WO2006116412A2 - Fused heterocyclic compounds - Google Patents

Fused heterocyclic compounds Download PDF

Info

Publication number
WO2006116412A2
WO2006116412A2 PCT/US2006/015646 US2006015646W WO2006116412A2 WO 2006116412 A2 WO2006116412 A2 WO 2006116412A2 US 2006015646 W US2006015646 W US 2006015646W WO 2006116412 A2 WO2006116412 A2 WO 2006116412A2
Authority
WO
WIPO (PCT)
Prior art keywords
methyl
optionally substituted
compound
mmol
chloro
Prior art date
Application number
PCT/US2006/015646
Other languages
French (fr)
Other versions
WO2006116412A3 (en
WO2006116412A8 (en
Inventor
Kazuyoshi Aso
Michiyo Mochizuki
Albert Charles Gyorkos
Christopher Peter Corrette
Suk Young Cho
Scott Alan Pratt
Christopher Stephen Siedem
Original Assignee
Takeda Pharmaceutical Company Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP2008509045A priority Critical patent/JP5061097B2/en
Priority to US11/919,435 priority patent/US8163935B2/en
Priority to MX2007013154A priority patent/MX2007013154A/en
Priority to CN2006800147137A priority patent/CN101166729B/en
Application filed by Takeda Pharmaceutical Company Limited filed Critical Takeda Pharmaceutical Company Limited
Priority to KR1020077024873A priority patent/KR101368037B1/en
Priority to CA002605453A priority patent/CA2605453A1/en
Priority to BRPI0610150-0A priority patent/BRPI0610150A2/en
Priority to EP06751379A priority patent/EP1874736A4/en
Priority to AU2006241210A priority patent/AU2006241210B2/en
Priority to NZ562235A priority patent/NZ562235A/en
Publication of WO2006116412A2 publication Critical patent/WO2006116412A2/en
Publication of WO2006116412A8 publication Critical patent/WO2006116412A8/en
Publication of WO2006116412A3 publication Critical patent/WO2006116412A3/en
Priority to IL186407A priority patent/IL186407A/en
Priority to NO20075936A priority patent/NO20075936L/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/02—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • 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
    • C07D409/10—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 linked by a carbon chain containing aromatic 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
    • C07D409/02—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
    • C07D409/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/10—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 two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel nitrogen- containing fused heterocyclic compounds having CRF (corticotropin releasing factor) antagonistic activity and pharmaceutical compositions containing them.
  • CRF corticotropin releasing factor
  • Corticotropin-releasing factor (hereinafter, abbreviated as "CRF”) is a neuropeptide composed of 41 amino acids, and was isolated and purified as a peptide promoting release of adrenocorticotropic hormone (ACTH) from pituitary gland.
  • ACTH adrenocorticotropic hormone
  • the structure thereof was determined from sheep hypothalamus and, thereafter, the presence thereof was confirmed also in a rat or a human, and the structure thereof was determined [Science, 213, 1394(1981); Proc. Natl. Acad. Sci USA, 80, 4851(1983); EMBO J. 5, 775(1983)].
  • An amino acid sequence is the same in a human and a rat, but differed in 7 amino acids in ovine.
  • CRF is synthesized as a carboxy-terminal of prepro CRF, cut and secreted.
  • the CRF peptide and a mRNA thereof are present at the largest amount in hypothalamus and pituitary gland, and are widely distributed in a brain such as cerebral cortex, cerebellum, hippocampus and corpus amygdaloideum.
  • a brain such as cerebral cortex, cerebellum, hippocampus and corpus amygdaloideum.
  • peripheral tissues the existence has been confirmed in placenta, adrenal gland, lung, liver, pancreas, skin and digestive tract [J. Clin. Endocrinol. Metab., 65, 176(1987); J. Clin. Endocrinol. Metab., 67, 768(1988); Regul .
  • a CRF receptor is a 7- transmembrane G protein-coupled receptor, and two subtypes of CRFl and CRF2 are present. It is reported that CRFl is present mainly in cerebral cortex, cerebellum, olfactory bulb, pituitary gland and tonsil nucleus. On the other hand, the CRF2 receptor has two subtypes of CRF2 ⁇ and CRF2 ⁇ .
  • the CRF2 ⁇ receptor is distributed much in hypothalamus, septal area and choroids plexus, and the CRF2 ⁇ receptor is present mainly in peripheral tissues such as skeletal muscle and is distributed in a blood vessel in a brain [J. Neurosci. 15, 6340(1995); Endocrinology, 137, 72(1996); Biochim. Biophys . Acta, 1352, 129(1997)]. Since each receptor differs in distribution in a living body, it is suggested that a role thereof is also different [Trends. Pharmacol. Sci. 23, 71(2002)].
  • CRF As a physiological action of CRF, the action on the endocrine system is known in which CRF is produced and secreted in response to stress in hypothalamus and acts on pituitary gland to promote the release of ACTH [Recent Prog. Horm. Res., 39, 245(1983)].
  • CRF acts as a neurotransmitter or a neuroregulating factor in a brain, and integrates electrophysiology, autonomic nerve and conducts to stress [Brain Res. Rev., 15, 71(1990); Pharmacol. Rev., 43, 425(1991)].
  • ⁇ - helical CRF (9-41) of a peptidergic CRF receptor antagonist exerts an anti-anxiety action in an animal model [Brain Res., 509, 80(1990); J. Neurosci., 14, 2579(1994)].
  • a blood pressure, a heart rate and a body temperature of a rat are increased by stress or CRF administration, but the ⁇ -helical CRF (9-41) of a peptidergic CRF antagonist inhibits the increase in a blood pressure, a heart rate and a body temperature due to stress [J. Physiol., 460, 221(1993)].
  • the ⁇ -helical CRF (9-41) of a peptidergic CRF receptor antagonist inhibits abnormal conducts due to withdrawal of a dependent drug such as an alcohol and a cocaine [Psychopharmacology, 103, 227(1991); Pharmacol. Rev.53, 209(2001)].
  • a dependent drug such as an alcohol and a cocaine
  • learning and memory are promoted by CRF administration in a rat [Nature, 375, 284(1995); Neuroendocrinology, 57, 1071(1993); Eur. J. Pharmacol., 405, 225(2000)].
  • CRF is associated with stress response in a living body
  • the CRF concentration in a cerebrospinal fluid of a depression patient is higher as compared with that of a normal person [Am. J. Psychiatry, 144, 873(1987)]
  • the mRNA level of CRF in hypothalamus of a depression patient is increased as compared with that of a normal person [Am. J. Psychiatry, 152, 1372(1995)].
  • a CRF binding site of cerebral cortex of a patient who suicided by depression is decreased [Arch. Gen. Psychiatry, 45, 577(1988)].
  • the increase in the plasma ACTH concentration due to CRF administration is small in a depression patient [N. Engl.
  • CRF In a CRF- overexpressing mouse, excessive secretions of ACTH and adrenal cortex steroid occur, and abnormalities analogous to Gushing' s syndrome such as atrophy of muscle, alopecia, infertility and the like are observed [Endorcrinology, 130, 3378(1992)].
  • CRF inhibits ingestion in an experimental animal such as a rat [Life Sci., 31, 363 (1982); Neurophamacology, 22, 337(1983)].
  • ⁇ -helical CRF (9-41) of a peptidergic CRF antagonist inhibited decrease of ingestion due to stress loading in an experimental model [Brain Res. Bull., 17, 285(1986)].
  • CRF inhibited weight gain in a hereditary obesity animal [Physiol. Behav.
  • CRF is centrally or peripherally associated with the digestive tract movement involved in stress or inflammation [Am. J. Physiol. Gastrointest . Liver Physiol. 280,
  • CRF acts centrally or peripherally, weakens the shrinkablity of stomach, and decreases the gastric excreting ability [Regulatory Peptides, 21, 173(1988); Am. J. Physiol., 253, G241(1987)].
  • ⁇ -helical CRF (9-41) of a peptidergic CRF antagonist has a restoring action for hypofunction of stomach by abdominal operation [Am. J. Physiol., 258, G152(1990)].
  • CRF inhibits secretion of a bicarbonate ion in stomach, decreases gastric acid secretion and inhibits ulcer due to cold restriction stress [Am. J. Physiol., 258, G152(1990)].
  • ⁇ -helical CRF (9-41) of a peptidergic CRF antagonist shows the inhibitory action on gastric acid secretion decrease, gastric excretion decrease, small intestinal transport decrease and large intestinal transport enhancement due to restriction stress [Gastroenterology, 95, 1510(1988)].
  • CRF decreases a threshold of discomfort [Gastroenterology, 109, 1772(1995); Neurogastroenterol . Mot., 8, 9 [1996].
  • a irritable bowel syndrome patient large intestinal , movement is excessively enhanced by CRF administration as compared with a healthy person [Gut, 42, 845(1998)].
  • CRF In an inflammatory site of an experimental animal and in a joint fluid of a rheumatoid arthritis patient, production of CRF is topically increased [Science, 254, 421(1991); J. Clin. Invest., 90, 2555(1992); J. Immunol., 151, 1587(1993)].
  • CRF induces degranulation of a mast cell and enhances the blood vessel permeability [Endocrinology, 139, 403(1998); J.Pharmacol. Exp. Ther., 288, 1349(1999)].
  • CRF can be detected also in a thyroid gland of autoimmune thyroiditis patient [Am. J. Pathol. 145, 1159(1994)].
  • CRF receptor antagonistic compound would exert an excellent effect for treating or preventing various diseases in which CRF is involved.
  • a CRF antagonist for example, peptide CRF receptor antagonists are reported in which a part of an amino acid sequence of CRF or associated peptides of a human or other mammals is altered or deleted, and they are reported to show a pharmacological action such as ACTH release- inhibiting action and anti-anxiety action [Science, 224, 889(1984); J. Pharmacol. Exp. Ther., 269, 564(1994); Brain Res. Rev., 15, 71(1990)].
  • peptide derivatives have a low utility value as a medicine.
  • R 1 is an optionally substituted hydrocarbyl, an_ optionally substituted C-linked heterocyclic group, an optionally substituted N-linked heteroaryl group, or an acyl, provided that methyl, and trifluoromethyl are excluded;
  • R 2 is an optionally substituted cyclic hydrocarbyl or an optionally substituted heterocyclic group, provided that 2- [2- (1, l-dimethylethyl)phenyloxy] -3-pyridinyl is excluded;
  • X is oxygen, sulfur or -NR 3 - (wherein R 3 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ;
  • Y 1 , Y 2 and Y 3 are each an optionally substituted carbon or a nitrogen, provided that one or less of Y 1 , Y 2 and Y 3 is nitrogen; and Z is a bond, -CO-, oxygen, sulfur, -SO-, -SO 2 -, -NR 4 -, -NR 4 - alk-, -CONR 4 - or -NR 4 CO- (wherein alk is an optionally substituted C 1 - 4 alkylene and R 4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ; provided that (i) the compound wherein X is -NH-, and R 2 is an optionally substituted thiophene ring, (ii) the compound wherein R 1 is cyano, Y 3 is carbon which is substituted with methyl substituted with three substituents, one of which is acyl, and other two of which may form a ring,
  • a process for producing the compound according to the above-mentioned (1) which comprises reacting a compound represented by the formula: wherein L represents a leaving group selected from halogen atom, sulfonyloxy group and acyloxy group, and other symbols are as defined in the above-mentioned (1), with a compound represented by the formula:
  • a pharmaceutical composition which comprises the compound according to the above-mentioned (1) ;
  • a CRF receptor antagonist which is the compound represented by the formula (I 1 ) :
  • R 1 is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic group, an optionally substituted N-linked heteroaryl group, a cyano or an acyl;
  • R 2 is an optionally substituted cyclic hydrocarbyl or an optionally substituted heterocyclic group
  • X is oxygen, sulfur or -NR - (wherein R is a hydrogen, an optionally substituted hydrocarbyl or an acyl)
  • Y 1 , Y 2 and Y 3 are each an optionally substituted carbon or a nitrogen, provided that one or less of Y 1 , Y 2 and Y 3 is nitrogen;
  • Z is a bond, -CO-, oxygen, sulfur, -SO-, -SO 2 -, -NR 4 -, -NR 4 - alk-, -CONR 4 - or -NR 4 CO- (wherein alk is an optionally substituted C ⁇ - 4 alkylene and R 4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ; or a salt thereof;
  • a method for treating or preventing a disease wherein a CRF receptor is implicated which comprises administering to a subject in need thereof an effective amount of the CRF receptor antagonist according to the above-mentioned (19); (21) The method according to the above-mentioned (20) wherein the disease being treated or prevented is selected from affective disorder, depression or anxiety;
  • composition according to the above- mentioned (24) wherein the disease being treated or prevented is selected from affective disorder, depression or anxiety; and the like.
  • hydrocarbyl means a univalent group containing only carbon and hydrogen.
  • X represents an oxygen, a sulfur or -NR 3 - (wherein R 3 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) . That is, examples of the 5-membered ring in the formula (I) and (I 1 ) include an oxazole ring, a thiazole ring and an imidazole ring.
  • Examples of the "hydrocarbyl" of the “optionally substituted hydrocarbyl” represented by R 3 of the formula: -NR 3 - include an optionally substituted aliphatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group, an optionally substituted alicyclic- aliphatic hydrocarbon group, an optionally substituted alicyclic-alicyclic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, an optionally substituted aromatic-aliphatic hydrocarbon group (an aralkyl group) , and the like.
  • aliphatic hydrocarbon group examples include a saturated aliphatic hydrocarbon group having 1-8 carbon atoms (e.g., alkyl group) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.; and an unsaturated aliphatic hydrocarbon group having 2-8 carbon atoms (e.g., alkenyl group, alkynyl group, alkadienyl group, alkadiynyl group, etc.) such as vinyl, allyl, 1-propenyl,- 2-methyl-l-propenyl, 1-butenyl, 2- butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-penten
  • alicyclic hydrocarbon group examples include a saturated alicyclic hydrocarbon group having 3-7 carbon atoms (e.g., cycloalkyl group, etc.) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like; an unsaturated alicyclic hydrocarbon group having 3-7 carbon atoms (e.g., cycloalkenyl group, cycloalkadienyl group, etc.) such as 1-cyclopentenyl, 2-cyclopentenyl, 3- cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3- cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3- cycloheptenyl, 2, 4-cycloheptadienyl, etc.; a partly saturated and fused bicyclic hydrocarbon group [preferably, Cg-io partly saturated and fused
  • Said alicyclic hydrocarbon group may be cross-linked.
  • alicyclic-aliphatic hydrocarbon group examples include those where the above-mentioned alicyclic hydrocarbon group and the above-mentioned aliphatic hydrocarbon group are combined, for example, those having 4-14 carbon atoms such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3- cyclopentenylmethyl, cyclopentylethyl, cyclohexylmethyl, 2- cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, 2- (3, 4-dihydro-2- naphtyl) ethyl, 2- (1, 2, 3, 4-tetrahydro-2-naphtyl) ethyl, 2- (3, 4-dihydro-2-na
  • C 3 _ 7 cycloalkyl- Ci_ 4 alkyl group e.g., C 3 _ 7 cycloalkyl- Ci_ 4 alkyl group, C 3 - 7 cycloalkenyl-Ci- 4 alkyl group, C3- 7 cycloalkyl-C2-4 alkenyl group, C3_ 7 cycloalkenyl-C2-4 alkenyl group, C 9 - 10 partly saturated and fused bicyclic hydrocarbon-Ci- 4 alkyl group, C 9 -. 3.0 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl groups, etc.).
  • alicyclic-alicyclic hydrocarbon group examples include a C 1 - 4 alkyl group substituted with two C 3 - 7 cycloalkyls selected from the above-mentioned alicyclic hydrocarbon group, for example, those represented by the formula:
  • aromatic hydrocarbon group examples include an aryl group having 6-10 carbon atoms (including that where a 5- to ⁇ -membered non-aromatic hydrocarbon ring is fused with phenyl group) such as phenyl, ⁇ -naphthyl, ⁇ -naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8- tetrahydro-1-naphthyl, 5, 6, 7, 8-tetrahydro-2-naphthyl, 5,6- dihydro-1-naphthyl, 5, 6-dihydro-2-naphthyl, 5, 6-dihydro-3- naphthyl, 5, 6-dihydro-4-naphthyl, etc.; and the like.
  • aryl group having 6-10 carbon atoms including that where a 5- to ⁇ -membered non-aromatic hydrocarbon ring is fused with
  • aromatic-aliphatic hydrocarbon group examples include an aralkyl group having 7-14 carbon atoms (C ⁇ -io aryl-Ci-4 alkyl group) such as phenyl-Ci_ 4 alkyl group, e.g., benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2- phenylpropyl, 3-phenylpropyl, etc.; naphthyl-Ci_4 alkyl group such as ⁇ -naphthylmethyl, ⁇ -naphthylethyl, ⁇ - naphthylmethyl, ⁇ -naphthylethyl, etc.; C 6 -I 0 aryl-C2-4 alkenyl group such as phenyl-C 2 - 4 alkenyl group, e.g., styryl, cinnamyl, etc.; and the like.
  • hydrocarbyl group may have a substituent at a substitutable position.
  • substituents include a halogen, nitro, cyano, oxo, (1) an optionally substituted heterocyclic group, (2) an optionally substituted sulfinyl group, (3) an optionally substituted sulfonyl group, (4) optionally substituted hydroxyl group, (5) optionally substituted thiol group, (6) an optionally substituted amino group, (7) an acyl group,
  • Examples of the substituent of above-mentioned (2) an optionally substituted sulfinyl group, (3) an optionally substituted sulfonyl group, (4) optionally substituted hydroxyl group, (5) optionally substituted thiol group and (6) an optionally substituted amino group include an optionally substituted hydrocarbyl.
  • hydrocarbyl of such optionally substituted hydrocarbyl include those exemplified above. Such hydrocarbyl may be substituted by one or more substituents at a substitutable position. Examples of the substituent group of the optionally substituted hydrocarbyl as a substituent group include halogen, nitro, cyano, hydroxyl, thiol, amino and carboxyl .
  • Ci_ 6 alkylsulfinyl e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl etc.
  • C ⁇ -io arylsulfinyl e.g., phenylsulfinyl, naphthylsulfinyl etc.
  • Ci_ 6 alkylsulfonyl e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl etc.
  • C ⁇ -io arylsulfonyl e.g., phenylsulfonyl, naphthylsulfonyl etc.
  • hydroxyl, Ci_ 6 alkoxy e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.
  • C ⁇ -io aryloxy e.g., phenoxy, naphthoxy, etc.
  • thiol As the optionally substituted thiol group of above- mentioned (5), specifically, thiol, C 1 - S alkylthio (e.g., methylthio, ethylthio, propylthio, etc.) and C ⁇ -IO arylthio (e.g., phenylthio, naphthylthio etc.) are exemplified.
  • C 1 - S alkylthio e.g., methylthio, ethylthio, propylthio, etc.
  • C ⁇ IO arylthio e.g., phenylthio, naphthylthio etc.
  • amino, mono-Ci_ 6 alkylamino e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino etc.
  • di-Ci- 6 alkylamino e.g., dimethylamino, diethylamino, ethylmethylamino, dipropylamino, diisopropylamino, dibutylamino etc.
  • Examples of the acyl group of above-mentioned (7) include the same group as the acyl for R 3 .
  • ester group or amide group of the optionally esterified or amidated carboxyl group of above- mentioned (8) examples include ester group with the same optionally substituted hydrocarbyl as the substituent of optionally substituted hydroxyl group of above-mentioned (4) or amide group with optionally substituted amino group of above- mentioned (6) .
  • carboxyl specifically, carboxyl, Ci_ 6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert- butoxycarbonyl etc.), C ⁇ -io aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), C 7 - I6 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, • phenetyloxycarbonyl etc.), and the like are exemplified.
  • carboxyl Ci_ 6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert- butoxycarbonyl etc.)
  • C ⁇ -io aryloxy-carbonyl e.g., phenoxycarbonyl etc.
  • C 7 - I6 aralkyloxy-carbonyl e.g., benz
  • carbamoyl mono-Ci_ 6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.), di-C ⁇ - 6 alkyl- carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), Ce-io aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), 5- to 6-membered heterocyclic carbamoyl (e.g., 2- pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl,
  • acyl represented by R 3 of the formula: -NR 3 - include a formyl and a group where the carbonyl group is combined with a Ci_io alkyl group, a C 2 - 10 alkenyl group, a C 2 -io alkynyl group, a C 3 -.7 cycloalkyl group, a C 5 - 7 cycloalkenyl group or an aromatic group (e.g., phenyl group, pyridyl group, etc.) (e.g., acetyl, propionyl, butyryl, isobytyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-
  • R 3 is preferably hydrogen, Ci_io alkyl, C 2 -io alkenyl, C2-10 alkynyl, and more preferably hydrogen, Ci- 10 alkyl.
  • R 3 methyl, ethyl, hydroxyethyl and the like are preferred.
  • R 1 in the formula (I) and (I 1 ) is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic group, an optionally substituted N-linked heteroaryl group, a cyano or an acyl.
  • C- linked of said “optionally substituted C-linked heterocyclic group” means that R 1 is linked via a carbon atom of the heterocyclic group of R 1 to the fused bicyclic ring represented by the formula (I) .
  • N- linked of the "optionally substituted N-linked heteroaryl group” means that R 1 is linked via a nitrogen atom of the heteroaryl group of R 1 to the fused bicyclic ring represented by the formula (I) .
  • Examples of the "optionally substituted hydrocarbyl” for R 1 include the same groups as those exemplified with respect to the optionally substituted hydrocarbyl of R 3 .
  • Examples of the "optionally substituted heterocyclic group" in the “optionally substituted C-linked heterocyclic group” for R 1 include the same groups as those exemplified below with respect to the optionally substituted heterocyclic group of R 2 .
  • heteroaryl group in the "optionally substituted N-linked heteroaryl group” for R 1 examples include a 5- to 10-membered aromatic heterocyclic group optionally containing 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom (e.g., pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3- oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, furazanyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1,3,4- thiadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triaziny
  • Said heteroaryl group may be substituted with 1 to 3 substituents selected from the group consisting of halogen, Ci- 6 alkyl, C 2 -6 alkenyl, Ci- 6 alkoxy-Ci- 6 alkyl, C 5 _ 7 cycloalkyl, C ⁇ -io aryl (said aryl may have 1 or 2 substituents selected from halogen, Ci- 6 alkyl, halogeno Ci- 6 alkyl and Ci_ 6 alkoxy) , C 7 - I4 aralkyl (said aralkyl may have 1 or 2 substituents selected from halogen, Ci-e alkyl, halogeno Ci_ 6 alkyl and Ci_ 6 alkoxy) , hydroxy, hydroxy-Ci_ 6 alkyl, C ⁇ -io aryloxy (said aryloxy may have 1 or 2 substituents selected from halogen, Ci- 6 alkyl, halogeno Ci_6 alkyl and Ci_ 6 al
  • acyl examples include the same groups as those exemplified with respect to the acyl of R 3 .
  • R 1 in the formula (I) and (I 1 ) is preferably an optionally substituted acyclic branched C 3 _ 14 hydrocarbyl (preferably acyclic branched C 3 _ 7 hydrocarbyl such as 2-propyl, 3-hexyl, 3-pentyl, 4-heptyl, etc. ) , an optionally substituted C ⁇ -io aryl, an optionally substituted C-linked 5- to 14-membered heterocyclic group or N-linked 5- to 10-membered heteroaryl group.
  • R 2 in the formula (I) and (I 1 ) is an optionally substituted cyclic hydrocarbyl or an optionally substituted heterocyclic group.
  • Examples of the "cyclic hydrocarbyl" of the "optionally substituted cyclic hydrocarbyl” for R 2 include a C 3 - 7 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc) , a C 3 - 7 cycloalkenyl group (e.g., 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3- cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3- cycloheptenyl, etc) , an aryl group having 6-10 carbon atoms
  • phenyl such as phenyl, ⁇ -naphthyl, ⁇ -naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5- indanyl, 5, 6, 7 , 8-tetrahydro-l-naphthyl, 5, 6, 7, 8-tetrahydro- 2-naphthyl, 5, 6-dihydro-l-naphthyl, 5, 6-dihydro-2-naphthyl, 5, 6-dihydro-3-naphthyl, 5, 6-dihydro-4-naphthyl, etc.; and the like.
  • each of the heterocyclic groups exemplified in (i) to (iv) may be a saturated or unsaturated heterocyclic group and the unsaturated heterocyclic group may be either aromatic or non-aromatic.
  • heterocyclic group for an optionally substituted heterocyclic group of R 2 examples include an aromatic monocyclic heterocyclic group and a non-aromatic heterocyclic group.
  • heterocyclic group for an optionally substituted heterocyclic group include (i) an aromatic monocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, furazanyl, 1,2,3- thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.) and (ii) a non-aromatic, heterocyclic group (e.g., oxiranyl, azetidiny
  • cycloalkyl may have the same substituent as those exemplified with respect to the optionally substituted hydrocarbyl group of R 3 and further may have the same group as optionally substituted hydrocarbyl group of R 3 as their substituent.
  • two of the substituents of the "cyclic hydrocarbyl” in the “optionally substituted cyclic hydrocarbyl” or “heterocyclic group” in the “optionally substituted heterocyclic group” for R 2 may be combined each other to form a fused ring with the cyclic hydrocarbyl or heterocyclic group.
  • fused ring examples include, for example, an aromatic fused heterocyclic group such as 8- to 12-membered aromatic fused heterocyclic group (preferably, heterocyclic group consisting of the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group fused with a benzene ring or heterocyclic group consisting of the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group fused with the same or different above- mentioned 5- or ⁇ -membered aromatic monocyclic heterocyclic group), etc. (e.g.
  • substituent of the "cyclic hydrocarbyl” in the “optionally substituted cyclic hydrocarbyl” or “heterocyclic group” in the “optionally substituted heterocyclic group” for R 2 may be combined together with the substituent: R 4 of -NR 4 -, -NR 4 -alk-, - CONR 4 - or -NR 4 CO- in Z of formula (I) or (I 1 ) to form a nitrogen-containing fused ring with the cyclic hydrocarbyl or heterocyclic group of R 2 .
  • fused ring examples include, for example, 8- to 12-membered bicyclic heterocyclic group formed by a fusion of a benzene ring with a saturated monocyclic heterocyclic group containing one nitrogen atom such as 1, 2, 3, 4-tetrahydroquinolyl, 2, 3, 4, 5-tetrahydro-lH-l-benzazepinyl, and the like.
  • fused ring and “nitrogen- containing fused ring” may further have one to three substituents selected from an acyl (e.g., acetyl, propionyl, etc.), an amide (e.g., dimethylaminocarbonyl, methylaminocarbonyl, etc.), an amine (e.g., dimethylamino, methylamino, amino, etc.), a halogen (e.g., fluorine, chlorine, bromine, etc.), a lower alkyl (e.g., methyl, ethyl, trifluoromethyl, etc.) and a lower alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, etc.), each of which may be substituted.
  • an acyl e.g., acetyl, propionyl, etc.
  • an amide e.g., dimethylaminocarbonyl, methylaminocarbonyl,
  • R 2 is preferably an optionally- substituted Ce-io aryl (more preferably phenyl) or an optionally substituted 5- to 8-membered (more preferably 5- to 6-membered) heterocyclic group (more preferably pyridyl) .
  • R 2 is more preferably phenyl which is 2, 4-disubstituted, 2, 4, 6-trisubstituted or 2, 4, 5-trisubstituted with two or three substituents, or pyridyl which is disubstituted or trisubstituted with two or three substituents.
  • the substituents for the phenyl and pyridyl may be the same or different and examples thereof include an acyl (e.g., acetyl, propionyl, etc.), an ' amide (e.g., dimethylaminocarbonyl, methylaminocarbonyl, etc.), an amine (e.g., dimethylamino, methylamino, amino, etc.), a halogen (e.g., fluorine, chlorine, bromine, etc.), a lower alkyl (e.g., methyl, ethyl, trifluoromethyl, etc.) and a lower alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, etc.), each of which may be substituted.
  • an acyl e.g., acetyl, propionyl, etc.
  • an ' amide e.g., dimethylaminocarbonyl, methylamino
  • Y 1 is CR 3a or a nitrogen
  • Y 2 is CR 3b or a nitrogen
  • Y 3 is CR 3c or a nitrogen
  • R 3a , R 3b and R 3c are independently a hydrogen, a halogen, a nitro, a cyano, an optionally substituted hydrocarbyl, an optionally substituted hydrocarbyloxy, an optionally substituted hydrocarbylthio, an optionally substituted amino or an acyl
  • the 6-membered ring with Y 1 , Y 2 and Y 3 of the formula (I) and (I 1 ) is a ring containing one or less nitrogen atom such as benzene ring and pyridine ring.
  • halogen include fluorine, chlorine, bromine, iodine, and the like, preferably, chlorine and bromine .
  • Examples of the "optionally substituted hydrocarbyl" in R 3a , R 3b and R 3c include the same groups as those exemplified with respect to the optionally substituted hydrocarbyl of R 3 .
  • an optionally substituted Ci_ 3 alkyl is preferred, and an unsubstituted Ci- 3 alkyl, C 1 - 3 alkyl substituted with hydroxy and C 1 - 3 alkyl substituted with an amine (e.g., dimethylamino, methylamino, pyrrolidine, etc.) are more preferred.
  • hydrocarbyl for said "optionally substituted hydrocarbyloxy" and “optionally substituted hydrocarbylthio" of R 3a , R 3b and R 3c include the same groups as those exemplified with respect to the optionally substituted hydrocarbyl of R 3 .
  • hydrocarbyl having 1 to 4 carbon atoms is preferred.
  • an optionally substituted C 1S alkoxy is preferred, and an substituted C 1 -. 3 alkoxy and halogenated substituted C1- 3 alkoxy are more preferred, and in particular, methoxy, difluoromethoxy and trifluoromethoxy are preferred.
  • the "optionally substituted amino" for R 3a , R 3b and R 3c include amino group, an N-mono- substituted amino group, and an N, N-di-substituted amino group.
  • substituted amino groups include that having one or two substituents of an optionally substituted hydrocarbyl group (e.g., a Ci_ 8 alkyl group, a C 3 _ 7 cycloalkyl group, a C 2 - 8 alkenyl group, a C 2 -8 alkynyl group, a C 3 - 7 cycloalkenyl group, a C 6 - I0 aryl group that may have a C 1 - 4 alkyl group, etc.), an optionally substituted heterocyclic group (e.g., the same group as an optionally substituted heterocyclic group of R 2 ), or the formula: COR 3d (wherein R 3d represents hydrogen atom or an optionally substituted hydrocarbyl group or an optionally substituted heterocyclic group.
  • an optionally substituted hydrocarbyl group e.g., a Ci_ 8 alkyl group, a C 3 _ 7 cycloalkyl group, a C 2 - 8 alkenyl
  • the hydrocarbyl group” or “the heterocyclic group” in “an optionally substituted hydrocarbyl group” or “an optionally substituted heterocyclic group” of R 3d may have the same substituent as that of "the hydrocarbyl group” or “the heterocyclic group” in “an optionally substituted hydrocarbyl” of R 3 or “an optionally substituted heterocyclic group” of R 2 ) , preferably a Ci- 10 acyl group (e.g., a C 2 - 7 alkanoyl, benzoyl, nicotinoyl, etc.).
  • a Ci- 10 acyl group e.g., a C 2 - 7 alkanoyl, benzoyl, nicotinoyl, etc.
  • methylamino dimethylamino, ethylamino, diethylamino, dipropylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino, and the like.
  • the two groups in said substituted amino groups may be combined to form a nitrogen-containing 5- to
  • 7-membered ring e.g., piperidino, piperazino, morpholino, thiomorpholino, etc.
  • acyl for R 3a , R 3b and R 3c examples include the same groups as those exemplified with respect to the acyl for R 3 .
  • an acyl having 2 to 4 carbon atoms is preferred.
  • Y 1 , Y 2 and Y 3 are preferably CR 3a , CR 3b and CR 3c respectively, or one of Y 1 , Y 2 and Y 3 is nitrogen.
  • R 3a , R 3b and R 3c are preferably hydrogen, halogen, cyano, acyl, C 1 - 4 alkyl optionally substituted by hydroxy (for example, methyl, ethyl, hydroxymethyl) , amino, and C 1 - 4 alkoxy (for example, methoxy, ethoxy) .
  • R 3a chlorine, bromine, methoxy and methyl are more preferred.
  • Z is a bond, -CO-, an oxygen (-0-) , a sulfur (-S-), -SO-, -SO 2 -, -NR 4 -, -NR 4 -alk-,
  • alk is an optionally substituted C 1 -4 alkylene such as methylene, ethylene, propylene, butylene and the like.
  • R 4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl.
  • the "optionally substituted hydrocarbyl” and “acyl” for R 4 include the same groups as those exemplified with respect to the optionally substituted hydrocarbyl group and acyl for R 3 .
  • R 4 may be combined together with the substituent of the cyclic hydrocarbyl or heterocyclic group in the optionally substituted hydrocarbyl or optionally substituted heterocyclic group of R 2 to form a ring.
  • Examples of said ring include the same rings as those exemplified with respect to the rings formed by the two substituents of R 2 mentioned above. Provided that (i) the compound wherein X is -NH-, and
  • R 2 is an optionally substituted thiophene ring, (ii) the compound wherein R 1 is cyano, R 3c is methyl substituted with three substituents, one of which is acyl, and other two of which may form a ring, (iii) a) 6-amino-2- [ (2, ⁇ -dichlorophenyl) amino] -1-methyl-lH- benzimidazole-7-carbonitrile, b) N- ⁇ 7-cyano-2- [ (2, ⁇ -dichlorophenyl) amino] -1-methyl-IH- benzimidazol- ⁇ -yl ⁇ acetamide, c) ⁇ -amino-2- [ (2, ⁇ -dichlorophenyl) amino] -1-methyl-lH- benzimidazole-7-carboxamide, and d) 6- ⁇ [ (allylamino) carbonothioyl] amino ⁇ -2- [ (2, 6- dichlorophenyl) amino]
  • a compound wherein X is NR 3 (wherein R 3 is preferably methyl, ethyl, hydroxyethyl, etc.); Y 1 is CR 3a (wherein R 3a is preferably H, Me, halogen (eg. F, Cl, Br), cyano, acyl, alkoxy, etc.), Y 2 is CR 3b (wherein R 3b is preferably H, Me, halogen (eg. F, Cl, Br), etc.) or nitrogen and Y 3 is CR 3c (wherein R 3c is preferably H, Me, halogen (eg.
  • Z is NR 4 (wherein R 4 is preferably H, Ci_ 4 alkyl, etc.) or oxygen;
  • R 1 is an optionally substituted acyclic branched C 3 _ 7 hydrocarbyl (in particular, 2-propyl, 3-hexyl, 3-pentyl, 4-heptyl) ;
  • R 2 is an optionally substituted C ⁇ -io aryl (in particular, phenyl, more preferably di- or tri-substituted phenyl) or an optionally substituted pyridyl (in particular, pyridyl, more preferably di- or tri-substituted pyridyl) is exemplified.
  • R 1 is 3-pentyl, 3-hexyl or 4-heptyl
  • X is NR 3
  • R 3 is methyl, ethyl or hydroxyethyl
  • Y 1 is CR 3a
  • Y 2 is CR 3b
  • Y 3 is CR 3c
  • R 3a is chloro, bromo, methoxy or methyl
  • R 3b is a hydrogen
  • R 3c is a hydrogen
  • R 2 is phenyl which is 2, 4, 6-trisubstituted, 2, 4, 5-trisubstituted or 2, 4-disubstituted with substituents or pyridyl which is trisubstituted or disubstituted with substituents.
  • substituents for the phenyl and pyridyl include an acyl such as acetyl and propionyl, an amide such as dimethylaminocarbonyl and methylaminocarbonyl, an amine such as dimethylamino, methylamino and amino, a halogen such as fluoro, chloro and bromo, a lower alkyl such as methyl, ethyl and trifluoromethyl and a lower alkoxy such as methoxy, ethoxy and trifluoromethoxy, each of which may be substituted.
  • an acyl such as acetyl and propionyl
  • an amide such as dimethylaminocarbonyl and methylaminocarbonyl
  • an amine such as dimethylamino, methylamino and amino
  • a halogen such as fluoro, chloro and bromo
  • a lower alkyl such as methyl, ethyl and trifluoromethyl
  • Compound (I) or (I 1 ) may be in the form of a prodrug thereof.
  • the prodrug of compound (I) or (I') refers to a compound that is converted into compound (I) or (I 1 ) by a reaction with an enzyme, gastric acid, or the like under a physiological condition in the living body, namely, (i) a compound that is converted into compound (I) or (I') by an enzymatic oxidation, reduction, hydrolysis, or the like, and (ii) a compound that is converted into compound (I) or (I 1 ) by hydrolysis with gastric acid or the like.
  • Examples of a prodrug of compound (I) or (!') to be used include a compound or its salt wherein hydroxyl group in compound (I) or (I 1 ) is acylated, alkylated, phosphorylated, or converted into borate (e.g., a compound or its salt wherein hydroxyl group in compound (I) or (I 1 ) is converted into acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, dimethylaminomethylcarbonyloxy, etc.), a compound or its salt wherein carboxyl group in compound (I) or (I 1 ) is esterified or amidated (e.g., a compound or its salt wherein carboxyl group in compound (I) or (I 1 ) is subjected to ethyl esterification, phenyl esterification, carboxyoxymethyl esterification, dimethylaminomethyl esterification,
  • prodrugs can be produced according to a per se known method or its modified method.
  • a prodrug of compound (I) or (I') may be a compound or its salt that is converted into compound (I) or (I 1 ) under physiological conditions as described in "Development of Drugs", Volume 7, Molecular Design, Hirokawa Shoten, 1990; pages 163-198.
  • General synthetic method
  • R la is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic, an optionally substituted N-linked heteroaryl and acyl
  • Ar is an optionally substituted aryl
  • L 1 is a leaving group (for example, halogen atom such as chlorine, bromine and iodine, etc, sulfonyloxy group such as p-toluenesulfonyloxy group, methanesulfonyloxy group and trifluoromethanesulfonyloxy group, etc., and acyloxy group such as acetyloxy group and benzoyloxy group, etc.) and each of other symbols has a meaning defined above.
  • Compound (III) or a salt thereof can be prepared by halogenation, sulfonylation or acylation of compound (II) or a salt thereof with a halogenation agent, sulfonylation agent or acylation agent, respectively.
  • a halogenation agent include phosphorous oxychloride, phosphorous oxybromide, phosphorous trichloride, phosphorous tribromide, phosphorous pentachloride, chlorine, bromine and thionyl chloride.
  • the halogenation agent is employed in an amount of 1 moles to excess per 1 mole of compound (II) or as a solvent.
  • solvent having no adverse effect on the reaction examples include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, dioxane and tetrahydrofuran, esters such as ethyl acetate, nitriles such as acetonitrile, halogenated hydrocarbon such as chloroform and dichloromethane, amides such as N,N- dimethlformamide, W ⁇ iV-dimethylacetamide and l-methyl-2- pirrolidinone, ketones such as acetone and 2-butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as diethyl ether, dioxane and tetrahydrofuran
  • esters such as ethyl acetate
  • reaction temperature may vary depending on compound (II) or a salt thereof employed as well as other conditions, it is 0 to 200 0 C, preferably 20 to 150 0 C.
  • the reaction time is 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
  • the thus obtained compound (III) can be isolated and purified by the known isolating and purifying methods, for example, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • compound (III) or a salt thereof can be prepared by reacting compound (II) with a sulfonylation agent or an acylation agent after base treatment of compound (II) .
  • a base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc.
  • a sulfonylation agent examples include p- toluenesulfonyl chloride, methanesulfonylchloride, trifluoromethanesulfonylchloride, etc.
  • the sulfonylation agent is employed in an amount of 1 to 10 moles, preferably 1 to 5 moles per 1 mole of compound (II) .
  • an acylation agent examples include acetylchloride, benzoyl chloride, etc.
  • the acylation agent is employed in an amount of 1 to 10 moles, preferably 1 to 5 moles per 1 mole of compound (II) .
  • Examples of the solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as W ⁇ i ⁇ -dimethylformamide and N ⁇ iV-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio.
  • reaction temperature may vary depending on compound (II) or a salt thereof employed as well as other conditions, it is 0 to 200 0 C, preferably 0 to 150 0 C.
  • the reaction time is 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
  • the thus obtained compound (III) can be isolated and purified by the known isolating and purifying methods, for example, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • Compound (Ia) or a salt thereof, which is encompassed within compound (I) of the invention, can be prepared by reacting compound (III) with ArZH. In this step, 1 to 20 moles, preferably 1 to 10 moles of a compound represented by ArZH or a salt thereof are employed per 1 mole of compound (III) or a salt thereof.
  • a base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkaline metal alkoxide such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc.
  • an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc.
  • an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc.
  • solvent having no adverse effect on the reaction examples include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as I ⁇ N-dimethylformamide, N,N-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio, or may not be used.
  • reaction temperature may vary depending on compound (III) or a salt thereof employed as well as other reaction conditions, it is 0 to 200 °C, preferably 20 to 150 °C, or the reaction may be heated by microwave irradiation.
  • the reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
  • the thus obtained compound (Ia) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • R 5 is hydrogen and an optionally substituted hydrocarbyl
  • R 3 and R 5 may be combined each other to form a ring
  • R 6 and R 7 are optionally substituted hydrocarbyl
  • L 2 and L 3 are halogen atoms such as chlorine, bromine and iodine and each of other symbols has a meaning defined above .
  • Compound (Ha) or a salt thereof can be prepared by treatment of compound (IV) with 1, 1' -carbonyl diimidazole, phosgene, triphosgene, alkyl haloformate such as ethyl chloroformate, phenyl haloformate such as phenyl chloroformate or urea, etc.
  • Compound (IV) or a salt thereof is mainly commercially available or can be prepared from the nitro derivatives corresponded to compound (IV) .
  • solvent having no adverse effect on the reaction examples include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N ⁇ iV-dimethylformamide, I ⁇ F,W-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio, or may not be used.
  • reaction temperature may vary depending on compound (IV) or a salt thereof employed as well as other reaction conditions, it is 0 to 150 °C, preferably 20 to
  • reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
  • compound (Ha) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • Compound (lib) or a salt thereof can be prepared by Grinard reaction of compound (Ha) or a salt thereof with R 6 MgL 2 and R 7 MgL 3 .
  • R 6 MgL 2 may be used in this step.
  • the Grinard reactions may be performed stepwise by R 6 MgL 2 and R 7 MgL 3 in this step. In this step, 1 to 20 moles, preferably 1 to 10 moles of a compound represented by R 6 MgL 2 and R 7 MgL 3 or a salt thereof are employed per 1 mole of compound (Ha) or a salt thereof.
  • solvent having no adverse effect on the reaction examples include ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform and dichloromethane, ketones such as acetone and 2-butanone and sulfoxides such as dimethylsulfoxide .
  • ethers such as diethyl ether, dioxane and tetrahydrofuran
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • ketones such as acetone and 2-butanone
  • sulfoxides such as dimethylsulfoxide .
  • reaction temperature may vary depending on compound (Ha) or a salt thereof employed as well as other reaction conditions, it is -20 to 150 0 C, preferably 0 to 100 °C.
  • the reaction time is 5 minutes to 24 hours, preferably 5 minutes to 12 hours.
  • the thus obtained compound (lib) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • Compound (lie) or a salt thereof can be prepared by dehydration of compound (lib) or a salt thereof with an acid, and the olefine is then reduced by an appropriate reducing agent or catalytic hydrogenation.
  • An acid may for example be an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and thionyl chloride, etc., and an ordinary organic acid such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid.
  • an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and thionyl chloride, etc.
  • an ordinary organic acid such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid.
  • 1 mole to excess of an acid is employed per 1 mole of compound (lib) or a salt thereof or an acid may be employed as a solvent.
  • solvent having no adverse effect on the reaction examples include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as 2V, ⁇ T-dimethylformamide, I ⁇ 7V ⁇ 7-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio, or may not be used.
  • reaction temperature may vary depending on compound (lib) or a salt thereof employed as well as other reaction conditions, it is 0 to 200 °C, preferably 20 to 150 °C.
  • the reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
  • a reducing agent is preferably sodium borohydride, lithium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride.
  • Catalytic hydrogenation may be performed in this step.
  • a catalyst include a palladium catalyst such as palladium black, palladium oxide, palladium barium sulfate, palladium on carbon, palladium hydroxide, a platinum catalyst such as platinum black, platinum oxide and platinum on carbon, or nickel catalyst such as reduced nickel, oxidized nickel, and Raney nickel.
  • solvent having no adverse effect on the reaction examples include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N,N ⁇ dimethylfor ⁇ a ⁇ ide, IV,I ⁇ /-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide.
  • alcohols such as methanol and ethanol
  • ethers such as diethyl ether, dioxane and tetrahydrofuran
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • esters
  • reaction temperature may vary depending on the olefine or a salt thereof employed as well as other reaction conditions, it is 0 to 150 °C, preferably 0 to 100 °C.
  • the reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
  • the thus obtained compound (lie) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • R lb is an optionally substituted hydrocarbyl and an optionally substituted C-linked heterocyclic
  • R lc is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic and an optionally substituted N-linked heteroaryl
  • R 8 and R 9 are independently hydrogen, optionally substituted hydrocarbyl, hydroxy and optionally substituted alkoxy and may be combined each
  • L 4 is a halogen atom such as chlorine, bromine and iodine each of other symbols has a meaning defined above.
  • Compound (VI) or a salt thereof can be prepared by halogenation of compound (V) or a salt thereof with a halogenation agent.
  • halogenation agent examples include chlorine, bromine, iodine, thionyl chloride, copper (I) chloride, copper (II) chloride, copper (I) bromide, copper (II) bromide, sodium chloride, sodium bromide, sodium iodide, potassium iodide, etc.
  • the halogenation agent is employed in an amount of 0.5 moles to 10 moles, preferably 0.5 moles to 5 moles, per 1 mole of compound (V) .
  • the diazonium type compound may be produced before introduction of a halogen atom.
  • an agent to produce the diazonium type compound include sodium nitrite, potassium nitrite and tert-butyl nitrite, etc.
  • the agent is employed in an amount of 1 mole to 10 moles, preferably 1 mole to 5 moles, per 1 mole of compound (V) .
  • This reaction can be carried out under an acidic condition.
  • an acid include an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, a nitric acid and copper sulfate, etc., as well as Lewis acid.
  • An acid is employed in an amount of 2 moles to excess per 1 mole of compound (V) .
  • solvent having no adverse effect on the reaction examples include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as NV-V-dimethylformamide, I ⁇ J>N-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio.
  • reaction temperature may vary depending on compound (V) or a salt thereof employed as well as other conditions, it is -20 to 150 0 C, preferably 0 to 100 0 C.
  • the reaction time is 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
  • the thus obtained compound (VI) can be isolated and purified by the known isolating and purifying methods, for example, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • R lc is an optionally substituted hydrocarbyl
  • an optionally substituted C-linked heterocyclic in compound (lie) or a salt thereof compound (lie) or a salt thereof can be prepared by reacting compound (VI) with R lb BR 8 R 9 or a salt thereof in the presence of a palladium catalyst, preferably tetrakis (triphenylphosphine) palladium(O) and tris (dibenzylidenacetate) dipalladium(O) , a catalytic amount of a phosphine ligand, preferably 2-
  • a palladium catalyst preferably palladium (II) acetate or a copper agent, preferably copper (II) acetate.
  • a catalytic amount of a phosphine ligand preferably 2- (dicyclohexylphosphino) biphenyl, may be employed. This reaction can be carried out according to the procedure of Buchwald et al. (J. Am. Chem. Soc. 1998, 120, 9722) and Lam et. al. (Tetrahedron Lett., 1998, 39, 2941) and the modified methods.
  • Compound (VII) or a salt thereof can be prepared by reaction of compound (VI) or a salt thereof via lithiation or coupling reaction with a boron agent.
  • examples of a boron agent include trialkyl borate, preferably triisopropyl borate.
  • a lithiation agent may for example be alkyl lithium, preferably ⁇ -butyl lithium, sec-butyl lithium and tert- butyl lithium and is employed in an amount of 1 to 5 moles, preferably 1 to 3 moles per 1 mole of compound (VI) or a salt thereof.
  • solvent having no adverse effect on the reaction examples include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, dioxane and tetrahydrofuran, and halogenated hydrocarbon such as chloroform and dichloromethane . These solvents may be used by mixing at an appropriate ratio.
  • reaction temperature may vary depending on compound (VI) or a salt thereof employed as well as other conditions, it is -100 to 100 0 C, preferably -80 to 50 0 C.
  • the reaction time is 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
  • examples of a boron agent include 4,4,5,5- tetramethyl-1, 3, 2-dioxaborolane and bis (pinacolato) diborane.
  • 1 to 10 moles, preferably 1 to 5 moles of a boron agent are employed per 1 mole of compound (VI) or a salt thereof.
  • a palladium catalyst preferably palladium (II) diacetate, a catalytic amount of a phosphine ligand, preferably 2- (dicyclohexylphosphino) biphenyl and a base can be employed according to the procedure described in J. Org.
  • solvent having no adverse effect on the reaction examples include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as A ⁇ N-dimethylformamide, N,N-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide . These solvents may be used by mixing at an appropriate ratio, or may not be used.
  • reaction temperature may vary depending on compound (VI) or a salt thereof employed as well as other conditions, it is 0 to 200 0 C, preferably 20 to 150 0 C.
  • the reaction time is 10 minutes to 48 hours, preferably 30 minutes to 24 hours.
  • the thus obtained compound (VII) can be isolated and purified by the known isolating and purifying methods, for example, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • Preparation of compound (VIII) or a salt thereof from compound (VI) or a salt thereof can be carried out similar to preparation of compound (III) or a salt thereof in Scheme 1.
  • Preparation of compound (IX) or a salt thereof from compound (VIII) or a salt thereof can be carried out similar to preparation of compound (Ia) or a salt thereof in Scheme 1.
  • Compound (X) or a salt thereof can be prepared by reaction of compound (V) or a salt thereof with sodium nitrite, and the obtained diazonium salt is reduced by an appropriate reducing agent.
  • Examples of a reducing agent include alkaline metal borohydride, preferably sodium borohydride, lithium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride, metal, preferably Fe, Zn, Sn and
  • a palladium catalyst such as palladium black, palladium oxide, palladium barium sulfate, palladium on carbon, palladium hydroxide, a platinum catalyst such as platinum black, platinum oxide and platinum on carbon, or nickel catalyst such as reduced nickel, oxidized nickel, and Raney nickel.
  • the reducing agent is employed in an amount of catalytic amount to excess per 1 mole of compound (V) .
  • solvent having no adverse effect on the reaction examples include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as _V,_V-dimethylformamide, N,N-dimethylacetamide and 1- methyl-2-pyrrolidinone, and sulfoxides such as dimethylsulfoxide . These solvents may be used by mixing at an appropriate ratio, or may not be used.
  • reaction temperature may vary depending on compound (V) or a salt thereof employed as well as other conditions, it is -20 to 150 0 C, preferably 0 to 100 0 C.
  • the reaction time is 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
  • compound (X) can be isolated and purified by the known isolating and purifying methods, for example, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • Compound (Hf) or a salt thereof can be prepared by reaction of compound (X) or a salt thereof with compound (XI) or a salt thereof.
  • An acid may be used and for example be an inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid, etc., and an ordinary organic acid such as formic acid, acetic acid, p-toluenesulfonic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid.
  • an inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid, etc.
  • an ordinary organic acid such as formic acid, acetic acid, p-toluenesulfonic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid.
  • solvent having no adverse effect on the reaction examples include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as IV,I ⁇ 7-dimethylformamide, WVN-dimethylacetamide and 1- methyl-2-pyrrolidinone, acids such as formic acid and acetic acid and sulfoxides such as dimethylsulfoxide . These solvents may be used by mixing at an appropriate ratio.
  • reaction temperature may vary depending on compound (V) or a salt thereof employed as well as other conditions, it is 0 to 200 0 C, preferably 20 to 150 0 C.
  • the reaction time is 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
  • the thus obtained compound (Hf) can be isolated and purified by the known isolating and purifying methods, for example, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • phenylcarbonyl for example. formyl, methylcarbonyl and ethylcarbonyl, etc.
  • phenylcarbonyl for example, a Ci- 6 alkyloxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl, etc.), phenyloxycarbonyl (for example, benzoxycarbonyl) , C 7 - IO aralkylcarbonyl (for example, benzyloxycarbonyl) , C 7 -io aralkyl (for example, benzyl and 4-methoxybenzyl, etc.), trityl, phthaloyl, etc.
  • a substituent on each of the groups listed above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine, etc.), a Ci_ 6 alkylcarbonyl (for example, methylcarbonyl, ethylcarbonyl and butylcarbonyl, etc.) and a nitro group, and each of other symbols has a meaning defined above.
  • Compound (Ha) or a salt thereof can be also prepared by the procedure as shown in scheme 11.
  • Compound (XIV) or a salt thereof can be prepared by nitration of compound (XIII) or a salt thereof with a nitration agent.
  • Compound (XIII) or a salt thereof is mainly commercially available or can be prepared from the aniline derivatives corresponded to compound (XIII) by a usual acetylation method.
  • nitration agent examples include nitric acids (for example, fuming nitric acid, a solution of nitric acid and sulfuric acid etc. ) , nitrates (for example, sodium nitrate, potassium nitrate, silver nitrate, ammonium nitrate, benzoyl nitrate, benzyltriphenylphosphonium nitrate, bismuth subnitrate, etc) .
  • the nitration agent is employed in an amount of 0.5 moles to 50 moles, or may be employed as a solvent, preferably 0.5 moles to 30 moles, per 1 mole of compound (XIII) .
  • additives include anhydrides (for example, acetic anhydride, trifluoroacetic anhydride, methanesulfonic anhydride, etc) , acid chlorides (for example, thionyl chloride, etc) , acids
  • the additives are employed in an amount of 0.5 moles to 50 moles, preferably 0.5 moles to 30 moles, per 1 mole of compound (XIII) .
  • solvent having no adverse effect on the reaction examples include water, acetic acid, halogenated hydrocarbons such as chloroform and dichloromethane, 1,2- dichloroethane, etc. These solvents may be used by mixing at an appropriate ratio, or may not be used.
  • the reaction temperature may vary depending on compound (XIII) or a salt thereof employed as well as other reaction conditions, it is -20 to 150 0 C, preferably 0 to 100 °C
  • the reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
  • The' thus obtained compound (XIV) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • Compound (XV) or a salt thereof can be prepared by deacetylation of compound (XIV) or a salt thereof with an acid or base, and then reduction of the nitro group by an appropriate reducing agent or catalytic hydrogenation.
  • An acid may for example be an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and thionyl chloride, etc., and an ordinary organic acid such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid.
  • an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and thionyl chloride, etc.
  • an ordinary organic acid such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid.
  • a base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc. , an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkaline metal alkoxide such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, etc.
  • solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as I ⁇ 7V.W-dimethylformamide, iV ⁇ iV-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio, or may not be used.
  • reaction temperature may vary depending on compound (XIV) or a salt thereof employed as well as other reaction conditions, it is 0 to 200 °C, preferably 20 to 150 °C.
  • the reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
  • nitro compounds can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • a reducing agent is preferably sodium borohydride, lithium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride .
  • Catalytic hydrogenation may be performed in this step.
  • a catalyst include a palladium catalyst such as palladium black, palladium oxide, palladium barium sulfate, palladium on carbon, palladium hydroxide, a platinum catalyst such as platinum black, platinum oxide and platinum on carbon, or nickel catalyst such as reduced nickel, oxidized nickel, and Raney nickel.
  • solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as A ⁇ AT-dimethylformamide, N,iV-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio.
  • reaction temperature may vary depending on compound (XIV) or a salt thereof employed as well as other reaction conditions, it is 0 to 150 0 C, preferably 0 to 100
  • reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
  • compound (XV) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • Preparation of compound (XVI) or a salt thereof from compound (XV) or a salt thereof can be carried out similar to preparation of compound (Ha) in Scheme 2.
  • Compound (XVII) or a salt thereof can be prepared by reacting compound (XVI) with R 12 -L 2 or anhydride (R 12 ) 2 O.
  • a base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkaline metal alkoxide such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, 4-dimethylaminopyridine, DBU, etc.
  • an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc.
  • an alkaline metal hydrogen carbonate such as sodium
  • solvent having no adverse effect on the reaction examples include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as WVN-dimethylformamide, N,W-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio, or may not be used. While the reaction temperature may vary depending on compound (XVI) or a salt thereof employed as well as other reaction conditions, it is 0 to 200 0 C, preferably 20 to
  • reaction 150 0 C or the reaction may be heated by microwave irradiation.
  • the reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
  • compound (XVII) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • Preparation of compound (XVIII) or a salt thereof from compound (XVII) or a salt thereof can be carried out similar to preparation of compound (XVII) .
  • Compound (Ha) or a salt thereof can be prepared by deprotection of compound (XVIII) or a salt thereof with an acid or a base, or catalytic hydrogenation.
  • An acid may for example be an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and thionyl chloride, etc., and an ordinary organic acid such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid.
  • an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and thionyl chloride, etc.
  • an ordinary organic acid such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid.
  • a base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkaline metal alkoxide such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, etc.
  • Catalytic hydrogenation may be performed in this step.
  • a catalyst include a palladium catalyst such as palladium black, palladium oxide, palladium barium sulfate, palladium on carbon, palladium hydroxide, a platinum catalyst such as platinum black, platinum oxide and platinum on carbon, or nickel catalyst such as reduced nickel, oxidized nickel, and Raney nickel.
  • solvent having no adverse effect on the reaction examples include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as i ⁇ 7,I ⁇ J-dimethylformamide, N,W-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio, or may not be used.
  • reaction temperature may vary depending on compound (XVIII) or a salt thereof employed as well as other reaction conditions, it is 0 to 200 0 C, preferably 20 to 150 °C.
  • the reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
  • the thus obtained compounds can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
  • a starting compound for compound (I) according to the invention may be in a form of a salt, including a salt with an inorganic acid (for example, hydrochloric acid, phosphoric acid, hydrobromic acid and sulfuric acid, etc.) and a salt with an organic acid (for example, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid and benzenesulfonic acid, etc.).
  • an inorganic acid for example, hydrochloric acid, phosphoric acid, hydrobromic acid and sulfuric acid, etc.
  • an organic acid for example, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid and benzenes
  • a salt with an inorganic base for example, an alkaline metal or an alkaline earth metal such as sodium, potassium, calcium and magnesium, ammonia, etc.
  • an organic base for example, tri-Ci_ 3 alkylamine such as triethylamine, etc.
  • a starting compound when carries as a substituent an amino group, an amide group, a hydrozino group, a urea group, a carboxyl group or a hydroxyl group, then such group may be derivatized with a protective group employed ordinarily in peptide chemistry, which is cleaved after a reaction if desired to yield an intended compound.
  • a protective group for an amino group, an amide group and a urea group may for example be an optionally substituted Ci_ 6 alkylcarbonyl (for example. formyl, methylcarbonyl and ethylcarbonyl, etc.), phenylcarbonyl, a Ci- 6 alkyloxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl, etc.), phenyloxycarbonyl (for example, benzoxycarbonyl) , C 7 -I 0 aralkylcarbonyl (for example, benzyloxycarbonyl) , C 7 -I 0 aralkyl (for example, benzyl and 4-methoxybenzyl, etc.), trityl, phthaloyl, etc.
  • Ci_ 6 alkylcarbonyl for example. formyl, methylcarbonyl and ethylcarbonyl, etc.
  • a substituent on each of the groups listed above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine, etc.), a C ⁇ - 6 alkylcarbonyl (for example, methylcarbonyl, ethylcarbonyl and butylcarbonyl, etc.) and a nitro group, which may occur 1 to about 3 times .
  • a halogen atom for example, fluorine, chlorine, bromine and iodine, etc.
  • a C ⁇ - 6 alkylcarbonyl for example, methylcarbonyl, ethylcarbonyl and butylcarbonyl, etc.
  • a nitro group which may occur 1 to about 3 times .
  • a protective group for a carboxyl group may for example be an optionally substituted Ci_ 6 alkyl (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, etc.), phenyl, trityl and silyl, etc.
  • a substituent on each of the groups listed above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine, etc.), a Ci_ 6 alkylcarbonyl (for example, formyl, methylcarbonyl, ethylcarbonyl and butylcarbonyl, etc.) and a nitro group, which may occur 1 to about 3 times.
  • a protective group for a hydroxyl group may for example be an optionally substituted Ci- 6 alkyl (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl, etc.), phenyl, a C 7 - I0 aralkyl (for example, benzyl, etc.), a Ci_6 alkylcarbonyl (for example, formyl, methylcarbonyl and ethylcarbonyl, etc.), phenyloxycarbonyl (for example, benzoxycarbonyl, etc.), C 7 - I0 aralkylcarbonyl (for example, benzyloxycarbonyl, etc.), pyranyl, furanyl, silyl, etc.
  • Ci- 6 alkyl for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl, etc
  • a substituent on each of the groups listed above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine, etc.), a Ci_ 6 alkyl, phenyl, a C 7 -io aralkyl, nitro, etc., which may occur 1 to about 4 times.
  • a method for cleaving a protective group is a method known per se or an analogous method, such as a treatment for example with an acid, a base, a reduction, UV light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc.
  • the pharmaceutical composition containing compound (I) or (I 1 ) of the present invention is expected to be useful in the treatment and prevention of diseases, in which CRF is involved, such as depression, major depression, bipolar depression, dysthymia, seasonal affective disorder, recurrent depression, postpartum depression, suppression symptom, mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, stress-induced insomnia, post psychic trauma stress disorder, Tourette' s syndrome, autism, passion disorder, adjustment disorder, dysthymic disorder, sleep disorder, insomnia, bipolar disorder, circulatory disease, neurosis, schizophrenia, digestive ulcer, irritable bowl syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, stress-induced gastrointestinal disorder, nervous emesis, peptic ulcer, diarrhea, constipation, postoperative ileus, gastrointestine dysfunction and nervous vomiting associated with stress, Alzheimer's disease, Alzheimer's type senile dementia, nervous degenerated disease such
  • Compound (I) or (I 1 ) of the present invention can be formulated with a pharmaceutically acceptable carrier and can be orally or parenterally administered as solid formulations such as tablets, capsules, granules, powders, or the like; or liquid formulations such as syrups, injections, or the like. Also, there can be prepared formulations for transdermal administration such as patchings, cataplasms, ointments (including creams) , plasters, tapes, lotions, liquids and solutions, suspensions, emulsions, sprays, and the like.
  • a variety of organic or inorganic carrier substances which have been conventionally employed as formulation materials, is used and compounded as a bulking agent, a lubricant, a binding agent, and a disintegrator in solid formulations; a vehicle, a solubilizing agent, a suspending agent, an isotonicity agent, a buffering agent, and an analgesic in liquid formulations.
  • formulation excipients such as a preservative, an antioxidant, a stabilizer, a coloring agent, a sweetening agent, and the like can be used.
  • Preferred examples of the bulking agent include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like.
  • Preferred examples of the lubricant include magnesium stearate, potassium stearate, talc, colloidal silica, and the like.
  • Preferred examples of the binding agent include crystalline cellulose, ⁇ -starch, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, and the like.
  • Preferred examples of the disintegrator include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and the like.
  • Preferred examples of the vehicle include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and the like. If necessary, for the purpose of taste masking, enteric coating, or prolonged action, oral formulations can be prepared by coating by a per se known method.
  • this coating agent examples include hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68 [polyoxyethylene (160) polyoxypropylene (30) glycol], cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate phthalate, Eudragit (manufactured by Rohm Company, methacrylic acid- acrylic acid copolymer), and the like.
  • Preferred examples of the solubilizing agent include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, trisamiomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like.
  • Preferred examples of the suspending agent include surface active agents such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, and the like; hydrophilic, high molecular substances such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like; and so on.
  • Preferred examples of the isotonicity agent include sodium chloride, glycerin, D- mannitol, and the like.
  • Preferred examples of the buffering agent include buffer solutions of a phosphate, an acetate, a carbonate, a citrate, or the like.
  • Preferable examples of the analgesic include benzyl alcohol and the like.
  • Preferred examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like.
  • Preferred examples of the antioxidant include sulfites, ascorbic acid, and the like.
  • the aqueous mixture was extracted with 50 mL of diethyl ether and twice with 50 mL of dichloromethane. The organics were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to a residue. This residue was dissolved in 50 mL of ethanol and 10 mL of 6N aqueous hydrochloric acid was added. The mixture was heated at 75 0 C for 2 h and then concentrated in vacuo. The resulting residue was dissolved in dichloromethane and washed with aqueous sodium bicarbonate.
  • Examples 16-54 in Table 4 were prepared as trifluoroacetic acid salt and examples 55-60 were prepared as free base in the similar method described in Example 15. Table 4
  • the mixture was alkalified by 12 N sodium hydroxide, followed by addition of ethyl acetate to the suspension. After addition of 24.6 mL of di-tert-butyl dicarbonate (107 mmol), the mixture was stirred at room temperature for 15 hours. The aqueous layer was separated and extracted with ethyl acetate (Xl) . The organic layer was washed with brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residual solids were washed with hexane to give 8.53 g of the Boc derivative of the title compound as yellow crystals.
  • 2-chloro-7- (2, 5- dimethyl-li ⁇ -pyrrol-1-yl) -1-methyl-lH-benzimidazole and 225 mg (1.04 mmol) of 4-bromo-2-methoxy-6-methylaniline was stirred at 110 0 C for 15 hours. After cooling, the reaction mixture was neutralized by saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (X2) .
  • Example 70 and 71 in Table 7 were prepared in the similar method described in Example 15. Table 7
  • This compound was prepared in a similar manner described in Example 66.
  • reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine.
  • N- (4-Bromo-2-methoxy-6-methylphenyl) -4-chloro-7- (1- ethylpropyl) -1-methyl-lH-benzimidazol-2-amine A mixture of 2, 4-dichloro-7- (1-ethylpropyl) -1-methyl- lff-benzimidazole (140 mg, 0.52 iranol) , 4-bromo-2-methoxy-6- methylaniline (335 mg, 1.55 mmol) and l-methyl-2- pyrrolidone (5 drops) was stirred at 130 0 C for 2 days under nitrogen atmosphere.
  • Examples 78 - 96 were prepared in the similar method described in Example 77.
  • Examples 98 - 99 were prepared in the similar method described in Example 97.
  • N- (4-Chloro-2-methoxy- ⁇ -methylphenyl) -7- (1-ethylpropyl) - 1, 4-dimethyl-lH-benzimidazol-2-amine A mixture of 2-chloro-7- (1-ethylpropyl) -1, 4-dimethyl- lH-benzimidazole (100 mg, 0.399 mmol), 4 ⁇ chloro-2-methoxy- 6-r ⁇ ethylaniline (205 mg, 1.20 mmol) and l-methyl-2- pyrrolidone (0.2 mL) was stirred at 120 0 C for 2 days under nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate, washed with brine.
  • the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with dichloromethane (X2) .
  • the combined organic layer was washed with water (Xl) and brine (Xl), dried over sodium sulfate and concentrated in vacuo.
  • the residue was purified by silica gel column chromatography eluting with a 10-50% ethyl acetate/hexane gradient mixture to give 3.83 g (11.3 mmol, 65.0%) of the title compound as a colorless solid.
  • Example 109 was prepared in the similar method described in Example 108. mp. 166-168 0 C.
  • Example 110-124 were prepared in the similar method described in Example 77.
  • Example 124-144 were prepared in the similar method described in Example 97.
  • Example 140 4-Chloro-2- [2, 6-dichloro-4- (trifluoromethoxy) phenoxy] -7- (1- ethylpropyl) -1-methyl-lH-benzimidazole
  • Example 146 was prepared in the similar method described in Example 145. mp 106-107 0 C.
  • Example 151 was ⁇ prepared in the similar method described in Example 150. rap 192-192 0 C.

Abstract

There is provided a CRF receptor antagonist comprising a compound of the formula (I) : wherein R1 is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic group, an optionally substituted N-linked heteroaryl group, a cyano or an acyl; R2 is an optionally substituted cyclic hydrocarbyl or an optionally substituted heterocyclic group; X is oxygen, sulfur or -NR3- (wherein R3 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ; Y1, Y2 and Y3 are each an optionally substituted carbon or a nitrogen, provided that one or less of Y1, Y2 and Y3 is nitrogen; and Z is a bond, -CO-, oxygen, sulfur, -SO-, -SO2-, -NR4-, -NR4-alk-, -CONR4- or -NR4CO- (wherein alk is an optionally substituted C3.-4 alkylene and R4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ; or a salt thereof or a prodrug thereof .

Description

DESCRIPTION FUSED HETEROCYCLIC COMPOUNDS
Technical Field The present invention relates to novel nitrogen- containing fused heterocyclic compounds having CRF (corticotropin releasing factor) antagonistic activity and pharmaceutical compositions containing them.
Background Art
Corticotropin-releasing factor (hereinafter, abbreviated as "CRF") is a neuropeptide composed of 41 amino acids, and was isolated and purified as a peptide promoting release of adrenocorticotropic hormone (ACTH) from pituitary gland. First, the structure thereof was determined from sheep hypothalamus and, thereafter, the presence thereof was confirmed also in a rat or a human, and the structure thereof was determined [Science, 213, 1394(1981); Proc. Natl. Acad. Sci USA, 80, 4851(1983); EMBO J. 5, 775(1983)]. An amino acid sequence is the same in a human and a rat, but differed in 7 amino acids in ovine. CRF is synthesized as a carboxy-terminal of prepro CRF, cut and secreted. The CRF peptide and a mRNA thereof are present at the largest amount in hypothalamus and pituitary gland, and are widely distributed in a brain such as cerebral cortex, cerebellum, hippocampus and corpus amygdaloideum. In addition, in peripheral tissues, the existence has been confirmed in placenta, adrenal gland, lung, liver, pancreas, skin and digestive tract [J. Clin. Endocrinol. Metab., 65, 176(1987); J. Clin. Endocrinol. Metab., 67, 768(1988); Regul . Pept., 18, 173(1987), Peptides, 5 (Suppl. 1), 71(1984)]. A CRF receptor is a 7- transmembrane G protein-coupled receptor, and two subtypes of CRFl and CRF2 are present. It is reported that CRFl is present mainly in cerebral cortex, cerebellum, olfactory bulb, pituitary gland and tonsil nucleus. On the other hand, the CRF2 receptor has two subtypes of CRF2α and CRF2β. It was made clear that the CRF2α receptor is distributed much in hypothalamus, septal area and choroids plexus, and the CRF2β receptor is present mainly in peripheral tissues such as skeletal muscle and is distributed in a blood vessel in a brain [J. Neurosci. 15, 6340(1995); Endocrinology, 137, 72(1996); Biochim. Biophys . Acta, 1352, 129(1997)]. Since each receptor differs in distribution in a living body, it is suggested that a role thereof is also different [Trends. Pharmacol. Sci. 23, 71(2002)].
As a physiological action of CRF, the action on the endocrine system is known in which CRF is produced and secreted in response to stress in hypothalamus and acts on pituitary gland to promote the release of ACTH [Recent Prog. Horm. Res., 39, 245(1983)]. In addition to the action on the endocrine system, CRF acts as a neurotransmitter or a neuroregulating factor in a brain, and integrates electrophysiology, autonomic nerve and conducts to stress [Brain Res. Rev., 15, 71(1990); Pharmacol. Rev., 43, 425(1991)]. When CRF is administered in a cerebral ventricle of experimental animal such as a rat, anxiety conduct is observed, and much more anxiety conduct is observed in a CRF-overexpressing mouse as compared with a normal animal [Brain Res., 574, 70(1992); J. Neurosci., 10,
176(1992); J. Neurosci., 14, 2579(1994)]. In addition, α- helical CRF (9-41) of a peptidergic CRF receptor antagonist exerts an anti-anxiety action in an animal model [Brain Res., 509, 80(1990); J. Neurosci., 14, 2579(1994)]. A blood pressure, a heart rate and a body temperature of a rat are increased by stress or CRF administration, but the α-helical CRF (9-41) of a peptidergic CRF antagonist inhibits the increase in a blood pressure, a heart rate and a body temperature due to stress [J. Physiol., 460, 221(1993)]. The α-helical CRF (9-41) of a peptidergic CRF receptor antagonist inhibits abnormal conducts due to withdrawal of a dependent drug such as an alcohol and a cocaine [Psychopharmacology, 103, 227(1991); Pharmacol. Rev.53, 209(2001)]. In addition, it has been reported that learning and memory are promoted by CRF administration in a rat [Nature, 375, 284(1995); Neuroendocrinology, 57, 1071(1993); Eur. J. Pharmacol., 405, 225(2000)].
Since CRF is associated with stress response in a living body, there are clinical reports regarding stress- associated depression or anxiety. The CRF concentration in a cerebrospinal fluid of a depression patient is higher as compared with that of a normal person [Am. J. Psychiatry, 144, 873(1987)], and the mRNA level of CRF in hypothalamus of a depression patient is increased as compared with that of a normal person [Am. J. Psychiatry, 152, 1372(1995)]. A CRF binding site of cerebral cortex of a patient who suicided by depression is decreased [Arch. Gen. Psychiatry, 45, 577(1988)]. The increase in the plasma ACTH concentration due to CRF administration is small in a depression patient [N. Engl. J. Med., 314, 1329(1986)]. In a patient with panic disorder, the increase of plasma ACTH concentration due to CRF administration is small [Am. J. Psychiatry, 143, 896(1986)]. The CRF concentration in a cerebrospinal fluid of a patient with anxiety induced by stress such as obsessive-compulsive neurosis, post-psychic trauma stress disorder, Tourette's syndrome and the like is higher as compared with that of a normal person [Arch. Gen. Psychiatry, 51, 794(1994); Am. J. Psychiatry, 154, 624(1997); Biol. Psychiatry, 39, 776(1996)]. The CRF concentration in a cerebrospinal fluid of schizophrenics is higher as compared with that of a normal person [Brain Res., 437, 355(1987); Neurology, 37, 905(1987)]. Thus, it has been reported that there is abnormality in the living body response system via CRF in stress-associated mental disease. The action of CRF on the endocrine system can be presumed by the characteristics of CRF gene-introduced animal and actions in an experimental animal. In a CRF- overexpressing mouse, excessive secretions of ACTH and adrenal cortex steroid occur, and abnormalities analogous to Gushing' s syndrome such as atrophy of muscle, alopecia, infertility and the like are observed [Endorcrinology, 130, 3378(1992)]. CRF inhibits ingestion in an experimental animal such as a rat [Life Sci., 31, 363 (1982); Neurophamacology, 22, 337(1983)]. In addition, α-helical CRF (9-41) of a peptidergic CRF antagonist inhibited decrease of ingestion due to stress loading in an experimental model [Brain Res. Bull., 17, 285(1986)]. CRF inhibited weight gain in a hereditary obesity animal [Physiol. Behav. , 45, 565(1989)]. In a nervous orexia inactivity patient, the increase of ACTH in plasma upon CRF administration is small [J. Clin. Endocrinol. Metab., 62, 319(1986)]. It has been suggested that a low CRF value is associated with obesity syndrome [Endocrinology, 130, 1931(1992)]. There has been suggested a possibility that ingestion inhibition and weight loss action of a serotonin reuptake inhibiting agent are exerted via release of CRF [Pharmacol. Rev., 43, 425(1991)].
CRF is centrally or peripherally associated with the digestive tract movement involved in stress or inflammation [Am. J. Physiol. Gastrointest . Liver Physiol. 280,
G315(2001)]. CRF acts centrally or peripherally, weakens the shrinkablity of stomach, and decreases the gastric excreting ability [Regulatory Peptides, 21, 173(1988); Am. J. Physiol., 253, G241(1987)]. In addition, α-helical CRF (9-41) of a peptidergic CRF antagonist has a restoring action for hypofunction of stomach by abdominal operation [Am. J. Physiol., 258, G152(1990)]. CRF inhibits secretion of a bicarbonate ion in stomach, decreases gastric acid secretion and inhibits ulcer due to cold restriction stress [Am. J. Physiol., 258, G152(1990)]. Furthermore, α-helical CRF (9-41) of a peptidergic CRF antagonist shows the inhibitory action on gastric acid secretion decrease, gastric excretion decrease, small intestinal transport decrease and large intestinal transport enhancement due to restriction stress [Gastroenterology, 95, 1510(1988)]. In a healthy person, mental stress increases a gas and abdominal pain due to anxiety and intestine dilation, and CRF decreases a threshold of discomfort [Gastroenterology, 109, 1772(1995); Neurogastroenterol . Mot., 8, 9 [1996]. In a irritable bowel syndrome patient, large intestinal , movement is excessively enhanced by CRF administration as compared with a healthy person [Gut, 42, 845(1998)].
It has been reported from studies on experimental animals and clinical studies that CRF is induced by inflammation and is involved in a inflammatory reaction.
In an inflammatory site of an experimental animal and in a joint fluid of a rheumatoid arthritis patient, production of CRF is topically increased [Science, 254, 421(1991); J. Clin. Invest., 90, 2555(1992); J. Immunol., 151, 1587(1993)]. CRF induces degranulation of a mast cell and enhances the blood vessel permeability [Endocrinology, 139, 403(1998); J.Pharmacol. Exp. Ther., 288, 1349(1999)]. CRF can be detected also in a thyroid gland of autoimmune thyroiditis patient [Am. J. Pathol. 145, 1159(1994)]. When CRF is administered to an experimental autoimmune cerebrospinal meningitis rat, the progression of symptom such as paralysis was remarkably inhibited [J. Immunil., 158, 5751(1997)]. In a rat, the immune response activity such as T-lymphocyte proliferation and the natural killer cell activity is reduced by CRF administration or stress loading [Endocrinology, 128, 1329(1991)].
From the above-mentioned reports, it is expected that the CRF receptor antagonistic compound would exert an excellent effect for treating or preventing various diseases in which CRF is involved. As a CRF antagonist, for example, peptide CRF receptor antagonists are reported in which a part of an amino acid sequence of CRF or associated peptides of a human or other mammals is altered or deleted, and they are reported to show a pharmacological action such as ACTH release- inhibiting action and anti-anxiety action [Science, 224, 889(1984); J. Pharmacol. Exp. Ther., 269, 564(1994); Brain Res. Rev., 15, 71(1990)]. However, from a pharmacokinetic point of view such as chemical stability and absorbability for oral administration in a living body, bioavailability and intracerebral transferability, peptide derivatives have a low utility value as a medicine.
Disclosure of Invention According to the present invention, there is provided: (1) A compound represented by the formula (I) :
Figure imgf000009_0001
wherein R1 is an optionally substituted hydrocarbyl, an_ optionally substituted C-linked heterocyclic group, an optionally substituted N-linked heteroaryl group, or an acyl, provided that methyl, and trifluoromethyl are excluded; R2 is an optionally substituted cyclic hydrocarbyl or an optionally substituted heterocyclic group, provided that 2- [2- (1, l-dimethylethyl)phenyloxy] -3-pyridinyl is excluded; X is oxygen, sulfur or -NR3- (wherein R3 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ;
Y1, Y2 and Y3 are each an optionally substituted carbon or a nitrogen, provided that one or less of Y1, Y2 and Y3 is nitrogen; and Z is a bond, -CO-, oxygen, sulfur, -SO-, -SO2-, -NR4-, -NR4- alk-, -CONR4- or -NR4CO- (wherein alk is an optionally substituted C1-4 alkylene and R4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ; provided that (i) the compound wherein X is -NH-, and R2 is an optionally substituted thiophene ring, (ii) the compound wherein R1 is cyano, Y3 is carbon which is substituted with methyl substituted with three substituents, one of which is acyl, and other two of which may form a ring,
(iii) a) 6-amino-2- [ (2, 6-dichlorophenyl) amino] -1-methyl-IH- benzimidazole-7-carbonitrile, b) 6-amino-2- [ (2, β-dichlorophenyl) amino] -1-methyl-lH- benzimidazole-7-carboxamide, and c) 6-{ [ (ally1amino) carbonothioyl] amino} -2- [ (2, 6- dichlorophenyl) amino] -l-methyl-liϊ-benzimidazole-7- carboxamide, (iv) 4- ({2-[ (4-chlorophenyl) amino] -1, 7-dimethyl-IH- benzimidazol-5-yl } oxy) -W-methylpyridine-2-carboxamide r (v) the compound wherein R3 is substituted heteroarylmethyl, R2 is 4-piperidinyl bearing a substituent at the 1- position,
(vi) the compound wherein R2 is substituted 8-oxo-5-thia-l- aza-bicyclo [4.2.0] oct-2-en-7-yl, and
(vii) 7-ethyl-l-methyl-N- [4- (trifluoromethoxy) phenyl] -5- (trifluoromethyl) -lH-benzimidazol-2-amine and 7-ethenyl-l- methyl-N- [4- (trifluoromethoxy) phenyl] -5- (trifluoromethyl) - lH-benzimidazol-2-amine are excluded; or a salt thereof;
(2) A prodrug of the compound according to the above- mentioned (1) ; (3) The compound according to the above-mentioned (1) wherein R1 is an optionally substituted acyclic branched C3- 11 hydrocarbyl;
(4) The compound according to the above-mentioned (1) wherein R1 is an optionally substituted C6-I0 aryl; (5) The compound according to the above-mentioned (1) wherein R1 is an optionally substituted C-linked 5- to 14- membered heterocyclic group or N-linked 5- to 10-membered heteroaryl group; (6) The compound according to the above-mentioned (1) wherein X is -NR3- (wherein R3 is as defined in the above- mentioned (1) ) ;
(7) The compound according to the above-mentioned (6) wherein R3 is methyl, ethyl or hydroxyethyl;
(8) The compound according to the above-mentioned (1) wherein Y1 is CR3a, Y2 is CR3b, and Y3 is CR3c (wherein R3a, R3b and R3c are independently a hydrogen, a halogen, a nitro, a cyano, an optionally substituted Ci_4 hydrocarbyl, an optionally substituted C1-.4 hydrocarbyloxy, an optionally substituted C1-.4 hydrocarbylthio, an optionally substituted amino or an acyl containing up to 4 carbon atoms;
(9) The compound according to the above-mentioned (8) wherein R3a is a hydrogen, a halogen, a cyano, an optionally substituted C3.-3 alkyl, or an optionally substituted C1-3 alkoxy, R3b is a hydrogen, and R3c is a hydrogen;
(10) The compound according to the above-mentioned (9) wherein R3a is chlorine, bromine, methoxy or methyl;
(11) The compound according to the above-mentioned (1) wherein one of Y1, Y2 and Y3 is nitrogen; (12) The compound according to the above-mentioned (1) wherein R2 is an optionally substituted Cε-io aryl or an optionally substituted 5- to 8-membered heterocyclic group; (13) The compound according to the above-mentioned (1) wherein R2 is phenyl which is 2, 4, 6-trisubstituted, 2,4,5- trisubstituted or 2, 4-disubstituted; (14) The compound according to the above-mentioned (1) wherein Z is -NR4- (wherein R4 is as defined in the above- mentioned (I)), or oxygen;
(15) The compound according to the above-mentioned (14) wherein R4 is a hydrogen;
(16) The compound according to the above-mentioned (1) which is
N- (4-chloro-2-methoxy-6-methylphenyl) -7- (2-ethylphenyl) -1- methyl-liϊ-benziinidazol-2-amine, N- (4-bromo-2-methoxy-6-methylphenyl) -7- (3, 5-diethyl-lH- pyrazol-1-yl) -1-methyl-lH-benzimidazol-2-amine, N- (4-bromo-2-methoxy-β-methylphenyl) -4-chloro-7- (1- ethylpropyl) -1-methyl-liϊ-benzimidazol-2-amine, 4-chloro-2- (2, 4-dichloro-6-methylphenoxy) -7- (1- ethylpropyl) -1-methyl-liϊ-benzimidazole,
JV- (4-chloro-2-methoxy-β-methylphenyl) -7- (1-ethylpropyl) - 1, 4-dimethyl-liϊ-benzimidazol-2-amine, or 2- (2, 4-dichloro-β-methylphenoxy) -7- (1-ethylpropyl) -A- methoxy-l-methyl-lH-benzimidazole, or a salt thereof; (17) A process for producing the compound according to the above-mentioned (1) , which comprises reacting a compound represented by the formula:
Figure imgf000014_0001
wherein L represents a leaving group selected from halogen atom, sulfonyloxy group and acyloxy group, and other symbols are as defined in the above-mentioned (1), with a compound represented by the formula:
R2-ZH ( ii ) wherein each symbol is as defined in the above-mentioned
(U;
(18) A pharmaceutical composition which comprises the compound according to the above-mentioned (1) ;
(19) A CRF receptor antagonist which is the compound represented by the formula (I1) :
Figure imgf000014_0002
wherein R1 is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic group, an optionally substituted N-linked heteroaryl group, a cyano or an acyl;
R2 is an optionally substituted cyclic hydrocarbyl or an optionally substituted heterocyclic group; X is oxygen, sulfur or -NR - (wherein R is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ; Y1, Y2 and Y3 are each an optionally substituted carbon or a nitrogen, provided that one or less of Y1, Y2 and Y3 is nitrogen;
Z is a bond, -CO-, oxygen, sulfur, -SO-, -SO2-, -NR4-, -NR4- alk-, -CONR4- or -NR4CO- (wherein alk is an optionally substituted Cχ-4 alkylene and R4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ; or a salt thereof;
(20) A method for treating or preventing a disease wherein a CRF receptor is implicated, which comprises administering to a subject in need thereof an effective amount of the CRF receptor antagonist according to the above-mentioned (19); (21) The method according to the above-mentioned (20) wherein the disease being treated or prevented is selected from affective disorder, depression or anxiety;
(22) Use of the CRF receptor antagonist according to the above-mentioned (19) for manufacturing a medicament for preventing or treating a disease wherein a CRF receptor is implicated;
(23) The use according to the above-mentioned (22) wherein the disease being treated or prevented is selected from affective disorder, depression or anxiety; (24) A pharmaceutical composition for preventing or treating a disease wherein a CRF receptor is implicated, which comprises the CRF receptor antagonist according to the above-mentioned (19) ;
(25) The pharmaceutical composition according to the above- mentioned (24) wherein the disease being treated or prevented is selected from affective disorder, depression or anxiety; and the like.
Best Mode for Carrying Out the Invention In the present specification, the term "hydrocarbyl" means a univalent group containing only carbon and hydrogen.
In the formula (I) and (I1), X represents an oxygen, a sulfur or -NR3- (wherein R3 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) . That is, examples of the 5-membered ring in the formula (I) and (I1) include an oxazole ring, a thiazole ring and an imidazole ring.
Examples of the "hydrocarbyl" of the "optionally substituted hydrocarbyl" represented by R3 of the formula: -NR3- include an optionally substituted aliphatic hydrocarbon group, an optionally substituted alicyclic hydrocarbon group, an optionally substituted alicyclic- aliphatic hydrocarbon group, an optionally substituted alicyclic-alicyclic hydrocarbon group, an optionally substituted aromatic hydrocarbon group, an optionally substituted aromatic-aliphatic hydrocarbon group (an aralkyl group) , and the like.
Examples of said aliphatic hydrocarbon group include a saturated aliphatic hydrocarbon group having 1-8 carbon atoms (e.g., alkyl group) such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, etc.; and an unsaturated aliphatic hydrocarbon group having 2-8 carbon atoms (e.g., alkenyl group, alkynyl group, alkadienyl group, alkadiynyl group, etc.) such as vinyl, allyl, 1-propenyl,- 2-methyl-l-propenyl, 1-butenyl, 2- butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2- pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1- hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2,4- hexadienyl, 1-heptenyl, 1-octenyl, ethynyl, 1-propynyl, 2- propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3- hexynyl, 4-hexynyl, 5-hexynyl, 2, 4-hexadiynyl, 1-heptynyl, 1-octynyl, etc.
Examples of said alicyclic hydrocarbon group include a saturated alicyclic hydrocarbon group having 3-7 carbon atoms (e.g., cycloalkyl group, etc.) such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like; an unsaturated alicyclic hydrocarbon group having 3-7 carbon atoms (e.g., cycloalkenyl group, cycloalkadienyl group, etc.) such as 1-cyclopentenyl, 2-cyclopentenyl, 3- cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3- cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3- cycloheptenyl, 2, 4-cycloheptadienyl, etc.; a partly saturated and fused bicyclic hydrocarbon group [preferably, Cg-io partly saturated and fused bicyclic hydrocarbon group, etc. (including those where the benzene ring is combined to 5- or β-membered non-aromatic cyclic hydrocarbon group) ] such as 1-indenyl, 2-indenyl, 1-indanyl, 2-indanyl, 1,2,3, 4-tetrahydro-l-naphthyl, 1,2, 3, 4-tetrahydro-2- naphthyl, 1, 2-dihydro-l-naphthyl, 1, 2-dihydro-2-naphthyl,
1, 4-dihydro-l-naphthyl, 1, 4-dihydro-2-naphthyl, 3,4- dihydro-1-naphthyl, 3, 4-dihydro-2-naphthyl, etc.; and the like. Said alicyclic hydrocarbon group may be cross-linked.
Examples of said alicyclic-aliphatic hydrocarbon group include those where the above-mentioned alicyclic hydrocarbon group and the above-mentioned aliphatic hydrocarbon group are combined, for example, those having 4-14 carbon atoms such as cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3- cyclopentenylmethyl, cyclopentylethyl, cyclohexylmethyl, 2- cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cycloheptylmethyl, cycloheptylethyl, 2- (3, 4-dihydro-2- naphtyl) ethyl, 2- (1, 2, 3, 4-tetrahydro-2-naphtyl) ethyl, 2- (3, 4-dihydro-2-naphtyl) ethenyl, etc. (e.g., C3_7 cycloalkyl- Ci_4 alkyl group, C3-7 cycloalkenyl-Ci-4 alkyl group, C3-7 cycloalkyl-C2-4 alkenyl group, C3_7 cycloalkenyl-C2-4 alkenyl group, C9-10 partly saturated and fused bicyclic hydrocarbon-Ci-4 alkyl group, C9-.3.0 partly saturated and fused bicyclic hydrocarbon-C2-4 alkenyl groups, etc.).
Examples of said alicyclic-alicyclic hydrocarbon group include a C1-4 alkyl group substituted with two C3-7 cycloalkyls selected from the above-mentioned alicyclic hydrocarbon group, for example, those represented by the formula:
Figure imgf000019_0001
Examples of said aromatic hydrocarbon group include an aryl group having 6-10 carbon atoms (including that where a 5- to β-membered non-aromatic hydrocarbon ring is fused with phenyl group) such as phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5-indanyl, 5,6,7,8- tetrahydro-1-naphthyl, 5, 6, 7, 8-tetrahydro-2-naphthyl, 5,6- dihydro-1-naphthyl, 5, 6-dihydro-2-naphthyl, 5, 6-dihydro-3- naphthyl, 5, 6-dihydro-4-naphthyl, etc.; and the like. Examples of said aromatic-aliphatic hydrocarbon group include an aralkyl group having 7-14 carbon atoms (Cβ-io aryl-Ci-4 alkyl group) such as phenyl-Ci_4 alkyl group, e.g., benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2- phenylpropyl, 3-phenylpropyl, etc.; naphthyl-Ci_4 alkyl group such as α-naphthylmethyl, α-naphthylethyl, β- naphthylmethyl, β-naphthylethyl, etc.; C6-I0 aryl-C2-4 alkenyl group such as phenyl-C2-4 alkenyl group, e.g., styryl, cinnamyl, etc.; and the like.
The above-mentioned "hydrocarbyl" group may have a substituent at a substitutable position. Examples of such substituent include a halogen, nitro, cyano, oxo, (1) an optionally substituted heterocyclic group, (2) an optionally substituted sulfinyl group, (3) an optionally substituted sulfonyl group, (4) optionally substituted hydroxyl group, (5) optionally substituted thiol group, (6) an optionally substituted amino group, (7) an acyl group,
(8) an optionally esterified or amidated carboxyl group, (9) an optionally substituted phosphoryl group, or the like.
Examples of the substituent of above-mentioned (2) an optionally substituted sulfinyl group, (3) an optionally substituted sulfonyl group, (4) optionally substituted hydroxyl group, (5) optionally substituted thiol group and (6) an optionally substituted amino group include an optionally substituted hydrocarbyl. Examples of
"hydrocarbyl" of such optionally substituted hydrocarbyl include those exemplified above. Such hydrocarbyl may be substituted by one or more substituents at a substitutable position. Examples of the substituent group of the optionally substituted hydrocarbyl as a substituent group include halogen, nitro, cyano, hydroxyl, thiol, amino and carboxyl .
As the optionally substituted sulfinyl group of above- mentioned (2), specifically, Ci_6 alkylsulfinyl (e.g., methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl etc.) and Cε-io arylsulfinyl (e.g., phenylsulfinyl, naphthylsulfinyl etc.) are exemplified.
As the optionally substituted sulfonyl group of above- mentioned (3), specifically, Ci_6 alkylsulfonyl (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl etc.) and Cε-io arylsulfonyl (e.g., phenylsulfonyl, naphthylsulfonyl etc.) are exemplified.
As the optionally substituted hydroxyl group of above- mentioned (4), specifically, hydroxyl, Ci_6 alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.) and Cβ-io aryloxy (e.g., phenoxy, naphthoxy, etc.) are exemplified. As the optionally substituted thiol group of above- mentioned (5), specifically, thiol, C1-S alkylthio (e.g., methylthio, ethylthio, propylthio, etc.) and CΘ-IO arylthio (e.g., phenylthio, naphthylthio etc.) are exemplified. As the optionally substituted amino group of above- mentioned (6), specifically, amino, mono-Ci_6 alkylamino (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino etc.), di-Ci-6 alkylamino (e.g., dimethylamino, diethylamino, ethylmethylamino, dipropylamino, diisopropylamino, dibutylamino etc.), and the like are exemplified.
Examples of the acyl group of above-mentioned (7) include the same group as the acyl for R3.
Examples of the ester group or amide group of the optionally esterified or amidated carboxyl group of above- mentioned (8) include ester group with the same optionally substituted hydrocarbyl as the substituent of optionally substituted hydroxyl group of above-mentioned (4) or amide group with optionally substituted amino group of above- mentioned (6) . -
As the optionally esterified carboxyl group, specifically, carboxyl, Ci_6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert- butoxycarbonyl etc.), Cδ-io aryloxy-carbonyl (e.g., phenoxycarbonyl etc.), C7-I6 aralkyloxy-carbonyl (e.g., benzyloxycarbonyl, • phenetyloxycarbonyl etc.), and the like are exemplified.
As the optionally amidated carboxyl group, specifically, carbamoyl, mono-Ci_6 alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl etc.), di-Cχ-6 alkyl- carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), Ce-io aryl-carbamoyl (e.g., phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl etc.), 5- to 6-membered heterocyclic carbamoyl (e.g., 2- pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienylcarbamoyl etc.), and the like are exemplified.
Examples of the "acyl" represented by R3 of the formula: -NR3- include a formyl and a group where the carbonyl group is combined with a Ci_io alkyl group, a C2-10 alkenyl group, a C2-io alkynyl group, a C3-.7 cycloalkyl group, a C5-7 cycloalkenyl group or an aromatic group (e.g., phenyl group, pyridyl group, etc.) (e.g., acetyl, propionyl, butyryl, isobytyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl, benzoyl, etc.) and the like.
R3 is preferably hydrogen, Ci_io alkyl, C2-io alkenyl, C2-10 alkynyl, and more preferably hydrogen, Ci-10 alkyl.
Specifically, as R3, methyl, ethyl, hydroxyethyl and the like are preferred.
R1 in the formula (I) and (I1) is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic group, an optionally substituted N-linked heteroaryl group, a cyano or an acyl. Here, the term "C- linked" of said "optionally substituted C-linked heterocyclic group" means that R1 is linked via a carbon atom of the heterocyclic group of R1 to the fused bicyclic ring represented by the formula (I) . Also, the term "N- linked" of the "optionally substituted N-linked heteroaryl group" means that R1 is linked via a nitrogen atom of the heteroaryl group of R1 to the fused bicyclic ring represented by the formula (I) . Examples of the "optionally substituted hydrocarbyl" for R1 include the same groups as those exemplified with respect to the optionally substituted hydrocarbyl of R3.
Examples of the "optionally substituted heterocyclic group" in the "optionally substituted C-linked heterocyclic group" for R1 include the same groups as those exemplified below with respect to the optionally substituted heterocyclic group of R2.
Examples of the "heteroaryl group" in the "optionally substituted N-linked heteroaryl group" for R1 include a 5- to 10-membered aromatic heterocyclic group optionally containing 1 to 3 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one nitrogen atom (e.g., pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3- oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, furazanyl, 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, 1,3,4- thiadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, etc) . Said heteroaryl group may be substituted with 1 to 3 substituents selected from the group consisting of halogen, Ci-6 alkyl, C2-6 alkenyl, Ci-6 alkoxy-Ci-6 alkyl, C5_7 cycloalkyl, Cδ-io aryl (said aryl may have 1 or 2 substituents selected from halogen, Ci-6 alkyl, halogeno Ci-6 alkyl and Ci_6 alkoxy) , C7-I4 aralkyl (said aralkyl may have 1 or 2 substituents selected from halogen, Ci-e alkyl, halogeno Ci_6 alkyl and Ci_6 alkoxy) , hydroxy, hydroxy-Ci_6 alkyl, Cε-io aryloxy (said aryloxy may have 1 or 2 substituents selected from halogen, Ci-6 alkyl, halogeno Ci_6 alkyl and Ci_6 alkoxy) , C7-I4 aralkyloxy, C6-io aryl-carbonyl, carboxyl, Cχ-6 alkoxy-carbonyl, carbamoyl, C6-io aryl- carbamoyl, amino, Cε-io aryl-carbonylamino, Ci_6 alkyl- carbonylamino, Ci_6 alkoxy-carbonylamino, Cβ-io arylthio, Ce- io arylsulfonyl, cyano, 5- to 7-membered heterocyclic group and oxo .
Examples of the "acyl" for R1 include the same groups as those exemplified with respect to the acyl of R3.
Among these, R1 in the formula (I) and (I1) is preferably an optionally substituted acyclic branched C3_14 hydrocarbyl (preferably acyclic branched C3_7 hydrocarbyl such as 2-propyl, 3-hexyl, 3-pentyl, 4-heptyl, etc. ) , an optionally substituted Cε-io aryl, an optionally substituted C-linked 5- to 14-membered heterocyclic group or N-linked 5- to 10-membered heteroaryl group. R2 in the formula (I) and (I1) is an optionally substituted cyclic hydrocarbyl or an optionally substituted heterocyclic group.
Examples of the "cyclic hydrocarbyl" of the "optionally substituted cyclic hydrocarbyl" for R2 include a C3-7 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc) , a C3-7 cycloalkenyl group (e.g., 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3- cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3- cycloheptenyl, etc) , an aryl group having 6-10 carbon atoms
(including that where a 5- to 6-membered non-aromatic hydrocarbon ring is fused with phenyl group) such as phenyl, α-naphthyl, β-naphthyl, 4-indenyl, 5-indenyl, 4-indanyl, 5- indanyl, 5, 6, 7 , 8-tetrahydro-l-naphthyl, 5, 6, 7, 8-tetrahydro- 2-naphthyl, 5, 6-dihydro-l-naphthyl, 5, 6-dihydro-2-naphthyl, 5, 6-dihydro-3-naphthyl, 5, 6-dihydro-4-naphthyl, etc.; and the like.
Examples of the "heterocyclic" of the "optionally substituted heterocyclic group" for R2 include (i) a 5- to 7-membered heterocyclic group containing one sulfur atom, one nitrogen atom or one oxygen atom, (ii) a 5- to 6- membered heterocyclic group containing 2-4 nitrogen atoms,
(iii) a 5- to β-membered heterocyclic group containing 1-2 nitrogen atoms and one sulfur or oxygen atom, (iv) a 8- to 12-membered fused bicyclic or tricyclic heterocyclic group containing 1-4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom, and the like. In addition, each of the heterocyclic groups exemplified in (i) to (iv) may be a saturated or unsaturated heterocyclic group and the unsaturated heterocyclic group may be either aromatic or non-aromatic.
Examples of the heterocyclic group for an optionally substituted heterocyclic group of R2 include an aromatic monocyclic heterocyclic group and a non-aromatic heterocyclic group.
Specific examples of the heterocyclic group for an optionally substituted heterocyclic group include (i) an aromatic monocyclic heterocyclic group (e.g., furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1, 2, 3-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl, furazanyl, 1,2,3- thiadiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 3-triazolyl, 1, 2, 4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, etc.) and (ii) a non-aromatic, heterocyclic group (e.g., oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, etc.) , and (iii) a fused heterocyclic group such as 8- to 12-membered bicyclic or tricyclic heterocyclic group (e.g., benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, lH-indazolyl, benzindazolyl, benzoxazolyl, 1,2- benzoisooxazolyl, benzothiazolyl, benzopyranyl, 1,2- benzoisothiazolyl, lH-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α- carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo [1, 2-b] pyridazinyl, pyrazolo [1, 5-a] pyridyl, irαidazo [1, 2-a] pyridyl, imidazo [1, 5-a] pyridyl, imidazo [1,2- b] pyridazinyl, imidazo [1, 2-a] pyrimidinyl, 1,2,4- triazolo [4, 3-a]pyridyl, 1, 2, 4-triazolo [4, 3-b] pyridazinyl, 1,2,5, 6-tetrahydro-4H-pyrrolo [3,2, 1-ij ] quinolinyl, etc. ) . The above-mentioned "cycloalkyl" , "cycloalkenyl" , "aryl" and "heterocyclic group" in R2 may have the same substituent as those exemplified with respect to the optionally substituted hydrocarbyl group of R3 and further may have the same group as optionally substituted hydrocarbyl group of R3 as their substituent. In addition, two of the substituents of the "cyclic hydrocarbyl" in the "optionally substituted cyclic hydrocarbyl" or "heterocyclic group" in the "optionally substituted heterocyclic group" for R2 may be combined each other to form a fused ring with the cyclic hydrocarbyl or heterocyclic group. Examples of the fused ring include, for example, an aromatic fused heterocyclic group such as 8- to 12-membered aromatic fused heterocyclic group (preferably, heterocyclic group consisting of the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group fused with a benzene ring or heterocyclic group consisting of the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group fused with the same or different above- mentioned 5- or β-membered aromatic monocyclic heterocyclic group), etc. (e.g. benzofuranyl, isobenzofuranyl, benzothienyl, indolyl, isoindolyl, lH-indazolyl, benzindazolyl, benzoxazolyl, 1, 2-benzoisooxazolyl, benzothiazolyl, benzopyranyl, 1, 2-benzoisothiazolyl, IH- benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolizinyl, pyrrolo [1, 2-b] pyridazinyl, pyrazolo[l, 5-a]pyridyl, imidazo [1, 2-a]pyridyl, imidazo[l,5- a]pyridyl, imidazo [1, 2-b] pyridazinyl, imidazo [1, 2- a]pyrimidinyl, 1, 2, 4-triazolo [4, 3-a]pyridyl, 1,2,4- triazolo [4, 3-b] pyridazinyl, etc.); etc.
Furthermore, the substituent of the "cyclic hydrocarbyl" in the "optionally substituted cyclic hydrocarbyl" or "heterocyclic group" in the "optionally substituted heterocyclic group" for R2 may be combined together with the substituent: R4 of -NR4-, -NR4-alk-, - CONR4- or -NR4CO- in Z of formula (I) or (I1) to form a nitrogen-containing fused ring with the cyclic hydrocarbyl or heterocyclic group of R2. Examples of the fused ring include, for example, 8- to 12-membered bicyclic heterocyclic group formed by a fusion of a benzene ring with a saturated monocyclic heterocyclic group containing one nitrogen atom such as 1, 2, 3, 4-tetrahydroquinolyl, 2, 3, 4, 5-tetrahydro-lH-l-benzazepinyl, and the like.
The above-mentioned "fused ring" and "nitrogen- containing fused ring" may further have one to three substituents selected from an acyl (e.g., acetyl, propionyl, etc.), an amide (e.g., dimethylaminocarbonyl, methylaminocarbonyl, etc.), an amine (e.g., dimethylamino, methylamino, amino, etc.), a halogen (e.g., fluorine, chlorine, bromine, etc.), a lower alkyl (e.g., methyl, ethyl, trifluoromethyl, etc.) and a lower alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, etc.), each of which may be substituted.
Among these, R2 is preferably an optionally- substituted Ce-io aryl (more preferably phenyl) or an optionally substituted 5- to 8-membered (more preferably 5- to 6-membered) heterocyclic group (more preferably pyridyl) . R2 is more preferably phenyl which is 2, 4-disubstituted, 2, 4, 6-trisubstituted or 2, 4, 5-trisubstituted with two or three substituents, or pyridyl which is disubstituted or trisubstituted with two or three substituents. The substituents for the phenyl and pyridyl may be the same or different and examples thereof include an acyl (e.g., acetyl, propionyl, etc.), an ' amide (e.g., dimethylaminocarbonyl, methylaminocarbonyl, etc.), an amine (e.g., dimethylamino, methylamino, amino, etc.), a halogen (e.g., fluorine, chlorine, bromine, etc.), a lower alkyl (e.g., methyl, ethyl, trifluoromethyl, etc.) and a lower alkoxy (e.g., methoxy, ethoxy, trifluoromethoxy, etc.), each of which may be substituted.
In the formula (I) and (I1), Y1 is CR3a or a nitrogen, Y2 is CR3b or a nitrogen, and Y3 is CR3c or a nitrogen (wherein R3a, R3b and R3c are independently a hydrogen, a halogen, a nitro, a cyano, an optionally substituted hydrocarbyl, an optionally substituted hydrocarbyloxy, an optionally substituted hydrocarbylthio, an optionally substituted amino or an acyl) , provided that one or less of Y1, Y2 and Y3 is nitrogen.
The 6-membered ring with Y1, Y2 and Y3 of the formula (I) and (I1) is a ring containing one or less nitrogen atom such as benzene ring and pyridine ring. Examples of halogen include fluorine, chlorine, bromine, iodine, and the like, preferably, chlorine and bromine .
Examples of the "optionally substituted hydrocarbyl" in R3a, R3b and R3c include the same groups as those exemplified with respect to the optionally substituted hydrocarbyl of R3. Among them, an optionally substituted Ci_ 3 alkyl is preferred, and an unsubstituted Ci-3 alkyl, C1-3 alkyl substituted with hydroxy and C1-3 alkyl substituted with an amine (e.g., dimethylamino, methylamino, pyrrolidine, etc.) are more preferred. Examples of the hydrocarbyl for said "optionally substituted hydrocarbyloxy" and "optionally substituted hydrocarbylthio" of R3a, R3b and R3c include the same groups as those exemplified with respect to the optionally substituted hydrocarbyl of R3. In particular, hydrocarbyl having 1 to 4 carbon atoms is preferred.
Among them, an optionally substituted C1S alkoxy is preferred, and an substituted C1-.3 alkoxy and halogenated substituted C1-3 alkoxy are more preferred, and in particular, methoxy, difluoromethoxy and trifluoromethoxy are preferred. Examples of the "optionally substituted amino" for R3a, R3b and R3c include amino group, an N-mono- substituted amino group, and an N, N-di-substituted amino group. Examples of said substituted amino groups include that having one or two substituents of an optionally substituted hydrocarbyl group (e.g., a Ci_8 alkyl group, a C3_7 cycloalkyl group, a C2-8 alkenyl group, a C2-8 alkynyl group, a C3-7 cycloalkenyl group, a C6-I0 aryl group that may have a C1-4 alkyl group, etc.), an optionally substituted heterocyclic group (e.g., the same group as an optionally substituted heterocyclic group of R2), or the formula: COR3d (wherein R3d represents hydrogen atom or an optionally substituted hydrocarbyl group or an optionally substituted heterocyclic group. As for "the hydrocarbyl group" or "the heterocyclic group" in "an optionally substituted hydrocarbyl group" or "an optionally substituted heterocyclic group" of R3d may have the same substituent as that of "the hydrocarbyl group" or "the heterocyclic group" in "an optionally substituted hydrocarbyl" of R3 or "an optionally substituted heterocyclic group" of R2) , preferably a Ci-10 acyl group (e.g., a C2-7 alkanoyl, benzoyl, nicotinoyl, etc.). Specific examples thereof include methylamino, dimethylamino, ethylamino, diethylamino, dipropylamino, dibutylamino, diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino, nicotinoylamino, and the like. In addition, the two groups in said substituted amino groups may be combined to form a nitrogen-containing 5- to
7-membered ring (e.g., piperidino, piperazino, morpholino, thiomorpholino, etc.).
Examples of the acyl for R3a, R3b and R3c include the same groups as those exemplified with respect to the acyl for R3. In particular, an acyl having 2 to 4 carbon atoms is preferred. In the formula (I) and (I1), Y1, Y2 and Y3 are preferably CR3a, CR3b and CR3c respectively, or one of Y1, Y2 and Y3 is nitrogen. R3a, R3b and R3c are preferably hydrogen, halogen, cyano, acyl, C1-4 alkyl optionally substituted by hydroxy (for example, methyl, ethyl, hydroxymethyl) , amino, and C1-4 alkoxy (for example, methoxy, ethoxy) . As R3a, chlorine, bromine, methoxy and methyl are more preferred.
In the formula (I) and (I'), Z is a bond, -CO-, an oxygen (-0-) , a sulfur (-S-), -SO-, -SO2-, -NR4-, -NR4-alk-,
-CONR4- or -NR4CO-. Said alk is an optionally substituted C1-4 alkylene such as methylene, ethylene, propylene, butylene and the like.
R4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl. The "optionally substituted hydrocarbyl" and "acyl" for R4 include the same groups as those exemplified with respect to the optionally substituted hydrocarbyl group and acyl for R3.
In addition, R4 may be combined together with the substituent of the cyclic hydrocarbyl or heterocyclic group in the optionally substituted hydrocarbyl or optionally substituted heterocyclic group of R2 to form a ring.
Examples of said ring include the same rings as those exemplified with respect to the rings formed by the two substituents of R2 mentioned above. Provided that (i) the compound wherein X is -NH-, and
R2 is an optionally substituted thiophene ring, (ii) the compound wherein R1 is cyano, R3c is methyl substituted with three substituents, one of which is acyl, and other two of which may form a ring, (iii) a) 6-amino-2- [ (2, β-dichlorophenyl) amino] -1-methyl-lH- benzimidazole-7-carbonitrile, b) N- { 7-cyano-2- [ (2, β-dichlorophenyl) amino] -1-methyl-IH- benzimidazol-β-yl } acetamide, c) β-amino-2- [ (2, β-dichlorophenyl) amino] -1-methyl-lH- benzimidazole-7-carboxamide, and d) 6-{ [ (allylamino) carbonothioyl] amino}-2- [ (2, 6- dichlorophenyl) amino] -l-methyl-lH-benzimidazole~7- carboxamide,
(iv) 4- ( {2- [ (4-chlorophenyl) amino] -1, 7-dimethyl-lH- benzimidazol-5-yl } oxy) -W-methylpyridine-2-carboxamide , (v) N- [3, 5-bis (trifluoromethyl) phenyl] -7-methyl-lH- benzimidazol-2-amine,
(vi) the compound wherein R3 is substituted heteroarylmethyl, R2 is 4-piperidinyl bearing a substituent at the 1- position,
(vii) 6-chloro-4-methyl-iV-piperidin-4-yl-lH-benzimidazol-2- amine, and
(viii) the compound wherein R2 is substituted 8-oxo-5-thia- 1-aza-bicyclo [4.2.0] oct-2-en-7-yl are excluded from the compounds of the formula (I).
As a preferred compound of the formula (I) and (I1), a compound wherein X is NR3 (wherein R3 is preferably methyl, ethyl, hydroxyethyl, etc.); Y1 is CR3a (wherein R3a is preferably H, Me, halogen (eg. F, Cl, Br), cyano, acyl, alkoxy, etc.), Y2 is CR3b (wherein R3b is preferably H, Me, halogen (eg. F, Cl, Br), etc.) or nitrogen and Y3 is CR3c (wherein R3c is preferably H, Me, halogen (eg. F, Cl, Br) , etc.) or nitrogen; Z is NR4 (wherein R4 is preferably H, Ci_4 alkyl, etc.) or oxygen; R1 is an optionally substituted acyclic branched C3_7 hydrocarbyl (in particular, 2-propyl, 3-hexyl, 3-pentyl, 4-heptyl) ; and R2 is an optionally substituted Cε-io aryl (in particular, phenyl, more preferably di- or tri-substituted phenyl) or an optionally substituted pyridyl (in particular, pyridyl, more preferably di- or tri-substituted pyridyl) is exemplified. Among them, particularly preferred is the compound wherein R1 is 3-pentyl, 3-hexyl or 4-heptyl, X is NR3, R3 is methyl, ethyl or hydroxyethyl, Y1 is CR3a, Y2 is CR3b, Y3 is CR3c, R3a is chloro, bromo, methoxy or methyl, R3b is a hydrogen, R3c is a hydrogen, R2 is phenyl which is 2, 4, 6-trisubstituted, 2, 4, 5-trisubstituted or 2, 4-disubstituted with substituents or pyridyl which is trisubstituted or disubstituted with substituents. Examples of the substituents for the phenyl and pyridyl include an acyl such as acetyl and propionyl, an amide such as dimethylaminocarbonyl and methylaminocarbonyl, an amine such as dimethylamino, methylamino and amino, a halogen such as fluoro, chloro and bromo, a lower alkyl such as methyl, ethyl and trifluoromethyl and a lower alkoxy such as methoxy, ethoxy and trifluoromethoxy, each of which may be substituted.
Compound (I) or (I1) may be in the form of a prodrug thereof. The prodrug of compound (I) or (I') refers to a compound that is converted into compound (I) or (I1) by a reaction with an enzyme, gastric acid, or the like under a physiological condition in the living body, namely, (i) a compound that is converted into compound (I) or (I') by an enzymatic oxidation, reduction, hydrolysis, or the like, and (ii) a compound that is converted into compound (I) or (I1) by hydrolysis with gastric acid or the like. Examples of a prodrug of compound (I) or (!') to be used include a compound or its salt wherein hydroxyl group in compound (I) or (I1) is acylated, alkylated, phosphorylated, or converted into borate (e.g., a compound or its salt wherein hydroxyl group in compound (I) or (I1) is converted into acetyloxy, palmitoyloxy, propanoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy, dimethylaminomethylcarbonyloxy, etc.), a compound or its salt wherein carboxyl group in compound (I) or (I1) is esterified or amidated (e.g., a compound or its salt wherein carboxyl group in compound (I) or (I1) is subjected to ethyl esterification, phenyl esterification, carboxyoxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-l, 3-dioxolan-4-yl) methyl esterification, cyclohexyloxycarbonyl esterification, or conversion into the methyl amide, etc.), or the like. These prodrugs can be produced according to a per se known method or its modified method. Further, a prodrug of compound (I) or (I') may be a compound or its salt that is converted into compound (I) or (I1) under physiological conditions as described in "Development of Drugs", Volume 7, Molecular Design, Hirokawa Shoten, 1990; pages 163-198. General synthetic method
Production of a compound of formula (I) or a salt thereof of the present invention is discussed below. The following examples are given to illustrate the invention and are not intended to be inclusive in any manner. Alternative methods may be employed by one skilled in the art.
A process for preparing compound (I) or a salt thereof of the present invention is shown in the following methods.
(Scheme 1)
Figure imgf000039_0001
wherein Rla is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic, an optionally substituted N-linked heteroaryl and acyl, Ar is an optionally substituted aryl, L1 is a leaving group (for example, halogen atom such as chlorine, bromine and iodine, etc, sulfonyloxy group such as p-toluenesulfonyloxy group, methanesulfonyloxy group and trifluoromethanesulfonyloxy group, etc., and acyloxy group such as acetyloxy group and benzoyloxy group, etc.) and each of other symbols has a meaning defined above. Compound (III) or a salt thereof can be prepared by halogenation, sulfonylation or acylation of compound (II) or a salt thereof with a halogenation agent, sulfonylation agent or acylation agent, respectively. Examples of a halogenation agent include phosphorous oxychloride, phosphorous oxybromide, phosphorous trichloride, phosphorous tribromide, phosphorous pentachloride, chlorine, bromine and thionyl chloride. The halogenation agent is employed in an amount of 1 moles to excess per 1 mole of compound (II) or as a solvent.
Examples of solvent having no adverse effect on the reaction include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, dioxane and tetrahydrofuran, esters such as ethyl acetate, nitriles such as acetonitrile, halogenated hydrocarbon such as chloroform and dichloromethane, amides such as N,N- dimethlformamide, W^iV-dimethylacetamide and l-methyl-2- pirrolidinone, ketones such as acetone and 2-butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio.
While the reaction temperature may vary depending on compound (II) or a salt thereof employed as well as other conditions, it is 0 to 200 0C, preferably 20 to 150 0C. The reaction time is 10 minutes to 24 hours, preferably 30 minutes to 12 hours. The thus obtained compound (III) can be isolated and purified by the known isolating and purifying methods, for example, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
When L1 is a sulfonyloxy or an a acyloxy group in compound (III) or a salt thereof, compound (III) or a salt thereof can be prepared by reacting compound (II) with a sulfonylation agent or an acylation agent after base treatment of compound (II) .
A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkoxide such as sodium methoxide and sodium ethoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc.
Examples of a sulfonylation agent include p- toluenesulfonyl chloride, methanesulfonylchloride, trifluoromethanesulfonylchloride, etc. The sulfonylation agent is employed in an amount of 1 to 10 moles, preferably 1 to 5 moles per 1 mole of compound (II) .
Examples of an acylation agent include acetylchloride, benzoyl chloride, etc. The acylation agent is employed in an amount of 1 to 10 moles, preferably 1 to 5 moles per 1 mole of compound (II) .
Examples of the solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as W^i^-dimethylformamide and N^iV-dimethylacetamide, and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio.
While the reaction temperature may vary depending on compound (II) or a salt thereof employed as well as other conditions, it is 0 to 200 0C, preferably 0 to 150 0C. The reaction time is 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
The thus obtained compound (III) can be isolated and purified by the known isolating and purifying methods, for example, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
Compound (Ia) or a salt thereof, which is encompassed within compound (I) of the invention, can be prepared by reacting compound (III) with ArZH. In this step, 1 to 20 moles, preferably 1 to 10 moles of a compound represented by ArZH or a salt thereof are employed per 1 mole of compound (III) or a salt thereof.
This reaction may be performed under basic conditions. A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkaline metal alkoxide such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, etc.
Examples of solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as I^N-dimethylformamide, N,N-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio, or may not be used.
While the reaction temperature may vary depending on compound (III) or a salt thereof employed as well as other reaction conditions, it is 0 to 200 °C, preferably 20 to 150 °C, or the reaction may be heated by microwave irradiation. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours. The thus obtained compound (Ia) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
(Scheme 2)
Figure imgf000044_0001
wherein R5 is hydrogen and an optionally substituted hydrocarbyl, R3 and R5 may be combined each other to form a ring, R6 and R7 are optionally substituted hydrocarbyl, L2 and L3 are halogen atoms such as chlorine, bromine and iodine and each of other symbols has a meaning defined above .
Compound (Ha) or a salt thereof can be prepared by treatment of compound (IV) with 1, 1' -carbonyl diimidazole, phosgene, triphosgene, alkyl haloformate such as ethyl chloroformate, phenyl haloformate such as phenyl chloroformate or urea, etc. Compound (IV) or a salt thereof is mainly commercially available or can be prepared from the nitro derivatives corresponded to compound (IV) .
In this step, 1 to 5 moles, preferably 1 to 3 moles of an agent for cyclization or a salt thereof are employed per 1 mole of compound (IV) or a salt thereof.
Examples of solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N^iV-dimethylformamide, I\F,W-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio, or may not be used.
While the reaction temperature may vary depending on compound (IV) or a salt thereof employed as well as other reaction conditions, it is 0 to 150 °C, preferably 20 to
100 °C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
The thus obtained compound (Ha) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. Compound (lib) or a salt thereof can be prepared by Grinard reaction of compound (Ha) or a salt thereof with R6MgL2 and R7MgL3. When R6 is equal to R7 in compound (lib), R6MgL2 may be used in this step. When R6 is not equal to R7 in compound (lib) , the Grinard reactions may be performed stepwise by R6MgL2 and R7MgL3 in this step. In this step, 1 to 20 moles, preferably 1 to 10 moles of a compound represented by R6MgL2 and R7MgL3 or a salt thereof are employed per 1 mole of compound (Ha) or a salt thereof.
Examples of solvent having no adverse effect on the reaction include ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform and dichloromethane, ketones such as acetone and 2-butanone and sulfoxides such as dimethylsulfoxide . These solvents may be used by mixing at • an appropriate ratio, or may not be used.
While the reaction temperature may vary depending on compound (Ha) or a salt thereof employed as well as other reaction conditions, it is -20 to 150 0C, preferably 0 to 100 °C. The reaction time is 5 minutes to 24 hours, preferably 5 minutes to 12 hours.
The thus obtained compound (lib) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
Compound (lie) or a salt thereof can be prepared by dehydration of compound (lib) or a salt thereof with an acid, and the olefine is then reduced by an appropriate reducing agent or catalytic hydrogenation.
An acid may for example be an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and thionyl chloride, etc., and an ordinary organic acid such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid. In dehydration step, 1 mole to excess of an acid is employed per 1 mole of compound (lib) or a salt thereof or an acid may be employed as a solvent.
Examples of solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as 2V,ΛT-dimethylformamide, I\7VΛ7-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio, or may not be used.
While the reaction temperature may vary depending on compound (lib) or a salt thereof employed as well as other reaction conditions, it is 0 to 200 °C, preferably 20 to 150 °C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
The thus obtained define can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. In reduction step, a reducing agent is preferably sodium borohydride, lithium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride. Catalytic hydrogenation may be performed in this step. Examples of a catalyst include a palladium catalyst such as palladium black, palladium oxide, palladium barium sulfate, palladium on carbon, palladium hydroxide, a platinum catalyst such as platinum black, platinum oxide and platinum on carbon, or nickel catalyst such as reduced nickel, oxidized nickel, and Raney nickel.
In this step, 1 to 20 moles, preferably 1 to 10 moles of a reducing agent are employed per 1 mole of the define or a salt thereof.
Examples of solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as N,N~dimethylforπιaπιide, IV,I\/-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio. While the reaction temperature may vary depending on the olefine or a salt thereof employed as well as other reaction conditions, it is 0 to 150 °C, preferably 0 to 100 °C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours. The thus obtained compound (lie) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
(Scheme 3)
Figure imgf000050_0001
(Ib) (Ic) (Id) wherein each symbol has a meaning defined above.
Preparation of compound (Ic) or a salt thereof, which is encompassed within compound (I) of the invention, from compound (Ib) or a salt thereof can be carried out similar to preparation of compound (lib) in Scheme 2.
Preparation of compound (Id) or a salt thereof, which is encompassed within compound (I) of the invention, from compound (Ic) or a salt thereof can be . carried out similar to preparation of compound (lie) in Scheme 2. ( Scheme 4 )
Figure imgf000051_0001
(Ha) (lid) wherein each symbol has a meaning defined above.
Preparation of compound (Hd) or a salt thereof from compound (Ha) or a salt thereof can be carried out similar to preparation of compound (lib) in Scheme 2.
Figure imgf000051_0002
wherein each symbol has a meaning defined above.
Preparation of compound (Ie) or a salt thereof, which is encompassed within compound (I) of the invention, from compound (Ib) or a salt thereof can be carried out similar to preparation of compound (lib) in Scheme 2.
( Scheme 6)
Figure imgf000051_0003
wherein Rlb is an optionally substituted hydrocarbyl and an optionally substituted C-linked heterocyclic, Rlc is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic and an optionally substituted N-linked heteroaryl, R8 and R9 are independently hydrogen, optionally substituted hydrocarbyl, hydroxy and optionally substituted alkoxy and may be combined each
other to form a ring,
Figure imgf000052_0001
is a heteroaryl, L4 is a halogen atom such as chlorine, bromine and iodine each of other symbols has a meaning defined above.
Compound (VI) or a salt thereof can be prepared by halogenation of compound (V) or a salt thereof with a halogenation agent.
Examples of a halogenation agent include chlorine, bromine, iodine, thionyl chloride, copper (I) chloride, copper (II) chloride, copper (I) bromide, copper (II) bromide, sodium chloride, sodium bromide, sodium iodide, potassium iodide, etc. The halogenation agent is employed in an amount of 0.5 moles to 10 moles, preferably 0.5 moles to 5 moles, per 1 mole of compound (V) .
In this step, the diazonium type compound may be produced before introduction of a halogen atom. Examples of an agent to produce the diazonium type compound include sodium nitrite, potassium nitrite and tert-butyl nitrite, etc. The agent is employed in an amount of 1 mole to 10 moles, preferably 1 mole to 5 moles, per 1 mole of compound (V) .
This reaction can be carried out under an acidic condition. Examples of an acid include an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, a nitric acid and copper sulfate, etc., as well as Lewis acid. An acid is employed in an amount of 2 moles to excess per 1 mole of compound (V) . Examples of solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as NV-V-dimethylformamide, I\J>N-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio.
While the reaction temperature may vary depending on compound (V) or a salt thereof employed as well as other conditions, it is -20 to 150 0C, preferably 0 to 100 0C. The reaction time is 10 minutes to 24 hours, preferably 30 minutes to 12 hours. The thus obtained compound (VI) can be isolated and purified by the known isolating and purifying methods, for example, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
When Rlc is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic in compound (lie) or a salt thereof, compound (lie) or a salt thereof can be prepared by reacting compound (VI) with RlbBR8R9 or a salt thereof in the presence of a palladium catalyst, preferably tetrakis (triphenylphosphine) palladium(O) and tris (dibenzylidenacetate) dipalladium(O) , a catalytic amount of a phosphine ligand, preferably 2-
(dicyclohexylphosphino) biphenyl, 2- (dicyclohexylphosphino) - 2' , 6' -dimethoxy-1, 1' -biphenyl (S-Phos) and 2- (dicyclohexylphosphino) -2" , A' , 6' -triisopropyl-1, 1' -biphenyl (X-Phos) and a base according to the procedure of Suzuki coupling (Organic Synthesis via Boranes, vol. 3: Suzuki coupling, A.Suzuki and H. C. Brown, Aldrich, 2002) and the modified methods, or a trialkyl aryl tin such as aryl trimethyltin or aryl tributyltin, etc. or a salt thereof and optional additives according to the procedure of Stille coupling (Angew. Chem. Int. Ed. Engl., 25, 504 (1986)) and the modified methods. When R,1c is
Figure imgf000055_0001
in compound (lie) , compound (lie) or
a salt thereof can be also prepared by reacting compound
(VI) or a salt thereof with
Figure imgf000055_0002
or a salt thereof in the presence of a palladium catalyst, preferably palladium (II) acetate or a copper agent, preferably copper (II) acetate. A catalytic amount of a phosphine ligand, preferably 2- (dicyclohexylphosphino) biphenyl, may be employed. This reaction can be carried out according to the procedure of Buchwald et al. (J. Am. Chem. Soc. 1998, 120, 9722) and Lam et. al. (Tetrahedron Lett., 1998, 39, 2941) and the modified methods.
( Scheme 7 )
Figure imgf000055_0003
wherein each symbol has a meaning defined above.
Compound (VII) or a salt thereof can be prepared by reaction of compound (VI) or a salt thereof via lithiation or coupling reaction with a boron agent.
When the reaction is performed via lithiation, examples of a boron agent include trialkyl borate, preferably triisopropyl borate.
In this step, 1 to 10 moles, preferably 1 to 5 moles of a boron agent are employed per 1 mole of compound (VI) or a salt thereof. A lithiation agent may for example be alkyl lithium, preferably π-butyl lithium, sec-butyl lithium and tert- butyl lithium and is employed in an amount of 1 to 5 moles, preferably 1 to 3 moles per 1 mole of compound (VI) or a salt thereof. Examples of solvent having no adverse effect on the reaction include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as diethyl ether, dioxane and tetrahydrofuran, and halogenated hydrocarbon such as chloroform and dichloromethane . These solvents may be used by mixing at an appropriate ratio.
While the reaction temperature may vary depending on compound (VI) or a salt thereof employed as well as other conditions, it is -100 to 100 0C, preferably -80 to 50 0C. The reaction time is 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
When the coupling reaction using a metal catalyst is carried out, examples of a boron agent include 4,4,5,5- tetramethyl-1, 3, 2-dioxaborolane and bis (pinacolato) diborane. In this step, 1 to 10 moles, preferably 1 to 5 moles of a boron agent are employed per 1 mole of compound (VI) or a salt thereof.
A palladium catalyst, preferably palladium (II) diacetate, a catalytic amount of a phosphine ligand, preferably 2- (dicyclohexylphosphino) biphenyl and a base can be employed according to the procedure described in J. Org.
Chem. , 62, 6458 (1997) and the modified methods.
Examples of solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as A^N-dimethylformamide, N,N-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide . These solvents may be used by mixing at an appropriate ratio, or may not be used.
While the reaction temperature may vary depending on compound (VI) or a salt thereof employed as well as other conditions, it is 0 to 200 0C, preferably 20 to 150 0C. The reaction time is 10 minutes to 48 hours, preferably 30 minutes to 24 hours.
The thus obtained compound (VII) can be isolated and purified by the known isolating and purifying methods, for example, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
Preparation of compound (lie) or a salt thereof from compound (VII) or a salt thereof can be carried out similar to preparation of compound (lie) in Scheme 6.
( Scheme 8 )
X JL1V v />-vz R9 »- ((sstteepp pp))
Figure imgf000058_0001
wherein each symbol has a meaning defined above.
Preparation of compound (VIII) or a salt thereof from compound (VI) or a salt thereof can be carried out similar to preparation of compound (III) or a salt thereof in Scheme 1. Preparation of compound (IX) or a salt thereof from compound (VIII) or a salt thereof can be carried out similar to preparation of compound (Ia) or a salt thereof in Scheme 1.
Preparation of compound (If) or a salt thereof, which is encompassed within compound (I) of the invention, from compound (IX) or a salt thereof can be carried out similar to preparation of compound (lie) or a salt thereof in Scheme 6. (Scheme' 9)
Figure imgf000059_0001
(V) (X) (iif) wherein R10 and R11 are hydrogen and optionally substituted hydrocarbyl and each of other symbols has a meaning defined above.
Compound (X) or a salt thereof can be prepared by reaction of compound (V) or a salt thereof with sodium nitrite, and the obtained diazonium salt is reduced by an appropriate reducing agent.
In this step, 1 to 5 moles, preferably 1 to 3 moles of sodium nitrite are employed per 1 mole of compound (V) or a salt thereof.
Examples of a reducing agent include alkaline metal borohydride, preferably sodium borohydride, lithium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride, metal, preferably Fe, Zn, Sn and
SnCl2 and metal catalyst, a palladium catalyst such as palladium black, palladium oxide, palladium barium sulfate, palladium on carbon, palladium hydroxide, a platinum catalyst such as platinum black, platinum oxide and platinum on carbon, or nickel catalyst such as reduced nickel, oxidized nickel, and Raney nickel. The reducing agent is employed in an amount of catalytic amount to excess per 1 mole of compound (V) . Examples of solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as _V,_V-dimethylformamide, N,N-dimethylacetamide and 1- methyl-2-pyrrolidinone, and sulfoxides such as dimethylsulfoxide . These solvents may be used by mixing at an appropriate ratio, or may not be used.
While the reaction temperature may vary depending on compound (V) or a salt thereof employed as well as other conditions, it is -20 to 150 0C, preferably 0 to 100 0C. The reaction time is 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
The thus obtained compound (X) can be isolated and purified by the known isolating and purifying methods, for example, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. Compound (Hf) or a salt thereof can be prepared by reaction of compound (X) or a salt thereof with compound (XI) or a salt thereof.
In this step, 1 to 5 moles, preferably 1 to 3 moles of compound (XI) or a salt thereof are employed per 1 mole of compound (X) or a salt thereof.
An acid may be used and for example be an inorganic acid such as hydrochloric acid, sulfuric acid and nitric acid, etc., and an ordinary organic acid such as formic acid, acetic acid, p-toluenesulfonic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid.
Examples of solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as IV,I\7-dimethylformamide, WVN-dimethylacetamide and 1- methyl-2-pyrrolidinone, acids such as formic acid and acetic acid and sulfoxides such as dimethylsulfoxide . These solvents may be used by mixing at an appropriate ratio.
While the reaction temperature may vary depending on compound (V) or a salt thereof employed as well as other conditions, it is 0 to 200 0C, preferably 20 to 150 0C. The reaction time is 10 minutes to 24 hours, preferably 30 minutes to 12 hours.
The thus obtained compound (Hf) can be isolated and purified by the known isolating and purifying methods, for example, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
(Scheme 10)
Figure imgf000062_0001
(V) (Hg) wherein each symbol has a meaning defined above.
Preparation of compound (Hg) or a salt thereof from compound (V) or a salt thereof can be carried out similar to preparation of compound (Hf) or a salt thereof in Scheme 9.
(Scheme 11)
Figure imgf000063_0001
wherein R12 is an optionally substituted Ci_6 alkylcarbonyl
(for example. formyl, methylcarbonyl and ethylcarbonyl, etc.), phenylcarbonyl, a Ci-6 alkyloxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl, etc.), phenyloxycarbonyl (for example, benzoxycarbonyl) , C7-IO aralkylcarbonyl (for example, benzyloxycarbonyl) , C7-io aralkyl (for example, benzyl and 4-methoxybenzyl, etc.), trityl, phthaloyl, etc. A substituent on each of the groups listed above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine, etc.), a Ci_6 alkylcarbonyl (for example, methylcarbonyl, ethylcarbonyl and butylcarbonyl, etc.) and a nitro group, and each of other symbols has a meaning defined above. Compound (Ha) or a salt thereof can be also prepared by the procedure as shown in scheme 11.
Compound (XIV) or a salt thereof can be prepared by nitration of compound (XIII) or a salt thereof with a nitration agent. Compound (XIII) or a salt thereof is mainly commercially available or can be prepared from the aniline derivatives corresponded to compound (XIII) by a usual acetylation method.
Examples of a nitration agent include nitric acids (for example, fuming nitric acid, a solution of nitric acid and sulfuric acid etc. ) , nitrates (for example, sodium nitrate, potassium nitrate, silver nitrate, ammonium nitrate, benzoyl nitrate, benzyltriphenylphosphonium nitrate, bismuth subnitrate, etc) . The nitration agent is employed in an amount of 0.5 moles to 50 moles, or may be employed as a solvent, preferably 0.5 moles to 30 moles, per 1 mole of compound (XIII) .
This reaction is also carried out in the presence of additives. Examples of additives include anhydrides (for example, acetic anhydride, trifluoroacetic anhydride, methanesulfonic anhydride, etc) , acid chlorides (for example, thionyl chloride, etc) , acids
(for example, acetic acid, methanesulfonic acid, etc) , metals (for example, iron, etc) .
The additives are employed in an amount of 0.5 moles to 50 moles, preferably 0.5 moles to 30 moles, per 1 mole of compound (XIII) .
Examples of solvent having no adverse effect on the reaction include water, acetic acid, halogenated hydrocarbons such as chloroform and dichloromethane, 1,2- dichloroethane, etc. These solvents may be used by mixing at an appropriate ratio, or may not be used. While the reaction temperature may vary depending on compound (XIII) or a salt thereof employed as well as other reaction conditions, it is -20 to 150 0C, preferably 0 to 100 °C The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours. The' thus obtained compound (XIV) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
Compound (XV) or a salt thereof can be prepared by deacetylation of compound (XIV) or a salt thereof with an acid or base, and then reduction of the nitro group by an appropriate reducing agent or catalytic hydrogenation.
An acid may for example be an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and thionyl chloride, etc., and an ordinary organic acid such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid.
A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc. , an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkaline metal alkoxide such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, etc.
In deacetylation step, 1 mole to excess of an acid or base is employed per 1 mole of compound (XIV) or a salt thereof, or an acid may be employed as a solvent. Examples of solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as I\7V.W-dimethylformamide, iV^iV-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio, or may not be used.
While the reaction temperature may vary depending on compound (XIV) or a salt thereof employed as well as other reaction conditions, it is 0 to 200 °C, preferably 20 to 150 °C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
The thus obtained nitro compounds can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. In reduction step, a reducing agent is preferably sodium borohydride, lithium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride . Catalytic hydrogenation may be performed in this step. Examples of a catalyst include a palladium catalyst such as palladium black, palladium oxide, palladium barium sulfate, palladium on carbon, palladium hydroxide, a platinum catalyst such as platinum black, platinum oxide and platinum on carbon, or nickel catalyst such as reduced nickel, oxidized nickel, and Raney nickel.
-In this step, 1 to 20 moles, preferably 1 to 10 moles of a reducing agent are employed per 1 mole of the nitro compounds or a salt thereof. Examples of solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as A^AT-dimethylformamide, N,iV-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio.
While the reaction temperature may vary depending on compound (XIV) or a salt thereof employed as well as other reaction conditions, it is 0 to 150 0C, preferably 0 to 100
°C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
The thus obtained compound (XV) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. Preparation of compound (XVI) or a salt thereof from compound (XV) or a salt thereof can be carried out similar to preparation of compound (Ha) in Scheme 2.
Compound (XVII) or a salt thereof can be prepared by reacting compound (XVI) with R12-L2 or anhydride (R12) 2O.
In this step, 1 to 10 moles, preferably 1 to 5 moles of a compound represented by R12-L2 or anhydride (R12) 2O or a salt thereof are employed per 1 mole of compound (XVI) or a salt thereof. This reaction may be performed under basic conditions. A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkaline metal alkoxide such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, etc., an amine such as trimethylamine, triethylamine and diisopropylethylamine, etc., a cyclic amine such as pyridine, 4-dimethylaminopyridine, DBU, etc.
Examples of solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as WVN-dimethylformamide, N,W-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio, or may not be used. While the reaction temperature may vary depending on compound (XVI) or a salt thereof employed as well as other reaction conditions, it is 0 to 200 0C, preferably 20 to
150 0C, or the reaction may be heated by microwave irradiation. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
The thus obtained compound (XVII) can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography. Preparation of compound (XVIII) or a salt thereof from compound (XVII) or a salt thereof can be carried out similar to preparation of compound (XVII) . Compound (Ha) or a salt thereof can be prepared by deprotection of compound (XVIII) or a salt thereof with an acid or a base, or catalytic hydrogenation.
An acid may for example be an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid and thionyl chloride, etc., and an ordinary organic acid such as formic acid, acetic acid, trifluoroacetic acid and methanesulfonic acid, etc. as well as a Lewis acid.
A base may for example be an alkaline metal hydroxide such as sodium hydroxide and potassium hydroxide, etc., an alkaline metal hydrogen carbonate such as sodium hydrogen carbonate and potassium hydrogen carbonate, etc., an alkaline metal carbonate such as sodium carbonate and potassium carbonate, etc., a cesium salt such as cesium carbonate, etc., an alkaline metal hydride such as sodium hydride and potassium hydride, etc., sodium amide, an alkaline metal alkoxide such as sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide, etc.
Catalytic hydrogenation may be performed in this step. Examples of a catalyst include a palladium catalyst such as palladium black, palladium oxide, palladium barium sulfate, palladium on carbon, palladium hydroxide, a platinum catalyst such as platinum black, platinum oxide and platinum on carbon, or nickel catalyst such as reduced nickel, oxidized nickel, and Raney nickel.
In this step, 1 mole to excess of an acid or a base is employed per 1 mole of compound (XVIII) or a salt thereof, or an acid may be employed as a solvent.
Examples of solvent having no adverse effect on the reaction include water, alcohols such as methanol and ethanol, ethers such as diethyl ether, dioxane and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, halogenated hydrocarbons such as chloroform and dichloromethane, nitriles such as acetonitrile, amides such as i\7,I\J-dimethylformamide, N,W-dimethylacetamide and 1- methyl-2-pyrrolidinone, ketones such as acetone and 2- butanone and sulfoxides such as dimethylsulfoxide. These solvents may be used by mixing at an appropriate ratio, or may not be used.
While the reaction temperature may vary depending on compound (XVIII) or a salt thereof employed as well as other reaction conditions, it is 0 to 200 0C, preferably 20 to 150 °C. The reaction time is 5 minutes to 48 hours, preferably 5 minutes to 24 hours.
The thus obtained compounds can be isolated and purified by the known isolating and purifying methods, for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, transfer dissolution and chromatography.
A starting compound for compound (I) according to the invention may be in a form of a salt, including a salt with an inorganic acid (for example, hydrochloric acid, phosphoric acid, hydrobromic acid and sulfuric acid, etc.) and a salt with an organic acid (for example, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid and benzenesulfonic acid, etc.). When any of these compounds carries an acidic group such as -COOH, etc., a salt with an inorganic base (for example, an alkaline metal or an alkaline earth metal such as sodium, potassium, calcium and magnesium, ammonia, etc.) or with an organic base (for example, tri-Ci_3 alkylamine such as triethylamine, etc.) may be formed.
In each of the reactions described above, when a starting compound carries as a substituent an amino group, an amide group, a hydrozino group, a urea group, a carboxyl group or a hydroxyl group, then such group may be derivatized with a protective group employed ordinarily in peptide chemistry, which is cleaved after a reaction if desired to yield an intended compound.
A protective group for an amino group, an amide group and a urea group may for example be an optionally substituted Ci_6 alkylcarbonyl (for example. formyl, methylcarbonyl and ethylcarbonyl, etc.), phenylcarbonyl, a Ci-6 alkyloxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl, etc.), phenyloxycarbonyl (for example, benzoxycarbonyl) , C7-I0 aralkylcarbonyl (for example, benzyloxycarbonyl) , C7-I0 aralkyl (for example, benzyl and 4-methoxybenzyl, etc.), trityl, phthaloyl, etc. A substituent on each of the groups listed above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine, etc.), a Cχ-6 alkylcarbonyl (for example, methylcarbonyl, ethylcarbonyl and butylcarbonyl, etc.) and a nitro group, which may occur 1 to about 3 times .
A protective group for a carboxyl group may for example be an optionally substituted Ci_6 alkyl (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl, etc.), phenyl, trityl and silyl, etc. A substituent on each of the groups listed above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine, etc.), a Ci_6 alkylcarbonyl (for example, formyl, methylcarbonyl, ethylcarbonyl and butylcarbonyl, etc.) and a nitro group, which may occur 1 to about 3 times.
A protective group for a hydroxyl group may for example be an optionally substituted Ci-6 alkyl (for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl, etc.), phenyl, a C7-I0 aralkyl (for example, benzyl, etc.), a Ci_6 alkylcarbonyl (for example, formyl, methylcarbonyl and ethylcarbonyl, etc.), phenyloxycarbonyl (for example, benzoxycarbonyl, etc.), C7-I0 aralkylcarbonyl (for example, benzyloxycarbonyl, etc.), pyranyl, furanyl, silyl, etc. A substituent on each of the groups listed above may be a halogen atom (for example, fluorine, chlorine, bromine and iodine, etc.), a Ci_6 alkyl, phenyl, a C7-io aralkyl, nitro, etc., which may occur 1 to about 4 times. A method for cleaving a protective group is a method known per se or an analogous method, such as a treatment for example with an acid, a base, a reduction, UV light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, etc.
The pharmaceutical composition containing compound (I) or (I1) of the present invention is expected to be useful in the treatment and prevention of diseases, in which CRF is involved, such as depression, major depression, bipolar depression, dysthymia, seasonal affective disorder, recurrent depression, postpartum depression, suppression symptom, mania, anxiety, generalized anxiety disorder, anxiety syndrome, panic disorder, phobia, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, stress-induced insomnia, post psychic trauma stress disorder, Tourette' s syndrome, autism, passion disorder, adjustment disorder, dysthymic disorder, sleep disorder, insomnia, bipolar disorder, circulatory disease, neurosis, schizophrenia, digestive ulcer, irritable bowl syndrome, inflammatory bowel disease, ulcerative colitis, Crohn's disease, stress-induced gastrointestinal disorder, nervous emesis, peptic ulcer, diarrhea, constipation, postoperative ileus, gastrointestine dysfunction and nervous vomiting associated with stress, Alzheimer's disease, Alzheimer's type senile dementia, nervous degenerated disease such as Parkinson' s disease and Huntington' s disease, multi-infarct dementia, senile dementia, nervous orexia inactivity, eating disorder, anorexia nervosa, hyperphagia and other ingestion disorder, obesity, diabetes, alcohol dependency, pharmacophinia, drug withdrawal, migraine, stress headache, tension headache, ischemic nervous disorder, nervous disorder, cerebral paralysis, progressive supranuclear palsy, amyotrophic lateral sclerosis, multiple sclerosis, muscular convulsion, chronic fatigue syndrome, glaucoma, Meniere syndrome, autonomic imbalance, alopecia, hypertension, cardiovascular disorder, tachycardia, congestive heart attack, hyperplea, bronchial asthma, apnea, infant sudden death syndrome, inflammatory disorder, pain, allergic disorder, impotence, menopausal disorder, fertilization disorder, infertility, cancer, immune function abnormality at HIV infection, immune functional abnormality due to stress, cerebrospinal meningitis, acromegaly, incontinence or osteoporosis.
Compound (I) or (I1) of the present invention can be formulated with a pharmaceutically acceptable carrier and can be orally or parenterally administered as solid formulations such as tablets, capsules, granules, powders, or the like; or liquid formulations such as syrups, injections, or the like. Also, there can be prepared formulations for transdermal administration such as patchings, cataplasms, ointments (including creams) , plasters, tapes, lotions, liquids and solutions, suspensions, emulsions, sprays, and the like.
As for a pharmaceutically acceptable carrier, a variety of organic or inorganic carrier substances, which have been conventionally employed as formulation materials, is used and compounded as a bulking agent, a lubricant, a binding agent, and a disintegrator in solid formulations; a vehicle, a solubilizing agent, a suspending agent, an isotonicity agent, a buffering agent, and an analgesic in liquid formulations. If necessary, formulation excipients such as a preservative, an antioxidant, a stabilizer, a coloring agent, a sweetening agent, and the like can be used. Preferred examples of the bulking agent include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid, and the like. Preferred examples of the lubricant include magnesium stearate, potassium stearate, talc, colloidal silica, and the like. Preferred examples of the binding agent include crystalline cellulose, α-starch, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, and the like. Preferred examples of the disintegrator include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and the like. Preferred examples of the vehicle include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, and the like. If necessary, for the purpose of taste masking, enteric coating, or prolonged action, oral formulations can be prepared by coating by a per se known method. Examples of this coating agent include hydroxypropylmethyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, polyoxyethylene glycol, Tween 80, Pluronic F68 [polyoxyethylene (160) polyoxypropylene (30) glycol], cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, hydroxymethyl cellulose acetate phthalate, Eudragit (manufactured by Rohm Company, methacrylic acid- acrylic acid copolymer), and the like.
Preferred examples of the solubilizing agent include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, trisamiomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, and the like. Preferred examples of the suspending agent include surface active agents such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate, and the like; hydrophilic, high molecular substances such as polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and the like; and so on. Preferred examples of the isotonicity agent include sodium chloride, glycerin, D- mannitol, and the like. Preferred examples of the buffering agent include buffer solutions of a phosphate, an acetate, a carbonate, a citrate, or the like. Preferable examples of the analgesic include benzyl alcohol and the like. Preferred examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, and the like. Preferred examples of the antioxidant include sulfites, ascorbic acid, and the like.
The following examples and experiments describe the manner and process of making and using the present invention and are illustrative rather than limiting. It is to be understood that there may be other embodiments which fall within the spirit and scope of the present invention as defined by the claims appended hereto.
In the following examples, preparative HPLC was carried out under a condition described below. Equipment: Gilson high through put purification system Column: YMC CombiPrep ODS-A S-5μm, 50x20 mm Solvent: A; 0.1% aqueous trifluoroacetic acid, B; 0.1% trifluoroacetic acid in acetonitrile
Gradient cycle: 0.00 min (A/B = 95/5), 1.00 min (A/B = 95/5), 5.20 min (A/B = 5/95), 6.40 min (A/B = 5/95), 6.50 min (A/B = 95/5), 6.60 min (A/B = 95/5) Flow rate: 20 mL/min Detection: UV 220 nm
Example 1
N- ( 4-Bromo-2-methoxy-6-methylphenyl ) -l-methyl-7- ( 1- propylbutyl ) -lϋ-benzimidazol-2-amine Hydrchloride
Figure imgf000080_0001
Methyl 2-chloro-3-nitrobenzoate
A slurry of 20 g (99 mmol) of 2-chloro-3-nitrobenzoic acid in 800 mL dichloromethane was cooled in an ice bath. Dimethylformamide (0.40 mL) was added to the reaction followed by drop wise addition of 13.85 g (109 mmol) of oxalyl chloride. The reaction was allowed to warm to room temperature and was stirred for 6 h. Methanol (200 mL) was added drop wise and the reaction was stirred overnight. The reaction was concentrated to a residue, dissolved in dichloromethane and passed through a plug of silica eluting with a 50% ethyl acetate/hexane mixture. The filtrate was concentrated In vacuo to give 21.5 g (100%) of the title compound. 1H NMR (CDCl3) δ 3.98 (s, 3H), 7.48 (t, J = 7.8 Hz, IH), 7.84 (d, J= 8.2 Hz, IH), 7.95 (d, J= 7.8 Hz, IH).
Methyl 2-Methylamino-3-nitrobenzoate
A solution of 21.5 g (99.5 mmol) of methyl 2-chloro-3- nitrobenzoate in 300 mL of tetrahydrofuran (THF) was treated with drop wise addition of 300 mL (597 mmol) of methylamine (2M solution in THF) and was stirred overnight at room temperature. The reaction was concentrated to dryness, dissolved in dichloromethane, and washed with aqueous sodium bicarbonate and water. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 20.8 g (100%) of the title compound. 1H NMR (CDCl3) δ 2.82 (d, J = 5.5 Hz, 3H), 3.9 (s, 3H), 6.65 (t, J= 7.8 Hz, IH), 7.97 (d, J= 8.2 Hz, IH), 8.04 (J = 7.8 Hz, IH) , 8.57 (s, IH) .
MS Calcd. : 210; Found: 211 (M+H) .
Methyl 3-amino-2-methylaminobenzoate
A solution of 20.7 g (98 mmol) of methyl 2- methylamino-3-nitrobenzoate in 1200 mL of methanol was inerted with nitrogen. To this solution was added 5 g (2.3 mmol) 10% palladium on carbon (50% wet) . The reaction was purged with hydrogen and stirred under balloon pressure hydrogen for 7 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 17.5 g (99%) of the title compound. MS Calcd. : 180; Found: 181 (M+H).
Methyl l-methyl-2-oxo-l, 3-dihydro-lH-benzimidazole-7- carboxylate
To a solution of 17.5 g (97 mmol) of Methyl 3-amino-2- methylaminobenzoate in 550 mL of tetrahydrofuran was added 20.5 g (146 mmol) of 1, 1' -carbonyldiimidazole and the reaction was stirred overnight at room temperature. The reaction was heated at 50 0C for 2 h and allowed to cool to room temperature overnight. The reaction was concentrated in vacuo and the residue was dissolved in 1 L ethyl acetate and washed with 400 mL of water. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to a residue. The residue was purified by flash chromatography eluting with a solution of 50% ethyl acetate/dichloromethane to give 7.22 g (78%) of the title compound. 1H NMR (CDCl3) δ 3.59 (s, 3H), 3.95 (s, 3H), 7.08 (t, J = 7.8 Hz, IH), 7.27 (d, J = 7.8 Hz, IH), 7.52 (d, J= 8.2 Hz, IH) .
MS Calcd. : 206; Found: 207 (M+H) .
l-Methyl-7- (1-propylbutyl) -1, 3-dihydro-2H-benzimidazol-2- one
A solution of 8.5 mL (17 mmol) of propylmagnesium chloride (2M solution in diethyl ether) was diluted with 10 mL of diethyl ether and cooled in an ice bath. To this solution was slowly added 1.0 g (4.85 mmol) of methyl 1- methyl-2-oxo-l, 3-dihydro-liT-benzimidazole-7-carboxylate and the reaction was stirred overnight at 35 0C. The reaction was quenched with 50 mL of methanol, 100 mL of water, and 10 mL of IN aqueous hydrochloric acid. The aqueous mixture was extracted with 50 mL of diethyl ether and twice with 50 mL of dichloromethane. The organics were combined, dried over sodium sulfate, filtered, and concentrated in vacuo to a residue. This residue was dissolved in 50 mL of ethanol and 10 mL of 6N aqueous hydrochloric acid was added. The mixture was heated at 75 0C for 2 h and then concentrated in vacuo. The resulting residue was dissolved in dichloromethane and washed with aqueous sodium bicarbonate. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 1.05 g of crude l-methyl-7- (1-propylbut-l-enyl) -1, 3-dihydro-2iϊ-benzimidazol-2-one, which was used without further purification in the next step. MS Calcd. : 244; Found: 245 (M+H) . The crude material was dissolved in 50 mL of methanol and inerted with nitrogen. This solution was treated with 300 mg (2.16 mmol) of 10% palladium on carbon (50% wet), purged with hydrogen, and stirred under balloon pressure hydrogen for 36 h. The catalyst was removed by filtration and the filtrate concentrated in vacuo. The crude residue thus obtained was purified by flash chromatography eluting with a mixture of 5% methanol/dichloromethane . The resulting impure mixture was triturated with diethyl ether and filtered. The filtrate contained the title compound along with a small amount of an unidentified impurity, was concentrated in vacuo. The residue thus obtained (710 mg) was used in the next reaction without further purification. MS Calcd.: 246; Found: 247 (M+H) .
2-Chloro-l-methyl-7- (1-propylbutyl) -liϊ-benzimidazole
The crude l-methyl-7- (1-propylbutyl) -1, 3- dihydrobenzimidazol-2-one (710 mg, 2.88 mmol) was dissolved in 10 mL of phosphorous oxychloride and heated at 100 0C overnight. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue thus obtained was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to give 655 mg (86%) of the title compound, which was used in the next step without further purification.
MS Calcd.: 264; Found: 265(M+H).
N- (4-Bromo-2-methoxy-6-methylphenyl) -l-methyl-7- (1- propylbutyl) -lJϊ-benzimidazol-2-amine Hydrochloride
A neat mixture of 100 mg (0.38 mmol) of 2-chloro-l- methyl-7- (1-propylbutyl) -liϊ-benzimidazole and 163 mg (0.76 mmol) of 4-bromo-2-methoxy-6-methylphenylamine was heated at 100 0C overnight. The reaction was cooled to room temperature and the residue was dissolved in 10 mL of dichloromethane, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. This residue thus obtained was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was dissolved in methanol and treated with hydrochloric acid (IN solution in diethyl ether) . The solution was concentrated in vacuo to give 40 mg (23%) of the title compound as the hydrochloric salt. 1H NMR (CDCl3) δ 0.87 (t, J = 7.4 Hz, 6H), 1.26 (m, 4H), 1.71 (m, 4H), 2.12 (s, 3H), 3.40 (m, IH), 3.82 (s, 3H), 3.89 (s, 3H), 6.93 (s, IH), 6.97-6.99 (m, IH), 7.03 (s, IH), 7.09 (t, J= 7.2 Hz, IH), 7.34 (br s, IH). MS Calcd. : 443; Found: 444 (M+H) . Compounds described below were prepared in a similar method. Table 1
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Example 8
{2- [ (4-Bromo-2-methoxy-6-methylphenyl) amino] ~1-methyl-IH- benzimidazol-7-yl } ( 4-methoxyphenyl) methanone .
Figure imgf000089_0001
7- (4-Methoxybenzoyl) -1-methyl-l, 3-dihydro-2H-benzimidazol- 2-one
A solution of 12 mL (6.00 mmol) of 4-methoxymagnesium bromide (0.5M solution in THF) was diluted with 15 mL of THF and cooled in an ice bath. To this solution was slowly added 309 mg (1.50 mmol) of l-methyl-2-oxo-2, 3-dihydro-lH- benzimidazole-7-carboxylic acid methyl ester and the reaction was stirred for 24 h at 60 °C. The reaction was quenched with water. The aqueous mixture was extracted with ethylacetate. The extract was washed with IN aqueous hydrochloric acid and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography eluting with 20 - 70% ethyl acetate / n-hexane to give the title compound (148 mg, 35%) .
1H NMR (DMSO-de) δ 3.00 (s, 3H), 3.87 (s, 3H), 6.98 (d, J = 8.1 Hz, IH), 7.00-7.15 (m, 3H), 7.19 (d, J = 8.1 Hz, IH), 7.81 (d, J = 7.2 Hz, 2H) . MS Calcd.: 282; Found: 283 (M+H) . (2-Chloro-l-methyl-l#-benzimidazol-7-yl) (4-inethoxyphenyl) - methanone
A mixture of 145 mg (0.514 iratiol) of 7-(4- methoxybenzoyl) -1-methyl-1, 3-dihydro-2iϊ-benzimidazol-2-one was dissolved in 1.5 mL of phosphorous oxychloride and heated at 100 0C for 18 h. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue thus obtained was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo to give 124 mg (80%) of the title compound, which was used in the next step without further purification. MS Calcd. : 300; Found: 301 (M+H) .
{2-[ (4-bromo-2-methoxy-6-methylphenyl) amino] -l-methyl-lff- benzimidazol-7-yl } ( 4-methoxyphenyl) methanone
A mixture of 120 mg (0.399 mmol) of (2-chloro-l- methyl-liT-benzimidazol-7-yl) (4-methoxyphenyl) -methanone and 216 mg (0.998 mmol) of 4-bromo-2-methoxy-β- methylphenylamine in 0.5 ml of l-methyl-2-pyrrolidone was heated at 100 0C for 20 h. The reaction was cooled to room temperature and the residue was dissolved in dichloromethane, washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. This residue thus obtained was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo to give 30 mg (16%) of the title compound.
1H NMR (CDCl3) δ 2.19 (s, 3H), 3.56 (s, 3H), 3.82 (s, 3H), 3.91 (s, 3H), 5.94 (m, IH), 6.94 (d, J = 1.8 Hz, IH), 6.99 (d, J= 8.7 Hz, 2H), 7.06 (d, J= 1.8 Hz, IH), 7.10-7.20 (m, 2H), 7.65 (d, J = 6.9 Hz, IH), 7.96 (d, J = 8.7 Hz, 2H); MS Calcd. : 481; Found: 482 (M+H) .
Example 9
N- ( 4~Bromo-2-methoxy-6-methylphenyl ) -4- ( 1-ethylbutyl ) -3- methyl-3iϊ-imidazo [ 4 , 5-c] pyridin-2-amine
Figure imgf000091_0001
4-Bromo-3-methyl-lH-imidazo [4, 5-c] pyridin-2 [3H) -one
A solution of 20.0 g (103 mmol) 3-methyl-4-nitro-2tf- imidazo [4, 5-c] pyridin-2 [3H) -one in 168 mL 48% hydrobromic acid was heated for 6 h at 135 0C. An additional 33 mL of 48% hydrobromic acid was added and the reaction was stirred at 135 °C overnight. The reaction was cooled to room temperature and quenched into 1675 mL ice water. The resulting slurry was adjusted to pH 9 by the addition of 125 mL saturated aqueous ammonium hydroxide. The precipitate was filtered and washed with 200 mL water and dried in a vacuum oven at 50 0C overnight to give 17.58 g (75%) of the title product as a light yellow solids. 1H NMR (DMSO-dg) δ 3.54 (3H,s), 7.08 (IH, d, J = 4.9 Hz), 7.94 (IH, d, J = 4.9 Hz), 11.71 (IH, s). MS Calcd. : 227; Found: 228 (M+H) .
(E) -A- (Hex-3-en-3-yl) -3-methyl-lH-imidazo [4, 5-c] pyridin- 2 [3H) -one
A mixture of 0.68 g (3.0 mmol) of 4-bromo-3-methyl-2H- imidazo[4,5-c]pyridin-2 (3H) -one and 0.17 g (0.20 mmol) of PdCl2dppf-dichloromethane complex was dissolved in 12 mL of toluene and treated with 3.8 mL (7.7 mmol) of 2N sodium carbonate and 0.72 g (3.6 mmol) of (Z) -2- (hex-3-en-3- yl)benzo [d] [1, 3, 2] dioxaborole. The resulting mixture was heated to 90 °C for 5 h, partitioned between water and ethyl acetate, filtered to remove fine precipitates and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The brown oil thus obtained was purified by flash chromatography eluting with a 25% methanol/dichloromethane mixture to give 0.40 g (58%) of the title compound as a cream colored solid.
1H NMR (CDCl3) δ 1.01 (3H, t, J = 7.6 Hz), 1.10 (3H, t, J = 7.6 Hz), 2.29-2.36 (2H, m) , 2.66 (2H, q, J = 7.4 Hz), 3.46 (3H, s), 5.46 (IH, t, J = 7.2 Hz), 6.98 (IH, d, J = 5.3 Hz), 8.28 (IH, d, J = 5.1 Hz), 10.83 (IH, br s) . MS Calcd. : 231; Found: 232 (M+H) .
4- (Hexan-3-yl) -3-methyl-2iϊ-imidazo [4 , 5-c] pyridin-2 (3H) -one To a solution of 0.36 g (1.6 mmol) of (E) -4- (hex-3- en-3-yl) -3-methyl-l.H-imidazo [4, 5-c] pyridin-2 (3H) -one in 30 mL of ethanol was added 0.99 g (10 mol% Pd) of palladium on carbon (50% wet, Degussa type) . The reaction was kept under a hydrogen atmosphere via a balloon and stirred at room temperature for 6 h. The catalyst was removed via filtration and the filtrate was concentrated in vacuo to give 0.33 g (91%) of the title compound as a grey oil that solidified upon standing.
1H NMR (CDCl3) δ 0.81 (3H, t, J = 7.4 Hz), 0.87 (3H, t, J = 7.4 Hz), 1.12-1.29 (2H, m) , 1.66-1.82 (2H, m) , 1.88-1.99 (2H, m) , 3.21-3.28 (IH, m) , 3.67 (3H, s) , 6.94 (IH, d, J = 5.2 Hz), 8.31 (IH, d, J = 5.2 Hz), 10.25 (IH, br s) . MS Calcd.: 233; Found: 234 (M+H).
2-Chloro-4- (hexan-3-yl) -3-methyl-3#-imidazo [4, 5-c] pyridine Prepared from 4- (hexan-3-yl) -3-methyl-liϊ-imidazo [4 , 5- c]pyridin-2 [3H) -one according to the method described previously for 2-chloro-l-methyl-7- (1-propylbutyl) -IH- benzimidazole in 68% isolated yield.
1H NMR (CDCl3) δ 0.80 (3H, t, J = 7.4 Hz), 0.86 (3H, t, J = 7.4 Hz), 1.06-1.31 (2H, m) , 1.68-1.93 (2H, m) , 1.95-2.04 (2H, m) , 3.30-3.37 (IH, m) , 4.05 (3H, s), 7.43 (IH, d, J = 5.4 Hz), 8.43 (IH, d, J = 5.4 Hz). MS Calcd. : 251; Found: 252 (M+H) .
N- (4-bromo-2-methoxy-6-methylphenyl) -4- (1-ethylbutyl) -3- methyl-3H-imidazo [4, 5-c] pyridin-2-amine
Prepared from according to the method described previously for 2-chloro-4- (hexan-3-yl) -3-methyl-3H- imidazo [4, 5-c] pyridine in 47% isolated yield. 1H NMR (CDCl3) δ 0.84 (3H, t, J = 7.4 Hz), 0.88 (3H, t, J = 7.4 Hz), 1.14-1.32 (2H, m) , 1.68-1.84 (2H, m) , 1.93-2.02 (2H, m) , 2.18 (3H, s) , 3.24-3.31 (IH, m) , 3.82 (3H, s) , 3.90 (3H, s), 5.98 (IH, br s) , 6.94 (IH, s) , 7.06 (IH, s) , 7.23 (IH, d, J = 4.5 Hz), 8.29 (IH, d, J = 5.3 Hz). MS Calcd.: 430; Found: 431 (M+H).
Compounds described below were prepared in a similar method. Table 2
Figure imgf000095_0001
Example 12
4- [2- [ ( 2 , 4-Dimethylphenyl ) amino] -1- ( 2 -hydroxy ethyl) -1IP- benzirαidazol-7-yl] heptan-4-ol
Figure imgf000096_0001
Methyl-2-chloro-3-nitrobenzoate
A slurry of 20 g (99 mmol) of 2-chloro-3-nitorobenzoic acid in 800 mL dichloromethane was cooled in an ice bath. Dimethylformamide (0.40 ml) was added to the reaction mixture followed by dropwise addition of 13.85 g (109 mmol) of oxalyl chloride. The reaction was allowed to warm to room temperature and was stirred for 6 h. Methanol (200 mL) was added dropwise and the reaction was stirred overnight. The solvent was evaporated in vacuo. The residue was triturated with n-hexane . The resulting solid was collected by filtration, washed with hexane and dried in vacuo to give 21.0 g (98%) of the title compound. 1H NMR (CDCl3) δ 3.98 (3H, s) , 7.49 (IH, t, J = 8.4 Hz), 7.84 (IH, dd, J = 1.8, 8.4 Hz), 7.96 (IH, dd, J = 1.8, 8.4 Hz) .
Methyl 2- [ (2-hydroxyethyl) amino] -3-nitrobenzoate
To a solution of 4.70 g (21.9 mmol) of methyl 2- chloro-3-nitrobenzoate in 300 mL of THF was added dropwise 300 mL of 2-ethanolamine (80 iranol) and the mixture was refluxed over night. The reaction was concentrated to dryness, dissolved in ethyl acetate, and washed aqueous sodium hydrogen carbonate and water. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 5.00 g (20.8 mmol, 95%) of the title compound. 1H NMR (CDCl3) δ 1.68 (IH, br) , 3.12 (2H, dd, J = 4.8, 10.2 Hz), 3.85 (2H, t, J = 4.8 Hz), 3.92 (IH, s) , 6.69 (IH, t, J = 8.1 Hz), 7.96 (IH, dd, J = 1.8, 8.1 Hz), 8.09 (IH, dd, J = 1.8, 8.1 Hz) , 8.72 (IH, br) . MS Calcd. : 240; Found: 241 (M+H) .
9-Nitro-2, 3-dihydro-4, l-benzoxazepin-5 (IH) -one To a solution of 2.00 g (8.32 mmol) of methyl 2- [ (2- hydroxyethyl) amino] -3-nitrobenzoate in 150 mL of THF was added dropwise 6N HCl (100 mL) at 0 0C and the mixture was stirred for 30 min. The reaction mixture was refluxed for 16 h. After being cooled to room temperature, the mixture was diluted with water (150 ml) , and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous sodium hydrogen sulfate and water. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1.03 g (5.00 mmol, 60%) of the title compound. 1H NMR (CDCl3) δ: 3.91-3.95 (2H, m) , 4.58-4.61 (2H, m) , 6.79 (IH, t, J = 8.4 Hz), 8.19 (IH, dd, J = 1.8, 8.4 Hz), 8.43 (IH, dd, J= 1.8, 8.4 Hz), 8.96 (IH, br) . MS Calcd. : 208; Found: 209 (M+H) .
9-Amino-2 , 3-dihydro-4 , l-benzoxazepin-5 (IH) -one
A solution of 500 mg (2.42 miuol) of 9-nitro-2,3- dihydro-4, l-benzoxazepin-5 (IH) -one in 500 mL of methanol was inerted with nitrogen. To this solution was added 100 mg of 10% palladium on carbon (50% wet) and the reaction was purged with hydrogen and stirred under balloon pressure hydrogen for 6 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 430 mg
(99%) of the title compound.
1H NMR (CD3OD) δ: 3.00-3.03 (2H, m) , 3.77-3.80 (2H, m) , 5.95 (IH, t, J = 8.4 Hz), 6.25 (IH, dd, J = 1.5, 8.4 Hz), 6.56 (IH, dd, J = 1.5, 8.4 Hz) . MS Calcd.: 178; Found: 179 (M+H).
4, 5-Dihydro-7iϊ-imidazo [4, 5, 1-jk] [4, 1] benzoxazepine-2, 7 (IH) - dione
To a solution of 200 mg (1.13 mmol) of 9-amino-2,3~ dihydro-4, l-benzoxazepin-5 (IH) -one in 20 mL of THF was added 280 mg (2 mmol) of 1, 1' -carbonyldiimidazole and the reaction mixture was stirred overnight at room temperature. The reaction mixture was heated at 50 0C for 4 h and allowed to cool to room temperature. The reaction was concentrated in vacuo and the residue was dissolved in a mixture of ethyl acetate/n-hexane (1:1) and washed with water. The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to give 286 mg (1.40 mmol, 70%) of the title compound. 1H NMR (CD3OD) δ: 4.25-4.27 (2H, m) , 4.75-4.77 (2H, m) , 7.23
(IH, t, J = 8.4 Hz), 7.37 (IH, dd, J = 1.2, 8.4 Hz), 7.78
(IH, dd, J = 1.5, 8.4 Hz) . MS Calcd. : 204; Found: 205 (M+H) .
2-ChIoro-4 , 5-dihydro-7H-imidaz [4, 5, 1-jk] [4,1] benzoxazepin- 7-one
4, 5-Dihydro- 7#-imidazo [4, 5, 1-jk] [4,1] benzoxazepine- 2,7 [IH) -dione (1.00 g, 4.89 mmol) was dissolved in 15 mL of phosphorous oxychloride and heated at 110 0C for βh. The reaction allowed to cool to room temperature, poured into water with an ice, and stirred for 1 h. The aqueous solution was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo to give 1.06 g (98%) of the title compound, which was used in the next reaction without further purification. MS Calcd.: 222; Found: 223 (M+H). 2-[ (2,4-Dimethylphenyl)amino]-4,5-dihydro-7#-imidazo[4, 5, 1- jk] [4, 1] benzoxazepin-7-one
A mixture of 2-chloro-4, 5-dihydro-7H-imidaz [4, 5, 1- jk] [4, 1] benzoxazepin-7-one 1.06 g (4.77 mmol) and 2,4- methylaniline 1.73 g (14.3 mmol) in 0.1 ml of I\7-methyl-2- pyrrolidone was heated at 100 0C overnight. The reaction was cooled to room temperature and the residue was dissolved in dichloromethane, washed with sodium bicarbonate and water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate/n-hexane (1:1) to give 0.96 g (66%) of the title compound.
1H NMR (CDCl3) δ: 2.14 (3H, s), 2.22 (3H, s) , 4.35-4.37 (2H, m) , 4.78-4.80 (2H, m) , 5.98 (IH, br) , 6.59 (IH, d, J = 7.2 Hz), 6.84 (IH, d, J = 7.2 Hz), 6.87 (IH, s) , 7.24 (IH, t, J
= 7.8 Hz), 7.72 (IH, d, J = 7.8 Hz), 7.86 (IH, d, J = 7.8
Hz) .
MS Calcd. : 307; Found: 308 (M+H) .
4- [2- [ (2, 4-Dimethylphenyl) amino] -1- (2-hydroxyethyl) -IH- benzimidazol-7-yl] heptan-4-ol
To a refluxing solution of 30 mL of n-propylmagnesium bromide (27% in tetrahydrofuran) was added 500 mg (1.63 mmol) of 2- [ (2, 4-dimethylphenyl) amino] -4, 5~dihydro-7H~ imidazo [4 , 5, 1-jk] [4, 1] benzoxazepin-7-one and the mixture was refluxed for 1 h. The reaction mixture was cooled to room temperature and diluted with 50 rriL of water and nutralization with IN HCl. The aqueous solution was extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue thus obtained was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo to give 161 mg (0.41 mmol, 25%) of the title compound.
1H NMR (CDCl3) δ: 0.92 (6H, t, J = 7,5 Hz), 1.23-1.41 (4H, m) , 1.81-1.91 (2H, m) , 1.98-2.09 (2H, m) , 2.13 (3H, s), 2.22 (3H, s), 4.21 (2H, t, J = 4.8 Hz), 4.45 (2H, t, J = 4.8 Hz), 6.59 (IH, d, J = 7.2 Hz), 6.84 (IH, d, J = 7.2 Hz), 6.87 (IH, s), 6.83 (IH, d, J = 8.1 Hz), 7.03 (IH, t, J = 8.1 Hz), 7.41 (IH, d, J = 8.1 Hz). MS Calcd. : 395; Found: 396 (M+H) .
Compounds described below were prepared in a similar method. Table 3
Figure imgf000102_0001
Example 14
2- [2- [ (2, 4-Dimethylphenyl) amino] -7- (1-propylbutyl) -IH- benzimidazol-1-yl] ethanol
Figure imgf000102_0002
A solution of 100 mg (0.25 mmol) of 9-nitro-2,3- dihydro-4, l-benzoxazepin-5 (IH) -one in 3 mL of ethanol was inerted with nitrogen. To this solution was added an ethanol solution of Raney nikel and the reaction was purged with hydrogen and stirred under balloon pressure hydrogen for 6 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue thus obtained was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo to give 27 mg (0.07 mmol, 28%) of the title compound. 1H NMR (CDCl3) δ: 0.92 (6H, t, J = 7,5 Hz), 1.22-1.41 (4H, m) , 1.79-1.89 (2H, m) , 1.98-2.09 (2H, m) , 2.12 (3H, s) , 2.22 (3H, s), 2.87 (IH, q, J = 7.2 Hz), 4.21 (2H, t, J = 4.8 Hz), 4.45 (2H, t, J = 4.8 Hz), 6.59 (IH, d, J = 7.2 Hz), 6.84 (IH, d, J = 7.2 Hz), 6.87 (IH, s) , 6.85 (IH, d, J = 8.1 Hz) , 7.05 (IH, t, J = 8.1 Hz) , 7.45 (IH, d, J = 8.1 Hz) .
MS Calcd. : 379; Found: 380 (M+H) .
Example 15
N- (4-Chloro-2-methoxy-6-methylphenyl) -7- (2-ethylphenyl) -1- methyl- lH-benzimidazol- 2 -amine
Figure imgf000103_0001
7-Bromo-2-chloro-l-methyl-lff-benzimidazole
7-Bromo-l-methyl-l, 3-dihydro-2H-benzimidazol-2-one (2.20 g, 9.69 mmol) was dissolved in 30 mL of phosphorous oxychloride and the mixture was heated at 110 0C for 2 days. The reaction allowed to cool to room temperature, poured into water with an ice, and stirred for 1 h. The aqueous solution was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo to give 2.32 g of the title compound, which was used in the next reaction without further purification. MS Calcd. : 243; Found: 244 (M+H) .
7-Bromo-IV- (4-chloro-2-methoxy-6-.nethylph.enyl) -l-methyl-lH- benzimidazol-2-amine
To a mixture of 7-bromo-l-methyl-l, 3-dihydro-2iϊ- benzimidazol-2-one 2.32 g (9.69 mmol) and 4-chloro-2- methoxy-6-methylaniline 4.98 g (29.1 mmol) in 0.5 mL of N- methyl-2-pyrrolidone was heated at 110 0C for 2 days. The reaction was cooled to room temperature and diluted with dichloromethane . The mixture was washed with sodium bicarbonate and water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with ethyl acetate/hexane (1 : 1) to give 3.13g (8.23 mmol, 85%) of the title compound. 1H NMR (CDCl3) δ: 2.17 (3H, s) , 3.82 (3H, s) , 4.04 (3H, s) , 6.80 (IH, d, J = 2.4 Hz), 6.89 (IH, d, J = 2.4 Hz), 6.56 (IH, t, J = 8.1 Hz), 7.21 (IH, d, J = 8.1 Hz), 7.42 (IH, d, J = 8.1 Hz) . MS Calcd. : 379; Found: 380 (M+H) .
W- (4-Chloro-2-methoxy-6-inethylphenyl) -7- (2-ethylphenyl) -1- methyl-2ff-benzimidazol-2-amine trifluoroacetic acid salt
To a mixture of 25 mg (65.6 μmol) of 7-bromo-iV- (4- chloro-2~methoxy-6-methylphenyl) -l-methyl-2Iϊ-benzimidazol-
2-amine, 11.8 mg (78.7 μmol) of 2-ethylphenylboronic acid,
12.0 mg (13.1 μmol) of tris (dibenzylideneacetone) dipalladium and 12.5 mg (26.2 μmol) of 2- (dicyclohexylphosphino) -2' , 4' , 6' -tri-i-propyl- 1, 1' -biphenyl in 1 mL of 1, 2-dimethoxyethane was added 131 μl of IM aqueous potassium phosphate tribasic solution. The reaction mixture was heated by microwave irradiation at 130 0C for 10 iriin, and allowed to cool to room temperature. The reaction mixture was diluted with dichloromethane and water, separated with a filter tube (made by Wattmann) and concentrated in vacuo. The residue was purified by preparative HPLC to give 2.5 mg (9.8%) of the title compound as a trifluoroacetic acid salt.
1H NMR (CDCl3) δ: 1.05 (3H, t, J = 7.5 Hz), 2.17 (3H, s) , 2.40-2.54 (2H, m) , 3.07 (3H, s) , 3.80 (3H, s), 6.78 (IH, d, J = 2.4 Hz), 6.89 (IH, d, J = 2.4 Hz), 6.89 (IH, d, J = 7.8 Hz), 7.13 (IH, t, J = 7.8 Hz), 7.23-7.41 (4H, m) , 7.51 (IH, d, J= 7.8 Hz). MS Calcd. : 405; Found: 406 (M+H) .
Example 16-60
Examples 16-54 in Table 4 were prepared as trifluoroacetic acid salt and examples 55-60 were prepared as free base in the similar method described in Example 15. Table 4
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Example 61
IV- (4-Bromo-2-methoxy-6-methylphenyl) -7- (2-ethylphenyl) -1- methyl-liϊ-benzimidazol-2-amine
Figure imgf000119_0001
7- (2-Ethylphenyl) -1-methyl-l, 3-dihydro-2H-benzimidazol-2- one A mixture of 280 mg (1.23 mmol) of 7-bromo-l-methyl- l,3-dihydro-2#-benzimidazol-2-one, 222 mg (1.48 mmol) of 2- ethylphenylboronic acid, 113 mg (0.0123 mmol) of tris (dibenzylideneacetone) dipalladium, 29 mg (0.0615 mmol) of X-Phos and 522 mg (2.46 mmol) of potassium phosphate in 9 mL of toluene was stirred at 100 0C for 4 hours. After cooling, the reaction mixture was diluted with water and ethyl acetate and passed through celite. The filtrate was extracted with ethyl acetate (X2) . The combined organic layer was washed with brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 25-65% ethylacetate/n-hexane gradient mixture to give 200 mg (64%) of the title compound. 1H NMR (CDCl3) δ 1.04 (3H, t, J = 7.7 Hz), 2.34-2.52 (2H, m) , 2.84 (3H, s) , 6.86-6.98 (2H, m) , 7.05-7.08 (2H, m) , 7.18-7.39 (3H, m), 8.58 (IH, br s). MS Calcd. : 252; Found: 253 (M+H) .
2~Chloro-7- (2-ethylphenyl) -1-methyl-liϊ-benzimidazole A mixture of 190 mg (0.753 mmol) of 7- (2-ethylphenyl) - 1-methyl-1, 3-dihydro-2iϊ-benzimidazol~2-one and 1.5 mL of phosphorus oxychloride was stirred at 80 0C for 5 hours. After cooling, the reaction mixture was poured into ice and neutralized by 12 N sodium hydroxide. The aqueous suspension was extracted with ethyl acetate (X2) . The combined organic layer was washed with brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 3-10% ethylacetate/n-hexane gradient mixture to give 123 mg (60%) of the title compound.
1H NMR (CDCl3) δ 1.02 (3H, t, J = 7.5 Hz), 2.30-2.48 (2H, m) , 3.19 (3H, s), 7.05-7.15 (IH, m) , 7.26-7.45 (5H, m) , 7.60 (IH, m) . MS Calcd.: 270, 272; Found: 271, 273 (M+H).
N- (4-Bromo-2-methoxy-6~methylphenyl) -7- (2-ethylphenyl) -1- methyl-lH-benzimidazol-2-amine
A mixture of 100 mg (0.369 mmol) of 2-chloro-7- (2- ethylphenyl) -l-methyl-lF-benzimidazole and 239 mg (1.11 mmol) of 4-bromo-2-methoxy-6-methylaniline was stirred at 120 0C for 15 hours. After cooling, the reaction mixture was neutralized by saturated aqueous sodium hydrogen carbonate, followed by addition of ethyl acetate. The resulting crystals were collected by filtration and washed with water and ethyl acetate, and suspended in hot ethyl acetate. After cooling to room temperature, the crystals were collected by filtration and washed with ethyl acetate and a 50% dimethylsulfoxde/methanol mixture to give 90 mg (54%) of the title compound.
1H NMR (CDCl3) δ 1.05 (3H, t, J = 7.4 Hz), 2.16 (3H, s) , 2.40-2.55 (2H, m) , 3.09 (3H, s) , 3.81 (3H, s) , 5.79 (IH, br s), 6.88-6.92 (2H, m) , 7.04 (IH, d, J = 1.5 Hz), 7.12 (IH, t, J = 7.8 Hz), 7.26-7.41 (4H, m) , 7.52 (IH, d, J = 7.8 Hz). MS Calcd. : 449, 451; Found: 450, 452 (M+H) .
Compounds described below were prepared in a similar method. Table 5
Figure imgf000121_0001
Figure imgf000122_0001
Example 64
N- (4-Chloro-2-methoxy-6-methylphenyl) -l-methyl-7- {2-
[ (methylamino) methyl] phenyl }-lH-benzimidazol-2-amine
Figure imgf000123_0001
A mixture of 33 mg (0.0813 mmol) of 2- [2- [ (4-chloro-2- methoxy-β-methylphenyl) amino] -l-methyl-lH-benzimidazol-7- yl]benzaldehyde, 0.033 mL (0.325 mmol) of 40% methanol solution of methyl amine and 1 mL of ethanol was refluxed for 4 hours. After cooling, 9.2 mg (0.244 mmol) of sodium borohydride was added. The mixture was stirred at room temperature for 4 hours, and 15 mg (0.407 mmol) of sodium borohydride was added. After stirring at room temperature for 15 hours, the reaction mixture was diluted with water and extracted with ethyl acetate (X2). The combined organic layer was washed with brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC and basic silica gel column chromatography eluting with a 50-100% ethylacetate/n-hexane gradient mixture to give 5 mg (17%) of the title compound. 1H NMR (CDCl3) δ 2.18 (3H, s) , 2.27 (3H, s) , 3.08 (3H, s), 3.57 (2H, s), 3.81 (3H, s) , 6.79 (IH, s) , 6.87-6.89 (2H, m) , 7.10-7.15 (IH, m) , 7.33-7.53 (5H, m) . Example 65
N- (4-Bromo-2-methoxy-6-methylphenyl) -l-methyl-7- (3-methyl- liϊ-pyrazol-1-yl) -lff-benzimidazol-2-amine
Figure imgf000124_0001
l-Methyl-7- (3-methyl-lH-pyrazol-l-yl) -1, 3-dihydro-2ff- benzimidazol-2-one
A suspension of 50 mg (0.220 mmol) of 7-bromo-l- methyl-1, 3-dihydro-2#-benzimidazol-2-one, 0.035 mL (0.440 mmol) of 3-methylpyrazole, 42 mg (0.0220 mmol) of copper (I) iodide and 61 mg (0.440 mmol) of potassium carbonate in 1 mL of l-methyl-2-pyrrolidinone was stirred by microwave irradiation at 190 0C for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (X2). The combined organic layer was washed with brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 25% ethylacetate/n-hexane mixture to give 57 mg of a mixture containing the title compound.
1H NMR (CDCl3) δ 2.34 (3H, s) , 2.98 (3H, s) , 6.26 (IH, d, J = 2.2 Hz), 6.97-7.18 (3H, m) , 7.57 (IH, d, J = 2.2 Hz), 9.60 (IH, br s) . MS Calcd. : 228; Found: 229 (M+H) .
N- (4-Bromo-2-methoxy-6-methylphenyl) -l-methyl-7- (3-methyl- lH-pyrazol-1-yl) -lH-benzimidazol-2-amine
A mixture of 17 mg (0.0745 iranol) of l-methyl-7- (3- methyl-lH-pyrazol-1-yl) -1, 3-dihydro-2H-benzimidazol-2-one in 0.5 mL of phosphorus oxychloride was stirred at 80 0C for 5 days. After cooling, phosphorus oxychloride was evaporated in vacuo. The residue was neutralized by 12 N aqueous sodium hydroxide. The aqueous suspension was extracted with ethyl acetate (X2) . The combined organic layer was washed with water (Xl) and brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC eluting with a 30% ethylacetate/n-hexane mixture to give 2-chloro-l-methyl-7- (3-methyl-lH-pyrazol-l-yl) -lH-benzimidazole . A mixture 2- chloro-l-methyl-7- (3-methyl-lH-pyrazol-l-yl) -IiT- benzimidazole obtained above, 48 mg (0.223 mmol) of 4- bromo-2-methoxy-6-methylaniline and 0.15 mL of l-methyl-2- pyrrolidinone was stirred at 120 0C for 3 days. After cooling, the reaction mixture was neutralized by saturated aqueous sodium hydrogen carbonate. The aqueous suspension was extracted with ethyl acetate (X2) . The combined organic layer was washed with water (Xl) and brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC eluting with a 75% ethylacetate/n-hexane mixture to give 5.7 mg (18%) of the title compound.
1H NMR (CDCl3) δ 2.17 (3H, s), 2.40 (3H, s) , 3.23 (3H, s), 3.80 (3H, s) , 5.87 (IH, br s) , 6.28 (IH, d, J = 2.1 Hz), 6.92 (IH, d, J = 2.4 Hz), 7.00-7.13 (3H, m) , 7.53 (IH, d, J = 7.8 Hz), 7.63 (IH, d, J= 2.1 Hz). MS Calcd. : 425, 427; Found: 426, 428 (M+H) .
Example 66 N- ( 4-Bromo-2-methoxy- 6-methylphenyl ) -7- ( 3 , 5 -diethyl- IH- pyrazol-1-yl ) -l-methyl-liϊ-benzimidazol-2-amine
Figure imgf000126_0001
7-Hydrazino-l-methyl-l , 3-dihydro-2H-benzimidazol-2-one To a suspension of 5.0 g (30.6 mmol) of 7-amino-l- methyl-1, 3-dihydro-2iϊ-benzimidazol-2-one in 16 mL of concentrated hydrochloric acid was added 8 mL of an aqueous solution of 2.18 g (31.6 mmol) of sodium nitrite, the mixture was stirred at 0 0C for 30 minutes. Tin (II) chloride (18.0 g, 94.9 mmol) was dissolved in 10 mL of concentrated hydrochloric acid, and the solution was added to the reaction mixture at 0 0C. After one hour, the mixture was alkalified by 12 N sodium hydroxide, followed by addition of ethyl acetate to the suspension. After addition of 24.6 mL of di-tert-butyl dicarbonate (107 mmol), the mixture was stirred at room temperature for 15 hours. The aqueous layer was separated and extracted with ethyl acetate (Xl) . The organic layer was washed with brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residual solids were washed with hexane to give 8.53 g of the Boc derivative of the title compound as yellow crystals. A suspension of 8.53 g (17.8 mmol) of the Boc derivative of the title compound in 100 mL of 4 N hydrogen chloride in methanol was stirred at room temperature for 12 hours. The resulting crystals were collected by filtration and washed with methanol to give 3.17 g (52%) of the title compound. 1H NMR (DMSO-d6) δ 3.52 (3H, s) , 6.79-6.82 (2H, m) , 6.98 (IH, t, J = 8.0 Hz), 8.02 (IH, s) , 10.03 (2H, s) , 11.00 (IH, s) . 7- (2, 4-Diethyl-lH-pyrazol-l-yl) -1-methyl-l, 3-dihydro-2H- benzimidazol-2-one
To a suspension of 211 rag (0.986 mmol) of 7-hydrazino- 1-methyl-1, 3-dihydro-2H-benzimidazol-2-one in 2 mL of acetic acid was added 0.13 mL (0.986 mmol) of 3,5- heptanedione, the mixture was stirred at 100 0C for 2 hours. After cooling, the reaction mixture was neutralized by saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (X2) . The combined organic layer was washed with brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 50-80% ethylacetate/n-hexane gradient mixture to give 221 mg (83%) of the title compound.
1H NMR (CDCl3) δ 1.16 (3H, t, J = 7.5 Hz), 1.29 (3H, t, J = 7.8 Hz), 2.35-2.53 (2H, br) , 2.69 (2H, q, J = 7.8 Hz), 2.85 (3H, s), 6.06 (IH, s), 7.01 (IH, dd, J= 7.8, 1.5 Hz), 7.08 (IH, t, J = 7.8 Hz), 7.14 (IH, dd, J = 7.8, 1.5 Hz), 9.49 (IH, br s) .
2-Chloro-7- (3, 5-diethyl-lH-pyrazol-l-yl) -l-methyl-lH- benzimidazole
A mixture of 220 mg (0.814 mmol) of 7- (2, 4-diethyl-lH- pyrazol-1-yl) -1-methyl-l, 3-dihydro~2H-benzimidazol-2-one in 2 itiL of phosphorus oxychloride was stirred at 85 0C for 4 hours. After cooling, phosphorus oxychloride was evaporated in vacuo. The residue was diluted with ice-cold water and neutralized by aqueous sodium hydroxide. The aqueous suspension was extracted with ethyl acetate (X2) . The combined organic layer was washed with water (Xl) and brine
(Xl) , dried over sodium sulfate and concentrated in vacuo.
The residue was purified by silica gel column chromatography eluting with a 25-50% ethylacetate/n-hexane gradient mixture to give 181 mg (77%) of the title compound. 1H NMR (CDCl3) δ 1.15 (3H, t, J = 7.5 Hz), 1.30 (3H, t, J = 7.5 Hz), 2.44 (2H, q, J = 7.5 Hz), 2.70 (2H, q, J = 7.5 Hz), 3.20 (3H, s), 6.10 (IH, s) , 7.21 (IH, dd, J= 7.8, 1.2 Hz), 7.30 (IH, t, J = 7.8 Hz), 7.76 (IH, dd, J= 7.8, 1.2 Hz). MS Calcd. : 288, 290; Found: 289, 291 (M+H) .
N- (4-Bromo-2-methoxy-6-methylphenyl) -7- (3, 5-diethyl-liT- pyrazol-1-yl) -l-methyl-lH-benzimidazol-2-amine
A mixture of 83 mg (0.287 mmol) of 2-chloro-7- (3, 5- diethyl-liϊ-pyrazol-1-yl) -l-methyl-lH-benzimidazole, 186 mg
(0.862 mmol) of 4-bromo-2-methoxy-6-methylaniline and 0.15 ml) of l-methyl-2-pyrrolidinone was stirred at 110 0C for 20 hours. After cooling, the reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, followed by addition of ethyl acetate. The resulting crystals were collected by filtration and washed with water and ethyl acetate to give 112 mg (83%) of the title compound. 1H NMR (CDCl3) δ 1.18 (3H, t, J = 7.4 Hz), 1.31 (3H, t, J = 7.6 Hz), 2.17 (3H, s), 2.49 (2H, q, J = 7.4 Hz), 2.72 (2H, q, J = 7.6 Hz), 3.07 (3H, s) , 3.81 (3H, s) , 5.81 (IH, br s), 6.09 (IH, s), 6.93-7.16 (4H, m) , 7.54 (IH, d, J = 8.8 Hz). MS Calcd. : 467, 469; Found: 468, 470 (M+H) .
Compounds described below were prepared in a similar method. Table 6
Figure imgf000130_0001
Figure imgf000131_0001
Example 69
N- (4-Bromo-2-methoxy-β-methylphenyl) -7- (2, 5-dimethyl-liϊ- pyrrol-1-yl) -l-methyl-lH-benzimidazol-2-amine
7- (2, 5-Dimethyl-liϊ-pyrrol-l-yl) -1-methyl-l, 3-dihydro-2ff- benzimidazol-2-one
To a suspension of 257 mg (1.57 mmol) of 7-amino-l- methyl-1, 3-dihydro-2iϊ-benzimidazol-2-one in 2 mL of acetic acid was added 0.18 itiL (1.57 mmol) of 2, 5-hexanedione, the mixture was stirred at 90 0C for 1 hour. After cooling, the reaction mixture was neutralized by saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (X2) . The combined organic layer was washed with brine (Xl), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 25-50% ethylacetate/n-hexane gradient mixture to give 258 mg (68%) of the title compound. 1H NMR (CDCl3) δ 1.97 (6H, s) , 2.79 (3H, s) , 5.92 (2H, s) , 6.93 (IH, dd, J= 7.5, 1.5 Hz), 7.08-7.16 (2H, m) , 9.45 (IH,
2-Chloro-7- (2, 5-dimethyl-lH-pyrrol-l-yl) -1-methyl-lF- benzimidazole
A mixture of 239 mg (0.991 mmol) of 7- (2, 5-dimethyl- IH-pyrrol-l-.yl) -1-methyl-l, 3-dihydro-2iJ-benzimidazol-2-one in 2 mL of phosphorus oxychloride was stirred at 85 0C for 4 hours. After cooling, phosphorus oxychloride was evaporated in vacuo. The residue was diluted with ice and neutralized by aqueous sodium hydroxide. The aqueous suspension was extracted with ethyl acetate (X2) . The combined organic layer was washed with water (Xl) and brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-20% ethylacetate/n-hexane gradient mixture to give 185 mg (72%) of the title compound. 1H NMR (CDCl3) δ 1.94 (6H, s), 3.09 (3H, s), 5.95 (2H, s) , 7.15 (IH, dd, J = 7.8, 1.0 Hz), 7.32 (IH, t, J = 7.8 Hz), 7.75 (IH, dd, J = 7.8, 1.0 Hz).
MS Calcd. : 259; Found: 260 (M+H) .
N- (4-Bromo-2-methoxy-6-inethylphenyl) -7- (2, 5-dimethyl-lH- pyrrol-1-yl) -l-methyl-lff-benzimidazol-2-amine A mixture of 90 mg (0.347 mmol) of 2-chloro-7- (2, 5- dimethyl-liϊ-pyrrol-1-yl) -1-methyl-lH-benzimidazole and 225 mg (1.04 mmol) of 4-bromo-2-methoxy-6-methylaniline was stirred at 110 0C for 15 hours. After cooling, the reaction mixture was neutralized by saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (X2) . The combined organic layer was washed with brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 60-90% ethylacetate/n-hexane gradient mixture. The desired fractions were collected and evaporated in vacuo, the residual solids were washed with diethyl ether to give 53.4 mg (35%) of the title compound. 1H NMR (CDCl3) δ 1.99 (6H, s) , 2.19 (3H, s), 2.96 (3H, s), 3.81 (3H, s), 5.94 (2H, s) , 6.92-6.96 (2H, m) , 7.05 (IH, d, J= 1.8 Hz), 7.15 (IH, t, J = 7.5 Hz), 7.54 (IH, d, J = 7.5 Hz) .
MS Calcd.: 438, 440; Found: 439, 441 (M+H) .
Example 70 - 71
Example 70 and 71 in Table 7 were prepared in the similar method described in Example 15. Table 7
Figure imgf000134_0001
Figure imgf000135_0002
Example 72
N- ( 4-Bromo-2-methoxy~6-methylphenyl) -l-rαethyl-7- ( 3-methyl-
5-phenyl-l#-pyrazol-l-yl ) -liY-benzimidazol-2-amine
Figure imgf000135_0001
This compound was prepared in a similar manner described in Example 66.
1H NMR (CDCl3) δ: 2.13 (3H, s) , 2.42 (3H, s) , 3.19 (3H, s) , 3.79 (3H, s), 5.81 (IH, br s), 6.45 (IH, s) , 6.91-6.96 (2H, m) , 7.03-7.08 (2H, m) , 7.23 (5H, s) , 7.51 (IH, d, J = 8.4 Hz) . MS Calcd. : 501, 503; Found: 502, 504 (M+H) .
Example 73
4- [1- (2-Hydroxyethyl) -2- (mesitylamino) -lH-benzimidazol-7- yl] heptan-4-ol
Figure imgf000136_0001
This compound was prepared in a similar manner described in Example 12. mp 267-270 0C
1H NMR (CD3OD) δ: 1.24 (6H, t, J = 7,5 Hz), 1.60-1.74 (4H, m) , 2.16-2.40 (4H, m) , 2.52 (6H, s) , 2.63 (3H, s) , 4.47 (2H, t, J = 4.8 Hz), 5.19 (2H, t, J = 4.8 Hz), 7.22 (IH, dd, J=
7.8, 1.2 Hz), 7.28 (2H, s) , 7.32 (IH, t, J = 7.8 Hz), 7.47
(IH, dd, J = 7.8, 1.2 Hz). MS Calcd. : 409; Found: 410
(M+H) .
Example 74
2- [2- (Mesitylamino) -7- (1-propylbutyl) -lH-benzimidazol-1- yl] ethanol
Figure imgf000136_0002
This compound was prepared in a similar manner described previously in Example 14.
1H NMR (CDCl3) δ: 0.92 (6H, t, J = 7,5 Hz), 1.20-1.40 (4H, m) , 1.77-1.88 (2H, m) , 1.98-2.09 (2H, m) , 2.53 (6H, s) , 2.63 (3H, s), 2.87 (IH, m) , 4.21 (2H, t, J = 4.8 Hz), 4.45 (2H, t, J = 4.8 Hz), 7.22 (IH, dd, J = 7.8, 1.2 Hz), 7.27 (2H, s), 7.32 (IH, t, J = 7.8 Hz), 7.46 (IH, dd, J = 7.8,
1.2 Hz) .
MS Calcd. : 393; Found: 394 (M+H) .
Example 75
2- [2- [ ( 4-Chloro-2-methoxy-6-methylphenyl) amino] -7- (1- hydroxy-1-propylbutyl) -IH-benzimidazol-l-yl] ethyl acetate
Figure imgf000137_0001
A solution of 4- [2- [ (4-chloro-2-methoxy-6- methylphenyl) amino] -1- (2-hydroxyethyl) -lff-benzimidazol-7- yl] heptan-4-ol (100 mg, 0.22 mmol) in pyridine (5 mL) was treated with acetic anhydride (1 mL) and stirred at room temperature overnight. The reaction mixture was concentrated to dryness, diluted with aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on a silica gel to give 97 mg (0.20 mmol, 89%) of the title compound. 1H NMR (CDCl3) δ: 0.92 (6H, t, J = 7,5 Hz) , 1.23-1.41 (4H, m) , 1.81-1.91 (2H, m) , 1.98-2.09 (2H, m) , 2.12 (3H, s) , 2.15 (3H, s) f 3.80 (3H, s) , 4.56 (2H, t, J = 4.8 Hz) , 4.85
(2H, t, J = 4.8 Hz), 6.80 (IH, d, J = 2.1 Hz), 6.83 (IH, d, J= 8.1 Hz), 6.88 (IH, d, J = 2.1 Hz), 7.03 (IH, t, J= 8.1 Hz), 7.41 (IH, d, J = 8.1 Hz). MS Calcd. : 487; Found: 488
(M+H) .
Example 76
2-{2- [ (4-Chloro-2-methoxy-6~methylphenyl)'amino] -7- [ {IE) -1- propylbut-1-en-l-yl] -lH-benzimidazol-1-yl } ethyl acetate and 2-{2-[ (4-Chloro-2-methoxy-6-methylphenyl) amino] -7- [ (IZ) -1- propylbut-1-en-l-yl] -liϊ-benzimidazol-l-yl } ethyl acetate
Figure imgf000138_0001
A solution of 2- [2- [ (4-chloro-2-methoxy-6- methylphenyl) amino] -7- (1-hydroxy-l-propylbutyl) -IH- benzimidazol-1-yl] ethyl acetate (50 mg, 0.10 mmol) and triethylsilane (1 itiL) in diethyl ether (10 mL) was stirred at room temperature for 14 h. The reaction mixture was diluted with aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on a silica gel to give 11 mg (0.023 mmol, 23%) of the title compounds.
1H NMR (CDCl3) δ: 0.92 (6H, t, J = 7,5 Hz), 1.28-1.49 (4H, m) , 1.78-1.91 (2H, m) , 2.08 (3H, s) , 2.17 (3H, s) , 3.79 (3H, s), 4.20-4.41 (4H, m) , 5.57 (0.8H, t, J = 7.2 Hz), 5.65 (0.2H, t, J = 7.2 Hz), 6.75 (IH, d, J = 7.2 Hz), 6.80 (IH, d, J = 2.1 Hz), 6.89 (IH, d, J = 2.1 Hz), 7.04 (IH, t, J = 7.2 Hz), 7.41 (IH, d, J = 7.2 Hz). MS Calcd. : 469; Found: 470 (M+H) .
Example 77
N- (4-Bromo-2-methoxy-6-methylphenyl) -4-chloro-7- (1- ethylpropyl ) -1 -methyl- liϊ-benzimidazol-2 -amine
Figure imgf000139_0001
7- (1-Ethyl-l-hydroxypropyl) -1-methyl-l, 3-dihydro-2H- benzimidazol-2-one
A solution of ethylmagnesium bromide (3M solution in diethyl ether; 32 mL, 96 mmol) was added dropwise to a suspension of methyl 3-methyl-2-oxo-2, 3-dihydro-liϊ- benzimidazole-4-carboxylate (5.00 g, 24.2 mmol) in tetrahydrofuran (50 itiL) at 0 °C. The mixture was stirred at 40 °C overnight. The reaction was quenched with water and IN HCl, extracted with ethyl acetate, washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was crystallized from ethanol/diethylether to afford the title compound as colorless crystals (3.39 g, 70%). mp 199-201 0C. 1H NMR (CDCl3) δ 0.90 (t, J = 7.5 Hz, 6H), 1.90-2.20 (m, 5H), 3.84 (s, 3H), 6.90-7.05 (m, 3H), 9.10-9.30 (m, IH). MS Calcd. : 234; Found: 235 (M+H) .
7- (1-Ethylpropyl) -1-methyl-l, 3-dihydro-2H-benzimidazol-2- one
A mixture of 7- (1-ethyl-l-hydroxypropyl) -1-methyl-l, 3- dihydro-2H-benzimidazol-2-one (6.00 g, 25.6 mmol) and 6N HCl (20 mL) in ethanol (100 inL) was stirred at 50 0C for 3 h. The mixture was concentrated in vacuo, and the resulting residue was dissolved in ethyl acetate, washed with aqueous potassium carbonate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give pale yellow oil, which was used in the next reaction without further purification. MS Calcd. : 216; Found: 217 (M+H) . The crude material was dissolved in ethanol (150 mL) . This solution was treated with 10% palladium on carbon (50% wet; 1.0Og), purged with hydrogen, and stirred under 5 atoms hydrogen for 7 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was crystallized from ethanol/diethylether to afford the title compound as colorless crystals (3.02 g, 54%) . mp 130-132 0C.
1H NMR (CDCl3) δ 0.82 (t, J = 6.6 Hz, 6H), 1.60-1.85 (m, 4H), 3.15-3.25 (m, IH), 3.65 (s, 3H), 6.85-6.98 (m, 2H), 7.00-7.10 (m, IH), 10.2-10.5 (m, IH). MS Calcd. : 218; Found: 219 (M+H) .
4-Chloro-7- (1-ethylpropyl) -1-methyl-l, 3-dihydro-2tf- benzimidazol-2-one
2,2' -Azobisisobutyronitrile (AIBN) (94 mg, 0.57 mmol) was added to a mixture of 7- (1-ethylpropyl) -1-methyl-l, 3- dihydro-2H-benzimidazol-2-one (2.90 g, 13.3 mmol) and N- chlorosuccinimide (1.95 g, 14.6 mmol) in carbon tetrachloride (250 mL) . The mixture was stirred at 70 0C for 2 days. The reaction was concentrated in vacuo, extracted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to give residue. The residue was crystallized from ethanol/iso-propanol to afford the title compound as colorless crystals (2.28 g, 68%). mp 165- 166 0C. 1H NMR (CDCl3) δ 0.81 (t, J = 7.2 Hz, 6H), 1.60-1.85 (m, 4H), 3.10-3.20 (m, IH), 3.64 (s, 3H), 6.87 (d, J = 8.7 Hz, IH), 7.03 (d, J = 8.7 Hz, IH), 8.55 (s, IH). MS Calcd. : 251; Found: 252 (M+H) .
2, 4-Dichloro-7- (1-ethylpropyl) -1-methyl-liϊ-benzimidazole
A mixture of 4-chloro-7- (1-ethylpropyl) -1-methyl-l, 3- dihydro-2H-benzimidazol-2-one (1.17 g, 4.63 mmol) in phosphorous oxychloride (28 g) was stirred at 90 0C for 3 h.
The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine.
The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was subjected to chromatography on silica gel (n-hexane/ethyl acetate = 10:1-1:1) and crystallized from ethyl acetate- hexane to afford the title compound as colorless crystals
(1.03 g, 82%) . mp 94-95 0C.
1H NMR (CDCl3) δ 0.82 (t, J = 7.5 Hz, 6H), 1.60-1.90 (m, 4H), 3.20-3.30 (m, IH), 4.01 (s, 3H), 7.05 (d, J = 8.4 Hz, IH), 7.26 (d, J = 8.4 Hz, IH). MS Calcd.: 270; Found: 271 (M+H) .
N- (4-Bromo-2-methoxy-6-methylphenyl) -4-chloro-7- (1- ethylpropyl) -1-methyl-lH-benzimidazol-2-amine A mixture of 2, 4-dichloro-7- (1-ethylpropyl) -1-methyl- lff-benzimidazole (140 mg, 0.52 iranol) , 4-bromo-2-methoxy-6- methylaniline (335 mg, 1.55 mmol) and l-methyl-2- pyrrolidone (5 drops) was stirred at 130 0C for 2 days under nitrogen atmosphere. The mixture was dissolved in ethyl acetate/water, extracted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, and concentrated to give a brown oil. The oil was subjected to chromatography on a silica gel (n- hexane/ethyl acetate = 10:1-1:1) and crystallized from iso- propanol to afford the title compound as colorless crystals (115 mg, 49%) . mp. 218-220 0C.
1H NMR (CDCl3) δ 0.83 (t, J = 7.2 Hz, 6H), 1.60-1.85 (m, 4H), 2.15 (s, 3H), 3.10-3.25 (m, IH), 3.76 (s, 3H), 3.79 (s, 3H), 6.08 (s, IH), 6.86 (d, J = 8.4 Hz, IH), 6.91 (s, IH), 7.03 (s, IH), 7.10-7.20 (m, IH). MS Calcd. : 449; Found: 450 (M+H) .
Examples 78 - 96 were prepared in the similar method described in Example 77.
Example 78
4-Chloro-lV- (4-chloro-2-methoxy-6-methylphenyl) -7- (1- ethylpropyl) -1-methyl-lH-benzimidazol-2-amine
Figure imgf000144_0001
mp 219-221 0C.
1H NMR (CDCl3) δ 0.83 (t, J = 7.2 Hz, 6H) , 1.60-1.85 (m,
4H) , 2.16 (s, 3H) , 3.10-3.20 (m, IH) , 3.75 (s, 3H) , 3.79 (s,
3H) , 6.07 (s, IH) , 6.77 (d, J = 2.1 Hz, IH) , 6.80-6.90 (m,
2H) , 7.05-7.20 (m, IH) .
MS Calcd. : 405; Found: 406 (M+H) .
Example 79 4-Chloro-N- [2, 6-dichloro-4- (trifluoromethoxy) phenyl] -7- (1- ethylpropyl) -1-methyl-lH-benzimidazol-2-amine
Figure imgf000144_0002
mp 147-149 0C.
1H NMR (CDCl3) δ 0.85 (t, J = 7.2 Hz, 6H), 1.60-1.85 (m, 4H), 3.10-3.20 (m, IH), 3.87 (s, 3H), 6.75-6.90 (m, IH), 6.98 (d, J = 8.4 Hz, IH), 7.20-7.45 (m, 2H), 8.30-8.40 (m, IH) .
MS Calcd.: 479; Found: 480 (M+H) .
Example 80
4-Chloro-N- (2, 4-dichlorophenyl) -7- (1-ethylpropyl) -1-methyl- liϊ-benzirαidazol-2-amine
Figure imgf000145_0001
mp 130-132 0C.
1H NMR (CDCl3) δ 0.84 (t, J = 7.5 Hz, 6H), 1.60-1.85 (m, 4H), 3.15-3.25 (m, IH), 3.84 (s, 3H), 6.72 (s, IH), 6.96 (d, J = 8.4 Hz, IH), 7.21 (d, J = 8.4 Hz, IH), 7.29 (d, J = 2.4 Hz, IH) , 7.41 (d, J = 2.4 Hz, IH) , 8.09 (d, J = 8.4 Hz, IH) . MS Calcd.: 395; Found: 396 (M+H).
Example 81
4-Chloro-iV- [4-chloro-2- (trif luoromethoxy) phenyl] -7- (1- ethylpropyl ) -l-methyl-liϊ-benziinidazol-2-amine
Figure imgf000146_0001
mp 126-128 0C.
1H NMR (CDCl3) δ 0.84 (t, J = 7.5 Hz, 6H), 1.60-1.85 (m, 4H), 3.15-3.30 (m, IH), 3.87 (s, 3H), 6.81 (s, IH), 6.98 (d, J = 8.4 Hz, IH), 7.20-7.40 (m, 3H), 8.30-8.40 (m, IH). MS Calcd. : 445; Found: 446 (M+H) .
Example 82
N- (4-Bromo-2, 6-dimethylphenyl) -4-chloro-7- (1-ethylpropyl) -
1-methyl-lfT-benzimidazol-2-amine
Figure imgf000146_0002
mp 247-249 °C.
1H NMR (CDCl3) δ 0.82 (t, J = 7.5 Hz, 6H), 1.55-1.80 (m, 4H), 2.17 (s, 6H), 3.00-3.20 (m, IH), 3.40-3.65 (m, 3H), 5.90-6.00 (m, IH), 6.70-6.90 (m, 2H), 7.00-7.20 (m, IH), 7.20-7.30 (m, IH). MS Calcd.: 434; Found: 435 (M+H). Example 83
4-Chloro-W- (4-chloro-2, β-dimethylphenyl) -7- (1-ethylpropyl) -
1-methyl-liϊ-benzimidazol-2-amine
Figure imgf000147_0001
mp 247-249 0C.
1H NMR (CDCl3) δ 0.82 (t, J = 7.5 Hz, 6H), 1.55-1.80 (m, 4H), 2.18 (s, 6H), 3.00-3.20 (m, IH), 3.40-3.65 (m, 3H), 5.90-6.00 (m, IH), 6.70-6.90 (m, 2H), 7.05-7.20 (m, 2H). MS Calcd. : 389; Found: 390 (M+H) .
Example 84
W- (2-Bromo-4-chlorophenyl) -4-chloro-7- (1-ethylpropyl) -1- methyl-lH-benzimidazol-2-amine
Figure imgf000147_0002
mp 136-138 0C.
1H NMR (CDCl3) δ 0.84 (t, J = 7.5 Hz, 6H), 1.60-1.85 (m, 4H), 3.15-3.25 (m, IH), 3.84 (s, 3H), 6.81 (s, IH), 6.96 (d, J = 8.4 Hz, IH), 7.21 (d, J = 8.4 Hz, IH), 7.32 (dd, J = 8.4, 2.4 Hz, IH), 7.56 (d, J = 2.4 Hz, IH), 8.06 (d, J - 8.4 Hz, IH). MS Calcd. : 440; Found: 441 (M+H) .
Example 85
N- (4-Bromo-2-chlorophenyl) -4-chloro-7- (1-ethylpropyl) -1- methyl-lH-benzimidazol-2-amine
Figure imgf000148_0001
mp 127-129 0C.
1H NMR (CDCl3) δ 0.84 (t, J = 7.5 Hz, 6H), 1.60-1.85 (in, 4H), 3.15-3.25 (m, IH), 3.85 (s, 3H), 6.80 (s, IH), 6.96 (d, J = 8.4 Hz, IH), 7.22 (d, J = 8.4 Hz, IH), 7.42 (dd, J = 8.8, 2.4 Hz, IH), 7.55 (d, J = 2.4 Hz, IH), 8.03 (d, J = 8.8 Hz, IH). MS Calcd.: 440; Found: 441 (M+H).
Example 86
N- ( 2-Bromo-4-methylphenyl ) -4-chloro-7- ( 1-ethylpropyl ) -1- methyl-liϊ-benzimidazol-2-amine
Figure imgf000149_0001
' nip 174 -17 6 0 C .
1H NMR (CDCl3) δ 0.84 (t, J = 7.5 Hz, 6H), 1.60-1.85 (m, 4H), 2.30 (s, 3H), 3.15-3.25 (m, IH), 3.80 (s, 3H), 6.74 (s, IH), 6.94 (d, J = 8.4 Hz, IH), 7.10-7.15 (m, IH), 7.20 (d, J = 8.4 Hz, IH), 7.38 (d, J = 1.2 Hz, IH), 7.77 (d, J = 8.4 Hz, IH). MS Calcd. : 420; Found: 421 (M+H) .
Example 87 4-Chloro-N- [2-chloro-4- (trifluoromethoxy) phenyl] -7- (1- ethylpropyl) -l-methyl-lH-benzimidazol-2-amine
Figure imgf000149_0002
mp 122-123 0C.
1H NMR (CDCl3) δ 0.84 (t, J = 7.5 Hz, 6H), 1.60-1.85 (m, 4H), 3.15-3.25 (m, IH), 3.87 (s, 3H), 6.81 (s, IH), 6.96 (d, J = 8.4 Hz, IH), 7.21 (d, J = 8.4 Hz, 2H), 7.31 (s, IH), 8.21 (d, J = 8.4 Hz, IH). MS Calcd. : 445; Found: 446 (M+H) .
Example 88
W5- [4-Chloro-7- (1-ethylpropyl) -l-methyl-lH-benzimidazol-2- yl] -IV2, W2, 4-trimethylpyridine-2 , 5-diamine
Figure imgf000150_0001
mp 224-226 0C.
1H NMR (CDCl3) δ 0.82 (t, J = 7.2 Hz, 6H), 1.60-1.85 (m, 4H), 2.26 (s, 3H), 3.00-3.20 (m, IH), 3.07 (s, 6H), 3.59 (s, 3H), 5.90 (s, IH), 6.41 (s, IH), 6.87 (d, J = 8.4 Hz, IH), 7.15 (d, J = 8.4 Hz, IH), 7.91 (s, IH). MS Calcd.: 385; Found: 386 (M+H) .
Example 89
N- ( 4-Bromo-2-methoxy-6-methylphenyl ) -4-chloro-l-methyl-7- ( 1-propylbutyl) -liϊ-benzimidazol-2 -amine
Figure imgf000151_0001
mp 210-211 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.5 Hz, 6H) , 1.15-1.35 (m, 4H) , 1.60-1.80 (m, 4H) , 2.15 (s, 3H) , 3.25-3.40 (m, IH) , 3.75 (s, 3H) , 3.79 (s, 3H) , 6.07 (s, IH) , 6.85-6.95 (m, 2H) , 7.00-7.20 (m, 2H) . MS Calcd. : 477; Found: 478 (M+H) .
Example 90
4-Chloro-iV- (4-chloro-2-methoxy-6-methylphenyl) -l-methyl-7- (1-propylbutyl) -liT-benzimidazol-2-amine
Figure imgf000151_0002
mp 204-206 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.2 Hz, 6H) , 1.10-1.30 (m, 4H) , 1.55-1.75 (m, 4H) , 2.15 (s, 3H) , 3.25-3.40 (m, IH) ,
3. (s, 3H) , 3.79 (s, 3H) , 6.08 (s, IH) , 6.77 (d, J = 2.1
Hz, IH) , 6.80-6.90 (m, 2H) , 7.10 (d, J = 8.4 Hz, IH) . MS Calcd. : 433; Found: 434 (M+H) . Example 91
4-Chloro-iV- ( 2 , 4-dichlorophenyl ) -l-methyl-7- ( 1-propylbutyl ) - liT-benzimidazol-2-amine
Figure imgf000152_0001
mp 146-148 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.2 Hz, 6H), 1.10-1.30 (m, 4H), 1.55-1.80 (m, 4H), 3.30-3.45 (m, IH), 3.84 (s, 3H), 6.79 (s, IH), 6.97 (d, J = 8.1 Hz, IH), 7.21 (d, J = 8.1 Hz, IH), 7.29 (d, J = 2.4 Hz, IH), 7.41 (d, J = 2.4 Hz, IH), 8.09 (d, J = 8.4 Hz, IH). MS Calcd. : 423; Found: 424 (M+H) .
Example 92
N- (2-Bromo-4-chlorophenyl) -4-chloro-l-methyl-7- (1- propylbutyl) -lH-benzimidazol-2-amine
Figure imgf000153_0001
mp 145-147 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.5 Hz, 6H), 1.10-1.30 (m, 4H), 1.55-1.80 (m, 4H), 3.30-3.45 (in, IH), 3.84 (s, 3H), 6.80 (s, IH), 7.00 (d, J = 8.1 Hz, IH), 7.20 (d, J= 8.1 Hz, IH), 7.31 (dd, J = 8.7, 2.4 Hz, IH), 7.55 (d, J = 2.4 Hz, IH), 8.04 (d, J = 8.7 Hz, IH). MS Calcd. : 469; Found: 470 (M+H) .
Example 93
N- (4-Bromo-2-chlorophenyl) -4-chloro-l-methyl-7- (1- propylbutyl) -lff-benzimidazol-2-amine
Figure imgf000153_0002
mp 145-147 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.5 Hz, 6H), 1.10-1.30 (m, 4H), 1.55-1.80 (m, 4H), 3.30-3.45 (rα, IH), 3.84 (s, 3H), 6.79 (s, IH), 7.00 (d, J = 8.1 Hz, IH), 7.21 (d, J = 8.1 Hz, IH), 7.41 (dd, J = 9.0, 2.4 Hz, IH), 7.54 (d, J = 2.4 Hz, IH), 8.03 (d, J = 9.0 Hz, IH). MS Calcd. : 469; Found: 470 (M+H) .
Example 94
4-Chloro-iV- [4-chloro-2- (trifluoromethoxy) phenyl] -1-methyl-
7- (1-propylbutyl) -lff-benzimidazol-2-amine
Figure imgf000154_0001
mp 130-132 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.5 Hz, 6H), 1.10-1.30 (m, 4H), 1.55-1.80 (m, 4H), 3.30-3.40 (m, IH), 3.81 (s, 3H), 6.56 (s, IH), 6.97 (d, J = 8.1 Hz, IH), 7.20 (d, J = 8.1 Hz, IH), 7.25-7.30 (m, 2H), 8.00-8.20 (m, IH). MS Calcd.: 473; Found: 474 (M+H) .
Example 95
4-Chloro-N- [2-chloro-4- (trifluoromethyl) phenyl] -7- (1- ethylpropyl) -l-methyl-lH-benzimidazol-2-amine
Figure imgf000155_0001
mp 128-129 0C.
1H NMR (CDCl3) δ 0.84 (6 H, t, J=7.4 Hz) 1.65 - 1.88 (4 H, m) 3.14 - 3.27 (1 H, m) 3.88 (3 H, s) 6.94 - 7.04 (2 H, m)
7.20 - 7.28 (1 H, m) 7.55 (1 H, dd, J=Q.8, 1.9 Hz) 7.66 (1
H, d, J=I.9 Hz) 8.20 (1 H, d, J=9.9 Hz)
MS Calcd. : 429; Found: 430 (M+H) .
Example 96 4-Bromo-iV- (4-chloro-2-methoxy-6-methylphenyl) -7- (1- ethylpropyl) -1 -methyl- lH-benzimidazol- 2 -amine
Figure imgf000155_0002
mp 198-199 0C.
1H NMR (CDCl3) δ 0.83 (t, J = 7.2 Hz, 6H) , 1.60-1.80 (m,
4H) , 2.17 (s, 3H) , 3.15 (m, IH) , 3.72 (s, 3H) , 3.78 (s, 3H) , 6.11 (bs, IH), 6.77 (s, IH), 6.81 (d, J = 8.4 Hz, IH), 6.87 (s, IH) , 7.20-7.30 (m, IH) . MS Calcd.: 449; Found: 450 (M+H) .
Example 97
4-Chloro-2- (2, 4-dichloro-6-methylphenoxy) -7- (1- ethylpropyl ) -l-methyl-lH-benzimidazole
Figure imgf000156_0001
A solution of 2, 4-dichloro-7- (1-ethylpropyl) -1-methyl- IH-benzimidazole (5.5 g, 20.2 rranol), 2, 4-dichloro-6- methylphenol (1Og, 56.5 mmol) and potassium carbonate (8.4g, 60.8 mmol) in N, I\7-dimethylformamide (55 inL) was heated at 100 0C for 9 h. To the mixture was added 2, 4-dichloro-6- methylphenol (5g, 28.3 mmol) and potassium carbonate (4.2g, 30.4 mmol) and heated at 100 0C for 16 h. Additional 2,4- dichloro-6-methylphenol (5g, 28.3 mmol) and potassium carbonate (4.2g, 30.4 mmol) were added and heated at 100 0C for 9 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on NH silica gel eluting with a 12.5% ethyl acetate/n-hexane . The resulting solids were recrystalized from a 10% ethyl acetate/n-hexane to give 5.3 g (64%) of the title compound as a colorless crystal, mp 155-157 0C.
1H NMR (CDCl3) δ 0.86 (t, J =7.2 Hz, 6H), 1.64-1.86 (m, 4H), 2.31 (s, 3H), 3.17-3.28 (m, IH), 3.99 (s, 3H), 6.93 (d, J = 8.4 Hz, IH), 7.14 (d, J = 8.4 Hz, IH), 7.20 (d, J= 2.4 Hz, IH), 7.31 (d, J= 2.4 Hz, IH).
MS Calcd. : 410; Found: 411 (M+H) .
Examples 98 - 99 were prepared in the similar method described in Example 97.
Examples 98
4-Chloro-2- (2, 4-dichlorophenoxy) -7- (1-ethylpropyl) -1- methyl-lH-benzimidazole
Figure imgf000157_0001
mp 87-89 0C.
1H NMR (CDCl3) δ 0.84 (6 H, t, J=7.3 Hz) 1.63 - 1.88 (4 H, m) 3.16 - 3.28 (1 H, m) 3.97 (3 H, s) 6.96 (1 H, d, J=8.2 Hz) 7.18 (1 H, d, J=8.2 Hz) 7.32 (1 H, dd, J=8.8, 2.5 Hz) 7.47 (1 H, d, J=2.5 Hz) 7.74 (1 H, d, J=8.8 Hz). MS Calcd. : 396; Found: 397 (M+H) .
Examples 99
4-Chloro-7- (1-ethylpropyl) -2- (mesityloxy) -1-methyl-lH- benzimidazole
Figure imgf000158_0001
mp 137-139 0C.
1H NMR (CDCl3) δ 0.87 (6 H, t, J=I .4 Hz) 1.65 - 1.87 (4 H, m) 2.17 (6 H, s) 2.30 (3 H, s) 3.17 - 3.29 (1 H, m) 3.97 (3 H, s) 6.87 - 6.95 (3 H, m) 7.12 '(I H, d, J=8.2 Hz). MS Calcd.: 370; Found: 371 (M+H) .
Examples 100
N- (4-Chloro-2-methoxy-6~methylphenyl) -7- (1-ethylpropyl) -A- methoxy-l-methyl-liϊ-benzimidazol-2-amine
Figure imgf000159_0001
7- (1-Ethylpropyl) -4-methoxy-l-methyl-l, 3-dihydro-2H- benzimidazol-2-one A solution of 4-bromo-7- (1-ethylpropyl) -1-methyl-l, 3- dihydro-2#-benziinidazol-2-one (250 mg, 0.841 mmol), anhydrous cuprus iodide (192 mg, 1.01 mmol) and 28% sodium methoxide in methanol (5.2 mL) in W, N-dimethylformamide (5 mL) was heated at 100 0C for 1 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (190 mg, 0.765 mmol, 91%). 1H NMR(CDCl3) δ 0.81 (6H, t, J = 7.5 Hz), 1.65-1.80 (4H, m) , 3.05-3.15 (IH, m) , 3.63 (3H, s) , 3.90(3H, s) , 6.63 (IH, d, J= 8.4 Hz), 6.85(1H, d, J = 8.4 Hz), 8.39(1H, br) . MS Calcd. : 248; Found: 249 (M+H).
2-Chloro-7- (1-ethylpropyl) -4-methoxy-l-methyl-lH- benzimidazole A mixture of 7- (1-ethylpropyl) -4-methoxy-l-methyl-l, 3- dihydro-2iϊ-benzimidazol-2-one (190 mg, 0.765 mmol) in phosphorous oxychloride (2.14 iriL) was stirred at 110 0C for 6 h. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n- hexane/ethyl acetate = 10:1-1:1) and crystallized from ethyl acetate/n-hexane to afford the title compound as colorless crystals (123 mg, 60%) . MS Calcd.: 266; Found: 267 (M+H) .
N- (4-Chloro-2-methoxy-6-methylphenyl) -7- (1-ethylpropyl) -A- methoxy-l-methyl-liϊ-benzimidazol-2-amine
A mixture of 2-chloro-7- (1-ethylpropyl) -4-methoxy-l- methyl-lH-benzimidazole (120 mg, 0.450 mmol), 4-chloro-2- methoxy-6-methylaniline (231 mg, 1.35 mmol) and l-methyl-2- pyrrolidone (0.5 mL) was stirred at 130 °C for 2 days under nitrogen atmosphere. The mixture was diluted with water, extracted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate = 10:1-1:1) and crystallized from iso-propanol to afford the title compound as colorless crystals (100 mg, 55%) . mp 188-189 0C.
1H NMR (CDCl3) δ 0.85 (t, J = 7.2 Hz, 6H), 1.60-1.80 (m, 4H), 2.08 (s, 3H), 3.10-3.20 (m, IH), 3.79 (s, 3H), 3.82 (s, 3H), 3.90 (s, 3H), 5.89 (m, IH), 6.61 (d, J = 8.7 Hz, IH), 6.75 (d, J = 1.8 Hz, IH), 6.83 (d, J = 1.8 Hz, IH), 6.86 (d, J = 8.7 Hz, IH). MS Calcd. : 401; Found: 402 (M+H) .
Examples 101
N- (4-Chloro-2-methoxy-6-methylphenyl) -7- (1-ethylpropyl) - 1, 4-dimethyl-liϊ-benzimidazol-2-amine
Figure imgf000161_0001
7- (1-Ethylpropyl) -1, 4-dimethyl-1, 3-dihydro-2H-benzimidazol- 2-one
A solution of 4-bromo-7- (1-ethylpropyl) -1-methyl-l, 3- dihydro-2#-benzimidazol-2-one (250 mg, 0.84 mmol) , tetrakis (triphenylphosphine) palladium (194 mg, 0.168 mmol), tetramethyltin (1.16 mL, 8.4 mmol) in hexamethylphosphoric triamide (5 mL) was refluxed for 18 h. After cooling, the mixture was diluted with water and extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on a silica gel (n- hexane/ethyl acetate = 90:10 - 50:50) to give the title compound (111 mg, 0.48 mmol, 57%).
1H NMR(CDCl3) δ 0.82 (6H, t, J = 7.5 Hz), 1.55-1.80 (4H, m) , 2.38 (3H, s), 3.10-3.20 (IH, m) , 3.65 (3H, s) , 6.84 (IH, d, J= 8.4 Hz), 6.87(1H, d, J = 8.4 Hz), 1O.15(1H, br) . MS Calcd. : 232; Found: 233 (M+H) .
2-Chloro-7- (1-ethylpropyl) -1, 4-dimethyl-lH-benzimidazole
A mixture of 7- (1-ethylpropyl) -1, 4-dimethyl-l, 3- dihydro-2iϊ-benzimidazol-2-one (105 mg, 0.452 mmol) in phosphorous oxychloride (1.23 mL) was stirred at 110 0C for 3 h. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n- hexane/ethyl acetate = 10:1-1:1) and crystallized from ethyl acetate/n-hexane to afford the title compound as colorless crystals (100 mg, 88%) . MS Calcd. : 250; Found: 251 (M+H) .
N- (4-Chloro-2-methoxy-β-methylphenyl) -7- (1-ethylpropyl) - 1, 4-dimethyl-lH-benzimidazol-2-amine A mixture of 2-chloro-7- (1-ethylpropyl) -1, 4-dimethyl- lH-benzimidazole (100 mg, 0.399 mmol), 4~chloro-2-methoxy- 6-rαethylaniline (205 mg, 1.20 mmol) and l-methyl-2- pyrrolidone (0.2 mL) was stirred at 120 0C for 2 days under nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate, washed with brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane : ethyl acetate = 10:1-1:1) and crystallized from iso-propanol to afford the title compound as colorless crystals (53 mg, 34%) . mp 201-202 0C.
1H NMR (CDCl3) δ 0.85 (t, J = 7.2 Hz, 6H), 1.60-1.80 (m, 4H), 2.11 (s, 3H), 2.45 (s, 3H), 3.10-3.20 (m, IH), 3.78 (s, 3H), 3.81 (s, 3H), 6.00 (m, IH), 6.78 (d, J = 2.1 Hz, IH), 6.80-6.95 (m, 3H). MS Calcd.: 385; FoundFound: 386 (M+H).
Example 102
Isopropyl [ 4-chloro-2- [ ( 4-chloro-2-methoxy-6- methylphenyl ) amino] -7- ( 1-ethylpropyl ) -liϊ-benzimidazol-1- yl ] acetate
Figure imgf000164_0001
Methyl 2, 3-diaminobenzoate
To a suspension of methyl 2-amino-3-nitrobenzoate (15 g, 76.5 mmol) in methanol (800 mL) was added 10% palladium on carbon (50% wet; 6.5 g) , and the mixture was stirred at room temperature for 20 hours under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residual solid was crystallized from diisopropyl ether-hexane to give 11.57 g (69.6 mmol, 91.0%) of the title compound as a dark yellow needle .
1H NMR (CDCl3) δ: 3.33 (2H, br s) , 3.07 (3H, s) , 5.56 (2H, br s), 6.60 (IH, dd, J = 8.1, 7.5 Hz), 6.85 (IH, dd, J = 7.5, 1.5 Hz), 7.47 (IH, dd, J= 8.1, 1.5 Hz). MS Calcd. : 166; Found: 167 (M+H) .
Methyl 2-oxo-2, 3-dihydro-lH-benzimidazole-4-carboxylate
To a solution of methyl 2, 3-diaminobenzoate (10.5 g, 63.2 mmol) in tetrahydrofuran (100 mL) was added N,N'- carbonyldiimidazole (10.2 g, 63.2 mmol) , and the mixture was stirred at room temperature for 60 hours. The resulting solid was collected by filtration and washed with ethyl acetate to give 10.2 g (53.1 mmol, 84.0%) of the title compound as a colorless crystal.
1H NMR (DMSO-de) δ: 3.87 (3H, s) , 7.03 (IH, dd, J = 8.1, 7.5 Hz), 6.85 (IH, dd, J= 7.5, 1.2 Hz), 7.48 (IH, dd, J= 8.1, 1.2 Hz) , 10.82 (2H, br s) . MS Calcd. : 192; Found: 193 (M+H) .
4- (1-Ethyl-l-hydroxypropyl) -1, 3-dihydro-22ϊ-benzimidazol-2- one
To a suspension of methyl 2-oxo-2, 3-dihydro-lff- benzimidazole-4-carboxylate (513 mg, 2.67 mmol) in tetrahydrofuran (5 mL) was added 3M solution of ethyl magnesium bromide in diethyl ether (3.6 ml, 10.7 mmol), and the mixture was stirred at room temperature for 1 hour and refluxed for 20 hours. Addition of 3M solution of ethyl magnesium bromide in diethyl ether (5.3 mL, 16.0 mmol) was followed by refluxing for 30 hours. The reaction mixture was acidified with 6 N hydrochloric acid and extracted with ethyl acetate (X2) . The combined organic layer was washed with brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give 440 mg (2.00 mmol, 74.8%) of the title compound.
1H NMR (CDCl3) δ: 0.83 (6H, t, J = 7.5 Hz), 1.76-1.98 (4H,- m) , 2.19 (IH, br s) , 6.72 (IH, d, J = 7.8 Hz), 6.92-7.02 (2H, m) , 9.16 (IH, br s) , 9.44 (IH, br s) . MS Calcd.: 220; Found: 203 (M-H2O+H) .
4- [ (IE) -1-Ethylprop-l-en-l-yl] -1, 3-dihydro-2ff-benzimidazol- 2-one and 4- [ (IZ) -1-Ethylprop-l-en-l-yl] -1, 3-dihydro-2iϊ~ benzimidazol-2-one To a solution of 4- (1-ethyl-l-hydroxypropyl) -1, 3- dihydro-2H-benzimidazol-2-one (410 mg, 1.86 mmol) in ethanol (6 itiL) was added 6N hydrochloric acid (1.2 mL) , and the mixture was stirred at 75 0C for 2 hours. After cooling, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate
(X2). The combined organic layer was washed with water (Xl) and brine (Xl) , dried over sodium sulfate, passed through silica gel and concentrated in vacuo to give 364 mg (1.80 mmol, 96.8%) of the title compound as a pale yellow solid. 1H NMR (CDCl3) δ: 0.95 (3H, t, J = 7.5 Hz), 1.49 (0.75H, d, J" = 6.9 Hz), 1.84 (2.25H, d, J = 6.9 Hz), 2.36 (0.5H, q, J = 7.5 Hz), 2.50 (1.5H, q, J = 7.5 Hz), 5.62-5.75 (IH, m) , 6.82-7.08 (3H, m) , 8.29 (0.25H, s), 8.42 (0.75H, s) , 9.30 (IH, s). MS Calcd.: 202; Found: 203 (M+H) . 4- (1-Ethylpropyl) -1, 3-dihydro-2iϊ-benzimidazol-2-one
To a suspension of a mixture of 4- [ (IS) -1-ethylprop-l- en-l-yl]-l,3-dihydro-2H-benzimidazol-2-one and 4- [ (IZ)-I- ethylprop-1-en-l-yl] -1, 3-dihydro-2H-benzimidazol-2-one (329 mg, 1.63 mmol) and ammonium formate (820 mg, 13.0 mmol) in ethanol (3 mL) was added 10% palladium on carbon (50% wet;
120 mg) , and the mixture was stirred at room temperature for 15 hours. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate (Xl) .
The organic layer was washed with brine (Xl) , dried over sodium sulfate and concentrated in vacuo to give 354 mg (>99%) of the title compound as a colorless solid. 1H NMR (CDCl3) δ: 0.80 (6H, t, J = 7.2 Hz), 1.57-1.82 (4H, m) , 2.50-2.62 (IH, m) , 6.88 (IH, d, J = 7.8 Hz), 6.92 (IH, d, J = 7.8 Hz), 7.03 (IH, t, J = 7.8 Hz), 9.44 (IH, s),
9.54 (IH, s) .
MS Calcd. : 204; Found: 205 (M+H) .
tert-Butyl 4- (1-ethylpropyl) -2-oxo-2, 3-dihydro-liϊ- benzimidazole-1-carboxylate
To a suspension of 4- (1-ethylpropyl) -1, 3-dihydro-2F- benzimidazol-2-one (7.25 g, 35.5 mmol) in 1,2- dichloroethane (5 mL) was added N,iV-dimethylairιinopyridine (4.34 g, 35.5 mmol) and di-tert-butyl dicarbonate (8.16 ml, 35.5 mmol) at 0 0C, and the mixture was stirred at 0 0C for 30 minutes. The reaction mixture was diluted with water and extracted with dichloromethane (X2) . The combined organic layer was washed with brine (X2), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 5-40% ethyl acetate/hexane gradient mixture to give 7.87 g (25.9 mmol, 72.8%) of the title compound as a colorless solid. 1H NMR (CDCl3) δ: 0.79 (6H, t, J = 7.4 Hz), 1.55-1.83 (4H, m) , 1.68 (9H, s) , 2.40-2.60 (IH, m) , 6.97 (IH, d, J = 8.0 Hz), 7.09 (IH, t, J = 8.0 Hz), 7.65 (IH, d, J = 8.0 Hz), 8.93 (IH, s) .
tert-Butyl 4- (1-ethylpropyl) -3- (2-isopropoxy-2-oxoethyl) -2- oxo-2 , 3-dihydro-lH-benzimidazole-l-carboxylate
To a suspension of tert-butyl 4- (1-ethylpropyl) -2-oxo- 2, 3-dihydro-lH-benzimidazole-l-carboxylate (7.70 g, 25.3 mmol) in Z\F,2\7-dimethylformamide (50 πiL) was added potassium carbonate (3.84 g, 27.8 mmol) and isopropyl bromoacetate
(3.60 ml, 27.8 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (X2) . The combined organic layer was washed with aqueous sodium chloride (X2) and brine (Xl), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 5-20% ethyl acetate/hexane gradient mixture to give 8.95 g (22.1 mmol, 87.5%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ: 0.82 (6H, t, J - 7.5 Hz), 1.26 (6H, d, J = 6.3 Hz), 1.53-1.76 (4H, m) , 1.67 (9H, s), 2.57-2.68 (IH, m) , 4.80 (2H, s), 5.02-5.14 (IH, m) , 7.03 (IH, dd, J = 8.1, 1.5 Hz), 7.11 (IH, t, J = 8.1 Hz), 7.79 (IH, dd, J = 8.1, 1.5 Hz) .
Isopropyl [7- (1-ethylpropyl) -2-oxo-2, 3-dihydro-liϊ- benzimidazol-1-yl] acetate
To a solution of tert-butyl 4- (1-ethylpropyl) -3- (2- isopropoxy-2-oxoethyl) -2-oxo-2, 3-dihydro-lH-benzimidazole- 1-carboxylate (8.95 g, 22.1 mmol) in ethyl acetate (10 ml) was added a 4N solution of hydrogen chloride in ethyl acetate (20 ml) , and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (X2) . The combined organic layer was washed with brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 5-20% ethyl acetate/hexane gradient mixture. The residual solid was washed with hexane to give 5.76 g (18.9 mmol, 85.6%) of the title compound as a colorless solid.
1H NMR (CDCl3) δ: 0.81 (6H, t, J = 7.5 Hz), 1.26 (6H, d, J = 6.3 Hz), 1.55-1.79 (4H, m) , 2.62-2.73 (IH, m) , 4.82 (2H, s) , 5.05-5.15 (IH, m) , 6.90-6.94 (2H, m) , 7.04 (IH, d, J = 7.8 Hz) , 9.12 (IH, s) .
MS Calcd. : 304; Found: 305 (M+H) .
Isopropyl [4-chloro-7- (1-ethylpropyl) -2-oxo-2, 3-dihydro-liϊ- benzimidazol-1-yl] acetate To a solution of isopropyl [7- (1-ethylpropyl) -2-oxo- 2, 3-dihydro-lH-benzimidazol-l-yl] acetate (5.29 g, 17.4 mmol) in carbon tetrachloride (350 inL) was added N- chlorosuccinimide (2.55 g, 19.1 mmol) and 2,2'- azobisisobutyronitrile (86 mg, 0.522 mmol), and the mixture was stirred at 70 0C for 3 days. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with dichloromethane (X2) . The combined organic layer was washed with water (Xl) and brine (Xl), dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-50% ethyl acetate/hexane gradient mixture to give 3.83 g (11.3 mmol, 65.0%) of the title compound as a colorless solid. 1H NMR (CDCl3) δ: 0.83 (6H, t, J = 7.5 Hz), 1.27 (6H, d, J = 6.3 Hz), 1.57-1.78 (4H, m) , 2.59-2.68 (IH, m) , 4.80 (2H, s) , it
170
5.02-5.14 (IH, m) , 6.86 (IH, d, J = 8.7 Hz), 7.04 (IH, d, J
= 8.7 Hz) , 8.67 (IH, s) .
MS Calcd.: 338; Found: 339 (M+H) .
Isopropyl [2, 4-dichloro-7- (1-ethylpropyl) -liϊ-benzimidazol- 1-yl] acetate
A mixture of isopropyl [4-chloro-7- (1-ethylpropyl) -2- oxo-2, 3-dihydro-lH-benzimidazol-l-yl] acetate (3.73 g, 11.0 iranol) and phosphorus oxychloride (20 mL) was stirred at 100 0C for 48 hours. After cooling, phosphorus oxychloride was evaporated in vacuo. The residue was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (X2). The combined organic layer was washed with brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 5-15% ethyl acetate/hexane gradient mixture to give 3.82 g (10.7 mmol, 97.2%) of the title compound as an oil. 1H NMR (CDCl3) δ: 0.81 (6H, t, J = 7.5 Hz), 1.28 (6H, d, J = 6.3 Hz), 1.62-1.83 (4H, m) , 2.72-2.82 (IH, m) , 5.06-5.21 (IH, m) , 5.08 (2H, s) , 7.05 (IH, d, J = 8.0 Hz), 7.28 (IH, d, J = 8.0 Hz) MS Calcd.: 356, 358; Found: 357, 359 (M+H).
Isopropyl [4-chloro-2- [ (4-chloro-2-methoxy-6- methylphenyl) amino] -7- (1-ethylpropyl) -lH-benzimidazol-1- yl] acetate
A mixture of isopropyl [2, 4-dichloro-7- (1- ethylpropyl) -lH-benzimidazol-1-yl] acetate (1.60 g, 4.48 mmol) , (4-chloro-2-methoxy-6-methyl) aniline (3.18 g, 18.6 iranol) and I\7-methyl-2-pyrrolidinone (1 mL) was stirred at 110 0C for 4.5 days. After cooling, the reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate (Xl) . The organic layer was washed with brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 5-20% ethyl acetate/hexane gradient mixture. The residual solid was washed with ethyl acetate/diisopropyl ether and n- hexane to give 1.18 g (2.40 mmol, 53.5%) of the title compound as a colorless solid. The filtrate was purified by preparative HPLC to give 204 mg (0.414 mmol, 9.2%) of the title compound as a solid, mp 205-207 0C.
1H NMR (CDCl3) δ: 0.82 (6H, t, J = 7.4 Hz), 1.30 (6H, d, J = 6.3 Hz), 1.58-1.81 (4H, m) , 2.11 (3H, s) , 2.80-2.92 (IH, m) , 3.83 (3H, s) , 4.89 (2H, s) , 5.09-5.20 (IH, m) , 6.56 (IH, s), 6.78 (IH, s), 6.87 (IH, d, J = 7.6 Hz), 6.87 (IH, s) ,
7.14 (IH, d, J = 7.6 Hz) .
MS Calcd. : 491, 493; Found: 492, 494 (M+H) . Example 103
2- [ 4-Chloro-2- [ ( 4-chloro-2-methoxy-6-inethylphenyl ) amino ] -7-
( 1-ethylpropyl ) -liϊ-benzimidazol-1-yl ] ethanol
Figure imgf000173_0001
To a solution of isopropyl [4-chloro-2- [ (4-chloro-2- methoxy-6-methylphenyl) amino] -7- (1-ethylpropyl) -IH- benzimidazol-1-yl] acetate (453 mg, 0.920 mmol) in tetrahydrofuran (5 mL) was added lithium tetrahydroborate
(60 mg, 2.76 mmol), and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (X2). The combined organic layer was washed with brine (Xl) , dried over sodium sulfate and concentrated in vacuo. The residual solid was recrystallized with ethyl acetate-n-hexane to give 250 mg (0.573 mmol, 62.3%) of the title compound as a colorless crystal. The filtrate was concentrated in vacuo, and the residual solid was recrystallized with ethyl acetate-hexane to give 91 mg (0.209 mmol, 22.7%) of the title compound as a colorless crystal. 1H NMR (CDCl3) δ: 0.85 (6H, t, J = 7.2 Hz), 1.65-1.83 (4H, m) , 2.16 (3H, s), 2.45-2.60 (IH, br) , 2.79-2.87 (IH, m) , 3.76 (3H, s), 4.14 (2H, t, J = 4.5 Hz), 4.43 (2H, t, J - 4.5 Hz), 6.76 (IH, d, J = 1.8 Hz), 6.83 (IH, d, J = 7.8 Hz), 6.87 (IH, d, J = 1.8 Hz), 6.99 (IH, d, J = 7.8 Hz), 7.50-7.70 (IH, br) . MS Calcd. : 435, 437; Found: 436, 438 (M+H) .
Example 104
[4-Chloro-2- [ (4-chloro-2-methoxy-6-methylphenyl) amino] -7-
(1-ethylpropyl) -lU-benzimidazol-1-yl] acetic acid
Figure imgf000174_0001
To a solution of 2- [4-chloro-2- [ (4-chloro-2-methoxy-6- methylphenyl) amino] -7- (1-ethylpropyl) -lϋ-benzimidazol-1- yl]ethanol (861 mg, 1.75 mmol) in methanol (5 mL) was added 8N aqueous sodium hydroxide (1.5 mL) , and the mixture was stirred at room temperature for 15 hours. Water was added to the reaction mixture, followed by neutralization with 6N hydrochloric acid. The mixture was concentrated in vacuo, and the residue was dissolved in methanol. The precipitate was removed by filtration, and the filtrate was concentrated in vacuo to give 781 mg (1.73 mmol, 99.1%) of the title compound as an amorphous. 1H NMR (CDCl3) δ: 0.76 (6H, t, J = 7.2 Hz), 1.52-1.73 (4H, m) , 2.07 (3H, s) , 3.06-3.15 (IH, m) , 3.76 (3H, s), 4.77 (2H, s), 6.77 (IH, d, J = 8.4 Hz), 6.93-6.99 (3H, m) , 8.64 (IH, s) . MS Calcd. : 449, 451; Found: 450, 452 (M+H) .
Example 105 l- { 4-Chloro-2- [ ( 4-chloro-2-methoxy- 6-methylphenyl ) amino] -1- methyl-lJϊ-benzimidazol-7-yl } -2 , 2-dimethylpropan-l-one
Figure imgf000175_0001
Methyl 7~chloro-3-methyl-2-oxo-2, 3-dihydro-lff- benzimidazole-4-carboxylate
A solution of methyl 3-methyl-2-oxo-2, 3-dihydro-liϊ- benzimidazole-4-carboxylate (500 mg, 2.42 mmol), N- chlorosuccinimide (355 mg, 2.66 mmol) and 2,2'- azobis (isobutyronitrile) (20 mg, 0.12 mmol) in carbon tetrachloride (40 mL) was refluxed for 2 days. After cooling, the reaction mixture was concentrated in vacuo. The resultant was extracted with ethyl acetate and water. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on a silica gel to give 167 mg (0.07 mmol, 29%) of the title compound.
1H NMR (CDCl3) δ 3.57(3H, s) , 3.95(3H, s) , 7.07(1H, d, J = 8.4 Hz), 7.50 (IH, d, J= 8.4 Hz), 8.03(1H, br) . MS Calcd. : 240; Found: 241 (M+H) .
Methyl 2, 4-dichloro-l-methyl-liϊ-benzimidazole-7-carboxylate Methyl 7-chloro-3-methyl-2-oxo-2, 3-dihydro-lH- benzimidazole-4-carboxylate (150 mg, 0.63 mmol) was dissolved in 3 mL of phosphorous oxychloride and heated at 110 0C overnight. The reaction mixture was allowed to cool to room temperature, poured into a crushed ice, and stirred for 1 h. The resultant was diluted in ethyl acetate, washed with aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuo. The obtained (147 mg, 90%) was used in the next reaction without further purification. MS Calcd. : 257; Found: 258 (M+H) .
Methyl 4-chloro-2-[ (4-chloro-2-methoxy-6- methylphenyl) amino] -l-methyl-lH-benzimidazole-7-carboxylate
A mixture of methyl 2, 4-dichloro-l-methyl-lH- benzimidazole-7-carboxylate (100 mg, 0.39 mmol) and 4- chloro-2-methoxy-6-methylaniline (200 mg, 1.17 mmol) was stirred at 130 0C overnight. After cooling, the reaction mixture was neutralized by aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on a silica gel column to give 68 mg (0.17 mmol, 44%) of the title compound.
1H NMR (CDCl3) δ 2.19(3H, s), 3.74(3H, s), 3.80(3H, s) , 3.95(3H, s), 6.17(1H, br) , 6.76(1H, d, J = 1.8 Hz), 6.88(1H, d, J = 1.8 Hz), 7.14(1H, d, J = 8.1 Hz), 7.53(1H, d, J = 8.1 Hz) . MS Calcd. : 393; Found: 394 (M+H) .
1- { 4~Chloro-2- [ (4-chloro-2-methoxy-6-inethylphenyl) amino] -1- methyl-lH-benzimidazol-7-yl}-2, 2-dimethylpropan-l-one
A n-pentane solution of tert-butyl lithium (1.46 M, 0.5 ml) was added to a solution of methyl 4-chloro-2- [ (4- chloro-2-methoxy-6-methylphenyl) amino] -1-methyl-IH- benzimidazole-7-carboxylate (100 mg, 0.23 mmol) in diethyl ether (5 mL) at -78 0C and stirred for Ih. The reaction mixture was diluted with water (5 mL) , stirred at room temperature for 0.5 h and extracted with ethyl acetate. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC. The resultant was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 31 mg (0.073 mmol, 32%) of the title compound. mp. 249-250 0C
1H NMR (CDCl3) δ 1.37(9H, s) , 2.20(3H, s) , 3.37(3H, s) , 3.80(3H, s), 6.1O(1H, br) , 6.78(1H, d, J = 1.8 Hz), 6.89(1H, d, J = 1.8 Hz), 7.08(1H, d, J = 8.1 Hz), 7.1O(1H, d, J = 8.1 Hz) . MS Calcd. : 419; Found: 420 (M+H) .
Example 106
3-{4-Chloro-2- [ (4-chloro-2~methoxy~6-methylphenyl) amino] -1- methyl-lH-benzimidazol-7-yl}-2, 2,4, 4-tetramethylpentan-3-ol
Figure imgf000178_0001
A n-pentane solution of tert-butyl lithium (1.46 M, 0.5 ml) was added to a solution of methyl 4-chloro-2- [ (4- chloro-2-methoxy-6-methylphenyl) amino] -1-methyl-lH- benzimidazole-7-carboxylate (100 mg, 0.23 mmol) in diethyl ether (5 ml) at -78 0C and stirred for Ih. The reaction mixture was diluted with water (5 mL) , stirred at room temperature for 0.5 h and extracted with ethyl acetate. The organics was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC. The resultant was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to give 5 mg (0.010 mmol, 5%) of the title compound, mp. 246-248 0C.
1H NMR (CDCl3) δ 1.12(18H, s), 2.20(3H, s) , 3.67(3H, s), 3.75(3H, s), 6.76(1H, s), 6.87(1H, s) , 7.09(1H, d, J = 9.0 Hz), 7.21(1H, d, J = 9.0 Hz). MS Calcd. : 477; Found: 478 (M+H) .
Example 107
3-{ 4-Chloro-2- [ (4-chloro-2-methoxy-6-methylphenyl) amino] -1- methyl-lH-benzimidazol-7-yl}-2, 4-dimethylpentan-3~ol
Figure imgf000179_0001
To a solution of methyl 4-chloro-2- [ (4-chloro-2- methoxy-6-methylphenyl) amino] -l-methyl-lH-benzimidazole~7- carboxylate (200 mg, 0.50 iranol) in diethylether (3 mL) was added dropwise a pentane solution of isopropyl lithium (0.7 M solution, 5 mL) at -780C, and stirred at 0 0C for 1 h. The reaction mixture was quenched with 6N hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC eluting with a 5-95% acetonitrile/water gradient mixture to give the title compound (153 mg, 68%) . mp. 218-219 0C.
1H NMR (CDCl3) δ 0.87 (d, J = 6.9 Hz, 6H), 0.93 (d, J = 6.9
Hz, 6H), 2.19 (s, 3H), 2.31-2.43 (m, 2H), 3.77 (s,3H), 3.87
(s, 3H), 6.76 (d, J= 2.1 Hz, IH), 6.79 (d, J= 8.4 Hz, IH), 6 . 88 ( d, J = 2 . 1 Hz , IH) , 7 . 08 (d, J = 8 . 4 Hz , IH) .
MS Calcd . : 449 ; Found: 450 (M+H) .
Example 108
4-Chloro-iV- (4~chloro-2-methoxy-6-methylphenyl) -7- (1- isopropyl-2-methylprop-l-en-l-yl) -l-methyl-lH-benzimidazol- 2-amine
Figure imgf000181_0001
A solution of 3-{ 4-chloro-2- [ (4-chloro-2-methoxy-6- methylphenyl) amino] -l-methyl-liϊ-benziπιidazol-7-yl}-2, A- dimethylpentan-3-ol (75 mg, 0.17 mmol) in trifluoroacetic acid (3 mL) was heated at 70 0C for Ih. After cooling, the reaction mixture was concentrated in vacuo, neutralized with saturated sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC eluting with a 5- 95% acetonitrile/water gradient mixture to give the title compound (58 mg, 80%). mp. 166-168 0C.
1H NMR (CDCl3) δ 0.65 (d, J = 6.6 Hz, 3H), 1.06 (d, J = 6.6 Hz, 3H), 1.40 (s, 3H), 1.82 (s,3H), 2.37 (s,3H), 3.02-3.08 (m, IH), 3.19 (s, 3H), 3.67 (s,3H), 6.70 (d, J= 8.7 Hz, IH), 6.76 (d, J = 2.1 Hz, IH), 6.90 (d, J= 2.1 Hz, IH), 7.22 (d, J = 8.7 Hz, IH) . MS Calcd. : 431; Found: 432 (M+H) . Example 109
4-Chloro-N- (4-chloro-2-methoxy-6-methylphenyl) -7- [ (IZ) -1- ethylprop-1-en-l-yl] -1-methyl-lH-benzimidazol-2-amine
Figure imgf000182_0001
Example 109 was prepared in the similar method described in Example 108. mp. 166-168 0C.
1H NMR (CDCl3) δ 0.96 (t, J = 7.5 Hz, 3H), 1.82 (d, J= 6.6 Hz, 3H), 2.19 (s, 3H), 2.32-2.57 (m, 2H), 3.58 (s, 3H), 3.80 (s, 3H), 5.52 (q, J= 6.6 Hz, IH), 6.04 (s, IH), 6.70 (d, J= 8.1 Hz, IH), 6.77 (d, J= 2.1 Hz, IH), 6.88 (d, J= 2.1 Hz, IH), 7.05 (d, J= 8.1 Hz, IH). MS Calcd. : 403; Found: 404 (M+H) .
Example 110-124 were prepared in the similar method described in Example 77.
Example 110
4-ChIOrO-AF- (2, 4-dichloro-6-methylphenyl) -7- (1-ethylpropyl) l-methyl-liT-benzimidazol-2-amine
Figure imgf000183_0001
mp 237-238 0C.
1H NMR (CDCl3) δ 0.85 (t, J = 7.2 Hz, 6H), 1.60-1.85 (m, 4H), 2.18 (s, 3H), 3.15-3.25 (m, IH), 3.71 (s, 3H), 6.00- 6.05 (m, IH), 6.87 (d, J = 8.4 Hz, IH), 7.05 (m, IH), 7.16 (d, J= 2.4 Hz, IH), 7.31(d, J= 2.4 Hz, IH). MS Calcd. : 409; Found: 410 (M+H) , 412.
Example 111 4-Chloro-iV- (2, 4-dimethoxy-6-methylpyridin-3-yl) -7- (1- ethylpropyl) -1-methyl-lH-benzimidazol-2-amine
Figure imgf000183_0002
1H NMR (CDCl3) δ 0.81 (t, J = 7.5 Hz, 6H), 1.60-1.80 (m, 4H), 2.43 (s, 3H), 3.15 (m, IH), 3.66 (s, 3H), 3.78 (s, 3H), 3.88 (s, 3H), 6.45 (s, IH), 6.85 (d, J = 8.1 Hz, IH), 7.11 (d, J = 8.1 Hz, IH), 7.25 (m, IH). MS Calcd.: 402; Found: 403 (M+H) , 405.
Example 112
4-Chloro-W- [2-methoxy-5- (trifluoromethyl) phenyl] -1-methyl-
7- (1-propylbutyl) -lH-benzimidazol-2-amine
Figure imgf000184_0001
mp 178-180 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.5 Hz, 6H), 1.10-1.30 (m,
4H), 1.55-1.80 (m, 4H), 3.30-3.45 (m, IH), 3.75 (s, 3H),
3.99 (s, 3H), 6.90-7.00 (m, 3H), 7.20-7.30 (m. 2H), 8.24 (s,
IH) .
MS Calcd.: 453; Found: 454 (M+H).
Example 113
4-Chloro-l\J- [2, 4-dichloro-5- (trifluoromethyl) phenyl] -1- methyl-7- (1-propylbutyl) -lH-benzimidazol-2-amine
Figure imgf000185_0001
mp 206-208 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.5 Hz, 6H), 1.10-1.30 (in,
4H), 1.55-1.80 (m, 4H), 3.30-3.45 (m, IH), 3.86 (s, 3H),
6.89 (s, IH), 7.00 (d, J = 8.4 Hz, IH), 7.23 (d, J = 8.4 Hz,
IH), 7.56 (s, IH), 8.25-8.65 (br, IH).
MS Calcd. : 493; Found: 494 (M+H) .
Example 114
4-Chloro-N- (4-chloro-2, 6-dimethylphenyl) -l-methyl-7- (1- propylbutyl) -lH-benzimidazol-2-amine
Figure imgf000185_0002
mp 230-232 0C.
1H NMR (CDCl3) δ 0.85 (t, J = 7.5 Hz, 6H), 1.10-1.30 (m, 4H), 1.55-1.80 (m, 4H), 2.10-2.20 (m, 6H), 3.20-3.90 (m, 4H), 6.00 (s, IH), 6.85 (d, J = 8.4 Hz, IH), 7.00-7.20 (m,
3H) .
MS Calcd. : 417; Found: 418 (M+H) .
Example 115
N- (4-Bromo-2, 6-dimethylphenyl) -4-chloro-l-methyl-7- (1- propylbutyl) -lH-benzimidazol-2-amine
Figure imgf000186_0001
mp 234-236 0C.
1H NMR (CDCl3) δ 0.85 (t, J = 7.5 Hz, 6H), 1.10-1.30 (m,
4H), 1.55-1.80 (m, 4H), 2.10-2.20 (m, 6H), 3.15-3.80 (m,
4H), 5.90-6.20 (br, IH), 6.85 (d, J = 8.4 Hz, IH), 7.00-
7.20 (m, IH), 7.20-7.25 (m, 2H).
MS Calcd.: 463; Found: 464 (M+H).
Example 116
5-{ [4-Chloro-l-methyl-7- (1-propylbutyl) -lH-benzimidazol-2- yl] amino }-4-methylpyridin-2 [IH) -one
Figure imgf000187_0001
mp 237-239 0C.
1H NMR (CDCl3) δ 0.80-0.95 (m, 6H), 1.00-1.80 (m, 8H), 2.10-2.30 (m, 3H), 3.20-4.85 (m, 4H), 5.55 (s, IH), 6.30- 7.70 (m, 4H), 8.35-8.60 (br, IH). MS Calcd. : 386; Found: 387 (M+H) .
Example 117
4-Chloro-l-methyl-7- (1-propylbutyl) -N- (5, 6,7,8- tetrahydronaphthalen-1-yl) -lH-benzimidazol-2-amine
Figure imgf000187_0002
mp 236-238 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.5 Hz, 6H), 1.10-1.30 (m, 4H), 1.60-1.95 (m, 8H), 2.66 (t, J = 6.3 Hz, 2H), 2.81 (t, J = 6.3 Hz, 2H), 3.20-3.40 (m, IH), 3.60 (s, 3H), 6.11 (s, IH), 6.69 (d, J = 7.8 Hz, IH), 6.81 (d, J = 7.8 Hz, IH), 6.96 (d, J = 8.4 Hz, IH), 7.03 (t, J = 7.8 Hz, IH), 7.20 (d,
J = 8.4 Hz, IH) .
MS Calcd. : 409; Found: 410 (M+H) .
Example 118
4-Chloro-2- (5-methoxy-2, 3-dihydro-lH-indol-l-yl) -1-methyl-
7- (1-propylbutyl) -lH-benzimidazole
Figure imgf000188_0001
1H NMR (CDCl3) δ 0.89 (t, J = 7.5 Hz, 6H), 1.15-1.30 (m, 4H) , 1.60-1.80 (m, 4H), 3.17 (t, J = 8.1 Hz, 2H), 3.30-3.50 (m, IH) , 3.76 (s, 6H), 4.20 (t, J = 8.1 Hz, 2H), 6.45-7.30 (m, 5H) . MS Calcd. : 411; Found: 412 (M+H) .
Example 119
1- [4-Chloro-l-methyl-7- (1-propylbutyl) -liT-benzimidazol-2- yl] -6-methoxy-l, 2, 3, 4-tetrahydroquinoline
Figure imgf000189_0001
1H NMR (CDCl3) δ 0.86 (t, J = 7.2 Hz, 6H), 1.15-1.30 (m, 4H), 1.55-1.75 (m, 4H), 2.05-2.20 (m, 2H), 2.88 (t, J = 6.6 Hz, 2H), 3.30-3.40 (m, IH), 3.58 (s, 3H), 3.75 (s, 3H), 3.88 (t, J = 6.6 Hz, 2H), 6.34 (d, J = 8.5 Hz, IH), 6.57 (dd, J = 8.5, 3.0Hz, IH), 6.69 (d, J = 3.0 Hz, IH), 6.97 (d, J = 8.1 Hz, IH) , 7.19 (d, J = 8.1 Hz, IH) . MS Calcd. : 425; Found: 426 (M+H) .
Example 120
1- [4-Chloro-l-methyl-7- (1-propylbutyl) -lH-benz±midazol-2- yl] -7-methoxy-2, 3, 4, 5-tetrahydro-liϊ-l-benzazepine
Figure imgf000189_0002
1H NMR (CDCl3) δ 0.80 (t, J = 7.2 Hz, 6H), 1.05-1.20 (m, 4H), 1.50-1.90 (m, 8H), 2.80-3.00 (m, 2H), 3.10-3.25 (m, IH), 3.19 (s, 3H), 3.79 (s, 3H), 3.80-4.30 (br, 2H), 6.95 (m, 2H), 6.79 (d, J = 2.4 Hz, IH), 6.87 (d, J = 8.4 Hz, IH), 7.14 (d, J= 8.4 Hz, IH) . MS Calcd. : 439; Found: 440 (M+H) .
Example 121
5-Bromo-IV- (4-chloro-2-methoxy-6-methylphenyl) -7- (1- ethylpropyl) -l-methyl-lH-benzimidazol-2-amine
Figure imgf000190_0001
mp. 276-278 0C.
1H NMR (CDCl3) δ 0.86 (t, J= 7.5 Hz, 3H), 1.66-1.84 (m,
4H), 2.01 (s, 3H), 2.14 (s, 3H), 3.13-3.21 (m, IH), 3.82 (s,
3H), 3.83 (s, 3H), 5.80-6.20 (br, IH), 6.80 (d, J= 2.4 Hz,
IH), 6.89 (d, J= 2.4 Hz, IH), 7.05 (s, IH), 7.47 (s, IH).
MS Calcd.: 493; Found: 494 (M+H).
Example 122
5-Chloro-4-{ [4-chloro-l-methyl-7- (1-propylbutyl) -IH- benzimidazol-2-yl] amino} -2- (trifluoromethyl) phenol
Figure imgf000191_0001
mp 197-199 0C.
1H NMR (CDCl3) δ 0.87 (t, J = 7.2 Hz, 6H), 1.15-1.35 (m,
4H), 1.60-1.80 (m, 5H), 3.30-3.40 (m, IH), 3.88 (s, 3H),
6.97 (d, J = 8.4 Hz, IH), 7.13 (s, IH), 7.19 (d, J = 8.4 Hz,
IH) , 7.20-7.30 (m, 2H) .
MS Calcd.: 473; Found: 474 (M+H) .
Example 123 4-Chloro-N-[2,4-dimethoxy-5- (trifluoromethyl) phenyl] -1- methyl-7- (1-propylbutyl) -l.H-benzimidazol-2-am.ine
Figure imgf000191_0002
mp 196-198 0C.
1H NMR (CDCl3) δ 0.85 (t, J = 7.2 Hz, 6H), 1.15-1.30 (m,
4H), 1.60-1.80 (m, 4H), 3.30-3.40 (m, IH), 3.78 (s, 3H), 3.88 (s, 3H), 3.99 (s, 3H), 6.57 (s, IH), 6.66 (s, IH), 6.92 (d, J = 8.4 Hz, IH), 7.17 (d, J = 8.4 Hz, IH), 8.22 (s, IH) . MS Calcd. : 483; Found: 484 (M+H) .
Example 124-144 were prepared in the similar method described in Example 97.
Example 124 4-Chloro-2- (mesityloxy) -l-methyl-7- (1-propylbutyl) -IH- benzimidazole
Figure imgf000192_0001
mp 165-167 0C.
1H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 6H), 1.20-1.40 (m, 4H), 1.60-1.80 (m, 4H), 2.17 (s, 6H), 2.30 (s, 3H), 3.30- 3.45 (m, IH), 3.96 (s, 3H), 6.85-6.95 (m, 3H), 7.10 (d, J = 8.1 Hz, IH) . MS Calcd.: 398; Found: 399 (M+H).
Example 125 4-Chloro-2- (4-chloro-2, β-dimethylphenoxy) -7- (1- ethylpropyl ) -1-methyl-lH-benzimidazole
Figure imgf000193_0001
mp 168-169 0C.
1H NMR (CDCl3) δ 0.87 (t, J = 7.5 Hz, 6H), 1.60-1.85 (m, 4H), 2.81 (s, 6H), 3.20-3.30 (m, IH), 3.98 (s, 3H), 6.92 (d, J= 8.1 Hz, IH), 7.10 (s, 2H), 7.13 (d, J= 8.1 Hz, IH). MS Calcd. : 390; Found: 391 (M+H) , 393.
Example 126
4-Chloro-2- (2, 6-dimethoxy-4-methylphenoxy) -7- (1- ethylpropyl ) -1-methyl-lH-benzimidazole
Figure imgf000193_0002
mp 161-162 0C.
1H NMR (CDCl3) δ 0.84 (t, J = 7.5 Hz, 6H) , 1.60-1.85 (m, 4H), 2.36 (s, 3H), 3.20-3.30 (m, IH), 3.77 (s, 6H), 3.95 (s, 3H), 6.47 (s, 2H), 6.89 (d, J = 8.4 Hz, IH), 7.10 (d, J = 8.4 Hz, IH) . MS Calcd. : 402; Found: 403 (M+H) , 405.
Example 127
4-Chloro-2- (2, 4-dichlorophenoxy) -1-methyl-7- (1- propylbutyl) -lH-benzimidazole
Figure imgf000194_0001
mp 87-88 0C.
1H NMR (CDCl3) δ 0.87 (t, J = 7.2 Hz, 6H), 1.10-1.40 (m, 4H), 1.60-1.90 (m, 4H), 3.30-3.45 (m, IH), 3.97 (s, 3H), 6.98 (d, J = 8.4 Hz, IH), 7.17 (d, J = 8.4 Hz, IH), 7.32 (dd, J = 8.8, 2.4 Hz, IH), 7.47 (d, J = 2.4 Hz, IH), 7.74 (d, J = 8.8 Hz, IH) .
MS Calcd.: 424; Found: 425 (M+H).
Example 128
2- (4-Bromo-2-chlorophenoxy) -4-chloro-l-methyl-7- (1- propylbutyl) -lH-benzimidazole 1,94
Figure imgf000195_0001
mp 97-99 0C.
1H NMR (CDCl3) δ 0.87 (t, J = 7.2 Hz, 6H) , 1.10-1.40 (m,
4H) , 1.60-1.90 (m, 4H) , 3.30-3.45 (m, IH) , 3.97 (s, 3H) , 6.98 (d, J = 8.4 Hz, IH) , 7.18 (d, J = 8.4 Hz, IH) , 7.47 (dd, J = 8.8, 2.4 Hz, IH) , 7.63 (d, J = 2.4 Hz, IH) , 7.70 (d, J = 8.8 Hz, IH) .
MS Calcd. : 470; Found: 471 (M+H) .
Example 129
4-Chloro-2- (2, 4-dichloro-6-methylphenoxy) -l-methyl-7- (1- propylbutyl) -lfl-benzimidazole
Figure imgf000195_0002
mp 148-150 0C.
1H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 6H), 1.10-1.40 (m, 4H), 1.60-1.80 (m, 4H), 2.31 (s, 3H), 3.30-3.45 (m, IH),
3.98 (s, 3H), 6.95 (d, J = 8.4 Hz, IH), 7.14 (d, J = 8.4 Hz,
IH) , 7.20 (d, J = 2.4 Hz, IH) , 7.31 (d, J = 2.4 Hz, IH) . MS Calcd. : 438; Found: 439 (M+H) .
Example 130
4-Chloro-2- (4-chloro-2, 6-dimethylphenoxy) -l-methyl-7- (1- propylbutyl) -lH-benzimidazole
Figure imgf000196_0001
mp 160-162 0C.
1H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 6H), 1.15-1.40 (m, 4H), 1.60-1.80 (m, 4H), 2.19 (s, 6H), 3.30-3.45 (m, IH), 3.97 (s, 3H), 6.94 (d, J = 8.4 Hz, IH), 7.10-7.20 (m, 3H). MS Calcd.: 418; Found: 419 (M+H).
Example 131
2- ( 4-Bromo-2 , 6-dimethylphenoxy) -4-chloro-l-methyl-7- ( 1- propylbutyl ) -liϊ-benzimidazole
Figure imgf000197_0001
mp 155-157 0C.
1H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 6H), 1.20-1.40 (m, 4H), 1.60-1.80 (m, 4H), 2.19 (s, 6H), 3.30-3.45 (m, IH), 3.97 (s, 3H), 6.94 (d, J = 8.4 Hz, IH), 7.13 (d, J = 8.4 Hz, IH) , 7.20-7.30 (m, 2H) . MS Calcd.: 464; Found: 465 (M+H) .
Example 132 4-Chloro-l-methyl-7- (1-propylbutyl) -2- (2,4,6- trichlorophenoxy) -lfl-benzimidazole
Figure imgf000197_0002
mp 148-150 0C.
1H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 6H), 1.20-1.40 (m, 4H), 1.60-1.80 (m, 4H) , 3.30-3.45 (m, IH), 3.99 (s, 3H) , 6.97 (d, J = 8.4 Hz, IH) , 7.15 (d, J = 8.4 Hz, IH) , 7.26 (s,
IH) , 7.43 (s, IH) .
MS Calcd. : 458; Found: 459 (M+H) .
Example 133
4-Chloro-2- (2, 6-dimethoxy-4-methylphenoxy) -l-methyl-7- (1- propylbutyl) -Iff-benzimidazole
Figure imgf000198_0001
mp 203-205 0C.
1H NMR (CDCl3) δ 0.87 (t, J = 7.2 Hz, 6H) , 1.15-1.40 (m,
4H) , 1.60-1.80 (m, 4H) , 2.36 (s, 3H) , 3.30-3.45 (m, IH) ,
3.77 (s, 6H) , 3.95 (s, 3H) , 6.47 (s, 2H) , 6.90 (d, J = 8.4
Hz, IH) , 7.10 (d, J = 8.4 Hz, IH) .
MS Calcd. : 430; Found: 431 (M+H) .
Example 134
9-{ [4-Chloro-l-methyl-7- (1-propylbutyl) -lH-benzimidazol-2- yl] oxy}-l, 2,5, 6-tetrahydro-4if-pyrrolo [3,2, 1-ij] quinolin-4- one
Figure imgf000199_0001
mp 150-152 0C.
1H NMR (CDCl3) δ 0.88 (t, J = 7.2 Hz, 6H), 1.15-1.40 (m,
4H), 1.60-1.80 (m, 4H), 2.70 (t, J = 7.8 Hz, 2H), 2.98 (t,
J = 7.8 Hz, 2H), 3.17 (t, J = 8.7 Hz, 2H), 3.30-3.45 (m,
IH), 3.92 (s, 3H), 4.10 (t, J = 8.7 Hz, 2H), 6.90-7.05 (m, 3H) , 7.17 (d, J = 8.1 Hz, IH) . MS Calcd.: 451; Found: 452 (M+H) .
Example 135
2- (2-Bromo-4-chlorophenoxy) -4-chloro-7- (1-ethylpropyl) -1- methyl-lH-benzimidazole
Figure imgf000199_0002
mp 114-115 0C. 1H NMR (CDCl3) δ 0.85 (t, J = 7.2 Hz, 6H), 1.60-1.85 (m, 4H), 3.15-3.30 (m, IH), 3.98 (s, 3H), 6.96 (d, J = 8.4 Hz, IH), 7.18 (d, J = 8.4 Hz, IH), 7.37 (dd, J = 2.4, 8.7 Hz, IH), 7.63 (d, J= 2.4 Hz, IH), 7.76 (d, J= 7.8 Hz, IH) MS Calcd. : 440; Found: 441 (M+H) , 443, 445.
Example 136
5-Bromo-2- (4-chloro-2, 6-dimethylphenoxy) -7- (1-ethylpropyl) -
1-methyl-liϊ-benzimidazole
Figure imgf000200_0001
mp 214-216 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.5 Hz, 6H), 1.65-1.83(m, 4H),
2.18(s, 6H), 3.18-3.26 (m, IH), 3.95 (s, 3H), 7.08-7.10 (m,
3H), 7.46 (d, J= 2.1 Hz, IH).
MS Calcd.: 433; Found: 434 (M+H).
Example 137
2- (4-Bromo-2, 6-dimethylphenoxy) -4-chloro-7- (1-ethylpropyl) -
1-methyl-liϊ-benzimidazole
Figure imgf000201_0001
mp 197-198 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.2 Hz, 6H), 1.75-1.82 (m, 4H), 2.18 (s, 6H), 3.19-3.25 (m, IH), 3.97 (s, 3H), 6.91 (d, J = 8.1 Hz, IH) , 7.12 (d, J= 8.1 Hz, IH) , 7.24 (s, 2H) . MS Calcd. : 434; Found: 435 (M+H) .
Example 138
4-Chloro-7- (1-ethylpropyl) -l-methyl-2- (2,4, 6- trichlorophenoxy) -lH-benzimidazole
Figure imgf000201_0002
mp 155-157 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.2 Hz, 6H), 1.65-1.77 (m, 4H), 3.18-3.25 (m, IH), 3.99 (s, 3H), 6.93 (d, J = 8.4 Hz, IH), 7.15 (d, J = 8.4 Hz, IH), 7.42 (s, 2H). MS Calcd. : 430; Found: 431 (M+H) .
Example 139
4-Chloro-7- (1-ethylpropyl) -2- [ (4-πιethoxy-2, 6- dimethylpyridin-3-yl) oxy] -1-methyl-lH-benzimidazole
Figure imgf000202_0001
mp 183-184 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.2 Hz, 6H), 1.68-1.82 (m,
4H), 2.45 (s, 3H), 2.52 (s, 3H), 3.20-3.26 (m, IH), 3.76 (s,
3H), 3.96 (s, 3H), 6.66 (s, IH), 6.91 (d, J = 8.4 Hz, IH),
7.12 (d, J = 8.4 Hz, IH) .
MS Calcd.: 387; Found: 388 (M+H).
Example 140 4-Chloro-2- [2, 6-dichloro-4- (trifluoromethoxy) phenoxy] -7- (1- ethylpropyl) -1-methyl-lH-benzimidazole
Figure imgf000203_0001
mp 145-147 0C.
1H NMR (CDCl3) δ 0.85 (t, J = 7.2 Hz, 6H), 1.68-1.82 (m,
4H), 3.20-3.24 (m, IH), 4.00 (s, 3H), 6.95 (d, J = 8.4 Hz,
IH), 7.16 (d, J = 8.4 Hz, IH), 7.32 (s, 2H).
MS Calcd. : 480; Found: 481 (M+H) .
Example 141
3-{ [4-Chloro-7- (1-ethylpropyl) -l-methyl-lH-benzimidazol-2- yl] oxy}-N,N, 2, 6-tetramethylpyridin-4-amine
Figure imgf000203_0002
mp 175-177 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.2 Hz, 6H), 1.70-1.82 (m, 4H), 2.27 (s, 3H), 2.46 (s, 3H), 2.92 (s, 6H), 3.20-3.24 (m, IH), 3.97 (s, 3H), 6.49 (s, IH), 6.91 (d, J = 8.1 Hz, IH), 7.12 (d, J = 8.1 Hz, IH) .
MS Calcd. : 400; Found: 401 (M+H) .
Example 142
3, 5-Dichloro-4-{ [4-chloro-7- (1-ethylpropyl) -1-methyl-liϊ- benzimidazol-2-yl] oxy}-N, N-dimethylaniline
Figure imgf000204_0001
mp 200-202 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.2 Hz, 6H), 1.68-1.81 (m, 4H), 2.97 (s, 6H), 3.20-3.26 (m, IH), 3.98 (s, 3H), 6.62 (s, 2H) , 6.91 (d, J = 8.4 Hz, IH) , 7.12 (d, J = 8.4 Hz, IH) . MS Calcd. : 439; Found: 440 (M+H) .
Example 143 3, 5-Dichloro-2-{ [4-chloro-7- (1-ethylpropyl) -1 -methyl -IH- benzimidazol-2-yl] oxy}--V,-V-dimethylbenzamide
Figure imgf000205_0001
mp 141-143 0C.
1H NMR (CDCl3) δ 0.84 (t, J = 7.2 Hz, 6H), 1.67-1.81 (m,
4H), 2.63 (s, 3H), 3.08 (s, 3H), 3.20-3.23 (m, IH), 3.95 (s,
3H), 6.95 (d, J = 8.4 Hz, IH), 7.14 (d, J = 8.4 Hz, IH),
7.18 (d, J = 2.4 Hz, IH) , 7.51 (d, J = 2.4 Hz, IH) .
MS Calcd. : 467; Found: 468 (M+H) .
Example 144 4-Chloro-2- (4-chloro-2-methoxy-6-methylphenoxy) -7- (1-ethyl-
-propyl) -1-methyl-lH-benzimidazole
Figure imgf000205_0002
mp 165-167 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.2 Hz, 6H), 1.75-1.82 (m, 4H), 2.27 (s, 3H), 3.20-3.24 (m, IH), 3.71 (s, 3H), 3.95 (s, 3H), 6.81 (d, J = 2.4 Hz, IH), 6.86 (d, J = 2.4 Hz, IH), 6.90 (d, J - 8.1 Hz, IH) , 7.11 (d, J = 8.1 Hz, IH) . MS Calcd. : 406; Found: 407 (M+H) .
Example 145
2- (2, 4-Dichloro-6-methylphenoxy) -7- (1-ethylpropyl) -A- methoxy-1-methyl-lH-benzimidazole
Figure imgf000206_0001
A mixture of 2, 4-dichloro-7- (1-ethylpropyl) -1-methyl- liϊ-benzimidazole (200 mg, 0.750 mmol) , 2, 4-dichloro-6- methylphenol (398 mg, 2.25 mmol), potassium carbonate (311 mg, 2.25 mmol) and l-methyl-2-pyrrolidone (0.5 ml) was stirred at 120 0C for 12 h under nitrogen atmosphere. The mixture was diluted with water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo.
The residue was purified by chromatography on silica gel with a 2-30% ethyl acetate/n-hexane gradient mixture and crystallized from methanol to afford the title compound as colorless crystals (109 mg, 36%) . mp 130-131 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.5 Hz, 6H), 1.60-1.85 (m,
4H), 2.30 (s, 3H), 3.15-3.25 (m, IH), 3.89 (s, 3H), 3.97 (s,
3H), 6.64 (d, J = 8.4 Hz, IH), 6.92 (d, J = 8.4 Hz, IH),
7.15 (d, J= 1.8 Hz, IH), 7.25 (d, J = 1.8 Hz, IH).
MS Calcd. : 406; Found: 407 (M+H) , 409.
Example 146
2- (2-Bromo-4-chlorophenoxy) -7- (1-ethylpropyl) -4-methoxy-l- methyl-lH-benzimidazole
Figure imgf000207_0001
Example 146 was prepared in the similar method described in Example 145. mp 106-107 0C.
1H NMR (CDCl3) δ 0.85 (t, J = 7.2 Hz, 6H), 1.50-1.85 (m, 4H), 3.10-3.25 (m, IH), 3.92 (s, 3H), 3.97 (s, 3H), 6.66 (d, J = 8.7 Hz, IH), 6.95 (d, J = 8.7 Hz, IH), 7.32 (dd, J = 2.4, 7.8 Hz, IH), 7.59 (d, J = 2.4 Hz, IH), 7.66 (d, J = 7.8 Hz, IH) MS Calcd.: 436; Found: 437 (M+H), 439, 441. Example 147
2- (2~Bromo~4-chlorophenoxy) -7- (1-ethylpropyl) -1-methyl-IH- benzimidazol-4-ol
Figure imgf000208_0001
To a solution of 2- (2-bromo-4-chlorophenoxy) -7- (1- ethylpropyl) -4-methoxy-l-methyl-l.H-benzimidazole (80 mg, 0.18 mmol) in dichloromethane (2 mL) was added dropwise a dichloromethane solution (IM, 2 mL) of boron tribromide at 0 0C, and stirred at room temperature for 1 h. The reaction mixture was cooled at 0 0C, quenched with water, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with isopropyl ether and hexane
(1:1) to give the title compound (67 mg, 86%) . mp 175-177 0C.
1H NMR (CDCl3) δ 0.85 (t, J = 7.5 Hz, 6H), 1.66-1.82 (m, 4H), 3.08-3.18 (m, IH), 3.96 (s, 3H), 6.00-6.40 (br, IH), 6.71 (d, J = 8.1 Hz, IH), 6.92 (d, J= 8.1 Hz, IH), 7.35
(dd, J= 2.4, 8.7 Hz, IH), 7.54 (d, J= 8.7 Hz, IH), 7.65
(d, J = 2.4 Hz, IH) . MS Calcd. : 422; Found: 423 (M+H) .
Example 148
2- ( 2-Bromo-4-chlorophenoxy) -4- (dif luoromethoxy) -7- ( 1- ethylpropyl ) -1-methyl-liϊ-benzimidazole
Figure imgf000209_0001
To a solution of aqueous potassium hydroxide (50% solution) was added dropwise a solution of 2- (2-bromo-4- chlorophenoxy) -7- (1-ethylpropyl) -l-methyl-lH-benzimidazol- 4-ol in dichloromethane (2 mL) at 0 0C. After stirring for 20 min, to the reaction mixture was bubbled chlorodifluoromethane at 0 0C for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC eluting with a 5-95% acetonitrile/water gradient mixture to give the title compound as an oil (24 mg, 43%) .
1H NMR (CDCl3) δ 0.85 (t, J= 7.2 Hz, 6H), 1.64-1.87 (m, 4H), 3.17-3.27 (m, IH), 3.99 (s, 3H), 6.94-7.00 (m, 2H), 7.09 (t, J = 76 Hz, IH)-, 7.38 (dd, J = 2.4, 8.7 Hz, IH), 7.65 (d, J = 2.4 Hz, IH), 7.68 (d, J= 8.7 Hz, IH). MS Calcd. : 472; Found: 473 (M+H) .
Example 149
2- (2-Bromo-4-chlorophenoxy) -7- (1-ethylpropyl) -4- (2-furyl) - 1-methyl-lH-benzimidazole
Figure imgf000210_0001
7- (1-Ethylpropyl) -4- (2-furyl) -1-methyl-l, 3-dihydro-2#- benzimidazole-2-one
To a mixture of 4-bromo-7- (1-ethylpropyl) -1-methyl- 1, 3-dihydro-2H-benzimidazole-2-one (150 nag, 0.505 mmol) and 2- (tributhylstanyl) furan (361 mg, 1.01 mmol) in toluene (2 ml) was added tetrakis (triphenylphosphine) palladium(O) (117 mg, 0.101 mmol) and the mixture was refluxed for 3 h. After cooling, the solvent was evaporated in vacuo and the residue was diluted with ethyl acetate. The ethyl acetate solution was washed with aqueous saturated sodium bicarbonate and brine, dried over magnesium sulfate filtered and concentrated under vacuum. The residue was purified by preparative HPLC eluting with a 5-95% acetonitrile/water gradient mixture to give 81 mg (0.285 mmol, 56%) of the title compound.
1H NMR (CDCl3) δ 0.83 (t, J = 7.5 Hz, 6H), 1.60-1.80 (m, 4H), 3.10-3.25 (m, IH), 3.66 (s, 3H), 6.52 (dd, J = 2.1, 3.3 Hz, IH), 6.68 (d, J = 3.3 Hz, IH), 6.95 (d, J= 8.1 Hz, IH), 7.25 (d, J = 8.4 Hz, IH), 7.51 (d, J = 2.1 Hz, IH), 8.74 (s, IH) . MS Calcd. : 284; Found: 285 (M+H) .
2-Chloro-7- (1-ethylpropyl) -4- (2-furyl) -l-methyl-lH- benzimidazole
A mixture of 7- (1-ethylpropyl) -4- (2-furyl) -1-methyl- 1, 3-dihydro-2iϊ-benzimidazole-2-one (79 mg, 0.278 mmol) in phosphorous oxychloride (0.78 ml, 8.33 mmol) was stirred at 120 0C for 2 h. The reaction was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with aqueous saturated sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel with a 1-30% ethyl acetate/n-hexane gradient mixture to give 44 mg (0.145 mmol, 52%) of the title compound. 1H NMR (CDCl3) δ 0.82 (t, J = 7.5 Hz, 6H), 1.65-1.85 (m, 4H), 3.20-3.35 (m, IH), 4.01 (s, 3H), 6.54 (dd, J = 1.8, 3 . 3 Hz , IH) , 7 . 15 ( d, J = 7 . 8 Hz , IH) , 7 . 40-7 . 50 (m, 2H) ,
7 . 67 (d, J = 7 . 8 Hz , IH) .
MS Calcd. : 302; Found: 303 (M+H) , 305.
2- (2-Bromo-4-chlorophenoxy) -7- (1-ethylpropyl) -4- (2-furyl) - 1-methyl-lβ-benzimidazole
A mixture of 2-chloro-7- (1-ethylpropyl) -4- (2-furyl) -1- methyl-lH-benzimidazole (42 mg, 0.139 mmol) , 2-bromo-4- chlorophenol (87 mg, 0.417 mmol)and potassium carbonate (58 mg, 0.417 mmol) was heated at 120 0C for 18 h under an argon atmosphere. The mixture was diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 1- 20% ethyl acetate/n-hexane gradient mixture to give 45 mg (0.0950 mmol, 68%) of the title compound) as a colorless crystal, mp 159-162 0C. 1H NMR (CDCl3) δ 0.86 (t, J = 7.5 Hz, 6H), 1.70-1.85 (m, 4H), 3.20-3.35 (m, IH), 4.01 (s, 3H), 6.47 (dd, J = 1.5, 3.3 Hz, IH), 7.09 (d, J = 8.1 Hz, IH), 7.20 (d, J = 3.3Hz, IH), 7.35-7.45 (m, 2H), 7.64 (d, J = 8.1 Hz, IH), 7.66 (s, IH) , 7.85 (d, J = 9.0 Hz, IH) . MS Calcd.: 472; Found: 473 (M+H), 475. Example 150
2- (2-Bromo-4-chlorophenoxy) -7- (1-ethylpropyl) -1-methyl-IH- benzimidazole-4-carbonitrile
Figure imgf000213_0001
7- (1-Ethylpropyl) -l-methyl-2-oxo-2, 3-dihydro-lE- benzimidazole-4-carbonitrile
A mixture of 4-bromo-7- (1-ethylpropyl) -1-methyl-l, 3- dihydro-2H-benzimidazol-2-one (300 mg, 1.01 mmol) and copper cyanide (116 mg, 1.30 mmol) in l-methyl-2- pyrrolidone (3 mL) was irradiated by microwave (20Ow) at 150 °C for 1 h. After cooling, to the reaction mixture was diluted with saturated sodium bicarbonate, and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with 50% diisopropyl ether/n-hexane to give the title compound (209 mg, 86%) . 1H NMR (CDCl3) δ 0.81 (t, J= 7.8 Hz, 6H), 1.57-1.83 (m, 4H), 3.18-3.27 (m, IH), 3.67 (s, 3H), 6.98 (d, J= 8.4 Hz, IH), 7.27 (d, J= 8.4 Hz, IH), 9.51 (s, IH). S Calcd. : 243; Found: 244 (M+H) .
2-Chloro-7- (1-ethylpropyl) -l-methyl-lE-benzimidazole-4- carbonitrile
A mixture of 7- (1-ethylpropyl) -1-methyl-l, 3-dihydro- 2H-benzimidazol-2-one (3.80 g, 15.6 mmol) and phosphorus oxychloride (5OmL) was heated at 120 0C for 6 h. After cooling, the reaction mixture was poured into a crushed ice and stirred for 30 min, neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was washed with diisopropyl ether to give the title compound (3.76 g, 92%). 1H NMR (CDCl3) δ 0.83 (t, J = 7.5 Hz, 6H), 1.65-1.91 (m, 4H), 3.27-3.36 (m, IH), 4.05 (s, 3H), 7.18 (d, J = 8.4 Hz, IH), 7.58 (d, J= 8.4 Hz, IH). MS Calcd. : 261; Found: 262 (M+H) .
2- (2-Bromo-4-chlorophenoxy) -7- (1-ethylpropyl) -1-methyl-lff- benzimidazole-4-carbonitrile
A mixture of 2-chloro-7- (1-ethylpropyl) -1-methyl-liϊ- benzimidazole-4-carbonitrile (250 mg, 0.957 mmol), 2-bromo- 4-chlorophenol (595 mg, 2.87 mmol), potassium carbonate (397 mg, 2.87 mmol) and l-methyl-2-pyrrolidone (0.5 ml) was stirred at 120 0C for 12 h under nitrogen atmosphere. The mixture was diluted with water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by chromatography on silica gel with a 2-30% ethyl acetate/n-hexane gradient mixture and crystallized from methanol to afford the title compound as colorless crystals (134 mg, 32%) . mp 136-137 0C.
1H NMR (CDCl3) δ 0.85 (t, J = 7.5 Hz, 6H), 1.65-1.90 (m, 4H), 3.25-3.35 (m, IH), 4.02 (s, 3H), 7.07 (d, J = 8.1 Hz, IH), 7.39 (dd, J = 2,4, 8.7 Hz, IH), 7.47 (d, J = 8.1 Hz, IH), 7.65 (d, J= 2.4 Hz, IH), 7.81 (d, J= 7.8 Hz, IH) MS Calcd. : 431; Found: 432 (M+H) , 434.
Example 151
2- (2, 4-Dichloro-6-methylphenoxy) -7- (1-ethylpropyl) -1- methyl-lH-benzimidazole-4-carbonitrile
Figure imgf000215_0001
Example 151 was ■ prepared in the similar method described in Example 150. rap 192-192 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.2 Hz, 6H), 1.65-1.90 (m,
4H) , 2.31 (s, 3H) , 3.20-3.35 (m, IH) , 4.01 (s, 3H), 7.04 (d,
J = 8.4 Hz, IH), 7.22 (d, J = 2.4 Hz, IH), 7.32 (d, J = 2.4
Hz, IH), 7.43 (d, J = 8.4 Hz, IH) .
MS Calcd. : 401; Found: 402 (M+H) , 404.
Example 152
2- [ (4-Chloro-2-methoxy-6-methylphenyl) amino] -7- (1- ethylpropyl) -l-methyl-lff-benzimidazole-4-carbonitrile
Figure imgf000216_0001
A mixture of 2-chloro-7- (1-ethylpropyl) -l-methyl-lH- benzimidazole-4-carbonitrile (1.00 g, 3.82 mmol) , 4-chloro- 2-methoxy-6-methylaniline (1.97 g, 11.50 mmol) and 1- methyl-2-pyrrolidone (0.5 ml) was heated at 130 0C for 48 h. After cooling, the reaction mixture was diluted with aqueous saturated sodium hydrogen carbonate. The mixture was extracted with ethyl acetate, dried over magnesium sulfate and concentrated In vacuo. The residue was purified by column chromatography on silica gel to give the title compound as a white powder (670 mg, 44%) .
1H NMR (CDCl3) δ 0.83 (t, J = 7.5 Hz, 6H), 1.64-1.85 (m,
4H), 2.20 (s, 3H), 3.17-3.27 (m, IH), 3.79 (s, 6H), 6.13 (s,
IH), 6.78 (d, J = 2.1 Hz, IH), 6.89 (d, J = 2.1 Hz, IH),
6.94 (d, J= 8.1 Hz, IH), 7.37 (d, J= 8.1 Hz, IH). MS Calcd.: 396; Found: 397 (M+H) . mp. 223-225 0C.
Example 153
Methyl 2- (2, 4-dichloro-6-methylphenoxy) -7- (1-ethylpropyl) -
1-methyl-liϊ-benzimidazole-4-carboxylate
Figure imgf000217_0001
Methyl 7- (1-ethylpropyl) -l-methyl-2-oxo-2, 3-dihydro- liϊ-benzimidazole-4-carboxylate A mixture of 7- (1-ethylpropyl) -l-methyl~2-oxo-2, 3- dihydro-lE-benzimidazole-4-cabonitrile (1.50 g,6.17 mmol) , patassium hydroxide (20.0 g, 356 mmol), water (30 ml) and ethanol (30 ml) was heated under reflux for 48 h. The reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and 2N hydrochloric acid was added and extracted. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo to give crude carboxylic acid. Trimethyl orthoacetate (10 ml) and toluene (10 ml) were added to the residue and heated at 100 0C for 6 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 35% ethyl acetate/n-hexane to give 1.31 g (4.74 itimol, 77%) of the title compound as a white powder. 1H NMR (CDCl3) δ 0.81 (t, J = 7.44 Hz, 6H), 1.57-1.88 (m, 4H), 3.15-3.31 (m, IH), 3.65 (s, 3H), 3.95 (s, 3H), 6.96 (d, J= 8.48 Hz, IH), 7.62 (d, J= 8.67 Hz, IH), 9.21 (s, IH). MS: Calcd. : 276; Found: 277 (M+H) .
Methyl 2-chloro-7- (1-ethylpropyl) -l-methyl-lif-benzimidazole -4-carboxylate
A mixture of methyl 7- (1-ethylpropyl) -l-methyl-2-oxo- 2, 3-dihydro-liT-benzimidazole-4-carboxylate (1.3Og, 4.70 mmol) and phosphoryl chloride (10 ml) was heated at 100 0C for 3 h. The mixture was diluted with toluene and concentrated in vacuo to remove excess reagent. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on column silica gel with a 10% ethyl acetate/n-hexane to give 1.18 g (4.00 πunol, 85%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 0.82 (t, J = 7.35 Hz, 6H), 1.64-1.91 (m, 4H), 3.27-3.40 (m, IH), 4.01 (s, 3H), 4.05 (s, 3H), 7.19 (d, J= 8.10 Hz, IH), 7.92 (d, J= 8.29 Hz, IH).
Methyl 2- (2, 4-dichloro-6-methylphenoxy) -7- (1-ethylpropyl) - l-methyl-lH-benzimidazole-4-carboxylate
A mixture of methyl 2-chloro-7- (1-ethylpropyl) -1- methyl-lH-benzimidazole-4-carboxylate (1.15 g, 3.90 mmol) , 4, 6-dichloro-o-cresol (2.07 g, 11.70 mmol), potassium carbonate (2.16 g, 15.60 mmol) and WVΪV-dimethylformamide (15 ml) was heated at 110 0C for 5 h. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on alumina with a 15% ethyl acetate/n-hexane to give 1.41 g (3.24 mmol, 83%) of the title compound as a white powder, mp 177-178 0C. 1H NMR (CDCl3) δ 0.86 (t, J = 7.44 Hz, 6H), 1.65-1.92 (m, 4H), 2.36 (s, 3H), 3.25-3.39 (m, IH), 3.84 (s, 3H), 4.03 (s, 3H) 7.06 (d, J = 8.29 Hz, IH), 7.21 (d, J = 1.88 Hz, IH), 7.30 (d, J= 2.64 Hz, IH), 7.79 (d, J= 8.29 Hz, IH). MS: Calcd. : 435; Found: 436 (M+H) . Example 154
[2- (2, 4-Dichloro-6-methylphenoxy) -7- (1-ethylpropyl) -1- methy1-lH-benzimidazol-4-yl] methanol
Figure imgf000220_0001
A mixture of methyl 2- (2, 4-dichloro-6-methylphenoxy) -
7- (1-ethylpropyl) -l-methyl-liϊ-benziinidazole-4-carboxylate
(1.00 g, 2.30 itimol) , lithium borohydride (100 rag, 4.60 mmol) and tetrahydrofuran (20 ml) was heated at 55 0C for 1 h. The reaction mixture was concentrated in vacuo. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 30% ethyl acetate/n- hexane to give 920 mg (2.26 mmol, 98%) of the title compound as a white powder . rap 141-143 0C
1H NMR (CDCl3) δ 0.87 (t, J = 7.35 Hz, 6H), 1.66-1.88 (m, 4H), 2.29 (s, 3H), 3.16-3.30 (m, IH), 3.90 (d, J= 6.31 Hz, IH), 3.99 (s, 3H), 4.85 (d, J = 6.22 Hz, 2H), 6.98 (s, 2H), 7.20 (d, J = 1.70 Hz, IH), 7.32 (d, J =2.45 Hz, IH). MS: Calcd.: 407; Found: 408 (M+H) .
Example 155
2- (2, 4-Dichloro-6-methylphenoxy) -7- (1-ethylpropyl) -1- methyl-lH-benz imidazole- 4 -carbaldehyde
Figure imgf000221_0001
A mixture of [2- (2, 4-dichloro-6-methylphenoxy) -7- (1- ethylpropyl) -l-methyl-lH-benzimidazol-4-yl] methanol (100 mg, 0.25 mmol) , manganese (IV) oxide (428 mg, 4.92 mmol) and tetrahydrofuran (5 ml) was stirred at room tenperature for 16 h. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on alumina with a 50% ethyl acetate/n-hexane to give 93 mg (0.23 mmol, 93%) of the title compound as a white powder, mp 148-149 0C
Λl NMR (CDCl3) δ 0.87 (t, J = 7.44 Hz, 6H), 1.70-1.93 (m, 4H), 2.32 (s, 3H), 3.25-3.39 (m, IH), 4.04 (s, 3H), 7.11 (d, J = 8.29 Hz, IH), 7.24 (d, J = 1.88 Hz, IH), 7.35 (d, J = 2.45 Hz, IH), 7.72 (d ,J= 8.10 Hz, IH), 10.55 (s, IH). Example 156
2- ( 2 , 4-Dichloro-6-methylphenoxy) -7- ( 1-ethylpropyl ) -1- methyl-4- (pyrrolidin-1-ylmethyl ) -liϊ-benzimidazole
Figure imgf000222_0001
To a mixture of 2- (2, 4-dichloro-6-methylphenoxy) -7- (1- ethylpropyl) -l-inethyl-lE-benz±midazole-4-carbaldehyde (93 mg, 0.23 mmol), pyrrolidine (33 mg, 0.46 mmol) , acetic acid (0.5 ml) and ethyl acetate (1.5 ml) was added sodium triacetoxyborohydride (244 mg, 1.15 mmol) and the reaction mixture was stirred at room temperature for 1 h. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on alumina with a 5% ethyl acetate/n-hexane to give 100 mg (0.22 mmol, 94%) of the title compound as a white powder, mp 107-108 0C 1H NMR (CDCl3) δ 0.87 (t, J = 7.35 Hz, 6H) , 1.65-1.86 (m, 8H), 2.30 (s, 3H), 2.47-2.59 (m, 4H), 3.20-3.26 (m, IH), 3.83 (sf 2H), 3.97 (s, 3H), 6.98 (d, J = 7.91 Hz, IH), 7.17 (d, J = 7.91 Hz, IH), 7.21 (d, J = 1.88 Hz, IH), 7.32 (d, J = 2.45 Hz, IH) . MS: Calcd. : 460; Found: 461 (M+H) .
Example 157
N- { [2- (2 , 4-Dichloro-6-methylphenoxy) -7- (1-ethylpropyl) -1- methyl-l#-benzimidazol-4-yl]methyl}-2\7-methylethanamine
Figure imgf000223_0001
To a mixture of 2- (2, 4-dichloro-6-methylphenoxy) -7- (1- ethylpropyl) -l-m.ethyl-liϊ-benzimidazole-4-carbaldehyde (120 mg, 0.296 mmol) , methyl amine (2M tetrahydrofuran solution, 1.48 ml, 2.96 mmol), acetic acid (0.5 ml) and ethyl acetate (2.0 ml) was added sodium triacetoxyborohydride (314 mg, 1.48 mmol) and the reaction mixture was stirred at room temperature for 48 h. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on alumina with a 5% ethyl acetate/n-hexane to give 93 mg (0.21 mmol, 70%) of the title compound as a white powder.
1H NMR (CDCl3) δ 0.87 (t, J - 7.35 Hz, 6H), 1.04 (t, J = 7.16 Hz, 3H), 1.65-1.87 (m, 4H), 2.18 (s, 3H), 2.29 (s, 3H), 2.42 (q, J = 7.16 Hz, 2H), 3.16-3.31 (m, IH), 3.72 (s, 2H), 3.97 (s, 3H), 6.98 (d, J = 7.91 Hz, IH), 7.14 (d, J = 7.91 Hz, IH), 7.18-7.23 (m, IH), 7.31 (d, J = 1.88 Hz, IH). MS: Calcd. : 448; Found: 449 (M+H) .
Example 158
N- ( 4-Chloro-2-methoxy-6-methylphenyl ) -7- ( 1-ethylpropyl ) -1- methyl-4- (trif luororaethyl ) -lff-benzimidazol-2-amine
Figure imgf000224_0001
Methyl 2-nitro-4- (trifluoromethyl)benzoate
A mixture of 2-nitro-4-trifluoromethylbenzoic acid (23.5 g, 0.10 mol) , trimethyl orthoacetate (60.1 g, 0.50 rαol) and toluene (60 ml) was heated at 80 0C for 16 h. The reaction mixture was concentrated in vacuo. Toluene was added and concentrated again to remove excess reagent. The residue was purified by column chromatography on silica gel with a 1-10% ethyl acetate/n-hexane gradient mixture to give 24.9g (0.50 mol 100%) of the title compound as a colorless oil.
1H NMR (CDCl3) δ.:3.97 (s, 3H), 7.87-7.90 (m, IH), 7.95- 7.97 (m, IH) , 8.22 (s, IH) .
Methyl 2-amino-4- (trifluoromethyl) benzoate
A mixture of methyl 2-nitro-4- (trifluoromethyl) benzoate (2.49 g 0.01 mol), sodium hydrosulfite (8.71 g, 0.05 mol), ethanol (20 ml) and water (20 ml) was heated at 50 0C for 3 h. Water was added and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 5% ethyl acetate/n-hexane to give 1.46 g
(6.67 mmol 67%) of the title compound as a white powder. 1H NMR (CDCl3) δ. 3.90 (s, 3H), 5.50-6,20 (brs, 2H), 6.85 (d, J = 8.48 Hz, IH), 6.90 (s, IH), 7.95 (d, J = 8.48 Hz, IH) . MS Calcd. : 219; Found: 220 (M+H) .
Methyl 2- (acetylamino) -4- (trifluoromethyl) benzoate A mixture of methyl 2-amino-4-
(trifluoromethyl)benzoate (8.00 g, 0.036 mol), acetic anhydride (11.18 g, 0.109 mol) , pyridine (8.62 g, 0.109 mol) and chloroform (20 ml) was stirred at room temperature for 48 h. The reaction mixture was concentrated in vacuo.
The residue was diluted with water and extracted with ethyl acetate. The extracts were washed with IN hydrochloric acid and water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 50% ethyl acetate/n-hexane to give 8.10 g (0.031 mol 86%) of the title compound as a white powder, mp 86-87 0C.
1H NMR (CDCl3) δ 2.26 (s, 3H), 3.97 (s, 3H), 7.32 (dd, J = 1.41, 8.38 Hz, IH), 8.14 (d, J = 8.29 Hz, IH), 9.08 (s, IH), 11.11 (s, IH) .
MS Calcd. : 261; Found: 262 (M+H) .
Methyl 2- (acetylamino) -3-nitro-4- (trifluoromethyl) benzoate To an ice-cooled nitric acid (fuming) (20 ml) was added methyl 2- (acetylamino) -4- (trifluoromethyl) benzoate
(7.30 g, 0.028 mol) portionwise and stirred for 30 min. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extracts were washed with aqueous saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 30% ethyl acetate/n-hexane to give 3.20 g (0.010 mol, 38%) of the title compound as a yellow powder.
1H NMR (CDCl3) δ 2.21 (s, 3H), 3.98 (s, 3H), 7.68 (d, J = 8.29 Hz, IH), 8.19 (d, J= 8.29 Hz, IH), 9.10 (s, IH).
Methyl 2-amino-3-nitro-4- (trifluoromethyl) benzoate
A mixture of methyl 2- (acetylamino) -3-nitro-4- (trifluoromethyl) benzoate (1.0Og, 3.27 mmol) and 10% hydrochloric acid in methanol solution (10 ml) was heated at 55 °C for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 30% ethyl acetate/n-hexane to give 780 mg (0.030 mol 90%) of the title compound as a yellow powder. 1H NMR (CDCl3) δ 3.95 (s, 3H), 6.90-7.15 (brs, 2H), 6.99 (d, J= 8.29 Hz, IH), 8.16 (d, J= 8.29 Hz, IH).
Methyl 2, 3-diamino-4- (trifluoromethyl) benzoate
To a stirring solution of methyl 2-amino-3-nitro-4-
(trifluoromethyl) benzoate (5.80 g, 0.022 mol), ammonium formate (30.0 g, 0.476 mol) in ethanol (300 ml) was added 10% palladium on carbon (500 rag) at room temperature and stirred for 2 h. Insolble was filtered off and filtrates were concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 20% ethyl acetate/n- hexane to give 5.10 g (0.022 mol, 99%) of the title compound as a yellow powder. 1H NMR (CDCl3) δ 3.87 (brs, 2H), 3.90 (s, 3H), 5.68 (brs, 2H), 6.88 (d, J= 8.67 Hz, IH), 7.47 (d, J= 8.67 Hz, IH). MS Calcd. : 234; Found: 235 (M+H) .
Methyl 2-oxo-7- (trifluoromethyl) -2, 3-dihydro-lH- benzimidazole-4-carboxylate
To a stirring solution of methyl 2, 3-diamino-4-
(trifluoromethyl) benzoate (5.10 g, 0.022 mol) and diisopropylethylamine (6.26 g, 0.048 mol) in toluene (50 ml) was added a solution of triphosgene (2.58 g, 0.0087 mol) in toluene (20 ml) dropwise and stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The residue was diluted with IN hydrochloric acid and extracted with ethyl acetate and tetrahydrofuran. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. A solution of 50% diisopropylether/n-hexane was added to the residue and white precipitates were filtered, washed with same solvent to give 5.00 g (0.019 mol 87%) of the title as a white powder mp. 281-283 0C
1H NMR (DMSO - d6) δ 3.92 (s, 3H) 7.32 (d, J = 8.48 Hz, IH), 7.61 (d, J = 8.48 Hz, IH), 11.23 (s, IH), 11.63 (s, IH). MS Calcd. : 260; Found: 261 (M+H)
Methyl 3-methyl-2-oxo-7- (trifluoromethyl) -2 , 3-dihydro-liϊ- benzimidazole-4-carboxylate
To a stirring mixture of methyl 2-oxo-7- (trifluoromethyl) -2, 3-dihydro-lif-benzimidazole-4-carboxylate (2.34 g, 9.00 mmol), di-t-butyl dicarbonate (4.32 g, 20.0 mmol) and N,N- dimethylformamide (240 ml) was added 60% sodium hydride (800 mg, 20.0 mmol) portionwise and stirred at 50 0C for 2 h. The reaction mixture was poured into IN hydrochloric acid and extracted with ethyl acetate. The extracts were washed with aqueous saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo. A solution of 50% diisopropylether/n-hexane was added to the residue and white precipitates (starting materials) were filtered off. The filtrates were concentrated in vacuo to give crude 1-tert-butyl 4-methyl 2-oxo-7- (trifluoro- methyl) -2, 3-dihydro-lJϊ-benzimidazole-l, 4-dicarboxylate as a colorless oil.
To a stirring mixture of obtained crude dicarboxylate, methyl iodide (2.82 g, 20.0 mmol) and Λ/VIV-dimethylformamide (10 ml) was added 60% sodium hydride (800 mg, 20.0 mmol) portionwise and stirred at room temperature for 30 min. The reaction mixture was poured into IN hydrochloric acid and extracted with ethyl acetate. The extracts were washed with aqueous saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo to give crude 1-tert-butyl 4-methyl 3-methyl-2-oxo-7- (trifluoromethyl) - 2, 3-dihydro-l.H-benzimidazole-l, 4-dicarboxylate as a colorless oil.
A mixture of obtained crude 1, 4-dicarboxylate and trifluoroacetic acid (5 ml) was stirred at 50 0C for 10 min and concentrated in vacuo. The residue was diluted with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 20% ethyl acetate/n-hexane to give 1.13 g (4.12 mmol 46%) of the title compound as a white powder. 1H NMR (CDCl3) δ 3.57 (s, 3H), 3.99 (s, 3H), 7.29 (d, J = 8.48 Hz, IH), 7.54 (dd, J = 0.75, 8.48 Hz, IH), 9.36 (brs, IH) . MS Calcd. : 274; Found: 275 (M+H) .
7- (1-Ethylprop-l-en-l-yl) -l-methyl-4- (trifluoromethyl) -1, 3- dihydro-2H-benzimidazol-2-one To an ice-cooled solution of methyl 3-methyl-2-oxo-7- (trifluoromethyl) -2, 3-dihydro-lH-benzimidazole-4- carboxylate (2.80 q, 10.2 mmol) in tetrahydrofuran (30 ml) was added a solution of 3M ethylmagnesium bromide in diethylether (13.6 ml, 40.8 mmol) dropwise and stirred at 45 0C for 16 h. Methanol and water were carefully added to decompose excess reagent. 2N hydrochloric acid was added and extracted with ethyl acetate. The extracts were washed with aqueous saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo. Ethanol (40 ml) and cone. hydrochloric acid (10 ml) were added to the residue and the resulting mixture was heated at 80 0C for 6 h. The reaction mixture was concentrated in vacuo. Aqueous saturated sodium bicarbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel with a 20% ethyl acetate/n- hexane to give 609 mg (2.14 mmol, 21%, cis/trans=3/l) of the title compound as a white powder. 1H NMR (CDCl3) δ 0.97 (t, J = 7.50 Hz, 3H x 0.75,), 1.06 (t, J= 7.44 Hz, 3H x 0.25,), 1.39-1.45 (m, 3H x 0.25), 1.83 (d, J = 6.78 Hz, 3H x 0.75), 2.19-2.68 (m, 2H), 3.44 (s, 3H), 5.49 (q, J = 6.78 Hz, IH x 0.75), 5.74 (q, J = 6.78 Hz, IH x 0.25), 6.80 (d, J = 8.10 Hz, IH x 0.25), 6.86 (d, J = 8.10 Hz, IH x 0.75), 7.19 (d, J= 8.29 Hz, IH x 0.75), 7.24 (d, J= 8.28 Hz, IH x 0.25), 9.07 (s, IH). MS Calcd. : 284; Found: 285 (M+H) .
7- (1-Ethylpropyl) -1-methyl-4- (trifluoromethyl) -1, 3-dihydro- 2iϊ-benzimidazol-2-one
A mixture of 7- (1-ethylprop-l-en-l-yl) -l-methyl-4- (trifluoromethyl) -1, 3-dihydro-2H-benzimidazol-2-one (486 mg, 1.71 mmol) , 10% palladium on carbon (200 mg) and acetic acid (5 ml) was hydrogenated under 5 atom of hydrogen at 50 0C for 2 h. Catalyst was filtered off and filtrates were concentrated in vacuo. Aqueous saturated sodium bicarbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by recrystallization from diisopropylether/n-hexane to give 350 mg (1.22 mmol, 72%) of the title compound as a white powder. mp. 205-206 0C 1H NMR (CDCl3) δ 0.82 (t, J = 7.44 Hz, 6H), 1.58-1.88 (m, 4H), 3.14-3.36 (m, IH), 3.67 (s, 3H), 7.02 (d, J= 8.48 Hz, IH), 7.21-7.27 (m, IH), 8.92 (brs, IH). MS Calcd. : 286; Found: 287 (M+H) .
2-Chloro-7- (1-ethylpropyl) -l-methyl-4- (trifluoromethyl) -IH- benzimidazole
A mixture of 7- (1-ethylpropyl) -l-methyl-4- (trifluoromethyl) -1, 3-dihydro-2H-benzimidazol-2-one (310 rng, 1.08 mmol) and phosphoryl chloride (5 ml) was heated at 110 0C for 1 h and concentrated in vacuo. Toluene was added and concentrated again to remove excess reagent. Aqueous saturated sodium bicarbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated In vacuo. The residue was purified by column chromatography on silica gel with a 20% ethyl acetate/n-hexane to give 300 mg (0.99 mmol, 91%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ 0.83 (t, J = 7.50 Hz, 6H), 1.65-1.91 (m, 4H), 3.24-3.40 (m, IH), 4.05 (s, 3H), 7.19 (d, J= 7.91 Hz, IH), 7.53 (d, J = 8.10 Hz, IH). MS Calcd. : 304; Found: 305 (M+H) .
N- (4-Chloro-2-methoxy-6-methylphenyl) -7- (1-ethylpropyl) -1- methyl-4- (trifluoromethyl) -liϊ-benzimidazol-2-amine
A mixture of 2-chloro-7- (1-ethylpropyl) -l-methyl-4- (trifluoromethyl) -lH-benzimidazole (290 mg, 0.95 mmol), 4- chloro-2-methoxy-β-methylaniline (491 mg, 2.86 mmol) and N- methyl-2-pyrrolidinone (3 drops) was heated at 110 0C for 72 h. Aqueous saturated sodium bicarbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel with a 10% ethyl acetate/n- hexane and recrystallized from diisopropylether/n-hexane to give 140 mg (0.32 mmol, 34%) of the title compound as a white powder, mp. 187-188 0C
1H NMR (CDCl3) δ 0.83 (t, J = 7.35 Hz, 6H), 1.63-1.89 (m, 4H), 2.18 (s, 3H), 3.20-3.30 (m, IH), 3.74 (s, 3H), 3.78 (s, 3H), 6.18 (s, IH), 6.78 (s, IH), 6.88 (d, J = 2.07 Hz, IH), 6.97 (d, J = 8.29 Hz, IH), 7.36 (d, J= 8.29 Hz, IH). MS Calcd. : 440; Found: 441 (M+H) .
Example 159
N- ( 2-Bromo-4-chlorophenyl ) -1- ( 1-ethylpropyl ) - 1 -methyl- 4- (trifluoromethyl ) -lH-benzimidazol-2-amine
Figure imgf000235_0001
Example 159 was prepared in the similar method described in Example 158. mp. 151-152 0C
1H NMR (CDCl3) δ 0.84 (t, J = 7.44 Hz, 6H), 1.65-1.91 (m, 4H), 3.19-3.34 (m, IH), 3.87 (s, 3H), 6.93 (s, IH), 7.07 (d, J= 8.10 Hz, IH), 7.34 (dd, J= 2.45, 8.85 Hz, IH), 7.45 (d, J = 7.35Hz, IH), 7.56 (d, J = 2.45 Hz, IH), 8.29 (d, J = 8.67 Hz, IH) . MS Calcd. : 474; Found: 475 (M+H) .
Example 160
2- ( 2 , 4-Dichloro-6-methylphenoxy) -7- ( 1-ethylpropyl ) -1- methyl-4- (trif luoromethyl ) -liϊ-benzimidazole
Figure imgf000236_0001
A mixture of 2-chloro-7- (1-ethylpropyl) -l-methyl-4-
(trifluoromethyl) -lif-benzimidazole (304 mg, 1.00 mmol) ,
4, 6-dichloro-o-cresol (531 mgr 3.00 mmol), potassium carbonate (553 mg,4.0 mmol) and _V,N-dimethylformamide (5 ml) was heated at 110 0C for 48 h. Aqueous saturated sodium bicarbonate was added to the residue and extracted with ethyl acetate. The extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 10% ethyl acetate/n-hexane and recrystallization from diisopropylether/n-hexane to give 290 mg (0.65 mmol, 65%) of the title compound as a white powder, mp. 149-151 0C 1H NMR (CDCl3) δ 0.87 (t, J = 7.35 Hz, 6H), 1.66-1.91 (m, 4H), 2.31 (s, 3H), 3.24-3.37 (m, IH), 4.02 (s, 3H), 7.05 (d, J = 8.10 Hz, IH), 7.21 (d, J = 1.88 Hz, IH), 7.31 (d, J = 2.45 Hz, IH), 7.39 (d, J= 8.10 Hz, IH). MS Calcd. : 445; Found: 446 (M+H) . Example 161
2- (2-Bromo~4-chlorophenoxy) -7- (1-ethylpropyl) -l-methyl-4-
(trifluoromethyl) -lH-benzimidazole
Figure imgf000237_0001
Example 161 was prepared in the similar method described in Example 160. mp. 119-120 0C
1H NMR (CDCl3) δ 0.85 (t, J = 7.44 Hz, 6H), 1.65-1.91 (m, 4H), 3.24-3.37 (m, IH), 4.02 (s, 3H), 7.10 (d, J = 8.10 Hz, IH), 7.39 (dd, J = 2.45, 8.85 Hz, IH), 7.44 (d, J= 8.29 Hz, IH), 7.64 (d, J= 2.45 Hz, IH), 7.95 (d, J= 9.04 Hz, IH). MS Calcd. : 475; Found: 476 (M+H) .
Example 162
2- (2, 4-Dichloro-6-methylphenoxy) -7- (3, 5-diethyl-lH-pyrazol- 1-yl) -1-methyl-liϊ-benzimidazole
Figure imgf000238_0001
A suspension of 2-chloro-7- (3, 5-diethyl-lH-pyrazol-l- yl)-l-methyl-liϊ-benzimidazole (92 mg, 0.318 mmol) , 2,4- dichloro-6-methylphenol (114 mg, 0.643 mmol), potassium carbonate (89 mg, 0.643 mmol) in N,_V-dimethylformainide (1.5 ml) was stirred at 90 0C for 5.5 days (2, 4-dichloro-6- methylphenol and potassium carbonate were added in three equal portions each over 5.5 days) . After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 10-25% ethyl acetate/n-hexane gradient mixture to give 107 mg (0.249 mmol, 78.3%) of the title compound as an oil. The oil was crystallized from hexane to give 70 mg (51%) as a pale yellow crystal, mp: 115-119 0C
1H NMR (CDCl3) . δ: 1.19 (3H, t, J = 7.5 Hz), 1.32 (3H, t, J = 7.5 Hz), 2.26 (3H, s) , 2.50 (2H, q, J = 7.5 Hz), 2.72 (2H, q, J = 7.5 Hz), 3.23 (3H, s) , 6.10 (IH, s) , 7.09-7.19 (3H, m) , 7.31 (IH, d, J = 2.4 Hz), 7.57 (IH, d, J = 6.9 Hz). MS Calcd. : 428; Found: 429 (M+H) , 431.
Example 163
3, 5-Dichloro-4-{ [7- (1-ethylpropyl) -4-methoxy-l-methyl-lH- benzimidazol-2-yl] oxy} -ATVlV-dimethylaniline
Figure imgf000239_0001
Example 163 was prepared in the similar method described in Example 145. mp 176-177 0C.
1H NMR (CDCl3) δ 0.86 (t, J = 7.5 Hz, 6H), 1.65-1.85 (m, 4H), 2.94 (s, 6H), 3.15-3.25 (m, IH), 3.89 (s, 3H), 3.97 (s, 3H), 6.63 (d, J = 8.4 Hz, IH), 6.63 (s, 2H), 6.91 (d, J = 8.4 Hz, IH) .
MS Calcd.: 435; Found: 436 (M+H), 438.
Experiment 1
Measurement of Corticotropin-Releasing Factor (CRF) binding inhibitory rate A receptor binding experiment was carried out using a human CRF receptor expressing CHO cellular membrane fraction and ovine CRF, [125I] -tyr° (125I-CRF) . 1000 nM of a test compound was incubated with 1 μg of human CRF receptor expressing CHO cellular membrane fraction and 50 pM of 125I- CRF in a binding assay buffer (50 mM Tris-HCl, 5 mM EDTA, 10 mM MgCl2, 0.05% CHAPS, 0.1% BSA, 0.5 mM PMSF, 0.1 μg/ml pepstatin, 20 μg/ml leupeptin, pH 7.5). In addition, for measuring nonspecific binding (NSB), 0.1 μM unlabelled human ϋrocortin was incubated with 1 μg of human CRF receptor expressing CHO cellular membrane fraction and 50 pM of 125I-CRF in a binding assay buffer. After a binding reaction was carried out at room temperature for 1.5 hour, the membrane was entrapped on a glass filter (UniFilter plate GF-C/Perkin Elmer) by suction filtration using a cell harvester (Perkin Elmer) , and washed with ice-cooled 50 mM Tris-HCl (pH 7.5). After drying the glass filter, a liquid scintillation cocktail (Microscinti 0, Perkin Elmer) was added, and the radioactivity of 125I-CRF remaining on a glass filter was measured using Topcount (Perkin Elmer) .
(TB-SB) /(TB-NSB) x 100 (SB: radioactivity when a compound is added, TB: maximum binding radioactivity, NSB: nonspecific binding radioactivity) was calculated to obtain a binding inhibitory rate under the presence of 1,000 nM of each test substances. The IC50 values were calculated by using GraphPad Prism software.
Binding inhibitory rates of respective compounds measured by the aforementioned method are shown in Table Table 8
Figure imgf000241_0001
Values of IC50 of respective compounds were measured by the aforementioned method, and are shown as A and B in Table 9. [A: less than 10 nM; B: 10-50 nM] Table 9
Figure imgf000241_0002
Industrial Applicability
Compound (I) or (I' ) of the present invention has an excellent CRF antagonistic activity, and therefore useful as drugs for treating or preventing affective disorder, depression, anxiety, and the like,

Claims

CLAIMS 1. A compound represented by the formula (I) :
Figure imgf000243_0001
wherein R1 is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic group, an optionally substituted N-linked heteroaryl group or an acyl, provided that methyl, and trifluoromethyl are excluded; R2 is an optionally substituted cyclic hydrocarbyl or an optionally substituted heterocyclic group, provided that 2- [2- (1, l-dimethylethyl)phenyloxy] -3-pyridinyl is excluded;
X is oxygen, sulfur or -NR3- (wherein R3 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ; Y1, Y2 and Y3 are each an optionally substituted carbon or a nitrogen, provided that one or less of Y1, Y2 and Y3 is nitrogen; and
Z is a bond, -CO-, oxygen, sulfur, -SO-, -SO2-, -NR4-, -NR4- alk-, -CONR4- or -NR4CO- (wherein alk is an optionally substituted C1-4 alkylene and R4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ; provided that (i) the compound wherein X is -NH-, and R2 is an optionally substituted thiophene ring, (ii) the compound wherein R1 is cyano, Y3 is carbon which is substituted with methyl substituted with three substituents, one of which is acyl, and other two of which may form a ring,
(iii) a) 6-amino-2- [ (2, 6-dichlorophenyl) amino] -1-methyl-liϊ- benzimidazole-7-carbonitrile, b) 6-amino-2- [ (2, 6-dichlorophenyl) amino] -l-methyl-lff- benzimidazole-7-carboxamide, and c) 6-{ [ (-allylamino) carbonothioyl] amino} -2- [(2,6- dichlorophenyl) amino] -l-methyl-liϊ-benzimidazole-7- carboxamide,
(iv) 4- ( {2- [ (4-chlorophenyl) amino] -1, 7-dimethyl-lH- benzimidazol-5-yl }oxy) -ΛT-methylpyridine-2-carboxamider
(v) the compound wherein R3 is substituted heteroarylmethyl,
R2 is 4-piperidinyl bearing a substituent at the 1- position,
(vi) the compound wherein R2 is substituted 8-oxo-5-thia-l- aza-bicyclo [4.2.0] oct-2-en-7-yl, and
(vii) 7-ethyl-l-methyl-N- [4- (trifluoromethoxy) phenyl] -5-
(trifluoromethyl) -lH-benzimidazol-2-amine and 7-ethenyl-l- methyl-N- [4- (trifluoromethoxy) phenyl] -5- (trifluoromethyl) - lH-benzimidazol-2-amine are excluded; or a salt thereof.
2. A prodrug of the compound according to claim 1.
3. The compound according to claim 1 wherein R1 is an optionally substituted acyclic branched C3-11 hydrocarbyl.
4. The compound according to claim 1 wherein R1 is an optionally substituted C6-io aryl .
5. The compound according to claim 1 wherein R1 is an optionally substituted C-linked 5- to 14-membered heterocyclic group or N-linked 5- to 10-membered heteroaryl group.
6. The compound according to claim 1 wherein X is -NR3- (wherein R3 is as defined in claim 1) .
7. The compound according to claim 6 wherein R3 is methyl, ethyl or hydroxyethyl .
8. The compound according to claim 1 wherein Y1 is CR3a, Y2 is CR3b, and Y3 is CR3c (wherein R3a, R3b and R3c are independently a hydrogen, a halogen, a nitro, a cyano, an optionally substituted C1-4 hydrocarbyl, an optionally substituted Ci_4 hydrocarbyloxy, an optionally substituted Ci-4 hydrocarbylthio, an optionally substituted amino or an acyl containing up to 4 carbon atoms .
9. The compound according to claim 8 wherein R3a is a hydrogen, a halogen, a cyano, an optionally substituted Ci_3 alkyl, or an optionally substituted C1-3 alkoxy, R3b is a hydrogen, and R3c is a hydrogen.
10. The compound according to claim 9 wherein R3a is chlorine, bromine, methoxy or methyl.
11. The compound according to claim 1 wherein one of Y1, Y2 and Y3 is nitrogen.
12. The compound according to claim 1 wherein R2 is an optionally substituted Cβ-io aryl or an optionally substituted 5- to 8-membered heterocyclic group.
13. The compound according to claim 1 wherein R2 is phenyl which is 2, 4, β-trisubstituted, 2, 4 , 5-trisubstituted or 2,4- disubstituted.
14. The compound according to claim 1 wherein Z is -NR4- (wherein R4 is as defined in claim 1), or oxygen.
15. The compound according to claim 14 wherein R4 is a hydrogen.
16. The compound according to claim 1 which is
N- (4-chloro-2-methoxy-6-methylphenyl) -7- (2-ethylphenyl) -1- methyl-lH-benzimidazo1-2-amine,
W- (4-bromo-2-methoxy-β-methylphenyl) -7- (3, 5-diethyl-liϊ- pyrazol-1-yl) -l-methyl-lH-benzimidazol-2-amine,
N- (4-bromo-2-methoxy-6-methylphenyl) -4-chloro-7- (1- ethylpropyl) -l-methyl-l.ff-benzimidazol-2-amine, 4-chloro-2- (2, 4-dichloro-β-methylphenoxy) -7- (1- ethylpropyl) -1-methyl-liϊ-benzimidazole, N- (4-chloro-2-methoxy-6-methylphenyl) -7- (1-ethylpropyl) - 1, 4-dimethyl-lH-benzimidazol-2-amine, or 2- (2, 4-dichloro-6-methylphenoxy) -7- (1-ethylpropyl) -4- methoxy-1-methyl-liϊ-benzimidazole, or a salt thereof.
17. A process for producing the compound according to claim 1, which comprises reacting a compound represented by
Figure imgf000247_0001
wherein L represents a leaving group selected from halogen atom, sulfonyloxy group and acyloxy group, and other symbols are as defined in claim 1, with a compound represented by the formula:
R2-ZH ( ii ) wherein each symbol is as defined in claim 1.
18. A pharmaceutical composition which comprises the compound according to claim 1.
19. A CRF receptor antagonist which is the compound represented by the formula (I1) :
Figure imgf000247_0002
wherein R1 is an optionally substituted hydrocarbyl, an optionally substituted C-linked heterocyclic group, an optionally substituted N-linked heteroaryl group, a cyano or an acyl;
R2 is an optionally substituted cyclic hydrocarbyl or an optionally substituted heterocyclic group; X is oxygen, sulfur or -NR3- (wherein R3 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ; Y1, Y2 and Y3 are each an optionally substituted carbon or a nitrogen, provided that one or less of Y1, Y2 and Y3 is nitrogen;
Z is a bond, -CO-, oxygen, sulfur, -SO-, -SO2-, -NR4-, -NR4- alk-, -CONR4- or -NR4CO- (wherein alk is an optionally substituted C3.-.4 alkylene and R4 is a hydrogen, an optionally substituted hydrocarbyl or an acyl) ; or a salt thereof.
20. A method for treating or preventing a disease wherein a CRF receptor is implicated, which comprises administering to a subject in need thereof an effective amount of the CRF receptor antagonist according to claim 19.
21. The method according to claim 20 wherein the disease being treated or prevented is selected from affective disorder, depression or anxiety.
22. Use of the CRF receptor antagonist according to claim 19 for manufacturing a medicament for preventing or treating a disease wherein a CRF receptor is implicated.
23. The use according to claim 22 wherein the disease being treated or prevented is selected from affective disorder, depression or anxiety.
24. A pharmaceutical composition for preventing or treating a disease wherein a CRF receptor is implicated, which comprises the CRF receptor antagonist according to claim 19.
25. The pharmaceutical composition according to claim 24 wherein the disease being treated or prevented is selected from affective disorder, depression or anxiety.
PCT/US2006/015646 2005-04-27 2006-04-26 Fused heterocyclic compounds WO2006116412A2 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
CA002605453A CA2605453A1 (en) 2005-04-27 2006-04-26 Novel benzimidazole compounds having crf antagonistic activity and pharmaceutical compositions containing them
MX2007013154A MX2007013154A (en) 2005-04-27 2006-04-26 Fused heterocyclic compounds.
CN2006800147137A CN101166729B (en) 2005-04-27 2006-04-26 Fused heterocyclic compounds
EP06751379A EP1874736A4 (en) 2005-04-27 2006-04-26 Fused heterocyclic compounds
KR1020077024873A KR101368037B1 (en) 2005-04-27 2006-04-26 Fused heterocyclic compounds
US11/919,435 US8163935B2 (en) 2005-04-27 2006-04-26 Fused heterocyclic compounds
BRPI0610150-0A BRPI0610150A2 (en) 2005-04-27 2006-04-26 compound, prodrug, process for producing the compound, pharmaceutical composition, crf receptor antagonist, and use of crf receptor antagonist
JP2008509045A JP5061097B2 (en) 2005-04-27 2006-04-26 Fused heterocyclic compounds
AU2006241210A AU2006241210B2 (en) 2005-04-27 2006-04-26 Fused heterocyclic compounds
NZ562235A NZ562235A (en) 2005-04-27 2006-04-26 Benzimidazole and pyridoimidazole derivatives as CRF receptor antagonists, for treating affective disorder, depression, or anxiety
IL186407A IL186407A (en) 2005-04-27 2007-10-07 Benzimidazole and imidazo[4,5-c]pyridine derivatives as crf receptor antagonists, production thereof, pharmaceutical compositions comprising them and use thereof for manufacturing medicaments
NO20075936A NO20075936L (en) 2005-04-27 2007-11-19 Fused heterocyclic compounds

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US67511305P 2005-04-27 2005-04-27
US60/675,113 2005-04-27
US74210105P 2005-12-02 2005-12-02
US60/742,101 2005-12-02

Publications (3)

Publication Number Publication Date
WO2006116412A2 true WO2006116412A2 (en) 2006-11-02
WO2006116412A8 WO2006116412A8 (en) 2007-03-01
WO2006116412A3 WO2006116412A3 (en) 2007-06-28

Family

ID=37215421

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2006/015646 WO2006116412A2 (en) 2005-04-27 2006-04-26 Fused heterocyclic compounds

Country Status (19)

Country Link
US (1) US8163935B2 (en)
EP (1) EP1874736A4 (en)
JP (1) JP5061097B2 (en)
KR (1) KR101368037B1 (en)
AR (1) AR053859A1 (en)
AU (1) AU2006241210B2 (en)
BR (1) BRPI0610150A2 (en)
CA (1) CA2605453A1 (en)
CR (1) CR9421A (en)
GE (1) GEP20104962B (en)
IL (1) IL186407A (en)
MA (1) MA29486B1 (en)
MX (1) MX2007013154A (en)
NO (1) NO20075936L (en)
NZ (1) NZ562235A (en)
PE (1) PE20061377A1 (en)
RU (1) RU2408586C2 (en)
TW (1) TWI370820B (en)
WO (1) WO2006116412A2 (en)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008051533A2 (en) 2006-10-25 2008-05-02 Takeda Pharmaceutical Company Limited Benzimidazole compounds
WO2008082003A1 (en) * 2006-12-29 2008-07-10 Takeda Pharmaceutical Company Limited Fused heterocyclic compounds having crf antagonistic activity
WO2009093747A1 (en) * 2008-01-22 2009-07-30 Takeda Pharmaceutical Company Limited Tricyclic compounds having corticotropin-releasing factor antagonistic activity and pharmaceutical compositions containing them
WO2010018874A1 (en) * 2008-08-12 2010-02-18 Takeda Pharmaceutical Company Limited Amide compound
WO2010032461A1 (en) * 2008-09-17 2010-03-25 武田薬品工業株式会社 Nitrogen-containing fused ring compound
US7812013B2 (en) 2005-06-14 2010-10-12 Schering Corporation Macrocyclic heterocyclic aspartyl protease inhibitors
WO2011078360A1 (en) 2009-12-24 2011-06-30 武田薬品工業株式会社 Amide compound
US8329914B2 (en) 2008-10-31 2012-12-11 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
WO2013024898A1 (en) 2011-08-18 2013-02-21 日本新薬株式会社 Heterocyclic derivative and pharmaceutical drug
US8394969B2 (en) 2008-09-26 2013-03-12 Merck Sharp & Dohme Corp. Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8410284B2 (en) 2008-10-22 2013-04-02 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8563746B2 (en) 2008-10-29 2013-10-22 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8895596B2 (en) 2010-02-25 2014-11-25 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8987250B2 (en) 2012-04-20 2015-03-24 Gilead Sciences, Inc. Therapeutic compounds
US9006229B2 (en) 2011-04-21 2015-04-14 Gilead Sciences, Inc. Benzothiazole compounds and their pharmaceutical use
WO2015112642A1 (en) 2014-01-21 2015-07-30 Neurocrine Biosciences, Inc. Crf1 receptor antagonists for the treatment of congenital adrenal hyperplasia
US9102614B2 (en) 2010-07-02 2015-08-11 Gilead Sciences, Inc. Naphth-2-ylacetic acid derivatives to treat AIDS
US9284323B2 (en) 2012-01-04 2016-03-15 Gilead Sciences, Inc. Naphthalene acetic acid derivatives against HIV infection
US9296758B2 (en) 2010-07-02 2016-03-29 Gilead Sciences, Inc. 2-quinolinyl-acetic acid derivatives as HIV antiviral compounds
US9376392B2 (en) 2012-01-04 2016-06-28 Gilead Sciences, Inc. 2-(tert-butoxy)-2-(7-methylquinolin-6-yl) acetic acid derivatives for treating AIDS
WO2016174183A1 (en) 2015-04-30 2016-11-03 Bayer Pharma Aktiengesellschaft Combinations of inhibitors of irak4 with inhibitors of btk
EP3195865A1 (en) 2016-01-25 2017-07-26 Bayer Pharma Aktiengesellschaft Combinations of inhibitors of irak4 with inhibitors of btk
EP3219329A1 (en) 2016-03-17 2017-09-20 Bayer Pharma Aktiengesellschaft Combinations of copanlisib
WO2017207386A1 (en) 2016-06-01 2017-12-07 Bayer Pharma Aktiengesellschaft Use of 2-substituted indazoles for the treatment and prophylaxis of autoimmune diseases
WO2017207481A1 (en) 2016-06-01 2017-12-07 Bayer Animal Health Gmbh Substituted indazoles ueful for treatment and prevention of allergic and/or inflammatory diseases in animals
WO2018095953A1 (en) 2016-11-23 2018-05-31 Bayer Cropscience Aktiengesellschaft 2-[3-(alkylsulfonyl)-2h-indazol-2-yl]-3h-imidazo[4,5-b]pyridine derivatives and similar compounds as pesticides
US10308634B2 (en) 2014-11-26 2019-06-04 Bayer Pharma Aktiengesellschaft Substituted indazoles, methods for the production thereof, pharmaceutical preparations that contain said new substituted indazoles, and use of said new substituted indazoles to produce drugs

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017155052A1 (en) * 2016-03-09 2017-09-14 日本曹達株式会社 Pyridine compound and use thereof

Family Cites Families (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4373497B2 (en) 1996-06-19 2009-11-25 ローン−プーラン・ロレ・リミテツド Substituted azabicyclo compounds and their use as inhibitors of TNF and cyclic AMP phosphodiesterase production
AU3899097A (en) * 1996-08-05 1998-02-25 Rhone-Poulenc Rorer Pharmaceuticals Inc. Substituted aromatic compounds
US6124463A (en) 1998-07-02 2000-09-26 Dupont Pharmaceuticals Benzimidazoles as corticotropin release factor antagonists
US6365589B1 (en) 1998-07-02 2002-04-02 Bristol-Myers Squibb Pharma Company Imidazo-pyridines, -pyridazines, and -triazines as corticotropin releasing factor antagonists
US6376664B1 (en) * 1999-03-17 2002-04-23 The Ohio State University Cyclic bis-benzimidazole ligands and metal complexes thereof
MXPA01012283A (en) 1999-06-23 2002-07-30 Aventis Pharma Gmbh Substituted benzimidazole.
EA004939B1 (en) 1999-06-28 2004-10-28 Янссен Фармацевтика Н.В. Respiratory syncytial virus replication inhibitors
AU7314200A (en) * 1999-09-17 2001-04-24 Yamanouchi Pharmaceutical Co., Ltd. Benzimidazole derivatives
WO2001021160A2 (en) 1999-09-23 2001-03-29 Axxima Pharmaceuticals Aktiengesellschaft Carboxymide and aniline derivatives as selective inhibitors of pathogens
US6506769B2 (en) 1999-10-06 2003-01-14 Boehringer Ingelheim Pharmaceuticals, Inc. Heterocyclic compounds useful as inhibitors of tyrosine kinases
JP5036112B2 (en) 1999-10-06 2012-09-26 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド Heterocyclic compounds useful as inhibitors of tyrosine kinases
KR100526487B1 (en) 2000-06-21 2005-11-08 에프. 호프만-라 로슈 아게 Benzothiazole derivatives
JP5000068B2 (en) 2000-08-11 2012-08-15 ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド Heterocyclic compounds useful as inhibitors of tyrosine kinases
DE10060292A1 (en) 2000-12-05 2002-06-20 Aventis Pharma Gmbh Use of substituted benzimidazoles for the manufacture of a medicament for the treatment of diseases which can be influenced by inhibition of the Na + / H + exchanger and medicament containing them
US20020146469A1 (en) 2000-12-20 2002-10-10 Benjamin Wiegand Methods for reducing chronic stress in mammals
CN1531530A (en) * 2001-02-05 2004-09-22 罗奇维生素股份公司 Novel 2-benzoxazolyl benzene derivatives and their use as UV screening agents
US7030150B2 (en) 2001-05-11 2006-04-18 Trimeris, Inc. Benzimidazole compounds and antiviral uses thereof
US6734179B2 (en) 2001-12-12 2004-05-11 Hoffmann-La Roche Inc. Benzothiazoles
GB0203045D0 (en) 2002-02-08 2002-03-27 Johnson & Johnson Consumer Method of afefecting sleep and sleep-related behaviours
PL402389A1 (en) 2002-03-29 2013-04-02 Novartis Ag Method for inhibiting Raf kinase activity in humans or inanimals
US8299108B2 (en) 2002-03-29 2012-10-30 Novartis Ag Substituted benzazoles and methods of their use as inhibitors of raf kinase
US7049333B2 (en) 2002-06-04 2006-05-23 Sanofi-Aventis Deutschland Gmbh Substituted thiophenes: compositions, processes of making, and uses in disease treatment and diagnosis
JP2006505570A (en) * 2002-10-17 2006-02-16 アムジエン・インコーポレーテツド Benzimidazole derivatives and their use as vanilloid receptor ligands
WO2004043913A2 (en) 2002-11-08 2004-05-27 Trimeris, Inc. Hetero-substituted benzimidazole compounds and antiviral uses thereof
CA2524352A1 (en) 2003-05-09 2004-11-18 Pharmacia & Upjohn Company Llc Substituted pyrimidine derivatives
US20040242560A1 (en) 2003-05-22 2004-12-02 Aventis Pharma Deutschland Gmbh Process for synthesizing heterocyclic compounds
JP2007521296A (en) 2003-07-01 2007-08-02 メルク　エンド　カムパニー　インコーポレーテッド Ophthalmic composition for the treatment of high intraocular pressure
US20050042212A1 (en) 2003-07-24 2005-02-24 Nanda Steven A. Method of reducing CRF receptor mRNA
DE10337942A1 (en) 2003-08-18 2005-03-17 Merck Patent Gmbh aminobenzimidazole derivatives
DE10349587A1 (en) 2003-10-24 2005-05-25 Merck Patent Gmbh Benzimidazolylderivate
JP4842829B2 (en) * 2003-10-31 2011-12-21 武田薬品工業株式会社 Nitrogen-containing fused heterocyclic compounds
AR046959A1 (en) 2003-12-18 2006-01-04 Tibotec Pharm Ltd MORFOLINILO CONTAINING BENCIMIDAZOLS AS INHIBITORS OF THE REPLICATION OF RESPIRATORY SYNTHETIC VIRUSES
ES2326813T3 (en) 2003-12-18 2009-10-20 Tibotec Pharmaceuticals Ltd. DERIVATIVES OF AMINO-BENCIMIDAZOLES AS INHIBITORS OF THE REPLICATION OF THE SYNTHETIC RESPIRATORY VIRUS.
ATE501135T1 (en) 2003-12-18 2011-03-15 Tibotec Pharm Ltd PIPERIDINAMINO-BENZIMIDAZOLE DERIVATIVES AL RESPIRATORY SYNCYTIALVIRUS REPLICATION INHIBITORS
AU2004312001B2 (en) 2003-12-19 2009-08-27 Merck & Co., Inc. Cyclic guanidines, compositions containing such compounds and methods of use
US7470712B2 (en) 2004-01-21 2008-12-30 Bristol-Myers Squibb Company Amino-benzazoles as P2Y1 receptor inhibitors
WO2005077936A1 (en) 2004-02-11 2005-08-25 Ulkar Kimya Sanayii Ve Ticaret A.S. Pyridine benzimidazole sulfoxides with high purity
US7429608B2 (en) 2005-01-20 2008-09-30 Amgen Inc. Benzo[d]imidazol analogs as vanilloid receptor ligands and their use in treatments
CA2600570C (en) 2005-03-14 2011-12-06 Transtech Pharma, Inc. Benzazole derivatives, compositions, and methods of use as .beta.-secretase inhibitors
WO2008013270A1 (en) 2006-07-28 2008-01-31 Ono Pharmaceutical Co., Ltd. Method for diagnosis of neuropsychiatric disease
WO2008082003A1 (en) * 2006-12-29 2008-07-10 Takeda Pharmaceutical Company Limited Fused heterocyclic compounds having crf antagonistic activity
MX2010008039A (en) * 2008-01-22 2010-08-10 Takeda Pharmaceutical Tricyclic compounds having corticotropin-releasing factor antagonistic activity and pharmaceutical compositions containing them.
UY32045A (en) * 2008-08-12 2010-03-26 Takeda Pharmaceutical AMIDA COMPOUND

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8557798B2 (en) 2005-06-14 2013-10-15 Merck Sharp & Dohme Corp. Macrocyclic heterocyclic aspartyl protease inhibitors
US7812013B2 (en) 2005-06-14 2010-10-12 Schering Corporation Macrocyclic heterocyclic aspartyl protease inhibitors
EP2088861A2 (en) * 2006-10-25 2009-08-19 Takeda Pharmaceutical Company Limited Benzimidazole compounds
EP2088861A4 (en) * 2006-10-25 2010-07-07 Takeda Pharmaceutical Benzimidazole compounds
WO2008051533A2 (en) 2006-10-25 2008-05-02 Takeda Pharmaceutical Company Limited Benzimidazole compounds
WO2008082003A1 (en) * 2006-12-29 2008-07-10 Takeda Pharmaceutical Company Limited Fused heterocyclic compounds having crf antagonistic activity
JP2010514672A (en) * 2006-12-29 2010-05-06 武田薬品工業株式会社 Fused heterocyclic compounds having CRF antagonist activity
US8039500B2 (en) 2006-12-29 2011-10-18 Takeda Pharmaceutical Company Limited Fused heterocyclic compounds
US8901141B2 (en) 2008-01-22 2014-12-02 Takeda Pharmaceutical Company, Limited Tricyclic compounds having corticotropin-releasing factor antagonistic activity and pharmaceutical compositions containing them
WO2009093747A1 (en) * 2008-01-22 2009-07-30 Takeda Pharmaceutical Company Limited Tricyclic compounds having corticotropin-releasing factor antagonistic activity and pharmaceutical compositions containing them
US8785460B2 (en) 2008-01-22 2014-07-22 Takeda Pharmaceutical Company Limited Tricyclic compounds and use thereof
JP2011509923A (en) * 2008-01-22 2011-03-31 武田薬品工業株式会社 Tricyclic compounds having antagonism of corticotropin releasing factor and pharmaceutical compositions containing them
WO2010018874A1 (en) * 2008-08-12 2010-02-18 Takeda Pharmaceutical Company Limited Amide compound
WO2010032461A1 (en) * 2008-09-17 2010-03-25 武田薬品工業株式会社 Nitrogen-containing fused ring compound
US8394969B2 (en) 2008-09-26 2013-03-12 Merck Sharp & Dohme Corp. Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8410284B2 (en) 2008-10-22 2013-04-02 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8563746B2 (en) 2008-10-29 2013-10-22 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8329914B2 (en) 2008-10-31 2012-12-11 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
WO2011078360A1 (en) 2009-12-24 2011-06-30 武田薬品工業株式会社 Amide compound
US8895596B2 (en) 2010-02-25 2014-11-25 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US9296758B2 (en) 2010-07-02 2016-03-29 Gilead Sciences, Inc. 2-quinolinyl-acetic acid derivatives as HIV antiviral compounds
US9102614B2 (en) 2010-07-02 2015-08-11 Gilead Sciences, Inc. Naphth-2-ylacetic acid derivatives to treat AIDS
US9006229B2 (en) 2011-04-21 2015-04-14 Gilead Sciences, Inc. Benzothiazole compounds and their pharmaceutical use
WO2013024898A1 (en) 2011-08-18 2013-02-21 日本新薬株式会社 Heterocyclic derivative and pharmaceutical drug
US9284323B2 (en) 2012-01-04 2016-03-15 Gilead Sciences, Inc. Naphthalene acetic acid derivatives against HIV infection
US9376392B2 (en) 2012-01-04 2016-06-28 Gilead Sciences, Inc. 2-(tert-butoxy)-2-(7-methylquinolin-6-yl) acetic acid derivatives for treating AIDS
US9096586B2 (en) 2012-04-20 2015-08-04 Gilead Sciences, Inc. Therapeutic compounds
US8987250B2 (en) 2012-04-20 2015-03-24 Gilead Sciences, Inc. Therapeutic compounds
WO2015112642A1 (en) 2014-01-21 2015-07-30 Neurocrine Biosciences, Inc. Crf1 receptor antagonists for the treatment of congenital adrenal hyperplasia
US11730739B2 (en) 2014-01-21 2023-08-22 Neurocrine Biosciences, Inc. Treatment of congenital adrenal hyperplasia
US11311544B2 (en) 2014-01-21 2022-04-26 Neurocrine Biosciences, Inc. Treatment of congenital adrenal hyperplasia
US10905690B2 (en) 2014-01-21 2021-02-02 Neurocrine Biosciences, Inc. Treatment of congenital adrenal hyperplasia
EP3674298A1 (en) 2014-11-26 2020-07-01 Bayer Pharma Aktiengesellschaft Substituted indazoles, process for their preparation, pharmaceutical formulations containing them, and their use for the preparation of medicaments
US10308634B2 (en) 2014-11-26 2019-06-04 Bayer Pharma Aktiengesellschaft Substituted indazoles, methods for the production thereof, pharmaceutical preparations that contain said new substituted indazoles, and use of said new substituted indazoles to produce drugs
US10793545B2 (en) 2014-11-26 2020-10-06 Bayer Pharma Aktiengesellschaft Substituted indazoles, methods for the production thereof, pharmaceutical preparations that contain said new substituted indazoles, and use of said new substituted indazoles to produce drugs
EP4260909A2 (en) 2014-11-26 2023-10-18 Bayer Pharma Aktiengesellschaft Substituted indazoles, process for their preparation, pharmaceutical preparations containing them and their use in the preparation of drugs
WO2016174183A1 (en) 2015-04-30 2016-11-03 Bayer Pharma Aktiengesellschaft Combinations of inhibitors of irak4 with inhibitors of btk
EP3195865A1 (en) 2016-01-25 2017-07-26 Bayer Pharma Aktiengesellschaft Combinations of inhibitors of irak4 with inhibitors of btk
WO2017157792A1 (en) 2016-03-17 2017-09-21 Bayer Pharma Aktiengesellschaft Combinations of copanlisib
EP3219329A1 (en) 2016-03-17 2017-09-20 Bayer Pharma Aktiengesellschaft Combinations of copanlisib
WO2017207386A1 (en) 2016-06-01 2017-12-07 Bayer Pharma Aktiengesellschaft Use of 2-substituted indazoles for the treatment and prophylaxis of autoimmune diseases
WO2017207481A1 (en) 2016-06-01 2017-12-07 Bayer Animal Health Gmbh Substituted indazoles ueful for treatment and prevention of allergic and/or inflammatory diseases in animals
WO2018095953A1 (en) 2016-11-23 2018-05-31 Bayer Cropscience Aktiengesellschaft 2-[3-(alkylsulfonyl)-2h-indazol-2-yl]-3h-imidazo[4,5-b]pyridine derivatives and similar compounds as pesticides

Also Published As

Publication number Publication date
EP1874736A4 (en) 2008-08-20
IL186407A (en) 2014-04-30
BRPI0610150A2 (en) 2012-09-25
IL186407A0 (en) 2008-01-20
RU2408586C2 (en) 2011-01-10
NO20075936L (en) 2007-11-19
TW200716639A (en) 2007-05-01
CA2605453A1 (en) 2006-11-02
GEP20104962B (en) 2010-04-26
AU2006241210B2 (en) 2011-11-17
US8163935B2 (en) 2012-04-24
KR20080000625A (en) 2008-01-02
JP2008539247A (en) 2008-11-13
WO2006116412A3 (en) 2007-06-28
EP1874736A2 (en) 2008-01-09
US20090312383A1 (en) 2009-12-17
AU2006241210A1 (en) 2006-11-02
TWI370820B (en) 2012-08-21
AR053859A1 (en) 2007-05-23
JP5061097B2 (en) 2012-10-31
PE20061377A1 (en) 2007-01-18
MX2007013154A (en) 2008-01-21
WO2006116412A8 (en) 2007-03-01
NZ562235A (en) 2010-03-26
MA29486B1 (en) 2008-05-02
KR101368037B1 (en) 2014-02-26
RU2007143966A (en) 2009-06-10
CR9421A (en) 2007-12-12

Similar Documents

Publication Publication Date Title
US8163935B2 (en) Fused heterocyclic compounds
KR102228764B1 (en) Heterocyclic amides as kinase inhibitors
CA2543707A1 (en) Nitrogen-containing fused heterocyclic compounds
EP2088861A2 (en) Benzimidazole compounds
CA3203080A1 (en) Preparation and application method of heterocyclic compound as kras inhibitor
HRP20040311A2 (en) Spiro-hydantoin compounds useful as anti-inflammatory agents
CA2873921A1 (en) 1,3-dihydro-2h-benzimidazol-2-one derivatives substituted with benzimidazoles as respiratory syncytial virus antiviral agents
KR20050084170A (en) 4-substituted benzimidazoles and their use as inhibitors of gastric secretion
KR20010049859A (en) NEW β-CARBOLINE COMPOUNDS, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
AU2007264791A1 (en) Derivatives of ureas of piperidine or pyrrolidine, their preparation and their therapeutical use
EP0682021A1 (en) Benzimidazoles, medicines containing them and process for their preparation
JPH06145170A (en) Heterocyclic compound, its preparation and medicinal composition for treatment of hypertension and congestive heart failure
JPWO2010035745A1 (en) Heterocyclic biaryl derivatives and PDE inhibitors containing them as active ingredients
JP2011516398A (en) Benzimidazole derivatives having heterospiro-decane residues as NPY-Y5 antagonists
EP2125753A1 (en) Fused heterocyclic compounds having crf antagonistic activity
CA2100927A1 (en) Benzimidazoles, pharmaceutical compositions containing these compounds and processes for preparing them
SK279409B6 (en) Benzimidazoles, pharmaceutical compositions containing them and process for their preparation
JP2012509249A (en) Glycogen synthase kinase-3 beta inhibitor comprising 7-hydroxy-benzimidazol-4-yl-methanone derivative
CN101166729B (en) Fused heterocyclic compounds
EP2197872A1 (en) Phenylisoquinoline and phenylquinazoline derivatives for the treatment of bone diseases
SK282473B6 (en) Benzimidazole compound, its production method, stable crystal, pharmaceutical preparation and intermediate

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 200680014713.7

Country of ref document: CN

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 562235

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 186407

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 3812/KOLNP/2007

Country of ref document: IN

Ref document number: CR2007-009421

Country of ref document: CR

WWE Wipo information: entry into national phase

Ref document number: 2006241210

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2605453

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: MX/a/2007/013154

Country of ref document: MX

Ref document number: 2006751379

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 12007502388

Country of ref document: PH

ENP Entry into the national phase

Ref document number: 2008509045

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 10339

Country of ref document: GE

Ref document number: 07113630

Country of ref document: CO

Ref document number: 1020077024873

Country of ref document: KR

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2006241210

Country of ref document: AU

Date of ref document: 20060426

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 2007143966

Country of ref document: RU

Ref document number: A20071447

Country of ref document: BY

WWE Wipo information: entry into national phase

Ref document number: 11919435

Country of ref document: US

ENP Entry into the national phase

Ref document number: PI0610150

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20071026