -pentyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-butyl- 1 -( 1 -((6-fluoropyridin-3 -yl)methyl)-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)piperidine-
4-carboxamide; Λ/-butyl- 1 -( 1 -(4-fluorobenzyl)-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-benzyl-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-(4-fluorobenzyl)- 1 -( 1 -isopropyl-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)piperidine-4- carboxamide;
Λ/-(3-isopropoxypropyl)-l -(I -isopropyl-5, 6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-(3,3-dimethylbutyl)-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
JV-(4-bromobenzyl)- 1 -(I -isopropyl-5, 6-dimethyl- 1 H-benzo [d]imidazol-2-yl)piperidine-4- carboxamide;
JV-cyclohexyl- 1 -( 1 -isopropyl-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-(4-cyanobenzyl)- 1 -( 1 -isopropyl-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)piperidine-4- carboxamide;
(S)- 1 -(5, 6-dimethyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
4-((2-(4-(cyclopentylcarbamoyl)piperidin- 1 -yl)-5, 6-dimethyl- lH-benzo[d]imidazol- 1 - yl)methyl)benzoic acid
1 -(I -isopropyl-5, 6-dimethyl- lH-benzo[d]imidazol-2-yl)-Λ/-(thiazol-2-ylmethyl)piperidine-4- carboxamide;
l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-(thiazol-2-ylmethyl)piperidine-4- carboxamide;
Λ/-(4-(lH-tetrazol-5-yl)benzyl)-l -(I -isopropyl-5, 6-dimethyl- lH-benzo[d]imidazo 1-2- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5, 6-dimethyl- 1 -(pentan-3-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
1 -(5, 6-dimethyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-fluorophenyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
l-(l-(4-bromophenyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -(I -(4-fluorophenyl)-5, 6-dimethyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide; l-(l-(3-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
l-(l-(3,5-difluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
l-(l-(4-chlorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -(5,6-dimethyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-JV-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
l-(l-(3,5-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -(5,6-dimethyl- 1 -(naphthalen-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -( 1 -(benzo[d] [1,3] dioxo 1-5 -yl)-5 ,6-dimethyl- lH-benzo [d]imidazo l-2-yl)-JV-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide;
l-(5,6-dichloro-l-(3-methoxyphenyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
l-(l-(benzo[d][l,3]dioxol-5-yl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
l-(5,6-dichloro-l-(4-cyanophenyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -m-tolyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -( 1 -(3 ,4-dimethylphenyl)-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-(4-fluoro-3-methylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl-l-(l-(4-ethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-(4-isopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -(quinolin-6-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -(quinoxalin-6-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
l-(5,6-dichloro-l-(4-(methylcarbamoyl)phenyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran- 3-yl)piperidine-4-carboxamide; (R)-l-(5,6-dichloro-l-(3-methoxyphenyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(pyridin-3-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(pyridin-3-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(6-methoxypyridin-2-yl)- lH-benzo[d]imidazol-2-yl)piperidine-
4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-cyanophenyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-fluorophenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3 -fluorophenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-methoxyphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-tert-butylphenyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-(trifluoromethoxy)phenyl)- lH-benzo[d]imidazol-2-yl)-JV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide;
1 -(5,6-dichloro- l-phenyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
1 -(5,6-dichloro- l-(pyridin-2-yl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-
4-carboxamide;
1 -(5,6-dichloro- l-(pyridin-3-yl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-
4-carboxamide;
1 -(5,6-dichloro- l-p-tolyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
(R)-l-(l-(4-chloro-3-methoxyphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/- (tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-chloro-3-methoxyphenyl)- lH-benzo[d]imidazol-2-yl)-JV-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;.
(R)-l-(l-(2,3-dihydrobenzofuran-5-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide; (R)- 1 -(5,6-dichloro- 1 -(2,3-dihydrobenzofuran-5-yl)- lH-benzo[d]imidazol-2-yl)-JV-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(3,5-diethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -(5,6-dichloro- l-(cyclobutylmethyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-fluoro-3-methylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(4-ethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(3,4-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -(quinolin-6-yl)- lH-benzo[d]imidazol-2-yl)-JV-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -( 1 -(4-isopropylphenyl)-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)-JV-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-tert-butylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(3-chlorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -(6-chloro-5 -methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
(R)- 1 -(5-chloro-6-methyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(6-chloro-5-methyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-carbamoylphenyl)-5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
l-(l-(4-carbamoylphenyl)-5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide;
l-(l-(4-carbamoylphenyl)-6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)-Λ/- cyclopentylpiperidine-4-carboxamide;
(R)-l-(l-(4-carbamoylphenyl)-6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide; (R)- 1 -(S-chloro-β-methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]-imidazol-2-yl)-/V-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
1 -(S-chloro-β-methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-/V- cyclopentylpiperidine-4-carboxamide;
1 -(S-chloro-β-methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-/V-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(β-chloro-S-methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]-imidazol-2-yl)-/V-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
1 -(6-chloro-5 -methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-/V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide;
1 -(6-chloro-5 -methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-/V- cyclopentylpiperidine-4-carboxamide;:
(R)- 1 -(6-chloro-5-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-/V-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(S)- l-(6-chloro-5-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-/V-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
/V-butyl- 1 -(5-chloro-6-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide; TV- butyl- 1 -(6-chloro-5-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
1 -(5-chloro-6-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine- 4-carboxamide;
1 -(6-chloro-5 -methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-
4-carboxamide;
1 -(5-chloro- 1 -cyclobutyl-6-methyl- lH-benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -(6-chloro- 1 -cyclobutyl-5 -methyl- lH-benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -(5-chloro- 1 -(cyclobutylmethyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-7V-cyclopentylpiperidine-
4-carboxamide;
1 -(6-chloro- 1 -(eye Io butylmethyl)-5 -methyl- lH-benzo[d]imidazol-2-yl)-7V-cyclopentylpiperidine- 4-carboxamide;
1 -(5-chloro-6-methyl- 1 -pentyl- lH-benzo[d]imidazol-2-yl)-7V-cyclopentylpiperidine-4- carboxamide;
1 -(6-chloro-5 -methyl- 1 -pentyl- lH-benzo[d]imidazol-2-yl)-7V-cyclopentylpiperidine-4- carboxamide; 1 -(5-chloro- 1 -(4-fluorophenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
1 -(6-chloro- 1 -(4-fluorophenyl)-5 -methyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
1 -(S-chloro-β-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
1 -(6-chloro-5 -methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
Λ/-butyl- 1 -(5-chloro- l-cyclobutyl-6-methyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-butyl- 1 -(6-chloro- 1 -eye Io butyl-5 -methyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -(3-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -(5-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(3-ethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(3-isopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(6-chloro- l-(4-isopropylphenyl)-5 -methyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-chlorophenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-fluoro-3-methylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(5 ,6-dichloro- 1 -(3 ,5-difluorophenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-cyanophenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide; (R)- 1 -(5,6-dichloro- 1 -(5-methylpyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(6-methoxypyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-isopropylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-methylpyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(6-methylpyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-(difluoromethoxy)phenyl)- lH-benzo[d]imidazol-2-yl)-JV-
(tetrahydro furan-3 -yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-(trifluoromethoxy)phenyl)- lH-benzo[d]imidazol-2-yl)-JV-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-isobutylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5 ,6-dichloro- 1 -(3 ,4-dimethylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-chlorophenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(5-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(5-fluoropyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -( 1 -(4-isobutylphenyl)-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)-N-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide;
(R)-l-(6-chloro-l-(3,5-dimethylphenyl)-5-methyl-lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(4-chloro-3-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-chloro-3 -fluorophenyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3,5-diethylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide; (R)-l-(l-(3-tert-butylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(3-tert-butylphenyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-ethylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -m-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydro furan-3 -yl)piperidine-4- carboxamide;
(R)- 1 -(5 ,6-dichloro- 1 -(3 ,5-dimethylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-ethylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(6-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydro furan-3 -yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-ethoxyphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-isopropoxyphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-propoxyphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -( 1 -(4-fluoro-3 ,5-dimethylphenyl)-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-chloro-3-methylphenyl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-chloro-4-methylphenyl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5 ,6-dimethyl- 1 -phenyl- 1 H-benzo [d]imidazol-2-yl)-N-(tetrahydro furan-3 -yl)piperidine-4- carboxamide;
(R)- 1 -(5 ,6-dimethyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
(R)- 1 -(5 ,6-dimethyl- 1 -m-tolyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide; (R)-l-(l-(3-cyanophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -(naphthalen-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-chloro-3-methylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(3-chloro-4-methylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(benzo[d]thiazol-6-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(benzo[d]thiazol-5-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
(R)-l-(5-chloro-l-(3,4-dimethylphenyl)-6-methyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(6-chloro-l-(3,4-dimethylphenyl)-5-methyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5-chloro- l-(4-isopropylphenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(6-chloro- l-(4-isopropylphenyl)-5 -methyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran- 3-yl)piperidine-4-carboxamide;
(S)- l-(5-chloro-6-methyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
(S)- l-(6-chloro-5-methyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(S)-l-(6-chloro-l-(3,5-dimethylphenyl)-5-methyl-lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3-yl)piperidine-4- carboxamide;
l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-((15f,25)-2- hydroxy cyclopentyl)piperidine-4-carboxamide;
l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-((lR,2R)-2- hydroxycyclopentyl)piperidine-4-carboxamide;
(R)-l-(l-(benzofuran-5-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide; (R)- 1 -(5,6-dichloro- 1 -(4-fluoro-3,5-dimethylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(3-fluoro-5-methylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-fluoro-5-methylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-cyclopropylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-cyclopropylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -( 1 -(benzo furan-6-yl)-5 ,6-dimethyl- lH-benzo [d]imidazo l-2-yl)-JV-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide;
(R)- 1 -(5-chloro- l-(4-ethylphenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(6-chloro- l-(4-ethylphenyl)-5 -methyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5-chloro- l-(4-ethylphenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-tert-butylphenyl)-6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide;
(R)-l-(l-(4-cyclopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(3-cyclopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-(cyclopentyloxy)phenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-cyclobutoxyphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
l-(5-chloro-6-fluoro-l-methyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
l-(6-chloro-5-fluoro-l-methyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
1 -(5-chloro- 1 -ethyl-6-fluoro- lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide; 1 -(6-chloro- 1 -ethyl-5-fluoro- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
l-(5-chloro-6-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
l-(6-chloro-5-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
l-(l-butyl-5-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
l-(l-butyl-6-chloro-5-fluoro-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
1 -(5 ,6-dimethyl- 1 -p-tolyl- 1 H-benzo [d]imidazo l-2-yl)-JV-(tetrahydrofuran-3 -yl)piperidine-4- carboxamide;
(R)- 1 -(6-chloro- l-(4-fluorophenyl)-5 -methyl- lH-benzo[d]imidazol-2-yl)-JV-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5-chloro- l-(4-fluorophenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-JV-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(6-chloro-5-methyl- 1 -m-tolyl- lH-benzo[d]imidazol-2-yl)-JV-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5-chloro-6-methyl- 1 -m-tolyl- lH-benzo[d]imidazol-2-yl)-JV-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5-chloro-6-methyl- 1 -(5-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-JV-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(6-chloro-5-methyl- 1 -(5-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-((2S)-2- methoxycyclopentyl)piperidine-4-carboxamide;
l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-((2S)-2- ethoxycyclopentyl)piperidine-4-carboxamide;
l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-((2S)-2- propoxycyclopentyl)piperidine-4-carboxamide;
l-(5,6-dichloro-l-(4-(dimethylcarbamoyl)phenyl)-lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)-N-((lS,2S)-2- hydroxycyclopentyl)piperidine-4-carboxamide; l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)-N-((lS,2S)-2- methoxycyclopentyl)piperidine-4-carboxamide;
l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)-N-((lS,2S)-2- ethoxycyclopentyl)piperidine-4-carboxamide;
1 -( 1 -cyclobutyl-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)-Λ/-(furan-2-ylmethyl)piperidine-4- carboxamide;
1 -( 1 -cyclobutyl-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)-Λ/-(thiophen-2-ylmethyl)piperidine-4- carboxamide;
(R)- 1 -( 1 -(5 -bromopyridin-2-yl)-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)-JV-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide;
(R)-l-(l-(5-ethylpyridin-2-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(3-chloro-5-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3 -chloro-5 -fluorophenyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(2,2-difluorobenzo[d] [ 1 ,3]dioxol-5-yl)- lH-benzo[d]imidazol-2-yl)-Λ/- (tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(S)- 1 -( 1 -(3 ,5-dimethylphenyl)-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(5-chloropyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(5-fluoro-6-methylpyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydro furan-3 -yl)piperidine-4-carboxamide;
(R)-l-(l-(3-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- l-(l-(3,5-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydro furan-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide; (R)-l-(l-(3,5-difluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-chlorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
(R)-l-(l-(5-chloropyridin-2-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -(4-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -( 1 -(5 -fluoro-6-methylpyridin-2-yl)-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-ethoxyphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-methoxy-3-methylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide; and
(R)- 1 -( 1 -cyclobutyl-5 ,6-dimethyl- 1 H-benzo [d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide;
or a pharmaceutically acceptable salt thereof.
The compounds of formula (I) of the invention can be prepared according to the synthetic routes outlined herein and by following the methods described herein below and illustrated in the Examples. Alternative synthetic routes to these compounds can easily be visualized by any person skilled in the art and the present synthetic routes are not limiting for the invention. With respect to the reaction schemes below, although the various R1, R2, R3, R4, R5, R6, Q and X moieties sometimes are specifically defined, unless otherwise indicated, it is to be understood that R1, R2, R3, R4 and X may be any of the groups encompassed thereby.
As a non- limiting example, a compound of formula (I) as defined herein may be formed in a three step procedure wherein, first, a suitable substituted 2-aminobenzoimidazol (i) is diazotizated and subjected to the Sandmeyer reaction, or any suitable modification of this method, the formed chloro intermediate (ii) is coupled with a piperidine-4-carboxamide derivative (iii) to form the product (iv), which subsequently is JV-alkylated or arylated by Y- (CR5R6)m-R1 (v) to yield the final compound of formula (I). The entire synthetic route is depicted below in Reaction Scheme 1.
Reaction Scheme 1
1 ) diazotization
2) Sandmeyer
Figure imgf000048_0002
Figure imgf000048_0001
Figure imgf000048_0003
The process of forming diazonium compounds from aromatic or heteroaromatic amines has been known for more than 150 years and involves an amine that reacts with a nitrite salt such as sodium nitrite to form a diazonium salt at low temperature, a procedure that should be well known for the one skilled in the art. Typically diazonium compounds are not isolated, but used immediately in further reactions as described below in the Sandmeyer reaction. Diazonium compounds can, however, also be isolated as tetrafluoroborate salts. Conditions suitable for the Sandmeyer reaction are well known to the person skilled in the art and comprise an diazonium salt of an aromatic or heterocyclic kept at low temperature, which is decomposed in the presence of copper(I) salts, such as copper(I) chloride or copper(I) bromide, to form the desired chloro or bromo derivative. Several modifications to the standard procedures above have been made and are exemplified by the use of t-butyl nitrite and anhydrous copper(II) chloride or copper(II) bromide at elevated temperatures [Doyle, M. P.; Siegfried, B.; Dellaria Jr, J. F. Alkyl nitrite- metal halide deamination reactions. 2. Substitutive deamination of arylamines by alkyl nitrites and copper(II) halides. A direct and remarkably efficient conversion of arylamines to aryl halides. J. Org. Chem. 1977, 42, 2426-2431], t-butyl thionitrite and copper(II) chloride or copper(II) bromide employed at room temperature [Oae, A.; Shinhama, K.; Kim, Y. H. Direct conversion of arylamines to the corresponding halides, biphenyls and sulfides with t-buty thionitrate. Chem. Lett., 1979, 939-942] and mixtures of Cu(I) and Cu(II) chloro and bromo salts, used in catalytic amounts in the presence of the bidentate ligand phenanthroline and phase- transfer catalyst dibenzo-18-crown-6 [Beletskaya, I, P.; Sigeev, A. S.; Peregudov, A. S.;
Petrovskii, P. V. Catalytic Sandmeyer Bromination. Synthesis, 2007, 2534-2538]. In this context, it should be contemplated that a wide variety of methods exists for the transformation of (i) into (ii) and several exhaustive review articles on the topic can be found in the literature.
Conditions suitable for the coupling of aromatic and heteroaromatic halides, such as chlorides, with aliphatic amine chains or secondary amine aliphatic ring structures such as piperidine derivatives as (iii) are well known for the one skilled in the art, and there exists a wealth of different methods in the scientific literature, summarized in for example: "Advanced Organic Chemistry", 4th edition, Jerry March, Wiley-Interscience publication, 1992, p 656-657, including the references cited therein. In the precent invention the chloro intermediate (ii) is reacted with the piperidine-4-carboxamide derivative (iii) to form the coupled product (iv) in the presence of a base, such as as N,Λ/-diisopropylethylamine (Hunig's base, DIEA, CAS Registry Number: 7087-68-5), in a suitable solvent, such as 1,4-dioxane. Obviously other alternative good bases that are poor nucleophiles can be employed, such as, but not limited to 2,2,6,6- tetramethylpiperidine (TMP, CAS Registry Number: 768-66-1).
In the transformation of (iv) into the final compound of formula (I), JV-alkylation or JV-arylation by Y-R1 (v) is employed. For the JV-alkylation, (iv) is treated with a chloro-, bromo or iodoalkyl electrophile in the presence of a base such as caesium carbonate in a solvent such as acetonitrile and/or N,Λ/-dimethylformamide. A palladium catalyst, such as, but not limited to [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), CAS Registry Number: 72287-26-4) can also be employed in this reaction. Possible use of alternative bidentate palladium-catalysts for a successful N-alkylation might involve [l,2-bis(diphenylphosphino)- ethane]dichloro-palladium(II) (PdCl2(dppe), CAS Registry Number: 19978-61-1), [1,4- bis(diphenylphosphino)-butane] dichloropalladium(II), PdCl2dppb), and the like, all well known for the one skilled in the art. For the JV-arylation, (iv) is treated with a haloaryl in the presence of a base such as caesium carbonate, and an agent as 1,10-phenanthroline, 4,7-dimethoxy-l,10- phenanthroline or 8-hydroxyquinoline, polyethylene glycol and copper(I) oxide in a solvent such as dimethylsulfoxide. Yet other combinations of bases, catalysts, solvents and agents can be appropriately employed and are well known for those skilled in the art [eg. Preston, P. N.
Synthesis, reactions, and spectroscopic properties of benzimidazoles. Chem. Rev., 1974, 74, 279- 314], and are well within the scope of the invention.
An alternative preparation of (ii) is depicted in Reaction Scheme 2 and involves the treatment of a suitable substituted diamine (vi) with excess stoichiometric amounts of the carbonyl source N,N-carbonyl dimidazole (CDI, CAS Registry Number: 530-62-1) in a solvent such as tetrahydrofuran, in order to achieve ring-closure to the corresponding tautomeric most stable benzoimidazol-2-one (vii). The ring-closure of aromatic or heteroaromatic diamines is well- known in the literature and might involve the use of alternative of carbonyl sources exemplified by the usage of carbon monoxide in the presence of catalytic amounts of tungsten hexacarbonyl (CAS Registry Number: 14040-11-0). Subsequently, the tautomeric -ol form (viii) can be transformed to the intermediary (ii) via treatment with phosphoryl trichloride (CAS Registry Number: 10025-87-3), as exemplified in the invention. Alternative reagents include phosphorus pentachloride (CAS Registry Number: 10026-13-8) or phosphorus trichloride (CAS Registry Number: 7719-12-2), the former also, alone or as mixtures in various ratios, or any other chlorination agent, all that exists in abundance in the scientific literature, for the purpose of transforming a hydroxyl group to a chlorine group. In this context, it should be contemplated that the corresponding bromo derivative of (ii) also can be useful as an intermediate in the reaction schemes, leading to the target compounds of the invention, and could be prepared by the action of phosphoryl bromide (CAS Registry Number: 7789-59-5) phosphorus tribromide (CAS
Registry Number: 7789-60-8) and/or phosphorus pentabromide (CAS Registry Number: 7789- 69-7), or any other brominating agent, all that exists in abundance in the scientific literature, for the purpose of transforming a hydroxyl group to a bromine group.
Reaction Scheme 2
(ii)
Figure imgf000050_0001
Alternative synthetic strategies for the preparation of a compound of formula (I) are shown in Scheme 3. For example, the chloro intermediate (ii), can be coupled with piperidine-4-carboxylic acid derivative (ix) to form the coupled product (x), which subsequently is N-alkylated by Y- (CR5R6)m-R1 (v), the ethyl ester saponificated to give the carboxylic acid derivative, which can be subjected to amide coupling with H2N-X-R2, to yield the final compound of formula (I). This method is foremost useful when the Reposition needs to be varied, while the R'-substituent is kept constant during the preparation.
Reaction Scheme 3
Figure imgf000051_0001
Figure imgf000051_0002
The carboxylic acid ester (xi) is saponified with a base such as aqueous sodium hydroxide and a solvent such as ethanol. Acidification of the completed reaction mixture is followed by standard work-up and crystallization or chromatography, to yield the carboxylic acid (xii). A wide variety of other protecting groups for the carboxylic acid can be employed, and their usage is known to those skilled in the art (references describing protecting group strategy include, for example, "Protecting Groups in Organic Chemistry", J. F. W. McOmie, Plenum Press, London, New York, 1973, and "Protective Groups in Organic Synthesis", T. W. Greene, Wiley, New York, 1984).
Conditions suitable for amide coupling, as exemplified herein by the acid derivative (xii) and the amine H2N-X-R2 (xiii), are well-known to the person of ordinary skill in the art, and may be eg. obtained by performing the reaction of acid and amine in the presence of a suitable amide coupling reagent, such as 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU; CAS Registry Number: 148893-10-1) and N,N- diisopropylethylamine in a suitable solvent, such as dichloromethane, or by reacting the acid derivative in the presence of e.g. triethylamine in a suitable solvent, such as chloroform or in the presence of N,7V-diisopropylethylamine in a suitable solvent, such as dichloromethane. A number of other chemical transformations may also be used within the present invention, all which readily could be modified and improved by the one skilled in the art.
Apart from traditional heating, such as the use of heating blocks, heat transfer via oil baths or the like, the present invention also involve the use of microwave irridation for heating purposes, which today is well known for the one skilled in the art, as witnessed by a large number of book chapters and published books [eg. Strauss, C. R., Application of microwaves for environmentally benign organic chemistry, In Handbook of Green Chemistry and Technology, Clark, J.;
Macquarrie, D., Eds. Blackwell Science Ltd: Oxford, 2002, pp 297-415; Kappe, C. O.; Stadler, A. Microwaves in Organic and Medicinal Chemistry, Wiley- VCH, Weinheim, 2005; Watley, B.; Tierney, J.; Lidstrόm, P.; Westman, J. The impact of microwave assisted organic chemistry on drug discovery. Drug Discov. Today, 2002, 7, 373-380].
All reaction mixtures are purified by standard purification procedures as extraction, washing, recrystallization, and column chromatography employing silica gel, aluminia or reverse phase and the like, employing the appropriate eluents for the purification of the Examples described herein.
The compounds of the invention can also be prepared by the application of combinatorical and/or parallell chemistry techniques eg. methods of making libraries of compounds, techniques well known for the one skilled in the art, which can include solution phase synthesis, and solid phase synthesis including design of resins, linkers and the like. For example (Scheme 4), (x) can be saponifϊcated to give the intermediate (xiv) that can serve as a suitable scaffold for further manipulation. It can then be contemplated that JV-alkylation with (v), followed by amide coupling with (xiii) can be conducted in one pot (in the same reaction vessel) if the two reactions are selective in terms of regioselectivity (a term that is well known for the one skilled in the art), which also includes the reverse reaction order eg. amide coupling followed by N-alkylation, or alternatively both reactions acting at the same time. This can lead to compounds of formula (I) of the invention in a shorther time than traditional consecutive synthesis, albeit an approach not excluded from the present invention.
Reaction Scheme 4 N-alkylation
Figure imgf000053_0001
(X) (xiv)
Figure imgf000053_0002
All above is provided when R3 and R4 is the same atom or group. On the other hand, when R3 and R4 is dissimilar, for instance when R3 is methyl and R4 is chlorine, then two tautomeric forms of (ii) will exist as shown in Reaction Scheme 6 (iia and iib). The knowledge of tautomers is well known for the one skilled in the art, and numerous scientific book chapters, reviews and papers have examined various aspects of this phenomenon, [eg. The Chemistry of Heterocyclic Compounds, Benzimidazoles and Cogeneric Tricyclic Compounds (Chemistry of Heterocyclic Compounds: A Series Of Monographs), Preston, P. N. Smith, D. M. and Tennant, G. (Eds), John Wiley & Sons Inc, 1981]. Reaction Scheme 5
Figure imgf000053_0003
(iia) (iib)
Outlined in Reaction Scheme 7 is the one of the synthetic strategies of the invention that involves tautomeric forms of the intermediate compounds. Accordingly, the tautomeric mixture of (iia) and (iib) is treated with a nucleophilic agent, as exemplified by (iii), but not restricted to, then yet two tautomeric compounds (iva) and (ivb) are formed. In the final step an N-alkylating agent (v) is employed and a regioisomeric mixture of end products (I) is formed, which might be tested directly in biological assays. Alternatively, the regioisomers of the mixture can be separated before biological testing, using for instance column chromatography, recrystallization, sublimation or any other methods available for the one skilled in the art of chemical separation. In the present method the final purification can only take palace after the final synthetic step, since all previous intermediates are tautomers. Reaction Scheme 6
Figure imgf000054_0001
(I) (I)
R 1 R '
Alternatively, and also within the scope of the invention, N-alkylation or N-arylation can be introduced at an earlier stage in the synthetic procedure, as exemplified shown in Reaction Scheme 7. This will provide the compounds (xia) and (xib), which already at this stage can be separated using any of the techniques mentioned above. As exemplified in Reaction Scheme 7, this strategy will ultimately lead to the end products (I). This synthetic strategy can, for example, be considered when the final Examples are difficult to separate, or because of any other advantageous reason. Reaction Scheme 7
Figure imgf000055_0001
(xia) (xib)
R1 R'
1 ) saponification ^ saponification
2) amide coupling 2) amide coupling
Figure imgf000055_0002
(I) (I)
R' R'
Furthermore, the invention at hand also comprises a synthetic method that is strictly
regioselective when R4 and R5 are dissimilar. This is outlined in Reaction Scheme 8 and the synthetic strategy involves the introduction of the N-arylating agent (v) at an early stage in the synthesis in order to obtain control over regioselectivity. The ortho-nitroanline (xiv) is arylated at the at the amine to give (xv), the nitro group reduced to the diamine (xvi), ring-closed to the tautomers (xvii) and (xviii) and finally chlorinated to give (xix). The resulting compound (xix) can then be transformed to the appropriate end-product by any of the methods described above.
Reaction Scheme 8 Reduction Ring-closure
Figure imgf000056_0001
R6)m R6),
Figure imgf000056_0002
Figure imgf000056_0003
Chlorination
(CR5R6), (CR5R6), (xix) (CRSR<%
(xvii) (xviii)
R1
In this context it should be understood that when N-alkylation is mentioned in the text or in the Reaction Schemes, then the N-arylation of the available -NH- or -NH2 group is not excluded, but an important aspect of the present invention. Also, when only N-arylation is mentioned, then should neither N-alkylation be excluded.
The present invention also comprises stereoisomers that, for example, are prepared with the available metods described above. A large number of available single enantiomers are available commercially or in the literature. The single enantiomers can be amines that are used in the amide coupling of present invention, such as, but not limited to, (R)-(+)-tetrahydrofuran-3 -amine 4-methylbenzenesulfonate (CAS Registry Number: 111769-27-8), (S)-(-)-tetrahydrofuran-3- amine hydrochloride (CAS Registry Number: 204512-95-8), (lS,2S)-trans-2- aminocyclopentanol hydrochloride (CAS Registry Number: 68327-04-8), (lR,2R)-trans-2- aminocyclopentanol hydrochloride (CAS Registry Number: 68327-11-7).
When Q is sulfonyl, this results in compounds of the invention that are sulfonamides, which can be prepared employing reaction conditions that are very well known from the scientific literature (see for example: "Advanced Organic Chemistry", 4th edition, Jerry March, Wiley-Interscience publication, 1992, p 499). For example, if a suitable substituted piperidine sulfonyl chloride (xv) is reacted with a suitable substituted amine derivative (xiii), a sulfonamide derivative of formula (I) can be formed as shown in Reaction Scheme 9. Reaction Scheme 9
Figure imgf000057_0001
Compounds wherein Q is sulfϊnyl can be prepared using an analogous method as described in Reaction Scheme 9, as well as treatment of sulfonamides with reductive agents, procedures well known for the one skilled in the art.
Alternatively, and within the scope of the invention, (xxii), which includes a protection group PG, is coupled with an amine (xiii) to give the sulphonamide (xxiii), that can be coupled, after de-protection with a suitable halobenzimidazole (ii), and finally N-alkylated or N-arylated with (v) to the end products (I). The synthetic procedure is shown in Reaction Scheme 10.
Reaction Scheme 10
Figure imgf000057_0002
The above methods, as outlined in Schemes 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 are only exemplary and it is contemplated that the skilled person will be able to modify them in view of the particular compound according to formula (I) that is to be prepared, or even to identify other equally suitable methods.
It should be contemplated that several spectroscopic methods are available for the structural determination of regio isomers. For example, when R3 is dissimilar to R4, the Nuclear Overhauser effect (NOE) can be utlilized to determine the exact structure of the Example, since the NOE is observed through space, and not through bonds. Consequently, all atoms that are in proximity to each other give a NOE. For example, and utilized in the present invention, the NMR tequnique NOESY (Nuclear Overhauser Effect Spectroscopy) is used for determination of the nature of the R3 and R4substituents. For example, A NOE effect can be seen between the Ha, Hb and Hc protons in (xxv), and reveals that Hb correlates with both Ha and Hc in the 2-dimensional plot. On the other hand, in (xxvi) Ha and Hd correlates as a pair, as Hb and Hc.
Reaction Scheme 11
Figure imgf000058_0001
The compounds according to formula (I) will be useful for treating various diseases such as inflammatory diseases, nociceptive pain, auto-immune disease, breathing disorders, fever, cancer, inflammation related anorexia, Alzheimer's disease and cardiovascular disease. The treatment may be preventive, palliative or curative. Examples of pharmaceutically acceptable addition salts for use in the pharmaceutical compositions of the present invention include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic acids. The pharmaceutically acceptable excipients described herein, for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public. The pharmaceutically acceptable carrier may be one that is chemically inert to the active compounds and that has no detrimental side effects or toxicity under the conditions of use. Pharmaceutical formulations are found e.g. in Remington: The Science and Practice of Pharmacy, 19th ed., Mack Printing Company, Easton, Pennsylvania (1995).
All stereoisomers of the compounds of the instant invention are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present invention can have asymmetric centers at any of the carbon atoms including any one of the R substitutents. Consequently, compounds of formula (I) can exist in enantiomeric or diasteromeric forms or in mixtures thereof. The processes for preparation can utilize racemates, enantiomers or diasteromers as starting materials. When diastereomeric or enantiomeric products are prepared, they can be separated by conventional methods, which for example is chromatographic or fractional crystallization.
Prodrugs of the compounds of formula (I) may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesizing the parent compound with a prodrug substituent. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, sulfhydryl, carboxy or carbonyl group in a compound of formula (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives, JV-Mannich bases. General information on prodrugs may be found in the scientific literature [eg. Bundegaard, H. "Design of Prodrugs" p 1-92, Elesevier, New York- Oxford, 1985; The Practice of Medicinal Chemistry, Camille G. Wermuth et al., chapter 31, Academic Press, 1996; A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. chapter 5, pgs 113 - 191, Harwood Academic Publishers, 1991). Said references are incorporated herein by reference. All prodrugs of the compounds of the invention are included within the scope of the invention. The compounds of the formula (I) can be administered for any of the uses described herein by any suitable means, for example, orally, such as in the form of tablets, aqueous or oily suspensions or solutions, elexirs, syrups, capsules, granules or powders; sublingually; buccally; ocular; parenterally, such as by subcutaneous, intravenous, intramuscular, or intrasternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions). Also, the compounds of the formula (I) may be applied as gargles and mouth washes. For parenteral administration, a parenterally acceptable aqueous or oily suspension, emulsion or solution is employed, which is pyrogen free and has requisite pH, isotonicity and stability. Those skilled in the art are well able to prepare suitable formulations and numerous methods are described in the literature. A brief review of methods of drug delivery is also found in the scientific literature [eg. Langer, Science 249:1527-1533 (1990)]. Furthermore, the compounds of the formula (I) can be administered nasally, including administration to the nasal membranes, such as by inhalation spray; topically, such as in the form of a gel, cream or ointment; or rectally such as in the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds can also be administered liposomally. The precise nature of the carrier or other material will depend on the route of administration and those skilled in the art are well able to prepare suitable solutions and numerous methods are described in the literature.
Exemplary compositions for oral administration include suspensions which can contain, for example, microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweeteners or flavoring agents such as those known in the art; and immediate release tablets which can contain, for example, microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and/or lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants such as those known in the art. The compounds of formula (I) can also be delivered through the oral cavity by sublingual and/or buccal administration. Molded tablets, compressed tablets or freeze-dried tablets are exemplary forms which may be used. Exemplary compositions include those formulating the present compound(s) with fast dissolving diluents such as mannitol, lactose, sucrose and/or cyclodextrins. Also included in such formulations may be high molecular weight excipients such as celluloses (avicel) or polyethylene glycols (PEG). Such formulations can also include an excipient to aid mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to control release such as polyacrylic copolymer (e.g. Carbopol 934). Lubricants, glidants, flavors, coloring agents and stabilizers may also be added for ease of fabrication and use.
Exemplary compositions for nasal aerosol or inhalation administration include solutions in saline which can contain, for example, benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other solubilizing or dispersing agents such as those known in the art.
Exemplary compositions for parenteral administration include injectable solutions, emulsions or suspensions which can contain, for example, suitable non-toxic, parenterally acceptable diluents or solvents, such as mannitol, 1,3-butanediol, water, Ringer's solution, an isotonic sodium chloride solution, oil or other suitable dispersing or wetting and suspending agents, including synthetic mono- or diglycerides, and fatty acids, including oleic acid, or Cremaphor. Exemplary compositions for rectal administration include suppositories which can contain, for example, a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the drug.
Exemplary compositions for topical administration include a topical carrier such as Plastibase (mineral oil gelled with polyethylene). The dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors including the potency of the specific compound, the age, condition and body weight of the patient, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration, as well as the stage and severity of the disease. The dose will also be determined by the route (administration form), timing and frequency of administration. Oral dosages of the present invention, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01 mg per kg of body weight per day (mg/kg/day) to 20 mg/kg/day, and most preferably 0.1 to 10 mg/kg/day, for adult humans. For oral administration, the compositions are preferably provided in the form of tablets or other forms of presentation provided in discrete units containing 0.5 to 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated, for example 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 200, 400, 500, 600 and 800 mg..
Parenterally, especially intravenously, the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during a constant rate infusion. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be
administered in divided doses of two, three or four times daily. Furthermore, preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen. A nasal, sublingual or buccal administration typically contains from about 0.01 mg to about 500 mg of the active ingredient, preferably from about 1 mg to about 100 mg of active ingredient, per dose.
The compounds of the present invention may be also be used or administered in combination with one or more additional drugs useful in the treatment of inflammatory diseases, nociceptive pain, auto-immune diseases, breathing disorders, fever, cancer, inflammation related anorexia, Alzheimer's disease and cardiovascular diseases. The components may be in the same formulation or in separate formulations for administration simultaneously or sequentially. The compounds of the present invention may also be used or administered in combination with other treatment such as irradiation for the treatment of cancer.
Accordingly, in a further aspect of the invention, there is provided a combination product comprising:
(A) a compound of the invention, as hereinbefore defined; and
(B) another therapeutic agent that is useful in the treatment of inflammatory diseases, nociceptive pain, auto-immune disease, breathing disorders, fever, cancer, inflammation related anorexia, Alzheimer's disease and cardiovascular diseases., wherein each of components (A) and
(B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier. Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).
Thus, there is further provided:
(1) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and
(2) a kit of parts comprising components:
(a) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation including another therapeutic agent in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other. Compounds of the formula (I) will be useful as partial or complete substitute for
cyclooxygenase-2 inhibitors and conventional NSAIDs in preparations wherein they are presently co-administered with other agents or ingredients.
Examples of such agents for the administration in combination with compounds of the invention, include suitable anti-inflammatory, anti-pain, anti-autoimmune, anti-fever, anti-cancer and anti- anorexia (inflammatoriy) agents, and agents for the treatment or prevention of breathing disorders, cardiovascular diseases and Alzheimer's disease, a potentiator including caffeine, an H2 antagonist, aluminium or magnesium hydroxide, simethicone, a decongestant, an antitussive, an antihistamine, a diuretic, a proton pump inhibitor, a bradykinin-1 antagonist, a sodium channel blocker, a 5 -HT agonist or a CGRP antagonist.
More specifically compounds for use in combination with the compounds of the present invention include, but is not limited to, prednisone (CAS Registry Number: 53-03-2);
dexamethasone (CAS Registry Number: 50-02-2); any of the selective glucocorticoid receptor agonists (SEGRAs) exemplified by All 6515 (Lin, C. et al. MoL Pharm., 2002, 62, 297-303), and ZK209614 (Schacke, H. et al, Proc. Natl. Acad. Sci. USA., 2004, 101, 227-232); aspirin (CAS Registry Number: 50-78-2); indomethacin (CAS Registry Number: 53-86-1) particularly dosed as local treatment with gel or spray; ibuprofen (CAS Registry Number: 15687-27-1); piroxicam (CAS Registry Number: 36322-90-4,; CTLA4-Ig agonists/antagonists (Kremer, J. M. et al, N EnglJ Med. 2003, 349, 1907-1915); Inosine-5 '-monophosphate dehydrogenase inhibitors (Whitby, F. G. et al., Biochemistry, 1997, 36, 10666-10674), such as mycophenolate (CAS Registry Number: 24280-93-1); tumor necrosis factor (TNF) antagonists as infliximab (CAS
Registry Number: 170277-31-3); adalimumab (CAS Registry Number: 331731-18-1); etanercept (CAS Registry Number: 185243-69-0) and pentoxifylline (CAS Registry Number: 6493-05-6); orazipone (OR- 1384); integrin antagonists; cell adhesion inhibitors interferon gamma
antagonists; budesonide (CAS Registry Number: 51333-22-3); clofazimine (CAS Registry Number: 2030-63-9); selective thyroid hormone agonists such as GC-I (Johansson, L. et al,Proc. Nαtl. Acαd. Sci. USA. 2005, 102, 10297-10302), KB2115 (Berkenstam, A. et al., Proc. Nαtl Acαd. Sci. USA. 2008, 105, 663-667); KB-141 (Graver, G. J. et al., Proc. Nαtl. Acαd. Sci. USA. 2003, 100, 10067-10072); and MB07811 (Erion, MD et al., Proc. Nαtl. Acαd. Sci. USA. 2007, 104, 15490-15495); selective farnesoid X receptor agonists (FXRs) such as WAY-362450 (Flatt, B. et al., J. Med. Chem. 2009, 52, 904-907); CD4 antagonists such as priliximab (CAS Registry Number: 147191-91-1); p38 mitogen-activated protein kinase inhibitors such as SB203580 (CAS Registry Number: 152121-47-6); mesalazine (CAS Registry Number: 89-57-6); azathioprine (CAS Registry Number: 446-86-6); sumatriptan (CAS Registry Number: 103628- 46-2); paracetamol (CAS Registry Number: 103-90-2); fast-acting bronchodilators such as salbutamol (CAS Registry Number: 18559-94-9) and ephedrine (CAS Registry Number: 299-42- 3); rituximab; NO-releasing drugs such as nitroglycerine (CAS Registry Number: 55-63-0) and isosorbide dinitrate (CAS Registry Number: 87-33-2); Selective Estrogen Receptor Modulators (SERMs) such as tamoxifen (CAS Registry Number: 10540-29-1); raloxifene (CAS Registry Number: 84449-90-1) and toremifene (CAS Registry Number: 89778-26-7); selective Liver X receptor (LXR) agonists such as T0901317 (CAS Registry Number: 293754-55-9, Repa, J. J. et al, Science, 2000, 289, 1524-1529) and GW3965 (CAS Registry Number: 405911-17-3); antidepressant drugs and pain-relivers, such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) such as desvenlafaxine (CAS Registry Number: 93413-62-8); duloxetine (CAS Registry Number:
116539-59-4); milnacipran (CAS Registry Number: 92623-85-3); tramadol (CAS Registry Number: 27203-92-5) and bicifadine (CAS Registry Number: 71195-57-8).
The term "treating" encompasses not only treating a patient to relieve the patient of the signs and symptoms of the disease or condition but also prophylactically treating an asymptomatic patient to prevent the onset or progression of the disease or condition.
The term "patients" include mammalian (including human) patients.
The term "effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated patient. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
The invention is illustrated by the following non-limiting Examples. In connection to these Examples, it should be noted that unless otherwise indicated, the expression "purified on reverse- phase hplc" will mean utilizing a preparative hplc-system comprising the following conditions and equipment: Shimadzu LC8A, C18 column (22 x 250 mm, lOμm), acetonitrile/water gradient (0.1% trifluoroacetic acid), flowrate 15 mL/min.
EXAMPLES Example 1: 7V-cyclopentyl-l-(l-ethyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide
Figure imgf000065_0001
(a) Preparation of the intermediary compound 2-chloro-5,6-dimethyl-lH-benzo[d]imidazole:
Figure imgf000065_0002
To a solution of sodium nitrite (3.77 g, 54.6 mmol) in water (220 mL) was added an aqueous solution of copper(II) chloride (12.24 g, 91.06 mmol, in 160 mL of water) The mixture was stirred at room temperature for 5 minutes and 5,6-dimethyl-lH-benzo[d]imidazol-2-amine (2.936 g, 18.21 mmol) was added to the mixture in portions for 5 minutes. The reaction mixture was stirred at room temperature for 1 hour, heated at 1000C for 1 hour and cooled down. The resulting reaction mixture was extracted with ethyl acetate (3 x300 mL), the combined organic phases washed with brine (200 mL) and dried over anhydrous magnesium sulphate. After concentration in vacuo, the residue was subjected to column chromathography (silica gel, methanol/dichloromethane gradient elution consisting of 1-5% methanol), to give 1.054 g (29 % yield, 90 % purity) of 2-chloro-5,6-dimethyl-lH-benzo[d]imidazole that was used directly in the next step.
(b) Preparation of the intermediary compound iV-cyclopentyl-l-(5,6-dimethyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide:
Figure imgf000065_0003
2-Chloro-5,6-dimethyl-lH-benzo[d]imidazole (3.59 mmol), iV-cyclopentylpiperidine-4- carboxamide (3.95mmol), JV,JV-diisopropylethylamine (Ηunig's base, DIEA, 927.3 mg, 7.18 mmol) and 1,4-dioxane (2 mL) were mixed in a microwave vial and sealed. The reaction mixture was heated at 18O0C in a microwave oven for 1 hour. After cooling down the reaction mixture, the resulting slurry was filtered, the precipitate washed with 1 ,4-dioxane (5 mL) and dried under vacuum over night. This gave 796 mg (65% yield) of N-cyclopentyl-1 -(5,6-dimethyl- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 341.2 (M+l).
(c) Λ/-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (17.0 mg, 0.05 mmol), iodoethane (9.4 mg, 0.06 mmol), caesium carbonate (32.6 mg, O.lmmol) and acetonitrile (2 mL) were mixed and heated at 1000C. After 2 hours additional iodoethane was added and the reaction mixture was continued to be stirred over night at 1000C. After concentration in vacuo, the residue was subjected to column chromatography (Silica gel, methanol/dichloromethane gradient elution 0-10% methanol) to afford 5.4 mg (29% yield) of the title N-cyclopentyl- 1 -( 1 -ethyl-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide. LC-MS (m/z) 369.3 (M+l).
Example 2: 7V-cyclopentyl-l-(5,6-dimethyl-l-propyl-lH-benzo[d]imidazol-2-yl)piperidine- 4-carboxamide
Figure imgf000066_0001
N-cyclopentyl- 1 -(5,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (17.0 mg, 0.05 mmol), 1-iodopropane (17.0 mg, 0.10 mmol), caesium carbonate (48.9 mg, 0.15 mmol) and acetonitrile (2 mL) were mixed and the reaction mixture heated at 1000C over night. After concentration in vacuo, the residue was subjected to column chromathography (Silica gel, methanol/dichloromethane gradient elution 0-10% methanol) to give lO.lmg (53% yield) of N- cyclopentyl- 1 -(5,6-dimethyl- 1 -propyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC- MS (m/z) 383.3 (M+l).
Example 3: l-(l-butyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V-cyclopentylpiperidine-4- carboxamide
Figure imgf000066_0002
l-(l-Butyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (17.0 mg, 0.05 mmol), 1-iodobutane (18.4 mg, 0.1 mmol), caesium carbonate (48.9 mg, 0.15 mmol) and acetonitrile (2 mL), using the method described in Example 2 to give 6.9 mg (36% yield) of the title compound. LC-MS (m/z) 397.3 (M+l).
Example 4: 7V-cyclopentyl-l-(l-heptyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide
Figure imgf000067_0001
N-cyclopentyl-l-(l-heptyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide was prepared fromΛ/-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (17.0 mg, 0.05 mmol), 1-bromo heptane (17.9 mg, 0.10 mmol), caesium carbonate (48.9 mg, 0.15 mmol) and acetonitrile (2 mL), using the method described in Example 2 to give 12.2 mg (56 % yield) of the title compound. LC-MS (m/z) 439.4 (M+l).
Example 5: 7V-cyclopentyl-l-(5,6-dimethyl-l-octyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide
Figure imgf000067_0002
N-cyclopentyl- 1 -(5,6-dimethyl- 1 -octyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide was prepared from N-cyclopentyl- 1 -(5,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (17.0 mg, 0.05 mmol), 1-bromooctane (19.3 mg, 0.1 mmol), caesium carbonate (48.9 mg, 0.15 mmol) and acetonitrile (2 mL), using the method described in Example 2. This gave 8.4 mg (37% yield) of the title compound. LC-MS (m/z) 453.4 (M+l). Example 6: 7V-cyclopentyl-l-(5,6-dimethyl-l-pentyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide
Figure imgf000068_0001
iV-cyclopentyl- 1 -(5,6-dimethyl- 1 -pentyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide was prepared from JV-cyclopentyl-1 -(5,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (17.0 mg, 0.05 mmol), 1-bromopentane (15.1 mg, 0.1 mmol), caesium carbonate (48.9 mg, 0.15 mmol) and acetonitrile (2 mL), using the method described in Example 2 to give 9.2 mg (45 % yield) of the title compound. LC-MS (m/z) 411.4 (M+l).
Example 7: 7V-cyclopentyl-l-(l-hexyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide
Figure imgf000068_0002
Λ/-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (34 mg, 0.10 mmol), 1-chlorohexane (14.5 mg, 16 mL, 0.120 mmol), caesium carbonate (65.2 mg, 0.20 mmol) and acetonitrile (2 mL) were mixed and stirred at 6O0C over night, filtered, concentrated in vacuo and subjected to column chromathography (silica gel, methanol/ dichloromethane gradient elution 3-10 % methanol) to give 4.7 mg (11 %) of iV-cyclopentyl-l-(l-hexyl-5,6- dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide.
Example 8: 7V-cyclopentyl-l-(5,6-dimethyl-l-(pyridin-2-ylmethyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000068_0003
jV-cyclopentyl- 1 -(5,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (17.0 mg, 0.05 mmol), 2-(chloromethyl)pyridine hydrochloride (16.4 mg, 0.1 mmol), caesium carbonate (65.16 mg, 0.3 mmol) and N,Λ/-dimethylformamide (1.0 niL) were mixed in a microwave vial. The vial was sealed and irridated in a microwave oven at 15O0C for 30 minutes. The reaction mixture was concentrated in vacuo and purified on preparative hplc (performed on a Gilson- Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using acetonitrile/water (0.05 % formic acid) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection). This gave 0.7 mg (3 % yield) of JV-cyclopentyl-1- (5,6-dimethyl-l-(pyridin-2-ylmethyl)-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC- MS (m/z) 432.3 (M+ 1).
Example 9: 7V-cyclopentyl-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000069_0001
Λ/-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (356 mg, 1.046 mmol), caesium carbonate (1022 mg, 3.137 mmol), acetonitrile (30 mL), N,N- dimethylformamide (3 mL) and 2-bromopropane (386 mg, 3.14 mmol) were mixed and heated at 6O0C over night. The reaction mixture was filtered, concentrated in vacuo and subjected to column chromatography (silica gel, methanol/dichloromethane, gradient elution using 1-5 % methanol) to give 314 mg (78 %) of N-cyclopentyl-l-(l-isopropyl-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 383.2 (M+ 1).
Example 10: 7V-cyclopentyl-l-(l-(2-(diethylamino)ethyl)-5,6-dichloro-lH-benzo[d]imidazol- 2-yl)piperidine-4-carboxamide
Figure imgf000069_0002
(a) Preparation of the intermediary compound 5,6-dichloro-lH-benzo[d]imidazol-2(3H)-one:
Figure imgf000070_0001
To a stirred solution of 4,5-dichlorobenzene-l,2-diamine (1.0 g, 5.6 mmol) in tetrahydrofuran (10 rnL) was added N,N-carbonyl diimidazole (CDI, 1.36g, 8.4 mmol). The mixture was stirred at room temperature for 8 hours under Argon. The reaction mixture was concentrated in vacuo, the residue partitioned between diethyl ether (60 mL) and aqueous sodium hydroxide (60 mL, 1.0 N). The aqueous extract was acidified to reach a pH of approximately 5 by careful addition of aqueous hydrochloric acid (1.5 N). The resulting off- white solid was filtered off, washed with water (3 χ20 mL) and dried under high vacuum to give 0.68 mg (60 % yield) 5,6-dichloro-lH- benzo[d]imidazol-2(3H)-one. (b) Preparation of the intermediary compound 2,5,6-trichloro-l -benzo[d]imidazole:
Figure imgf000070_0002
To 5,6-dichloro-lH-benzo[d]imidazol-2(3H)-one (1.0 g, 4.5 mmol) was added phosphoryl trichloride (4 mL) and the reaction mixture was heated in a screw-cap pressure tube at 12O0C for 2 hours. The reaction mixture was concentrated in vacuo, the residue was diluted with water (30 mL) and the resulting off-white solid was filtered off. The precipitate was washed with water (3x20 mL) and dried under high vacuum to afford 0.77 g (71 % yield) of 2,5,6-trichloro-lH- benzo[d]imidazole.
(c) Preparation of the intermediary compound N-cyclopentyl-l-(5,6-dichloro-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide:
Figure imgf000070_0003
To a suspension of 2,5,6-trichloro-lH-benzo[d]imidazole (Ig, 4.5mmol) in 1,4-dioxane (5 mL) was added iV,jV-diisopropylethylamine (Ηunig's base, DIEA, 0.094 mL, 5.4 mmol) followed by N-cyclopentylpiperidine-4-carboxamide. The mixture was heated in a screw cap pressure tube at 18O0C for 2 hours. The reaction mixture was concentrated in vacuo, the residue washed with water and filtered off to afford 1.1 g (65 % yield) of N-cyclopentyl-l-(5,6-dichloro-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 381.3 (M+l).
(d) To a suspension of sodium hydride (0.021 g, 0.52 mmol) in N,Λ/-dimethylformamide (0.5 rnL) was added N-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (0.10 g, 0.26 mmol) in N,Λ/-dimethylformamide (0.5 mL) drop-wise at O0C under Nitrogen. The reaction mixture was stirred at room temperature for 30 min and 2-bromo-N,N- diethylethylamine (0.101 g, 0.39 mmol) was added drop-wise. The reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was quenched with ice-water and extracted with ethyl acetate (2 x 15 mL). The combined organic phases were washed with water (3 x 15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel) to obtain 12 mg (9.6 % yield) of N-cyclopentyl- l-(l-(2-(diethylamino)ethyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 480.3 (M+l).
Example 11: 7V-cyclopentyl-l-(5,6-dichloro-l-(pyridin-4-ylmethyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000071_0001
To a suspension of sodium hydride (0.021 g, 0.52 mmol) in N,Λ/-dimethylformamide (0.5 mL) was added Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (0.10 g, 0.26mmol) in Λ/,iV-dimethylformamide (0.5 mL) drop-wise at O0C under nitrogen gas. The reaction mixture was stirred at room temperature for 30 minutes and 4-
(bromomethyl)pyridine hydrochloride (110 mg, 0.46 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours, quenched with ice and extracted with ethyl acetate (2 x15 mL). The combined organic phases were washed with water (3χ 15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to preparative reverse-phase hplc to afford 81 mg (74 %) of Λ/-cyclopentyl-l-(5,6-dichloro-l-(pyridin-4- ylmethyl)-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 472.1 (M+l).
Example 12: 7V-cyclopentyl-l-(5,6-dichloro-l-(pyridin-3-ylmethyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000072_0001
N-cyclopentyl- 1 -(5,6-dichloro- 1 -(pyridin-3-ylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide was prepared from sodium hydride (72 mg, 0.30 mmol) in N,Λ/-dimethylformamide (2 mL), Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (80 mg, 0.20 mmol) in N,Λ/-dimethylformamide (2 mL) and 3 -bromo methyl pyridinium
hydrobromide (0.063g, 0.25mmol), using the method described in Example 11 to give 5 mg (5 % yield) of the title compound. LC-MS (m/z) 472.3 (M+l).
Example 13: 7V-cyclopentyl-l-(5,6-dichloro-l-(pyridin-2-ylmethyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000072_0002
N-cyclopentyl- 1 -(5,6-dichloro- 1 -(pyridin-2-ylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide was prepared from sodium hydride (72 mg, 0.30 mmol) in N,Λ/-dimethylformamide (2 mL), Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (80 mg, 0.20 mmol) in N,Λ/-dimethylformamide (2 mL) and 2-bromomethyl pyridinium
hydrobromide (0.063g, 0.25mmol), using the method described in Example 11 to give 5 mg (5 % yield) of the title compound. LC-MS (m/z) 472.2 (M+l).
Example 14: l-(l-sec-butyl-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide
Figure imgf000072_0003
To a solution of Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (0.10 g, 0.26 mmol) in N,Λ/-dimethylformamide (0.5 mL) caesium carbonate (0.33 g, 1.0 mmol) and dichloro-bis(triphenylphosphine)palladium (II) (Pd(PPh3)2Cl2, (0.019 g, 0.026 mmol) were added, followed by 2-bromobutane (0.07 mL, 0.46 mmol). The resulting reaction mixture was subjected to microwave irradiation for 45 min at 12O0C. The reaction mixture was concentrated in vacuo, the solid residue filtered off, washed with ethyl acetate and the filtrate extracted with ethyl acetate (2 x 15 mL). The combined organic phases were washed with water (3 x 15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to column chromatography (silica gel) to give 81 mg (74 % yield) of l-(l-sec-butyl- 5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide. LC-MS (m/z) 437.5 (M+l). Example 15: 7V-cyclopentyl-l-(5,6-dichloro-l-(pentan-3-yl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000073_0001
To a solution of Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (0.10 g, 0.26 mmol) in N,Λ/-dimethylformamide (0.5 mL) caesium carbonate (0.33g, 1 mmol) and [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), 1.0 mg, 0.0026 mmol) were added, followed by 3-bromopentane (59 mg, 0.39 mmol). The reaction mixture was heated at 12O0C for 12 hours, concentrated in vacuo and the residue extracted with ethyl acetate (2 x15 mL). The combined organic phases were washed with water (3 x 15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to column chromatography (silica gel) to give 10 mg (17%) of N-cyclopentyl-l-(5,6- dichloro- 1 -(pentan-3-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 451.3 (M+l).
Example 16: 7V-cyclopentyl-l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000073_0002
To a solution of Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (0.050 g, 0.13 mmol) in N,Λ/-dimethylformamide (0.5 niL) caesium carbonate (169 mg, 0.52 mmol) and [l,r-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), 1.0 mg, 0.0013 mmol) were added, followed by cyclobutyl bromide (26 mg, 0.19 mmol). The reaction mixture was heated at 1000C for 12 hours, concentrated in vacuo and the residue extracted with ethyl acetate (2 x 15 mL). The combined organic phases were washed with water (3 x 15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to column chromatography (silica gel) to give 31 mg (54 %) of N-cyclopentyl-l-(5,6- dichloro-1 -cyclobutyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 435.3 (M+l).
Example 17: 7V-cyclopentyl-l-(5,6-dichloro-l-(l-phenylethyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000074_0001
To a suspension of sodium hydride (0.01 Ig, 0.46 mmol) in N,Λ/-dimethylformamide (0.5 mL) was added Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (100 mg, 0.26 mmol) in N,Λ/-dimethylformamide (0.5 mL) drop-wise at O0C under nitrogen gas. The reaction mixture was stirred at room temperature for 30 min, 2-bromoethylbenzene (57 mg, 0.31 mmol) was added in portions and stirred at room temperature for 16 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate (2xl5mL). The collected organic phases were washed with water (3χ 15mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel) to obtain 8 mg (6 % yield) of N-cyclopentyl-l-(5,6-dichloro-l-(l-phenylethyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide. LC-MS (m/z) 485.3 (M+l).
Example 18 : 7V-cyclopentyl- l-(5,6-dichloro- 1-methyl- lH-benzo [d] imidazol-2-yl)piperidine- 4-carboxamide
Figure imgf000074_0002
jV-cyclopentyl- 1 -(5 ,6-dichloro- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (10 mg, 0.026 mmol), caesium carbonate (25.6 mg, 0.079 mmol), acetonitrile (2 mL), N, N- dimethylformamide (0.5 mL), iodomethane (5.6 mg, 0.039 mmol) were mixed and stirred at room temperature over night. The reaction mixture was filtered, cooncentrated in vacuo and subjected to preparative hplc (performed on a Gilson-Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using acetonitrile/water (0.05 % formaldehyde) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 1.9 mg (18 %) of the title compound. LC-MS (m/z) 395.2 (M+ 1).
Example 19: 7V-cyclopentyl-l-(5,6-dichloro-l-ethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide
Figure imgf000075_0001
N-cyclopentyl- 1 -(5,6-dichloro- 1 -ethyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide was prepared from Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (10 mg, 0.026 mmol), caesium carbonate (25.6 mg, 0.079 mmol), acetonitrile (2 mL), Λ/,Λ/-dimethylformamide (0.5 mL), iodoethane (6.1 mg, 0.039 mmol) using the method described in Example 18 to give 5.4 mg (50 % yield) of the title compound. LC-MS (m/z) 409.2 (M+l).
Example 20: 7V-cyclopentyl-l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000075_0002
N-cyclopentyl- 1 -(5,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide was prepared from Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (10 mg, 0.026 mmol), caesium carbonate (25.6 mg, 0.079 mmol), acetonitrile (2 mL), Λ/,Λ/-dimethylformamide (0.5 mL), 2-bromopropane (9.7 mg, 0.079 mmol) using the method described in Example 18 to give 5.0 mg (45 % yield) of the title compound. LC-MS (m/z) 423.2 (M+l). Example 21: 7V-cyclopentyl-l-(5,6-dichloro-l-(4-fluorobenzyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000076_0001
N-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-fluorobenzyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide was prepared from Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (10 mg, 0.026 mmol), caesium carbonate (25.6 mg, 0.079 mmol), acetonitrile (2 mL), N,Λ/-dimethylformamide (0.5 mL), l-(bromomethyl)-4-fluorobenzene (4.96 mg, 0.026 mmol) using the method described in Example 18 to give 4.2 mg (33 % yield) of the title compound. LC-MS (m/z) 489.2 (M+ 1). Example 22: 7V-cyclopentyl-l-(l-(3,5-difluorobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000076_0002
Λ/-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (20 mg, 0.059 mmol), caesium carbonate (57.4 mg, 0.176 mmol), N,Λ/-dimethylformamide (4 mL), 1- (bromomethyl)-3,5-difluorobenzene (15.2 mg, 0.073 mmol) was stirred at room temperature for 3-4 hours. The reaction mixture was filtered, the filtrate concentrated in vacuo and subjected to column chromatography (Silica gel, methanol/dichloromethane, gradient elution 1-15 % methanol) to give 14.2 mg (52 % yield) of N-cyclopentyl-l-(l-(3,5-difluorobenzyl)-5,6- dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 467.3 (M+l). Example 23: methyl 4-((2-(4-(cyclopentylcarbamoyl)piperidin-l-yl)-5,6-dimethyl-lH- benzo[d]imidazol-l-yl)methyl)benzoate
Figure imgf000077_0001
Methyl 4-((2-(4-(cyclopentylcarbamoyl)piperidin- 1 -yl)-5,6-dimethyl- lH-benzo[d]imidazol- 1 - yl)methyl)benzoate was prepared from Λ/-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (20 mg, 0.059 mmol), caesium carbonate (57.4 mg, 0.176 mmol), Λ/,Λ/-dimethylfbrmamide (4 mL), methyl 4-(bromomethyl)benzoate (16.8 mg, 0.073 mmol) using the method described in Example 22 to give 20.4 mg (71 % yield) of the title compound. LC-MS (m/z) 489.3 (M+l).
Example 24: 7V-cyclopentyl-l-(5,6-dimethyl-l-((2-methylthiazol-4-yl)methyl)- IH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000077_0002
Λ/-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (20 mg, 0.059 mmol), caesium carbonate (76.6 mg, 0.235 mmol), N,Λ/-dimethylformamide (2 mL) and 4- (chloromethyl)-2-methylthiazole hydrochloride (16.2 mg, 0.088 mmol) were mixed in a microwave vial and irridated in a microwave oven at 6O0C for 1 hour and then at 1000C over night. The reaction mixture was filtered, concentrated in vacuo and subjected to preparative hplc (performed on a Gilson-Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using acetonitrile/water (0.05% ΗCOOΗ) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 3.1 mg (12 % yield) of N-cyclopentyl- 1 -(5,6-dimethyl- 1 -((2-methylthiazol-4-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide. LC-MS (m/z) 452.3 (M+l).
Example 25: 7V-cyclopentyl-l-(5,6-dichloro-l-phenyl-lH-benzo[d]imidazol-2-yl)piperidine- 4-carboxamide
Figure imgf000078_0001
To a solution of Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (0.1 g, 0.26 mmol) in dimethylsulfoxide (1 niL) was added caesium carbonate (119 mg, 0.36 mmol), followed by bromobenzene (0.033 mL, 0.31 mmol), 1,10-phenanthroline (9 mg, 0.39 mmol), polyethylene glycol (294 mg) and copper(I) oxide (1.8 mg, 0.013 mmol). The reaction mixture was refluxed at 1100C for 24 hours, quenched with water and extracted with ethyl acetate (2 x15 mL). The combined organic phases were washed with water (3 x15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to column chromatography (silica gel) to give 5 mg (4 % yield) of N-cyclopentyl-l-(5,6-dichloro-l- phenyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 457.3 (M+ 1).
Example 26: 7V-cyclopropyl-l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000078_0002
(a) Preparation of the intermediary compound ethyl l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylate
Figure imgf000078_0003
To a suspension of 2,5,6-trichloro-lH-benzo[d]imidazole (2.8 g, 12.6 mmol) in 1,4-dioxane (15 mL) was added Λ/,Λ/-diisopropylethylamine (Ηunig's base, DIEA, 6.5 mL, 38 mmol) followed by ethyl piperidine-4-carboxylate (2.38 g, 15 mmol), and the reaction mixture was heated in a screw cap pressure tube at 18O0C for 2 hours. The reaction mixture was concentrated in vacuo, the residue formed washed with water and filtered off to give 2.5 g (58 % yield) of ethyl l-(5,6- dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate as an off-white solid. (b) Preparation of the intermediary compound l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylic acid
Figure imgf000079_0001
Ethyl l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (2.5 g), aqueous sodium hydroxide (10 mL, IN) and ethanol (20 mL) was stirred for 5 hours at room temperature. The reaction mixture was concentrated in vacuo, the residue partitioned between water and ethyl acetate and the aqueous layer acidified with aqueous hydrochloric acid (1.5 N) to neutral pΗ. The precipitate was filtered off and dried in air to give 2.3 g (99 % yield) of l-(5,6-dichloro-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid as a brown solid. (c) Preparation of the intermediary compound N-cyclopropyl- 1 -(5 ,6-dichloro- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide:
Figure imgf000079_0002
To a solution of l-(5,6-dichloro-lH-benzoimidazol-2-yl)-piperidine-4-carboxylic acid (0.05 g, 0.16 mmol) in N,Λ/-dimethylformamide (2 mL) was added 2-(7-Aza-lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 91 mg, 0.24 mmol) followed by N,N- diisopropylethylamine (Ηunig's base, DIEA, 0.04 mL, 0.32 mmol) and cyclopropylamine (0.13 mL, 0.19 mmol). The reaction mixture was stirred at room temperature for 5 hours, concentrated in vacuo and extracted with ethyl acetate (2 x20 mL). The combined organic phases were dried over anhydrous sodium sulphate and finally recrystallized from dichloromethane/n-hexane to give 10 mg (18 % yield) of N-cyclopropyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine- 4-carboxamide. LC-MS (m/z) 353.3 (M+l).
(d) N-cyclopropyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (0.09 g, 0.25 mmol) was dissolved in N,Λ/-dimethylformamide (1 mL). Caesium carbonate (332 mg, 1 mmol) and isopropyl bromide (56 mg, 0.45 mmol) were added, and the reaction mixture irradiated under microwave conditions at 1200C for 60 minutes. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (2 x25 mL). The combined organic phases were washed with water (5 x25 mL), once with brine and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo and the residue subjected to column chromatography (silica gel, chloroform/methanol 99:1), to give 25 mg (12 % yield) of N- cyclopropyl- 1 -(5,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a light yellow solid. LC-MS (m/z) 395.3 (M+l).
Example 27: 7V-cyclobutyl-l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000080_0001
(a) Preparation of the intermediary compound N-cyclo butyl- 1 -(5,6-dichloro- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide:
Figure imgf000080_0002
N-cyclobutyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide was prepared from 1 -(5,6-dichloro- lH-benzoimidazol-2-yl)-piperidine-4-carboxylic acid (0.05 g, 0.16 mmol), Λ/,Λ/-dimethylformamide (2 mL), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 91 mg, 0.24 mmol), Λ/,Λ/-diisopropylethylamine (Ηunig's base, DIEA, 0.04 mL, 0.32 mmol) and cyclobutylamine (0.16 mL, 0.19 mmol), using the method described in Example 26(c) to give 43 mg of N-cyclobutyl-1 -(5,6-dichloro- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 367.3 (M+l).
(b) N-cyclo butyl- 1 -(5,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide was prepared from N-cyclobutyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.28g, 0.76mmol), N,Λ/-dimethylformamide (3 mL), caesium carbonate (0.99 g, 3 mmol) and isopropyl bromide (168 mg, 1.3 mmol) using the method described in Example 26(d) to give 61 mg (20 % yield) of the title compound as a light yellow solid. LC-MS (m/z) 409.5 (M+l).
Example 28: l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-7V-propylpiperidine-4- carboxamide
Figure imgf000081_0001
(a) Preparation of the intermediary compound l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- propylpiperidine-4-carboxamide :
Figure imgf000081_0002
l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-propylpiperidine-4-carboxamide was prepared from l-(5,6-dichloro-lH-benzoimidazol-2-yl)-piperidine-4-carboxylic acid (0.07 g, 0.22 mmol), N,Λ/-dimethylformamide (4 mL), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 127 mg, 0.33 mmol), JV,JV-diisopropylethylamine (Ηunig's base, DIEA, 0.052 mL, 0.45 mmol) and propan-1 -amine (0.27 mmol), using the method described in Example 26(c) to give 10 mg (13 % yield) of l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- propylpiperidine-4-carboxamide. LC-MS (m/z) 355.3 (M+ 1).
(b) 1 -(5 ,6-Dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)-N-propylpiperidine-4-carboxamide was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-propylpiperidine-4- carboxamide (0.05 g, 0.14 mmol), N,Λ/-dimethylformamide (1 mL), caesium carbonate (0.19 g, 0.58 mmol) and isopropyl bromide (26 mg, 0.21 mmol), using the method described in Example 26(d) to give 10 mg (17 % yield) of the title compound as a light yellow solid. LC-MS (m/z) 397.2 (M+l).
Example 29: l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-7V-(2- methoxyethyl)piperidine-4-carboxamide
Figure imgf000081_0003
(a) Preparation of the intermediary compound l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-(2- methoxyethyl)piperidine-4-carboxamide:
Figure imgf000082_0001
To a solution of l-(5,6-dichloro-lH-benzoimidazol-2-yl)-piperidine-4-carboxylic acid (0.07 g, 0.22 mmol) in N,N-dimethylformamide (2 niL) was added 2-(7-Aza-lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 0.127 g, 0.33 mmol) followed by N5N- diisopropylethylamine (Ηunig's base, DIEA, 0.052 mL, 0.44 mmol) and 2-methoxy-ethylamine (0.0198g, 0.24 mmol). The reaction mixture was stirred at room temperature for 5 hours, concentrated in vacuo and extracted with ethyl acetate (2 x50 mL). The combined organic phases were dried over anhydrous sodium sulphate and recrystallized from ethyl acetate/n-hexane to give 20 mg (24 % yield) of l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-(2- methoxyethyl)piperidine-4-carboxamide . LC-MS (m/z) 371.2 (M+ 1 ) .
(b) l-(5,6-Dichloro-lH-benzo[d]imidazol-2-yl)-N-(2-methoxyethyl)piperidine-4-carboxamide (0.1 g, 0.27 mmol) was dissolved in N,N-dimethylformamide (4 mL). Caesium carbonate (0.527 mg, 1.6 mmol) and isopropyl bromide (66 mg, 0.54 mmol) were added, and the reaction mixture irradiated under microwave conditions at 1200C for 60 minutes. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (2 x25 mL). The combined organic phases were washed with water (5 x25 mL), once with brine and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo and the residue recrystallized from ethyl acetate and n-hexane to give 20 mg (18 % yield) of 1 -(5, 6-dichloro-l -isopropyl- IH- benzo[d]imidazol-2-yl)-Ν-(2-methoxyethyl)piperidine-4-carboxamide. LC-MS (m/z) 413.3 (M+l).
Example 30: l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-JV- (isopropoxymethyl)piperidine-4-carboxamide
Figure imgf000082_0002
(a) Preparation of the intermediary compound l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-(2- isopropoxyethyl)piperidine-4-carboxamide:
Figure imgf000083_0001
l-(5,6-Dichloro-lH-benzo[d]imidazol-2-yl)-N-(2-isopropoxyethyl)piperidine-4-carboxamide was prepared from l-(5,6-dichloro-lH-benzoimidazol-2-yl)-piperidine-4-carboxylic acid (0.3 g, 0.95 mmol) in N,N-dimethylformamide (5 mL), 2-(7-aza-lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (ΗATU, 0.544 g, 1.4 mmol), N5N- diisopropylethylamine (Ηunig's base, DIEA, 0.33 mL, 1.9 mmol) and 2-isopropoxyethanamine (0.118 g, 1.1 mmol), using the method described for Example 29(a) to give 0.35 g (92% yield) of l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-(2-isopropoxyethyl)piperidine-4-carboxamide. LC-MS (m/z) 399.2 (M+l). (b) 1 -(5 ,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)-N-(2-isopropoxyethyl)piperidine-4- carboxamide was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-(2- isopropoxyethyl)piperidine-4-carboxamide (0.1 g, 0.25 mmol), N,N-dimethylformamide (1 mL), caesium carbonate (0.5 g, 1.5 mmol) and isopropyl bromide (55 mg, 0.45 mmol) using the method described in Example 29(b) to give 60 mg (18 % yield) of the title compound as a light yellow solid. LC-MS (m/z) 441.3 (M+l). 1H ΝMR (300 MHz, DMSO-d6) δ 7.84 (s, IH), 7.66 (s, IH), 4.54 (m, IH), 3.53 (m, IH), 3.47-3.28 (m, 4H), 3.18 (dd, 2H), 2.89 (dd, 2H), 2.36 (m, IH), 1.79 (m, 4H), 1.51 (d, 6H), 1.09 (d, 6H).
Example 31: l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-iV-(tetrahydrofuran-3- yl)piperidine-4-carboxamide
Figure imgf000083_0002
(a) Preparation of the intermediary compound l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000083_0003
To a solution of l-(5,6-dichloro-lH-benzoimidazol-2-yl)-piperidine-4-carboxylic acid (0.3 g, 0.95 mmol) in N,Λ/-dimethylformamide (5 niL) was added 2-(7-aza-lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 0.544 g, 1.4 mmol) followed by N,N- diisopropylethylamine (Ηunig's base, DIEA, 0.33 mL, 1.9 mmol) and tetrahydrofuran-3 -amine (0.1 g, 1.1 mmol). The reaction mixture was stirred at room temperature for 5 hours,
concentrated in vacuo and extracted with ethyl acetate (2 x50 mL). The combined organic phases were dried over anhydrous sodium sulphate and subjected to column chromatography
(chloroform/methanol 95:5) to give 0.135 g (37 % yield) of l-(5,6-dichloro-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 383.2 (M+l).
(b) l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide (0.1 g, 0.25 mmol) was dissolved in N,Λ/-dimethylformamide (1 mL). Caesium carbonate (0.5 g, 1.5 mmol) and isopropyl bromide (60 mg, 0.46 mmol) were added, and the reaction mixture irradiated under microwave conditions at 1200C for 60 minutes. The reaction mixture was quenched with water (2 mL) and extracted with ethyl acetate (2 x25 mL). The combined organic phases were washed with water (5 x25 mL), once with brine and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo to give 75 mg (68 % yield) of 1 -(5,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide. LC-MS (m/z) 425.3 (M+l).
Example 32 : TV-(cyclohexylmethyl)- l-(5,6-dichloro- 1-isopropyl- lH-benzo [d] imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000084_0001
(a) Preparation of the intermediary compound N-(cyclohexylmethyl)- 1 -(5 ,6-dichloro- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide:
Figure imgf000085_0001
(a) To a solution of l-(5,6-dichloro-lH-benzoimidazol-2-yl)-piperidine-4-carboxylic acid (0.07 g, 0.22 mmol) in N,Λ/-dimethylformamide (2 niL) was added 2-(7-aza-lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 0.127 g, 0.33 mmol) followed by N,N- diisopropylethylamine (Ηunig's base, DIEA, 0.05 mL, 0.44 mmol) and cyclohexylmethanamine (0.049 g, 0.44 mmol). The reaction mixture was stirred at room temperature for 5 hours, quenced with water to give a precipitate that was filtered off, washed with water and dried in air, to give 0.1 g (76 %) yield of N-(cyclohexylmethyl)-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 409.3 (M+l). (b) N-(cyclohexylmethyl)- 1 -(5,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide was prepared from N-(cyclohexylmethyl)-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.15 g, 0.36 mmol), N,Λ/-dimethylformamide (3 mL), caesium carbonate (0.716 g, 2.2 mmol) and isopropyl bromide (0.09 g, 0.72 mmol) using the method described in Example 29(b) to give 20 mg (12 % yield) of the title compound. LC-MS (m/z) 451.4 (M+l).
Example 33: l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-7V-((tetrahydro-2H- pyran-4-yl)methyl)piperidine-4-carboxamide
Figure imgf000085_0002
(a) Preparation of the intermediary compound l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- ((tetrahydro-2H-pyran-4-yl)methyl)piperidine-4-carboxamide.
Figure imgf000085_0003
To a solution of l-(5,6-dichloro-lH-benzoimidazol-2-yl)-piperidine-4-carboxylic acid (0.3 g, 0.95 mmol) in N,Λ/-dimethylformamide (2 niL) was added 2-(7-aza-lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 0.544 g, 1.4 mmol) followed by N,N- diisopropylethylamine (Ηunig's base, DIEA, 0.33 mL, 1.9 mmol) and (tetrahydro-2H-pyran-4- yl)methanamine (0.131 g, 1.1 mmol) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, the residue partionated between water and ethyl acetate (1:3), the organic phase washed with brine and dried over anhydrous sodium sulphate. The organic phase was filtered and the filtrate concentrated in vacuo to give 0.13 g (79 %) of l-(5,6- dichloro-lH-benzo[d]imidazol-2-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-4- carboxamide. LC-MS (m/z) 411.3 (M+l).
(b) 1 -(5 ,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)-N-((tetrahydro-2H-pyran-4- yl)methyl)piperidine-4-carboxamide was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)piperidine-4-carboxamide (0.09 g, 0.19 mmol), N,N- dimethylformamide (1 mL), caesium carbonate (0.38 g, 1.1 mmol) and isopropyl bromide (43 mg, 0.35 mmol) using the method described in Example 26(d) to give 20 mg (7 % yield) of the title compound. LC-MS (m/z) 453.3 (M+l).
Example 34: 7V-butyl-l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide
Figure imgf000086_0001
(a) The the intermediary compound l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylic acid was prepared in a similar way as described in Example 101.
(b) l-(5,6-Dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (0.05 g, 0.16 mmol) was treated with 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 0.96 g, 0.25 mmol) in N,Λ/-dimethylformamide (Im L) followed by Λ/,Λ/-diisopropylethylamine (Ηunig's base, DIEA, 0.05 mL, 0.32 mmol), and butan-1-amine (0.18 mL, 0.19 mmol). The reaction mixture was stirred at room temperature for 4 hours, quenched with with water (1 mL), extracted with ethyl acetate (2 x20 mL), washed once with brine (1OmL) and dried over anhydrous sodium sulfate. The organic phase was filtered, the filtrate concentrated in vacuo and subjected to column chromatography (silica gel, chloroform/methanol 98:2) to give 20 mg (29 % yield) of iV-butyl-l-(5,6-dichloro-l-isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 411.4 (M+l).
Example 35 : 7V-(cy clopentylm ethyl)- l-(5,6-dichloro- 1-isopropyl- lH-benzo [d] imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000087_0001
l-(5,6-Dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (0.15 g, 0.42 mmol) was treated with 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 0.24g, 0.63mmol) in N,Λ/-dimethylformamide (2 mL) followed by Λ/,Λ/-diisopropylethylamine (Ηunig's base, DIEA, 0.14 mL, 0.84 mmol), and
cyclopentylmethanamine hydrochloride (0.069 mL, 0.5 mmol). The reaction mixture was stirred at room temperature for 12 hours, quenched with water (1 mL), extracted with ethyl acetate (2 x20 mL), washed with brine (10 mL) and dried over anhydrous sodium sulfate. The organic phase was concentrated in vacuo, recrystallized with petroleum ether to give to give 0.02 g (11 % yield) of N-(cyclopentylmethyl)-l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 437.3 (M+l).
Example 36: 7V-cyclopentyl-l-(l-((6-fluoropyridin-3-yl)methyl)-5,6-dimethyl-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000087_0002
To a solution of Λ/-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (0.06 g,0.14 mmol), N,Λ/-dimethylformamide (2mL) was added caesium carbonate (0.255 g, 0.87 mmol) followed by 5-(bromomethyl)-2-fluoropyridine (0.04 g, 0.26 mmol). The reaction mixture was irradiated under microwave conditions at 12O0C for 1 hour. The reaction mixture was concentrated in vacuo and residue was extracted with ethyl acetate (2x15 mL). The combined organic phases were washed with water (3x 15 mL), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to column chromatography (silica gel, 1 % chloroform/methanol, 99:1) to give 5 mg (6 % yield) of Λ/-cyclopentyl-l-(l-((6-fluoropyridin-3- yl)methyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 450.1 (M+l).
Example 37: l-(l-(4-cyanobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide
Figure imgf000088_0001
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.29 mmol), N,Λ/-dimethylformamide (2 mL), caesium carbonate (0.566 g, 1.7 mmol) and 4-(bromomethyl)benzonitrile (0.103 g, 0.52 mmol), using the method described in Example 36 to give 0.08 g (62 % yield) of l-(l-(4-cyanobenzyl)-5,6- dimethyl-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as a white solid. LC-MS (m/z) 456.2 (M+l). Example 38: 7V-cyclopentyl-l-(l-(cyclopropylmethyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000088_0002
To a solution of N-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (0.08 g, 0.23 mmol) in N,Λ/-dimethylformamide (3 mL) cesium carbonate (0.459 g, 1.4 mmol) was added, followed by (bromomethyl)cyclopropane (0.037 g, 0.276 mmol). The reaction mixture was irradiated under microwave conditions at 12O0C for 45 minutes. The reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2 x 15 mL). The combined organic phases were washed with water (3><15 mL), dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized to give 0.05 g (54 %) ofN-cyclopentyl-l-(l-(cyclopropylmethyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine- 4-carboxamide as an orange solid. LC-MS (m/z) 395.3 (M+l).
Example 39: 7V-cyclopentyl-l-(5,6-dimethyl-l-((tetrahydrofuran-2-yl)methyl)-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000089_0001
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.29 mmol), Λ/,Λ/-dimethylformamide (2 mL), caesium carbonate (0.566 g, 1.7 mmol) and 2-(bromomethyl)tetrahydrofuran (0.08 g, 0.52 mmol), using the method described in Example 36, to give 11 mg (9 % yield) of N-cyclopentyl-l-(5,6- dimethyl- 1 -((tetrahydrofuran-2-yl)methyl)- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 425.2 (M+l).
Example 40: l-(l-(4-(lH-l,2,4-triazol-l-yl)benzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)- 7V-cyclopentylpiperidine-4-carboxamide
Figure imgf000089_0002
The title compound was prepared from N-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.29 mmol), N,7V-dimethylformamide (2 mL), caesium carbonate (0.566 g, 1.7 mmol) and l-(4-(bromomethyl)phenyl)-lH-l,2,4-triazole (0.1 g, 0.52 mmol), using the method described in Example 36, to give 28 mg (19 % yield) of 1-(1-(4-(1H- l,2,4-triazol-l-yl)benzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4- carboxamide as an off-white solid. LC-MS (m/z) 498.0 (M+l).
Example 41: l-(l-cyclobutyl-5,6-dimethyl-l//-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide
Figure imgf000090_0001
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.29 mmol), N,Λ/-dimethylformamide (2 mL), caesium carbonate (0.566 g, 1.7 mmol) and cyclobutylbromide (0.07 g, 0.527 mmol), using the method described in Example 36, to give 9 mg (8 % yield) of l-(l-cyclobutyl-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 395.2 (M+l).
Example 42: l-(l-(4-bromobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide
Figure imgf000090_0002
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.9 g, 2.6 mmol), N,Λ/-dimethylformamide (5 mL), caesium carbonate (5 g, 15.6 mmol) and l-bromo-4-(bromomethyl)benzene (1.18 g, 4.7 mmol), using the method described in Example 36, to give 0.5 g (38 % yield) of l-(l-(4-bromobenzyl)-5,6- dimethyl- lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 509.6 (M+l).
Example 43: 7V-cyclopentyl-l-(5,6-dimethyl-l-(4-(methylcarbamoyl)benzyl)-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000091_0001
A reaction mixture consisting of l-(l-(4-bromobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)-N-cyclopentylpiperidine-4-carboxamide (0.1 g, 0.19 mmol), £ra/?s-di(μ-acetato)-bis[o-(di-o- tolylphosphino)-benzyl]dipalladium(II) (Hermann palladacycle, 0.089 g, 0.095 mmol), N5N- diisopropylethylamine (Hunig's base, DIEA, 0.07 mL, 0.39 mmol), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU, 0.19 mmol), tri tertiarybutyl phosphonium
hexafluoborate ([(t-Bu)sPH]BF4, 5.5 mg, 0.019 mmol), molybdenum hexacarbonyl (Mo(CO)6, 0.025 g, 0.095 mmol) and methyl amine hydrochloride (0.1 mg, 1.52 mmol) in 1,4-dioxane (3 mL), was irradiated under microwave conditions at 1500C for 30 minutes. The reaction mixture was quenched with water (5 mL), extracted with dichloro methane (2 x50 mL) and the combined organic phases dried over anhydrous sodium sulphate. After concentration in vacuo, the residue was subjected to column chromatography (basic aluminia, chloroform/methanol 99:1) to give 45 mg (50 % yield) of N-cyclopentyl-l-(5,6-dimethyl-l-(4-(methylcarbamoyl)benzyl)-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 488.1 (M+l). Example 44: 7V-cyclopentyl-l-(l-(4-(dimethylcarbamoyl)benzyl)-5,6-dimethyl-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000091_0002
The title compound was prepared from l-(l-(4-bromobenzyl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide (0.1 g, 0.19 mmol), trans-di(μ- acetato)-bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II) (Hermann palladacycle, 0.089 g, 0.095 mmol), N,N-diisopropylethylamine (Hunig's base, 0.07 mL, 0.39 mmol), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU, 0.028 mL, 0.19 mmol), tri tertiarybutyl phosphonium hexafluoborate ([(t-Bu)3PH]BF4, 0.0055 g, 0.019 mmol), molybdenum hexacarbonyl (Mo(CO)6, 0.025 g, 0.095 mmol), dimethyl amine hydrochloride (0.1 g, 1.23 mmol) and 1,4-dioxane (3mL), using the method described in Example 43, to give 5 mg (5.5 % yield) of N-cyclopentyl-l-(l-(4- (dimethylcarbamoyl)benzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 502.1 (M+ 1).
Example 45: l-(l-(4-carbamoylbenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide
Figure imgf000092_0001
To a solution of l-(l-(4-bromobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide (0.1 g, 0.29 mmol) in N,Λ/-dimethylformamide (0.5 mL) was added caesium carbonate (0.566 g, 1.7 mmol), followed by 4-(bromomethyl)benzamide (0.112 g, 0.52 mmol, which was prepared from 4-(bromomethyl)benzoic acid by reaction with thionyl chloride (SOCl2) and quenching the formed acid chloride with aqueous ammonia (28 %)). The resulting mixture was irradiated under microwave conditions at 1200C for 45 min. The reaction mixture was concentrated in vacuo, the residue extracted with ethyl acetate (2 x15 mL), the combined organic phases washed with water (3χ15mL) and dried over anhydrous sodium sulphate. This gave 3.6 g (2.6 % yield) of l-(l-(4-carbamoylbenzyl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as a white solid. LC-MS (m/z) 474.1 (M+l). Example 46: 7V-cyclopentyl-l-(5,6-dimethyl-l-(4-(methylsulfonylcarbamoyl)benzyl)-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000093_0001
l-(l-(4-bromobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4- carboxamide (O.lg, 0.19mmol), £rans-di(μ-acetato)-bis[o-(di-o-tolylphosphino)- benzyl]dipalladium(II) (Hermann palladacycle, 0.089 g, 0.095 mmol), N5N- diisopropylethylamine (Hunig's base, DIEA, 0.07 niL, 0.39 mmol), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU, 0.028 mL, 0.19 mmol) tri tertiarybutyl phosphonium hexafluoborate ([(t-Bu)3PH]BF4, 5.5 mg, 0.019 mmol), molybdenum hexacarbonyl (Mo(CO)6, 0.025 g, 0.095 mmol), methane sulfonamide (0.037 g, 0.39 mmol) and 1,4-dioxane (3 mL) was irradiated under microwave conditions at 1500C for 30 minutes. The reaction mixture was quenched with water (5 mL) and extracted with dichloro methane (2 x50 mL), the combined organic phases dried over anhydrous sodium sulfate and subjected to column chromatography (basic alumina, chloroform/methanol 99:1) to give 36 mg (33 % yield) of N-cyclopentyl-l-(5,6- dimethyl- 1 -(4-(methylsulfonylcarbamoyl)benzyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide as a white solid. LC-MS (m/z) 552.0 (M+ 1).
Example 47: l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-iV-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide
Figure imgf000093_0002
(a) Preparation of the intermediary compound tert-butyi 4-(tetrahydrofuran-3- ylcarbamoyl)piperidine- 1 -carboxylate.
Figure imgf000094_0001
To a solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.0 g, 4.37 mmol) in dry dichloromethane (10 rnL), cooled to 0 0C, was added JV,JV-diisopropylethylamine (Hunig's base, DIEA, 8.7 mmol), Λ/-(3-Dimethylaminopropyl)-Λf'-ethylcarbodiimide hydrochloride (EDCΗC1, CAS Registry Number: 25952-53-8, 8.7 mmol), 1-hydroxybenzotriazole (HOBt, CAS Registry Number: 2592-95-2, 2.2 mmol) and tetrahydrofuran-3 -amine hydrochloride (5.2 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 10 hours. The reaction mixture was washed with aqueous hydrochloric acid (3 x15 mL, 2N), saturated aqueous sodium bicarbonate (2 x15 mL), dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was recrystallized from dichloro methane/pet ether to give 1.15 g (88%) of tert-butyl 4-(tetrahydrofuran-3-ylcarbamoyl)piperidine-l-carboxylate.
(b) Preparation of the intermediary compound 4-(tetrahydrofuran-3-ylcarbamoyl)piperidinium 2,2,2-trifluoroacetate:
Figure imgf000094_0002
To a solution of tert-butyl 4-(tetrahydrofuran-3-ylcarbamoyl)piperidine-l-carboxylate (1.0 g, 3.36 mmol) in dichloromethane (10 mL), cooled to 0 0C, was added 2,2,2-trifluoroacetic acid (8.4 mmol). The reaction was allowed to warm to room temperature and stirred for 16 hours. The mixture was concentrated in vacuo (repeated co-evaporation with toluene), and dried under vacuum to give 4-(tetrahydrofuran-3-ylcarbamoyl)piperidinium 2,2,2-trifluoroacetate in quantitative yield.
(c) Preparation of the intermediary compound l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-JV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide.
Figure imgf000094_0003
To a suspension of 2-chloro-5,6-dimethyl-lH-benzo[d]imidazole (0.3 g, 1.6 mmol) in 1,4- dioxane (5 mL), 4-(tetrahydrofuran-3-ylcarbamoyl)piperidinium 2,2,2-trifluoroacetate (0.38 g, 1.9 mmol) in 1,4-dioxane (3 mL) was added. Λ/,Λ/-diisopropylethylamine (Ηunig's base, DIEA 0.89 mL, 5.0 mmol) was added and the reaction mixture was heated in a sealed tube at 18O0C for 3 hours. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulphate and subjected to column chromatography (silica gel,
chloroform/methanol 95:5), to give 0.12 g (18 % yield) of l-(5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid.
(d) To a solution of l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide (0.05 g, 0.14 mmol) in N,Λ/-dimethylformamide (2 mL) was added caesium carbonate (0.285 g, 0.87 mmol), followed by cyclobutylbromide (0.02 mL, 0.21 mmol).
The reaction mixture was irradiated under microwave conditions at 12O0C for 1 hour, concentrated in vacuo and extracted with ethyl acetate (2><15mL). The combined organic phases were washed with water (3 ><15 mL), dried over anhydrous sodium sulfate and subjected to column chromatography (silica gel, chloroform/methanol 97.5:2.5) to give 6 mg (10 % yield) of l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a brown solid. LC-MS (m/z) 397.2 (M+ 1).
Example 48: l-(l-(4-fluorobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000095_0001
To a solution of l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide (0.05 g, 0.14 mmol) in N,Λ/-dimethylformamide (2 mL) was added caesium carbonate (0.285 g, 0.87 mmol), followed by l-(bromomethyl)-4-fluorobenzene (0.032 mL, 0.17 mmol). The reaction mixture was irradiated under microwave conditions at 12O0C for 1 hour, concentrated in vacuo and extracted with ethyl acetate (2><15mL). The combined organic phases were washed with water (3 ><15 mL), dried over anhydrous sodium sulfate and recrystallized with dichloromethane and n-hexane to give 0.01 g (15 % yield) of l-(l-(4- fluorobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a yellow solid. LC-MS (m/z) 451.1 (M+l). Example 49: l-(5-chloro-l-cyclobutyl-6-methyl-lH-benzo[d]imidazol-2-yl)-7V-cyclopentyl- piperidine-4-carboxamide and l-(6-chloro-l-cyclobutyl-5-methyl-lH-benzo[d]imidazol-2- yl)-7V-cyclopentylpiperidine-4-carboxamide
Figure imgf000096_0001
(a) Preparation of the intermediate compound 5-chloro-6-methyl-lH-benzo[d]imidazol-2(3Η)- one:
Figure imgf000096_0002
To a stirred solution of 4-chloro-5-methylbenzene-l,2-diamine (0.3 g, 1.9 mmol) in
tetrahydrofuran (5 mL) was added JV,iV-carbonyl dimidazole (CDI, 0.465 g, 2.8 mmol). The reaction mixture was stirred at room temperature for 3 hours under Argon gas, concentrated in vacuo and the residue partitioned between ethyl acetate (50 mL) and aqueous sodium hydroxide (50 mL, IN). The aqueous extract was acidified to pH 5 via addition of aqueous hydrochloric acid (1.57V) and the resulting brown precipitate was filtered, washed with water (3χ20mL) and dried under high vacuum to obtain 0.28 g (80 % yield) of 5-chloro-6-methyl-lH- benzo[d]imidazol-2(3H)-one.
(b) Preparation of the intermediate compound 2,5-dichloro-6-methyl-lH-benzo[d]imidazole:
Figure imgf000096_0003
To 5-chloro-6-methyl-lH-benzo[d]imidazol-2(3H)-one (0.25 g), phosphoryl trichloride (POCI3, 4 mL) was added, the reaction mixture was heated in a screw cap pressure tube at 12O0C for 2 hours and concentrated in vacuo. The residue was neutralized with sodium hydroxide, the resulting off-pale yellow solid was filtered, washed with water (3χ50 mL) and dried under high vacuum to give 0.27 g (98 % yield) of 2,5-dichloro-6-methyl-lH-benzo[d]imidazole. (c) Preparation of the intermediary compound tert-butyl 4-(cyclopentylcarbamoyl)piperidine-l- carboxylate.
M
Figure imgf000097_0001
To a mixture consisting of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (6.4 g, 27.9 mmol), dry dichloromethane (66 mL), triethylamine (4.24 g, 41.9 mmol) was carefully added thionyl chloride (3.99 g, 33.5 mmol) in 16 mL dry dichloromethane. The reaction mixture was stirred for 20 minutes at room temperature, cyclopentanamine (5.94 g, 69.8 mmol) was added and the reaction mixture was heated at reflux over night under nitrogen gas. The reaction mixture was washed with aqueous hydrochloric acid (3 x60 mL, 2N), saturated aqueous sodium bicarbonate (2 x60 mL), dried over magnesium sulphate, filtered and the filtrate concentrated in vacuo. The residue was dried under vacuum to give 5.859 g of tert-butyl 4- (cyclopentylcarbamoyl)piperidine-l-carboxylate. LC-MS (m/z) 297.3 (M+l).
(d) Preparation of the intermediary compound 4-(cyclopentylcarbamoyl)piperidine:
Figure imgf000097_0002
tert-EvΛy\ 4-(cyclopentylcarbamoyl)piperidine-l-carboxylate (5.859 g, 19.77 mmol), 2,2,2- trifluoroacetic acid (22.54 g, 197.66 mmol) and dichloromethane (70 mL) was stirred at room temperature. The reaction mixture was concentrated in vacuo (co-evaporation with toluene), dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The aqueous phase was concentrated in vacuo, the residue extracted with dichloromethane to give 3.21 g (83 % yield) of 4-(cyclopentylcarbamoyl)piperidine.
(e) Preparation of the intermediate compound l-(6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)- JV-cyclopentylpiperidine-4-carboxamide:
Figure imgf000097_0003
To a suspension of 2,5-dichloro-6-methyl-lH-benzo[d]imidazole (0.1 g, 0.49 mmol) in 1,4- dioxane (4 niL), 4-(cyclopentylcarbamoyl)piperidine (0.185 g) in 1,4-dioxane (2 niL) was added N,Λ/-diisopropylethylamine (Ηunig's base, DIEA, 0.25 mL, 1.4 mmol) and heated at 18O0C for 3 hours. The reaction mixture was concentrated in vacuo, partitioned between ethyl acetate (15 mL) and water (15 mL). The aqueous phase was extracted with ethyl acetate, the combined organic phases dried over anhydrous sodium sulphate and subjected to chromatography (silica gel, chloroform/methanol 98:2) to give 46 mg (26 % yield) of l-(6-chloro-5-methyl-lH- benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4-carboxamide. LC-MS (m/z) 361.2 (M+l).
(f) To a solution of l-(6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine- 4-carboxamide (0.1 g, 0.27 mmol) in N,Λ/-dimethylformamide (2 mL), caesium carbonate (0.541 g, 1.6 mmol) was added, followed by cyclobutylbromide (0.032 mL, 0.33 mmol) and [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf) in catalytic amounts. The reaction mixture was irradiated under microwave conditions at 12O0C for 1 hour, concentrated in vacuo and the residue extracted with ethyl acetate (2x15mL). The combined organic phases were washed with water (3χ 15mL), dried over anhydrous sodium sulphate, concentrated in vacuo and subjected to column chromatography (silica gel, chloroform/methanol 98:2) to give 13 mg (11 %) of a 1 :1 mixture of l-(5-chloro-l -cyclobutyl-6-methyl- lH-benzo[d]imidazol-2-yl)-JV- cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro- 1 -cyclobutyl-5 -methyl- IH- benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4-carboxamide in a mixture as a yellow solid. LC-MS (m/z) 415.3 (M+l).
Example 50 : 7V-cyclopentyl- l-(5,6-dichloro- 1-cyclopentyl- lH-benzo [d] imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000098_0001
To a solution of Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (100 mg, 0.26 mmol) in N,Λ/-dimethylformamide (0.5 mL) was added caesium carbonate (500 mg, 1.53 mmol), followed by cyclopentylbromide (70 mg, 0.46 mmol). The reaction mixture was irradiated under microwave conditions at 1200C for 60 minutes, concentrated in vacuo and the residue extracted with ethyl acetate (2x15 mL). The combined organic phases were washed with water (3><15 mL), dried over anhydrous sodium sulfate concentrated in vacuo. The residue was subjected to column chromathography (silica gel) to give 75 mg (64 % yield) Λ/-cyclopentyl-l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 449.3 (M+ 1).
Example 51: l-(l-(4-bromobenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide
Figure imgf000099_0001
l-(l-(4-bromobenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4- carboxamide was prepared from Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (100 mg, 0.26 mmol) in N,Λ/-dimethylformamide (0.5 mL), caesium carbonate (512 mg, 1.57 mmol) and l-bromo-4-(bromomethyl)benzene (120 mg, 0.47 mmol), using the method described in Example 50 to give 60 mg (41 % yield) of the title compound. LC-MS (m/z) 550.6 (M+l).
Example 52: 7V-cyclopentyl-l-(5,6-dichloro-l-((6-fluoropyridin-3-yl)methyl)-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000099_0002
To a solution of l-(5,6-dichloro-lH-benzoimidazole-2-yl)-piperdine-4-carboxylic acid cyclopentylamide (60 mg, 0.16 mmol) in N,Λ/-dimethylformamide (0.5 mL) was added caesium carbonate (300 mg, 0.94 mmol), followed by 2-fluoro-5-bromomethylpyridine (36 mg, 0.19 mmol). The reaction mixture was irradiated under microwave conditions at 1200C for 45 minutes, concentrated in vacuo and the residue extracted with ethyl acetate (2 x15 mL). The combined organic phases were washed with water (3 x15 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was subjected to column chromatography (silica gel) to give 20 mg (26 %) N-cyclopentyl-l-(5,6-dichloro-l-((6-fluoropyridin-3-yl)methyl)-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 490.3 (M+l).
Example 53: 7V-cyclopentyl-l-(5,6-dichloro-l-(4-cyanobenzyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000100_0001
N-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-cyanobenzyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide was prepared from Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (50 mg, 0.13 mmol), N,Λ/-dimethylformamide (0.5 mL), caesium carbonate (171 mg, 0.52 mmol) and 4-(bromomethyl)benzonitrile (31 mg, 0.15 mmol), using the method described in Example 52 to give 20 mg (15 % yield) of the title compound. LC-MS (m/z) 496.2 (M+l).
Example 54: 7V-cyclopentyl-l-(5,6-dichloro-l-(cyclopropylmethyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000100_0002
N-cyclopentyl- 1 -(5,6-dichloro- 1 -(cyclopropylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide was prepared from Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (100 mg, 0.26 mmol), N,Λ/-dimethylformamide (0.5 mL), caesium carbonate (512 mg, 1.5 mmol) and (bromomethyl)cyclopropane (43 mg, 0.32 mmol), using the method described in Example 52 to give 19 mg (17 % yield) of the title compound. LC-MS (m/z) 435.3 (M+l).
Example 55: 7V-cyclopentyl-l-(5,6-dichloro-l-((tetrahydrofuran-2-yl)methyl)-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000101_0001
To a solution of Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (100 mg, 0.26mmol) in N,N-dimethylformamide (0.5 niL) was added cesium carbonate (512 mg, 1.5 mmol), followed by 2-(bromomethyl)tetrahydrofuran (77 mg, 0.47 mmol). The reaction mixture was irradiated under microwave conditions at 12O0C for 45 min, concentrated in vacuo and the residue extracted with ethyl acetate (2 x15 mL). The combined organic phases were washed with water (3 x15 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was washed with n-hexane to afford 50 mg (41 % yield) of N-cyclopentyl- 1 -(5,6-dichloro- 1 -((tetrahydrofuran-2-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide. LC-MS (m/z) 465.2 (M+ 1).
Example 56: 7V-cyclopentyl-l-(5,6-dichloro-l-((tetrahydro-2H-pyran-4-yl)methyl)-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000101_0002
N-cyclopentyl- 1 -(5,6-dichloro- 1 -((tetrahydro-2H-pyran-4-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide was prepared from N-cyclopentyl- 1 -(5 ,6-dichloro- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide (100 mg, 0.26 mmol), N,N-dimethylformamide (0.5 mL), caesium carbonate (512 mg, 1.5 mmol), and 4-(bromomethyl)tetrahydro-2H-pyran (80 mg, 0.47 mmol), using the method described in Example 55 to give 70 mg (57 % yield) of the title compound. LC-MS (m/z) 479.3 (M+l). Example 57: 7V-cyclopentyl-l-(5,6-dichloro-l-(4-(methylcarbamoyl)benzyl)-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000102_0001
A reaction mixture consisting of l-(l-(4-bromobenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)- N-cyclopentylpiperidine-4-carboxamide (Example 51, 100 mg, 0.182 mmol), trans-di(μ- acetato)-bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II) (Hermann palladacycle, 9 mg, 0.009 mmol), Λ/,Λ/-diisopropylethylamine (Hunig's base, DIEA, 0.06 mL, 0.36 mmol), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU, 0.028 mL, 1.82 mmol), tri tertiarybutyl phosphonium hexafluoborate ([(t-Bu)sPH]BF4, 5 mg, 0.018 mmol), molybdenum hexacarbonyl (Mo(CO)6, 0.024 g, 0.09 mmol) and methyl amine (25 mg, 0.36 mmol) in 1,4-dioxane, was irradiated under microwave conditions at 15O0C for 30 minutes. The reaction mixture was quenched with water (5 mL), extracted with dichloro methane (2 x50 mL) and the combined organic phases dried over anhydrous sodium sulphate. After concentration in vacuo, the residue was subjected to column chromatography (basic aluminia, chloroform/methanol 96:4) to give 12 mg (12 % yield) of N- cyclopentyl- 1 -(5 ,6-dichloro- 1 -(4-(methylcarbamoyl)benzyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 528.4 (M+l). Example 58: 7V-cyclopentyl-l-(5,6-dichloro-l-(4-(dimethylcarbamoyl)benzyl)-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000102_0002
jV-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-(dimethylcarbamoyl)benzyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide was prepared from l-(l-(4-bromobenzyl)-5,6-dichloro-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide (Example 51, 100 mg, 0.182 mmol), trα/?5-di(μ-acetato)-bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II) (Hermann palladacycle, 9 mg, 0.009 mmol), Λ/,Λ/-diisopropylethylamine (Hunig's base, DIEA, 0.06 mL, 0.36 mmol), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.028 mL, 1.82 mmol), tri tertiarybutyl phosphonium tetrafluoborate [(t-Bu)sPH]BF4 (0.005g, 0.018mmol), molybdenum hexacarbonyl (Mo(CO)6, 24 mg, 0.09 mmol), dimethyl amine (0.029g, 0.36mmol) and 1,4-dioxane, using the method described for Example 57 to give 22 mg (22 % yield) of the title compound. LC-MS (m/z) 542.3 (M+l). Example 59: l-(l-(4-carbamoylbenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide
Figure imgf000103_0001
To a solution of l-(5,6-dichloro-lH-benzoimidazole-2-yl)-piperdine-4-carboxylic acid cyclopentylamide (50 mg, 0.13 mmol) in N,Λ/-dimethylformamide (0.5 mL) was added caesium carbonate (260 mg, 0.28 mmol), followed by 4-(bromomethyl)benzamide (34 mg, 0.15 mmol, that was prepared from 4-(bromomethyl)benzoic acid by reacting with thionyl chloride (SOCl2) and quenching the resulting acid chloride with aqueous ammonia (28 %)). The reaction mixture was irradiated under microwave conditions at 12O0C for 45 minutes and concentrated in vacuo. The residue was extracted with ethyl acetate (2 x15 mL), the collected organic phases washed with water (3 x15 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to afford 20 mg (30 % yield) of l-(l-(4-carbamoylbenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2- yl)-N-cyclopentylpiperidine-4-carboxamide as a white solid. LC-MS (m/z) 514.6 (M+l).
Example 60: 7V-cyclopentyl-l-(l-cyclopentyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000103_0002
Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (20 mg, 0.059 mmol), caesium carbonate (76.6 mg, 0.235 mmol), N,Λ/-dimethylformamide (4 mL) and bromocyclopentane (4.96 mg, 0.026 mmol) were mixed in a microwave vial and irridated in a microwave oven at 600C over night. The reaction mixture was filtered, concentrated in vacuo and subjected to preparative hplc (performed on a Gilson-Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using acetonitrile/water (0.05% HCOOH) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 3.6 mg (15 %) of the title compound. LC-MS (m/z) 409.3 (M+ 1).
Example 61: l-(l-(4-chlorobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-iV- cyclopentylpiperidine-4-carboxamide
Figure imgf000104_0001
l-(l-(4-chlorobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4- carboxamide was prepared from N-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (20 mg, 0.059 mmol), caesium carbonate (57.4 mg, 0.176 mmol), N,N-dimethylformamide (4 mL), l-chloro-4-(chloromethyl)benzene (11.8 mg, 0.073 mmol) using the method described in Example 60 to give 9.9 mg (27 % yield) of the title compound. LC-MS (m/z) 465.3 (M+l). Example 62: l-(l-(4-(lH-tetrazol-5-yl)benzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide
Figure imgf000104_0002
N-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-cyanobenzyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (Example 53, 50 mg, 0.1 mmol), sodium azide (78 mg, 1.2 mmol), ammonium chloride (64 mg, 1.2 mmol), lithium chloride (catalytic amount) was refluxed in N5N- dimethylformamide (3 mL) for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate (2 x25 mL), the organic phase was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo, to give 15 mg (28 % yield) of l-(l-(4-(lH-tetrazol- 5-yl)benzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as a white solid. LC-MS (m/z) 539.3 (M+l).
Example 63: 7V-cyclopentyl-l-(5,6-dichloro-l-(4-(methylsulfonylcarbamoyl)benzyl)-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000105_0001
(l-(l-(4-Bromobenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4- carboxamide) (Example 51, 0.1 g, 0.182 mmol), £rαns-di(μ-acetato)-bis[o-(di-o-tolylphosphino)- benzyl]dipalladium(II) (Hermann palladacycle, 9 mg, 0.009 mmol), Λ/,Λ/-diisopropylethylamine (Hύnig's base, DIEA, 0.06 mL, 0.36 mmol), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.028 mL, 1.82 mmol), tri tertiarybutyl phosphonium hexafluoborate [(t-Bu)sPH]BF4 (5 mg, 0.018 mmol), molybdenum hexacarbonyl (Mo(CO)6, 24 mg, 0.09 mmol), methane sulfonamide (34 mg, 0.36 mmol) and 1,4-dioxane was irradiated under microwave conditions at 15O0C for 30 minutes. The reaction mixture was quenched with water (5 mL), extracted with dichloromethane (2 x50 mL), the combined organic phases dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (basic aluminia,
chloroform/methanol 96:4) to give 80 mg (74 % yield) of N-cyclopentyl-l-(5,6-dichloro-l-(4- (methylsulfonylcarbamoyl)benzyl)- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 592.4 (M+l). Example 64: 7V-butyl-l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide
Figure imgf000105_0002
(a) Preparation of the intermediate compound N-butyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide:
Figure imgf000106_0001
To a suspension of 2,5,6-trichloro-lH-benzo[d]imidazole (0.3 g, 1.35 mmol) in 1,4-dioxane (6 mL) was added Λ/,Λ/-diisopropylethylamine (Ηunig's base, DIEA, 0.67 mL, 4.0 mmol) followed by N-butylpiperidine-4-carboxamide (0.3 g, 1.6 mmol). The reaction mixture was heated in a sealed tube at 18O0C for 3 hours, concentrated in vacuo, the residue washed with water and filtered off to give 0.3 g (60 %) of N-butyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 369.5 (M+l).
(b) To a solution of Λ/-butyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (0.3 g, 0.81 mmol) in N,Λ/-dimethylformamide (2 mL) was added caesium carbonate (0.79 g, 2.4 mmol), followed by cyclobutylbromide (0.164 mL, 1.2 mmol). The reaction mixture was irradiated under microwave conditions at 12O0C for 45 minutes, concentrated in vacuo and the residue extracted with ethyl acetate (2 x15 mL). The combined organic phases were washed with water (3 x15 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was subjected to column chromatography (silica gel, chloroform/methanol 98:2) to give 0.09 g (26 % yield) of iV-butyl-l-(5,6-dichloro-l-cyclobutyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 423.3 (M+l).
Example 65: 7V-butyl-l-(5,6-dichloro-l-pentyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide
Figure imgf000106_0002
To a solution of N-butyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (0.1 g, 0.27 mmol) in N,Λ/-dimethylformamide (2 niL) was added caesium carbonate (0.527 g, 1.6 mmol), followed by 1-bromopentane (0.035 mL, 0.32 mmol). The resulting reaction mixture was irradiated under microwave conditions at 12O0C for lhour, concentrated in vacuo and the residue extracted with ethyl acetate (2 x15 mL). The combined organic phases were washed with water (3 x15 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was recrystallized from dichloromethane and n-hexane to give 17 mg (16 % yield) of N-butyl-1- (5,6-dichloro-l-pentyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 439.4 (M+ 1). Example 66: 7V-butyl-l-(5,6-dichloro-l-(4-fluorobenzyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000107_0001
The title compound was prepared fromN-butyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.27 mmol), N,Λ/-dimethylformamide (2 mL), caesium carbonate (0.527 g, 1.6 mmol) and l-(bromomethyl)-4-fluorobenzene (0.164 mL, 1.2 mmol) using the method described in Example 64(b), to give 0.02 g (16 % yield) of iV-butyl-l-(5,6- dichloro-l-(4-fluorobenzyl)-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a off-white solid. LC-MS (m/z) 411.2 (M+l).
Example 67: 7V-butyl-l-(5,6-dichloro-l-((6-fluoropyridin-3-yl)methyl)- IH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000107_0002
The title compound was prepared fromN-butyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.27 mmol), N,Λ/-dimethylformamide (2 mL), caesium carbonate (0.527 g, 1.6 mmol) and 5-(bromomethyl)-2-fluoropyridine (0.092 g, 0.48 mmol) using the method described in Example 64(b), to give 2 mg (1.5 % yield) of N-butyl-l-(5,6- dichloro- 1 -((6-fluoropyridin-3-yl)methyl)- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a off-white solid. LC-MS (m/z) 478.3 (M+ 1).
Example 68: l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3- yl)piperidine-4-carboxamide
Figure imgf000108_0001
(a) Preparation of the intermediary compound l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide:
Figure imgf000108_0002
To a suspension of 2,5,6-trichloro-lH-benzo[d]imidazole (0.3 g, 1.36 mmol) in 1,4-dioxane (6 mL) was added Λ/,Λ/-diisopropylethylamine (Ηunig's base, DIEA, 0.36 mL, 2.0 mmol) followed by Λ/-(tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.636 g, 2.0 mmol) and the reaction mixture was heated in a sealed tube at 18O0C for 3 hours. The reaction mixture was concentrated in vacuo, the residue washed with water and filtered off, to give 0.14 g (26 % yield) of l-(5,6- dichloro- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 383.1 (M+l).
(b) The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-JV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.05 g, 0.13 mmol), N,Λ/-dimethylformamide (2 mL), caesium carbonate (0.254 g, 0.78 mmol) and cyclobutylbromide(0.025 mL, 0.26 mmol) using the method described in Example 64(b), to give 0.011 g (19 % yield) of l-(5,6-dichloro-l- cyclo butyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 437.4 (M+l). Example 69: l-(5,6-dichloro-l-pentyl-lH-benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3- yl)piperidine-4-carboxamide
Figure imgf000109_0001
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.1 g, 0.26 mmol), N,Λ/-dimethylformamide (2 mL), caesium carbonate (0.508 g, 1.56 mmol) and 1-bromopentane (0.033 mL, 0.31mmol) using the method described in Example 64(b), to give 17 mg (14 % yield) of l-(5,6-dichloro-l-pentyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 453.3 (M+ 1). Example 70: l-(5,6-dichloro-l-(4-cyanobenzyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000109_0002
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.1 g, 0.26 mmol), N,Λ/-dimethylformamide (2 mL), caesium carbonate (0.508 g, 1.56 mmol) and 4-(bromomethyl)benzonitrile (0.062 g, 0.31 mmol) using the method described in Example 64(b), to give 13 mg (10 % yield) of l-(5,6- dichloro- 1 -(4-cyanobenzyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a white solid. LC-MS (m/z) 498.1 (M+l).
Example 71: l-(5,6-dichloro-l-(cyclopropylmethyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000110_0001
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-JV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.1 g, 0.26 mmol), N,Λ/-dimethylformamide (2 mL), caesium carbonate (0.508 g, 1.56 mmol) and (bromomethyl)cyclopropane (0.031 mL, 0.31 mmol) using the method described in Example 64(b), to give 14 mg (11 % yield) of l-(5,6- dichloro- 1 -(cyclopropylmethyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine- 4-carboxamide as an off-white solid. LC-MS (m/z) 437.2 (M+ 1).
Example 72: l-(5,6-dichloro-l-((6-fluoropyridin-3-yl)methyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000110_0002
To a solution of N-butyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (0.1 g, 0.26 mmol) in N,Λ/-dimethylformamide (2 mL) was added caesium carbonate (0.508 g, 1.56 mmol), followed by 5-(bromomethyl)-2-fluoropyridine (0.059 mL, 0.31 mmol). The reaction mixture was irradiated under microwave conditions at 12O0C for 45 minutes, concentrated in vacuo and the residue extracted with ethyl acetate (2 x15 mL). The combined organic phases were washed with water (3 x15 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was subjected to column chromatography (silica gel, chloroform/methanol 97:3) to give 25 mg (19 % yield) of l-(5,6-dichloro-l-((6-fluoropyridin-3- yl)methyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 492.5 (M+l).
Example 73: 7V-cyclopentyl-l-(5,6-dimethyl-l-((tetrahydro-2H-pyran-4-yl)methyl)-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000111_0001
To a solution of N-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (0.1 g, 0.29 mmol) in N,Λ/-dimethylformamide (2 niL) was added caesium carbonate (0.566 g, 1.7 mmol), followed by 4-(bromomethyl)tetrahydro-2H-pyran (0.08 g, 0.52 mmol). The reaction mixture was irradiated under microwave conditions at 12O0C for 1 hour, concentrated in vacuo and the residue extracted with ethyl acetate (2 x15 mL). The combined organic phases were washed with water (3 x15 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was subjected to column chromatography (silica gel, chloroform/methanol 99:1) to give 0.043 g (33.5 % yield) ofN-cyclopentyl-l-(5,6-dimethyl-l- ((tetrahydro-2H-pyran-4-yl)methyl)-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 439.2 (M+l).
Example 74: l-(5,6-dichloro-l-cyclopentyl-lH-benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide
Figure imgf000111_0002
To a solution of l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine- 4-carboxamide (0.1 g, 0.26 mmol) in N,Λ/-dimethylformamide (2 mL) was added caesium carbonate (0.508 g, 1.56 mmol), followed by cyclopentylbromide (0.046 mL, 0.31 mmol). The resulting reaction mixture was irradiated under microwave conditions at 12O0C for 45 minutes, concentrated in vacuo and the residue extracted with ethyl acetate (2 x15 mL). The combined organic phases were washed with water (3 x15 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was recrystallized from dichloro methane and n-hexane to give 0.02 g (17 % yield) of l-(5,6-dichloro-l-cyclopentyl-lH-benzo[d]imidazol-2-yl)-Λ/- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 451.3 (M+l). Example 75: l-(l-(4-bromobenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000112_0001
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.1 g, 0.26 mmol), N,Λ/-dimethylformamide (2 mL), caesium carbonate (0.508 g, 1.56 mmol) and l-bromo-4-(bromomethyl)benzene (0.078 g, 0.31 mmol) using the method described in Example 74, to give 22 mg (15 % yield) of l-(l-(4- bromobenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a white solid. LC-MS (m/z) 552.5 (M+l). 1U NMR (300.1 MHz, DMSO-d6) δ 8.04 (s, IH), 7.67 (s, IH), 7.54 (d, 2H), 7.53 (s, IH), 5.29 (s, 2H), 4.21 (m, IH), 3.70 (m, 2H), 3.53 (m, 2H), 2.91 (m, 2H), 2.05 (m, IH), 1.70 (m).
Example 76: 7V-cyclopentyl-l-(5,6-dimethyl-l-phenyl-lH-benzo[d]imidazol-2-yl)piperidine- 4-carboxamide
Figure imgf000112_0002
To a solution of N-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (0.3 g, 0.87 mmol) in dimethylsulfoxide (2 mL) was added caesium carbonate (0.4 g, 1.2 mmol), followed by bromobenzene (0.011 mL, 1.0 mmol), 1,10-phenanthroline (0.031 g, 0.13 mmol), polyethylene glycol (0.882 g) and copper(I) oxide (0.006 g, 0.043 mmol). The reaction mixture was refluxed at 12O0C for 24 hours, quenched with water and extracted with ethyl acetate (3 x 15 mL). The combined organic phases were washed with water (3 x 15 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was subjected to column chromatography (silica gel, chloroform/methanol 99.5:0.5) to give 5 mg of N- cyclopentyl- 1 -(5,6-dimethyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC- MS (m/z) 417.1 (M+l).
I l l Example 77: l-(l-(4-(lH-tetrazol-5-yl)benzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide
Figure imgf000113_0001
l-(l-(4-Cyanobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4- carboxamide (Example 37, 0.06 g, 0.13 mmol), sodium azide (0.102 g, 1.5 mmol), ammonium chloride (0.08 g, 1.5 mmol), lithium chloride (catalytic amount) was refluxed in N5N- dimethylformamide (2 mL) for 1 hour. The reaction mixture was quenched with water and extracted with ethyl acetate (2 x25 mL), the organic phase was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo, to give 0.016 g (25 % yield) of l-(l-(4-(lH-tetrazol- 5-yl)benzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as a white solid. LC-MS (m/z) 499.0 (M+ 1).
Example 78: l-(5,6-dichloro-l-(4-fluorobenzyl)-lH-benzo[d]imidazol-2-yl)-JV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000113_0002
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.1 g, 0.26 mmol), N,N-dimethylformamide (2 mL), caesium carbonate (0.508 g, 1.56 mmol) and l-(bromomethyl)-4-fluorobenzene (0.058 mL, 0.31 mmol) using the method described in Example 74, to give 27 mg (21 % yield) of l-(5,6- dichloro- 1 -(4-fluorobenzyl)- lH-benzo[d]imidazol-2-yl)-Ν-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a brown solid.
Example 79: l-(l-(4-(lH-l,2,4-triazol-l-yl)benzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)- JV-cyclopentylpiperidine-4-carboxamide
Figure imgf000114_0001
To a solution of N-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (0.1 g, 0.26mmol) in N,Λ/-dimethylformamide (0.5 niL) was added cesium carbonate (0.512 g, 1.5 mmol), followed by l-(4-(bromomethyl)phenyl)-lH-l,2,4-triazole (0.112 g, 0.47 mmol). The reaction mixture was irradiated under microwave conditions at 12O0C for 45 minutes, concentrated in vacuo and the residue extracted with ethyl acetate (2 x15 mL). The organic layer was washed with water (3 x15 mL), dried over anhydrous sodium sulphate, concentrated in vacuo and subjected to column chromatography (silica gel, chloroform/methanol 99:1), to give 0.04 g (28 % yield) of l-(l-(4-(lH-l,2,4-triazol-l-yl)benzyl)-5,6-dichloro-lH- benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4-carboxamide as a white solid. LC-MS (m/z) 538.3 (M+l).
Example 80: 7V-cyclopentyl-l-(5,6-dichloro-l-(2-methoxyethyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000114_0002
To a solution of Λ/-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (0.1 g, 0.26 mmol) in N,Λ/-dimethylformamide (0.5 mL) was added cesium carbonate (0.5g, 1.5mmol), followed by l-bromo-2-methoxyethane (0.065 g, 0.47mmol). The reaction mixture was irradiated under microwave conditions at 1200C for 60 minutes, concentrated in vacuo and the residue was extracted with ethyl acetate (2 x15 mL). The combined organic phases were washed with water (3 xl5 mL), dried over anhydrous sodium sulphate, concentrated in vacuo and the residue washed with n-hexane to give 0.075 g (65 % yield) ofΛ/-cyclopentyl-l-(5,6-dichloro-l-(2-methoxyethyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 439.3 (M+l). Example 81: 7V-cyclopentyl-l-(l-(4-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000115_0001
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.30 g, 0.829 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.316 mmol), l-bromo-4-iodobenzene (3.316 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.132 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.044 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 20 mg (5.2 % yield) of N-cyclopentyl- 1 -( 1 -(4-fluorophenyl)-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide as an off- white solid. LC-MS (m/z) 435.1 (M+ 1).
Example 82: l-(l-(cyclobutylmethyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide
Figure imgf000115_0002
The title compound was prepared from N-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.293 mmol), N,Λ/-dimethylformamide (3 mL), caesium carbonate (1.172 mmol), (bromomethyl)cyclo butane (1.172 mmol) and dichlorobis(triphenyl- phosphine)palladium (II) (Pd(PPhS)2Cl2 (0.0293 mmol) using the method described in Example 14. The reaction mixture was heated at 12O0C for 1 hour under microwave conditions and purified with column chromathography, to give 30 mg (25 % yield) of l-(l-(cyclobutylmethyl)- 5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as a white solid. LC-MS (m/z) 409.1 (M+ 1).
Example 83: 7V-cyclopentyl-l-(5,6-dimethyl-l-(prop-2-ynyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000116_0001
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.293 mmol), N,Λ/-dimethylformamide (3 mL), caesium carbonate (1.172 mmol), 3-bromoprop-l-yne (1.172 mmol) and dichlorobis(triphenyl- phosphine)palladium (II) (Pd(PPlIs)2Cl2 (0.0293 mmol) using the method described in Example 14. The reaction mixture was heated at 12O0C for 1 hour under microwave conditions and purified with column chromathography, to give 15 mg (13 % yield) of N-cyclopentyl-l-(5,6- dimethyl-l-(prop-2-ynyl)-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 379.0 (M+ 1). Example 84: 7V-cyclopentyl-l-(l-(2-ethylbutyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000116_0002
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.293 mmol), N,Λ/-dimethylformamide (3 mL), caesium carbonate (1.172 mmol), 3-(bromomethyl)pentane (1.172 mmol) and dichlorobis(triphenyl- phosphine)palladium (II) (Pd(PPh3)2Cl2 (0.0293 mmol) using the method described in Example 14. The reaction mixture was heated at 12O0C for 1 hour under microwave conditions and purified with column chromathography, to give 26 mg (22 % yield) of N-cyclopentyl-l-(l-(2- ethylbutyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 425.1 (M+l).
Example 85: 7V-cyclopentyl-l-(5,6-dimethyl-l-neopentyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000117_0001
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.293 mmol), N,Λ/-dimethylformamide (3 mL), caesium carbonate (1.172 mmol), l-bromo-2,2-dimethylpropane (1.172 mmol) and dichlorobis(triphenyl- phosphine)palladium (II) (Pd(PPh3)2Cl2 (0.0293 mmol) using the method described in Example 14. The reaction mixture was heated at 12O0C for 1 hour under microwave conditions and purified with column chromathography, to give 55 mg (23 % yield) of N-cyclopentyl-l-(5,6- dimethyl-l-neopentyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as an off- white solid. LC-MS (m/z) 411.0 (M+ 1). Example 86: l-(l-cyclohexyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide
Figure imgf000117_0002
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.293 mmol), N,Λ/-dimethylformamide (3 mL), caesium carbonate ( 1.172 mmo 1), bromocyclohexane ( 1.172 mmo 1) and dichlorobis(triphenyl- phosphine)palladium (II) (Pd(PPh3)2Cl2 (0.0293 mmol) using the method described in Example 14. The reaction mixture was heated at 12O0C for 1 hour under microwave conditions and purified with column chromathography, to give 8 mg (3.2 % yield) of l-(l-cyclohexyl-5,6- dimethyl-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as an off- white solid. LC-MS (m/z) 423.1 (M+l).
Example 87: l-(l-sec-butyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V-cyclopentyl- piperidine-4-carboxamide
Figure imgf000118_0001
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.293 mmol), N,Λ/-dimethylformamide (3 mL), caesium carbonate (1.172 mmol), 2-bromobutane (1.172 mmol) and dichlorobis(triphenylphosphine)- palladium (II) (Pd(PPlIs)2Cl2 (0.0293 mmol) using the method described in Example 14. The reaction mixture was heated at 12O0C for 1 hour under microwave conditions and purified with column chromathography, to give 20 mg (8.6 % yield) of l-(l-sec-butyl-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-cyclopentyl-piperidine-4-carboxamide as a white solid. LC-MS (m/z) 397.0 (M+l). Example 88: 7V-cyclopentyl-l-(5,6-dichloro-l-(2-hydroxyethyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000118_0002
N-cyclopentyl- 1 -(5 ,6-dichloro- 1 -(2-methoxyethyl)- lH-benzo [d]imidazol-2-yl)piperidine-4- carboxamide was dissolved in dichloromethane and stirred under nitrogen at O0C for 15 minutes, treated with tribromoborane via drop-wise addition and gradually warmed to room temperature. The reaction mixture was stirred at room temperature for 1 hour, quenched with aqueous sodium hydrogencarbonate (10%) to ashive neutral pΗ and extracted with dichloromethane (2x 50 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo to give 0.02 g (42 % yield) of Λ/-cyclopentyl-l-(5,6-dichloro-l-(2-hydroxyethyl)-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 425.3 (M+l).
Example 89: 7V-cyclopentyl-l-(l,5,6-trimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide
Figure imgf000118_0003
Λ/-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (6.8 mg, 0.02 mmol), iodomethane (3.4 mg, 1.5 niL, 0.024 mmol), caesium carbonate (13 mg, 0.04 mmol) and acetonitrile (0.5 mL) were mixed and stirred at room temperature. After 1 hour, additional iodoethane (3.4 mg, 1.5 mL, 0.024 mmol) was added and the reaction mixture was briefly stirred at 5O0C, stirred at room temperature over night, filtered and concentrated in vacuo. The residue was subjected to column chromatography (silica gel, methanol/dichloromethane gradient elution to give 2.3 mg (32 % yield) of Λ/-cyclopentyl-l-(l,5,6-trimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide. LC-MS (m/z) 355.2 (M+ 1).
Example 90: 7V-cyclopentyl-l-(l-isobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000119_0001
Λ/-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (6.8 mg, 0.02 mmol), l-bromo-2-methylpropane (3.3 mg, 2.6 mL, 0.024 mmol), caesium carbonate (13 mg, 0.04 mmol) and acetonitrile (1.0 mL) and N,N-dimethylformamide (5 drops) were mixed and stirred at 5O0C. After 75 minutes, additional l-bromo-2-methylpropane (3.3 mg, 2.6 mL, 0.024 mmol) was added and the reaction mixture was stirred at 6O0C over night, filtered and concentrated in vacuo. The residue was and purified on preparative hplc (performed on a Gilson- Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using acetonitrile/water (0.05 % formic acid) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 1.7 mg (22 % yield) of N-cyclopentyl-l-(l- isobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 397.2 (M+ 1).
Example 91: l-(l-benzyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V-cyclopentylpiperidine- 4-carboxamide
Figure imgf000119_0002
Λ/-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (34 mg, 0.1 mmol), (bromomethyl)benzene (20.5 mg, 15 mL, 0.120 mmol), caesium carbonate (65 mg, 0.20 mmol) and acetonitrile (2 mL) were mixed and stirred at 6O0C over night. The reaction mixture was filtered, concentrated in vacuo and purified on preparative hplc (performed on a Gilson- Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using acetonitrile/water (0.05 % formic acid) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 8.3 mg (19 % yield) of l-(l-benzyl-5,6- dimethyl- lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide. LC-MS (m/z) 431.5 (M+l). Example 92: 7V-cyclopentyl-l-(l-(2-methoxyethyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000120_0001
Λ/-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (34 mg, 0.10 mmol), l-bromo-2-methoxyethane (16.7 mg, 11 mL, 0.120 mmol), caesium carbonate (65.2 mg, 0.20 mmol) and acetonitrile (2 mL) were mixed and stirred at 1000C over night, filtered, concentrated in vacuo and subjected to column chromathography (silica gel, methanol/ dichloromethane gradient elution 3-20 % methanol) to give 4.7 mg (12 %) of N-cyclopentyl-1- (l-(2-methoxyethyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 399.2 (M+l). Example 93: 7V-cyclopentyl-l-(l-(4-fluorobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000120_0002
The title compound was prepared from l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-JV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (34 mg, 0.10 mmol), acetonitrile (2 mL), caesium carbonate (65.2 mg, 0.20 mmol) and l-(bromomethyl)-4-fluorobenzene (16.7 mg, 0.12 mmol) using the method described in Example 92, to give 4.7 mg (12 % yield) of iV-cyclopentyl- l-(l-(4-fluorobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC- MS (m/z) 449.2 (M+ 1). Example 94: l-(5-chloro-l-cyclobutyl-6-fluoro-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide and l-(6-chloro-l-cyclobutyl-5-fluoro-lH- benzo [d] imidazol-2-yl)-7V-cyclopentylpiperidine-4-carboxamide
Figure imgf000121_0001
(a) Preparation of the intermediate compound 5-chloro-6-fluoro-lH-benzo[d]imidazol-2(3Η)- one:
Figure imgf000121_0002
To a stirred solution of 4-chloro-5-fluorobenzene-l,2-diamine (1 g, 6.22 mmol) in
tetrahydrofuran (10 mL) was added JV,iV-carbonyl dimidazole (CDI, 9.33 mmol). The reaction mixture was stirred at room temperature for 3 hours under Argon gas, concentrated in vacuo and the residue partitioned between ethyl acetate and aqueous sodium hydroxide. The aqueous extract was acidified to pH 5 via addition of aqueous hydrochloric acid and the resulting brown precipitate was filtered, washed with water and dried to obtain 0.8 g (68 % yield) of 5-chloro-6- fluoro-lH-benzo[d]imidazol-2(3H)-one after recrystallization from petroleum ether.
(b) Preparation of the intermediate compounds 2,5-dichloro-6-fluoro-lH-benzo[d]imidazole and 2,6-dichloro-5-fluoro-lH-benzo[d]imidazole.
Figure imgf000121_0003
To 5-chloro-6-fluoro-lH-benzo[d]imidazol-2(3Η)-one (1 g, 5.3 mmol), phosphoryl trichloride (POCI3, 132 mmol)) was added, the reaction mixture was heated at 12O0C for 2 hours and then concentrated in vacuo. The residue was neutralized with sodium hydroxide, the resulting was filtered off, washed with water and dried to give 0.85 g (77 % yield) of 2,5-dichloro-6-fluoro- lH-benzo[d]imidazole and 2,6-dichloro-5-fluoro-lH-benzo[d]imidazole after recrystallization after petroleum ether. No effort was made to determine the ratios of the tautomers. (c) Preparation of the intermediary compound 4-(cyclopentylcarbamoyl)piperidinium 2,2,2- trifluoroacetate.
Figure imgf000122_0001
To a solution of tert-EvXy\ 4-(cyclopentylcarbamoyl)piperidine-l-carboxylate (1.0 g, 3.37 mmol) in dichloromethane (10 mL), cooled to 0 0C, was added 2,2,2-trifluoroacetic acid (8.4 mmol). The reaction was allowed to warm to room temperature and stirred for 16 hours. The mixture was concentrated in vacuo (repeated co-evaporation with toluene), and dried under vacuum to give 4-(cyclopentylcarbamoyl)piperidinium 2,2,2-trifluoroacetate in quantitative yield.
(d) Preparation of the intermediary compounds l-(5-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)- N-cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro-5-fluoro- lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide.
Figure imgf000122_0002
To a suspension of the tautomeric compounds 2,5-dichloro-6-fluoro-lH-benzo[d]imidazole and 2,6-dichloro-5-fluoro-lH-benzo[d]imidazole (1 g, 4.87 mmol), 1,4-dioxane (10 mL) and 4- (cyclopentylcarbamoyl)piperidinium 2,2,2-trifluoroacetate (7.3 mmol) was added NJSf- diisopropylethylamine (Ηunig's base, DIEA, 14.6 mmol) and heated at 18O0C for 4 hours. After the appropriate work-up, the residue was recrystallized from a mixture of dichloromethane, petroleum ether and diethyl ether, to give 0.8 g (45 % yield) of l-(5-chloro-6-fluoro-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro-5-fluoro- IH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide. (e) A tautomeric mixture of l-(5-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro-5-fluoro- lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide (0.1 g, 0.274 mmol), bromocyclo butane (1.096 mmol), caesium carbonate (1.096 mmol), [l,r-bis(diphenyl-phosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), 0.0274 mmol) and N,Λ/-dimethyl-formamide (3 mL) was subjected to microwave conditions at 12O0C for one hour in a sealed tube and purified with column chromathography, to give 5 mg (4.4 % yield) of l-(5-chloro-l-cyclobutyl-6-fluoro-lH-benzo[d]imidazol-2-yl)-N- cyclopentyl-piperidine-4-carboxamide and 1 -(6-chloro- 1 -cyclobutyl-5-fluoro- IH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as an off-white solid. No effort was made to determine the ratio of the regioisomers. LC-MS (m/z) 419.1 (M+l).
Example 95: 7V-cyclopentyl-l-(5,6-dimethyl-l-(pentan-2-yl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000123_0001
Λ/-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (20 mg, 0.059 mmol), 2-bromopentane (17.8 mg, 0.117 mmol), caesium carbonate (57.4 mg, 0.176 mmol), Λ/,Λ/-dimethylformamide (3.0 mL) was heated at 6O0C over night. The reaction mixture was filtered, concentrated in vacuo and purified on preparative hplc (performed on a Gilson- Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 μm, 21.2 xl50 mm) column, using acetonitrile/water (0.05 % formic acid) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection). This gave 7.2 mg (30 % yield) of JV-cyclopentyl- 1 -(5 ,6-dimethyl- 1 -(pentan-2-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 411.4 (M+l).
Example 96: 7V-butyl-l-(l-cyclobutyl-5,6-dimethyl-l//-benzo[d]imidazol-2-yl)piperidine-4- carboxamide
Figure imgf000123_0002
(a) Preparation of the intermediary compound tert-butyl 4-(/?-butylcarbamoyl)piperidine-l- carboxylate.
Figure imgf000124_0001
To a solution of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (1.0 g, 4.37 mmol) in dry dichloromethane (10 rnL), cooled to 0 0C, was added JV,JV-diisopropylethylamine (Hunig's base, DIEA, 8.7 mmol), Λ/-(3-dimethylaminopropyl)-Λf'-ethylcarbodiimide hydrochloride (EDCΗC1, , 8.7 mmol, CAS Registry Number: 25952-53-8), 1-hydroxybenzotriazole (HOBt, CAS Registry Number: 2592-95-2, 2.2 mmol) and n-butylamine (5.2 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 8 hours. The reaction mixture was washed with aqueous hydrochloric acid (3 x15 mL, 2 N), saturated aqueous sodium bicarbonate (2 x15 mL), dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was recrystallized from dichloro methane/pet ether to give 1.1 g (92%) of tert-butyl A-(n- butylcarbamoyl)piperidine- 1 -carboxylate.
(b) Preparation of the intermediary compound 4-(/?-butylcarbamoyl)piperidinium 2,2,2- trifluoroacetate :
Figure imgf000124_0002
To a solution of tert-Butyl 4-(/?-butylcarbamoyl)piperidine-l -carboxylate (1.0 g, 3.52 mmol) in dichloromethane (10 mL), cooled to 0 0C, was added 2,2,2-trifluoroacetic acid (8.4 mmol). The reaction was allowed to warm to room temperature and stirred for 16 hours. The mixture was concentrated in vacuo (repeated co-evaporation with toluene), and dried under vacuum to give A- (ft-butylcarbamoyl)piperidinium 2,2,2-trifluoroacetate in quantitative yield. (c) Preparation of the intermediate compound N-butyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide:
Figure imgf000124_0003
To a suspension of 2-chloro-5,6-dimethyl-lH-benzo[d]imidazole (0.3 g, 1.6 mmol), 4-(n- butylcarbamoyl)piperidinium 2,2,2-trifluoroacetate (0.45 g, 2.5 mmol) and 1,4-dioxane (4 mL), was added N,Λ/-diisopropyl-ethylamine (Ηunig's base, DIEA, 0.32 mL, 2.5 mmol). The reaction mixture was heated in a sealed tube at 18O0C for 3 hours, poured out into ice-water, the precipitate filtered off, to give 0.2 g (36 % yield) of N-butyl-l-(5,6-dimethyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a yellow solid. LC-MS (m/z) 329.3 (M+l).
(d) To a solution of ΛMxityl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide (0.1 g, 0.3 mmol) in N,Λ/-dimethylformamide (2 mL), caesium carbonate (0.6 g, 1.8 mmol) was added cyclobutylbromide (0.074 g, 0.54 mmol). The reaction mixture was irradiated under microwave conditions at 12O0C for 1 hour, concentrated in vacuo and the residue extracted with ethyl acetate (2 x15 mL). The combined organic phases were washed with water (3 x15 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was subjected to column chromatography (silica gel, chloroform/methanol 99:8) to give 23 mg (20 % yield) ofN-butyl-l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide as a white solid. LC-MS (m/z) 383.3 (M+l).
Example 97: 7V-butyl-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide
Figure imgf000125_0001
To a solution of Λ/-butyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide (0.1 g, 0.3 mmol) in N,7V-dimethylformamide (2 mL), was added caesium carbonate (0.6 g, 1.8 mmol), followed by 2-bromopropane (67 mg, 0.54 mmol). The reaction mixture was irradiated under microwave conditions at 12O0C for 1 hour, concentrated in vacuo, the residue extracted with ethyl acetate (2 x15 mL). The combined organic phases were washed with water (3 x15 mL), dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was subjected to column chromatography (silica gel, chloroform/methanol 99: 1) to give 49 mg (44 % yield) ofN-butyl-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamid. LC-MS (m/z) 371.3 (M+l).
Example 98: 7V-butyl-l-(5,6-dimethyl-l-pentyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide
Figure imgf000126_0001
The title compound was prepared fromΛMxityl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.3 mmol), N,Λ/-dimethylformamide (2 mL), caesium carbonate (0.6 g, 1.8 mmol) and 1-bromopentane (0.082 g, 0.54 mmol) using the method described in Example 97, to give 25 mg (21 % yield) of ΛMxityl-l-(5,6-dimethyl-l-pentyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 399.4 (M+l).
Example 99: TV-butyl-Ηl-ftό-fluoropyridin-S-yOmethyO-S^-dimethyl- IH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000126_0002
The title compound was prepared from ΛMxityl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.3 mmol), N,Λ/-dimethylformamide (2 mL), caesium carbonate (0.6 g, 1.8 mmol) and 5-(bromomethyl)-2-fluoropyridine (0.1 g, 0.54 mmol) using the method described in Example 97, to give 5 mg of Λ/-butyl-l-(l-((6-fluoropyridin-3-yl)methyl)- 5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 438.2 (M+l). Example 100: 7V-butyl-l-(l-(4-fluorobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000126_0003
The title compound was prepared fromΛMxityl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.3 mmol), N,Λ/-dimethylformamide (2 mL), caesium carbonate (0.6 g, 1.8 mmol) and l-(bromomethyl)-4-fluorobenzene (0.1 g, 0.54 mmol) using the method described in Example 97, to give 28 mg (28 % yield) of JV-butyl-l-(l-(4-fluorobenzyl)- 5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide. LC-MS (m/z) 437.1 (M+l).
Example 101: 7V-benzyl-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine- 4-carboxamide
Figure imgf000127_0001
(a) Preparation of the intermediate compound ethyl l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylate.
Figure imgf000127_0002
5,6-Dimethyl-lH-benzo[d]imidazol-2-amine (180.6 mg, 1 mmol), ethyl piperidine-4-carboxylate (157.2, 1 mmol) and 1,4-dioxane (4 mL) were mixed in a 5 mL microwave vial and irradiated under microwave conditions at 18O0C for 1 hour. The reaction mixture was concentrated in vacuo, subjected to column chromatography (silica gel, dichloromethane/methanol 90:10), to give 288 mg (96 % yield) of ethyl l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxylate. LC-MS (m/z) 302.2 (M+l).
(b) Preparation of the intermediate compound ethyl l-(l-isopropyl-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate.
Figure imgf000127_0003
Ethyl l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (280 mg, 0.929 mmol) was dissolved in acetonitrile (25 mL) and Λ/,Λ/-dimethylformamide (5 mL). 2-
Bromopropane (342.8 mg, 2.79 mmol) and potassium carbonate (385.2 mg, 2.79 mmol) was added and the reaction mixture was heated at 6O0C over night. 2-Bromopropane (342.8 mg, 2.79 mmol) and potassium carbonate (128.4 mg, 0.929 mmol) was added, the reaction mixture was heated at 6O0C for 7 hours, filtered and the filtrate concentrated in vacuo. The residue was subjected to column chromatography (silica gel, dichloromethane/methanol, gradient elution 2- 10 % methanol) to give 143 mg (45 % yield, 90 % pure) of ethyl l-(l-isopropyl-5,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate. LC-MS (m/z) 344.3 (M+ 1).
(c) Preparation of the intermediate compound l-(l-isopropyl-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid.
Figure imgf000128_0001
A mixture of ethyl l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxylate (143 mg, 0.416 mmol), sodium hydroxide (83.3 mg, 2.08 mmol) and water (1 mL) was heated at reflux for 50 minutes. Aqueous hydrochloric acid (1 mL, 2N) was added and the reaction mixture concentrated in vacuo. LC-MS (m/z) 344.3 (M+l). This gave l-(l-isopropyl- 5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid in a mixture with sodium chloride. LC-MS (m/z) 316.2 (M+l). (d) l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (10 mg, 0.0317 mmol) was dissolved in N,Λ/-dimethylformamide (2 mL). 2-(7-Aza-lH-benzotriazo Ie-I- yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (13.3 mg, 0.0349 mmol), N,N- diisopropylethylamine (8.2 mg, 0.0634 mmol) and phenylmethanamine (4.08 mg, 0.0380 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour, concentrated in vacuo and filtered through a pad of silica gel (dichloromethane/methanol 95:5). The pooled fractions containg the title compound was concentrated in vacuo and subjected to purification on hplc (performed on a Gilson-Finnigan ThermoQuest AQA system equipped with a Zorbax SB- C8 (5 μm, 21.2 x 150 mm) column with UV (214 or 254 nm) and MS (ESI) detection), using acetonitrile/water (containing 0.05 % formic acid) gradient elution 10-50 %), to give 7.3 mg (57 % yield) of 7V-benzyl-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide. LC-MS (m/z) 405.3 (M+l).
Example 102: 7V-(4-fluorobenzyl)-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000129_0001
The title compound was prepared from l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylic acid (10 mg, 0.0317 mmol), N,N-dimethylformamide (2 mL), 2-(7- aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (13.3 mg, 0.0349 mmol), N,N-diisopropylethylamine (8.2 mg, 0.0634 mmol) and (4-fluorophenyl)methanamine (4.76 mg, 0.0380 mmol) using the method described in Example 101, to give 8.5 mg (63 % yield) ofN-(4-fluorobenzyl)-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine- 4-carboxamide. LC-MS (m/z) 423.3 (M+l).
Example 103: 7V-(3-isopropoxypropyl)-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000129_0002
l-(l-Isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (10 mg, 0.0317 mmol) was dissolved in N,Λ/-dimethylformamide (2 mL). 2-(7-Aza-lH-benzotriazole-l- yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (13.3 mg, 0.0349 mmol), N5TV- diisopropylethylamine (8.2 mg, 0.0634 mmol) and 3-isopropoxypropan-l -amine (4.50 mg,
0.0380 mmol) was added and the reaction mixture was stirred at room temperature for 1 hour, and concentrated in vacuo. The residue was subjected to purification on hplc (performed on a Gilson-Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 μm, 21.2 xl50 mm) column with UV (214 or 254 nm) and MS (ESI) detection, using acetonitrile/water (containing 0.05 % formic acid) gradient elution 10-50 %), to give 9.2 mg (70 % yield) of N-(3- isopropoxypropyl)-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide. LC-MS (m/z) 415.3 (M+l).
Example 104: 7V-(3,3-dimethylbutyl)-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000130_0001
The title compound was prepared from l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylic acid (10 mg, 0.0317 mmol), N,N-dimethylformamide (1 mL), 2-(7- Aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (13.3 mg, 0.0349 mmol), N,N-diisopropylethylamine (8.2 mg, 0.0634 mmol) and 3,3-dimethylbutan-l -amine (3.85 mg, 0.0380 mmol) using the method described in Example 103, to give 6.1 mg (48 % yield) of Λ/-(3,3-dimethylbutyl)-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide. LC-MS (m/z) 399.4 (M+l).
Example 105: 7V-(4-bromobenzyl)-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000130_0002
l-(l-Isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (40 mg, 0.127 mmol) was dissolved in N,N-dimethylformamide (4 mL). 2-(7-Aza-lH-benzotriazo Ie-I- yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (53.0 mg, 0.140 mmol), N,N- diisopropylethylamine (49.2 mg, 0.380 mmol) and (4-bromophenyl)methanamine hydrochloride (33.9 mg, 0.152 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes, concentrated in vacuo and subjected to column chromatography (silica gel, dichloromethane/methanol, gradient elution 1-6 % methanol). This gave quantitative yield of N- (4-bromobenzyl)-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide. LC-MS (m/z) 483.2 (M+l).
Example 106: 7V-cyclohexyl-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000130_0003
l-(l-Isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (10 mg, 0.0317 mmol) was dissolved in N,Λ/-dimethylformamide (2 niL). 2-(7-Aza-lH-benzotriazo Ie-I- yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (13.3 mg, 0.0349 mmol), N,N- diisopropylethylamine (8.2 mg, 0.0634 mmol) and cyclohexanamine (3.77 mg, 0.0380 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes, concentrated in vacuo and filtered through a pad of silica gel (dichloromethane/methanol 95:5). The pooled fractions containg the title compound was concentrated in vacuo and subjected to purification on hplc (performed on a Gilson-Finnigan ThermoQuest AQA system equipped with a Zorbax SB- C8 (5 μm, 21.2 x 150 mm) column with UV (214 or 254 nm) and MS (ESI) detection), using acetonitrile/water (containing 0.05 % formic acid) gradient elution 10-50 %), to give 5.6 mg (45 % yield) ofN-cyclohexyl-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide. LC-MS (m/z) 397.3 (M+l).
Example 107: 7V-(4-cyanobenzyl)-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000131_0001
JV-(4-Bromobenzyl)- 1 -( 1 -isopropyl-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)piperidine-4- carboxamide (20 mg, 0.0414 mmol), dicyanozinc (ZnCN2, 4.9 mg, 0.0414 mmol), bis(tri-tert- butylphosphine)palladium (Pd[P(t-bu)3]2, 2.1 mg, 0.00414 mmol) and N,Λ/-dimethylformamide (1 mL) was irridated in a microwave oven at 15O0C for 30 minutes. The reaction mixture was filtred, concentrated in vacuo, subjected to column chromatography (silica gel), to give 8.8 mg (50 % yield) of Λ/-(4-cyanobenzyl)-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide. LC-MS (m/z) 430.3 (M+l).
Example 108: (S)- l-(5,6-dimethyl- 1-p-tolyl- lH-benzo [d] imidazol-2-yl)-7V-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide
Figure imgf000132_0001
(a) Preparation of the intermediate compound ethyl l-(5,6-dimethyl-l-p-to IyI- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate:
Figure imgf000132_0002
Ethyl l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (80.5 mg, 0.267 mmol), l-iodo-4-methylbenzene (116 mg, 0.534 mmol), 8-hydroxyquinoline (7.8 mg, 0.053 mmol), copper(I) oxide (3.8 mg, 0.027 mmol), polyethylene glycol 400 (107 mg, 0.267 mmol), caesium carbonate (122 mg, 0.374 mmol) and dimethylsulfoxide (0.5 mL) were mixed in a sealed reaction tube. The reaction mixture was heated to 1500C for one hour in a heating block and then diluted with ethylacetate and water. The water phase was extracted with ethyl acetate, the combined organic phases dried over magnesium sulphate and concentrated in vacuo. The residue was purified on automated flash chromatography (silica gel, ethyl acetate/ώo-hexane, gradient elution from 20 to 60% ethyl acetate) to give 40 mg (38 % yield) of ethyl l-(5,6- dimethyl-l-p-tolyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate. LC-MS (m/z) 392.0 (M+l).
(b) Preparation of the intermediate compound l-(5,6-dimethyl-l-p-tolyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylic acid:
Figure imgf000132_0003
To ethyl l-(5,6-dimethyl-l-p-tolyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (40 mg, 0.10 mmol) was added ethanol (2 mL) and aqueous sodium hydroxide (1 mL, 1 N) and the reaction mixture was stirred at 50 0C for one hour. The reaction mixtures were neutralized with aqueous hydrochloric acid (1 N), concentrated in vacuo to give l-(5,6-dimethyl-l-p-to IyI- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid in quantitative yield. LC-MS (m/z) 364.0 (M+l). (c) l-(5,6-Dimethyl-l-p-tolyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (37 mg, 0.10 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 58 mg, 0.153 mmol), (S)-tetrahydrofuran-3 -amine hydrochloride (18.9 mg, 0.153 mmol) and iV,jV-diisopropyl-ethylamine (Ηunig's base, DIEA, 170 μL, 1.02 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction mixture was stirred overnight at ambient temperature, filtered and subjected to preparative hplc (preparative RP-LC was performed on a Gilson system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using methano I/water (0.05% formic acid) gradients at a flow rate of 4 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 33 mg (75 % yield) of (S)-l-(5,6-dimethyl-l-p-tolyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 433.0. (M+l).
Example 109: 4-((2-(4-(cyclopentylcarbamoyl)piperidin-l-yl)-5,6-dimethyl-lH- benzo[d]imidazol-l-yl)methyl)benzoic acid
Figure imgf000133_0001
Methyl 4-((2-(4-(cyclopentylcarbamoyl)piperidin- 1 -yl)-5,6-dimethyl- lH-benzo[d]imidazol- 1 - yl)methyl)benzoate (17 mg, 0.035 mmol) was dissolved in methanol (1 mL). Sodium hydroxide (13.9 mg, 0.348 mmol) and water (0.17 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. Aqueous hydrochloride (0.085 mL, 2N) was added, the reaction mixture concentrated in vacuo and subjected to preparative hplc (performed on a Gilson- Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 μm, 21.2 xl50 mm) column, using acetonitrile/water (0.05 % formic acid) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 8.1 mg (49 % yield) of 4-((2-(4- (cyclopentylcarbamoyl)-piperidin- 1 -yl)-5,6-dimethyl- lH-benzo[d]imidazol- 1 -yl)methyl)benzoic acid. LC-MS (m/z) 475.3 (M+l). Example 110: l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V-(thiazol-2- ylmethyl)piperidine-4-carboxamide
Figure imgf000134_0001
(a) Preparation of the intermediate compound tert-butyl 4-(thiazol-2-ylmethylcarbamoyl)- piperidine- 1 -carboxylate :
Figure imgf000134_0002
To a mixture of l-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (500 mg, 2.18 mmol), triethylamine (220.7 mg, 2.18 mmol) and dichloromethane (10 mL) was carefully added thionyl chloride (311.3 mg, 2.62 mmol) and the reaction mixture was stirred at room temperature (reaction mixture 1). In a separate vial was mixed 2-(chloromethyl)thiazole, triethylamine (882.7 mg, 8.723 mmol) and dichloromethane (10 mL) that was stirred and cooled on ice-batch and reaction micture 1 was added over 5 minutes while stirring. The reaction mixture was allowed to reach room temperature, washed with aqueous hydrochloric acid (2 x20 mL, 2 N), aqueous saturated sodium bicarbonate (2 x20 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. The residue was collected and the acidic and basic washes were combined and extracted with dichloromethane (3 x30 mL), the organic phase dried over magnesium sulphate and concentrated. The two residues were combined to give 474 mg (67 % yield) of tert- butyl 4-(thiazol-2-ylmethylcarbamoyl)-piperidine-l -carboxylate. LC-MS (m/z) 326.2 (M+ 1).
(b) Preparation of the intermediate compound 2-((4-piperidiniumcarboxamido)methyl)-3- thiazolium dichloride:
Figure imgf000134_0003
To a solution of tert-butyl 4-(thiazol-2-ylmethylcarbamoyl)-piperidine-l-carboxylate (474 mg, 1.457 mmol) and 2-propanol (10 mL), was drop-wise added concentrated hydrochloric acid (0.18 mL) in 2-propanol (10 mL) and the reaction mixture was stirred at room temperature. After 30 minutes additional concentrated hydrochloric acid (0.18 mL) in 2-propanol (5 mL) was added and after 30 minutes followed by additional concentrated hydrochloric acid (0.54 mL). After stirring over night yet additional concentrated hydrochloric acid (2 mL) was added and the reaction mixture was refluxed for 1 hour, concentrated in vacuo and co-eluted with acetonitrile (20 mL). This gave 470 mg of 2-((4-piperidiniumcarboxamido)methyl)-3-thiazolium dichloride.
(c) Preparation of the intermediate compound l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-JV- (thiazo l-2-ylmethyl)piperidine-4-carboxamide :
Figure imgf000135_0001
2-Chloro-5,6-dimethyl-lH-benzo[d]imidazole (54.2 mg, 0.30 mmol), 2-((4-piperidinium- carboxamido)methyl)-3-thiazolium dichloride (113.4 mg, 0.39 mmol, 90 % purity), N,N- diisopropylethylamine (116.3 mg, 0.9 mmol) and 1,4-dioxane (2 mL) was irridated in a microwave oven at 17O0C for 1 hour. The reaction mixture was concentrated in vacuo and the residue subjected to column chromatography (silica gel, dichloromethane/methanol, gradient elution using 5-20 % methanol) to give 83 mg (75 % yield) of l-(5,6-dichloro-lH- benzo[d]imidazol-2-yl)-Λ/-(thiazol-2-ylmethyl)piperidine-4-carboxamide. LC-MS (m/z) 370.3 (M+ 1). (d) The title compound was prepared from l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-JV-
(thiazol-2-ylmethyl)piperidine-4-carboxamide (11.1 mg, 0.03 mmol), N,Λ/-dimethylformamide (1 mL), acetonitrile (3 mL), caesium carbonate (29.3 mg, 0.09 mmol) and 2-bromopropane (11.1 mg, 0.09 mmol) using the method described in Example 111, to give 2.7 mg (22 % yield) of 1- (l-Isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(thiazol-2-ylmethyl)piperidine-4- carboxamide. LC-MS (m/z) 412.3 (M+l).
Example 111: l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-7V-(thiazol-2- ylmethyl)piperidine-4-carboxamide
Figure imgf000136_0001
(a) Preparation of the intermediate compound l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-JV- (thiazo l-2-ylmethyl)piperidine-4-carboxamide :
Figure imgf000136_0002
2,5,6-Trichloro-lH-benzo[d]imidazole (30 mg, 0.135 mmol), 2-((4-piperidinium- carboxamido)methyl)-3-thiazolium dichloride (51.2 mg, 0.176 mmol, 90 % purity), N,N- diisopropylethylamine (116.3 mg, 0.9 mmol) and 1,4-dioxane (2 mL) was irridated in a microwave oven at 17O0C for 1 hour. The reaction mixture was concentrated in vacuo and the residue subjected to column chromatography (silica gel, dichloromethane/methanol, gradient elution using 5-20 % methanol) to give 42.2 mg (76 % yield) of l-(5,6-dichloro-lH- benzo[d]imidazol-2-yl)-Λ/-(thiazol-2-ylmethyl)piperidine-4-carboxamide. LC-MS (m/z) 410.1 (M+ 1).
(b) l-(5,6-Dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-(thiazol-2-ylmethyl)piperidine-4-carboxamide (12.3 mg, 0.03 mmol), 2-bromopropane (11.1 mg, 0.09 mmol), caesium carbonate (29.3 mg, 0.09 mmol), acetonitrile (3 mL) and Λ/,Λ/-dimethylformamide (1 mL) was mixed and heated at 6O0C over night. The reaction mixture concentrated in vacuo and subjected to preparative hplc (performed on a Gilson-Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 μm, 21.2 Xx 150 mm) column, using acetonitrile/water (0.05 % formic acid) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 1.6 mg (12 % yield) of l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-(thiazol-2- ylmethyl)piperidine-4-carboxamide. LC-MS (m/z) 452.2 (M+ 1).
Example 112: 7V-(4-(lH-tetrazol-5-yl)benzyl)-l-(l-isopropyl-5,6-dimethyl-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000137_0001
JV-(4-Bromobenzyl)- 1 -( 1 -isopropyl-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)piperidine-4- carboxamide (20 mg, 0.0414 mmol), dicyanozinc (ZnCN2, 4.9 mg, 0.0414 mmol), bis(tri-tert- butylphosphine)palladium (Pd[P(t-bu)3]2, 2.1 mg, 0.00414 mmol) and Λ/,Λ/-dimethylformamide (1 mL) were irridated in a microwave oven at 14O0C for 10 minutes. Sodium azide (NaNi, 32.3 mg, 0.496 mmol) and ammonium chloride (26.6 mg, 0.496 mmol) was added to the reaction mixture, which was heated at 15O0C for 40 minutes. The reaction mixture was filtered, the filtrate concentrated in vacuo and the residue subjected to preparative hplc (performed on a Gilson-Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 μm, 21.2 xl50 mm) column, using acetonitrile/water (0.05 % formic acid) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 3.5 mg (18 % yield) of N-(4-(lH- tetrazol-5-yl)benzyl)-l -(I -isopropyl-5, 6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide. LC-MS (m/z) 473.3 (M+ 1).
Example 113: 7V-cyclopentyl-l-(5,6-dimethyl-l-(pentan-3-yl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000137_0002
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.1 g, 0.293 mmol), N,Λ/-dimethylformamide (3 mL), caesium carbonate (1.172 mmol), 3-bromopentane (1.172 mmol) and dichlorobis(triphenylphosphine)- palladium (II) (Pd(PPhS)2Cl2 (0.0293 mmol) using the method described in Example 14. The reaction mixture was heated at 12O0C for 1 hour under microwave conditions and purified with column chromathography, to give 27 mg (11.2 % yield) ofN-cyclopentyl-l-(5,6-dimethyl-l- (pentan-3-yl)-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 411.1 (M+l). Example 114: l-(5,6-dimethyl-l-phenyl-lH-benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3- yl)piperidine-4-carboxamide
Figure imgf000138_0001
The title compound was prepared from l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.30 g, 0.877 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.51 mmol), iodobenzene (3.51 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.132 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0438 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 2.9 mg (0.8 % yield) of 1 -(5,6-dimethyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a brown solid. LC-MS (m/z) 419.2 (M+ 1).
Example 115: 7V-cyclopentyl-l-(5,6-dichloro-l-(4-fluorophenyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000138_0002
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.3 g, 0.78 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.092 mmol), l-fluoro-4-iodobenzene (0.936 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.117 mmol), polyethylene glycol (0.039 mmol) and copper(I) oxide (0.039 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 18 hours in a sealed tube and purified with column chromathography, to give 21 mg (6 % yield) of N-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-fluorophenyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide as a white solid. LC-MS (m/z) 475.5 (M+ 1).
Example 116: l-(l-(4-bromophenyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000139_0001
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.3 g, 0.78 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.092 mmol), 1 ,4-dibromobenzene (0.936 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.117 mmol), polyethylene glycol (0.039 mmol) and copper(I) oxide (0.039 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 18 hours in a sealed tube and purified with column chromathography, to give 6 mg (1.4 % yield) of l-(l-(4-bromophenyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as a white solid. Example 117: l-(l-(4-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000139_0002
(a) Preparation of the intermediate compound l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylic acid:
Figure imgf000139_0003
Ethyl l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (1.00 g, 3.31 mmol) was dissolved in ethanol (50 mL) and aqueous sodium hydroxide (1 N, 17.0 mL) was added. The reaction mixture was stirred at room temperature 1 hour, concentrated in vacuo and pΗ adjusted to 4-5 with addition of aqueous hydrochloric acid (6 N). The formed precipitate was filtered off, the aqueous mother liquid extracted three times with dichloromethane (50 mL) and the combined organic layers were dried with MgSO4 and concentrated in vacuo. The precipitate and the residue from the extraction were combined and rechrystallized in petroleum ether to give 0.538 g (59%) of l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid.
(b) Preparation of the intermediate compound l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-iV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000140_0001
l-(5,6-Dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (1.0 g, 3.7 mmol), tetrahydrofuran-3 -amine hydrochloride (0.54 g, 4.4 mmol), 2-(7-aza-lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 2.8 g, 7.4 mmol), N,N- diisopropylethylamine (Ηunig's base, DIEA, 0.96 g, 7.4 mmol) and N,N-dimethylformamide (25 mL) were stirred at room temperature for 1 hour. After an extractive work-up, the crude was chrystallized from dichloromethane/petroleum ether to give 1.0 g (83% yield) of l-(5,6- dimethyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide.
(c) The title compound was prepared from l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-JV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.30 g, 0.87 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.48 mmol), l-fluoro-4-iodobenzene (3.48 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.130 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0435 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 9 mg (2.3 % yield) of l-(l-(4-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as a pale green solid. LC-MS (m/z) 437.2 (M+l).
Example 118: l-(l-(3-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000140_0002
The title compound was prepared from l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.30 g, 0.87 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.48 mmol), l-bromo-3-fluorobenzene (3.48 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.130 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0435 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 22 mg (6 % yield) of l-(l-(3-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as a pale green solid. LC-MS (m/z) 437.1 (M+l).
Example 119: l-(l-(3,5-difluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000141_0001
The title compound was prepared from l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-iV-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.30 g, 0.87 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.48 mmol), l-bromo-3,5-difluorobenzene (3.48 mmol), 4,7-dimethoxy- 1,10-phenanthroline (0.130 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0435 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 32 mg (8 % yield) of l-(l-(3,5-difluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as a off-white solid. LC-MS (m/z) 455.2 (M+l).
Example 120: l-(l-(4-chlorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000141_0002
The title compound was prepared from l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-JV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.30 g, 0.87 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.48 mmol), l-bromo-4-chlorobenzene (3.48 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.130 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0435 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 61 mg (15 % yield) of l-(l-(4-chlorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as a off-white solid. LC-MS (m/z) 453.3 (M+l).
Example 121: l-CS^-dimethyl-l-C^CtrifluoromethyOpheny^-lH-benzoIdlimidazol-l-yO-TV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000142_0001
The title compound was prepared from l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-iV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.30 g, 0.87 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.48 mmol), l-bromo-4-(trifluoromethyl)benzene (3.48 mmol), 4,7- dimethoxy-l,10-phenanthroline (0.130 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0435 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 54 mg (12 % yield) of l-(5,6-dimethyl-l-(4-(trifluoromethyl)phenyl)-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale green solid. LC-MS (m/z) 487.2 (M+l).
Example 122: l-(l-(3,5-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000142_0002
The title compound was prepared from l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-JV-(tetra- hydrofuran-3-yl)piperidine-4-carboxamide (0.30 g, 0.87 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.48 mmol), l-bromo-3,5-dimethylbenzene (3.48 mmol), 4,7-dimethoxy- 1,10-phenanthroline (0.130 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0435 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 24 mg (6.1 % yield) of l-(l-(3,5-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydro- furan-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 447.2 (M+l).
Example 123: l-(5,6-dimethyl-l-(naphthalen-2-yl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000143_0001
The title compound was prepared from l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-iV-(tetra- hydrofuran-3-yl)piperidine-4-carboxamide (0.30 g, 0.87 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.48 mmol), 2-bromonaphthalene (3.48 mmol), 4, 7-dimethoxy- 1,10- phenanthroline (0.130 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0435 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 5 mg (1.2 % yield) of 1 -(5,6-dimethyl- 1 -(naphthalen-2-yl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)- piperidine-4-carboxamide as a pale green solid. LC-MS (m/z) 469.1 (M+l).
Example 124: l-(l-(benzo[d] [l,3]dioxol-5-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000143_0002
The title compound was prepared from l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V-(tetra- hydrofuran-3-yl)piperidine-4-carboxamide (0.30 g, 0.87 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.48 mmol), 5-bromobenzo[d][l,3]dioxole (3.48 mmol), 4,7-dimethoxy- 1,10-phenanthroline (0.130 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0435 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 24 mg (6 % yield) of 1 -( 1 -(benzo[d] [1,3] dioxo 1-5 -yl)-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)-N-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 463.2 (M+ 1). Example 125: l-(5,6-dichloro-l-(3-methoxyphenyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000144_0001
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.3 g, 0.78 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.092 mmol), l-bromo-3-methoxybenzene (0.936 mmol), 4,7-dimethoxy-
1,10-phenanthroline (0.117 mmol), polyethylene glycol (0.039 mmol) and copper(I) oxide (0.039 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 18 hours in a sealed tube and purified with column chromathography, to give 52 mg (13.6 % yield) of 1 -(5,6-dichloro- 1 -(3-methoxyphenyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 489.4 (M+ 1).
Example 126: l-(l-(benzo[d] [l,3]dioxol-5-yl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000144_0002
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.3 g, 0.78 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.092 mmol), 5-bromobenzo[d][l,3]dioxole (0.936 mmol), 4,7-dimethoxy- 1,10-phenanthroline (0.117 mmol), polyethylene glycol (0.039 mmol) and copper(I) oxide (0.039 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 18 hours in a sealed tube and purified with column chromathography, to give 41 mg (10.5 % yield) of l-(l-(benzo[d][l,3]dioxol-5-yl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 503.4 (M+l). Example 127: l-(5,6-dichloro-l-(4-cyanophenyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000145_0001
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.3 g, 0.78 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.092 mmol), 4-bromobenzonitrile (0.936 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.117 mmol), polyethylene glycol (0.039 mmol) and copper(I) oxide (0.039 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 18 hours in a sealed tube and purified on preperative reverse-phase hplc, to give 13 mg (3.4 % yield) of 1 -(5,6-dichloro- 1 -(4-cyanophenyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 484.4 (M+l).
Example 128: 7V-cyclopentyl-l-(5,6-dimethyl-l-m-tolyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000145_0002
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.30 g, 0.87 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.48 mmol), l-bromo-3-methylbenzene (3.48 mmol), 4,7-dimethoxy-l,10-phenanthroline (0.130 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.044 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 12 mg (3.2 % yield) of N-cyclopentyl-1- (5,6-dimethyl-l-m-tolyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 431.2 (M+ 1).
Example 129: 7V-cyclopentyl-l-(l-(3,4-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol- 2-yl)piperidine-4-carboxamide
Figure imgf000146_0001
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.30 g, 0.829 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.316 mmol), 4-bromo-l,2-dimethylbenzene (3.316 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.132 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.044 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 2 mg (0.52 % yield) of N-cyclopentyl- 1 -( 1 -(3 ,4-dimethylphenyl)-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide as a white solid. LC-MS (m/z) 445.2 (M+l). Example 130: 7V-cyclopentyl-l-(l-(4-fluoro-3-methylphenyl)-5,6-dimethyl-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000146_0002
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.30 g, 0.829 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.316 mmol), 4-bromo-l-fluoro-2-methylbenzene (3.316 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.132 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.044 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 5 mg (1.3 % yield) of N-cyclopentyl-l-(l-(4-fluoro-3-methylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 449.1 (M+ 1).
Example 131: 7V-cyclopentyl-l-(l-(4-ethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000147_0001
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.30 g, 0.829 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.316 mmol), l-bromo-4-ethylbenzene (3.316 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.132 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.044 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 10 mg (2.5 % yield) of N-cyclopentyl-l-(l-(4-ethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide as an off-white solid. LC-MS (m/z) 445.2 (M+ 1).
Example 132: 7V-cyclopentyl-l-(l-(4-isopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000147_0002
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.30 g, 0.829 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.316 mmol), l-bromo-4-isopropylbenzene (3.316 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.132 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.044 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 6 mg (1.5 % yield) of N-cyclopentyl-l-(l-(4-isopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide as an off-white solid. LC-MS (m/z) 459.2 (M+ 1).
Example 133: 7V-cyclopentyl-l-(5,6-dimethyl-l-(quinolin-6-yl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000148_0001
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.30 g, 0.829 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.316 mmol), 6-bromoquinoline (3.316 mmol), 4,7-dimethoxy-l,10-phenanthroline (0.132 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.044 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 16 mg (3.9 % yield) of N-cyclopentyl-1- (5,6-dimethyl-l-(quinolin-6-yl)-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 468.2 (M+l).
Example 134: 7V-cyclopentyl-l-(5,6-dimethyl-l-(quinoxalin-6-yl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000148_0002
The title compound was prepared fromN-cyclopentyl-l-(5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.30 g, 0.829 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.316 mmol), 6-bromoquinoxaline (3.316 mmol), 4,7-dimethoxy-l,10-phenanthroline (0.132 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.044 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 15 mg (3.6 % yield) of N-cyclopentyl-1- (5 ,6-dimethyl- 1 -(quinoxalin-6-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a yellow solid. LC-MS (m/z) 469.2 (M+l).
Example 135: l-(5,6-dichloro-l-(4-(methylcarbamoyl)phenyl)-lH-benzo[d]imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000149_0001
A reaction mixture consisting of l-(l-(4-bromophenyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)- N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.19 mmol), trans -di(μ-acQtato)- bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II) (Hermann palladacycle, 0.0095 mmol), N,N- diisopropylethylamine (Hunig's base, DIEA, 0.38 mmol), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.19 mmol), tri tertiarybutyl phosphonium tetrafluoborate ([(t-Bu)3PH]BF4, 0.019 mmol), molybdenum hexacarbonyl (Mo(CO)6, 0.095 mmol) and methyl amine hydrochloride (0.38 mmol) in 1,4-dioxane (3 mL), was irradiated under microwave conditions at 15O0C for 30 minutes. The reaction mixture was quenched with water (5 mL), extracted with dichloromethane (2 x50 mL) and the combined organic phases dried over anhydrous sodium sulphate. After concentration in vacuo, the residue was subjected to column chromatography to give 10 mg (10 % yield) of l-(5,6-dichloro-l-(4-(methylcarbamoyl)phenyl)-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide.
Example 136: (R)-l-(5,6-dichloro-l-(3-methoxyphenyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000149_0002
(a) Preparation of the intermediate compound ethyl l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylate
Figure imgf000150_0001
2,5,6-trichloro-lH-benzo[d]imidazole (1 g, 5.0 mmol) was mixed with 1,4-dioxane (9 mL) and ethyl piperidine-4-carboxylate (0.85 g, 5.0 mmol) was added, followed by JV,iV-diisopropyl- ethylamine (Ηunig's base, DIEA, 1.034 g, 8 mmol). The reaction mixture was subjected to microwave conditions for one hour at 18O0C, purified on column (silica gel, hexane/ethyl acetate, gradient elution, 20-70 % ethyl acetate) to give 1.33 g (87 % yield) of ethyl l-(5,6- dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate as a brown solid. LC-MS (m/z) 342.0 (M+l).
(b) Preparation of the intermediate compound l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylic acid
Figure imgf000150_0002
Ethyl l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (0.60 g, 2.0 mmol) was dissolved in ethanol (150 mL) and aqueous sodium hydroxide (1 N, 17.5 mL) was added. The reaction mixture was stirred at room temperature for two days, concentrated in vacuo and pΗ adjusted to 4-5 with addition of aqueous hydrochloric acid (1 N). The formed precipitate was filtered off, the aqueous mother liquid extracted three times with dichloromethane (100 mL) and the combined organic phases concentrated in vacuo. The crude carboxylic acid (precipitate and the residue from the extraction) was purified on column (silica gel, ethyl acetate/methanol/formic acid, gradient elution 10-15 % methanol, 0.1 % formic acid) to give 0.53 g (90% purity) of 1- (5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid that was used directly in the next step.
(c) Preparation of the intermediate compound (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000150_0003
l-(5,6-Dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (628 mg, 2.0 mmol), (R)-(+)-tetrahydrofuran-3-amine 4-methylbenzenesulfonate (622 mg, 2.4 mmol), 2-(7-aza-lH- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU, 912 mg, 2.4 mmol), JV,JV-diisopropylethylamine (Hunig's base, DIEA, 775 mg, 6.0 mmol) and N5N- dimethylformamide (25 niL) was stirred at room temperature for 100 minutes. The reaction mixure was concentrated in vacuo, the residue purified on column (silica gel, flash
chromatography, dichloromethane/methanol, gradient elution 4-20 % methanol) and finally precipitated from chloroform to give 378 mg (49 % yield) of (R)-l-(5,6-dichloro-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid. LC- MS (m/z) 382.9 (M+ 1).
(d) A mixture of (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide (57.5 mg, 0.15 mmol), dimethylsulfoxide (0.7 mL), caesium carbonate (68.4 mg, 0.21 mmol), l-iodo-3-methoxybenzene (70.2 mg, 0.3 mmol), 8- hydroxyquinoline (4.4 mg, 0.03 mmol), polyethylene glycol 400 (60 mg, 0.15 mmol) and copper(I) oxide (2.1 mg, 0.015 mmol) was subjected to microwave conditions for one hour at 15O0C. The reaction mixture was filtered and subjected to preparative hplc (performed on a Gilson-Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using methano I/water (0.05 % formic acid) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 21.7 mg (30 % yield) of (R)- 1 -(5,6- dichloro-l-(3-methoxyphenyl)-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide. LC-MS (m/z) 488.9 (M+ 1). Example 137: 7V-cyclopentyl-l-(5,6-dichloro-l-(pyridin-3-yl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000151_0001
The title compound was prepared fromN-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (38 mg, 0.0997 mmol), dimethylsulfoxide (0.7 mL), caesium carbonate (32 mg, 0.0997 mmol), 3-iodopyridine (61.3 mg, 0.299 mmol), 8-hydroxyquinoline (3 mg, 0.0199 mmol), polyethylene glycol 400 (20 mg, 0.0498 mmol) and copper(I) oxide (1.4 mg, 0.00997 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for one hour at 15O0C and subsequently purified on reverse-phase hplc, to give 12 mg (26 % yield) of N-cyclopentyl-l-(5,6-dichloro-l-(pyridin-3-yl)-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a brown solid. LC-MS (m/z) 458.0 (M+l).
Example 138: 7V-cyclopentyl-l-(5,6-dichloro-l-(pyridin-3-yl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000152_0001
The title compound was prepared fromN-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (38 mg, 0.0997 mmol), dimethylsulfoxide (0.7 mL), caesium carbonate (32 mg, 0.0997 mmol), 2-bromopyridine (47.2 mg, 0.299 mmol), 8-hydroxyquinoline (3 mg, 0.0199 mmol), polyethylene glycol 400 (20 mg, 0.0498 mmol) and copper(I) oxide (1.4 mg, 0.00997 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for one hour at 15O0C and subsequently purified on reverse- phase hplc, to give 13 mg (28 % yield) of N-cyclopentyl-l-(5,6-dichloro-l-(pyridin-3-yl)-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a brownish solid. LC-MS (m/z) 458.0 (M+l). Example 139: 7V-cyclopentyl-l-(5,6-dichloro-l-(6-methoxypyridin-2-yl)-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000152_0002
The title compound was prepared from N-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (38 mg, 0.0997 mmol), dimethylsulfoxide (0.5 mL), caesium carbonate (32 mg, 0.0997 mmol), 2-bromo-6-methoxypyridine (56.2 mg, 0.299 mmol), 8- hydroxyquinoline (3 mg, 0.0199 mmol), polyethylene glycol 400 (20 mg, 0.0498 mmol) and copper(I) oxide (1.4 mg, 0.00997 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for one hour at 15O0C and subsequently purified on reverse-phase hplc, to give 22 mg (45 % yield) of N-cyclopentyl-l-(5,6-dichloro-l- (pyridin-3-yl)-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a beige solid. LC-MS (m/z) 488.0 (M+ 1).
Example 140: 7V-cyclopentyl-l-(5,6-dichloro-l-(4-cyanophenyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000153_0001
The title compound was prepared fromN-cyclopentyl-l-(5,6-dichloro-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (38 mg, 0.0997 mmol), dimethylsulfoxide (0.7 mL), caesium carbonate (45.5 mg, 0.14 mmol), 4-iodobenzonitrile (68.5 mg, 0.299 mmol), 8-hydroxyquinoline (3 mg, 0.0199 mmol), polyethylene glycol 400 (20 mg, 0.0498 mmol) and copper(I) oxide (1.4 mg, 0.00997 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for one hour at 15O0C and subsequently purified on reverse- phase hplc, to give 10.5 mg (22 % yield) of N-cyclopentyl-l-(5,6-dichloro-l-(4-cyanophenyl)- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a brownish solid. LC-MS (m/z) 482.0 (M+l). Example 141: (R)-l-(5,6-dichloro-l-(4-fluorophenyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000153_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (38.3 mg, 0.10 mmol), dimethylsulfoxide (0.7 mL), caesium carbonate (45.6 mg, 0.14 mmol), l-fluoro-4-iodobenzene (44.4 mg, 0.20 mmol), 8-hydroxyquinoline (2.9 mg, 0.02 mmol), polyethylene glycol 400 (40 mg, 0.1 mmol) and copper(I) oxide (1.4 mg, 0.01 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for one hour at 15O0C and subsequently purified on reverse-phase hplc, to give 14 mg (29 % yield) of (R)-l-(5,6-dichloro-l-(4-fluorophenyl)-lH- benzo[d]-imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 476.9 (M+l).
Example 142: (R)-l-(5,6-dichloro-l-(3-fluorophenyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000154_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (38.3 mg, 0.10 mmol), dimethylsulfoxide (0.7 mL), caesium carbonate (45.6 mg, 0.14 mmol), l-fluoro-3-iodobenzene (44.4 mg, 0.20 mmol), 8-hydroxyquinoline (2.9 mg, 0.02 mmol), polyethylene glycol 400 (40 mg, 0.1 mmol) and copper(I) oxide (1.4 mg, 0.01 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for one hour at 15O0C and subsequently purified on reverse-phase hplc, to give 6 mg (13 % yield) of (R)-l-(5,6-dichloro-l-(3-fluorophenyl)-lH- benzo[d]-imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 477.0 (M+l).
Example 143: (R)-l-(5,6-dichloro-l-(4-methoxyphenyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000154_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (38.3 mg, 0.10 mmol), dimethylsulfoxide (0.7 mL), caesium carbonate (45.6 mg, 0.14 mmol), l-iodo-4-methoxybenzene (46.8 mg, 0.20 mmol), 8-hydroxyquinoline (2.9 mg, 0.02 mmol), polyethylene glycol 400 (40 mg, 0.1 mmol) and copper(I) oxide (1.4 mg, 0.01 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for one hour at 15O0C and subsequently purified on reverse-phase hplc, to give 9.5 mg (49 % yield) of (R)-l-(5,6-dichloro-l-(4- methoxyphenyl)- lH-benzo [d]imidazo l-2-yl)-N-(tetrahydrofuran-3 -yl)piperidine-4-carboxamide . LC-MS (m/z) 489.0 (M+l).
Example 144: (R)-l-(l-(4-tert-butylphenyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000155_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (38.3 mg, 0.10 mmol), dimethylsulfoxide (0.7 mL), caesium carbonate (45.6 mg, 0.14 mmol), l-bromo-4-tert-butylbenzene (42.6 mg, 0.20 mmol), 8-hydroxyquinoline (5.8 mg, 0.04 mmol), polyethylene glycol 400 (40 mg, 0.1 mmol) and copper(I) oxide (2.9 mg, 0.02 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for one hour at 15O0C and subsequently purified on reverse-phase hplc, to give 8.2 mg (16 % yield) of (R)-l-(l-(4-tert-butylphenyl)-5,6- dichloro-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 515.0 (M+l).
Example 145: (R)-l-(5,6-dichloro-l-(4-(trifluoromethoxy)phenyl)-lH-benzo[d]imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000155_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (38.3 mg, 0.10 mmol), dimethylsulfoxide (0.7 mL), caesium carbonate (45.6 mg, 0.14 mmol), l-iodo-4-(trifluoromethoxy)benzene (57.6 mg, 0.20 mmol), 8-hydroxyquinoline (2.9 mg, 0.02 mmol), polyethylene glycol 400 (40 mg, 0.1 mmol) and copper(I) oxide (1.4 mg, 0.01 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 15O0C, filtered and subsequently purified on reverse-phase hplc, to give 15.2 mg (28 % yield) of (R)-I -(5,6- dichloro- 1 -(4-(trifluoromethoxy)phenyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide. LC-MS (m/z) 543.0 (M+ 1).
Example 146: l-(5,6-dichloro-l-phenyl-lH-benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3- yl)piperidine-4-carboxamide
Figure imgf000156_0001
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.3 g, 0.78 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.092 mmol), iodobenzene (0.936 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.117 mmol), polyethylene glycol (0.039 mmol) and copper(I) oxide (0.039 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 18 hours in a sealed tube and purified with column chromathography, to give 10 mg (2.8 % yield) of l-(5,6-dichloro-l-phenyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as a brown solid. LC-MS (m/z) 459.1 (M+ 1).
Example 147: l-(5,6-dichloro-l-(pyridin-2-yl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000156_0002
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.3 g, 0.78 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.092 mmol), 2-bromopyridine (0.936 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.117 mmol), polyethylene glycol (0.039 mmol) and copper(I) oxide (0.039 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 18 hours in a sealed tube and purified with column chromathography, to give 26 mg (7.2 % yield) of 1 -(5,6-dichloro- 1 -(pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 460.6 (M+l).
Example 148: l-(5,6-dichloro-l-(pyridin-3-yl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000157_0001
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.3 g, 0.78 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.092 mmol), 3-bromopyridine (0.936 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.117 mmol), polyethylene glycol (0.039 mmol) and copper(I) oxide (0.039 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 18 hours in a sealed tube and purified with column chromathography, to give 5 mg (1.4 % yield) of 1 -(5,6-dichloro- l-(pyridin-3-yl)-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 460.5 (M+l).
Example 149: l-(5,6-dichloro-l-p-tolyl-lH-benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3- yl)piperidine-4-carboxamide
Figure imgf000157_0002
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.3 g, 0.78 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.092 mmol), 4-bromotoluene (0.936 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.117 mmol), polyethylene glycol (0.039 mmol) and copper(I) oxide (0.039 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 18 hours in a sealed tube and purified with column chromathography, to give 27 mg (7.3 % yield) of 1 -(5,6-dichloro- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 473.4 (M+l). Example 150: (R)- l-(l-(4-chloro-3-methoxyphenyl)-5,6-dimethyl- lH-benzo [d] imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000158_0001
(a) Preparation of the intermediate compound (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)- N-(tetrahydrofuran-3 -yl)piperidine-4-carboxamide :
Figure imgf000158_0002
l-(5,6-Dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (1.0 g, 3.6 mmol), (R)- (+)-tetrahydrofuran-3 -amine 4-methylbenzenesulfonate (4.3 mmol), 2-(7-aza-lH-benzotriazole- l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 7.2 mmol), N5N- diisopropylethylamine (Ηunig's base, DIEA, 7.2 mmol) and N,N-dimethylformamide (25 mL) was stirred at room temperature for 1 hour. After the appropriate work-up, the residue was recrystallized from dichloromethane/petroleum ether to give 0.96 g (77 % yield) of (R)-l-(5,6- dimethyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide.
(b) The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.584 mmol), 4-bromo-l-chloro-2-methoxybenzene (0.876 mmol), 8- hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase hplc, to give 15 mg (10 % yield) of (R)-l-(l-(4-chloro-3-methoxyphenyl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a yellow solid. LC-MS (m/z) 483.3 (M+l).
Example 151: (R)- l-(5,6-dichloro- l-(4-chloro-3-methoxyphenyl)- lH-benzo [d] imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000159_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 4-bromo-l-chloro-2-methoxybenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase hplc, to give 23 mg (17 % yield) of (R)-l-(5,6-dichloro-l-(4-chloro-3-methoxyphenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a yellow solid. LC-MS (m/z) 523.5 (M+l).
Example 152: (R)-l-(l-(2,3-dihydrobenzofuran-5-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000159_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.584 mmol), 5-bromo-2,3-dihydrobenzofuran (0.876 mmol), 8- hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase hplc, to give 5 mg (3.7 % yield) of (R)-l-(l-(2,3-dihydrobenzofuran-5-yl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 461.2 (M+l).
Example 153: (R)-l-(5,6-dichloro-l-(2,3-dihydrobenzofuran-5-yl)-lH-benzo[d]imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000160_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 5-bromo-2,3-dihydrobenzofuran (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase hplc, to give 7 mg (5.3 % yield) of (R)-l-(5,6-dichloro-l-(2,3-dihydrobenzofuran-5-yl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a yellow solid. LC-MS (m/z) 501.6 (M+l).
Example 154: (RJ-l-Cl-CS^-diethylpheny^-S^-dimethyl-lH-benzoIdlimidazoU-yO-TV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000160_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (200 mg, 0.584 mmol) dimethylsulfoxide (2 mL), caesium carbonate (1.17 mmol), l-bromo-3,5-diethylbenzene (1.75 mmol), 8- hydroxyquinoline (0.234 mmol), polyethylene glycol (0.292 mmol) and copper(I) oxide (0.117 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase hplc, to give 4 mg (1.5 % yield) of (R)-l-(l-(3,5-diethylphenyl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a brown solid. LC- MS (m/z) 475.2 (M+l).
Example 155: l-(5,6-dichloro-l-(cyclobutylmethyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000161_0001
The title compound was prepared from l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.1 g, 0.26 mmol), (bromomethyl)cyclobutane (1.04 mmol), caesium carbonate (1.04 mmol), [l,r-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), 0.026 mmol) and N,Λ/-dimethylformamide (8 mL) using the method described in Example 16. The reaction mixture was heated at 13O0C for two hours in a sealed tube and purified with column chromathography, to give 15 mg (12.8 % yield) of l-(5,6- dichloro-l-(cyclobutylmethyl)-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a pale yellow solid. LC-MS (m/z) 449.3 (M+l). Example 156: (R)-l-(l-(4-fluoro-3-methylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000161_0002
(c) The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.35 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.4 mmol), 4-bromo-l-fluoro-2-methylbenzene (1.4 mmol), 8- hydroxyquinoline (0.07 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0175 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on column chromatography, to give 30.5 mg (30 % yield) of (R)-l-(l-(4-fluoro-3-methylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol- 2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 451.1 (M+l).
Example 157: (R)-l-(l-(4-ethylphenyl)-5,6-dimethyl-lΗ-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000162_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.35 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.4 mmol), l-bromo-4-ethylbenzene (1.4 mmol), 8-hydroxyquinoline (0.07 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0175 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on column chromatography (silica gel), to give 19 mg (12 % yield) of (R)-l-(l-(4-ethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 447.2 (M+l). 1H NMR (400 MHz, DMSO-d6): (for the aromatic region and -NH-)
δ 8.03 (IH, NH), 7.44 (4H), 7.21 (IH), 6.82 (IH).
Example 158: (RJ-l-Cl-CS^-dimethylphenylJ-S^-dimethyl-lH-benzoIdlimidazol-l-yl)-^- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000162_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.35 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.4 mmol), 4-bromo-l,2-dimethylbenzene (1.4 mmol), 8- hydroxyquinoline (0.07 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0175 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on column chromatography, to give 25 mg (16 % yield) of (R)-l-(l-(3,4-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)- N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 447.1 (M+l). Example 159: (R)- l-(5,6-dimethyl- l-(quinolin-6-yl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000163_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.35 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.4 mmol), 6-bromoquinoline (1.4 mmol), 8-hydroxyquinoline (0.07 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0175 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on column chromatography, to give 15 mg (9 % yield) of (R)- 1 -(5,6-dimethyl- 1 -(quinolin-6-yl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 470.1 (M+ 1).
Example 160: (R)-l-(l-(4-isopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000163_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.35 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.4 mmol), l-bromo-4-isopropylbenzene (1.4 mmol), 8-hydroxyquinoline (0.07 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0175 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on column chromatography, to give 5 mg (3 % yield) of (R)-l-(l-(4-isopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale green solid. LC-MS (m/z) 461.2 (M+l). Example 161: (R)- l-(l-(4-tert-butylphenyl)-5,6-dimethyl- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000164_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.35 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.4 mmol), l-bromo-4-tert-butylbenzene (1.4 mmol), 8-hydroxy- quinoline (0.07 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0175 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on column chromatography, to give 27 mg (16 % yield) of (R)-l-(l-(4-tert-butylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 475.2 (M+l).
Example 162: (R)-l-(l-(3-chlorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000164_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.35 mmol), dimethylsulfoxide (6 mL), caesium carbonate (1.4 mmol), l-bromo-3-chlorobenzene (1.4 mmol), 8-hydroxy-quinoline (0.07 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0175 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on column chromatography, to give 54 mg (34 % yield) of (R)-l-(l-(3-chlorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 453.2 (M+l). Example 163: l-(6-chloro-5-methyl-l-phenyl-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide
Figure imgf000165_0001
(a) Preparation of the intermediary compound N-(5-chloro-4-methyl-2-nitrophenyl)acetamide:
Figure imgf000165_0002
Potassium nitrate (10.11 g, 0.10 mol) in concentrated sulphuric acid (21.3 mL) was added drop- wise to N-(3-chloro-4-methylphenyl)acetamide (18.36 g, 0.10 mol) in concentrated sulphuric acid (101.3 mL) at 5°C. After 5 hours stirring below 5°C, the reaction mixture was carefully poured out on ice water (500 mL), the formed precipitate filtered off, and washed with water (50 mL), ώo-propanol (10 mL) and ώo-hexane (30 mL). The precipitate was recrystallized from ethanol (160 mL, 95 %) to give 10.3 g (45 % yield) of N-(5-chloro-4-methyl-2-nitrophenyl)- acetamide.
(b) Preparation of the intermediary compound 5-chloro-4-methyl-2-nitroaniline:
Figure imgf000165_0003
Sodium ethoxide (8.27 g, 45.9 mmol) in ethanol (10 mL) was added to (N-(5-chloro-4-methyl-2- nitrophenyl)acetamide (7.0 g, 30.6 mmol) in ethanol (10 mL) while stirring at room temperature. After one hour the reaction mixture was poured out in water (100 mL), the precipitate filtered off, and washed with a mixture of ώo-propanol and ώo-hexane (1:3, 10 mL) followed by iso- hexane (10 mL). This gave 5.71 g (85 % yield) of 5-chloro-4-methyl-2-nitroaniline. LC-MS (m/z) 187.0 (M+l).
(c) Preparation of the intermediary compound 5-chloro-4-methyl-2-nitro-N-phenylaniline
Figure imgf000166_0001
5-Chloro-4-methyl-2-nitroaniline (560 mg, 3.0 mmol), bromobenzene (3.0 g, 0.019 mmol), tripotassium phosphate (1.27 g, 6 mmol), bis(tri-tert-butylphosphine)palladium(0) (Pd[P(t- Bu)3]2, 0.05, 0.0978 mmol) and toluene (5 mL) was heated at 1200C under nitrogen gas over night. The reaction mixture was purified on column (silica gel, flash chromatography, gradient elution iso-hexane/ethyl acetate 100-90 % : 0-10 %) to give 503 mg (64 %) of 5-chloro-4- methyl-2-nitro-N-phenylaniline. LC-MS (m/z) 262.9 (M+l).
(d) Preparation of the intermediary compound 5-chloro-4-methyl-N1-phenylbenzene-l,2-diamine
Figure imgf000166_0002
A solution of tin(II) chloride dehydrate (1.89 g, 8.39 mmol) in concentrated hydrochloric acid (2.5 mL) was added to a stirred suspension of 5-chloro-4-methyl-2-nitro-N-phenylaniline in a mixture of ethanol and concentrated hydrochloric acid (4 mL, 1 :1 mixture) at room temperature. The reaction mixture was heated at 9O0C, poured out on water (20 mL), stirred for 5 minutes and filtered. The solid was added to water, the mixture made alkaline with sodium hydroxide and stirred for 5 minutes. The precipitate was filtered off, washed with water (5 mL) and dried under vacuum to give 395 mg (91 % yield) of 5-chloro-4-methyl-N1-phenylbenzene-l,2-diamine. LC- MS (m/z) 233.0 (M+l).
(e) Preparation of the intermediary compound 6-chloro-5-methyl-l -phenyl- IH- benzo[d]imidazol-2(3Η)-one.
Figure imgf000166_0003
To a stirred slurry of 5-chloro-4-methyl-N1-phenylbenzene-l,2-diamine (100 mg, 0.43 mmol) in tetrahydrofuran (5 rnL) at room temperature was added lj'-carbonyldiimidazole (CDI, 104.5 mg, 0.645 mmol) over 10 min. The reaction mixture was stirred at 4O0C over night, concentrated in vacuo, and partitioned between diethyl ether (10 mL) and aqueous sodium hydroxide (I N, 10 mL). The aqueous layer was washed with diethyl ether (10 mL) and neutralized with aqueous hydrochloric acid. The formed precipitate was washed with water (2 mL) and dried under vacuum to give 66.6 mg (60 %) of 6-chloro-5-methyl-l -phenyl- lH-benzo[d]imidazol-2(3H)-one. LC-MS (m/z) 258.9 (M+l).
(f) 6-Chloro-5-methyl-l -phenyl- lH-benzo[d]imidazol-2(3H)-one (42.4 mg, 0.164 mmol) was stirred in phosphoryl trichloride (POCI3, 5 g) at reflux for 6 hours and concentrated in vacuo (co- evaporation with toluene). Water (10 ml) was added to the residue, followed by an aqueous saturated sodium bicarbonate solution (10 mL). The aqueous layer was extracted twice with dichloromethane (20 mL), the combined organic layer dried over magnesium sulfate and concentrated in vacuo. The residue, N-cyclopentylpiperidine-4-carboxamide (29. mg, 0.136 mmol) and 1 ,2-dimethoxyethane (DME, 0.8 mL) was subjected to microwave conditions for one hour at 18O0C. After work-up, the residue was subjected to preparative hplc (performed on a Gilson-Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using methano I/water (0.05 % formic acid) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 2.8 mg of l-(6-chloro-5-methyl-l- phenyl- lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide. LC-MS (m/z) 437.1 (M+l).
Example 164 : (R)- l-(5-chloro-6-methyl- 1-p-tolyl- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000167_0001
(a) Preparation of the intermediary tautomeric compounds 2,5-dichloro-6-methyl-lH- benzo[d]imidazole hydrochloride and 2,6-dichloro-5-methyl-lH-benzo[d]imidazole
hydrochloride :
Figure imgf000168_0001
To 5-chloro-6-methyl-lH-benzo[d]imidazol-2(3H)-one (0.627 g, 3.43 mmol), phosphoryl trichloride (POCI3, 21.1 g, 0.137 mol) was added, the reaction mixture was heated at 1000C for 6 hours and subsequently cooled down to room temperature. The formed precipitate was filtered off and washed with toluene. The filtrate was concentrated in vacuo and collected. This gave 674 mg (83 % yield) of 2,5-dichloro-6-methyl-lH-benzo[d]imidazole hydrochloride and 2,6- dichloro-5-methyl-lH-benzo[d]imidazole hydrochloride. LC-MS (m/z) 200.9 (M+ 1).
(b) Preparation of the intermediary tautomeric compounds ethyl l-(5-chloro-6-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate and ethyl l-(6-chloro-5-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate :
Figure imgf000168_0002
2,5-dichloro-6-methyl-lH-benzo[d]imidazole hydrochloride and 2,6-dichloro-5-methyl-lH- benzo[d]imidazole hydrochloride (0.60 g, 2.526 mmol), 1,4-dioxane (10 mL), N,N- diisopropylethylamine (Ηunig's base, DIEA, 0.979 g, 7.578 mmol) and ethyl piperidine-4- carboxylate (0.477 g, 3.03 mmol) was subjected to microwave conditions for one hour at 19O0C. The reaction mixture was concentrated in vacuo and purified on column (silica gel,
dichloromethane/methanol 98:2) to give 0.498 g (61 % yield) of ethyl l-(5-chloro-6-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate and ethyl l-(6-chloro-5-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate. No effort was done to to determine the ratio of the tautomers. LC-MS (m/z) 321.9 (M+ 1 )
(c) Preparation of the intermediary intermediate compound ethyl l-(5-chloro-6-methyl-l-p-tolyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate:
Figure imgf000168_0003
A mixture of ethyl l-(5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate and its tautomer ethyl l-(6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (56 mg, 0.174 mmol), dimethylsulfoxide (0.5 mL), caesium carbonate (79.4 mg, 0.24 mmol), 1-iodo- 4-methylbenzene (75.9 mg, 0.348 mmol), 8-hydroxyquinoline (5.1 mg, 0.035 mmol), polyethylene glycol 400 (34.8 mg) and copper(I) oxide (2.5 mg, 0.017 mmol) was subjected to microwave conditions for 50 minutes at 15O0C. The reaction mixture was poured out on aqueous saturated sodium bicarbonate (50 mL), extracted three times with dichloromethane (30 mL), the combined organic phases washed with water, dried over magnesium sulphate and finally purified on column (Silica gel, automated flash chromatography, dichloromethane/methanol, gradient elution using 0.6-0.9 % methanol). This gave 7.0 mg of ethyl l-(5-chloro-6-methyl-l -p-tolyl- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate that eluted before ethyl l-(6-chloro-5-methyl-l- p-tolyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate on the column. The identity of ethyl l-(5-chloro-6-methyl-l-p-tolyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate and ethyl 1- (6-chloro-5-methyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate was confirmed using the Nuclear Overhauser enhancement spectroscopy (NOESY) experiment. Separate NMR spectas was also runned for ethyl l-(5-chloro-6-methyl-l -p-tolyl- lH-benzo[d]imidazo 1-2- yl)piperidine-4-carboxylate: 1H NMR (400 MHz, CDCl3): δ 7.56 (s, IH), 7.38-7.31 (m, 4H), 6.89 (s, IH), 4.11 (q, J=7.1 Hz, 2H), 3.63-3.55 (m, 2H), 2.94-2.84 (m, 2H), 2.48-2.33 (m, 7H), 1.90-1.81 (m, 2H), 1.73-1.58 (m, 2H), 1.25 (t, J=7.1 Hz, 3H); as well as for ethyl l-(6-chloro-5- methyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate: 1H NMR (400 MHz, CDCl3): δ 7.43 (s, IH), 7.38-7.31 (m, 4H), 7.04 (s, IH), 4.13 (q, J=7.1 Hz, 2H), 3.66-3.52 (m, 2H), 2.97-2.86 (m, 2H), 2.48-2.36 (m, 7H), 1.91-1.83 (m, 2H), 1.74-1.62 (m, 2H), 1.25 (t, J=7.1 Hz, 3H). NMR spectra were conducted on a Varian Mercury plus spectrometer, 1H at 400 MHz and 13C at 100.6 MHz at ambient temperature. (d) Ethyl l-(5-chloro-6-methyl-l -p-tolyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (7 mg), ethanol (1 mL) and aqueous sodium hydroxide (1 mL, 1 N) was stirred at room temperature for two hours. Aqueous hydrochloric acid (0.5 mL, 2 N) was added and the reaction mixture concentrated in vacuo. The residue was mixed with N,N-dimethylformamide (3 mL), N,N- diisopropylethylamine (Ηunig's base, DIEA, 0.02 mL), 2-(7-aza-lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (ΗATU, 10 mg) and (R)-(+)-tetrahydro-3-furylamine p-toluenesulfonate salt (6.5 mg, CAS Registry Number: 111769-27-8). The reaction mixture was stirred at room temperature for one hour, concentrated in vacuo and purified on column (silica gel, dichloromethane/methanol, gradient elution using 2.5-5.0 % methanol) to give 11.2 mg of : (R)- 1 -(S-chloro-β-methyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide. LC-MS (m/z) 452.9 (M+ 1).
Example 165: (R)- l-(6-chloro-5-methyl- 1-p-tolyl- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000170_0001
Ethyl 1 -(β-chloro-S-methyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (4.5 mg, eluting second after (R)- l-(5-chloro-6-methyl- 1-p-tolyl- lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as described in example 164d), ethanol (1 mL) and aqueous sodium hydroxide (1 mL, 1 N) was stirred at room temperature for two hours. Aqueous hydrochloric acid (0.5 mL, 2 N) was added and the reaction mixture concentrated in vacuo. The residue was mixed with N,N-dimethylformamide (3 mL), JV,iV-diisopropylethyl- amine (Ηunig's base, DIEA, 0.02 mL), 2-(7-aza-lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (ΗATU, 10 mg) and (R)-(+)-tetrahydro-3-furylamine p-toluenesulfonate salt (6.5 mg, CAS Registry Number: 111769-27-8). The reaction mixture was stirred at room temperature for one hour, concentrated in vacuo and purified on column (silica gel, dichloromethane/methanol, gradient elution using 2.5-5.0 % methanol) to give 3.3 mg of : (R)- 1 -(5-chloro-6-methyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide after further purification on preparative reverse-phase hplc
(performed on a Gilson-Finnigan ThermoQuest AQA system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using methano I/water (0.05 % formic acid) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection). LC-MS (m/z) 452.9 (M+ 1).
Example 166: (R)- l-(l-(4-carbamoylphenyl)-5-chloro-6-methyl- lH-benzo [d] imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000170_0002
(a) Preparation of the intermediary compound ethyl l-(5-chloro-l-(4-cyanophenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate:
Figure imgf000171_0001
A tautomeric mixture of ethyl l-(5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxylate and ethyl l-(6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (80.4 mg, 0.25 mmol), dimethylsulfoxide (0.5 mL), caesium carbonate (114 mg, 0.35 mmol), 4- iodobenzonitrile (115.5 mg, 0.5 mmol), 8-hydroxy-quinoline (7.3 mg, 0.05 mmol), polyethylene glycol 400 (100 mg, 0.25 mmol) and copper(I) oxide (3.6 mg, 0.025 mmol) was subjected to microwave conditions for one hour at 15O0C. The reaction mixture was poured out on water (5 mL) and loaded on a short column reverse-phase material (Silica gel 60, C18). The short column was washed with a mixture of acetonitrile and water (approximately 10 mL, 1 :3), and then eluted with acetonitrile. The elute was concentrated in vacuo and further purified on column (silica gel, iso-hexane/ethyl acetate, gradient elution using 25-40 % ethyl acetate), to give 23.2 mg (22 % yield ) of ethyl l-(5-chloro-l-(4-cyanophenyl)-6-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxylate, eluting ahead of ethyl l-(6-chloro-l-(4-cyanophenyl)-5-methyl-lH-benzo[d]- imidazol-2-yl)piperidine-4-carboxylate (22.1 mg, 21 % yield) on the column. LC-MS (m/z) 422.9 (M+l).
(b) Preparation of the intermediate compound l-(l-(4-carbamoylphenyl)-5-chloro-6-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid:
Figure imgf000171_0002
Ethyl 1 -(5-chloro- 1 -(4-cyanophenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxylate (23.2 mg), ethanol (2 mL) and aqueous sodium hydroxide (1 mL, 1 N) was stirred at 5O0C for one hour. The reaction mixture was neutralized with aqueous hydrochloric acid and concentrated in vacuo to give l-(l-(4-carbamoylphenyl)-5-chloro-6-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid in quantitative yield. LC-MS (m/z) 412.9 (M+l).
(c) l-(l-(4-carbamoylphenyl)-5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxylic acid (11.6 mg, 0.0281 mmol), N,N-dimethylformamide (3.0 niL), JV,iV-diisopropyl- ethylamine (Ηunig's base, DIEA, 10.9 mg, 0.0843 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-
1,1,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 12.8 mmol, 0.034 mmol) and (R)-(+)- tetrahydro-3-furylamine p-toluenesulfonate salt (8.7 mg, 0.0337 mmol, CAS Registry Number: 111769-27-8). The reaction mixture was stirred at room temperature over night, concentrated in vacuo and purified on column (silica gel, dichloromethane/methanol, gradient elution using 5.0- 10 % methanol) to give 10.3 mg (76 % yield) of (R)-l-(l-(4-carbamoylphenyl)-5-chloro-6- methyl- 1 H-benzo [d]imidazo l-2-yl)-N-(tetrahydrofuran-3 -yl)piperidine-4-carboxamide . LC-MS (m/z) 481.9 (M+l).
Example 167: l-(l-(4-carbamoylphenyl)-5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide
Figure imgf000172_0001
The title compound was prepared from l-(l-(4-carbamoylphenyl)-5-chloro-6-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (11.6 mg, 0.0281 mmol), N ,N- dimethylformamide (3.0 mL), JV,jV-diisopropyl-ethylamine (Ηunig's base, DIEA, 10.9 mg, 0.0843 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluoro- phosphate (ΗATU, 12.8 mmol, 0.034 mmol) and cyclopentanamine (2.9 mg, 0.0337 mmol) using the method described in Example 166 c). The reaction mixture was purified on column (silica gel, dichloromethane/methanol, gradient elution using 2.5-7.0 % methanol), to give 10.6 mg (79 % yield) of l-(l-(4-carbamoylphenyl)-5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide. LC-MS (m/z) 480.0 (M+l). Example 168: l-(l-(4-carbamoylphenyl)-6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide
Figure imgf000173_0001
(a) Preparation of the intermediate compound l-(l-(4-carbamoylphenyl)-6-chloro-5-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid:
Figure imgf000173_0002
Ethyl 1 -(6-chloro- 1 -(4-cyanophenyl)-5 -methyl- lH-benzo[d]-imidazol-2-yl)piperidine-4- carboxylate (22.1 mg, eluting second after ethyl l-(5-chloro-l-(4-cyanophenyl)-6-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate as described in Example 166), ethanol (2 mL) and aqueous sodium hydroxide (1 mL, 1 N) was stirred at 5O0C for one hour. The reaction mixture was neutralized with aqueous hydrochloric acid and concentrated in vacuo to give 1-(1- (4-carbamoylphenyl)-6-chloro-5-methyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid in quantitative yield. LC-MS (m/z) 412.9 (M+ 1).
(b) The title compound was prepared from l-(l-(4-carbamoylphenyl)-6-chloro-5-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (11 mg, 0.0266 mmol), N5N- dimethylformamide (3.0 mL), JV,jV-diisopropyl-ethylamine (Ηunig's base, DIEA, 10.3 mg, 0.0799 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluoro- phosphate (ΗATU, 12.2 mg, 0.033 mmol) and cyclopentanamine (2.7 mg, 0.032 mmol) using the method described in Example 166 c). The reaction mixture was purified on column (silica gel, dichloromethane/methanol, gradient elution using 2.5-7.0 % methanol), to give 10.0 mg (78 % yield) of l-(l-(4-carbamoylphenyl)-6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide. LC-MS (m/z) 480.0 (M+l).
Example 169: (R)- l-(l-(4-carbamoylphenyl)-6-chloro-5-methyl- lH-benzo [d] imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000174_0001
The title compound was prepared from l-(l-(4-carbamoylphenyl)-6-chloro-5-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (11 mg, 0.0266 mmol), N5N- dimethylformamide (3.0 mL), JV,JV-diisopropylethylamine (Ηunig's base, DIEA, 10.3 mg, 0.0799 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate
(ΗATU, 12.2 mmol, 0.033 mmol) and (R)-(+)-tetrahydro-3-furylamine p-toluenesulfonate salt (8.3 mg, 0.032 mmol, CAS Registry Number: 111769-27-8) using the method described in Example 166 c). The reaction mixture was purified on column chromatography (silica gel, dichloromethane/methanol, gradient elution using 5-10 % methanol), to give 10.9 mg (85 % yield) of (R)- 1 -( 1 -(4-carbamoylphenyl)-6-chloro-5-methyl- lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 481.9 (M+ 1).
Example 170 : (R)- l-(5-chloro-6-methyl- l-(4-(trifluoromethyl)phenyl)- lH-benzo [d] - imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000174_0002
a) Preparation of the intermediate compound ethyl l-(5-chloro-6-methyl-l-(4-(trifluoromethyl)- phenyl)-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate:
Figure imgf000174_0003
This compound was prepared from a tautomeric mixture of ethyl l-(5-chloro-6-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate and ethyl l-(6-chloro-5-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate (80.4 mg, 0.25 mmol), dimethylsulfoxide (0.7 niL), caesium carbonate (114 mg, 0.35 mmol), l-iodo-4-(trifluoromethyl)benzene (136 mg, 0.5 mmol), 8-hydroxyquinoline (7.3 mg, 0.05 mmol), polyethylene glycol 400 (100 mg, 0.25 mmol) and copper(I) oxide (3.6 mg, 0.025 mmol) using the method described in Example 166. This gave, after column chromathography (silica gel), 30.4 mg (26 % yield) of ethyl l-(5-chloro-6- methyl- 1 -(4-(trifluoromethyl)-phenyl)- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (26.4 mg, 23 % yield) eluting ahead of ethyl l-(6-chloro-5-methyl-l-(4-(trifluoromethyl)phenyl)-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate on the column. LC-MS (m/z) 465.9 (M+l). b) Preparation of the intermediate compound l-(5-chloro-6-methyl-l-(4-(trifluoromethyl)- phenyl)- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid:
Figure imgf000175_0001
Ethyl 1 -(5-chloro-6-methyl- 1 -(4-(trifluoromethyl)-phenyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylate (30.4 mg), ethanol (2 mL) and aqueous sodium hydroxide (0.5 mL, 1 N) was stirred at room temperature for one hour. The reaction mixture was neutralized with aqueous hydrochloric acid and concentrated in vacuo to give l-(l-(4-carbamoylphenyl)-5- chloro-6-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid in quantitative yield. LC-MS (m/z) 437.8 (M+l). c) The title compound was prepared from l-(l-(4-carbamoylphenyl)-5-chloro-6-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (9.4 mg, 0.021 mmol), N ,N- dimethylformamide (3.0 mL), JV,jV-diisopropylethylamine (Ηunig's base, DIEA, 8.3 mg, 0.064 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate
(ΗATU, 9.8 mg, 0.026 mmol) and (R)-(+)-tetrahydro-3-furylamine p-toluenesulfonate salt (6.7 mg, 0.026 mmol, CAS Registry Number: 111769-27-8) using the method described in Example 166 c). The reaction mixture was purified on column chromatography (silica gel,
dichloromethane/methanol, gradient elution using 2-10 % methanol), to give (R)-l-(5-chloro-6- methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]-imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide in quantitative yield. LC-MS (m/z) 506.9 (M+l).
Example 171: l-(5-chloro-6-methyl-l-(4-(trifluoromethyl)phenyl)-lH-benzo[d]imidazol-2- yl)-7V-cyclopentylpiperidine-4-carboxamide
Figure imgf000176_0001
The title compound was prepared from l-(l-(4-carbamoylphenyl)-5-chloro-6-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (9.4 mg, 0.0215 mmol), N5N- dimethylformamide (3.0 mL), JV,jV-diisopropyl-ethylamine (Ηunig's base, DIEA, 8.3 mg, 0.0644 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluoro-phosphate
(ΗATU, 9.79 mg, 0.026 mmol) and cyclopentanamine (2.2 mg, 0.0258 mmol) using the method described in Example 166 c). The reaction mixture was purified on column (silica gel, dichloromethane/methanol, gradient elution using 2-7 % methanol), to give l-(5-chloro-6- methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4- carboxamide in quantitative yield. LC-MS (m/z) 504.9 (M+ 1).
Example 172: l-(5-chloro-6-methyl-l-(4-(trifluoromethyl)phenyl)-lH-benzo[d]imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000176_0002
The title compound was prepared from l-(l-(4-carbamoylphenyl)-5-chloro-6-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (9.4 mg, 0.021 mmol), N5N- dimethylformamide (3.0 mL), N,Λ/-diisopropylethylamine (Ηunig's base, DIEA, 8.3 mg, 0.064 mmol), 2-(7-aza- lH-benzotriazole- 1 -yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 9.8 mg, 0.026 mmol) and cyclopentanamine hydrochloride (3.2 mg, 0.026 mmol) using the method described in Example 166. The reaction mixture was purified on column
chromatography (silica gel, dichloromethane/methanol, gradient elution using 2 to 8 % methanol), to give l-(5-chloro-6-methyl-l-(4-(trifluoromethyl)phenyl)-lH-benzo[d]imidazol-2- yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide in quantitative yield. LC-MS (m/z) 506.9 (M+ 1). Example 173 : (R)- l-(6-chloro-5-methyl- l-(4-(trifluoromethyl)phenyl)- lH-benzo [d] - imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000177_0001
a) Preparation of the intermediate compound l-(6-chloro-5-methyl-l-(4-(trifluoromethyl)- phenyl)- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid:
Figure imgf000177_0002
Ethyl 1 -(6-chloro-5-methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)piperidine- 4-carboxylate (26.4 mg, eluting after of ethyl l-(5-chloro-6-methyl-l-(4-(trifluoromethyl)- phenyl)-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate as described in Example 170), ethanol (2 mL) and aqueous sodium hydroxide (0.5 mL, 1 N) was stirred at room temperature for one hour. The reaction mixture was neutralized with aqueous hydrochloric acid and concentrated in vacuo to give l-(6-chloro-5-methyl-l-(4-(trifluoromethyl)-phenyl)-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylic acid in quantitative yield. LC-MS (m/z) 437.8 (M+l).
(b) The title compound was prepared from l-(6-chloro-5 -methyl- l-(4-(trifluoromethyl)-phenyl)- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (8.3 mg, 0.019 mmol), N5N- dimethylformamide (3.0 mL), JV,JV-diisopropylethylamine (Ηunig's base, DIEA, 7.4 mg, 0.0569 mmol), 2-(7-aza- lH-benzotriazole- 1 -yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 8.6 mg, 0.023 mmol) and (R)-(+)-tetrahydro-3-furylamine p-toluenesulfonate salt (5.9 mg, 0.023 mmol, CAS Registry Number: 111769-27-8) using the method described in Example 166 c). The reaction mixture was purified on column chromatography (silica gel,
dichloromethane/methanol, gradient elution using 2-8 % methanol), to give (R)-l-(l-(4- carbamoylphenyl)-6-chloro-5 -methyl- 1 H-benzo [d]imidazo l-2-yl)-N-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide in quantitative yield. LC-MS (m/z) 506.9 (M+l). Example 174: l-(6-chloro-5-methyl-l-(4-(trifluoromethyl)phenyl)-lH-benzo[d]imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000178_0001
The title compound was prepared from l-(6-chloro-5-methyl-l-(4-(trifluoromethyl)-phenyl)-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (8.5 mg, 0.019 mmol), N5N- dimethylformamide (3.0 mL), N57V-diisopropylethylamine (Ηunig's base, DIEA, 7.5 mg, 0.058 mmol), 2-(7-aza- lH-benzotriazole- 1 -yl)- 1 , 1 ,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 8.8 mg, 0.023 mmol) and tetrahydrofuran-3 -amine hydrochloride (2.9 mg, 0.023 mmol, CAS Registry Number: 204512-94-7) using the method described in Example 166 c). The reaction mixture was purified on column chromatography (silica gel, dichloromethane/methanol, gradient elution using 2-8 % methanol), to give l-(6-chloro-5-methyl-l-(4- (trifluoromethyl)phenyl)-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide in quantitative yield. LC-MS (m/z) 506.9 (M+ 1).
Example 175: l-(6-chloro-5-methyl-l-(4-(trifluoromethyl)phenyl)-lH-benzo[d]imidazol-2- yl)-7V-cyclopentylpiperidine-4-carboxamide:
Figure imgf000178_0002
The title compound was prepared from l-(6-chloro-5-methyl-l-(4-(trifluoromethyl)-phenyl)-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (8.3 mg, 0.019 mmol), N5N- dimethylformamide (3.0 mL), N,7V-diisopropyl-ethylamine (Ηunig's base, DIEA, 7.4 mg, 0.057 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluoro-phosphate
(ΗATU, 8.6 mg, 0.023 mmol) and cyclopentanamine (1.9 mg, 0.0227 mmol) using the method described in Example 166. The reaction mixture was purified on column (silica gel,
dichloromethane/methanol, gradient elution using from 2 to 8 % methanol), to give l-(6-chloro- 5-methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4- carboxamide in quantitative yield. LC-MS (m/z) 504.9 (M+ 1).
Example 176 : (R)- l-(6-chloro-5-methyl- 1-phenyl- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000179_0001
(a) Preparation of the intermediate compound 2,6-dichloro-5-methyl- 1-phenyl- IH- benzo[d]imidazole hydrochloride
Figure imgf000179_0002
6-Chloro-5-methyl-l -phenyl- lH-benzo[d]imidazol-2(3Η)-one (100 mg, 0.387 mmol) was stirred in phosphoryl trichloride (POCI3, 5.926 g) over night at relux, and concentrated in vacuo (co- evaporation with toluene), to give 2,6-dichloro-5-methyl-l -phenyl- lH-benzo[d]imidazo Ie hydrochloride in quantitative yield.
(b) Preparation of the intermediary compound ethyl l-(6-chloro-5-methyl- 1-phenyl- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate:
Figure imgf000179_0003
2,6-dichloro-5-methyl-l -phenyl- lH-benzo[d]imidazole hydrochloride (121.2 mg, 0.387 mmol), ethyl piperidine-4-carboxylate (303.8 mg, 0.2 mmol), toluene (2 mL) and N,N-dimethyl- formamide (0.5 mL) was subjected to microwave conditions at 2000C. After 30 minutes the reaction mixture was concentrated in vacuo, the residue purified on column (silica gel, iso- hexane/ethyl acetate, gradient elution from 10 to 100 % ethyl acetate) to give 27.5 mg (18 % yield) of ethyl l-(6-chloro-5-methyl-l -phenyl- lH-benzo[d]-imidazol-2-yl)piperidine-4- carboxylate. LC-MS (m/z) 398.0 (M+l).
(c) Preparation of the intermediary compound l-(6-chloro-5-methyl-l -phenyl- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid:
Figure imgf000180_0001
A mixture of ethyl l-(6-chloro-5-methyl-l -phenyl- lH-benzo[d]-imidazol-2-yl)piperidine-4- carboxylate (17.5 mg, 0.044 mmol), sodium hydroxide (8.8 mg in 1 mL water), ethanol (1 mL) was stirred at 4OC for two hours. The reaction mixture was neutralized with hydrochloric acid (2 N) and concentrated in vacuo, to give a quantitative yield of l-(6-chloro-5-methyl-l -phenyl- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid. LC-MS (m/z) 369.9 (M+l).
(d) The title compound was prepared from l-(6-chloro-5 -methyl- 1 -phenyl- lH-benzo[d]imidazol- 2-yl)piperidine-4-carboxylic acid (9.3 mg, 0.025 mmol), N,N-dimethylformamide (3.0 mL), Λ/,Λ/-diisopropyl-ethylamine (Ηunig's base, DIEA, 6.5 mg, 0.050 mmol), 2-(7-aza-lH- benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluoro-phosphate (ΗATU, 9.6 mg, 0.025 mmol) and (R)-(+)-tetrahydro-3-furylamine p-toluenesulfonate salt (6.5 mg, 0.025 mmol, CAS Registry Number: 111769-27-8) using the method described in Example 166. The reaction mixture was purified on column (silica gel, dichloromethane/methanol, gradient elution using 0 to 8 % methanol), to give 7.3 mg (66 % yield) of (R)-I -(6-chloro-5-methyl-l -phenyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 439.0 (M+l). On measure on optical rotation this compound gave (+)-rotation. 1H NMR (400 MHz, CD3OD): δ 7.67-7.60 (m, 2H), 7.55-7.48 (m, 3H), 7.34 (s, IH), 7.01 (s, IH), 4.34-4.28 (m, IH), 3.91-3.72 (m, 3H), 3.65-3.52 (m, 3H), 2.90-2.81 (m, 2H), 2.40 (s, 3H), 2.36-2.27 (m, IH), 2.23- 2.13 (m, IH), 1.83-1.74 (m, IH), 1.70-1.60 (m, 4H).
Example 177: (S)-l-(6-chloro-5-methyl-l-phenyl-l//-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000181_0001
The title compound was prepared from l-(6-chloro-5 -methyl- 1 -phenyl- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylic acid (16.3 mg, 0.044 mmol), N,N-dimethylformamide (4.0 mL), N5N- diisopropyl-ethylamine (Ηunig's base, DIEA, 17.1 mg, 0.132 mmol), 2-(7-aza-lH-benzotriazole- l-yl)-l,l,3,3-tetramethyluronium hexafluoro -phosphate (ΗATU, 20.1 mg, 0.053 mmol) and (S)- tetrahydrofuran-3 -amine hydrochloride (6.5 mg, 0.0529 mmol) using the method described in Example 166 c). The reaction mixture was purified on column (silica gel,
dichloromethane/methanol, gradient elution using from 2 to 8 % methanol), to give 15.5 mg (81 % yield) of (S)- l-(6-chloro-5 -methyl- 1 -phenyl- lH-benzo[d]imidazo l-2-yl)-N-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide. On measure on optical rotation this compound gave (-)-rotation. LC-MS (mix) 438.9 (M+ 1). 1H NMR (400 MHz, CD3OD): δ 7.67-7.60 (m, 2H), 7.55-7.48 (m, 3H), 7.34 (s, IH), 7.01 (s, IH), 4.34-4.28 (m, IH), 3.91-3.72 (m, 3H), 3.65-3.52 (m, 3H), 2.90- 2.81 (m, 2H), 2.40 (s, 3H), 2.36-2.27 (m, IH), 2.23-2.13 (m, IH), 1.83-1.74 (m, IH), 1.70-1.60 (m, 4H). Example 178: 7V-butyl-l-(5-chloro-6-methyl-l-phenyl-lH-benzo[d]imidazol-2-yl)piperidine- 4-carboxamide and 7V-butyl-l-(6-chloro-5-methyl-l-phenyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide
Figure imgf000181_0002
(a) Preparation of the intermediary tautomeric compounds 2,5-dichloro-6-methyl-lH- benzo[d]imidazole and 2,6-dichloro-5-methyl- lH-benzo[d]imidazole:
Figure imgf000181_0003
To 5-chloro-6-methyl-lH-benzo[d]imidazol-2(3H)-one (1.0 g, 5.48 mmol), phosphoryl trichloride (POCl3, 0.137 mol) was added, the reaction mixture was heated at 12O0C for 3 hours and subsequently cooled down to room temperature. The reaction mixture was quenched with ice (without evaporating POCI3) and neutralized with aqueous sodium hydroxide (10%) to pH 7. The solid thus obtained was filtered off and the residue was recrystallized from petroleum ether to give 850 mg (86 % yield) of 2,5-dichloro-6-methyl-lH-benzo[d]imidazole and 2,6-dichloro-5- methyl- 1 H-benzo [d]imidazo Ie.
(b) Preparation of the intermediary tautomeric compounds N-butyl- l-(5-chloro-6-methyl- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide and N-butyl- 1 -(6-chloro-5-methyl- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide:
Figure imgf000182_0001
2,5-dichloro-6-methyl-lH-benzo[d]imidazole and 2,6-dichloro-5-methyl-lH-benzo[d]imidazole (1 g, 4.98 mmol), 1,4-dioxane (10 mL), JV,JV-diisopropylethylamine (Ηunig's base, DIEA, 14.9 mmol) and 4-(n-butylcarbamoyl)piperidin-l-yl 2,2,2-trifluoroacetate (7.47 mmol) was heated at 18O0C for 4 hours. The reaction mixture was concentrated in vacuo and recrystallized from methanol and methyl tert-butyl ether to give 1.1 g (65 % yield) of N-butyl- l-(5-chloro-6-methyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide and N-butyl- 1 -(6-chloro-5-methyl- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide. No effort was done in order to determine the ratios of the tautomers.
(c) The title compounds was prepared from N-butyl- l-(5-chloro-6-methyl-lH-benzo[d]imidazol- 2-yl)piperidine-4-carboxamide and N-butyl- 1 -(6-chloro-5-methyl- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide (0.30 g, 0.87 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.48 mmol), iodobenzene (3.48 mmol), 4,7-dimethoxy-l,10-phenanthroline (0.130 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0435 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 10 mg (2.7 % yield) of N-butyl- l-(5-chloro-6-methyl-l- phenyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide and N-butyl- 1 -(6-chloro-5-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as an off- white solid. LC-MS (m/z) 425.3 (M+l). Example 179: l-(5-chloro-6-methyl-l-phenyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide and l-(6-chloro-5-methyl-l-phenyl-lH- benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000183_0001
(a) Preparation of the intermediate tautomeric compounds l-(5-chloro-6-methyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide and 1 -(6-chloro-5- methyl- 1 H-benzo [d]imidazo l-2-yl)-N-(tetrahydrofuran-3 -yl)piperidine-4-carboxamide :
Figure imgf000183_0002
2,5-dichloro-6-methyl- lH-benzo[d]imidazole and 2,6-dichloro-5-methyl- lH-benzo[d]imidazole (1 g, 4.98 mmol), 1,4-dioxane (10 mL), JV,JV-diisopropylethylamine (Ηunig's base, DIEA, 14.9 mmol) and 4-(tetrahydrofuran-3-ylcarbamoyl)piperidinium 2,2,2-trifluoroacetate (7.47 mmol) was heated at 18O0C for 4 hours. The reaction mixture was concentrated in vacuo and
recrystallized from petrolium ether to give 1.1 g (65 % yield) l-(5-chloro-6-methyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide and 1 -(6-chloro-5- methyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. No effort was done in order to determine the ratios of the tautomers.
(b) The title compounds was prepared from l-(5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide and 1 -(6-chloro-5-methyl- lH-benzo[d]imidazol- 2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.30 g, 0.83 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.32 mmol), iodobenzene (3.32 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.124 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0415 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 22 mg (6 % yield) of 1 -(5-chloro-6-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine- 4-carboxamide and l-(6-chloro-5-methyl-l -phenyl- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid. No effort was done in order to determine the ratios of the compounds. LC-MS (m/z) 439.1 (M+ 1). Example 180: l-(5-chloro-l-cyclobutyl-6-methyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide compound and l-(6-chloro-l-cyclobutyl- 5-methyl- lH-benzo [d] imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000184_0001
1 -(S-Chloro-β-methyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide and 1 -(β-chloro-S-methyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide (0.1 g, 0.28 mmol), bromocyclobutane (1.12 mmol), caesium carbonate (1.12 mmol), [l,r-bis(diphenylphosphino)ferrocene] dichloropalladium(II)
(PdCl2(dppf), 0.028 mmol) and N,Λ/-dimethylformamide (3 mL) was subjected to microwave conditions at 12O0C for one hour. The reaction mixture was purified with column
chromathography, to give 12 mg (10 % yield) of l-^-chloro-l-cyclobutyl-β-methyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide and l-(6-chloro-l- cyclobutyl-5-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a brown solid. No effort was done in order to determine the ratios of the compounds. LC-MS (m/z) All .1 (M+l).
Example 181: l-(5-chloro- l-(cyclobutylmethyl)-6-methyl- lH-benzo [d] imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide and l-(6-chloro-l-(cyclobutylmethyl)-5-methyl-lH- benzo [d] imidazol-2-yl)-7V-cyclopentylpiperidine-4-carboxamide
Figure imgf000184_0002
(a) Preparation of the intermediate tautomeric compounds l-(5-chloro-6-methyl-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro-5-methyl- IH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide.
Figure imgf000184_0003
2,5-dichloro-6-methyl- lH-benzo[d]imidazole and 2,6-dichloro-5-methyl- lH-benzo[d]imidazole (1 g, 4.98 mmol), 1,4-dioxane (10 niL), JV,JV-diisopropylethylamine (Ηunig's base, DIEA, 14.9 mmol) and 4-(cyclopentylcarbamoyl)piperidinium 2,2,2-trifluoroacetate (7.47 mmol) was heated at 18O0C for 4 hours. The reaction mixture was concentrated in vacuo and recrystallized from petrolium ether to give 1.1 g (65 % yield) of l-(5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)- N-cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro-5-methyl- 1 H-benzo [d]imidazol-2-yl)- N-cyclopentylpiperidine-4-carboxamide. No effort was done in order to determine the ratios of the tautomers.
(b) The title compounds were prepared from a tautomeric mixture of l-(5-chloro-6-methyl-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide and l-(6-chloro-5-methyl-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide (0.1 g, 0.28 mmol),
bromocyclobutane (1.12 mmol), caesium carbonate (1.12 mmol), [l,l'-bis(diphenylphosphino)- ferrocene] dichloropalladium(II) (PdCl2(dppf), 0.028 mmol) and N,Λ/-dimethylformamide (3 mL) using the method described in Example 180. This gave 20 mg (17 % yield) of l-(5-chloro-l- (cyclobutylmethyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4- carboxamide and 1 -(6-chloro- 1 -(eye Io butylmethyl)-5 -methyl- 1 H-benzo [d]imidazo l-2-yl)-N- cyclopentylpiperidine-4-carboxamide as a brown solid. No effort was done in order to determine the regioisomeric ratio of the compounds. LC-MS (m/z) 429.1 (M+l).
Example 182: l-(5-chloro-6-methyl-l-pentyl-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide and l-(6-chloro-5-methyl-l-pentyl-lH- benzo [d] imidazol-2-yl)-7V-cyclopentylpiperidine-4-carboxamide
Figure imgf000185_0001
The title compounds were prepared from 1 -(5 -chloro-6-methyl-l H-benzo [d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro-5 -methyl- 1 H-benzo [d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide (0.1 g, 0.28 mmol), 1-bromopentane (1.12 mmol), caesium carbonate (1.12 mmol), [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II)
(PdCl2(dppf), 0.028 mmol) and N,Λ/-dimethylformamide (3 mL) using the method described in Example 180. This gave 20 mg (17 % yield) of l-(5-chloro-6-methyl-l-pentyl-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro-5-methyl- 1 - pentyl-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as an off-white solid. No effort was done in order to determine the ratios of the compounds. LC-MS (m/z) 431.3 (M+l).
Example 183 : l-(5-chloro- l-(4-fluorophenyl)-6-methyl- lH-benzo [d] imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide and l-(6-chloro-l-(4-fluorophenyl)-5-methyl-lH- benzo [d] imidazol-2-yl)-7V-cyclopentylpiperidine-4-carboxamide
Figure imgf000186_0001
The title compounds was prepared from l-(5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro-5 -methyl- lH-benzo [d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide (0.30 g, 0.83 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.32 mmol), l-fluoro-4-iodobenzene (3.32 mmol), 4,7-dimethoxy-l,10- phenanthroline (0.124 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0415 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 11 mg (2.9 % yield) of 1 -(5-chloro- 1 -(4-fluorophenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4- carboxamide and 1 -(6-chloro- 1 -(4-fluorophenyl)-5 -methyl- lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide as a brown solid. No effort was done in order to determine the regioisomeric ratio of the compounds.
Example 184: l-(5-chloro-6-methyl-l-phenyl-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide and l-(6-chloro-5-methyl-l-phenyl-lH- benzo [d] imidazol-2-yl)-7V-cyclopentylpiperidine-4-carboxamide
Figure imgf000186_0002
The title compounds was prepared from l-(5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro-5 -methyl- lH-benzo [d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide (0.30 g, 0.83 mmol), dimethylsulfoxide (6 niL), caesium carbonate (3.32 mmol), iodobenzene (3.32 mmol), 4,7-dimethoxy-l,10-phenanthroline (0.124 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0415 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 5 mg (1.4 % yield) of l-(5-chloro-6-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro-5- methyl-1 -phenyl- lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as a white solid. No effort was done in order to determine the ratios of the compounds. LC-MS (m/z) 437.7 (M+l). Example 185: 7V-butyl-l-(5-chloro-l-cyclobutyl-6-methyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide and 7V-butyl-l-(6-chloro-l-cyclobutyl-5-methyl-lH- benzo [d] imidazol-2-yl)piperidine-4-carboxamide
Figure imgf000187_0001
The title compounds were prepared from N-butyl- 1 -(5 -chloro-6-methyl-lH-benzo[d]imidazo 1-2- yl)piperidine-4-carboxamide and N-butyl- 1 -(6-chloro-5 -methyl- lH-benzo [d]imidazo 1-2- yl)piperidine-4-carboxamide (0.1 g, 0.28 mmol), bromocyclobutane (1.12 mmol), caesium carbonate (1.12 mmol), [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II)
(PdCl2(dppf), 0.028 mmol) and N,Λ/-dimethylformamide (3 mL) using the method described in Example 180. This gave 15 mg (13 % yield) of N-butyl-l-(5-chloro-l-cyclobutyl-6-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxamide and N-butyl- 1 -(6-chloro- 1 -cyclobutyl-5- methyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide as a white solid. No effort was done in order to determine the ratios of the compounds. LC-MS (m/z) 403.3 (M+l).
Example 186: (R)- l-(5,6-dimethyl- l-(3-(trifluoromethyl)phenyl)- lH-benzo [d] imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000187_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (150 mg, 0.438 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.657 mmol), l-bromo-3-(trifluoromethyl)benzene (1.31 mmol), 8- hydroxyquinoline (0.175 mmol), polyethylene glycol (0.219 mmol) and copper(I) oxide (0.0876 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 15O0C and subsequently purified on reverse-phase hplc, to give 63 mg (30 % yield) of (R)-l-(5,6-dimethyl-l-(3-(trifiuoromethyl)phenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 487.1 (M+l). Example 187: (R)-l-(l-(2>difluorobenzo[d] [l,3]dioxol-5-yl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000188_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (150 mg, 0.438 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.657 mmol), 5-bromo-2,2-difluorobenzo[d][l,3]dioxole (1.31 mmol), 8-hydroxyquinoline (0.175 mmol), polyethylene glycol (0.219 mmol) and copper(I) oxide (0.0876 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 15O0C and subsequently purified on reverse-phase hplc, to give 10 mg (4.6 % yield) of (R)-l-(l-(2,2-difiuorobenzo[d][l,3]dioxol-5-yl)-5,6- dimethyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 499.2 (M+l).
Example 188: (R)- l-(5,6-dimethyl- l-(5-(trifluoromethyl)pyridin-2-yl)- IH- benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000189_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (150 mg, 0.438 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.657 mmol), 2-bromo-5-(trifluoromethyl)pyridine (1.31 mmol), 8- hydroxyquinoline (0.175 mmol), polyethylene glycol (0.219 mmol) and copper(I) oxide (0.0876 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 15O0C and subsequently purified on reverse-phase hplc, to give 37 mg (17 % yield) of (R)-l-(5,6-dimethyl-l-(5-(trifluoromethyl)pyridin-2-yl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 488.1 (M+l).
Example 189: (R)-l-(l-(3-ethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000189_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (150 mg, 0.438 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.657 mmol), l-bromo-3-ethylbenzene (1.31 mmol), 8- hydroxyquinoline (0.175 mmol), polyethylene glycol (0.219 mmol) and copper(I) oxide (0.0876 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on reverse-phase hplc, to give 15 mg (7.6 % yield) of (R)-l-(l-(3-ethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale green solid. LC-MS (m/z) 447.2 (M+l).
Example 190: (R)-l-(l-(3-isopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000190_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (150 mg, 0.438 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.657 mmol), l-bromo-3-isopropylbenzene (1.31 mmol), 8- hydroxyquinoline (0.175 mmol), polyethylene glycol (0.219 mmol) and copper(I) oxide (0.0876 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on reverse-phase hplc, to give 5 mg (2.5 % yield) of (R)-l-(l-(3-isopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol- 2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 461.4 (M+l).
Example 191: (R)- l-(6-chloro- l-(4-isopropylphenyl)-5-methyl- lH-benzo [d] imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000190_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-4-isopropylbenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on reverse-phase hplc, to give 6 mg (5 % yield) of (R)-l-(l-(4-isopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 501.5 (M+l).
Example 192 : (R)- l-(5,6-dichloro- l-(3-chlorophenyl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000191_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-3-chlorobenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 2 mg (2 % yield) of (R)-l-(5,6-dichloro-l-(3-chlorophenyl)-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 493.1 (M+l).
Example 193 : (R)- l-(5,6-dichloro- l-(4-fluoro-3-methylphenyl)- lH-benzo [d] imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000191_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 4-bromo-l-fluoro-2-methylbenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on reverse-phase hplc, to give 15 mg (12 % yield) of (R)-l-(5,6-dichloro-l-(4-fiuoro-3-methylphenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale green solid. LC-MS (m/z) 491.1 (M+l).
Example 194 : (R)- l-(5,6-dichloro- l-(3,5-difluorophenyl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000192_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-3,5-difluorobenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 3 mg (2.3 % yield) of (R)-l-(5,6-dichloro-l-(3,5-difluorophenyl)-lH-benzo[d]imidazol-2- yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 495.4 (M+l).
Example 195: (R)- l-(5,6-dichloro- l-(3-cyanophenyl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000192_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 3-bromobenzonitrile (0.783 mmol), 8 -hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 5 mg (3.9 % yield) of (R)- 1 -(5,6-dichloro- 1 -(3-cyanophenyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 484.1 (M+l).
Example 196: (R)- l-(5,6-dichloro- l-(pyridin-2-yl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000193_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 2-iodopyridine (0.783 mmol), 8-hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 30 mg (25 % yield) of (R)- 1 -(5,6-dichloro- 1 -(pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 460.3 (M+l). Example 197: (RJ-l-CS^-dichloro-l-CS-methylpyridin-l-yO-lH-benzoIdlimidazol-l-yO-TV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000193_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 2-bromo-5-methylpyridine (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 13 mg (11 % yield) of (R)-l-(5,6-dichloro-l-(5-methylpyridin-2-yl)-lH-benzo[d]imidazol- 2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 474.4 (M+l).
Example 198: (R)- l-(5,6-dichloro- l-(6-methoxypyridin-2-yl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000194_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 2-bromo-6-methoxypyridine (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 3 mg (2.3 % yield) of (R)-l-(5,6-dichloro-l-(6-methoxypyridin-2-yl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 490.4 (M+ 1).
Example 199: (R)- l-(5,6-dichloro- l-(3-isopropylphenyl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000194_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-3-isopropylbenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 5 mg (3.8 % yield) of (R)-l-(5,6-dichloro-l-(3-isopropylphenyl)-lH-benzo[d]imidazol-2- yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off- white solid. LC-MS (m/z) 501.2 (M+l).
Example 200 : (R)- l-(5,6-dichloro- l-(4-methylpyridin-2-yl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000195_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 2-bromo-4-methylpyridine (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 5 mg (3.9 % yield) of (R)-l-(5,6-dichloro-l-(4-methylpyridin-2-yl)-lH-benzo[d]imidazol- 2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 474.2 (M+l).
Example 201: (R)- l-(5,6-dichloro- l-(6-methylpyridin-2-yl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000195_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 2-bromo-6-methylpyridine (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 25 mg (20 % yield) of (R)-l-(5,6-dichloro-l-(6-methylpyridin-2-yl)-lH-benzo[d]imidazol- 2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 474.2 (M+l).
Example 202 : (R)- l-(5,6-dichloro- l-(3-(difluoromethoxy)phenyl)- lH-benzo [d] imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000196_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-3-(difluoromethoxy)benzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 5 mg (3.6 % yield) of (R)-l-(5,6-dichloro-l-(3-(difluoromethoxy)phenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a gray solid. LC- MS (m/z) 525.2 (M+ 1).
Example 203 : (R)- l-(5,6-dichloro- l-(3-(trifluoromethoxy)phenyl)- lH-benzo [d] imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000196_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-3-(trifluoromethoxy)benzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 9 mg (6.4 % yield) of (R)-l-(5,6-dichloro-l-(3-(trifiuoromethoxy)phenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 543.0 (M+l).
Example 204: (R)-l-(5,6-dichloro-l-(4-isobutylphenyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000197_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-4-isobutylbenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase hplc, to give 10 mg (7.4 % yield) of (R)-l-(5,6-dichloro-l-(4-isobutylphenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 515.5 (M+l).
Example 205 : (R)- l-(5,6-dichloro- l-(3,4-dimethylphenyl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000197_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.313 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.470 mmol), l-bromo-3-(cyclopentyloxy)benzene (0.939 mmol), 8- hydroxyquinoline (0.125 mmol), polyethylene glycol (0.157 mmol) and copper(I) oxide (0.0626 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 5 mg (3.2 % yield) of (R)-l-(5,6-dichloro-l-(3,4-dimethylphenyl)-lH-benzo[d]imidazol-2- yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale green solid. LC-MS (m/z) 487.2 (M+l). Example 206 : (R)- l-(5,6-dichloro- l-(4-chlorophenyl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000198_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (200 mg, 0.522 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.783 mmol), l-chloro-4-iodobenzene (1.565 mmol), 8- hydroxyquinoline (0.209 mmol), polyethylene glycol (0.261 mmol) and copper(I) oxide (0.104 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 9 mg (3.6 % yield) of (R)-l-(5,6-dichloro-l-(4-chlorophenyl)-lH-benzo[d]imidazol-2-yl)- N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 493.5 (M+l).
Example 207: (R)-l-(5,6-dichloro-l-(5-(trifluoromethyl)pyridin-2-yl)-lH-benzo[d]imidazol- 2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000198_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (150 mg, 0.391 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.587 mmol), 2-bromo-5-(trifluoromethyl)pyridine (1.17 mmol), 8- hydroxyquinoline (0.157 mmol), polyethylene glycol (0.196 mmol) and copper(I) oxide (0.0783 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 5 mg (2.5 % yield) of (R)-l-(5,6-dichloro-l-(5-(trifluoromethyl)pyridin-2-yl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale green solid. LC-MS (m/z) 528.3 (M+l). Example 208 : (R)- l-(5,6-dichloro- l-(5-fluoropyridin-2-yl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000199_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (150 mg, 0.391 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.587 mmol), 2-bromo-5-fluoropyridine (1.17 mmol), 8-hydroxy- quinoline (0.157 mmol), polyethylene glycol (0.196 mmol) and copper(I) oxide (0.0783 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 35 mg (19 % yield) of (R)-l-(5,6-dichloro-l-(5-fluoropyridin-2-yl)-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 478.2 (M+l).
Example 209: (R)-l-(l-(4-isobutylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000199_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (120 mg, 0.350 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.701 mmol), l-bromo-4-isobutylbenzene (1.051 mmol), 8- hydroxyquinoline (0.140 mmol), polyethylene glycol (0.175 mmol) and copper(I) oxide (0.0701 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase hplc, to give 19 mg (11 % yield) of (R)-I -(I -(4-isobutylphenyl)-5,6-dimethyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 475.2 (M+l). Example 210: (R)- l-(6-chloro- l-(3,5-dimethylphenyl)-5-methyl- lH-benzo [d] imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000200_0001
a) Preparation of the intermediate compound ethyl l-(6-chloro-l-(3,5-dimethylphenyl)-5-methyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate
Figure imgf000200_0002
A tautomeric mixture of ethyl l-(5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxylate and ethyl l-(6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (80 mg, 0.249 mmol), dimethylsulfoxide (0.5 mL), caesium carbonate (113 mg, 0.348 mmol), 1- bromo-3,5-dimethylbenzene (138 mg, 0.746 mmol), 8-hydroxy-quinoline (14.4 mg, 0.099 mmol), polyethylene glycol 400 (50.0 mg, 0.124 mmol) and copper(I) oxide (7.1 mg, 0.05 mmol) was heated at 15O0C for 4 hours. The reaction mixture was filtered, washed with N ,N- dimethylformamide, the filtrated concentrated in vacuo (co-evaporation with N5N- dimethylformamide) and purified on column (silica gel, iso-hexane/ethyl acetate, gradient elution from 20 to 30 % ethyl acetate). This gave 16.3 mg (15 % yield) of ethyl l-(6-chloro-l- (3,5-dimethylphenyl)-5-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (LC-MS (m/z) 426.0 (M+ 1)) that eluted as the second peak after ethyl l-(5-chloro-l-(3,5- dimethylphenyl)-6-methyl-lH-benzo[d]-imidazol-2-yl)piperidine-4-carboxylate (18.0 mg, 17 % yield). (b) To ethyl l-(6-chloro-l-(3,5-dimethylphenyl)-5-methyl-lH-benzo[d]imidazol-2-yl)piperidine- 4-carboxylate (8.6 mg) was added ethanol (2 mL) and aqueous sodium hydroxide (1 mL, 2 N). The reaction mixture was stirred at 4O0C for two hours, neutralized with aqueous hydrochloric acid (2 N) and concentrated in vacuo. The residue was mixed (R)-(+)-tetrahydrofuran-3 -amine A- methylbenzenesulfonate (6.3 mg, 0.024 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (HATU, 9.2 mg, 0.024 mmol), 7V,iV-diisopropyl- ethylamine (Hunig's base, DIEA, 7.8 mg, 0.060 mmol) and N,N-dimethylformamide (5 mL) was stirred at room temperature over the weekend. The reaction mixure was concentrated in vacuo, the residue subjected to preperative hplc (Preparative RP-LC was performed on a Gilson system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using methano I/water (0.05% formic acid) gradients at a flow rate of 15 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 7.7 mg (82 % yield) (R)-l-(6-chloro-l-(3,5-dimethylphenyl)-5-methyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. MS (m/z) 467.0 (M+l). Example 211: (R)-l-(l-(4-chloro-3-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000201_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (120 mg, 0.350 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.701 mmol), 4-bromo-l-chloro-2-fluorobenzene (1.051 mmol), 8- hydroxyquinoline (0.140 mmol), polyethylene glycol (0.175 mmol) and copper(I) oxide (0.0701 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase hplc, to give 3 mg (1.8 % yield) of (R)-l-(l-(3-fluoro-5-methylphenyl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 471.2 (M+l).
Example 212: (R)-l-(5,6-dichloro-l-(4-chloro-3-fluorophenyl)-lH-benzo[d]imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000201_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 4-bromo-l-chloro-2-fluorobenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase hplc, to give 13 mg (9.9 % yield) of (R)-l-(5,6-dichloro-l-(4-chloro-3-fiuorophenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a yellow solid. LC-MS (m/z) 511.8 (M+l). Example 213: (RJ-l-CS^-dichloro-l-CS^-diethylphenyO-lH-benzoIdlimidazoU-yO-TV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000202_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (200 mg, 0.522 mmol) dimethylsulfoxide (2 mL), caesium carbonate (1.04 mmol), l-bromo-3,5-diethylbenzene (1.57 mmol), 8- hydroxyquinoline (0.209 mmol), polyethylene glycol (0.261 mmol) and copper(I) oxide (0.104 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase hplc, to give 5 mg (1.9 % yield) of (R)-l-(5,6-dichloro-l-(3,5-diethylphenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid. LC- MS (m/z) 515.5 (M+l).
Example 214: (R)-l-(l-(3-tert-butylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000202_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.584 mmol), l-bromo-3-tert-butylbenzene (0.876 mmol), 8- hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase hplc, to give 2 mg (1.4 % yield) of (R)-I -(I -(3-tert-butylphenyl)-5,6-dimethyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 475.2 (M+ 1). Example 215: (RΗ-CΗS-tert-butylphenyO-S^-dichloro-lH-benzoIdlimidazol^-yO-TV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000203_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-3-tert-butylbenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase hplc, to give 5 mg (3.7 % yield) of (R)-I -(I -(3-tert-butylphenyl)-5,6-dichloro- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off- white solid. LC-MS (m/z) 515.5 (M+l).
Example 216: (R)- l-(5,6-dichloro- 1-phenyl- lH-benzo [d] imidazol-2-yl)-7V-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide
Figure imgf000203_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), iodobenzene (0.783 mmol), 8-hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 13 mg (11 % yield) of (R)- 1 -(5,6-dichloro- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a pale brown solid. LC-MS (m/z) 459.1 (M+l).
Example 217: (R)- l-(5,6-dichloro- l-(4-ethylphenyl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000204_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-4-ethylbenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 34 mg (27 % yield) of (R)-l-(5,6-dichloro-l-(4-ethylphenyl)-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale green solid. LC-MS (m/z) 487.1 (M+l).
Example 218: (R)- l-(5,6-dichloro- 1-m-tolyl- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000204_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-3-methylbenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 13 mg (10 % yield) of (R)-l-(5,6-dichloro-l-m-tolyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off- white solid. LC-MS (m/z) 473.1 (M+l). Example 219: (RJ-l-CS^-dichloro-l-CS^-dimethylphenyO-lH-benzoIdlimidazoU-yO-TV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000205_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-3,5-dimethylbenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 5 mg (4 % yield) of (R)-l-(5,6-dichloro-l-(3,5-dimethylphenyl)-lH-benzo[d]imidazol-2- yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a yellow solid. LC-MS (m/z) 487.1 (M+l).
Example 220: (R)-l-(5,6-dichloro-l-(3-ethylphenyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000205_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-3-ethylbenzene (0.783 mmol), 8-hydroxy- quinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 31 mg (24 % yield) of (R)-l-(5,6-dichloro-l-(3-ethylphenyl)-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 487.2 (M+l).
Example 221 : (R)- l-(5,6-dichloro- l-(6-(trifluoromethyl)pyridin-2-yl)- lH-benzo [d] imidazol- 2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000206_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 2-bromo-6-(trifluoromethyl)pyridine (0.783 mmol), 8- hydroxy-quinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 25 mg (18 % yield) of (R)-l-(5,6-dichloro-l-(6-(trifluoromethyl)pyridin-2-yl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid. LC- MS (m/z) 528.4 (M+l). 1H NMR (400 MHz, CDCl3): δ 8.11-8.06 (m, IH), 7.98-7.93 (m,
1H),7.74 (s, IH), 7.71-7.68 (m, IH), 7.61 (s, IH), 5.77 (br s, IH), 4.48-4.40 (m, IH), 3.90-3.82 (m, IH), 3.77-3.68 (m, 2H), 3.65-3.55 (m, 3H), 3.07-2.91 (m, 2H), 2.26-2.16 (m, 2H), 1.86-1.77 (m, 6H).
Example 222: (R)-l-(5,6-dichloro-l-(3-ethoxyphenyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000207_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-3-ethoxybenzene (0.783 mmol, CAS Registry Number: 2655-84-7), 8-hydroxy-quinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 5 mg (3.8 % yield) of (R)-l-(5,6-dichloro-l-(3-ethoxyphenyl)-lH- benzo[d]-imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 503.2 (M+ 1).
Example 223 : (R)- l-(5,6-dichloro- l-(3-isopropoxyphenyl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000207_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-3-isopropoxybenzene (0.783 mmol, CAS Registry Number: 131738-73-3), 8-hydroxy-quinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 2 mg (1.2 % yield) of (R)-l-(5,6-dichloro-l-(3- isopropoxyphenyl)-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a pale green solid. LC-MS (m/z) 517.2 (M+l).
Example 224 : (R)- l-(5,6-dichloro- l-(3-propoxyphenyl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000208_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-3-propoxybenzene (0.783 mmol, CAS Registry Number: 149557-17-5), 8-hydroxy-quinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 14 mg (10 % yield) of (R)-l-(5,6-dichloro-l-(3-propoxyphenyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 517.5 (M+l).
Example 225: (R)-l-(l-(4-fluoro-3,5-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000208_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.584 mmol), 5-bromo-2-fluoro-l,3-dimethylbenzene (0.876 mmol), 8- hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase hplc, to give 17 mg (13 % yield) of (R)-I -(I -(4-fiuoro-3,5-dimethylphenyl)-5,6-dimethyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 465.2 (M+l).
Example 226: (R)-l-(5,6-dichloro-l-(4-chloro-3-methylphenyl)-lH-benzo[d]imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000209_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 4-bromo-l-chloro-2-methylbenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc (Shimadzu LC8A, C18 column (22 x 250 mm, lOμm), acetonitrile/water gradient (0.1% trifluoroacetic acid), flowrate 15 mL/min) , to give 15 mg (11 % yield) of (R)-l-(5,6-dichloro-l- (4-chloro-3-methylphenyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a pale brown solid. LC-MS (m/z) 507.8 (M+ 1).
Example 227: (R)-l-(5,6-dichloro-l-(3-chloro-4-methylphenyl)-lH-benzo[d]imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000209_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.313 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.470 mmol), 4-bromo-2-chloro-l-methylbenzene (0.939 mmol), 8- hydroxyquinoline (0.125 mmol), polyethylene glycol (0.157 mmol) and copper(I) oxide (0.0626 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 3 mg (2 % yield) of (R)-l-(5,6-dichloro-l-(3-chloro-4-methylphenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a gray solid. LC- MS (m/z) 507.3 (M+ 1). Example 228: (R)-l-(5,6-dimethyl-l-phenyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000210_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.438 mmol), iodobenzene (0.876 mmol), 8-hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on reverse-phase hplc, to give 34 mg (28 % yield) of (R)- 1 -(5 ,6-dimethyl- 1 -phenyl- 1 H-benzo [d]imidazol-2-yl)-N-(tetrahydrofuran-3 -yl)piperidine-4- carboxamide as a pale yellow solid. LC-MS (m/z) 419.1 (M+ 1).
Example 229 : (R)- l-(5,6-dimethyl- 1-p-tolyl- lH-benzo [d] imidazol-2-yl)-7V-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide
Figure imgf000210_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.438 mmol), l-bromo-4-methylbenzene (0.876 mmol), 8- hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on reverse-phase hplc, to give 3 mg (2.3 % yield) of (R)-l-(5,6-dimethyl-l-p-tolyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 433.3 (M+l). Example 230: (R)-l-(5,6-dimethyl-l-m-tolyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000211_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.438 mmol), l-bromo-3-methylbenzene (0.876 mmol), 8- hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on reverse-phase hplc, to give 4 mg (2.6 % yield) of (R)-l-(5,6-dimethyl-l-m-tolyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 433.3 (M+l).
Example 231: (R)-l-(l-(3-cyanophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000211_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.438 mmol), 3-bromobenzonitrile (0.876 mmol), 8-hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on reverse-phase hplc, to give 8 mg (4.6 % yield) of (R)- 1 -( 1 -(3 -cyanophenyl)-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)-N-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide as a pale green solid. LC-MS (m/z) 444.1 (M+l). Example 232 : (R)- l-(5,6-dimethyl- l-(naphthalen-2-yl)- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000212_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.438 mmol), 2-bromonaphthalene (0.876 mmol), 8-hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on reverse-phase hplc, to give 3 mg (2.2 % yield) of (R)- 1 -(5,6-dimethyl- 1 -(naphthalen-2-yl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 469.1 (M+l).
Example 233 : (R)- l-(l-(4-chloro-3-methylphenyl)-5,6-dimethyl- lH-benzo [d] imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000212_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.438 mmol), 4-bromo-l-chloro-2-methylbenzene (0.876 mmol), 8- hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on reverse-phase hplc, to give 35 mg (26 % yield) of (R)-I -(I -(4-chloro-3-methylphenyl)-5,6-dimethyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 467.2 (M+l). Example 234 : (R)- l-(l-(3-chloro-4-methylphenyl)-5,6-dimethyl- lH-benzo [d] imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000213_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.438 mmol), 4-bromo-2-chloro-l-methylbenzene (0.876 mmol), 8- hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on reverse-phase hplc, to give 20 mg (15 % yield) of (R)-l-(l-(3-chloro-4-methylphenyl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale green solid. LC-MS (m/z) 467.2 (M+l).
Example 235 : (R)- l-(l-(benzo [d] thiazol-6-yl)-5,6-dimethyl- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000213_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (120 mg, 0.350 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.526 mmol), 6-bromobenzo[d]thiazole (1.051 mmol), 8- hydroxyquinoline (0.140 mmol), polyethylene glycol (0.175 mmol) and copper(I) oxide (0.0701 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on reverse-phase hplc, to give 3 mg (1.8 % yield) of (R)-l-(l-(benzo[d]thiazol-6-yl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 476.2 (M+l). Example 236 : (R)- l-(l-(benzo [d] thiazol-5-yl)-5,6-dimethyl- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000214_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (120 mg, 0.350 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.526 mmol), 5-bromobenzo[d]thiazole (1.051 mmol), 8- hydroxyquinoline (0.140 mmol), polyethylene glycol (0.175 mmol) and copper(I) oxide (0.0701 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 12O0C and subsequently purified on reverse-phase hplc, to give 5 mg (3 % yield) of (R)-l-(l-(benzo[d]thiazol-5-yl)-5,6-dimethyl-lH-benzo[d]imidazol- 2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale green solid. LC-MS (m/z) 476.1 (M+l).
Example 237: (R)-l-(5-chloro-l-(3,4-dimethylphenyl)-6-methyl-lH-benzo[d]imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000214_0002
(a) Preparation of the intermediate tautomeric mixture l-(5-chloro-6-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid and l-(6-chloro-5-methyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid
Figure imgf000214_0003
A tautomeric mixture of 1 -(5 -chloro-6-methyl-l H-benzo [d]imidazol-2-yl)piperidine-4- carboxylic acid ethyl ester and l-(6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxylic acid ethyl ester (1.0 g, 3.1 mmol) was dissolved in ethanol (70 mL) and aqueous sodium hydroxide (1 N, 16 mL) was added. The reaction mixture was stirred at room
temperature two hours, concentrated in vacuo and pΗ adjusted to 4-5 with addition of aqueous hydrochloric acid (6 N). The formed precipitate was filtered off, the aqueous mother liquid extracted three times with dichloro methane (50 mL) and the combined organic layers were dried with MgSO4 and concentrated in vacuo. The precipitate and the residue from the extraction were combined and rechrystallized in petroleum ether to give 0.82 g (90%) of a tautomeric mixture of l-(5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid and l-(6-chloro-5- methyl- 1 H-benzo [d]imidazo l-2-yl)piperidine-4-carboxylic.
(b) Preparation of the intermediate tautomeric mixture of (R)-I -(5-chloro-6-methyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide and (R)- 1 -(6-chloro- 5-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide:
Figure imgf000215_0001
A tautomeric mixture of 1 -(5 -chloro-6-methyl-l H-benzo [d]imidazol-2-yl)piperidine-4- carboxylic acid and l-(6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (1.0 g, 3.4 mmol), (R)-(+)-tetrahydrofuran-3 -amine 4-methylbenzenesulfonate (4.1 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 6.8 mmol), Λ/,Λ/-diisopropylethylamine (Ηunig's base, DIEA, 6.8 mmol) and N5N- dimethylformamide (25 mL) was stirred at room temperature for 1 hour. After the appropriate work-up, the residue was recrystallized from dichloromethane/petroleum ether to give 1.0 g (83 % yield) of a tautomeric mixture of (R)-I -(5-chloro-6-methyl- lH-benzo[d]imidazo l-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide and (R)-l-(6-chloro-5-methyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide.
(c) The title compound was prepared from a tautomeric mixture of (R)-I -(5-chloro-6-methyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide and (R)- 1 -(6-chloro- 5-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide (500 mg, 1.38 mmol) dimethylsulfoxide (2 mL), caesium carbonate (2.07 mmol), 4-bromo-l,2- dimethylbenzene (4.13 mmol), 8-hydroxyquinoline (0.551 mmol), polyethylene glycol (0.689 mmol) and copper(I) oxide (0.276 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 15 mg (2.3 % yield) of (R)-l-(5-chloro-l-(3,4- dimethylphenyl)-6-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as an off-white solid, eluting after (R)-l-(6-chloro-l-(3,4-dimethylphenyl)-5- methyl- lH-benzo[d]-imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide on the column. LC-MS (m/z) 467.2 (M+l).
Example 238: (RJ-l-Cό-chloro-l-CS^-dimethylphenylJ-S-methyl-lH-benzoIdlimidazol-l-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000216_0001
The title compound was obtained as described in Example 237 eluting ahead of (R)-l-(5-chloro- l-(3,4-dimethylphenyl)-6-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide on the column. This gave 16 mg (2.5 % yield) of (R)-I -(6-chloro-l- (3,4-dimethylphenyl)-5-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine- 4-carboxamide as an off-white solid. MS (m/z) 467.2 (M+l).
Example 239: (R)-l-(5-chloro-l-(4-isopropylphenyl)-6-methyl-lH-benzo[d]imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000216_0002
The title compound was prepared from a tautomeric mixture of (R)-I -(5-chloro-6-methyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide and (R)-l-(6-chloro- 5-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide (500 mg, 1.38 mmol) dimethylsulfoxide (2 mL), caesium carbonate (2.07 mmol), l-bromo-4- isopropylbenzene (4.13 mmol), 8-hydroxyquinoline (0.551 mmol), polyethylene glycol (0.689 mmol) and copper(I) oxide (0.276 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 27 mg (4.3 % yield) of (R)-l-(5-chloro-l-(4- isopropylphenyl)-6-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a white solid, eluting after (R)-l-(6-chloro-l-(4-isopropylphenyl)-5-methyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide on the column. LC- MS (m/z) 481.2 (M+l).
Example 240 : (R)- l-(6-chloro- l-(4-isopropylphenyl)-5-methyl- lH-benzo [d] imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000217_0001
The title compound was obtained as described in Example 239 eluting ahead of (R)-l-(5-chloro- l-(4-isopropylphenyl)-6-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine- 4-carboxamide on the column. This gave 4 mg (6 % yield) of (R)-I -(6-chloro-l -(4-isopropyl- phenyl)-5 -methyl- 1 H-benzo [d]imidazo l-2-yl)-N-(tetrahydrofuran-3 -yl)piperidine-4-carboxamide as an off-white solid. MS (m/z) 481.3 (M+ 1).
Example 241: (S)-l-(5-chloro-6-methyl-l-p-tolyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000217_0002
A tautomeric mixture of ethyl l-(6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxylate and ethyl l-(5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (80.5 mg, 0.25 mmol) dimethylsulfoxide (0.5 mL), caesium carbonate (114 mg, 0.35 mmol), 1- iodo-4-methylbenzene (109 mg, 0.50 mmol), 8-hydroxyquinoline (7.3 mg, 0.05 mmol), polyethylene glycol 400 (60.4 mg, 0.515 mmol) and copper(I) oxide (3.6 mg, 0.025 mmol) was heated at 15O0C for 4 hours. The temperature was lowered to 9O0C and water (0.004 mL) was added to the reaction mixture, which was stirred for one hour. Aqueous sodium hydroxide (0.5 mL, 1 N) and ethanol (1 mL) was added and the reaction mixture stirred over night. Aqueous hydrochloric acid (0.25 mL, 2 N) was added and the reaction mixture concentrated in vacuo. The residue was mixed with N,N-dimethylformamide (5 mL), JV,jV-diisopropylethylamine (Hunig's base, DIEA, 97 mg, 0.75 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluoro-phosphate (ΗATU, 114 mg, 0.3 mmol) and (S)-tetrahydrofuran-3 -amine
hydrochloride (31 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 90 minutes, concentrated in vacuo and purified on column (silica gel, dichloromethane/methanol 96:4) to give 4.6 mg (4 % yield) of (S)-l-(5-chloro-6-methyl-l-p-tolyl-lH-benzo[d]imidazol-2- yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 452.9 (M+l). Also eluting from the column was the other regioisomer (S)-l-(6-chloro-5-methyl-l-p-tolyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide.
Example 242: (S)-l-(6-chloro-5-methyl-l-p-tolyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000218_0001
The title compound was obtained as described in Example 241 to give 5.8 mg (5 % yield) of (S)- 1 -(6-chloro-5 -methyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine- 4-carboxamide. LC-MS (m/z) 452.9 (M+l).
Example 243: (S)-l-(6-chloro-l-(3,5-dimethylphenyl)-5-methyl-lH-benzo[d]imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000218_0002
A tautomeric mixture of ethyl l-(6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxylate and ethyl l-(5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (100 mg, 0.311 mmol) dimethylsulfoxide (0.5 mL), caesium carbonate (142 mg, 0.435 mmol), 1- l-bromo-3,5-dimethylbenzene (115 mg, 0.621 mmol), 8-hydroxyquinoline (9.0 mg, 0.062 mmol), polyethylene glycol 400 (75 mg, 0.188 mmol) and copper(I) oxide (4.4 mg, 0.031 mmol) was heated at 15O0C for 4 hours. The reaction mixture was purified using column
chromathography, the appropriate combined fractions concentrated in vacuo and dissolved in ethanol. Aqueous sodium hydroxide (0.5 mL, 1 N) was added and the reaction mixture was stirred at room temperature over night. Aqueous hydrochloric acid (0.25 mL, 2 N) was added and the reaction mixture concentrated in vacuo. The residue was mixed with N ,N- dimethylformamide (5 mL), JV,jV-diisopropylethylamine (Ηunig's base, DIEA, 73 mg, 0.563 mmol), 2-(7-aza- lH-benzotriazole- 1 -yl)- 1 , 1 ,3,3-tetramethyluronium hexafluoro-phosphate (ΗATU, 85.7 mg, 0.225 mmol) and (S)-tetrahydrofuran-3 -amine hydrochloride (23 mg, 0.188 mmol). The reaction mixture was stirred at room temperature for 105 minutes, concentrated in vacuo and purified on column (silica gel, dichloromethane/methanol, gradient elution using from 3 to 7 % methanol) and further on hplc (preparative RP-LC was performed on a Gilson system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using methano I/water (0.05% formic acid) gradients at a flow rate of 15 niL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 1.9 mg of (S)-l-(6-chloro-l-(3,5-dimethylphenyl)-5-methyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 466.9 (M+l).
Example 244 : (R)- l-(5,6-dichloro- 1-p-tolyl- lH-benzo [d] imidazol-2-yl)-7V-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide
Figure imgf000219_0001
Ethyl l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (110 mg, 0.321 mmol) dimethylsulfoxide (1 mL), caesium carbonate (147 mg, 0.45 mmol), l-iodo-4-methylbenzene (140 mg, 0.643 mmol), 8-hydroxyquinoline (9.3 mg, 0.064 mmol), polyethylene glycol 400 (64.3 mg, 0.161 mmol) and copper(I) oxide (4.6 mg, 0.032 mmol) was subjected to microwave conditions for one hour at 15O0C. The reaction mixture was diluted with N,N-dimethyl- formamide (4 mL), filtered and the filtrate concentrated in vacuo. The residue was dissolved in ethanol (4 mL) and aqueous sodium hydroxide (2 mL, 1 N), and stirred at room temperature over the weekend. The reaction mixture was treated with aqueous hydrochloric acid (1 mL, 2 N) and concentrated. The residue was mixed with N,N-dimethylformamide (13 mL), N,7V-diisopropyl- ethylamine (Hunig's base, DIEA, 19.2 mg, 0.148 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-
1,1,3,3-tetramethyluronium hexafluoro-phosphate (ΗATU, 14.1 mg, 0.037 mmol) and (R)-(+)- tetrahydrofuran-3 -amine 4-methylbenzenesulfonate (9.6 mg, 0.0371 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated in vacuo and purified on hplc (preparative RP-LC was performed on a Gilson system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using methano I/water (0.05% formic acid) gradients at a flow rate of 4 niL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 7.7 mg of (R)- 1 -(5,6- dichloro- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide. LC-MS (m/z) 473.1 (M+ 1).
Example 245: l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V-((lS,25)-2- hydroxycyclopentyl)piperidine-4-carboxamide
Figure imgf000220_0001
(a) Preparation of the intermediate compound ethyl l-(l-cyclobutyl-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate:
Figure imgf000220_0002
This compound was prepared from ethyl l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine- 4-carboxylate (1 g, 3.3 mmol), bromocyclo butane (13.2 mmol), caesium carbonate (13.2 mmol), [l,l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), 0.033 mmol) and Λ/,Λ/-dimethylformamide (8 mL) using the method described in Example 16. The reaction mixture was heated at 13O0C for two hours in a sealed tube and purified with column
chromathography, to give 510 mg (43 % yield) of ethyl l-(l-cyclobutyl-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate. (b) Preparation of the intermediate compound l-(l-cyclobutyl-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid:
Figure imgf000221_0001
Ethyl l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (1 g, 2.79 mmol), aqueous sodium hydroxide (14 mmol), ethanol and water (50 mL) was stirred at room temperature for 30 minutes. After the appropriate work-up, the target compound was recrystallized from petroleum ether to give 500 mg (54 % yield) of l-(l-cyclobutyl-5,6- dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid.
(c) The title compound was prepared from l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol- 2-yl)piperidine-4-carboxylic acid (0.1 g, 0.3 mmol), N,N-dimethylformamide (3 mL), N,N- diisopropylethylamine (Ηϋnig's base, DIEA, 0.6 mmol), 2-(7-aza-lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 0.6 mmol) and (lS,2S)-2- aminocyclopentanol (0.36 mmol) using the method described in Example 166. The reaction mixture was stirred at room temperature for one hour and purified with recrystallization from petroleum ether, to give 47 mg (37 % yield) of l-(l-cyclobutyl-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-((15',25)-2-hydroxycyclopentyl)piperidine-4-carboxamide as an off- white solid. LC-MS (m/z) 410.9 (M+l).
Example 246: l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V-((lR,2R)-2- hydroxycyclopentyl)piperidine-4-carboxamide
Figure imgf000221_0002
The title compound was prepared from l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylic acid (0.1 g, 0.3 mmol), N,N-dimethylformamide (3 mL), N,N- diisopropylethylamine (Ηϋnig's base, DIEA, 0.6 mmol), 2-(7-aza-lH-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 0.6 mmol) and (lR,2R)-2- aminocyclopentanol (0.36 mmol) using the method described in Example 166. The reaction mixture was stirred at room temperature for one hour and purified with recrystallization from petroleum ether, to give 10 mg (8 % yield) of l-(l-cyclobutyl-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-((lR,2R)-2-hydroxycyclopentyl)piperidine-4-carboxamidee as an off- white solid. LC-MS (m/z) 410.9 (M+l). Example 247: (R)-l-(l-(benzofuran-5-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000222_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (120 mg, 0.350 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.701 mmol), 5-bromobenzofuran (1.051 mmol), 8-hydroxyquinoline (0.140 mmol), polyethylene glycol (0.175 mmol) and copper(I) oxide (0.0701 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on preperative hplc (Shimadzu LC8A, C18 column (22 x 250 mm, lOμm), acetonitrile/water gradient (0.1% trifluoroacetic acid), flowrate 15 mL/min), to give 5 mg (3.1 % yield) of (R)-l-(l-(benzofuran-5-yl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 459.2 (M+l).
Example 248: (R)-l-(5,6-dichloro-l-(4-fluoro-3,5-dimethylphenyl)-lH-benzo[d]imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000222_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 5-bromo-2-fluoro-l,3-dimethylbenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on preparative hplc (Shimadzu LC8A, C18 column (22 x 250 mm, lOμm), acetonitrile/water gradient (0.1% trifluoroacetic acid), flowrate 15 niL/min), to give 10 mg (7.6 % yield) of (R)-l-(5,6-dichloro-l- (4-fluoro-3,5-dimethylphenyl)-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a pale yellow, solid. LC-MS (m/z) 505.4 (M+ 1).
Example 249 : (R)- l-(l-(3-fluoro-5-methylphenyl)-5,6-dimethyl- lH-benzo [d] imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000223_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (120 mg, 0.350 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.701 mmol), l-bromo-3-fluoro-5-methylbenzene (1.051 mmol), 8- hydroxyquinoline (0.140 mmol), polyethylene glycol (0.175 mmol) and copper(I) oxide (0.0701 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 3 mg (1.9 % yield) of (R)-l-(l-(3-fluoro-5-methylphenyl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid. LC- MS (m/z) 451.1 (M+ 1). Example 250: (R)-l-(5,6-dichloro-l-(3-fluoro-5-methylphenyl)-lH-benzo[d]imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000223_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.313 mmol) dimethylsulfoxide (2 niL), caesium carbonate (0.470 mmol), l-bromo-3-fluoro-5-methylbenzene (0.939 mmol), 8- hydroxyquinoline (0.125 mmol), polyethylene glycol (0.157 mmol) and copper(I) oxide (0.0626 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 14 mg (9.1 % yield) of (R)-l-(5,6-dichloro-l-(3-fiuoro-5-methylphenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 491.5 (M+l).
Example 251: (R)-l-(5,6-dichloro-l-(4-cyclopropylphenyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000224_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.313 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.470 mmol), l-bromo-4-cyclopropylbenzene (0.939 mmol), 8- hydroxyquinoline (0.125 mmol), polyethylene glycol (0.157 mmol) and copper(I) oxide (0.0626 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 5 mg (3.2 % yield) of (R)-l-(5,6-dichloro-l-(4-cyclopropylphenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 499.3 (M+l). Example 252: (R)-l-(5,6-dichloro-l-(3-cyclopropylphenyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000224_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.313 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.470 mmol), l-bromo-3-cyclopropylbenzene (0.939 mmol), 8- hydroxyquinoline (0.125 mmol), polyethylene glycol (0.157 mmol) and copper(I) oxide (0.0626 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 17 mg (11 % yield) of (R)-l-(5,6-dichloro-l-(3-cyclopropylphenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 499.4 (M+l). Example 253: (R)-l-(l-(benzofuran-6-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000225_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (120 mg, 0.350 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.701 mmol), 6-bromobenzofuran (1.051 mmol), 8-hydroxyquinoline (0.140 mmol), polyethylene glycol (0.175 mmol) and copper(I) oxide (0.0701 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 20 mg (12 % yield) of (R)-I -(l-(benzofuran-6-yl)-5,6-dimethyl- lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 459.1 (M+l).
Example 254: (R)-l-(5-chloro-l-(4-ethylphenyl)-6-methyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000226_0001
The title compound was prepared from a tautomeric misture of (R)-I -(5-chloro-6-methyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide and (R)- 1 -(6-chloro- 5-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide (500 mg, 1.38 mmol) dimethylsulfoxide (2 mL), caesium carbonate (2.76 mmol), l-bromo-4- ethylbenzene (4.13 mmol), 8-hydroxyquinoline (0.551 mmol), polyethylene glycol (0.689 mmol) and copper(I) oxide (0.276 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase reverse-phase hplc, to give 20 mg (3.3 % yield) of (R)-l-(5-chloro-l- (4-ethylphenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as an off-white solid solid, eluting after (R)-l-(6-chloro-l-(4-ethylphenyl)-5- methyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide on the column. LC-MS (m/z) 467.2 (M+l).
Example 255: (R)-l-(6-chloro-l-(4-ethylphenyl)-5-methyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000226_0002
The title compound was obtained as described in Example 254 as eluting before (R)-l-(5-chloro- 1 -(4-ethylphenyl)-6-methyl- lH-benzo [d]imidazo l-2-yl)-N-(tetrahydrofuran-3 -yl)piperidine-4- carboxamide on the column. This gave 24 mg (3.7 % yield) of (R)-l-(6-chloro-l-(4- ethylphenyl)-5 -methyl- 1 H-benzo [d]imidazo l-2-yl)-N-(tetrahydrofuran-3 -yl)piperidine-4- carboxamide as an off-white solid. MS (m/z) 467.2 (M+l).
Example 256: (R)-l-(5-chloro-l-(4-ethylphenyl)-6-methyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000227_0001
The title compound was prepared from a tautomeric mixture of (R)-I -(5-chloro-6-methyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide and (R)- 1 -(6-chloro- 5-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide (500 mg, 1.38 mmol) dimethylsulfoxide (2 mL), caesium carbonate (2.76 mmol), l-bromo-4-tert- butylbenzene (4.13 mmol), 8-hydroxyquinoline (0.551 mmol), polyethylene glycol (0.689 mmol) and copper(I) oxide (0.276 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase reverse-phase hplc, to give 69 mg (10 % yield) of (R)-l-(l-(4-tert- butylphenyl)-5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine- 4-carboxamide as a white solid, eluting after (R)-l-(l-(4-tert-butylphenyl)-6-chloro-5-methyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide on the column. LC-MS (m/z) 495.3 (M+ 1).
Example 257: (R)-l-(l-(4-tert-butylphenyl)-6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000227_0002
The title compound was obtained as described in Example 256 eluting before (R)-l-(l-(4-tert- butylphenyl)-5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine- 4-carboxamide on the column. This gave 63 mg (9 % yield) of (R)-I -(I -(4-tert-butylphenyl)-6- chloro-5 -methyl- 1 H-benzo [d]imidazo l-2-yl)-N-(tetrahydrofuran-3 -yl)piperidine-4-carboxamide as a white solid. MS (m/z) 495.3 (M+l).
Example 258: (R)-l-(l-(4-cyclopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000228_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (120 mg, 0.350 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.701 mmol), l-bromo-4-cyclopropylbenzene (1.051 mmol), 8- hydroxyquinoline (0.140 mmol), polyethylene glycol (0.175 mmol) and copper(I) oxide (0.0701 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hours at 14O0C and subsequently purified on reverse-phase hplc, to give 13 mg (8.1 % yield) of (R)-I -(I -(4-cyclopropylphenyl)-5,6-dimethyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a pale yellow. solid. LC-MS (m/z) 459.1 (M+ 1).
Example 259: (R)-l-(l-(3-cyclopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000228_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (120 mg, 0.350 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.701 mmol), l-bromo-3-cyclopropylbenzene (1.051 mmol), 8- hydroxyquinoline (0.140 mmol), polyethylene glycol (0.175 mmol) and copper(I) oxide (0.0701 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 5 mg (3.1 % yield) of (R)-I -(I -(3-cyclopropylphenyl)-5,6-dimethyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 459.2 (M+l). Example 260 : (R)- l-(5,6-dichloro- l-(3-(cyclopentyloxy)phenyl)- lH-benzo [d] imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000229_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-3-(cyclopentyloxy)benzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 2 mg (1.4 % yield) of (R)-l-(5,6-dichloro-l-(3-(cyclopentyloxy)phenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid. LC- MS (m/z) 543.2 (M+ 1).
Example 261: (R)-l-(5,6-dichloro-l-(3-cyclobutoxyphenyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000229_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), l-bromo-3-cyclobutoxybenzene (0.783 mmol, prepared by alkylation of 3-bromophenol using bromocyclobutane and potassium carbonate in N ,N- dimethylformamide), 8-hydroxy-quinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for two hour at 12O0C and subsequently purified on reverse-phase hplc, to give 2 mg (1.5 % yield) of (R)-l-(5,6-dichloro-l-(3- cyclobutoxyphenyl)-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a pale yellow solid. LC-MS (m/z) 529.4 (M+ 1).
Example 262: l-(5-chloro-6-fluoro-l-methyl-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide and l-(6-chloro-5-fluoro-l-methyl-lH- benzo [d] imidazol-2-yl)-7V-cyclopentylpiperidine-4-carboxamide
Figure imgf000230_0001
The title compound was prepared from a tautomeric mixture of l-(5-chloro-6-fluoro-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro-5-fluoro- IH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide (0.1 g, 0.27 mmol), methyl iodide (1.096 mmol), caesium carbonate (1.096 mmol), [l,l'-bis(diphenyl-phosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), 0.0274 mmol) and N,Λ/-dimethyl-formamide (3 mL) using the method described in Example 94. This gave 30 mg (29 % yield) of l-(5-chloro-6-fluoro-l- methyl- lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro-5- fluoro-l-methyl-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as an off- white solid. No effort was made to determine the ratio of the regioisomers. LC-MS (m/z) 379.1 (M+l).
Example 263: l-(5-chloro-l-ethyl-6-fluoro-l//-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide and l-(6-chloro-l-ethyl-5-fluoro-lH- benzo [d] imidazol-2-yl)-7V-cyclopentylpiperidine-4-carboxamide
Figure imgf000230_0002
The title compound was prepared from a tautomeric mixture of l-(5-chloro-6-fluoro-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide and l-(6-chloro-5-fluoro-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide (0.1 g, 0.27 mmol), ethyl iodide (1.096 mmol), caesium carbonate (1.096 mmol), [l,l'-bis(diphenyl-phosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), 0.0274 mmol) and N,Λ/-dimethyl-formamide (3 mL) using the method described in Example 94. This gave 35 mg (33 % yield) of l-(5-chloro-l-ethyl-6- fluoro-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide and l-(6-chloro-l- ethyl-5-fluoro-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as an off- white solid. No effort was made to determine the ratio of the regioisomers. LC-MS (m/z) 393.0 (M+l).
Example 264: l-(5-chloro-6-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide and l-(6-chloro-5-fluoro-l-isopropyl-lH- benzo [d] imidazol-2-yl)-7V-cyclopentylpiperidine-4-carboxamide
Figure imgf000231_0001
The title compound was prepared from a tautomeric mixture of l-(5-chloro-6-fluoro-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro-5-fluoro- IH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide (0.1 g, 0.27 mmol), isopropyl iodide (1.096 mmol), caesium carbonate (1.096 mmol), [l,l'-bis(diphenyl-phosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), 0.0274 mmol) and N,Λ/-dimethyl-formamide (3 mL) using the method described in Example 94. This gave 50 mg (45 % yield) of l-(5-chloro-6-fluoro-l- isopropyl- lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro- 5-fluoro-l -isopropyl- lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide as an off-white solid. No effort was made to determine the ratio of the regioisomers. LC-MS (m/z) 407.1 (M+l).
Example 265: l-(l-butyl-5-chloro-6-fluoro-l//-benzo[d]imidazol-2-yl)-7V- cyclopentylpiperidine-4-carboxamide and l-(l-butyl-6-chloro-5-fluoro-l//- benzo [d] imidazol-2-yl)-7V-cyclopentylpiperidine-4-carboxamide
Figure imgf000231_0002
The title compound was prepared from a tautomeric mixture of l-(5-chloro-6-fluoro-lH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide and 1 -(6-chloro-5-fluoro- IH- benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4-carboxamide (0.1 g, 0.27 mmol), 1- bromobutane (1.096 mmol), caesium carbonate (1.096 mmol), [l,l'-bis(diphenyl- phosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), 0.0274 mmol) and N,7V-dimethyl- formamide (3 niL) using the method described in Example 94. This gave 8 mg (6.8 % yield) of l-(l-butyl-5-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-N-cyclopentylpiperidine-4- carboxamide and l-(l-butyl-6-chloro-5-fluoro-lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide as an off-white solid. No effort was made to determine the ratio of the regioisomers. LC-MS (m/z) 421.1 (M+ 1).
Example 266: l-(5,6-dimethyl-l-p-tolyl-lH-benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3- yl)piperidine-4-carboxamide
Figure imgf000232_0001
The title compound was prepared from l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-iV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (0.30 g, 0.877 mmol), dimethylsulfoxide (6 mL), caesium carbonate (3.51 mmol), l-iodo-4-methylbenzene (3.51 mmol), 4,7-dimethoxy- 1,10-phenanthroline (0.132 mmol), polyethylene glycol (0.89 g) and copper(I) oxide (0.0438 mmol) using the method described in Example 76. The reaction mixture was heated at 12O0C for 12 hours in a sealed tube and purified with column chromathography, to give 43 mg (11.3 % yield) of l-(5,6-dimethyl-l-p-tolyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)- piperidine-4-carboxamide as a pale green solid. LC-MS (m/z) 432.2 (M+ 1).
Example 267: (R)-l-(6-chloro-l-(4-fluorophenyl)-5-methyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000232_0002
The title compound was prepared from a tautomeric misture of (R)-I -(5-chloro-6-methyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide and (R)- 1 -(6-chloro- 5-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide (500 mg, 1.38 mmol) dimethylsulfoxide (2 mL), caesium carbonate (2.76 mmol), 4-fluoro iodobenzene (4.13 mmol), 8-hydroxyquinoline (0.551 mmol), polyethylene glycol (0.689 mmol) and copper(I) oxide (0.276 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase reverse-phase hplc, to give 42 mg (6.6 % yield) of (R)-I -(6-chloro-l- (4-fluorophenyl)-5-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as an off-white solid, eluting ahead of (R)-l-(5-chloro-l-(4-fluorophenyl)-6- methyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide on the column. MS (m/z) 457.1 (M+l).
Example 268 : (R)- l-(5-chloro- l-(4-fluorophenyl)-6-methyl- lH-benzo [d] imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000233_0001
The title compound was obtained as described in Example 267 eluting after (R)-l-(6-chloro-l- (4-fluorophenyl)-5-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide on the column. This gave 47 mg (7.4 % yield) of (R)-l-(5-chloro-l-(4- fluorophenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as an off-white solid. LC-MS (m/z) 457.1 (M+l).
Example 269: (R)-l-(6-chloro-5-methyl-l-m-tolyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000233_0002
The title compound was prepared from a tautomeric misture of (R)-I -(5-chloro-6-methyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide and (R)- 1 -(6-chloro- 5-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide (500 mg, 1.38 mmol) dimethylsulfoxide (2 niL), caesium carbonate (2.76 mmol), l-bromo-3- methylbenzene (4.13 mmol), 8-hydroxyquinoline (0.551 mmol), polyethylene glycol (0.689 mmol) and copper(I) oxide (0.276 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase reverse-phase hplc, to give 24 mg (3.8 % yield) of (R)-I - (6-chloro-5-methyl-l-m-tolyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4- carboxamide as a pale yellow solid, eluting ahead of (R)-I -(5-chloro-6-methyl- 1-m-to IyI- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide on the column. LC- MS (m/z) 453.2 (M+l). Example 270: (R)-l-(5-chloro-6-methyl-l-m-tolyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000234_0001
The title compound was obtained as described in Example 269 eluting after (R)-l-(6-chloro-5- methyl- 1 -m-tolyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide on the column. This gave 23 mg (3.7 % yield) of (R)-I -(5-chloro-6-methyl- 1-m-to IyI- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (mix) 453.3 (M+l).
Example 271: (R)-l-(5-chloro-6-methyl-l-(5-(trifluoromethyl)pyridin-2-yl)-lH- benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000234_0002
The title compound was prepared from a tautomeric misture of (R)-I -(5-chloro-6-methyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide and (R)- 1 -(6-chloro- 5-methyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide (500 mg, 1.38 mmol) dimethylsulfoxide (2 niL), caesium carbonate (2.76 mmol), 2-bromo-5- (trifluoromethyl)pyridine (4.13 mmol), 8-hydroxyquinoline (0.551 mmol), polyethylene glycol (0.689 mmol) and copper(I) oxide (0.276 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 12O0C and subsequently purified on reverse-phase reverse-phase hplc, to give 12 mg (1.7 % yield) of (R)-I- (5-chloro-6-methyl- 1 -(5-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as a yellow solid, eluting ahead of (R)-I -(6- chloro-5-methyl- 1 -(5-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide on the column. LC-MS (m/z) 508.3 (M+l). Example 272: (R)-l-(6-chloro-5-methyl-l-(5-(trifluoromethyl)pyridin-2-yl)-lH- benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000235_0001
The title compound was obtained as described in Example 271 eluting after (R)-l-(5-chloro-6- methyl- 1 -(5-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide on the column. This gave 16 mg (2.3 % yield) of (R)-I -(6-chloro-5- methyl- 1 -(5-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as an yellow solid. LC-MS (m/z) 508.2 (M+l).
Example 273: l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V-((2S)-2- methoxycyclopentyl)piperidine-4-carboxamide
A solution of l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-((15f,25)-2- hydroxycyclopentyl)piperidine-4-carboxamid (0.10 g, 0.24 mmol) in N,N-dimethylformamide (DMF, 2 mL) was cooled to 0 0C. Sodium hydride (0.26 mmol) was added followed by methyl iodide (0.24 mmol) and the reaction was stirred at 0 0C for 3 h. The reaction mixture was poured onto ice and the precipitate was collected by filtration. The crude was rechrystallized from petroleum ether to give 17 mg (17%) of l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)-N-((2S)-2-methoxycyclopentyl)piperidine-4-carboxamide as a pale yellow solid. LC-MS (m/z) 425.2 (M+l). Example 274: l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V-((2S)-2- ethoxycyclopentyl)piperidine-4-carboxamide
Figure imgf000236_0001
A solution of l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-((lS,25)-2- hydroxycyclopentyl)piperidine-4-carboxamid (0.10 g, 0.24 mmol) in N,N-dimethylformamide (DMF, 2 mL) was cooled to 0 0C. Sodium hydride (0.48 mmol) was added followed by ethyl iodide (0.48 mmol) and the reaction was stirred at 0 0C for 3 h. The reaction mixture was poured onto ice and the precipitate was collected by filtration. The crude was rechrystallized from petroleum ether to give 42 mg (39%) of l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)-N-((2S)-2-ethoxycyclopentyl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 439.2 (M+l).
Example 275: l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V-((2S)-2- propoxycyclopentyl)piperidine-4-carboxamide
Figure imgf000236_0002
A solution of l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-((lS,25)-2- hydroxy cyclopentyl)piperidine-4-carboxamid (0.10 g, 0.24 mmol) in N,N-dimethylformamide (DMF, 2 mL) was cooled to 0 0C. Sodium hydride (0.48 mmol) was added followed by 1- iodopropane (0.48 mmol) and the reaction was stirred at 0 0C for 3 hours. The reaction mixture was concentrated under reduced pressure and the crude purified by silica chromatography (chloroform/methanol gradient) to give 51 mg (46%) of l-(l-cyclobutyl-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-((2S)-2-propoxycyclopentyl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 453.2 (M+ 1).
Example 276: l-(5,6-dichloro-l-(4-(dimethylcarbamoyl)phenyl)-lH-benzo[d]imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000237_0001
A reaction mixture consisting of l-(l-(4-bromophenyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)- N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.19 mmol), trans-di(μ-acetato)- bis[o-(di-o-tolylphosphino)-benzyl]dipalladium(II) (Hermann palladacycle, 0.0095 mmol), N5N- diisopropylethylamine (Hunig's base, DIEA, 0.38 mmol), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.19 mmol), tri tertiarybutyl phosphonium tetrafluoborate ([(t-Bu)3PH]BF4, 0.019 mmol), molybdenum hexacarbonyl (Mo(CO)6, 0.095 mmol) and N, N-dimethyl amine hydrochloride (0.38 mmol) in 1,4-dioxane (3 mL), was irradiated under microwave conditions at 15O0C for 30 minutes. The reaction mixture was quenched with water (5 mL), extracted with dichloromethane (2 x50 mL) and the combined organic phases dried over anhydrous sodium sulphate. After concentration in vacuo, the residue was subjected to column chromatography to give 5 mg (5 % yield) of 1 -(5,6-dichloro- 1 -(4-(dimethylcarbamoyl)phenyl)- lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 530.5 (M+l).
Example 277: l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)-iV-((lS,2S)-2- hydroxycyclopentyl)piperidine-4-carboxamide
Figure imgf000237_0002
(a) Preparation of the intermediate compound ethyl 1 -(5,6-dichloro- 1-cyclo butyl- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxylate:
Figure imgf000238_0001
Ethyl 1 -(5,6-dichloro- 1 -cyclobutyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate was prepared from ethyl l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (1.0 g, 2.9 mmol), (bromomethyl)cyclo butane (11.6 mmol), caesium carbonate (11.6 mmol), [1,1'- bis(diphenylphosphino)ferrocene] dichloropalladium(II) (PdCl2(dppf), 0.29 mmol) and N,N- dimethylformamide (8 mL) using the method described in Example 16. The reaction mixture was heated at 1300C for two hours in a sealed tube and purified with column chromathography, to give 480 mg (42 % yield) of ethyl l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxylate as a pale yellow solid. LC-MS (m/z) 451.3 (M+l). (b) Preparation of the intermediate compound 1 -(5,6-dichloro- 1 -cyclobutyl- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid:
Figure imgf000238_0002
Ethyl l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylate (1.0 g, 2.5 mmol), aqueous sodium hydroxide (12.5) and ethano I/water (4:1) was stirred for 30 minutes at room temperature. After the appropriate work-up, the residue was recrystallized from petroleum ether, to give 0.70 g (83 % yield) of 1 -(5,6-dichloro- 1 -cyclobutyl- IH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid.
(c) l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (1.0 mg, 2.7 mmol), N,N-dimethylformamide (10 mL), N,7V-diisopropyl-ethylamine (Ηunig's base, DIEA, 5.4 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium
hexafluorophosphate (ΗATU, 5.4 mmol) and (lS,2S)-2-aminocyclopentanol (3.24 mmol) was stirred at room temperature for one hour. After the appropriate work-up, the residue was recrystallized from petroleum ether, to give 1.0 g (83 % yield) of 1 -(5,6-dichloro- 1-cyclobutyl- lH-benzo[d]imidazol-2-yl)-N-((lS,2S)-2-hydroxycyclopentyl)piperidine-4-carboxamide. Example 278: l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)-7V-((lS,2S)-2- methoxycyclopentyl)piperidine-4-carboxamide
Figure imgf000239_0001
A solution of l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)-N-((lS,2S)-2- hydroxy cyclopentyl)piperidine-4-carboxamide (0.10 g, 0.22 mmol) in N,N-dimethylformamide (DMF, 3 mL) was cooled to 0 0C. Sodium hydride (0.24 mmol) was added followed by methyl iodide (0.22 mmol) and the reaction was stirred at 0 0C for 30 minutes. The reaction mixture was poured onto ice and the precipitate was collected by filtration. The crude was recrystallized from petroleum ether to give 5 mg (5%) of l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)- N-((lS,2S)-2-methoxycyclopentyl)piperidine-4-carboxamide as a yellow solid. LC-MS (m/z) 465.4 (M+l).
Example 279: l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)-7V-((lS,2S)-2- ethoxycyclopentyl)piperidine-4-carboxamide
Figure imgf000239_0002
A solution of l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)-N-((lS,2S)-2- hydroxycyclopentyl)piperidine-4-carboxamide (0.10 g, 0.22 mmol) in N,N-dimethylformamide (DMF, 3 mL) was cooled to 0 0C. Sodium hydride (0.44 mmol) was added followed by ethyl iodide (0.44 mmol) and the reaction was stirred at 0 0C for 3 hours. The reaction mixture was poured onto ice and the precipitate was collected by filtration. The crude was recrystallized from petroleum ether to give 30 mg (28 % yield) of 1 -(5,6-dichloro-l -cyclo butyl- IH- benzo[d]imidazol-2-yl)-N-((lS,2S)-2-ethoxycyclopentyl)piperidine-4-carboxamide as an yellow solid. LC-MS (m/z) 479.5 (M+l).
Example 280: l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V-(furan-2- ylmethyl)piperidine-4-carboxamide
Figure imgf000240_0001
l-(l-Cyclobutyl-5,6-dimethyl-lH-benzoimidazol-2-yl)-piperidine-4-carboxylic acid (30 mg, 0.092 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 42 mg, 0.11 mmol), 2-aminomethylfϊιrane (25 μL, 0.28 mmol) and JV,iV-diisopropyl- 5 ethylamine (Ηunig's base, DIEA, 46 μL, 0.28 mmol) were dissolved in N, N-dimethylformamide (DMF, 1 mL). The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was filtered and the crude product was purified on preparative hplc (preparative RP-LC was performed on a Gilson system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using methano I/water (0.05% formic acid) gradients at a flow rate of 4 mL/min with UV 10 (214 or 254 nm) and MS (ESI) detection) to give 18.2 mg (72 % yield) of l-(l-cyclobutyl-5,6- dimethyl-lH-benzo[d]imidazol-2-yl)-N-(furan-2-ylmethyl)piperidine-4-carboxamide as an off- white solid. LC-MS (m/z) 407.0 (M+l).
Example 281: l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V-(thiophen-2- ylmethyl)piperidine-4-carboxamide
Figure imgf000240_0002
l-(l-Cyclobutyl-5,6-dimethyl-lH-benzoimidazol-2-yl)-piperidine-4-carboxylic acid (30 mg, 0.092 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 42 mg, 0.11 mmol), 2-thiophenemethylamine (28 μL, 0.28 mmol) and JV,iV-diisopropyl- ethylamine (Ηunig's base, DIEA, 153 μL, 0.916 mmol) were dissolved in N5N- 0 dimethylformamide (DMF, 1 mL). The reaction mixture was stirred overnight at ambient
temperature. The reaction mixture was filtered and the crude product was purified on preparative hplc (preparative RP-LC was performed on a Gilson system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using methano I/water (0.05% formic acid) gradients at a flow rate of 4 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 2.5 mg (6 % yield) of 1- 5 (1 -cyclobutyl-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)-N-(thiophen-2-ylmethyl)piperidine-4- carboxamide as an off-white solid. LC-MS (m/z) 423.0 (M+l). Example 282: (R)-l-(l-(5-bromopyridin-2-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000241_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (290 mg, 0.757 mmol) dimethylsulfoxide (1 mL), caesium carbonate (345 mg, 1.06 mmol), 2,5-dibromopyridine (0.72 g, 3.0 mmol), 8- hydroxyquinoline (0.15 mmol), polyethylene glycol 400 (0.38 mmol) and copper(I) oxide (0.076 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 60 minutes at 15O0C. Most of the DMSO was removed under reduced pressure and the residue purified by silica chromatography (0-6% MeOH in dichloromethane) to give 97 mg (37 % yield) of (R)-l-(l-(5-bromopyridin-2-yl)-5,6-dimethyl-lH-benzo[d]imidazol- 2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a brown solid. LC-MS (m/z) 540.2 (M+l).
Example 283: (R)-l-(l-(5-ethylpyridin-2-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000241_0002
To a solution of (R)-l-(l-(5-bromopyridin-2-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (20 mg, 0.037 mmol) and bis(tri-tert- butylphosphine)palladium(O) (CAS Registry Number: 53199-31-8, 1.2 mg, 0.0024 mmol) in dry tetrahydrofurane under nitrogen was added diethylzinc (1 N in hexane, 0.11 mL, 0.11 mmol) and the mixture microwave heated at 120 0C for 1 hour. The reaction mixture was purified by preparative reversed phase ΗPLC to give 7.7 mg (43 % yield) of (R)-l-(l-(5-ethylpyridin-2-yl)- 5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as a white solid. LC-MS (m/z) 488.2 (M+l). Example 284: (R)-l-(l-(3-chloro-5-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000242_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.584 mmol), 3-chloro-5-fluoro-bromobenzene (0.876 mmol), 8- hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 10 mg (7 % yield) of (R)-l-(l-(3-chloro-5-fiuorophenyl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 471.2 (M+l).
Example 285: (R)-l-(5,6-dichloro-l-(3-chloro-5-fluorophenyl)-lH-benzo[d]imidazol-2-yl)- 7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000242_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol), dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 3-chloro-5-fluoro-bromobenzene (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 9 mg (7 % yield) of (R)-l-(5,6-dichloro-l-(3-chloro-5-fluoro-phenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 511.3 (M+l). Example 286: (R)-l-(5,6-dichloro-l-(3-(trifluoromethyl)phenyl)-lH-benzo[d]imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000243_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol), dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 3-bromo-benzotrifluoride (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 12 mg (9 % yield) of (R)-l-(5,6-dichloro-l-(3-trifluoromethylphenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 521 A (M+l).
Example 287: (R)-l-(5,6-dichloro-l-(2,2-difluorobenzo[d] [l,3]dioxol-5-yl)-lH- benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000243_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol), dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 5-bromo-2,2-difluorobenzo[d][l,3]dioxol (0.783 mmol), 8-hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 11 mg (8 % yield) of (R)-l-(5,6-dichloro-l-(2,2-difiuorobenzo[d][l,3]dioxol-5-yl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 539.3 (M+l). Example 288 (SJ-l-Cl-CS^-dimethylpheny^-S^-dimethyl-lH-benzoIdlimidazoH-yO-TV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000244_0001
(a) Preparation of the intermediate compound l-(l-(3,5-dimethylphenyl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid:
Figure imgf000244_0002
Ethyl l-(l-(3,5-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxylate (80.5 mg, 0.267 mmol), l-bromo-3,5-dimethylbenzene (73 μL, 0.534 mmol), 8- hydroxyquinoline (7.8 mg, 0.053 mmol), copper(I) oxide (3.8 mg, 0.027 mmol), polyethylene glycol 400 (107 mg, 0.267 mmol), caesium carbonate (122 mg, 0.374 mmol) and dimethyl- sulfoxide (0.5 mL) were mixed in a sealed reaction tube. The reaction mixture was heated at 1500C for two hour in a heating block and then diluted with ethylacetate and water. The water phase was extracted with ethyl acetate, the combined organic phases was dried over magnesium sulphate and concentrated in vacuo. To the residue was added ethanol (2 mL) and aquesous sodium hydroxide (1 mL, 1 N). The reaction mixture was stirred at 50 0C for one hour, neutralized with aqueous hydrochloric acid (1 N) and concentrated in vacuo. This gave 90 mg of l-(l-(3,5-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid. LC-MS (m/z) 378.0 (M+l).
(b) l-(l-(3,5-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (90 mg, 0.24 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (ΗATU, 136 mg, 0.358 mmol), (S)-(-)-tetrahydrofuran-3 -amine
hydrochloride (29.5 mg, 0.238 mmol) and JV,JV-diisopropyl-ethylamine (Ηunig's base, DIEA, 994 μL, 5.96 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction mixture was stirred overnight at ambient temperature, filtered and subjected to preparative hplc
(preparative RP-LC was performed on a Gilson system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using methano I/water (0.05% formic acid) gradients at a flow rate of 4 niL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 2 mg (2 % yield) of (S)-I -(I - (3,5-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 447.0 (M+l). Example 289: (R)-l-(5,6-dichloro-l-(4-(trifluoromethyl)pyridin-2-yl)-lH- benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000245_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol), dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 2-bromo-4-trifluoromethylpyridine (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 41 mg (30 % yield) of (R)-l-(5,6-dichloro-l-(4-(trifluoromethyl)pyridin-2-yl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 528.2 (M+l).
Example 290: (R)-l-(5,6-dichloro-l-(5-chloropyridin-2-yl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000245_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide (100 mg, 0.261 mmol), dimethylsulfoxide (2 mL), caesium carbonate (0.392 mmol), 2-bromo-4-chloropyridine (0.783 mmol), 8- hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 20 mg (17 % yield) of (R)-l-(5,6-dichloro-l-(5-chloropyridin-2-yl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 494.3 (M+l).
Example 291: (R)-l-(5,6-dichloro-l-(5-fluoro-6-methylpyridin-2-yl)-lH-benzo[d]imidazol- 2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000246_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.313 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.470 mmol), 2-bromo-5-fluoro-6-methylpyridine (0.939 mmol), 8- hydroxyquinoline (0.125 mmol), polyethylene glycol (0.157 mmol) and copper(I) oxide (0.0626 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 5 mg (3.2 % yield) of (R)-l-(5,6-dichloro-l-(5-fiuoro-6-methylpyridin-2-yl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamid. LC-MS (m/z) 492.3 (M+l).
Example 292: (R)-l-(l-(3-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000246_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.584 mmol), 3-fluoro-bromobenzene (0.876 mmol), 8- hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 7 mg (6 % yield) of (R)-l-(l-(3-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol- 2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 437.1 (M+ 1).
Example 293: (R)-l-(l-(3,5-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000247_0001
l-(l-(3,5-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (90 mg, 0.24 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium
hexafluorophosphate (ΗATU, 136 mg, 0.358 mmol), (R)-(+)-tetrahydrofuran-3 -amine 4- methylbenzenesulfonate (61.8 mg, 0.238 mmol) and iV,jV-diisopropyl-ethylamine (Ηunig's base, DIEA, 994 μL, 5.96 mmol) were dissolved in N,N-dimethylformamide (1 mL). The reaction mixture was stirred overnight at ambient temperature, filtered and subjected to preparative hplc (preparative RP-LC was performed on a Gilson system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using methano I/water (0.05% formic acid) gradients at a flow rate of 4 niL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 11 mg (10 % yield) of (R)-I- (l-(3,5-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamid as an off-white solid. LC-MS (m/z) 447.0 (M+l). Example 294: (R)-l-(l-(4-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000247_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 niL), caesium carbonate (0.584 mmol), 4-fluoro-bromobenzene (0.876 mmol), 8- hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 25 mg (22 % yield) of (R)-I -(I -(4-fiuorophenyl)-5,6-dimethyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 437.1 (M+l).
Example 295: (RJ-l-Cl-CS^-difluoropheny^-S^-dimethyl-lH-benzoIdlimidazoU-yO-TV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000248_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (120 mg, 0.350 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.701 mmol), 3,5-difluoro-bromobenzene (1.05 mmol), 8- hydroxyquinoline (0.140 mmol), polyethylene glycol (0.175 mmol) and copper(I) oxide (0.0701 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 31 mg (19 % yield) of (R)-l-(l-(3,5-difiuorophenyl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 455.1 (M+l). Example 296: (R)-l-(l-(4-chlorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000248_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (120 mg, 0.350 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.701 mmol), 4-chloro-bromobenzene (1.05 mmol), 8- hydroxyquinoline (0.140 mmol), polyethylene glycol (0.175 mmol) and copper(I) oxide (0.0701 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 10 mg (6 % yield) of (R)-I -(I -(4-chlorophenyl)-5,6-dimethyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 453.2 (M+l). Example 297: (R)-l-(5,6-dimethyl-l-(4-(trifluoromethyl)phenyl)-lH-benzo[d]imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000249_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (120 mg, 0.350 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.701 mmol), 4-bromo-benzotrifluoride (1.05 mmol), 8- hydroxyquinoline (0.140 mmol), polyethylene glycol (0.175 mmol) and copper(I) oxide (0.0701 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 3 mg (1.8 % yield) of (R)-I -(I -(4-trifluoromethyl-phenyl)-5,6-dimethyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 487.1 (M+l).
Example 298: (R)-l-(5,6-dimethyl-l-p-tolyl-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000249_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.584 mmol), 3-chloro-5-fluoro-benzene (0.876 mmol), 8- hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 39 mg (31 % yield) of (R)-I -(I -(4-methyl-phenyl)-5,6-dimethyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 434.1 (M+l). Example 299: (RJ-l-Cl-CS-chloropyridin-l-ylJ-S^-dimethyl-lH-benzoIdlimidazol-l-ylJ-TV- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000250_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (120 mg, 0.350 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.701 mmol), 2-bromo-5-chloropyridine (1.05 mmol), 8- hydroxyquinoline (0.140 mmol), polyethylene glycol (0.175 mmol) and copper(I) oxide (0.0701 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 18 mg (12 % yield) of (R)-l-(l-(5-chloropyridin-2-yl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 454.2 (M+l).
Example 300: (R)-l-(5,6-dimethyl-l-(4-(trifluoromethyl)pyridin-2-yl)-lH- benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000250_0002
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (100 mg, 0.292 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.584 mmol), 2-bromo-4-trifluoromethylpyridine (0.876 mmol), 8- hydroxyquinoline (0.117 mmol), polyethylene glycol (0.146 mmol) and copper(I) oxide (0.0584 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 25 mg (18 % yield) of (R)-I -(I -(4-(trifiuoromethyl)pyridin-2-yl)-5,6-dimethyl- IH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 488.1 (M+l). Example 301: (R)-l-(l-(5-fluoro-6-methylpyridin-2-yl)-5,6-dimethyl-lH-benzo[d]imidazol- 2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000251_0001
The title compound was prepared from (R)-l-(5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide, (120 mg, 0.350 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.701 mmol), 2-bromo-5-fluoro-6-methylpyridine (1.05 mmol), 8- hydroxyquinoline (0.140 mmol), polyethylene glycol (0.175 mmol) and copper(I) oxide (0.0701 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 11 mg (7 % yield) of (R)-l-(l-(5-fiuoro-6-methylpyridin-2-yl)-5,6-dimethyl-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 452.1 (M+l).
Example 302: (R)-l-(5,6-dichloro-l-(4-ethoxyphenyl)-lH-benzo[d]imidazol-2-yl)-7V- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000251_0002
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.313 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.470 mmol), 4-ethoxybenzene (0.783 mmol), 8-hydroxyquinoline (0.104 mmol), polyethylene glycol (0.511 mmol) and copper(I) oxide (0.0522 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 35 mg (30 % yield) of (R)- 1 -(5,6-dichloro- 1 -(4-ethoxyphenyl)- lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 503.5 (M+ 1).
Example 303: (R)-l-(5,6-dichloro-l-(4-methoxy-3-methylphenyl)-lH-benzo[d]imidazol-2- yl)-7V-(tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000252_0001
The title compound was prepared from (R)-l-(5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide (120 mg, 0.313 mmol) dimethylsulfoxide (2 mL), caesium carbonate (0.470 mmol), 4-methoxy-3-methylbenzene (0.939 mmol), 8- hydroxyquinoline (0.125 mmol), polyethylene glycol (0.157 mmol) and copper(I) oxide (0.0626 mmol) using the method described in Example 136. The reaction mixture was subjected to microwave conditions for 150 minutes at 14O0C and subsequently purified on reverse-phase hplc, to give 15 mg (10 % yield) of (R)-l-(5,6-dichloro-l-(4-methoxy-3-methylphenyl)-lH- benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide. LC-MS (m/z) 503.4 (M+l).
Example 304: (RJ-l-Cl-cyclobutyl-S^-dimethyl-lH-benzoIdlimidazoU-yl)-^- (tetrahydrofuran-3-yl)piperidine-4-carboxamide
Figure imgf000252_0002
l-(l-Cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxylic acid (30 mg, 0.092 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (ΗATU (42 mg, 0.11 mmol), (R)-(+)-tetrahydrofuran-3 -amine 4-methylbenzenesulfonate (71 mg, 0.28 mmol) and JV,JV-diisopropyl-ethylamine (Ηunig's base, DIEA, 153 μL, 0.916 mmol) were dissolved in N,N-dimethylformamide (1 mLThe reaction mixture was stirred overnight at ambient temperature, filtered and subjected to preparative hplc (preparative RP-LC was performed on a Gilson system equipped with a Zorbax SB-C8 (5 μm, 21.2 x 150 mm) column, using methano I/water (0.05% formic acid) gradients at a flow rate of 4 mL/min with UV (214 or 254 nm) and MS (ESI) detection) to give 17 mg (46 % yield) of (R)-l-(l-cyclobutyl-5,6- dimethyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3-yl)piperidine-4-carboxamide as an off-white solid. LC-MS (m/z) 397.0 (M+l).
BIOLOGICAL TESTS
Prostaglandin detection kits were purchased from Cayman Chemicals and used according to the instruction of the manufacturer.
Thiobarbituric acid assay (TBA-MDA assay or Malondialdehyde assay):
Malondialdehyde is a product of lipid peroxidation and reacts with thiobarbituric acid forming a red product that absorbs at 535 nm (W.G. Niehaus, Jr and B. Samuelsson, Eur. J. Biochem 6, 126 (1968) and is also fluorescent. The extinction coefficient of the TBA-MDA conjugate is 1.56 x 105 M"1 cm"1 (E.D. Wills. Biochem. J. 113, 315 (1969). The method used for detection of inhibition of mPGEs-1 is based on the detection of the amount of remaining PGH2. This method was described more than 20 years ago by Basevich et al (Bioorg. Khim. 1983, 9(5), 658-665).
The assay used was a modified variant and used citric acid instead of the TCA-TBA-HCl reagent described in the original assay. In this assay recombinant, membrane-bound human or rat mPGEs-1 was incubated with PGH2. The reaction was stopped by adding citric acid with a final pH of 3 and a large excess of iron(II) chloride (20 mM) to convert any remaining PGH2 into MDA and 12-HHT. TBA reagent was finally added (0.67 %) and the samples were heated at 80 0C for 30 min. The fluorescence of the conjugate was measured at 485/545 nm.
The product of mPGEs-1 (PGE2) was not measured directly in this assay, but rather the remaining substrate (PGH2) indirectly by adding FeCl2 that converts PGH2 into MDA and 12- HHT. As a positive control a known mPGEs-1 inhibitor, MK-886, was used and the new inhibitors were compared with the inhibition of MK-886. Selected results from the human and rat mPGEs-1 TBA-MDA assay (IC50 in μM) are shown in Table 1.
A549 cell-assay
A549 lung carcinoma cells, seeded at a density of 10, 000 cells/well, were grown in 96 well tissue culture plates. TNFalfa (5 ng/mL) and IL-I beta (5 ng/mL) were added and the cells were incubated for 16 hours. Cells were washed in PBS and test compounds at the appropriate concentration in HBSS/0.1% BSA were added. After 30 minutes incubation with test compounds, 10 μM arachidonic acid was added and cells were further incubated for 30 minutes. Supernatant was collected and analyzed for PGE2 content by EIA according to manufacturer's instructions. Selected results from the A549 cell-assay are shown in Table 1.
Table 1. Inhibition of human and rat mPGEs-1 and cellular PGE2 synthesis.
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
Figure imgf000261_0001
Figure imgf000262_0001
Figure imgf000263_0001
Figure imgf000264_0001
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
Figure imgf000269_0001
The human mPGEs-1 IC50 values of the compounds of Examples 284-287, 289-292 and 294-303 are within the range of 10-250 nM (i.e. 0.01-0.25 iM).
Carrageenan-induced paw edema
Method
Chemicals
λ-Carrageenan (Fluka, Switzerland), Carboxymethyl cellulose (CMC) (Sigma, USA), Dimethyl sulfoxide (DMSO) (Merck, Germany), Pyrogen free saline (Sintong, R. O. C.) and Tween 80 (Sigma, USA).
Equipment
Animal cage (Allentown, USA), Glass syringes (1 mL, 2 mL, Mitsuba, Japan), Hypodermic needle 27G x 1" (Top Corporation, Japan), Paw/Tail stimulator analgesia meter (IITC Model- 336G, IITC, USA), Plethysmometer (PV-Ol, Paw Volume Apparatus, SINGA Technology Co., R. O .C), Rat oral needle (Natsume, Japan) and Rat scale (1 g ~ 1000 g, TANITA, Japan).
Animals
Male Wistar rats weighing 165 ± 15 g were provided by BioLasco Taiwan (under Charles River Laboratories Technology Licensee). Space allocation for 5 animals was 45 x 23 x 21 cm.
Animals were housed in animal cages and maintained in a controlled temperature (21 - 230C) and humidity (50% - 70%) environment with 12 hours light/dark cycles for at least three days at test site prior to use. The rats were divided into groups of eight, each group to receive either vehicle (1% Tween 80/0.5% CMC), or 10, 30 or 100 mg/kg bodyweight of the compound of EXAMPLE 41 (in the following referred to as "EXAMPLE 41"). The rats were fasted overnight prior to use. EXAMPLE 41 was suspended in vehicle and administered intraperitoneally immediately before the right hind paw received intraplantar injection of carrageenan (0.1 mL of 1% suspension). Hind paw edema, a measure of inflammation, was recorded 6 hours after carrageenan administration using a plethysmometer.
Results
Intraperitoneal administration of EXAMPLE 41 at 10, 30 and 100 mg/kg bodyweight to rats resulted in a decrease in paw swelling of 22%, 34% and 39%, respectively, compared to vehicle- treated rats (figure qzl).
Conclusion
EXAMPLE 41 is capable of reducing carrageenan- induced paw swelling, a symptom of inflammation, in rats.
Complete Freund's Adjuvant-induced arthritis
EXAMPLE 41, was evaluated for anti- inflammatory activity in Complete Freund's Adjuvant (CFA)-induced arthritis in rats. EXAMPLE 41 at 3, 10 and 30 mg/kg was administered orally once daily for 5 consecutive days; the first dose given one hour before CFA was injected into the right hind paw on day 1. The right hind paw volume was measured on day 0 (before CFA), 4 hours after the single CFA injection (denoted day 1) and on days 5, 8, 11, 14, 18 and 21 (acute phase), while the left hind paw (without CFA) volume was measured on days 0 (before CFA), 14, 18 and 21 (delayed phase).
Method
Test Substance and Dosing Pattern
EXAMPLE 41 at 3, 10 and 30 mg/kg was administered orally once daily for 5 consecutive days, with the first dose given one hour before CFA (Complete Freund's Adjuvant) challenge. A dosing volume of 2 mL/kg was used.
Animals
Female Lewis rats weighing 210 ± 10 g were obtained from Charles River USA Inc. Space allocation for 5 animals was 45 x 23 x 21 cm. All animals were maintained in a controlled temperature (21-230C) and humidity (50% - 70%) environment with 12 hours light/dark cycles for at least three days at test site prior to use. Free access to standard lab chow for rats and water was granted.
EXAMPLE 41 at 3, 10 and 30 mg/kg was administered orally (PO) on day 1 beginning one hour before injection of CFA; once daily dosing was performed for 5 consecutive days. A well-ground suspension of killed Mycobacterium butyricum (0.3 mg in 0.1 mL of light mineral oil; CFA, was administered in a single dose into the subplantar region of the right hind paw 1 hour following the first dose of test substance (denoted day 1). Right hind paw volume was measured by plethysmometry on day 0 (before CFA treatment), day 1 (4 hr after CFA treatment) and days 5, 8, 11, 14, 18 and 21 after CFA treatment.The left paw volume measured days 0 (before CFA treatment), 14, 18 and 21 after administration of CFA in the right paw. For CFA-injected rats, the increase in paw volume (net swelling) on days 1 5, 8, 11, 14, 18 and 21 was obtained by subtracting the volume at day 0 (acute phase of inflammation); and the left paw volume on days 14, 18 and 21 was obtained by subtracting the volume at day 0 (delayed phase of inflammation). The net swelling of each treatment group was then compared to vehicle-treated group and expressed as percentage of inhibition. Anti- inflammatory activity in this model was denoted by values calculated during the acute phase as well as the delayed phase.
Equipment
Animal cage (Allentown, USA), Glass syringe (1 mL, Mitsuba, Japan), Hypodermic needle (27G x 1", Top Corporation, Japan), Stainless forceps (Klappenecker, Germany), Stainless scissors (Klappenecker, Germany) and TERUMO Syringe with the needle (1 mL, TERUMO CO., Philippines). Plethysmometer (PV-Ol Paw volume apparatus, SINGA Technology Co. R. O. C), Rat scale (1 ~ 1000 g, TANITA, Japan) and Rat oral needle (Natsume, Japan), Centrifuge 5810R (Eppendrof, Germany), Eppendorf tube (2 mL, Safe-lock, Eppendorf, Germany), Micropipettes (100 P & 200 P, Gilson, France)
Results
Maximum inhibition of paw swelling in EXAMPLE 41 -treated animals compared to vehicle- treated animals was recorded on day 1 and 14 for acute and delayed phase, respectively (figure qz2).
Conlusion
Oral administration of EXAMPLE 41 inhibits CF A- induced paw swelling in rats.

Claims

1. A compound of formula (I)
Figure imgf000272_0001
(I)
wherein
R1 is selected from branched or unbranched C1-C10 alkyl, C2-C10 alkenyl or C2-C10 alkynyl; C3- Cio cycloalkyl; C4-C10 cycloalkenyl; Cs-Cio cycloalkynyl; C1-Cg heterocyclyl; and C6-CiO aryl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or cycloalkynyl moiety optionally is substituted with 1, 2 or 3 groups Ra; and any heterocyclyl or aryl moiety optionally is substituted with 1, 2, 3, 4 or 5 groups Rb;
R2 is selected from branched or unbranched C1-Cg alkyl, C2-C9 alkenyl, or C2-C9 alkynyl; C3-C6 cycloalkyl; C4-C6 cycloalkenyl; C8-C10 cycloalkynyl; C1-Cg heterocyclyl; and C6-CiO aryl;
wherein any alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety optionally is substituted with 1 , 2 or 3 groups Ra; and any heterocyclyl or aryl moeiety optionally is substituted with 1, 2, 3, 4 or 5 groups Rb;
R3 and R4 are each independently selected from Ci -C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C3-C4 cycloalkyl; C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; Ci-C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; halogen; C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amino; and C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl carbonyl; wherein any alkyl, alkenyl, alkynyl or cycloalkyl moiety optionally is substituted with 1, 2, or 3 groups Rc; R5 and R6 are independently selected from hydrogen; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; and halogen; wherein any alkyl; alkenyl or alkynyl moiety optionally is substituted with 1, 2, or 3 groups Rc;
X represents a bond or branched or unbranched C1-C3 alkyl, C2-C3 alkenyl or C2-C3 alkynyl;
Q represents carbonyl, sulfonyl or sulfmyl; m is an integer of 0, 1 or 2; each Rais independently selected from halogen; hydroxy; C1-C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C1-C4 alkyloxy; C2-C4 alkenyloxy; C2-C4 alkynyloxy; C1-C4 alkyl, C2-C4 alkenyl or C2- C4 alkynyl secondary or tertiary amino; C1-C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; wherein any alkyl, alkenyl or alkynyl moiety optionally is substituted with 1, 2 or 3 groups Rc; each Rb is independently selected from halogen; carboxy; hydroxy; cyano; C1-C5 heteroaryl; C1- C4 alkyl; C2-C4 alkenyl; C2-C4 alkynyl; C3-C5 cycloalkyl; Ci-C4 alkyloxy; C2-C4 alkenyloxy; C2- C4 alkynyloxy; C3-C5 cycloalkyloxy; Ci-C4 alkylthio; C2-C4 alkenylthio; C2-C4 alkynylthio; C3- C5 cycloalkylthio; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amino; aminocarbonyl; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary amido; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl carbonyl; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl sulfonyl; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary sulphonamido; Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl secondary or tertiary acylsulphonamido; Ci-C4 alkyloxy, C2-C4 alkenyloxy, or C2-C4 alkynyloxy carbonyl; C1-C5 heterocyclyl; wherein any alkyl, alkenyl or alkynyl moiety optionally is substituted with 1, 2 or 3 groups Rc; each Rc is independently selected from fluorine and chlorine; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, wherein
R1 is selected from branched or unbranched C1-C10 alkyl, C3-C10 cycloalkyl; C1-Cg heterocyclyl; and C6-CiO aryl; wherein any alkyl or cycloalkyl moiety optionally is substituted with 1, 2 or 3 groups Ra; and any heterocyclyl or aryl moiety optionally is substituted with 1, 2, 3, 4 or 5 groups Rb;
R2 is selected from branched or unbranched C1-Cg alkyl; C3-C6 cycloalkyl; C1-Cg heterocyclyl; and C6-CiO aryl; wherein any alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynyl moiety optionally is substituted with 1, 2 or 3 groups Ra; and any heterocyclyl or aryl moeiety optionally is substituted with 1, 2, 3, 4 or 5 groups Rb; R3 and R4 are each independently selected from Ci -C4 alkyl and halogen, wherein any alkyl moiety optionally is substituted with 1, 2 or 3 groups Rc;
R5 and R6 are independently selected from hydrogen and Ci-C4 alkyl, wherein any alkyl moiety optionally is substituted with 1 , 2 or 3 groups Rc;
X represents a bond or branched or unbranched C1-C3 alkyl;
Q represents carbonyl; m is 0 or 1; each Rais independently selected from hydroxy; C1-C4 alkyloxy; C1-C4 alkyl secondary or tertiary amino; wherein any alkyl moiety optionally is substituted with 1, 2 or 3 groups Rc; each Rb is independently selected from halogen; carboxy; cyano; C1-C5 heteroaryl, C1-C4 alkyl; C3-C5 cycloalkyl; C1-C4 alkyloxy; C3-C5 cycloalkyloxy; aminocarbonyl; C1-C4 alkyl secondary or tertiary amido; C1-C4 alkyl carbonyl; C1-C4 alkyloxy carbonyl; C1-C4 alkyl secondary or tertiary acylsulphonamido; and C1-C5 heterocyclyl; wherein any alkyl, alkenyl or alkynyl moiety optionally is substituted with 1 , 2 or 3 groups Rc; each Rc is fluoro or is absent; or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 or claim 2, wherein
R1 is selected from branched or unbranched C1-C10 alkyl; C3-C6 cycloalkyl; 5- or 6-membered C3-C5 heterocyclyl; and phenyl; wherein any alkyl or cycloalkyl moiety optionally is substituted with 1 or 2 groups Ra; and any heterocyclyl or phenyl moiety optionally is substituted with 1 or 2 groups Rb;
or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 3, wherein R1 is selected from branched or unbranched C1- Cio alkyl, optionally substituted with 1 or 2 groups Ra;
or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 3, wherein R1 is selected from C3-C6 cycloalkyl, optionally substituted with 1 or 2 groups Ra;
or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 3, wherein R1 is selected from 5- or 6-membered C3-C5 heterocyclyl optionally substituted with 1 or 2 groups Rb;
or a pharmaceutically acceptable salt thereof.
7. A compound according to any one of the claims 1-6, wherein R2 is selected from branched or unbranched Ci-C6 alkyl; C3-C6 cycloalkyl; 5- or 6-membered C3-C5 heterocyclyl; and phenyl; wherein any alkyl or cycloalkyl moiety optionally is substituted with 1 or 2 groups Ra; and any heterocyclyl or phenyl moiety optionally is substituted with 1 or 2 groups Rb;
or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 7, wherein R2 is selected from C3-C6 cycloalkyl, 5-membered C3-C4 heterocyclyl and 6-membered C3-C5 heterocyclyl, wherein any cycloalkyl moiety optionally is substituted with 1 or 2 groups Ra; and any heterocyclyl moiety optionally is substituted with 1 or 2 groups Rb;
or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 7, wherein R2 is selected from C4-C6 cycloalkyl and 5- or 6- membered C4-C5 heterocyclyl, wherein any cycloalkyl moiety optionally is substituted with 1 or 2 groups Ra; and any heterocyclyl moiety optionally is substituted with 1 or 2 groups Rb; or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 7, wherein R2 is selected from C4-C6 cycloalkyl and 5- membered C3-C4 heterocyclyl, wherein any cycloalkyl moiety optionally is substituted with 1 or 2 groups Ra; and any heterocyclyl moiety optionally is substituted with 1 or 2 groups Rb;
or a pharmaceutically acceptable salt thereof.
11. A compound according to claim 7, wherein R2 is selected from pentyl, optionally substituted with 1 or 2 groups Ra; and tetrahydrofuryl, optionally substituted with 1 or 2 groups Rb;
or a pharmaceutically acceptable salt thereof.
12. A compound according to claim 7, wherein R2 is selected from branched or unbranched C1-
C6 alkyl;
or a pharmaceutically acceptable salt thereof.
13. A compound according to any one of the claims 1-12, wherein R3 and R4 are each independently selected from methyl and chloro, wherein any methyl optionally is substituted with 1 , 2 or 3 groups Rc;
or a pharmaceutically acceptable salt thereof.
14. A compound according to any one of the claims 1-13, wherein R5 and R6 are each independently selected from hydrogen and methyl, wherein any methyl optionally is substituted with 1 , 2 or 3 groups Rc;
or a pharmaceutically acceptable salt thereof.
15. A compound according to claim 14, wherein R5 and R6 are each hydrogen;
or a pharmaceutically acceptable salt thereof.
16. A compound according to claim 14, wherein R5 is hydrogen and R6 is methyl;
or a pharmaceutically acceptable salt thereof.
17. A compound according to any one of the claims 1-16, wherein X represents a bond or methylene;
or a pharmaceutically acceptable salt thereof.
18. A compound according to claim 17, wherein X represents a bond;
or a pharmaceutically acceptable salt thereof.
19. A compound according to any one of the claims 1 to 18, wherein m is 0;
or a pharmaceutically acceptable salt thereof.
20. A compound according to any one of the claims 1 to 19, wherein Rc is absent;
or a pharmaceutically acceptable salt thereof.
21. A compound according to claim 1, wherein R1 represents C1-C10 alkyl; R2 represents C4-C6 cycloalkyl or C4-C5 heterocyclyl; R3 and R4 are independently selected from methyl and chlorine; R5 is hydrogen; X represents a bond; and Q represents carbonyl;
or a pharmaceutically acceptable salt thereof.
22. A compound according to claim 1, wherein R1 represents C3-C6 cycloalkyl; R2 represents C4- C6 cycloalkyl or C4-C5 heterocyclyl; R3 and R4 are independently selected from methyl and chlorine; X represents a bond and Q represents carbonyl;
or a pharmaceutically acceptable salt thereof.
23. A compound according to claim 1, wherein R1 represents phenyl or C4-C5 heterocyclyl; R2 represents C4-C6 cycloalkyl or C4-C5 heterocyclyl; R3 and R4 are independently selected from methyl or chlorine; X represents a bond; and Q represents carbonyl;
or a pharmaceutically acceptable salt thereof.
24. A compound according to claim 1, wherein R1 represents phenyl or C4-C5 heterocyclyl, optionally substituted with one or more Rb; R2 represents cyclopentyl; R3 and R4 are
independently selected from methyl and chlorine; the integer m is equal to 1 or 0 (zero); R5 and R6 are hydrogen; X represents a bond; and Q represents carbonyl;
or a pharmaceutically acceptable salt thereof.
25. A compound according to claim 1, wherein R1 represents Ci -C 10 alkyl; R2 represents C1-C9 alkyl; R3 and R4 are independently selected from methyl and chlorine; R5 and R6 are hydrogen; and Q represents carbonyl;
or a pharmaceutically acceptable salt thereof.
26. A compound according to claim 1, wherein R1 represents C4-C5 saturated heterocyclyl; R2 represents cyclopentyl; R3 and R4 are independently selected from methyl and chlorine; the iinntteeggeerr mm iiss eeqquuaall ttoo 11 ;; RR55 aanndd RR66 aarree hhyyddrrooggξen; X represents a bond; and Q represents carbonyl; or a pharmaceutically acceptable salt thereof.
27. A compound according to claim 1, wherein R1 represents C3-C5 cycloalkyl; R2 represents cyclopentyl or tetrahydrofuranyl; R3 and R4 are independently selected from methyl and chlorine; the integer m is equal to either 0 (zero) or 1 ; R5 and R6 are hydrogen; X represents a bond; and Q represents carbonyl; or a pharmaceutically acceptable salt thereof.
28. A compound according to claim 1, selected from
Λ/-cyclopentyl-l-(l-ethyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide; Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -propyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide; l-(l-butyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4-carboxamide;
Λ/-cyclopentyl-l-(l-heptyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -octyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -pentyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide; Λ/-cyclopentyl- 1 -( 1 -hexyl-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -(pyridin-2-ylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -( 1 -isopropyl-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-(2-(diethylamino)ethyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)piperidine-
4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(pyridin-4-ylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(pyridin-3-ylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(pyridin-2-ylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
1 -( 1 -sec-butyl-5 ,6-dichloro- lH-benzo [d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(pentan-3-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5 ,6-dichloro- 1 -cyclobutyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl-l -(5,6-dichloro- l-(l-phenylethyl)-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -methyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -ethyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5 ,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-fluorobenzyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide; Λ/-cyclopentyl-l-(l-(3,5-difluorobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
methyl 4-((2-(4-(cyclopentylcarbamoyl)piperidin- 1 -yl)-5,6-dimethyl- lH-benzo[d]imidazol- 1 - yl)methyl)benzoate;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -((2-methylthiazol-4-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -phenyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
JV-cyclopropyl- 1 -(5 ,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclo butyl- 1 -(5,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
1 -(5,6-dichloro- l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-propylpiperidine-4-carboxamide;
1 -(5,6-dichloro- l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-(2-methoxyethyl)piperidine-4- carboxamide;
1 -(5,6-dichloro- l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-(isopropoxymethyl)piperidine-4- carboxamide;
1 -(5,6-dichloro- l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
Λ/-(cyclohexylmethyl)-l -(5,6-dichloro- l-isopropyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
1 -(5,6-dichloro- l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-((tetrahydro-2H-pyran-4- yl)methyl)piperidine-4-carboxamide;
Λ/-butyl- 1 -(5,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-(cyclopentylmethyl)- 1 -(5,6-dichloro- 1 -isopropyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-((6-fluoropyridin-3-yl)methyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
l-(l-(4-cyanobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-(cyclopropylmethyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -((tetrahydrofuran-2-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
1 -( 1 -(4-( IH- 1 ,2,4-triazol- 1 -yl)benzyl)-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide; 1 -( 1 -cyclobutyl-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
l-(l-(4-bromobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -(4-(methylcarbamoyl)benzyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl-l-(l-(4-(dimethylcarbamoyl)benzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
l-(l-(4-carbamoylbenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5 ,6-dimethyl- 1 -(4-(methylsulfonylcarbamoyl)benzyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3-yl)piperidine-4- carboxamide;
1 -( 1 -(4-fluorobenzyl)-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)-JV-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide;
1 -(5-chloro- 1 -cyclobutyl-6-methyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentyl-piperidine-4- carboxamide;
1 -(6-chloro- 1 -cyclobutyl-5 -methyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -cyclopentyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
l-(l-(4-bromobenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -((6-fluoropyridin-3-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-cyanobenzyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(cyclopropylmethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -((tetrahydrofuran-2-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -((tetrahydro-2H-pyran-4-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide; Λ/-cyclopentyl- 1 -(5 ,6-dichloro- 1 -(4-(methylcarbamoyl)benzyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-(dimethylcarbamoyl)benzyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
l-(l-(4-carbamoylbenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-cyclopentyl-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4- carboxamide;
l-(l-(4-chlorobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
l-(l-(4-(lH-tetrazol-5-yl)benzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5 ,6-dichloro- 1 -(4-(methylsulfonylcarbamoyl)benzyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
N-butyl- 1 -(5,6-dichloro- 1 -cy clo butyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-butyl- 1 -(5 ,6-dichloro- 1 -pentyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
N-butyl- 1 -(5 ,6-dichloro- 1 -(4-fluorobenzyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-butyl- 1 -(5,6-dichloro- 1 -((6-fluoropyridin-3-yl)methyl)- lH-benzo[d]imidazol-2-yl)piperidine- 4-carboxamide;
1 -(5,6-dichloro- 1-cyclo butyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
1 -(5,6-dichloro- l-pentyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
1 -(5,6-dichloro- l-(4-cyanobenzyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -(5,6-dichloro- l-(cyclopropylmethyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -(5,6-dichloro- l-((6-fluoropyridin-3-yl)methyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -((tetrahydro-2H-pyran-4-yl)methyl)- lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide;
1 -(5,6-dichloro- l-cyclopentyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide; l-(l-(4-bromobenzyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide; l-(l-(4-(lH-tetrazol-5-yl)benzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- cyclopentylpiperidine-4-carboxamide;
l-(5,6-dichloro-l-(4-fluorobenzyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
1.( 1.(4-( IH- 1 ,2,4-triazol- 1 -yl)benzyl)-5 ,6-dichloro- lH-benzo[d]imidazol-2-yl)-JV- cyclopentylpiperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(2-methoxyethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-(4-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
l-(l-(cyclobutylmethyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
JV-cyclopentyl- 1 -(5,6-dimethyl- 1 -(prop-2-ynyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-(2-ethylbutyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5 ,6-dimethyl- 1 -neopentyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
l-(l-cyclohexyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
l-(l-sec-butyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentyl-piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(2-hydroxyethyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -( 1 ,5 ,6-trimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl-l-(l-isobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide; l-(l-benzyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4-carboxamide;
Λ/-cyclopentyl-l-(l-(2-methoxyethyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-(4-fluorobenzyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide; 1 -(5-chloro- 1 -cyclobutyl-6-fluoro- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
1 -(6-chloro- 1 -cyclobutyl-5-fluoro- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -(pentan-2-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-butyl-l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-butyl-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
N-butyl- 1 -(5,6-dimethyl- 1 -pentyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
TV-butyl- 1 -( 1 -((6-fluoropyridin-3 -yl)methyl)-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)piperidine-
4-carboxamide;
Λ/-butyl- 1 -( 1 -(4-fluorobenzyl)-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-benzyl-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide; JV-(4-fluorobenzyl)- 1 -(I -isopropyl-5,6-dimethyl- 1 H-benzo [d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-(3-isopropoxypropyl)-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-(3,3-dimethylbutyl)-l-(l-isopropyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-(4-bromobenzyl)- 1 -( 1 -isopropyl-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)piperidine-4- carboxamide;
Λ/-cyclohexyl- 1 -( 1 -isopropyl-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-(4-cyanobenzyl)- 1 -( 1 -isopropyl-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)piperidine-4- carboxamide;
(S)- 1 -(5,6-dimethyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3-yl)piperidine-4- carboxamide;
4-((2-(4-(cyclopentylcarbamoyl)piperidin- 1 -yl)-5,6-dimethyl- lH-benzo[d]imidazol- 1 - yl)methyl)benzoic acid
1 -(I -isopropyl-5, 6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(thiazol-2-ylmethyl)piperidine-4- carboxamide;
l-(5,6-dichloro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-(thiazol-2-ylmethyl)piperidine-4- carboxamide;
Λ/-(4-(lH-tetrazol-5-yl)benzyl)-l -(I -isopropyl-5, 6-dimethyl-lH-benzo[d]imidazo 1-2- yl)piperidine-4-carboxamide; Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -(pentan-3-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
1 -(5,6-dimethyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-fluorophenyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
l-(l-(4-bromophenyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
l-(l-(4-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
l-(l-(3-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
l-(l-(3,5-difluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
l-(l-(4-chlorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
1 -(5,6-dimethyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
l-(l-(3,5-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
1 -(5,6-dimethyl- 1 -(naphthalen-2-yl)- lH-benzo[d]imidazol-2-yl)-JV-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -( 1 -(benzo[d] [1,3] dioxo 1-5 -yl)-5 ,6-dimethyl- lH-benzo [d]imidazo l-2-yl)-JV-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide;
1 -(5,6-dichloro- l-(3-methoxyphenyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
l-(l-(benzo[d][l,3]dioxol-5-yl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
1 -(5,6-dichloro- l-(4-cyanophenyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -m-tolyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -( 1 -(3 ,4-dimethylphenyl)-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)piperidine-4- carboxamide;
N-cyclopentyl-l-(l-(4-fluoro-3-methylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2- yl)piperidine-4-carboxamide; Λ/-cyclopentyl-l-(l-(4-ethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl-l-(l-(4-isopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -(quinolin-6-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dimethyl- 1 -(quinoxalin-6-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
l-(5,6-dichloro-l-(4-(methylcarbamoyl)phenyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide;
(R)-l-(5,6-dichloro-l-(3-methoxyphenyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(pyridin-3-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
JV-cyclopentyl- 1 -(5,6-dichloro- 1 -(pyridin-3-yl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(6-methoxypyridin-2-yl)- lH-benzo[d]imidazol-2-yl)piperidine-
4-carboxamide;
Λ/-cyclopentyl- 1 -(5,6-dichloro- 1 -(4-cyanophenyl)- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-fluorophenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3 -fluorophenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-methoxyphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-tert-butylphenyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-(trifluoromethoxy)phenyl)- lH-benzo[d]imidazol-2-yl)-Λ/- (tetrahydrofuran-3-yl)piperidine-4-carboxamide;
1 -(5,6-dichloro- l-phenyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
1 -(5,6-dichloro- l-(pyridin-2-yl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-
4-carboxamide; l-(5,6-dichloro-l-(pyridin-3-yl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-
4-carboxamide;
l-(5,6-dichloro-l-p-tolyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
(R)-l-(l-(4-chloro-3-methoxyphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-chloro-3-methoxyphenyl)- lH-benzo[d]imidazol-2-yl)-JV-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;.
(R)-l-(l-(2,3-dihydrobenzoflιran-5-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(2,3-dihydrobenzofuran-5-yl)- lH-benzo[d]imidazol-2-yl)-JV-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(3,5-diethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -(5,6-dichloro- l-(cyclobutylmethyl)-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-fluoro-3-methylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(4-ethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(3,4-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -(quinolin-6-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-isopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-tert-butylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(3-chlorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -(6-chloro-5 -methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
(R)- 1 -(5-chloro-6-methyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide; (R)- 1 -(β-chloro-S-methyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-/V-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-carbamoylphenyl)-5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
l-(l-(4-carbamoylphenyl)-5-chloro-6-methyl-lH-benzo[d]imidazol-2-yl)-Λ/- cyclopentylpiperidine-4-carboxamide;
l-(l-(4-carbamoylphenyl)-6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)-Λ/- cyclopentylpiperidine-4-carboxamide;
(R)-l-(l-(4-carbamoylphenyl)-6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)-Λ/- (tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5-chloro-6-methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]-imidazol-2-yl)-/V-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
1 -(5-chloro-6-methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-/V- cyclopentylpiperidine-4-carboxamide;
1 -(5-chloro-6-methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-/V-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(6-chloro-5-methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]-imidazol-2-yl)-/V-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
1 -(6-chloro-5 -methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-Λ/- (tetrahydrofuran-3-yl)piperidine-4-carboxamide;
1 -(6-chloro-5 -methyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-Λ/- cyclopentylpiperidine-4-carboxamide;:
(R)- 1 -(6-chloro-5-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
(S)- l-(6-chloro-5-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
Λ/-butyl- 1 -(5-chloro-6-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide; TV- butyl- 1 -(6-chloro-5-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)piperidine-4-carboxamide;
1 -(5-chloro-6-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine- 4-carboxamide;
1 -(6-chloro-5 -methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3-yl)piperidine-
4-carboxamide;
1 -(5-chloro- 1 -cyclobutyl-6-methyl- lH-benzo[d]imidazol-2-yl)-7V-(tetrahydrofuran-3- yl)piperidine-4-carboxamide; 1 -(6-chloro- 1 -cyclobutyl-5 -methyl- lH-benzo[d]imidazol-2-yl)-JV-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
1 -(5-chloro- 1 -(cyclobutylmethyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-
4-carboxamide;
1 -(6-chloro- 1 -(eye Io butylmethyl)-5 -methyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-
4-carboxamide;
1 -(5-chloro-6-methyl- 1 -pentyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
1 -(6-chloro-5 -methyl- 1 -pentyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
1 -(5-chloro- 1 -(4-fluorophenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
1 -(6-chloro- 1 -(4-fluorophenyl)-5 -methyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
1 -(5-chloro-6-methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
1 -(6-chloro-5 -methyl- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
Λ/-butyl- 1 -(5-chloro- l-cyclobutyl-6-methyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
Λ/-butyl- 1 -(6-chloro- 1 -cyclobutyl-5 -methyl- lH-benzo[d]imidazol-2-yl)piperidine-4- carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -(3-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -(5-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(3-ethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(3-isopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(6-chloro- l-(4-isopropylphenyl)-5 -methyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-
3-yl)piperidine-4-carboxamide; (R)- 1 -(5,6-dichloro- 1 -(3-chlorophenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-fluoro-3-methylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(5 ,6-dichloro- 1 -(3 ,5-difluorophenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-cyanophenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(5-methylpyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(6-methoxypyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-isopropylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-methylpyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(6-methylpyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-(difluoromethoxy)phenyl)- lH-benzo[d]imidazol-2-yl)-JV-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-(trifluoromethoxy)phenyl)- lH-benzo[d]imidazol-2-yl)-JV-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-isobutylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5 ,6-dichloro- 1 -(3 ,4-dimethylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-chlorophenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(5-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(5-fluoropyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide; (R)- 1 -( 1 -(4-isobutylphenyl)-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)-JV-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide;
(R)-l-(6-chloro-l-(3,5-dimethylphenyl)-5-methyl-lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(4-chloro-3-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-
3 -yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-chloro-3 -fluorophenyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3,5-diethylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -( 1 -(3 -tert-butylphenyl)-5 ,6-dimethyl- 1 H-benzo [d]imidazol-2-yl)-N-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide;
(R)-l-(l-(3-tert-butylphenyl)-5,6-dichloro-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -phenyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-ethylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -m-to IyI- 1 H-benzo [d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3 -yl)piperidine-4- carboxamide;
(R)- 1 -(5 ,6-dichloro- 1 -(3 ,5-dimethylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-ethylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(6-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-ethoxyphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-isopropoxyphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-propoxyphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -( 1 -(4-fluoro-3 ,5-dimethylphenyl)-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide; (R)- 1 -(5,6-dichloro- 1 -(4-chloro-3-methylphenyl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-chloro-4-methylphenyl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5 ,6-dimethyl- 1 -phenyl- 1 H-benzo [d]imidazol-2-yl)-JV-(tetrahydrofuran-3 -yl)piperidine-4- carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3-yl)piperidine-4- carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -m-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3-yl)piperidine-4- carboxamide;
(R)-l-(l-(3-cyanophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -(naphthalen-2-yl)- lH-benzo[d]imidazol-2-yl)-JV-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-chloro-3-methylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(3-chloro-4-methylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(benzo[d]thiazol-6-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(benzo[d]thiazol-5-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
(R)-l-(5-chloro-l-(3,4-dimethylphenyl)-6-methyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(6-chloro-l-(3,4-dimethylphenyl)-5-methyl-lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5-chloro- l-(4-isopropylphenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(6-chloro- l-(4-isopropylphenyl)-5 -methyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran- 3-yl)piperidine-4-carboxamide;
(S)- l-(5-chloro-6-methyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide;
(S)- l-(6-chloro-5-methyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydroflιran-3- yl)piperidine-4-carboxamide; (S)-l-(6-chloro-l-(3,5-dimethylphenyl)-5-methyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-((15f,25)-2- hydroxycyclopentyl)piperidine-4-carboxamide;
l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-((lR,2R)-2- hydroxycyclopentyl)piperidine-4-carboxamide;
(R)- 1 -( 1 -(benzo furan-5 -yl)-5 ,6-dimethyl- lH-benzo [d]imidazo l-2-yl)-JV-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-fluoro-3,5-dimethylphenyl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(3-fluoro-5-methylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-fluoro-5-methylphenyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-cyclopropylphenyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-cyclopropylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -( 1 -(benzo furan-6-yl)-5 ,6-dimethyl- lH-benzo [d]imidazo l-2-yl)-N-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide;
(R)- 1 -(5-chloro- l-(4-ethylphenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(6-chloro- l-(4-ethylphenyl)-5 -methyl- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5-chloro- l-(4-ethylphenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-tert-butylphenyl)-6-chloro-5-methyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran- 3-yl)piperidine-4-carboxamide;
(R)-l-(l-(4-cyclopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(3-cyclopropylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide; (R)- 1 -(5,6-dichloro- 1 -(3-(cyclopentyloxy)phenyl)- lH-benzo[d]imidazol-2-yl)-JV-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-cyclobutoxyphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
l-(5-chloro-6-fluoro-l-methyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
l-(6-chloro-5-fluoro-l-methyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
1 -(5-chloro- 1 -ethyl-6-fluoro- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
1 -(6-chloro- 1 -ethyl-5-fluoro- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
l-(5-chloro-6-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
1 -(6-chloro-5-fluoro- 1-isopropyl- lH-benzo[d]imidazol-2-yl)-JV-cyclopentylpiperidine-4- carboxamide;
l-(l-butyl-5-chloro-6-fluoro-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
l-(l-butyl-6-chloro-5-fluoro-lH-benzo[d]imidazol-2-yl)-Λ/-cyclopentylpiperidine-4- carboxamide;
1 -(5 ,6-dimethyl- 1 -p-tolyl- 1 H-benzo [d]imidazo l-2-yl)-JV-(tetrahydrofuran-3 -yl)piperidine-4- carboxamide;
(R)- 1 -(6-chloro- l-(4-fluorophenyl)-5 -methyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5-chloro- l-(4-fluorophenyl)-6-methyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(6-chloro-5-methyl- 1 -m-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5-chloro-6-methyl- 1 -m-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5-chloro-6-methyl- 1 -(5-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(6-chloro-5-methyl- 1 -(5-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-JV-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide; l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-((2S)-2- methoxycyclopentyl)piperidine-4-carboxamide;
l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-((2S)-2- ethoxycyclopentyl)piperidine-4-carboxamide;
l-(l-cyclobutyl-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-N-((2S)-2- propoxycyclopentyl)piperidine-4-carboxamide;
l-(5,6-dichloro-l-(4-(dimethylcarbamoyl)phenyl)-lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)-N-((lS,2S)-2- hydroxycyclopentyl)piperidine-4-carboxamide;
l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)-N-((lS,2S)-2- methoxycyclopentyl)piperidine-4-carboxamide;
l-(5,6-dichloro-l-cyclobutyl-lH-benzo[d]imidazol-2-yl)-N-((lS,2S)-2- ethoxycyclopentyl)piperidine-4-carboxamide;
1 -( 1 -cyclobutyl-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)-Λ/-(furan-2-ylmethyl)piperidine-4- carboxamide;
1 -( 1 -cyclobutyl-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)-Λ/-(thiophen-2-ylmethyl)piperidine-4- carboxamide;
(R)- 1 -( 1 -(5 -bromopyridin-2-yl)-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)-Λ/-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide;
(R)-l-(l-(5-ethylpyridin-2-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(3-chloro-5-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3 -chloro-5 -fluorophenyl)- lH-benzo[d]imidazol-2-yl)-N-(tetrahydrofuran-
3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(3-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(2,2-difluorobenzo[d] [ 1 ,3]dioxol-5-yl)- lH-benzo[d]imidazol-2-yl)-N- (tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(S)- 1 -( 1 -(3 ,5-dimethylphenyl)-5 ,6-dimethyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide; (R)- 1 -(5,6-dichloro- 1 -(5-chloropyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(5-fluoro-6-methylpyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-JV-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)-l-(l-(3-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(3,5-dimethylphenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-fluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(3,5-difluorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)-l-(l-(4-chlorophenyl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -(4-(trifluoromethyl)phenyl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -p-tolyl- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3-yl)piperidine-4- carboxamide;
(R)-l-(l-(5-chloropyridin-2-yl)-5,6-dimethyl-lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dimethyl- 1 -(4-(trifluoromethyl)pyridin-2-yl)- lH-benzo[d]imidazol-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -( 1 -(5 -fluoro-6-methylpyridin-2-yl)-5 ,6-dimethyl- 1 H-benzo [d]imidazo l-2-yl)-N-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-ethoxyphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3- yl)piperidine-4-carboxamide;
(R)- 1 -(5,6-dichloro- 1 -(4-methoxy-3-methylphenyl)- lH-benzo[d]imidazol-2-yl)-Λ/-
(tetrahydrofuran-3-yl)piperidine-4-carboxamide; and
(R)- 1 -( 1 -cyclobutyl-5 ,6-dimethyl- 1 H-benzo [d]imidazol-2-yl)-Λ/-(tetrahydrofuran-3 - yl)piperidine-4-carboxamide;
or a pharmaceutically acceptable salt thereof.
29. A compound according to any one of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use as a medicament.
30. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, in admixture with at least one pharmaceutically acceptable adjuvant, diluent or carrier.
31. A compound according to any one of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of an inflammatory disease, said disease preferably being selected from rheumatoid arthritis, inflammatory bowel disease, osteoarthritis, psoriasis, eczema, swelling and periodontitis.
32. A compound according to any one of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of nociceptive pain, said pain preferably being selected from inflammatory pain, post-operative pain, fibromyalgia, dysmenorrhea, migraine, arthrotic pain, arthritic pain, pain in connection with osteoarthritis, cephalalgia, pain due to gall-stones, pain due to metastasis, pain due to ankylosing spondylitis, pain due to gout, toothache and pain due to rheumatic fever, or for use in the preemptive treatment of surgical pain.
33. A compound according to any one of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of an autoimmune disease, said autoimmune disease preferably being selected from rheumatoid arthritis and multiple sclerosis.
34. A compound according to any one of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of a breathing disorder, said disorder preferably being selected from apnea or other respiratory distress symptoms in adults and children, sudden infant death syndrome (SIDS), asthma and other chronic obstructive lung- diseases and sarcoidosis.
35. A compound according to any one of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cancer, said cancer preferably being selected from familial adenomatous polyposis (FAP) condition, colorectal cancer, breast cancer, gastric tumorigenesis and epithelial ovarian cancer, or cellular neoplastic transformations and metastatic tumor growth.
36. A compound according to any one of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of a cardiovascular disease due to atherosclerosis, such as myocardial infarction and stroke.
37. A compound according to any one of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of fever-related or inflammation-related anorexia.
38. A compound according to any one of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of Alzheimer's disease.
39. A compound according to any one of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of endometriosis.
40. A compound according to any one of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of hemophilic arthropathy.
41. A compound according to any one of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of diabetic retinopathy.
42. A compound according to any one of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of and tumor angiogenesis.
43. A compound according to any one of the claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of premature labor.
44. A combination product comprising: (A) a compound according to any one of the claims 1 to 28, or a pharmaceutically-acceptable salt thereof, and (B) another therapeutic agent, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
45. A combination product as claimed in claim 44, wherein the other therapeutic agent is an agent useful in the treatment of inflammation.
46. A combination product as claimed in claim 44 or claim 45, which comprises a kit of parts comprising components: (A) a pharmaceutical formulation including a compound as defined above, or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically- acceptable adjuvant, diluent or carrier; and (B) a pharmaceutical formulation including another therapeutic agent in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier, which components (A) and (B) are each provided in a form that is suitable for administration in conjunction with the other.
47. A method of treatment of a disorder selected from an inflammatory disease, nociceptive pain, an autoimmune disease, a breathing disorder, cancer, a cardiovascular disease due to
atherosclerosis, fever or inflammation-related anorexia, or Alzheimer's disease, which method comprises administration of a therapeutically effective amount of a compound according to any one of the claims 1 to 28, or a pharmaceutically-acceptable salt thereof, to a mammal subject suffering from, or susceptible to, such a disorder.
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