AU2004272306A1 - Benzimidazole acetonitriles - Google Patents

Description

WO 2005/026155 PCT/EP2004/052137 Benzimidazole Acetonitriles Field of the invention 5 The present invention is related to benzimidazole acetonitriles, as well as pharmaceutical compositions containing such benzimidazole acetonitriles. The compounds of the present invention are 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 10 compounds of the 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 15 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 20 maintain blood glucose levels within the physiological range. Conventionally, Type I 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 25 concentrations, the latter of which is required to maintain normal blood glucose levels. As described below, GSK3 inhibition stimulates insulin-dependent processes and is WO 2005/026155 PCT/EP2004/052137 -2 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 ofMedicine, 60, 80 (1976)) used a continuous infusion of glucose 5 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. 10 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 IDDM subjects, as a consequence of over injection of insulin 15 compared with normal physiological release of the 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 20 Syndrome (PCOS) is also well acknowledged (Diamanti-Kandarakis et al.; Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome; European Joumal ofEndocrinology 138, 269-274 (1998), Andrea Dunaif; Insulin Resistance and the Polycystic Ovary Syndrome : Mechanism and Implications for Pathogenesis; Endocrine Reviews 18(6), 774-800 (1997)).

WO 2005/026155 PCT/EP2004/052137 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 Idnase 3 (GSK3) is a serine/threonine kinase for which two isoforms, a 5 and D, 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. 10 Subsequently, it has been shown that GSK3 activity is also inactivated by other growth factors that, like insulin, signal through receptor tyrosine kinases (RTKs). Examples of such signalling molecules include IGF- I 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 15 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-I 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 20 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 25 neuronal disorders, autoimmune diseases, cancer and cardiovascular diseases.

WO 2005/026155 PCT/EP2004/052137 -4 R2 N >=<G R (A) X CN 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 5 resistance, obesity, polycystic ovary syndrome (PCOS). Summary of the invention The present invention relates to benzimidazole acetonitriles of formula (I) R 2 N CN R N G-L H as well as their pharmaceutically acceptable salts. 10 Also, the present invention relates to the use of compounds of fonnula (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 15 The following paragraphs provide definitions of the various chemical moieties that make up the compounds according to the invention and are intended to apply uniformly WO 2005/026155 PCT/EP2004/052137 throughout the specification and claims unless an otherwise expressly set out definition provides a broader definition.

"C

1

-C

6 -alkyl" refers to alkyl groups having I to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-butyl, 5 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

1

-C

6 -alkyl aryl" refers to C 1

-C

6 -alkyl groups having an aryl substituent, including benzyl, 10 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-triazoly, 1,2,3-oxadiazolyl, 1,2,4-oxadia 15 zolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,1,3,4-triazinyl, 1,2,3-triazinyl, benzofuryl, [2,3 dihydro]benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, isobenzothienyl, indolyl, isoindolyl, 3 H--indolyl, benzinidazolyl, imidazo[1,2-a]pyridy], benzothiazolyl, benzoxa zolyl, quinolizinyl, quinazolinyl, pthalazinyl, quinoxalinyl, cinnolinyl, napthyridinyl, pyrido[3,4-b]pyridyl, pyrido[3,2-b)pyridy1, pyrido[4,3 -b]pyridyl, quinolyl, isoquinolyl, 20 tetrazolyl, 5,6,7,8-tetrahydroquinoly, 5,6,7,8-tetrahydroisoquinoly, purinyl, pteridinyl, carbazolyl, xanthenyl or benzoquinolyl.

"C

1 -C6-alky] heteroaryl" refers to C 1

-C

6 -alkyl groups having a heteroaryl substituent, including 2-furylmethyl, 2-thienylmethyl, 2-(1H-indol-3-yl)ethyl and the like.

WO 2005/026155 PCT/EP2004/052137 -6

"C

2

-C

6 -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=CH 2 ), n-2-propenyl (allyl, -CI-2CH=CH2) and the like.

"C

2 -Cs-alkenyl aryl" refers to C 2

-C

6 -alkenyl groups having an aryl substituent, including 2 5 phenylvinyl and the like.

"C

2 -C6-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-alkynyl" 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 10 (-C=CH), propargyl (-CH 2 C=CH), and the like.

"C

2

-C

6 -alkynyl aryl" refers to C 2

-C

6 -alkynyl groups having an aryl substituent, including phenylethynyl and the like.

"C

2

-C

6 -alkynyl heteroaryl" refers to C 2

-C

6 -alkynyl groups having a heteroaryl substituent, including 2-thienylethynyl and the like. 15 "C 3 -Cs-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.

"C-C

6 -alkyl cycloalkyl" refers to C-C 6 -alkyl groups having a cycloalkyl substituent, including cyclohexylmethyl, cyclopentylpropyl, and the like. 20 "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 0, S, NR, R being defined as hydrogen or CI-C 6 alkyl. Preferred heterocycloalkyl include pyrrolidine, piperidine, piperazine, 1 -methylpiperazine, morpholine, and the like.

WO 2005/026155 PCT/EP2004/052137

"C-C

6 -alkyl heterocycloalkyl" refers to C-C 6 -alkyl groups having a heterocycloalkyl substituent, including 2-(1-pyrrolidinyl)ethyl, 4-morpholinylnethyl, (1-methyl-4 piperidinyl)methyl and the like. "Carboxy" refers to the group -C(O)OH. 5 "C -C 6 -alkyl carboxy" refers to C -C 6 -alkyl groups having a carboxy substituent, including 2-carboxyethyl and the like. "Acyl" refers to the group -C(O)R where R includes H, "C-C 6 -alkyl", "C 2

-C

6 -alkenyl",

"C

2

-C

6 -alkynyl", "C 3 -Ce-cycloalkyl", "heterocycloalkyl", "ary1", "heteroaryl", "C-C 6 -alkyl aryl" or "C-C 6 -alkyl heteroaryl", "C 2

-C

6 -alkenyl aiyl", "C 2

-C

6 -alkenyl heteroaryl", s'C 10 C 6 -alkynyl aryl", "C 2 -Cr-alkynylhetcroaryl", "CI-Cs-alkyl cycloalkyl", "C-C 6 -alkyl heterocycloalkyl". "Ci-Cs-alkyl acyl" refers to Cl-C 6 -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 15 the like. "Heteroaryl acyl" refers to hetereoaryl groups having an acyl substituent, including 2 acetylpyridyl and the like.

"C

3 -Ce-(hetero)cycloalkyl acyl" refers to 3 to 8 membered cycloalkyl or heterocycloalkyl groups having an acyl substituent. 20 "Acyloxy" refers to the group -OC(O)R where R includes H, "C-C 6 -alkyl", "C 2

-C

6 alkenyl", "C 2

-C

6 -alkynyl", "C 3 -Cs-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl",

"C-C

6 -alkyl aryl" or "Cl-C 6 -alkyl heteroary", "C 2

-C

6 -alkenyl aryl", "C 2

-C

6 -alkenyl heteroaryl", "C 2

-C

6 -alkynyl aryl", "C 2

-C

6 -alkynylheteroaryl", "C-C 6 -alkyl cycloalkyl",

"C-C

6 -alkyl heterocycloalkyl".

WO 2005/026155 PCT/EP2004/052137 -8 "C1-C 6 -alkyl acyloxy" refers to C1-C 6 -alkyl groups having an acyloxy substituent, including 2-(acetyloxy)ethyl and the like. "Alkoxy" refers to the group -O-R where R includes "C1-C 6 -alkyl", "C 2

-C

6 -alkenyl", "C 2 C6-alkynyl", "C3-Cs-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C 1

-C

6 -alkyl 5 aryl" or "C1-C 6 -alkyl heteroaryl", "C 2

-C

6 -alkenyl aryl", "C2-C 6 -alkenyl heteroaryl", "C 2 C 6 -alkynyl aryl", "C 2

-C

6 -alkynylheteroaryl", "C 1

-C

6 -alkyl cycloalkyl", "C 1

-C

6 -alkyl heterocycloalkyl". "C1-C 6 -alkyl alkoxy" refers to C1-C6-alkyl groups having an alkoxy substituent, including 2-ethoxyethyl and the like. 10 "Alkoxycarbonyl" refers to the group -C(O)OR where R includes "C 1

-C

6 -alkyl", "C 2 -C6 alkenyl", "C 2

-C

6 -alkynyl", "C 3 -Cs-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl",

"C

1

-C

6 -alkyl aryl" or "CI -C 6 -alkyl heteroaryl", "C 2

-C

6 -alkenyl aryl", "C 2

-C

6 -alkenyl heteroaryl", "C 2

-C

6 -alkynyl aryl", "C 2 -C6-alkynylheteroary", "Ci-C 6 -alkyl cycloalkyl", "C1-C 6 -alkyl heterocycloalkyl". 15 "C1-C 6 -alkyl alkoxycarbonyl" refers to C1-C 6 -alkyl groups having an alkoxycarbonyl substituent, including 2-(benzyloxycarbonyl)ethyl and the like. "Aninocarbonyl" refers to the group -C(O)NRR' where each R, R' includes independently hydrogen, "C 1

-C

6 -alkyl", "C 2

-C

6 -alkenyl", "C2-C 6 -alkynyl", "C 3 -Cs-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C 1

-C

6 -alkyl aryl" or "C 1

-C

6 -alkyl heteroaryl", 20 "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 6 -alkyl cycloalkyl", "C1-C 6 -alkyl heterocycloallcyl". "C1-C 6 -alkyl aminocarbonyl" refers to C1-C 6 -alkyl groups having an aminocarbonyl substituent, including 2-(dimethylaminocarbonyl)ethyl and the like.

WO 2005/026155 PCT/EP2004/052137 -9 "Acylamino" refers to the group -NRC(O)R' where each R, R' is independently hydrogen,

"C-C

6 -alkyl", "C2-C 6 -alkenyl", "C2-C 6 -alkynyl", "C-Cs-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C-C 6 -alkyl aryl" or "C-C -alkyl heteroaryl", "C-C 6 -alkenyl aryl",

"C

2

-C

6 -alkenyl heteroaryl", "C 2

-C

6 -alkyny1 aryl", "C 2

-C

6 -alkynylheteroaryl", "C-C 6 -alkyl 5 cycloalkyl", "C-C 6 -alkyl heterocycloalkyl".

"C-C

6 -alkyl acylamino" refers to C-C 6 -alkyl groups having an acylamino substituent, including 2-(propionylamino)ethyl and the like. "Ureido" refers to the group -NRC(O)NR'R" where each R, R', R" is independently hydrogen, "C-C-alkyl", "C 2

-C

6 -alkenyl", "C 2

-C

6 -alkynyl", "C 3 -C-cycloalkyl", 10 "heterocycloalkyl", "aryl", "heteroaryl", "CIC 6 -alkyl aryl" or "C-C 6 -alkyl heteroaryl",

"C

2

-C

6 -alkenyl aryl", "C 2

-C

6 -alkenyl heteroaryl", "C-C 6 -alkynyl aryl", "C 2

-C

6 alkynylheteroaryl", "C-C 6 -alkyl cycloalkyl", "CrC6-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. 15 "C-C 6 -alkyl ureido" refers to C-C 6 -alkyl groups having an ureido substituent, including 2 (]V-methylureido)cthyl and the like. "Carbamate" refers to the group -NRC(O)OR' where each R, R' is independently hydrogen, "C-C-alkyl", "C 2

-C

6 -alkenyl", "C 2

-C

6 -alkynyl", "C 3 -CS-cycloalkyl" "heterocycloalkyl", "aryl", "heteroaryl", "C-C 6 -alkyl aryl" or "C-Cr-alkyl heteroaryl", 20 "C 2

-C

6 -alkenyl aryl", "C 2

-C

5 -alkenyl heteroaryl", "C 2

-C

6 -alkynyl aryl", "C 2

-C

6 alkynylheteroaryl", "Cl-C 6 -alkyl cycloalkyl", "C-C 6 -alkyl heterocycloalkyl". "Amino" refers to the group -NRR' where each R, R' is independently hydrogen, "Cl -C 6 alkyl", "C 2

-C

6 -alkenyl", "C 2

-C

6 -alkynyl", "C-Cs-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C-C 6 -alkyl aryl" or "C -C 6 -alkyl heteroaryl", "C 2 -Cs-alkenyl aryl", "C 2

-C

25 alkenyl heteroaryl", "C-C 6 -alkynyl aryl", "C2-C 6 -alkynylheteroaryl", "CrC 6 -alkyl cycloalkyl", "C-C 6 -alkyl heterocycloalkyl", and where R and R', together with the WO 2005/026155 PCT/EP2004/052137 -10 nitrogen atom to which they are attached, can optionally form a 3-8-membered hetero cycloalkyl ring. "CICs-alkyl amino" refers to C-C 6 -alkyl groups having an amino substituent, including 2 (1-pyrrolidinyl)ethyl and the like. 5 "Ammonium" refers to a positively charged group -N*RR'R", where each R, R',R" is independently, "C-C5-alkyl", "C 2

-C

6 -alkenyl", "C 2 -C6-alkynyl", "C 3 -Cs-cycloalkyl", "heterocycloalkyl", "C I-C6-alkyl aryl" or "C-C 6 -alkyl heteroaryl", "C 2 -C6-alkenyl aryl",

"C

2

-C

6 -alkenyl heteroaryl", "C 2

-C

6 -alkynyl aryl", "C2-C 6 -alkynylheteroaryl", "C-C 6 -alkyl cycloalkyl", "C-C 6 -alkyl heterocycloalkyl", and where R and R', together with the 10 nitrogen atom to which they are attached, can optionally form a 3-8-membered heterocycloalkyl ring.

"C

1

-C

6 -alkyl ammonium" refers to C -C 6 -alkyl groups having an ammonium substituent, including 2-(1-pyrrolidinyl)ethyl and the like. "Halogen" refers to fluoro, chloro, bromo and iodo atoms. 15 "Sulfonyloxy" refers to a group -OS0 2 -R wherein R is selected from H, "C-C 6 -alkyl", "C-Cs-alkyl" substituted with halogens, e.g., an -0S0 2

-CF

3 group, "C 2 -Cs-alkenyl", "C 2 C 6 -alkynyl", "C3-Cs-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C1-C6-alkyl aryl" or "C-C6-alkyl heteroaryl", "C2-C 6 -alkenyl aryl", "C 2

-C

6 -alkenyl heteroaryl", "C 2 Cs-alkynyl aryl", "C2-C6-alkynylheteroaryl", "C1 -C 6 -alkyl cycloalkyl", "C -C6-alkyl 20 heterocycloalkyl". "Cl-Cs-alkyl sulfonyloxy" refers to Cl-C 6 -alkyl groups having a sulfonyloxy substituent, including 2-(methylsulfonyloxy)ethyl and the like. "Sulfonyl" refers to group " -S0 2 -R" wherein R is selected from H, "aryl", "heteroaryl", "C-Cs-alkyl", "C-C 6 -alkyl" substituted with halogens, e.g., an -S0 2

-CF

3 group, "C 2

-C

6

-

WO 2005/026155 PCT/EP2004/052137 - 11 alkenyl", "C 2

-C

6 -alkynyl", "C 3 -C8-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl",

"C-C

6 -alkyl aryl" or "C-C 6 -alkyl heteroaryl", "C 2

-C

6 -alkenyl aryl", "C-C 6 -alkenyl heteroaryl", "C 2 -C6-alkynyl aryl", "C 2

-C

6 -alkynylheteroaryl", "Ci-C 6 -alkyl cycloalkyl",

"C-C

6 -alkyl heterocycloalkyl". 5 "C-C 6 -alkyl sulfonyl" refers to CI-C 6 -alkyl groups having a sulfonyl substituent, including 2-(methylsulfonyl)ethyl and the like. "Sulfinyl" refers to a group "-S(O)-R" wherein R is selected from H4, "C-C 6 -alkyl", "C

C

6 -alkyl" substituted with halogens, e.g., an -SO-CF 3 group, "C2-C 6 -alkenyl", "C 2

-C

6 alkynyl", "C 3 -Cs-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "C-C 6 -alkyl aryl" 10 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", "Cl-C 6 -alkyl cycloalkyl", "C-C 6 -alkyl heterocycloalkyl".

"C-C

6 -alkyl sulfinyl" refers to C-C 6 -alkyl groups having a sulfinyl substituent, including 2-(methylsulfinyl)ethyl and the like. 15 "Sulfanyl" refers to groups -S-R where R includes H, "Ci-C 6 -alkyl", "C -C-alkyl" substituted with halogens, e.g., an -SO-CF 3 group, "C 2

-C

6 -alkenyl", "C 2

-C

6 -alkynyl", "C 3 Cs-cycloalkyl", "heterocycloalkyl", "aryl", "heteroaryl", "CrC 6 -alkyl aryl" or "CI-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", "C-C 6 -alkyl cycloalkyl", "C-C 6 -alkyl heterocycloalkyl". Preferred 20 sulfanyl groups include methylsulfanyl, ethylsulfanyl, and the like.

"C-C

6 -alkyl sulfanyl" refers to C-C 6 -alkyl groups having a sulfany] substituent, including 2-(ethylsulfanyl)ethyl and the like. "Sulfonylamino" refers to a group -NRSO 2 -R' where each R, R' includes independently hydrogen, "CrC 6 -alkyl", "C 2

-C

6 -alkenyl", "C 2

-C

6 -alkynyl", "C 3 -Cs-cycloalkyl", 25 "heterocycloalkyl", "aryl", "heteroaryl", "Cr .C 6 -alkyl ary]" or "C -C 6 -alkyl heteroaryl", WO 2005/026155 PCT/EP2004/052137 - 12 "C2-C6-alkenyl aryl", "C 2

-C

6 -alkenyl heteroaryl", "C 2

-C

6 -alkynyl aryl", "C 2

-C

6 alkynylheteroaryl", "C-C 6 -alkyl cycloalkyl", "C-C 6 -alkyl heterocycloalkyl".

"C-C

6 -alkyl sulfonylamino" refers to C-C 6 -alkyl groups having a sulfonylanino substituent, including 2-(ethylsulfonylamino)ethyl and the like. 5 "Aminosulfony1" refers to a group -S0 2 -NRR' where each R, R' includes independently hydrogen, "Cr-C 6 -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 1

-C

6 -alkyl heteroaryl",

"C

2

-C

6 -alkenyl ary1", "C 2 -Cs-alkenyl heteroaryl", "C 2

-C

6 -alkynyl aryl", "C 2 -C6 alkynylheteroaryl", "C-C 6 -alkyl cycloalkyl", "Cl-C 6 -alkyl heterocycloalkyl". 10 "C-C 6 -alkyl aminosulfonyl" refers to C-C 6 -alkyl groups having an aminosulfonyl substituent, including 2-(cyclohexylaminosulfonyl)ethyl and the like. "Substituted or unsubstituted" : Unless otherwise constrained by the definition of the indi vidual 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 15 from the group consisting of "CrC 6 -alkyl", "C 2

-C

6 -alkenyl", "C 2

-C

6 -alkynyl", "cycloalkyl", "heterocycloalkyl", "C-C-alkyl aryl", "C-Cs-alkyl heteroaryl", "C 1

-C

6 alkyl cycloalkyl", "C-Cs-alkyl heterocycloalkyl", "amino", "ammonium", "acyl", "acyloxy", "acylamino", "aminocarbonyl", "alkoxycarbonyl", "ureido", "carbamate", "aryl", "heteroaryl", "sulfinyl", "sulfonyl", "alkoxy", "sulfanyl", "halogen", "carboxy", 20 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 functional 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. 25 "Pharmaceutically acceptable salts or complexes" refers to salts or complexes of the below identified compounds of formula (1) that retain the desired biological activity. Examples of WO 2005/026155 PCT/EP2004/052137 - 13 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, 5 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 of the formula NR,R',R" _ Z, wherein R, R', R" is independently hydrogen, alkyl, or benzyl, CI-C 6 -alkyl, 10 C 2

-C

6 -alkenyl, C 2

-C

6 -alkynyl, C1-C 6 -alkyl aryl, C1-C 6 -alkyl heteroaryl, cycloalkyl, heterocycloalkyl, and Z is a counterion, including chloride, bromide, iodide, -0-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, fumarate, citrate, tartrate, ascorbate, cinnamoate, mandeloate, and diphenylacetate). 15 "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 syn thesis, i.e. a synthesis involving non-racemic starting materials and/or reagents or a syn thesis comprising at least one enantioselective step, whereby a surplus of one enantiomer in 20 the order of at least about 52% ee is yielded.

WO 2005/026155 PCT/EP2004/052137 -14 A first aspect of the invention consists in benzimidazole acetonitriles of formula I: R2 R ~ _CN RR N G-L H G is an unsubstituted or substituted pyrimidinyl. In particular, G may be either of the substituted pyrimidinyl moieties N L L N N N R3 5 Aa Ab L is an amino group, or an unsubstituted or a substituted 3-8 membered heterocycloalkyl, containing at least one heteroatom selected from N, 0, S or L is an acylamino moiety. R' is selected from the group comprising or consisting of hydrogen, sulfonyl, amino, carboxy, amino carbonyl, unsubstitutcd or substituted CI-C 6 -alkyl, unsubstituted or 10 substituted C 2

-C

6 -alkenyl, unsubstituted or substituted C 2

-C

6 -alkynyl or C-Cs-alkoxy, unsubstituted or substituted aryl (e.g. phenyl), halogen, cyano or hydroxy. Preferably R 1 is H or Cr-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 15 substituted C 2

-C

6 -alkeny], unsubstituted or substituted CrC 6 -alkynyl, unsubstituted or substituted cycloalkyl or C-C 6 -alkoxy.

WO 2005/026155 PCT/EP2004/052137 - 15 PreferablyR2 is a C-C 3 alkyl (e.g. an ethyl group).

R

3 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 5 substituted cycloalkyl or Cl-C6-alkoxy. Preferably R 3 is hydrogen or a CI-C 3 alkyl (e.g. a methyl or an ethyl group). The compounds of the 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 10 salts of the 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 para-toluenesulfonate salts. 15 More specifically, the benzimidazole acetonitriles of the present invention comprise the tautomeric forms, e.g. the below ones: R 2

R

2 '~ N CN N CN R R H SN G-L -~ N G-L H (I) (1*) A specific embodiment of the present invention consists in benzimidazole acetonitriles of formula (Ia) in its tautomeric forms, e.g. the below ones : WO 2005/026155 PCT/EP2004/052137 -16

R

2

R

2 N

:

1 N CN R L RN -N L R3 NNC (l)(la') R 3 'N R2 R N L L NI~ Rt N R1, R 2 , R 3 and L are as defined for formula (I). According to a specific embodiment, the moiety L is an amino group of the formula

NR

5 R6 wherein R and R 6 are each independently from each other H, unsubstituted or 5 substituted CI-C 6 -alkyl, unsubstituted or substituted C 2 -Cs-alkenyl, unsubstituted or substituted C 2

-C

6 -alkynyl, unsubstituted or substituted Cl-C 6 -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 10 groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group), unsubstituted or substituted Cl-C 6 -alkyl aryl, unsubstituted or substituted C-C 6 alkyl heteroaryl, unsubstituted or substituted CI-C 6 -alkenyl aryl, unsubstituted or substituted C-C 6 -alkenyl heteroaryl, unsubstituted or substituted CI-C 6 -alkynyl aryl, unsubstituted or substituted C -C 6 -alkynyl heteroaryl, unsubstituted or substituted C-C 6 15 alkyl cycloalkyl, unsubstituted or substituted C -C 6 -alkyl heterocycloalkyl, unsubstituted or substituted CI-C 6 -alkenyl cycloalkyl, unsubstituted or substituted CI-C6-alkenyl heterocycloalkyl, unsubstituted or substituted C -C-alkynyl cycloalkyl, unsubstituted or substituted CrC 6 -alkynyl heterocycloalkyl.

WO 2005/026155 PCT/EP2004/052137 - 17 Alternatively, R and R 6 may form a ring together with the nitrogen to which they are bound. In a specific embodiment, R is hydrogen or a methyl or ethyl or propyl group and R 6 is selected from the group consisting of unsubstituted or substituted C-C 6 -alkyl, 5 unsubstituted or substituted CI-C 6 alkyl-aryl, unsubstituted or substituted C-C 6 -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 R 5 is H and R 6 is selected from the group consisting of C 1

-C

6 10 alkyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, heteroaryl, Ci-C 6 -alkyl heteroaryl, C 1 -C-alkyl cycloalkyl, C -Co-alkyl heterocycloalkyl. Examples of cycloalkyl are cyclopropyl, cyclopentyl or cyclohexyl. More specifically R may be a C 2

-C

4 alkyl, in particular an ethylene or propylene moiety, optionally substituted with an unsubstituted or substituted heteroaryl group, e.g., an 15 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(O)R wherein R 5 and R 6 are each independently from each other H, unsubstituted or substituted C-C6-alkyl, unsubstituted or substituted C 2

-C

6 -alkenyl, 20 unsubstituted or substituted C 2

-C

6 -alkynyl, unsubstituted or substituted C-C 6 -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 C 1

-C

6 -alkyl aryl, unsubstituted or substituted C-C 6 -alkyl heteroaryl, unsubstituted or substituted C-C 6 25 alkenyl aryl, unsubstituted or substituted C-C 6 -alkenyl heteroaryl, unsubstituted or substituted C-C 6 -alkynyl aryl, unsubstituted or substituted C-C 6 -alkynyl heteroaryl, WO 2005/026155 PCT/EP2004/052137 unsubstituted or substituted C 1

-C

6 -a~lkYl cycloalkyl, unsubstituted or substituted C 1

-C

6 -- alkyl heterocycloalkcyl, unsubstituted or substituted Cl-C 6 -alkenyl cycloalkyl, unsubstituted or substituted CI-C 6 -alkenyl heterocycloalkyl, unsubstituted or substituted CI-Cr-alkynyl cycloalkyi, unsubstituted or substituted CI-C 6 -alkynyl heterocycloalkyl. 5 Specific benzimidazole acetonitriles according to formula (I) include : (2Z)-(l -ethyl-I ,3-dihyclro-214-benzimidazol-2-ylidene)(2- { [3-(lT{-pyrazol- 1 -yl)propyl] .aninolpyrimidin-4-yl)acetonitrile (2Z)-(l -ethyl-l1,3-dihydro-2H-bcnzimidazol-2-ylidene)(5-methyl-2- {[3 -(I TI-pyrazol- 1 yl)propyllam-inolpyrimidin-4-yl)acetonitrile 10 (2Z)-[2-(cyclobutylamino)-5-methylpyrimidin-4-yl](1 -ethyl- 1,3 -dihydro-211-benzimidazol 2-ylidene)acetonitrile (2Z)-(1 -ethyl-i 1,3 -dihydro-2H-benzimidazol-2-ylidene)(5-methyl-2- f [3 -(2-oxopynrolidin- 1 yl)propyl]amnino}pyrimnidin-4-yl)acetoniirile (2Z)-(l -ethyl-i ,3-dihydro-2H4-benzimidazol-2-ylidene)(2- f{[3-(2-oxopyrrolidin- 1 15 yl)propyl]amino~pyrimidin-4-yl)acetonitrile (2Z)-(l -ethyl-I ,3-dihyd-ro-2H-benizimidazol-2-ylidene)(2- f{[3-(1 H-i ,2,4-tria.zol-l yl)propyllamino}pyrimidin-4-yl)acetonitrile (2Z)-(l -ethyl-i ,3-dihydro-2H-benzimidazol-2-ylidene)(5-methyl-2-{[3 -(1H- 1,2,4-triazol- 1 yl)propyllaminolpyrimnidin-4-yl)acetonitrile 20 [2-(cyclopentylamnino)-5-methylpyrimnidin-4-yl](I -ethyl- IHf-benzimnidazol-2-yl)acetonitrile (2Z)-(2- {[3-(2-oxopyrrolidin-l -yl)propyllaminolpyrimidin-4-y)(1 -propyl- 1,3 -dihydro-211 benzimidazol-2-ylidene)acetonitrile WO 2005/026155 PCT/EP2004/052137 -19 (1-ethyl-1H-benzimidazol-2-yl){5-methyl-2-[(2-pyridin-3-ylethyl)aminojpyrimidin-4 yl}acetonitrile (2Z)-[2-(cyclobutylamino)pyrimidin-4-yl](1 -ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)acetonitrile 5 (2Z)-[2-(cycloheptylamino)-5-methylpyrimidin-4-y](1 -ethyl-1,3-dihydro-2H benzimidazol-2-ylidene)acetonitrile [2-(cyclopentylamino)pyrimidin-4-yl](1 -ethyl- 1H-benzimidazol-2-yl)acetonitrile 1,3-dihydro-211-benzimidazol-2-ylidene(5-methyl-2-{[3-(2-oxopyrrolidin-1 y1)propy1]amino}pyrimidin-4-yl)acetonitrile 10 (2Z)-(1 -cyclobutyl- 1,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[3-(2-oxopyrrolidin-1 yl)propy1]amino}pyrimidin-4-yl)acetonitrile (1 -ethyl- 1H-benzimidazol-2-yl) {2-[(2-pyridin-3 -ylethyl)amino]pyrimidin-4-yl} acetonitrile (2Z)-(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene) [2-(isobutylamino)-5 methylpyrimidin-4-yl]acetonitrile 15 (2Z)-( 1-ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)(2- {[2-(iH-imidazol-4 yl)ethyl]amino}pyrimidin-4-yl)acetonitrile (2Z)-(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)[2-(isobutylamino)pyrimidin-4 yl]acetonitrile [2-(cyclopropylamino)pyrimidin-4-yl](1 -ethyl-1H-benzimidazol-2-yl)acetonitrile 20 [2-({2- [6-(dimethylamino)pyridin-3-yl]ethyl}amino)pyrimidin-4-yl](1 -ethyl-1 H benzimidazol-2-yl)acetonitrile WO 2005/026155 PCT/EP2004/052137 - 20 (1 -ethyl-1IH-benzimidazol-2-yl)(2- I [2-(1 H-i ,2,4-triazol- 1 -yl)ethyljamino}pyrimidin-4 yl)acetonitrile (2Z)-(1 -ethyl-I ,3-dihydro-2H-benzimiclazol-2-ylidene)(2- {[2-(1I -imidazol-4 yl)ethyllamino}-5-methylpyrimidin-4-yl)acetonitrile :5 [2-({2- [6-(dimethylamino)pyridin-3 -yl] ethyl}I amino)-5-methylpyrimidin-4-yl](I -ethyl- 1Hf benzimidazol-2-yI)acetonitrile (2Z)-[2-(cycloheptylamino)pyrimilin-4-y](I -ethyl-I 1,3 -dihydro -2H-benzimidazol-2 yiidene)acetenitrile [2-(cyclopropylamxino)-5-methylpyrimidin-4-yl](l -ethyl- 1H-benziriidazol-2-yl)acetonitrile 10 (1 -ethyl-IH-benzimidazol-2-yI){2-[(2-pyridin-2-ylethyl)amino]pyrimidin-4-y} acetonitrile F 2-(cyclopentylainino)-5-methylpyrimidin-4-yl](I ,3 -dihydro-2H-benzimidazol-2 yiidene)acetonitrfle [2- (cyclohexylwnino)pyrimidin-4-yl](l -ethyl-i 1Hl-benzimidazol-2-yl)acetonitrile (2Z)-(l -ethyl-I ,3-dihydro-2T1-benzimidazol-2-ylidene)(2- {[2-(1T--indol-3-yl)ethyllamino) 15 5-methylpyriinidin-4-yl)acetonitrile (1 -ethyl- 1H-benzimidazol-2-yl){ 5-methyl-2- [(2-pyridii-2-ylethyl)amino]pyrimidin-4 yl} acetonitrile {2-[(2-ethoxyethyl)amino]pyrimidin-4-yl}(I -ethyl- IH1-benzimida7.oI-2-yl)acetonitrile (1 -ethyl- lll-benzimidazo-2-yl){5-methyl-2-[(l -methylbutyl)amino]pyrixnidin-4 20 yllacetonitrile (1 -ethiyl-i1H-benzimidazol-2-yl)[2-(methylamino)pyrmidin-4-yl]acetonirile WO 2005/026155 PCT/EP2004/052137 -21 (1 -ethyl-1H-benzimidazol-2-yl)(5-methyl-2-{[2-(1H-pyrazol- I -y1)ethy1]amino}pyrimidin 4-yl)acetonitrile 1H-benzimidazol-2-yl{5-methyl-2-[(2-pyridin-3-ylethyl)amino]pyrimidin-4-y}acetonitrile (2Z)-(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)(2- {[2-(1H-imidazol-1 5 yl)ethyl]amino} -5-methylpyrimidin-4-yl)acetonitrile 1H-benzimidazol-2-yl {2-[(2-pyridin-3 -ylethyl)amino]pyrimidin-4-yl} acetonitrile (1 -ethyl- 1H-benzimidazol-2-yl) {2-[(1 -methylbutyl)aminolpyrimidin-4-yl acetonitrile

{

2 -[(cyclohexylmethyl)amino]-5-methylpyrimidin-4-yl} (1 -ethyl-i H-benzimidazol-2 yl)acetonitrile 10 1H-benzimidazol-2-yl[2-(cyclopentylamino)pyrimidin-4-yl]acetonitrile (1 -ethyl-H-benzimidazol-2-yl){6-methyl-2-[(2-pyridin-3-ylethyl)amino]pyrimidin-4 yl} acetonitrile IH-benzimidazol-2-yl[2-(cyclopropylamino)pyrimidin-4-yl]acetonitrile

[

2 -(cyclopentylanino)-6-methylpyrimidin-4-yl](1 -ethyl- 1H-benzimidazol-2-yl)acetonitrile 15 {2-[(cyclohexylmethyl)amino]pyrimidin-4-yl} (1-ethyl-i H-benzinidazol-2-yl)acetonitrile (1-ethyl- 1H-benzimidazol-2-yl){6-[(2-pyridin-3 -ylethyl)amino]pyrimidin-4-yl} acetonitrile. (1 -ethyl-1IH-benzimidazol-2-yl) {2-[(3-pyrrolidin-1 -ylpropyl)amino]pyrimidin-4 yl}acetonitrile (1 -ethyl-1H-benzimidazol-2-y1)[2-(4-ethypiperazin- 1 -yl)-5 -methylpyrimidin-4 20 yl]acetonitrile WO 2005/026155 PCT/EP2004/052137 - 22 (1 -ethyl-1II-benzimidazol-2-yl){2-[(2-furylmethyl)aniino]-5-methylpyrimidin-4 yl} acetonitrile (2Z)-(l -ethiyl-I ,3-dihydro-2H-benzimidazol-2-ylidene) f{5-methyl-2-[(1 -methyilpiperidin-4 yl)amiino]pyirimidin-4-yl}acetonitrile 5 (2Z) -[2-(cyclohexylamino)-5-methylpyrimidin-4-yl](I -ethyl-i 1,3 -dihydro-2H-benizimidazol 2-ylidene)acetonitrile (2Z)-[2-(ethylamino)-5-methylpyrimidin-4-yl(1 -ethyl-i ,3-dihydro-2H-benzimidazol-2 ylidene)acetonitrile [2-(cyclopentylamino)-5-methylpyri-tnidin-4-yl](1 ,3-diethyl-1 ,3-dihydro-2H-benzimidazol 10 2-ylidene)acetonitrile (2Z) -(l -ethyl- 1, 3-dihydro-2T4-benzimidazol-2-ylidene)[5-methyl-2-(piperidin-4 ylamino)pyrimidin-4-yl]acetonitrile, and (2Z)-(l -ethyl-I ,3-dihydro-2H--benzimidazol-2-ylidene){5-methyl-2-[(2-piperidin- 1 yiethyl)amino]pyrirnidin-4-yll acetonitrile, or it a tautomer formn thereof. 15 N- {4- [(Z)-cyano(l -ethyl- 1,3 -dihydro-2H-benzimidazo1-2-ylidene~methyl1 -5 methylpyrimnidin -2-yI }-4-(4-methylpiperazin- I -yl)-4-oxob-utanamide N- {4- [(Z)-cyano(l -ethyl-i 1,3 -dihydro-21-benzimklazol-2-ylidene)methyl]pyrimnidin-2-ylI 4-(4-methylpipera~in- 1-yI)-4-oxobutanamide (I R,5R,7R)--N- 14- [(Z)-cyano( 1-ethyl-i ,3-dihydro-2H4-benzimidazol-2-ylidene)methyl] -5 20 methylpyrimnidin-2-yl} -6,8 -dioxa-3 -azabicyclo[3 .2. 1] octane-7-carboxamide (1 S, 5 S,7S)-N- {4-f (Z)-cyano(1 -ethyl-I ,3-dihydro-211-benzirniidazol-2-ylidene)met'hyl] -5 methylpyrimnidin-2-yl} -6,8 -dioxa-3 -azabicyclo[3 .2. 1 ]octane-7-carboxamide WO 2005/026155 PCT/EP2004/052137 - 23 (1 S,4S,5S,7R)-N- {4-[(Z)-cyano(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)metbyl] 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-21-benzimidazol-2-ylidcne)mcthyl] 5-methylpyrimidin-2-yl}-4-methyl-6,8-dioxa-3-azabicyclo[3.2.1]octane-7-carboxamide 5 N-{4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl}piperazine-2-carboxamide (4S)-N-{4-[(Z)-cyano( 1-ethyl-1,3-dihydro-2H-benzhnidazol-2-ylidene)methyl]-5 methylpyrimidin-2-y} -1,3-thiazolidine-4-carboxamide (4R)-N- {4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 10 methylpyrimidin-2-yl} -1,3-thiazolidine-4-carboxamide N- {4-[(Z)-cyano(I -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl] -5 methylpyrimidin-2-yl} -5-oxo-L-prolinamide 4-tert-butyl 1-(9H-fluoren-9-ylmethyl) 2-[({4-[(Z)-cyano(1 -ethyl-1,3 -dihydro-2H benzimidazol-2-ylidene)methyl]-5-methypyrimidin-2-y}amino)carbonyl]piperazine-1,4 15 dicarboxylate tert-butyl (4S)-4-[({4-[(Z)-cyano(1-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(1 -ethyl- 1,3-dihydro-2H-benzimidazol-2-ylidene)methyl] 5-methylpyrinidin-2-yl}amino)carbonyl]-5-oxopyrrolidine-1-carboxylate 20 tert-butyl (4R)-4-[({4-[(Z)-cyano(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl] 5-methylpyrimidin-2-yl}amino)carbonyl]-1,3-thiazoiidine-3-carboxylate 2-(1 -acetylpiperidin-4-yl)-N- {4-[(Z)-cyano(l -ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)methyl]-5-methylpyrimidin-2-yl}acetamide WO 2005/026155 PCT/EP2004/052137 -24 N-{4-[(Z)-cyano(1-ethyl-1,3-dihydro-2H1-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl}-4-methylmorpholine-2-carboxamide 4-acetyl-N- {4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl}morpholine-2-carboxamide 5 N- {4- [(Z)-cyano(i -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl] -5 methylpyrimidin-2-yl}-4-[(4-methylpiperazin-1-yl)methyl]benzamide tert-butyl 3 -[({4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methy]-5 methylpyrimidin-2-yl} amino)carbonyl]piperidine-1-carboxylate tert-butyl 4-[2-({4-[(Z)-cyano(1-ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 10 methylpyrimidin-2-yl} amino)-2-oxoethyl]piperidine-1-carboxylate N-{4-[(Z)-cyano(l -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-y}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 15 N- {4-[(Z)-cyano( 1-ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)methylI -5 methylpyrimidin-2-y}piperidine-3-carboxamide tert-butyl 2-[({4-[(Z)-cyano(i -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl}amino)carbonyllmorpholine-4-carboxylate N-[3-({4-[(Z)-cyano(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 20 methylpyrimidin-2-yl} amino)-3-oxopropy1]benzamide tert-butyl [2-({4-[(Z)-cyano(I -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methy]-5 metbylpyrimidin-2-yl}amino)-2-oxoethyl]methylcarbanate WO 2005/026155 PCT/EP2004/052137 -25 N- t4-[RZ)-cyano(l -ethyl-i ,3-dihydro-211-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl} -l -methylpiperidine-3-carboxamide N-1 -14- [(Z)-eyano(i -ethyl-i 1,3 -dihydro-211-benzimidazol-2-ylidene)methyl] -5 methylpyrimidin-2-y} -N-2.--methylglycinamide 5 N- {4- [(Z)-cyano(1 -ethyl-i ,3-dihydro-2H-benzimnidazol-2-ylidene)methyl]-5 methylpyrimnidin-2-yllpyrrolidine-3-carboxamnide tert-butyl 3-II({4-[(Z)-cyano(l -ethyl-i 1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimnidin-2-yl} amino)carbonyl]pyrrolidine-1 -carbcoxylate (2S)-N- {4-[(Z)-cyano(1 -ethyl-i ,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 10 methylpyrimidin-2-yl) -2,5-dihydro- 1 1I-pyrrole-2-carboxamnide tert-butyl (2S)-2-[({4-[(.Z)-cyano(1 -ethyl-i ,3-dihydro-214-benzimidazol-2-ylidene)methyl] 5-methylpyrinidin-2-yl} anino)carbonyl] -2,5-dihydro-1I-pyrrole-1 -carboxylate 'N- {4- [(Z)-cyano(l -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl} -2-(2-xnethoxyphenyl)acetamnide 15 1 -acetyl-N- 14-r(Z)-cyano(I -ethyl- 1,3 -dihydro-2H-benzimnidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl}piperidine-4-carboxamide N- {4-[(Z)-cyano(1 -ethyl-I ,3-dihydro-2H-benzimidazol-2-ylidene)mehyl]-5 methylpyrimidin-2-yl} -1I -methylpiperidine-4-caboxamide 4-ainino-N- 14-[(Z)-cyano(i -ethyl- 1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 20 methlylpyrixnidin-2-yllbutanamide tert-butyl 4-[({4-[(Z)-cyano(l -ethyl- 1,3 -diliydro-2H4-benzi-midazol-2-ylidene)methyl]-5 methylpyrimidin-2-yI} amino)carbonyllpiperidine- 1 -carboxylate WO 2005/026155 PCT/EP2004/052137 -26 N- {4- [(Z)-cyano(l -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl}piperidine-4-carboxamide tert-butyl [4-({4-[(Z)-cyano(I -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl} amino)-4-oxobutyl]earbamate 5 N- {4- [(Z)-cyano(l -ethyl-1,3 -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-methylpiperazin- 1 -yl)butanamide N-1-- {4-[(Z)-cyano(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 10 methylpyrinidin-2-yl} -N-3,N~3--dimethyl-beta-alaninamide N-{4- [(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-y}-4-(dimethylamino)butanamide (2Z)-(2-amino-5-methylpyrimidin-4-yl)(1 -ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)acetonitrile 15 N-{4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-y} -2-morpholin-4-ylacetamide N-2--benzyl-N-1-- {4- [(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)methyl]-5-methylpyrimidin-2-yl} glycinamide N- {4- [(Z)-cyano(i -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 20 methylpyrimidin-2-yl} -2-(1, 1 -dioxidothiomorpholin-4-yl)acetamide N~1-- {4-[(Z)-cyano(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrinidin-2-yl} -N-2--formylglycinamide WO 2005/026155 PCT/EP2004/052137 - 27 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 II, inadequate glucose tolerance, insulin resistance, obesity, polycystic ovary syndrome (PCOS). 5 The compounds 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 of the present invention is a process for preparing the benzimidazole 10 acetonitriles according to formula . 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 15 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. 20 The general synthetic approach for obtaining compounds of formula (I) is depicted in Scheme 1. Therein, benzimidazole acetonitriles 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.

WO 2005/026155 PCT/EP2004/052137 - 28 Scheme 1 R N N CI- G N CN N N G-L H R IV V In a more specific method, the benzimidazole acetonitrile derivative VI with R being as above defined - is reacted with the electrophile VII (e.g. alkyl chloride) to give the 5 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 Ri, R6 are as above defined to give the final benzimidazole acetonitrile derivatives I, utilizing well known solution-phase chemistry protocols, such as 10 those described in the Examples and shown in Scheme 2, below: Scheme 2 WO 2005/026155 PCT/EP2004/052137 -29 R2 H N --. N N + R2\x N N NI N R IV R VI VII [X CI, Br, I, OMs] 2 R 2 R\N CN N I N + G R N G-CI N :1 IV v' Il R2 Ri N C N =<CN RC + R5N RR N -L -~N G-CI 11 1 jL = NR5RG] 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 5 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 of the benzimidazole compound VI 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. by the use of PS-TBD (7-methyl-1,5,7 10 triazabicyclo[4.4.0]dec-5-en' on polystyrene HL) a polymer immobilised reagent as a base in presence of various electrophilic 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 WO 2005/026155 PCT/EP2004/052137 -30 depending of the intrinsic reactivity of compounds VI and VII, 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 R\ H_ NN SN + R7 / N - / N R I R IV R VI VI 5 [X = CI, Br, I, OMs] In a subsequent step, the benzimidazole acetonitriles derivatives II, whereby the substituents R' and R 2 are as above defined, are isolated after condensation of the benzimidazole compound IV with bis-chloro derivative V'. This reaction step is 10 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 of the intrinsic reactivity of compounds 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 15 the Examples.

WO 2005/026155 PCT/EP2004/052137 - 31 Scheme 4

RR

2 N C11 CI ------- I- R 1 N CN N + OlG'C: R-C - +G N G-CI H R IV y 11 In a following step, as shown in Scheme 5, the chloro benzimidazole acetonitriles 5 derivatives II may treated with various nucleophiles, e.g. an amine III, to give the expected benzimidazole acetonitriles 1. The nucleophilic displacement of the chloro atom of the pyrimidinyl moiety by the amine III, is accomplished by treatment with several equivalents of the 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 10 reaction can be performed at various temperatures depending of the intrinsic reactivity of compounds II and I, 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. 15 Scheme 5 H H I Ill [L = NR 5

R

6 ] The benzimidazole acetonitriles derivatives according to the general formula I can be further isolated from the intermediate I', whereby L is the moiety -NR 5 R, with R 5 being hydrogen and R6 is as above defined, as shown in Scheme 6. The benzimidazole derivatives WO 2005/026155 PCT/EP2004/052137 -32 I may be obtained by treatment of the 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 5 triethylamine, pyridine etc, and activating agents e.g, TOBt, EDC or similar reagents in an appropriate solvent such as THF or DMF. This reaction can be performed at various temperature depending of the intrinsic reactivity of compounds Ib 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. 10 Scheme 6 R2 RN CN H .+ R5- R N/C R5 H \ H R a lb VIII [R5 = H] [Y = Cl, OH] [R5 = R-C=O, R-SO2] A specific functional moiety (R 1 ) may be converted into a different one (R ), using any known functional group interconversion protocols. As illustrated in Scheme 7, the choice of the best synthetic strategy will be governed by the nature of the functional groups to be 15 interconverted, and the compatibility of the 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, I and IV and VII, are those wherein R' is -Br, -Cl, -I, -OH, -NH2, -CH 2 OH, -CHO, -COOH, -NO 2 , and/or -CH2COOH, which are either obtained from commercial sources or made by one of 20 the numerous processes described in the literature, From the intermediates (XXI, XXV, XXVII) 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", R 7 , are as defined below, can be WO 2005/026155 PCT/EP2004/052137 - 33 obtained by reaction sequences including oxidations, reductions, 0- 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 5 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), (H), (IV), and (VI), wherein R', R 2 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. 10 R 9 , R", R", R!, are each independently from each other H, unsubstituted or substituted C

C

6 -alkyl, unsubstituted or substituted C 2

-C

6 -alkenyl, unsubstituted or substituted C 2

-C

6 alkynyl, unsubstituted or substituted C1-C 6 -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, 15 (wherein said cycloalkyl, heterocycloalkyl, aryl or heteroaryl groups may be fused with 1-2 further cycloalkyl, heterocycloalkyl, aryl or heteroaryl group), unsubstituted or substituted Cl-C6-alkyl aryl, unsubstituted or substituted Ci-C 6 -alkyl heteroaryl, unsubstituted or substituted C-C6-alkenyl aryl, unsubstituted or substituted CI-C 6 -alkenyl heteroaryl, unsubstituted or substituted Cr-Cs-alkynyl aryl, unsubstituted or substituted Ci-Cs-alkynyl 20 heteroaryl, unsubstituted or substituted CI-C 6 -alkyl cycloalkyl, unsubstituted or substituted

CI-C

6 -alkyl heterocycloalkyl, unsubstituted or substituted C-C 6 -alkenyl cycloalkyl, unsubstituted or substituted C-C 6 -alkenyl heterocycloalkyl, unsubstituted or substituted CrC 6 -alkynyl cycloalkyl, unsubstituted or substituted C-C 6 -alkynyl heterocycloalkyl.

WO 2005/026 155 PCT/EP2004/052137 - 34 Scheme 7 ( funtioa group R~ NT interconversion)M,- I :R0L 1r R=G-L R = GR"CI fl, R =G-CI IV :R=H IV* :R=H VI :R=H,R2=H VI' :R=H, R 2 =I Exampules: 0 0 IN A, HO 11 - r ~N Suzuki, StNNo4HRN Ai, eterot~r NR2 Peptide couplingj ftr,CI, I agent ft XXX' XXXI I. N' R\ N N ' N Serogashira ~jNH 2 N ~ ~ ~ ~ - -___N~uR 5 NA Br~l, m N / HOt~ i n.N Cyclisotlon N2 / NXI XiCN4' Br,CI, I NR xXI XXIV 0 N O-alkylalion, 1) MaCN. or related N~ ~ Mittunobv, acylolion, ) /N 2iRoduclion PI Hx Ny --. uuYlatlun. etc. N,. -, -j Nil 2 y ,- 'N _ _ _ N"\ - r N Lan~s N -N HErCl,I1, OH XXVI Xxv IL H. - ~ -. R 5 CHO (Md. "4 RCOCI,NOSO CI, RtiCO, R0 -'N

NH

2 N N N N - 1) Oxidation0 N HO IT' N (Swonm, Dose-Niartin, O-fl\ N) N \C11N NPOC, or related) 'N 3) Witth 0 XXIX 3) Hydrogetonom 4) Saponification WO 2005/026155 PCT/EP2004/052137 -35 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 of the benzimidazole compound II with a 5 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 of the 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 10 Scheme 9 R

R

1 ~~ ~ ~ NNO CN RN C + NH0H , R N -NH2 H0 N GC H 2 H Il XOO C 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 15 C(O)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 I' with either an acyl chloride or a carboxylic acid using standard conditions well known to the person skilled in the art, such as aide bond formation protocols using the appropriate reactants as those mentioned above and reagents such as bases like triethylamine, pyridine etc, and activating 20 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. 25 WO 2005/026155 PCT/EP2004/052137 -36 Scheme 10

R

2 SN CM 0 R '_C N CN R -+ R _ N NH 2 + 1R N G-L HH [X CI, OH] [L = NC(O)RB] When employed as pharmaceuticals, the benzimidazole acetonitriles of the present invention are typically administered in the form of a pharmaceutical composition. Hence, 5 pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier, diluent or excipient therefore are also within the scope of the 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 of the invention, together with a conventionally employed adjuvant, car 10 rier, 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 15 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 the active ingredient commensurate with the intended daily dosage range to be employed. When employed as pharmaceuticals, benzimidazole acetonitriles of this invention are 20 typically administered in the form 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 WO 2005/026155 PCT/EP2004/052137 -37 pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the 5 severity of the 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 compounds are preferably formulated as either injectable, topical or oral compositions. The 10 compositions for oral administration may take the form of bulk liquid solutions or suspen sions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term "unit dosage fonns" refers to physi cally 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 15 desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of the 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 20 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 of the following ingredients, or compounds of a 25 similar nature: a binder such as microcrystalline cellulose, gum tragacanth 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- WO 2005/026155 PCT/EP2004/052137 - 38 xide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as pepper mint, 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 5 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 10 set out in Part 5 of Remington's Pharmaceutical Sciences, 20t" 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 15 Pharmaceutical Sciences. A further aspect of the 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 20 mirnicks), 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 of the present invention include rapid acting insulins, intermediate acting insulins, long acting insulins and combination of intermediate and rapid 25 acting insulins.

WO 2005/026155 PCT/EP2004/052137 -39 Among the more preferred aldose reductase inhibitors of this invention are minalrestat, Tolrestat, Sorbinil, Methosorbinil, Zopolrestat, Epalrestat, Zenarestat, Imirestat and Ponalrestat or the pharmaceutically acceptable salt forms thereof. The alpha-glucosidase inhibitors useful for the method of the present invention include 5 miglitol or acarbose, or the pharmaceutically acceptable salt form thereof. Sulfonylurea agents useful with the method of the present invention include glipizide, Glyburide (Glibenclamide), Clorpropamide, Tolbutamide, Tolazamide and Glimepiride, or the pharmaceutically acceptable salt forms thereof. Preferably, said supplementary pharmaceutically active agent is selected from the group 10 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, er SNK-860, Miglitol, Acarbose, Glipizide, Glyburide, Chlorpropamide, 15 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 (min ute), hr (hour), g (gram), mmol (millimole), m.p. (melting point), eq (equivalents), mL 20 (milliliter), pL (microliters), mL (milliliters), ACN (Acetonitrile), Boc (butoxycarbonyl), CDCl 3 (deuterated chloroform), CsCO 3 (Cesium carbonate), cHex (Cyclohexanes), DCM (Dichloromethane), DIC (Diisopropyl carbodiiide), DIPEA (Diisopropylamine), DMA (Dimethylacetamide), DMAP (4- Dimethylaminopyridine) DMF (Dimethylformamide), DMSO (Dimethyl-sulfoxide), DMSO-d 6 (deuterated dimethylsulfoxide), EDC (1-(3 25 Dimethyl-aniino-propyl)-3-ethylcarbodiimide), Et 3 N (Triethylamine), EtOAc (Ethyl acetate), EtOH (Ethanol), Et 2 O (Diethyl ether), Fmoc (9-fluorenyl-methoxycarbonyl), WO 2005/026155 PCT/EP2004/052137 - 40 HOBt (1-Hydroxybenzotriazole), iPrOH (Isopropanol), K 2 C0 3 (potassium carbonate), LiH (Lithium Hydride), NaI (Sodium Iodine), NaH (Sodium hydride), NaHCO 3 (Sodium bicarbonate), NH 4 C1 (Amiionium chloride), nBuLi (n Butyllithium), Pd(PPh 3

)

4 (Palladium triphenylphosphine tetrakis), (TBTU (O-Benzotriazolyl-N,N,N',N'-tetramethyluronium 5 tetrafluoroborate), Mukayama reagent (1-methyl-2-chloropyridinium iodide), TEA (Triethyl amine), TFA (Trifluoro-acetic acid), THF (Tetrahydrofuran), TBD-resin (7 methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene on polystyrene.HL), TMOF (trimethylorthoformate), MgSO 4 (Magnesium sulfate), PetEther (Petroleum ether), rt (room temperature). 10 The HPLC, NMR and MS data provided in the examples described below were obtained as. followed: HPLC: column Waters Symmetry CS 50 x 4.6 mm, Conditions: MeCN/TH 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); 1 H-NMR: Bruker DPX-300MHz. The purifications were obtained as followed: Preparative HPLC Waters Prep LC 4000 15 System equipped with columns Prep Nova-Pak*HR C186 pm 60A, 40x3Omm (up to 100mg) or 40x300 mm (up to Ig). All the purifications were perfonned with a gradient of MeCN/H 2 O 0.09% TFA. Examples 20 Intermediate 1: (1-ethyl-2.,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (cf. Scheme 4, compound IV) N C~ N / C N WO 2005/026155 PCT/EP2004/052137 -41 To a suspension of 2-benzimidazolylacetonitrile (6.0g, 38.17mmol) in DCM (200mL) was added TBD-resin (17.6g, 45.81mnol, 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 5 was concentrated to give the pure (1-ethyl-2,3-dihydro-1HT-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. 1H NMR (300Mz, 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, 111). MS(ESI*): 188.4; MS(ESI-): 186.5. 10 Intermediate 2: (1-propyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (cf. Scheme 4, compound IV) N SN '~N Following the general methods as outlined in Intermediate 1, starting from 2 benzimidazolylacetonitrile and 1 -bromopropane, the title compound was isolated, after 15 filtration and evaporation, as an orange solid in 49% yield (98.5 % purity by HPLC). IH NMR (300MHz, CDCl3); 1.5 (t, 3H), 1.6 (m, 2H), 4.0 (s, 2H), 4.1 (m, 211), 7.3-7.45 (m, 3H), 7.6 (d, J = 7.0Hz, 111). MS(ESI1): 202.3; MS(ESI): 200.4. Intermediate 3: (1-cyclobutyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (cf. Scheme 4, compound IV) WO 2005/026155 PCT/EP2004/052137 -42 N 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 HIPLC). 5 1H NMR (300MHz, CDCl3); 1.6-1.9 (m, 611), 4.1 (s, 2H), 4.8 (m, 111), 7.3-7.5 (m, 3H), 7.6 (d, J =7.0Hz, 1H). MS(ESI): 214.3; MS(ESI-): 212.4. Intermediate 6: (2-chloro-5-methylpyrimidin-4-y)(1 -ethyl-2,3-dihydro- 1IT-benzimidazol 2-yl)acetonitrile (cf. Scheme 9, compound V'c) N H N, >-N 10 CI Method A: To a suspension of Cesium carbonate (13.85g, 42.55mmol) in dioxane (5OmL), was added a solution of (I -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 15 temperature for 3 hours. A solution of 2,4-dichloro-5-methyl-pyrimidine (5.54g, 34.01mmol) in dioxane (1 00ml), 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 WO 2005/026155 PCT/EP2004/052137 -43 50mL and a solution of IN HClI (50mL) was added at zero degree. The solution was then diluted to 1/3 with acetonitrile and concentrated under vacuum to 5OmL. The precipitate was filtered and washed with water (1OmL), acetonitrile (OmL) and diethyl ether (1OmL) to give a yellow solid which was dried under vacuum. The yellow crystalline product (2 5 chloro-5-methylpyrimidin-4-yl)(1-ethyl-2,3-dihydro-1H-benzimidazol-2-y)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 (I -ethyl-2,3-dihydro-1H-benzimidazol-2-y)acetonitrile (Intermediate 1, 50mg, 10 0.27mmol) in dioxane (2mL). Then a solution of 2,4-dichloro-5-methyl-pyrimidine (57mg, 0.37mmol) in dioxane (1m1), 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 (ImL). The solvents were concentrated under vacuum to 5mL and a solution of IN HCI (5mL) was added at zero degree. The 15 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-chloro-5-methylpyrimidin-4-yl)(1 -ethyl-2,3-dihydro-1H-benzimidazol-2 yl)acetonitrile was isolated in 92% HPLC purity (Yield 45mg, 53%). 20 (2-chloro-5-methylpyrimidin-4-y)(1 -ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile: I H NMR (300MHz, CDCl3); 1.6 (t, J= 7.5Hz, 31-1), 4.7 (q, J = 7.5Hz, 21H), 2.3 (s, 3H), 7.2 7.45 (m, 4H), 8.2 (d, J = 7.0Hz, 1H), 13.7 (s(broad), 11). MS(ESI): 314.8; MS(ESI~): 312.6. Intermediate 7: (2-chloropyrimidin-4-vl)(1 -ethVl-2,3 -dihydro-1H-benzimidazol-2 25 yl)acetonitrile (cf. Scheme 5, compound II) WO 2005/026155 PCT/EP2004/052137 -44 N H N/ -N Cl Following the general method A as outlined in Intermediate 6, starting from (1-ethyl-2,3 dihydro-1H-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). 5 1H NMR (300MHz, CDCl3); 1.6 (t, I = 7.5Hz, 3H), 4.7 (q, J = 7.5Hz, 2H), 7.2-7.5 (m, 5H), 8.2 (d, J = 7.0Hz, 1H), 13.7 (s(broad), 1H). MS(ESI): 300.8; MS(EST~): 298.8. Intermediate 8: (2-chloro-5-methylpyrimidin-4-yl)(2,3-dihydro-1H-benzimidazo-2 yl)acetonitrile (cf. Scheme 5, compound II) N H N/ 10 C1 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 TTPLC). MS(ESI'): 286.8(ESI~): 284.7 15 Intermediate 9: (2-chloropyrimidin-4-yl)(2.3-dihydro-1H-benzimidazol-2-yl)acetonitrile (cf. Scheme 5, compound II) WO 2005/026155 PCT/EP2004/052137 -45 H N N Cl 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). 5 MS(ESI*): 272.7(ESI): 270.6 Intermediate 10: (2-chloro-6-methylpyrimidin-4-yl)(1-ethyl-2,3-dihydro-lH-benzimidazol 2-yl)acetonitrile (cf. Scheme 5, compound II) 4 N - N H N H N CI Following the general method A as outlined in Intermediate 6, starting from (1 -ethyl-2,3 10 dihydro-lH-benzimidazol-2-yl)acetonitrile (Intermediate 1) 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(ESI-): 312.7 Intermediate 11: (6-chloropyrimidin-4-yl)(1-ethyl-2,3-dihydro-IH-benzimidazol-2 15 y1)acetonitrile (cf Scheme 5, compound II) WO 2005/026155 PCT/EP2004/052137 - 46 /I N SN H N 1 \C1 N Following the general method A as outlined in Intermediate 6, starting from (1 -ethyl-2,3 dihydro-I H-benzimidazol-2-yl)acetonitrile (Intermediate 1) and 4,6-dichloropyrimidine, the title compound was isolated, as a yellow solid in 46% yield (92 % purity by HPLC). 5 MS(ESI*): 300.7; MS(ESI-): 298.4. Intermediate 15: (2-chloro-5-methylpyrimidin-4-yl)(1,3-diethyl-2,3-dihydro-1H benzimidazol-2-yl)acetonitrile (cf. Scheme 5, compound II) / N N N N C Following the general method A as outlined in Intermediate 6, starting from (1,3 -diethyl 10 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(ESI*): 342.9; MS(ESI): 340.8. Intermediate 17: (2-chloropyrimidin-4-y)(l -propyl-2,3 -dihydro- 1 -benzimidazol-2 yl)acetonitrile 15 (cf. Scheme 5, compound II) WO 2005/026155 PCT/EP2004/052137 - 47 QI N N H N -N CI. Following the general method A as outlined in Intermediate 6, starting from from (1 propyl-2,3 -dihydro-H If-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 s by HPLC). MS(ESI'): 314.8; MS(ESI~): 312.6. Intermediate 18: (2-chloropyrimidin-4-y)(1 -cyclobutyl-2.3 -dihydro- 1H -benimidazol-2 yl)acetonitrile (cf. Scheme 5, compound II) N N

-

/ H

N

1 1 >-N 10 CI Following the general method A as outlined in Intermediate 6, starting from from (1 cyclobutyl-2,3 -dihydro-1H-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 IPLC). 15 MS(ESI): 326.9; MS(ESI): 324.8.

WO 2005/026155 PCT/EP2004/052137 -48 Intermediate 19: (2Z)-(2-amino-5-methylpyrimidin-4-yl)(1-ethyl-1.,3-dihydro-2H benzimidazol-2-ylidene)acetonitrile (cf. Scheme 9, compound II') /I N ON H

N

1 --N

H

2 N To a solution of (2-chloro-5-methylpyrimidin-4-yl)(1-ethyl-2,3-dihydro-1H-benzimidazol 5 2-yl)acetonitrile (Intermediate 6, 1.5g, 5.05mmol) in iPrOH (2mL), were added ammonium hydroxide (3.14mL, 81.59mmol, l6eq) 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 of the reaction, the reaction mixture was cooled down to room temperature and the yellow precipitate was filtered off, washed with water and dried under vacuum 10 overnight to give the expected compound (2Z)-(2-amino-5-methylpyrimidin-4-yl)(1 -ethyl 1,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile as a yellow solid (1.41mg, 82% yield, 95% HPLC purity) (2Z)-(2-amino-5-methylpyrimidin-4-yl)(1 -ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)acetonitrile: 1H NMR (300MHz, CDC13); 1.55 (t, J = 7.4Hz, 3H), 4.6 (q, J 15 7.4Hz, 2H), 2.4 (s, 3H), 7.2-7.5 (m, 4H), 8.2 (d, J = 7.0Hz, 1HT), 14.1 (s(broad), 111). MS(ESI ): 293.5; MS(ESI): 291.4. Intermediate 20: (2Z)-(2-amino-pyrimidin-4-v1)(1 -ethyl- 1,3 -dihydro-211-benzimidazol-2 ylidene)acetonitrile (cf. Scheme 9, compound II') WO 2005/026155 PCT/EP2004/052137 -49 N N H N >-- N

H

2 N Following the general method as outlined in Intermediate 19, starting from (2 chloropyrimidin-4-yl)(1-ethyl-2,3-dihydro-1H-benzimidazol-2-y1)acetonitrile (Intermediate 7) and ammonium hydroxide, the title compound was isolated, as a yellow solid in 75% 5 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 10 6): (2Z)-(l -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)(2-{ [3-(1 H-pyrazol-1 yl)propyl]amino}pyrimidin-4-yl)acetonitrile CN N ,, N N _ N NH/\ N Method C: To a solution of (2-chloropyrimidin-4-yl)(1-ethyl-2,3-dihydro-1H-benzimidazol-2 15 yl)acetonitrile (intermediate 7) (150mg, 0.5mmol, leq) in 4mL of DMA:iPrOH (1:3)) was added DIEA (0.345mL, 2.Ommol, 4eq), 3-(1H-pyrazol- I -yl)propan- 1-amine hydrochloride (325mg, 2.Ommol, 4eq) and Nal (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 WO 2005/026155 PCT/EP2004/052137 - 50 and the residue redissolved in 3mL of DCM. This solution was loaded onto a lOg SCX SPE syringe (0.4mmol.g') and eluted with DCM, then DCM:MeOH (1:1), 0. 1M NH 3 in MeOH and IM 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 5 residue redissolved in DCM and washed with NaHCO3 sat. and brine. The organic layer was dried over MgSO 4 , 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). 10 MethodD: 10 mg of Building Blocks were dissolved in 0.3 mL of DMA. Et 3 N (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 15 reaction mixtures were then transferred into a 2 mL plate and the solvent was removed in the Genevac. Work up: 1 mL of water/CH 3 COOH (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 20 was collected using the Lissy. Analytical plates were made and the solvents were removed in the Genevac. (2Z)-( 1-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)(2- {[3-(1H-pyrazol-1 yl)propylamino}pyrimidin-4-yl)acetonitrile: yellow solid; 1H NMR (300 MHz, CDC 3 ); 1.5 (t, 3H), 2.6-2.8 (m, 2H), 3.5-3.7 (m, 2H), 4.4-4.6 (m, 2H1), 4.7-4.85 (q, 211), 6.8-6.9 (m, 25 1H), 7.4-7.7 (in, 3H), 7.75 (in, 1H), 7.85 (in, 1H), 10.1 (in, 11). MS (ESI+) 387.5, (ESI-) 385.6.

WO 2005/026155 PCT/EP2004/052137 - 51 Example 2: (2Z)-(1-ethyl-1.3-dihydro-2H-benzimidazo1-2-ylidene)(5-methyl-2-{[3-(1H pyrazol-1-yl)propyl]anino}pyrimidin-4-yl)acetonitrile N N,, NH\ N Following the general methods as outlined in Example 1 (Method C), starting from (2 5 chloro-5-methylpyrimidin-4-yl)(1-ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (intermediate 6), and 3 -(1 H-pyrazol-l -yl)propan-1 -amine hydrochloride, the title compound was isolated, as a yellow solid in 82% yield (99% purity by HPLC). MS(ESI): 401.5; MS(ESI~): 399.2. Example 3: (2Z)-r2-(cclobutylamino)-5-methylpyrimidin-4-yl](l-ethyl-L,3-dihydro-2H 10 benzimidazol-2-ylidene acetonitrile CN H N N >,N _NHN /\NH ,N Following the general methods as outlined in Example 1 (Method C), starting from (2 chloro-5-methylpyrimidin-4-y)(1 -ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (intermediate 6), and cyclobutylamine, the title compound was isolated, as a yellow solid in 15 78% yield (99% purity by IPLC). 114 NM (300 MHz, CDCl 3 ); 1.5 (t, 311), 1.8-2.45 (m, 6H), 2.3 (s, 31), 4.1-4.3 (m, 1H), 4.5-4.65 (q, 211), 7.4-7.65 (m, 3H), 7.75-7.85 (m, 1H), 9.55 (m, 1HI). MS(ESI): 347.6; MS(ESI~): 345.3.

WO 2005/026155 PCT/EP2004/052137 -52 Example 4: (2Z)-(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)(5-iLethyl-2--1[3-(2 oxopyrrolidin-1-yl)propyllanino}pyrimidin-4-yl)acetonitrile CN H N N N A N / NH N 0 Following the general methods as outlined in Example 1 (Method C), starting from (2 5 chloro-5-methylpyrimidin-4-yl)(1 -ethyl-2,3-dihydro- 1H-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). 1 14 NMR (300 M-Hz, CDCl 3 ); 1.5 (t, 311), 1.75-1.95 (m, 4H), 2.1-2.25 (m, 211), 2.29 (s, 311), 3.3-3.45 (m, 61), 4.4-4.6 (q, 21-), 7.2-7.3 (m, 11-), 7.4-7.65 (m, 311), 7.75-7.85 (m, 11-), 8.3 10 (m, 1H). MS(ESI 4 ): 418.6; MS(ESIT-): 416.8. Example 5: (2Z)-(1-ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[3-(2-oxopyrrolidin 1-y1)propyllamino}pyrimidin-4-yl)acetonitrile CN H N , N N N /\ NH N O Following the general methods as outlined in Example 1 (Method C), starting from (2 15 chloropyrimidin-4-yl)(1-ethyl-2,3-dihydro-1-1-benzimidazol-2-yl)acetonitrile (intermediate 7), and N-(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(ESI): 402.8.

WO 2005/026155 PCT/EP2004/052137 - 53 Example 6: (2Z)-(l-ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[3-(11-1,2,4-triazol I-yl)propy1]amino}pyrimidin-4-yl)acetonitrile CN H N N N N NgN /\NH N Following the general methods as outlined in Example I (Method C), starting from (2 5 chloropyrimidin-4-yl)(1-ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (intermediate 7), and 3-(1T-1,2,4-triazol-1-yl)propan-1-amine hydrochloride, the title compound was isolated, as a yellow solid in 72% yield (98% purity by HPLC). MS(ESI): 388.7; MS(ESI-): 386.5. Example 7: (2Z)-(1-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)(5-methyl-2-{ [3-(1H 10 1,2,4-triazol-1-y)propyllamino}pyrimidin-4-yl)acetonitrile CN H==\ ONN N N N , N NH -N Following the general methods as outlined in Example 1 (Method C), starting from (2 chloro-5-methylpyrimidin-4-yl)(1-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 3-(1H-1,2,4-triazol-1-yl)propan-l-amine hydrochloride, the title 15 compound was isolated, as a yellow solid in 78% yield (98% purity by HPLC). 1 H NMR (300 MIz, CDC1 3 ); 1.55 (t, 3H), 2.2-2.35 (m, 211), 2.4 (s, 311), 3.4-3.6 (m, 2H), 4.3-4.45 (m, 211), 4.6-4.75 (q, 2H), 7.2-7.3 (m, 1H), 7.4-7.65 (m, 31), 7.75-7.85 (m, 1), 7.9 (s,lH), 8.3 (m, IH), 9.8 (s, 1H). MS(ESI 4 ): 402.6; MS(ESI-): 400.2. Example 8: [2-(cyclopentylanino)-5-methylpyrimidin-4-yll -ethyl-1H-benzimidazol-2 20 yl)acetonitrile WO 2005/026155 PCT/EP2004/052137 - 54 GCN H NH /\NH ,N L Following the general methods as outlined in Example 1 (Method C), starting from (2 chloro-5-methylpyrimidin-4-y1)(1 -ethyl-2,3-dihydro-1I-benzimidazol-2-yl)acetonitrile (intermediate 6), and cyclopentylamine, the title compound was isolated, as a yellow solid 5 in 69% yield (99% purity by HPLC). MS(ESI): 361.4; MS(ESI~): 359.5. Example 9: (2Z)-(2-jf3-(2-oxopyrrolidin-1-yl)Tropvllaminolpyrimidin-4-yl)(1-propyl-1.3 dihydro-2fH-benzimidazol-2-ylidene)acetonitrile CN N NN N NH -N 10 Following the general methods as outlined in Example 1 (Method C), starting (2 chloropyrimidin-4-y)(1 -propyl-2,3-dihydro- I H-benzimidazol-2-yl)acetonitrile (intermediate 17), and N-( 3 '-aminopropyl)-2-pyrrolidinone, the title compound was isolated, as a yellow solid in 79% yield (99% purity by HPLC). MS(ESI*): 418.6; MS(ESI): 416.5. 15 Example 10: (1-ethyl-1H-benzimidazol-2-v1){5-methyl-2-[(2-pyridin-3-ylethyl)amino] pyrimidin-4-yl}acetonitrile WO 2005/026155 PCT/EP2004/052137 - 55 ~CN NH Following the general methods as outlined in Example 1 (Method C), starting from (2 chloro-5-methylpyrimidin-4-yl)(1 -ethyl-2,3-dihydro-1T-benzimidazol-2-yl)acetonitrile (intermediate 6), and 3 -(2-aminoethyl)pyridine, the title compound was isolated, as a 5 yellow solid in 69% yield (96% purity by HPLC). MS(ESI*): 398.6; MS(ESI-): 396.4. Example 11: (2Z)-[2-(cyclobutylamino)pyrimidin-4-yll(1 -ethyl-13-dihydro-2H benzimidazol-2-ylidene)acetonitrile CN H N N /\ H ,-N 10 Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin 4-yl)(1-ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (intermediate 7), and cyclobutylamine, the title compound was isolated, as a yellow solid in 80% yield (97% purity by HfPLC). MS(ESI): 333.2; MS(ESI): 331.6. 15 Example 12: (2Z)-[2-(cycloheptylamino)-5-methylpyrimidin-4-yll(1-ethyl-1,3-dihydro-2H benzimidazol-2-ylidene)acetonitrile

-

CN H N N /NH, N - WO 2005/026155 PCT/EP2004/052137 - 56 Following the general methods as outlined in Example 1 (Method C), starting from (2 chloro-5-methylpyrimidin-4-yl)(1-ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (intermediate 6), and cycloheptylamine, the title compound was isolated, as a yellow solid in 71% yield (97% purity by HPLC). 5 MS(ESI): 389.8; MS(ESI): 387.6. Example 13: [2-(cyclopentylamino)pyrimidin-4-yll(1 -ethyl- 1H-benzimidazol-2 yl)acetonitrile CN H N N /NH .,NL Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin 10 4-yl)(1-ethyl-2,3-dihydro-1H-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 (EST+) 347.6, (ESI-) 345.8. Example 14: 1,3-dihydro-2H-benzimidazol-2-ylidene(5-mctbyl-2-{[3-(2-oxopyrrohidin-1 15 yl)propllaminohpyrimidin-4-y)acetonitrile HCN H / N NN NH IN O Following the general methods as outlined in Example 1 (Method C) (2-chloro-5 methylpyrimidin-4-yl)(2,3-dihydro-1H-benzimidazol-2-y)acetonitrile (intermediate 8), and WO 2005/026155 PCT/EP2004/052137 - 57 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)-(1-cyclobutyl-1,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[3-(2 5 oxopyrrolidin-l-yllpopylplamino}pyrimidin-4-yl)acetonitrile CN H N N N NH N 0 Following the general methods as outlined in Example 1 (Method C), starting from (2 chloropyrimidin-4-yl)(l -cyclobutyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (intermediate 18), and N-(3'-aminopropyl)-2-pyrrolidinone, the title compound was 10 isolated, as a yellow solid in 77% yield (98% purity by HPLC). MS(ESr): 430.6; MS(ESI): 428.7. Example 16: (1-ethvl-1H-benzimidazol-2-vl){2-[(2-pyridin-3-ylethyl)aminogpyrimidin-4 yl}acetonitrile NCNN N , ,;,. N N _ N -NH -,N 15 Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin 4-yl)(1-ethyl-2,3-dihydro-1H-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 TPLC).

WO 2005/026155 PCT/EP2004/052137 -58 MS(ESI'): 384.4; MS(ESI): 382.6. Example 17: (2Z)-(1-ethyl- 1,3-dihydro-2H-benzimidazol-2-ylidene)[2-(isobutylamino)-5 methylpyrimidin-4-ylacetonitrile --) N H N NyN NH -N 5 Following the general methods as outlined in Example 1 (Method D), starting from (2 chloro-5-methylpyrimidin-4-y)(1 -ethyl-2,3-dihydro- 1H-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(ESI): 347.5. 10 Example 18: (2Z)-(1 -ethv1-1,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[2-(1 H-imidazol-4 vl)ethyllamino}pyrimidin-4-y)acetonitrile CGN H N T:). N>N N NH Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin 4-yl)(1-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 7), and 15 histamine base, the title compound was isolated, as a yellow solid in 65% yield (95% purity by HPLC). MS(ESI*): 373.3; MS(ESI): 371.2. Example 19: (2Z)-(1-ethyl-1,3-dihydro-2H-benzimidazol-2-vlidene)[2 (isobutylamino)pyrimidin-4-yllacetonitrile WO 2005/026155 PCT/EP2004/052137 -59 N N, NN NH N Following the general methods as outlined in Example 1 (Method C), (2-chioropyrimidin 4-yl)(1-ethyl-2,3-dihydro-1H-benzimidazol-2-y)acetlonitrile (intermediate 7), and isobutylamine, the title compound was isolated, as a yellow solid in 74% yield (99% purity 5 by HPLC). MS(ESI): 335.4; MS(ESI-): 333.6. Example 20: [2-(cycloprpylamino)pyrimidin-4-yl](1-ethyl-lH-benzimidazol-2-yl) cetonitrile ~CN H N * - I'7 H -NH -N 10 Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin 4-yl)(1 -ethyl -2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (intermediate 7), and cyclopropylamine, the title compound was isolated, as a yellow solid in 70% yield (98% purity by HPLC). 15 MS(ESI*): 319.4; MS(ESI): 317.3. Example 21: [2-({2- [6-(dimethylamino pridin-3-vlethv1 amino)pyrimidin-4-yll(l -ethyl 1H-benzimidazol-2-yl)acetonitrile WO 2005/026155 PCT/EP2004/052137 -60 CN H N N N / \ NH NH N -N N Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin 4-yl)(1-ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitr1le (intermediate 7), and 2-(N,N dimethylamino)-5-aminoethylpyridine, the title compound was isolated, as a yellow solid in 5 78% yield (96% purity by HPLC). MS(ESI): 427.5; MS(ESI): 425.6. Example 22: (1-ethyl-1 H-benzimidazol-2-vl)(2-{[2-(1H-1.2,4-triazol- 1 -yl)ethyllamino} pyrimidin-4-yl)acetonitrile --- I H N N N NH N N 10 Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin 4-yl)(1 -ethyl-2,3 -dihydro-l1H-benzimidazol-2-yl)acetonitrile (intermediate 7), and 2-(1H 1,2,4-triazole-1 -YL)ethanamine hydrochloride, the title compound was isolated, as a yellow solid in 75% yield (99% purity by HPLC). MS(ESI'): 374.6; MS(ESI~): 373.5 15 Example 23: (2Z)-(1-ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)(2-{[2-(1H-imidazol-4 yl)ethyllamino}-5-methlpyrimidin-4-y1)acetonitrile WO 2005/026155 PCT/EP2004/052137 -61 N -,N<N N / HNH -N N H Following the general methods as outlined in Example 1 (Method D), starting from (2 chloro-5-methylpyrimidin-4-yl)(1-ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (intermediate 6), and histamine base, the title compound was isolated, as a yellow solid in 5 69% yield (93% purity by HTPLC). MS(ESI+): 387.4; MS(ESI): 385.6. Example 24: f2-({2-[6-(dimethylamino)pyridin-3-v11ethylhamino)-5-methylpyrimidin-4 yl](1 -ethyl-1 H-benzimidazol-2-yl)acetonitrile CN H N - N N NH NN N 10 Following the general methods as outlined in Example 1 (Method C), starting from (2 chloro-5-methylpyrimidin-4-y)(1 -ethyl-2,3-dihydro- 1 H-benzimidazol-2-yl)acetonitrile (intermediate 6), and 2-(NN-dimethylamino)-5-aminoethylpyridine, the title compound was isolated, as a yellow solid in 68% yield (97% purity by HPLC). MS(ESI-): 441.3; MS(ESI~): 439.5. 15 Example 25: (2Z)-F2-(cycloheptylamino)pyrimidin-4-y1]( -ethyl-1 3-dihydro-2H benzimidazol-2-ylidenelacetonitrile WO 2005/026155 PCT/EP2004/052137 -62 CN H 'NN Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin 4-yXl-ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (intermediate 7), and cycloheptylamine, the title compound was isolated, as a yellow solid in 76% yield (98% 5 purity by HPLC). MS(ESI*): 375.7; MS(ESI): 373.2. Example 26: F 2 -(cycloproplamino-5-methylprimidin-4-y(1-ethyl-1H1-benzimidazol-2 yl)acetonitrile CN H / H NN 10 Following the general methods as outlined in Example 1 (Method D), starting from (2 chloro-5-methylpyrimidin-4-yl)(1 -ethyl-2,3-dihydro-1H-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(ESI-): 331.3. 15 Example 27: (1-ethyl- 1H-benzimidazol-2-vl){ 2

-[(

2 -pyridin-2-ylethyl)aminolpyrimidin-4 v1}acetonitrile WO 2005/026155 PCT/EP2004/052137 -63 ON H NN N N, / NH ., N Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin 4-yl)(1-ethyl-2,3-dihydro-1I-benzimidazol-2-yl)acetonitrile (intermediate 7), and 2-(2 aminoethyl)pyridine, the title compound was isolated, as a yellow solid in 80% yield (94% 5 purity by HPLC). MS(ESI*): 384.8; MS(ESI-): 382.2. Example 28: [2-(cyclopentylamino)-5-methylpyrimidin-4-yl](1,3-dihydro-2H benzimidazol-2-ylidenelacetonitrile ON N N_ NyN> / NH ~N 10 Following the general methods as outlined in Example 1 (Method C), (2-chloro-5 methylpyrimidin-4-yl)(2,3-dihydro-11H-benzimidazol-2-yl)acetonitrile (intermediate 8), and cyclopentylamine, the title compound was isolated, as a yellow solid in 80% yield (77% purity by HPLC). MS(ESI*): 333.3; MS(ESI~): 331.2. 15 Example 29: [2-(cyclohexylamino)pyrimidin-4-yll(1-ethyl-1H-benzimidazol-2 yl)acetonitrile WO 2005/026155 PCT/EP2004/052137 -64 CN H NN /\NH ,-N Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin 4-yl)(1-ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (intermediate 7), and cyclohexylamine, the title compound was isolated, as a yellow solid in 70% yield (97% 5 purity by HPLC). MS(ESI*): 361.2; MS(ESI-): 359.4. Example 30: (2Z)-(1-ethvl-1.3-dihydro-21-benzimidazol-2-ylidene)(2-([2-(1H-indol-3 y l)ethyllamino}-5-methylpyrimidin-4-yl)acetonitrile CN H NN H 10 Following the general methods as outlined in Example 1 (Method C), starting from (2 chloro-5-methylpyrimidin-4-yl)(1 -ethyl-2,3-dihydro-1H-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(ESI*): 436.5; MS(ESI-): 434.6. 15 Example 31: (1 -ethyl-1H-benzimidazol-2-y1){5-methyl-2-[(2-pyridin-2 ylethyl)aminolpyrimidin-4-yllacetonitrile WO 2005/026155 PCT/EP2004/052137 - 65 CN H /\N HT - NN N Following the general methods as outlined in Example 1 (Method C), starting from (2 chloro-5-methylpyrimidin-4-y)(1-ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (intermediate 6), and 2-(2-aminoethyl)pyridine), the title compound was isolated, as a 5 yellow solid in 77% yield (98% purity by HPLC). MS(ESI*): 398.6; MS(ESI-): 396.4. Example 32: {2-[(2-ethoxyethyL)aminolpyrimidin-4-y1}(1-ethyl-T1--benzimidazol-2 yl)acetonitrile CN H N N 10 Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin 4-yl)(1 -ethyl-2,3-dihydro- 1H-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). 15 MS(ESI+): 351.7; MS(ESI): 349.6. Example 33: (1-ethyl-1HI-benzimidazol-2-yl){5-methyl-2-[(1 methylbutyl)amino]pyrimidin-4-y1lacetonitrile WO 2005/026155 PCT/EP2004/052137 - 66 CN H N /\NH .. N Following the general methods as outlined in Example 1 (Method D), starting from (2 chloro-5-methylpyrimidin-4-yl)(1 -ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and (+/-)-2-aminopentane, the title compound was isolated, as a yellow 5 solid in 70% yield (92% purity by HPLC). MS(ESI*): 363.5; MS(ESI~): 361.8. Example 34: (1-ethyl-IH-benzimidazol-2-y1)[2-(methylamino)pyrimidin-4-yllacetonitrile ON H N N N, -NH N Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin 10 4-yl)(1-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(ESI~): 291.6 Example 35: (1-ethyl- 1H-benzimidazol-2-yl)(5-methyl-2-{[2-(1H-pyrazol-l 15 yl)ethyllamino}pyrmidin-4-y)acetonitrile CN H N N / NH -N WO 2005/026155 PCT/EP2004/052137 - 67 Following the general methods as outlined in Example 1 (Method D), starting from (2 chloro-5-methylpyrimidin-4-y)(1-ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (intermediate 6), and 1-(2'-amninoethyl)pyrazole), the title compound was isolated, as a yellow solid in 74% yield (97% purity by HPLC). 5 MS(ESI): 387.6; MS(ESI): 385.2. Example 36: 1H-benzimidazol-2-vl{5-methy-2-4(2-pyridin-3-ylethv1)amino pyrimidin-4 yl}acetonitrile CN H N T - N~ NH -N Following the general methods as outlined in Example 1 (Method C), (2-chloro-5 10 methylpyrimidin-4-yl)(2,3-dihydro-1H-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-ylidene)(2-{F2-(lH-imidazol-l 15 yl)ethyllaino} -5-methylpyrimidin-4-y)acetonitrile CN H NN N /\ NH .NIN Following the general methods as outlined in Example 1 (Method C), starting from (2 chloro-5-methylpyrimidin-4-yl)(1 -ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile WO 2005/026155 PCT/EP2004/052137 - 68 (intermediate 6), and 2-(imidazol-1 -yl)-ethylamine, the title compound was isolated, as a yellow solid in 60% yield (97% purity by IIPLC). MS(ESI+): 387.2; MS(ESI): 385.4. Example 38: 1H-benzimidazol-2-y1{2-[(2-pyidin-3-ylethylamino]pyrimidin-4 5 ylacetonitrile CN H CN H N -rN NN / NH -N N Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin 4-yl)(2,3-dihydro-1 H-benzimidazol-2-yl)acetonitrile (intermediate 9), and 3 -(2 aminoethyl)pyridine, the title compound was isolated, as a yellow solid in 73% yield (98% 10 purity by HPLC). MS(ESI ): 356.2; MS(ESI): 354.3. Example 39: (1 -ethyl-1H-benzimidazol-2-vl) {2-[(1 -methylbutyl)aminolpyrimidin-4 yl acetonitrile CN H N N /NH ~.N 15 Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin 4-yl)(1-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 IHPLC).

WO 2005/026155 PCT/EP2004/052137 - 69 MS(ESI'): 349.4; MS(ESI~): 347.2. Example 40: {2-[(cyclohexylmethvl)aminol -5-methylpyrimidin-4-y1}(1-ethyl-1H benzimidazol-2-yl)acetonitrile ~GN H 5 Following the general methods as outlined in Example 1 (Method C), starting from (2 chloro-5-methylpyrimidin-4-yl)(1 -ethyl-2,3-dihydro- 1H-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. 10 Example 41: 1H-benzimidazo-2-yl[2-(cyclopentylamino)pyrimidin-4-yllacetonitrile H N H N .N,.N /NH YN Following the general methods as outlined in Example 1 (Method C), (2-chloropyrimidin 4-yl)(2,3-dihydro-i1H-benzimidazol-2-yl)acetonitrile (intermediate 9), and cyclopentyamine, the title compound was isolated, as a yellow solid in 74% yield (96% 15 purity by HPLC). MS(ESI ): 319.4; MS(ESI-): 317.3. Example 42: (1-ethyl-1H-benzimidazol-2-y){6-methyl-2-[(2-pyridin-3 ylethyl)aminolpyrimidin-4-y1}acetonitrile WO 2005/026155 PCT/EP2004/052137 - 70 CN H N f I N N N / \NH .- N j Following the general methods as outlined in Example 1 (Method D), (2-chloro-6 methylpyrinidin-4-yl)(1 -ethyl-2,3 -dihydro- 1H-benzimidazol-2-yl)acetonitrile (intermediate 10), and 3-(2-aminoethyl)pyridine, the title compound was isolated, as a yellow solid in 5 72% yield (97% purity by HPLC). MS(ESI*): 398.5; MS(ESI-): 396.4. Example 43: lH-benzimidazo-2-ylr2-(cyclopopylamino)pyrimidii4-v1]acetonitrile CN H HT ' N N N. Following the general methods as outlined in Example I (Method D), (2-chloropyrimidin 10 4-yl)(2,3-dihydro-1H-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(ESIi: 291.4; MS(ESI-): 289.4. Example 44: [2-(cyclopentvlamino)-6-methvlpyrimidin-4-yl(1 -ethyl-1H-benzimidazol-2 15 yl)acetonitrile CN H N NyN NH N K/ WO 2005/026155 PCT/EP2004/052137 - 71 Following the general methods as outlined in Example 1 (Method D), (2-chloro-6 methylpyrimidin-4-yl)(1-ethyl-2,3-dihydro-1H-benzimidazol-2-y)acetonitrile (intermediate 10), and cyclopentylamine, the title compound was isolated, as a yellow solid in 72% yield (98% purity by HPLC). 5 MS(ESI*): 361.6; MS(ESI-): 359.5. Example 45: {2-I(cyclohexylmethyl)aminolpyrimidin-4-v1}(1-ethvl-1H-benzimidazol-2 yl)acetonitrile H /\NH -N Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin 10 4-yL)(1 -ethyl-2,3-dihydro-1H-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(ESI*): 375.2; MS(EST): 373.2. Example 46: (1 -ethyl-1 H-benzimidazol-2-yl){6-[(2-pyridin-3-ylethv1)amino]pyrimidin- 4 15 v1}acetonitrile CN H N N /\ NH N.N N Following the general methods as outlined in Example 1 (Method D), starting from (6 chloropyrimidin-4-yl)(1-ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (intermediate WO 2005/026155 PCT/EP2004/052137 -72 11), and 3

-(

2 -aminoethyl)pyridine, the title compound was isolated, as a yellow solid in 72% yield (88% purity by IPLC). MS(ESI*): 384.6; MS(ESI): 382.4. Example 47: (1-ethyl-1H-benzimidazo1-2-1)(2-[(3-pyrrolidin-1-vlpropy11aminol 5 pyrimidin-4-yl}acetonitrile C' H CN N Following the general methods as outlined in Example 1 (Method D), (2-chloropyrimidin 4 -yl)(1-ethyl-2,3-dihydro-lH-benzimidazo-2-y1)acetonitrile (intermediate 7), and 1-amino 3-(N-piperidino)propane, the title compound was isolated, as a yellow solid in 74% yield 10 (94% purity by HPLC). MS(ESI*): 390.4; MS(EST): 388.2. Example 48: (1-ethyl-iH-benzinidazol-2-vl)2-(4-ethypiperazin-1-v1)-5-methylpyrimidin 4-v1]acetonitrile CN /N NJ NH N 15 Following the general methods as outlined in Example I (Method D), starting from (2 chloro-5-methylpyrinidin-4-y1)(1-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and I -ethylpiperazine, the title compound was isolated, as a yellow solid in 76% yield (99% purity by HPLC).

WO 2005/026155 PCT/EP2004/052137 - 73 MS(ESI'): 390.5; MS(ESI): 388.4. Example 49: (1 -ethyl-iH-benzimidazol-2-y1){2-f(2-furylmethyamiol-5 methvlpyrimidin-4-yl} acetonitrile CN H N -7 _N N -'0 5 Following the general methods as outlined in Example 1 (Method D), starting from (2 chloro-5-methylpyrimiidin-4-y)(1 -ethyl -2,3-dihydro-1 H-benzimidazol-2-yl)acetonitrile (intermediate 6), and furfurylamine, the title compound was isolated, as a yellow solid in 71% yield (92% purity by RPLC). MS(ESI*): 373.3; MS(ESF): 371.5. 10 Example 50: (2Z)-(1-ethyl-1.3-dihydro-2H-benzimidazol-2-vlidene){5-methvl-2-[(1 methylpiperidin-4-Vl)amino]pyrimidin-4-yl}acetonitrile CN /\NH .N N Following the general methods as outlined in Example 1 (Method D), starting from (2 chloro-5-methylpyrimidin-4-y)(1 -ethyl-2,3-dihydro- I H-benzimidazol-2-yl)acetonitrile 15 (intermediate 6), and 4-amino-1-methyl-piperidine, the title compound was isolated, as a yellow solid in 79% yield (98% purity by HPLC). MS(ESI*): 390.2; MS(ESI-): 388.3. Example 51: (2Z)-[ 2 -(cyclohexylamino-5-methlpyrimidin-4-1](1 -ethyl- 3-dihydro-2H benzimidazol-2-ylidenelacetonitrile WO 2005/026155 PCT/EP2004/052137 - 74 m CN N N /\NH I Following the general methods as outlined in Example 1 (Method C), starting from (2 chloro-5-methylpyrinidin-4-yl)(1-ethyl-2,3-dihydro-1lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and cyclohexylamine, the title compound was isolated, as a yellow solid 5 in 74% yield (97% purity by HPLC). MS(ESI*): 375.8; MS(EST): 373.2. Example 52: (2Z)-[2-(ethylamino)-5-methylpyrimidin-4-vI(1-ethyl-1,3-dihydro-2H benzimidazol-2-ylidene)acetonitrile CN H N N N NH ,N 10 Following the general methods as outlined in Example 1 (Method D), starting from (2 chloro-5-methylpyrimidin-4-yl)(1 -ethyl-2,3-dihydro-1H-benzimidazol-2-yl)acetonitrile (intermediate 6), and ethylamine, the title compound was isolated, as a yellow solid in 76% yield (99% purity by TPLC). MS(ESI*): 321.2; MS(ESI): 319.3. 15 Example 53: [2-(cyclopentylamino)-5-methylpyrimidin-4-vll(1,3-diethyl-1.3-dihydro-2H benzimidazol-2-ylidene)acetonitrile H /\ N -7_N WO 2005/026155 PCT/EP2004/052137 - 75 Following the general methods as outlined in Example 1 (Method D), starting from (2 chloro-5-methylpyrimidin-4-yl)(1,3-diethyl-2,3-dihydro-IH-benzimidazol-2-yl)acetonitrile (intermediate 15), and cyclopentylamine, the title compound was isolated, as a yellow solid 5 in 80% yield (97% purity by HPLC). MS(ESI'): 389.2; MS(ESI~): 387.3. Example 54: (2Z)-(1-ethyl-1.,3-dihydro-2H-benzimidazol-2-vlidene)[5-methl-2-pipeiin 4-ylamino)pyrimidin-4-yl]acetonitrile CN H /NH K-N N 10 N Following the general methods as outlined in Example 1 (Method D), starting from (2 chloro-5-methylpyrimidin-4-yl)(1-ethyl-2,3-dihydro-lH-benzimidazol-2-yl)acetonitrile (intermediate 6), and 4-amino-I-piperidine, the title compound was isolated, as a yellow 15 solid in 70% yield (97% purity by HPLC). MS(ESI): 376.2; MS(ESI): 374.3. Example 55: (2Z)-(1-ethyl-1,3-dihydro-2H-benzimidazol-2-vlidene){5-methyl-2-[(2 piperidin-1 -vlethvl)aminolpyrimidin-4-yl acetonitrile CN 0NHN 20

-~

WO 2005/026155 PCT/EP2004/052137 -76 Following the general methods as outlined in Example 1 (Method D), starting from (2 chloro-5-methylpyrimidin-4-yl)(1 -ethyl-2,3-dihydro-1H-benzimidazol-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). 5 MS(ESI'): 418.6; MS(ESI~): 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-butyl (4S)-4-[({4-[(Z)-cyano(1-ethyl-1.3-dihydro-2H1-benzimidazol-2-ylidene)methyl] 5-methylpyrimidin-2-yl}amino)carbonyll-1.3-thiazolidine-3-carboxylate H N N S N 0 100 To a solution of (2Z)-(2-amino-pyrimidin-4-yl)(1 -ethyl-1,3-dihydro-21-benzimidazol-2 ylidene)acetonitrile (intermediate 20) (300mg, 1.08mmol, I eq) 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 (371tL, 2.16mmol, 2eg). The 15 reaction mixture was stirred at room temperature for 6days. The reaction mixture was diluted with DCM (50mL), washed with NH4C1, NaHCO3 and brine and dried over MgSO 4 . The solvent was removed by evporation and the residue purified by FC using a gradient AcOEt:CycloH (4:6) to neat AcOEt then to AcOEt:MeOH (7:3) for Ihour. The expected product tert-butyl (4S)-4-[({4-[(Z)-cyano(1-ethyl-1,3-dihydro-2H-benzimidazol 20 2-ylidene)methyl]-5-methylpyrinidin-2-yl} amino)carbonyl]-1,3-thiazolidine-3-carboxylate was isolated as a yellow solid (292mg, 55% yield, 99% HIPLC purity WO 2005/026155 PCT/EP2004/052137 - 77 MS (ESI+) 494.5, (ESI-) 492.3. Example 57: (4S)-N-{4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)methyl-pyrimidin-2-yl}-1,3-thiazolidine-4-carboxamide N S NH 5 To a solution of tert-butyl (4S)-4-[({4-[I(Z)-cyano(1 -ethyl-1,3-dihydro-2H1-benzimidazol-2 ylidene)methyl]-5-methylpyrimidin-2-y1} amino)carbonyl]-1I,3-thiazolidine-3-carboxylate (292mg, 0.591lmmol) was added at zero degree a solution of 10%TFA in DCM (10OmL) and the reaction mixture was stirred for 1 h. The solvent was evaporated and the expected product (4S)-N-{4-[(Z)-cyano(1 -ethyl-i1,3-dihydro-2H-benzimidazol-2-ylidene)methyl] 10 pyrimidin-2-yl}-1,3-thiazolidine-4-carboxamhide was isolated as a yellow solid (252mg, 98% yield, 99% HIPLC purity) MS(ESI*): 394.5; .MS(ES[ ): 392.2. Example 58: N- {4-[(Zl-evano(1 -ethyl-1,.3-dihydro-2HI-benzimidazo1-2-vlidene~methyll-5 methylpyrimidin-2-v1} -4-(4-methvlpiperazin-1 -v1)-4-oxobutanamide N H 0 N N N N H 150 WO 2005/026155 PCT/EP2004/052137 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-y)(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 4-(4-methyl-piperazin-1-y)-4-oxo-butyric acid, the title compound was isolated, as a yellow solid in 65% yield (99% purity by IHPLC). 5 MS(ESI'): 475.6; MS(ESI): 473.6. Example 59: N-(4-[(Z)-cyano(1-ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyll pyrimidin-2-y1}-4-(4-methylvpiperazin-1-yl)-4-oxobutanamide N N N H N N 0 Following the general method as outlined in Example 56, starting (2Z)-(2-amino 10 pyrimidin-4-yl)(1-ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (intermediate 20), and 4-(4-methyl-piperazin-1 -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(ESI): 459.2. Example 60: (1R,5R.7R)-N- {4-[(Z)-cyano(l -ethyl-1,3-dihydro-2H-benzimidazol-2 15 ylidene)methyl-5-methylpyrimidin-2-1} -6,8-dioxa-3-azabicyclo[3.2. 1]octane-7 carboxamide WO 2005/026155 PCT/EP2004/052137 - 79 N H N" HN 0 N H Following the general methods as outlined in Examples 56 and 57, starting from (2Z)-(2 amino-5-methylpyrimidin-4-yl)(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene) acetonitrile (Intermediate 19), and Boc-7-endo-BTG-OH, the title compound was isolated, 5 as a yellow solid in 71% yield (98% purity by HPLC). MS(ESI): 434.5; MS(ESI): 432.3. Example 61: (1S,5S.7S)-N-{4-[(Z)-cyano(1-ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)methv11-5-methylpyrimidin-2-yl}-6,8-dioxa-3-azabicyclo[3.2.1]octane-7 carboxamide N N HN to N 10 H Following the general methods as outlined in Example 56 and 57, starting from (2Z)-(2 amino-5-methylpyrimidin-4-yl)(1 -ethyl-1,3-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).

WO 2005/026155 PCT/EP2004/052137 - 80 MS(ESI-'): 434.5; MS(ESLD: 433.4. Example 62:- 4-tert-butyl 1 -(91--fuoren-9-ylmejty) 2-[( {4-[(Z -cyano(l1 ethyl-i 2-dihydro 2H-benzimidazol-2-lidene)methyl-5-mthylp rmidin-2-l lIflo)carboflyllp pra ne 1 .4-dicarboxyate /I N N H N OKN HN 5 0 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(l -ethyl-i ,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 1 -finoc-4-boc-piperazine-2-carbocxylic acid, the title compound was isolated, as a yellow solid in 70% yield (97% purity by T-1PLC). 10 MS(ESI+): 727.9; MS(ESIV): 725.6. Exaple63:N- 4-[Z)cyao~l-etyl- .3diydro-211-benzitmidazol-2-ylidene)methyl]-5 mgflhvlpyrimidin-2-ylI iperazine-2-carboxamide H N

WNH

WO 2005/026155 PCT/EP2004/052137 -81 Following the general method as outlined in Example 57, starting 4-tert-butyl 1-(911 fluoren-9-yhnethyl) 2-[({4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)methyl]-5-methylpyrimidin-2-yl} amino)carbonyl]piperazine-1,4-dicarboxylate (Example 63), the title compound was isolated, as a yellow solid in 90% yield (91% purity 5 by HPLC). MS(ESI*): 404.6; MS(ESI): 402.2. Example 64: tert-butyl (2S) -2-f({4-[(Z)-cyano(1 -ethyl-1 3-dihydro-21-benzimidazol-2 ylidene)methyll-5-methlpyrimidin-2-vl} amino)carbonyl-5-oxopyrrolidine-1-carboxylate N N H N HN 0 10 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1 -ethyl-1,3-dihydro-2H--benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and Boc-pyroglutamic acid, the title compound was isolated, as a yellow solid in 72% yield (98% purity by H-PLC). MS(ESI*): 504.3; MS(ESI): 502.2. 15 Example 65: N- {4-((Z)-cyano(l -ethyl- 1,3 -dihydro-2H-benzimidazol-2-vlidene)methyll-5 methylpyrimidin-2-vl}-5-oxo-L-prolinamide WO 2005/026155 PCT/EP2004/052137 - 82 H N N HN NH0 0 Following the general method as outlined in Example 57, starting from: tert-butyl (2S)-2 [({4- [(Z)-cyano(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)methy]-5 -methyl pyriidin-2-yl}amino)carbonyl]-5-oxopyrrolidine-1 -carboxylate (Example 65), , the title 5 compound was isolated, as a yellow solid in 96% yield (97% purity by ITPLC). MS(ESI*): 404.6; MS(ESI): 402.2. Example 66: tert-butyl (4R)-4-[({4-F(Z)-cyano(1 -ethyl- .3-dihydro-21--benzimidazol-2 ylidene)methyll-5-methylpyrimidin-2-y)aTnino)carbonyl]-L 3-thiazolidine-3-carboxylate /I N N N H N\ ON H 10 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and (S)-boc-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid, the title compound was isolated, as a yellow solid in 80% yield (98% purity by HPLC).

WO 2005/026155 PCT/EP2004/052137 - 83 MS(ESI*7): 508.9; MS(ESI): 506.5. Example 67: (4R)-N- 14-](Z)-cyano( -ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)methy1-5-methylovrimidin-2-yl} -1.3 -thiazolidine-4-carboxamide XN CEN> H N o W N N "H S y NH 5 Following the general method as outlined in Example 57, starting tert-butyl (4R)-4-[({4 [(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5-methylpyrimidin-2 yl}amino)carbonyl]-1,3-thiazolidine-3-carboxylate (Example 66), the title compound was isolated, as a yellow solid in 94% yield (97% purity by TPLC). MS(ESI*): 408.6; MS(ESI-): 406.2. 10 Example 68: (1 S,4S.5 .7R)-N- {4-[(Z)-cvano(1 -ethyl-1.,3-dihydro-2H-benzimidazol-2 ylidene)methv11-5-methylpyrimidin-2-yl}-4-methvn-6,8-dioxa-3-azabicyclo[3.2.1]octane-7 carboxamide ZN H N\ HN N

HN

WO 2005/026155 PCT/EP2004/052137 Following the general methods as outlined in Examples 56 and 57, starting from (2Z)-(2 amino-5-methylpyrimidin-4-yl)(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene) acetonitrile (Intermediate 19), and Boc-BTA-OH, the title compound was isolated, as a yellow solid in 80% yield (93% purity by HPLC). 5 MS(ESI): 448.7; MS(ESI~): 446.3. Example 69: N-{4-F(Z)-evano(1 -ethyl-1,3-dihydro-21-benzimidazol-2-ylidene)methyll-5 methylpyrimidin-2-v1} -4-(dimethylamino)butanamide N N HN N Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 10 methylpyrimidin-4-yl)(1 -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 H4PLC). MS(ESI*): 406.6; MS(ESI-): 404.2. Example 70: N~1--{4-[(Z)-cyano(1-ethyl-1,3-dihydro-2H-benzimidazol-2 15 vlidene)methyll-5-methylprimidin-2-1 -N~3~,N~3~-dimetyl-beta-alaninamide / N N H N N

H

WO 2005/026155 PCT/EP2004/052137 -85 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-y)(1 -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). 5 MS(ESI*): 392.5; MS(ESI-): 390.6. Example 71: N-{4-r(Z)-cyano(1-ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methy11-5 methylpyrimidin-2-yl}-4-(4-methylpiperazin-1-yl)butanamide /I N N N H N O N N N Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 10 methylpyrimidin-4-yl)(1 -ethyl- 1,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and (4-methylpiperazin- 1 -yl)butanoic acid, the title compound was isolated, as a yellow solid in 52% yield (96% purity by HfPLC). MS(ESI*): 461.7; MS(EST): 459.2. Example 72: N-{4-[(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene)methyl1-5 15 methylpyrimidin-2-yl}cyclopentanecarboxamide H N N

HN

WO 2005/026155 PCT/EP2004/052137 - 86 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and cyclopentanopic acid, the title compound was isolated, as a yellow solid in 65% yield (97% purity by HPLC). 5 MS(ESI): 389.5; MS(ESI-): 387.6. Example 73: tert-butyl l4-(_ 4-[(Z)-cyano( -ethyl-I 3 -dihydro-211-benzimidazol-2 ylidene)methyl-5-methylpyrimidin-2-yl}anino)-4-oxobulyL]]carbamate ~A N N/ H N H HN 0 NH Osz( 0 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 10 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 H-PLC). MS(ESI*): 478.6; MS(ESI-): 476.5. Example 74: 4-amino-N-{4-[(Z)-cyano(1-ethyl-1,3-dihydro-2--benzimidazol-2 15 ylidene)methyll-5-methylpyrimidin-2-yl}butanamide WO 2005/026155 PCT/EP2004/052137 - 87 H N N H N N HN

NH

2 Following the general methods as outlined in Examples 56 and 57, starting from tert-butyl [4-({4-[(Z)-cyano(1 -ethyl- 1,3 -dihydro-21-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl} amino)-4-oxobutyl]carbamate (Example 73), the title compound was 5 isolated, as a yellow solid in 90% yield (96% purity by HPLC). MS(ESI): 378.6; MS(ESI): 376.7. Example 75: lert-butyl 4-[({4-[(Z)-cyano(1-ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)'methyll-5-methylpyrimidin-2-ylamino)carbonyl]piperidine-1-carboxylate N H N' ) 2N N N-' N 0 10 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 1-(tert-butoxycarbonyl)isonipecotic acid, the title compound was isolated, as a yellow solid in 84% yield (98% purity by HPLC).

WO 2005/026155 PCT/EP2004/052137 MS(ESI*): 504.6; MS(ESI): 502.3. Example 76: -{4-FTZ)-cyano(1 -ethy1-1,3 -dihydro-2H-benzimidazol-2-vlidene)methv11]-5 methylpyrimidin-2-yl}piperidine-4-carboxamide N H N *-' N N 0 N 5 Following the general methods as outlined in Examples 56 and 57, starting from tert-butyl 4-(({4-[(Z)-cyano(l -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)mnethyl]-5 methylpyrimidin-2-y I }amino)carbonyl]piperidine- I -carboxylate (Example 75), the title compound was isolated, as a yellow solid in 95% yield (97% purity by IHPLC). MS(ESI*: 404.6; MS(ESI~): 402.8. 10 Example 77: N-{4-f(Z)-cvano(l-ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methv11-5 methvypyrimidin-2-yl} -1 -methylpiperidine-4-carboxamide N N N Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1 -ethyl- 1,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile WO 2005/026155 PCT/EP2004/052137 - 89 (Intermediate 19), and 1 -methyl-piperidine-4-carboxylic acid HC1, the title compound was isolated, as a yellow solid in 82% yield (92% purity by HPLC). MS(ESI'): 418.8; MS(ESI): 416.5. Example 78: 1 -acetyl-N- f4-[(Z)-cvano(1 -ethyl-I,3 -dihydro-2H-benzimidazol-2 5 ylidene)methyll-5-methylpyrimidin-2-yl}piperidine-4-carboxamide / N N H N\ N 0 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 1 -acetyl-4-piperidine carboxylic acid, the title compound was 10 isolated, as a yellow solid in 82% yield (98% purity by HPLC). MS(ESI): 446.5; MS(ESI): 444.9. Example 79: N-{4-[(Z)-cyano(l-ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methy-5 methyvpyrimidin-2-yl}-2-(2-methoxypheny1)acetamide WO 2005/026155 PCT/EP2004/052137 -90 N N H N N 00 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-y)(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 2-methoxy-phenylacetic acid, the title compound was isolated, as a 5 yellow solid in 60% yield (95% purity by HPLC). MS(ESI*): 441.8; MS(ESI): 439.4. Example 80: tert-butyl (2S)-2-[({4-[(Z)-cyano(l-ethyl-1,3-dihydiro-2H-benzimidazol-2 ylidene)methyll-5-methylpyrimidin-2-y}amino)carbonvl-2,5-dihydro-LT-pyrole-1 carboxylate N HN" H-I N N 0 0 10 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile WO 2005/026155 PCT/EP2004/052137 - 91 (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(ESI): 486.6. Example 81: (2S)-N- {4-[(Z)-cyano(1-ethyl-1,3-dihydro-2H-benzimidazo-2 5 ylidene)methyll-5-methylpyrimidin-2-y} -2,5-dihydro-1H-pyrole-2-carboxamide N 'N Following the general method as outlined in Example 56, starting from tert-butyl (2S)-2 [(f4-[(Z)-cyano(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl}amino)carbonyl]-2,5-dihydro-1 H-pyrrole-1 -carboxylate (Example 10 80), the title compound was isolated, as a yellow solid in 95% yield (96% purity by ITPLC). MS(ESI): 388.5; MS(EST): 386.6. Example 82: tert-butyl 3-[({4-[(Z)-cvano(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2 ylidene)methyll-5-methylpyrimidin-2-vl }amino)carbonvipyrrolidine-1-carboxylate WO 2005/026155 PCT/EP2004/052137 - 92 N H N\ N C o N Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and boc-l-pyrrolidine-3-carboxylic acid, the title compound was 5 isolated, as a yellow solid in 70% yield (98% purity by HPLC). MS(ESI*): 490.4; MS(ESI): 488.3. Example 83: N-{4-[Z)-cyano(l -ethyl-1 3-dihydro-2H-benzimidazol-2-ylidene)methyll-5 methylpyrimidin-2-yl}pyrrolidine-3-carboxanide / N N N 10 Following the general method as outlined in Example 57, starting tert-butyl 3-[({4-[(Z) cyano(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5-methylpyrimidin-2 yl} amino)carbonyl]pyrrolidine-1 -carboxylate (Example 82), the title compound was isolated, as a yellow solid in 96% yield (99% purity by IPLC). MS(ESI): 388.4; MS(ESI ): 386.4.

WO 2005/026155 PCT/EP2004/052137 - 93 Example 84: tert-butyl 2-[({4-[(Z)-cyano(1 -ethyl-L,3-dihydro-2H-benzimidazol-2 ylidene)methv11-5-methpyrmidin-2-1)amino)crbonyl]mphlne4-carboxylate N H N I--N HN 00 V N O Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 5 methylpyrimidin-4-y)(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and Boc-COP-OT compound was isolated, as a yellow solid in 70% yield (97% purity by HPLC). MS(ESI): 506.3 (ESI~): 504.6 Example 85: N- {4-f(Z)-cyano(1 -ethyl- 1.3 -dihydro-2H-benzimidazol-2-vlidene)methyll-5 10 methylpyrimidin-2-yl}morpholine-2-carboxamide N N N H N\ HN HN 0 Following the general method as outlined in Example 56, starting from tert-butyl 2-[({4 [(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5-methylpyrinidin-2- WO 2005/026155 PCT/EP2004/052137 -94 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(ESI): 404.7 Example 86: tert-butyl f2-({4-[(Z)-cyano( -ethyl-1,3-dihydro-2H-benzimidazol-2 5 ylidene)methy1]-5-methylpyrimidin-2-yl} amino)-2-oxoethyl]methylcarbarnate /N H N N HN 0 Following the general method as outlined in Example 56, starting from (2Z)-(2-amnino-5 methylpyrimidin-4-yl)(1 -ethyl-1,3-dihydro-21-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and boc-sarcosine, the title compound was isolated, as a yellow solid in 10 82% yield (98% purity by HPLC). MS(ESI): 464.6; MS(ESI~): 462.2. Example 87: N~1--{4-[(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidene) methyl]-5-methvlpyrmidin-2-y1} -N-2-methvLglvcinamide N HN

H

WO 2005/026155 PCT/EP2004/052137 -95 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-ylidene)methy1I-5-methylpyrimidin- 2 yl} amino)-2-oxoethyllmethylcarbamate (Example 86), the title compound was isolated, as a yellow solid in 98% yield (97% purity by HPLC). 5 MS(ESI-): 364.5; MS(FST~): 362.5. Example 88: N-{4-(Z)-cyano(1-ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyll-5 methylpyrimidin-2-y}-l-methylpiperidine-3-carboxamide N HN -N Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 10 methylpyrimidin-4-yl)(1-ethyl- 1,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 1 -methyl-piperidine-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(ESI): 416.4. Example 89: N-[3-({4-(Z)-cyano(1-ethyl-1,3-dihydro-21-benzimidazol-2-ylidene) 15 methyl]-5-methvlpyrimidin-2-yl} amino) -3-oxopropyl]benzamide WO 2005/026155 PCT/EP2004/052137 - 96 /N H N' \ N H N N N O H Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and benzoyl-beta-alanine, the title compound was isolated, as a yellow 5 solid in 40% yield (91% purity by HPLC). MS(ESI*): 468.6; MS(ESI): 466.1. Example 90: tert-butyl 4-[2-({4-[(Z)-cyano(1-ethyl- 1,3-dihydro-2H-benzimidazol-2 vlidene)methyl]-5-methylpyrimidin-2-v1}anino)-2-oxoethyl]piperidine-1 -carboxylate H N N 0:N H N HN 0 10 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 1 -boc-4-piperidineacetic acid, the title compound was isolated, as a yellow solid in 70% yield (97% purity by H-PLC).

WO 2005/026155 PCT/EP2004/052137 -97 MS(ESI*): 518.6; MS(ESI): 516.2. Example 91: 2-(1-aceiylpiperidin-4-yl)-N-{4-[(Z)-cyano(1-ethyl-1.3-dihydro-2H benzimidazol-2-ylidene)methyl]-5-methylpyrimidin-2-yl}acetamide H N N HN HN 0 0 5 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-y)(1 -ethyl-1,3-dihydro-2H-benzimidazol-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(ESI*): 460.8; MS(ESI): 458.3. 10 Example 92: N-{4-r(Z)-cyano(1-ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)methyll-5 methvlpyrimidin-2-yl} -2-piperidin-4-ylacetamide WO 2005/026155 PCT/EP2004/052137 - 98 H N' N N HN Following the general method as outlined in Example 57, starting from tert-butyl 4-[2-({4 [(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl-5-mthylpyrimidin-2 yl}amino)-2-oxoethyl]piperidine-1 -carboxylate (Example 90), the title compound was 5 isolated, as a yellow solid in 98% yield (97% purity by HPLC). MS(ESI*): 418.6; MS(ESI): 416.3. Example 93: tert-butyl 3-[({4-[(Z)-cyano(1-ethyl- 1,3-dihydro-21-benzimidazol-2 ylideneymethyll-5-methylpyrimidin-2-yl}aminolcarbonyllpIperidine-1-carboxylate N H N\ HN 0 10 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1 -ethyl-1,3-dihydro-21-benzimidazol-2-ylidene)acetonitrile WO 2005/026155 PCT/EP2004/052137 - 99 (Intermediate 19), and (RS)-boc-nipecotic acid, the title compound was isolated, as a yellow solid in 69% yield (99% purity by HPLC). MS(ESI: 504.6; MS(ESI): 502.6. Example 94:_N-{4-[(Z)-cyano(1-ethyl-1,3-dihydro-2H-benzimidazol-2-vlidene)iethyll-5 5 methylpyrimidin-2-yl}piperidine-3-carboxamide IN N H N C 0 N H Following the general method as outlined in Example 57, starting from tert-butyl 3-[({4 [(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5-methylpyrimidin-2 yl} amino)carbonyl]piperidine-1 -carboxylate (Example 93), the title compound was 10 isolated, as a yellow solid in 95% yield (97% purity by TPLC). MS(ESI*): 404.9; MS(ESI-): 402.6. Example 95: N-{4-[(Z)-cyano(1-ethyl-1,3-dihydro-2H-benzimidazo-2-vliden)rnethy]-5 methylpyrimidin-2-yl}-4-[(4-methylpiperazin-1-yl)methyllbenzainide WO 2005/026155 PCT/EP2004/052137 - 100 N / H N" >-N HN 0 -N N Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1-ethy,-1,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 4-[(4-methylpiperazin-1-yl)methylbenzamide, the title compound 5 was isolated, as a yellow solid in 58% yield (92% purity by HPLC). MS(ESI*): 509.6; MS(ESI-): 507.5. Example 96: 4-acetyl-N-{4-[(Z)-cvano(l-ethy1-1.3-dihydro-211-benzimidazol-2 ylidene)methyll-5-methylpyrimidin-2-y}morpholine-2-carboxamide / N N HN 0N O= 10 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and 4-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(ESI): 446.3.

WO 2005/026155 PCT/EP2004/052137 - 101 Example 97: N-{4-[WZ)-cyano(1-ethyl-1.3-dihydro-2H-benzimidazol-2-ylidenemeth1]-5 methylpyrimidin-2-yl -4-methylmorpholine-2-carboxanide N N H N N 0 -N O, Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 5 methylpyrfinidin-4-y)(1 -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(ESI): 418.2. Example 98: N-{4-{(Z)-cyano(1-ethyl-1.3-dihydro-2T-ben7imidazol-2-ylidene)methyl1]-5 10 methylpyimidin-2-yll-2-morpholin-4-ylacetamnide N ( N H N 0 N N N Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)( -ethyl- 1,3 -dihydro-2H-benzimidazol-2-yidene)acetonitrile WO 2005/026155 PCT/EP2004/052137 - 102 (Intermediate 19), and 4-morpholinoacetic acid, the title compound was isolated, as a yellow solid in 82% yield (99% purity by HPLC). MS(ESI): 420.1; MS(ESI): 418.3. Example 99: N-2--benzv1-N-1~-{4-f(Z)-cyano(l -ethyl-1,3-dihydro-2H-benzimidazol-2 5 ylidene)methyll-5-methylpyrimidin-2-vl}glycinamide N H N O N DN N Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1 -ethyl-i1, 3 -dihydro-2H-benzimidazol-2-ylidene)acetonitrile (Intermediate 19), and N-alpha-tert-butoxycarbonyl,benzyl-glycine which was further 10 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(ESI): 438.5. Example 100: N-{4-~(Z)-cyano(i-ethyl-1, 3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl} -2-(l 1-dioxidothiomornholin-4-yl)acetamide WO 2005/026155 PCT/EP2004/052137 - 103 / N -N H N N N 0 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1 -ethyl-1,3-dihydro-2H-benzimidaol-2-ylidene)acetonitrile (Intermediate 19), and 4-thiomorpholine acetic acid, the title compound was isolated, as a 5 yellow solid in 59% yield (98% purity by HPLC). MS(ESI): 468.6; MS(ESI~): 466.2. Example 101: N---{4-r(Z)-cyano(l-ethyl-1.3-dihydro-2H-benzimidazol-2 ylidene)methyll-5-methylpyrimidin-2-yll-N-2--formylg1ycinamide / N N H N O N N -N

H

0 10 Following the general method as outlined in Example 56, starting from (2Z)-(2-amino-5 methylpyrimidin-4-yl)(1 -ethyl-1,3-dihydro-2T-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(ESI): 376.6.

WO 2005/026155 PCT/EP2004/052137 -104 Example 102: Preparation of a pharmaceutical formulation The following formulation examples illustrate representative pharmaceutical compositions according to the present invention being not restricted thereto. 5 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 benzirnidazole acetonitrile compound per tablet) in a tablet press. 10 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). 15 Formulation 3 - Liquid A benzimidazole acetonitrile of formula I (1250 mg), sucrose (1.75 g) and xantban 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 20 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 25 as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active benzimidazole acetonitrile compound) in a tablet press.

WO 2005/026155 PCT/EP2004/052137 -105 Formulation 5 - Injection A benzimidazole acetonitrile of formula (1) is dissolved in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/ml. 5 Biological Assays The compounds of the present invention may be subjected to the following assays: a) GSK3 in vitro assay: GSK3 $ Assay (see Bioorg. Med. Chem. Lett by Naerum et al. 12 p.1525-1528 (2002)) In a final reaction volume of 2 5pl, GSK3P (h) (5-lOmU) is incubated with 8 mM MOPS 10 pH 7.0, 0.2 mM EDTA, 20gM YRRAAVPPSPSLSRHSSPHQS(p)EDEEE (being the GSK3 substrate; a phospho, GS2 peptide), 10mM Mg Acetate and [y- 3 3 P-ATP] (Specific activity approx. 500cpm/pmol, concentration as required). The reaction is initiated by the addition of Mge [y- 3 3 P-ATP]. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 5pl of a 3% phosphoric acid solution. I Og1 of the 15 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 (IC 5 o) with regard to GSK3 of less than 20 pM, preferably less than 10 and even more preferred less than I RM. 20 The binding affinities of the compounds of formula (I) were assessed using the above described in vitro biological assay. Representative values for some example compounds are given in Tables I and 2 below. The values in Table 1 refer to the binding affinity (IC 5 o; piM) of the example compounds according to formula I to GSK3.

WO 2005/026155 PCT/EP2004/052137 -106 Table 1: - i vitro potency of benzimidazole derivatives on human GSK3 beta Structure Compound IC 50 (gAM) GSK3beta CN H (2Z)-[2-(cycloheptylamino)-5- <10 N y~j) N,, Nmethylpyrimidin-4-yl](1 -ethyl-l1,3 _NH '1'dihydro-2H4-benzimidazol-2 NH .- Nylidene)acetonitrile (2Z)-(1 -cyclobutyl- 1,3 -dihydro-214- < 10 Q> N Hbenzimnidazol-2-ylidene)(2-{L3-(2 N N, N~r , oxiopyrrolidin-1 Y yl)propyllmino~pyrimidin-4 / \NH -,N 0 yl)acetonitrile i-i H [2-(cyclopentylamino)-5- <10 N N NO methylpyrimidin-4-yl]j(1,3-dihydro / 1 1 NH 2H4-benzimidlazol-2 N H N ylidene)acetonitrile ON H (1 -ethyl-1lH-benzimidazol-2-yl) {6-[(2- <10 N N, pyridin-.3-ylethyl)amnino~pyrimidin-4 yI }acetonitrile O\NH N,,,N N tert-butyl 2-[({4-[(Z)-cyano(1 -ethyl- <1110 N 1,3 -dihydro-2ff-benzimidazol-2 0 N _ /ylidne)mthyl]-5-mthylpyrimidin-2 I 0yIamnocabony]]morpholine-4 N -N Hcarboxylate 'N N 0 0 _ _ _ _ _ _ _ _ _ WO 2005/026155 PCT/EP2004/052137 - 1071 NN- (4-[(Z)-cyano( 1 -ethyl-i 1,3 -dihydro- <10 N ~ 2H-benzimidazol-2-ylidcne)methyl]-5 methylpyrinaid-in-2-yIlt-2-(2 OZ , N _NHmethoxyphenyl)acetamide 0 Ntert-butyl [4-({4- [(Z)-cyano(1 -ethyl- <10 /I 1,3 -dihYdrO-2H1-benzimidazol-2 - N -Ylidene)methYll]-5-methylPyrimnidin-2 N -N HY1}amino)-4-oxobuty1carbaanate, H N 0 0 WO 2005/026155 PCT/EP2004/052137 -108 b) In vivo assay : Experimental model of type II diabetes (oral postprandial glycemia in db/db mice) The following assay aims at determining the anti-diabetic effect of the test compounds of formula (I) in a model of posiprandial glycemia in db/db mice, in vivo. 5 The assay was performed as follows : A total of 24 db/db mice (about 8-9 weeks; obtained from IFFACREDO, I'Arbreste, France) were fasted during 20 hours. 2 groups, each consisting of 6 animals were formed: e Group I : The animals were administered (per os) a dose of 10 mg/kg of 10 vehicle. * Group 2 : The animals were administered (per os) a dose of 50 mg/kg of the 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 15 access to commercial food (D04, UAR, Villemoisson/Orge, France) ad libitumn. The diabetic state of the 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 of the blood glucose level was performed using a glucometer (Precision 20 Q.I.D., Medisense, Abbot, ref. 212.62.3 1). The determination of the Insulin level was performed using an ELISA kit (Crystal CHEM, Ref. INSK R020).

WO 2005/026155 PCT/EP2004/052137 - 109 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 5 induced by food intake by about 20-40%. For instance, upon using the compound of example 3, i.e. (2Z)-[2-(cyclobutylamino)-5 methylpyrimidin-4-yl](l -ethyl-1,3-dihydro-2H4-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. 10 WO 2005/026155 PCT/EP2004/052137 - 110 Reference List 1. Woodgett et al: Trends Biochem. Sci., 16p.177-81 (1991); 2. Reaven et al (American Journal ofMedicine, 60, 80 (1976); 5 3. Stout, Metabolism, 34, 7 (1985) 4. Diamanti-Kandarakis et al.; European Joumal ofEndocrinology 138, 269 -274 (1998), 5. Andrea Dunaif; Endocrine Reviews 18(6), 774-800 (1997)); 6. WO O1/47920 10

Claims (18)

1. A benzimidazole acetonitrile according to formula (1) Ra N CN (I N G-L 5 H as well as its tautomers, its geometrical isomers, its optically active forms as enantio mers, diastereomers and its racemate forms, as well as phannaceutically acceptable salts thereof, wherein G is a pyrimidinyl; 10 L is an amino group, or a 3-8 membered heterocycloalkyl, containing at least one heteroatom selected from N, 0, S or L is an acylamino moiety; R' is selected from the group comprising or consisting of hydrogen, sulfonyl, amino, carboxy, amino carbonyl, C-C 6 -alkyl, C 2 -C 6 -alkenyl, C2-C6-alkynyl or CIC 6 -alkoxy, aryl, halogen, cyano or hydroxy; 15 R2 is selected from the group comprising or consisting of hydrogen, Cl-C 6 -alkyl, C 2 C 6 -alkenyl, C 2 -C 6 -alkynyl, or C] -C 6 -alkoxy.

2. The benzimidazole acetonitrile according to claim 1, wherein R is H or C-C 3 alkyl.

3. The benzimidazole acetonitrile according to any of claims 1 or 2, wherein R 2 is a C 1 C 3 alkyl. WO 2005/026155 PCT/EP2004/052137 - 112

4. The benzimidazole acetonitrile according to any of claims 1 to 3, having any of the formulae R 2 R 2 :~N CN N C NH N R N (1a 3 N a) )-N R 2 -,z N CN / H N N wherein R' is as above defined, and 5 R is selected from the group comprising or consisting of hydrogen, CI-C 6 -alkyl, C 2 C6-alkenyl, C 2 -C 6 -alkynyl, or CI-C 6 -alkoxy; L is an amino group of the formula -NRR 6 wherein R 5 and R 6 are each independently from each other H, CI-C 6 -alkyl, C 2 -C 6 -alkenyl, C2-C 6 -alkynyl, C 1 -C 6 alkoxy, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, 3-8 10 membered heterocycloalkyl, C-C 6 -alkyl aryl, C-C 6 -alkyl heteroaryl, C-C 6 -alkenyl aryl, CI-C 6 -alkenyl heteroaryl, CI-C 6 -alkynyl aryl, CI-C 6 -alkynyl heteroaryl, C 1 -C 6 alkyl cycloalkyl, CI-C 6 -alkyl heterocycloalkyl, Ci-C 6 -alkenyl cycloalkyl, C-C 6 alkenyl heterocycloalkyl, C-Cr-alkynyl cycloalkyl, CI-C 6 -alkynyl heterocycloalkyl, or 15 R and R 6 may form a ring together with the nitrogen to which they are bound.

5. The benzimidazole acetonitrile according to any of the preceding claims, wherein R 5 is hydrogen or a methyl or ethyl or propyl group and R 6 is a selected from the group consisting of H, (CI-C20)-alkyl, CI-C 6 alkyl-aryl, C-C6-alkyl-heteroaryl, cycloalkyl, WO 2005/026155 PCT/EP2004/052137 - 113 heterocycloalkyl, aryl or heteroaryl and 4-8 membered saturated or unsaturated cycloalkyl.

6. The benzimidazole acetonitrile according to any -of the preceding claims, wherein R? is H and R 6 is selected from the group consisting of C-C 6 alkyl, 3-8 membered 5 cycloalkyl, 3-8 membered heterocycloalkyl, beteroaryl, CI-C6-alkyl heteroaryl, C C 6 -alkyl cycloalkyl, CI-C 6 -alkyl heterocycloalkyl.

7. The benzoxazole acetonitrile according to any of claims 1 to 3, wherein L is an acylamino moiety of the formula -NRC(O)R 6 wherein R' and R 6 are each independently from each other H, C-C6-alkyl, C 2 -C 6 -alkenyl, C2-C6-alkynyl, C 1 -C 6 10 alkoxy, aryl, heteroaryl, saturated or unsaturated 3-8-membered cycloalkyl, 3-8 membered heterocycloalkyl, C-C 6 -alkyl aryl, Cr-C 6 -alkyl heteroaryl, C-Cs-alkenyl aryl, CI-C 6 -alkenyl heteroaryl, C-C 6 -alkynyl aryl, Cl-C6-alkynyl heteroaryl, C 1 -C 6 alkyl cycloalkyl, C-C 6 -alkyl heterocycloalkyl, C-C 6 -alkenyl cycloalkyl, C-C 6 alkenyl heterocycloalkyl, C-C 6 -alkynyl cycloalkyl, C-C 6 -alkynyl heterocycloalkyl. 15

8. The benzimidazole acetonitrile according to any of the preceding claims selected from the group consisting of: (2Z)-(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)(2-{[3-(TT-pyrazol-1 yl)propyl]amino}pyrimidin-4-yl)acetonitrile (2Z)-(1.-ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)(5-methyl-2-{[3-(1H-pyrazol 20 1 -yl)propyl]amino}pyrimidin-4-yl)acetonitrile (2Z)-[2-(cyclobutylamino)-5-methylpyrimidin-4-ylj(I -ethyl-1,3-dihydro-2H benzimidazol-2-ylidene)acetonitrile (2Z)-(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)(5-methyl-2- {[3-(2 oxopyrrolidin- 1-yl)propyl]amino}pyrimidin-4-yl)acetonitrile WO 2005/026155 PCT/EP2004/052137 -114 (2Z)-(] -ethiyl-1,3-dihydro-2T1-benzimidazol-2-ylidene)(2- {[3-(2-oxopyirrolidin-1 yl)propyl]amnino}pyrimidin4-yl)acetonitrile (2Z)-(l -ethyl-1,3 -dihydro-2H--benzimidazol-2-ylidene)(2- ft3-(1H-1 ,2,4-triazol-1 yl)propyl]amninojpyrirmidin-4-yl)acetonitrile 5 (2Z)-(] -ethyl-L1,3 -dihydro-2H-benzimidazol-2-ylidene)(5-methyl-2- I [3 -(I H- 1,2,4 triazol- 1 -yl)propyllamino~pyrimidin-4-yl)acetonitrile [2-(cyclopentylamino)-5-miethylpyrimidin-4-yl](1 -ethyl- I1H-benzimidazol-2 yl)acetonitrfle (2Z)-(-2- {[3-(2-oxopyr-rolidin-1I-yl)propyl] amino }pyrimidin-4-yl)(l -propyl-l ,3 10 dihydro-2H-benziimidazol-2--ylidene)acetonitrile (I -ethyl-11{-benzimidazol-2-yl){5-methyl-2-[(2-pyridin-3 -ylethyl)aminolpyrimidin 4 -yl} acetonitile (2Z)-[2-(cyclobutylamino)pyrimidin-4-yl](l -ethyl- I ,3-dihydro-2H-benzimidazol-2 ylide-ne)acetonitrile 15 (2Z)-[ 2-(cycloheptylamino)-5-methylpyrimidin-4-yll(1 -ethyl- 1 ,3-dihydro-2H benzimidazol-2-ylidene)acetonitrile [2-(cyclopentylamino)pyrimilin-4-yJ(1 -ethyl- IH-benzimidazol-2-y)acetonil-ile 1,3 -dihydro-2H4-benzimidazol-2-ylilene(5-methyl-2-{[3-(2-oxopyrrolidin-lI yl)propyljaminolpyrimnidin-4-yl)acetonitrile 20 (2Z)-(1 -cyclobutyl-1 ,3-dihydro-2H-benzimidazol-2-ylidene)(2- 1[3-(2-oxopyrrolidin 1 -yl)propyl]amino~pyrimiidin-4-yl)ar-etonitrile WO 2005/026155 PCT/EP2004/052137 -115 (1 -ethyl- lH-benzimidazol-2-yl){2-[(2-pyridin-3-ylethyl)amino]pyrimidin-4 yl}acetonitrile (2Z)-(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)[2-(isobutylamino)-5 methylpyrimidin-4-y1]acetonitrile 5 (2Z)-(l -ethyl-1,3-dihydro-21-benzimidazol-2-ylidene)(2- {[2-(1H-imidazol-4 yl)ethyl]amino}pyrimidin-4-y1)acetonitrile (2Z)-(l -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)[2-(isobutylamino)pyrimidin 4-yl]acetonitrile [2-(cyclopropylamino)pyrimidin-4-yl](l -ethyl- 1H-benzimidazol-2-yl)acetonitrile 10 [2-({2-[6-(dimethylamino)pyridin-3-yl]ethyl}amino)pyrimidin-4-yl](1-ethyl-1H benzimidazol-2-yl)acetonitrile (1-ethyl- 1H-benzimidazol-2-yl)(2- {[2-(1H-1,2,4-triazol-1 -yl)ethyl]amino}pyrimidin 4-yl)acetonitrile (2Z)-(1 -ethyl-1,3 -dihydro-2H1-benzimidazol-2-ylidene)(2- {[2-(1 H-imidazol-4 15 yl)ethyl]amino}-5-methylpyrimidin-4-y1)acetonitrile [ 2 -({ 2 -[6-(dimethylamino)pyridin-3-yl]ethyl}amino)-5-methylpyrimidin-4-yl](1 ethyl-IH-benzimidazol-2-yl)acetonitrile (2Z) - [2-(cycloheptylamino)pyrimidin-4-yl](1 -ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)acetonitrile 20 [2-(cyclopropylamino)-5-methylpyrimidin-4-yl](1 -ethyl-i H-benzimidazol-2 yl)acetonitrile WO 2005/026155 PCT/EP2004/052137 -116 (1 -ethyl-1IHf-benzimidazol-2-yI){f2-[(2-pyridin-2-ylethyl)amino]pyrimilin-4 yl} acetorntrile [2-(cyclopentylamino)-5-methylpyrimidin-4-yl](1 ,3-dihydro-2H4-benzinaidazol-2 ylidene)acetonitrile 5 [2-(cyelohexylamnino)pyrtmidin-4-yl](l -ethyl- I H-benzimidazol-2-yl)acetonit-ile (2Z) -(1 -ethyl-i ,3 -dihydro-2f1-benzimnidazol-2-ylidene)(2-t[2-(1 J--indol-3 yI)ethyljamino) -5 -methylpyrimidin-4-yl)acetonitrile (1 -ethyl-lH-benzimiddazol-2-yI){5-methylb2-[(2-pyridin-2-ylethyl)amiino]pyrimidin 4-yllacetonitrile 10 {2-[(2-e-thoxyethyl)aminolpyrimidin-4-yl}(1 -ethyl- I H-.-benzimidazol-2-yl)acetonitrile (I -ethyl-I}T-benzimiclazol-2-yl){5-methyl-2- [(1 -metliylbutyl)amino]pyrimidin-4 yl} acetonitrile (1 -ethyl-1H-benzimidazol-2-yI)[2 -(methylamnino)pyrimidin-4-yl]aceonitrile (I-ethyl-1ll-benzimiidazol-2-yI)(5 -methyl-2- {[2-(1H--pyrazol- 1 15 yl)ethyljanunolpyrimidin-4-yI)acetonitrile 1 TI-benzimidazol-2-yl {5-methyl-2-[(2-pyridin-3 -ylethyl)aminolpyrimidin-4 yl} acetonitrile (2Z)-(l -ethyl-l,3 -dihydro-2Uf-1enzimidazol-2-ylidene)(2- {12-(l 1--imidazol-l yl)ethyl]amino} -5-methylpyrmidin-4-yl)acetonitrile 20 1 T--benzimridazol-2-yl {2-[(2-pyridin-3 -ylethyl)amiino]pyrimidin-4-yllacetonitrile (1 -ethyl-ITT-benzimidazol-2-yI){f2-[(l -methylbulyl)amino]pyrimidin-4-yl} acetonitile WO 2005/026155 PCT/EP2004/052137 -117 {2-[(cyclohexylmethyl)amino]-5-methylpyrimidin-4-yl}(1 -ethyl-1 H-benzimidazol-2 yl)acetonitrile IH-benzimidazol-2-yl[2-(cyclopentylamino)pyrimidin-4-yl]acetonitrile (1-ethyl-I TI-benzimidazol-2-yl) {6-methyl-2-[(2-pyridin-3-ylethyl)amino]pyrimidin 5 4-yl}acetonitrile 11H-benzimidazol-2-yl[2-(cyclopropylamino)pyrimidin-4-yl]acetonitrile [2-(cyclopentylamino)-6-methylpyrimidin-4-yl](1 -ethyl- 1T-benzimidazol-2 yl)acetonitrile {2- [(cyclohexylmethyl)amino]pyrimidin-4-yl} (1 -ethyl-1H-benzimidazol-2 10 yl)acetonitrile (1-ethyl-1H-benzimidazol-2-yl){6-[(2-pyridin-3-ylethyl)amino]pyrimidin-4 yl}acetonitrile (1-ethyl- 1H-benzimidazol-2-yl){2-[(3-pyrrolidin- 1 -ylpropy])amino]pyrimidin-4 yl} acetonitrile 15 (1 -ethyl-1H-benzimidazol-2-yl)[2-(4-ethylpiperazin- I -yl)-5-methylpyrimidin-4 yl]acetonitrile (I -ethyl-1H-benzimidazol-2-yl){2-[(2-furylmethyl)amino]-5-methylpyrimidin-4 yl}acetonitrile (2Z)-( 1 -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene) {5-methyl-2- [(1 20 methylpiperidin-4-yl)aminolpyrimidin-4-yl}acetonitrile (2Z)-[2-(cyclohexylamino)-5-methylpyrimidin-4-yl](1-ethyl-1,3-dihydro-2H benzimidazol-2-ylidene)acetonitrile WO 2005/026155 PCT/EP2004/052137 (2Z)-j[2-(ethylamtino)-5-methylpyrimidifl-4-yl](l -ethyl-i ,3-dihydro-2H-benzinhidazo 2-ylidene)acetonitrile [2-(cyclopentylanino)-5-methylpyrinidil- 4 -yl](l ,3-diethyl-1,3-dihydro-211, benzimidazol-2-ylidene)aoetoflitrile 5 (2Z)-(l -ethyl- 1,3 -dhdo2-ezmdzl2yidn)5mty--pprdn4 ylamnino)pyrimidin-4-yllacetonitrile (2Z)-(l -ethyl-i ,3-dihydro-2TE-benzimidazo1-2-ylidefe) {5-methyl-2-[X2-piperidin- 1 ylethyl)aminolpyrimidin-4-yl} acetonitrile N- {4-[(Z)-eyano(l -ethyl-i 1,3 -dihydro-2H-benzimidazo1-2-ylidele)mlethylY- 5 10 mcnthylpyriniidin-2-yl} -4-(4-tnethylpiperazin-1 -yl)-4-oxobutanamnide N-{14- [(Z)-cyano(l -ethyl-i 1,3 -dihydro-2H4-benzimidazol-2-ylidele)methyl]pyrTnidin-f 2-yl} -4-(4-methylpiperazin-l1 -yI)-4-oxobutanamide (I1RSR,7R)-N- [4-II(Z)-cyano(i -ethyl- 1,3 -dihydro-21--benzimidazol-2 ylidene)methyl] -5 -methylpyrimidin-2-yll -6, 8-dioxa-3 -azabicyClo [3.2. 1i]octane -7 15 carboxamide (I S, 5S,7 S)-N-{ 4-[(Z)-cyalo(l -ethyl- 1,3 -dihydro-214-benzimidaz.o]-2 ylidene)methy11 -5methylpyrimidil-2-yl6, 8dioxa 3 abicyclo[ 3 2 ]octane-7 carboxamide (I S,4S,5 S,7R)-N- 14- [(Z)-cyano(1 -ethyl-I ,3-dihydro-2H-benzimidazol-2 20 ylidene)methyll -5-methylpyrimidifl- 2 -yl} -4-methyl-6,8-dioxa-3 azabicyclo[13 .2.1]octane-7-carboxamide WO 2005/026155 PCT/EP2004/052137 -119 (1 S,4R,5S,7R)-N-{4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazo-2 ylidene)methyl]-5-methylpyrimidin-2-yl}-4-methyl-6,8-dioxa-3 azabicyclo[3.2.1]octane-7-carboxamide N-{4-[(Z)-cyano(1-ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 5 methylpyrimidin-2-y1}piperazine-2-carboxanide (4S)-N- {4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methy]-5 methylpyrimidin-2-y1} - 1,3 -thiazolidine-4-carboxamide (4R)-N-{4-[(Z)-cyano(I -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl] -5 methylpyrimidin-2-y1)-1,3-thiazolidine-4-carboxamide 10 N- {4-[(Z)-cyano(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)methy]-5 methylpyrimidin-2-y1}-5-oxo-L-prolinamide 4-tert-butyl 1-(9H-fluoren-9-yhnethyl) 2-[({4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H1 benzimidazol-2-ylidene)methyl]-5-methylpyrimidin-2-yl}amino)carbonyl]piperazine 1,4-dicarboxylate 15 tert-butyl (4S)-4-[({4-[(Z)-cyano(1-ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)methyl]-5-methylpyrimidin-2-y}amino)carbonyl]-1,3-thiazolidine-3 carboxylate tert-butyl (2S)-2-[({4-[(Z)-cyano(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2 ylidene)methyl]-5-methylpyrimidin-2-y}amino)carbonyl]-5-oxopyrrolidine-l 20 carboxylate tert-butyl (4R)-4-[({4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)methyl]-5-methylpyrinidin-2-yl)amino)carbonyl]-1,3-thiazolidine-3 carboxylate WO 2005/026155 PCT/EP2004/052137 -120 2-(1-acetylpiperidin-4-y)-N-4-[(Z)-cyano(l-etbyl-1,3-dihydro-2H-benzimidazol-2 ylidene)methy]-5-methypyrimidin-2-yl}acetamide N- {4-[(Z)-cyano(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-y1} -4-methylmorpholine-2-carboxamide 5 4-acetyl-N- {4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl] -5 methy1pyrimidin-2-y1}morpholine-2-carboxamide N- {4-[(Z)-cyano(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-y} -4-[(4-methylpiperazin-1 -yl)methy]]benzamide tert-butyl 3 -[({4-[(Z)-cyano(i -ethyl- 1,3 -dihydro-2H-benzimidazol-2 10 ylidene)methyl]-5-methylpyrimidin-2-y} amino)carbonyl]piperidine- 1 -carboxylate tert-butyl 4-[2-({4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)methyl]-5-methylpyrimidin-2-y}amino)-2-oxoethyl]piperidine-1-carboxylate N- {4-[(Z)-cyano(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl}morpholine-2-carboxamide 15 N- {4-[(Z)-cyano(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl-5 methylpyrimidin-2-y}-2-piperidin-4-ylacetamide N- {4-[(Z)-cyano(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)methy]-5 methylpyrimidin-2-y}piperidine-3-carboxamide tert-buty 2-[({ 4-[(Z)-cyano(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2 20 ylidene)methy]-5-methylpyrimidin-2-y) amino)carbonyl]morpholine-4-carboxylate N-[3-({4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl} amino)-3-oxopropyl]benzamide WO 2005/026155 PCT/EP2004/052137 - 121 tert-butyl [2-({4-[(Z)-cyano(1-ethyl- 1,3-dihydro-21-benzimidazol-2 ylidene)methyl]-5-methylpyrimidin-2-y} amino)-2-oxoethyl]methylcarbamate N- {4-[(Z)-cyano(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-y}-1-methylpiperidine-3-carboxamide 5 N-I -- {4-[(Z)-cyano(1-ethyl- 1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-y}-N~2~-methylglycinamide N- {4-[(Z)-cyano(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-y1}pyrrolidine-3-carboxamide tert-butyl 3-[({4-[(Z)-cyano(1 -ethyl- 1,3-dihydro-2H-benzimidazol-2 10 ylidene)methyl]-5-methylpyrimidin-2-yl} amino)carbonyl]pyrrolidine-1-carboxylate (2S)-N- {4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl}-2,5-dihydro- 1H-pyrrole-2-carboxamide tert-butyl (2S)-2-[({4-[(Z)-cyano(1 -ethyl-1,3-dihydro-21H-benzimidazol-2 ylidene)methyl]-5-methylpyrimidin-2-y}amino)carbonyl]-2,5-dihydro-1H-pyrrole-1 15 carboxylate N- {4-[(Z)-cyano(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl}-2-(2-methoxypheny)acetamide 1 -acetyl-N-{4-[(Z)-cyano(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)methy]-5 methylpyrimidin-2-y}piperidine-4-carboxamide 20 N- {4- [(Z)-cyano(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-y}-1-methylpiperidine-4-carboxamide 4-amino-N-{4-[(Z)-cyano(1 -ethyl- 1,3-dihydro-2H-benzimidazol-2-ylidene)methyl] 5-methylpyrimidin-2-yl)butananiide WO 2005/026155 PCT/EP2004/052137 - 122 tert-butyl 4-[({4- [(Z)-cyano(l -ethyl-1,3-dihydro-2H-benzimidazol-2 ylidene)methy]-5-methylpyrimidin-2-y1}amino)carbony]piperidine-1-carboxylate N- {4-[(Z)-cyano(1 -ethyl-1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-yl}piperidine-4-carboxamide 5 tert-butyl [4-({4- [(Z)-cyano(1 -ethyl- 1,3-dihydro-2H-benzimidazol-2 ylidene)methyl]-5-methylpyrimidin-2-y}amino)-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(1 -ethyl- 1,3 -dihydro-2H-benzimidazol-2-ylidene)methyl]-5 10 methylpyrimidin-2-yl}-4-(4-methylpiperazin-1-yl)butanamide N~1-{4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-y}-N~3-,N-3~-dimethyl-beta-alaninamide N-{4-[(Z)-cyano(1 -ethyl- 1,3 -dihydro-2H-ben7imidazol-2-ylidene)methy]-5 methylpyrimidin-2-y} -4-(dimethylamino)butanamide 15 (2Z) -(2-amino-5-methylpyrimidin-4-yl)(1 -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-morpholin-4-ylacetamide N-2--benzyl-N1-- {4-[(Z)-cyano(1-ethyl-1,3 -dihydro-21-benzimidazol-2 20 ylidene)methyl]-5-methylpyrimidin-2-y} glycinamide N- 14-[(Z)-cyano(1 -ethyl-1,3 -dihydro-21-benzimidazol-2-ylidene)methyl]-5 metby1pyrimidin-2-y} -2-(1,l -dioxidothiomorpholin-4-y)acetamide WO 2005/026155 PCT/EP2004/052137 - 123 N-1~-- {4-[(Z)-cyano(1 -ethyl-1,3-dihydro-2H-benzimidazol-2-ylidene)methyl]-5 methylpyrimidin-2-y} -N-2--fornylglycinaiide

9. A benzimidazole acetonitrile according to any of the preceding claims for use as a medicament. 5 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).

10

11. Use of an benzimidazole acetonitrile according to claim 9 wherein the disease is diabetes type 11.

12. A pharmaceutical composition containing a benzimidazole acetonitrile according to any of the claims 1 to 8 and a pharmaceutically acceptable carrier, diluent or excipient thereof. 15

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 20 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, hnirestat, Ponalrestat, ONO-223 5, GP- 1447, CT-112, BAL-ARI 8, AD-5467, ZD5522, M 16209, NZ-314, M-79175, SPR-2 10, ADN 138, or SNK-860, Miglitol, Acarbose, 25 Glipizide, Glyburide, Chlorpropamide, Tolbutamide, Tolazamide, or Glimepriride. WO 2005/026155 PCT/EP2004/052137 - 124

15. A method of preparing a benzimidazole acetonitrile of formula (1) according to any of the claims 1 to 8, comprising the following step: R\R N NG +nN CN N L N G-L H R IV V wherein R', R 2 , G, L are as above described. 5

16. A method of preparing a benzimidazole acetonitrile of formula (I) according to any of the claims 1 to 8, comprising the following step: R 2 2 N CN RB N CN R+ N G-NH N G-L H N2 xH [X = C1, OH] [L = C(O)R 6]

17. A method according to claim 15 or 16, comprising the following steps: N II N N+ C NI CI H N CI N -N R' N R-R R; (IV) I)(1 N N H I I H N/ N C+ R R N N, N, R N RR (11) 111)(1) WO 2005/026155 PCT/EP2004/052137 - 125 wherein Ri, R 3 and R 4 are as above defined. 17. A method according to claim 15, comprising the following steps: N N CI Cl CI N N R N N N R (IV) (I N N R H H6 R N - 01 R~ N,- kN.6 N N NN H N N N () ( 5 wherein R 1 , R 3 and R 4 are as above defined.

18. An intermediate compound of formula (I), selected from the group consisting of: 1,3-benzimidazol-2(3H)-ylidene(2-chloro-6-methylpyrimidin-4-yl)acetonitrile 1,3- benzimidazol -2(3H)-ylidene(2-chloro-6-methylpyrimidin-4-yl)acetonitrile 1,3- benzimidazol -2(3H)-ylidene(6-chloropyrimidin-4-yl)acetonitrile 10