MXPA99011183A - New derivatives of 2- (2-oxo-etilidene) -imidazolidin-4-ona, and compositions and methods for inhibiting abnormal cell growth that understands derivatives - Google Patents

Abstract

The present invention relates to compounds of the formula (I), in which R1, R2, R3 and R4 are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formula I and to methods of inhibiting the abnormal growth of cells, including cancer, in a mammal for administration of the compounds of formula I to said mammal.

Description

NEW DERIVATIVES OF 2- (2-OXO-ETILIDENO.-IMIDAZOLIDIN-4-ONA, AND COMPOSITIONS AND METHODS TO INHIBIT GROWTH ABNORMAL CELLS THAT INCLUDE SUCH DERIVATIVES BACKGROUND OF THE INVENTION This invention relates to a series of novel derivatives of 2- (2-oxo-ethylidene) -imidazolidin-4-one. The compounds exhibit activity as inhibitors of the famesyl protein transferase enzyme, and are considered useful as an anti-cancer and anti-tumor agent. This invention also relates to methods of using such compounds in the treatment or prevention of cancer in a mammal, in particular a human, and to pharmaceutical compositions comprising such compounds. Other compounds that inhibit farnesyl protein transferase and are considered useful as anti-cancer and anti-tumor agents are cited in U.S. Patent Application 08 / 863,514, entitled "Adamantyl Substituted Oxindoles as Pharmaceutical Agents", filed on April 27, 1977, and in document PCT / IB97 / 00584, entitled "Derivatives of 2- (2-Oxo-Ethylidene) -lidazolidin-4-One", assigned to the United States, filed on May 22, 1997 U.S. Provisional Application 60 / 065,097, entitled "Thieno Pyrimidine and Thienopyridine De vatives Useful as Anti-Cancer Agents", filed November 11, 1997, also refers to compounds that are considered useful as agents for treating cancer and other hyperproliferative diseases, for example psoriasis. The foregoing patent applications are incorporated herein by reference in their entireties. Oncogenes frequently encode pro-tein components of signal transduction pathways that lead to the stimulation of cell growth and mitogenesis. The expression of oncogenes in cultured cells leads to cell transformation, characterized by the ability of cells to grow on soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by untransformed cells. The mutation and / or overexpression of certain oncogenes is frequently associated with human cancer. To acquire transformation potential, the precursor of the Ras oncoprotein must undergo farnesylation of the cysteine residue located in a tetrapeptide of the carboxyl terminal. The inhibitors of the enzyme that catalyze this modification, famesyl protein transferase, have therefore been proposed as anti-cancer agents for tumors in which Ras contributes to the transformation. Mutated oncogenic forms of Ras are frequently found in many human cancers, most notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837, 1993). The compounds of the present invention can be active against any tumors that proliferate due to famesyl protein transferase.

The publication by Kohl et al. which precedes, as well as all the other references set forth later in this application, are therefore also incorporated herein by reference in their totalities.

SUMMARY OF THE INVENTION The present invention relates to compounds of the formula I and pharmaceutically acceptable salts thereof, wherein: R1 and R2 are each independently selected from the group consisting of C1-C10 alkyl, C2-C2 alkenyl, C2-C2 alkynyl, or - (CH2) p (C- aryl) C10), and - (CH2) p (4-10 membered unsaturated heterocyclyl), where p is an integer from 0 to 3, or R1 and R2 form a C3-C6 cycloalkyl ring, and wherein any of said groups R1 and R2 are optionally substituted with 1 to 3 R6 groups, with the proviso that, when R1 and R2 form a C3-C6 cycloalkyl ring, said C3-C6 cycloalkyl ring is substituted with at least one R6 group selected from C2- alkenyl. C 2, C 2 -C 8 alkynyl, and - (CH 2) t (aryl Cedo) where t is an integer from 1 to 3; R3 is - (CH2) m (1- or 2-adamantyl), C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) m (halo Ce-Cio), X1, X2, and X3 are each independently C1-C7 alkylene optionally containing 1 or 2 double or triple carbon-carbon bonds, X4 is a C1-C7 bond or alkylene optionally containing 1 or 2 double or triple carbon-carbon bonds , and, in the formula (Ib), the X4 moiety is linked to the X1 moiety at any available carbon from the X1 moiety, and each of the above R3 groups is substituted with a R5 group and optionally with 1 to 4 R6 groups; or R3 is -SO2R9, -C (0) R9, or - (CH2) m (4-10 membered heterocyclyl) optionally substituted with 1 to 5 R6 groups; m, in the R3 groups mentioned above, is independently an integer from 0 to 6; and R 4 is Ce-Cι aryl, 4-10 membered heterocyclyl, or CI-CT alkyl, and each of said R4 groups is optionally substituted with 1 to 3 R6 groups; each R5 is independently selected from halo, C1-C3 alkyl substituted with 1 to 3 halo, nitro, cyano, -OR9, -C (0) R9, -SR9, -S02R9, -SO3H, -S (0) R7 groups, -NR7R8, -C (0) OR9, -OC (0) R9, -S02NR9R8, -C (0) NR9R8, -NR8C (0) R9, -OC (0) NR9R8, -C (0) ONR7R9, -NR8C (0) NR 9 R 8, -NR 8 C (0) 0 (C 1 -C 4 alkyl), -C (NR 8) NR 9 R 8, -C (NCN) NR 9 R 8, -C (NCN) S (C 1 -C 4 alkyl or C 1 -C 4 haloalkyl) , -NR8C (NCN) S (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (NCN) NR7R8, -NR8S02- (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (0) C (0) R8, -NR8C (0) C (0) NR9R8, -P (0) (OR7) 2, and - (CH2) q- (4-10 membered heterocyclyl), q is an integer from 0 to 3, and the alkyl and heterocyclyl radicals of the above-mentioned R5 groups are optionally substituted with 1 to 3 R10 groups; each R6 is independently selected from R5, Ci-Cß alkyl, C2-C10 alkenyl, C2-C10 alkynyl and - (CH2) t (Ce-Cι aryl), such as phenyl or naphthyl, optionally substituted with 1 to 3 R10 groups, where t is an integer from 0 to 3; each R7 is independently hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 halo groups; each R8 is independently R7 or -OR7; each R9 is independently selected from hydrogen, Ci-Cß alkyl, - (CH2) q (aryl Ce-Cio), and - (CH2) q (4-10 membered heterocyclyl), said R9 groups, except H, being optionally substituted with 1 to 3 groups R10, and each q being independently an integer from 0 to 3; and, each R is independently selected from halo, nitro, cyano, C1-C6 alkyl, Ci-Cß haloalkyl, Ci-Cß alkoxy, Ci-Cß haloalkoxy, -C (0) O (d-Ce alkyl), and Ce-Cι aryl, with the proviso that R 1 and R 2 are not both simultaneously C 1 -C 10 alkyl Preferably, in the compounds of formula I, each integer p in R 1 and R 2 is an integer independently selected from 0 to 3, more preferably an integer selected independently from 1 to 3, with 1 being the most preferred value Preferred compounds of formula I include those in which one or both of R1 and R2 is / are - (CH2) P (heterocyclyl 4-10 membered unsaturated) optionally substituted with 1 to 3 R6 groups, more preferably - (CH2) p (5- or 6-membered unsaturated heterocyclyl) Preferably, each heterocyclyl of R1 and R2 is independently imidazolyl or pyridinyl. , one or both of R1 and R2 is / are 2-, 3- or 4-pyridinylmethyl, preferably a or both of R1 and R2 is / are 4-pyridinylmethyl. In other embodiments, R1 and R2 are each independently imidazol-1-ylmethyl, imidazol-2-ylmethyl, or imidazol-4-ylmethyl, optionally substituted with 1 to 3 R6 groups; preferably, R1 and R2 are both imidazol-4-ylmethyl, each optionally substituted with 1 to 3 R6 groups; for example, R1 and R2 are both unsubstituted 3-methyl-imidazol-4-ylmethyl or imidazole-4-ylmethyl. Other preferred compounds of formula I include those in which one or both of R and R is / are C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl, optionally substituted with 1 to 3 R 6 groups, with the proviso that that R1 and R2 are not both simultaneously C1-C10 alkyl. For example, one or both of R 1 and R 2 may be (n) allyl, 3-methyl-but-2-enyl, or 3-chloro-but-2-enyl. When R9 is a group - (CH2) q (heterocyclic 4-10 members), the heterocyclyl ring of R9 preferably has 5 or 6 members in its ring. Said 5- or 6-membered heterocyclyl can, however, be substituted with 1 to 3 R10 groups as defined above. When R9 is a group - (CH2) q (aryl CT-CIO), the aryl ring of R9 is preferably phenyl or naphthyl, which may be substituted with 1 to 3 R groups as defined above. Other preferred compounds of formula I include those in which R3 is - (4-10 membered heterocyclyl Ch) optionally substituted with 1 to 5 R groups, preferably in which m is an integer 0 or 1. Preferably, a R3 group of this type is not substituted or is substituted with 1 to 3 R groups. In a preferred embodiment, R is - (CH 2) m (4-10 membered azacyclyl), preferably saturated. Still more preferably, R3 is saturated (4-10 membered azabicyclyl) - (CH2) m. For example, R3 can be - (CH2) m (azabicyclohexyl), - (CH2) m (azabicycloheptyl), or - (CH2) m (azabicyclooctyl), optionally substituted with 1 to 3 R6 groups. Other preferred compounds of the invention include those in which a nitrogenous ring member of an azacyclyl group R3 is substituted with R5, wherein R5 is -S02R9, -S02NR9R8, or -C (0) OR9. In another embodiment of the invention, R3 is (CH2) m (4-10 membered monocyclic azacyclyl), preferably saturated. Other preferred compounds of the invention include compounds of formula I in which R is - (CH 2) m (Ce-Cι aryl) substituted with a R group and optionally with 1 to 4 R 6 groups. Preferred compounds of the invention in which R3 is a 1a, 5a, 6a-3-azabicyclo [3.1.0] hex-6-yl group include the following: 4 { [1- (1a, 5a, 6a-3-tert-butoxycarbonyl-3-aza-bicyclo- [3.1.0] hex-6-yl) -5-oxo-4, 4-bis-pyridin-4-ylmethyl- imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4 { [1- (1a, 5a, 6a-aza-bicyclo- [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl } -benzonitrile; 4- ( { 5-oxo-1 - [1, 5a, 6a-3- (1-phenyl-1 H-tetrazol-5-yl) -3-aza-bicyclo- [3.1.Ojhex-e-ilH ^ -bis-pyridin-^ - ylmethyl-imidazolidin ^ -ylidenoj-acetyl-benzonitrile, benzyl ester of 1a.5a.6a-6- { 2- [2- (4-cyano-phenyl) -2-oxo) -ethylidene] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-yl.} - 3-aza-bicyclo. {3.1.0.} hexane-3-carboxylic acid; - ( { 1 - [1 a, 5a, 6a-3- (3,3-dimethyl-butyryl) -3-aza-bicyclo [3.1.0] hex-6-yl] -5-oxo-4, 4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} -acetyl) -benzonitrile; 4- (. {5-oxo-4,4-bis-pyridin-4-ylmethyl-1- [1a 5a, 6a-3- (thiophen-2-yl-acetyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -imidazolidin-2-ylidene} - acetyl) -benzonitrile diethyl ester of the acid 1a, 5a, 6a- (6- { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4-ylmethyl- imidazolidin-1-yl.} - 3-aza-bicyclo [3.1.0] hex-3-yl) -phosphonic acid: 4- { [1- (1, 5, 6a-3-benzenesulfonyl-3-aza -bicyclo [3.1.0] -hex-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; ( { 1 - [1, 5a, 6a-3- (4-methoxy-benzenesulfonyl) -3-aza-bicyclo [3.1.0] hex-yl) -5-oxo-4, 4-bis-pyridine- 4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4- ( { 1 - [1 a, 5a, 6 -3- (4-fluoro-benzenesulfonyl) -3-aza-bicyclo [3.1.0] hex-yl) -5-oxo-4,4-bis -pyridin-4-ylmethyl-imidazolidin-2-ylidene} -acetyl) -benzonitrile; 4-. { [5-oxo-1- (1 a, 5a, 6a-3-phenylmethanesulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl) -4,4-bis-pyridin-4-ylmethyl -imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4-. { [1- (1a, 5a, 6a-3- (4-chlorobenzene) sulfonyl-3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4- ilmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4- ( { 1 - [1 a, 5a, 6a-3- (naphthalene-2-sulfonyl-3-aza-bicyclo- [3.1.0] hex-6-yl) -5-oxo-4.4 bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -be-nzonitrile; 4- ( { 5-Oxo-4,4-bis-pyridin-4-ylmethyl-1- [1a, 5a, 6a-3- (toluene-4-sulfonyl) -3-aza-bicyclo [3.1.0 ] hex-6-yl] -imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 5-Oxo-4,4-bis-pyridin-4-ylmethyl-1- [1a, 5a, 6a-3- (toluene-2-sulfonyl) -3-aza-bicyclo [3.1 .0] hex-6-yl] -imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 5-oxo-1 - [1 a, 5a, 6a-3- (piperidine-1-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -4.4 bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 1 - [1 a, 5a, 6a-3- (4-methyl-piperazine-1-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -5-oxo 4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 5-oxo-4,4-bis-pyridin-4-ylmethyl-1- [1, 5a, 6a-3- (thiophene-2-sulfonyl) -3-aza-bicyclo [3.1.0 ] hex-6-yl] -imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- (1, 5, 6a-6- { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis- tert -butyl ester pyridin-4-ylmethyl-imidazolidin-1-yl.} - 3-aza-bicyclo [3.1.0] hexane-3-sulfonyl) -piperazine-1-carboxylic acid; 4- ( { 1 - [1 a, 5a, 6a-3- (5-bromo-thiophene-2-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -5-oxo 4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 1 - [1 a, 5a, 6a-3- (4-ethyl-piperazine-1-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -5- oxo-4,4-bis-pyridin-4-methyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 1 - [1, 5, 6a-3- (3-chloro-propane-1-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] - 5-oxo- 4, 4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 5-oxo-1 - [1 a, 5a, 6a-3- (propane-1-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -4.4 Bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; ethyl ester of 1- (1a, 5a, 6a-6- { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4, 4-bis-pyridine- 4-ylmethyl-imidazolidin-1-yl.} - 3-aza-bicyclo [3.1.0] hexane-3-sulfonyl) piperidine-4-carboxylic acid; 4- ( { 5-oxo-1 - [1 a, 5a, 6a-3- (4-propyl-piperidine-1-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] 4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 1 - [1 a, 5a, 6a-3- (2,5-dichloro-thiophene-3-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -5 -oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 1 - [1 a, 5a, 6a-3- (4-isopropyl-piperazine-1-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -5-oxo 4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; dimethylamide of acid 1a, 5a, 6a-6. { 2- [2- (4-cyano-phenyl] -2-oxo-ethylidene] -5-oxo-4, 4-bis-pyridin-4-ylmethyl-imidazolidin-1-yl}. -3-aza-bicyclo [3.1.0] hexane-3-sulphonic; 4- { [1- (1a, 5a, 6a-3-chloromethanesulfonyl-3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo 4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4- { [1a, 5a, 6β-1- (3-benzenesulfonyl-3-aza- bicyclo [3.1.0] hex-6-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-lidazolidin-2-ylidene] -acetyl} -benzonitrile; 4- { [ 1, 5a, 6a-1 - (3-benzenesulfonyl-3-aza-bicyclo [3.1.0] hex-6-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2- ylidene] -acetyl} -benzonitrile; and 4- { [1a, 5a, 6β-1- (3-benzenesulfonyl-3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo 4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile Further preferred compounds of the invention in which R3 is a group - (CH2) m (1a, 5a, 6a-3-aza-bicyclo [3.1.0] hex-6-yl) include: tert-butyl ester of acid 1a, 5a, 6a-6-. {4-allyl-2- [2- (4-cyano phenyl) -2-oxo-ethylidene] -5-oxo-4-pyridi n-4-ylmethyl-imidazolidin-1-yl} -3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid; 4-. { [4-allyl-1 - (1 a, 5a, 6a-3-benzenesulfonyl-3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4-pyridin-4-ylmethyl-imidazolidin- 2-ylidene] -acetyl} -benzonitrile; 4-. { [5-oxo-4-allyl-4-pyridin-4-ylmethyl-1 - [1 a, 5, 6a-3- (thiophene-2-acetyl) -3-aza-bicyclo [3.1.0] hex-6 -yl) -imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4- ( { 4-allyl-5-oxo-4-pyridin-4-ylmethyl-1- [1a, 5a, 6a-3- (thiophen-2-yl-sulfonyl) -3-aza-bicyclo [3.1 .0] hex-6-yl) -imidazolidin-2-ylidene] -acetyl} -benzonitrile; tert-butyl ester of acid 1a, 5a, 6a-6- [2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -4- (3-methyl-but-2-enyl) -5 -oxo-4-pyridin-4-ylmethyl-imidazolidin-1-yl] -3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid; 4-. { [1 - [1 a, 5a, 6a-3- (5-bromo-thiophene-2-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -4- (3-methyl-but -2-enyl) -5-oxo-4-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} - benzonitrile; tert-butyl ester of acid 1a, 5a, 6a-6-. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4-pyridin-4-ylmethyl-4-thiophen-3-methyl-imidazolidin-1-yl} -3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid; 4-. { [1- (1a, 5, 6a-3-benzenesulfonyl-3-aza-bicyclo [3.1.0] -hex-6-yl) -5-oxo-4-pyridin-4-ylmethyl-4-thiophen-3- Lmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; tert-butyl ester of acid 1a, 5a, 6a-6-. { 4- (3-chloro-but-2-enyl) -2- [2- (4-cyano-phenyl) -2-oxo-etlidene] -5-oxo-4-pyridin-4-ylmethyl-imidazolidin- 1-il} -3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid; and 4-. { [1 - [1 a, 5a, 6a-3- (5-bromo-thiophene-2-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -4- (3-chloro-but -2-enyl) -5-oxo-4-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile. Other compounds of the invention include compounds of formula I in which R3 is - (CH2) m (piperidin-2-yl), - (CH2) m- (piperidin-3-yl), or - (CH2) m (piperidin -4-ilo). Preferred examples of such compounds include: 4-. { [1- (1-Benzenesulfonyl-piperidin-4-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4-dimethylamide. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-ylmethyl} -piperidine-1-sulfonic acid; 4- ( { 5-oxo-1 - [1 - (1-phenyl-1 H-tetrazol-5-yl) -piperidin-4-ylmethyl] -4,4-bis-pyridin-4-ylmethyl-imidazolidin -2-ylidene.} - acetyl) -benzonitrile; 4- ( { 1 - [1 - (1-methyl-1 H-imidazol-4-sulfonyl) -piperidin-4-ylmethyl] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin -2-ylidene.} - acetyl) -benzonitrile; and 4- (. {5-oxo-4,4-bis-pyridin-4-ylmethyl-1- [1- (thiophene-2-sulfonyl) -piperidin-4-ylmethyl] -imidazolidin-2-ylidene}. .-acetyl) -benzonitrile. Other compounds of the invention include compounds of formula I in which R3 is - (CH2) m (pyrrolidin-2-yl) or (CH2) m (pyrrolidin-3-yl). Preferred examples of such compounds include: 4-. { [1- (1-Benzenesulfonyl-pyrrolidin-3-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl] -benzonitrile; 4-. { [1- (1-benzenesulfonyl-pirtolidin-3-methylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl] -benzonitrile; and 4- (. {5-oxo-4,4-bis-pyridin-4-ylmethyl-1 - [1 - (thiophene-2-sulfonyl) -pyrrolidin-3-ylmethyl] -imidazolidin-2-ylidene} .-acetyl) -benzonitrile. Other compounds of the invention include compounds of formula I in which R3 is - (CH2) m (1a, 6a, 7a-3-aza-bicyclo [4.1.0] hept-7-yl), optionally substituted with 1 to 3 R6 groups. Specific examples of such compounds include: 4-. { [1, 6, 7a-1- (3-Benzenesulfonyl-3-aza-bicyclo [4.1.0] hept-7-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2 -ylidene] -acetyl} -benzonitrile; and 4-. { [1, 6a, 7a-1 - (3-benzenesulfonyl-3-aza-bicyclo [4.1.0] hept-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2 -ylidene] -acetyl} -benzonitrile. Other preferred compounds of the invention are those in which R3 is (CH2) m (4-10 membered heterocyclyl) and R1 and R2 are both an imidazolyl group optionally substituted with 1 to 3 R6 groups. Examples include: 4-. { [1- (1a, 5a, 6a-3-Benzenesulfonyl-3-aza-bicyclo [3.1.0] -hex-6-yl) -4,4-bis- (1 H-imidazol-4-ylmethyl) -5 -oxo-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4- ( {4,4-bis- (1 H-imidazol-4-ylmethyl) -1 - [1 a, 5a, 6a-3- (4-methyl-piperidine-1-sulfonyl) -3-aza -bicyclo [3.1.0] hex-6-yl] -5-oxo-imidazolidin-2-ylidene] -acetyl) -benzonitrile; 4-. { [1 - [1 a, 5a, 6a-3- (5-bromo-thiophene-2-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -4,4-bis- (1 H-imidazol-4-ylmethyl) -5-oxo-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4-. { [1- (1a, 5a, 6a-3-aza-3- (tert-butoxycarbonyl) -bicyclo [3.1.0] hex-6-yl) -4,4-bis- (3-methyl-3H-imidazole- 4-ylmethyl) -5-oxo-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4-. { [1- (1, 5a, 6a-3-aza-3-bicyclo [3.1.0] hex-6-yl) -4,4-bis- (3-methyl-3H-imidazol-4-ylmethyl) -5 -oxo-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4-. { [1- (1a, 5a, 6 -3-benzenesulfonyl-3-aza-3-bicyclo [3.1.0] -hex-6-yl) -4,4-bis- (3-methyl-3H-imidazole-4) -ylmethyl) -5-oxo-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4- ( { 4,4-bis- (3-methyl-3H-imidazol-4-ylmethyl) -1 - [1 a, 5a, 6a-3- (4-methyl-piperazine-1-sulfonyl) - 3-aza-bicyclo [3.1.0] hex-6-yl] -5-oxo-imidazolidin-2-ylidene} - acetyl) -benzonitrile; and 4-. { [1- [1a, 5a, 6a-3- (5-bromo-thiophene-2-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -4,4-bis- (3- methyl-3H-imidazol-4-ylmethyl) -5-oxo-imidazolidin-2-ylidene] -acetyl} -benzonitrile. Other preferred compounds of the invention include compounds of formula I in which R3 is - (CH2) m [8a-aza-bicyclo [3.2.1] octane) or - (CH2) m (8β-aza-bicyclo [3.2.1 ] octane), optionally substituted with 1 to 3 R6 groups.

Preferred examples of such compounds include: 3- tert -butyl ester. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-ylmethyl} -8a-aza-bicyclo [3.2.1] octane-8-carboxylic acid; 4-. { [1- (8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4-. { [1 - (8-acetyl-8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pi-rid-4-ylmethyl-imidazolidin-2-ylidene] -acety} -benzonitrile; 4-. { [1- (8-methanesulfonyl-8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 3-ethyl ester. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-ylmethyl} -8a-aza-bicyclo [3.2.1] octane-8-carboxylic acid; 4-. { [1- (8-formyl-8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] - acetyl } -benzonitrile; 3- methyl acid ester. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-ylmethyl} -8a-aza-bicyclo [3.2.1] octane-8-carboxylic acid; 4-. { [1- (8-Benzenesulfonyl-8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 3- acid dimethylamide. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-ylmethyl} -8a-aza-bicyclo [3.2.1] octane-8-sulphonic; 4-. { [1- (8-ethanesulfonyl-8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4- ( { 5-oxo-1- [8- (propane-1-sulfonyl) -8a-aza-bicyclo [3.2.1] oct-3-ylmethyl] -4,4-bis-pyridin-4- ilmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 3- {2- [2- (4-cyano-phenyl) -2-oxo-ethylidene} -5-oxo) tert-butyl ester 4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-methylmethyl] -8β-aza-bicyclo [3.2.1] octane-8-carboxylic acid; 4- { [1 - (8β-aza -bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl] -benzonitrile; 4- { [ 1- (8-acetyl-8β-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} .benzonitrile; 4- { [1 - (8-methanesulfonyl-8β-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl- imidazolidin-2-ylidene] -acetyl}. -benzonitrile; 4- { [1- (8-benzenesulfonyl-8β-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4, 4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 3- {2- [2- (4-cyano-phenyl) -2-oxo-ethylidene} dimethylamide ] -5-oxo-4,4-bis-pyrid in-4-ylmethyl-imidazolidin-1-ylmethyl} -8a-aza-bicyclo [3.2.1] octane-8-sulphonic; and 4- ( { 1- [8- (1-methyl-1 H-imidazol-4-sulfonyl) -8β-aza-bicyclo [3.2.1] oct-3-ylmethyl] -5-oxo-4, 4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile. Other preferred compounds of the invention include compounds of formula I in which R 3 is - (CH 2) m (Ce-Cι aryl) substituted with a group R 5 and optionally with 1 to 4 R 6 groups. Preferred compounds in which R3 is - (CH2) m- (Ce-Cryl aryl) substituted with a group R5 and optionally with 1 to 4 R6 groups include: 4-. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolin-1-ylmethyl} -N, N-dimethyl-benzenesulfonamide; 4-. { [1- (3-Chloro-benzyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4-. { [1- (3-methoxy-benzyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4-. { [1- (3-Fluoro-benzyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4-. { [1- (2-Chloro-benzyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4-. { [1- (4-methanesulfonyl-benzyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; and 4-. { [1- (2-methoxy-benzyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-lmidazolidin-2-ylidene] -acetyl} -benzonitrile. This invention also provides a compound of the formula VIII wherein: R1 and R2 are each independently selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) P (aryl Ce-C10), and - (CH2) P (4-10 membered unsaturated heterocyclyl), where p is an integer from 0 to 3, or R1 and R2 form a C3-C6 cycloalkyl ring, and wherein any of said groups R1 and R2 are optionally substituted with 1 to 3 groups R6; R3 is - (CH2) m (1- or 2-adamantyl), C1-C10 alkyl, C2-C10 alkenyl, alkynyl- (CH2) m (aryl CT-CIO), (b) (Ib) X1, X2, and X3 are each independently C1-C7 alkylene optionally containing 1 or 2 double or triple carbon-carbon bonds, X4 is a C1-C7 bond or alkylene optionally containing 1 or 2 double or triple carbon-carbon bonds , and, in the formula (Ib), the X4 moiety is linked to the X1 moiety at any available carbon from the X1 moiety, and each of the above R3 groups is substituted with a R5 group and optionally with 1 to 4 R6 groups; or R3 is SO2R9, -C (0) R9, or - (CH2) m (4-10 membered heterocyclyl) optionally substituted with 1 to 5 R groups; m, in the R3 groups mentioned above, is independently an integer from 0 to 6; and R 4 is Ce-Cι aryl, 4-10 membered heterocyclyl, or Ci-Ce alkyl, and each of said R4 groups is optionally substituted with 1 to 3 R6 groups; each R5 is independently selected from halo, C1-C3 alkyl substituted with 1 to 3 halo, nitro, cyano, -OR9, -C (0) R9, -SR9, -S02R9, -SO3H, -S (0) R7 groups, -NR7R8, -C (0) OR9, -OC (0) R9, -S02NR9R8, -C (0) NR9R8, -NR8C (0) R9, -OC (0) NR9R8, -C (0) ONR7R9, -NR8C (0) NR 9 R 8, -NR 8 C (0) 0 (C 1 -C 4 alkyl), -C (NR 8) NR 9 R 8, -C (NCN) NR 9 R 8, -C (NCN) S (C 1 -C 4 alkyl or C 1 -C 4 haloalkyl), -NR8C (NCN) S (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (NCN) NR7R8, -NR8S02- (C? -C4 alkyl or C1-C4 haloalkyl), -NR8C (0) C (0) R8, -NR8C (0) C (0) NR9R8, -P (0) (OR7) 2, and - (CH2) q- (4-10 membered heterocyclyl), q is an integer from 0 to 3, and the alkyl and heterocyclyl radicals of the above-mentioned groups R5 are optionally substituted with 1 to 3 R groups; each R6 is independently selected from R5, Ci-Cd alkyl, C2-C10 alkenyl, C2-C10 alkynyl and - (CH2) t (C6-C10 aryl), optionally substituted with 1 to 3 R10 groups, where t is an integer 0 to 3; each R7 is independently hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 halo groups; each R8 is independently R7 or -OR7; each R9 is independently selected from hydrogen, Ci-Cß alkyl, - (CH2) q (aryl CT-CIO), and - (CH2) q (4-10 membered heterocyclyl), said R groups being 10, except H, optionally substituted with 1 to 3 R groups, and each q being independently an integer from 0 to 3; and, each R10 is independently selected from halo, nitro, cyano, CI-CT alkyl, Ci-Cß haloalkyl, CI-CT alkoxy, Ci-Cß halo-alkoxy, -C (0) 0 (d-Ce alkyl), and aryl Ce-Cío; with the proviso that R1 and R2 are not both simultaneously C1-C10 alkyl. The compounds of formula VIII are useful as intermediates for preparing compounds of formula I. This invention also provides a compound of the formula xrv in which: R1 and R2 are each independently selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) p (aryl Ce-C10), and - (CH2) ( 4-10 membered unsaturated heterocyclyl), wherein p is an integer from 0 to 3, or R1 and R2 form a C3-C6 cycloalkyl ring, and wherein any of said R1 and R2 groups are optionally substituted with 1 to 3 R6 groups; is a saturated heteroazacyclyl group of 4-10 members, optionally substituted with 1 to 4 additional R groups; m is an integer from 0 to 6; and R 4 is Ce-Cι aryl, 4-10 membered heterocyclyl, or Ci-Ce alkyl, and each of said R4 groups is optionally substituted with 1 to 3 RDF groups each R is independently selected from R, CI- alkyl CT, C2-C10 alkenyl, C2-C10 alkynyl and - (Ch Maryl Ce-Cio) optionally substituted with 1 to 3 R groups, where t is an integer from 0 to 3; each R5 is independently selected from halo, C1-C6 alkyl substituted with 1 to 3 halo groups, nitro, cyano, -OR9, -C (0) R9, -SR9, -SO2R9, -SO3H, -S (0) R7, -NR7R8, -C (0) OR9, -OC (0) R9, -S02NR9R8, -C (0) NR9R8, -NR8C (0) R9, -OC (0) NR9R8, -C (0) ONR7R9, -NR8C (0) NR 9 R 8, -NR 8 C (0) 0 (C 1 -C 4 alkyl), -C (NR 8) NR 9 R 8, -C (NCN) NR 9 R 8, -C (NCN) S (C 1 -C 4 alkyl or C 1 -C 4 haloalkyl), -NR8C (NCN) S (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (NCN) NR7R8, -NR8S02- (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (0) C (0) R8 , -NR8C (0) C (0) NR R8, -P (0) (OR7) 2, and - (CH2) q- (heterocyclyl of 4-10 members), q is an integer from 0 to 3, and the alkyl and heterocyclyl radicals of the above-mentioned groups R5 are optionally substituted with 1 to 3 R groups; each R7 is independently hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 halo groups; each R8 is independently R7 or -OR7; each R9 is independently selected from hydrogen, alkyl Ci-Cß, - (CH2) q (aryl Ce-Cio), and - (CH2) q (heterocyclyl of 4-10 members), said groups being R 10, except H, optionally substituted with 1 to 3 R groups, and each q being independently an integer from 0 to 3; and, each R10 is independently selected from halo, nitro, cyano, Ci-Cß alkyl, Ci-Cß haloalkyl, d-Cß alkoxy, Ci-Cß haloalkoxy, -C (0) 0 (Ci-Ce alkyl), and aryl Ce-Cío; with the proviso that R1 and R2 are not both simultaneously C1-C10 alkyl. The compounds of formula XIV are useful as intermediates for preparing compounds of formula I. This invention also provides a compound of the formula wherein: R1 and R2 are each independently selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) p (C10-C10 aryl), and - (CH2) P ( 4-10 membered unsaturated heterocyclyl), wherein p is an integer from 0 to 3, or R and R form a C3-C6 cycloalkyl ring, and wherein any of said R and R groups are optionally substituted with 1 to 3 R6 groups; is a saturated heteroazacyclyl group of 4-10 members; m is an integer from 0 to 6; and R 4 is Ce-Cι aryl, 4-10 membered heterocyclyl, or C 1 -C β alkyl, and each of said R 4 groups is optionally substituted with 1 to 3 R 6 groups; each R6 is independently selected from R5, Ci-Cβ alkyl, C2-C10 alkenyl, C2-C10 alkynyl, and - (C6-C10-C-aryl) optionally substituted with 1 to 3 R groups, where t is an integer from 0 to 3; each R5 is independently selected from halo, C1-C3 alkyl substituted with 1 to 3 halo, nitro, cyano, -OR9, -C (0) R9, -SR9, -SO2R9, -SO3H, -S (0) R7 groups, -NR7R8, -C (0) OR9, -OC (0) R9, -S02NR9R8, -C (0) NR9R8, -NR8C (0) R9, -OC (0) NR9R8, -C (0) ONR7R9, -NR8C (0) NR 9 R 8, -NR 8 C (0) 0 (C 1 -C 4 alkyl), -C (NR 8) NR 9 R 8, -C (NCN) NR 9 R 8, -C (NCN) S (C 1 -C 4 alkyl or C 1 -C 4 haloalkyl), -NR8C (NCN) S (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (NCN) NR7R8, -NR8SO2- (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (0) C (0) R8 , -NR8C (0) C (0) NR9R8, -P (0) (OR7) 2, and - (CH2) q- (4-10 membered heterocyclyl), q is an integer from 0 to 3, and alkyl and heterocyclyl moieties of the above-mentioned groups R5 are optionally substituted with 1 to 3 R groups; each R7 is independently hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 halo groups; each R8 is independently R7 or -OR7; each R9 is independently selected from hydrogen, Ci-Cß alkyl, - (CH2) q (aryl Ce-Cio), and - (CH2) q (4-10 membered heterocyclyl), said R groups being 10, except H, optionally substituted with 1 to 3 R groups, and each q being independently an integer from 0 to 3; and, each R is independently selected from halo, nitro, cyano, alkyl CI-CT, haloalkyl Ci-Cß, alkoxy Ci-Cß, halo-alkoxy Ci-Cß, -C (0) 0 (Ci-Ce alkyl), and Ce-Cío aryl; with the proviso that R1 and R2 are not both simultaneously C1-C10 alkyl. The compounds of formula I are a subset of compounds of formula I. In addition to their use described herein in the inhibition of farnesyl protein transferase activity, the compounds of formula I are useful as intermediates for synthesizing additional compounds encompassed by the formula I. This invention also relates to a method for inhibiting the abnormal growth of cells in a mammal, including a human being, which comprises administering to said mammal an amount of a compound of the formula I, as defined above, or a pharmaceutically acceptable salt thereof, which is effective to inhibit famesyl protein transferase. This invention also relates to a method for inhibiting abnormal cell growth in a mammal, including a human, which comprises administering to said mammal an amount of a compound of formula I, as defined above, or one of its pharmaceutically acceptable salts, which is effective to inhibit the abnormal growth of cells. This invention also relates to a composition for inhibition of abnormal cell growth in a mammal, including a human being, which comprises administering to said mammal an amount of a compound of formula I, as defined above, or a pharmaceutically acceptable salt thereof, which is effective to inhibit farnesyl protein transferase , and a pharmaceutically acceptable vehicle. This invention also relates to a composition for inhibiting abnormal cell growth in a mammal, including a human, which comprises administering to said mammal an amount of a compound of formula I, as defined above, or one of its pharmaceutically acceptable salts, which is effective to inhibit the abnormal growth of cells, and a pharmaceutically acceptable carrier. This invention also provides a method for inhibiting abnormal cell growth in a mammal, which comprises administering to said mammal an amount of a compound according to formula I and an amount of an anti-tumor agent selected from the group consisting of mitotic inhibitors. , alkylating agents, anti-metabolites, intercalation antibiotics, inhibitors of growth factors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, and anti-hormones, in which the amount of said agent Anti-tumor is, in combination with the amount of the compound of formula I, effective to inhibit the abnormal growth of cells in the mammal. This invention further provides a composition for inhibition of abnormal cell growth in a mammal, which comprises administering to said mammal an amount of a compound according to formula I; an amount of an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalation antibiotics, inhibitors of growth factors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, response modifiers biological, and anti-hormones; and a pharmaceutically acceptable vehicle; wherein the amount of said anti-tumor agent is, in combination with the amount of the compound of formula I, effective to inhibit the abnormal growth of cells in the mammal. The term "abnormal cell growth", as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (eg, loss of contact inhibition). . This includes the abnormal growth of: (1) tumor cells (tumors) that express an activated Ras oncogene; (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative disorders in which an aberrant activation of Ras occurs. "Abnormal cell growth" further includes any unregulated cell growth caused by the activity of famesyl protein transferase. Examples of benign proliferative diseases include, but are not limited to, psoriasis, benign prostatic hypertrophy and restenosis. The term "halo", as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo. The term "alkyl", as used herein, unless otherwise indicated, means linear, cyclic, and branched monovalent hydrocarbon radicals. For example, a Ci-Cd alkyl group includes, but is not limited to, a n-butyl radical and a tere-butyl radical. It should be understood that at least three carbon atoms in said alkyl group must be present for the cyclic moieties. The term "alkenyl", as used herein, unless otherwise indicated, means linear and branched monovalent hydrocarbon radicals comprising at least one carbon-carbon double bond. It should be understood that at least two carbon atoms must be present for each carbon-carbon double bond in said moieties. The term "alkynyl", as used herein, unless otherwise indicated, means linear and branched monovalent hydrocarbon radicals comprising at least one carbon-carbon triple bond. It should be understood that at least two carbon atoms must be present for each triple carbon-carbon bond in said residues. The term "cycloalkyl", as used herein, unless otherwise indicated, includes saturated cyclic alkyl groups as well as cyclic alkyl groups comprising one or more points of unsaturation, i.e. one or more carbon double bonds -carbon. The term "alkylene", as used herein, unless otherwise indicated, means bivalent hydrocarbon radicals which are linear or branched. The term "haloalkyl", as used herein, unless otherwise indicated, means alkyl groups, in which "alkyl" is as defined above, substituted with one or more halo groups, in one or more carbon atoms. Preferably, the haloalkyl comprises one to three halo groups, such as a hydrocarbon comprising a trifluoromethyl or trichloromethyl group, or a hydrocarbon monosubstituted with halogen. The term "alkoxy," as used herein, unless otherwise indicated, means -O-alkyl groups in which "alkyl" is as defined above. "Haloalkoxy", as used herein, unless otherwise indicated, means a -O-haloalkyl group in which "haloalkyl" is as defined above. The term "aryl", as used herein, unless otherwise indicated, means an organic radical derived from an aromatic hydrocarbon by removal of a hydrogen, such as phenyl, naphthyl and fluorene. The term "heterocyclyl", as used herein, unless otherwise indicated, means aromatic and non-aromatic heterocyclic groups (including saturated heterocyclic groups) containing one or more heteroatoms each selected from O, S and N, in which each ring of a heterocyclic group has from 4 to 10 atoms. Non-aromatic heterocyclic groups may include rings having only 4 atoms, but the aromatic heterocyclic rings must have at least 5 atoms. The heterocyclic groups of this invention, unless otherwise indicated, may contain a ring or more than one ring, ie they may be monocyclic or multicyclic, for example bicyclics (which may contain non-aromatic and / or aromatic rings) . Preferably, the bicyclic heterocyclic groups of this invention contain 6-9 members in their ring systems. The monocyclic heterocyclic groups of this invention preferably contain 5 or 6 members. Examples of bicyclic heterocyclyls include, but are not limited to, non-aromatic azabicyclohexane, azabicycloheptane and azabicyclooctane groups. Aromatic multicyclic heterocyclic groups include benzocondensate ring systems. The heterocyclic groups of this invention also include ring systems substituted with one or more oxo moieties. An example of a 4-membered heterocyclic group is azetidinyl (azetidine derivative). An example of a 5-membered heterocyclic group is thiazolyl, and an example of a 10-membered heterocyclic group is quinolinyl. Examples of non-aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, piperidinyl, 1, 2,3,6-tetrahydropyridinyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H - pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanil, 3H-indolyl and quinolizinyl . Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups, as derived from the compounds listed above, may be attached to C or attached to N when possible. For example, a pyrrole derivative group can be pyrrol-1-yl (attached to N) or pyrrole-3-yl (attached to C). The terms "azacyclyl", "azacyclic group", "azabicyclyl", and the like, as used herein, unless otherwise indicated, mean a heterocyclyl group as defined above, in which at least one member of the ring is a nitrogen atom. Examples of azacyclyl groups include, but are not limited to, radicals that can be obtained from 1-azabicyclo [2.2.2] oct-3-ylamine, 1,8-octalactam, N-amino-3-azabicyclo (3.3, 0) -octane, perhydroindol, azacyclohepta-no, 3-azabicyclo (3.2.2) nonane, 3-amino-2-oxohexamethylene-imine, azacyclooctane, 3-azabicyclo [3.1.0] hexane, 8-azabicyclo [3.2.1 ] octane, and 3-azabicyclo [4.1.OJheptane. The term "treat"as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which that term applies, or one or more symptoms of said disorder or condition. condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating, as "treating" is defined in the immediately preceding sentence. The term "pharmaceutically acceptable salt (s)", as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of formula I. For example , pharmaceutically acceptable salts include sodium, calcium and potassium salts of carboxylic acid groups and hydrochloride salts of amino groups. Other pharmaceutically acceptable salts of amino groups are hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. The preparation of said salts is described below. Certain compounds of formula I can have asymmetric centers and therefore can exist in different enantiomeric forms. It is considered that all optical isomers and stereoisomers of the compounds of formula I, and mixtures thereof, are within the scope of the invention. With respect to the compounds of formula I, the invention includes the use of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, or mixtures thereof. The compounds of formula I can also exist as tautomers. This invention relates to the use of all of said tautomers and mixtures thereof. The present invention also includes isotope-labeled compounds, which are identical to those cited in formula I, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number that is usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36CI, respectively. The compounds of the present invention and the pharmaceutically acceptable salts of said compounds containing the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain compounds of the present invention labeled with isotopes, for example those in which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and / or tissue substrate distribution assays. Tritiated isotopes, ie labeled with 3H, and those containing carbon 14, ie, 14C, are particularly preferred for their ease of preparation and detectability. Additionally, replacement with heavier isotopes such as deuterium, i.e., 2H, may provide certain therapeutic advantages resulting from their greater metabolic stability, for example increased half-life in vivo or reduced dosage requirements and, therefore, may be preferred in some circumstances The compounds of formula I of this invention labeled with isotopes can generally be prepared by performing the procedures described in the Schemes and / or the following examples, by replacing an easily available isotope-labeled reagent in place of a non-isotope-labeled reagent. Any patient suffering from abnormal cell growth as defined above can be treated with the compounds of formula I according to the methods of this invention. Patients that can be treated with compounds of formula I, as defined above, or their pharmaceutically acceptable salts, according to the methods of this invention include, for example, patients who have been diagnosed for lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or infra-ocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecological tumors (eg, uterine sarcomas, carcinoma of the fallopian tubes, endometrial carcinoma, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (eg cancer of the thyroid, parathyroid or adrenal glands), soft tissue sarcomas, urethral cancer, penile cancer, prostate cancer, chronic leukemia or acute, solid childhood tumors, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer (eg, renal cell carcinoma, renal pelvis carcinoma), or neo plasmas of the central nervous system (e.g., CNS primary lymphoma, spinal axis tumors, brainstem gliomas, or pituitary adenomas. Other examples of patients that can be treated with compounds of formula I or pharmaceutically acceptable salts of said compounds according to the methods of the invention include patients suffering from benign proliferative diseases, such as psoriasis, benign prostatic hypertrophy or restenosis.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula I are prepared as described below. In the Reaction Schemes and the discussion that follows, R1, R2, R3, R4, R6 and "m" are as defined above. The symbol "Me" in the following diagrams represents a methyl group.

SCHEME I VI SCHEME I (continued) VI Vil VIII Scheme I illustrates the synthesis of the compounds of formula I. In Step 1, the ester of formula II is reacted with potassium bis (trimethylsilyl) amide in tetrahydrofuran (THF) at a temperature of about -70 ° C. The reaction mixture is stirred for about 30 minutes, and then a compound of the formula R1-X is added, wherein R1 is as defined above and X is an appropriate leaving group, such as chloride or bromide, a the reaction mixture, which is then allowed to warm to room temperature (20-25 ° C). This results in the compound of formula III, which can be isolated or reacted in situ to form the compound of formula IV). In Step 2, the substituent R2, in which R2 is as defined above, is added to the compound of formula III to provide the compound of formula IV) according to the procedure of Step 1, except that R2 is employed -X to replace R1-X. In Step 3, the intermediate of formula V is formed by reacting the compound of formula IV with an acid, preferably a mineral acid such as hydrochloric, nitric or sulfuric acid, in an organic co-solvent such as ethyl ether, THF or acetonitrile, preferably THF, at a temperature comprised between about -5 ° C and 35 ° C, preferably from about 0 ° C to room temperature. Steps 4 and 5 can be performed as a single step or as separate steps. In general, the imidazolidine intermediate of formula VII is formed by reacting the intermediate compound of formula V with a compound of formula R3-NCS, in which R3 is as defined above. R3-NCS can be synthesized by reacting R3-NH2 with a thiophosgene or 1, 1-thiocarbonyldiimidazole (ImCSIm), in a solvent such as methylene chloride (CH2Cl2), and stirring the reaction mixture for about 12 hours. In this process, the intermediate compound of formula V and R3-NCS are reacted in a protic solvent, such as methanol or ethanol, preferably ethanol, at a temperature between about room temperature and 78 ° C, preferably about the reflux temperature of the solvent. The reaction is preferably carried out for about 12 to 24 hours, but this period may be longer or shorter depending on the substituent R3 to be added. When R3 is 1- or 2-adamantyl, it is preferable to use a large excess of the R3-NCS reactant and let the reaction proceed for a period of about two days to a week. In those cases where the intermediate compound of formula VI is isolated before the formation of the intermediate compound of formula VII, a catalytic amount of potassium cyanide is added to the reaction mixture to catalyze the formation of the intermediate compound of formula VII. In Step 6, the intermediate compound of formula VII is reacted with a compound of the formula R -C (0) CH2-X, in which R4 is as defined above and X is a leaving group, such as chloride or bromide, to provide the intermediate compound of formula VIII. In this process, the intermediate compound of formula VII is reacted with a strong base, such as sodium hydride, potassium tert-butoxide or potassium bis (trimethylsilyl) amide, preferably potassium bis (trimethylsilyl) amide, in a solvent polar aprotic such as THF, ethyl ether, dimethoxyethane (DME) or dimethylformamide (DMF), preferably THF, at a temperature between about -78 ° C and 35 ° C, preferably about 0 ° C. The reaction mixture is stirred for about 30 minutes, then the compound of formula R4-C (0) CH2-X is added to the reaction mixture, and the mixture is then allowed to warm to room temperature. Alternatively, the intermediate compound of formula VII is reacted with the compound of formula R4C (0) CH2-X in a polar solvent, such as THF, DMF, acetonitrile or acetone, preferably acetone, in the presence of an acid scavenging agent. , such as a carbonate or a tertiary organic amine, preferably potassium carbonate. The reaction temperature is maintained between about -78 ° C and 140 ° C, preferably between about 0 ° C and room temperature, to provide the intermediate compound of formula VIII. In Step 7, the compound of formula I is formed by treatment of the intermediate compound of formula VIII with a thiophile, such as triphenylphosphine, tributylphosphine or trimethyl phosphite, preferably triphenylphosphine, in a solvent such as toluene, pyridine or benzene, preferably toluene or pyridine, at a temperature between about 25 ° C and 120 ° C, preferably about 100 ° C. The starting materials used in the procedure of Scheme 1 are either known in the literature, or are commercially available. The following Schemes 2 and 3 illustrate the preparation of compounds of the invention in which R3 is - (CH2) m (4-10 membered heterocyclyl) optionally substituted with 1 to 5 R6 groups or, said heterocyclyl being an azacyclic group as previously defined, in which hetero-nitrogen of the azacyclic group is linked by single bond with all adjacent atoms and is unsubstituted or substituted with a group R6: SCHEME 2 SCHEME 3 Schemes 2 and 3 are basically variations of Scheme 1. In Schemes 2 and 3, represent heteroazacyclyl groups of 4-10 members as described above, in which N is linked by a single bond to all atoms that are adjacent to it and in which R6 is as described above. The symbol "BOC" represents a f-butyl-xicarbonyl group. In Step 2A of Scheme 2, R3-SCN (formula X) is prepared by reaction of R3-NH2 (formula IX) with a thiophosgene1,1-thiocarbonyldiimidazole, in a solvent such as methylene chloride, with the reaction mixture being stirred during a period of approximately 12 hours. Step 2B corresponds to Steps 4 and 5 of Scheme 1. The starting material of formula XI can be synthesized according to Steps 1 to 3 of Scheme 1. The starting material of formula XI is reacted with the intermediate of formula X in a protic solvent, such as methanol or ethanol, preferably ethanol, at a temperature between about room temperature and about 78 ° C, preferably about the reflux temperature of the solvent. Step 2C corresponds to Step 6 of Scheme 1. The intermediate of formula XII is reacted with a strong base in a polar aprotic solvent at a temperature between about -78 ° C and about 35 ° C and is stirred for about 30 minutes. minutes A compound of formula XIII is then added, in which X is a leaving group such as chloride or bromide, and the reaction mixture is allowed to warm to room temperature. Alternatively, the intermediate compound of formula XII is reacted with a compound of formula XIII in a polar solvent in the presence of an acid scavenging agent, the temperature being maintained between about -78 ° C and about 140 ° C. Step 2D corresponds to Step 7 of Scheme 1. The intermediate compound of formula XIV is treated with a thiophile, such as triphenylphosphine, tributylphosphine or trimethyl phosphite, in a solvent such as toluene or benzene, at a temperature comprised between about 25 ° C and about 120 ° C, forming the compounds of the invention of formula la. Step 3A of Scheme 3 is the same as Step 2A of Scheme 2. Steps 3B, 3C, and 3D are the same as Steps 2B, 2C and 2D of Scheme 2, respectively. Step 2D results in the formation of a compound of formula 1b of the invention. In Step 3E, the α-butyloxycarbonyl group of the compound of formula 1b is removed by addition of TFA (trifluoroacetic acid) to the compound of formula 1b in a solvent such as methylene chloride, thereby forming a compound of formula 1c of the invention .

In Step 3F, the hetero-nitrogen of the R3 group of a compound of formula 1c is replaced by an R group by methods known in the art, resulting in a compound of formula 1a of the invention. In one method, a compound of formula 1c is reacted with a compound R6-X, in which formula X is a leaving group such as chloride or bromide and R6 is as described above, in a polar solvent such as THF or methylene chloride, in the presence of an acid scavenger, such as a carbonate, for example sodium bicarbonate or a tertiary organic amine such as dimethylaminopyridine. The reaction temperature is maintained between about -78 ° C and 140 ° C, preferably between about 0 ° C and room temperature. The compounds of formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts have to be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula I from the reaction mixture as a pharmaceutically unacceptable salt, then simply convert the latter back into the free basic compound again. by treatment with an alkaline reagent, and subsequently converting the last free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. By evaporation of the solvent, the desired solid salt is easily obtained. The desired acid addition salt can also be precipitated from a solution of the free base in an organic solvent by addition of an appropriate mineral or organic acid to the solution. The cationic salts of the compounds of formula I are prepared analogously except by reaction of a carboxy group, for example wherein R5 is carboxy, with an appropriate cationic saline reagent such as sodium, potassium, calcium, magnesium, ammonium, N, N '-dibenzyl-ethylenediamine, N-methylglucamine (meglumine), ethanolamine, tromethamine, or diethanolamine. The compounds of formula I and their pharmaceutically acceptable salts (hereinafter collectively referred to as "the therapeutic compounds") can be administered orally, transdermally (e.g., by the use of a patch), parenterally or topically. Oral administration is preferred. In general, the compounds of the formula I and their pharmaceutically acceptable salts are most desirably administered in doses between about 1.0 mg and about 1000 mg per day, preferably from about 1 to about 500 mg per day in doses simple or divided (that is, multiple). The compounds of formula I and their pharmaceutically acceptable salts will ordinarily be administered in daily doses between about 0.01 and about 10 mg per kg of body weight per day, in single or divided doses. Variations may occur depending on the weight and condition of the person being treated and the particular route of administration selected. In some cases, dosage levels lower than the lower limit of the range indicated above may be greater than adequate, while in other cases even higher doses may be used without causing any harmful side effects. The higher doses are preferably divided into several small doses for administration throughout the day. The compounds of formula I can also be administered in combination with an amount of an anti-tumor agent, in which case the amount of said anti-tumor agent is, in combination with the amount of the compound of formula I, effective to inhibit abnormal growth of the cells in the mammal. An amount of an anti-tumor agent useful in the present invention can be determined by a person of ordinary skill in the art. For example, an amount of a particular anti-tumor agent can be based on amounts already known to be useful for said anti-tumor agent. This amount can be adjusted, for example, reduced, after being combined with a compound of formula I and tested for inhibition of abnormal growth of cells in laboratory animals using known techniques. Anti-tumor agents are known in the art, and include mitotic inhibitors, alkylating agents, anti-metabolites, intercalation antibiotics, inhibitors of growth factors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, response modifiers. biological, and anti-hormones, as examples.

The therapeutic compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the two routes indicated above, and such administration can be carried out in single or multiple doses. More particularly, the novel therapeutic compounds of this invention can be administered in a wide variety of different dosage forms, ie, they can be combined with various inert pharmaceutically acceptable carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders. , sprays, creams, ointments, suppositories, jellies, gels, pastes, lotions, ointments, elixirs, syrups, et cetera. Such vehicles include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, the oral pharmaceutical compositions may be conveniently sweetened and / or flavored. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, together with various disintegrants such as starch (and preferably corn starch, potato or tapioca), alginic acid may be employed. and certain complex silicates, together with granulation binders such as polyvinylpyrrolidone, sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tablet manufacturing purposes. Solid compositions of a similar type can also be used as fillers in gelatin capsules; Preferred materials in this sense also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matters or dyes, and, if desired, also emulsifying agents and / or suspending agents, together with such diluents such as water, ethanol, propylene glycol, glycerin and various analogous combinations thereof. For parenteral administration, solutions of a therapeutic compound in sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions should be suitably buffered if necessary and the liquid diluent first made isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical methods well known to those skilled in the art. Additionally, it is also possible to administer the therapeutic compounds by the local route, and this can be done preferably by means of creams, jellies, gels, pastes, ointments and the like, according to standard pharmaceutical practice. The therapeutic compounds can also be administered to a mammal other than a human. The dose to be administered to a mammal will depend on the animal species and the disease or disorder being treated. The therapeutic compounds can be administered to animals in the form of a capsule, bolus, tablet or liquid for drinking. The therapeutic compounds can also be administered to animals by injection or as an implant. Said formulations are prepared in a conventional manner in accordance with standard veterinary practice. Alternatively, the therapeutic compounds can be administered with the animal's food and for this purpose a concentrated feed additive or premix can be prepared for incorporation with the normal animal feed. The compounds of formula I exhibit activity as inhibitors of Ras famesilation and are useful in the treatment of cancer and the inhibition of abnormal cell growth in mammals., including human beings. The activity of the compounds of formula I as inhibitors of ras farnesylation can be determined by their ability, relative to a control, to inhibit ras farnesyl transferase in vitro. An example of a method of this type is described below. A crude human farnesyl transferase (FTase) preparation comprising the cytosolic fraction of homogenized brain tissue is used to evaluate the compounds in a 96-well assay format. The cytosolic fraction is prepared by homogenizing approximately 40 grams of fresh tissue in 100 ml of sucrose buffer / MgCb / EDTA (using a Dounce homogenizer; 10-15 runs), centrifugation of the homogenates at 1000 grams for 10 minutes at 4G, recentrifugation of the supernatant at 17,000 grams for 15 minutes at 4G, and subsequent collection of the resulting supernatant. This supernatant is diluted to a final concentration of 50 mM Tris-HCl (pH 7.5), 5 mM DTT, 0.2 M KCl, 20 mM ZnCI, 1 mM PMSF and recentrifuged at 178,000 grams for 90 minutes at 4G. . The supernatant, called "crude FTase" was assayed for protein concentration, divided into aliquots, and stored at -70 ° C. The assay used to measure the in vitro inhibition of human FTase is a modification of the method described by Amersham LifeScience to use its kit (kit) Farnesyl-Transferase (3H) Scintillation Proximity Assay (SPA) (TRKQ 7010). The activity of the enzyme FTase is determined in a volume of 100 ml containing 50 mM N- (2-hydroxyethyl) -piperazine-N- (2-ethanesulfonic acid) (HEPES), pH 7.5, 30 mM MgCl2, KCl 20 μM, 5 mM Na2HPO4, 5 mM dithiothreitol (DTT), 0.01% Triton X-100, 5% dimethyl sulfoxide (DMSO), 20 mg crude FTase, [3H] -hamesyl-pyrophosphate ([3HJ] -FPP; 36000 dpm / picomol, Amersham LifeScience) 0.12 mM, and 0.2 mM of biotinylated Ras-peptide KTKCVIS (Bt-KTKCVIS) which is biotinylated at the N-terminal in its amino group a and synthesized and purified by HPLC in the authors' laboratory. The reaction is initiated by the addition of the enzyme and terminated by the addition of EDTA (supplied as the STOP reagent in the TRKQ 7010 kit) after incubation for 45 minutes at 37 ° C. The prenated and non-prenylated Bt-KTKCVIS is captured by addition of 10 ml of SPA beads coated with streptavidin (TRKQ 7010) per well and incubation of the reaction mixture for 30 minutes at room temperature. The amount of radioactivity bound to the SPA beads is determined using a MicroBeta 1450 plate counter. Under these test conditions, the activity of the enzyme is linear with respect to the concentrations of the prenyl acceptor group, Bt-KTKCVIS, and crude FTase, and inhibition of the interaction of Bt-KTKCVIS with FTase can be detected. The enzymatic activity is saturating with respect to the prenyl donor, FPP. The reaction time of the test is also in the linear range. The test compounds are routinely dissolved in 100% DMSO. The inhibition of famesyl transferase activity is determined by calculating the percentage of incorporation of tritiated farnesil in the presence of the test compound against its incorporation into the control wells (in the absence of inhibitor). The IC 50 values, that is, the concentration required to produce a semi-maximal farnesylation of Bt-KTKCVIS, are determined from the dose-response graphs obtained. The following examples are provided to illustrate aspects of the present invention. They are not intended to limit the invention as described more fully in this specification and are indicated in the claims, nor should they be construed in that sense. In the following examples, "DMF" means dimethylformamide, and "THF" means tetrahydrofuran. "Et" represents an ethyl moiety; therefore, "OEt" means ethoxy, "Et2?" means diethyl ether, "EtOH" means ethanol, and "NEt3M means triethylamine.

EXAMPLE 1 4-fri-f1a.5a.6 (x-3-Benzenesulfonyl-3-aza-bicichlor3.1.01hex-6-yl-5-oxo-4,4-bis-pyridin-4-ylmethyl-im Dazolidin-2-ylidene-1-acetyl) -benzonitrile 1A. 1 .5 .6 -3-Benzenesulfonyl-6-isothiocyanato-3-aza-bicichlor3.1.01hexane To a solution of 3-benzenesulfonyl-3-aza-bicyclo [3.1.0] -hex-6-ylamine (476 mg, 2.00 mmol) in methylene chloride (10 ml) was added 1,1-thiocarbonyldiimidazole (350 mg, 2.00 mmol). The reaction mixture was stirred overnight and was subsequently taken up in water and CH2Cl2. After separation, the organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the crude title compound of 1A. 1 B. 3- (1a, 5a, 6a-3-Benzenesulfonyl-3-aza-bicyclo [3.1.0] -hex-6-yl) -5,5-bis-pyridin-4-ylmethyl-2-thioxo- imidazolidin-4-one To the title compound of crude 1A (2 mmol) in absolute ethanol (5 ml) was added a solution of 2-amino-3-pyridin-4-yl-2-pyridin-4-methyl ester ILYMETHYL-propionic (200 mg, 0.73 mmol) in absolute ethanol (5 mL). The reaction mixture was heated to reflux overnight under a dry N2 atmosphere. The same was then poured into an aqueous solution of 10% K2CO3 and extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4 and concentrated to give the crude 1B title compound (390 mg, 0.73 mmol). CI-MS: m / e 520.2 [M + 1]. 4-. { [1- (1a, 5a, 6a-3-Benzenesulfonyl-3-aza-bicyclo [3.1.0] -hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-4, 5-dihydro-1 H-imidazol-2-ylsulfanyl] -acetyl} -benzonitrile The crude 1B title compound (390 mg, ca. 0.73 mmol) was dissolved in anhydrous THF (3.0 ml) and cooled to 0 ° C. To the solution was added bis (trimethylsilyl) potassium amide (165 mg, 0.83 mmol). After stirring for 15 minutes, 4-cyanophenacyl bromide (185 mg, 0.83 mmol) was added and the reaction mixture was stirred at 0 ° C for another 30 minutes. The mixture was subsequently partitioned between CH2Cl2 and saturated sodium bicarbonate solution (NaHCOs). The CH2Cl2 layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give the crude 1C title compound as a brown solid (430 mg, 0.65 mmol, 89% yield). CI-MS: m / e 663.1 [M + 1]. 1 D. 4-. { [1- (1a, 5a, 6a-3-Benzenesulfonyl-3-aza-bicyclo- [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin- 2-ylidene] -acetyl} -benzonitrile The crude 1C title compound (420 mg, 0.63 mmol) was dissolved in anhydrous toluene (10 ml) under N2 atmosphere. Triphenylphosphine (665 mg, 2.53 mmol) was added to the solution. The reaction mixture was subsequently heated to 100 ° C. After stirring for 40 hours, the reaction mixture was concentrated in vacuo and then partitioned between 0.1 N HCl and ethyl ether. The aqueous layer was washed twice with ethyl ether and subsequently alkalized to pH = 8 with K2CO3. The product was then extracted into CH 2 Cl 2, dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude product. The crude product was chromatographed on silica gel with MeOH-CHCl3-NH4OH (1: 99: 0.1) as eluents to give the title compound of Example 1 as a white solid, 151 mg (0.24 mmol, yield 38 %). CI-MS: m / z 631 [M + 1].

EXAMPLE 2 4 ri- (1 (x.5re, 6 -3-tert-Butoxylcarbonyl-3-aza-bicyclo-r3.1.01-hex-6-yl) -5-oxo-4,4-bis-pyridine -4-ylmethyl-imidazolidin-2-ylidene-acetyl-benzonitrile 2A. 3- (1 a, 5,6-tert-Butoxylcarbonyl) -6-isothiocyanato-3-azabicyclof3.1.Olhexane To a solution of 3- (3-butoxylcarbonyl) -3-aza-bicyclo [3.1.0] hex-6-ylamine (9 g, 45.45 mmol) in methylene chloride (80 ml) was added 1, 1- thiocarbonyldiimidazole (8.10 g, 45.45 mmol). The reaction mixture was stirred overnight. It was then partitioned between water and CH2Cl2. After separation, the organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the crude 2A title compound, 10.46 g (43.58 mmol, 96% yield). 2B. 3- (1a, 5a, 6a-3-tert-Butoxylcarbonyl-3-aza-bicyclo- [3.1.0] hex-6-yl) -5,5-bis-pyridin-4-ylmethyl-2-thioxo-imidazolidin-4-one A solution of the crude 2A title compound (10.46 g, 43.58 mmol) and 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester , 91 g, 21.8 millimoles) in absolute ethanol (60 ml) was heated to reflux for 16 hours. The reaction mixture was poured into 10% aqueous K2CO3 solution and extracted with CH2Cl2. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated to give the crude 2B title compound. CI-MS: m / z 480 [M + 1], 380 [(M-BOC) +1]. 2 C. 4-. { [1 -3- (1 a, 5a, 6a-tert-Butoxylcarbonyl) -3-aza-bicyclo- [3.1.0] hex-6-yl) -5-5-oxo-4,4-bis-pyridine-4- ilmethyl-4,5-dihydro-1 H-imidazol-2-ylsulfanyl] -acetyl} -benzonitrile A solution of the crude 2B title compound (21.8 mmol) in anhydrous THF (15 ml) was added to a suspension of potassium bis (trimethylsilyl) amide (5.04 g, 23.98 mmol) in THF (30 ml) at -78 ° C. The reaction mixture was warmed to room temperature and stirred for 15 minutes. 4-Cyanophenacyl bromide (5.37 g, 23.98 mmol) was added to the solution. The mixture was stirred for 60 minutes. After cooling rapidly with water, the THF was removed. The reaction mixture was subsequently partitioned between CH 2 Cl 2 and saturated sodium bicarbonate solution (NaHC 3). The CH2Cl2 layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude product as a brown solid. The crude product was chromatographed on silica gel with MeOH-CHC-NH 4 H (2: 98: 0.1) as eluents to give the title compound of 2C, 11.52 g (18.52 mmol, yield 85% in two steps). CI-MS: m / z 663.1 [M + 1]. 2D 4-. { [1 - (1 a, 5a, 6a-3-tert-Butoxylcarbonyl-3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl- imidazolidin-2-ylidene] -acetyl} -benzonitrile A solution of the title compound of 2C (11.52 g, 18.52 mmol) and triphenylphosphine (14.6 g, 55.55 mmol) in anhydrous toluene (40 mL) was heated to reflux. After 40 hours, the reaction mixture was concentrated in vacuo and then partitioned between 0.1 N HCl and ethyl ether. The aqueous layer was washed twice with ethyl ether and subsequently alkalized to pH = 8 with K2CO3. The product was then extracted into CH 2 Cl 2, dried over MgSO 4, filtered and concentrated in vacuo to give the crude product. The crude product was chromatographed on silica gel with MeOH-CHC-NH 4 H (2: 98: 0.1) as eluants to give the title compound of Example 2 as a white solid, 8.56 g (14 g). , 48 millimoles, yield 78.2%). CI-MS: m / z 592.1 [M + 1].

EXAMPLE 3 4-ff 1 -f 1 a.5a.6a-3-Aza-bicichlor3.1.01hex-6-iD-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolid-n-2-ylidenol- Acetyl-benzonitrile The title compound of Example 2 (6.79 g, 11.51 mmol) was dissolved in CH2Cl2 (5 mL). TFA (5 ml) was added dropwise at 0 ° C. The mixture was stirred for 16 hours at room temperature, after which time the acid was removed. The reaction mixture was partitioned between CH 2 Cl 2 and 10% K 2 C 3. The CH2Cl2 layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound of Example 3 as a white solid, 5.13 g (10.46 mmol, 91%).

CI-MS: m / z 374 [M + 1].

EXAMPLE 4 4 - ((1H a.5a.6a-3- (4-Methoxy-benzenesulfonyl) -3-aza-bicyclo3.1.01hex-6-in-5-oxo 4-bis-pyridine-4 -ylmethyl-imidazolidin-2-ylidene > -acetyl) -benzonitrile Using the same procedure as described in Example 1, 6-isothiocyanato-3- (4-methoxy-benzenesulfonyl) -3-aza-bicyclo [3.1.0] hexane (1.94 mmol) was used instead of -benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo- [3.1.0] hexane. After delation with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester as described in 1B, sulfur-alkylation of 4-cyanophenacyl bromide in the presence of bis ( trimethylsilyl) potassium amide as described in 1C and sulfur-extrusion in the presence of triphenylphosphine as described in 1 D, 159.5 mg of the title compound was obtained as a white solid. CI-MS: m / z 661, 1 [M + 1].

EXAMPLE 5 Dimethylamide of acid 1a.5a.6a-6-f2-f2-. { 4-cyano-pheyp-2-oxo-ethylidene-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-yl) -3-aza-bicyclo3.1.0lhexane-3 sulphonic Using the same procedure as described in Example 1, 6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane-3-sulfonic acid dimethylamide (1.33 mmol) was used instead of 3-benzenesulfonyl- 6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane. After delation with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (as described in 1B), sulfur-alkylation of 4-cyanophenacyl bromide in the presence of bis (trimethylsilyl) potassium amide (as described in 1C) and sulfur-extrusion in the presence of triphenylphosphine as described in 1D), 25 mg of the title compound was obtained as a white solid. CI-MS: m / z [M + 1].

EXAMPLE 6 4-1 (1 -ri .5ra.6 -3- (4-Fluoro-benzenesulfonyl) -3-aza-biciclof3.1.01hex-6-ill-5-oxo-4.4-b1s-pyridin-4 -ylmethyl-imidazolidin-2-ylidene > -acetih-benzonitrile Using the same procedure as described in Example 1, 3- (4-fluorobenzenesulfonyl) -6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane (2.62 mmol) was used instead of 3-benzenesulfonyl. -6- isothiocyanato-3-aza-bicyclo- [3.1.0] hexane. After delation with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (as described in 1 B), sulfur-alkylation of 4-cyanophenacyl bromide in the presence of potassium bis (trimethylsilyl) amide (as described in 1C) and sulfur-extrusion in the presence of triphenylphosphine (as described in 1 D), 125 mg of the title compound was obtained as a white solid. CI-MS: m / z 649.3 [M + 1].

EXAMPLE 7 4 -.l5-Oxo-1- (1 .5re, 6 -3-phenylmethanesulfonyl-3-aza-bicyclo3.1.01hex-6-in-4,4-bis-pyridin-4-ylmethyl-! midazolidin-2-ylidene-acetyl-benzonitrile Using the same procedure as described in Example 1, 6-isocyanato-3-phenylmethanesulfonyl-3-aza-bicyclo [3.1.0] hexane (1.80 mmol) was used in place of 3-benzenesulfonyl-6-isothiocyanate -3-aza-bicyclo [3.1.0] hexane. After delation with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (as described in 1 B), sulfur-alkylation of 4-cyanophenacyl bromide in the presence of Potassium bis (trimethylsilyl) amide (as described in 1C) and sulfur-extrusion in the presence of triphenylphosphine (as described in 1 D), 20 mg of the title compound was obtained as a white solid. CI-MS: m / z 645.2 [M + 1].

EXAMPLE 8 4-fp-f 1 a, 5a, 6a-3-.4-Chlorobenzene.sulfonyl-3-aza-bicyclo-.3.1.01hex-6-yl.-5-oxo-4,4-bis -pyridin-4-ylmethyl-imidazolidin-2-ylidene-acetyl-benzontrile Using the same procedure as described in Example 1, 3- (4-chlorobenzenesulfonyl) -6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane (1.48 millimoles) was used in place of 3-benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane. After delation with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (as described in 1B), sulfur-alkylation of 4-cyanophenacyl bromide in the presence of bis (trimethylsilyl) potassium amide (as described in 1C) and sulfur-extrusion in the presence of triphenylphosphine (as described in 1 D), 60 mg of the title compound was obtained as a white solid. CI-MS: m / z 667.4, 665.4 [M + 1].

EXAMPLE 9 4- (f1-ri. 5a, 6a-3- (Naphthalene-2-sulfoni -3-aza-bicyclo-r3.1.01hex-6-in-5-oxo-4,4-bis-pyridin-4-ylmethyl -imidazolidin-2-ylidene) -acetyl) -benzonitrile Using the same procedure as described in Example 1, 6-isothiocyanato-3- (naphthalene-1-sulfonyl) -3-aza-bicyclo [3.1.0] hexane (1.48 mmol) was used instead of 3 -benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane. After delation with 2-amino-3-pyridin-4-yl-2-pyridin-4-methylpropionic acid methyl ester (as described in 1B), sulfur-alkylation of 4-cyanophenacyl bromide in the presence of Potassium bis (trimethylsilyl) amide (as described in 1C) and sulfur-extrusion in the presence of triphenylphosphine (as described in 1 D), 79.1 mg of the title compound was obtained as a white solid. CI-MS: m / z 681 [M + 1].

EXAMPLE 10 4- (f5-Oxo-4.4-bis-pyridin-4-ylmethyl-1-ria.5o-.6 (x-3-ftoluene-4-sulfonyl) -3-azabicyclo3.1.01hex-6- ill-imidazolidin-2-ylidene > -acetyl-benzonitrile Using the same procedure as described in Example 1, 6-isothiocyanato-3-toluene-4-sulfonyl) -3-aza-bicyclo [3.1.0] hexane (1.29 mmol) was used instead of 3- benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane. After delation with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (as described in 1B), sulfur-alkylation of 4-cyanophenacyl bromide in the presence of bis (trimethylsilyl) potassium amide (as described in 1C) and sulfur-extrusion in the presence of triphenylphosphine (as described in 1 D), 45.4 mg of the title compound was obtained as a white solid. CI-MS: m / z 645.2 [M + 1].

EXAMPLE 11 4-ff5-Oxo-4.4-bis-pyridin-4-ylmethyl-1-ria.5a.6a-3- (toluene-2-sulfonyl) -3-azabiciclof3.1.01hex-6-in-imidazolidin -2-ilidene} -acetyl -benzonitrile Using the same procedure as described in Example 1, 6-isothiocyanato-3-toluene-2-sulfonyl) -3-aza-bicyclo [3.1.0] hexane (0.78 mmol) was used instead of 3-benzenesulfonyl-6-isothiocyanato-3-azane. bicyclo [3.1.0] hexane. After delation with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester as described in 1B, sulfur-alkylation of 4-cyanophenacyl bromide in the presence of bis (trimethylsilyl) potassium amide as described in 1C and sulfur-extrusion in the presence of triphenylphosphine as described in 1 D, 86.7 mg of the title compound was obtained as a white solid, 86.7 mg of the title of Example 11 as a white solid. CI-MS: m / z 645.3 [M + 1].

EXAMPLE 12 4-fi 5-Oxo-l -f 1 a.5a.6a-3-f piperidine-1-sulfonyl-3-aza-bicyclo.3.1.Olhex-6-ill-4,4-bis-pyridine -4-ylmethyl-imidazolidin-2-ylidene) -acetyl) -benzonitrile Using the same procedure as described in Example 1, 6-isothiocyanato-3-piperidine-1-sulfonyl) -3-azabicyclo [3.1.0] hexane (1.55 mmol) was used instead of 3- benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane. After cyclization with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester as described in 1B, sulfur-alkylation of 4-cyanophenacyl bromide in the presence of bis ( trimethylsilyl) potassium amide as described in 1C and sulfur-extrusion in the presence of triphenylphosphine as described in 1 D, 140 mg of the title compound was obtained as a white solid. CI-MS: m / z 638 [M + 1].

EXAMPLE 13 4 - ((1-f 1 a, 5a, 6a-3-, 4-Methyl-piperazine-1-sulfonyl) -3-aza-bicyclo.3.1.Plhex-ß-ill-5-oxo-4.4- bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene-acetyl) -benzonitrile A solution of 4-methyl-piperazine-1-sulfonyl chloride (61 mg, 0.31 mmol) in CH2Cl2 (0.5 mL) was added to a solution of the title compound of Example 3, 4-. { [1- (3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (72 mg, 0.155 mmol) and triethylamine (43 ml, 0.31 mmol) in CH2Cl2 (0.5 ml). The reaction mixture was stirred at room temperature overnight and was subsequently partitioned between CH 2 Cl 2 and saturated sodium bicarbonate solution (NaHCOs). The CH2Cl2 layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel with MeOH-CHC-NH 4 H (1: 99: 0.1) as eluents to give the title compound as a light yellow solid, 11 mg (0.017 mmol), 11% yield ).

EXAMPLE 14 4- (f5-Oxo-4.4-bis-pyridin-4-ylmethyl-1-f1a.5a.6a-3-phthiophene-2-sulfonyl) -3-azabicyclic3.1.0lhex-6-in-im Dazolidin-2-ylidene) -acetyl) -benzonitrile In accordance with the procedure of Example 13, 4- were reacted. { [1 - (3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (70 mg, 0.142 mmol) and chloride 2-thiophenesulfonyl (53 mg, 0.246 mmol) to generate the title compound (28 mg, 0.044 mmol, yield 31%). CI-MS: m / z 637.1 [M + 1].

EXAMPLE 15 4- (1a, 5, 6a-6- {2-r2- (4-cyano-phenyl) -2-oxo-ethylidene-5-oxo-4,4-bis- tert -butyl ester pyridin-4-ylmethyl-amidazolidin-1-yl-3-azabicyclo, 3.1.01hexane-3-sulfonyl) -piperazine-1-carboxylic acid In accordance with the procedure of Example 13, 4- were reacted. { [1 - (3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (100 mg, 0.204 mmol) and 4-chlorosulfonyl-piperazine-1-carboxylic acid tert-butyl ester (174 mg, 0.612 mmol) to generate the title compound (62.3 mg, 0.084 mmol, 41% yield) ). CI-MS: m / z 739.3 [M + 1].

EXAMPLE 16 4- ( { 1 1 a.5a.6a-3- (5-Bromo-thiophene-2-sulfonyl) -3-aza-bicichlor3.1.01hex-6-ill-5-oxo-4.4-bis -pyridin-4-ylmethyl-imidazolidin-2-ylidene} -acetyl-benzonitrile In accordance with the procedure of Example 13, 4- were reacted. { [1 - (3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (50 mg, 0.102 mmol) and 5-bromothiophene-2-sulfonyl chloride (40 mg, 0.153 mmol) to generate the title compound (43.2 mg, 0.060 mmol, 59% yield). CI-MS: m / z 716.9 [M + 1].

EXAMPLE 17 44 < i 41 a.5a.6a-3- (4-Ethyl-piperazine-1-sulfonyl-3-aza-bicicior3.1.01hex-ip-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2 -ylidene > -acetl) -benzonitril In accordance with the procedure of Example 13, 4- were reacted. { [1- (3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (50 mg, 0.102 mmol) and 4-ethyl-piperazine-1-sulfonyl chloride (130 mg, 0.612 mmol) to generate the title compound as an off-white solid (47.8 mg, 0.072 mmol, 70% yield) ). CI-MS: m / z 667.2 [M + 1].

EXAMPLE 18 44 (141 (x.5o-.6a-343-Chloro-propane-1-sulfonip-3-aza-bicichlor3.1.01hex-in-5-oxo ^^ -bis-pyridin-1-methylmethyl-imidazolidin ^ -ylidene-acetyl-benzonitrile In accordance with the procedure of Example 13, 4- were reacted. { [1- (3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (50 mg, 0.102 mmol) and 3-chloropropanesulfonyl chloride (54.2 mg, 0.306 mmol) to generate the title compound as an off-white solid (37.9 mg, 0.060 mmol, yield 70%). CI-MS: m / z 631, 2 [M + 1].

EXAMPLE 19 4-U1 -f 3-, 4-Met.l-piperidine-1-sulfonyl.-3-aza-bicyclo.3.1.01hex-6-ill-5-oxo-4.4-bis-pyridin-4-ylmethyl -imidazolidin-2-ylidene-acetyl) -benzonitrile In accordance with the procedure of Example 13, 4- were reacted. { [1 - (3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (50 mg, 0.102 mmol) and 4-methyl-piperidine-1-sulfonyl chloride (60.2 mg, 0.306 mmol) to generate the title compound as an off-white solid (62 mg, 0.095 mmol, 93% yield) ). CI-MS: m / z 652.3 [M + 1].

EXAMPLE 20 Ethyl ester of acid 141a.5a.6a-6424244-cyano-phenyl) -2-oxo-ethylidene-5-oxo-4,4-bis-pyridin-4-methyl-imidazolidin-1-yl -3- aza-biciclor3.1.01hexano-3- sulfoniQ-piperidina-4-carboxílico In accordance with the procedure of Example 13, 4- were reacted. { [1- (3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (50 mg, 0.102 mmol) and 1-chlorosulfonyl-piperidine-4-carboxylic acid (153 mg, 0.60 mmol) to generate the title compound as an off-white solid (10 mg, 0.014 mmol, 14% yield) . CI-MS: m / z 597.3 [M + 1].

EXAMPLE 21 44 5-Oxo-l 41 a.5a.6a-3- (4-propyl-piperidine-1-sulfonyl) -3-aza-b.cycloy3.1.01hex-6-in-4,4-bis- pyridin-4-methyl-imidazolidin-2-ylidene > -acetyl.- benzonitrile In accordance with the procedure of Example 13, 4- were reacted. { [1 - (3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (50 mg, 0.102 mmol) and 4-propyl-piperidine-1-sulfonyl chloride (135 mg, 0.60 mmol) to generate the title compound as an off-white solid (40 mg, 0.059 mmol, 59% yield) ). CI-MS: m / z 680.3 [M + 1].

EXAMPLE 22 44 (141 «.5a.6a-342.5-Dichloro-thiophene-3-sulfonyl-3-aza-bicyclo.3.1.01hex-6-ill-5-oxo-4.4-bs-pyridine- 4-ylmethyl-1-ylazolidin-2-ylidene > -acetyl) -benzonitrile In accordance with the procedure of Example 13, 4- were reacted. { [1 - (3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (50 mg, 0.102 mmol) and 2,5-dichlorothiophene-3-sulfonyl chloride (77 mg, 0.306 mmol) to generate the title compound as an off-white solid (20 mg, 0.028 mmol, 28% yield).

CI-MS: m / z 705.1 [M + 1].

EXAMPLE 23 44f1 1a.5a, 6a-3-Chloromethanesulfonyl-3-aza-biciclof3.1.0l-hex-6-ill-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene-acetyl) -benzonitrile In accordance with the procedure of Example 13, 4- were reacted. { [1- (3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (50 mg, 0.102 mmol) and 3-chloromethanesulfonyl chloride (45.6 mg, 0.306 mmol) to generate the title compound as an off-white solid (21 mg, 0.035 mmol, 34% yield). CI-MS: m / z 603.1 [M + 1].

EXAMPLE 24 44 (141 a.5a.6a-344-lsopropyl-piperazine-1-sulfonip-3-aza-biciclof3.1.Olhex-6-in-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolid N-2-ylidene) -acetyl-benzonthi-1 In accordance with the procedure of Example 13, 4- were reacted. { [1- (3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (100 mg, 0.204 mmol) and 4-isopropylpiperazine-1-sulfonyl chloride (169 mg, 0.754 mmol) to generate the title compound as an off-white solid (25 mg, 0.027 mmol, 13% yield). CI-MS: m / z 681, 3 [M + 1].

EXAMPLE 25 44 (5-Oxo-141a.5 .6fx-341-phenyl-1 H-tetrazol-5-yl-3-aza-bicichlor3.1.01hex-6-ip-4,4-bis-pyridine n-4-methyl-1-ylazolidin-2-ylidene) -acetyl) -benzonitrile Using the same procedure as described in Example 1, 6-isothiocyanato-3- (1-phenyl-1 H-tetrazol-5-yl) -3-aza-bicyclo [3.1.0] hexane (0, 74 millimoles) in place of 3-benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo- [3.1.0] hexane. After delation with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (as described in 1 B), sulfur-alkylation of 4-cyanophenacyl bromide in the presence of of potassium bis (trimethylsilyl) amide (as described in 1C) and sulfur-extrusion in the presence of triphenylphosphine (as described in 1D), 78.5 mg of the title compound was obtained as a white solid. CI-MS: m / z 635.2 [M + 1].

EXAMPLE 26 Benzyl Ester of 1a.5a.6a-6424244-cyano-phenyl) -2-oxo-ethylidene-5-oxo-4,4-bis-pyridin-4-methylmethyl-1-ylazolidin-1-yl -3-aza-bic¡clof3.1.0l-hexane-3-carboxylic acid To a solution of 4-. { [5-oxo-4,4-bis-pyridin-4-ylmethyl-1- (3-aza-b-cyclo [3.1.0] hex-6-yl) -imidazolidin-2-ylidene] -acetyl} -benzonitrile (70 mg, 0.143 mmol) in THF (1 ml) was added 3 ml of 1 N aqueous solution of NaHCO 3, followed by the addition of benzyl chloroformate (0.025 ml, 0.171 mmol) in THF (2 ml). The mixture was stirred overnight. After removing the THF, the reaction mixture was partitioned between CH2Cl2 and H2O. After separation, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated. The crude product was chromatographed on silica gel with MeOH-CHCl 3 -NH 4 H H (1: 99: 0.1) as eluents to give the title compound as a white solid, 33 mg (0.053 mmol, yield 37%). CI-MS: m / z 625.2 [M + 1].

EXAMPLE 27 44 (141 a5a, 6a-343,3-Dimethyl-butyryl) -3-aza-bicyclo.3.1.01-hex-6-ill-5-oxo-4.4-bis-pyridin-4-ylmethyl- imidazolidin-2-yldene > -acetl) -benzontrile Using the same procedure as described in Example 26, 4- were reacted. { [5-oxo-4,4-bis-pyridin-4-ylmethyl-1- (3-aza-bicyclo [3.1.0] hex-6-yl) -imidazolidin-2-ylidene] -acetyl} -benzonitrile (70 mg, 0.143 mmol) and 3,3-dimethyl-butyryl chloroformate (23 mg, 0.171 mmol) to generate the title compound as a white solid, 56 mg (0.095 mmol, 67% yield). CI-MS: m / z 589.3 [M + 1].

EXAMPLE 28 44 (5-Oxo-4,4-bis-pyridin-4-yl-ethyl-141a.5a.6a-34-tofen-2-yl-acety-3-azabicyclof3.1.01hex-6-in-imidazolidin-2- ilidene > -acetyl) -benzonitrile Using the same procedure as described in Example 26, 4- were reacted. { [5-oxo-4,4-bis-pyridin-4-ylmethyl-1- (3-aza-bicyclo [3.1.0] hex-6-yl) -imidazolidin-2-ylidene] -acetyl} -benzonitrile (70 mg, 0.143 mmol) and thiophene-2-yl-acetyl chloride (23 mg, 0.171 mmol) to generate the title compound as a white solid, 56 mg (0.095 mmol, 67% yield). CI-MS: m / z 589.3 [M + 1].

EXAMPLE 29 Diethyl ester of acid 1a.5a.6a4642-r244-cyano-phenyl-2-oxo-ethylidene-1-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-yl > -3-aza-biciclof3.1.0lhex-3-p-phosphonic To a solution of 4-. { [5-oxo-4,4-bis-pyridin-4-ylmethyl-1- (3-aza-bicyclo [3.1.0] hex-6-yl) -imidazolidin-2-ylidene] -acetyl} -benzonitrile (200 mg, 0.408 mmol) in CH2Cl2 (2.5 mL) was added 4-dimethylaminopyridine (150 mg, 1.224 mmol) followed by the addition of diethyl chlorophosphate (141 mg, 0.816 mmol) at 0 ° C. The mixture was stirred for 1 h at room temperature. The reaction mixture was partitioned between CH 2 Cl 2 and H 20. After separation, the organic layer was washed with CUSO4 solution and with brine, dried over Na2S4 and concentrated. The crude product was chromatographed on silica gel with MeOH-CHCl 3 -NH 4 HH (2: 98: 0.2) as eluants to give the title compound as a white solid, 169.6 mg (0.27 mmol, yield 66%). CI-MS: m / z 627.1 [M + 1].

EXAMPLE 30 Tert-Butyl Ester of 1a.5a.6a-644-allyl-24244-cyano-phenyl-2-oxo-ethylidene-15-oxo-4-pyridin-4-ylmethyl-1-aidazolidin-1-yl; -3-azabicyclo3.1.0lhexane-3 -carboxylic 30A. 6- (4-Allyl-5-oxo-4-pyridin-4-ylmethyl-2-thioxo-imidazolidin-1-yl) -3-aza-bicyclo [3.1.0] hexane-3-tert-butyl ester carboxylic acid Using the same procedure as described in Example 2B, 3- (tert-butoxycarbonyl) -6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane (23.4 mmol, prepared in 1A) was reacted and acid methyl ester 2-amino-2-allyl-3-pyridin-4-yl-propionic acid (11.6 mmol) to give the title compound of 30A (4.37 g, 10.2 mmol, yield 88%). CI-MS: m / z 480 [M + 1], 380 [(M-BOC) +1]. 30B. 6- Tertiary butyl ester. { 4-allyl-2- [2- (4-cyano-phenyl) -2-oxo-ethylsulfanyl] -5-oxo-4-pyridin-4-ylmethyl-4,5-dihydro-imidazol-1-yl} -3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid Using the same procedure as described in Example 2C, the reaction of the title compound of 30A (10.3 millimoles) and 4-cyanophenacyl bromide (11.3 millimoles) in the presence of potassium bis (trimethylsilyl) amide (11.3 millimoles) generated the title compound of 30B, 4.82 g (8.4 millimoles, yield 84%). 30C. 6- Tertiary butyl ester. { 4-allyl-2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4-pyridin-4-ylmethyl-imidazolidin-1-yl} 3-azabicyclo [3.1.0] hexane-3-carboxylic acid Using the same procedure as described in Example 2D, reaction of the title compound of 30B and triphenylphosphine in refluxing toluene generated the title compound of Example 30, 2.97 g (5.95 millimoles, yield 71%). CI-MS: m / z 540.1 [M + 1].

EXAMPLE 31 44_4-Allyl-141a.5a.6a-3-benzenesulfonyl-3-aza-bicyclo -3.1.0lhex-6-y-5-oxo-4-pyridin-4-ylmethyl-imidazolidin-2-ylidene-1-acetyl - benzonitrile 31 A. 4- (ri- (3-Aza-bicichlor3.1.01hex-6-yl) -5-oxo-4-allyl-4-pyridin-4-ylmethyl-imidazolidin-2-ylidene-1-acetyl) -benzonitrile Using the same procedure as described in Example 3, the title compound of Example 30 (3.07 g, 5.70 mmol) was treated with TFA (5 mL) in CH2Cl2 to give the title compound of 31 A, 2.17 g. (4.94 millimoles, 87%). CI-MS: m / z 440.2 [M + 1]. 31 B. 4-. { [4-Allyl-1- (1a, 5a, 6 -3-benzenesulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4-pyridin-4-ylmethyl-imidazolidin- 2-ylidene] -acetyl} -benzonitrile According to the procedure of Example 13, the title compound of 31 A (100 mg, 0.23 mmol) and benzenesulfonyl chloride (0.043 mL, 0.34 mmol) were reacted to generate the title compound as a white solid (65.1 mg, 0.112 mmol, yield 49%). CI-MS: m / z 580.2 [M + 1].

EXAMPLE 32 44r5-Oxo-4-allyl-4-pyridin-4-methylmethyl-141a.5a.6o, -34thiophene-2-acetyl-3-azabicyclo3.1.01hex-6-yl) -imidazolidin-2- ilideno1-acetyl-benzonitrile In accordance with the procedure of Example 13, 4- were reacted. { [1- (3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (100 mg, 0.23 mmol) and thiophene-2-yl-acetyl chloride (63 mg, 0.34 mmol) to generate the title compound (15 mg, 0.026 mmol, 11% yield). CI-MS: m / z 586.1 [M + 1].

EXAMPLE 33 44 (4-Allyl-5-oxo-4-pyridin-4-ylmethyl-1434-thiophene-2-sulfonyl) -3-azabicyclo3.1.01hex-6-in-imidazolidin-2-ylidene > -acetyl) -benzonitrile In accordance with the procedure of Example 13, 4- were reacted. { [1- (3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (100 mg, 0.23 mmol) and 3- (thiophene-2-acetyl) sulfonyl chloride (0.04 ml, 0.34 mmol) to generate the title compound (5 mg, 0.009 mmol, yield 4 %). CI-MS: m / z 564.2 [M + 1].

EXAMPLE 34 Tert-butyl ester of 1a, 5a.6a-6424244-cyano-phenyl) -2-oxo-ethylidene-1,43-methyl-but-2-enyl) -5-oxo-4- pyridin-4-ylmethyl-imidazolidin-1-yl-3-aza-bicyclo3.1.01hexane-3-carboxylic acid Using the same procedure as described in Example 1, 3- (tert-butoxycarbonyl) -6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane (14 mmol, prepared in 2A) was used in place of 3-benzenesulfonyl-6-isothiocyanato-3-aza -bicycle [3.1.Ojhexano. After delation with 2-amino-2- (3-methyl-2-buten-1-yl) -3-pyridin-4-yl-propionic acid methyl ester (1.24 g, 5 mmol) as described in 1 B, sulfur-alkylation of 4-cyanophenacyl bromide in the presence of potassium bis (trimethylsilyl) amide (as described in 1C) and sulfur-extrusion in the presence of triphenylphosphine (as described in 1 D), obtained 1.53 g (2.22 mmol) of the title compound as a white solid. CI-MS: m / z 568.3 [M + 1].

EXAMPLE 35 44ri41a.5a.6a-345-Bromo-thiophene-2-sulfonip-3-aza-bicyclo43.1.01hex-6-n-443-methyl-but-2-enyl) -5-oxo-4 -pyridin-4-methyl-imidazolidin-2-yl-deno-1-acetyl-benzonitrile 35A. 4-. { [1 - (3-Aza-bicyclo [3.1.0] hex-6-yl] -4- (3-methyl-but-2-enyl) -5-oxo-4-pyridin-4-ylmethyl-imidazolidin-2 -ylidene] -acetyl} -benzonitrile Using the same procedure as described in Example 3, the title compound of Example 34 (1.23 g, 2.45 mmol) was treated with TFA (2.25 mL) in CH2Cl2 to give the title compound of 35A (0.831 g, 1.77 mmol, yield 73 %). CI-MS: m / z 468.2 [M + 1]. 35B. 4-. { [1- [1a, 5a, 6a-3- (5-Bromo-thiophene-2-sulfonyl) -3-aza-bici-clo [3.1.0] hex-6-yl] -4- (3-methyl- but-2-enyl) -5-oxo-4-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile According to the procedure of Example 13, the title compound of Example 35A (35 mg, 0.075 mmol) and 5-bromo-thiophene-2-sulfonyl chloride (29 mg, 0.112 mmol) were reacted to generate the compound of the title as a white solid (11 mg, 0.016 mmol, 22% yield). 1 H-NMR (CDCl 3): d 8.70 (br d, 2 H), 8.00 (d, J = 8.3 Hz, 2 H), 7.87 (d, J = 4.8 Hz, 2H ); 7.82 (d, J = 8.1 Hz, 2 H), 7.42 (d, J = 3.9 Hz, 1 H), 7.27 (d, J = 3.9 Hz, 1 H) , 4.95 (t, J = 7.3 Hz, 2 H), 3.74 (d, J = 10.0 Hz, 1 H), 3.70 (d, J = 10.0 Hz, 1 H ), 3.47 (s, 2 H), 3.29 (m, 2 H), 2.68 (m, 2 H), 2.3 (s, 1 H), 1.85 (s, 2 H) ), 1, 63 (s, 3 H), 1, 61 (s, 3 H).

EXAMPLE 36 Tert-butyl ester of acid 1a.5a.6ra-6424244-cyano-phenyl) -2-oxo-ethylidene-5-oxo-4-pyridin-4-ylmethyl-4-thiophen-3-ylmet L-imidazolidin-1-yl > -3-azabicyclo3.1.0lhexane-3-carboxylic acid Using the same general procedure described in Example 1, 3- (tert-butoxycarbonyl) -6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane (8.81 mmol, prepared in 2A) was used instead of 3 -benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane. After delation with acid methyl ester-amino-3-pyridin-4-yl-2-thiophen-3-ylmethyl-propionic acid 2 (0.77 g, 2.81 mmol) as described in 1 B, sulfur-alkylation of 4-cyanophenacyl bromide in the presence of potassium bis- (trimethylsilyl) amide as described in 1C and sulfur-extrusion in the presence of triphenylphosphine as described in 1 D, there were obtained 0.739 g (1.24 mmol) of the compound of the title. CI-MS: m / z 596.0 [M + 1].

EXAMPLE 37 44M 41 a.5a.6a-3-Benzenesulfonyl-3-aza-bicyclo.3.1.01hex-6-ih-5-oxo-4-pyridin-4-ylmethyl-44iophen-3-ylmethyl- Midazolidin-2-ylidene-1-acetyl > -benzontril 37A. 44.1 - (3-Aza-bicyclo.3.1.01hex-6-yl. -5-oxo-4-pyridin-4-ylmethyl-4-thiophen-3-ylmethyl-imidazolidin-2-yldeno-1-acetyl) ) -benzonitrile Using the same procedure as described in Example 3, the title compound of Example 36 (0.653 g, 1, 10 mmol) with TFA (1, 10 ml) was treated in CH2CI2 to give the title compound of 37A (0.311 g, 0.63 mmol, yield 57%). CI-MS: m / z 496.2 [M + 1]. 37B. 4-. { [1- (3-Benzenesulfonyl-3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4-pyridin-4-ylmethyl-4-thiophen-3-ylmethyl-imidazolidin-2-ylidene ] -acetyl} -benzonitrile According to the procedure of Example 13, the title compound of 37A (60 mg, 0.12 mmol) and benzenesulfonyl chloride (0.023 mL, 0.18 mmol) were reacted to generate the title compound as a white solid (58 mg, 0.091 mmol, yield 76%). CI-MS: m / z 637.2 [M + 1].

EXAMPLE 38 Tert-butyl ester of acid 1a.5a.6a-64443-chloro-but-2-eniD-24244-cyanophenyl) -2-oxo-ethylidene-5-oxo-4-pyridin-4-ylmethyl-imidazolidin -1-il > -3-azabicyclo3.1.0lhexane-3-carboxylic acid Employing the same procedure as described in Example 1, it was used 3- (tert-butoxilcarbonil) -6-isothiocyanato-3-azabicyclo [3.1.0] hexane (7.25 mmol, prepared in 2A) in Instead of 3-benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane. After delation with 2-amino-5-chloro-2-pyridin-4-ylmethyl-hex-4-enoic acid methyl ester (0.5 g, 1.87 mmol), as described in 1 B, sulfur -alkylation of 4-cyanophenacyl bromide in the presence of potassium bis (trimethylsilyl) amide (as described in 1 C) and sulfur-extrusion in the presence of triphenylphosphine (as described in 1 D), gave 0.774 g ( 1.32 mmol) of the title compound. CI-MS: m / z 588.1 [M + 1].

EXAMPLE 39 44M 41 a.5a.βa-345-Bromo-thiophene-2-sulfonyl) -3-aza-bicyclo43.1.01hex-6-ill-443-chloro-but-2-eni0-5-oxo-4- pyridin-4-methyl-imidazolidin-2-ylidene-acetyl} - benzonitrile 39A. 4-. { [1 - (3-Aza-bicyclo [3.1.0] hex-6-yl] -4- (3-chloro-but-2-enyl) -5-oxo-4-pyridin-4-ylmethyl-imidazolidin-2 -ylidene] -acetyl.}. -benzonitrile Using the same procedure as described in Example 3, the title compound of 38 (0.774 g, 1.32 mmol) was treated with TFA (1.30 mL) in CH2Cl2. to give the title compound of 39A (0.527 g, 1.08 mmol, yield 82%) CI-MS: m / z 488.0 [M + 1] .39B. 4- { [1- [3 - (5-Bromo-thiophene-2-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -4- (3-chloro-but-2-enyl) -5-oxo-4- pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl}. -benzonitrile According to the procedure of Example 13, the compound of Example 39A (35 mg, 0.072 mmol) and 5-bromothiophene chloride were reacted 2-sulfonyl (28 mg, 0.108 mmol) to generate the title compound as a white solid (7 mg, 0.010 mmol, 14% yield) CI-MS: m / z 712.0, 714.0 [M + 1 ] EXAMPLE 40 44ri41-Benzenesulfonyl-piperidin-4-ilmet¡p-5-oxo-4,4-bis-pyridin-4-ylmethyl- imidazolidin-2-ilideno1-acetyl} -bßnzonitrile 40A. 4- Tertiary butyl ester. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-ylmethyl} -piperidine-1-carboxylic acid Using the same procedure as described in Example 1, 4-isothiocyanatomethyl-piperidine-1-carboxylic acid tert -butyl ester (6.04 mmol) was used instead of 3-benzenesulfonyl. -6-isothiocyanato-3-aza-bicyclo- [3.1.0] hexane. After cyclization with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (1.36 g, 5.03 mmol), as described in 1 B. sulfur- Alkylation of 4-cyanophenacyl bromide in the presence of potassium bis (trimethylsilyl) amide as described in 1 C and sulfur-extrusion in the presence of triphenylphosphine as described in 1 D, afforded 1.036 g (1.78 millimoles) of the 40A title compound. CI-MS: m / z 607.3 [M + 1]. 40B. 4 - [(5-Oxo-1-piperidin-4-ylmethyl-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl}. -benzonitrile Using the same procedure as described in Example 3, the title compound of 40A (0.958 g, 1.58 millimoles) was treated with TFA (3 mL) in CH2Cl2 to give the title compound of 40B (0.621 g, 1.23 mmol, yield 78%) CI-MS: m / z 488.0 [M + 1] .40C 4- {[1- (1-Benzenesulfonyl-piperidin-4-ylmethyl) -5-oxo-4,4-bis-pyridine. 4-ylmethyl-imidazolidin-2-ylidene] -acetyl.}. -benzonitrile According to the procedure of Example 13, the title compound of 40B (50 mg, 0.099 mmol) and benzenesulfonyl chloride (0.025 ml, 0.198 mmol) ) were reacted to generate the title compound as a white solid (25 mg, 0.037 mmol, 37% yield) CI-MS: m / z 677.2 [M + 1].

EXAMPLE 41 Dimethylamide of 4424244-cyano-phenoxy-2-oxo-ethylidene-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-ylmethylene-1-pyrimidine-1-sulfonic acid According to the procedure of Example 13, the title compound of 40B (50 mg, 0.099 mmol) and N, N-dimethylsulfamyl chloride (0.025 mL, 0.237 mmol) were reacted to generate the title compound as a white solid. (14 mg, 0.023 mmol, yield 19%). CI-MS: m / z 614.2 [M + 1].

EXAMPLE 42 44 (5-Oxo-4141-phenyl-1 H-tetrazol-5-yl) -p-perdin-4-ylmethyl-4,4-bys-pyridin-4-ylmethyl-imidazolidin-2 -ylidene) -acetyl) -benzonitrile To a solution of the title compound of 40B (100 mg, 0.20 mmol) and (1-phenyl-1 H-tetrazol-5-yl) chloride (50 mg, 0.30 mmol) in CH3CN (1 mL) K2CO3 (0.08 g, 0.06 mmol) was added. The mixture was stirred overnight. After removal of CH3CN, the reaction mixture was partitioned between CH2Cl2 and H2O. After separation, the organic layer was washed with brine, dried over Na 2 SO 4 and concentrated. The crude product was chromatographed on silica gel with MeOH-CHCl3-NH4ΔH (1: 99: 0.1) as eluents to give the title compound as a white solid, 5 mg (0.077 mmol, 4% yield).

CI-MS: m / z 651, 2 [M + 1].

EXAMPLE 43 44 (1 141 -Methyl-1 H-imidazo-sulfonyl-piperidin-4-ylmethyl-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene > -acetl) -benzonitri According to the procedure of Example 13, the title compound of 40B (100 mg, 0.20 mmol) and 1-methylimidazol-4-ylsulfonyl chloride (50 mg, 0.30 mmol) were reacted to generate the compound of the title as a white solid (9 mg, 0.014 mmol, yield 7%). CI-MS: m / z 651, 0 [M + 1].

EXAMPLE 44 44 (5-Oxo-4,4-bis-pyridin-4-ylmethyl-14-1,4-thiophene-2-sulfonip-piperidin-4-ylmethyl-1-imidazolidin-2-ylidene) -acetyl) -benzonitrile According to the procedure of Example 13, the title compound of 40B (36 mg, 0.071 mmol) and thiophene-2-sulfonyl chloride (16 mg, 0.085 mmol) were reacted to generate the title compound (9 mg, 0.014 millimoles, yield 19%). CI-MS: m / z 653.0 [M + 1].

EXAMPLE 45 44- (1-Benzenesulfonyl-pyrrolidin-3-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene-acetyl) -benzonitrile Using the same procedure as described in Example 1, 1-phenylsulfonylpyrrolidin-3-yl isocyanate (1.38 millimoles) was used in place of 3-benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane. After delation with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (1.10 mmol) as described in 1 B, sulfur-alkylation of bromide of 4 -cianofenacil in the presence of potassium bis (trimethylsilyl) amide as described in 1C and sulfur-extrusion in the presence of triphenylphosphine as described in 1 D, 40 mg of the title compound was obtained as a white solid. CI-MS: m / z 619.2 [M + 1].

EXAMPLE 46 4414-Benzenesulfonyl-pyrrolidin-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazoHdin-2-lidenol-acetyl) -benzonitrile 46A. 4-. { [5-Oxo-4,4-bis-pyridin-4-ylmethyl-1- (1-butoxylcarbonyl-pyrrolidin-3-ylmethyl) -imidazolidin-2-ylidene] -acetyl} -benzonitrile Using the same procedure as described in Example 1, 3-isothiocyanatomethyl-pyrrolidine-1-carboxylic acid tert -butyl ester (21.2 millimoles) was used instead of 3-benzenesulfonyl-6-isothiocyanato-3-aza -bicyclo [3.1.0] hexane. After delation with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (14.1 mmol) as described in 1 B, sulfur-alkylation of bromide of 4 -cianofenacil in the presence of potassium bis (trimethylsilyl) amide as described in 1C and sulfur-extrusion in the presence of triphenylphosphine as described in 1 D, 4.0 g (6.75 mmol) of the title compound were obtained of 46A. CI-MS: m / z 594.3 [M + 1]. 46B. 4 - [(5-Oxo-4,4-bis-pyridin-4-ylmethyl-1-pyrrolidin-3-ylmethyl-imidazolidin-2-ylidene) -acetyl] -benzonitrile Using the same procedure as described in the Example 3, the title compound of 46A (6.73 mmol) was treated with TFA (10 ml) in CH2Cl2 to give the title compound of 46B (2.232 g, 4.53 mmol, yield 78%). CI-MS: m / z 494.3 [M + 1]. 46C. 4-. { [1- (1-Benzenesulfonyl-pyrrolidin-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile According to the procedure of Example 13, the title compound of 46B (100 mg, 0.20 mmol) and benzenesulfonyl chloride (0.04 ml, 0.198 mmol) were reacted to generate the title compound of Example 46 as a white solid (25 mg, 0.037 mmol, yield 37%). CI-MS: m / z 677.2 [M + 1].

EXAMPLE 47 44 (5-Oxo-4,4-bis-pyridin-4-methyl-1,4-thiophene-2-sulfonyl) -pyrrolidin-3-ylmethin-imidazolidin-2-ylidene) -acetyl) -benzonitrile According to the procedure of Example 13, the title compound of 46B (70 mg, 0.14 mmol) and thiophen-2-ylsulfonyl chloride (38.4 mg, 0.21 mmol) were reacted to generate the compound of the title as a white solid (60 mg, 0.093 mmol, yield 67%). CI-MS: m / z 639.2 [M + 1].

EXAMPLE 48 44.1 (x.5a.6β-143-Benzenesulfonyl-3-aza-bicichlor3.1.01hex-6-ylmethyl) -5-oxo-4,4-byspyridin-4-ylmethyl-imidazolidin-2-ylidene-1 acetyl } -benzonitrile Using the same procedure as described in Example 1, 1, 5, 6β-6-isothiocyanatomethyl-3-benzenesulfonyl-3-aza-bicyclo [3.1.0] hexane (1.36 millimoles) was used in place of 3-benzenesulfonyl-6-isothiocyanato-3-aza -bicyclo [3.1.0] hexane. After cyclization with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (1.48 mmol) as described in 1 B, sulfur-alkylation of bromide of 4 -cianofenacil in the presence of potassium bis- (trimethylsilyl) amide as described in 1C and sulfur-extrusion in the presence of triphenylphosphine as described in 1 D, 111 mg (0.172 mmol) of the title compound was obtained as a solid White. 13C NMR (CDC): d 187 (s), 173.2 (s), 158.7 (s), 149.6 (d), 142.7 (s), 142.3 (s), 135.7 (s), 132.6 (d), 132.1 (d), 128.8 (d), 127.5 (d), 127.3 (d), 118.2 (s), 114.5 ( s), 75.65 (d), 66.7 (s), 48.9 (t), 42.5 (t), 40.5 (t), 21, 4 (d), 18.0 (d) ).

EXAMPLE 49 44rim.5o-.6 «-143-Benzenesulfonyl-3-aza-biciclof3.1.01hex-6-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene-1-acetyl > -benzonitrile Using the same procedure as described in Example 1, 1a, 5a, 6a-6-isothiocyanatomethyl-3-benzenesulfonyl-3-aza-bicyclo [3.1.0] hexane (0.38 mmol) was used instead of 3 -benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane. After delation with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (0.42 mmol) as described in 1 B, sulfur-alkylation of bromide of 4 -cianofenacil in the presence of potassium bis- (trimethylsilyl) amide as described in 1C and sulfur-extrusion in the presence of triphenylphosphine as described in 1D, 16 mg (0.025 mmol) of the title compound was obtained as a white solid . CI-MS: m / z 645.3 [M + 1].

EXAMPLE 50 44f1a.6a.7a-143-Benzenesulfonyl-3-aza-bicichlor4.1.01hept-7-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-midezolidin -2-ylidene-acetyl > -benzonitri Using the same procedure as described in Example 1, 1, 6a, 7a-7-isothiocyanatomethyl-3-benzenesulfonyl-3-aza-bicyclo [4.1.0] heptane (0.529 millimole) was used in place of 3-benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane. After cyclization with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (0.635 mmol) as described in 1B, sulfur-alkylation of 4-cyanophenacyl bromide in the presence of potassium bis- (trimethylsilyl) amide as described in 1C and sulfur-extrusion in the presence of triphenylphosphine as described in 1 D, 10 mg (0.16 mmol) of the title compound was obtained as a solid White. CI-MS: m / z 658.5 [M + 1].

EXAMPLE 51 44ria.6a, 7a-143-Benzenesulfonyl-3-aza-bicyclo4.1.0lhept-7-ip-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene-1-acetyl > -benzonitrile Using the same procedure as described in Example 1, 1, 6a, 7a-7-isothiocyanatomethyl-3-benzenesulfonyl-3-aza-bicyclo [4.1.0] heptane (0.529 mmol) was used instead of 3-benzenesulfonyl -6- isothiocyanato-3-aza-bicyclo [3.1.0] hexane. After delation with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (0.635 mmol) as described in 1B, sulfur-alkylation of 4-cyanophenacyl bromide in the presence of potassium bis- (trimethylsilyl) amide as described in 1C and sulfur-extrusion in the presence of triphenylphosphine as described in 1 D, 10 mg (0.16 mmol) of the title compound was obtained as a solid White. CI-MS: m / z 658.5 [M + 1], EXAMPLE 52 44f 1 a.5a.6β-143-Benzenesulfonyl-3-aza-bicycloclo 3.1.01hex-6-yl. -5-oxo-4.4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene-1-acetyl} -benzonitrile Using the same procedure as described in Example 1, 1a, 5a, 6β-6-isothiocyanatomethyl-3-benzenesulfonyl-3-aza-bicyclo [3.1.0] hexane (0.529 mmol) was used instead of 3-benzenesulfonyl -6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane. After cyclization with 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid methyl ester (0.635 mmol) as described in 1B, sulfur-alkylation of 4-cyanophenacyl bromide in the presence of potassium bis- (trimethylsilyl) amide as described in 1C and sulfur-extrusion in the presence of triphenylphosphine as described in 1 D, 10 mg (0.16 mmol) of the title compound was obtained as a solid White.

CI-MS: m / z 658.5 [M + 1].

EXAMPLE 53 44-i1.5ra.6a-3-Benzenesulfonyl-3-aza-bicyclo3.1.01hex-6-yl) -4,4-b1s-1 H- midazol-4-ylmethyl) -5-oxo -imidazolidin-2-ylidene-1-acetyl) -benzonitrile 53A. 2- (Benzylidene-amino) -3- (1 -trityl-1H-imidazol-4-yl) -2- (1 -trityl-1H-imidazol-4-ylmethyl) -propionic acid methyl ester solution of potassium bis (trimethylsilyl) amide (11.34 g, 54 mmol) in THF (100 ml) was added dropwise to a mixture of (benzylidene-amino) -acetic acid methyl ester (3.83 g, 21, 63 mmol) and 4-chloromethyl-1-trityl-1 H-imidazole (21.6 g, 60.18 mmol) in THF (200 ml) at -78 ° C. The resulting solution was warmed to room temperature and stirred for 24 hours. After removal of THF, the reaction mixture was subsequently partitioned between ethyl acetate and brine. The aqueous layer was washed twice with ethyl acetate. The ethyl acetate extracts were combined, dried over MgSO4, filtered and concentrated to give the crude title compound 53A. 53B. 2- (Amino-3- (1-trityl-1 H -imidazol-4-yl) -2- (1 -trityl-1 H -imidazol-4-ylmethyl) -propionic acid methyl ester The crude title compound of 53A was dissolved in anhydrous THF (40 ml), 10 ml of a 2.0 M aqueous hydrochloric acid (HCl) solution at 0 ° C. was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was subsequently concentrated in vacuo to remove the THF.The reaction mixture was then partitioned between ethyl ether and water.The aqueous layer was washed twice more with ethyl ether.The pH of the aqueous layer was then adjusted to 9 with sodium carbonate (Na? COs) and the solution was extracted with methylene chloride until practically no product remained in the methylene chloride layer (CH2CI2) .The extracts in CH2CI2 were combined, dried over MgSO4, they were filtered and concentrated in vacuo to give the crude product.The crude product was chromatographed on silica gel with M eOH-CHCb-NH4? H (1: 99: 0.1) as eluents to provide the title compound of 53B as a white foam, 10.78 g (14.7 mmol, 68% yield in two steps). 53C. 3- (3-Benzenesulfonyl-3-aza-bicyclo [3.1.0] hex-6-yl) -2-thioxo-5,5-bis- (1-trityl-1 H-imidazol-4-ylmethyl) -imidazolidin -4-one Using the same procedure as described in Example 1 B, the reaction mixture of the title compound of 53B (0.68 mmol) and 3-benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo [3.1 .0] hexane (6.71 mmol, prepared in 1A) was heated to reflux overnight under a dry N2 atmosphere. It was then poured into 10% aqueous solution of K2CO3 and extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO 4 and concentrated to give the crude product. The crude product was chromatographed on silica gel with MeOH-CHCb-NH4OH (1: 99: 0.1) as eluents to give the title compound of 56B as a yellow solid, 0.548 g (0.558 mmol, 82% yield).

CI-MS: m / e 982.4 [M + 1]. 53D. 4-. { [1- (3-Benzenesulfonyl-3-aza-bicyclo [3.1.0] hex-6-yl) -4,4-bis- (1-trityl-1 H-imidazol-4-ylmethyl) -4,5- dihydro-5-oxo-1 H-imidazol-2-ylsulfanyl] -acetyl-benzonitrile Using the same procedure as described in Example 1C, the title compound of 53C (0.548 g, 0.558 mmol) and cyanophenacyl bromide (138 mg, 0.614 mmol), in the presence of potassium bis (trimethylsilyl) amide (129 mg, 0.614 mmol) were reacted give the title compound of 53D, after chromatographic purification, 0.46 g (0.41 mmol, 73% yield). 53E. 4-. { [1- (3-Benzenesulfonyl-3-aza-bicyclo [3.1.0] hex-6-yl) -4,4-bis- (1-trityl-1 H-imidazol-4-ylmethyl) -5-oxo- imidazolidin-2-ylidene] -acetyl} -benzonitrile Using the same procedure as described in Example 1 D, the title compound of 53D (460 mg, 0.41 mmol) and triphenylphosphine (320 mg, 1.23 mmol) in refluxing toluene afforded the title compound of 53E, after chromatographic purification, 0.324 g (0.35 millimoles, 86% yield). CI-MS: m / z 923.4 [M + 1]. 53F. 4-. { [1 - (3-Benzenesulfonyl-3-aza-bicyclo [3.1.0] hex-6-yl) -4,4-bis- (1-trityl-1 H-imidazol-4-ylmethyl) -5-oxo- imidazolidin-2-ylidene] -acetyl} -benzonitrile To a solution of the title compound of 53E (0.324 g, 0.33 mmol) in CH 2 Cl 2 (3 mL) were added NH 4 F (48 mg, 1.01 mmol) and triethyl silane (0.21 mL, 1.30 mmol) followed by addition of 3 ml of TFA. The reaction mixture was stirred at room temperature for 12 h. It was partitioned between CH2Cl2 and saturated sodium bicarbonate solution (NaHCOs). The CH2Cl2 layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude product. The crude product was chromatographed on silica gel with MeOH-CHCb-NH4ΔH (6: 94: 0.1) as eluents to give the title compound of Example 53, 20 mg (0.033 mmol, 10% yield). CI-MS: m / z 609.2 [M + 1].

EXAMPLE 54 44 (4,4-Bis41H-imidazol-4-ylmethi-141 a, 5a, 6a-344-methyl-piperidine-1-sulfonyl) -3-aza-bicycloi 3.1.1hex-6-ip-5- oxo-imidazoMdin-2-yldene) -acetyl) - benzonitrile Using the same procedure as described in Example 53, 6-isothiocyanato-3- (4-methyl-piperidine-1-sulfonyl) -3-aza-bicyclo [3.1.0] hexane (6.8 mmol) was used. instead of 3-benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo- [3.1.0] hexane. After delation with 2-amino-3- (1-trityl-1 H -imidazol-4-yl) -2- (1 -trityl-1 H -imidazol-4-ylmethyl) -propionic acid methyl ester (0, 68 mmol), as described in 53C, sulfur-alkylation of 4-cyanophenacyl bromide in the presence of potassium bis (trimethylsilyl) amide as described in 53D, sulfur-extrusion in the presence of triphenylphosphine as described in 53E and removal of the trifly groups as described in 53F, 4 mg (0.006 mmol) of the title compound was obtained as a white solid. CI-MS: m / z 630.3 [M + 1].

EXAMPLE 55 44.sub.41 -5a.6a-345-Bromo-thiophene-2-sulfonyl) -3-aza-bicyclo3.1.01hex-6-in. 4,4-bis41H-imidazol-4-ylmethyl) -5-oxo- imidazolidin-2-ylidene-acetyl) -benzonitrile Using the same procedure as described in Example 53, 6-isothiocyanato-3- (5-bromothiophene-2-sulfonyl) -3-aza-bicyclo [3.1.0] hexane (7.17 mmol) was used instead of 3-benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo- [3.1.0] hexane. After delation with 2-amino-3- (1-trityl-1 H -imidazol-4-yl) -2- (1 -trityl-1 H -imidazol-4-ylmethyl) -propionic acid methyl ester (0, 68 mmol), as described in 53C, sulfur-alkylation of 4-cyanophenacyl bromide in the presence of potassium bis (trimethylsilyl) amide as described in 53D, sulfur-extrusion in the presence of triphenylphosphine as described in 53E and removal of the trifly groups as described in 53F, 20 mg (0.03 mmol) of the title compound was obtained as a white solid. CI-MS: m / z 693.1 [M + 1].

EXAMPLE 56 44f 141 a5a, 6a-3-Aza-34-tert-butoxycarbonyl) -bicyclo-f3.1.0lhex-6-yl) -4,4-bis43-methyl-3H-imidazol-4-ylmetip-5-oxo -imidazolidin-2-ylidene-acetyl-benzonitrile 56A. 2- (Benzhydrylidene-amino) -3- (3-methyl-3H-imidazol-4-yl) -2- (3-methyl-3H-imidazol-4-ylmethyl) -propionic acid methyl ester Using the same procedure as The reaction of 4-chloromethyl-1-methyl-1H-imidazole (2.5 g, 12.5 mmol) and (benzhydrylidene-amino) -acetic acid methyl ester (1.056 g, 4.17 mmol) in the presence of potassium bis (trimethylsilyl) -amide (5.24 g, 25.02 mmol) in THF afforded 1.40 g (3.181 millimole, 76% yield) of the title compound of 56A, then of chromatographic purification. 56B. 2- (Amino-3- (3-methyl-3H-imidazol-4-yl) -2- (3-methyl-3H-imidazol-4-ylmethyl) -propionic acid methyl ester Using the same procedure as described in Example 53B, the title compound of 56A (960 mg, 2.17 mmol) was treated with HCl in THF to give the title compound of 56B, 652 mg (77% yield). 6- [4,4-bis- (3-methyl-3H-imidazol-4-ylmethyl) -5-oxo-2-thioxo-imidazolidin-1-yl] -3-aza-bicyclo [3.1.0] hexane acid -3-carboxylic acid Using the same procedure as described in Example 1 B, the reaction mixture of the title compound of 56B (0.39 g, 1.01 mmol) and 3- (tert-butoxycarbonyl) -6- isothiocyanate-3-aza-bicyclo [3.1.Ojhexane (2.53 mmol, prepared in 2A) was heated in refluxing ethanol to yield 0.448 g (0.92 mmol, 92% yield) of the title compound of 56C, after chromatographic purification CI-MS: m / e 486.2 [M + 1]. 56D.St-butyl ester of 6- [2- [2- (4-ci) acid. ano-phenyl) -2-oxo-ethylsulfanyl] -4,4-bis- (3-methyl-3H-imidazol-4-ylmethyl) -5-oxo-4,5-dihydro-imidazol-1-yl] -3 -aza-bicyclo [3.1.0] hexane-3-carboxylic acid Using the same procedure as described in Example 1C, the title compound of 56C (0.448 g, 0.924 mmol) and 4-cyanophenacyl bromide (228 mg, 1. 02 mmol) in the presence of potassium bis (trimethylsilyl) -amide (214 mg, 1.02 mmol) was reacted to give the title compound of 56 D, 0.554 g (0.882 mmol, 95% yield). CI-MS: m / z 629.3 [M + 1]. 56E. 4-. { [1 - (1 a, 5a, 6a-3-Aza-3-tert-butoxycarbonyl) -bicyclo [3.1.0] hex-6-yl) -4,4-bis- (3-methyl-3H-imidazole- 4-ylmethyl) -5-oxo-imidazolidin-2-ylidene] -acetyl} -benzonitrile Using the same procedure as described in Example 1 D, the title compound of 56D (318 mg, 0.998 mmol) and triphenylphosphine (776 mg, 2.96 mmol) in refluxing toluene gave the title compound of Example 56, after chromatographic purification, 0.196 g (0.63 mmol, 63% yield).

CI-MS: m / z 597.3 [M + 1].

EXAMPLE 57 44M 41 n_.5a.6a-3-Aza-bicycloi3.1.0.hex-6-il, -4,4-b¡s-, 3-metíl-3H-¡m¡dazol-4- ¡ lmethyl) -5-oxo-imidazolidin-2-yl-deno-1-acetyl > -benzonitrile Using the same procedure as described in Example 3, the title compound of 56 (196.4 mg, 0.33 mmol) was treated with TFA (0.3 mL) in CH2Cl2 to provide the title compound, 99 , 5 mg (0.2 mmol, yield 61%). 1H NMR (CDCb): d 7.87, (d, J = 8.3 Hz, 2 H), 7.70 (d, J = 8.3 Hz, 2 H), 7.33 (s, 2 H) ), 6.77 (s, 2 H), 5.53 (s, 1 H), 3.56 (s, 6 H), 3.21 (d, J = 15.2 Hz, 2 H), 3 , 20 (d, J = 11, 1 Hz, 2 H), 3.07 (d, J = 15.2 Hz, 2 H), 2.98 (d, J = 11, 1 Hz, 2 H), 2.15 (s, 1 H), 1.50 (s, 2 H).

EXAMPLE 58 441 - (1 a, 5a, 6a-3-Benzenesulfonyl-3-aza-bicyclo.3.1.01hex-6-yl) -4,4-bis43-methyl-3H-imidazol-4-ylmethyl) -5-oxo- imidazolidin-2-ylidene-acetyl > - benzonitrile According to the procedure of Example 13, the title compound of 57, 4-. { [1- (3-aza-bicyclo [3.1.0] hex-6-yl) -4,4-bis- (3-methyl-3H-imidazol-4-ylmethyl) -5-oxo-imidazolidin-2-ylidene ] -acetyl} -benzonitrile (25 mg, 0.05 mmol) and benzenesulfonyl chloride (0.0096 ml, 0.075 mmol) were reacted to generate the title compound (20 mg, 0.031 mmol, 63% yield). CI-MS: m / z 637.2 [M + 1].

EXAMPLE 59 44 (4.4-Bis43-methyl-3H-imidazol-4-ylmethyl) -141a.5a, 6a-344-methyl-piperazine-1-sulfonyl) -3-aza-bicichlor31.0hex-6-ill-5- oxo-imidazolidin-2-ylidene} -acetyl.- benzonitrile According to the procedure of Example 13, the title compound of 57, 4-. { [1- (3-aza-bicyclo [3.1.0] hex-6-yl) -4,4-bis- (3-methyl-3H-imidazol-4-ylmethyl) -5-oxo-imidazolidin-2-ylidene ] -acetyl} -benzonitrile (25 mg, 0.05 mmol) and 4-methyl-piperazine-1-sulfonyl chloride (0.05 mg, 0.25 mmol) were reacted to generate the title compound (10 mg, 0.016 mmol, 30% yield). CI-MS: m / z tbd [M + 1].

EXAMPLE 60 44H 41 a.5a.6a-345-Bromo-thiophene-2-sulfonip-3-aza-bicyclo43.1.01hex-6-in- 4.4-bis43-methyl-3H-imidazol-4-ylmethyl) - 5-Oxo-Midazolidin-2-ylidene-1-acetyl-benzonitrile According to the procedure of Example 13, the title compound of 57, 4-. { [1- (3-aza-bicyclo [3.1.0] hex-6-yl) -4,4-bis- (3-methyl-3H-imidazol-4-ylmethyl) -5-oxo-imidazolidin-2-ylidene ] -acetyl} -benzonitrile (25 mg, 0.05 mmol) and 5-bromo-thiophene-2-sulfonyl chloride (0.02 mg, 0.075 mmol) were reacted to generate the title compound (10 mg, 0.014 mmol, yield 28). %). CI-MS: m / z 721.1, 723.1 [M + 1].

EXAMPLE 61 Tert-butyl ester of 3424244-cyano-phene-2-oxo-ethylidene-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-ylmethyl acid > -8a-aza-bichlor3.2.1-octane-8-carboxylic acid A. 3-Ethoxycarbonylmethyl-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 8a-aza-bicyclo [3.2.2] oct-3-yl) ethyl ester was dissolved -acetic (2.64 g, 13.4 mmol) in CH2Cl2 (40 mL) under dry N2. To this solution was added di-tert-butyl dicarbonate (3.33 g, 15.2 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between CH2Cl2 and 10% NaHS04. The product was extracted into CH 2 Cl 2, dried over MgSO 4, filtered and concentrated (vacuum) to give an oil. The oil was purified by flash column chromatography on silica gel (eluent: ethyl acetate / hexanes 20/80). The relevant fractions were collected and concentrated (vacuum) to give 2.32 g of the title compound. C.l. m / z 198 [M + 1 - Boc]; 1 H NMR (CDCb): d 4.10 (m, 2 H), 4.08 (q, J = 7.1 Hz, 2 H), 2.41 (m, 2 H), 2.15 (m, 3 H), 1.95 (m, 2 H), 1.64 (m, 2 H), 1, 42 (s, 9 H), 1, 21 (t, J = 7.1 Hz, 3 H) . B. 3-Carboxymethyl-8a-aza-bike-clo [3.2.1] octane-8-carboxylic acid tert-butyl ester 3-Ethoxycarbonylmethyl-8a-aza-bicyclo-tert-butyl ester [3.2.1] ] octane-8-carboxylic acid (2.40 g, 8.08 mmol) in EtOH (50 ml). To the mixture was added 1.0 N NaOH (16.2 ml) and the reaction mixture was stirred overnight at room temperature. The mixture was then concentrated (vacuum) and then partitioned between Et2? and water. The water layer was then acidified to pH = 2 using 0.5 N HCl, and the product was extracted into CH 2 Cl 2, dried over MgSO 4, filtered and concentrated (vacuum) to give 1.13 g of the Title. C.l. m / z 170 [M + 1 - Boc]; 1 H NMR (CDCb) d 4.11 (m, 2 H), 2.50 (m, 2 H), 2.20 (m, 3 H), 1.97 (m, 2 H), 1.65 ( m, 2 H), 1, 41 (s, 9 H). C. 3- (Benzyloxycarbonyl-amino-methyl) -8a-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 3-carboxymethyl-8a-aza-bicyclo-tert-butyl ester was dissolved [3.2.1] octane-8-carboxylic acid (1.13 g, 4.20 mmol) in anhydrous toluene (40 ml) under dry N2. To this solution were added triethylamine (760 ml, 5.46 mmol) and diphenylphosphoryl azide (1.10 ml, 5.03 mmol). The mixture was stirred at room temperature for 1.5 hours, after which benzyl alcohol (520 ml, 5.03 mmol) was added. The reaction mixture was heated to 96 ° C. The mixture was stirred at this temperature for 3 hours, after which it was cooled to 70 ° C and stirred overnight. The mixture was then cooled to room temperature and diluted with ethyl acetate. The mixture was partitioned between ethyl acetate and 0.1 N NaOH. The organic layer was dried over MgSO4, filtered and concentrated (vacuum) to give 1.79 g of the title compound as a yellow oil. C.l. m / z 275 [M + 1 - Boc]; 1 H NMR (CDCb) d 7.35 (m, 5 H), 5.09 (s, 2 H), 4.11 (m, 3 H), 3.25 (m, 2 H), 1, 70- 2.20 (m, 7 H), 1.42 (s, 9 H), 1.31 (m, 2 H). D. 3-Aminomethyl-8a-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 3- (benzyloxycarbonylamino-methyl) -8-aza-tert-butyl ester -bicyclo [3.2.1] octane-8-carboxylic acid (1.49 g, 3.97 mmol) and 500 ml of acetic acid in EtOH (25 ml) in a Paar flask. 148 mg of 10% palladium on carbon were added to the mixture. The reaction vessel was placed in a Paar shaker and loaded with 3.37 kg / cm 2 of hydrogen. The reaction mixture was stirred by shaking overnight at room temperature, after which it was filtered through Celite. The Celite was washed with ethanol and the combined filtrates were concentrated (vacuum) to give 732 mg of the title compound. C.l. m / z 241 [M + 1]; 1 H NMR (CDCb) d 4.10 (m, 4 H), 3.27 (m, 2 H), 1, 20-2.20 (m, 9 H), 1.44 (s, 9 H). E. 3-isothiocyanatomethyl-8a-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 3-aminomethyl-8a-aza-bicyclo [3.2.1] octane tert-butyl ester was dissolved -8-carboxylic acid (725 mg, 3.02 mmol) and 1,1'-thiocarbonyldiimidazole (718 mg, 3.62 mmol) in CH2Cl2 (15 mL) under dry N2 at room temperature. The reaction mixture was stirred for 4 hours and then partitioned between 10% NaHS04 and CH2Cl2. The organic layer was washed again with 10% NaHS.sub.4, followed by water, and finally saturated NaHCO 3. The organic layer was dried over MgSO4, filtered and concentrated (vacuum) to give 822 mg of the title compound. C.l. m / z 183 [M + 1-Boc]; 1 H NMR (CDCb) d 4.17 (m, 2 H), 3.57 (d, J = 7.1 Hz, 2 H), 1, 40-2.20 (m, 7 H), 1.42 (s, 9 H), 1, 20 (m, 2 H). F. 3- (5-Oxo-4,4-bis-pyridin-4-ylmethyl-2-thioxo-imidazolidin-1-ylmethyl) -8-aza-bicyclo [3.2.1] octane- tert -butyl ester 8-carboxylic acid 3-isothiocyanatomethyl-8a-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (819 mg, 3.02 mmol) and 2-amino-3-methyl ester were dissolved pyridin-4-yl-2-pyridin-4-ylmethyl-propionic acid (853 mg, 3.02 mmol) in EtOH (10 mL) under dry N2. The reaction mixture was heated to 75 ° C and the reaction was prolonged at this temperature for 2 days. The reaction mixture was concentrated (vacuum) to give 1.83 g of a black residue. The residue was purified by flash column chromatography on silica gel (eluent: gradient from ethyl acetate to CHsOH / ethyl acetate 6/94) to give 678 mg of the title compound. C.l. m / z 522 [M + 1]; 1 H NMR (CDCb) d = 8.50 (m, 4H); 8.20 (br s, 1 H), 7.12 (m, 4 H), 4.01 (m, 2 H), 3.50 (d, J = 7.1 Hz, 2 H), 3, 21 (d, J = 13.1 Hz, 2 H), 3.07 (d, J = 13.1 Hz, 2 H), 1, 50-1, 95 (m, 7 H), 1.47 ( s, 9 H), 0.79 (m, 2 H). G. 3- tertiary butyl ester. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylsulfanyl} -5-oxo-4,4-bis-pyridin-4-ylmethyl-4,5-dihydro-imidazol-1-ylmethyl} -8-Aza-bicyclo [3.2.1] octane-8-carboxylic acid To a solution maintained at -78 ° C of potassium bis (trimethylsilyl) amide (272 mg, 1.36 millimoles) in anhydrous THF (15 ml) in dry N2 atmosphere was added 3- (5-oxo-4,4-bis-pyridin-4-ylmethyl-2-thioxo-imidazolidin-1-ylmethyl) -8a-aza-bicyclo [3,2. 1] octane-8-carboxylic acid (678 mg, 1.30 mmol). The solution was warmed to room temperature, and after 15 minutes it was cooled to -78 ° C. To this solution was added 4-cyanophenacyl bromide (305 mg, 1.36 mmol). The reaction mixture was warmed to room temperature and stirred for 1 hour. The mixture was partitioned between CH2Cl2 and saturated NaHCO3. The organic layer was dried over MgSO 4, filtered and concentrated (vacuum) to give 1.50 g of an orange residue. The residue was purified by flash column chromatography on silica gel (eluent: gradient from ethyl acetate to MeOH / ethyl acetate 5/95) to give 744 mg of the title compound. C.l. m / z 665 [M + 1]; 1 H NMR (CDCb) d = 8.40 (m, 4 H), 8.19 (d, J = 8.4 Hz, 2 H), 7.90 (d, J = 8.4 Hz, 2 H) , 6.96 (m, 4 H), 4.61 (s, 2 H), 3.99 (m, 2 H), 3.50 (d, J = 7.1 Hz, 2 H), 3, 11 (m, 2 H), 3.01 (m, 4 H), 1, 50-1, 95 (m, 7 H), 1.45 (s, 9 H), 0.73 (m, 2 H) ). H. 3- tertiary butyl ester. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-ylmethyl} -8a-aza-bicyclo [3.2.1] octane-8-carboxylic acid 3-tert-butyl ester was dissolved. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylsulfanyl} -5-oxo-4,4-bis-pyridin-4-ylmethyl-4,5-dihydro-imidazol-1-ylmethyl} -8a-aza-bicyclo [3.2.1] octane-8-carboxylic acid (34 mg, 0.059 mmol) in anhydrous toluene (5.0 ml) under dry N2. To this solution were added triphenylphosphine (62 mg, 0.23 mmol) and 18 ml of N-ethyldiisopropylamine, and the mixture was heated to 100 ° C. After stirring for 48 hours, the reaction mixture was concentrated (vacuum) and then partitioned between 0.01 N HCl and Et20. The aqueous layer was washed twice with Et20 and then basified to pH = 8 with NaHCO3. The product was extracted into CH 2 Cl 2, dried over MgSO 4, filtered and concentrated (vacuum) to give a tan solid. The solid was triturated with CH2Cl2 / hexanes to give 29 mg of the title compound as a white solid. C.l. m / z 633 [M + 1]; 1 H NMR (CDCb) d 10.42 (br s, 1 H), 8.46 (m, 4 H), 7.86 (d, J = 8.4 Hz, 2 H), 7.71 (d, J = 8.4 Hz, 2 H), 7.12 (m, 4 H), 5.10 (s, 1 H), 4.00 (m, 2 H), 3.29 (d, J = 13 , 2 Hz, 2 H), 3.20 (m, 2 H), 3.10 (d, J = 13.2 Hz, 2 H), 1.95 (m, 2 H), 1, 5-1 , 7 (m, 5 H), 1, 4 (s, 9 H), 0.71 (m, 2 H).

EXAMPLE 62 44f148 -Aza-bicichlor3.2.1loct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene-acetyl} -benzonitrile 3-tert-butyl ester was dissolved. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-ylmethyl} -8a-aza-bicyclo [3.2.1] octane-8-carboxylic acid (713 mg, 1.12 mmol) in 10 ml of TFA under dry N2. The mixture was heated at 40 ° C for 10 minutes. The mixture was then concentrated (vacuum) and the residue was partitioned between CH 2 Cl 2 and 0.01 N NaOH. The CH 2 Cl 2 layer was dried over MgSO 4, filtered and concentrated (vacuum) to give 545 mg of the title compound as a foam. of cinnamon color. C.l. m / z 533 [M + 1]; 1 H NMR (CDCb) d 10.38 (br s, 1 H), 8.46 (m, 4 H), 7.88 (d, J = 8.3 Hz, 2 H), 7.72 (d, J = 8.3 Hz, 2 H), 7.12 (m, 4 H), 5.12 (s, 1 H), 3.05-3.36 (m, 9 H), 1, 3-1 , 7 (m, 5 H), 0.70 (m, 2 H).

EXAMPLE 63 44- (8-Acetyl-8-aza-b-cyclo [3.2.1-octyl-3-ylmethyl] -5-oxo-4,4-bis-pyridin-4-lmethyl-imidazolidin-2-ylidene -acetyl-benzonitrile It was dissolved 4-. { [1- (8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (54 mg, 0.10 mmol) in 1.0 mL of CH2Cl2 under a dry N2 atmosphere. To this solution was added NEt3 (36 ml, 0.26 mmol) and acetic anhydride (24 ml, 0.26 mmol). The mixture was stirred overnight at room temperature and then partitioned between CH 2 Cl 2 and saturated NaHC 3. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (in vacuo) to give 59 mg of a brown residue. The residue was triturated with C ^ C / hexanes to give 45 mg of the title compound as a white solid. C.l. m / z 575 [M + 1]; 1 H NMR (CDCb) d 10.44 (br s, 1 H), 8.47 (m, 4 H), 7.85 (d, J = 8.4 Hz, 2 H), 7.71 (d, J = 8.4 Hz, 2 H), 7.15 (m, 4 H), 5.11 (s, 1 H), 4.46 (m, 1 H), 3.90 (m, 1 H) , 3.00-3.36 (m, 6 H), 1.96 (s, 3 H), 0.70-1, 7 (m, 9 H).

EXAMPLE 64 44148-Methanesulfonyl-8-aza-b1-chloro-2,3-nit-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene-acetyl) -benzonitrile It was dissolved 4-. { [1- (8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-lidazolidin-2-ylidene] -acetyl} -benzonitrile (54 mg, 0.10 mmol) in 1.0 mL of CH2Cl2 under a dry N2 atmosphere. To this solution was added NEt3 (18 ml, 0.13 mmol) and methanesulfonyl chloride (9.5 ml, 0.13 mmol). The mixture was stirred overnight at room temperature and then partitioned between CH 2 Cl 2 and saturated NaHC 3. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (in vacuo) to give 56 mg of a brown residue. The residue was triturated with C ^ C / hexanes to give 49 mg of the title compound as a white solid. C.l. m / z 611 [M + 1]; 1 H NMR (CDCb) d 10.39 (br s, 1 H), 8.48 (m, 4 H), 7.88 (d, J = 8.4 Hz, 2 H), 7.72 (d, J = 8.4 Hz, 2 H), 7.16 (m, 4 H), 5.10 (s, 1 H), 4.03 (m, 2 H), 3.10-3.30 (m , 6 H), 2.82 (s, 3 H), 2.05 (m, 2 H), 0.70-1, 80 (m, 7 H).

EXAMPLE 65 Ethyl ester of 3424244-cyano4-inip-2-oxo-ethylidene-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazole-din-1-ylmethyl) -8a-aza-biciclof3.2.1loctane- 8-carboxylic It was dissolved 4-. { [1- (8-methanesulfonyl-8a-aza-bicyclo- [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acety} -benzonitrile (54 mg, 0.10 mmol) in 1.0 mL of CH2Cl2 under a dry N2 atmosphere. To this solution was added NEt3 (21 ml, 0.15 mmol) and ethyl chloroformate (12 ml, 0.12 mmol). The mixture was stirred overnight at room temperature and then partitioned between CH 2 Cl 2 and NaHC 3. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated in vacuo to give 87 mg of a brown residue. The residue was triturated with CH2C / hexanes to give 54 mg of the title compound as a white solid. C.l. m / z 605 [M + 1]; 1 H NMR (CDCb) d 10.42 (br s, 1 H), 8.45 (m, 4 H), 7.85 (d, J = 8.3 Hz, 2 H), 7.70 (d, J = 8.3 Hz, 2 H), 7.10 (m, 4 H), 5.10 (s, 1 H), 4.03 (m, 4 H), 3.05-3.30 (m, 6 H), 2.82 (s, 3 H), 1.95 (m, 2 H) , 0.70-1, 70 (m, 10 H).

EXAMPLE 66 44f148-Formyl-8a-aza-bicyclo3.2.noct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-lmethyl-imidazolidin-2-ylidene-acetyl) -benzonitrile It was dissolved 4-. { [1- (8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (54 mg, 0.10 mmol) in 1.0 ml of CH2Cb under dry N2. To this solution NEÍ3 (28 ml, 0.20 mmol) and acetic-formic anhydride (23 ml, 0.26 mmol) were added. The mixture was stirred overnight at room temperature and then partitioned between CH2Cl2 and saturated aqueous bicarbonate solution. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (in vacuo) to give 58 mg of a brown residue. The residue was triturated with CH2Cb / hexanes to give 45 mg of the title compound as a tan powder. C.l. m / z 561 [M + 1]; 1 H NMR (CDCb) d 10.40 (br s, 1 H), 8.47 (m, 4 H), 8.01 (s, 1 H), 7.89 (d, J = 8.4 Hz, 2 H), 7.73 (d, J = 8.4 Hz, 2 H), 7.12 (m, 4 H), 5.10 (s, 1 H), 4.40 (m, 1 H) , 3.80 (m, 1 H), 3.05-3.30 (m, 6 H), 0.70-2.00 (m, 9 H).

EXAMPLE 67 3424244-Cyano-phenyl-2-oxo-ethylidene-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidyl-n-1-ylmethyl acid methyl ester; -8a-aza-biciclor3.2.noctano-8-carboxylic It was dissolved 4-. { [1- (8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (54 mg, 0.10 mmol) in 1.0 mL of CH2Cl2 under a dry N2 atmosphere. To this solution NEÍ3 (21 ml, 0.15 mmol) and methyl chloroformate (9.3 ml, 0.12 mmol) were added. The mixture was stirred for 48 hours at room temperature and then partitioned between CH 2 Cl 2 and saturated NaHCO 3. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (in vacuo) to give a brown residue. The residue was triturated with CH? C / hexanes to give 51 mg of the title compound as a white solid. C.l. m / z 591 [M + 1]; 1 H NMR (CDCb) d 10.38 (br s, 1 H), 8.46 (m, 4 H), 7.88 (d, J = 8.4 Hz, 2 H), 7.71 (d, J = 8.4 Hz, 2 H), 7.13 (m, 4 H), 5.11 (s, 1 H), 3.62 (s, 3 H), 3.05-3.30 (m, 6 H), 0.70-2.00 (m, 9 H).

EXAMPLE 68 44f148-Benzenesulfonyl-8-aza-biciclof3.2.1loct-3-methylmethyl) -5-oxo-4,4-bis-pyridn-4-methyl-imidazolidin-2-ylidene acetyl) -benzonitrile It was dissolved 4-. { [1- (8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (54 mg, 0.10 mmol) in 1.0 mL of CH2Cl2 under a dry N2 atmosphere. To this solution was added NEt3 (21 ml, 0.15 mmol) and benzenesulfonyl chloride (15 ml, 0.12 mmol). The mixture was stirred overnight at room temperature and then partitioned between CH 2 Cl 2 and saturated NaHC 3. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (in vacuo) to give a brown residue. The residue was triturated with CH2C / hexanes to give 67 mg of the title compound as a white solid. C.l. m / z 673 [M + 1]; 1 H NMR (CDCb) d 10.45 (br s, 1 H), 8.44 (m, 4 H), 7.40-7.90 (m, 9 H), 7.10 (m, 4 H) , 5.09 (s, 1 H), 4.05 (m, 2 H), 3.05-3.30 (m, 6 H), 0.70-2.00 (m, 9 H).

EXAMPLE 69 Dimethylamide of 3424244-cyano-phenyl-2-oxo-ethylidene-1-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-ylmethyl) -8g-aza-biciclof3.2.noctane-8 acid - sulphonic It was dissolved 4-. { [1 - (8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (54 mg, 0.10 mmol) in 1.0 mL of CH2Cl2 under a dry N2 atmosphere. Nei3 (42 ml, 0.30 mmol) and dimethylsulphamoyl chloride (26 ml, 0.24 mmol) were added to this solution. The mixture was stirred overnight at room temperature and then partitioned between CH 2 Cl 2 and saturated NaHC 3. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (in vacuo) to give a brown residue. The residue was triturated with C ^ C / hexanes to give 72 mg of the title compound as a tan powder. C.l. m / z 640 [M + 1]; 1 H NMR (CDCb) d 10.40 (br s, 1 H), 8.47 (m, 4 H), 7.86 (d, J = 8.3 Hz, 2 H), 7.71 (d, J = 8.3 Hz, 2 H), 7.13 (m, 4 H), 5.11 (s, 1 H), 3.90 (m, 2 H), 3.05-3.30 (m, 6 H), 2.71 (s, 6 H), 0.70-2.00 (m , 9 H).

EXAMPLE 70 44ri48-Ethanesulfonyl-8a-aza-bicyclo3.2.11oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-lidenol acetyl } -benzonitrile It was dissolved 4-. { [1- (8-Aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (54 mg, 0.10 mmol) in 1.0 mL of CH2Cl2 under a dry N2 atmosphere. To this solution was added NEt3 (42 ml, 0.30 mmol) and ethylsulfonyl chloride (22 ml, 0.24 mmol). The mixture was stirred overnight at room temperature and then partitioned between CH 2 Cl 2 and saturated NaHC 3. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (vacuum) to give a brown residue. The residue was triturated with CH2Cb / hexanes to give 64 mg of the title compound as a tan powder. C.l. m / z 625 [M + 1]; 1 H NMR (CDCb) d 10.38 (br s, 1 H), 8.43 (m, 4 H), 7.88 (d, J = 8.4 Hz, 2 H), 7.71 (d, J = 8.4 Hz, 2 H), 7.12 (m, 4 H), 5.11 (s, 1 H), 3.98 (m, 2 H), 3.05-3.30 (m , 6 H), 2.90 (m, 2 H), 0.70-2.05 (m, 12 H).

EXAMPLE 71 44 (5-0x0-1484propane-1-sulfonyl) -8a-aza-bicyclo3.2.noct-3-ylmethin-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene > -acetyl) -benzonitrile It was dissolved 4-. { [1- (8-Aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolin-2-ylidene] -acetyl} -benzonitrile (54 mg, 0.10 mmol) in 1.0 mL of CH2Cl2 under a dry N2 atmosphere. To this solution was added NEt3 (42 ml, 0.30 mmol) and propylsulfonyl chloride (28 ml, 0.24 mmol). The mixture was stirred overnight at room temperature and then partitioned between CH 2 Cl 2 and saturated NaHC 3. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (vacuum) to give a brown residue. The residue was triturated with CH2Cb / hexanes to give 47 mg of the title compound as a tan powder. C.l. m / z 639 [M + 1]; 1 H NMR (CDCb) d 10.40 (br s, 1 H), 8.45 (m, 4 H), 7.88 (d, J = 8.4 Hz, 2 H), 7.71 (d, J = 8.4 Hz, 2 H), 7.11 (m, 4 H), 5.11 (s, 1 H), 4.00 (m, 2 H), 3.05-3.30 (m , 6 H), 2.89 (m, 2 H), 0.70-2.05 (m, 14 H).

EXAMPLE 72 Tert-butyl ester of 3424244-cyano-phenyl) -2-oxo-ethylidene-1-oxo-4,4-bis-pyridin-4-ylmethyl-1-ylazolidin-1-ylmethyl acid > -8β-aza-bicyclo3.2.noctane-8-carboxylic A. 3-Oxo-8-aza-bicyclo- [3.2.1] octane-8-carboxylic acid tert-butyl ester 8-aza-bicyclo [3.2.1] octan-3-one (9.64 g) , 77.1 mmol) in CH2CI2 (100 ml) under dry N2 atmosphere at room temperature. To this solution was added di-tert-butyl dicarbonate (20.2 g, 92.7 mmol). The reaction mixture was stirred at room temperature for 48 hours and then partitioned between NaH 4 4% and CH 2 Cl 2. The CH 2 Cl 2 layer was washed with saturated NaHC 3 3 followed by brine. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (vacuum) to give 23.1 g of the title compound as an oil. C.l. m / z 126 [M + 1 - Boc]; 1 H NMR (CDCb) d 4.41 (m, 2 H), 2.62 (m, 2 H), 2.32 (m, 2 H), 2.06 (m, 2 H), 1, 40- 1.50 (m, 11 H). B. 3-Methylene-8-aza-bicyclo-clo [3.2.1] octane-8-carboxylic acid tert-butyl ester. Methyltriphenylphosphonium iodide (40.0 g, 99.1 mmol) was suspended in anhydrous THF (200 ml) in dry N2 atmosphere. To this solution was added 1.0 M potassium tert-butoxide in THF (100 ml). The mixture was stirred for 30 minutes. A solution of 3-oxo-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (14.9 g, 66.0 mmol) in anhydrous THF (100 ml) was added to the mixture, which was then stirred overnight. The mixture was concentrated (vacuum) and the resulting residue was taken up in ethyl acetate / hexanes (10/90). The solution was filtered and the filtrate was concentrated (vacuum) to give 27.1 g of a brown oil which was subsequently purified using flash column chromatography on silica gel (eluent: gradient of ethyl acetate / hexanes 1/99 to 20/80 ethyl acetate / hexanes) to give 9.50 g of the title compound as an oil. C.l. m / z 124 [M + 1 - Boc]; 1 H NMR (CDCb) d 4.26 (m, 2 H), 2.50 (m, 2 H), 2.04 (m, 2 H), 1.85 (m, 2 H), 1.55 (m, 2 H), 1.46 (s, 9 H). O 3-hydroxymethyl-8a-aza-bike-clo [3.2.1] octane-8-carboxylic acid tert-butyl ester 3-methylene-8-aza-bicyclo-tert-butyl ester [3.2.1] octane-8-carboxylic acid (8.52 g, 38.2 mmol) in anhydrous THF (100 ml) under dry N2 at room temperature. The solution was then cooled to 0 ° C and 1.0 M borane in THF (42 ml) was added to this solution. After 10 minutes, the mixture was warmed to room temperature and stirred overnight. The mixture was cooled to 0 ° C, and 2.0 N NaOH (45 ml) and 30% hydrogen peroxide (15 ml) were added thereto. After 10 minutes, the reaction mixture was warmed to room temperature and stirred for 3.5 hours. The THF was then removed in vacuo and the mixture was partitioned between CH2Cl2 and water. The CH2Cl2 layer was then washed successively with 10% NaHS? 3 and brine. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (vacuum) to give 10.3 g of an oil. The oil was purified by flash column chromatography on silica gel (eluent: a gradient 10/90 ethyl acetate / hexanes to 50/50 ethyl acetate / hexanes) to give 8.26 g of the title compound as a colorless oil. . C.l. m / z 142 [M + 1 - Boc]; 1 H NMR (CD 3 OD) d 4.10 (m, 2 H), 3.54 (m, 2 H), 2.06 (m, 2 H), 1.95 (m, 2 H), 1.80 ( m, 1 H), 1.64 (m, 2 H), 1.45 (m, 2 H), 1.44 (s, 9 H). D. 3-Hydroxymethyl-8β-aza-bicyclo-clo [3.2.1] octane-8-carboxylic acid tert-butyl ester PCC (4.40 g, 20.4 mmol) in CH2Cl2 (30 mL) was dissolved in N2 atmosphere dry at room temperature. 10 g of 4A molecular sieves were added to this solution, followed by a solution of 3-hydroxymethyl-8a-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (3.28 g, 13%). 6 mmol) in CH2CI2 (30 ml). The reaction mixture was stirred for 4 hours and then diluted with Et2? (200 ml). The resulting solution was decanted and passed through a plug of silica gel eluting with CH2Cl2. The combined extracts were concentrated (vacuum) to give 3-formyl-8a-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester (2.70 g, 11.3 millimoles) as an oil. The aldehyde was epimerized by dissolving in anhydrous CH 2 Cl 2 oil (45 ml) and treating the resulting solution with 1,8-diazabicyclo [5.4.0] undec-7-ene (350 ml, 2.33 mmol). The mixture was stirred overnight at room temperature and then concentrated (vacuum) to give an oil. The oil was dissolved in MeOH (50 ml) and then treated with NaBH 4 (515 mg, 13.6 mmol). The mixture was stirred for 5 hours and then concentrated (vacuum) to give an oil. The oil was partitioned between CH2Cl2 and water. The CH2Cl2 layer was washed with brine, dried over MgSO4, filtered and concentrated (vacuum) to give 2.58 g of an oil. The oil was purified by flash column chromatography on silica gel (eluent: a gradient of ethyl acetate / hexanes 25/75 to ethyl acetate / hexanes 50/50) to give 1.88 g of the title compound. C.l. m / z 186 [M + 1 - isobutylene]; 1 H NMR (CD 3 OD) d 4.16 (m, 2 H), 3.31 (m, 2 H), 2.03 (m, 1 H), 1.99 (m, 2 H), 1.70 ( m, 2 H), 1.60 (m, 2 H), 1.44 (s, 9 H), 1.38 (m, 2 H). E. 3-Methanesulfonyl-oxymethyl-8β-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 3-hydroxymethyl-8β-aza-bici-clo-tert -butyl ester [3.2 .1] octane-8-carboxylic acid (1.35 g, 5.60 mmol) in CH2Cl2 (25 mL) under dry N2. The solution was cooled to 0 ° C, and NEt3 (910 ml, 6.50 mmol) and methanesulfonyl chloride (500 ml, 6.46 millimoles) were added thereto. After 10 minutes, the mixture was warmed to room temperature and stirred at this temperature for 45 minutes. The mixture was concentrated (vacuum) and then partitioned between Et2? and 0.01 N HCl. The Et2? layer it was washed successively with 0.01 N HCl, saturated NaHCO3 and brine. The layer of Et2? dried over MgSO4, filtered and concentrated (vacuum) to give 1.77g of the title compound as a colorless oil. C.l. m / z 264 [M + 1 - sobutylene]; 1 H NMR (CD3CI) d 4.11 (m, 2 H), 3.98 (m, 2 H), 2.97 (s, 3 H), 2.28 (m, 1 H), 1.95 ( m, 2 H), 1, 70 (m, 2 H), 1, 60 (m, 4 H), 1.44 (s, 9 H). F. 3- (1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -8β-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester Tertiary ester was dissolved. 3-methanesulfonyloxymethyl-8β-aza-bicyclo [3.2.1] octane-8-carboxylic acid butyl ester (1.70 g, 5.33 mmol) in anhydrous DMF (25 ml) under dry N2. Phthalimide of potassium (1.35 g, 7.30 mmol) was added to this solution. The mixture was heated to 80 ° C and stirred for 48 hours. The mixture was concentrated (vacuum) and then partitioned between Et2? and water. The layer of Et2? it was washed twice with water and then with brine. The layer of Et2? dried over MgSO4, filtered and concentrated (vacuum) to give 1.90 g of a white foam.

C.l. m / z 315 [M + 1 - isobutylene]; 1 H NMR (CDCI) d 7.69-87 (m, 5 H), 4.09 (m, 2 H), 3.51 (m, 2 H), 2.32 (m, 1 H), 1, 88 (m, 2 H), 1, 46-1, 60 (m, 6 H), 1.44 (s, 9 H). G. 3-Aminomethyl-8β-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester 3- (1,3-dioxo-1,3-dihydroxy) tert-butyl ester was dissolved. isoindol-2-ylmethyl) -8β-aza-bicyclo [3.2.1] octane-8-carboxylic acid (1.88 g, 5.08 mmol) in EtOH (45 mL) under dry N2. Hydrazine hydrate (500 ml) was added to this solution. The mixture was heated to 80 ° C and stirred for 1 hour. The mixture was filtered and the resulting filtrate was concentrated (vacuum) to give 1.47 g of a white semi-solid. The semi-solid was triturated with CH2Cl2. The washings with CH2Cl2 were combined and concentrated (vacuum) to give 970 mg of the title compound as a colorless oil. C.l. m / z 185 [M + 1 - isobutylene]; 1 H NMR (CD 3 OD) d 4.16 (m, 2 H), 2.44 (m, 2 H), 1.93 (m, 3 H), 1, 60-1, 80 (m, 4 H), 1, 44 (s, 9 H), 1, 25 (m, 2 H). H. 3-isothiocyanatomethyl-8β-aza-bicyclo [3.2.1] octane-8-caboxylic acid tert-butyl ester 3-aminomethyl-8β-aza-bicyclo-tert-butyl ester [3.2.1] ] octane-8-carboxylic acid (940 mg, 3.92 mmol) and 1,1'-thiocarbonyldiimidazole (800 mg, 4.04 mmol) in CH2Cl2 (20 ml) under dry N2 at room temperature. The reaction mixture was stirred overnight and then partitioned between 10% NaHS04 and CH2Cl2. The CH2Cl2 layer was washed successively with 10% NaHS04, water and saturated NaHCC.

The organic layer was dried over MgSO 4, filtered and concentrated (vacuum) to give 1.18 g of the title compound. C.l. m / z (227 [M + 1 -isobutylene]; 1 H NMR (CDCb) d = 4.22 (m, 2 H), 3.55 (m, 2 H), 2.19 (m, 1 H), 1, 96 (m, 2 H), 1, 48-1, 78 (m, 6 H), 1.45 (s, 9 H) I. 3- (5-Oxo-4) tert-butyl ester , 4-bis-pyridin-4-ylmethyl-2-thioxo-imidazolidin-1-ylmethyl) -8β-aza-bicyclo [3.2.1] octane-8-carboxylic acid 3-isothiodanatomethyl-8β tert-butyl ester was dissolved -aza-bicyclo [3.2.1] octane-8-carboxylic acid (1.15 g, 4.08 mmol) and 2-amino-3-pyridin-4-yl-2-pyridin-4-ylmethyl methyl ester Propionic acid (1.66 g, 6.13 mmol) in EtOH (10 ml) under dry N2 atmosphere The mixture was heated to 80 ° C and the reaction was continued at this temperature overnight. (vacuum) and the resulting residue was purified by flash column chromatography on silica gel (eluent: a gradient from ethyl acetate to MeOH / ethyl acetate 6/94) to give 1.20 g of the title compound as a foam yellow Cl m / z 522 [M + 1]; 1 H NMR (CDCb) d = 8.50 (m, 4 H), 7.98 (br s, 1 H), 7.11 (m, 4 H), 4.00 (m, 2 H), 3.16 ( m, 4 H), 3.04 (d, J = 13.2 Hz, 2 H), 1, 60-2.00 (m, 5 H), 1.44 (s, 9 H), 1.33 (m, 2 H), 0.75 (m, 2 H). J. 3- tertiary butyl ester. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylsulfanyl] -5-oxo-4,4-bis-pyridin-4-ylmethyl-4,5-dihydro-imidazol-1-ylmethyl} -8β-aza-bicyclo [3.2.1] octane-8-carboxylic acid To a solution maintained at -78 ° C of potassium bis (trimethylsilyl) -amide (500 mg, 2.39 mmol) in anhydrous THF (5 ml) under a dry N2 atmosphere, 3- (5-oxo-4,4-bis-pyridin-4-ylmethyl-2-thioxo-imidazolidin-1-ylmethyl) -8β-aza-bicyclo-tert-butyl ester was added. [3.2.1] octane-8-carboxylic acid (1.13 mg, 2.17 mmol). The solution was warmed to room temperature and 15 minutes later it was cooled to -78 ° C. To this solution was added 4-cyanophenacyl bromide (486 mg, 2.17 mmol) and the mixture was warmed to room temperature and stirred for 1 hour. The mixture was then partitioned between CH2Cl2 and saturated NaHCO3. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (vacuum) to give 1.52 g of an orange colored residue. The residue was purified by flash column chromatography on silica gel (eluent: a gradient from ethyl acetate to MeOH / ethyl acetate 5/95) to give 980 mg of the title compound as a yellow oil. C.l. m / z 665 [M + 1]; 1 H NMR (CDCb) d = 8.42 (m, 4 H), 8.19 (d, J = 8. 4 Hz, 2 H), 7.90 (d, J = 8.4 Hz, 2 H), 6.96 (m, 4 H), 4.59 (s, 2 H), 4.01 (m, 2 H), 3. 05 (m, 4 H), 2.80 (m, 2 H), 1, 82 (m, 2 H), 1, 75 (m, 1 H), 1, 43 (s, 9 H), 1, 33 (m, 2 H), 0.62 (m, 2 H). K. 3- tertiary butyl ester. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-ylmethyl} -8β-aza-bicyclo [3.2.1] octane-8-carboxylic acid 3-tert-butyl ester was dissolved. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylsulfanyl] -5-oxo-4,4-bis-pyridin-4-ylmethyl-4,5-dihydro-imidazol-1-ylmethyl} -8β-aza-bicyclo [3.2.1] -octane-8-carboxylic acid (950 mg, 1.43 mmol) and triphenylphosphine (1.50 g, 5.73 mmol) in anhydrous toluene (15.0 ml) under dry N2.

The mixture was heated to 100 ° C and stirred for 13 hours. The mixture was concentrated (vacuum) and then partitioned between 0.01 N HCl and Et2 ?. The aqueous layer was washed twice with Et2? and then alkalized to pH = 8 with NaHC 3. The product was extracted into CH2Cl2, dried over MgSO4, filtered and concentrated (vacuum) to give a tan solid. The solid was triturated with CH2Cb / hexa-nos to give 810 mg of the title compound as a white solid. C.l. m / z 633 [M + 1]; 1 H NMR (CDCb) d 10.40 (br s, 1 H), 8.46 (m, 4 H), 7.83 (d, J = 8.4 Hz, 2 H), 7.71 (d, J = 8.4 Hz, 2 H), 7.11 (m, 4 H), 5.10 (s, 1 H), 4.00 (m, 2 H), 3.26 (d, J = 13 , 2 Hz, 2 H), 3.07 (d, J = 13.2 Hz, 2 H), 2.86 (m, 2 H), 1.85 (m, 2 H), 1.70 (m , 1 H), 1, 43 (s, 9 H), 1, 30 (m, 2 H), 0.65 (m, 2 H).

EXAMPLE 73 44ri.sup.44-Aza-b.cycloi3.2.1loct-3-ylmethyl) -5-oxo-4,4-bis-pi-ridin-4-ylmethyl-imidazolidin-2-ylidene-1-acetyl) -benzonitrile 3-tert-butyl ester was dissolved. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-ylmethyl} -8β-aza-bicyclo [3.2.1] octane-8-carboxylic acid (780 mg, 1.23 mmole) in 5 ml of TFA under dry N2. The mixture was stirred at room temperature for 1 hour and then concentrated (vacuum). The resulting residue was partitioned between CH 2 Cl 2 and 0.01 N NaOH. The CH 2 Cl 2 layer was dried over MgSO 4, filtered and concentrated (vacuum) to give 550 mg of the title compound as a tan foam. C.l. m / z [M + 1]; 1 H NMR (CDCb) d 10.40 (br s, 1 H), 8.46 (m, 4 H), 7.86 (m, 2 H), 7.71 (m, 2 H), 7.10 (m, 4 H), 5.20 (s, 1 H), 3.38 (m, 2 H), 3.25 (d, J = 13.5 Hz, 2 H), 3.06 (d, J = 13.5 Hz, 2 H), 2.88 (d, J = 8.5 Hz, 2 H), 1, 5-1, 8 (m, 3 H), 1, 39 (m, 2 H) ), 1, 07 (m, 2 H), 0.73 (m, 2 H).

EXAMPLE 74 44f148-Acetyl-8β-aza-bicyclo3.2.noct-3-ylmethyl-5-oxo-4,4-bis-pyridine "4-ylmethyl-imidazolidin-2-ylidene-acetyl) -benzonitrile It was dissolved 4-. { [1 - (8β-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (51 mg, 0.096 mmol) in 1.0 ml of CH2Cl2 under a dry N2 atmosphere. To this solution was added NEt3 (20 ml, 0.14 mmol) and acetic anhydride (11 ml, 0.12 mmol) and the mixture was stirred overnight at room temperature. The mixture was then partitioned between CH2Cl2 and saturated NaHCO3. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (vacuum) to give a brown residue. The residue was triturated with CH2Cb / hexanes to give 46 mg of the title compound as a tan powder. C.l. m / z 575 [M + 1]; 1 H NMR (CDCb) d 10.55 (br s, 1 H), 8.46 (m, 4 H), 7.83 (m, 2 H), 7.72 (m, 2 H), 7.12 (m, 4 H), 5.08 (s, 1 H), 4.51 (m, 1 H), 3.89 (m, 1 H), 3.25 (m, 2 H), 3.08 (m, 2 H), 2.84 (m, 2 H), 1, 98 (s, 3 H), 1, 70-1, 97 (m, 3 H), 1.38 (m, 2 H) , 1, 22 (m, 2 H), 0.60 (m, 2 H).

EXAMPLE 75 44ri48-Methanesulfonyl-8β-aza-biciclof3.2.noct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene-acetyl) -benzonitrile It was dissolved 4-. { [1- (8β-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (50 mg, 0.094 mmol) in 1.0 mL of CH2Cl2 under a dry N2 atmosphere. To this solution was added NEt.3 (20 ml, 0.14 mmol) and methanesulfonyl chloride (9.0 ml, 0.12 mmol). The mixture was stirred overnight at room temperature and then partitioned between CH2Cl2 and saturated NaHCO3. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (vacuum) to give a brown residue. The residue was triturated with CH2Cl2 / hexanes to give 52 mg of the title compound as a tan powder. C.l. m / z 611 [M + 1]; 1 H NMR (CDCb) d 10.43 (br s, 1 H), 8.47 (m, 4 H), 7.84 (m, 2 H), 7.72 (m, 2 H), 7.11 (m, 4 H), 5.10 (s, 1 H), 4.04 (m, 2 H), 3.25 (d, J = 13.5 Hz, 2 H), 3.08 (d, J = 13.5 Hz, 2 H), 2.90 (d, J = 7.5 Hz, 2 H), 2.81 (s, 3 H), 1.93 (m, 2 H), 1, 45 (m, 2 H), 1, 22 (m, 2 H), 0.77 (m, 2 H).

EXAMPLE 76 44ri48-Benzenesulfonyl-8β-aza-bichloro3.2.11oct-3-ylmethyl-5-oxo-4,4-bis-pyridin-4-ylmethyl-2-yldazolidin-2-ylidene-acetyl) -benzontril It was dissolved 4-. { [1- (8β-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (50 mg, 0.094 mmol) in 1.0 mL of CH2Cl2 under a dry N2 atmosphere. Nei3 (20 ml, 0.14 mmol) and benzenesulfonyl chloride (14 ml, 0.11 mmol) were added to this solution. The mixture was stirred overnight at room temperature and then partitioned between CH 2 Cl 2 and saturated NaHC 3. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (vacuum) to give a brown residue. The residue was triturated with CH2C / hexanes to give 63 mg of the title compound as a tan powder. C.l. m / z 673 [M + 1]; 1 H NMR (CDCb) d 10.40 (br s, 1 H), 8.44 (m, 4 H), 7.84 (m, 2 H), 7.78 (m, 2 H), 7.72 (m, 2 H), 7.55 (m, 1 H), 7.46 (m, 2 H), 7.09 (m, 4 H), 5.10 (s, 1 H), 4.05 (m, 2 H), 3.24 (d, J = 13.4 Hz, 2 H), 3.07 (d, J = 13.4 Hz, 2 H), 2.87 (d, J = 7) , 5 Hz, 2 H), 0.70-1, 80 (m, 9 H).

EXAMPLE 77 Dimethylamide of 3424244-cyano-phenyl) -2-oxo-ethylidene-1-oxo-414-bis-pyridin-4-ylmethyl-amidazolidin-1-ylmethyl acid > -8g-aza-biciclof3.2.noctano-8- sulphonic It was dissolved 4-. { [1- (8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (50 mg, 0.094 mmol) in 1.0 mL of CH2Cl2 under a dry N2 atmosphere. Nei3 (20 ml, 0.14 mmol) and dimethylsulphamoyl chloride (12 ml, 0.11 mmol) were added to this solution. The mixture was stirred overnight at room temperature and then partitioned between CH2Cl2 and saturated NaHCO3. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (vacuum) to give a brown residue. The residue was triturated with CH2Cb / hexanes to give 67 mg of the title compound as a yellow powder. C.l. m / z 640 [M + 1]; 1 H NMR (CDCb) d 10.38 (br s, 1 H), 8.46 (m, 4 H), 7.84 (d, J = 8.1 Hz, 2 H), 7.72 (d, J = 8.1 Hz, 2 H), 7.11 (m, 4 H), 5.13 (s, 1 H), 3.89 (m, 2 H), 3.26 (d, J = 13.3 Hz, 2 H), 3.09 (d, J = 13.3 Hz, 2 H) , 2.91 (d, J = 7.2 Hz, 2 H), 2.74 (s, 6 H), 1.98 (m, 2 H), 0.70-1, 80 (m, 7 H) ).

EXAMPLE 78 44 (14841 -Methyl-1 H-imidazole-4-sulfonyl) -8β-biciclof3.2.n-oct-3-ylmetin-5-oxo-4,4-bis-pyridin-4-ylmethyl- imidazolidin-2-ylidene-acetyl-benzonitrile It was dissolved 4-. { [1 - (8β-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile (50 mg, 0.094 mmol) in 1.0 mL of CH2Cl2 under a dry N2 atmosphere. Nei3 (20 ml, 0.14 mmol) and 1-methylimidazole-4-sulfonyl chloride (21 mg, 0.11 mmol) were added to this solution. The mixture was stirred overnight at room temperature and then partitioned between CH2 and saturated NaHCO3. The CH2Cl2 layer was dried over MgSO4, filtered and concentrated (vacuum) to give a brown residue. The residue was triturated with CH2Cb / hexanes to give 55 mg of the title compound as a yellow powder. C.l. m / z 677 [M + 1]; 1 H NMR (CDCb) d 10.43 (br s, 1 H), 8.43 (m, 4 H), 7.84 (m, 2 H), 7.71 (m, 2 H), 7.39 (d, J = 1, 3 Hz, 1 H), 7.35 (d, J = 1, 3 Hz, 1 H), 7.09 (m, 4 H), 5.12 (s, 1 H), 4.09 (m, 2 H), 3.71 (s, 3 H), 3.23 (d, J = 13.3 Hz, 2 H), 3.06 (d, J = 13.3 Hz, 2 H), 2.87 (d, J = 7.3 Hz, 2 H), 0, 70-2.00 (m, 9 H).

EXAMPLE 79 4424244-Cyano-4-ol) -2-oxo-ethylidene-1-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-ylmethyl-N, N-dimethyl-benzenesulfonamide The same procedure used in Example 61 was followed, except that 4-aminomethyl-N, N-dimethyl-benzenesulfonamide was used in place of the 3-aminomethyl-8a-aza-bicyclo [3.2.1] octane tert-butyl ester -8-carboxylic acid in Step E of Example 61 to give the title compound as a white solid. 1 H NMR (CDCb) d 10.42 (br s, 1 H), 8.48 (m, 4 H), 7.84 (m, 2 H), 7.69 (m, 2 H), 7.66 (m, 2 H), 7.55 (d, J = 8.2 Hz, 1 H), 7.14 (m, 4 H), 6.48 (d, J = 8.2 Hz, 1 H), 4.96 (s, 1 H), 4.39 (s, 2 H), 3.33 (d, J = 13.1 Hz, 2 H) , 3.15 (d, J = 13.1 Hz, 2 H), 2.69 (s, 6 H).

EXAMPLE 80 44f143-Chloro-benzyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene-1-acetyl-benzonitrile The same procedure used in Example 61 was followed, except that 1-chloro-3-isothiocyanatomethyl-benzene was used in place of the 3-isothiocyanatomethyl-8-aza-bicyclo [3.2.1] -octane tert-butyl ester -8-carboxylic acid in Step F of Example 61 to give the title compound as a white solid.

C.l. m / z 534 [M + 1]; 1 H NMR (CDCb) d 10.44 (br s, 1 H), 8.40 (m, 4 H), 7.68 (d, J = 8.2 Hz, 2 H), 7.64 (d, J = 8.2 Hz, 2 H), 7.15 (m, 5 H), 7.02 (t, J = 7.8 Hz, 1 H), 6.82 (s, 1 H), 6, 01 (d, J = 7.8 Hz, 1 H), 5.03 (s, 1 H), 4.20 (s, 2 H), 3.31 (d, J = 13.3 Hz, 2 H ), 3.16 (d, J = 13.3 Hz, 2 H).

EXAMPLE 81 44ri43-Methoxy-benzyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene-1-acetyl) -benzon itri The same procedure used in Example 61 was followed, except that 1-isothiocyanatomethyl-3-methoxy-benzene was used in place of the 3-isothiocyanatomethyl-8a-aza-bicyclo [3.2.1] -octane tert-butyl ester -8-carboxylic acid in Step F of Example 61 to give the title compound as a white solid. C.l. m / z 530 [M + 1]; 1 H NMR (CDCb) d 10.44 (br s, 1 H), 8.44 m, 4 H), 7.72 (m, 2 H), 7.64 (m, 2 H), 7.11 (m, 4 H), 7.04 (t, J = 8.1 Hz, 1 H), 6.74 (m, 1 H), 6.44 (s, 1 H), 5.72 (m, 1 H), 5.10 (s, 1 H), 4.24 (s, 2 H), 3.74 (s, 3 H), 3.32 (d, J = 13.3 Hz, 2 H), 3.09 (d, J = 13.3 Hz, 2 H).

EXAMPLE 82 44ri43-Fluoro-benzip-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene-1-acetyl-benzonitrile The same procedure used in Example 61 was followed, except that 1-fluoro-3-isothiocyanatomethyl-benzene was used in place of the 3-isothiocyanatomethyl-8a-aza-bicyclo [3.2.1] -octane tert-butyl ester -8-carboxylic acid in Step F of Example 61 to give the title compound as a white solid. C.l. m / z 518 [M + 1]; 1 H NMR (CDCb) d 10.40 (br s, 1 H), 8.45 (m, 4 H), 7.71 (d, J = 8.4 Hz, 2 H), 7.65 (d, J = 8.4 Hz, 2 H), 7.12 (m, 5 H), 6.91 (m, 1 H), 6.44 (m, 1 H), 5.99 (m, 1 H), 5.05 (s, 1 H), 4.26 (s, 2 H), 3.33 (d, J = 13.3 Hz, 2 H), 3.12 (d, J = 13.3 Hz, 2 H).

EXAMPLE 83 44142-Chloro-benzyl) -5-ox? "4,4-bis-pyridin-4-methylmethyl-imidazolidin-2-ylidene-1-acetyl-benzonitrile The same procedure used in Example 61 was followed, except that 1-chloro-2-isothiocyanatomethyl-benzene was used in place of the 3-isothiocyanatomethyl-8-aza-bicyclo [3.2.1] -octane tert-butyl ester -8-carboxylic acid in Step F of Example 61 to give the title compound as a white solid.

C.l. m / z 534 [M + 1]; 1 H NMR (CDCb) d 10.42 (br s, 1 H), 8.41 (m, 4 H), 7.69 (m, 2 H), 7.62 (m, 2 H), 7.24 (m, 1 H), 7.17 (m, 4 H), 7.09 (m, 1 H), 6.86 (m, 1 H), 5.38 (d, J = 7.7 Hz, 1 H), 4.99 (s, 1 H), 4.35 (s, 2 H), 3.32 (d, J = 13.3 Hz, 2 H), 3.18 (d, J = 13 , 3 Hz, 2 H).

EXAMPLE 84 44ri44-Methanesulfonyl-benzyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene-acetyl-benzonitrile The same procedure used in Example 61 was followed, except that 4-methanesulfonyl-benzylamine was used in place of the 3-aminomethyl-8a-aza-bicyclo [3.2.1] -octane tert-butyl ester -8-carboxylic acid in the Step E of Example 61 to give the title compound as a white solid. C.l. m / z 578 [M + 1]; 1 H NMR (CDCb) d 10.43 (br s, 1 H), 8.46 (d, J = 5.9 Hz, 4 H), 7.65-7.72 (m, 6 H), 7, 11 (d, J = 5.9 Hz, 4 H), 6.50 (d, J = 8.0 Hz, 1 H), 4.97 (s, 1 H), 4.35 (s, 2 H), 3.32 (d, J = 13.1 Hz, 2 H), 3.13 (d, J = 13 , 1 Hz, 2 H), 3.05 (s, 3 H).

EXAMPLE 85 44142-Methoxy-benzyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene-1-acetyl-benzonitrile The same procedure used in Example 61 was followed, except that 1-isothiocyanatomethyl-2-methoxy-benzene was used in place of the 3-aminomethyl-8a-aza-bicyclo [3.2.1] -octane tert-butyl ester -8-carboxylic acid in Step F of Example 61 to give the title compound as a white solid. C.l. m / z 530 [M + 1]; 1 H NMR (CDCb) d 10.41 (br s, 1 H), 8.44 (d, J = 5.4 Hz, 4 H), 7.75 (d, J = 8.4 Hz, 2 H), 7.66 (d, J = 8.4 Hz, 2 H), 7.17 (m, 5H); 6.79 (d, J = 8.3 Hz, 1 H), 6.71 (t, J = 8.3 Hz, 1 H), 5.94 (d, J = 8.3 Hz, 1 H) , 5.29 (s, 1 H), 4.30 (s, 2 H), 3.74 (s, 3 H), 3.35 (d, J = 13.3 Hz, 2 H), 3, 14 (d, J = 13.3 Hz, 2 H).

EXAMPLE 86 4424244-Cyano-phenyl) -2-oxo-etlidene-4,4-bis-3-methyl-3H-imidazol-4-ylmethyl) -5-oxo-imidazolidin-1-ylmethyl, N- dimethyl-benzenesulfonamide Using the same procedure as described in Example 53, 4-isothiocyanatomethyl-N, N-dimethyl-benzenesulfonamide (0.36 mmol) was used in place of 3-benzenesulfonyl-6-isothiocyanato-3-aza-bicyclo [3.1.0] hexane. After delation with 2-amino-3- (3-methyl-3H-imidazol-4-yl) -2- (3-methyl-3H-imidazol-4-ylmethyl-propionic acid methyl ester, sulfur-alkylation of bromide) of 4-cyanophenacyl in the presence of potassium bis (trimethylsilyl) amide, and sulfur-extrusion (in the presence of triphenylphosphine, 9 mg of the title compound was obtained as a white solid CI-MS: m / z 613.2 [M +1]

Claims (6)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of the formula or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are each independently selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH) p (C6-C10 aryl) , and - (CH2) P (4-10 membered unsaturated heterocyclyl), wherein p is an integer from 0 to 3, or R1 and R2 form a C3-C6 cycloalkyl ring, and wherein any of said R >groups; 1 . Y. r R-? 2 are optionally substituted with 1 to 3 R6 groups, with the proviso that, when R1 and R2 form a C3-C6 cycloalkyl ring, said C3-C6 cycloalkyl ring is substituted with at least one R6 group selected from alkenyl C2-C10, C2-C10 alkynyl, and - (CH2) t (aryl CT-CIO) where t is an integer from 1 to 3; R3 is - (CH2) m (1- or 2-adamantyl), C1-C10 alkyl, C2-C10 alkenyl, C2-C1C alkynyl - (CH2) m (C-C-io aryl),

X1, X2, and X3 are each independently C? -C alkylene optionally containing 1 or 2 double or triple carbon-carbon bonds, X4 is a C1-C7 bond or alkylene optionally containing 1 or 2 double carbon-carbon bonds or triples, and, in formula (Ib), residue X4 is attached to residue X1 at any available carbon from residue X1, and each of the above R3 groups is substituted with a group R5 and optionally with 1 to 4 groups R6; or R3 is -S02R9, -C (0) R9, or - (CH2) m (4-10 membered heterocyclyl) optionally substituted with 1 to 5 R6 groups; m, in the R3 groups mentioned above, is independently an integer from 0 to 6; and R 4 is aryl CT-C-10, heterocyclyl of 4-10 members, or Ci-C 1 alkyl, each of said groups R 4 being optionally substituted with 1 to 3 fi c groups R; each R is independently selected from halo, d-C alquilo alkyl substituted with 1 to 3 halo groups, nitro, cyano, -OR 9, C (0) R 9, -SR 9, -SO 2 R 9, -SO 3 H, -S (0) R 9, - NR7R8, -C (0) OR9, -OC (0) R9, -S02NR9R8, -C (0) NR9R8, -NR8C (0) R9, -OC (0) NR9R8, -C (0) ONR7R9, -NR8C ( 0) NR9R8, -NR8C (0) 0 (C1-C4 alkyl), -C (NR8) NR9R8, -C (NCN) NR9R8, -C (NCN) S (C1-C4 alkyl or C1-C4 haloalkyl), - NR8C (NCN) S (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (NCN) NR7R8, - NR8S02 (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (0) C (0) R8, - NR8C (0) C (0-) NR9R8, -P (0) (OR7) 2, and - (CH2) q- (4-10 membered heterocyclyl), q is an integer from 0 to 3, and the residues alkyl and heterocyclyl of the above R5 groups are optionally substituted with 1 to 3 R10 groups; each R6 is independently selected from R5, d-Cd alkyl, C2-C10 alkenyl, C2-C10 alkynyl and - (CH2) t (aryl Ce-Cio), such as phenyl or naphthyl, optionally substituted with 10 to 3 groups R, where t is an integer from 0 to 3; each R is independently hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 halo groups; each R8 is independently R7 or -OR7; each R9 is independently selected from hydrogen, C1-C6 alkyl, - (CH2) q (C10-C10 aryl), and - (CH2) q (4-10 member heterocyclyl), said groups being R9, 10 except H, substituted optionally with 1 to 3 R groups, and each q 10 being independently an integer from 0 to 3; and, each R is independently selected from halo, nitro, cyano, Ci-Cß alkyl, d-Cß haloalkyl, Ci-Cß alkoxy, halo-C 1 -C 6 alkoxy, -C (0) 0 (Ci-Cß alkyl), and aryl Ce-Cío; with the proviso that R1 and R2 are not both simultaneously C1-C10 alkyl. 2. The compound of claim 1, wherein one or both of R1 and R2 is - (CH2) P (4-10 membered unsaturated heterocyclyl) optionally substituted with 1 to 3 R6 groups.

3. The compound of claim 1, wherein R1 and R2 are independently selected from C1-C10 alkyl, C2-C10 alkenyl, and C2-C10 alkynyl, each optionally substituted with one to three Rd groups, with the proviso that R1 and R2 are not both simultaneously C1-C10 alkyl.

4. - The compound of claim 1, wherein R3 is (CH2) m (4-10 membered heterocyclyl) optionally substituted with 1 to 5 16 groups R The compound of claim 4, wherein R3 is (CH2) m (4-10 membered azacyclyl), optionally substituted with 1 to 3 R6 groups. 6. The compound of claim 5, selected from the group consisting of: 4 { [1 - (1 a, 5a, 6a-3-tert-butoxycarbonyl-3-aza-bicyclo- [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl -imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4 { [1- (1a, 5a, 6a-aza-bicyclo- [3.1.0] hex-6-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl } -benzonitrile; 4- ( { 5-oxo-1 - [1 a, 5a, 6a-3- (1-phenyl-1 H-tetrazol-5-yl) -3-aza-bicyclo- [3.1.0] hex- 6-yl) -4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; benzyl ester of acid 1a, 5a, 6 -6-. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-b¡s-pyridin-4-ylmethyl-imidazolidin-1-yl} -3-aza-bicycles { 3.1.0} hexane-3-carboxylic acid; 4- ( { 1- [1a, 5a, 6a-3- (3,3-dimethyl-butyryl) -3-aza-bicyclo- [3.1.0] hex-6-yl] -5-oxo-4 4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 5-oxo-4,4-bis-pyridin-4-ylmethyl-1 - [1 a.5a.6a-3- (thiophen-2-yl-acetyl) -3-aza-bicyclo [ 3.1.0] hex-6-yl] -imidazolidin-2-ylidene} - acetyl) -benzonitrile; diethyl ester of 1a.5a, 6a- (6- { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4- ilmethyl-imidazolidin-1-yl.} - 3-aza-bicyclo [3.1.0] hex-3-yl) -phosphonic acid; 4-. { [1- (1a, 5a, 6a-3-benzenesulfonyl-3-aza-bicyclo [3.1.0] -hex-yl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2- ilidene] -acetyl} -benzonitrile; 4- ( { 1 - [1 a, 5a, 6a-3- (4-methoxy-benzenesulfonyl) -3-aza-bicyclo [3.1.0] hex-yl) -5-oxo-4,4-bis -pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4-. { [5-oxo-1- (1a, 5a, 6a-3-phenylmethanesulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl) -4,4-bis-pyridin-4-ylmethyl-midazole -din-2-ylidene] -acetyl} -benzonitrile; 4- ( { 5-Oxo-4,4-bis-pyridin-4-ylmethyl-1 - [1 a, 5a, 6a-3- (toluene-4-sulfonyl) -3-aza-bicyclo [3.1. 0] hex-6-yl] -imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 5-Oxo-4,4-bis-pyridin-4-ylmethyl-1 - [1 a, 5a, 6a-3- (toluene-2-sulfonyl) -3-aza-bicyclo [3.1. 0] hex-6-yl] -imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 5-oxo-1 - [1 a, 5a, 6a-3- (piperidine-1-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -4.4 bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 5-Oxo-4,4-bis-pyridin-4-ylmethyl-1 - [1 a, 5a, 6a-3- (thiophene-2-sulfonyl) -3-aza-bicyclo [3.1. 0] hex-6-yl] -imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 1- [1a, 5a, 6a-3- (5-bromo-thiophene-2-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -5-oxo- 4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 1 - [1 a, 5a, 6a-3- (4-ethyl-piperazine-1-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -5-oxo 4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 5-oxo-1 - [1 a, 5a, 6a-3- (propane-1-sulfonyl) -3-aza-bici-clo [3.1.0] hex-6-il] -4 , 4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitri-lo; ethyl ester of 1- (1a, 5a, 6a-6- { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4, 4-bis-pyridine- 4-ylmethyl-imidazolidin-1-yl.} - 3-aza-bicyclo [3.1.0] hexane-3-sulfonyl) piperidine-4-carboxylic acid; 4- ( { 5-oxo-1 - [1, 5a, 6a-3- (4-propyl-piperidine-1-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-il ] -4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4- ( { 1 - [1 a, 5a, 6a-3- (4-isopropyl-piperazine-1-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -5-oxo 4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} - acetyl) -benzonitrile; 4-. { [1a, 5a, 6β-1- (3-benzenesulfonyl-3-aza-bicyclo [3.1.0] -hex-6-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazole din-2-ylidene] -acetyl} -benzonitrile; tert-butyl ester of acid 1a.5a.6a-6-. { 4-allyl-2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4-pyridin-4-ylmethyl-imidazolidin-1-yl} -3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid; 4-. { [4-allyl-1 - (1 a5a, 6a-3-benzenesulfonyl-3-aza-bicyclo [3.1.0] hex-6-yl) -5-oxo-4-pyridin-4-ylmethyl-imidazolidin- 2-ylidene] -acetyl} -benzonitrile; 4-. { [5-oxo-4-allyl-4-pyridin-4-ylmethyl-1- [1a, 5a, 6a-3- (thiophene-2-acetyl) -3-aza-bicyclo [3.1.0] hex-6-] il) -imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4- ( { 4-allyl-5-oxo-4-pyridin-4-ylmethyl-1- [1a, 5, 6 -3- (thiophen-2-yl-sulfonyl) -3-aza-bicyclo [3.1 .0] hex-6-yl) -imidazolidin-2-ylide-no] -acetyl} -benzonitrile; tert-butyl ester of acid 1a, 5a, 6a-6- [2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -4- (3-methyl-but-2-en-1) -5-oxo-4-pyridin-4-methyl-1-imidazolidin-1-yl] -3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid; 4-. { [1 - [1 a, 5a, 6a-3- (5-bromo-thiophene-2-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -4- (3-methyl) -but-2-enyl) -5-oxo-4-pyridin-4-ylmethyl-imydazolidin-2-ylidene] -acetyl} -benzonitrile; tert-butyl ester of acid 1a, 5a, 6a-6-. { 2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4-pyridin-4-ylmethyl-4-thiophen-3-ylmethyl-imidazolidin-1-yl} -3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid; 4-. { [1 - (1, 5a, 6a-3-benzenesulfonyl-3-aza-bicyclo [3.1.0] -hex-6-yl) -5-oxo-4-pyridin-4-ylmethyl-4-thiophen-3- ilmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; tert-butyl ester of acid 1a, 5, 6a-6-. { 4- (3-chloro-but-2-enyl) -2- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4-pyridin-4-ylmethyl-imidazolidide n-1-il} -3-aza-bicyclo [3.1.0] hexane-3-carboxylic acid; 4-. { [1 - [1 a, 5a, 6 -3- (5-bromo-thiophene-2-sulfonyl) -3-aza-bicyclo [3.1.0] hex-6-yl] -4- (3-chloro-but -2-enyl) -5-oxo-4-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4-. { [1 a, 6a, 7a-1 - (3-benzenesulfonyl-3-aza-bic-clo [4.1.0] -hept-7-ylmethyl) -5-oxo-4,4-bis-pyridin-4- ilmethyl-imidazolidin-2-ylidene] -acetyl-benzonitrile; 4-. { [1 a, 6, 7a-1 - (3-benzenesulfonyl-3-aza-bicyclo [4.1.0] -hept-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis -pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 44 [1- (8-Benzenesulfonyl-8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl } -benzonitrile; 342- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-1-methylmethyl dimethylamide} -8a-aza-bicyclo [3.2.1] octane-8-sulphonic; 4-. { [1- (8-Ethanesulfonyl-8a-aza-bicyclo [3.2.1] oct-3-ylmethyl) -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene] -acetyl} -benzonitrile; 4- ( { 5-oxo-1 - [8- (propane-1-sulfonyl) -8a-aza-bicyclo- [3.2.1] oct-3-ylmethylH, 4-bis-pyridin-4-ylmethyl- imidazolidin-2-ylidene] -acetyl} -benzonitrile; 342- [2- (4-cyano-phenyl) -2-oxo-ethylidene] -5-oxo-4,4-bis-pyridin-4-dimethylamide -ylmethyl-imidazolidin-1-methylmethyl] -8a-aza-bicyclo [3.2.1] octane-8-sulphonic acid, and 4- (. {1 - [8- (1-methyl-1 H-imidazol- 4-sulfonyl) -8β-aza-bicyclo [3.2.1] oct-3-ylmethyl] -5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene} -acetyl) - benzonitrile 7. The compound of claim 1, wherein R3 is - (CH2) m (C6-C6 aryl) substituted with a group R5 and optionally with 1 to 4 R6 groups 8.- The use of a compound according to claim 1 for the manufacture of a medicament for inhibiting abnormal cell growth in a mammal, wherein the amount of said compound is effective to inhibit farnesyl protein transferase. inhibit the abnormal growth of cells in a mammal or, comprising an amount of a compound according to claim 1 which is effective to inhibit farnesyl protein transferase and a pharmaceutically acceptable carrier. 10. The use of a compound according to claim 1 for the manufacture of a medicament for inhibiting the abnormal growth of cells in a mammal, wherein the amount of said compound is effective to inhibit the abnormal growth of cells. 11. A pharmaceutical composition for inhibiting abnormal cell growth in a mammal, comprising an amount of a compound according to claim 1 which is effective to inhibit normal cell growth and a pharmaceutically acceptable carrier. 12. The use of a compound according to claim 1, in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalation antibiotics, inhibitors of growth factors, inhibitors of the cell cycle, enzymes, inhibitors of topoisomerases, biological response modifiers, and anti-hormones, for the manufacture of a medicament for inhibiting the abnormal growth of cells in a mammal. 13. A pharmaceutical composition for inhibiting the abnormal growth of cells in a mammal, comprising an amount of a compound according to claim 1; an amount of an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalation antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, response modifiers biological, and anti-hormones; and a pharmaceutically acceptable vehicle; wherein the amount of said anti-tumor agent, in combination with the amount of the compound of claim 1, is effective to inhibit the abnormal growth of cells in a mammal. 14.- A compound of the formula VIII wherein: R1 and R2 are each independently selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) P (aryl Ce-C10), and - (CH2) P ( 4-10 membered unsaturated heterocyclyl), wherein p is an integer from 0 to 3, or R1 and R2 form a C3-C6 cycloalkyl ring, and wherein any of said groups R1 and R2 are optionally substituted with 1 to 3 R6 groups; R3 is - (CH2) m (1- or 2-adamantyl), C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, - (CH2) m (Ce-Cio aryl), X1, X2, and X3 are each independently C? -C alkylene optionally containing 1 or 2 double or triple carbon-carbon bonds, X4 is a bond 0 C1-C7 alkylene optionally containing 1 or 2 double or triple carbon-carbon bonds, and, in the formula (Ib), the X4 moiety is attached to the X1 moiety at any available carbon of the X1 moiety, and each of the groups R3 above is substituted with a group R5 and optionally with 1 to 4 groups R6; or R3 is SO2R9, -C (0) R9, or - (CH2) m (4-10 membered heterocyclyl) optionally substituted with 1 to 5 R6 groups; m, in the R3 groups mentioned above, is independently an integer from 0 to 6; and R4 is aryl CT-CIO, heterocyclyl of 4-10 members, or Ci-Cs alkyl, and each of said groups R4 is optionally substituted with 1 to 3 R6 groups; each R5 is independently selected from halo, d-Cß alkyl substituted with 1 to 3 halo groups, nitro, cyano, -OR9, -C (0) R9, -SR9, -S02R9, -SO3H, -S (0) R7, -NR7R8, -C (0) OR9, -OC (0 ) R9, -S02NR9R8, -C (0) NR9R8, -NR8C (0) R9, -OC (0) NR9R8, -C (0) ONR7R9, -NR8C (0) NR9R8, -NR8C (0) 0 (C1 alkyl) -C4), -C- (NR8) NR9R8, -C (NCN) NR9R8, -C (NCN) S (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (NCN) S (C1-C4 alkyl or haloalkyl) C1-C4), -NR8C (NCN) NR7R8, -NR8S02- (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (0) C (0) R8, -NR8C (0) C (0) NR9R8, - P (0) (OR7) 2, and - (CH2) q- (4-10 membered heterocyclyl), q is an integer from 0 to 3, and the alkyl and heterocyclyl moieties of the above R5 groups are optionally substituted with 1 to 3 R10 groups; each R6 is independently selected from R5, Ci-Cß alkyl, C2-C10 alkenyl, C2-C10 alkynyl and - (CH2) t (C-6-C10 aryl), optionally substituted with 1 to 3 R10 groups, where t is a number whole from 0 to 3; each R is independently hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 halo groups; each R8 is independently R7 or -OR7; each R9 is independently selected from hydrogen, alkyl CI-CT, - (CH2) (aryl Ce-Cio), and - (CH2) q (heterocyclyl of 4-10 members), said groups R9, except H, being optionally substituted with 1 to 3 groups R, and each q being independently an integer from 0 to 3; and, each R10 is independently selected from halo, nitro, cyano, Ci-Cß alkyl, Ci-Ce haloalkyl, Ci-Cß alkoxy, Ci-Cß halo-alkoxy, -C (0) 0 (Ci-Cß alkyl), and aryl Ce-Cío; with the proviso that R1 and R2 are not both simultaneously C1-C10 alkyl. 15.- A compound of the formula XIV wherein: R1 and R2 are each independently selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C2 alkynyl, or - (CH2) p (C-C10 aryl), and - (CH2) P (4-10 membered unsaturated heterocyclyl), wherein p is an integer from 0 to 3, or R1 and R2 form a C3-C6 cycloalkyl ring, and wherein any of said groups R1 and R2 are optionally substituted with 1 to 3 R6 groups; m is an integer from 0 to 6; is a 4-10 membered saturated heteroazacyclyl group, optionally substituted with 1 to 4 additional R6 groups; and R is Ce-Cι aryl, 4-10 membered heterocyclyl, or d-Cß alkyl, and each of said R 4 groups is optionally substituted with 1 to 3 R groups; each R is independently selected from R5, Ci-Cß alkyl, C2-C10 alkenyl, C2-C10 alkynyl and -10 (CH2) t (Ce-Cι aryl) optionally substituted with 1 to 3 R groups, where t is an integer 0 to 3; each R5 is independently selected from halo, CI-CT alkyl substituted with 1 to 3 halo groups, nitro, cyano, -OR9, -C (0) R9, -SR9, -SO2R9, -SO3H, -S (0) R7, -NR7R8, -C (0) OR9, -OC (0) R9, -S02NR9R8 , -C (0) NR9R8, -NR8C (0) R9, -OC (0) NR9R8, -C (0) ONR7R9, -NR8C (0) NR9R8, -NR8C (0) 0 (C1-C4 alkyl), - C (NR8) NR9R8, -C (NCN) NR9R8, -C (NCN) S (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (NCN) S (C1-C4 alkyl or C1-C4 haloalkyl), - NR8C (NCN) NR7R8, -NR8S02 (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (0) C (0) R8, -NR8C (0) C (0) NR9R8, -P (0) (OR7) 2, and - (CH2) q- (4-10 membered heterocyclyl), q is an integer from 0 to 3, and the alkyl and heterocyclyl moieties of the above R5 groups are optionally substituted with 10 to 3 groups R; each R is independently hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 halo groups; each R8 is independently R7 or -OR7; each R9 is independently selected from hydrogen, C1-C6 alkyl, - (CH2) q (aryl Ce-Cio), and - (CH2) q (heterocyclyl of 4-10 members), said R9 groups, except H, being optionally substituted with 1 to 3 groups R10, and each q being independently an integer 10 from 0 to 3; and, each R is independently selected from halo, nitro, cyano, C 1 -C 6 alkyl, C 1 β haloalkyl, Ci-Ce alkoxy, halo-C 1 -C 6 alkoxy, -C (0) 0 (d-Cß alkyl), and aryl Ce-Cío; with the proviso that R1 and R2 are not both simultaneously C1-C10 alkyl. 16.- A compound of the formula wherein: R1 and R2 are each independently selected from the group consisting of C1-C10 alkyl, C2-C10 alkenyl, C2-C2 alkynyl, - (CH2) P (aryl Cedo), and - (CH2) P ( 4-10 membered unsaturated heterocyclyl), wherein p is an integer from 0 to 3, or R1 and R2 form a C3-C6 cycloalkyl ring, and wherein any of said R1 and R2 groups are optionally substituted with 1 to 3 R6 groups; is a saturated heteroazacyclyl group of 4-10 members, optionally substituted with 1 to 5 R6 groups; m is an integer from 0 to 6; and R 4 is Ce-Cι aryl, 4-10 membered heterocyclyl, or Ci-Cß alkyl, and each of said R4 groups is optionally substituted with 1 to 3 R6 groups; each R6 is independently selected from R5, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl and - (CH2) t (Ce-Cio aryl) optionally substituted with 1 to 3 R10 groups, where t is an integer of 0 to 3; each R5 is independently selected from halo, C1-C6 alkyl substituted with 1 to 3 halo groups, nitro, cyano, -OR9, -C (0) R9, -SR9, -S02R9, -SO3H, -S (0) R7, -NR7R8, -C (0) OR9, -OC (0) R9, -S02NR9R8, -C (0) NR9R8, -NR8C (0) R9, -OC (0) NR9R8, -C (0) ONR7R9, -NR8C (0) NR 9 R 8, -NR 8 C (0) 0 (C 1 -C 4 alkyl), -C (NR 8) NR 9 R 8, -C (NCN) NR 9 R 8, -C (NCN) S (C 1 -C 4 alkyl or C 1 -C 4 haloalkyl), -NR8C (NCN) S (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (NCN) NR7R8, -NR8S02 (C1-C4 alkyl or C1-C4 haloalkyl), -NR8C (0) C (0) R8, -NR8C (0) C (0) NR9R8, -P (0) (OR7) 2, and - (CH2) q- (4-10 membered heterocyclyl), q is an integer from 0 to 3, and the alkyl and heterocyclyl radicals of the above-mentioned R5 groups are optionally substituted with 1 to 3 R10 groups; each R7 is independently hydrogen or C1-C4 alkyl optionally substituted with 1 to 3 halo groups; each R8 is independently R7 or -OR7; each R9 is independently selected from hydrogen, C1-C6 alkyl, - (CH2) q (aryl Ce-Cio), and - (CH2) q (4-10 membered heterocyclyl), said R9 groups, except H, being optionally substituted 10 with 1 to 3 groups R, and each q being independently an integer 10 from 0 to 3; and, each R is independently selected from halo, nitro, cyano, Ci-Ce alkyl, haloalkyl CI-CT, C-C alco alkoxy, Ci-Cß halo-alkoxy, -C (0) 0 (Ci-Cß alkyl), and aryl Ce-Cío; with the proviso that R1 and R2 are not both simultaneously C1-C10 alkyl.