WO2013054338A1 - 2-thio-imidazole derivatives as tgr5 modulators - Google Patents

2-thio-imidazole derivatives as tgr5 modulators Download PDF

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Publication number
WO2013054338A1
WO2013054338A1 PCT/IN2012/000471 IN2012000471W WO2013054338A1 WO 2013054338 A1 WO2013054338 A1 WO 2013054338A1 IN 2012000471 W IN2012000471 W IN 2012000471W WO 2013054338 A1 WO2013054338 A1 WO 2013054338A1
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Prior art keywords
propan
fluorophenyl
thio
imidazol
dimethoxyphenyl
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PCT/IN2012/000471
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French (fr)
Inventor
Sameer Agarwal
Mukul R Jain
Pankaj R Patel
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Cadila Healthcare Limited
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Publication of WO2013054338A1 publication Critical patent/WO2013054338A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • 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
    • C07D233/84—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to compounds of the general Formula I their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, prodrugs, their N-oxide, metabolites, polymorphs, use of these compounds in medicine and the intermediates involved in their preparation.
  • the compounds of the invention are suitable for the treatment of diabetes and associated disorders. Additionally, these- compounds may also be useful in the management of obesity.
  • Diabetes is a major worldwide health problem. In 2000, 171 million people were living with diabetes, and this number is projected to rise to 366 million in 2030. [Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004, 27, 1047- 53.]
  • Type II diabetes also known as diabetes mellitus, is now internationally recognized as one of the major threats to human health in the 21st century. According to the International Diabetes Federation (IDF), diabetes is expected to cause 3.8 million deaths worldwide in 2007, roughly 6% of total world mortality, about the same as HIV/AIDS and malaria combined. Those that suffer from type II diabetes have too little insulin or cannot use insulin effectively.
  • TGR5 is a novel GPCR mediating several non-genomic functional responses induced by binding of bile acids.
  • TGR5 also known as BG37, M-BAR, or hGPCR19, is a bile acid G protein-coupled receptor primarily expressed in monocytes and macrophages, lung, spleen, and the intestinal tract.
  • Bile acids are known to be key regulators of lipid, glucose and overall energy metabolism.
  • TGR5 is a G protein- coupled receptor that is activated by bile acids, resulting in an increase in cAMP levels and the subsequent modulation of energy expenditure in brown adipose tissue and muscle. Therefore, the development of a TGR5-specific agonist could lead to the prevention and treatment of various metabolic disorders related to obesity.
  • GLP-1 has an insulinotropic effect in the pancreas and reduces the appetite.
  • the combined effects of FXR and TGR5 in metabolically-active tissues leads to a reduction of hyperglycaemia and insulin resistance.
  • TGR5 activation is followed by release of the Gas subunit and activates the transcription of target genes by binding to cAMP response elements (CREs) contained in their promoter.
  • CREs cAMP response elements
  • BAT brown adipose tissue
  • TGR5 activation of TGR5 leads to the activation of type 2 iodothyronine deiodinase 2 (D2) which converts thyroxine (T4) to triiodothyronine (T3) and up-regulates (PPARa), uncoupling protein, (UCP-1, UCP2) and PPAR-coactivator (PGCla) activity inducing beta-oxidation, oxidative phosphorylation and energy uncoupling.
  • D2 type 2 iodothyronine deiodinase 2
  • T4 thyroxine
  • T3 triiodothyronine
  • PPARa up-regulates
  • UCP-1, UCP2
  • FXR in the liver stimulates beta-oxidation, downregulates FA synthesis. FXR also stimulates adipocyte differentiation, augmenting the production of leptin and adiponectin. These two hormones enhance energy uncoupling, b-oxidation, oxidative phosphorylation and reduce appetite.
  • WO/2008/097976 Heterocyclic Modulators of TGR5 for Treatment of Disease
  • WO/2008/091540 Substituted Bile Acids as TGR5 Modulators and Methods of Use
  • WO/2008/067219 Quinazolinone Modulators of TGR5
  • WO/2008/067222 Heterocyclic Modulators of TGR5
  • the present invention relates to new heterocyclic compounds which are effective modulators of TGR5 agonists of structural formula I,
  • Y, R 1 , R 2 , R 3 R 4 , R 5 and R 6 are defined herein below, and includes their solvates, hydrates pharmaceutically acceptable salts, enantiomers, diastereomers, prodrugs, their N-oxide, metabolites, as well as their polymorphs.
  • the invention further comprises compositions comprising the compounds of formula (I) and/or their pharmaceutically acceptable salts thereof.
  • the invention also comprises use of the compounds of formula (I) and compositions for treating diseases or disorders in which TGR5 is a mediator or is implicated.
  • the invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases and disorders in which TGR5 is a mediator or its implicated.
  • the present invention also provides compositions and combinations thereof and methods for using such compounds, compositions and combinations to treat these and related disorders.
  • all of the compounds of Formula I disclosed herein may have quaternary ammonium ion moieties, and in such cases, it is understood to one skilled in the art that these compounds may preferably be in the presence of a pharmaceutically acceptable counter ion.
  • the pharmaceutically acceptable counter ion for each of the quaternary ammonium ion moieties when present in the compounds of the invention can be any pharmaceutically acceptable counter ion.
  • the source of the counter ions can be from either intermolecular sources, or, when possible, intramolecular sources.
  • the present invention relates to the compounds of the general Formula I represented below and includes their solvates, hydrates pharmaceutically acceptable salts, enantiomers, diastereomers, prodrugs, their N-oxides, metabolites, as well as their polymorphs
  • Y S, -S(O)-, -S(0) 2 -;
  • R 1 is selected from aryl, heteroaryl, heterocyclyl or aryl(C]-C6)alkyl, wherein said aryl, heteroaryl, heterocyclyl or aryl(Ci-C 6 )alkyl can optionally be substituted with one, two, or three R la groups, wherein R ,a at each occurrence independently represents halogen, Ci-C4alkyl, C 1 -C4 haloalkyl, C3-C 8 cycloalkyl, heteroaryl, heterocyclyl, the group representing -R ,b , -Q-C 4 alkyl-R lb , or -OC r C 4 alkyl-R lb wherein
  • R 2 is selected from -Z - R z , wherein
  • R Z is -C(R Y ) 2 -, -C(H)(OH)-, -N(R Y )-, -0-, -C(R Y ) 2 0-, -S-, -S(O)-, -S(0) 2 -, -C(O)- wherein R Y at each occurrence independently represents hydrogen, Q ⁇ haloalkyl, Ci-Gialkyl, or hydroxy(Ci- C 4 )alkyl groups; and R z is aryl or heteroaryl, heterocyclyl wherein said aryl or heteroaryl or heterocyclyl groups can optionally substituted with one, two, or three R ZI groups,
  • R Z1 at each occurrence is cyano, halogen, nitro, -R z,b ' -N(R zlb ) 2 , -O R zib , -S R z,b , -C(0) R zlb , -C(0)0 R zlb , -C(0)N(R ZIb ) 2 , -S(0)N(R z, ) 2 , -S(0) 2 N(R zlb ) 2 , or - S(0) 2 R z,b , -OC(O) R zlb , -OC(0)0 R zlb , -OC(0)N(R zlb ) 2 , -N(R lc )C(0) R zlb , - N(R z,b )C(0)0 R zlb , -N(R zlb )C(0)N(R zlb ) 2 , or -N
  • aryl, heteroaryl, or aryl(Ci-C 2 )alkyl wherein said aryl, heteroaryl, or aryl(Ci- C 2 )alkyl can optionally be substituted with one, two, or three R 3a groups, wherein R 3a at each occurrence independently represents hydrogen, halogen, cyano, nitro, C ⁇ - C 4 alkyl, C1-C 4 haloalkyl, acyl, optionally substituted C3-C 8 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the group representing -R 3b , -Ci-C 4 alkyl-R 3b , or -OC1-C 4 alkyl; wherein the substituted group on C3-C 8 cycloalkyl, aryl, heteroaryl or heterocyclyl are selected from hydrogen, nitro, cyano, halogen, acyl, C 1 -C
  • R 3b at each occurrence is independently selected from
  • R 4 is selected from hydrogen, nitro, cyano, halogen, acyl, Ci-C 4 alkyl, C1-C 4 haloalkyi, aryl, or heteroaryl heterocyclyl, or -N(R 4a ) 2 groups; wherein R 4a at each occurrence is independently is selected from hydrogen, acyl, C]-C 4 alkyl or -S(0) 2 R 4b ; wherein R 4b at each occurrence is selected from amino, acyl or C 1 -C 4 alkyl groups;
  • R 5 and R 6 each independently represents hydrogen, C C 4 alkyl or alternatively, R 5 and R 6
  • R 6 together with carbon atom to which they are attached form a 3-7 membered ring, optionally comprising 1 or 2 hetroatom .selected from O, N and S.
  • R 1 is selected from aryl wherein aryl is substituted with one, two, or three R la group, wherein R Ia group is independently selected from halogen or Ci-C 4 alkyl.
  • R 2 is selected from -Z-R z , wherein Z is -
  • R at each occurrence independently represents hydrogen, C - C 4 alkyl; and R z is aryl wherein said aryl can optionally substituted with one, two, or three R groups selected from cyano, halogen, -O R , wherein R is independently selected from hydrogen or C]-C 4 alkyl.
  • R is aryl, heteroaryl, or aryl(CrC 2 )alkyl, wherein said aryl, heteroaryl, or aryl(Ci-C 2 )alkyl can optionally be substituted with one, two, or three R 3a groups, wherein R 3a at each occurrence independently represents hydrogen, halogen, cyano, nitro, Ci-C 4 alkyl, C1-C 4 haloalkyi, acyl, optionally substituted C 3 -Cgcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the group representing -R 3b , -Ci- C 4 alkyl-R 3b , or -OC1-C4 alkyl; wherein the substituted group on C 3 -C 8 cycloalkyl, aryl, heteroaryl or heterocyclyl are selected from hydrogen, nitro, cyano, halogen, acyl, C
  • N(R 3d )C( NR 3d )N(R 3d ) 2 groups, wherein R 3d at each occurrence is independently selected from hydrogen, Ci-C4alkyl, or C1-C4 haloalkyl groups.
  • R 3 is selected from Ci-C4alkyl, -Cj- C 4 alkyl-OR 3d , wherein R 3d at each occurrence is independently selected from hydrogen, C]-C 4 alkyl, or Q-C4 haloalkyl groups.
  • the various groups as defined above may be selected from: "Alkyl", as well as other groups having the prefix “alk”, such as alkoxy and alkanoyl, means carbon chain which may either be linear or branched, and combinations thereof, unless the carbon chain is defined otherwise.
  • alkyl group include, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, ter/.-butyl, pentyl, hexyl etc. Where the specified number of carbon atoms permits e.g.
  • alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures.
  • the alkyl group may be optionally substituted with nitro, cyano, halogen, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups;
  • amino refers to a -N(R) 2 radical group, where each R is independently hydrogen, alkyl, aryl, acyl, heterocyclyl, or heteroaryl group.
  • an amino group may be optionally substituted by one or more substituents which independently are with nitro, cyano, halogen, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
  • Cycloalkyl is the subset of alkyl and means saturated carbocyclic ring having a specified number of carbon atoms, preferably 3-10 carbon atoms.
  • Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.
  • cycloalkyl group may be optionally substituted with nitro, cyano, halogen, Ci-C4alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
  • Aryl means a mono- or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems.
  • the aryl group may be selected from but not limited to phenyl and naphthyl.
  • aryl group may be optionally substituted with nitro, cyano, halogen, Ci-C 4 alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
  • acyl used herein, refers to group R-C(O)-, wherein R is independently selected from hydrogen or alkyl, cycloalkyl, aryl as defined elsewhere in the specification.
  • R is independently selected from hydrogen or alkyl, cycloalkyl, aryl as defined elsewhere in the specification.
  • the acyl group represents formyl, acetyl and the like.
  • acyl group may be optionally substituted with nitro, cyano, halogen, Q- C 4 alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
  • Heterocycle and “heterocyclyl” refer to saturated or unsaturated non-aromatic rings or ring systems containing at least one heteroatom selected from O, S, N further including the oxidized forms of sulfur and nitrogen, namely SO, S0 2 , NO, N0 2 .
  • the heterocyclyl group may be selected from but not limited to tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, pyridine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3- dithiane, oxathiane, thiomorpholine,
  • the heterocycle group may be optionally substituted with nitro, cyano, halogen, Cj.-C 4 alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
  • Heteroaryl means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N.
  • heteroaryl group includes heteroaryl fused to the other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic.
  • the heteroaryl group may be selected from but not limited to ; pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, fury], triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, ' indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnoliny
  • heteroaryl groups rings and ring systems containing from 3-15 carbon atoms are included, forming 1-3 rings.
  • the heteroaryl group may be optionally substituted with nitfo, cyano, halogen, CrC 4 alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
  • halogen refers to fluorine, chlorine, bromine and iodine. Chlorine and fluorine are generally preferred.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • substituted means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • “Pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the basic residues.
  • the pharmaceutically acceptable salts include the conventional quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • combination therapy means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous ' manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herei .
  • terapéuticaally acceptable refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • patient means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.
  • Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein.
  • prodrug refers to a precursor of a biologically active compound that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
  • prodrugs are also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of an active compound, as described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
  • Optional' or 'optionally' means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not.
  • Optionally substituted alkyl' means either 'alkyl' or 'substituted alkyl'.
  • an optionally substituted group includes the unsubstituted group also.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • compounds having the present structures wherein hydrogen is replaced by deuterium or tritium, or wherein carbon atom is replaced by 13 C- or I4 C- enriched carbon are within the scope of this invention.
  • Particularly preferred compounds may be selected from:
  • the compounds of present invention may be prepared by different synthetic schemes 1 wherein the groups R Z1 , R 1 , R 3 , & Y are as defined earlier. Synthesis of the compounds of Formula I disclosed herein, and embodiments thereof, are not limited by these examples and schemes. One skilled in the art will know that other procedures can be used to synthesize the compounds of Formulae I disclosed herein, in combination with the processes described herein. In the descriptions below, one of ordinary skill in the art would recognize that specific reaction conditions, added reagents, solvents, and reaction temperatures can be modified for the synthesis of specific compounds that fall within the scope of this disclosure. All intermediate compounds described below, for which there is no description of how to synthesize such intermediates within these examples below, are commercially available compounds unless otherwise specified.
  • Step (I): An aldehyde of formula (3) may be prepared by reaction of nitrile (2) with diisobutylaluminum hydride in a suitable solvent, such as THF or toluene.
  • Step (II): Formation of carbinol (4) may be achieved by treatment of aldehyde (3) with methylmagnesium bromide in a suitable solvent, such as diethyl ether or THF.
  • Step (III): . Conversion of carbinol (4) to ketone (5) may occur under standard conditions, such as the Swern oxidation— known to one skilled in the art of synthetic organic chemistry.
  • Step (IV): Bromoketone (6) may be prepared by bromination of ketone (5) under typical conditions, such as with tetrabutylammonium tribromide in solvent mixture of MeOH/DCM.
  • a suitable solvent such as acetone or MeCN
  • a base such as potassium carbonate
  • Reaction of thioether (I) with a suitable oxidant, such as mCPBA, in a suitable solvent such as DCM may yield compound of formula 1-1 or 1-2.
  • the title compound was prepared from 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethanol and 2-(bromomethyl)-l-chloro-3-fluorobenzene.
  • the title compound was prepared from 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethanol and 2-(bromomethyl)-l,3-difluorobenzene.
  • Example 2 In a manner similar to that described for Example 1, the title compound was prepared from 2-((5-(2-(3 ,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethanol and l-(bromomethyl)-3-chlorobenzene.
  • Example 2 In a manner similar to that described for Example 1, the title compound was prepared from 2-((5-(2-(3 ,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethanol and l-(bromomethyl)-3-fluorobenzene.
  • Example 2 In a manner similar to that described for Example 1, the title compound was prepared from 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethanol and 4-(chloromethyl)-3,5-dimethylisoxazole.
  • the title compound was prepared from 3-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)propan-l-ol and 2-(bromomethyl)-l-chloro-3-fluorobenzene.
  • the title compound was prepared from 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethanol and N-(4-(bromomethyl)benzyl)methanesulfonamide.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l -(4-fluorophenyl)-lH- imidazole-2-thiol and 2-(2-bromoethoxy)-l,3-difluorobenzene.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichIorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-lH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 4-(2-bromo ethoxy)- 1, 2 -dimethoxybenzene.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and l-(4-(2-bromo ethoxy)phenyl)-lH-pyrrole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2 -thiol and 2-(2-bromo ethoxy)-l,3-difluorobenzene.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2 -thiol and 4-(2-bromo ethoxy)-l ,2-dimethoxybenzene.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yi)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 4-(2-bromo ethoxy)benzonitrile.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 3-(2-bromo ethoxy)pyridine.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2 -thiol and l-(4r(2-bromoethoxy)phenyl)-4-methyl-lH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-2 -methyl- lH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-IH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(2,4-difluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-2-methyl-lH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyI)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-lH-pyrazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-lH-pyrazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5 -(2-(3 ,4-dichloropheny l)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and l-(4-(2-bromoethoxy)-3-fluorophenyl)-lH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 1 -(4-(2-bromoethoxy)-3 -fluorophenyl)-2-methyl- 1 H-imidazole .
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 2-((5-(2-(3 ,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethanol and 3-fluora-4-(2-methyl-lH-imidazol-l-yl)phenol.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-2-methyl-l H-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-lH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-lH-pyrazole.
  • the title compound was prepared from 2-((4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4- fluorophenyl)- 1 H-imidazol-2-yl)thio)ethanol and 4-(2-methyl- 1 H-imidazol- 1 - yl)phenol.
  • the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 3-(2-(2-bromoethoxy)phenyl)-lH-pyrazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-lH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5 -(2-(4-chloro-3 -methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and 5-(2-bromoethoxy)-lH-indole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)- 1H- imidazole-2-thiol and 3-(2-bromoethoxy)-N,N-dimethylaniline.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-2-methyl-lH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5 -(2-(4-chloro-3 -methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-4-methyl-lH-imidazole.
  • the title compound was prepared from 5-(2-(3, 4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 3-(4-cyanophenoxy)propyl methanesulfonate.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and 5-(2-bromoethoxy)-lH-indole.
  • Example 45 In a manner similar to that described for Example 45, the title compound was prepared from 2-((4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4- fluorophenyl)- lH-imidazol-2-yl)thio)ethanol and 4-(lH-pyrazol-l-yl)phenol.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazol-2- yl)thio)ethanol and 3-(2-methyl-lH-imidazol-l-yl)phenol.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 1 -(4-(2-bromoethoxy)-3-fluorophenyl)-2-methyl-lH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-fluoro-3-methoxyphenyl) propan-2-yl)-l -(4-fluorophenyl)- 1H- imidazole-2-thiol and l-(4-(2-bromoethoxy) phenyl)-lH-l, 2, 4-triazole.
  • the title compound was prepared from 2-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)- lH-imidazol-2-yl)thio)ethanol and 1 3-fluoro-4-(2-methyl-lH-imidazol-l-yl)phenol.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5 -(2-(4-chloro-3 -methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and 3-(4-(2-bromoethoxy)phenyl)thiophene.
  • IR KBr (cm '1 ): 3154, 3104, 3044, 2972, 2932, 2870, 1605, 1578, 1537, 1435, 1287, 1225, 1061, 965, 843, 779, 677.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from l-(4-fluorophenyl)-5-(2-phenylpropan-2-yl)-lH-imidazole-2 -thiol and 1- (4-(2-bromoethoxy) phenyl)- lH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-chloro-3-methoxyphenyl) propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromOethoxy)-3-fluorophenyl)-lH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)-lH- imidazole-2-thiol and 5-(2-bromoethoxy)-lH-indazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 2-fluoro-5-(2-( 1 -(4-fiuorophenyl)-2-mercapto-l H-imidazol-5-yl)propan- 2-yl)benzonitrile and 2-fluoro-5-(2-(l-(4-fluorophenyl)-2-mercapto-lH-imidazol-5- yl)propan-2-yl)benzonitrile.
  • Example 84 5-(2-(3,4-dimethoxyphenyl)propan-2-yI)-l-(4-fluorophenyl)-2-((2-methyl-l-(4-(2- methyI-lH-imidazoI-l-yl)phenoxy)propan-2-yI)thio)-lH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 2-fluoro-5-(2-( 1 -(4-fluorophenyl)-2-mercapto- 1 H-imidazol-5-yl)propan- 2-yl)benzonitrile and l-(4-(2-bromoethoxy)phenyl)-lH-imidazole.
  • Example 92 In a manner similar to that described for Example 92, the title compound was prepared from 4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(3-fluoro-4-(2- methyl-lH-imidazol-l-yl)phenoxy)ethyl)thio)-l-(4-fluorophenyl)-lH-imidazole and Copper Cyanide.
  • Example 95 In a manner similar to that described in Example 95, the title compound was prepared from 4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethoxy)benzoic acid and 2-amino-N,N,N-trimethylethanaminium.
  • Example 99 In a manner similar to that described for Example 99, the title compound was prepared from 2-((2-((2,6-difluorobenzyl)oxy)ethyl)thio)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl) -lH-imidazole.
  • Example 99 In a manner similar to that described for Example 99, the title compound was prepared from 2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)-l-(4-fluoro phenyl)- lH-imidazole.
  • Example 99 In a manner similar to that described for Example 99, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)-2-((2-(4-(2- methyl-lH-imidazol-l-yl)phenoxy)ethyl)thio)-lH-imidazole.
  • Example 105 In a manner similar to that described for Example 105, the title compound was prepared from 4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethoxy) methyl)benzonitrile.
  • Example 105 In a manner similar to that described for Example 105, the title compound was prepared from 2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazole and mCPBA.
  • Example 108 In a manner similar to that described for Example 108, the title compound was prepared from 4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethoxy) methyl)benzonitrile.
  • % Purity 95.39 % (By HPLC), IR KBr (crn 1 ): 3416, 3117, 3075, 2932, 2594, 1728, 1616, 1540, 1447, 1254, 1054, 840.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-4-methyl- lH-imidazole-2-thiol and l-(4-(2rbromoethoxy)phenyl)-2-methyl-lH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)-3-fluorophenyl)-lH-pyrazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)-4-methyl- lH-imidazole-2 -thiol and l-(4-(2-bromoethoxy)phenyl)-lH-imidazole.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5 -(2-(3,4-dimethoxypheny l)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and 4-(3-(2-bromoethoxy)phenyl)morpholine.
  • Example 13 In a manner similar to that described for Example 13, the title compound was prepared from 5 -(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)- 1H- imidazole-2-thiol and l-(3-(2-bromoethoxy)phenyl)-lH-imidazole.
  • reaction mixture was warmed to room temperature and stirred at room temperature for lh. Reaction mixture was quenched by ice and extracted with ethyl acetate. Organic extract was washed with water, saturated brine solution and dried over (Na 2 S0 4 ). Crude product was purified by column chromatography to provide the 2-(3,4- dimethoxyphenyl)-2-methylpropanenitrile (11.5 g, 93% yield).
  • Oxalyl chloride 38.39 mL, 78 mmol
  • DCM 140mL
  • Dimethyl sulfoxide (12.98 mL, 153mmol ) was added drop wise within 30 min at -78 °C and stirring was continued at - 78 °C for 30 min.3-(3, 4-dimethoxyphenyl) -3-methylbutan-2-ol (8.6 g, 38 mmol) dissolved in DCM (40 mL) was charged drop wise within 15 min.
  • Reaction mixture was diluted with dichloromethane (100 mL) and washed with water saturated brine solution dried over sodium sulfate, filtered and organic extract was concentrated in vacuo to afford brown colored oil. (25g crude material).Crude oil (25 g) was mixed with dichloromethane (100 mL), stirred vigorously for 10 minutes, slowly add n-hexane (100 mL) under stirring. Off white solid product thus obtained was filtered through filter paper in vacuo and Washed with n-hexane (50 mL).
  • hTGRS Reporter Gene Assay: Chinese Hamster Ovarian (CHO) Kl cells were plated in 24 well tissue culture plate at a density of 4 X 10 4 cells/well in a Nutrient Mixture F-12 HAM containing 10 % Fetal Bovine Serum, cultured for 24 hrs at 37°C/5% C0 2 , and then transfected with 50 ng of human (h) TGR5 expression plasmid (pCMV SPORT6 - hTGR5), 300 ng of cAMP-responsive element (CRE)-driven luciferase reporter plasmid (pCRE-Luc) and 100 ng of ⁇ -galactosidase reporter vector in each well using Polyfect Transfection Reagent (QIAGEN, Cat.
  • luciferase assays 20 /*L of cell lysate was mixed with 100 ,uL of Luciferase Assay Substrate (Promega, Cat. No.: El 501) & Luminescence was measured in HIDEX Multitechnology Plate Reader.
  • 30 //L of cell lysate was mixed with 30y*L of 2X ONPG Buffer [20 mM sodium phosphate buffer - pH 7.3, 2 mM MgCl 2 , 100 mM ⁇ -mercaptoethanol, and 1.33 mg/mL o-nitrophenyl- ?-D- galactopyranoside (ONPG)] and incubated at 37°C for 2-10 mins. The optical density at 415 nm was determined in SpectraMax 190.
  • Normalized luciferase values were determined by dividing the luciferase activity by the galactosidase activity and expressed as fold induction with respect to (w.r.t.) DMSO control.
  • mice of 8-12 week age Male C57 mice of 8-12 week age, bred in Zydus research Centre Animal house will be used for this experiment. Animal will be issued and subjected for 3-7 days acclimatization. On first day animal will be grouped based on non fasting serum glucose levels and kept on fasting for overnight. On second day of the experiment, formulation of test compounds will be prepared and fasting body weight of animals will be recorded. Each animal will receive a single dose of vehicle/test compounds administered per orally as per specified group and dose levels. Exactly 15 min post dosing glucose load (3gm/kg/10ml) will be administered orally to all the groups. Then exactly after 10 min of glucose load animal will bled from retro orbital plexus.
  • novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • the compounds of Formula (I) or pharmaceutical compositions containing them are useful as antidiabetic and antiobesity compounds suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
  • the compounds described herein or a pharmaceutically acceptable salt, ester, or prodrug thereof in combination with another therapeutic agent.
  • a combination therapy Several reasons can be attributed for using a combination therapy depending on the need of the patient.
  • one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer an anti-hypertensive agent in combination with the initial therapeutic agent.
  • the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.
  • another therapeutic agent which also includes a therapeutic regimen
  • the use of combination therapy may be envisaged for all such situations.
  • the overall benefit experienced by the patient may simply be . additive of the two therapeutic agents or the patient may experience a synergistic benefit.
  • combination therapies include use of certain compounds disclosed herein with agents found in the following pharmacotherapeutic classifications as indicated below. These lists should not be construed to be closed, but should instead serve as illustrative examples common to the relevant therapeutic area at present.
  • combination regimens may include a variety of routes of administration and should include oral, intravenous, intraocular, subcutaneous, dermal, and inhaled topical.
  • compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like peptide-1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-119 inhibitors, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type PPAR.delta. agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and anti-platelet agents and anti-obesity agents.
  • an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucos
  • compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, metformin, Glipizide, glyburide, Amaryl, gliclazide, meglitinides, nateglinide, repaglinide, amylin mimetics (for example, pramlintide), acarbose, miglitol, voglibose, Exendin-4, , vildagliptin, Liraglutide, .
  • an agent selected from the group comprising: insulin, metformin, Glipizide, glyburide, Amaryl, gliclazide, meglitinides, nateglinide, repaglinide, amylin mimetics (for example, pramlintide), acarbose, miglitol, voglibose, Exendin-4, , vildagliptin, Liraglutide, .
  • naliglutide for example, rosuvastatin, atrovastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin, rosuvastatin, pravastatin and like
  • HMG- CoA reductase inhibitors for example, rosuvastatin, atrovastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin, rosuvastatin, pravastatin and like
  • cholesterol-lowering drugs for example, fibrates which include: fenofibrate, benzafibrate, clofibrate, gemfibrozil and like; cholesterol absorption inhibitors such as Ezetimibe, eflucimibe etc.

Abstract

The present invention relates to compounds of the general Formula I their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, prodrugs, their N-oxide, metabolites, polymorphs, use of these compounds in medicine for treating diabetes (TGR5 modulators) and the intermediates involved in their preparation.

Description

2-THIO-IMIDAZOLE DERIVATIVES AS TGR5 MODULATORS
FIELD OF THE INVENTION
The present invention relates to compounds of the general Formula I their pharmaceutically acceptable salts, pharmaceutically acceptable solvates, enantiomers, diastereomers, prodrugs, their N-oxide, metabolites, polymorphs, use of these compounds in medicine and the intermediates involved in their preparation. The compounds of the invention are suitable for the treatment of diabetes and associated disorders. Additionally, these- compounds may also be useful in the management of obesity.
Figure imgf000002_0001
Formula 1
BACKGROUND OF THE RELATED ART
Diabetes is a major worldwide health problem. In 2000, 171 million people were living with diabetes, and this number is projected to rise to 366 million in 2030. [Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004, 27, 1047- 53.] Type II diabetes, also known as diabetes mellitus, is now internationally recognized as one of the major threats to human health in the 21st century. According to the International Diabetes Federation (IDF), diabetes is expected to cause 3.8 million deaths worldwide in 2007, roughly 6% of total world mortality, about the same as HIV/AIDS and malaria combined. Those that suffer from type II diabetes have too little insulin or cannot use insulin effectively. As a result, glucose levels build up in the blood and urine and, if left untreated, can cause life-threatening complications, including blindness, kidney failure, and heart disease. The huge human and economic costs of diabetes and associated complications prompted the research for appropriate and efficient treatments. Recently several new targets have been identified and are being explored for the treatment and/or management of diabetes. One of them is TGR5.
TGR5 is a novel GPCR mediating several non-genomic functional responses induced by binding of bile acids. TGR5, also known as BG37, M-BAR, or hGPCR19, is a bile acid G protein-coupled receptor primarily expressed in monocytes and macrophages, lung, spleen, and the intestinal tract. Bile acids are known to be key regulators of lipid, glucose and overall energy metabolism. TGR5 is a G protein- coupled receptor that is activated by bile acids, resulting in an increase in cAMP levels and the subsequent modulation of energy expenditure in brown adipose tissue and muscle. Therefore, the development of a TGR5-specific agonist could lead to the prevention and treatment of various metabolic disorders related to obesity. [Thomas et al. Nature 2008, 7, 678.] Bile acid activation of the G protein-coupled receptor TGR5 has been shown to induce energy expenditure in muscle and brown fat, thereby conferring resistance to weight gain. Now, a paper published in the current issue of Cell Metabolism (Vol. 10, Issue 3, Sept. 2, 2009) elaborates on a separate TGR5-regulated mechanism in the gut that drives secretion of the hormone glucagon-like peptide (GLP- 1) and resulting insulin sensitization. Binding of TGR5 agonist increases cAMP stimulates the secretion of (GLP)-l from intestinal endocrine cells. [Katsuma, et al, Biochem. Biophys. Res. Commun. 2005, 329(1), 386-390.] GLP-1 has an insulinotropic effect in the pancreas and reduces the appetite. The combined effects of FXR and TGR5 in metabolically-active tissues leads to a reduction of hyperglycaemia and insulin resistance.
Upon ligand binding, TGR5 activation is followed by release of the Gas subunit and activates the transcription of target genes by binding to cAMP response elements (CREs) contained in their promoter. In the brown adipose tissue (BAT) and muscle, activation of TGR5 leads to the activation of type 2 iodothyronine deiodinase 2 (D2) which converts thyroxine (T4) to triiodothyronine (T3) and up-regulates (PPARa), uncoupling protein, (UCP-1, UCP2) and PPAR-coactivator (PGCla) activity inducing beta-oxidation, oxidative phosphorylation and energy uncoupling. [Watanabe et al, Nature 2006, 439(7075) 484-489.] FXR in the liver stimulates beta-oxidation, downregulates FA synthesis. FXR also stimulates adipocyte differentiation, augmenting the production of leptin and adiponectin. These two hormones enhance energy uncoupling, b-oxidation, oxidative phosphorylation and reduce appetite.
TGR5 and modulators of it has been the subject of several patent applications:
WO/2008/097976 - Heterocyclic Modulators of TGR5 for Treatment of Disease WO/2008/091540 - Substituted Bile Acids as TGR5 Modulators and Methods of Use WO/2008/067219 - Quinazolinone Modulators of TGR5 WO/2008/067222 - Heterocyclic Modulators of TGR5
WO/2004/067008 - Receptor Agonists
WO/2004/043468 - Screening Method
US 2006/0199795 - Receptor Agonists
US 2008/0031968 - Methods for Increasing Cellular Energy Expenditure
WO/2010/014739 - Heterocyclic Modulators of TGR5
WO/2010/016846 - Heterocyclic Modulators of TGR5
WO/2010/093845 - Heterocyclic Modulators of TGR5
WO/201 1/071565 - Heterocyclic Modulators of TGR5
However, none of these compounds have become successful as drugs and looking at the huge unmet medical needs, there is a need to develop further compounds which modulate the TGR5 receptor and can be used for the treatment and/or management of diabetes, obesity and their associated disorders.
SUMMARY OF THE INVENTION
The present invention relates to new heterocyclic compounds which are effective modulators of TGR5 agonists of structural formula I,
Figure imgf000004_0001
Formula I
wherein Y, R1, R2, R3 R4, R5 and R6 are defined herein below, and includes their solvates, hydrates pharmaceutically acceptable salts, enantiomers, diastereomers, prodrugs, their N-oxide, metabolites, as well as their polymorphs.
The invention further comprises compositions comprising the compounds of formula (I) and/or their pharmaceutically acceptable salts thereof. The invention also comprises use of the compounds of formula (I) and compositions for treating diseases or disorders in which TGR5 is a mediator or is implicated.
The invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases and disorders in which TGR5 is a mediator or its implicated. The present invention also provides compositions and combinations thereof and methods for using such compounds, compositions and combinations to treat these and related disorders.
DETAILED DESCRIPTION OF THE INVENTION
In an embodiment, all of the compounds of Formula I disclosed herein may have quaternary ammonium ion moieties, and in such cases, it is understood to one skilled in the art that these compounds may preferably be in the presence of a pharmaceutically acceptable counter ion. The pharmaceutically acceptable counter ion for each of the quaternary ammonium ion moieties when present in the compounds of the invention can be any pharmaceutically acceptable counter ion. It is also understood that the source of the counter ions can be from either intermolecular sources, or, when possible, intramolecular sources.
Accordingly, the present invention relates to the compounds of the general Formula I represented below and includes their solvates, hydrates pharmaceutically acceptable salts, enantiomers, diastereomers, prodrugs, their N-oxides, metabolites, as well as their polymorphs
Figure imgf000005_0001
Formula I
wherein, Y is = S, -S(O)-, -S(0)2-;
n is O, 1, 2, 3 or 4; m is 0, l, or 2;
R1 is selected from aryl, heteroaryl, heterocyclyl or aryl(C]-C6)alkyl, wherein said aryl, heteroaryl, heterocyclyl or aryl(Ci-C6)alkyl can optionally be substituted with one, two, or three Rla groups, wherein R,a at each occurrence independently represents halogen, Ci-C4alkyl, C1-C4 haloalkyl, C3-C8cycloalkyl, heteroaryl, heterocyclyl, the group representing -R,b, -Q-C4 alkyl-Rlb, or -OCrC4 alkyl-Rlb wherein
Rl at each occurrence independently represents cyano, nitro, -N(Rlc)2, -OR,c, -SRlc, - C(0)R1C, -C(0)ORlc, -C(0)N(R,c)2, -S(0)N(R,c)2, -S(0)2N(Rlc)2, or -S(0)2Rlc, - OC(0)Rlc, -OC(0)ORlc, -OC(0)N(Rlc)2, -N(Rlc)C(0)R,c, -N(R,c)C(0)ORlc, - N(Rlc)C(0)N(Rlc)2, or -N(R,c)C(=NRlc)N(Rlc)2, wherein each Rlc is independently hydrogen, Ci-C4alkyl, or C1-C4 haloalkyl;
R2 is selected from -Z - Rz, wherein
Z is -C(RY)2-, -C(H)(OH)-, -N(RY)-, -0-, -C(RY)20-, -S-, -S(O)-, -S(0)2-, -C(O)- wherein RY at each occurrence independently represents hydrogen, Q^haloalkyl, Ci-Gialkyl, or hydroxy(Ci- C4)alkyl groups; and Rz is aryl or heteroaryl, heterocyclyl wherein said aryl or heteroaryl or heterocyclyl groups can optionally substituted with one, two, or three RZI groups,
wherein RZ1 at each occurrence is cyano, halogen, nitro, -Rz,b' -N(Rzlb)2, -O Rzib, -S Rz,b, -C(0) Rzlb, -C(0)0 Rzlb, -C(0)N(RZIb)2, -S(0)N(Rz, )2, -S(0)2N(Rzlb)2, or - S(0)2 Rz,b, -OC(O) Rzlb, -OC(0)0 Rzlb , -OC(0)N(Rzlb)2, -N(Rlc)C(0) Rzlb, - N(Rz,b)C(0)0 Rzlb, -N(Rzlb)C(0)N(Rzlb)2, or -N(Rzlb)C(=N RZ]b)N(Rz,b)2, wherein at each occurrence Rzlb is independently hydrogen, Ci-Qalkyl, or C)-C4haloalkyl groups; R3 is
(i) aryl, heteroaryl, or aryl(Ci-C2)alkyl, wherein said aryl, heteroaryl, or aryl(Ci- C2)alkyl can optionally be substituted with one, two, or three R3a groups, wherein R3a at each occurrence independently represents hydrogen, halogen, cyano, nitro, C\- C4alkyl, C1-C4 haloalkyl, acyl, optionally substituted C3-C8cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the group representing -R3b, -Ci-C4alkyl-R3b, or -OC1-C4 alkyl; wherein the substituted group on C3-C8cycloalkyl, aryl, heteroaryl or heterocyclyl are selected from hydrogen, nitro, cyano, halogen, acyl, C1-C4alkyl, aryl, or heteroaryl;
wherein, R3b at each occurrence is independently selected from
cyano, nitro, -N(R3c)2, -OR3c, -SR,C, -C(0)R3c, -C(0)OR3c, -C(0)N(R3c)2, -C(0)N(R3c)- N[(CrC3)alkyl]3 +, -S(0)N(R3c)2, -S(0)2N(R3c)2, or -S(0)2R3c,- (R3c)-N-S(0)2-R3c, - S(0)2N(R3c)-N[(Ci-C3)alkyl]3 +, -OC(0)R3c, -OC(0)OR3c, -OC(0)N(R3c)2, - N(R c)C(0)R3c, -N(R3c)C(0)OR3c, -N(R3c)C(0)N(R3c)2, or -N(R3c)C(=NR3c)N(R3c)2, wherein R3c at each occurrence independently selected from hydrogen, C C4alkyl, Q-C4 haloalkyl, cycloalkyl, heteroaryl, aryl heterocyclyl, -C(0)OR3d or N(R3d)C(=NR3d)N(R3d)2 groups, wherein R3d is defined hereinafter; or,
(ii) C,-C4alkyl, -Ci-C4alkyl-N(R3d)2, -Ci-C4alkyl-OR3d, -CrC4alkyl-SR3d , C3-C8 cycloalkyl, or heterocyclyl groups, wherein the cycloalkyl, and heterocyclyl groups are each optionally substituted with 1 to 6 groups which are each independently selected from -R or -CrC4alkyl-R e, wherein R at each occurrence is independently selected from hydrogen, Ci-C4alkyl, or C1-C4 haloalkyi groups and R3e at each occurrence is independently selected from cyano, nitro, -N(R3f)2, -OR3f, -SR3f, -C(0)R3f, -C(0)OR3f, -C(0)N(R3f)2, -C(0)N(R3f)rN[(C,-C3)alkyl]3 +, -S(0)N(R3f)2, -S(0)2N(R3f)2, -S(0)2N(R3f)-N[(Ci-C3)alkyl]3 +, -S(0)2R3f, -OC(0)R3f, -OC(0)OR3f, -OC(0)N(R3f)2, - N(R2c)C(0)R3f, -N(R2c)C(0)OR3f, -N(R3f)C(0)N(R3f)2, or -N(R3f)C(=NR3f)N(R3f)2, wherein R3f at each occurrence is independently represent hydrogen, Q^alkyl, or Ci- C4haloalkyl groups;
R4 is selected from hydrogen, nitro, cyano, halogen, acyl, Ci-C4alkyl, C1-C4 haloalkyi, aryl, or heteroaryl heterocyclyl, or -N(R4a)2 groups; wherein R4a at each occurrence is independently is selected from hydrogen, acyl, C]-C4alkyl or -S(0)2R4b; wherein R4b at each occurrence is selected from amino, acyl or C1-C4alkyl groups;
R5 and R6 each independently represents hydrogen, C C4alkyl or alternatively, R5 and
R6 together with carbon atom to which they are attached form a 3-7 membered ring, optionally comprising 1 or 2 hetroatom .selected from O, N and S.
In a preferred embodiment R1 is selected from aryl wherein aryl is substituted with one, two, or three Rla group, wherein RIa group is independently selected from halogen or Ci-C4alkyl.
In another preferred embodiment R2 is selected from -Z-Rz, wherein Z is -
Y Y
C(R )2-, wherein R at each occurrence independently represents hydrogen, C - C4alkyl; and Rz is aryl wherein said aryl can optionally substituted with one, two, or three R groups selected from cyano, halogen, -O R , wherein R is independently selected from hydrogen or C]-C4alkyl.
In a still preferred embodiment R is aryl, heteroaryl, or aryl(CrC2)alkyl, wherein said aryl, heteroaryl, or aryl(Ci-C2)alkyl can optionally be substituted with one, two, or three R3a groups, wherein R3a at each occurrence independently represents hydrogen, halogen, cyano, nitro, Ci-C4alkyl, C1-C4 haloalkyi, acyl, optionally substituted C3-Cgcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the group representing -R3b, -Ci- C4alkyl-R3b, or -OC1-C4 alkyl; wherein the substituted group on C3-C8cycloalkyl, aryl, heteroaryl or heterocyclyl are selected from hydrogen, nitro, cyano, halogen, acyl, C\- C4alkyl, aryl, or heteroaryl; wherein, R3b at each occurrence is independently selected from cyano, nitro, -N(R3c)2, -OR3c, -SRlc, -C(0)R3c, -C(0)OR3c, -C(0)N(R3c)2, - C(0)N(R3c)-N[(C, -C3)alkyl]3+, -S(0)N(R3c)2, -S(0)2N(R3c)2, or -S(0)2R3c,- (R3c)-N- S(0)2-R3c, -S(0)2N(R3c)-N[(C, -C3)alkyl]3 +, -OC(0)R3c, -OC(0)OR3c, -OC(0)N(R3c)2, - N(R3c)C(0)R3c, -N(R3c)C(0)OR3c, -N(R3c)C(0)N(R3c)2, or -N(R3c)C(=NR3c)N(R3c)2, wherein R3c at each occurrence independently selected from hydrogen, CrC4alkyl, C1-C4 haloalkyl, cycloalkyl, heteroaryl, aryl heterocyclyl, -C(0)OR3d or
N(R3d)C(=NR3d)N(R3d)2 groups, wherein R3d at each occurrence is independently selected from hydrogen, Ci-C4alkyl, or C1-C4 haloalkyl groups.
In a still further preferred embodiment R3 is selected from Ci-C4alkyl, -Cj- C4alkyl-OR3d, wherein R3d at each occurrence is independently selected from hydrogen, C]-C4alkyl, or Q-C4 haloalkyl groups.
In an embodiment, the various groups as defined above may be selected from: "Alkyl", as well as other groups having the prefix "alk", such as alkoxy and alkanoyl, means carbon chain which may either be linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl group include, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, ter/.-butyl, pentyl, hexyl etc. Where the specified number of carbon atoms permits e.g. from C3-io, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. In an embodiment, the alkyl group may be optionally substituted with nitro, cyano, halogen, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups;
"Amino" or "amine" refers to a -N(R)2 radical group, where each R is independently hydrogen, alkyl, aryl, acyl, heterocyclyl, or heteroaryl group. In a preferred embodiment, an amino group may be optionally substituted by one or more substituents which independently are with nitro, cyano, halogen, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.,
"Cycloalkyl" is the subset of alkyl and means saturated carbocyclic ring having a specified number of carbon atoms, preferably 3-10 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. In a embodiment, cycloalkyl group may be optionally substituted with nitro, cyano, halogen, Ci-C4alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
"Aryl" means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. In a preferred embodiment the aryl group may be selected from but not limited to phenyl and naphthyl. In an embodiment, aryl group may be optionally substituted with nitro, cyano, halogen, Ci-C4alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
"Acyl" used herein, refers to group R-C(O)-, wherein R is independently selected from hydrogen or alkyl, cycloalkyl, aryl as defined elsewhere in the specification. In a preferred embodiment the acyl group represents formyl, acetyl and the like. In an embodiment, acyl group may be optionally substituted with nitro, cyano, halogen, Q- C4alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
"Heterocycle" and "heterocyclyl" refer to saturated or unsaturated non-aromatic rings or ring systems containing at least one heteroatom selected from O, S, N further including the oxidized forms of sulfur and nitrogen, namely SO, S02, NO, N02. In a preferred embodiment the heterocyclyl group may be selected from but not limited to tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, pyridine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3- dithiane, oxathiane, thiomorpholine, In an embodiment, the heterocycle group may be optionally substituted with nitro, cyano, halogen, Cj.-C4alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
"Heteroaryl" means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. In an embodiment heteroaryl group includes heteroaryl fused to the other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic. In a preferred embodiment the heteroaryl group may be selected from but not limited to ; pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, fury], triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl,' indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, · indolyl, isoquinolyl, dibenzofuranyl etc. For heterocyclyl and heteroaryl groups, rings and ring systems containing from 3-15 carbon atoms are included, forming 1-3 rings. In an embodiment, the heteroaryl group may be optionally substituted with nitfo, cyano, halogen, CrC4alkyl, cycloalkyl, acyl, aryl, or heteroaryl or heterocyclyl groups.
The term "halogen" refers to fluorine, chlorine, bromine and iodine. Chlorine and fluorine are generally preferred.
The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. The term "substituted," as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
The term "Pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of the basic residues. The pharmaceutically acceptable salts include the conventional quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous' manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herei .
• The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder.
The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
As used herein, reference to "treatment" of a patient is intended to include prophylaxis. The term "patient" means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.
The term Prodrug is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche,- American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein. The term "prodrug" is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound. Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
The term Optional' or 'optionally' means that the subsequent described event or circumstance may or may not occur, and the description includes instances where the event or circumstance occur and instances in which it does not. For example, Optionally substituted alkyl' means either 'alkyl' or 'substituted alkyl'. Further an optionally substituted group includes the unsubstituted group also.
Unless otherwise stated in the specification, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures wherein hydrogen is replaced by deuterium or tritium, or wherein carbon atom is replaced by 13C- or I4C- enriched carbon, are within the scope of this invention.
Particularly preferred compounds may be selected from:
2-((2-((2-chloro-6-fluorobenzyl)oxy)ethyl)thio)-5-(2-(3,4-dichlorophenyl)propan-2- yl)-l-(4-fluorophenyl)-lH-imidazole;
2-((2-((2-chloro-6-fluorobenzyl)oxy)ethyl)thio)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole;
4- ((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazol-2- yl)thio) ethoxy) methyl)benzonitrile;
4-((2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l -(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy) methyl)benzonitrile;
2- ((2-((2,6-difluorobenzyl)oxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2- yl)-l -(4-fluoro phenyl)-! H-imidazole;
3- ((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)methyl)benzonitrile;
2-((2-((3-chlorobenzyl)oxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l- (4-fluoro phenyl)- 1 H-imidazole;
5- (2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-((3-fluorobenzyl)oxy)ethyl)thio)- 1 - (4-fluoro phenyl)- 1 H-imidazole;
4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)methyl)-3,5-dimethylisoxazole;
2-((3-((2-chloro-6-fluorobenzyl)oxy)propyl)thio)-5-(2-(3,4-dichlorophenyl)propan- 2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2- ((tetrahydrofuran-3-yl) methoxy)ethyl)thio)-lH-imidazole;
N-(4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)methyl)benzyl)methanesulfonamide; 2-((2-(2-chloro-5-methylphenoxy)ethyl)thio)-5-(2-(3,4-dichlorophenyl)propan-2- yl)- 1 -(4-fluoro phenyl)- 1 H-imidazole;
5-(2-(3,4-dichlorophenyl)propan-2-yl)-2-((2-(2,6-difluorophenoxy)ethyl)thio)- 1 -(4- fluoro phenyl)- 1 H-imidazole;
2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4-dichlorophenyl)propan- 2-yl)- 1 -(4-fluoropheny 1)- 1 H-im idazole ;
4- (2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazol-2- yl)thio) ethoxy) benzonitrile;
5- (2-(3,4-dichlorophenyl)propan-2-yl)-2-((2-(3,4-dimethoxyphenoxy)ethyl)thio)-l- (4-fluoro phenyl)- 1 H-imidazole;
2-((2-(4-(lH-pyrrol-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2- yl)- 1 -(4-fluorophenyl)- 1 H-imidazole;
2-((2-(4-(l H-imidazol- 1 -yl)phenoxy)ethyl)thio)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(thiophen-3- yl)phenoxy) ethyl)thio)- 1 H-imidazole;
2-((2-(2,6-difluorophenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l- (4-fluoro phenyl)-lH-imidazole;
2-((2-(3,4-dimethoxyphenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- l-(4-fluoro phenyl)-lH-imidazole;
4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluoropheny])-lH-imidazol-2- yl)thio) ethoxy)benzonitrile;
methyl 4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethoxy)benzoate;
3-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)pyridine;
N-cyclopropyl-4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- lH-imidazol-2-yl)thio)ethoxy)benzamide;
N-(4-(2-((5-(2-(3, 4-dimethoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)- 1H- imidazol-2-yl)thio) ethoxy)phenyl)acetamide;
N-(4-(2-((5 -(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl) thio) ethoxy)phenyl)methanesulfonamide; 3-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)benzonitrile;
3-chloro-4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl) thio)ethoxy)-5-fluorobenzaldehyde;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(4-methyl- 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)-l H-imidazole;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2-methyl- 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole;
1 -(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)-l H-imidazol 2-yl)thio) ethoxy)phenyl)-lH-l,2,4-triazole;
2-((2-(4-( 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 -(4-fluorophenyl)-5-(2-(3 - methoxyphenyl) propan-2-yl)- 1 H-imidazole;
l-(2,4-difluorophenyl)-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(4-(2- methyl-lH-imidazol-l-yl)phenoxy)ethyl)thio)-lH-imidazole;
1- (4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol
2- yl)thio) ethoxy)phenyl)-lH-pyrazole;
1 -(4-(2-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl) thio)ethoxy)phenyl)-lH-pyrazole;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-(lH-imidazol-l- yl)phenoxy) ethyl) thio)- 1 -(4-fluorophenyl)- 1 H-imidazole;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-(2-methyl-lH-imidazol- 1 -yl)phenoxy) ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(3-fluoro-4-(2-methyl-lH-imidazol- l-yl)phenoxy) ethyl)thio)-l -(4-fluorophenyl)- 1 H-imidazole;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(3-fluoro-4-(2-methyl-lH-imidazol-
1- yl)phenoxy) ethyl)thio)-l-(4-fluorophenyl)-lH-imidazole;
5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2- methyl- 1 H-im idazol- 1 -y l)phenoxy)ethy l)thio)- 1 H-imidazole;
2- ((2-(4-( 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)-5 -(2-(4-fluoro-3- methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazole;
1 -(4-(2-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethoxy)phenyl)- 1 H-pyrazole; 2- ((2-(4-( 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)-4-bromo-5-(2-(3,4- dimethoxyphenyl) propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole;
4- bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-(lH-imidazol- 1 -yl) phenoxy) ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole;
4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)-2-((2-(4-(2- methyl- 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole;
3- (2-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol- 2-yl)thio) ethoxy)phenyl)- 1 H-pyrazole;
2-((2-(4-( 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)-5-(2-(4-chloro-3- methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole;
5- (2-(4-chloro-3-methoxyphenyl)propan-2-yl)-2-((2-(3,4- dimethoxyphenoxy)ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole;
5-(2-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethoxy)-l H-indole;
3-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)-N,N-dimethylaniline;
2-((2-(2-chloro-5-methylphenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2- y 1)- 1 -(4-fluorophenyl)- 1 H-im idazole;
4- (2-((5-(2-(3 ,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazol-2- yl)thio) ethoxy)-N,N-dimethylaniline;
2-fluoro-5-(2-( 1 -(4-fluorophenyl)-2-((2-(4-(2-methyl- 1 H-imidazol- 1 - yl)phenoxy)ethyl)thio)-lH-imidazol-5-yl)propan-2-yl)benzonitrile;
5- (2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2- methyl-1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole;
5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(4- methyl- 1 H-imidazol- 1 -y l)phenoxy)ethyl)thio)- 1 H-imidazole;
2-((l-(4-(lH-imidazol-l-yl)phenoxy)-2-methylpropan-2-yl)thio)-5-(2-(3,4- dimethoxyphenyl) propan-2-yl)-l-(4-fluorophenyl)-lH-imidazole;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)-2-((l -((4-(2-methyl- 1 H-imidazol- 1 -yl)phenoxy)methyl)cyclobutyl)thio)- 1 H-imidazole;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-(( 1 -((2-fluoro-4-( 1 H-imidazol- 1 - yl)phenoxy) methyl)cyclobutyl)thio)-l-(4-fluorophenyl)-lH-imidazole; 4-(3-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazol-2- yl)thio) propoxy)benzonitrile;
2-(((benzyloxy)methyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4- fluorophenyl)- 1 H-imidazole;
2-(((4-(lH-imidazol-l-yl)phenoxy)methyl)thio)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole;
4- (((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) methoxy) benzonitrile;
5- (2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(2- methoxyethoxy) ethyl)thio) -1 H-imidazole;
4- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)-N-(pyridin-4-ylmethyl)benzamide;
5- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)-lH-iiidole;
N-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)-2-fluorophenyl)methanesulfonamide;
5-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazol- 2-yl)thio) ethoxy)phenyl)-2-methoxypyridine;
4- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)quinazoline;
2-(2-((5-(2-(3,4-dimethoxyphenyl)p"ropan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazol-2- yl)thio) ethoxy)benzo[d]thiazole;
l-(4-(2-((4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethoxy)phenyl)-lH-pyrazole;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)-2-((2-(3-(2-methyl-
1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole;
5- (2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-(2-methyl-lH- imidazol- 1 -yl) phenoxy)ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole;
l-(4-(2-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl) thio)ethoxy)phenyl)-lH-l,2,4-triazole;
5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-2-((2-(3-fluoro-4-(2-methyl-lH- imidazol-l-yl) phenoxy)ethyl)thio)-l -(4-fluorophenyl)- 1 H-imidazole; 5-(2-(4-chloro-3-methoxyphenyl)pr pan-2-yl)-l-(4-fluorophenyl)-2-((2-(4- (thiophen-3-yl) phenoxy)ethyl)thio)-lH-imidazole;
5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)-2-((2-(3-(2- methyl- 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole;
2-((2-(4-( 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 -(4-fluorophenyl)-5-(2- phenylpropan-2-y 1)- 1 H-imidazole;
5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-(lH-imidazol-l- yl)phenoxy) ethyl)thio)-l-(4-fluorophenyl)-l H-imidazole;
5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-(2-methyl-lH- imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole;
5-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)-lH-indazole;
5-(2-(2-((2-(4-( 1 H-pyrazol- 1 -yl)phenoxy)ethyl)thio)- 1 -(4-fluorophenyl)-l H- imidazol-5-yl) propan-2-yl)-2-fluorobenzonitrile;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-methyl-l-(4-(2- methyl- 1 H-imidazol- 1 -y l)phenoxy)propan-2-yl)thio)- 1 H-imidazole;
5- (2-(3,4-dimethoxyphenyl)propan-2-yl)-2-(( 1 -(2-fluoro-4-( 1 H-imidazol- 1 - y l)phenoxy)-2-methy lpropan-2-y l)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole;
1 -(4-fluorophenyl)-5-(2-(3-methoxyphenyl)propan-2-yl)-2-((2-(4-(2-methyl- 1 H- imidazol- l-yI)phenoxy)ethyl)thio)-l H-imidazole;
6- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)-2H-chromen-2-one;
5-(2-(2-((2-(4-( 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 -(4-fluorophenyl)- 1 H- imidazol-5-yl) propan-2-yl)-2-fluorobenzonitrile;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2- phenoxyethyl)thio)- 1 H-imidazole;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(2- methoxyethoxy) ethyl)thio)-lH-imidazole;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)-2-((2- methoxyethyl)thio)-l H-imidazole;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2-methyl- 1 H-imidazol - 1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole-4-carbonitrile; 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(3-fluoro-4-(2-methyl-lH-imidazol- 1 -yl) phenoxy) ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole-4-carbonitrile;
5-(2-(benzo[d][l,3]dioxol-5-yl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2-methyl- 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole ;
(S)-methyl 2-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)- lH-imidazol-2-yl)thio)ethoxy)benzamido)-5-guanidinopentanoate;
(S)-2-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)- 1H- imidazol-2-yl)thio)ethoxy)benzamido)-5-guanidinopentanoic acid;
2-(4-(2-((5-(2-(3,4-diraethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol- 2-yl)thio) ethoxy)benzamido)-N,N,N-trimethylethanaminium chloride;
4-(2-(2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-l-(4-fluorophenyl)-lH- imidazol-5-yl) propan-2-yl)benzene-l,2-diol;
4-((2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l -(4-fluorophenyl)- 1 H-imidazol-2- yl)sulfinyl) ethoxy)methyl)benzonitrile;
2-((2-((2,6-difluorobenzyl)oxy)ethyl)sulfinyl)-5-(2-(3,4-dimethoxyphenyl)propan-
2-yl)- 1 -(4-fluorophenyl)- 1 H-im idazole;
2-((2-(4-( 1 H-pyrrol- 1 -yl)phenoxy)ethyl)sulfinyl)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole ;
2-((2-(4-(l H-imidazol- 1 -yl)phenoxy)ethyl)sulfinyl)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazole;
4- (2-((5-(2-(3,4-dimethoxypheny l)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazol-2- yl) sulfinyl) ethoxy)benzonitrile;
5- (2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2-methyl- 1 H-im idazol- 1 -y l)phenoxy)ethyl)sulfiny 1)- 1 H-imidazole ;
4-((2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazol-2- yl)sulfonyl) ethoxy)methyl)benzonitrile;
4- ((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl) sulfonyl) ethoxy)methyl)benzonitrile;
2-((2-(4-(l H-imidazol- l-yl)phenoxy)ethyl)sulfonyl)-5-(2-(3,4- dimethoxypherryl)propan-2-yl)-l -(4-fluorophenyl)- 1 H-imidazole;
5- (4-((2-((5-(2 (3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol- 2-yl)thio) ethoxy)methyl)phenyl)-lH-tetrazole; 5-(4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl) thio) ethoxy)methyl)phenyl)-lH-tetrazole;
5-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol- 2-yl)thio) ethoxy)phenyl)-lH-tetrazole;
5-(4-(2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)phenyl)-lH-tetrazole;
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-4-methyl-2-((2-(4-(2- methyl- 1 H-im idazol- 1 -y l)phenoxy)ethy l)thio)- 1 H-imidazole;
1- (4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazol-
2- yl)thio)ethoxy)-3-fluorophenyl)-lH-pyrazole
2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)-4-methy 1- 1 H-imidazole
4-(3-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol- 2-yl)thio)ethoxy)phenyl)morpholine
2-((2-(3-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(4-chloro-3- methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole.
General Process for Preparation
The compounds of present invention may be prepared by different synthetic schemes 1 wherein the groups RZ1, R1, R3, & Y are as defined earlier. Synthesis of the compounds of Formula I disclosed herein, and embodiments thereof, are not limited by these examples and schemes. One skilled in the art will know that other procedures can be used to synthesize the compounds of Formulae I disclosed herein, in combination with the processes described herein. In the descriptions below, one of ordinary skill in the art would recognize that specific reaction conditions, added reagents, solvents, and reaction temperatures can be modified for the synthesis of specific compounds that fall within the scope of this disclosure. All intermediate compounds described below, for which there is no description of how to synthesize such intermediates within these examples below, are commercially available compounds unless otherwise specified.
General Synthetic Methods for Preparing Compounds
The following schemes can be used to practice the present invention.
Certain compounds as disclosed herein can be synthesized using the following general synthetic procedure set forth in Scheme 1.
Figure imgf000020_0001
Synthesis
Compounds of formula (2) are commercially available or may be prepared from known compounds using standard methodologies.
Step (I): An aldehyde of formula (3) may be prepared by reaction of nitrile (2) with diisobutylaluminum hydride in a suitable solvent, such as THF or toluene. Step (II): Formation of carbinol (4) may be achieved by treatment of aldehyde (3) with methylmagnesium bromide in a suitable solvent, such as diethyl ether or THF. Step (III): . Conversion of carbinol (4) to ketone (5) may occur under standard conditions, such as the Swern oxidation— known to one skilled in the art of synthetic organic chemistry. Step (IV): Bromoketone (6) may be prepared by bromination of ketone (5) under typical conditions, such as with tetrabutylammonium tribromide in solvent mixture of MeOH/DCM. Step (V): Reaction of bromoketone (6) with hexamethylenetetramine in a suitable solvent, such as DCM, followed by acidic treatment under standard conditions, such as hydrochloric acid in ethanol, may afford amino-ketone hydrochloride (6). Step (VI): Substituted isothiocyanate, which may be optionally substituted suitably, may react with amino-ketone hydrochloride (7) in a suitable solvent, such as DCM or toluene, and in the presence of a base, such as triethylamine, at room temperature to yield the corresponding thiourea, which may condense upon treatment with HOAc at elevated temperature to give a compound of formula (8). Step (VII): Alkylation of imidazol-2-thione (8) with a reagent such as bromoethanol or protected bromomethanol in a suitable solvent, such as acetone or MeCN, and in the presence of a base, such as potassium carbonate, may afford a compound of formula (9). Step (VIII): Benzylation of compound of formula (9) with a substituted benzyl bromide in a suitable solvent, such as acetone or MeCN, and in the presence of a base, such as potassium carbonate, may afford a compound of formula (I).
Certain compounds as disclosed herein can be synthesized using the following general synthetic procedure set forth in Scheme 2.
Scheme-2
Figure imgf000021_0001
1-2
Reaction of thioether (I) with a suitable oxidant, such as mCPBA, in a suitable solvent such as DCM may yield compound of formula 1-1 or 1-2.
The following compounds were prepared using the process described above in combination, when required, with other processes, reagents, conditions as are well known to persons skilled in the art. Such obvious modifications/alterations etc. carried out to obtain further compounds of formula (I), should, based on the disclosures herein provided in combination with the knowledge of a skilled person be considered to be within the scope of the invention.
Example 1
Figure imgf000021_0002
To a solution of 2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)- lH-imidazol-2-yl)thio)ethanol (100 mg, 0.235 mmol) in DMF was added sodium hydride (17 mg, 0.705 mmol) and 2-(bromomethyl)-l-chloro-3-fluorobenzene (63 mg, 0.282 mmol) and stirred at room temperature for 3 h. Reaction mixture was quenched with dichloro methane and extracted with brine, combined organic layers were dried over sodium sulphate and distilled the solvent under vacuum. Crude product was purified by column chromatography to afford the desired product (92 mg, 69% yield). Ή MR (CDC13, 400MHz): 7.24 - 7.16 (m, 3H), 7.13 (s, 1H), 7.01 (d, J = 2Hz, 1H), 7.00 - 6.95 (m, 1H), 6.88 - 6.82 (m, 3H), 6.58 - 6.53 (m, 2H), 4.65 (d, J = 2Hz, 2H), 3.75 (t, J = 6.4Hz, 2H), 3.27 (t, J = 6.4Hz, 2H), 1.48 (s, 6H). m/z Relative intensities = 566.8 (M+l)+100%. % Purity = 96.21% (By HPLC), Retention time =15.95 min. IR CHCI3 (cm 1): 3302, 1606, 1581, 1510, 1215.
The following compounds were prepared by following a similar process as described in Example 1 along with suitable modifications as are well known to those skilled in the art.
Example 2
2-((2-((2-chloro-6-fluorobenzyl)oxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan- 2-yl)-l-(4-fluorophenyl)-lH-imidazole
In a manner similar to that described for Example 1, the title compound was prepared from 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethanol and 2-(bromomethyl)-l-chloro-3-fluorobenzene. Ή NMR (DMSO, 400MHz): 7.25-7.16 (m,2H), 7.12(s,lH), 6.99-6.95 (m,lH), 6.81 (t, J = 8.4Hz 2H), 6.65(d, J = 8.8Hz, 1H), 6.55-6.47(m,4H), 4.64(d, J = 2Hz, 2H), 3.87(s, 3H), 3.75- 3.72 (m, 5H), 3.24 (t, J = 6.4Hz, 2H), 1.54(s, 6H). m/z Relative intensities =558.9 (M+)+100 %. % Purity = 97.21% (By HPLC). IR CHCI3 (cm 1): 671, 1103, 1175, 1215, 1384, 1464, 1510, 1582, 1606, 2839, 2972, 3021, 3406, 3684.
Example 3
4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yI)-l-(4-fluoroplienyl)-lH-imidazol-2- yl)thio) ethoxy) methyl)benzonitrile
In a manner similar to that described for Example 1, the title compound was prepared from 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethanol and 4-(brbmomethyl)benzonitrile. Ή NMR (DMSO, 400MHz): 7.60 (d, J = 8.4HZ, 2H), 7.39 (d, J = 8.4Hz, 2H), 7.12 (s, 1H). 6.82 (t, J = 6Hz, 2H), 6.66-6.64 (dd, Jl= 2.4Hz, J2 = 6.8Hz, 1H), 6.56-6.51 (m,4H), 4.55 (s,2H), 3.85 (s, 3H), 3.76 (t J = 6Hz, 2H), 3.72 (s, 3H), 3.29 (t, J = 6.4Hz, 2H), 1.48 (s, 6H). m/z Relative intensities =532.1 (]ν )+100 %, 533.1 (M+H)+30%. % Purity = 97.36% (By HPLC). IR CHCI3 (cm-1): 843, 1028, 1105, 1215, 1385, 1510, 1603, 2232, 2974, 3021, 3406.
Example 4
4-((2-((5-(2-(3,4-dichIorophenyI)propan-2-yI)-l-(4-fluorophenyl)-lH-imidazol-2- yI)thio) ethoxy) methyl)benzonitrile
In a manner similar to that described for Example 1, the title compound was prepared from 2-((5-(2-(3,4-dichlorophenyI)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethanol and 4-(bromomethyl)benzonitrile. 1H NMR (CDC13, 400MHz): 7.62 - 7.60 (dd, Jl = 6.8Hz," 1H, J2 = 1.6Hz, 1H), 7.40 (d, J = 8.4Hz, 2H), 7.23 (d, J = 8.4Hz,lH), 7.13 (s, 1H ), 7.00 (d, J = 2Hz,lH), 6.89 - 6.84 (m, 2H ), 6.81 - 6.81 (m, 1H ), 6.58 - 6.55 (m, 2H ), 4.56 (s, 2H ), 3.77 (t, J = 6Hz, 2H), 3.32 (t, J = 6Hz, 2H), 1.51 (s, 6H). m/z Relative intensities = 540.0 (M+l)+100%. % Purity = 95.16 % (By HPLC). IR CHCI3 (cm-1): 2972, 2933, 2231, 1508, 1471, 1271.
Example 5
2- ((2-((2,6-di£luorobenzyl)oxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyI)propan-2-yl)- l-(4-fluoro phenyI)-lH-imidazole
In a manner similar to that described for Example 1, the title compound was prepared from 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethanol and 2-(bromomethyl)-l,3-difluorobenzene. Ή NMR (CDC13, 400MHz): 7.29-1.22 (m,lH), 7.13 (s, 1H), 6.90-6.78 (m,4H), 6.66-6.64 (m,lH), 6.54-6.46 (m,4H), 4.57 (s,2H), 3.85 (s,3H), 3.73 (s, 3H), 3.72 (t,J = 6.4Hz, 2H), 3.25 (t, J = 6.4Hz, 2H), 1.48 (s, 6H). m/z Relative intensities = 543.1 (M+)+100 %, 544.1 (M+H)+ 30%. % Purity = 96.21 % (By HPLC). IR CHCI3 (cm"1): 756, 1215, 1236, 1472, 1501, 1628, 2836, 2876, 2974, 3021, 3424.
Example 6
3- ((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yI)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)methyl)benzonitriIe
In a manner similar to that described for Example 1, the title compound was prepared from 2-((5-(2-(3,4-dimethoxypheny l)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethanol and 3-(bromomethyl)benzonitrile. Ή NMR (CDC13, 400MHz): 7.61(s, 1H), 7.56 (d, J = 7.6Hz, 1H), 7.51(d, J = 8Hz, 1H). 7.44-7.60 (m,lH), 7.14(s, 1H), 6.85-6.81 (m,2H), 6.65 (d, J = 8.8Hz, 1H), 6.55-6.46(m,4H), 4.53(s, 2H), 3.85(s, 3H), 3.76 (t, J = 6.4Hz, 2H), 3.72 (s,3H), 3.29 ( t, J = 6.4Hz, 2H), 1.48 (s, 3H). m/z Relative intensities = 532.1(M+)+100 %, 533.1(M+H)+30%. % Purity = 94.65 % (By HPLC). IR CHCI3 (cm 1): 823, 1028, 1153, 1175, 1256, 1510, 1603, 2234, 2839, 2976, 3021, 3433.
Example 7
2-((2-((3-chIorobenzyl)oxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l- (4-fluoro phenyl)-lH-imidazoIe
In a manner similar to that described for Example 1, the title compound was prepared from 2-((5-(2-(3 ,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethanol and l-(bromomethyl)-3-chlorobenzene. Ή NMR (CDC13, 400MHz): 7.32-7.23 (m, 3H), 7.17-1.13 (m, 2H), 6.82 (t, J = 3.2Hz, 2H), 6.64 (d, J = 8.8Hz, IH), 6.55-6.50 (m,4H), 4.47 (s, 2H), 3.85 (s, 3H), 3.73-3.67 (m, 5H), 3.28 (t, J =2H), 1.74 (s, 6H). m/z Relative intensities = 541.1(M+)+100 %. % Purity = 95.37 % (By HPLC). IR CHCI3 (cm-1): 669, 843, 1256, 1410, 1510, 1601, 2839, 2870, 2974, 3019, 3408.
Example 8
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-((3-fluorobenzyI)oxy)ethyI)thio)-l- (4-fluoro phenyl)-lH-imidazole
In a manner similar to that described for Example 1, the title compound was prepared from 2-((5-(2-(3 ,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethanol and l-(bromomethyl)-3-fluorobenzene. Ή NMR (CDC13, 400MHz): 7.29 - 7.24 (m, IH ), 7.13 (s, IH), 7.05 - 7.00 (m, 2H ), 6.9.7 - 6.93 (m, IH), 6.84 - 6.80 (m, 2H), 6.64 (d, J = 8.8Hz,lH) 6.54 - 6.51 (m, 2H ), 6.48 - 6.46 (m, 2H), 4.49 (s, 2H), 3.85 (s, 3H), 3.74 - 3.71 (m, 5H), 3.29 (t, J = 64Hz, 2H), 1.47 (s, 6H). m/z Relative intensities = 525.1 (M)+100 %. % Purity = 93.33 % (By HPLC).
Example 9
4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)methyl)-3,5-dimethylisoxazole
In a manner similar to that described for Example 1, the title compound was prepared from 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethanol and 4-(chloromethyl)-3,5-dimethylisoxazole. 1H NMR (CDCI3, 400MHz): 7.12 (s, IH ), 6.85 - 6.79 (m, 2H ), 6.67 - 6.64 (m, IH ), 6.54 - 6.47 (m, 4H ), 4.26 (s, 2H), 3.86 (s, 3H), 3.74 (s, 3H), 3.66 (t, J = 6Hz, 2H), 3.25 (t, J = 6Hz, 2H), 2.32 (s, 3H), 2.19 (s, 3H), 1.48 (s, 6H). m/z Relative intensities = 526.1 (M)+100 %. % Purity = 94.55 % (By HPLC). IR CHCI3 (cm-1): 3020, 1602, 1512, 1475, 1215.
Example 10
2-((3-((2-chloro-6-fluorobenzyl)oxy)propyl)thio)-5-(2-(3,4-dichlorophenyl)propan- 2-yl)-l-(4-fluorophenyl)-lH-imidazole
In a manner similar to that described for Example 1, the title compound was prepared from 3-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)propan-l-ol and 2-(bromomethyl)-l-chloro-3-fluorobenzene. Ή NMR (CDCI3, 400MHz): 7.25 - 7.19 (m, 2H), 7.18 - 7.17 (m, IH), 7.13 (s, IH), 7.00 - 6.96 (m, IH), (dd, Jl = 7.6Hz, IH, J2 = 2Hz, IH), 6.88 - 6.82 (m, 3H), 6.55 - 6.52 (m, 2H), 4.60 (s, 2H), 3.54 (t, J = 6Hz, 2H), 3.09 (t, J = 7.6Hz, 2H), 1,93 (m, 2H), 1.48 (s, 6H). m/z Relative intensities = 5 2.9 (M+l)+100 %. % Purity = 90.42 % (By HPLC). IR CHCI3 (cm-'): 3423, 2976, 2935, 1606, 1581, 121 .
Example 11
5-(2-(3,4-dimethoxypbenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2- ((tetrahydrofuran-3-yl) methoxy)ethyl)thio)-lH-imidazoIe
In a manner similar to that described for Example 1, the title compound was prepared from 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethanol and (tetrahydrofuran-3-yl)methyl methanesulfonate. Ή NMR (CDCI3, 400MHz): 7.13 (s, IH), 6.83 (t, J = 8.4Hz, 2H), 6.66 - 6.64 (m, IH), 6.55 - 6.50 (m, 2H), 6.49 - 6.47 (m, 2H), 3.85 (s, 3H), 3.82 - 3.76 (m, 2H), 3.75 - 3.70 (m, 4H), 3.68 - 3.65 (m, 2H), 3.53 - 3.50 (m, IH), 3.40 - 3.36 (m, IH), 3.33 - 3.29 (m, IH), 3.23 (t, J = 6Hz, 2H), 2.49 - 2.42 (m, IH), 1.99 - 1.95 (m, IH), 1.61 - 1.50 (m, IH), 1.48 (s, 6H). m/z Relative intensities = 501.2 (M+l)+100 %. % Purity = 93.59 % (By HPLC).
Example 12
N-(4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)methyl)benzyl)methanesulfonamide
In a manner similar to that described for Example 1, the title compound was prepared from 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethanol and N-(4-(bromomethyl)benzyl)methanesulfonamide. Ή NMR (CDC , 400MHz): 7.29 (s, 4H), 7.13 (s, lH), 6.82 (t, J = 8.4Hz, 2H), 6.65 (d, J = 8.8Hz, 1H), 4.71 - 4.68 (m, 3H), 4.49 (s, 2H), 4.31 (d, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.73 - 3.70 (s, 5H), 3.28 (t, J = 6.4Hz, 2H), 2.88 (s, 3H), 1.47 (s, 6H). m/z Relative intensities = 614.3 (M+l)+100 %. % Purity = 93.76 % (By HPLC).
Example 13
2-((2-(2-chloro-5-methylphenoxy)ethyl)thio)-5-(2-(3,4-dichlorophenyl)propan-2- yI)-l-(4-fluoro phenyl)-lH-imidazole
Figure imgf000026_0001
To a solution of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol (120 mg, 0.314 mmol) in acetone was added potassium carbonate (130 mg, 0.942 mmol) and 2-(2-bromoethoxy)-l-chloro-4-methylbenzene (94 mg, 0.377 mmol) and stirred at room temperature for 15 h. Reaction mixture was quenched with ethyl acetate and extracted with brine, combined organic layers were dried over sodium sulphate and distilled the solvent under reduced vacuum. Crude product was purified by column chromatography to afford the desired product (104 mg, 60% yield). Ή NMR (CDC13, 400MHz): 7.26 - 7.17 (m, 3H), 7.00 (d, J = 2.4Hz, 1H), 6.89 - 6.82 (m, 4H), 6.72 - 6.69 (dd, Jl = 8Hz, J2 = 1.2Hz,lH), 6.58 - 6.55 (m, 2H), 4.30 (t, J = 6.4Hz, 2H), 3.50 (t, J = 6.4Hz, 2H), 2.32 (s, 3H), 1.50 (s, 6H). m/z Relative intensities = 550.9 (M+l)+100%. % Purity = 96.67% (By HPLC), Retention time = 21.59 min. IR CHCI3 (cm'1): 2928, 2947, 1597, 1538, 1504, 1219.
Example 14
5-(2-(3,4-dichlorophenyl)propan-2-yl)-2-((2-(2,6-difluorophenoxy)ethyl)thio)-l-(4- fluoro phenyl)-lH-imidazole
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l -(4-fluorophenyl)-lH- imidazole-2-thiol and 2-(2-bromoethoxy)-l,3-difluorobenzene. Ή NMR (CDCI3, 400MHz): 7.23 (d, J = 8.4Hz,lH), 7.13 (s, 1H), 7.01 (d, J = 2.4Hz,lH), 6.96 - 6.92 (m, 1H), 6.89 - 6.82 (m, 5H), 6.58 - 6.54 (m, 2H), 4.35 (t, J = 6Hz, 2H), 3.41 (t, J = 6Hz, 2H), 1.49 (s, 6H). m/z Relative intensities = 537.0 (M)+100 %. % Purity = 99.74 % (By HPLC). IR CHCIs Ccm 1): 3416, 1599, 1508, 1496, 1224.
Example 15
2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4-dichlorophenyl)propan-2- yl)-l-(4-fluorophenyl)-lH-imidazole
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichIorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-lH-imidazole. Ή NMR (CDC13, 400MHz): 7.85 (s, 1H), 7.37 - 7.33 (m, 2H), 7.26 - 7.22 (m, 2H), 7.07 - 7.03 (m, 2H), 6.99 - 6.97 (m, 2H), 6.91 - 6.87 (m, 2H), 6.78 - 6.75 (dd, Jl = 8.4Hz, J2 = 2.4Hz,lH), 6.62 - 6.58 (m, 2H), 4.58 (t, J = 4.8Hz, 2H), 4.45 (t, J = 4.8Hz, 2H), 1.25 (s, 6H). m/z Relative intensities = 567.1 (M)+100 %. % Purity = 95.68 % (By HPLC). IR CHCI3 (cm-1): 3416, 1602, 1514, 1469, 1236.
Example 16
4-(2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy) benzonitrile
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 4-(2-bromo ethoxy)benzonitrile. !H NMR (CDC13, 400MHz): 7.58 - 7.55 (m, 2H), 7.24 (d, J = 8.4Hz,lH), 7.14 (s, 1H), 7.01 (d, J = 2Hz,lH), 6.99 - 6.96 (m, 3H), 6.57 - 6.53 (m, 2H), 4.31 (t, J = 6.4Hz, 2H), 3.44 (t, J = 6.4Hz, 2H), 1.50 (s, 6H). m/z Relative intensities = 526.0 (M)+100%. % Purity = 97.01 % (By HPLC). IR CHCI3 (cm 1): 3020, 2227, 1606, 1510, 1215.
Example 17
5-(2-(3,4-dichlorophenyl)propan-2-yl)-2-((2-(3,4-dimethoxyphenoxy)ethyl)thio)-l- (4-fluoro phenyl)-lH-imidazole
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 4-(2-bromo ethoxy)- 1, 2 -dimethoxybenzene. 1H NMR (CDCI3, 400MHz): 7.23 (d, J = 8.4Hz,lH), 7.14 (s, 1H), 7.01 (d, J = 2Hz,lH), 6.88 - 6.82 (m, 3H), 6.75 (d, J = 8.8Hz,lH), 6.57 - 6.53 (s, 2H), 6.52 (d, J = 2.8Hz,lH), 6.40 - 6.37 (dd, J = 8.4Hz, J = 2.8Hz, 1H), 4.19 (t, J = 6Hz, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.41 (t, J = 6 Hz, 2H), 1.49 (s, 6H). m/z Relative intensities = 561.0 (M)+100%. % Purity = 95.09 % (By HPLC). IR CHCI3 (cm-1): 3435, 3020, 1512, 1215.
Example 18
2-((2-(4-(lH-pyrrol-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2- yl)-l-(4-fluorophenyl)-lH-imidazole
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and l-(4-(2-bromo ethoxy)phenyl)-lH-pyrrole. Ή NMR (CDC13, 400MHz): 7.29 - 7.27 (m, 2H), 7.20 (s, 1H), 6.99 (t, J = 2Hz, 2H), 6.92 (d, J = 8Hz,2H), 6.85 - 6.80 (m, 2H), 6.65 - 6.63 (m, 1H), 6.54 - 6.52 (m, 2H), 6.49 - 6.47 (m, 2H), 6.3 l(t, J = 2Hz, 2H), 3.84 (s, 3H), 3.71 (s, 3H), 3.49 - 3.44 (m, 2H), 1.49 (s, 6H). m/z Relative intensities = 558.0 (M)+100%. % Purity = 92.67 % (By HPLC). IR CHCI3 (cm"1): 3020, 2974, 1512, 1404, 1215.
Example 19
2-((2-(4-(lH-imidazol-l -yI)phenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan- 2-yl)-l-(4-fluorophenyl)-lH-imidazole.
1H NMR (CDC , 400MHz): 7.64 (s, 1H), 7.29 - 7.27 (dd, Jl = 2Hz, J2 = 6.8Hz, 2H), 7.19 (d, J = 7.2Hz, 2H), 7.15 (s, 1H), 7.00 - 6.98 (dd, Jl = 2.4Hz, J2 = 6.8Hz, 2H), 6.82 (t, J = 9.2Hz, 2H), 6.65 (d, J = 9.2Hz, 1H), 6.53 - 6.48 (m, 4H), 4.27 (t, J = 6.4Hz, 2H), 3.84 (s, 3H), 3.73 (s, 3H), 3.43 (t, J = 6.4Hz, 2H), 1.49(s, 6H). m/z Relative intensities = 559 (M)+100 %. % Purity = 95.51%-(By HPLC). IR KBr (cm 1): 3424, 3021, 2938, 1602, 1516, 1438, 1386, 1300, 1215, 1175, 1099, 754.
Example 20
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(thiophen-3- yI)phenoxy) ethyl)thio)-lH-imidazoIe.
H NMR (CDCI3, 400MHz): 7.51 - 7.48 (dd, Jl = 2Hz, J2 = 6.8HZ, 2H), 7.37 - 7.32 (m, 3H), 7.15 (s, 1H), 6.91 - 6.89 (dd, Jl = 2Hz, J2 = 6.8Hz, 2H), 6.83 (t, J = 8.4Hz, 2H), 6.64 (d, J = 8.8Hz, 1H), 6.53 - 6.47 (m, 4H), 4.25 ( t, J = 6.4Hz, 2H), 3.83 (s, 3H), 3.71 (s, 3H), 3.72 (t, J = 6.4Hz, 2H), 1.53 (s, 6H). m/z Relative intensities = 575.1 (M)+100 %. % Purity = 97.87 % (By HPLC). IR KBr (cm"1): 3456, 3069, 2938, 2837, 1607, 1506, 1432, 1246, 799. Example 21
2-((2-(2,6-difluorophenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l- (4-fluoro phenyl)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2 -thiol and 2-(2-bromo ethoxy)-l,3-difluorobenzene. Ή NMR (CDC13, 400MHz): 7.13 (s, 1H), 6.99 - 6.92 (m, 1H), 6.89 - 6.80 (m, 4H), 6.65 (d, J = 8.4Hz, 1H), 6.54 - 6.49 (m, 4H), 4.33 (t , J = 6.8Hz, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 3.39 (t, J = 6.4Hz, 2H), 1.48 (s, 6H). m/z Relative intensities = 529.1 (M)+100 %. % Purity = 97.91% (By HPLC). IR CDCI3 (cm 1): 3416, 3084, 2999, 2982, 2910, 2833, 1510, 1408, 1292, 1240, 1173, 1026, 978, 777.
Example 22
2-((2-(3,4-dimethoxyphenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyI)propan-2-yI)- l-(4-fluoro phenyl)-lH-imidazole
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2 -thiol and 4-(2-bromo ethoxy)-l ,2-dimethoxybenzene. Ή NMR (CDCI3, 400MHz): 7.14 (s, 1H), 6.81( t, J = 8.4Hz, 2H), 6.75 (d, J = 8.8Hz, 1H), 6.75 (d, J = 8.8Hz, 1H), 6.53 (m, 5H), 6.39 - 6.36 (dd, Jl = 2.8Hz, 52 = 8.8Hz, 1H), 4.17 (t J = 6.4Hz, 2H), 3.85 (s, 6H), 3.84 (s, 3H), 3.71 (s, 3H), 3.38 (t, J = 6.4Hz, 2H), 1.48 (s, 6H). m/z Relative intensities = 553.3 (M)+100 %. % Purity = 93.82 % (By HPLC). IR CHCI3 (cm-1): 3680, 3630, 3021, 2974, 2839, 1512, 1465, 1212, 1028.
Example 23
4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidaz0l-2- yl)thio) ethoxy)benzonitrile.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yi)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 4-(2-bromo ethoxy)benzonitrile. Ή NMR (CDC13, 400MHz): 7.58 - 7.55 (dd, Jl = 2Hz, J2 = 6.8Hz, 2H), 7.14 (s, 1H), 6.98 - 6.96 (dd, Jl = 2Hz, J2 = 6.8Hz, 2H), 6.84-6.80 (m,2H), 6.65 (d, J = 9.2Hz, 1H), 6.53 - 6.48 (m, 4H), 4.32 ( t, J = 6.8Hz. 2H), 3.85 (s, 3H), 3.71 (s, 3H), 3.41 (t, J = 6.8Hz, 2H), 1.49 (s, 6H). m/z Relative intensities = 518.1 (M)+100 %. % Purity = 95.27 % (By HPLC). IR KBr (cm" '): 3416, 31 19, 2972, 2834, 1035, 1502, 1256, 1236, 1 173, 1024, 836. Example 24
methyl 4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethoxy)benzoate.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and methyl 4-(2-bromoethoxy)benzoate.Ή NMR (CDC13) 400MHz): 7.98 - 7.96 (dd, Jl = 2Hz, 32 = 6.4Hz, 2H), 7.26 (s, 1H), 6.92 - 6.89 (dd, Jl = 2Hz, J2 = 6.4Hz, 2H), 6.84 - 6.78 (m, 2H), 6.65 (d, J = 8.8Hz, 1H), 6.54 - 6.48 (m, 4H), 4.29 ( t, J = 6.8Hz. 2H), 3.96 (s, 3H), 3.88 (s, 3H), 3.69 (s, 3H) 3.42 (t, J = 6.8Hz, 2H), 1.49 (s, 6H). m/z Relative intensities = 551.4 (M)+100 %. % Purity = 95.77 % (By HPLC). IR CHCI3 (cm-1): 3397, 2937, 2839, 1713, 1606, 1512, 1 107, 843.
Example 25
3-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)pyridine.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 3-(2-bromo ethoxy)pyridine. Ή NMR (CDC13, 400MHz): 8.30 (d, J = 1.6Hz, 1H), 8.21 (d, J = 2.8Hz, lH), 7.28 - 7.19 (m, 2H), 7.15 (s, 1H), 6.85 - 6.80 (m, 2H), 6.65 d, J = 8.8Hz, 1H), 6.65 - 6.50 (m, 4H), 4.30 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.7 l (s, 3H) 3.43 (t, J = 6.4Hz, 2H), 1.49 (s, 6H). m/z Relative intensities = 494.1 (M)+100 %. % Purity = 96.16 % (By HPLC), IR CHC13 (cm-1): 3680, 3434, 3020, 2876, 1603, 1512, 1333, 1026, 843.
Example 26
N-cyclopropyl-4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)- lH-imidazol-2-y])thio)ethoxy)benzamide.
In a manner similar to that described for Example 13, the title compound was prepared " from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 4-(2-bromoethoxy)-N-cyclopropylbenzamide. Ή NMR (CDCI3, 400MHz): 7.69 - 7.65 (m,2H), 7.15 (s, 1H), 6.90 - 6.86 (m, 2H), 6.83 - 6.79 (m, 2H), 6.64 (d, J = 8.8Hz, 1H), 6.52 - 6.46 (m, 4H), 6.16 (brs, 1H), 4.25 (t, J = 6.4Hz, 2H), 3.87 (s, 3H), 3.70 (s, 3H), 3.41 (t J = 6.4Hz, 2H), 2.90 - 2.86 (m, 1H), 1.48 (s, 6H), 0.88 - 0.83 (m, 2H), 0.62 - 0.58 (m ,2H). m/z Relative intensities = 576.1(M)+100 %. % Purity = 94.76 % (By HPLC), IR CHC13 (cm 1): 3808, 2968, 2850, 1640, 1510, 1254, 845.
Example 27
N-(4-(2-((5-(2-(3, 4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yI)thio) ethoxy)phenyI)acetamide.
Ή NMR (CDCI3, 400MHz): 9.77 (s, 1H), 7.44 (d, J = 9.2 Hz, 2H), 7.11 (s, 3H), 6.99 (d, J = 8.8 Hz, 2H), 6.72 (d, J = 8.4 Hz, 1H), 6.63 (d, J = 4.8 Hz, 2H), 6.42 (s, 2H), 4.12 - 4.0 (m, 4H), 3.77 (s, 3H), 3.55 (s, 3H), 3.16 (s, 6H), 1.99 (s, 3H). m/z Relative intensities = 550.1 (M)+ 100 %. % Purity = 96.76%.
Example 28
N-(4-(2-((5-(2-(3,4-dimethoxyphenyI)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-
2- yl) thio) ethoxy)phenyl)methanesulfonamide.
Ή NMR (CDCI3, 400MHz): 7.15 (dt, Ji = 4.4 Hz J2 = 2.4 Hz, 3H), 6.87 (dt, J, - 4.4 Hz, J2 = 2.4 Hz, 2H), 6.80 (dt, Ji = 4.4 Hz, J2 = 2.4 Hz, 2H), 6.53 - 6.51 (m, 1H), 6.5 - 6.4 (m, 3H), 6.15 (s, 1H), 4.21 (t, J= 8.0 Hz, 2H), 3.85 (s, 3H), 3.71 (s, 3H), 3.38 (t, J= 8.0 Hz, 2H), 2.94 (s, 3H), 1.49 (s,6H). m/z Relative intensities = 586.3 (M)+ 100 %. % Purity = 97.60 %.
Example 29
3- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yI)thio) ethoxy)benzonitrile
Ή NMR (CDCI3, 400MHz): 7.33 (t, J= 8.4 Hz, 1H), 7.25 (t, J= 5.2 Hz, 1H), 7.23 (t, J = 1.2 Hz, 1H), 7.16 (s, lH), 7.15 - 7.12 (m, 1H), 6.82 (dd, J, = 8.8 Hz, J2 = 2.4 Hz, 2H), 6.64 (m, 1H), 6.54 (s, 1H), 6.5 (dt, Ji = 5.2 Hz, J2 = 2.8 Hz, 2H), 6.41 (s, 1H), 4.26 (t, J= 6.8 Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.39 (t, J= 6.8 Hz, 2H), 1.49 (s,6H). m/z Relative intensities = 518.1 (M)+ 100 %. % Purity = 90.60 %.
Example 30
3-chloro-4-(2-((5-(2-(3,4-dimethoxyphenyI)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl) thio)ethoxy)-5-fluorobenzaldehyde.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 4-(2-bromoethoxy)-3-chloro-5-fluorobenzaldehyde. Ή NMR (CDCI3, 400MHz)r9.84 (s, 1H), 7.68 (t, J = 1.6Hz, 1H), 7.53 - 7.50 (dd, JI = 2Hz, J2 = 5.2Hz, 1H), 7.12 (s, 1H), 6.85 - 6.79 (m, 2H), 6.63 (d, J = 7.2Hz, 1H), 6.54 - 6.49 (m, 4H), 4.48 (t, J = 6.4Hz, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 3.44 (t, J = 6.4Hz, 2H), 1.48 (s, 6H). m/z Relative intensities = 573.1 (M)+100 %, % Purity = 95.94 % ( By HPLC), IR CHCl3 (cm"1): 3433, 3021, 1701, 1287, 1256, 1028, 843.
Example 31
5-(2-(3,4-dimethoxyphenyI)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(4-methyl-lH- imidazoI-l-yl)phenoxy)ethyl)thio)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2 -thiol and l-(4r(2-bromoethoxy)phenyl)-4-methyl-lH-imidazole. Ή NMR (CDCI3, 400MHz): 8.25 (s, IH), 7.30 - 7.21 (m, 2H), 7.16 (s, IH), 7.05 - 7.02 (dd, Jl = 2Hz,J2 =6.8Hz, 2H), 6.85 - 6.81 (m, 2H), 6.65 (d, J = 9.2Hz, IH), 6.55 - 6.48 (m, 4H), 4.30 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.44 (t, J = 6.4Hz, 2H), 2.40 (s, 3H), 1.49 (s,6H). m/z Relative intensities = 573.1(M)+100 %, % Purity = 98.58% (By HPLC), IN KBr (cm 1): 3433, 2835, 1688, 1512, 1254, 1024, 839.
Example 32
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2-methyl-lH- imidazoI-l-yl)phenoxy)ethyl)thio)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-2 -methyl- lH-imidazole. Ή NMR (CDCI3, 400MHz): 7.20 - 7.17 (dd, Jl = 2.4Hz, J2 = 6.8Hz, 2H), 7.14 (s, IH), 7.05 (s, IH), 7.01 - 7.69 (dd, Jl = 2Hz, J2 = 6.8Hz, 2H), 6.97(s, IH), 6.85 - 6.81 (m, 2H), 6.65 (d, J = 9.2Hz, IH),' 6.65 - 6.52 (m, 2H), 6.50 - 6.48 (m, 2H), 4.30 (t, J = 6.8Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.44 (t, J = 6.8Hz, 2H), 2.86 (s, 3H), 1.49 (s, 6H). m/z Relative intensities = 573.4 (M)+100 %, % Purity = 95.82% ( By HPLC). IR KBr (cm- .*): 3433, 3115, 2967, 2932, 2833, 1605, 1464, 841.
Example 33
1- (4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-
2- yl)thio) ethoxy)phenyI)-lH-il,2,4-triazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and (4-(2-bromoethoxy)phenyl)-lH-l,2,4-triazole. 1H NMR (CDC13, 400MHz): 8.42 (s, IH), 8.07 (s, IH), 7.57 - 7.52 (m, 2H), 7.15 (s, IH), 7.04 - 6.99 (m, 2H), 6.85 - 6.80 (m, 2H), 6.66 - 6.64 (m, IH), 6.55 - 6.51 (m, 4H), 4.29 (t, J = 6.4Hz, 2H), 3.84 (s, 3H), 3.72 (s, 3H), 3.43 (t ,J = 6.4Hz, 2H), 1.49 (s, 6H). m/z Relative intensities =560.0(M)+100 %, % Purity = 95.86 % (By HPLC. IR KBr (cm"1): 3433, 3119, 2932, 1734, 1464, 1254, 1150, 1026, 841.
Example 34
2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-l-(4-fluorophenyl)-5-(2-(3- methoxyphenyl) propan-2-yl)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-IH-imidazole. Ή NMR (CDC13, 400MHz): 7.77 (s, IH), 7.29 - 7.27 (m, 2H), 7.20 - 7.19 (m, 2H), 7.15 (s, IH), 7.08 (t, J = 8Hz, IH), 7.00 - 6.98 (m, 2H), 6.82 - 6.78 (m, 2H), 6.70 - 6.68 (m, IH), 6.60 - 6.58 (m, IH), 6.54 - 6.51 (m, 3H), 4.29 (t, J = 6.4Hz, 2H), 3.71 (s, 3H), 3.43 (t, J = 6.4 Hz, 2H), 1.49 (s, 6H). m/z Relative intensities = 529.0 (M)+100 %. % Purity = 91.40 % (By HPLC).
Example 35
l-(2,4-difluorophenyl)-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(4-(2-methyl- lH-imidazol-l-yl)phenoxy)ethyl)thio)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(2,4-difluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-2-methyl-lH-imidazole. 1H NMR (CDC13, 400MHz): 7.19 - 7.17 (m, 3H), 7.02 - 6.95 (m, 4H), 6.77 - 6.73 (m, IH), 6.72 - 6.50 (m, 2H), 6.49 - 6.47 (m, 2H), 6.47- 6.30 (m, IH), 4.24 (t, J = 6.8Hz, 2H), 3.84 (s, 3H), 3.72 (s, 3H), 3.49 - 3.34 (m, 2H), 2.32 (s, 3H), 1.60 (s, 3H), 1.45 (s, 3H). m/z Relative intensities - 591.1 (M)+100 %. % Purity = 98.98% (By HPLC). IR KBr (cm' '): 3443, 3005, 2926, 2855, 1609, 1464, 1258, 1244, 1134, 962.
Example 36
1- (4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazoI-
2- yl)thio) ethoxy)phenyl)-lH-pyrazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyI)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-lH-pyrazole. Ή NMR (CDC13, 400MHz): 7.38 - 7.82 (dd, Jl = 0.4Hz, J2 = 2.4Hz, IH), 7.68 (d, J = 1.2Hz, IH), 7.58 - 7.55 (dd, Jl= 2.4Hz, J2 = 7.2Hz, 2H), 7.15 (s, 1H), 6.97 - 6.95 (dd, Jl = 2Hz, J2 = 7.2Hz, 2H), 6.82 (t J = 8.4Hz, 2H), 6.64 (d, J = 8.8Hz, 2H), 6.54 - 6.48 (m, 4H), 6.43 (t, J = 2.4Hz, 1H), 4.26 (t, J = 6.4Hz, 2H), 3.84 (s, 3H), 3.71 (s, 3H) 3.43 (t ,J = 6.4Hz, 2H), 1.49 (s> 6H) . m/z Relative intensities = 559 (M)+, 100 %. % Purity = 98.59% (By HPLC). IR KBr (cm-1): 3418, 3154, 3109, 2969, 2636, 2835, 1599, 1393, 1170, 1030, 849.
Example 37
l-(4-(2-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl) thio)ethoxy)phenyl)-lH-pyrazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-lH-pyrazole. Ή NMR (CDC13, 400MHz): 7.84 - 7.38 (m, 1H), 7.70 (d, J = 1.2Hz, 1H), 7.60 - 7.56 (m, 2H), 7.17 - 7.14 (m, 2H), 6.69 - 6.95 (m, 2H), 6.88 - 6.83 (m, 2H), 6.58 - 6.53 (m, 3H), 6.50 (d, J = 2Hz, 1H), 6.45 - 6.44 (m, 1H), 4.27 (t, J = 6.4Hz, 2H), 3.73 (s, 3H), 3.45 (t, J = 6.4Hz, 2H), 1.51 (s, 6H). m/z Relative intensities = 563.1 (M)+, 100 %. % Purity = 97.23% (By HPLC). IR KBr (cm"1): 3439, 3119, 2857, 1647, 1489, 1396, 1242, 1059, 1032, 841.
Example 38
5-(2-(3,4-dimethoxyphenyI)propan-2-yl)-2-((2-(2-fluoro-4-(lH-imidazol-l- yI)phenoxy) ethyl) thio)-l-(4-fluorophenyl)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5 -(2-(3 ,4-dichloropheny l)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and l-(4-(2-bromoethoxy)-3-fluorophenyl)-lH-imidazole. Ή NMR (CDCI3, 400MHz): .7.77 (s, 1H), 7.20 (t, J = 7.6Hz, 3H), 7.14 - 7.09 (m, 3H), 6.85 - 6,80 (m, 2H), 6.66 - 6.64 (m, lH), 6.56 - 6.50 (m, 4H), 4.37 (t, J = 6.4 Hz, 2H), 3.85 ( s, 3H), 3.72 (s, 3H), 3.43 (t, J = 6.4Hz, 2H), 1.49 (s, 6H). m/z Relative intensities = 577.1 (M)+100 %, %· Purity = 98.01 % (By HPLC), IR CHC13 (cm"1) : 3410, 3021, 2974, 2934, 1519, 1439, 1134, 1028.
Example 39
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-(2-methyl-lH-imidazoI- l-yl)phenoxy) ethyl)thio)-l-(4-fluorophenyl)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 1 -(4-(2-bromoethoxy)-3 -fluorophenyl)-2-methyl- 1 H-imidazole . Ή NMR (CDCI3, 400MHz): 7.20 (t, J = 8.8Hz, 1H), 7.14 (s, 1H), 7.04 - 7.01 (m, 3H), 6.95 (s, 1H), 6.84 (t, J = 8.8Hz, 2H), 6.65 (d, J = 8.8Hz, 1H), 6.58 - 6.48 (m, 4H), 4.39 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.44 (t, J = 6.4Hz, 2H), 2.34 (s, 3H), 1.49 (s, 6H). m/z Relative intensities = 591.2 (M)+100 %. % Purity = 98.76 % (By HPLC). IR CHCl3 (crn '): 3406, 3019, 2972, 2938, 2939, 1599, 1514, 1132, 1026.
Example 40
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(3-fluoro-4-(2-methyl-lH-iinidazoI- l-yl)phenoxy) ethyl)thio)-l-(4-fluorophenyl)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 2-((5-(2-(3 ,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethanol and 3-fluora-4-(2-methyl-lH-imidazol-l-yl)phenol.,H NMR (CDCI3, 400MHz): (CDC13, 400MHz): 7.26 - 7.19 (m, 1H), 7.17 - 7.15 (m, 1H), 7.03 (d, J = 1.2Hz, 1H), 6.90 - 6.78 (m, 5H), 6.67 -6.64 (dd, Jl = 3.6Hz, J2 = 5.2Hz, 1H), 6.56 - 6.48 (m, 4H), 4.30 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.43 (t, J = 6.4 Hz, 2H), 2.26 (s, 3H), 1.49 (s, 6H). m/z Relative intensities = 591.4(M)+100 %. % Purity = 97.26% (By HPLC).
Example 41
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(3-fluoro-4-(2-methyl-lH-imidazol- l-yl)phenoxy) ethyl)thio)-l-(4-fluorophenyl)-lH-imidazole
In a manner similar to that described for Example 13, the title compound was prepared from 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethanol and S-fluoro^- H-imidazol-l-y phenol.'H NMR (CDCI3, 400MHz): 7.72 (s, 1H), 7.28 - 7.14 (m, 1H), 7.20 -7.12 (m, 3H), 6.92 - 6.88 (dd, Jl = 2.4Hz, J2 = 12 Hz, lH), 6.88 - 6.78 (m, 3H), 6.66 - 6.64 (m, 1H), 6.55 - 6.48 (m, 4H), 4.20 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.73 (s, 3H), 3.42 (t, J = 6.4Hz, 2H), 1.49 (s, 6H). m/z Relative intensities = 577.0 (M)+ 100 %. % Purity = 92.93% (By HPLC).
Example 42
5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yI)-l-(4-fluorophenyl)-2-((2-(4-(2- methyl-lH-imidazoI-l-yl)phenoxy)ethyl)thio)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-2-methyl-l H-imidazole. Ή NMR (CDCI3, 400MHz): 7.18 (d, J = 8.8 Hz, 2H), 7.15 (s, 1H), 7.01 (d, J = 1.2 Hz, 1H), 6.98 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 1.2 Hz, 1H), 6.88 - 6.85 (m, 3H), 6.57 - 6.53 (m, 3H), 6.52 - 6.49 (m, 1H), 4.29 (t, J = 6.4 Hz," 2H), 3.73 (s, 3H), 3.45 (t, J = 6.4 Hz, 2H), 2.32 (s, 3H), 1.50 (s, 6H). m/z Relative intensities = 561.2 (M)+ 100%. % Purity = 99.29% (By HPLC). IR KBr (cm 1): 3433, 1606, 1514, 1228, 1028, 850, 721.
Example 43
2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(4-fluoro-3- methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-lH-imidazole. Ή NMR (CDC13, 400MHz): 7.86 - 7.85 (m, 1H), 7.30 - 7.24 (m, 4H), 7.16 (s, lH), 7.00 (d, J = 8.0 Hz, 2H), 6.88 - 6.86 (m, 1H), 6.85 (d, J = 8.0 Hz, 2H), 6.56 - 6.48 (m, 4H), 4.29 (t, J = 6.4 Hz, 2H), 3.73 (s, 3H), 3.45 (t, J = 6.4 Hz, 2H), 1.50 (s, 6H).. m/z Relative intensities = 547.0 (M)+ 100%. % Purity = 98.69% (By HPLC). IR KBr (cm"1): 3416, 2976, 1608, 1516, 1401, 1263, 1057, 1031, 850, 783.
Example 44
1- (4-(2-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyI)-lH- imidazoI-2-yl)thio)ethoxy)phenyl)-lH-pyrazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-lH-pyrazole. 1H NMR (CDC13, 400MHz): 7.82 (d, J = 2.8 Hz, 1H), 7.68 (d, J = 2.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.15 (s, lH), 6.96 (d, J = 9.2 Hz, 2H), 6.87 - 6.83 (m, 3H), 6.56 - 6.48 (m, 4H), 6.44 (t, J = 2.0 Hz, 1H), 4.26 (t, J = 6.4 Hz, 2H), 3.72 (s, 3H), 3.43 (t, J = 6.4 Hz, 2H), 1.50 (s, 6H). m/z Relative intensities = 547.1 (M)+100%. % Purity = 99.07% (By HPLC). IR KBr (cm-1): 3439, 2976, 1608, 1519, 1444, 1244, 1033, 844, 771.
Example 45
2- ((2-(4-(lH-imidazol-l-yI)phenoxy)ethyI)thio)-4-bromo-5-(2-(3,4- dimethoxyphenyI).propan-2-yl)-l-(4-fluorophenyl)-lH-imidazoIe.
To a solution of triphenyl phosphine (318 mg, 0.60 mmol) in Tetrahydrofuran (5 mL) was added DEAD (diethyl azodicarboxylate) 245 mg, 0.12 mmol), at 0 °C and stirred for 5 min, followed by addition of 4-(lH-imidazol-l-yl)phenol (97 mg, 0.60 mmol) and 2-((4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- lH-imidazol-2-yl)thio)ethanol (300 mg, 0.60 mmol) respectively. Reaction mixture was stirred at room temperature for 4h and quenched with water and extracted with ethyl acetate, combined organic layers were dried over sodium sulphate and distilled the solvent under vacuum. Crude product was purified by column chromatography to afford the desired product (150 mg, 39 % yield). Ή NMR (CDC13, 400MHz): 7.77 (s, 1H), 7.30 (d, J = 8.8Hz, 2H), 7.20 (d, J = 8.4Hz, 2H), 7.08 (d, J = 8.8Hz, 2H), 6.84 (t, J = 8.4Hz, 2H), 6.64 (d, J = 7.6Hz, 1H), 6.55 - 6.52 (m, 2H), 6.47 - 6.46 (m, 2H), 4.29 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.73 (s, 3H), 3.44 (t, J = 6.4 Hz, 2H), 1.64 (s, 6H). m/z Relative intensities^ 639.6 (M)+100 %, % Purity = 98.07 % (By HPLC).
Example 46
4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yI)-2-((2-(2-fluoro-4-(lH-imidazol- 1-yl) phenoxy) ethyl)thio)-l-(4-fluorophenyl)-lH-imidazoIe.
In a manner similar to that described for Example 13, the title compound was prepared from 2-((4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4- fluorophenyl)- 1 H-imidazol-2-yl)thio)ethanol and 2-fluoro-4-( 1 H-imidazol- 1 - yl)phenol.'H NMR (CDC13, 400MHz): 7.79 (s, 1H), 7.47 (d, J = 8.8Hz, 1H), 7.20 (d, J = 4.4Hz, 2H), 7.18 - 7.12 (m, 2H), 6.87 - 6.85 (m, 2H), 6.66 - 6.63 (m, 1H), 6.56 - 6.53 (m, 2H), 6.48 - 6.46 (m, 2H), 4.39 (t, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.73 (s, 3H), 3.44 ( t, J = 6.4Hz, 2H), 4.61 (s, 6H). m/z Relative intensities = 656.8 (M)+100 %. % Purity = 93.28 % (By HPLC). IR KBr (cm 1): 3430, 3115, 2961, 2835, 1730, 1599, 1464, 1175, 1026.
Example 47
4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2- methyl-lH-imidazol-l-yl)phenoxy)ethyl)thio)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 2-((4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4- fluorophenyl)- 1 H-imidazol-2-yl)thio)ethanol and 4-(2-methyl- 1 H-imidazol- 1 - yl)phenol. Ή NMR (CDC13, 400MHz): 7.18 (d, J = 2.8Hz, 2H), 7.09 - 7.07 (m, 2H), 7.04 (s, 1H), 6.95 (s, 1H), 6.86 - 6.82 (m, 2H), 6.65 - 6.63 (m, 1H), 6.56 - 6.52 (m, 2H), 6.48 - 6.46 (m,2H), 4.30 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.73 (s, 3H), 3.45 (t, J = 6.4Hz, 2H), 2.36 (s, 3H), 1.64 (s, 6H). m/z Relative intensities = 652.7 (M)+100 %. % Purity = 91.94 % (By HPLC), IR KBr (cm 1): 3150, 3113, 2928, 1728, 1603, 1466,
1242, 1026, 843.
Example 48
3-(2-(2-((5-(2-(3,4-dimethoxyphenyI)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol- 2-yl)thio) ethoxy)phenyl)-lH-pyrazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 3-(2-(2-bromoethoxy)phenyl)-lH-pyrazole. 'HNMR (CDC13, 400MHz): 7.54 - 7.52 (dd, Jl = 8Hz, J2 = 1.6Hz, 1H), 7.47 (d, J = 2.4Hz, 1H), 7.21 - 7.17 (m, 1H), 7.16 (s, 1H), 7.00 - 6.98 (dd, Jl = 8.4Hz, J2 = 1.2Hz, 1H), 6.91 - 6.87 (m, . 1H), 6.82 - 6.77 (m, 2H), 6.68 - 6.64 (m,lH), 6.57 (d, J = 2.8Hz, 1H), 6.52 - 6.47 (m, 4H), 4.53 (t, J = 6:8Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.45 (t, J = 6.4Hz, 2H), 1.52 (s,6H). m/z Relative intensities = 559.1 (M)+100 %. % Purity = 94.27 % (By HPLC). IR CHC13 (cm-1): 3020, 2976, 2931, 1737, 1639.
Example 49
2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(4-chloro-3- methoxyphenyl)propan-2-yI)-l-(4-fluorophenyl)-lH-imidazole
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-lH-imidazole. Ή NMR (CDCI3, 400MHz): 8.13 (s, 1H), 7.33 - 7.29 (m, 3H), 7.18 (s, 1H), 7.15 (d, J= 8.4Hz, 1H), 7.05 - 7.02 ( m, 2H), 6.88 - 6.84 ( m, 2H), 6.57 - 6.52 (m, 3H), 6.49 (d, J = 2Hz, 1H), 4.29 (t, J = 6.4Hz, 2H),' 3.74 (s, 3H ), 3.46 (t, J = 6.4Hz, 2H), 1.51 (s, 6H). m/z Relative intensities = 563.1 (M)+ 100 %. % Purity = 94.53 % (By HPLC). IR CHCI3 (cm-1): 3443, 1681, 1512, 1246.
Example 50
5-(2-(4-chloro-3-meth0xyphenyl)propan-2-yl)-2-((2-(3,4- dimethoxyphenoxy)ethyI)thio)-l-(4-fluorophenyl)-lH-imidazole In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 4-(2-bromoethoxy)-l,2-dimethoxybenzene. Ή NMR (CDCI3, 400MHz): 7.15 - 7.13 (m, 2H), 6.86 - 6.81 (m, 2H), 6.75 (d, J = 8.8 Hz, 1H), 6.56 - 6.53 (m, 2H), 6.52 - 6.49 (m, 3H), 6.39 - 6.36 (dd, Ji = 8.4 Hz, J2 - 2.8 Hz, 1H), 4.17 (t, J = 6 Hz, 2H), 3.84 (s, 3H), 3.71 (s, 3H), 3.40 (t, J = 6 Hz, 2H), 1.45 (s, 6H). m/z Relative intensities^ 557.0, (M)+ 100%. % Purity =94.11 % (By HPLC). CHCI3 (cm"1): 3020, 1599, 1579, 1512, 1271.
Example 51
5-(2-((5-(2-(4-chIoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyI)-lH- imidazol-2-yl)thio)ethoxy)-lH-indole
In a manner similar to that described for Example 13, the title compound was prepared from 5 -(2-(4-chloro-3 -methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and 5-(2-bromoethoxy)-lH-indole. Ή NMR (CDC13, 400MHz): 8.08 (s,lH), 7.26 - 7.24 (m, 2H), 7.19 - 7.17 (m, 1H), 7.16 (s,lH), 7.11 - 7.07 (m, 2H), 6.84 - 6.77 (m, 3H), 6.54 - 6.50 (m, 3H), 6.48 - 6.46 (m, 2H), 4.23 (t, J= 6.4Hz, 2H), 3.69 (s, 3H). 3.43 (t, J = 6.4Hz, 2H), 1.49 (s, 6H). m/z Relative intensities = 536.1, (M)+ 100%. % Purity = 91.10 % (By HPLC). IR CHCI3 (cm-1): 3020, 2927, 1600, 1589, 1215.
Example 52
3-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yI)thio) ethoxy)-N,N-dimethylaniline
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)- 1H- imidazole-2-thiol and 3-(2-bromoethoxy)-N,N-dimethylaniline. Ή NMR (CDC13, 400MHz): 7.14 (s, 1H), 7.13 - 7.11 (m, 1H), 6.10 (t, J = 8.4Hz, 2H), 6.64 (t, J= 8.8Hz, 1H), 6.53 - 6.47 (m, 4H), 6.36 - 6.33 (m, 1H), 6.25 - 6.23 (m, 2H), 4.21 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.71 (s, 3H), 3.40 (t, J = 6.4Hz, 2H), 2.92 (s, 6H), 1.48 (s, 6H). m/z Relative intensities ^ 536.1 (M)+ 100 %. % Purity = 89.87 % (By HPLC).
Example 53
2-((2-(2-chloro-5-methylphenoxy)ethyl)tliio)-5-(2-(3,4-dimetlioxyphenyl)propan-2- yl)-l-(4-fluorophenyl)-lH-imidazole
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and . 2-(2-bromoethoxy)-l-chloro-4-methylbenzene. Ή NMR (CDC13, 400MHz): 7.19 (d, J= 8 Hz, 1H), 7.14 (s, 1H ), 6.88 (d, J= 1.2 Ηζ,ΙΗ), 6.84 - 6.80 (m, 2H), 6.71 - 6.69 (m, 1H), 6.66 - 6.64 (m, 1H), 6.55 - 6.53 (m, 2H), 6.52 - 6.48 (m, 2Ή), 4.29 (t, J = 6.8Hz, 2H), 3.85 (s, 3H ), 3.71 (s, 3H ), 3.43 (t, J = 6.8Hz, 2H), 2.32 (s, 3H), 1.49 (s, 6H). m/z Relative intensities = 541.2, (M)+ 100%. % Purity =96.36 % (By HPLC). IR CHCI3 (cm-1): 3018, 1600, 1583, 1510, 1215.
Example 54
4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyI)-lH-imidazol-2- yI)thio) ethoxy)-N,N-dimethylaniIine
Ή NMR (CDC13, 400MHz): 7.14 (s, 1H), 6.83 - 6.78 (m, 4H), 6.72 - 6.70 (m, 2H), 6.65 - 6.63 (m, 1H), 6.54 - 6.51 (m, 1H), 6.50 - 6.47 (m,3H), 4.15 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.71 (s, 3H), 3.37 (t, J = 6.4Hz, 2H), 2.86 (s, 6H ), 1.49 (s, 6H ). m/z Relative intensities = 536.1, (M)+ 100%. % Purity = 97.38% (By HPLC). IR CHCI3 (cm-1): 2964, 1595, 1512, 1467, 1240.
Example 55
2-fluoro-5-(2-(l-(4-fluorophenyl)-2-((2-(4-(2-methyl-lH-imidazol-l- yI)phenoxy)ethyl)thio)-lH-imidazol-5-yl)propan-2-yl)benzonitrile
In a manner similar to that described for Example 13, the title compound was prepared from 2-fluoro-5-(2-(l-(4-fluorophenyl)-2-mercapto-lH-imidazol-5-yl)propan- 2-yl)benzonitrile and l-(4-(2-bromoethoxy)phenyl)-2-methyl-lH-imidazole. Ή NMR (CDC13, 400MHz): 7.26 - 7.23 (m, 2H), 7.22 - 7.17 (m, 3H), 7.05 (t, J = 8.4 Hz, 1H), 7.02 - 6.99 (m, 3H), 6.99 (s, 1H), 6.92 - 6.88 (m, 2H), 6.58 - 6.54 (m, 2H), 4.32 (t, J = 6.4 Hz, 2H), 3.48 (t, J = 6.4Hz, 2H), 2.32 (s, 3H), 1.58 (s, 6H). m/z Relative intensities = 556.3, (M)+ 100 %. % Purity = 95.98 % (By HPLC). IR CHCI3 (cm-1): 3437, 2934, 1606, 1512.
Example 56
5-(2-(4-chloro-3-methoxyphenyI)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2- methyl-lH-imidazol-l-yl)phenoxy)ethyl)thio)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-2-methyl-lH-imidazole. 'H NMR (CDCI3, 400MHz): 7.19 - 7.14 (m, 4H), 7.01 - 6.95 (m, 4H), 6.87 - 6.83 (m, 2H), 6.75 - 6.53 (m, 2H), 6.50 (d, J= 2 Hz, 2H), 4.29 (t, J = 6.4 Hz, 2H), 3.72 (s, 3H), 3.44 (t, J = 6.4 Hz, 2H), 2.32 (s, 3H), 1.51 (s, 6H). m/z Relative intensities = 577.1 (M)+ 100 %. % Purity =97.03 % (By HPLC). IR CHCD (cm-1): 3437, 1643, 1597, 1512.
Example 57 5-(2-(4-chIoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(4- methyHH-imidazol-l-yl)phenoxy)ethyl)thio)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5 -(2-(4-chloro-3 -methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and l-(4-(2-bromoethoxy)phenyl)-4-methyl-lH-imidazole. 1H NMR (CDCI3, 400MHz): 7.66 (s, 1H), 7.24-7.23 (m, 2H), 7.16 - 7.13 (m, 2H), 6.98 - 6.95 (m, 2H), 6.92 (s, 1H), 6.87 - 6.82 (m, 2H), 6.56-6.52 (m, 2H), 6.50 (d, J= 2 Hz, 2H), 4.26 (t, J= 6.4 Hz, 2H), 3.72 (s, 3H), 3.43 (t, J= 6.4Hz, 2H), 2.95 (s, 3H), 1.50 (s, 6H). m/z Relative intensities = 576.9 (M)+ 100 % . % Purity = 99.19 % (By HPLC). IR KBr (cm" '): 3439, 1595, 1514, 1489.
Example 58
2-((l-(4-(lH-imidazoI-l-yl)phenoxy)-2-methylpropan-2-yl)thio)-5-(2-(3,4- dimethoxyphenyl) propan-2-yl)-l-(4-fluorophenyl)-lH-imidazole
Ή NMR (CDC13, 400MHz): 7.78 (s, 1H), 7.26 - 7.22 (m, 2H), 7.22 - 7.21 (m, 2H), 7.13 (s, 1H), 7.03 - 6.97 (m, 2H), 6.87 - 6.82 (m, 2H), 6.64 (d, J = 8 Ηζ,ΙΗ), 6.58 - 6.54 (m, 2H), 6.50 - 6.46 (m, 2H), 3.84 (s, 3H), 3.73 (s, 3H), 3.48 (s, 2H), 1.48 (s, 6H), 1.35 (s, 6H). m/z Relative intensities = 587.2, (M)+ 100 %. % Purity = 90 % (By HPLC). IR KBr (cm-1): 3417, 1602, 1514, 1462.
Example 59
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l -(4-fluorophenyI)-2-((l -((4-(2-methyI- lH-imidazoI-l-yl)phenoxy)methyl)cyclobutyl)thio)-lH-imidazoIe.
1H NMR (CDC13, 400MHz): 7.11 (d, J = 8.8 Hz, 2H), 7.07 (s, 1H), 7.0 (s, 1H), 6.94 (s, 1H), 6.84 - 6.80 (m, 4H),.6.65 - 6.63 (m, 1H), 6.55 - 6.51 (m, 2H), 6.48 - 6.46 (m, 2H), 3.85 (s, 3H), 3.78 (s, 2H), 3.71 (s, 3H), 2.43 - 2.40 (m, 2H), 2.37 - 2.32 (m, 5H), 1.88 - 1.73 (m, 2H), 1.47 (s, 6H). m/z Relative intensities =613.1 (M)+ 100 %. % Purity = 94.59 % (By HPLC).
Example 60
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((l-((2-fluoro-4-(lH-imWazol-l- yl)phenoxy) methyl)cyclobutyl)thio)-l-(4-fluorophenyl)-lH-imidazole.
1H NMR (CDC13, 400MHz): 7.77 (s, 1H), 7.19 (s, 2H), 7.11 - 7.08 (dd, J1 = 10.8 Hz, f = 2.8 Hz, 1H) 7.05 - 7.02 (m, 2H), 6.97 (t, J= 8.4 Hz, 1H), 6.85 - 6.80 (m, 2H), 6.64 (d, J = 8.4 Hz, 1H), 6.58 - 6.53 (m, 2H), 6.48 - 6.46 (m, 2H), 3.85 (s, 3H), 3.76 (s, 2H), 3.71 (s, 3H), 2.40 - 2.32 (m, 2H), 2.26 - 2.19 (m, 2H), 1.81 - 1.70 (m, 2H), 1.41 (s, 6H). m/z Relative intensities = 616.1 (M)+ 100 %.
Example 61
4-(3-((5-(2-(3,4-dimethpxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazoI-2- yl)thio) propoxy)benzonitriIe.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3, 4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 3-(4-cyanophenoxy)propyl methanesulfonate. Ή NMR (CDC13, 400MHz): 7.57 - 7.54 (m, 2H), 7.14 (s, 1H), 6.90 - 6.87 (m, 2H), 6.83 - 6.79 (m, 2H), 6.65 (d, J= 8.8 Ηζ,ΙΗ), 6.53 - 6.46 (m, 4H), 4.04 (t, J= 6.4 Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.17 (t, J = 6.4 Hz, 2H), 2.16 (qui, J = 6.4 Hz, 2H), 1.48 (s, 6H ). m/z Relative, intensities = 532.0 (M)+100%, (+ve-mode) . % Purity = 97.78 % (By HPLC). IR CHCI3 (cm-1): 3020, 1512, 1464, 1215.
Example 62
2-(((benzyloxy)methyl)thio)-5-(2-(3,4rdimethoxyphenyI)propan-2-yl)-l-(4- fluorophenyl)-lH-imidazole
In a manner similar to that described for Example 13, the title compound was prepared.
Ή NMR (CDC13, 400MHz): 7.42-7.31 (m, 5H), 6.92 (s, 1H), 6.87 (t, J = 3.6Hz, 2H), 6.65 (d, J = 4.2Hz, 1H), 6.52-6.46 (m, 2H), 6.45-6.41 (m, 2H), 5.86 (s, 2H) 4.77 (s, 2H), 3.86 (s, 3H), 3.68 (s, 3H), 1.92 (s, 6H). m/z Relative intensities = 493.2 (M+H)+100%. % Purity = 93.87 % (By HPLC). IR CHCI3 (cm 1): 625, 738, 1026, 1153, 1258, 1410, 1510, 1601, 2936, 2997, 3028, 3121, 3417.
Example 63
2-(((4-(lH-imidazol-l-yI)phenoxy)methyI)thio)-5-(2-(3,4-dimethoxyphenyl)propan- 2-yl)-l-(4-fluorophenyl)-lH-imidazole
In a manner similar to that described for Example 13, the title compound was prepared.
1H NMR (CDCI3, 400MHz): 7.76 (s, 1H), 7.27 - 7.24 (m, 3H), 7.19 (s, 2H),6.95 - 6.91 (m, 2H), 6.73 - 6.69 (m, 2H), 6.64 - 6.61 (m, 1H), 6.42 - 6.38 (m, 2H), 5.67 (s, 2H), 3.84 (s, 3H), 3.71 (s, 3H), 1.49 (s, 6H). m/z Relative intensities = 545.1 (M)+100 %. % Purity = 94.40 % (By HPLC). IR CHCI3 (cm-1): 2929, 1664, 1602, 1514, 1211.
Example 64 4-(((5-(2-(3,4-dichlorophenyl)prbpan-2-yl)-l-(4-fluorophenyl)-lH-imida2ol-2- yl)thio) methoxy) benzonitrile
In a manner similar to that described for Example 13, the title compound was prepared.
Ή NMR (CDCI3, 400MHz): 7.57 - 7.53 (m, 2H), 7.26 - 7.22 (m, 2H), 6.98 (d, J = 2.4Hz, 1H), 6.93 - 6.89 (m, 2H), 6.81 - 6.74 (m, 3H), 6.42 - 6.37 (m, 2H), 5.71 (s, 2H), 1.49 (s, 6H). m/z Relative intensities = 512.1 (M)+ 100%. % Purity = 97.10 % (By HPLC). IR CHCI3 (cm-1): 3020, 2229, 1604, 1510, 1215.
Example 65
5-(2-(3,4-dimethoxyphenyl)propan-2-yI)-l-(4-fluorophenyI)-2-((2-(2- methoxyethoxy) ethyl)thio) -lH-imidazole
In a manner similar to that described for Example 13, the title compound was prepared from 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethanol and l-bromo-2-methoxyethane. 'H NMR (CDC13, 400MHz): 7.12 (s, 1H), 6.80 (t, J = 2.4Hz, 2H), 6.66 - 6.64 (m, 1H), 6.56 - 6.51 (m, 2H), 6.50 - 6.47 (m, 2H), 3.85 (s, 3H), '3.72 - 3.70 (m, 5H), 3.59 - 3.57 (m, 2H), 3.50 - 3.48 (m, 2H),3.35 (s, 3H), 3.23 (t, J = 6.4Hz, 2H), 1.48 (s, 6H). m/z Relative intensities = 475.0 (M+l)+100 %. % Purity = 93.66 % (By HPLC).
Example 66
4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)-N'(pyridin-4-ylmethyl)benzamide.
To a solution of 4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4- fluorophenyl)-lH-imidazol-2-yl)thio)ethoxy)benzoic acid (150 mg, 0.28 mmol) in DMF (5 mL) was pyridin-4-ylmethanamine (108 mg, 0.31 mmol) at 0°C followed by addition of HBTU (379 mg, 0.31 mmol), DIPEA (0.24 mL, 1.4 mmol) and stirred for 5- 6 hr at room temperature. Reaction mixture was quenched with water and extracted with ethyl acetate, combined organic layers were dried over sodium sulphate and distilled the solvent under vacuum. Crude product was purified by column chromatography to afford the desired product (90 mg, 52% yield).
Ή NMR (DMSO, 400MHz): 8.96 (t, J = 5.6Hz, 1H), 8.49 (d, J = 6.Hz, 2H), 7.88 (dd, Jl = 1.6Hz, J2 = 6.4Hz, 2H), 7.28 (d, J = 6.4Hz, 2H), 7.12 (s, 1H), 7.04 - 7.00 (m , 4H), 6.73 (d, J = 7.6Hz, 1H), 6.65 - 6.61 (m, 2H), 6.45 - 6.42 (m, 2H), 4.47 (d, J = 5.6Hz, 2H), 4.24 (t, J = 6.4Hz, 2H), 3.70 (s, 3H), 3.55 (s, 3H), 3.36 (t, J= 6.4Hz, 2H), 1.43 (s, 6H). m/z Relative-intensities = 627.5(M)+100 %. % Purity = 98.39 % (By HPLC). IR KBr (cm 1): 3356, 3071, 2932, 1645, 1605, 1412, 1177, 1024, 845.
Example 67
5-(2-((5-(2-(3,4-dimethoxyphenyI)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yI)thio) ethoxy)-lH-indole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and 5-(2-bromoethoxy)-lH-indole. Ή NMR (DMSO, 400MHz): 10.9 (s,lH), 7.28 - 7.26 (m, 1H), 7.24 (s, 1H), 7.11(s,lH), 7.03 - 6.99 (m,3H), 6.71 (d, J = 8.8Hz, 1H), 6.67 - 6.62 (m, 3H), 6.44 - 6.42 (m, 2H), 6.31 (s,lH), 4.13 (t, J = 6.4Hz, 2H), 3.69 (s,3H), 3.43 (s,3H), 3.35 - 3.29 (m,2H), 1.43 (s, 6H). m/z Relative intensities = 532.3 (M)+100 %. % Purity = 91.92 % (By HPLC). IR CHC13 (cm'1): 3421, 3020, 2945, 1604.
Example 68
N-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol- 2-yl)thio) ethoxy)-2-fluorophenyl)methanesulfonamide.
To a solution of 4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4- fluorophenyl)-lH-imidazol-2-yl)thio)ethoxy)-2-fluoroaniline (130 mg, 0.25 mmol) in pyridine was added methane sulfonyl chloride (57 mg, 0.5 mmol) at 0°C. Reaction mixture then stirred at room temperature for 1 h. Reaction mixture was quenched with water and extracted with ethyl acetate, combined organic layers were dried over sodium sulphate and distilled the solvent under vacuum. Crude product was purified by column chromatography to- afford the desired product (35 mg, 24% yield) (CDCI3, 400MHz): 7.42 (t, J = 8.8Hz, 1H), 7.14 (s, 1H), 6.85 - 6.80 (m, 2H), 6.77 (d, J = 2.8Hz, 1H), 6.74 (d, J= 1.2Hz, 1H), 6.66 (d, J = 9.2Hz, 1H), 6.54 - 6.50 (m, 2H), 6.48 (d, J = 2Hz, 2H), 6.23 (s, 1H), 4.23 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.41 - 3.37 (m, 2H), 2.96 (s,3H), 1.49 (s,6H). m/z Relative intensities = 604.1(M)+100 %. % Purity = 94.27 % (By HPLC). IR KBr (cm-1): 3482, 2968, 2930, 1624.
Example 69
5-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazoI- 2-yI)thio) ethoxy)phenyl)-2-methoxypyridine.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l -(4-fluorophenyl)- 1H- imidazole-2-thiol and 5-(4-(2-bromoethoxy)phenyl)-2-methoxypyridine.'HNMR (CDCI3, 400MHz): 8.33 (d, J = 2.4Hz, 1H), 7.74 - 7.72 (dd; Jl = 8.4Hz, J2 = 2.4Hz, 1H), 7.42 (d, J = 8.4Hz, 2H), 7.15 (s, 1H), 6.95 (d, J = 8.4Hz, 2H), 6.84 - 6.78 (m, 3H) ,6.65 - 6.64 (m, 1H), 6.54 - 6.48 (m, 4H),4.26 (t, J = 6.4Hz, 2H), 3.93 (s, 3H), 3.84 (s, 3H), 3.71 (s, 3H), 3.42 (t, J = 6.4Hz, 2H), 1.49 (s, 6H). m/z Relative intensities = 600.5 (M)+100 %. % Purity = 92.66 % (By HPLC). IR CHC13 (cm-1): 3020, 2976, 294, 1604.
Example 70
4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazoI-2- yl)thio) ethoxy)quinazoline.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 4-(2-bromoethoxy)quinazoline.IHNMR (CDC13, 400MHz): 8.29 - 8.27 (dd, Jl = 8Hz, J2 = 1.6Hz, 1H), 8.11 (s, 1H), 7.75 - 7.73 (m, 1H), 7.69 (d, J = 8Hz, 1H), 7.51 - 7.47 (m, 1H), 7.06 (s, 1H), 6.82 - 6.77 (m, 2H), 6.67 (d, J = 8.8Hz, 1H), 6.54 - 6.52 (m, 2H), 6.49 - 6.47 (m, 2H), 4.42 (t, J= 6Hz, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 3.42 (t, J = 6Hz, 2H), 1.48 (s, 6H). m/z Relative intensities = 545.1(M)+100 %. % Purity = 94.79 % (By HPLC). IR CHC13 (cm-1): 3020. 2976, 2937, 1610.
Example 71
2-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yI)thio) ethoxy)benzo[d]thiazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dichlorophenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and 2-(2-bromoethoxy)benzo[d]thiazole. 'HNMR (DMSO, 400MHz): 7.65 - 7.63 (dd, Jl = 7.6Hz, J2 = 0.8Hz, 1H), 7.46 (d, J = 8Hz, 1H), 7.36 (m, 1H), 7.22 - 7.20 (rri, 1H), 7.16 (s, 1H), 7.00 (t, J = 8.8Hz, 2H), 6.75 (d, J = 8.8Hz, 1H), 6.57 - 6.54 (m, 2H), 6.43 (d, J = 7.6Hz, 2H),4.24 (t, J = 6.8Hz, 2H), 3.72 (s, 3H), 3.58 (s, 3H), 3.31 (d, J = 8.8Hz, 2H), 1.44 (s,6H). m/z Relative intensities = 550.1 (M)+100 %, % Purity = 91.29 % (By HPLC). IR CHCI3 (cm'1): 3020, 2974, 2935, 1672.
Example 72
l-(4-(2-((4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yI)-l-(4-fluorophenyI)-lH- imidazol-2-yl)thio)ethoxy)phenyl)-lH-pyrazole.
In a manner similar to that described for Example 45, the title compound was prepared from 2-((4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4- fluorophenyl)- lH-imidazol-2-yl)thio)ethanol and 4-(lH-pyrazol-l-yl)phenol. Ή NMR (CDCI3, 400MHz): 7.83 (d, J = 2.4 Hz, 1H), 7.69 (d, J = 1.6 Hz, lH), 7.60 - 7.56 (m, 2H), 7.04 - 7.01 (m, 2H), 6.86 - 6.80 (m, 2H), 6.65 - 6.62 (m, 1H), 6.55 - 6.51 (m, 2H), 6.50 - 6.43 (m, 3H), 4.26 (t, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.73 (s, 3H), 3.44 (t, J = 6.4 Hz, 2H), 1.63 (s, 6H). m/z Relative intensities = 639.2 (M+2)+ 100 %. % Purity = 94.05% (By HPLC). IR KBr (cm 1): 3319, 3076, 2384, 1732, 1716, 1519.
Example 73
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(3-(2-methyI-lH- imidazol-l-yl)phenoxy)ethyI)thio)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazol-2- yl)thio)ethanol and 3-(2-methyl-lH-imidazol-l-yl)phenol. Ή NMR (CDCI3, 400MHz): 7.36 (t, J = 8Hz, 1H), 7.10 (s, 1H), 7.04 - 7.01 (m, 2H), 6.97 - 6.95 (m, 2H), 6.88 - 6.86 (m, 1H), 6.84 - 6.79 (m, 2H), 6.66 - 6.64 (m, 1H), 6.55 - 6.51 (m, 2H), 6.50 - 6.47 (m, 2H), 4.29 (t, J = 6.6Hz, 2H), 3.85 (s, 3H), 3.71 (s, 3H), 3.42 (t, J = 6.6Hz, 2H), 2.39 (s, 3H), 1.48 (s, 6H). m/z Relative intensities = 573.1 (M)+ 100 %. % Purity = 93.38 % (By HPLC). IR CHC13: 2974, 2933, 1734, 1604, 1464.
Example 74
5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-(2-methyl-lH- imidazol-l-yl) phenoxy)ethyl)thio)-l-(4-fluorophenyl)-lH-imidazo!e.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 1 -(4-(2-bromoethoxy)-3-fluorophenyl)-2-methyl-lH-imidazole. Ή NMR (CDCI3, 400MHz): 7.19 (t, J = 8.8 Hz, 1H), 7.14 (s, 1H), 7.05 - 6.99 (m, 3H), 6.95 (d, J = 1.6 Hz, 1H), 6.89 - 6.84 (m, 3H), 6.58-6.49 (m, 4H), 4.39 (t, J = 6.4 Hz, 2H), 3.73 (s, 3H), 3.46 (t, J = 6.4 Hz, 2H), 2.34 (s, 3H), 1.50 (s, 6H). m/z Relative intensities = 579.1 (M)+, 100% %. Purity = 98.33% (By HPLC). IR KBr (cm 1): 3439, 2976, 1606, 1514, 1410, 1267, 1016, 850, 721.
Example 75
l-(4-(2-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl) thio)ethoxy)phenyl)-lH-l ,2,4-triazole
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-fluoro-3-methoxyphenyl) propan-2-yl)-l -(4-fluorophenyl)- 1H- imidazole-2-thiol and l-(4-(2-bromoethoxy) phenyl)-lH-l, 2, 4-triazole. Ή NMR (CDCI3, 400MHz):- 8.45 (s, IH), 8.08 (s, IH), 7.55 (d, J = 8.8 Hz, 2H), 7.15 (s, IH), 7.02 (d, J = 8.8 Hz, 2H), 6.89-6.83 (m, 3H), 6.56 - 6.48 (m, 4H), 4.29 (t, J = 6.4 Hz, 2H), 3.73 (s, 3H), 3.44 (t, J = 6.4 Hz, 2H), 1.50 (s, 6H). m/z Relative intensities = 548.1 (M)+100 %. % Purity = 98.26% (By HPLC). IR KBr (cm'1): 3456, 2976, 1610, 1514, 1263, 1224, 1030, 673.
Example 76
5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-2-((2-(3-fluoro-4-(2-methyI-lH- imidazol-l-yl) phenoxy)ethyl)thio)-l-(4-fluorophenyl)-lH-imidazoIe.
In a manner similar to that described for Example 13, the title compound was prepared from 2-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)- lH-imidazol-2-yl)thio)ethanol and 1 3-fluoro-4-(2-methyl-lH-imidazol-l-yl)phenol. Ή NMR (CDCI3, 400MHz): 7.19 (t, J = 8.8 Hz, IH), 7.15 (s, IH), 7.08 (d, J = 1.6 Hz, IH), 6.93 - 6.88 (m, 3H), 6.87 - 6.80 (m, 3H), 6.57 - 6.49 (m, 4H), 4.31 (t, J = 6.4 Hz, 2H), 3.73 (s, 3H), 3.44 (t, J = 6.4 Hz, 2H), 2.31 (s, 3H), 1.50 (s, 6H).. m/z Relative intensities = 579.2 (M)+ 100%. % Purity = % Purity = 99.54% (By HPLC). IR KBr (cm'1): 3441, 2966, 1624, 1604, 1437, 1288, 1222, 1020, 850, 630.
Example 77
5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4- (thiophen-3-yl) phenoxy)ethyl)thio)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5 -(2-(4-chloro-3 -methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and 3-(4-(2-bromoethoxy)phenyl)thiophene. 1H NMR (CDC13, 400MHz): 7.50-7.48 (m, 2H), 7.37 - 7.32 (m, 3H), 7.15 (d, J= 5.2 Hz, IH), 7.13 (s, IH), 6.92 - 6.89 (m, 2H), 6.85 - 6.81 (m, 2H), 6.55 - 6.52 (m, 2H), 6.49 (d, J = 2Hz, 2H), 4.25 (t, J = 6.4Hz, 2H), 3.71 (s, 3H), 3.43 (t, J = 6.4Hz, 2H), 1.50 (s, 6H). m/z Relative intensities = 579.1 (M)+100 %. % Purity = 95.20 % (By HPLC). IR KBr (cm'1): 3154, 3104, 3044, 2972, 2932, 2870, 1605, 1578, 1537, 1435, 1287, 1225, 1061, 965, 843, 779, 677.
Example 78
5-(2-(4-chIoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(3-(2- methyl-lH-imidazoI-l-yl)phenoxy)ethyl)thio)-lH-imidazole. In a manner similar to that described for Example 13, the title compound was prepared 5-(2-(4-chloro-3-methoxyphenyl) propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(3-(2-bromoethoxy) phenyl)-2-methyl-lH-imidazole. Ή NMR (CDC13, 40aMHz) :- 7.36 (t, J = 8.8Hz, 1H), 7.15 - 7.11 (m, 2H), 7.04 - 6.99 (m, 2H), 6.95 (bs, 2H), 6.89 - 6.82 (m, 3H), 6.56 - 6.52 (m, 3H), 6.49 (d, J = 2Hz, 1H), 4.29 (t, J = 6.4Hz, 2H), 3.71 (s, 3H), 3.43 (t, J = 6.4Hz, 2H), 2.38 (s, 3H), 1.50 (s, 6H). m/z Relative intensities = 577.2 (M)+100 %. % Purity = 93.53 % (By HPLC). IR KBr (cm- '): 3437, 2856, 1730, 1602, 1464.
Example 79
2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-l-(4-fluorophenyl)-5-(2- phenylpropan-2-yl)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from l-(4-fluorophenyl)-5-(2-phenylpropan-2-yl)-lH-imidazole-2 -thiol and 1- (4-(2-bromoethoxy) phenyl)- lH-imidazole. 'HNMR (CDC13, 400MHz): 7.76 (s, 1H), 7.30 - 7.26 (m, 2H), 7.20 - 7.14 (m, 6H), 7.01 - 6.97 ( m, 4H), 6.79 - 6.75 (m, 2H), 6.49 - 6.45 (m , 2H), 4.28 (t, J = 6.4Hz, 2H), 3.43 ( t , J = 6.4Hz , 2H), 1.50 (s, 6H). m/z Relative intensities = 499.0 (M )+100 %. % Purity = 98.47 % (By HPLC). IR KBr (cm- '): 2972, 2924, 2853, 1630, 1516, 1242, 1229, 1159, 1028, 845.
Example 80
5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-(lH-imidazol-l- yl)phenoxy) ethyI)thio)-l-(4-fluorophenyl)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-chloro-3-methoxyphenyl) propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromOethoxy)-3-fluorophenyl)-lH-imidazole. 'HNMR (CDC13, 400MHz): 7.77 (S, 1H), 7.21 * 7.19 (m, 3H), 7.17 - 7.12 (m, 2H), 7.11 - 7.09 (m, 2H), 6.88 - 6.84 (m, 2H), 6.58 - 6.56 (m, 2H), 6.55 - 6.54 (m, 2H), 4.37 (t, J = 6.8Hz, 2H), 3.72 (s, 3H), 3.44 (t, J = 6.8Hz, 2H), 1.51 (s, 6H). m/z Relative intensities = 581.1 (M)+100 %, % Purity = 93.50 % (By HPLC). IR CHC13 (cm 1): 3021, 2967, 2930, 2857, 1524, 1215, 1055, 928, 845.
Example 81
5-(2-(4-chloro-3-methoxyphenyl)propan-2-yI)-2-((2-(2-fluoro-4-(2-methyl-lH- imidazol-l-yI)phenoxy)ethyl)thio)-l-(4-fluoropheny!)-lH-imidazole. In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(4-chloro-3-methoxyphenyl) propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and 1 -(4-(2-bromoethoxy)-3 -fluorophenyl)-2-methyl- 1 H-imidazole. 'HNMR (CDCI3, 400MHz): 7.20 (d, J = 8.4Hz, 1H), 7.17 - 7.14 (m, 2H), 7.05 - 6.95 (m, 2H), 6.88 - 6.83 (m, 2H), 6.59 - 6.55 (m, 2H), 6.53 - 6.50 ( dd, Jl = 12.8Hz, J2 = 2Hz, 2H), 4.39 (t, J= 6.8Hz, 2H), 3.72 (s, 3H), 3.45 (t, J = 6.8Hz, 2H), 2.32 (s, 3H), 1.51 (s, 6H). m/z Relative intensities = 595 (M)+100 %, % Purity = 93.62 % (By HPLC). IR CHCI3 (cm"1): 3021, 2967, 2930, 2857, 1512, 1215, 1095, 1061, 928, 845.
Example 82
5-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yI)thio) ethoxy)-lH-indazole.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)-lH- imidazole-2-thiol and 5-(2-bromoethoxy)-lH-indazole. 'HNMR (CDCI3, 400MHz): 7.97 (s, 1Η), 7.36 (d, J = 8.8Hz, 1H), 7.16 (s, 1H), 7.12 (d, J = 2.4Hz, 1H), 7.02 (dd, Jl = 2Hz, J2 = 8.8Hz, 1H), 6.18 (t, J = 8:8Hz, 2H), 6.64 - 6.62 (m, 1H), 6.54 - 6.47 (m, 4H), 4.26 (t, J = 6.4Hz, 2H), 3.84 (s, 3H), 3.70 (s, 3H), 3.44 (t, J = 6.4Hz, 2H), 1.49 (s, 6H). m/z Relative intensities = 533.2 (M)+ 100%. % Purity = 93.11% (By HPLC). IR KBr (cm-1): 3313, 3061, 2833, 1629, 1589, 1465, 1433.
Example 83
5-(2-(2-((2-(4-(lH-pyrazoI-l-yl)phenoxy)ethyl)thio)-l-(4-fluorophenyl)-lH- imidazol-5-yl) propan-2-yI)-2-fluorobenzonitrile.
In a manner similar to that described for Example 13, the title compound was prepared from 2-fluoro-5-(2-( 1 -(4-fiuorophenyl)-2-mercapto-l H-imidazol-5-yl)propan- 2-yl)benzonitrile and 2-fluoro-5-(2-(l-(4-fluorophenyl)-2-mercapto-lH-imidazol-5- yl)propan-2-yl)benzonitrile. "HNMR (CDCI3, 400MHz): 7.83 (d, J = 2.4Hz, 1H), 7.69 (d, J = 1.6Hz, 1H), 7.57 (d, J = 8.8Hz," 2H), 7.27 - 7.24 (m, 1H), 7.20 - 7.17 (m, 2H), 7.04 (t, J = 8.4Hz, 1H), 6.97 (d, J = 8.8Hz, 2H), 6.89 (t, J = 8.4Hz, 2H), 6.56 - 6.53 (m, 2H), 6.44 (t, J = 2Hz, 1H), 4.29 (t, J = 6.4Hz, 2H), 3.47 (t, J = 6.4Hz, 2H), 1.52 (s, 6H). m/z Relative intensities = 542.1 (M)+ 100%. % Purity = 95.12% (By HPLC). IR KBr (cm 1): 3439, 2235, 1730, 1608, 1467.
Example 84 5-(2-(3,4-dimethoxyphenyl)propan-2-yI)-l-(4-fluorophenyl)-2-((2-methyl-l-(4-(2- methyI-lH-imidazoI-l-yl)phenoxy)propan-2-yI)thio)-lH-imidazole.
In a manner similar to that described for Example 45, the title compound was prepared 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol- 2-yl)thio)-2-methylpropan-l-ol and 4-(2-methyl-lH-imidazol-l-yl)phenol. 'HNMR (CDCI3, 400MHz): 7.15 - 7.12 (m, 3H), 7.02 - 6.99 (m, 3H), 6.96 (brs, 1H), 6.87 - 6.82 (m, 2H), 6.65 (d, J = 8Hz, 1H), 6.58 - 6.54 (m, 2H), 6.50 - 6.47 (m, 2H), 3.85 (s, 3H), 3.69 (s, 3H), 3.49 (s, 2H), 2.31 (s, 3H), 1.48 (s, 6H), 1.37 (s, 6H). m/z Relative intensities - 601.1 (M)+ 100%, % Purity = 94.00 % (By HPLC).
Example 85
5- (2-(3,4-dimethoxyphenyI)propan-2-yl)-2-((l-(2-fluoro-4-(lH-imidazol-l- yl)phenoxy)-2-methyIpropan-2-yl)thio)-l-(4-fluorophenyl)-lH-iiiiidazoIe.
In a manner similar to that described for Example 45, the title compound was prepared 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol- 2-yl)thio)-2-methylpropan-l-ol and 2-fluoro-4-(lH-imidazol-l-yl)phenol. !HNMR (CDCI3, 400MHz): 7.83 (s, 1H), 7.23 - 7.21 (m, 2H), 7.18 - 7.10 (m, 3H), 7.06 - 7.03 (m, 1H), 6.87 - 6.83 (m, 2H), 6.65 (d, J = 8.4Hz, 1H), 6.58 - 6.55 (m, 2H), 6.49 - 6.46 (m, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.53 (s, 2H), 1.47 (s, 6H), 1.35 (s, 6H). m/z Relative intensities = 605.4 (M)+100%. % Purity = 93.38 % (By HPLC).
Example 86
l-(4-fluorophenyl)-5-(2-(3-methoxyphenyl)propan-2-yl)-2-((2-(4-(2-methyI-lH- imidazoI-l-yl)phenoxy)ethyl)thio)-lH-imidazole.
In a manner similar to that described for Example 13, the title compound was prepared 1 -(4-fluorophenyl)-5-(2-(3-methoxyphenyl)propan-2-yl)- 1 H-imidazole-2-thiol and l-(4-(2-bromo ethoxy)phenyl)-2-methyl-lH-imidazole. 'HNMR (CDCI3, 400MHz): 7.17 (d, J = 8.8 Hz, 2H), 7.15 (s, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.00 - 6.94 (m,4H), 6.80 (t, J = 8.4 Hz, 2H), 6.69 (dd, Jl = 8.0 Hz, J2 = 2.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H),6.56 - 6.51 (m, 3H), 4.30 (t, J = 6.8 Hz, 2H), 3.71 (s, 3H), 3.44 (t, J = 6.8 Hz, 2H), 2.31 (s, 3H), 1.49 (s, 6H). m/z Relative intensities = 543.1 (M)+, 100%. % Purity = 92.44 % (By HPLC). IR KBr (cm"1): 3417, 2920, 1599, 1512, 1246, 837.
Example 87
6- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)thio) ethoxy)-2H-chromen-2-one. In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3 ,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and 6-(2-bromoethoxy)-2H-chromen-2-one. Ή NMR (CDC13, 400MHz): 7.65 (d, J = 9.6Hz, IH), 7.26 - 7.23 (m, IH), 7.15 (s, IH), 7.11 - 7.08 (dd, Jl = 8.8Hz, 52 = 2.8Hz, IH), 7.04 - 7.03 (m, IH), 6.83 (t, J = 8.4Hz, 2H), 6.66 - 6.64 (m, IH), 6.54 - 6.48 (m, 4H), 6.43 (d, J = 9.6Hz, IH), 4.28 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.71 (s, 3H), 3.41 (t, J = 6.4Hz, 2H), 1.49 (s, 6H). m/z Relative intensities = 561.2 (M)+100 %. % Purity = 97.03% (By HPLC). IR KBr (cm-1): 3458, 3066, 2933, 1710, 1599, 1435.
Example 88
5-(2-(2-((2-(4-(lH-imidazol-l-yI)phenoxy)ethyl)thio)-l-(4-fluorophenyl)-lH- imidazol-5-yl) propan-2-yl)-2-fluorobenzonitrile.
In a manner similar to that described for Example 13, the title compound was prepared from 2-fluoro-5-(2-( 1 -(4-fluorophenyl)-2-mercapto- 1 H-imidazol-5-yl)propan- 2-yl)benzonitrile and l-(4-(2-bromoethoxy)phenyl)-lH-imidazole. Ή NMR (CDC13, 400MHz): 7.77 (s, IH ), 7.30 - 7.19 (m, 6H ), 7.17 (s, IH), 7.05 (m, 3H ), 6.99 - 6.88 ( m, 2H ), 6.57 - 6.54 (m, 2H ), 4.30 (t, J = 6.4Hz, 2H), 3.47 (t, J = 6.4Hz, 2H), 1.52 (s, 6H ) m/z Relative intensities = 542.1 (M)+100 %. % Purity = 93.38 % (By HPLC). IR CHCI3 (cm-1): 3443, 2231, 1514, 1496, 1251.
Example 89
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2- phenoxyethyl)thio)-lH-imidazoIe.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazole-2-thiol and (2-bromoethoxy)benzene. Ή NMR (CDC13, 400MHz): 7.28 - 7.27 (m, IH), 7.25 - 7.24 (m, IH), 7.14 (s, IH), 6.95 - 6.91 (m, IH), 6.88 - 6.85 (m, 2H), 6.83 - 6.79 (fn, 2H), 6.64 (d, J = 8.8Hz,lH), 6.53 - 6.47 (m, 4H), 4.21 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.71 (s, 3H), 3.41 (t, J = 6.4Hz, 2H), 1.48 (s, 6H). m/z Relative intensities = 493.1 (M)+100 %. % Purity = 93.41% (By HPLC). IR CHCI3 (cm-1): 3020, 2927, 1600, 1589, 1215.
Example 90
5-(2-(3,4-dimethoxyphenyI)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(2- methoxyethoxy) ethyl)thio)-lH-imidazole. In a manner similar to that described for Example 13, the title compound was prepared from 2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethanol and l-bromo-2-methoxyethane. !H NMR (CDCI3, 400MHz): 7.12 (s, 1H), 6.80 (t, J = 2.4Hz, 2H), 6.66 - 6.64 (m, 1H), 6.56 - 6.51 (m, 2H), 6.50 - 6.47 (m, 2H), 3.85 (s, 3H), 3.72 - 3.70 (m, 5H), 3.59 - 3.57 (m, 2H), 3.50 - 3.48 (m, 2H), 3.35 (s, 3H), 3.23 (t, J = 6.4Hz, 2H), 1.48 (s, 6H). m/z Relative intensities = 475.0 (M)+, 100%. % Purity = 93.66% (By HPLC).
Example 91
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2- methoxyethyl)thio)-lH-imidazole
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and l-bromo-2-methoxyethane. Ή NMR (CDC13, 400MHz): 7.13 (s, 1H ), 6.84 - 6.79 (m, 2H ), 6.66 - 6.64 (m, 1H ), 6.56 - 6.51 (m, 2H ), 6.49 - 6.47 (m, 2H ), 3.85 (s, 3H ), 3.73 (s, 3H ), 3.62 (t, J = 6.4Hz, 2H), 3.31 (s, 3H), 3.24 (t, J = 6.4Hz, 2H), 1.48 (s, 6H). m/z Relative intensities = 531.2 (M)+, 100%. % Purity = 94.55 % (By HPLC). IR KBr (cm-1): 3020,1510,1464,1215.
Example 92
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fl orophenyl)-2-((2-(4-(2-methyl-lH- imidazol -l-yl)phenoxy)ethyl)thio)-lH-imidazole-4-carbonitriIe.
To a solution of 4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4- fluorophenyl)-2-((2-(4-(2-methyl- 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- lH-imidazole (500 mg, 0.77 mmol) in NMP was added Copper cyanide (273 mg, 3.08 mmol) and stirred at 120°C temperature for 30 h. Reaction mixture was quenched with water and extracted with ethyl acetate, combined organic layers were dried over sodium sulphate and distilled the solvent under vacuum. Crude product was purified by column chromatography to afford the desired product (28 mg, 6% yield). Ή NMR (CDCI3, 400 MHz): 7.2 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 2H), 6.95 (s, 2H), 6.89 -6.85 (m, 2H), 6.66 (d, J = 8.8 Hz, 1H), 6.54 - 6.51 (m, 2H), 6.64 - 6.44 (m, 1H), 6.40 (d, J = 2 Hz, 1H), 4.32 (t, J = 6.4 Hz, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 3.42 (t, J = 6.4 Hz, 2H), 2.32 (s, 3H), 1.69 (s, 6H). m/z Relative intensities = 598.1 (M)+100 % . % Purity = 92.49 % (By HPLC). IR CHCb icm"1): 3447, 3067, 2924, 2226, 1736, 1464, 1026, 842.
Example 93 5-(2-(3,4-dimethoxyphenyI)propan-2-yI)-2-((2-(3-fluoro-4-(2-methyI-lH-imidazol- 1-yl) phenoxy) ethyl)thio)-l-(4-fluorophenyl)-lH-imidazole-4-carbonitriIe.
In a manner similar to that described for Example 92, the title compound was prepared from 4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(3-fluoro-4-(2- methyl-lH-imidazol-l-yl)phenoxy)ethyl)thio)-l-(4-fluorophenyl)-lH-imidazole and Copper Cyanide. Ή NMR (DMSO-d6, 400MHz): 7.42 (d, J = 8.8 Hz, 1H), 7.19 - 7.17 (m, 1H), 7.15 (d, J = 2.8 Hz, 1H), 7.11-7.07 (m, 2H), 6.93 - 6.91 (m, 2H), 6.82 - 6.79 (m, 2H), 6.75 (d, J = 8.4 Hz, 1H), 6.47 - 6.44 (dd, Jl = 8 Hz, J2 = 2 Hz, 1H), 6.42 (d, J = 2 Hz, 1H), 4.30 (t, J = 6.4 Hz, 2H), 3.71 (s, 3H), 3.59 (s, 3H), 3.47 (t, J = 6.4 Hz, 2H), 2.14 (s, 3H), 1.61 (s, 6H). m/z Relative intensities = 616.2 (M)+, 100%. % Purity = 89.69% (By HPLC). IR KBr (cm 1): 3435, 3117, 2227, 1624, 1593.
Example 94 .
5-(2-(benzo[d][l,3]dioxol-5-yI)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2-methyl- lH-imidazol-l-yl)phenoxy)eth l)thio)-lH-imidazole.
To a solution of 4-(2-(l-(4-fluorophenyl)-2-((2-(4-(2-methyl-lH-imidazol-l- yl)phenoxy) ethyl)thio)-lH-imidazol-5-yl)propan-2-yl)benzene-l,2-diol (100 mg, 0.18 mmol) in DMF was added cesium carbonate (89mg, 0.27 mmol) and chloro iodo methane (.02 mL, 0.27 mmol) and stirred at 100°C temperature for 3 h. Reaction mixture was quenched with water and extracted with ethyl acetate, combined organic layers were dried over sodium sulphate and distilled the solvent under vacuum. Crude product was purified by column chromatography to afford the desired product (23 mg, 22% yield). Ή NMR (DMSO, 400 MHz): 7.35 (d, J = 8.8Hz, -2H), 7.26 (s, 1H), 7.11 - 7.06 (m, 5H), 6.96 (s, 1H), 6.71 - 6.68 (m, 3H), 6.47 (d, J = 1.6Hz, 1H), 6.38 - 6.35 (m, 1H), 5.75 (s, 2H), 4.25 (t, J = 5.6Hz, 2H), 3.38 (t, J = 5.6Hz, 2H), 2.62 (s, 3H), 1.40 (s, 6H). m/z Relative intensities = 557.3 (M)+100 %. % Purity = 92.16 % (By HPLC).
Example 95
(S)-methyl 2-(4-(2-((5-(2-(3,4-dimethoxyphenyI)propan-2-yl)-l-(4-fluorophenyl)- lH-imidazol-2-yl)thio)ethoxy)benzamido)-5-guanidinopentanoate.
To a solution of 4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4- fluorophenyl)- lH-imidazol-2-yl)thio)ethoxy)benzoic acid (400 mg, 0.75 mmol) in DMF (5mL) was added (S)-methyl 2-amino-5-guanidinopentanoate hydrochloride (148 mg, 0.48 mmol) at 0°C followed by addition of HBTU (O-Benzotriazole-Ν,Ν,Ν',Ν'- tetramethyl-uronium-hexafluoro-phosphate) (370 mg, 0.819 mmol), DIPEA(diisopropylethylamine) 0.63 mL, 0.82 mmol) and stirred for 5-6 hr at room temperature.. Reaction mixture was quenched with water and extracted with ethyl acetate, combined organic layers were dried over sodium sulphate and distilled the solvent under vacuum. Crude product was purified by column chromatography to afford the desired product (360 mg, 68% yield). Ή NMR (CDC13, 400MHz): 7.73 (d, J = 8.4Hz, 2H), 7.14 (s, 2H), 6.84 - 6.80 (m, 4H), 6.65 (d, J = 8.4Hz, 2H), 6.54 - 6.47 (m, 2H), 6.47 - 6.44 (m, 3H), 6.30 - 6.10 (brs, 2H), 4.61 (brs, 1H), 4.13 (t, J = 6.4Hz, 2H), 3.82 (s, 3H), 3.69 (s, 3H), 3.67 (s, 3H), 3.2 2 (brs, 1H), 3.14 - 3.10 (m,3H), 1.91 - 1.81 (m, lH), 1.81 - 1.79 (m, 1H), 1.63 - 1.61 (m, 2H), 1.47 (s, 6H). m/z Relative intensities = 707.3 (M)+100 %. % Purity = 97.65 % (By HPLC). IR KBr (crn 1): 3366, 2965, 2872, 1744, 1645, 1607, 1410, 1177, 845.
Example 96
(S)-2-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazoI-2-yl)thio)ethoxy)benzamido)-5-guanidinopentanoic acid.
To a solution of (S)-methyl 2-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-
1 -(4-fluorophenyl)- 1 H-imidazol-2-yl)thio)ethoxy)benzamido)-5-guanidinopentanoate (100 mg, 0.14 mmol) in THF-H20 (1 :1, 5mL) was added LiOH.H20 (18 mg, 0.42 mmol) at room temperature and stirred for 12hr. Reaction mixture was acidify with dil HC1, quenched with water and extracted with ethyl acetate, combined organic layers were dried over sodium sulphate and distilled the solvent under vacuum afforded 95 mg, 96 % product. 1H NMR (MeOD, 400MHz): 7.83 (d, J = 8.8Hz, 2H), 7.21 (s, 1H), 6.90 - 6.85 (m, 4H), 6.73 (d, J= 8Hz, 1H), 6.59 - 6.55 (m, 2H), 6.52 (d, J = 2Hz, 1H), 6.49 - 6.48 (m, 1H) 4.58 - 4.54 (m, 1H), 4.16 (t, J = 6Hz, 2H), 3.79 (s, 3H), 3.63 (s, 3H), 3.31 - 3.32 (m, 4H), 2.02 - 2.01 (m, 1H), 1.87 (m, 1H), 1.73 - 1.64 (m, 2H), 1.52 (s, 6H). m/z Relative intensities = 693.4 (M)+100 %. % Purity = 91.36 % (By HPLC). IR CHC (cm 1): 3619, 3368, 3188, 1751, 1410, 1254, 1028, 831.
Example 97
2-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol- 2-yI)thio) ethoxy)benzamido)-N,N -trimethylethanaminium chloride.
In a manner similar to that described in Example 95, the title compound was prepared from 4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethoxy)benzoic acid and 2-amino-N,N,N-trimethylethanaminium. Ή NMR (DMSO, 400MHz): 8.67 (t, J = 2.4Hz, 1H), 7.81 (d, J = 8.8Hz, 2H), 7.11 (s, 1H), 7.04 - 7.00 (m, 4H), 6.73 (d, J = 8Hz, 1H), 6.65 - 6.61 (m, 2H), 6.64 (d, J =2Hz, 1H), 6.42 (s, 1H), 4.24 (t, J = 6.4Hz, 2H), 3.70 (s, 3H), 3.66 (d, J = 6Hz, 2H), 3.55 (s, 3H), 3.48 (t, J = 6.4Hz, 2H), 3.36 (d, J= 6.4Hz, 2H), 3.32 (s, 9H), 1.43 (s, 6H). m/z Relative intensities = 621.5 (M-35.5)"100 %, % Purity = 90.54 % (By HPLC). IR KBr (cm"1): 3441, 3119, 2936, 1649, 1607, 1256, 842.
Example 98
4-(2-(2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-l-(4-fluorophenyl)-lH- imidazol-S-yl) propan-2-yl)benzene-l,2-diol.
To a solution of 2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4- dimethoxy phenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazole (150 mg, 0.29 mmol) in DCM (5 mL) was added 1M BBr3 (1.07 mL, 1.07 mmol) at -60°C to -40°C and stirred for 30 min. Reaction mixture was basify with sodium bicarbonate solution, quenched with water and extracted with dichloromethane, combined organic layers were dried over sodium sulphate and distilled the solvent under vacuum. Crude product was purified by column chromatography to afford the desired product (45 mg, 30 % yield).'H NMR (DMSO, 400MHz): 8.73 (s, 1H), 8.69 (s, 1H), 8.15 (s, 1H), 7.65 (s, 1H), 7.54 (d, J = 8.8Hz, 2H), 7.08 - 7.00 (m, 6H), 6.68 - 6.64 (m, 2H), 6.51 (d, J = 8Hz, lH), 6.37 (d, J = 2Hz, 1H), 6.17 - 6.14 (m, 1H), 4.22 (t, J = 6.8Hz, 2H), 3.37 (t, J = 6.8Hz, 2H), 1.35 (s, 6H). m/z Relative intensities = 531(M)+100 %, % Purity = 88.09% (By HPLC).
Example 99
4-((2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)sulflnyl) ethoxy)methyl)benzonitrile
Figure imgf000055_0001
To a solution of 4-((2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4- fluorophenyl -lH-imidazol-2-yl)thio)ethoxy)methyl)benzonitrile (185 mg, 0.342 mmol) in chloroform was added mCPBA (63 mg, 0.442 mmol) at 0 - 5 °C and stirred for 0.5 h. Reaction mixture was quenched with chloroform and extracted with bririe, combined organic layers were dried over sodium sulphate and distilled the solvent under reduced vacuum. Crude product was purified by column chromatography to afford the desired product (135 mg, 71% yield). 1H NMR (CDC13, 400MHz): 7.60 (d, J = 8.4Hz, 2H), 7.36- 7.33 (m, 3H), 7.26 - 7.24 (m, 3H), 6.97 - 6.91 (m, 3H), 6.84 - 6.78 (m, 3H), 6.52 - 6.48 (m, 1H), 4.59 - 4.50 (m, 2H), 4.01 - 3.95 (m, 1H), 3.92 - 3.86 (m, 2H), 3.85 - 3.37 (m, 1H), 1.56 (s, 6H).- m/z Relative intensities = 556.1 (M+l)+100%; % Purity = 94.81% (By HPLC), Retention time = 21.84 min. IR CHCI3 (cm"1): 3020, 1602, 1510, 1215.
Example 100
2-((2-((2,6-difluorobenzyl)oxy)ethyl)sulfinyl)-5-(2-(3,4-dimethoxyphenyI)propan-2- yl)-l-(4-fluorophenyl)-lH-imidazole
In a manner similar to that described for Example 99, the title compound was prepared from 2-((2-((2,6-difluorobenzyl)oxy)ethyl)thio)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl) -lH-imidazole. Ή NMR (CDC13, 400MHz): 7.31-7.25 (m, 2H), 6.89-6.85 (m, 4H), 6.80-6.76 (m, 1H), 6.66 (d J = 8.4Hz, 1H), 6.47-6.43 (m, 3H), 4.60(d, J = 10Hz, 1H), 4.52(d, J = 11.2 Hz, 1H), 3.90-3.71 (m, 9H), 3.47-3.43 (m, 1H), 1.51(s, 6H). m/z Relative intensities = 559.4 (M+)+ 100%; % Purity = 96.73% (By HPLC). IR CHCI3 (cm'1): 667, 843, 1215, 1258, 1472, 1510, 1628, 2840, 2936, 3019, 3435.
Example 101
2-((2-(4-(lH-pyrrol-l-yl)phenoxy)ethyl)sulfinyI)-5-(2-(3,4- dimethoxypbenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazole.
Ή NMR (CDC13, 400MHz): 7.34 (s, 1H), 7.29 - 7.26 (m, 2H), 6.98 (d, J = 2Hz, 2H),
6.93 - 6.86 (m, 4H), 6.82 - 6.77 (m, 1H), 6.65 (d, J = 8Hz, 2H), 6.47 - 6.43 (m, 3H), 6.31 - 6.30 (m, 2H), 4.49 - 4.44 (m, 1H), 4.35 - 4.30 (m, 1H), 4.01 - 3.96 (m, 1H), 3.84 (s, 3H), 3.71(s, 3H), 3.66 - 3.59 (m, 1H), 1.57 (s, 6H). m/z Relative intensities: 574.3 (M+l)+ 100 %. % Purity =89.45% (By HPLC). IR CHCI3 (cm'1): IR CHCI3 (cm'1): 3433, 3020, 1602, 1518, 1215.
Example 102
2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)sulfinyl)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazole.
'H NMR (DMSO, 400MHz): 8.14 (s, 1H), 7.65 (s, 1H), 7.53 (d, = 8.8Hz,2H), 7.90 (s, 1H), 7.11-7.00 (m,5H), 6.82 (t, J = 2.4Hz, 1H), 6.73 (t, J = 3.6Hz, 2H), 6.43 - 6.41 (m, 2H), 4.36 - 4.33 (dd, Jl = 4.4Hz, J2 = 6.8Hz, 2H), 3.90 - 3.87 (m, IH), 3.67 (s, 3H), 3.62 - 3.59 (m, IH), 3.56 (s, 3H), 1.51(m, 6H). m/z Relative intensities = 575.1 (M)+100 %. % Purity = 91.49 % (By HPLC). IR KBr (cm 1): 3433, 3117, 29326, 3832, 1603, 1512, 1259, 1059, 1041, 536.
Example 103
4- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl) sulfinyl) ethoxy)benzonitrile.
In a manner similar to that described for Example 99, the title compound was prepared from 2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)-l-(4-fluoro phenyl)- lH-imidazole. Ή NMR (CDC13, 400MHz): 7.58 - 7.55 (dd, Jl = 2.8Hz, J2 = 4.8Hz, 2H), 7.54 (s, IH), 6.94 - 6.84 (m, 4H), 6.83 - 6.79 (m, IH), 6.67 - 6.65 (m, IH), 6.49 - 6.43 (m, 3H), 4.55 - 4.49 (m, IH), 4.43 - 4.38 (m, IH), 4.07 - 4.02 (m, IH), 3.85 (s, 3H), 3.70 (s, 3H), 3.59 - 3.53 (m, IH), 1.53 (s, 3H), 1.43 (s, 3H). m/z Relative intensities = 534.1 (M)+100 %. % Purity = 96.54 % (By HPLC). IR KBr (on 1): 3431, 31 17, 3040, 2936, 2833, 2224, 1225, 1047, 843.
Example 104
5- (2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2-methyl-lH- imidazol-l-yl)phenoxy)ethyI)sulfinyI)-lH-iinidazoIe.
In a manner similar to that described for Example 99, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)-2-((2-(4-(2- methyl-lH-imidazol-l-yl)phenoxy)ethyl)thio)-lH-imidazole.1H NMR (CDC13, 400MHz): 7.34 (s, IH), 7.18 - 7.14 (m, 2H), 6.99 (d, J = 1.2Hz, IH), 6.94 - 6.90 (m, 5H), 6.84 - 6.80 (m, IH), 6.62 (d, J = 8.4Hz, IH), 6.52 - 6.44 (m, 3H), 4.53 - 4.48 (m, IH), 4.42 - 4.38 (m, IH), 4.08 -4 .03 (m, IH), 3.85 (s, 3H), 3.72 (s, 3H), 3.62-3.55 (m, IH), 2.29 (s, 3H), 1.58 (s, 3H), 1.54 (s, 3H). m/z Relative intensities = 588.9 (M)+ 100 %, % Purity = 96.80% (By HPLC). IR KBr (cm 1): 3437, 3117, 2928, 2330, 1605, 1464, 1244, 1049.
Example 105
4-((2-((5-(2-(3,4-dichlorophenyI)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yl)sulfonyl) ethoxy)methyI)benzonitrile
Figure imgf000058_0001
To a solution of 4-((2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4- fluorophenyl)-lH-imidazol-2-yl)thio)ethoxy)methyl)benzonitrile (250 mg, 0.462 mmol) in chloroform was added mCPBA (311 mg, 1.802 mmol) at room temperature and stirred for 0.5 - 1 h. Reaction mixture was quenched with chloroform and extracted with brine, combined organic layers were dried over sodium sulphate and distilled the solvent under reduced vacuum. Crude product was purified by column chromatography to afford the desired product (225 mg, 89% yield). Ή NMR (CDC13, 400MHz): 7.65 - 7.63 (m, 2H), 7.38 (d, J = 8.4Hz, 2H), 7.26 - 7.24 (m, 1H), 7.21 (d, J = 8.4Hz, 1H), 6.90 - 6.82 (m, 3H), 6.72 - 6.67 (m, 3H), 4.52 (s, 2H), 3.97 (t, J = 6Hz, 2H), 3.61 (t, J = 6Hz, 2H), 1.50 (s, 6H). .m/z Relative intensities = 572.1 (M+l)+100%; % Purity = 94.81% (By HPLC), Retention time =22.99 min. IR CHCI3 (cm"1): 3020, 2231, 1602, 1510, 1215.
Example 106
4-((2-((5-(2-(3,4-dimethoxyphenyI)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazoI-2- yl) sulfonyl) ethoxy)methyl)benzonitrile
In a manner similar to that described for Example 105, the title compound was prepared from 4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethoxy) methyl)benzonitrile. Ή NMR (CDC13, 400MHz): 7.64-7.62 (dd, Jl = 1.6Hz, J2 = 6.8Hz, 2H), 7.38 (d, J = 8.4Hz, 2H), 7.23(s, 1H), 6.84-6.81 (m, 2H), 6.69-6.62 (m,3H), 6.39-6.35 (m, 2H), 4.52 (s, 2H), 3.97 (t, J = 6Hz, 2H), 3.85 (s, 3H), 3.68 (s, 3H), 3.61 (t, J = 6Hz, 2H), 1.49 (s, 6H). m/z Relative intensities = 564.31 (M+)+ 100%; % Purity = >90 (By NMR). IR CHCI3 (cm 1): 850, 1028, 1258, 1333," 1512, 1606, 1728, 2222, 2833, 2930, 3082, 3122, 3439.
Example 107
2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)sulfonyl)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyi)-lH-imidazoIe.
In a manner similar to that described for Example 105, the title compound was prepared from 2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazole and mCPBA. 'HNMR (DMSO, 400MHZ): 7.84(S, lH), 7.32-7.30 (dd, Jl= 2Hz, J2 = 6.8Hz, 2H), 7.27(s, 1H), 7.22(s, 1H), 6.96-6.94(dd, Jl = 2.4Hz, J2 = 7.2Hz, 2H), 6.85-6.81(m, 2H), 6.72-6.68(m, 2H), 6.65(d, J = 8.4Hz, 1H), 6.45-6.42 (dd, Jl = 2.4Hz, J2 = 8.4Hz, 2H), 6.38(d, J = 2Hz, 1H), 4.49(t J = 6.4Hz, 2H), 3.85(s, 3H), 3.81(t J = 6.4Hz, 2H), 3.62(s,3H), 1.47(s,~ 6H). m/z Relative intensities = 591.1 (M)+, 100%. % Purity = 92.61% (By HPLC). IR KBr (cm-1): 3433, 3121, 2970, 2835, 1726, 1603, 1135.
Example 108
5-(4-((2-((5-(2-(3,4-dichIorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-iiiiidazol-2-
Figure imgf000059_0001
To a solution of 4-((2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4- fluorophenyl)-lH-imidazol-2-yl)thio)ethoxy)methyl)benzonitrile (100 mg, 0.188 mmol) in DMF was added sodium azide (97 mg, 1.504 mmol) and ammonium chloride (203 mg, 3.76 mmol) and heated at 80 °C for 20 h. Reaction mixture was quenched with ethyl acetate and extracted with brine, combined organic layers were dried over sodium sulphate and distilled the solvent under reduced vacuum. Crude product was purified by column chromatography to afford the desired product (46 mg, 44% yield). Ή NMR (CDCI3, 400MHz): 7.98 (d, J-= 7.6Hz, 2H), 7.28 - 7.24 (m, 4H), 6.99 (d, J = 2Hz,lH), 6.93 - 6.89 (m, 2H), 6.84 - 6.81 (dd, Jl = 8.4Hz, 1H, J2 = 2Hz, 1H), 6.62 - 6.59 (m, 2H), 4.42 (s, 2H), 3.65 (t, J = 6Hz, 2H), 3.19 (t, J = 6Hz, 2H), 1.50 (s, 6H). m/z Relative intensities = 583.0 (M)+100%; % Purity = 97.08% (By HPLC), Retention time = 17.07 min. IR CHCI3 (cm 1): 2974, 2924, 1600, 1510, 1469.
Example 109
5-(4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazoI-2-yl) thio) ethoxy)methyl)phenyI)-lH-tetrazole
In a manner similar to that described for Example 108, the title compound was prepared from 4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethoxy) methyl)benzonitrile. 1H NMR (DMSO, 400MHz): 8.0 (d, J = 8Hz,2H), 7.49 (d, J = 8.4Hz,2H), 7.11 (s, 1H), 7.05 - 7.01 (m, 2H), 6.73 (d, J = 8.4Ηζ,1Η), 6.64 - 6.61 (m, 2H), 6.42 - 6.41 (m, 2H), 4.54 (s, 2H), 3.70 (s, 3H), 3.65 (t, J = 6.4Hz, 2H), 3.55 (s, 3H), 3.21 (t, J = 6.4Hz, 2H), 1.41 (s, 6H). m/z Relative intensities = 575.1 ( +l)+ 100%; % Purity = 95.07% (By HPLC). IR CHCI3 (cm"1): 3020, 1510, 1215.
Example 110
5-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yI)-l-(4-fluorophenyl)-lH-imidazol- 2-yl)thio) ethoxy)phenyl)-lH-tetrazole.
In a manner similar to that described for Example 13, the title compound was prepared.
Ή NMR (CDCI3, 400MHz): 7.95 (d, J = 8.4Hz, 2H), 7.25 (d, J = 3.2Hz, 1H), 6.88 (d, J= 8.4H, 2H), 6.75 (d, J = 8.8Hz, 2H), 6.67 (d, J = 8.4Hz, 1H), 6.85 - 6.54 (m, 2H), 6.51 - 6.48 (m, 2H), 4.11 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.22 (t, J = 6.4Hz, 2H), 1.52 (s, 6H). m/z Relative intensities = 561.(M)+100 %. % Purity = 95.39 % (By HPLC), IR KBr (crn 1): 3416, 3117, 3075, 2932, 2594, 1728, 1616, 1540, 1447, 1254, 1054, 840.
Example 111
5-(4-(2-((5-(2-(3,4-dichlorophenyI)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol-2- yI)thio) ethoxy)phenyI)-lH-tetrazole.
In a manner similar to that described for Example 13, the title compound was prepared.
Ή NMR (CDCI3, 400MHz): 7.96 (d, J = 8.8Hz,2H), 7.28 - 7.26 (m, 2H), 7.02 (d, J = 2.4Hz,lH), 6.96 - 6.90 (m, 2H), 6.87 - 6.84 (dd, Jl = 8.4Hz, 1H, J2 = 2.4Hz, 1H),6.76 (d, J = 8.8Hz,2H), 6.67 - 6.65 (m, 2H), 4.12 (t, J = 6.4Hz, 2H), 3.24 (t, J = 6.4Hz, 2H), 1.54 (s, 6H). m/z Relative intensities = 569 (M)+100 %. % Purity = 98.61 % (By HPLC). IR KBr (cm 1): 3431, 2976, 1616, 1510, 1467.
Example 112
5-(2-(3,4-dimethoxyphenyI)propan-2-yl)-l-(4-fluorophenyl)-4-methyl-2-((2-(4-(2- methyI-lH-imidazol-l-yl)phenoxy)ethyI)thio)-lH-imidazoIe.
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-4-methyl- lH-imidazole-2-thiol and l-(4-(2rbromoethoxy)phenyl)-2-methyl-lH-imidazole. lH NMR (CDCI3, 400MHz): 7.19 - 7.16 (m, 2H), 7.05 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 1.2 Hz, 1H), 6.95 (d, J = 1.2 Hz, 1H), 6.84 - 6.80 (m, 2H), 6.65 (d, J = 8 Hz, 2H), 6.57 - 6.54 (m, 2H), 6.50 - 6.46 (m, 2H), 4.27 (t, J = 6.8 Hz, 2H), 3.85 (s, 3H), 3.76 (s, 3H), 3.38 (t, J = 6.8 Hz, 2H), 2.48 (s, 3H), 2.27 (s, 3H), 1.53(s, 6H). m/z Relative intensities = 587.3 (M)+ 100%. % Purity = 92.45% (By HPLC). IR KBr (cm 1): 3020, 1604, 1514, 1215.
Example 113
1- (4-(2-((5-(2-(3,4-dimethoxyphenyI)propan-2-yI)-l-(4-fluorophenyl)-lH-imidazoI-
2- yl)thio)ethoxy)-3-fluorophenyl)-lH-pyrazole
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)-lH- imidazole-2-thiol and l-(4-(2-bromoethoxy)-3-fluorophenyl)-lH-pyrazole. Ή NMR (CDCI3, 400MHz): 7.81 (d, J = 2.4Hz, 1H), 7.69 (d, J = 1.6Hz, 1H), 7.48 - 7.44 (dd, Jl = 2.4Hz, 52 = 12Hz, 1H), 7.37 - 7.33 (m, 1H), 7.16 - 7.1 1 (m, 2H), 6.85 - 6.80 (m, 2H), 6.66 - 6.64 (m, 1H), 6.56 - 6.48 (m, 5H), 4.35 (t, J = 6.4Hz, 2H), 3.83 (s, 3H), 3.72 (s, 3H), 3.43 (t, J = 6.4Hz, 2H), 1.42 (s, 6H). m/z Relative intensities = 577.1 (M)+ 100%. % Purity = 94.87% (By HPLC). IR KBr (cm 1): 3432, 31 13, 2969, 1599, 1510, 1277, 1 153, 1028.
Example 114
2-((2-(4-(lH-imidazoI-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan- 2-yl)-l-(4-fluorophenyl)-4-methyl-lH-imidazole
In a manner similar to that described for Example 13, the title compound was prepared from 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)-4-methyl- lH-imidazole-2 -thiol and l-(4-(2-bromoethoxy)phenyl)-lH-imidazole. Ή NMR (CDCI3, 400MHz): 7.76 (s, 1H), 7.30 - 7.26 (m, 3H), 7.19 (d, J = 7.6 Hz, 2H), 7.07 - 7.03 (m, 2H), 6.85 - 6.79 (m, 2H), 6.64 (d, J = 8 Hz, 1H), 6.57 - 6.52 (m, 2H), 6.50 - 6.46 (m, 2H), 4.26 (t, J = 6.4 Hz, 2H), 3.86 (s, 3H), 3.72 (s, 3H), 3.37 (t, J = 6.4 Hz, 2H), 2.49 (s, 3H), 1.53 (s, 6H). m/z Relative intensities = 573.1 (M)+ 100%. % Purity = 95.82% (By HPLC). IR KBr (cm-1): 3416, 1672, 1602, 1519.
Example 115
4-(3-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol- 2-yl)thio)ethoxy)phenyI)morpho!ine.
In a manner similar to that described for Example 13, the title compound was prepared from 5 -(2-(3,4-dimethoxypheny l)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazole-2-thiol and 4-(3-(2-bromoethoxy)phenyl)morpholine. Ή NMR (CDCI3, 400MHz): 7.17-7,12 (m, 2H), 6.81 (t, J = 8.4 Hz, 2H), 6.64 (d, J = 8.8 Hz, 1H), 6.53- 6.48 (m, 6H), 6.41-6.39 (dd, Jl = 8.0 Hz, J2 = 2.0 Hz, 1H), 4.22 (t, J = 6.4 Hz, 2H), 3.86-3.83 (m, 7H), 3.71 (s, 3H), 3.39 (t, J = 6.4 Hz, 2H), 3.16-3.13 (m, 4H), 1.48 (s, 6H). m/z Relative intensities = 578.3 (M+H)+ 100%. % Purity = 98.14% (By HPLC). IR KBr (cm 1): 3435, 2964, 2931, 2852, 1600, 1446, 1257, 1026, 842, 765.
Example 116 .
2-((2-(3-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(4-chloro-3- methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazole
In a manner similar to that described for Example 13, the title compound was prepared from 5 -(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)- 1H- imidazole-2-thiol and l-(3-(2-bromoethoxy)phenyl)-lH-imidazole. 1H NMR (CDC13, 400MHz): 7.95 (s, 1H), 7.38 - 7.33 (m, 2H), 7.23 (s, lH), 7.16 - 7.13 (m, 3H), 7.00 - 6.97 (dd, Jl = 2Hz, J2 = 8Hz, 1H), 6.91 - 6.88 (dd, Jl = 2Hz, J2 = 8Hz, 1H), 6.87 - 6.82 (m, 2H), 6.56 - 6.52 (m, 3H), 6.49 (d, J = 2Hz, 1H), 4.32 (t, J = 6.4Hz, 2H), 3.71 (s, 3H), 3.43 (t, J = 6.4Hz, 2H), 1.50 (s, 6H). m/z Relative intensities = 563.3 (M)+ 100%. % Purity = 92.61% (By HPLC).
Process for the preparation of intermediate used for the synthesis of above described compound of Formula I
Figure imgf000062_0001
Synthetic procedure
Step l
Charge sodium hydride (7.2 g, 300 mmol) to a three neck R.B.Flask (500 mL) capacity (equipped with Nitrogen gas inlet and CaCl2 guard tube) Cooled to 0°C in an ice-salt bath followed by addition of THF (80 mL). 3, 4-dimethoxy phenylacetonitrile (10.6 g, 60 mmol) was charged at 0°C and stirring was continued at 0°C for 30 min. Methyl iodide (18.8 mL, 180 mmol) was charged drop wise within 30 min and stirred at 0°C for additional 1.5h after completion of addition of methyl iodide. Reaction mixture was warmed to room temperature and stirred at room temperature for lh. Reaction mixture was quenched by ice and extracted with ethyl acetate. Organic extract was washed with water, saturated brine solution and dried over (Na2S04). Crude product was purified by column chromatography to provide the 2-(3,4- dimethoxyphenyl)-2-methylpropanenitrile (11.5 g, 93% yield).
Step 2
Charge 2-(3, 4-dimethoxyphenyl)-2-methylpropanenitrile (10 g, 49 mmol) dissolved in toluene (100 mL) to a three neck R.B.Flask (500mL) capacity (equipped with N2 gas inlet and CaCl2 guard tube) and cooled to -78 °C in (acetone dry ice bath). DIBAL (63 mL, 63 mmol) [1M solution in toluene] was added drop wise at -78 °C within 15 min. Reaction mixture was stirred at -78°C for 2h, after completion of addition of DIBAL. Monitor the completion of reaction by TLC. 6N HC1 (85 mL) was added drop wise at -78 °C. Reaction mixture was allowed to warm to room temperature and extracted with ethyl acetate. Organic extract was dried over (Na2S04). Distilled out solvent under reduced pressure to afford 2-(3,4-dimethoxyphenyl)-2-methylpropanal (9.5 g, 93 %).
Step 3
Charge 2-(3, 4-dimethoxyphenyl)-2-methylpropanal (10 g dissolved in diethyl ether, 48 mmol) [50 mL] to a three neck R.B.Flask (500mL) capacity (equipped with N2 gas inlet and CaCl2 guard tube) Cooled to 0 °C in an ice-salt bath. Methyl magnesium chloride (3M solution in THF, 14 mmol) [53.15 mL] was added drop wise under inert conditions at 0 °C Reaction mixture was warmed to room temperature and stirred at room temperature for lh. Add 3N HC1 (42 mL) at 0 °C warm slowly to rt and stir at rt for lh. Extract with ethyl), Organic extract was washed with water, saturated brine soln. and dried over (Na S04). Distilled out solvent under reduced pressure to afford yellowish oil. This was purified by column chromatography to afford 3-(3,4- dimethoxyphenyl)-3 -methylbutan-2-ol .
Step 4
Charge Oxalyl chloride (38.39 mL, 78 mmol) to a three neck R.B.Flask (500mL) capacity (equipped with N2 gas inlet and CaCl2 guard tube) add DCM (140mL). Cooled to -78 °C in an acetone dry ice bath. Dimethyl sulfoxide (12.98 mL, 153mmol ) was added drop wise within 30 min at -78 °C and stirring was continued at - 78 °C for 30 min.3-(3, 4-dimethoxyphenyl) -3-methylbutan-2-ol (8.6 g, 38 mmol) dissolved in DCM (40 mL) was charged drop wise within 15 min. Reaction mixture was allowed to stir at -78 °C for 30 min. Triethyl amine (32.1 mL, 230 mmol) was added drop wise within 10 min. at -78 °C Reaction mixture was warmed to room temperature and stirred at room temperature for 30 min. Reaction mixture was diluted with DCM and quenched with water. Organic phase was separated and washed with water, saturated brine solution and dried over (Na2S04). Distilled out solvent under reduced pressure to afford 3-(3,4-dimethoxyphenyl)-3-methylbutan-2-one (12 g crude material).
Step 5
Charge 3-(3, 4-dimethoxyphenyl) -3-methylbutan-2-one. (13.3 g, 60 mmol) dissolved in DCM (139 mL), to a three neck RJB.Flask (500mL) capacity (equipped CaCl2 guard tube) and cooled to 0 °C in (Ice bath), add methanol (68 mL). Tetra butyl ammonium tribromide (30.72 g, 63 mmol) was added. Reaction mixture was warmed to rt and stirred at rt for 7h. Reaction mixture was concentrated in vacuo to remove methanol from the reaction mixture, residue was dissolved in ethyl acetate. Organic phase was washed with water, dil HC1 saturated brine soln. and dried over (Na2S04). Distilled out solvent under reduced pressure to afford l-bromo-3-(3,4- dimethoxyphenyl)-3-methylbutan-2-one (18.1 g crude material), which was used for next reaction without any purification.
Step 6
Charge 3-(3, 4-dimethoxyphenyl) -3-methylbutan-2-one. (18.1 g, 60 mmol) and add DCM (108.6 mL), HMTA (9 g. 63 mmol) to a single neck RJB.Flask (500mL) capacity (equipped CaCl2 guard tube).Reaction mixture was stirred for 48h at room temperature. Dichloromethane was distilled out and residue was dissolved in ethanol (181 mL) and cooled in an ice bath to 0 °C. Concentrated hydrochloric acid (90 mL) was added slowly. Reaction mixture Was refluxed for 3h. Reaction mixture was diluted with ethyl acetate thus obtained white solid impurity was filtered through filter paper in vacuo and washed with ethyl acetate. Combined organic extract was concentrated in vacuo to afford l-amino-3-(3,4-dimethoxyphenyl)-3-methylbutan-2-one hydrochloride which was used for next reaction without any purification.
Step ? .
Charge l-amino-3-(3, 4-dimethoxyphenyl)-3-methylbutan-2-one hydrochloride salt. (14 g, 44 mmol) and add DCM (140 mL), to a three neck R.B.Flask (500 mL) capacity (equipped with nitrogen gas inlet and CaCl2 guard tube). Cool to 0 °C in an ice bath, add Triethyl amine (24 mL, 176 mmol) slowly. 4-fluorophenyl isothiocyanate (8.07 g, 53 mmol) was added. Reaction mixture was stirred at room temperature for lh. Reaction mixture was diluted with dichloromethane (100 mL) and washed with water saturated brine solution dried over sodium sulfate, filtered and organic extract was concentrated in vacuo to afford brown colored oil. (25g crude material).Crude oil (25 g) was mixed with dichloromethane (100 mL), stirred vigorously for 10 minutes, slowly add n-hexane (100 mL) under stirring. Off white solid product thus obtained was filtered through filter paper in vacuo and Washed with n-hexane (50 mL). Solid product was dried in vacuo to afford l-(3-(3,4-dimethoxyphenyl)-3-methyl-2-oxobutyl)-3-(4- fluorophenyl)thiourea (7.3 g, 42 %).
Step 8
Charge l-(3-(3, 4-dimethoxyphenyl)-3-methyl-2-oxobutyl)-3-(4-fluorophenyl) thiourea (7.3 g, 19 mmol) and add acetic acid (70 mL), to a three neck R.B.Flask (250 mL) capacity (equipped with condenser and CaCl2 guard tube).Reaction mixture was stirred and refluxed for 3h. Reaction mixture was cooled to room temperature and dumped in to ice, stir for 10 minutes. Off white solid material was filtered in vacuo through filter paper on Buchner funnel. Solid product was washed with n-hexane, followed by washing with di isopropyl ether. Solid product was dried in vacuo. White solid product was dried over P205 in vacuum desiccator to afford 5-(2-(3,4- dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazole-2-thiol (5.1 g) dry powder.
Biological studies; 1
In-vitro studies; hTGRS. Reporter Gene Assay: Chinese Hamster Ovarian (CHO) Kl cells were plated in 24 well tissue culture plate at a density of 4 X 104 cells/well in a Nutrient Mixture F-12 HAM containing 10 % Fetal Bovine Serum, cultured for 24 hrs at 37°C/5% C02, and then transfected with 50 ng of human (h) TGR5 expression plasmid (pCMV SPORT6 - hTGR5), 300 ng of cAMP-responsive element (CRE)-driven luciferase reporter plasmid (pCRE-Luc) and 100 ng of ^-galactosidase reporter vector in each well using Polyfect Transfection Reagent (QIAGEN, Cat. No: 301107) according to the manufacturer's instructions. After 4 hrs of incubation, cells were washed once with phosphate-buffered saline (PBS) and medium was exchanged to Nutrient Mixture F-12 HAM containing 0.5% Fatty acid free bovine serum albumin (FAFBSA) and ImM Sodium Pyruvate Solution. After incubation for another 18 hrs, cells were treated for 5 hrs with different concentrations of each compound. After treatment, the cells were lysed with 100 μΐ, of Glo Lysis buffer (Promega, Cat. No.: E2661) and subjected to Luciferase and S-Galactosidase assays as described below.
Luciferase and //-Galactosidase Assays.
For luciferase assays, 20 /*L of cell lysate was mixed with 100 ,uL of Luciferase Assay Substrate (Promega, Cat. No.: El 501) & Luminescence was measured in HIDEX Multitechnology Plate Reader. For galactosidase assays, 30 //L of cell lysate was mixed with 30y*L of 2X ONPG Buffer [20 mM sodium phosphate buffer - pH 7.3, 2 mM MgCl2, 100 mM β-mercaptoethanol, and 1.33 mg/mL o-nitrophenyl- ?-D- galactopyranoside (ONPG)] and incubated at 37°C for 2-10 mins. The optical density at 415 nm was determined in SpectraMax 190.
Normalized luciferase values were determined by dividing the luciferase activity by the galactosidase activity and expressed as fold induction with respect to (w.r.t.) DMSO control.
TGR5 Assay Results
In the following table, EC5o values determined according to the TGR5/CRE- Luciference Assay described herein (CRE-Luc). Table below display h-TGR5 CRE- Luc percentage activity of the compounds at 100 nM and ΙμΜ w.r.t. control (RG-239 at 1 μΜ) data. The following compounds in Table 1 were made by procedure described in above scheme and examples, and, where applicable, by making any necessary substituent of known material that one skilled in the art would ordinarily understand.
Figure imgf000067_0001
Figure imgf000068_0001
. In-vitro (h CRE Luciference
Example assay) ,
Number % Control wrt 1μΜ RG-239
100nM 1μΜ
88 95.24 115.88
89 93.43 116.83
90 84.84 85.11
91 121.17 102.70
94 100.07 92.86
95 132.09 123.64
96 129.35 139.84
97 123.88 122.73
98 85.28 88.02
100 116.27 117.38
101 99.94 113.48
102 94.71 85.13
104 106.59 96.56
107 103.48 141.03
109 142.01 127.43
110 129.52 140.93
Protocol for GLP-1 secretion activity in C57 mice Model
Male C57 mice of 8-12 week age, bred in Zydus research Centre Animal house will be used for this experiment. Animal will be issued and subjected for 3-7 days acclimatization. On first day animal will be grouped based on non fasting serum glucose levels and kept on fasting for overnight. On second day of the experiment, formulation of test compounds will be prepared and fasting body weight of animals will be recorded. Each animal will receive a single dose of vehicle/test compounds administered per orally as per specified group and dose levels. Exactly 15 min post dosing glucose load (3gm/kg/10ml) will be administered orally to all the groups. Then exactly after 10 min of glucose load animal will bled from retro orbital plexus. Blood collection will be done in micro centrifuge tube containing 30μ1 of 2% EDTA and 5μ1 of DPP-IV inhibitor. Blood samples immediately after collection will be centrifuged and plasma will be separated and analyzed for Total GLP-1 level using ELISA kit. The percent or fold change Vs Vehicle will be calculated to determine the total GLP-1 secretion activity for the test compound. Following table shows the total GLP-1 secretion activity for the selected test compound: Test Substance and Fold change Vs
Model Route
Dose (mg/kg) vehicle control
Example 1 1 C57-N Oral 2.03 0.39
Example 96 C57-N Oral 2.01 ± 0.23
Example 100 C57-N Oral 1.98 ±. 0.35
Example 102 C57-N Oral 2.24 ± 0.59
The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The compounds of Formula (I) or pharmaceutical compositions containing them are useful as antidiabetic and antiobesity compounds suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.
In certain instances, it may be appropriate to administer at least one of the compounds described herein or a pharmaceutically acceptable salt, ester, or prodrug thereof in combination with another therapeutic agent. Several reasons can be attributed for using a combination therapy depending on the need of the patient. As an example, if one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer an anti-hypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the benefit experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. Several such instances are well known to a skilled person and the use of combination therapy may be envisaged for all such situations. In any case, regardless of the disease, disorder or ondition being treated, the overall benefit experienced by the patient may simply be .additive of the two therapeutic agents or the patient may experience a synergistic benefit.
Specific, non-limiting examples of possible combination therapies include use of certain compounds disclosed herein with agents found in the following pharmacotherapeutic classifications as indicated below. These lists should not be construed to be closed, but should instead serve as illustrative examples common to the relevant therapeutic area at present. Moreover, combination regimens may include a variety of routes of administration and should include oral, intravenous, intraocular, subcutaneous, dermal, and inhaled topical.
For the treatment of metabolic disorders, compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, insulin derivatives and mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like peptide-1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-119 inhibitors, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type PPAR.delta. agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and anti-platelet agents and anti-obesity agents.
For the treatment of metabolic disorders, compounds disclosed herein may be administered with an agent selected from the group comprising: insulin, metformin, Glipizide, glyburide, Amaryl, gliclazide, meglitinides, nateglinide, repaglinide, amylin mimetics (for example, pramlintide), acarbose, miglitol, voglibose, Exendin-4, , vildagliptin, Liraglutide, . naliglutide, saxagliptin, pioglitazone, rosiglitazone, HMG- CoA reductase inhibitors (for example, rosuvastatin, atrovastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin, rosuvastatin, pravastatin and like), cholesterol-lowering drugs (for example, fibrates which include: fenofibrate, benzafibrate, clofibrate, gemfibrozil and like; cholesterol absorption inhibitors such as Ezetimibe, eflucimibe etc.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions. Such different embodiments are also to be considered to be within the scope of the present invention.

Claims

We claim:
1. A compound of Formula I, including their pharmaceutically acceptable salts, their enantiomers, their diastereomers, and pharmaceutical compositions containing them
Figure imgf000072_0001
Formula I
wherein,
Y is S, -S(O)-, -S(0)2-;
n is 0,1, 2, 3 or 4;
m is 0, 1, or 2;
R1 is selected from aryl, heteroaryl, heterocyclyl or aryl(Ci-Ce)alkyl, wherein said aryl, heteroaryl, heterocyclyl or aryl(CrC6)alkyl is optionally substituted with one, two, or three RIa groups, wherein RIa at each occurrence independently represents halogen, Ci-C4alkyl, CrQ haloalkyl, C3-C8cycloalkyl, heteroaryl, heterocyclyl, the group representing -Rlb, -Ci-C4 alkyl-Rlb, or -OCj- C4 alkyl-Rlb wherein
Rlb at each occurrence independently represents cyano, nitro, -N(Rlc)2, -ORlc, - SRlc, -C(0)R,c, -C(0)OR,c, -C(0)N(R!C)2, -S(0)N(R,c)2, -S(0)2N(R,c)2, or - S(0)2Rlc, -OC(0)R,c, -OC(0)ORlc, -OC(0)N(Rlc)2, -N(Rlc)C(0)Rlc, - N(Rlc)C(0)ORlc, -N(Rlc)C(0)N(Rlc)2, or -N(Rlc)C(=NRIc)N(RIC)2, wherein each Rlc is independently hydrogen, C]-C4alkyl, or Ci-C4 haloalkyl; R2 is selected from -Z - Rz, wherein Z is -C(RY)2-, -C(H)(OH)-, -N(RY)-, -0-, - C(RY)20-, -S-, -S(O)-, -S(0)2-, -C(O)- wherein RY at each occurrence independently represents hydrogen, Ci-C4haloalkyl, Ci-C4alkyl, or hydroxy(Ci- C4)alkyl groups; and Rz is aryl or heteroaryl, heterocyclyl wherein said aryl or heteroaryl or heterocyclyl groups is optionally substituted with one, two, or three RZI groups,
wherein R at each occurrence is cyano, halogen, nitro, -R ' -N(R ¾, -O
Rz,b, -S Rzlb, -C(O) Rzl , -C(0)0 Rz,b, -C(0)N(Rzl )2, -S(0)N(Rzlb)2, - S(0)2N(Rzlb)2, or -S(0)2 RZIb, -OC(0) Rzib, -OC(0)0 Rzl , -OC(0)N(Rzlb)2, - N(Ric)C(0) Rzlb, -N(Rzlb)C(0)0 Rzlb, -N(Rzlb)C(0)N(Rz,b)2, or - N(Rzlb)C(=N Rzlb)N(R Ib)2, wherein at each occurrence RZIb is independently hydrogen, Ci-C4alkyl, or Ci-C-Jialoalkyl groups;
R3 is
(i) aryl, heteroaryl, or aryl(Ci-C2)alkyl, wherein said aryl, heteroaryl, or aryl(Ci-C2)alkyl is optionally substituted with one, two, or three R3a groups, wherein R3a at each occurrence independently represents hydrogen, halogen, cyano, nitro, Ci-C4alkyl, C1-C4 haloalkyl, acyl, optionally substituted C3- Cgcycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the group representing -R3b, -Ci-C4alkyl- R3b, or -OC1-C4 alkyl; wherein the substituted group on C3-C8cycloalkyl, aryl, heteroaryl or heterocyclyl are selected from hydrogen, nitro, cyano, halogen, acyl, Ci-C4alkyl, aryl, or heteroaryl;
wherein, R3b at each occurrence is independently selected from cyano, nitro, - N(R3c)2, -OR3c, -SRlc, -C(0)R3c, -C(0)OR3c, -C(0)N(R3c)2, -C(0)N(R3c)-N[(C C3)alkyl]3 +, -S(0)N(R3c)2, -S(0)2N(R3c)2, or -S(0)2R3c,- (R3c)-N-S(0)2-R3c, - S(0)2N(R3c)-N[(C C3)alkyl]3 +, -OC(0)R3c, -OC(0)OR3c, -OC(0)N(R3c)2, - N(R3c)C(0)R3c, -N(R3c)C(0)OR3c, -N(R3c)C(0)N(R3c)2, or N(R3c)C(=NR3c)N(R3c)2, wherein R3c at each occurrence is independently selected from hydrogen, Ci-C4alkyl, C1-C4 haloalkyl, cycloalkyl, heteroaryl, aryl heterocyclyl, -C(0)OR3d or -N(R3d)C(=NR3d)N(R3d)2 groups, wherein R3d at each occurrence is independently selected from Ci-C4alkyl, or C1-C4 haloalkyl groups; or,
(ii) CrQalkyl, -C C4alkyl-N(R3d)2, -Q-Qalkyl-OR3", -Q-C4alkyl-SR3d , C3-C8 cycloalkyl, or heterocyclyl groups, wherein the cycloalkyl, and heterocyclyl groups are each optionally substituted with 1 to 6 groups which are each independently selected from -R3e or -C]-C4alkyl-R3e,
wherein R3e at each occurrence is independently selected from cyano, nitro, - N(R3f)2, -OR3f, -SR3f, -C(0)R3f, -C(0)OR3f, -C(0)N(R3f)2, -C(0)N(R3f)-N[(d- C3)alkyl]3 +, -S(0)N(R3f)2, -S(0)2N(R3f)2, -S(0)2N(R3f)-N[(C,-C3)alkyl]3 +, - S(0)2R3f, -OC(0)R3f, -OC(0)OR3f, -OC(0)N(R3f)2, -N(R2c)C(0)R3f, - N(R2c)C(0)OR3f, -N(R3f)C(0)N(R3f)2, or -N(R3f)C(=NR3f)N(R3f)2, wherein R3f at each occurrence is independently represent hydrogen, Ci-C4alkyl, or C\- C4haloalkyl groups;
R4 is selected from hydrogen, nitro, cyano, halogen, acyl, Ci-C4alkyl, Q-C4 haloalkyl, aryl, or heteroaryl heterocyclyl, or -N(R4a)2 groups; wherein R4a at each occurrence is independently is selected from hydrogen, acyl, Ci-C4alkyl or -S(0)2R4b group; wherein R4b at. each occurrence is selected from amino, acyl or C C4alkyl groups;
R5 and R6 each independently represents hydrogen, Ci-C4alkyl or alternatively, R5 and R6 together with carbon atom to which they are attached form a 3-7 membered ring, optionally comprising 1 or 2 hetroatom selected from O, N and S.
The compound as claimed in claim 1, wherein R1 is selected from optionally substituted aryl group.
The compound as claimed in claim 2, wherein the substitution on the aryl group is selected from halogen or Ci-C4alkyl.
The compound as claimed in claim 1, wherein R2 is selected from -Z-Rz, wherein Z is -C(RY)2-, wherein RY at each occurrence independently represents hydrogen, C]-C4alkyl; and Rz is aryl wherein said aryl is optionally substituted with one, two, or three RZ1 groups independently selected from cyano, halogen or -O Rzlb, wherein Rzl is independently selected from hydrogen or Cr C4alkyl.
The compound as claimed in claim 1, wherein R3 is aryl, heteroaryl, or aryl(C)- C2)alkyl, wherein said aryl, heteroaryl, or aryl(Ci-C2)alkyl is optionally substituted with one, two, or three R3a groups, wherein R3a at each occurrence independently represents hydrogen, halogen, cyano, nitro, Ci-C4alkyl, C1-C4 haloalkyl, acyl, optionally substituted C3-C8cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, the group representing -R3b, -Ci-C4alkyl-R3b, or -OC C4 alkyl; wherein, R3b at each occurrence is independently selected from cyano, nitro, -N(R3c)2, -OR3c, - SR,C, -C(0)R3c, -C(0)OR3c, -C(0)N(R3c)2, -C(0)N(R3c)-N[(Ci-C3)alkyl]3 +, - S(0)N(R3c)2, -S(0)2N(R3c)2, or -S(0)2R3c,- (R3c)-N-S(0)2-R3c, -S(0)2N(R3c)- N[(Ci-C3)alkyl]3 +, -OC(0)R3c, -OC(0)OR3c, -OC(0)N(R3c)2, -N(R3c)C(0)R3c, - N(R3c)C(0)OR3c, -N(R3c)C(0)N(R3c)2, or -N(R3c)C(=NR3c)N(R3c)2, wherein R3c at each occurrence independently selected from hydrogen, C1-C4alkyl, C1-C4 haloalkyl, cycloalkyl, heteroaryl, aryl heterocyclyl, -C(0)OR3d or N(R3d)C(=NR3d)N(R3d)2 groups, wherein R3d at each occurrence is independently selected from hydrogen, Ci-C4alkyl, or d-C4 haloalkyl groups.
6. The compound as claimed in claim 5, wherein the substituents on C3- Cgcycloalkyl, aryl, heteroaryl or heterocyclyl groups are selected from hydrogen, nitro, cyano, halogen, acyl, Ci-C4alkyl, aryl, or heteroaryl.
7. The compound as claimed in claim 1, wherein R3 is selected from C1-C4alkyl, - Ci-C4alkyl-OR3d, wherein R3d at each occurrence is independently selected from hydrogen, C]-C4alkyl, or C1-C4 haloalkyl groups.
8. The compounds of Formula I are selected from
2-((2-((2-chloro-6-fluorobenzyl)oxy)ethyl)thio)-5-(2-(3,4- dichlorophenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole.
2-((2-((2-chloro-6-fluorobenzyl)oxy)ethyl)thio)-5-(2-(3,4- dimethoxypheny l)propan-2-yl)- 1 -(4-fluorophenyl)- lH-imidazole
4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio) ethoxy) methyl)benzonitrile
4- ((2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol- 2-yl)thio) ethoxy) methyl)benzonitrile
2-((2-((2,6-difluorobenzyl)oxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-
2- yl)-l-(4-fluoro phenyl)- 1 H-imidazole
3- ((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy )methyl)benzonitrile
2-((2-((3-chlorobenzyl)oxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2- yl)- 1 -(4-fluoro phenyl)- 1 H-imidazole
5- (2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-((3- fluorobenzyl)oxy)ethyl)thio)- 1 -(4-fluoro phenyl)- 1 H-imidazole
4- ((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio) ethoxy)methyl)-3,5-dimethylisoxazole
2-((3-((2-chloro-6-fluorobenzyl)oxy)propyl)thio)-5-(2-(3,4- dichlorophenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole
5- (2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2- ((tetrahydrofuran-3-yl) methoxy)ethyl)thio)- 1 H-imidazole N-(4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)methyl)benzyl)methanesulfonamide
2-((2-(2-chloro-5-methylphenoxy)ethyl)thio)-5-(2-(3,4-dichlorophenyl)propan- 2-yl)- 1 -(4-fluoro phenyl)- 1 H-imidazole
5-(2-(3,4-dichlorophenyl)propan-2-yl)-2-((2-(2,6-difluorophenoxy)ethyl)thio)-
1 - (4-fluoro phenyl)- 1 H-imidazole
2- ((2-(4-( 1 H-imidazol-l -yl)phenoxy)ethyl)thio)-5-(2-(3,4- dichlorophenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole
4- (2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol- 2-yl)thio) ethoxy) benzonitrile
5- (2-(3,4-dichlorophenyl)propan-2-yl)-2-((2-(3,4- dimethoxyphenoxy)ethyl)thio)-l -(4-fluoro phenyl)-lH-imidazole
2-((2-(4-(lH-pyrrol-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole
2- ((2-(4-(lH-imidazol-l-yl)phehoxy)ethyl)thio)-5-(2-(3 4- dimethoxyphenyl)propan-2-yl)-l -(4-fluorophenyl)- 1 H-imidazole.
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(thiophen-
3- yl)phenoxy) ethyl)thio)-lH-imidazole.
2-((2-(2,6-difluorophenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2- yl)- 1 -(4-fluoro phenyl)- 1 H-imidazole.
2- ((2-(3,4-dimethoxyphenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2- yl)- 1 -(4-fluoro phenyl)- 1 H-imidazole
4- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)benzonitrile.
methyl 4-(2-((5 -(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethoxy)benzoate.
3- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)pyridine.
N-cyclopropyl-4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4- fluorophenyl)- 1 H-imidazol-2-yl)thio)ethoxy)benzamide.
N-(4-(2-((5-(2-(3, 4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio) ethoxy)phenyl)acetamide. N-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl) thio) ethoxy)phenyl)methanesulfonamide.
3-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio) ethoxy)benzonitrile
3-chloro-4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)- lH-imidazol-2-yl) thio)ethoxy)-5-fluorobenzaldehyde.
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(4- methyl- 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)-l H-imidazole.
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2- methy 1- 1 H-imidazol- 1 -y l)phenoxy)ethyl)thio)- 1 H-imidazole.
1 -(4-(2-((5-(2-(3 ,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio) ethoxy)phenyl)- lH-l,2,4-triazole.
2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-l-(4-fluorophenyl)-5-(2-(3- methoxypheny 1) propan-2-yl)- 1 H-imidazole.
1- (2,4-difluorophenyl)-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(4-(2- methyl-1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)-l H-imidazole.
1 -(4-(2-((5-(2-(3 ,4-dimethoxyphenyl)propan-2-y 1)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio) ethoxy)phenyl)-lH-pyrazole.
1 -(4-(2-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl) thio)ethoxy)phenyl)-lH-pyrazole.
5-(2-(3 ,4-dimethoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-( 1 H-imidazol- 1 - yl)phenoxy) ethyl) thio)- 1 -(4-fluorophenyl)- 1 H-imidazole.
5-(2-(3 ,4-dimethoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-(2-methyl- 1 H- imidazol- 1 -yl)phenoxy) ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole.
5-(2-(3 ,4-dimethoxyphenyl)propan-2-yI)-2-((2-(3-fluoro-4-(2-methyl- 1 H- imidazol- 1 -yl)phenoxy) ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole.
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(3-fluoro-4-(2-methyl-lH- imidazol- 1 -yl)phenoxy) ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole
5-(2-(4-fluoro-3 -methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)-2-((2-(4-(2- methyl- 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)-l H-imidazole.
2- ((2-(4-(lH-imidazol-l -yl)phenoxy)ethyl)thio)-5-(2-(4-fluoro-3- methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole. 13/054338
1- (4-(2-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethoxy)phenyl)-lH-pyrazole.
2- ((2-(4-( 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)-4-bromo-5-(2-(3,4- dimethoxyphenyl) propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole.
4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-( 1 H- imidazol- 1 -yl) phenoxy) ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole.
4- bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)-2-((2-(4- (2 -methyl- 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole.
3- (2-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio) ethoxy)phenyl)-lH-pyrazole.
2- ((2-(4-( 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)-5-(2-(4-chloro-3- methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole
5- (2-(4-chloro-3-methoxyphenyl)propan-2-yl)-2-((2-(3,4- dimethoxyphenoxy)ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole
5-(2-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio)ethoxy)- 1 H-indole
3- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio) ethoxy)-N,N-dimethylaniline
2-((2-(2-chloro-5-methylphenoxy)ethyl)thio)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole
4- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)-N,N-dimethylaniline
2-fluoro-5-(2-( 1 -(4-fluorophenyl)-2-((2-(4-(2-methyl- 1 H-imidazol- 1 - yl)phenoxy)ethyl)thio)-lH-imidazol-5-yl)propan-2-yl)benzonitrile
5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2- methyl- 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole.
5- (2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(4- methyl- 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole.
2-((l-(4-(lH-imidazol-l-yl)phenoxy)-2-methylpropan-2-yl)thio)-5-(2-(3,4- dimethoxyphenyl) propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((l-((4-(2- methyl- 1 H-imidazol- 1 -yl)phenoxy)methyl)cyclobutyl)thio)- 1 H-imidazole. 013/054338
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((l-((2-fluoro-4-(lH-imidazol-l- yl)phenoxy) methyl)cyclobutyl)thio)-l-(4-fluorophenyl)-lH-imidazole.
4-(3-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio) propoxy)benzonitrile.
2-(((benzyloxy)methyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4- fluorophenyl)- 1 H-imidazole
2-(((4-(lH-imidazol-l-yl)phenoxy)methyl)thio)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole
4- (((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazoi-2- yl)thio) methoxy) benzonitrile
5- (2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(2- methoxyethoxy) ethyl)thio) -1 H-imidazole
4- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)-N-(pyridin-4-ylmethyl)benzamide.
5- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)- 1 H-indole.
N-(4-(2-((5 -(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio) ethoxy)-2-fluorophenyl)methanesulfonamide.
5-(4-(2-((5-(2-(3>4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)phenyl)-2-methoxypyridine.
4- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)quinazoline.
2-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)benzo[d]thiazole.
l-(4-(2-((4-bromo-5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)- 1 H-imidazol-2-yl)thio)ethoxy)phenyl)- 1 H-pyrazole .
5- (2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(3-(2- methyl- 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole.
5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-(2-methyI-lH- imidazol- 1 -yl) phenoxy)ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole.
l-(4-.(2-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl) thio)ethoxy)phenyl)-lH-l,2,4-triazole 5-(2-(4-fluoro-3 -methoxyphenyl)propan-2-yI)-2-((2-(3-fluoro-4-(2 -methyl- 1H- imidazol- 1 -yl) phenoxy)ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole.
5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4- (thiophen-3-yl) phenoxy)ethyl)thio)-l H-imidazole.
5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(3-(2- methyl- 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole .
2-((2-(4-( 1 H-imidazol-1 -yl)phenoxy)ethyl)thio 1 -(4-fluorophenyl)-5-(2- phenylpropan-2-yl)- 1 H-imidazole.
5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-(lH-imidazol- l-yl)phenoxy) ethyl)thio)-l-(4-fluorophenyl)-lH-imidazole.
5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-2-((2-(2-fluoro-4-(2-methyl-lH- imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole.
5-(2-((5-(2-'(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio) ethoxy)-lH-indazole.
5-(2-(2-((2-(4-( 1 H-pyrazol- 1 -yl)phenoxy)ethyl)thio)- 1 -(4-fluorophenyl)- 1 H- imidazol-5-yl) propan-2-yl)-2-fluorobenzonitrile.
5-(2-(3 ,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)-2-((2-rnethyl- 1 -(4- (2-methyl- 1 H-imidazol-1 -yl)phenoxy)propan-2-y l)thio)- 1 H-imidazole.
5- (2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((l-(2-fluoro-4-(lH-imidazol-l- yl)phenoxy)-2-methylpropan-2-yl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole. l-(4-fluorophenyl)-5-(2-(3-methoxyphenyl)propan-2-yl)-2-((2-(4-(2-methyl- 1 H-imidazol-1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole.
6- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)-2H-chromen-2-one.
5-(2-(2-((2-(4-( 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 -(4-fluorophenyl)- 1H- imidazol-5-yl) propan-2-yl)-2-fluorobenzonitrile.
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2- phenoxyethyl)thio)- 1 H-imidazole.
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(2- methoxyethoxy) ethyl)thio)-l H-imidazole.
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2- methoxyethyl)thio)- 1 H-imidazole 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2- methyl- lH-imidazol - 1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole-4-carbonitrile. 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-2-((2-(3-fluoro-4-(2-methyl-lH- imidazol- 1 -yl) phenoxy) ethyl)thio)- 1 -(4-fluorophenyl)- 1 H-imidazole-4- carbonitrile.
5-(2-(benzo[d][ 1 ,3]dioxol-5-yl)propan-2-yl)- 1 -(4-fluorophenyl)-2-((2-(4-(2- methyl-lH-imidazol-l-yl)phenoxy)ethyl)thio)-lH-imidazole.
(S)-methyl 2-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4- fluorophenyl)- 1 H-imidazol-2-yl)thio)ethoxy)benzamido)-5- guanidinopentanoate.
(S)-2-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethoxy)benzamido)-5-guanidinopentanoic acid.
2-(4-(2-((5-(2-(3,4-dimethOxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio) ethoxy)benzamido)-N,N,N-trimethylethanaminium chloride. 4-(2-(2-((2-(4-( 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 -(4-fluorophenyl)- 1 H- imidazol-5-yl) propan-2-yl)benzene- 1 ,2-diol.
4-((2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazol- 2-yl)sulfinyl) ethoxy)methyl)benzonitrile
2-((2-((2,6-difluorobenzyl)oxy)ethyl)sulfinyl)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazole
2-((2-(4-(lH-pyrrol-l-yl)phenoxy)ethyl)sulfmyl)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole.
2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)sulfinyl)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH-imidazole.
4- (2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl) sulfinyl) ethoxy)benzonitrile.
5- (2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-2-((2-(4-(2- methyl-1 H-imidazol- 1 -yl)phenoxy)ethyl)sulfinyl)- 1 H-imidazole.
4-((2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazol- 2-yl)sulfonyl) ethoxy)methyl)benzonitrile
4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl) sulfonyl) ethoxy)methyl)benzonitrile 2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)sulfonyl)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole.
5-(4-((2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)methyl)phenyl)-lH-tetrazole
5-(4-((2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl) thio) ethoxy)methyl)phenyl)-lH-tetrazole
5-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio) ethoxy)phenyl)-lH-tetrazole.
5-(4-(2-((5-(2-(3,4-dichlorophenyl)propan-2-yl)-l-(4-fluorophenyl)-lH- imidazol-2-yl)thio) ethoxy)phenyl)-lH-tetrazole
5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-l-(4-fluorophenyl)-4-methyl-2-((2-(4-
(2 -methyl- 1 H-imidazol- 1 -yl)phenoxy)ethyl)thio)- 1 H-imidazole
1 -(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethoxy)-3-fluorophenyl)- 1 H-pyrazole
2-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4- dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)-4-methyl- 1 H-imidazole
4-(3-(2-((5-(2-(3 ,4-dimethoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H- imidazol-2-yl)thio)ethoxy)phenyl)morpholine
2-((2-(3-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(4-chloro-3- methoxyphenyl)propan-2-yl)- 1 -(4-fluorophenyl)- 1 H-imidazole
9. The compounds of formula (I) or their pharmaceutical compositions for the treatment of diabetes and associated disorders.
10. Use of the compounds of formula (I) or their pharmaceutical compositions for the treatment of diabetes or its associated disorders.
11. A method of treating disorders caused by metabolic disorder comprising administering to a patient in need thereof an effective amount of a compound of formula (I) according to any of the preceding claims or its pharmaceutical composition according to any of the preceding claims.
12. A pharmaceutical composition comprising a therapeutically effective amount of formula (I) or salt thereof along with one or more additional therapeutically active compounds for the treatment of metabolic disorders.
13. The pharmaceutical composition as claimed in claim 12, wherein one or more additional therapeutically active compounds for the treatment of metabolic disorders are selected from insulin, insulin derivatives or mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like peptide- 1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-119 inhibitors, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type PPAR delta agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and anti-platelet agents or anti-obesity agents.
14. The pharmaceutical composition as claimed in claim 12, wherein therapeutically effective amount of formula (I) is combine with agents selected from insulin, metformin, Glipizide, glyburide, amaryl, gliclazide, meglitinides, nateglinide, repaglinide, amylin mimetics wherein amylin mimetics is selected from pramlintide; acarbose, "miglitol, voglibose, Exendin-4, vildagliptin, Liraglutide, naliglutide, saxagliptin, pioglitazone, rosiglitazone, HMG-CoA reductase inhibitors, wherein HMG-CoA reductase inhibitors are selected from rosuvastatin, atrovastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin; cholesterol-lowering drugs wherein cholesterol-lowering drugs are selected from fenofibrate, benzafibrate, clofibrate, gemfibrozil; cholesterol absorption inhibitors wherein cholesterol absorption inhibitors are selected from ezetimibe, eflucimibe or suitable mixture thereof.
15. Use of the compounds of formula (I) or their pharmaceutical compositions along with additional therapeutically active compounds as claimed in claim 12, 13 and 14 for the treatment of metabolic disorders.
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