WO2005026155A1 - Benzimidazole acetonitriles - Google Patents

Benzimidazole acetonitriles Download PDF

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Publication number
WO2005026155A1
WO2005026155A1 PCT/EP2004/052137 EP2004052137W WO2005026155A1 WO 2005026155 A1 WO2005026155 A1 WO 2005026155A1 EP 2004052137 W EP2004052137 W EP 2004052137W WO 2005026155 A1 WO2005026155 A1 WO 2005026155A1
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Prior art keywords
ethyl
benzimidazol
dihydro
ylidene
acetonitrile
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PCT/EP2004/052137
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French (fr)
Inventor
Mattias Schwarz
Pascale Gaillard
Patrick Page
Jean-Pierre Gotteland
Russell J. Thomas
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Applied Research Systems Ars Holding N.V.
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Priority to CA002534317A priority Critical patent/CA2534317A1/en
Priority to US10/571,470 priority patent/US20070203134A1/en
Priority to AU2004272306A priority patent/AU2004272306A1/en
Priority to JP2006525833A priority patent/JP2007505085A/en
Priority to EP04766767A priority patent/EP1667995A1/en
Publication of WO2005026155A1 publication Critical patent/WO2005026155A1/en
Priority to IL174135A priority patent/IL174135A0/en
Priority to NO20061614A priority patent/NO20061614L/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • 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
    • C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D403/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention is related to benzimidazole acetonitriles, as well as pharmaceutical compositions containing such benzimida_.ole acetonitriles.
  • the compounds ofthe present invention axe useful in the treatment of metabolic disorders mediated by insulin resistance or hyperglycemia, comprising diabetes type II, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS).
  • the compounds ofthe present invention are inhibitors of Glycogen Synthase Kinase 3 (GSK3).
  • the present invention furthermore relates to methods for the preparation of benzimidazole acetonitriles.
  • Diabetes mellitus is a serious metabolic disease that is defined by the presence of chemically elevated levels of blood glucose (hyperglycemia).
  • diabetes mellitus encompasses several different hyperglycemic states. These states include Type 1 (insulin- dependent diabetes mellitus or IDDM) and Type 2 (non- insulin dependent diabetes mellitus or NIDDM) diabetes.
  • IDDM insulin-dependent diabetes mellitus
  • NIDDM non- insulin dependent diabetes mellitus
  • the hyperglycemia present in individuals with Type 1 diabetes is associated with deficient, reduced, or nonexistent levels of insulin that are insufficient to maintain blood glucose levels within the physiological range.
  • Type 1 diabetes is treated by administration of replacement doses of insulin, generally by a parenteral route.
  • Type 2 diabetes is an increasingly prevalent disease of aging. It is initially characterized by decreased sensitivity to insulin and a compensatory elevation in circulating insulin concentrations, the latter of which is required to maintain normal blood glucose levels. As described below, GSK3 inhibition stimulates insulin-dependent processes and is consequently viewed to be useful in the treatment of type 2 diabetes. Recent data obtained using lithium salts provides evidence for this notion.
  • Hyperinsulinemia may be present as a result of insulin resistance, such as is in obese and/or diabetic (NIDDM) subjects and/or glucose intolerant subjects, or in TDDM subjects, as a consequence of over injection of insulin compared with normal physiological release ofthe hormone by the endocrine pancreas.
  • NIDDM diabetic diabetic
  • PCOS Polycystic Ovary Syndrome
  • Type II diabetes mellitus is currently treated with sulfonylureas, biguanides, such as Metformin and thiazolidenediones, such as Troglitazone, Rosiglitazone or Pioglitazone, as oral hypoglycemic agents.
  • biguanides such as Metformin
  • thiazolidenediones such as Troglitazone, Rosiglitazone or Pioglitazone
  • Glycogen synthase kinase 3 is a serine/threonine kinase for which two isoforms, and ⁇ , have been identified (Trends Biochem. Sci., 16 p.177-81 (1991) by Woodgett et al.). Both GSK3 isoforms are constitutively active in resting cells. GSK3 was originally identified as a kinase that inhibits glycogen synthase by direct phosphorylation. Upon insulin activation, GSK3 is inactivated, thereby allowing the activation of glycogen synthase and possibly other insulin-dependent events, such glucose transport.
  • GSK3 activity is also inactivated by other growth factors that, like insulin, signal through receptor tyrosine Mnases (RTKs).
  • RTKs receptor tyrosine Mnases
  • Examples of such signalling molecules include IGF-1 and EGF.
  • GSK3 beta activity is regulated by serine (inhibitory) and tyrosine (stimulatory) phosphorylation, by protein complex formation, and by its intracellular localization. GSK3 beta phosphorylates and thereby regulates the functions of many metabolic, signalling and structural proteins. Notable among the signalling proteins regulated by GSK3 beta are the many transcription factors, including activator protein- 1 cells, Myc, beta-catenin, CCAAT/enhancer binding protein, and NFkappaB.
  • GSK3 inhibitors e.g. WO 02/20495, Chiron Corporation; WO 02/10141, Pfizer Products Inc.; WO 02/22608, Vertex Pharmaceuticals Inc.).
  • WO 01/47920 discloses benzazoles of formula (A) in particular for the treatment of neuronal disorders, autoimmune diseases, cancer and cardiovascular diseases.
  • the present invention relates to benzimidazole acetonitriles of formula (I)
  • the present invention relates to the use of compounds of formula (I) as medicament, in particular for the treatment and/or prevention of metabolic disorders mediated by insulin resistance or hyperglycemia, such as diabetes type II, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS).
  • metabolic disorders mediated by insulin resistance or hyperglycemia such as diabetes type II, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS).
  • Ci-C ⁇ -alkyl refers to alkyl groups having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-butyl, n-pentyl, n-hexyl and the like.
  • Aryl refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl).
  • Preferred aryl include phenyl, naphthyl, phenantrenyl and the like.
  • C ⁇ -C6-alkyl aryl refers to Ci-Ce-alkyl groups having an aryl substituent, including benzyl, phenethyl and the like.
  • Heteroaryl refers to a monocyclic heteroaromatic, or a bicyclic or a tricyclic fused-ring heteroaromatic group.
  • Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1 ,2,4-oxadia- zolyl, 1,2,5-oxadiazolyl, l,3,4-oxadiazolyl,l,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3- dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl,
  • Ci-C ⁇ -alkyl heteroaryl refers to Ci-C ⁇ -alkyl groups having a heteroaryl substituent, including 2--_urylmethyl, 2-thienylmethyl, 2-(lH-indol-3-yl)et__yl and the like.
  • C 2 -C6-alkenyl aryl refers to Gj-C ⁇ -alkenyl groups having an aryl substituent, including 2- phenylvinyl and the like.
  • C 2 -C 6 -alkenyl heteroaryl refers to C 2 -C 6 -alkenyl groups having a heteroaryl substituent, including 2-(3-pyridinyl)vinyl and the like.
  • C 2 -C 6 -alkyny_ refers to alkynyl groups preferably having from 2 to 6 carbon atoms and having at least 1-2 sites of alkynyl unsaturation, preferred alkynyl groups include ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), and the like.
  • C 2 -C6-alkynyl aryl refers to C 2 -C 6 -aIkynyl groups having an aryl substituent, including phenylethynyl and the like.
  • C 2 -C6-alkynyl heteroaryl refers to C 2 -C6-alkynyl groups having a heteroaryl substituent, including 2-thienylethynyl and the like.
  • C 3 -C 8 -cycloalkyl refers to a saturated carbocyclic group of from 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl).
  • Preferred cycloalkyl include cyclopentyl, cyclohexyl, norbornyl and the like.
  • Ci-C ⁇ -alkyl cycloalkyl refers to Ci-C 6 -alkyl groups having a cycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl, and the like.
  • heterocycloalkyl refers to a C 3 -Cs-cycloalkyl group according to the definition above, in which 1 to 3 carbon atoms are replaced by hetero atoms chosen from the group consisting of O, S, NR, R being defined as hydrogen or Ci-C- ⁇ alkyl.
  • Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, and the like.
  • Ci-C ⁇ -alkyl heterocycloalkyl refers to C ⁇ -C 6 -alkyl groups having a heterocycloalkyl substituent, including 2-(l-pyrro_idiny_)ethyl, 4-mo holinylmethyl, (l-methyl-4- piperidinyl)methyl and the like.
  • Carboxy refers to the group -C(0)OH.
  • Ci-C ⁇ -alkyl carboxy refers to Ct-C ⁇ -alkyl groups having a carboxy substituent, including 2-carboxyethyl and the like.
  • Acyl refers to the group -C(0)R where R includes H, "Ci- -alkyl”, “C 2 -C 6 -alkenyl”, “C 2 -C6-alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl", “C 2 - Ce-alkynyl aryl”, “C -C 6 -alkynylhetcroaryl", “C ⁇ -C 5 -alkyl cycloalkyl", “C]-C 5 -alkyl heterocycloalkyl”.
  • Ci-C ⁇ -alkyl acyl refers to Ci-C ⁇ -alkyl groups having an acyl substituent, including 2- acetylethyl and the like.
  • Aryl acyl refers to aryl groups having an acyl substituent, including 2-acetylphenyl and the like.
  • Heteroaryl acyl refers to hetereoaryl groups having an acyl substituent, including 2- acetylpyridyl and the like.
  • C 3 -C 8 -(hetero)cycloalkyl acyl refers to 3 to 8 membered cycloalkyl or heterocycloalkyl groups having an acyl substituent.
  • Acyloxy refers to the group -OC(0)R where R includes H, "C ⁇ -C 6 -alkyl", “C 2 -C 6 - alkenyl", “C 2 -C 6 -alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 -alkynylhetero_ ⁇ ry_", “d-Ce-alkyl cycloalkyl", “Ci-Ce-alkyl heterocycloalkyl”.
  • Ci-C ⁇ -alkyl acyloxy refers to Ci
  • Alkoxy refers to the group -O-R where R includes "C ⁇ -C 6 -alkyl”, “C 2 -C 6 -alkenyl”, “C 2 - Ce-alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “C ⁇ -C 6 -alkyl aryl” or “Ci-Ce-alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl", “C 2 - Ce-alkynyl aryl", “C2-C 6 -alkynylheteroaryl", “C ⁇ -C 6 -alkyl cycloalkyl", “C ⁇ -C 6 -alkyl heterocycloalkyl”.
  • Ci-C ⁇ -alkyl alkoxy refers to Ci-Cg-alkyl groups having an alkoxy substituent, including 2-ethoxyethyl and the like.
  • Alkoxycarbonyl refers to the group -C(0)OR where R includes "C ⁇ -C 6 -alkyl", “C 2 -C 6 - alkenyl", “C 2 -C 5 -alkynyl", “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “CfCg-alkyl aryl” or "C.-C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 -alkynylheteroaryl", “d-Ce-alkyl cycloalkyl", “Ci-Ce-alkyl heterocycloalkyl”.
  • Ci-C ⁇ -alkyl alkoxycarbonyl refers to C ⁇ -C6-alkyl groups having an alkoxycarbonyl substituent, including 2-(ben..yloxycarbonyl)ethyl and the like.
  • Aminocarbonyl refers to the group -C(0)NRR' where each R, R' includes independently hydrogen, "C ⁇ -C 5 -alkyl", “C 2 -C 6 -alkenyl", “C2-C 6 -alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “C,-C 6 -alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 - alkynylheteroaryl", “Ci-C ⁇ -alkyl cycloalkyl", “Ci-C ⁇ -alkyl heterocycloalkyl”.
  • C ⁇ -C 6 -alkyl aminocarbonyl refers to Ci-C ⁇ -alkyl groups having an aminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl and the like.
  • ⁇ cylamino refers to the group -NRC(0)R' where each R, R' is independently hydrogen, "Ci-Ce-alkyl", “C 2 -C 6 -alkenyl”, “C 2 -C 6 -alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “C ⁇ -C 6 -alkyl aryl” or "C ⁇ -C 6 -alkyl heteroaryl", "C 2 -C 6 -alkenyl aryl”, “C 2 -C 6 -alkenyl heteroaryl", "C 2 -C 6 -alkynyl aryl", “Cz-Ce-al
  • C ⁇ -C6-alkyl acylamino refers to Ci-C ⁇ -alkyl groups having an acylamino substituent, including 2-(propionylamino)ethyl and the like.
  • “Ureido” refers to the group -NRC(0)NR'R” where each R, R', R" is independently hydrogen, "C 2 -C 6 -alkenyl", “C 2 -C 6 -alkynyl", “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “C ⁇ -C 5 -alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 - alkynylheteroaryr', "Ci-C ⁇ -alkyl cycloalkyl", “Ci-Ce-alkyl heterocycloalkyl”, and where R' and R", together with the nitrogen atom to which they are
  • C ⁇ -C6-alkyl ureido refers to C ⁇ -C 6 -alkyl groups having an ureido substituent, including 2- (iV-methylureido)ethyl and the like. ⁇
  • “Carbamate” refers to the group -NRC(0)OR' where each R, R' is independently hydrogen, "Ci-Ce-alkyl", “C 2 -C 6 -alkenyl”, “C 2 -C 6 -alkynyl", “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “C ⁇ -C 6 -alkyl aryl” or “Ci-Ce-alkyl heteroaryl", “Ca-Ce-alkenyl aryl", “C 2 -C 5 -alkenyl heteroaryl", “C 2 -C 6 -alkvnyl aryl", “C 2 -C 6 - alkynylheteroaryl", “Ci-Ce-alkyl cycloalkyl", “C ⁇ -C 6 -alkyl heterocycloalkyl”.
  • Amino refers to the group -NRR' where each R, R' is independently hydrogen, "Ci-Ce- alkyl", “d-Ce-alkenyl”, “C 2 -C 6 -alkvnyl", “d-Cg-cycloalkyl”, “heterocycloalkyl”, “aryl”, “heteroaryl”, “d-C 6 -alkyl aryl” or “Ci-Ce-alkyl heteroaryl", “d-Ce-alkenyl aryl”, “C 2 -C 6 - alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 -alkynylheteroaryl", “C ⁇ -C 6 -alkyl cycloalkyl", “Ci-Ce-alkyl heterocycloalkyl”, and where R and R ⁇ together with the nitrogen atom to which they are attached, can optionally form a 3-8
  • C ⁇ -C6-alkyl amino refers to Ci-Ce-alkyl groups having an amino substituent, including 2- (l-pyrrolidinyl)ethyl and the like.
  • Ammonium refers to a positively charged group -N + RR'R", where each R, R ⁇ R" is independently, “Ci-Ce-alkyl", “C 2 -C 6 -alkenyl”, “Ca-Ce-alkynyl", “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “C ⁇ -C 6 -alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", “C 2 -C 6 -alkenyl aryl”, “d-Ce-alkenyl heteroaryl", “C 2 -C 6 -alkynyl aryl", “C 2 -C 6 -alkynylheteroaryl", “Ci-Ce-alkyl cycloalkyl", “Ci-C ⁇ -alkyl heterocycloalkyl”, and where R and R', together with the nitrogen atom to which they are attached, can optionally form a
  • C ⁇ -C6-alkyl ammonium refers to Ci-Ce-alkyl groups having an ammonium substituent, including 2-(l-pyrrolidinyl)ethyl and the like.
  • Halogen refers to fluoro, chloro, bromo and iodo atoms.
  • “Sulfonyloxy” refers to a group -OS0 2 -R wherein R is selected from H, "Ci-Ce-alkyl", “Ci-Ce-alkyl” substituted with halogens, e.g., an -0S0 2 -CF 3 group, "C 2 -C 6 -alkenyl", “C 2 - Ce-alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl", “Ci-Ce-alkyl aryl” or “Ci-Ce-alkyl heteroaryl", "C 2 -C 6 -a_kenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 - Ce-alkynyl aryl”, “C2-C6-alkynylheteroaryl", "C,-C 6 -alkyl cyclo
  • C ⁇ -C_ -alkyl sulfonyloxy refers to C ⁇ -C6-alkyl groups having a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and the like.
  • “Sulfonyl” refers to group “-SO 2 -R" wherein R is selected from H, "aryl", “heteroaryl”, “Ci-C ⁇ -alkyl", “Ci-Ce-alkyl” substituted with halogens, e.g., an -S0 2 -CF 3 group, "C 2 -C 6 - alkenyl”, “C 2 -C 6 -alkynyl”, “C 3 -C 8 -cycloalkyl”, “heterocycloalkyl", “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “Ci-Ce-alkyl heteroaryl", "C -C 6 -alkenyl axyl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 -Ce-alkynyl aryl”, “C 2 -Ce-alkynylheteroaryl", "C
  • Ci-C ⁇ -alkyl sulfonyl refers to Ci-C ⁇ -alkyl groups having a sulfonyl substituent, including 2-(methylsulfonyl)ethyl and the like.
  • “Sulfinyl” refers to a group “-S(0)-R” wherein R is selected from H, "Ci-Ce-alkyl", “Ci- C6-alkyl” substituted with halogens, e.g., an -SO-CF3 group, "C2-C6-alkenyl”, “C2-C6- alkynyl”, “d-Cg-cycloalkyl", “heterocycloalkyl”, “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “Ci-Ce-alkyl heteroaryl", "C 2 -C 6 -alkenyl aryl", “C 2 -Ce-alkenyl heteroaryl", “C 2 -C 6 - alkynyl aryl", “C 2 -C 6 -alkynylheteroaryl", “Ci-Ce-alkyl cycloalkyl", "Ci-Ce-
  • Ci-C ⁇ -alkyl sulfinyl refers to C ⁇ -C6-alkyl groups having a sulfinyl substituent, including 2-(methylsulfinyl)ethyl and the like.
  • Sulfanyl refers to groups -S-R where R includes H, "Ci-Ce-alkyl", “C_ -C 6 -alkyl” substituted with halogens, e.g., an -SO-CF3 group, "C 2 -C6-alkenyl”, “C 2 -Ce-alkynyl”, “C 3 - C 8 -cycloalkyl", "heterocycloalkyl", “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “Ci-Ce-alkyl heteroaryl", "C 2 -C 6 -alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “Ca-Ce-alkynyl aryl", “C 2 - C 6 -alkynylheteroaryl”, “C ⁇ -C 6 -alkyl cycloalkyl", "Ci-Ce-al
  • C ⁇ -C6-alkyl sulfanyl refers to Ci-C ⁇ -alkyl groups having a sulfanyl substituent, including 2-(ethylsulfanyl)ethyl and the like.
  • “Sulfonylamino” refers to a group -NRS0 2 -R' where each R, R' includes independently hydrogen, "Ci-Ce-alkyl", “C 2 -C 3 -alkenyl", “d-Ce-alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “d -C 6 -alkyl aryl” or “Ci -C 6 -alkyl heteroaryl", “d-Ce-alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “C 2 -Ce-alkynyl aryl", “C 2 -C 6 - alkynylheteroaryl", “Ci-Ce-alkyl cycloalkyl", “d-Ce-alkyl heterocycloalkyl”.
  • C ⁇ -C 6 -alkyl sulfonylamino refers to Ci-C ⁇ -alkyl groups having a sulfonylamino substituent, including 2 ⁇ (ethylsulfonylamino)ethyl and the like.
  • Aminosulfonyl refers to a group -S0 2 -NRR' where each R, R' includes independently hydrogen, "Ci-Ce-alkyl", “C 2 -C 6 -alkenyl”, “d-Ce-alkynyl”, “C 3 -C 8 -cycloalkyl", “heterocycloalkyl", “aryl”, “heteroaryl”, “Ci-Ce-alkyl aryl” or “C ⁇ -C 6 -alkyl heteroaryl", “d-Ce-alkenyl aryl", “C 2 -C 6 -alkenyl heteroaryl", “d-Ce-alkynyl aryl", “C 2 -C 6 - alkynylheteroaryl”, “Ci-Ce-alkyl cycloalkyl", “Ci-Ce-alkyl heterocycloalkyl”.
  • C ⁇ -C 6 -alkyl aminosulfonyl refers to C ⁇ -C 6 -alkyl groups having an aminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)e_hyl and the like.
  • cycloalkyl "heterocycloalkyl”, “C ⁇ -C 6 -alkyl aryl”, “C ⁇ -C 6 -alkyl heteroaryl", “C ⁇ -C 6 - alkyl cycloalkyl”, “Ci-C ⁇ -alkyl heterocycloalkyl”, "amino”, “ammonium”, “acyl”, “acyloxy”, “acylamino”, “aminocarbonyl”, “alkoxycarbonyl”, “ureido”, “carbamate”, "aryl”, “heteroaryl”, “sulfinyl”, “sulfonyl”, “alkoxy”, “sulfanyl”, “halogen”, “carboxy”, trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like.
  • said substitution could also comprise situations where neighbouring substituents have undergone ring closure, notably when vicinal i ⁇ tnctional substituents are involved, thus forming, e.g., lactams, lactons, cyclic anhydrides, but also acetals, thioacetals, aminals formed by ring closure for instance in an effort to obtain a protective group.
  • “Pharmaceutically acceptable salts or complexes” refers to salts or complexes ofthe below- identified compounds of formula (I) that retain the desired biological activity.
  • Examples of such salts include, but are not restricted to acid addition salts formed with inorganic acids (e.g.
  • hydrochloric acid hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
  • salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, methanesulfonic acid and poly-galacturonic acid.
  • Said compounds can also be administered as pharmaceutically acceptable quaternary salts known by a person skilled in the art, which specifically include the quarternary ammonium salt ofthe formula - NR,R',R" + Z " , wherein R, R R" is independently hydrogen, alkyl, or benzyl, C ⁇ -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C ⁇ -C 6 -alkyl aryl, Ci-C ⁇ -alkyl heteroaryl, cycloalkyl, heterocycloalkyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, as
  • “Pharmaceutically active derivative” refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the activity disclosed herein.
  • Enantiomeric excess refers to the products that are obtained by an asymmetric synthesis, i.e. a synthesis involving non-racemic starting materials and/or reagents or a synthesis comprising at least one enantioselective step, whereby a surplus of one enantiomer in the order of at least about 52% ee is yielded.
  • a first aspect ofthe invention consists in benzimidazole acetonitriles of formula I
  • G is an unsubstituted or substituted pyrimidinyl.
  • G may be either ofthe substituted pyrimidinyl moieties
  • L is an amino group, or an unsubstituted or a substituted 3-8 membered heterocycloalkyl, containing at least one heteroatom selected from N, O, S or L is an acylamino moiety.
  • R 1 is selected from the group comprising or consisting of hydrogen, sulfonyl, amino, carboxy, amino carbonyl, unsubstituted or substituted C ⁇ -C6-alkyl, unsubstituted or substituted C 2 -C6-alkenyl, unsubstituted or substituted d-Ce-alkynyl or Ci-C ⁇ -alkoxy, unsubstituted or substituted aryl (e.g. phenyl), halogen, cyano or hydroxy.
  • aryl e.g. phenyl
  • R 1 is II or C ⁇ -C 3 alkyl (e.g. a methyl or ethyl group).
  • R 2 is selected from the group comprising or consisting of hydrogen, unsubstituted or substituted C ⁇ -C 6 -alkyl, unsubstituted or substituted aryl (e.g. phenyl), unsubstituted or substituted C 2 -C 6 -alkenyl, unsubstituted or substituted C 2 -C 6 -alkynyl, unsubstituted or substituted cycloalkyl or Ci-Ce-alkoxy.
  • R 2 is a Ci-d alkyl (e.g. an ethyl group).
  • R 3 is selected from the group comprising or consisting of hydrogen, unsubstituted or substituted Ci-C ⁇ -alkyl, unsubstituted or substituted aryl (e.g. phenyl), unsubstituted or substituted C 2 -C 6 -alkenyl, unsubstituted or substituted d-Ce-alkynyl, unsubstituted or substituted cycloalkyl or C ⁇ -C6-alkoxy.
  • aryl e.g. phenyl
  • R 3 is selected from the group comprising or consisting of hydrogen, unsubstituted or substituted Ci-C ⁇ -alkyl, unsubstituted or substituted aryl (e.g. phenyl), unsubstituted or substituted C 2 -C 6 -alkenyl, unsubstituted or substituted d-Ce-alkynyl, unsubstituted or substituted cycloalkyl or
  • R 3 is hydrogen or a C 1 -C 3 alkyl (e.g. a methyl or an ethyl group).
  • the compounds ofthe present invention also comprises their tautomers, their geometrical isomers, their optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof.
  • Preferred pharmaceutically acceptable salts ofthe formula (I) are acid addition salts formed with pharmaceutically acceptable acids like hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, trifluoroacetate, and/. ⁇ r ⁇ -toluenesulfonate salts.
  • the benzimidazole acetonitriles ofthe present invention comprise the tautomeric forms, e.g. the below ones :
  • a specific embodiment of he present invention consists in benzimidazole acetonitriles of formula (la) in its tautomeric forms, e.g. the below ones :
  • R 1 , R 2 , R 3 and L are as defined for formula (I).
  • the moiety L is an amino group ofthe formula - NR 5 R 6 wherein R 5 and R 6 are each independently from each other H, unsubstituted or substituted Ci-Ce-alkyl, unsubstituted or substituted C 2 -C6-alkenyl, unsubstituted or substituted C 2 -C 6 -alkynyl, unsubstituted or substituted Ci-C ⁇ -alkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, unsubstituted or substituted 3-8- membered heterocycloalkyl, (wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group), unsubsti
  • R 3 is hydrogen or a methyl or ethyl or propyl group and R 6 is selected from the group consisting of unsubstituted or substituted Ci-C ⁇ -alkyl, unsubstituted or substituted Ci-C ⁇ alkyl-aryl, unsubstituted or substituted Ci-Ce-alkyl- heteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl or heteroaryl and unsubstituted or substituted 4-8 membered saturated or unsaturated cycloalkyl.
  • R 5 is H and R 6 is selected from the group consisting of Ci-d alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, heteroaryl, Ci-Ce-alkyl heteroaryl, C ⁇ -C 6 -alkyl cycloalkyl, C ⁇ -C 6 -alkyl heterocycloalkyl.
  • Examples of cycloalkyl are cyclopropyl, cyclopentyl or cyclohexyl.
  • R 6 may be a d- alkyl, in particular an ethylene or propylene moiety, optionally substituted with an imsubstituted or substituted heteroaryl group, e.g., an unsubstituted or substituted pyridyl or a 2-pyrrolidinone (2-oxopyrrolidine) or a triazolyl moiety.
  • an imsubstituted or substituted heteroaryl group e.g., an unsubstituted or substituted pyridyl or a 2-pyrrolidinone (2-oxopyrrolidine) or a triazolyl moiety.
  • the moiety L is an acylamino moiety of the formula -NR 5 C(0)R 6 wherein R 5 andR 6 are each independently from each other H, unsubstituted or substituted C ⁇ -C6-alkyl, unsubstituted or substituted d-d-a-kenyl, unsubstituted or substituted C2-C6-alkynyl, unsubstituted or substituted C ⁇ -C6-alkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, unsubstituted or substituted 3-8-membered heterocycloalkyl, unsubstituted or substituted Ci-d-alkyl aryl, unsubstituted or substituted Ci-d-all yl heteroaryl, unsubstituted or substituted Ci-d- al
  • the compounds of formula (I) are useful in inhibiting Glycogen Synthase Kinase 3
  • Still a further object ofthe present invention is a process for preparing the benzimidazole acetonitriles according to formula I.
  • benzimidazole acetonitriles exemplified in this invention may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e., reaction temperatures, time, moles of reagents, solvents, etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimisation procedures.
  • the benzimidazole acetonitriles derivatives according to the general formula I may be obtained by several processes using solution-phase chemistry protocols.
  • the benzimidazole acetonitrile derivative VI with R 1 being as above defined - is reacted with the electrophile VII (e.g. alkyl chloride) to give the corresponding benzimidazole compounds IV.
  • the intermediate IV is treated with a bis-chloro derivative V, wherein G is as above defined, to give the intermediate of synthesis II.
  • the intermediate II may be treated with an amine III, whereby the substituents R 5 , R 6 are as above defined to give the final benzimidazole acetonitrile derivatives I, utilizing well known solution-phase chemistry protocols, such as those described in the Examples and shown in Scheme 2, below :
  • Electrophiles VII as well as bis-chloro derivative V and amines III are commercially available.
  • the benzimidazole acetonitriles derivatives according to the general formula I may be obtained in 2-6 subsequent steps depending the availability of starting materials and building blocks. As shown in Scheme 3.
  • the benzimidazole acetonitriles derivatives IV are isolated after condensation ofthe benzimidazole compound VT with an electrophile VII, whereby R 2 is as above defined.
  • Several reaction conditions may be utilised for performing this first reaction step, e.g.
  • PS-TBD (7-methyl-l,5,7- triazabicyclo[4.4.0]dec-5-en' on polystyrene HL) a polymer immobilised reagent as a base in presence of various electrophihc reactants such as alkyl chlorine, bromide, iodide or also activated alcohol through mesylate formation.
  • This reaction may be performed in solvents like DCM or DCM/dioxane.
  • This reaction can be performed at various temperature depending of he intrinsic reactivity of compounds VI and VH, by traditional thermal method, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples.
  • the benzimidazole acetonitriles derivatives II whereby the substituents R 1 and R 2 are as above defined, are isolated after condensation ofthe benzimidazole compound IV with bis-chloro derivative V.
  • This reaction step is performed, using, e.g. lithium hydride or sodium hydride, cesium carbonate or similar reagents in an appropriate solvent such as Dioxane, THF, DMA or DMF.
  • This reaction can be performed at various temperature depending ofthe intrinsic reactivity of compoimds IV and V, by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples.
  • the chloro benzimidazole acetonitriles derivatives II may treated with various nucleophiles, e.g. an amine III, to give the expected benzimidazole acetonitriles I.
  • the nucleophilic displacement ofthe chloro atom ofthe pyrimidinyl moiety by the amine HI is accomplished by treatment with several equivalents ofthe nucleophile, e.g. the amine III, in presence or absence of e.g. sodium iodine as catalyst and a base such as triethylamine of diisopropylethylamine or similar reagents.
  • This reaction can be performed at various temperatures depending of the intrinsic reactivity of compounds II and III, by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples.
  • the benzimidazole derivatives I may be obtained by treatment ofthe intermediate I' with either an acyl chloride, a carboxylic acid or a sulfonyl chloride using standard conditions well known to the person skilled in the art, such as amide bond formation protocols or sulfonamide formation using the appropriate reactants as those mentioned above and reagents such as bases like triethylamine, pyridine etc, and activating agents e.g, HOBt, EDC or similar reagents in an appropriate solvent such as THF or DMF.
  • This reaction can be performed at various temperature depending ofthe intrinsic reactivity of compounds lb and VIII, by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples.
  • R 1 A specific functional moiety (R 1 ) may be converted into a different one (R 1 ), using any known functional group interconversion protocols.
  • any known functional group interconversion protocols As illusttated in Scheme 7, the choice of the best synthetic strategy will be governed by the nature ofthe functional groups to be interconverted, and the compatibility of he required reaction conditions with other functional groups present in the corresponding compounds, as will be well appreciated by the person skilled in the art.
  • starting materials I, ⁇ and IV and VII are those wherein R 1 is -Br, -CI, -I, -OH, -NH2, -CH 2 OH, -CHO, -COOH, -N0 2 , and/or -CH 2 COOH, which are either obtained from commercial sources or made by one of the numerous processes described in the literature. From the intermediates (XXI, XXV,
  • XXV ⁇ derived thereof, in which R is as defined in Scheme 7, a wide range of derivatives, such as e.g. (XXII)-(XXXV), in which R 9 , R 10 , R 11 , R 7 , are as defined below, can be obtained by reaction sequences including oxidations, reductions, O- and N-alkylations, reductive alkylations and aminations, chain-elongations, Mitsunobu reactions, acylation, debocylation, Wittig reactions, acylations, sulfonylations, Stille, Suzuki, Sonogashira and any other appropriate transformations leading to functional group interconversions, some of which being exemplified in Scheme 8.
  • reaction sequences including oxidations, reductions, O- and N-alkylations, reductive alkylations and aminations, chain-elongations, Mitsunobu reactions, acylation, debocylation, Wittig reactions, acylations,
  • R 9 , R 10 , R 11 , R 7 are each independently from each other H, unsubstituted or substituted Ci- d-alky], unsubstituted or substituted C 2 -C 6 -alkenyl, unsubstituted or substituted C 2 -Ce- alkynyl, unsubstituted or substituted Ci-Ce-alkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, unsubstituted or substituted 3-8-membered heterocycloalkyl, (wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group), unsubstituted or substituted Ci-C ⁇ -alkyl aryl
  • the benzimidazole acetonitriles derivatives according to the general formula I may be obtained in 2-6 subsequent steps depending the availability of starting materials and building blocks.
  • Scheme 9 the benzimidazole acetonitriles derivatives II' are isolated after condensation ofthe benzimidazole compound II with a solution of ammonium hydroxide.
  • This reaction may be performed in solvents like DMA, isopropanol or solution containing both solvents in various ratio.
  • This reaction can be performed at various temperature depending ofthe intrinsic reactivity of compounds II, by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples
  • the benzimidazole acetonitriles derivatives according to the general formula I can be further isolated from the intermediate III', whereby L is the moiety— C(0)R 6 , with R 6 is as above defined, as shown in Scheme 10.
  • the benzimidazole derivatives I may be obtained by treatment of the intermediate II' with either an acyl chloride or a carboxylic acid using standard conditions well known to the person skilled in the art, such as amide bond formation protocols using the appropriate reactants as those mentioned above and reagents such as bases like triethylamine, pyridine etc, and activating agents e.g, HOBt, EDC, Mukayama reagent or similar reagents in an appropriate solvent such as DCM, THF or DMF.
  • This reaction can be performed at various temperature depending of the intrinsic reactivity of compounds II' and III', by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples.
  • compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient therefore are also within the scope ofthe present invention.
  • a pharmaceutically acceptable carrier, diluent or excipient therefore are also within the scope ofthe present invention.
  • a person skilled in the art is aware of a whole variety of such carrier, diluent or excipient compounds suitable to formulate a pharmaceutical composition.
  • compositions and unit dosages thereof may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous use).
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of he active ingredient commensurate with the intended daily dosage range to be employed.
  • benzimidazole acetonitriles of this invention are typically administered in the foim of a pharmaceutical composition.
  • Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the compounds of this invention are administered in a pharmaceutically effective amount.
  • the amount ofthe compound actually administered will typically be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response ofthe individual patient, the severity ofthe patient's symptoms, and the like.
  • compositions of these inventions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, intra- thecal, intraperitoneal and intranasal.
  • the compoimds are preferably formulated as either injectable, topical or oral compositions.
  • the compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes ofthe liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the benzimidazole acetonitrile compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any ofthe following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum ttagacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dio- xide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum ttagacanth or gelatine
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or
  • Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable carriers known in the art.
  • the benzimidazole acetonitriles of formula I in such compositions is typically a minor component, frequently ranging between 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • the compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can also be found in the incorporated materials in Remington 's Pharmaceutical Sciences.
  • a further aspect ofthe present invention is related to a pharmaceutical composition composition a comprising a benzimidazole derivative according to formula (I) and at least one further drug (in particular an anti-diabetes agent).
  • the further diabetes agents are selected from the group comprising or consisting of insulin (or insulin mimicks), aldose reductase inhibitors, alpha-glucosidase inhibitors, sulfonyl urea agents, biguanides (e.g. metformin), thiazolidines (e.g. pioglitizone, rosiglitazone, cf. WO 02/100396), a PTP1B inhibitor, a PPAR agonists or a GSK-3 inhibitor.
  • Insulins useful with the method ofthe present invention include rapid acting insulins, intermediate acting insulins, long acting insulins and combination of intermediate and rapid acting insulins.
  • aldose reductase inhibitors of this invention are minalrestat, Tolrestat, Sorbinil, Methosorbinil, Zopofrestat, Epalrestat, Zenarestat, Imirestat and Ponalrestat or the pharmaceutically acceptable salt forms thereof.
  • alpha-glucosidase inhibitors useful for the method ofthe present invention include miglitol or acarbose, or the pharmaceutically acceptable salt form thereof.
  • Sulfonylurea agents useful with the method ofthe present invention include glipizide, Glyburide (Ghbenclamide), Clorpropamide, Tolbutamide, Tolazamide and Glimepiride, or the pharmaceutically acceptable salt forms thereof.
  • said supplementary pharmaceutically active agent is selected from the group consisting of a rapid acting insulin, an intermediate acting insulin, a long acting insulin, a combination of intermediate and rapid acting insulins, Inalrestat, Tolrestat, Sorbinil, Methosorbinil, Zopolrestat, Epalrestat, Zenarestat, Imirestat, Ponalrestat, ONO-2235, GP- 1447, CT-112, BAL-ARI 8, AD-5467, ZD5522, M- 16209, NZ-314, M-79175, SPR-210, ADN 138, or SNK-860, Miglitol, Acarbose, Glipizide, Glyburide, Chlorpropamide, Tolbutamide, Tolazamide, or Glimepriride.
  • HPLC column Waters Symmetry C8 50 x 4.6 mm, Conditions: MeC ⁇ /H 2 0, 5 to 100% (8 min), max plot 230-400 nm; Mass spectra: PE-SCIEX API 150 EX (APCI and ESI), LC/MS spectra: Waters ZMD (ES); 1H-NMR: Bruker DPX-300MHz.
  • the purifications were obtained as followed: Preparative HPLC Waters Prep LC 4000 System equipped with columns Prep Nova-Pak ® HR CI 86 ⁇ m 6 ⁇ A, 40x30mm (up to lOOmg) or 40x300 mm (up to lg). All the purifications were performed with a gradient of MeCN/H 2 0 0.09% TFA.
  • Example 1 General procedure for the solution-phase synthesis of benzimidazoles acetonitriles derivatives of general formula I. with G and L as above defined (Schemes 1- 6.: f2ZVri-ethyl-1.3-dihvdro-2H-benzimidazol-2-ylidene ⁇ 2-ir3- ⁇ H-pyrazol-l- yl ⁇ ropyl]amino ⁇ pyrimidin-4-yl)acetonitrile
  • the isopropanol was evaporated and the residue redissolved in 3mL of DCM.
  • This solution was loaded onto a lOg SCX- SPE syringe (O ⁇ mmol.g "1 ) and eluted with DCM, then DCM:MeOH (1:1), 0.1M NH 3 in MeOH and 1M NH 3 in MeOH.
  • he 4 fraction were analyzed by HPLC and LC-MS and the fractions contained the product were mixed together.
  • the solvents were evaporated and the residue redissolved in DCM and washed with NaHC03 sat. and brine.
  • the organic layer was dried over MgS0 , filtered and the solvent evaporated.
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- cWoro-5-me ylpyrimidin-4-yl)(l -ethyl-2,3-dihydro- 1 H-benzimidazol-2-yl)acetonitrile (intermediate 6), and3-(lH- ⁇ yrazol-l-yl)propan-l-amine hydrochloride, the title compound was isolated, as a yellow solid in 82% yield (99% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-rne ylpyrin ⁇ idm-4-yl)(l-ethyl-2,3-cfihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and N-(3'-aminopropyl)-2-pyrrolidinone, the title compound was isolated, as a yellow solid in 77% yield (99% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloropyrimidin-4-yl)(l -ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), andN-(3'-aminopropyl)-2-pyrrolidinone, the title compound was isolated, as a yellow solid in 70% yield (98% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloropyrimidin-4-yl)(l -ethyl-2,3-(Mhydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and 3-(lH-l,2,4-triazol-l-yl)propan-l-amine hydrochloride, the title compound was isolated, as a yellow solid in 72% yield (98% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memylpyrimidin-4-yl)(l -ethyl-2,3 -dihydro- lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and3-(lH-l,2,4-triazol-l-yl)propan-l-amine hydrochloride, the title compound was isolated, as a yellow solid in 78% yield (98% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzi ⁇ nidazol-2-yl)acetonitrile (intermediate 6), and cyclopentylamine, the title compound was isolated, as a yellow solid in 69% yield (99% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memyl ⁇ yrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 3 -(2-aminoethyl)pyridine, the title compound was isolated, as a yellow solid in 69% yield (96% purity by HPLC).
  • Example 14 1.3-dihydro-2H-benzimidazol-2-ylidene(5-methyl-2- ⁇ [3-(2-oxopyrrolidin-l- vDpropyl lamino ⁇ p yrimidin-4- vPacetonitrile
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloropyrimidin-4-yl)(l-cyclobutyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 18), andN-(3'-aminopropyl)-2-pyrrolidinone, the title compound was isolated, as a yellow solid in 77% yield (98% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-me ylpy ⁇ midin-4-yl)(l-ethy]-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and isobutylamine, the title compound was isolated, as a yellow solid in 72% yield (99% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-me ylpy ⁇ imidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and histamine base, the title compound was isolated, as a yellow solid in 69% yield (93% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-methylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 2-(N,N-dimemylan ino)-5-aminoethyl ⁇ yridine, the title compound was isolated, as a yellow solid in 68% yield (97% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-memylpyrimidin-4-y])(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and cyclopropylamine, the title compound was isolated, as a yellow solid in 75% yield (96% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memylpy ⁇ imidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and2-(2-aminoethyl)pyridine), the title compound was isolated, as a yellow solid in 77% yield (98% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-memylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and (+/-)-2-aminopentane, the title compound was isolated, as a yellow solid in 70% yield (92% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-memylpvrin ⁇ idin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 1 -(2 I -aminoethyl)pyrazole), the title compound was isolated, as a yellow solid in 74% yield (97% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-me ylpyrimidm-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and2-(imidazol-l-yl)-ethylamine, the title compound was isolated, as a yellow solid in 60% yield (97% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (6- chloropyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 11), and 3-(2-aminoethyl)pyridine, the title compound was isolated, as a yellow solid in 72% yield (88% purity by HPLC).
  • Example 48 (1 -etfayl-lH-penzimidazol-2-yl)[2-(4-e ⁇ hylpi ⁇ erazin-l -yl -5-methyl ⁇ yrimidin- 4-yl]acetonitrile-
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-me ylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 1 -ethylpiperazine, the title compound was isolated, as a yellow solid in 76% yield (99% purity by HPLC). MS(ESI + ): 390.5; MS(ESF): 388.4.
  • Example 1 Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memyl ⁇ yrimidin-4-yl)(l-ethyl-2,3-dihydro-lII-benzimidazol-2-yl)acetonitrile (intermediate 6), and cyclohexylamine, the title compound was isolated, as a yellow solid in 74% yield (97% purity by HPLC).
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-memylpyrimidm-4-yl)(l,3-die1hyl-2,3-dihydro-lH-benzimidazol-2-yl)acetoniteile (intermediate 15), and cyclopentylamine, the title compound was isolated, as a yellow solid in 80% yield (97% purity by HPLC). MS(EST): 389.2; MSfESF): 387.3.
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- cMoro-5-inethylpyriinidin-4-yl)(l-ethyl-2,3-chhydro-lH-benziniidazol-2-yl)acetonitrile (intermediate 6), and 4 -amino- 1 -piperidine, the title compound was isolated, as a yellow solid in 70% yield (97% purity by HPLC). MS(ESI 4 : 376.2; MS(ESF): 374.3.
  • Example 1 Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-methylpyrimidm-4-yl)(l-ethyl-2,3-dihydro-lH-benzinfidazol-2-yl)acetonitrile (intermediate 6), and 1 -amino-3-(N-piperidino)propane, the title compound was isolated, as a yellow solid in 70% yield (97% purity by HPLC). MS(ESI + ): 418.6; MS(ESF): 416.2.
  • Example 56 General procedure for the solution-phase synthesis of benzimidazoles acetonitriles derivatives of general formula I. with G and L as above defined (Schemes 10): tert-bu1yl (4S)-4-[( ⁇ 4-r(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene.methyl]- 5 -methylpyrimidin-2- yl amino)cafbonyl] -1.3 -thiazolidine-3 -carboxylate
  • reaction mixture was diluted with DCM (50mL), washed with NH4C1, NaHC03 and brine and dried over MgS0 .
  • the solvent was removed by evporation and the residue purified by FC using a gradient AcOE CycloH (4:6) to neat AcOEt then to AcOEt:MeOH (7:3) for lhour.
  • Example 61 ⁇ S.5S.7SVN-U-rfZVcvanofl-ethyl-1.3-dihvdro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidin-2-yl ⁇ -6.8-dioxa-3-azabicyclo
  • Example 62 4-tert-butyl l-(9H-fluoren-9-ylmethyl. 2-[( ⁇ 4-[(Z)-cyanofl-ethyl-l-3-dihvdro- 2H-benzimidazol-2-ylidene)memyl]-5-n ethylpyr-midm-2-yl ⁇ --mino)carbonyl]pi ⁇ erazine- 1 ,4-dicarboxylate
  • Example 63 4-tert-butyl 1-(9H- fluoren-9-ylmethyl) 2-[( ⁇ 4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidin-2-yl ⁇ amino)carbonyl] ⁇ iperazine- 1 ,4-dicarboxylate (Example 63), the title compound was isolated, as a yellow solid in 90% yield (91% purity by HPLC).
  • Example 64 tert-butyl (2S)-2-[( ⁇ 4-[(Z)-cyano(l-eti ⁇ yl-13-dihydro-2H-benzimidazol-2- ylidene .methyl]-5-methylpyrimidin-2-yl ⁇ amino)carbonyl]-5-oxopyrrolidine- 1 -carboxylate
  • Example 65 N-(4-f Z)-cvano(l -ethyl-1.3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- ine ylpyrimidin-2-yl ⁇ -5-oxo-L-prolinamide
  • Example 66 tert-butyl (4R)-4-[( ⁇ 4-[(Z)-cyano(l -ethyl-1.3-dihydro-2H-benzimidazol-2- ylidene)memyl1-5-methylpyrimidin-2-yl ⁇ amino)carbonyl]-1.3-thiazolidine-3-carboxylate
  • Example 68 (lS.4S.5S.7RVN- ⁇ 4-[(Z)-cvano(l-ethyl-1.3-dihydro-2H-benzimidazol-2- ylidene)me yl1-5-methyl ⁇ yrimidin-2-yl ⁇ -4-methyl-6.8-dioxa-3-azabicyclo[3.2.1]octane-7- carboxamide
  • Example 70 N ⁇ l — ⁇ 4-[(Z)-cyano(l -ethyl-1.3 -dihydro-2H-benzimidazol-2- ylidene)memyl1-5-methylpyrimidin-2-yl ⁇ -N ⁇ 3 ⁇ .N ⁇ 3 ⁇ -dimethyl-beta-alaninamide
  • Example 72 N- ⁇ 4-[TZ)-cyano(l -ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrin idin-2-yl ⁇ cyclopentanecarboxamide
  • Example 73 tert-butyl r4-( ⁇ 4-r(Z -cvano(l-ethyl-L3-dihvdro-2H-benzimidazol-2- ylidene)n emyl]-5-n e1hyl ⁇ yrimidin-2-yl ⁇ ajmno)-4-oxobutyl]carban ⁇ ate
  • Example 74 4-amino-N- ⁇ 4-[(Z -cyano(l-ethyl-1.3-dihydro-2FI-benzimidazol-2- ylidene)methyll-5-methylpyrimidin-2-yl ⁇ butanamide
  • Example 75 tert-butyl 4-[( ⁇ 4-[(Z)-cyano(l-ethyl-l,3-d-hvdro-2H-benzimidazol-2- ylidene)me yl]-5-methylpyrimidin-2-yl ⁇ amino)carbonyl]piperidine-l-carboxylate
  • Example 77 N- ⁇ 4- . (Z -cyano( 1 -ethyl- 1.3 -dihydro-2H-benzimidazol-2- ylidenetoethyl] -5- methylpyrimidin-2-yl ⁇ -1 -methylpiperidine-4-carboxamide
  • Example 78 1 -acetyl-N- ⁇ 4- [(Z)-cyano(l -ethyl- 1.3 -dihydro-2H-benzimidazol-2- ylidene)me yll-5-methylpyrimidin-2-yl ⁇ piperidine-4-carboxan ide
  • Example 80 tert-butyl (2S)-2-[( ⁇ 4-[(Z)-cyano(l-eti ⁇ yl-1.3-dihydro-2H-benzimidazol-2- ylidene)methyll-5-methylpyrimidin-2-y] ⁇ amino)carbonyl]-2.5-dihydro-lH-pyrrole-l- carboxylate
  • Example 80 Following the general method as outlined in Example 56, starting from tert-butyl (2S)-2- [( ⁇ 4-[(Z)-cyano(l -ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyri ⁇ mdin-2-yl ⁇ amino)carbonyl]-2,5-dihydro-lH-pyrrole-l -carboxylate (Example 80), the title compound was isolated, as a yellow solid in 95% yield (96% purity by HPLC). MS(ESI + ): 388.5; MS(ESF): 386.6.
  • Example 82 tert-butyl 3-[( ⁇ 4-f(Z)-cvano(l -ethyl-1.3 -dihvdro-2H-benzimidazol-2- ylidene)me yll-5-methylp ⁇ midin-2-yI ⁇ amino carbonyl] ⁇ yrrolidine-l-carboxylate
  • Example 84 tert-butyl 2-[( ⁇ 4-[(Z)-cyanofl -ethyl-1.3-dihvdro-2H-benzimidazol-2- ylidene)me yll-5-methylpyrimidin-2-yl ⁇ arnino carbonyl morpholine-4-carboxylate
  • Example 84 Following the general method as outlined in Example 56, starting from tert-butyl 2-[( ⁇ 4- [(Z)-cyano(l -ethyl-1, 3-dihydro-2H-benzimidazol-2-yhdene)me yl]-5-methylpyrimidin-2- yl ⁇ amino)carbonyl]morpholine-4-carboxylate (Example 84), the title compound was isolated, as a yellow solid in 95% yield (99% purity by HPLC). MS(ESI + ): 406.6; MS(ESF): 404.7
  • Example 86 Following the general method as outlined in Example 56, starting from tert-butyl [2-( ⁇ 4- [(Z)-cy-mo(l-ethyl-l,3-dihydro-2H-ben_ midazol-2-yhdene)methyl]-5-memylpyri ⁇ r ⁇ din-2- yl ⁇ amino)-2-oxoethyl]methylcarbamate (Example 86), the title compound was isolated, as a yellow sohd in 98% yield (97% purity by HPLC). MS(ESI + ): 364.5; MS(ESF): 362.5.
  • Example 88 N ⁇ f4-. fZ.-cvanof 1 -ethyl-1 ,3-dihvcfro-2H-benz-midazol-2-V-idene)methyl 1-5- methyl ⁇ yrimidin-2-yl ⁇ - 1 -methyl ⁇ iperidine-3 -carboxamide
  • Example 90 tert-butyl 4-[2-( ⁇ 4-[(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidm-2-yl ⁇ amino)-2-oxoethyl]piperidine-l-carboxylate
  • Example 90 Following the general method as outlined in Example 57, starting from tert-butyl 4-[2-( ⁇ 4- [(Z)-cy-mo(l-ethyl-l,3-chhydro-2H-bcnzimidazol-2-yhdene)methyl]-5-mc ⁇ ylpyrin idin-2- yl ⁇ amino)-2-oxoethyl]piperidine-l -carboxylate (Example 90), the title compound was isolated, as a yellow solid in 98% yield (97% purity by HPLC). MS(EST): 418.6; MS(ESF>: 416.3.
  • Example 93 tert-butyl 3-[( ⁇ 4-[(Z)-cyano(l -ethyl- 1.3-dihydro-2H-benzimic-azol-2- ylidene)memyl1-5-methylpyrimidin-2-yl ⁇ amino)carbonyllpiperidine-l-carboxylate
  • Example 93 Following the general method as outlined in Example 57, starting from tert-butyl 3-[( ⁇ 4- [(Z)-cyano(l -ethyl- 1 ,3-dihydro-2H-benzimidazol-2-yhdene)methyl]-5-memylpyrimidin-2- yl ⁇ amino)carbonyl]piperidine-l -carboxylate (Example 93), the title compound was isolated, as a yellow solid in 95% yield (97% purity by HPLC). MS(ESI + ): 404.9; MS(ESF): 402.6.
  • Example 96 4-acetyl-N- ⁇ 4- [(Z)-cyano(l -ethyl- 1.3-dihydro-2H-benzimidazol-2- ylidene memyl]-5-methylpyrimidm-2-yl ⁇ mo ⁇ holine-2-carboxamide
  • Example 100 N- ⁇ 4-[(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)methyl1-5- methylpyrimidin-2-yl ⁇ -2-( 1.1 -dioxidothiomorpholin-4-yl)acetamide
  • a benzimidazole acetonitrile of formula I is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ration. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active benzimidazole acetonitrile compound per tablet) in a tablet press.
  • a benzimidazole acetonitrile of formula I is admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active benzimidazole acetonitrile compound per capsule).
  • a benzimidazole acetonitrile of formula I (1250 mg), sucrose (1.75 g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 mL.
  • a benzimidazole acetonitrile of formula I is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active benzimidazole acetonitrile compound) in a tablet press. Formulation 5 - Injection
  • a benzimidazole acetonitrile of formula (I) is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/ml.
  • the compounds ofthe present invention may be subjected to the following assays :
  • GSK3 ⁇ (h) (5-10mTJ) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 20 ⁇ M YRRAAVPPSPSLSRHSSPHQS(p)EDEEE (being the
  • GSK3 substrate aphospho GS2 peptide
  • lOmM Mg Acetate aphospho GS2 peptide
  • [ ⁇ - 33 P-ATP] Specific activity approx. 500cpm/pmol, concentration as required.
  • the reaction is initiated by the addition of Mg 2+ [ ⁇ -33p_ATP].
  • the reaction is stopped by the addition of 5 ⁇ l of a 3% phosphoric acid solution. 1 O ⁇ l of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 50mM phosphoric acid and once in methanol prior to drying and the degree of phosphorylation of the substrate is determined by scintillation counting.
  • the tested compounds according to formula I display an inhibition (IC50) with regard to GSK3 of less than 20 ⁇ M, preferably less than 10 and even more preferred less than 1 ⁇ M.
  • binding affinities ofthe compounds of formula (I) were assessed using the above described in vitro biological assay. Representative values for some example compounds are given in Tables 1 and 2 below.
  • Table 1 In vitro potency of benzimidazole derivatives on human GSK3 beta
  • I ⁇ vivo assay Experimental model of type II diabetes (oral postprandial glvcemia in db/db mice)
  • the following assay aims at determining the anti-diabetic effect ofthe test compounds of formula (I) in a model of postprandial glycemia in db/db mice, in vivo.
  • the assay was performed as follows :
  • mice A total of 24 db/db mice (about 8-9 weeks; obtained from IFFACREDO, l'Arbreste, France) were fasted during 20 hours.
  • Group 1 The animals were administered (per os) a dose of 10 mg/kg of vehicle.
  • Group 2 The animals were administered (per os) a dose of 50 mg/kg ofthe test compound according to formula (I).
  • mice After oral administration of the compounds of formula (I) solubilized or suspended in CarboxyMethylCellulose (0.5%), Tween 20 (0.25%) and water as vehicle, the animals had access to commercial food (D04, UAR, Villemoisson/Orge, France) ad libitum. The diabetic state ofthe mice was verified by determining the blood glucose level before drug administration. Blood glucose and serum insulin levels were then determined 4 hrs after drug administration.
  • the determination ofthe blood glucose level was performed using a glucometer (Precision Q.I.D., Medisense, Abbot, ref. 212.62.31).
  • the determination ofthe Insulin level was performed using an ELISA kit (Crystal CHEM, Ref. INSK R020). Changes in blood glucose and serum insulin of drug treated mice were expressed as a percentage of control (group 1 : vehicle treated mice).

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Abstract

The present invention is related to benzimidazole acetonitriles as well as to pharmaceutical formulations containing such benzimidazole acetonitriles of formula (I). Said benzimidazole acetonitriles are useful in the treatment of metabolic disorders mediated by insulin resistance or hyperglycemia, comprising diabetes type II, inadequate glucosetolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS) (I). The present invention is furthermore related to methods of preparing ben7.oxazole acetonitriles. G is pyrimidinyl; L is an amino group, or a 3-8 membered heterocycloalkyl, containing at least one heteroatorn selected from N, O, S or L is an acylamino moiety; R1 is selected from the group comprising or consisting of hydrogen, sulfonyl, amino, carboxy, aminocarbonyl, CI-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or Cl-C6-alkoxy, aryl,halogen, cyano or hydroxy;R2 is selected from the group comprising or consisting of hydrogen, CI -C6-alkyl, C2-C6alkenyl, C2-C6-alkynyl, or CI -C6-alkoxy.

Description

Benzimidazole Acetonitriles
Field ofthe invention The present invention is related to benzimidazole acetonitriles, as well as pharmaceutical compositions containing such benzimida_.ole acetonitriles. The compounds ofthe present invention axe useful in the treatment of metabolic disorders mediated by insulin resistance or hyperglycemia, comprising diabetes type II, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS). In one embodiment, the compounds ofthe present invention are inhibitors of Glycogen Synthase Kinase 3 (GSK3). The present invention furthermore relates to methods for the preparation of benzimidazole acetonitriles.
Background of the invention
Diabetes mellitus is a serious metabolic disease that is defined by the presence of chemically elevated levels of blood glucose (hyperglycemia). The term diabetes mellitus encompasses several different hyperglycemic states. These states include Type 1 (insulin- dependent diabetes mellitus or IDDM) and Type 2 (non- insulin dependent diabetes mellitus or NIDDM) diabetes. The hyperglycemia present in individuals with Type 1 diabetes is associated with deficient, reduced, or nonexistent levels of insulin that are insufficient to maintain blood glucose levels within the physiological range. Conventionally, Type 1 diabetes is treated by administration of replacement doses of insulin, generally by a parenteral route.
Type 2 diabetes is an increasingly prevalent disease of aging. It is initially characterized by decreased sensitivity to insulin and a compensatory elevation in circulating insulin concentrations, the latter of which is required to maintain normal blood glucose levels. As described below, GSK3 inhibition stimulates insulin-dependent processes and is consequently viewed to be useful in the treatment of type 2 diabetes. Recent data obtained using lithium salts provides evidence for this notion.
The prevalence of insulin resistance in glucose intolerant subjects is well known. Reaven et al (American Journal of Medicine, 60, 80 (1976)) used a continuous infusion of glucose and insulin (insulin/glucose clamp technique) and oral glucose tolerance tests to demonstrate that insulin resistance exists in a diverse group of non-obese, non-ketotic subjects. These subjects ranged from borderline glucose tolerant to overt, fasting hyperglycemia. The diabetic groups in these studies included both insulin dependent (IDDM) and non-insulin dependent (NIDDM) subjects.
Coincident with sustained insulin resistance is the more easily determined hyper- insulinemia, which may be measured by accurate determination of circulating plasma insulin concentration in the plasma of subjects. Hyperinsulinemia may be present as a result of insulin resistance, such as is in obese and/or diabetic (NIDDM) subjects and/or glucose intolerant subjects, or in TDDM subjects, as a consequence of over injection of insulin compared with normal physiological release ofthe hormone by the endocrine pancreas.
The association of hyperinsulinemia and insulin resistance with obesity has been well established by numerous experimental, clinical and epidemiological studies (Stout, Metabolism, 34, 7 (1985)).
The association of hyperinsulinemia and insulin resistance with Polycystic Ovary Syndrome (PCOS) is also well acknowledged (Diamanti-Kandarakis et al.; Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome; European Journal of Endocrinology 138, 269-274 (1998), Andrea Dunaif; Insulin Resistance and the Polycystic Ovary Syndrome : Mechanism and Implications for ΨaHhogenβήs; Endocrine Reviews 18(6), 774-800 (1997)). Type II diabetes mellitus is currently treated with sulfonylureas, biguanides, such as Metformin and thiazolidenediones, such as Troglitazone, Rosiglitazone or Pioglitazone, as oral hypoglycemic agents.
Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase for which two isoforms, and β, have been identified (Trends Biochem. Sci., 16 p.177-81 (1991) by Woodgett et al.). Both GSK3 isoforms are constitutively active in resting cells. GSK3 was originally identified as a kinase that inhibits glycogen synthase by direct phosphorylation. Upon insulin activation, GSK3 is inactivated, thereby allowing the activation of glycogen synthase and possibly other insulin-dependent events, such glucose transport. Subsequently, it has been shown that GSK3 activity is also inactivated by other growth factors that, like insulin, signal through receptor tyrosine Mnases (RTKs). Examples of such signalling molecules include IGF-1 and EGF. GSK3 beta activity is regulated by serine (inhibitory) and tyrosine (stimulatory) phosphorylation, by protein complex formation, and by its intracellular localization. GSK3 beta phosphorylates and thereby regulates the functions of many metabolic, signalling and structural proteins. Notable among the signalling proteins regulated by GSK3 beta are the many transcription factors, including activator protein- 1 cells, Myc, beta-catenin, CCAAT/enhancer binding protein, and NFkappaB.
Agents that inhibit GSK3 activity are viewed to be useful in the treatment of type II diabetes.
In the patent literature, different classes of GSK3 inhibitors have been disclosed (e.g. WO 02/20495, Chiron Corporation; WO 02/10141, Pfizer Products Inc.; WO 02/22608, Vertex Pharmaceuticals Inc.).
WO 01/47920 discloses benzazoles of formula (A) in particular for the treatment of neuronal disorders, autoimmune diseases, cancer and cardiovascular diseases.
Figure imgf000005_0001
X = N, S, O
It was now found that certain compounds of formula (A), surprisingly, are in addition useful in the treatment of metabolic disorders mediated by insulin resistance or hyperglycemia, comprising diabetes type II, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS).
Summary ofthe invention
The present invention relates to benzimidazole acetonitriles of formula (I)
Figure imgf000005_0002
as well as their pharmaceutically acceptable salts.
Also, the present invention relates to the use of compounds of formula (I) as medicament, in particular for the treatment and/or prevention of metabolic disorders mediated by insulin resistance or hyperglycemia, such as diabetes type II, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS).
Detailed description of the invention
The following paragraphs provide definitions ofthe various chemical moieties that make up the compounds according to the invention and are intended to apply uniformly throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.
"Ci-Cβ -alkyl" refers to alkyl groups having 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-butyl, n-pentyl, n-hexyl and the like.
"Aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl). Preferred aryl include phenyl, naphthyl, phenantrenyl and the like.
"Cι-C6-alkyl aryl" refers to Ci-Ce-alkyl groups having an aryl substituent, including benzyl, phenethyl and the like.
"Heteroaryl" refers to a monocyclic heteroaromatic, or a bicyclic or a tricyclic fused-ring heteroaromatic group. Particular examples of heteroaromatic groups include optionally substituted pyridyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1 ,2,4-oxadia- zolyl, 1,2,5-oxadiazolyl, l,3,4-oxadiazolyl,l,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3- dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3H-indolyl, benzimidazolyl, imidazo[l,2-a]pyridyl, benzothiazolyl, benzoxazolyl, quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3;2-b]pyridyl, pyrido[4,3-b]pyridyι, quinolyl, isoquinolyl, tetrεizolyl, 5,6,7,8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolyl, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.
"Ci-Cέ-alkyl heteroaryl" refers to Ci-Cβ-alkyl groups having a heteroaryl substituent, including 2--_urylmethyl, 2-thienylmethyl, 2-(lH-indol-3-yl)et__yl and the like. "C2-C6-alkenyl" refers to alkenyl groups preferably having from 2 to 6 carbon atoms and having at least 1 or 2 sites of alkenyl unsaturation. Preferable alkenyl groups include ethenyl (-CH=CH2), n-2-propenyl (allyl, -CH2CH=CH2) and the like.
"C2-C6-alkenyl aryl" refers to Gj-Cβ-alkenyl groups having an aryl substituent, including 2- phenylvinyl and the like.
"C2-C6-alkenyl heteroaryl" refers to C2-C6-alkenyl groups having a heteroaryl substituent, including 2-(3-pyridinyl)vinyl and the like.
"C2-C6-alkyny_" refers to alkynyl groups preferably having from 2 to 6 carbon atoms and having at least 1-2 sites of alkynyl unsaturation, preferred alkynyl groups include ethynyl (-C≡CH), propargyl (-CH2C≡CH), and the like.
"C2-C6-alkynyl aryl" refers to C2-C6-aIkynyl groups having an aryl substituent, including phenylethynyl and the like.
"C2-C6-alkynyl heteroaryl" refers to C2-C6-alkynyl groups having a heteroaryl substituent, including 2-thienylethynyl and the like.
"C3-C8-cycloalkyl" refers to a saturated carbocyclic group of from 3 to 8 carbon atoms having a single ring (e.g., cyclohexyl) or multiple condensed rings (e.g., norbornyl). Preferred cycloalkyl include cyclopentyl, cyclohexyl, norbornyl and the like.
"Ci-Cδ-alkyl cycloalkyl" refers to Ci-C6-alkyl groups having a cycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl, and the like.
"heterocycloalkyl" refers to a C3-Cs-cycloalkyl group according to the definition above, in which 1 to 3 carbon atoms are replaced by hetero atoms chosen from the group consisting of O, S, NR, R being defined as hydrogen or Ci-C-β alkyl. Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, 1-methylpiperazine, morpholine, and the like. "Ci-Cβ-alkyl heterocycloalkyl" refers to Cι-C6-alkyl groups having a heterocycloalkyl substituent, including 2-(l-pyrro_idiny_)ethyl, 4-mo holinylmethyl, (l-methyl-4- piperidinyl)methyl and the like.
"Carboxy" refers to the group -C(0)OH.
"Ci-Cβ-alkyl carboxy" refers to Ct-Cβ-alkyl groups having a carboxy substituent, including 2-carboxyethyl and the like.
"Acyl" refers to the group -C(0)R where R includes H, "Ci- -alkyl", "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Ce-alkyl aryl" or "Cι-C6-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2- Ce-alkynyl aryl", "C -C6-alkynylhetcroaryl", "Cι-C5-alkyl cycloalkyl", "C]-C5-alkyl heterocycloalkyl".
"Ci-Cδ-alkyl acyl" refers to Ci-Cβ-alkyl groups having an acyl substituent, including 2- acetylethyl and the like.
"Aryl acyl" refers to aryl groups having an acyl substituent, including 2-acetylphenyl and the like.
"Heteroaryl acyl" refers to hetereoaryl groups having an acyl substituent, including 2- acetylpyridyl and the like.
"C3-C8-(hetero)cycloalkyl acyl" refers to 3 to 8 membered cycloalkyl or heterocycloalkyl groups having an acyl substituent.
"Acyloxy" refers to the group -OC(0)R where R includes H, "Cι-C6-alkyl", "C2-C6- alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Ce-alkyl aryl" or "Cι-C6-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "C2-C6-alkynylhetero_ιry_", "d-Ce-alkyl cycloalkyl", "Ci-Ce-alkyl heterocycloalkyl". "Ci-Cβ-alkyl acyloxy" refers to Ci-Cβ-alkyl groups having an acyloxy substituent, including 2-(acetyloxy)ethyl and the like.
"Alkoxy" refers to the group -O-R where R includes "Cι-C6-alkyl", "C2-C6-alkenyl", "C2- Ce-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Cι-C6-alkyl aryl" or "Ci-Ce-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2- Ce-alkynyl aryl", "C2-C6-alkynylheteroaryl", "Cι-C6-alkyl cycloalkyl", "Cι-C6-alkyl heterocycloalkyl".
"Ci-Cβ-alkyl alkoxy" refers to Ci-Cg-alkyl groups having an alkoxy substituent, including 2-ethoxyethyl and the like.
"Alkoxycarbonyl" refers to the group -C(0)OR where R includes "Cι-C6-alkyl", "C2-C6- alkenyl", "C2-C5-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "CfCg-alkyl aryl" or "C.-C6-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "C2-C6-alkynylheteroaryl", "d-Ce-alkyl cycloalkyl", "Ci-Ce-alkyl heterocycloalkyl".
"Ci-Cβ-alkyl alkoxycarbonyl" refers to Cι-C6-alkyl groups having an alkoxycarbonyl substituent, including 2-(ben..yloxycarbonyl)ethyl and the like.
"Aminocarbonyl" refers to the group -C(0)NRR' where each R, R' includes independently hydrogen, "Cι-C5-alkyl", "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C,-C6-alkyl aryl" or "Cι-C6-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "C2-C6- alkynylheteroaryl", "Ci-Cδ-alkyl cycloalkyl", "Ci-Cβ-alkyl heterocycloalkyl".
"Cι-C6-alkyl aminocarbonyl" refers to Ci-Cβ-alkyl groups having an aminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl and the like. "Λcylamino" refers to the group -NRC(0)R' where each R, R' is independently hydrogen, "Ci-Ce-alkyl", "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Cι-C6-alkyl aryl" or "Cι-C6-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "Cz-Ce-alkynylheteroaryl", "d-Cβ-alkyl cycloalkyl", "Cι-C6-alkyl heterocycloalkyl".
"Cι-C6-alkyl acylamino" refers to Ci-Cό-alkyl groups having an acylamino substituent, including 2-(propionylamino)ethyl and the like.
"Ureido" refers to the group -NRC(0)NR'R" where each R, R', R" is independently hydrogen,
Figure imgf000010_0001
"C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Cι-C5-alkyl aryl" or "Cι-C6-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "C2-C6- alkynylheteroaryr', "Ci-Cβ-alkyl cycloalkyl", "Ci-Ce-alkyl heterocycloalkyl", and where R' and R", together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
"Cι-C6-alkyl ureido" refers to Cι-C6-alkyl groups having an ureido substituent, including 2- (iV-methylureido)ethyl and the like. ι
"Carbamate" refers to the group -NRC(0)OR' where each R, R' is independently hydrogen, "Ci-Ce-alkyl", "C2-C6-alkenyl", "C2-C6-alkynyl", "C3-C8 -cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Cι-C6-alkyl aryl" or "Ci-Ce-alkyl heteroaryl", "Ca-Ce-alkenyl aryl", "C2-C5-alkenyl heteroaryl", "C2-C6-alkvnyl aryl", "C2-C6- alkynylheteroaryl", "Ci-Ce-alkyl cycloalkyl", "Cι-C6-alkyl heterocycloalkyl".
"Amino" refers to the group -NRR' where each R, R' is independently hydrogen, "Ci-Ce- alkyl", "d-Ce-alkenyl", "C2-C6-alkvnyl", "d-Cg-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "d-C6-alkyl aryl" or "Ci-Ce-alkyl heteroaryl", "d-Ce-alkenyl aryl", "C2-C6- alkenyl heteroaryl", "C2-C6-alkynyl aryl", "C2-C6-alkynylheteroaryl", "Cι-C6-alkyl cycloalkyl", "Ci-Ce-alkyl heterocycloalkyl", and where R and R\ together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
"Cι-C6-alkyl amino" refers to Ci-Ce-alkyl groups having an amino substituent, including 2- (l-pyrrolidinyl)ethyl and the like.
"Ammonium" refers to a positively charged group -N+RR'R", where each R, R\R" is independently, "Ci-Ce-alkyl", "C2-C6-alkenyl", "Ca-Ce-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "Cι-C6-alkyl aryl" or "Cι-C6-alkyl heteroaryl", "C2-C6-alkenyl aryl", "d-Ce-alkenyl heteroaryl", "C2-C6-alkynyl aryl", "C2-C6-alkynylheteroaryl", "Ci-Ce-alkyl cycloalkyl", "Ci-Cβ-alkyl heterocycloalkyl", and where R and R', together with the nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.
"Cι-C6-alkyl ammonium" refers to Ci-Ce-alkyl groups having an ammonium substituent, including 2-(l-pyrrolidinyl)ethyl and the like.
"Halogen" refers to fluoro, chloro, bromo and iodo atoms.
"Sulfonyloxy" refers to a group -OS02-R wherein R is selected from H, "Ci-Ce-alkyl", "Ci-Ce-alkyl" substituted with halogens, e.g., an -0S02-CF3 group, "C2-C6-alkenyl", "C2- Ce-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Ce-alkyl aryl" or "Ci-Ce-alkyl heteroaryl", "C2-C6-a_kenyl aryl", "C2-C6-alkenyl heteroaryl", "C2- Ce-alkynyl aryl", "C2-C6-alkynylheteroaryl", "C,-C6-alkyl cycloalkyl", "d-Ce-alkyl heterocycloalkyl".
"Cι-C_ -alkyl sulfonyloxy" refers to Cι-C6-alkyl groups having a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and the like.
"Sulfonyl" refers to group "-SO2-R" wherein R is selected from H, "aryl", "heteroaryl", "Ci-Cδ-alkyl", "Ci-Ce-alkyl" substituted with halogens, e.g., an -S02-CF3 group, "C2-C6- alkenyl", "C2-C6-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Ce-alkyl aryl" or "Ci-Ce-alkyl heteroaryl", "C -C6-alkenyl axyl", "C2-C6-alkenyl heteroaryl", "C2-Ce-alkynyl aryl", "C2-Ce-alkynylheteroaryl", "Ci-C6-alkyl cycloalkyl", "Ci-Ce-alkyl heterocycloalkyl".
"Ci-Cβ-alkyl sulfonyl" refers to Ci-Cβ-alkyl groups having a sulfonyl substituent, including 2-(methylsulfonyl)ethyl and the like.
"Sulfinyl" refers to a group "-S(0)-R" wherein R is selected from H, "Ci-Ce-alkyl", "Ci- C6-alkyl" substituted with halogens, e.g., an -SO-CF3 group, "C2-C6-alkenyl", "C2-C6- alkynyl", "d-Cg-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Ce-alkyl aryl" or "Ci-Ce-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-Ce-alkenyl heteroaryl", "C2-C6- alkynyl aryl", "C2-C6-alkynylheteroaryl", "Ci-Ce-alkyl cycloalkyl", "Ci-Ce-alkyl heterocycloalkyl".
"Ci-Cβ-alkyl sulfinyl" refers to Cι-C6-alkyl groups having a sulfinyl substituent, including 2-(methylsulfinyl)ethyl and the like.
"Sulfanyl" refers to groups -S-R where R includes H, "Ci-Ce-alkyl", "C_ -C6-alkyl" substituted with halogens, e.g., an -SO-CF3 group, "C2-C6-alkenyl", "C2-Ce-alkynyl", "C3- C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Ce-alkyl aryl" or "Ci-Ce-alkyl heteroaryl", "C2-C6-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "Ca-Ce-alkynyl aryl", "C2- C6-alkynylheteroaryl", "Cι-C6-alkyl cycloalkyl", "Ci-Ce-alkyl heterocycloalkyl". Preferred sulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.
"Cι-C6-alkyl sulfanyl" refers to Ci-Cβ-alkyl groups having a sulfanyl substituent, including 2-(ethylsulfanyl)ethyl and the like.
"Sulfonylamino" refers to a group -NRS02-R' where each R, R' includes independently hydrogen, "Ci-Ce-alkyl", "C2-C3-alkenyl", "d-Ce-alkynyl", "C3-C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "d -C6-alkyl aryl" or "Ci -C6-alkyl heteroaryl", "d-Ce-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "C2-Ce-alkynyl aryl", "C2-C6- alkynylheteroaryl", "Ci-Ce-alkyl cycloalkyl", "d-Ce-alkyl heterocycloalkyl".
"Cι-C6-alkyl sulfonylamino" refers to Ci-Cβ-alkyl groups having a sulfonylamino substituent, including 2~(ethylsulfonylamino)ethyl and the like.
"Aminosulfonyl" refers to a group -S02-NRR' where each R, R' includes independently hydrogen, "Ci-Ce-alkyl", "C2-C6-alkenyl", "d-Ce-alkynyl", "C3-C8 -cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "Ci-Ce-alkyl aryl" or "Cι-C6-alkyl heteroaryl", "d-Ce-alkenyl aryl", "C2-C6-alkenyl heteroaryl", "d-Ce-alkynyl aryl", "C2-C6- alkynylheteroaryl", "Ci-Ce-alkyl cycloalkyl", "Ci-Ce-alkyl heterocycloalkyl".
"Cι-C6-alkyl aminosulfonyl" refers to Cι-C6-alkyl groups having an aminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)e_hyl and the like.
"Substituted or unsubstituted" : Unless otherwise constrained by the definition ofthe individual substituent, the above set out groups, like "alkyl", "alkenyl", "alkynyl", "aryl" and "heteroaryl" etc. groups can optionally be substituted with from 1 to 5 substituents selected from the group consisting of "Ci -C6-alkyl", "C2-C6-alkeny_", "d-Ce-alkynyl",
"cycloalkyl", "heterocycloalkyl", "Cι-C6-alkyl aryl", "Cι-C6-alkyl heteroaryl", "Cι-C6- alkyl cycloalkyl", "Ci-Cβ-alkyl heterocycloalkyl", "amino", "ammonium", "acyl", "acyloxy", "acylamino", "aminocarbonyl", "alkoxycarbonyl", "ureido", "carbamate", "aryl", "heteroaryl", "sulfinyl", "sulfonyl", "alkoxy", "sulfanyl", "halogen", "carboxy", trihalomethyl, cyano, hydroxy, mercapto, nitro, and the like. Alternatively, said substitution could also comprise situations where neighbouring substituents have undergone ring closure, notably when vicinal iϊtnctional substituents are involved, thus forming, e.g., lactams, lactons, cyclic anhydrides, but also acetals, thioacetals, aminals formed by ring closure for instance in an effort to obtain a protective group.
"Pharmaceutically acceptable salts or complexes" refers to salts or complexes ofthe below- identified compounds of formula (I) that retain the desired biological activity. Examples of such salts include, but are not restricted to acid addition salts formed with inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalene sulfonic acid, naphthalene disulfonic acid, methanesulfonic acid and poly-galacturonic acid. Said compounds can also be administered as pharmaceutically acceptable quaternary salts known by a person skilled in the art, which specifically include the quarternary ammonium salt ofthe formula - NR,R',R" + Z", wherein R, R R" is independently hydrogen, alkyl, or benzyl, Cι-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cι-C6-alkyl aryl, Ci-Cβ-alkyl heteroaryl, cycloalkyl, heterocycloalkyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate).
"Pharmaceutically active derivative" refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the activity disclosed herein.
"Enantiomeric excess" (ee) refers to the products that are obtained by an asymmetric synthesis, i.e. a synthesis involving non-racemic starting materials and/or reagents or a synthesis comprising at least one enantioselective step, whereby a surplus of one enantiomer in the order of at least about 52% ee is yielded.
A first aspect ofthe invention consists in benzimidazole acetonitriles of formula I
Figure imgf000015_0001
G is an unsubstituted or substituted pyrimidinyl.
In particular, G may be either ofthe substituted pyrimidinyl moieties
Figure imgf000015_0002
A'a A'b
L is an amino group, or an unsubstituted or a substituted 3-8 membered heterocycloalkyl, containing at least one heteroatom selected from N, O, S or L is an acylamino moiety.
R1 is selected from the group comprising or consisting of hydrogen, sulfonyl, amino, carboxy, amino carbonyl, unsubstituted or substituted Cι-C6-alkyl, unsubstituted or substituted C2-C6-alkenyl, unsubstituted or substituted d-Ce-alkynyl or Ci-Cβ-alkoxy, unsubstituted or substituted aryl (e.g. phenyl), halogen, cyano or hydroxy.
Preferably R1 is II or Cι-C3 alkyl (e.g. a methyl or ethyl group).
R2 is selected from the group comprising or consisting of hydrogen, unsubstituted or substituted Cι-C6-alkyl, unsubstituted or substituted aryl (e.g. phenyl), unsubstituted or substituted C2-C6-alkenyl, unsubstituted or substituted C2-C6-alkynyl, unsubstituted or substituted cycloalkyl or Ci-Ce-alkoxy. Preferably R2 is a Ci-d alkyl (e.g. an ethyl group).
R3 is selected from the group comprising or consisting of hydrogen, unsubstituted or substituted Ci-Cβ-alkyl, unsubstituted or substituted aryl (e.g. phenyl), unsubstituted or substituted C2-C6-alkenyl, unsubstituted or substituted d-Ce-alkynyl, unsubstituted or substituted cycloalkyl or Cι-C6-alkoxy.
Preferably R3 is hydrogen or a C1-C3 alkyl (e.g. a methyl or an ethyl group).
The compounds ofthe present invention also comprises their tautomers, their geometrical isomers, their optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof. Preferred pharmaceutically acceptable salts ofthe formula (I) are acid addition salts formed with pharmaceutically acceptable acids like hydrochloride, hydrobromide, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, methanesulfonate, benzenesulfonate, trifluoroacetate, and/.αrα-toluenesulfonate salts.
More specifically, the benzimidazole acetonitriles ofthe present invention comprise the tautomeric forms, e.g. the below ones :
Figure imgf000016_0001
(I) («")
A specific embodiment of he present invention consists in benzimidazole acetonitriles of formula (la) in its tautomeric forms, e.g. the below ones :
Figure imgf000017_0001
R1, R2, R3 and L are as defined for formula (I).
According to a specific embodiment, the moiety L is an amino group ofthe formula - NR5R6 wherein R5 and R6 are each independently from each other H, unsubstituted or substituted Ci-Ce-alkyl, unsubstituted or substituted C2-C6-alkenyl, unsubstituted or substituted C2-C6-alkynyl, unsubstituted or substituted Ci-Cβ-alkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, unsubstituted or substituted 3-8- membered heterocycloalkyl, (wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group), unsubstituted or substituted Ci-Ce-alkyl aryl, unsubstituted or substituted Ci-Ce- alkyl heteroaryl, unsubstituted or substituted Ci-Cβ-alkenyl aryl, unsubstituted or substituted Ci-Cβ-alkenyl heteroaryl, unsubstituted or substituted Ci-Cβ-alkynyl aryl, unsubstituted or substituted Ci-Cβ-alkynyl heteroaryl, unsubstituted or substituted C1-C-6- alkyl cycloalkyl, unsubstituted or substituted Ci -Cβ-alkyl heterocycloalkyl, unsubstituted or substituted Cι-C6-alkenyl cycloalkyl, unsubstituted or substituted Ci-Cβ-alkenyl heterocycloalkyl, unsubstituted or substituted Ci-Cβ-alkynyl cycloalkyl, unsubstituted or substituted Ci-Cβ-alkynyl heterocycloalkyl. Λlternatively, R5 and R6 may form a ring together with the nitrogen to which they are bound.
In a specific embodiment, R3 is hydrogen or a methyl or ethyl or propyl group and R6 is selected from the group consisting of unsubstituted or substituted Ci-Cβ-alkyl, unsubstituted or substituted Ci-Cβ alkyl-aryl, unsubstituted or substituted Ci-Ce-alkyl- heteroaryl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted heterocycloalkyl, unsubstituted or substituted aryl or heteroaryl and unsubstituted or substituted 4-8 membered saturated or unsaturated cycloalkyl.
In a preferred embodiment R5 is H and R6 is selected from the group consisting of Ci-d alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, heteroaryl, Ci-Ce-alkyl heteroaryl, Cι-C6-alkyl cycloalkyl, Cι-C6-alkyl heterocycloalkyl. Examples of cycloalkyl are cyclopropyl, cyclopentyl or cyclohexyl.
More specifically R6 may be a d- alkyl, in particular an ethylene or propylene moiety, optionally substituted with an imsubstituted or substituted heteroaryl group, e.g., an unsubstituted or substituted pyridyl or a 2-pyrrolidinone (2-oxopyrrolidine) or a triazolyl moiety.
According to a further specific embodiment, the moiety L is an acylamino moiety of the formula -NR5C(0)R6 wherein R5 andR6 are each independently from each other H, unsubstituted or substituted Cι-C6-alkyl, unsubstituted or substituted d-d-a-kenyl, unsubstituted or substituted C2-C6-alkynyl, unsubstituted or substituted Cι-C6-alkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, unsubstituted or substituted 3-8-membered heterocycloalkyl, unsubstituted or substituted Ci-d-alkyl aryl, unsubstituted or substituted Ci-d-all yl heteroaryl, unsubstituted or substituted Ci-d- alkenyl aryl, unsubstituted or substituted Ci-Cβ-alkenyl heteroaryl, unsubstituted or substituted Ci-d-alkynyl aryl, unsubstituted or substituted Cι-C6-alkynyl heteroaryl, unsubstituted or substituted Ci-Cβ-alkyl cycloalkyl, unsubstituted or substituted Cι-C6-aIkyl heterocycloalkyl, unsubstituted or substituted Ci-Cβ-alkenyl cycloalkyl, unsubstituted or substituted Cι-C6-alkenyl heterocycloalkyl, unsubstituted or substituted Cι-C6-alkynyl cycloalkyl, unsubstituted or substituted Ci-Ce-alkynyl heterocycloalkyl.
Specific benzimidazole acetonitriles according to formula (I) include :
(2Z)-(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[3-(lH-pyrazol-l-yl)proρyl]- .amino}pyrimidin-4-yl)acetonitrile
(2Z)-(1 -ethyl- 1 ,3-dihydro-2H-benzimidazol-2-ylidene)(5-methyl-2- { [3 -(lH-pyrazol- 1 - yl)proρyl]annno}pyτimidin-4-yl)acetonitrile
(2Z)-[2-(cyclobutylamino)-5-memylpyrimi(_in-4-yl](l-ethyl-l,3-dιhydro-2H-benzimidazol- 2-ylidene)acetonitrile
(2Z)-(l-e1hyl-l,3-(3ihydro-2H-benzimidazol-2-ylidene)(5-methyl-2-{[3-(2-oxopy_τolidin-l- yl)propyl]anιino}pyrimidin-4-yl)acetonitrile
(2Z)-(1 -ethyl-1 ,3-dihydro-2H-benzimidazol-2-ylidene)(2- {[3-(2-oxopyrrohdin- 1 - yl)propyl]amino}ρyτimidin-4-yl)acetonitrile
(2Z)-(1 -ethyl-1 ,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[3-(lH-l ,2,4-triazol-l - yl)propyl]amino}pyrimidin-4-yl)acetonitrile
(2Z)-(1 -ethyl- 1 ,3-dihydro-2H-benzimidazol-2-ylidene)(5-methyl-2-{[3-(lH- 1 ,2,4-triazol- 1 - yl)propyl]amino}pyrimidin-4-yl)acetonitrile
[2-(cyclopen1ylamino)-5-methylpyrirnidin-4-yl](l-ethyl-lH-benzimidazol-2-yl)acetonitrile
(2Z)-(2- { [3- (2-oxopyrrolidin- 1 -yl)propyl]amino }pyrimidin-4-yl)( 1 -propyl- 1 ,3 -dihydro-2H- benzimidazol-2-ylidene)acetonitrile (l-emyl-lH-benzimidazol-2-yl){5-methyl-2-[(2-pyridin-3-ylethyl)amino]pyrimidin-4- yl} acetonitrile
(2Z)-[2-(cyclobutylamino)pyrimidin-4-yl](l -ethyl- 1 ,3-dihydro-2H-benzimidazol-2- ylidene)acetonitrile
(2Z)-[2-(cycloheptylamino)-5-methylpyrimidin-4-yl](l -ethyl- 1 ,3-dihydro-2H- benzimidazol-2-ylidene)acetonitrile
[2-(cyclopentylamino)pyrimidin-4-yl](l -ethyl- lH-benzimidazol-2-yl)acetonitrile
l,3-dihydro-2H-benzimidazol-2-ylidene(5-methyl-2-{[3-(2-oxoρyrrolidin-l- yl)propyl]amino}ρyrimidin-4-yl)acetonitrile
(2Z)-(l-cyclobutyl-l,3-dihydro-2H-benzirnidazol-2-yhdene)(2-{[3-(2-oxopyrrolidin-l- yl)ρropyl]arnino}ρyrimidin-4-yl)acetonitrile
( 1 -ethyl- 1 H-benzimidazol-2-yl) {2- [(2-pyridin-3 -ylethyl)amino]pyrimidin-4-yl} acetonitrile
(2Z)-(l-ethyl-l,3-dihydro-2H-benzimiάazol-2-ylidene)[2-(isobu1ylan_ino)-5- ιnethylpyrirnidin-4-yl]acetonitrile
(2Z)-(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[2-(lH-imidazol-4- yl)emyl]amino}pyrimidin-4-yl)acetonitrile
(2Z)-(l-ethyl-l,3-dihydro-2H-ben__imidazol-2-ylidene)[2-(isobutylamino)pyrimidin-4- yljacetonitrile
[2-(cyclopropylamino)pyrimidin-4-yl](l-ethyl-lH-benzimidazol-2-yl)acetonitrile
[2-( {2- [6-(dimethylamino)pyridin-3-yl]ethyl} amino)pyrimidin-4-yl](l -ethyl- 1 H- benzimidazol-2-yl)acetonitrile (l-ethyl-lH-benzimidazol-2-yl)(2-{[2-(lH-l,2,4-1riazol-l-yl)e1hyl]amino}pyrimidin-4- yl)acetonitrile
(2Z)-(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[2-(lH-imidazol-4- yl)ethyl]arnino}-5-methylpyrimidin-4-yl)acetonitrile
[2-({2-[6-(dimethylamino)pyridin-3-yl]ethyl} amino)-5-memylpyrimidin-4-yl](l -ethyl- 1H- benzimidazol-2-yl)acetonitrile
(2Z)-[2-(cycloheptylamino)pvrimidrn-4-yl](l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2- ylidene)acetonitrile
[2-(cyclopropylamino)-5-memylpyrimidin-4-yl](l-e1hyl-lH-benzimidazol-2-yl)acetonitrile
(1 -ethyl- 1 H-benzimidazol-2-yl) {2- [(2-pyridin-2-ylethyl)amino]pyrimidin-4-yl} acetonitrile
[2-(cyclopentylammo)-5-nιethylpyrimidin-4-yl](l,3-dihydro-2H-benzimidazol-2- ylidene)acetoniτrile
[2-(cyclohexylamino)ρyrimidin-4-yl](l-ethyl-lH-benzimidazol-2-yl)acetonitrile
(2Z)-(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[2-(lH-indol-3-yl)ethyl]amino}- 5-methylpyrimidin-4-yl)acetonitrile
(l-emyl-lH-benzimidazol-2-yl){5-methyl-2-[(2-pyridin-2-ylethyl)amino]pyrimidin-4- yl} acetonitrile
{2-[(2-ethoxyethyl)amino]pyrimidin-4-yl}(l-ethyl-lH-benzimidazol-2-yl)acetonitrile
(l-ethyl-lH-benzimidazol-2-yl){5-methyl-2-[(l-methylbutyl)amino]pyrimidin-4- yl} acetonitrile
(l-ethyl-lH-ber_zimi(_azol-2-yl)[2-(me1hylamino)pyrimidin-4-yl]acetonitrile ( 1 -ethyl- lH-benzimidazol-2-yl)(5 -methyl-2- { [2-(lH-pyrazol- 1 -yl)ethyl]amino}ρyrimidin- 4-yl)acetonitrile
lH-benzimi(3azol-2-yl{5-me1hyl-2-[(2-pyridin-3-yle1_hιyl)amino]pyrimidin-4-yl}acetonitrile
(2Z)-(1 -ethyl-1 ,3-dihydro-2H-benzimidazol-2-ylidene)(2- {[2-(lH-imidazol- 1 - yl)ethyl]amino} -5-methylpyrimidin-4-yl)acetonitrile
lH-benzimid^ol-2-yl{2-[(2-ρyridin-3-ylethyl)amino]ρyrimidin-4-yl}acetonitrile
( 1 -ethyl- lH-benzimidazol-2-yl) {2-[(l -methylbutyl)amino]pyrimidin-4-yl} acetonitrile
{2-[(cyclohexylmemyl)ammo]-5-memylpyτimidin-4-yl}(l-ethyl-lH-benzimidazol-2- yl)acetonitrile
lH-benzimidazol-2-yl[2-(cyclopentylamino)pyrimidin-4-yl]acetonitrile
(l-e1hyl-lH-benzimidazol-2-yl){6-me yl-2-[(2-pyridin-3-ylethyl)amino]pyrimidin-4- yl} acetonitrile
lH-benzimidazol-2-yl[2-(cyclopropylamino)pyrimidin-4-yl]acetonitrile
[2-(cyclopentylammo)-6-methylpyτimidin-4-yl](l-ethyl-lH-benzimidazol-2-yl)acetonitrile
{2- [(cyclohexylmethyl)amino]pyrimidin-4-yl} ( 1 -ethyl- 1 H-benzimidazol-2-yl)acetonitrile
( 1 -ethyl- lH-benzimidazol-2-yl){6-[(2-pyridin-3 -ylethyl)amino]pyrimidin-4-yl} acetonitrile .
(l-ethyl-lH-benzimidazol-2-yl){2-[(3-pyτrolidin-l-ylpropyl)ammo]pyrimidin-4- yl} acetonitrile
(l-ethyl-lH-ber_zimidcizol-2-yl)[2-(4-ethylpiperazin-l-yl)-5-memylpyrimidin-4- yl]acetonitrile (l-ethyl-lH-benzimid-izol-2-yl){2-[(2-furylmemyl)ammo]-5-methylpyrimidin-4- yl} acetonitrile
(2Z)-(l-ethyl-l,3-dmydτo-2H-benzimidazol-2-ylidene){5-methyl-2-[(l-methylpiperidin-4- yl)an_ino]pyrimidin-4-yl} acetonitrile
(2Z)-[2-(cyclohexylammo)-5-memylpyrimidin-4-yl](l-ethyl-l,3-dihydro-2H-benzimidazol- 2-ylidene)acetonitrile
(2Z)-[2-(e1hylan_ no)-5-me ylpyιitnidin-4-yl](l-e1hyl-l,3-dihydro-2H-benzimidazol-2- ylidene)acetonitrile
[2-(cyclopentylamino)-5-memylpyrimidin-4-yl](l,3-diethyl-l,3-dihydro-2H-benzimidazol- 2-ylidene)acetonitrile
(2Z)-(1 -ethyl-1, 3-dihydro-2H-benzimidazol-2-ylidene)[5-methyl-2-(piperidin-4- ylamino)ρvrimidin-4-yl]acetonitrile, and
(2Z)-(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene){5-methyl-2-[(2-piperidin-l- ylethyl)amino]ρyrimidin-4-yl} acetonitrile, or it a tautomer form thereof.
N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyll-5- methylpyrimidin-2-yl } -4-(4-methylpiperazin- 1 -yl)-4-oxobutanamide
N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]pyrimidin-2-yl}- 4-(4-methylpiperazin- 1 -yl)-4-oxobutanamide
(lR,5R57R)-N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-carboxamide
(lS,5S,7S)-N-{4-[(Z)-cyano(l -ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-carboxamide (1 S,4S,5S57R)-N-{4-[(Z)-cyano(l -ethyl-1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]- 5-memylp rimidin-2-yl}-4-methyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-carboxamide
(lS,4R,5S,7R)-N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]- 5-memylpyrimidin-2-yl}-4-me yl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-carboxamide
N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}ρiperazine-2-carboxamide
(4S)-N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- rnethylpyτirmdin-2-yl}-l,3-thiazolidine-4-carboxarnide
(4R)-N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl} -1 ,3-thiazolidine-4-carboxarnide
N- {4- [(Z)-cyano(l -ethyl-1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl] -5- methylpyrimidin-2-yl}-5-oxo-L-prolinanιide
4-tert-butyl l-(9H-fluoren-9-ylmethyl) 2-[({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H- benzimidazol-2-ylidene)methyl]-5-methylρyrimidin-2-yl}amino)carbonyl]piperazine-l,4- dicarboxylate
tert-butyl (4S)-4-[({4-[(Z)-cyano(l -ethyl-1 , 3-dihydro-2H-benzimidazol-2-ylidene)methyl]- 5-methylpyrimidin-2-yl} amino)carbonyl]- 1 ,3 -thiazolidine-3-carboxylate
tert-butyl (2S)-2-[({4-[(Z)-cyano(l -ethyl- 1 ,3-dihydro-2H-benzimidazol-2-ylidene)methyl]- 5-ιne1hylpyrimidin-2-yl}amino)carbonyl]-5-oxopyrrolidine-l-C-irboxylate
tert-bu1yl (4R)-4-[({4-[(Z)-cyano(l-e1hyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]- 5-memylpyrimidm-2-yl}amino)carbonyl]-l,3-thiazolidine-3-carboxylate
2-(l-acetylpiperidin-4-yl)-N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidin-2-yl}acetamide N- {4- [(Z)-cyano( 1 -ethyl-1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl] -5 - me ylρyriιrύdin-2-yl}-4-memylmoφholine-2-carboxa_nide
4-acetyl-N- {4-[(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-ben__imidazol-2-ylidene)methyl]-5- me ylpyτintidin-2-yl}moφholine-2-carboxamide
N- {4- [(Z)-cyano( 1 -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl] -5 - methylpvrirnidin-2-yl}-4-[(4-methylpiperazin-l-yl)methyl]benzam.ide
tert-butyl 3-[({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl } amino)carbonyl]piperidine- 1 -carboxylate
tert-bu1yl 4-[2-({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl} a_nino)-2-oxoethyl]piperidine-l -carboxylate
N- {4- [(Z)-cyano( 1 -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl] -5 - methylpyrimidin-2-yl}moφholine-2-carboxamide
N- {4- [(Z)-cyano( 1 -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl] -5 - methylpyrirnidin-2-yl } -2-piperidin-4-ylacetamide
N- {4- [(Z)-cyano( 1 -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyll -5 - methylpyrimidin-2-yl}piperidine-3-carboxamide
tert-butyl 2-[({4-[(Z)-cyano(l -ethyl-1, 3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}amino)carbonyl]morpholine-4-carboxylate
N-[3-({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrirnidin-2-yl} amino)-3-oxopropyl]benzamide
tert-butyl [2-({4-[(Z)-cyano(l -ethyl-1 ,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrirnidin-2-yl}amino)-2-oxoethyl]ιnethylcarbamate N- {4-[(Z)-cyano(l -ethyl-1 ,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}-l-methylpiperidine-3-carboxamide
N~l — {4- [(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl] -5- methylpyτimidin-2-yl}-N~2 — methylglycinamide
5 N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- me ylpyrirriidin-2-yl}pyrroHdine-3-carboxamide tert-butyl 3 - [( {4- [(Z)-cyano( 1 -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- m^emylpyrirmdin-2-yl}amino)caτbonyl]pyrrolidine-l-carboxylate
(2S)-N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- l o memylpyrimidin-2-yl} -2,5-dihydro- 1 H-pyrrole-2-carboxamide tert-butyl (2S)-2-[({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)men yl]- 5-methylpyrimidin-2-yl} amino)carbonyl] -2,5 -dihydro- 1 H-pyrrole- 1 -carboxylate
N-{4-[(Z)-cyano(l -ethyl-1, 3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- nιethylpyrimidin-2-yl}-2-(2-methoxyphenyl)acetamide
15 1 -acetyl-N- {4-[(Z)-cyano(l -ethyl- 1 ,3-dihydro-2H-benzimidazol-2-ylidene)methyll-5- methylpyrimidin-2-yl}piperidine-4-carboxamide
N-{4-[(Z)-cyano(l-e1hyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl } - 1 -methylpiperidine-4-carboxamide
4-amino-N-{4-[(Z)-cyano(l -ethyl-1, 3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- 20 memylpyrimidin-2-yl}butana_nide tert-butyl 4-[({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- nιethylpyrimidin-2-yl} amino)carbonyl]piperidine- 1 -carboxylate N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- memylpyrimidin-2-yl}piperidine-4-carboxamide
tert-butyl [4-({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- memylpyrimidin-2-yl}arnino)-4-oxobutyl]carbamate
N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}cyclopentanecarboxamide
N- {4- [(Z)-cyano( 1 -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl] -5 - methylpyrimidin-2-yl} -4-(4-methylpiperazm- 1 -yl)butanamide
N~l — {4-[(Z)-cyano(l-etiιyl-l,3-dihydro-2H-benzimidazol-2-ylidene)memyl]-5- methylpyrimidin-2-yl} -N~3~,N~3~-dimethyl-beta-alaninamide
N- {4- [(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrinιidin-2-yl}-4-(dirnethylanιino)butanamide
(2Z)-(2-amino-5-methylpyrimidin-4-y])(l -ethyl-1, 3-dihydro-2H-benzimidazol-2- ylidene)acetonitrile
N- {4- [(Z)-cyano( 1 -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl] -5 - methylpyrimidin-2-yl}-2-mo_pholin-4-ylacetamide
N~2~-benzyl-N~l~- {4- [(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidin-2-yl } glycinamide
N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpvrimidin-2-yl} -2-(l , 1 -dioxidothiomoφholin-4-yl)acetamide
]Sr~l — {4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}-N~2 — formylglycinamide Compounds of formula (I) are suitable for the use as medicament, in particular for the treatment and/or prevention of metabolic disorders mediated by insulin resistance or hyperglycemia, comprising diabetes type π, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS).
The compoimds according to formula I could be employed alone or in combination with further pharmaceutical agents.
In one embodiment, the compounds of formula (I) are useful in inhibiting Glycogen Synthase Kinase 3
Still a further object ofthe present invention is a process for preparing the benzimidazole acetonitriles according to formula I.
The benzimidazole acetonitriles exemplified in this invention may be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred experimental conditions (i.e., reaction temperatures, time, moles of reagents, solvents, etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimisation procedures.
Generally, the benzimidazole acetonitriles derivatives according to the general formula I may be obtained by several processes using solution-phase chemistry protocols.
The general synthetic approach for obtaining compounds of formula (I) is depicted in Scheme 1. Therein, benzimidazole acetomtriles derivatives according to the general formula I, whereby the substituents L and G are as above defined, may be prepared from the corresponding acetonitrile derivatives IV and chloro derivatives V. Scheme 1
Figure imgf000029_0001
In a more specific method, the benzimidazole acetonitrile derivative VI with R1 being as above defined - is reacted with the electrophile VII (e.g. alkyl chloride) to give the corresponding benzimidazole compounds IV. In a subsequent step, the intermediate IV is treated with a bis-chloro derivative V, wherein G is as above defined, to give the intermediate of synthesis II. In a final step, the intermediate II may be treated with an amine III, whereby the substituents R5, R6 are as above defined to give the final benzimidazole acetonitrile derivatives I, utilizing well known solution-phase chemistry protocols, such as those described in the Examples and shown in Scheme 2, below :
Scheme 2
Figure imgf000030_0001
Figure imgf000030_0002
Electrophiles VII as well as bis-chloro derivative V and amines III are commercially available.
The benzimidazole acetonitriles derivatives according to the general formula I, may be obtained in 2-6 subsequent steps depending the availability of starting materials and building blocks. As shown in Scheme 3. In a first step, the benzimidazole acetonitriles derivatives IV are isolated after condensation ofthe benzimidazole compound VT with an electrophile VII, whereby R2 is as above defined. Several reaction conditions may be utilised for performing this first reaction step, e.g. by the use of PS-TBD (7-methyl-l,5,7- triazabicyclo[4.4.0]dec-5-en' on polystyrene HL) a polymer immobilised reagent as a base in presence of various electrophihc reactants such as alkyl chlorine, bromide, iodide or also activated alcohol through mesylate formation. This reaction may be performed in solvents like DCM or DCM/dioxane. This reaction can be performed at various temperature depending of he intrinsic reactivity of compounds VI and VH, by traditional thermal method, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples.
Scheme 3
Figure imgf000031_0001
[X = CI, Br, I, OMs]
In a subsequent step, the benzimidazole acetonitriles derivatives II, whereby the substituents R1 and R2 are as above defined, are isolated after condensation ofthe benzimidazole compound IV with bis-chloro derivative V. This reaction step is performed, using, e.g. lithium hydride or sodium hydride, cesium carbonate or similar reagents in an appropriate solvent such as Dioxane, THF, DMA or DMF. This reaction can be performed at various temperature depending ofthe intrinsic reactivity of compoimds IV and V, by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples.
Scheme 4
Figure imgf000032_0001
In a following step, as shown in Scheme 5, the chloro benzimidazole acetonitriles derivatives II may treated with various nucleophiles, e.g. an amine III, to give the expected benzimidazole acetonitriles I. The nucleophilic displacement ofthe chloro atom ofthe pyrimidinyl moiety by the amine HI, is accomplished by treatment with several equivalents ofthe nucleophile, e.g. the amine III, in presence or absence of e.g. sodium iodine as catalyst and a base such as triethylamine of diisopropylethylamine or similar reagents. This reaction can be performed at various temperatures depending of the intrinsic reactivity of compounds II and III, by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples.
Scheme 5
Figure imgf000032_0002
II III [L = NR5R6] The benzimidazole acetonitriles derivatives according to the general formula I can be further isolated from the intermediate F, whereby L is the moiety -NR5R6, with R5 being hydrogen and R6 is as above defined, as shown in Scheme 6. The benzimidazole derivatives I may be obtained by treatment ofthe intermediate I' with either an acyl chloride, a carboxylic acid or a sulfonyl chloride using standard conditions well known to the person skilled in the art, such as amide bond formation protocols or sulfonamide formation using the appropriate reactants as those mentioned above and reagents such as bases like triethylamine, pyridine etc, and activating agents e.g, HOBt, EDC or similar reagents in an appropriate solvent such as THF or DMF. This reaction can be performed at various temperature depending ofthe intrinsic reactivity of compounds lb and VIII, by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples.
Scheme 6
Figure imgf000033_0001
lb VIII [R5 = H] [Y = CI, OH] [R5 = R-C=0, R-S02]
A specific functional moiety (R1) may be converted into a different one (R1 ), using any known functional group interconversion protocols. As illusttated in Scheme 7, the choice of the best synthetic strategy will be governed by the nature ofthe functional groups to be interconverted, and the compatibility of he required reaction conditions with other functional groups present in the corresponding compounds, as will be well appreciated by the person skilled in the art. Amongst the most preferred starting materials I, π and IV and VII, are those wherein R1 is -Br, -CI, -I, -OH, -NH2, -CH2OH, -CHO, -COOH, -N02, and/or -CH2COOH, which are either obtained from commercial sources or made by one of the numerous processes described in the literature. From the intermediates (XXI, XXV,
XXVπ) derived thereof, in which R is as defined in Scheme 7, a wide range of derivatives, such as e.g. (XXII)-(XXXV), in which R9, R10, R11, R7, are as defined below, can be obtained by reaction sequences including oxidations, reductions, O- and N-alkylations, reductive alkylations and aminations, chain-elongations, Mitsunobu reactions, acylation, debocylation, Wittig reactions, acylations, sulfonylations, Stille, Suzuki, Sonogashira and any other appropriate transformations leading to functional group interconversions, some of which being exemplified in Scheme 8. The synthetic examples cited in Scheme 8 are meant to illustrate the concept of functional group interconversion as applied to compounds of general structures (I), (II), (IV), and (VI), wherem R1, R2 are as defined in the above description and in Scheme 7, and are not construed to be viewed as limiting the scope of said synthetic approach.
R9, R10, R11, R7, are each independently from each other H, unsubstituted or substituted Ci- d-alky], unsubstituted or substituted C2-C6-alkenyl, unsubstituted or substituted C2-Ce- alkynyl, unsubstituted or substituted Ci-Ce-alkoxy, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, unsubstituted or substituted saturated or unsaturated 3-8-membered cycloalkyl, unsubstituted or substituted 3-8-membered heterocycloalkyl, (wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group), unsubstituted or substituted Ci-Cβ-alkyl aryl, unsubstituted or substituted Ci-d-alkyl heteroaryl, unsubstituted or substituted Ci-d-alkenyl aryl, unsubstituted or substituted Ci-d-alkenyl heteroaryl, unsubstituted or substituted Cι-C6-alkynyl aryl, unsubstituted or substituted Ci-Ce-alkynyl heteroaryl, imsubstituted or substituted Ci-d-allcyl cycloalkyl, unsubstituted or substituted Ci-Ce-alkyl heterocycloalkyl, unsubstituted or substituted Ci-Cβ-alkenyl cycloalkyl, unsubstituted or substituted Cι-C6-alkenyl heterocycloalkyl, unsubstituted or substituted Ci-Cβ-alkynyl cycloalkyl, unsubstituted or substituted Ci-Cβ-alkynyl heterocycloalkyl.
Scheme 7
(functional group interconversion)
Figure imgf000035_0001
Figure imgf000035_0002
: R = G-L : R = G-L II : R a G-CI : R = G-CI IV : R = H IV : R = H VI :R = H, R2 VI' :R=H, R* = H
Figure imgf000035_0003
XXV
Figure imgf000035_0004
The benzimidazole acetonitriles derivatives according to the general formula I, may be obtained in 2-6 subsequent steps depending the availability of starting materials and building blocks. As shown in Scheme 9. In a first step, the benzimidazole acetonitriles derivatives II' are isolated after condensation ofthe benzimidazole compound II with a solution of ammonium hydroxide. This reaction may be performed in solvents like DMA, isopropanol or solution containing both solvents in various ratio. This reaction can be performed at various temperature depending ofthe intrinsic reactivity of compounds II, by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples
Scheme 9
Figure imgf000036_0001
n xxxx
In a following step, the benzimidazole acetonitriles derivatives according to the general formula I can be further isolated from the intermediate III', whereby L is the moiety— C(0)R6, with R6 is as above defined, as shown in Scheme 10. The benzimidazole derivatives I may be obtained by treatment of the intermediate II' with either an acyl chloride or a carboxylic acid using standard conditions well known to the person skilled in the art, such as amide bond formation protocols using the appropriate reactants as those mentioned above and reagents such as bases like triethylamine, pyridine etc, and activating agents e.g, HOBt, EDC, Mukayama reagent or similar reagents in an appropriate solvent such as DCM, THF or DMF. This reaction can be performed at various temperature depending of the intrinsic reactivity of compounds II' and III', by traditional thermal method or using microwave technology, using standard conditions well known to the person skilled in the art, such as those described hereinafter in the Examples. Scheme 10
Figure imgf000037_0001
II' III' I [X = CI, OH] [L = NC(0)R6]
When employed as pharmaceuticals, the benzimidazole acetonitriles ofthe present invention are typically administered in the form of a pharmaceutical composition. Hence, pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient therefore are also within the scope ofthe present invention. A person skilled in the art is aware of a whole variety of such carrier, diluent or excipient compounds suitable to formulate a pharmaceutical composition.
The compounds ofthe invention, together with a conventionally employed adjuvant, carrier, diluent or excipient may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, or in the form of sterile injectable solutions for parenteral (including subcutaneous use). Such pharmaceutical compositions and unit dosage forms thereof may comprise ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of he active ingredient commensurate with the intended daily dosage range to be employed.
When employed as pharmaceuticals, benzimidazole acetonitriles of this invention are typically administered in the foim of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound. Generally, the compounds of this invention are administered in a pharmaceutically effective amount. The amount ofthe compound actually administered will typically be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response ofthe individual patient, the severity ofthe patient's symptoms, and the like.
The pharmaceutical compositions of these inventions can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, intra- thecal, intraperitoneal and intranasal. Depending on the intended route of delivery, the compoimds are preferably formulated as either injectable, topical or oral compositions. The compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes ofthe liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the benzimidazole acetonitrile compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any ofthe following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum ttagacanth or gelatine; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dio- xide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable carriers known in the art. As mentioned above, the benzimidazole acetonitriles of formula I in such compositions is typically a minor component, frequently ranging between 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
The above described components for orally administered or injectable compositions are merely representative. Further materials as well as processing techniques and the like are set out in Part 5 of Remington 's Pharmaceutical Sciences, 20th Edition, 2000, Marck Publishing Company, Easton, Pennsylvania, which is incorporated herein be reference.
The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can also be found in the incorporated materials in Remington 's Pharmaceutical Sciences.
A further aspect ofthe present invention is related to a pharmaceutical composition composition a comprising a benzimidazole derivative according to formula (I) and at least one further drug (in particular an anti-diabetes agent). In one embodiment the further diabetes agents are selected from the group comprising or consisting of insulin (or insulin mimicks), aldose reductase inhibitors, alpha-glucosidase inhibitors, sulfonyl urea agents, biguanides (e.g. metformin), thiazolidines (e.g. pioglitizone, rosiglitazone, cf. WO 02/100396), a PTP1B inhibitor, a PPAR agonists or a GSK-3 inhibitor.
Insulins useful with the method ofthe present invention include rapid acting insulins, intermediate acting insulins, long acting insulins and combination of intermediate and rapid acting insulins. Among the more preferred aldose reductase inhibitors of this invention are minalrestat, Tolrestat, Sorbinil, Methosorbinil, Zopofrestat, Epalrestat, Zenarestat, Imirestat and Ponalrestat or the pharmaceutically acceptable salt forms thereof.
The alpha-glucosidase inhibitors useful for the method ofthe present invention include miglitol or acarbose, or the pharmaceutically acceptable salt form thereof.
Sulfonylurea agents useful with the method ofthe present invention include glipizide, Glyburide (Ghbenclamide), Clorpropamide, Tolbutamide, Tolazamide and Glimepiride, or the pharmaceutically acceptable salt forms thereof.
Preferably, said supplementary pharmaceutically active agent is selected from the group consisting of a rapid acting insulin, an intermediate acting insulin, a long acting insulin, a combination of intermediate and rapid acting insulins, Inalrestat, Tolrestat, Sorbinil, Methosorbinil, Zopolrestat, Epalrestat, Zenarestat, Imirestat, Ponalrestat, ONO-2235, GP- 1447, CT-112, BAL-ARI 8, AD-5467, ZD5522, M- 16209, NZ-314, M-79175, SPR-210, ADN 138, or SNK-860, Miglitol, Acarbose, Glipizide, Glyburide, Chlorpropamide, Tolbutamide, Tolazamide, or Glimepriride.
In the following the present invention shall be illustrated by means of some examples which are not construed to be viewed as limiting the scope of the invention.
The following abbreviations are hereinafter used in the accompanying examples: min (minute), hr (hour), g (gram), mmol (millimole), .p. (melting point), eq (equivalents), mL (milliliter), μL (microhters), mL (milliliters), ACN (Acetonitrile), Boc (butoxycarbonyl), CDCI3 (deuterated chloroform), CsC03 (Cesium carbonate), cHex (Cydohexanes), DCM (Dichloromethane), DIG (Diisopropyl carbodiimide), DIPEA (Diisopropylamine), DMA (Dimethylacetamide), DMAP (4- Dimethylaminopyridine) DMF (Dimethylformamide), DMSO (Dimethyl-sulfoxide), DMSO-e (deuterated dimethylsulfoxide), EDC (l-(3- Dimethyl-amino-propyl)-3-ethylcarbodiimide), Et3N (Triethylamine), EtOAc (Ethyl acetate), EtOH (Ethanol), Et O (Diethyl ether), Fmoc (9-fluorenyl-methoxycarbonyl), HOBt (1-Hydroxybenzotriazole), iPrOH f sopropanol), K2C03 (potassium carbonate), LiH (Lithium Hydride), Nal (Sodium Iodine), NaH (Sodium hydride), NaHC03 (Sodium bicarbonate), NH C1 (Ammonium chloride), nBuLi (n Butyllithium), Pd(PPh3) (Palladium triphenylphosphine tetrakis), (TBTU (O-Benzotri-tzolyl-NN.iV^-N'-tetramethyluronium- tetrafluoroborate), Mukayama reagent (1 -methyl-2-chloropyridinium iodide), TEA (Triethyl amine), TFA (Trifluoro-acetic acid), THF (Tetrahydrofuran), TBD-resin (7- methyl-l,5,7-triazabicyclo[4.4.0]dec-5-ene on polystyrene.HL), TMOF (trimethylorthoformate), MgS0 (Magnesium sulfate), PetEther (Petroleum ether), rt (room temperature).
The HPLC, ΝMR and MS data provided in the examples described below were obtained as. followed: HPLC: column Waters Symmetry C8 50 x 4.6 mm, Conditions: MeCΝ/H20, 5 to 100% (8 min), max plot 230-400 nm; Mass spectra: PE-SCIEX API 150 EX (APCI and ESI), LC/MS spectra: Waters ZMD (ES); 1H-NMR: Bruker DPX-300MHz. The purifications were obtained as followed: Preparative HPLC Waters Prep LC 4000 System equipped with columns Prep Nova-Pak®HR CI 86 μm 6θA, 40x30mm (up to lOOmg) or 40x300 mm (up to lg). All the purifications were performed with a gradient of MeCN/H20 0.09% TFA.
Examples
Intermediate 1 : (l-ethyl-2.3-dihydro-lH-benzimidazol-2-yl)acetonittile (cf. Scheme 4, compound IV)
Figure imgf000041_0001
To a suspension of 2-benzimidazolylacetonitrile (6.0g, 38.17mmol) in DCM (200mL) was added TBD-resin (17.6g, 45.81mmol, loading 2.6mmol/g) followed by bromoethane (4.08mL, 38.17mmol) at room temperature. The reaction mixture was shaken for 4days at room temperature, then the resin was filtered and washed with 50mL of DCM. The filtrate was concentrated to give the pure (l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile as an yellow-orange solid (5.25g, 74.2% yield, 98% HPLC purity). This compound was utilised as such for the next reaction.
IH NMR (300MHz, CDC13); 1.5 (t, 3H), 4.0 (s, 2H), 4.2 (q, J = 7.5Hz, 2H), 7.2-7.45 (m, 3H), 7.7 (d, J = 7.0Hz, IH). MS(ESI+): 188.4; MS(ESI ): 186.5.
Intermediate 2: (l-propyl-2.3-dihydro-lH-ben_πmidazol-2-yl, acetonitrile (cf. Scheme 4, compound IV)
Figure imgf000042_0001
Following the general methods as outlined in Intermediate 1, starting from 2- benzimidazolylacetonitrile and 1-bromopropane, the title compound was isolated, after filtration and evaporation, as an orange solid in 49% yield (98.5 % purity by HPLC).
IH NMR (300MHz, CDC13); 1.5 (t, 3H), 1.6 (m, 2H), 4.0 (s, 2H), 4.1 (m, 2H), 7.3-7.45 (m, 3H), 7.6 (d, J = 7.0Hz, IH). MS(ESI+): 202.3; MS(ESF): 200.4.
Intermediate 3 : (1 -cyclobutyl-2.3-dihydro- lH-benzimidazol-2-yl)acetonitrile (cf. Scheme 4, compound IV)
Figure imgf000043_0001
Following the general methods as outlined in Intermediate 1, starting from 2- benzimidazolylacetonitrile and bromocyclobutane, the title compound was isolated, after filtration and evaporation, as an orange solid in 22% yield (97 % purity by HPLC).
IH NMR (300MHz, CDC13); 1.6-1.9 (m, 6H), 4.1 (s, 2H), 4.8 (m, IH), 7.3-7.5 (m, 3H), 7.6 (d, J = 7.0Hz, IH). MS(ESI+): 214.3; MS(ESI~): 212.4.
Intermediate 6: (2-chloro-5-methylpyrimidin-4-yl)(l -ethyl-2.3-dihydro-lH-benzimidazol- 2-yl,acetonitrile
(cf. Scheme 9, compound V'c)
Figure imgf000043_0002
Method A:
To a suspension of Cesium carbonate (13.85g, 42.55mmol) in dioxane (50mL), was added a solution of (l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (Intermediate 1, 5.25g, 28.34mmol) in dioxane (50mL). The reaction mixture was stirred at room temperature for 3 hours. A solution of 2,4-dichloro-5-methyl-pyrimidine (5.54g, 34.01mmol) in dioxane (100ml), was added dropwise at room temperature. The reaction mixture was stirred and heated to reflux for 24 hours. The reaction mixture was allowed to warm to r.t. and water was added (50mL). The solvents were concentrated under vacuum to 50mL and a solution of IN HCI (50mL) was added at zero degree. The solution was then diluted to 1/3 with acetonitrile and concentrated under vacuum to 50mL. The precipitate was filtered and washed with water (lOmL), acetonitrile (lOmL) and diethyl ether (lOmL) to give a yellow solid which was dried under vacuum. The yellow crystalline product (2- chloro-5-memylpyrirnidin-4-yl)(l -ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile was isolated in 95% HPLC purity ( Yield 5.1g, 50%).
Method B:
To a suspension of Cesium carbonate (96mg, 0.3mmol) in dioxane (2mL), was added a solution of (l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (Intermediate 1, 50mg, 0.27mmol) in dioxane (2mL). Then a solution of 2,4-dichloro-5-methyl-pyrimidine (57mg, 0.37mmol) in dioxane (1ml), was added at room temperature. The reaction mixture was stirred and heated to 160 degrees in the microwave for 25 minutes . The reaction mixture was allowed to warm to r.t. and water was added (lmL). The solvents were concentrated under vacuum to 5mL and a solution of IN HCI (5mL) was added at zero degree. The solution was then diluted to 1/3 with acetonitrile and concentrated under vacuum to 5mL. The precipitate was filtered and washed with water (2mL), acetonitrile (2mL) and diethyl ether (2mL) to give a yellow solid which was dried under vacuum. The yellow crystalline product (2-cUoro-5-rnethylpyrimidin-4-yl)(l -ethyl-2,3-dihydro-lH-benzimi__azol-2- yl)acetonitrile was isolated in 92% HPLC purity ( Yield 45mg, 53%).
(2-chloro-5-memylpyrimidm-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonittile: IH NMR (300MHz, CDC13); 1.6 (t, J= 7.5Hz, 3H), 4.7 (q, J = 7.5Hz, 2H), 2.3 (s, 3H), 7.2- 7.45 (m, 4H), 8.2 (d, J = 7.0Hz, IH), 13.7 (s(broad), IH). MS(ESI+): 314.8; MS(ESF): 312.6.
Intermediate 7: (2-chloropyrimidin-4-yl)(l -ethyl-2.3-dihydro-lH-benzimidazol-2- yl')acetonitrile
(cf. Scheme 5, compound II)
Figure imgf000045_0001
Following the general method A as outlined in Intermediate 6, starting from (l-ethyl-2,3- dihydro-lH-benzimidazol-2-yl)acetonitrile (Intermediate 1) and 2,4-dichloropyrimidine, the title compound was isolated, as a yellow solid in 51% yield (96 % purity by HPLC).
IH NMR (300MHz, CDC13); 1.6 (t, J = 7.5Hz, 3H), 4.7 (q, J = 7.5Hz, 2H), 7.2-7.5 (m, 5H), 8.2 (d, J = 7.0Hz, IH), 13.7 (s(broad), IH). MS ES ): 300.8; MS(ESI ): 298.8.
Intermediate 8: (2-cMoro-5-me ylpyrimidin-4-yl)(2.3-dihydro-lH-benzimidazol-2- yl.acetonitrile
(cf. Scheme 5, compound II)
Figure imgf000045_0002
Following the general method A as outlined in Intermediate 6, starting from 2- benzimidazolylacetonitrile and 2,4-dichloro-5-methyl-pyrimidine, the title compound was isolated, as a yellow solid in 60% yield (95 % purity by HPLC).
MStESI "): 286.8(ESF): 284.7
Intermediate 9: (2-chloropyrimidin-4-yl)(2.3-dihydτo-lH-benzimidazol-2-yl)acetoni1rile
(cf. Scheme 5, compound II)
Figure imgf000046_0001
Following the general method B as outlined in Intermediate 6, starting from 2- benzimidazolylacetonitrile and 2,4-dichloro-pyrimidine, the title compound was isolated, as a yellow solid in 55% yield (94 % purity by HPLC).
MS(ESI+): 272.7(ESr): 270.6
Intermediate 10: (2-cMoro-6-rnethylpyriιτndin-4-yl)(l-e1hyl-2.3-dihydro-lH-benzin_idazol- 2-yl)acetonitrile (cf. Scheme 5, compound II)
Figure imgf000046_0002
Following the general method A as outlined in Intermediate 6, starting from (l-ethyl-2,3- dihydro-lH-benzimidazol-2-yl)acetonitrile (Intermediate l) and 2,4-dichloro-6-methyl- pyrimidine, the title compound was isolated, as a yellow solid in 49% yield (97 % purity by HPLC).
MS(ESI+): 314.9(ESF): 312.7
Intermediate 11 : (6-chloropyrimidin-4-yl'.(l-ethyl-2.3-dihvdro-lH-benzimidazol-2- yl)acetonitrile (cf. Scheme 5, compound II)
Figure imgf000047_0001
Following the general method A as outlined in Intermediate 6, starting from (l-ethyl-2,3- dihydro-lH-benzimidazol-2-yl)acetonitrile (Intermediate 1) and 4,6-dichloroρyrimidine, the title compound was isolated, as a yellow solid in 46% yield (92 % purity by HPLC).
MS(ESI+): 300.7; MS(ESI ): 298.4.
Intermediate 15: (2-cMoro-5-memylpyrimidin-4-yl)(1.3-diethyl-2.3-dihvdro-lH- benzimidazol-2-yl)acetonitrile (cf. Scheme 5, compound II)
Figure imgf000047_0002
Following the general method A as outlined in Intermediate 6, starting from (1,3-diethyl- benzimidazol-2-yl)acetonitrile and 2,4-dichloro-5-methyl-pyrimidine, the title compound was isolated, as a yellow solid in 39% yield (94 % purity by HPLC).
MS(ESr 342.9; MS(EST): 340.8.
Intermediate 17 : (2-chloropyrimidin-4-yiχ 1 -propyl-2.3 -dihydro- 1 H-benzimidazol-2- yl acetonitrile
(cf. Scheme 5, compound II)
Figure imgf000048_0001
Following the general method A as outlined in Intermediate 6, starting from from (1- propyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (Intermediate 2) and 2,4-dichloro- pyrimidine, the title compound was isolated, as a yellow solid in 66% yield (99 % purity by HPLC).
MS(ESI'): 314.8; MS(EST): 312.6.
Intermediate 18: (2-chloropyrimidin-4-yl)(l-cyclobutyl-2.3-dihydro-lH-benzimidazol-2- yl)acetonitrile
(cf. Scheme 5, compound II)
Figure imgf000048_0002
Following the general method A as outlined in Intermediate 6, starting from from (1- cyclobutyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (Intermediate 3) and 2,4- dichloro-pyrimidine, the title compound was isolated, as a yellow solid in 50% yield (99 % purity by HPLC).
MStESI4): 326.9; MS(ESI"): 324.8. Intermediate 19: (2ZV(2-amino-5-methylρyrimidin-4-viχi-ethyl-1.3-dihydro-2H- benzimidazol-2-ylidene,)acetonitrile (cf. Scheme 9, compound II')
Figure imgf000049_0001
To a solution of (2-chloro-5-memylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol- 2-yl)acetonitrile (Intermediate 6, 1.5g, 5.05mmol) in iPrOH (2mL), were added ammonium hydroxide (3.14mL, 81.59mmol, 16eq) and sodium iodide (378mg, 2.52mmol, 0.5eq). The reaction mixture was heated up to 160 degree for 60min in a microwave device. After completion ofthe reaction, the reaction mixture was cooled down to room temperature and the yellow precipitate was filtered off, washed with water and dried under vacuum overnight to give the expected compound (2Z)-(2-amino-5-methylpyrimidin-4-yl)(l -ethyl- l,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile as a yellow solid (1.41mg, 82% yield, 95% HPLC purity)
(2Z)-(2-amino-5-memylpyrimidin-4-yl)(l-ethyl-l,3-dihydro-2H-benzimidazόl-2- ylidene)acetonitrile: IH NMR (300MHz, CDC13); 1.55 (t, J = 7.4Hz, 3H), 4.6 (q, J = 7.4Hz, 2H), 2.4 (s, 3H), 7.2-7.5 (m, 4H), 8.2 (d, J = 7.0Hz, IH), 14.1 (s(broad), IH). MS(ESI+): 293.5; MS(ESF): 291.4.
Intermediate 20: (2ZV(2-amino-pyrimidin-4-yl.(l -ethyl- 1.3 -dihvdro-2H-benzimidazol-2- ylidene)acetonitrile
(cf. Scheme 9, compound IF)
Figure imgf000050_0001
Following the general method as outlined in Intermediate 19, starting from (2- chloropyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (Intermediate 7) and ammonium hydroxide, the title compound was isolated, as a yellow solid in 75% yield (96 % purity by HPLC).
MS(ESI+): 279.5; MS(ESI): 277.4.
Example 1: General procedure for the solution-phase synthesis of benzimidazoles acetonitriles derivatives of general formula I. with G and L as above defined (Schemes 1- 6.: f2ZVri-ethyl-1.3-dihvdro-2H-benzimidazol-2-ylidene¥2-ir3-πH-pyrazol-l- yl^ropyl]amino}pyrimidin-4-yl)acetonitrile
Figure imgf000050_0002
Method C:
To a solution of (2-chloropyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2- yl)acetonitrile (intermediate 7) (150mg, 0.5mmol, leq) in 4mL of DMΛ PrOH (1:3)) was added DIEA (0.345mL, 2.0mmol, 4eq), 3-(lH-pyrazol-l-yl)propan-l-amine hydrochloride (325mg, 2.0mmol, 4eq) andNal (38mg, 0.25mmol, 0.5eq). The reaction mixture was heated up to 180°C for 2.5hours in a microwave device. The isopropanol was evaporated and the residue redissolved in 3mL of DCM. This solution was loaded onto a lOg SCX- SPE syringe (O^mmol.g"1) and eluted with DCM, then DCM:MeOH (1:1), 0.1M NH3 in MeOH and 1M NH3 in MeOH. he 4 fraction were analyzed by HPLC and LC-MS and the fractions contained the product were mixed together. The solvents were evaporated and the residue redissolved in DCM and washed with NaHC03 sat. and brine. The organic layer was dried over MgS0 , filtered and the solvent evaporated. The residue was then purified by preparative HPLC with a gradient 10 to 100& acetonitrile in 0.1M TFA. The solution was evaporated and the desired compound as a TFA salt, was isolated as a yellow solid (180mg, 0.36mmol, yield: 72%, 99% HPLC purity).
Method D:
10 mg of Building Blocks were dissolved in 0.3 mL of DMA. Et3N (4eq.) and the amines (4 eq.)dissolved in DMA (0.3mL) were then added to the reaction mixtures and the plate was sealed and heated in a microwave (Mars 5) as follow: 2 plates at a time were heated 4 min at 300 Watts and then left to cool down for 10 min. This was repeated 4 times. The reaction mixtures were then transferred into a 2 mL plate and the solvent was removed in the Genevac. Work up: 1 mL of water/CH3COOH (2%) was then added and the plate was shaken for 3h00. The aqueous layer was removed using the Zymark, leaving the solid behind. This solid was further washed with water (twice). 1 mL of MeOH/TFA (20%) was added to the plates, which were shaken at room temperature for 48h00 and the supernatant was collected using the Lissy. Analytical plates were made and the solvents were removed in the Genevac.
(2Z)-(l-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)(2-{[3-(lH-pyrazol-l- yl)propyl1amino}pyrimidin-4-yl)acetonitrile: yellow solid; 1H NMR (300 MHz, CDC13); 1.5 (t, 3H), 2.6-2.8 (m, 2H), 3.5-3.7 (m, 2H), 4.4-4.6 (m, 2H), 4.7-4.85 (q, 2H), 6.8-6.9 (m, IH), 7.4-7.7 (m, 3H), 7.75 (m, IH), 7.85 (m, IH), 10.1 (m, IH). MS (ESI+) 387.5, (ESI-) 385.6. Exa ple 2: (2Z)-(1 -ethyl- 1 ■3-dihvdro-2H-benzimidazol-2-ylidene)(5-methyl-2- [3-(lH- ρyrazol-l-yl)ρroρyllammo}pyrimidin-4-yl)acetonitrile
Figure imgf000052_0001
Following the general methods as outlined in Example 1 (Method C), starting from (2- cWoro-5-me ylpyrimidin-4-yl)(l -ethyl-2,3-dihydro- 1 H-benzimidazol-2-yl)acetonitrile (intermediate 6), and3-(lH-ρyrazol-l-yl)propan-l-amine hydrochloride, the title compound was isolated, as a yellow solid in 82% yield (99% purity by HPLC).
MS(ESI+): 401.5; MS(ESF): 399.2.
Example 3: (2Z)-r2-(cvclobutylamino)-5-me ylpyrimidin-4-yl](l -ethyl-1.3-dihvdro-2H- benzinfidazol-2-ylidene ace.onitrile
Figure imgf000052_0002
Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and cyclobutylamine, the title compound was isolated, as a yellow solid in 78% yield (99% purity by HPLC).
Η NMR (300 MHz, CDC13); 1.5 (t, 3H), 1.8-2.45 (m, 6H), 2.3 (s, 3H), 4.1-4.3 (m, IH), 4.5-4.65 (q, 2H), 7.4-7.65 (m, 3H), 7.75-7.85 (m, IH), 9.55 (m, IH). MSOESI ): 347.6; MS(EST): 345.3. Example 4: (2Z,-(l-ethyl-l .3-dihydro-2H-benzimidazol-2-ylidene)(5-methyl-2-{r3-(2- oxopyrrolidin- 1 -yl)ρropyl]amino}pyrirr-idin-4-yl)acetonitrile
Figure imgf000053_0001
Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-rne ylpyrinιidm-4-yl)(l-ethyl-2,3-cfihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and N-(3'-aminopropyl)-2-pyrrolidinone, the title compound was isolated, as a yellow solid in 77% yield (99% purity by HPLC).
XH NMR (300 MHz, CDC13); 1.5 (t, 3H), 1.75-1.95 (m, 4H), 2.1-2.25 (m, 2H), 2.29 (s, 3H), 3.3-3.45 (m, 611), 4.4-4.6 (q, 2H), 7.2-7.3 (m, IH), 7.4-7.65 (m, 311), 7.75-7.85 (m, III), 8.3 (m, IH). MS(ESI4): 418.6; MS(ESI ): 416.8.
Example 5: (2ZV(l-ethyl-1.3-dihvdro-2H-ben_-imidazol-2-ylidene)(2-{[3-(2-oxopyrrohdin- 1 -yl.propyl. amino }ρyrimidin-4-yl')acetonitrile
Figure imgf000053_0002
Following the general methods as outlined in Example 1 (Method C), starting from (2- chloropyrimidin-4-yl)(l -ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), andN-(3'-aminopropyl)-2-pyrrolidinone, the title compound was isolated, as a yellow solid in 70% yield (98% purity by HPLC).
MS(ESI+): 404.6; MS(ESO: 402.8. Example 6: r2ZVri-ethyl-1.3-dihvdro-2H-benzimidazol-2-ylidene¥2-fr3-(lH-1.2.4-triazol- l-yl)propyl]amino}ρyrimidin-4-yl)acetonitrile
Figure imgf000054_0001
Following the general methods as outlined in Example 1 (Method C), starting from (2- chloropyrimidin-4-yl)(l -ethyl-2,3-(Mhydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and 3-(lH-l,2,4-triazol-l-yl)propan-l-amine hydrochloride, the title compound was isolated, as a yellow solid in 72% yield (98% purity by HPLC).
MS(ESI+): 388.7; MS(ESF): 386.5.
Example 7: (2ZV(l-ethyl-l,3-dihvdro-2H-benzimidazol-2-ylidene)(5-methyl-2-{[3-(lH- 1.2.4-triazol-l-yl.propyl1amino}pyrimidin-4-yDacetonitrile
Figure imgf000054_0002
Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memylpyrimidin-4-yl)(l -ethyl-2,3 -dihydro- lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and3-(lH-l,2,4-triazol-l-yl)propan-l-amine hydrochloride, the title compound was isolated, as a yellow solid in 78% yield (98% purity by HPLC).
XH NMR (300 MHz, CDC13); 1.55 (t, 3H), 2.2-2.35 (m, 2H), 2.4 (s, 3H), 3.4-3.6 (m, 2H), 4.3-4.45 (m, 2H), 4.6-4.75 (q, 2H), 7.2-7.3 (m, IH), 7.4-7.65 (m, 3H), 7.75-7.85 (m, IH), 7.9 (s,lH), 8.3 (m, IH), 9.8 (s, IH). MS(ESI+): 402.6; MS(ESI~): 400.2.
Example 8: [2-(cyclopentylamino)-5-methylρyrimidin-4-yl](l -ethyl- lH-benzimidazol-2- vDacetonitrile
Figure imgf000055_0001
Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benziιnidazol-2-yl)acetonitrile (intermediate 6), and cyclopentylamine, the title compound was isolated, as a yellow solid in 69% yield (99% purity by HPLC).
MS(ESF 361.4; MS(ESF): 359.5.
Example 9: (2Z)-(2-{[3-(2-oxopyrrolidin-l-v propyl1amino}pyτimidin-4-yiχi-propyl-1.3- dihydro-2H-benzimidazol-2-ylidene)acetonitrile
Figure imgf000055_0002
Following the general methods as outlined in Example 1 (Method C), starting (2- chloropyrimidin-4-yl)(l-propyl-2,3-dihydro-lH-benzimidazo]-2-yl)acetonitrile (intermediate 17), andN-(3,-aminopropyl)-2-pyrrolidinone, the title compound was isolated, as a yellow solid in 79% yield (99% purity by HPLC).
MS(ESf): 418.6; MS(EST): 416.5.
Example 10: (l-ethyl-lH-ben-gmidazol-2-yl {5-methyl-2-f(2-pyridin-3-ylethyl)arnino1- pyrimidin-4-yl} acetonitrile
Figure imgf000056_0001
Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memylρyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 3 -(2-aminoethyl)pyridine, the title compound was isolated, as a yellow solid in 69% yield (96% purity by HPLC).
MS(ESF 398.6; MS(ESF): 396.4.
Example 11: (2Z)-[2-(cyclobutylamino^pyrimidin-4-yiχi -ethyl- 1.3 -dihydro-2H- benzimidazol-2-ylidene)acetonitrile
Figure imgf000056_0002
Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and cyclobutylamine, the title compound was isolated, as a yellow solid in 80% yield (97% purity by HPLC).
MS(ESI+): 333.2; MS(ESr>: 331.6.
Example 12: (2Z . - [2-(cycloheptylamino)-5-methylpyrimidin-4-yl (l -ethyl- 1.3 -dihydro-2H- benzimidazol-2-ylidene)acetonitrile-
Figure imgf000056_0003
Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memylpyrimidm-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and cycloheptylamine, the title compound was isolated, as a yellow solid in 71% yield (97% purity by HPLC).
MStESI""): 389.8; MS(ESF): 387.6.
Example 1 : f2-(cvclopentylamino)pyrimidin-4-viχi -ethyl- lH-benzimidazol-2- yl)acetonitrile
Figure imgf000057_0001
Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and cyclopentylamine, the title compound was isolated, as a yellow solid in 75% yield (97% purity by HPLC).
MS (ESI+) 347.6, (ESI-) 345.8.
Example 14: 1.3-dihydro-2H-benzimidazol-2-ylidene(5-methyl-2-{[3-(2-oxopyrrolidin-l- vDpropyl lamino } p yrimidin-4- vPacetonitrile
Figure imgf000057_0002
Following the general methods as outlined in Example 1 (Method C) (2-chloro-5- methylpyrimidin-4-yl)(2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 8), and N-(3,-aminopropyl)-2-pyrrolidinone, the title compound was isolated, as a yellow solid in 76% yield (99% purity by HPLC).
MS(ESI+): 390.3; MS(ESI ): 388.6.
Example 15: (2Z)-(l-cyclobutyl- 3-dihydro-2H-benzimidazol-2-ylidene)(2-{[3-(2- oxopyτrolidm-l-yl)pτopyl]amino}pyrimidin-4-yl)acetonitrile
Figure imgf000058_0001
Following the general methods as outlined in Example 1 (Method C), starting from (2- chloropyrimidin-4-yl)(l-cyclobutyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 18), andN-(3'-aminopropyl)-2-pyrrolidinone, the title compound was isolated, as a yellow solid in 77% yield (98% purity by HPLC).
MS(ESI+): 430.6; MS(ESF): 428.7.
Example 16: (1 -ethyl- lH-benzimidazol-2-y {2-[(2-pyri<3m-3-yle.hyl)amino1pyrimidin-4- yl} acetonitrile
Figure imgf000058_0002
Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and and 3 -(2- aminoethyl)pyridine, the title compound was isolated, as a yellow solid in 70% yield (98% purity by HPLC). MS(ESI+): 384.4; MS(ESF): 382.6.
Example 17: (2ZV(l-ethyl-1.3-dihv( o-2H-benzimidazol-2-ylidene)[2-(isobutylamino)-5- methylpyrimidin-4-yljacetonitrile
Figure imgf000059_0001
Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-me ylpyι±midin-4-yl)(l-ethy]-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and isobutylamine, the title compound was isolated, as a yellow solid in 72% yield (99% purity by HPLC).
MS(ESI+): 349.6; MS(ESF): 347.5.
Example 18: (2Z)-(l-emyl-1.3-dihydro-2H-benzimidazol-2-ylideneX2-{r2-(lH-imidazol-4- yl.ethyl]amino}pyrimidin-4-yl)acetonitrile
Figure imgf000059_0002
Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and histamine base, the title compound was isolated, as a yellow solid in 65% yield (95% purity by HPLC).
MS(ESr*): 373.3; MS(ESF): 371.2.
Example 19: (2Z)-(1 -ethyl- 1.3-dihydro-2H-benzimidazol-2-ylideneX2- (isobutylamino)pyrimidin-4-yl1acetonitrile
Figure imgf000060_0001
Following the general methods as outlined in Example 1 (Method C), (2-chloroρyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and isobutylamine, the title compound was isolated, as a yellow solid in 74% yield (99% purity by HPLC).
MS(ESI+): 335.4; MS(ESF): 333.6.
Example 20: [2-(cyclopropylaminoχ.yrimidin-4-yl](l -ethyl- lH-benzimidazol-2-yl)- cetonitrile
Figure imgf000060_0002
Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and cyclopropylamine, the title compound was isolated, as a yellow solid in 70% yield (98% purity by HPLC).
MS(ESI+): 319.4; MS(ESF): 317.3.
Example 21: [2-f {2- 6-(dimethylammo)pyrichn-3-yllethyllarmno)pyrimidin-4-yllf 1 -ethyl- 1 H-benzimidazol-2-yl)acetonitrile
Figure imgf000061_0001
Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and2-(N,N- dimethylamino)-5-aminoethylpyridine, the title compound was isolated, as a yellow sohd in 78% yield (96% purity by HPLC).
MS(ESI+): 427.5; MS(ESF): 425.6.
Example 22: (l-ethyl-lH-benzimidazol-2-yl)(2-{r2-(lH-1.2.4-ttiazol-l-yl')ethyllamino}- ρyrimidin-4-yl)acetonitrile
Figure imgf000061_0002
Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and2-(lH- l,2,4-1riazole-l-YL)ethanamine hydrochloride, the title compound was isolated, as a yellow solid in 75% yield (99% purity by HPLC).
MS(ESI+): 374.6; MSfESI"): 373.5
Example 23: (2Z)-(l-emyl-1.3-dihydro-2H-benzimidazol-2-ylideneX2-{[2-(lH-imidazol-4- vDethynamino} -5 -methylpyrimidin-4- vDacetonitrile
Figure imgf000062_0001
Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-me ylpyτimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and histamine base, the title compound was isolated, as a yellow solid in 69% yield (93% purity by HPLC).
MStESI4): 387.4; MS(ESF): 385.6.
Example 24: f2-({2-[6-(dime1faylammo)pyridin-3-yllethyl}aminoV5-methylpyrimidin-4- yl] ( 1 -ethyl- 1 H-benzimidazol-2-yl)acetonitrile
Figure imgf000062_0002
Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-methylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 2-(N,N-dimemylan ino)-5-aminoethylρyridine, the title compound was isolated, as a yellow solid in 68% yield (97% purity by HPLC).
MS(ESI4): 441.3; MS(ESF): 439.5.
Example 25: (2Z)-[2-(cycloheptylamino)pyrimidin-4-yl](l -ethyl-1.3-dihydro-2H- benzimidazol-2-ylidene. acetonitrile
Figure imgf000063_0001
Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and cycloheptylamine, the title compound was isolated, as a yellow solid in 76% yield (98% purity by HPLC).
MS ESI4): 375.7; MS(ESF): 373.2.
Example 26: [2-(cyclopropylaminoV5-methylpyrimidin-4-yll(l -ethyl- lH-benzimidazol-2- yl)acetonitrile
^ H ryhJL i
Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-memylpyrimidin-4-y])(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and cyclopropylamine, the title compound was isolated, as a yellow solid in 75% yield (96% purity by HPLC).
MS(ESI+): 333.5; MS(ESF): 331.3.
Example 27: (1 -ethyl-1 H-benzimidazol-2-yl){2-[(2-ρyridin-2-ylethyl)amino1pyrimidin-4- yl} acetonitrile
Figure imgf000064_0001
Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonittile (intermediate 7), and 2-(2- aminoethyl)ρyridine, the title compound was isolated, as a yellow solid in 80% yield (94% purity by HPLC).
MS(ESf): 384.8; MS(ESF): 382.2.
Example 28: [2-(cyclopentylaιr--no)-5-me ylpyrimidin-4-yl](1.3-dihvdro-2H- benzimidazol-2-ylidene')acetonitrile
Figure imgf000064_0002
Following the general methods as outlined in Example 1 (Method C), (2-chloro-5- methylpyrimidm-4-yl)(2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 8), and cyclopentylamine, the title compound was isolated, as a yellow solid in 80% yield (77% purity by HPLC).
MSfESi ): 333.3; MS(ESF): 331.2.
Example 29: 2-(cyclohexyIamino)pyrimidin-4-yl](l -ethyl-lH-benzimidazol-2- yDacetonitrile
Figure imgf000065_0001
Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and cyclohexylamine, the title compound was isolated, as a yellow solid in 70% yield (97% purity by HPLC).
MS(ESI+): 361.2; MS(ESF): 359.4.
Example 30: (2ZV(l-emyl-1.3-dThydro-2H-ben_amidazol-2-ylidene¥2- r2-(lH-indol-3- yl .ethyllaminol -5 -methylpyrimidin-4-yl)acetonitrile
Figure imgf000065_0002
Following the general methods as outlined in Example 1 (Method C), starting from (2- cUoro-5-memylpyτimiά-in-4-yl)(l-e1hyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and tryptamine, the title compound was isolated, as a yellow solid in 77% yield (98% purity by HPLC).
MS(ESr 436.5; MS(ESF): 434.6.
Example 31: (l-ethyl-lH-benzimidazol-2-y {5-methyl-2-f(2-pyridin-2- ylethyr)ammolpyrimidin-4-yl] acetonitrile
Figure imgf000066_0001
Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memylpyτimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and2-(2-aminoethyl)pyridine), the title compound was isolated, as a yellow solid in 77% yield (98% purity by HPLC).
MS(ESf): 398.6; MS(ESF): 396.4.
Example 32: {2-[(2-ethoxyethyl)amino1pyrimidin-4-yl}(l-ethyl-lH-benzimidaz:ol-2- yl)acetonitrile
Figure imgf000066_0002
Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and 2- ethoxyethylamine, the title compound was isolated, as a yellow solid in 78% yield (92% purity by HPLC).
MS(ESI+): 351.7; MS(ESF): 349.6.
Example 33: (l-ethyl-lH-benzimidazol-2-yl){5-methyl-2-f(l- methylbutyl)an ino]pyrirmdin-4-yl}acetonitrile
Figure imgf000067_0001
Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-memylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and (+/-)-2-aminopentane, the title compound was isolated, as a yellow solid in 70% yield (92% purity by HPLC).
MS(ESl ): 363.5; MS(ESF): 361.8.
Example 34: (1 -emyl-lH-benzimidazol-2-yl)[2-(memylammo)pyrimidin-4-yl1acetonitrile
Figure imgf000067_0002
Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and methylamine, the title compound was isolated, as a yellow solid in 78% yield (98% purity by HPLC).
MS(ESI+): 293.4; MS(ESF): 291.6
Example 35 : ( 1 -ethyl- 1 H-benzimidazol-2-yl)(5 -methyl-2- { [2-( 1 H-pyrazol- 1 - yl)ethyllamino}pyrimidin-4-yl)acetonittile
Figure imgf000067_0003
Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-memylpvrinιidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 1 -(2I-aminoethyl)pyrazole), the title compound was isolated, as a yellow solid in 74% yield (97% purity by HPLC).
MS(ESI^): 387.6; MS(ESF): 385.2.
Example 36: lH-benzimidazol-2-yl{5-methyl-2-r(2-pyridin-3 -ylethyl)amino]pyrimidin-4- yl} acetonitrile
Figure imgf000068_0001
Following the general methods as outlined in Example 1 (Method C), (2-chloro-5- methylpyrimidin-4-yl)(2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 8), and 3-(2-aminoethyl)pyridine, the title compound was isolated, as a yellow solid in 68% yield (88% purity by HPLC).
MS(ESI+): 370.3; MS(ESI'): 368.8.
Example 37: (2Z)-( 1 -ethyl- 1 ,3-dihydro-2H-benzimidazol-2-ylideneχ2- { [2-f 1 H-imidazol- 1 - yl)ethyllamino}-5-methylpyrimidin-4-yl)acetonitrile
Figure imgf000068_0002
Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-me ylpyrimidm-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and2-(imidazol-l-yl)-ethylamine, the title compound was isolated, as a yellow solid in 60% yield (97% purity by HPLC).
MS(ESI+): 387.2; MS(ESF): 385.4.
Example 38: lH-benzimidazol-2-yl{2-[(2-pyridin-3-ylethyl)ammo]pyrimidin-4- yl} acetonitrile-
Figure imgf000069_0001
Following the general methods as outlined in Example 1 (Method C), (2-chloroρyrimidin- 4-yl)(2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 9), and 3 -(2- aminoethyl)pyridine, the title compound was isolated, as a yellow sohd in 73% yield (98% purity by HPLC).
MS(ESI+): 356.2; MS(ESF): 354.3.
Example 39: (l-ethyl-lH-benzimidazol-2-y {2- (l-methylbutyl)-imino]pyrimidin-4- yl} acetonitrile
Figure imgf000069_0002
Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and (+/-)-2- aminopentane, the title compound was isolated, as a yellow solid in 74% yield (97% purity by HPLC). MS(ESI+): 349.4; MS(ESF): 347.2.
Example 40: {2-r(cyclohexylmethyl)εtmino1-5-memylpyrirnidin-4-yl}(l-ethyl-lH- benzimidazol-Σ-vDacetonitrile
Figure imgf000070_0001
Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-rnethylρyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and (aminomethyl)cyclohexane, the title compound was isolated, as a yellow solid in 77% yield (94% purity by HPLC).
MS ESI÷): 389.5; MS(ESI ): 387.6.
Example 41 : lH-benziϊtιidazol-2-yl[2-(cvclopentylamino')pyrimidin-4-yl]acetonitrile
Figure imgf000070_0002
Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin- 4-yl)(2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 9), and cyclopentyamine, the title compound was isolated, as a yellow solid in 74% yield (96% purity by HPLC).
MS(ESF 319.4; MS(ESF): 317.3.
Example 42: (l-ethyl-lH-benzimidazol-2-yl){6-methyl-2-[(2-pyridin-3- ylethyDamino]pyrimidin-4-yl}acetonitrile
Figure imgf000071_0001
Following the general methods as outlined in Example 1 (Method D), (2-chloro-6- methylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 10), and3-(2-aminoethyl)pyrid_ne, the title compound was isolated, as a yellow solid in 72% yield (97% purity by HPLC).
MSφSI÷): 398.5; MS(ESF): 396.4.
Example 43: lH-benzimidazol-2-yl[2-(cyclopropylan ino)pyrimidin-4-yl1acetonitrile
Figure imgf000071_0002
Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin- 4-yl)(2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 9), and cyclopropylamine, the title compound was isolated, as a yellow solid in 79% yield (97% purity by HPLC).
MS(ESI4}: 291.4; MSfESF): 289.4.
Example 44: [2-(cyclopentyl-Unino)-6-methylpyrimidin-4-yl](l -ethyl- lH-benzimidazol-2- yl)acetonitrile
Figure imgf000071_0003
Following the general methods as outlined in Example 1 (Method D), (2-chloro-6- methylpyrin_idin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 10), and cyclopentylamine, the title compound was isolated, as a yellow sohd in 72% yield (98% purity by HPLC).
MS(ESI+): 361.6; MS(ESF): 359.5.
Example 45: {2-[(cyclohexylme1hyl)ammo]pyrimidin-4-yl}(l-ethyl-lH-benzimidazol-2- yl)acetonitrile
Figure imgf000072_0001
Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and
(aminomethyl)cyclohexane, the title compound was isolated, as a yellow solid in 72% yield (98% purity by HPLC).
MS ESI4): 375.2; MSQESF): 373.2.
Example 46: (l-ethyl-lH-benzimidazol-2-yl){6-[(2-pyridin-3-ylethyl.amino1pyrimidin-4- vU acetonitrile
Figure imgf000072_0002
Following the general methods as outlined in Example 1 (Method D), starting from (6- chloropyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 11), and 3-(2-aminoethyl)pyridine, the title compound was isolated, as a yellow solid in 72% yield (88% purity by HPLC).
MS(ESI4): 384.6; MS(ESF): 382.4.
Example 47: ( 1 -ethyl- 1 H-benzimidazol-2-yl) {2- [(3 -pyrrolidin- 1 -ylpropyDamino - pyrimidin-4-yl}acetonitrile
Figure imgf000073_0001
Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin- 4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and 1-amino- 3-(N-piperidino)propane, the title compound was isolated, as a yellow solid in 74% yield (94% purity by HPLC).
MS(ESI^): 390.4; MS(ESF): 388.2.
Example 48: (1 -etfayl-lH-penzimidazol-2-yl)[2-(4-eτhylpiρerazin-l -yl -5-methylρyrimidin- 4-yl]acetonitrile-
Figure imgf000073_0002
Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-me ylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 1 -ethylpiperazine, the title compound was isolated, as a yellow solid in 76% yield (99% purity by HPLC). MS(ESI+): 390.5; MS(ESF): 388.4.
Example 49: (l-etfayl-lH-benzimidazol-2-ylι{2-f(2-fti-ylmemyl)aminoj|-5- methylpyrimidin-4-yl} acetonitrile
Figure imgf000074_0001
Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-methylpyr_midin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and furfurylamine, the title compound was isolated, as a yellow solid in 71% yield (92% purity by HPLC).
MS(ESI+): 373.3; MS(ESI0: 371.5.
Example 50: (2Z)-(l-ethyl-1.3-dihydro-2H-benzimidazol-2-vIidene){5-methyl-2-[(l - mcmylpipcri n-4-yl)ammo]pyrimidin-4-yl}acetonitrilc
Figure imgf000074_0002
Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-memylpyrimidin-4-yl)(l-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 4-ammo-l-methyl-piperidine, the title compound was isolated, as a yellow solid in 79% yield (98% purity by HPLC). MS(ESI+): 390.2; MS(ESF): 388.3.
Example 51: (2Z)-[2-(cyclohexylamino)-5-methylpyrimidin-4-yl](l -ethyl-1.3-dihydro-2H- benzimidazol-2-ylidene)acetonitrile
Figure imgf000075_0001
Following the general methods as outlined in Example 1 (Method C), starting from (2- chloro-5-memylρyrimidin-4-yl)(l-ethyl-2,3-dihydro-lII-benzimidazol-2-yl)acetonitrile (intermediate 6), and cyclohexylamine, the title compound was isolated, as a yellow solid in 74% yield (97% purity by HPLC).
MS(ESI+): 375.8; MS(ESF): 373.2.
Example 52: (2ZV[2-(e1hylaminoV5-methylpyrimidin-4-yiχi -ethyl-1.3 -dihydro-2H- benzimidazol-2-ylidene)acetonitrile
Figure imgf000075_0002
Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-methylpyrimidin-4-yl)(l -ethyl-2,3 -dihydro- lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and ethylamine, the title compound was isolated, as a yellow solid in 76% yield (99% purity by HPLC). MS(ESI+): 321.2; MS(ESF): 319.3.
Example 53: 2-(cvclopentylaιmno 5-methylpyrimidin-4-yliri.3-diethyl-1.3-dihydro-2H- benzimidazol-2-ylidene.acetonitrile
Figure imgf000075_0003
Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-memylpyrimidm-4-yl)(l,3-die1hyl-2,3-dihydro-lH-benzimidazol-2-yl)acetoniteile (intermediate 15), and cyclopentylamine, the title compound was isolated, as a yellow solid in 80% yield (97% purity by HPLC). MS(EST): 389.2; MSfESF): 387.3.
Example 54: (2Z)-(l-emyl-1.3-dihydro-2H-benzimidazol-2-ylidene)[5-methyl-2-(piperidin- 4-yl-_mino)pyrimidin-4-yllacetonitrile
Figure imgf000076_0001
Following the general methods as outlined in Example 1 (Method D), starting from (2- cMoro-5-inethylpyriinidin-4-yl)(l-ethyl-2,3-chhydro-lH-benziniidazol-2-yl)acetonitrile (intermediate 6), and 4 -amino- 1 -piperidine, the title compound was isolated, as a yellow solid in 70% yield (97% purity by HPLC). MS(ESI4 : 376.2; MS(ESF): 374.3.
Example 55: (2Z)-(l-ethyl-1.3-dihvdro-2H-benzimidazol-2-ylidene.{5-methyl-2-[(2- piperidin- -ylethyl . ammo .ρyrimidin-4-yl } acetonitrile
Figure imgf000076_0002
Following the general methods as outlined in Example 1 (Method D), starting from (2- chloro-5-methylpyrimidm-4-yl)(l-ethyl-2,3-dihydro-lH-benzinfidazol-2-yl)acetonitrile (intermediate 6), and 1 -amino-3-(N-piperidino)propane, the title compound was isolated, as a yellow solid in 70% yield (97% purity by HPLC). MS(ESI+): 418.6; MS(ESF): 416.2.
Example 56: General procedure for the solution-phase synthesis of benzimidazoles acetonitriles derivatives of general formula I. with G and L as above defined (Schemes 10): tert-bu1yl (4S)-4-[({4-r(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene.methyl]- 5 -methylpyrimidin-2- yl amino)cafbonyl] -1.3 -thiazolidine-3 -carboxylate
Figure imgf000077_0001
To a solution of (2Z)-(2-annno-pyrimidin-4-yl)(l-ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)acetonitrile (intermediate 20) (300mg, 1.08mmol, leq) in 8mL of DCM:THF (6:2)) were added Boc-D-thiazolidine-4-carboxylic acid 8377mg, 1.62mmol, 1.5eq) followed by the Mukaiyama reagent (826mg, 3.23mmol, 3eq) and DIEA (371 μL, 2.16mmol, 2eq). The reaction mixture was stirred at room temperature for 6days. The reaction mixture was diluted with DCM (50mL), washed with NH4C1, NaHC03 and brine and dried over MgS0 . The solvent was removed by evporation and the residue purified by FC using a gradient AcOE CycloH (4:6) to neat AcOEt then to AcOEt:MeOH (7:3) for lhour. The expected product tert-butyl (4S)-4-[({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol- 2-ylidene)methyl]-5-me ylpyrimid -2-yl}amino)carbonyl]-l,3-thiazolidine-3-carboxylate was isolated as a yellow solid (292mg, 55% yield, 99% HPLC purity MS (ESI+) 494.5, (ESI-) 492.3.
Example 57: (4S -N-f4-[(Z)-cyano(l-ethyl-1.3-dihvdro-2H-benzimidazol-2- ylidene .methyl]-pyrimidin-2-yl} -1.3 -thiazolidine-4-carboxamide
Figure imgf000078_0001
To a solution of tert-butyl (4S)-4-[({4-[(Z)-cyano(l -ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidin-2-yl} amino)carbonyl]- 1 ,3-thiazolidine-3-carboxylate (292mg, 0.591mmol) was added at zero degree a solution of 10%TFA in DCM (lOmL) and the reaction mixture was stirred for lh. The solvent was evaporated and the expected product (4S)-N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]- pyrimidin-2-yl}-l,3-thiazolidine-4-carboxamide was isolated as a yellow solid (252mg, 98% yield, 99% HPLC purity)
MS(ESI+): 394.5; MS(ESF): 392.2.
Example 58: N-{4-[(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)methvn-5- methylpyrimidin-2-yl} -4-(4-methylpiρerazin- 1 -yl)-4-oxobutanamide
Figure imgf000078_0002
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimidin-4-yl)(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and4-(4-methyl-pipera-_in-l-yl)-4-oxo-butyric acid, the title compound was isolated, as a yellow solid in 65% yield (99% purity by HPLC). MS(ESI+): 475.6; MS(ESF): 473.6.
Example 59: N--,4-[(Z)-cyano(l -ethyl- 1.3 -dihydro-2H-benzimidazol-2-yhdene)methyl]- pyrimidin-2-yl> -4-( 4-methylpiperazin- 1 -yl . -4-oxobutanamide
Figure imgf000079_0001
Following the general method as outlined in Example 56, starting (2Z)-(2-amino- pyrimidin-4-yl)(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (intermediate 20), and4-(4-methyl-pipeτazin-l-yl)-4-oxo-butyric acid, the title compound was isolated, as a yellow solid in 65% yield (89% purity by HPLC). MS(ESI+): 461.6; MS(ESF): 459.2.
Example 60: (lR.5R.7R)-N-(4-r(Z)-cvano(l-ethyl-1.3-dihvdro-2H-benzimidazol-2- ylidene)methyll-5-methylpyrimidin-2-yl}-6.8-dioxa-3-azabicyclor3.2.1]octane-7- carboxamide
Figure imgf000080_0001
Following the general methods as outlined in Examples 56 and 57, starting from (2Z)-(2- amino-5-memylpyrimidin-4-yl)(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)- acetonitrile (Intermediate 19), and Boc-7-endo-BTG-OH, the title compound was isolated, as a yellow solid in 71% yield (98% purity by HPLC). MS(ESF 434.5; MS(ESI0: 432.3.
Example 61: πS.5S.7SVN-U-rfZVcvanofl-ethyl-1.3-dihvdro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidin-2-yl}-6.8-dioxa-3-azabicyclo|"3.2.11octane-7- carboxamide
Figure imgf000080_0002
Following the general methods as outlined in Example 56 and 57, starting from (2Z)-(2- amino-5-methylpyrimidin-4-yl)(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)- acetonitrile (Intermediate 19), and Boc-7-endo-BTG-OH, the title compound was isolated, as a yellow solid in 72% yield (97% purity by HPLC). MS(ESI+): 434.5; MS(ESF): 433.4.
Example 62: 4-tert-butyl l-(9H-fluoren-9-ylmethyl. 2-[({4-[(Z)-cyanofl-ethyl-l-3-dihvdro- 2H-benzimidazol-2-ylidene)memyl]-5-n ethylpyr-midm-2-yl}--mino)carbonyl]piρerazine- 1 ,4-dicarboxylate
Figure imgf000081_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyriιmdin-4-yl)(l-ethyl-l,3-dihydro-2H-benzimiα^zol-2-ylidene)acetonitrile (Intermediate 19), and l-fmoc-4-boc-piperazine-2-carbocxylic acid, the title compound was isolated, as a yellow solid in 70% yield (97% purity by HPLC). MS(ESI+): 727.9; MS(ESF): 725.6.
Example 63: N-{4-[(Z)-cyano(l -ethyl-1 ,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}piperazine-2-carboxamide
Figure imgf000081_0002
Following the general method as outlined in Example 57, starting 4-tert-butyl 1-(9H- fluoren-9-ylmethyl) 2-[({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidin-2-yl} amino)carbonyl]ρiperazine- 1 ,4-dicarboxylate (Example 63), the title compound was isolated, as a yellow solid in 90% yield (91% purity by HPLC).
MS(EST): 404.6; MSfESF): 402.2.
Example 64: tert-butyl (2S)-2-[({4-[(Z)-cyano(l-etiιyl-13-dihydro-2H-benzimidazol-2- ylidene .methyl]-5-methylpyrimidin-2-yl } amino)carbonyl]-5-oxopyrrolidine- 1 -carboxylate
Figure imgf000082_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimidin-4-yl)(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-y_idene)acetonitri_e (Intermediate 19), and Boc-pyroglutamic acid, the title compound was isolated, as a yellow solid in 72% yield (98% purity by HPLC). MS(ESI+): 504.3; MS(ESF): 502.2.
Example 65: N-(4-f Z)-cvano(l -ethyl-1.3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- ine ylpyrimidin-2-yl}-5-oxo-L-prolinamide
Figure imgf000083_0001
Following the general method as outlined in Example 57, starting from: tert-butyl (2S)-2- [({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5-methyl- pyrimidin-2-yl}amino)carbonyl]-5-oxopyrrolidine-l -carboxylate (Example 65), , the title compound was isolated, as a yellow solid in 96% yield (97% purity by HPLC). MS(ESI+): 404.6; MS(ESF): 402.2.
Example 66: tert-butyl (4R)-4-[({4-[(Z)-cyano(l -ethyl-1.3-dihydro-2H-benzimidazol-2- ylidene)memyl1-5-methylpyrimidin-2-yl}amino)carbonyl]-1.3-thiazolidine-3-carboxylate
Figure imgf000083_0002
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrirmdin-4-yl)(l-ethyl-l,3-dihydro-2H-ben-dmidazol-2-ylidene)acetonitrile (Intermediate 19), and (S)-boc-5,5-dimethyl-l,3-thiazolidine-4-carboxylic acid, the title compound was isolated, as a yellow solid in 80% yield (98% purity by HPLC). MS(ESI+): 508.9; MS(ESr): 506.5.
Example 67: (4R -N-{4-rfZVcvano(l-emyl-1.3-dihydro-2H-benzirnidazol-2- ylideneYmethyl1-5-methylpyrimidrn-2- yl} - 1.3 -thiazolidine-4-carboxamide
Figure imgf000084_0001
Following the general method as outlined in Example 57, starting tert-butyl (4R)-4-[({4- [(Z)-cy- o(l-ethyl-l,3-dihydro-2H-benzinfidazol-2-yhdene)methyl]-5-me ylpyrimidin-2- yl}amino)carbonyl]-l,3-thiazolidine-3-carboxylate (Example 66), the title compound was isolated, as a yellow solid in 94% yield (97% purity by HPLC). MS(ESI+): 408.6; MS(ESF): 406.2.
Example 68: (lS.4S.5S.7RVN-{4-[(Z)-cvano(l-ethyl-1.3-dihydro-2H-benzimidazol-2- ylidene)me yl1-5-methylρyrimidin-2-yl}-4-methyl-6.8-dioxa-3-azabicyclo[3.2.1]octane-7- carboxamide
Figure imgf000084_0002
Following the general methods as outlined in Examples 56 and 57, starting from (2Z)-(2- amino-5-me ylρyrimidin-4-yl)(l-ethyl-l,3-dihydro-2H-benzimid-izol-2-yhdene)- acetonitrile (Intermediate 19), and Boc-BTA-OH, the title compound was isolated, as a yellow solid in 80% yield (93% purity by HPLC). MS(ESI4): 448.7; MS(ESF): 446.3.
Example 69: N-f4-r(Z.-cvano(l -ethyl-1.3-dihvdro-2H-benzimidazol-2-ylidene)methvn-5- methylpyrimidin-2-yl}-4-(dimethylamino)butanamide
Figure imgf000085_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimidin-4-yiχi -ethyl-1, 3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile
(Intermediate 19), and 4-(dimethylamino)butyric acid hydrochloride, the title compound was isolated, as a yellow solid in 50% yield (97% purity by HPLC). MS(ESI+): 406.6; MS(ESI"): 404.2.
Example 70: N~l — {4-[(Z)-cyano(l -ethyl-1.3 -dihydro-2H-benzimidazol-2- ylidene)memyl1-5-methylpyrimidin-2-yl}-N~3~.N~3~-dimethyl-beta-alaninamide
Figure imgf000085_0002
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- memylpyrimidin-4-yl)(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 3-(dimethylamino)propanoic acid, the title compound was isolated, as a yellow solid in 80% yield (94% purity by HPLC). MS(ESI+): 392.5; MSQESF): 390.6.
Example 71: N-{4-r(Z)-cvano(l-ethyl-l,3-dihvdro-2H-benzimidazol-2-ylidene)methvn-5- methylpyrimidin-2-yl} -4-(4-methylpiperazin- 1 -yl)butanamide
Figure imgf000086_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- memylpyrimidin-4-yl)(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and (4-methylpiperazin-l-yl)butanoic acid, the title compound was isolated, as a yellow solid in 52% yield (96% purity by HPLC). MStESF1"): 461.7; MSfESF): 459.2.
Example 72: N-{4-[TZ)-cyano(l -ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrin idin-2-yl}cyclopentanecarboxamide
Figure imgf000086_0002
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- me ylpyri nidin-4-yl)(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)acetonitιile (Intermediate 19), and cyclopentanopic acid, the title compound was isolated, as a yellow solid in 65% yield (97% purity by HPLC). MS(ESI+): 389.5; MS(ESF): 387.6.
Example 73: tert-butyl r4-({4-r(Z -cvano(l-ethyl-L3-dihvdro-2H-benzimidazol-2- ylidene)n emyl]-5-n e1hylρyrimidin-2-yl}ajmno)-4-oxobutyl]carbanιate
Figure imgf000087_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimidin-4-yl)(l -ethyl-1 ,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile
(Intermediate 19), and 4-(boc-amino)butyric acid, the title compound was isolated, as a yellow solid in 48% yield (95% purity by HPLC). MS(ESI+): 478.6; MS(ESF): 476.5.
Example 74: 4-amino-N-{4-[(Z -cyano(l-ethyl-1.3-dihydro-2FI-benzimidazol-2- ylidene)methyll-5-methylpyrimidin-2-yl}butanamide
Figure imgf000088_0001
Following the general methods as outlined in Examples 56 and 57, starting from tert-butyl [4-({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- memylpyri_nidin-2-yl}amino)-4-oxobutyl]carbamate (Example 73), the title compound was isolated, as a yellow solid in 90% yield (96% purity by HPLC). MS(ESI4): 378.6; MS(ESF): 376.7.
Example 75: tert-butyl 4-[({4-[(Z)-cyano(l-ethyl-l,3-d-hvdro-2H-benzimidazol-2- ylidene)me yl]-5-methylpyrimidin-2-yl}amino)carbonyl]piperidine-l-carboxylate
Figure imgf000088_0002
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimidin-4-yl)(l -ethyl- 1 ,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and l-(tert-butoxycarbonyl)isonipecotic acid, the title compound was isolated, as a yellow solid in 84% yield (98% purity by HPLC). MS(ESI+): 504.6; MS(ESF): 502.3.
Example 76: N-{4-[(Z)-cyano(l -ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- n ethylpyrirmdin-2-yl}ρiperidine-4-carboxamide
Figure imgf000089_0001
Following the general methods as outlined in Examples 56 and 57, starting from tert-butyl 4-[({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}amino)carbonyl]piperidine-l -carboxylate (Example 75), the title compound was isolated, as a yellow solid in 95% yield (97% purity by HPLC). MS(ESI+): 404.6; MS(ESF): 402.8.
Example 77: N- {4- . (Z -cyano( 1 -ethyl- 1.3 -dihydro-2H-benzimidazol-2- ylidenetoethyl] -5- methylpyrimidin-2-yl} -1 -methylpiperidine-4-carboxamide
Figure imgf000089_0002
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimidin-4-yl)(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 1 -methyl-piperidine-4-carboxylic acid HCI, the title compound was isolated, as a yellow solid in 82% yield (92% purity by HPLC). MS(ESI+ : 418.8; MSfESI"): 416.5.
Example 78: 1 -acetyl-N- {4- [(Z)-cyano(l -ethyl- 1.3 -dihydro-2H-benzimidazol-2- ylidene)me yll-5-methylpyrimidin-2-yl}piperidine-4-carboxan ide
Figure imgf000090_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-aπ_ino-5- methylpyrimidin-4-yl)(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 1 -acetyl-4-piperidine carboxylic acid, the title compound was isolated, as a yellow solid in 82% yield (98% purity by HPLC). MS(ESI4): 446.5; MS(ESF): 444.9.
Example 79: N-{4-[(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl } -2-(2-methoxyρhenyl)acetamide
Figure imgf000091_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2--unino-5- me1hylpyrimidin-4-yl)(l -ethyl-1, 3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 2-methoxy-phenylacetic acid, the title compound was isolated, as a yellow solid in 60% yield (95% purity by HPLC). MS(ESI+): 441.8; MS(ESF): 439.4.
Example 80: tert-butyl (2S)-2-[({4-[(Z)-cyano(l-etiιyl-1.3-dihydro-2H-benzimidazol-2- ylidene)methyll-5-methylpyrimidin-2-y]}amino)carbonyl]-2.5-dihydro-lH-pyrrole-l- carboxylate
Figure imgf000091_0002
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimidin-4-yl)(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and boc-3,4-dehydro-L-proline, the title compound was isolated, as a yellow solid in 65% yield (99% purity by HPLC). MS(ESI ): 488.6; MS(ESF): 486.6.
Example 81: (2S)-N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)memyl]-5-nιethylpyrimidin-2-yl}-2.5-dihycbo-lH-pyrrole-2-c--rbox---πide
Figure imgf000092_0001
Following the general method as outlined in Example 56, starting from tert-butyl (2S)-2- [({4-[(Z)-cyano(l -ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyriιmdin-2-yl}amino)carbonyl]-2,5-dihydro-lH-pyrrole-l -carboxylate (Example 80), the title compound was isolated, as a yellow solid in 95% yield (96% purity by HPLC). MS(ESI+): 388.5; MS(ESF): 386.6.
Example 82: tert-butyl 3-[({4-f(Z)-cvano(l -ethyl-1.3 -dihvdro-2H-benzimidazol-2- ylidene)me yll-5-methylp\^midin-2-yI}amino carbonyl]ρyrrolidine-l-carboxylate
Figure imgf000093_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimidin-4-yl)(l -ethyl- 1 ,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), andboc-l-pyrrolidine-3-carboxylic acid, the title compound was isolated, as a yellow solid in 70% yield (98% purity by HPLC). MS(ESI+): 490.4; MS(ESO: 488.3.
Example 83 : N- {4-[f ZVcyanofl -ethyl- 1.3 -dihydro-2H-benzimidazol-2- ylidene)methyl]-5- methylpyrimidin-2-yl}ρyrrolidine-3-carboxamide
Figure imgf000093_0002
Following the general method as outlined in Example 57, starting tert-butyl 3-[({4-[(Z)- cyano(l -ethyl-1, 3-dihydro-2H-benzimidazol-2-ylidene)memyl]-5-methylpyrimidin-2- yl}amino)carbonyl]pyrrolidine-l -carboxylate (Example 82), the title compound was isolated, as a yellow solid in 96% yield (99% purity by HPLC). MS(ESI+): 388.4; MS(ESF): 386.4. Example 84: tert-butyl 2-[({4-[(Z)-cyanofl -ethyl-1.3-dihvdro-2H-benzimidazol-2- ylidene)me yll-5-methylpyrimidin-2-yl}arnino carbonyl morpholine-4-carboxylate
Figure imgf000094_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyτimidin-4-yl)(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and Boc-COP-OH compound was isolated, as a yellow sohd in 70% yield (97% purity by HPLC). MS(ESI+): 506.3 (ESF): 504.6
Example 85: N-{4-f(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}morpholine-2-carboxamide
Figure imgf000094_0002
Following the general method as outlined in Example 56, starting from tert-butyl 2-[({4- [(Z)-cyano(l -ethyl-1, 3-dihydro-2H-benzimidazol-2-yhdene)me yl]-5-methylpyrimidin-2- yl}amino)carbonyl]morpholine-4-carboxylate (Example 84), the title compound was isolated, as a yellow solid in 95% yield (99% purity by HPLC). MS(ESI+): 406.6; MS(ESF): 404.7
Example 86: tert-butyl [2-({4-[<Z)-cyano(l-ethyl- 3-dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimiά^-2-yl}amino)-2-oxoethyl]methylcarbamate
Figure imgf000095_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimidin-4-yl)(l -ethyl-1, 3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and boc-sarcosine, the title compound was isolated, as a yellow solid in 82% yield (98% purity by HPLC). MS(ESI4 : 464.6; MS(ESF): 462.2.
Example 87: N~l — {4-[(Z)-cyano(l -ethyl- 1.3 -dihydro-2H-benzimidazol-2-ylidene)- methyl]-5-methylpyrimid_n-2-yl}-N~2 — methyl glycinamide
Figure imgf000095_0002
Following the general method as outlined in Example 56, starting from tert-butyl [2-({4- [(Z)-cy-mo(l-ethyl-l,3-dihydro-2H-ben_ midazol-2-yhdene)methyl]-5-memylpyriιrύdin-2- yl}amino)-2-oxoethyl]methylcarbamate (Example 86), the title compound was isolated, as a yellow sohd in 98% yield (97% purity by HPLC). MS(ESI+): 364.5; MS(ESF): 362.5.
Example 88: N~f4-. fZ.-cvanof 1 -ethyl-1 ,3-dihvcfro-2H-benz-midazol-2-V-idene)methyl 1-5- methylρyrimidin-2-yl} - 1 -methylρiperidine-3 -carboxamide
Figure imgf000096_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylρyrimidin-4-yl)(l -ethyl-1, 3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile
(Intermediate 19), and 1 -methyl-piperidme-3-carboxylic acid HCL, the title compound was isolated, as a yellow solid in 79% yield (94% purity by HPLC). MS(ESI ): 418.9; MS(ESF): 416.4.
Example 89: N- 3-({4-[(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)- methyl] -5 -me1hylpyrirnidin-2-yl} amino) -3 -oxopropyl]benzamide
Figure imgf000097_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimidin-4-yl)(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and benzoyl-beta-alanine, the title compound was isolated, as a yellow solid in 40% yield (91 % purity by HPLC). MS(ESF 468.6; MS(ESF): 466.1.
Example 90: tert-butyl 4-[2-({4-[(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidm-2-yl}amino)-2-oxoethyl]piperidine-l-carboxylate
Figure imgf000097_0002
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methy]pyrimidin-4-yiχi -ethyl-1, 3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 1 -boc-4-ρiperidineacetic acid, the title compound was isolated, as a yellow solid in 70% yield (97% purity by HPLC). MS(ESI+): 518.6; MS(ESO: 516.2.
Example 91: 2-(l-acetylpiperidin-4-yl)-N-{4-[(Z)-cyano(l-ethyl-1.3-dihydro-2H- ben2 mid^zol-2-yhdene)n emyl]-5-methylpyrimidin-2-yl}acetaπ ide
Figure imgf000098_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- me ylpyrimidin-4-yl)(l-ethyl-l,3-dihydro-2H-benzimida^ol-2-ylidene)acetonitrile (Intermediate 19), and 2-(N-acetylpiperidin-4-yl)-carboxylic acid, the title compound was isolated, as a yellow solid in 85% yield (94% purity by HPLC). MS(ESI4): 460.8; MSfESF): 458.3.
Example 92: N- 14- [(Z)-cyano(l -ethyl- 1.3 -dihydro-2H-benzimidazol-2-ylidene)methylj-5- methylpyrimidin-2-yl}-2-piperidin-4-ylacetamide
Figure imgf000099_0001
Following the general method as outlined in Example 57, starting from tert-butyl 4-[2-({4- [(Z)-cy-mo(l-ethyl-l,3-chhydro-2H-bcnzimidazol-2-yhdene)methyl]-5-mcΛylpyrin idin-2- yl}amino)-2-oxoethyl]piperidine-l -carboxylate (Example 90), the title compound was isolated, as a yellow solid in 98% yield (97% purity by HPLC). MS(EST): 418.6; MS(ESF>: 416.3.
Example 93: tert-butyl 3-[({4-[(Z)-cyano(l -ethyl- 1.3-dihydro-2H-benzimic-azol-2- ylidene)memyl1-5-methylpyrimidin-2-yl}amino)carbonyllpiperidine-l-carboxylate
Figure imgf000099_0002
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimidin-4-yiχi -ethyl-1, 3-dihydro-2H-benzimidazol-2-ylidene)-icetonitrile (Intermediate 19), and (R,S)-boc-niρecotic acid, the title compound was isolated, as a yellow solid in 69% yield (99% purity by HPLC). MS(ESl ): 504.6; MS(ESF): 502.6.
Example 94: N--,4-[(Z)-cyano(l -ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)methyll-5- nιethylpyrimidin-2-yl}piperidine-3-carboxamide
Figure imgf000100_0001
Following the general method as outlined in Example 57, starting from tert-butyl 3-[({4- [(Z)-cyano(l -ethyl- 1 ,3-dihydro-2H-benzimidazol-2-yhdene)methyl]-5-memylpyrimidin-2- yl}amino)carbonyl]piperidine-l -carboxylate (Example 93), the title compound was isolated, as a yellow solid in 95% yield (97% purity by HPLC). MS(ESI+): 404.9; MS(ESF): 402.6.
Example 95: N-{4-[(Z)-cyano(l -ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylρyrirridin-2-yl}-4-[(4-methylpiperazin--l-yl)me-hyl]benzamide
Figure imgf000101_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimi(hn-4-yl)(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 4-[(4-methylpiperazin-l-yl)methyl]benzamide, the title compound was isolated, as a yellow solid in 58% yield (92% purity by HPLC). MS(ESI+): 509.6; MS(ESr): 507.5.
Example 96: 4-acetyl-N- {4- [(Z)-cyano(l -ethyl- 1.3-dihydro-2H-benzimidazol-2- ylidene memyl]-5-methylpyrimidm-2-yl}moφholine-2-carboxamide
Figure imgf000101_0002
Following the general method as outlined in Example 56, starting from (2Z)-(2-amiao-5- methylpyrimidin-4-yl)(l -ethyl- 1 ,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and4-acetyl-morpholine-2-carboxylic acid, the title compound was isolated, as a yellow solid in 62% yield (94% purity by HPLC). MS(ESI+): 448.2; MS(ESF): 446.3. Example 97: N- {4-[fZ)-cyano(l -ethyl- 1.3 -dihydro-2H-benzimidazol-2-ylidene)methyn-5- memylpyrimidin-2-yl}-4-methylmorpholine-2-carboxamide
Figure imgf000102_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-axnino-5- methylpyri_r_idin-4-yl)(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 4-methylmorpholine-2-carboxylic acid, the title compound was isolated, as a yellow solid in 82% yield (96% purity by HPLC). MS(ESI ): 420.6; MS(ESF): 418.2.
Example 98: N- 4-[(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)methyl1-5- n ethylpyrimidin-2-yl}-2-ιnorpholin-4-ylacetamide
Figure imgf000102_0002
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimidin-4-yl)(l -ethyl- 1 , 3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 4-morpholinoacetic acid, the title compound was isolated, as a yeUow solid in 82% yield (99% purity by HPLC). MSζESI÷): 420.1; MS(ESF): 418.3.
Example 99: N~2~-benzyl-N~l~-{4-[(Z)-cyano(l -ethyl- 1,3 -dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidin-2-yl}glycinamide
Figure imgf000103_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimidin-4-yl)(l -ethyl-1, 3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and N-alpha-tert-butoxycarbonyl,benzyl-glycine which was further debocyclated by a solution of TFA:DCM (10:90), the title compound was isolated, as a yellow solid in 23% yield (97% purity by HPLC). MS(ESI+): 440.6; MS(ESF): 438.5.
Example 100: N-{4-[(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)methyl1-5- methylpyrimidin-2-yl } -2-( 1.1 -dioxidothiomorpholin-4-yl)acetamide
Figure imgf000104_0001
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrimidin-4-yl)(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 4-thiomorpholine acetic acid, the title compound was isolated, as a yellow solid in 59% yield (98% purity by HPLC). MS(ESI+): 468.6; MS(ESI ): 466.2.
Example 101 : N~l~-f4-r(Z)-cvano(l-ethyl-1.3-dihydro-2H-benzimidazol-2- ylidene)methyl"|-5-methylpyrimidm-2-vU-N~2 — formylglycinamide
Figure imgf000104_0002
Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5- methylpyrirmdin-4-yiχi -ethyl- 1 ,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and formyl glycine the title compound was isolated, as a yellow solid in 21% yield (96% purity by HPLC). MS(ESI+): 378.8; MS(ESF): 376.6. Example 102: Preparation of a pharmaceutical formulation
The following formulation examples illustrate representative pharmaceutical compositions according to the present invention being not restricted thereto.
Formulation 1 - Tablets
A benzimidazole acetonitrile of formula I is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ration. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active benzimidazole acetonitrile compound per tablet) in a tablet press.
Formulation 2 — Capsules
A benzimidazole acetonitrile of formula I is admixed as a dry powder with a starch diluent in an approximate 1 : 1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active benzimidazole acetonitrile compound per capsule).
Formulation 3 - Liquid
A benzimidazole acetonitrile of formula I (1250 mg), sucrose (1.75 g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 mL.
Formulation 4 - Tablets
A benzimidazole acetonitrile of formula I is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active benzimidazole acetonitrile compound) in a tablet press. Formulation 5 - Injection
A benzimidazole acetonitrile of formula (I) is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/ml.
Biological Assays
The compounds ofthe present invention may be subjected to the following assays :
a) GSK3 in vitro assay:
GSK3β Assay (see Bioorg. Med. Chem. Lett by Naeru et al. 12 p.1525- 1528 (2002))
In a final reaction volume of 25μl, GSK3β (h) (5-10mTJ) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 20μM YRRAAVPPSPSLSRHSSPHQS(p)EDEEE (being the
GSK3 substrate; aphospho GS2 peptide), lOmM Mg Acetate and [γ-33P-ATP] (Specific activity approx. 500cpm/pmol, concentration as required). The reaction is initiated by the addition of Mg2+ [γ-33p_ATP]. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 5μl of a 3% phosphoric acid solution. 1 Oμl of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 50mM phosphoric acid and once in methanol prior to drying and the degree of phosphorylation of the substrate is determined by scintillation counting.
The tested compounds according to formula I display an inhibition (IC50) with regard to GSK3 of less than 20 μM, preferably less than 10 and even more preferred less than 1 μM.
The binding affinities ofthe compounds of formula (I) were assessed using the above described in vitro biological assay. Representative values for some example compounds are given in Tables 1 and 2 below.
The values in Table 1 refer to the binding affinity (IC50; μM) of the example compounds according to formula I to GSK3. Table 1: In vitro potency of benzimidazole derivatives on human GSK3 beta
Figure imgf000107_0001
Figure imgf000108_0001
b) Iα vivo assay : Experimental model of type II diabetes (oral postprandial glvcemia in db/db mice)
The following assay aims at determining the anti-diabetic effect ofthe test compounds of formula (I) in a model of postprandial glycemia in db/db mice, in vivo.
The assay was performed as follows :
A total of 24 db/db mice (about 8-9 weeks; obtained from IFFACREDO, l'Arbreste, France) were fasted during 20 hours.
2 groups, each consisting of 6 animals were formed :
• Group 1 : The animals were administered (per os) a dose of 10 mg/kg of vehicle.
• Group 2 : The animals were administered (per os) a dose of 50 mg/kg ofthe test compound according to formula (I).
After oral administration of the compounds of formula (I) solubilized or suspended in CarboxyMethylCellulose (0.5%), Tween 20 (0.25%) and water as vehicle, the animals had access to commercial food (D04, UAR, Villemoisson/Orge, France) ad libitum. The diabetic state ofthe mice was verified by determining the blood glucose level before drug administration. Blood glucose and serum insulin levels were then determined 4 hrs after drug administration.
The determination ofthe blood glucose level was performed using a glucometer (Precision Q.I.D., Medisense, Abbot, ref. 212.62.31).
The determination ofthe Insulin level was performed using an ELISA kit (Crystal CHEM, Ref. INSK R020). Changes in blood glucose and serum insulin of drug treated mice were expressed as a percentage of control (group 1 : vehicle treated mice).
Treatment (per os) of the animals with typical substituted benzimidazole acetonitrile compounds of formula (I), at a dosage of 50 mg/kg, decreased the blood glucose level induced by food intake by about 20-40%.
For instance, upon using the compound of example 3, i.e. (2Z)-[2-(cyclobutylamino)-5- methylρyrirmdin-4-yl](l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile, the blood glucose level was found to be reduced at about 28% and the insulin level was found to be reduced at about 58%, compared to the animals of Group 1.
Reference List
1. Woodgett et al : Trends Biochem. Sci., 16p.l77-81 (1991);
2. Reaven et al (American Journal of Medicine, 60, 80 (1976);
3. Stout, Metabolism, 34, 7 (1985)
4. Diamanti-Kandarakis et al.; European Journal of Endocrinology 138, 269-274 (1998),
5. Andrea Dunaif; Endocrine Reviews 18(6), 774-800 (1997));
6. WO 01/47920

Claims

Claims
1. A benzimidazole acetonitrile according to formula (I)
Figure imgf000112_0001
as well as its tautomers, its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, as well as pharmaceutically acceptable salts thereof, wherein
G is a pyrimidinyl; L is an amino group, or a 3-8 membered heterocycloalkyl, containing at least one heteroatom selected from N, O, S or L is an acylamino moiety;
R1 is selected from the group comprising or consisting of hydrogen, sulfonyl, amino, carboxy, amino carbonyl, Cι-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl or Ci-Cg-alkoxy, aryl, halogen, cyano or hydroxy; R2 is selected from the group comprising or consisting of hydrogen, Ci-Ce-alkyl, C2- C6-alkenyl, C2-C6-alk nyl, or Ci -Cδ-alkoxy.
2. The benzimidazole acetonitrile according to claim 1, wherein R1 is H or C1-C3 alkyl.
3. The benzimidazole acetonitrile according to any of claims 1 or 2, wherein R2 is a Ci- C3 alkyl. The benzimidazole acetonitrile according to any of claims 1 to 3, having any ofthe formulae
Figure imgf000113_0001
wherein R1 is as above defined, and R3 is selected from the group comprising or consisting of hydrogen, Ci-Cή-alkyl, C - Cβ-alkenyl, C2-C6-a]kynyl, or Ci-Cδ-alkoxy;
L is an amino group o the formula -NR5R6 wherein R5 and R6 are each independently from each other H, Ci- -alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Cβ- alkoxy, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, 3-8- membered heterocycloalkyl, Ci-Ce-alkyl aryl, Ci -Ce-alkyl heteroaryl, Ci-Cβ-alkenyl aryl, Cι-C6-alkenyl heteroaryl, Ci-Cβ-alkynyl aryl, Ci-Cβ-alkynyl heteroaryl, Ci-Cβ- alkyl cycloalkyl, Ci-Cβ-alkyl heterocycloalkyl, -Cό-alkenyl cycloalkyl, Ci-Ce- alkenyl heterocycloalkyl, Cι-C6-alkynyl cycloalkyl, Ci-Ce-alkynyl heterocycloalkyl, or R5 and R6 may form a ring together with the nitrogen to which they are bound.
5. The benzimidazole acetonitrile according to any ofthe preceding claims, wherein R5 is hydrogen or a methyl or ethyl or propyl group and R6 is a selected from the group consisting of H, (Cι-Cι0)-alkyl, Ci-Cβ alkyl-aryl, Ci-Cβ-alkyl-heteroaryl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl and 4-8 membered saturated or unsaturated cycloalkyl.
6. The benzimidazole acetonitrile according to any ofthe preceding claims, wherein R5 is H and R6 is selected from the group consisting of Cj-Cβ alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, heteroaryl, Ci-Cβ-alkyl heteroaryl, C_- C6-alkyl cycloalkyl, Ci-Ce-alkyl heterocycloalkyl.
7. The benzoxazole acetonitrile according to any of claims 1 to 3, wherein L is an acylamino moiety ofthe formula — NR5C(0)R6 wherein R5 and R6 are each independently from each other H, Ci-Cβ-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Ci-Cβ- alkoxy, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, 3-8- membered heterocycloalkyl, -Cβ-alkyl aryl, Ci-Cβ-alkyl heteroaryl, Ci-Cβ-alkenyl aryl, Ci-Cg-alkenyl heteroaryl, Ci-Cβ-alkynyl aryl, Ci-Cβ-alkynyl heteroaryl, Ci-Ce- alkyl cycloalkyl, Ci-Cβ-alkyl heterocycloalkyl, Ci-Cβ-alkenyl cycloalkyl, Ci-Cβ- alkenyl heterocycloalkyl, Ci-Cβ-alkynyl cycloalkyl, Cι-C6-alkynyl heterocycloalkyl.
8. The benzimidazole acetonitrile according to any ofthe preceding claims selected from the group consisting of :
(2Z)-(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[3-(lH-pyrazol-l- yl)propyl]amino}pyrimidin-4-yl)acetonitrile
(2Z)-(l-etihιyl-l,3-dihydro-2H-benzimidazol-2-ylidene)(5-methyl-2-{[3-(lH-pyrazol- 1 -yl)propy]]amino}pyrimidin-4-yl)acetonitrile
(2Z)-[2-(cyclobu1ylamino)-5-memylpyrimidin-4-yl](l-ethyl-l,3-dihydro-2H- benzimidazol-2-ylidene)acetonitrile
(2Z)-(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)(5-methyl-2-{[3-(2- oxopyrrolidin- 1 -yl)propyl]arnino}ρyrimidin-4-yl)acetonitrile (2Z)-(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[3-(2-oxopyιτohdin-l- yl)propyl]amino}pyrimidin-4-yl)acetonitrile
(2Z)-(l-ethyl-l,3-cHhydro-2H-benzimid_-zol-2-ylidene)(2-{[3-(lH-l,2,4-triazol-l- yl)propyl]amino } pyrimidin-4-yl)acetoni1rile
(2Z) -( 1 -ethyl- 1 , -dihydro-2H-benzimidazol-2-ylidene)(5-methyl-2- { [3 -( 1 H- 1 ,2,4- triazol- 1 -yl)proρyl]amino}pyrimidin-4-yl)acetonitrile
[2-(cyclopentylamino)-5-methylpyrimidin-4-yl](l-ethyl-lH-benzimidazol-2- yl)acetonitrile
(2Z)-(2-{[3-(2-oxopyrrolidin-l-yl)proρyl]amino}ρyrimidin-4-yl)(l-propyl-l,3- dihydro-2H-benzimidazol-2-ylidene)acetonitrile
(l-ethyl-lH-benzinndazol-2-yl){5-methyl-2-[(2-pyridm-3-ylethyl)aniino]pyrimidin- 4-yl} acetonitrile
(2Z)-[2-(cyclobutylamino)pyrimidin-4-yl](l-ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)acetonitrile
(2Z)-r2-(cycloheptylamino)-5-methylpyrimidin-4-yll(l -ethyl- l,3-dihydro-2H- benzimidazol-2-ylidene)acetonitrile
[2-(cyclopen1 lamino)pyrimidin-4-yl](l-ethyl-lH-benzimidazol-2-yl)acetonitrile
l,3-dihydro-2H-berιzimidazol-2-ylidene(5-methyl-2-{[3-(2-oxopyrrolidin-l- yl)propyl]amino}pyrimidin-4-yl)acetonitrile
(2Z) -( 1 -cyclobutyl- 1 ,3-dihydro-2H-benzimidazol-2-yUdene)(2- { [3 -(2-oxopyrrolidin- l-yl)propyl]amino}pyrimidin-4-yl)acetonitrile (l-ethyl-lH-benzimidazol-2-yl){2-[(2-pyrid_n-3-ylethyl)amino]pyrimidin-4- yl} acetonitrile
(2Z)-(l-emyl-l,3-ά^ydro-2H-benzimiα^ol-2-ylidene)[2-(isobutylamino)-5- me1hylpyrimidin-4-yl]acetonitrile
(2Z)-(1 -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)(2- { [2-( 1 H-imidazol-4- yl)ethyl]amino}pyrimidin-4-yl)acetonitrile
(2Z)-(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)[2-(isobu1ylamino)pyrimidin- 4-yl]acetonitrile
[2-(cyclopropylamino)pyrirnidin-4-yl](l-ethyl-lH-benzimidazol-2-yl)acetonitrile
[2-({2-[6-(dimethylamino)pyridin-3-yl]ethyl}amino)pyrimidin-4-yl](l-ethyl-lH- benzimidazol-2-yl)acetonitrile
( 1 -ethyl-1 H-benzimidazol-2-yl)(2 - { [2-(lH- 1 ,2,4-triazol- 1 -yl)ethyl] amino } pyrimidin- 4-yl)acetonitrile
(2Z)-(1 -ethyl-1 ,3 -dihydro-2H-benzimidazol-2-ylidene)(2- {[2-(lH-imidazol-4- yl)ethyllamino}-5-methylpvrimidin-4-yl)acetonitrile
[2-({2-[6-(mmemylam o)pyridin-3-yl]ethyl}ammo)-5-methylpyrimidin-4-yl](l- ethyl-lH-benzimidazol-2-yl)acetonitrile
(2Z)-[2-(cycloheptylamino)pyrimidin-4-yl](l-ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)acetonitrile
[2-(cyclopropylamino)-5-me1hylpyrimidin-4-yl](l -ethyl- 1 H-benzimidazol-2- yl)acetonitrile (l-ethyl-lH-benzimidazol-2-yl){2-[(2-pyridin-2-ylethyl)amino]pyrimidin-4- yl} acetonitrile
[2-(cyclopentylaιn-no)-5-me ylpyriιrύdin-4-yl](l,3-d^ydro-2H-benzimidazol-2- ylidene)acetonitrile
[2-(cyclohexylamino)pyrimidin-4-yl](l-ethyl-lH-benzimidazol-2-yl)acetonitrile
(2Z)-(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[2-(lH-indol-3- yl)ethyl]amino}-5-methylpyrimidin-4-yl)acetonitrile
(l-emyl-lH-benzimidazol-2-yl){5-methyl-2-[(2-pyridin-2-ylethyl)amino]pyrimidin- 4-yl} acetonitrile
{2-[(2-ethoxyethyl)amino]pyrimidin-4-yl}(l-ethyl-lH-benzimidazol-2-yl)acetonitrile
(l-ethyl-lH-benzimidazol-2-yl){5-methyl-2-[(l-methylbutyl)amino]pyrimidin-4- yl} acetonitrile
(l-ethyl-lH-benzimidazol-2-yl)[2-(methylantino)pyrimidin-4-yl]acetonitrile
(l-ethyl-lH-benzimidazol-2-yl)(5-methyl-2-{[2-(lH-pyrazol-l- yl)ethyl]amino}pyrimidin-4-yl)acetonitrile
1 H-benzimidazol-2-yl {5-methyl-2-[(2-pyridin-3 -ylethyl)amino]pyrimidin-4- yl} acetonitrile
(2Z)-(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[2-(lH-imidazol-l- yl)ethyl]amino}-5-methylpyrimidin-4-yl)acetonitrile
lH-benzinύdazol-2-yl{2-[(2-pyridin-3-ylethyl)amino]pyrimidin-4-yl}acetonitrile
(l-emyl-lH-benzimid^ol-2-yl){2-[(l -methylbutyl)amino]pyrimidin-4-yl} acetonittile {2-[(cyclohexylmemy])amino]-5-memylpv-_midin-4-yl}(l-ethyl-lH-benzimidazol-2- yl)acetonitrile
lH-benzimidazol-2-yl[2-(cyclopentylamino)pyrimidin-4-yl]acetonitrile
( 1 -ethyl- 1 H-benzimidazol-2-yl) { 6-methyl-2-[(2-pyridin-3 -ylethyl)amino]pyrimidin- 4-yl}acetonitrile
1 H-benzimidazol-2-yl [2-(cyclopropylamino)pyrimidin-4-yl]acetonitrile
[2-(cyclopentylam o)-6-methylpyrimidin-4-yl](l -ethyl- lH-benzimidazol-2- yl)acetonitrile
{2- [(cyclohexylmethyl)-unino]pyrimidin-4-yl} ( 1 -ethyl- 1 H-benzimidazol-2- yl)acetonitrile
(l-emyl-lH-benzimidazol-2-yl){6-[(2-pyridin-3-ylethyl)aniino]pyrimidin-4- yl} acetonitrile
(l-ethyl-lH-benzimidazol-2-y]){2-[(3-pyrrolidin-l-ylpropyl)amino]pyrimidin-4- yl} acetonitrile
(1 -ethyl-lH-benzimidazol-2-yl)[2-(4-ethylpiperazin- 1 -yl)-5-methylpyrimidin-4- yl]acetonitrile
(l-ethyl-lH-benzimidazol-2-yl){2-[(2-ftιtylmethyl)amino]-5-methy]pyrimidin-4- yl} acetonitrile
(2Z)-(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene){5-methyl-2-[(l- methylpiperidin-4-y])amino]pyrimidin-4-yl } acetonitrile
(2Z) - [2-(cyclohexylammo)-5-meώylpyrimidin-4-yl]( 1 -ethyl- 1 ,3 -dihydro-2H- benzimidazol-2-ylidene)acetonitrile (2Z)-[2-(ethylamino)-5-memylpyrimidin-4-yl](l-ethyl-l,3-dihydro-2H-ben__imidazol- 2-ylidene)acetonitrile
[2-(cyclopentylamino)-5-methylpyi__midin-4-yl](l,3-diethyl-l,3-dihydro-2H- benzimidazol-2-y_idene)acetonitrile
(2Z)-(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)[5-methyl-2-(piperidin-4- ylamino)pyrimidin-4-yl]acetoni1rile
(2Z)-(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene){5-methyl-2-[(2-piperidin-l- ylethyl)amino]pyrimidin-4-yl}acetonitrile
N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl} -4-(4-methylpiperazin- 1 -yl) -4-oxobutanamide
N- {4- [(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-ben_dmidazol-2-ylidene)methyl]pyrimidin- 2-yl} -4-(4-methylpiρerazin-l -yl)-4-oxobutanamide
(lR,5R,7R)-N-{4-[(Z)-cyano( -ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidin-2-yl}-6,8-dioxa-3-azabicyclo[3.2.1]octane-7- carboxamide
(lS,5S,7S)-N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)methylj -5 -methylpyrimidin-2-yl} -6, 8-dioxa-3 -azabicyclo[3.2.1 ]octane-7- carboxamide
(lS,4S,5S,7R)-N-{4-[(Z)-cyano(l-emyl-l,3-dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidin-2-yl}-4-methyl-6,8-dioxa-3- azabicyclo[3.2.1]octane-7-carboxamide (1 S,4R,5S,7R)-N-{4-[(Z)-cyano(l -ethyl- 1 ,3-dihydro-2H-benzimidazol-2- ylidene)methyl] -5 -methylρyrimidin-2-yl} -4-methyl-6,8-dioxa-3 - azabicyclo[3.2.1]octane-7-carboxamide
N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpy_±nidin-2-yl}piperazine-2-carboxamide
(4S)-N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl} - 1 ,3 -thiazolidine-4-carboxamide
(4R)-N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl} - 1 ,3 -thiazolidine-4-carboxamide
N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-y]}-5-oxo-L-prolinamide
4-tert-butyl l-(9H-fluoren-9-ylmethyl) 2-[({4-[(Z)-cyano(l -ethyl-l,3-dihydro-2H- benzimidazol-2-ylidene)methyl]-5-methylpyrimidin-2-yl}amino)carbonyl]piperazine- 1 ,4-dicarboxylate
tert-butyl (4S)-4-[({4-[(Z)-cyano(l -ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)me yl]-5-memylpyrimidin-2-yl} amino)carbonyl]- 1 ,3-thiazolidine-3- carboxylate
tert-butyl (2S)-2-[({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)memyl]-5-me ylpyrimidin-2-yl}amino)carbonyl]-5-oxopvrrolidine-l- carboxylate
tert-butyl (4R)-4-[({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)memyl]-5-methylpyrimidin-2-yl}amino)carbonyl]-l,3-thiazolidine-3- carboxylate 2-(l -acetylpϊperidin-4-yl)-N- {4-[(Z)~cyano(l -ethyl-1 ,3-dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylρyrimidin-2-yl}acetamide
N- {4-[(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl] -5- methylpyrimidin-2-yl}-4-methylmo-pholine-2-carboxam.ide
4-acetyl-N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrintid^-2-yl}πιoφholine-2-carboxamide
N- {4-[(Z)-cyano( 1 -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl] -5- methylpyrimidin-2-yl} -4-[(4-methylpipera__in-l -yl)methyl]benzamide
tert-butyl 3 - [( {4- [(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2- ylidene)me yl]-5-methylpyrimidm-2-yl}amino)carbonyl]piperidine-l -carboxylate
tert-butyl 4-[2-( {4-[(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidin-2-yl}amino)-2-oxoethyl]ρiperidine-l-carboxylate
N- {4-[(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrirnid_n-2-yl}morpholine-2-carboxamide
N- {4-[(Z)-cyano( 1 -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}-2-piperidin-4-ylacetamide
N- {4-[(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)me1hyl]-5- methylpyrimidin-2-yl}piperidine-3-carboxamide
tert-butyl 2-[( {4-[(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2- ylidene)methyl]-5-methylpyrimidin-2-yl}amino)carbonyl]morpholine-4-carboxylate
N-[3-({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-ben__imidazol-2-ylidene)methyl]-5- methylpyτimidin-2-yl}amino)-3-oxopropyl]benzamide tert-butyl [2-( {4- [(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2- ylidene)me yl]-5-me ylpyriιrtidin-2-yl}aιτώιo)-2-oxoe1hyl]methylc-ub__mate
N- {4-[(Z)-cyano(l -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-y]} - 1 -methylpiperidine-3-carboxamide
N~l~-{4-[(Z)-cyano(l-e1hyl-l,3-dihydro-2H-ben__imidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}-N~2 — methylglycinamide
N- {4- [(Z)-cyano( 1 -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl] -5- methylpyrimidin-2-yl}pynOlidine-3-carboxamide
tert-butyl 3 -[({4- [(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2- ylidene)me yl]-5-me ylpyri mdin-2-yl}amino)carbonyl]pyrroliά,ine-l -carboxylate
(2S)-N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)memyl]-5- methylpyrimidin-2-yl}-2,5-dihydro-lH-py_role-2-carboxamide
tert-butyl (2S)-2-[({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)n ethyl]-5-n ethylpyrimidin-2-yl}amino)carbonyl]-2,5-dihydro-lH-pyrrole-l- carboxylate
N-{4-[(Z)-cyano(l -ethyl-1, 3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}-2-(2-methoxyphenyl)acetamide
1 -acetyl-N- {4- [(Z)-cyano(l -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrintidin-2-yl}piperidine-4-carboxamide
N- {4- [(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}-l-methylpiperidine-4-carboxamide
4-amino-N-{4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]- 5-memylpyrimidin-2-yl}butanamide tert-butyl 4-[({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)meώyl]-5-me1hylpyrimidm-2-yl}ammo)carbonyl]ρiperidine-l -carboxylate
N- {4-[(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl] -5- nιethylpyrimidin-2-yl}piperidine-4-carbox_-_nide
5 tert-butyl [4-({4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2- ylidene)memyl]-5-methylpyrimidin-2-yl}aιrιino)-4-oxobutyl]carbamate
N- {4-[(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}cyclopentanecarboxamide
N- {4-[(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)mefhyl]-5- l o methylpyrimidin-2-yl} -4-(4-methylpiperazin-l -yl)butanamide
N~l -- {4-[(Z)-cyano(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}-N~3~,N~3~-dimethyl-beta-al-ininamide
N-{4-[(Z)-cyano(l -ethyl-1, 3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- me ylpyrimidin-2-yl}-4-(dimethylamino)butanamide
15 (2Z) -(2-amino-5-me1hylpyriιmdin-4-yl)(l -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2- ylidene)acetonitrile
N-{4-[(Z)-cyano(l -ethyl-1, 3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}-2-morpholin-4-ylacetamide
N~2—benzyl-N~l~- {4-[(Z)-cyano( 1 -ethyl- 1 ,3 -dihydro-2H-benzimidazol-2- 20 ylidene)methyl]-5-methylpyrimidin-2-yl} glycinamide
N-{4-[(Z)-cyano(l -ethyl-1, 3 -dihydro-2H-benzimidazoI-2-ylidene)methyl]-5- methylpyrimidin-2-yl}-2-(l,l-dioxidothiomorpholin-4-yl)acetamide N~l — {4-[(Z)-cyano(l-ethyl-l,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5- methylpyrimidin-2-yl}-N~2 — formylglycinamide
9. A benzimidazole acetonitrile according to any ofthe preceding claims for use as a medicament.
10. Use of a benzimidazole acetonitrile according to any of claims 1 to 8 in the preparation of a medicament for the prevention and/or treatment of metabolic disorders mediated by insulin resistance or hyperglycemia, comprising diabetes type II, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS).
11. Use of an benzimidazole acetonitrile according to claim 9 wherein the disease is diabetes type II.
12. A pharmaceutical composition containing a benzimidazole acetonitrile according to any ofthe claims 1 to 8 and a pharmaceutically acceptable carrier, diluent or excipient thereof.
13. A composition according to claim 12, further comprising at least one supplementary drug selected from the group consisting of insulin, aldose reductase inhibitors, alpha- glucosidase inhibitors, sulfonyl urea agents, biguanides, thiazolidines, PPARs agonists, GSK-3 inhibitors.
14. Composition according to claim 13 wherein said supplementary drug is selected from the group consisting of a rapid acting insulin, an intermediate acting insulin, a long acting insulin, a combination of intermediate and rapid acting insulins, Minalrestat, Tolrestat, Sorbinil, Methosorbinil, Zopolrestat, Epalrestat, Zenarestat, Imirestat, Ponalrestat, ONO-2235, GP-1447, CT-112, BAL-ARI 8, AD-5467, ZD5522, M- 16209, NZ-314, M-79175, SPR-210, ΛDN 138, or SNK-860, Miglitol, Acarbose, Glipizide, Glyburide, Chlorpropamide, Tolbutamide, Tolazamide, or Glimepriride.
15. A method of preparing a benzimidazole acetonitrile of formula (I) according to any of the claims 1 to 8, comprising the following step:
Figure imgf000125_0001
wherein R\ R2, G, L are as above described.
16. A method of preparing a benzimidazole acetonitrile of formula (I) according to any of the claims 1 to 8, comprising the following step:
Figure imgf000125_0002
II' III' [X = CI, OH] [L = C(0)R6]
17. A method according to claim 15 or 16, comprising the following steps :
Figure imgf000125_0003
OO (II)
Figure imgf000125_0004
(III) (ii) (0 wherein R1, R3 andR4 are as above defined.
17. A method according to claim 15, comprising the following steps :
Figure imgf000126_0001
Figure imgf000126_0002
wherein R , R andR are as above defined.
18. An intermediate compound of formula (II), selected from the group consisting of : l,3-benzimidazol-2(3H)-ylidene(2-chloro-6-methylpyrimidin-4-yl)acetonitrile 1,3- benzimidazol -2(3H)-ylidene(2-chloro-6-rnethylpyrin id_n-4-yl)acetonitrile 1,3- benzimidazol -2(3H)-ylidene(6-chloropyrimidin-4-yl)acetonitrile
PCT/EP2004/052137 2003-09-12 2004-09-10 Benzimidazole acetonitriles WO2005026155A1 (en)

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US8288536B2 (en) 2004-10-15 2012-10-16 Takeda Pharmaceutical Company Limited Kinase inhibitors
US7713973B2 (en) 2004-10-15 2010-05-11 Takeda Pharmaceutical Company Limited Kinase inhibitors
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US8119655B2 (en) 2005-10-07 2012-02-21 Takeda Pharmaceutical Company Limited Kinase inhibitors
EP2377530A2 (en) 2005-10-21 2011-10-19 Braincells, Inc. Modulation of neurogenesis by PDE inhibition
EP2314289A1 (en) 2005-10-31 2011-04-27 Braincells, Inc. Gaba receptor mediated modulation of neurogenesis
EP2382975A2 (en) 2006-05-09 2011-11-02 Braincells, Inc. Neurogenesis by modulating angiotensin
EP2377531A2 (en) 2006-05-09 2011-10-19 Braincells, Inc. Neurogenesis by modulating angiotensin
US8278450B2 (en) 2007-04-18 2012-10-02 Takeda Pharmaceutical Company Limited Kinase inhibitors
WO2010099217A1 (en) 2009-02-25 2010-09-02 Braincells, Inc. Modulation of neurogenesis using d-cycloserine combinations
WO2011063115A1 (en) 2009-11-19 2011-05-26 Braincells Inc. Combination of nootropic agent with one or more neurogenic or neurogenic sensitizing agents for stimulating or increasing neurogenesis
WO2011091033A1 (en) 2010-01-20 2011-07-28 Braincells, Inc. Modulation of neurogenesis by ppar agents

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