WO2010014794A1 - Benzoimidazole derivatives and glycogen synthase kinase-3 beta inhibitors containing the same - Google Patents

Benzoimidazole derivatives and glycogen synthase kinase-3 beta inhibitors containing the same Download PDF

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Publication number
WO2010014794A1
WO2010014794A1 PCT/US2009/052225 US2009052225W WO2010014794A1 WO 2010014794 A1 WO2010014794 A1 WO 2010014794A1 US 2009052225 W US2009052225 W US 2009052225W WO 2010014794 A1 WO2010014794 A1 WO 2010014794A1
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Prior art keywords
benzo
imidazole
hydroxy
thiophen
group
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PCT/US2009/052225
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French (fr)
Inventor
Mitsuaki Ohtani
Yo Matsuo
Yingfu Li
Joel R. Walker
David M. Jenkins
Feryan Ahmed
Ryuji Ohsawa
Shoji Hisada
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Oncotherapy Science, Inc.
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Priority to AU2009276548A priority Critical patent/AU2009276548A1/en
Priority to BRPI0916726A priority patent/BRPI0916726A2/en
Priority to EP09803582A priority patent/EP2309855A4/en
Priority to CA2732280A priority patent/CA2732280A1/en
Priority to MX2011001170A priority patent/MX2011001170A/en
Priority to CN2009801387112A priority patent/CN102170785A/en
Priority to US13/056,591 priority patent/US20110190351A1/en
Priority to JP2011521313A priority patent/JP2011529903A/en
Publication of WO2010014794A1 publication Critical patent/WO2010014794A1/en
Priority to IL210863A priority patent/IL210863A0/en
Priority to ZA2011/01160A priority patent/ZA201101160B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • 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
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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 a compound for inhibiting glycogen synthase kinase-3 (GSK3) activity, a method for the preparation thereof, and a pharmaceutical composition containing the compound as an active ingredient.
  • GSK3 glycogen synthase kinase-3
  • Glycogen synthase kinase-3 (GSK3) is a proline-directed serine-threonine kinase that was initially identified as a protein which inactivates glycogen synthase through phosphorylation. Two isoforms have been identified, alpha (GSK3 alpha) and beta (GSK3beta), which show a high degree of amino acid homology to each other. Previous studies have reported that the GSK3beta is involved in energy metabolism, neural cell development, and body pattern formation (Plyte SE, et al., Biochim. Biophys. Acta, 1114:147-162, 1992).
  • Neurodegenerative naturopathies including Alzheimer disease, are characterized by abnormal hyperphosphorylation of the microtubule-associated protein tau at proline-directed serine/threonine phosphorylation sites (Lee VM, et al., Annu. Rev. Neurosci. 24: 1121-1159, 2001.).
  • GSK3beta has been identified as a prime candidate mediating aberrant tau phosphorylation at disease-associated sites (Hanger DP, et al., Neurosci. Lett. 147: 58-62, 1992., Ishiguro K, et al., J. Biol. Chem. 267: 10897-10901, 1992., Mandelkow EM, et al., FEBS Lett.
  • GSK3beta is a promising target for therapeutic intervention in neurodegenerative tauopathies including Alzheimer disease.
  • Lithium carbonate, lithium citrate and lithium chloride are commonly used for the treatment of various disorders like mania, depression and migraine, and also used as an "augmenting" agent to increase the benefits of other standard drugs used for unipolar depression.
  • Lithium is a GSK3beta inhibitor, and therefore, GSK3beta inhibition is a promising target for the treatment of various such disorders.
  • GSK3 inhibitors are available for treatment of type 2 diabetes by reducing the activity of glucose synthase.
  • GSK3beta inhibitors can be used for a broad spectrum of diseases such as Alzheimer disease, mania, depression, migraine and type 2 diabetes and there is a strong need to develop such inhibitors for the treatment and/or prevention of GSK3beta dependent diseases.
  • benzoimidazole derivatives can selectively inhibit the activity of GSK3beta and are therefore useful for treatment and/or prevention of GSK3beta dependent diseases.
  • ring A is (II), (III), (IV) (V), or (VI)
  • X is halogen or hydroxyl
  • Y is hydrogen, phenyl, thiophen-2-yl, furan-2-yl, cyclopropyl, or cyclopentyl;
  • Z is a 5-10 membered heterocycle substituted carbonylamino; and Ring A is substituted by -L'-(CH 2 ) a -L 2 -M at position *;
  • L 1 is -CONH-, -NHCO-, or a single bond;
  • M is selected from the group consisting of hydroxyl, carboxyl, amide, Ci-C 6 alkyl, Ci-C 6 alkylcarbonyl, C 6 -Ci 4 aryl, C 6 -Ci 4 aryl Ci-C 6 alkyl, C 6 -Ci 4 arylcarbonyl, C 6 -Ci 4 arylsulfonyl, 5-14 membered saturated, unsaturated or aromatic heterocyclic group, 5-14 membered unsaturated or aromatic heterocyclic group substituted Ci-C 6 alkyl, 5-14 membered unsaturated or aromatic heterocyclic group substituted sulfonyl or -NR R ; wherein R 2 and R 3 are independently Cj-C 6 alkyl; the CpC 6 alkyl, CpC 6 alkylcarbonyl, C 6 -C 14 aryl, C 6 -Ci 4 aryl Ci-C 6 alkyl, C 6 -Cj 4 arylcarbonyl, C 6 -
  • alkyl refers to a straight chain or a branched chain hydrocarbon group which does not contain any hetero atoms or unsaturated carbon-carbon bonds.
  • Ci-C 6 alkyl refers to an alkyl group which has 1-6 carbon atoms.
  • Ci-C 4 alkyl refers to an alkyl group which has 1-4 carbon atoms.
  • Ci-C 6 alkyl examples include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, 2 -methyl- 1 -propyl, 2-methyl-2-propyl, 1 -butyl, 2-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2,2-dimethyl-l -propyl, 1-hexyl, 2-hexyl, 3-hexyl, 2 -methyl- 1-pentyl, 3 -methyl- 1-pentyl, 4-methyl- 1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methy-3-pentyl, 3-methyl-3-pentyl, 2,3 -dimethyl- 1 -butyl, 3, 3
  • alkoxy refers to a group represented by -OR, wherein R is alkyl.
  • Ci-C 6 alkoxy refers to an alkoxy group which has 1-6 carbon atoms.
  • Cj-C 4 alkoxy refers to an alkoxy group which has 1-4 carbon atoms.
  • Examples OfCi-C 6 alkoxy include, but are not limited to, methoxy, ethoxy, 1-propyloxy, 2-propyloxy, 2 -methyl- 1-propyloxy, 2-methyl-2-propyloxy, and 1-butyloxy, and 2- butyloxy.
  • Ci-C 6 alkylcarbonyl refers to a carbonyl group bound to the Ci-C 6 alkyl.
  • C]-C 4 alkylcarbonyl refers to a carbonyl group bound to theCj-C 4 alkyl.
  • Examples of “CpC 6 alkylcarbonyl” include, but are not limited to, methylcarbonyl, ethylcarbonyl, 1-propylcarbonyl, 2-propylcarbonyl, n-butylcarbonyl, s-butylcarbonyl, t-butylcarbonyl, and 2-ethylbutylcarbyl.
  • amino refers to a group represented by -NH 2 in which the hydrogens are optionally replaced by a substituent.
  • Cj-C 6 alkyl carbonylamino refers to an amino group bound to the
  • Ci-C 6 alkylcarbonyl Ci-C 6 alkylcarbonyl.
  • Cj-C 4 alkylcarbonylamino refers to an amino group bound to the CpC 4 alkylcarbonyl.
  • C 1 -C 6 alkylcarbonylamino examples include, but are not limited to, methylcarbonylamino, ethylcarbonylamino, 1 -propylcarbonylamino, 2-propylcarbonylamino, n-butylcarbonylamino, s-butylcarbonylamino, t-butylcarbonylamino, and 2-ethylbutylcarbonylamino.
  • sulfonyl is a group represented by -SO 2 -.
  • CpC 6 alkylsulfonyl refers to a sulfonyl group bound to the CpC 6 alkyl.
  • CpC 4 alkylsulfonyl refers to a sulfonyl group bound to the Cj-C 4 alkyl.
  • CpC 6 alkylsulfonyl examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, 1-propylsulfonyl, 2-propylsulfonyl, n-butylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, and 2-ethylbutylsulfonyl.
  • CpC 6 alkylsulfonylamino refers to an amino group bound to the"CpC 6 alkylsulfonyl.
  • CpC 4 alkylsulfonylamino refers to an amino group bound to the"CpC 4 alkylsulfonyl.
  • Cj-C 6 alkylsulfonylamino examples include, but are not limited to, methylsulfonylamino, ethylsulfonylamino, 1 -propylsulfonylamino, 2-propylsulfonylamino, n-butylsulfonylamino, s-butylsulfonylamino, t-butylsulfonylamino, and 2-ethylbutylsulfonylamino. Page: 4/97
  • aryl refers to an aromatic carbon ring system.
  • C 6 -Cj 4 aryl refers to a 6-14 membered aryl ring.
  • C 6 -Ci 0 aryl refers to a 6-10 membered aryl ring.
  • C 6 -Ci 4 aryl examples include, but are not limited to, phenyl, naphthyl, and anthryl.
  • C 6 -Ci 4 aryl Cj-C 6 alkyl refers to the"Cj-C 6 alkyl" in which a hydrogen atom is substituted by the"C 6 -Cj 4 aryl.
  • C 6 -Cj 0 arylC r C 4 alkyl refers to the"Cj-C 4 alkyl” in which a hydrogen atom is substituted by the"C 6 -Cjo aryl".
  • C 6 -Cj 4 arylCj-C 6 alkyl examples include, but are not limited to, benzyl, phenethyl, and anthrylmethyl.
  • C 6 -Cj 4 arylcarbonyl refers to a carbonyl group bound to the"C 6 -Cj 4 aryl.
  • C 6 -Ci 0 arylcarbonyl refers to a carbonyl group bound to the"C 6 -C] 0 aryl.
  • C 6 -Cj 4 arylcarbonyl examples include, but are not limited to, phenylcarbonyl, naphthylcarbonyl, and anthrylcarbonyl.
  • C 6 -Cj 4 arylsulfonyl refers to a sulfonyl group bound to the"C 6 -Cj 4 aryl.
  • C 6 -CjO arylsulfonyl refers to a sulfonyl group bound to the"C 6 -Cj 0 aryl.
  • Examples of “C 6 -Ci 4 arylsulfonyl” include, but are not limited to, phenylsulfonyl, naphthylsulfonyl, and anthrylsulfonyl.
  • an unsaturated or aromatic heterocyclic group refers to an unsaturated or aromatic heterocyclic group having one or more hetero atom in the ring system.
  • “5-14 membered unsaturated or aromatic heterocyclic group” refers to an unsaturated or aromatic heterocyclic group in which the ring consists of 5- 14 atoms.
  • “5-10 membered unsaturated or aromatic heterocyclic group” refers to a unsaturated or aromatic heterocyclic group in which the ring consists of 5-10 atoms.
  • Examples of "5-14 membered unsaturated or aromatic heterocyclic group” include, but are not limited to, imidazolyl, pyrrolyl, pyridyl, thienyl, furyl, thiazolyl, pyrazolyl, pyrazolinyl, oxazolyl, isoxazolyl and indolyl.
  • 5-14 membered unsaturated or aromatic heterocyclic group substituted Cj-C 6 alkyl refers to the "Cj-C 6 alkyl” in which a hydrogen atom is substituted by the"5-14 membered unsaturated or aromatic heterocyclic group.
  • 5-10 membered unsaturated or aromatic heterocyclic group substituted Cj-C 4 alkyl refers to the "Cj-C 4 alkyl” in which a hydrogen atom is substituted by the"5-10 membered unsaturated or aromatic heterocyclic group”.
  • Examples of “5-14 membered unsaturated or aromatic heterocyclic group substituted Cj-C 6 alkyl” include, but are not limited to, imidazolylmethyl, pyrrolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, thiazolylmethyl, pyrazolylmethyl, pyrazolinylmethyl, oxazolylmethyl, isoxazolylmethyl, and indolylmethyl.
  • “5-14 membered unsaturated or aromatic heterocyclic group substituted sulfonyl” refers to a sulfonyl group bound to the 5-14 membered unsaturated or aromatic heterocyclic group”.
  • 5-10 membered unsaturated or aromatic heterocyclic group substituted sulfonyl refers to a sulfonyl group bound to "5-10 membered unsaturated or aromatic heterocyclic group”.
  • Examples of "5-14 membered unsaturated or aromatic heterocyclic group substituted sulfonyl” include, but are not limited to, imidazolylsulfonyl, pyrrolylsulfonyl, pyridylsulfonyl, thienylsulfonyl, furylsulfonyl, thiazolylsulfonyl, pyrazolylsulfonyl, pyrazolinylsulfonyl, oxazolylsulfonyl, isoxazolylsulfonyl, and indolylsulfonyl. Page: 5/97
  • 5-10 membered unsaturated or aromatic heterocyclic group substituted carbonylamino refers to an amino group bound to a carbonyl group bound to the "5-10 membered unsaturated or aromatic heterocyclic group”.
  • Examples of "5-10 membered unsaturated or aromatic heterocyclic group substituted carbonylamino” include, but are not limited to, imidazolylcarbonylamino, pyrrolylcarbonylamino, pyridylcarbonylamino, thienylcarbonylamino, furylcarbonylamino, thiazolylcarbonylamino, pyrazolylcarbonylamino, pyrazolinylcarbonylamino, oxazolylcarbonylamino, isoxazolylcarbonylamino, and indolylcarbonylamino.
  • a saturated heterocyclic group refers to a saturated heterocyclic group having one or more hetero atom in the ring system.
  • “5-14 membered saturated heterocyclic group” refers to a saturated heterocyclic group in which the ring consists of 5-14 atoms.
  • “5-10 membered saturated heterocyclic group” refers to a saturated heterocyclic group in which the ring consists of 5-10 atoms.
  • Examples of “5-14 membered saturated heterocyclic group” include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
  • a salt is defined as the product formed from the neutralisation reaction of acids and bases. Salts are ionic compounds composed of cations (positively charged ions) and anions (negative ions) so that the product is electrically neutral. These component ions can be inorganic as well as organic.
  • Hydrate is a term used in inorganic chemistry and organic chemistry to indicate that a substance contains water.
  • Solvate refers to a molecule in a solution complexed by solvent molecules.
  • Isomers are compounds with the same molecular formula but different structural formulae. More specifically, isomer includes geometric isomer, optical isomer, stereoisomer, tautomer of the compound, and mixtures thereof.
  • the present invention provides a compound represented by formula (I):
  • X is halogen or hydroxyl
  • Y is phenyl, thiophen-2-yl, furan-2-yl, cyclopropyl, or cyclopentyl; Ring (II) is substituted by -L 1 -(CH 2 ) a -L 2 -M at position *; L 1 is -CONH- or -NHCO-; Page: 6/97
  • L 2 is selected from the group consisting of -NH-, -O-, -CH(COOR 1 )-, -CH(CH 2 OH)-, and a single bond, wherein R ! is hydrogen or C 1 -C 6 alkyl;
  • M is selected from the group consisting of hydroxyl, carboxyl, amide, Ci-C 6 alkyl, Ci-C 6 alkylcarbonyl, C 6 -Cj 4 aryl, C 6 -Ci 4 aryl C]-C 6 alkyl, C 6 -Ci 4 arylcarbonyl, C 6 -Ci 4 arylsulfonyl, 5-14 membered saturated, unsaturated or aromatic heterocyclic group, 5-14 membered unsaturated or aromatic heterocyclic group substituted C]-C 6 alkyl, 5-14 membered unsaturated or aromatic heterocyclic group substituted sulfonyl or -NR 2 R 3 ; wherein R 2 and R 3 are independently Ci-C 6 alkyl; the Ci-C 6 alkyl, Ci-C 6 alkylcarbonyl, C 6 -C] 4 aryl, C 6 -C] 4 aryl Ci-C 6 alkyl, C 6 -Ci 4 arylcarbonyl,
  • the present invention provides compounds represented by following formula (I-II) or a salt, hydrate, solvate, or isomer thereof:
  • L 1 is -CONH-;
  • L 2 is a single bond;
  • M is C 6 -Ci O aryl or 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, which are optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
  • X, Y, and a are defined as in above embodiment represented by formula (I).
  • M is selected from the group consisting of phenyl, imidazole- 1-yl, imdazole-2-yl, imidazole- 5 -yl, thiophen-2-yl, pyrole-2-yl, l,3-thiazole-2-yl, 2-pyrazoline-4-yl, and isoxazole-4-yl, which are optionally substituted by 1-2 substituent(s) each independently selected from following group B, and Y is selected from the group consisting of thiophen-2-yl, furan-2-yl, phenyl, cyclopropyl, and cyclopentyl.
  • Group B consists of fluoro, hydroxyl, oxo, amino, methyl, methoxy, and sulfamoyl.
  • Preferred compounds include those selected from the group consisting of: Example Nos. 8, 9, 10, 20, 21, 22, 23, 35, 37, 44, 45, 57, 62, 76, 77, 78, 79, 80, 84, 85, 86, 90, 91, 92, 93, 94, 95, 96, 101 and 102 listed in Table 1 below; and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds. Page: 7/97
  • the present invention provides a compound represented by following formula (I- II) or a salt, hydrate, solvate, or isomer thereof : Page: 1 1/97
  • L 2 is -NH-;
  • M is Ci-C4 alkyl, Cj-C 4 alkylcarbonyl, C 6 -Ci 0 arylcarbonyl, C 6 -Ci 0 arylsulfonyl, 5-10 membered unsaturated or aromatic heterocyclic group having 1 -2 hetero atom(s) selected from the group consisting of N, O, and S or sulfonyl substituted by 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, which are optionally substituted by 1 or 2 substituent(s) each independently selected form the group A; and
  • X, Y, and a are defined as in the above embodiment represented by formula (I).
  • M is selected from the group consisting of ethyl, isopropyl, methylcarbonyl, pyridine-2-yl, phenylcarbonyl, phenylsulfonyl, and 4-pyridilsulfonyl, which are optionally substituted by 1 -2 substituent(s) each independently selected from following group C, and Y is selected from the group consisting of thiophen-2-yl and furan-2-yl.
  • Group C consists of chloro, hydroxyl, methyl, methylcarbonylamino, methylsulfonylamino, and p-toluenesulfonylamino.
  • the present invention provides the compound selected from the group consisting of: Example Nos. 11, 12, 38, 39, 40, 41, 42, 43, 69, 70 and 89 listed in Table 2 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
  • the present invention provides a compound represented by following formula (I-II) or a salt thereof:
  • L 1 is -CONH-
  • L 2 is -CH(COOR 1 )-, wherein R 1 is hydrogen or Ci-C 4 alkyl;
  • M is C 1 -C 4 alkyl, C 6 -C 10 aryl Ci-C 4 alkyl or Ci-C 4 alkyl substituted by 5-10 membered unsaturated or aromatic heterocyclic group having 1 -2 hetero atom(s) selected from the group consisting of N, O, and S , which are optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
  • X, Y, and a are defined as in the above embodiment represented by formula (I).
  • M is selected from the group consisting of methyl, phenylmethyl, indole-3-ylmethyl, and imidazole-4-ylmethyl, which are optionally substituted by 1-2 hydroxyl
  • Y is thiophen-2-yl.
  • the present invention provides the compound selected from the group consisting of: Example Nos. 13, 14, 15, 16, 71 and 72 listed in Table 3 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
  • the present invention provides a compound represented by following formula (I- II) or a salt, hydrate, solvate, or isomer thereof:
  • L 2 is - 0-
  • M is C 6 -C] 0 aryl or 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, which are optionally substituted by 1 or 2 substituent(s) each independently selected from the group A;
  • X, Y, and a are defined in the above embodiment represented by formula (I).
  • M is phenyl or pyridine-2-yl, which is optionally substituted by 1 or 2 substituent(s) each independently selected from following group D, and Y preferably consists of thiophen-2-yl.
  • Group D consists of amide, nitro, trifluoromethyl, and p-toluenesulfonylamino. Page: 15/97
  • the present invention provides the compound selected from the group consisting of: Example Nos. 49, 50, 73 and 74 listed in Table 4 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
  • the present invention provides the compounds represented by following formula (I-II) or a salt, hydrate, solvate, or isomer thereof:
  • L 1 is -CONH-
  • L 2 is - CH(CH 2 OH)-; Page: 16/97
  • M is selected from the group consisting of hydroxyl, Ci-C 4 alkyl, C 6 -Ci 0 aryl Ci-C 4 alkyl, and Cj-C 4 alkyl substituted by 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, the C]-C 4 alkyl, C 6 -Ci 0 aryl Ci-C 4 alkyl, and 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) are optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
  • X, Y, and a are defined as in the above embodiment represented by formula (I).
  • M is preferably hydroxyl, phenylmethyl, t-butyl, or imidazole-5-ylmethyl
  • Y is selected from the group consisting of thiophen-2-y and cyclopropyl.
  • the present invention provides the compound selected from the group consisting of: Example Nos. 17, 18, 19 and 97 listed in Table 5 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
  • the present invention provides a compound represented by following formula (I-II) or a salt, hydrate, solvate, or isomer thereof : Page: 17/97
  • Y is selected from the group consisting of thiophen-2-yl and cyclopropyl.
  • the present invention provides the compound selected from the group consisting of: Example Nos. 36 and 98 listed in Table 6 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
  • the present invention provides a compound represented by following formula (I-II) or a salt, hydrate, solvate, or isomer thereof:
  • L 1 is -NHCO-
  • M is C 6 -Ci O aryl or 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, which are optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
  • X, Y, and a are defined as in the above embodiment represented by formula (I).
  • M is preferably phenyl optionally having 1 or 2 hydroxyl, or imidazol-5-yl and Y is cyclopropyl or thiophen-2-yl.
  • the present invention provides the compound selected from the group consisting of: Example Nos. 107, 108, 120 and 121 listed in Table 7 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
  • L is -CONH- or a single bond
  • L 2 is a single bond
  • M is amide or 5-10 membered unsaturated or aromatic heterocyclic group having 1 or 2 hetero atom(s) selected from the group consisting of N, O, and S optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
  • X, Y, and a are defined in the above embodiment represented by formula (I).
  • Y is thiophen-2-yl.
  • the present invention provides the compound selected from the group consisting of: Example Nos. 65 and 66 listed in Table 8 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
  • the present invention provides a compound represented by following formula (I-IV) or a salt, hydrate, solvate, or isomer thereof :
  • L 1 is -CONH-;
  • L 2 is a single bond;
  • M is 5-10 membered unsaturated or aromatic heterocyclic group having 1 or 2 hetero atom(s) selected from the group consisting of N, O, and S optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
  • X, Y, and a are defined as in the embodiment represented by formula (I).
  • Y is hydrogen.
  • the present invention provides the compound of Example No. 110 listed in Table 9 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compound. Page: 20/97
  • the present invention provides compounds represented by following formula (I- V), (I- VI) or a salt, hydrate, solvate, or isomer thereof :
  • L 1 is -CONH-;
  • L 2 is a single bond;
  • M is 5-10 membered saturated, unsaturated or aromatic heterocyclic group having 1 or 2 hetero atom(s) selected from the group consisting of N, O, and S optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
  • X, Z, and a are defined as in the above embodiment represented by formula (I).
  • Z is preferably thiophen-2-ylcarbonylamino.
  • the present invention provides the compound of Example Nos. 112 and 122 listed in Table 10 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compound.
  • the present invention provides a compound represented by formula (I- VI) or a salt, hydrate, solvate, or isomer thereof:
  • Ring A is represented by the formula below;
  • M is carboxyl
  • X, Y, Z and a are defined as in the above embodiment represented by formula (I).
  • ring A is preferably the formula (II).
  • the present invention provides the compound of: Example No. 1 listed in Table 11 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
  • the compound of formula (I) of the present invention may be in the form of a pharmaceutically acceptable salt derived from an inorganic or organic acid
  • representative examples of the pharmaceutically acceptable salt derived from an inorganic or organic acid include salts obtained by adding an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfonic acid, or organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, Page: 22/97 mandelic acid, ascorbic acid or malic acid, methanesulfonic acid, or para toluenesulfonic acid, which do not limit its scope, to the compound of formula (I).
  • Such acids may be prepared by the conventional processes, and other acids, which themselves are not pharmaceutically acceptable, including oxalic acid may be employed in the preparation of the bases.
  • the compound of formula (I) of the present invention may also be in the form of a pharmaceutically acceptable salt derived from an inorganic or organic base include salts obtained by adding an inorganic or organic base.
  • a pharmaceutically acceptable salt derived from an inorganic or organic base include salts obtained by adding an inorganic or organic base.
  • alkalis including sodium hydroxide or potassium hydroxide, or alkaline earth metal hydroxides including calcium hydroxide, magnesium hydroxide, aluminum hydroxide or ammonium hydroxide may be used for the preparation of inorganic salt of the compound.
  • organic bases including triethylamine or diisopropylethylamine may also be used for the preparation of organic salt of the compound.
  • p-TSA is p-toluenesulfonic acid
  • HATU is
  • Aniline A is reacted with a nitrile in the presence of p-toluenesulfonic acid to afford amidine B.
  • Amidine B is chlorinated with sodium hypochlorite and cyclized using sodium bicarbonate to form benzimidazole C.
  • Intermediate C is saponified with sodium hydroxide to afford methoxy acid D.
  • Compound D is treated with boron tribromide to afford hydroxy acid E.
  • Hydroxy acid E is reacted with various amines using HATU to afford compounds of formula I-II.
  • Compound D is also reacted with various amines in the presence of HATU to afford amides F.
  • Amides F are treated with boron tribromide to afford compounds of formula (I-III).
  • the preferred inventive compound of formula (I- V) can be prepared as shown in Scheme (III).
  • Aniline A is coupled with a carboxylic acid derivative to give the corresponding amide I.
  • the ester and ether are cleaved with boron tribromide and the resulting acid is coupled with an amine derivative to give compounds of formula (I- V).
  • Acid D is treated with diphenylphosphoryl azide, triethyl amine and r-butanol to afford intermediate J.
  • the boc-group is removed by treatment with hydrogen chloride to afford the amine K.
  • Amine K is treated with the requisite acid in the presence of HATU to afford amide L.
  • Compound L is reacted with boron tribromide to afford the phenol M.
  • Compound M is treated with hydrogen in the presence of palladium to afford compound N (Scheme IV).
  • Acid O is coupled with the requisite amine to afford amide P.
  • Compound P is reduced under standard hydrogenation conditions to afford aniline Q.
  • the aniline is reacted with the requisite Page: 25/97 acid chloride to afford intermediate R.
  • a final deprotection using boron tribromide affords compound S.
  • a salt, hydrate, solvate and isomer of the inventive compound of formula (I) may be prepared by employing any of the known methods.
  • the inventive compound of formula (I), a salt, hydrate, solvate or isomer thereof may be used for the treatment of GSK3beta dependent diseases such as Alzheimer disease, mania, depression, migraine and type 2 diabetes, by way of inhibiting GSK3beta activity, the inventive compound having an IC 50 value (micro M), generally in the range of 0.0001 to 100, for example 0.001 to 50, preferably 0.001 to 10, more preferably 0.001 to 5.
  • the present invention includes a pharmaceutical composition which includes a therapeutically effective amount of the compound of formula (I), a salt, hydrate, solvate or isomer thereof as an active ingredient and a pharmaceutically acceptable carrier; therefore, the pharmaceutical composition of the present invention exerts superior preventive and treating effects on GSKbeta dependent diseases.
  • a pharmaceutical formulation may be prepared in accordance with any of the conventional procedures.
  • the active ingredient is preferably admixed or diluted with a carrier, or enclosed within a carrier, sachet or other container.
  • the carrier serves as a diluent, it may be a solid, semi-solid or liquid material acting as a vehicle, excipient or medium for the active ingredient.
  • the formulations may be in the form of a tablet, pill, powder, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, soft and hard gelatin capsule, sterile injectable solution, sterile packaged powder and the like.
  • Suitable carriers, excipients, and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, and mineral oil.
  • the formulations may additionally include fillers, antiemulsifiers, preservatives and the like.
  • the compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after their administration to a mammal by employing any of the procedures well known in the art.
  • the pharmaceutical composition of the present invention can be administered via various routes including oral, transdermal, subcutaneous, intravenous and intramuscular introduction.
  • the dosage and method of administration vary according to the body- weight and age of a patient and the administration method; however, one skilled in the art can routinely select a suitable method of administration. If the compound is encodable by a DNA, the DNA can be inserted into a vector for gene therapy and the vector administered to a patient to perform the therapy.
  • the dosage and method of administration vary according to the body- weight, age, and symptoms of the patient; however, one skilled in the art can suitably select them.
  • the dose of a compound of the present invention that regulates its activity depends on the symptoms, the dose is generally about 0.1 mg to about 100 mg per day, preferably about 1.0 mg to about 50 mg per day and more preferably about 1.0 mg to about 20 mg per day, when administered orally to a normal adult human (weight 60 kg).
  • the dose is generally about 0.1 mg to about 100 mg per day, preferably about 1.0 mg to about 50 mg per day and more preferably about 1.0 mg to about 20 mg per day, when administered orally to a normal adult human (weight 60 kg).
  • the appropriate dosage amount may be routinely calculated by converting to 60 kg of body-weight.
  • p-Toluenesulfonic acid monohydrate (42 g, 110 mmol) was heated at 120 degrees and once the solid completely melted, it was placed under high vacuum for 1 h to remove the water. The vacuum was released, aniline (20 g, 55 mmol) and 2-thiophenecarbonitrile (24 g, 110 mmol) were added, and the reaction mixture was heated at 160 degrees for 4 h. The reaction mixture was cooled to room temperature followed by addition of satd. aq NaHCO 3 (250 mL) and ethyl acetate (250 mL).
  • the combined organic layer was dried OVCr Na 2 SO 4 , concentrated, and purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA).
  • the desired product was obtained as the trifluoroacetic acid salt which was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired products.
  • the desired product was treated with TFA (1-2 mL) for 1 h, concentrated and purified by preparative HPLC (Cl 8 silica, 10-90% acetonitrile/water with 0.05% TFA).
  • the desired product was obtained as the trifluoroacetic acid salt which was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired products
  • N-(2-(5-aminopyridin-2-ylamino)ethyl)-7-hydroxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4- carboxamide hydrochloride (0.29 g, 0.68 mmol) in DMF (5 mL) was added DIPEA (0.44 g, 3.4 mmol) and methanesulfonyl chloride (0.085 g, 0.75 mmol) and the reaction mixture was stirred for 16 h at room temperature.
  • reaction mixture was stirred at room temperature for 16 h, quenched with satd. aq NaCl (50 mL), and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with satd.
  • NHTs means p-toluenesulfonamido.
  • the filtrate was concentrated under reduced pressure and the crude residue was triturated in methanol and filtered.
  • the filtrate was concentrated and purified by flash chromatography (silica, 0-20% methanol/dichloromethane) to afford crude product.
  • the crude product was purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA).
  • Example 106 1 -(2-Cyclopropyl-7-methoxy- 1 H-benzo[d]imidazol-4-yl)-3-(4-methoxyphenyl)urea
  • the resulting solids were filtered and dried to obtain the crude acid (1.0 g) as an off-white solid.
  • the crude acid intermediate (0.5 g) was dissolved in DMF (5 mL) followed by the addition of HATU (0.84 g, 2.2 mmol), DIPEA (1.2 mL, 6.6 mmol), histamine (0.50 g, 4.5 mmol) and the reaction mixture was stirred at room temperature for 18 h.
  • the reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were dried over Na 2 SO 4 , concentrated, and the residue was triturated with CH 2 Cl 2 (20 mL).
  • the crude acid was dissolved in DMF (5 mL) followed by the addition of HATU (0.15 g, 0.46 mmol), DIPEA (0.20 mL, 1.1 mmol), and histamine (0.051 g, 0.46 mmol) and the reaction mixture was heated at 80 degrees for 18 h.
  • the reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (3x30 mL). The combined organic layers were dried over Na 2 SO 4 , concentrated, and the residue was purified by preparative HPLC (Cl 8 silica, 10-90% acetonitrile/water with 0.05% TFA).
  • GSK3beta activity was measured in the presence or absence of compounds using Z'-LYTE kinase assay (Rodems SM, et al., Assay Drug Dev Technol. 1 : 9-19, 2002.) kit with SER/THR 9 peptide (Invitrogen) following the manufacturer's instruction.
  • the Z'-LYTE kinase assay kit Page: 85/97 employs a fluorescence resonance energy transfer (FRET) between two fluorophores, coumarin and fluorescein, attached to each end of a substrate peptide.
  • FRET fluorescence resonance energy transfer
  • Test compounds were dissolved in DMSO at 12.5 mM and then serially diluted as the DMSO concentration in the assays to be 1%.
  • the serially diluted compounds, 0.04 ng/mcl GSKbeta (Invitrogen) and 2 mcM SER/THR 9 peptide were reacted in a reaction buffer (50 mM HEPES pH 7.5, 0.01% Brij-35, 10 mM MgCl 2 , 1 mM EGTA, 15 mcM ATP).
  • a reaction buffer 50 mM HEPES pH 7.5, 0.01% Brij-35, 10 mM MgCl 2 , 1 mM EGTA, 15 mcM ATP.
  • ATP was omitted from the reaction mixture.
  • SER/THR 9 phosphopeptide was used in place of the SER/THR 9 peptide.
  • % phosphorylation 1 - (Co% - Cioo%) + [emission ratio x (Fioo% - Fo%)]
  • coumarin emission signal (445nm) emission ratio fluorescein emission signal (520nm)
  • Cioo% coumarin emission signal of the 100% phosphorylation control
  • Co% coumarin emission signal of the 0% phosphorylation control
  • Fioo% fluorescein emission signal of the 100% phosphorylation control
  • Fo% fluorescein emission signal of the 0% phosphorylation control
  • the present invention provides a novel benzoimidazole compound having GSK3beta inhibitory effect.
  • the compounds of the present invention may be used for pharmaceutical composition for inhibiting GSK3-beta.
  • Such pharmaceutical compositions are suitable for treating or preventing diseases involving GSK3beta.

Abstract

Benzoimidazole Derivatives are provided. The compounds of the present invention are useful for Glycogen Synthase Kinase-3 Beta Inhibitors.

Description

Page: 1/97
Benzoimidazole Derivatives and Glycogen Synthase Kinase-3 Beta Inhibitors Containing the
Same Priority
The present application claims the benefit of U.S. Provisional Application No. 61/084,770, filed on July 30, 2008, the entire contents of which are incorporated by reference herein.
Technical Field
The present invention relates to a compound for inhibiting glycogen synthase kinase-3 (GSK3) activity, a method for the preparation thereof, and a pharmaceutical composition containing the compound as an active ingredient. Background Art
Glycogen synthase kinase-3 (GSK3) is a proline-directed serine-threonine kinase that was initially identified as a protein which inactivates glycogen synthase through phosphorylation. Two isoforms have been identified, alpha (GSK3 alpha) and beta (GSK3beta), which show a high degree of amino acid homology to each other. Previous studies have reported that the GSK3beta is involved in energy metabolism, neural cell development, and body pattern formation (Plyte SE, et al., Biochim. Biophys. Acta, 1114:147-162, 1992).
Neurodegenerative naturopathies, including Alzheimer disease, are characterized by abnormal hyperphosphorylation of the microtubule-associated protein tau at proline-directed serine/threonine phosphorylation sites (Lee VM, et al., Annu. Rev. Neurosci. 24: 1121-1159, 2001.). GSK3beta has been identified as a prime candidate mediating aberrant tau phosphorylation at disease-associated sites (Hanger DP, et al., Neurosci. Lett. 147: 58-62, 1992., Ishiguro K, et al., J. Biol. Chem. 267: 10897-10901, 1992., Mandelkow EM, et al., FEBS Lett. 314: 315-321, 1992. and Paudel HK, et al., J. Biol. Chem. 268: 23512-23518, 1993.). Hence, GSK3beta is a promising target for therapeutic intervention in neurodegenerative tauopathies including Alzheimer disease.
Lithium carbonate, lithium citrate and lithium chloride are commonly used for the treatment of various disorders like mania, depression and migraine, and also used as an "augmenting" agent to increase the benefits of other standard drugs used for unipolar depression. Lithium is a GSK3beta inhibitor, and therefore, GSK3beta inhibition is a promising target for the treatment of various such disorders.
There have been reports that the activity of GSK3 in obese diabetic mice is about twice as high as that in control (Eldar-Finkelman H, et al., Diabetes, 48:1662-1666, 1999), and the activity and expression of GSK3 in patients with type 2 diabetes is significantly higher relatively to that in normal persons (Nikoulina SE, et al., Diabetes, 49:263-271, 2000). Therefore, GSK3 inhibitors are available for treatment of type 2 diabetes by reducing the activity of glucose synthase.
Taken together, GSK3beta inhibitors can be used for a broad spectrum of diseases such as Alzheimer disease, mania, depression, migraine and type 2 diabetes and there is a strong need to develop such inhibitors for the treatment and/or prevention of GSK3beta dependent diseases.
The present inventors have found that benzoimidazole derivatives can selectively inhibit the activity of GSK3beta and are therefore useful for treatment and/or prevention of GSK3beta dependent diseases.
Summary of Invention
Accordingly, it is an object of the present invention to provide GSK3beta inhibitors having high inhibitory activity against GSK3beta. It is another object of the present invention to provide a method for preparing such inhibitors. Page: 2/97
It is a further object of the present invention to provide a pharmaceutical composition including said compounds, pharmaceutically acceptable salts, hydrates, solvates, and isomers thereof.
In accordance with one aspect of the present invention, there is provided a compound of formula (I), and a pharmaceutically acceptable salt, hydrate, solvate, or isomer thereof:
Figure imgf000003_0001
wherein, ring A is (II), (III), (IV) (V), or (VI)
Figure imgf000003_0002
wherein X is halogen or hydroxyl;
Y is hydrogen, phenyl, thiophen-2-yl, furan-2-yl, cyclopropyl, or cyclopentyl; Z is a 5-10 membered heterocycle substituted carbonylamino; and Ring A is substituted by -L'-(CH2)a-L2-M at position *; L1 is -CONH-, -NHCO-, or a single bond; L2 is selected from the group consisting of -NH-, -O-, -CH(COOR1)-, -CH(CH2OH)-, -CH=CH- and a single bond, wherein R1 is hydrogen or CpC6 alkyl;
M is selected from the group consisting of hydroxyl, carboxyl, amide, Ci-C6 alkyl, Ci-C6 alkylcarbonyl, C6-Ci4 aryl, C6-Ci4 aryl Ci-C6 alkyl, C6-Ci4 arylcarbonyl, C6-Ci4 arylsulfonyl, 5-14 membered saturated, unsaturated or aromatic heterocyclic group, 5-14 membered unsaturated or aromatic heterocyclic group substituted Ci-C6 alkyl, 5-14 membered unsaturated or aromatic heterocyclic group substituted sulfonyl or -NR R ; wherein R2 and R3 are independently Cj-C6 alkyl; the CpC6 alkyl, CpC6 alkylcarbonyl, C6-C14 aryl, C6-Ci4 aryl Ci-C6 alkyl, C6-Cj4 arylcarbonyl, C6-C]4 arylsulfonyl, 5-14 membered unsaturated or aromatic heterocyclic group, 5-14 membered unsaturated or aromatic heterocyclic group substituted C]-C6alkyl, and 5-14 membered unsaturated or aromatic heterocyclic group substituted sulfonyl are optionally substituted by 1 -3 substituent(s) each independently selected from group A; wherein group A consists of hydroxyl, oxo, nitro, amino, amide, halogen, sulfamoyl, trifluolomethyl, p-toluenesulfonylamino, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 alkylcarbonylamino, and C]-C6 alkylsulfonylamino; and a is 0-5 integer.
Description of Embodiments Definitions Page: 3/97
In this invention, "alkyl" refers to a straight chain or a branched chain hydrocarbon group which does not contain any hetero atoms or unsaturated carbon-carbon bonds. "Ci-C6 alkyl" refers to an alkyl group which has 1-6 carbon atoms. "Ci-C4 alkyl" refers to an alkyl group which has 1-4 carbon atoms. Examples of "Ci-C6 alkyl" include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, 2 -methyl- 1 -propyl, 2-methyl-2-propyl, 1 -butyl, 2-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 2,2-dimethyl-l -propyl, 1-hexyl, 2-hexyl, 3-hexyl, 2 -methyl- 1-pentyl, 3 -methyl- 1-pentyl, 4-methyl- 1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methy-3-pentyl, 3-methyl-3-pentyl, 2,3 -dimethyl- 1 -butyl, 3, 3 -dimethyl- 1 -butyl, 2,2-dimethyl-l -butyl, 2-ethyl-l -butyl, 3,3-dimethyl-2-butyl, and 2,3-dimethyl-2-butyl.
In the present invention, "alkoxy" refers to a group represented by -OR, wherein R is alkyl.
"Ci-C6 alkoxy" refers to an alkoxy group which has 1-6 carbon atoms. "Cj-C4 alkoxy" refers to an alkoxy group which has 1-4 carbon atoms. Examples OfCi-C6 alkoxy" include, but are not limited to, methoxy, ethoxy, 1-propyloxy, 2-propyloxy, 2 -methyl- 1-propyloxy, 2-methyl-2-propyloxy, and 1-butyloxy, and 2- butyloxy.
In the present invention, "carbonyl" refers to a group represented by -(C=O)-.
In this invention, "Ci-C6 alkylcarbonyl" refers to a carbonyl group bound to the Ci-C6 alkyl. "C]-C4 alkylcarbonyl" refers to a carbonyl group bound to theCj-C4 alkyl. Examples of "CpC6 alkylcarbonyl" include, but are not limited to, methylcarbonyl, ethylcarbonyl, 1-propylcarbonyl, 2-propylcarbonyl, n-butylcarbonyl, s-butylcarbonyl, t-butylcarbonyl, and 2-ethylbutylcarbyl.
In this invention, "amino" refers to a group represented by -NH2 in which the hydrogens are optionally replaced by a substituent. In the present invention, "Cj-C6 alkyl carbonylamino" refers to an amino group bound to the
Ci-C6 alkylcarbonyl. "Cj-C4 alkylcarbonylamino" refers to an amino group bound to the CpC4 alkylcarbonyl.
Examples of "C1-C6 alkylcarbonylamino" include, but are not limited to, methylcarbonylamino, ethylcarbonylamino, 1 -propylcarbonylamino, 2-propylcarbonylamino, n-butylcarbonylamino, s-butylcarbonylamino, t-butylcarbonylamino, and 2-ethylbutylcarbonylamino.
In this invention, "sulfonyl" is a group represented by -SO2-.
In this invention, "CpC6 alkylsulfonyl" refers to a sulfonyl group bound to the CpC6 alkyl. "CpC4 alkylsulfonyl" refers to a sulfonyl group bound to the Cj-C4 alkyl.
Examples of "CpC6 alkylsulfonyl" include, but are not limited to, methylsulfonyl, ethylsulfonyl, 1-propylsulfonyl, 2-propylsulfonyl, n-butylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, and 2-ethylbutylsulfonyl.
In the present invention, "CpC6 alkylsulfonylamino" refers to an amino group bound to the"CpC6 alkylsulfonyl". "CpC4 alkylsulfonylamino" refers to an amino group bound to the"CpC4 alkylsulfonyl". Examples of "Cj-C6 alkylsulfonylamino" include, but are not limited to, methylsulfonylamino, ethylsulfonylamino, 1 -propylsulfonylamino, 2-propylsulfonylamino, n-butylsulfonylamino, s-butylsulfonylamino, t-butylsulfonylamino, and 2-ethylbutylsulfonylamino. Page: 4/97
In the present invention, "aryl" refers to an aromatic carbon ring system. "C6-Cj4 aryl" refers to a 6-14 membered aryl ring. "C6-Ci0 aryl" refers to a 6-10 membered aryl ring.
Examples of "C6-Ci4 aryl" include, but are not limited to, phenyl, naphthyl, and anthryl.
In the invention, "C6-Ci4 aryl Cj-C6 alkyl" refers to the"Cj-C6 alkyl" in which a hydrogen atom is substituted by the"C6-Cj4 aryl". "C6-Cj0 arylCrC4 alkyl" refers to the"Cj-C4 alkyl" in which a hydrogen atom is substituted by the"C6-Cjo aryl".
Examples of "C6-Cj4arylCj-C6alkyl" include, but are not limited to, benzyl, phenethyl, and anthrylmethyl.
In the present invention, "C6-Cj4 arylcarbonyl" refers to a carbonyl group bound to the"C6-Cj4 aryl". "C6-Ci0 arylcarbonyl" refers to a carbonyl group bound to the"C6-C]0 aryl".
Examples of "C6-Cj4 arylcarbonyl" include, but are not limited to, phenylcarbonyl, naphthylcarbonyl, and anthrylcarbonyl.
In this invention, "C6-Cj4 arylsulfonyl" refers to a sulfonyl group bound to the"C6-Cj4 aryl". "C6-CjO arylsulfonyl" refers to a sulfonyl group bound to the"C6-Cj0 aryl". Examples of "C6-Ci4arylsulfonyl" include, but are not limited to, phenylsulfonyl, naphthylsulfonyl, and anthrylsulfonyl.
In the present invention, "an unsaturated or aromatic heterocyclic group" refers to an unsaturated or aromatic heterocyclic group having one or more hetero atom in the ring system. "5-14 membered unsaturated or aromatic heterocyclic group" refers to an unsaturated or aromatic heterocyclic group in which the ring consists of 5- 14 atoms. "5-10 membered unsaturated or aromatic heterocyclic group" refers to a unsaturated or aromatic heterocyclic group in which the ring consists of 5-10 atoms.
Examples of "5-14 membered unsaturated or aromatic heterocyclic group" include, but are not limited to, imidazolyl, pyrrolyl, pyridyl, thienyl, furyl, thiazolyl, pyrazolyl, pyrazolinyl, oxazolyl, isoxazolyl and indolyl.
In this invention, "5-14 membered unsaturated or aromatic heterocyclic group substituted Cj-C6 alkyl" refers to the "Cj-C6 alkyl" in which a hydrogen atom is substituted by the"5-14 membered unsaturated or aromatic heterocyclic group". "5-10 membered unsaturated or aromatic heterocyclic group substituted Cj-C4 alkyl" refers to the "Cj-C4 alkyl" in which a hydrogen atom is substituted by the"5-10 membered unsaturated or aromatic heterocyclic group".
Examples of "5-14 membered unsaturated or aromatic heterocyclic group substituted Cj-C6 alkyl" include, but are not limited to, imidazolylmethyl, pyrrolylmethyl, pyridylmethyl, thienylmethyl, furylmethyl, thiazolylmethyl, pyrazolylmethyl, pyrazolinylmethyl, oxazolylmethyl, isoxazolylmethyl, and indolylmethyl. In this invention, "5-14 membered unsaturated or aromatic heterocyclic group substituted sulfonyl" refers to a sulfonyl group bound to the 5-14 membered unsaturated or aromatic heterocyclic group". "5-10 membered unsaturated or aromatic heterocyclic group substituted sulfonyl" refers to a sulfonyl group bound to "5-10 membered unsaturated or aromatic heterocyclic group". Examples of "5-14 membered unsaturated or aromatic heterocyclic group substituted sulfonyl" include, but are not limited to, imidazolylsulfonyl, pyrrolylsulfonyl, pyridylsulfonyl, thienylsulfonyl, furylsulfonyl, thiazolylsulfonyl, pyrazolylsulfonyl, pyrazolinylsulfonyl, oxazolylsulfonyl, isoxazolylsulfonyl, and indolylsulfonyl. Page: 5/97
In this invention, "5-10 membered unsaturated or aromatic heterocyclic group substituted carbonylamino" refers to an amino group bound to a carbonyl group bound to the "5-10 membered unsaturated or aromatic heterocyclic group".
Examples of "5-10 membered unsaturated or aromatic heterocyclic group substituted carbonylamino" include, but are not limited to, imidazolylcarbonylamino, pyrrolylcarbonylamino, pyridylcarbonylamino, thienylcarbonylamino, furylcarbonylamino, thiazolylcarbonylamino, pyrazolylcarbonylamino, pyrazolinylcarbonylamino, oxazolylcarbonylamino, isoxazolylcarbonylamino, and indolylcarbonylamino.
In the present invention, "a saturated heterocyclic group" refers to a saturated heterocyclic group having one or more hetero atom in the ring system. "5-14 membered saturated heterocyclic group" refers to a saturated heterocyclic group in which the ring consists of 5-14 atoms. "5-10 membered saturated heterocyclic group" refers to a saturated heterocyclic group in which the ring consists of 5-10 atoms.
Examples of "5-14 membered saturated heterocyclic group" include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
A salt is defined as the product formed from the neutralisation reaction of acids and bases. Salts are ionic compounds composed of cations (positively charged ions) and anions (negative ions) so that the product is electrically neutral. These component ions can be inorganic as well as organic.
Hydrate is a term used in inorganic chemistry and organic chemistry to indicate that a substance contains water. Solvate refers to a molecule in a solution complexed by solvent molecules. Isomers are compounds with the same molecular formula but different structural formulae. More specifically, isomer includes geometric isomer, optical isomer, stereoisomer, tautomer of the compound, and mixtures thereof.
The present invention provides a compound represented by formula (I):
Figure imgf000006_0001
Among the compounds of formula (I) of the present invention, the preferred are those wherein: A is (II),
Figure imgf000006_0002
X is halogen or hydroxyl;
Y is phenyl, thiophen-2-yl, furan-2-yl, cyclopropyl, or cyclopentyl; Ring (II) is substituted by -L1-(CH2)a-L2-M at position *; L1 is -CONH- or -NHCO-; Page: 6/97
L2 is selected from the group consisting of -NH-, -O-, -CH(COOR1)-, -CH(CH2OH)-, and a single bond, wherein R! is hydrogen or C1-C6 alkyl;
M is selected from the group consisting of hydroxyl, carboxyl, amide, Ci-C6 alkyl, Ci-C6 alkylcarbonyl, C6-Cj4 aryl, C6-Ci4 aryl C]-C6 alkyl, C6-Ci4 arylcarbonyl, C6-Ci4 arylsulfonyl, 5-14 membered saturated, unsaturated or aromatic heterocyclic group, 5-14 membered unsaturated or aromatic heterocyclic group substituted C]-C6alkyl, 5-14 membered unsaturated or aromatic heterocyclic group substituted sulfonyl or -NR2R3; wherein R2 and R3 are independently Ci-C6 alkyl; the Ci-C6 alkyl, Ci-C6 alkylcarbonyl, C6-C]4 aryl, C6-C]4 aryl Ci-C6 alkyl, C6-Ci4 arylcarbonyl, C6-Ci4 arylsulfonyl, 5-14 membered unsaturated or aromatic heterocyclic group, 5-14 membered unsaturated or aromatic heterocyclic group substituted by Cj-C6 alkyl, and 5-14 membered unsaturated or aromatic heterocyclic group substituted sulfonyl are optionally substituted by 1-3 substituent(s) each independently selected from group A; wherein group A consists of hydroxyl, oxo, nitro, amino, amide, halogen, sulfamoyl, trifluolomethyl, p-toluenesulfonylamino, Ci-C6 alkyl, Ci-C6 alkoxy, Ci-C6 alkylcarbonylamino, and C]-C6 alkylsulfonylamino; and a is an integer from 0-5.
In a preferred embodiment, the present invention provides compounds represented by following formula (I-II) or a salt, hydrate, solvate, or isomer thereof:
Figure imgf000007_0001
L1 is -CONH-; L2 is a single bond;
M is C6-CiO aryl or 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, which are optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
X, Y, and a are defined as in above embodiment represented by formula (I).
In this embodiment, M is selected from the group consisting of phenyl, imidazole- 1-yl, imdazole-2-yl, imidazole- 5 -yl, thiophen-2-yl, pyrole-2-yl, l,3-thiazole-2-yl, 2-pyrazoline-4-yl, and isoxazole-4-yl, which are optionally substituted by 1-2 substituent(s) each independently selected from following group B, and Y is selected from the group consisting of thiophen-2-yl, furan-2-yl, phenyl, cyclopropyl, and cyclopentyl.
Group B consists of fluoro, hydroxyl, oxo, amino, methyl, methoxy, and sulfamoyl.
Preferred compounds include those selected from the group consisting of: Example Nos. 8, 9, 10, 20, 21, 22, 23, 35, 37, 44, 45, 57, 62, 76, 77, 78, 79, 80, 84, 85, 86, 90, 91, 92, 93, 94, 95, 96, 101 and 102 listed in Table 1 below; and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds. Page: 7/97
Table 1
Figure imgf000008_0001
Page: 8/97
Figure imgf000009_0001
Page: 9/97
Figure imgf000010_0001
Page: 10/97
Figure imgf000011_0001
In another preferred embodiment, the present invention provides a compound represented by following formula (I- II) or a salt, hydrate, solvate, or isomer thereof : Page: 1 1/97
Figure imgf000012_0001
L2 is -NH-; M is Ci-C4 alkyl, Cj-C4 alkylcarbonyl, C6-Ci0 arylcarbonyl, C6-Ci0 arylsulfonyl, 5-10 membered unsaturated or aromatic heterocyclic group having 1 -2 hetero atom(s) selected from the group consisting of N, O, and S or sulfonyl substituted by 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, which are optionally substituted by 1 or 2 substituent(s) each independently selected form the group A; and
X, Y, and a are defined as in the above embodiment represented by formula (I).
In this embodiment, M is selected from the group consisting of ethyl, isopropyl, methylcarbonyl, pyridine-2-yl, phenylcarbonyl, phenylsulfonyl, and 4-pyridilsulfonyl, which are optionally substituted by 1 -2 substituent(s) each independently selected from following group C, and Y is selected from the group consisting of thiophen-2-yl and furan-2-yl.
Group C consists of chloro, hydroxyl, methyl, methylcarbonylamino, methylsulfonylamino, and p-toluenesulfonylamino.
In one preferred embodiment, the present invention provides the compound selected from the group consisting of: Example Nos. 11, 12, 38, 39, 40, 41, 42, 43, 69, 70 and 89 listed in Table 2 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
Table 2
Figure imgf000012_0002
Page: 12/97
Figure imgf000013_0001
Page: 13/97
Figure imgf000014_0002
In another preferred embodiment, the present invention provides a compound represented by following formula (I-II) or a salt thereof:
Figure imgf000014_0001
wherein L1 is -CONH-;
L2 is -CH(COOR1)-, wherein R1 is hydrogen or Ci-C4 alkyl;
M is C1-C4 alkyl, C6-C10 aryl Ci-C4 alkyl or Ci-C4 alkyl substituted by 5-10 membered unsaturated or aromatic heterocyclic group having 1 -2 hetero atom(s) selected from the group consisting of N, O, and S , which are optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
X, Y, and a are defined as in the above embodiment represented by formula (I).
In this embodiment, M is selected from the group consisting of methyl, phenylmethyl, indole-3-ylmethyl, and imidazole-4-ylmethyl, which are optionally substituted by 1-2 hydroxyl, and Y is thiophen-2-yl. In one preferred embodiment, the present invention provides the compound selected from the group consisting of: Example Nos. 13, 14, 15, 16, 71 and 72 listed in Table 3 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
Table 3
Figure imgf000014_0003
Page: 14/97
Figure imgf000015_0002
In another preferred embodiment, the present invention provides a compound represented by following formula (I- II) or a salt, hydrate, solvate, or isomer thereof:
Figure imgf000015_0001
L2 is - 0-;
M is C6-C]0 aryl or 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, which are optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; X, Y, and a are defined in the above embodiment represented by formula (I).
In this embodiment, M is phenyl or pyridine-2-yl, which is optionally substituted by 1 or 2 substituent(s) each independently selected from following group D, and Y preferably consists of thiophen-2-yl.
Group D consists of amide, nitro, trifluoromethyl, and p-toluenesulfonylamino. Page: 15/97
In one preferred embodiment, the present invention provides the compound selected from the group consisting of: Example Nos. 49, 50, 73 and 74 listed in Table 4 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
Table 4
Figure imgf000016_0002
In another preferred embodiment, the present invention provides the compounds represented by following formula (I-II) or a salt, hydrate, solvate, or isomer thereof:
Figure imgf000016_0001
wherein
L1 is -CONH-;
L2 is - CH(CH2OH)-; Page: 16/97
M is selected from the group consisting of hydroxyl, Ci-C4 alkyl, C6-Ci0 aryl Ci-C4 alkyl, and Cj-C4 alkyl substituted by 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, the C]-C4 alkyl, C6-Ci0 aryl Ci-C4 alkyl, and 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) are optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
X, Y, and a are defined as in the above embodiment represented by formula (I).
In this embodiment, M is preferably hydroxyl, phenylmethyl, t-butyl, or imidazole-5-ylmethyl, and Y is selected from the group consisting of thiophen-2-y and cyclopropyl.
In one preferred embodiment, the present invention provides the compound selected from the group consisting of: Example Nos. 17, 18, 19 and 97 listed in Table 5 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
Table 5
-2
Figure imgf000017_0001
In another preferred embodiment, the present invention provides a compound represented by following formula (I-II) or a salt, hydrate, solvate, or isomer thereof : Page: 17/97
Figure imgf000018_0001
wherein L1 is -CONH-; L2 is a single bond; M is -NR2R3; wherein R and R are independently Ci-C4 alkyl optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
X, Y, and a are defined in the above embodiment represented by formula (I).
In this embodiment, Y is selected from the group consisting of thiophen-2-yl and cyclopropyl.
In one preferred embodiment, the present invention provides the compound selected from the group consisting of: Example Nos. 36 and 98 listed in Table 6 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
Table 6
Figure imgf000018_0003
In another preferred embodiment, the present invention provides a compound represented by following formula (I-II) or a salt, hydrate, solvate, or isomer thereof:
I)
Figure imgf000018_0002
Page: 18/97
L1 is -NHCO-;
L2 is -NH-, -CH=CH- or a single bond;
M is C6-CiO aryl or 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, which are optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
X, Y, and a are defined as in the above embodiment represented by formula (I).
In this embodiment, M is preferably phenyl optionally having 1 or 2 hydroxyl, or imidazol-5-yl and Y is cyclopropyl or thiophen-2-yl.
In one preferred embodiment, the present invention provides the compound selected from the group consisting of: Example Nos. 107, 108, 120 and 121 listed in Table 7 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
Table 7
H-imid
Figure imgf000019_0001
by following formula (I-III) or a salt, hydrate, solvate, or isomer thereof:
Figure imgf000019_0002
wherein Page: 19/97
L is -CONH- or a single bond; L2 is a single bond;
M is amide or 5-10 membered unsaturated or aromatic heterocyclic group having 1 or 2 hetero atom(s) selected from the group consisting of N, O, and S optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
X, Y, and a are defined in the above embodiment represented by formula (I). In this embodiment, Y is thiophen-2-yl.
In one preferred embodiment, the present invention provides the compound selected from the group consisting of: Example Nos. 65 and 66 listed in Table 8 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
Table 8
Figure imgf000020_0002
In another preferred embodiment, the present invention provides a compound represented by following formula (I-IV) or a salt, hydrate, solvate, or isomer thereof :
Figure imgf000020_0001
wherein L1 is -CONH-; L2 is a single bond;
M is 5-10 membered unsaturated or aromatic heterocyclic group having 1 or 2 hetero atom(s) selected from the group consisting of N, O, and S optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
X, Y, and a are defined as in the embodiment represented by formula (I). In this embodiment, Y is hydrogen.
In one preferred embodiment, the present invention provides the compound of Example No. 110 listed in Table 9 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compound. Page: 20/97
Table 9
Figure imgf000021_0002
In another preferred embodiment, the present invention provides compounds represented by following formula (I- V), (I- VI) or a salt, hydrate, solvate, or isomer thereof :
Figure imgf000021_0001
wherein
L1 is -CONH-; L2 is a single bond;
M is 5-10 membered saturated, unsaturated or aromatic heterocyclic group having 1 or 2 hetero atom(s) selected from the group consisting of N, O, and S optionally substituted by 1 or 2 substituent(s) each independently selected from the group A; and
X, Z, and a are defined as in the above embodiment represented by formula (I). In this embodiment, Z is preferably thiophen-2-ylcarbonylamino.
In one preferred embodiment, the present invention provides the compound of Example Nos. 112 and 122 listed in Table 10 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compound.
Table 10
Figure imgf000021_0003
Page: 21/97
Figure imgf000022_0001
In another preferred embodiment, the present invention provides a compound represented by formula (I- VI) or a salt, hydrate, solvate, or isomer thereof:
Figure imgf000022_0002
wherein Ring A is represented by the formula below;
Figure imgf000022_0003
(H)
M is carboxyl;
X, Y, Z and a are defined as in the above embodiment represented by formula (I). In this embodiment, ring A is preferably the formula (II).
In one preferred embodiment, the present invention provides the compound of: Example No. 1 listed in Table 11 below, and the pharmaceutically acceptable salts, prodrugs, hydrates and solvates of the forgoing compounds.
Table 11
Figure imgf000022_0004
The compound of formula (I) of the present invention may be in the form of a pharmaceutically acceptable salt derived from an inorganic or organic acid, and representative examples of the pharmaceutically acceptable salt derived from an inorganic or organic acid include salts obtained by adding an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfonic acid, or organic carboxylic acids such as acetic acid, trifluoroacetic acid, citric acid, formic acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, Page: 22/97 mandelic acid, ascorbic acid or malic acid, methanesulfonic acid, or para toluenesulfonic acid, which do not limit its scope, to the compound of formula (I). Such acids may be prepared by the conventional processes, and other acids, which themselves are not pharmaceutically acceptable, including oxalic acid may be employed in the preparation of the bases.
Alternatively, the compound of formula (I) of the present invention may also be in the form of a pharmaceutically acceptable salt derived from an inorganic or organic base include salts obtained by adding an inorganic or organic base. For example, alkalis including sodium hydroxide or potassium hydroxide, or alkaline earth metal hydroxides including calcium hydroxide, magnesium hydroxide, aluminum hydroxide or ammonium hydroxide may be used for the preparation of inorganic salt of the compound. Further, organic bases including triethylamine or diisopropylethylamine may also be used for the preparation of organic salt of the compound.
The preferred inventive compound of formula (I-II) and (I-III) may be prepared as in Scheme (I).
Scheme (I)
YCN NaOCl p-TSA then NaHCO,
Figure imgf000023_0001
Figure imgf000023_0002
Figure imgf000023_0003
H2N (CH2)a L2 — M — (CH2)a V— M
HATU, DIPEA HATU, DIPEA
Figure imgf000023_0004
Wherein, p-TSA is p-toluenesulfonic acid, HATU is
2-(lH-7-Azabenzotriazol-l-yl)-l,l,3,3-tetramethyl uronium hexafluorophosphate Methanaminium, DIPEA is N,N-diisopropylethylamine and Y (except when Y is a hydrogen), a, L2 and M have the same meaning as defined previously. Page: 23/97
Aniline A is reacted with a nitrile in the presence of p-toluenesulfonic acid to afford amidine B. Amidine B is chlorinated with sodium hypochlorite and cyclized using sodium bicarbonate to form benzimidazole C. Intermediate C is saponified with sodium hydroxide to afford methoxy acid D. Compound D is treated with boron tribromide to afford hydroxy acid E. Hydroxy acid E is reacted with various amines using HATU to afford compounds of formula I-II. Compound D is also reacted with various amines in the presence of HATU to afford amides F. Amides F are treated with boron tribromide to afford compounds of formula (I-III).
The preferred inventive compound of formula (I-IV) can be prepared as shown in Scheme (II).
Scheme (II)
Figure imgf000024_0001
Compound G is reacted with TFAA (trifluoroacetic acid anhydride) followed by hydrolysis with base to afford the intermediate carboxylic acid, which is coupled using HATU to afford compound H. Compound H is hydrogenated to afford compounds of formula (I-VI).
The preferred inventive compound of formula (I- V) can be prepared as shown in Scheme (III).
Scheme (III)
Figure imgf000024_0002
Aniline A is coupled with a carboxylic acid derivative to give the corresponding amide I. The ester and ether are cleaved with boron tribromide and the resulting acid is coupled with an amine derivative to give compounds of formula (I- V).
Scheme (IV)
Page: 24/97
Figure imgf000025_0001
K
Figure imgf000025_0002
Acid D is treated with diphenylphosphoryl azide, triethyl amine and r-butanol to afford intermediate J. The boc-group is removed by treatment with hydrogen chloride to afford the amine K. Amine K is treated with the requisite acid in the presence of HATU to afford amide L. Compound L is reacted with boron tribromide to afford the phenol M. Compound M is treated with hydrogen in the presence of palladium to afford compound N (Scheme IV).
Scheme V
HATU, DlPEA
Figure imgf000025_0004
Figure imgf000025_0003
O
Figure imgf000025_0005
Acid O is coupled with the requisite amine to afford amide P. Compound P is reduced under standard hydrogenation conditions to afford aniline Q. The aniline is reacted with the requisite Page: 25/97 acid chloride to afford intermediate R. A final deprotection using boron tribromide affords compound S.
A salt, hydrate, solvate and isomer of the inventive compound of formula (I) may be prepared by employing any of the known methods. The inventive compound of formula (I), a salt, hydrate, solvate or isomer thereof may be used for the treatment of GSK3beta dependent diseases such as Alzheimer disease, mania, depression, migraine and type 2 diabetes, by way of inhibiting GSK3beta activity, the inventive compound having an IC50 value (micro M), generally in the range of 0.0001 to 100, for example 0.001 to 50, preferably 0.001 to 10, more preferably 0.001 to 5. Accordingly, the present invention includes a pharmaceutical composition which includes a therapeutically effective amount of the compound of formula (I), a salt, hydrate, solvate or isomer thereof as an active ingredient and a pharmaceutically acceptable carrier; therefore, the pharmaceutical composition of the present invention exerts superior preventive and treating effects on GSKbeta dependent diseases. A pharmaceutical formulation may be prepared in accordance with any of the conventional procedures. In preparing the formulation, the active ingredient is preferably admixed or diluted with a carrier, or enclosed within a carrier, sachet or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material acting as a vehicle, excipient or medium for the active ingredient. Thus, the formulations may be in the form of a tablet, pill, powder, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, soft and hard gelatin capsule, sterile injectable solution, sterile packaged powder and the like.
Examples of suitable carriers, excipients, and diluents are lactose, dextrose, sucrose, sorbitol, mannitol, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, and mineral oil. The formulations may additionally include fillers, antiemulsifiers, preservatives and the like. The compositions of the invention may be formulated so as to provide quick, sustained or delayed release of the active ingredient after their administration to a mammal by employing any of the procedures well known in the art.
The pharmaceutical composition of the present invention can be administered via various routes including oral, transdermal, subcutaneous, intravenous and intramuscular introduction. The dosage and method of administration vary according to the body- weight and age of a patient and the administration method; however, one skilled in the art can routinely select a suitable method of administration. If the compound is encodable by a DNA, the DNA can be inserted into a vector for gene therapy and the vector administered to a patient to perform the therapy. The dosage and method of administration vary according to the body- weight, age, and symptoms of the patient; however, one skilled in the art can suitably select them.
For example, although the dose of a compound of the present invention that regulates its activity depends on the symptoms, the dose is generally about 0.1 mg to about 100 mg per day, preferably about 1.0 mg to about 50 mg per day and more preferably about 1.0 mg to about 20 mg per day, when administered orally to a normal adult human (weight 60 kg). When administering the compound parenterally, in the form of an injection to a normal adult human (weight 60 kg), although there are some differences according to the patient, target organ, symptoms and method of administration, it is convenient to intravenously inject a dose of about 0.01 mg to about 30 mg per day, preferably about 0.1 to about 20 mg per day, and more preferably about 0.1 to about 10 mg per day. In the case of other animals, the appropriate dosage amount may be routinely calculated by converting to 60 kg of body-weight.
Examples Page: 26/97
The following examples are intended to further illustrate the present invention without limiting its scope.
Example 1 STEP 1 : Synthesis of Methyl 4-Methoxy-3-(thiophene-2-carboximidamido)benzoate
Figure imgf000027_0001
p-Toluenesulfonic acid monohydrate (42 g, 110 mmol) was heated at 120 degrees and once the solid completely melted, it was placed under high vacuum for 1 h to remove the water. The vacuum was released, aniline (20 g, 55 mmol) and 2-thiophenecarbonitrile (24 g, 110 mmol) were added, and the reaction mixture was heated at 160 degrees for 4 h. The reaction mixture was cooled to room temperature followed by addition of satd. aq NaHCO3 (250 mL) and ethyl acetate (250 mL). The layers were separated, the aqueous layer was extracted with ethyl acetate (100 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography to obtain 16 g of the crude amidine intermediate. The crude intermediate was dissolved in ethyl acetate (350 mL) and HCl (2.0 M in diethyl ether, 55 mL, 110 mmol) was added. The resulting precipitate was filtered to obtain the desired product (16 g, 42% yield) as an off-white solid: ESI MS m/z 291 [CJ4H14N3O2S + H]+. STEP 2: Synthesis of Methyl 7-Methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylate
Figure imgf000027_0002
To a solution of the product from step 1 (16 g, 49 mmol) in methanol (100 mL) was added 5% aq NaOCl (75 mL, 55 mmol) and the reaction mixture was stirred at room temperature for 2 h. Next, satd. aq NaHCO3 (150 mL) and methanol (150 mL) were added and the resulting reaction mixture was heated at 60 degrees for 2 d. The reaction mixture was cooled to room temperature and concentrated to remove methanol. The reaction mixture was acidified to pH 4 using 6 N HCl and the resulting precipitate was filtered and dried to obtain the desired product (8 g, 57% yield) as a brown solid: 1H NMR (500 MHz, CDCl3) delta 7.86 (d, J = 8.5 Hz, IH), 7.71-7.68 (m, IH), 7.48-7.45 (m, IH), 7.17-7.14 (m, IH), 7.73 (d, J = 8.5 Hz, IH), 4.16 (m, 3H), 3.98 (m, 3H); ESI MS m/z 289 [C4Hi2N2O3S + H]+.
STEP 3: Synthesis of 7-Methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic Acid
Figure imgf000027_0003
Page: 27/97
To a solution of the product from step 2 (4.2 g, 14 mmol) in ethanol (30 mL) and water (15 mL) was added 6 N NaOH (55 mL) and the reaction mixture was heated at 90 degrees for 2 h. The reaction mixture was cooled and concentrated to dryness. The crude residue was dissolved in water (30 ml) and acidified to pH 4 using 6 N HCl. The resulting precipitate was filtered and dried to obtain the desired product (2.2 g, 58% yield) as a brown solid: 1H NMR (500 MHz, DMSO-d6) delta 8.25 (d, J = 3.0 Hz, IH), 7.77 (d, J = 8.0 Hz, IH), 7.73-7.68 (m, IH), 7.22-7.18 (m, IH), 6.82 (d, J = 8.5 Hz, IH), 3.97 (m, 3H); ESI MS m/z 275 [Ci3H10N2O3S + H]+.
STEP 4: Synthesis of 7-Hydroxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic Acid
Figure imgf000028_0001
To a solution of the product from step 3 (2.5 g, 9.1 mmol) in dichloroethane (100 mL) was added BBr3 (23g, 91 mmol) and the reaction mixture was heated at 90 degrees for 2 d. The reaction mixture was cooled and poured onto ice. The resulting solids were filtered to obtain the desired product (0.45 g, 19% yield) as a brown solid. The filtrate was acidified to pH 4 using 6 N HCl and the resulting precipitate was filtered to obtain a second batch of the desired product (Example No. 1, 1.6 g, 88% yield) as a brown solid: 1H NMR (300 MHz, CD3OD) delta 7.93-7.90 (m, IH), 7.75 (d, J = 8.5 Hz, IH), 7.62-7.58 (m, IH), 7.19-7.14 (m, IH), 6.65 (d, J = 8.1 Hz, IH); ESI MS m/z 261 [Ci2H8N2O3S + H]+.
Example 2
STEP 1 : Synthesis of Methyl 3-Methoxy-4-(thiophene-2-carboximidamido)benzoate Hydrochloride
Figure imgf000028_0002
Following the procedure outlined for step 1 in Example 1, methyl 4-amino-3-methoxybenzoate (5.0 g, 27 mmol) was reacted with 2-thiophenecarbonitrile (4.4 g, 41 mmol) to afford the desired product (4.5 g, 50 % yield) as a brown solid: ESI MS m/z 291 [C]4Hi4N2O3S + H]+.
STEP 2: Synthesis of Methyl 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-5-carboxylate
Figure imgf000028_0003
Following the procedure outlined for step 2 in Example 1 , methyl
3-methoxy-4-(thiophene-2-carboximidamido)benzoate hydrochloride (4.5 g, 13 mmol) was reacted with NaOCl followed by satd. aq NaHCO3 to afford the desired product (3.1 g, 78 % yield) as a brown solid: 1H NMR (300 MHz, DMSO-d6) delta 13.50 (s, IH), 13.27 (s, tautomer), 8.05-7.72 (m, 3H), 7.36-7.22 (m, 2H), 4.02 (s, 3H), 3.94 (s, 3H,); ESI MS m/z 289 [C4Hi2N2O3S + H]+. Page: 28/97
STEP 3: Synthesis of 7-Methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-5-carboxylic Acid
Figure imgf000029_0001
Following the procedure outlined for step 3 in Example 1 , methyl
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-5-carboxylate (1.5 g, 5.4 mmol) was reacted with sodium hydroxide to afford the desired product (quant.) as a brown solid: 1H NMR (300 MHz, DMSOd6) delta 8.05 (s, J = 3.0 Hz, IH), 7.83 (d, J = 4.8 Hz, IH), 7.80 (s, IH), 7.35 (s, IH), 7.29-7.26 (m, IH), 4.01 (s, 3H); ESI MS m/z 275 [Ci3Hi0N2O3S + H]+.
Example 3
STEP 1 : Synthesis of Methyl 3-(Furan-2-carboximidamido)-4-methoxybenzoate Hydrochloride
Figure imgf000029_0002
Following the procedure outlined for step 1 in Example 1, methyl 3-amino-4-methoxybenzoate (10 g, 55.2 mmol) was reacted with 2-furylcarbonitrile (8.0 g, 86 mmol) to afford the desired product (8.5 g, 49% yield) as an off-white solid: ESI MS m/z 275 [C]4Hi4N3O4 + H]+.
STEP 2: Synthesis of 2-(Furan-2-yl)-7-methoxy-lH-benzo[d]imidazole-4-carboxylic Acid
Figure imgf000029_0003
To a solution of methyl 3-(furan-2-carboximidamido)-4-methoxybenzoate Hydrochloride (8.5 g, 27 mmol) in methanol (60 mL) was added 5% aq NaOCl (60 mL, 41 mmol) and the reaction mixture was stirred at room temperature for 2 h. Next, satd. aq NaHCO3 (70 mL) and methanol (60 mL) were added and the resulting reaction mixture was heated at 90 degrees for 16 h. Then, 6 N NaOH (50 mL, 300 mmol) was added and the reaction mixture was heated at 90 degrees for an additional 3 h. The reaction mixture was cooled to room temperature and concentrated to remove methanol. The reaction mixture was acidified to pH 5 using 6 N HCl and the resulting precipitate was filtered and dried to afford desired product (4.0 g, 57% yield) as a brown solid: ESI MS m/z 261 [Ci3Hi0N2O4 + H]+.
STEP 3: Synthesis 2-(Furan-2-yl)-7-hydroxy-lH-benzo[d]imidazole-4-carboxylic Acid Page: 29/97
Figure imgf000030_0001
Following the procedure outlined for step 4 in Example 1 ,
2-(Furan-2-yl)-7-methoxy-lH-benzo[d]imidazole-4-carboxylic acid (2.0 g, 7.7 mmol) was reacted with boron tribromide (15 g, 60 mmol) to afford the desired product (1.2 g, 63% yield) as a brown solid: ESI MS m/z 245 [Ci2H8N2O4 + H]+.
Example 4 STEP 1 : Synthesis of Methyl 4-fluoro-3-(thiophene-2-carboximidamido)benzoate Hydrochloride
Figure imgf000030_0002
Following the procedure outlined for step 1 in Example, methyl 3-amino-4-fluorobenzoate (5 g, 29.6 mmol) was reacted with 2-thiophenecarbonitrile (6.5 g, 59.2 mmol) to afford the desired product (1.8 g) as a light brown solid: ESI MS m/z 279 [Ci3Hi 1FN2O2S + H]+. STEP 2: Synthesis of Methyl 7-fluoro-2-(thiophen-2-yl)- 1 H-benzo[d]imidazole-4-carboxylate
Figure imgf000030_0003
Following the procedure outlined for step 2 in Example 1 , methyl
4-fluoro-3-(thiophene-2-carboximidamido)benzoate hydrochloride (1.7 g, 6.0 mmol) was reacted with 5% aq NaOCl and satd. aq NaHCO3 to afford the desired product (0.21 g, 3% yield) as a yellow solid: ESI MS m/z 277 [Ci3H9FN2O2S + H]+.
STEP 3: Synthesis of 7-Fluoro-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic Acid
Figure imgf000030_0004
Following the procedure outlined for step 4 in Example 1 , methyl 7-fluoro-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylate (0.2 g, 0.7 mmol) was reacted Page: 30/97 with 3 N NaOH (10 mL) to afford the desired product (0.1 g crude) as an off-white solid: ESI MS m/z 263 [Ci2H7FN2O2S + H]+.
Example 5
STEP 1 : Synthesis of Methyl 3-(Cyclopropanecarboximidamido)-4-methoxybenzoate Hydrochloride
Figure imgf000031_0001
Following the procedure outlined for step 1 in Example 1, methyl 3-amino-4-methoxybenzoate (10 g, 55 mmol) was reacted with cyclopropanecarbonitrile (7.4 g, 110 mmol) to afford the desired product (lo g crude) as a black solid: ESI MS m/z 249 [C13H16N2O3 + H]+.
STEP 2: Synthesis of Methyl 2-Cyclopropyl-7-memoxy-lH-benzo[d]imidazole-4-carboxylate
Figure imgf000031_0002
Following the procedure outlined for step 2 in Example 1 , methyl
3-(cyclopropanecarboximidamido)-4-methoxybenzoate hydrochloride (15 g, 50 mmol) was reacted with aq NaOCl followed by satd. aq NaHCO3 to afford the desired product (12 g crude) as a brown solid: ESI MS mlz 247 [C13Hi4N2O3 + H]+.
STEP 3: Synthesis of 2-Cyclopropyl-7-methoxy-lH-benzo[d]imidazole-4-carboxylic Acid
Figure imgf000031_0003
Following the procedure outlined for step 3 in Example 1 , methyl
2-cyclopropyl-7-methoxy-lH-benzo[^irnidazole-4-carboxylate (2.0 g, 8.0 mmol) was reacted with sodium hydroxide to afford the desired product (1.7 g crude) as a black solid: ESI MS m/z 233 [Ci2Hi2N2O3 + H]+.
STEP 4: Synthesis of 2-Cyclopropyl-7-hydroxy-l/f-benzo[d]imidazole-4-carboxylic Acid Page: 31/97
Figure imgf000032_0001
Following the procedure outlined for step 4 in Example 1,
2-cyclopropyl-7-methoxy-lH-benzo[d]imidazole-4-carboxylic acid (1.5 g, 6.1 mmol) was reacted with boron tribromide to afford the desired product (1.2 g crude) as a black solid: ESI MS m/z 219 [C, 1Hi0N2O3 + H]+.
Example 6
STEP 1 : Synthesis of Methyl 3-(Cyclopentanecarboximidamido)-4-methoxybenzoate Hydrochloride
Figure imgf000032_0002
Following the procedure outlined for step 1 in Example 1, methyl 3-amino-4-methoxybenzoate (5.0 g, 27 mmol) was reacted with cyclopentanecarbonitrile (5.2 g, 55 mmol) to afford the desired product (7.7 g crude) as a brown solid: ESI MS m/z 277 [CiSH20N2O3+ H]+.
STEP 2: Synthesis of Methyl 2-Cyclopentyl-7-methoxy-lH-benzo[d]imidazole-4-carboxylate
Figure imgf000032_0003
Following the procedure outlined for step 2 in Example 1 , methyl
3-(cyclopentanecarboximidamido)-4-methoxybenzoate hydrochloride (5.6 g, 18 mmol) was reacted with aq NaOCl followed by satd. aq NaHCO3 to afford the desired product (4.9 g crude) as a black solid: ESI MS m/z 275 [Ci5H18N2O3 + H]+.
STEP 3: Synthesis of 2-Cyclopentyl-7-hydroxy-lH-benzo[d]imidazole-4-carboxylic Acid
Figure imgf000032_0004
Following the procedure outlined for step 4 in Example 1 , methyl 2-cyclopentyl-7-methoxy-lH-benzo[d]imidazole-4-carboxylate (1.1 g, 4.0 mmol) was reacted Page: i'lm with boron tribromide to afford the desired product (0.92 g crude) as a black solid: ESI MS m/z 247 [CnH14N2O3 + H]+.
Example 7
STEP 1 : Synthesis of Methyl 3-Benzimidamido-4-methoxybenzoate Hydrochloride
Figure imgf000033_0001
Following the procedure outlined for step 1 in Example 1, methyl 3-amino-4-methoxybenzoate (5.0 g, 27 mmol) was reacted with benzonitrile (5.7 g, 55 mmol) to afford the desired product (7.8 g crude) as a black solid: ESI MS m/z 285 [Ci6Hi6N2O3+ H]+.
STEP 2: Synthesis of Methyl 7-Methoxy-2-phenyl-lH-benzo[d]imidazole-4-carboxylate
Figure imgf000033_0002
Following the procedure outlined for step 2 in Example 1 , methyl
3-benzimidamido-4-methoxybenzoate hydrochloride (2.0 g, 8.0 mmol) was reacted with aq NaOCl followed by satd. aq NaHCO3 to afford the desired product (1.7 g crude) as an off-white solid: ESI MS m/z 283 [C]6H]4N2O3 + H]+.
STEP 3: Synthesis of 7-Hydroxy-2-phenyl-lH-benzo[d]imidazole-4-carboxylic Acid
Figure imgf000033_0003
Following the procedure outlined for step 4 in Example 1 , methyl 7-methoxy-2-phenyl-lH-benzo[d]imidazole-4-carboxylate (4.0 g, 12 mmol) was reacted with boron tribromide to afford the desired product (2.1 g, crude) as a black solid: ESI MS mlz 255 [Ci4H10N2O3 + H]+.
General Procedure A - synthesis of compounds of formula I-II as described in Scheme (1): To a solution of acid (1.0 equiv) in DMF (5-10 mL) was added HATU (1.2-1.5 equiv), DIPEA (3.0-5.0 equiv), and the amine (1.5-2.0 equiv) and the reaction mixture was either stirred at room temperature for 16 h or heated at 50-70 degrees for 16 h. The reaction mixture was diluted with Page: 33/97 satd. aq NaHCO3 (20 mL) and extracted with ethyl acetate (3x20 niL). The combined organic layer was dried OVCr Na2SO4, concentrated, and purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA). The desired product was obtained as the trifluoroacetic acid salt which was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired products. In some instances the desired product was treated with TFA (1-2 mL) for 1 h, concentrated and purified by preparative HPLC (Cl 8 silica, 10-90% acetonitrile/water with 0.05% TFA). The desired product was obtained as the trifluoroacetic acid salt which was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired products
Example 8 7-Hydroxy-N-(4-sulfamoylbenzyl)-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamide
Figure imgf000034_0001
Following General Procedure A,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (125 mg, 0.36 mmol) was reacted with 4-(aminomethyl)benzenesulfonamide (0.13 g, 0.72 mmol) to afford the desired product (30 mg, 19% yield) as a light yellow solid: 1H NMR (300 MHz, CD3OD) delta 7.94-7.79 (m, 4H), 7.67-7.59 (m, 3H), 7.20-7.16 (m, IH), 6.71 (d, J = 8.1 Hz, IH), 4.82 (s, 2H); ESI MS m/z 429 [C19H16N4O4S2 + H]+; HPLC 98.4% (AUC), tR = 11.94 min.
Example 9 N-(2,4-Difluorobenzyl)-7-hydroxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamide
Figure imgf000034_0002
Following General Procedure A,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (125 mg, 0.36 mmol) was reacted with (2,4-difluorophenyl)methanamine (0.10 g, 0.72 mmol) to afford the desired product (33 mg, 24% yield) as an off-white solid: 1H NMR (300 MHz, CD3OD) delta 7.85-7.78 (m, 2H), 7.62-7.57 (m, 2H), 7.20-7.17 (m, IH), 7.01-6.95 (m, 2H), 6.71 (d, J = 8.4 Hz, IH), 4.75 (s, 2H); ESI MS m/z 368 [C19H13F2N3O2S + H]+; HPLC 96.2% (AUC), tR = 14.47 min.
Example 10 Page: 34/97
7-Hydroxy-N-(thiazol-2-yl)-2-(thiophen-2-yl)-l//-benzo[^]imidazole-4-carboxaniide
Figure imgf000035_0001
Following General Procedure A,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (146 mg, 0.43 mmol) was reacted with thiazol-2-amine (0.072 g, 0.72 mmol) to afford the desired product (15 mg, 10% yield) as a light brown solid: 1H NMR (300 MHz, CD3OD) delta 8.02-8.00 (m, IH), 7.93 (d, J = 8.4 Hz, IH), 7.69 (d, J = 5.1 Hz, IH), 7.54-7.53 (m, IH), 7.25-7.17 (m, 2H), 6.79 (d, J = 8.4 Hz, IH); ESI MS m/z 343 [C15H10N4O2S2 + H]+; HPLC >99% (AUC), tR = 14.10 min.
Example 11
7-Hydroxy-N-[2-(pyridin-2-ylamino)ethyl]-2-(thiophen-2-yl)-lH- benzo[d]imidazole-4-carboxamide
Figure imgf000035_0002
Following General Procedure A,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (0.24 g, 0.91 mmol) was reacted with N1-(pyridin-2-yl)ethane-l,2-diamine (0.098 g, 0.72 mmol) to afford the desired product (114 mg, 33% yield) as a white solid: 1H NMR (500 MHz, DMSO-d6) 8.00-7.96 (m, 2H), 7.72-7.70 (m, 2H), 7.36 (dd, J = 3.0, 1.5 Hz, IH), 7.21 (t, J = 4.0 Hz, IH), 6.73 (d, J = 8.5 Hz, IH), 6.53 (d, J = 8.5 Hz, IH), 6.48 (t, J = 1.0 Hz, IH), 3.62 (t, J = 6.5 Hz, 2H), 3.48 (t, J = 6.5 Hz, 2H); ESI MS m/z 380 [C]9Hi7N5O2S + H]+; HPLC >99% (AUC), tR = 11.12 min.
Example 12
7-Hydroxy-N-[3-(2-hydroxyethylamino)propyl]-2-(thiophen-2-yl)-lH- benzo [d] imidazole-4-carboxamide Page: 35/97
Figure imgf000036_0001
Following General Procedure A,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (0.15 g, 0.58 mmol) was reacted with 2-(3-aminopropylamino)ethanol (0.084 g, 0.72 mmol) to afford the desired product (31 mg, 15% yield) as a yellow-brown solid: 1B. NMR (500 MHz, CD3OD) 7.86 (dd, J = 3.5, 1.0 Hz, IH), 7.76 (d, J = 8.5 Hz, IH), 7.62 (dd, J = 5.0, 1.0 Hz, IH), 6.66 (d, J = 8.5 Hz, IH), 3.73 (t, J = 5.0 Hz, 2H), 3.64 (t, J = 6.5 Hz, 2H), 2.99 (t, J = 7.0 Hz, 2H), 2.94 (t, J = 5.5 Hz, 2H), 2.02-1.99 (m, 2H); ESI MS m/z 361 [C17H20N4O3S + H]+.
Example 13
(S)-Methyl 2-[7-Hydroxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamido]-
3-(lH-imidazol-5-yl)propanoate
Figure imgf000036_0002
Following General Procedure A, 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (150 mg, 0.57 mmol) was reacted with (S)-methyl 2-amino-3-(lH-imidazol-5-yl)propanoate (0.12 g, 0.72 mmol) to afford the desired product (66 mg, 23% yield) as a light yellow solid: 1H NMR (500 MHz, CD3OD) delta 7.85 (d, J = 3.6 Hz, 1H),7.74 (d, J = 8.3 Hz, IH), 7.62 (d, J = 4.2 Hz, IH) 7.58 (s, IH) 7.19 (t, J = 4.9 Hz, IH), 7.03 (s, IH), 6.69 (d, J = 8.3 Hz, IH) 5.01-4.99 (m, IH), 3.77 (s, 3H); ESI MS m/z 412 [C19H17N5O4S + H]+; HPLC 96.3% (AUC), tR = 7.94 min.
Example 14
(S)-Methyl 2- [7-Hydroxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazole-4-carboxamido] -
3 -( 1 H-indol-3 -yl)propanoate Page: 36/97
Figure imgf000037_0001
Following General Procedure A,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (150 mg, 0.57 mmol) was reacted with (S)-methyl 2-amino-3-(lH-indol-3-yl)propanoate (0.16 g, 0.72 mmol) to afford the desired product (65 mg, 13% yield) as a light yellow solid: 1H NMR (500 MHz, CD3OD) delta 7.77-7.58 (m, 2H), 7.58-7.56 (m, 2H), 7.28 (d, J = 6.0 Hz, 2H), 7.16 (t, J = 4.9 Hz, IH), 7.04 (t, J = 7.5 Hz, IH), 6.94 (t, J = 15.1 Hz, IH), 6.68 (d, J = 8.3 Hz, IH), 5.04 (t, J = 6.3 Hz, IH), 3.69 (s, 3H) 3.45 (d, J = 6.25 Hz, 2H); ESI MS m/z 461 [C24H20N4O4S + H]+; HPLC 98.7% (AUC), tR = 13.03 min.
Example 15
Methyl 3 -Hydroxy-2- [7-hydroxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazole-4- carboxamidojpropanoate
Figure imgf000037_0002
Following General Procedure A,
7-methoxy-2-(thiophen-2-yl)-l H-benzo [d]imidazole-4-carboxylic acid (150 mg, 0.57 mmol) was reacted with methyl 2-amino-3-hydroxypropanoate (0.084 g, 0.72 mmol) to afford the desired product (20 mg, 10% yield) as a light yellow solid: 1H NMR (500 MHz, CD3OD) delta 7.94 (d, J = 3.2 Hz, IH), 7.80 (d, J = 8.3 Hz, IH), 7.67 (d, J = 4.8 Hz, IH), 7.21 (d, J = 4.8 Hz, IH), 6.73 (d, J = 8.3 Hz, IH), 4.11-4.05 (m, IH), 4.01-3.98 (m, IH), 3.82 (s, 3H); ESI MS m/z 362 [Ci6Hi5N3O5S + H]+; HPLC 95.0% (AUC), tR = 11.36 min.
Example 16
Methyl 2-[7-Hydroxy-2-(thiophen-2-yl)- 1 H-benzo [d]imidazole-4- carboxamido]-3-(4-hydroxyphenyl)propanoate Page: 37/97
Figure imgf000038_0001
Following General Procedure A,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (150 mg, 0.57 mmol) was reacted with methyl 2-amino-3-(4-hydroxyphenyl)propanoate (0.14 g, 0.72 mmol) to afford the desired product (15 mg, 6% yield) as a light yellow solid: 1H NMR (500 MHz, DMSO-d6) delta 13.45 (s, IH), 10.86 (s,lH), 9.85 (d, J = 6.8 Hz, IH), 9.18 (s, IH), 8.07 (d, J = 3.6 Hz, IH), 7.81 (d, J = 5.0 Hz, IH), 7.65 (d, J = 8.3 Hz, IH), 7.27 (t, J = 4.9 Hz, IH), 7.16 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 8.2 Hz, IH), 6.67 (d, J = 8.4 Hz, 2H), 4.71^1.68 (m, IH), 3.64 (s, 3H), 3.16-3.10 (m, IH), 3.01-2.96 (m, IH); ESI MS m/z 362 [C16Hi5N3O5S + H]+; HPLC 95.0% (AUC), tR = 11.36 min.
Example 17
(R)-7-Hydroxy-N- [ 1 -hydroxy-3 -( 1 H-imidazol-4-yl)propan-2-yl] -2-(thiophen-2-yl)- 1 H-benzo[d]i midazole-4-carboxamide
Figure imgf000038_0002
Following General Procedure A,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (150 mg, 0.57 mmol) was reacted with (R)-2-amino-3-(lH-imidazol-4-yl)propan-l-ol (0.10 g, 0.72 mmol) to afford the desired product (41 mg, 18% yield) as a light yellow solid: 1H NMR (500 MHz, CD3OD) delta 7.86 (d, J = 3.6 Hz, IH), 7.73 (d, J = 8.3 Hz, IH), 7.62 (d, J = 5.0 Hz, IH), 7.59 (s, IH), 7.20-7.18 (m, IH), 6.96 (s, IH), 6.68 (d, IH), 4.44^.41 (m, IH), 3.75 (d, J = 4.8 Hz, 2H), 3.16-3.09 (m, IH), 3.04-3.00 (m, IH); ESI MS m/z 383 [Ci8HnN5O3S + H]+.
Example 18
(S)-7-Hydroxy-N-(l -hydroxy-3, 3 -dimethylbutan-2-yl)-2-(thiophen-2-yl)- IH- benzo[d]imidazole-4-carboxamide Page: 38/97
Figure imgf000039_0001
Following General Procedure A,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (150 mg, 0.57 mmol) was reacted with (S)-2-amino-3,3-dimethylbutan-l-ol (0.084 g, 0.72 mmol) to afford the desired product (24 mg, 12% yield) as a light yellow solid: 1H NMR (500 MHz, CD3OD) delta 7.86 (d, J = 3.6 Hz, IH), 7.80 (d, J = 8.3 Hz, IH), 7.60 (d, J = 5.0 Hz, IH), 7.19 (t, J = 5.0 Hz, IH), 6.71 (d, J = 8.3 Hz, IH), 4.08^1.06 (m, IH), 3.96-3.93 (m, IH), 3.73-3.69 (m, IH), 1.14 (s, 9H); ESI MS m/z 362 [C18H21N3O3S + H]+; HPLC > 99% (AUC), tR = 13.85 min.
Example 19
(S)-7-Hydroxy-N-( 1 -hydroxy-3 -phenylpropan-2-yl)-2-(thiophen-2-yl)- 1 H- benzo[d]imidazole-4-carboxamide
Figure imgf000039_0002
Following General Procedure A,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (200 mg, 0.73 mmol) was reacted with (S)-2-amino-3-phenylpropan-l-ol (0.11 g, 0.72 mmol) to afford the desired product (55 mg, 19% yield) as a light yellow solid: 1H NMR (500 MHz, CD3OD) delta 7.87 (d, J = 3.7 Hz, IH), 7.73 (d, J = 8.3 Hz, IH), 7.63 (d, J = 4.0 Hz, IH), 7.38 (d, J = 7.1 Hz, 2H), 7.21-7.19 (m, 3H), 7.11 (t, J = 13.6 Hz, IH), 6.67 (d, J = 8.3 Hz, IH), 4.40^.37 (m, IH), 3.75-3.68 (m,
2H), 3.16-3.12 (m, IH) 3.01-2.97 (m, IH); ESI MS m/z 394 [C21Hi9N3O3S + H]+; HPLC > 99% (AUC), tR = 13.67 min.
Example 20 7-Hydroxy-2-(thiophen-2-y I)-N- [2-(thiophen-2-yl)ethyl] - 1 H-benzo [d] imidazole-4-carboxamide Page: 39/97
Figure imgf000040_0001
Following General Procedure A,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (150 mg, 0.577 mmol) was reacted with 2-(thiophen-2-yl)ethanamine (0.087 g, 0.72 mmol) to afford the desired product (42 mg, 20% yield) as a light yellow solid: 1H NMR (500 MHz, CD3OD) delta 7.82 (d, J = 3.3 Hz, IH) 7.79 (d, J = 8.3 Hz, IH), 7.62-7.61 (m, IH), 7.18 (t, J = 9.9 Hz, 2H), 6.99 (s, IH), 6.91 (t, J = 8.6 Hz, IH), 6.69 (d, J = 8.3 Hz, IH), 3.81 (t, J = 6.7 Hz, 2H), 3.23 (t, J = 6.7 Hz, 2H); ESI MS m/z 370 [Ci8Hi5N3O2S2 + H]+; HPLC > 99% (AUC), tR = 12.80 min.
Example 21
7-Hydroxy-N-(4-sulfamoylphenethyl)-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamide
Figure imgf000040_0002
Following General Procedure A, 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (150 mg, 0.577 mmol) was reacted with 4-(2-aminoethyl)benzenesulfonamide (0.14 g, 0.72 mmol) to obtain the desired product (18.3 mg, 7%) as an off-white solid: 1H NMR (500 MHz, CD3OD) delta 7.83-7.81 (m, 3H), 7.76 (d, J = 8.1 Hz, IH) 7.62 (d, J = 4.8 Hz, IH), 7.54 (d, J = 7.6 Hz, 2H), 7.18 (t, J = 8.8 Hz, IH), 6.68 (d, J = 8.2 Hz, IH), 3.85 (t, J = 11.5 Hz, 2H), 3.11 (t, J = 6.1 Hz, 2H); ESI MS m/z 443 [C20Hi8N4O4S2 + H]+; HPLC >99% (AUC), tR = 12.14 min.
Example 22 7-Hydroxy-N-(3-methoxyphenethyl)-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamide Page: 4ϋ/y7
Figure imgf000041_0001
Following General Procedure A,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (150 mg, 0.58 mmol) was reacted with 2-(3-methoxyphenyl)ethanamine (0.11 g, 0.72 mmol) to obtain the desired product (24 mg, 11% yield) as a light yellow solid: 1H NMR (500 MHz, DMSO-d6) delta 8.14 (d, J = 0.5 Hz, IH), 8.00 (d, J = 1.0 Hz, IH), 7.78 (d, J = 4.0 Hz, IH), 7.77-7.17 (m, 2H), 6.93-6.82 (m, 2H), 6.75-6.70 (m, IH). 3.73-3.65 (m, 5H), 2.92-2.82 (m, 2H); ESI MS m/z 394 [C2[H19N3O3S + H]+; HPLC 95.7% (AUC), tR = 14.24 min.
Example 23 7-hydroxy-N-(3-methoxyphenethyl)-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamide
Figure imgf000041_0002
Following General Procedure A,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (150 mg, 0.58 mmol) was reacted with 2-(4-methoxyphenyl)ethanamine (0.11 g, 0.72 mmol) to obtain the desired product (30 mg, 9% yield) as a light yellow solid: 1H NMR (500 MHz, DMSOd6) 8.01 (d, J = 3.5 Hz, IH), 7.81 (s, IH), 7.77 (d, J = 5.0, IH), 7.26-7.23 (m, 3H), 6.86-6.82 (m, 2H), 6.73-6.70 (m, 2H), 3.71-3.63 (m, 5H), 2.87-2.63 (m, 2H); ESI MS m/z 394 [C2iH19N3O3S + H]+; HPLC 94.5% (AUC), tR = 14.29 min.
General Procedure B - synthesis of amides F as described in Scheme (1):
To a suspension of 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (1.0 equiv) in toluene (5-15 mL) was added thionyl chloride (4.0 equiv). After stirring at room temperature for 16 h, the reaction mixture was heated at 70 degrees for 2 h. The reaction mixture was cooled, and concentrated, and the residue was suspended in THF (10-20 mL) followed by the addition of pyridine (2.0 equiv) and the corresponding amine (2.0 equiv) and the reaction mixture was heated at 70 degrees for 16 h. The reaction mixture was concentrated and the residue was diluted with water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with satd. aq NaHCO3 (20 mL), concentrated, and purified by flash chromatography (silica, 0-15% methanol/dichloromethane) to afford amides F. In Page: 41/97 most cases these intermediates were isolated as crude products and were carried forward without extensive characterization or further purification.
Example 24
7-Methoxy-N-[2-(l-methyl-lH-imidazol-5-yl)ethyl]-2-(thiophen-2-yl)-lH- benzo [d] imidazole-4-carboxamide
Figure imgf000042_0001
Following General Procedure B, 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (170 mg, 0.62 mmol) was reacted with 2-(l -methyl- lH-imidazol-5-yl)ethanamine (0.15 g, 1.2 mmol) to afford the desired product (170 mg) as a yellow solid: ESI MS m/z 382 [C19H19N5O2S + H]'
Example 25
N-[2-(Dimethylamino)ethyl]-7-methoxy-2-(thiophen-2-yl)-lH- benzo [d] imidazole-4-carboxamide
Figure imgf000042_0002
Following General Procedure B, 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (160 mg, 0.58 mmol) was reacted with N τl , xNτl -dimethylethane- 1 ,2-diamine (0.10 g, 1.2 mmol) to afford the desired product (136 mg) as a brown glass: ESI MS m/z 345 [Ci7H20N4O2S + H]+.
Example 26 N-(3,4-Dimethoxybenzyl)-7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamide Page: 4^/y /
Figure imgf000043_0001
Following General Procedure B,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (158 mg, 0.58 mmol) was reacted with (3,4-dimethoxyphenyl)methanamine (0.20 g, 1.2 mmol) to afford the desired product (248 mg) as a brown solid: ESI MS m/z 424 [C22H2[N3O4S + H]+.
Example 27
7-Methoxy-N-[2-(phenylsulfonamido)ethyl]-2-(thiophen-2-yl)-lH- benzo [d] imidazole-4-carboxamide .
Figure imgf000043_0002
Following General Procedure B,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (0.18 g, 0.65 mmol) was reacted with N-(2-aminoethyl)benzenesulfonamide (0.26 g, 1.3 mmol) to afford the desired product (0.15 g, 51% yield) as an off-white solid: ESI MS m/z 457 [C21H20N4O4S2 + H]+.
Example 28
N-[2-(4-Chlorophenylsulfonamido)ethyl]-7-methoxy-2-(thiophen-2-yl)-lH- benzo [d] imidazole-4-carboxamide
Figure imgf000043_0003
Following General Procedure B,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (0.20 g, 0.73 mmol) was reacted with N-(2-aminoethyl)-4-chlorobenzenesulfonamide (0.34 g, 1.5 mmol) to afford the desired product (0.16 g, 45% yield) as an off-white solid: ESI MS m/z 491 [C2IHi9ClN4O4S2 + H]+. Page: 43/97
Example 29
7-Methoxy-N-[2-(pyridine-4-sulfonamido)ethyl]-2-(thiophen-2-yl)-lH- benzo[d]imidazole-4-carboxamide
Figure imgf000044_0001
Following General Procedure B,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (0.20 g, 0.73 mmol) was reacted with N-(2-aminoethyl)pyridine-4-sulfonamide (0.29 g, 1.5 mmol) to afford the desired product (0.069 g, 21% yield) as an off-white solid: ESI MS m/z 458 [C20H19N5O4S2 + H]+.
Example 30
7-Methoxy-N-[2-(4-methylbenzamido)ethyl]-2-(thiophen-2-yl)-lH- benzo [d] imidazole-4-carboxamide
Figure imgf000044_0002
Following General Procedure B,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (0.20 g, 0.73 mmol) was reacted with N-(2-aminoethyl)-4-methylbenzamide (0.27 g, 1.5 mmol) to afford the desired product (0.24 g, 76% yield) as an off-white solid: ESI MS m/z 435 [C23H22N4O3S + H]+.
Example 31 N-(2-Acetamidoethyl)-7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamide
Figure imgf000044_0003
Following General Procedure B,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (0.10 g, 0.36 mmol) was Page: 44/97 reacted with N-(2-aminoethyl)acetamide (0.073 g, 0.72 mmol) to afford the crude desired product as an off-white solid: ESI MS m/z 356 [C17Hi8N4O3S + H]+.
Example 32
N- [3 -(Isopropylamino)propyl] -7-methoxy-2-(thiophen-2-yl)- 1 H- benzo[d]imidazole-4-carboxamide
Figure imgf000045_0001
Following General Procedure B, 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (0.20 g, 0.73 mmol) was reacted with N '-isopropylpropane- 1,3 -diamine (0.17 g, 1.5 mmol) to afford the desired product as an off-white solid: ESI MS m/z 373 [C19H24N4O2S + H]+.
Example 33 N-(4-Fluorophenethyl)-7-methoxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazole-4-carboxamide
Figure imgf000045_0002
Following General Procedure B,
7-methoxy-2-(thiophen-2-yl)-l H-benzo [d]imidazole-4-carboxylic acid (0.20 g, 0.73 mmol) was reacted with 2-(4-fluorophenyl)ethanamine (0.21 g, 1.5 mmol) to afford the desired product (0.14 g) as an off-white solid: ESI MS m/z 396 [C2]Hi8FN3O2S + H]+.
Example 34 N-(4-Hydroxyphenethyl)-7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamide Page: 45/97
Figure imgf000046_0001
Following General Procedure B,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (0.20 g, 0.73 mmol) was reacted with 4-(2-aminoethyl)phenol (0.20 g, 1.5 mmol) to afford the desired product (0.31 g) as an off-white solid: ESI MS m/z 393 [C2iH19N3O3S + H]+.
General Procedure C - synthesis of compounds of formula (I-III) as described in Scheme (1):
To a suspension of amides F (1.0 equiv) in dichloroethane (10-25 mL) was added boron tribromide (6.0-10 equiv) and the reaction mixture was heated at 80 degrees for 16 h. The reaction mixture was poured over ice and the resulting mixture was concentrated. The crude residue was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) as a crude purification. The crude product was further purified by preparative HPLC (Cl 8 silica, 10-90% acetonitrile/water with 0.05% TFA). The desired product was obtained as the trifluoroacetic acid salt which was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired products.
Example 35
7-Hydroxy-N- [2-( 1 -methyl- 1 H-imidazol-5-yl)ethyl] -2-(thiophen-2-yl)- 1 H- benzo[d]imidazole-4-carboxamide.
Figure imgf000046_0002
Following General Procedure C,
7-Methoxy-N-[2-(l-methyl-l//-imidazol-5-yl)ethyl]-2-(thiophen-2-yl)-l//-benzo[ύ0imidazole-4- carboxamide (170 mg) was reacted with boron tribromide to afford the desired product (36 mg, 16% yield) as a white solid: 1H NMR (300 MHz, DMSO-d6) delta 13.40 (s, IH), 10.78 (s, IH), 9.55 (s, IH), 8.03 (s, IH), 7.79-7.69 (m, 2H), 7.51 (s, IH), 7.26-7.23 (m, IH), 6.96 (s, IH), 6.72 (d, J = 8.1 Hz, IH), 3.68-3.66 (m, 2H), 3.56 (s, 3H), 2.76 (t, J = 6.9 Hz, IH); ESI MS m/z 368 [Ci8H17N5O2S + H]+; HPLC >99% (AUC), tR = 10.67 min. Page: 46/97
Example 36 N-[2-(dimethylamino)ethyl]-7-hydroxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamide
Figure imgf000047_0001
Following General Procedure C,
N- [2-(Dimethylamino)ethyl] -7-methoxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazole-4- carboxamide (136 mg) was reacted with boron tribromide to afford the desired product (69 mg, 35% yield) as a light yellow solid: 1H NMR (300 MHz, CD3OD) delta 7.88-7.87 (m, IH), 7.76 (d, J = 8.4 Hz, IH), 7.64-7.62 (m, IH), 7.22-7.19 (m, IH), 6.68 (d, J = 8.4 Hz, IH), 3.69 (t, J = 6.6 Hz, 2H), 2.75 (t, J = 6.6 Hz, IH), 2.43 (s, 6H); ESI MS m/z 331 [Ci6Hi8N4O2S + H]+; HPLC >99% (AUC), tR = 8.68 min.
Example 37
N-(3,4-Dihydroxybenzyl)-7-hydroxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamide
Figure imgf000047_0002
Following General Procedure C,
JV-(3,4-Dimethoxybenzyl)-7-methoxy-2-(thiophen-2-yl)-lH-benzo[<i]imidazole-4-carboxamide (248 mg) was reacted with boron tribromide to afford the desired product (18 mg, 8% yield) as a brown solid: 1H NMR (300 MHz, CD3OD) delta 7.98-7.97 (m, IH), 7.82 (d, J = 8.4 Hz, IH), 7.77 (d, J = 4.5 Hz, IH), 7.28-7.25 (m, IH), 6.90 (s, IH), 6.83-6.77 (m, 3H), 4.55 (s, 2H); ESI MS m/z 382 [C]9H15N3O4S + H]+; HPLC 97.0% (AUC), tR = 11.73 min.
Example 38 7-Hydroxy-N-[2-(phenylsulfonamido)ethyl]-2-(thiophen-2-yl)- 1 H- benzo [d] imidazole-4-carboxamide Page: 47/97
Figure imgf000048_0001
Following General Procedure C,
7-Methoxy-N-[2-(phenylsulfonamido)ethyl]-2-(thiophen-2-yl)-lH-benzo[(f]imidazole-4- carboxamide (150 mg) was reacted with boron tribromide to afford the desired product (36 mg, 37% yield) as an off-white solid: 1U NMR (500 MHz, CD3OD) delta 7.91 (t, J = 3.6 Hz, IH), 7.82 (d, J = 7.5 Hz, 2H), 7.74 (d, J = 8.2 Hz, IH), 7.64 (d, J = 4.9 Hz, IH), 7.40 (t, J = 7.1 Hz, IH), 7.34-7.3 l(m, 2H), 7.21 (dd, J = 5.0, 3.7 Hz, IH), 6.69 (d, J = 8.3 Hz, IH), 3.60 (t, J = 6.1 Hz, 2H), 3.19 (t, J = 5.9 Hz, 2H); ESI MS m/z 443 [C20H18N4O4S2 + H]+; HPLC >99% (AUC), tR = 12.63 min.
Example 39
N-[2-(4-Chlorophenylsulfonamido)ethyl]-7-hydroxy-2-(thiophen-2-yl)-lH- benzo [d] imidazole-4-carboxamide
Figure imgf000048_0002
Following General Procedure C,
N-[2-(4-Chlorophenylsulfonamido)ethyl]-7-methoxy-2-(thiophen-2-yl)-l//-benzo[<i]imidazole-4 -carboxamide (160 mg) was reacted with boron tribromide to afford the desired product (17 mg, 18% yield) as an off-white solid: 1H NMR (500 MHz, CD3OD) delta 7.90 (d, J = 0.9 Hz, IH), 7.74-7.69 (m, 3H), 7.64 (d, J = 4.8 Hz, IH), 7.22 (t, J = 3.9 Hz, IH), 7.14 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.4 Hz, IH), 3.59-3.57 (m, 2H), 3.26-3.24 (m, 2H); ESI MS m/z 477 [C20Hi7ClN4O4S2 + H]+; HPLC >99% (AUC), tR = 13.39 min.
Example 40 7-Hydroxy-N-[2-(pyridine-4-sulfonamido)ethyl]-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-car boxamide
Figure imgf000048_0003
Page: 48/97
Following General Procedure C,
7-Methoxy-N-[2-(pyridine-4-sulfonamido)ethyl]-2-(thiophen-2-yl)-lH-benzo[tf]imidazole-4- carboxamide (69 mg) was reacted with boron tribromide to afford the desired product (14 mg, 21% yield) as an off-white solid: 1H NMR (500 MHz, CD3OD) delta 8.93 (d, J = 2.0 Hz, IH), 8.52 (d, J = 4.2 Hz, IH), 8.19 (d, J = 8.0 Hz, IH), 8.02 (d, J = 3.4 Hz, IH), 7.80 (d, J = 5.0 Hz, IH), 7.72 (d, J = 8.4 Hz, IH), 7.39-7.35 (m, IH), 7.29 (dd, J = 4.9, 3.9 Hz, IH), 6.78 (d, J = 8.4 Hz, IH), 3.58 (t, J = 6.0 Hz, 2H), 3.27-3.25 (m, 2H); ESI MS m/z 444 [Ci9HnN5O4S2 + H]+; HPLC 98.5% (AUC), tR = 11.28 min.
Example 41
7-Hydroxy-N-[2-(4-methylbenzamido)ethyl]-2-(thiophen-2-yl)-lH- benzo[d]imidazole-4-carboxamide
Figure imgf000049_0001
Following General Procedure C,
7-Methoxy-7V- [2-(4-methylbenzamido)ethyl] -2-(thiophen-2-yl)- 1 H-benzo [d]imidazole-4- carboxamide (0.24 g) was reacted with boron tribromide to afford the desired product (165 mg, 71% yield) as an off-white solid: 1H NMR (500 MHz, CD3OD) delta 8.26 (dd, J = 3.8, 1.0 Hz, IH), 8.10 (dd, J = 5.0, 1.0 Hz, IH), 7.82 (d, J = 8.4 Hz, IH), 7.70 (d, J = 8.2 Hz, 2H), 7.42 (dd, J = 4.9, 3.9 Hz, IH), 7.23 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.4 Hz, IH), 3.68 (s, 4H), 2.35 (s, 3H); ESI MS m/z 421 [C9H17N5O4S2 + H]+; HPLC 95.8% (AUC), tR = 12.69 min.
Example 42 N-(2-Acetamidoethyl)-7-hydroxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamide
Figure imgf000049_0002
Following General Procedure C,
N-(2-Acetamidoethyl)-7-methoxy-2-(thiophen-2-yl)-l//-benzo[<i]imidazole-4-carboxamide (73 mg) was reacted with boron tribromide to afford the desired product (28 mg, 25% yield) as a light brown solid: 1H NMR (500 MHz, CD3OD) 7.88 (d, J = 3.5 Hz, IH), 7.79 (d, J = 8.5 Hz, IH), 7.63 (d, J = 5.0 Hz, IH), 7.20 (t, J = 4.5 Hz, IH), 6.70 (d, J = 8.0 Hz, IH), 3.67 (t, J = 6.0 Hz, 2H), 3.47 (t, J = 6.0 Hz, 2H), 1.96 (s, 3H); ESI MS m/z 345 [Ci6Hi6N4O3S + H]+. Page: 49/97
Example 43
N-[3-(Isopropylamino)propyl]-7-hydroxy-2-(thiophen-2-yl)-lH- benzo [d] imidazole-4-carboxamide
Figure imgf000050_0001
Following General Procedure C,
N- [3 -(Isopropylamino)propyl] -7-methoxy-2-(thiophen-2-yl)- 1 H-benzo [ </]imidazole-4- carboxamide (170 mg) was reacted with boron tribromide to afford the desired product (32 mg, 12% yield) as a light brown solid: 1H NMR (500 MHz, DMSO-d6) 9.50 (s, IH), 8.06 (d, J = 2.5 Hz, IH), 7.76 (d, J = 4.5 Hz, IH), 7.66 (d, J = 8.5 Hz, IH), 7.23 (dd, J = 5.0, 4.0 Hz, IH), 6.68 (d, J = 8.0 Hz, IH), 3.46 (t, J = 6.0 Hz, 2H), 2.81-2.78 (m, IH), 2.72 (t, J = 7.0 Hz, 2H), 1.75-1.72 (m, 6H); ESI MS m/z 359 [CnH18N4O3S + H]+; HPLC 98.2% (AUC), tR = 8.30 min.
Example 44 N-(4-Fluorophenethyl)-7-hydroxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamide
Figure imgf000050_0002
Following General Procedure C,
7V-(4-Fluorophenethyl)-7-methoxy-2-(thiophen-2-yl)-lH-benzo[(i]imidazole-4-carboxamide (140 mg) was reacted with boron tribromide to afford the desired product (17 mg, 13% yield) as a light brown solid: 1H NMR (500 MHz, DMSO-d6) 7.67 (bs, IH), 7.41-7.36 (m, 4H), 7.10-7.07 (m, 3H), 6.17 (d, J = 7.5 Hz, IH), 3.63-3.60 (m, 2H), 2.90 (t, J = 7.0 Hz, 2H); ESI MS m/z 382 [C20Hi6FN3O2S + H]+; HPLC 92.4% (AUC), tR = 14.48 min.
Example 45
7-Hydroxy-N-(4-hydroxyphenethyl)-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamide Page: 50/97
Figure imgf000051_0001
Following General Procedure C,
N-(4-Hydroxyphenethyl)-7-methoxy-2-(thiophen-2-yl)-l//-benzo[ύ(]imidazole-4-carboxamide (310 mg) was reacted with boron tribromide to afford the desired product (19 mg, 7% yield) as a brown solid: 1H NMR (500 MHz, CD3OD) 7.79-7.74 (m, 2H), 7.61-7.60 (m, IH), 7.19-7.15 (m, 3H), 6.71-6.65 (m, 3H), 3.74-3.71 (m, 2H), 2.92-2.89 (m, 2H); ESI MS m/z 380 [C20Hi7N3O3S + H]+; HPLC >99% (AUC), tR = 12.54 min.
Example 46 N-(2-Hydroxyethyl)-7-methoxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazole-4-carboxamide
Figure imgf000051_0002
A suspension of methyl 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylate (970 mg, 3.36 mmol) in ethanolamine (5 rnL) was heated at 100 degrees for 18 h. The reaction mixture was cooled and diluted with water (50 mL). The resulting precipitate was filtered and washed with water to afford the desired product (850 mg, 80% yield) as a brown solid: ESI MS m/z 318 [C15H15N3O3S + H]+.
Example 47
N-[2-(5-Carbamoylpyridin-2-yloxy)ethyl]-7-methoxy-2-(thiophen-2-yl)-lH- benzo [d] imidazole-4-carboxamide
Figure imgf000051_0003
Page: 51/97
To a solution of 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylate (100 mg, 0.31 mmol) in DMF (5 mL) was added NaH (60 mg, 1.5 mmol, 60% dispersion) and the suspension was stirred at room temperature for 1 h. Following the addition of 6-chloro-nicotinamide (74 mg, 0.47 mmol), the reaction mixture was heated at 85 degrees for 18 h. The reaction mixture was cooled and quenched with water (20 mL) and the pH was adjusted to 7. The resulting precipitate was filtered and washed with water to afford the desired product (105 mg, crude) as a brown solid: ESI MS m/z 438 [C2]Hi9N5O4S + H]+.
Example 48
7-methoxy-2-(thiophen-2-yl)-N-(2-(5-(trifluoromethyl)pyridin-2-yloxy)ethyl)- lH-benzo[d]imidazole-4-carboxamide
Figure imgf000052_0001
To a solution of 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylate (125 mg, 0.39 mmol) in DMF (5 mL) was added NaH (75 mg, 1.95 mmol, 60% dispersion) and the suspension was stirred at room temperature for 1 h. Following the addition of 2-chloro-5-trifluoromethyl-pyridine (143 mg, 0.78 mmol), the reaction mixture was heated at 85 degrees for 18 h. The reaction mixture was cooled and quenched with water (20 mL) and the pH was adjusted to 7. The resulting precipitate was filtered and washed with water to afford the desired product (180 mg, crude) as a brown solid: ESI MS m/z 463 [C2iH) 7F3N4O3S + H]+.
Example 49
N-[2-(5-Carbamoylpyridin-2-yloxy)ethyl]-7-hydroxy-2-(thiophen-2-yl)- lH-benzo[d]imidazole-4-carboxamide
Figure imgf000052_0002
Following General Procedure C,
N-(2-(5-carbamoylpyridin-2-yloxy)ethyl)-7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4 -carboxamide (0.24 mmol) was reacted with boron tribromide to afford the desired product (28 Page: 52/97 mg, 28% yield) as a light yellow solid: 1H NMR (300 MHz, CD3OD) delta 8.69-8.68 (m, IH), 8.12-8.09 (m, IH), 7.74-7.69 (m, 2H), 7.49 (d, J = 5.1 Hz, IH), 7.15-7.13 (m, IH), 6.98 (d, J = 8.7 Hz, IH), 6.48 (d, J = 8.4 Hz, IH), 4.64 (t, J = 5.1 Hz, 2H), 3.93 (t, J = 5.1 Hz, 2H); ESI MS m/z 424 [C20H17N5O4S + H]+; HPLC 98.9% (AUC), tR = 11.01 min.
Example 50
7-Hydroxy-2-(thiophen-2-yl)-N-[2-(5-(trifluoromethyl)pyridin-2-yloxy)ethyl]- lH-benzo[d]imidazole-4-carboxamide
Figure imgf000053_0001
Following General Procedure C,
7-methoxy-2-(thiophen-2-yl)-N-(2-(5-(trifluoromethyl)pyridin-2-yloxy)ethyl)-lH- benzo[d]imidazole-4-carboxamide (0.39 mmol) was reacted with boron tribromide to obtain the desired product (33 mg, 19% yield over 2 steps) as a white solid: 1H NMR (300 MHz, CD3OD) delta 8.42 (s, IH), 7.96-7.87 (m, 2H), 7.80-7.72 (m, 2H), 7.26-7.23 (m, IH), 7.01 (d, J = 9.0 Hz, IH), 6.77 (d, J = 8.4 Hz, IH), 4.67 (t, J = 5.1 Hz, 2H), 3.92 (t, J = 5.1 Hz, 2H); ESI MS m/z 449 [C20Hi5F3N4O3S + H]+; HPLC >99% (AUC), tR = 14.71 min.
Example 51 Methyl 3-(l-tosyl-lH-imidazol-2-yl)acrylate
Figure imgf000053_0002
To a suspension of l-tosyl-lH-imidazole-2-carbaldehyde (1.54 g, 6.2 mmol) in THF (75 mL) was added methyl(triphenylphosphoranylidene) acetate (2.46 g, 7.4 mmol) and the reaction mixture was heated at 75 degrees for 18 h. The reaction mixture was cooled, diluted with satd. aq NaHCO3, extracted with ethyl acetate (100 mL), dried over Na2SO4, and purified by column chromatography (silica, 0-50% ethyl acetate/heptane) to afford the desired product (1.43 g, 76 % yield) as a clear oil: ESI MS m/z 307 [Ci4H14N2O4S + H]+.
Example 52 Methyl 3-(l-tosyl-lH-imidazol-2-yl)propanoate
Figure imgf000053_0003
Page: 53/97
To a solution of methyl 3-(l-tosyl-lH-imidazol-2-yl)acrylate (1.43 g, 4.67 mmol) in MeOH (50 mL) was added cat. 10 wt % Pd/C (200 mg) and the reaction mixture was stirred under an atmosphere of hydrogen gas (1 atm) at room temperature for 18 h. The reaction mixture was filtered through diatomaceous earth, washed with MeOH, and concentrated to afford the desired product (1.35 g, 94 % yield) as a waxy solid: ESI MS m/z 309 [C]4Hi6N2O4S + H]+.
Example 53
Synthesis of 3 -( 1 -Tosyl- 1 H-imidazol-2-yl)propan- 1 -ol
Figure imgf000054_0001
To a solution of methyl 3-(l-tosyl-lH-imidazol-2-yl)propanoate (1.35 g, 4.39 mmol) in THF (50 mL) at 0 degree was added DIBAL (11.8 mL, 11.8 mmol, 1.0 M) and the reaction mixture was stirred forl .5 h. The reaction mixture was warmed to room temperature over 2 h, concentrated, and purified by column chromatography (silica gel, 0-75% ethyl acetate/heptane) to afford the desired product (492 mg, 40 % yield) as a white solid: ESI MS m/z 281 [C0H16N2O3S + H]+.
Example 54 2- [3 -( 1 -Tosyl- 1 H-imidazol-2-yl)propyl]isoindoline- 1 ,3 -dione
Figure imgf000054_0002
A solution of 3-(l-Tosyl-lH-imidazol-2-yl)propan-l-ol (492 mg, 1.75 mmol), triphenylphosphine (636 mg, 2.63 mmol), and phthalimide (386 mg, 2.63 mmol) in THF (20 mL) was cooled to 0 degree and diisopropyl azodicarboxylate (532 mg, 2.63 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate (75 mL), washed with water (30 mL) and brine (30 mL), dried over Na2SO4, and purified by column chromatography (silica gel, 0-75% ethyl acetate/heptane) to afford the desired product (698 mg, 97 % yield) as a white foam: ESI MS m/z 410 [C2iHi9N3O4S + H]+.
Example 55 3 -( 1 H-Imidazol-2-yl)propan- 1 -amine
Figure imgf000054_0003
Page: 54/97
To a suspension of 2-[3-(l-tosyl-lH-imidazol-2-yl)propyl]isoindoline-l,3-dione (698 mg, 1.70 mmol) in EtOH (25 mL) was added hydrazine hydrate (1.9 mL, 34 mmol) and the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled and the resulting solids were filtered and washed with EtOH. The filtrate was concentrated and the crude product was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to afford the desired product (330 mg, crude) as a clear oil: 1H NMR (300 MHz, CD3OD) delta 6.90 (s, 2H), 2.82-2.65 (m, 4H), 1.86 (p, J = 7.2 Hz, 2H).
Example 56
N-[3-(lH-Imidazol-2-yl)propyl]-7-methoxy-2-(thiophen-2-yl)-lH- benzo [d] imidazole-4-carboxamide.
Figure imgf000055_0001
Following General Procedure B, 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (0.15 g, 0.56 mmol) was reacted with 3-(lH-Imidazol-2-yl)propan-l-amine (0.14 g, 1.2 mmol) to afford the desired product (56 mg crude) as a tan solid: ESI MS m/z 382 [C19Hi9N5O2S + H]+.
Example 57
N-3-(lH-Imidazol-2-yl)propyl)-]7-hydroxy-2-(thiophen-2-yl)- lH-benzo[d] imidazole-4-carboxamide
Figure imgf000055_0002
Following General Procedure C,
N- [3 -( 1 H-Imidazol-2-yl)propyl] -7-methoxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazole-4-carboxa mide (0.15 mmol) was reacted with boron tribromide to afford the desired product (20 mg, 37% yield) as a light brown solid: 1H NMR (300 MHz, DMSO-d6) delta 13.45 (s, IH), 11.86 (s, IH), 10.81 (s, IH), 9.63 (s, IH), 8.07 (s, IH), 7.77-7.68 (m, 2H), 7.25-7.22 (m, IH), 6.88 (s, 2H), 6.73 (d, J = 8.1 Hz, IH,), 3.47-3.45 (m, 2H), 2.82-2.73 (m, 2H), 1.97 (p, J = 7.2 Hz, 2H); ESI MS m/z 368 [Ci8Hi7N5O2S + H]+; HPLC >99% (AUC), tR = 9.21 min.
Example 58 Page: 55/97 tert-Butyl 3-oxopropylcarbamate
Figure imgf000056_0001
To a solution of tert-butyl 3-hydroxypropylcarbamate (0.50 g, 2.8 mmol) in CH2Cl2 (30 niL) was added Dess-Martin periodinane (1.3 g, 3.1 mmol) and pyridine (450 mg, 5.7 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched by the addition of satd. aq NaHCO3 (20 mL) and solid Na2S2O3 (1.0 g). The layers were separated and the aqueous layer was extracted with diethyl ether (25 mL). The combined organic layers were dried over Na2SO4, concentrated, and purified by column chromatography (silica gel, 0-75% ethyl acetate/heptane) to afford the desired product (360 mg, 73 % yield) as an oil: 1H NMR (300 MHz, CDCl3) delta 9.83 (s, IH), 4.91 (s, IH), 3.44 (q, J = 5.9 Hz, 2H), 2.73 (t, J = 5.9 Hz, 2H), 1.45 (s, 9H).
Example 59 tert-Butyl 2-(4,5-dihydro-lH-imidazol-2-yl)ethylcarbamate
Figure imgf000056_0002
To a solution of tert-Butyl 3-oxopropylcarbamate (360 mg, 2.09 mmol) in t-BuOH (20 mL) was added ethylenediamine (138 mg, 2.3 mmol) and the reaction mixture was stirred at room temperature for 18 h. Potassium carbonate (867 mg, 6.27 mmol) and iodine (690 mg, 2.72 mmol) were added and the reaction mixture was heated at 70 degrees for 2 h. The reaction mixture was quenched by the addition of satd. aq Na2S2O3 (20 mL) and the pH was adjusted to 12 with 1 M NaOH. The reaction mixture was extracted with 3 : 1 CHC13/IPA (50 mL) and concentrated to afford the desired product (370 mg, 83% yield) as an orange oil: ESI MS m/z 214 [C10H19N3O2 + H]+.
Example 60 2-(lH-imidazol-2-yl)ethanamine
Figure imgf000056_0003
To a solution of tert-Butyl 2-(4,5-dihydro-lH-imidazol-2-yl)ethylcarbamate (370 mg, 1.73 mmol) in DMSO (5 mL) was added potassium carbonate (528 mg, 3.82 mmol) and iodobenzene diacetate (1.23 g, 3.82 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was heated at 50 degrees for 3 h, cooled, diluted with water (25 mL) and extracted with 3 : 1 CHCls/i-propanol (50 mL). The organic layer was dried over Na2SO4, Fage: 56/y/ concentrated, and the crude product was dissolved in CH2Cl2 (10 mL) followed by the addition of trifluoroacetic acid (2 mL) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated and the crude residue was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to afford the desired product (140 mg) as a brown solid: 1H NMR (300 MHz, CD3OD) delta 6.95 (s, 2H), 3.04-2.91 (m, 2H), 2.87-2.76 (m, 2H).
Example 61
N-[2-(lH-Imidazol-2-yl)ethyl]-7-methoxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazole-4-carboxamide
Figure imgf000057_0001
To a suspension of 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (0.34 g, 1.3 mmol) in toluene (15 mL) was added thionyl chloride (0.61 g, 5.2 mmol). After stirring at room temperature for 16 h, the reaction mixture was heated at 70 degrees for 2 h. The reaction mixture was cooled to room temperature and concentrated. The residue was suspended in THF (20 mL) followed by the addition of pyridine (98 mg, 2.6 mmol) and 2-(lH-imidazol-2-yl)ethanamine (140 mg) and the reaction mixture was heated at 70 degrees for 16 h. The reaction mixture was concentrated and the residue was diluted with water (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with satd. aq NaHCO3 (20 mL), concentrated, and purified by flash chromatography (silica, 0-15% methanol/dichloromethane) to afford the desired product: ESI MS m/z 368 [C1SHi7N5O2S + H]+.
Example 62 N-[2-(l H-Imidazol-2-y l)ethy 1] -7-hydroxy-2-(thiophen-2-yl)-
1 H-benzo [d] imidazole-4-carboxamide
Figure imgf000057_0002
Following General Procedure C, N-(2-(lH-imidazol-2-yl)ethyl)-7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxami de from Example 59 was reacted with boron tribromide to afford the desired product (5 mg, 3% Page: 57/97 yield) as a light brown solid: 1H NMR (300 MHz, CD3OD) delta 7.85-7.84 (m, IH), 7.74 (d, J = 8.4 Hz, IH), 7.63 (d, J = 5.1 Hz, IH), 7.21-7.18 (m, IH), 7.06 (s, 2H), 6.69 (d, J = 8.4 Hz, IH), 3.90 (t, J = 6.6 Hz, 2H), 3.15 (d, J = 6.6 Hz, IH); ESI MS m/z 354 [C17H15N5O2S + H]+; HPLC 97.7% (AUC), tR = 9.56 min.
Example 63 7-Methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-5-carboxamide
Figure imgf000058_0001
Following General Procedure B,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-5-carboxylic acid (150 mg, 0.55 mmol) was reacted with excess NH4OH to afford the desired product (42 mg) as a brown solid: ESI MS m/z 274 [Ci3HnN3O2S + H]+.
Example 64 N- [2-( 1 H-Imidazol-5 -yl)ethyl] -7-methoxy-2-(thiophen-2-yl)-
1 H-benzo [d] imidazole-5 -carboxamide
Figure imgf000058_0002
Following General Procedure B,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-5-carboxylic acid (150 mg, 0.55 mmol) was reacted with histamine (0.14 g, 1.1 mmol) to afford the desired product (92 mg) as a brown solid: ESI MS m/z 368 [C18H17N5O2S + H]+.
Example 65
7-Hydroxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-5-carboxamide
Figure imgf000058_0003
Following General Procedure C,
7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-5-carboxamide (40 mg) was reacted with boron tribromide to afford the desired product (13 mg, 32% yield) as an off-white solid: 1H NMR (500 MHz, CD3OD) delta 7.83-7.82 (m, IH), 7.65-7.63 (m, IH), 7.61 (s, IH), 7.22-7.20 (m, IH), 7.18 (s, IH); ESI MS m/z 260 [Ci2H9N3O2S + H]+; HPLC >99% (AUC), tR = 9.32 min. Page: 58/97
Example 66
N-[2-(lH-Imidazol-5-yl)emyl]-7-hydroxy-2-(thiophen-2-yl)-lH- benzo [d] imidazole-5 -carboxamide
Figure imgf000059_0001
Following General Procedure C,
N-[2-(lH-imidazol-5-yl)ethyl]-7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-5-carboxami de was reacted with boron tribromide to afford the desired product (12 mg, 14% yield) as a light yellow solid: 1H NMR (500 MHz, CD3OD) delta 7.82 (s, IH), 7.69 (s, IH), 7.64-7.63 (m, IH), 7.53 (s, IH), 7.21-7.20 (m, IH), 7.10 (s, IH), 6.93 (s, IH), 3.64 (t, J = 7.0 Hz, 2H), 2.93 (t, J = 7.0 Hz, 2H); ESI MS m/z 354 [C17Hi5N5O2S + H]+; HPLC 98.9% (AUC), tR = 7.57 min. Example 67
7-Hydroxy-N-[2-(5-nitropyridin-2-ylamino)ethyl]-2-(thiophen-2-yl)-lH- benzo[d]imidazole-4-carboxamide
Figure imgf000059_0002
To a suspension of 7-hydroxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (0.65 g, 2.5 mmol) in dichloromethane (25 mL) was added N1-(5-nitropyridin-2-yl)ethane-l,2-diamine (0.50 g, 2.75 mmol), EDC (0.58 g, 3.0 mmol), HOBt (0.40 g, 3.0 mmol), and DIPEA (0.97 g, 7.5 mmol) and the reaction mixture was stirred at room temperature for 16 h. Analysis by LC-MS indicated that the reaction was not complete, therefore, the dichloromethane was removed under reduced pressure, the residue was dissolved in DMF (5 mL), and the reaction mixture was heated at 50 degrees for 16 h. The reaction mixture was cooled, concentrated under reduced pressure, and triturated with water (20 mL) to afford the desired product (0.45 g, 42% yield) as a yellow-brown solid: ESI MS m/z 425 [Ci9Hj6N6O4S + H]+. This intermediate was used without further purification or characterization.
Example 68
N- [2-(5 - Aminopyridm-2-ylamino)ethyl] -7-hydroxy-2-(thiophen-2-yl)- 1 H-benzo[d]imidazole-4-carboxamide Hydrochloride Page: 59/97
Figure imgf000060_0001
To a solution of
7-hydroxy-N-(2-(5-nitropyridin-2-ylamino)ethyl)-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4- carboxamide (0.22 g, 0.52 mmol) in ethanol (5 mL) and 6 N HCl (5 niL) was added iron powder (0.12 g, 2.1 mmol) and the reaction mixture was heated at reflux for 4 h. The reaction mixture was cooled to room temperature and concentrated to provide the desired product which was immediately carried forward without further purification or characterization: ESI MS m/z 395 [C19H18N6O2S + H]+.
Example 69
7-Hydroxy-N- { 2- [5 -(methylsulfonamido)pyridin-2-ylamino]ethyl } ■ 2-(thiophen-2-yl)- 1 H-benzo[d]imidazole-4-carboxamide
Figure imgf000060_0002
To a solution of crude
N-(2-(5-aminopyridin-2-ylamino)ethyl)-7-hydroxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4- carboxamide hydrochloride (0.29 g, 0.68 mmol) in DMF (5 mL) was added DIPEA (0.44 g, 3.4 mmol) and methanesulfonyl chloride (0.085 g, 0.75 mmol) and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (silica, 0-20% methanol/dichloromethane) to afford the desired product (59 mg, 18% yield) as a white solid: 1H NMR (500 MHz, CD3OD) delta 7.87 (d, J = 2.5 Hz, IH), 7.82-7.78 (m, 2H), 7.59 (d, J = 4.5 Hz, IH), 7.37 (dd, J = 8.5, 2.5 Hz, IH), 7.17 (s, IH), 6.69 (d, J = 8.5 Hz, IH), 6.62 (d, J = 8.5 Hz, IH), 3.78 (bs, 2H), 3.64 (bs, 2H), 2.83 (s, 3H); ESI MS m/z 473 [C20H20N6O4S2 + H]+; HPLC >99% (AUC), tR = 10.42 min.
Example 70
N-[2-(5-Acetamidopyridin-2-ylamino)ethyl]-7-hydroxy-2-(thiophen-2-yl)- lH-benzo[d]imidazole-4-carboxamide Page: 60/97
Figure imgf000061_0001
To a solution of
N-(2-(5 -aminopyridin-2-ylamino)ethyl)-7-hydroxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazole-4-c arboxamide hydrochloride (0.22 g, 0.52 mmol) in DMF (5 mL) was added DIPEA (0.34 g, 2.6 mmol) and acetyl chloride (0.045 g, 0.57 mmol) and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was concentrated under reduced pressure and purified by flash chromatography (silica, 0-20% methanol/dichloromethane) to afford the desired product (55 mg, 24% yield) as an off-white solid: 1H NMR (500 MHz, CD3OD) delta 8.42 (s, IH), 7.85 (d, J = 3.5 Hz, IH), 7.80 (d, J = 6.5 Hz, IH), 7.69 (dd, J = 9.5, 2.0 Hz, IH), 7.61 (d, J = 4.5 Hz, IH), 7.21 (d, J = 4.0 Hz, IH), 7.07 (d, J = 9.0 Hz, IH), 6.71 (d, J = 8.5 Hz, IH), 3.82-3.81 (m, 2H), 3.71-3.68 (m, 2H) 2.12 (s, 3H); ESI MS m/z 437 [C2iH20N6O3S + H]+; HPLC 96.0% (AUC), tR = 9.97 min.
Example 71
(S)-2-[7-Hydroxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamido]- 3 -( 1 H-imidazol-5 -yl)propanoic Acid
Figure imgf000061_0002
A solution of (S)-methyl
2-(7-hydroxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazole-4-carboxamido)-3 -( 1 H-imidazol-5-yl) propanoate (30 mg, 0.062 mmol) in 3 M NaOH (10 ml) was heated at 80 degrees for 4 h. The reaction mixture was cooled to room temperature and acidified to pH 5 with 3 M HCl. The resulting precipitate was filtered and the crude solid was purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA). The desired product was obtained as the trifluoroacetic acid salt which was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to afford the desired product (9.1 mg, 31% yield) as a yellow solid: 1H NMR (500 MHz, CD3OD) delta 8.22 (s, IH), 7.86 (d, J = 2.9 Hz, IH), 7.70 (d, J = 8.2 Hz, IH), 7.58 (d, J = 4.7 Hz, IH), 7.22 (s, IH), 7.15 (t, J = 4.2 Hz, IH), 6.66 (d, J = 8.3 Hz, IH), 3.38-3.33 (m, 2H); ESI MS m/z 398 [Ci8Hi5N5O4S + H]+; HPLC 97.8% (AUC), tR = 7.07 min.
Example 72
(S)-2- [7-Hydroxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazole-4-carboxamido] - 3-(lH-indol-3-yl)propanoic Acid Page: 61/97
Figure imgf000062_0001
A solution of (S)-methyl
2-(7-hydroxy-2-(thiophen-2-yl)- 1 H-benzo[d]imidazole-4-carboxamido)-3-(l H-indol-3-yl) propanoate (40 mg, 0.060 mmol) in 3 M NaOH (10 ml) was heated at 80 degrees for 4 h. The reaction mixture was cooled to room temperature and acidified to pH 5 with 3 M HCl. The resulting precipitate was filtered and the crude solid was purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA). The desired product was obtained as the trifluoroacetic acid salt which was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to afford the desired product (25 mg, 64% yield) as a yellow solid: 1H NMR (500 MHz, CD3OD) delta 7.76 (bs, IH), 7.63 (bs, 2H), 7.49 (bs, IH), 7.29 (bs, IH), 7.21 (d, J = 4.2 Hz, IH), 7.10 (bs, IH), 6.99 (t, J = 7.5 Hz, IH), 6.89 (d, J = 3.2 Hz, IH), 6.56 (bs, IH), 3.51 (bs, IH), 3.51-3.38 (m, IH); ESI MS m/z 447 [C23Hi8N4O4S + H]+; HPLC 97.8% (AUC), tR = 7.07 min.
Example 73
7-Hydroxy-N-[2-(4-nitrophenoxy)ethyl]-2-(thiophen-2-yl)- 1 H- benzo[d]imidazole-4-carboxamide.
Figure imgf000062_0002
Following General Procedure A,
7-hydroxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (0.25 g, 0.95 mmol) was reacted with 2-(4-nitrophenoxy)ethanamine (0.34 g, 1.9 mmol) to obtain the desired product (230 mg, 57%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) delta 13.44 (s, IH), 10.83 (s, IH), 9.85 (s, IH), 8.23-8.20 (m, 2H), 8.03-8.02 (m, IH), 7.75-7.71 (m, 2 H), 7.28-7.21 (m, 3H), 6.73 (d, J = 8.3 Hz, IH), 4.35 (t, J = 10.0 Hz, 2H), 3.88 (t, J = 11.0 Hz, 2H); ESI MS m/z 425 [C20H16N4O5S + H]+; HPLC 98.2% (AUC), tR = 13.25 min.
Example 74 7-Hydroxy-N-{2-[4-(4-methylphenylsulfonamido)phenoxy]ethyl}-2-(thiophen-2-yl)-lH- benzo [d] imidazole-4-carboxamide Page: 62/97
Figure imgf000063_0001
To a solution of
7-hydroxy-N-(2-(4-nitrophenoxy)ethyl)-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxamide (0.20 g, 0.48 mmol) in EtOH (20 mL) was added iron filings (160 mg, 2.8 mmol) and 6 N HCl (15 mL, 90 mmol) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was cooled to room temperature and concentrated. The resulting crude aniline was dissolved in DMF (5 mL) followed by the addition of p-toluenesulfonyl chloride (0.13 g, 0.72 mmol) and DIPEA (0.16 g, 1.3 mmol). The reaction mixture was stirred at room temperature for 16 h, quenched with satd. aq NaCl (50 mL), and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with satd. aq NaCl (50 mL), dried over Na2SO4, concentrated, and purified by preparatory HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA) to afford the desired product (15 mg, 6% yield) as a light yellow solid: 1H NMR (300 MHz, CD3OD) delta 7.81-7.76 (m, 2H), 7.54-7.51 (m, 3H), 7.21 (d, J = 8.0 Hz, 2H), 7.13 (t, J = 8.3 Hz, IH), 6.92 (q, J = 8.8 Hz, 4H), 6.69 (d, J = 8.3 Hz, IH), 4.18 (t, J = 5.0 Hz, 2H), 3.86 (t, J = 5.1 Hz, 2H), 2.32 (s, 3H); ESI MS m/z 549 [C27H24N4O5S2 + H]+; HPLC > 99% (AUC), tR = 14.76 min.
Wherein, NHTs means p-toluenesulfonamido.
Example 75
N-[3 -( 1 H-Imidazol- 1 -yl)propyl] -7-methoxy-2-(thiophen-2-yl)- 1 H- benzo [d] imidazole-4-carboxamide
Figure imgf000063_0002
Following General Procedure B,
7-Methoxy-2-(thiophen-2-yl)-l//-benzo[d]imidazole-4-carboxylic Acid (150 mg, 0.55 mmol) was reacted with 3-(lH-imidazol-l-yl)propan-l-amine (0.14 g, 1.1 mmol) to afford the desired product (117 mg) as a light yellow oil: ESI MS m/z 382 [Ci9H19N5O2S + H]+.
Example 76
N-[3-(lH-Imidazol-l-yl)propyl]-7-hydroxy-2-(thiophen-2-yl)-lH- benzo[d]imidazole-4-carboxamide Page: 63/97
Figure imgf000064_0001
Following General Procedure C,
N-(3 -( 1 H-imidazol- 1 -yl)propyl)-7-methoxy-2-(thiophen-2-yl)- 1 H-benzo [d]imidazole-4- carboxamide (115 mg) was reacted with boron tribromide to afford the desired product (41 mg, 20% yield) as a light yellow-brown solid: 1H NMR (300 MHz, CD3OD) delta 7.89-7.88 (m, IH), 7.80-7.77 (m, IH), 7.64-7.63 (m, IH), 7.24-7.20 (m, IH), 6.99 (s, IH), 6.71 (d, IH, J = 8.3 Hz), 4.29-4.25 (m, 2H), 3.53-3.49 (m, 2H), 2.24-2.19 (m, 2H); ESI MS m/z 368 [Ci8Hi7N5O2S + H]+; HPLC 97.3% (AUC), tR = 9.69 min.
Example 77 2-(Furan-2-yl)-7-hydroxy-N-phenethyl-lH-benzo[d]imidazole-4-carboxamide
Figure imgf000064_0002
To a solution of 2-(furan-2-yl)-7-hydroxy-lH-benzo[d]imidazole-4-carboxylic acid (150 mg,
0.58 mmol) in DMF (5 mL) was added HATU (0.26 g, 0.69 mmol) 2-phenylethanamine (0.14 g, 1.2 mmol), and DIPEA (0.22 g, 1.7 mmol) and the reaction mixture was stirred at 80 degrees for 16 h. The reaction mixture was cooled to room temperature, diluted with satd. aq NaHCO3 (50 mL), and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with satd. aq NaCl (50 mL), concentrated, and purified by flash chromatography (silica, 0-15% methanol/dichloromethane) to afford the desired product (15 mg, 6.7 % yield) as a light yellow solid: 1H NMR (500 MHz, CD3OD) delta 7.80 (d, J = 4.3 Hz, IH), 7.75 (s, IH), 7.35 (d, J = 3.7 Hz, IH), 7.27 (m, J = 7.5 Hz, 2H), 7.19 (t, J = 7.6 Hz, IH), 7.08 (d, J = 3.0 Hz, IH), 6.70-6.66 (m, 2H), 3.79 (t, J = 7.0 Hz, 2H), 3.00 (t, J = 7.0 Hz, 2H); ESI MS m/z 348 [C20H17N3O3 + H]+; HPLC 98.6% (AUC), tR = 13.12 min.
Example 78 Synthesis of 2-(Furan-2-yl)-7-hydroxy-N -phenyl- 1 H-benzo [d]imidazole-4-carboxamide Page: 64/97
Figure imgf000065_0001
To a solution of 2-(furan-2-yl)-7-hydroxy-lH-benzo[d]imidazole-4-carboxylic acid (150 mg, 0.58 mmol) in DMF (5 mL) was added HATU (0.26 g, 0.69 mmol,) aniline (0.11 g, 1.2 mmol), and DIPEA (0.22 g, 1.7 mmol) and the reaction mixture was stirred at 80 degrees for 16 h. The reaction mixture was cooled to room temperature, diluted with satd. aq NaHCO3 (50 mL), and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with satd. aq NaCl (50 mL), concentrated, and purified by flash chromatography (silica, 0-15% methanol/dichloromethane) to afford the desired product (21 mg, 10 % yield) as a light yellow solid: 1H NMR (500 MHz, CD3OD) delta 7.90 (d, J = 8.6 Hz, IH), 7.82 (s, 1 H), 7.81 (d, J = 5.8 Hz, 2 H), 7.40 (t, J =14.9 Hz, 2H), 7.33 (d, J = 3.3 Hz, IH), 7.13 (t, J = 14.6 Hz, IH), 6.76 (d, J = 8.2 Hz, IH), 6.71 (s, IH); ESI MS m/z 320 [Ci8Hi3N3O3 + H]+; HPLC 92.7% (AUC), tR = 13.27 min.
Example 79
7-Hydroxy-N- [3 -(5-oxo-4,5 -dihydro- 1 H-pyrazol-4-yl)propyl] -2-(thiophen-2-yl)- 1 H- benzo[d]imidazole-4-carboxamide
Figure imgf000065_0002
To a solution of 2-(furan-2-yl)-7-hydroxy-lH-benzo[d]imidazole-4-carboxylic acid (150 mg, 0.58 mmol) in DMF (5 mL) was added HATU (0.26 g, 0.69 mmol)
4-(3-aminopropyl)-lH-pyrazol-5(4H)-one (0.17 g, 1.2 mmol) and DIPEA (0.22 g, 1.7 mmol) and the reaction mixture was stirred at 80 degrees for 16 h. The reaction mixture was cooled to room temperature, diluted with satd. aq NaHCO3 (50 mL), and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with satd. aq NaCl (50 mL), concentrated, and purified by flash chromatography (silica, 0-15% methanol/dichloromethane) to afford the desired product (15 mg, 5% yield) as a light yellow solid: 1H NMR (300 MHz, CD3OD) delta 7.76-7.59 (m, 2H), 7.35(s, IH), 7.27 (d, J = 3.4 Hz, IH), 6.71-6.66 (m, 2H) 3. 54 (t, J = 15.7 Hz, 2H), 2.57 (t, J = 14.5 Hz, 2H), 1.96-1.92 (m, 2H); ESI MS m/z 368 [Ci8HnN5O4 + H]+; HPLC >95.9% (AUC), tR = 9.59 min.
Example 80 Page: 65/97
N-(3,4-Dihydroxyphenethyl)-2-(furan-2-yl)-7-hydroxy-lH-benzo[d]imidazole-4-carboxamide
Figure imgf000066_0001
To a solution of 2-(furan-2-yl)-7-hydroxy-lH-benzo[d]imidazole-4-carboxylic acid (150 mg, 0.58 mmol) in DMF (5 niL) was added HATU (0.26 g, 0.69 mmol),
4-(2-aminoethyl)benzene-l,2-diol (0.18 g, 1.2 mmol), and DIPEA (0.22 g, 1.7 mmol) and the reaction mixture was stirred at 80 degrees for 16 h. The reaction mixture was cooled to room temperature, diluted with satd. aq NaHCO3 (50 mL), and extracted with ethyl acetate (3x30 mL). The combined organic layers were washed with satd. aq NaCl (50 mL), concentrated, and purified by flash chromatography (silica, 0-15% methanol/dichloromethane) to afford the desired product (20 mg, 6% yield) as an off-white solid: 1H NMR (500 MHz, CD3OD) delta 7.80 (d, J = 8.1 Hz, IH), 7.74 (s, IH), 7.08 (s, IH), 6.76 (s, IH), 6.68-6.66 (m, 4H), 3.74 (t, J = 6.5 Hz, 2H), 2.84 (t, J = 6.6 Hz, 2H) ; ESI MS m/z 380 [C20H17N3O5 + H]+.
Example 81
2-(Furan-2-yl)-7-methoxy-N-(2-( 1 -methyl- 1 H-pyrrol-2-yl)ethyl)- 1 H- benzo [d] imidazole-4-carboxamide
Figure imgf000066_0002
Following General Procedure B, 2-(furan-2-yl)-7-methoxy-lH-benzo[d]imidazole-4-carboxylic acid (0.15 g, 0.57 mmol) was reacted with 2-(l -methyl- lH-pyrrol-2-yl)ethanamine (0.14 g, 1.2 mmol) to afford the desired product (135 mg) as a light yellow oil: ESI MS m/z 365 [C20H20N4O3 + H]+.
Example 82
N-[2-(3,5-Dimethylisoxazol-4-yl)ethyl]-2-(furan-2-yl)-7-methoxy-lH- benzo [d] imidazole-4-carboxamide Page: 66/97
Figure imgf000067_0001
Following General Procedure B, 2-(furan-2-yl)-7-methoxy-lH-benzo[d]imidazole-4-carboxylic acid (0.15 g, 0.57 mmol) was reacted with 2-(3,5-dimethylisoxazol-4-yl)ethanamine (0.17 g, 1.2 mmol) to afford the desired product (230 mg) as a light yellow oil: ESI MS m/z 381
[C20H20N4O4+ H]+.
Example 83 2-(Furan-2-yl)-7-methoxy-N-(thiazol-2-yl)-lH-benzo[d]imidazole-4-carboxamide
Figure imgf000067_0002
Following General Procedure B, 2-(furan-2-yl)-7-methoxy-lH-benzo[d]imidazole-4-carboxylic acid (17 mg, 0.64 mmol) was reacted with thiazol-2-amine (0.12 g, 1.2 mmol) to afford the desired product (194 mg) as a brown solid: ESI MS m/z 341 [C16H12N4O3S + H]+.
Example 84
2-(Furan-2-yl)-7-hydroxy-N- [2-( 1 -methyl- 1 H-pyrrol-2-yl)ethyl]- 1 H- benzo [d] imidazole-4-carboxamide
Figure imgf000067_0003
Following General Procedure C,
2-(Furan-2-yl)-7-methoxy-N-(2-(l-methyl-lH-pyrrol-2-yl)ethyl)-lH-benzo[d]imidazole-4- carboxamide (135 mg) was reacted with boron tribromide to afford the desired product (18 mg, 7% yield) as a light yellow-brown solid: 1U NMR (300 MHz, CD3OD) delta 7.81 (d, J = 8.3 Page: 67/97
Hz, IH), 7.75 (s, IH), 7.19 (d, J = 3.3 Hz, IH, ), 6.71-6.66 (m, 2H), 6.56 (t, J = 4.3 Hz, IH), 6.02-5.97 (m, 2H), 3.77 (t, J = 6.9 Hz, 2H), 3.60 (s, 3H), 2.96, (t, J = 6.8 Hz, 2H) (ESI MS m/z 351 [C19Hi8N4O3 + H]+; HPLC 96.7% (AUC), tR = 12.53 min.
Example 85
N-(2-(3,5-dimethylisoxazol-4-yl)ethyl)-2-(furan-2-yl)-7-hydroxy-lH- benzo [d] imidazole-4-carboxamide
Figure imgf000068_0001
Following General Procedure C,
N-[2-(3,5-Dimethylisoxazol-4-yl)ethyl]-2-(furan-2-yl)-7-methoxy-lH-benzo[d]imidazole-4- carboxamide (230 mg) was reacted with boron tribromide to afford the desired product (18 mg, 7% yield) as an off-white solid: 1H NMR (500 MHz, CD3OD) delta 7.77-7.75 (m, 2H), 7.31 (bs, IH), 6.75-6.69 (m, 2H) 3.62 (t, J = 12.6 Hz, 2H), 2.74 (t, J =11.8 Hz, 2H), 2.27 (s, 3H), 2.24 (s, 3H) ESI MS m/z 367 [C]9Hi8N4O4 + H]+; HPLC 96.8% (AUC), tR = 11.65 min.
Example 86 2-(Furan-2-yl)-7-hydroxy-N-(thiazol-2-yl)-lH-benzo[d]imidazole-4-carboxamide
Figure imgf000068_0002
Following General Procedure C,
2-(Furan-2-yl)-7-methoxy-N-(thiazol-2-yl)-lH-benzo[d]imidazole-4-carboxamide (194 mg) was reacted with boron tribromide to afford the desired product (25 mg, 12% yield) as a light yellow solid: 1H NMR (300 MHz, CD3OD) delta 7.95 (d, J = 8.4 Hz, IH), 7.63 (d, J = 3.6 Hz, IH), 7.53 (d, J = 3.6 Hz, IH), 7.19 (d, J = 3.6 Hz, IH), 6.80 (d, J = 8.4 Hz, IH), 6.73-6.71 (m, IH); ESI MS m/z 327 [C15H10N4O3S + H]+; HPLC >99% (AUC), tR = 12.88 min.
Example 87
2-(Furan-2-yl)-7-hydroxy-N- [2-(5 -nitropyridin-2-ylamino)ethyl] - 1 H- benzo [d] imidazole-4-carboxamide Page: 68/97
Figure imgf000069_0001
To a suspension of 2-(furan-2-yl)-7-hydroxy-lH-benzo[d]imidazole-4-carboxylic acid (0.50 g, 2.0 mmol) in DMF (4 mL) was added N1-(5-nitropyridin-2-yl)ethane-l,2-diamine (0.41 g, 2.2 mmol), HATU (0.93 g, 2.5 mmol), DMAP (0.025 g, 0.20 mmol), and diisopropylethylamine
(0.79 g, 6.2 mmol) and the reaction mixture stirred for 16 h at 50 degrees. The reaction mixture was quenched by the addition of water (25 mL) and extracted with dichloromethane (3x50 mL). The combined organic layers were dried over NaSO4, filtered, and concentrated under reduced pressure. The crude residue was triturated in dichloromethane (10 mL) to afford the first batch of 50. The filtrate was concentrated and purified by flash chromatography (silica, 0-20% methanol/dichloromethane) and combined with the first batch to afford the desired product (0.30 g, 36% yield) as a yellow solid: ESI MS m/z 409 [C19Hi6N6O5 + H]+.
Example 88 N-[2-(5-Aminopyridin-2-ylamino)ethyl]-2-(furan-2-yl)-7-hydroxy- 1 H- benzo [d] imidazole-4-carboxamide hydrochloride
Figure imgf000069_0002
To a solution of 2-(Furan-2-yl)-7-hydroxy-N-[2-(5-nitropyridin-2-ylamino)ethyl]-lH- benzo[d] imidazole-4-carboxamide (0.30 g, 0.73 mmol) in ethanol (7 mL) and 6 N HCl (7 mL) was added iron powder (0.20 g, 3.7 mmol) and the reaction mixture was heated at reflux for 4 h. The reaction mixture was concentrated under reduced pressure to afford the desired product which was used immediately in the next step without further purification: ESI MS m/z 379 [C19H18N6O3 + H]+.
Example 89
2-(Furan-2-yl)-7-hydroxy-N-{2-[5-(4-methylphenylsulfonamido)pyridin-2-ylamino]ethyl}-lH- benzo [d] imidazole-4-carboxamide . Page: 69/97
Figure imgf000070_0001
To a solution of N-[2-(5-Aminopyridin-2-ylamino)ethyl]-2-(furan-2-yl)-7-hydroxy-lH- benzo[d]imidazole-4-carboxamide hydrochloride (0.73 mmol) in DMF (7 mL) was added DIPEA (0.47 g, 3.7 mmol) and p-toluenesulfonyl chloride (0.15 g, 0.80 mmol) and the reaction mixture was stirred for 16 h at room temperature. The reaction mixture was quenched by the addition of water (25 mL) and the black solid was removed by vacuum filtration. The filtrate was concentrated under reduced pressure and the crude residue was triturated in methanol and filtered. The filtrate was concentrated and purified by flash chromatography (silica, 0-20% methanol/dichloromethane) to afford crude product. The crude product was purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA). The desired product was obtained as the trifluoroacetic acid salt which was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to afford the desired product (42 mg, 11% yield) as a white solid: 1H NMR (500 MHz, CD3OD) delta 7.74 (bs, IH), 7.51-7.49 (m, 3H), 7.25-7.23 (m, 2H), 7.15 (dd, J = 9.0, 2.5 Hz, 2H), 6.69 (d, J = 8.5 Hz, IH), 6.66 (d, J = 1.5 Hz, 2H), 6.49 (d, J = 9.0 Hz, IH), 3.71 (bs, 2H), 3.54 (bs, 2H), 2.35 (s, 3H); ESI MS m/z 533 [C26H24N6O5S + H]+; HPLC >99% (AUC), tR = 1 1.73 min.
Example 90 N- [2-( 1 H-Imidazol-5 -yl)ethyl] -7-fluoro-2-(thiophen-2-yl)- 1 H-benzo [d]imidazole-4-carboxamide
Figure imgf000070_0002
To a solution of 7-fluoro-2-(thiophen-2-yl)-l H-benzo [d]imidazole-4-carboxylic acid (100 mg, 0.38 mmol) in DMF (3 mL) was added HATU (160 mg, 0.41 mmol), DIPEA (0.35 mL, 1.9 mmol), and 2-(lH-imidazol-4-yl)ethanamine (100 mg, 0.57 mmol) and the reaction mixture stirred at 60 degrees for 5 h. The reaction mixture was cooled to room temperature, concentrated, and the crude residue was purified by column chromatography (silica, 5:95 methanol/methylene chloride) to afford the desired product (110 mg, 43%) as an off-white solid: 1H NMR (500 MHz, DMSO) delta 9.42 (bs, IH), 8.10 (s, IH), 7.82 (d, J = 4.6 Hz, IH), 7.78 (s, IH), 7.57 (s, IH), 7.26 (t, J = 8.40 Hz, IH), 7.15 (t, J = 9.3 Hz, IH), 6.91 (s, IH), 3.67-3.65 (m, 2H), 2.84 (t, J = 6.9 Hz, 2H); ESI MS m/z 356 [Ci7Hi4FN5OS + H]+; HPLC 98.8% (AUC), tR = 9.41 min. Page: 70/97
Example 91 2-Cyclopropyl-N-(4-hydroxyphenyl)-4-methoxy-lH-benzo[d]imidazole-7-carboxamide
Figure imgf000071_0001
Following General procedure A, 2-cyclopropyl-7-hydroxy-lH-benzo[d]imidazole-4-carboxylic acid (40 mg, 0.18 mmol) was reacted with 4-aminophenol (31 mg, 0.28 mmol) to afford the desired productl (18 mg, 32% yield) as a brown yellow solid: 1H NMR (500 MHz, CD3OD) delta 7.76 (d, J = 8.5 Hz, IH), 7.51 (d, J = 8.5 Hz, 2H), 6.80 (m, 2H), 6.65 (d, J = 8.5 Hz, IH), 2.21 (m, IH), 1.23-1.18 (m, 4H); ESI MS m/z 310 [C17H15N3O3 + H]+; HPLC >99% (AUC), tR = 9.06 min.
Example 92 4-Hydroxy-N-(4-hydroxyphenethyl)-2-phenyl-lH-benzo[d]imidazole-7-carboxamide
Figure imgf000071_0002
Following General procedure A, 7-hydroxy-2-phenyl-lH-benzo[d]imidazole-4-carboxylic acid (63 mg, 0.25 mmol) was reacted 4-aminophenol (52 mg, 0.38 mmol) to afford the desired product (20 mg, 21% yield) as a light brown solid: 1H NMR (500 MHz, DMSO-d6) delta 13.30 (s, IH), 10.71 (s, IH), 9.69-9.67 (m, IH), 9.20 (s, IH), 8.13-8.12 (m, 2H), 7.73 (d, 8.5 Hz, IH), 7.58-7.55 (m, 3H), 7.15 (d, J = 8.5 Hz, 2H), 6.74-6.71 (m, 3H), 3.72-3.69 (m, 2H), 3.32 (bs, IH), 2.51-2.50 (m, 2H); ESI MS m/z 374 [C22Hi9N3O3 + H]+; HPLC >99% (AUC), tR = 11.91 min.
Example 93 N-(4-Aminophenethyl)-4-hydroxy-2-phenyl-lH-benzo[d]imidazole-7-carboxamide Page: 71/97
Figure imgf000072_0001
Following General procedure A, 7-hydroxy-2-phenyl-lH-benzo[d]imidazole-4-carboxylic acid (63 mg, 0.25 mmol) was reacted with benzene- 1,4-diamine (52 mg, 0.38 mmol) to afford the desired product (15 mg, 16% yield) as a light brown solid: 1H NMR (500 MHz, DMSOd6) delta 13.28 1 (s, IH), 10.70 (s, IH), 9.68 (s, IH), 8.16 (d, J = 7.5 Hz, 2H), 7.72 (d, J = 6.0 Hz, IH), 7.607.57 (m, 2H), 7.52 (d, J = 7.5 Hz, IH), 7.02 (d, J = 6.0 Hz, 2H), 6.72 (d, J = 8.5 Hz, IH), 6.54 (d, J = 8.5 Hz, 2H), 3.66 (d, J = 6.0 Hz, 2H), 2.78-2.75 (m, 2H); ESI MS m/z 373 [C22H20N4O2 + H]+; HPLC 95.7% (AUC), tR = 9.07 min.
Example 94 4-Hydroxy-N-phenethyl-2-phenyl-lH-benzo[d]imidazole-7-carboxamide
Figure imgf000072_0002
Following General procedure A, 7-hydroxy-2-phenyl-lH-benzo[d]imidazole-4-carboxylic acid (63 mg, 0.25 mmol) was reacted with 4-(2-aminoethyl)aniline (46 mg, 0.38 mmol) to afford the desired product (28 mg, 27% yield) as a white solid: 1H NMR (500 MHz, DMSO-d6) delta 13.30 (s, IH), 10.71 (s, IH), 9.70 (s, IH), 8.12 (d, J = 5.5 Hz, 2H), 7.72 (d, J = 8.0 Hz, IH), 7.56-7.52 (m, 3H), 7.37-7.22 ( m, 5H), 6.72 (d, J = 8.0 Hz, IH), 3.76 (d, J = 5.5 Hz, 2H), 2.96-2.93 (m, 2H); ESI MS m/z 358 [C22Hi9N3O2 + H]+; HPLC >99% (AUC), tR = 14.39 min.
Example 95 2-Cyclopentyl-4-hydroxy-N-(4-hydroxyphenethyl)-lH-benzo[d]imidazole-7-carboxamide
Figure imgf000072_0003
Following General procedure A, 2-cyclopentyl-7-hydroxy-lH-benzo[d]imidazole-4-carboxylic acid (80 mg, 0.28 mmol) was reacted with 4-(2-aminoethyl)phenol (58 mg, 0.42 mmol) to afford Page: 72/97 the desired product (28 mg, 27% yield) as a white solid: 1H NMR (500 MHz, DMSOd6) delta 12.56c(s, IH), 10.46 (s, IH), 9.71 (s, IH), 9.13 (s, IH), 7. 61 (d, J = 8.5 Hz, IH), 7.08 (d, J = 8.5 Hz, 2H), 6.67-6.62 (m, 3H), 3.59-3.31 (m, 2H), 3.25-3.23 (m, IH), 2.51-2.49 (m, 2H), 2.05-2.01 (m, 2H), 1.85-1.66 (m, 6H); ESI MS m/z 366 [C2IH23N3O3 + H]+; HPLC >99% (AUC), tR = 10.44 min.
Example 96 N-(4-Aminophenethyl)-2-cyclopentyl-4-hydroxy- 1 H-benzo [d] imidazole-7-carboxamide
Figure imgf000073_0001
Following General procedure A, 2-cyclopentyl-7-hydroxy-lH-benzo[d]imidazole-4-carboxylic acid (80 mg, 0.28 mmol) was reacted with 4-(2-aminoethyl)aniline (58 mg, 0.42 mmol) to afford the desired product (25 mg, 25% yield) as an off-white solid: 1H NMR (500 MHz, DMSOd6) delta 12.56 (s, IH), 10.45 (s, IH), 9.72-9.70 (m, IH), 7. 61 (d, J = 8.5 Hz, IH), 6.94 (d, J = 8.5 Hz, 2H), 6.62 (d, J = 8.5 Hz, IH), 6.49-6.47 (m, 2H), 4.83 (bs, 2H), 3.56-3.52 (m, 2H),
3.33-3.25 (m, IH), 2.51-2.49 (m, 2H), 2.07-2.02 (m, 2H), 1.89-1.79 (m, 4H), 1.68-1.66 (m, 2H); ESI MS m/z 365 [C2]H24N4O2 + H]+; HPLC >99% (AUC), tR = 7.97 min.
Example 97 2-Cyclopropyl-N-(2,3-dihydroxypropyl)-4-hydroxy-lH-benzo[d]imidazole-7-carboxamide
Figure imgf000073_0002
Following General procedure A, 2-cyclopropyl-7-hydroxy-lH-benzo[d]imidazole-4-carboxylic acid (55 mg, 0.25 mmol) was reacted with 3-aminopropane-l,2-diol (33 mg, 0.38 mmol) to afford the desired product (23 mg, 32% yield) as a light brown-yellow solid: 1H NMR (500 MHz, CD3OD) delta 7.69 (bs, IH), 6.62-6.60 (m, IH), 3.85-3.82 (m, IH), 3.68 (bs, IH), 3.60-3.59 (m, 2H), 3.51-3.47 (m, IH), 2.15 (bs, IH), 1.21-1.10 (m, 4H); ESI MS m/z 292 [Ci4Hi7N3O4 + H]+; HPLC >99% (AUC), tR = 7.55 min.
Example 98
2-Cyclopropyl-N-(2-(dimethylamino)ethyl)-4-hydroxy- 1 H-benzo [d]imidazole-7-carboxamide Page: 73/97
Figure imgf000074_0001
Following General procedure A, 2-cyclopropyl-7-hydroxy-lH-benzo[d]imidazole-4-carboxylic acid (55 mg, 0.25 mmol) was reacted with N^N'-dimethylethane-l^-diamine (33 mg, 0.38 mmol) to afford the desired product (35 mg, 49% yield) as a light brown-yellow solid: 1H NMR (500 MHz, CD3OD) delta 7.66 (d, J = 8.5 Hz, IH), 6.60 (d, J = 8.5 Hz, IH), 3.65 (t, J = 6.5 Hz, 2H), 2.77 (t, J = 6.5 Hz, 2H), 2.46 (s, 6H), 2.17 (bs, IH), 1.19-1.12 (m, 4H); ESI MS m/z 289 [Ci5H20N4O2 + H]+; HPLC >99% (AUC), tR = 6.47 min.
Example 99 2-Cyclopropyl-4-methoxy-N-(4-sulfamoylphenethyl)-lH-benzo[d]imidazole-7-carboxamide
Figure imgf000074_0002
Following General procedure B, 2-cyclopropyl-7-methoxy-lH-benzo[d]imidazole-4-carboxylic acid (80 mg, 0.34 mmol) was reacted with 4-(2-aminoethyl)benzenesulfonamide (103 mg, 0.52 mmol) to afford the desired product (66 mg, 46% yield) as a brown solid: ESI MS m/z 415 [C20H22N4O4S + H] +.
Example 100 2-Cyclopropyl-N-(4-fluorophenethyl)-4-methoxy- 1 H-benzo [d]imidazole-7-carboxamide Fage: /4/y /
Figure imgf000075_0001
Following General procedure B, 2-cyclopropyl-7-methoxy-lH-benzo[d]imidazole-4-carboxylic acid (80 mg, 0.34 mmol) was reacted with 2-(4-fluorophenyl)ethanamine (72 mg, 0.52 mmol) to afford the desired product (80mg, 66% yield) as a white solid: ESI MS m/z 354 [C20H20FN3O2 + H]+.
Example 101 2-Cyclopropyl-4-hydroxy-N-(4-sulfamoylphenethyl)-lH-benzo[d]imidazole-7-carboxamide
Figure imgf000075_0002
Following General procedure C,
2-Cyclopropyl-4-methoxy-N-(4-sulfamoylphenethyl)-lH-benzo[d]imidazole-7-carboxamide (60 mg, 0.15 mmol) was reacted with boron tribromide to afford the desired product (15 mg, 26% yield) as a off-white solid: 1H NMR (500 MHz, CD3OD) delta 7.84-7.82 (m, 2H), 7.69 (d, J = 8.0 Hz, IH), 7.48 (d, J = 8.0 Hz, 2H), 6.59 (d, J = 8.0 Hz, IH), 3.81-3.79 (m, 2H), 3.06-3.03 (m, 2H), 2.08 (bs, IH), 1.12-1.00 (m, 4H); ESI MS m/z 401 [Ci9H20N4O4S + H]+; HPLC 96.5% (AUC), tR = 9.05 min.
Example 102 2-Cyclopropyl-N-(4-fluorophenethyl)-4-hydroxy-lH-benzo[d]imidazole-7-carboxamide Page: 75/97
Figure imgf000076_0001
Following General procedure C,
2-Cyclopropyl-N-(4-fluorophenethyl)-4-methoxy-lH-benzo[d]imidazole-7-carboxamide (60 mg, 0.17 mmol) was reacted with boron tribromide to afford the desired product (15 mg, 26% yield) as a off-white solid: 1H NMR (500 MHz, CD3OD) delta 7.69 (bs, IH), 7.30-7.27 (m, 2H), 7.02-6.99 (m, 2H), 6.60 (d, J = 8.0 Hz, IH), 3.72 (bs, 2H), 2.94-2.91 (m, 2H), 2.11 (bs, IH), 1.00-1.00 (m, 4H); ESI MS m/z 340 [Ci9H]8FN3O2 + H]+; HPLC 98.9% (AUC), tR = 11.49 min.
Example 103 tert-Butyl 2-cyclopropyl-7-methoxy-lH-benzo[d]imidazol-4-ylcarbamate and 1 ,3 -bis(2-cyclopropyl-7-methoxy- 1 H-benzo [d] imidazol-4-yl)urea
Figure imgf000076_0002
To the solution of 2-cyclopropyl-7-methoxy-l H-benzo [d]imidazole-4-carboxylic acid (1.4 g, 6.0 mmol) in 1,4-dioxane (100 mL) was added t-butanol (4 mL), triethylamine (2.0 mL, 15 mmol), and DPPA (2.5 g, 9.0 mmol) and the reaction mixture was stirred at room temperature for 2 h. Additional t-butanol (4 mL) was added and the reaction mixture was heated at 100 degrees for 18 h. The reaction mixture was cooled to room temperature, concentrated, diluted with ice water (40 mL), and the mixture was extracted with EtOAc (3x60 mL). The combined organic layers were washed with 5% aq NaHCO3 (50 mL); brine (50 mL), dried over Na2SO4, and concentrated to afford a mixture of products (1.4 g) as dark blue solid which was carried forward without further purification: ESI MS m/z 304 [C16H2iN3O3 + H]+ and ESI MS m/z 433 [C23H24N6O3 + H]+.
Example 104 2-Cyclopropyl-7-methoxy-lH-benzo[d]imidazol-4-amine
Figure imgf000076_0003
Page: 76/97
To a solution of tert-butyl 2-cyclopropyl-7-methoxy-lH-benzo[d]imidazol-4-ylcarbamate and l,3-bis(2-cyclopropyl-7-methoxy-lH-benzo[d]imidazol-4-yl)urea (1.4 g) in 1,4-dioxane (30 mL) was added a solution of KOH (1.3 g, 24 mmol) in water (5mL) and the reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to room temperature, concentrated, and diluted with ice water (30 mL). The pH of the mixture was adjusted to 7 using glacial acetic acid followed by extraction with EtOAc (3x80 mL). The combined organic layers were dried over Na2SO4 and concentrated. The crude residue was dissolved in CH2Cl2 (5 mL) and cooled to 0 degree followed by the addition of TFA (2 mL). The reaction mixture was stirred at room temperature for 2 h, concentrated, and diluted with ice water (20 mL). The pH of the mixture was adjusted to 7 using glacial acetic acid followed by extraction with EtOAc (3x60 mL). The combined organic layers were dried over Na2SO4, concentrated, and the residue was purified by flash chromatography (silica gel, 33-50 % EtOAc/Hexanes) to afford the desired product (0.88 g, 72% yield) as dark blue solid: ESI MS m/z 204 [CnH13N3O + H]+.
Example 105
N-(2-Cyclopropyl-7-methoxy-lH-benzo[d]imidazol-4-yl)-2-(4-methoxyphenyl)acetamide
Figure imgf000077_0001
To the solution of 2-cyclopropyl-7-methoxy-lH-benzo[d]imidazol-4-amine (50 mg, 0.24 mmol) in THF ( 5 mL) was added triethylamine (48 micro L, 0.36 mmol) and 2-(4-methoxyphenyl)acetyl chloride (44 mg, 0.24 mmol) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (20 mL) and washed with 5% aq NaHCO3 (50 mL) and brine (50 mL). The layers were separated and the organic layer was dried over Na2SO4, concentrated, and the residue was purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA) to afford the desired product (60 mg, 71% yield) as dark purple-blue solid: ESI MS m/z 352 [C20H2,N3O3 + H]+.
Example 106 1 -(2-Cyclopropyl-7-methoxy- 1 H-benzo[d]imidazol-4-yl)-3-(4-methoxyphenyl)urea
Figure imgf000077_0002
To the solution of 2-cyclopropyl-7-methoxy-lH-benzo[d]imidazol-4-amine (50 mg, 0.24 mmol) in THF (5 mL) was added triethylamine (48 micro L, 0.36 mmol) and 4-methoxyphenylcarbamic chloride (44 mg, 0.24 mmol) and the reaction mixture was stirred at room temperature for 30 Page: 77/97 min. The reaction mixture was diluted with EtOAc (20 mL) and washed with 5% aq NaHCO3 (50 mL) and brine (50 mL). The layers were separated and the organic layer was dried over Na2SO4, concentrated, and the residue was purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA) to afford the desired product (66 mg, 78% yield) as dark purple-blue solid: ESI MS m/z 353 [C9H20N4O3 + H]+.
Example 107 N-(2-cyclopropyl-7-hydroxy- 1 H-benzo [d] imidazol-4-yl)-2-(4-hydroxyphenyl)acetamide
Figure imgf000078_0001
To the solution of
N-(2-cyclopropyl-7-methoxy- 1 H-benzo[d]imidazol-4-yl)-2-(4-methoxyphenyl)acetamide (45 mg, 0.13 mmol) in CH2Cl2 (15 mL) was added BBr3 (2.1 mL, 1 M in CH2Cl2) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into ice water (15 mL) and the pH was adjusted to 6 using cone. NH4OH. The reaction mixture was extracted with EtOAc (3x20 mL) and the combined organic layers were washed with 5% aq NaHCO3 (50 mL) and brine (50 mL). The layers were separated and the organic layer was dried over Na2SO4, concentrated, and the residue was purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA) to afford the desired product (22 mg, 53% yield) as light purple-blue solid: 1H NMR (500 MHz, CD3OD) delta 7.28-7.20 (m, 3H), 6.77-6.75 (m, 2H), 6.50 (d, J = 8.5 Hz, IH), 3.64 (s, 2H), 2.15 (bs, IH), 1.13-1.11 (m, 4H); ESI MS m/z 324 [C]8H17N3O3 + H]+; HPLC 95.7% (AUC), tR = 8.40 min.
Example 108 1 -(2-Cyclopropyl-7-hydroxy- 1 H-benzo [d]imidazol-4-yl)-3- (4-hydroxyphenyl)urea
Figure imgf000078_0002
To the solution of l-(2-cyclopropyl-7-methoxy-lH-benzo[d]imidazol-4-yl)-3-(4-methoxyphenyl)urea (50 mg, 0.13 mmol) in CH2Cl2 (15 mL) was added BBr3 (2.13 mL, 1 M in CH2Cl2,) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was poured into ice water (15 Page: 78/97 mL) and the pH was adjusted to 6 using cone. NH4OH. The reaction mixture was extracted with EtOAc (3x20 mL) and the combined organic layers were washed with 5% NaHCO3 (50 mL), brine (50 mL), dried over Na2SO4, concentrated, and the residue was purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA) to afford the desired product (19 mg, 42% yield) as a light blue solid: 1H NMR (500 MHz, CD3OD) delta 7.21 (d, J = 9.0 Hz, 2H), 7.05 (bs, IH), 6.73 (d, J = 9.0 Hz, 2H), 6.52 (d, J = 8.0 Hz, IH), 2.17-2.13 (m, IH), 1.13-1.09 (m, 4H); ESI MS m/z 325 [Ci7Hi6N4O3 + H]+; HPLC 95.6% (AUC), tR = 8.99 min.
Example 109 N- [2-( 1 H-Imidazol-5-yl)ethyl] -7-(benzyloxy)- 1 H-indole-3 -carboxamide
Figure imgf000079_0001
To a solution of 7-(benzyloxy)-lH-indole (1.0 g, 4.5 mmol) in DMF (10 mL) was added TFAA (2.0 g, 9.0 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched by the addition of water (50 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were dried over Na2SO4, concentrated, and the crude residue was diluted in 6 N NaOH (15 mL) and ethanol (15 ml) and heated at reflux for 18 h. The reaction mixture was cooled to room temperature and acidified to pH 2 using 6 N HCl. The resulting solids were filtered and dried to obtain the crude acid (1.0 g) as an off-white solid. The crude acid intermediate (0.5 g) was dissolved in DMF (5 mL) followed by the addition of HATU (0.84 g, 2.2 mmol), DIPEA (1.2 mL, 6.6 mmol), histamine (0.50 g, 4.5 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were dried over Na2SO4, concentrated, and the residue was triturated with CH2Cl2 (20 mL). The solids were filtered to afford the desired product (0.15 g, 19% for two steps): 1H NMR (300 MHz, CD3OD) delta 7.79 (s, IH), 7.59-7.51 (m, 4H), 7.47-7.28 (m, 3H), 7.04 (t, J = 7.8 Hz, IH), 6.88 (bs, IH), 6.79 (d, J = 7.8 Hz, IH), 5.24 9s, 2H), 3.62 (t, J = 7.2 Hz, 2H), 2.91 (t, J = 7.2 Hz, 2H); ESI MS m/z 361 [C2iH20N4O2 + H]+.
Example 110 N-[2-(l H-Imidazol-5 -yl)ethyl] -7-hydroxy- 1 H-indole-3 -carboxamide
Figure imgf000079_0002
To a solution of N-(2-(lH-imidazol-5-yl)ethyl)-7-(benzyloxy)-l H-indole-3 -carboxamide (0.15 g, 0.42 mmol) in methanol (20 mL) was added 10 wt % Pd on carbon (cat.) and the reaction mixture was stirred under an atmosphere (1 atm) of hydrogen at room temperature for 18 h.
The reaction mixture was filtered over diatomaceous earth and the filtrate was concentrated and h'age: /y/y / purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA). The desired product was obtained as the trifluoroacetic acid salt which was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to afford the desired product (24 mg, 22% yield): 1H NMR (300 MHz, DMSOd6) delta 7.92-7.84 (m, 2H), 7.58-7.53 (m, 2H), 6.89-6.82 (m, 2H), 6.54 (d, J = 7.5 Hz, IH), 3.48-3.42 (m, 2H), 2.74 (t, J = 7.2 Hz, 2H); ESI MS m/z 271 [Ci4H14N4O2 + H]+.
Example 111
Methyl 4-Methoxy-3-(thiophene-2-carboxamido)benzoate
Figure imgf000080_0001
To a solution of methyl 3-amino-4-methoxybenzoate (0.31 g, 1.7 mmol) in CH2Cl2 (15 mL) was added EDC (0.48 g, 2.6 mmol), HOBt (0.23 g, 1.7 mmol), and thiophene-2-carboxylic acid (0.27 g, 2.1 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated and purified by chromatography (silica gel, 0-70% EtO Ac/Heptane) to afford the desired product (0.19 g, 39% yield) as an off-white solid: ESI MS m/z 292 [C14H13NO4S + H]+.
Example 112 N-{5-[2-(lH-Imidazol-5-yl)ethylcarbamoyl]-2-hydroxyphenyl} thiophene-2-carboxamide
Figure imgf000080_0002
To a solution of methyl 4-methoxy-3-(thiophene-2-carboxamido)benzoate (0.19 g, 0.65 mmol) in dichloroethane ( 20 mL) was added boron tribromide (6.5 mL, 1.0 M in CH2Cl2) and the reaction mixture was heated at 80 degrees for 16 h. The reaction was incomplete by LCMS analysis, therefore, additional boron tribromide (3.3 mL, 1.0 M in CH2Cl2) was added and the reaction mixture was heated at 80 degrees for 24 h. The reaction mixture was cooled to room temperature, quenched by the addition of water (15 mL) and the resulting solids were filtered to afford crude hydroxy acid. The crude acid was dissolved in DMF (5 mL) followed by the addition of HATU (0.15 g, 0.46 mmol), DIPEA (0.20 mL, 1.1 mmol), and histamine (0.051 g, 0.46 mmol) and the reaction mixture was heated at 80 degrees for 18 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL), and extracted with EtOAc (3x30 mL). The combined organic layers were dried over Na2SO4, concentrated, and the residue was purified by preparative HPLC (Cl 8 silica, 10-90% acetonitrile/water with 0.05% TFA). The desired product was obtained as the trifluoroacetic acid salt which was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to afford the desired Fage: sυ/y / product (36 mg, 27% yield for two steps): 1K NMR (300 MHz, CD3OD) delta 8.48 (s, IH), 8.25 (d, J = 3.0 Hz, IH), 7.86 (d, J = 3.9 Hz, IH), 7.75-7.73 (m, IH), 7.52 (dd, J = 8.4, 2.1 Hz, IH), 7.23-7.18 (m, 2H), 6.95 (d, J = 8.4 Hz, IH), 3.65 (t, J = 6.9 Hz, 2H), 2.98 (t, J = 6.9 Hz); ESI MS m/z 357 [C17Hi6N4O3S + H]+; HPLC 96.3% (AUC), tR = 9.15 min. General Procedure D - synthesis of amines: To a solution of tert-butyl 2-aminoethylcarbamate (1.0 equiv) in dichloromethane (10 mL) was added triethylamine (3.0 equiv) and the requisite sulfonyl chloride or acid chloride (1.2 equiv) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated to afford the crude intermediate were dissolved in ethyl acetate (40 mL) followed by the addition of 2 N HCl in diethyl ether (2.85 equiv). The reaction mixture was stirred for 16 h at room temperature. The resulting solids were collected by filtration to afford the desired products. These amines were used in subsequent reactions without further purification.
Example 113 N-(2-Aminoethyl)benzenesulfonamide Trifluoroacetic Acid Salt
Figure imgf000081_0001
•TFA
Following General Procedure D, tert-butyl 2-aminoethylcarbamate (0.50 g, 2.8 mmol) was reacted with benzenesulfonylchloride (0.54 g, 3.4 mmol) to afford the intermediate (ESI MS m/z 201 [C]3H20N2O4S - Boc + H]+) which was treated with 2 N HCl. The reaction did not go to completion by LCMS analysis and was concentrated, dissolved in trifluoroacetic acid (5 mL) and stirred for 4 h at room temperature. The reaction mixture was concentrated under reduced pressure to afford the desired product (1.2 g, 99% yield) as a tan solid: 1H NMR (500 MHz, DMSO-d6) delta 7.90 (t, J = 5.9 Hz, IH), 7.83-7.81 (m, 4H), 7.69-7.63 (m, 3H), 2.94 (d, J = 6.2 Hz, 2H), 2.86 (d, J = 5.6 Hz, 2H).
Example 114
N-(2-Aminoethyl)-4-chlorobenzenesulfonamide Hydrochloride
Figure imgf000081_0002
Following General Procedure D, tert-butyl 2-aminoethylcarbamate (0.50 g, 2.8 mmol) was reacted with 4-chlorobenzenesulfonylchloride (0.72 g, 3.4 mmol) to afford the intermediate (ESI MS m/z 235 [Ci3H19ClN2O4S - Boc + H]+) which was treated with 2 N HCl to afford the desired product (0.60 g, 79% yield) as a white solid: ESI MS m/z 235 [C8HHCIN2O2S + H]+.
Example 115
N-(2-Aminoethyl)pyridine-4-sulfonamide Dihydrochloride Page: 81/97
Figure imgf000082_0001
Following General Procedure D, tert-butyl 2-aminoethylcarbamate (0.54 g, 2.8 mmol) was reacted with 4-pyridylsulfonylchloride (0.73 g, 3.4 mmol) to afford the intermediate which was reacted with 2 N HCl to afford the desired product (0.72 g, 94% yield) as a white solid: 1H NMR (500 MHz, CD3OD) delta 9.19 (d, J = 2.0 Hz, IH), 8.97 (dd, J = 5.3, 1.4 Hz, IH), 8.66-8.64 (m, IH), 7.99 (dd, J = 8.2, 5.3 Hz, IH), 3.24-3.19 (m, 2H), 3.11-3.09 (m, 2H).
Examples 116
N-(2-aminoethyl)benzamide Hydrochloride
Figure imgf000082_0002
Following General Procedure D, tert-butyl 2-aminoethylcarbamate (0.50 g, 2.8 mmol) was reacted with 4-tolylbenzoylchloride (0.47 g, 3.4 mmol) to afford the intermediate (ESI MS m/z 179 [Ci5H22N2O3 - Boc+ H]+) which was reacted with 2 N HCl to afford the desired product (0.40 g, 67% yield) as a white solid: 1H NMR (500 MHz, CD3OD) delta 7.86 (t, J = 8.5 Hz, 2H), 7.56-7.55 (m, IH), 7.48 (t, J = 7.5 Hz, 2H), 3.67 (t, J = 5.5 Hz, 2H), 3.17 (t, J = 6.0 Hz, 2H).
Example 117 tert-Butyl 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazol-4-ylcarbamate
Figure imgf000082_0003
A solution 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxylic acid (0.60 g, 2.2 mmol), (PhO)2P(O)N3 (0.78 g, 3.0 mmol) and triethylamine (0.70 mL, 5.0 mmol) in 1,4-dioxane (35 mL) were stirred for 4 h at room temperature. Following the addition of t-BuOH (2 mL) the reaction mixture was stirred at 100 degrees for 16 h. The reaction mixture was cooled, concentrated, and the residue was purified by column chromatography (silica gel, methanol/methylene chloride gradient) to afford the desired product (360 mg, 47% yield) as a yellow solid: ESI MS m/z 346 [C17H19N3O3S + H]+.
Example 118
7-methoxy-2-(thiophen-2-yl)- 1 H-benzo [d]imidazol-4-amine Hydrochloride
Figure imgf000082_0004
Fage: 82/y /
To a solution of tert-Butyl 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazol-4-ylcarbamate (0.44 g, 1.2 mmol) in CH2Cl2 (5 niL) was added a 2.0 M HCl in diethyl ether (3.5 mL) and the reaction mixture was stirred at room temperature for 5 h. The resulting precipitate was filtered and washed with CH2Cl2 (2x10 mL) to afford the desired product (290 mg, 855 yield) as a white solid: ESI MS mlz 246 [Ci2Hi !N3OS + H]+.
Example 119 (E)-3-(lH-imidazol-5-yl)-N-(7-methoxy-2-(thiophen-2-yl)- lH-benzo[d]imidazol-4-yl)acrylamide
Figure imgf000083_0001
A solution of (E)-3-(lH-imidazol-5-yl)acrylic acid (0.13 g, 0.94 mmol) and HATU (0.36 g, 1.1 mmol) in THF (4 mL) was stirred at room temperature for 30 min. A solution of 7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazol-4-amine hydrochloride (0.18 g, 0.63 mmol) and DIPEA (0.33 mL, 1.9 mmol) in THF (4 mL) was added and the reaction mixture was heated at 60 degrees for 64 h. The reaction mixture cooled, diluted with water (50 mL), and extracted with EtOAc (2x30 mL). The combined organic layers were washed with brine (2x50 mL), dried over sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, methanol/methylene chloride gradient) to afford the desired product (200 mg, 87% yield) as an off-white solid: ESI MS mlz 366 [C18Hi5N5O2S + H]+.
Example 120
(E)-3-(lH-imidazol-5-yl)-N-(7-methoxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazol-4-yl) acrylamide
Figure imgf000083_0002
A solution of
(E)-3 -( 1 H-imidazol-5 -yl)-N-(7-methoxy-2-(thiophen-2-yl)- 1 H-benzo [d]imidazol-4-yl)acrylamid e (0.20 g, 0.55 mmol) in CH2Cl2 (12 mL) was cooled to 0 degree and BBr3 (1.6 g, 6.5 mmol) was added drop wise and the reaction mixture was warmed to room temperature and stirred for 16 h. The reaction mixture was concentrated, the residue was stirred in methanol (5 mL) and purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA). The desired fractions were concentrated and eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to obtain the desired product (25 mg, 13% yield) as an off-white solid: 1H NMR (500 MHz, CD3OD) 7.81 (d, J = 4.5 Hz, IH) 7.78 (s, IH), 7.6 (d, J = 8.5 Hz, IH), 7.59 (s, IH), 7.51 (d, J = 8.5 Hz, IH), 7.4 (s, IH), 7.18, (t, J = 4.25 Hz, IH), 6.78 (d, J = 15.5, IH), 6.58 (d, J = 8.5 Hz, IH); ESI MS mlz 352 [C17Hi3N5O2S + H]+.
Example 121 Page: 83/97
N-(7-hydroxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazol-4-yl)-3 -( 1 H-imidazol-5-yl)propanamide
Figure imgf000084_0001
A solution of
(E)-3 -( 1 H-imidazol-5 -yl)-N-(7-methoxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazol-4-yl) acrylamide (19 mg, 0.054 mmol) and 10 wt % Palladium upon carbon (50 mg) in ethanol (20 niL) was placed in a parr shaker with hydrogen gas (50 psi) for 2 h. The reaction mixture was transferred into a round bottom flask, placed under an atmosphere of hydrogen gas (1 atm), and stirred for 16 h. The reaction mixture was filtered through diatomaceous earth, the filtrate was concentrated, and the residue was suspended in CH2Cl2 (10 mL). The resulting precipitate was filtered and dried to afford the desired product (12 mg, 63% yield) as a green solid: 1H NMR (500 MHz, CD3OD); 8.16 (s, IH), 7.82, (d, J = 4.0 Hz, IH), 7.38 (d, J = 5.5 Hz, IH), 7.33 (d, J = 8.0 Hz, IH), 7.19 (t, J = 4.2 Hz, IH), 7.13 (s, IH), 6.58 (d, J = 8.5 Hz, IH), 3.09 (t, J = 7.3 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H); ESI MS mlz 354 [Cj7H15N5O2S + H]+.
Example 122 STEP 1 : Synthesis of tert-hnty\ 3-(4-methoxy-2-nitrobenzamido)piperidine-l-carboxylate
Figure imgf000084_0002
To a solution of 4-methoxy-2-nitrobenzoic acid (200 mg, 1.0 mmol) and tert-butyl 3-aminopiperidine-l-carboxylate (200 mg, 1.0 mmol) in DMF (2 mL) was added DIPEA (0.20 mL, 1.2 mmol) and HATU (460 mg, 1.2 mmol). The reaction mixture was stirred at room temperature for 18 h, diluted with water (10 mL) and ethyl acetate (30 mL), and the layers were separated. The organic phase was washed with water (20 mL), brine (20 mL), dried over Mg2SO4, and purified by flash chromatography (silica gel, ethyl acetate/hexanes gradient) to provide the desired product (330 mg, 88%) as a white solid: ESI MS m/z 402 [Ci8H25N3O6 + Na]+.
STEP 2:
Figure imgf000084_0003
3-(2-amino-4-methoxybenzamido)piperidine-l-carboxylate
Figure imgf000084_0004
To a solution of ter/-butyl 3-(4-methoxy-2-nitrobenzamido)piperidine-l-carboxylate (190 mg, 0.50 mmol) in EtOH/EtOAc (5 mL each) was added 10 wt % palladium upon carbon (20 mg) and the reaction mixture was stirred under an atmosphere of hydrogen for 3 h. The reaction Fage: 84/y / mixture was filtered through diatomaceous earth and the filtrate was concentrated to afford the desired product (170 mg, quant.) as a white solid: ESI MS m/z 351 [Ci8H27N3O4 + H]+.
STEP 3: Synthesis of fert-butyl 3-(4-methoxy-2-(thiophene-2-carboxamido)benzamido) piperidine- 1 -carboxylate
Figure imgf000085_0001
To a solution of tert-bvΛy\ 3-(2-amino-4-methoxybenzamido)piperidine-l -carboxylate (170 mg, 0.50 mmol) and DIPEA (120 mg, 1.0 mmol) in CH2Cl2 (5 mL) and pyridine (1 rnL) at 0 degree was added thiophene-2-carbonyl chloride (88 mg, 0.60 mmol) dropwise. The reaction mixture was stirred for 18 h, concentrated, purified by flash chromatography (silica gel, ethyl acetate/hexanes gradient) to afford the desired product (200 mg, 89%) as a white solid: ESI MS m/z 460 [C23H29N3O5S + H]+.
STEP 4: Synthesis of iV-(5-hydroxy-2-(piperidin-3-ylcarbamoyl)phenyl)thiophene-2-carboxamide
Figure imgf000085_0002
To a solution of tert-hυXy\ 3-(4-methoxy-2-(thiophene-2-carboxamido) benzamido) piperidine- 1 -carboxylate (91 mg, 0.20 mmol) in CH2Cl2 (3 mL) at -78 degrees was added BBr3 (2.0 mL, 1.2 mmol, 1 M in CH2Cl2) and the reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was quenched by the addition of ice and methanol (2 mL) and concentrated. The residue was purified by preparative HPLC (C 18 silica, 10-90% acetonitrile/water with 0.05% TFA). The desired product was obtained as the trifluoroacetic acid salt which was eluted through an ion-exchange column (using methanol and 7 N methanol in ammonia) to afford the desired product (12 mg, 94%) as a white solid: 1H NMR (500 MHz, DMSO-J6) delta 12.93 (s, IH), 10.28 (s, IH), 8.57 (d, J= 12.5 Hz, IH), 8.09 (d, J= 3.5 Hz, IH), 7.89 (d, J= 8.0 Hz, IH), 7.82 (d, J= 15.0 Hz, IH), 7.70 (d, J= 4.5 Hz, IH), 7.28 - 7.25 (m, IH), 6.58 - 6.55 (m, IH), 4.19 (s, IH), 3.57 - 3.55 (m, IH), 3.46 - 3.33 (m, 2H), 1.91 - 1.87 (m, 2H), 1.68 - 1.30 (m, 5H); ESI MS m/z 346 [C]7Hi9N3O3S + H]+; HPLC > 99% (AUC), rR = 9.16 min.
Examples 123 Kinase assay
GSK3beta activity was measured in the presence or absence of compounds using Z'-LYTE kinase assay (Rodems SM, et al., Assay Drug Dev Technol. 1 : 9-19, 2002.) kit with SER/THR 9 peptide (Invitrogen) following the manufacturer's instruction. The Z'-LYTE kinase assay kit Page: 85/97 employs a fluorescence resonance energy transfer (FRET) between two fluorophores, coumarin and fluorescein, attached to each end of a substrate peptide.
Test compounds were dissolved in DMSO at 12.5 mM and then serially diluted as the DMSO concentration in the assays to be 1%. The serially diluted compounds, 0.04 ng/mcl GSKbeta (Invitrogen) and 2 mcM SER/THR 9 peptide were reacted in a reaction buffer (50 mM HEPES pH 7.5, 0.01% Brij-35, 10 mM MgCl2, 1 mM EGTA, 15 mcM ATP). For 0% phosphorylation control, ATP was omitted from the reaction mixture. For 100% phosphorylation control, SER/THR 9 phosphopeptide was used in place of the SER/THR 9 peptide. Following 1 hour incubation at room temperature, the reaction was stopped by the addition of half assay volume of development solution and further incubated for 1 hour at room temperature. After adding the half assay volume of stop reagent, emission signals of coumarin and fluorescein were measured by Wallac EnVision 2103 multilabel reader (PerkinElmer). The extent of phosphorylation was determined according to the 0% and 100% phosphorylation control samples using the following equation:
(emission ratio x Fioo%) - Cioo%
% phosphorylation = 1 - (Co% - Cioo%) + [emission ratio x (Fioo% - Fo%)] where: coumarin emission signal (445nm) emission ratio = fluorescein emission signal (520nm) Cioo% = coumarin emission signal of the 100% phosphorylation control Co% = coumarin emission signal of the 0% phosphorylation control Fioo% = fluorescein emission signal of the 100% phosphorylation control Fo% = fluorescein emission signal of the 0% phosphorylation control
IC5O values were calculated by nonlinear four parameter fit using SigmaPlot, version 10.0 (Systat
Software, Inc.).
IC5O values of the typical compounds of the present invention are shown in following table 12:
Table 12
Figure imgf000086_0001
Page: 86/97
Figure imgf000087_0001
Page: 87/97
Figure imgf000088_0001
Industrial Applicability
The present invention provides a novel benzoimidazole compound having GSK3beta inhibitory effect. The compounds of the present invention may be used for pharmaceutical composition for inhibiting GSK3-beta. Such pharmaceutical compositions are suitable for treating or preventing diseases involving GSK3beta.

Claims

Page: 88/97Claims
1. A compound represented by formula (I), or a salt, hydrate, solvate, or isomer thereof:
Figure imgf000089_0001
wherein Ring A is represented by the formula:
Figure imgf000089_0002
wherein
X is halogen or hydroxyl;
Y is hydrogen, phenyl, thiophen-2-yl, furan-2-yl, cyclopropyl, or cyclopentyl;
Z is a 5-10 membered heterocycle substituted carbonylamino; and -lΛ(CH2)a-L2-M is at position *; wherein, L1 is -CONH-, -NHCO-, or a single bond;
L2 is selected from the group consisting of -NH-, -O-, -CH(COOR1)-, -CH(CH2OH)-, -CH=CH- and a single bond, and wherein R1 is hydrogen or Cj-C6 alkyl; and
M is selected from the group consisting of hydroxyl, carboxyl, amide, Ci-C6 alkyl, Ci-C6 alkylcarbonyl, C6-Ci4 aryl, C6-Cj4 aryl Cj-C6 alkyl, C6-Ci4 arylcarbonyl, C6-Ci4 arylsulfonyl, a 5-14 membered saturated, unsaturated or aromatic heterocyclic group, a 5-14 membered unsaturated or aromatic heterocyclic group substituted Cj-C6 alkyl, a 5-14 membered unsaturated or aromatic heterocyclic group substituted sulfonyl, and -NR2R3 , wherein R2 and R3 are each independently Cj-C6 alkyl; wherein the Cj-C6 alkyl, the Cj-C6 alkylcarbonyl, the C6-Cj4 aryl, the C6-Cj4 aryl Cj-C6 alkyl, the C6-Ci4 arylcarbonyl, the C6-Cj4 arylsulfonyl, the 5-14 membered unsaturated or aromatic heterocyclic group, the 5-14 membered unsaturated or aromatic heterocyclic group substituted Cj-C6 alkyl, or the 5-14 membered unsaturated or aromatic heterocyclic group substituted sulfonyl is optionally substituted by 1 -3 substituent(s), each independently selected from group A; wherein group A is selected from the group consisting of hydroxyl, oxo, nitro, amino, amide, halogen, sulfamoyl, trifluoromethyl, p-toluenesulfonylamino, Cj-C6 alkyl, Cj-C6 alkoxy, Cj-C6 alkylcarbonylamino, and Cj-C6 alkylsulfonylamino; and a is an integer from 0-5.
2. The compound of Claim 1 , which is represented by formula (I-II): Fage: 89/y /
Figure imgf000090_0001
wherein
L1 is -CONH-;
L2 is a single bond; and
M is C6-CiO aryl or a 5-10 membered unsaturated or aromatic heterocycle group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, each of which is optionally substituted by 1 or 2 substituent(s) each independently selected from the group A.
3. The compound of Claim 2, wherein M is phenyl, imidazole- 1-yl, imdazole-2-yl, imidazole-5-yl, thiophen-2-yl, pyrole-2-yl, l,3-thiazole-2-yl, 2-pyrazoline-4-yl, or isoxazole-4-yl, each of which is optionally substituted by 1-2 substituent(s) each independently selected from group B; wherein group B is selected from the group consisting of fluoro, hydroxyl, oxo, amino, methyl, methoxy, and sulfamoyl.
4. The compound of Claim 1, which is represented by formula (I-II):
Figure imgf000090_0002
wherein
L1 is -CONH-;
L2 is -NH-; and
M is C]-C4 alkyl, Cj-C4 alkylcarbonyl, C6-Ci0 arylcarbonyl, C6-Ci0 arylsulfonyl, a 5-10 membered unsaturated or aromatic heterocyclic group having 1 -2 hetero atom(s) selected from the group consisting of N, O, and S or sulfonyl substituted by a 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, each of which is optionally substituted by 1 or 2 substituent(s) each independently selected form the group A.
5. The compound of Claim 4, wherein M is ethyl, isopropyl, methyl carbonyl, pyridine-2-yl, phenylcarbonyl, phenylsulfonyl, or 4-pyridylsulfonyl, each of which is optionally substituted by 1-2 substituent(s) each independently selected from group C; wherein group C is selected from the group consisting of chloro, hydroxyl, methyl, methylcarbonylamino, methylsulfonylamino, and p-toluenesulfonylamino.
6. The compound of Claim 1, which is represented by formula (I-II): Page: 90/97
Figure imgf000091_0001
wherein L1 is -CONH-;
L2 is -CH(COOR1)-, wherein R1 is hydrogen or Cj-C4 alkyl; and M is Cj-C4 alkyl, C6-Cj0 aryl C1-C4 alkyl or Cj-C4 alkyl substituted by a 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, each of which is optionally substituted by 1 or 2 substituent(s) each independently selected from the group A.
7. The compound of Claim 6, wherein M is methyl, phenylmethyl, indole-3-ylmethyl, or imidazole-4-ylmethyl, each of which is optionally substituted by 1-2 hydroxyl group(s).
8. The compound of Claim 1 , which is represented by formula (I-II):
Figure imgf000091_0002
wherein
L1 is -CONH-;
L2 is - O-; and
M is C6-Cj0 aryl or a 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, each of which is optionally substituted by 1 or 2 substituent(s) each independently selected from the group A.
9. The compound of Claim 8, wherein M is phenyl or pyridine-2-yl, each of which is optionally substituted by 1 or 2 substituent(s) each independently selected from group D; wherein group D is selected from the group consisting of amide, nitro, trifluoromethyl, and p-toluenesulfonylamino.
10. The compound of Claim 1, which is represented by formula (I- II):
Figure imgf000091_0003
wherein L1 is -CONH-; Page: 91/97
L2 is - CH(CH2OH)-; and
M is selected from the group consisting of hydroxyl, Cj-C4 alkyl, C6-Ci0 aryl Cj-C4 alkyl, and C]-C4 alkyl substituted by a 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, wherein the Ci-C4 alkyl, C6-C]0 aryl C]-C4 alkyl, and 5-10 membered unsaturated or aromatic heterocyclic group, are each optionally substituted by 1 or 2 substituent(s) each independently selected from the group A.
11. The compound of Claim 10, wherein M is hydroxyl, phenylmethyl, t-butyl, or imidazole-5 -ylmethyl .
12. The compound of Claim 1 , which is represented by formula (I- II):
Figure imgf000092_0001
wherein
Figure imgf000092_0002
wherein R2 and R3 are each independently C]-C4 alkyl optionally substituted by 1 or 2 substituent(s) each independently selected from the group A.
13. The compound of Claim 1 , which is represented by formula (I- II):
Figure imgf000092_0003
wherein
L1 is -NHCO-;
L2 is -NH-, -CH=CH- or a single bond; and
M is C6-Ci0 aryl or a 5-10 membered unsaturated or aromatic heterocyclic group having 1-2 hetero atom(s) selected from the group consisting of N, O, and S, each of which is optionally substituted by 1 or 2 substituent(s) each independently selected from the group A.
14. The compound of Claim 13, wherein M is phenyl optionally having 1 or 2 hydroxyl or imidazol-5-yl group(s).
15. The compound of Claim 1 , which is represented by formula (I-III): i^age: yz/y /
Figure imgf000093_0001
wherein
L1 is -CONH- or a single bond;
L2 is a single bond; and
M is amide or a 5-10 membered unsaturated or aromatic heterocyclic group having 1 or 2 hetero atom(s) selected from the group consisting of N, O, and S, optionally substituted by 1 or 2 substituent(s) each independently selected from the group A.
16. The compound of Claim 1 , which is represented by formula (I-IV):
Figure imgf000093_0002
wherein
L1 is -CONH-;
L2 is a single bond; and
M is a 5-10 membered unsaturated or aromatic heterocyclic group having 1 or 2 hetero atom(s) selected from the group consisting of N, O, and S, optionally substituted by 1 or 2 substituent(s) each independently selected from the group A.
17. The compound of Claim 1 , which is represented by formula (I- V) or (I- VI):
Figure imgf000093_0003
wherein
L1 is -CONH-;
L2 is a single bond; and
M is a 5-10 membered saturated, unsaturated or aromatic heterocyclic group having 1 or 2 hetero atom(s) selected from the group consisting of N, O, and S, optionally substituted by 1 or 2 substituent(s) each independently selected from the group A.
18. The compound of Claim 1 , wherein
L1 and L2 are both a single bond; M is carboxyl or amide; and a is 0.
19. The compound of any one of Claims 1-16 and 18, wherein Y is thiophen-2-yl. Page: 93/97
20. The compound of any one of Claims 1-16 and 18, wherein Y is furan-2-yl.
21. The compound of any one of Claims 1-16 and 18, wherein Y is phenyl.
22. The compound of any one of Claims 1-16 and 18 , wherein Y is cyclopropyl.
23. The compound of any one of Claims 1-16 and 18, wherein Y is cyclopentyl.
24. The compound of any one of Claims 1-16 and 18, wherein Y is hydrogen.
25. The compound of any one of Claims 1, 17, and 18, wherein Z is thiophen-2-ylcarbonylamino.
26. The compound of Claim 1, which is selected from the group consisting of: 7-Hydroxy-iV-[2-(phenylsulfonamido)ethyl]-2-(thiophen-2-yl)-lH-benzo[(f]imidazole-4-car boxamide,
N- [2-(4-Chlorophenylsulfonamido)ethyl] -7-hydroxy-2-(thiophen-2-yl)- 1 H-benzo [d\ imidazo le-4-carboxamide,
N-[2-(5-Carbamoylpyridin-2-yloxy)ethyl]-7-hydroxy-2-(thiophen-2-yl)-lH-benzo[(i]imidaz ole-4-carboxamide, 7V-(2,4-Difluorobenzyl)-7-hydroxy-2-(thiophen-2-yl)-lH-benzo[ύT]imidazole-4-carboxamide
7-Ηydroxy-N-(4-sulfamoylbe^^
7-Hydroxy-N-(3-methoxyphenethyl)-2-(thiophen-2-yl)-l//-benzo[(/Iimidazole-4-carboxami de, iV-[2-(5-Acetamidopyridin-2-ylamino)ethyl]-7-hydroxy-2-(thiophen-2-yl)-lH-benzo[d]imid azole-4-carboxamide,
N-[3-(l//-Imidazol-l-yl)propyl]-7-hydroxy-2-(thiophen-2-yl)-lH-benzo[tf]imidazole-4-carb oxamide, 7-Hydroxy-7V-(4-sulfamoylphenethyl)-2-(thiophen-2-yl)-l//-benzo[<f]imidazole-4-carboxam ide,
7-Hydroxy-N-{2-[5-(methylsulfonamido)pyridin-2-ylamino]ethyl}-2-(thiophen-2-yl)-lH-be nzo[tf]imidazole-4-carboxamide,
7-Ηydroxy-7V-[2-(l -methyl- lH-imidazol-5-yl)ethyl]-2-(thiophen-2-yl)-lH-benzo[<i] imidazo le-4-carboxamide,
7-Hydroxy-N- [2-(4-nitrophenoxy)ethyl] -2-(thiophen-2-yl)- 1 H-benzo [d] imidazole-4-carbox amide,
Methyl
3 -Hydroxy-2- [7-hydroxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazole-4-carboxamido]propano ate, jV-[2-(dimethylamino)ethyl]-7-hydroxy-2-(thiophen-2-yl)-li/-benzo[d]imidazole-4-carboxa mide,
(S)-2- [7-Hydroxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazole-4-carboxamido] -3 -( 1 H-indol-3 - yl)propanoic Acid, 7-Hydroxy-2-(thiophen-2-yl)-iV-[2-(thiophen-2-yl)ethyl]-l H-benzo [d] imidazole-4-carboxa mide, iV-(2-Acetamidoethyl)-7-hydroxy-2-(thiophen-2-yl)-lH-benzo[</]imidazole-4-carboxamide, jV-3-(lH-Imidazol-2-yl)propyl)-]7-hydroxy-2-(thiophen-2-yl)-l H-benzo [β(]imidazole-4-carb oxamide, Page: y4/y /
Methyl
2- [7-Hydroxy-2-(thiophen-2-yl)- 1 H-benzo [d\ imidazole-4-carboxamido] -3 -(4-hydroxyphen yl)propanoate,
N-[2-(l/f-Imidazol-2-yl)ethyl]-7-hydroxy-2-(thiophen-2-yl)-li7-benzo[t/]imidazole-4-carbo xamide,
2-(Furan-2-yl)-7-hydroxy-7V-phenethyl-l//-benzo[c/]imidazole-4-carboxamide,
2-(Furan-2-yl)-7-hydroxy-iV-phenyl-l//-benzo[<f]imidazole-4-carboxamide,
2-(Furan-2-yl)-7-hydroxy-iV- [2-( 1 -methyl- 1 H-pyrrol-2-yl)ethyl] - 1 H-benzo [ύT]imidazole-4-c arboxamide, 2-(Furan-2-yl)-7-hydroxy-N-(thiazol-2-yl)-lH-benzo[<i]imidazole-4-carboxamide,
7-Hydroxy-N-[3-(5-oxo-4,5-dihydro-l/f-pyrazol-4-yl)propyl]-2-(thiophen-2-yl)-l//-benzo[ d] imidazole-4-carboxamide,
N-(2-(3,5-dimethylisoxazol-4-yl)ethyl)-2-(furan-2-yl)-7-hydroxy-l//-benzo[βf]iniidazole-4-c arboxamide, 1 -(2-Cyclopropyl-7-hydroxy- 1 H-benzo [d] imidazol-4-yl)-3 -(4-hydroxyphenyl)urea, iV-(2-cyclopropyl-7-hydroxy-l//-benzo[<i]imidazol-4-yl)-2-(4-hydroxyphenyl)acetamide,
2-Cyclopentyl-4-hydroxy-jV-(4-hydroxyphenethyl)- 1 //-benzo [d] imidazole-7-carboxamide,
N-(4-Aminophenethyl)-2-cyclopentyl-4-hydroxy-lH-benzo[(f]imidazole-7-carboxamide,
4-Hydroxy-iV-(4-hydroxyphenethyl)-2-phenyl-l//-benzo[cf] imidazole-7-carboxamide, N-(4-Aminophenethyl)-4-hydroxy-2-phenyl-li:/-benzo [d\ imidazole-7-carboxamide,
4-Hydroxy-N-phenethyl-2-phenyl-l//-benzo[<f|imidazole-7-carboxamide ,
7-hydroxy-N-(3-methoxyphenethyl)-2-(thiophen-2-yl)-lH-benzo[d]imidazole-4-carboxami de, iV-(4-Fluorophenethyl)-7-hydroxy-2-(thiophen-2-yl)-l/f-benzo [d] imidazole-4-carboxamide, 7-Hydroxy-N-[2-(pyridine-4-sulfonamido)ethyl]-2-(thiophen-2-yl)-l//-benzo[(i]imidazole-4
-carboxamide,
7-Hydroxy-N-[2-(4-methylbenzamido)ethyl]-2-(thiophen-2-yl)-lH-benzo[(f]imidazole-4-car boxamide,
7-Hydroxy-7V-(thiazol-2-yl)-2-(thiophen-2-yl)-l//-benzo[tf]imidazole-4-carboxamide, 7-Hydroxy-2-(thiophen-2-yl)-N-[2-(5-(trifluoromethyl)pyridin-2-yloxy)ethyl]-lH-benzo[(/]i midazole-4-carboxamide,
7-Hydroxy-N- [2-(pyridin-2-ylamino)ethyl]-2-(thiophen-2-yl)- 1 H-benzo [d] imidazole-4-carb oxamide,
7-Hydroxy-N-(4-hydroxyphenethyl)-2-(thiophen-2-yl)-l//-benzo[(i]imidazole-4-carboxami de,
7-Hydroxy-iV-{2-[4-(4-methylphenylsulfonamido)phenoxy]ethyl}-2-(thiophen-2-yl)-lH-be nzo[tf]imidazole-4-carboxamide,
(5)-2-[7-Hydroxy-2-(thiophen-2-yl)-l//-benzo [d] imidazole-4-carboxamido] -3 -(lH-imidazo l-5-yl)propanoic Acid, (5)-Methyl 2-[7-Hydroxy-2-(thiophen-2-yl)-l//-benzo[<i]imidazole-4-carboxa mido]-3 -( 1 /f-indol-3 -yl)propanoate,
(5)-Methyl 2- [7-Hydroxy-2-(thiophen-2-yl)- 1 //-benzo [d] imidazole-4-carboxa mido]-3-(l//-imidazol-5-yl)propanoate,
7-Hydroxy-N-[3-(2-hydroxyethylamino)propyl]-2-(thiophen-2-yl)-l//-benzo[fif]imidazole-4 -carboxamide,
N-[3-(Isopropylamino)propyl]-7-hydroxy-2-(thiophen-2-yl)-l//-benzo[i/]imidazole-4-carbo xamide,
(5)-7-Hydroxy-N-( 1 -hydroxy-3 -phenylpropan-2-yl)-2-(thiophen-2-yl)- 1 /f-benzo [d] imidazol e-4-carboxamide, 7-Hydroxy-2-(thiophen-2-yl)- l/f-benzo[β(]imidazole-4-carboxylic acid, Page: 95/97
(<S)-7-Hydroxy-iV-( 1 -hydroxy-3 ,3 -dimethylbutan-2-yl)-2-(thiophen-2-yl)- 1 //-benzo [JJimida zole-4-carboxaniide,
(i?)-7-Hydroxy-N- [ 1 -hydroxy-3 -( 1 H-imidazol-4-yl)propan-2-yl] -2-(thiophen-2-yl)- 1 H-benz
0 [d] imidazole-4-carboxamide, iV-(3,4-Dihydroxybenzyl)-7-hydroxy-2-(thiophen-2-yl)-lH-benzo[(f]imidazole-4-carboxami de, 2-(Furan-2-yl)-7-hydroxy-N-{2-[5-(4-methylphenylsulfonamido)pyridin-2-ylamino]ethyl}-
1 H-benzo [d] imidazole-4-carboxamide, N-(3,4-Dihydroxyphenethyl)-2-(furan-2-yl)-7-hydroxy-l//-benzo[(i]imidazole-4-carboxami de,
2-Cyclopropyl-N-(4-hydroxyphenyl)-4-methoxy- 1 /f-benzo [d] imidazole-7-carboxamide, 2-Cyclopropyl-4-hydroxy-N-(4-sulfamoylphenethyl)-lH-benzo[J]imidazole-7-carboxamide
2-Cyclopropyl-N-(4-fluorophenethyl)-4-hydroxy-l//-benzo[cT|imidazole-7-carboxamide, 2-Cyclopropyl-N-(2,3-dihydroxypropyl)-4-hydroxy-l//-benzo[ύT] imidazole-7-carboxamide,
2-Cyclopropyl-iV-(2-(dimethylamino)ethyl)-4-hydroxy-l//-benzo[<f]imidazole-7-carboxami de,
7-Hydroxy-2-(thiophen-2-yl)-lH-benzo[tf]imidazole-5-carboxamide (Example No. 65),
N-[2-(lH-Imidazol-5-yl)ethyl]-7-hydroxy-2-(thiophen-2-yl)-li/-benzo[tf]imidazole-5-carbo xamide,
N-{5-[2-(lH-Imidazol-5-yl)ethylcarbamoyl]-2-hydroxyphenyl}thiophene-2-carboxamide,
N- [2-( 1 H-Imidazol-5 -yl)ethyl] -7-fluoro-2-(thiophen-2-yl)- 1 /f-benzo [d] imidazole-4-carboxa mide,
N-[2-(lH-Imidazol-5-yl)ethyl]-7-hydroxy-lH-indole-3-carboxamide, (E)-3-(lH-imidazol-5-yl)-N-(7-methoxy-2-(thiophen-2-yl)-lH-benzo[d]imidazol-4-yl) acrylamide,
N-(7-hydroxy-2-(thiophen-2-yl)- 1 H-benzo [d] imidazol-4-yl)-3 -( 1 H-imidazol-5-yl)propanam ide, and iV-(5-hydroxy-2-(piperidin-3-ylcarbamoyl)phenyl)thiophene-2-carboxamide.
27. A method for preparing a compound of any one of Claims 2- 15 which comprises the steps of: reacting a carboxyalkyl substituted aniline derivative with nitrile in the presence of an acid; cyclizing the intermediate amidine to obtain a benzimidazole derivative; saponifying the carboxyalkyl of the benzimidazole derivative; and forming an amide by either coupling the obtained carboxylic acid with an amine derivative, which may be further modified and extended after coupling, or converting the carboxylic acid to an amine and then coupling with a carboxylic acid derivative, which may be further modified and extended after coupling, to obtain the amide compounds of any one of Claims 2-15.
28. A method for preparing a compound of Claim 16 which comprises the steps of: treating an indole derivative with trifluoroacetic acid anhydride to obtain a trifluoromethylketone ; hydrolyzing to the carboxylic acid; and coupling the carboxylic acid with an amine derivative to obtain the compound of Claim 16.
29. A method of preparing a compound of Claim 17 which comprises the steps of: coupling a carboxyalkyl substituted aniline derivative with a carboxylic acid derivative; hydrolyzing the carboxymethyl of the obtained amide to obtain a carboxylic acid; and coupling the carboxylic acid with an amine derivative to obtain the compound of Claim 17. Fage: yo/y /
30. A pharmaceutical composition comprising at least one compound of Claim 1 and a pharmaceutically acceptable carrier.
31. A pharmaceutical composition of Claim 30 which is available for preventing or treating diseases selected from the group consisting of Alzheimer disease, mania, depression, migraine and type 2 diabetes.
32. A glycogen synthase kinase-3 Beta inhibitor comprising at least one compound of Claim 1.
***************************************
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WO2012004269A1 (en) 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
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