WO2001034578A1 - Compounds with anti-helicobacter pylori activity - Google Patents

Compounds with anti-helicobacter pylori activity Download PDF

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WO2001034578A1
WO2001034578A1 PCT/SE2000/002193 SE0002193W WO0134578A1 WO 2001034578 A1 WO2001034578 A1 WO 2001034578A1 SE 0002193 W SE0002193 W SE 0002193W WO 0134578 A1 WO0134578 A1 WO 0134578A1
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methyl
imidazol
ethyl
sulfanyl
alkyl
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PCT/SE2000/002193
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French (fr)
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Daniel Carcanague
Youe-Kong Shue
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Astrazeneca Ab
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Priority to AU15647/01A priority Critical patent/AU1564701A/en
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07—ORGANIC CHEMISTRY
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    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds which have anti-Helicobacter pylori activity, i.e. compounds which can be administered to a mammalian patient therapeutically to treat Helicobacter pylori infection in the patient.
  • the invention also relates to pharmaceutical formulations, use of a compound of the invention in the manufacture of a medicament, and processes for preparing the compounds. 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]sulf ⁇ nyl]-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.
  • 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.
  • the present invention provides compounds of formula I or pharmaceutically acceptable salts or solvates thereof which are active against Helicobacter pylori, but lack the benzylic sulfide linkage of omeprazole and its analogues which is necessary for rearrangement in acidic media.
  • the compounds of the invention are more stable in acid media.
  • Formula I is as follows:
  • A optionally contains N as a heteroatom
  • W is a 5- or 6-membered heterocyclic ring containing N as a heteroatom and linked by said heteroatom and optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S, the ring being optionally substituted and optionally fused to an optionally substituted 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring or heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from O, N and S;
  • X is S, SO 2 , NH, N(C ⁇ -6 alkyl), O or CH 2 ;
  • R 1 is -(CH 2 ) a -R 3 ; -((CH 2 ) b O) c -R 3 ; -(CH 2 ) d -R 3' ; -(CH 2 ) e -O-(CH 2 ) f - R 3' ; R 3 or R 3' ;
  • R 2 is C,. 6 alkyl; O(C 3 . 8 cycloalkyl); O(C 1-6 alkyl); Hal; CHal 3 , CHHal 2 , CH 2 Hal ,
  • OCHal 3 OCHal 3 , OCHHal 2 or OCH 2 Hal, wherein Hal represents halogen; NR 4 R 5 , wherein R 4 and R 5 independently represent H or C ⁇ -8 alkyl, or NR 4 R 5 represents an optionally substituted C 3-8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; H; COOR' or COR', R' representing H or C 1-6 alkyl; or CH 2 OH;
  • R 3 is H; C ⁇ -6 alkyl; optionally substituted C 3 . 8 cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted C 5- ⁇ o aromatic ring structure optionally N and S; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered mono- or bi-cyclic heterocyclic ring structure containing 1, 2, 3, 4 or 5 heteroatoms independently selected from O, N and S;
  • R 6 and R 7 either:
  • R is H; C ⁇ . 8 alkyl; optionally substituted C 3 . 8 cycloalkyl optionally fused to a benzo
  • Z (C ⁇ -8 alkyl)aryl wherein Z represents O or a bond, and the aryl is C ⁇ -io, optionally substituted and optionally fused to a C 5- ⁇ o heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S; optionally substituted C 5- ⁇ o aromatic ring structure; an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from O, N and S; (C ⁇ .
  • R 8 and R 9 either: (i) R 8 is H; . ⁇ alkyl; optionally substituted C 3 . 8 cycloalkyl optionally fused to a benzo ring; optionally substituted (C ⁇ _ 8 alkyl)aryl wherein the aryl is C 6- ⁇ o; optionally substituted (C ⁇ -8 alkyl)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 O, N and S or R represents a mono-, bi- or tri-cyclic C 3 .
  • 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.
  • a compound of formula I or a pharmaceutically acceptable salt or solvate thereof
  • A optionally contains N as a heteroatom
  • W represents a 5- or 6-membered heterocyclic ring containing N as a heteroatom and linked by said heteroatom and optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S.
  • Preferred examples of the heterocyclic ring are imidazolyl (preferably, imidazol-1-yl), tetraazolyl (preferably, l,2,3,4-tetraazol-2-yl or 1,2,3,4-tetraazol-l-yl), triaazolyl (preferably, 1,2,3-triaazol-l-yl or l,2,3-triaazol-2-yl), pyrrolyl (preferably, pyrrol- 1-yl), pyridazinyl (preferably, pyridazin-3-yl), pyrimidinyl
  • heterocyclic ring is optionally substituted.
  • NRR' represents an optionally substituted C 3-8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; and -NR'(CO)NHR", or
  • the heterocyclic ring is optionally fused to a second ring, the second ring being an optionally substituted 3-, 4-, 5-, 6-, 7- or 8- membered carbocyclic ring or heterocyclic ring containing 1 , 2 or 3 heteroatoms independently selected from O, N and S.
  • the second ring is benzo or imidazole.
  • NRR' represents an optionally substituted C .
  • R" and R'" independently represent C h alky! (preferably, Ci or C ) and j represents an integer 1, 2, 3, 4, 5 or 6, preferably, 1 or 2.
  • W represents
  • N X N ⁇ / Y V
  • Q is C-R 10 or N
  • V is C-R" or N
  • R 10 represents H; Hal; C ⁇ . 8 alkyl; C ⁇ . 8 thioalkyl; C 5 . 10 aromatic ring structure optionally
  • Z represents O, NH or S and the aryl is C 6- ⁇ 0 and optionally contains from 1, 2 or 3 heteroatoms independently selected from O, N and S; nitro;
  • 8 alkyl or the structure -NR I5 R 16 represents an optionally substituted C 3 . 8 heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S.
  • R 10 is selected from nitro; carboxylate;
  • NRR' represents an optionally substituted C 3-8 heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S ; and -NR' ' (CO)NHR' " , or -NH(CO)NHR' " , or
  • R" and R'" independently represent C ⁇ _ 6 alkyl (preferably, Ci or C ) and j represents an integer 1, 2, 3, 4, 5 or 6, preferably, 1 or 2.
  • R 1 1 is H; Hal; C ⁇ -8 alkyl; C ⁇ -8 alkylthio; C 5 . 10 aromatic ring structure optionally
  • R is H; Hal; C ⁇ . 8 alkyl; C ⁇ _ 8 alkylthio; C 5 . 10 aromatic ring structure optionally
  • R 1 ' and R 12 are such that Y and V together represent an optionally substituted unsaturated C 3-8 carbocyclic ring optionally containing 1 , 2 or 3 heteroatoms independently selected from O, N and S. Benzo or imidazole are preferred for the carbocyclic ring.
  • halogen preferably, F or Cl
  • phenyl preferably, -O(C ⁇ -8 alkyl), preferably, -O-methyl, -O-ethyl or -O(C 3-6 alkyl); -S(C ⁇ . 8 alkyl), preferably, -S-methyl, -S-ethyl or -S(C 3-6 alkyl); OH; OCHF 2 , OCH 2 F, OCF3; CHF 2 , CH 2 F,
  • R" and R'" independently represent C ⁇ -6 alkyl (preferably, Q or C?) and j represents an integer 1, 2, 3, 4, 5 or 6, preferably, 1 or 2.
  • W is G, H, I, J, K or L,
  • R, R' and R" are independently selected from H; Hal; C ⁇ -8 alkyl; C ⁇ -8 thioalkyl; C 5- ⁇ o aromatic ring structure optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; -Z -aryl, - Z -(C ⁇ -8 alkyl) or Z -(C 3-8 cycloalkyl), wherein Z represents O,
  • aryl is C 6 .
  • 0 and optionally contains from 1, 2 or 3 heteroatoms independently selected from O, N and S; nitro; C ⁇ . 8 alkylthio; -C( O)OR 22 wherein R 22 represents H or
  • Ci_ 8 alkyl; or -C( O)NR 23 R 24 wherein either R 23 and R 24 independently represent H or C ⁇ . 8 alkyl or the structure NR 23 R 24 represents an optionally substituted C . 8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S.
  • R, R' and R" are independently selected from nitro; carboxylate;
  • -S( O) 2 (C ⁇ -8 alkyl), the alkyl preferably being methyl, ethyl or C . 6 alkyl; halogen (preferably, F or Cl); phenyl; -O(C,. 8 alkyl), preferably, -O-methyl, -O-ethyl or -O(C 3-6 alkyl); -S(d -8 alkyl), preferably, -S-methyl, -S-ethyl or -S(C 3 . 6 alkyl); OH; OCHF 2 , OCH 2 F, OCF 3 ; CHF 2 , CH 2 F,
  • R* and R** independently represent C ⁇ _ 6 alkyl (preferably, Ci or C ) and j represents an integer 1, 2, 3, 4, 5 or 6, preferably, 1 or 2.
  • I, J and L are optionally fused to an optionally substituted unsaturated C 3-8 carbocyclic ring optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S. Benzo is preferred for the carbocyclic ring.
  • X represents S; SO2; NH; O or CH2.
  • X represents N(C ⁇ . 6 alkyl), more preferably, N-methyl or N(C . 4 alkyl).
  • R 1 represents -(CH 2 ) a - 3 ; -((CH 2 ) b O) c -R 3 ; -(CH 2 ) d -R 3' ; -(CH 2 )e-O-(CH 2 )f-R 3' ; R 3 or
  • R 1 represents -(CH 2 ) a -CH 3 or -((CH 2 )bO) c -CH 3 . More preferably, R 1 is
  • R " represents C ⁇ _ 6 alkyl (preferably, C 2 . 4 alkyl, and most preferably, methyl);
  • Hal represents halogen (preferably, F); NR 4 R 5 , wherein R 4 and R 5 independently represent H or C ⁇ . 8 alkyl (preferably, methyl or C . 6 alkyl or C -4 alkyl) , or NR 4 R 5 represents an optionally substituted C 3-8 , preferably, C 3-6 , heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and
  • halogen e.g., F, Cl or Br
  • R 3 represents H; C ⁇ _ 6 alkyl; optionally substituted C . 8 , preferably, C . 6 , cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted C 5-) o aromatic ring structure (e.g., phenyl) optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered mono- or bi-cyclic heterocyclic ring structure containing 1, 2, 3, 4 or 5 heteroatoms independently selected from O, N and S.
  • the cycloalkyl contains heteroatoms and is selected from morpholinyl (4-morpholinyl), piperazinyl (preferably, 1 -piperazinyl), tetrazolyl (preferably, l,2,3,4-tetrazol-2-yl), imidazolyl (e.g., 1-imidazolyl) and triazolyl (e.g., l-(l,2,4-triazolyl)).
  • Preferred examples of the C ⁇ -6 alkyl are preferably, C . 4 alkyl, methyl and butyl (e.g., isobutyl).
  • heterocyclic ring structure are imidazopyridazine (more preferably, 6-imidazo[l,2-b]pyridazine) and imidazolyl (more preferably, 1-imidazolyl).
  • imidazopyridazine more preferably, 6-imidazo[l,2-b]pyridazine
  • imidazolyl more preferably, 1-imidazolyl
  • at least one (e.g., one, two or three) substituents may be provided independently selected from C ⁇ . 6 alkyl (preferably, C 2-4 alkyl, more preferably, methyl) and nitro.
  • Z represents O, 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,
  • the heterocyclic ring structure is selected from imidazopyridazine (more preferably, 6-imidazo[l,2- ⁇ ]pyridazine) and imidazolyl (more preferably, 1-imidazolyl).
  • imidazopyridazine more preferably, 6-imidazo[l,2- ⁇ ]pyridazine
  • imidazolyl more preferably, 1-imidazolyl
  • at least one (e.g., one, two or three) substituents may be provided independently selected from C ⁇ _ 6 alkyl (preferably, C 2 . alkyl, more preferably, methyl) and nitro.
  • R 6 and R 7 either: (i) R 6 is H; C ⁇ . 8 alkyl; optionally substituted C 3 . 8 cycloalkyl optionally fused to a benzo
  • . 8 alkyl)aryl wherein Z represents O or a bond, and the aryl is C 6 .
  • R 7 is H; C ⁇ -8 alkyl; optionally substituted C 3-8 cycloalkyl optionally fused to a benzo ring; (C ⁇ _ 8 alkyl)aryl wherein the aryl is C 6- ⁇ o and optionally substituted; optionally substituted C ⁇ -ioaryl; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring structure containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or (ii) the structure -NR R 7 represents a C -8 heterocyclic ring optionally containing from 1, 2 or 3 further heteroatoms independently selected from O, N and S and optionally fused to a C 6 . ⁇ o ring structure, -NR 6 R 7 being optionally substituted.
  • the aryl is phenyl.
  • Z (C ⁇ -8 alkyl)aryl represents Z (C ⁇ . 8 alkyl)benzodioxol.
  • R 6 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-l,2,3,6-tetrahydro- purin-7-yl), benzofuranyl
  • furyl e.g
  • 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-l,2,3,6-tetrahydro-purine), benzofuran, pyridine, quinoline, pyrrolidine/piperazine, imidazopyridazine (e.g., imidazo[l,2-6]pyridazine) and tetrazole (e.g., 1,2,3,4-tetrazole).
  • a heterocyclic ring structure selected from furan, tetrahydrofuran, thiophene, morpholine, isoxazole, dioxoimidazolidine (e.
  • the C . 8 cycloalkyl is selected from cyclopropyl C 4-6 cycloalkyl and cyclopentyl.
  • the C . 8 heterocyclic ring is preferably, selected from piperidinyl (e.g., 1 -piperidinyl), piperazinyl (e.g., 1 -piperazinyl), morpholinyl (e.g., 4-morpholinyl) and tetrazolyl (e.g., l,2,3,4-tetrazol-2-yl).
  • the C 6- ⁇ 0 ring structure is selected from cyclohexyl and a benzo ring.
  • at least one(e.g., one, two or three) substituents may be provided independently selected from C ⁇ -6 alkyl (preferably,
  • R 8 and R 9 either: (i) R 8 is H; Q. ⁇ alkyl; optionally substituted C 3-8 cycloalkyl optionally fused to a benzo ring; optionally substituted (Cj. 8 alkyl)aryl wherein the aryl is C 6- ⁇ o . optionally substituted (C t .
  • C ⁇ - ⁇ 2 alkyl is selected from C ⁇ . 8 alkyl, C 2 . 6 alkyl, methyl, propyl (e.g., isopropyl), butyl (e.g., isobutyl or tert-butyl), pentyl and adamantyl (e.g., 1-adamantyl).
  • alkyl is selected from C 2-6 alkyl, methyl, propyl (e.g., isopropyl), butyl (e.g., isobutyl or tert-butyl) and pentyl.
  • propyl e.g., isopropyl
  • butyl e.g., isobutyl or tert-butyl
  • pentyl e.g., where C 6- ⁇ o aryl is mentioned, the aryl is phenyl.
  • Z 2 (C ⁇ _ 8 alkyl)aryl represents Z 2 (C ⁇ -8 alkyl)benzodioxol.
  • 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-diox 0-1,2,3,6- tetrahydro-purin-7-yl)
  • benzofuranyl e.g., 2-benzofuranyl
  • the C 3-8 cycloalkyl is selected from cyclopropyl C 4-6 cycloalkyl and cyclopentyl.
  • the C 3 . 8 heterocyclic ring is preferably, selected from piperidinyl (e.g., 1 -piperidinyl), piperazinyl (e.g., 1 -piperazinyl), morpholinyl (e.g., 4-morpholinyl) and tetrazolyl (e.g., l,2,3,4-tetrazol-2-yl).
  • the C 6 . ⁇ o ring structure is selected from cyclohexyl and a benzo ring.
  • at least one (e.g., one, two or three) substituents may be provided independently selected from C ⁇ . 6 alkyl (preferably, C 2 .
  • 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); each c independently represents 1, 2, 3, 4 or 5 (preferably, 1 or 2); d represents 1, 2, 3, 4 or 5 (preferably, 1 or 2); e 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 1, 2, 3, 4 or 5 (preferably, 1).
  • an alkyl substituent may be linear or branched. Where optional substitution of aryl or an unsaturated C 3-8 carbocyclic ring is mentioned, the substituent can be selected from Cj -6 alkyl (preferably, C 2- alkyl, and most preferably, methyl); O(C 3-8 cycloalkyl), preferably, O-cyclopropyl, or O-cyclobutyl or O- cyclopentyl; O(C 1-6 alkyl), preferably, Omethyl or O(C 2- alkyl); Hal, preferably, Cl or F;
  • Hal represents halogen (preferably, F); NRR', wherein R and R' independently represent H or C 1-8 alkyl (preferably, methyl or C 2 . 6 alkyl or C -4 alkyl) , or NRR' represents an optionally substituted C 3-8 , preferably, C 3-6 , heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; H; COOR" or COR", R" representing H or C ⁇ -6 alkyl
  • At least one (e.g., one, two or three) substituents may be provided independently selected from C ⁇ -6 alkyl (preferably, C - alkyl, more preferably, methyl); phenyl;
  • OCF 3 ; OCHF 2 ; -O(C ⁇ -8 alkyl), preferably, -O-methyl, -O-ethyl or -O(C 3-6 alkyl);
  • R 1 is -(CH 2 ) a -R 3 ; -((CH 2 ) b O) c -R 3 ; -(CH 2 ) d -R 3' or
  • R 2 is C 1-6 alkyl; O(C 3-8 cycloalkyl); O(C,. 6 alkyl); Hal; CHal 3 , CHHab,
  • R 4 and R 5 independently represent H or C ⁇ . 8 alkyl; or CH2OH; R 3 is optionally substituted
  • C 3-8 cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted Cs-io aromatic ring structure optionally N and S; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered mono- or bi-cyclic heterocyclic ring structure containing 1, 2, 3, 4 or 5 heteroatoms independently selected from O, 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;
  • R 3 is -Z-M wherein Z represents O, 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 O, 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
  • Preferred compounds are selected from compounds ⁇ , in and IV
  • Z represents S; preferably, d represents 3.
  • 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 or p- toluenesulfonate, or an alkali metal salt such as a sodium or potassium salt.
  • an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p- toluenesulfonate
  • 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
  • L 1 is a leaving group and B represents an optionally substituted 5- or 6-membered heterocyclic ring that is optionally fused to a 3, 4, 5, 6, 7 or 8 membered carbocyclic ring or heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from O, ⁇ and S; or (b) reacting compound VII with H-R'
  • L 2 is a leaving group
  • R' represents (CH2)d or (CH2) e -O-(CH2)f
  • R" represents
  • certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups.
  • 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.
  • R 1 represents -(CH2)d-NHR and R is H or an alkyl group, a suitable amine protecting group can be used during the reaction.
  • L 5 is preferably, sulfonate ester or halogen (more preferably, chlorine).
  • the compounds of the present invention have an ⁇ -Helicobacter pylori activity, ie 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 advantage of compounds of the invention is that they are particularly selective for Helicobacter pylori.
  • the resultant bright yellow suspension was diluted to 100 mL with ethyl acetate, washed with 100 mL water, 100 mL brine, dried, evaporated, and purified by flash chromatography, silica gel, 30 - 60 % ethyl acetate Hexane. Crystallization from ethyl acetate / Hexane gave
  • 2-thiomethylimidazole 0.3 g K2CO3, and 2 mL DMF were combined and stirred at rt for 4 days, diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and evaporated.
  • 2-Methyl-3-(hydroxymethyl)aniline 5 g was combined with 100 mL THF, 50 mL acetone, 10 mL water, and 2.2 g NaOH .
  • Di-t-butyl-dicarbonate 9.6 g was added, and the mixture was warmed to 50 °C for 3 h, 3g additional di-t-butyl-dicarbonate was added, followed by 0.72 g NaOH, and 5 mL water.
  • the mixture was kept at 50 °C for 2 h more, diluted with water, and extracted with EtOAc, the org layer was washed with 1M HCI, and dried over MgSO4. Evaporation gave a slurry, hexane was added to precipitate further solids.
  • [3-(2-Aminoethoxy)-2-methylphenyl]methanol 1.04 g, was combined with 1-ethyl- 3-methyl-lH-pyrazole-5-carboxylic acid, 0.88 g, and dissolved in 40 mL methylene chloride.
  • EDAC- ⁇ Cl, 1.59 g, triethylamine, 2 mL and catalytic 4-dimethylaminopyridine were added and the resulting suspension was stirred at RT for 18 h.
  • the mixture was diluted with ethyl acetate, washed with water, IN ⁇ C1, sat. Na ⁇ C03, and sat. NaCl, then dried over MgSO4.
  • Methyl l-[3-(2- ⁇ [(l-ethyI-3-methyI-l_H-pyrazol-5-yl)carbonyl]amino ⁇ ethoxy)- 2-methylbenzyl]-l_H-imidazole-4-carboxylate 1 g N- ⁇ 2-[3-(chloromethyl)-2-methylphenoxyJethyl ⁇ -l-ethyl-3-methyl-lH-pyrazole-5- carboxamide was dissolved in 5 mL DMF. 0.5 g methyl lH-imidazole-4-carboxylate, and 2 g
  • Compound 136 can be prepared by a similar scheme by replacing (3-methyl-lH- pyrazol-5-yl)(4-mo ⁇ holinyl)methanone in place of l(2H)-phthalazinone.
  • Scheme 19
  • 3-nitroimidazo[l,2-b]pyridazine prepared by reacting the sodium salt of 1,3-propane-diol with 6-chloro-3-nitroimidazo[l,2-b]pyridazine: Kobe, J.; Stanovnik, B.; Tisler, Miha. Tetrahedron (1968), 24(1), 239 , then treating the product with triphenylphosphine and N- bromosuccinimide], and 1 g K2CO3 were combined in 6 mL DMF. The suspension was warmed to 70 °C for 2.5 h. The mixture was filtered, evaporated, and purified by column chromatography (Si ⁇ 2, 1: 1 ethyl acetate / hexane) to give (2-methyl-3- ⁇ 3-[(3-nitroimidazo-
  • Table 1 shows which compounds can be made by each of Schemes 1 to 29 or by schemes that are similar to schemes 1 to 29, but differ in one or more reagents as will be readily apparent to the skilled person taking into account the final compound.
  • the microdilution assay tests the anti-H. pylori activity of compounds.
  • MICs Minimum Inhibitory Concentrations
  • MIC values ⁇ 10 ⁇ g/mL are indicative of an ⁇ -Helicobacter pylori activity.
  • Compounds according to the invention were tested in this assay and give MIC values in this range.
  • 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 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 aslo 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).
  • 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 fomulation 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.
  • routes of administration such as parenteral or rectal administration.
  • the patient may receive a daily dose of 5 mgkg "
  • the intravenous, subcutaneous and intramuscular 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 100 mg and 1 g 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)
  • Buffers e.g., pharmaceutically acceptable cosolvents (e.g., polyethylene glycol, propylene glycol, glycerol or EtOH) or complexing agents such as hydroxy-propyl ⁇ cyclodextrin may be used to aid formulation.
  • pharmaceutically acceptable cosolvents e.g., polyethylene glycol, propylene glycol, glycerol or EtOH
  • complexing agents such as hydroxy-propyl ⁇ 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.
  • therapeutic treatment we mean the eradication or suppression of a pre-existing Helicobacter pylori infection in the host.
  • a method of therapeutically treating or preventing Helicobacter pylori infection in a mammal comprising administering (e.g., orally) to the mammal a compound of formula I or a pharmaceutical formulation as described above.
  • a mammal e.g., a human
  • administering e.g., orally
  • a compound of formula I or a pharmaceutical formulation as described above.

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Abstract

The invention relates to compounds of formula (I) which have anti-Helicobacter pylori activity.

Description

Compounds with anti-Helicobacter pylori activity
The present invention relates to compounds which have anti-Helicobacter pylori activity, i.e. compounds which can be administered to a mammalian patient therapeutically to treat Helicobacter pylori infection in the patient. The invention also relates to pharmaceutical formulations, use of a compound of the invention in the manufacture of a medicament, and processes for preparing the compounds. 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]sulfιnyl]-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. Summary 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 benzylic sulfide linkage 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:
Figure imgf000003_0001
wherein:
A optionally contains N as a heteroatom;
W is a 5- or 6-membered heterocyclic ring containing N as a heteroatom and linked by said heteroatom and optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S, the ring being optionally substituted and optionally fused to an optionally substituted 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring or heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from O, N and S;
X is S, SO2, NH, N(Cι-6alkyl), O or CH2;
R1 is -(CH2)a-R3; -((CH2)bO)c-R3; -(CH2)d-R3'; -(CH2)e-O-(CH2)f- R3'; R3 or R3';
R2 is C,.6alkyl; O(C3.8 cycloalkyl); O(C1-6alkyl); Hal; CHal3, CHHal2, CH2Hal ,
OCHal3, OCHHal2 or OCH2Hal, wherein Hal represents halogen; NR4R5, wherein R4 and R5 independently represent H or Cι-8alkyl, or NR4R5 represents an optionally substituted C3-8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; H; COOR' or COR', R' representing H or C1-6alkyl; or CH2OH;
R3 is H; Cι-6alkyl; optionally substituted C3.8 cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted C5-ιo aromatic ring structure optionally N and S; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered mono- or bi-cyclic heterocyclic ring structure containing 1, 2, 3, 4 or 5 heteroatoms independently selected from O, N and S;
R3 is -Z-M wherein Z represents O, 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 O, N and S, or an optionally substituted C5_ιo aromatic ring structure optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or -Z-M represents -C(=O)NR6R7, -NR6R7, -OC(=O)NR8R9, -NC(=O)NR8R9, -NC(=O)R8 or -NC(=O)OR8; For R6 and R7, either:
(i) R is H; Cι.8alkyl; optionally substituted C3.8cycloalkyl optionally fused to a benzo
2 2 ring; Z (Cι-8alkyl)aryl, wherein Z represents O or a bond, and the aryl is Cβ-io, optionally substituted and optionally fused to a C5-ιo heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S; optionally substituted C5-ιo aromatic ring structure; an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from O, N and S; (Cι.8alkyl)-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 O, N and S; optionally substituted -C(=O)O(Cι-8alkyl); optionally substituted -C(=O)O-phenyl; optionally substituted -C(=O)(Cι-8alkyl); optionally substituted -C(=O)- phenyl; or -NC(=O)R8 and R7 is H; Cι_8alkyl; optionally substituted C -8cycloalkyl optionally fused to a benzo ring; (Cι-8alkyl)aryl wherein the aryl is C6-10 and optionally substituted; optionally substituted Cs-io aromatic ring structure; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring structure containing 1 , 2 or 3 heteroatoms independently selected from O, N and S; or (ii) the structure -NR6R7 represents a C3-8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S and optionally fused to a C6-ιo ring structure, -NR6R7 being optionally substituted;
For R8 and R9, either: (i) R8 is H; .^alkyl; optionally substituted C3.8 cycloalkyl optionally fused to a benzo ring; optionally substituted (Cι_8alkyl)aryl wherein the aryl is C6-ιo; optionally substituted (Cι-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 O, N and S or R represents a mono-, bi- or tri-cyclic C3.)3 cycloalkyl; optionally substituted C5-ι0 aromatic ring structure; 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 O, N and S; or -C(=O)-O-Ar, wherein Ar represents optionally substituted C5-ιo aromatic ring structure; and R9 is H; or (n) the structure -NR R represents a C -8 heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S, -NR8R9 being optionally substituted; a represents 1, 2, 3, 4 or 5; each b independently represents 1 , 2, 3, 4 or 5; each c independently represents 1, 2, 3, 4 or 5; d represents 1, 2, 3, 4 or 5; e represents 1, 2, 3, 4 or 5; f represents 1, 2, 3, 4 or 5; and g represents 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
Figure imgf000005_0001
wherein:
A optionally contains N as a heteroatom; W represents a 5- or 6-membered heterocyclic ring containing N as a heteroatom and linked by said heteroatom and optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S. Preferred examples of the heterocyclic ring are imidazolyl (preferably, imidazol-1-yl), tetraazolyl (preferably, l,2,3,4-tetraazol-2-yl or 1,2,3,4-tetraazol-l-yl), triaazolyl (preferably, 1,2,3-triaazol-l-yl or l,2,3-triaazol-2-yl), pyrrolyl (preferably, pyrrol- 1-yl), pyridazinyl (preferably, pyridazin-3-yl), pyrimidinyl
(preferably, pyrimidin-2-yl) and piperazinyl (preferably, piperazin-1-yl). The heterocyclic ring is optionally substituted. 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; -S(=O)-(Cι.8alkyl), the alkyl preferably being methyl, ethyl or C3-6alkyl; -S(=O)-(=O)-(Cι-8alkyl), the alkyl preferably being methyl, ethyl or C3-6alkyl; halogen (preferably, F or Cl); phenyl; -O(Cι-8alkyl), preferably, -O-methyl, -O-ethyl or -O(C3-6alkyl); -S(C,.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
C|.8alkyl (preferably, methyl, ethyl, propyl, isopropyl, or C .6alkyl), or the structure NRR' represents an optionally substituted C3-8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; and -NR'(CO)NHR", or
-NH(CO)NHR", or -(CH2)i-(CO)NHR", or -(CH2)j-(CO)R", or -NR'(SO2)R", or -
NH(SO2)R", wherein R' and R" independently represent Cι_6alkyl (preferably, Ci or C ) and i represents an integer 1, 2, 3, 4, 5 or 6, preferably, 1 or 2. The heterocyclic ring is optionally fused to a second ring, the second ring being an optionally substituted 3-, 4-, 5-, 6-, 7- or 8- membered carbocyclic ring or heterocyclic ring containing 1 , 2 or 3 heteroatoms independently selected from O, N and S. Preferably, the second ring is benzo or imidazole. For optional substitution of the second ring, at least one (e.g., one, two or three) substituents may be provided independently selected from nitro; carboxylate; -COOH; -S(=O)(Cι-8alkyl), the alkyl preferably being methyl, ethyl or C3.6alkyl; -S(=O) (Cι-8alkyl), the alkyl preferably being methyl, ethyl or C3-6alkyl; halogen (preferably, F or Cl); phenyl; -O(Cι-8alkyl), preferably, -O-methyl, -O-ethyl or -O(C3.6alkyl); -S(Cι-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 Cι-8alkyl (preferably, methyl, ethyl, propyl, isopropyl, or C -6alkyl), or the structure NRR' represents an optionally substituted C .8 heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S; and -NR"C(=O)NHR"\ or -NH(CO)NHR"\ or -(CH2)j-(CO)NHR"\ or
-(CH2)j-(CO)R"\ or -NR"(SO2)R"\ or -NH(SO2)R'", wherein R" and R'" independently represent Chalky! (preferably, Ci or C ) and j represents an integer 1, 2, 3, 4, 5 or 6, preferably, 1 or 2.
In one preferred embodiment, W represents
N XN \ / Y=V wherein: Q is C-R10 or N; V is C-R" or N; Y is C-R12 or N with the proviso that Q = V = Y = N is excluded; R10 represents H; Hal; Cι.8alkyl; Cι.8thioalkyl; C5.10 aromatic ring structure optionally
2 containing 1, 2 or 3 heteroatoms independently selected from O, N and S; -Z aryl,
2 7 2
-Z (Cι.8alkyl) or Z (C3.8cycloalkyl),wherein Z represents O, NH or S and the aryl is C6-ι0 and optionally contains from 1, 2 or 3 heteroatoms independently selected from O, N and S; nitro;
-C(=O)OR13 wherein R13 represents H or C,.8alkyl; or -C(=O)NR14R15 wherein either R14 and R15 independently represent H or C].8alkyl or the structure -NRI5R16 represents an optionally substituted C3.8heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S. Preferably, R10 is selected from nitro; carboxylate;
-COOH; -S(=O)(C1-8alkyl), the alkyl preferably being methyl, ethyl or C3-6alkyl;
-S(=O)2(Cι.8alkyl), the alkyl preferably being methyl, ethyl or C3-6alkyl; halogen (preferably, F or Cl); phenyl; -O(Cι-8alkyl), preferably, -O-methyl, -O-ethyl or -O(C3.6alkyl); -S(Cι.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 Cι-8alkyl
(preferably, methyl, ethyl, propyl, isopropyl, or C2.6alkyl), or the structure NRR' represents an optionally substituted C3-8 heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S ; and -NR' ' (CO)NHR' " , or -NH(CO)NHR' " , or
-(CH2)j-(CO)NHR"\ or -(CH2)j-(CO)R"\ or -NR"(SO2)R"\ or -NH(SO2)R"\ wherein
R" and R'" independently represent Cι_6alkyl (preferably, Ci or C ) and j represents an integer 1, 2, 3, 4, 5 or 6, preferably, 1 or 2. For R" and R12, either: (i) R1 1 is H; Hal; Cι-8alkyl; Cι-8alkylthio; C5.10 aromatic ring structure optionally
3 containing 1, 2 or 3 heteroatoms independently selected from O, N and S; -Z aryl,
3 3 3
-Z (Cι_8alkyl) or Z (C3-8cycloalkyl),wherein Z represents O, NH or S and the aryl is C6-ιo and optionally contains from 1, 2 or 3 heteroatoms independently selected from O, N and S; nitro; -C(=O)O-R16 wherein R16 represents H or C|.8alkyl; or -C(=O)NRI7R18 wherein either R17 and R18 independently represent H or Cι_8alkyl or the structure -NR17R18 represents an optionally substituted C3-8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; and
R is H; Hal; Cι.8alkyl; Cι_8alkylthio; C5.10 aromatic ring structure optionally
4 containing 1, 2 or 3 heteroatoms independently selected from O, N and S; -Z -aryl,
4 4 4 -Z -(Ci.8alkyl) or Z -(C .8cycloalkyl),wherein Z represents O, NH or S and the aryl is C6.)0 and optionally contains from 1, 2 or 3 heteroatoms independently selected from O, N and S; nitro; -C(=O)OR19 wherein R19 represents H or d.8alkyl; or -C(=O)NR20R21 wherein either R20 and R21 independently represent H or Cι-8alkyl or the structure -NR20R21 represents an optionally substituted C3-8 heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S; or
(ii) R1 ' and R12 are such that Y and V together represent an optionally substituted unsaturated C3-8carbocyclic ring optionally containing 1 , 2 or 3 heteroatoms independently selected from O, N and S. Benzo or imidazole are preferred for the carbocyclic ring. For option (i), R1 1 and R1 " are preferably, independently selected from nitro; carboxylate; -COOH; -S(=O)-(C].8alkyl), the alkyl preferably being methyl, ethyl or C3-6alkyl; -S(=O)2(Cι.8alkyl), the alkyl preferably being methyl, ethyl or C3.6alkyl; halogen (preferably, F or Cl); phenyl; -O(Cι-8alkyl), preferably, -O-methyl, -O-ethyl or -O(C3-6alkyl); -S(Cι.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 Cι-8alkyl (preferably, methyl, ethyl, propyl, isopropyl, or C2.6alkyl), or the structure NR R' represents an optionally substituted C3-8 heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S; and -NR"(CO)NHR'", or -NH(CO)NHR"\ or -
(CH2)j-(CO)NHR"\ or -(CH2)j-(CO)R"\ or -NR"(SO2)R'", or -NH(SO2)R'", wherein R" and R'" independently represent Cι-6alkyl (preferably, Q or C?) and j represents an integer 1, 2, 3, 4, 5 or 6, preferably, 1 or 2. In another preferred embodiment, W is G, H, I, J, K or L,
Figure imgf000009_0001
H
Figure imgf000009_0002
wherein R, R' and R" are independently selected from H; Hal; Cι-8alkyl; Cι-8 thioalkyl; C5-ιo aromatic ring structure optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; -Z -aryl, - Z -(Cι-8alkyl) or Z -(C3-8 cycloalkyl), wherein Z represents O,
NH or S and the aryl is C6.|0 and optionally contains from 1, 2 or 3 heteroatoms independently selected from O, N and S; nitro; Cι.8alkylthio; -C(=O)OR22 wherein R22 represents H or
Ci_8alkyl; or -C(=O)NR23R24 wherein either R23 and R24 independently represent H or Cι.8alkyl or the structure NR23R24 represents an optionally substituted C .8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S.
Preferably, one or more of R, R' and R" are independently selected from nitro; carboxylate;
-COOH; -S(=O)(Cι-8alkyl), the alkyl preferably being methyl, ethyl or C3.6alkyl;
-S(=O)2(Cι-8alkyl), the alkyl preferably being methyl, ethyl or C .6alkyl; halogen (preferably, F or Cl); phenyl; -O(C,.8alkyl), preferably, -O-methyl, -O-ethyl or -O(C3-6alkyl); -S(d-8alkyl), preferably, -S-methyl, -S-ethyl or -S(C3.6alkyl); OH; OCHF2, OCH2F, OCF3; CHF2, CH2F,
1 2 1 7
CF3; -C(=O)NR R , wherein R and R" are independently selected from H and Cι.8alkyl
1 2 (preferably, methyl, ethyl, propyl, isopropyl, or C2-6alkyl), or the structure NR R represents an optionally substituted C3.8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; and -NR*C(=O)NHR**, or -NHC(=O)NHR**, or -(CH2)j-(CO)NHR**, or -(CH2)j-C(=O)R**, or -NR*(SO2)R**, or
-NH(SO )R**, wherein R* and R** independently represent Cι_6alkyl (preferably, Ci or C ) and j represents an integer 1, 2, 3, 4, 5 or 6, preferably, 1 or 2. I, J and L are optionally fused to an optionally substituted unsaturated C3-8carbocyclic ring optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S. Benzo is preferred for the carbocyclic ring.
X represents S; SO2; NH; O or CH2. Alternatively, X represents N(Cι.6alkyl), more preferably, N-methyl or N(C .4alkyl). R1 represents -(CH2)a- 3; -((CH2)bO)c-R3; -(CH2)d-R3'; -(CH2)e-O-(CH2)f-R3'; R3 or
R3'. Preferably, R1 represents -(CH2)a-CH3 or -((CH2)bO)c-CH3. More preferably, R1 is
selected from -iso-Bu; -(CH2CH2O)3CH3; -(CH2CH2)-4-morpholinyl; -(CH2CH2O)5CH3;
.(CH2CH2)-l-(2-methyl-5-nitro-imidazolyl); -(CH2CH2)-l-(l,2,4-triazolyl); and -(CH2CH2)-
OC(=O)NH-Ph. R" represents Cι_6alkyl (preferably, C2.4alkyl, and most preferably, methyl);
O(C3-8cycloalkyl), preferably, O-cyclopropyl, or O-cyclobutyl or O-cyclopentyl; O(Cι-6alkyl), preferably, O-methyl or O(C2.4alkyl); Hal, preferably, Cl or F; CHal3, CHHal2, CH2Hal,
OCHal3, OCHHal2 or OCH2Hal, wherein Hal represents halogen (preferably, F); NR4R5, wherein R4 and R5 independently represent H or Cι.8alkyl (preferably, methyl or C .6alkyl or C -4alkyl) , or NR4R5 represents an optionally substituted C3-8, preferably, C3-6, heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and
S; H; COOR' or COR', R' representing H or Cι.6alkyl (preferably, methyl, ethyl); or CH2OH.
For optional substitution of the heterocyclic ring represented by NR4R5, at least one (e.g., one, two or three) substituents may be provided independently selected from C1- alkyl (preferably, C2-4 alkyl, more preferably, methyl); phenyl; OCF3; OCHF2; -O(C1-8alkyl), 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)(C,-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 Cι-6alkyl (preferably, C2.4 alkyl, more preferably, methyl, most preferably, R=R'=methyl); and nitro.
R3 represents H; Cι_6alkyl; optionally substituted C .8, preferably, C .6, cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted C5-)o aromatic ring structure (e.g., phenyl) optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered mono- or bi-cyclic heterocyclic ring structure containing 1, 2, 3, 4 or 5 heteroatoms independently selected from O, N and S. Preferably, the cycloalkyl contains heteroatoms and is selected from morpholinyl (4-morpholinyl), piperazinyl (preferably, 1 -piperazinyl), tetrazolyl (preferably, l,2,3,4-tetrazol-2-yl), imidazolyl (e.g., 1-imidazolyl) and triazolyl (e.g., l-(l,2,4-triazolyl)). Preferred examples of the Cι-6alkyl are preferably, C .4alkyl, methyl and butyl (e.g., isobutyl). Preferred examples of the heterocyclic ring structure are imidazopyridazine (more preferably, 6-imidazo[l,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 Cι.6alkyl (preferably, C2-4alkyl, more preferably, methyl) and nitro.
R3 represents -Z-M wherein Z represents O, 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 O, N and S, or an optionally substituted C5-10 aromatic ring structure (e.g., phenyl) optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or -Z-M represents -C(=O)NR6R7, -NR6R7, -OC(=O)NR8R9, -NC(=O)NR8R9, -NC(=O)R8 or -NC(=O)OR8.
Preferably, the heterocyclic ring structure is selected from imidazopyridazine (more preferably, 6-imidazo[l,2-ό]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 Cι_6alkyl (preferably, C2. alkyl, more preferably, methyl) and nitro.
Most preferably, R3 is selected from -4-morpholinyl; -l-(2-methyl-5-nitro-imidazolyl); -l-(l,2,4-triazolyl); and -OC(=O)NH-Ph. For R6 and R7, either: (i) R6 is H; Cι.8alkyl; optionally substituted C3.8cycloalkyl optionally fused to a benzo
2 2 ring; Z (C|.8alkyl)aryl, wherein Z represents O or a bond, and the aryl is C6.|0, optionally substituted and optionally fused to a Cs,ιo heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S; optionally substituted C6-ι0aryl; an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from O, N and S; (Cι-8alkyl)-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 O, N and S; optionally substituted -C(=O)O(Cι-8alkyl); optionally substituted -C(=O)O-phenyl; optionally substituted -C(=O)(Cι.8alkyl); optionally substituted -C(=O)phenyl; or -NC(=O)R8 and
R7 is H; Cι-8alkyl; optionally substituted C3-8cycloalkyl optionally fused to a benzo ring; (Cι_8alkyl)aryl wherein the aryl is C6-ιo and optionally substituted; optionally substituted Cό-ioaryl; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring structure containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or (ii) the structure -NR R7 represents a C -8 heterocyclic ring optionally containing from 1, 2 or 3 further heteroatoms independently selected from O, N and S and optionally fused to a C6.ιo ring structure, -NR6R7 being optionally substituted.
For R6 in option (i), preferably, the Cι_8alkyl or the Cι-8alkyl in Z~(Cι.8alkyl)aryl or the C,.8alkyl in (Cι-8alkyl)-R or the C1-8alkyl in -C(=O)O(C,.8alkyl) or the Cι-8alkyl in -C(=O)(Cι-8alkyl) is selected from C2.6alkyl, methyl, ethyl, propyl (e.g., isopropyl), butyl (e.g., isobutyl or tert-butyl) and pentyl. Preferably, where C .i0aryl is mentioned, the aryl is phenyl.
Preferably, Z (Cι-8alkyl)aryl represents Z (Cι.8alkyl)benzodioxol. Preferably, for R6, 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-l,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[l,2-b]pyridazinyl) and tetrazolyl (e.g., tetrazol-2-yl, 1,2,3,4-
2 tetrazol-2-yl). Preferably, for Z (Cι-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-l,2,3,6-tetrahydro-purine), benzofuran, pyridine, quinoline, pyrrolidine/piperazine, imidazopyridazine (e.g., imidazo[l,2-6]pyridazine) and tetrazole (e.g., 1,2,3,4-tetrazole). Preferably, the C .8cycloalkyl 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 Cι-6alkyl (preferably, C2- alkyl, more preferably, methyl); phenyl; -O(Cι-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(C3.6alkyl); -C(=O)O-phenyl; -O-phenyl; -C(=O)(Cι-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
Figure imgf000013_0001
(preferably, C2.4alkyl, more preferably, methyl, most preferably, R=R'=methyl); and nitro.
For option (ii), the C .8 heterocyclic ring is preferably, selected from piperidinyl (e.g., 1 -piperidinyl), piperazinyl (e.g., 1 -piperazinyl), morpholinyl (e.g., 4-morpholinyl) and tetrazolyl (e.g., l,2,3,4-tetrazol-2-yl). Preferably, the C6-ι0 ring 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 Cι-6alkyl (preferably,
C2-4alkyl, more preferably, methyl); phenyl; OCF3; OCHF2; -O(Cι-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); -O-phenyl; -C(=O)(Cι-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 Cι_6alkyl (preferably, C2- alkyl, more preferably, methyl, most preferably, R=R'=methyl); and nitro. For R8 and R9, either: (i) R8 is H; Q.^alkyl; optionally substituted C3-8cycloalkyl optionally fused to a benzo ring; optionally substituted (Cj.8alkyl)aryl wherein the aryl is C6-ιo. optionally substituted (Ct.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 O, N and S or R represents a mono-, bi- or tri-cyclic C -ι cycloalkyl; optionally substituted C6_ι0aryl; 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 O, N and S; or -C(=O)OAr, wherein Ar represents optionally substituted C6-ιoaryl; and R9 is H; or (ii) the structure -NR R represents a C .8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S and optionally fused to a C6-ιo ring structure, -NR8R9 being optionally substituted.
For R8 in option (ii), preferably, Cι-ι2alkyl is selected from Cι.8alkyl, C2.6alkyl, methyl, propyl (e.g., isopropyl), butyl (e.g., isobutyl or tert-butyl), pentyl and adamantyl (e.g., 1-adamantyl). For Cι-8alkyl in (Cι.8alkyl)aryl or (Cι_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-ιo aryl is mentioned, the aryl is phenyl. Preferably, Z2(Cι_8alkyl)aryl represents Z2(Cι-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-diox 0-1,2,3,6- 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[l,2-b]pyridazinyl) and tetrazolyl (e.g., tetrazol-2-yl, l,2,3,4-tetrazol-2-yl). Preferably, the C3-8cycloalkyl 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(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, -C(=O)O-tert-butyl or -C(=O)O(C3.6alkyl); -C(=O)O-phenyl; -O-phenyl; -C(=O)(C,.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 Cι-6alkyl (preferably, C2-4alkyl, more preferably, methyl, most preferably, R=R'=methyl); and nitro.
For option (ii), the C3.8 heterocyclic ring is preferably, selected from piperidinyl (e.g., 1 -piperidinyl), piperazinyl (e.g., 1 -piperazinyl), morpholinyl (e.g., 4-morpholinyl) and tetrazolyl (e.g., l,2,3,4-tetrazol-2-yl). Preferably, the C6.ιo ring structure is selected from cyclohexyl and a benzo ring. For optional substitution of -NR8R9, at least one (e.g., one, two or three) substituents may be provided independently selected from Cι.6alkyl (preferably, C2. alkyl, more preferably, methyl); phenyl; OCF3; OCHF ; -O(Cι.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(C3-6alkyl); -O-phenyl; -C(=O)(C,.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 Cι-6alkyl (preferably, C -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); each c independently represents 1, 2, 3, 4 or 5 (preferably, 1 or 2); d represents 1, 2, 3, 4 or 5 (preferably, 1 or 2); e 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 1, 2, 3, 4 or 5 (preferably, 1).
In the present specification, unless otherwise indicated, an alkyl substituent may be linear or branched. Where optional substitution of aryl or an unsaturated C3-8carbocyclic ring is mentioned, the substituent can be selected from Cj-6alkyl (preferably, C2- alkyl, and most preferably, methyl); O(C3-8cycloalkyl), preferably, O-cyclopropyl, or O-cyclobutyl or O- cyclopentyl; O(C1-6alkyl), preferably, Omethyl or O(C2- alkyl); Hal, preferably, Cl or F;
CHal3, CHHal2, CH2Hal, OCHal , 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 C -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 O, N and S; H; COOR" or COR", R" representing H or Cι-6alkyl
(preferably, methyl, ethyl); or CH2OH. 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 Cι-6alkyl (preferably, C - alkyl, more preferably, methyl); phenyl;
OCF3; OCHF2; -O(Cι-8alkyl), preferably, -O-methyl, -O-ethyl or -O(C3-6alkyl);
-C(=O)O(Cι-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)(C,.8alkyl), preferably, -C(=O)- methyl, -C(=O)-ethyl or -C(=O)(C3.6alkyl); -C(=O)OH; -S(Cι.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 one embodiment, a is 2 or 3; b is 2; d is 2 or 3; and g is 1, 2 or 3.
In an alternative embodiment, R1 is -(CH2)a-R3; -((CH2)bO)c-R3; -(CH2)d-R3' or
-(CH2)e-O-(CH2)f- R3'; R2 is C1-6alkyl; O(C3-8 cycloalkyl); O(C,.6alkyl); Hal; CHal3, CHHab,
CH2Hal, OCHal3, OCHHal2 or OCH2Hal, wherein Hal represents halogen; NR4R5, wherein
R4 and R5 independently represent H or Cι.8alkyl; or CH2OH; R3 is optionally substituted
C3-8cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted Cs-io aromatic ring structure optionally N and S; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered mono- or bi-cyclic heterocyclic ring structure containing 1, 2, 3, 4 or 5 heteroatoms independently selected from O, 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 O, 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 O, 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 C5_10 aromatic ring structure optionally containing from 1, 2 or 3 heteroatoms independently selected from O, N and S; or -Z-M represents -C(=O)NR6R7, -NR6R7, -OC(=O)NR8R9, -NC(=O)NR8R9, -NC(=O)R8 or -NC(=O)OR8; For R6 and R7, either: (i) R6 is H; C,.8alkyl; optionally
7 2 substituted C3-8 cycloalkyl optionally fused to a benzo ring; Z"(Cι.8alkyl)aryl, wherein Z represents O or a bond, and the aryl is C6_IQ, optionally substituted and optionally fused to a C5.10 heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S; optionally substituted C5.10 aromatic ring structure; an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from O, N and S; (Cι.8alkyl)-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 O, 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; optionally substituted -C(=O)O(Cι.8alkyl); optionally substituted -C(=0)O-phenyl; optionally substituted -C(=O)(Cι_8alkyl); optionally substituted -C(=O)- phenyl; or -NC(=O)R8 and R7 is H; Cι_8alkyl; optionally substituted C .8cycloalkyl optionally fused to a benzo ring; (C|.8alkyl)aryl wherein the aryl is C6-ιo and optionally substituted; optionally substituted C5.10 aromatic ring structure; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring structure containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or (ii) the structure -NR6R7 represents a C -8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S and optionally fused to a C6.ιo ring structure, -NR6R7 being optionally substituted; and for R8 and R9, either: (i) R8 is H; Cι_ι2alkyl; optionally substituted C3.8 cycloalkyl optionally fused to a benzo ring; optionally substituted (Cι.8alkyl)aryl wherein the aryl is C6-ιo; optionally substituted (Cι-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 O, 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 C -ι3cycloalkyl; optionally substituted C5-10 aromatic ring structure; 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 O, 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 Cs-io aromatic ring structure; and R9 is H; or (ii) the structure -NR8R9 represents a C3-8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S, -NR8R9 being optionally substituted.
Preferred compounds are selected from compounds π, in and IV
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000018_0001
For formula IV, preferably, Z represents S; preferably, d represents 3.
Specific examples of compounds according to the invention are given in below. Mass spectral molecular ion data are reported in units of m/z (mass/charge) in Daltons. Compound 1
Figure imgf000018_0002
2-{ [3-(lH-imidazol-l-ylmethyl)-2-methylphenyl]sulfanyl}ethyl phenylcarbamate Mass spec' molecular ion: M+Η=368. Compound 2
Figure imgf000018_0003
2-{[2-methyl-3-(2H-l,2,3,4-tetraazol-2-ylmethyl)phenyl]sulfanyl}ethyl phenylcarbamate Mass spec' molecular ion: M+Η=370 Compound 3
Figure imgf000018_0004
2-{ [2-methyl-3-(lH-l,2,3,4-tetraazol-l-ylmethyl)phenyl]sulfanyl}ethyl phenylcarbamate Mass spec' molecular ion: M+H=370. Compound 4
Figure imgf000018_0005
2-( { 2-methyl-3- [(4-nitro- 1 H-imidazol- 1 -yl)methyl]phenyl } sulfanyl)ethyl phenylcarbamate Mass spec' molecular ion: M+Η=413. Compound 5
Figure imgf000019_0001
2-( { 2-methyl-3- [(2-nitro- IH-imidazol- 1 -yl)methyl]phenyl } sulfanyl)ethyl phenylcarbamate Mass spec' molecular ion: M+Η=413. Compound 6
Figure imgf000019_0002
2-{ [3-( lH-benzimidazol-l-ylmethyl)-2-methylphenyl]sulfanyl }ethyl phenylcarbamate Mass spec' molecular ion: M+Η=418 Compound 7
Figure imgf000019_0003
2-({2-methyl-3-[(2-phenyl-lH-imidazol-l-yl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate Mass spec' molecular ion: M+Η=444. Compound 8
Figure imgf000019_0004
2-( { 2-methyl-3-[(2-methyl- 1 H-imidazol- 1 -yl)methyl]phenyl } sulfanyl)ethyl phenylcarbamate Mass spec' molecular ion: M+Η=382 Compound 9
Figure imgf000020_0001
2-({3-[(4,5-dichloro- IH-imidazol- l-yl)methyl]-2-methylphenyl}sulfanyl)ethyl phenylcarbamate
Mass spec' molecular ion: [M-Η]- = 434.
Compound 10
Figure imgf000020_0002
2-({ 3-[(4,5-diphenyl-lH-imidazol-l-yl)methyl]-2-methylphenyl}sulfanyl)ethyl phenylcarbamate
Mass spec' molecular ion: M+Η=520
Compound 11
Figure imgf000020_0003
2-{ [3-({4-[2-(acetylamino)ethyl]-lH-imidazol-l-yl }methyl)-2-methylphenyl]sulfanyl}ethyl phenylcarbamate
Mass spec' molecular ion: M+Η=453
Compound 12
Figure imgf000020_0004
2-({ 3-[(2-isopropyl-l H-imidazol- l-yl)methyl]-2-methylphenyl }sulfanyl)ethyl phenylcarbamate
Mass spec' molecular ion: M+Η=410
Compound 13
Figure imgf000021_0001
2-[(2-methyl-3-{ [2-(trifluoromethyl)-lH-benzimidazol-l-yl]methyl}phenyl)sulfanyl]ethyl phenylcarbamate
Mass spec' molecular ion: M+Η=486
Compound 14
Figure imgf000021_0002
2-({2-methyl-3-[(2-propyl- IH-imidazol- l-yl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate Mass spec' molecular ion: M+Η=410 Compound 15
Figure imgf000021_0003
2-{ [2-methyl-3-(9H-purin-9-ylmethyl)phenyl]sulfanyl } ethyl phenylcarbamate Mass spec' molecular ion: M+Η=420 Compound 16
Figure imgf000022_0001
methyl l-[3-({2-[(anilinocarbonyl)oxy]ethyl}sulfanyl)-2-methylbenzyl]-lH-imidazole-4- carboxylate Mass spec' molecular ion: M+Η=426, M+Na=448 Compound 17
Figure imgf000022_0002
2-{ [2-methyl-3-(7H-purin-7-ylmethyl)phenyl]sulfanyl}ethyl phenylcarbamate Mass spec' molecular ion: M+Η=420 Compound 18
Figure imgf000022_0003
methyl 1 -[3-( { 2-[(anilinocarbonyl)oxy]ethyl } sulfanyl)-2-methylbenzyl]- lH-imidazole-5- carboxylate
Mass spec' molecular ion: M+Η=426, M+Na=448 Compound 19
Figure imgf000022_0004
2-[(2-methyl-3- { [2-(methylsulfanyl)- 1 H-imidazol- 1 -yljmethyl } phenyl)sulfanyl]ethyl phenylcarbamate
Mass spec' molecular ion: M+Na=436
Compound 20
Figure imgf000023_0001
2-[(2-methyl-3-{ [2-(methylsulfinyl)-lH-imidazol-l-yl]methyl}phenyl)sulfanyl]ethyl phenylcarbamate
Mass spec' molecular ion: M+Na=452
Compound 21
Figure imgf000023_0002
2-[(2-methyl-3-{[2-(methylsulfonyl)-lH-imidazol-l-yl]methyl}phenyl)sulfanyl]ethyl phenylcarbamate
Mass spec' molecular ion: M+Na=468
Compound 22
Figure imgf000023_0003
2- { [3-( 1 H- 1 ,2,3-benzotriazol- 1 -ylmethyl)-2-methylphenyl]sulfanyl } ethyl phenylcarbamate Mass spec' molecular ion: M+Na=441 Compound 23
Figure imgf000024_0001
2-{[3-(2H-l,2,3-benzotriazol-2-ylmethyl)-2-methylphenyl]sulfanyl}ethyl phenylcarbamate Mass spec' molecular ion: M+Na=441 Compound 24
Figure imgf000024_0002
2-(2-methyl-3- { [2-oxo-2-( 1 -piperidinyl)ethyl]sulfanyl } benzyl)- IH-isoindole- 1 ,3(2H)-dione NMR data: Η NMR (dmso- 6, ppm); 1.41-1.57 (3 x m, 6H, pip-H), 2.40 (s, 3H, Ph-CH3),
3.90 (s, 2H, SCH2), 4.79 (s, 2H, PhCH2N), 6.97 (d, IH, J=7.7 Hz, Ph-H), 7.12 (t, IH, J=7.7 Hz, Ph-H), 7.36 (d, IH, J=7.7 Hz, Ph-H), 7.88-7.94 (2 x m, 4H, Phth-H). Compound 25
Figure imgf000024_0003
6-[(2-{ [3-(lH-benzimidazol-l-ylmethyl)-2-methylphenyl]sulfanyl}ethyl)sulfanyl]- 3-nitroimidazo[ 1 ,2-b/pyridazine Mass spec' molecular ion: M+Η=477 Compound 26
Figure imgf000025_0001
l-(2-methyl-3-{ [2-(2-pyrimidinylsulfanyl)ethyl]sulfanyl}benzyl)-lH-benzimidazole Mass spec' molecular ion: M+Η=393 Compound 27
Figure imgf000025_0002
1 -(2-methyl-3- { [2-(4-moφholinyl)ethyl]sulfanyl } benzyl)- 1 H-benzimidazole
M+Η=368
Compound 28
Figure imgf000025_0003
2-methyl-3-[(2-nitro- IH-imidazol- l-yl)methyl]phenyl 2-[(3-nitroimidazo[l,2-£/pyridazin-6- yl)sulfanyl]ethyl sulfide
Mass spec' molecular ion: M+Η=472
Compound 29
Figure imgf000025_0004
2-methyl-3-[(2-nitro-l H-imidazol- l-yl)methyljphenyl 2-(2-pyrimidinylsulfanyl)ethyl sulfide Mass spec' molecular ion: M+Η=388 Compound 30
Figure imgf000026_0001
2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenyl 2-(4-morpholinyl)ethyl sulfide Mass spec' molecular ion: M+Η=363 Compound 31
Figure imgf000026_0002
6-( { 2-[(2-methyl-3- { [2-(methylsulfanyl)- 1 H-imidazol- 1 -yljmethyl } phenyl)sulfanylj- ethyl } sulfanyl)-3-nitroimidazo[ 1 ,2-b/pyridazine Mass spec' molecular ion: M+Η=473 Compound 32
Figure imgf000026_0003
2-( { 2-[(2-methyl-3- { [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl } phenyl)sulfanyljethyl } - sulfanyl)pyrimidine
Mass spec' molecular ion: M+Η=389 Compound 33
Figure imgf000027_0001
4-{2-[(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol-l-ylJmethyl}phenyl)sulfanylJ- ethyljmorpholine
Mass spec' molecular ion: M+Η=364
Compound 34
Figure imgf000027_0002
2-{[2-methyl-3-({2-[(3-nitroimidazo[l,2-b7pyridazin-6-yl)sulfanylJ-lH-imidazol- 1 -yl } methyl)phenyl]sulfanyl } ethyl phenylcarbamate Mass spec' molecular ion: M+Η=562 Compound 35
Figure imgf000027_0003
l-(2-methyl-3-{ [2-(2-pyridinylsulfanyl)ethylJsulfanyl}benzyl)-lH-benzimidazole Mass spec' molecular ion: M+Η=392 Compound 36
Figure imgf000027_0004
l-(2-methyl-3-{ [2-(4-pyridinylsulfanyl)ethylJsulfanyl}benzyl)-lH-benzimidazole Mass spec' molecular ion: M+Η=392, M+Na=414 Compound 37
Figure imgf000028_0001
1 -(2-methyl-3- { [2-( 1 ,3-thiazol-2-ylsulfanyl)ethyl]sulfanyl } benzyl)- 1 H-benzimidazole Mass spec' molecular ion: M+Η=398 Compound 38
Figure imgf000028_0002
3-( 1 H-benzimidazol- 1 -ylmethyl)-2-methylphenyl 2-[( 1 -methyl- IH- 1 ,2,3,4-tetraazol-5- yl)sulfanyljethyl sulfide
Mass spec' molecular ion: M+Η=397
Compound 39
Figure imgf000028_0003
3-(lH-benzimidazol-l-ylmethyl)-2-methylphenyl 2-[(4-methyl-4H-l,2,4-triazol-
3-yl)sulfanylJethyl sulfide
Mass spec' molecular ion: M+Η=396
Compound 40
Figure imgf000028_0004
2- { [3-( 1 H-benzimidazol- 1 -ylmethyl)-2-methylphenylJsulfanyl } -N-methyl-N- [2-(2-pyridinyl)ethylJ-l-ethan amine Mass spec' molecular ion: M+Η=417 Compound 41
Figure imgf000029_0001
l-(2-methyl-3-{ [2-(4-methyl-l-piperazinyl)ethylJsulfanyl } benzyl)- IH-benzimidazole Mass spec' molecular ion: M+Η=381 Compound 42
Figure imgf000029_0002
l-(2-methyl-3-{[2-(l-piperazinyl)ethylJsulfanyl} benzyl)- IH-benzimidazole Mass spec' molecular ion: M+Η=367 Compound 43
Figure imgf000029_0003
1 -[2-methyl-3-( { 2-[4-(2-pyrimidinyl)- 1 -piperazinyl Jethyl } sulfanyl)benzylj- IH-benzimidazole Mass spec' molecular ion: M+Η=445 Compound 44
Figure imgf000029_0004
2-[3-( 1 H-benzimidazol- l-ylmethyl)-2-methylphenoxyJethyl phenylcarbamate Mass spec' molecular ion: M+Η=402 Compound 45
Figure imgf000030_0001
2-{2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenoxy Jethyl phenylcarbamate
NMR data: lH NMR (dmso-^6, ppm); 2.17 (s, 3Η, Ph-CH3), 4.25 (t, 2H, J=4.3 Hz, OCH2), 4.48 (t, 2H, J=4.3 Hz, OCH2), 5.64 (s, 2H, PhCH2N), 6.20 (d, IH, J=7.7 Hz, Ar-H), 7.00 (m,
2H, Ar-H), 7.14 (t, IH, J=8.0 Hz, Ar-H), 7.29 (m, 3H, Ar-H), 7.49 (d, 2H, J=7.9 Hz, Ar-H) Compound 46
Figure imgf000030_0002
2-(3-isobutoxy-2-methylphenyl)-lH-benzimidazole Mass spec' molecular ion: M+Η=281 Compound 47
Figure imgf000030_0003
1 -(3 -isobutoxy-2-methylbenzyl)- 1 H-benzimidazole Mass spec' molecular ion: M+Η=295 Compound 48
Figure imgf000030_0004
6-{ [3-(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol-l-ylJmethyl}phenoxy)propyl]sulfanyl}- 3-nitroimidazo[ 1 ,2-b/pyridazine Mass spec' molecular ion: M+Η=471 Compound 49
Figure imgf000031_0001
2- { [3-(2-methyl-3- { [2-(methylsulfanyl)- 1 H-imidazol- 1 -yljmethyl } phenoxy)propylJ- sulfanyl } pyrimidine
Mass spec' molecular ion: M+Η=387
Compound 50
Figure imgf000031_0002
6- { [3-(2-methyl-3- { [2-(methylsulfonyl)- IH-imidazol- 1 -yljmethyl } phenoxy)propyl]sulfanyl } ■ 3-nitroimidazo[ 1 ,2-b/pyridazine Mass spec' molecular ion: M+Η=503 Compound 51
Figure imgf000031_0003
2- { [3-(2-methyl-3- { [2-(methylsulfonyl)- IH-imidazol- 1 -yljmethyl } phenoxy)propyl]- sulfanyl } pyrimidine
Mass spec' molecular ion: M+Η=419
Compound 52
Figure imgf000031_0004
2-{[3-(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol-l-ylJmethyl}phenoxy)propyl]sulfanyl}- lH-imidazo[4,5-cJpyridine
Mass spec' molecular ion: M+Η=426 Compound 53
Figure imgf000032_0001
l-{3-[3-(lH-imidazol-2-ylsulfanyl)propoxy]-2-methylbenzyl}-2-(methylsulfanyl)-lH- imidazole
Mass spec' molecular ion: M+Η=375
Compound 54
Figure imgf000032_0002
2-{ [3-(2-methyl-3-{[2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}phenoxy)propylJ- sulfanyljpyridine Mass spec' molecular ion: M+Η=386 Compound 55
Figure imgf000032_0003
4-{ [3-(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}phenoxy)propylJ- sulfanyljpyridine Mass spec' molecular ion: M+Η=386 Compound 56
Figure imgf000032_0004
2-{ [3-(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol-l-ylJmethyl}phenoxy)ρropyl]sulfanyl}- 1,3-thiazole Mass spec' molecular ion: M+Η=392 Compound.57
Figure imgf000032_0005
3- { [3-(2-methyl-3- { [2-(methylsulfanyl)- 1 H-imidazol- 1 -yljmethyl } phenoxy)propyl]sulfanyl } -
5-phenyl- IH- 1 ,2,4-triazole
Mass spec' molecular ion: M+Η=452
Compound 58
Figure imgf000033_0001
2- { [3-(2-methyl-3- { [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl } phenoxy)propylJsulfanyl } -
5-phenyl- 1 ,3,4-oxadiazole
Mass spec' molecular ion: M+Η=453
Compound 59
Figure imgf000033_0002
5-{ [3-(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}phenoxy)propyl]sulfanylJ- 1 -phenyl- 1 H- 1 ,2,3 ,4-tetraazole Mass spec' molecular ion: M+Η=453 Compound 60
Figure imgf000033_0003
2-methyl-3- { [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl } phenyl 3-[( 1-methyl- IH- 1 ,2,3,4- tetraazol-5-yl)sulfanylJpropyl ether Mass spec' molecular ion: M+Η=391 Compound 61
Figure imgf000033_0004
2-methyl-3- { [2-(methylsulfanyl)- 1 H-imidazol- 1 -yljmethyl } phenyl 3-[( 1 -methyl- 1 H- 1 ,2,4- triazol-5-yl)sulfanyl]propyl ether Mass spec' molecular ion: M+Η=390 Compound 62
Figure imgf000034_0001
2- { [3-(2-methyl-3- { [2-(methylsulfonyl)- IH-imidazol- 1 -yljmethyl } phenoxy)propyl]sulfanyl } -
1,3-thiazole
Mass spec' molecular ion: M+Na=445
Compound 63
Figure imgf000034_0002
methyl 1 -(2-methyl-3- { 3- [( 1 -methyl- IH- 1 ,2,3,4-tetraazol-5-yl)sulfanyl]propoxy } benzyl)- 1H- imidazol-2-yl sulfone Mass spec' molecular ion: M+Η=423 Compound 64
Figure imgf000034_0003
2- { [3-(2-methyl-3- { [2-(methylsulfonyl)- 1 H-imidazol- 1 -yljmethyl } phenoxy)propylJ- sulfanyljpyridine Mass spec ' molecular ion : M+Η=418 Compound 65
Figure imgf000034_0004
2-methyl-3-[(2-nitro- 1 H-imidazol- 1 -yl)methyljphenyl 3-( 1 ,3-thiazol-2-ylsulfanyl)propyl ether Mass spec' molecular ion: M+Η=391 Compound 66
Figure imgf000035_0001
2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenyl 3-[(l -methyl- 1H-1, 2,3,4-tetraazol-5- yl)sulfanyl]propyl ether
Mass spec' molecular ion: M+Η=390
Compound 67
Figure imgf000035_0002
2-methyl-3-[(2-nitro- IH-imidazol- l-yl)methyl]phenyl 3-(2-pyrimidinylsulfanyl)propyl ether Mass spec' molecular ion: M+Η=386 Compound 68
Figure imgf000035_0003
2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenyl 3-(2-pyridinylsulfanyl)propyl ether Mass spec' molecular ion: M+Η=385 Compound 69
Figure imgf000035_0004
l-{2-methyl-3-[3-(l,3-thiazol-2-ylsulfanyl)propoxyJbenzyl}-lH-benzimidazole Mass spec' molecular ion: M+Η=396 Compound 70
Figure imgf000036_0001
3-( 1 H-benzimidazol- 1 -ylmethyl)-2-methylphenyl 3- [( 1 -methyl- IH- 1 ,2,3 ,4-tetraazol-5- yl)sulfanyl]propyl ether
Mass spec' molecular ion: M+Η=395
Compound 71
Figure imgf000036_0002
l-{2-methyl-3-[3-(2-pyrimidinylsulfanyl)propoxy]benzyl}- IH-benzimidazole Mass spec' molecular ion: M+Η=391 Compound 72
Figure imgf000036_0003
l-{2-methyl-3-[3-(2-pyridinylsulfanyl)propoxy]benzyl}-lH-benzimidazole Mass spec' molecular ion: M+Η=390 Compound 73
Figure imgf000036_0004
3- [(2-isopropyl- 1 H-imidazol- 1 -yl)methyl J -2-methylphenyl 3-( 1 ,3-thiazol-2-ylsulfanyl)propyl ether
Mass spec' molecular ion: M+Η=388 Compound 74
Figure imgf000037_0001
3 - [(2-isopropyl- 1 H-imidazol- 1 -yl)methylJ-2-methylphenyl 3-[( 1 -methyl- IH- 1 ,2,3,4-tetraazol-
5-yl)sulfanyl]propyl ether
Mass spec' molecular ion: M+Η=387
Compound 75
Figure imgf000037_0002
3-[(2-isopropyl- IH-imidazol- 1 -yl)methyl]-2-methylphenyl 3-(2-pyrimidinylsulfanyl)propyl ether Mass spec' molecular ion: M+Η=383 Compound 76
Figure imgf000037_0003
3-[(2-isopropyl-lH-imidazol-l-yl)methyl]-2-methylphenyl 3-[(3-nitroimidazo[l,2-bJ- pyridazin-6-yl)sulfanyl]propyl ether Mass spec' molecular ion: M+Η=467 Compound 77
Figure imgf000037_0004
3-[(2-isopropyl-lH-imidazol-l-yl)methylJ-2-methylphenyl 3-(2-pyridinylsulfanyl)propyl ether Mass spec' molecular ion: M+Η=382 Compound 78
Figure imgf000038_0001
2-methyl-3-[(2-propyl- IH-imidazol- 1 -yl)methyl]phenyl 3-( 1 ,3-thiazol-2-ylsulfanyl)propyl ether
Mass spec' molecular ion: M+Η=388
Compound 79
Figure imgf000038_0002
2-methyl-3-[(2-propyl- IH-imidazol- l-yl)methyl]phenyl 3-[(l -methyl- 1H-1, 2,3,4-tetraazol-5- yl)sulfanyl]propyl ether
Mass spec' molecular ion: M+Η=387
Compound 80
Figure imgf000038_0003
2-methyl-3-[(2-propyl-lH-imidazol-l-yl)methyl]phenyl 3-(2-pyrimidinylsulfanyl)propyl ether Mass spec' molecular ion: M+Η=383 Compound 81
Figure imgf000038_0004
2-methyl-3-[(2-propyl-lH-imidazol-l-yl)methyl]phenyl 3-[(3-nitroimidazo[l,2-b7pyridazin-6- yl)sulfanyl]propyl ether
Mass spec' molecular ion: M+Η=467 Compound 82
Figure imgf000039_0001
2-methyl-3-[(2-propyl-lH-imidazol-l-yl)methyl]phenyl 3-(2-pyridinylsulfanyl)propyl ether Mass spec' molecular ion: M+Η=382 Compound 83
Figure imgf000039_0002
2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methylJphenyl 3-[(3-nitroimidazo[l,2-b pyridazin-6- yl)sulfanyl]propyl ether
Mass spec' molecular ion: M+Η=470
Compound 84
Figure imgf000039_0003
3-(l H-benzimidazol- l-ylmethyl)-2-methylphenyl 3-[(3-nitroimidazo[l,2-b7pyridazin-6- yl)sulfanylJpropyl ether
Mass spec' molecular ion: M+Η=476
Compound 85
Figure imgf000039_0004
2-methyl-3- { [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl } phenol Mass spec' molecular ion: M+Η=235 Compound 86
Figure imgf000040_0001
2-{2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methylJanilino}ethyl phenylcarbamate Mass spec' molecular ion: M+Η=396 Compound 87
Figure imgf000040_0002
l-(3-isobutoxybenzyl)-l H-benzimidazole Mass spec' molecular ion: M+Η=281 Compound 88
Figure imgf000040_0003
3-[(3-methyl-2-{ [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl } -4-pyridinyl)sulfanylJ- 1-propanol
Mass spec' molecular ion: M+Η=310 Compound 89
Figure imgf000040_0004
2-[(3-methyl-2- { [2-(methyIsulfanyl)- IH-imidazol- 1 -yljmethyl } -4-pyridinyl)sulfanylJ- 1 -ethanol Mass spec' molecular ion: M+H=296 Compound 90
Figure imgf000041_0001
2- [(3-methyl-2- { [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl } -4-pyridinyl)sulfanylJethyl phenylcarbamate
Mass spec' molecular ion: M+Η=415 Compound 91
Figure imgf000041_0002
1 -[(3-methyl-4-phenoxy-2-pyridinyl)methylJ - 1 H-benzimidazole Mass spec' molecular ion: M+Η=316 Compound 92
Figure imgf000041_0003
3-methyl-2-[(2-nitro- IH-imidazol- l-yl)methyl]-4-phenoxypyri dine Mass spec' molecular ion: M+Η=31 1 Compound 93
Figure imgf000042_0001
3-methyl-2- { [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl } -4-phenoxypyridine Mass spec' molecular ion: M+Η=312 Compound 94
Figure imgf000042_0002
6-( { 3-[(3-methyl-2- { [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl } -4-pyridinyl)sulfanylJ- propyl } sulfanyl)-3-nitroimidazo[ 1 ,2-b/pyridazine Mass spec' molecular ion: M+Η=488 Compound 95
Figure imgf000042_0003
6-[(3-{ [2-(lH-benzimidazol-l-ylmethyl)-3-methyl-4-pyridinylJsulfanyl}propyl)sulfanylJ- 3-nitroimidazo[ 1 ,2-b7pyridazine Mass spec' molecular ion: M+Η=492 Compound 96
Figure imgf000042_0004
l-[(3-methyl-4-{ [3-(l,3-thiazol-2-ylsulfanyl)propylJsulfanyl}-2-pyridinyl)methylJ- IH- benzimidazole Mass spec' molecular ion: M+Η=414 Compound 97
Figure imgf000043_0001
l-[(3-methyl-4-{ [3-(2-pyrimidinylsulfanyl)propyl]sulfanyl}-2-pyridinyl)methyl]- IH- benzimidazole Mass spec' molecular ion: M+Η=409 Compound 98
Figure imgf000043_0002
2-{ [2-methyl-3-(l-piperazinylmethyl)phenylJsulfanyl Jethyl phenylcarbamate Mass spec' molecular ion: M+H=386 Compound 99
Figure imgf000043_0003
2-( { 2-methyl-3-[(4-methyl- 1 -piperazinyl)methyl]phenyl } sulfanyl)ethyl phenylcarbamate Mass spec' molecular ion: M+H=400 Compound 100
Figure imgf000043_0004
2-[3-(lH-benzimidazol-l-ylmethyl)phenoxyJethyl phenylcarbamate Mass spec' molecular ion: M+Η=388 Compound 101
Figure imgf000044_0001
2-( { 2-methyl-3-[(2-nitro- IH-imidazol- 1 -yl)methyl]phenyl } sulfonyl)ethyl phenylcarbamate Mass spec' molecular ion: M+Η=445 Compound 102
Figure imgf000044_0002
methyl l-[3-(2-{ [(l-ethyl-3-methyl-lH-pyrazol-5-yl)carbonyl]amino}ethoxy)- 2-methylbenzyl]-lH-imidazole-4-carboxylate Mass spec' molecular ion: M+Η=426 Compound 103
Figure imgf000044_0003
1 - [3-(2- { [( 1 -ethyl-3 -methyl- 1 H-pyrazol-5-yl)carbonyl J amino } ethoxy)-2-methylbenzylJ - 1 H- imidazole-4-carboxylic acid
Mass spec' molecular ion: M+Η=412 Compound 104
Figure imgf000045_0001
1 -ethyl-3-methyl-N-[2-(2-methyl-3- { [4-(4-moφholinylcarbonyl)- lH-imidazol- 1 -yljmethyl } phenoxy)ethyl J- 1 H-pyrazole-5-carboxamide Mass spec' molecular ion: M+Η=481
Compound 105
Figure imgf000045_0002
N-[2-(3-{ [4-({ [2-(dimethylamino)ethylJamino}carbonyl)-lH-imidazol-l-yl]methyl}- 2-methylphenoxy)ethylJ-l-ethyl-3-methyl-lH-pyrazole-5-carboxamide Mass spec' molecular ion: M+Η=482 Compound 106
Figure imgf000045_0003
1 -ethyl-N- { 2-[3-( { 4-[(isobutylamino)carbonylJ- IH-imidazol- 1 -yl } methyl)- 2-methylphenoxyJethyl}-3-methyl-lH-pyrazole-5-carboxamide Mass spec ' molecular ion : M+Η=467 Compouiid 107
Figure imgf000046_0001
N-{2-[3-({4-[(diethylamino)carbonylJ-lH-imida2ol-l-yl}methyl)-2-m«ihylphenoxy]etliyl}- 1 -ethyl-3-meώyI- l_H-ρyrazole-5-carboxamide Mass spec" molecular ion: M+H=467 Compound 108
Figure imgf000046_0002
-V- { 2-[3-( [ 4-[(benzylamino)carbonyl]- 1 Mmidazol- 1 -yl } methyl)-2-me th> lphenoxy]ett yl } - l-ethyl-3-mechyl-lH-pyrazole-5-carboxamide Mass spec ' molecular ion : M+H=501 Compound 109
Figure imgf000046_0003
2-[3-(lH-ben2imidazol-l-ylmethyl)-2-met ylanilino]ethyl phenyIcarbamaιe Mass spec" molecular ion: M+H= 01 Compound 110
Figure imgf000047_0001
2-( 1 H-benzimidazol- 1 -ylmethyl)-3-methyl-4-pyridinyl 3-[(3-nitroimidazo[ 1 ,2-6/pyπdazin-6- yl)oxyJpropyl ether
Mass spec' molecular ion: M+Η=460
Compound 111
Figure imgf000047_0002
3-[3-(lH-benzimidazol-l-ylmethyl)-2-methylphenoxy]propyl 3-nitroimidazo[l,2-& pyridazin- 6-yl ether Mass spec' molecular ion: M+Η=459 Compound 112
Figure imgf000047_0003
3- { [2-( 1 H-benzimidazol- 1 -ylmethyl)-3-methyl-4-pyridinylJoxy } propyl phenylcarbamate Mass spec' molecular ion: M+Η=417 Compound 113
Figure imgf000047_0004
2- { [2-(lH-benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyl]oxy Jethyl phenylcarbamate Mass spec' molecular ion: M+Η=403 Compound 114
Figure imgf000048_0001
2-( IH-benzimidazol- 1 -ylmethyl)-3-methyl-4-pyridinyl 3-(imidazo[ 1 ,2-b/pyridazin-6- yloxy)propyl ether Mass spec' molecular ion: M+Η=415 Compound 115
Figure imgf000048_0002
N-(3- { [2-( 1 H-benzimidazol- 1 -ylmethyl)-3-methyl-4-pyridinyl]oxy } propyl)-N-phenylurea Mass spec' molecular ion: M+Η=416 Compound 116
Figure imgf000048_0003
N-(3-{ [2-(lH-benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyl]oxy}propyl)-l-ethyl-3-methyl- lH-pyrazole-5-carboxamide
Mass spec' molecular ion: M+Η=434 Compound 117
Figure imgf000049_0001
3-{ [2-(lH-benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyl]oxyJpropyl 3-methoxyphenylcarbamate Mass spec' molecular ion: M+Η=448 Compound 118
Figure imgf000049_0002
3- { [2-( IH-benzimidazol- 1 -ylmethyl)-3-methyl-4-pyridinyl]oxy } propyl 3 ,4- difluorophenylcarbamate Mass spec' molecular ion: M+Η=453 Compound 119
Figure imgf000049_0003
ethyl 4- { [(3- { [2-( IH-benzimidazol- l-ylmethyl)-3-methyl-4-pyridinyl]oxy}- propoxy)carbonyl J amino } benzoate Mass spec' molecular ion: M+Η=490 Compound 120
Figure imgf000050_0001
4- { [(3- { [2-( IH-benzimidazol- 1 -ylmethyl)-3-methyl-4-pyridinyl]oxy } propoxy)- carbonyljaminojbenzoic acid Mass spec' molecular ion: M+Η=461 Compound 121
Figure imgf000050_0002
3-[3-(lH-benzimidazol-l-ylmethyl)-2-methoxyphenoxy]propyl 3-nitroimidazo- [l,2-b7pyridazin-6-yl ether Mass spec' molecular ion: M+Η=475 Compound 122
Figure imgf000050_0003
2-[3-(lH-benzimidazol-l-ylmethyl)-2-(trifluoromethyl)phenoxyJethyl phenylcarbamate Mass spec' molecular ion: M+Η=456 Compound 123
Figure imgf000050_0004
2-[3-(lH-benzimidazol-l-ylmethyl)-2-chlorophenoxyJethyl phenylcarbamate Mass spec' molecular ion: M+Η=422 Compound 124
Figure imgf000051_0001
l-ethyl-3-methyl-N-(2-{2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methylJphenoxy}ethyl)-lH- pyrazole-5-carboxamide Mass spec' molecular ion: M+Η=413 Compound 125
Figure imgf000051_0002
N- { 2-[3-( 1 H-benzimidazol- 1 -ylmethyl)-2-methylphenoxyJethyl } - 1 -ethyl-3-methyl- 1H- pyrazole-5-carboxamide Mass spec' molecular ion: M+Η=419 Compound 126
Figure imgf000051_0003
1 -ethyl-3-methyl-N-[2-(2-methyl-3- { [2-(methylsulfanyl)- 1 H-imidazol- 1 -yljmethyl } - phenoxy)ethylJ-lH-pyrazole-5-carboxamide Mass spec' molecular ion: M+Η=415 Compound 127
Figure imgf000052_0001
methyl 1 -(3- { 2-[(tert-butoxycarbonyl)aminoJethoxy } -2-methylbenzyl)- lH-imidazole-4- carboxylate Mass spec' molecular ion: M+Η=390 Compound 128
Figure imgf000052_0002
methyl l-(3-{2-[(tert-butoxycarbonyl)amino]ethoxy}-2-methylbenzyl)-lH-imidazole-5- carboxylate Mass spec' molecular ion: M+Η=390 Compound 129
Figure imgf000052_0003
1 -(3- { 2- [(tert-butoxycarbonyl)aminojethoxy } -2-methylbenzyl)- lH-imidazole-4-carboxylic acid Mass spec' molecular ion: M+Η=376 Compound 130
Figure imgf000053_0001
l-(3-{2-[(tert-butoxycarbonyl)aminoJethoxy}-2-methylbenzyl)-lH-imidazole-5-carboxylic acid
Mass spec' molecular ion: M+Η=376
Compound 131
Figure imgf000053_0002
1 - { [3-methyl-4-(3-phenoxypropoxy)-2-pyridinyl]methyl } - IH-benzimidazole Mass spec' molecular ion: M+Η=374 Compound 132
Figure imgf000053_0003
l-({3-methyl-4-[3-(2-pyrimidinyloxy)propoxyJ-2-pyridinyl} methyl)- IH-benzimidazole Mass spec' molecular ion: M+Η=376 Compound 133
Figure imgf000053_0004
2-(2-methyl-3- { [2-(2H- 1 ,2,3, 4-tetraazol-2-yl)ethylJsulfanyl } benzyl)- IH-isoindole- 1 ,3(2H)- dione NMR data: H NMR (dmso-J6, ppm); 2.19(s, 3H), 3.28(t, J=6.5 Hz, 2H), 4.60(s, 2H), 4.70(t,
J=6.5Hz, 2H), 6.83(d, J=7.7Hz, IH), 6.98(t, J=7.7Hz, IH), 7.18(d, J=7.7Hz, IH), 7.69-7.77(2 x m, 4H), 8.79 (s, IH). Compound 134
Figure imgf000054_0001
l-ethyl-3-methyl-N-[2-(2-methyl-3-{ [l-oxo-2(lH)-phthalazinylJmethyl}phenoxy)ethylJ-lH- pyrazole-5-carboxamide
Mass spec' molecular ion: M+Η=446
Compound 135
Figure imgf000054_0002
1 -ethyl-3-methyl-N- [2-(2-methyl-3- { [6-oxo- 1 (6H)-pyridazinyl] methyl } phenoxy)ethyl] - 1 H- pyrazole-5-carboxamide
Mass spec' molecular ion: M+Η=396
Compound 136
Figure imgf000054_0003
l-ethyl-3-methyl-N-[2-(2-methyl-3-{ [3-methyl-5-(4-moφholinylcarbonyl)-lH-pyrazol- l-yl]methyl}phenoxy)ethyl]-lH-pyrazole-5-carboxamide Mass spec' molecular ion: M+Η=495 Compound 137
Figure imgf000055_0001
1 -ethyl-3-methyl-N- { 2-[2-methyl-3-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)phenoxy]ethyl } - 1H- pyrazole-5-carboxamide
Mass Spec M+Η = 369
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 or p- 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 (c) as follows: (a) reacting compound V with compound VI
Figure imgf000055_0002
wherein L1 is a leaving group and B represents an optionally substituted 5- or 6-membered heterocyclic ring that is optionally fused to a 3, 4, 5, 6, 7 or 8 membered carbocyclic ring or heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from O, Ν and S; or (b) reacting compound VII with H-R'
Figure imgf000056_0001
wherein L2 is a leaving group, R' represents (CH2)d or (CH2)e-O-(CH2)f , and R" represents
R3', with the proviso that R3' does not represent -C(=O)NR6R7, -NR6R7, -OC(=O)NR8R9,
-NC(=O)NR8R9, -NC(=O)R8 or -NC(=O)OR8; or
(c) reacting compound Vm with R8-N=C=O or R8-COOH or R6-N=C=O or L3-M
Figure imgf000056_0002
wherein R' represents (CH2) , L3 representing a leaving group, and Z and M being as defined in claim 1, with the proviso that Z-M does not represent -C(=O)NR 6°rR>7', -NR >6°τR>7',
-OC(=O)NR8R9, -NC(=O)NR8R9, -NC(=O)R8 or -NC(=O)OR8;
(d) reacting compound DC with R'-L4, wherein L4 represents a leaving group, and with the proviso that X is not CH2 or SO2 and that when R*= R3 , Z-M does not represent
-C(=O)NR >6°Rr>7', -NR >6°RD7', -OC(=O)NRδRv, -NC(=O)NR8R9, -NC(=O)R8 or -NC(=O)OR8;
Figure imgf000056_0003
(e) reacting compound X with R'-XH
Figure imgf000056_0004
R£ wherein L represents a leaving group, A contains N as a heteroatom either at the 2- or 4- position relative to L , and with the proviso that X is not CH2 or SO2 and that when R = R >3'
Z-M does not represent -C(=O)NR >6°Rr,7',
Figure imgf000056_0005
-NC(=O)NR ) 88R>9v, -NC(=O)R' or -NC(=O)OR8. 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. Thus, in process (a) above, where
R1 represents -(CH2)d-NHR and R is H or an alkyl group, a suitable amine protecting group can be used during the reaction.
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).
In process (e) above, L5 is preferably, sulfonate ester or halogen (more preferably, chlorine).
The compounds of the present invention have anύ-Helicobacter pylori activity, ie 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 advantage of compounds of the invention is that they are particularly selective for Helicobacter pylori.
Experimental
Scheme 1
Figure imgf000057_0001
MethyI 2-{[3-({[/ert-butyl(dimethyI)silyIJoxy}methyl)-2-methylphenyl]sulfanyI}acetate
To a solution of 15 mL DMF, 9.8 g methyl 2-{ [3-(hydroxymethyl)-2-methylphenylJ- sulfanyl} acetate, and 5 g imidazole was added 8 g TBS-C1. The mixture was stirred at room temp, for 45 min, diluted with ethyl acetate, washed with IN HCI, water, brine (2X), dried over MgSO4, evaporated to give 16 g of methyl 2-{ [3-({ [tert-butyl(dimethyl)silylj- oxy}methyl)-2-methylphenyl]sulfanyl} acetate as a yellow liquid. 2-{[3-({[te^Butyl(dimethyl)siIyl]oxy}methyI)-2-methylphenyl]sulfanyl}-l-ethanoI
To stirred 0 °C solution of 14.8 g methyl 2-{ [3-({ [tert-butyl(dimethyl)silylJ- oxy } me thyl)-2-methylphenyl]sulfanyl} acetate in 50 mL THF was added 2 g LiAlH4 very slowly and carefully. The resulting suspension was stirred at 0 °C for 30 min, then quenched with -2 mL water and ~ 1 mL 4 M NaOH. The mixture was filtered, and the solids were rinsed with THF, the filtrate was diluted with ethyl acetate. The solution was washed with IN
HCI, brine, dried over MgSO4, and evaporated to give 11 g of 2-{ [3-({ [tert- butyl(dimethyl)silyl]oxy}methyl)-2-methylphenyl]sulfanyl}-l-ethanol as a yellow liquid. 2-{[3-({[fer^Butyl(dimethyl)silyl]oxy}methyI)-2-methylphenyl]sulfanyl}ethyl phenylcarbamate
11 g of 2- { [3-( { [tert-butyl(dimethyl)silyl]oxy } methyl)-2-methylphenylJsulfanyl } - 1 -ethanol was dissolved in 10 mL THF, 6 mL phenyl isocyanate, and 10 mg 4- dimethylaminopyridine were added, and the mixture was stirred 2 h at 50 °C. The reaction was diluted with ethyl acetate, washed with IN HCI (2X), brine, dried over MgSO4, and evaporated to give 2-{ [3-({ [tert-butyl(dimethyl)silyl]oxy}methyl)-2-methylphenylJsulfanylJ- ethyl phenylcarbamate as a crude thick oily solid residue. Used without further purification in the next step. 2-{[3-(Hydroxymethyl)-2-methylphenyl]sulfanyl}ethyl phenylcarbamate To a solution of the crude 2- { [3-( { [tert-butyl(dimethyl)silylJoxy } methyl)-2-methyl- phenyljsulfanyl Jethyl phenylcarbamate prepared as above in 20 mL THF was added 17 mL 75% aq. TBAF (tetrabutylammonium fluoride). The mixture was stirred at RT for 1 hr, diluted with IN HCI, extracted with ethyl acetate, washed with brine, dried over MgSO4, and purified by flash chromatography over silica gel, 10-30% EtOAc/Hexane. An oily yellowish solid was obtained, this was triturated with hexane, collected on a sintered glass frit and rinsed with hexane to yield 4.43 g 2- { [3-(hydroxymethyl)-2-methylphenylJsulfanyI Jethyl phenylcarbamate as a white powder. 2-{[3-(Chloromethyl)-2-methylphenyl]sulfanyl}ethyl phenylcarbamate
A solution of 0.5 g of 2- { [3-(hydroxymethyl)-2-methylphenyl]sulfanyl Jethyl phenylcarbamate in 3 mL THF was cooled to 0 °C, 1 mL SOCI2 was added, the cold bath was removed, and the mixture was stirred for 45 min. Evaporation and trituration with hexane gave 0.525 g of 2-{ [3-(chloromethyl)-2-methylphenyl]sulfanyl}ethyl phenylcarbamate as an off-white solid.
2-({2-Methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate
0.5 g of 2- { [3-(chloromethyl)-2-methylphenyl]sulfanyl Jethyl phenylcarbamate, 0.66 g
2-nitroimidazole, 2 g K2CO3, and 10 mL DMF were combined and stirred at rt overnight.
The resultant bright yellow suspension was diluted to 100 mL with ethyl acetate, washed with 100 mL water, 100 mL brine, dried, evaporated, and purified by flash chromatography, silica gel, 30 - 60 % ethyl acetate Hexane. Crystallization from ethyl acetate / Hexane gave
2-( { 2-methyl-3-[(2 -nitro- IH-imidazol- 1 -yl)methyljphenyl } sulfanyl)ethyl phenylcarbamate as an off-white crystalline solid, 0.49 g. Mass spec; M+Η=413. Scheme 2
Figure imgf000059_0001
Figure imgf000059_0002
-{[2-Methyl-3-(2H-l,2,3,4-tetraazoI-2-ylmethyl)phenyl]sulfanyl}ethyl phenylcarbamate 2-{[2-Methyl-3-(lH-l,2,3,4-tetraazol-l-ylmethyl)phenyl]sulfanyl}ethyl phenylcarbamate
Prepared as described in scheme 5, with 2-nitroimidazole being replaced by 1H- 1,2,3,4-tetraazole, the product mixture obtained was separated by reverse phase preparative ΗPLC to give pure samples of 2-{ [2-methyl-3-(2H-l,2,3,4-tetraazol- 2-ylmethyl)phenyl]sulfanyl}ethyl phenylcarbamate and 2-{ [2-methyl-3-(lH- 1,2,3, 4-tetraazol- l-ylmethyl)phenyl]sulfanyl Jethyl phenylcarbamate.
2-{[3-(2_H-l,2,3-Benzotriazol-2-ylmethyl)-2-methylphenyl]sulfanyl}ethyl phenylcarbamate
2-{[3-(l^-l,2,3-Benzotriazol-l-ylmethyl)-2-methylphenylJsulfanyl}ethyl phenylcarbamate
Prepared as described in scheme 5, with 2-nitroimidazole being replaced by 1H- 1,2,3-benzotriazole, the product mixture obtained was separated by reverse phase preparative ΗPLC to give pure samples of 2-{ [2-methyl-3-(2H- 1,2,3, 4-tetraazol-
2-ylmethyl)phenylJsulfanyl Jethyl phenylcarbamate and 2-{ [2-methyl-3-(lH-l,2,3,4-tetraazol- l-ylmethyl)phenyl]sulfanyl Jethyl phenylcarbamate.
Scheme 3
Figure imgf000060_0001
2-{[3-(Ηydroxymethyl)-2-methyIphenyl]sulfanyl}acetic acid
To a solution of 5 g methyl 2-{ [3-(hydroxymethyl)-2-methylphenylJsulfanyl}acetate in 50 mL dioxane was added a solution of an excess amount of lithium hydroxide in 5 mL water. The solution was stirred at it for 2 hours, diluted with water, acidified with cone HCI, extracted exhaustively with 1:1 THF : ethyl acetate, dried over MgSO4, and evaporated to yield 2- { [3-(hydroxymethyl)-2-methylphenyl]sulfanylJ acetic acid, 3.5 g. 2-{[3-(Hydroxymethyl)-2-methylphenyl]sulfanyl}-l-(l-piperidinyl)-l-ethanone To a solution of 2 g of 2- { [3-(hydroxymethyl)-2-methylphenyl]sulfanylJ acetic acid and 1 g of piperidine in DMF, 10 mL, was added 10 mg DMAP and 2.7 g EDAC-HC1. The mixture was stirred at rt overnight, diluted with water, extracted twice with ethyl acetate, washed with IN HCI dried over MgSO4, and evaporated to give 2-{ [3-(hydroxymethyl)-
2-methylphenyl]sulfanyl}-l-(l-piperidinyl)-l-ethanone, 2.1 g. 2-{[3-(Chloromethyl)-2-methylphenylJsulfanyl}-l-(l-piperidinyl)-l-ethanone The alcohol prepared as above, 1 g was dissolved in 20 mL THF, cooled to 0°C, treated with thionyl chloride, 0.5 mL, and stirred at room temp, for 4 hours. The solvents were evaporated to yield 0.95 g 2-{ [3-(chloromethyl)-2-methylphenyl]sulfanylJ- 1 -( 1 -piperidinyl)- 1 -ethanone.
2-(2-Methyl-3-{[2-oxo-2-(l-piperidinyl)ethyI]sulfanyl}benzyl)-lH-isoindole-l,3(2 )- dione
0.95 g of 2-{ [3-(chloromethyl)-2-methylphenyl]sulfanylJ-l-(l-piρeridinyl)-l-ethanone was combined with 0.11 g phthallimide and 2.2 g K2CO3 in 5 mL DMF. The mixture was stirred at rt overnight, diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and evaporated to yield 2-(2-methyl-3-{ [2-oxo-2-(l-piperidinyl)ethyl]sulfanyl}benzyl)-lH- isoindole-l,3(2H)-dione, 0.78 g. !Η NMR (dmso-^6, ppm); 1.41-1.57 (3 x m, 6H, pip-H),
2.40 (s, 3H, Ph-CH3), 3.90 (s, 2H, SCH2), 4.79 (s, 2H, PhCH2N), 6.97 (d, IH, J=7.7 Hz, Ph-
H), 7.12 (t, IH, J=7.7 Hz, Ph-H), 7.36 (d, IH, J=7.7 Hz, Ph-H), 7.88-7.94 (2 x m, 4H, Phth- H).
Scheme 4
Figure imgf000062_0001
2-{[3-(HydroxymethyI)-2-methylphenyl]sulfanyl}-l-ethanol
4.65 g methyl 2- { [3-(hydroxymethyl)-2-methylphenylJsulfanylJ acetate was dissolved in 40 mL THF at 0 °C. 1.2 g lithium aluminum hydride was added and the mixture was stirred for 10 min. A few drops of water, then a few drops of 4 M NaOH were added, and the suspension was filtered. The filtrate was concentrated to yield 2-{ [3-(hydroxymethyl)- 2-methylphenyl]sulfanyl}-l-ethanol as a thick yellow oil, 3.7. l-[(2-Chloroethyl)sulfanyl]-3-(chloromethyl)-2-methylbenzene 2-{ [3-(hydroxymethyl)-2-methylphenyl]sulfanyl }-l-ethanol, 3.7 g, was dissolved in
40 mL methylene chloride, cooled to 0 °C, and SOCI2, 7 mL, was added to give a clear solution. The mixture was stirred 1 hr at 0 °C, concentrated, and purified by flash chromatography, silica gel, 9: 1 Hexane:CH2θ2 to l-[(2-chloroethyl)sulfanyl]-
3-(chloromethyl)-2-methylbenzene as a clear oil, 3.8 g. l-(2-MethyI-3-{[2-(4-morpholinyl)ethyl]sulfanyl}benzyl)-li7-benzimidazole
80 mg of l-[(2-chloroethyl)sulfanylJ-3-(chloromethyl)-2-methylbenzene was combined with 40 mg benzimidazole, 0.1 g K2CO3, 0.08 mL DMF and stirred at rt overnight to give a crude solution of l-{3-[(2-chloroethyl)sulfanyl]-2-methylbenzylJ- IH-benzimidazole. To the above solution was added 0.15 mL moφholine and 0.2 g K2CO3. The suspension was warmed at 70 °C for 1 day, filtered, and purified by reverse phase HPLC to give pure l-(2-methyl-3-{ [2-(4-moφholinyl)ethyl]sulfanyl}benzyl)-lH-benzimidazole as 30 mg thick oil. Mass spec; M+Η=368. l-(2-Methyl-3-{[2-(2-pyrimidinylsulfanyl)ethyl]sulfanyl}benzyl)-lH-benzimidazole
80 mg of l-[(2-chloroethyl)sulfanyl]-3-(chloromethyl)-2-methylbenzene was combined with 40 mg benzimidazole, 0.1 g K2CO3, 0.08 mL DMF and stirred at rt overnight to give a crude solution of l-{3-[(2-chloroethyl)sulfanyl]-2-methylbenzylJ- IH-benzimidazole.
To the above solution was added 0.04 g 2-mercaptopyrimidine and 0.2 g K2CO3. The suspension was warmed at 70 °C for 1 day, filtered, and purified by reverse phase ΗPLC to give pure l-(2-methyl-3-{ [2-(2-pyrimidinylsulfanyl)ethyl]sulfanyl} benzyl)- IH-benzimidazole as 87 mg thick oil. Scheme 5
Figure imgf000063_0001
Figure imgf000063_0002
Figure imgf000063_0003
Methyl 2-[3-(hydroxymethyl)-2-methylphenoxy]acetate
3.5 g 2-Methyl-3-hydroxymethylphenol [prepared by lithium aluminum hydride reduction of 2-methyl-3-hydroxybenzoic acid], 2.9 mL methyl bromoacetate, and 10 g
K2CO3, were combined in 25 mL anhy. methanol. The suspension was warmed to 50 °C for 2.5 h, then an additional 1 mL methyl bromoacetate was added, and warming at 50 °C was continued for 45 min. The mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and evaporated to give methyl 2-[3-(hydroxymethyl)-
2-methylphenoxy] acetate as a clear yellow oil, 2.8 g. Methyl 2-[3-(chIoromethyl)-2-methylphenoxy]acetate
Methyl 2-[3-(hydroxymethyl)-2-methylphenoxy]acetate, 0.6 g, was dissolved in 3 mL
CH2CI2 and cooled to 0 °C. SOCI2, 0.9 mL, was added. The cold bath was removed, stirring was continued for 50 min at RT, and the solution was concentrated in vacuo to give methyl 2-[3-(chloromethyl)-2-methylphenoxyJacetate as a yellowish solid residue, used directly in the next step.
Methyl 2-{2-methyl-3-[(2-nitro-lET-imidazol-l-yI)methylJphenoxy}acetate
The crude methyl 2-[3-(chloromethyl)-2-methylphenoxy]acetate prepared as above was dissolved in 5 mL DMF, 0.28 g 2-nitroimidazole, 1.4 g K2CO3 added, and the mixture was stirred at rt for 19 h. The reaction mixture was diluted with ethyl acetate, washed with water, then brine. The solution was dried over MgSO4, and evaporated to give methyl
2- { 2-methyl-3- [(2-nitro- 1 H-imidazol- 1 -yl)methylJphenoxy } acetate, 0.87 g. 2- {2-Methy 1-3- [(2-nitro-lH-imidazoI-l -y l)methy 1] phenoxy} acetic acid
Methyl 2-{2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methylJphenoxyJacetate, 0.87 g, was dissolved in 8 mL dioxane, and a solution of 0.3g LiOΗ in 8 mL water was added. The solution was stirred for 1.5 h at rt. The mixture was diluted with water, acidified with cone ΗC1, extracted with ethyl acetate, then TΗF. The combined organic layers were dried over
Na2SO4, and evaporated to give 2-{2-methyl-3-[(2-nitro-lH-imidazol- l-yl)methyl]phenoxyJ acetic acid as a yellow solid, 0.65g,. 2-{2-Methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenoxy}-l-ethanol 2- {2-Methyl-3-[(2-nitro-l H-imidazol- l-yl)methyl]phenoxyJ acetic acid, 0.65 g, was suspended in 10 mL TΗF, and cooled to 0 °C, 7 mL 1M BΗ3.TΗF was added, and the mixture was stirred 50 min at 0 °C. 3 mL more BH3-THF solution was added, and stirring was continued for 50 min more at 0 °C. The mixture was quenched with a few drops of methanol, poured into water, extracted with EtOAc, washed with brine, dried over M SO4, and evaporated to give 2-{2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenoxy}-l-ethanol as 0.61 g thick yellow oil. 2-{2-Methyl-3-[(2-nitro-l_fiT-imidazol-l-yl)methyl]phenoxy}ethyl phenylcarbamate
0.6 g 2- {2-methyl-3-[(2-nitro- IH-imidazol- l-yl)methyl]phenoxy}-l-ethanol was dissolved in 3 mL TΗF, and 0.4 mL DMF. 0.35 mL phenyl isocyanate was added. The solution was stirred at rt for 15 min, then 50 °C for 1.5 hr. The mixture was evaporated, and purified by flash chromatography, silica gel, 40 - 80% ethyl acetate / Hexane.
2-{2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenoxy Jethyl phenylcarbamate was obtained as a light yellow foam, 0.38 g. Η NMR (dmso-^6, ppm); 2.17 (s, 3Η, Ph-CH3),
4.25 (t, 2H, J=4.3 Hz, OCH2), 4.48 (t, 2H, J=4.3 Hz, OCH2), 5.64 (s, 2H, PhCH2N), 6.20 (d,
IH, J=7.7 Hz, Ar-H), 7.00 (m, 2H, Ar-H), 7.14 (t, IH, J=8.0 Hz, Ar-H), 7.29 (m, 3H, Ar-H), 7.49 (d, 2H, J=7.9 Hz, Ar-H). Scheme 6
Figure imgf000065_0001
3-Isobutoxy-2-methylbenzoic acid lg of 2-methyl-3-hydroxybenzoic acid, 3.6 mL isobutyl bromide, and 9 g K2CO3 were combined in 7.5 mL DMF. The mixture was stirred at 70 °C for 3 h, diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and evaporated to give the isobutylester intermediate as a clear yellow oil, 1.73g. The ester, 1.17 g was combined with 25 mL dioxane and excess aqueous KOH to give a clear solution. The mixture was warmed at 55 °C for 2h, diluted with water, acidified with cone HCI, extracted with CH2CI2 (2X) , dried over MgSO4, and evaporated to give 3-isobutoxy-2-methylbenzoic acid as an off-white solid, 0.94g. 7V-(2-Aminophenyl)-3-isobutoxy-2-methylbenzamide
3-Isobutoxy-2-methylbenzoic acid, 0.94 g, 1,2-phenylenediamine, 2.4 g, EDAC-HC1,
1.7 g, DMAP, 10 mg, and 5 mL CH2CI2 were combined and stirred at rt for 30 min. The
solution was diluted with methylene chloride, washed with water, brine, dried over MgSO4, and evaporated. Flash chromatography, silica gel, 20-50% ethyl acetate/hexane gave N- (2-aminophenyl)-3-isobutoxy-2-methylbenzamide as a yellow solid, 0.72 g. 2-(3-Isobutoxy-2-methylphenyl)-lH-benzimidazole
0.1 g N-(2-aminophenyl)-3-isobutoxy-2-methylbenzamide was combined with 2 mL acetic acid and warmed to 100 °C for 3 h. The mixture was evaporated and the residue was dissolved in 2 mL ethanol, treated with 3 drops cone HCI, evaporated, and crystallized from ethyl acetate to give 2-(3-isobutoxy-2-methylphenyl)- IH-benzimidazole as a light pink solid: 95 mg. Mass spec; M+Η=281. Scheme 7
Figure imgf000066_0001
(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, 3g, 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 MgSO4, and evaporated to give (3-isobutoxy-2-methylphenyl)methanol as a yellow waxy solid, 1.15 g. l-(3-Isobutoxy-2-methylbenzyl)-li/-benzimidazole
0.5 g (3-isobutoxy-2-methylphenyl)methanol was dissolved in 3 mL CH2CI2, and
0.7 mL SOCI2 was carefully added. The mixture was stirred for 30 min., then concentrated to give crude l-(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 MgSO4, and evaporated to give a residue which was purified by flash chromatography, silica gel, 20-50% ethyl acetate/Hexane. l-(3-isobutoxy- 2-methylbenzyl)- IH-benzimidazole was thus obtained as an off-white solid, 0.6g. Mass spec; M+Η=295. Scheme 8
Figure imgf000067_0001
[3-(3-Chloropropoxy)-2-methylphenyI]methanol 2-Methyl-3-hydroxymethylphenol [prepared by lithium aluminum hydride reduction of
2-methyl-3-hydroxybenzoic acidj, 2.03 g, l-bromo-3-chloropropane, 4 mL, and K2CO3, 10 g, were combined in 20 mL abs. ethanol and warmed at 60 °C for 3 h. The mixture was filtered through celite, and the filtrate was concentrated and purified by flash chromatography, silica gel, 98:2 CH2Cl2/ethyl acetate to give [3-(3-chloropropoxy)-2-methylphenylJmethanol as a white solid, 2.9g. l-(ChIoromethyl)-3-(3-chloropropoxy)-2-methylbenzene
1 g [3-(3-chloropropoxy)-2-methylphenylJmethanol was dissolved in 10 mL THF, cooled to 0 °C, and 1 mL SOCI2 was added. The solution was stirred 1 h at 0 °C, and concentrated. The residue was purified by flash chromatography, silica gel, 5 to 10% CH2Cl2/Ηexane, to give l-(chloromethyl)-3-(3-chloropropoxy)-2-methylbenzene as a waxy white solid, 700 mg. l-[3-(3-Chloropropoxy)-2-methylbenzyl]-2-(methylsulfanyl)-lH-imidazole l-(chloromethyl)-3-(3-chloropropoxy)-2-methylbenzene, 0.3 g was combined with
2-thiomethylimidazole, 0.146g, and K2CO3, 0.55 g in 3 mL DMF and stirred 6 h at rt. The suspension was diluted with water, extracted with ethyl acetate, washed with brine, dried over MgSO4, and evaporated to give l-[3-(3-chloropropoxy)-2-methylbenzyl]-2-(methylsulfanyl)- lH-imidazole as a clear yellow oil, 0.387 g. 6-{[3-(2-Methyl-3-{[2-(methylsulfanyl)-lH-imidazol-l-yl]methyI}phenoxy)propyl]- suIfanyl}-3-nitroimidazo[l,2-£]pyridazine l-[3-(3-Chloropropoxy)-2-methylbenzyl]-2-(methylsulfanyl)-lH-imidazole, 0.6 g, was combined with 3-nitroimidazo[l,2-bJpyridazine-6-thiol (prepared according to WO
9828299), 0.474 g, and K2CO3, 1.3 g in 6 mL DMF. The mixture was warmed at 60 °C for 18 h, diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and purified
by flash chromatography, silica gel, 30-50% ethyl acetate:CΗ2θ2. 6-{ [3-(2-methyl-
3-{ [2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}phenoxy)propyl]sulfanylJ- 3-nitroimidazo[l,2-bJpyridazine was obtained as a light green crystalline solid, 0.54 g. Mass spec; M+Η=471. Scheme 9
Figure imgf000068_0001
2-Methyl-3-(chloromethyl)phenol
1 g 2-methyl-3-(hydroxymethyl)phenol [prepared by lithium aluminum hydride reduction of 2-methyl-3-hydroxybenzoic acid] was dissolved in 10 mL THF, and cooled to
0 °C. 1.1 mL SOCI2 was added, the mixture was stirred 1.5 h at 0 °C, evaporated and purified by flash chromatography, silica gel, 9: 1 hexane : ethyl acetate to give 2-methyl- 3-(chloromethyl)phenol as a white solid, 0.74 g. tert-Butyl(dimethyl)silyl 3-(chloromethyI)-2-methylphenyI ether
0.74 g of 2-methyl-3-(chloromethyl)phenol, 1.4 g tert-butyldimethylsilyl chloride, 1.1 mL pyridine, 10 mg DMAP, and 3 mL DMF were combined to give a clear solution. The mixture was stirred at rt overnight, diluted with ethyl acetate, washed with 0.5N HCI, sat
NaHCO3, brine, dried over MgSO4 and evaporated. Purification by flash chromatography, silica gel, 5 to 50% ethyl acetate / hexane gave tert-butyl(dimethyl)silyl 3-(chloromethyl)- 2 -methylphenyl ether as a clear oil, 0.2 g, and unreacted phenol starting material, 0.2 g. 2-Methyl-3-{[2-(methylsulfanyl)-l_H-imidazol-l-yl]methyl} phenol
0.195 g of tert-butyl(dimethyl)silyl 3-(chloromethyl)-2-methylphenyl ether, 82 mg
2-thiomethylimidazole, 0.3 g K2CO3, and 2 mL DMF were combined and stirred at rt for 4 days, diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and evaporated.
Purification by reverse phase prep HPLC gave 2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol- 1 -yljmethyl} phenol as a white powder, 65 mg. Mass spec; M+Η=235. Scheme 10
Figure imgf000069_0001
tert-Butyl 3-(hydroxymethyl)-2-methylphenylcarbamate
2-Methyl-3-(hydroxymethyl)aniline, 5 g, was combined with 100 mL THF, 50 mL acetone, 10 mL water, and 2.2 g NaOH . Di-t-butyl-dicarbonate, 9.6 g was added, and the mixture was warmed to 50 °C for 3 h, 3g additional di-t-butyl-dicarbonate was added, followed by 0.72 g NaOH, and 5 mL water. The mixture was kept at 50 °C for 2 h more, diluted with water, and extracted with EtOAc, the org layer was washed with 1M HCI, and dried over MgSO4. Evaporation gave a slurry, hexane was added to precipitate further solids.
Filtration gave tert-butyl 3-(hydroxymethyl)-2-methylphenylcarbamate as a white crystalline solid, 7.02 g. /er/-Butyl 3-(chloromethyl)-2-methylphenylcarbamate
5 g tert-Butyl 3-(hydroxymethyl)-2-methylphenylcarbamate was dissolved in 40 mL
THF and cooled to 0 °C. SOCI2, 5 mL, was added and the ice bath was removed after 5 min.
The reaction was kept at rt for 1 hour, concentrated and co-evaporated with toluene to yield tert-butyl 3-(chloromethyl)-2-methylphenylcarbamate as a thick yellow oil, 4.8 g. tert-Butyl 2-methyl-3-[(2-nitro-lH-imidazol-l-yI)methyl]phenylcarbamate tert-Butyl 3-(chloromethyl)-2-methylphenylcarbamate, 1 g, was combined with 0.45 g
2-nitroimidazole and 5 g K2CO3 in 10 mL DMF and stirred at rt for 20 h. The mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, evaporated and crystallized from hexane/ethyl acetate to give tert-butyl 2-methyl-3-[(2-nitro-lH-imidazol- l-yl)methyl]phenylcarbamate as a white solid, 0.6 g.
/er/-ButyI 2-{[ter/-butyl(dimethyl)silyl]oxy}ethyl{2-methyl-3-[(2-nitro-l f- imidazol-l-yl)methyl]phenyl}carbamate tert-Butyl 2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenylcarbamate, 0.2 g, was dissolved in 2.5 mL DMF and Cooled to 0 °C. 60% NaΗ, 0.05g, was added and the suspension was stirred 15 min at 0 °C, 0.25 mL (2-bromoethoxy)(tert-butyl)dimethylsilane was added, and the reaction was allowed to slowly warm to rt over 4 h. The dark greenish brown mixture was diluted with water, extracted with ethyl acetate, dried over MgSO4, evaporated and chromatographed over 25 mL flash silica gel, 8:2 Ηexane:EtOAc to give tert- butyl 2- { [tert-butyl(dimethyl)silyl]oxy } ethyl { 2-methyl-3-[(2-nitro- 1 H-imidazol- l-yl)methyl]phenyl}carbamate as a thick yellow oil. 0.145 g. tert-Butyl 2-hydroxyethyI{2-methyl-3-[(2-nitro-lH-imidazoI-l-yI)methyl]phenyI}- carbamate tert-Butyl 2-{ [tert-butyl(dimethyl)silyl]oxy}ethyl{2-methyl-3-[(2-nitro-lH-imidazol- l-yl)methyl] phenyl} carbamate, 0.14 g, was dissolved in 3 mL TΗF and 0.2 mL 2.73 M aq. tetrabutyl ammonium fluoride was added. The reaction was stirred 45 min, poured into water, extracted with methylene chloride, dried over MgSO4, evaporated and chromatographed over
20 mL flash silica gel, ethyl acetate, to give tert-butyl 2-hydroxyethyl{2-methyl-3-[(2-nitro- lH-imidazol-l-yl)methyl]phenyl}carbamate as a clear oil, 0.075g.
/er^Butyl 2-[(anilinocarbonyl)oxy]ethyl{2-methyl-3-[(2-nitro-l /-imidazol- l-yl)methyljphenyl}carbamate tert-Butyl 2-hydroxyethyl { 2-methyl-3-[(2-nitro- IH-imidazol- 1 -yl)methyl]phenyl } - carbamate, 70 mg, was dissolved in 3 mL TΗF, 3 mg DMAP, and 0.04 mL phenyl isocyanate were added, and the mixture was stirred at rt for 3.5 h An additional 0.05 mL phenyl isocyanate was added, and the mixture was stirred 1.5 hr more. Evaporation and purification over flash silica gel, 20 - 50% ethyl acetate / hexane, gave tert-butyl
2-[(anilinocarbonyl)oxyJethyl { 2-methyl-3- [(2-nitro- IH-imidazol- 1 -yl)methyl]phenyl } - carbamate as a foamy white oil, 55 mg. 2-{2-Methyl-3-[(2-nitro-l_flr-imidazol-l-yl)methyl]anilino}ethyl phenylcarbamate tert-Butyl 2-[(anilinocarbonyl)oxy]ethyl { 2-methyl-3- [(2-nitro- lH-imidazol- l-yl)methyl]phenyl} carbamate, 55 mg, was dissolved in 2 mL CΗ2CI2, and 2 mL trifluoroacetic acid was added. The reaction was stirred at rt overnight and concentrated to give a residue. Purification over flash silica gel, 20 - 100% ethyl acetate / Hexane gave 2- {2-methyl-3- [(2-nitro- 1 H-imidazol- l-yl)methylJanilino Jethyl phenylcarbamate as a yellow powder, 40 mg. Compound 109 can be prepared by a similar scheme, replacing 2-nitroimidazole with benzimidazole. Scheme 11
Figure imgf000071_0001
The procedure was carried out as for scheme 7, with the following exception: 3-(hydroxymethyl)phenol was used in place of 2-methyl-3-(hydroxymethy)phenol. Scheme 12
Figure imgf000072_0001
4-Chloro-3-methyl-2-{[2-(methylsulfanyI)-l_H-imidazol-l-yl]methyl}pyridine
To a solution of 4-chloro-3-methyl-2-(chloromethyl)pyridine hydrochloride [prepared according to WO 9854172], 0.46 g, and 2-thiomethylimidazole, 0.3 g, in 5 mL DMF was added 1.5 g K2CO3. The mixture was stirred at rt for 18 h, diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and evaporated to yield 4-chloro-3-methyl-
2-{ [2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}pyridine as a It brown oil, 467 mg.
2-[(3-Methyl-2-{[2-(methylsulfanyl)-l_H-imidazol-l-yl]methyl}-4-pyridinyl)sulfanyl]-
1-ethanol
4-Chloro-3-methyl-2-{ [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl} pyridine, 0.13 g, 2-mercaptoethanol, 0.14 mL, and K2CO3, 0.35 g were combined in 3 mL DMF and warmed to 80 °C for 1.5 h. The mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, evaporated, and triturated with hexane/ether to give 2-[(3-methyl-
2-{ [2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}-4-pyridinyl)sulfanyl]-l-ethanol as an off- white solid, 0.1 lg. 2-[(3-Methyl-2-{[2-(methyIsulfanyl)-lH-imidazol-l-yl]methyl}-4-pyridinyl)sulfanyI]ethyI phenylcarbamate
85 mg of 2-[(3-methyl-2-{ [2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}-4- pyridinyl)sulfanyl]-l -ethanol, 0.1 mL phenyl isocyanate, 5 mg DMAP, 3 mL TΗF, and 0.5 mL DMF were combined and warmed at 50 °C for 45 min. The mixture was concentrated and purified by flash chromatography, silica gel, 4:4:2 ethyl acetate : acetone : acetonitrile, followed by preparative reverse phase ΗPLC to give 2-[(3-methyl-2-{ [2-(methylsulfanyl)-lH- imidazol-1 -yljmethyl }-4-pyridinyl)sulfanyl]ethyl phenylcarbamate as 60 mg oily solid. Mass spec; M+H=415. Scheme 13
Figure imgf000073_0001
4-Phenoxy-2,3-dimethylpyridine-l-oxide
0.5 g 4-chloro-2,3-dimethylpyridine-l -oxide (Agrawal, Krishna C; Booth, Barbara A.; DeNuzzo, Suzanne M.; Sartorelli, Alan C. J. Med. Chem. (1976), 19(10), 1209), 0.59 g phenol, 1.5 g K2CO3, and 3 mL DMF were combined and warmed to 100 °C for 4 days. The mixture was filtered, evaporated and chromatographed over flash silica gel, (4:4:2: 1
EtOAc:acetone:CH3CN:CH3OH) to give 4-phenoxy-2,3-dimethylpyridine-l -oxide as a light brown solid: 0.155 g (23%).
(3-Methyl-4-phenoxy-2-pyridinyl)methanol
57 mg of 4-phenoxy-2,3-dimethylpyridine-l -oxide was dissolved in 0.5 mL acetic anhydride, and heated at 90 °C for 12 h. The reaction mixture was evaporated to yield crude (3-methyl-4-phenoxy-2-pyridinyl)methyl acetate. The (3-methyl-4-phenoxy- 2-pyridinyl)methyl acetate was dissolved in 1 mL MeOH, 2 mL 1M KOH was added, and the solution was stirred for 15 min, diluted with water, extracted with ethyl acetate, dried over
MgSU4, evaporated and purified by flash chromatography, silica gel, (1: 1 ethyl acetate:hexane)to yield (3-methyl-4-phenoxy-2-pyridinyl)methanol as a white solid: 32 mg. Mass spec; M+H=238. 2-(Chloromethyl)-3-methyI-4-phenoxypyridine 80 mg of (3-methyl-4-phenoxy-2-pyridinyl)methanol was dissolved in 5 mL THF at
0 °C, then 0.5 mL SOCI2 was added. The bath was removed, and the reaction'was stirred at rt
30 min. The mixture was then evaporated, and triturated with etheπHexane to give 2-(chloromethyl)-3-methyl-4-phenoxypyridine as a white solid, 78 mg. l-[(3-Methyl-4-phenoxy-2-pyridinyI)methyl]-l_H-benzimidazole
To a solution of 78 mg of 2-(chloromethyl)-3-methyl-4-phenoxypyridine in 0.8 L
DMF was added 21 mg benzimidazole, and 50 mg K2CO3. The mixture was stirred at rt for
18 h, filtered, evaporated, and purified by reverse phase HPLC to give 20 mg of l-[(3-methyl- 4-phenoxy-2-pyridinyl)methylJ-lH-benzimidazole. Mass spec; M+Η=316. Scheme 14
Figure imgf000074_0001
3-[(3-Methyl-2-{[2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}-4-pyridinyI)sulfanyl]- l-propanol 4-Chloro-3-methyl-2-{ [2-(methylsulfanyl)-lH-imidazol-l-ylJmethyl}ρyridine, 0.2 g , was combined with 0.27 mL 3-mercapto-l-propanol, 0.54 g K2CO3, and 5 mL DMF and warmed to 80 °C for 4 h. The mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over MgSU4, evaporated and purified by flash chromatography, silica gel, 45:45:10 acetone : ethyl acetate : acetonitrile to give 3-[(3-methyl- 2-{ [2-(methylsulfanyl)-lH-imidazol-l-ylJmethyl}-4-pyridinyl)sulfanylJ-l-propanol as a waxy off-white solid, 173 mg. 4-[(3-Chloropropyl)sulfanyl]-3-methyl-2-{[2-(methylsulfanyl)-lH-imidazol- l-yl]methyl}pyridine
3-[(3-Methyl-2- { [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl } -4-pyridinyl)sulfanylJ-
1-propanol, 125 mg, was dissolved in 10 mL TΗF, cooled to 0 °C, and 0.5 mL SOCI2 was added. The reaction was allowed to come to rt over 1.5 h, concentrated, and triturated with hexane/Et2θ, then Et2θ to give 4-[(3-chloropropyl)sulfanylJ-3-methyl-
2-{ [2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}pyridine as a grey powder, 158 mg.
6-({3-[(3-MethyI-2-{[2-(methylsulfanyl)-l/7-imidazoI-l-yI]methyl}-4- pyridinyl)sulfanyl]propyl}sulfanyl)-3-nitroimidazo[l,2-Z>]pyridazine
To a solution of 140 mg of 4-[(3-chloropropyl)sulfanylJ-3-methyl-2-{ [2- (methylsulfanyl)-lH-imidazol-l-ylJmethylJpyridine in 5 mL DMF was added 0.11 g
3-nitroimidazo[l,2-b]pyridazine-6-thiol, and 0.4 g K2CO3. The mixture was warmed at 60 °C for 24 h, diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and evaporated. The product was purified by flash chromatography, silica gel, 45:45: 10 ethyl acetate : acetone : acetonitrile, to give 6-({3-[(3-methyl-2-{ [2-(methylsulfanyl)-lH-imidazol- 1 -yljmethyl }-4-pyridinyl)sulfanylJpropyl}sulfanyl)-3-nitroimidazo[l,2-b]pyridazine as a light brown foam, 85 mg. Mass spec; M+Η=488. Scheme 15
Figure imgf000075_0001
2-({2-Methyl-3-[(4-methyl-l-piperazinyl)methyl]phenyl}suIfanyl)ethyl phenylcarbamate
50 mg of 2- {[3-(chloromethyl)-2-methylphenyl]sulfanyl Jethyl phenylcarbamate, 0.16 mL 1-methylpiperazine, and 0.5 mL DMF were combined and heated at 80 °C for 2 h. The mixture was evaporated and purified by reverse phase preparative HPLC to give 2-( { 2-methyl-3-[(4-methyl- 1 -piperazinyl)methyl]phenyl } sulfanyl)ethyl phenylcarbamate as 48 mg thick oil. Scheme 16
Figure imgf000076_0001
2-[3-(lH-Benzimidazol-l-ylmethyl)phenoxy]ethyl phenylcarbamate
Procedure was the same as used to carry out scheme 5; with the following changes: 3-hydroxymethyl phenol was used in place of 2-methyl-3-hydroxymethyl phenol, and benzimidazole was used in place of 2-nitroimidazole. Scheme 17
Figure imgf000076_0002
2-({2-Methyl-3-[(2-nitro-lH-imidazoI-l-yl)methyl]phenyl}sulfonyl)ethyl phenylcarbamate 22 mg of 2-({2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate was dissolved in 0.5 mL TΗF / 1 mL MeOΗ / 1 mL water. 65 mg OXONE
® ® was added and the suspension was stirred for 3 h. An additional 65 mg OXONE 1 1 mL water was added. The mixture was warmed to reflux for 5 minutes to dissolve most of the solids and stirred at rt for 1.5 h more. The reaction was diluted with water, extracted with ethyl acetate, washed with brine, dried over MgSO4, and evaporated. The residue was triturated with (1: 1: 1) methylene chloride : ether : hexane to give 2-({2-methyl-3-[(2-nitro- lH-imidazol-l-yl)methyl]phenyl}sulfonyl)ethyl phenylcarbamate as a white solid, 19 mg. Scheme 18
Figure imgf000077_0001
2-[3-(Mydroxymethyl)-2-methylphenoxy]acetonitrile
3.5 g 2-methyl-3-hydroxymethylphenol [prepared by lithium aluminum hydride reduction of 2-methyl-3-hydroxybenzoic acid], 5 mL bromoacetonitrile, and 10 g K2CO3, were combined in 25 mL anhy. methanol. The suspension was warmed to 50 °C for 2.5 h.
The mixture was diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and evaporated to give 2-[3-(hydroxymethyl)-2-methylphenoxy]acetonitrile, 2.8 g. [3-(2-Aminoethoxy)-2-methylphenyl]methanol 2-[3-(hydroxymethyl)-2-methylphenoxy]acetonitrile, 2.8 g, was dissolved in 100 mL THF. Lithium aluminum hydride, 0.5 g, was added, and the mixture was stirred at 65 °C for 18 h. After cooling, 10 drops 4M NaOH, and 5 drops water were added. The mixture was stirred for 5 minutes, filtered through celite, and the solids were rinsed with THF. The filtrate was evaporated to give [3-(2-aminoethoxy)-2-methylphenyl]methanol, 2.5 g. l-Ethyl-N-{2-[3-(hydroxymethyl)-2-methylphenoxy]ethyI}-3-methyl-l//-pyrazole-5- carboxamide
[3-(2-Aminoethoxy)-2-methylphenyl]methanol, 1.04 g, was combined with 1-ethyl- 3-methyl-lH-pyrazole-5-carboxylic acid, 0.88 g, and dissolved in 40 mL methylene chloride. EDAC-ΗCl, 1.59 g, triethylamine, 2 mL and catalytic 4-dimethylaminopyridine were added and the resulting suspension was stirred at RT for 18 h. The mixture was diluted with ethyl acetate, washed with water, IN ΗC1, sat. NaΗC03, and sat. NaCl, then dried over MgSO4.
Evaporation gave l-ethyl-N-{2-[3-(hydroxymethyl)-2-methylphenoxyJethyl}-3-methyl-lH- pyrazole-5-carboxamide as a foamy oil, 1.19 g. N-{2-[3-(ChIoromethyl)-2-methylphenoxy]ethyl}-l-ethyl-3-methyl-l_flr-pyrazole-5- carboxamide
Thionyl chloride, 1 mL, was added to a solution of 1.19 g l-ethyl-N-{2-[3-(hydroxy- methyl)-2-methylphenoxy]ethyl}-3-methyl-lH-pyrazole-5-carboxamide in 10 mL methylene chloride at 0 °C. After 30 minutes, the solution was concentrated to yield N- {2-[3-(chloromethyl)-2-methylphenoxy]ethylJ-l-ethyl-3-methyl-lH-pyrazole-5-carboxamide as a foamy white solid, 1.38 g. l-Ethyl-3-methyI-N-[2-(2-methyI-3-{[l-oxo-2(lH)-Phthalazinyl]methyl}phenoxy)ethyl]- l_H-pyrazole-5-carboxamide
50 mg N- { 2-[3-(chloromethyl)-2-methylphenoxy]ethyl } - 1 -ethyl-3-methyl- 1H- pyrazole-5-carboxamide was dissolved in 1 mL DMF. 35 mg l(2H)-phthalazinone, and
100 mg K2CO3 were added, and the mixture was warmed to 80 °C for 5 h. The solids were filtered off and rinsed with acetone, and the filtrate was evaporated. Purification by reversed phase preparative ΗPLC yielded pure l-ethyl-3-methyl-N-[2-(2-methyl-3-{ [l-oxo-2(lH)- phthalazinyljmethyl Jphenoxy)ethyl]-lH-pyrazole-5-carboxamide, 32 mg. Methyl l-[3-(2-{[(l-ethyI-3-methyI-l_H-pyrazol-5-yl)carbonyl]amino}ethoxy)- 2-methylbenzyl]-l_H-imidazole-4-carboxylate 1 g N-{2-[3-(chloromethyl)-2-methylphenoxyJethyl }-l-ethyl-3-methyl-lH-pyrazole-5- carboxamide was dissolved in 5 mL DMF. 0.5 g methyl lH-imidazole-4-carboxylate, and 2 g
K2CO3 were added, and the mixture was warmed to 80 °C for 6 h. The solids were filtered off and rinsed with acetone, and the filtrate was evaporated. Purification by column chromatography (Siθ2, EtOAc) yielded pure methyl l-[3-(2-{ [(l-ethyl-3-methyl-lH-pyrazol-
5-yl)carbonylJaminoJethoxy)-2-methylbenzyl]-lH-imidazole-4-carboxylate, 1.1 g. l-[3-(2-{[(l-Ethyl-3-methyl-lH-pyrazol-5-yl)carbonylJamino}ethoxy)-2-methylbenzyl]- lH-imidazole-4-carboxylic acid
0.13 g methyl l-[3-(2-{ [(l-ethyl-3-methyl-lH-pyrazol-5-yl)carbonyl]aminoJethoxy)- 2-methylbenzyl]-lH-imidazole-4-carboxylate was dissolved in 5 mL dioxane / 2 mL water. 0.8 mL 2M LiOΗ was added and the solution was stirred at RT for 45 minutes. 2 mL IN ΗC1 was added, and the suspension was extracted exhaustively with EtOAc. The combined organic extracts were dried over MgSO4 and evaporated to give l-[3-(2-{ [(l-ethyl-3-methyl- lH-pyrazol-5-yl)carbonyl]amino}ethoxy)-2-methylbenzyl]-lH-imidazole-4-carboxylic acid, 0.12 g. l-EthyI-3-methyl-N-[2-(2-methyl-3-{[4-(4-morpholinylcarbonyl)-l_H-imidazol- l-yl]methyl}phenoxy)ethyl]-lH-pyrazole-5-carboxamide
100 mg of l-[3-(2-{ [(l-ethyl-3-methyl-lH-pyrazol-5-yl)carbonylJaminoJethoxy)- 2-methylbenzyl]-lH-imidazole-4-carboxylic acid was dissolved in 2 mL of DMF, 30 mg moφholine and 120 mg of ΗBTU were added. The mixture was stirred for 18 hours, diluted with ethyl acetate, washed with 5% ΝaΗCU3, saturated NaCl, dried over MgSO4, and evaporated to give l-ethyl-3-methyl-N-[2-(2-methyl-3-{ [4-(4-moφholinylcarbonyl)-lH- imidazol-l-yl]methylJphenoxy)ethyl]-lH-pyrazole-5-carboxamide, 110 mg.
Compound 136 can be prepared by a similar scheme by replacing (3-methyl-lH- pyrazol-5-yl)(4-moφholinyl)methanone in place of l(2H)-phthalazinone. Scheme 19
Figure imgf000080_0001
l-[(4-ChIoro-3-methyl-2-pyridinyl)methyl]-l /-benzimidazole To a solution of 4-chloro-3-methyl-2-(chloromethyl)pyridine hydrochloride hydrochloride [prepared according to WO 9854172], 1 g, benzimidazole, 0.66 g, in 10 mL
DMF was added 2 g K2CO3. The mixture was stirred at rt for 18 h, filtered, and evaporated to
yield a residue which was purified by column chromatography (Siθ2, 20% acetone in ethyl acetate). l-[(4-chloro-3-methyl-2-pyridinyl)methylJ-lH-benzimidazole was obtained as a tan solid, 1.23 g.
3-{[2-(lH-Benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyl]oxy}-l-propanol
0.08 g 60% NaΗ dispersion was added to a solution of 0.7 mL 1,3-propane diol in
5 mL DMF. After 10 minutes, 0.25 g l-[(4-chloro-3-methyl-2-pyridinyl)methyl]-lH- benzimidazole was added. The mixture was warmed to 80 °C for 20 h, evaporated and purified by column chromatography (6:4: 1, acetone : acetonitrile : methanol). 3-{ [2-(lH- benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyl]oxyJ-l-propanol was obtained as a thick oil,
0.14 g.
2-(l/ -Benzimidazol-l-ylmethyl)-3-methyI-4-pyridinyl
3-[(3-Nitroimidazo [1 ,2-b] pyridazin-6-yl)oxy] propyl ether To a solution of 330 mg 3- { [2-( IH-benzimidazol- 1 -ylmethyl)-3-methyl-4- pyridinyljoxyj-l-propanol 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[l,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 purified by reverse phase preparative ΗPLC to yield 2-(l H-benzimidazol - l-ylmethyl)-3-methyl-4-pyridinyl 3-[(3-nitroimidazo[l,2-ό]pyridazin-6-yl)oxy]propyl ether, 140 mg. Scheme 20
Figure imgf000081_0001
(2-Methyl-3-{3-[(3-nitroimidazo[l,2-ό]pyridazin-6-yl)oxy]propoxy}phenyI)methanol
0.23 g 2-methyl-3-hydroxymethylphenol [prepared by lithium aluminum hydride reduction of 2-methyl-3-hydroxybenzoic acid], 0.4 g 6-(3-bromopropoxy)-
3-nitroimidazo[l,2-b]pyridazine [prepared by reacting the sodium salt of 1,3-propane-diol with 6-chloro-3-nitroimidazo[l,2-b]pyridazine: Kobe, J.; Stanovnik, B.; Tisler, Miha. Tetrahedron (1968), 24(1), 239 , then treating the product with triphenylphosphine and N- bromosuccinimide], and 1 g K2CO3 were combined in 6 mL DMF. The suspension was warmed to 70 °C for 2.5 h. The mixture was filtered, evaporated, and purified by column chromatography (Siθ2, 1: 1 ethyl acetate / hexane) to give (2-methyl-3-{3-[(3-nitroimidazo-
[l,2-bJpyridazin-6-yl)oxy]propoxy}phenyl)methanol as a light yellow solid, 0.18 g. 3-[3-(l_H-Benzimidazol-l-ylmethyl)-2-methylphenoxy]propyl 3-nitroimidazo- [l,2-6]pyridazin-6-yI ether 0.095 g (2-methyl-3-{3-[(3-nitroimidazo[l,2-ό]pyridazin-6-yl)oxy]propoxy}phenyl)- methanol, and 0.21 g triphenylphosphine combined in 5 mL DMF at 0 °C. 0.3-5 g carbon tetrabromide was added and the dark solution was stirred for 1.5 hours at 0 °C. 0.06 g benzimidazole, and 0.23 g K2CO3 were added, and the suspension was stirred at RT for 3 hours. The mixture was filtered, evaporated, and purified by reverse phase preparative HPLC to give 3-[3-(lH-benzimidazol-l-ylmethyl)-2-methylphenoxy]propyl 3-nitroimidazo[l,2-6]pyridazin-6-yl ether as an off-white solid, 30 mg. Scheme 21
Figure imgf000082_0001
3-{[2-(lH-Benzimidazol-l-yImethyl)-3-methyl-4-pyridinyl]oxy}propyl phenylcarbamate
3-{ [2-(lH-Benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyl]oxy}-l-propanol, 0.13 g, was dissolved in 5 mL TΗF. Phenyl isocyanate, 0.15 mL, and catalytic 4-dimethylaminopyridine were added. After 45 minutes at RT, the mixture was concentrated and purified by column chromatography (Siθ2, 60:35:5 acetone : acetonitrile : methanol) to yield 125 mg of
3- { [2-(l H-benzimidazol- l-ylmethyl)-3-methyl-4-pyridinyl]oxy} propyl phenylcarbamate as a white foam. Scheme 22
Figure imgf000083_0001
l-{[4-(3-Chloropropoxy)-3-methyl-2-pyridinyl]methyl}-lH-benzimidazole
3-{ [2-(lH-Benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyl]oxy}-l-propanol, 1.01 g, was dissolved in 15 mL TΗF. 1 mL thionyl chloride was added and the suspension was warmed to 50 °C for 1.5 h. The mixture was concentrated and dissolved in a minimum amount of methanol, the addition of ether precipitated a solid. The solid was collected and rinsed with ether to give 0.93 g of l-{[4-(3-chloropropoxy)-3-methyl-2-pyridinyl]methyl}- IH- benzimidazole hydrochloride salt as an off white solid. l-{[4-(3-Azidopropoxy)-3-methyl-2-pyridinyl]methyI}-lH-benzimidazole l-{ [4-(3-Chloropropoxy)-3-methyl-2-pyridinyl]methyl} -IH-benzimidazole hydrochloride salt, 0.25 g, was dissolved in 5 mL DMF / 2 mL water / 1 mL triethylamine. 0.48 g sodium azide was added, and the mixture was warmed at 90 °C for 3 h. The solution was allowed to cool, diluted with water, extracted with ethyl acetate (3X), dried over MgSO4 and evaporated. The residue was treated with ethereal ΗC1, and the solids were collected and rinsed with ether to give l-{ [4-(3-azidopropoxy)-3-methyl-2-pyridinyl]methylJ- IH- benzimidazole hydrochloride salt as a white solid, 0.23 g. 3-{[2-(l /-Benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyl]oxy}-l-propanamine
1 - { [4-(3- Azidopropoxy)-3-methyl-2-pyridinyl]methyl } - IH-benzimidazole hydrochloride salt, 0.1 g, was dissolved in 6 mL ethanol / 1 mL water. A catalytic amount of 10% palladium on carbon was added and the mixture was stirred under 1 atmosphere of hydrogen for 40 minutes. Filtration and evaporation yielded 3-{ [2-(lH-benzimidazol- l-ylmethyl)-3-methyl-4-pyridinyl]oxy}-l-propanamine as 95 mg clear thick oil. 7V-(3-{[2-(l_H-Benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyI]oxy}propyl)-iV-phenylurea 45 mg 3- { [2-( IH-benzimidazol- l-ylmethyl)-3-methyl-4-pyridinyl]oxy}- 1-propanamine, 1 mL TΗF, 0.5 mL DMF, 0.06 mL phenyl isocyanate and catalytic 4- dimethylaminopyridine were combined. The solution was stirred at RT for 30 minutes, evaporated and purified by reverse phase preparative ΗPLC to yield 47 mg N-(3-{ [2-(lH- benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyl]oxy}propyl)-N-phenylurea as a foamy oil. N-(3-{[2-(lH-benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyl]oxy}propyl)-l-ethyl- 3-methyl-lH-pyrazole-5-carboxamide
45 mg 3-{ [2-(lH-benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyl]oxyJ- 1-propanamine, 42 mg l-ethyl-3-methyl-lH-pyrazole-5-carboxylic acid,l mL TΗF, 0.5 mL DMF, 0.1 g BOP-Cl and 0.25 mL triethylamine were combined. The solution was stirred at RT for 30 minutes, evaporated and purified by reverse phase preparative ΗPLC to yield 23 mg N-(3-{ [2-(lH-benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyl]oxyJpropyl)-l-ethyl-3-methyl- lH-pyrazole-5-carboxamide as a foamy oil. Scheme 23
Figure imgf000084_0001
{ [(3-{ [2-(lJΪ-Benzimidazol-l -ylmethyl)-3-methyl-4-pyridinyl] oxy } propoxy)- carbonyl] amino} benzoic acid
25 mg of ethyl 4-{ [(3-{ [2-(lH-benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyl]oxyJ- propoxy)carbonyl] amino Jbenzoate was combined with 0.1 mL IM KOΗ, and 0.5 mL dioxane to give a clear solution. After stirring for 1 h at rt the reaction was diluted with water, extracted twice with ethyl acetate, the aq layer was acidified with cone ΗC1 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 4-{ [(3-{ [2-(lH-benzimidazol- l-ylmethyl)-3-methyl-4-pyridinyl]oxyJpropoxy)carbonyl]amino}benzoic acid as a white solid: 20 mg. Scheme 24
Figure imgf000085_0001
2-Methoxy-3-(hydroxymethyl)phenol 2 g 2-methoxy-3-hydroxybenzaldehyde (Kessar, Satinder V.; Gupta, Yash P.;
Mohammad, Taj; Goyal, Manju; Sawal, Kewal K J. Chem. Soc, Chem. Commun. (1983),
(7), 400) was dissolved in 30 mL THF / 10 mL methanol / 20 mL IN KOH. 1 g NaBH4 was added. After stirring at RT for 1.5 h, the mixture was diluted with water and extracted with ether (2X). The aqueous layer was acidified with cone HCI, and extracted with ethyl acetate (2X). The pooled ethyl acetate layer was dried over MgSO4 and evaporated to give
2-methoxy-3-(hydroxymethyl)phenol as a white solid, 2.02 g.
(2-Methoxy-3- {3- [(3-nitroimidazo [1 ,2-b] pyridazin-6-y l)oxy ] propoxy } pheny l)methanol
0.23 g 2-methoxy-3-hydroxymethylphenol, 0.4 g 6-(3-bromopropoxy)-
3-nitroimidazo[l,2-b]pyridazine, and 1 g K2CO3 were combined in 6 mL DMF. The suspension was warmed to 70 °C for 2.5 h. The mixture was filtered, evaporated, and purified by column chromatography (Siθ2, 1:1 ethyl acetate / hexane) to give (2-methoxy-
3-{3-[(3-nitroimidazo[l,2- >]pyridazin-6-yl)oxy]propoxy}phenyl)methanol as a light yellow solid, 0.2 g.
3-[3-(l_ _T-Benzimidazol-l-ylmethyl)-2-methoxyphenoxy]propyl 3-nitroimidazo- [l,2-6]pyridazin-6-yl ether
0.095 g (2-methoxy-3-{3-[(3-nitroimidazo[l,2-b]pyridazin-6-yl)oxy]propoxy}phenyl)- methanol, and 0.21 g triphenylphosphine combined in 5 mL DMF at 0 °C. 0.35 g carbon tetrabromide was added and the dark solution was stirred for 1.5 hours at 0 °C. 0.06 g benzimidazole, and 0.23 g K2CO3 were added, and the suspension was stirred at RT for 3 hours. The mixture was filtered, evaporated, and purified by reverse phase preparative HPLC to give 3-[3-( IH-benzimidazol- l-ylmethyl)-2-methoxyphenoxy]ρropyl 3-nitroimidazo[l,2-b]pyridazin-6-yl ether as an off-white solid, 42 mg. Scheme 25
Figure imgf000086_0001
Ethyl 3-(2-{[fer/-butyl(dimethyI)silyl]oxy}ethoxy)-2-(trifluoromethyl)benzoate
Ethyl 3-hydroxy-2-(trifluoromethyl)benzoate [Barlow, Michael G.; Suliman, Nadia N.
E.; Tipping, Anthony E. J. Fluorine Chem. (1995), 70(1), 59], 0.184 g, K2CO3, 0.12 g, and
(2-bromoethoxy)(tert-butyl)dimethylsilane, 0.221 g, were combined in 5 mL acetonitrile. The suspension was refluxed for 18 h, filtered, and evaporated to give ethyl 3-(2- {[tert- butyl(dimethyl)silyl]oxy}ethoxy)-2-(trifluoromethyl)benzoate, 0.24g.
[3-(2-{[ter^Butyl(dimethyl)silyI]oxy}ethoxy)-2-(trifluoromethyl)phenyl]methanol
0.24 g ethyl 3-(2-{ [tert-butyl(dimethyl)silyl]oxy}ethoxy)-2-(trifluoromethyl)benzoate was dissolved in 10 mL TΗF. 0.1 g lithium aluminum hydride was added and the mixture was stirred at RT for 18 h. After the sequential addition of water, 0.1 mL, 5 M NaOΗ,
0.1 mL, water, 0.3 mL, and Na2SO4, the mixture was filtered and evaporated to give
[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)-2-(trifluoromethyl)phenyl]methanol as a clear oil, 0.14g.
2-[3-(Bromomethyl)-2-(trifluoromethyI)phenoxy]-l-ethanol N-Bromosuccinimide, 0.157 g, was dissolved in 5 mL methylene chloride and cooled to 0 °C. Dimethylsulfide, 0.071 mL, was added slowly and the mixture was stirred for 30 minutes at 0 °C. A solution of 0.14 g [3-(2-{ [tert-butyl(dimethyl)silyl]oxy}ethoxy)- 2-(trifluoromethyl)phenyl]methanol in 2 mL methylene chloride was added, and the reaction was allowed to proceed at RT for 18 h. The mixture was concentrated and purified by chromatography to give the desilylated product, 2-[3-(bromomethyl)- 2-(trifluoromethyl)phenoxy]-l -ethanol, 60 mg. 2-[3-(lH-Benzimidazol-l-ylmethyI)-2-(trifluoromethyl)phenoxy]-l-ethanol
60 mg 2-[3-(bromomethyl)-2-(trifluoromethyl)phenoxy]-l -ethanol was combined with 24 mg benzimidazole and 55 mg K2CO3 in 2 mL DMF. The mixture was stirred at RT for 18
h, diluted with water, extracted with ethyl acetate and dried over MgSO4 to give 2-[3-( IH- benzimidazol- l-ylmethyl)-2-(trifluoromethyl)phenoxy]-l -ethanol as a clear oil, 50 mg. 2-[3-(lH-BenzimidazoI-l-ylmethyl)-2-(trifluoromethyl)phenoxy]ethyI phenylcarbamate
50 mg 2-[3-(lH-benzimidazol-l-ylmethyl)-2-(trifluoromethyl)phenoxy]-l-ethanol was combined with 20 mg phenyl isocyanate in 3 mL methylene chloride. The solution was stirred at RT for 18 h, concentrated and purified by reverse phase preparative ΗPLC to give 2-[3-( IH-benzimidazol- l-ylmethyl)-2-(trifluoromethyl)phenoxy]ethyl phenylcarbamate as a white solid, 30 mg.
Scheme 26
Figure imgf000087_0001
2-[3-(lH-Benzimidazol-l-yImethyl)-2-ch ^loroophenoxy]-l-eth-anol
1.2 g { 2-[3-(bromomethyl)-2-chlorophenoxy]ethoxy } (tert-butyl)dimethylsilane,
0.372 g benzimidazole, 0.87 g K2CO3 and 10 mL DMF were combined and stirred at RT for 18 h. The mixture was filtered, evaporated and purified by reverse phase preparative ΗPLC using a mobile phase containing 0.1% trifluoroacetic acid. 0.18 g of the desilylated product 2-[3-(lH-benzimidazol-l-ylmethyl)-2-chlorophenoxy]-l-ethanol was thus obtained. 2-[3-(l -Benzimidazol-l-ylmethyI)-2-chlorophenoxy] ethyl phenylcarbamate
0.1 g 2-[3-( IH-benzimidazol- l-ylmethyl)-2-chlorophenoxy]-l -ethanol was dissolved in 2 mL chloroform and 0.05 mL phenyl isocyanate was added. The mixture was stirred at RT for 18 h, evaporated and purified by reverse phase preparative ΗPLC to yield 2-[3-( IH- benzimidazol- l-ylmethyl)-2-chlorophenoxy]ethyl phenylcarbamate as 75 mg white solid. Scheme 27
Figure imgf000088_0001
tert-Butyl 2-[3-(hydroxymethyl)-2-methylphenoxy]ethylcarbamate 1.28 g [3-(2-aminoethoxy)-2-methylphenyl]methanol [prepared by reaction of
2-methyl-3-(hydroxymethyl)phenol with bromoacetonitrile, followed by reduction of the product with lithium aluminum hydride] was dissolved in 15 mL THF / 15 mL acetonitrile.
2 mL di-tert-butyl-dicarbonate and a solution of 5 g K2CO3 in 20 mL water were added, and the mixture was vigorously stirred for 3 hours. The mixture was diluted with ethyl acetate, washed with water, 1 N HCI, and sat. NaCl, dried over MgSO4, evaporated and dried in vacuo. tert-Butyl 2-[3-(hydroxymethyl)-2-methylphenoxy]ethylcarbamate was obtained as a waxy yellow solid, 2.1 g. /erf-Butyl 2-[3-(chloromethyl)-2-methyIphenoxy]ethylcarbamate
2.08 g N-chlorosuccinimide was dissolved in 50 mL CH2CI2 and cooled to 0 °C. 1.03 mL dimethylsulfide was added dropwise over 30 min to give a cloudy white suspension. After 10 minutes at 0 °C, a solution of 1.98 g tert-butyl 2-[3-(hydroxymethyl)-
2-methylphenoxy]ethylcarbamate in 20 mL CH2CI2 was added. The cold bath was removed and the mixture was stirred for 1 hour. The resultant clear solution was concentrated and purified by column chromatography (Siθ2, 5% ethyl acetate / methylene chloride). tert-Butyl
2-[3-(chloromethyl)-2-methylphenoxy]ethylcarbamate was obtained as a white solid, 1.5 g. Methyl l-(3-{2-[(tert-butoxycarbonyl)amino]ethoxy}-2-methylbenzyl)-lH-imidazole-5- carboxylate, methyl l-(3-{2-[(tert-butoxycarbonyl)amino]ethoxy}-2-methylbenzyI)-lH- imidazole-4-carboxylate
0.5 g tert-butyl 2-[3-(chloromethyl)-2-methylphenoxy]ethylcarbamate, 0.265 g methyl lH-imidazole-4-carboxylate, 1.2 g K2CO3, and 5 mL DMF were combined and stirred at
80 °C for 45 minutes. The mixture was filtered, concentrated, and purified by column chromatography to give 0.17 g methyl l-(3-{2-[(tert-butoxycarbonyl)amino]ethoxy}- 2-methylbenzyl)-lH-imidazole-5-carboxylate, and 0.32 g methyl l-(3-{2-[(tert- butoxycarbonyl)amino]ethoxy}-2-methylbenzyl)-lH-imidazole-4-carboxylate. l-(3-{2-[(/er/-Butoxycarbonyl)amino]ethoxy}-2-methylbenzyl)-lJϊr-imidazole-4- carboxylic acid
0.13 g methyl l-(3-{2-[(tert-butoxycarbonyl)amino]ethoxy}-2-methylbenzyl)-lH- imidazole-4-carboxylate was dissolved in 5 mL dioxane / 2 mL water. 0.8 mL 2M LiOΗ was added and the solution was stirred at RT for 45 minutes. 2 mL IM ΗC1 was added and the suspension was extracted with ethyl acetate. The organic extract was washed with brine, dried over MgSO4, and evaporated to give l-(3-{2-[(tert-butoxycarbonyl)amino]ethoxy}-
2-methylbenzyl)-lH-imidazole-4-carboxylic acid as a white solid, 0.119 g. Scheme 28
Figure imgf000089_0001
l-{[3-MethyI-4-(3-phenoxypropoxy)-2-pyridinyl]methyl}-lH-benzimidazole
1 - { [4-(3-Chloropropoxy)-3-methyl-2-pyridinyl]methyl } - 1 H-benzimidazole hydrochloride salt, 50 mg, phenol, 45 mg, K2CO3, 500 mg, and DMF, 3 mL, were combined and stirred at 80 °C for 3 days. The mixture was filtered, evaporated and purified by reverse phase HPLC to give l-{ [3-methyl-4-(3-phenoxypropoxy)-2-pyridinyl]methyl }- IH- benzimidazole as 27 mg thick oil. Scheme 29
Figure imgf000090_0001
2-(2-{[3-({[/ert-Butyl(dimethyl)silyl]oxy}methyl)-2-methylphenyl]sulfanyl}ethyl)-2JH- 1,2,3,4-tetraazole
2- { [3-( { [tert-Butyl(dimethyl)silyl]oxy } methyl)-2-methylphenyl]sulfanyl } - 1 -ethanol, 1.2 g, triphenylphosphine, 1.6 g, and tetrazole, 0.42 g, were combined in 10 mL TΗF 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]oxyJmethyl)-2-methylphenyl]sulfanyl}ethyl)-2H-l,2,3,4- tetraazole as an oil, 770 mg. (2-Methyl-3-{[2-(2 -l,2,3,4-tetraazol-2-yl)ethyl]suIfanyl}phenyl)methanol
2-(2-{ [3-({ [tert-Butyl(dimethyl)silyl]oxyJmethyl)-2-methylphenyl]sulfanyl}ethyl)-2H- 1,2,3,4-tetraazole, 770 mg, was dissolved in 20 mL TΗF and treated with 3 mL 75% aq. TBAF. 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-{ [2-(2H-l,2,3,4-tetraazol-2-yl)ethyl]sulfanyl}phenyl)methanol, 500 mg. 2-(2-{[3-(Chloromethyl)-2-methylphenyl]sulfanyl}ethyl)-2H-l,2,3,4-tetraazoIe 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 h. Evaporation to dryness gave 2-(2-{ [3-(chloromethyl)-2-methylphenyl]sulfanyl}ethyl)-2H- 1,2,3,4-tetraazole, 105 mg.
2-(2-Methyl-3-{[2-(2JH-l,2,3,4-tetraazol-2-yl)ethyl]sulfanyl}benzyl)-lH-isoindoIe-l,3(2H)- dione
0.95 g of 2-(2-{ [3-(chloromethyl)-2-methylphenyl]sulfanyl}ethyl)-2H- 1,2,3,4- tetraazole was combined with 0.11 g phthallimide and 2.2 g K2CO3 in 5 mL DMF. The mixture was stirred at rt overnight, diluted with ethyl acetate, washed with water, brine, dried over MgSO4, and evaporated to yield 2-(2-methyl-3-{ [2-(2H-l,2,3,4-tetraazol-
2-yl)ethyl]sulfanyl}benzyl)-lH-isoindole-l,3(2H)-dione, 0.78 g. Scheme 30
Figure imgf000091_0001
2-{3-[(2-Formyl-l//-imidazoI-l-yl)methyl]-2-methyIphenoxy}ethyl phenylcarbamate
To a solution of 0.5 g of 2-[3-(chloromethyl)-2-methylphenoxy]ethyl phenylcarbamate (prepared as described in scheme 1, replacing methyl 2-{[3-(hydroxymethyl)- 2-methylphenyl]sulfanylJ acetate with methyl 2-[3-(hydroxymethyl)-2-methylphenoxy]acetate) in 3 mL of DMSO was added 0.23 g lH-imidazole-2-carbaldehyde and 2 g potassium carbonate. The mixture was stirred at room temperature for 1 hour, filtered and purified by reverse phase preparative ΗPLC. 2-{3-[(2-formyl-lH-imidazol-l-yl)methyl]- 2-methylphenoxy Jethyl phenylcarbamate was obtained as a white solid, 0.4 g. 2-(3-{[2-(Hydroxymethyl)-lH-imidazoI-l-yl]methyl}-2-methylphenoxy)ethyl phenylcarbamate
0.2 g 2- {3-[(2-formyl-lH-imidazol-l-yl)methylJ-2-methylphenoxy Jethyl phenylcarbamate was dissolved in 5 mL TΗF. 3 mL methanol, 2 mL water, and 0.5 mL IM KOΗ were added. Sodium borohydride, 95 mg, was added and the mixture was stirred for 30 minutes. The reaction was neutralized with IM ΗC1, filtered, and purified by reverse phase preparative ΗPLC. 2-(3-{ [2-(hydroxymethyl)- IH-imidazol- 1 -yljmethyl }- 2-methylphenoxy)ethyl phenylcarbamate was obtained as a white solid, 0.16g. 2-(3-{[2-(Chloromethyl)-l_H-imidazol-l-yl]methyl}-2-methylphenoxy)ethyl phenylcarbamate
To an ice-cold solution of 2-(3-{ [2-(hydroxymethyl)- IH-imidazol- 1-ylJmethylJ- 2-methylphenoxy)ethyl phenylcarbamate, 0.27 g, in 10 mL TΗF was added thionyl chloride, 1 mL. The mixture was stirred under ice bath cooling for 20 minutes, then concentrated in vacuo. The residue was triturated with 1:1 hexane:diethyl ether to yield 2-(3- { [2-(chloromethyl)- 1 H-imidazol- 1 -yljmethyl } -2-methylphenoxy)ethyl phenylcarbamate as a white solid, 0.24 g.
2-(2-Methyl-3-{[2-(4-morpholinyImethyl)-lH-imidazol-l-yl]methyl}phenoxy)ethyl phenylcarbamate
To a solution of 2-(3-{ [2-(chloromethyl)-lH-imidazol-l-yl]methylJ- 2-methylphenoxy)ethyl phenylcarbamate, 50 mg, in 0.75 mL DMF was added moφholine, 0.15 mL. The solution was warmed at 802C for 1.5 h. Purification by reverse phase ΗPLC gave 2-(2-methyl-3-{ [2-(4-moφholinylmethyl)-lH-imidazol-l-yl]methyl}phenoxy)ethyl phenylcarbamate as an off-white solid, 32 mg. Scheme 31
Figure imgf000092_0001
2-[5-(HydroxymethyI)-2-methoxyphenoxy]-l-ethanol
5-(Hydroxymethyl)-2-methoxyphenol, 5g, ethylene carbonate, 3.43 g, potassium carbonate, 5g, and DMF, 20 mL were combined and warmed at 100 9C for 4 hours. The mixture was filtered, evaporated and purified by chromatography (silica, hexane/ethyl acetate) to give 2-[5- (hydroxymethyl)-2-methoxyphenoxy]-l -ethanol as a thick clear yellow oil, 4.98 g. 5-(Chloromethyl)-2-methoxyphenol
1.15 g of 2-[5-(hydroxymethyl)-2-methoxyphenoxy]-l -ethanol was dissolved in 5.8 mL 4M HCI in dioxane. The solution was stirred at room temperature for 3.5 hours, concentrated in vacuo, and purified by chromatography (silica, hexane/ethyl acetate). 5- (chloromethyl)-2-methoxyphenol was obtained as a white solid, 1 g. 2-[5-(lH-Imidazol-l-ylmethyl)-2-methoxyphenoxyJ-l-ethanol
0.5 g of 5-(chloromethyl)-2-methoxyphenol was combined with 0.24 g imidazole, 1.6 g potassium carbonate, and 5 mL DMF. The mixture was stirred at room temperature overnight, filtered, evaporated, and purified by chromatography (silica, ethyl acetate / methanol / acetonitrile). 2-[5-(lH-imidazol-l-ylmethyl)-2-methoxyphenoxy]-l-ethanol was obtained as a thick yellow oil, 0.64 g. 2-[5-(l_Η-Imidazol-l-yImethyl)-2-methoxyphenoxy]ethyl phenylcarbamate
0.118 g 2-[5-( IH-imidazol- l-ylmethyl)-2-methoxyphenoxy]-l -ethanol was dissolved in 1 mL TΗF. Phenyl isocyanate, 0.1 mL, and a catalytic amount of 4-(dimethylamino)- pyridine were added. The mixture was stirred overnight at room temperature, and purified by chromatography (silica, ethyl acetate / acetonitrile / methanol). 2-[5-(lH-imidazol- l-ylmethyl)-2-methoxyphenoxy]ethyl phenylcarbamate was obtained as a white solid, 50 mg. Scheme 32
Figure imgf000093_0001
/er/-ButyI 2-[2-methyI-3-({4-[(methyIamino)carbonyl]-l_H-imidazol- l-yl}methyl)phenoxy]ethylcarbamate To a solution of 100 mg l-(3-{2-[(tert-butoxycarbonyl)amino]ethoxyJ- 2-methylbenzyl)-lH-imidazole-4-carboxylic acid, 0.2 mL methylamine (2M TΗF solution), and 34 mg diisopropylethyl amine in 5 mL dichloromethane was added 25 mg (1H- l,2,3-benzotriazol-l-yloxy)[tri(l-pyrrolidinyl)Jphosphonium hexafluorophosphate (PyBop). The mixture was stirred overnight, subjected to an aqueous workup and purification by reverse phase ΗPLC to yield 78 mg tert-butyl 2-[2-methyl-3-({4-[(methylamino)carbonylJ- lH-imidazol-l-yl}methyl)phenoxy]ethylcarbamate as a white solid. l-[3-(2-Aminoethoxy)-2-methylbenzyl]-7V-methyl-lH-imidazole-4-carboxamide
To a solution of 100 mg tert-butyl 2-[2-methyl-3-({4-[(methylamino)carbonyl]-lH- imidazol-l-yl}methyl)phenoxy]ethylcarbamate in 1 mL dioxane was added 0.16 mL 4M ΗC1 in dioxane. The mixture was stirred for 3 hours at room temperature and concentrated in vacuo to yield l-[3-(2-arninoethoxy)-2-methylbenzyl]-N-methyl-lH-imidazole-4-carboxamide as a white solid, 70 mg. l-(3-{2-[(Anilinocarbonyl)amino]ethoxy}-2-methylbenzyl)-N-methyl-l_H-imidazole-4- carboxamide
To a solution of l-[3-(2-aminoethoxy)-2-methylbenzyl]-N-methyl-lH-imidazole-4- carboxamide, 20 mg, and diisopropylethyl amine, 54 mg, in methylene chloride, 2 mL, was added phenyl isocyanide, 8 mg. The mixture was stirred overnight and purified by reverse phase preparative ΗPLC. l-(3-{2-[(anilinocarbonyl)aminoJethoxy}-2-methylbenzyl)-N- methyl- lH-imidazole-4-carboxamide was obtained as a white solid, 20 mg. Scheme 33
Figure imgf000094_0001
tert-Butyl 2-{3-[(2-amino-l -imidazol-l-yl)methyI]-2-methylphenoxy}ethylcarbamate
To a solution of 380 mg of tert-butyl 2-{2-methyl-3-[(2-nitro-lH-imidazol- l-yl)methylJphenoxy} ethylcarbamate (scheme 27) in 10 mL ethanol was added 100 mg 10% palladium on carbon. The suspension was hydrogenated under 65 PSI hydrogen gas pressure in a shaker for 2 hours. The mixture was filtered and evaporated to yield tert-butyl
2-{3-[(2-amino-lH-imidazol-l-yl)methyl]-2-methylphenoxy}ethylcarbamate as a white solid, 310 mg. ter/-ButyI 2-(3-{[2-(acetylamino)-l/_ midazoI-l-yl]methyl}-2-methylphenoxy)- ethylcarbamate 62 mg of tert-butyl 2-{3-[(2-amino-lH-imidazol-l-yl)methyl]-2-methylphenoxy}- ethylcarbamate, 19 mg acetic anhydride, and 0.1 mL diisopropylethyl amine were combined in 1 mL dichloromethane and stirred overnight at room temperature. The reaction was concentrated and purified with reverse phase preparative ΗPLC to yield tert-butyl 2-(3-{ [2-(acetylamino)-lH-imidazol-l-ylJmethyl}-2-methylphenoxy)ethylcarbamate as a white solid, 40 mg. V-{l-[3-(2-Aminoethoxy)-2-methylbenzyI]-lJΪ-imidazol-2-yl}acetamide
To a solution of 78 mg of tert-butyl 2-(3-{[2-(acetylamino)-lH-imidazol- 1 -yljmethyl }-2-methylphenoxy)ethylcarbamate in 1 mL dioxane was added 0.16 mL 4M ΗC1 in dioxane. After stirring for 3 hours at room temperature, the mixture was concentrated to yield N-{ l-[3-(2-aminoethoxy)-2 -methylbenzyl]- lH-imidazol-2-yl} acetamide as the ΗC1 salt, 50 mg.
7V-[2-(3-{[2-(Acetylamino)-l_flr-imidazol-l-yI]methyl}-2-methylphenoxy)ethyI]-l-ethyl- 3-methyI-lH-pyrazole-5-carboxamide
To a solution of 27 mg l-ethyl-3-methyl-lH-pyrazole-5-carboxylic acid, 40 mg N- { l-[3-(2-aminoethoxy)-2-methylbenzyl]-lH-imidazol-2-yl} acetamide and 69 mg diisopropylethyl amine in 1 mL dichloromethane was added 90 mg (lH-l,2,3-benzotriazol- l-yloxy)[tri(l-pyrrolidinyl)]phosphonium hexafluorophosphate (PyBop). The solution was stirred at room temperature overnight, concentrated and purified by reverse phase preparative ΗPLC. N-[2-(3-{ [2-(acetylamino)- IH-imidazol- 1 -yljmethyl }-2-methylphenoxy)ethyl]- l-ethyl-3-methyl-lH-pyrazole-5-carboxamide was obtained as a white solid, 50 mg. Scheme 34
Figure imgf000096_0001
2-({l-[3-(2-{[(l-EthyI-3-methyl-lH-pyrazol-5-yl)carbonyl]amino}ethoxy)- 2-methylbenzyl]-lH-imidazol-2-yl}suIfanyl)acetic acid
To a solution of 230 mg methyl 2-({ l-[3-(2-{ [(l-ethyl-3-methyl-lH-ρyrazol-5- yl)carbonyl]amino}ethoxy)-2-methylbenzylJ-lH-imidazol-2-yl}sulfanyl)acetate in 3 mL methanol / 1.5 mL water was added 41 mg lithium hydroxide. The mixture was stirred at room temperature for 1 hour, neutralized with IM ΗC1, and extracted with ethyl acetate. The solution was dried over sodium sulfate, filtered and evaporated to yield 2-({ l-[3-(2-{ [(1-ethyl- 3-methyl-lH-pyrazol-5-yl)carbonylJamino}ethoxy)-2-methylbenzylJ-lH-imidazol- 2-yl}sulfanyl)acetic acid as a white solid, 175 mg. l-Ethyl-3-methyI-N-(2-{2-methyl-3-[(2-{[2-(4-morpholinyl)-2-oxoethyI]sulfanyl}-lH- imidazol-l-yl)methyl]phenoxy}ethyI)-lH-pyrazole-5-carboxamide To 1 mL of dichloromethane was added 32 mg 2-({ l-[3-(2-{ [(l-ethyl-3-methyl-lH- pyrazol-5-yl)carbonyl]amino}ethoxy)-2-methylbenzyl]-lH-imidazol-2-yl}sulfanyl)acetic acid, 6 mg moφholine, 36 mg (lH-l,2,3-benzotriazol-l-yloxy)[tri(l-pyrrolidinyl)]phosphonium hexafluorophosphate (PyBop) and 9 mg diisopropylethyl amine. The solution was stirred at room temperature overnight, concentrated and purified by reverse phase preparative ΗPLC. l-ethyl-3-methyl-N-(2-{2-methyl-3-[(2-{[2-(4-moφholinyl)-2-oxoethyl]sulfanyl}-lH- imidazol-l-yl)methylJphenoxy} ethyl)- lH-pyrazole-5-carboxamide was obtained as a white solid, 22mg. Scheme 35
Figure imgf000096_0002
3-(l /-Imidazol-l-ylmethyl)-2-methyIaniline To a solution of 360 mg tert-butyl 3-( IH-imidazol- 1-ylmethyl)- 2-methylphenylcarbamate (prepared according to scheme 10, replacing 2-nitroimidazole with imidazole) in 5 mL dioxane was added 1 mL 4M ΗC1 in dioxane. The mixture was stirred for 2 hours at room temperature, and concentrated to give 3-( IH-imidazol- 1-ylmethyl)- 2-methylaniline as an off-white solid, 235 mg.
N-[3-(l_H-Imidazol-l-ylmethyl)-2-methylphenyl]acetamide
To a solution of 55 mg of 3-( IH-imidazol- l-ylmethyl)-2-methylaniline in 1 mL methylene chloride was added 0.1 mL diisopropylethyl amine and 0.1 mL acetic anhydride. The mixture was stirred at room temperature overnight and methanol was added to consume excess reagents. Concentration and purification by reverse phase preparative ΗPLC yielded N-[3-( IH-imidazol- l-ylmethyl)-2-methylphenyl] acetamide as a white solid, 30 mg. Scheme 36
Figure imgf000097_0001
2-[3-(lH-Imidazol-l-yImethyl)-2-methyIphenoxy]ethyl 2-pyridinyl carbonate
To a solution of 2-[3-(lH-imidazol-l-ylmethyl)-2-methylphenoxy]-l-ethanol (prepared according to scheme 31, replacing 5-(hydroxymethyl)-2-methoxyphenol with 3-(hydroxymethyl)-2-methylphenol), 2 g, in 25 mL dichloromethane was added 2.8 g di(2-pyridinyl) carbonate and 1.8 mL triethylamine. The mixture was stirred at room temperature overnight, evaporated and purified by chromatography (hexane / ethyl acetate) to give 2-[3-( IH-imidazol- l-ylmethyl)-2-methylphenoxy]ethyl 2-pyridinyl carbonate as an off- white solid, 1.8 g.
2-[3-(lH-Imidazol-l-ylmethyl)-2-methylphenoxy]ethyI 4-morpholinecarboxylate To a solution of 50 mg 2-[3-(lH-imidazol-l-ylmethyl)-2-methylphenoxy]ethyl 2-pyridinyl carbonate in 1 mL dichloromethane was added 0.05 mL moφholine. The mixture was stirred at room temperature overnight, concentrated and purified by reverse phase preparative ΗPLC. 2-[3-(l H-imidazol- l-ylmethyl)-2-methylphenoxy]ethyl 4- moφholinecarboxylate was obtained as a white solid, 41 mg. Scheme 37
Figure imgf000098_0001
2-[3-(lH-Imidazol-l-ylmethyl)-2-methylphenoxy]-l-ethanamine
To a solution of 1.05 g tert-butyl 2-[3-(lH-imidazol-l-ylmethyl)- 2-methylphenoxy]ethylcarbamate in 8 mL dioxane / 3 mL water was added 6 mL 4M ΗC1 in dioxane. The mixture was stirred at room temperature for 2 hours, concentrated in vacuo, and triturated with diethyl ether to yield 2-[3-( IH-imidazol- l-ylmethyl)-2-methylphenoxy]- 1-ethanamine as a white solid, 0.94 g. N-{2-[3-(lHr-Imidazol-l-ylmethyl)-2-methylphenoxy]ethyl}-2-thiophenecarboxamide
To a solution of 50 mg 2-[3-(lH-imidazol-l-ylmethyl)-2-methylphenoxy]- 1-ethanamine in 1.5 mL DMF was added 31 mg 2-thiophenecarboxylic acid, 0.1 mL triethylamine and 82 mg bis(2-oxo-l,3-oxazolidin-3-yl)phosphinic chloride (Bop-Cl). The mixture was stirred at room temperature for 1 day, filtered, and purified by reverse phase ΗPLC to yield N-{2-[3-(lH-imidazol-l-ylmethyl)-2-methylphenoxy]ethyl}- 2-thiophenecarboxamide as a white solid, 35 mg.
Table 1 shows which compounds can be made by each of Schemes 1 to 29 or by schemes that are similar to schemes 1 to 29, but differ in one or more reagents as will be readily apparent to the skilled person taking into account the final compound.
Table 1
Figure imgf000099_0001
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 (OD60o of 0.6) and 50 μl of these cultures were inoculated into each well to give a final concentration of 10 cells per mL (OD6oo 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 (OD60o) with a plate reader (Molecular Devices, Sunnyvale, California). The plates were incubated in a controlled microaerophilic atmosphere (5% O2, 10% CO2 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 <10μg/mL are indicative of anύ-Helicobacter pylori 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 aslo 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 fomulation 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 intramuscular administration, the patient may receive a daily dose of 5 mgkg"
to 20 mgkg of the compound, the compound being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular 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 100 mg and 1 g 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)
Figure imgf000101_0001
(b)
Figure imgf000102_0001
Buffers, pharmaceutically acceptable cosolvents (e.g., polyethylene glycol, propylene glycol, glycerol or EtOH) or complexing agents such as hydroxy-propyl β 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 Helicobacter pylori 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.

Claims

CLAIMS:
A compound of formula I or a pharmaceutically acceptable salt or solvate thereof,
Figure imgf000104_0001
wherein:
A optionally contains N as a heteroatom;
W is a 5- or 6-membered heterocyclic ring containing N as a heteroatom and linked by said heteroatom and optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S, the ring being optionally substituted and optionally fused to an optionally substituted 3-, 4-, 5-, 6-, 7- or 8-membered carbocyclic ring or heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from O, N and S;
X is S, SO, SO2, NH; N(C,.6alkyl), O or CH2;
R1 is -(CH2)a-R3, -((CH2)bO)c-R3, -(CH2)d-R3', -(CH2)e-O-(CH2)f- R3', R3 or R3';
R2 is Cι.6alkyl, O(C3.6 cycloalkyl), O(Cι-6alkyl), Hal, CHal3, CHHal2, CH2Hal,
OCHal3, OCHHal2 or OCH2Hal, wherein Hal represents halogen; NR R5, wherein R4 and R5 independently represent H or C1-8alkyl, or NR4R5 represents an optionally substituted C3- heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S; H; COOR' or COR', R' representing H or Cι-6alkyl; or CH2OH;
R3 is H; Cι.6alkyl; optionally substituted C3. cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted C5-1o aromatic ring structure optionally N and S; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered mono- or bi-cyclic heterocyclic ring structure containing 1, 2, 3, 4 or 5 heteroatoms independently selected from O, N and S;
R3 is -Z-M wherein Z represents O, 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 O, N and S, or an optionally substituted C5.10 aromatic ring structure optionally containing from 1, 2 or 3 heteroatoms independently selected from O, N and S; or -Z-M represents -C(=O)NR6R7, -NR6R7, -OC(=O)NR8R9, -NC(=O)NR8R9, -NC(=O)R8 or -NC(=O)OR8; For R6 and R7, either:
(i) R6 is H; Cι-8alkyl; optionally substituted C3.8 cycloalkyl optionally fused to a benzo
2 2 ring; Z (Cι-8alkyl)aryl, wherein Z represents O or a bond, and the aryl is C -ιo, optionally substituted and optionally fused to a C5-ιo heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S; optionally substituted C5.10 aromatic ring structure; an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from O, N and S; (Cι-8alkyl)-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 O, N and S; optionally substituted -C(=O)O(Cι-8alkyl); optionally substituted -C(=O)O-phenyl; optionally substituted -C(=O)(Cι-8alkyl); optionally substituted -C(=O)- phenyl; or -NC(=O)R8 and R7 is H; C1-8alkyl; optionally substituted C3-8cycloalkyl optionally fused to a benzo ring; (Cι-8alkyl)aryl wherein the aryl is C6-10 and optionally substituted; optionally substituted C5-1o aromatic ring structure; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring structure containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or (ii) the structure -NR6R7 represents a C3-8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S and optionally fused to a C6-1o ring structure, -NR R being optionally substituted; For R8 and R9, either:
(i) R is H; Cι_ι2alkyl; optionally substituted C3-8 cycloalkyl optionally fused to a benzo ring; optionally substituted (Cι-8alkyl)aryl wherein the aryl is C6-ι0; 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 O, N and S or R represents a mono-, bi- or tri-cyclic C3-ι3cycloalkyl; optionally substituted C5.10 aromatic ring structure; 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 O, N and S; or -C(=O)O-Ar, wherein Ar represents optionally substituted C5_ι0 aromatic ring structure; and R9 is H; or (ii) the structure -NR R represents a C3-8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S, -NR R being optionally substituted; a represents 1, 2, 3, 4 or 5; each b independently represents 1, 2, 3, 4 or 5; each c independently represents 1, 2, 3, 4 or 5; d represents 1, 2, 3, 4 or 5; e represents 1, 2, 3, 4 or 5; f represents an integer from lto 5; and g represents 1, 2, 3, 4 or 5.
2. A compound according to Claim 1, wherein: a is 2 or 3; b is 2; d is 2 or 3; and g is 1, 2 or 3.
3. A compound according to either Claim 1 or 2, wherein:
R1 is -(CH2)a-R3; -((CH2)bO)c-R3; -(CH2)d-R3' or -(CH2)e-O-(CH2)f- R3'; R2 is Cι-6alkyl; O(C3.8 cycloalkyl); O(Cι.6alkyl); Hal; CHal3, CHHal2, CH2Hal,
OCHal3, OCHHal2 or OCH2Hal, wherein Hal represents halogen; NR4R5, wherein R4 and R5
independently represent H or Cι.8alkyl; or CH2OH;
R3 is optionally substituted C3.8cycloalkyl optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S; optionally substituted C5- 10 aromatic ring structure optionally N and S; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered mono- or bi- cyclic heterocyclic ring structure containing 1, 2, 3, 4 or 5 heteroatoms independently selected from O, 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 O, 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 O, 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 C _ιo aromatic ring structure optionally containing from 1, 2 or 3 heteroatoms independently selected from O, N and S; or -Z-M represents -C(=O)NR6R7, -NR6R7, -OC(=O)NR8R9, -NC(=O)NR8R9, -NC(=O)R8 or -NC(=O)OR8;
For R6 and R7, either:
(i) R6 is H; Cι-8alkyl; optionally substituted C3-8 cycloalkyl optionally fused to a benzo
2 2 ring; Z (C1-8alkyl)aryl, wherein Z represents O or a bond, and the aryl is C6-ιo, optionally substituted and optionally fused to a C5-ιo heterocyclic ring structure containing 1, 2, 3, 4, 5 or 6 heteroatoms independently selected from O, N and S; optionally substituted C5-1o aromatic ring structure; an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocycle containing 1, 2 or 3 heteroatoms independently selected from O, N and S; (Cι-8alkyl)-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 O, 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; optionally substituted -C(=O)O(C1-8alkyl); optionally substituted -C(=O)O-phenyl; optionally substituted -C(=O)(C1-8alkyl); optionally substituted -C(=O)-phenyl; or -NC(=O)R8 and
R7 is H; Cι_8alkyl; optionally substituted C3-8cycloalkyl optionally fused to a benzo ring; (C1-8alkyl)aryl wherein the aryl is C6.ι0 and optionally substituted; optionally substituted C5-ιo aromatic ring structure; or an optionally substituted 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic ring structure containing 1 , 2 or 3 heteroatoms independently selected from O, N and S; or
(ii) the structure
Figure imgf000107_0001
represents a C -8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S and optionally fused to a C6-ιo ring structure, -NR6R7 being optionally substituted; and For R8 and R9, either:
(i) R is H; .^alkyl; optionally substituted C3.8 cycloalkyl optionally fused to a benzo ring; optionally substituted (C[.8alkyl)aryl wherein the aryl is C6-ιo. optionally substituted (Cι-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 O, 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-ι cycloalkyl; optionally substituted C5.10 aromatic ring structure; 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 O, 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 C5.10 aromatic ring structure; and
R9 is H; or (ii) the structure -NR R represents a C3-8 heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S, -NR R being optionally substituted.
A compound according to Claim 1 , wherein W represents
Figure imgf000108_0001
wherein: Q is C-R10 or N;
V is C-Rn or N; Y is C-R12 or N with the proviso that Q = V = Y = N is excluded;
R10 is H; Hal; Cι.8alkyl; C1-8thioalkyl; C5.ι0 aromatic ring structure optionally
2 containing 1, 2 or 3 heteroatoms independently selected from O, N and S; -Z aryl,
2 2 2
-Z (Cι-8alkyl) or Z (C3.8 cycloalkyl),wherein Z represents O, NH or S and the aryl is -io and optionally contains from 1, 2 or 3 heteroatoms independently selected from O, N and S; nitro; -C(=O)O-R13 wherein R13 represents H or C,.8alkyl; or -C(=O)NR14R15 wherein either R14 and R15 independently represent H or Cι-8alkyl or the structure -NRI5R16 represents an optionally substituted C3.8 heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S; For R11 and R12, either:
(i) Rn is H; Hal; Cι_8alkyl; Cι-8alkylthio; C5.10 aromatic ring structure optionally
3 containing 1, 2 or 3 heteroatoms independently selected from O, N and S; -Z aryl,
3 3 3 -Z (C)-8alkyl) or Z (C3.8cycloalkyl),wherein Z represents O, NH or S and the aryl is C6_IQ and optionally contains from 1, 2 or 3 heteroatoms independently selected from O, N and S; nitro; -C(=O)O-R16 wherein R16 represents H or C,.8alkyl; or -C(=O)NRl7R18 wherein either R17 and R18 independently represent H or C).8alkyl or the structure -NRI7R18 represents an optionally substituted C3.8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; and R12 is H; Hal; Cι-8alkyl;
Cι-8alkylthio; C5-ι0 aromatic ring structure optionally containing 1, 2 or 3 heteroatoms
4 4 independently selected from O, N and S; -Z -aryl, - Z -(Cι-8alkyl) or
4 4
Z (C3-8cycloalkyl),wherein Z represents O, NH or S and the aryl is C6-ιo and optionally contains from 1, 2 or 3 heteroatoms independently selected from O, N and S; nitro; -C(=O)OR19 wherein R19 represents H or Cι-8alkyl; or -C(=O)NR20R21 wherein either R20 and
R21 independently represent H or C1-8alkyl or the structure -NR20R21 represents an optionally substituted C3-8 heterocyclic ring optionally containing 1 , 2 or 3 further heteroatoms independently selected from O, N and S; or
(ii) R1 ' and R12 are such that Y and V together represent an unsaturated C3-8 carbocyclic ring optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S.
5. A compound according to Claim 1 or 3, wherein W is G, H, I, J, K or L
Figure imgf000109_0001
H
Figure imgf000109_0002
wherein R, R' and R" are independently selected from H; Hal; Cι-8alkyl; C|.8thioalkyl; C5.|0 aromatic ring structure optionally containing 1 , 2 or 3 heteroatoms independently selected from O, N and S; -Z -aryl, - Z -(Cι-8alkyl) or Z -(C -8 cycloalkyl), wherein Z represents O,
NH or S and the aryl is C6_ιo and optionally contains from 1, 2 or 3 heteroatoms independently selected from O, N and S; nitro; Cι-8alkylthio; -C(=O)OR22 wherein R22 represents H or Cι-8alkyl; or -C(=O)NR23R24 wherein either R23 and R24 independently represent H or Cι.8alkyl or the structure -NR R" represents an optionally substituted C3-8 heterocyclic ring optionally containing 1, 2 or 3 further heteroatoms independently selected from O, N and S; and I, J and L are optionally fused to an optionally substitued unsaturated C3-8carbocyclic ring optionally containing 1, 2 or 3 heteroatoms independently selected from O, N and S.
6. A compound of according to any one of Claims 1 , 2 or 3, wherein R1 is -(CH2)a-CH3
or -((CH2)bO)c-CH3.
7. A compound of any one of Claims 1, 2 or 3, wherein R3 is selected from -4- moφholinyl; -l-(2-methyl-5-nitro-imidazolyl); -l-(l,2,4-triazolyl); and -OC(=O)NH-Ph.
8. A compound of any one of Claims 1 through 7, wherein g = 1.
9. A compound according to any one of Claims 1 through 8, wherein the compound has the formula II
Figure imgf000110_0001
10. A compound according to any one of claims 1, 2 or 3, wherein the compound has the formula IQ
Figure imgf000111_0001
1 1. A compound according to any one of claims 1 , 2 or 3, wherein the compound has the formula IV
Figure imgf000111_0002
12. A compound according to claim 1, wherein the compound is selected from
2- { [3-( IH-imidazol- 1 -ylmethyl)-2-methylphenyl]sulfanyl } ethyl phenylcarbamate; 2-{ [2-methyl-3-(2H-l,2,3,4-tetraazol-2-ylmethyl)phenyl]sulfanyl}ethyl phenylcarbamate;
2-{ [2-methyl-3-(lH-l,2,3,4-tetraazol-l-ylmethyl)phenyl]sulfanyl}ethyl phenylcarbamate;
2-( { 2-methyl-3-[(4-nitro- IH-imidazol- 1 -yl)methyl]phenyl } sulfanyl)ethyl phenylcarbamate;
2-( { 2-methyl-3- [(2-nitro- 1 H-imidazol- 1 -yl)methyl] phenyl } sulfanyl)ethyl phenylcarbamate ;
2- { [3-( IH-benzimidazol- 1 -ylmethyl)-2-methylphenyl]sulfanyl } ethyl phenylcarbamate; 2-( {2-methyl-3-[(2-phenyl- IH-imidazol- 1 -yl)methyl]phenyl }sulfanyl)ethyl phenylcarbamate;
2-({2-methyl-3-[(2-methyl-lH-imidazol-l-yl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate;
2-( { 3-[(4,5-dichloro- IH-imidazol- 1 -yl)methyl]-2-methylphenyl }sulfanyl)ethyl phenylcarbamate;
2-( { 3-[(4,5-diphenyl- IH-imidazol- 1 -yl)methyl] -2-methylphenyl } sulfanyl)ethyl phenylcarbamate;
2- { [3-( { 4-[2-(acetylamino)ethyl]- IH-imidazol- 1 -yl } methyl)-2-methylphenyl]sulfanyl } ethyl phenylcarbamate;
2-({3-[(2-isopropyl-lH-imidazol-l-yl)methyl]-2-methylphenyl}sulfanyl)ethyl phenylcarbamate; 2- [(2-methyl-3- { [2-(trifluoromethyl)- 1 H-benzimidazol- 1 -yl] methyl } phenyl)sulfanyl]ethyl phenylcarbamate;
2-({2-methyl-3-[(2-propyl- IH-imidazol- l-yl)methyl]phenyl}sulfanyl)ethyl phenylcarbamate; - Ill -
2- { [2-methyl-3-(9H-purin-9-ylmethyl)phenyl]sulfanyl Jethyl phenylcarbamate; methyl 1 -[3-( { 2-[(anilinocarbonyl)oxy]ethyl } sulfanyl)-2-methylbenzyl]- lH-imidazole-4- carboxylate;
2-{ [2-methyl-3-(7H-purin-7-ylmethyl)phenyl]sulfanyl Jethyl phenylcarbamate; methyl l-[3-({2-[(anilinocarbonyl)oxy]ethyl}sulfanyl)-2-methylbenzylJ-lH-imidazole-5- carboxylate;
2-[(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}phenyl)sulfanyl]ethyl phenylcarbamate;
2-[(2-methyl-3-{ [2-(methylsulfinyl)-lH-imidazol-l-ylJmethylJphenyl)sulfanyl]ethyl phenylcarbamate;
2-[(2-methyl-3-{ [2-(methylsulfonyl)-lH-imidazol-l-ylJmethyl}phenyl)sulfanyl]ethyl phenylcarbamate;
2-{ [3-(lH-l,2,3-benzotriazol-l-ylmethyl)-2-methylphenyl]sulfanyl}ethyl phenylcarbamate;
2-{ [3-(2H-l,2,3-benzotriazol-2-ylmethyl)-2-methylphenyl]sulfanyl Jethyl phenylcarbamate; 2-(2-methyl-3- { [2-oxo-2-( l-piperidinyl)ethyl]sulfanyl } benzyl)- IH-isoindole- 1 ,3(2H)-dione;
6-[(2-{ [3-(lH-benzimidazol-l-ylmethyl)-2-methylphenylJsulfanyl}ethyl)sulfanylJ-
3-nitroimidazo[ 1 ,2-b/pyridazine; l-(2-methyl-3-{ [2-(2-pyrimidinylsulfanyl)ethylJsulfanyl}benzyl)-lH-benzimidazole; l-(2-methyl-3-{ [2-(4-moφholinyl)ethyl]sulfanyl}benzyl)-lH-benzimidazole; 2-methyl-3-[(2-nitro- IH-imidazol- l-yl)methyl]phenyl 2-[(3-nitroimidazo[l,2-6 ρyridazin-6- yl)sulfanyl]ethyl sulfide;
2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methylJphenyl 2-(2-pyrimidinylsulfanyl)ethyl sulfide;
2-methyl-3-[(2-nitro- IH-imidazol- l-yl)methyl]phenyl 2-(4-moφholinyl)ethyl sulfide;
6-( { 2- [(2-methyl-3- { [2-(methylsulf anyl)- lH-imidazol- l-yl]methyl}phenyl)sulfanylJethyl}sulfanyl)-3-nitroimidazo[l,2-b7pyridazine;
2-({2-[(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol-
1 -yljmethyl } phenyl)sulfanyl]ethyl } sulfanyl)pyrimidine;
4-{2-[(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol-
1 -yl] methyl } phenyl)sulfanyl]ethyl } moφholine ; 2-{ [2-methyl-3-({2-[(3-nitroimidazo[l,2-b7pyridazin-6-yl)sulfanyl]-lH-imidazol-
1 -yl } methyl)phenyl]sulfanyl } ethyl phenylcarbamate;
1 -(2-methyl-3- { [2-(2-pyridinylsulfanyl)ethyl] sulfanyl } benzyl)- 1 H-benzimidazole ; l-(2-methyl-3-{ [2-(4-pyridinylsulfanyl)ethyl]sulfanyl }benzyl)- IH-benzimidazole; l-(2-methyl-3-{ [2-(l,3-thiazol-2-ylsulfanyl)ethyl]sulfanyl} benzyl)- IH-benzimidazole;
3-( IH-benzimidazol- 1 -ylmethyl)-2-methylphenyl 2-[( 1 -methyl- IH- 1 ,2,3,4-tetraazol-5- yl)sulfanyl]ethyl sulfide;
3-( 1 H-benzimidazol- 1 -ylmethyl)-2-methylphenyl 2- [(4-methyl -4H- 1 ,2,4-triazol- 3-yl)sulfanyl]ethyl sulfide;
2-{ [3-(lH-benzimidazol-l-ylmethyl)-2-methylphenyl]sulfanyl}-N-methyl-N-
[2-(2-pyridinyl)ethyl]-l-ethanamine; l-(2-methyl-3-{[2-(4-methyl-l-piperazinyl)ethyl]sulfanyl}benzyl)-lH-benzimidazole;
1 -(2-methyl-3- { [2-( 1 -piperazinyl)ethyl] sulfanyl } benzyl)- 1 H-benzimidazole ; 1 -[2-methyl-3-( { 2-[4-(2-pyrimidinyl)- 1 -piperazinyl]ethyl } sulfanyl)benzyl]- IH-benzimidazole;
2-[3-(lH-benzimidazol-l-ylmethyl)-2-methylphenoxy]ethyl phenylcarbamate;
2-{2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenoxy}ethyl phenylcarbamate;
2-(3-isobutoxy-2-methylphenyl)-lH-benzimidazole;
1 -(3-isobutoxy-2-methylbenzyl)- IH-benzimidazole; 6-{ [3-(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}phenoxy)propyl]sulfanyl}-
3-nitroimidazo[ 1 ,2-b/pyridazine;
2-{ [3-(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol-
1 -yljmethyl } phenoxy)propyl] sulfanyl } pyrimidine ;
6-{ [3-(2-methyl-3-{ [2-(methylsulfonyl)-lH-imidazol-l-yl]methyl}phenoxy)propyl]sulfanyl}- 3-nitroimidazo[l,2-b/pyridazine;
2-{ [3-(2-methyl-3-{ [2-(methylsulfonyl)-lH-imidazol-
1 -yljmethyl }phenoxy)propyl] sulfanyl Jpyrimidine;
2- { [3-(2-methyl-3- { [2-(methylsulfanyl)- 1 H-imidazol- 1 -yl]methyl } phenoxy)propyl] sulfanyl } - lH-imidazo[4,5-c]pyridine; 1 - { 3-[3-( lH-imidazol-2-ylsulfanyl)propoxy]-2-methylbenzyl } -2-(methylsulfanyl)- 1H- imidazole;
2-{ [3-(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol- l-yl]methyl}phenoxy)propyl]sulfanyl}pyridine;
4-{ [3-(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol- l-yl]methyl}phenoxy)propyl]sulfanyl}pyridine;
2-{ [3-(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}phenoxy)propyl]sulfanyl}-
1 ,3-thiazole; 3- { [3-(2-methyl-3- { [2-(methylsulfanyl)- IH-imidazol- 1 -yl]methyl } phenoxy)propyl]sulfanyl } -
5-phenyl- lH-l,2,4-triazole;
2-{ [3-(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}phenoxy)propyl]sulfanyl}-
5-phenyl- 1 ,3,4-oxadiazole; 5-{ [3-(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}phenoxy)propyl]sulfanyl}-
1 -phenyl- IH- 1,2,3,4-tetraazole;
2-methyl-3- { [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl } phenyl 3-[( 1 -methyl- IH- 1 ,2,3,4- tetraazol-5-yl)sulfanyl]propyl ether;
2-methyl-3- { [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl } phenyl 3-[( 1 -methyl- IH- 1 ,2,4- triazol-5-yl)sulfanyl]propyl ether;
2- { [3-(2-methyl-3- { [2-(methylsulfonyl)- IH-imidazol- 1 -yljmethyl } phenoxy)propyl] sulfanyl } -
1,3-thiazole; methyl l-(2-methyl-3-{3-[(l-methyl-lH-l,2,3,4-tetraazol-5-yl)sulfanyl]propoxy}benzyl)-lH- imidazol-2-yl sulfone; 2-{ [3-(2-methyl-3-{ [2-(methylsulfonyl)-lH-imidazol- l-yl]methyl }phenoxy)propyl] sulfanyl Jpyridine;
2-methyl-3-[(2-nitro- IH-imidazol- 1 -yl)methyl]phenyl 3-( 1 ,3-thiazol-2-ylsulfanyl)propyl ether;
2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenyl 3-[(l-methyl-lH-l,2,3,4-tetraazol-5- yl)sulfanyljpropyl ether; 2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenyl 3-(2-pyrimidinylsulfanyl)propyl ether;
2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenyl 3-(2-pyridinylsulfanyl)propyl ether;
1 - { 2-methyl-3-[3-( 1 ,3-thiazol-2-ylsulfanyl)propoxyJbenzyl } - IH-benzimidazole;
3-( 1 H-benzimidazol- 1 -ylmethyl)-2-methylphenyl 3-[( 1 -methyl- 1 H- 1 ,2,3,4-tetraazol-5- yl)sulfanyl]propyl ether; l-{2-methyl-3-[3-(2-pyrimidinylsulfanyl)propoxy]benzyl}-lH-benzimidazole;
1 -{ 2-methyl-3-[3-(2-pyridinylsulfanyl)propoxyJbenzyl }- IH-benzimidazole;
3-[(2-isopropyl-lH-imidazol-l-yl)methylJ-2-methylphenyl 3-(l,3-thiazol-2-ylsulfanyl)propyl ether;
3-[(2-isopropyl-lH-imidazol-l-yl)methylj-2-methylphenyl 3-[(l-methyl-lH-l,2,3,4-tetraazol- 5-yl)sulfanyl]propyl ether;
3-[(2-isopropyl-lH-imidazol-l-yl)methyl]-2-methylphenyl 3-(2-pyrimidinylsulfanyl)propyl ether; 3-[(2-isopropyl-lH-imidazol-l-yl)methyl]-2-methylphenyl
3-[(3-nitroimidazo[l,2-ό/pyridazin-6-yl)sulfanylJpropyl ether;
3-[(2-isopropyl- IH-imidazol- l-yl)methyl] -2-methylphenyl 3-(2-pyridinylsulfanyl)propyl ether; 2-methyl-3-[(2-propyl- IH-imidazol- 1 -yl)methyl]phenyl 3-( 1 ,3-thiazol-2-ylsulfanyl)propyl ether;
2-methyl-3-[(2-propyl- IH-imidazol- l-yl)methyl]phenyl 3-[(l -methyl- 1H-1, 2,3,4-tetraazol-5- yl)sulfanyl]propyl ether;
2-methyl-3-[(2-propyl-lH-imidazol-l-yl)methyl]phenyl 3-(2-pyrimidinylsulfanyl)propyl ether; 2-methyl-3-[(2-propyl-l H-imidazol- l-yl)methyl]phenyl 3-[(3-nitroimidazo[l,2-b7pyridazin-6- yl)sulfanyl]propyl ether;
2-methyl-3-[(2-propyl-lH-imidazol-l-yl)methyl]phenyl 3-(2-pyridinylsulfanyl)propyl ether;
2-methyl-3-[(2-nitro- IH-imidazol- 1 -yl)methyl]phenyl 3-[(3-nitroimidazo[ 1 ,2-b pyridazin-6- yl)sulfanyl]propyl ether; 3-( IH-benzimidazol- 1 -ylmethyl)-2-methylphenyl 3-[(3-nitroimidazo[ 1 ,2-b/pyridazin-6- yl)sulfanyl]propyl ether;
2-methyl-3- { [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl Jphenol;
2- { 2-methyl-3- [(2-nitro- 1 H-imidazol- 1 -yl)methyl] anilino } ethyl phenylcarbamate; l-(3-isobutoxybenzyl)-lH-benzimidazole; 3-[(3-methyl-2-{ [2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}-4-pyridinyl)sulfanylJ-
1-propanol;
2-[(3-methyl-2- { [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl } -4-pyridinyl)sulfanylJ-
1 -ethanol;
2-[(3-methyl-2- { [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl } -4-pyridinyl)sulfanylJethyl phenylcarbamate; l-[(3-methyl-4-phenoxy-2-pyridinyl)methylJ-lH-benzimidazole;
3-methyl-2- [(2-nitro- 1 H-imidazol- 1 -yl)methyl] -4-phenoxypyridine ;
3-methyl-2-{ [2-(methylsulfanyl)-lH-imidazol-l-yl]methyl}-4-phenoxypyridine;
6-( { 3-[(3-methyl-2- { [2-(methylsulfanyl)- IH-imidazol- 1 -yljmethyl } -4- pyridinyl)sulfanyl]propyl}sulfanyl)-3-nitroimidazo[l,2-b7pyridazine;
6-[(3-{ [2-(lH-benzimidazol-l-ylmethyl)-3-methyl-4-pyridinyl]sulfanyl }propyl)sulfanylJ-
3-nitroimidazo[ 1 ,2-b pyridazine; l-[(3-methyl-4-{ [3-(l,3-thiazol-2-ylsulfanyl)propyl]sulfanyl }-2-pyridinyl)methyl]-lH- benzimidazole; l-[(3-methyl-4-{ [3-(2-pyrimidinylsulfanyl)propylJsulfanyl}-2-pyridinyl)methyl]- IH- benzimidazole; 2- { [2-methyl-3-(l-piperazinylmethyl)phenylJ sulfanyl Jethyl phenylcarbamate;
2-( { 2-methyl-3-[(4-methyl- 1 -piperazinyl)methyl]phenyl } sulfanyl)ethyl phenylcarbamate;
2-[3-( IH-benzimidazol- l-ylmethyl)phenoxy]ethyl phenylcarbamate;
2-({2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenyl}sulfonyl)ethyl phenylcarbamate; methyl 1 -[3-(2- { [( 1 -ethyl-3-methyl- lH-pyrazol-5-yl)carbonyljamino } ethoxy)- 2-methylbenzylJ- lH-imidazole-4-carboxylate; l-[3-(2-{ [(l -ethyl-3-methyl- 1 H-pyrazol-5-yl)carbonyl] amino } ethoxy)-2-methylbenzylJ- 1 H- imidazole-4-carboxylic acid;
1 -ethyl-3-methyl-N-[2-(2-methyl-3- { [4-(4-moφholinylcarbonyl)- lH-imidazol-
1 -yljmethyl } phenoxy)ethylJ- lH-pyrazole-5-carboxamide; N-[2-(3-{ [4-({ [2-(dimethylamino)ethyl]amino}carbonyl)-lH-imidazol-l-yl]methylJ-
2-methylphenoxy)ethylJ-l-ethyl-3-methyl-lH-pyrazole-5-carboxamide;
1 -ethyl-N- { 2- [3-( { 4-[(isobutylamino)carbonyl J - 1 H-imidazol- 1 -yl } methyl)-
2-methylphenoxyJethyl}-3-methyl-lH-pyrazole-5-carboxamide;
N- { 2-[3-( { 4-[(diethylamino)carbonylJ- IH-imidazol- 1 -yl } methyl)-2-methylphenoxyjethyl } - l-ethyl-3-methyl-lH-pyrazole-5-carboxamide;
N- { 2-[3-( { 4- [(benzylamino)carbonylj - 1 H-imidazol- 1 -yl } methyl)-2-methylphenoxy]ethyl } -
1 -ethyl-3-methyl- lH-pyrazole-5-carboxamide;
2-[3-(l H-benzimidazol- l-ylmethyl)-2-methylanilino]ethyl phenylcarbamate;
2-( IH-benzimidazol- l-ylmethyl)-3-methyl-4-pyridinyl 3-[(3-nitroimidazo[l,2-67pyridazin-6- yl)oxy]propyl ether;
3-[3-( IH-benzimidazol- l-ylmethyl)-2-methylphenoxy]propyl 3-nitroimidazo[l,2-b7pyridazin-
6-yl ether;
3-{ [2-(lH-benzimidazol-l-ylmethyl)-3-methyl-4-pyridinylJoxy}propyl phenylcarbamate;
2- { [2-( IH-benzimidazol- 1 -ylmethyl)-3-methyl-4-pyridinylJoxy Jethyl phenylcarbamate; 2-( IH-benzimidazol- l-ylmethyl)-3-methyl-4-pyridinyl 3-(imidazo[l,2-b/pyridazin-6- yloxy)propyl ether;
N-(3-{ [2-( IH-benzimidazol- l-ylmethyl)-3-methyl-4-pyridinyl]oxy}ρropyl)-N-phenylurea; N-(3- { [2-( IH-benzimidazol- 1 -ylmethyl)-3-methyl-4-pyridinylJoxy } propyl)- 1 -ethyl-3-methyl- lH-pyrazole-5-carboxamide;
3-{ [2-(lH-benzimidazol-l-ylmethyl)-3-methyl-4-pyridinylJoxy}propyl
3-methoxyphenylcarbamate ; 3- { [2-( IH-benzimidazol- l-ylmethyl)-3-methyl-4-pyridinylJoxy } propyl 3,4- difluorophenylcarbamate; ethyl 4-{ [(3-{ [2-( IH-benzimidazol- l-ylmethyl)-3-methyl-4- pyridinyl] oxy } propoxy)carbonyl] amino } benzoate ;
4-{ [(3-{ [2-(lH-benzimidazol-l-ylmethyl)-3-methyl-4- pyridinyl]oxy}propoxy)carbonylJamino}benzoic acid;
3- [3-( 1 H-benzimidazol- 1 -ylmethyl)-2-methoxyphenoxyJpropyl
3-nitroimidazo[ 1 ,2-b pyridazin-6-yl ether;
2-[3-( IH-benzimidazol- 1 -ylmethyl)-2-(trifluoromethyl)phenoxyJethyl phenylcarbamate;
2-[3-( IH-benzimidazol- 1 -ylmethyl)-2-chlorophenoxyjethyl phenylcarbamate; l-ethyl-3-methyl-N-(2-{2-methyl-3-[(2-nitro-lH-imidazol-l-yl)methyl]phenoxy}ethyl)-lH- pyrazole-5-carboxamide;
N- { 2-[3-( IH-benzimidazol- 1 -ylmethyl)-2-methylphenoxy]ethyl } - 1 -ethyl-3 -methyl- 1H- pyrazole-5 -carboxamide ; l-ethyl-3-methyl-N-[2-(2-methyl-3-{ [2-(methylsulfanyl)-lH-imidazol- l-ylJmethyl}phenoxy)ethylJ-lH-pyrazole-5-carboxamide; methyl 1 -(3- { 2-[(tert-butoxycarbonyl)amino]ethoxy } -2-methylbenzyl)- lH-imidazole-4- carboxylate; methyl 1 -(3- { 2-[(tert-butoxycarbonyl)amino]ethoxy } -2-methylbenzyl)- lH-imidazole-5- carboxylate; 1 -(3- { 2-[(tert-butoxycarbonyl)amino]ethoxy } -2-methylbenzyl)- lH-imidazole-4-carboxylic acid;
1 -(3- { 2-[(tert-butoxycarbonyl)amino]ethoxyJ -2-methylbenzyl)- lH-imidazole-5-carboxylic acid; l-{ [3-methyl-4-(3-phenoxypropoxy)-2-pyridinyl]methyl}-lH-benzimidazole; l-({3-methyl-4-[3-(2-pyrimidinyloxy)propoxy]-2-pyridinyl} methyl)- IH-benzimidazole;
2-(2-methyl-3-{ [2-(2H-l,2,3,4-tetraazol-2-yl)ethyl]sulfanyl}benzyl)-lH-isoindole-l,3(2H)- dione; 1 -ethyl-3-methyl-N-[2-(2-methyl-3- { [ 1 -oxo-2( lH)-phthalazinyl]methyl } phenoxy)ethyl]- 1H- pyrazole-5-carboxamide; l-ethyl-3-methyl-N-[2-(2-methyl-3-{ [6-oxo-l(6H)-pyridazinyl]methyl}phenoxy)ethyl]-lH- pyrazole-5-carboxamide; l-ethyl-3-methyl-N-[2-(2-methyl-3-{ [3-methyl-5-(4-moφholinylcarbonyl)-lH-pyrazol- 1 -yljmethyl Jphenoxy)ethylJ-lH-pyrazole-5-carboxamide; or a pharmaceutically acceptable salt or solvate thereof.
13. A compound according to any one of Claims 1 through 12 for use as a medicament.
14. A pharmaceutical formulation comprising a compound according to any any one of Claims 1 through 12; and a pharmaceutically acceptable diluent or carrier.
15. Use of a compound according to any one of Claims 1 through 12, in the manufacture of a medicament, for the therapeutic and/or prophylactic treatment of Helicobacter pylori infection in a mammalian host.
16. A method of therapeutically treating and/or preventing Helicobacter pylori infection in a mammal, comprising administering to the patient a compound according to any one of claims 1 through 12.
17. A process for preparing a compound according to any one of claims 1 through 12, wherein the process comprises: (a) reacting compound V with compound VI
Figure imgf000118_0001
wherein L1 is a leaving group and B represents an optionally substituted 5- or 6-membered heterocyclic ring that is optionally fused to a 3-, 4-, 5-, 6-, 7- or 8-membered carbocyclic ring or heterocyclic ring containing 1, 2 or 3 heteroatoms independently selected from O, N and S; or
(b) reacting compound VII with H-R"
Figure imgf000119_0001
wherein L 2 i •s a leaving group, R' represents (CH2)d or (CH2)e-O-(CH2)f , and R" represents
RJ , with the proviso that RJ does not represent -C(=O)NR 6°rR>7',
Figure imgf000119_0002
-NC(=O)NR8R9, -NC(=O)R8 or -NC(=O)OR8; or (c) reacting compound Vm with R8-N=C=O or R8-COOH or R6-N=C=O or L -M
Figure imgf000119_0003
wherein R' represents (CH2)d_ L representing a leaving group, and Z and M being as defined in claim 1, with the proviso that Z-M does not represent -C(=O)NR6R7, -NR6R7, -OC(=O)NR8R9, -NC(=O)NR8R9, -NC(=O)R8 or -NC(=O)OR8; (d) reacting compound IX with R'-L4 wherein L4 represents a leaving group, and with the proviso that X is not CH2 or SO2 and that when R = R3', Z-M does not represent -C(=O)NR6R7, -NR6R7, -OC(=O)NR8R9,
-NC(=O)NR > 8δτRj9y, -NC(=O)Ra or -NC(=O)OR8;
Figure imgf000119_0004
(e) reacting compound X with R -XH
Figure imgf000120_0001
R" wherein L5 represents a leaving group, A contains N as a heteroatom either at the 2- or 4- position relative to L5, and with the proviso that X is not CH2 or SO2 and that when R1 is R3 ,
Z Z--MM ddooeess nnoott rreeppresent -C(=O)NR6R7, -NR6R7, -OC(=O)NR8R9, -NC(=O)NR8R9, -NC(=O)R8 or -NC(=O)OR8.
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Cited By (9)

* Cited by examiner, † Cited by third party
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WO2002094832A1 (en) * 2001-05-18 2002-11-28 Altana Pharma Ag New benzylaminopyrimidines
EP1295880A1 (en) * 2000-06-28 2003-03-26 SSP Co., Ltd. Imidazole derivatives or salts thereof and drugs containing the derivatives or the salts
JP2008303211A (en) * 2003-03-13 2008-12-18 Idemitsu Kosan Co Ltd New nitrogen-containing heterocyclic derivative and organic electroluminescent device by using the same
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WO2015153304A1 (en) 2014-04-01 2015-10-08 Merck Sharp & Dohme Corp. Prodrugs of hiv reverse transcriptase inhibitors
CN106432098A (en) * 2016-09-07 2017-02-22 华中师范大学 Carbamate compound and preparation method and application thereof
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

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EP1295880A1 (en) * 2000-06-28 2003-03-26 SSP Co., Ltd. Imidazole derivatives or salts thereof and drugs containing the derivatives or the salts
EP1295880A4 (en) * 2000-06-28 2004-05-06 Ssp Co Ltd Imidazole derivatives or salts thereof and drugs containing the derivatives or the salts
US6958353B2 (en) * 2000-06-28 2005-10-25 Hisamitsu Medical Co., Ltd. Imidazole derivatives or salts thereof and drugs containing the derivatives or the salts
US6818642B2 (en) 2001-05-18 2004-11-16 Altana Pharma Ag Benzylaminopyrimidines
WO2002094832A1 (en) * 2001-05-18 2002-11-28 Altana Pharma Ag New benzylaminopyrimidines
JP2008303211A (en) * 2003-03-13 2008-12-18 Idemitsu Kosan Co Ltd New nitrogen-containing heterocyclic derivative and organic electroluminescent device by using the same
US8404856B2 (en) 2007-11-20 2013-03-26 Merck Sharp & Dohme Corp. Non-nucleoside reverse transcriptase inhibitors
EP2924034A1 (en) 2010-03-30 2015-09-30 Merck Canada Inc. Pharmaceutical composition comprising a non-nucleoside reverse transcriptase inhibitor
US9469634B2 (en) 2012-10-08 2016-10-18 Merck Sharp & Dohme Corp. Non-nucleoside reverse transcriptase inhibitors
WO2014058747A1 (en) 2012-10-08 2014-04-17 Merck Sharp & Dohme Corp. 5-phenoxy-3h-pyrimidin-4-one derivatives and their use as hiv reverse transcriptase inhibitors
US9718819B2 (en) 2012-10-08 2017-08-01 Merck Sharp & Dohme Corp. Non-nucleoside reverse transcriptase inhibitors
EP3295942A1 (en) 2012-10-08 2018-03-21 Merck Sharp & Dohme Corp. Combinations comprising 5-phenoxy-3h-pyrimidin-4-one derivatives and their use for the prophylaxis or treatment of infection by hiv
US10189831B2 (en) 2012-10-08 2019-01-29 Merck Sharp & Dohme Corp. Non-nucleoside reverse transcriptase inhibitors
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WO2015153304A1 (en) 2014-04-01 2015-10-08 Merck Sharp & Dohme Corp. Prodrugs of hiv reverse transcriptase inhibitors
US10004740B2 (en) 2014-04-01 2018-06-26 Merck Sharp & Dohme Corp. Prodrugs of HIV reverse transcriptase inhibitors
EP3785714A1 (en) 2014-04-01 2021-03-03 Merck Sharp & Dohme Corp. Prodrugs of hiv reverse transcriptase inhibitors
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CN106432098B (en) * 2016-09-07 2018-09-18 华中师范大学 Carbamate compound and its preparation method and application
US11034669B2 (en) 2018-11-30 2021-06-15 Nuvation Bio Inc. Pyrrole and pyrazole compounds and methods of use thereof

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