Background to the Invention Helicobacter pylori is a gram negative bacterium which infects the human gastric mucosa. Infection with the bacterium causes inflammation of the gastric mucosa. Peptic ulceration of the duodenum or stomach can develop as well as adenocarcinomas or lymphomas of the stomach wall. Omeprazole (5-methoxy-2- [ [ (4-methoxy-3, 5-dimethyl-2- pyridinyl) methyl] sulfinyl]-lH-benzimidazole) is active against Helicobacter pylori (see Vogt, K and Hahn, H (1998),"Bactericidal Activity of Lansoprazole and Omeprazole against Helicobacter pylori in vitro", Drug Res. 48 (1), No. 6, 694-697), and is labile towards rearrangement in acidic media. Omeprazole is a sulfoxide. This sulfoxide is labile towards rearrangement in acidic media and the rearrangement gives an intermediate, which is a potent proton pump inhibitor. Thus, the parent compound does not persist in the acidic environment of the stomach. Compounds related to omeprazole, where the sulphur atom is unoxidized are also active against Helicobacter pylori. However, these related compounds can undergo metabolic oxidation in vivo to give the corresponding sulfoxide, analagous to omeprazole, and have a propensitiy towards rearrangement in acidic media in vivo [J. Med. Chem. 1988, 41, 1777-1788]. Analogues which are potent against Helicobacter pylori, but not acid labile and thus stable in acidic media are desirable. Such analogues could be administered to a mammalian patient therapeutically to treat Helicobacter pylori infection.

In addition, it would be preferable for such analogues to be selective for Helicobacter pylori, since this is desirable to avoid the disruption of the normal gastrointestinal flora, and to reduce the incidence of bacterial resistance development.

Summarv of the Invention Accordingly, the present invention provides compounds of formula I or pharmaceutically acceptable salts or solvates thereof which are active against Helicobacter pylori, but lack the pyridine nitrogen of omeprazole and its analogues which is necessary for rearrangement in acidic media. Thus, the compounds of the invention are more stable in acid media. Formula I is as follows :

wherein : X is S ; SO2 ; NH ; N (C1-6alkyl) ; 0 or CH2 ; Y is Cl. -6alkyl ; O (C3-gcycloalkyl) ; O (C1-6alkyl) ; Hal ; CHal3, CHHal2, CH2HaI, OCHal3, OCHHal2 or OCH2Hal, wherein Hal represents halogen ; NRR', wherein R and R' independently represent H or Cl 8alkyl, or NRR'represents an optionally substituted C3 8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from 0, N and S ; H ; COOR"or COR", R"representing H or Cl 6alkyl ; or CH20H ; R1-(CH2)a-R3;-((CH2)bO)c-R3;-(CH2)d-R3;-(CH2)aC(=O)R3;-(CH2) dC (=O) R3; - ( (CH2) e-0) c'- (CH2) f-R"; R3 orR3'.

R2 is an optionally substituted mono-or bi-cyclic 5-, 6-, 7-, 8-, 9-or 10-membered heterocycle containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S ; R3 is H ; C1-6alkyl ; optionally substituted Cs. scycloalkyi optionally containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; optionally substituted Cs-ioaromatic ring structure optionally containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; or an optionally substituted 5-to 10-membered mono-or bi-cyclic heterocyclic ring structure containing 1, 2, 3, 4 or 5 heteroatoms independently selected from 0, N and S ; R3' is-Z-M wherein Z represents 0, S or NH and M represents H, an optionally substituted mono-or bi-cyclic 5-, 6-, 7-, 8-, 9-or 10-membered heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S, or an optionally substituted C5 0aromatic ring structure optionally containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; or-Z-M represents-C(=O)NR6R7,-NR6R7, -OC (=O) NR8R9,-NC (=O) NR8R9 or-NC (=O) R8 ; For R4 and R5, either : (i) R4 is H ; Cl 8alkyl ; optionally substituted C3 8cycloalkyl optionally fused to a benzo ring ; Z2- (C1-8alkyl) aryl, wherein Z2 represents O or a bond, and the aryl is C6-10, optionally substituted and optionally fused to a CS_, o heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S ; optionally substituted C6 0are ; an

optionally substituted 5-, 6-, 7-, 8-, 9-or 10-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; (C1 8alkyl)-R, wherein R represents an optionally substituted mono-or bi-cyclic 5 to 10 membered heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S ; optionally substituted-C (=O) O (C, 8alkyl) ; optionally substituted-C (=O) O-phenyl ; optionally substituted -C (=O) (C1 -8alkyl) ; optionally substituted-C (=O)-phenyl ; or-NC (=O) R and R5 is H ; C1-8-alkyl ; optionally substituted C3 8cycloalkyl optionally fused to a benzo ring ; (Cl 8alkyl) aryl wherein the aryl is C6. 0 and optionally substituted ; optionally substituted C6 0are ; or an optionally substituted 5-, 6-, 7-, 8-, 9-or 10-membered heterocyclic ring structure containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; or (ii) the structure-NR4R5 represents a C3 8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from 0, N and S and optionally fused to a C6-10 ring structure,-NR4R5 being optionally substituted ; For R6 and R7, either : (i) R is H ; C,, 2alkyl ; optionally substituted C3-8cycloalkyl optionally fused to a benzo ring ; optionally substituted (C1-8alkyl) aryl wherein the aryl is C6-1o ; optionally substituted (C1-8alkyl) R, where R represents a mono-or bi-cyclic 5-, 6-, 7-, 8-, 9-or 10-membered heterocycle containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S or R represents a mono-, bi-or tri-cyclic C3, 3cycloalkyl ; optionally substituted C6-10aryl ; an optionally substituted mono-or bi-cyclic 5-, 6-, 7-, 8-, 9-or 10-membered heterocycle containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S ; or-C (=O) O- Ar, wherein Ar represents optionally substituted C6-loaryl ; and R is H ; or (ii) the structure-NR6R7 represents a C3 8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from 0, N and S,-NR being optionally substituted ; a represents an integer 1, 2, 3, 4 or 5 ; each b independently represents an integer 1, 2, 3, 4 or 5 ; c represents an integer 1, 2, 3, 4 or 5 ; c'represents an integer 1, 2, 3, 4 or 5 ; d represents an integer 1, 2, 3, 4 or 5 ; each e independently represents an integer 1, 2, 3, 4 or 5 ; f represents an integer 1, 2, 3, 4 or 5 ; and

g represents zero or an integer 1, 2, 3, 4 or 5.

The invention also relates to pharmaceutical formulations, use of a compound of the invention in the manufacture of a medicament, processes for preparing the compounds and intermediates for use in such processes.

Detailed Description of the Invention The present invention provides a compound of formula I or a pharmaceutically acceptable salt or solvate thereof wherein : X represents S ; S02 ; NH ; O or CH2. Alternatively, X represents N (C1-6alkyl), more preferably N-methyl or N (C2-4alkyl).

Y represents Chalky ! (preferably C2-4alkyl, and most preferably methyl) ; O (C3-8cycloalkyl), preferably O-cyclopropyl, or O-cyclobutyl or O-cyclopentyl ; O (C1-6alkyl), preferably Omethyl or O (C2-4alkyl) ; Hal, preferably Cl or F ; CHal3, CHHal2, CH2Hal, OCHal3, OCHHal2 or OCH2Hal, wherein Hal represents halogen (preferably F) ; NRR', wherein R and R'independently represent H or C1-8alkyl (preferably methyl or C2-6alkyl or C2-4alkyl), or NRR'represents an optionally substituted C3 8, preferably C3-6, heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from 0, N and S ; H ; COOR"or COR", R"representing H or C1-6alkyl (preferably methyl, ethyl) ; or CH20H.

For optional substitution of the heterocyclic ring represented by NRR', at least one (e. g., one, two or three) substituents may be provided independently selected from C, 6alkyl (preferably C2-4alkyl, more preferably methyl) ; phenyl ; OCF3 ; OCHF2 ;-O (Cl 8alkyl), preferably-O- methyl,-O-ethyl or-O (C3-6alkyl) ;-C (=O) O (C, 8alkyl), preferably-C (=O) O-methyl, -C (=O) O-ethyl,-C (=O) O-tert-butyl or-C (=O) O (C3 6alkyl) ;-C (=O) O-phenyl ;-O-phenyl ; -C (=O) (C1-8alkyl), preferably-C (=O)-methyl,-C (=O)-ethyl or-C (=O) (C3-6alkyl) ; -C (=O) OH ;-S (C1-8alkyl), preferably-S-methyl,-S-ethyl or-S (C3. 6alkyl) ; OH ; halogen (e. g., F, Cl or Br) ; NRR'where R and R'are independently H or Cl 6alkyl (preferably C2-4alkyl, more preferably methyl, most preferably R=R'=methyl) ; and nitro.

R1 represents-(CH2)a-R3;-((CH2)bO)c-R3;-(CH2)d-R3';-((CH2)3-O)c '-(CH2)f-R3' (preferably where e=2 and f=2) ; R3 or R3'. Preferably, R'represents- (CH2) a-CH3 or

-((CH2)bO)c-CH3. More preferably, R'is selected from-iso-Bu ;- (CH2CH20) 3CH3 ; -(CH2CH2)-4-morpholinyl;-(CH2CH2O)5CH3;-(CH2CH2)-1-(2-methyl -5-nitro-imiazolyl) ; -(CH2CH2)-1-(1, 2, 4-triazolyl) ; and- (CH2CH2)-OC (=O) NH-Ph.

R represents an optionally substituted mono-or bi-cyclic 5-, 6-, 7-, 8-, 9-or 10- membered heterocycle containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S. Preferred examples of the heterocycle are benzimidazoly (preferably benzimidazol-2-yl), imidazolyl (preferably imidazol-2-yl), oxadiazolyl (preferably 1, 3, 4- oxadiazol-2-yl), pyrimidinyl (preferably pyrimidin-2-yl), tetrazolyl (preferably 1, 2, 3, 4- tetrazol-5-yl), pyridinyl (preferably pyridin-2-yl or pyridin-4-yl), thiazolyl (preferably 1, 3- thiazol-2-yl), pyridineimidazolyl (preferably pyridineimidazol-2-yl), benzoxazolyl (preferably 1, 3-benzoxazol-2-yl), indolyl (preferably indol-2-yl). For optional substitution of the heterocycle, at least one (e. g., one, two or three) substituents may be provided independently selected from nitro ; carboxylate ;-COOH ; =O ;-S (=O)- (C1-8alkyl), the alkyl preferably being methyl, ethyl or C3-6alkyl ;-S (=O)-(=O)-(C1-8alkyl), the alkyl preferably being methyl, ethyl or C3-6alkyl ; halogen (preferably F or Cl) ; phenyl ; -O (Cl 8alkyl), preferably-O-methyl,-O-ethyl or-O (C3 6alkyl) ;-S (C1-8alkyl), preferably-S- methyl,-S-ethyl or-S (C3 6alkyl) ; OH ; OCHF2, OCH2F, OCF3 ; CHF2, CH2F, CF3 ; -C (=O) NRR', wherein R and R'are independently selected from H and Ct. galkyi (preferably methyl, ethyl, propyl, isopropyl, or C2 6alkyl), or the structure NRR'represents an optionally substituted C3 8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from 0, N and S ; and -R"-NH (CO) R"', wherein R"represents Cl 6alkylene (preferably C, or C2) and R''' represents C1-6alkyl (preferably Cl or C2).

In one preferred embodiment, R represents wherein : Q is CH or N ; Q'isNH, OorS ; W is CH or N ; W'isCHorN : and

R8 represents C1-6alkyl (preferably C2-4alkyl, and most preferably methyl) ; O (C3-8cycloalkyl), preferably O-cyclopropyl, or O-cyclobutyl or O-cyclopentyl ; O (Cl 6alkyl), preferably Omethyl or O (Cr 4alkyl) ; Hal, preferably Cl or F ; CHal3, CHHal2, CH2Hal, OCHal3, OCHHal2 or OCH2Hal, wherein Hal represents halogen (preferably F) ; NRR', wherein R and R'independently represent H or C1-8alkyl (preferably methyl or C2-6alkyl or C2-4alkyl), or NRR'represents an optionally substituted C3 8, preferably C3 6, heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from 0, N and S ; H ; COOR9 or COR9, R9 representing H or Cz 6alkyl (preferably methyl, ethyl) ; or CH20H.

For optional substitution of the heterocyclic ring represented by NRR', at least one (e. g., one, two or three) substituents may be provided independently selected from C, 6alkyl (preferably C2-4alkyl, more preferably methyl) ; phenyl ; OCF3 ; OCHF2 ;-O (Cl 8alkyl), preferably-O- methyl,-O-ethyl or-O (C3 6alkyl) ;-C (=O) O (C, 8alkyl), preferably-C (=O) O-methyl, -C (=O) O-ethyl,-C (=O) O-tert-butyl or-C (=O) O (C3 6alkyl) ;-C (=O) O-phenyl ;-O-phenyl ; -C (=O) (C1-8alkyl), preferably-C (=O)-methyl,-C (=O)-ethyl or-C (=O) (C3 6alkyl) ; -C (=O) OH ;-S (Ct 8alkyl), preferably-S-methyl,-S-ethyl or-S (C3 6alkyl) ; OH ; halogen (e. g., F, Cl or Br), NRR'where R and R'are independently H or C1-6alkyl (preferably C2-4alkyl, more preferably methyl, most preferably R=R'=methyl) ; and nitro.

R3 represents H ; C1-6alkyl ; optionally substituted C3 8, preferably C3-6, cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; optionally substituted C5-10aromatic ring structure (e. g., phenyl) optionally containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; or an optionally substituted 5-to 10- membered mono-or bi-cyclic heterocyclic ring structure containing 1, 2, 3, 4 or 5 heteroatoms independently selected from 0, N and S. Preferably, the cycloalkyl contains heteroatoms and is selected from morpholinyl (4-morpholinyl), piperazinyl (preferably 1-piperazinyl), tetrazolyl (preferably 1, 2, 3, 4-tetrazol-2-yl), imidazolyl (e. g., 1-imidazolyl) and triazolyl (e. g., 1- (1, 2, 4-triazolyl)). Preferred examples of the C, 6alkyl are preferably C2-4alkyl, methyl and butyl (e. g., isobutyl). preferred examples of the heterocyclic ring structure are imidazopyridazine (more preferably 6-imidazo [1, 2-b] pyridazine) and imidazolyl (more preferably 1-imidazolyl). For optional substitution of the cycloalkyl, aryl or heterocyclic ring, at least one (e. g., one, two or three) substituents may be provided independently selected from C, 6alkyl (preferably C2-4alkyl, more preferably methyl) and nitro.

R3'represents-Z-M wherein Z represents 0, S or NH and M represents H, an optionally substituted mono-or bi-cyclic 5-, 6-, 7-, 8-, 9-or 10-membered heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S, or an optionally substituted Cs-loaromatic ring structure (e. g., phenyl) optionally containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; or-Z-M-C (=O) NR R,-NR R -OC (=O) NR8R9,-NC (=O) NR8R9 or-NC (=O) R8 ; Preferably, the heterocyclic ring structure is selected from imidazopyridazine (more preferably 6-imidazo [1, 2-b] pyridazine) and imidazolyl (more preferably 1-imidazolyl). For optional substitution of the aromatic or heterocyclic ring structure, at least one (e. g., one, two or three) substituents may be provided independently selected from C1-6alkyl (preferably C2-4alkyl, more preferably methyl) and nitro.

Most preferably, R3'is selected from-4-morpholinyl ;-1- (2-methyl-5-nitro- imidazolyl) ;-1- (1, 2, 4-triazolyl) ; and-OC (=O) NH-Ph.

For R4 and R5, either : (i) R4 is H ; Ci-salkyi ; optionally substituted C3 8cycloalkyl optionally fused to a benzo ring ; Z2- (C1-8alkyl) aryl, wherein Z2 represents O or a bond, and the aryl is C6-10, optionally substituted and optionally fused to a CS-lo heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S ; optionally substituted C6-toaryl ; an optionally substituted 5-, 6-, 7-, 8-, 9-or 10-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; (Cl galkyl)-R, wherein R represents an optionally substituted mono-or bi-cyclic 5-, 6-, 7-, 8-, 9-or 10-membered heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S ; optionally substituted-C (=O) O (C1-8alkyl) ; optionally substituted-C (=O) O-phenyl ; optionally substituted-C (=O) (Ct 8alkyl) ; optionally substituted-C (=O)-phenyl ; or-NHC (=O) R6 ; and R is H ; C1-8alkyl ; optionally substituted C3-gcycloalkyl optionally fused to a benzo ring ; (Cl 8alkyl) aryl wherein the aryl is C6 z0 and optionally substituted ; optionally substituted C6-10aryl ; or an optionally substituted 5-, 6-, 7-, 8-, 9-or 10-membered heterocyclic ring structure containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; or (ii) the structure-NR4R5 represents a C3-gheterocycHc ring optionally containing 1, 2 or 3 further heteroatoms independently selected from 0, N and S and optionally fused to a C6-10ring structure, -NR4R5 being optionally substituted.

For R4 in option (i), preferably the Cf. galky ! or the C1-8alkyl in Z2-(Cl 8alkyl) aryl or the C1-8alkyl in (C, 8alkyl)-R or the C1-8alkyl in-C (=O) O (C108alkyl) or the C1-8alkyl in -C (=O) (C, 8alkyl) is selected from C2-6alkyl, methyl, ethyl, propyl (e. g., isopropyl), butyl (e. g., isobutyl or tert-butyl) and pentyl. Preferably, where C6 zoaryl is mentioned, the aryl is phenyl.

Preferably, Z2- (C, _galkyl) aryl represents Z2-(C1-8alkyl)benzodioxol. Preferably, for R4, where a heterocyclic ring structure is mentioned, this is selected from furyl (e. g., 2-furyl), tetrahydrofuranyl (e. g., tetrahydro-2-furanyl), thienyl (e. g., 2-thienyl), morpholinyl (e. g., 4- morpholinyl), isoxazolyl (e. g., 4-isoxazolyl or 5-isoxazolyl), dioxoimidazolidinyl (e. g., 2, 5- dioxoimidazolidinyl), pyrazinyl, dioxotetrahydropurinyl (e. g., 2, 6-dioxo-1, 2, 3, 6-tetrahydro- purin-7-yl), benzofuranyl (e. g., 2-benzofuranyl), pyridyl (e. g., 2-pyridyl or 3-pyridyl), quinolyl (e. g., 4-quinolyl), pyrrolidinyl (e. g., 2-pyrrolidinyl), piperazinyl (e. g., 1-piperazinyl), imidazopyridazinyl (e. g., imidazo [1, 2-b] pyridazinyl) and tetrazolyl (e. g., tetrazol-2-yl, 1, 2, 3, 4- tetrazol-2-yl). Preferably, for Z2- 8alkyl) aryl, the aryl is optionally fused to a heterocyclic ring structure selected from furan, tetrahydrofuran, thiophene, morpholine, isoxazole, dioxoimidazolidine (e. g., 2, 5-dioxoimidazolidine), pyrazine, dioxotetrahydropurine (e. g., 2, 6- dioxo-1, 2, 3, 6-tetrahydro-purine), benzofuran, pyridine, quinoline, pyrrolidine, piperazine, imidazopyridazine (e. g., imidazo [1, 2-b] pyridazine) and tetrazole (e. g., 1, 2, 3, 4-tetrazole).

Preferably, the C3-gcycloalkyl is selected from cyclopropyl C4 6cycloalkyl and cyclopentyl. For optional substitution of the cycloalkyl, aryl, heterocycle or heterocyclic ring structure, at least one (e. g., one, two or three) substituents may be provided independently selected from CI-6alkyl (preferably C2-4alkyl, more preferably methyl) ; phenyl ;-O (C, 8alkyl), preferably-O- methyl,-O-ethyl or-O (C3-6alkyl) ;-C (=O) O (C1-8alkyl), preferably-C (=O) O-methyl, -C (=O) O-ethyl or-C (=O) O (C3-6alkyl) ;-C (=O) O-phenyl ;-O-phenyl ;-C (=O) (C1-8alkyl), preferably-C (=O)-methyl,-C (=O)-ethyl or-C (=O) (C3 6alkyl) ;-S (Cl 8alkyl), preferably-S- methyl,-S-ethyl or-S (C3 6alkyl) ; OH ; halogen (e. g., F, Cl or Br), NRR'where R and R'are independently H or C106alkyl(preferably C-24alkyl, more preferably methyl, most preferably R=R'=methyl) ; and nitro.

For option (ii), the C3-8heterocyclic ring is preferably selected from piperidinyl (e. g., 1- piperidinyl), piperazinyl (e. g., 1-piperazinyl), morpholinyl (e. g., 4-morpholinyl) and tetrazolyl (e. g., 1, 2, 3, 4-tetrazol-2-yl). Preferably, the C6, 0 ring structure is selected from cyclohexyl and a benzo ring. For optional substitution of-NR4R5, at least one (e. g., one, two or three) substituents may be provided independently selected from C1-6alkyl(preferably C2-4alkyl, more preferably methyl) ; phenyl ; OCF3 ; OCHF2 ;-O (Cl galkyl), preferably-O-methyl,-O-

ethyl or-O (C3 6alkyl) ;-C (=O) O (C1-8alkyl), preferably-C (=O) O-methyl,-C (=O) O-ethyl, -C (=O) O-tert-butyl or-C (=O) O (C3-6alkyl) ;-O-phenyl ;-C (=O) (Cl 8alkyl), preferably -C (=O)-methyl,-C (=O)-ethyl or-C (=O) (C3-6alkyl) ;-C (=O) OH ;-S (C, 8alkyl), preferably-S- methyl,-S-ethyl or-S (C3 6alkyl) ; OH ; halogen (e. g., F, Cl or Br), NRR'where R and R'are independently H or Cl 6alkyl (preferably C2-4alkyl, more preferably methyl, most preferably R=R'=methyl) ; and nitro.

For R6 andR7, either : (i) R6 is H ; Cl l2alkyl ; optionally substituted C3 scycloalkyl optionally fused to a benzo ring ; optionally substituted (C1-8alkyl)aryl wherein the aryl is C_, o ; optionally substituted (Cl 8alkyl) R, where R represents a mono-or bi-cyclic 5-, 6-, 7-, 8-, 9-or 10-membered heterocycle containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S or R represents a mono-, bi-or tri-cyclic C3-13cycloalkyl ; optionally substituted C6-10alkyl ; an optionally substituted mono-or bi-cyclic 5-, 6-, 7-, 8-, 9-or 10-membered heterocycle containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S ; or-C (=O)- O-Ar, wherein Ar represents optionally substituted C6-10aryl ; and R7 is H ; or (ii) the structure-NR6R7 represents a C3-8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from 0, N and S and optionally fused to a C6-10ring structure, -NR6R7 being optionally substituted.

For R6 in option (ii), preferably Ct, 2alkyl is selected from C1-8alkyl, C2-6alkyl, methyl, propyl (e. g., isopropyl), butyl (e. g., isobutyl or tert-butyl), pentyl and adamantyl (e. g., 1- adamantyl). For Cl 8alkyl in (C1-8alkyl) aryl or (C1-8alkyl)R, the alkyl is selected from C2 6alkyl, methyl, propyl (e. g., isopropyl), butyl (e. g., isobutyl or tert-butyl) and pentyl.

Preferably, where C6-loaryl is mentioned, the aryl is phenyl. Preferably, Z2- 8alkyl) aryl represents Z2_ (C 1. 8alkyl) benzodioxol. Preferably, where a 5-, 6-, 7-, 8-, 9-or 10-membered heterocycle is mentioned, this is selected from benzofuryl (e. g., benzofur-2-yl), furyl (e. g., 2- furyl), tetrahydrofuranyl (e. g., tetrahydro-2-furanyl), thienyl (e. g., 2-thienyl), morpholinyl (e. g., 4-morpholinyl), isoxazolyl (e. g., 4-isoxazolyl or 5-isoxazolyl), dioxoimidazolidinyl (e. g., 2, 5-dioxoimidazolidinyl), pyrazinyl, dioxotetrahydropurinyl (e. g., 2, 6-dioxo-1, 2, 3, 6- tetrahydro-purin-7-yl), benzofuranyl (e. g., 2-benzofuranyl), pyridyl (e. g., 2-pyridyl or 3- pyridyl), quinolyl (e. g., 4-quinolyl), pyrrolidinyl (e. g., 2-pyrrolidinyl), piperazinyl (e. g., 1- piperazinyl), imidazopyridazinyl (e. g., imidazo [1, 2-b] pyridazinyl) and tetrazolyl (e. g., tetrazol-2-yl, 1, 2, 3, 4-tetrazol-2-yl). Preferably, the C3 gcycloalkyl is selected from cyclopropyl C4-6cycloalkyl and cyclopentyl. For optional substitution of the cycloalkyl, alkylaryl, aryl or

heterocycle, at least one (e. g., one, two or three) substituents may be provided independently selected from C1-6alkyl (preferably C2-4alkyl, more preferably methyl) ; phenyl ; OCF3 ; OCHF2 ; -O (Cl 8alkyl), preferably-O-methyl,-O-ethyl or-O (C3 6alkyl) ;-C (=O) O (C1-8alkyl), preferably-C (=O) O-methyl,-C (=O) O-ethyl,-C (=O) O-tert-butyl or-C (=O) O (C3 6alkyl) ; -C (=O) O-phenyl ;-O-phenyl ;-C (=O) (Cl galkyl), preferably-C (=O)-methyl,-C (=O)-ethyl or -C (=O) (C3-6alkyl) ;-C (=O) OH ;-S (C, 8alkyl), preferably-S-methyl,-S-ethyl or-S (C3 6alkyl) ; OH ; halogen (e. g., F, Cl or Br), NRR'where R and R'are independently H or C1-6alkyl (preferably C2-4alkyl, more preferably methyl, most preferably R=R'=methyl) ; and nitro.

For option (ii), the C3-8heterocyclic ring is preferably selected from piperidinyl (e. g., 1- piperidinyl), piperazinyl (e. g., 1-piperazinyl), morpholinyl (e. g., 4-morpholinyl) and tetrazolyl (e. g., 1, 2, 3, 4-tetrazol-2-yl). Preferably, the C6. loring structure is selected from cyclohexyl and a benzo ring. For optional substitution of-NR6R7, at least one (e. g., one, two or three) substituents may be provided independently selected from C1-6alkyl (preferably C2-4alkyl, more preferably methyl) ; phenyl ; OCF3 ; OCHF2 ;-O (C, 8alkyl), preferably-O-methyl,-O- ethyl or-O (C3 6alkyl) ;-C (=O) O (C, 8alkyl), preferably-C (=O) O-methyl,-C (=O) O-ethyl or -C (=O) O (C-36alkyl); -O-phenyl ;-C (=O) (Cl 8alkyl), preferably-C (=O)-methyl,-C (=O)-ethyl or-C (=O) (C3 6alkyl) ;-S (C, 8alkyl), preferably-S-methyl,-S-ethyl or-S (C3-6alkyl) ; OH ; halogen (e. g., F, Cl or Br), NRR'where R and R'are independently H or C, 6alkyl (preferably C2-4alkyl, more preferably methyl, most preferably R=R'=methyl) ; and nitro.

In formula I, a represents 1, 2, 3, 4 or 5 (preferably 1 or 2) ; each b independently represents 1, 2, 3, 4 or 5 (preferably 1 or 2) ; c represents 1, 2, 3, 4 or 5 (preferably 1 or 2) ; c' represents 1, 2, 3, 4 or 5 (preferably 1 or 2) ; d represents 1, 2, 3, 4 or 5 (preferably 1 or 2) ; each e independently represents 1, 2, 3, 4 or 5 (preferably 1 or 2) ; f represents 1, 2, 3, 4 or 5 (preferably 1 or 2) ; and g represents zero or represents 1, 2, 3, 4 or 5 (preferably 1 or 2).

In the present specification, unless otherwise indicated, an alkyl substituent may be linear or branched.

Where optional substitution of aryl is mentioned, the substituent can be selected from C1-6alkyl (preferably C2-4alkyl, and most preferably methyl) ; O (C3-8cycloalkyl), preferably 0- cyclopropyl, or O-cyclobutyl or O-cyclopentyl ; O (C1-6alkyl), preferably Omethyl or O (C2-4alkyl) ; Hal, preferably Cl or F ; CHal3, CHHal2, CH2Hal, OCHal3, OCHHal2 or OCH2Hal, wherein Hal represents halogen (preferably F) ; NRR', wherein R and R' independently represent H or C1-8alkyl (preferably methyl or C2-6alkyl or C2-4alkyl), or NRR' represents an optionally substituted C3 8, preferably C3 6, heterocyclic ring optionally

containing 1, 2 or 3 further heteroatoms independently selected from 0, N and S ; H ; COOR" or COR", R"representing H or C1-6alkyl (preferably methyl, ethyl) ; or CH20H. For optional substitution of the heterocyclic ring represented by NRR', at least one (e. g., one, two or three) substituents may be provided independently selected from C1-6alkyl (preferably C2-4alkyl, more preferably methyl) ; phenyl ; OCF3 ; OCHF2 ;-O (C1-8alkyl), preferably -O-methyl, -O- ethy or-O (C3 6alkyl) ;-C (=O) O (C, 8alkyl), preferably-C (=O) O-methyl,-C (=O) O-ethyl, -C (=O) O-tert-butyl or-C (=O) O (C3 6alkyl) ;-C (=O) O-phenl ;-O-phenyl ;-C (=O) (Cl 8alkyl), preferably-C (=O)-methyl,-C (=O)-ethyl or-C (=O) (C3 6alkyl) ;-C (=O) OH ;-S (C1-8alkyl), preferably-S-methyl,-S-ethyl or-S (C3 6alkyl) ; OH ; halogen (e. g., F, Cl or Br), NRR'where R and R'are independently H or C1-6alkyl (preferably C2-4alkyl, more preferably methyl, most preferably R=R'=methyl) ; and nitro.

In one embodiment, a is 1, 2 or 3 ; b is 2 ; c'is 1, 2, 3, 4 or 5 ; dis 1, 2 or 3 ; e is 2 ; fis 1, 2 or 3 ; andgis lor2.

Another embodiment has the general structure Ib wherein : X is S, S (=O), S (=0) 2 or 0.

Y is C1-6alkyl, O(C1-6alkyl), Hal ; CHal3, CHHal2, CH2Hal, OCHal3, OCHHal2 or <BR> <BR> <BR> <BR> OCH2Hal.<BR> <BR> <BR> <BR> <P> R'is- (CH2) a-R3,-WH2) 20) -R3,- (CH2) d-R3',- (CH2) aC () R3,- (CH2) dC 0) R3',<BR> <BR> <BR> <BR> <BR> <BR> - ( (CH2) 20) c'-(CH2) f-R3'.

R3 is Cl 6alkyl ; optionally substituted C3 8cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; optionally substituted Cs loaromatic ring structure optionally containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; or an optionally substituted 5-to 10-membered mono-or bi-cyclic heterocyclic ring structure containing 1, 2, 3, 4 or 5 heteroatoms independently selected from 0, N and S, wherein the heterocyclic ring contains at least one carbon atom and contains no more than one O and no more than one S per cycle.

R3'is-Z-M wherein Z represents 0, S or NH and M represents H, an optionally substituted mono-or bi-cyclic 5-, 6-, 7-, 8-, 9-or 10-membered heterocyclic ring structure

containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S, wherein the heterocyclic ring contains at least one carbon atom and contains no more than one O and no more than one S per cycle ; or an optionally substituted Cl_ 10 aromatic ring structure optionally containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; or-Z-M represents -C (=O) NR6R7, -NR6R7, -OC(=O)NR8R9, -NC(=O)NR8R9 or-NC (=O) R8.

For R6 and R7, either : (i) R6 is H ; C1-12alkyl ; optionally substituted C3-8CYCloalkyl optionally fused to a benzo ring ; optionally substituted (C1-8alkyl)aryl wherein the aryl is Cl-fi ; optionally substituted (C, 8alkyl) R, where R represents a mono-or bi-cyclic 5-, 6-, 7-, 8-, 9-or 10-membered heterocycle containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S, wherein the heterocyclic ring contains at least one carbon atom and contains no more than one O and no more than one S per cycle ; or R represents a mono-, bi-or tri-cyclic C3-13cycloalkyl ; optionally substituted C6. loaryl ; an optionally substituted mono-or bi-cyclic 5-, 6-, 7-, 8-, 9-or 10-membered heterocycle containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from 0, N and S, wherein the heterocyclic ring contains at least one carbon atom and contains no more than one O and no more than one S per cycle ; or-C (=O)-O-Ar, wherein Ar represents optionally substituted C6-loaryl ; and R is H ; or (ii) the structure-NR6R7 represents a C3-8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from 0, N and S, wherein the heterocyclic ring contains at least one carbon atom and contains no more than one O and no more than one S per cycle ;-NR6R7 being optionally substituted.

In one variation of the above embodiments, X is S or O ; R1 is -(CH2)2R3, -(CH2)2R3, -CH2C (=O) R3 or-CH2C (=O) R3' ; and R3 is optionally substituted C3 8cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; optionally substituted Cs zoaromatic ring structure optionally containing 1, 2 or 3 heteroatoms independently selected from 0, N and S ; or an optionally substituted 5-to 10-membered mono-or bi-cyclic heterocyclic ring structure containing 1, 2, 3, 4 or 5 heteroatoms independently selected from 0, N and S.

In another variation of the above embodiments, Rl is selected from-iso-Bu, <BR> <BR> <BR> <BR> -(CH2CH20) 3CH3,-(CH2CH2)-4-morpholinyl,-(CH2CH20) 5CH3,-(CH2CH2)-1-(2-methyl-5- nitro-imidazolyl),-(CH2CH2)-1-(1, 2, 4-triazolyl), and-(CH2CH2)-OC(=O) NH-Ph.

In still another variation of the above embodiments, R represents

wherein : Q is CH or N ; Q'isNH, OorS ; W is CH or N ; W CH or N ; and R8 is C1-6alkyl ; O (C3-scycloalkyl) ; O (C, 6alkyl) ; Hal ; CHal3, CHHal2, CH2Hal, OCHal3, OCHHal2 or OCH2Hal, wherein Hal represents halogen ; NRR', wherein R and R' independently represent H or C, galkyl, or NRR'represents an optionally substituted C3-8heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from 0, N and S, wherein the heterocyclic ring contains at least one carbon atom and contains no more than one O and no more than one S ; H ; COOR9 or COR9, R9 representing H or C1-6alkyl; or CH2OH.

Preferred compounds are selected from compounds II, III, IV and V Specific examples of compounds according to the invention are given below. Mass spectral molecular ion data are reported in units of m/z (mass/charge) in Daltons.

Compound 1

Mass spec'molecular ion : M+H= 331 <BR> <BR> 2-( {3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-1-ethanol Compound 2

Mass spec'molecular ion : M+H=417 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl isopropylcarbamate Compound 3

Mass spec'molecular ion : M+H= 450 <BR> <BR> 2- ( {3- [ (1H-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl phenylcarbamate Compound 4

NMR : 'H NMR (dmso-d6) ppm 2. 42 (s, 3H), 3. 26 (t, J=6. 7 Hz, 2H), 4. 22 (t, J=6. 7 Hz, 2H), 4. 62 (s, 2H), 6. 95-7. 68 (m, 16H), 9. 57 (s, 1H, NH), 12. 61 (s, 1H, NH), 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl 4- phenoxyphenylcarbamate Compound 5

Mass spec'molecular ion : M+H= 445 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl pentylcarbamate Compound 6

Mass spec'molecular ion : M+H= 479 2- ( {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl 2, 5- dimethylphenylcarbamate Compound 7 Mass spec'molecular ion : M+H= 490 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl (1S,2R)-2- phenylcyclopropylcarbamate Compound 8

Mass spec'molecular ion : M+H= 456 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl cyclohexylcarbamate Compound 9

Mass spec'molecular ion : M+H= 496 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl) ethyl 3- (methylsulfanyl) phenylcarbamate Compound 10 Mass spec'molecular ion : M+H= 478 <BR> <BR> 2- ( {3- [ ( lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl<BR> <BR> phenethylcarbamate Compound 11

Mass spec'molecular ion : M+H= 484 <BR> <BR> 2- ( {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl 2- (2- thienyl) ethylcarbamate Compound 12 Mass spec'molecular ion : M+H= 388 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl methylcarbamate Compound 13 Mass spec'molecular ion : M+H= 464 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl 2- methylphenylcarbamate Compound 14

Mass spec'molecular ion : M+H= 480 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl3- methoxyphenylcarbamate Compound 15

Mass spec'molecular ion : M+H= 468 <BR> <BR> 2-( {3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl 4- fluorophenylcarbamate Compound 16

Mass spec'molecular ion : M+H= 464 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl benzylcarbamate Compound 17

Mass spec'molecular ion : M+H= 508 <BR> <BR> methyl 3- ( { [2- ( {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)- ethoxy] carbonyl} amino) benzoate Compound 18

Mass spec'molecular ion : M+H= 532 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl 3, 4- dichlorobenzylcarbamate Compound 19 Mass spec'molecular ion : M+H= 486 2-( {3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl 3, 4- difluorophenylcarbamate Compound 20

Mass spec'molecular ion : M+H= 494 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl phenyl dicarbonimidoate Compound 21

Mass spec'molecular ion : M+H= 529 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl3- bromophenylcarbamate Compound 22

Mass spec'molecular ion : M+H= 478 <BR> <BR> 2-({3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl 3- methylbenzylcarbamate Compound 23

Mass spec'molecular ion : M+H= 550 ethyl 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)sufanyl) ethoxy]- carbonyl} amino)-3-phenylpropanoate Compound 24

Mass spec'molecular ion : M+H= 469 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl) ethyl 3, 5-dimethyl-4- isoxazolylcarbamate Compound 25

Mass spec'molecular ion : M+H= 492 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl 3- acetylphenylcarbamate Compound 26

Mass spec'molecular ion : M+H= 478 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl benzoylcarbamate Compound 27 Mass spec'molecular ion : M+H= 499 <BR> <BR> 2- ( {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl 4-chloro-2-<BR> <BR> methylphenylcarbamate Compound 28

Mass spec'molecular ion : M+H= 494 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl 4- methoxybenzylcarbamate Compound 29

Mass spec'molecular ion : M+H= 518 2-( {3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl 3, 4- dichlorophenylcarbamate Compound 30

Mass spec'molecular ion : M+H= 493 <BR> <BR> 2- ( {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl<BR> <BR> 4- (dimethylamino) phenylcarbamate Compound 31

Mass spec'molecular ion : M+H= 518 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl 2, 5- dichlorophenylcarbamate Compound 32

Mass spec'molecular ion : M+H= 510 2- {3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl 3, 5- dimethoxyphenylcarbamate Compound 33 Mass spec'molecular ion : M+H= 510 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl 2, 4- dimethoxyphenylcarbamate Compound 34

Mass spec'molecular ion : M+H= 478 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl) ethyl (1R)-1- phenylethylcarbamate Compound 35

Mass spec'molecular ion : M+H= 522 ethyl 4-({[2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl} sulfanyl) ethoxy] carbonyl} amino) benzoate Compound 36

Mass spec'molecular ion : M+H= 478 2-( {3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl 2- ethylphenylcarbamate Compound 37

Mass spec'molecular ion : M+H= 496 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)ethyl4- fluorobenzoylcarbamate Compound 38 Mass spec'molecular ion : M+H= 330 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl) ethylamine Compound 39 Mass spec'molecular ion : M+H= 434 N- [2- ( {3- [ ( 1H-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl] benzamide Compound 40

Mass spec'molecular ion : M+H= 440 N- [2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl} sulfanyl) ethyl] cyclohexanecarboxamide Compound 41

Mass spec'molecular ion : M+H= 470 N-[2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphen yl}sulfanyl)ethyl]-2-[(4S)- 2, 5-dioxoimidazolidinyl] acetamide Compound 42

Mass spec'molecular ion : M+H= 541 tert-butyl 4-({[2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2- <BR> <BR> methylphenyl} sulfanyl) ethyl] amino} carbonyl)-1-piperidinecarboxylate Compound 43

Mass spec'molecular ion : M+H= 436 N-[2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphen yl}sulfanyl)ethyl]2- pyrazinecarboxamide Compound 44

Mass spec'molecular ion : M+H= 506 2-(1-adamantyl)-N-[2-({3-[(1H-benzimidazol-2-ylsulfanyl)meth yl]-2- methylphenyl} sulfanyl) ethyl] acetamide Compound 45

Mass spec'molecular ion : M+H= 550 N-[2-( {3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl]-2-(1, 3- dimethyl-2, 6-dioxo-1, 2, 3, 6-tetrahydro-7H-purin-7-yl) acetamide Compound 46 Mass spec'molecular ion : M+H= 424 N-[2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphen yl}sulfanyl)ethyl]-2-furamide Compound 47

Mass spec'molecular ion : M+H= 469 N-[2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphen yl}sulfanyl)ethyl]-5-nitro-2- furamide Compound 48

Mass spec'molecular ion : M+H= 440 N- [2-( {3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl]-2- thiophenecarboxamide Compound 49

Mass spec'molecular ion : M+H= 474 N-[2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphen yl}sulfanyl)ethyl]-1- benzofuran-2-carboxamide Compound 50

Mass spec'molecular ion : M+H= 466 N- [22-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylpheny l}sulfanyl)ethyl]-1-ethyl-3- methyl-lH-pyrazole-5-carboxamide Compound 51

Mass spec'molecular ion : M+H= 435 N-[2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl} sulfanyl) ethyl] nicotinamide Compound 52

Mass spec'molecular ion : M+H= 485 <BR> <BR> N-[2-( {3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl]-4- quinolinecarboxamide Compound 53

Mass spec'molecular ion : M+H= 453 N-[2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphen yl}sulfanyl) ethyl]-3, 5- dimethyl-4-isoxazolecarboxamide Compound 54

Mass spec'molecular ion : M+H= 425 <BR> <BR> N- [2- ( {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl]-5- isoxazolecarboxamide Compound 55 Mass spec'molecular ion : M+H= 344 2- ( { 3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) acetamide Compound 56

Mass spec'molecular ion : M+H= 384 <BR> <BR> 2- ( 3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-N-<BR> <BR> cyclopropylacetamide Compound 57

Mass spec'molecular ion : M+H= 478 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)-N-(1, 3-benzodioxol- 5-ylmethyl) acetamide Compound 58

Mass spec'molecular ion : M+H= 412 <BR> <BR> 2- ( {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-1- (l-piperidinyl)-1- ethanone Compound 59 Mass spec'molecular ion : M+H= 424 2- ( { 3- [ (1H-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-N- (2- furylmethyl) acetamide Compound 60

Mass spec'molecular ion : M+H= 426 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)-N- cyclohexylacetamide Compound 61

Mass spec'molecular ion : M+H= 428 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)-N-(tetrahydro-2- furanylmethyl) acetamide Compound 62

Mass spec'molecular ion : M+H= 412 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)-N- cyclopentylacetamide Compound 63

Mass spec'molecular ion : M+H= 440 <BR> <BR> 2- ( 3- [ (1H-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-N- (2- thienylmethyl) acetamide Compound 64

Mass spec'molecular ion : M+H= 457 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)-N-[2-(4- morpholinyl) ethyl] acetamide Compound 65

Mass spec'molecular ion : M+H= 460 2- ( {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-N- (2, 3-dihydro-1H- inden-2-yl) acetamide Compound 66

Mass spec'molecular ion : M+H= 434 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)-N-benzylacetamide Compound 67

Mass spec'molecular ion : M+H= 508 2- ( { 3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-N- (2, 5- dimethoxyphenethyl) acetamide Compound 68 NMR :

'H NMR (dmso-d6) ppm 2. 42 (s, 3H), 2. 71 (m, 2H), 3. 77 (s, 2H), 4. 37 (m, 2H), 4. 62 (s, 2H), 7. 10-7. 16 (m, 7H), 7. 56 (m, 1H), 7. 66 (m, 1H), 8. 49 (m, 1H), 8. 75 (m, 1H), 12. 61 (s, 1H, NH). <BR> <BR> <P>2- ( { 3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-N- [2- (2-<BR> <BR> pyridinyl) ethyl] acetamide Compound 69

Mass spec'molecular ion : M+H= 455 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)-N-[2-(1-methyl-2- pyrrolidinyl) ethyl] acetamide Compound 70

Mass spec'molecular ion : M+H= 538 2- ( { 3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-N- (3, 3- diphenylpropyl) acetamide Compound 71

Mass spec'molecular ion : M+H= 449 <BR> <BR> 2-( {3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-N- phenethylacetamide Compound 72

Mass spec'molecular ion : M+H= 479 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)-N-(4- methoxyphenethyl) acetamide Compound 73 Mass spec'molecular ion : M+H= 429 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)-N-hexylacetamide Compound 74 Mass spec'molecular ion : M+H= 401 <BR> <BR> 2- ( {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-N-isobutylacetamide Compound 75

Mass spec'molecular ion : M+H= 436 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)-N-(4- pyridinylmethyl) acetamide Compound 76

N'-[2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphe nyl}sulfanyl)acetyl]-2- furohydrazide Compound 77

Mass spec'molecular ion : M+H= 467 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)-1-octahydro-1(2H)- quinolinyl-1-ethanone Compound 78

Mass spec'molecular ion : M+H= 450 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)- N- (benzyloxy) acetamide Compound 79 Mass spec'molecular ion : M+H= 519 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)-1-[4-(2- methoxyphenyl)-1-piperazinyl]-1-ethanone Compound 80

Mass spec'molecular ion : M+H= 521 2-( {3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-1-[6, 7-dimethoxy- 3, 4-dihydro-2 (lH)-isoquinolinyl]-1-ethanone Compound 81

Mass spec'molecular ion : M+H= 477 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)-N-(4- butylphenyl) acetamide Compound 82

Mass spec'molecular ion : M+H= 427 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl} sulfanyl)-1-(4-methyl-1- piperazinyl)-1-ethanone Compound 83 Mass spec'molecular ion : M+H= 400 2-[(2-methyl-3-{[2-(4-morpholinyl)ethyl]sulfanyl}benzyl)sulf anyl]-1H-benzimidazole Compound 84

Mass spec'molecular ion : M+H= 413 2- [ (2-methyl-3- { [2- (4-methyl-1-piperazinyl) ethyl] sulfanyl} benzyl) sulfanyl]-1H- benzimidazole Compound 85 Mass spec'molecular ion : M+H= 400 2-({3-[1H-imaidzol-2-ylsulfanyl)methyl]-2-methylphenyl}sulfa nyl}ethyl phenylcarbamate Compound 86

Mass spec'molecular ion : M+H= 478 2-[(2-methyl-3-{[5-phenyl-1, 3, 4-oxadiazol-2-yl) sulfanyl] methyl} phenyl) sulfanyl] ethyl phenylcarbamate Compound 87 Mass spec'molecular ion : M+H= 412 <BR> <BR> 2-( {2-methyl-3-[(2-pyrimidinylsulfanyl) methyl] phenyl} sulfanyl) ethyl phenylcarbamate Compound 88

Mass spec'molecular ion : M+H= 478 2-[(2-methyl-3- { [(1-phenyl-1H-1, 2, 3, 4-tetrazol-5-yl) sulfanyl] methyl} phenyl) sulfanyl] ethyl phenylcarbamate Compound 89

Mass spec'molecular ion : M+H= 552 2-[(3-{[(4,5-diphenyl-1H-imdiazol-2-yl)sufanyl]methyl}-2-met hylphenyl)sulfanyl]ethyl phenylcarbamate Compound 90

Mass spec'molecular ion : M+H= 451 2- ( {3- [ (3H-imidazo [4, 5-c] pyridin-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl phenylcarbamate Compound 91 Mass spec'molecular ion : M+H= 451 <BR> <BR> 2-({3-[(1, 3-benzoxazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl phenylcarbamate Compound 92

Mass spec'molecular ion : M+H= 411 <BR> <BR> 2-({2-methyl-3-[(2-pyridinylsulfanyl) methyl] phenyl} sulfanyl) ethyl phenylcarbamate Compound 93 Mass spec'molecular ion : M+H= 411 2-({2-methyl-3-[(4-pyridinylsulfanyl) methyl] phenyl} sulfanyl) ethyl phenylcarbamate Compound 94

Mass spec'molecular ion : M+H= 493 2-[(2-methyl-3-{[(4-phenyl-1,3-thiazol-2-yl)sufanyl]methyl}- 2-methylphenyl)sulfanyl]ethyl phenylcarbamate Compound 95 Mass spec'molecular ion : M+H= 417 2-( {2-methyl-3- [(1, 3-thiazol-2-ylsulfanyl) methyl] phenyl} sulfanyl) ethyl phenylcarbamate Compound 96

Mass spec'molecular ion : M+H= 480 2-[(c-{[(5-methoxy-1H-benzimidazol-2-yl)sufanyl]methyl}-2-me thylphenyl) sulfanyl] ethyl phenylcarbamate Compound 97

Mass spec'molecular ion : M+H= 449 N- [2-({3-[(1H-benzimidzol-2-yl)sufanyl]methyl}-2-methylphenyl) sulfanyl]ethyl]-N'- phenylurea Compound 98

Mass spec'molecular ion : M+H= 451 N-[2-({3-[(1H-benzimidzol-2-yl)sufanyl]methyl}-2-methylpheny l)sulfanyl]ethyl]-N'-(2- pyrazinyl) urea Compound 99

Mass spec'molecular ion : M+H= 493 <BR> <BR> 6- [2- ( {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethoxy]-3- nitroimidazo [1, 2-b] pyridazine Compound 100

Mass spec'molecular ion : M+H= 522 N- { [2-({3-[(1H-benzimidazol-2-yl)sufanyl]methyl}-2- methylphenyl)sulfanyl]ethyl) ethoxy] carbonyl} phenylalanine Compound 101 Mass spec'molecular ion : M+H= 383 2-[(2-methyl-3-{[2-(2H-1, 2, 3, 4-tetrazol-2-yl) ethyl] sulfanyl} benzyl) sulfanyl]-1H- benzimidazole Compound 102 Mass spec'molecular ion : M+H= 384 2-[(2-methyl-3- { [2-(2H-1, 2, 3, 4-tetrazol-2-yl) ethyl] sulfanyl} benzyl) sulfanyl]-3H-imidazo [4, 5- pyridine Compound 103

NMR : 400 MHz H-NMR (CHCI3-o) ppm 1. 03 (d, 6H), 2. 10 (m, 1H), 2. 29 (s, 3H), 3. 70 (d, 2H), 4. 56 (s, 2H), 6. 75 (d, 1 H), 6. 90 (d, 1 H), 7. 05 (t, 1 H), 7. 20 (t, 1 H), 7. 21 (t, 1 H), 7. 29 (d, 1 H), 7. 70 (d, 1 H).

2- [ (3-isobutoxy-2-methylbenzyl) sulfanyl]-lH-benzimidazole Compound 104

NMR : 500 MHz H-NMR (CHCI3-¢ ppm 2. 30 (s, 3H), 2. 65 (m, 4H), 2. 87 (m, 2H), 3. 75 (m, 4H), 4. 13 (m, 2H), 4. 60 (s, 2H), 6. 80 (d, 1H), 6. 97 (d, 1H), 7. 09 (t, 1H), 7. 19-7. 30 (m, 2H), 7. 33 (d, 1H), 7. 74 (d, 1 H).

2-({2-methyl-3-[2-(4-morpholinyl_ ethoxy] benzyl} sulfanyl)-lH-benzimidazole Compound 105 Mass spec'molecular ion : [M-H] = 324 <BR> <BR> 2- [ (3-isobutoxy-2-methylbenzyl) sulfanyl]-lH-indole Compound 106

Mass spec'molecular ion : M+Na= 439 2-[(3-{2-(2-methoxyethoxy) ethoxy] ethoxy}-2-methvlbenzyl) sulfanyl]-lH-benzimidazole Compound 107 Mass spec'molecular ion : M+Na = 527 2-{[2-methyl-3-(3, 6, 9, 12, 15-pentaoxahexadec-1-yloxy) benzyl] sulfanyl}-lH-benzimidazole Compound 108

NMR : 500 MHz H-NMR (CHCI3-¢ ppm 2. 43 (s, 3H), 3. 02 (t, 2H), 3. 35 (s, 3H), 3. 52-3. 55 (m, 2H), 3. 56-3. 68 (m, 8H), 4. 55 (s, 2H), 7. 01 (t, 1H), 7. 12 (d, 1H), 7. 19-7. 23 (m, 2H), 7. 25 (d, 1 H), 7. 50-7. 55 (m, 2H).

2-t [3-(t 2-[2-(2-methoxyethoxy) ethoxy] ethyl} sulfanyl)-2-methylbenzyl] sulfanyl}-1H- benzimidazole Compound 109 Mass spec'molecular ion : M+Na= 543 2- { [2-methyl-3- (3, 6, 9, 12, 15-pentaoxahexadec-1-ylsulfanyl) benzyl] sulfanyl}-1H- benzimidazole Compound 110

NMR : 600 MHz H-NMR (CHCI3-¢ ppm 1. 05 (d, 3H), 1. 06 (d, 3H), 2. 15 (m, 1H), 2. 34 (s, 3H), 3. 73 (d, 2H), 4. 65 (s, 2H), 6. 79 (d, 1 H), 7. 02 (d, 1 H), 7. 11 (t, 1 H), 7. 31 (t, 1 H), 7. 44 (t, 1 H), 7. 77 (d, 1 H), 7. 92 (d, 1 H).

2- [ (3-isobutoxy-2-methylbenzyl) sulfanyl]-1, 3-benzothiazole Compound 111

NMR : 600 MHz 1H-NMR (CHC13-d) ppm 1. 10 (d, 6H), 2. 16 (m, 1H), 2. 39 (s, 3H), 3. 76 (d, 2H), 4. 66 (s, 2H), 6. 83 (d, 1H), 7. 07 (d, 1H), 7. 15 (t, 1H), 7. 28 (t, 1H), 7. 32 (t, 1H), 7. 47 (d, 1 H), 7. 68 (d, 1 H).

2- [ (3-isobutoxy-2-methylbenzyl) sulfanyl]-1, 3-benzoxazole Compound 112

Mass spec'molecular ion : M+H= 343 _ 2-{[3-(siobutylsulfanyl)-2-methylphenyl)sulfanyyl}-1H-benzim idazole Compound 113

NMR : 300 MHz H-NMR (CH30H-d4) ppm 2. 26 (s, 3H), 2. 43 (s, 3H), 3. 29 (t, 2H), 4. 40 (t, 2H), 4. 49 (s, 2H), 4. 89 (broad, >3H, exchangeable with D20), 7. 02 (t, 1 H), 7. 09-7. 19 (m, 3H), 7. 29 (d, 1 H), 7. 36-7. 49 (m, 2H), 7. 79 (s, 1 H).

2-[2-methyl-3-{[2-methyl-5-nitro-1H-imidizol-1-yl)ethyl]s ulfanyl}benzyl)sulfanyl]-1H- benzimidazole Compound 114

NMR : 300 MHz H-NMR (CHCts-d) ppm 2. 37 (s, 3H), 3. 28 (t, 2H), 4. 30 (t, 2H), 4. 43 (s, 2H), 6. 86-7. 00 (m, 2H), 7. 10-7. 22 (m, 3H), 7. 32-7. 72 (broad, 2H), 7. 87 (s, 1H), 7. 91 (s, 1H).

2-[2-methyl3-{[2-1H-1. 2, 4-triazol-1-yl) ethyl] sulfanyl benzyl) sulfanyl]-lH-benzimidazole Compound 115

Mass spec'molecular ion : M+H= 593 ethyl 2-{2-methyl-3-(3, 6, 9, 12, 15-pentaoxahexadec-1-ylsulfanyl) benzyl] sulfanyl}-1H- benzimidazole-5-carboxylate Compound 116.

Mass spec'molecular ion : M+Na= 599 1-(2-{[2-methyl-3-(3, 6, 9, 12, 15-pentaoxahexadec-1-ylsulfanyl) benzyl] sulfanyl}-1H- benzimidazol-5-yl)-1-propanone Compound 117 Mass spec'molecular ion : M+Na= 558 2-{[2-methyl-3-(3, 6, 9, 12, 15-pentaoxahexadec-1-ylsulfanyl) benzyl] sulfanyl}-1H- benzimidazol-5-amine Compound 118

Mass spec'molecular ion : M+Na= 573 (2-{[2-methyl-3-(3, 6, 9, 12, 15-pentaoxahexadec-1-ylsulfanyl) benzyl] sulfanyl}-1H- benzimidazol-5-yl) methanol Compound 119

Mass spec'molecular ion : Mass spec'molecular ion : [M-H]-= 329 <BR> <BR> 2- {3- [(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methoxyphenoxy}-1-ethanol Compound 120 Mass spec'molecular ion : M+H= 450 2- {3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methoxyphenoxy} ethyl phenylcarbamate Compound 121

Mass spec'molecular ion : M+H= 335 2-{3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-cjhlorophenoxy }-1-ethanol Compound 122

Mass spec'molecular ion : M+H= 454 2- {3- [ (1H-benzimidazol-2-ylsulfanyl) methyl]-2-chlorophenoxy} ethyl phenylcarbamate The compounds of formula I above may be converted to a pharmaceutically-acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate orp- toluenesulfonate, or an alkali metal salt such as a sodium or potassium salt.

The compounds of formula I can be prepared by a process comprising any one of steps (a) to (h) as follows : (a) reducing compound VI wherein Rl° represents (CH2) d or-(CH2) f-O-(CH2) e-and Rl t represents H or Cl 6alkyl ; or (b) reacting compound VII with R6-NCO wherein Z3 represents O or NH ; or (c) reducing compound VIII

wherein Rl° represents a bond, (CH2) dor-(CH2)f-O-(CH2)e- ; or (d) reacting compound VII with R6-COOH ; or (e) reacting compound IX with NHR4R5 ; or

(f) reacting compound X with NHR4R5 wherein Ll represents a leaving group and R10, represents (CH2d or-(CH2)f-O-(CH2)e-; or

(g) reacting compound XI with R2-SH wherein L represents a leaving group ; or (h) reducing compound XII wherein R'° represents (CH2) dor-(CH2)f-1-O-(CH2)e-.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected. by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the addition and subsequent removal of one or more protecting groups.

The protection and deprotection of functional groups is described in'Protective Groups in Organic Chemistry', edited by J. W. F. McOmie, Plenum Press (1973) and'Protective Groups in Organic Synthesis', 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

The compounds of the present invention have anti-Helicobacterpylori activity, i. e., they can be administered to a mammalian patient therapeutically to treat Helicobacter pylori infection in the patient and/or to prevent such infection. A further avantage of compounds of the invention is that they are particularly selective for Helicobacter pylori.

Experimental Scheme 1 3-[(2-Methoxy-2-oxoethyl) sulfanyl]-2-methylbenzoic acid 3-amino-2-methylbenzoic acid, 11. 3 g, was dissolved in H20 (100 mL) and conc. HCL (IS mL) was added at 0 °C NaN02 (5. 5 g) in H20 (40 mL) was added to the above

suspension over 30min. The above diazonium salt was kept at 0°C and added slowly (over 40 min) to a solution of methyl thioglycolate, 8. 48 g in 50 mL of MeOH at 60 °C. During the addition, the pH of the reaction medium was kept around 5-6 by adding sat. Na2CO3 very carefully. After the end of addition, the reaction was heated at 60 to 70 °C for additional 45min. The mixture was cooled to 0 °C and pH was adjusted to-1 with conc. HCL & extracted with EtOAc, dried over Na2SO4, filtered, and the solvent was evaporated to give 17. 4 g of crude 3-[(2-methoxy-2-oxoethyl) sulfanyl]-2-methylbenzoic acid.

Methyl 2-{[3-(hydroxymethyl)-2-methylphenyl] sulfanyl} acetate 3-[(2-methoxy-2-oxoethyl) sulfanyl]-2-methylbenzoic acid, 15. 4 g, was dissolved in 120 mL THF and cooled on an ice bath. Borane-THF solution, 130 mL (1M in THF) was added slowly. The reaction was stirred for 1 hour then quenched with ice water, extracted with EtOAc, dried over Na2S04, purified by flash chromatography (silica gel, CH2CI2/EtOAc = 20/1) to give 5 grams of methyl 2-{ [3-(hydroxymethyl)-2-methylphenyl] sulfanyl} acetate.

Methyl 2-{[3-(chloromethyl)-2-methylphenyl] sulfanyl} acetate Methyl 2-{[3-(hydroxymethyl)-2-methylphenyl] sulfanyl} acetate, 4. 4 g was dissolved in 220 mL methylene chloride, treated with thionyl chloride, 5 mL, and stirred at room temp. for 4 hours. The solvents were evaporated to yield 4. 3 g of methyl 2-{[3-(chloromethyl)-2. methylphenyl] sulfanyl} acetate as a slightly brown oil.

Methyl 2-({3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) acetate 2-mercaptobenzimidazole, 2 g, was dissolved in a solution of 10 mL water, 30 mL methanol, and 0. 53 g NaOH, and cooled on an ice bath. A solution of 3. 2 g of methyl 2- { [3- (chloromethyl)-2-methylphenyl] sulfanyl} acetate in 50 mL methanol was added and the reaction was stirred at room temp. for 6 hours. The solvents were evaporated and the residue was partitioned between 600 mL CH2C12 and 300 mL of 5% Na2CO3, the org. layer was collected, dried over Na2SO4 and evaporated to give 3. 1 g methyl 2- (13- [ (IH-benzimidazol- 2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) acetate as a light yellow solid.

2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphen yl]sulfanyl)-1-ethanol Methyl 2- {3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2- methylphenyl} sulfanyl) acetate, 5. 7 g, was dissolved in 100 mL THF and cooled on a ice-bath.

Lithium aluminum hydride, 0. 5 g was added portion-wise under ca 5 min. After 30 min the reaction was quenched with Glauber salt (Na2S04x10H20). Filtration and evaporation afforded 2- ( {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-1-ethanol, 4. 1 g.

Mass spec. ; M+H=331.

2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphen yl]sulfanyl)ethyl phenylcarbamate 100 mg of 2-({3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-1- ethanol was dissolved in 2 mL DMF, and 35 mg phenyl isocyanate was added, the mixture was stirred for 18 hours at room temp., and concentrated in vacuo. Purification by reverse phase HPLC gave 60 mg 2- ( {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl}- sulfanyl) ethyl phenylcarbamate as a white solid.

Mass spec. ; M+H=450.

Scheme 2 2- ( {3- [ (2-Azidoethyl) sulfanyl]-2-methylbenzyl} sulfanyl)-lH-benzimidazole<BR> <BR> <BR> <BR> <BR> <BR> 2- ( { 3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-1-ethanol, 0. 165 g, triphenylphosphine, 0. 184 g, and sodium azide, 0. 13 g, were combined with stirring in 4 mL DMF on an ice bath, carbon tetrabromide, 0. 25 g, was added, and the reaction was allowed to proceed for 18 hours. 20 mL methylene chloride was added, the resulting suspension was filtered, the solids were rinsed with methylene chloride and the filtrate washed with brine, dried over Na2SO4, and evaporated. Purification of the residue by flash chromatography (silica gel, EtOAc/Hexane = 1 : 5) gave 2- ( {3- [ (2-azidoethyl) sulfanyl]-2- methylbenzyl} sulfanyl)-lH-benzimidazole, 0. 85 g. Mass spec. ; M+H=356 2- ( {3- [ (lH-Benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethylamine 2-( {3-[(2-azidoethyl) sulfanyl]-2-methylbenzyl} sulfanyl)-lH-benzimidazole, 0. 42 g, was added to a suspension of 0. 3 g lithium aluminum hydride in 10 mL THF over an ice bath.

After 45 minutes, the reaction was quenched with Na2SO4. 10H2O until H2 evolution ceased.

The mixture was filtered, evaporated, dissolved in ethyl acetate and extracted with IN HCI.

The aqueous layer was washed with ethyl acetate and evaporated to give 275 mg of 2-({3- [(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethylamine as a white solid. Mass spec. ; M+H=330 N- [2- ( {3- [ (lH-Benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl]-2- pyrazinecarboxamide To a solution of 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2- methylphenyl} sulfanyl) ethylamine (658 mg), 2-pyrazinecarboxylic acid (248 mg), diisopropylethylamine (1 mL) and DMF (8 mL) was added HBTU (829 mg). The resulting mixture was stirred overnight. The mixture was transferred to a sep. funnel and diluted with EtOAc (200 mL) and washed with water (2 x 100 mL). The organic layer was washed with Sat. Brine, dried over MgS04, filtered and concentrated. The crude residue was purified by reverse phase HPLC, Cl8 column (10-100% MeCN/H2O) to give N-[2-({3-[(1H- <BR> <BR> <BR> <BR> benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyl]-2-pyrazinecarboxamide as 600mg white solid. Mass spec. ; M+H=436 Scheme 3 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl] sulfanyl)acetic acid Methyl 2- ( {3- [ (IH-benzimidazol-2-ylsulfanyl) methyl]-2- methylphenyl} sulfanyl) acetate, 0. 68 g, was dissolved in 14 mL MeOH and treated with excess LiOH dissolved in 2 mL H20 for 1 h. The solvents were evaporated and the residue was partitioned between 100 mL 5% Na2CO3 and 100 mL EtOAc. The aq layer was collected and the pH was adjusted to about 4 with 4M HCL The aq layer was extracted with a 2 : 1 ethyl acetate/THF mixture. The combined organic layers were dried over MgS04 and evaporated to leave 2- ( {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) acetic acid as a white solid, 0. 5 g.

2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphen yl]sulfanyl)-1-(1- piperidinyl)-1-ethanone 100 mg of 2-({3-[(lH-Benzimidazol-2-ylsulfanyl) methyl]-2- methylphenyl} sulfanyl) acetic acid was dissolved in 2 mL of DMF, 30 mg piperidine and 120 mg of HBTU were added. The mixture was stirred for 18 hours, diluted with ethyl acetate, washed with 5% NaHC03, saturated NaCl, dried over MgS04, and evaporated to give 2-({3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl)-1- (1-piperidinyl)-1- ethanone, 110 mg. Mass spec. ; M+H=412.

Scheme 4 2-({3-[(2-Chloroethylsulfanyl]-2-ylsulfanyl)methyl]-2-methyl phenyl]sulfanyl)-1H-benzimidzole 0. 38 g 2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl] sulfanyl)-1- ethanol was combined with 5 mL CH2CI2 and cooled to 0 °C. Excess SOC12 was added. Cold bath removed. Suspension stirred at RT for 2 hours. Concentrated in vacuo, 0. 39 g crude 2- ( { 3- [ (2-chloroethyl) sulfanyl]-2-methylbenzyl} sulfanyl)-lH-benzimidazole obtained.

2-[(2-methyl-3-{[2-(4-morpholinyl) ethyl] sulfanyl} benzyl) sulfanyl]-lH-benzimidazole 2-({3-[(2-Chloroethyl)sulfanyl)-2-methylphenyl]sulfanyl)-1H- benzimidazole, 0. 202 g, 1. 3 mL morpholine, 3 mL DMF, and 1 mL DMSO combined and warmed at 80 °C for 1 day.

Diluted to 100 mL with ethyl acetate. Washed with water, brine (2X), dried over MgSO4, evaporated to give a thick oil. Purified via preparative HPLC to give 2- [ (2-methyl-3- ( [2- (4- morpholinyl) ethyl] sulfanyl} benzyl) sulfanyl]-lH-benzimidazole as a fine powder, 0. 12 g.

Mass spec. ; M+H=400.

Compound 113 can be prepared by a similar scheme by using 2-methyl-5-nitro-lH- imidazole in place of morpholine.

Compound 114 can be prepared by a similar scheme by using IH-triazole in place of morpholine.

Scheme 5

Methyl 2-{3-[(lH-benzimidazol-2-ylsul&nyl) methyl]-2-methylphenoxy} acetate 2-Mercaptobenzimidazole, 2 g, was dissolved in a solution of 10 mL water, 30 mL methanol, and 0. 53 g NaOH, and cooled on an ice bath. A solution of 3. 2 g of methyl 2- [3-(chloromethyl)-2-methylphenoxy] acetate in 50 mL methanol was added and the reaction was stirred at room temp. for 6 hours. The solvents were evaporated and the residue was partitioned between 600 mL CH2CI2 and 300 mL of 5% Na2O3, the org. layer was collected, dried over Na2SO4 and evaporated to give 3. 1 g methyl 2- {3- [ (IH-benzimidazol-2- ylsulfanyl) methyl]-2-methylphenoxy} acetate as a light yellow solid.

2- {3- [ (lH-Benzimidazol-2-ylsulfanyl) methyl]-2-methylphenoxy} acetic acid Methyl 2-{3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenoxy} acetate, 0. 68 g, was dissolved in 14 mL MeOH and treated with excess LiOH dissolved in 2 mL H20 for 1 h. The solvents were evaporated and the residue was partitioned between 100 mL 5% Nal-C03 and 100 mL EtOAc. The aq layer was collected and the pH was adjusted to about 4 with 4M HCI. The aq layer was extracted with a 2 : 1 ethyl acetate/THF mixture. The combined organic layers were dried over MgSO4 and evaporated to leave 2-{3-[(1H-benzimidazol-2- ylsulfanyl) methyl]-2-methylphenoxy} acetic acid as a white solid, 0. 5 g.

2-({3-[(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphen yl)-1-(4-morpholinyl)-1- ethanone

100 mg of 2- {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenoxy} acetic acid was dissolved in 2 mL of DMF, 30 mg morpholine and 120 mg of HBTU were added. The mixture was stirred for 18 hours, diluted with ethyl acetate, washed with 5% NaHC03, saturated NaCl, dried over MgS04, and evaporated to give 2- (3- [ (lH-benzimidazol-2- ylsulfanyl) methyl]-2-methylphenoxyl-l- (4-morpholinyl)-l-ethanone, 110 mg. <BR> <BR> <BR> <BR> <P>2-({2-Methyl-3-[2-(4-morpholinyl) ethoxy] benzyl} sulfanyl)-lH-benzimidazole<BR> <BR> <BR> <BR> <BR> <BR> 2- {3- [ (lH-Benzimidazol-2-ylsulfanyl) methyl]-2-methylphenoxy}-1- (4-morpholinyl)- 1-ethanone, 0. 7 g, was dissolve in 20 mL THF. 0. 2 g lithium aluminum hydride was added, and the mixtue was warmed to 70 °C for 45 minutes. Na2S04-10H20 was added, the mixture was filtered, concentrated and purified by column chromatography (Si02, ethyl acetate) to gi ve 2-( {2-methyl-3-[2-(4-morpholinyl) ethoxy] benzyl} sulfanyl)-lH-benzimidazole as a white foam, 0. 42 g.

Scheme 6 (3-Isobutoxy-2-methylphenyl) methanol 2-Methyl-3-hydroxymethylphenol [prepared by lithium aluminum hydride reduction of 2-methyl-3-hydroxybenzoic acid], 1 g, isobutyl bromide, 1. 6 mL, and K2CO3, 3 g, were combined in 10 mL DMF and stirred at 70 °C for 1 day. The mixture was diluted with ethyl acetate, washed with water and brine, dried over MgS04, and evaporated to give (3-isobutoxy- 2-methylphenyl) methanol as a yellow waxy solid, 1. 15 g.

1- (3-Isobutoxy-2-methylbenzyl)-lH-benzimidazole 0. 5 g (3-isobutoxy-2-methylphenyl) methanol was dissolved in 3 mL CH2CI2, and 0. 7 mL SOC12 was carefully added. The mixture was stirred for 30 min., then concentrated to give crude 1- (chloromethyl)-3-isobutoxy-2-methylbenzene. The crude chloride sample was dissolved in 3 mL DMF, and 0. 26 g benzimidazole and 0. 6 g K2CO3 were added. The

suspension was stirred at rt overnight. The mixture was diluted with ethyl acetate, washed with water and brine, dried over MgS04, and evaporated to give a residue which was purified by flash chromatography, silica gel, 20-50% ethyl acetate/Hexane. 1- (3-isobutoxy-2- methylbenzyl)-1H-benzimidazole was thus obtained as an off-white solid, 0. 6g. Mass spec. ; M+H=295.

2- [ (3-Isobutoxy-2-methylbenzyl) sulfanyl]-lH-benzimidazole 2-Mercaptobenzimidazole, 2 g, was dissolved in a solution of 10 mL water, 30 mL methanol, and 0. 53 g NaOH, and cooled on an ice bath. A solution of 3. 2 g 1- (chloromethyl)- 3-isobutoxy-2-methylbenzene in 50 mL methanol was added and the reaction was stirred at room temp. for 6 hours. The solvents were evaporated and the residue was partitioned between 600 mL CH2CI2 and 300 mL of 5% Na2CO3, the org. layer was collected, dried over Na2SO4 and evaporated to give 3. 1 g 2- [ (3-isobutoxy-2-methylbenzyl) sulfanyl]-lH- benzimidazole as a light yellow solid.

Compound 105 can be made by a similar scheme by using 2-mercaptoindole in place of 2-mercaptobenzimidazole.

Compound 110 can be made by a similar scheme by using 2-mercaptobenzothiazole in place of 2-mercaptobenzimidazole.

Compound 111 can be made by a similar scheme by using 2-mercaptobenzoxazole in place of 2-mercaptobenzimidazole.

Scheme 7 2-({2-Methyl-3-[(2-pyrimidinylsulfanyl) methyl] phenylesulfanyl) ethyl phenylcarbamate To a solution of 135 mg of 2-{ [3-(chloromethyl)-2-methylphenyl] sulfanyl} ethyl phenylcarbamate in 2 mL DMF was added 65 mg of 2-thiopyrimidine, and 600 mg K2CO3.

The suspension was stirred vigorously at RT for 1. 5 hrs. The mixture was diluted to 25 mL with ethyl acetate, washed with 15 mL water, 2 X 15mL IN KOH, 15mL brine, and dried over MgS04. Evaporation gave a thick oil. Purification by flash chromatography, silica gel, 10- 30% ethyl acetate/hexane gave 2-({2-methyl-3-[(2- pyrimidinylsulfanyl) methyl] phenyl} sulfanyl) ethyl phenylcarbamate as a waxy solid, 130 mg.

Mass spec. ; M+H=412.

Scheme 8

N- [2- ( {3- [ (lH-Benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethyt]-N'- phenylurea 100 mg of the 2-({3-[(lH-benzimidazol-2-ylsulfanyl) methyl]-2- methylphenyl} sulfanyl)-1-ethanamine was dissolved in 2 mL of DMF and 36 mg of phenyl isocyanate was added. The mixture was stirred at rt overnight. The reaction was evaporated, and the crude compound was purified by reverse phase preparative HPLC to give N- [2- ( {3- [(1H-benzimidazol-2-ylsulfanyl)methyl]-2-methylphenyl]sulfan yl)ethyl]-N'-phenylurea as a white powder, 85 mg. Mass spec. ; M+H=449.

Scheme 9 6-[2-({3-[(lH-Benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethoxy]-3- nitroimidazo [1, 2-b] pyridazine To a solution of 330 mg of 2-({3-[(lH-benzirnidazol-2-ylsulfanyl) methyl]-2- methylphenyl} sulfanyl)-1-ethanol in 30 mL DMF was added 160 mg sodium hydride (60% dispersion in oil), the suspension was stirred for 30 min, then 199 mg of 6-chloro-3- nitroimidazo [1, 2-b] pyridazine (Kobe, J. ; Stanovnik, B. ; Tisler, Miha. Tetrahedron (1968), 24 (1), 239) was added. After stirring the suspension overnight at rt, 5 mL water was added carefully, then the mixture was concentrated under vacuum to leave a brown solid residue.

The residue was stirred with acetone and filtered, the filtrate was concentrated and the resulting solids were rinsed with hot ethanol to yield 6-[2-({3-[(lH-benzimidazol-2- ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethoxy]-3-nitroimidazo [1, 2-b] pyridazine as a light brown powder, 140 mg.

Scheme 10

N-{ [2-({3-[(lH-Benzimidazol-2-ylsulfanyl) methyl]-2- methylphenyl} sulfanyl) ethoxy] carbonyl} phenylalanine 25 mg of ethyl 2-({[2-({3-[(1H-benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl}- sulfanyl) ethoxy] carbonyl} amino)-3-phenylpropanoate was combined with 0. 1 mL 1M KOH, and 0. 5 mL dioxane to give a clear solution. After stirring for lhr at rt the reaction was diluted with water, extracted twice with ethyl acetate, the aq layer was acidified with conc HCl and extracted three times with ethyl acetate. The organic layer was dried over MgSO4 and evaporated to yield a clear oil. Trituration with 1 : 1 ether/hexane gave N-{[2-({3-[1H- benzimidazol-2-ylsulfanyl) methyl]-2-methylphenyl} sulfanyl) ethoxy] carbonyl} phenylalanine as a white solid : 20 mg. Mass spec. ; M+H=522.

Scheme 11 2-(2-{ [3-({ [tert-Butyl (dimethyl) silyl] oxy} methyl)-2-methylphenyl] sulfanyl} ethyl)-2H- 1, 2, 3, 4-tetraazole

2-1 [3- (f [tert-Butyl (dimethyl) silyl] oxy I methyl)-2-methylphenyl] sulfanyl I-I-ethanol, 1. 2 g, triphenylphosphine, 1. 6 and tetrazole, 0. 42 g, were combined in 10 mL THF to give a clear solution. The mixture was cooled to 0 °C, and 0. 94 mL diethylazodicarboxylate was added. The reaction was allowed to slowly come to rt while stirring overnight. Evaporation and purification by flash chromatography, silica gel, 9 : 1 hexane : ethyl acetate, gave 2- (2- { [3-( ( [tert-butyl (dimethyl) silyl] oxy} methyl)-2-methylphenyl] sulfanyl} ethyl)-2H-1, 2, 3, 4- tetraazole as an oil, 770 mg.

(2-Methyl-3-{[2-(2H-1, 2, 3, 4-tetraazol-2-yl) ethyl] sulfanyl} phenyl) methanol 2-(2-{[3-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-2-methylph enyl]sulfanyl}ethyl)-2H- 1, 2, 3, 4-tetraazole, 770 mg, was dissolved in 20 mL THF and treated with 3 mL 75% aq.

TBAF (tetrabutylammonium fluoride). The solution was stirred at rt overnight, concentrated, diluted with ethyl acetate, washed with 10% citric acid, then brine and dried over Na2SO4, Evaporation and purification by flash chromatography, silica gel, 1 : 1 hexane : ethyl acetate, gave (2-methyl-3-i [2- (2H-1, 2, 3, 4-tetraazol-2-yl) ethyl] sulfanyl} phenyl) methanol, 500 mg.

2 (2-{[3-(CHloromethyl)-2-methylphenyl]sulfanyl}ethyl)-2H-1, 2, 3, 4-tetraazole To a solution of 100 mg of (2-methyl-3-{[2-(2H-1, 2, 3, 4-tetraazol-2- yl) ethyl] sulfanyl} phenyl) methanol in 4 mL methylene chloride at 0 °C was added 1 mL thionyl chloride. The cold bath was removed and the mixture was stirred at rt for 1. 5 hrs.

Evaporation to dryness gave 2-(2-{[3-(chloromethyl)-2-methylphenyl] sulfanyl} ethyl)-2H- 1, 2, 3, 4-tetraazole, 105 mg.

1H-Beznimidazol-2-yl 2-methyl-3-{[2-(2H-1, 2, 3, 4-tetraazol-2-yl) ethyl] sulfanyl} benzyl sulfide 2-(2-{[3-(chloromethyl)-2-methylphenyl]sulfanyl}ethyl)-2H-1, 2, 3, 4-tetraazole, 105 mg, was dissolved in 2 mL DMF, 1 g K2CO3 and 100 mg 2-thiobenzimidazole were added and the suspension was stirred at rt overnight. The mixture was diluted with water, extracted with methylene chloride, washed with brine, dried over MgS04, and evaporated. Purification by flash chromatography, silica gel, 1. 5 : 1 ethyl acetate : hexane gave lH-benzimidazol-2-yl 2-methyl-3-{[2-(2H-1, 2, 3, 4-tetraazol-2-yl) ethyl] sulfanyl} benzyl sulfide as an off-white solid, 70 mg. Mass spec. ; M+H=383.

Scheme 12

2-Chloro-3- (hydroxymethyl) phenol 2 g 2-chloro-3-hydroxybenzaldehyde (Ginsburg, D. J. Amer. Chem. Soc. 1951 (73), 702) was dissolved in 30 mL THF/10 mL methanol/20 mL 1N KOH. 1 g NaBH4 was added.

After stirring at RT for 1. 5 hrs, the mixture was diluted with water and extracted with ether (2X). The aqueous layer was acidified with conc. HCI, and extracted with ethyl acetate (2X).

The pooled ethyl acetate layer was dried over MgS04 and evaporated to give 2-chloro- 3- (hydroxymethyl) phenol as a white solid, 2. 02 g.

[3-(2-{[tert-Butyl (dimethyl) silyl] oxy} ethoxy)-2-chlorophenyl] methanol 2-Chloro-3- (hydroxymethyl) phenol, 0. 317 g, K2CO3, 0. 264 g, and (2- bromoethoxy) (tert-butyl) dimethylsilane, 0. 429 mL, were combined in 10 mL acetonitrile.

The suspension was refluxed for 18 hrs, and an additional 0. 2 mL (2-bromoethoxy) (tert- butyl) dimethylsilane was added. After refluxing the mixture an additional 24 hrs, it was filtered, and evaporated to give a crude residue. Purification by column chromatography (8 : 2 hexane : ethyl acetate) gave [3-(2-{[tert-butyl (dimethyl) silyl] oxyXethoxy)-2- chlorophenyl] methanol as a clear oil, 0. 42 g.

{2- [3- (Bromomethyl)-2-chlorophenoxy] ethoxy} (tert-butyl) dimethylsilane N-bromosuccinimide, 0. 47 g, was dissolved in 20 mL methylene chloride and cooled to 0 °C. Dimethylsulfide, 0. 213 mL, was added slowly and the mixture was stirred for 30 minutes at 0 °C. A solution of 0. 42 g [3-(2-{[tert-butyl (dimethyl) silyl] oxylethoxy)-2- chlorophenyl] methanol in 5 mL methylene chloride was added, and the reaction was allowed to proceed at RT for 2 h. The mixture was concentrated to give crude {2- [3- (bromomethyl)-2-

chlorophenoxy] ethoxy} (tert-butyl) dimethylsilane, 0. 56 g, used in the next step without any further purification.

2-{[3-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethoxy)-2-chorob enyzl]sulfanyl}-1H- benzimidazole 0. 5 g {2- [3- (bromomethyl)-2-chlorophenoxy] ethoxy) (tert-butyl) dimethylsilane was combined with 0. 2 g benzimidazole and 4 mL 1 M NaOH in 12 mL ethanol. The solution was stirred for 2. 5 hrs, and the ethanol was evaporated to yield a slurry. Dilution with ethyl acetate, extraction with water, then sat. NaCl gave a clear solution. The solution was dried over MgSO4, and evaporated to give 2- { [3-(2- { [tert-butyl (dimethyl) silyl] oxy} ethoxy)-2- chlorobenzyl] sulfanyl}-lH-benzimidazole as a white foam, 0. 53 g.

2-{3-[(1H-Benzimidazol-2-ylsuflfnayl)methyl]-2-chloropehn oxy}-1-ethanol 0. 53 g 2-{ [3-(2-{ [tert-butyl (dimethyl) silyl] oxy} ethoxy)-2-chlorobenzyl] sulfanyl}-1H- benzimidazole was dissolved in 10 mL THF and 0. 52 mL 2. 73 M aqueous tetrabutylammonium fluoride was added. The solution was stirred for 2 hrs, diluted with water, and extracted with ethyl acetate. The organic phase was washed with sat. NaCl, dried over MgS04 and evaporated to yield 2- {3- [ (IH-benzimidazol-2-ylsulfanyl) methyl]-2- chlorophenoxy}-1-ethanol as 0. 4 g white foamy oil. <BR> <BR> <BR> <P>2- {3- [ (lH-benzimidazol-2-ylsulfanyl) methyl]-2-chlorophenoxy} ethyl phenylcarbamate 0. 4 g 2- {3-[(1H-benzimiadzol-2-ylsulfanyl)methyl]-2-chlorophenoxy}-1 -ethanol was dissolved in 5 mL chloroform and 0. 15 mL phenyl isocyante was added. The mixture was stirred at RT for 2 hrs, diluted with chloroform, washed with water, and sat. NaCI. The solution was dried over MgSO4 and evaporated to yield 2-{3-[(lH-benzimidazol-2- ylsulfanyl) methyl]-2-chlorophenoxy} ethyl phenylcarbamate as 0. 52g white solid.

Compounds 119 and 120 can be made by a similar route, but using 2-methoxy- 3- (hydroxymethyl) phenol (see Chemistry Letters, 1986, 871) in place of 2-chloro- 3- (hydroxymethyl) phenol.

Scheme 13

Methyl 2-methyl-3-[2-(2-(2-methoxyethoxy) ethoxy) ethoxy] benzoate Methyl 2-methyl-3-hydroxybenzoate [Fringuelli, F. ; Mancini, V. ; Taticchi, A.

Tetrahedron, 1969, 25, 4249] (0. 5 g) was dissolved in 10 mL MeCN, anhydrous K2CO3 (1 g) was added followed by 2- [2- (2-methoxyethoxy) ethoxy] ethyl methanesulfonate [prepared by reaction of the corresponding alcohol with methanesulfonyl chloride] (1. 09 g). The mixture was allowed to react at reflux over night, cooled, filtered, and taken to dryness. The residue was dissolved in CH2C12 and washed with diluted NaOH (aq) and brine. The organic layer was collected, dried, and evaporated furnishing 0. 56g of the title compound which was used without further purification.

2-Methyl-3- [2- (2- (2-methoxyethoxy) ethoxy) ethoxy] benzyl alcohol A solution of Methyl 2-methyl-3- [2- (2- (2-methoxyethoxy) ethoxy) ethoxy] benzoate (2. 1 mmol) in THF (10 mL) was gently added to a stirred suspension of LiAIH4 (4. 5 mmol) in 20 n-iL THF, then heated to reflux for 2 hours. The reaction was quenched with 0. 25 mL water, 0. 5 mL 2M NaOH, and 0. 25 mL water. The mixture was refluxed for another hour and then filtered to remove the solids. The filtrate was evaporated affording 0. 28 g of the title compound.

2-Methyl-3- [2- (2- (2-methoxyethoxy) ethoxy) ethoxy] benzyt chloride 2-Methyl-3- [2- (2- (2-methoxyethoxy) ethoxy) ethoxy] benzyl alcohol (1. 1 mmol) was dissolved 5 mL CH2CI2 and treated with 0. 2 mL SOCI, for 30 min at ambient temperature.

The solvent and excess reagent were evaporated leaving a quantitative yield of the title compound which was used immediately in the next step.

2- [ (3- {2- [2- (2-Methoxyethoxy) ethoxy] ethoxy}-2-methylbenzyl) sulfanyl]-lH- benzimidazole 2-mercaptobenzimidazole (0. 18 g, 1. 18 mmol), suspended in 3 mL MeOH, was treated with 2 M NaOH (1. 3 mL, 2. 6 mmol) and allowed to form a solution. 2-Methyl-3- [2- (2- (2- methoxyethoxy) ethoxy) ethoxy] benzyl chloride (0. 33 g, 1. 08 mmol) was added and reacted for 18 h at ambient temperature. The solvents were evaporated and the residue partitioned between water and CH2Cl2 (4 x 25 mL). The organic layers were combined, dried, and evaporated. Reverse phase preparative LC afforded 115 mg (26%) of the title compound.

Compound 107 can be prepared by a similar scheme by replacing 2- [2- (2- methoxyethoxy) ethoxy] ethyl methanesulfonate with 3, 6, 9, 12, 15-pentaoxahexadec-1-yl methanesulfonate.

Scheme 14

2-Methyl-3-mercapto-benzoic acid 3-Amino-2-methylbenzoic acid, 11. 3 g, was dissolved in H20 (100 mL) and conc.

HCL (15 mL) was added at 0 °C. NaN02 (5. 5g) in H20 (40 mL) was added to the above suspension over 30min. The above diazonium salt was kept at 0 °C and added slowly (over 40 min) to a solution of potassium ethylxanthogenate (14 g) while the pH continually was adjusted to 8 with Na2CO3. The mixture was stirred for 30 minutes, cooled to ambient temperature, and poured onto a mixture of 300 mL concentrated HCI and 700 mL of ice water.

The precipitate was collected, taken up in water (300 mL), and treated with NaOH (6 g) at reflux for 20 h. The mixture was poured onto a mixture of 40 mL concentrated HCl in 300 mL ice water and extracted with 3 x 500 mL CH2C12. The combined organic layers were dried and evaporated furnishing 7 g of the title compound as yellow crystals (which slowly oxidized to the corresponding disulfide upon standing)

2-Methyl-3-mercapto-methylbenzoate 2-Methyl-3-mercapto-benzoic acid (14. 7 g) was dissolved in 250 mL of MeOH and a few drops of conc. H2SO4 was added. The mixture was heated to reflux for 48 hours and then allowed to cool to ambient temperature before the bulk MeOH was evaporated. The residue was dissolved in Et, and washed with 4 x 50 mL H20 and 50 mL brine. The organic layer was collected, dried, and evaporated leaving 14. 8 g of the title compound as a viscous yellow oil (which slowly oxidized to the corresponding disulfide upon standing.

2-Methyl-3-mercapto-benzylalcohol A solution of 2-Methyl-3-mercapto-methylbenzoate (2. 0 g) in THF (5 mL) was added drop wise to a suspension of LiAIH4 (1. 32 g) in THF (100 mL) under dry and inert conditions. The mixture was heated to reflux for 2 h and then quenched with 2 mL of water, 4 mL of 2 M NaOH, and another 2 mL of water. After refluxing for another hour, solids were filtered off and washed with THF and methanol. The combined filtrates were evaporated and the residue partitioned between 2M HCl and EtOAc. The organic layer was collected, dried, and evaporated to yield 1. 9 g 2-Methyl-3-mercapto-benzylalcohol, contaminated with the corresponding disulfide as an oil. This material could be used in the next step without further purification.

2-Methyl-3- (2- (2- (2-methoxyethoxy) ethoxy) ethylthio) benzyl alcohol A mixture of 2-Methyl-3-mercapto-benzylalcohol and its disulfide (50 mg, 0. 325 mmol monomer) in dioxane/water (4/1) (1 mL) and a small amount of concentrated HCl was reacted with PPh3 (26 mg, 0. 1 mmol) for 1 h at ambient temperature in an inert atmosphere.

The solvents were removed and the residue taken up in MeCN (1 mL) and reacted with Et3N (290 mL, 2. 08 mmol) and 2- [2- (2-methoxyethoxy) ethoxy] ethyl methanesulfonate [prepared by reaction of the corresponding alcohol with methanesulfonyl chloride] (0. 30 g, 1. 24 mmol) for 3 days at ambient temperature. The solvent was evaporated and the residue partitioned between EtOAc and water. The organic layer was collected, dried, and taken to dryness. The product was purified on silica gel (pentane/Et20 ; 6/4 to 0/10) furnishing 50 mg of the title compound as a colorless oil.

2-Methyl-3- [2- (2- (2-methoxyethoxy) ethoxy) ethylthio] benzyl chloride 2-Methyl-3- (2- (2- (2-methoxyethoxy) ethoxy) ethylthio) benzyl alcohol (0. 17 mmol) was dissolved in 2 mL CH2CI2 and treated with 0. 1 mL SOC12 for 30 min at ambient temperature.

The solvent and excess reagent were evaporated leaving a quantitative yield of the title compound which was used immediately in the next step.

2-{[3-({2-[2-(2-l\/lethoxyethoxy) ethoxy] ethyl} sulfanyl)-2-methylbenzyl] sulfanyl}-lH- benzimidazole 2-Mercaptobenzimidazole (0. 33 g, 2. 16 mmol), suspended in 6 mL MeOH, was treated with 2 M NaOH (2. 6 mL) and allowed to form a solution. 2-Methyl-3- [2- (2- (2- methoxyethoxy) ethoxy) ethylthio] benzyl chloride (0. 58 g, 1. 80 mmol) was added and reacted for 18 h at ambient temperature. The solvents were evaporated and the residue partitioned between water and CH2Cl2 (4 x 25 mL). The organic layers were combined, dried, and evaporated. Reverse phase preparative LC afforded 0. 47 g of the title compound.

Compound 109 can be prepared by a similar scheme by replacing 2- [2- (2- methoxyethoxy) ethoxy] ethyl methanesulfonate with 3, 6, 9, 12, 15-pentaoxahexadec-1-yl methanesulfonate.

Compound 112 can be prepared by a similar scheme by replacing 2- [2- (2- methoxyethoxy) ethoxy] ethyl methanesulfonate with isobutyl bromide.

Compound 115 can be prepared by a similar scheme by replacing 2- [2- (2- methoxyethoxy) ethoxy] ethyl methanesulfonate with 3, 6, 9, 12, 15-pentaoxahexadec-1-yl methanesulfonate, and 2-mercaptobenzimidazole replaced with 5-carboethoxy-2- mercaptobenzimidazole.

Compound 116 can be prepared by a similar scheme by replacing 2- [2- (2- methoxyethoxy) ethoxy] ethyl methanesulfonate with 3, 6, 9, 12, 15-pentaoxahexadec-1-yl methanesulfonate, and 2-mercaptobenzimidazole replaced with 5- (propan-l-one)-2- mercaptobenzimidazole.

Compound 117 can be prepared by a similar scheme by replacing 2- [2- (2- methoxyethoxy) ethoxy] ethyl methanesulfonate with 3, 6, 9, 12, 15-pentaoxahexadec-1-yl methanesulfonate, and 2-mercaptobenzimidazole replaced with 5-amino-2- mercaptobenzimidazole.

Compound 118 can be prepared by a similar scheme by replacing 2- [2- (2- methoxyethoxy) ethoxy] ethyl methanesulfonate with 3, 6, 9, 12, 15-pentaoxahexadec-1-yl methanesulfonate, and 2-mercaptobenzimidazole replaced with 5- (hydroxymethyl)-2- mercaptobenzimidazole.

Table 1 shows which compounds can be made by each of Schemes 1 to 14 or by schemes that are similar to schemes 1 to 14, but differ in one or more reagents as will be readily apparent to the skilled person taking into account the final compound.

Table 1 SCHEME COMPOUND NO. 1 1-37 2 38-54 3 55-82 4 83, 84, 113, 114 5 104 6 103, 105, 110, 111 7 85-96 8 97, 98 99 10 100 11 101, 102 12 119-122 13 106, 107 14 108, 109, 112, 115-118

ASSAYS Microdilution assay The microdilution assay tests the anti-H. pylori activity of compounds. In this assay, MICs (Minimum Inhibitory Concentrations) were determined against four H. pylori strains, including ATCC 43504, that exhibit different susceptibilities to known antibiotics. The tests were performed in 24-well microtiter plates in which the medium, the inoculum, and the antibiotic solutions were distributed in the wells. Serial dilutions were prepared in 24-well plates containing a total volume of 2 mL medium per well. Cultures were resuspended in Brucella broth (OD600 of 0. 6) and 50 gel of these cultures were inoculated into each well to give a final concentration of 107 cells per mL (OD600 of less than 0. 03, which is the same as that of the non-inoculated control). The plates were then incubated for two days and the amount of growth recorded (OD6oo) with a plate reader (Molecular Devices, Sunnyvale, California). The plates were incubated in a controlled microaerophilic atmosphere (5% 02, 10% C02 and 85% N2) that assured optimal growth of the bacterial strains and high

reproducibility of results. The MIC was defined as the lowest concentration of antibiotic resulting in complete inhibition of growth.

MIC values <10, ug/mL are indicative of anti-Helicobacterpylori activity. Compounds according to the invention were tested in this assay and give MIC values in this range.

Selectivity Assays Standard agar dilution protocols were used to determine the effect of compounds of the invention on panels of Gram negative and Gram positive bacteria. The effects on both aerobic ["Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Fourth Edition ; Approved Standard"NCCLS Document M7-A4 Vol. 17 No. 2, January 1997] and anaerobic ["Methods for Antimicrobial Susceptibility Testing of anaerobic Bacteria-Third Edition ; Approved Standard"NCCLS Document Ml 1-A3 Vol. 13 No. 26, December 1993] organisms were measured. Compounds of the invention had no effect in these assays at concentrations of greater than ten times the corresponding MICs determined vs. Helicobacter pylori in the microdilution assay.

The invention relates in one aspect to a compound of formula I for use as a medicament. The compound can be provided as part of a pharmaceutical formulation which alo includes a pharmaceutically acceptable diluent or carrier (e. g., water). The formulation may be in the form of tablets, capsules, granules, powders, syrups, emulsions (e. g., lipid emulsions), suppositories, ointments, creams, drops, suspensions (e. g., aqueous or oily suspensions) or solutions (e. g., aqueous or oily solutions). If desired, the formulation may include one or more additional substances independently selected from stabilising agents, wetting agents, emulsfying agents, buffers, lactose, sialic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter and ethylene glycol. The formulation may contain or be co-administered with one or more known drugs selected from other clinically useful antibacterial agents.

The compound is preferably orally administered to a patient, but other routes of administration are possible, such as parenteral or rectal administration. For intravenous, subcutaneous or intra-muscular administration, the patient may receive a daily dose of 5 mgkg''to 20 mgkg-l of the compound, the compound being administered 1 to 4 times per day. The intravenous, subcutaneous and intra-muscular dose may be given by means of a bolus injection. Alternatively, the intravenous dose may be given by continuous infusion over a period of time. Alternatively, the patient may receive a daily oral dose which is

approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day. A suitable pharmaceutical formulation is one suitable for oral administration in unit dosage form, for example as a tablet or capsule, which contains between 100mg and I of the compound of the invention.

The following illustrate representative pharmaceutical dosage forms containing the compound of the invention, or a pharmaceutically acceptable salt or solvate thereof (hereafter referred to as"compound X"), for therapeutic or prophylactic use in humans.

(a) Tablet I mg/tablet Compound X. 100 Lactose Ph. Eur. 179 Croscarmellose sodium 12. 0 Polyvinylpyrrolidone 6 Magnesium stearate 3. 0

(b) Tablet II mg/tablet Compound X 50 Lactose Ph. Eur. 229 Croscarmellose sodium 12. 0 Polyvinylpyrrolidone 6 Magnesium stearate 3. 0 (c) Tablet III mg/tablet Compound X 1. 0 Lactose Ph. Eur. 92 Croscarmellose sodium 4. 0 Polyvinylpyrrolidone 2. 0 Magnesium stearate 1. 0 (d) Capsule mg/capsule Compound X 10 Lactose Ph. Eur. 389 Croscarmellose sodium 100 Magnesium stearate 1.

(e) Injection I (50 mg/mL) Compound X 5. 0% w/v Isotonic aqueous solution to 100%

Buffers, pharmaceutically acceptable co-solvents (e. g., polyethylene glycol, propylene glycol, glycerol or EtOH) or complexing agents such as hydroxy-propyl P cyclodextrin may be used to aid formulation.

Another aspect of the invention relates to the use of a compound of formula I, in the manufacture of a medicament, for the therapeutic and/or prophylactic treatment of Helicobacter pylori infection in a mammalian host, e. g. a human. By"therapeutic treatment", we mean the eradication or suppression of a pre-existing Helicobacter pylori infection in the host.

In a further aspect of the invention, there is provided a method of therapeutically treating or preventing Helicobacterpylori infection in a mammal (e. g., a human), the method comprising administering (e. g., orally) to the mammal a compound of formula I or a pharmaceutical formulation as described above. By"therapeutically treating", we mean bringing about the eradication or suppression of a pre-existing Helicobacter pylori infection in the host.