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WO2015028960A1 - Substituted heterocyclic derivatives as gpr agonists and uses thereof - Google Patents

Substituted heterocyclic derivatives as gpr agonists and uses thereof Download PDF

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WO2015028960A1
WO2015028960A1 PCT/IB2014/064110 IB2014064110W WO2015028960A1 WO 2015028960 A1 WO2015028960 A1 WO 2015028960A1 IB 2014064110 W IB2014064110 W IB 2014064110W WO 2015028960 A1 WO2015028960 A1 WO 2015028960A1
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alkyl
oxetan
phenyl
ethyl
acetate
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Rajiv Sharma
Somnath HALDER
Sanjay Kumar
Malcolm Mascarenhas
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Piramal Enterprises Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
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    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/02—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D305/04—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D305/06—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the present invention generally relates to substituted heterocyclic derivatives (the compounds of Formula (I)), processes for their preparation, pharmaceutical compositions containing said compounds, their use as G-protein coupled receptor (GPR) agonists, particularly as GPR40 agonists and methods of using these compounds in the treatment of GPR40 mediated diseases or conditions such as Type 2 diabetes, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.
  • GPR G-protein coupled receptor
  • Obesity is a major health problem throughout the world. It is a risk factor for developing insulin resistance, type 2 diabetes, hypertension, and cardiovascular diseases (Circulation, 2003, 107:1448-1453). Obesity is typically associated with elevated levels of free fatty acids (FFAs) and is linked to glucose intolerance and type 2 diabetes (Cell Metab., 2005, l(4):245-58).
  • FFAs free fatty acids
  • Type 2 diabetes accounts for 90-95% of all diabetes. Complex networks of signaling pathways are activated when the insulin receptor is stimulated, but in patients who suffer from type 2 diabetes, those receptors on cells in tissues such as muscle, fat and liver become less responsive or resistant to insulin. In addition, patients with type 2 diabetes are typically characterized by reduced glucose stimulated insulin secretion (GSIS) (Expert Opin. Ther. Patents, 2009, 19(2): 237-264).
  • GSIS glucose stimulated insulin secretion
  • Metabolic syndrome also known as Syndrome-X, is characterized by a cluster of conditions, including insulin resistance, obesity, hypertension and dyslipidemia. Persistent obesity disregulates metabolic processes including action of insulin on glucose-lipid-free fatty acid metabolism and severely affects processes controlling blood glucose, blood pressure, and lipids. It is also well recognized that people with obesity and metabolic syndrome are at an increased risk of developing type 2 diabetes and cardiovascular diseases. Prevalence of obesity and metabolic syndrome has shown a rapid rise in developing countries in the past few decades and has led to increased risk of cardiovascular diseases and consequent morbidity and mortality (JRAAS, 2006, 7(1):S12-S18; J. Clin. Endocrinol. Metab., 2008, 93(11):S9-S30).
  • G-protein coupled receptor 40 G- protein coupled receptor 40
  • G-protein coupled receptors constitute a super family of membrane proteins activated by a variety of endogenous ligands such as hormones, neurotransmitters, peptides, proteins, steroids as wells as fatty acids (FAs) and other lipids (Diabetes Obes. Metab., 2009, 11(4): 1-18). Impaired GSIS are a prominent feature of overt type 2 diabetes and FFAs are known to influence insulin secretion from ⁇ -cells primarily by enhancing GSIS.
  • G-protein coupled receptors such as GPR40, whose endogenous ligands are medium and long chain free fatty acids, are known to play an important role in insulin release.
  • the G-protein coupled receptor, GPR40 is G a q-coupled Class 1 GPCR and a member of a small family of fatty acid sensing GPCRs.
  • GPR40 is preferentially expressed in ⁇ -cells and is activated by medium to long chain FFAs, thereby triggering a signaling cascade that results in increased levels of [Ca 2+ ] in ⁇ -cell lines (Diabetes, 2008, 57:2280-87 and Bioorganic & Medicinal Chemistry Letters, 2012, 22:1267- 1270).
  • mice Studies conducted in animals (mice) further established that loss of GPR40 protects mice from obesity induced hyperglycemia, glucose intolerance, hyperinsulinemia, fatty liver development, hepatic glucose output and hypertriglyceridemia (Diabetes, 2008, 57:2280-87).
  • PCT published application WO2005086661A2 discloses compounds capable of modulating the G-protein coupled receptor GPR40, compositions comprising the compounds and methods for their use in controlling insulin levels in vivo and for the treatment of conditions such as type 2 diabetes, hypertension, ketoacidosis, obesity, glucose intolerance and hypercholesterolemia and related disorders associated with abnormally high or low plasma lipoprotein, triglyceride or glucose levels.
  • PCT published application WO200801931A1 discloses fused cyclic compounds which are useful as insulin secretagogues or agents for the prophylaxis or treatment of diabetes and related disorders.
  • PCT published applications WO2009111056 Al and WO2010045258 A2 disclose spirocyclic compounds which act as GPR40 modulators, compositions comprising the compounds and methods for their use in the treatment or prevention of metabolic disorders, especially type 2 diabetes, obesity and related disorders.
  • PCT published application WO2010123016A1 disclose carboxylic acid compounds which have GPR40 agonist activity and are useful as prophylactic and therapeutic agent for diabetes.
  • PCT published application W0199965881 disclose heterocylic compounds as hypoglycemic agents.
  • WO2012011125A1 discloses compounds that have the ability to modulate the activity of GPR40, compositions comprising these compounds and their use in the treatment of disorders related to GPR40 activity, especially metabolic conditions, such as diabetes, obesity, hyperglycemia, insulin resistance, hypercholesteremia and related disorders.
  • the present invention relates to a compound of Formula (I) (as described herein), an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S- oxide, or a carboxylic acid isostere thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; and at least one pharmaceutically acceptable carrier or excipient.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; and one further therapeutically active agent and at least one pharmaceutically acceptable carrier or excipient.
  • the present invention relates to a method for modulating GPR40 function in a cell comprising contacting the cell with an effective amount of compound of Formula (I).
  • the present invention provides a compound of Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; for use in the treatment or prophylaxis of a disease or a condition mediated by GPR40.
  • the present invention provides a method for the treatment or prophylaxis of a disease or a condition mediated by GPR40, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
  • the present invention relates to use of the compound of Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof in the manufacture of a medicament, for the treatment or prophylaxis of a disease or a condition mediated by GPR40.
  • the present invention relates to use of the compound of Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; in combination with one further therapeutically active agent for the treatment or prophylaxis of a disease or a condition mediated by GPR40.
  • Rj is hydrogen or (Ci-Ce)alkyl
  • R2 and R3 together form a saturated or a partially unsaturated 3- to 6- membered heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
  • R 4 at each occurrence is independently selected from the group consisting of hydrogen, (Q- Ce)alkyl, halogen, hydroxy, amino, cyano, nitro, -C(0)R7 and -S(0) p R 6 ;
  • R x and R y are independently selected from the group consisting of A-Li-X- and R5 ; provided that at least one of R x and R y is A-Lj-X-;
  • R5 is hydrogen, (Ci-C 6 ) alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-C6)alkyl, (C 6 - Cio)aryl, amino, cyano, nitro, -C(0)R ? or -S(0) p R6;
  • R6 is hydrogen, (Ci-Ce)alkyl or amino
  • X is -0-, -(CH 2 ) n O-, -(CH 2 ) p (CR 8 R9)nCH 2 0-, -(CH 2 ) p (C 6 -C 10 aryl) k CH 2 O- or -(CR'R") P 0-; Li is absent or is selected from the group consisting of -0-, -S(0) p -, -C(0)NH-,
  • R 7 is (d-Ce) alkyl, -0(d-C6)alkyl, -O(C 1 -C 6 )alkyl(C 6 -C 10 )aryl, hydroxy or amino;
  • Rio is hydrogen, (Ci-Ce)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci- Ce)alkoxy, -S(0) P R6, amino, cyano, nitro or -C(0)R7; wherein R6 and R 7 are as defined above;
  • k is an integer 1 or 2;
  • n is an integer from 1 to 3;
  • n is an integer from 1 to 4.
  • p is an integer from 0 to 2;
  • s is an integer from 1 to 4.
  • (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (C6-Cio)aryl, heterocyclyl, - heterocyclyl-(Ci-C6)alkyl-OH, heteroaryl, amino, cyano, nitro, -C(0)R 7 , -S(0) P R6, and - 0(Ci-C6)alkyl-S(0) p R6; wherein R6, R7, and p are as defined above;
  • -0(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, (C3-Cg)cycloalkyl, (C 6 - Cio)aryl, heterocyclyl, hydroxy, halogen, amino, cyano, (Ci-C6)alkyl-S(0) p R6, -S(0) P R6, - NR8R and -(CH2) s NRgR ; wherein R6, Rs, R9, p and s are as defined above;
  • (C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, halo(Ci- C 6 )alkoxy, -OCH 2 -(CR'R") p -(C 1 -C 6 )alkyl and -0(C 1 -C 6 )alkyl(C 6 -C 1 o)aryl, wherein R ⁇ R" and p are as defined above;
  • (C6-Cjo)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, haloCd-Q alkyl, hydroxy, -0(C C 6 )alkyl, -O(C C 6 )alkyl(C 6 -C 10 )aryl, halo(C C 6 ) alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R 7 , -OCH 2 -(CR'R") p -(C 1 -C 6 )alkyl and -0(Ci-C 6 )
  • heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 - C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(d-C 6 ) alkyl, hydroxy, -(XCi-C 6 )alkyl, halo(C C 6 ) alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (Q- C 6 )alkyl-OH, (C 1 -C 6 )alkyl-0-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 6 -C 1 o)aryl, -C(0)R 7 , S(0) p R 6 and -
  • heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 - C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(C !
  • halogen is chlorine, bromine, iodine or fluorine; provided that (i) when X is -(CH 2 ) n O- and n is 1, A is not (C3-C 10 ) cycloalkyl, (Ce-Cio)aryl, heterocyclyl or heteroaryl;
  • substitution means that one or more hydrogens of the specified moiety are replaced with a suitable substituent and includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound.
  • (Ci-C6)alkyl or "alkyl”, as used herein, alone or as part of a substitutent group refers to an aliphatic group, including straight or branched chain alkyl group.
  • a straight-chain or branched chain alkyl has six or fewer carbon atoms in its backbone, for instance, Ci-C 6 for straight- chain and C3-C6 for branched chain.
  • Suitable alkyl groups containing from one to six carbon atoms include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, 1- methylbutyl, secondary butyl, tertiary pentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl or 3-methylpentyl.
  • the alkyl groups may be unsubstituted or substituted with one or more substituents, for instance, from one to five substituents independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cg)alkenyl, (C 2 -Cg) alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -O(Ci-Ce) alkyl, (C3-Cg)cycloalkyl, (C 6 - Cio)aryl, heterocyclyl, -heterocyclyl-(Ci-C6)alkyl-OH, heteroaryl, amino, cyano, nitro, - C(0)R 7 , -S(0)pR 6 , and -0(Ci-C 6 )alkyl-S(0)pR6; wherein R 6 , R 7 , and p are as defined above.
  • substituted alkyl include but are not limited to hydroxymethyl
  • (C2-Cg)aikenyl or “alkenyl”, as used herein, alone or as part of a substituent group, refers to an unsaturated straight or branched chain hydrocarbon radical containing at least one carbon-carbon double bond (two adjacent sp carbon atoms).
  • (C2-Cg)aikenyl refers to an alkenyl group having two to eight carbon atoms.
  • the geometry of the double bond may be
  • the geometry of the double bond may be
  • E), or sixteen (Z), cis or trans examples of alkenyl include, but are not limited to, vinyl, allyl or 2-propenyl.
  • the alkenyl groups may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce) alkyl, hydroxy, -0(Ci-C6)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, nitro, cyano and -C(0)R7; wherein R 7 is as defined above.
  • alkynyl refers to an unsaturated, branched or straight chain having from two to eight carbon atoms and at least one carbon-carbon triple bond (two adjacent sp carbon atoms).
  • alkynyl include, but are not limited to, ethynyl, 1-propynyl, 3-propynyl and 4-butynyl.
  • the alkynyl groups may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-C 6 )alkyl, halogen, halo(C !
  • haloalkyl or "halo(Ci-C6)alkyl” refers to radicals wherein one or more of the hydrogen atoms of the alkyl group are substituted with one or more halogens.
  • a monohaloalkyl radical for example, may have a chlorine, bromine, iodine or fluorine atom.
  • Dihalo and polyhaloalkyl radicals may have two or more of the same or different halogen atoms.
  • haloalkyl or “halo(Ci-Ce) alkyl” include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, hepta fluoropropyl, difluorochloromethyl, dichlorofluoro methyl, difluoroethyl or difluoropropyl.
  • alkoxy refers to (Ci-Ce)alkyl group having an oxygen radical attached thereto.
  • alkoxy or - 0(Ci-C6)alkyl wherever used in this specification have the same meaning.
  • Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy and tert-butoxy.
  • the -0(Ci-C6)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci- Ce)alkyl, (C3-C8)cycloalkyl, (C6-Cio)aryl, heterocyclyl, hydroxy, halogen, amino, cyano, (Ci- C 6 )alkyl-S(0) p R 6 , -S(0) p R 6 , -NR 8 R 9 , and -(CH 2 ) S NR 8 R 9 ; wherein R 6 , R 8 , R 9 , p and s are as defined above.
  • haloalkoxy or halo(Ci-C6)alkoxy refers to radicals wherein one or more of the hydrogen atoms of the alkoxy group are substituted with one or more halogens.
  • Representative examples of "haloalkoxy” or “halo(Ci-C6)alkoxy” groups include, but are not limited to, difluoromethoxy (OCHF2), trifluoromethoxy (OCF 3 ) or trifluorethoxy (OCH2CF 3 ).
  • (C3- Cio)cycloalkyl or "cycloalkyl” refers to a monocyclic or bicyclic hydrocarbon ring containing three to ten carbon atoms, wherein at least one hydrocarbon ring is a saturated ring system which does not contain any double bond within the ring or a partially unsaturated ring system which may contain one or more double bonds within the ring system that is stable, and do not form an aromatic ring system.
  • cycloalkyl can also include ring systems in which a cycloalkyl ring is optionally fused with an aryl ring e.g. phenyl .
  • cycloalkyl would include ring systems such as indane, with attachment possible to either the cycloalkyl or aryl ring.
  • Representative (C3-Cio)cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl or indenyl.
  • (C3-C 1 o)cycloalkyl may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-Ce)alkyl, halogen, halo(d-C 6 )aikyl, halo(C C 6 )alkoxy, hydroxy, -0(C C 6 )alkyl, -0(C C 6 )alkyl(C 6 - Cio)aryl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, - C(0)R 7 and -OCH 2 -(CR'R") P -(Ci-C6)alkyl, wherein R 7 , R', R" and p are as defined above.
  • (C6- Cio)aryl or "aryl” refers to a monocyclic or bicyclic hydrocarbon ring system having up to ten ring carbon atoms, wherein at least one carbocyclic ring is having a ⁇ electron system.
  • Examples of (C6-C 10 ) aryl ring systems include, but are not limited to, phenyl or naphthyl.
  • aryl group may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-Ce)alkyl, (C2- Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(Ci-Ce) alkyl, hydroxy, thiol, -O(Ci-Ce) alkyl, halo(C !
  • Aryl groups can be substituted in any desired position.
  • the substituted may be located in the 2-position, the 3-position, the 4-position or the 5-position. If the phenyl carries two substituents, they can be located in 2, 3- position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4-position, 3, 5-position or 3, 6- position.
  • -0(C6-C 1 o)aryl refers to (C6-Qo)aryl group having an oxygen radical attached thereto.
  • aryloxy or -0(C6-Cio)aryl wherever used in this specification have the same meaning. Representative example includes, but is not limited to, phenoxy.
  • - 0(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, hydroxy, halogen, amino, cyano, (Ci-Ce)alkyl- S(0) p R 6 , -S(0) p R 6 , -NR 8 R 9 , and -(CH 2 ) s NRgR 9 ; wherein R 6 , Rg, R9, p and s are as defined above.
  • heterocyclyl refers to 3- to 9-membered saturated or partially unsaturated monocyclic or bicyclic ring system containing one to four hetero atoms independently selected from the group consisting of a nitrogen (N), a sulfur (S) and an oxygen (O) atom.
  • Heterocyclyl includes saturated heterocyclic ring systems, which do not contain any double bond. Partially unsaturated heterocyclic ring systems, contain at least one double bond, but do not form an aromatic system containing hetero atom.
  • heterocyclyl encompasses fused, brigded or spiro rings.
  • Heterocyclic ring can form fused or spiro ring system with cycloalkyl, aryl, heterocyclyl or heteroaryl rings.
  • Suitable saturated and partially unsaturated non- aromatic heterocyclic groups include, but are not limited to, oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, dihydropyranyl, tetrahydropyranyl, thio-dihydropyranyl, thio-tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 1,3- oxazinanyl, 1,3-thiazinanyl, 4,5,6-tetrahydropyrimidinyl, 2,3-dihydrofuranyl, dihydrothienyl, dihydropyridinyl, tetrahydropyridiny
  • heterocyclyl may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 - Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci- Ce)alkoxy, (C3-C8)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (Ci- C 6 )alkyl-OH, (C 1 -C 6 )alkyl-0-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 6 -C 1 o)aryl, -C(0)R 7 , -S(0) p R 6 , and -0(Ci-C6)alkyl
  • heteroaryl Heterocyclyl monocyclic or bicyclic ring systems having an aromatic ring containing hetero atom/s are herein referred to as "heteroaryl".
  • heteroaryl refers to 3- to 10-membered aromatic monocyclic or bicyclic ring system containing one to four hetero atoms independently selected from the group consisting of a nitrogen (N), a sulfur (S) and an oxygen (O) atom.
  • heteroaryl include but are not limited to thiene, furan, pyridine, oxazole, thiazole, pyrazine, pyrimidine, pyrrole, pyrazole, isooxazole, triazole, tetrazole, pyridazine, isothiazole, benzothiazole, benzooxazole, benzimidazole, quinoline or isoquinoline.
  • Heteroaryl group may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 - Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(Ci-Ce) alkyl, hydroxy, thiol, -0(Ci-Ce)alkyl, halo(Ci-C6)alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -(Ci-C 6 )alkyl-OH, -(C 1 -C 6 )alkyl-0-(C 1 -C 6 )alkyl, -C(0)R 7 , -OC(0)CH 3 , -S(0) p R 6 and - 0(Ci-C6)alkyl-S(0) p R6;
  • heteroatom includes nitrogen (N), oxygen (O) and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom to satisfy the valency or when the heteroatom is N, it may be substituted with a group selected from (Ci-C 6 )alkyl, -C(0)(Ci-C 6 )alkyl or -S(0) 2 (C 1 -C 6 )alkyl.
  • Suitable (Ci-Ce)alkyl groups may be selected from, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or isobutyl.
  • (Ci-C6)alkyl(C6-Cio)aryl refers to an alkyl group substituted with aryl, wherein the terms alkyl and aryl are as defined above.
  • (Ci-C6)alkylheterocyclyl refers to an alkyl group substituted with heterocylyl, wherein the terms alkyl and heterocyclyl are as defined above.
  • halogen or "halo" as used herein, unless otherwise indicated refers to bromine, chlorine, fluorine or iodine atom.
  • amino refers to the group “NH2" which may be unsubstituted or substituted by one or more substituents.
  • substituents include, but are not limited to, (Cj-C4)alkyl, (C6-Qo)aryl or the like groups.
  • the terms “compounds of Formula (I)", “heterocyclic derivatives of Formula (I)” and “compounds of the present invention” include all the isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, carboxylic acid isosteres, N-oxides and S-oxides.
  • reference to the compounds of Formula (I) may include reference to the compounds represented herein by the compounds of Formula (la) and/or the compounds represented herein by the compounds of Formula (lb).
  • isotopic forms or “isotopically labeled forms” is a general term used for isotopic forms of compounds of Formula (I), wherein one or more atoms of compounds of Formula (I) are replaced by their respective isotopes. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention.
  • isotopes examples include, but are not limited to, isotopes of hydrogen such as 2 H (deuterium or D) and 3 H, carbon such as n C, 13 C and 14 C, nitrogen such as 13 N and 15 N, oxygen such as 15 0, 17 0 and 18 0, chlorine such as 36 C1, fluorine such as 18 F and sulphur such as 35 S.
  • isotopes of hydrogen such as 2 H (deuterium or D) and 3 H
  • carbon such as n C, 13 C and 14 C
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 0, 17 0 and 18
  • chlorine such as 36 C1
  • fluorine such as 18 F
  • sulphur such as 35 S.
  • Substitution with heavier isotopes, for example, replacing one or more key carbon-hydrogen bonds with carbon-deuterium bond may show certain therapeutic advantages, resulting from longer metabolism cycles, (e.g., increased in vivo half life or reduced dosage requirements), improved safety or greater effectiveness and hence may be preferred in certain
  • isotopic forms of the compounds of Formula (I) may include, without limitation, deuterated compounds of Formula (I).
  • deuterated as used herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), which is attached to carbon(s), with a deuterium atom.
  • the compounds of Formula (I) may include in the definitions of one or more of the various variables Ri, R2, R3, R4, R5, R6, R7, Rs, R and Rio wherever applicable, deuterium, deuterated-alkyl, deuterated-alkoxy, deuterated-cycloalkyl, deuterated-heterocyclyl, deuterated-aryl, deuterated-heteroaryl and the like.
  • deuterated-alkyl refers to an (Ci-C6)alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced by a deuterium. That is, in a deuterated alkyl group, at least one carbon atom is bound to a deuterium. In a deuterated alkyl group, it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium.
  • deuterated and the terms deuterated-heterocyclyl, deuterated- heteroaryl, deuterated-cycloalkyl, deute- rated-aryl and deuterated-alkoxy each refer to the corresponding chemical moiety wherein at least one carbon is bound to a deuterium.
  • stereoisomer is a general term used for all isomers of individual compounds that differ only in the orientation of their atoms in space.
  • stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
  • tautomer refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers.
  • pharmaceutically acceptable salts includes salts of the active compounds i.e. the compounds of Formula (I) which are prepared by treating said compounds with a suitable acid or a base, depending on the particular substituents found on the compounds described herein.
  • N-oxide refers to the oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle. N-oxide can be formed in the presence of an oxidizing agent for example peroxide such as m-chloro- perbenzoic acid or hydrogen peroxide. N-oxide refers to an amine oxide, also known as amine-N-oxide, and is a chemical compound that contains N- ⁇ O bond.
  • S-oxide refers to the oxide of the sulfur atom (S-oxide) or dioxide of the sulfur atom (S,S-dioxide) of a sulfur- containing heteroaryl or heterocycle.
  • S-oxide and S,S-dioxides can be formed in the presence of an oxidizing agent for example peroxide such as m-chloro-perbenzoic acid or oxone.
  • solvate or “solvates” describe a complex wherein the compound of Formula (I) of the present invention, is coordinated with a proportional amount of a solvent molecule.
  • prodrug or “prodrugs” refer to the compounds that are drug precursors, which following administration, release the drug in vivo via a chemical or metabolic process, for example, a prodrug on being brought to the physiological pH or through an enzyme action is converted to the desired drug.
  • polymorph or “polymorphic form” or “polymorphs” refer to crystals of the same compound that differs only in the arrangement and/or conformation of the molecule in the crystal lattice.
  • carboxylic acid isosteres refer to groups or molecules that have physical and chemical similarities to a carboxylic acid group, producing similar biological effects as those produced by a carboxylic acid group.
  • Examples of carboxylic acid isosteres include groups selected from hydroxamic, acylcyanamide, phosphonate, sulfonate, sulfonamide, tetrazole, hydroxyisoxazole and oxadiazolone (The Practice of Medicinal Chemistry, Edited by Camille G. Wermuth, Second Edition, 2003, 189-214).
  • GPR agonist(s) refer to the compound(s) of Formula (I) of the present invention which binds to, activates, increases, stimulates, potentiates, sensitizes or upregulates one or more of the G- protein coupled receptors which are reported to play an important physiological role in insulin release.
  • the G-protein coupled receptor may be GPR40 that has been reported to play a physiological role in insulin release.
  • GPR40 agonist(s) refer to the compound(s) of Formula (I) of the present invention which binds to, activates, increases, stimulates, potentiates, sensitizes or upregulates GPR40 receptor and promotes glucose induced insulin secretion.
  • therapeutically effective amount generally refers to the amount of the compound (e.g. the compound of Formula (I)) or a composition containing the said compound that will elicit the biological or medical response of a tissue or a subject when treated with the compound.
  • therapeutically effective amount includes the amount of a compound, when administered that induces a positive modification in the disease or condition to be treated or is sufficient to prevent development of, or alleviate to some extent one or more of the symptoms of the condition or disorder being treated in a subject.
  • the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgement.
  • the therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the end user, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized and other factors.
  • treatment is intended to mean to alleviate, slow the progression, prophylaxis, attenuation or cure of existing disease (for example, metabolic disorders). Treatment also includes preventing development of, or alleviating to some extent, one or more of the symptoms of the disease or condition being treated.
  • the term “prophylaxis” covers within its scope the preventive treatment of a subclinical disease-state or a condition in a subject (e.g. a human), aimed at reducing the probability of the occurrence of a clinical disease-state.
  • Subjects are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state or a condition compared to the general population.
  • "Prophylaxis" therapies can be divided into (a) primary prevention and (b) secondary prevention.
  • Primary prevention is defined as treatment in a subject that has not yet presented with a clinical disease state or a condition, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.
  • subject refers to an animal, preferably a mammal, and most preferably a human.
  • mammal refers to warm-blooded vertebrate animals of the class Mammalia, including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young.
  • mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
  • a subject in need thereof means a subject (patient) in need of the treatment for the disease or condition that is mediated by GPR40.
  • a subject in need thereof means a subject (patient) diagnosed having a disease or a condition that is mediated by GPR40.
  • the present invention encompasses a compound of Formula (I), wherein Rj is hydrogen, methyl, ethyl or propyl.
  • the present invention encompasses a compound of Formula (I), wherein R2 and R 3 together form a saturated or a partially unsaturated
  • the present invention encompasses a compound of Formula (I), wherein R2 and R 3 together form a saturated or a partially unsaturated 3- to 6-membered heterocyclyl ring containing one or two O atoms.
  • the present invention encompasses a compound of Formula (I), wherein R2 and R 3 together form an oxetane ring.
  • the present invention encompasses a compound of Formula (I), wherein R2 and R 3 together form a saturated or a partially unsaturated 3- to 6-membered heterocyclyl ring containing one or two heteroatoms independently selected from N and S atoms; when the heteroatom is N, it is substituted with hydrogen, (C 1 -C6)alkyl, -C(0)(Q- C 6 )alkyl or -S(0) 2 (C 1 -C 6 )alkyl.
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Lj-X and R y is R5; wherein A, Lj, X and R5 are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is R5 and R y is A-Li-X; wherein A, Li, X and R5, are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is R5 and R y is A-Lj-X; wherein X is O, Lj is absent or is selected from the group consisting of -S(0) p -, -C(0)NH-, -NHC(O)-,
  • the present invention encompasses a compound of Formula (I), wherein R x is A-L X and R y is R 5 ; wherein X is -(CH 2 ) n O-; and R 5 , L l 5 A and n are as defined above; provided that when n is 1; A is not (C3-C 10 ) cycloalkyl, (Ce-Cio)aryl, heterocyclyl or heteroaryl.
  • the present invention encompasses a compound of Formula (I), wherein R x is R5 and R y is A-Lj-X; wherein X is -(CH 2 ) n O- and R5, Lj, A and n are as defined above; provided that when n is 1; A is not (C3-C 10 ) cycloalkyl, (Ce-Cio)aryl, heterocyclyl or heteroaryl.
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Lj-X and R y is R5; wherein X is
  • the present invention encompasses a compound of Formula (I), wherein R x is R5 and R y is A-Lj-X; wherein X is
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Lj-X and R y is R5 ; wherein X is -(CH 2 ) p (C 6 -Cio aryl) k CH 2 0-; and R 5 , L l 5 A, k and p are as defined above; provided that when p is 0 then Lj is not absent.
  • the present invention encompasses a compound of Formula (I), wherein R x is R5 and R y is A-Li-X; wherein X is -(CH2) p (C6-Cio aryl)kCH20-; and R5, Lj, A, k and p are as defined above; provided that when p is 0 then Lj is not absent.
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Lj-X and R y is R5; wherein X is
  • the present invention encompasses a compound of Formula (I), wherein R x is R5 and R y is A-Li-X; wherein X is
  • R 5 , , A, R' , R" and p are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Lj-X and R y is R5; wherein Lj is O, X is
  • R 5 , R 8 , R9, R' , R", A, n, p and k are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is R 5 and R y is A-L X; wherein Lj is O, X is
  • R 5 , R 8 , R9, R' , R", A, n, p, and k are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Lj-X and R y is R5; wherein Lj is -S(0) p -; and R5, X, p and A are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is R5 and R y is A-Lj-X; wherein Lj is -S(0) p -; and R5, X, p and A are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Lj-X and R y is R5 ; wherein Lj is -C(0)NH-; and R5, X and A are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is R5 and R y is A-Lj-X; wherein Lj is -C(0)NH- and R5, X and A are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Lj-X and R y is R5 ; wherein Lj is -NHC(O)-; and R5, X and A are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Li-X and R y is R5; wherein Li is
  • the present invention encompasses a compound of Formula (I), wherein R x is R5 and R y is A-Lj-X; wherein Lj is
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Li-X and R y is R 5 ; wherein Li is -(CR'R") P -CH 2 0; and R', R", p, R5, X, and A are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is R 5 and R y is A-Lj-X; wherein is -(CR'R") P -CH 2 0; and R', R", p, R5, X and A are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Lj-X and R y is R5; wherein Lj is
  • the present invention encompasses a compound of Formula (I), wherein R x is R 5 and R y is A-L X; wherein Lj is
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Lj-X and R y is R5; wherein Lj is
  • the present invention encompasses a compound of Formula (I), wherein R x is R5 and R y is A-Lj-X; wherein Lj is
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Lj-X and R y is R5; wherein Lj is
  • R 5 , R', R", X, and A are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is R5 and R y is A-Lj-X; wherein Lj is
  • R 5 , R' , R", X, and A are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Lj-X and R y is R 5 ; wherein Lj is
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Lj-X and R y is R5; wherein Lj is and Rg, R9, R5, X, n and A are as defined above, provided that when n is 1, X is -0-, and one of the variable Rg and R of is hydrogen, the other variable is not hydrogen or (Ci-C6)alkyl.
  • the present invention encompasses a compound of Formula (I), wherein R x is R5 and R y is A-Lj-X; wherein Lj is -(CRgR9) n - and Rg, R9, R5, X, n and A are as defined above, provided that when n is 1, X is -0-, and one of the variable Rg and R of -(CRgR9) n - is hydrogen, the other variable is not hydrogen or (Ci-C6)alkyl.
  • the present invention encompasses a compound of Formula (I), wherein R x is A-Lj-X and R y is R5; wherein X is -(CH 2 ) p (C6-Cio aryl) k CH 2 0-; Lj is selected from the group consisting of -0-, -(CR'R") P -CH 2 0- and -C(R'R")-; and R 5 , R', R", A, k and p are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein R x is R 5 and R y is A-L X; wherein X is -(CH 2 ) p (C 6 -C 1 o aryl) k CH 2 0-; Lj is selected from the group consisting of -0-, -(CR'R") P -CH 2 0- and -C(R'R")-; and R 5 , R', R", A, k and p are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein A is
  • Rjo is hydrogen, (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci-C6)alkoxy, -S(0) P R6, amino, cyano, nitro or -C(0)R 7 ; wherein R6, R 7 and p are as defined above.
  • the present invention encompasses a compound of Formula (I), wherein A is (Ci-Ce) alkyl, (C3-Cio)cycloalkyl, (Ce-Cio)aryl,
  • Rio is hydrogen, (Ci-Ce)alkyl, -0(Ci-Ce)alkyl, -S(0) P R6 or -C(0)R?; wherein R6, R7 and p are as defined above, provided that when A is (C3-Cio)cycloalkyl or (Ce-Cio)aryl, and X is -(CH 2 ) n O- , then n is not 1.
  • the present invention encompasses a compound of Formula (I), wherein A is (Ci-Ce)alkyl, wherein (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, halo(Ci- Ce)alkyl, hydroxy, -0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl and heteroaryl.
  • A is (Ci-Ce)alkyl
  • (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, halo(Ci- Ce)alkyl, hydroxy, -0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl and heteroaryl.
  • the present invention encompasses a compound of Formula (I), wherein A is (C3-Cg)cycloalkyl, wherein (C3-Cg)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci- C 6 )alkyl, (C C 6 )alkoxy, halo(C !
  • the present invention encompasses a compound of Formula (I), wherein A is (Ce-Cio)aryl; wherein (Ce-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, halogen, halo(C 1 -C 6 )alkyl, hydroxy, -0(C !
  • the present invention encompasses a compound of Formula (I), wherein A is
  • the compound of Formula (I) encompasses a compound of Formula (la),
  • Rj is hydrogen or (Ci-C 6 ) alkyl
  • R2 and R3 together form a saturated or a partially unsaturated 3- to 6- membered heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
  • R 4 is hydrogen
  • R5 is hydrogen, (Ci-C 6 ) alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy,
  • R6 is hydrogen, (Ci-Ce)alkyl or amino
  • X is -0-, -(CH 2 ) n O-, -(CH 2 ) p (CR 8 R9)nCH 2 0-, -(CH 2 ) p (C 6 -C 10 aryl) k CH 2 O-, or
  • Lj is absent or is selected from the group consisting of -0-, -S(0) p -, -C(0)NH-,
  • R 7 is (d-Ce) alkyl, -0(d-C6)alkyl, -O(C 1 -C 6 )alkyl(C 6 -C 10 )aryl, hydroxy or amino;
  • A is (Ci-C6)alkyl, (C3-Cio)cycloaikyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl,
  • Rio is hydrogen, (Ci-Ce)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci- Ce)alkoxy, -S(0) p R6, amino, cyano, nitro or -C(0)R 7 ; wherein R 6 and R 7 are as defined above;
  • k is an integer 1 or 2;
  • n is an integer from 1 to 3;
  • n is an integer from 1 to 4.
  • p is an integer from 0 to 2;
  • s is an integer from 1 to 4.
  • (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, (C3-Cg)cycloaikyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R 7 and -0(Ci-C6)alkyl-S(0) p R6; wherein R6, R 7 , and p are as defined above;
  • -0(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (C 1 -C6)alkyl, (C3-Cg)cycloaikyl, heterocyclyl, hydroxy, halogen, amino, cyano, (C!-C6)alkyl-S(0) p R6, -S(0) p R6, -NR 8 R 9 and -(CH 2 ) s NRgR 9 ; wherein R 6 , Rg, R 9 , p and s are as defined above;
  • (C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, halo(Ci- C 6 )alkoxy, -OCH 2 -(CR'R") p -(C 1 -C 6 )alkyl and -0(C 1 -C 6 )alkyl(C 6 -C 1 o)aryl, wherein R ⁇ R" and p are as defined above;
  • (C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(C !
  • heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 - C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(d-C 6 ) alkyl, hydroxy, -(XCi-C 6 )alkyl, halo(C C 6 ) alkoxy, (C3-Cg)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (Ci- C 6 )alkyl-OH, (C 1 -C 6 )alkyl-0-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C
  • heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 - C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(C !
  • halogen is chlorine, bromine, iodine or fluorine
  • A is not (C3-C 10 ) cycloalkyl, (Ce-Cio)aryl, heterocyclyl or heteroaryl;
  • the compound of Formula (I) encompasses a compound of Formula (la); wherein R y is R5.
  • the compound of Formula (I) encompasses a compound of Formula (la); wherein R 2 and R 3 together form a saturated or a partially unsaturated 3- to 6- membered heterocyclyl ring containing one or two oxygen atoms; and R y is R5, wherein R5 is as defined above.
  • the compounds of Formula (I) encompasses a compound of Formula (la); wherein R 2 and R 3 together form an oxetane ring; and R y is R5, wherein R5 is as defined above.
  • the compounds of Formula (I) encompasses a compound of Formula (la); wherein R 2 and R 3 together form an oxetane ring; R 4 is hydrogen and R y is R 5 , wherein R5 is as defined above.
  • the compounds of Formula (I) encompasses a compound of Formula (la); wherein, R 2 and R 3 together form an oxetane ring; and R y is R5 ; wherein R5 is hydrogen.
  • the compounds of Formula (I) encompasses a compound of Formula (la); wherein R 2 and R 3 together form an oxetane ring; R4 is hydrogen; R y is R5; wherein o)cycloalkyl, (C6-Cio)aryl,
  • Rio is hydrogen, -C(0)R 7 , S(0) p R 6 or (d-C 6 )alkyl;
  • (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0) p R6; wherein R6 and p are as defined above;
  • -0(Ci-C6)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, (C3-Cg)cycloalkyl, heterocyclyl, hydroxy and halogen;
  • (C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(C ! -C 6 )alkoxy, -OCH 2 -(CR'R")p-(C 1 -C 6 )alkyl and -O(C 1 -C 6 )alkyl(C 6 -C 10 )aryl wherein R', R" and p are as defined above;
  • (C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 -Cs)alkenyl, (C 2 -Cs)alkynyl, halogen, halo(C C 6 ) alkyl, hydroxy, -0(C C 6 )alkyl, -O(C 1 -C 6 )alkyl(C 6 -C 10 )aryl, halo(C C 6 ) alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R 7 , and -0(C C 6 )alkyl- S(0) p R6; wherein R6, R7, R'
  • heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 - C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, haloCQ-Ce) alkyl, hydroxy, -0(C !
  • heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(C ! -C 6 )alkyl, hydroxy, -0(C !
  • halogen is chlorine, bromine, iodine or fluorine
  • the compounds of Formula (I) encompasses a compound of Formula (la); wherein R2 and R3 together form an oxetane ring; R4 is hydrogen; R y is R5; wherein R5 is hydrogen; and
  • (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0) p R6; wherein R6 and p are as defined above;
  • -0(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, (C3-Cg)cycloalkyl, heterocyclyl, hydroxy and halogen; wherein R6, Rs, R9, p and s are as defined above; (C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(C !
  • (C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(C 1 -C 6 )alkyl, hydroxy, -0(d-C6)alkyl, -O(C 1 -C 6 )alkyl(C 6 -C 10 )aryl, halo(C !
  • heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(C ! -C 6 )alkyl, hydroxy, -0(C !
  • heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci- Ce)alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, - C(0)R 7 and -0(Ci-C6)alkyl-S(0) p R6; wherein R6, R 7 , and p are as defined above;
  • halogen is chlorine, bromine, iodine or fluorine
  • the compounds of Formula (I) encompasses a compound of Formula (la); wherein R2 and R3 together form an oxetane ring; R4 is hydrogen; R y is R5; wherein R 5 is hydrogen; X is -0-, -(CH 2 ) p (CR 8 R9) n CH 2 0-, -(CH 2 ) p (C6-C 10 aryl) k CH 2 O- or - (CR'R") P 0-; and A is (C6-Cio)aryl; wherein R 8 , R9, R', R", p, n and k are are defined above; wherein,
  • (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0) p R6; wherein R6 and p are as defined above;
  • -0(Ci-C6)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C3-C 8 )cycloalkyl, heterocyclyl, hydroxy and halogen wherein R6, R 8 , R9, p and s are as defined above;
  • (C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(C ! -C 6 )alkoxy, -OCH 2 -(CR'R") p -(C 1 -C 6 )alkyl and -O(C 1 -C 6 )alkyl(C 6 -C 10 )aryl wherein R', R" and p are as defined above;
  • (C6-Cjo)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(C C 6 ) alkyl, hydroxy, -0(C C 6 )alkyl, -O(C 1 -C 6 )alkyl(C 6 -C 10 )aryl, halo(C C 6 ) alkoxy, (C3-C 8 )cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R 7 , -OCH 2 -(CR'R") p -(C 1 -C 6 )alkyl
  • heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 - C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, haloCQ-Ce) alkyl, hydroxy, -0(C!-C 6 )alkyl, halo(C C 6 ) alkoxy, (C3-C 8 )cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (Q- C 6 )alkyl-OH, (C 1 -C 6 )alkyl-0-(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl(C 6 -C 1 o)aryl, -C(0)R 7 , S(0) p R 6 and -
  • heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 - C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(C ! -C 6 )alkyl, hydroxy, -0(C !
  • halogen is chlorine, bromine, iodine or fluorine
  • Rio is hydrogen, -C(0)R 7 , S(0) p R 6 or (Ci-C 6 )alkyl
  • k is an integer 1 or 2 and p is an integer from 0 to 2;
  • (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0) p R 6 ;
  • (C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 -Cs)alkenyl, (C 2 -Cs)alkynyl, halogen, halo(C 1 -C 6 )alkyl, hydroxy, -0(d-C6)alkyl, -O(C 1 -C 6 )alkyl(C 6 -C 10 )aryl, halo(Ci-C 6 )alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R 7 , -OCH 2 -(CR'R") P -(C 1 -C 6 )alky
  • R6, R7, R', R" p and k are as defined above;
  • Lj is not absent. or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof.
  • (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0) p R 6 ;
  • (C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 -Cs)alkenyl, (C 2 -Cs)alkynyl, halogen, halo(C !
  • R6, R7, R', R" p and k are as defined above;
  • the compounds of Formula (I) encompasses a compound of Formula (la);
  • R 2 and R3 together form a saturated or a partially unsaturated 3- to 6- membered heterocyclyl ring containing one or two heteroatoms selected from N or S; when the heteroatom is N, it is substituted with hydrogen, (C ! -C 6 )alkyl, -C(0)(C ! -C 6 )alkyl or -S(0) 2 (C ! -C 6 )alkyl;
  • R y is R5; wherein R5 is hydrogen;
  • X is -(CH 2 ) p (C6-C 10 aryl) k CH 2 O-;
  • (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0) P R6; wherein R6 and p are as defined above;
  • (C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 -Cs)alkenyl, (C 2 -Cs)alkynyl, halogen, halo(C !
  • the compound of Formula (I) encompasses a compound of Formula (lb),
  • Rj is hydrogen or (Ci-Ce)alkyl
  • R 2 and R3 together form a saturated or a partially unsaturated 3- to 6- membered heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
  • R 4 is hydrogen
  • R 5 is hydrogen, (Ci-C 6 ) alkyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(C 1 -C6)alkyl, (C 6 - Cjo)aryl, amino, cyano, nitro, -C(0)R 7 or -S(0) p Re;
  • R6 is hydrogen, (Ci-Ce)alkyl or amino;
  • X is -0-, -(CH 2 ) n O-, -(CH 2 )p(CR 8 R9)nCH 2 0-, -(CH 2 )p(C6-C 10 aryl) k CH 2 O-, or -(CR'R") P 0-;
  • R 7 is (d-Ce) alkyl, -0(d-C6)alkyl, -O(C 1 -C 6 )alkyl(C 6 -C 10 )aryl, hydroxy or amino;
  • Rio is hydrogen, (Ci-Ce)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci- Ce)alkoxy, -S(0) p R6, amino, cyano, nitro or -C(0)R 7 ; wherein R 6 and R 7 are as defined above;
  • k is an integer 1 or 2;
  • n is an integer from 1 to 3;
  • n is an integer from 1 to 4.
  • p is an integer from 0 to 2;
  • s is an integer from 1 to 4.
  • (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 -Cg)alkenyl, (C 2 -Cg)alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R 7 and -0(Ci-C6)alkyl-S(0) p R6; wherein R6, R 7 , and p are as defined above;
  • -0(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, (C3-Cg)cycloalkyl, heterocyclyl, hydroxy, halogen, amino, cyano, (Ci-C6)alkyl-S(0) p R6, -S(0) P R6, -NRgRg and -(CH2) s NRgR ; wherein R6, Rs, R9, p and s are as defined above;
  • (C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(C ! -C 6 )alkoxy, -OCH 2 -(CR'R") p -(C 1 -C 6 )alkyl and -O(C 1 -C 6 )alkyl(C 6 -C 10 )aryl, wherein R', R" and p are as defined above;
  • (C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 -Cs)alkenyl, (C 2 -Cs)alkynyl, halogen, halo(C !
  • heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 - C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, haloCQ-Ce) alkyl, hydroxy, -0(C !
  • heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 - C 8 )alkenyl, (C 2 -C 8 )alkynyl, halogen, halo(C ! -C 6 )alkyl, hydroxy, -0(C !
  • halogen is chlorine, bromine, iodine or fluorine
  • A is not (C3-C 10 ) cycloalkyl, (Ce-Cio)aryl, heterocyclyl or heteroaryl;
  • the present invention encompasses a compound of Formula (lb), wherein,
  • R2 and R3 together form an oxetane ring
  • Rx is R5
  • R5 is hydrogen, (Ci-Ce)alkyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-Ce)alkyl, (C 6 - Cio)aryl, amino, cyano, nitro, -C(0)R7 or -S(0) p R6; wherein R6 and R 7 are as defined above.
  • the present invention encompasses a compound of Formula (lb), wherein,
  • R2 and R3 together form an oxetane ring
  • R x is R5; wherein R5 is hydrogen;
  • X is -(CH 2 ) p (C6-C 10 aryl) k CH 2 O-;
  • Li is absent or is selected from the group consisting of -0-, -(CR'R") P -CH 2 0- and
  • Rio is hydrogen, (Ci-Ce)alkyl or -S(0) p R6;
  • R6, p and k are as defined above;
  • (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0) p R6; wherein R6 and p are as defined above; (C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 -Cs)alkenyl, (C 2 -Cs)alkynyl, halogen, halo(C 1 -C 6 )alkyl, hydroxy, -0(C !
  • the present invention encompasses a compound of Formula (lb), wherein
  • R 2 and R3 together form an oxetane ring
  • R x is R5; wherein R5 is hydrogen;
  • X is -(CH 2 ) p (C6-Cioaryl) k CH 2 0-; wherein p and k are as defined above;
  • Lj is -0-, -(CR'R") P -CH 2 0- or -C(R'R")-;
  • A is (C 6 -C 10 )aryl
  • (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Cj-C6)alkyl, (C3-Cg)cycloalkyl, (C6-Qo)aryl, heterocyclyl, heteroaryl and -0(C 1 -C6)alkyl- S(0) p R6; wherein R6 and p are as defined above;
  • (C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C 2 -Cs)alkenyl, (C 2 -Cs)alkynyl, halogen, halo(C !
  • Representative compounds of the present invention include:
  • the present invention also relates to processes for the preparation of the compounds of Formula (I) or pharmaceutically acceptable salts thereof.
  • the compounds of Formula (I) can be prepared by the schemes depicted herein below, but are not limited thereto.
  • the starting materials and reagents employed in the processes for preparation of the compounds of Formula (I) are commercially available or can be prepared by processes known in the art.
  • Step la Ethyl 2-(triphenylphosphoranylidene)acetate (PPhsCHCCKX ⁇ Hs), dichloromethane (DCM), room temperature (RT) (20 °C-25 °C);
  • Step lb Cyclooctadiene rhodium chloride dimer (Rh(COD)2Cl2), potassium hydroxide (KOH), dioxane.
  • This process step involves reacting compound (1), (wherein R2 and R 3 are as defined above for any one of the embodiments of the compounds of Formula (I)), with a reagent such as ethyl 2-(triphenylphosphoranylidene)acetate in a solvent such as dichloromethane at room temperature, according to the method described in Angew Chem. Intl. Ed. , 2006, 45:7736- 39, to obtain compound (2), (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl; R2 and R 3 are as defined above).
  • Compound (3) is reacted with the compound (2) (obtained in Step la) in the presence of a suspension comprising a catalyst selected from cyclooctadiene rhodium chloride dimer or trimethylsilylchloride in a solvent selected from dioxane, tetrahydrofuran (THF), toluene, acetonitrile or dimethoxyethane and a base selected from potassium hydroxide (KOH), sodium hydroxide (NaOH), potassium bicarbonate (KHCO 3 ), sodium bicarbonate (NaHCOs), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyrrolidine or triethylamine, according to the method described in Angew Chem.
  • a suspension comprising a catalyst selected from cyclooctadiene rhodium chloride dimer or trimethylsilylchloride in a solvent selected from dioxane, tetra
  • R- is (C r C 6 )alkyl (wherein R-, is hydrogen)
  • Step 2a Sodium hydride, carbon disulfide, methyl 2-bromoacetate, dimethylformamide (DMF);
  • Step 2b meta-Chloroperoxybenzoic acid, dichloromethane (DCM);
  • Step 2c Aqueous sodium hydroxide, ethanol
  • Step 2d Sodium acetate, acetic acid
  • Step 2e borane dimethylsulfide, THF
  • Step 2f Phosphorus tribromide, DCM
  • Step 2g Cesium carbonate, DMF
  • Step 2h L1OH.H 2 O, THF, MeOH, water, aqueous ammonium chloride, RT.
  • 1-tetralone is reacted with carbon disulfide and methyl 2-bromoacetate in the presence of a base selected from n-butyllithium, sodium hydride, NaOH, KOH, potassium carbonate (K2CO 3 ) or triethylamine and a solvent such as dimethylformamide to obtain compound (5).
  • a base selected from n-butyllithium, sodium hydride, NaOH, KOH, potassium carbonate (K2CO 3 ) or triethylamine and a solvent such as dimethylformamide
  • the compound (5) is oxidized in the presence of an oxidizing agent such as meta- chloroperoxybenzoic acid in a solvent selected from DCM, 1,2-dichloroethane, chloroform, ether, EtOAc or a mixture thereof to obtain compound (6).
  • an oxidizing agent such as meta- chloroperoxybenzoic acid in a solvent selected from DCM, 1,2-dichloroethane, chloroform, ether, EtOAc or a mixture thereof to obtain compound (6).
  • the compound (6) is hydrolyzed in the presence of a base selected from NaOH, KOH, K2CO 3 or triethylamine and a solvent selected from ethanol, methanol, isopropyl alcohol or a mixture thereof to obtain compound (7).
  • a base selected from NaOH, KOH, K2CO 3 or triethylamine
  • a solvent selected from ethanol, methanol, isopropyl alcohol or a mixture thereof to obtain compound (7).
  • the compound (7) is treated with acetic acid in the presence of catalytic amount of sodium acetate to obtain compound (8), wherein R 10 is -S(0) p Re; I3 ⁇ 4 is methyl and p is an integer from 0 to 2.
  • the compound (8) is subjected to reduction in the presence of a reducing agent such as borane-dimethyl sulfide and a solvent such as THF to obtain compound (9) (wherein Rio is -S(0) p R6; R6 is methyl and p is an integer from 0 to 2).
  • a reducing agent such as borane-dimethyl sulfide
  • a solvent such as THF
  • Step 2f
  • the compound (9) is subjected to bromination in the presence of a brominating agent such as phosphorus tribromide in a solvent such as DCM to obtain compound (10) (wherein Rio is -S(0) p R6; R6 is methyl and p is an integer from 0 to 2).
  • a brominating agent such as phosphorus tribromide
  • a solvent such as DCM
  • the compound (10) is treated with compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a base selected from CS2CO 3 or K2CO 3 and a solvent such as DMF to obtain compound of Formula (I) (wherein Ri is (Ci-C6)alkyl, e.g. ethyl; Rio is -S(0) P R6, R6 is methyl and p is an integer from 0 to 2).
  • the compound of Formula (I) (wherein Ri is (Ci-C6)alkyl, e.g. ethyl) as obtained in Step 2g, is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, lithium hydroxide (LiOH) or barium hydroxide (Ba(OH)2), followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I), (wherein Ri is hydrogen; Rio is -S(0) P R6, R6 is methyl and p is an integer from 0 to 2).
  • Step 3a Cesium carbonate (CS2CO 3 ), dimethylformamide (DMF);
  • Step 3b Triethylamine, DCM, 4-dimethyl.am.inopyridine;
  • Step 3c Sodium azide, DMF;
  • Step 3d Hydrogen /palladium on carbon, MeOH;
  • Step 3e (0-(7-azabenzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexafluoro
  • Step 3f THF, RT;
  • Steps 3g and 3h L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT;
  • Step 3i Triethylamine, DCM.
  • step lb of the process depicted in scheme 1 compound (11) (wherein n is 1 to 3) is reacted with the compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a base selected from CS2CO 3 or K2CO 3 and a solvent such as DMF to obtain compound (12) (wherein Rj is (Q- Ce)alkyl, e.g. ethyl; R2, R 3 , R 4 , R5, m and n are as defined above for any one of the embodiments of the compounds of Formula (I)).
  • the compound (12) is treated with p-tosyl chloride in the presence of a catalyst such as 4-dimethylaminopyridine (DMAP) and a base selected from triethylamine, NaOH, KOH or K2CO 3 ; in a solvent selected from dichloromethane, 1,2-dichloroethane, chloroform, ether, ethyl acetate or a mixture thereof; to obtain a compound (13) (wherein Rj is (Ci-C6)alkyl, e.g. ethyl; R2, R 3 , R 4 , R5, m and n are as defined above for any one of the embodiments of the compounds of Formula (I)).
  • a catalyst such as 4-dimethylaminopyridine (DMAP) and a base selected from triethylamine, NaOH, KOH or K2CO 3 ; in a solvent selected from dichloromethane, 1,2-dichloroethane, chloroform, ether, eth
  • the compound (13) is treated with sodium azide in a solvent such as DMF to obtain compound (14) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl; R2, R 3 , R 4 , R5, m and n are as defined above for any one of the embodiments of the compounds of Formula (I)).
  • the compound (14) is subjected to catalytic reduction in the presence of a catalyst such as palladium on carbon in a solvent selected from MeOH, ethanol, isopropanol or a mixture thereof to obtain compound (15), (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl; I3 ⁇ 4, R3, R 4 , R5, m and n are as defined above for any one of the embodiments of the compounds of Formula (I)).
  • a catalyst such as palladium on carbon in a solvent selected from MeOH, ethanol, isopropanol or a mixture thereof.
  • step 2d of the process depicted in scheme 2 the compound (15) is reacted with the compound (8) (obtained in step 2d of the process depicted in scheme 2), in the presence of a coupling reagent such as HATU, a base such as Hunig' s base and in a solvent such as dimethylformamide to obtain a compound of Formula (I) (wherein Rj is (Ci-C 6 ) alkyl, e.g. ethyl; Rjo is -S(0) P R6, R6 is methyl and p is an integer from 0 to 2).
  • a coupling reagent such as HATU
  • a base such as Hunig' s base
  • a solvent such as dimethylformamide
  • the compound of Formula (I) (wherein Ri is (Ci-Ce)alkyl, e.g. ethyl) as obtained in Step 3e/ 3f, is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or barium hydroxide Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain a compound of Formula (I) (wherein Rj is hydrogen).
  • step 3d the compound (15) as obtained in step 3d, is reacted with a compound of formula: A-S(0) P C1 (wherein p is 2 and A is as defined above for any one of the embodiments of the compounds of Formula (I)), in the presence of a base such as triethylamine and a solvent selected from DCM, dichloroethane, chloroform, ether, ethyl acetate or a mixture thereof; to obtain the compound of Formula (I) (wherein Rj is (Ci-C 6 ) alkyl, e.g. ethyl).
  • the compound of Formula (I) thus obtained can be optionally hydrolyzed to obtain a compound of Formula (I) (wherein Rj is hydrogen).
  • the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 4.
  • Step 4a Cesium carbonate (Cs 2 C0 3 ), DMF;
  • Step 4b L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT;
  • Step 4c and 4d Potassium peroxymonosuifate (oxone®), methanol (MeOH).
  • compound (13) is reacted with compound (16) of Formula: A-Lj-H (wherein Lj is O or S and A is as defined above for any one of the embodiments of the compounds of Formula (I)), in the presence of a base selected from CS2CO3 or K2CO 3 and a solvent such as dimethylformamide to obtain the compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl).
  • the compound of Formula (I) (wherein Li is S and Ri is (Ci-Ce)alkyl, e.g. ethyl) as obtained in Step 4a; is treated with oxone® in a solvent selected from ethanol, MeOH, isopropanol or mixture thereof to obtain the compound of Formula (I) (wherein Li is S(O) and Rj is (Ci-Ce)alkyl, e.g. ethyl).
  • the compound of Formula (I) (wherein Rj is (Ci-C 6 ) alkyl, e.g. ethyl) thus obtained, can be optionally hydrolyzed to obtain a compound of Formula (I) wherein Rj is hydrogen.
  • the compound of Formula (I), (obtained in Step 4c) (wherein Lj is S(O) and Rj is (Ci-C6)alkyl, e.g. ethyl); is treated with oxone® in a solvent selected from ethanol, methanol, isopropanol or a mixture thereof; to obtain the compound of Formula (I), (wherein Lj is S(0)2 and Rj is (Ci-Ce)alkyl, e.g. ethyl).
  • the compound of Formula (I) (wherein Rj is (Ci-C 6 ) alkyl, e.g. ethyl) thus obtained, can be optionally hydrolyzed to obtain a compound of Formula (I) (wherein Rj is hydrogen).
  • Step 5a Pyridine
  • Step 5d L1OH.H 2 O, THF, MeOH, water, aqueous ammonium chloride, RT.
  • the compound (17) is treated with a compound of formula: A-OH, (wherein A is as defined above for any one embodiments of the compounds of Formula (I)) in the presence of a base such as n-butyllithium, sodium hydride, NaOH, KOH, K2CO 3 or triethylamine and a solvent such as DMF to obtain compound (18) (wherein A is as defined above for the compounds of Formula (I)).
  • a base such as n-butyllithium, sodium hydride, NaOH, KOH, K2CO 3 or triethylamine
  • a solvent such as DMF
  • step lb of the process depicted in scheme 1 compound (18) is treated with the compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a base selected from sodium hydride, n-butyllithium, NaOH, KOH, K2CO 3 , triethylamine or cesium carbonate and a solvent such as DMF to obtain compound of Formula (I) (wherein Rj is (Ci-C6)alkyl, e.g. ethyl).
  • a base selected from sodium hydride, n-butyllithium, NaOH, KOH, K2CO 3 , triethylamine or cesium carbonate and a solvent such as DMF to obtain compound of Formula (I) (wherein Rj is (Ci-C6)alkyl, e.g. ethyl).
  • the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 6.
  • Step 6a Diisopropyl azodicarboxylate (DIAD), triphenylphosphine;
  • Step 6b Phosphorus tribromide, DCM
  • Step 6c Cesium carbonate, DMF
  • Step 6d L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT.
  • compound of formula: A-OH (wherein A is as defined above for any one embodiments of the compounds of formula (I)) is reacted with cyclopropyldimethanol in the presence of a reagent such as diisopropyl azodicarboxylate or diethylazodicarboxylate and triphenylphosphine to obtain compound (19) (wherein A is as defined above).
  • the compound (19) is subjected to bromination in the presence of a brominating agent such as phosphorus tribromide in a solvent selected from DCM, dichloroethane, chloroform, ether, EtOAc or a mixture thereof to obtain compound (20) (wherein A is as defined above).
  • a brominating agent such as phosphorus tribromide in a solvent selected from DCM, dichloroethane, chloroform, ether, EtOAc or a mixture thereof to obtain compound (20) (wherein A is as defined above).
  • step lb of the process depicted in scheme 1 the compound (20) is reacted with the compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a base selected from CS2CO 3 or K2CO 3 and a solvent such as DMF to obtain the compound of Formula (I) (wherein Rj is (Q- C 6 )alkyl, e.g. ethyl).
  • the compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl) as obtained in Step 6c, is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or barium hydroxide (Ba(OH) 2 ), followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I), (wherein Rj is hydrogen).
  • the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 7.
  • Step 7a Trifluoroacetic acid, sodium borohydride, toluene, acetonitrile;
  • Step 7b Formaldehyde, sodium cyanoborohydride, acetic acid, MeOH;
  • Step 7c Palladium on carbon, hydrogen, ammonium formate, MeOH;
  • Step 7d and Step 7e Cesium carbonate, DMF
  • Step 7f L1OH.H 2 O, THF, MeOH, water, aqueous ammonium chloride, RT.
  • Step 7b phenyl hydrazine is reacted with benzyl 4-formylpiperidine-l- carboxylate, in the presence of trifluoroacetic acid and a reducing agent such as sodium borohydride, in a solvent selected from toluene, acetonitrile, dioxane, DCM or a mixture thereof to obtain compound (21).
  • a reducing agent such as sodium borohydride
  • the compound (21) is subjected to reductive methylation using formaldehyde in the presence of acetic acid and a reducing agent such as sodium cyanoborohydride in a solvent selected from MeOH, ethanol, isopropanol or a mixture thereof; to obtain compound (22) (wherein Rjo is methyl).
  • a reducing agent such as sodium cyanoborohydride in a solvent selected from MeOH, ethanol, isopropanol or a mixture thereof.
  • the compound (22) is subjected to deprotection in the presence of deprotecting agent such as palladium catalyst (Palladium on carbon) and ammonium formate in methanol, followed by hydrogenation to obtain compound (23) (wherein Rjo is methyl).
  • deprotecting agent such as palladium catalyst (Palladium on carbon) and ammonium formate in methanol
  • the compound (24), (wherein p is as defined above) is treated with compound (4) (obtained in step lb of the process depicted in scheme 1) in presence of a base selected from CS2CO 3 or K2CO 3 and a solvent such as DMF to obtain the compound (25) (wherein Rj is (C C 6 )alkyl, e.g. ethyl; R 2 , R 3 , R4, R5, m, n and p are as defined for any one of the embodiments of the compounds of Formula (I)).
  • the compound (23) (wherein Rjo is methyl) is reacted with the compound (25) (wherein Rj is (Ci-C6)alkyl, e.g. ethyl; R2, R 3 , R4, R5, m, n and p are as defined above) in presence of a base selected from CS2CO 3 or K2CO 3 and a solvent such as DMF to obtain the compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl).
  • the compound of Formula (I) (wherein Rj is (Cj-C6)alkyl, e.g. ethyl) as obtained in Step 7e, is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I) (wherein Rj is hydrogen).
  • the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 8.
  • Step 8a Lithium hexainethyldisilazide, tetrahydrofuran
  • Step 8b Trifluoroacetic acid, DCM
  • Step 8c Cesium carbonate, DMF
  • Step 8d L1OH.H 2 O, THF, MeOH, water, aqueous ammonium chloride, RT.
  • the compound (28) is subjected to deprotection in the presence of a deprotecting agent such as trifluoroacetic acid and a solvent selected from DCM, toluene, acetonitrile, dioxane or a mixture thereof; to obtain the compound (29).
  • a deprotecting agent such as trifluoroacetic acid and a solvent selected from DCM, toluene, acetonitrile, dioxane or a mixture thereof.
  • compound (29) can be obtained from commercial sources.
  • the compound (29) is reacted with the compound (25) (wherein Rj is (Q- Ce)alkyl, e.g. ethyl); R2, R3, R4, R5, m, n and p are as defined for Formula (I)), in presence of a base selected from CS2CO 3 or K2CO 3 and a solvent such as DMF to obtain the compound of Formula (I), (wherein Rj is (Ci-C6)alkyl, e.g. ethyl).
  • the compound of Formula (I) (wherein Ri is (Ci-Ce)alkyl, e.g. ethyl) as obtained in Step 8c, is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or barium hydroxide (Ba(OH)2), followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I) (wherein Ri is hydrogen).
  • the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 9.
  • Step 9a Sodium hydride, DMF;
  • Step 9b Phosphorus tribromide, DCM
  • Step 9c Cesium carbonate, DMF
  • Step 9d LiOH.F ⁇ O, THF, MeOH, water, aqueous ammonium chloride, RT.
  • compound (30a) (wherein k is 1 or 2) is reacted with compound (30b) (wherein Rio is as defined above) in the presence of a base selected from sodium hydride, n- butyllithium, NaOH, KOH, K2CO 3 or triethylamine and a solvent such as DMF to obtain compound (30c) (wherein k is 1 or 2 and Rio is as defined above for any one of the embodiments of the compounds of Formula (I)).
  • a base selected from sodium hydride, n- butyllithium, NaOH, KOH, K2CO 3 or triethylamine and a solvent such as DMF
  • the compound (30c) is treated with a brominating agent such as
  • step lb of the process depicted in scheme 1 the compound (30) is reacted with compound (4) (obtained in step lb of the process depicted in scheme 1), in the presence of a base selected from CS2CO3 or K2CO 3 and a solvent such as DMF to obtain the compound of Formula (I), (wherein Ri is (Ci-C6)alkyl, e.g. ethyl).
  • the compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl) as obtained in Step 9c, is taken in a solvent selected from THF, ethanol, methanol, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain the compound of Formula (I) (wherein Rj is hydrogen).
  • the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 10.
  • Step 10a Methoxylamine hydrochloride, sodium acetate, glacial acetic acid
  • Step 10b Cesium carbonate, DMF
  • Step 10c and Step 10c' Potassium carbonate, acetonitrile, reflux;
  • Step 10c Sodium borohydride, methanol, RT;
  • Step lOd Phosphorus tribromide, DCM, RT;
  • Step lOe Triphenylphosphine, diethyl azodicarboxylate (DEAD), THF;
  • Step 10e' Cesium carbonate, DMF
  • Step lOf LiOH.H 2 0, THF, MeOH, water, aqueous ammonium chloride, RT.
  • the compound (31) (wherein A is as defined above for any one embodiments of the compounds of formula (I)) is treated with methoxylamine hydrochloride in the presence of a base such as sodium acetate and a solvent such as glacial acetic acid to obtain compound (32) (wherein A is as defined above).
  • the compound (32) is treated with 4-hydroxybenzaldehyde in the presence of a base selected from CS2CO 3 , K2CO 3 or sodium carbonate and a solvent such as DMF to obtain compound (33) (wherein A is as defined above).
  • Step 10c and Step 10c' are identical to Step 10c and Step 10c' :
  • a reducing agent such as sodium borohydride and a solvent selected from methanol, ethanol, isopropanol or a mixture thereof.
  • step 10c the compound (34) (wherein R' and R" together form as obtained in step 10c" is subjected to bromination in the presence of a brominating agent such as phosphorus tribromide and a solvent selected from DCM, dichloroethane, acetonitrile, ether, toluene or a mixture thereof; to obtain compound (35) (wherein A is as defined above and R' and R" together form
  • a reagent such as diisopropyl azodicarboxylate or diethylazodicarboxylate and triphenylphosphine
  • Step 10e'
  • the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 11.
  • Step 11a Cesium carbonate, DMF, RT;
  • Step l ib L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT.
  • the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 12.
  • R- is (C C 6 ) alkyl
  • Step 12a N ⁇ hromosuccimmide or bromine, carbon tetrachloride, RT;
  • Step 12b Cesium carbonate, DMF
  • Step 12c methoxylamine, ethanol, pyridine, reflux;
  • Step 12d and Step 12e LiOH.H 2 0, THF, MeOH, water, aqueous NH 4 C1, RT.
  • brominating agent such as N-bromosuccinimide or bromine
  • a base such as pyridine
  • a solvent selected from methanol, ethanol, n- propanol, isopropanol, acetonitrile or a mixture thereof to obtain the compound of Formula (I) (wherein R' and R" together form and Ri is (Ci-C 6 )alkyl, e.g. ethyl
  • the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 13.
  • Step 13a Rn -halogen, potassium carbonate, acetonitrile
  • Step 13b Lithium aluminum hydride, THF
  • Step 13c Tosyl chloride, triethylamine or pyridine;
  • Step 13d Cesium carbonate, DMF
  • Step 13e hydrogen, palladium on carbon, methanol
  • Step 13f and Step 13g L1OH.H 2 O, THF, MeOH, water, aqueous ammonium chloride, RT.
  • the compound (39) (wherein Ri is (Ci-C6)alkyl, e.g. ethyl, R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloaikyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S; R 4 and n are as defined for Formula (I)
  • a compound of formula: Rn-halogen wherein Rn is unsubstituted or substituted (Ci-Ce)alkyl
  • a base selected from K2CO 3 , sodium carbonate, CS2CO3, NaOH or KOH
  • R' and R" together form a saturated or a partially unsaturated (C3-C8)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
  • Rn is unsubstituted or substituted (Ci-Ce)alkyl;
  • R 4 and n are as defined for Formula (I)).
  • the compound (40) is subjected to reduction in the presence of a base such as lithium aluminum hydride and a solvent such as THF to obtain a compound (41) (wherein R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S; Rn is unsubstituted or substituted (Ci-Ce)alkyl; R 4 and n are as defined for Formula (I)).
  • a base such as lithium aluminum hydride
  • a solvent such as THF
  • the compound (41) is treated with tosyl chloride in the presence of a base such as triethylamine or pyridine and a solvent selected from dichloroe thane, DCM, diethylether, THF or a mixture thereof to obtain compound (42) (wherein R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S; Rn is unsubstituted or substituted (Ci-Ce)alkyl, P2 is tosyl, R ⁇ and n are as defined for Formula (I)) ⁇
  • a base such as triethylamine or pyridine
  • a solvent selected from dichloroe thane, DCM, diethylether, THF or a mixture thereof to obtain compound (42) (wherein R' and R" together form a saturated or a partially unsaturated (C3
  • the compound (42) is reacted with the compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a base selected from CS2CO3 or K2CO 3 and a solvent such as DMF to obtain the compound of Formula (I) (wherein Rn is unsubstituted or substituted (Ci-Ce)alkyl; R' and R" together form a saturated or a partially unsaturated (C3- Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S and Rj is (Ci-C6)alkyl, e.g. ethyl).
  • Step 13d the compound of Formula (I) obtained in Step 13d (wherein R n is substituted (Ci-Ce)alkyl such as benzyl) is subjected to palladium catalyzed hydrogenation in the presence of palladium catalyst such as palladium on carbon to obtain compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl and R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S).
  • Rj is (Ci-Ce)alkyl, e.g. ethyl and R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms
  • the compound of Formula (I), (wherein Ri is (Ci-Ce)alkyl, e.g. ethyl) obtained in Step 13d is taken in a solvent selected from THF, ethanol, methanol, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I) (wherein Ri is hydrogen and Rn is unsubstituted or substituted (Ci-Ce)alkyl and R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S).
  • the compound of Formula (I), (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl) obtained in Step 13e is taken in a solvent selected from THF, ethanol, methanol, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I) (wherein Rj is hydrogen and R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S).
  • the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 14.
  • Step 14a n-Butyl lithium, THF
  • Step 14b Triphenyl phosphine, Diethyl azodicarboxylate (DEAD), THF;
  • Step 14c L1OH.H 2 O, THF, MeOH, water, aqueous ammonium chloride, RT.
  • step lb of the process depicted in scheme 1 compound (44) is reacted with a compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a reagent such as diethylazodicarboxylate or diisopropyl azodicarboxylate and triphenylphosphine to obtain the compound of Formula (I) (wherein Rj is (Ci-C6)alkyl, e.g.
  • Rn is unsubstituted or substituted (Ci-Ce)alkyl such as benzyl; and R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S).
  • a solvent selected from THF, ethanol, MeOH, water or a mixture thereof
  • the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 15.
  • Step 15a Triphenyl phosphine, Diethyl azodicarboxylate (DEAD), THF;
  • Step 15b L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT.
  • the compound (45) (wherein R 1 2 is halogen, (Ci-Ce)alkyl, cyano, nitro, amino, halo(Ci-C6)alkyl, -S02(Ci-Ce)alkyl or (Ce-Cio)aryl; m is an integer from 1 to 4 and R 2 is bonded to any atom of the indane ring) is reacted with the compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a reagent such as diethylazodicarboxylate or diisopropyl azodicarboxylate and triphenylphosphine to obtain the compound of Formula (I), (wherein Rj is (Ci-Ce)alkyl, e.g.
  • Rj2 is halogen, (Q- Ce)alkyl, cyano, nitro, amino, halo(Ci-Ce)alkyl, -S02(Ci-C6)alkyl or (C6-Cio)aryl and m is an integer from 1 to 4).
  • the compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl) , obtained in Step 15a, is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, lithium hydroxide (LiOH) or Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I) (wherein Rj is hydrogen and Rj2 is halogen, (Ci-Ce)alkyl, cyano, nitro, amino, halo(C 1 -C 6 )alkyl, -S0 2 (Ci-C 6 )alkyl or (C 6 -C 10 )aryl).
  • the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 16.
  • Steps 16a and 16c Cesium carbonate ( €3 ⁇ 4 €(3 ⁇ 4), DMF; Step 16b: Triethylamine, 4-methylbenzene-l-sulfonyl chloride and dichloromethane.
  • the compound (4) (obtained in step lb of the process depicted in scheme 1), is reacted with the compound (46) (wherein R' and R" together form a saturated or a partially unsaturated (C3-C8)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S) in the presence of a base such as CS2CO 3 and a solvent such as DMF to obtain the compound (47) (wherein Ri is (Ci-Ce)alkyl, e.g.
  • R' and R" together form a saturated or a partially unsaturated (C 3 -Cg)cycloaikyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S; R2, R 3 , R4, R5, m and n are as defined for Formula (I)).
  • the compound (47) is reacted with 4-methylbenzene-l-sulfonyl chloride in presence of a base such as triethylamine and a solvent such as DCM to obtain the compound (48) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl, R' and R" together form a saturated or a partially unsaturated (C 3 -Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S; R2, R 3 , R 4 , R5, m and n are as defined for Formula (I)).
  • a base such as triethylamine
  • a solvent such as DCM
  • the compound (48) is reacted with a compound of formula A-OH (wherein A is as defined above for any one embodiments of the compounds of formula (I)) in presence of a base such as CS2CO 3 and a solvent such as DMF to obtain the compound of Formula (I) (wherein Rj is (Q-Ce ⁇ lkyl, e.g. ethyl and R' and R" together form a saturated or a partially unsaturated (C 3 -Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S; R2, R 3 , R 4 , R5, m and n are as defined for Formula (I)).
  • the compound of Formula (I) thus obtained, can be optionally hydrolyzed to obtain a compound of Formula (I) (wherein Rj is hydrogen).
  • the compounds of Formula (I) of the present invention contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms, as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image cohort, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers and enantiomers, as well as mixtures thereof such as racemic mixtures, geometric isomers form part of the present invention.
  • the compounds of Formula (I) of the present invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixtures.
  • the enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which can be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer- specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • the "R” forms of the compounds are substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the "S” forms.
  • “S” forms of the compounds are substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the "R” forms.
  • Enantiomeric excess is the presence of a particular enantiomer at greater than 50%. In a particular embodiment when a specific absolute configuration is designated, the enantiomeric excess of depicted compounds is at least about 90%.
  • a compound of Formula (I) of the present invention has two or more chiral carbons it can have more than two optical isomers and can exist in diastereoisomeric forms.
  • the compound when there are two chiral carbons, the compound can have up to 4 optical isomers and 2 pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)).
  • the pairs of enantiomers e.g., (S,S)/(R,R)
  • the stereoisomers that are not mirror-images e.g., (S,S) and (R,S)
  • the diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair can be separated as described above.
  • the present invention includes each diastereoisomer of such compounds and mixtures thereof.
  • the isotopically labeled forms of the compounds of Formula (I), can be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described above or in the subsequent section on examples by using a corresponding isotopically labeled reagent in place of the non-labeled reagent.
  • the compounds of Formula (I) exists as tautomers, and it is intended to encompass all the tautomeric forms of the compounds within the scope of the present invention.
  • the compounds of Formula (I) in their free base form are converted to their corresponding pharmaceutically acceptable salts.
  • the pharmaceutically acceptable salt of the compounds of Formula (I) are prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compound described herein.
  • pharmaceutically acceptable base addition salts of the compounds of the present invention may include their alkali metal salts such as sodium, potassium, calcium, magnesium, ammonium or an organic base addition salt.
  • pharmaceutically acceptable organic base addition salts of the compounds of the present invention include those derived from organic bases like lysine, arginine, metformin, guanidine, diethanolamine, or other organic bases known to a person skilled in the art.
  • the compounds of Formula (I) of the present invention can form an addition salt with an inorganic or an organic acid.
  • pharmaceutically acceptable acid addition salts include those derived from inorganic acids like boric acid, perchloric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydriodic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, phosphorous acids or other inorganic acids known to the person skilled in the art.
  • examples of pharmaceutically acceptable acid addition salts include the salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, oxalic acid, malic acid acid, tartaric acid, citric acid, ascorbic, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, glucuronic acid, galacturonic acid, naphthoic acid, camphoric acid or other organic acids known to the person skilled in the art.
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of compounds of Formula (I) are selected from glucoronate, glutarate, lactate, oxalate, acetate, cinnamate, malonate, maleate, citrate, crotonate, ascorbate, toluenesulfonate, methanesulfonate, tartrate, hydrochloride or metformin salt.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the subject compound i.e. the compound of Formula (I) which contains a basic or acidic moiety by conventional chemical methods.
  • the salts are prepared by contacting the free base or acid with desired salt-forming inorganic or organic acid or a base in a suitable solvent or dispersant or by anion exchange or cation exchange with other salts.
  • suitable solvents are, for example, ethyl acetate, ethers, alcohols, acetone, or mixtures of these solvents.
  • the present invention furthermore includes all the solvates of the compounds of Formula (I), for example, hydrates and the solvates formed with other solvents of crystallisation, selected from alcohols such as methanol, ethanol, 1-propanol or 2-propanol, ethers such as diethyl ether, isopropyl ether or THF, esters such as methyl acetate or ethyl acetate, ketone such as acetone or their mixtures thereof.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
  • polymorphs of the compounds of Formula (I) within the scope of the present invention.
  • Various polymorphs of the compounds of the present invention can be prepared by standard crystallisation procedures known in the art. The crystallisation technique employed can utilize various solvents or their mixtures, temperature conditions and various modes of cooling, ranging from very fast to very slow cooling. The presence of polymorphs can be determined by IR (Infra-red) spectroscopy, solid probe NMR (Nuclear Magnetic Resonance) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other standard techniques. Furthermore, the present invention also includes prodrugs of the compounds of Formula (I).
  • the prodrugs of the compounds of the present invention are relatively simple derivatives of the aforesaid compounds of the invention which upon administration to a subject in need thereof undergoes chemical conversion by metabolic or chemical processes to release the parent drug in vivo from which the prodrug is derived.
  • the preferred prodrugs are pharmaceutically acceptable ester derivatives e.g., alkyl esters, cycloalkyl esters, alkenyl esters, benzyl esters, mono- or di-substituted alkyl esters convertible by solvolysis under physiological conditions to the parent carboxylic acid, and those conventionally used in the art.
  • the present invention further relates to carboxylic acid isosteres of the compounds of Formula (I).
  • the present invention also relates to N-oxide derivatives of the compounds of Formula (I).
  • the present invention also relates to S-oxide derivatives of the compounds of Formula
  • the present invention relates to a method for modulating GPR40 function in a cell comprising contacting the cell with an effective amount of compound of Formula (I).
  • the compounds of Formula (I) are GPR40 agonists.
  • the compounds of Formula (I) find use in the treatment of a disease or a condition mediated by GPR40.
  • the present invention relates to a method for the treatment of a disease or a condition mediated by GPR40, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, a carboxylic acid isostere, an N-oxide or a S-oxide thereof.
  • the present invention relates to a method for the treatment of a disease or a condition mediated by GPR40, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof.
  • the present invention provides use of the compound of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, a carboxylic acid isostere, an N-oxide or a S-oxide thereof; for the treatment of a disease or a condition mediated by GPR40.
  • the present invention relates to use of the compound of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof; for the treatment of a disease or a condition mediated by GPR40.
  • the present invention relates to use of the compounds of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, a carboxylic acid isostere, an N-oxide or a S-oxide thereof; in the manufacture of a medicament for the treatment of a disease or a condition mediated by GPR40.
  • the present invention relates to use of compounds of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof; in the manufacture of a medicament for the treatment of a disease or a condition mediated by GPR40.
  • a disease or a condition mediated by GPR40 refers to a disease or a disorder or a condition characterized by inappropriate, for example, less than or greater than normalGPR40 activity.
  • a GPR40-mediated disease or disorder may be completely or partially mediated by inappropriate GPR40 activity.
  • the disease or condition mediated by GPR40 is selected from the group consisting of diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, cardiovascular disease, atherosclerosis, kidney disease, polycystic ovary syndrome, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, fatty liver development, dermatopathy, dyspepsia, hypoglycemia, cancer, edema and a disorder related to glucose levels such as pancreatic beta cell regeneration.
  • the disease or condition mediated by GPR40 is selected from the group consisting of diabetes, obesity, insulin resistance, hyperglycemia, glucose intolerance, hypercholesterolemia, hypertriglylceridemia, dyslipidemia, hyperlipoproteinemia, hyperinsulinemia, atherosclerosis, diabetic neuropathy, diabetic retinopathy, metabolic syndrome, hypertension and pancreatic beta cell degeneration.
  • the disease or condition mediated by GPR40 is selected from the group consisting of diabetes, obesity, insulin resistance, hyperglycemia, glucose intolerance, metabolic syndrome and pancreatic beta cell degeneration.
  • diabetes is Type 2 diabetes.
  • the disease or condition mediated by GPR40 is a metabolic disorder which refers to one or more diseases or conditions as identified above.
  • the present invention relates to a method for the treatment of a metabolic disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof.
  • the present invention provides use of the compound of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof for the treatment of a metabolic disorder.
  • the present invention relates to use of the compounds of Formula (I) or pharmaceutically acceptable salts thereof in the manufacture of a medicament, for the treatment of a metabolic disorder.
  • metabolic disorder refers a disorder relating to abnormality of metabolism. Accordingly, in the context of the present invention all. the disorders relating to abnormility of metabolism are encompassed in the term "metabolic disorders”.
  • the metabolic disorders are selected from diabetes, obesity, cardiovascular disease, hypertension, ketoacidosis, insulin resistance, glucose intolerance, hyperglycemia, hypertriglylceridemia, polycystic ovary syndrome, hypercholesterolemia, hyperlipoproteinemia, dyslipidemia, metabolic syndrome, hyperlipidemia, diabetic neuropathy, diabetic retinopathy, edema and related disorders associated with abnormal plasma lipoprotein, triglycerides or pancreatic beta cell degeneration.
  • diabetes mellitus refers to a chronic disease or condition, which occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. This leads to an increased concentration of glucose in the blood (hyperglycaemia).
  • Type 1 diabetes Insulin- dependent diabetes mellitus
  • Type 2 diabetes Non-insulin dependent diabetes mellitus (NIDDM)
  • Type 1 diabetes is an autoimmune condition in which the insulin-producing ⁇ - cells of the pancreas are destroyed which generally results in an absolute deficiency of insulin, the hormone that regulates glucose utilization.
  • Type 2 diabetes often occurs in the face of normal or even elevated levels of insulin and can result from the inability of tissues to respond appropriately to insulin.
  • Other categories of diabetes include gestational diabetes (a state of hyperglycemia which develops during pregnancy) and "other" rarer causes (genetic syndromes, acquired processes such as pancreatitis, diseases such as cystic fibrosis, and exposure to certain drugs, viruses, and unknown causes).
  • diabetes refers to Type 2 diabetes.
  • metabolic syndrome refers to a cluster of metabolic abnormalities including abdominal obesity, insulin resistance, glucose intolerance, diabetes, hypertension and dyslipidemia. These abnormalities are known to be associated with an increased risk of vascular events.
  • cardiovascular disease refers to any disease of the heart or blood vessels.
  • One or more diseases of heart encompassed in the term “cardiovascular disease” is selected from, but is not limited to, angina, arrhythmia, coronary artery disease (CAD), cardiomyopathy, myocardial infarction, heart failure, hypertrophic cardiomyopathy, mitral regurgitation, mitral valve prolapse, pulmonary stenosis, etc.
  • the blood vessel disease encompassed in the term “cardiovascular diseases” is selected from, but is not limited to, for example, peripheral vascular disease, artery disease, carotid artery disease, deep vein thrombosis, venous diseases, atherosclerosis and the like.
  • the metabolic disorder is selected from: diabetes, obesity, insulin resistance, hyperglycemia, glucose intolerance, hypercholesterolemia, hypertriglylceridemia, dyslipidemia, hyperlipoproteinemia, hyperinsulinemia, atherosclerosis, diabetic neuropathy, diabetic retinopathy, metabolic syndrome, hypertension or pancreatic beta cell degeneration.
  • the metabolic disorder is selected from diabetes, obesity, insulin resistance, glucose intolerance, dyslipidemia, hyperinsulinemia, metabolic syndrome or pancreatic beta cell degeneration.
  • the metabolic disorder is Type 2 diabetes.
  • the present invention furthermore relates to pharmaceutical compositions that contain a therapeutically effective amount of at least one compound of Formula (I) or its pharmaceutically acceptable salt in addition to a customary pharmaceutically acceptable carrier, and to a process for the production of a pharmaceutical composition, which includes bringing at least one compound of Formula (I), into a suitable administration form using a pharmaceutically suitable and physiologically tolerable excipient and, if appropriate, further suitable active compounds, additives or auxiliaries.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising substituted heterocyclic derivatives, the compounds of Formula (I) or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient for use as GPR40 agonists and in the treatment of a disease or a condition mediated by GPR40.
  • pharmaceutically acceptable means that the carrier, diluents, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
  • pharmaceutically acceptable carrier means a non-toxic, inert, solid, semi-solid, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; malt; gelatin; talc; as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents; preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
  • the present invention provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one further therapeutically active agent, together with a pharmaceutically acceptable carrier.
  • the present invention relates to use of the compound of Formula (I) or a pharmaceutically acceptable salt thereof; in combination with a further therapeutically active agent, in the treatment of a disease or a condition mediated by GPR40.
  • the therapeutically active agent used in combination with one or more of the compounds of Formula (I) can be selected from the compounds or active substances known to be used in the treatment of diabetes and other conditions such as obesity, insulin resistance, hyperglycemia, glucose intolerance, hypercholesterolemia, hypertriglylceridemia, dyslipidemia, hyperlipoproteinemia, hyperinsulinemia or atherosclerosis.
  • the therapeutically active agent, used in combination with the compounds of Formula (I) of the present invention can be selected from, but not limited to, insulin, sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, inhibitors of glycogen phosphorylase, glucagon antagonists, HMGCoA reductase inhibitor, GLP-1 (Glucogen-like peptide- 1) agonists, potassium channel openers, inhibitors of dipeptidylpeptidase IV (DPP-IV), insulin sensitizers, modulators of glucose uptake, of glucose transport and of glucose reabsorption, modulators of the sodium- dependent glucose transporter 1 or 2 (SGLTl, SGLT2), compounds which alter lipid metabolism such as antihyperlipidemic active ingredients and antilipidemic active ingredients, PPARgamma agonists and agents with combined PPARalpha and gamm
  • the compound of Formula (I) can be used in combination with a PPAR gamma agonist selected from rosiglitazone, pioglitazone, rivoglitazone and the like.
  • the compound of Formula (I) can be used in combination with a HMGCoA reductase inhibitor selected from simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin and the like.
  • a HMGCoA reductase inhibitor selected from simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin and the like.
  • the compound of Formula (I) can be used in combination with a sulfonylurea selected from tolbutamide, glibenclamide, glipizide, glimepiride and the like.
  • the compound of the Formula (I) can be used in combination with a meglitinide selected from repaglinide, nateglinide, mitiglinide and the like.
  • the compound of the Formula (I) can be used in combination with GLP-1 agonist selected from exenatide, liraglutide, taspoglutide albiglutide, lixisenatide and the like.
  • the compound of the Formula (I) can be used in combination with DPP-IV inhibitor selected from alogliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin and the like.
  • the further therapeutically active agent that can be used in combination with one or more compounds of Formula (I) encompassed in the present invention can be selected from one or more of the agents including, but not limited to, insulin, rosiglitazone, pioglitazone, rivoglitazone, simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, tolbutamide, glibenclamide, glipizide, glimepiride, repaglinide, nateglinide, mitiglinide, exenatide, liraglutide, taspoglutide albiglutide, lixisenatide, alogliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin and the like.
  • the agents including, but not limited to, insulin, rosiglitazone
  • the compounds of Formula (I) alone or in combination with other active substances can be administered in conjunction with physical excercises and/ or with diet restriction as advisable by a person skilled in the art.
  • compositions according to the present invention are prepared in a manner known and familiar to one skilled in the art.
  • Pharmaceutically acceptable inert inorganic and/or organic carriers and/or additives can be used in addition to the compounds of Formula (I) and/or its pharmaceutically acceptable salts.
  • Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils, etc.
  • Suitable carriers for the production of solutions for example injection solutions, or of emulsions or syrups are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the various solvents which have been mentioned.
  • the pharmaceutical composition of the present invention also contains additives such as, for example, fillers, antioxidants, emulsifiers, preservatives, flavours, solubilisers or colourants.
  • additives such as, for example, fillers, antioxidants, emulsifiers, preservatives, flavours, solubilisers or colourants.
  • the pharmaceutical composition of the present invention may also contain two or more substituted heterocyclic_derivatives i.e. compounds of Formula (I) and/or its physiologically tolerable salts, the pharmaceutical compositions can also contain one or more other therapeutically or prophylactically active ingredients.
  • compositions normally contain about 1 to 99%, for example, about 10 to 80%, by weight of the compounds of Formula (I) or their pharmaceutically acceptable salts.
  • the amount of the active ingredient, substituted heterocyclic derivative i.e. the compound of Formula (I) or its pharmaceutically acceptable salt in the pharmaceutical compositions can, for example, vary from about 1 to 500 mg. In case of higher body weight of the mammal in need of the treatment, the pharmaceutical composition may contain the compound of Formula (I) in an amount ranging from 5 mg to 1000 mg.
  • the desirable dosage of the substituted heterocyclic derivatives i.e. the compounds of Formula (I) can be selected over a wide range.
  • the daily dosage to be administered is selected to achieve the desired therapeutic effect in subjects being treated for metabolic disorders.
  • a dosage of about 0.05 to 50 mg/kg/day of the substituted heterocyclic derivatives i.e. the compounds of Formula (I) or its pharmaceutically acceptable salt may be administered.
  • a dosage of about 0.1 to 100 mg/kg/day of the compound of Formula (I) or its pharmaceutically acceptable salt may be administered. If required, higher or lower daily dosages can also be administered.
  • Actual dosage levels of the active ingredients in the pharmaceutical composition of this present invention can be varied so as to obtain an amount of the active ingredient, which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.
  • the selected dosage level can be readily determined by a skilled medical practitioner in the light of the relevant circumstances, including the condition (diseases or disorder) to be treated, the chosen route of administration depending on a number of factors, such as age, weight and physical health and response of the individual patient, pharmacokinetics, severity of the disease and the like, factors known in the medical art.
  • compositions according to the present invention can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of solutions or transdermal patches, or in other ways, for example in the form of aerosols or nasal sprays.
  • Nomenclature of the compounds exemplified in the present invention was derived from Chemdraw Ultra version 9.0.1 CambridgeSoft Corporation, Cambridge.
  • reaction mixture was then stirred for 45 minutes. After the completion of reaction, the reaction mixture was diluted with ethyl acetate (25 mL), washed with 5% aqueous ammonia, brine, dried over Na 2 S0 4 and concentrated. The residue was purified by flash column chromatography (silica gel column, 10%-20% ethyl acetate/ petroleum ether).
  • reaction mixture was poured in ice-cold water, extracted with diethyl ether, dried over Na 2 S0 4 , concentrated and purified by flash column chromatography (silica gel column, 0-40% DCM/petroleum ether).
  • Trifluoroacetic acid (0.4 mL) was added to an ice-cold solution of teri-butyl spiro[indene-l,4'-piperidine]- -carboxylate (compound of step 1, 1.226 mmol) in DCM (5 mL) and the reaction mixture was stirred for 2-4 h. The solvent is evaporated to obtain the title compound.
  • ni-Chioroperoxybenzoic acid (44.4 mmol) was added drop wise to the cold solution of methyl 3-((2-methoxy-2-oxoethyl)thio)-4,5-dihydronaphtho[ 1 ,2-c]thiophene- 1 -carboxylate (compound of step 1, 14.1 mmol) in DCM and the reaction mixture was stirred at RT for 4 h. After completion of the reaction, the reaction mixture was filtered over celite® bed and the residue was washed with EtOAc. The filtrate was stirred with aqueous sodium carbonate and sodium bisulfite (NaHSOs). The organic layer was dried over Na 2 S0 4 and concentrated under high vacuum to obtain the title compound.
  • Phosphorus tribromide (2.038 mmol) was added to an ice-cold solution of (3- (methylsulfonyl)-4,5-dihydronaphtho [l,2-c]thiophen-l-yl)methanol (compound of step 5, 3.40 mmol) in dry DCM (20 mL). The reaction mixture was stirred at 0 °C for 1 h. After completion of the reaction, DCM was added to the reaction mixture. The reaction mixture was washed with water, aqueous sodium bicarbonate, dried over Na 2 S0 4 and concentrated to obtain the title compound.
  • DMAP 4- dimethylaminopyridine
  • p-TsCl 4-toiuenesulfonyl chloride
  • Ethyl 2-(3-(4-(3-(phenylthio)propoxy)phenyl)oxetan-3-yl)acetate (Compound 7) A solution of thiophenol (0.557 mmol), ethyl 2-(3-(4-(3-(tosyloxy)propoxy) phenyl)oxetan-3-yl)acetate (compound of step 2 of Example 5, 0.557 mmol) and CS2CO 3 (1.115 mmol) in DMF (4 mL) was stirred at RT for 3 h. After completion of the reaction, the solvent was evaporated and the residue was quenched with ice-cold water and extracted with ethyl acetate.
  • Ethyl 2-(3-(4-(3-(phenylsulfonyl)propoxy)phenyl)oxetan-3-yl)acetate (Compound 10) A solution of ethyl 2-(3-(4-(3-(phenylthio)propoxy)phenyl)oxetan-3-yl)acetate (Compound 7, 0.316 mmol) in MeOH (5 mL) and water (5 mL) was cooled to 10-15 °C. Potassium peroxymonosulfate (Oxone®) (0.789 mmol) was added to the reaction mixture in portions. The reaction mixture was stirred overnight at RT. After the completion of the reaction the reaction mixture was filtered over celite® bed.

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Abstract

The present invention generally relates to substituted heterocyclic derivatives (the compounds of Formula (I)), processes for their preparation, pharmaceutical compositions containing said compounds, their use as G-protein coupled receptor (GPR) agonists, particularly as GPR40 agonists and methods of using these compounds in the treatment of GPR40 mediated diseases or conditions such as Type 2 diabetes, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.

Description

Substituted Heterocyclic Derivatives as GPR agonists and Uses Thereof
Field of the Invention
The present invention generally relates to substituted heterocyclic derivatives (the compounds of Formula (I)), processes for their preparation, pharmaceutical compositions containing said compounds, their use as G-protein coupled receptor (GPR) agonists, particularly as GPR40 agonists and methods of using these compounds in the treatment of GPR40 mediated diseases or conditions such as Type 2 diabetes, obesity, dyslipidemia, hyperlipidemia, hypercholesterolemia, and hypertriglyceridemia.
Background of the Invention
Obesity is a major health problem throughout the world. It is a risk factor for developing insulin resistance, type 2 diabetes, hypertension, and cardiovascular diseases (Circulation, 2003, 107:1448-1453). Obesity is typically associated with elevated levels of free fatty acids (FFAs) and is linked to glucose intolerance and type 2 diabetes (Cell Metab., 2005, l(4):245-58).
According to one report, the prevalence of diabetes was 347 million patients worldwide in the year 2004 (The Lancet, 2011, 378 (9785): 31-40) and is expected to grow to 439 million adult patients by 2030 (Diabetes Res. Clin. Pract., 2010, 87(1):4-14). The increasing incidence is largely driven by the dramatic rise in obesity, especially in Western societies. Type 2 diabetes accounts for 90-95% of all diabetes. Complex networks of signaling pathways are activated when the insulin receptor is stimulated, but in patients who suffer from type 2 diabetes, those receptors on cells in tissues such as muscle, fat and liver become less responsive or resistant to insulin. In addition, patients with type 2 diabetes are typically characterized by reduced glucose stimulated insulin secretion (GSIS) (Expert Opin. Ther. Patents, 2009, 19(2): 237-264).
Metabolic syndrome, also known as Syndrome-X, is characterized by a cluster of conditions, including insulin resistance, obesity, hypertension and dyslipidemia. Persistent obesity disregulates metabolic processes including action of insulin on glucose-lipid-free fatty acid metabolism and severely affects processes controlling blood glucose, blood pressure, and lipids. It is also well recognized that people with obesity and metabolic syndrome are at an increased risk of developing type 2 diabetes and cardiovascular diseases. Prevalence of obesity and metabolic syndrome has shown a rapid rise in developing countries in the past few decades and has led to increased risk of cardiovascular diseases and consequent morbidity and mortality (JRAAS, 2006, 7(1):S12-S18; J. Clin. Endocrinol. Metab., 2008, 93(11):S9-S30).
Relatively recently the function of the G-protein coupled receptor, particularly G- protein coupled receptor 40 (GPR40) is recognised in modulating insulin secretion, which has provided insight into regulation of carbohydrate and lipid metabolism. This has lead to the targets for the development of therapeutic agents for disorders such as obesity, diabetes, cardiovascular disease and dyslipidemia.
G-protein coupled receptors (GPCRs) constitute a super family of membrane proteins activated by a variety of endogenous ligands such as hormones, neurotransmitters, peptides, proteins, steroids as wells as fatty acids (FAs) and other lipids (Diabetes Obes. Metab., 2009, 11(4): 1-18). Impaired GSIS are a prominent feature of overt type 2 diabetes and FFAs are known to influence insulin secretion from β-cells primarily by enhancing GSIS. G-protein coupled receptors (GPCRs) such as GPR40, whose endogenous ligands are medium and long chain free fatty acids, are known to play an important role in insulin release.
The G-protein coupled receptor, GPR40, alternatively called the FFA receptor 1, is Gaq-coupled Class 1 GPCR and a member of a small family of fatty acid sensing GPCRs. GPR40 is preferentially expressed in β-cells and is activated by medium to long chain FFAs, thereby triggering a signaling cascade that results in increased levels of [Ca2+] in β-cell lines (Diabetes, 2008, 57:2280-87 and Bioorganic & Medicinal Chemistry Letters, 2012, 22:1267- 1270).
Studies conducted in animals (mice) further established that loss of GPR40 protects mice from obesity induced hyperglycemia, glucose intolerance, hyperinsulinemia, fatty liver development, hepatic glucose output and hypertriglyceridemia (Diabetes, 2008, 57:2280-87).
Several small molecule GPR agonists are known and have been reported in various publications and patents. PCT published application WO2005086661A2, discloses compounds capable of modulating the G-protein coupled receptor GPR40, compositions comprising the compounds and methods for their use in controlling insulin levels in vivo and for the treatment of conditions such as type 2 diabetes, hypertension, ketoacidosis, obesity, glucose intolerance and hypercholesterolemia and related disorders associated with abnormally high or low plasma lipoprotein, triglyceride or glucose levels.
PCT published application WO200801931A1, discloses fused cyclic compounds which are useful as insulin secretagogues or agents for the prophylaxis or treatment of diabetes and related disorders. PCT published applications WO2009111056 Al and WO2010045258 A2 disclose spirocyclic compounds which act as GPR40 modulators, compositions comprising the compounds and methods for their use in the treatment or prevention of metabolic disorders, especially type 2 diabetes, obesity and related disorders. PCT published application WO2010123016A1 disclose carboxylic acid compounds which have GPR40 agonist activity and are useful as prophylactic and therapeutic agent for diabetes. PCT published application W0199965881 disclose heterocylic compounds as hypoglycemic agents. PCT published application WO2012011125A1 discloses compounds that have the ability to modulate the activity of GPR40, compositions comprising these compounds and their use in the treatment of disorders related to GPR40 activity, especially metabolic conditions, such as diabetes, obesity, hyperglycemia, insulin resistance, hypercholesteremia and related disorders.
Thus, in view of the role of GPR such as GPR40 in the pathophysiology of metabolic disorders, there exists a continuing medical need for safe and efficacious compounds which can function as GPR agonists.
Summary of the Invention
In one aspect, the present invention relates to a compound of Formula (I) (as described herein), an isotopic form, or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S- oxide, or a carboxylic acid isostere thereof.
In another aspect of the present invention, there is provided a process for the preparation of the compound of Formula (I).
In a further aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; and at least one pharmaceutically acceptable carrier or excipient.
In a further aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; and one further therapeutically active agent and at least one pharmaceutically acceptable carrier or excipient.
In another further aspect, the present invention relates to a method for modulating GPR40 function in a cell comprising contacting the cell with an effective amount of compound of Formula (I). In yet another aspect, the present invention provides a compound of Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; for use in the treatment or prophylaxis of a disease or a condition mediated by GPR40.
In yet another further aspect, the present invention provides a method for the treatment or prophylaxis of a disease or a condition mediated by GPR40, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.
In a still further aspect, the present invention relates to use of the compound of Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof in the manufacture of a medicament, for the treatment or prophylaxis of a disease or a condition mediated by GPR40.
In another further aspect, the present invention relates to use of the compound of Formula (I) or a stereoisomer, a tautomer, a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof; in combination with one further therapeutically active agent for the treatment or prophylaxis of a disease or a condition mediated by GPR40.
These and other objectives and advantages of the present invention will be apparent to those skilled in the art from the following description.
Detailed Description of the Invention
The present inventi ):
Figure imgf000005_0001
Formula (I)
wherein,
Rj is hydrogen or (Ci-Ce)alkyl;
R2 and R3 together form a saturated or a partially unsaturated 3- to 6- membered heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
R4 at each occurrence is independently selected from the group consisting of hydrogen, (Q- Ce)alkyl, halogen, hydroxy, amino, cyano, nitro, -C(0)R7 and -S(0)pR6;
Rx and Ry are independently selected from the group consisting of A-Li-X- and R5 ; provided that at least one of Rx and Ry is A-Lj-X-;
R5 is hydrogen, (Ci-C6) alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-C6)alkyl, (C6- Cio)aryl, amino, cyano, nitro, -C(0)R? or -S(0)pR6;
R6 is hydrogen, (Ci-Ce)alkyl or amino;
X is -0-, -(CH2)nO-, -(CH2)p(CR8R9)nCH20-, -(CH2)p(C6-C10aryl)kCH2O- or -(CR'R")P0-; Li is absent or is selected from the group consisting of -0-, -S(0)p-, -C(0)NH-,
-NHC(O)-, -NHC(0)NH-, -(CR'R")P-CH20-, -S(0)pNH-, -NHS(0)p-, -C(R'R")-,
-CH=CR8- and -(CR8R9)n-;
R' and R" together form =N(0-(Ci-C6)alkyl), =0, a saturated or a partially unsaturated (C3- C8) cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
R7 is (d-Ce) alkyl, -0(d-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, hydroxy or amino;
R8 and R9 at each occurrence are independently selected from the group consisting of hydrogen, (Ci-Ce) alkyl, (Ce-Cio)aryl and heteroaryl; or R8 and R9 together form =N(0-(Ci- C ) alkyl), =0, a saturated or a partially unsaturated (C3-Q) cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
-C6)alkyl, (C3-Cio)cycloaikyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl,
Figure imgf000006_0001
Rio is hydrogen, (Ci-Ce)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci- Ce)alkoxy, -S(0)PR6, amino, cyano, nitro or -C(0)R7; wherein R6 and R7 are as defined above;
k is an integer 1 or 2;
n is an integer from 1 to 3;
m is an integer from 1 to 4;
p is an integer from 0 to 2;
s is an integer from 1 to 4;
* indicates the point of attachment to Lj ; wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (C6-Cio)aryl, heterocyclyl, - heterocyclyl-(Ci-C6)alkyl-OH, heteroaryl, amino, cyano, nitro, -C(0)R7, -S(0)PR6, and - 0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
-0(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, (C3-Cg)cycloalkyl, (C6- Cio)aryl, heterocyclyl, hydroxy, halogen, amino, cyano, (Ci-C6)alkyl-S(0)pR6, -S(0)PR6, - NR8R and -(CH2)sNRgR ; wherein R6, Rs, R9, p and s are as defined above;
(C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, halo(Ci- C6)alkoxy, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C1-C6)alkyl(C6-C1o)aryl, wherein R\ R" and p are as defined above;
(C6-Cjo)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, haloCd-Q alkyl, hydroxy, -0(C C6)alkyl, -O(C C6)alkyl(C6-C10)aryl, halo(C C6) alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(Ci-C6)alkyl- S(0)pR6; wherein R6, R7, R', R" and p are as defined above;
heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, halogen, halo(d-C6) alkyl, hydroxy, -(XCi-C6)alkyl, halo(C C6) alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (Q- C6)alkyl-OH, (C1-C6)alkyl-0-(C1-C6)alkyl, (C1-C6)alkyl(C6-C1o)aryl, -C(0)R7, S(0)pR6 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, halogen, halo(C!-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci-Ce) alkoxy, (C3-Cg)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, - C(0)R7 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
halogen is chlorine, bromine, iodine or fluorine; provided that (i) when X is -(CH2)nO- and n is 1, A is not (C3-C10) cycloalkyl, (Ce-Cio)aryl, heterocyclyl or heteroaryl;
(ii) when X is -(CH2)p(C6-Cioaryl)kCH20- and p is 0 then Lj is not absent;
(iii) when X is -0-, Li is -(CRsR^n-, n is 1 and one of the variable Rs and R9 is hydrogen, the other variable is not hydrogen or (Ci-C6) alkyl; and
(iv) when either one of X and Li is -0-, the other is not -0-;
or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof.
Definitions
Unless otherwise indicated, the following definitions are set forth to illustrate and define the meaning and scope of the various terms used to describe the invention herein and the appended claims. These definitions should not be interpreted in the literal sense as they are not general definitions and are relevant only for this application.
It will be understood that "substitution," "substituted" or "substituted with" means that one or more hydrogens of the specified moiety are replaced with a suitable substituent and includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and results in a stable compound.
The terms "a", "an" and "the" refers to "one or more" when used in the subject specification, including the claims. Thus, for example, reference to "a. compound" may include a plurality of such compounds, or reference to "a disease" or "a condition" includes a plurality of diseases or disorders.
Also, use of "(s)" as part of a term, includes reference to the term singly or in plurality, for example, the term pharmaceutically acceptable salt(s) indicates a single salt or more than one salt of the compound of formula (I).
Within the context of the present invention, the term "(Ci-C6)alkyl" or "alkyl", as used herein, alone or as part of a substitutent group refers to an aliphatic group, including straight or branched chain alkyl group. A straight-chain or branched chain alkyl has six or fewer carbon atoms in its backbone, for instance, Ci-C6 for straight- chain and C3-C6 for branched chain. Suitable alkyl groups containing from one to six carbon atoms include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, 1- methylbutyl, secondary butyl, tertiary pentyl, neopentyl, 2,2-dimethylbutyl, 2-methylpentyl, 3-methylpentyl or 3-methylpentyl.
Furthermore, unless stated otherwise, the alkyl groups may be unsubstituted or substituted with one or more substituents, for instance, from one to five substituents independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cg)alkenyl, (C2-Cg) alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -O(Ci-Ce) alkyl, (C3-Cg)cycloalkyl, (C6- Cio)aryl, heterocyclyl, -heterocyclyl-(Ci-C6)alkyl-OH, heteroaryl, amino, cyano, nitro, - C(0)R7, -S(0)pR6, and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above. Examples of substituted alkyl include but are not limited to hydroxymethyl, trifluoromethyl or benzyl.
Within the context of the present application, the term "(C2-Cg)aikenyl" or "alkenyl", as used herein, alone or as part of a substituent group, refers to an unsaturated straight or branched chain hydrocarbon radical containing at least one carbon-carbon double bond (two adjacent sp carbon atoms). For example, the term "(C2-Cg)aikenyl" refers to an alkenyl group having two to eight carbon atoms. Depending upon the placement of double bond and substituents if any, the geometry of the double bond may be entgegen (E), or zusammen (Z), cis or trans. Examples of alkenyl include, but are not limited to, vinyl, allyl or 2-propenyl. Unless indicated otherwise, the alkenyl groups may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce) alkyl, hydroxy, -0(Ci-C6)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, nitro, cyano and -C(0)R7; wherein R7 is as defined above.
Within the context of the present application, and as used herein, the term "(C2- Cg)alkynyl" or "alkynyl" refers to an unsaturated, branched or straight chain having from two to eight carbon atoms and at least one carbon-carbon triple bond (two adjacent sp carbon atoms). Examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 3-propynyl and 4-butynyl. Unless stated otherwise, the alkynyl groups may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(C!-C6)alkyl, hydroxy, -0(C!-C6)alkyl, (C3-Cg)cycloalkyl, (C6- Cio)aryl, heterocyclyl, heteroaryl, amino, nitro, and cyano.
Within the context of the present application and as used herein, the term "haloalkyl" or "halo(Ci-C6)alkyl" refers to radicals wherein one or more of the hydrogen atoms of the alkyl group are substituted with one or more halogens. A monohaloalkyl radical, for example, may have a chlorine, bromine, iodine or fluorine atom. Dihalo and polyhaloalkyl radicals may have two or more of the same or different halogen atoms. Examples of "haloalkyl" or "halo(Ci-Ce) alkyl" include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, hepta fluoropropyl, difluorochloromethyl, dichlorofluoro methyl, difluoroethyl or difluoropropyl.
Within the context of the present application and as used herein, the term "alkoxy" refers to (Ci-Ce)alkyl group having an oxygen radical attached thereto. The terms alkoxy or - 0(Ci-C6)alkyl wherever used in this specification have the same meaning. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy and tert-butoxy. Unless stated otherwise, the -0(Ci-C6)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci- Ce)alkyl, (C3-C8)cycloalkyl, (C6-Cio)aryl, heterocyclyl, hydroxy, halogen, amino, cyano, (Ci- C6)alkyl-S(0)pR6, -S(0)pR6, -NR8R9, and -(CH2)SNR8R9; wherein R6, R8, R9, p and s are as defined above.
Within the context of the present application and as used herein, the term "haloalkoxy" or "halo(Ci-C6)alkoxy" refers to radicals wherein one or more of the hydrogen atoms of the alkoxy group are substituted with one or more halogens. Representative examples of "haloalkoxy" or "halo(Ci-C6)alkoxy" groups include, but are not limited to, difluoromethoxy (OCHF2), trifluoromethoxy (OCF3) or trifluorethoxy (OCH2CF3).
Within the context of the present application and as used herein, the term "(C3- Cio)cycloalkyl" or "cycloalkyl" refers to a monocyclic or bicyclic hydrocarbon ring containing three to ten carbon atoms, wherein at least one hydrocarbon ring is a saturated ring system which does not contain any double bond within the ring or a partially unsaturated ring system which may contain one or more double bonds within the ring system that is stable, and do not form an aromatic ring system. The term "cycloalkyl" can also include ring systems in which a cycloalkyl ring is optionally fused with an aryl ring e.g. phenyl . For example, "cycloalkyl" would include ring systems such as indane, with attachment possible to either the cycloalkyl or aryl ring. Representative (C3-Cio)cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, indanyl or indenyl. Unless stated otherwise, (C3-C1o)cycloalkyl may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-Ce)alkyl, halogen, halo(d-C6)aikyl, halo(C C6)alkoxy, hydroxy, -0(C C6)alkyl, -0(C C6)alkyl(C6- Cio)aryl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, - C(0)R7 and -OCH2-(CR'R")P-(Ci-C6)alkyl, wherein R7, R', R" and p are as defined above.
Within the context of the present application and as used herein, the term "(C6- Cio)aryl" or "aryl" refers to a monocyclic or bicyclic hydrocarbon ring system having up to ten ring carbon atoms, wherein at least one carbocyclic ring is having a π electron system. Examples of (C6-C10) aryl ring systems include, but are not limited to, phenyl or naphthyl. Unless indicated otherwise, aryl group may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-Ce)alkyl, (C2- Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(Ci-Ce) alkyl, hydroxy, thiol, -O(Ci-Ce) alkyl, halo(C!-C6)alkoxy, (C3-C8)cycloalkyl, (C6-C10)aryl, -O(C6-C10)aryl, -0(C1-C6)alkyl(C6- Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, - OC(0)CH3, -S(0)pR6, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C1-C6)alkyl-S(0)pR6; wherein R6, R7, R', R" and p are as defined above.
Aryl groups can be substituted in any desired position. For example, in monosubstituted phenyl, the substituted may be located in the 2-position, the 3-position, the 4-position or the 5-position. If the phenyl carries two substituents, they can be located in 2, 3- position, 2, 4-position, 2, 5-position, 2, 6-position, 3, 4-position, 3, 5-position or 3, 6- position.
Within the context of the present application and as used herein, the term
"-0(C6-C1o)aryl" refers to (C6-Qo)aryl group having an oxygen radical attached thereto. The terms aryloxy or -0(C6-Cio)aryl wherever used in this specification have the same meaning. Representative example includes, but is not limited to, phenoxy. Unless stated otherwise, - 0(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, hydroxy, halogen, amino, cyano, (Ci-Ce)alkyl- S(0)pR6, -S(0)pR6, -NR8R9, and -(CH2)sNRgR9; wherein R6, Rg, R9, p and s are as defined above.
Within the context of the present application and as used herein, the term "heterocyclyl" refers to 3- to 9-membered saturated or partially unsaturated monocyclic or bicyclic ring system containing one to four hetero atoms independently selected from the group consisting of a nitrogen (N), a sulfur (S) and an oxygen (O) atom. Heterocyclyl includes saturated heterocyclic ring systems, which do not contain any double bond. Partially unsaturated heterocyclic ring systems, contain at least one double bond, but do not form an aromatic system containing hetero atom. The term "heterocyclyl" encompasses fused, brigded or spiro rings. Heterocyclic ring can form fused or spiro ring system with cycloalkyl, aryl, heterocyclyl or heteroaryl rings. Suitable saturated and partially unsaturated non- aromatic heterocyclic groups include, but are not limited to, oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, dihydropyranyl, tetrahydropyranyl, thio-dihydropyranyl, thio-tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, 1,3- oxazinanyl, 1,3-thiazinanyl, 4,5,6-tetrahydropyrimidinyl, 2,3-dihydrofuranyl, dihydrothienyl, dihydropyridinyl, tetrahydropyridinyl, isoxazolidinyl, pyrazolidinyl, azabicyclo-octanyl or diazabicyclo-octanyl.
Unless stated otherwise, heterocyclyl may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-Ce)alkyl, (C2- Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci- Ce)alkoxy, (C3-C8)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (Ci- C6)alkyl-OH, (C1-C6)alkyl-0-(C1-C6)alkyl, (C1-C6)alkyl(C6-C1o)aryl, -C(0)R7, -S(0)pR6, and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7 and p are as defined above.
Heterocyclyl monocyclic or bicyclic ring systems having an aromatic ring containing hetero atom/s are herein referred to as "heteroaryl". Within the context of the present invention and as used herein, the term "heteroaryl" refers to 3- to 10-membered aromatic monocyclic or bicyclic ring system containing one to four hetero atoms independently selected from the group consisting of a nitrogen (N), a sulfur (S) and an oxygen (O) atom. Representative examples of heteroaryl include but are not limited to thiene, furan, pyridine, oxazole, thiazole, pyrazine, pyrimidine, pyrrole, pyrazole, isooxazole, triazole, tetrazole, pyridazine, isothiazole, benzothiazole, benzooxazole, benzimidazole, quinoline or isoquinoline. Heteroaryl group may be unsubstituted or substituted with one or more substituents independently selected from the group consisting of (Ci-Ce)alkyl, (C2- Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(Ci-Ce) alkyl, hydroxy, thiol, -0(Ci-Ce)alkyl, halo(Ci-C6)alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -(Ci-C6)alkyl-OH, -(C1-C6)alkyl-0-(C1-C6)alkyl, -C(0)R7, -OC(0)CH3, -S(0)pR6 and - 0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above. The nitrogen or sulfur atom of the "heterocyclyl" or "heteroaryl" can be optionally oxidized to the corresponding N- oxide, S-oxide or S,S-dioxide.
The term "heteroatom" as used herein, includes nitrogen (N), oxygen (O) and sulfur (S). Any heteroatom with unsatisfied valency is assumed to have a hydrogen atom to satisfy the valency or when the heteroatom is N, it may be substituted with a group selected from (Ci-C6)alkyl, -C(0)(Ci-C6)alkyl or -S(0)2(C1-C6)alkyl. Suitable (Ci-Ce)alkyl groups may be selected from, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl or isobutyl.
The term "(Ci-C6)alkyl(C6-Cio)aryl" refers to an alkyl group substituted with aryl, wherein the terms alkyl and aryl are as defined above.
The term "-0-(Ci-C6)alkyl(C6-Cio)aryl" as used herein refers to (Ci-Ce)alkyl(C6- Cio)aryl group attached to an oxygen atom, wherein the term (Ci-C6)alkyl(C6-Cio)aryl is as defined above.
The term "(Ci-C6)alkylheterocyclyl" as used herein refers to an alkyl group substituted with heterocylyl, wherein the terms alkyl and heterocyclyl are as defined above.
The term "halogen" or "halo" as used herein, unless otherwise indicated refers to bromine, chlorine, fluorine or iodine atom.
The term "amino" refers to the group "NH2" which may be unsubstituted or substituted by one or more substituents. Examples of substituents include, but are not limited to, (Cj-C4)alkyl, (C6-Qo)aryl or the like groups.
Within the context of the present invention and as used herein interchangeably throughout this application, the terms "compounds of Formula (I)", "heterocyclic derivatives of Formula (I)" and "compounds of the present invention" include all the isotopic forms, stereoisomeric and tautomeric forms and mixtures thereof in all ratios, and their pharmaceutically acceptable salts, solvates, polymorphs, prodrugs, carboxylic acid isosteres, N-oxides and S-oxides. Further, in the context of the present invention, reference to the compounds of Formula (I) may include reference to the compounds represented herein by the compounds of Formula (la) and/or the compounds represented herein by the compounds of Formula (lb).
Within the context of this present application and as used herein the term "isotopic forms" or "isotopically labeled forms" is a general term used for isotopic forms of compounds of Formula (I), wherein one or more atoms of compounds of Formula (I) are replaced by their respective isotopes. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention. Examples of isotopes that may be incorporated into the compounds disclosed herein include, but are not limited to, isotopes of hydrogen such as 2H (deuterium or D) and 3H, carbon such as nC, 13C and 14C, nitrogen such as 13N and 15N, oxygen such as 150, 170 and 180, chlorine such as 36C1, fluorine such as 18 F and sulphur such as 35 S. Substitution with heavier isotopes, for example, replacing one or more key carbon-hydrogen bonds with carbon-deuterium bond may show certain therapeutic advantages, resulting from longer metabolism cycles, (e.g., increased in vivo half life or reduced dosage requirements), improved safety or greater effectiveness and hence may be preferred in certain circumstances.
Representative examples of isotopic forms of the compounds of Formula (I) may include, without limitation, deuterated compounds of Formula (I). The term "deuterated" as used herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), which is attached to carbon(s), with a deuterium atom. For example, the compounds of Formula (I) may include in the definitions of one or more of the various variables Ri, R2, R3, R4, R5, R6, R7, Rs, R and Rio wherever applicable, deuterium, deuterated-alkyl, deuterated-alkoxy, deuterated-cycloalkyl, deuterated-heterocyclyl, deuterated-aryl, deuterated-heteroaryl and the like.
The term "deuterated-alkyl" refers to an (Ci-C6)alkyl group as defined herein, wherein at least one hydrogen atom bound to carbon is replaced by a deuterium. That is, in a deuterated alkyl group, at least one carbon atom is bound to a deuterium. In a deuterated alkyl group, it is possible for a carbon atom to be bound to more than one deuterium; it is also possible that more than one carbon atom in the alkyl group is bound to a deuterium. Analogously, the term "deuterated" and the terms deuterated-heterocyclyl, deuterated- heteroaryl, deuterated-cycloalkyl, deute- rated-aryl and deuterated-alkoxy each refer to the corresponding chemical moiety wherein at least one carbon is bound to a deuterium.
Within the context of the present invention and as used herein, the term "stereoisomer" is a general term used for all isomers of individual compounds that differ only in the orientation of their atoms in space. The term stereoisomer includes mirror image isomers (enantiomers), mixtures of mirror image isomers (racemates, racemic mixtures), geometric (cis/trans or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).
Within the context of the present invention and as used herein, the term "tautomer" refers to the coexistence of two (or more) compounds that differ from each other only in the position of one (or more) mobile atoms and in electron distribution, for example, keto-enol tautomers.
The term "pharmaceutically acceptable salts" as used herein includes salts of the active compounds i.e. the compounds of Formula (I) which are prepared by treating said compounds with a suitable acid or a base, depending on the particular substituents found on the compounds described herein.
Within the context of the present invention and as used herein "N-oxide" refers to the oxide of the nitrogen atom of a nitrogen-containing heteroaryl or heterocycle. N-oxide can be formed in the presence of an oxidizing agent for example peroxide such as m-chloro- perbenzoic acid or hydrogen peroxide. N-oxide refers to an amine oxide, also known as amine-N-oxide, and is a chemical compound that contains N-^O bond.
Within the context of the present invention and as used herein "S-oxide" refers to the oxide of the sulfur atom (S-oxide) or dioxide of the sulfur atom (S,S-dioxide) of a sulfur- containing heteroaryl or heterocycle. S-oxide and S,S-dioxides can be formed in the presence of an oxidizing agent for example peroxide such as m-chloro-perbenzoic acid or oxone.
Within the context of the present invention and as used herein, the term "solvate" or "solvates" describe a complex wherein the compound of Formula (I) of the present invention, is coordinated with a proportional amount of a solvent molecule. Specific solvates, wherein the solvent is water, are referred to as hydrates.
Within the context of the present invention and as used herein the term "prodrug" or "prodrugs" refer to the compounds that are drug precursors, which following administration, release the drug in vivo via a chemical or metabolic process, for example, a prodrug on being brought to the physiological pH or through an enzyme action is converted to the desired drug.
Within the context of the present invention and as used herein the term "polymorph" or "polymorphic form" or "polymorphs" refer to crystals of the same compound that differs only in the arrangement and/or conformation of the molecule in the crystal lattice.
Within the context of the present invention and as used herein the term "carboxylic acid isosteres" refer to groups or molecules that have physical and chemical similarities to a carboxylic acid group, producing similar biological effects as those produced by a carboxylic acid group. Examples of carboxylic acid isosteres include groups selected from hydroxamic, acylcyanamide, phosphonate, sulfonate, sulfonamide, tetrazole, hydroxyisoxazole and oxadiazolone (The Practice of Medicinal Chemistry, Edited by Camille G. Wermuth, Second Edition, 2003, 189-214).
Within the context of the present invention and as used herein, the term "GPR agonist(s)" refer to the compound(s) of Formula (I) of the present invention which binds to, activates, increases, stimulates, potentiates, sensitizes or upregulates one or more of the G- protein coupled receptors which are reported to play an important physiological role in insulin release. For instance, the G-protein coupled receptor may be GPR40 that has been reported to play a physiological role in insulin release.
Within the context of the present invention and as used herein, the term "GPR40 agonist(s)" refer to the compound(s) of Formula (I) of the present invention which binds to, activates, increases, stimulates, potentiates, sensitizes or upregulates GPR40 receptor and promotes glucose induced insulin secretion.
The term "therapeutically effective amount" as used herein in the present invention generally refers to the amount of the compound (e.g. the compound of Formula (I)) or a composition containing the said compound that will elicit the biological or medical response of a tissue or a subject when treated with the compound. Particularly, the term "therapeutically effective amount" includes the amount of a compound, when administered that induces a positive modification in the disease or condition to be treated or is sufficient to prevent development of, or alleviate to some extent one or more of the symptoms of the condition or disorder being treated in a subject. In respect of the therapeutic amount of the compound, consideration is also given that the amount of the compound used for the treatment of a subject is low enough to avoid undue or severe side effects, within the scope of sound medical judgement. The therapeutically effective amount of the compound or composition will vary with the particular condition being treated, the age and physical condition of the end user, the severity of the condition being treated or prevented, the duration of the treatment, the nature of concurrent therapy, the specific compound or composition employed, the particular pharmaceutically acceptable carrier utilized and other factors.
The term "treatment", "treat" or "therapy" as used herein; is intended to mean to alleviate, slow the progression, prophylaxis, attenuation or cure of existing disease (for example, metabolic disorders). Treatment also includes preventing development of, or alleviating to some extent, one or more of the symptoms of the disease or condition being treated.
As used herein, the term "prophylaxis" covers within its scope the preventive treatment of a subclinical disease-state or a condition in a subject (e.g. a human), aimed at reducing the probability of the occurrence of a clinical disease-state. Subjects are selected for preventative therapy based on factors that are known to increase risk of suffering a clinical disease state or a condition compared to the general population. "Prophylaxis" therapies can be divided into (a) primary prevention and (b) secondary prevention. Primary prevention is defined as treatment in a subject that has not yet presented with a clinical disease state or a condition, whereas secondary prevention is defined as preventing a second occurrence of the same or similar clinical disease state.
The term "subject" as used herein refers to an animal, preferably a mammal, and most preferably a human. The term "mammal" as used herein refers to warm-blooded vertebrate animals of the class Mammalia, including humans, characterized by a covering of hair on the skin and, in the female, milk-producing mammary glands for nourishing the young. The term mammal includes animals such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
In the context of the present invention the phrase "a subject in need thereof means a subject (patient) in need of the treatment for the disease or condition that is mediated by GPR40. Alternatively, the phrase "a subject in need thereof means a subject (patient) diagnosed having a disease or a condition that is mediated by GPR40.
Embodiments
In an embodiment, the present invention encompasses a compound of Formula (I), wherein Rj is hydrogen, methyl, ethyl or propyl.
In another embodiment, the present invention encompasses a compound of Formula (I), wherein R2 and R3 together form a saturated or a partially unsaturated
3- to 6-membered heterocyclyl ring containing one or two heteroatoms independently selected from the group consisting of O, N and S.
In another embodiment, the present invention encompasses a compound of Formula (I), wherein R2 and R3 together form a saturated or a partially unsaturated 3- to 6-membered heterocyclyl ring containing one or two O atoms.
In another embodiment, the present invention encompasses a compound of Formula (I), wherein R2 and R3 together form an oxetane ring.
In another embodiment, the present invention encompasses a compound of Formula (I), wherein R2 and R3 together form a saturated or a partially unsaturated 3- to 6-membered heterocyclyl ring containing one or two heteroatoms independently selected from N and S atoms; when the heteroatom is N, it is substituted with hydrogen, (C1-C6)alkyl, -C(0)(Q- C6)alkyl or -S(0)2(C1-C6)alkyl.
In another embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5; wherein A, Lj, X and R5 are as defined above. In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-Li-X; wherein A, Li, X and R5, are as defined above.
In yet another embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5 ; wherein X is O; Lj is absent or is selected from the group consisting of -S(0)p-, -C(0)NH-, -NHC(O)-, -NHC(0)NH-, -(CR'R")P- CH2O-, -S(0)pNH-, -NHS(0)p-, -C(R'R")-, -CH=CR8- and -(CRgR9)n-; provided that when Li is -(CRgR9)n-, n is 1 and one of the variable Rg and R9 is hydrogen, the other variable is not hydrogen or (Ci-Ce)alkyl; and R5 and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-Lj-X; wherein X is O, Lj is absent or is selected from the group consisting of -S(0)p-, -C(0)NH-, -NHC(O)-,
-NHC(0)NH-, -(CR'R")P-CH20-, -S(0)pNH-, -NHS(0)p-, -C(R'R")-, -CH=CR8- and -(CRgR9)n-; provided that when Lj is -(CRgR9)n- and either one of Rg and R9 is hydrogen, the other is not hydrogen or (Cj-C6)alkyl; and R5, and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-L X and Ry is R5; wherein X is -(CH2)nO-; and R5, Ll 5 A and n are as defined above; provided that when n is 1; A is not (C3-C10) cycloalkyl, (Ce-Cio)aryl, heterocyclyl or heteroaryl.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-Lj-X; wherein X is -(CH2)nO- and R5, Lj, A and n are as defined above; provided that when n is 1; A is not (C3-C10) cycloalkyl, (Ce-Cio)aryl, heterocyclyl or heteroaryl.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5; wherein X is
-(CH2)p(CRgR9)nCH20- and R5, Lj, A, Rg, R9, n and p are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-Lj-X; wherein X is
-(CH2)p(CRgR9)nCH20-; and R5, Lj, A, Rg, R9, n and p are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5 ; wherein X is -(CH2)p(C6-Cio aryl)kCH20-; and R5, Ll 5 A, k and p are as defined above; provided that when p is 0 then Lj is not absent. In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-Li-X; wherein X is -(CH2)p(C6-Cio aryl)kCH20-; and R5, Lj, A, k and p are as defined above; provided that when p is 0 then Lj is not absent.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5; wherein X is
-(CR'R")pO; and R5, Li, A, R' , R" and p are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-Li-X; wherein X is
-(CR'R")pO; and R5, , A, R' , R" and p are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5; wherein Lj is O, X is
-(CH2)nO-, -(CH2)p(CR8R9)nCH20-, -(CH2)p(C6-C10aryl)kCH2O- or -(CR'R")P0-; and R5, R8, R9, R' , R", A, n, p and k are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-L X; wherein Lj is O, X is
-(CH2)nO-, -(CH2)p(CR8R9)nCH20-, -(CH2)p(C6-C10aryl)kCH2O- or -(CR'R")P0-; and R5, R8, R9, R' , R", A, n, p, and k are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5; wherein Lj is -S(0)p-; and R5, X, p and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-Lj-X; wherein Lj is -S(0)p-; and R5, X, p and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5 ; wherein Lj is -C(0)NH-; and R5, X and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-Lj-X; wherein Lj is -C(0)NH- and R5, X and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5 ; wherein Lj is -NHC(O)-; and R5, X and A are as defined above. In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Li-X and Ry is R5; wherein Li is
-NHC(0)NH-; and R5, X and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-Lj-X; wherein Lj is
-NHC(0)NH-; and R5, X and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Li-X and Ry is R5; wherein Li is -(CR'R")P-CH20; and R', R", p, R5, X, and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-Lj-X; wherein is -(CR'R")P-CH20; and R', R", p, R5, X and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5; wherein Lj is
-S(0)pNH-; and R5, p, X, and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-L X; wherein Lj is
-S(0)pNH-; and R5, p, X, and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5; wherein Lj is
-NHS(0)p-; and R5, p, X, and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-Lj-X; wherein Lj is
-NHS(0)p-; and R5, p, X, and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5; wherein Lj is
-C(R'R")- and R5, R', R", X, and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-Lj-X; wherein Lj is
-C(R'R")-; and R5, R' , R", X, and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5; wherein Lj is
-CH=CR8-; and Rg, R5, X, and A are as defined above. In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-Li-X; wherein Li is -CH=CRs- and Rs, R5, X, and A are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5; wherein Lj is
Figure imgf000021_0001
and Rg, R9, R5, X, n and A are as defined above, provided that when n is 1, X is -0-, and one of the variable Rg and R of is hydrogen, the other variable is not hydrogen or (Ci-C6)alkyl.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-Lj-X; wherein Lj is -(CRgR9)n- and Rg, R9, R5, X, n and A are as defined above, provided that when n is 1, X is -0-, and one of the variable Rg and R of -(CRgR9)n- is hydrogen, the other variable is not hydrogen or (Ci-C6)alkyl.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is A-Lj-X and Ry is R5; wherein X is -(CH2)p(C6-Cio aryl)kCH20-; Lj is selected from the group consisting of -0-, -(CR'R")P-CH20- and -C(R'R")-; and R5, R', R", A, k and p are as defined above.
In yet another further embodiment, the present invention encompasses a compound of Formula (I), wherein Rx is R5 and Ry is A-L X; wherein X is -(CH2)p(C6-C1o aryl)kCH20-; Lj is selected from the group consisting of -0-, -(CR'R")P-CH20- and -C(R'R")-; and R5, R', R", A, k and p are as defined above.
In another embodiment, the present invention encompasses a compound of Formula (I), wherein A is
Figure imgf000021_0002
wherein Rjo is hydrogen, (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci-C6)alkoxy, -S(0)PR6, amino, cyano, nitro or -C(0)R7; wherein R6, R7 and p are as defined above.
In another embodiment, the present invention encompasses a compound of Formula (I), wherein A is (Ci-Ce) alkyl, (C3-Cio)cycloalkyl, (Ce-Cio)aryl,
Figure imgf000022_0001
wherein Rio is hydrogen, (Ci-Ce)alkyl, -0(Ci-Ce)alkyl, -S(0)PR6 or -C(0)R?; wherein R6, R7 and p are as defined above, provided that when A is (C3-Cio)cycloalkyl or (Ce-Cio)aryl, and X is -(CH2)nO- , then n is not 1.
In another embodiment, the present invention encompasses a compound of Formula (I), wherein A is (Ci-Ce)alkyl, wherein (Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, halo(Ci- Ce)alkyl, hydroxy, -0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl and heteroaryl.
In another embodiment, the present invention encompasses a compound of Formula (I), wherein A is (C3-Cg)cycloalkyl, wherein (C3-Cg)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci- C6)alkyl, (C C6)alkoxy, halo(C!-C6)alkoxy, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C C6)alkyl(C6-Cio)aryl; wherein R', R" and p are as defined above, provided that when X is - (CH2)nO- , then n is not 1 .
In further embodiment, the present invention encompasses a compound of Formula (I), wherein A is (Ce-Cio)aryl; wherein (Ce-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, halogen, halo(C1-C6)alkyl, hydroxy, -0(C!-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, haloCQ-Ce) alkoxy, (C6-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, cyano, -0(Ci-C6)alkyl-S(0)pR6 and - OCH2-(CR'R")P-(C1-C6)alkyl; wherein R6, R', R" and p are as defined above, provided that when X is -(CH2)nO- , then n is not 1.
In further embodiment, the present invention encompasses a compound of Formula (I), wherein A is
Figure imgf000022_0002
wherein Rio is hydrogen, (Ci-Ce)alkyl or -S(0)PR6; wherein R6 and p are as defined above. In an embodiment, the compound of Formula (I) encompasses a compound of Formula (la),
Figure imgf000023_0001
Formula (la)
Rj is hydrogen or (Ci-C6) alkyl;
R2 and R3 together form a saturated or a partially unsaturated 3- to 6- membered heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
R4 is hydrogen;
Figure imgf000023_0002
R5 is hydrogen, (Ci-C6) alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy,
-0(Ci-C6)alkyl, (Ce-Cio)aryl, amino, cyano, nitro, -C(0)R? or -S(0)pR6;
R6 is hydrogen, (Ci-Ce)alkyl or amino;
X is -0-, -(CH2)nO-, -(CH2)p(CR8R9)nCH20-, -(CH2)p(C6-C10aryl)kCH2O-, or
-(CR'R")pO-;
Lj is absent or is selected from the group consisting of -0-, -S(0)p-, -C(0)NH-,
-NHC(O)-, -NHC(0)NH-, -(CR'R")P-CH20-, -S(0)pNH-, -NHS(0)p-, -C(R'R")-,
-CH=CR8- and -(CR8R9)n-;
R' and R" together form =N(0-(Ci-C6)alkyl), =0, a saturated or a partially unsaturated (C3- C8) cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
R7 is (d-Ce) alkyl, -0(d-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, hydroxy or amino;
R8 and R9 at each occurrence are independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ce-Cio)aryl and heteroaryl; or R8 and R together form =N(0-(Ci- C6) alkyl), =0, a saturated or a partially unsaturated (C3-Q) cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
A is (Ci-C6)alkyl, (C3-Cio)cycloaikyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl,
Figure imgf000024_0001
Rio is hydrogen, (Ci-Ce)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci- Ce)alkoxy, -S(0)pR6, amino, cyano, nitro or -C(0)R7; wherein R6 and R7 are as defined above;
k is an integer 1 or 2;
n is an integer from 1 to 3;
m is an integer from 1 to 4;
p is an integer from 0 to 2;
s is an integer from 1 to 4;
* indicates the point of attachment to Lj ;
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, (C3-Cg)cycloaikyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
-0(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (C1-C6)alkyl, (C3-Cg)cycloaikyl, heterocyclyl, hydroxy, halogen, amino, cyano, (C!-C6)alkyl-S(0)pR6, -S(0)pR6, -NR8R9 and -(CH2)sNRgR9; wherein R6, Rg, R9, p and s are as defined above;
(C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, halo(Ci- C6)alkoxy, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C1-C6)alkyl(C6-C1o)aryl, wherein R\ R" and p are as defined above;
(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(C!-C6) alkyl, hydroxy, -0(d-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, halo(C C6) alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C!-C6)alkyl- S(0)pR6; wherein R6, R7, R', R" and p are as defined above; heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, halogen, halo(d-C6) alkyl, hydroxy, -(XCi-C6)alkyl, halo(C C6) alkoxy, (C3-Cg)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (Ci- C6)alkyl-OH, (C1-C6)alkyl-0-(C1-C6)alkyl, (C1-C6)alkyl(C6-C1o)aryl, -C(0)R7, S(0)pR6 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, halogen, halo(C!-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci-Ce) alkoxy, (C3-C8)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, - C(0)R7 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
halogen is chlorine, bromine, iodine or fluorine;
provided that (i) when X is -(CH2)nO- and n is 1, A is not (C3-C10) cycloalkyl, (Ce-Cio)aryl, heterocyclyl or heteroaryl;
(ii) when X is -(CH2)p(C6-C1oaryl)kCH20- and p is 0 then Lj is not absent;
(iii) when X is -0-, Lj is -(CRsR^n-, n is 1 and one of the variable Rg and R is hydrogen, the other variable is not hydrogen or (C1-C6)alkyl; and
(iv) when either one of X and Lj is -0-, the other is not -0-;
or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof.
In an embodiment, the compound of Formula (I) encompasses a compound of Formula (la); wherein Ry is R5.
In an embodiment, the compound of Formula (I) encompasses a compound of Formula (la); wherein R2 and R3 together form a saturated or a partially unsaturated 3- to 6- membered heterocyclyl ring containing one or two oxygen atoms; and Ry is R5, wherein R5 is as defined above.
In an embodiment, the compounds of Formula (I) encompasses a compound of Formula (la); wherein R2 and R3 together form an oxetane ring; and Ry is R5, wherein R5 is as defined above.
In an embodiment, the compounds of Formula (I) encompasses a compound of Formula (la); wherein R2 and R3 together form an oxetane ring; R4 is hydrogen and Ry is R5, wherein R5 is as defined above. In an embodiment, the compounds of Formula (I) encompasses a compound of Formula (la); wherein, R2 and R3 together form an oxetane ring; and Ry is R5 ; wherein R5 is hydrogen.
In further embodiment, the compounds of Formula (I) encompasses a compound of Formula (la); wherein R2 and R3 together form an oxetane ring; R4 is hydrogen; Ry is R5; wherein o)cycloalkyl, (C6-Cio)aryl,
Figure imgf000026_0001
Rio is hydrogen, -C(0)R7, S(0)pR6 or (d-C6)alkyl;
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0)pR6; wherein R6 and p are as defined above;
-0(Ci-C6)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, (C3-Cg)cycloalkyl, heterocyclyl, hydroxy and halogen;
(C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(C!-C6)alkoxy, -OCH2-(CR'R")p-(C1-C6)alkyl and -O(C1-C6)alkyl(C6-C10)aryl wherein R', R" and p are as defined above;
(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(C C6) alkyl, hydroxy, -0(C C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, halo(C C6) alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7,
Figure imgf000026_0002
and -0(C C6)alkyl- S(0)pR6; wherein R6, R7, R', R"and p are as defined above;
heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, halogen, haloCQ-Ce) alkyl, hydroxy, -0(C!-C6)alkyl, halo(C C6) alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (Q- C6)alkyl-OH, (C1-C6)alkyl-0-(C1-C6)alkyl, (C1-C6)alkyl(C6-C1o)aryl, -C(0)R7, S(0)pR6 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7 and p are as defined above;
heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, halogen, halo(C!-C6)alkyl, hydroxy, -0(C!-C6)alkyl, halo d-Ce) alkoxy, (C3-C8)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, - C(0)R7 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
halogen is chlorine, bromine, iodine or fluorine;
provided that
(i) when X is -(CH2)nO- and n is 1 , A is not (C3-C10) cycloalkyl or (C6-Cio)aryl;
(ii) when X is -(CH2)p(C6-Cioaryl)kCH20- and p is 0 then Lj is not absent;
(iii) when X is -0-, Li is
Figure imgf000027_0001
n is 1 and one of the variable Rs and R9 is hydrogen, the other variable is not hydrogen or (Ci-C ) alkyl; and
(iv) when either one of X and Lj is -0-, the other is not -0-;
or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof.
In further embodiment, the compounds of Formula (I) encompasses a compound of Formula (la); wherein R2 and R3 together form an oxetane ring; R4 is hydrogen; Ry is R5; wherein R5 is hydrogen; and
Figure imgf000027_0002
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0)pR6; wherein R6 and p are as defined above;
-0(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, (C3-Cg)cycloalkyl, heterocyclyl, hydroxy and halogen; wherein R6, Rs, R9, p and s are as defined above; (C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(C!-C6)alkoxy, -OCH2-(CR'R")p-(C1-C6)alkyl and -O(C1-C6)alkyl(C6-C10)aryl; wherein R' , R" and p are as defined above;
(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(C1-C6)alkyl, hydroxy, -0(d-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, halo(C!-C6)alkoxy, (C3-Cg)cycloalkyl, (C6-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C!-C6)alkyl- S(0)PR6; wherein R6, R7, R' , R"and p are as defined above;
heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, halogen, halo(C!-C6)alkyl, hydroxy, -0(C!-C6)alkyl, haloCQ-Ce) alkoxy, (C3-Cg)cycloaikyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (Q- C6)alkyl-OH, (C1-C6)alkyl-0-(C1-C6)alkyl, (C1-C6)alkyl(C6-C10)aryl, -C(0)R7, S(0)pR6 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci- Ce)alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, - C(0)R7 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
halogen is chlorine, bromine, iodine or fluorine;
provided that (i) when X is -(CH2)nO- and n is 1, A is not (C3-Cio)cycloalkyl or (Ce-Cio)aryl;
(ii) when X is -(CH2)p(C6-Cioaryl)kCH20- and p is 0 then Lj is not absent;
(iii) when X is -0-, Lj is -(CRgR^n-, n is 1 and one of the variable Rg and R is hydrogen, the other variable is not hydrogen or (Ci-C ) alkyl; and
(iv) when either one of X and Lj is -0-, the other is not -0-;
or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof.
In further embodiment, the compounds of Formula (I) encompasses a compound of Formula (la); wherein R2 and R3 together form an oxetane ring; R4 is hydrogen; Ry is R5; wherein R5 is hydrogen; X is -0-, -(CH2)p(CR8R9)nCH20-, -(CH2)p(C6-C10aryl)kCH2O- or - (CR'R")P0-; and A is (C6-Cio)aryl; wherein R8, R9, R', R", p, n and k are are defined above; wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0)pR6; wherein R6 and p are as defined above;
-0(Ci-C6)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C3-C8)cycloalkyl, heterocyclyl, hydroxy and halogen wherein R6, R8, R9, p and s are as defined above;
(C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(C!-C6)alkoxy, -OCH2-(CR'R")p-(C1-C6)alkyl and -O(C1-C6)alkyl(C6-C10)aryl wherein R', R" and p are as defined above;
(C6-Cjo)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, halogen, halo(C C6) alkyl, hydroxy, -0(C C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, halo(C C6) alkoxy, (C3-C8)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C!-C6)alkyl- S(0)pR6; wherein R6, R7, R', R"and p are as defined above;
heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, halogen, haloCQ-Ce) alkyl, hydroxy, -0(C!-C6)alkyl, halo(C C6) alkoxy, (C3-C8)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (Q- C6)alkyl-OH, (C1-C6)alkyl-0-(C1-C6)alkyl, (C1-C6)alkyl(C6-C1o)aryl, -C(0)R7, S(0)pR6 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, halogen, halo(C!-C6)alkyl, hydroxy, -0(C!-C6)alkyl, haloCQ-Ce) alkoxy, (C3-C8)cycloalkyl, (C6-Qo)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, - C(0)R7 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
halogen is chlorine, bromine, iodine or fluorine;
provided that (i) when X is -(CH2)p(C6-Cioaryl)kCH20- and p is 0 then Lj is not absent;
(ii) when X is -0-, Li is
Figure imgf000030_0001
n is 1 and one of the variable Rs and R is hydrogen, the other variable is not hydrogen or (Ci-C6) alkyl; and
(iii) when either one of X and Li is -0-, the other is not -0-.
or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof.
In further embodiment, the compounds of Formula (I) encompasses a compound of Formula (la); wherein R2 and R3 together form an oxetane ring; R4 is hydrogen; Ry is R5; wherein R5 is hydrogen; X is -(CH2)p(C6-Cioaryl)kCH20-; Lj is absent or is selected from the group consisting of -0-, -(CR'R")P-CH20- and -C(R'R")-; R' and R" together form =N(0- (Ci-C6) -C6)alkyl, (C3-C10)cycloalkyl, (C6-C10)aryl,
Figure imgf000030_0002
Rio is hydrogen, -C(0)R7, S(0)pR6 or (Ci-C6)alkyl;
k is an integer 1 or 2 and p is an integer from 0 to 2;
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0)pR6;
(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(C1-C6)alkyl, hydroxy, -0(d-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, halo(Ci-C6)alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")P-(C1-C6)alkyl and -0(Ci-C6)alkyl- S(0)pR6;
wherein R6, R7, R', R" p and k are as defined above;
provided that when X is -(CH2)p(C6-Cioaryl)kCH20- and p is 0 then Lj is not absent. or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof.
In further embodiment, the compounds of Formula (I) encompasses a compound of Formula (la); wherein R2 and R3 together form an oxetane ring; R4 is hydrogen; Ry is R5; X is -(CH2)p(C6-Cioaryl)kCH20-; Lj is selected from the group consisting of -0-, -(CR'R")P- CH20- and -C(R'R")-; and A is (C6-C10)aryl; wherein R5 is hydrogen, R' and R" together form
Figure imgf000031_0001
or =0; k is an integer 1 or 2 and p is an integer from 0 to 2;
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0)pR6;
(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(C!-C6) alkyl, hydroxy, -0(d-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, halo(C C6) alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C!-C6)alkyl- S(0)pR6;
wherein R6, R7, R', R" p and k are as defined above;
or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof.
In further embodiment, the compounds of Formula (I) encompasses a compound of Formula (la);
wherein,
R2 and R3 together form a saturated or a partially unsaturated 3- to 6- membered heterocyclyl ring containing one or two heteroatoms selected from N or S; when the heteroatom is N, it is substituted with hydrogen, (C!-C6)alkyl, -C(0)(C!-C6)alkyl or -S(0)2(C!-C6)alkyl;
Ry is R5; wherein R5 is hydrogen;
X is -(CH2)p(C6-C10aryl)kCH2O-;
Lj is -0-, -(CR'R")P-CH20- or -C(R'R")-; R' and R" together form =N(0-(Ci-C6)alkyl) or =0;
Figure imgf000032_0001
wherein p and k are as defined above;
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0)PR6; wherein R6 and p are as defined above;
(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(C!-C6) alkyl, hydroxy, -0(d-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, halo(C C6) alkoxy, (C3-Cg)cycloalkyl, (C6-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(Ci-C6)alkyl- S(0)pR6; wherein R6, R7, R', R" and p are as defined above;
or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof.
In an embodiment, the compound of Formula (I) encompasses a compound of Formula (lb),
Figure imgf000032_0002
Formula (lb)
wherein,
Rj is hydrogen or (Ci-Ce)alkyl;
R2 and R3 together form a saturated or a partially unsaturated 3- to 6- membered heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
R4 is hydrogen;
Figure imgf000032_0003
R5 is hydrogen, (Ci-C6) alkyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(C1-C6)alkyl, (C6- Cjo)aryl, amino, cyano, nitro, -C(0)R7 or -S(0)pRe; R6 is hydrogen, (Ci-Ce)alkyl or amino;
X is -0-, -(CH2)nO-, -(CH2)p(CR8R9)nCH20-, -(CH2)p(C6-C10aryl)kCH2O-, or -(CR'R")P0-; Lj is absent or is selected from the group consisting of -0-, -S(0)p-, -C(0)NH-, -NHC(O)-, - NHC(0)NH-, -(CR'R")P-CH20-, -S(0)pNH-, -NHS(0)p-, -C(R'R")-, -CH=CR8-, and -
R' and R" together form =N(0-(Ci-C6)alkyl), =0, a saturated or a partially unsaturated (C3- Cg) cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
R7 is (d-Ce) alkyl, -0(d-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, hydroxy or amino;
Rg and R9 at each occurrence are independently selected from the group consisting of hydrogen, (Ci-Ce) alkyl, (Ce-Cio)aryl and heteroaryl; or Rg and R together form =N(0-(Ci- C6) alkyl), =0, a saturated or a partially unsaturated (C3-Cg) cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
-C6)alkyl, (Cs-Qrxtcycloaikyl, (Ce-Cjrxtaryl, heterocyclyl, heteroaryl,
Figure imgf000033_0001
Rio is hydrogen, (Ci-Ce)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci- Ce)alkoxy, -S(0)pR6, amino, cyano, nitro or -C(0)R7; wherein R6 and R7 are as defined above;
k is an integer 1 or 2;
n is an integer from 1 to 3;
m is an integer from 1 to 4;
p is an integer from 0 to 2;
s is an integer from 1 to 4;
* indicates the point of attachment to Lj ;
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
-0(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, (C3-Cg)cycloalkyl, heterocyclyl, hydroxy, halogen, amino, cyano, (Ci-C6)alkyl-S(0)pR6, -S(0)PR6, -NRgRg and -(CH2)sNRgR ; wherein R6, Rs, R9, p and s are as defined above;
(C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(C!-C6)alkoxy, -OCH2-(CR'R")p-(C1-C6)alkyl and -O(C1-C6)alkyl(C6-C10)aryl, wherein R', R" and p are as defined above;
(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(C!-C6) alkyl, hydroxy, -0(d-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, halo(C C6) alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C C6)alkyl-S(0)pR6; wherein R6, R7, R' , R" and p are as defined above;
heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, halogen, haloCQ-Ce) alkyl, hydroxy, -0(C!-C6)alkyl, halo(C C6) alkoxy, (C3-Cg)cycloaikyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (Q- C6)alkyl-OH, (C1-C6)alkyl-0-(C1-C6)alkyl, (C1-C6)alkyl(C6-C1o)aryl, -C(0)R7, S(0)pR6 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, halogen, halo(C!-C6)alkyl, hydroxy, -0(C!-C6)alkyl, haloCQ-Ce) alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, - C(0)R7 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
halogen is chlorine, bromine, iodine or fluorine;
provided that (i) when X is -(CH2)nO- and n is 1 , A is not (C3-C10) cycloalkyl, (Ce-Cio)aryl, heterocyclyl or heteroaryl;
(ii) when X is -(CH2)p(C6-Cioaryl)kCH20- and p is 0 then Lj is not absent;
(iii) when X is -0-, Lj is -(CRgRg),,-, n is 1 and one of the variable R8 and R9 is hydrogen, the other variable is not hydrogen or (Q-Ce) alkyl; and (iv) when either one of X and Lj is -0-, the other is not -0-.
or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof.
In one embodiment, the present invention encompasses a compound of Formula (lb), wherein,
R2 and R3 together form an oxetane ring;
Rx is R5;
R5 is hydrogen, (Ci-Ce)alkyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-Ce)alkyl, (C6- Cio)aryl, amino, cyano, nitro, -C(0)R7 or -S(0)pR6; wherein R6 and R7 are as defined above.
In another embodiment, the present invention encompasses a compound of Formula (lb), wherein,
R2 and R3 together form an oxetane ring;
Rx is R5; wherein R5 is hydrogen;
X is -(CH2)p(C6-C10aryl)kCH2O-;
Li is absent or is selected from the group consisting of -0-, -(CR'R")P-CH20- and
-C(R'R")-;
R' and R" together form =N(0-(Ci-C6)alkyl) or =0;
-Ce) alkyl, (C3-C10)cycloalkyl, (C6-C10)aryl,
Figure imgf000035_0001
Rio is hydrogen, (Ci-Ce)alkyl or -S(0)pR6;
wherein R6, p and k are as defined above;
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-C6)alkyl, (C3-C8)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0)pR6; wherein R6 and p are as defined above; (C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(C1-C6)alkyl, hydroxy, -0(C!-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, haloCQ-Ce) alkoxy, (C3-Cg)cycloalkyl, (C6-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C!-C6)alkyl- S(0)PR6; wherein R6, R7, R', R"and p are as defined above;
provided that when X is -(CH2)p(C6-Cioaryl)kCH20- and p is 0 then Lj is not absent.
or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof.
In another embodiment, the present invention encompasses a compound of Formula (lb), wherein
R2 and R3 together form an oxetane ring;
Rx is R5; wherein R5 is hydrogen;
X is -(CH2)p(C6-Cioaryl)kCH20-; wherein p and k are as defined above;
Lj is -0-, -(CR'R")P-CH20- or -C(R'R")-;
R' and R" together form =N(0-(C!-C6)alkyl) or =0;
A is (C6-C10)aryl;
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Cj-C6)alkyl, (C3-Cg)cycloalkyl, (C6-Qo)aryl, heterocyclyl, heteroaryl and -0(C1-C6)alkyl- S(0)pR6; wherein R6 and p are as defined above;
(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(C!-C6) alkyl, hydroxy, -0(d-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, halo(C C6) alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C!-C6)alkyl- S(0)pR6; wherein R6, R7, R', R" and p are as defined above;
or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof. Representative compounds of the present invention include:
Ethyl 2-(3-(4-((l-(methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophen-3-yl)methoxy) phenyl)oxetan-3-yl)acetate ;
2-(3-(4-((l-(methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophen-3-yl)methoxy)
phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(l-(methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophene-3- carboxamido)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(l-(Methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophene-3- carboxamido)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(o-tolyloxy)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(o-Tolyloxy)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(phenylthio)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(Phenylthio)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(phenylsulfinyl)propoxy)phenyl)oxetan-3-yl)acetate;
Ethyl 2-(3-(4-(3-(phenylsulfonyl)propoxy)phenyl)oxetan-3-yl)acetate;
Ethyl 2-(3-(4-(3-(3-([l,l'-biphenyl]-4-yl)ureido)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(3-([l,l'-Biphenyl]-4-yl)ureido)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(4-fluorophenoxy)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(4-fluorophenoxy)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(3-chlorophenoxy)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(3-chlorophenoxy)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(3-(trifluoromethyl)phenoxy)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(3-(Trifluoromethyl)phenoxy)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(4-cyanophenoxy)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(4-cyanophenoxy)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-([l,l'-biphenyl]-4-yloxy)propoxy) phenyl) oxetan-3-yl)acetate;
2-(3-(4-(3-([l,l'-biphenyl]-4-yloxy)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(2,2-dimethyl-3-(4-(trifluoromethyl)phenoxy)propoxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-(2,2-Dimethyl-3-(4-(trifluoromethyl)phenoxy)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((l-((o-tolyloxy)methyl)cyclopropyl)methoxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((l-((o-Tolyloxy)methyl)cyclopropyl)methoxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((l -((3-(trifluoromethyl)phenoxy)methyl)cyclopropyl)methoxy)phenyl) oxetan- 3 -yl) acetate;
2-(3-(4-((l-((3-(Trifluoromethyl)phenoxy)methyl)cyclopropyl)methoxy)phenyl) oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((l - ((3 -chlorophenoxy)methyl)cyclopropyl) methoxy)phenyl)oxetan-3 - yl)acetate;
2-(3-(4-((l-((3-chlorophenoxy)methyl)cyclopropyl)methoxy) phenyl)oxetan-3-yl) acetic acid; Ethyl 2-(3-(4-((4-((l-methylspiro[indoline-3,4'-piperidin]- -yl)methyl)benzyl)oxy) phenyl)oxetan-3-yl)acetate;
2- (3-(4-((4-((l-Methylspiro[indoline-3,4'-piperidin]- -yl)methyl)benzyl)oxy)phenyl)oxetan-
3- yl)acetic acid;
Ethyl 2-(3-(4-((4-(spiro[indene-l,4'-piperidin]- -ylmethyl) benzyl)oxy)phenyl) oxetan-3- yl)acetate;
2-(3-(4-((4-(Spiro[indene- 1 ,4'-piperidin] - 1 '-ylmethyl)benzyl)oxy)phenyl)oxetan-3-yl) acetic acid;
Ethyl 2-(3-(4-(3-(methylsulfonamido)propoxy)phenyl)oxetan-3-yl)acetate;
Ethyl 2-(3^4-((4'-((4-benzylmorpholin-2-yl)methoxy)-2',6'-dimethyl-[l,l'-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4'-((4-benzylmoφholin-2-yl)methoxy)-2 6'-(hmethyl-[l,l'-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-phenylethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((4-(2-(Methoxyimino)-2-phenylethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-(4-methoxyphenyl)ethoxy)benzyl)oxy) phenyl) oxetan-3-yl)acetate;
2- (3-(4-((4-(2-(Methoxyimino)-2-(4-methoxyphenyl)ethoxy) benzyl)oxy)phenyl) oxetan-3- yl)acetic acid;
Ethyl 2-(3 -(4-((4-(2-(4-chlorophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy)phenyl) oxetan-
3- yl)acetate;
2-(3-(4-((4-(2-(4-chlorophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy)phenyl)oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-(4-cyanophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy)phenyl) oxetan-3- yl)acetate; 2-(3-(4-((4-(2-(4-cyanophenyl)-2-(methoxyimino) ethoxy)benzyl)oxy)phenyl)oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-(p-tolyl)ethoxy)benzyl)oxy) phenyl)oxetan-3- yl)acetate;
2-(3-(4-((4-(2-(methoxyimino)-2-(p-tolyl)ethoxy)benzyl) oxy)phenyl) oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-(4-(trifluoromethoxy)phenyl)ethoxy)benzyl) oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-(2-(methoxyimino)-2-(4-(trifluoromethoxy)phenyl)ethoxy)benzyl)oxy) phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-([l,l'-biphenyl]-4-yl)-2-(methoxyimino)ethoxy)benzyl)oxy)phenyl) oxetan-3-yl)acetate;
2-(3-(4-((4-(2-([l,l'-biphenyl]-4-yl)-2-(methoxyimino)ethoxy)benzyl)oxy)phenyl) oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-(4-fluorophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy)phenyl) oxetan-3- yl)acetate;
2-(3-(4-((4-(2-(4-fluorophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy)phenyl) oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-(3-methoxyphenyl)ethoxy)benzyl)oxy)phenyl) oxetan-3-yl)acetate;
2-(3-(4-((4-(2-(methoxyimino)-2-(3-methoxyphenyl)ethoxy)benzyl)oxy)phenyl) oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-(2-(methoxyimino)-2-phenylethoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(2-(methoxyimino)-2-phenylethoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-benzoylbenzyl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((3-benzoylbenzyl)oxy) phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-((methoxyimino)(phenyl)methyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((3-((methoxyimino) (phenyl)methyl)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((4-benzoylbenzyl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-benzoylbenzyl)oxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((4-((methoxyimino)(phenyl)methyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((4-((methoxyimino) (phenyl)methyl)benzyl)oxy)phenyl)oxetan-3-yl) acetic acid; Ethyl 2-(3-(4-((4-(2-oxo-2-phenylethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((4-(2-oxo-2-phenylethoxy) benzyl)oxy) phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-(4-methoxyphenyl)-2-oxoethoxy) benzyl)oxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((4-(2-(4-methoxyphenyl)-2-oxoethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((4-(2-(4-fluorophenyl)-2-oxoethoxy) benzyl)oxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((4-(2-(4-fluorophenyl)-2-oxoethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-(2-(3-(4-methoxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-(2-(3-(4-methoxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(2-(3-(4-(benzyloxy)phenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl) acetate; 2-(3-(4-(2-(3-(4-(benzyloxy)phenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-(2-(3-(4-hydroxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(2-(3-(4-hydroxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(2-(3-(4-((3-methyloxetan-3-yl)methoxy)phenyl)oxetan-3- yl)ethoxy)phenyl)oxetan-3-yl)acetate;
2- (3-(4-(2-(3-(4-((3-methyloxetan-3-yl)methoxy)phenyl)oxetan-3-yl)ethoxy)phenyl) oxetan-
3- yl)acetic acid;
Ethyl 2-(3-(4-(2-(3-(4-(3-(methylsulfonyl)propoxy)phenyl)oxetan-3- yl)ethoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(2-(3-(4-(3-(methylsulfonyl)propoxy)phenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((3-(4-(benzyloxy)phenyl)oxetan-3-yl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((3-(4-(benzyloxy)phenyl)oxetan-3-yl)oxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((4-chloro-2,3-dihydro-lH-inden- l-yl)oxy) phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-chloro-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((5-methoxy-2,3-dihydro-lH-inden-l-yl)oxy) phenyl) oxetan-3-yl)acetate; 2-(3-(4-((5-methoxy-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((6-((3-methyloxetan-3-yl)methoxy)-2,3-dihydro-lH-inden-l-yl)oxy) phenyl)oxetan-3-yl)acetate;
2- (3-(4-((6-((3-methyloxetan-3-yl)methoxy)-2,3-dihydro- lH-inden-l-yl)oxy)phenyl)oxetan-
3- yl)acetic acid;
Ethyl 2-(3-(4-((6-(isopentyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((6-(isopentyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((6-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl) oxetan-3- yl)acetate;
2-(3-(4-((6-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl) acetic acid;
Ethyl 2-(3-(4-((6-(benzyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl) acetate; 2-(3-(4-((6-(benzyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((5-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((5-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((5-(isopentyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((5-(isopentyloxy)-2,3-dihydro-lH-inden-l-yl)oxy) phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((5-((3-methyloxetan-3-yl)methoxy)-2,3-dihydro-lH-inden-l-yl)oxy) phenyl)oxetan-3-yl)acetate;
2- (3-(4-((5-((3-methyloxetan-3-yl)methoxy)-2,3-dihydro-lH-inden-l-yl)oxy) phenyl)oxetan-
3- yl)acetic acid;
Ethyl 2-(3-(4-((3-phenoxybenzyl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((3-phenoxybenzyl)oxy) phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-(4-fluorophenoxy) benzyl) oxy) phenyl) oxetan-3-yl) acetate;
2-(3-(4-((3-(4-fluorophenoxy) benzyl) oxy) phenyl) oxetan-3-yl) acetic acid;
Ethyl 2-(3-(4-((4-phenoxybenzyl) oxy) phenyl) oxetan-3-yl) acetate;
2-(3-(4-((4-phenoxybenzyl) oxy) phenyl) oxetan-3-yl) acetic acid;
Ethyl 2-(3-(4-((2-phenoxybenzyl) oxy) phenyl) oxetan-3-yl) acetate; 2-(3-(4-((2- phenoxybenzyl) oxy) phenyl) oxetan-3-yl) acetic acid;
Ethyl 2-(3-(4-((4-(2,6-dimethylphenoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-(2,6-dimethylphenoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-phenyl-3-(pyridin-3-yl)propoxy)phenyl) oxetan-3-yl)acetate;
2-(3-(4-(3-phenyl-3-(pyridin-2-yl)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3,3-diphenylallyl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((3,3-diphenylallyl) oxy)phenyl)oxetan-3-yl)acetic acid;
Benzyl l-(4-((4-(3-(2-ethoxy-2-oxoethyl)oxetan-3-yl)phenoxy)methyl)benzyl)
spiro[indoline-3 ,4'-piperidine] - 1 '-carboxylate; Ethyl 2-(3 -(4-((4-(( 1 -(methylsulfonyl)spiro[indoline-3 ,4'-piperidin] - 1 '-yl)methyl) benzyl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-((l-(Methylsulfonyl) spiro[indoline-3,4'-piperidin]- -yl)methyl)benzyl)oxy) phenyl)oxetan-3-yl)acetic acid;
ethyl 2-(3-(4-((4-(( -(methylsulfonyl)spiro[indoline-3,4'-piperidin]-l-yl)methyl)benzyl) oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-((l'-(methylsulfonyl) spiro[indoline-3,4'-piperidin]-l-yl)methyl)benzyl)oxy) phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(2-(5-methyl-2-phenylthiazol-4-yl)ethoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(2-(5-methyl-2-phenylthiazol-4-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-((4-chlorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((3-((4-Chlorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((3-((o-tolyloxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((3-((o-Tolyloxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-((naphthalen-2-yloxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((3-((Naphthalen-2-yloxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-((4-cyanophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((3-((4-Cyanophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((3-((4-fluorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((3-((4-Fluorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((3-((4-chlorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((3-((4-Chlorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((3-((2-fluorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((3-((2-Fluorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-(3-([l,l'4jiphenyl]-4-ylsulfonamido)propoxy)phenyl) oxetan-3-yl)acetate; 2-(3-(4-(3-([l,l'4jiphenyl]-4-ylsulfonamido)propoxy) phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((2-(spiro[indene-l,4'-piperidin]- -methyl)benzyl) oxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((2-(Spiro[indene- 1 ,4'-piperidin] - 1 '-ylmethyl)benzyl) oxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-((l-methylspiro[indoline-3,4'-piperidin]- -yl)methyl)benzyl)oxy) phenyl)oxetan-3-yl)acetate;
2-(3-(4-((3-(Spiro[indene-l,4'-piperidin]- -ylmethyl)benzyl)oxy) phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-((l-methylspiro[indoline-3,4'-piperidin]- -yl)methyl)benzyl)oxy) phenyl)oxetan-3-yl)acetate;
2- (3-(4-((3-((l-Methylspiro[indoline-3,4'-piperidin]- -yl)methyl)benzyl)oxy)phenyl) oxetan-
3- yl)acetic acid;
Ethyl 2-(3-(4-((6-(spko[indene-l,4'^iperidin]- -ylmemyl)pyridin-2-yl)methoxy)phenyl) oxetan-3-yl)acetate;
2-(3-(4-((6-(Spko[indene-l,4'-piperidin]- -ylmethyl)pyridin-2-yl)methoxy)phenyl) oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((6-((l-methylspiro[indoline-3,4'-piperidin]- -yl)methyl)pyridin-2- yl)methoxy)phenyl)oxetan-3-yl)acetate; and
2-(3-(4-((6-((l-Methylspiro[indoline-3,4'-piperidin]- -yl)methyl)pyridin-2- yl)methoxy)phenyl)oxetan-3-yl)acetic acid; or
an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, a carboxylic acid isostere, an N-oxide or a S-oxide thereof.
The present invention also relates to processes for the preparation of the compounds of Formula (I) or pharmaceutically acceptable salts thereof. The compounds of Formula (I) can be prepared by the schemes depicted herein below, but are not limited thereto. The starting materials and reagents employed in the processes for preparation of the compounds of Formula (I) are commercially available or can be prepared by processes known in the art.
Figure imgf000044_0001
Figure imgf000044_0002
Reaction conditions:
Step la: Ethyl 2-(triphenylphosphoranylidene)acetate (PPhsCHCCKX^Hs), dichloromethane (DCM), room temperature (RT) (20 °C-25 °C);
Step lb: Cyclooctadiene rhodium chloride dimer (Rh(COD)2Cl2), potassium hydroxide (KOH), dioxane.
The reaction steps as outlined in the above Scheme 1 are described herein below: Step la:
This process step involves reacting compound (1), (wherein R2 and R3 are as defined above for any one of the embodiments of the compounds of Formula (I)), with a reagent such as ethyl 2-(triphenylphosphoranylidene)acetate in a solvent such as dichloromethane at room temperature, according to the method described in Angew Chem. Intl. Ed. , 2006, 45:7736- 39, to obtain compound (2), (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl; R2 and R3 are as defined above).
Step lb:
Compound (3) is reacted with the compound (2) (obtained in Step la) in the presence of a suspension comprising a catalyst selected from cyclooctadiene rhodium chloride dimer or trimethylsilylchloride in a solvent selected from dioxane, tetrahydrofuran (THF), toluene, acetonitrile or dimethoxyethane and a base selected from potassium hydroxide (KOH), sodium hydroxide (NaOH), potassium bicarbonate (KHCO3), sodium bicarbonate (NaHCOs), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyrrolidine or triethylamine, according to the method described in Angew Chem. Intl. Ed. 2006, 45:7736-39 and J. Med. Chem., 2010, 53(8):3227-3246, to obtain the compound (4) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl; R2, R3, R4, R5 m and n are as defined above for any one of the embodiments of the compounds of Formula (I)).
Figure imgf000045_0001
Formula (I) Formula (I)
(wherein R-, is (CrC6)alkyl) (wherein R-, is hydrogen)
Reaction conditions:
Step 2a: Sodium hydride, carbon disulfide, methyl 2-bromoacetate, dimethylformamide (DMF);
Step 2b: meta-Chloroperoxybenzoic acid, dichloromethane (DCM);
Step 2c: Aqueous sodium hydroxide, ethanol;
Step 2d: Sodium acetate, acetic acid;
Step 2e: borane dimethylsulfide, THF;
Step 2f: Phosphorus tribromide, DCM;
Step 2g: Cesium carbonate, DMF;
Step 2h: L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT.
The reaction steps as outlined in the above Scheme 2 are described herein below: Step 2a:
In this step, 1-tetralone is reacted with carbon disulfide and methyl 2-bromoacetate in the presence of a base selected from n-butyllithium, sodium hydride, NaOH, KOH, potassium carbonate (K2CO3) or triethylamine and a solvent such as dimethylformamide to obtain compound (5).
Step 2b:
In this step, the compound (5) is oxidized in the presence of an oxidizing agent such as meta- chloroperoxybenzoic acid in a solvent selected from DCM, 1,2-dichloroethane, chloroform, ether, EtOAc or a mixture thereof to obtain compound (6).
Step 2c:
In this step, the compound (6) is hydrolyzed in the presence of a base selected from NaOH, KOH, K2CO3 or triethylamine and a solvent selected from ethanol, methanol, isopropyl alcohol or a mixture thereof to obtain compound (7).
Step 2d:
In this step, the compound (7) is treated with acetic acid in the presence of catalytic amount of sodium acetate to obtain compound (8), wherein R10 is -S(0)pRe; I¾ is methyl and p is an integer from 0 to 2.
Step 2e:
In this step, the compound (8) is subjected to reduction in the presence of a reducing agent such as borane-dimethyl sulfide and a solvent such as THF to obtain compound (9) (wherein Rio is -S(0)pR6; R6 is methyl and p is an integer from 0 to 2).
Step 2f :
In this step, the compound (9) is subjected to bromination in the presence of a brominating agent such as phosphorus tribromide in a solvent such as DCM to obtain compound (10) (wherein Rio is -S(0)pR6; R6 is methyl and p is an integer from 0 to 2).
Step 2g:
In this step, the compound (10) is treated with compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a base selected from CS2CO3 or K2CO3 and a solvent such as DMF to obtain compound of Formula (I) (wherein Ri is (Ci-C6)alkyl, e.g. ethyl; Rio is -S(0)PR6, R6 is methyl and p is an integer from 0 to 2).
Step 2h:
The compound of Formula (I) (wherein Ri is (Ci-C6)alkyl, e.g. ethyl) as obtained in Step 2g, is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, lithium hydroxide (LiOH) or barium hydroxide (Ba(OH)2), followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I), (wherein Ri is hydrogen; Rio is -S(0)PR6, R6 is methyl and p is an integer from 0 to 2).
Alternatively, the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 3:
Figure imgf000047_0001
(wherein is hydrogen) Reaction conditions:
Step 3a: Cesium carbonate (CS2CO3), dimethylformamide (DMF);
Step 3b: Triethylamine, DCM, 4-dimethyl.am.inopyridine;
Step 3c: Sodium azide, DMF;
Step 3d: Hydrogen /palladium on carbon, MeOH;
Step 3e: (0-(7-azabenzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexafluoro
phosphate) (HATU), N,N-Diisopropylethylamine (Hunig's base), DMF;
Step 3f: THF, RT;
Steps 3g and 3h: L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT;
Step 3i: Triethylamine, DCM.
The reaction steps as outlined in the above Scheme 3 are described herein below: Step 3a:
In this step, compound (11) (wherein n is 1 to 3) is reacted with the compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a base selected from CS2CO3 or K2CO3 and a solvent such as DMF to obtain compound (12) (wherein Rj is (Q- Ce)alkyl, e.g. ethyl; R2, R3, R4, R5, m and n are as defined above for any one of the embodiments of the compounds of Formula (I)).
Step 3b:
In this step, the compound (12) is treated with p-tosyl chloride in the presence of a catalyst such as 4-dimethylaminopyridine (DMAP) and a base selected from triethylamine, NaOH, KOH or K2CO3; in a solvent selected from dichloromethane, 1,2-dichloroethane, chloroform, ether, ethyl acetate or a mixture thereof; to obtain a compound (13) (wherein Rj is (Ci-C6)alkyl, e.g. ethyl; R2, R3, R4, R5, m and n are as defined above for any one of the embodiments of the compounds of Formula (I)).
Step 3c:
In this step, the compound (13) is treated with sodium azide in a solvent such as DMF to obtain compound (14) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl; R2, R3, R4, R5, m and n are as defined above for any one of the embodiments of the compounds of Formula (I)).
Step 3d:
In this step, the compound (14) is subjected to catalytic reduction in the presence of a catalyst such as palladium on carbon in a solvent selected from MeOH, ethanol, isopropanol or a mixture thereof to obtain compound (15), (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl; I¾, R3, R4, R5, m and n are as defined above for any one of the embodiments of the compounds of Formula (I)).
Step 3e:
In this step, the compound (15) is reacted with the compound (8) (obtained in step 2d of the process depicted in scheme 2), in the presence of a coupling reagent such as HATU, a base such as Hunig' s base and in a solvent such as dimethylformamide to obtain a compound of Formula (I) (wherein Rj is (Ci-C6) alkyl, e.g. ethyl; Rjo is -S(0)PR6, R6 is methyl and p is an integer from 0 to 2).
Step 3f:
In this step, the compound (15) as obtained in step 3d is reacted with a compound of formula: A-N=C=0 (wherein A is as defined above for any one of the embodiments of the compounds of Formula (I)) in a solvent selected from THF, dioxane, toluene, acetonitrile, dimethoxyethane or a mixture thereof; to obtain a compound of Formula (I) (wherein Rj is (Cj-Ce) alkyl, e.g. ethyl).
Steps 3g and 3h:
The compound of Formula (I) (wherein Ri is (Ci-Ce)alkyl, e.g. ethyl) as obtained in Step 3e/ 3f, is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or barium hydroxide Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain a compound of Formula (I) (wherein Rj is hydrogen).
Step 3i:
In this step, the compound (15) as obtained in step 3d, is reacted with a compound of formula: A-S(0)PC1 (wherein p is 2 and A is as defined above for any one of the embodiments of the compounds of Formula (I)), in the presence of a base such as triethylamine and a solvent selected from DCM, dichloroethane, chloroform, ether, ethyl acetate or a mixture thereof; to obtain the compound of Formula (I) (wherein Rj is (Ci-C6) alkyl, e.g. ethyl). The compound of Formula (I) thus obtained, can be optionally hydrolyzed to obtain a compound of Formula (I) (wherein Rj is hydrogen). Alternatively, the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 4.
Scheme 4
Figure imgf000050_0001
Formula (I) Formula (I)
(wherein L-| is O or S and R1 is (CrC6)alkyl) (wherein L-i is O or S and R-i is hydrogen)
Figure imgf000050_0002
Formula (I) Formula (I)
is S and R-, is (CrC6)alkyl) (wherein L-| is S(O) and R-,
Figure imgf000050_0003
Formula (I)
(wherein L-| is S(0)2 and R-, is (CrC6)alkyl)
Reaction conditions:
Step 4a: Cesium carbonate (Cs2C03), DMF;
Step 4b: L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT;
Step 4c and 4d: Potassium peroxymonosuifate (oxone®), methanol (MeOH).
The reaction steps as outlined in the above Scheme 4 are described herein below:
Step 4a:
In this step, compound (13) is reacted with compound (16) of Formula: A-Lj-H (wherein Lj is O or S and A is as defined above for any one of the embodiments of the compounds of Formula (I)), in the presence of a base selected from CS2CO3 or K2CO3 and a solvent such as dimethylformamide to obtain the compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl).
Step 4b:
The compound of Formula (I) (obtained in Step 4a), wherein Rj is (Ci-Ce)alkyl, e.g. ethyl is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I) (wherein Rj is hydrogen).
Step 4c:
In this step, the compound of Formula (I) (wherein Li is S and Ri is (Ci-Ce)alkyl, e.g. ethyl) as obtained in Step 4a; is treated with oxone® in a solvent selected from ethanol, MeOH, isopropanol or mixture thereof to obtain the compound of Formula (I) (wherein Li is S(O) and Rj is (Ci-Ce)alkyl, e.g. ethyl). The compound of Formula (I) (wherein Rj is (Ci-C6) alkyl, e.g. ethyl) thus obtained, can be optionally hydrolyzed to obtain a compound of Formula (I) wherein Rj is hydrogen.
Step 4d:
In this step, the compound of Formula (I), (obtained in Step 4c) (wherein Lj is S(O) and Rj is (Ci-C6)alkyl, e.g. ethyl); is treated with oxone® in a solvent selected from ethanol, methanol, isopropanol or a mixture thereof; to obtain the compound of Formula (I), (wherein Lj is S(0)2 and Rj is (Ci-Ce)alkyl, e.g. ethyl). The compound of Formula (I) (wherein Rj is (Ci-C6) alkyl, e.g. ethyl) thus obtained, can be optionally hydrolyzed to obtain a compound of Formula (I) (wherein Rj is hydrogen).
Alternatively, the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 5. Scheme 5
Figure imgf000052_0001
Formula (I) (18)
Figure imgf000052_0002
Formula (I)
(wherein is hydrogen)
Reaction conditions:
Step 5a: Pyridine;
Steps 5b and 5c: Sodium hydride, DMF
Step 5d: L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT.
The reaction steps as outlined in the above Scheme 5 are described herein below:
Step 5a:
In this step, 4-methylbenzene-l-sulfonyl chloride is treated with 2,2- dimethylpropane -1 ,3-diol in a solvent such as pyridine to obtain the compound (17).
Step 5b:
In this step, the compound (17) is treated with a compound of formula: A-OH, (wherein A is as defined above for any one embodiments of the compounds of Formula (I)) in the presence of a base such as n-butyllithium, sodium hydride, NaOH, KOH, K2CO3 or triethylamine and a solvent such as DMF to obtain compound (18) (wherein A is as defined above for the compounds of Formula (I)).
Step 5c:
In this step, compound (18) is treated with the compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a base selected from sodium hydride, n-butyllithium, NaOH, KOH, K2CO3, triethylamine or cesium carbonate and a solvent such as DMF to obtain compound of Formula (I) (wherein Rj is (Ci-C6)alkyl, e.g. ethyl).
Alternatively, the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 6.
Figure imgf000053_0001
Formula (I) Formula (I)
(wherein is hydrogen) (wherein is (CrC6)alkyl)
Reaction conditions:
Step 6a: Diisopropyl azodicarboxylate (DIAD), triphenylphosphine;
Step 6b: Phosphorus tribromide, DCM;
Step 6c: Cesium carbonate, DMF;
Step 6d: L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT.
The reaction steps as outlined in the above Scheme 6 are described herein below: Step 6a:
In this step, compound of formula: A-OH (wherein A is as defined above for any one embodiments of the compounds of formula (I)) is reacted with cyclopropyldimethanol in the presence of a reagent such as diisopropyl azodicarboxylate or diethylazodicarboxylate and triphenylphosphine to obtain compound (19) (wherein A is as defined above).
Step 6b:
In this step, the compound (19) is subjected to bromination in the presence of a brominating agent such as phosphorus tribromide in a solvent selected from DCM, dichloroethane, chloroform, ether, EtOAc or a mixture thereof to obtain compound (20) (wherein A is as defined above).
Step 6c:
In this step, the compound (20) is reacted with the compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a base selected from CS2CO3 or K2CO3 and a solvent such as DMF to obtain the compound of Formula (I) (wherein Rj is (Q- C6)alkyl, e.g. ethyl).
Step 6d:
The compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl) as obtained in Step 6c, is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or barium hydroxide (Ba(OH)2), followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I), (wherein Rj is hydrogen).
Alternatively, the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 7.
Scheme 7
Reaction conditions:
Step 7a: Trifluoroacetic acid, sodium borohydride, toluene, acetonitrile;
Step 7b: Formaldehyde, sodium cyanoborohydride, acetic acid, MeOH;
Step 7c: Palladium on carbon, hydrogen, ammonium formate, MeOH;
Step 7d and Step 7e: Cesium carbonate, DMF;
Step 7f: L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT.
Figure imgf000055_0001
Figure imgf000055_0002
Figure imgf000055_0003
Formula (I)
(wherein is hydrogen)
The reaction steps as outlined in the above Scheme 7 are described herein below: Step 7a:
In this step, phenyl hydrazine is reacted with benzyl 4-formylpiperidine-l- carboxylate, in the presence of trifluoroacetic acid and a reducing agent such as sodium borohydride, in a solvent selected from toluene, acetonitrile, dioxane, DCM or a mixture thereof to obtain compound (21). Step 7b:
In this step, the compound (21) is subjected to reductive methylation using formaldehyde in the presence of acetic acid and a reducing agent such as sodium cyanoborohydride in a solvent selected from MeOH, ethanol, isopropanol or a mixture thereof; to obtain compound (22) (wherein Rjo is methyl).
Step 7c:
In this step, the compound (22) is subjected to deprotection in the presence of deprotecting agent such as palladium catalyst (Palladium on carbon) and ammonium formate in methanol, followed by hydrogenation to obtain compound (23) (wherein Rjo is methyl).
Step 7d:
In this step, the compound (24), (wherein p is as defined above) is treated with compound (4) (obtained in step lb of the process depicted in scheme 1) in presence of a base selected from CS2CO3 or K2CO3 and a solvent such as DMF to obtain the compound (25) (wherein Rj is (C C6)alkyl, e.g. ethyl; R2, R3, R4, R5, m, n and p are as defined for any one of the embodiments of the compounds of Formula (I)).
Step 7e:
In this step, the compound (23) (wherein Rjo is methyl) is reacted with the compound (25) (wherein Rj is (Ci-C6)alkyl, e.g. ethyl; R2, R3, R4, R5, m, n and p are as defined above) in presence of a base selected from CS2CO3 or K2CO3 and a solvent such as DMF to obtain the compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl).
Step 7f:
The compound of Formula (I) (wherein Rj is (Cj-C6)alkyl, e.g. ethyl) as obtained in Step 7e, is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I) (wherein Rj is hydrogen).
Alternatively, the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 8.
Figure imgf000057_0001
(26) (27) (28) (29)
Figure imgf000057_0002
(wherein R.| is ( r 6)alkyl)
Figure imgf000057_0003
w ere n s r 6 a y
Reaction conditions:
Step 8a: Lithium hexainethyldisilazide, tetrahydrofuran;
Step 8b: Trifluoroacetic acid, DCM;
Step 8c: Cesium carbonate, DMF;
Step 8d: L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT.
The reaction steps as outlined in the above Scheme 8 are described herein below: Step 8a:
In this step, lH-indene of formula (26) is reacted with compound (27), which is
a Boc -protected amine, in the presence of a base such as lithium
hexainethyldisilazide and a solvent selected from THF, acetonitrile, ethanol, isopropanol, methanol or a mixture thereof; to obtain compound (28). Step 8b:
In this step, the compound (28) is subjected to deprotection in the presence of a deprotecting agent such as trifluoroacetic acid and a solvent selected from DCM, toluene, acetonitrile, dioxane or a mixture thereof; to obtain the compound (29).
Alternatively, compound (29) can be obtained from commercial sources.
Step 8c:
In this step, the compound (29) is reacted with the compound (25) (wherein Rj is (Q- Ce)alkyl, e.g. ethyl); R2, R3, R4, R5, m, n and p are as defined for Formula (I)), in presence of a base selected from CS2CO3 or K2CO3 and a solvent such as DMF to obtain the compound of Formula (I), (wherein Rj is (Ci-C6)alkyl, e.g. ethyl).
Step 8d:
The compound of Formula (I) (wherein Ri is (Ci-Ce)alkyl, e.g. ethyl) as obtained in Step 8c, is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or barium hydroxide (Ba(OH)2), followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I) (wherein Ri is hydrogen).
Alternatively, the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 9.
Scheme 9
Reaction conditions:
Step 9a: Sodium hydride, DMF;
Step 9b: Phosphorus tribromide, DCM;
Step 9c: Cesium carbonate, DMF;
Step 9d: LiOH.F^O, THF, MeOH, water, aqueous ammonium chloride, RT.
Figure imgf000059_0001
(wherein is (C-|-C6)alkyl)
Figure imgf000059_0002
(wherein R1 is hydrogen)
The reaction steps as outlined in the above Scheme 9 are described herein below: Step 9a:
In this step, compound (30a) (wherein k is 1 or 2) is reacted with compound (30b) (wherein Rio is as defined above) in the presence of a base selected from sodium hydride, n- butyllithium, NaOH, KOH, K2CO3 or triethylamine and a solvent such as DMF to obtain compound (30c) (wherein k is 1 or 2 and Rio is as defined above for any one of the embodiments of the compounds of Formula (I)).
Step 9b:
In this step, the compound (30c) is treated with a brominating agent such as
phosphorus tribromide and a solvent selected from DCM, dichloroethane, ether,
acetonitrile, toluene or a mixture thereof; to obtain compound (30) (wherein k is 1 or 2 and Rio is as defined above for any one of the embodiments of the compounds of Formula (I)). Step 9c:
In this step, the compound (30) is reacted with compound (4) (obtained in step lb of the process depicted in scheme 1), in the presence of a base selected from CS2CO3 or K2CO3 and a solvent such as DMF to obtain the compound of Formula (I), (wherein Ri is (Ci-C6)alkyl, e.g. ethyl).
Step 9d:
The compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl) as obtained in Step 9c, is taken in a solvent selected from THF, ethanol, methanol, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain the compound of Formula (I) (wherein Rj is hydrogen).
Alternatively, the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 10.
Scheme 10
Reaction conditions:
Step 10a: Methoxylamine hydrochloride, sodium acetate, glacial acetic acid;
Step 10b: Cesium carbonate, DMF;
Step 10c and Step 10c' : Potassium carbonate, acetonitrile, reflux;
Step 10c": Sodium borohydride, methanol, RT;
Step lOd: Phosphorus tribromide, DCM, RT;
Step lOe: Triphenylphosphine, diethyl azodicarboxylate (DEAD), THF;
Step 10e' : Cesium carbonate, DMF;
Step lOf: LiOH.H20, THF, MeOH, water, aqueous ammonium chloride, RT.
0 C C alk l
Figure imgf000061_0001
(wherein R-, is hydrogen)
The reaction steps as outlined in the above Scheme 10 are described herein below: Step 10a:
In this step, the compound (31) (wherein A is as defined above for any one embodiments of the compounds of formula (I)) is treated with methoxylamine hydrochloride in the presence of a base such as sodium acetate and a solvent such as glacial acetic acid to obtain compound (32) (wherein A is as defined above).
Step 10b:
In this step, the compound (32) is treated with 4-hydroxybenzaldehyde in the presence of a base selected from CS2CO3, K2CO3 or sodium carbonate and a solvent such as DMF to obtain compound (33) (wherein A is as defined above).
Step 10c and Step 10c' :
The compounds (31) and (32) (wherein A is as defined above) are treated with 4- (hydroxymethyl)phenol in the presence of a base selected from K2CO3, sodium carbonate, CS2CO3, potassium bicarbonate or NaOH and a solvent selected from acetonitrile, ether, toluene, DCM or a mixture thereof; to obtain the compound (34) (wherein A is as defined above and R' and R" together form
Figure imgf000061_0002
or =0). Step 10c":
In this step, the compound (33) (wherein A is as defined above) is subjected to reduction in the presence of a reducing agent such as sodium borohydride and a solvent selected from methanol, ethanol, isopropanol or a mixture thereof to obtain compound (34) (wherein A is as defined above and R' and R" together form =N(0-(C1-C6)alkyl).
Step lOd:
In this step, the compound (34) (wherein R' and R" together form
Figure imgf000062_0001
as obtained in step 10c" is subjected to bromination in the presence of a brominating agent such as phosphorus tribromide and a solvent selected from DCM, dichloroethane, acetonitrile, ether, toluene or a mixture thereof; to obtain compound (35) (wherein A is as defined above and R' and R" together form
Figure imgf000062_0002
Step lOe:
In this step, the compound (34) (wherein R' and R" together form =N(0-(C1-C6)alkyl) or =0) as obtained in steps 10c and 10c' is reacted with the compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a reagent such as diisopropyl azodicarboxylate or diethylazodicarboxylate and triphenylphosphine to obtain the compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl) and R' and R" together form =N(0- (Ci-C6)alkyl) or =0).
Step 10e' :
In this step, the compound (35) (wherein R' and R" together form =N(0-(C1-C6)alkyl)) as obtained in step lOd is reacted with the compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a base selected from CS2CO3, K2CO3 or sodium carbonate and a solvent selected from DMF, dime thylsulf oxide, acetonitrile or mixture thereof to obtain the compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl) and R' and R" together form =N(0-(C1-C6)alkyl)).
Step lOf:
The compound of Formula (I) (wherein Rj is (Ci-C6)alkyl, e.g. ethyl) and R' and R" together form
Figure imgf000062_0003
or =0) obtained in Step lOe and step 10e', is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain the compound of Formula (I) (wherein Rj is hydrogen and R' and R" together form
Figure imgf000063_0001
or =0).
Alternatively, the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 11.
Figure imgf000063_0002
Formula (I) Formula (I)
(wherein F^ is (C1-C6) alkyl) (wherein is hydrogen)
Reaction conditions:
Step 11a: Cesium carbonate, DMF, RT;
Step l ib: L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT.
The reaction steps as outlined in the above Scheme 11 are described herein below: Step 11a:
In this step, the compound (36) (wherein A is as defined above for any one embodiments of the compounds of formula (I) and R' and R" together form
Figure imgf000063_0003
or =0) is reacted with a compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a base selected from CS2CO3 or K2CO3 and a solvent such as DMF to obtain the compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl) and R' and R" together form =N(0-(d-C6)alkyl) or =0).
Step l ib:
The compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl) and R' and R" together form =N(0-(Ci-C6)alkyl) or =0) obtained in Step 11a, is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain the compound of Formula (I) (wherein Rj is hydrogen and R' and R" together form
Figure imgf000064_0001
or =0).
Alternatively, the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 12.
Figure imgf000064_0002
', R" together form oxo) (wherein R', R" together form oxo)
Figure imgf000064_0003
Formula (I)
(wherein R-, is (C C6) alkyl and
R', R" together form =N(0-(C C6)alkyl))
Reaction conditions:
Step 12a: N~hromosuccimmide or bromine, carbon tetrachloride, RT;
Step 12b: Cesium carbonate, DMF;
Step 12c: methoxylamine, ethanol, pyridine, reflux;
Step 12d and Step 12e: LiOH.H20, THF, MeOH, water, aqueous NH4C1, RT.
The reaction steps as outlined in the above Scheme 12 are described herein below: Step 12a:
In this step, compound (37) (wherein A is as defined above for any one embodiments of the compounds of formula (I) and R' and R" together form =0) is subjected to bromination in the presence of brominating agent such as N-bromosuccinimide or bromine and a solvent selected from carbontetrachloride, xylene, toluene, di-isopropyl ether or a mixture thereof to obtain the compound (38) (wherein A is as defined above for any one embodiments of the compounds of formula (I) and R' and R" together form =0).
Step 12b:
In this step, the compound (38) (wherein A, R' and R" are as defined above) is reacted with the compound (4) (obtained in step lb of the process depicted in scheme 1), to obtain compound of Formula (I) (wherein R' and R" together form =0 and Rj is (Ci-Ce)alkyl, e.g. ethyl).
Step 12c:
In this step, the compound of Formula (I), (wherein R' and R" together form =0 and Ri is (Ci-Ce)alkyl, e.g. ethyl), obtained in Step 12b is treated with methoxylamine hydrochloride in presence of a base such as pyridine and a solvent selected from methanol, ethanol, n- propanol, isopropanol, acetonitrile or a mixture thereof; to obtain the compound of Formula (I) (wherein R' and R" together form
Figure imgf000065_0001
and Ri is (Ci-C6)alkyl, e.g. ethyl).
Steps 12d and 12e:
The compounds of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl and R' and R" together form
Figure imgf000065_0002
or =0),obtained in Steps 12b and 12c are taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I) (wherein R' and R" together form
Figure imgf000065_0003
or =0 and Rj is hydrogen).
Alternatively, the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 13.
Figure imgf000066_0001
Formula (I) Formula (I)
(wherein R, is hydrogen) (wherein R, is hydrogen)
Reaction conditions:
Step 13a: Rn -halogen, potassium carbonate, acetonitrile;
Step 13b: Lithium aluminum hydride, THF;
Step 13c: Tosyl chloride, triethylamine or pyridine;
Step 13d: Cesium carbonate, DMF;
Step 13e: hydrogen, palladium on carbon, methanol;
Step 13f and Step 13g: L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT.
The reaction steps as outlined in the above Scheme 13 are described herein below: Step 13a:
In this step, the compound (39) (wherein Ri is (Ci-C6)alkyl, e.g. ethyl, R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloaikyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S; R4 and n are as defined for Formula (I)), is reacted with a compound of formula: Rn-halogen (wherein Rn is unsubstituted or substituted (Ci-Ce)alkyl), in the presence of a base selected from K2CO3, sodium carbonate, CS2CO3, NaOH or KOH and a solvent selected from acetonitrile, dioxane, DMF, dimethylsulfoxide or a mixture thereof to obtain compound (40) (wherein Rj is (Ci-C6)alkyl, e.g. ethyl; R' and R" together form a saturated or a partially unsaturated (C3-C8)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S; Rn is unsubstituted or substituted (Ci-Ce)alkyl; R4 and n are as defined for Formula (I)).
Step 13b:
In this step, the compound (40) is subjected to reduction in the presence of a base such as lithium aluminum hydride and a solvent such as THF to obtain a compound (41) (wherein R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S; Rn is unsubstituted or substituted (Ci-Ce)alkyl; R4 and n are as defined for Formula (I)).
Step 13c:
In this step, the compound (41) is treated with tosyl chloride in the presence of a base such as triethylamine or pyridine and a solvent selected from dichloroe thane, DCM, diethylether, THF or a mixture thereof to obtain compound (42) (wherein R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S; Rn is unsubstituted or substituted (Ci-Ce)alkyl, P2 is tosyl, R^ and n are as defined for Formula (I))·
Step 13d:
In this step, the compound (42) is reacted with the compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a base selected from CS2CO3 or K2CO3 and a solvent such as DMF to obtain the compound of Formula (I) (wherein Rn is unsubstituted or substituted (Ci-Ce)alkyl; R' and R" together form a saturated or a partially unsaturated (C3- Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S and Rj is (Ci-C6)alkyl, e.g. ethyl).
Step 13e:
In this step, the compound of Formula (I) obtained in Step 13d (wherein Rn is substituted (Ci-Ce)alkyl such as benzyl) is subjected to palladium catalyzed hydrogenation in the presence of palladium catalyst such as palladium on carbon to obtain compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl and R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S).
Step 13f:
The compound of Formula (I), (wherein Ri is (Ci-Ce)alkyl, e.g. ethyl) obtained in Step 13d is taken in a solvent selected from THF, ethanol, methanol, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I) (wherein Ri is hydrogen and Rn is unsubstituted or substituted (Ci-Ce)alkyl and R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S).
Step 13g:
The compound of Formula (I), (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl) obtained in Step 13e is taken in a solvent selected from THF, ethanol, methanol, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I) (wherein Rj is hydrogen and R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S).
Alternatively, the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 14.
Figure imgf000069_0001
(wherein R-| is (Ci-C6)alkyl)
Figure imgf000069_0002
Formula (I)
(wherein R-| is hydrogen)
Reaction conditions:
Step 14a: n-Butyl lithium, THF;
Step 14b: Triphenyl phosphine, Diethyl azodicarboxylate (DEAD), THF;
Step 14c: L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT.
The reaction steps as outlined in the above Scheme 14 are described herein below: Step 14a:
In this step, the compound (43), (wherein Rn is unsubstituted (Ci-Ce)alkyl or substituted (Q- Ce)alkyl such as benzyl) is treated with a compound of formula: R'(C=0)R" (wherein R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S); in the presence of a base such as n-butyllithium and a solvent selected from THF, EtOAc, chloroform, dioxane or a mixture thereof; to obtain compound (44) (wherein Rn is unsubstituted (Ci-Ce)alkyl or substituted (Ci-Ce)alkyl such as benzyl; and R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S).
Step 14b:
In this step, compound (44) is reacted with a compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a reagent such as diethylazodicarboxylate or diisopropyl azodicarboxylate and triphenylphosphine to obtain the compound of Formula (I) (wherein Rj is (Ci-C6)alkyl, e.g. ethyl; Rn is unsubstituted or substituted (Ci-Ce)alkyl such as benzyl; and R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S).
Step 14c:
The compound of Formula (I), (wherein Rj is (Cj-C6)alkyl, e.g. ethyl) obtained in Step 14b, is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, LiOH or barium hydroxide (Ba(OH)2), followed by neutralization with aqueous ammonium chloride to obtain the compound of Formula (I) (wherein Rj is hydrogen; Rn is unsubstituted (Ci-C6)alkyl or substituted (Ci-Ce)alkyl such as benzyl; and R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S).
Alternatively, the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 15.
Scheme 15
Figure imgf000070_0001
Formula (I)
rein Ri is hydrogi
Reaction conditions:
Step 15a: Triphenyl phosphine, Diethyl azodicarboxylate (DEAD), THF;
Step 15b: L1OH.H2O, THF, MeOH, water, aqueous ammonium chloride, RT.
The reaction steps as outlined in the above Scheme 15 are described herein below: Step 15a:
In this step, the compound (45), (wherein R12 is halogen, (Ci-Ce)alkyl, cyano, nitro, amino, halo(Ci-C6)alkyl, -S02(Ci-Ce)alkyl or (Ce-Cio)aryl; m is an integer from 1 to 4 and R 2 is bonded to any atom of the indane ring) is reacted with the compound (4) (obtained in step lb of the process depicted in scheme 1) in the presence of a reagent such as diethylazodicarboxylate or diisopropyl azodicarboxylate and triphenylphosphine to obtain the compound of Formula (I), (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl; Rj2 is halogen, (Q- Ce)alkyl, cyano, nitro, amino, halo(Ci-Ce)alkyl, -S02(Ci-C6)alkyl or (C6-Cio)aryl and m is an integer from 1 to 4).
Step 15b:
The compound of Formula (I) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl) , obtained in Step 15a, is taken in a solvent selected from THF, ethanol, MeOH, water or a mixture thereof, and is hydrolysed using a base selected from NaOH, KOH, lithium hydroxide (LiOH) or Ba(OH)2, followed by neutralization with aqueous ammonium chloride to obtain compound of Formula (I) (wherein Rj is hydrogen and Rj2 is halogen, (Ci-Ce)alkyl, cyano, nitro, amino, halo(C1-C6)alkyl, -S02(Ci-C6)alkyl or (C6-C10)aryl).
Alternatively, the compounds of Formula (I) of certain embodiments of the present invention can be prepared in accordance with a process involving the reaction steps depicted in the following Scheme 16.
Figure imgf000071_0001
Reaction conditions:
Steps 16a and 16c: Cesium carbonate (€¾€(¾), DMF; Step 16b: Triethylamine, 4-methylbenzene-l-sulfonyl chloride and dichloromethane.
The reaction steps as outlined in the above Scheme 16 are described herein below: Step 16a:
In this step, the compound (4) (obtained in step lb of the process depicted in scheme 1), is reacted with the compound (46) (wherein R' and R" together form a saturated or a partially unsaturated (C3-C8)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S) in the presence of a base such as CS2CO3 and a solvent such as DMF to obtain the compound (47) (wherein Ri is (Ci-Ce)alkyl, e.g. ethyl, R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloaikyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S; R2, R3, R4, R5, m and n are as defined for Formula (I)).
Step 16b:
In this step, the compound (47), is reacted with 4-methylbenzene-l-sulfonyl chloride in presence of a base such as triethylamine and a solvent such as DCM to obtain the compound (48) (wherein Rj is (Ci-Ce)alkyl, e.g. ethyl, R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S; R2, R3, R4, R5, m and n are as defined for Formula (I)).
Step 16c:
In this step, the compound (48) is reacted with a compound of formula A-OH (wherein A is as defined above for any one embodiments of the compounds of formula (I)) in presence of a base such as CS2CO3 and a solvent such as DMF to obtain the compound of Formula (I) (wherein Rj is (Q-Ce^lkyl, e.g. ethyl and R' and R" together form a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S; R2, R3, R4, R5, m and n are as defined for Formula (I)). The compound of Formula (I) thus obtained, can be optionally hydrolyzed to obtain a compound of Formula (I) (wherein Rj is hydrogen).
Those skilled in the art will recognize that the compounds of Formula (I) of the present invention contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms, as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds. The term "chiral" refers to molecules which have the property of non-superimposability of the mirror image cohort, while the term "achiral" refers to molecules which are superimposable on their mirror image partner. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers and enantiomers, as well as mixtures thereof such as racemic mixtures, geometric isomers form part of the present invention.
When the compounds of Formula (I) of the present invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixtures. The enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which can be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer- specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation. Designation of a specific absolute configuration at a chiral carbon of the compounds of the invention is understood to mean that the designated enantiomeric form of the compounds is in enantiomeric excess (ee) or in other words is substantially free from the other enantiomer. For example, the "R" forms of the compounds are substantially free from the "S" forms of the compounds and are, thus, in enantiomeric excess of the "S" forms. Conversely, "S" forms of the compounds are substantially free of "R" forms of the compounds and are, thus, in enantiomeric excess of the "R" forms. Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%. In a particular embodiment when a specific absolute configuration is designated, the enantiomeric excess of depicted compounds is at least about 90%. When a compound of Formula (I) of the present invention has two or more chiral carbons it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to 4 optical isomers and 2 pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g., (S,S)/(R,R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) are diastereomers. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair can be separated as described above. The present invention includes each diastereoisomer of such compounds and mixtures thereof.
The isotopically labeled forms of the compounds of Formula (I), can be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described above or in the subsequent section on examples by using a corresponding isotopically labeled reagent in place of the non-labeled reagent.
In one embodiment, the compounds of Formula (I) exists as tautomers, and it is intended to encompass all the tautomeric forms of the compounds within the scope of the present invention.
In an embodiment, the compounds of Formula (I) in their free base form are converted to their corresponding pharmaceutically acceptable salts. The pharmaceutically acceptable salt of the compounds of Formula (I) are prepared with relatively non-toxic acids or bases, depending on the particular substituents found on the compound described herein. When the compounds of Formula (I) of the present invention contain an acidic group they can form an addition salt with a suitable base. For example, pharmaceutically acceptable base addition salts of the compounds of the present invention may include their alkali metal salts such as sodium, potassium, calcium, magnesium, ammonium or an organic base addition salt. Examples of pharmaceutically acceptable organic base addition salts of the compounds of the present invention include those derived from organic bases like lysine, arginine, metformin, guanidine, diethanolamine, or other organic bases known to a person skilled in the art.
When the compounds of Formula (I) of the present invention contain one or more basic groups, they can form an addition salt with an inorganic or an organic acid. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like boric acid, perchloric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydriodic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, phosphorous acids or other inorganic acids known to the person skilled in the art. Furthermore, examples of pharmaceutically acceptable acid addition salts include the salts derived from organic acids such as acetic acid, propionic acid, isobutyric acid, oxalic acid, malic acid acid, tartaric acid, citric acid, ascorbic, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, glucuronic acid, galacturonic acid, naphthoic acid, camphoric acid or other organic acids known to the person skilled in the art. Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
In an embodiment of the present invention, the pharmaceutically acceptable salts of compounds of Formula (I) are selected from glucoronate, glutarate, lactate, oxalate, acetate, cinnamate, malonate, maleate, citrate, crotonate, ascorbate, toluenesulfonate, methanesulfonate, tartrate, hydrochloride or metformin salt.
The pharmaceutically acceptable salts of the present invention can be synthesized from the subject compound i.e. the compound of Formula (I) which contains a basic or acidic moiety by conventional chemical methods. Generally the salts are prepared by contacting the free base or acid with desired salt-forming inorganic or organic acid or a base in a suitable solvent or dispersant or by anion exchange or cation exchange with other salts. Suitable solvents are, for example, ethyl acetate, ethers, alcohols, acetone, or mixtures of these solvents.
The present invention furthermore includes all the solvates of the compounds of Formula (I), for example, hydrates and the solvates formed with other solvents of crystallisation, selected from alcohols such as methanol, ethanol, 1-propanol or 2-propanol, ethers such as diethyl ether, isopropyl ether or THF, esters such as methyl acetate or ethyl acetate, ketone such as acetone or their mixtures thereof. Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
It is further intended to encompass various polymorphs of the compounds of Formula (I) within the scope of the present invention. Various polymorphs of the compounds of the present invention can be prepared by standard crystallisation procedures known in the art. The crystallisation technique employed can utilize various solvents or their mixtures, temperature conditions and various modes of cooling, ranging from very fast to very slow cooling. The presence of polymorphs can be determined by IR (Infra-red) spectroscopy, solid probe NMR (Nuclear Magnetic Resonance) spectroscopy, differential scanning calorimetry, powder X-ray diffraction or such other standard techniques. Furthermore, the present invention also includes prodrugs of the compounds of Formula (I). The prodrugs of the compounds of the present invention are relatively simple derivatives of the aforesaid compounds of the invention which upon administration to a subject in need thereof undergoes chemical conversion by metabolic or chemical processes to release the parent drug in vivo from which the prodrug is derived. The preferred prodrugs are pharmaceutically acceptable ester derivatives e.g., alkyl esters, cycloalkyl esters, alkenyl esters, benzyl esters, mono- or di-substituted alkyl esters convertible by solvolysis under physiological conditions to the parent carboxylic acid, and those conventionally used in the art.
The present invention further relates to carboxylic acid isosteres of the compounds of Formula (I).
The present invention also relates to N-oxide derivatives of the compounds of Formula (I).
The present invention also relates to S-oxide derivatives of the compounds of Formula
(I)·
In one aspect, the present invention relates to a method for modulating GPR40 function in a cell comprising contacting the cell with an effective amount of compound of Formula (I).
In another aspect of the present invention, i.e. the compounds of Formula (I) are GPR40 agonists.
In an embodiment of the present invention, the compounds of Formula (I) find use in the treatment of a disease or a condition mediated by GPR40.
In another aspect, the present invention relates to a method for the treatment of a disease or a condition mediated by GPR40, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, a carboxylic acid isostere, an N-oxide or a S-oxide thereof.
In an embodiment, the present invention relates to a method for the treatment of a disease or a condition mediated by GPR40, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof.
In yet another aspect, the present invention provides use of the compound of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, a carboxylic acid isostere, an N-oxide or a S-oxide thereof; for the treatment of a disease or a condition mediated by GPR40.
In an embodiment, the present invention relates to use of the compound of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof; for the treatment of a disease or a condition mediated by GPR40.
According to an aspect, the present invention relates to use of the compounds of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, a carboxylic acid isostere, an N-oxide or a S-oxide thereof; in the manufacture of a medicament for the treatment of a disease or a condition mediated by GPR40.
According to one embodiment, the present invention relates to use of compounds of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof; in the manufacture of a medicament for the treatment of a disease or a condition mediated by GPR40.
As used herein, the term "a disease or a condition mediated by GPR40" or "GPR40 mediated disease(s) or condition(s)" refers to a disease or a disorder or a condition characterized by inappropriate, for example, less than or greater than normalGPR40 activity. A GPR40-mediated disease or disorder may be completely or partially mediated by inappropriate GPR40 activity.
In an embodiment of the invention the disease or condition mediated by GPR40 is selected from the group consisting of diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, cardiovascular disease, atherosclerosis, kidney disease, polycystic ovary syndrome, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, fatty liver development, dermatopathy, dyspepsia, hypoglycemia, cancer, edema and a disorder related to glucose levels such as pancreatic beta cell regeneration.
In an embodiment of the invention, the disease or condition mediated by GPR40 is selected from the group consisting of diabetes, obesity, insulin resistance, hyperglycemia, glucose intolerance, hypercholesterolemia, hypertriglylceridemia, dyslipidemia, hyperlipoproteinemia, hyperinsulinemia, atherosclerosis, diabetic neuropathy, diabetic retinopathy, metabolic syndrome, hypertension and pancreatic beta cell degeneration. In an embodiment of the invention the disease or condition mediated by GPR40 is selected from the group consisting of diabetes, obesity, insulin resistance, hyperglycemia, glucose intolerance, metabolic syndrome and pancreatic beta cell degeneration.
In an embodiment of the invention, diabetes is Type 2 diabetes.
In an embodiment the disease or condition mediated by GPR40 is a metabolic disorder which refers to one or more diseases or conditions as identified above.
Accordingly, the present invention relates to a method for the treatment of a metabolic disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof.
In an embodiment, the present invention provides use of the compound of Formula (I) or a stereoisomer or a tautomer or a pharmaceutically acceptable salt thereof for the treatment of a metabolic disorder.
According to one embodiment, the present invention relates to use of the compounds of Formula (I) or pharmaceutically acceptable salts thereof in the manufacture of a medicament, for the treatment of a metabolic disorder.
The term "metabolic disorder" as used herein refers a disorder relating to abnormality of metabolism. Accordingly, in the context of the present invention all. the disorders relating to abnormility of metabolism are encompassed in the term "metabolic disorders".
In one embodiment, the metabolic disorders are selected from diabetes, obesity, cardiovascular disease, hypertension, ketoacidosis, insulin resistance, glucose intolerance, hyperglycemia, hypertriglylceridemia, polycystic ovary syndrome, hypercholesterolemia, hyperlipoproteinemia, dyslipidemia, metabolic syndrome, hyperlipidemia, diabetic neuropathy, diabetic retinopathy, edema and related disorders associated with abnormal plasma lipoprotein, triglycerides or pancreatic beta cell degeneration.
The term "diabetes mellitus" or "diabetes" refers to a chronic disease or condition, which occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. This leads to an increased concentration of glucose in the blood (hyperglycaemia). Two major forms of diabetes are Type 1 diabetes (Insulin- dependent diabetes mellitus) and Type 2 diabetes (Non-insulin dependent diabetes mellitus (NIDDM)). Type 1 diabetes is an autoimmune condition in which the insulin-producing β- cells of the pancreas are destroyed which generally results in an absolute deficiency of insulin, the hormone that regulates glucose utilization. Type 2 diabetes often occurs in the face of normal or even elevated levels of insulin and can result from the inability of tissues to respond appropriately to insulin. Other categories of diabetes include gestational diabetes (a state of hyperglycemia which develops during pregnancy) and "other" rarer causes (genetic syndromes, acquired processes such as pancreatitis, diseases such as cystic fibrosis, and exposure to certain drugs, viruses, and unknown causes). In an embodiment of the invention, diabetes refers to Type 2 diabetes.
The term "metabolic syndrome" refers to a cluster of metabolic abnormalities including abdominal obesity, insulin resistance, glucose intolerance, diabetes, hypertension and dyslipidemia. These abnormalities are known to be associated with an increased risk of vascular events.
The term "cardiovascular disease" as used herein refers to any disease of the heart or blood vessels. One or more diseases of heart encompassed in the term "cardiovascular disease" is selected from, but is not limited to, angina, arrhythmia, coronary artery disease (CAD), cardiomyopathy, myocardial infarction, heart failure, hypertrophic cardiomyopathy, mitral regurgitation, mitral valve prolapse, pulmonary stenosis, etc. The blood vessel disease encompassed in the term "cardiovascular diseases", is selected from, but is not limited to, for example, peripheral vascular disease, artery disease, carotid artery disease, deep vein thrombosis, venous diseases, atherosclerosis and the like.
In an embodiment, the metabolic disorder is selected from: diabetes, obesity, insulin resistance, hyperglycemia, glucose intolerance, hypercholesterolemia, hypertriglylceridemia, dyslipidemia, hyperlipoproteinemia, hyperinsulinemia, atherosclerosis, diabetic neuropathy, diabetic retinopathy, metabolic syndrome, hypertension or pancreatic beta cell degeneration.
In an embodiment, the metabolic disorder is selected from diabetes, obesity, insulin resistance, glucose intolerance, dyslipidemia, hyperinsulinemia, metabolic syndrome or pancreatic beta cell degeneration.
In an embodiment, the metabolic disorder is Type 2 diabetes.
Pharmaceutical compositions
The present invention furthermore relates to pharmaceutical compositions that contain a therapeutically effective amount of at least one compound of Formula (I) or its pharmaceutically acceptable salt in addition to a customary pharmaceutically acceptable carrier, and to a process for the production of a pharmaceutical composition, which includes bringing at least one compound of Formula (I), into a suitable administration form using a pharmaceutically suitable and physiologically tolerable excipient and, if appropriate, further suitable active compounds, additives or auxiliaries.
According to one embodiment, the present invention relates to a pharmaceutical composition comprising substituted heterocyclic derivatives, the compounds of Formula (I) or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient for use as GPR40 agonists and in the treatment of a disease or a condition mediated by GPR40.
The term "pharmaceutically acceptable" as used herein in the present invention means that the carrier, diluents, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
The term "pharmaceutically acceptable carrier" as used herein means a non-toxic, inert, solid, semi-solid, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; malt; gelatin; talc; as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents; preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.
It is further intended to include within the scope of the present invention the use of the compounds of Formula (I) or its pharmaceutically acceptable salts thereof in combination with at least one therapeutically active compound as GPR40 agonists.
According to one embodiment, the present invention provides a pharmaceutical composition, comprising a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof and at least one further therapeutically active agent, together with a pharmaceutically acceptable carrier.
In an embodiment, the present invention relates to use of the compound of Formula (I) or a pharmaceutically acceptable salt thereof; in combination with a further therapeutically active agent, in the treatment of a disease or a condition mediated by GPR40.
The therapeutically active agent used in combination with one or more of the compounds of Formula (I) can be selected from the compounds or active substances known to be used in the treatment of diabetes and other conditions such as obesity, insulin resistance, hyperglycemia, glucose intolerance, hypercholesterolemia, hypertriglylceridemia, dyslipidemia, hyperlipoproteinemia, hyperinsulinemia or atherosclerosis. According to the present invention, the therapeutically active agent, used in combination with the compounds of Formula (I) of the present invention can be selected from, but not limited to, insulin, sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, inhibitors of glycogen phosphorylase, glucagon antagonists, HMGCoA reductase inhibitor, GLP-1 (Glucogen-like peptide- 1) agonists, potassium channel openers, inhibitors of dipeptidylpeptidase IV (DPP-IV), insulin sensitizers, modulators of glucose uptake, of glucose transport and of glucose reabsorption, modulators of the sodium- dependent glucose transporter 1 or 2 (SGLTl, SGLT2), compounds which alter lipid metabolism such as antihyperlipidemic active ingredients and antilipidemic active ingredients, PPARgamma agonists and agents with combined PPARalpha and gamma activity and active ingredients which act on the ATP-dependent potassium channel of the beta cells.
In an embodiment, the compound of Formula (I) can be used in combination with a PPAR gamma agonist selected from rosiglitazone, pioglitazone, rivoglitazone and the like.
In an embodiment, the compound of Formula (I) can be used in combination with a HMGCoA reductase inhibitor selected from simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin and the like.
In an embodiment, the compound of Formula (I) can be used in combination with a sulfonylurea selected from tolbutamide, glibenclamide, glipizide, glimepiride and the like.
In another embodiment, the compound of the Formula (I) can be used in combination with a meglitinide selected from repaglinide, nateglinide, mitiglinide and the like.
In another embodiment, the compound of the Formula (I) can be used in combination with GLP-1 agonist selected from exenatide, liraglutide, taspoglutide albiglutide, lixisenatide and the like.
In another embodiment, the compound of the Formula (I) can be used in combination with DPP-IV inhibitor selected from alogliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin and the like.
Accordingly, in an embodiment the further therapeutically active agent that can be used in combination with one or more compounds of Formula (I) encompassed in the present invention, can be selected from one or more of the agents including, but not limited to, insulin, rosiglitazone, pioglitazone, rivoglitazone, simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, rosuvastatin, tolbutamide, glibenclamide, glipizide, glimepiride, repaglinide, nateglinide, mitiglinide, exenatide, liraglutide, taspoglutide albiglutide, lixisenatide, alogliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin and the like.
The compounds of Formula (I) alone or in combination with other active substances can be administered in conjunction with physical excercises and/ or with diet restriction as advisable by a person skilled in the art.
The pharmaceutical compositions according to the present invention are prepared in a manner known and familiar to one skilled in the art. Pharmaceutically acceptable inert inorganic and/or organic carriers and/or additives can be used in addition to the compounds of Formula (I) and/or its pharmaceutically acceptable salts. For the production of pills, tablets, coated tablets and hard gelatin capsules it is possible to use, for example, lactose, corn starch or derivatives thereof, gum arabic, magnesia or glucose, etc. Carriers for soft gelatin capsules and suppositories are, for example, fats, waxes, natural or hardened oils, etc. Suitable carriers for the production of solutions, for example injection solutions, or of emulsions or syrups are, for example, water, physiological sodium chloride solution or alcohols, for example, ethanol, propanol or glycerol, sugar solutions, such as glucose solutions or mannitol solutions, or a mixture of the various solvents which have been mentioned.
Further, the pharmaceutical composition of the present invention also contains additives such as, for example, fillers, antioxidants, emulsifiers, preservatives, flavours, solubilisers or colourants. The pharmaceutical composition of the present invention may also contain two or more substituted heterocyclic_derivatives i.e. compounds of Formula (I) and/or its physiologically tolerable salts, the pharmaceutical compositions can also contain one or more other therapeutically or prophylactically active ingredients.
The pharmaceutical compositions normally contain about 1 to 99%, for example, about 10 to 80%, by weight of the compounds of Formula (I) or their pharmaceutically acceptable salts.
The amount of the active ingredient, substituted heterocyclic derivative i.e. the compound of Formula (I) or its pharmaceutically acceptable salt in the pharmaceutical compositions can, for example, vary from about 1 to 500 mg. In case of higher body weight of the mammal in need of the treatment, the pharmaceutical composition may contain the compound of Formula (I) in an amount ranging from 5 mg to 1000 mg. The desirable dosage of the substituted heterocyclic derivatives i.e. the compounds of Formula (I) can be selected over a wide range. The daily dosage to be administered is selected to achieve the desired therapeutic effect in subjects being treated for metabolic disorders. A dosage of about 0.05 to 50 mg/kg/day of the substituted heterocyclic derivatives i.e. the compounds of Formula (I) or its pharmaceutically acceptable salt may be administered. In case of higher body weight of the mammal in need of the treatment, a dosage of about 0.1 to 100 mg/kg/day of the compound of Formula (I) or its pharmaceutically acceptable salt may be administered. If required, higher or lower daily dosages can also be administered. Actual dosage levels of the active ingredients in the pharmaceutical composition of this present invention can be varied so as to obtain an amount of the active ingredient, which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient. The selected dosage level can be readily determined by a skilled medical practitioner in the light of the relevant circumstances, including the condition (diseases or disorder) to be treated, the chosen route of administration depending on a number of factors, such as age, weight and physical health and response of the individual patient, pharmacokinetics, severity of the disease and the like, factors known in the medical art.
The pharmaceutical compositions according to the present invention can be administered orally, for example in the form of pills, tablets, coated tablets, capsules, granules or elixirs. Administration, however, can also be carried out rectally, for example in the form of suppositories, or parenterally, for example intravenously, intramuscularly or subcutaneously, in the form of injectable sterile solutions or suspensions, or topically, for example in the form of solutions or transdermal patches, or in other ways, for example in the form of aerosols or nasal sprays.
It is understood that modifications that do not substantially affect the activity of the various embodiments of this invention are included within scope of the invention disclosed herein. Accordingly, the following examples are intended to illustrate but not to limit scope of the present invention.
Experimental
Nomenclature of the compounds exemplified in the present invention was derived from Chemdraw Ultra version 9.0.1 CambridgeSoft Corporation, Cambridge.
Reagents were purchased from commercial suppliers such as A.K Scientific, Inc., US; Ark Pharma, Inc., US; Combi-Blocks Inc., CA; Spectrochem Pvt. Ltd, India, Tokyo Chemical Industry, USA (TCI USA), Maybridge Inc. US and Sigma Aldrich Chemical company and were used as such. Unless otherwise stated all temperatures are in degree celsius. Also, in the examples and elsewhere, abbreviations have the following meanings:
The abbreviations and terms that are used herein are as follows:
Figure imgf000084_0001
Intermediates
Intermediate 1 : Ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate
Step 1
Synthesis of Ethyl 2-(oxetan-3-ylidene)acetate An ice cold solution of oxetone (69.4 mM) in anhydrous DCM (70 mL) was treated with the reagent, PPf^CHCCKX^Hs (76 mM). The reaction mixture obtained was allowed to warm to RT and stirred for 1 h. The reaction mixture was concentrated to obtain a crude product, which was purified by column chromatography (silica gel, 100-200 mesh, eluted with 3% ethyl acetate in petroleum ether) to afford the title compound as colorless oil. Yield: 60.7%; JH NMR (CDC13, 300 MHz): δ 5.64 (bs, 1H), 5.53-5.51 (m, 2H), 5.32-5.31 (m, 2H), 4.18 (q, J=6.89, 2H), 1.28 (t, J=6.89, 3H); MS: m/z 143 (M+l).
Step 2
Synthesis of Ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate
Aqueous KOH (46.9 mL, 70.3 mM) was added to a suspension of Rh(COD)2Cl2 in dioxane (15 mL) and the mixture was stirred for 10 minutes, (4-hydroxyphenyl)boronic acid (9.70 g, 70.3 mM) and successively ethyl 2-(oxetan-3-ylidene)acetate (compound of Step la, 5 g, 35.2 mM) in dioxane were added and the reaction mixture was stirred for 6 h. The reaction mixture was extracted using ethyl acetate. The organic layer was washed with brine, dried over Na2S04 and concentrated to obtain a crude product, which was purified by column chromatography (silica gel, 100-200 mesh, eluted with 10% ethyl acetate in hexane) to afford ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate. Yield: 4.2 g (50.5%); JH NMR (CDC13, 300 MHz): δ 7.07 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.4 Hz, 2H), 5.18 (bs, 1H), 5.01 (d, J=6.0 Hz, 2H), 4.88 (d, J=6.0 Hz, 2H), 4.07 (q, J=6.90 Hz, 2H), 3.11 (s, 2H), 1.15 (t, J=6.90 Hz, 3H); MS: m/z 259 (M+Na).
Intermediate 2: Ethyl 2-(3-(4-(3-aminopropoxy)phenyl)oxetan-3-yl)acetate
Step 1
Ethyl 2-(3-(4-(3-hydroxypropoxy)phenyl)oxetan-3-yl)acetate
A solution of Intermediate 1 (16.93 mmol), 3-bromo-l-propanol (20.32 mmol) and CS2CO3 (33.9 mmol) in DMF (40 mL) was stirred at RT for 4 h. After completion of the reaction, water (150 mL) was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with water and brine and concentrated to obtain the crude product, which was purified by flash chromatography (silica gel column, 1-50% EtOAc/petroleum ether as eluent). Yield: 86%; JH NMR (CDCI3, 300 MHz): δ 7.115 (/ = 8.4, 2H), 6.901 (d, / = 8.4, 2H), 5.000 (d, / = 6, 2H), 4.866 (d, / = 6, 2H), 4.143 (d, / = 6, 2H), 4.056 (q, / = 7.2, 2H), 3.869 (s, 2H), 3.102 (s, 2H), 2.090 (m, 2H), 1.170 (t, / = 7.2, 3H); MS: (m/z) 295.3 (M+H), 317.2 (M+Na). Step 2
Ethyl 2-(3-(4-(3-(tosyloxy)propoxy)phenyl)oxetan-3-yl)acetate
A solution of ethyl 2-(3-(4-(3-hydroxypropoxy)phenyl)oxetan-3-yl)acetate (compound of step 1, 4.46 mmol), triethylamine (13.38 mmol) and 4-dimethylaminopyridine (0.446 mmol) in DCM (50 mL) was stirred for 30 minutes. 4-methylbenzene-l-sulfonyl chloride (4.91 mmol) was added to the reaction mixture slowly while maintaining the reaction temperature below 5 °C. The reaction mixture was stirred at RT overnight. After completion of the reaction, the reaction mixture was poured into ice-cold water, extracted with EtOAc, the organic layer was washed with brine and water, dried over Na2S04 and concentrated to obtain the title compound. Yield: 73.3 %. JH NMR (CDC13, 300 MHz): δ 7.789 (d, / = 10.5, 2H), 7.295 (d, / = 5.4, 2H), 7.098 (d, / = 8.4, 2H), 6.776 (d, / = 8.7, 2H), 4.997 (d, / = 5.7, 2H), 4.874 (d, / = 6, 2H), 4.268 (t, / = 6, 2H), 4.268 (m, 4H), 3.107 (s, 2H), 2.418 (s, 3H), 2.163 (m, 2H), 1.177 (s, 3H); MS: (m/z) 471.3 (M+Na).
Step 3
Ethyl 2-(3-(4-(3-azidopropoxy)phenyl)oxetan-3-yl)acetate
A solution of ethyl 2-(3-(4-(3-(tosyloxy)propoxy)phenyl)oxetan-3-yl)acetate (compound of step 2, 8.03 mmol) and sodium azide (8.03 mmol) in DMF (50 mL) was stirred at 80 °C for 3 h. After the completion of reaction, the solvent was evaporated and the residue was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine and water, and concentrated to obtain the title compound. Yield: 90%. JH NMR (DMSO-d6, 300 MHz): δ 7.123 (d, / = 8.4, 2H), 6.896 (d, / = 8.7, 2H), 5.005 (d, / = 5.7, 2H), 4.871 (d, / = 6, 2H), 4.071 (m, 4H), 3.555 (t, / = 6.3, 2H), 3.109 (s, 2H), 2.104 (m, 2H), 1.173 (t, / = 7.2, 3H); MS: (m/z) 320.1 (M+H), 342.1 (M+Na).
Step 4
Ethyl 2-(3-(4-(3-aminopropoxy)phenyl)oxetan-3-yl)acetate
A solution of ethyl 2-(3-(4-(3-azidopropoxy)phenyl)oxetan-3-yl)acetate (compound of step 3, 6.61 mmol) and palladium on carbon (0.141 g) in ethanol (30 mL) was subjected to hydrogenation in a parr shaker apparatus at 50 psi for 4 h. After completion of reaction, the reaction mixture was filtered through celite®. The residue was washed with ethanol. The filtrate was concentrated to obtain the title compound. Yield: 57.6%. JH NMR (DMSO-d6, 300 MHz): δ 7.106 (d, / = 8.4, 2H), 6.889 (d, / = 8.1, 2H), 4.997 (d, / = 5.7, 2H), 4.862 (d, / = 5.7, 2H), 4.047 (m, 4H), 3.099 (s, 2H), 2.949 (t, / = 6.6, 2H), 1.961 (t, / = 6.3, 2H), 1.167 (t, / = 6.9, 3H); MS: (m z) 294.1 (M+H), 316 (M+Na).
Intermediate 3 : 1 -(( 1 -(bromomethyl)cyclopropyl)methoxy)-2-methylbenzene
A solution of (l-((o-tolyloxy)methyl)cyclopropyl)methanol (2.60 mmol) and carbon tetrabromide (2.86 mmol) in DCM (20 mL) was cooled to 0°C. Triphenyl phospine (0.750 g, 2.86 mmol) was added with vigorous stirring. The reaction mixture was further stirred for 24 h at RT. After completion of the reaction, the solvent was evaporated and the residue was purified by column chromatography (silica gel column, 1-5% ethyl acetate/petroleum ether). Yield: 93%; JH NMR (CDC13, 300 MHz): δ 0.79 (s, 2H), 0.94 (s, 2H), 2.27 (s, 3H), 3.63 (s, 2H), 3.94 (s, 2H), 6.84 (d, / = 8.1 Hz, 1H), 6.89 (t, / = 7.2 Hz, 1H), 7.17(d, / = 3.6 Hz, 2H); MS (m/z): 256.2 (M+H).
Intermediate 4: l-Methylspiro[indoline-3,4'-piperidine]
Step 1
Benzyl spiro[indoline-3,4'-piperidine]- -carboxylate
A solution of phenyl hydrazine (5.96 mmol) and trifluoroacetic acid (1.5 mL) in a solvent system of toluene: acetonitrile (49:1) (25 mL) was stirred at 35 °C. To this reaction mixture, a solution of benzyl 4-formylpiperidine-l-carboxylate (5.46 mmol) in a solvent system of toluene: acetonitrile (49: 1) (5 mL) was added drop wise. The reaction mixture was stirred overnight at 35 °C. The reaction mixture was then cooled in ice bath and MeOH (2.5 mL) was added, followed by the addition of sodium borohydride (8.16 mmol) in portions. The reaction mixture was then stirred for 45 minutes. After the completion of reaction, the reaction mixture was diluted with ethyl acetate (25 mL), washed with 5% aqueous ammonia, brine, dried over Na2S04 and concentrated. The residue was purified by flash column chromatography (silica gel column, 10%-20% ethyl acetate/ petroleum ether). Yield: 74%; JH NMR (CDCI3, 300 MHz): δ 7.391 (m, 5H), 7.100 (m, 2H), 6.789 (t, / = 7.5, 1H), 6.686 (d, / = 7.5, 1H), 5.182 (s, 2H), 4.153 (bs, 2H), 3.501 (s, 2H), 3.067 (t, / = 14.1, 2H), 1.895 (m, 4H); MS (m/z): 323.1 (M+H) and 345.1 (M+Na).
Step 2
Benzyl 1 -methylspiro[indoline-3,4'-piperidine] - l'-carboxylate
Sodium cyanoborohydride (6.23 mmol) was added to the reaction mixture of benzyl spiro[indoline-3,4'-piperidine]- l'-carboxylate (compound of step 1, 2.078 mmol), acetic acid (10.39 mmol) and formaldehyde (8.31 mmol) in MeOH (20 mL) at 0 °C. The reaction mixture was stirred overnight at RT. After the completion of reaction, the reaction mixture was poured into ice-cold water (100 mL) and basified by 10% sodium bicarbonate to obtain the crude product, which was filtered and washed with water to obtain the title compound. Yield: 92%; JH NMR (CDC13, 300 MHz): δ 1.60 (s, 2H), 1.75 (bs, 2H), 2.78 (s, 3H), 3.03 (bs, 2H), 3.26 (s, 2H), 4.15 (bs, 2H), 5.18 (s, 2H), 6.53 (d, / = 7.5 Hz, 1H), 6.73 (t, / = 7.2 Hz, 1H), 7.03 (d, / = 7.2 Hz, 1H), 7.14 (t, / = 7.5 Hz, 1H), 7.28-7.41 (m, 5H); MS: (m/z) 338.3 (M+H).
Step 3
l-Methylspiro[indoline-3,4'-piperidine]
Benzyl l-methylspiro[indoline-3,4'-piperidine]- -carboxylate (compound of step 2, 2.97 mmol) was suspended in MeOH (40 mL) and slowly Pd/C (0.188 mmol) was added, followed by the addition of ammonium formate (1.2 g, 19.03 mmol) in portions at RT. The reaction mixture was heated to reflux and maintained for 2 h. After completion of reaction, the reaction mixture was filtered through celite® bed and the residue was purified by flash column chromatography (silica gel column, 2% MeOH/ chloroform +1% aqueous NH3). Yield: 92%. JH NMR (CDC13, 300 MHz): δ 1.50-1.67 (m, 4H), 2.59 (t, / = 12 Hz, 2H), 2.69 (bs, 2H), 2.87 (bd, / = 10.5 Hz, 2H), 3.18 (s, 3H), 6.48 (d, / = 7.5 Hz, 1H), 6.60 (t, / = 7.2 Hz, 1H), 6.99 (d, / = 7.2 Hz, 2H); MS: (m z) 203.2 (M+H).
Intermediate 5: Spiro[indene-l,4'-piperidine]
Step 1
teri-Butyl spiro[indene- 1 ,4'-piperidine] - l'-carboxylate
A solution of lithium hexamethyldisilazide (8.61 mmol) in hexane was added to a solution of indene (4.3 mmol) in THF (5 mL) at 0 °C under an argon atmosphere. The resultant was stirred at the same temperature for 1 h. Then a solution of N-i- butyloxycarbonylbis(2-chloroethyl)amine (4.3 mmol) in THF (2 mL) was added and the reaction mixture was further stirred at the same temperature for 2 h. After completion of reaction, the reaction mixture was poured in ice-cold water, extracted with diethyl ether, dried over Na2S04, concentrated and purified by flash column chromatography (silica gel column, 0-40% DCM/petroleum ether). Yield: 28.6 % JH NMR (CDC13, 300 MHz): δ 7.341 (m, 4H), 6.877 (d, / = 5.7, 1H), 6.817 (d, / = 5.7, 1H), 4.189 (bs, 2H), 3.179 (t, / = 12.3, 2H), 2.064 (m, 2H), 1.527 (s, 9H), 1.371 (d, / = 13.2, 2H); MS: (m/z) 308.3 (M+Na). Step 2
Spiro[indene- 1 ,4'-piperidine]
Trifluoroacetic acid (0.4 mL) was added to an ice-cold solution of teri-butyl spiro[indene-l,4'-piperidine]- -carboxylate (compound of step 1, 1.226 mmol) in DCM (5 mL) and the reaction mixture was stirred for 2-4 h. The solvent is evaporated to obtain the title compound. Yield: 98%; JH NMR (CDCI3, 300 MHz): δ 8.875 (bs, 1H), 8.624 (bs, 1H), 7.383 (m, 2H), 7.294 (m, 2H), 7.135, (d, / = 5.7, 1H), 6.883 (d, / = 5.4, 1H), 3.408 (m, 2H), 3.305 (m, 2H), 2.266 (t, / = 13.2, 2H), 1.402 (t, / = 15.3, 2H); MS: (m/z) 298.6 (M-H).
Intermediate 6: Ethyl 2-(3-(4-((4-(bromomethyl)benzyl)oxy)phenyl)oxetan-3-yl) acetate
The reaction mixture of Intermediate 1 (2.116 mmol), dibromo-p-xylene (2.54 mmol) and CS2CO3 (2.116 mmol) was stirred in dry DMF (10 mL) at RT for 2 h. After completion of reaction, the reaction mixture was diluted with EtOAc (50 mL), washed with water, brine, dried over Na2S04, concentrated and purified by flash column chromatography (silica gel column, 0-30% ethyl acetate/petroleum ether) to obtain the title compound. Yield: 90%; ^ NMR (CDCI3, 300 ΜΗζ):δ 7.426 (s, 4H), 7.128 (d, / = 8.7, 2H), 6.961 (d, / = 8.7, 2H), 5.061 (s, 2H), 5.006 (d, / = 5.7, 2H), 4.871 (d, / = 6, 2H), 4.523 (s, 2H), 4.059 (q, / = 7.2, 2H), 3.109 (s,2H), 1.163 (t, / = 7.2, 3H); MS (m/z): 443.3 (M+Na).
Examples
Example 1
Ethyl 2-(3-(4-((l-(methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophen-3-yl) methoxy) phenyl)oxetan-3-yl)acetate (Compound 1)
Step 1
Methyl 3-((2-methoxy-2-oxoethyl)thio)-4,5-dihydronaphtho[ 1 ,2-c] thiophene- 1 -carboxylate
Sodium hydride was added to a solution of 1-tetralone (68.4 mmol) and carbon disulfide (75 mmol) in DMF (25 mL) at 0 °C (171 mmol) and the reaction mixture was stirred for 2 h at the same temperature. Methyl bromoacetate (150 mmol) was added drop wise and the reaction mixture was allowed to warm to RT. The reaction mixture was further stirred for 12 h. After completion of the reaction, the reaction mixture was quenched with water and organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over Na2S04. The solvent was evaporated and the residue was purified using column chromatography (silica gel column, 1 to 5 % EtOAc/petroleum ether as eluent) to obtain the title compound. Yield: 23 %; NMR (DMSO-d6, 300 MHz): δ 8.14 (d, J = 3.6 Hz, 1H), 7.28 -7.32 (m, 3H), 4.14 (s, 3H), 3.97 (s, 3H), 3.57 (s, 2H), 2.83 (s, 4H); MS (m/z):] 349.1 [M+H], 371 [M+Na]
Step 2
Methyl 3-((2-methoxy-2-oxoethyl)sulfonyl)-4,5-dihydronaphtho[ 1 ,2-c] thiophene- 1 - carboxylate
ni-Chioroperoxybenzoic acid (44.4 mmol) was added drop wise to the cold solution of methyl 3-((2-methoxy-2-oxoethyl)thio)-4,5-dihydronaphtho[ 1 ,2-c]thiophene- 1 -carboxylate (compound of step 1, 14.1 mmol) in DCM and the reaction mixture was stirred at RT for 4 h. After completion of the reaction, the reaction mixture was filtered over celite® bed and the residue was washed with EtOAc. The filtrate was stirred with aqueous sodium carbonate and sodium bisulfite (NaHSOs). The organic layer was dried over Na2S04 and concentrated under high vacuum to obtain the title compound. Yield: 95 %; JH NMR (DMSO d6, 300 MHz): δ 8.05 (d, J = 6.9 Hz, 1H), 7.33 -7.34 (m, 3H), 4.32 (s, 2H), 3.95 (s, 3H), 3.77 (s, 3H), 3.11 (t, J = 6 Hz, 2H), 2.91 (t, J = 6 Hz, 2H); MS (m/z): 381 [M+H] 381, 403 [M+Na]
Step 3
3-((Carboxymethyl)sulfonyl)-4,5-dihydronaphtho[ 1 ,2-c] thiophene- 1 -carboxylic acid
NaOH solution (29.5 mmol) was added to the ice-cold ethanolic solution of methyl 3- ((2-methoxy-2-oxoethyl)sulfonyl)-4,5-dihydronaphtho[ 1 ,2-c]thiophene- 1 -carboxylate (compound of step 2, 13.41 mmol). The reaction mixture was stirred at RT for 2 h. After completion of the reaction, the reaction mixture was cooled, acidified with dilute hydrochloric acid and partitioned with EtOAc. The organic layer was dried over Na2S04 and concentrated under high vacuum to obtain the title compound. Yield: 99%; JH NMR (DMSO d6, 300 MHz): δ 13.64 (br s, 2H), 8.03 (d, J = 5.4 Hz, 1H), 7.35 (m, 3H), 4.61 (s, 2H), 3.03 (t, J = 6.0 Hz, 2H), 2.82 (t, J = 6.0 Hz, 2H); MS (m/z): 353.3 [M+H], 374.9 [M+Na].
Step 4
3-(Methylsulfonyl)-4,5-dihydronaphtho[ 1 ,2-c]thiophene- 1 -carboxylic acid
3-((Carboxymethyl)sulfonyl)-4,5-dihydronaphtho[l,2-c]thiophene-l-carboxylic acid (compound of step 3, 0.2 g, 0.57 mmol) and catalytic amount of (10-15 mg) sodium acetate was stirred in acetic acid (5 mL) at 120°C -130 °C for 1 to 3 h. The solvent was evaporated and the residue was purified using flash column chromatography (silica gel column, 1-5% MeOH/DCM + 1% acetic acid). Yield: 0.13g, 74.3%; JH NMR (DMSO-d6, 300 MHz): δ 13.91 (brs, 1H), 8.04 (d, J = 7.2 Hz, 1H), 7.27 -7.35 (m, 3H), 3.39 (s, 3H), 3.01 (d, J = 6.9 Hz, 2H), 2.87 (d, J = 6.3 Hz, 2H); MS (m/z): 309.2 [M+H], 307.0 [M-H].
Step 5
(3-(methylsulfonyl)-4,5-dihydronaphtho[ 1 ,2-c]thiophen- 1 -yl)methanol
Borane-methyl sulfide complex (19.99 mmol) was added drop wise to an ice-cold solution of 3-(methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophene-l-carboxylic acid (compound of step 4, 6.66 mmol) in dry THF (50 mL) under inert atmosphere. The reaction mixture was stirred at RT for 8 to 12 h. After completion of the reaction, the reaction mixture was poured in ice-cold water, extracted with ethyl acetate, dried over Na2S04 and concentrated under high vacuum to obtain the title compound. Yield: 98%; JH NMR (CDCI3, 300 MHz): δ 7.51 (d, J = 6.9 Hz, 1H), 7.28 -7.37 (m, 3H), 5.12 (d, J = 3.9 Hz, 2H), 3.17 (s, 3H), 3.15 (t, J = 7.5 Hz, 2H), 2.91 (t, J = 7.2 Hz, 2H); MS (m/z): 295.8 [M+H], 317.8 [M+Na].
Step 6
l-(Bromomethyl)-3-(methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophene
Phosphorus tribromide (2.038 mmol) was added to an ice-cold solution of (3- (methylsulfonyl)-4,5-dihydronaphtho [l,2-c]thiophen-l-yl)methanol (compound of step 5, 3.40 mmol) in dry DCM (20 mL). The reaction mixture was stirred at 0 °C for 1 h. After completion of the reaction, DCM was added to the reaction mixture. The reaction mixture was washed with water, aqueous sodium bicarbonate, dried over Na2S04 and concentrated to obtain the title compound. (Yield: 81%); JH NMR (CDC13, 300 MHz): δ 7.84 (d, J = 7.5 Hz, 1H), 7.40 -7.42 (m, 3H), 4.91 (s, 2H), 3.19 (s, 3H), 3.16 (t, J = 6.6 Hz, 2H), 2.91 (t, J = 6.9 Hz, 2H); MS (m/z): 358.9 [M+H] and 380.8 [M+Na].
Step 7
Ethyl 2-(3-(4-((l-(methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophen-3-yl)methoxy) phenyl)oxetan-3-yl)acetate
A solution of ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 0.550 mmol), l-(Bromomethyl)-3-(methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophene (compound of step 6, 0.550 mmol) and CS2CO3 (1.100 mmol) in DMF (5 mL) was stirred at RT for 3 h. After completion of the reaction, the excess solvent was evaporated. The residue was quenched with ice cold water and extracted with EtOAc. The organic layer was washed with brine and water. The solvent was evaporated and the residue was purified using flash column chromatography (silica gel column, 10 to 30 % EtOAc/petroleum ether as eluent) to obtain the title compound. (Yield 78%); JH NMR (CDC13, 300 MHz): δ 7.49 (d, J = 5.7 Hz, 1H), 7.32-7.33 (m, 3H), 7.19 (d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 5.40 (s, 2H), 5.02 (d, J = 5.7 Hz, 2H), 4.88 (d, J = 5.7 Hz, 2H), 4.07 (q, J = 7.2 Hz, 2H), 3.19 (s, 5H), 3.16 (d, J = 8.4 Hz, 2H), 2.95 (t, J = 7.2 Hz, 2H), 1.18 (t, J = 6.9 Hz, 3H); MS (m/z): 513.5 [M+H] and 535.1 [M+Na].
Example 2
2-(3-(4-((l-(Methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophen-3-yl)methoxy)
phenyl)oxetan-3-yl)acetic acid (Compound 2)
To a solution of ethyl 2-(3-(4-((l-(methylsulfonyl)-4,5-dihydronaphtho[l,2- c]thiophen-3-yl)methoxy)phenyl)oxetan-3-yl)acetate (compound of Example 1, 0.365 mmol) in THF (4 mL), MeOH (1.2 mL) and water (4 mL) was added aqueous LiOH monohydrate (2.189 mmol) and the reaction mixture was stirred at RT for 3 h. The solvent was removed and the residue was washed with EtOAc. The reaction mixture was neutralized with saturated aqueous NH4CI and extracted with EtOAc acetate. The organic layer was washed with brine, dried with Na2S04 and concentrated to obtain the title compound. (Yield 73.5%); JH NMR (CDCI3, 300 MHz): δ 12.13 (br s, 1H), 7.59 (d, J = 6.6 Hz, 1H), 7.39 (s, 1H), 7.33 (s, 2H), 7.287 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 5.55 (s, 2H), 4.76 (s, 4H), 3.32 (s, 3H), 3.04 (s, 4H), 2.87 (s, 2H); MS (m/z): 485.1 [M+H], 507 [M+Na].
Example 3
Ethyl 2-(3-(4-(3-(l-(methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophene-3- carboxamido)propoxy)phenyl)oxetan-3-yl)acetate (Compound 3)
A solution of 3-(methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophene-l-carboxylic acid (Compound of step 4 of Example 1, 0.341 mmol,) , ethyl 2-(3-(4-(3- aminopropoxy)phenyl) oxetan-3-yl)acetate (Intermediate 2, 0.341 mmol), HATU (0.511 mmol) and Hunig's base (1.023 mmol) in DMF was stirred in an inert atmosphere at ambient temperature for 4 h. After completion of the reaction, the solvent was evaporated and the residue was quenched with ice cold water, extracted with ethyl acetate and the organic layer was washed with brine and water, dried over Na2S04, concentrated and purified by flash column chromatography (silica gel column, 10 to 25 % ethyl acetate/petroleum ether as eluent) to obtain the title compound. Yield: 58.3%; JH NMR (CDC13, 300 MHz): δ 7.72 (d, J = 6.3 Hz, 1H), 7.30 (m, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 2H), 6.54 (br s, 1H), 4.98 (d, J = 6.0 Hz, 2H), 4.86 (d, J = 6.0 Hz, 2H), 3.99-4.03 (m, 4H), 3.69 (d, J = 6.0 Hz, 2H), 3.10-3.18 (m, 7H), 2.94 (t, J = 6.9 Hz, 2H), 2.12 (t, J = 6.0 Hz, 2H), 1.17 (t, J = 6.9 Hz, 3H); MS (m z): 584.1 [M+H] and 581.9 [M-H].
Example 4
2-(3-(4-(3-(l-(Methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophene-3-carboxamido) propoxy)phenyl)oxetan-3-yl)acetic acid (Compound 4)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 4 was obtained by hydrolyzing the compound of Example 3. Yield: 38%; JH NMR (DMSO de, 300 MHz): δ 8.92 (s, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H), 7.29 (t, J = 7.2 Hz, 1H), 7.20 (d, J = 8.1 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 4.74 (s, 4H), 3.99 (s, 2H), 3.33 (s, 3H), 3.00-3.05 (m, 4H), 2.87 (s, 2H), 1.98 (d, J = 6.9 Hz, 2H), 1.23 (s, 2H); MS (m/z): 555.9 [M+H], 577.9 [M+ Na].
Example 5
Ethyl 2-(3-(4-(3-(o-tolyloxy)propoxy)phenyl)oxetan-3-yl)acetate (Compound 5)
Step 1
Ethyl 2-(3-(4-(3-hydroxypropoxy)phenyl)oxetan-3-yl)acetate
A solution of Intermediate 1 (1.5 g, 6.35 mmol), 3-bromo-l-propanol (1.148 mL, 12.7 mmol) and Cs2C03 (4.14 g, 12.7 mmol) in DMF (30 mL) was stirred at RT for 4 h. After completion of reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc. The organic layer was washed with water, brine, concentrated and purified by flash column chromatography (silica gel column, 1-50% EtOAc/ petroleum ether as eluent) to obtain the title compound (1.417 g). Yield: 76%; JH NMR (CDC13, 300 MHz): δ 7.11 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H), 5.00 (d, J = 6.0 Hz, 2H), 4.86 (d, J = 6.0 Hz, 2H), 4.12 (t, J = 5.7 Hz, 2H), 4.05 (q, J = 7.2 Hz, 2H), 3.10 (s, 2H), 2.09 (m, 2H), 1.89 (brs, 1H), 1.72 (s, 1H), 1.17 (t, J = 7.2 Hz, 3H); MS: (m/z): 295.3 [M+H], 317.2 [M+Na].
Step 2
Ethyl 2-(3-(4-(3-(tosyloxy)propoxy)phenyl)oxetan-3-yl)acetate
A reaction mixture of ethyl 2-(3-(4-(3-hydroxypropoxy)phenyl)oxetan-3-yl)acetate (compound of step 1, 1.313 g, 4.46 mmol), triethylamine (1.865 mL, 13.38 mmol) and 4- dimethylaminopyridine (DMAP) (0.054 g, 0.446 mmol) in DCM (50 mL) was stirred for 30 minutes followed by slow addition of 4-toiuenesulfonyl chloride (p-TsCl) (0.935 g, 4.91 mmol). The temperature was maintained below 5 °C. After complete addition of p-TsCl, the reaction mixture stirred overnight at 25 °C. After completion of reaction, the reaction mixture was poured in ice-cold water and the product was extracted with ethylacetate. The organic layer was washed with water, brine and dried over anhydrous Na2S04 (1.467 g). Yield: 73.3 %; JH NMR (CDC13, 300 MHz): δ 7.78 (d, J = 7.8 Hz, 2H), 7.29 (d, J = 5.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 8.7 Hz, 2H), 4.99 (d, J = 5.7 Hz, 2H), 4.87 (d, J = 5.7 Hz, 2H), 4.26 (t, J = 6.0 Hz, 2H), 4.00-4.06 (m, 4H), 3.10 (s, 2H), 2.41 (s, 3H), 2.16 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H).
Step 3
Ethyl 2-(3-(4-(3-(o-tolyloxy)propoxy)phenyl)oxetan-3-yl)acetate
Flame-dried CS2CO3 (1.115 mmol) was added to a solution of o-cresol (0.557 mmol) in DMF (10 mL). After about 10 minutes ethyl 2-(3-(4-(3-(tosyloxy)propoxy)phenyl) oxetan-3- yl)acetate (compound of step 2, 0.557 mmol) was added slowly to the reaction mixture at RT. The reaction mixture was stirred overnight. The reaction mixture was filtered and the residue was washed with DMF. The filtrate was concentrated and then diluted with ice-cold water. The compound was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2S04 and purified using column chromatography (silica gel column, 15 to 40 % EtOAc/petroleum ether) to obtain the title compound. (Yield 72.3%); JH NMR (CDCI3, 300 MHz): δ 7.08-7.18 (m, 4H), 6.84-6.91 (m, 4H), 5.00 (d, J = 6.0 Hz, 2H), 4.86 (d, J = 5.7 Hz, 2H), 4.21 (q, J = 6.3 Hz, 4H), 4.05 (q, J = 7.2 Hz, 2H), 3.10 (s, 2H), 2.31 (t, J = 6.0 Hz, 2H), 2.23 (s, 3H), 1.16 (t, J = 6.9 Hz, 3H); MS (m/z): 407.1 [M+ Na].
Example 6
2-(3-(4-(3-(o-Tolyloxy)propoxy)phenyl)oxetan-3-yl)acetic acid (Compound 6)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 6 was obtained by hydrolyzing the compound of Example 5. Yield: 41.6%; JH NMR (CDCI3, 300 MHz): δ 7.21 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 7.2 Hz, 2H), 6.94 (t, J = 8.7 Hz, 2H), 6.84 (t, J = 7.2 Hz, 2H), 4.75 (dd, J = 5.1, 15.6 Hz, 4H), 4.16 (dd, J = 5.1,15.6 Hz, 4H), 2.89 (s, 2H), 2.19 (s, 2H), 2.14 (s, 3H); MS (m/z): 357 ]M+H], 379 [M+Na] and 354.7 [M-H]..
Example 7
Ethyl 2-(3-(4-(3-(phenylthio)propoxy)phenyl)oxetan-3-yl)acetate (Compound 7) A solution of thiophenol (0.557 mmol), ethyl 2-(3-(4-(3-(tosyloxy)propoxy) phenyl)oxetan-3-yl)acetate (compound of step 2 of Example 5, 0.557 mmol) and CS2CO3 (1.115 mmol) in DMF (4 mL) was stirred at RT for 3 h. After completion of the reaction, the solvent was evaporated and the residue was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine and water and purified by flash column chromatography (silica gel column, 10 to 20 % ethylacetate / petroleum ether as eluent) to obtain the title compound. (Yield: 84%); JH NMR (CDC13, 300 MHz): δ 7.38 (m, 4H), 7.21 (m, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 5.00 (d, J = 5.7 Hz, 2H), 4.87 (d, J = 6.0 Hz, 2H), 4.00-4.09 (m, 4H), 3.51 (d, J = 4.8 Hz, 1H), 3.11-3.15 (m, 1H), 3.10 (s, 2H), 2.11-2.19 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H); MS (m/z): 387.3 [M+H], 409.1 [M+Na].
Example 8
2-(3-(4-(3-(Phenylthio)propoxy)phenyl)oxetan-3-yl)acetic acid (Compound 8)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 8 was obtained by hydrolyzing the compound of Example 7. (Yield 69.4%); JH NMR (300 MHz, CDCI3): δ 12.26 (br s, 1H), 7.30-7.33 (m, 4H), 7.10-7.20 (m, 3H), 6.90 (d, J = 8.4 Hz, 2H), 4.73 (s, 4H), 4.07 (t, J = 5.7 Hz, 2H), 3.10-3.13 (m, 4H), 2.00 (t, J = 6.3 Hz, 2H); HPLC: 98.41%: MS: (m/z) 358.9 [M+H], 356.7 [M-H].
Example 9
Ethyl 2-(3-(4-(3-(phenylsulfinyl)propoxy)phenyl)oxetan-3-yl)acetate (Compound 9)
A solution of ethyl 2-(3-(4-(3-(phenylthio)propoxy)phenyl)oxetan-3-yl)acetate (Compound 7, 0.776 mmol) in MeOH (5 mL) and water (5 mL) was cooled to 10-15 °C. Potassium peroxymonosulfate (Oxone®) (0.776 mmol) was added to the reaction mixture in portions. The reaction mixture was stirred overnight at RT. After the completion of the reaction the reaction mixture was filtered over celite® bed. The residue was washed with MeOH and the filtrate was concentrated to obtain the title compound. Yield: 48 %; JHNMR (CDCI3, 300MHz): δ 7.60-7.64 (m, 2H), 7.51-7.55 (m, J = 5.7, 3H), 7.10 (d, J = 8.1, 2H), 6.84 (d, J = 8.4 Hz, 2H), 4.98 (d, J = 5.4 Hz, 2H), (d, J = 5.7 Hz, 2H), 4.05 (t, J = 6.3 Hz, 2H), 4.03 (q, J = 6.9 Hz, 2H), 3.10 (s, 2H), 2.97 (m, 2H), 2.28 (m,lH), 2.12 (m,lH), 1.16 (t, J = 6.9 Hz, 3H); MS (m/z): 403 [M+H].
Example 10
Ethyl 2-(3-(4-(3-(phenylsulfonyl)propoxy)phenyl)oxetan-3-yl)acetate (Compound 10) A solution of ethyl 2-(3-(4-(3-(phenylthio)propoxy)phenyl)oxetan-3-yl)acetate (Compound 7, 0.316 mmol) in MeOH (5 mL) and water (5 mL) was cooled to 10-15 °C. Potassium peroxymonosulfate (Oxone®) (0.789 mmol) was added to the reaction mixture in portions. The reaction mixture was stirred overnight at RT. After the completion of the reaction the reaction mixture was filtered over celite® bed. The residue was washed with MeOH and the filtrate was concentrated to obtain the title compound. Yield: 53.7 %; JH NMR (CDCI3, 300 MHz): δ 7.97 (d, J = 7.5 Hz, 2H), 7.58-7.72 (m, 3H), 7.05 (d, J = 8.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 2H), 4.72 (d, J = 9.0 Hz, 2H), 4.41(d, J = 9.0 Hz, 2H), 4.14 (q, J = 6.9 Hz, 2H), 4.10 (t, J = 6.0 Hz, 3H), 3.35 (t, J = 7.5 Hz, 2H), 2.21-2.29 (m, 3H), 1.65-1.67 (m, 3H); MS (m/z): 416.9 [M-H]
Example 11
Ethyl 2-(3-(4-(3-(3-([l,l'-biphenyl]-4-yl)ureido)propoxy) phenyl)oxetan-3-yl)acetate (Compound 11)
The solution of ethyl 2-(3-(4-(3-aminopropoxy)phenyl)oxetan-3-yl)acetate (Intermediate 2, 0.583 mmol) and 4-biphenylisocyanate (0.583 mmol) in THF was stirred overnight at RT to obtain the crude product, which was purified by using flash column chromatography (silica gel column, 10 to 20 % EtOAc/ petroleum ether) to obtain the title compound. (Yield: 82 ); JH NMR (CDC13, 300 MHz): δ 7.53-7.55 (m, 4H), 7.28-7.46 (m, 6H), 7.04 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 5.34 (d, J = 6.9 Hz, 1H), 4.96 (d, J = 6.0 Hz, 2H), 4.84 (d, J = 6.0 Hz, 2H), 4.02 (d, J = 7.2 Hz, 4H), 3.49 (d, J = 5.4 Hz, 2H), 3.07 (s, 2H), 2.02 (d, J=5.7 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H); MS (m/z): 489.1 [M+H] and 511.0 [M+Na].
Example 12
2-(3-(4-(3-(3-([l,l'-Biphenyl]-4-yl)ureido)propoxy)phenyl) oxetan-3-yl)acetic acid (Compound 12)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 12 was obtained by hydrolyzing the compound of Example 11. Yield: 45%; ¾ NMR (DMSO-d6, 300 MHz): δ 8.63 (s, 1H), 7.61 (d, J = 7.2 Hz, 2H), 7.39-7.55 (m, 6H), 7.30 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 8.1 Hz, 2H), 6.93 (d, J = 7.8 Hz, 2H), 6.34 (s, 1H), 4.74 (s, 4H), 4.00 (s, 2H), 3.25-3.49 (m, 4H), 2.99 (s, 2H), 1.84-1.98 (m, 2H); MS: 461.2 [M+H]. Example 13
Ethyl 2-(3-(4-(3-(4-fluorophenoxy)propoxy)phenyl)oxetan-3-yl)acetate (Compound 13)
A solution of 4-fluorophenol (0.07g, 0.622 mmol), ethyl 2-(3-(4-(3- (tosyloxy)propoxy)phenyl)oxetan-3-yl)acetate (compound of step 2 of Example 5, 0.279 g, 0.622 mmol) and Cs2C03 (0.405 g, 1.244 mmol) in DMF (15 mL) was stirred at RT for 3 h. After completion of the reaction, the solvent was evaporated and the residue was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine and water and purified by flash column chromatography (silica gel column, 10 to 20 % EtOAc/ petroleum ether as eluent) to obtain the title compound (169 g). (Yield: 69.9%); JH NMR (CDC13, 300 MHz): δ 7.11 (d, J = 8.4 Hz, 2H), 7.00 (t, J = 8.4 Hz, 2H), 6.87-6.90 (m, 4H), 5.00 (d, J = 5.7 Hz, 2H), 4.86 (d, J = 5.7 Hz, 2H), 4.11-4.17 (m, 4H), 4.05 (q, J = 7.2 Hz, 2H), 3.10 (s, 2H), 2.27 (t, J = 6.0 Hz, 2H), 1.16 (t, J = 6.9 Hz, 3H); MS: (m/z) 411.0 (M+Na).
Example 14
2-(3-(4-(3-(4-fluorophenoxy)propoxy)phenyl)oxetan-3-yl)acetic acid (Compound 14)
The title compound was prepared in an analogous manner as the compound
2 of Example 2. Compound 14 was obtained by hydrolyzing the compound of
Example 13. Yield: 55.8%; JH NMR (300 MHz, CDCI3): δ 7.21 (d, J = 8.4 Hz, 2H), 7.13 (t, J = 8.7 Hz, 2H), 6.88-6.97 (m, 4H), 4.75 (d, J = 5.4 Hz, 2H), 4.70 (d, J = 5.7 Hz, 2H), 4.09 (s, 4H), 2.90 (s, 2H), 2.15 (t, J = 6.0 Hz, 2H); MS (m/z): 361.1 [M+H].
Example 15
Ethyl 2-(3-(4-(3-(3-chlorophenoxy)propoxy)phenyl)oxetan-3-yl)acetate (Compound 15)
A solution of 3-chlorophenol (0.669 mmol), ethyl 2-(3-(4-(3-(tosyloxy)propoxy) phenyl)oxetan-3-yl)acetate (compound of step 2 of Example 5, 0.669 mmol) and CS2CO3 (1.338 mmol) in DMF (10 mL) was stirred at RT for 3 h. After completion of the reaction, the solvent was evaporated and the residue was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with brine and water and purified by flash column chromatography (silica gel column, 10 to 20 % EtOAc/ petroleum ether as eluent) to obtain the title compound. Yield: 89%; JH NMR (CDC13, 300 MHz): δ 7.23 (t, J = 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 2H), 6.88-6.94 (m, 4H), 6.82 (d, J = 8.4 Hz, 1H), 5.00 (d, J = 5.7 Hz, 2H), 4.86 (d, J = 5.7 Hz, 2H), 4.15 (d, J = 5.1 Hz, 4H), 4.05 (q, J = 6.9 Hz, 2H), 3.10 (s, 2H), 2.28 (t, J = 5.7 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H); MS (m/z): 426.9 [M+Na]. Example 16
2-(3-(4-(3-(3-chlorophenoxy)propoxy)phenyl)oxetan-3-yl)acetic acid (Compound 16)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 16 was obtained by hydrolyzing the compound of Example 15. Yield: 37.2 ; JHNMR (300 MHz, DMSO-d6): δ 12.05 (br s, 1H), 7.32 (t, J = 8.1 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 7.03 (brs, 1H), 6.99 (d, J = 8.1 Ηζ,ΙΗ), 6.90-6.94 (m, 3H), 4.76 (s, 4H), 4.09-4.16 (m, 4H), 3.00 (s, 2H), 2.11-2.19 (m, 2H); MS (m/z): 377.1 [M+H].
Example 17
Ethyl 2-(3-(4-(3-(3-(trifluoromethyl)phenoxy)propoxy)phenyl)oxetan-3-yl)acetate (Compound 17)
A solution of 3-trifluoromethylphenol (0.622 mmol), ethyl 2-(3-(4-(3- (tosyloxy)propoxy)phenyl)oxetan-3-yl)acetate (compound of step 2 of Example 5, 0.622 mmol) and Cs2C03 (1.244 mmol) in DMF (15 mL) was stirred at RT for 3 h. After completion of the reaction, the solvent was evaporated and the residue was quenched with ice-cold water and extracted with EtOAc. The organic layer was washed with brine and water and purified by flash column chromatography (silica gel column, 10 to 20 % EtOAc/ petroleum ether as eluent) to obtain the title compound. Yield: 96%; JHNMR (CDC13, 300 MHz): δ 7.42 (t, J = 7.5 Hz, 1H), 7.09-7.22 (m, 5H), 6.91 (d, J = 8.4 Hz, 2H), 5.00 (d, J = 6.0 Hz, 2H), 4.86 (d, J = 6.0 Hz, 2H), 4.15-4.22 (m, 4H), 4.05 (q, J = 6.9 Hz, 2H), 3.10 (s, 2H), 2.31 (t, J = 6.0 Hz, 2H), 1.16 (t, J = 6.9 Hz, 2H); MS: (m/z) 460.9 [M+Na].
Example 18
2-(3-(4-(3-(3-(Trifluoromethyl)phenoxy)propoxy)phenyl) oxetan-3-yl)acetic acid (Compound 18)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 18 was obtained by hydrolyzing the compound of Example 17. Yield: 47.56 %; JHNMR (DMSO-de, 300 MHz): δ 7.49-7.53 (m, 1H), 7.10-7.28 (m, 5H), 6.89 (d, J = 8.4 Hz, 2H), 4.77 (d, J = 5.4 Hz, 2H), 4.67 (d, J = 5.4 Hz, 2H), 4.22 (t, J = 5.7 Hz, 2H), 4.11 (t, J = 5.7 Hz, 2H), 2.78 (s, 2H), 2.18 (t, J = 5.7 Hz, 2H); MS (m/z): 411.1 [M+H] and 433.1 [M+Na].
Example 19
Ethyl 2-(3-(4-(3-(4-cyanophenoxy)propoxy)phenyl)oxetan-3-yl)acetate (Compound 19) A solution of 4-hydroxybenzonitrile (0.613 mmol), ethyl 2-(3-(4-(3- (tosyloxy)propoxy)phenyl)oxetan-3-yl)acetate (compound of step 2 of Example 5, 0.557 mmol) and CS2CO3 (1.115 mmol) in DMF (15 mL) was stirred at RT for 3 h. After completion of the reaction, the solvent was evaporated and the residue was quenched with ice-cold water and extracted with EtOAc. The organic layer was washed with brine and water and purified by flash column chromatography (silica gel column, 10 to 20 % EtOAc/ petroleum ether as eluent) to obtain the title compound. Yield: 98 %; JHNMR (CDCI3, 300 MHz) : δ 7.61 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 6.4, 2H), 4.99 (d, J = 5.7 Hz, 2H), 4.87 (d, J = 5.7 Hz, 2H), 4.14-4.22 (m, 4H),.4.05 (q, J = 7.2 Hz, 2H), 3.106 (s, 2H), 2.31 (t, J = 6.0 Hz, 2H), 1.17 (t, J = 6.9 Hz, 3H); MS (m/z): M+H 396, M+Na 417.9.
Example 20
2-(3-(4-(3-(4-Cyanophenoxy)propoxy)phenyl)oxetan-3-yl)acetic acid (Compound 20)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 20 was obtained by hydrolyzing the compound of Example 19. Yield: 58.8%; JHNMR (DMSO-d6, 300 MHz): δ 7.768 (d, J=7.8, 2H), 7.129 (d, J=7.8,4H), 6.924 (d, J=8.1,2H), 4.212 (s, 2H), 4.106 (s, 2H), 3.35-3.45 (m, 2H), 2.73-2.800 (m, 2H), 2.497 (s, 2H), 2.170 (brs, 2H); MS (m/z): 366.0 [M-H] and 390.3 [M+Na].
Example 21
Ethyl 2-(3-(4-(3-([l,l'-biphenyl]-4-yloxy)propoxy) phenyl) oxetan-3-yl)acetate (Compound 21)
A solution of [l,l'-biphenyl]-4-ol (0.613 mmol), ethyl 2-(3-(4-(3-(tosyloxy) propoxy)phenyl)oxetan-3-yl)acetate (compound of step 2 of Example 5, 0.557 mmol) and CS2CO3 (1.115 mmol) in DMF (15 mL) was stirred at RT for 3 h. After completion of the reaction, the solvent was evaporated and the residue was quenched with ice-cold water and extracted with EtOAc. The organic layer was washed with brine and water and purified by flash column chromatography (silica gel column, 10 to 20 % EtOAc / petroleum ether as eluent) to obtain the title compound. Yield: 93 %; JHNMR (300 MHz, CDCI3): δ 7.52-7.57 (m, 4H), 7.45 (t, J = 7.2 Hz, 2H), 7.32-7.34 (m, 1H), 7.12 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 5.00 (d, J = 5.7 Hz, 2H), 4.87 (d, J = 5.7 Hz, 2H), 4.17-4.23 (m, 4H), 4.05 (q, J = 7.2 Hz, 2H) 3.10 (s, 2H), 2.31 (t, J = 5.7 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H); MS (m z): 446.9 [M+H]. Example 22
2-(3-(4-(3-([l,l'-biphenyl]-4-yloxy)propoxy)phenyl)oxetan-3-yl)acetic acid (Compound 22)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 22 was obtained by hydrolyzing the compound of Example 21. Yield: 89%; JH NMR (300 MHz, CDCI3): δ 11.89 (br s,lH), 7.57-7.61 (m, 4H), 7.44 (t, J = 7.5 Hz, 2H), 7.28-7.32 (m, 1H), 7.21 (d, J = 7.8 Hz, 2H), 7.05 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 4.73 (s, 4H), 4.12-4.19 (m, 4H), 2.99 (s, 2H), 2.16-2.20 (m, 2H); MS (m/z): 416.9 [M-H] and 441.0 [M+Na].
Example 23
Ethyl 2-(3-(4-(2,2-dimethyl-3-(4-(trifluoromethyl)phenoxy)propoxy)phenyl)oxetan-3- yl)acetate (Compound 23)
Step 1
2,2-dimethyl-3-(4-(trifluoromethyl)phenoxy)propyl 4-methylbenzenesulfonate
Sodium hydride (7.40 mmol) was added to a solution of 4-(trifluoromethyl)phenol (6.17 mmol) in DMF (20 mL) and the reaction mixture was stirred for 30 minutes. 2,2- dimethylpropane-l,3-diyl bis(4-methylbenzenesulfonate) (12.34 mmol) was added and the reaction mixture was heated to 100 °C and maintained for 20 h. After completion of the reaction, the reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate. The organic layer was washed with water, brine and purified by flash column chromatography (silica gel column, 1-30% ethyl acetate/petroleum ether as eluent) to obtain the title compound. Yield: 72%; JH NMR (CDC13, 300 MHz): δ 0.90 (s, 3H), 1.04 (s, 3H), 2.48 (s, 3H), 3.73 (s, 2H), 3.89 (s, 2H), 6.82 (d, J = 8.4 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 7.8 Hz, 2H), 7.58 (d, J = 8.1 Hz, 1H), 7.70-7.76 (m, 3H).
Step 2
Ethyl 2-(3-(4-(2,2-dimethyl-3-(4-(trifluoromethyl)phenoxy)propoxy) phenyl)oxetan-3- yl)acetate
Sodium hydride (5.08 mmol) was added to the solution of ethyl 2-(3-(4- hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 4.23 mmol) in DMF (20 mL) at RT. The reaction mixture was stirred for 20 minutes followed by the addition of 2,2-dimethyl-3-(4- (trifluoromethyl)phenoxy)propyl 4-methylbenzenesulfonate (4.23 mmol) and the reaction mixture was further stirred at 80 °C for 26 h. After the completion of reaction, water (40 mL) was added to the reaction mixture and the residue was extracted with ethyl acetate twice. The organic layer was washed with water, brine, dried over Na2S04, concentrated and purified by flash column chromatography (silica gel column, 1-30% ethyl acetate/petroleum ether as eluent) to obtain the title compound.
Example 24
2-(3-(4-(2,2-Dimethyl-3-(4-(trifluoromethyl)phenoxy)propoxy)phenyl)oxetan-3-yl)acetic acid (Compound 24)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 24 was obtained by hydrolyzing the compound of Example 23. Yield: 5.5%; JH NMR (DMSO-d6, 300 MHz): δ 1.17 (s, 6H), 1.66 (s, 2H), 2.89 (q, 2H), 3.70 (br s, 2H), 3.83 (s, 2H), 3.90 (s, 2H), 6.91-6.98 (dd, J = 9 Hz, 4H), 7.06 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.7 Hz, 2H); MS (m/z): 440.2 [M+H].
Example 25
Ethyl 2-(3-(4-((l-((o-tolyloxy)methyl)cyclopropyl)methoxy)phenyl)oxetan-3-yl)acetate (Compound 25)
A solution of l-((l-(bromomethyl)cyclopropyl)methoxy)-2-methylbenzene (Intermediate 3, 1.176 mrnol), ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate
(Intermediate 1, 1.176 mmol) and CS2CO3 (1.411 mmol) in DMF (10 mL) was stirred at RT for 20 h. After the completion of reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04, concentrated and purified by flash chromatography (silica gel column, 1-30% EtOAc/petroleum ether as eluent) to obtain the title compound. Yield: 58%; JH NMR (CDCI3, 300 MHz): δ 0.75 (s, 2H), 0.77 (s, 2H), 1.14 (t, J = 7.2 Hz, 3H), 2.24 (s, 3H), 3.10 (s, 2H), 4.00 (s, 4H), 4.02 (q, J = 7.2 Hz, 2H), 4.86 (d, J = 5.7 Hz, 2H), 5.00 (d, J = 5.7 Hz, 2H), 6.78-6.89 (m, 4H), 7.07-7.14 (m, 4H); MS (m/z): 433.2 [M+Na].
Example 26
2-(3-(4-((l-((o-Tolyloxy)methyl)cyclopropyl)methoxy)phenyl)oxetan-3-yl)acetic acid (Compound 26)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 26 was obtained by hydrolyzing the compound of Example 25. Yield: 85%; JH NMR (DMSO-d6, 300 MHz): δ 0.70 (s, 4H), 2.15 (s, 3H), 2.91 (s, 2H), 3.98 (d, J = 6.3 Hz, 4H), 4.73 (br s, J = 9 Hz, 4H), 6.81 (t, J = 7.2 Hz, 1H), 6.78-6.90 (m, 3H), 7.10 (brs, 2H), 7.19 (d, J = 8.4 Hz, 2H); MS (m/z): 405.2 [M+Na].
Example 27
Ethyl 2-(3-(4-((l -((3-(trifluoromethyl)phenoxy)methyl)cyclopropyl)methoxy)phenyl) oxetan- 3 -yl) acetate (Compound 27)
Step 1
( 1 -((3 -(Trifluoromethyl)phenoxy)methyl)cyclopropyl)methanol
A solution of 3-trifluoromethylphenol (1.0 g, 6.17 mmol), cyclopropane-dimethanol (0.630 g, 6.17 mmol) and triphenylphosphine (2.43 g, 9.25 mmol) in DCM (15 mL) was cooled to 10°C. Diethylazodicarboxyiate (1.610 mL, 9.25 mmol) was slowly added and the reaction mixture was stirred at RT for 24 h. After completion of reaction, the reaction mixture was purified by flash column chromatography (silica gel column, 10-50% ethyl acetate- petroleum ether as eluent) to obtain the title compound (0.28 g). Yield: 29%; JH NMR (CDC13, 300 MHz): δ 7.15 (s, 2H), 6.91 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 8.1 Hz, 1H), 3.95 (s, 2H), 3.67 (s, 2H), 0.675 (s, 4H).
Step 2
l-((l-(Bromomethyl)cyclopropyl)methoxy)-3-(trifluoromethyl)benzene
A solution of (l-((3-(trifluoromethyl)phenoxy)methyl)cyclopropyl)methanol (compound of step 1, 0.21 g, 0.853 mmol) and carbon tetratbromide (CBr4) (0.311 g, 0.938 mmol) in DCM (10 mL) was cooled to 0°C. Triphenylphosphine (Ph3P) (0.246 g, 0.938 mmol) was added with vigorous stirring. The stirring continued for 2 h at RT. After completion of reaction, the reaction mixture was concentrated to obtain brown oil, which was purified by flash column chromatography (silica gel column, 1-10% ethyl acetate/petroleum ether as eluent) to obtain the title compound (0.17 g). Yield: 64.5%; JH NMR (CDC13, 300 MHz): δ 7.43 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 7.5 Hz, 1H), 7.15 (s, 1H), 7.11 (d, J = 7.8 Hz, 1H), 3.97 (s, 2H), 3.59 (s, 2H), 0.93 (s, 2H), 0.82 (s, 2H); MS (m/z): 310.8 [M+H].
Step 3
A solution of l-((l-(bromomethyl)cyclopropyl)methoxy)-3-(trifluoromethyl)benzene (compound of step 2, 0.485 mmol), ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 0.485 mmol) and Cs2C03 (0.582 mmol) in DMF (10 mL) was stirred at RT for 20 h. After the completion of reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04, concentrated and purified flash column chromatography (silica gel column, 1-30% EtO Ac/petroleum ether as eluent) to obtain the title compound. Yield: 71%; JH NMR (CDC13, 300 MHz): δ 0.78 (s, 4H), 1.13 (t, J = 7.2 Hz, 3H), 3.09 (s, 2H), 3.97-4.04 (m, 6H), 4.86 (d, J = 6 Hz, 2H), 4.99 (d, J = 6.0 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 7.10 (m, 3H), 7.14 (s, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 7.8 Hz, 1H); MS: (m/z) 487.2 [M+Na].
Example 28
2-(3-(4-((l-((3-(Trifluoromethyl)phenoxy)methyl)cyclopropyl)methoxy)phenyl) oxetan-3- yl)acetic acid (Compound 28)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 28 was obtained by hydrolyzing the compound of Example 27. Yield: 84%; JH NMR (CDC13, 300 MHz): δ 0.71 (s, 4H), 2.98 (s, 2H), 3.96 (s, 2H), 4.05 (s, 2H), 4.73 (br s, 4H), 6.91 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.23 (br s, 3H), 7.49 (t, J = 7.8 Hz, 1H); MS (m/z): 459.1 [M+Na].
Example 29
Ethyl 2-(3-(4-((l - ((3 -chlorophenoxy)methyl)cyclopropyl) methoxy)phenyl)oxetan-3 - yl)acetate (Compound 29)
Step 1
( 1 -((3 -Chlorophenoxy)methyl)cyclopropyl)methanol
A solution of 3-Chlorophenol (1 equivalent), cyclopropane-dimethanol (1 equivalent) and triphenylphosphine (1.5 equivalent) in DCM (15 mL) was cooled to 10°C. Diethylazodicarboxylate (1.5 equivalent) was slowly added and the reaction mixture was stirred at RT for 1 h. After completion of reaction, the reaction mixture was poured in water, extracted with ethyl acetate, concentrated and purified by flash column chromatography (silica gel column, 0-30% ethyl acetate -petroleum ether as eluent) to obtain the title compound (0.4 g). Yield: 0.4 37%; JHNMR (CDC13, 300 MHz): δ 7.279 (m, 1H), 6.962 (m, 2H), 6.926 (d, J = 8.4 Hz, 1H), 3.931 (s, 2H), 3.660 (d, J = 4.2 Hz, 2H), 0.661 (s, 4H); MS: (m/z) M+H 279, M+Na 301, M-H 276.6.
Step 2
l-((l-(Bromomethyl)cyclopropyl)methoxy)-3-chlorobenzene
Phosphorus tribromide was added to a cold, stirred solution of (l-((3- chlorophenoxy)methyl)cyclopropyl)methanol (compound of step 1) in dry DCM (2 mL). The reaction mixture was stirred at 0 °C for 1 h. After completion of reaction, the reaction mixture was poured into diethyl ether (20 mL). The organic layer was washed with water, aqueous sodium bicarbonate (NaHCC ), dried over Na2S04 and concentrated to obtain the title compound. Yield: 61.7%; JHNMR (CDC13, 300 MHz): δ 7.278 (m, 1H), 6.966 (m, 2H), 6.834 (m, 1H), 3.921 (s, 2H), 3.578 (s, 2H), 0.661 (s, 4H); MS: (m/z) M+H 277.0, M+Na 299, M-H 274.7.
Step 3
Ethyl 2-(3-(4-((l - ((3 -chlorophenoxy)methyl)cyclopropyl) methoxy)phenyl)oxetan-3 - yl)acetate
A solution of l-((l-(bromomethyl)cyclopropyl)methoxy)-3-chlorobenzene (compound of step 2, 0.15 g, 0.544 mmol), ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 0. 129 g, 0.544 mmol) and CS2CO3 (0.176 g, 0.544 mmol) was stirred in dry DMF (2 mL) at RT for 24 h. After the completion of reaction, the reaction mixture was diluted with water (20 mL) and extracted with EtOAc. The organic layer was evaporated and the residue was purified by flash column chromatography (silica gel column, 0-30% EtOAc/petroleum ether as eluent) to obtain the title compound (0.1 g). Yield: 42.6 %; JH NMR (CDCI3, 300 MHz): δ 7.235 (t, J = 8.1, 1H), 7.096 (d, J = 8.4, 2H), 6.932 (m, 4H), 6.803 (d, J = 7.8, 1H), 4.989 (d, J = 6, 2H), 4.857 (d, J = 6, 2H), 4.048 (m, 6H), 3.094 (s, 2H), 1.159 (t, J = 7.2, 3H), 0.758 (s, 4H); MS (m/z): 430.9 (M+H), 452.9 (M+Na).
Example 30
2-(3-(4-((l-((3-Chlorophenoxy)methyl)cyclopropyl)methoxy)phenyl)oxetan-3-yl) acetic acid (Compound 30)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 30 was obtained by hydrolyzing the compound of Example 29. Yield: 94%; JH NMR (DMSO-d6, 300 MHz): δ 12.08 (br s, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.17 (d, 2H), 7.01 (m, 5H), 4.72 (s, 4H), 3.97 (d, J = 14.4 Hz, 4H), 2.99 (s, 2H), 0.87 (m, 4H); MS (m/z): 400.9 ]M-H].
Example 31
Ethyl 2-(3-(4-((4-((l-methylspiro[indoline-3,4'-piperidin]-r-yl)methyl)benzyl)oxy) phenyl)oxetan-3-yl) (Compound 31) The reaction mixture of ethyl 2-(3-(4-((4-(bromomethyl)benzyl)oxy)phenyl)oxetan-3- yl)acetate (Intermediate 6, 0.572 mmol), l-Methylspiro[indoline-3,4'-piperidine] (Intermediate 4, 0.572 mmol) and CS2CO3 (1.259 mmol) in DMF (10 mL) was stirred overnight at RT. After completion of reaction, the reaction mixture was diluted with water (20 mL), extracted with EtO Ac acetate, washed with brine, dried over Na2S04 and concentrated to obtain the crude product, which was purified by flash column chromatography (silica gel column, 1-30% EtO Ac/petroleum ether) to obtain the title compound. Yield: 48.5%; JH NMR (CDCI3, 300 MHz): δ 1.14 (t, J = 6.9 Hz, 3H), 1.71 (s, 4H), 1.96 (t, J = 12.6 Hz, 2H), 2.16 (t, J = 11.7 Hz, 2H), 2.78 (s, 3H), 2.91 (d, J = 11.1 Hz, 2H), 3.11 (s, 2H), 3.22 (s, 2H), 4.04 (q, J = 6.9 Hz, 2H), 4.87 (d, J = 5.7 Hz, 2H), 5.01 (d, J =
5.7 Hz, 2H), 5.06 (s, 2H), 6.51 (d, J = 7.8 Hz, 1H), 6.72 (dd, J = 7.2, 7.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 7.07-7.13 (m, 4H), 7.40 (s, 4H); MS (m/z): 541.5 (M+H).
Example 32
2-(3-(4-((4-((l-Methylspiro[indoline-3,4'-piperidin]-r-yl)methyl)benzyl)oxy)phenyl) oxetan-3-yl)acetic acid (Compound 32)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 32 was obtained by hydrolyzing the compound of Example 31. Yield: 73%; JH NMR (DMSO d6, 300 MHz): δ 1.58 (d, J = 12.6 Hz, 2H), 1.78 (t, J = 12 Hz, 2H),
2.08 (t, J = 11.1 Hz, 2H), 2.60 (s, 2H), 2.73 (s, 3H), 2.77 (d, J = 11.1 Hz, 2H), 3.14 (s, 2H), 3.49 (s, 2H), 4.64 (d, J = 5.4 Hz, 2H), 4.81 (d, J = 5.4 Hz, 2H), 5.05 (br s, 2H), 6.48 (d, J = 7.2 Hz, 1H), 6.60 (t, J = 7.2 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 7.02 (dd, J = 7.5, 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 7.5 Hz, 2H), 7.47 (7.5 Hz, 2H); MS (m/z): 513.6 [M+H].
Example 33
Ethyl 2-(3-(4-((4-(spiro[indene-l,4'-piperidin]-r-ylmethyl) benzyl)oxy)phenyl) oxetan-3- yl)acetate (Compound 33)
A reaction mixture of ethyl 2-(3-(4-((4-(bromomethyl)benzyl)oxy)phenyl) oxetan-3- yl) acetate (Intermediate 7, 1.002 mmol), trifluoroacetic acid salt of spiro[indene-l,4'- piperidine] (Intermediate 5, 1.202 mmol) and CS2CO3 (3.00 mmol) in DMF (15 mL) was stirred at RT for 2 h. After completion of reaction, the reaction mixture was diluted with water (20 mL), extracted with ethyl, washed with water and brine and dried over Na2S04. The solvent was evaporated to obtain the crude product which was purified by column chromatography to obtain the title compound. Yield: 12%. Example 34
2-(3-(4-((4-(Spiro[indene-l,4'-piperidin]- -ylmethyl)benzyl) oxy)phenyl)oxetan-3-yl)acetic acid (Compound 34)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 34 was obtained by hydrolyzing the compound of Example 33. Yield: 61%; JH NMR (DMSO-d6, 300 MHz): δ 1.21 (d, J = 12.3 Hz, 2H), 2.08 (t, J = 11.4 Hz, 2H), 2.36 (t, J = 11.4 Hz, 2H), 2.87 (s, 4H), 3.32 (s, 2H), 4.75 (d, J = 12.3 Hz, 4H), 5.06 (s, 2H), 6.79 (d, J = 5.4 Hz, 1H), 6.96 (d, J = 6.0 Hz, 3H), 7.14-7.23 (m, 4H), 7.33 (d, J = 6.6 Hz, 1H), 7.36-7.43 (m, 5H); HPLC: 93.86%; MS: (m/z): 496.4 [M+H].
Example 35
Ethyl 2-(3-(4-(3-(methylsulfonamido)propoxy)phenyl)oxetan-3-yl)acetate (Compound 35)
The reaction mixture of ethyl 2-(3-(4-(3-aminopropoxy)phenyl)oxetan-3- yl)acetate (Intermediate 2, 0.511 mmol) in DCM (10 mL) containing triethylamine (1.534 mmol) was stirred for 15 minutes followed by drop wise addition of methanesulfonyl chloride (0.562 mmol). The reaction mixture was stirred further at RT for 2 h. After completion of reaction, the reaction mixture was quenched with ice cold water, extracted with DCM, washed with brine and water. The solvent was evaporated and the residue obtained as crude product was purified by column chromatography (silica gel column, 10 to 25 % ethyl acetate /petroleum ether) to obtain the title compound. Yield: 61%; JH NMR (CDC13, 300 MHz) : δ 7.13 (d, J = 8.7, 2H), 6.89 (d, J = 8.4 Hz, 2H), 5.00 (d, J = 6.0 Hz, 2H), 4.87 (d, J = 6.0 Hz, 2H), 4.58 (br s, 1H), 4.11 (t, J = 5.7 Hz, 2H), 3.99 (q, J = 7.2 Hz, 2H), 3.42 (q, J = 6.3 Hz, 2H), 3.11 (s, 2H), 2.97 (s, 3H), 2.04-2.10 (m, 2H), 1.18 (t, J = 7.2 Hz, 3H); MS (m z): 372.6 [M+H], 394.5 [M+Na].
Example 36
Ethyl 2-(3-(4-((4'-((4-benzylmorpholin-2-yl)methoxy)-2',6'-dimethyl-[l,l'-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (Compound 36)
Step 1
(4'-((4-Benzylmorpholin-2-yl)methoxy)-2',6'-dimethyl-[l,r-biphenyl]-3-yl)methanol
3'-(hydroxymethyl)-2,6-dimethyl-[l,l'-biphenyl]-4-ol (0.632 g, 2.77 mmol, prepared by following the procedure as described in Reference Example 20, of WO 2008001931) was added to a solution of sodium hydride (0.122 g, 3.04 mmol) in DMF (15 mL). The reaction mixture was stirred for 30 minutes, followed by the addition of (4-benzylmorpholin-2- yl)methyl 4-methyl benzenesulfonate (1 g, 2.77 mmol, prepared by following the procedure as described in Example 7, of GB 1427097). The resulting reaction mixture was further stirred at RT for 30 minutes and refluxed for 3 h at 100 °C. After completion of reaction, aqueous sodium carbonate was added to the reaction mixture. The compound was extracted with ethyl acetate. The solvent was evaporated and the residue was purified by column chromatography (silica gel column, 3 to 4 % MeOH/Chloroform as eluent) to obtain the title compound (0.897 g). Yield: 78 ; JHNMR (CDC13, 300 MHz) : δ 7.28-7.36 (m, 5H), 7.13 (s, 1H), 7.08 (d, / = 6.9 Hz, 1H), 6.68 (s, 2H), 4.74 (s, 2H), 4.13-4.15 (m, 1H), 3.94-4.05 (m, 3H), 3.81 (t, / = 9.9 Hz, 1H), 3,57 (s, 1H), 2.94 (d, / = 11.1 Hz, 1H), 2.73 (d, / = 11.4 Hz, 1H), 2.29 (t, / = 8.7 Hz, 1H), 2.10-2.16 (m, 2H), 2.00 (s, 6H); MS (m/z): 418.5 [M+H].
Step 2
4-Benzyl-2-(((3'-(bromomethyl)-2,6-dimethyl-[ 1 , 1 '-biphenyl] -4-yl)oxy)methyl) morpholine
A solution of phosphorus tribromide (0.014 mL, 0.144 mmol) in DCM (10 mL) was added drop wise to a cold (0°C) solution of (4'-((4-benzylmo holin-2-yl)methoxy)-2',6'- dimethyl-[l,l'-biphenyl]-3-yl)methanol (Compound of step 1, 0.1 g, 0.239 mmol) in DCM (15 mL). The reaction mixture was stirred for 2 h at 0°C. The solvent was evaporated and the title compound obtained was used in step 3 as such.
Step 3
Ethyl-2-(3-(4-((4'-((4-benzylmoφholin-2-yl)methoxy)-2',6'-dimethyl-[l,l'-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetate
Ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 0.054 g, 0.229 mmol) was dissolved in DMF (15 mL) and flame dried CS2CO3 (0.271 g, 0.833 mmol) was added. After about 10 minutes, 4-benzyl-2-(((3'-(bromomethyl)-2,6-dimethyl-[l,l'-biphenyl]- 4-yl)oxy)methyl)morpholine (compound of step 2, 0.1 g, 0.208 mmol) was added slowly at RT. The reaction mixture was stirred overnight. The reaction mixture was filtered and the residue was washed with DMF (15 mL). The filtrate was concentrated and ice-cold water (150 mL) was added to the residue. The compound was extracted with EtOAc. The organic layer was washed with water, brine and dried over Na2S04. The solvent was evaporated and the residue was purified on column chromatography (silica gel column, 15 to 40 % EtOAc/ petroleum ether) to obtain the title compound (0.08 g). Yield : 60.5 %; JH NMR (CDC13, 300 MHz): δ 7.445 (m, 6H), 7.123 (m, 3H), 7.069 (d, J = 8.4, 2H), 6.817 (d, J = 8.4, 2H), 6.681 (s, 2H), 5.156 (s, 2H), 5.009 (d, J = 6, 2H), 4.876 (d, J = 6, 2H), 4.066 (m, 4H), 3.820 (t, J = 11.1, 1H), 3.585 (s, 2H), 3.108 (s, 2H), 2.954 (d, J = 11.1, 1H), 2.755 (d, J = 11.4, 1H), 2.320 (m, 1H), 2.180 (m, 3H), 2.002 (s, 6H), 1.175 (t, J = 6.9, 3H); MS (m/z): 633.6 [M-H].
Example 37
2-(3-(4-((4'-((4-benzylmoφholin-2-yl)methoxy)-2',6'-dimethyl-[l,l'-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetic acid (Compound 37)
The title compound was prepared in an analogous manner as the compound 2 of Example 2. Compound 37 was obtained by hydrolyzing the compound of Example 36. JH NMR (DMSO-d6,300 MHz) : δ 7.26-7.40 (m, 9H), 7.02 (s, 2H), 6.96 (d, J = 7.2 Hz, 2H), 6.67 (s, 2H), 5.18-5.19 (m, 2H), 4.54 (d, J = 5.1 Hz, 4H), 3.93 (s, 2H), 3.84 (m, 2H), 3.59 (m, 1H), 3.51 (s, 3H), 3.33 (s, 2H), 2.84 (d, J = 11.1 Hz, 2H), 2.65 (d, J = 11.1 Hz, 2H), 2.14 (t, J = 9.0 Hz, 2H), 1.99-2.02 (m, 2H), 1.92 (s, 6H); MS (m/z): 606.4 [M-H].
Example 38
Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-phenylethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 38)
Step 1
2-bromo-l-phenylethanone O-methyl oxime
2-Bromo acetophenone (lg, 5.02 mmol) and sodium acetate (493 mg, 6 mmol) was dissolved in glacial acetic acid (10 mL) and the mixture was allowed to stir for 10 minutes. To the resulting solution o-methoxyamine hydrochloride (400 mg, 4.79 mmol) was added and the resulting mixture was heated at 100 °C for 3 h. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate. The organic layer was washed with brine (20 mL) and dried over anhydrous Na2S04. The solvent was evaporated and the residue was purified by flash column chromatography (silica gel column, petroleum ether/ ethyl acetate as eluent) to obtain the title compound (800 mg). Yield:, 70%; JH NMR (CDC13, 300 MHz): δ 7.72-7.73 (m, 2H), 7.42-7.43 (m, 3H), 4.37 (s, 2H), 3.11 (s, 3H).
Step 2
4-(2-(Methoxyimino)-2-phenylethoxy)benzaldehyde
CS2CO3 (570 mg, 1.75 mmol) was added to the solution of 4-hydroxy benzaldehyde (107 mg, 0.876 mmol) in dry DMF (2 mL) at RT and the resulting reaction mixture was stirred for 10 minutes followed by the addition of 2-bromo-l-phenylethanone O-methyl oxime (compound of step 1, 200 mg, 0.876 mmol) in dry DMF (2 mL). The reaction mixture was further allowed to stir at RT. After 2 h the reaction mixture was quenched with water (5 mL) and allowed to stir for 10 minutes followed by extraction with EtOAc. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SC¼ and concentrated and the residue was purified by flash column chromatography to obtain the title compound (150 mg). Yield: 63.5 ; JH NMR (CDC13, 300 MHz): δ 9.89 (s, 1H), 7.82 (d, / = 8.4 Hz, 2H), 7.65- 7.68 (m, 2H), 7.36-7.38 (m, 3H), 7.01 (d, / = 8.4 Hz, 2H), 5.31 (s, 2H), 4.10 (s, 3H); MS: (m/z) 270.0 [M+H].
Step 3
2-(4-(Hydroxymethyl)phenoxy)-l-phenylethanone O-methyl oxime
Sodium borohydride (10 mg, 0.26 mmol) was added to a solution of 4-(2- (methoxyimino)-2-phenylethoxy)benzaldehyde (compound of step 2, 140 mg, 0.52 mmol) in dry MeOH (2 mL) at 0 °C under nitrogen and the resulting solution was stirred at RT for 1 h. After completion of reaction, the reaction mixture was quenched with ice-cold water (2 mL) and extracted with ethyl acetate. The organic layer was washed with brine (20 mL), dried over anhydrous Na2S04, concentrated and the residue was purified by flash column chromatography to obtain the title compound. Yield: 92 %; JH NMR (CDCI3, 300 MHz): δ 7.67-7.68 (m, 2H), 7.36-7.38 (m, 3H), 7.26-7.29 (m, 2H), 6.91 (d, / = 8.1 Hz, 2H), 5.21 (s, 2H), 4.62 (s, 2H), 4.07 (s, 3H). MS (m/z): 272.0 [M+H].
Step 4
2-(4-(bromomethyl)phenoxy)-l-phenylethanone O-methyl oxime
To a stirred solution of 2-(4-(hydroxymethyl)phenoxy)-l-phenylethanone O-methyl oxime (compound of step 3, 300 mg, 1.1 mmol) in dry DCM (10 mL) was cooled to 0 °C and PBr3 (140 mg, 0.52 mmol) in DCM (2 mL) and the resulting solution was stirred at 0 °C for 2 h. Reaction mixture was extracted with DCM washed with water (20 mL), saturated sodium bicarbonate solution (20 mL) and brine (20 mL), dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography to obtain the title compound (189 mg). Yield: 51 ; JH NMR (CDC13, 300 MHz): δ 7.66-7.68 (m, 2H), 7.36- 7.38 (m, 2H), 7.30-7.32 (m, 3H), 6.91 (d, / = 8.4 Hz, 2H), 5.21 (s, 2H), 4.49 (s, 2H), 4.07 (s, 3H); MS: (m/z) 351.0 [M+NH4]. Step 5
Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-phenylethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetate To a solution of ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 127 mg, 0.538 mmol) in dry DMF (2 mL) was added Cs2C03 (351 mg, 1.07 mmol) at RT and stirred for 10 minutes followed by the addition of 2-(4-(bromomethyl) phenoxy)-l- phenylethanone O-methyl oxime (Compound of step 4, 180 mg, 0.538 mmol) in dry DMF (2 mL). The reaction mixture was allowed to stir at RT for 2 h. After completion of the reaction, the reaction mixture was quenched with water (5 mL) and allowed to stir for 10 minutes then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2S04, concentrated and purified by flash column chromatography to obtain title compound (191 mg). Yield: 72 ; JH NMR (CDC13, 300 MHz): δ 7.64-7.69 (m, 2H), 7.32-7.37 (m, 5H), 7.1 (d, / = 8.4 Hz, 2H), 6.92-6.95 (m, 4H), 5.22 (s, 2H), 4.97-5.01 (m, 4H), 4.87 (d, / = 6.0 Hz, 2H) 4.07 (s, 3H), 3.98 (q, / = 6.9 Hz, 2H), 3.11 (s, 2H), 1.13 (t, / = 7.2 Hz, 3H); MS: (m/z) 490.0 [M+H] and 512.0 [M+ Na].
Example 39
2-(3-(4-((4-(2-(methoxyimino)-2-phenylethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 39)
To a stirred solution of ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-phenylethoxy) benzyl)oxy)phenyl)oxetan-3-yl)acetate (compound of step 5, 86 mg, 0.175 mmol) in THF (1 mL) and MeOH (2 mL) was added LiOH (0.878 mmol) in water (1 mL) at RT. The resulting solution was stirred at RT for 2 h. After completion of the reaction, solvent was removed and residue was acidified with saturated NH4C1 solution then extracted with ethyl acetate, dried over anhydrous Na2S04 and evaporated to dryness to obtain the title compound (60 mg). Yield: 74%; JH NMR (CDC13, 300 MHz): δ 7.64-7.69 (m, 2H), 7.29-7.37 (m, 5H), 7.1 (d, / = 8.4 Hz, 2H), 6.90-6.95 (m, 4H), 5.20 (s, 2H), 4.92-4.95 (m, 4H), 4.83 (d, / = 5.4 Hz, 2H), 4.61 (br s, 1H), 4.06 (s, 3H), 3.05 (s, 2H); MS: (m/z) 462.2 [M+H] and 484.2 [M+ Na].
Example 40
Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-(4-methoxyphenyl)ethoxy)benzyl)oxy) phenyl)oxetan-3-yl)acetate (Compound 40)
Step 1
2-bromo-l-(4-methoxyphenyl)ethanone O-methyl oxime 2-Bromo-l-(4-methoxyphenyl)ethanone (1 equivalent) and sodium acetate (1.2 equivalent) were dissolved in glacial acetic acid (10 to 15 mL) and the mixture was allowed to stir for 10 minutes. To the resulting solution o-methoxylamine hydrochloride (0.96 equivalents) was added and the resulting mixture was heated at 100 °C for 3 to 4 h. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2S04, concentrated and the residue was purified by flash column chromatography (silica gel column, ethyl acetate/petroleum ether) to obtain the title compound. JH NMR (CDCI3, 300 MHz): δ 7.67 (d, / = 8.7 Hz, 2H), 6.93 (d, / = 8.4 Hz, 2H), 4.35 (s, 2H), 4.08 (s, 3H), 3.85 (s, 3H); MS: (m/z) 259.9 [M+2H].
Step 2
2-(4-(hydroxymethyl)phenoxy)- 1 -(4-methoxyphenyl)ethanone O-methyl oxime
To a stirred solution of 4-hydroxy-benzyl alcohol (1 equivalent) in acetonitrile (30 mL) was added potassium carbonate (1.5 equivalent) and the resulting mixture was stirred at RT for 10 minutes. To the stirred reaction mixture, 2-bromo-l-(4-methoxyphenyl)ethanone O-methyl oxime (compound of step 1 , 1 equivalent) was added and the reaction mixture was heated at 80 to 100 °C for 4 to 5 h. After completion of the reaction, the reaction mixture was filtered, the solvent was evaporated and the residue was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2S04, concentrated and the residue was purified by flash column chromatography (silica gel column, ethyl acetate/ petroleum ether as eluent) to obtain the title compound. JH NMR (CDCI3, 300 MHz): δ 7.63 (d, / = 8.4 Hz, 2H), 7.26-7.28 (m, 2H), 6.87-6.97 (m, 4H), 5.19 (s, 2H), 4.62 (s, 2H), 4.05 (s, 3H), 3.82 (s, 3H); MS (m/z): 302.1 [M+H].
Step 3
Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-(4-methoxyphenyl)ethoxy)benzyl)oxy) phenyl)oxetan-3-yl)acetate
To a stirred solution of 2-(4-(hydroxymethyl)phenoxy)-l-(4-methoxy phenyl)ethanone O- methyl oxime (compound of step 2, 1 equivalent) in dry THF was added ethyl 2-(3-(4- hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 1 equivalent) and the resulting solution was cooled at 0 °C under nitrogen atmosphere. Triphenylphosphene (1.5 equivalent) was added and the reaction mixture was stirred for 15 minutes, followed by the addition of diethylazadicarboxylate (1.5 equivalent). The reaction mixture was warmed to RT and stirred for 10 to 12 h. After completion of reaction, the solvent was removed and the residue was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated. The residue was purified by flash column chromatography (petroleum ether/ethyl acetate) to obtain the title compound. JH NMR (CDCI3, 300 MHz): δ 7.64 (d, / = 9.0 Hz, 2H), 7.33 (d, / = 8.1 Hz, 2H), 7.10 (d, / = 8.4 Hz, 2H), 6.87-6.95 (m, 6H), 5.19 (s, 2H), 4.97-5.00 (m, 4H), 4.86 (d, / = 6.0 Hz, 2H) 4.05 (s, 3H), 4.01 (q, / = 6.9 Hz, 2H), 3.83 (s, 3H), 3.10 (s, 2H), 1.13 (t, / = 7.2 Hz, 3H); MS: (m/z) 520.0 [M+H] and 541.9 [M+ Na].
Example 41
2- (3-(4-((4-(2-(methoxyimino)-2-(4-methoxyphenyl)ethoxy)benzyl)oxy)phenyl) oxetan-3- yl)acetic acid (Compound 41)
LiOH (5 equivalent) in water (2-3 mL) was added to a solution of ethyl 2-(3-(4-((4-(2- (methoxyimino)-2-(4-methoxyphenyl)ethoxy)benzyl)oxy)phenyl) oxetan-3-yl)acetate (Compound 40, 1 equivalent) in MeOH and THF (1 :4) at RT. The resulting solution was stirred at RT for 2 to 3 h. After completion of the reaction, solvent was removed under reduced pressure and acidified with saturated NH4CI solution then extracted with ethyl acetate. The organic layer was washed with brine (20 mL), dried over anhydrous Na2S04 and evaporated to dryness to obtain the title compound. JH NMR (CDCI3, 300 MHz): δ 7.63 (d, / = 8.4 Hz, 2H), 7.31 (d, / = 8.4 Hz, 2H), 7.10-7.13 (m, 2H), 6.86-6.94 (m, 6H), 5.18 (s, 2H), 4.97-5.00 (m, 4H), 4.85 (br s, 2H) 4.04 (s, 3H), 3.82 (s, 3H), 3.14 (s, 2H); MS: (m/z) 491.9 [M+H] and 513.9 [M+ Na].
Example 42
Ethyl 2-(3-(4-((4-(2-(4-chlorophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy) phenyl) oxetan-
3 - yl) acetate (Compound 42)
The title compound was prepared in an analogous manner as Compound 40 of Example 40 involving reaction of 2-bromo-l-(4-chlorophenyl)ethanone with o- methoxyamine hydrochloride. JH NMR (CDC13, 300 MHz): δ 7.63 (d, / = 8.4 Hz, 2H), 7.33 (d, / = 8.1 Hz, 4H), 7.10 (d, / = 8.4 Hz, 2H), 6.90-6.95 (m, 4H), 5.20 (s, 2H), 4.97-5.00 (m, 4H), 4.86 (d, / = 6.0 Hz, 2H) 4.07 (s, 3H), 4.01 (q, / = 6.9 Hz, 2H), 3.11 (s, 2H), 1.14 (t, / = 7.2 Hz, 3H); MS (m/z): 523.9 [M+H] and 545.9 [M+ Na]. Example 43
2-(3-(4-((4-(2-(4-chlorophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy)phenyl) oxetan-3- yl)acetic acid (Compound 43)
The title compound was prepared in an analogous manner as compound 41 of Example 41. Compound 43 was obtained by hydrolyzing the compound of Example 42. JH NMR (CDCI3, 300 MHz): δ 7.62 (d, / = 8.4 Hz, 2H), 7.32 (d, / = 8.4 Hz, 4H), 7.11 (d, / = 8.4 Hz, 2H), 6.92 (t, / = 8.4 Hz, 4H), 5.19 (s, 2H), 4.96-5.00 (m, 4H), 4.84 (d, / = 6.0 Hz, 2H) 4.07 (s, 3H), 3.15 (s, 2H); MS (m/z): 495.9 [M+H] and 517.9 [M+ Na].
Example 44
Ethyl 2-(3-(4-((4-(2-(4-cyanophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy) phenyl)oxetan-3- yl)acetate (Compound 44)
The title compound was prepared in an analogous manner as Compound 40 of Example 40 involving reaction of 4-(2-bromoacetyl)benzonitrile with o-methoxyamine hydrochloride. JH NMR (CDC13, 300 MHz): δ 7.81 (d, / = 8.1 Hz, 2H), 7.33 (d, / = 7.8 Hz, 2H), 7.34 (d, / = 8.1 Hz, 2H), 7.1 (d, / = 8.1 Hz, 2H), 6.92 (t, / = 9.0 Hz, 4H), 5.22 (s, 2H), 4.97-5.00 (m, 4H), 4.86 (d, / = 5.7 Hz, 2H) 4.11 (s, 3H), 4.01 (q, / = 6.9 Hz, 2H), 3.11 (s, 2H), 1.14 (t, / = 7.2 Hz, 3H); MS (m/z): 515.1 [M+H] and 537.0 [M+ Na].
Example 45
2-(3-(4-((4-(2-(4-cyanophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy)phenyl) oxetan-3- yl)acetic acid (Compound 45)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 45 was obtained by hydrolyzing the compound of Example 44. JH NMR (CDCI3, 300 MHz): δ 7.80 (d, / = 8.1 Hz, 2H), 7.64 (d, / = 8.1 Hz, 2H), 7.33 (d, / = 8.1 Hz, 2H), 7.12 (d, J = 8.1 Hz, 2H), 6.88-6.85 (m, 4H), 5.32 (s, 2H), 4.96-4.99 (m, 4H), 4.85 (d, / = 5.7 Hz, 2H) 4.10 (s, 3H), 3.15 (s, 2H), 2.90 (br s, 1H); MS (m/z): 487.1 [M+H] and 509.1 [M+ Na].
Example 46
Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-(p-tolyl)ethoxy)benzyl)oxy)phenyl) oxetan-3- yl)acetate (Compound 46)
The title compound was prepared in an analogous manner as the Compound 40 of Example 40 involving reaction of 2-bromo-l-(p-tolyl)ethanone with o-methoxyamine hydrochloride. H NMR (CDCI3, 300 MHz): δ 7.49-7.54 (m, 2H), 7.32 (d, / = 7.8 Hz, 2H), 7.13-7.23 (m, 3H), 6.89-7.00 (m, 4H), 6.69 (d, / = 8.4 Hz, 1H), 5.19 (s, 2H), 4.90-4.97 (m, 2H), 4.73-4.74 (m, 4H), 3.97 (s, 3H), 3.88 (q, / = 6.0 Hz, 2H), 3.03-3.07 (m, 2H), 2.30 (s, 3H), 1.02 (t, / = 6 Hz, 3H); MS (m/z): 502.9 [M]+.
Example 47
2-(3-(4-((4-(2-(methoxyimino)-2-(p-tolyl)ethoxy)benzyl)oxy)phenyl)oxetan-3-yl) acetic acid (Compound 47)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 47 was obtained by hydrolyzing the compound of Example 46. JH NMR (CDCI3, 300 MHz): δ 7.51-7.56 (m, 2H), 7.32 (d, / = 9.0 Hz, 2H), 7.10-7.23 (m, 4H), 6.93 (d, / = 8.4 Hz, 4H), 5.19 (s, 2H), 4.95-5.00 (m, 4H), 4.83 (d, / = 6.0 Hz, 2H) 4.05 (s, 3H), 3.16 (s, 2H), 2.36 (s, 3H); MS (m/z): 476.0 [M+H] and 498.0 [M+ Na].
Example 48
Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-(4-(trifluoromethoxy)phenyl)ethoxy) benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 48)
The title compound was prepared in an analogous manner as the Compound 40 of Example 40 involving reaction of 2-bromo-l-(4-(trifluoromethoxy) phenyl)ethanone with o- methoxyamine hydrochloride. JH NMR (CDCI3, 300 MHz): δ 7.73 (d, / = 8.4 Hz, 2H), 7.34 (d, / = 8.1 Hz, 2H), 7.20 (d, / = 8.4 Hz, 2H), 7.10 (d, / = 8.1 Hz, 2H), 6.92-6.95 (m, 4H), 5.21 (s, 2H), 4.97-5.00 (m, 4H), 4.86 (d, / = 5.7 Hz, 2H) 4.08 (s, 3H), 4.01 (q, / = 7.2 Hz, 2H), 3.11 (s, 2H), 1.14 (t, / = 7.2 Hz, 3H); MS (m/z): 573.9 [M+H] and 595.9 [M+ Na].
Example 49
2-(3-(4-((4-(2-(methoxyimino)-2-(4-(trifluoromethoxy)phenyl)ethoxy)benzyl)
oxy)phenyl)oxetan-3-yl)acetic acid (Compound 49)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 49 was obtained by hydrolyzing the compound of Example 48. JH NMR (CDCI3, 300 MHz): δ 7.72 (d, / = 8.4 Hz, 2H), 7.33 (d, / = 8.1 Hz, 2H), 7.20 (d, / = 8.4 Hz, 2H), 7.13 (d, / = 8.4 Hz, 2H), 6.90-6.95 (m, 4H), 5.20 (s, 2H), 4.96-5.00 (m, 4H), 4.84 (d, / = 5.7 Hz, 2H), 4.07 (s, 3H), 3.16 (s, 2H); MS (m/z): 545.8 [M+H] and 567.8 [M+ Na]. Example 50
Ethyl 2-(3-(4-((4-(2-([l,l'-biphenyl]-4-yl)-2-(methoxyimino)ethoxy)benzyl)oxy) phenyl)oxetan-3-yl)acetate (Compound 50)
The title compound was prepared in an analogous manner as the Compound 40 of Example 40 involving reaction of l-([l,l'-biphenyl]-4-yl)-2-bromoethanone with o- methoxyamine hydrochloride. JH NMR (CDCI3, 300 MHz): δ 7.77 (d, / = 8.1 Hz, 2H), 7.59- 7.61 (m, 4H), 7.46 (t, / = 7.2 Hz, 2H), 7.34-7.39 (m, 3H), 7.10 (d, J = 8.4 Hz, 2H), 6.93-6.98 (m, 4H), 5.25 (s, 2H), 4.98-5.01 (m, 4H), 4.86 (d, / = 5.7 Hz, 2H) 4.09 (s, 3H), 4.01 (q, / = 6.9 Hz, 2H), 3.11 (s, 2H), 1.14 (t, / = 6.9 Hz, 3H); LCMS (m/z): 566.1 [M+H] and 588.9 [M+ Na].
Example 51
2- (3-(4-((4-(2-([l,l'-Biphenyl]-4-yl)-2-(methoxyimino)ethoxy)benzyl)oxy) phenyl)oxetan-3- yl)acetic acid (Compound 51)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 51 was obtained by hydrolyzing the compound of Example 50. JH NMR (CDCI3, 300 MHz): δ 7.77 (d, / = 8.1 Hz, 2H), 7.59-7.61 (m, 4H), 7.46 (t, / = 7.5 Hz, 2H), 7.33-7.39 (m, 3H), 7.12 (d, / = 8.1 Hz, 2H), 6.93-6.98 (m, 4H), 5.25 (s, 2H), 4.97-5.01 (m, 4H), 4.85 (d, / = 5.7 Hz, 2H) 4.09 (s, 3H), 3.16 (s, 2H); MS (m/z): 537.9 [M+H] and 559.9 [M+ Na].
Example 52
Ethyl 2-(3-(4-((4-(2-(4-fluorophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy) phenyl) oxetan-
3- yl)acetate (Compound 52)
The title compound was prepared in an analogous manner as the Compound 40 of Example 40 involving reaction of 2-bromo-l-(4-fluorophenyl)ethanone with o- methoxyamine hydrochloride. JH NMR (CDC13, 300 MHz): δ 7.65-7.67 (m, 2H), 7.33 (d, / = 8.1 Hz, 2H), 7.01-7.11 (m, 4H), 6.90-6.95 (m, 4H), 5.31 (s, 2H), 4.97-5.00 (m, 4H), 4.86 (d, / = 5.7 Hz, 2H) 4.15 (s, 3H), 4.01 (q, / = 7.2 Hz, 2H), 3.10 (s, 2H), 1.13 (t, / = 6.9 Hz, 3H); MS (m/z): 507.9 [M+H] and 529.9 [M+ Na].
Example 53
2-(3-(4-((4-(2-(4-Fluorophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy)phenyl) oxetan-3- yl)acetic acid (Compound 53) The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 53 was obtained by hydrolyzing the compound of Example 52.1H NMR (CDCI3, 300 MHz): δ 7.64-7.66 (m, 2H), 7.32 (d, / = 8.1 Hz, 2H), 7.01-7.13 (m, 4H), 6.93 (t, / = 8.1 Hz, 4H), 5.20 (s, 2H), 4.95-4.99 (m, 4H), 4.84 (d, / = 5.7 Hz, 2H), 4.06 (s, 3H), 3.15 (s, 2H); MS (m/z): 477.7 [M+H] and 501.9 [M+ Na].
Example 54
Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-(3-methoxyphenyl)ethoxy) benzyl)oxy) phenyl)oxetan-3-yl)acetate (Compound 54)
The title compound was prepared in an analogous manner as the Compound 40 of Example 40 involving reaction of 2-bromo-l-(3-methoxyphenyl)ethanone with o- methoxyamine hydrochloride. JH NMR (CDC13, 300 MHz): δ 7.33 (d, / = 8.4 Hz, 2H), 7.26- 7.28 (m, 3H), 7.04-7.11 (m, 3H), 6.92-6.95 (m, 4H), 5.19 (s, 2H), 4.97-5.05 (m, 4H), 4.86 (d, / = 6.0 Hz, 2H), 4.07 (s, 3H), 4.01 (q, / = 7.2 Hz, 2H), 3.82 (s, 3H), 3.10 (s, 2H), 1.13 (t, / = 7.2 Hz, 3H); MS (m/z): 520.0 [M+H] and 541.9 [M+ Na].
Example 55
2-(3-(4-((4-(2-(Methoxyimino)-2-(3-methoxyphenyl)ethoxy)benzyl)oxy)phenyl) oxetan-3- yl)acetic acid (Compound 55)
The title compound was prepared in an analogous manner as the compound
41 of Example 41. Compound 55 was obtained by hydrolyzing the compound of Example 54. JH NMR (CDCI3, 300 MHz): δ 7.27-7.33 (m, 6H), 7.01-7.09 (m, 2H), 6.92 (d, / = 7.8 Hz, 4H), 5.18 (s, 2H), 4.94-5.00 (m, 4H), 4.85 (brs, 2H), 4.06 (s, 3H), 3.81 (s, 3H), 3.11 (s, 2H); MS (m/z): 492.0 [M+H] and 513.9 [M+ Na].
Example 56
Ethyl 2-(3-(4-(2-(methoxyimino)-2-phenylethoxy)phenyl)oxetan-3-yl)acetate (Compound 56) To a solution of ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 104 mg, 0.44 mmol) in dry DMF (2 mL) was added Cs2C03 (287 mg, 0.88 mmol) at RT and the solution was stirred for 10 minutes followed by the addition of 2-bromo-l-phenylethanone O- methyl oxime (Compound of step 1 of Example 38, 228 mg, 0.44 mmol) in dry DMF (2 mL). The reaction mixture was allowed to stir at RT for 2 h. Reaction was quenched with addition of water (5 mL) and allowed to stir for 10 minutes then extracted with ethyl acetate. The organic layer was washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain the title compound. Yield: 62 ; JH NMR (CDCI3, 300 MHz): δ 7.64-7.69 (m, 2H), 7.32- 7.37 (m, 3H), 7.1 (d, / = 8.4 Hz, 2H), 6.90 (d, / = 8.7 Hz, 2H), 5.19 (s, 2H), 4.92 (dd, / = 6.0 Hz, 39 Hz, 4H), 4.07 (s, 3H), 3.98 (q, / = 6.9 Hz, 2H), 3.09 (s, 2H), 1.12 (t, / = 7.2 Hz, 3H); MS: (m/z) 384.0 [M+H] and 406.0 [M+ Na].
Example 57
2-(3-(4-(2-(methoxyimino)-2-phenylethoxy)phenyl)oxetan-3-yl)acetic acid (Compound 57)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 57 was obtained by hydrolyzing the compound of Example 56. JH NMR (CDCI3, 300 MHz): δ 7.64-7.69 (m, 2H), 7.32-7.37 (m, 3H), 7.1 (d, / = 8.4 Hz, 2H), 6.90 (d, / = 8.4 Hz, 2H), 5.18 (s, 2H), 4.90 (dd, / = 6.0 Hz, 24 Hz, 4H), 4.06 (s, 3H), 3.14 (s, 2H); MS (m/z): 356.0 [M+H] and 377.9 [M+ Na].
Example 58
Ethyl 2-(3-(4-((3-benzoylbenzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 58)
Step 1
(3-(Bromomethyl)phenyl)(phenyl)methanone
The procedure was followed as described under the title Intermediate 1 of Example 1 of the PCT publication WO2012/011125.
Step 2
Ethyl 2-(3-(4-((3-benzoylbenzyl)oxy)phenyl)oxetan-3-yl)acetate
To a solution of ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 170 mg, 0.72 mmol) in dry DMF (3 mL) was added Cs2C03 (473 mg, 1.45 mmol) at RT and the reaction mixture was stirred for 10 minutes followed by the addition of (3- (bromomethyl)phenyl)(phenyl)methanone (Compound of step 1, 200 mg, 0.72 mmol) in dry DMF (2 mL). The reaction mixture was allowed to stir at RT for 2 h. After completion of the reaction, the reaction mixture was quenched with water (5 mL) and allowed to stir for 10 minutes and then extracted with ethyl acetate. The organic layer was washed with brine (20 mL), dried over anhydrous Na2S04) and concentrated under reduced pressure. The residue was purified by flash column chromatography to obtain the title compound (87 mg). Yield: 27.8 ; JH NMR (CDC13, 300 MHz): δ 7.50-7.89 (m, 8H), 6.79-7.13 (m, 5H), 5.13 (s, 2H), 4.99 (d, / = 5.7 Hz, 2H), 4.86 (d, / = 5.7 Hz, 2H), 4.00 (q, / = 6.9 Hz, 2H), 3.11 (s, 2H), 1.13 (t, / = 6.9 Hz, 3H); MS: (m/z) 431.1 [M+H] and 453.1 [M+ Na].
Example 59
2-(3-(4-((3-benzoylbenzyl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 59)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 59 was obtained by hydrolyzing the compound of Example 58. JH NMR (CDC13, 300 MHz): δ 7.88 (s, 1H), 7.47-7.82 (m, 8H), 6.94-7.15 (m, 4H), 5.12 (s, 2H), 4.99 (d, / = 6.0 Hz, 2H), 4.84 (d, / = 5.7 Hz, 2H), 3.16 (s, 2H); MS (m/z): 403.0 [M+H] and 425.0 [M+ Na].
Example 60
Ethyl 2-(3-(4-((3-((methoxyimino)(phenyl)methyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 60)
To a stirred solution of ethyl 2-(3-(4-((3-benzoylbenzyl)oxy)phenyl)oxetan-3- yl)acetate (Compound 58, 40 mg, 0.093 mmol) in ethanol (2 mL) and pyridine (1 mL) was added methoxyamine hydrochloride (39 mg, 0.46 mmol) at RT under nitrogen. The resulting mixture was refluxed at 80-90 °C for 6 h. The reaction mixture was concentrated under reduce pressure, extracted with ethyl acetate, washed with IN HCl and water (20 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography to the title compound (53 mg). Yield: 71%; JH NMR (CDCI3, 300 MHz): δ JH NMR (CDC13, 300 MHz): δ 7.36-7.59 (m, 8H), 6.79-7.11 (m, 5H), 5.08 (s, 2H), 4.99 (d, / = 5.7 Hz, 2H), 4.86 (d, / = 5.7 Hz, 2H), 3.99-4.03 (m, 5H), 3.10 (s, 2H), 1.13 (t, / = 6.6 Hz, 3H); MS: (m/z) 460.0 [M+H] and 482.0 [M+ Na].
Example 61
2-(3-(4-((3-((Methoxyimino)(phenyl)methyl)benzyl)oxy)phenyl)oxetan-3-yl) acetic acid (Compound 61)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 61 was obtained by hydrolyzing the compound of Example 60. JH NMR (CDCI3, 300 MHz): δ JH NMR (CDCI3, 300 MHz): δ 7.58 (s, 1H), 7.35-7.47 (m, 8H), 6.94-7.13 (m, 4H), 5.08 (s, 2H), 4.98 (d, / = 6.0 Hz, 2H), 4.84 (d, / = 5.7 Hz, 2H), 3.99 (s, 3H), 3.15 (s, 2H); MS (m/z): 432.0 [M+H] and 453.9 [M+ Na].
Example 62
Ethyl 2-(3-(4-((4-benzoylbenzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 62) Step 1
(4-(Bromomethyl)phenyl)(phenyl)methanone
The procedure was followed as described in J. Med. Chem 2007, 50, 6104-6115.
Step 2
Ethyl 2-(3-(4-((4-benzoylbenzyl)oxy)phenyl)oxetan-3-yl)acetate
To a solution of ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 100 mg, 0.42 mmol) in dry DMF (5 mL) was added Cs2C03 (276 mg, 0.84 mmol) at RT and the reaction mixture was stirred for 10 minutes followed by the addition of (4- (bromomethyl)phenyl)(phenyl)methanone (compound of step 1, 116.6 mg, 0.42 mmol) in dry DMF (2 mL). The reaction mixture was allowed to stir at RT for 1 h. Reaction was quenched by addition of water (5 mL) and allowed to stir for 10 minutes followed by extraction with ethyl acetate. The organic layer was washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel column, 40% ethyl acetate/petroleum ether as eluent) to obtain title compound (60 mg). Yield: 43%; JH NMR (CDC13, 300 MHz): δ 7.81-7.86 (m, 4H), 7.48-7.61 (m, 5H), 6.95-7.14 (m, 4H), 5.16 (s, 2H), 4.99 (d, / = 5.7 Hz, 2H), 4.86 (d, / = 5.7 Hz, 2H), 4.01 (q, / = 6.9 Hz, 2H), 3.11 (s, 2H), 1.14 (t, / = 7.2 Hz, 3H); MS (m/z): 431.0 [M+H] and 452.9 [M+ Na].
Example 63
2-(3-(4-((4-Benzoylbenzyl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 63)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 63 was obtained by hydrolyzing the compound of Example 62. JH NMR (CDCI3, 300 MHz): δ 7.81-7.86 (m, 4H), 7.50-7.61 (m, 5H), 6.96-7.17 (m, 4H), 5.16 (s, 2H), 4.99 (d, / = 5.7 Hz, 2H), 4.86 (d, / = 5.7 Hz, 2H), 3.18 (s, 2H); MS: (m/z) 403.0 [M+H] and 425.0 [M+ Na].
Example 64
Ethyl 2-(3-(4-((4-((methoxyimino)(phenyl)methyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 64)
To a stirred solution of ethyl 2-(3-(4-((4-benzoylbenzyl)oxy)phenyl)oxetan-3- yl)acetate (Compound 62, 50 mg, 0.116 mmol) in ethanol (2 mL) and pyridine (0.3 mL), was added methoxyamine hydrochloride (48.5 mg, 0.58 mmol) at RT under nitrogen. The resulting mixture was refluxed at 80-90 °C for 12 h. The reaction mixture was concentrated under reduce pressure, extracted with ethyl acetate, washed with IN HC1 and water (20 mL), dried over Na2S04 and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel column, 10% ethyl acetate/petroleum ether as eluent) to obtain the title compound (40 mg). Yield: 74.9 %; JH NMR (CDC13, 300 MHz): δ 7.29-7.50 (m, 9H), 6.92-7.12 (m, 4H), 5.10 (d, J = 9.3 Hz, 2H), 4.86-5.00 (m, 4H), 3.00-4.05 (m, 5H), 3.20 (brs, 2H), 1.13 (t, / = 7.2 Hz, 3H); MS (m/z): 460.0 [M+H] and 481.9 [M+ Na].
Example 65
2-(3-(4-((4-((Methoxyimino)(phenyl)methyl)benzyl)oxy)phenyl)oxetan-3-yl) acetic acid (Compound 65)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 65 was obtained by hydrolyzing the compound of Example 64. JH NMR (CDCI3, 300 MHz): δ JH NMR (CDC13, 300 MHz): δ 7.29-7.49 (m, 9H), 6.92-7.17 (m, 4H), 5.10 (d, / = 8.7 Hz, 2H), 4.86-5.00 (m, 4H), 3.99 (s, 3H), 3.18 (brs, 2H); MS (m z): 432.0 [M+H] and 453.9 [M+ Na].
Example 66
Ethyl 2-(3-(4-((4-(2-oxo-2-phenylethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound
66)
Step 1
2-(4-(Hydroxymethyl)phenoxy)- 1 -phenylethanone
To a stirred solution of 2-bromoacetophenone (1 g, 5.02 mmol) in acetonitrile (30 mL) was added potassium carbonate (1.04 g, 7.53 mmol) and 4-hydroxy-benzyl alcohol (623 mg, 5.02 mmol) and the resulting mixture was stirred at RT for 10 minutes. The reaction mixture was refluxed at 80-100 °C for 1.5 h. After completion of reaction, the reaction mixture was filtered and the solvent was removed under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over anhydrous Na2S04. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (petroleum ether/ ethyl acetate) to obtain the title compound (1.13 g). Yield: 92.6%; JH NMR (CDC13, 300 MHz): δ 8.00 (d, / = 7.5 Hz, 2H), 7.49-7.66 (m, 3H), 7.30 (d, / = 8.4 Hz, 2H), 6.94 (d, / = 8.4 Hz, 2H), 5.30 (s, 2H), 4.63 (d, / = 3.9 Hz, 2H); MS (m/z): 265.0 [M+Na] . Step 2
Ethyl 2-(3-(4-((4-(2-oxo-2-phenylethoxy)benzyl)oxy)phenyl)oxetan-3-yl) acetate A solution of 2-(4-(hydroxymethyl)phenoxy)-l-phenylethanone (Compound of step 1, 300 mg, 1.23 mmol) and ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl) acetate (Intermediate 1, 292 mg, 1.23 mmol) in dry THF (5 mL) was cooled to 0 °C and PPI13 (1.84 mmol) was added. The reaction mixture was stirred for 15 minutes followed by the addition of DEAD (0.28 mL, 1.84 mmol). The resulting mixture was stirred overnight at RT. The solvent was removed under reduced pressure. Water (5 mL) was added and extracted with EtOAc. The organic layer was dried over Na2S04. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (petroleum ether/ ethyl acetate) to obtain the title compound (500 mg). Yield: 68.4%; JH NMR (CDC13, 300 MHz): δ 8.00 (d, / = 7.5 Hz, 2H), 7.35-7.64 (m, 5H), 6.92-7.11 (m, 6H), 5.31 (s, 2H), 4.96-4.98 (m, 4H), 4.85 (d, / = 5.7 Hz, 2H), 4.00 (q, / = 7.2 Hz, 2H), 3.10 (s, 2H), 1.16 (t, / = 7.2 Hz, 3H); MS (m/z): 461.2 [M+H] and 483.1 [M+ Na].
Example 67
2-(3-(4-((4-(2-Oxo-2-phenylethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 67)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 67 was obtained by hydrolyzing the compound of Example 66. JH NMR (CDCI3, 300 MHz): δ 8.00 (d, / = 7.5 Hz, 2H), 7.34-7.64 (m, 5H), 6.92-7.13 (m, 6H), 6.46 (brs, 1H), 5.30 (s, 2H), 4.97-4.99 (m, 4H), 4.84 (d, / = 5.7 Hz, 2H), 3.10 (s, 2H); MS (m/z): 433.0 [M+H] and 455.0 [M+ Na].
Example 68
Ethyl 2-(3-(4-((4-(2-(4-methoxyphenyl)-2-oxoethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 68)
The title compound was prepared in an analogous manner as Compound 66 of Example 66 involving reaction of 2-bromo-l-(4-methoxyphenyl)ethanone with 4-hydroxy- benzyl alcohol. JH NMR (CDC13, 300 MHz): δ 8.00 (d, / = 9.0 Hz, 2H), 7.34 (d, / = 9.0 Hz, 2H), 7.08 (d, / = 9.0 Hz, 2H), 6.92-6.99 (m, 6H), 5.24 (s, 2H), 4.98-5.00 (m, 4H), 4.84 (d, / = 6.0 Hz, 2H), 3.98- 4.05 (m, 2H), 3.90 (s, 3H), 3.10 (s, 2H), 1.11-1.16 (m, 3H); MS (m/z): 488.7 [M-H]. Example 69
2-(3-(4-((4-(2-(4-methoxyphenyl)-2-oxoethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 69)
The title compound was prepared in an analogous manner as compound 41 of Example 41. Compound 69 was obtained by hydrolyzing the compound of Example 68. JH NMR (CDCI3, 300 MHz): δ 8.02 (d, / = 8.7 Hz, 2H), 7.33 (d, / = 8.1Hz, 2H), 6.91-7.12 (m, 8H), 5.23 (s, 2H), 4.96-4.99 (m, 4H), 4.83 (d, / = 6.0 Hz, 2H), 3.90 (s, 3H), 3.14 (s, 2H); MS (m/z): 461.2 [M-H].
Example 70
Ethyl 2-(3-(4-((4-(2-(4-fluorophenyl)-2-oxoethoxy)benzyl)oxy)phenyl)oxetan-3-yl) acetate (Compound 70)
The title compound was prepared in an analogous manner as Compound 66 of Example 66 involving reaction of 2-bromo-l-(4-fluorophenyl)ethanone with 4-hydroxy- benzyl alcohol. JH NMR (CDC13, 300 MHz): δ 8.04 - 8.09 (m, 2H), 7.35 (d, / =9.0 Hz, 2H), 7.16 - 7.22 (m, 2H), 7.09 (d, / = 9.0 Hz, 2H), 6.92-6.97 (m, 4H), 5.24 (s, 2H), 4.98-5.00 (m, 4H), 4.84 (d, / = 6.0 Hz, 2H), 3.98- 4.05 (m, 2H), 3.10 (s, 2H), 1.14 (t, / = 6.0, 6.0 Hz, 3H); MS (m/z): 501.2 [M+Na].
Example 71
2-(3-(4-((4-(2-(4-fluorophenyl)-2-oxoethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 71)
The title compound was prepared in an analogous manner as compound 41 of Example 41. Compound 71 was obtained by hydrolyzing the compound of Example 70. JH NMR (CDCI3, 300 MHz): δ 8.05- 8.07 (m, 2H), 7.33 (d, / = 7.5 Hz, 2H), 6.95-7.27 (m, 8H), 5.24 (s, 2H), 4.97-4.99 (m, 4H), 4.84 (d, / = 5.4 Hz, 2H), 3.16 (s, 2H); MS (m/z): 449.2 [M- H].
Example 72
Ethyl 2-(3-(4-(2-(3-(4-methoxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl) acetate (Compound 72)
Step 1
Ethyl 2-(3-(4-methoxyphenyl)oxetan-3-yl)acetate Ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 500 mg, 2.11 mmol) and potassium carbonate (585.4 mg, 4.236 mmol) was dissolved in acetonitrile (10 mL) and the mixture was allowed to stir at RT for 10 minutes. To the resulting solution methyl iodide (360.8 mg, 2.54 mmol) was added and the resulting mixture was refluxed at 90-100 °C for 2 h. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over Na2S04. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (petroleum ether/ ethyl acetate) to obtain the title compound (350 mg). Yield: 66 ; JH NMR (CDC13, 300 MHz): δ 7.12 (d, / = 8.4 Hz, 2H), 6.90 (d, / = 8.1 Hz, 2H), 4.99 (d, / = 5.7 Hz, 2H), 4.87 (d, / = 5.7 Hz, 2H), 4.03 (t, J = 6.9 Hz, 2H), 3.81 (s, 3H), 3.10 (s, 2H), 1.14 (t. / = 6.9 Hz, 3H); MS (m/z): 273.0 [M+ Na].
Step 2
2-(3-(4-Methoxyphenyl)oxetan-3-yl)ethanol
Ethyl 2-(3-(4-methoxyphenyl)oxetan-3-yl)acetate (compound of step 1, 100 mg, 0.4 mmol) was dissolved in dry THF (10 mL). The reaction mixture was cooled to -30 °C. L1AIH4 in THF (1M, 0.407 mL, 0.41 mmol) was added at -30 °C and the resulting reaction mixture was stirred at -30 °C for 1.5 h. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over Na2S04. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (petroleum ether /ethyl acetate) to obtain the title compound (50 mg). Yield: 60%; JH NMR (CDC13, 300 MHz): δ 7.27 (d, / = 8.1 Hz, 2H), 6.92 (d, / = 8.1 Hz, 2H), 4.98 (d, / = 5.4 Hz, 2H), 4.79 (d, / = 5.4 Hz, 2H), 3.82 (s, 3H), 3.55 (s, 2H), 2.34 (t. / = 6.3 Hz, 2H).
Step 3
2-(3-(4-Methoxyphenyl)oxetan-3-yl)ethyl 4-methylbenzenesulfonate
To a stirred solution of 2-(3-(4-methoxyphenyl)oxetan-3-yl)ethanol (compound of step 2, 50 mg, 0.24 mmol) in dry DCM (5 mL), was added p-toluenesulfonyl chloride (54.99 mg, 0.28 mmol) at 0 °C followed by addition of pyridine. The resulting reaction mixture was stirred overnight at RT. After completion of the reaction, the reaction mixture was poured into water and extracted with DCM. The organic layer was dried over Na2S04. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (petroleum ether/ ethyl acetate) to obtain the title compound (25 mg). Yield: 49%; H NMR (CDCI3, 300 MHz): δ 7.75 (d, / = 8.1 Hz, 2H), 7.36 (d, / = 8.1 Hz, 2H), 6.80- 6.88 (m, 4H), 4.92 (d, / = 6.0 Hz, 2H), 4.72 (d, / = 6.0 Hz, 2H), 3.86 (t, / = 6.3 Hz, 2H), 3.81 (s, 3H), 2.47 (s, 3H), 2.40 (t. / = 6.3 Hz, 2H); MS: (m/z) 361.0 [M- H].
Step 4
Ethyl 2-(3-(4-(2-(3-(4-methoxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl) acetate
Ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 12 mg, 0.05 mmol) was dissolved in DMF and the solution was stirred for 10 minutes. To the resulting solution, 2-(3-(4-methoxyphenyl)oxetan-3-yl)ethyl 4-methylbenzene- sulfonate (compound of step 3, 20 mg, 0.05 mmol) was added and the resulting reaction mixture was stirred for 2 h. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over Na2S04. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography (petroleum ether/ ethyl acetate) to obtain the title compound (20 mg). Yield: 55%; JH NMR (CDCI3, 300 MHz): δ, 7.07 (d, / = 8.4 Hz, 2H), 7.01 (d, / = 8.4 Hz, 2H), 6.86 (d, / = 8.4 Hz, 2H), 6.77 (d, / = 8.4 Hz, 2H), 5.04 (d, / = 5.7 Hz, 2H), 4.99 (d, / = 6.0 Hz, 2H), 4.90 (d, / = 5.7 Hz, 2H), 4.86 (d, / = 6.0 Hz, 2H), 4.03 (q, / = 7.2 Hz, 2H), 3.81 (s, 3H), 3.76 (t, / = 6.3 Hz, 2H), 3.09 (s, 2H), 2.47-2,54 (m, 2H), 1.14 ( t, / = 5.7 Hz, 3H); MS (m/z): 449.2 [M + Na].
Example 73
2-(3-(4-(2-(3-(4-Methoxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid (Compound 73)
The title compound was prepared in an analogous manner as compound 41 of Example 41. Compound 73 was obtained by hydrolyzing the compound of Example 72. JH NMR (CDCI3, 300 MHz): δ 7.10 (d, / = 8.4 Hz, 2H), 7.01 (d, / = 8.7 Hz, 2H), 6.87 (d, / = 8.7 Hz, 2H), 6.77 (d, / = 8.4 Hz, 2H), 5.04 (d, / = 5.4 Hz, 2H), 4.99 (d, / = 5.7 Hz, 2H), 4.90 (d, / = 5.7 Hz, 2H), 4.85 (d, / = 6.0 Hz, 2H), 3.81 (s, 3H), 3.76 (t, / = 6.3 Hz, 2H), 3.14 (s, 2H), 2.50-2,53 (m, 2H); MS (m/z): 396.9 [M-H].
Example 74
Ethyl 2-(3-(4-(2-(3-(4-(benzyloxy)phenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl) acetate (Compound 74)
Step 1
Ethyl 2-(3-(4-(benzyloxy)phenyl)oxetan-3-yl)acetate The title compound was prepared by a method analogous to the method described in step 1 of Example 72, using benzyl bromide instead of methyl iodide.
JH NMR (CDC13, 300 MHz): δ 7.34-7.45 (m, 5H), 7.12 (d, J = 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 5.07 (s, 2H), 5.01 (d, / = 6.0 Hz, 2H), 4.87 (d, / = 6.0 Hz, 2H), 4.05 (q, 7.2 Hz, 2H), 3.10 (s, 2H), 1.13 (t, J = 6.0 Hz, 3H); MS: (m/z) 349.3 [M+ Na].
Step 2
2-(3-(4-(Benzyloxy)phenyl)oxetan-3-yl)ethanol
Ethyl 2-(3-(4-(benzyloxy)phenyl)oxetan-3-yl)acetate (compound of step 1, 500 mg, 1.53 mmol) was dissolved in dry THF (5 mL) and the mixture was cooled to -30 °C. L1AIH4 in THF (1 M, 1.53 mL, 1.53 mmol) was added at -30 °C and the resulting reaction mixture was stirred at -30 °C for 1.5 h. After completion of reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over Na2S04. The solvent was removed and the residue was purified by flash column chromatography (petroleum ether/ ethyl acetate) to obtain the title compound (401 mg). Yield: 92%; JH NMR (CDCI3, 300 MHz): δ 7.35-7.46 (m, 5H), 6.96-7.03 (m, 4H), 5.08 (s, 2H), 4.98 (d, / = 5.7 Hz, 2H), 4.79 (d, / = 5.7 Hz, 2H), 3.52-3.58 (m, 2H), 2.34 (t, / = 6.6 Hz, 2H); MS (m z): 283.0 [M-H].
Step 3
2-(3-(4-(Benzyloxy)phenyl)oxetan-3-yl)ethyl 4-methylbenzenesulfonate
To a stirred solution of 3-(4-(benzyloxy)phenyl)-3-(2-methoxyethyl)oxetane
(compound of step 2, 500 mg, 1.75 mmol) in dry DCM (10 mL), was added p- toluenesulfonyl chloride (402 mg, 2.11 mmol) at 0 °C followed by addition of triethyl amine (0.73 mL, 5.25 mmol). The resulting reaction mixture was stirred overnight at RT. After completion of the reaction, the reaction mixture was poured into water, extracted with DCM and washed with saturated NaHC03 solution. The organic layer was dried over Na2S04. The solvent was removed and the residue was purified by flash column chromatography (petroleum ether/ ethyl acetate) to obtain the title compound (560 mg). Yield: 72.6 %; JH NMR (CDCI3, 300 MHz): δ 7.75 (d, / = 8.1 Hz, 2H), 7.32-7.44 (m, 7H), 6.84-6.98 (m, 4H), 5.06 (s, 2H), 4.99 (d, / = 5.7 Hz, 2H), 4.71 (d, / = 5.7 Hz, 2H), 3.87 (t, / = 6.3 Hz, 2H), 2.47 (s, 3H), 2.40 (t, / = 6.3 Hz 2H); MS: (m/z) 361.1 [M+ Na]. Step 4
Ethyl 2-(3-(4-(2-(3-(4-(benzyloxy)phenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl) acetate
Ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 275 mg, 1.16 mmol) was dissolved in DMF (95 mL). The resulting solution was stirred for 10 minutes, followed by addition of 2-(3-(4-(benzyloxy)phenyl)oxetan-3-yl)ethyl 4- methylbenzenesulfonate (Compound of step 3, 510 mg, 1.16 mmol). The resulting reaction mixture was stirred at 70-75 °C for 2 h. After completion of reaction, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and dried over Na2S04. The solvent was removed and the residue was purified by flash column chromatography (petroleum ether/ EtOAc) to obtain the title compound (481 mg). Yield: 82%; JHNMR (CDC13, 300 MHz): δ 7.34-7.43 (m, 5H), 6.93-7.07 (m, 6H), 6.75 (d, / = 8.4 Hz, 2H), 4.97-5.02 ( m, 6H), 4.88 (d, / = 5.4 Hz, 2H), 4.84 (d, / = 5.7 Hz, 2H), 4.01 (q, / = 7.2 Hz, 2H), 3.76 (t, / = 5.7 Hz, 2H), 3.09 (s, 2H), 2.52 (t, 5.7 Hz, 2H), 1.14 (t, / = 6.9 Hz, 3H).
Example 75
2-(3-(4-(2-(3-(4-(Benzyloxy)phenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid (Compound 75)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 75 was obtained by hydrolyzing the compound of Example 74. JH NMR (CDCI3, 300 MHz): δ 7.34-7.43 (m, 5H), 6.93-7.09 (m, 6H), 6.75 (d, / = 8.4 Hz, 2H), 5.01-5.06 (m, 4H), 4.98 (d, / = 6.0 Hz, 2H), 4.90 (d, / = 5.4 Hz, 2H), 4.82 (d, / = 6.0 Hz, 2H), 3.76 (t, / = 6.0 Hz, 2H), 3.13 (s, 2H), 2.51 (t, 5.7 Hz, 2H); MS (m/z): 475.1 [M+ H].
Example 76
Ethyl 2-(3-(4-(2-(3-(4-hydroxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl) acetate (Compound 76)
Pd-C (80 mg, 14 mol%) was added to ethanolic solution of ethyl 2-(3-(4-(2-(3-(4- (benzyloxy)phenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl) acetate (Compound 76, 100 mg, 0.198 mmol) under ¾ atmosphere. The reaction mixture was stirred at RT for 2 h and then filtered over celite® bed. The filtrate was concentrated and the residue was purified by flash column chromatography (EtOAc/petroleum ether) to obtain the title compound (50 mg). Yield: 41.3 %; JH NMR (CDC13, 300 MHz): δ 7.07 (d, / = 8.4 Hz, 2H), 6.94 (d, / = 8.4 Hz, 2H), 6.80 (d, / = 8.7 Hz, 2H), 6.76 (d, / = 8.7 Hz, 2H), 5.24 (brs, 1H), 5.03 (d, / = 5.4 Hz, 2H), 4.99 (d, / = 6.0 Hz, 2H), 4.89 (d, / = 6.0 Hz, 2H), 4.86 (d, / = 6.0 Hz, 2H), 4.04 (t, / = 6.9 Hz, 2H), 3.75 ( t, J = 6.0 Hz, 2H), 3.09 (s, 2H), 2.51 (t, 5.7 Hz, 2H), 1.15 (t, / = 7.2 Hz, 3H); MS (m/z): 435.4 [M+ Na].
Example 77
2-(3-(4-(2-(3-(4-hydroxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid
(Compound 77)
The title compound was prepared in an analogous manner as the compound
41 of Example 41. Compound 77 was obtained by hydrolyzing the compound of Example 76. JH NMR (CDC13, 300 MHz): δ 8.18 (brs, 1H), 7.06 (d, / = 8.4 Hz, 2H), 6.83 (d, / = 8.4 Hz, 2H), 6.75 (d, / = 8.4 Hz, 2H), 6.70 (d, / = 8.4 Hz, 2H), 4.99 (d, / = 5.7 Hz, 2H), 4.95 (d, / = 6.0 Hz, 2H), 4.83-4.85 (m, 4H), 3.70 (t, / = 6.0 Hz, 2H), 3.05 (s, 2H), 2.48 (t, 5.7 Hz, 2H); MS (m/z): 407.2 [M+ Na].
Example 78
Ethyl 2-(3-(4-(2-(3-(4-((3-methyloxetan-3-yl)methoxy)phenyl)oxetan-3-yl)ethoxy) phenyl)oxetan-3-yl)acetate (Compound 78)
Cs2C03 (165.1 mg, 0.507 mmol) was added to a solution of ethyl 2-(3-(4-(2-(3-(4- hydroxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetate (Compound 76, 161 mg, 0.390 mmol) in DMF. The reaction mixture was stirred for 10 minutes at RT, followed by the addition of (3-methyloxetan-3-yl)methyl 4-methylbenzenesulfonate (100 mg, 0.390 mmol). The reaction mixture was refluxed at 80 °C for 1 h. After completion of reaction, the solvent was evaporated and the residue was dissolved in EtOAc. The organic layer was washed with water, dried over anhydrous Na2S04 and concentrated. The crude compound was purified by flash column chromatography (5-30% EtOAc in petroleum ether as eluent) to obtain the title compound (150 mg) as sticky liquid. Yield: 74.8 %; JH NMR (CDC13, 300 MHz): δ 7.05 (d, / = 9.0 Hz, 2H), 6.99 (d, / = 9.0 Hz, 2H), 6.90 (d, / = 9.0 Hz, 2H), 6.74 (d, / = 9.0 Hz, 2H), 5.02 (d, / = 6.0 Hz, 2H), 4.97 (d, / = 6.0 Hz, 2H), 4.89 (d, / = 6.0 Hz, 2H), 4.84 (d, / = 6.0 Hz, 2H), 4.63 (d, / = 6.0 Hz, 2H), 4.46 ( d, / = 6.0 Hz, 2H), 3.99-4.06 (m, 4H), 3.76 (t, / = 6.0 Hz, 2H), 3.09 (s, 2H),2.53 (t, / = 6.0 Hz, 2H), 1.45 (s, 3H), 1.14 (t, / = 6.0, Hz, 3H); MS (m/z): 519.1 [M+ Na]. Example 79
2- (3-(4-(2-(3-(4-((3-methyloxetan-3-yl)methoxy)phenyl)oxetan-3-yl)ethoxy)phenyl) oxetan-
3 - yl) acetic acid (Compound 79)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 79 was obtained by hydrolyzing the compound of Example 78. JH NMR (CDCI3, 300 MHz): δ 7.05 (d, / = 9.0 Hz, 2H), 6.92 (d, / = 9.0 Hz, 2H), 6.81 (d, / = 9.0 Hz, 2H), 6.66 (d, / = 9.0 Hz, 2H), 5.04 (d, / = 6.0 Hz, 2H), 4.97 (d, / = 6.0 Hz, 2H), 4.84- 4.88 (m, 4H), 4.61 (d, / = 6.0 Hz, 2H), 4.48 (d, / = 6.0 Hz, 2H), 4.01( s, 2H) 3.72 (t, / = 6.0 Hz, 2H), 3.14 (s, 2H), 2.53 (t, / = 6.0 Hz, 2H), 1.43 (s, 3H); MS (m/z): 491.0 [M+ Na], 469.0 [M +H].
Example 80
Ethyl 2-(3-(4-(2-(3-(4-(3-(methylsulfonyl)propoxy)phenyl)oxetan-3-yl)ethoxy)phenyl) oxetan-3-yl)acetate (Compound 80)
Cs2C03 (72.4 mg, 0.222 mmol) was added to a solution of ethyl 2-(3-(4-(2-(3-(4- hydroxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetate (Compound 76, 70.54 mg, 0.171 mmol) in DMF. The reaction mixture was stirred at RT for 10 minutes, followed by the addition of 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (50 mg, 0.171 mmol). The reaction mixture was refluxed at 80 °C for 1 h. After completion of reaction, the solvent was evaporated and the residue was dissolved in EtOAc. The organic layer was washed with water, dried over anhydrous Na2S04 and concentrated. The crude compound was purified by flash column chromatography (1-50 % EtOAc in petroleum ether as eluent) to obtain the title compound (68 mg) as sticky liquid. Yield: 74.3 ; JH NMR (CDC13, 300 MHz): δ 7.05 (d, / = 9.0 Hz, 2H), 6.99 (d, / =9.0Hz, 2H), 6.84 (d, / = 9.0Hz, 2H), 6.74 (d, / = 9.0 Hz, 2H), 5.01 (d, / = 6.0Hz, 2H), 4.96 (d, / = 6.0 Hz, 2H), 4.88 (d, / = 9.0 Hz, 2H), 4.84 (d, / = 6.0 Hz, 2H), 4.11 (t, / = 6.0, 6.0 Hz, 2H), 3.99-4.06 (m, 2H), 3.75 (t, / = 6.0, 6.0 Hz, 2H), 3.27 (t, / = 9.0, 9.0 Hz, 2H), 3.09 (s, 2H), 2.97 (s, 3H), 2.52 (t, / = 6.0, 6.0 Hz, 2H), 2.33-2.38 (m, 2H), 1.15 (t, / = 6.0, 6.0 Hz, 3H); MS (m/z): 555.1 [M+ Na].
Example 81
2-(3-(4-(2-(3-(4-(3-(methylsulfonyl)propoxy)phenyl)oxetan-3-yl)ethoxy)phenyl) oxetan-3- yl)acetic acid (Compound 81)
The title compound was prepared in an analogous manner as compound 41 of Example 41. Compound 81 was obtained by hydrolyzing the compound of Example 80. JH NMR (DMSO-d6, 300 MHz): δ 12.10 (br, m, 1H), 7.14 (d, / = 9.0 Hz, 2H), 7.08 (d, / =9.0Hz, 2H), 6.89 (d, / = 9.0Hz, 2H), 6.77 (d, / = 9.0 Hz, 2H), 4.76-4.81 (m, 4H), 4.72-4.75 (m, 4H), 4.06 (t, / = 6.0, 6.0 Hz, 2H), 3.72 (t, J = 6.0, 6.0 Hz, 2H), 3.17 - 3.25 (m, 3H), 2.99 (d, / = 3.0 Hz, 4H), 2.41 (t, / = 6.0, 6.0 Hz, 2H), 2.12 - 2.14 (m, 2H); MS (m/z): 527.1 [M+ Na].
Example 82
Ethyl 2-(3-(4-((3-(4-(benzyloxy)phenyl)oxetan-3-yl)oxy)phenyl)oxetan-3-yl)acetate
(Compound 82)
Step 1
3-(4-(Benzyloxy)phenyl)oxetan-3-ol
n-BuLi (10.03 mmol) was added to a cold (-78 °C) solution of 1 -(benzyloxy)-4- bromobenzene (2 g, 7.60 mmol) in dry THF (20 mL). The resulting mixture was stirred at -78 °C for 0.5 h followed by the addition of oxetan-3-one (0.53 mL, 9.12 mmol) and the reaction mixture was further stirred for 2 h. After completion of the reaction, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2S04. The solvent was removed and the residue was purified by flash column chromatography (petroleum ether/ EtOAc) to obtain the title compound (1 g). Yield: 51.3 ; JH NMR (CDC13, 300 MHz): δ 7.35-7.52 (m, 7H), 7.05 (d, / = 8.7 Hz, 2H), 5.10 (s, 2H), 4.89-4.94 (m, 4H), 2.51 (s, 1H); MS (m/z): 257.3 [M+ H].
Step 2
Ethyl 2-(3-(4-((3-(4-(benzyloxy)phenyl)oxetan-3-yl)oxy)phenyl)oxetan-3-yl)acetate
3-(4-(Benzyloxy)phenyl)oxetan-3-ol (compound of step 1, 200 mg, 0.78 mmol) was dissolved in dry THF and cooled to 0 °C. To this solution was added ethyl 2-(3-(4- hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 221 mg, 0.94 mmol) followed by the addition of PPI13 (307 mg, 1.17 mmol) and the resulting mixture was stirred at 0 °C for 15 minutes. Diethyl azodicarboxylate (204 mg, 1.17 mmol) was added and the reaction mixture was stirred at RT for 12 h. After completion of the reaction, the reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over Na2S04. The solvent was removed and the residue was purified by flash column chromatography (petroleum ether and EtOAc as an eluent) to obtain the title compound (70 mg). Yield: 19 ; JH NMR (CDCI3, 300 MHz): δ 7.34-7.50 (m, 7H), 6.79-7.07 (m, 5H), 6.51 (d, / = 8.4 Hz, 1H), 4.81- 5.09 (m, 10H), 4.00 (q, / = 6.9 Hz, 2H), 3.05 (s, 2H), 1.14 (t, J = 6.9 Hz, 3H); MS (m/z): 497.2 [M+ Na].
Example 83
2-(3-(4-((3-(4-(Benzyloxy)phenyl)oxetan-3-yl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 83)
The title compound was prepared in an analogous manner as compound 41 of Example 41. Compound 83 was obtained by hydrolyzing the compound of Example 82. JH NMR (CDC13, 300 MHz): δ 7.37-7.50 (m, 7H), 6.78-7.02 (m, 5H), 6.51 (d, / = 8.4 Hz, 1H), 4.79-5.09 (m, 10H), 3.11 (s, 2H); MS (m/z): 447.0 [M+H].
Example 84
Ethyl 2-(3-(4-((4-chloro-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetate
(Compound 84)
Step 1
4-Chloro-2,3-dihydro- 1 H-inden- 1 -ol
NaBH4 (227 mg, 6 mmol) was added to the solution of 4-Chloro-2,3-dihydro-lH- inden-l-one (500 mg, 3 mmol) in MeOH (5 mL) and the reaction mixture was stirred at RT for 2 h. After completion of reaction, the solvent was evaporated and the residue obtained was dissolved in EtOAc and was washed with water. Organic layer was collected and dried over Na2S04 and evaporated to obtain the title compound (422 mg). Yield: 83 ; JH NMR (CDCI3, 300 MHz): δ 7.18-7.32 (m, 3H), 5.27-5.30 (m, 1H), 3.06-3.16 (m, 1H), 2.80-2.90 (m, 1H), 2.47-2.58 (m, 1H), 1.91-2.05 (m, 2H).
Step 2
Ethyl 2-(3-(4-((4-chloro-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetate
Ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 308 mg, 1.30 mmol) was added to a solution of 4-Chloro-2,3-dihydro-lH-inden-l-ol
(Compound of step 1 , 200 mg, 1.18 mmol) in dry THF (4 mL) and the reaction mixture was cooled to 0 °C. PPI13 (1.78 mmol) was added and the reaction mixture was stirred for 15 minutes followed by the addition of diethyl azodicarboxylate (0.28 mL, 1.78 mmol). The resulting reaction mixture was further stirred for 5 h at RT. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was separated and dried over anhydrous Na2S04. Solvent was removed and the crude material was purified by flash column chromatography to obtain the title compound (86 mg). Yield: 18 %; H NMR (CDCI3, 300 MHz): δ 7.19-7.33 (m, 3H), 7.15 (d, / = 8.7 Hz, 2H), 6.97 (d, / = 8.4 Hz, 2H), 5.79 (t, / = 4.8 Hz, IH), 5.02 (d, J = 6.0 Hz, 2H), 4.88 (d, / = 6.0 Hz, 2H), 4.08 (q, / = 7.2 Hz, 2H), 3.15-3.24 (m, IH), 3.13 (s, 2H), 2.92-3.03 (m, IH), 2.54-2.66 (m, IH), 2.18-2.29 (m, IH), 1.16 (t, / = 7.2 Hz, 3H); MS (m/z): 387.5 [M+H].
Example 85
2-(3-(4-((4-chloro-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid
(Compound 85)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 85 was obtained by hydrolyzing the compound of Example 84. JH NMR (CDCI3, 300 MHz): δ 7.04-7.32 (m, 5H), 6.98 (d, / = 8.4 Hz, 2H), 5.78(t, / = 4.5 Hz, IH), 5.02 (d, / = 6.0 Hz, 2H), 4.87 (d, / = 6.0 Hz, 2H), 3.12-3.18 (m, 3H), 2.91-3.01 (m, IH), 2.53-2.65 (m, IH), 2.19-2.28 (m, IH); MS (m/z): 381.6 [M+Na].
Example 86
Ethyl 2-(3-(4-((5-methoxy-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl) acetate (Compound 86)
Step 1
5 -methoxy-2, 3 -dihydro- 1 H-inden- 1 -one
Potassium carbonate (1.39 g, 10.1 mmol), followed by methyl iodide (527 mg, 3.71 mmol) were added to the solution of 2,3-dihydro-lH-indene-l, 5-diol 500 mg, 3.37 mmol) in acetonitrile (5 mL) at RT. The resulting reaction mixture was refluxed for 5 h. After completion of reaction, the reaction mixture was filtered through sintered crucible. The filtrate was subjected to evaporation. The residue was extracted with ethyl acetate, washed with water and dried over Na2S04. Solvent was removed and the crude material and was purified by flash column chromatography to obtain the title compound (337 mg). Yield: 61%; JH NMR (CDCI3, 300 MHz): δ 7.73-7.70 (m, IH), 6.95 (br s, 2H), 3.82 (s, 3H), 3.11 (t, J = 6.0 Hz, 2H), 2.70 (t, J = 6.0 Hz, 2H); MS (m/z): 163.1 [M+H].
Step 2
5 -methoxy-2, 3 -dihydro- 1 H-inden- 1 -ol
NaBH4 (93 mg, 2.46 mmol) was added to a methanolic solution of 5-methoxy-2,3- dihydro-1 H-inden- 1 -one (Compound of step 1, 200 mg, 1.23 mmol) and the reaction mixture was stirred for 2 h at RT. After completion of reaction, methanol was evaporated and the solid obtained was dissolved in ethyl acetate and washed with water. Organic layer was collected and dried over Na2S04 and solvent was evaporated obtain the title compound (182 mg). Yield: 90%. JH NMR (CDC13, 300 MHz): δ 7.32-7.35 (m, 1H), 6.80 (brs, 2H), 5.20-5.22 (m, 1H), 3.82 (s, 3H), 3.02-3.12 (m, 1H), 2.75-2.86 (m, 1H), 2.46-2.53 (m, 1H), 1.95-2.04 (m, 1H).
Step 3
Ethyl 2-(3-(4-((5-methoxy-2,3-dihydro-lH-inden-l-yl)oxy)phenyl) oxetan-3-yl) acetate
Ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 187 mg, 0.79 mmol) was added to a solution of 5-methoxy-2,3-dihydro-lH-inden-l-ol (Compound of step 2, 130 mg, 0.79 mmol) in dry THF (4 mL) and the reaction mixture was cooled to 0 °C. PPI13 (518 mg, 1.97 mmol) was added and the reaction mixture was stirred for 15 minutes followed by the addition of diethyl azodicarboxylate (0.30 mL, 1.97 mmol). The resulting reaction mixture was further stirred at RT for 5 h. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated and dried over anhydrous Na2S04. Solvent was removed and the crude material was purified by flash column chromatography to obtain the title compound (56 mg). Yield: 18.5%; JH NMR (CDC13, 300 MHz): δ 7.34 (d, / = 8.1 Hz, 1H), 7.14 (d, / = 8.7 Hz, 2H), 6.98 (d, / = 8.4 Hz, 2H), 6.80-6.84 (m, 2H), 5.70-5.79(m, 1H), 5.02 (d, / = 6.0 Hz, 2H), 4.88 (d, / = 6.0 Hz, 2H), 4.08 (q, / = 6.9 Hz, 2H), 3.83 (s, 3H), 3.12-3.17 (m, 3H), 2.85-2.95 (m, 1H), 2.49-2.61 (m, 1H), 2.22-2.27 (m, 1H), 1.16 (t, / = 7.2 Hz, 3H); MS (m/z): 405.0 [M+Na].
Example 87
2-(3-(4-((5-methoxy-2,3-dihydro-lH-inden-l-yl)oxy)phenyl) oxetan-3-yl)acetic acid (Compound 87)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 87 was obtained by hydrolyzing the compound of Example 86. JH NMR (CDCI3, 300 MHz): δ 7.34 (d, / = 8.1 Hz, 1H), 7.16 (d, / = 8.4 Hz, 2H), 6.99 (d, / = 8.4 Hz, 2H), 6.80-6.83 (m, 2H), 5.68-5.79 (m, 1H), 5.02 (d, / = 6.0 Hz, 2H), 4.87 (d, / = 6.0 Hz, 2H), 3.82 (s, 3H), 3.18 (s, 2H), 3.08-3.13 (m, 1H), 2.85-2.91 (m, 1H), 2.50-2.58 (m, 1H), 2.22-2.26 (m, 1H); MS (m/z): 355.0 [M+H]. Example 88
Ethyl 2-(3-(4-((6-((3-methyloxetan-3-yl)methoxy)-2,3-dihydro-lH-inden-l-yl)oxy) phenyl)oxetan-3-yl)acetate (Compound 88)
Step 1
6-((3-methyloxetan-3-yl)methoxy)-2,3-dihydro-lH-inden-l-one
CS2CO3 (781 mg, 4.05 mmol) was added to a solution of 6-hydroxy-2,3-dihydro-lH- inden-l-one (300 mg, 2.025 mmol) and (3-methyloxetan-3-yl)methyl 4- methylbenzenesulfonate (519 mg, 2.025 mmol) (synthesized according to the literature procedure J. Am. Chem. Soc. 1999, 121 , 5459-5466) in DMF (5 mL). The reaction mixture was stirred at 80 °C for 4h. After completion of reaction, the reaction mixture was quenched with water, extracted with ethyl acetate and purified by column chromatography (silica gel column, 20% ethylacetate/petroleum ether as eluent) to obtain the title compound (385 mg) as white solid. Yield: 81.7 %; JH NMR (CDC13,300 MHz) δ: 7.40 (d, / = 7.8 Hz, 1H), 7.26- 7.23 (m, 2H), 4.64 (d, / = 5.7 Hz, 2H), 4.48 (d, / = 5.7 Hz, 2H), 4.05 (s, 2H), 3.09 (d, / = 5.1 Hz, 2H), 2.74 (t, / = 5.4 Hz, 2H), 1.45 (s, 3H); MS (m/z): 254.9 [M + Na]
Step 2
6-((3-methyloxetan-3-yl)methoxy)-2,3-dihydro-lH-inden-l-ol
Sodium borohydride (26.1 mg, 0.689 mmol) was added to a solution of 6-((3- methyloxetan-3-yl)methoxy)-2,3-dihydro-lH-inden-l-one (Compound of step 1 , 160 mg, 0.689 mmol) in MeOH (3 mL). The reaction mixture was stirred at RT for 2 to 3 h. After completion of reaction, the solvent was evaporated and the residue was extracted with ethyl acetate and purified by column chromatography (silica gel column, 30% ethylacetate/petroleum ether as eluent) to obtain the title compound (137 mg). Yield: 85 % JH NMR (CDCI3, 300 MHz) δ: 7.18 (d, / = 8.1 Hz, 1H), 7.01 (s, 1H), 6.87 (d, / = 6.9 Hz, 1H), 5.22-5.20 (m, 1H), 4.64 (d, / = 5.7 Hz, 2H), 4.47 (d, / = 5.7 Hz, 2H), 4.04 (s, 2H), 3.04-298 (m, 2H), 2.79-2.72 (m, 1H), 2.59-2.49 (m, 1H), 2.01-1.90 (m, 1H),1.45 (s, 3H); MS (m/z): 257.0 [M + Na].
Step 3
Ethyl 2-(3-(4-((6-((3-methyloxetan-3-yl)methoxy)-2,3-dihydro-lH-inden- l-yl)oxy) phenyl)oxetan-3-yl)acetate
Diisopropyl diazene-l ,2-dicarboxylate (478 μΐ, 0.491 mmol) was added to a solution of ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 116 mg, 0.491 mmol), 6-((3-methyloxetan-3-yl)methoxy)-2,3-d ydro-l H-inden- l-ol (Compound of step 2, 115 mg, 0.491 mmol) and triphenylphosphine (129 mg, 0.491 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at RT for 4 to 8 h. After completion of the reaction, the crude compound obtained was subjected to column chromatography (silica gel column, 30% ethylacetate/ petroleum ether as eluent) to obtain the title compound (192 mg). Yield: 64.5 %; JH NMR (CDC13, 300 MHz) δ: 7.13-7.22 (m, 3H), 6.82 -7.00 (m, 4H), 5.72 (t, / = 5.7 Hz, 1H), 5.02 (d, / = 5.4 Hz, 2H), 4.86 (d, / = 6.0 Hz, 2H), 4.63 (d, / = 5.7 Hz, 2H), 4.46 (d, / = 5.4 Hz, 2H), 3.99-4.06 (m, 4H), 3.13 (s, 2H), 3.03-3.10 (m, 1H), 2.83-2.92 (m, 1H), 2.55-2.66 (m, 1H), 2.14-2.26 (m, 1H), 1.44 (s, 3H), 1.17 (t, / = 7.2 Hz, 3H); MS (m/z): 453.0 [M+H], 475.0 [M + Na].
Example 89
2- (3-(4-((6-((3-methyloxetan-3-yl)methoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl) oxetan-
3- yl)acetic acid (Compound 89)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 89 was obtained by hydrolyzing the compound of Example 88. JH NMR (300 MHz, DMSO-d6) δ: 12.17 (br s, 1H), 7.22 (d, / = 8.1Hz, 3H), 6.92-7.01 (m, 4H), 5.76 (t, / = 8.7 Hz, 2H), 4.75 (s, 4H), 3.94 (t, / = 6.0 Hz, 2H), 3.02 (s, 2H), 2.92-2.96 (m, 1H), 2.73-2.82 (m, 1H), 1.93-2.04 (m, 1H), 1.68-1.80 (m, 1H), 1.54-1.61 (m, 2H), 0.90 (d, / = 6.3 Hz, 4H); MS (m/z): 425.2 [M+H], 447.0 (M + Na).
Example 90
Ethyl 2-(3 -(4-((6-(isopentyloxy)-2,3 -dihydro- 1 H-inden- 1 -yl)oxy)phenyl)oxetan-3-yl)acetate (Compound 90)
Step 1
6-(Isopentyloxy)-2,3-dihydro- 1 H-inden- 1 -one
CS2CO3 (781 mg, 4.05 mmol) was added to a solution of 6-hydroxy-2,3-dihydro-lH- inden-l-one (300 mg, 2.025 mmol) and isopentyl 4-methylbenzenesulfonate (589 mg, 2.430 mmol), (synthesized according to the literature procedure, Synth. Commun. 2002, 32, 2651- 2656) in DMF (5 mL). The reaction mixture was stirred at 80 °C for 4 h. After completion of reaction, the reaction mixture was quenched with water, extracted with ethyl acetate and purified by column chromatography to obtain the title compound (410 mg). Yield: 83.7 %. JH NMR (CDCI3, 300 MHz) δ: 7.37 (d, / = 8.7 Hz, 1H), 7.17-7.20 (m, 2H), 4.02 (t, / = 6.6 Hz, 2H), 3.08 (t, / = 5.4 Hz, 2H), 2.73 (t, / = 5.4 Hz, 2H), 1.80-1.86 (m, 1H), 1.69-1.73 (m, 2H), 0.97 (d, / = 6.3 Hz, 6H); MS (m/z): 219.1 [M + H], 241.0 [M+ Na].
Step 2
6-(Isopentyloxy)-2,3-dihydro- 1 H-inden- 1 -ol
Sodium borohydride (26.0 mg, 0.687 mmol) was added to the solution of 6- (isopentyloxy)-2,3-dihydro-lH-inden-l-one (Compound of step 1, 150 mg, 0.687 mmol) in MeOH (5 mL). The reaction mixture was stirred at RT for 2 to 3 h. After completion of reaction, the solvent was evaporated and the residue was extracted with ethyl acetate and purified by column chromatography (silica gel column, 30% ethylacetate/petroleum ether as eluent) to obtain the title compound (132 mg) as colorless thick liquid. Yield: 82.3 %; JH NMR (300 MHz, CDC13) δ: 7.14 (d, / = 8.1 Hz, 1H), 6.97(s, 1H), 6.83 (d, / = 6.9 Hz, 1H), 5.22-5.20 (m, 1H), 4.00 (t, / = 6.6 Hz, 2H), 2.98-2.97 (m, 1H), 2.81-2.87 (m, 1H), 2.54-2.51 (m, 1H), 1.96-1.80 (m, 2H), 1.731.67 (m, 3H),0.97 (d, / = 6.3 Hz, 6H); MS (m/z): 218.9 [M- H].
Step 3
Ethyl 2-(3 -(4-((6-(isopentyloxy)-2,3 -dihydro- 1 H-inden- 1 -yl)oxy)phenyl)oxetan-3-yl) acetate Diisopropyl diazene- 1 ,2-dicarboxylate (0.268 mL, 1.362 mmol) was added to a solution of ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 322 mg, 1.362 mmol), 6-(isopentyloxy)-2,3-dihydro-lH-inden-l-ol (Compound of step 2, 300 mg, 1.362 mmol) and triphenylphosphine (714 mg, 2.72 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at RT for 4 to 8 h. After completion of reaction, the crude compound obtained was subjected to column chromatography (silica gel column, 30% EtOAc/petroleum ether as eluent) to obtain the title compound (394 mg). Yield: 63.5 %; JH NMR (300 MHz, CDCI3) δ: 7.20-7.12 (m, 3H), 7.00-6.87 (m, 4H), 5.71 (t, / = 8.7 Hz, 1H), 5.02 (d, / = 6.0 Hz, 2H), 4.87 (d, / = 5.7 Hz, 2H), 4.08-3.98 (m, 4H), 3.12 (s, 2H), 3.10-3.07 (m, 1H), 2.88-2.86 (m, 1H), 2.60-2.58 (m, 1H), 2.24-2.20 (m, 1H), 1.84-1.82 (m, 1H), 1.68-1.57 (m, 2H), 0.96 (t, / = 6.9 Hz, 3H), 5.71 (d / = 6.3 Hz, 6H); MS (m/z): 439.0 [M + H], 461.0 [M + Na].
Example 91
2-(3-(4-((6-(Isopentyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 91)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 91 was obtained by hydrolyzing the compound of Example 90. H NMR (300 MHz, DMSO-d6) δ: 12.14 (br s, 1H), 7.23-7.20 (m, 3H), 7.01-6.86 (m, 4H), 5.76 (t, / = 8.7 Hz, 2H), 4.75 (s, 4H), 3.94 (t, / = 6.0 Hz, 2H), 3.02 (s, 2H), 2.96-2.92 (m, 1H), 2.82-2.73 (m, 1H), 2.04-1.93 (m, 1H), 1.80-1.68 (m, 1H), 1.61-1.54 (m, 2H), 0.90 (d, / = 6.3 Hz, 6H); MS (m/z): 408.9 [M - H], 433.0 [M + Na].
Example 92
Ethyl 2-(3-(4-((6-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl) oxetan-3- yl)acetate (Compound 92)
Step 1
6-(4,4,4-Trifluorobutoxy)-2,3-dihydro-lH-inden-l-one
CS2CO3 (195 mg, 1.012 mmol) was added to a solution of 6-hydroxy-2,3-dihydro-lH- inden-l-one 150 mg, 1.012 mmol) and 4,4,4-trifluorobutyl 4-methylbenzenesulfonate (286 mg, 1.012 mmol) (prepared according to the procedure described in Bioorg. Med. Chem. 2011, 19, 134-144), in DMF (5 mL). The reaction mixture was stirred at 80 °C for 4 h. After completion of reaction, the reaction mixture was quenched with water, extracted with ethyl acetate and purified by column chromatography (silica gel column, 20% ethylacetate/petroleum ether as eluent) to obtain the title compound (231 mg). Yield: 87.2 %. JH NMR (CDCI3, 300 MHz) δ: 7.39 (d, / = 8.1 Hz, 1H), 7.20-7.18 (m, 2H), 4.06 (t, / = 5.7 Hz, 2H), 3.08 (t, / = 5.7 Hz, 2H), 2.73 (t, / = 5.7 Hz, 2H), 2.37-2.29 (m, 2H), 2.08-2.06 (m, 2H); MS (m z): 259.0 [M + H].
Step 2
6-(4,4,4-Trifluorobutoxy)-2,3-dihydro-lH-inden-l-ol
Sodium borohydride (29.3 mg, 0.774 mmol) was added to a solution of 6-(4,4,4- trifluorobutoxy)-2,3-dihydro-lH-inden-l-one (Compound of step 1, 200 mg, 0.774 mmol) in MeOH (5 mL) at 0 °C. The reaction mixture was stirred at RT for 2 to 3 h. After completion of reaction, the solvent was evaporated and the residue was extracted with EtOAc and purified by column chromatography (30% EtOAc /petroleum ether as eluent) to obtain the title compound (187 mg). Yield: 86.2 %; JH NMR (CDC13, 300 MHz) δ: 7.16 (d, / = 7.8 Hz, 1H), 6.95 (s, 1H), 6.83 (d, / = 6.0 Hz, 1H), 5.22 (s, 1H), 4.03 (t, / = 5.1 Hz, 2H), 3.02-2.95 (m, 1H), 2.81-2.71 (m, 1H), 2.54-2.52 (m, 1H), 2.37-2.28 (m, 2H), 2.08-1.93 (m, 4H); MS (m/z): 282.9 [M + Na].
Step 3 Ethyl 2-(3-(4-((6-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl) oxetan-3- yl)acetate
Diisopropyl diazene-l,2-dicarboxylate (200 μΐ, 1.016 mmol) was added to a solution of ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (120 mg, 0.508 mmol), 6-(4,4,4- trifluorobutoxy)-2,3-dihydro-lH-inden-l-ol (Compound of step 2, 132 mg, 0.508 mmol) and triphenylphosphine (133 mg, 0.508 mmol) in DCM (5 mL) at 0 °C. The reaction mixture was stirred at RT for 4-8 h. After completion of reaction, the crude compound obtained was purified by column chromatography (silica gel column, 30% ethylacetate/petroleum ether as eluent) to obtain the title compound (158 mg). Yield: 63.3 %; JH NMR (CDC13, 300 MHz) δ: 7.22-7.12 (m, 3H), 7.00-6.86 (m, 4H), 5.71 (t, / = 5.7 Hz, 1H), 5.01 (d, / = 5.7 Hz, 2H), 4.86 (d, / = 6.0 Hz, 2H), 4.06-4.01 (m, 4H), 3.13 (s, 2H), 3.05-307 (m, 1H), 289-2.87 (m, 1H), 2.56-2.58 (m, 1H), 2.31-2.24 (m, 3H), 2.01-2.04 (m, 2H), 1.17 (t, / = 6.9 Hz, 3H); MS (m/z): 479.2 [M + H].
Example 93
2-(3-(4-((6-(4,4,4-Trifluorobutoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3- yl)acetic acid (Compound 93)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 93 was obtained by hydrolyzing the compound of Example 92. JH NMR (DMSO-d6, 300 MHz) δ: 12.14 (br s, 1H), 7.22 (d, / = 8.1 Hz, 3H), 7.01-6.89 (m, 4H), 5.77 (t, / = 8.7 Hz, 2H), 4.76 (s, 4H), 3.99 (t, / = 6.0 Hz, 2H), 3.02 (s, 2H), 2.98-2.90 (m, 1H), 2.84-2.74 (m, 2H), 2.59-255 (m, 1H), 2.45-2.32 (m, 1H), 2.01-1.88 (m, 2H); MS (m/z): 451.2 [M + H], 473.1 [M + Na]
Example 94
Ethyl 2-(3-(4-((6-(benzyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl) acetate (Compound 94)
Step 1
6-(Benzyloxy)-2,3-dihydro-lH-inden-l-one
To the stirred solution of 6-hydroxy-2,3-dihydro-lH-inden-l-one (4 g, 27.0 mmol) and CS2CO3 (6.77 g, 35.1 mmol) dissolved in DMF (5 mL) was added benzyl bromide (3.21 mL, 27.0 mmol) slowly at RT and stirred at same temperature for 3 h. After completion of reaction was quenched with water and extracted with ethyl acetate and purified by column chromatography to give the pure compound 6-(benzyloxy)-2,3-dihydro-lH-inden-l-one (5.96 g) as white solid. Yield: 92.2 %; H NMR (300 MHz, CDCI3): δ 7.34-7.46 (m, 6H), 7.27-7.29 (m, 2H), 5.10 (s, 2H), 3.09 (t, / = 5.1 Hz, 2H), 2.73 (t, / = 5.4 Hz, 2H); MS (m/z): 239.4 [M + H].
Step 2
6-(Benzyloxy)-2,3-dihydro-lH-inden-l-ol
Sodium borohydride (41.3 mg, 1.091 mmol) was added to a solution of 6- (benzyloxy)-2,3-dihydro-lH-inden-l-one (Compound of step 1, 200 mg, 0.839 mmol) in MeOH (5 mL). The reaction mixture was stirred at RT for 2 to 3 h. After completion of reaction, the solvent was evaporated; the residue was extracted with ethyl acetate and purified by column chromatography (silica gel column, 30% ethylacetate/petroleum ether as eluent) to obtain the title compound (189 mg). Yield: 94.3 %; JH NMR (CDC13, 300 MHz) δ: 7.33- 7.62 (m, 5H), 7.16 (d, / = 8.1 Hz, 1H), 7.05 (s, 1H), 6.91 (d, / = 6.6 Hz, 1H), 5.22-5.32 (m, 1H), 5.08 (s, 2H), 2.95-3.04 (m, 1H), 2.71-2.81 (m, 2H), 2.58-2.47 (m, 1H), 2.01-1.90 (m, 1H); MS (m/z): 239.0 [M-H].
Step 3
Ethyl 2-(3-(4-((6-(benzyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl) acetate
Diisopropyl diazene-l,2-dicarboxylate (615 μΐ, 3.12 mmol) was added to a solution of 6-(benzyloxy)-2,3-dihydro-lH-inden-l-ol (compound of step 2, 300 mg, 1.248 mmol), ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 295 mg, 1.248 mmol), and triphenylphosphine (819 mg, 3.12 mmol) in DCM (7 mL) at 0 °C. The reaction mixture was stirred at RT for 4 to 8 h. After completion of reaction, the crude compound obtained was purified by column chromatography (silica gel column, 30% EtOAc-petroleum ether as eluent) to obtain the title compound (433 mg). Yield: 76 %; JH NMR (CDC13, 300 MHz) δ: 7.42-7.33 (m, 4H), 7.22-7.12 (m, 4H), 7.00-6.95 (m, 4H), 5.71 (t, / = 5.4 Hz, 1H), 5.06-5.01 (m, 4H), 4.87 (d, / = 6.0 Hz, 2H), 4.04 (q, / = 6.0 Hz, 2H), 3.13 (s, 2H), 3.07-3.03 (m, 1H), 2.92-2.82 (m, 1H), 2.60-2.58 (m, 1H), 2.21-2.20 (m, 1H), 1.16 (t, / = 7.2 Hz, 3H); MS (m/z): 459.0 [M+H].
Example 95
2-(3-(4-((6-(Benzyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 95) The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 95 was obtained by hydrolyzing the compound of Example 94. JH NMR (DMSO-d6, 300 MHz) δ: 7.42-7.32 (m, 6H), 7.21-7.14 (m, 3H), 7.02-6.95 (m, 3H), 5.70 (t, / = 5.4 Hz, 1H), 5.09-4.97 (m, 4H), 4.86 (d, / = 6.0 Hz, 2H), 3.18 (s, 2H), 3.12-3.02 (m, 1H), 2.90-2.81 (m, 2H), 2.61-2.55 (m, 1H), 2.21-2.20 (m, 1H); MS (m/z): 453.0 [M + Na].
Example 96
Ethyl 2-(3-(4-((5-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl) oxetan-3- yl)acetate (Compound 96)
Step 1
5-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-one
CS2CO3 (300 mg, 0.921 mmol) was added to a solution of 5-hydroxy-2,3-dihydro-lH- inden-l-one (105 mg, 0.709 mmol) in DMF at RT. The reaction mixture was stirred for 10 minutes, followed by the addition of 4,4,4-trifluorobutyl 4-methylbenzenesulfonate (200 mg, 0.709 mmol). The reaction mixture was stirred at 75 °C for 2 h. After completion of reaction, the solvent was evaporated and the residue was dissolved in ethylacetate. The organic layer was washed with water, dried over Na2S04 and concentrated. The residue was purified by flash column chromatography (5-20% ethylacetate in petroleum ether as eluent) to obtain the title compound (169 mg). Yield: 92.3%; JH NMR (CDC13, 300 MHz) : δ 7.69-7.72 (m, 1H), 6.90 (s, 2H), 4.11 (t, / = 6.0 Hz, 2H), 3.10 (t, J = 6.0 Hz, 2H), 2.69 (t, / = 6.0 Hz, 2H), 2.27-
2.43 (m, 2H), 2.06-2.15 (m, 2H); MS (m/z): 259.1 [M+H].
Step 2
5-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-ol
NaBH4 (26.00 mg, 0.687 mmol) was added to a solution of 5-(4,4,4-trifluorobutoxy)- 2,3-dihydro-lH-inden-l-one (Compound of step 1, 147 mg, 0.569 mmol) in MeOH at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at 0 °C for 4 h. After completion of reaction, the solvent was removed and the residue was dissolved in ethyl acetate. The organic layer was washed with water, dried over anhydrous Na2S04 and concentrated to obtain the title compound (140 mg). JH NMR (CDC13, 300 MHz) : δ 7.31-7.34 (m, 1H), 6.79 (s, 2H), 5.21-5.22 (m, 1H), 4.02 (t, / = 6.0 Hz, 2H), 3.01 - 3.11 (m, 1H), 2.75 - 2.85 (m, 1H),
2.44 - 2.55 (m, 1H), 2.25 - 2.37 (m, 2H), 1.93-2.01 (m, 3H); MS (m/z): 258.4 [M-2H]. Step 3
Ethyl 2-(3-(4-((5-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl) oxetan-3- yl)acetate
Ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl) acetate (Intermediate 1, 1 equivalent) was added to a solution of 5-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-ol (1 equivalent) in THF and the reaction mixture was cooled to 0 °C. Triphenyl phosphine (ΡΡ1¾) (2.5 equivalents) was added and the reaction mixture was stirred for 10 minutes, followed by the addition of DEAD (2.5 equivalents). The reaction mixture was further stirred for 6 h at RT. After completion of reaction, the reaction mixture was concentrated. Water was added to the residue and the compound was extracted by addition of ethyl acetate. The organic layer was separated, dried over anhydrous Na2S04, concentrated and purified by falsh column chromatography (5-20% ethyl acetate in petroleum ether as eluent) to obtain the title compound. Yield: 18.1 %;JH NMR (CDC13, 300 MHz): δ 7.27 - 7.34 (m, 2H), 7.11 (d, / = 9.0 Hz, 2H), 6.95 (d, / = 9.0 Hz, 2H), 6.78 - 6.82 (m, 2H), 5.70 (br s, 1H), 5.00 (d, / = 6.0 Hz, 2H), 4.88 (d, / = 6.0 Hz, 2H), 4.01-4.08 (m, 4H), 3.08-3.19 (s, 2H), 2.90-2.92 (m, 1H), 2.37-2.59 (m, 1H), 2.21-2.34 (m, 3H), 2.02-2.11 (m, 2H), 1.16 (t, / = 6.0 Hz, 3H); MS (m/z): 501.1 [M+Na].
Example 97
2-(3-(4-((5-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 97)
LiOH (9.0 mg, 0.376 mmol) in water (2-3 mL) was added to a solution of ethyl 2-(3- (4-((5-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl) oxetan-3-yl)acetate (Compound 96, 20 mg, 0.042 mmol ) in MeOH and THF (1 :4) (2 mL:0.5 mL) at RT. The resulting solution was stirred at RT for 12 h. After completion of the reaction, solvent was removed and residue was washed with diethylether. The ether layer was removed and the residue was acidified with saturated NH4C1 solution then extracted with EtOAc. The organic layer was washed with brine (20 mL), dried over anhydrous Na2S04 and concentrated. The crude compound was triturated with petroleum ether to obtain the title compound. JH NMR (CDCI3, 300 MHz): δ 6.79-7.34 (m, 7H), 5.70 (br s, 1H), 5.00 (d, / = 6.0 Hz, 2H), 4.86 (d, / = 6.0 Hz, 2H), 4.00 (t, / = 5.7 Hz, 2H), 3.18 (s, 2H), 2.91-3.14 (m, 2H), 2.06-2.56 (m, 6H ); MS (m/z): 448.8 [M-H]. Example 98
Ethyl 2-(3-(4-((5-(isopentyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetate (Compound 98)
The title compound was prepared in an analogous manner as Compound 96 of Example 96 involving reaction of 5-hydroxy-2,3-dihydro-lH-inden-l-one with isopentyl 4- methylbenzenesulfonate. JH NMR (CDCI3, 300 MHz) : δ 7.30 - 7.33 (m, 1H), 7.11 (d, / = 9.0 Hz, 2H), 6.95 (d, / = 9.0 Hz, 2H), 6.79 - 6.83 (m, 2H), 5.69 - 5.70 (m, 1H), 5.00 (d, / = 6.0 Hz, 2H), 4.86 (d, / = 6.0 Hz, 2H), 3.98 - 4.08 (m, 4H), 3.08 - 3.18 (m, 3H), 2.84 - 2.94 (m, 1H), 2.48 - 2.58 (m, 1H), 2.20 - 2.27 (m, 1H), 1.81- 1.89 (m, 1H), 1.68- 1.72 (m, 2H), 1.16 (t, / = 6.0 Hz, 3H), 0.98 (d, / = 6.0 Hz, 6H); MS (m/z): 461.1 [M+Na].
Example 99
2-(3-(4-((5-(isopentyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 99)
The title compound was prepared in an analogous manner as compound 97 of Example 97. Compound 99 was obtained by hydrolyzing the compound of Example 98. JH NMR (CDCI3, 300 MHz): δ 6.79-7.32 (m, 7H), 5.70 (brs, 1H), 5.00 (d, / = 6.0 Hz, 2H), 4.86 (d, / = 5.7 Hz, 2H), 4.00 (t, / = 6.6 Hz, 2H), 3.18 (s, 2H), 2.19-3.10 (m, 5H), 1.7-1.8 (m, 2H), 0.97 (d, / = 6.6 Hz, 6H); MS (m/z): 433.0 [M+Na].
Example 100
Ethyl 2-(3-(4-((5-((3-methyloxetan-3-yl)methoxy)-2,3-dihydro-lH-inden-l-yl)oxy) phenyl)oxetan-3-yl)acetate (Compound 100)
The title compound was prepared in an analogous manner as Compound 96 of Example 96 involving reaction of 5-hydroxy-2,3-dihydro-lH-inden-l-one with (3- methyloxetan-3-yl)methyl 4-methylbenzenesulfonate. JH NMR (CDC13, 300 MHz) : δ 7.32 - 7.35 (m, 1H), 7.11 (d, / = 9.0 Hz, 2H), 6.95 (d, / = 9.0 Hz, 2H), 6.83 - 6.88 (m, 2H), 5.70 - 5.71 (m, 1H), 5.00 (d, / = 6.0 Hz, 2H), 4.86 (d, / = 6.0 Hz, 2H), 4.63 (d, / = 6.0 Hz, 2H), 4.47 (d, / = 6.0 Hz, 2H), 4.01 - 4.08 (m, 4H), 3.12 (m, 3H), 2.91 -2.92 (m, 1H), 2.54 - 2.56 (m, 1H), 2.24 - 2.27 (m, 1H), 1.45 (s, 3H), 1.16 (t, / = 6.0 Hz, 3H); MS (m/z): 453.2 [M+H].
Example 101
2- (3-(4-((5-((3-Methyloxetan-3-yl)methoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl) oxetan-
3 - yl) acetic acid (Compound 101) The title compound was prepared in an analogous manner as compound 97 of Example 97. Compound 101 was obtained by hydrolyzing the compound of Example 100. JH NMR (CDCI3, 300 MHz): δ 6.82-7.34 (m, 7H), 5.70 (br s, 1H), 5.01 (d, / = 5.7 Hz, 2H), 4.86 (d, / = 5.7 Hz, 2H), 4.64 (d, / = 5.7 Hz, 2H), 4.48 (d, / = 6.0 Hz, 2H), 4.04 (s, 2H), 3.18 (s, 2H), 2.91-3.14 (m, 2H), 2.19-2.56 (m, 2H ), 1.45 (s, 3H); MS (m/z): 447.0 [M+Na].
Example 102
Ethyl 2-(3-(4-((3-phenoxybenzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 102)
CS2CO3 (207 mg, 0.635 mmol) was added to the solution of ethyl 2-(3-(4- hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 150 mg, 0.635 mmol) and 1- (bromomethyl)-3-phenoxybenzene (167 mg, 0.635 mmol) in anhydrous DMF (2 mL). The reaction mixture was heated at 50 °C for 2 h. After completion of reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2S04, concentrated and purified by column chromatography to obtain the title compound (160 mg). Yield: 60.2 %; JH NMR (300 MHz, CDCI3): δ 7.32-7.55 (m, 3H), 6.91-7.18 (m, 10H), 5.03 (s, 2H), 4.98 (d, J = 6.0 Hz, 2 H), 4.87 (d, J = 6.0 Hz, 2 H), 4.05 (q, / = 6.9 Hz, 2 H), 3.10 (s, 2 H), 1.14 (t, / = 7.2 Hz, 3 H); MS: m/z 441 [M+Na].
Example 103
2-(3-(4-((3-phenoxybenzyl) oxy) phenyl) oxetan-3-yl) acetic acid (Compound 103)
Lithium hydroxide (3183 μL·, 4.77 mmol) was added to a solution of ethyl 2-(3-(4-((3- phenoxybenzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 102, 333 mg, 0.796 mmol) in 15 mL of THF and MeOH (4: 1) and the mixture was stirred at RT for 4 h. After completion of reaction the solvent was removed. The reaction mixture was neutralized with saturated NH4CI and the mixture was the extracted with EtOAc. The organic layer was washed with brine, dried over Na2S04 and concentrated to obtain the title compound (250 mg). Yield: 80 % yield; JH NMR (300 MHz, DMSO-d6): δ 12.8 (s, 1H), 7.37-7.42 (m, 3H), 7.12-7.22 (m, 5H), 7.07 (s, 1 H), 7.02 (d, / = 8.4 Hz, 2H), 6.94 (d, / = 8.4 Hz, 2H) 5.07 (s, 2H), 4.76 (d, / = 6.0 Hz, 2H), 4.71 (d, J = 6.0 Hz, 2H), 2.91 (s, 2H); MS: m/z 391 [M+H].
Example 104
Ethyl 2-(3-(4-((3-(4-fluorophenoxy)benzyl)oxy)phenyl)oxetan-3-yl) acetate (Compound 104) The title compound was prepared in an analogous manner as Compound 102 of Example 102 involving reaction of l-(bromomethyl)-3-(4-fluorophenoxy) benzene with ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1). Yield: 49 %; JH NMR (300 MHz, DMSO d6): δ 7.38-7.36 (m, 2H), 7.26-7.14 (m, 5H), 7.08-7.04 (m, 2H), 6.96-6.90 (m, 3H), 5.08 (s, 2H), 4.75 (s, 4H), 3.90 (q, J = 7.2 Hz, 2H), 3.07 (s, 2H), 1.04 (t, J = 6.9 Hz, 3H); MS (m/z): 459 [M+Na]+.
Example 105
2-(3-(4-((3-(4-Fluorophenoxy)benzyl)oxy)phenyl)oxetan-3-yl)aceticacid (Compound 105)
The title compound was prepared in an analogous manner as compound 103 of Example 103. Compound 105 was obtained by hydrolyzing the compound of Example 104. Yield: 79%; JH NMR (300 MHz, DMSO d6): δ 12.11 (s, 1H), 7.36-7.41 (m ,1H), 7.18-7.26 (m, 5H), 7.05-7.09 (m, 3H), 6.91-6.96 (m, 3H), 5.07 (s, 2H), 4.73 (s, 4H), 3.00 (s, 2H); MS (m/z): 431 [M+Na]+.
Example 106
Ethyl 2-(3-(4-((4-phenoxybenzyl)oxy)phenyl)oxetan-3-yl) acetate (Compound 106)
The title compound was prepared in an analogous manner as Compound 102 of Example 102 involving reaction of l-(bromomethyl)-4-phenoxybenzene with ethyl 2-(3-(4- hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1). Yield: 68%; JH NMR (300 MHz, DMSO-de): δ 7.37-7.47 (m, 5H), 7.12-7.18 (m, 3H), 6.96 -7.03 (m, 5H), 5.05 (s, 2H), 4.75 (s, 4H), 3.93 (q, / = 7.2 Hz, 2H), 3.08 (s, 2H), 1.05 (t, / = 6.9 Hz, 3H); MS (m/z): 441 [M+Na].
Example 107
2-(3-(4-((4-phenoxybenzyl) oxy) phenyl)oxetan-3-yl) acetic acid (Compound 107)
The title compound was prepared in an analogous manner as compound 103 of Example 103. Compound 107 was obtained by hydrolyzing the compound of Example 106. Yield: 100%; JH NMR (300 MHz, DMSO-d6): δ 12.11 (s, 1H), 7.37-7.47 (m, 4H), 7.12-7.22 (m, 4H), 6.95-7.03 (m, 5H), 5.04 (s, 2H), 4.74 (s, 4H), 2.96 (s, 2H); MS (m/z): 413 [M+Na]
Example 108
Ethyl 2-(3-(4-((2-phenoxybenzyl) oxy) phenyl) oxetan-3-yl) acetate (Compound 108)
The title compound was prepared in an analogous manner as Compound 102 of Example 102 involving reaction of l-(bromomethyl)-2-phenoxybenzene with ethyl 2-(3-(4- hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1). Yield: 72%; JH NMR (300 MHz, DMSO-d6): δ 7.58 (d, J= 7.5 Hz, 1H), 7.40-7.35 (m, 3H), 7.19-7.12 (m, 4H), 6.99 (d, J = 7.8 Hz, 2H), 6.93-6.90 (m, 3H), 5.09 (s, 2H), 4.73 (s, 4H), 3.93 (q, J= 6.9 Hz, 2H), 3.06 (s, 2H), 1.03 (t, J = 6.9 Hz, 3H); MS (m/z): 441 [M+Na].
Example 109
2-(3-(4-((2-Phenoxybenzyl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 109)
The title compound was prepared in an analogous manner as compound 103 of Example 103. Compound 109 was obtained by hydrolyzing the compound of Example 108. Yield: 88%; JH NMR (300 MHz, DMSO-d6): δ 11.75 (s, 1H), 7.58 (d, J= 7.2 Hz, 1H), 7.40- 7.35 (m, 3H), 7.22-7.10 (m, 4H), 6.99 (d, / = 8.1 Hz, 2H), 6.92 (d, J= 8.1 Hz, 3H), 5.09 (s, 2H), 4.72 (s, 4H), 2.97 (s, 2H); MS (m/z): 413 [M+Na].
Example 110
Ethyl 2-(3-(4-((4-(2,6-dimethylphenoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound
110)
Step 1
Methyl 4-(2,6-dimethylphenoxy)benzoate
Di-teri-butyl(2',4',6'-triisopropyl-[l,l'-biphenyl]-2-yl)phosphine (20.60 mg, 0.070 mmol), potassium phosphate (987 mg, 4.65 mmol) and palladium diacetate (10.44 mg, 0.047 mmol) was added to a solution of methyl 4-bromobenzoate (500 mg, 2.325 mmol) and 2,6- dimethylphenol (341 mg, 2.79 mmol) in toluene under argon atmosphere. The reaction mixture was stirred at 100 °C for 12-15 h. After completion of reaction, the reaction mixture was filtered over celite® bed, washed with ethyl acetate, concentrated and purified by column chromatography (silica gel column, 15% ethylacetate/petroleum ether as eluent) to obtain the title compound (459 mg). Yield: 76.7 %; JH NMR (300 MHz, CDC13) δ: 9.97 (d, / = 8.7 Hz, 2H), 7.12 (s, 3H), 6.80 (d, / = 8.7 Hz, 2H), 3.89 (s, 3H), 2.12 (s, 6H); MS (m/z): 257.1 [M + H].
Step 2
(4-(2,6-Dimethylphenoxy)phenyl)methanol
Lithium aluminum hydride (1609 μΐ, 1.609 mmol) (1 molar solution in THF) was added to methanolic solution of methyl 4-(2,6-dimethylphenoxy)benzoate (compound of step 1, 165 mg, 0.644 mmol) at 0 °C and the reaction mixture was stirred at RT for 2-3 h. After completion of reaction, methanol was evaporated and the residue was extracted with ethyl acetate and purified by column chromatography to obtain the title compound (127 mg). Yield: 85.3 %; JH NMR (300 MHz, CDCI3): δ 7.27 (d, / = 9.0 Hz, 2H), 7.13-7.05 (m, 3H), 6.76 (d, / = 8.4 Hz, 2H), 4.63 (d, / = 5.4 Hz, 2H), 2.13 (s, 6H); MS (m/z): 229.6 [M + H].
Step 3
Ethyl 2-(3-(4-((4-(2,6-dimethylphenoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 110)
Diisopropyl diazene-l,2-dicarboxylate (216 μΐ, 1.095 mmol) was added to a solution of (4-(2,6-dimethylphenoxy)phenyl)methanol (Compound of step 2, 100 mg, 0.438 mmol),ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 103 mg, 0.438 mmol) and triphenylphosphine (230 mg, 0.876 mmol) in DCM (5 mL) at 0 °C and the reaction mixture was stirred at RT for 4-8 h. After completion of reaction, the reaction mixture was purified by column chromatography (silica gel column, 30% EtOAc/petroleum ether as eluent) to obtain the title compound (166 mg). Yield: 85.3%; JH NMR (300 MHz, CDCI3) δ: 7.32 (d, / = 8.4 Hz, 2H), 7.12-7.10 (m, 5H), 6.96 (d, / = 8.4 Hz, 2H), 6.78 (d, / = 8.4 Hz, 2H), 5.01-4.97 (m, 4H), 4.86 (d, / = 6.0 Hz, 2H), 4.02 (q, / = 7.2 Hz, 2H), 3.11 (s, 2H), 2.14 (s, 6H), 1.14 (t, / = 7.2 Hz, 3H); MS (m/z): 469.1 [M + Na].
Example 111
2-(3-(4-((4-(2,6-dimethylphenoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 111)
The title compound was prepared in an analogous manner as compound 103 of Example 103. Compound 111 was obtained by hydrolyzing the compound of Example 110. Yield: 85.3 %; JH NMR (300 MHz, DMSO-d6) δ: 12.13 (br s, 1H), 7.38 (d, / = 8.1 Hz, 2H), 7.21-7.07 (m, 5H), 6.96 (d, / = 8.4 Hz, 2H), 6.74 (d, / = 8.4 Hz, 2H), 4.98 (m, 2H), 4.74 (m, 4H), 3.00 (s, 2H), 2.05 (s, 6H); MS (m/z): 417.7 [M-H].
Example 112
Ethyl 2-(3-(4-(3-phenyl-3-(pyridin-3-yl)propoxy)phenyl)oxetan-3-yl)acetate (Compound
112)
Step 1
Phenyl(pyridin-2-yl)methanol
Phenyl magnesium bromide solution (3.31 g, 18.67 mmol) in THF (20 mL of 1 M solution) was added drop-wise to the ice-cold solution of pyridine-2-aldehyde (2 g, 18.67 mmol) in dry THF (10 mL) under Argon atmosphere. The reaction mixture was stirred in ice bath for 1 h. After completion of reaction, the reaction mixture was added to water (50 mL), extracted with EtOAc, dried over Na2S04, concentrated and purified by flash column chromatography (0-40% EtOAc-PE, silica gel column) to obtain the title compound (2.6 g). Yield: 75%; JH NMR (CDC13, 300 MHz): δ 8.59 (d, J = 2.4 Hz, 1H), 7.65 (t, J = 4.5 Hz, 1H), 7.41 (d, J = 4.5 Hz, 2H), 7.37 (t, J = 4.5 Hz, 2H), 7.31 (t, J = 4.2 Hz, 1H), 7.23 (t, J = 3.6 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 5.77 (d, J = 1.8 Hz, 1H), 5.32(d, J = 1.8 Hz, 1H); MS (m/z): (M-18) 168.
Step 2
Phenyl(pyridin-2-yl)methanone
A solution of phenyl(pyridin-2-yl)methanol (2.0 g, 10.8 mmol) and Mn(¾ (9.4 g, 108 mmol) in THF (30 mL) was stirred at RT for 2 h. After completion of reaction, the reaction mixture was filtered over celite® bed and washed with EtOAc. The filtrate was concentrated to obtain the title compound (1.9 g). Yield: 96 %; JH NMR (CDC13, 300 MHZ): δ 8.75 (d, J = 2.4 Hz, 1H), 8.09 (d, J = 5.1 Hz, 3H), 7.94 (t, J = 4.5 Hz, 1H), 7.63 (t, J = 4.5 Hz, 1H), 7.52 (t, J = 4.5 Hz, 3H); MS (m/z): [M+H] 184.2, [M+Na] 206.1.
Step 3
Ethyl 3-phenyl-3-(pyridin-2-yl)acrylate
Triethylphosphonoacetate (2.458 g, 10.96 mmol) was added to an ice-cold suspension of NaH (0.3 g, 12.5 mmol) in dry THF (20 mL). The reaction mixture was stirred at RT for 15 minutes, followed by the addition of a solution of phenyl(pyridin-2-yl)methanone (compound of step 2, 1.9 g, 10.37 mmol) in dry THF (8 mL) in dry THF (8 mL). The reaction mixture was further stirred at RT for 1 h. After completion of reaction, the reaction mixture was poured into ice water (25 mL), extracted with ethyl acetate, concentrated and purified by flash column chromatography (silica gel column, 0-30% ethyl acetate/petroleum ether) to obtain the title compound (1 g). Yield: 38 %; JH NMR (CDC13, 300 MHz): δ 8.69 (d, J = 2.4 Hz, 1H), 7.62 (t, J = 4.2 Hz, 1H), 7.44 (d, J = 3.9 Hz, 3H), 7.27 (d, J = 4.5, 3H), 7.19 (s, 1H), 7.03 (d, J = 4.8 Hz, 1H), 4.09 (q, J = 4.2 Hz, 2H), 1.13 (t, J = 4.2 Hz, 3H). MS (m/z): [M+H] 254.2.
Step 4
3 -phenyl- 3- (pyridin-2-yl)prop-2-en- 1 -ol Diisobutylaluminium hydride (DiBAL-H) (1.344 g) was added drop-wise to an ice- cold solution of ethyl 3-phenyl-3-(pyridin-2-yl)acrylate (0.8 g, 3.16 mmol) in dry THF (8 mL). The reaction mixture was stirred overnight at RT. After completion of reaction, the reaction mixture was quenched by adding aq. sodium-potassium tartrate. The compound was extracted with ethyl acetate, concentrated and purified by flash column chromatography (silica gel column, 0-70% ethyl acetate/petroleum ether) to obtain the title compound (0.66 g). Yield: 99%; JH NMR (CDC13, 300 MHz): δ 8.63 (d, J = 2.4 Hz, 1H), 7.60 (m, 1H), 7.44 (m, 2H), 7.35 (m, 1H), 7.25 (m, 2H), 7.18 (m, 1H), 6.98 (m, 2H), 4.27 (d, J = 3.9 Hz, 2H); MS (m/z): [M+H] 212.2, [M-H] 209.9.
Step 5
2- (3-bromo- 1 -phenylprop- 1 -en- 1 -yl)pyridine
Potassium tribromide (PBr3) was added drop-wise to an ice-cold solution of 3-phenyl-
3- (pyridin-2-yl)prop-2-en-l-ol in dry DCM (8 mL). The reaction mixture was stirred for 1 h. After completion of reaction, the reaction mixture is diluted with ethyl acetate and petroleum ether (1 : 1, 25 mL). The reaction mixture is washed with saturated aqueous NaHC(¾ and dried over Na2S04, concentrated and purified by flash column chromatography (silica gel column, 0-5% ethyl acetate/petroleum ether) to obtain the title compound. Yield: 85%; JH NMR (CDCI3, 300 MHz): δ 8.65 (d, J = 2.4 Hz, 1H), 7.58 (t, J = 4.5 Hz, 1H), 7.49 (m, 2H), 7.44 (m, 1H), 7.33 (m, 2H), 7.20 (m, 2H), 6.95 (d, J = 4.8 Hz, 1H), 4.05 (s, 2H); MS (m/z): [M+H] 275.1, [M-H] 272.8.
Step 6
Ethyl 2-(3-(4-((3-phenyl-3-(pyridin-2-yl)allyl)oxy)phenyl)oxetan-3-yl)acetate
A solution of ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 0.2 g), 2-(3-bromo-l -phenylprop- 1 -en- l-yl)pyridine (compound of step 5, 0.232 g) and CS2CO3 in dry DMF (2 mL) was stirred overnight. After completion of reaction, the reaction mixture was poured in ice-cold water, extracted with ethyl acetate, concentrated and purified by flash column chromatography and preparative HPLC (2% acetonitrile in water to 100% acetonitrile) to obtain the title compound (0.1 g). Yield: 30 %; JH NMR (CDCI3, 300 MHz): δ
7.60 (m, 2H), 7.45 (m, 2H), 7.28 (s, 1H), 7.21 (m, 1H), 7.05 (m, 4H), 6.83 (d, J = 5.1 Hz, 1H), 6.80 (d, J = 4.8 Hz, 2H), 5.43 (s, 1H), 5.00 (d, J = 3.6 Hz, 2H), 4.87 (d, J = 3.6 Hz, 2H),
4.61 (s, 2H), 4.04 (q, J = 4.5 Hz, 2H), 3.11 (s, 2H), 1.15 (t, J = 4.5 Hz, 3H); MS (m/z): [M+H] 430.4. Step 7
Ethyl 2-(3-(4-(3-phenyl-3-(pyridin-2-yl)propoxy)phenyl)oxetan-3-yl)acetate
A solution of ethyl 2-(3-(4-((3-phenyl-3-(pyridin-2-yl)allyl)oxy)phenyl) oxetan-3- yl)acetate and 10% Pd-C in ethanol (10 mL) is shaken in a Parr hydrogenator at 60 psi for 4 h. After completion of reaction, the reaction mixture is filtered and washed with ethanol. The filtrate is concentrated to obtain the title compound (0.04 g). Yield: 87%; JH NMR (CDC13, 300 MHz): δ 8.60 (d, J = 2.1 Hz, 1H), 7.59 (t, J = 4.2 Hz, 1H), 7.37 (d, J = 4.5 Hz, 2H), 7.31 (d, J = 4.5 Hz, 2H), 7.22 (t, J = 5.1 Hz, 2H), 7.13 (t, J = 3.6 Hz, 1H), 7.06 (d, J = 5.1 Hz, 2H), 6.82 (d, J = 5.1 Hz, 2H), 4.98 (d, J = 3.6 Hz, 2H), 4.85 (d, J = 3.6 Hz, 2H), 4.41 (t, J = 4.5 Hz, 1H), 4.04 (q, J = 4.2 Hz, 2H), 3.92 (m, 2H), 3.09 (s, 2H), 2.82 (m, 1H), 2.56 (m, 1H), 1.15 (t, J = 4.2 Hz, 3H).
Example 113
2-(3-(4-(3-phenyl-3-(pyridin-2-yl)propoxy)phenyl)oxetan-3-yl)acetic acid (Compound 113)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 113 was obtained by hydrolyzing the compound of Example 112. Yield: 49%; JH NMR (CDC13, 300 MHz): δ 8.54 (s, 1H), 7.70 (t, J = 4.5 Hz, 1H), 7.38 (m, 3H), 7.29 (t, J = 4.5 Hz, 2H), 7.20 (m, 3H), 7.09 (d, J = 5.1 Hz, 1H), 6.83 (t, J = 6.6 Hz, 2H), 4.74 (d, J = 3.3 Hz, 2H), 4.69 (d, J = 3.3 Hz, 2H), 4.37 (t, J = 4.5 Hz, 1H), 3.83 (s, 2H), 3.47 (m, 2H), 2.90 (s, 1H), 2.44 (m, 2H); MS (m/z): [M+H] 404.6, [M-H] 402.1.
Example 114
Ethyl 2-(3-(4-((3,3-diphenylallyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 114)
Step 1
Ethyl 3,3-diphenylacrylate
Triethylphosphonoacetate (2.46 g, 10.98 mmol) in dry THF (5 mL) was added drop-wise to an ice-cold suspension of NaH (0.263 g, 10.98 mmol) in dry THF (15 mL). The reaction mixture was stirred 0 °C for 15 minutes, followed by the drop-wise addition of benzophenone (2 g, 10.98 mmol) in dry THF (10 mL). The reaction mixture was stirred overnight at RT. After completion of the reaction, the reaction mixture was poured in ice-cold aqueous HC1 (2 N, 50 mL) and the compound was extracted by ethyl acetate. The organic layer was dried over Na2S04 and concentrated to obtain the title compound. JH NMR (CDCI3, 300 MHz): δ 7.84 (d, J = 4.2 Hz, 2H), 7.63 (t, J = 4.5 Hz, 1H), 7.52 (t, J = 4.8 Hz, 2H), 6.38 (s, 1H), 7.41 (m, 5H), 4.13 (q, J = 4.5 Hz, 2H), 1.48 (t, J = 4.5 Hz, 3H).; MS (m/z): [M+H] 253.2, [M-H] 250.8.
Step 2
3 ,3-diphenylprop-2-en- 1 -ol
MeOH (4 mL) was added drop-wise to a solution of ethyl 3,3-diphenylacrylate (Compound of step 1, 2.8 g, 11.1 mmol) and NaBH4 (1.684 g, 44.4 mmol) in THF (30 mL) and the reaction mixture was stirred at RT for 12 h and refluxed at 65 °C for 1 h. After completion of reaction, the reaction mixture was poured into water (50 mL), extracted with ethyl acetate and petroleum ether (1 : 1). The organic solvent was evaporated and the residue was purified by flash column chromatography (silica gel column, 0-5% ethyl acetate/petroleum ether) to obtain the title compound (0.57 g). Yield: 24.43%; JH NMR (CDC13, 300 MHz): δ 7.39 (m, 3H), 7.29 (m, 5H), 7.20 (d, J = 6.3 Hz, 2H), 6.29 (t, J = 6.6 Hz, 1H), 4.24 (m, 2H); MS (m/z): [M]+ 210.1.
Step 3
(3-Bromoprop- 1 -ene- 1 , 1 -diyl)dibenzene
PBr3 (0.644 g, 2.37 mmol) was added to an ice-cold solution of 3,3-diphenylprop-2- en-l-ol (compound of step 2, 0.5 g, 2.37 mmol) in DCM (5 mL) and the reaction mixture was stirred in ice bath for 1 h. After completion of reaction, petroleum ether was added to the reaction mixture. The mixture was washed with water, aqueous NaHCC>3, brine, dried over Na2S04 and concentrated to obtain the title compound. Yield: 92%; JH NMR (CDCI3, 300 MHz): δ 7.46-7.52 (m, 4H), 7.21-7.32 (m, 6H), 6.38 (t, J = 5.1 Hz, 1H), 4.09 (d, J=5.1 Hz, 2H); MS (m/z): [M+H] 274.1.
Step 4
Ethyl 2-(3-(4-((3,3-diphenylallyl)oxy)phenyl)oxetan-3-yl)acetate
A solution of (3-Bromoprop-l-ene-l,l-diyl)dibenzene (Compound of step 3, 0.2g, 0.72mmol), and ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 0.173 g, 0.72 mmol) in DMF (3 mL) was added to flame dried Cs2C03 (0.329 g, 0.72 mmol) and the reaction mixture was stirred at RT for 1 h. After completion of reaction, the reaction mixture was diluted with ethyl acetate (30 mL). The organic layer was washed with water, brine, dried over Na2S04, concentrated and purified by flash column chromatography (silica gel column, 0-30% ethyl acetate/petroleum ether) to obtain the title compound (0.2 g). Yield: 63.7%; JH NMR (CDCI3, 300 MHz): δ 7.41-7.46 (m, 3H), 7.20-7.29 (m, 4H), 7.24 (d, J = 7.5 Hz, 3H), 7.08 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 6.34 (t, J = 6.6 Hz, 1H), 4.99 (d, J = 6.0 Hz, 2H), 4.86 (d, J = 6.0 Hz, 2H), 4.61 (d, J = 6.6 Hz, 2H), 4.04 (q, J = 6.9 Hz, 2H), 3.09 (s, 2H), 1.15 (t, J = 6.9 Hz, 3H); MS (m/z): [M+H] 429.0
Example 115
2-(3-(4-((3,3-Diphenylallyl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 115)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 115 was obtained by hydrolyzing the compound of Example 114. Yield: 73.8 %; JH NMR (DMSO-d6, 300 MHz): δ 7.46 (t, J = 4.5 Hz, 2H), 7.41 (d, J = 4.5 Hz, 1H), 7.34-7.35 (m, 3H), 7.17-7.24 (m, 6H), 6.83 (d, J = 4.8 Hz, 2H), 6.35 (t, J = 3.9 Hz, 1H), 4.74 (d, J = 3.3 Hz, 2H), 4.70 (d, J = 3.3 Hz, 2H), 4.54 (d, J = 3.9 Hz, 2H), 2.93 (s, 2H); MS (m/z): [M]+ 400.3, [M+H] 401.2.
Example 115a
2-(3-(4-(3,3-diphenylpropoxy)phenyl)oxetan-3-yl)acetic acid (Compound 115a)
A mixture of 2-(3-(4-((3,3-diphenylallyl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 115, 0.040 g, 0.14 mmol) and 10% Pd-C (10 mg) in ethanol (10 mL) was shaken in a Parr hydrogenator at 60 psi for 8 h. The reaction mixture was filtered through celite® bed, washed with ethanol and the filtrate was concentrated to obtain the title compound (0.040 g) as white solid. Yield: 98%; JH NMR 300 MHz, DMSO-d6: δ 7.35-7.34 (m, 4H), 7.30-7.27 (m, 4H), 7.23 (d, J = 5.1Hz, 2H), 7.18-7.16 (m, 2H), 6.76 (d, J = 5.1Hz, 2H), 4.80 (d, J = 3.3 Hz, 2H), 4.61 (d, J = 3.5 Hz, 2H), 4.21 (s, 1H), 3.81 (s, 2H), 2.57 (s, 2H), 1.074 (t, J = 4.2 Hz, 2H); MS (m/z): 403.2 (M+H).
Example 116
Benzyl l-(4-((4-(3-(2-ethoxy-2-oxoethyl)oxetan-3-yl)phenoxy)methyl)benzyl)
spiro[indoline-3,4'-piperidine]-r-carboxylate (Compound 116)
Step 1
Benzyl spiro[indoline-3,4'-piperidine]-r-carboxylate
A solution of 4-formyl-N-Cbz-piperidine (20 g, 81 mmol) in toluene: acetonitrile (49: 1, 60 mL) was added drop-wise to a solution of phenylhydrazine (8.75 g, 81 mmol) and trifluoroacetic acid (20.56 mL, 267 mmol) in toluene: acetonitrile (49:1, 300 mL). The reaction mixture was stirred overnight at 35 °C. The reaction mixture was then cooled in ice- bath (0 to 5 °C), followed by the addition of MeOH (30 mL) and sodium borohydride (4.59 g, 121 mmol). The reaction mixture was further stirred for 45 minutes. After completion of reaction, the reaction mixture was diluted with ethyl acetate (75 mL), washed with 5% aq. ammonia, brine, dried over Na2S04 and concentrated. The residue was purified by flash column chromatography (silica gel column, 1-40% ethyl acetate/petroleum ether as eluent) to obtain the title compound (11.2 g). Yield: 34.7%; JH NMR (CDCI3, 300 MHz): δ 7.32-7.40 (m, 4H), 7.27 (s, 1H), 7.04-7.10 (m, 2H), 6.74-6.79 (m,lH), 6.68 (d, J = 7.5 Hz, 1H), 5.18 (s, 2H), 4.15 (br s,2H), 3.78 (s,lH), 3.50 (s, 2H), 3.06 (t, J = 12.3 Hz, 2H), 1.84-1.88 (m, 4H); MS (m/z): [M+H] 323.2, [M+2H] 324.1, [M-H] 321.5.
Step 2
B enzyl 1 - (4- ((4- (3 -(2-ethoxy-2-oxoethyl)oxetan-3 -yl)phenoxy)methyl)benzyl)spiro
[indoline-3 ,4'-piperidine] - 1 '-carboxylate
A reaction mixture of benzyl spiro[indoline-3,4'-piperidine]-r-carboxylate (Compound of step 1, 0.1 g, 0.310 mmol), ethyl 2-(3-(4-((4-(bromomethyl)benzyl) oxy)phenyl)oxetan-3-yl)acetate (Intermediate 7, 0.156 g, 0.372 mmol) and K2CO3 (0.094 g, 0.682 mmol) in DMF (5 mL) was heated to 80°C for 3 h. After completion of reaction, the solvent was removed and the residue was extracted with EtOAc (15 mL), washed with water, brine and concentrated. The residue was purified by column chromatography (silica gel column, 1-50% EtOAc/petroleum ether as eluent) to obtain the title compound (0.17 g). Yield: 78%; JH NMR (CDC13, 300 MHZ): δ 1.17 (t, / = 7.2 Hz, 3H), 1.72-1.85 (m, 4H), 2.95 (br s, 2H), 3.11 (s, 2H), 3.28 (s, 2H), 4.05 (q, / = 7.2 Hz, 2H), 4.14 (q, / = 7.2 Hz, 2H), 4.32 (s, 2H), 4.86 (d, / = 6.0 Hz, 2H), 5.00 (d, / = 6.0 Hz, 2H), 5.05 (s, 2H), 5.17 (s, 2H), 6.53 (d, / = 7.8 Hz, 1H), 6.73 (t, / = 7.2 Hz, 1H), 6.97 (d, / = 8.4 Hz, 2H), 7.04 (d, / = 7.2 Hz, 1H), 7.09-7.13 (m, 3H), 7.28-7.35 (m, 9H); MS (m/z): [M+H] 661.2.
Example 116a
2-(3-(4-((4-((r-((Benzyloxy)carbonyl)spiro[indoline-3,4'-piperidin]-l-yl)methyl) benzyl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 116a)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 116a was obtained by hydrolyzing the compound of Example 116. Yield 61%; JH NMR (300 MHz, DMSO-d6): δ 1.26 (d, 2H), 1.66 (m, 4H), 3.00 (s, 2H), 3.31 (d, / = 9.0 Hz, 2H), 3.98 (d, / = 13.2 Hz, 2H), 4.33 (s, 2H), 4.74 (s, 4H), 5.07 (d, / = 9.3 Hz, 4H), 6.53-6.62 (m, 3H), 6.96-7.05 (m, 4H), 7.19 (d, / = 8.4 Hz, 2H), 7.33-7.43 (m, 8H), 12.16 (br s, 1H); MS (m/z) 633.1 (M+H) Example 117
Ethyl 2-(3 -(4-((4-(( 1 -(methylsulfonyl)spiro[indoline-3 ,4'-piperidin] - 1 '-yl)methyl)
benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 117)
Step 1
Benzyl l-(methylsulfonyl)spiro[indoline-3,4'-piperidine]- -carboxylate
Methanesulfonyl chloride (0.145 mL, 1.861 mmol) was added to a solution of benzyl spiro[indoline-3,4'-piperidine]- -carboxylate (Compound of step 1 of Example 116, 0.5 g, 0. 1.551 mmol) and triethylamine (0.648 mL, 4.65 mmol) in DCM (20 mL) at 0-5 °C. The reaction mixture was stirred at RT for 3h. After completion of reaction, water (20 mL) and DCM (20 mL) was added to the reaction mixture. The organic layer was separated and dried over Na2S04. The solvent was evaporated and the residue was purified by flash column chromatography (silica gel column, 1-70% EtO Ac/petroleum ether as eluent) to obtain the title compound (0.42 g). Yield: 68%; JH NMR (DMSO-d6, 300 MHz): δ 1.60 (s, 3H), 1.70- 1.74 (m, 2H), 2.93 (s, 3H), 2.97-3.02 (m, 1H), 3.87 (s, 2H), 4.25 (br s, 2H), 5.19 (s, 2H), 7.09 (t, / = 7.2 Hz, 1H), 7.15 (d, / = 7.2 Hz, 1H), 7.25 (d, / = 7.2 Hz, 1H), 7.40 (brs, 6H); MS (m/z): [M]+ 400.1.
Step 2
l-(Methylsulfonyl)spiro[indoline-3,4'-piperidine]
Benzyl 1 -(methylsulfonyl)spiro[indoline-3 ,4'-piperidine] - 1 '-carboxylate (Compound of step 1, 0.4 g, 0.999 mmol) and ammonium formate (0.315 g, 4.99 mmol) were added to a suspension of Pd/C (0.1 g, 0.999 mmol) in MeOH (30 mL) at RT. The reaction mixture was refluxed for 2 h. After completion of reaction, the reaction mixture was filtered over celite® bed. The filtrate was concentrated and the residue was purified by flash column chromatography (1-3% MeOH / chloroform as eluent, silica gel column) to obtain the title compound (0.17 g). Yield: 64%; JH NMR (DMSO d6, 300 MHZ): δ 1.65 (h, 2H), 1.93 (m, 2H), 2.77 (t, / = 12 Hz, 2H), 2.92 (s, 3H), 3.10 (d, / = 12 Hz, 2H), 3.87 (s, 2H), 7.09 (t, / = 7.2 Hz, 1H), 7.23 (d, / = 8.7 Hz, 2H), 7.41 (d, / = 7.8 Hz, 1H); HPLC: 99.36%; MS (m/z): [M+H] 267.2.
Step 3
Ethyl 2-(3 -(4-((4-(( 1 -(methylsulfonyl)spiro[indoline-3 ,4'-piperidin] - 1 '-yl)methyl)
benzyl)oxy)phenyl)oxetan-3-yl)acetate A reaction mixture of l-(methylsulfonyl)spiro[indoline-3,4'-piperidine] (Compound of step 2, 0.09 g, 0.338 mmol), ethyl 2-(3-(4-((4-(bromomethyl)benzyl) oxy)phenyl)oxetan-3- yl)acetate (Intermediate 7, 0.142 g, 0.338 mmol) and potassium carbonate (0.103 g, 0.743 mmol) in DMF (10 mL) was heated to 80°C for 3 h. After completion of reaction, the solvent was removed and the residue was extracted with ethyl acetate (20 mL), washed with water, brine and concentrated. The residue was purified by column chromatography (silica gel column, 1-50% ethyl acetate/ petroleum ether as eluent) to obtain the title compound (0.069 g). Yield: (34%); LCMS [M+H] 605.2.
Example 118
2-(3-(4-((4-((l-(Methylsulfonyl)spiro[indoline-3,4'-piperidin]-r-yl)methyl)benzyl) oxy)phenyl)oxetan-3-yl)acetic acid (Compound 118)
The title compound was prepared in an analogous manner as the compound 41 of Example 41. Compound 118 was obtained by hydrolyzing the compound of Example 117. Yield: 99%; JH NMR (DMSO-d6, 300 MHz): δ 1.63 (d, / = 12.6 Hz, 2H), 1.85 (t, / = 12.6 Hz, 2H), 2.08 (d, / = 10.8 Hz, 2H), 2.80 (d, / = 10.8 Hz, 2H), 2.96 (s, 2H), 3.02 (s, 3H), 3.52 (s, 2H), 3.78 (s, 2H), 4.73 (d, / = 3.9 Hz, 4H), 5.06 (s, 2H), 6.97 (d, / = 8.4 Hz, 2H), 7.04 (t, / = 6.9 Hz, 1H), 7.19-7.23 (m, 4H), 7.30-7.42 (m, 5H); MS (m/z): [M+H] 577.1.
Example 119
Ethyl 2-(3-(4-((4-((r-(methylsulfonyl)spiro[indoline-3,4'-piperidin]-l-yl)methyl)
benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 119)
Step 1
Spiro[indoline-3,4'-piperidine]
Benzyl spiro[indoline-3,4'-piperidine]-l'-carboxylate (Compound of step 1 of Example 116, 0.7 g, 2.171 mmol) and ammonium formate (0.685 g, 10.86 mmol) were added to a suspension of Pd/C (0.231 g, 2.171 mmol) in MeOH (20 mL) at RT. The reaction mixture was refluxed for 2 h. After completion of reaction, the reaction mixture was filtered over celite® bed. The filtrate was concentrated and the residue was purified by flash column chromatography (0-3 % MeOH/ chloroform with 0.5% aqueous ammonia as eluent, silica gel column) to obtain the title compound (0.32 g). Yield: 78%; lU NMR (CDC13, 300 MHz): δ 1.71-1.88 (m, 4H), 1.76 (t, / = 12.0 Hz, 2H), 3.09 (d, 12.0 Hz, 2H), 3.50 (s, 2H), 6.66 (d, / = 7.2 Hz, 1H), 6.77 (t, / = 7.5 Hz, 1H), 7.05 (d, / = 7.5 Hz, 1H), 7.11 (d, / = 7.2 Hz, 1H); MS (m/z): [M+H]+ 189.1.
Step 2
-(Methylsulfonyl)spiro[indoline-3,4'-piperidine]
Methanesulfonyl chloride (0.046 mL, 0.584 mmol) was added to a solution of spiro[indoline-3,4'-piperidine] (Compound of step 1, 0.1 g, 0.531 mmol) in DCM (10 mL) at 10 °C. The reaction mixture was stirred at RT for 2 h. After completion of reaction; water (10 mL) was added to the reaction mixture. The organic layer was separated and dried over Na2S04. The solvent was evaporated and the residue was purified by flash column chromatography (silica gel column, 0-90% ethyl acetate/ petroleum ether as eluent) to obtain the title compound (0.11 g). Yield: 78%; JH NMR (CDC13, 300 MHz): δ 1.88 (d, / = 13.5 Hz, 2H), 1.97-2.07 (m, 2H), 2.85 (s, 4H), 2.90 (s, 2H), 3.48 (s, 2H), 3.80 (d, / = 12.0 Hz, 2H), 6.68 (d, / = 7.8 Hz, 1H), 6.79 (t, / = 7.2 Hz, 1H), 7.08 (d, / = 7.8 Hz, 1H), 7.11 (d, / = 7.2 Hz, 1H); MS (m/z): [M+H]+ 267.2.
Step 3
Ethyl 2-(3-(4-((4-((r-(methylsulfonyl)spiro[indoline-3,4'-piperidin]-l-yl)methyl)benzyl) oxy)phenyl)oxetan-3-yl)acetate
A reaction mixture of l'-(methylsulfonyl)spiro[indoline-3,4'-piperidine]
(Compound of step 2, 0.095 g, 0.358 mmol), ethyl 2-(3-(4-((4-(bromomethyl) benzyl)oxy)phenyl)oxetan-3-yl)acetate (Intermediate 6, 0.15 g, 0.358 mmol) and CS2CO3 (0.11 g, 0.787 mmol) in DMF (10 mL) was stirred for 2 h. After completion of reaction, the reaction mixture was diluted with ethyl acetate (20 mL) and washed with water, brine and dried over Na2S04. The solvent was removed and the residue was purified by flash column chromatography (silica gel column, 0-40% ethyl acetate/ petroleum ether as eluent) to obtain the title compound (0.06 g). Yield: (27%); LCMS: [M+H]+ 605.2.
Example 120
2-(3-(4-((4-(( l'-(Methylsulfonyl)spiro [indoline-3 ,4'-piperidin] - 1 -yl)methyl)
benzyl)oxy)phenyl)oxetan-3-yl)acetic acid (Compound 120)
Ethyl 2-(3-(4-((4-((l'-(methylsulfonyl)spiro[indoline-3,4'-piperidin]-l-yl) methyl) benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound 119, 0.055 g, 0.091 mmol) was dissolved in mixture of THF (5 mL), MeOH (2 mL) and water (5 mL) followed by the addition of L1OH.H2O (0.023 g, 0.546 mmol). The reaction mixture was stirred overnight at RT. After completion of reaction, the solvent was evaporated and the residue was stirred in 20 mL saturated NH4CI solution and extracted with ethyl acetate at 60°C. The organic layer was washed with brine, dried over Na2S04 and concentrated to obtain the title compound (0.028 g). Yield: 53%; JH NMR (DMSO d6, 300 MHz): δ 1.71 (d, / = 12.9 Hz, 2H), 1.82 (h, 2H), 2.79 (d, / = 11.4 Hz, 2H), 3.02 (br s, 2H), 3.26 (s, 3H), 3.50 (d, / = 11.4 Hz, 2H), 4.34 (s, 2H), 4.61 (br s, 4H), 5.06 (s, 2H), 6.61 (q, / = 7.2 Hz, 2H), 6.97 (d, / = 8.4 Hz, 2H), 7.03 (d, / = 7.8 Hz, 1H), 7.10 (d, / = 6.9 Hz, 1H), 7.21 (d, / = 8.4 Hz, 2H), 7.35 (d, / = 7.5 Hz, 2H), 7.43 (d, / = 7.5 Hz, 2H), 12.16 (h, 1H); MS (m/z): [M+H]+ 577.1
Example 121
Ethyl 2-(3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)oxetan-3-yl)acetate (Compound 121)
Step 1
Synthesis of 2-(5-methyl-2-phenyloxazol-4-yl)ethyl 4-methylbenzenesulfonate
Triethyl amine (179 mg, 1.771 mmol) was added to a stirred solution of 2-(5-methyl- 2-phenyloxazol-4-yl)ethanol (120 mg, 0.590 mmol) in DCM (5 mL). The reaction mixture was stirred for 5 minutes at 0 °C, followed by the addition of p-toluene sulphonyl chloride (135 mg, 0.709 mmol) and DMAP (2 mg catalytic amount) and reaction mixture was stirred for 2 h. After completion of reaction, the reaction mixture was concentrated and purified by column chromatography (10 % ethyl acetate in petroleum ether) to obtain the title compound (142 mg, 0.397 mmol) as a white solid. Yield: 67.3 %; JH NMR (300 MHz, CDCI3): δ 7.88 (m, 2H), 7.69 (d, / = 8.4 Hz, 2H), 7.44-7.43 (m, 3H), 7.20 (d, / = 8.4 Hz, 2H), 4.34 (t, / = 6 Hz, 2H), 2.85 (t, / = 6 Hz, 2H), 2.32 (s, 3H), 2.21 (s, 3 H); MS (m/z): 358 (M+l).
Step 2
Synthesis of ethyl 2-(3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)oxetan-3- yl)acetate
To a stirred solution of 2-(5-methyl-2-phenyloxazol-4-yl)ethyl 4- methylbenzenesulfonate (100 mg, 0.280 mmol) and ethyl 2-(3-(4-hydroxyphenyl) oxetan-3- yl)acetate (Intermediate 1, 66.1 mg, 0.280 mmol) in anhydrous DMF (2 mL) was added CS2CO3 (182 mg, 0.560 mmol). The reaction mixture was heated at 50 °C for 2 h. After completion of the reaction the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2S04, concentrated and purified by column chromatography to to obtain the title compound (110 mg) as colorless oil. Yield: 93 %. JH NMR (300 MHz, CDCI3): δ 7.99-7.96 (m, 2H), 7.44- 7.42 (m, 3H), 7.09 (d, / = 8.4 Hz, 2H), 6.89 (d, / = 8.4 Hz, 2H), 4.99 (d, / = 6 Hz, 2H), 4.86 (d, / = 6 Hz, 2H), 4.26 (t, / = 6 Hz, 2H), 4.04 (q, / = 6.2 Hz, 2H) 3.09 (s, 2H), 2.99 (t, / = 6 Hz, 2H), 2.39 (s, 3H), 1.13 ( t, / = 6.2 Hz, 3H); MS (m/z) : 422 (M+l).
Example 122
2-(3-(4-(2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid (Compound 122)
To a stirred solution of ethyl 2-(3-(4-(2-(5-methyl-2-phenyloxazol-4- yl)ethoxy)phenyl)oxetan-3-yl)acetate (compound of step 1, 100 mg, 0.237 mmol) in a mixture of THF and MeOH (4: 1) (4 mL) was added aqueous lithium hydroxide (949 μΐ, 1.424 mmol) and the mixture was allowed to stir at RT for 4 h. After completion of the reaction, the solvent was removed. The reaction mixture was neutralized with saturated NH4CI solution and the compound was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2S04 and concentrated to obtain the title compound (55 mg, 0.140 mmol) as white solid. Yield: 58.9 ; JH NMR (300 MHz, DMSO- d6): δ 12.8 (br s, 1H), 7.92-7.89 (m, 2H), 7.46-7.50 (m, 3 H), 7.19 (d, / = 8.4 Hz, 2H), 6.91 (d, / = 8.4 Hz, 2H), 4.73 (s, 4H), 4.19 (t, J= 6 Hz, 2H), 2.99 (s, 2H), 2.92 (t, / = 6 Hz, 2H), 2.35 (s, 3H); MS (m/z): 394 (M+l).
Example 123
Ethyl 2-(3-(4-(2-(5-methyl-2-phenylthiazol-4-yl)ethoxy)phenyl)oxetan-3-yl)acetate (Compound 123)
Step 1
Synthesis of 2-(5-methyl-2-phenylthiazol-4-yl)ethyl 4-methylbenzenesulfonate
Triethyl amine (763 μΐ, 5.47 mmol) was added to a stirred solution of 2-(5-methyl-2- phenylthiazol-4-yl)ethanol (400 mg, 1.824 mmol) in DCM (5 mL). The reaction mixture was stirred for 5 minutes at 0 °C, followed by the addition of triethyl amine (763 μΐ, 5.47 mmol) and DMAP (2 mg catalytic amount) and reaction mixture was stirred for 2 h. After completion of reaction, the reaction mixture was concentrated and purified by column chromatography (10 % ethyl acetate in petroleum ether) to obtain the title compound (550 mg, 1.473 mmol) as white solid. Yield: 81 ; JH NMR (300 MHz, CDCI3): δ 7.75-7.74 (m, 2H), 7.66 (d, / = 8.4 Hz, 2H), 7.41-7.43 (m, 3 H), 7.20 (d, / = 8.4 Hz, 2H), 4.41 (t, / = 6 Hz, 2H), 3.046 (t, / = 6 Hz, 2H), 2.41 (s, 3H), 2.23 (s, 3H); MS (m/z): 374 (M+l).
Step 2
Synthesis of ethyl 2-(3-(4-(2-(5-methyl-2-phenylthiazol-4-yl)ethoxy)phenyl)oxetan-3- yl)acetate
The title compound was prepared in an analogous manner as Compound 121 of Example 121 involving reaction of 2-(5-methyl-2-phenylthiazol-4-yl)ethyl 4- methylbenzenesulfonate (120 mg, 0.321 mmol) with ethyl 2-(3-(4-hydroxyphenyl)oxetan-3- yl)acetate (Intermediate 1, 76 mg, 0.321 mmol). Yield: 89 ; JH NMR (300 MHz, CDCI3): δ 7.89 (d, / = 6.0 Hz, 2H), 7.43-7.40 (m, 3H), 7.09 (d, / = 8.4 Hz, 2H), 6.90 (d, / = 8.4 Hz, 2H), 4.99 (d, / = 6 Hz, 2H), 4.86 (d, / = 6 Hz, 2H), 4.32 (t, / = 6 Hz, 2H), 4.02 (q, / = 6.2 Hz, 2H) 3.20 (t, / = 6 Hz, 2H), 3.18 (s, 2H), 2.48 (s, 3H), 1.01 ( t, / = 6.2 Hz, 3H); MS (m/z): 438 (M+l).
Example 124
2-(3-(4-(2-(5-Methyl-2-phenylthiazol-4-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid (Compound 124)
The title compound was prepared in an analogous manner as the compound 122 of Example 122. Compound 124 was obtained by hydrolyzing the compound of Example 123. Yield: 68.0 ; JH NMR (300 MHz, DMSO-d6): δ 12.11 (br s, 1H), 7.86 (d, / = 6 Hz, 2H), 7.46-7.50 (m, 3H), 7.19 (d, / = 8.4 Hz, 2H), 6.92 (d, / = 8.4 Hz, 2H), 4.73 (s, 4H), 4.27 (t, / = 6 Hz, 2H), 3.12 (t, / = 6 Hz, 2H), 2.99 (s, 2H), 2.44 (s, 3H); MS (m/z): 410 (M+l).
Example 125
Ethyl 2-(3-(4-((3-((4-chlorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetate (Compound 125)
Step 1
Synthesis of ethyl 2-(3-(4-((3-(hydroxymethyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate
To a stirred solution of (3-(bromomethyl)oxetan-3-yl)methanol (800 mg, 4.42 mmol) and ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 1044 mg, 4.42 mmol) in dry DMF (10 ml) was added CS2CO3 (1705 mg, 8.84 mmol) and the reaction mixture was allowed to stir at RT for 2 h. After completion of reaction, the reaction mixture was quenched with water, extracted with ethyl acetate, dried over anhydrous Na2S04, concentrated and purified by column chromatography to obtain the title compound (945 mg) as off-white solid. Yield: 60.8 ; JH NMR (300 MHz, CDCI3): δ 7.17 (d, / = 8.1 Hz, 2H), 6.94 (d, / = 8.1 Hz, 2H), 4.99 (t, / = 5.1 Hz, 1H), 4.76 (s, 4H), 4.40 (s, 4H), 4.12 (s, 2H), 3.91 (q, / = 6.9 Hz, 2H), 3.70 (d, / = 5.1 Hz, 2H), 3.09 (s, 2H), 1.05 (t, / = 7.2 Hz, 3H); MS (m/z): 359.0 (M + Na).
Step 2
Synthesis of ethyl 2-(3-(4-((3-((tosyloxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate
To a stirred solution of ethyl 2-(3-(4-((3-(hydroxymethyl)oxetan-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (compound of step 1, 400 mg, 1.189 mmol) in DCM (7 ml) was added triethylamine (241 mg, 2.378 mmol) at 0 °C followed by addition of 4- methylbenzene-l-sulfonyl chloride (227 mg, 1.189 mmol). The reaction mixture was stirred at RT for 5 h. After completion of the reaction, the reaction mixture was quenched with water, extracted with ethyl acetate and purified by column chromatography to obtain the title compound (562 mg) as white solid. Yield: 88 ; JH NMR (300 MHz, CDC13): δ 7.77 (d, J= 8.1 Hz, 2H), 7.28 (s, 2H), 7.12 (d, J= 8.1 Hz, 2H), 6.78 (d, J= 8.4 Hz, 2H), 4.99 (d, / = 6.0 Hz, 2H), 4.87 (d, J= 8.1 Hz, 2H), 4.55-4.47 (m, 4H), 4.40 (s, 2H), 4.13 (s, 2H), 4.04 (q, / = 6.9 Hz, 2H), 3.12 (s, 2H), 2.42 (s, 3H), 1.17 (t, / = 6.9 Hz, 3H); MS (m/z): 491.0 (M + 1), 513.1 (M + Na).
Step 3
Synthesis of ethyl 2-(3-(4-((3-((4-chlorophenoxy)methyl)oxetan-3- yl)methoxy)phenyl)oxetan-3-yl)acetate
To a stirred solution of ethyl 2-(3-(4-((3-((tosyloxy)methyl)oxetan-3-yl)methoxy) phenyl)oxetan-3-yl)acetate (Compound of step 2, 65 mg, 0.133 mmol) and 4-chlorophenol (17.03 mg, 0.133 mmol) in dry DMF (7 mL) was added Cs2C03 (51.1 mg, 0.265 mmol) and the reaction mixture was stirred at 80 °C for 2 to 3 h. After completion of reaction, reaction mixture was quenched with water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous Na2S04, concentrated and purified by column chromatography to obtain the title compound (52.7 mg) as pale yellow thick liquid. JH NMR (300 MHz, CDCI3): δ 7.26 (d, / = 8.4 Hz, 2H), 7.12 (d, / = 8.4 Hz, 2H), 6.92-6.85 (m, 4H), 4.98 (d, / = 6.0 Hz, 2H), 4.85 (d, / = 6.0 Hz, 2H), 4.68 (s, 4H), 4.30 (s, 2H), 4.29 (s, 2H), 4.02 (q, / = 7.2 Hz, 2H), 3.11 (s, 2H), 1.15 (t, / = 7.2 Hz, 3H); MS (m/z): 469.0 (M + Na).
Example 126
2-(3-(4-((3-((4-Chlorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid (Compound 126)
The title compound was prepared in an analogous manner as the compound 122 of Example 122. Compound 126 was obtained by hydrolyzing the compound of Example 125. Yield: 84.7 ; JH NMR (300 MHz, DMSO-d6) δ: 12.15 (br s, 1H), 7.33 (d, J= 8.4 Hz, 2H), 7.20 (d, J= 8.4 Hz, 2H), 7.02 (d, J= 8.7 Hz, 2H), 6.96 (d, J= 8.7 Hz, 2H), 4.73 (s, 4H), 4.54 (s, 4H), 4.27 (s, 4H), 3.00 (s, 2H); MS (m/z): 418.9 (M + 1).
Example 127
Ethyl 2-(3-(4-((3-((o-tolyloxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetate (Compound 127)
The title compound was prepared in an analogous manner as the compound of step 3 of Example 125 involving reaction of ethyl 2-(3-(4-((3-((tosyloxy)methyl)oxetan-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (105 mg, 0.214 mmol) with o-cresol (27.8 mg, 0.257 mmol). Yield: 84.2 ; JH NMR (300 MHz, CDCI3): δ 7.21-7.11 (m, 4H), 6.94-6.88 (m, 4H), 4.99 (d, / = 6.0 Hz, 2H), 4.86 (d, / = 6.0 Hz, 2H), 4.74-4.69 (m, 4H), 4.33-4.32 (m, 4H), 4.02 (q, / = 6.0 Hz, 2H), 3.11 (s, 2H), 2.21 (s, 3H), 1.15 (t, / = 7.2 Hz, 3H); MS (m/z): 449.1 (M + Na).
Example 128
2-(3-(4-((3-((o-Tolyloxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid (Compound 128)
The title compound was prepared in an analogous manner as the compound 122 of Example 122. Compound 128 was obtained by hydrolyzing the compound of Example 127. Yield: 83.7 ; JH NMR (300 MHz, DMSO-d6): δ 12.13 (br s, 1H), 7.20-7.12 (m, 4H), 7.01- 6.83 (m, 4H), 4.74 (s, 4H), 4.58 (s, 4H), 4.31-4.27 (m, 4H), 3.01 (s, 2H), 2.13 (s, 3H); MS (m/z): 399.2 (M+l), 421.1 (M + Na).
Example 129
Ethyl 2-(3-(4-((3-((naphthalen-2-yloxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate (Compound 129)
The title compound was prepared in an analogous manner as the compound of step 3 of Example 125 involving reaction of ethyl 2-(3-(4-((3-((tosyloxy)methyl)oxetan-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (70 mg, 0.143 mmol) with naphthalen-2-ol (20.57 mg, 0.143 mmol). Yield: 82.0 ; JH NMR (300 MHz, CDCI3): δ 7.84-7.78 (m, 4H), 7.48- 7.32 (m, 3H), 7.20-7.15 (m, 2H), 6.98 (d, / = 8.4 Hz, 2H), 4.74 (s, 4H), 4.62-4.57 (m, 4H), 4.42 (s, 2H), 4.33 (s, 2H), 3.88 (q, / = 7.2 Hz, 2H), 3.07 (s, 2H), 1.02 (t, / = 6.0 Hz, 3H); MS (m/z): 485.1 (M + Na).
Example 130
2-(3-(4-((3-((Naphthalen-2-yloxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid (Compound 130)
The title compound was prepared in an analogous manner as the compound 122 of Example 122. Compound 130 was obtained by hydrolyzing the compound of Example 129. Yield: 82.8 ; JH NMR (300 MHz, DMSO-d6): δ 12.11 (br s, 1H), 7.84-7.79 (m, 3H), 7.48- 7.32 (m, 4H), 7.20 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 4.73 (s, 4H), 4.60-4.59 (m, 4H), 4.42 (s, 2H), 4.33 (s, 2H), 3.00 (s, 2H); MS (m/z): 457.0 (M+Na).
Example 131
Ethyl 2-(3-(4-((3-((4-cyanophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetate (Compound 131)
The title compound was prepared in an analogous manner as the compound of step 3 of Example 125 involving reaction of ethyl 2-(3-(4-((3-((tosyloxy)methyl)oxetan-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (71 mg, 0.145 mmol) with 4-hydroxybenzonitrile (17.24 mg, 0.145 mmol). JH NMR (300 MHz, CDCI3): δ 7.77 (d, / = 8.7 Hz, 2H), 7.17 (d, / = 8.4 Hz, 4H), 6.95 (d, / = 8.4 Hz, 2H), 4.74 (s, 4H), 4.54 (s, 4H), 4.39 (s, 2H), 4.28 (s, 2H), 3.89 (q, J = 7.2 Hz, 2H), 3.07 (s, 2H), 1.02 (t, / = 6.0 Hz, 3H); MS (m/z): 438.1 (M+l), 460.1 (M+Na).
Example 132
2-(3-(4-((3-((4-Cyanophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid (Compound 132)
The title compound was prepared in an analogous manner as the compound 122 of Example 122. Compound 132 was obtained by hydrolyzing the compound of Example 131. Yield: 81.3 ; JH NMR (300 MHz, DMSO-d6): δ 12.10 (br s, 1H), 7.77 (d, / = 7.8 Hz, 2H), 7.18 (bs, 4H), 6.95 (d, / = 7.5 Hz, 2H), 4.73 (s, 4H), 4.55 (s, 4H), 4.39 (s, 2H), 4.28 (s, 2H), 3.00 (s, 2H); MS (m/z): 432.0 (M + Na).
Example 133
Ethyl 2-(3-(4-((3-((4-fluorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetate (Compound 133)
The title compound was prepared in an analogous manner as the compound of step 3 of Example 125 involving reaction of ethyl 2-(3-(4-((3-((tosyloxy)methyl)oxetan-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (80 mg, 0.163 mmol) with 4-fluorophenol (18.28 mg, 0.163 mmol). Yield: 82.3 ; JH NMR (300 MHz, CDCI3): δ 7.12 (d, / = 8.7 Hz, 2H), 7.02-6.99 (m, 2H), 6.96-6.85 (m, 4H), 4.98 (d, / = 6.0 Hz, 2H), 4.85 (d, / = 6.0 Hz, 2H), 4.68 (s, 4H), 4.30 (s, 2H), 4.28 (s, 2H), 4.02 (q, J=7.2 Hz, 2H), 3.11 (s, 2H), 1.15 (t, / = 7.2 Hz, 3H); MS (m/z): 431.0 (M+l).
Example 134
2-(3-(4-((3-((4-Fluorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid (Compound 134)
The title compound was prepared in an analogous manner as the compound 122 of Example 122. Compound 134 was obtained by hydrolyzing the compound of Example 133. Yield: 84.3 ; JH NMR (300 MHz, DMSO-d6) δ: 12.11 (bs, 1H), 7.20 (d, / = 8.4 Hz, 2H), 7.12 (t, / = 8.4 Hz, 2H), 7.01-6.95 (m, 4H), 4.73 (s, 4H), 4.54 (s, 4H), 4.26 (s, 4H), 3.01 (s, 2H); MS (m/z): 403.0 (M + 1).
Example 135
Ethyl 2-(3-(4-((3-((4-chlorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetate (Compound 135)
The title compound was prepared in an analogous manner as the compound of step 3 of Example 125 involving reaction of ethyl 2-(3-(4-((3-((tosyloxy)methyl)oxetan-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (65 mg, 0.133 mmol) with 4-chlorophenol (17.03 mg, 0.133 mmol). Yield: 83.3 ; JH NMR (300 MHz, CDCI3): δ 7.26 (d, / = 8.4 Hz, 2H), 7.12 (d, / = 8.4 Hz, 2H), 6.92-6.85 (m, 4H), 4.98 (d, / = 6.0 Hz, 2H), 4.85 (d, / = 6.0 Hz, 2H), 4.68 (s, 4H), 4.30 (s, 2H), 4.29 (s, 2H), 4.02 (q, / = 7.2 Hz, 2H), 3.11 (s, 2H), 1.15 (t, / = 7.2 Hz, 3H); MS (m/z) 469.0 (M + Na). Example 136
2-(3-(4-((3-((4-Chlorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid (Compound 136)
The title compound was prepared in an analogous manner as the compound 122 of Example 122. Compound 134 was obtained by hydrolyzing the compound of Example 133. Yield: 84.7 ; JH NMR (300 MHz, DMSO-d6) : 512.15 (br s, 1H), 7.33 (d, J= 8.4Hz, 2H), 7.20 (d, J= 8.4Hz, 2H), 7.02 (d, J= 8.7Hz, 2H), 6.96 (d, J=8.7 Hz, 2H), 4.73 (s, 4H), 4.54 (s, 4H), 4.27 (s, 4H), 3.00 (s, 2H); MS (m/z): 418.9 (M + 1).
Example 137
Ethyl 2-(3-(4-((3-((2-fluorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate (Compound 137)
The title compound was prepared in an analogous manner as the compound of step 3 of Example 125 involving reaction of ethyl 2-(3-(4-((3-((tosyloxy)methyl)oxetan-3- yl)methoxy)phenyl)oxetan-3-yl)acetate (70 mg, 0.143 mmol) with 2-fluorophenol (16 mg, 0.143 mmol). Yield: 85.5 ; JH NMR (300 MHz, CDC13) δ: 7.12-7.03 (m, 5H), 6.92 (d, / = 8.4 Hz, 3H), 4.98 (d, / = 6.0 Hz, 2H), 4.85 (d, / = 6.0 Hz, 2H), 4.70 (s, 4H), 4.39 (s, 2H), 4.35 (s, 2H), 4.02 (q, / = 6.9 Hz, 2H), 3.10 (s, 2H), 1.14 (t, / = 6.9 Hz, 3H); MS (m/z): 453.1 (M + Na).
Example 138
2-(3-(4-((3-((2-Fluorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid (Compound 138)
The title compound was prepared in an analogous manner as the compound 122 of Example 122. Compound 134 was obtained by hydrolyzing the compound of Example 133. Yield 81.0 ;JH NMR (300 MHz, DMSO-d6): δ 12.10 (br s, 1H), 7.25-7.13 (m, 6H), 6.96 (d, / = 8.1 Hz, 2H), 4.73 (s, 4H), 4.55 (s, 4H), 4.36 (s, 2H), 4.29 (s, 2H), 3.01 (s, 2H); MS (m/z): 403.0 (M + 1).
Example 139
Ethyl 2-(3-(4-(3-([l,l'-biphenyl]-4-ylsulfonamido)propoxy)phenyl) oxetan-3-yl)acetate (Compound 139)
Step 1
Synthesis of ethyl 2-(3-(4-(3-hydroxypropoxy)phenyl)oxetan-3-yl)acetate A solution of ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 1.5 g, 6.35 mmol), 3-bromo-l-propanol (1.148 mL, 12.70 mmol) and Cs2C03 (4.14 g, 12.70 mmol) in DMF (30 mL) was stirred at RT for 4 h. After completion of reaction, the reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate. The organic layer was washed with water (50 mL), brine (50 mL), dried over Na2S04, concentrated and purified by flash column chromatography to obtain the title compound (1.41 g). Yield: 76%; JH NMR (300 MHz, CDC13): δ 7.11 (d, J = 8.4Hz, 2H), 6.901 (d, J = 8.4Hz, 2H), 5.00 (d, J = 6 Hz, 2H), 4.86 (d, J = 6 Hz, 2H), 4.12 (t, J = 5.7 Hz, 2H), 4.05 (q, J = 7.2Hz, 2H), 3.86 (bs, 2H), 3.10 (s, 2H), 2.09 (bs, 2H), 2.090 (m, 2H), 1.17 (t, J = 7.2Hz, 3H); MS (m/z): 294.34 (M+).
Step 2
Synthesis of ethyl 2-(3-(4-(3-(tosyloxy)propoxy)phenyl)oxetan-3-yl)acetate
A solution of ethyl 2-(3-(4-(3-hydroxypropoxy)phenyl)oxetan-3-yl)acetate (Compound of step 1, 1.313 g, 4.46 mmol), triethylamine (1.86 mL, 13.38 mmol) and DMAP (0.054 g, 0.446 mmol) in DCM (50 ml) was stirred for 30 minutes, followed by slow addition of p-toluenesulfonyl chloride (0.935 g, 4.91 mmol) while maintaining the temperature below 5 °C. After complete addition the reaction mixture was stirred overnight at RT. After completion of reaction, the reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed the brine, water and dried over Na2S04, concentrated and purified by flash column chromatography to obtain the title compound (1.46 g). Yield: 70.2%; JH NMR (300 MHz, CDCI3): δ 7.789 (d, J = 7.8 Hz, 2H), 7.295 (d, J = 5.4 Hz, 2H), 7.09 (d, J = 8.4 Hz, 2H), 6.776 (d, J = 8.7 Hz, 2H), 4.997 (d, J = 5.7 Hz, 2H), 4.874 (d, J = 5.0 Hz, 2H), 4.268 (d, J = 6.0 Hz, 2H), 4.064 (q, J = 7.2 Hz, 2H), 3.982 (t, J =6.0 Hz, 2H), 3.107 (s, 2H), 2.419 (s, 3H), 2.163 -2.061 (m, 2H), 1.177 (t, J = 7.2 Hz, 3H); MS (ESI) (m/z): 471.3 (M+Na).
Step 3
Synthesis of ethyl 2-(3-(4-(3-azidopropoxy)phenyl)oxetan-3-yl)acetate
A stirred solution of ethyl 2-(3-(4-(3-(tosyloxy)propoxy)phenyl)oxetan-3-yl)acetate (Compound of step 2, 3.6 g, 8.06 mmol) and sodium azide (0.522 gm, 8.06 mmol) in DMF (50 mL) was heated at 80 °C for 3 h. After completion of reaction, DMF was removed and the residue was quenched with water and extracted with ethyl acetate. The organic layer was washed the brine, water and dried over Na2S04 and concentrated to obtain the title compound (0.176 g). Yield: 90%; JH NMR (300 MHz, CDCI3): δ 7.12 (d, J= 8.4 Hz, 2H), 6.89 (d, J = 8.7Hz, 2H), 5.00 (d, J = 5.7Hz, 2H), 4.87 (d, J = 6Hz, 2H), 4.07 (m, 4H), 3.55 (t, J = 6.3Hz, 2H), 3.10 (s, 2H), 2.10 (quintet, J = 6.3Hz, 2H), 1.17 (t, J = 7.2Hz, 3H); MS (m/z): 342.1 (M+Na).
Step 4
Synthesis of ethyl 2-(3-(4-(3-aminopropoxy)phenyl)oxetan-3-yl)acetate
A mixture of ethyl 2-(3-(4-(3-azidopropoxy)phenyl)oxetan-3-yl)acetate
(Compound of step 3, 2.11 g, 6.61 mmol), 10% Pd-C (0.14 g, 1.32 mmol) and ethanol (30 ml) was hydrogenated at 50 psi for 4 h. The reaction mixture was filtered through celite bed®, washed with ethanol and concentrated to obtain the title compound (1.12 g). Yield: 57.6%; JH NMR (300 MHz, CDCI3): δ 7.10 (d, J = 8.4Hz, 2H), 6.88 (d, J = 8.4Hz, 2H), 4.99 (d, J = 5.7Hz, 2H), 4.86 (d, J = 5.7Hz, 2H), 4.07 (m, 3H), 3.04 (s, 2H), 2.94 (m, 2H), 1.96 (t, J = 6.3Hz, 2H), 1.70 (s, 4H), 1.16 (t, J = 6.4Hz, 2H); MS (m/z): 294.1 (M+H).
Step 5
Preparation of ethyl 2-(3-(4-(3-([l,l'-biphenyl]-4-ylsulfonamido)propoxy)phenyl) oxetan-3- yl)acetate
To a stirred the solution of biphenyl-4-sulfonyl chloride (0.165 g, 0.651 mmol) was added ethyl 2-(3-(4-(3-aminopropoxy)phenyl)oxetan-3-yl)acetate (Compound of step 4, 0.191 g, 0.651 mmol) followed by the addition of triethylamine (0.18 mL, 1.30 mmol) in DCM (20 mL) at RT and the reaction mixture was stirred for 5 h. Then organic layer was washed with brine, water, dried over Na2S04, concentrated and purified by flash column chromatography to obtain the title compound (0.276 g). Yield: 83%; JH NMR (300 MHz, CDCI3): δ 7.86 (s, 4H), 7.74 (d, J = 6.9 Hz, 3H), 7.51 (m, 3H), 7.11 (d, J = 8.4Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 4.72 (s, 4H), 3.91 (m, 4H), 3.04 (s, 3H), 2.96 (d, J = 6.3Hz, 2H), 1.84 (t, J = 6.3Hz, 2H), 1.05 (t, J = 7.2Hz, 2H); MS (m/z): 510.2 (M+H), 532.2 (M+Na).
Example 140
2-(3-(4-(3-([l,l'-biphenyl]-4-ylsulfonamido)propoxy) phenyl)oxetan-3-yl)acetic acid (Compound 140)
The title compound was prepared in an analogous manner as the compound 122 of Example 122. Compound 140 was obtained by hydrolyzing the compound of Example 139. Yield: 60.3%; JH NMR (300 MHz, DMSO-d6): δ 12.10 (s, 1H), 7.870 (s, 4H), 7.745 (d, J = 6.9 Hz, 3H), 7.539-7.438 (m, 3H), 7.158 (d, J = 8.4 Hz, 2H), 6.833 (d, J = 8.4 Hz, 2H), 4.740 (q, J = 5.7 Hz, 4H), 3.940 (t, J = 11.4 Hz, 2H), 2.985-2.946 (m, 4H), 1.851 (t, J = 6.0 Hz, 2H); MS (m/z): 504.1 (M+Na).
Example 141
Ethyl 2-(3-(4-((2-(spiro[indene-l,4'-piperidin]- -methyl)benzyl)oxy)phenyl)oxetan-3- yl)acetate (Compound 141)
Step 1
Synthesis of ethyl 2-(3-(4-((2-(bromomethyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate
A mixture of ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 1 g, 4.23 mmol), 1 ,2-bis(bromomethyl)benzene (1.34 g, 5.08 mmol) and Cs2C03 (1.38 g, 4.23 mmol) was stirred in dry DMF (10 ml) at RT for 2 h. The reaction mass was diluted with EtOAc, washed with water, brine, dried over Na2S04, concentrated and purified by flash column chromatography to obtain the title compound (0.45 g). Yield: 25.6%; JH NMR (300 MHz, DMSO-d6): δ 1.15 (t, J = 6.0 Hz, 3H), 3.12 (s, 2H), 4.04 (q, J = 6.0 Hz, 2H), 4.64 (s, 2H), 4.87 (d, J = 6.0 Hz, 2H), 5.00 (d, J = 6.0 Hz, 2H), 5.21 (s, 2H), 7.00 (d, J = 6.0 Hz, 2H), 7.14 (d, J = 6.0 Hz, 2H), 7.35-7.43 (m, 4H); MS (m/z) 441.3 (M+Na).
Step 2
Synthesis of 1 '-(2,2,2-trifluoroacetoxy)spiro[indene- 1 ,4'-piperidin] - 1 '-ium
Trifluoroacetic acid (6.07 mL, 79 mmol) was added to solution of teri-butyl spiro[indene-l,4'-piperidine]-r-carboxylate (3 g, 10.51 mmol) in DCM (15 mL) at 10 °C. The reaction mixture was stirred for 22 h. After completion of reaction the solvent was removed. On removal of solvent from a reaction mass the residue was azeotroped with toulene and suspended with petroleum ether (40 mL) and decanted. The residue was dried to obtain the title compound (3.1 g). Yield: 99%; JH NMR (300 MHz, DMSO-d6): δ 1.59 (d, J = 12.0 Hz, 2H), 2.42 (t, J = 12.0 Hz. 2H), 3.29 (q, J = 9.0 Hz, 2H), 3.62 (d, J = 2H), 6.79 (d, J = 1H), 6.89 (d, J = 3.0 Hz, 1H), 7.28-7.50 (m, 3H), 9.29 (s, 1H), 9.72 (s, 1H); MS (m/z) 186.3 (free base).
Step 3
Synthesis of ethyl 2-(3-(4-((2-(spiro[indene-l,4'-piperidin]-r- methyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate
A mixture of r-(2,2,2-trifluoroacetoxy)spiro[indene-l,4'-piperidin]-r-ium (Compound of step 2, 0.14 g, 0.48 mmol) and CS2CO3 (0.34 g, 1.05 mmol) was suspended in DMF (5 mL) and stirred for 10 minutes. Then ethyl 2-(3-(4-((2- (bromomethyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound of step 1, 0.2 g, 0.48 mmol) was added and the reaction mixture was stirred for 2h. The reaction mass was diluted with water (10 mL) and extracted with EtOAc (20 mL). The organic layer was washed with water, brine, dried over Na2S04, concentrated and purified by flash column chromatography to obtain the title compound (0.15 g) as semisolid. Yield: 60.1%; JH NMR (300 MHz, DMSO-de): δ 1.13 (t, J = 7.2 Hz, 3H), 1.33 (d, J = 14.7 Hz, 2H), 2.09-2.14 (m, 2H), 2.40 (t, J = 11.1 Hz, 2H), 2.94 (d, J = 11.1 Hz, 2H), 3.12 (s, 2H), 3.70 (s, 2H), 4.02 (q, J = 7.2 Hz, 2H), 4.87 (d, J = 6.0 Hz, 2H), 5.02 (d, J = 6.0 Hz, 2H), 5.36 (s, 2H), 6.76 (d, J = 5.7 Hz, 1H), 6.89 (d, J = 5.7 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 2H), 7.21-7.38 (m, 6H), 7.39 (bs, 1H), 7.31 (bs, 1H); LCMS 524.2 (M+H).
Example 142
2-(3-(4-((2-(Spiro[indene-l,4'-piperidin]-r-ylmethyl)benzyl) oxy)phenyl)oxetan-3-yl)acetic acid (Compound 142)
The title compound was prepared in an analogous manner as the compound 122 of Example 122. Compound 142 was obtained by hydrolyzing the compound of Example 141. Yield: 98%; JH NMR (300 MHz, DMSO-d6): δ 1.15-1.27 (m, 2H), 1.99-2.05 (m, 2H), 2.40 (t, J = 11.1 Hz, 2H), 2.83 (bs, 2H), 2.98 (s, 2H), 3.68 (s, 2H), 4.75-4.78 (m, 4H), 5.32 (s, 2H), 6.78 (d, J = 5.4 Hz, 1H), 6.97 (d, J = 5.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 2H), 7.15 (t, J = 7.2 Hz, 2H), 7.23-7.31 (m, 6H), 7.38 (bs, 1H), 7.45 (br s, 1H); MS (m/z): 496.4 (M+H).
Example 143
Ethyl 2-(3-(4-((3-((l-methylspiro[indoline-3,4'-piperidin]-r-yl)methyl)benzyl)oxy) phenyl)oxetan-3-yl)acetate (Compound 143)
Step 1
Synthesis of ethyl 2-(3-(4-((3-(bromomethyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate
A mixture of ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 2 g, 8.47 mmol), dibromo-meta-xylene (2.68 g, 10.16 mmol) and CS2CO3 (2.76 g, 8.47 mmol) in DMF (15 mL) was stirred at RT for 60 minutes. The reaction mass was diluted with EtOAc (75 ml) and insoluble solid was filtered. The organic layer was washed with water, brine, dried over Na2S04, concentrated and purified by flash column chromatography to obtain the title compound (1.84 g). Yield: 51.8%; JH NMR (300 MHz, CDCI3): δ 1.14 (t, J = 6.0 Hz, 3H), 3.11 (s, 2H), 4.02 (q, J = 6.0 Hz, 2H), 4.53 (s, 2H), 4.87 (d, J = 6.0 Hz, 2H), 5.00 (d, J = 6.0 Hz, 2H), 5.06 (s, 2H), 6.96 (d, J = 6.0 Hz, 2H), 7.13 (d, J = 6.0 Hz, 2H), 7.38 (br s, 3H), 7.48 (s, 1H); LCMS 420.0 (M+H).
Step 2
Preparation of Ethyl 2-(3-(4-((3-(spiro[indene- 1 ,4'-piperidin] - 1 '-ylmethyl)benzyl)oxy) phenyl)oxetan-3-yl)acetate (5562-01)
A mixture of -(2,2,2-trifluoroacetoxy)spiro[indene-l,4'-piperidin]- -ium (Compound of step 2 of Example 141, 0.26 g, 0.86 mmol) and CS2CO3 (0.75 g, 2.29 mmol) were suspended in DMF (10 mL) and stirred for 10 minutes, followed by the addition of ethyl 2-(3-(4-((2-(bromomethyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound of step 1, 0.3 g, 0.72 mmol). The reaction mixture was further stirred for 2 h. After completion of reaction, the reaction mass was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04, concentrated and purified by flash column chromatography to obtain the title compound (28 g) as semisolid. Yield: 75 ; JH NMR (300 MHz, CDCI3): δ 1.13 (t, J = 7.2 Hz, 3H), 1.33 (d, J = 14.7 Hz, 2H), 2.09-2.14 (m, 2H), 2.40 (t, J = 11.1 Hz, 2H), 2.94 (d, J = 11.1 Hz, 2H), 3.12 (s, 2H), 3.70 (s, 2H), 4.02 (q, J = 7.2 Hz, 2H), 4.87 (d, J = 6.0 Hz, 2H), 5.02 (d, J = 6.0 Hz, 2H), 5.36 (s, 2H), 6.76 (d, J = 5.7 Hz, 1H), 6.89 (d, J = 5.7 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 7.21-7.38 (m, 6H), 7.39 (br s, 1H), 7.31 (br s, 1H); MS (m/z): 524.4 (M+H).
Example 144
2-(3-(4-((3-(Spiro[indene-l,4'-piperidin]-r-ylmethyl)benzyl)oxy) phenyl)oxetan-3-yl)acetic acid (Compound 144)
The title compound was prepared in an analogous manner as the compound 122 of Example 122. Compound 144 was obtained by hydrolyzing the compound of Example 143. Yield: 65%; JH NMR (300 MHz, DMSO-d6): δ 1.19 (d, J = 12.0 Hz, 2H), 2.08 (d, J = 9.0 Hz, 2H), 2.36 (d, J = 9.0 Hz, 2H), 2.88 (d, J = 9.0 Hz, 2H), 2.98 (s, 2H), 3.61 (s, 2H), 4.73 (br s, 4H), 5.09 (s, 2H), 6.78 (d, J = 3.0 Hz, 1H), 6.94-7.0 (m, 3H), 7.14-7.22 (m, 4H), 7.31-7.34 (m, 4H), 7.43 (m, 2H); MS (m/z): 496.4 (M+H).
Example 145
Ethyl 2-(3-(4-((3-((l-methylspiro[indoline-3,4'-piperidin]-r-yl)methyl)benzyl)oxy) phenyl)oxetan-3-yl)acetate (Compound 145) A mixture of ethyl 2-(3-(4-((3-(bromomethyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate (Compound of step 1 of Example 143, 0.3 g, 0.715 mmol), l-methylspiro[indoline-3,4'- piperidine] (Intermediate 4, 0.174 g, 0.859 mmol) and CS2CO3 (0.051 g, 1.57 mmol) was stirred in dry DMF (5 ml) at RT for 2 h. After completion of reaction, the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2S04, concentrated and purified by flash column chromatography to obtain the title compound (0.3 g). Yield: 78% ; JH NMR (300 MHz, CDCI3): δ 7.43 (s, 1H), 7.35 (s, 2H), 7.13-7.07 (m, 4H), 6.98 (d, J = 8.4 Hz, 2H), 6.73 (t, J = 7.5 Hz, 1H), 6.50 (t, J = 7.8 Hz, 2H), 5.00 (d, J = 5.7 Hz, 2H), 4.87 (d, J = 5.7 Hz, 2H), 4.06 (q, J = 6.9 Hz, 2H), 3.58 (s, 2H), 3.21 (s, 2H), 3.11 (s, 2H), 2.90-2.862 (m, 2H), 2.78 (s, 3H), 2.19-2.117 (m, 4H), 1.99-1.92 (m, 4H), 1.16 (t, J = 6.9 Hz, 3H); MS (m/z): 541.4 (M+H).
Example 146
2- (3-(4-((3-((l-Methylspiro[indoline-3,4'-piperidin]-r-yl)methyl)benzyl)oxy)phenyl) oxetan-
3 - yl) acetic acid (Compound 146)
The title compound was prepared in an analogous manner as the compound 122 of Example 122. Compound 146 was obtained by hydrolyzing the compound of Example 145. Yield: 61%; JH NMR (300 MHz, DMSO-d6): δ 7.40 (s, 1H), 7.36-7.27 (m, 3H), 7.21 (d, J = 8.1 Hz, 2H), 7.03-6.97 (m, 4H), 6.62 (t, J = 7.2 Hz, 1H), 6.48 (d, J = 7.8 Hz, 1H), 5.08 (s, 2H), 4.73 (s, 4H), 3.50 (s, 2H), 3.14 (s, 2H), 3.00 (s, 2H), 2.77 (d, J = 11.1 Hz, 2H), 2.69 (s, 3H), 2.12 (t, J = 11.1 Hz, 2H), 1.81 (t, J = 12 Hz, 2H), 1.57 (d, J = 12.3 Hz, 2H); MS (ESI): m/z [M+H]+ 513.3; HPLC 99.56 %.
Example 147
Ethyl 2-(3-(4-((6-(spko[indene-l,4'-piperidin]-r-ylmethyl)pyridin-2-yl)methoxy)phenyl) oxetan-3-yl)acetate (Compound 147)
Step 1
Synthesis of ethyl 2-(3-(4-((6-(bromomethyl)pyridin-2-yl)methoxy)phenyl)oxetan-3- yl)acetate
A mixture of ethyl 2-(3-(4-hydroxyphenyl)oxetan-3-yl)acetate (Intermediate 1, 0.3 g, 1.270 mmol) and Cs2C03 (1.034 g, 3.17 mmol) in DMF (15 mL) was stirred at RT for 30 minutes, followed by the addition of 2,6-bis(bromomethyl)pyridine (0.505 g, 1.905 mmol). The reaction mixture was stirred at RT for 4 h. After completion of the reaction, the organic solvent was removed. The residue was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous Na2S04, concentrated and purified by flash column chromatography to obtain the title compound (0.139 g). Yield: 26%; JH NMR (300 MHz, CDCI3): δ 7.77 (t, J=7.5 Hz, 1H), 7.48 (d, J=7.5 Hz , 1H), 7.40 (d, J=7.5 Hz, 1H), 7.13 (d, J = 8.7 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 5.19 (s, 2H), 5.00 (d, J = 5.7 Hz, 2H), 4.87 (d, J = 6 Hz, 2H), 4.57 (s, 2H), 4.05 (q, J = 7.2 Hz, 2H), 3.10 (s, 2H), 1.15 (t, J = 7.2 Hz, 3H); MS (m/z): 421.7 (M+H).
Step 2
Synthesis of ethyl 2-(3-(4-((6-(spiro[indene-l ,4'-piperidin]- -ylmethyl)pyridin-2- yl)methoxy)phenyl)oxetan-3-yl)acetate
To a stirred solution of r-(2,2,2-trifluoroacetoxy)spiro[indene-l,4'-piperidin]-r-ium (Compound of step 2 of Example 141, 0.106 g, 0.357 mmol) and K2C03 (0.099 g, 0.714 mmol) in dry DMF (10 mL) was added drop-wise a solution of ethyl 2-(3-(4-((6- (bromomethyl)pyridin-2-yl)methoxy)phenyl) oxetan-3-yl)acetate (Compound of step 1, 0.15 g, 0.357 mmol) in DMF (5 mL) and stirred at RT for 6 h. After completion of reaction, the solvent was removed and the residue was quenched with ice-cold water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous Na2S04, concentrated and purified by flash column chromatography to obtain the title compound (0.14 g, 52% yield). JH NMR (300 MHz, CDC13): δ. 7.76 (t, J = 7.5 Hz, 1H), 7.47-7.403 (m, 3H), 7.34 (d, J = 6.3 Hz, 1H), 7.12 (d, 8.4 Hz, 2H), 6.99 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 5.7 Hz, 2H), 6.77 (d, J = 5.7 Hz, 2H), 5.22 (s, 2H), 5.00 (d, J = 6 Hz, 2H), 4.86 (d, J = 5.7 Hz, 2H), 4.05 (q, J = 7.2 Hz, 2H), 3.83 (s, 2H), 3.10 (s, 2H), 3.05 (d, J = 11.7 Hz, 2H), 2.54 (t, J = 11.7 Hz, 2H), 2.30 (t, J = 10.5 Hz, 2H), 1.40 (d, J = 12.9 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H); MS (m/z) 525.3 (M+H).
Example 148
2-(3-(4-((6-(Spiro[indene- 1 ,4'-piperidin] - 1 '-ylmethyl)pyridin-2-yl)methoxy)phenyl) oxetan-3-yl)acetic acid (Compound 148)
The title compound was prepared in an analogous manner as the compound 122 of Example 122. Compound 148 was obtained by hydrolyzing the compound of Example 147. Yield: 41%; JH NMR (300 MHz, DMSO-d6): δ 7.85 (t, J = 7.5 Hz, 1H), 7.49 (m, 4H), 7.23 (d, J = 7.8 Hz, 4H), 7.00 (d, J = 7.5 Hz, 3H), 6.80 (d, J = 5.4 Hz, 1H), 5.14 (s, 2H), 4.73 (d, J = 3.9 Hz, 4H), 3.74 (s, 2H), 2.95-2.89 (m, 4H), 2.16 (t, 11.7 Hz, 2H), 1.22 (d, J = 12.9 Hz, 4H); MS (m/z): 497.2 (M+H). Example 149
Ethyl 2-(3-(4-((6-((l-methylspiro[indoline-3,4'-piperidin]- -yl)methyl)pyridin-2- yl)methoxy)phenyl)oxetan-3-yl)acetate (Compound 149)
To a stirred solution of l-methylspiro[indoline-3,4'-piperidine] (Intermediate 4, 0.072 g, 0.357 mmol) and K2C03 (0.099 g, 0.714 mmol) in dry DMF (10 ml) was added drop-wise solution of ethyl 2-(3-(4-((6-(bromomethyl)pyridin-2-yl)methoxy) phenyl)oxetan-3-yl)acetate (compound of step 1 of Example 141 , 0.150 g, 0.357 mmol) in DMF (5 mL). The reaction mixture was stirred at RT for 6 h. After completion of reaction the solvent was evaporated and the residue was quenched with ice-cold water and extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous Na2S04, concentrated and purified by flash column chromatography to obtain the title compound (0.117 g). Yield: 30%; JH NMR (300 MHz, CDCI3): δ 7.72 (t, J=7.5 Hz, 2H), 7.44 (d, J=7.5 Hz, 2H), 7.14-7.08 (m, 3H), 6.98 (d, J=8.7 Hz, 2H), 6.74 (t, J=7.2 Hz, 1H), 6.51 (d, J=7.8 Hz, 1H), 5.21 (s, 2H), 5.00 (d, J=5.7 Hz, 2H), 4.86 (d, J=6 Hz, 2H), 4.05 (q, J= 6.9 Hz, 2H), 3.73 (s, 2H), 3.24 (s, 2H), 3.10 (s, 2H), 2.93 (d, J=U A Hz, 2H), 2.53 (s, 3H), 2.30 (t, J=U Hz, 2H), 2.06-1.97 (m, 2H), 1.30-1.272 (m, 2H), 1.15 (t, J= 6.9 Hz, 3H); MS (m/z): 542.1 (M+H).
Example 150
2-(3-(4-((6-((l-Methylspiro[indoline-3,4'-piperidin]-r-yl)methyl)pyridin-2- yl)methoxy)phenyl)oxetan-3-yl)acetic acid (Compound 150)
The title compound was prepared in an analogous manner as the compound 122 of Example 122. Compound 150 was obtained by hydrolyzing the compound of Example 149. Yield: 8%; JH NMR (300 MHz, DMSO-d6): δ 12.32 (s, 1H), 7.84 (t, J = 7.5 Hz, 1H), 7.45- 7.37 (m, 2H), 7.22 (d, J = 8.1 Hz, 2H), 7.00- 6.98 (m, 4H), 6.630 (t, J = 6.9 Hz, 1H), 6.48 (d, J = 7.5 Hz, 1H), 5.13 (s, 2H), 4.73 (s, 4H), 3.64 (s, 2H), 3.16 (s, 2H), 2.98 (s, 2H), 2.81 (d, J = 10.8 Hz, 2H), 2.69 (s, 3H), 2.22 (t, J = 11.1 Hz, 2H), 1.85 (t, J = 11.1 Hz, 2H), 1.60 (d, J = 12.6 Hz, 2H); MS (m/z): 514.1 (M+H).
Pharmacological assays
The pharmacological activity of the compounds of the present invetion as GPR40 agonists can be confirmed by a number of pharmocological assays known in the art. The exemplified pharmacological assay, given below, has been carried out with the compounds of the present invention synthesized in the above Examples. Example 151
Inositol Phosphate Accumulation Assay
The inositol phosphate accumulation assay was performed to characterise the GPR40 agonist activity of the compounds of the present invention. The assay was carried out in accordance with the method substantially as described in Diabetes, 2008, 57(8):2211-2219 and PLoS One, 2011, 6(1 l):e27270.
a) Generation of FFAR1 (GPR40) CHOK1 clone
A stable FFAR1 (GPR40) CHOK1 clone was used to determine the GPR40 agonist activity of the test compounds (representative compounds of the present invention). The stable FFAR1 (GPR40) CHOK1 clone expressing recombinant human GPR40 was generated according to the procedure described herein below.
Full-length human GPR40 cDNA (Accession Number: NM_005303) was cloned into mammalian expression vector (pReceiver) and was stably transfected into (Chinese Hamster Ovary) CHOK1 cells using Amaxa technology. 2 μg of pReceiver hGPR40 were transfected into lxlO6 CHOK1 cells in 6 well plates. The cells were split into three 100 mm cell culture plates on the second day and geneticin (800 μg/mL) was added to the cell culture on the third day. The selection medium comprising Ham's F-12 K supplemented with FBS (10%) and geneticin (800 μg/mL) was changed every three days until colonies were formed. The colonies isolated were further purified (single cell cloning) after 14 days to obtain pure isogenic single cell homogenous population of cells expressing the GPR40 receptor protein on the cell surface. GPR40 receptor expression on cell surface was measured by flow cytometry. The in-house transgenic cell line (clone) created was labeled as FFAR1 (GPR40) CHOK1 clone.
b) Determination of intracellular Inositol Phosphate release
FFARl (GPR40) CHOK1 cells were suspended in culture medium comprising Ham's F-12 K supplemented with FBS (10%) and geneticin (800 μg/mL). Cells were seeded at a density of 2xl04 cells per well in a 384 well tissue culture plate and cultured overnight. The medium was discarded and the cells were further resuspended in a stimulation buffer comprising HEPES (10 mM), glucose (5.5 mM), CaCl2 (1 mM), NaCl (150 mM), KC1 (4.2 mM), MgCl2 (0.5 mM) and LiCl (50 mM) having a pH of 7.6. The test compounds (representative compounds of Formula (I)) 10 mM stock were prepared in DMSO and subsequently log fold dilution of the test compounds were carried out in the stimulation buffer. Various concentrations of the test compounds and the standard DMSO solution were added to each well. The plates were further incubated at 37°C, 5% C(¾ incubator for 1 h. The final concentration of the test compounds in the each well varied from 1 pM to 10 μΜ. The DMSO concentration in the assay was 0.1% or less. After incubation, lysis reagent and anti- Tb conjugate were added to each well. The intracellular Inositol Phosphate release and accumulation in the test compounds were measured by the binding ability of the anti-Tb conjugate with the inositol phosphate inherently produced in each well as compared with the inositol phosphate coupled to dye d2 added externally to each well. The plates were then read using Perkin Elmer (Envision) plate reader and the fluorescence signal was captured. The EC50 values for the test compounds were calculated from the non linear regression sigmoidal curve graphs plotted between the concentrations of the test compounds and the fluorescence intensity. The EC50 values for the test compounds (representative compounds of Formula (I)) are provided in Table 1 below:
Figure imgf000172_0001
Symbol EC50 range class
+++ >5 nM but <200nM
++ >200 nM but <500nM
+ >500nM but < ΙΟΟΟηΜ
c) Conclusion:
The EC50 values determined for the test compounds by the inositol phosphate accumulation assay is indicative of GPR40 agonist activity of the compounds of the present invention.
It should be noted that, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents unless the content clearly dictates otherwise. Thus, for instance, reference to a composition comprising "a compound" includes a mixture of two or more compounds.
It should be further noted that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.

Claims

A compound of Formula (I);
Figure imgf000173_0001
Formula (I)
wherein,
Rj is hydrogen or (Ci-Ce)alkyl;
R2 and R3 together form a saturated or a partially unsaturated 3- to 6- membered heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
R4 at each occurrence is independently selected from the group consisting of hydrogen, (Ci-
Ce)alkyl, halogen, hydroxy, amino, cyano, nitro, -C(0)R7 and -S(0)pR6;
Rx and Ry are independently selected from the group consisting of A-Lj-X- and R5 ; provided that at least one of Rx and Ry is A-Lj-X-;
R5 is hydrogen, (Ci-Ce)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-Ce)alkyl, (C6- Cio)aryl, amino, cyano, nitro, -C(0)R? or -S(0)pR6;
R6 is hydrogen, (Ci-C6)alkyl or amino;
X is -0-, -(CH2)nO-, -(CH2)p(CR8R9)nCH20-, -(CH2)p(C6-C10aryl)kCH2O- or -(CR'R")P0-; Lj is absent or is selected from the group consisting of -0-, -S(0)p-, -C(0)NH-, -NHC(O)-, - NHC(0)NH-, -(CR'R")P-CH20-, -S(0)pNH-, -NHS(0)p-, -C(R'R")-, -CH=CR8- and
R' and R" together form =N(0-(C1-C6)aikyl), =0, a saturated or a partially unsaturated (C3- Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
R7 is (d-C6)alkyl, -0(C!-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, hydroxy or amino; Rg and R at each occurrence are independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (Ce-Cio)aryl and heteroaryl; or Rg and R together form =N(0-(Ci- Ce)alkyl), =0, a saturated or a partially unsaturated (C3-Cg)cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S;
A is (C1-C6) alkyl, (C3-Cio)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl,
Figure imgf000174_0001
Rio is hydrogen, (Ci-Ce)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-Ce)alkyl, halo(Ci- Ce)alkoxy, -S(0)pR6, amino, cyano, nitro or -C(0)R7; wherein R6 and R7 are as defined above;
k is an integer 1 or 2;
n is an integer from 1 to 3;
m is an integer from 1 to 4;
p is an integer from 0 to 2;
s is an integer from 1 to 4;
* indicates the point of attachment to Lj ;
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-C6)alkyl, (C3-Cg)cycloaikyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
-0(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Cj-C6)alkyl, (C3-Cg)cycloaikyl, heterocyclyl, hydroxy, halogen, amino, cyano, (C C6)alkyl-S(0)pR6, -S(0)pR6, -NR8R9 and -(CH2)SNR8R9; wherein R6, R8, R9, p and s are as defined above;
(C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, halo(Ci- C6)alkoxy, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C1-C6)alkyl(C6-C1o)aryl; wherein R\ R" and p are as defined above;
(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(CrC6)alkyl, hydroxy, -0(Ci-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, halo(C!-C6)alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C C6)alkyl-S(0)pR6; wherein R6, R7, R', R" and p are as defined above; heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, (C2- Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(Ci-Ce) alkyl, hydroxy, -0(Ci-Ce)alkyl, halo(Ci- C6) alkoxy, (C3-Cg)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (C1-C6)alkyl-OH, (C1-C6)alkyl-0-(C1-C6)alkyl, (C1-C6)alkyl(C6-C10)aryl, -C(0)R7, S(0)pR6 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, (C2- Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-Ce)alkyl, halo(Ci- C6) alkoxy, (C3-Cg)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, - C(0)R7 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
halogen is chlorine, bromine, iodine or fluorine;
provided that (i) when X is -(CH2)nO- and n is 1, A is not (C3-C10) cycloalkyl, (Ce-Cio)aryl, heterocyclyl or heteroaryl;
(ii) when X is -(CH2)p(C6-C1oaryl)kCH20- and p is 0 then Lj is not absent;
(iii) when X is -0-, Lj is -(CRgR^n-, n is 1 and one of the variable Rg and R is hydrogen, the other variable is not hydrogen or (Cj-C6)alkyl; and
(iv) when either one of X and Lj is -0-, the other is not -0-;
or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof.
2. The compound ac a (la);
Figure imgf000175_0001
wherein,
Ri, R2, R3, R4, Ry, X, Lj, A, m and n are as defined in claim 1 for Formula (I);
or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, a prodrug, a polymorph, N-oxide, S-oxide, or a carboxylic acid isostere thereof.
3. The compound according to claim 1 or claim 2, wherein R2 and R3 together form a saturated or a partially unsaturated 3- to 6- membered heterocyclyl ring containing one or two oxygen atoms.
4. The compound according to any one of claims 1 to 3, wherein R2 and R3 together form an oxetane ring; R4 is hydrogen and Ry is R5; wherein R5 is hydrogen, (Ci-C6) alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, -0(Ci-Ce)alkyl, (Ce-Cio)aryl, amino, cyano, nitro, - C(0)R7 or -S(0)pR6.
5. The compound according to any one of claims 1 to 4, wherein R2 and R3 together form an oxetane ring; R4 is hydrogen; Ry is R5; wherein R5 is hydrogen;
A is (d-C6)alkyl, (C3-C
Figure imgf000176_0001
Rio is hydrogen, -C(0)R7, S(0)pR6, or (C!-C6)alkyl;
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0)pR6; wherein R6 and p are as defined above;
-0(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, (C3-Cg)cycloaikyl, heterocyclyl, hydroxy and halogen; wherein R6, Rs, R9, p and s are as defined above;
(C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(C!-C6)alkoxy, -OCH2-(CR'R")p-(C1-C6)alkyl and -O(C1-C6)alkyl(C6-C10)aryl; wherein R', R" and p are as defined above;
(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(C1-C6)alkyl, hydroxy, -0(d-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, halo(C!-C6)alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(Ci-C6)alkyl- S(0)PR6; wherein R6, R7, R', R"and p are as defined above;
heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, halogen, halo(C!-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci-Ce) alkoxy, (C3-Cg)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (Ci- C6)alkyl-OH, (C1-C6)alkyl-0-(C1-C6)alkyl, (C1-C6)alkyl(C6-C1o)aryl, -C(0)R7, S(0)pR6 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- Cg)alkenyl, (C2-Cs)alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci- Ce)alkoxy, (C3-Cg)cycloalkyl, (C6-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, - C(0)R7 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
halogen is chlorine, bromine, iodine or fluorine;
provided that (i) when X is -(CH2)nO- and n is 1, A is not (Cs-Cu^cycloalkyl or (C6-Cio)aryl;
(ii) when X is -(CH2)p(C6-Cioaryi)kCH20- and p is 0 then Lj is not absent;
(iii) when X is -0-, Lj is -(CRgRg),,-, n is 1 and one of the variable R8 and R9 is hydrogen, the other variable is not hydrogen or (Ci-C6) alkyl; and
(iv) when either one of X and Lj is -0-, the other is not -0-.
6. The compound according to any one of claims 1 to 4, wherein R2 and R3 together form an oxetane ring; R4 is hydrogen; Ry is R5; wherein R5 is hydrogen;
A is
Figure imgf000177_0001
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0)pR6; wherein R6 and p are as defined above; -0(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, (C3-Cg)cycloalkyl, heterocyclyl, hydroxy and halogen; wherein ]¾, Rs, R9, p and s are as defined above;
(C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-Ce)alkyl, (Ci-Ce)alkoxy, halo(Ci-C6)alkoxy, -OCH2-(CR'R")p-(Ci-C6)alkyl and -0(Ci-C6)alkyl(C6-Cio)aryl; wherein R' , R" and p are as defined above;
(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, -0(Ci-C6)alkyl(C6-Cio)aryl, halo(Ci-C6)alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")P-(Ci-C6)alkyl and -0(Ci-C6)alkyl- S(0)pR6; wherein R6, R7, R' , R" and p are as defined above;
heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Cj-C6)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, halogen, halo(C!-C6)alkyl, hydroxy, -0(C!-C6)alkyl, haloCQ-Ce) alkoxy, (C3-Cg)cycloaikyl, (Ce-Cu taryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (Q- C6)alkyl-OH, (C1-C6)alkyl-0-(C1-C6)alkyl, (C1-C6)alkyl(C6-C1o)aryl, -C(0)R7, S(0)pR6 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- Cg)alkenyl, (C2-Cs)alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci- Ce)alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, - C(0)R7 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
halogen is chlorine, bromine, iodine or fluorine;
provided that (i) when X is -(CH2)nO- and n is 1 , A is not (C3-Cio)cycloalkyl or (Ce-Cio)aryl;
(ii) when X is -(CH2)p(C6-Cioaryl)kCH20- and p is 0 then Lj is not absent;
(iii) when X is -0-, Lj is -(CRsR^n-, n is 1 and one of the variable Rg and R is hydrogen, the other variable is not hydrogen or (Ci-C ) alkyl; and
(iv) when either one of X and Lj is -0-, the other is not -0-.
7. The compound according to any one of claims 1 to 5, wherein R2 and R3 together form an oxetane ring; R4 is hydrogen; Ry is R5; wherein R5 is hydrogen; X is -0-, - (CH2)p(CR8R9)nCH20-, -(CH2)p(C6-C10aryl)kCH2O-, or -(CR'R")P0- and A is (C6-C10)aryl; wherein Rg and R at each occurrence are independently selected from the group consisting of hydrogen, (Ci-Ce)alkyl, (C6-Cio)aryl and heteroaryl; or Rg and R9 together form =N(0-(Ci- Ce)alkyl), =0, a saturated or a partially unsaturated (C3-Cg) cycloalkyl ring or a saturated or a partially unsaturated heterocyclyl ring containing one or two heteroatoms selected from O, N or S; p is an integer from 0 to 2; n is an integer from 1 to 3 and k is an integer 1 or 2;
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0)PR6; wherein R6 and p are as defined above;
-0(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from (Ci-C6)alkyl, (C3-Cg)cycloalkyl, heterocyclyl, hydroxy and halogen; wherein R6, Rg, R9, p and s are as defined above;
(C3-Cio)cycloalkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of halogen, -0(Ci-C6)alkyl, (C C6)alkoxy, halo(C!-C6)alkoxy, -OCH2-(CR'R")p-(C1-C6)alkyl and -O(C1-C6)alkyl(C6-C10)aryl; wherein R', R" and p are as defined above;
(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(C1-C6)alkyl, hydroxy, -0(d-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, halo(C!-C6)alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C!-C6)alkyl- S(0)pR6; wherein R6, R7, R', R"and p are as defined above;
heterocyclyl is a 3- to 9-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- Cg)alkenyl, (C2-Cg)alkynyl, halogen, halo(Ci-C6)alkyl, hydroxy, -0(Ci-C6)alkyl, halo(Ci- Ce)alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, (Ci- C6)alkyl-OH, (C1-C6)alkyl-0-(C1-C6)alkyl, (C1-C6)alkyl(C6-C1o)aryl, -C(0)R7, S(0)pR6 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
heteroaryl is a 3- to 10-membered ring, which is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2- C8)alkenyl, (C2-Cg)alkynyl, halogen, halo(C1-C6)alkyl, hydroxy, -0(C1-C6)alkyl, halo(C Ce)alkoxy, (C3-Cg)cycloaikyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl, amino, cyano, nitro, - C(0)R7 and -0(Ci-C6)alkyl-S(0)pR6; wherein R6, R7, and p are as defined above;
halogen is chlorine, bromine, iodine or fluorine;
provided that
(i) when X is -(CH2)p(C6-Cioaryi)kCH20- and p is 0 then Lj is not absent;
(ii) when X is -0-, Li is
Figure imgf000180_0001
n is 1 and one of the variable Rs and R9 is hydrogen, the other variable is not hydrogen or (Ci-Ce)alkyl; and
(iii) when either one of X and Li is -0-, the other is not -0-.
8. The compound according to any one of claims 1 to 5, wherein R2 and R3 together form an oxetane ring; R4 is hydrogen; Ry is R5; wherein R5 is hydrogen;
X is -(CH2)p(C6-Cioaryl)kCH20-; Lj is absent or is selected from the group consisting of - -(CR'R")P-CH20- and -C(R'R")-; R' and R" together form =N(0-(C1-C6)alkyl) or =0;
-C6)alkyl, (C3-C10)cycloalkyl, (C6-C10)aryl,
Figure imgf000180_0002
Rio is hydrogen, (Ci-Ce)alkyl or -S(0)pR6;
p is an integer from 0 to 2 and k is an integer 1 or 2;
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0)pR6; wherein R6 and p are as defined above;
(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(C1-C6)alkyl, hydroxy, -0(d-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, halo(C!-C6)alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7, -OCH2-(CR'R")p-(C1-C6)alkyl and -0(C!-C6)alkyl- S(0)pR6; wherein R6, R7, R', R"and p are as defined above;
provided that when X is -(CH2)p(C6-Cioaryi)kCH20- and p is 0 then Lj is not absent.
9. The compound according to any one of claims 1 to 5, 7 and 8, wherein R2 and R3 together form an oxetane ring; R4 is hydrogen; Ry is R5 ; wherein R5 is hydrogen;
X is -(CH2)p(C6-Cioaryl)kCH20-; Lj is selected from the group consisting of -0-, -(CR'R")P- CH2O- and -C(R'R")-; R' and R" together form =N(0-(Ci-C6)alkyl) or =0; A is (C6- Cio)aryl; p is an integer from 0 to 2 and k is an integer 1 or 2;
wherein,
(Ci-Ce)alkyl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-C6)alkyl, halogen, halo(Ci-Ce)alkyl, hydroxy, - 0(Ci-Ce)alkyl, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, heterocyclyl, heteroaryl and -0(Ci-C6)alkyl- S(0)PR6; wherein R6 and p are as defined above;
(C6-Cio)aryl is unsubstituted or substituted with one or more groups independently selected from the group consisting of (Ci-Ce)alkyl, (C2-Cs)alkenyl, (C2-Cs)alkynyl, halogen, halo(C!-C6) alkyl, hydroxy, -0(d-C6)alkyl, -O(C1-C6)alkyl(C6-C10)aryl, halo(C C6) alkoxy, (C3-Cg)cycloalkyl, (Ce-Cio)aryl, -0(C6-Cio)aryl, (Ci-C6)alkylheterocyclyl, heterocyclyl, heteroaryl, amino, cyano, nitro, -C(0)R7,
Figure imgf000181_0001
and -0(C C6)alkyl- S(0)pR6; wherein R6, R7, R', R" and p are as defined above.
10. The compound according to any one of claims 1 to 9 selected from the group consisting of:
Ethyl 2-(3-(4-((l-(methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophen-3-yl) methoxy) phenyl)oxetan-3-yl)acetate;
2-(3-(4-((l-(methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophen-3-yl)methoxy)
phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(l-(methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophene-3- carboxamido)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(l-(Methylsulfonyl)-4,5-dihydronaphtho[l,2-c]thiophene-3- carboxamido)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(o-tolyloxy)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(o-Tolyloxy)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(phenylthio)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(Phenylthio)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(phenylsulfinyl)propoxy)phenyl)oxetan-3-yl)acetate;
Ethyl 2-(3-(4-(3-(phenylsulfonyl)propoxy)phenyl)oxetan-3-yl)acetate;
Ethyl 2-(3-(4-(3-(3-([l,l'-biphenyl]-4-yl)ureido)propoxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-(3-(3-([l,l'-Biphenyl]-4-yl)ureido)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(4-fluorophenoxy)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(4-fluorophenoxy)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(3-chlorophenoxy)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(3-chlorophenoxy)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(3-(trifluoromethyl)phenoxy)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(3-(Trifluoromethyl)phenoxy)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-(4-cyanophenoxy)propoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(3-(4-cyanophenoxy)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-([l,l'-biphenyl]-4-yloxy)propoxy) phenyl) oxetan-3-yl)acetate;
2-(3-(4-(3-([l,l'-biphenyl]-4-yloxy)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(2,2-dimethyl-3-(4-(trifluoromethyl)phenoxy)propoxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-(2,2-Dimethyl-3-(4-(trifluoromethyl)phenoxy)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((l-((o-tolyloxy)methyl)cyclopropyl)methoxy)phenyl)oxetan-3-yl)acetate;
2- (3-(4-((l-((o-Tolyloxy)methyl)cyclopropyl)methoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((l -((3-(trifluoromethyl)phenoxy)methyl)cyclopropyl)methoxy)phenyl) oxetan-
3- yl)acetate;
2-(3-(4-((l-((3-(Trifluoromethyl)phenoxy)methyl)cyclopropyl)methoxy)phenyl) oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((l - ((3 -chlorophenoxy)methyl)cyclopropyl) methoxy)phenyl)oxetan-3 - yl)acetate;
2-(3-(4-((l-((3-chlorophenoxy)methyl)cyclopropyl)methoxy) phenyl)oxetan-3-yl) acetic acid; Ethyl 2-(3-(4-((4-((l-methylspiro[indoline-3,4'-piperidin]- -yl)methyl)benzyl)oxy) phenyl)oxetan-3-yl);
2- (3-(4-((4-((l-Methylspiro[indoline-3,4'-piperidin]- -yl)methyl)benzyl)oxy)phenyl) oxetan-
3- yl)acetic acid;
Ethyl 2-(3-(4-((4-(spiro[indene-l,4'-piperidin]- -ylmethyl) benzyl)oxy)phenyl) oxetan- 3-yl)acetate;
2-(3-(4-((4-(Spiro[indene-l,4'-piperidin]- -ylmethyl)benzyl)oxy)phenyl)oxetan-3-yl) acetic acid;
Ethyl 2-(3-(4-(3-(methylsulfonamido)propoxy)phenyl)oxetan-3-yl)acetate; Ethyl 2-(3-(4-((4'-((4-benzylmorpholin-2-yl)methoxy)-2',6'-dimethyl-[l,l'-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4'-((4-Benzylmoφholin-2-yl)methoxy)-2 6'-(hmethyl-[l,l'-biphenyl]-3- yl)methoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-phenylethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((4-(2-(methoxyimino)-2-phenylethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-(4-methoxyphenyl)ethoxy)benzyl)oxy)phenyl) oxetan-3-yl)acetate;
2- (3-(4-((4-(2-(Methoxyimino)-2-(4-methoxyphenyl)ethoxy) benzyl) oxy)phenyl) oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-(4-chlorophenyl)-2-(methoxyimino) ethoxy) benzyl)oxy)phenyl) oxetan-
3 - yl) acetate;
2-(3-(4-((4-(2-(4-Chlorophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy)phenyl) oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-(4-cyanophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy)phenyl) oxetan-3- yl)acetate;
2-(3-(4-((4-(2-(4-Cyanophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy)phenyl)oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-(p-tolyl)ethoxy)benzyl)oxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((4-(2-(Methoxyimino)-2-(p-tolyl)ethoxy)benzyl) oxy)phenyl) oxetan-3-yl)acetic acid;
Ethyl 2-(3 -(4-((4-(2-(methoxyimino)-2-(4-(trifluoromethoxy) phenyl)ethoxy)benzyl) oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-(2-(Methoxyimino)-2-(4-(trifluoromethoxy)phenyl)ethoxy)benzyl)
oxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-([l,l'-biphenyl]-4-yl)-2-(methoxyimino)ethoxy)benzyl)oxy)
phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-(2-([l,l'-Biphenyl]-4-yl)-2-(methoxyimino)ethoxy)benzyl)oxy) phenyl)oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-(4-fluorophenyl)-2-(methoxyimino)ethoxy) benzyl)oxy)phenyl)oxetan-3- yl)acetate; E2-(3-(4-((4-(2-(4-Fluorophenyl)-2-(methoxyimino)ethoxy)benzyl)oxy)phenyl) oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-(methoxyimino)-2-(3-methoxyphenyl)ethoxy)
benzyl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-(2-(Methoxyimino)-2-(3-methoxyphenyl)ethoxy)benzyl) oxy)phenyl)oxetan-3- yl)acetic acid;
Ethyl 2-(3 -(4-(2-(Methoxyimino)-2-phenylethoxy)phenyl)oxetan-3-yl)acetate ;
2-(3-(4-(2-(Methoxyimino)-2-phenylethoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-benzoylbenzyl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((3-Benzoylbenzyl)oxy) phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-((methoxyimino)(phenyl)methyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((3-((Methoxyimino) (phenyl)methyl)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((4-benzoylbenzyl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-Benzoylbenzyl)oxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((4-((methoxyimino)(phenyl)methyl)benzyl)oxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((4-((Methoxyimino) (phenyl)methyl)benzyl)oxy)phenyl)oxetan-3-yl) acetic acid; Ethyl 2-(3-(4-((4-(2-oxo-2-phenylethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-(2-Oxo-2-phenylethoxy) benzyl)oxy) phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((4-(2-(4-methoxyphenyl)-2-oxoethoxy) benzyl)oxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((4-(2-(4-methoxyphenyl)-2-oxoethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid; ethyl 2-(3-(4-((4-(2-(4-fluorophenyl)-2-oxoethoxy) benzyl)oxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((4-(2-(4-fluorophenyl)-2-oxoethoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-(2-(3-(4-methoxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-(2-(3-(4-methoxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(2-(3-(4-(benzyloxy)phenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl) acetate; 2-(3-(4-(2-(3-(4-(benzyloxy)phenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-(2-(3-(4-hydroxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-(2-(3-(4-hydroxyphenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(2-(3-(4-((3-methyloxetan-3-yl)methoxy)phenyl)oxetan-3- yl)ethoxy)phenyl)oxetan-3-yl)acetate;
2- (3-(4-(2-(3-(4-((3-methyloxetan-3-yl)methoxy)phenyl)oxetan-3-yl)ethoxy)phenyl) oxetan-
3- yl)acetic acid; Ethyl 2-(3-(4-(2-(3-(4-(3-(methylsulfonyl)propoxy)phenyl)oxetan-3- yl)ethoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(2-(3-(4-(3-(methylsulfonyl)propoxy)phenyl)oxetan-3-yl)ethoxy)phenyl)oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((3-(4-(benzyloxy)phenyl)oxetan-3-yl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((3-(4-(benzyloxy)phenyl)oxetan-3-yl)oxy)phenyl)oxetan-3-yl)acetic acid;
ethyl 2-(3-(4-((4-chloro-2,3-dihydro-lH-inden-l-yl)oxy) phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-chloro-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((5-methoxy-2,3-dihydro-lH-inden-l-yl)oxy) phenyl) oxetan-3-yl)acetate; 2-(3-(4-((5-methoxy-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((6-((3-methyloxetan-3-yl)methoxy)-2,3-dihydro-lH-inden-l-yl)oxy) phenyl)oxetan-3-yl)acetate;
2- (3-(4-((6-((3-methyloxetan-3-yl)methoxy)-2,3-dihydro- lH-inden-l-yl)oxy)phenyl)oxetan-
3- yl)acetic acid;
Ethyl 2-(3-(4-((6-(isopentyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((6-(isopentyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((6-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden- l-yl)oxy)phenyl) oxetan-3-yl)acetate;
2-(3-(4-((6-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl) acetic acid;
Ethyl 2-(3-(4-((6-(benzyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl) acetate; 2-(3-(4-((6-(benzyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((5-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden- l-yl)oxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((5-(4,4,4-trifluorobutoxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((5-(isopentyloxy)-2,3-dihydro-lH-inden-l-yl)oxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((5-(isopentyloxy)-2,3-dihydro-lH-inden-l-yl)oxy) phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((5-((3-methyloxetan-3-yl)methoxy)-2,3-dihydro-lH-inden-l-yl)oxy) phenyl)oxetan-3-yl)acetate;
2- (3-(4-((5-((3-methyloxetan-3-yl)methoxy)-2,3-dihydro- lH-inden-l-yl)oxy) phenyl)oxetan-
3- yl)acetic acid;
Ethyl 2-(3-(4-((3-phenoxybenzyl)oxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((3-phenoxybenzyl)oxy) phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-(4-fluorophenoxy) benzyl) oxy) phenyl) oxetan-3-yl) acetate;
2-(3-(4-((3-(4-fluorophenoxy) benzyl) oxy) phenyl) oxetan-3-yl) acetic acid;
Ethyl 2-(3-(4-((4-phenoxybenzyl) oxy) phenyl) oxetan-3-yl) acetate;
2-(3-(4-((4-phenoxybenzyl) oxy) phenyl) oxetan-3-yl) acetic acid;
Ethyl 2-(3-(4-((2-phenoxybenzyl) oxy) phenyl) oxetan-3-yl) acetate; 2-(3-(4-((2- phenoxybenzyl) oxy) phenyl) oxetan-3-yl) acetic acid;
Ethyl 2-(3-(4-((4-(2,6-dimethylphenoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-(2,6-dimethylphenoxy)benzyl)oxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(3-phenyl-3-(pyridin-3-yl)propoxy)phenyl) oxetan-3-yl)acetate;
2-(3-(4-(3-phenyl-3-(pyridin-2-yl)propoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3,3-diphenylallyl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((3,3-diphenylallyl) oxy)phenyl)oxetan-3-yl)acetic acid;
Benzyl l-(4-((4-(3-(2-ethoxy-2-oxoethyl)oxetan-3-yl)phenoxy)methyl)benzyl)
spiro[indoline-3 ,4'-piperidine] - 1 '-carboxylate;
Ethyl 2-(3-(4-((4-((l-(methylsulfonyl)spiro[indoline-3,4'-piperidin]- -yl)methyl) benzyl)oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-((l-(Methylsulfonyl) spiro[indoline-3,4'-piperidin]- -yl)methyl)benzyl)oxy) phenyl)oxetan-3-yl)acetic acid;
ethyl 2-(3-(4-((4-(( -(methylsulfonyl)spiro[indoline-3,4'-piperidin]-l-yl)methyl)benzyl) oxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-((4-((l'-(methylsulfonyl) spiro[indoline-3,4'-piperidin]-l-yl)methyl)benzyl)oxy) phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(2-(5-methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(2-(5-Methyl-2-phenyloxazol-4-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-(2-(5-methyl-2-phenylthiazol-4-yl)ethoxy)phenyl)oxetan-3-yl)acetate;
2-(3-(4-(2-(5-methyl-2-phenylthiazol-4-yl)ethoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-((4-chlorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((3-((4-Chlorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((3-((o-tolyloxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetate; 2-(3-(4-((3-((o-Tolyloxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((3-((naphthalen-2-yloxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((3-((Naphthalen-2-yloxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-((4-cyanophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((3-((4-Cyanophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((3-((4-fluorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((3-((4-Fluorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((3-((4-chlorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((3-((4-Chlorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-((3-((2-fluorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((3-((2-Fluorophenoxy)methyl)oxetan-3-yl)methoxy)phenyl)oxetan-3-yl)acetic acid; Ethyl 2-(3-(4-(3-([l,l'-biphenyl]-4-ylsulfonamido)propoxy)phenyl) oxetan-3-yl)acetate; 2-(3-(4-(3-([l,l'-biphenyl]-4-ylsulfonamido)propoxy) phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((2-(spiro[indene-l,4'-piperidin]- -methyl)benzyl) oxy)phenyl)oxetan-3- yl)acetate;
2-(3-(4-((2-(Spiro[indene- 1 ,4'-piperidin] - 1 '-ylmethyl)benzyl) oxy)phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-((l-methylspiro[indoline-3,4'-piperidin]- -yl)methyl)benzyl)oxy) phenyl)oxetan-3-yl)acetate;
2-(3-(4-((3-(Spiro[indene-l,4'-piperidin]- -ylmethyl)benzyl)oxy) phenyl)oxetan-3-yl)acetic acid;
Ethyl 2-(3-(4-((3-((l-methylspiro[indoline-3,4'-piperidin]- -yl)methyl)benzyl)oxy) phenyl)oxetan-3-yl)acetate;
2- (3-(4-((3-((l-Methylspiro[indoline-3,4'-piperidin]- -yl)methyl)benzyl)oxy)phenyl) oxetan-
3- yl)acetic acid;
Ethyl 2-(3-(4-((6-(spko[indene-l,4'^iperidin]- -ylmethyl)pyridin-2-yl)methoxy)phenyl) oxetan-3-yl)acetate; 2-(3-(4-((6-(Spko[indene-l,4'-piperidin]- -ylmethyl)pyridin-2-yl)memoxy)pheny oxetan-3- yl)acetic acid;
Ethyl 2-(3-(4-((6-((l-methylspiro[indoline-3,4'-piperidin]- -yl)methyl)pyridin-2- yl)methoxy)phenyl)oxetan-3-yl)acetate; and
2-(3-(4-((6-((l-Methylspiro[indoline-3,4'-piperidin]- -yl)methyl)pyridin-2- yl)methoxy)phenyl)oxetan-3-yl)acetic acid; or
an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt, a solvate, a prodrug, a polymorph, a carboxylic acid isostere, an N-oxide or a S-oxide thereof.
11. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 10, or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, and a pharmaceutically acceptable excipient.
12. A compound according to any one of claims 1 to 10, or an isotopic form or a stereoisomer or a tautomer or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof, for use in the treatment of a disease or a condition mediated by GPR40.
13. A compound for use according to claim 12, wherein the disease or condition mediated by GPR40 is selected from the group consisting of diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, cardiovascular disease, atherosclerosis, kidney disease, polycystic ovary syndrome, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, fatty liver development, dermatopathy, dyspepsia, hypoglycemia, cancer, edema and pancreatic beta cell degeneration.
14. A compound for use according to claim 12 or claim 13, wherein the disease or condition mediated by GPR40 is selected from the group consisting of diabetes, obesity, insulin resistance, hyperglycemia, glucose intolerance, hypercholesterolemia, hypertriglylceridemia, dyslipidemia, hyperlipoproteinemia, hyperinsulinemia, atherosclerosis, diabetic neuropathy, diabetic retinopathy, metabolic syndrome, hypertension and pancreatic beta cell degeneration.
15. A compound according to any one of claims 12 to 14, wherein the disease or condition mediated by GPR40 is selected from the group consisting of diabetes, obesity, insulin resistance, hyperglycemia, glucose intolerance, metabolic syndrome and pancreatic beta cell degeneration.
16. A compound according to any one of claims 12 to 15, wherein the disease or condition mediated by GPR40 is diabetes.
17. A compound according to any one of claims 12 to 16, wherein the diabetes is Type 2 diabetes.
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