WO2006117743A1 - Substituted aromatic compounds as antidiabetic agents - Google Patents

Substituted aromatic compounds as antidiabetic agents Download PDF

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Publication number
WO2006117743A1
WO2006117743A1 PCT/IB2006/051346 IB2006051346W WO2006117743A1 WO 2006117743 A1 WO2006117743 A1 WO 2006117743A1 IB 2006051346 W IB2006051346 W IB 2006051346W WO 2006117743 A1 WO2006117743 A1 WO 2006117743A1
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ethoxy
benzyl
carbonyl
methyl
ethyl
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PCT/IB2006/051346
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French (fr)
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Jitendra A. Sattigeri
Mrinalkanti Kundu
Lalima Sharma
Priya Gupta
Sachin Ramesh Kandalkar
Srinivasan Thangathirupathy
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Ranbaxy Laboratories Limited
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Publication of WO2006117743A1 publication Critical patent/WO2006117743A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • 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
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring

Definitions

  • the present invention relates to substituted aromatic compounds, which have
  • PPAR modulating activity and hence can be used as anti-diabetic agents.
  • PPAR peroxisome proliferation activated receptor
  • Such compounds can also be used as therapeutic agents for treating diseases and conditions mediated through any of the isoforms of PPAR, diabetes and diabetes-associated complications, diseases or conditions in which insulin resistance is the central pathophysiological mechanism and diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, nephrosclerosis, polycystic ovarian syndrome, eating disorders, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, psoriasis or obesity.
  • Processes for the preparation of the described compounds, pharmaceutical compositions containing such compounds, and methods for treating diabetes mellitus and diseases and conditions mediated through insulin resistance are also provided.
  • Type II insulin-resistant diabetes mellitus also known as non insulin-dependent diabetes mellitus afflicts an estimated 6 % of the adult population in western society and is expected to grow at a rate of 6 % per annum worldwide.
  • Type II diabetes is a complex metabolic disorder and is characterized by hyperglycemia, which results from impaired insulin secretion from the pancreas and insulin resistance mainly in muscle and liver. Insulin-resistant individuals also exhibit a variety of closely related clinical indications, which include obesity, hypertension, dyslipidaemia, and premature atherosclerosis. 80 % of diabetic mortality arises from atherosclerotic cardiovascular disease (ASCVD). Uncontrolled hyperglycemia can further lead to late-stage complications, such as nephropathy, neuropathy and retinopathy.
  • ASCVD atherosclerotic cardiovascular disease
  • Non-pharmacological approaches to lower high blood sugar include a strict control of diet followed by vigorous exercise.
  • several pharmacological agents are also available as hypoglycemic agents including insulin secretogogues e.g., sulphonyl ureas (for example, glimeperide) and non sulphonyl ureas (for example, repaglinide), which increase insulin secretion from pancreatic cells; biguanides (metformin), which lower hepatic glucose production; and ⁇ -glucosidase inhibitors (acarbose), which delay intestinal absorption of carbohydrates.
  • insulin secretogogues e.g., sulphonyl ureas (for example, glimeperide) and non sulphonyl ureas (for example, repaglinide), which increase insulin secretion from pancreatic cells; biguanides (metformin), which lower hepatic glucose production; and ⁇ -glucosidase inhibitors (acarb
  • PPAR Peroxisome-Proliferator- Activated Receptor
  • PPAR ⁇ is abundantly expressed in adipose tissues. Direct activation of PPAR ⁇ leads to induction of adipocyte genes, such as for fatty acid transporter 1, which in turn contributes to lowering of triglycerides and free fatty acid (FFA) levels.
  • FFA free fatty acid
  • Glitazones for example, rosiglitazone and pioglitazone
  • rosiglitazone and pioglitazone belong to this class of drug and are now proven insulin sensitizers (Moller, D.E.; Nature, (2001), 414, 6865, 821-827).
  • PCT Publication No. WO 01/21602 and U.S. Patent No. 6,414,002 disclose oxa and thiazole derivatives, which have been described to be useful as antidiabetic and antiobesity agents.
  • PCT Publication No. WO 02/040481 discloses adenine-based inhibitors of adenylyl cyclase, pharmaceutical compositions and a method of use thereof.
  • PCT Publication No. WO 04/004655 discloses substituted heterocyclic derivatives that have been said to be useful as antidiabetic and antiobesity agents.
  • PCT Publication No. WO 03/082841 discloses 5-substituted 1 , 1 -dioxo- 1 ,2,5 thiazolidine-3-one derivatives that have been said to be useful as PTPASE inhibitors.
  • the present invention relates to substituted aromatic compounds, which have PPAR modulating activity, and accordingly can be used as anti-diabetic agents.
  • the present invention also relates to processes for synthesizing such compounds.
  • compositions containing one or more compound(s) provided herein, optionally together with one or more pharmaceutically acceptable carriers or diluents.
  • Such pharmaceutical compositions can be used for treating diseases and conditions mediated through any of the isoforms ( ⁇ , ⁇ or ⁇ ) of PPAR, diabetes mellitus or diseases or conditions mediated through insulin resistance.
  • X 12 and X 13 can each independently be CR' or N, wherein R' can be hydrogen or alkyl;
  • X] 5 can be CH or N;
  • X 16 and V can each independently be O, NR', or S, wherein R' can be the same as defined earlier;
  • D and E can be substituted or unsubstituted alkyl, aryl or a bond
  • R 1 -Rs and R 1O -Rn can each independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino
  • A can be N(CH 3 ), O, C(O), NH, S or a bond
  • Y can be COOR 28 (wherein R 28 can be hydrogen or substituted or unsubstituted alkyl) or
  • a 1 , A 2 or A 3 can be substituted or unsubstituted C 1-4 alkylene.
  • the compounds can include one or more of the following embodiments.
  • the compound can be:
  • Formula ⁇ Q _ Formula in pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, wherein: Het, A 1 -A 3 , Z, Y, R 18 and R ⁇ can be the same as defined above.
  • compositions comprising therapeutically effective amounts of one or more compounds described herein together with one or more pharmaceutically acceptable carriers, excipients or diluents.
  • provided herein are methods of treating a mammal suffering from a disease or condition mediated through ⁇ , ⁇ or ⁇ isoforms comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds (or one or more pharmaceutical compositions) described herein.
  • provided herein are methods of treating a mammal suffering from diabetes or associated diabetes complications comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds (or one or more pharmaceutical compositions) described herein.
  • Formula IV with a compound of Formula Het-A]-OH or HeI-A 1 -L 1 (wherein L 1 can be a leaving group selected from Cl, Br, I, acetate, 4-methylbenzenesulfonate, 4- bromobenzenesulfonate, 4-nitrobenzenesulfonate, methanesulfonate, or trifluoromethanesulfonate) to form a compound of Formula V,
  • Het is selected from: wherein:
  • X 12 and X 13 are each independently CR' or N, wherein R' is hydrogen or alkyl;
  • X 15 is CH or N;
  • X 16 and V are each independently O, NR', or S, wherein R' is the same as defined earlier;
  • D and E are substituted or unsubstituted alkyl, aryl or a bond;
  • R 1 -R 5 and R 1O -Rn are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino;
  • A is N(CH 3 ), O, C(O), NH, S or a bond;
  • R 28 is substituted or unsubstituted alkyl or aryl;
  • Z is O, S, NH, N-Me or a bond;
  • a 1 is substituted or unsubstituted C 1-4 alkylene.
  • X 12 and X 13 are each independently CR' or N, wherein R' is hydrogen or alkyl;
  • X 15 is CH or N;
  • X 16 and V are each independently O, NR', or S, wherein R' is the same as defined earlier;
  • D and E are substituted or unsubstituted alkyl, aryl or a bond;
  • R 1 -R 5 and R 1O -Rn are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino;
  • A is N(CH 3 ), O, C(O), NH, S or a bond;
  • R 28 is substituted or unsubstituted alkyl or aryl
  • Z is O, S, NH, N-Me or a bond
  • a 1 is substituted or unsubstituted C 1-4 alkylene.
  • X 12 and X 13 each can independently be CR' or N, wherein R' can be hydrogen or alkyl;
  • X] 5 can be CH or N; X 16 and V each can independently be O, NR' or S;
  • D and E each can independently be substituted or unsubstituted alkyl, aryl or a bond;
  • R 1 -R 5 and R 1O -Rn each can independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino;
  • A can be N(CH 3 ), O, C(O), NH, S, or a bond;
  • Formula II pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof wherein Het, A 1 -A 3 , Z, Y, R 18 and R ⁇ are the same as defined for Formula I above.
  • kits for treating patients e.g., mammals
  • methods for treating patients comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein.
  • provided herein are methods for treating patients (e.g., mammals) suffering from diseases or conditions in which insulin resistance is the central pathophysiological mechanism, comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein.
  • patients e.g., mammals
  • diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis, polycystic ovarian syndrome, and eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia, psoriasis or obesity, comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein.
  • diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis, polycystic ovarian syndrome, and eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia, p
  • the compounds described herein can also be used in combination with another type(s) of anti-diabetic agent(s) and/or hypolipidemic agent(s) and/or anti-hypertensive agent(s) and/or platelet aggregation inhibitor(s) and/or anti-osteoporosis agent(s) for the treatment of patients (e.g., mammals) suffering from diseases and conditions described herein.
  • patients e.g., mammals
  • PPAR agonists e.g., biguanides, protein tyrosine phosphate- IB inhibitors, dipeptidyl peptidase inhibitors), insulin or insulin mimetics, sulphonylureas, ⁇ -glucosidase inhibitors, cholesterol lowering agents (HMG-CoA reductase inhibitors, sequesterants, nicotinyl alcohol, nicotinic acid or salt thereof, PPAR ⁇ agonists, PPAR ⁇ / ⁇ agonists, inhibitors of cholesterol absorption, Acyl CoA: cholesterol acyl tranferase inhibitors, antioxidants), PPAR ⁇ agonists, antiobesity compounds, an ideal bile acid transporter inhibitor, agents intended to be used in inflammatory for the treatment of mammal suffering from diseases and conditions described herein.
  • PPAR agonists e.g., biguanides, protein tyrosine phosphate- IB inhibitors, dipeptidyl
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms.
  • Alkyl groups can be optionally interrupted by atom(s) or group(s) independently selected from oxygen, sulfur, a phenylene, sulphinyl, sulphonyl group or -NR 8 -, wherein R 3 can be hydrogen, alkyl, alkenyl, alkynyl cycloalkyl or aryl.
  • This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like.
  • alkylene refers to the divalent radical of the above defined alkyl. It may optionally be substituted with the substituents as defined for alkyl.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans, or geminal geometry. It can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and - NR a -, wherein R 3 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl. In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom.
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms. It can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -NR 8 -, wherein R 3 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl. In the event that alkynyl is attached to a heteroatom, the triple bond cannot be alpha to the heteroatom.
  • alkynyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF 3 , -NR p R q , -C(O)NR p R,, -NHC(O)NR p R q , -C(O)NR p R, (wherein R p and R q are the same as defined earlier), cyano, or S(O) D1 R 66 (wherein m is an integer from 0-2 and R 66 is same as defined earlier).
  • cycloalkyl refers to saturated or unsaturated cyclic alkyl of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings.
  • Groups such cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclopropylene, cyclobutylene, and the like exemplify single ring structures.
  • Groups such as adamantanyl, bicyclo [2.2.1]heptane, and the like exemplify fused ring structures.
  • Cycloalkyl can also be fused with an aryl, for example indane, and the like.
  • alkoxy denotes the group O-alkyl, wherein alkyl is the same as defined above.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • optionally substituted amino herein refers to NR g R h , wherein R g and R h can be hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, -S(O) a R b or COR d (wherein a and R d are the same as defined earlier).
  • aryl herein refers to aromatic system having 2 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups.
  • aryl groups include, but are not limited to, phenyl, biphenyl, anthryl or naphthyl ring and the like.
  • the aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
  • a cycloalkyl group may optionally contain heteroatoms selected from O, N or S.
  • Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
  • heteroaryl refers to an aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic or tricyclic aromatic group having from 8 to 14 ring atoms, with one or more heteroatom(s) independently selected from N, O or S.
  • the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring.
  • heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, or benzoxazolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl, quinazonyl, carbazolyl phenothiazinyl, phen
  • heterocyclyl refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members and/or optionally are substituted, wherein the substituents are selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, haloalkyl, cyano, nitro, COR S , COOR s (wherein R 3 is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), oxo, carboxy, heterocyclyl, heteroaryl
  • Carbonyl or sulfonyl group can replace carbon atom(s) of heterocyclyl.
  • the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring.
  • the heterocyclyl ring optionally may contain one or more olefinic bond(s).
  • heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, benzoxazinyl, benzthiazinyl, imidazolyl, benzimidazolyl, tetrazolyl, carbaxolyl, indolyl, phenoxazinyl, phenothiazinyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, thiazolidinyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl, tetrahydropyranyl, piperazinyl and the like.
  • solvates refers to solvates with water (i.e., hydrates, hemihydrate or sesquihydrate) or pharmaceutically acceptable solvents, for example solvates with common organic solvents as ethanol and the like. Such solvates are also encompassed within the scope of the disclosure.
  • the present invention also includes, within its scope, prodrugs of the compounds described herein.
  • prodrugs can be functional derivatives of these compounds, which can be readily convertible in vivo to the required compound, and they may be carrier-linked or bioprecursors.
  • Carrier-linked prodrugs may be bipartite, tripartite or mutual prodrugs. Prodrugs are intended to improve drug efficacy by improving solubility and consequently absorption and distribution as desired.
  • W is a group that can be easily removed under physiological conditions during or after administration to a patient (e.g., mammal) to form a compound having Formula I, or the carboxylate anion thereof, or a pharmaceutically acceptable salt, wherein W is selected from -OR 25 , -OCH 2 OR 25 , -OCH(CH 3 )OR 25 , -OCH 2 OC(O)R 25 , -OCH(CH 3 )OC(O)R 25 , -OCH 2 OC(O)OR 25 , -OCH(CH 3 )OC(O)OR 25 and -N(R 26 ) 2 (wherein R 25 can be independently selected from C 1-6 alkyl optionally substituted with one or two groups selected from -CO 2 H, -CONH 2 , -NH 2 , -OH, -OAc, -NHAc or phenyl;
  • the described compounds may get metabolized in vivo and these metabolites are also encompassed within the scope of this invention.
  • polymorphs includes all crystalline forms, as well as amorphous forms, of the compounds described herein and are encompassed within the scope of the present invention.
  • phrases "pharmaceutically acceptable carriers” is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • salts refers to salts prepared from pharmaceutically acceptable monovalent, divalent or trivalent non-toxic metals or organic bases.
  • monovalent, divalent or trivalent metals include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, zinc or aluminum and the like.
  • organic bases include, but are not limited to, amino acids, ammonia, mono-alkyl ammoniums, dialkyl ammoniums, trialkyl ammoniums or N-methyl glucamine and the like.
  • free acid forms of compounds of the present invention may be prepared from salt forms, for example, by contacting the salt with dilute aqueous solution of an acid, such as hydrochloric acid.
  • Base addition salts may differ from the free acid forms of the compounds described herein in physical characteristics, for example, solubility or melting point.
  • the salt forms differ from the compound described herein in certain physical properties such as solubility or melting point, but the salts are otherwise equivalent for purposes of this invention.
  • stereoisomer refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space.
  • Stereoisomers include enantiomers, diastereomers, geometrical isomers, atropisomer or conformational isomers as defined by the IUPAC 1974 Recommendations for Section E. AU such stereoisomers are encompassed within the scope of this invention.
  • modulate refers to the ability of a modulator for a member of the nuclear hormone receptor superfamily to either directly (e.g., by binding to the receptor as a ligand) or indirectly (e.g., as precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.
  • pharmaceutically acceptable refers to being approved by a regulatory agency of the federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • Reactions of compounds of Formula IV with compounds of Formula Het- Ai -OH to form a compound of Formula V can be carried out in one or more solvents, for example, tetrahydrofuran, dimethylformamide, dichloromethane, toluene, diethylether, dioxane, ethylacetate, acetonitrile, benzene or mixtures thereof.
  • Reactions of compounds of Formula IV with compounds of Formula Het-Ai-Li to form compounds of Formula V can be carried out in one or more solvents, for example, acetone, diethyl ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile or mixtures thereof.
  • Reactions of compounds of Formula IV with compounds of Formula Het-Ai-Li to form compounds of Formula V can be carried out in the presence of one or more organic bases (e.g., triethylamine, diethylamine, tributylamine, diisopropylamine, 4-dimethylaminopyridine, 1 ,8-diazabicyclo[5,4,0]-undec-7-ene, l,4-diazabicyclo[2,2,2]octane, N-methylmorpholine, diisopropylethylamine, pyridine, sodium hydride or mixtures thereof); one or more inorganic bases (e.g., potassium carbonate, cesium carbonate or mixtures thereof) or mixtures thereof.
  • organic bases e.g., triethylamine, diethylamine, tributylamine, diisopropylamine, 4-dimethylaminopyridine, 1 ,8-diazabicyclo[5,4,
  • Reactions of compounds of Formula IV to form compounds of Formula V can be carried out in the presence of one or more redox couple agents, which can be one or more of those known to one of ordinary skill in the art.
  • the oxidizing part of the redox couple can be selected from diisopropylazodicarboxylate (DIAD), diethylazo-dicarboxylate (DEAD), N,N,N',N'-tetramethylazodicarboxamide (TMAD), 1,1 '- (azodicarbonyl)dipiperidine (ADDP), cyanomethylenetributylphosphorane (CMBP), 4,7- dimethyl-3,5,7-hexahydro-l ,2,4,7-tetrazocin-3,8-dione (DHTD), N,N,N'N'-tetraisopropyl- azodicarboxamide (TIPA) or mixtures thereof.
  • DIAD diisopropylazodicarboxylate
  • DEAD diethy
  • the reduction part of the redox couple can be one or more phosphines selected from trialkylphosphines (e.g., tributylphosphine), triarylphosphines (e.g., triphenylphosphine), tricycloalkylphosphines (e.g., tricyclohexylphosphine), triheteroarylphosphine, 4-(diphenylphosphino)-N,N'-dimethyl- aniline or mixtures thereof.
  • Phosphine reagents having a combination of aryl, alkyl or heteroaryl substituents may also be used (e.g., diphenylpyridylphosphine).
  • HC1 to form compounds of Formula VI can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, toluene, diethylether, dioxane, ethylacetate, acetonitrile or mixtures thereof.
  • Reactions of compounds of Formula V to form compounds of Formula VI can be carried out in the presence of one or more organic bases, for example, triethylamine, pyridine, 4-dimethylaminopyridine or mixtures thereof.
  • These reactions can also be carried out in the presence of one or more reducing agents, for example, sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, or mixtures thereof, or any methods known to in the art.
  • Hydrolyzing compounds of Formula VII to form compounds of Formula VIII can be carried out in the presence of one or more inorganic bases (e.g. , lithium hydroxide, sodium hydroxide, potassium hydroxide or mixtures thereof) and one or more solvents (e.g., tetrahydrofuran, methanol, water, dimethylformamide, diethylether, or mixtures thereof).
  • inorganic bases e.g. , lithium hydroxide, sodium hydroxide, potassium hydroxide or mixtures thereof
  • solvents e.g., tetrahydrofuran, methanol, water, dimethylformamide, diethylether, or mixtures thereof.
  • reaction temperatures and duration may be adjusted according to the desired needs and are well within the capabilities of one of ordinary skill in the art without undue experimentation.
  • the present invention encompasses pharmaceutical compositions comprising, as an active ingredient, one or more compounds described herein and/or one or more pharmaceutically acceptable salts together with one or more pharmaceutically acceptable carriers or diluents.
  • Compounds described herein may be administered to a patient, i.e., human or animal, for treatment by any route, which effectively transports the active compound(s) to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral (rectal, subcutaneous, intravenous, intraurethral, intramuscular, intranasal) routes of administration.
  • a preferred administration route is oral administration.
  • compositions of the present invention comprise pharmaceutically effective amounts of one or more compounds of the present invention formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carriers includes non-toxic, inert solid, semi-solid or liquid filler, diluents, encapsulating material or formulation of any type.
  • Solid form preparations for oral administration include capsules, tablet, pills, powder, granules, sachets or suppositories.
  • Active compounds for solid form preparations can be mixed with one or more inert, pharmaceutically acceptable excipients or carriers, for example, sodium citrate, dicalcium phosphate or mixtures thereof; binders, for example, carboxymethyl cellulose, alginates, gelatins, polyvinylpyrolidinone, acacia or mixtures thereof; disintegrating agents, for example, agar-agar, calcium carbonate, alginic acid, certain silicates, sodium carbonate or mixtures thereof; absorption acceptors, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, glycerol monostearate or mixtures thereof; adsorbents, for example, kaolin; lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate or mixtures thereof; or mixtures thereof.
  • dosage forms may also comprise one or more buffering agents.
  • granules can be prepared with coating and shells, for example, enteric coatings or other coatings known to one of ordinary skill in the art.
  • Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solution, suspensions, syrups or elixirs.
  • active compounds can be mixed with water or one or more other solvents, solubilizing agents, emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, custard sesame oil), glycerol, or fatty acid esters of sorbitan or mixtures thereof.
  • Oral compositions can also include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.
  • Injectable preparations for example, sterile injections or aqueous solutions may be formulated by methods known by one of ordinary skill in the art using one or more suitable dispersing or wetting suspending agents.
  • Acceptable vehicles and solvents include, for example, water, Ringer's solutions, isotonic sodium chloride or mixtures thereof.
  • Formulation described herein may be formulated to provide quick, sustained, or delayed release of active ingredients after administration to patients in need thereof by employing procedures well known to one of ordinary skill in the art.
  • Example 1 Preparation of compounds of Formula V An aldehyde, triphenyl phosphine and a heterocycle (in a ratio of 1.0: 1.4: 1.2 respectively) were added to a dry two-necked round bottom flask containing dry tetrahydrofuran and fitted with a septum and nitrogen balloon. The solution was cooled to -5 0 C to 0 0 C and diisopropylazodicarboxylate was added (1.3 equiv. with respect to aldehyde) dropwise with stirring. After complete addition, the resultant mixture was allowed to come to room temperature and stirred overnight. Volatiles were removed under reduced pressure and a residue was purified over a silica column using a mixture of ethyl acetate and hexane as a mobile phase, yielding a compound of Formula V.
  • a compound of Formula V and the hydrochloride salt of a compound of Formula RCH(NH 2 )COOEt were placed under vacuum for about 20 minutes, then dissolved in dry dichloromethane followed by the addition of dry triethylamine (2.5 equiv.). After stirring the resultant mixture for about 1-2 hours at room temperature, sodium triacetoxyborohydride (3.0 equiv.) was added and mixture was stirred was overnight at room temperature under inert atmosphere. The mixture was then poured into water and the organic layer was extracted with dichloromethane. The organic (dichloromethane) layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure.
  • a compound of Formula R 1 C 1 -Cl (either neat or in dry dichloromethane) and triethylamine in dichloromethane was added dropwise to a cold stirred solution (at 0 0 C to -5 0 C) of a compound of Formula VI and the resulting mixture was stirred overnight while being allowed to come to room temperature.
  • Dichloromethane was removed by rotary evaporation and the residue was purified over silica gel column using ethyl acetate :hexane as mobile phase to yield the desired carbamate ester.
  • a compound of Formula VII and lithium hydroxide (1 :2.1) in a mixture of tetrahydrofuran, methanol & water (3:1 :1 v/v) were stirred overnight at room temperature. After removing volatiles under reduced pressure the residue was dissolved in water. ⁇ on- polar impurities were washed with hexane successively, followed by the acidification of the aqueous layer to p ⁇ 4.0-5.0 using IN hydrochloric acid, and the product was extracted with ethyl acetate. The ethyl acetate layer was concentrated and the residue was washed with hexane to yield an acid of Formula VIII.
  • the acid of Formula VIII is chromatographically homogenous and spectroscopically pure.
  • HEK-293 cells purchased from ATCC (USA) cell bank, maintained in Minimum essential medium (Eagle) withlO % charcoal dextran treated serum, were inoculated in 6- well plates (Ix 10 6 cells/well) and cultured approximately 18 hours in Minimum essential medium (Eagle) with 2 mM L- glutamine and Earle's BSS adjusted to contain 1.5 g/L sodium bicarbonate, and 1.0 mM sodium pyruvate in 5% CO 2 at 37 0 C.
  • Cells were transfected with each PPAR expression plasmid, pCMV Script- (PPAR ⁇ l/PPAR ⁇ /PPAR ⁇ ) full length (2 ⁇ g in 2 mL/well), pTAL-PPRE-Luc (4 ⁇ g), pAdvantage and pRL-CMV by Lipofection using Lipofectamine-2000 (Invitrogen, Carlsbad, USA) in abovementioned media but without antibiotics. Transfection mixture was replaced by fresh media (without antibiotics) after 5 hours duration.
  • the cells were harvested and seeded into 96-well plate (LumiNuncTM Plates, NUNC, Roskilde, Denmark) at a density of 3 x 10 4 cells/well in 100 ⁇ L of medium with Phenol-red free MEM with 10 % charcoal dextran-treated serum and other components. After the cells adhered, 100 ⁇ L of Phenol-red free MEM with 10 % charcoal dextran treated serum containing compound/standards were added. No drug controls cells were added with DMSO concentration of 0.3 % as final.
  • the firefly luciferase activity was divided by the sea pansy luciferase activity to adjust for the transfection efficiency, and the value was defined as the normalized luciferase activity.
  • Fold activation is calculated as the ratio of PPAR-mediated transcriptional activity in the cells treated with each drug to that in DMSO-treated control cells.
  • Compound EC 50 was calculated with GraphPad Prism 4.0 software. % Maximum standard was calculated as the ratio of maximum firefly (standard) reading and firefly test reading multiplied by 100. Rosiglitazone (BRL-49653) and Ragaglitazar (DRF-2725) were used as standards for PPAR ⁇ l and PP ARa, respectively.
  • the compounds described herein exhibited EC 50 values at PPAR ⁇ from about 0.15 nM to about 30 nM, from about 0.15 nM to about 15.5 M, and even from about 0.15 nM to about 4.75 nM.
  • the compounds described herein exhibited EC 50 at PPAR n from about 0.5 nM to about 30 nM, from about 0.5 nM to about 15.5 nM, and even from about 0.15 nM to about 4.2 nM.

Abstract

The present invention relates to substituted aromatic compounds, which have PPAR modulating activity, and hence can be used as anti-diabetic agents. Compounds described herein can be used as peroxisome proliferation activated receptor (PPAR) modulators. Such compounds can also be used as therapeutic agents for treating diseases and conditions mediated through any of the isoforms of PPAR, diabetes and diabetes-associated complications, diseases or conditions in which insulin resistance is the central pathophysiological mechanism and diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, nephrosclerosis, polycystic ovarian syndrome, eating disorders, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, psoriasis or obesity. Processes for the preparation of the described compounds, pharmaceutical compositions containing such compounds, and methods for treating diabetes mellitus and diseases and conditions mediated through insulin resistance are also provided.

Description

SUBSTITUTED AROMATIC COMPOUNDS AS ANTIDIABETIC AGENTS
Field of the Invention The present invention relates to substituted aromatic compounds, which have
PPAR modulating activity, and hence can be used as anti-diabetic agents.
Compounds described herein can be used as peroxisome proliferation activated receptor (PPAR) modulators. Such compounds can also be used as therapeutic agents for treating diseases and conditions mediated through any of the isoforms of PPAR, diabetes and diabetes-associated complications, diseases or conditions in which insulin resistance is the central pathophysiological mechanism and diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, nephrosclerosis, polycystic ovarian syndrome, eating disorders, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, psoriasis or obesity.
Processes for the preparation of the described compounds, pharmaceutical compositions containing such compounds, and methods for treating diabetes mellitus and diseases and conditions mediated through insulin resistance are also provided.
Background of the Invention
Type II insulin-resistant diabetes mellitus (also known as non insulin-dependent diabetes mellitus) afflicts an estimated 6 % of the adult population in western society and is expected to grow at a rate of 6 % per annum worldwide. Type II diabetes is a complex metabolic disorder and is characterized by hyperglycemia, which results from impaired insulin secretion from the pancreas and insulin resistance mainly in muscle and liver. Insulin-resistant individuals also exhibit a variety of closely related clinical indications, which include obesity, hypertension, dyslipidaemia, and premature atherosclerosis. 80 % of diabetic mortality arises from atherosclerotic cardiovascular disease (ASCVD). Uncontrolled hyperglycemia can further lead to late-stage complications, such as nephropathy, neuropathy and retinopathy.
Non-pharmacological approaches to lower high blood sugar include a strict control of diet followed by vigorous exercise. Presently, several pharmacological agents are also available as hypoglycemic agents including insulin secretogogues e.g., sulphonyl ureas (for example, glimeperide) and non sulphonyl ureas (for example, repaglinide), which increase insulin secretion from pancreatic cells; biguanides (metformin), which lower hepatic glucose production; and α-glucosidase inhibitors (acarbose), which delay intestinal absorption of carbohydrates.
PPAR (Peroxisome-Proliferator- Activated Receptor) are ligand-activated transcription factors (members of nuclear receptor family), which offer promising therapeutic approaches to Type II diabetes mellitus. PPAR exists in three subtype forms: α, γ and δ (or β). PPAR γ is abundantly expressed in adipose tissues. Direct activation of PPAR γ leads to induction of adipocyte genes, such as for fatty acid transporter 1, which in turn contributes to lowering of triglycerides and free fatty acid (FFA) levels. As FFA is a potential mediator of insulin resistance, lowering of FFA levels contributes to efficacy of PPAR γ activation in increasing insulin sensitivity and consequently glucose uptake in skeletal muscle cell. Glitazones (for example, rosiglitazone and pioglitazone) belong to this class of drug and are now proven insulin sensitizers (Moller, D.E.; Nature, (2001), 414, 6865, 821-827).
PCT Publication No. WO 01/21602 and U.S. Patent No. 6,414,002 disclose oxa and thiazole derivatives, which have been described to be useful as antidiabetic and antiobesity agents. PCT Publication No. WO 02/040481 discloses adenine-based inhibitors of adenylyl cyclase, pharmaceutical compositions and a method of use thereof. PCT Publication No. WO 04/004655 discloses substituted heterocyclic derivatives that have been said to be useful as antidiabetic and antiobesity agents. PCT Publication No. WO 03/082841 discloses 5-substituted 1 , 1 -dioxo- 1 ,2,5 thiazolidine-3-one derivatives that have been said to be useful as PTPASE inhibitors.
However, there remains a need for novel compounds having PPAR modulating activity that can be used as anti-diabetic agents.
Summary of the Invention
The present invention relates to substituted aromatic compounds, which have PPAR modulating activity, and accordingly can be used as anti-diabetic agents. The present invention also relates to processes for synthesizing such compounds.
Pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, racemates, stereoisomers, tautomeric forms, N-oxides or metabolites of the compounds provided herein having the same type of activity are also provided. Also provided are pharmaceutical compositions containing one or more compound(s) provided herein, optionally together with one or more pharmaceutically acceptable carriers or diluents. Such pharmaceutical compositions can be used for treating diseases and conditions mediated through any of the isoforms (α, γ or δ) of PPAR, diabetes mellitus or diseases or conditions mediated through insulin resistance.
In particular, provided herein are compounds having the structure of Formula I,
Figure imgf000004_0001
Formula I pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, wherein Het can be selected from:
Figure imgf000004_0002
wherein:
X1-X11 can each independently be CH, C, CH2, N, NH, O, S, S(=O) or S(O)2;
X12 and X13 can each independently be CR' or N, wherein R' can be hydrogen or alkyl; X14 can be (CH2)X (wherein x =0-2), NR', O, S, S(=O) or S(=O)2, wherein R can be the same as defined above; X]5 can be CH or N; X16 and V can each independently be O, NR', or S, wherein R' can be the same as defined earlier;
D and E can be substituted or unsubstituted alkyl, aryl or a bond; R1-Rs and R1O-Rn can each independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino; A can be N(CH3), O, C(O), NH, S or a bond;
R6-R9 can each independently be hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkoxy, halogen, optionally substituted amino; =" can be an optional double bond; R18 can be hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, COOR2O, C(= V)R21 (wherein V can be as defined earlier), OR2O, SR20 or N(R22)2 {wherein R20 can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; R21 can be R20, N(R2o)2 (wherein R20 can be the same as defined above); and R22 can be R20, COOR20, C(=V)R21, or S(O)qR23 (wherein V, R20 and R21 can be the same as defined above and R23 can be R20 except hydrogen and q can be an integer l or 2)}; R]9 can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, COOR20, C(=V)R21, C(=V)(NR20)2, SO2R23, C(=V)NR'SO2-R23, C(=V)NR"R" {wherein V, R20, R21, R and R23 can be the same as defined earlier; R" and R" together with nitrogen to which they are attached can form a ring which contain additional one or more heteroatom(s) selected from O, S or N and the ring so formed can be further substituted with SO2R23 (wherein R23 can be the same as defined earlier), alkyl, aryl, heteroaryl} ; X can be CH, N or N(-O); Z can be O, S, NH, N-Me or a bond;
Y can be COOR28 (wherein R28 can be hydrogen or substituted or unsubstituted alkyl) or
CONR1R22 (wherein R and R22 can be the same as defined above); and A1, A2 or A3 can be substituted or unsubstituted C1-4 alkylene. The compounds can include one or more of the following embodiments. For example, the compound can be:
Figure imgf000006_0001
Formula π Q_ Formula in pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, wherein: Het, A1-A3, Z, Y, R18 and R^ can be the same as defined above.
In another aspect, provided herein are compounds selected from:
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methoxyphenoxy)carbonyl] glycinate;
Ethyl N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(2- methoxyphenoxy) carbonyl] glycinate;
Ethyl N- {4-[2-(4-ethylphenyl)ethoxy]benzyl} -N-[(4-fluorophenoxy) carbonyljglycinate;
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N- {[3-(trifluoromethyl)phenoxy] carbonyl} glycinate;
Ethyl N-[(4-chlorophenoxy)methyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycinate;
Ethyl N-(4-{2-[l,3-benzoxazol-2-yl (methyl) amino]ethoxy}benzyl)-N-[(4- methoxyphenoxy) carbonyljglycinate; Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-methoxy- phenoxy) carbonyljglycinate;
Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- [(benzyloxy)carbonyl]glycinate;
Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy) carbonyljglycinate;
Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- {[3- (trifluoromethyl) phenoxyjcarbonyl} glycinate;
Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methyl phenoxy) carbonyljglycinate; Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-benzoyl glycinate; Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(3-methoxybenzoyl) glycinate;
Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(4-methoxybenzoyl) glycinate;
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methoxyphenoxy) carbonyl] glycinate; Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(2-methoxyphenoxy)carbonyl] glycinate;
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4- fluorophenoxy)carbonyl]glycinate;
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N- {[3-(trifluoromethyl)phenoxy] carbonyl} glycinate;
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4- methylphenoxy)carbonyl]glycinate;
Ethyl N-[(benzyloxy)carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycinate;
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}-4-methoxybenzyl)-N-[(4- methoxyphenoxy) carbonyljglycinate;
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-[(4-methoxy phenoxy) carbonyljglycinate; Ethyl N-benzoyl-N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycinate;
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(2-fluorobenzoyl)glycinate;
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(4-fluorobenzoyl)glycinate;
Ethyl N-benzoyl-N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy} benzyl)glycinate;
Ethyl N-(2-fluorobenzoyl)-N-(4-{2-[methyl (pyridin-2-yl)amino]ethoxy} benzyl)glycinate;
Ethyl N-(4-fluorobenzoyl)-N-(4-{2-[methyl (pyridin-2-yl)amino]ethoxy} benzyl)glycinate;
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(phenoxycarbonyl) glycinate;
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methylphenoxy) carbonyl] glycinate;
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(3-methyl- phenoxy)carbonyl] glycinate; Ethyl N-[(benzyloxy)carbonyl]-N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycinate;
Ethyl N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl) glycinate;
Ethyl N-[(4-methylphenoxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy} benzyl) glycinate; Ethyl N-[(3-methylphenoxy) carbonyl]-N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy} benzyl) glycinate;
Ethyl N-[(benzyloxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl) glycinate;
Ethyl N- {4- [2-(3 -oxo-2,3 -dihydro-4H-l ,4-benzoxazin-4-yl)ethoxy]benzyl}-N-(phenoxy carbonyl)glycinate;
Ethyl N-[(2-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin- 4-yl) ethoxyjbenzyl} glycinate;
Ethyl N-[(4-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin- 4-yl) ethoxyjbenzyl} glycinate; Ethyl N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} -N-(phenoxycarbonyl) glycinate;
Ethyl N- [(2-methoxyphenoxy)carbonyl] -N- {4- [2-(2-methyl-4-oxoquinazolin-3 (4H)-yl) ethoxyjbenzyl} glycinate;
Ethyl N- [(4-methoxyphenoxy)carbonyl] -N- {4- [2-(2-methyl-4-oxoquinazolin-3 (4H)-yl) ethoxyjbenzyl} glycinate;
Ethyl N-[(2-chlorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl) ethoxyjbenzyl} glycinate;
Ethyl N-[(4-chlorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl) ethoxyjbenzyl} glycinate;
Ethyl N- [(3 -chlorophenoxy)carbonyl] -N- {4- [2-(2-methyl-4-oxoquinazolin-3(4H)-yl) ethoxyjbenzyl} glycinate;
Ethyl N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} -N-[(4- methylphenoxy) carbonyljglycinate; Ethyl N-[(4-fluorophenoxy) carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl) ethoxyjbenzyl} glycinate;
Ethyl N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} -N- {[3- (trifluoromethyl) phenoxyjcarbonyl} glycinate; Ethyl N-(isobutoxycarbonyl)-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycinate;
Ethyl N-[(benzyloxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycinate;
Ethyl N-[(3-methoxy- phenoxy)carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl) ethoxyjbenzyl} glycinate; Ethyl N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethoxy]benzyl}-N-{[3- (trifluoromethyl)phenoxy]carbonyl}glycinate;
Ethyl N-[(4-fluorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl) ethoxyjbenzyl} glycinate;
Ethyl N-[(2-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzoxazin-4- yl) ethoxyjbenzyl} glycinate;
Ethyl N-[(benzyloxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl) ethoxyjbenzyl} glycinate;
Ethyl N-[(3-methylphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl) ethoxyjbenzyl} glycinate; Ethyl N-(isobutoxycarbonyl)-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl)ethoxy]benzyl} glycinate;
Ethyl N-[(4-chlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl) ethoxyjbenzyl} glycinate;
Ethyl N-[(4-methylphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl) ethoxyjbenzyl} glycinate;
Ethyl N-[(3-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzoxazin-4- yl)ethoxy]benzyl} glycinate;
Ethyl N-[(2,5-dichlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4- benzoxazin-4-yl) ethoxyjbenzyl} glycinate; Ethyl N-[(4-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4- benzothiazin-4-yl)ethoxy]benzyl}glycinate;
Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(2-fluorobenzoyl) glycinate;
Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy} benzyl)-N-[(4-methoxy phenoxy) carbonyljglycinate;
Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- chlorophenoxy)carbonyl]glycinate; Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3- chlorophenoxy)carbonyl]glycinate; Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- methylphenoxy) carbonyljglycinate;
Ethyl N-[(4-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzothiazin-4- yl) ethoxy]benzyl}glycinate;
Ethyl N-[(2-chlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin- 4-yl) ethoxy]benzyl}glycinate;
Ethyl N- {4- [2-(3 -oxo-2,3 -dihydro-4H- 1 ,4-benzothiazin-4-yl)ethoxy]benzyl} -N-(phenoxy- carbonyl) glycinate;
Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2- chlorophenoxy) carbonyljglycinate; Ethyl N-[(2,5-dichlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4- benzothiazin-4-yl)ethoxy]benzyl}glycinate;
Ethyl N-(4-{2-[l,3-benzothiazol-2-yl (methyl)amino]ethoxy} benzyl)-N- (isobutoxycarbonyl) glycinate;
Ethyl N-(isobutoxycarbonyl)-N- {4- [2-(3 -oxo-2,3 -dihydro-4H- 1 ,4-benzothiazin-4- yl)ethoxy]benzyl} glycinate;
Ethyl N-[(4-methylphenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin- 4-yl)ethoxy]benzyl} glycinate;
Ethyl N-[(3-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzothiazin-4- yl)ethoxy]benzyl} glycinate; Ethyl N- [(3 -methylphenoxy)carbonyl] -N- {4- [2-(3 -oxo-2,3-dihydro-4H- 1 ,4-benzothiazin- 4-yl)ethoxy]benzyl} glycinate;
Ethyl N-[(2-methoxyphenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4- benzothiazin-4-yl)ethoxy]benzyl}glycinate;
Ethyl N-[(4-fluorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4- yl)ethoxy]benzyl} glycinate;
Ethyl N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4-yl)ethoxy]benzyl}-N-{[3- (trifluoromethyl)phenoxy]carbonyl}glycinate;
Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2-methoxy phenoxy)carbonyl]glycinate; Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-[(4- fluorophenoxy) carbonyljglycinate;
Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl (methyl)amino]ethoxy}benzyl)-N- {[3- (trifluoromethyl) phenoxy]carbonyl}glycinate;
Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl (methyl)amino]ethoxy}benzyl)-N-[(2,5-dichloro phenoxy)carbonyl]glycinate; Ethyl N-(3-{2-[l,3-benzothiazol-2-yl(methyl) amino]ethoxy}-4-methoxybenzyl)-N-[(4- methoxyphenoxy) carbonyl]-D-alaninate;
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-{[3-(trifluoromethyl) phenoxyjcarbonyl} glycinate;
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-[(4-methylphenoxy) carbonyljglycinate;
Ethyl N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-[(3-methylphenoxy) carbonyljglycinate;
Ethyl N-[(3-chlorophenoxy) carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxy benzyl} glycinate; Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}-4-methoxybenzyl)-N-[(4- methylphenoxy) carbonyljglycinate;
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methoxyphenoxy)carbonyl]-L- alaninate;
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methyl phenoxy)carbonyl]-L- alaninate;
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(phenoxy carbonyl)-L-alaninate;
Ethyl N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl)-L- alaninate;
Ethyl N-[(2-methoxyphenoxy) carbonyl]-N-(4-{2-[methyl (pyridin-2-yl)amino]ethoxy} benzyl)-L-alaninate;
N-[(4-methylphenoxy) carbonyl]-N-(4- {2-[methyl(pyridin-2-yl) amino]ethoxy}benzyl)-L- alanine; Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- methoxyphenoxy) carbonyljglycinate;
Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2- methoxyphenoxy) carbonyljglycinate; Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy) carbonyljglycinate;
Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(isobutoxycarbonyl) glycinate;
Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-chlorophenoxy) carbonyljglycinate; Ethyl N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl) glycinate;
Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(benzyloxy) carbonyljglycinate;
Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy} benzyl)-N-[(3-chlorophenoxy) carbonyljglycinate;
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl (methyl)amino]ethoxy}benzyl)-N-[(4- methoxyphenoxy) carbonyljglycinate;
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2- methoxyphenoxy) carbonyljglycinate; Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy) carbonyljglycinate;
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N- (isobutoxycarbonyl) glycinate;
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl (methyl)amino]ethoxy}benzyl)-N-[(4- chlorophenoxy) carbonyljglycinate;
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl) glycinate;
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(benzyloxy) carbonyljglycinate; Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3- chlorophenoxy) carbonyljglycinate;
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- methylphenoxy) carbonyljglycinate;
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N- {[3- (trifluoromethyl) phenoxyjcarbonyl} glycinate;
Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methylphenoxy) carbonyljglycinate; Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- {[3- (trifluoromethyl) phenoxyjcarbonyl} glycinate; Ethyl N- {3-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-(phenoxycarbonyl)glycinate;
Ethyl N-(3-{2-[l,3-benzoxazol-2-yl (methyl) amino]ethoxy}benzyl)-N-[(3- methylphenoxy) carbonyljglycinate; Ethyl N- [(4-methoxyphenoxy)carbonyl] -N- {3 - [2-(2-methyl-4-oxoquinazolin-3 (4H)- yl)ethoxy]benzyl} glycinate;
Ethyl N- {3-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} -N-[(4- methylphenoxy) carbonyljglycinate;
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(3- methylphenoxy)carbonyl]glycinate;
Ethyl N-[(3-chlorophenoxy)carbonyl]-N- {3-[2-(5-ethylpyridin-2- yl)ethoxy]benzyl} glycinate;
Ethyl N-[(2-chlorophenoxy)carbonyl]-N- {3-[2-(5-ethylpyridin-2- yl)ethoxy]benzyl} glycinate; Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(isobutoxycarbonyl)glycinate;
Ethyl N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy} benzyl)-N-{[3- (trifluoromethyl)phenoxy] carbonyl} glycinate;
Ethyl N-(2-fluorobenzoyl)-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)glycinate;
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(2-methoxybenzoyl)glycinate; N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methoxyphenoxy)carbonyl]glycine; N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(2-methoxyphenoxy)carbonyl]glycine;
N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-fluorophenoxy)carbonyl]glycine;
N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-{[3-(trifluoromethyl)phenoxy]carbonyl] glycine;
N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methoxyphenoxy) carbonyljglycine;
N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-methoxyphenoxy) carbonyljglycine; N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(benzyloxy)carbonyl] glycine;
N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy) carbonyljglycine;
N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-{[3-(trifluoromethyl) phenoxyjcarbonyl} glycine;
N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methylphenoxy) carbonyljglycine;
N-(4- {2-[ 1 ,3-benzoxazol-2-yl (methyl)amino]ethoxy}benzyl)-N-(4-methoxybenzoyl) glycine; N-(4- {2-[ 1 ,3-benzoxazol-2-yl (methyl)amino]ethoxy}benzyl)-N-(3-methoxybenzoyl) glycine;
N-(4- {2-[ 1 ,3-benzoxazol-2-yl (methyl)amino]ethoxy}benzyl)-N-(4-methoxybenzoyl) glycine; N- {3-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-[(4-methoxyphenoxy)carbonyl]glycine;
N- {3-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-[(2-methoxyphenoxy)carbonyl]glycine;
N- {3-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-[(4-fluorophenoxy)carbonyl]glycine;
N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-{[3-(trifluoromethyl)phenoxy]carbonyl} glycine;
N- {3-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-[(4-methylphenoxy)carbonyl]glycine;
N-[(benzyloxy)carbonyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}glycine;
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy} -4-methoxybenzyl)-N-[(4- methoxyphenoxy) carbonyljglycine;
N- {3 - [2-(5-ethylpyridin-2-yl)ethoxy] -4-methoxybenzyl} -N- [(4- methoxyphenoxy)carbonyl]glycine;
N-benzoyl-N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}glycine;
N- {4-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-(2-fluorobenzoyl)glycine;
N- {4-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-(4-fluorobenzoyl)glycine; N-benzoyl-N-(4- {2- [methyl(pyridin-2-yl)amino]ethoxy} benzyl) glycine;
N-(2-fluorobenzoyl)-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)glycine;
N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-(2-methoxy benzoyl)glycine; N- {4-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-(phenoxycarbonyl)glycine; N- {4-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-[(4-methyl phenoxy)carbonyl]glycine; N- {4-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N- [(3 -methyl phenoxy)carbonyl]glycine; N-[(benzyloxy)carbonyl]-N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}glycine;
N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy} benzyl)-N-(phenoxycarbonyl) glycine;
N-[(4-methylphenoxy)carbonyl]-N-(4- {2-[methyl (pyridin-2-yl)amino]ethoxy} benzyl) glycine;
N-[(3-methylphenoxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl) glycine;
N-[(benzyloxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)glycine;
N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethoxy]benzyl}-N- (phenoxycarbonyl)glycine;
N- [(2-methoxyphenoxy) carbonyl] -N- {4- [2-(3 -oxo-2,3 -dihydro-4H- 1 ,4-benzoxazin-4- yl)ethoxy]benzyl} glycine; N- [(4-methoxyphenoxy) carbonyl] -N- {4- [2-(3 -oxo-2,3 -dihydro-4H- 1 ,4-benzoxazin-4-yl) ethoxyjbenzyl} glycine;
N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl}-N-(phenoxycarbonyl) glycine;
N- [(2-methoxyphenoxy) carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycine;
N- [(4-methoxyphenoxy) carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycine;
N-[(2-chlorophenoxy) carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycine; N-[(4-chlorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycine;
N-[(3-chlorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl) ethoxy] benzyl} glycine;
N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl}-N-[(4-methylphenoxy) carbonyljglycine;
N-[(4-fluorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycine; N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} -N- {[3-(trifluoromethyl) phenoxyjcarbonyl} glycine; N-(isobutoxycarbonyl)-N-{4-[2-(2-methyl-4-oxoquinazolin-3 (4H)- yl)ethoxy]benzyl} glycine;
N-[(benzyloxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} glycine;
N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl}-N-[(3-methylphenoxy) carbonyljglycine;
N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethoxy]benzyl}-N-{[3-(trifluoro methyl)phenoxy]carbonyl} glycine;
N-[(3-fluorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4- yl)ethoxy]benzyl} glycine; N-[(2-chlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl)ethoxy]benzyl} glycine;
N-[(benzyloxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethoxy] benzyl} glycine;
N- [(3 -methylphenoxy)carbonyl] -N- {4- [2-(3 -oxo-2,3 -dihydro-4H- 1 ,4-benzoxazin-4-yl) ethoxyjbenzyl} glycine;
N-(isobutoxycarbonyl)-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl)ethoxy] benzyl} glycine;
N-[(4-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4- yl)ethoxy]benzyl} glycine; N- [(4-methylphenoxy)carbonyl] -N- {4- [2-(3 -oxo-2,3 -dihydro-4H- 1 ,4-benzoxazin-4- yl)ethoxy]benzyl} glycine;
N-[(3-chlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl)ethoxy]benzyl} glycine;
N-[(2,5-dichlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl) ethoxyjbenzyl} glycine;
N- [(4-methoxyphenoxy) carbonyl] -N- {4- [2-(3 -oxo-2,3 -dihydro-4H- 1 ,4-benzothiazin-4- yl)ethoxy]benzyl} glycine;
N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(2-fluorobenzoyl)glycine;
N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-[(4-methoxyphenoxy) carbonyljglycine; N-(4- {2-[ 1 ,3-benzothiazol-2-yl (methyl) amino]ethoxy}benzyl)-N-[(4-chlorohenoxy) carbonyljglycine; N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy} benzyl)-N-[(3-chlorohenoxy) carbonyljglycine;
N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-[(4-methylhenoxy) carbonyljglycine;
N-[(4-chlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-yl) ethoxyjbenzyl} glycine;
N-[(2-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4-yl) ethoxyjbenzyl} glycine;
N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-yl)ethoxy]benzyl} -N- (phenoxycarbonyl) glycine; N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2-chlorophenoxy) carbonyljglycine;
N-[(2,5-dichlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4- yl)ethoxy]benzyl} glycine;
N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-(isobutoxycarbonyl) glycine;
N-(isobutoxycarbonyl)-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-yl)ethoxy] benzyl} glycine;
N- [(4-methylphenoxy)carbonyl] -N- {4- [2-(3 -oxo-2,3 -dihydro-4H- 1 ,4-benzothiazin-4-yl) ethoxyjbenzyl} glycine; N-[(3-chlorophenoxy) carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4-yl) ethoxyjbenzyl} glycine;
N-[(3-methylphenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-yl) ethoxyjbenzyl} glycine;
N-[(2-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-yl) ethoxyjbenzyl} glycine;
N-[(4-fluorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4-yl) ethoxyjbenzyl} glycine;
N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-yl)ethoxy]benzyl} -N- {[3- (trifluoromethyl)phenoxy]carbonyl}glycine; N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2-methoxyphenoxy) carbonyljglycine;
N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy} benzyl)-N-[(4-fluorophenoxy) carbonyljglycine;
N-(4-{2-[l,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-{[3-(trifluoromethyl) phenoxyjcarbonyl} glycine; N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-[(2,5-dichlorophenoxy) carbonyljglycine;
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl) aminojethoxy} -4-methoxybenzyl)-N-[(4- methoxyphenoxy) carbonyl]-L-alanine;
N-{3-[2-(5-ethylpyridin-2-yl) ethoxy]-4-methoxybenzyl}-N-{[3-(trifluoromethyl) phenoxyjcarbonyl} glycine;
N- {3-[2-(5-ethylpyridin-2-yl) ethoxy]-4-methoxybenzyl}-N-[(4-methylphenoxy) carbonyl] glycine;
N- {3-[2-(5-ethylpyridin-2-yl) ethoxy]-4-methoxybenzyl}-N-[(3-methylphenoxy) carbonyl] glycine;
N-[(3-chlorophenoxy) carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxy benzyl} glycine;
N-(3- {2-[ 1 ,3-benzothiazol-2-yl (methyl)amino]ethoxy} -4-methoxy benzyl)-N-[(4-methyl phenoxy)methyl]glycine; N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-[(4-methoxyphenoxy)carbonyl]-L-alanine; N- {4-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-[(4-methyl phenoxy)carbonyl]-L-alanine;
N- {4-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-(phenoxy carbonyl)-L-alanine;
N-(phenoxycarbonyl)-N-[4-(2-pyridin-2-ylethoxy)benzyl]-L-alanine;
N-[(2-methoxy- phenoxy)carbonyl]-N-(4- {2-[methyl (pyridin-2-yl)amino]ethoxy} benzyl)-L-alanine;
N- [(4-methylphenoxy)carbonyl] -N-(4- {2- [methyl(pyridin-2-yl) amino] ethoxy} benzyl)-L- alanine;
N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methoxy- phenoxy)carbonyl]glycine;
N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy} benzyl)-N-[(2-methoxyphenoxy) carbonyljglycine; N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy) carbonyljglycine;
N-(3- {2-[ 1 ,3-benzoxazol-2-yl (methyl)amino]ethoxy}benzyl)-N-(isobutoxycarbonyl) glycine;
N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-chlorophenoxy) carbonyljglycine; N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl) glycine;
N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(benzyloxy)carbonyl] glycine; N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-chlorophenoxy) carbonyljglycine;
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methoxyphenoxy) carbonyljglycine;
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy} benzyl)-N-[(2-methoxyphenoxy) carbonyljglycine;
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl) aminojethoxy} benzyl)-N-[(4-fluorophenoxy) carbonyljglycine;
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-(isobutoxycarbonyl) glycine; N-(3- {2-[ 1 ,3-benzothiazol-2-yl (methyl)amino]ethoxy}benzyl)-N-[(4-chlorophenoxy) carbonyljglycine;
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl) glycine;
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(benzyloxy)carbonyl] glycine;
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-chlorophenoxy) carbonyljglycine;
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methyl phenoxy) carbonyljglycine; N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-{[3-(trifluoromethyl) phenoxyjcarbonyl} glycine;
N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl) amino] ethoxy}benzyl)-N-[(4-methylphenoxy) carbonyljglycine; N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-{[3-(trifluoromethyl) phenoxyjcarbonyl} glycine;
N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(phenoxycarbonyl)glycine;
N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-methylphenoxy) carbonyljglycine;
N-[(4-methoxyphenoxy)carbonyl]-N-{3-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycine;
N- {3 - [2-(2-methyl-4-oxoquinazolin-3 (4H)-yl)ethoxy]benzyl} -N- [(4-methylphenoxy) carbonyljglycine; N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-[(3-methylphenoxy)carbonyl]glycine; N-[(3-chlorophenoxy)carbonyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}glycine;
N-[(2-chlorophenoxy)carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycine; N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(isobutoxycarbonyl)glycine;
N-[(4-chlorophenoxy)carbonyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}glycine;
N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-N-{[3-(trifluoromethyl)phenoxy] carbonyl} glycine;
N-[(4-fluorophenoxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl) glycine; Ν-[(4-methylphenoxy)carbonyl]-Ν-{4-[2-(l-oxido-3-oxo-2,3-dihydro-4Η-l,4- benzothiazin-4-yl)ethoxy]benzyl}glycine;
N-[(3-methylphenoxy)carbonyl]-N- {4-[2-(5-methyl-2-phenyl- 1 ,3-oxazol-4- yl)ethoxy]benzyl} glycine;
N-[(4-methylphenoxy)carbonyl]-N- {4-[2-(5-methyl-2-phenyl- 1 ,3-oxazol-4- yl)ethoxy]benzyl} glycine;
N-[(4-fluorophenoxy)carbonyl]-N-{4-[2-(5-methyl-2-phenyl-l,3-oxazol-4- yl)ethoxy]benzyl} glycine;
N-[(4-methoxyphenyl)sulfonyl]-N- {4-[2-(5-methyl-2-phenyl- 1 ,3-oxazol-4- yl)ethoxy]benzyl} glycine; N-[(2-methoxyphenoxy)carbonyl]-N-(4- {2-[methyl(pyridin-2- yl)amino] ethoxy } benzyl)glycine;
N- [(4-methoxyphenoxy)carbonyl] -N-(4-methoxy-3 - {2- [4- (trifluoromethoxy)phenoxy]ethoxy}benzyl)glycine; N- {3 - [2-(4-te?t-butylphenoxy)ethoxy] -4-methoxybenzyl} -N- [(4- methoxyphenoxy)carbonyl]glycine;
Ν-(4-methoxybenzoyl)-Ν- {4-[2-(5-methyl-2-phenyl- 1 ,3-oxazol-4- yl)ethoxy]benzyl} glycine; or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof.
In one aspect, provided herein are pharmaceutical compositions comprising therapeutically effective amounts of one or more compounds described herein together with one or more pharmaceutically acceptable carriers, excipients or diluents.
In another aspect, provided herein are methods of treating a mammal suffering from a disease or condition mediated through α, β or γ isoforms comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds (or one or more pharmaceutical compositions) described herein.
In yet another aspect, provided herein are methods of treating a mammal suffering from diabetes or associated diabetes complications comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds (or one or more pharmaceutical compositions) described herein. In another aspect, provided herein are methods of treating a mammal suffering from a disease or condition selected from Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis, polycystic ovarian syndrome, psoriasis, obesity, eating disorders, for improving cognitive functions in dementia or as aldose reductase inhibitors comprising administering to a mammal in need thereof therapeutically effective amounts of one or more compounds (or one or more pharmaceutical compositions) described herein.
In another aspect, provided herein are methods for preparing compounds of Formula VII,
Figure imgf000021_0001
(Formula I wherein X=CH, A2=CH2, A3=CHR, Y=COOH) pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof comprising the steps of:
(a) reacting a compound of Formula IV
Figure imgf000022_0001
Formula IV with a compound of Formula Het-A]-OH or HeI-A1-L1 (wherein L1 can be a leaving group selected from Cl, Br, I, acetate, 4-methylbenzenesulfonate, 4- bromobenzenesulfonate, 4-nitrobenzenesulfonate, methanesulfonate, or trifluoromethanesulfonate) to form a compound of Formula V,
Figure imgf000022_0002
(b) treating the compound of Formula V with a compound of Formula H2NCH
R1COOR28 HCl to form a compound of Formula VI, and
Figure imgf000022_0003
(c) treating the compound of Formula VI with a compound of Formula R1C1-Cl or R1P-N=C=W to form a compound of Formula VII, wherein
Het is selected from:
Figure imgf000023_0001
wherein:
X1-X11 are each independently CH, C, CH2, N, NH, O, S, S(=O) or S(=O)2; X12 and X13 are each independently CR' or N, wherein R' is hydrogen or alkyl; X14 is (CH2)χ (wherein x =0-2), NR', O, S, S(=O) or S(=O)2, wherein R' is the same as defined above; X15 is CH or N; X16 and V are each independently O, NR', or S, wherein R' is the same as defined earlier; D and E are substituted or unsubstituted alkyl, aryl or a bond;
R1-R5 and R1O-Rn are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino; A is N(CH3), O, C(O), NH, S or a bond;
R6-R9 are each independently hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkoxy, halogen, optionally substituted amino; ^= is an optional double bond; is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, COOR2O, C(=V)R21 (wherein V is as defined earlier), OR2O, SR2O or N(R22)2 {wherein R20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; R21 is R2o, N(R2o)2 (wherein R20 is the same as defined above); and R22 is R20, COOR2O, C(= V)R21, or S(O)qR23 (wherein V, R2o and R21 are the same as defined above and R23 is R2o except hydrogen and q is an integer 1 or 2)} ;
R]9 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, COOR20, C(=V)R21, C(=V)(NR20)2, SO2R23, C(=V)N RSO2- R23, C(=V)NR"R'" {wherein V, R20, R2i, R and R23 are the same as defined earlier; R" and R" together with nitrogen to which they are attached form a ring which contain additional one or more heteroatom(s) selected from O, S or N and the ring so formed is further substituted with SO2R23 (wherein R23 is the same as defined earlier), alkyl, aryl, heteroaryl};
R28 is substituted or unsubstituted alkyl or aryl; Z is O, S, NH, N-Me or a bond; and
A1 is substituted or unsubstituted C1-4 alkylene.
In yet another aspect, provided herein are methods for preparing compounds of Formula VIII,
Figure imgf000024_0001
(Formula I wherein X = CH, A2 = CH2, A3 = CHR', Y = COOH) pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, comprising: hydrolyzing a compound of Formula VII
Figure imgf000024_0002
to form a compound of Formula VIII, wherein Het is selected from:
Figure imgf000025_0001
wherein:
X1-X11 are each independently CH, C, CH2, N, NH, O, S, S(=O) or S(=O)2; X12 and X13 are each independently CR' or N, wherein R' is hydrogen or alkyl; X14 is (CH2)χ (wherein x =0-2), NR', O, S, S(=O) or S(=O)2, wherein R' is the same as defined above; X15 is CH or N; X16 and V are each independently O, NR', or S, wherein R' is the same as defined earlier; D and E are substituted or unsubstituted alkyl, aryl or a bond;
R1-R5 and R1O-Rn are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino; A is N(CH3), O, C(O), NH, S or a bond;
R6-R9 are each independently hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkoxy, halogen, optionally substituted amino; ^= is an optional double bond; is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, COOR2O, C(=V)R21 (wherein V is as defined earlier), OR2O, SR2O or N(R22)2 {wherein R20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; R21 is R2o, N(R2o)2 (wherein R20 is the same as defined above); and R22 is R20, COOR2O,
C(= V)R21, or S(O)qR23 (wherein V, R2o and R21 are the same as defined above and R23 is R2o except hydrogen and q is an integer 1 or 2)} ;
R]9 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, COOR20, C(=V)R21, C(=V)(NR20)2, SO2R23, C(=V)NR'SO2- R23, C(=V)NR"R'" {wherein V, R20, R2I, R and R23 are the same as defined earlier; R" and R" together with nitrogen to which they are attached form a ring which contain additional one or more heteroatom(s) selected from O, S or N and the ring so formed is further substituted with SO2R23 (wherein R23 is the same as defined earlier), alkyl, aryl, heteroaryl};
R28 is substituted or unsubstituted alkyl or aryl;
Z is O, S, NH, N-Me or a bond; and
A1 is substituted or unsubstituted C1-4 alkylene.
Detailed Description of the Invention
In accordance with one aspect, there are provided compounds having the structure of Formula I,
Figure imgf000026_0001
Formula I pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof, wherein Het can be selected from:
Figure imgf000027_0001
wherein:
X1-X11 each can independently be CH, C, CH2, N, NH, O, S, S(=O) or S(O)2;
X12 and X13 each can independently be CR' or N, wherein R' can be hydrogen or alkyl;
X14 can be (CH2)X (wherein x = 0-2), NR', O, S, S(=O), or S(=O)2, wherein R' can be the same as defined above;
X]5 can be CH or N; X16 and V each can independently be O, NR' or S;
D and E each can independently be substituted or unsubstituted alkyl, aryl or a bond;
R1-R5 and R1O-Rn each can independently be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino; A can be N(CH3), O, C(O), NH, S, or a bond;
R6-R9 each can independently be hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkoxy, halogen, optionally substituted amino; can be an optional double bond, i.e., a single bond or a double bond; 18 can be hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, COOR2O, C(= V)R21 (wherein V is as defined earlier), OR20, SR20 or N(R22)2 {wherein R2o can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; R21 can be R20, N(R2o)2 (wherein R20 is the same as defined above); R22 can be R20, COOR2O, C(= V)R21, S(O)qR23, (wherein V, R20 and R21 are the same as defined above and R23 can be R20 except hydrogen and q can be an integer 1 or 2)} ; R]9 can be hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, COOR20, C(=V)R21, C(=V)(NR20)2, SO2R23, C(=V)NR'SO2-R23, C(=V)NR"R" {wherein V, R20, R21, R and R23 are the same as defined earlier; R" and R", together with nitrogen to which they are attached, can form a ring which may contain one or more heteroatoms, e.g., O, S or N, and the ring so formed may be further substituted with SO2R23 (wherein R23 is the same as defined earlier), alkyl, aryl, heteroaryl} ; X can be CH, N or N(-O); Z can be O, S, NH, N-Me or a bond; Y can be COOR28 or CONR1R22 (wherein R and R22 are the same as defined above); A1, A2 or A3 can be substituted or unsubstituted C1-4 alkylene.
Also provided are compounds having a structure of Formula II or Formula III,
Figure imgf000028_0001
Formula II Formula III pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides and metabolites thereof wherein Het, A1-A3, Z, Y, R18 and R^ are the same as defined for Formula I above.
In accordance with a second aspect, also provided are methods for treating patients (e.g., mammals) suffering from diabetes or diabetes-associated complications comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein.
In accordance with a third aspect, provided herein are methods for treating patients (e.g., mammals) suffering from diseases or conditions in which insulin resistance is the central pathophysiological mechanism, comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein. In accordance with a fourth aspect, also provided are methods of treating patients (e.g., mammals) suffering from diseases or conditions such as Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis, polycystic ovarian syndrome, and eating disorders, as aldose reductase inhibitors and for improving cognitive functions in dementia, psoriasis or obesity, comprising administering to a patient in need thereof a therapeutically effective amount of one or more compounds described herein.
In accordance with fifth aspect, there are provided processes for preparing compounds described herein.
The compounds described herein can also be used in combination with another type(s) of anti-diabetic agent(s) and/or hypolipidemic agent(s) and/or anti-hypertensive agent(s) and/or platelet aggregation inhibitor(s) and/or anti-osteoporosis agent(s) for the treatment of patients (e.g., mammals) suffering from diseases and conditions described herein. Other agents, for example, PPAR agonists (e.g., biguanides, protein tyrosine phosphate- IB inhibitors, dipeptidyl peptidase inhibitors), insulin or insulin mimetics, sulphonylureas, α-glucosidase inhibitors, cholesterol lowering agents (HMG-CoA reductase inhibitors, sequesterants, nicotinyl alcohol, nicotinic acid or salt thereof, PPAR α agonists, PPAR α/γ agonists, inhibitors of cholesterol absorption, Acyl CoA: cholesterol acyl tranferase inhibitors, antioxidants), PPAR δ agonists, antiobesity compounds, an ideal bile acid transporter inhibitor, agents intended to be used in inflammatory for the treatment of mammal suffering from diseases and conditions described herein. The following definitions apply to terms as used herein. The term "alkyl," unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. Alkyl groups can be optionally interrupted by atom(s) or group(s) independently selected from oxygen, sulfur, a phenylene, sulphinyl, sulphonyl group or -NR8-, wherein R3 can be hydrogen, alkyl, alkenyl, alkynyl cycloalkyl or aryl. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may be substituted further (referred herein as "substituted alkyl") with one or more substituents selected from alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, aryl (for R6-R9, alkyl is not substituted with aryl), heterocyclyl, heteroaryl, arylthio, thiol, alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino, - NHC(=O)Rk, -NRpRq, -C(=O)NRpRq, -NHC(=O)NRpRq, -C(=O)heteroaryl, C(=O)heterocyclyl, -O-C(=O)NRpRq, {wherein Rp and Rqare independently selected from alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl}, nitro, hydroxyamino, alkoxyamino or S(O)mR66 (wherein m is an integer from 0-2 and R66 is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, alkyl substituents may be further substituted by 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy, -NRpRq, -C(=O)NRpRq, -
OC(=O) NRpRq , -NHC(=O)NRφRq (wherein Rp and Rq are the same as defined earlier), hydroxy, alkoxy, halogen, CF3, cyano, and S(O)mR66 (wherein m is an integer from 0-2 and R66 are the same as defined earlier); or an alkyl group also may be interrupted by 1-5 atoms of groups independently selected from oxygen, sulfur or -NR8- {wherein R3 is selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl,-C(=O)ORp (wherein Rp is the same as defined earlier), S(O)mR66 (wherein m is an integer from 0-2 and R66 is as defined earlier), or -C(=O)NRpRq (wherein Rp and R, are as defined earlier)} . Unless otherwise constrained by the definition, all substituents may be substituted further by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, -NRpRq, -C (=O)NRpRq, -O-C(=O)NRpRq (wherein Rp and R, are the same as defined earlier) hydroxy, alkoxy, halogen, CF3, cyano, and S(O)mR66 (wherein m is an integer from 0-2 and R66 is same as defined earlier); or an alkyl group as defined above that has both substituents as defined above and is also interrupted by 1-5 atoms or groups as defined above. The term "alkylene" refers to the divalent radical of the above defined alkyl. It may optionally be substituted with the substituents as defined for alkyl.
The term "alkenyl," unless otherwise specified, refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group having from 2 to 20 carbon atoms with cis, trans, or geminal geometry. It can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and - NRa-, wherein R3 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl. In the event that alkenyl is attached to a heteroatom, the double bond cannot be alpha to the heteroatom. Alkenyl groups may be substituted further (referred to herein as "substituted alkenyl") with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, -NHC(=O)RP, -NRpRq, -C(=O)NRpRq, -NHC(=O)NRpRq, -O-C(=O)NRpRq (wherein Rp and R, are the same as defined earlier), alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, carboxyalkyl, thiocarbonyl, carboxy, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl, heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylamino, alkoxyamino, hydroxyamino, alkoxyamino, nitro, or SO2R66 (wherein R66 are is same as defined earlier). Unless otherwise constrained by the definition, alkenyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, -CF3, cyano, -NRpR,, -C(O)NRpR,, -O-C(=O)NRpRq (wherein R5 and R, are the same as defined earlier) and -SO2R66 (wherein R66 is same as defined earlier). Groups such as ethenyl or vinyl (CH=CH2), 1 -propylene or allyl (-CH2CH=CH2), iso-propylen (- C(CH3)=CH2), bicyclo[2.2.1]heptene, and the like, exemplify this term.
The term "alkynyl," unless otherwise specified, refers to a monoradical of an unsaturated hydrocarbon, having from 2 to 20 carbon atoms. It can be optionally interrupted by atom(s) or group(s) independently chosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl and -NR8-, wherein R3 can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl. In the event that alkynyl is attached to a heteroatom, the triple bond cannot be alpha to the heteroatom. Alkynyl groups may be substituted further (referred to herein as "substituted alkynyl") with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, hydroxyamino, alkoxyamino, nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, -NHC(O)Rp, -NRpR,, -NHC(=O)NRpRq , - C(O)NRpRq, -0-C(O)NRpRq (wherein Rp and Rq are the same as defined earlier), S(O)1nR66 (wherein m is an integer from 0-2 and R66 is as defined earlier). Unless otherwise constrained by the definition, alkynyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, hydroxy, alkoxy, halogen, CF3, -NRpRq, -C(O)NRpR,, -NHC(O)NRpRq, -C(O)NRpR, (wherein Rp and Rq are the same as defined earlier), cyano, or S(O)D1R66 (wherein m is an integer from 0-2 and R66 is same as defined earlier). Groups such as ethynyl, (-C≡ CH), propargyl (or propynyl, -CH2C= CH), and the like exemplify this term.
The term "cycloalkyl" refers to saturated or unsaturated cyclic alkyl of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Groups such cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, cyclopropylene, cyclobutylene, and the like exemplify single ring structures. Groups such as adamantanyl, bicyclo [2.2.1]heptane, and the like exemplify fused ring structures. Cycloalkyl can also be fused with an aryl, for example indane, and the like. Spiro and fused ring structures can also be included. Cycloalkyl groups may be substituted further (referred to herein as "substituted cycloalkyl") with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy, carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy, aminosulfonyl, aminocarbonylamino, hydroxyamino, alkoxyamino, -NRpRq, -NHC(=O)NRpRq,
-NHC(=O)RP, -C(=O)NRpRq, -O-C(=O)NRpRq (wherein Rp and R, are the same as defined earlier), nitro, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, or S(O)mR66 (wherein m is an integer from 0-2 and R66 is same as defined earlier). Unless otherwise constrained by the definition, cycloalkyl substituents optionally may be substituted further by 1-3 substituents selected from alkyl, carboxy, hydroxy, alkoxy, halogen, CF3, -NRpRq, -C(=O)NRpRq, -NHC(=O)NRpRq, -O-C(=O)NRpRq (wherein R1, and R, are the same as defined earlier), cyano or S(O)1nR66 (wherein m is an integer from 0-2 and R66 is same as defined earlier).
The term "alkoxy" denotes the group O-alkyl, wherein alkyl is the same as defined above.
The term "halogen" refers to fluorine, chlorine, bromine or iodine. The term "optionally substituted amino" herein refers to NRgRh, wherein Rg and Rh can be hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, -S(O)aRb or CORd (wherein a and Rd are the same as defined earlier). The term "aryl" herein refers to aromatic system having 2 to 14 carbon atoms, wherein the ring system can be mono-, bi- or tricyclic and are carbocyclic aromatic groups. For example, aryl groups include, but are not limited to, phenyl, biphenyl, anthryl or naphthyl ring and the like. Aryl groups can be optionally substituted with 1 to 3 substituents (referred to herein as "substituted aryl") selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryl, aryloxy, CF3, cyano, nitro, CORS, COOR3 (wherein Rs is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), NHC(=O)RP, -NRpRq, -C(=O)NRpRq, -NHC(=O)NRpRq, -O-C(=O)NRpRq> CSRP, -OCORP, -(CH2)O-3NRpRq (wherein Rp and R, are the same as defined earlier), S(O)1nR66 (wherein m is an integer from 0-2 and R66 is same as defined earlier), carboxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, haloalkyl, or amino carbonyl amino. The aryl group optionally may be fused with a cycloalkyl group, wherein the cycloalkyl group may optionally contain heteroatoms selected from O, N or S. Groups such as phenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.
The term "heteroaryl," unless otherwise specified, refers to an aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic or tricyclic aromatic group having from 8 to 14 ring atoms, with one or more heteroatom(s) independently selected from N, O or S. Heteroaryl groups can be optionally substituted with 1 to 4 substituent(s) (referred herein as "substituted heteroaryl") selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy, aryl, haloalkyl, alkoxy, aralkyl, cyano, nitro, CORS, COORS (wherein Rs is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), heterocyclyl, heteroaryl, -NRpRq, CH=NOH, -(CH2)wC(=O)Rt {wherein w is an integer from 0-4 and Rt is hydrogen, hydroxy, ORP, NRpRq, -NHOR2 or -NHOH}, -C(=O)NRpRq, -NHC(=O)NRpRq, S(O)1nR66^O- C(O)NRpRq, -O-C(=O)RP, -O-C(=O)ORp, CSRP, -OCORP, -(CH2)O-3NRpRq (wherein m, R66, Rp and Rq are as defined earlier, and R2 is alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, heteroarylalkyl or heterocyclylalkyl). Unless otherwise constrained by the definition, the substituents are attached to a ring atom, i.e., carbon or heteroatom in the ring. Examples of heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl, 1,2,3- triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl, benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl, indolyl, benzothiazolyl, or benzoxazolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl, quinazonyl, carbazolyl phenothiazinyl, phenoxazinyl and the like.
The term 'heterocyclyl," unless otherwise specified, refers to a non-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10 atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatoms selected from O, S or N, and optionally are benzofused or fused heteroaryl having 5-6 ring members and/or optionally are substituted, wherein the substituents are selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, aryl, alkoxy, alkaryl, haloalkyl, cyano, nitro, CORS, COORs (wherein R3 is hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl), oxo, carboxy, heterocyclyl, heteroaryl, -O-C(=O)RP, -O-C(=O)ORP> -C(=O)NRpRq, S(O)1nR66, -O-C(=O)NRpRq, -NHC(=O)NRpRq, -NRpRq, CSRP, -OCORP, -(CH2)O-3NRpRq (wherein m, R66, Rp and Rq are as defined earlier) or guanidine. Carbonyl or sulfonyl group can replace carbon atom(s) of heterocyclyl. Unless otherwise constrained by the definition, the substituents are attached to the ring atom, i.e., carbon or heteroatom in the ring. Also, unless otherwise constrained by the definition, the heterocyclyl ring optionally may contain one or more olefinic bond(s). Examples of heterocyclyl groups include oxazolidinyl, tetrahydrofuranyl, dihydrofuranyl, benzoxazinyl, benzthiazinyl, imidazolyl, benzimidazolyl, tetrazolyl, carbaxolyl, indolyl, phenoxazinyl, phenothiazinyl, dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl, thiazolidinyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione, piperidinyl, tetrahydropyranyl, piperazinyl and the like.
The term "pharmaceutically acceptable solvates" refers to solvates with water (i.e., hydrates, hemihydrate or sesquihydrate) or pharmaceutically acceptable solvents, for example solvates with common organic solvents as ethanol and the like. Such solvates are also encompassed within the scope of the disclosure.
The present invention also includes, within its scope, prodrugs of the compounds described herein. In general, such prodrugs can be functional derivatives of these compounds, which can be readily convertible in vivo to the required compound, and they may be carrier-linked or bioprecursors. Carrier-linked prodrugs may be bipartite, tripartite or mutual prodrugs. Prodrugs are intended to improve drug efficacy by improving solubility and consequently absorption and distribution as desired.
Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H Bundgaard and, Elsevier, 1985. The present invention provides prodrugs of Formula Ia,
Figure imgf000034_0001
Formula Ia wherein
Het, A1-A3, Z, X, R18 and R^ are the same as defined above; W is a group that can be easily removed under physiological conditions during or after administration to a patient (e.g., mammal) to form a compound having Formula I, or the carboxylate anion thereof, or a pharmaceutically acceptable salt, wherein W is selected from -OR25, -OCH2OR25, -OCH(CH3)OR25, -OCH2OC(O)R25, -OCH(CH3)OC(O)R25, -OCH2OC(O)OR25, -OCH(CH3)OC(O)OR25 and -N(R26)2 (wherein R25 can be independently selected from C1-6 alkyl optionally substituted with one or two groups selected from -CO2H, -CONH2, -NH2, -OH, -OAc, -NHAc or phenyl; and R26 is independently selected from H or R25).
The described compounds may get metabolized in vivo and these metabolites are also encompassed within the scope of this invention.
The term "polymorphs" includes all crystalline forms, as well as amorphous forms, of the compounds described herein and are encompassed within the scope of the present invention.
The phrase "pharmaceutically acceptable carriers" is intended to include non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
The term "pharmaceutically acceptable salts," as used herein, refers to salts prepared from pharmaceutically acceptable monovalent, divalent or trivalent non-toxic metals or organic bases. Examples of such monovalent, divalent or trivalent metals include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, zinc or aluminum and the like. Examples of such organic bases include, but are not limited to, amino acids, ammonia, mono-alkyl ammoniums, dialkyl ammoniums, trialkyl ammoniums or N-methyl glucamine and the like. If desired, free acid forms of compounds of the present invention may be prepared from salt forms, for example, by contacting the salt with dilute aqueous solution of an acid, such as hydrochloric acid. Base addition salts may differ from the free acid forms of the compounds described herein in physical characteristics, for example, solubility or melting point.
The salt forms differ from the compound described herein in certain physical properties such as solubility or melting point, but the salts are otherwise equivalent for purposes of this invention.
Compounds described herein include all stereoisomers thereof. The term "stereoisomer," as used herein, refers to compounds, which have identical chemical composition, but differ with regard to arrangement of the atoms and the groups in space. Stereoisomers include enantiomers, diastereomers, geometrical isomers, atropisomer or conformational isomers as defined by the IUPAC 1974 Recommendations for Section E. AU such stereoisomers are encompassed within the scope of this invention.
The phrase "modulate," as used herein, refers to the ability of a modulator for a member of the nuclear hormone receptor superfamily to either directly (e.g., by binding to the receptor as a ligand) or indirectly (e.g., as precursor for a ligand or an inducer which promotes production of ligand from a precursor) induce expression of gene(s) maintained under hormone expression control, or to repress expression of gene(s) maintained under such control.
The term "pharmaceutically acceptable," as used herein, refers to being approved by a regulatory agency of the federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
The compounds described herein may be prepared by techniques well known in the art and familiar to one of ordinary skill in the art. In addition, the compounds of the present invention may be prepared by the following reaction sequences as depicted in Scheme I.
Scheme I
Figure imgf000036_0001
Compounds of Formula VIII can be prepared according to Scheme I. Thus, compounds of Formula VIII can be formed by processes comprising the steps of: (a) reacting a compound of Formula IV with either a compound of Formula:
Figure imgf000037_0001
(ii) Het-Aϊ-L] (wherein L1 is a leaving group selected from Cl, Br, I, A- methylbenzenesulfonate, 4-bromo benzenesulfonate, A- nitrobenzenesulfonate, methanesulfonate, or trifluoromethanesulfonate and the like) to form a compound of Formula V;
(b) treating the compound of Formula V with a compound of Formula H2NCHR' -COOR28 HCl (wherein R28 can be substituted or unsubstituted alkyl or aryl) to form a compound of Formula VI (wherein R' is the same as defined earlier);
(c) reacting the compound of Formula VI with a compound of Formula R1C1-Cl or R1P-N=C=W (wherein W is O or S) to form a compound of Formula VII; and
(d) hydrolyzing the compound of Formula VII to form a compound of Formula VIII (wherein Het, A1, Z, R18, and Ri 9 are the same as defined for Formula I).
Reactions of compounds of Formula IV with compounds of Formula Het- Ai -OH to form a compound of Formula V can be carried out in one or more solvents, for example, tetrahydrofuran, dimethylformamide, dichloromethane, toluene, diethylether, dioxane, ethylacetate, acetonitrile, benzene or mixtures thereof. Reactions of compounds of Formula IV with compounds of Formula Het-Ai-Li to form compounds of Formula V can be carried out in one or more solvents, for example, acetone, diethyl ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetonitrile or mixtures thereof.
Reactions of compounds of Formula IV with compounds of Formula Het-Ai-Li to form compounds of Formula V can be carried out in the presence of one or more organic bases (e.g., triethylamine, diethylamine, tributylamine, diisopropylamine, 4-dimethylaminopyridine, 1 ,8-diazabicyclo[5,4,0]-undec-7-ene, l,4-diazabicyclo[2,2,2]octane, N-methylmorpholine, diisopropylethylamine, pyridine, sodium hydride or mixtures thereof); one or more inorganic bases (e.g., potassium carbonate, cesium carbonate or mixtures thereof) or mixtures thereof.
Reactions of compounds of Formula IV to form compounds of Formula V can be carried out in the presence of one or more redox couple agents, which can be one or more of those known to one of ordinary skill in the art. The oxidizing part of the redox couple can be selected from diisopropylazodicarboxylate (DIAD), diethylazo-dicarboxylate (DEAD), N,N,N',N'-tetramethylazodicarboxamide (TMAD), 1,1 '- (azodicarbonyl)dipiperidine (ADDP), cyanomethylenetributylphosphorane (CMBP), 4,7- dimethyl-3,5,7-hexahydro-l ,2,4,7-tetrazocin-3,8-dione (DHTD), N,N,N'N'-tetraisopropyl- azodicarboxamide (TIPA) or mixtures thereof. The reduction part of the redox couple can be one or more phosphines selected from trialkylphosphines (e.g., tributylphosphine), triarylphosphines (e.g., triphenylphosphine), tricycloalkylphosphines (e.g., tricyclohexylphosphine), triheteroarylphosphine, 4-(diphenylphosphino)-N,N'-dimethyl- aniline or mixtures thereof. Phosphine reagents having a combination of aryl, alkyl or heteroaryl substituents may also be used (e.g., diphenylpyridylphosphine). Reactions of compounds of Formula V with compounds of Formula
RCH(NH2)COOR28 "HC1 to form compounds of Formula VI can be carried out in one or more solvents, for example, dichloromethane, dichloroethane, tetrahydrofuran, dimethylformamide, toluene, diethylether, dioxane, ethylacetate, acetonitrile or mixtures thereof. Reactions of compounds of Formula V to form compounds of Formula VI can be carried out in the presence of one or more organic bases, for example, triethylamine, pyridine, 4-dimethylaminopyridine or mixtures thereof. These reactions can also be carried out in the presence of one or more reducing agents, for example, sodium borohydride, sodium triacetoxy borohydride, sodium cyanoborohydride, or mixtures thereof, or any methods known to in the art.
Reactions of compounds of Formula VI with compounds of Formula R1C1-Cl or R1C,- N=C=W (wherein W is the same as defined earlier) to form compounds of Formula VII can be carried out in one or more solvents, for example, dichloromethane, dichloroethane tetrahydrofuran, dimethylformamide, toluene, diethylether, dioxane, ethylacetate, acetonitrile or mixtures thereof. These reactions can also be carried out in the presence or absence of one or more bases. When present, the one or more bases can be selected from triethylamine, pyridine, 4-dimethylaminopyridine, diisopropylethylamine and the like, or mixtures thereof.
Hydrolyzing compounds of Formula VII to form compounds of Formula VIII can be carried out in the presence of one or more inorganic bases (e.g. , lithium hydroxide, sodium hydroxide, potassium hydroxide or mixtures thereof) and one or more solvents (e.g., tetrahydrofuran, methanol, water, dimethylformamide, diethylether, or mixtures thereof). In Scheme I where specific bases, solvents, reducing agents etc. are mentioned, it is to be understood that other bases, solvents, reducing agents etc. known to one of ordinary skill in the art may be used. Similarly reaction temperatures and duration may be adjusted according to the desired needs and are well within the capabilities of one of ordinary skill in the art without undue experimentation.
Compounds provided herein in include, but are not limited to, for example:
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methoxyphenoxy) carbonyljglycinate (Compound No. 1); Ethyl N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(2- methoxyphenoxy)carbonyl] glycinate (Compound No. 2);
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4- fluorophenoxy)carbonyl]glycinate (Compound No. 3);
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N- {[3- (trifluoromethyl)phenoxy]carbonyl} glycinate (Compound No. 4);
Ethyl N-[(4-chlorophenoxy)carbonyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycinate (Compound No. 5);
Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl) amino]ethoxy}benzyl)-N-[(4- methoxyphenoxy) carbonyljglycinate (Compound No. 6); Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-methoxy- phenoxy) carbonyljglycinate (Compound No. 7);
Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- [(benzyloxy)carbonyl] glycinate (Compound No. 8);
Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy) carbonyljglycinate (Compound No. 9);
Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- {[3- (trifluoromethyl) phenoxyjcarbonyl} glycinate (Compound No. 10);
Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methylphenoxy) carbonyljglycinate (Compound No. 11); Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-benzoyl glycinate (Compound No. 12);
Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(3-methoxybenzoyl) glycinate (Compound No. 13);
Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(4-methoxybenzoyl) glycinate (Compound No. 14); Ethyl N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methoxyphenoxy) carbonyl] glycinate (Compound No. 15); Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(2- methoxyphenoxy)carbonyl]glycinate (Compound No. 16);
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4- fluorophenoxy)carbonyl]glycinate (Compound No. 17);
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N- {[3- (trifluoromethyl)phenoxy]carbonyl}glycinate (Compound No. 18);
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4- methylphenoxy)carbonyl]glycinate (Compound No. 19);
Ethyl N-[(benzyloxy)carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycinate (Compound No. 20); Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}-4-methoxybenzyl)-N-[(4- methoxyphenoxy)carbonyl]glycinate (Compound No. 21);
Ethyl N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-[(4-methoxy phenoxy)carbonyl]glycinate (Compound No. 22);
Ethyl N-benzoyl-N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycinate (Compound No. 23);
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(2-fluorobenzoyl)glycinate (Compound No. 24);
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(4-fluorobenzoyl)glycinate (Compound No. 25); Ethyl N-benzoyl-N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)glycinate (Compound No. 26);
Ethyl N-(2-fluorobenzoyl)-N-(4- {2-[methyl (pyridin-2-yl)amino]ethoxy}benzyl)glycinate (Compound No. 27);
Ethyl N-(4-fluorobenzoyl)-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)glycinate (Compound No. 28);
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(phenoxycarbonyl)glycinate (Compound No. 29);
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4- methylphenoxy)carbonyl]glycinate (Compound No. 30); Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(3- methylphenoxy)carbonyl]glycinate (Compound No. 31);
Ethyl N-[(benzyloxy)carbonyl]-N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycinate (Compound No. 32);
Ethyl N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl) glycinate (Compound No. 33); Ethyl N-[(4-methylphenoxy)carbonyl]-N-(4- {2-[methyl(pyridin-2- yl)amino]ethoxy} benzyl) glycinate (Compound No. 34);
Ethyl N- [(3 -methylphenoxy)carbonyl] -N-(4- {2-[methyl(pyridin-2-yl)amino] ethoxy} benzyl) glycinate (Compound No. 35);
Ethyl N-[(benzyloxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl) glycinate] (Compound No. 36);
Ethyl N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzoxazin-4-yl)ethoxy]benzyl}-N-(phenoxy carbonyl)glycinate (Compound No. 37);
Ethyl N-[(2-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin- 4-yl) ethoxyjbenzyl} glycinate (Compound No. 38); Ethyl N-[(4-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin- 4-yl) ethoxyjbenzyl} glycinate (Compound No. 39);
Ethyl N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} -N-(phenoxycarbonyl) glycinate (Compound No. 40);
Ethyl N- [(2-methoxyphenoxy)carbonyl] -N- {4- [2-(2-methyl-4-oxoquinazolin-3 (4H)- yl)ethoxy]benzyl} glycinate (Compound No. 41);
Ethyl N- [(4-methoxyphenoxy)carbonyl] -N- {4- [2-(2-methyl-4-oxoquinazolin-3 (4H)- yl)ethoxy]benzyl} glycinate (Compound No. 42);
Ethyl N-[(2-chlorophenoxy)carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycinate (Compound No. 43); Ethyl N-[(4-chlorophenoxy)carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycinate (Compound No. 44);
Ethyl N- [(3 -chlorophenoxy)carbonyl] -N- {4- [2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycinate (Compound No. 45);
Ethyl N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} -N-[(4- methylphenoxy) carbonyl] glycinate (Compound No. 46);
Ethyl N-[(4-fluorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl) ethoxyjbenzyl} glycinate (Compound No. 47); Ethyl N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} -N- {[3- (trifluoromethyl)phenoxy]carbonyl}glycinate (Compound No. 48); Ethyl N-(isobutoxycarbonyl)-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycinate (Compound No. 49);
Ethyl N-[(benzyloxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycinate (Compound No. 50);
Ethyl N- [(3 -methoxyphenoxy)carbonyl] -N- {4- [2-(2-methyl-4-oxoquinazolin-3 (4H)-yl) ethoxyjbenzyl} glycinate (Compound No. 51);
Ethyl N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethoxy]benzyl}-N-{[3- (trifluoromethyl)phenoxy]carbonyl} glycinate (Compound No. 52);
Ethyl N-[(4-fluorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl) ethoxyjbenzyl} glycinate (Compound No. 53); Ethyl N-[(2-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzoxazin-4- yl) ethoxyjbenzyl} glycinate (Compound No. 54);
Ethyl N-[(benzyloxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl) ethoxyjbenzyl} glycinate (Compound No. 55);
Ethyl N-[(3-methylphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl) ethoxyjbenzyl} glycinate (Compound No. 56);
Ethyl N-(isobutoxycarbonyl)-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl)ethoxy]benzyl} glycinate (Compound No. 57);
Ethyl N-[(4-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzoxazin-4- yl) ethoxyjbenzyl} glycinate (Compound No. 58); Ethyl N- [(4-methylphenoxy)carbonylJ -N- {4- [2-(3 -oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl) ethoxyjbenzyl} glycinate (Compound No. 59);
Ethyl N-[(3-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzoxazin-4- yl) ethoxyjbenzyl} glycinate (Compound No. 60);
Ethyl N-[(2,5-dichlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4- benzoxazin-4-yl) ethoxyjbenzyl} glycinate (Compound No. 61);
Ethyl N-[(4-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4- benzothiazin-4-yl)ethoxy]benzyl} glycinate (Compound No. 62);
Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(2-fluorobenzoyl) glycinate (Compound No. 63); Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- methoxyphenoxy) carbonyl] glycinate (Compound No. 64);
Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- chlorophenoxy) carbonyljglycinate (Compound No. 65);
Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3- chlorophenoxy) carbonyljglycinate (Compound No. 66); Ethyl N-(4-{2-[l, 3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- methylphenoxy) carbonyljglycinate (Compound No. 67);
Ethyl N-[(4-chlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin- 4-yl) ethoxy]benzyl}glycinate (Compound No. 68);
Ethyl N-[(2-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzothiazin-4- yl) ethoxy]benzyl}glycinate (Compound No. 69);
Ethyl N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4-yl)ethoxy]benzyl}-N-(phenoxy- carbonyl) glycinate (Compound No. 70);
Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2- chlorophenoxy) carbonyljglycinate (Compound No. 71); Ethyl N-[(2,5-dichlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4- benzothiazin-4-yl)ethoxy]benzyl} glycinate (Compound No. 72);
Ethyl N-(4-{2-[l,3-benzothiazol-2-yl (methyl)amino]ethoxy}benzyl)-N- (isobutoxycarbonyl) glycinate (Compound No. 73);
Ethyl N-(isobutoxycarbonyl)-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-yl) ethoxyjbenzyl} glycinate (Compound No. 74);
Ethyl N-[(4-methylphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin- 4-yl)ethoxy]benzyl} glycinate (Compound No. 75);
Ethyl N-[(3-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzothiazin-4- yl)ethoxy]benzyl} glycinate (Compound No. 76); Ethyl N-[(3-methylphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin- 4-yl)ethoxy]benzyl} glycinate (Compound No. 77);
Ethyl N-[(2-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4- benzothiazin-4-yl)ethoxy]benzyl} glycinate (Compound No. 78);
Ethyl N-[(4-fluorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4- yl)ethoxy]benzyl} glycinate (Compound No. 79);
Ethyl N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4-yl)ethoxy]benzyl}-N-{[3- (trifluoromethyl)phenoxy] carbonyl} glycinate (Compound No. 80); Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2- methoxyphenoxy) carbonyljglycinate (Compound No. 81); Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy) carbonyljglycinate (Compound No. 82);
Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl (methyl)amino]ethoxy}benzyl)-N- {[3- (trifluoromethyl) phenoxy]carbonyl}glycinate (Compound No. 83);
Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl (methyl)amino]ethoxy}benzyl)-N-[(2,5- dichlorophenoxy)carbonyl]glycinate (Compound No. 84);
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}-4-methoxybenzyl)-N-[(4- methoxyphenoxy)carbonyl] -D-alaninate (Compound No . 85) ;
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-{[3-(trifluoromethyl) phenoxy]carbonyl}glycinate (Compound No. 86); Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-[(4-methylphenoxy) carbonyljglycinate (Compound No. 87);
Ethyl N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-[(3-methylphenoxy) carbonyljglycinate (Compound No. 88);
Ethyl N-[(3-chlorophenoxy) carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxy benzyl} glycinate (Compound No. 89);
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}-4-methoxybenzyl)-N-[(4- methylphenoxy) carbonyljglycinate (Compound No. 90);
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methoxyphenoxy)carbonyl]-L- alaninate (Compound No. 91); Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methyl phenoxy)carbonyl]-L- alaninate (Compound No. 92);
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(phenoxy carbonyl)-L-alaninate (Compound No. 93);
Ethyl N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl)-L- alaninate (Compound No. 94);
Ethyl N-[(2-methoxyphenoxy) carbonyl]-N-(4-{2-[methyl (pyridin-2-yl)amino]ethoxy} benzyl)-L-alaninate (Compound No. 95);
N- [(4-methylphenoxy)carbonyl] -N-(4- {2- [methyl(pyridin-2-yl) amino] ethoxy} benzyl)-L- alanine (Compound No. 96); Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy} benzyl)-N-[(4- methoxyphenoxy) carbonyljglycinate (Compound No. 97);
Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2- methoxyphenoxy) carbonyljglycinate (Compound No. 98);
Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy) carbonyljglycinate (Compound No. 99); Ethyl N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(isobutoxycarbonyl) glycinate (Compound No. 100);
Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-chlorophenoxy) carbonyljglycinate (Compound No. 101);
Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl) glycinate (Compound No. 102);
Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- [(benzyloxy)carbonyl] glycinate (Compound No. 103);
Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-chlorophenoxy) carbonyljglycinate (Compound No. 104); Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- methoxyphenoxy) carbonyljglycinate (Compound No. 105);
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2- methoxyphenoxy) carbonyljglycinate (Compound No. 106);
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy) carbonyljglycinate (Compound No. 107);
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N- (isobutoxycarbonyl) glycinate (Compound No. 108);
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- chlorophenoxy) carbonyljglycinate (Compound No. 109); Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl) glycinate (Compound No. 110);
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(benzyloxy) carbonyljglycinate (Compound No. I l l);
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3- chlorophenoxy) carbonyljglycinate (Compound No. 112);
Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- methylphenoxy) carbonyljglycinate (Compound No. 113); Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N- {[3- (trifluoromethyl) phenoxy]carbonyl}glycinate (Compound No. 114); Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methylphenoxy) carbonyljglycinate (Compound No. 115);
Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- {[3- (trifluoromethyl) phenoxy]carbonyl}glycinate (Compound No. 116);
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(phenoxycarbonyl)glycinate (Compound No. 117);
Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-methylphenoxy) carbonyl] glycinate (Compound No . 118);
Ethyl N- [(4-methoxyphenoxy)carbonyl] -N- {3 - [2-(2-methyl-4-oxoquinazolin-3 (4H)- yl)ethoxy]benzyl} glycinate (Compound No. 119); Ethyl N- {3-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} -N-[(4- methylphenoxy) carbonyljglycinate (Compound No. 120);
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(3- methylphenoxy)carbonyl]glycinate (Compound No. 121);
Ethyl N-[(3-chlorophenoxy) carbonyl]-N-{3-[2-(5-ethylpyridin-2- yl)ethoxy]benzyl} glycinate (Compound No. 122);
Ethyl N-[(2-chlorophenoxy)carbonyl]-N- {3-[2-(5-ethylpyridin-2- yl)ethoxy]benzyl} glycinate (Compound No. 123);
Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(isobutoxycarbonyl)glycinate (Compound No. 124);
Ethyl N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-N- {[3- (trifluoromethyl)phenoxy] carbonyl} glycinate (Compound No. 125);
Ethyl N-(2-fluorobenzoyl)-N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl) glycinate (Compound No. 126); Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(2-methoxybenzoyl)glycinate (Compound No. 127);
N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methoxyphenoxy)carbonyl]glycine (Compound No. 128);
N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(2-methoxyphenoxy)carbonyl]glycine (Compound No. 129);
N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-fluorophenoxy)carbonyl]glycine (Compound No. 130); N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-{[3-(trifluoromethyl) phenoxy]carbonyl]glycine (Compound No.131 ); N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl) amino] ethoxy}benzyl)-N-[(4-methoxyphenoxy) carbonyl] glycine (Compound No.132);
N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-methoxyphenoxy) carbonyl] glycine (Compound No.133);
N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- [(benzyloxy)carbonyl] glycine (Compound No.134);
N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy) carbonyl] glycine (Compound No .135) ;
N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-{[3-(trifluoromethyl) phenoxy]carbonyl} glycine (Compound No.136); N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methylphenoxy) carbonyl] glycine (Compound No.137);
N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(4-methoxybenzoyl) glycine (Compound No.138);
N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl) amino] ethoxy}benzyl)-N-(3-methoxybenzoyl) glycine (Compound No.139);
N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(4-methoxybenzoyl) glycine (Compound No .140) ;
N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methoxyphenoxy)carbonyl]glycine (Compound No .141 ) ; N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(2-methoxyphenoxy)carbonyl]glycine (Compound Νo.142);
N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-fluorophenoxy)carbonyl]glycine (Compound No .143 ) ;
N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-{[3-(trifluoromethyl)phenoxy]carbonyl} glycine (Compound No.144);
N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methylphenoxy)carbonyl]glycine (Compound No.145);
N-[(benzyloxy)carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycine (Compound No. 146); N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy} -4-methoxybenzyl)-N-[(4- methoxyphenoxy)carbonyl]glycine (Compound No. 147);
N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-[(4-methoxyphenoxy) carbonyl] glycine (Compound No. 148);
N-benzoyl-N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}glycine (Compound No. 149);
N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-(2-fluorobenzoyl)glycine (Compound No. 150);
N-{4-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-(4-fluorobenzoyl)glycine (Compound No. 151); N-benzoyl-N-(4- {2- [methyl(pyridin-2-yl)amino] ethoxy} benzyl)glycine (Compound No . 152);
N-(2-fluorobenzoyl)-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)glycine (Compound No. 153);
N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-(2-methoxy benzoyl)glycine (Compound No. 154);
N- {4-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl} -N-(phenoxycarbonyl)glycine (Compound No. 155);
N- {4-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-[(4-methyl phenoxy)carbonyl] glycine (Compound No. 156); N- {4-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-[(3-methyl phenoxy)carbonyl] glycine (Compound No. 157);
N-[(benzyloxy)carbonyl]-N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycine (Compound No. 158);
N-(4- {2-[methyl(pyridin-2-yl) amino]ethoxy}benzyl)-N-(phenoxycarbonyl)glycine (Compound No. 159);
N- [(4-methylphenoxy)carbonyl] -N-(4- {2- [methyl(pyridin-2-yl) amino] ethoxy} benzyl) glycine (Compound No. 160);
N- [(3 -methylphenoxy)carbonyl] -N-(4- {2- [methyl(pyridin-2-yl) amino] ethoxy} benzyl) glycine (Compound No. 161); N-[(benzyloxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)glycine (Compound No. 162);
N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethoxy]benzyl}-N- (phenoxycarbonyl)glycine (Compound No. 163); N-[(2-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl)ethoxy]benzyl} glycine (Compound No. 164);
N- [(4-methoxyphenoxy) carbonyl] -N- {4- [2-(3 -oxo-2,3 -dihydro-4H- 1 ,4-benzoxazin-4- yl)ethoxy]benzyl} glycine (Compound No. 165);
N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl}-N-(phenoxycarbonyl) glycine (Compound No. 166); N-[(2-methoxyphenoxy) carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycine (Compound No. 167);
N- [(4-methoxyphenoxy) carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycine (Compound No. 168);
N-[(2-chlorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycine (Compound No. 169);
N-[(4-chlorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycine (Compound No. 170);
N-[(3-chlorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycine (Compound No. 171); N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} -N-[(4-methylphenoxy) carbonyl] glycine (Compound No. 172);
N-[(4-fluorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycine (Compound No. 173);
N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} -N- {[3-(trifluoromethyl) phenoxyjcarbonyl} glycine (Compound No. 174);
N-(isobutoxycarbonyl)-N- {4-[2-(2-methyl-4-oxoquinazolin-3 (4H)- yl)ethoxy]benzyl} glycine (Compound No. 175);
N-[(benzyloxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} glycine (Compound No. 176); N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} -N-[(3-methylphenoxy) carbonyl] glycine (Compound No. 177);
N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethoxy]benzyl}-N-{[3- (trifluoromethyl)phenoxy] carbonyl} glycine (Compound No. 178);
N-[(3-fluorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4- yl)ethoxy]benzyl} glycine (Compound No. 179);
N-[(2-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4- yl)ethoxy]benzyl} glycine (Compound No. 180); N-[(benzyloxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4- yl)ethoxy]benzyl} glycine (Compound No. 181); N- [(3 -methylphenoxy)carbonyl] -N- {4- [2-(3 -oxo-2,3 -dihydro-4H- 1 ,4-benzoxazin-4- yl)ethoxy]benzyl} glycine (Compound No. 182);
N-(isobutoxycarbonyl)-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl)ethoxy]benzyl} glycine (Compound No. 183);
N-[(4-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4- yl)ethoxy]benzyl} glycine (Compound No. 184);
N- [(4-methylphenoxy)carbonyl] -N- {4- [2-(3 -oxo-2,3 -dihydro-4H- 1 ,4-benzoxazin-4- yl)ethoxy]benzyl} glycine (Compound No. 185);
N-[(3-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4- yl)ethoxy]benzyl} glycine (Compound No. 186);
N-[(2,5-dichlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl)ethoxy]benzyl} glycine (Compound No. 187);
N-[(4-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4- yl)ethoxy]benzyl} glycine (Compound No. 188);
N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(2-fluorobenzoyl)glycine (Compound No. 189); N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-[(4-methoxy phenoxy)carbonyl]glycine (Compound No. 190);
N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-[(4-chlorohenoxy) carbonyl] glycine (Compound No. 191);
N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-[(3-chlorohenoxy) carbonyl] glycine (Compound No. 192);
N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methylhenoxy) carbonyl] glycine (Compound No. 193);
N-[(4-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4-yl) ethoxy]benzyl} glycine (Compound No. 194); N-[(2-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzothiazin-4-yl) ethoxy]benzyl} glycine (Compound No. 195);
N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-yl)ethoxy]benzyl} -N- (phenoxycarbonyl) glycine (Compound No. 196); N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy} benzyl)-N-[(2-chlorophenoxy) carbonyl] glycine (Compound No. 197);
N-[(2,5-dichlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4- yl)ethoxy]benzyl} glycine (Compound No. 198);
N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-(isobutoxycarbonyl) glycine (Compound No. 199); N-(isobutoxycarbonyl)-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4- yl)ethoxy]benzyl} glycine (Compound No. 200);
N- [(4-methylphenoxy)carbonyl] -N- {4- [2-(3 -oxo-2,3 -dihydro-4H- 1 ,4-benzothiazin-4-yl) ethoxyjbenzyl} glycine (Compound No. 201);
N-[(3-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4- yl)ethoxy]benzyl} glycine (Compound No. 202);
N- [(3 -methylphenoxy)carbonyl] -N- {4- [2-(3 -oxo-2,3 -dihydro-4H- 1 ,4-benzothiazin-4-yl) ethoxyjbenzyl} glycine (Compound No. 203);
N-[(2-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4- yl)ethoxy]benzyl} glycine (Compound No. 204); N-[(4-fluorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzothiazin-4-yl) ethoxyjbenzyl} glycine (Compound No. 205);
N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-yl)ethoxy]benzyl} -N- {[3- (trifluoromethyl)phenoxy] carbonyl} glycine (Compound No. 206);
N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2-methoxyphenoxy) carbonyl] glycine (Compound No. 207);
N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-[(4- fluorophenoxy)carbonyl]glycine (Compound No. 208);
N-(4-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy} benzyl)-N-{[3-(trifluoromethyl) phenoxyjcarbonyl} glycine (Compound No. 209); N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-[(2,5- dichlorophenoxy)carbonyl]glycine (Compound No. 210);
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy} -4-methoxybenzyl)-N-[(4-methoxy phenoxy)carbonyl]-D-alanine (Compound No. 211);
N-{3-[2-(5-ethylpyridin-2-yl) ethoxy]-4-methoxybenzyl}-N-{[3-(trifluoromethyl) phenoxyjcarbonyl} glycine (Compound No. 212);
N-{3-[2-(5-ethylpyridin-2-yl) ethoxy]-4-methoxybenzyl}-N-[(4-methylphenoxy) carbonyl] glycine (Compound No. 213); N-{3-[2-(5-ethylpyridin-2-yl) ethoxy]-4-methoxybenzyl}-N-[(3-methylphenoxy) carbonyl] glycine (Compound No. 214); N-[(3-chlorophenoxy)carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxy benzyl} glycine (Compound No. 215);
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl) aminojethoxy} -4-methoxy benzyl)-N-[(4-methyl phenoxy)methyl] glycine (Compound No. 216);
N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methoxyphenoxy)carbonyl]-L-alanine (Compound No. 217);
N- {4-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-[(4-methyl phenoxy)carbonyl]-L-alanine (Compound No. 218);
N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-(phenoxy carbonyl)-L-alanine (Compound No. 219); N-(phenoxycarbonyl)-N-[4-(2-pyridin-2-ylethoxy)benzyl]-L-alanine (Compound No. 220);
N-[(2-methoxyphenoxy) carbonyl]-N-(4-{2-[methyl (pyridin-2-yl)amino]ethoxy} benzyl)- L-alanine (Compound No. 221);
N- [(4-methylphenoxy)carbonyl] -N-(4- {2- [methyl(pyridin-2-yl) amino] ethoxy} benzyl)-L- alanine (Compound No. 222);
N-(3-{2-[l,3-benzoxazol-2-yl (methyl)amino] ethoxy} benzyl)-N-[(4- methoxyphenoxy)carbonyl] glycine (Compound No. 223);
N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2-methoxyphenoxy) carbonyl] glycine (Compound No. 224); N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy) carbonyl] glycine (Compound No. 225);
N-(3- {2-[ 1 ,3-benzoxazol-2-yl (methyl)amino] ethoxy} benzyl)-N-(isobutoxycarbonyl) glycine (Compound No. 226);
N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-chlorophenoxy) carbonyl] glycine (Compound No. 227);
N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl) glycine (Compound No. 228);
N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl) amino] ethoxy} benzyl)-N- [(benzyloxy)carbonyl] glycine (Compound No. 229); N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-chlorophenoxy) carbonyl] glycine (Compound No. 230);
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methoxyphenoxy) carbonyl] glycine (Compound No . 231 ) ;
N-(3- {2-[ 1 ,3-benzothiazol-2-yl (methyl)amino]ethoxy}benzyl)-N-[(2-methoxyphenoxy) carbonyl] glycine (Compound No. 232); N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy) carbonyl] glycine (Compound No. 233);
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(isobutoxycarbonyl) glycine (Compound No. 234);
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-chlorophenoxy) carbonyl] glycine (Compound No. 235);
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N- (phenoxycarbonyl)glycine (Compound No. 236);
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N- [(benzyloxy)carbonyl] glycine (Compound No. 237); N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-chlorophenoxy) carbonyl] glycine (Compound No. 238);
N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methylphenoxy) carbonyl] glycine (Compound No. 239);
N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-{[3-(trifluoromethyl) phenoxy]carbonyl} glycine (Compound No. 240);
N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl) amino] ethoxy}benzyl)-N-[(4-methylphenoxy) carbonyl] glycine (Compound No . 241 ) ;
N-(3 - {2-[ 1 ,3 -benzoxazol-2-yl(methyl)amino]ethoxy } benzyl)-N- { [3 -(trifluoromethyl) phenoxy]carbonyl} glycine (Compound No. 242); N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-(phenoxycarbonyl)glycine (Compound No. 243);
N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-methylphenoxy) carbonyl] glycine (Compound No. 244); N-[(4-methoxyphenoxy)carbonyl]-N-{3-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycine (Compound No. 245);
N- {3 - [2-(2-methyl-4-oxoquinazolin-3 (4H)-yl)ethoxy]benzyl} -N- [(4-methylphenoxy) carbonyl] glycine (Compound No. 246); N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(3-methylphenoxy)carbonyl]glycine (Compound No. 247);
N-[(3-chlorophenoxy)carbonyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}glycine (Compound No. 248);
N-[(2-chlorophenoxy)carbonyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}glycine (Compound No. 249); N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-(isobutoxycarbonyl)glycine (Compound No. 250);
N-[(4-chlorophenoxy) carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycine (Compound No. 251);
N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-N- {[3- (trifluoromethyl)phenoxy]carbonyl} glycine (Compound No. 252);
N-[(4-fluorophenoxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl) glycine (Compound No. 253),
N-[(4-methylphenoxy)carbonyl]-N-{4-[2-(l-oxido-3-oxo-2,3-dihydro-4H-l,4- benzothiazin-4-yl)ethoxy]benzyl} glycine (Compound No. 254),
N-[(3-methylphenoxy)carbonyl]-N- {4-[2-(5-methyl-2-phenyl- 1 ,3-oxazol-4- yl)ethoxy]benzyl} glycine (Compound No. 255),
N-[(4-methylphenoxy)carbonyl]-N- {4-[2-(5-methyl-2-phenyl- 1 ,3-oxazol-4- yl)ethoxy]benzyl} glycine (Compound No. 256),
N-[(4-fluorophenoxy)carbonyl]-N-{4-[2-(5-methyl-2-phenyl-l,3-oxazol-4- yl)ethoxy]benzyl} glycine (Compound No. 257),
N-[(4-methoxyphenyl)sulfonyl]-N- {4-[2-(5-methyl-2-phenyl- 1 ,3-oxazol-4- yl)ethoxy]benzyl} glycine (Compound No. 258)
N-[(2-methoxyphenoxy)carbonyl]-N-(4-{2-[methyl(pyridin-2- yl)amino]ethoxy}benzyl)glycine (Compound No. 259) N-[(4-methoxyphenoxy)carbonyl]-N-(4-methoxy-3- {2-[4-
(trifluoromethoxy)phenoxy]ethoxy}benzyl)glycine (Compound No. 260),
N- {3 - [2-(4-te?t-butylphenoxy)ethoxy] -4-methoxybenzyl} -N- [(4- methoxyphenoxy)carbonyl] glycine (Compound No. 261),
N-(4-methoxybenzoyl)-N- {4-[2-(5-methyl-2-phenyl- 1 ,3-oxazol-4- yl)ethoxy]benzyl} glycine (Compound No. 262), or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites. Table 1
Figure imgf000056_0001
Formula III
Z= -O-, R18= H, A2=CH2, A3=-CH2, Y= COOEt
Figure imgf000056_0002
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
= point of attachment
Table 2
Figure imgf000067_0001
Formula III
Z= -O-, R18= H, A2=CH2, A3= CH2, Y= COOH
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0002
Figure imgf000077_0001
point of attachment In another aspect, the present invention encompasses pharmaceutical compositions comprising, as an active ingredient, one or more compounds described herein and/or one or more pharmaceutically acceptable salts together with one or more pharmaceutically acceptable carriers or diluents. Compounds described herein may be administered to a patient, i.e., human or animal, for treatment by any route, which effectively transports the active compound(s) to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral (rectal, subcutaneous, intravenous, intraurethral, intramuscular, intranasal) routes of administration. For example, a preferred administration route is oral administration. Pharmaceutical compositions of the present invention comprise pharmaceutically effective amounts of one or more compounds of the present invention formulated together with one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carriers" includes non-toxic, inert solid, semi-solid or liquid filler, diluents, encapsulating material or formulation of any type. Solid form preparations for oral administration include capsules, tablet, pills, powder, granules, sachets or suppositories. Active compounds for solid form preparations can be mixed with one or more inert, pharmaceutically acceptable excipients or carriers, for example, sodium citrate, dicalcium phosphate or mixtures thereof; binders, for example, carboxymethyl cellulose, alginates, gelatins, polyvinylpyrolidinone, acacia or mixtures thereof; disintegrating agents, for example, agar-agar, calcium carbonate, alginic acid, certain silicates, sodium carbonate or mixtures thereof; absorption acceptors, for example, quaternary ammonium compounds; wetting agents, for example, cetyl alcohol, glycerol monostearate or mixtures thereof; adsorbents, for example, kaolin; lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethyleneglycol, sodium lauryl sulphate or mixtures thereof; or mixtures thereof. For capsules, tablets, or pills, dosage forms may also comprise one or more buffering agents.
For solid tablet, capsule or pill preparations, granules can be prepared with coating and shells, for example, enteric coatings or other coatings known to one of ordinary skill in the art.
Liquid form preparations for oral administration include pharmaceutically acceptable emulsions, solution, suspensions, syrups or elixirs. For such liquid preparation, active compounds can be mixed with water or one or more other solvents, solubilizing agents, emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, custard sesame oil), glycerol, or fatty acid esters of sorbitan or mixtures thereof. Oral compositions can also include one or more adjuvants, for example, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents and perfuming agents.
Injectable preparations, for example, sterile injections or aqueous solutions may be formulated by methods known by one of ordinary skill in the art using one or more suitable dispersing or wetting suspending agents. Acceptable vehicles and solvents that may be employed include, for example, water, Ringer's solutions, isotonic sodium chloride or mixtures thereof.
Formulation described herein may be formulated to provide quick, sustained, or delayed release of active ingredients after administration to patients in need thereof by employing procedures well known to one of ordinary skill in the art.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. Examples set forth below demonstrate the general synthetic procedure for the preparation of representative compounds. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.
Examples
Example 1: Preparation of compounds of Formula V An aldehyde, triphenyl phosphine and a heterocycle (in a ratio of 1.0: 1.4: 1.2 respectively) were added to a dry two-necked round bottom flask containing dry tetrahydrofuran and fitted with a septum and nitrogen balloon. The solution was cooled to -5 0C to 0 0C and diisopropylazodicarboxylate was added (1.3 equiv. with respect to aldehyde) dropwise with stirring. After complete addition, the resultant mixture was allowed to come to room temperature and stirred overnight. Volatiles were removed under reduced pressure and a residue was purified over a silica column using a mixture of ethyl acetate and hexane as a mobile phase, yielding a compound of Formula V.
Example 2: Preparation of compounds of Formula VI
A compound of Formula V and the hydrochloride salt of a compound of Formula RCH(NH2)COOEt (in a ratio of 1.0:2.25) were placed under vacuum for about 20 minutes, then dissolved in dry dichloromethane followed by the addition of dry triethylamine (2.5 equiv.). After stirring the resultant mixture for about 1-2 hours at room temperature, sodium triacetoxyborohydride (3.0 equiv.) was added and mixture was stirred was overnight at room temperature under inert atmosphere. The mixture was then poured into water and the organic layer was extracted with dichloromethane. The organic (dichloromethane) layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting product was purified by column chromatography over silica gel column using either a mixture of ethyl acetate and hexane or methanol and dichloromethane as eluent, yielding a compound of Formula VI.
Example 3: Preparation of compound of Formula VII
A compound of Formula R1C1-Cl (either neat or in dry dichloromethane) and triethylamine in dichloromethane was added dropwise to a cold stirred solution (at 0 0C to -5 0C) of a compound of Formula VI and the resulting mixture was stirred overnight while being allowed to come to room temperature. Dichloromethane was removed by rotary evaporation and the residue was purified over silica gel column using ethyl acetate :hexane as mobile phase to yield the desired carbamate ester. The following are examples of compounds that were prepared following the above procedure:
Compound No. 1: Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4- methoxyphenoxy)carbonyl]glycinate; Mass (m/z) (M+ 1): 493.15; m.pt: liquid, Compound No. 2: Ethyl N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(2- methoxyphenoxy) carbonyljglycinate; Mass (m/z) (M+l): 493.1; m.pt.: liquid,
Compound No. 3: Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4- fluorophenoxy) carbonyljglycinate; Mass (m/z) (M+l): 481.08; m.pt.: liquid,
Compound No. 4: EthylN-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N- {[3(trifluoromethyl)phenoxy]carbonyl}glycinate; Mass (m/z) (M+l): 531.12; m. pt: liquid, Compound No. 5 : Ethyl N-[(4-chlorophenoxy)carbonyl]-N- {3-[2-(5-ethylpyridin-2- yl)ethoxy]benzyl}glycinate; Mass (m/z) (M+l): 497.1; m. pt.: liquid,
Compound No. 6: Ethyl N-(4-{2-[l,3-benzoxazol-2-yl(methyl) amino]ethoxy}benzyl)-N- [(4-methoxyphenoxy) carbonyljglycinate; Mass (m/z) (M+l): 534; m. pt.: liquid,
Compound No. 7: Ethyl N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- [(3-methoxy-phenoxy) carbonyljglycinate; Mass (m/z) (M+l): 534; m. pt.: liquid,
Compound No. 8: Ethyl N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- [(benzyloxy)carbonyl]glycinate; Mass (m/z) (M+l): 518.32; m. pt.: liquid, Compound No. 9: Ethyl N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- [(4-fluorophenoxy) carbonyljglycinate; Mass (m/z) (M+l): 522.1; m. pt: liquid,
Compound No. 10: Ethyl N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- {[3-(trifluoromethyl) phenoxy]carbonyl}glycinate; Mass (m/z) (M+l): 572.1; m. pt.: liquid,
Compound No. 11 : Ethyl N-(4- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- [(4-methylphenoxy) carbonyljglycinate; Mass (m/z) (M+l): 518.14; m. pt.: liquid,
Compound No. 12: Ethyl N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- benzoyl glycinate; Mass (m/z) (M+l): 488.10; m. pt.: liquid,
Compound No. 13: Ethyl N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- (3-methoxybenzoyl) glycinate; Mass (m/z) (M+l): 518.2; m. pt.: liquid,
Compound No. 14: Ethyl N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- (4-methoxybenzoyl) glycinate; Mass (m/z) (M+l): 518.2; m. pt.: liquid, Compound No. 15: Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4- methoxyphenoxy)carbonyl] glycinate; Mass (m/z) (M+l): 493.19; m. pt.: liquid,
Compound No. 16: Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(2- methoxyphenoxy)carbonyl] glycinate; Mass (m/z) (M+l): 493.25; m. pt.: liquid,
Compound No. 17: Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4- fluorophenoxy)carbonyl] glycinate; Mass (m/z) (M+l): 481.1; m. pt: liquid,
Compound No. 18: Ethyl N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-{[3-(trifluoro methyl)phenoxy] carbonyl} glycinate; Mass (m/z) (M+l): 531.2; m. pt.: liquid,
Compound No. 19: Ethyl N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methyl phenoxy)carbonyl]glycinate; Mass (m/z) (M+l): 477.2; m. pt.: liquid, Compound No. 20: Ethyl N-[(benzyloxy)carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} glycinate; Mass (m/z) (M+l): 477.24; m. pt.: liquid,
Compound No. 21: Ethyl N-(3-{2-[l, 3-benzothiazol-2-yl(methyl)amino]ethoxy}-4- methoxybenzyl)-N-[(4-methoxyphenoxy) carbonyljglycinate; Mass (m/z) (M+l): 580; m. pt.: liquid,
Compound No. 22: Ethyl N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-[(4- methoxy phenoxy)carbonyl]glycinate; Mass (m/z) (M+l): 523.1; m. pt.: liquid, Compound No. 23 : Ethyl N-benzoyl-N- {4-[2-(5-ethylpyridin-2- yl)ethoxy]benzyl} glycinate; Mass (m/z) (M+l): 447.1; m. pt.: liquid,
Compound No. 24: Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N-(2- fluorobenzoyl)glycinate; Mass (m/z) (M+l): 465.1; m. pt.: liquid, Compound No. 25: Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(4- fluorobenzoyl)glycinate; Mass (m/z) (M+l): 465.1; m. pt: liquid,
Compound No. 26: Ethyl N-benzoyl-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl) glycinate; Mass (m/z) (M+l): 448.1; m. pt: liquid,
Compound No. 27: Ethyl N-(2-fluorobenzoyl)-N-(4-{2-[methyl (pyridin-2- yl)amino]ethoxy} benzyl)glycinate; Mass (m/z) (M+l): 466.1; m. pt.: liquid, Compound No. 28: Ethyl N-(4-fluorobenzoyl)-N-(4-{2-[methyl (pyridin-2- yl)amino]ethoxy} benzyl)glycinate; Mass (m/z) (M+l): 466.2; m. pt.: liquid,
Compound No. 29: Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N- (phenoxycarbonyl) glycinate; Mass (m/z) (M+l): 463.1; m. pt.: liquid,
Compound No. 30: Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N-[(4-methyl phenoxy) carbonyl] glycinate; Mass (m/z) (M+l): 477.0; m. pt.: liquid,
Compound No. 31: Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N-[(3-methyl phenoxy)carbonyl] glycinate; Mass (m/z) (M+l): 477.1; m. pt.: liquid,
Compound No. 32: Ethyl N-[(benzyloxy)carbonyl]-N-{4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} glycinate; Mass (m/z) (M+l): 477.0; m. pt.: liquid, Compound No. 33 : Ethyl N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-N- (phenoxy carbonyl) glycinate; Mass (m/z) (M+l): 464.1; m. pt.: liquid,
Compound No. 34: Ethyl N-[(4-methylphenoxy)carbonyl]-N-(4-{2-[methyl(pyridin-2- yl)amino]ethoxy} benzyl) glycinate; Mass (m/z) (M+l): 478.0; m. pt.: liquid,
Compound No. 35: Ethyl N-[(3-methylphenoxy) carbonyl] -N-(4- {2- [methyl(pyridin-2- yl)amino]ethoxy} benzyl) glycinate; Mass (m/z) (M+l): 478.1; m. pt.: liquid,
Compound No. 36: Ethyl N-[(benzyloxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl)amino] ethoxy}benzyl) glycinate; Mass (m/z) (M+l): 478.0; m. pt.: liquid,
Compound No. 37: Ethyl N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethoxy] benzyl} -N-(phenoxycarbonyl) glycinate; Mass (m/z) (M+l): 505.2; m. pt.: liquid, Compound No. 38: Ethyl N-[(2-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro- 4H-l,4-benzoxazin-4-yl) ethoxyjbenzyl} glycinate; Mass (m/z) (M+l): 535.2; m. pt.: liquid,
Compound No. 39: Ethyl N-[(4-methoxyphenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro- 4H-l,4-benzoxazin-4-yl) ethoxyjbenzyl} glycinate; Mass (m/z) (M+l): 535.2; m. pt.: liquid,
Compound No. 40: Ethyl N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl}-N- (phenoxycarbonyl) glycinate; Mass (m/z) (M+l): 516.3; m. pt.: liquid, Compound No. 41 : Ethyl N-[(2-methoxyphenoxy)carbonyl]-N- {4-[2-(2-methyl-4- oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycinate; Mass (m/z) (M+l): 540.3; m. pt: liquid, Compound No. 42: Ethyl N-[(4-methoxyphenoxy)carbonyl]-N- {4-[2-(2-methyl-4- oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycinate; Mass (m/z) (M+l): 540.2; m. pt.: liquid,
Compound No. 43: Ethyl N-[(2-chlorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4- oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycinate; Mass (m/z) (M+l): 550.2; m. pt.: liquid,
Compound No. 44: Ethyl N-[(4-chlorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4- oxoquinazolin-3(4H)-yl)ethoxy]benzyl} glycinate; Mass (m/z) (M+l): 550.2; m. pt.: liquid,
Compound No. 45: Ethyl N-[(3-chlorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4- oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycinate; Mass (m/z) (M+l): 550.2; m. pt.: liquid,
Compound No. 46: Ethyl N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl}- N-[(4-methylphenoxy) carbonyljglycinate; Mass (m/z) (M+l): 530.2; m. pt.: liquid,
Compound No. 47: Ethyl N-[(4-fluorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4- oxoquinazolin-3(4H)-yl) ethoxy] benzyl} glycinate; Mass (m/z) (M+l): 534.2; m. pt.: liquid,
Compound No. 48: Ethyl N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl}-N- {[3-(trifluoromethyl) phenoxy] carbonyl} glycinate; Mass (m/z) (M+l): 584.2; m. pt.: liquid,
Compound No. 49: Ethyl N-(isobutoxycarbonyl)-N-{4-[2-(2-methyl-4-oxoquinazolin- 3(4H)-yl)ethoxy]benzyl} glycinate; Mass (m/z) (M+l): 496.3; m. pt.: liquid, Compound No. 50: Ethyl N-[(benzyloxy)carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin- 3(4H)-yl)ethoxy] benzyl} glycinate; Mass (m/z) (M+l): 530.2; m. pt.: liquid,
Compound No. 51 : Ethyl N-[(3-methoxyphenoxy)carbonyl]-N- {4-[2-(2-methyl-4- oxoquinazolin-3(4H)-yl) ethoxyjbenzyl} glycinate; Mass (m/z) (M+l): 530.2; m. pt.: liquid,
Compound No. 52: Ethyl N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethoxy] benzyl}-N-{[3-(trifluoromethyl) phenoxy] carbonyl} glycinate; Mass (m/z) (M+l): 573.2; m. pt.: liquid,
Compound No. 53: Ethyl N-[(4-fluorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H- l,4-benzoxazin-4-yl) ethoxyjbenzyl} glycinate; Mass (m/z) (M+l): 523.2; m. pt.: liquid,
Compound No. 54: Ethyl N-[(2-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H- l,4-benzoxazin-4-yl) ethoxyjbenzyl} glycinate; Mass (m/z) (M+l): 539.1; m. pt.: liquid, Compound No. 55: Ethyl N-[(benzyloxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4- benzoxazin-4-yl)ethoxy]benzyl}glycinate; Mass (m/z) (M+l): 519.3; m. pt: liquid, Compound No. 56: Ethyl N-[(3-methylphenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro- 4H-l,4-benzoxazin-4-yl) ethoxy]benzyl}glycinate; Mass (m/z) (M+l): 519.3; m. pt.: liquid,
Compound No. 57: Ethyl N-(isobutoxycarbonyl)-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4- benzoxazin-4-yl)ethoxy] benzyl} glycinate; Mass (m/z) (M+l): 485.3; m. pt.: liquid,
Compound No. 58: Ethyl N-[(4-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H- l,4-benzoxazin-4-yl) ethoxyjbenzyl} glycinate; Mass (m/z) (M+l): 539.2; m. pt.: liquid, Compound No. 59: Ethyl N-[(4-methylphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro- 4H-l,4-benzoxazin-4-yl) ethoxyjbenzyl} glycinate; Mass (m/z) (M+l): 519.3; m. pt.: liquid,
Compound No. 60: Ethyl N-[(3-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H- l,4-benzoxazin-4-yl) ethoxyjbenzyl} glycinate; Mass (m/z) (M+l): 539.1; m. pt.: liquid,
Compound No. 61 : Ethyl N-[(2,5-dichlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro- 4H-l,4-benzoxazin-4-yl) ethoxyjbenzyl} glycinate; Mass (m/z) (M+l): 573.1; m. pt.: liquid,
Compound No. 62: Ethyl N-[(4-methoxyphenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro- 4H-l,4-benzothiazin-4-yl)ethoxy] benzyl} glycinate; Mass (m/z) (M+l): 451.14; m. pt.: liquid, Compound No. 63: Ethyl N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- (2-fluorobenzoyl) glycinate; Mass (m/z) (M+l): 506.1; m. pt.: liquid,
Compound No. 64: Ethyl N-(4-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy} benzyl)- N-[(4-methoxyphenoxy) carbonyljglycinate; Mass (m/z) (M+l): 550.0; m. pt.: liquid,
Compound No. 65: Ethyl N-(4-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-[(4-chlorophenoxy) carbonyljglycinate; Mass (m/z) (M+l): 555.1; m. pt.: liquid,
Compound No. 66: Ethyl N-(4-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-[(3-chlorophenoxy)carbonyl] glycinate; Mass (m/z) (M+l): 555.2; m. pt.: liquid,
Compound No. 67: Ethyl N-(4-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-[(4-methylphenoxy) carbonyljglycinate; Mass (m/z) (M+l): 534.2; m. pt.: liquid, Compound No. 68: Ethyl N-[(4-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- l,4-benzothiazin-4-yl) ethoxyjbenzyl} glycinate; Mass (m/z) (M+l): 555.2; m. pt.: liquid,
Compound No. 69: Ethyl N- [(2-chlorophenoxy) carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro- 4H-l,4-benzothiazin-4-yl) ethoxyjbenzyl} glycinate; Mass (m/z) (M+l): 555.2; m. pt.: liquid, Compound No. 70: Ethyl N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4-yl)ethoxy] benzyl} -N-(phenoxy- carbonyl) glycinate; Mass (m/z) (M+l): 521.2; m. pt: liquid,
Compound No. 71: Ethyl N-(4-{2-[l, 3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-[(2-chlorophenoxy) carbonyl] glycinate; Mass (m/z) (M+l): 554.1; m. pt: liquid,
Compound No. 72: Ethyl N-[(2,5-dichlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro- 4H- l,4-benzothiazin-4-yl)ethoxy]benzyl} glycinate; Mass (m/z) (M+l): 589.1; m. pt.: liquid,
Compound No. 73: Ethyl N-(4-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-(isobutoxycarbonyl) glycinate; Mass (m/z) (M+l): 500.2; m. pt.: liquid,
Compound No. 74: Ethyl N-(isobutoxycarbonyl)-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4- benzothiazin-4-yl)ethoxy] benzyl} glycinate; Mass (m/z) (M+l): 501.2; m. pt.: liquid,
Compound No. 75: Ethyl N-[(4-methylphenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro- 4H- l,4-benzothiazin-4-yl)ethoxy]benzyl} glycinate; Mass (m/z) (M+l): 535.2; m. pt.: liquid,
Compound No. 76: Ethyl N-[(3-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H- l,4-benzothiazin-4-yl)ethoxy]benzyl}glycinate; Mass (m/z) (M+l): 555.2; m. pt.: liquid,
Compound No. 77: Ethyl N-[(3-methylphenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro- 4H-l,4-benzothiazin-4-yl) ethoxy] benzyl} glycinate; Mass (m/z) (M+l): 535.2; m. pt.: liquid,
Compound No. 78: Ethyl N-[(2-methoxyphenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro- 4H- l,4-benzothiazin-4-yl)ethoxy]benzyl} glycinate; Mass (m/z) (M+l): 551.2; m. pt.: liquid,
Compound No. 79: Ethyl N-[(4-fluorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H- l,4-benzothiazin-4-yl)ethoxy]benzyl}glycinate; Mass (m/z) (M+l): 539.2; m. pt.: liquid, Compound No. 80: Ethyl N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4- yl)ethoxy]benzyl}-N-{[3-(trifluoromethyl)phenoxy] carbonyl} glycinate; Mass (m/z) (M+l): 589.2; m. pt: liquid,
Compound No. 81 : Ethyl N-(4- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-[(2-methoxyphenoxy) carbonyljglycinate; Mass (m/z) (M+l): 550.2; m. pt.: liquid,
Compound No. 82: Ethyl N-(4-{2-[l,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)- N-[(4-fluorophenoxy) carbonyljglycinate; Mass (m/z) (M+l): 538.2; m. pt.: liquid, Compound No. 83: Ethyl N-(4-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-{[3-(trifluoromethyl) phenoxyjcarbonyl} glycinate; Mass (m/z) (M+l): 588.2; m. pt.: liquid,
Compound No. 84: Ethyl N-(4-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-[(2,5-dichlorophenoxy)carbonyl]glycinate; Mass (m/z) (M+l): 588.1; m. pt.: liquid, Compound No. 85: Ethyl N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino] ethoxy}-4- methoxybenzyl)-N-[(4-methoxyphenoxy)carbonyl]-D-alaninate; Mass (m/z) (M+l): 594.1; m. pt.: liquid,
Compound No. 86: Ethyl N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-{[3- (trifluoromethyl)phenoxy]carbonyl} glycinate; Mass (m/z) (M+l): 561.4; m. pt.: liquid,
Compound No. 87: Ethyl N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-[(4- methylphenoxy) carbonyl] glycinate; Mass (m/z) (M+l): 507.2; m. pt.: liquid,
Compound No. 88: Ethyl N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-[(3- methylphenoxy) carbonyl] glycinate; Mass (m/z) (M+l): 507.3; m. pt.: liquid, Compound No. 89: Ethyl N-[(3-chlorophenoxy) carbonyl]-N- {3-[2-(5-ethylpyridin-2- yl)ethoxy]-4-methoxy benzyl} glycinate; Mass (m/z) (M+l): 527.2; m. pt.: liquid,
Compound No. 90: Ethyl N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}-4- methoxybenzyl)-N-[(4-methylphenoxy) carbonyl] glycinate; Mass (m/z) (M+l): 564.2; m. pt.: liquid,
Compound No. 91: Ethyl N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methoxy phenoxy)carbonyl]-L-alaninate; Mass (m/z) (M+l): 507.1; m. pt.: liquid, Compound No. 92: Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methyl phenoxy)carbonyl]-L-alaninate; Mass (m/z) (M+l): 491.1; m. pt.: liquid,
Compound No. 93: Ethyl N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(phenoxy carbonyl)-L-alaninate; Mass (m/z) (M+l): 477.1; m. pt.: liquid,
Compound No. 94: Ethyl N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-N- (phenoxycarbonyl)-L-alaninate; Mass (m/z) (M+l): 478.1; m. pt.: liquid,
Compound No. 95: Ethyl N- [(2-methoxyphenoxy) carbonyl]-N-(4-{2-[methyl (pyridin-2- yl)amino]ethoxy} benzyl)-L-alaninate; Mass (m/z) (M+l): 508.2; m. pt.: liquid,
Compound No. 96: N-[(4-methylphenoxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl) amino] ethoxy}benzyl)-L-alanine; Mass (m/z) (M+l): 492.2; m. pt.: liquid, Compound No. 97: Ethyl N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- [(4-methoxyphenoxy) carbonyl]glycinate; Mass (m/z) (M+l): 534.2; m. pt.: liquid,
Compound No. 98: Ethyl N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- [(2-methoxyphenoxy) carbonyl]glycinate; Mass (m/z) (M+l): 534.2; m. pt.: liquid,
Compound No. 99: Ethyl N-(3-{2-[l,3-benzoxazol-2-yl(methyl) amino]ethoxy}benzyl)-N- [(4-fluorophenoxy) carbonyl]glycinate; Mass (m/z) (M+l): 522.2; m. pt.: liquid,
Compound No. 100: Ethyl N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)- N-(isobutoxycarbonyl) glycinate; Mass (m/z) (M+l): 484.2; m. pt.: liquid, Compound No. 101 : Ethyl N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)- N-[(4-chlorophenoxy) carbonyl] glycinate; Mass (m/z) (M+l): 538.2; m. pt.: liquid,
Compound No. 102: Ethyl N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)- N-(phenoxycarbonyl) glycinate; Mass (m/z) (M+l): 504.2; m. pt.: liquid,
Compound No. 103: Ethyl N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy} benzyl)- N-[(benzyloxy)carbonyl] glycinate; Mass (m/z) (M+l): 518.2; m. pt.: liquid, Compound No. 104: Ethyl N-(3-{2-[l,3-benzoxazol-2-yl(methyl) amino]ethoxy}benzyl)- N-[(3-chlorophenoxy) carbonyl] glycinate; Mass (m/z) (M+l): 538.2; m. pt.: liquid,
Compound No. 105: Ethyl N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-[(4-methoxyphenoxy)carbonyl] glycinate; Mass (m/z) (M+l): 550.2; m. pt.: liquid,
Compound No. 106: Ethyl N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-[(2-methoxyphenoxy) carbonyljglycinate; Mass (m/z) (M+l): 550.2; m. pt.: liquid,
Compound No. 107: Ethyl N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino] ethoxy}benzyl)- N-[(4-fluorophenoxy) carbonyljglycinate; Mass (m/z) (M+l): 538.2; m. pt.: liquid,
Compound No. 108: Ethyl N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-(isobutoxycarbonyl) glycinate; Mass (m/z) (M+l): 500.2; m. pt.: liquid, Compound No. 109: Ethyl N-(3-{2-[l, 3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-[(4-chlorophenoxy) carbonyljglycinate; Mass (m/z) (M+l): 554.1; m. pt: liquid,
Compound No. 110: Ethyl N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-(phenoxycarbonyl) glycinate; Mass (m/z) (M+l): 520.2; m. pt.: liquid,
Compound No. I ll: Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-[(benzyloxy) carbonyljglycinate; Mass (m/z) (M+l): 534.2; m. pt.: liquid,
Compound No. 112: Ethyl N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino] ethoxy}benzyl)- N-[(3-chlorophenoxy) carbonyljglycinate; Mass (m/z) (M+l): 554.1; m. pt: liquid,
Compound No. 113: Ethyl N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N-[(4-methylphenoxy) carbonyljglycinate; Mass (m/z) (M+l): 534.2; m. pt.: liquid, Compound No. 114: Ethyl N-(3- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)- N- {[3-(trifluoromethyl)phenoxy]carbonyl} glycinate; Mass (m/z) (M+l): 588.1; m. pt.: liquid,
Compound No. 115: Ethyl N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy} benzyl)- N-[(4-methylphenoxy) carbonyljglycinate; Mass (m/z) (M+l): 518.2; m. pt.: liquid,
Compound No. 116: Ethyl N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino] ethoxy}benzyl)- N-{[3-(trifluoromethyl) phenoxyjcarbonyl} glycinate; Mass (m/z) (M+l): 572.2; m. pt.: liquid, Compound No. 117: Ethyl N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(phenoxy carbonyl)glycinate; Mass (m/z) (M+l): 463.1; m. pt: liquid,
Compound No. 118: Ethyl N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)- N-[(3-methylphenoxy) carbonyljglycinate; Mass (m/z) (M+l): 518.1; m. pt.: liquid,
Compound No. 119: Ethyl N-[(4-methoxyphenoxy)carbonyl]-N-{3-[2-(2-methyl-4- oxoquinazolin-3(4H)-yl) ethoxy]benzyl}glycinate; Mass (m/z) (M+l): 546.1; m. pt.: liquid,
Compound No. 120: Ethyl N- {3-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl}- N-[(4-methylphenoxy) carbonyljglycinate; Mass (m/z) (M+l): 530.1; m. pt.: liquid,
Compound No. 121 : Ethyl N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(3-methyl phenoxy)carbonyl]glycinate; Mass (m/z) (M+l): 437.1; m. pt.: liquid,
Compound No. 122: Ethyl N-[(3-chlorophenoxy) carbonyl]-N-{3-[2-(5-ethylpyridin-2- yl)ethoxy]benzyl}glycinate; Mass (m/z) (M+l): 497.1; m. pt.: liquid, Compound No. 123 : Ethyl N-[(2-chlorophenoxy) carbonyl]-N- {3-[2-(5-ethylpyridin-2- yl)ethoxy]benzyl}glycinate; Mass (m/z) (M+l): 497.1; m. pt.: liquid,
Compound No. 124: Ethyl N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(isobutoxy carbonyl)glycinate; Mass (m/z) (M+l): 443.2; m. pt.: liquid,
Compound No. 125: Ethyl N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-N-{[3- (trifluoromethyl)phenoxy]carbonyl} glycinate; Mass (m/z) (M+l): 532.2; m. pt.: liquid,
Compound No. 126: Ethyl N-(2-fluorobenzoyl)-N-(4-{2-[methyl(pyridin-2-yl)amino] ethoxy}benzyl) glycinate; Mass (m/z) (M+l): 466.1; m. pt.: liquid,
Compound No. 127: Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(2- methoxybenzoyl) glycinate; Mass (m/z) (M+l): 477.2; m. pt.: liquid,
Example 4: Preparation of compounds of Formula VIII
A compound of Formula VII and lithium hydroxide (1 :2.1) in a mixture of tetrahydrofuran, methanol & water (3:1 :1 v/v) were stirred overnight at room temperature. After removing volatiles under reduced pressure the residue was dissolved in water. Νon- polar impurities were washed with hexane successively, followed by the acidification of the aqueous layer to pΗ 4.0-5.0 using IN hydrochloric acid, and the product was extracted with ethyl acetate. The ethyl acetate layer was concentrated and the residue was washed with hexane to yield an acid of Formula VIII. The acid of Formula VIII is chromatographically homogenous and spectroscopically pure.
The following are examples of compounds that were prepared following the above procedure: Compound No. 128: N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4- methoxyphenoxy)carbonyl]glycine; Mass (m/z) (M+l): 465.1; m. pt: 104.2-104.9 0C,
Compound No. 129: N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(2- methoxyphenoxy) carbonyljglycine; Mass (m/z) (M+l): 465.1; m. pt: 106.8-107.4 0C,
Compound No. 130: N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-fluorophenoxy) carbonyljglycine; Mass (m/z) (M+l): 453.1; m. pt: 102-103.8 δC, Compound No. 131 : N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-{[3-(trifluoromethyl) phenoxyjcarbonyl] glycine; Mass (m/z) (M+l): 503.1; m. pt: 116.2-117.6 0C,
Compound No. 132: N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- methoxyphenoxy) carbonyljglycine; Mass (m/z) (M+l): 506.12; m. pt.: 78.7-89 0C,
Compound No. 133: N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3- methoxyphenoxy) carbonyljglycine; Mass (m/z) (M+l): 506.31; m. pt: 132.2-147 0C,
Compound No. 134: N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy} benzyl)-N- [(benzyloxy)carbonyl] glycine; Mass (m/z) (M+l): 490.09; m. pt: 106.9-109.8 0C,
Compound No. 135: N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- fluorophenoxy)carbonyl]glycine; Mass (m/z) (M+l): 494.06; m. pt.: 88.3-100.7 0C, Compound No. 136: N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-{[3- (trifluoromethyl) phenoxyjcarbonyl} glycine; Mass (m/z) (M+l): 544.04; m. pt.: 159.6- 167.6 0C,
Compound No. 137: N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- methylphenoxy) carbonyljglycine; Mass (m/z) (M+l): 490.0; m. pt: 137.2-143.5 0C,
Compound No. 138: N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(4- methoxybenzoyl)glycine; Mass (m/z) (M+l): 460.07; m. pt: 100.7-105.1 0C, Compound No. 139: N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(3- methoxybenzoyl)glycine; Mass (m/z) (M+l): 490.0; m. pt: 164.0-168.0 0C,
Compound No. 140: N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(4- methoxybenzoyl)glycine; Mass (m/z) (M+l): 490.0; m. pt: 142.7-151.4 0C,
Compound No. 141 : N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4- methoxyphenoxy)carbonyl]glycine; Mass (m/z) (M+l): 465.1; m. pt.: semisolid,
Compound No. 142: N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(2- methoxyphenoxy)carbonyl]glycine; Mass (m/z) (M+l): 465.08; m. pt.: semisolid,
Compound No. 143: N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-fluorophenoxy) carbonyljglycine; Mass (m/z) (M+l): 453.0; m. pt: semisolid, Compound No. 144: N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-{[3-(trifluoromethyl) phenoxyjcarbonyl} glycine; Mass (m/z) (M+l): 503.0; m. pt: semisolid,
Compound No. 145: N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methylphenoxy) carbonyljglycine; Mass (m/z) (M+l): 449.0; m. pt.: semisolid,
Compound No. 146: N-[(benzyloxy)carbonyl]-N-{3-[2-(5-ethylpyridin-2- yl)ethoxy]benzyl} glycine; Mass (m/z) (M+l): 449.07; m. pt.: semisolid,
Compound No. 147: N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}-4-methoxy benzyl)-N-[(4-methoxyphenoxy)carbonyl] glycine; Mass (m/z) (M+l): 552.0; m. pt.: 67.3- 69.5 0C,
Compound No. 148: N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-[(4- methoxy phenoxy) carbonyljglycine; Mass (m/z) (M+l): 495.0; m. pt.: semisolid,
Compound No. 149: N-benzoyl-N-{4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 419.1; m. pt: semisolid,
Compound No. 150: N-{4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N-(2-fluorobenzoyl) glycine; Mass (m/z) (M+l): 437.0; m. pt: semisolid,
Compound No. 151: N-{4-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-(4-fluorobenzoyl) glycine; Mass (m/z) (M+l): 437.1; m. pt: semisolid, Compound No. 152: N-benzoyl-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl) glycine; Mass (m/z) (M+l): 420.0; m. pt: semisolid,
Compound No. 153: N-(2-fluorobenzoyl)-N-(4-{2-[methyl(pyridin-2-yl)amino] ethoxy} benzyl)glycine; Mass (m/z) (M+l): 438.0; m. pt: semisolid,
Compound No. 154: N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(2-methoxy benzoyl) glycine; Mass (m/z) (M+l): 449.1; m. pt: semisolid,
Compound No. 155: N-{4-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-(phenoxycarbonyl) glycine; Mass (m/z) (M+l): 435.3; m. pt: semisolid,
Compound No. 156: N-{4-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-[(4-methyl phenoxy) carbonyljglycine; Mass (m/z) (M+l): 449.3; m. pt.: semisolid, Compound No. 157: N-{4-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-[(3-methyl phenoxy) carbonyljglycine; Mass (m/z) (M+l): 449.3; m. pt.: semisolid,
Compound No. 158: N-[(benzyloxy)carbonyl]-N-{4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 449.3; m. pt: semisolid,
Compound No. 159: N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy} benzyl)-N-(phenoxy carbonyl)glycine; Mass (m/z) (M+l): 438.3; m. pt.: semisolid,
Compound No. 160: N-[(4-methylphenoxy)carbonyl]-N-(4-{2-[methyl(pyridin-2- yl)amino]ethoxy}benzyl)glycine; Mass (m/z) (M+l): 449.3; m. pt.: semisolid, Compound No. 161 : N-[(3-methylphenoxy)carbonyl]-N-(4-{2-[methyl(pyridin-2- yl)amino]ethoxy}benzyl)glycine; Mass (m/z) (M+l): 450.3; m. pt: semisolid, Compound No. 162: N-[(benzyloxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl)amino] ethoxy}benzyl)glycine; Mass (m/z) (M+l): 450.3; m. pt.: semisolid,
Compound No. 163: N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethoxy] benzyl} -N-(phenoxycarbonyl) glycine; Mass (m/z) (M+l): 477.2; m. pt: 144.3-146.1 0C,
Compound No. 164: N-[(2-methoxyphenoxy) carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H- l,4-benzoxazin-4-yl)ethoxy]benzyl} glycine; Mass (m/z) (M+l): 507.2; m. pt.: 64.6-73.78 °C, Compound No. 165 : N-[(4-methoxyphenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl)ethoxy]benzyl} glycine; c
Compound No. 166: N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl}-N- (phenoxycarbonyl) glycine; Mass (m/z) (M+l): 488.3; m. pt.: 131.6-137.6 0C,
Compound No. 167: N-[(2-methoxyphenoxy) carbonyl]-N-{4-[2-(2-methyl-4- oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 518.3; m. pt: 131.2- 137.6 0C, Compound No. 168 : N-[(4-methoxyphenoxy) carbonyl]-N- {4-[2-(2-methyl-4- oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 518.2; m. pt: 128.6- 136.1 0C,
Compound No. 169: N-[(2-chlorophenoxy) carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin- 3(4H)-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 522.2; m. pt: 149.4-153.2 0C,
Compound No. 170: N-[(4-chlorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin- 3(4H)-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 522.2; m. pt.: 137.6-139.2 0C, Compound No. 171 : N-[(3-chlorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin- 3(4H)-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 522.2; m. pt: 168.1-172.2 0C,
Compound No. 172: N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl}-N-[(4- methylphenoxy) carbonyljglycine; Mass (m/z) (M+l): 502.3; m. pt: 163.5-166.1 0C,
Compound No. 173: N-[(4-fluorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin- 3(4H)-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 502.3; m. pt: 163.5-166.1 0C,
Compound No. 174: N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl}-N-{[3- (trifluoromethyl) phenoxyjcarbonyl} glycine; Mass (m/z) (M+l): 556.2; m. pt.: 161.5- 167.5 0C,
Compound No. 175: N-(isobutoxycarbonyl)-N-{4-[2-(2-methyl-4-oxoquinazolin-3 (4H)- yl)ethoxy]benzyl} glycine; Mass (m/z) (M+l): 468.2; m. pt: 74.3-78.4 0C, Compound No. 176: N-[(benzyloxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 502.3; m. pt: 132.8-134.4 0C,
Compound No. 177: N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl}-N-[(3- methylphenoxy)carbonyl]glycine; Mass (m/z) (M+l): 502.3; m. pt: 132.8-134.4 0C,
Compound No. 178: {4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethoxy] benzyl} - N- {[3-(trifluoromethyl)phenoxy]carbonyl} glycine; Mass (m/z) (M+l): 545.2; m. pt.: 46.3- 49.9 0C,
Compound No. 179: N-[(3-fluorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4- benzoxazin-4-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 495.2; m. pt.: 47.8-53.9 0C,
Compound No. 180: N-[(2-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4- benzoxazin-4-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 511.2; m. pt: 50.8-56.8 0C,
Compound No. 181 : N-[(benzyloxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4- benzoxazin-4-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 491.2; m. pt.: semisolid, Compound No. 182: N-[(3-methylphenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4- benzoxazin-4-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 491.2; m. pt.: 48.8-57.9 0C,
Compound No. 183 : N-(isobutoxycarbonyl)-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4- benzoxazin-4-yl)ethoxy]benzyl} glycine; Mass (m/z) (M+l): 475.3; m. pt.: semisolid,
Compound No. 184: N-[(4-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4- benzoxazin-4-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 511.1; m. pt.: semisolid,
Compound No. 185: N-[(4-methylphenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4- benzoxazin-4-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 491.2; m. pt.: semisolid,
Compound No. 186: N-[(3-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4- benzoxazin-4-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 511.2; m. pt.: semisolid, Compound No. 187: N-[(2,5-dichlorophenoxy) carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H- l,4-benzoxazin-4-yl)ethoxy]benzyl} glycine; Mass (m/z) (M+l): 545.1; m. pt.: semisolid,
Compound No. 188: N-[(4-methoxyphenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H- l,4-benzothiazin-4-yl) ethoxyjbenzyl} glycine; Mass (m/z) (M+l): 545.2; m. pt.: 60.9-71.1 0C,
Compound No. 189: N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(2- fluorobenzoyl)glycine; Mass (m/z) (M+l): 478.0; m. pt: 78.1-83.3 0C, Compound No. 190: N-(4-{2-[l,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N- [(4-methoxyphenoxy) carbonyljglycine; Mass (m/z) (M+l): 521.9; m. pt: 149.7-150.5 0C,
Compound No. 191 : N-(4-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy} benzyl)-N- [(4-chlorohenoxy) carbonyljglycine; Mass (m/z) (M+l): 527.0; m. pt.: 63.2-68.2 0C, Compound No. 192: N-(4-{2-[l,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N- [(3-chlorohenoxy) carbonyljglycine; Mass (m/z) (M+l): 526.2; m. pt: semisolid,
Compound No. 193: N-(4-{2-[l,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N- [(4-methylhenoxy) carbonyljglycine; Mass (m/z) (M+l): 506.3; m. pt.: semisolid,
Compound No. 194: N-[(4-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4- benzothiazin-4-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 527.2; m. pt.: 56.4-64.3 0C, Compound No. 195: N-[(2-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4- benzothiazin-4-yl) ethoxy]benzyl}glycine; Mass (m/z) (M+l): 527.2; m. pt.: 59.4-65.2 0C,
Compound No. 196: N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4- yl)ethoxy]benzyl}-N-(phenoxycarbonyl) glycine; Mass (m/z) (M+l): 493.3; m. pt.: 159.2- 161.9 0C,
Compound No. 197: N-(4-{2-[l,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N- [(2-chlorophenoxy) carbonyljglycine; Mass (m/z) (M+l): 526.2; m. pt.: 79.1-81.7 0C, Compound No. 198 : N-[(2,5-dichlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- l,4-benzothiazin-4-yl)ethoxy]benzyl}glycine; Mass (m/z) (M+l): 561.2; m. pt: 62.1-64.3 °C,
Compound No. 199: N-(4-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N- (isobutoxycarbonyl)glycine; Mass (m/z) (M+l): 572.3; m. pt.: semisolid,
Compound No. 200: N-(isobutoxycarbonyl)-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzo thiazin-4-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 473.2; m. pt.: semisolid, Compound No. 201 : N-[(4-methylphenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4- benzothiazin-4-yl) ethoxyjbenzyl} glycine; Mass (m/z) (M+l): 507.2; m. pt.: 58.02-63.7 °C,
Compound No. 202: N-[(3-chlorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4- benzothiazin-4-yl) ethoxy]benzyl}glycine; Mass (m/z) (M+l): 527.2; m. pt: 129.2-143.5 °C,
Compound No. 203: N-[(3-methylphenoxy) carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H- l,4-benzothiazin-4-yl) ethoxyjbenzyl} glycine; Mass (m/z) (M+l): 507.2; m. pt.: 64.1-65.4 0C,
Compound No. 204: N-[(2-methoxyphenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H- l,4-benzothiazin-4-yl) ethoxyjbenzyl} glycine; Mass (m/z) (M+l): 523.2; m. pt.: 63.4-64.8 °C,
Compound No. 205: N-[(4-fluorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4- benzothiazin-4-yl) ethoxyjbenzyl} glycine; Mass (m/z) (M+l): 511.2; m. pt: 59.0-65.3 0C, Compound No. 206: N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4- yl)ethoxy]benzyl}-N-{[3-(trifluoro- methyl)phenoxy]carbonyl}glycine; Mass (m/z) (M+l): 561.2; m. pt: 92.1-105.2 0C, Compound No. 207: N-(4- {2-[l ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2- methoxyphenoxy) carbonyljglycine; Mass (m/z) (M+l): 522.2; m. pt.: 57.2-63.5 0C,
Compound No. 208: N-(4-{2-[l,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N- [(4-fluorophenoxy) carbonyljglycine; Mass (m/z) (M+l): 510.2; m. pt: 141.1-145.3 0C,
Compound No. 209: N-(4-{2-[l,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N- {[3-(trifluoromethyl) phenoxyjcarbonyl} glycine; Mass (m/z) (M+l): 560.3; m. pt.: 61.4-
70.3 0C, Compound No. 210: N-(4-{2-[l,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N- [(2,5-dichlorophenoxy) carbonyljglycine; Mass (m/z) (M+l): 560.2; m. pt: 124.7-132.8 °C,
Compound No. 211 : N-(3-{2-[l,3-benzothiazol-2-yl(methyl) amino]ethoxy}-4- methoxybenzyl)-N-[(4-methoxyphenoxy) carbonyl]-L-alanine; Mass (m/z) (M+l): 566.0; m. pt: 93.8-95.7 0C,
Compound No. 212: N-{3-[2-(5-ethylpyridin-2-yl) ethoxy]-4-methoxybenzyl}-N-{[3- (trifluoro methyl)phenoxy] carbonyl} glycine; Mass (m/z) (M+l): 533.4; m. pt.: semisolid,
Compound No. 213: N-{3-[2-(5-ethylpyridin-2-yl) ethoxy]-4-methoxybenzyl}-N-[(4- methylphenoxy) carbonyl] glycine; Mass (m/z) (M+l): 479.3; m. pt.: 58.2-61.3 0C,
Compound No. 214: N-{3-[2-(5-ethylpyridin-2-yl) ethoxy]-4-methoxybenzyl}-N-[(3- methylphenoxy) carbonyl] glycine; Mass (m/z) (M+l): 479.3; m. pt.: 95.3-97.8 0C,
Compound No. 215: N-[(3-chlorophenoxy) carbonyl]-N-{3-[2-(5-ethylpyridin-2- yl)ethoxy]-4-methoxy benzyl} glycine; Mass (m/z) (M+l): 499.0; m. pt.: 65.1-67.3 0C, Compound No. 216: N-(3-{2-[l,3-benzothiazol-2-yl (methyl)amino]ethoxy}-4-methoxy benzyl)-N-[(4-methylphenoxy)methyl] glycine; Mass (m/z) (M+l): 536.1; m. pt.: 81.3-
83.4 0C,
Compound No. 217: N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4- methoxyphenoxy) carbonyl]-L-alanine; Mass (m/z) (M+l): 479.1; m. pt.: 52.6-57.9 0C,
Compound No. 218: N-{4-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-[(4-methyl phenoxy)carbonyl]-L-alanine; Mass (m/z) (M+l): 463.1; m. pt: 61.8-63.2 0C, Compound No. 219: N-{4-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-(phenoxy carbonyl)- L-alanine; Mass (m/z) (M+l): 449.1; m. pt: liquid,
Compound No. 220: N-(phenoxycarbonyl)-N-[4-(2-pyridin-2-ylethoxy)benzyl]-L-alanine; Mass (m/z) (M+l): 450.1; m. pt: 62.2-65.4 0C, Compound No. 221: N-[(2-methoxyphenoxy) carbonyl]-N-(4-{2-[methyl (pyridin-2- yl)amino]ethoxy} benzyl)-L-alanine; Mass (m/z) (M+l): 480.0; m. pt: liquid,
Compound No. 222: N-[(4-methylphenoxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl) amino]ethoxy}benzyl)-L-alanine; Mass (m/z) (M+l): 464.2; m. pt.: liquid,
Compound No. 223: N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- methoxyphenoxy);carbonyl]glycine; Mass (m/z) (M+l): 506.2; m. pt.: 66-67 0C, Compound No. 224: N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2- methoxyphenoxy) carbonyljglycine; Mass (m/z) (M+l): 506.2; m. pt.: 66.5-67.5 0C,
Compound No. 225: N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino] ethoxy}benzyl)-N-[(4- fluorophenoxy) carbonyljglycine; Mass (m/z) (M+l): 494.2; m. pt.: 68-69 0C,
Compound No. 226: N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- (isobutoxycarbonyl)glycine; Mass (m/z) (M+l): 456.3; m. pt.: liquid,
Compound No. 227: N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- chlorophenoxy) carbonyljglycine; Mass (m/z) (M+l): 510.2; m. pt.: 70-71 0C,
Compound No. 228: N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- (phenoxycarbonyl)glycine; Mass (m/z) (M+l): 476.2; m. pt: 70.5-71.5 0C, Compound No. 229: N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- [(benzyloxy)carbonyl] glycine; Mass (m/z) (M+l): 490.3; m. pt.: liquid,
Compound No. 230: N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3- chlorophenoxy)carbonyl] glycine; Mass (m/z) (M+l): 510.2; m. pt.: 56-57 0C,
Compound No. 231 : N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- methoxyphenoxy) carbonyljglycine; Mass (m/z) (M+l): 522.2; m. pt.: 54-55 0C,
Compound No. 232: N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2- methoxyphenoxy) carbonyljglycine; Mass (m/z) (M+l): 522.2; m. pt.: 57.5-58.5 0C,
Compound No. 233: N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy} benzyl)-N- [(4-fluorophenoxy) carbonyljglycine; Mass (m/z) (M+l): 510.2; m. pt.: 56-570C, Compound No. 234: N-(3- {2-[l ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N- (isobutoxycarbonyl)glycine; Mass (m/z) (M+l): 472.3; m. pt.: liquid,
Compound No. 235: N-(3-{2-[l,3-benzothiazol-2-yl (methyl)amino]ethoxy}benzyl)-N- [(4-chlorophenoxy) carbonyljglycine; Mass (m/z) (M+l): 526.2; m. pt.: 67-68 0C,
Compound No. 236: N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N- (phenoxycarbonyl)glycine; Mass (m/z) (M+l): 492.2; m. pt.: 59-600C,
Compound No. 237: N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N- [(benzyloxy)carbonyl] glycine; Mass (m/z) (M+l): 506.2; m. pt.: 44-45 0C, Compound No. 238: N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3- chlorophenoxy)carbonyl] glycine; Mass (m/z) (M+l): 526.2; m. pt: 58-59 0C,
Compound No. 239: N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- methylphenoxy) carbonyljglycine; Mass (m/z) (M+l): 506.2; m. pt.: 50.8-51.8 0C,
Compound No. 240: N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy} benzyl)-N- {[3-(trifluoromethyl) phenoxyjcarbonyl} glycine; Mass (m/z) (M+l): 560.2; m. pt.: 53.4- 54.4 0C,
Compound No. 241 : N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4- methylphenoxy) carbonyljglycine; Mass (m/z) (M+l): 490.3; m. pt.: 56.5-57.5 0C,
Compound No. 242: N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-{[3- (trifluoromethyl) phenoxyjcarbonyl} glycine; Mass (m/z) (M+l): 544.2; m. pt.: liquid,
Compound No. 243: N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(phenoxycarbonyl) glycine; Mass (m/z) (M+l): 435.0; m. pt: semisolid, Compound No. 244: N-(3- {2-[l ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3- methylphenoxy) carbonyljglycine; Mass (m/z) (M+l): 490.1; m. pt.: 76-77 0C,
Compound No. 245: N-[(4-methoxyphenoxy)carbonyl]-N-{3-[2-(2-methyl-4- oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 518.0; m. pt.: 88.5- 89.5 0C,
Compound No. 246: N-{3-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl}-N-[(4- methylphenoxy) carbonyljglycine; Mass (m/z) (M+l): 502.1; m. pt: 76.5.5-77.5 0C, Compound No. 247: N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(3-methylphenoxy) carbonyljglycine; Mass (m/z) (M+l): 449.1; m. pt: semisolid,
Compound No. 248: N-[(3-chlorophenoxy)carbonyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 469.0; m. pt: semisolid,
Compound No. 249: N-[(2-chlorophenoxy)carbonyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 469.0; m. pt: semisolid,
Compound No. 250: N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(isobutoxycarbonyl) glycine; Mass (m/z) (M+l): 415.1; m. pt: semisolid,
Compound No. 251 : N-[(4-chlorophenoxy)carbonyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} glycine; Mass (m/z) (M+l): 469.0; m. pt: semisolid, Compound No. 252: N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-N- {[3-(trifluoro methyl)phenoxy] carbonyl} glycine; Mass (m/z) (M+l): 504.0; m. pt.: 85.6-87.2 0C,
Compound No. 253: N-[(4-fluorophenoxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl)amino] ethoxy}benzyl)glycine; Mass (m/z) (M+l): 454.0; m. pt.: 97.8-99.4 0C, Compound No. 254: N-[(4-methylphenoxy)carbonyl]-N-{4-[2-(l-oxido-3-oxo-2,3- dihydro-4H-l,4-benzothiazin-4-yl)ethoxy]benzyl} glycine; Mass (m/z) (M+l): 523.0; m. pt: 87.6-96.9 0C. Compound No. 255 : N-[(3-methylphenoxy)carbonyl]-N- {4-[2-(5-methyl-2-phenyl- 1 ,3- oxazol-4-yl)ethoxy]benzyl}glycine; Mass (m/z) (M+l): 500.24, m.pt: 65.6-68.7 0C,
Compound No. 256: N-[(4-methylphenoxy)carbonyl]-N-{4-[2-(5-methyl-2-phenyl-l,3- oxazol-4-yl)ethoxy]benzyl}glycine; Mass (m/z) (M+l): 500.24, m.pt.: 65.4-67.3 0C,
Compound No. 257: N-[(4-fluorophenoxy)carbonyl]-N-{4-[2-(5-methyl-2-phenyl-l,3- oxazol-4-yl)ethoxy]benzyl}glycine; Mass (m/z) (M+l): 504.51, m.pt: 71.2-75.9 0C,
Compound No. 258 : N-[(4-methoxyphenyl)sulfonyl]-N- {4-[2-(5-methyl-2-phenyl- 1 ,3- oxazol-4-yl)ethoxy]benzyl}glycine; Mass (m/z) (M+l): 536.50, m.pt: 142.2-143.4 0C,
Compound No. 259: N-[(2-methoxyphenoxy)carbonyl]-N-(4-{2-[methyl(pyridin-2- yl)amino]ethoxy}benzyl)glycine; Mass (m/z) (M+l): 465.50, m.pt: 90.3-92.4 0C, Compound No. 260: N-[(4-methoxyphenoxy)carbonyl]-N-(4-methoxy-3-{2-[4-
(trifluoromethoxy)phenoxy]ethoxy}benzyl)glycine; Mass (m/z) (M+l): 551.47, m.pt.: semisolid,
Compound No. 261 : N- {3-[2-(4-tert-butylphenoxy)ethoxy]-4-methoxybenzyl}-N-[(4- methoxyphenoxy)carbonyl]glycine; Mass (m/z) (M+l): --, m.pt: semisolid,
Compound No. 262: N-(4-methoxybenzoyl)-N-{4-[2-(5-methyl-2-phenyl-l,3-oxazol-4- yl)ethoxy]benzyl} glycine; Mass (m/z) (M+l): 500.54, m.pt: 134.2-136.8 0C,
Example 5: Functional and Binding Assay
Transient Transfection and Transcription Assay: HEK-293 cells, purchased from ATCC (USA) cell bank, maintained in Minimum essential medium (Eagle) withlO % charcoal dextran treated serum, were inoculated in 6- well plates (Ix 106 cells/well) and cultured approximately 18 hours in Minimum essential medium (Eagle) with 2 mM L- glutamine and Earle's BSS adjusted to contain 1.5 g/L sodium bicarbonate, and 1.0 mM sodium pyruvate in 5% CO2 at 37 0C. Cells were transfected with each PPAR expression plasmid, pCMV Script- (PPAR γl/PPARα/PPARδ) full length (2 μg in 2 mL/well), pTAL-PPRE-Luc (4 μg), pAdvantage and pRL-CMV by Lipofection using Lipofectamine-2000 (Invitrogen, Carlsbad, USA) in abovementioned media but without antibiotics. Transfection mixture was replaced by fresh media (without antibiotics) after 5 hours duration. After transfection, the cells were harvested and seeded into 96-well plate (LumiNunc™ Plates, NUNC, Roskilde, Denmark) at a density of 3 x 104 cells/well in 100 μL of medium with Phenol-red free MEM with 10 % charcoal dextran-treated serum and other components. After the cells adhered, 100 μL of Phenol-red free MEM with 10 % charcoal dextran treated serum containing compound/standards were added. No drug controls cells were added with DMSO concentration of 0.3 % as final. After 24 hours, cells were lysed and the luciferase activity was measured in a Luminescence-Scintillation counter (Wallac MicroBeta® TriLux, PerkinElmer, CT, USA) using the Dual-Luciferase Reporter Assay System (Promega, Madison, WI, USA). (1)
Calculation of Transcriptional Activity: The firefly luciferase activity was divided by the sea pansy luciferase activity to adjust for the transfection efficiency, and the value was defined as the normalized luciferase activity. Fold activation is calculated as the ratio of PPAR-mediated transcriptional activity in the cells treated with each drug to that in DMSO-treated control cells. Compound EC50 was calculated with GraphPad Prism 4.0 software. % Maximum standard was calculated as the ratio of maximum firefly (standard) reading and firefly test reading multiplied by 100. Rosiglitazone (BRL-49653) and Ragaglitazar (DRF-2725) were used as standards for PPARγl and PP ARa, respectively. The compounds described herein exhibited EC50 values at PPARγ from about 0.15 nM to about 30 nM, from about 0.15 nM to about 15.5 M, and even from about 0.15 nM to about 4.75 nM.
The compounds described herein exhibited EC50 at PPARn from about 0.5 nM to about 30 nM, from about 0.5 nM to about 15.5 nM, and even from about 0.15 nM to about 4.2 nM.
Reference: Minoura H. et ah, (2004). Pharmacological characteristics of a novel nonthiazolidinedione insulin sensitizer, FK614. European Journal of Pharmacology. 494, 273-281.

Claims

WE CLAIM:
1. A compound having the structure of Formula I,
Figure imgf000099_0001
Formula I or pharmaceutically acceptable salt, pharmaceutically acceptable solvate, polymorph, prodrug, stereoisomer, tautomeric form, N-oxide or metabolite thereof, wherein Het is selected from:
Figure imgf000099_0002
wherein: X1-X1 ! are each independently CH, C, CH2, N, NH, O, S, S(=O) or S(O)2; X12 and X13 are each independently CR' or N, wherein R' is hydrogen or alkyl; X14 is (CH2)χ (wherein x =0-2), NR', O, S, S(=O) or S(O)2, wherein R' is the same as defined above; X15 is CH or N; X16 and V are each independently O, NR', or S, wherein R' is the same as defined earlier; D and E are substituted or unsubstituted alkyl, aryl or a bond; R1-R5 and R1O-Rn are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino; A is N(CH3), O, C(O), NH, S or a bond; R6-R9 are each independently hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkoxy, halogen, optionally substituted amino; — is an optional double bond; R18 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, COOR2O, C(=V)R21 (wherein V is as defined earlier), OR2O, SR20 or N(R22)2 {wherein R20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; R21 is R20, N(R2o)2 (wherein R20 is the same as defined above); and R22 is R20, COOR20, C(=V)R21, or S(O)qR23 (wherein V, R20 and R21 are the same as defined above and R23 is R20 except hydrogen and q is an integer 1 or 2)} ; R]9 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, COOR20, C(=V)R21, C(=V)(NR20)2, SO2R23, C(=V)NR'SO2-R23, C(=V)NRV'R'" {wherein V, R20, R21 R' and R23 are the same as defined earlier; R" and R" together with nitrogen to which they are attached form a ring which contain additional one or more heteroatom(s) selected from O, S or N and the ring so formed is further substituted with SO2R23 (wherein R23 is the same as defined earlier), alkyl, aryl, heteroaryl}; X is CH, N or N(-O); Z is O, S, NH, N-Me or a bond; Y is COOR28 (wherein R28 is hydrogen or substituted or unsubstituted alkyl) or CONR1R22 (wherein R and R22 are the same as defined above); and A1, A2 or A3 is substituted or unsubstituted C1-4 alkylene.
2. The compound of claim 1, wherein the compound is:
Figure imgf000100_0001
Formula π Formula HI pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof, wherein: Het, A1-A3, Z, Y, R18 and R19 are the same as defined in claim 1.
3. A compound selected from:
Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-[(4-methoxyphenoxy)carbonyl] glycinate; Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-[(2- methoxyphenoxy) carbonyljglycinate; Ethyl N- {4-[2-(4-ethylphenyl)ethoxy]benzyl} -N-[(4-fluorophenoxy) carbonyljglycinate; Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N- {[3-(trifluoromethyl)phenoxy] carbonyl} glycinate; Ethyl N-[(4-chlorophenoxy)methyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycinate; Ethyl N-(4-{2-[l,3-benzoxazol-2-yl (methyl) amino]ethoxy}benzyl)-N-[(4-methoxyphenoxy) carbonyljglycinate; Ethyl N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-methoxy-phenoxy) carbonyljglycinate; Ethyl N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(benzyloxy)carbonyl] glycinate; Ethyl N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy) carbonyljglycinate; Ethyl N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino] ethoxy}benzyl)-N-{[3-(trifluoromethyl) phenoxyjcarbonyl} glycinate; Ethyl N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methyl phenoxy) carbonyljglycinate; Ethyl N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-benzoyl glycinate; Ethyl N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(3-methoxybenzoyl) glycinate; Ethyl N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(4-methoxybenzoyl) glycinate; Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-[(4-methoxyphenoxy) carbonyl] glycinate; Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-[(2-methoxyphenoxy)carbonyl] glycinate; Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N-[(4-fluorophenoxy)carbonyl] glycinate; Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N- {[3-(trifluoromethyl)phenoxy] carbonyljglycinate; Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-[(4-methylphenoxy)carbonyl] glycinate; Ethyl N-[(benzyloxy)carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycinate; Ethyl N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy} -4-methoxybenzyl)-N-[(4- methoxyphenoxy) carbonyljglycinate; Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl} -N-[(4-methoxy phenoxy)carbonyl] glycinate; Ethyl N-benzoyl-N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}glycinate; Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N-(2-fluorobenzoyl)glycinate; Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N-(4-fluorobenzoyl)glycinate; Ethyl N-benzoyl-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy} benzyl)glycinate; Ethyl N-(2-fluorobenzoyl)-N-(4-{2-[methyl (pyridin-2-yl)amino]ethoxy} benzyl)glycinate; Ethyl N-(4-fluorobenzoyl)-N-(4-{2-[methyl (pyridin-2-yl)amino]ethoxy} benzyl)glycinate; Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N-(phenoxycarbonyl) glycinate; Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N-[(4-methylphenoxy) carbonyljglycinate; Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N-[(3-methyl- phenoxy)carbonyl] glycinate; Ethyl N-[(benzyloxy)carbonyl]-N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycinate; Ethyl N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl) glycinate; Ethyl N-[(4-methylphenoxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy} benzyl) glycinate; Ethyl N-[(3-methylphenoxy) carbonyl]-N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy} benzyl) glycinate; Ethyl N-[(benzyloxy)carbonyl]-N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl) glycinate; Ethyl N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl)ethoxy]benzyl} -N-(phenoxy carbonyl)glycinate; Ethyl N-[(2-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl) ethoxyjbenzyl} glycinate; Ethyl N-[(4-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4- yl) ethoxyjbenzyl} glycinate; Ethyl N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl}-N- (phenoxycarbonyl)glycinate; Ethyl N-[(2-methoxyphenoxy)carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy] benzyl} glycinate; Ethyl N-[(4-methoxyphenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy] benzyl} glycinate; Ethyl N-[(2-chlorophenoxy)carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycinate; Ethyl N-[(4-chlorophenoxy)carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)- yl)ethoxy]benzyl} glycinate; Ethyl N-[(3-chlorophenoxy)carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycinate; Ethyl N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl} -N-[(4- methylphenoxy)carbonyl]glycinate; Ethyl N-[(4-fluorophenoxy) carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl) ethoxy] benzyl} glycinate; Ethyl N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl}-N-{[3-(trifluoromethyl) phenoxy] carbonyl} glycinate; Ethyl N-(isobutoxycarbonyl)-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl} glycinate; Ethyl N-[(benzyloxy)carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl} glycinate; Ethyl N-[(3-methoxy- phenoxy)carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl) ethoxyjbenzyl} glycinate; Ethyl N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl)ethoxy]benzyl} -N- { [3- (trifluoromethyl)phenoxy] carbonyl} glycinate; Ethyl N-[(4-fluorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl) ethoxyjbenzyl} glycinate; Ethyl N-[(2-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl) ethoxy] benzyl} glycinate; Ethyl N-[(benzyloxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzoxazin-4- yl)ethoxy]benzyl} glycinate; Ethyl N-[(3-methylphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl) ethoxyjbenzyl} glycinate; 101 Ethyl N-(isobutoxycarbonyl)-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl)ethoxy]
102 benzyl} glycinate;
103 Ethyl N-[(4-chlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl)
104 ethoxyjbenzyl} glycinate;
105 Ethyl N-[(4-methylphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl)
106 ethoxyjbenzyl} glycinate;
107 Ethyl N-[(3-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-
108 yl)ethoxy] benzyl} glycinate;
109 Ethyl N-[(2,5-dichlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-
110 yl) ethoxyjbenzyl} glycinate;
111 Ethyl N-[(4-methoxyphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-
112 yl)ethoxy] benzyl} glycinate;
113 Ethyl N-(4-{2-[l,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(2-fluorobenzoyl)
114 glycinate;
115 Ethyl N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy} benzyl)-N-[(4-
116 methoxyphenoxy) carbonyljglycinate;
117 Ethyl N-(4-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-
118 chlorophenoxy)carbonyl]glycinate;
119 Ethyl N-(4-{2-[l,3-benzothiazol-2-yl(methyl)amino] ethoxy}benzyl)-N-[(3-
120 chlorophenoxy)carbonyl] glycinate;
121 Ethyl N-(4-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methylphenoxy)
122 carbonyljglycinate;
123 Ethyl N-[(4-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-yl)
124 ethoxyjbenzyl} glycinate;
125 Ethyl N-[(2-chlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-
126 yl) ethoxyjbenzyl} glycinate;
127 Ethyl N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-yl)ethoxy]benzyl} -N-(phenoxy-
128 carbonyl) glycinate;
129 Ethyl N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2-chlorophenoxy)
130 carbonyljglycinate;
131 Ethyl N-[(2,5-dichlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-
132 4-yl)ethoxy]benzyl} glycinate;
133 Ethyl N-(4- {2-[ 1 ,3-benzothiazol-2-yl (methyl)amino]ethoxy} benzyl)-N-(isobutoxycarbonyl)
134 glycinate; 135 Ethyl N-(isobutoxycarbonyl)-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1, 4-benzothiazin-4-
136 yl)ethoxy]benzyl} glycinate;
137 Ethyl N-[(4-methylphenoxy) carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4-
138 yl)ethoxy]benzyl} glycinate;
139 Ethyl N-[(3-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-
140 yl)ethoxy]benzyl} glycinate;
141 Ethyl N-[(3-methylphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1, 4-benzothiazin-4-
142 yl)ethoxy] benzyl} glycinate;
143 Ethyl N-[(2-methoxyphenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzothiazin-4-
144 yl)ethoxy]benzyl} glycinate;
145 Ethyl N-[(4-fluorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1, 4-benzothiazin-4-
146 yl)ethoxy]benzyl} glycinate;
147 Ethyl N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-yl)ethoxy]benzyl} -N- { [3-
148 (trifluoromethyl)phenoxy] carbonyl} glycinate;
149 Ethyl N-(4-{2-[l, 3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2-
150 methoxyphenoxy)carbonyl]glycinate;
151 Ethyl N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-[(4-fluorophenoxy)
152 carbonyljglycinate;
153 Ethyl N-(4-{2-[l,3-benzothiazol-2-yl (methyl)amino]ethoxy}benzyl)-N-{[3-(trifluoromethyl)
154 phenoxy] carbonyl} glycinate;
155 Ethyl N-(4- {2-[ 1 ,3-benzothiazol-2-yl (methyl)amino]ethoxy}benzyl)-N-[(2,5-
156 dichlorophenoxy)carbonyl]glycinate;
157 Ethyl N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino] ethoxy} -4-methoxybenzyl)-N-[(4-
158 methoxyphenoxy) carbonyl]-D-alaninate;
159 Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl} -N- {[3-
160 (trifluoromethyl)phenoxy] carbonyl} glycinate;
161 Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl}-N-[(4-methylphenoxy)
162 carbonyl] glycinate;
163 Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl} -N-[(3-methylphenoxy)
164 carbonyl] glycinate;
165 Ethyl N-[(3-chlorophenoxy) carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxy
166 benzyl} glycinate;
167 Ethyl N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy} -4-methoxybenzyl)-N-[(4-
168 methylphenoxy) carbonyl]glycinate; 169 Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-[(4-methoxyphenoxy)carbonyl]-L-
170 alaninate;
171 Ethyl N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methyl phenoxy)carbonyl]-L-
172 alaninate;
173 Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N-(phenoxy carbonyl)-L-alaninate;
174 Ethyl N-(4- {2-[methyl(pyridin-2-yl)amino] ethoxy}benzyl)-N-(phenoxycarbonyl)-L-
175 alaninate;
176 Ethyl N-[(2-methoxyphenoxy) carbonyl]-N-(4- {2-[methyl (pyridin-2-yl)amino]ethoxy}
177 benzyl)-L-alaninate;
178 N-[(4-methylphenoxy) carbonyl]-N-(4-{2-[methyl(pyridin-2-yl) amino]ethoxy}benzyl)-L-
179 alanine;
180 Ethyl N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methoxyphenoxy)
181 carbonyl] glycinate;
182 Ethyl N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2-methoxyphenoxy)
183 carbonyljglycinate;
184 Ethyl N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino] ethoxy}benzyl)-N-[(4-fluorophenoxy)
185 carbonyljglycinate;
186 Ethyl N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(isobutoxycarbonyl)
187 glycinate;
188 Ethyl N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-chlorophenoxy)
189 carbonyljglycinate;
190 Ethyl N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl)
191 glycinate;
192 Ethyl N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(benzyloxy) carbonyl]
193 glycinate;
194 Ethyl N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy} benzyl)-N-[(3-chlorophenoxy)
195 carbonyljglycinate;
196 Ethyl N-(3- {2-[ 1 ,3-benzothiazol-2-yl (methyl)amino] ethoxy}benzyl)-N-[(4-
197 methoxyphenoxy) carbonyljglycinate;
198 Ethyl N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(2-methoxyphenoxy)
199 carbonyl] glycinate;
200 Ethyl N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy)
201 carbonyljglycinate;
202 Ethyl N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino] ethoxy}benzyl)-N-(isobutoxycarbonyl)
203 glycinate; 204 Ethyl N-(3- {2-[ 1 ,3-benzothiazol-2-yl (methyl)amino]ethoxy}benzyl)-N-[(4-chlorophenoxy)
205 carbonyljglycinate;
206 Ethyl N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl)
207 glycinate;
208 Ethyl N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(benzyloxy)
209 carbonyl] glycinate;
210 Ethyl N-(3 - {2-[ 1 ,3 -benzothiazol-2-yl(methyl)amino]ethoxy } benzyl)-N- [(3 -chlorophenoxy)
211 carbonyljglycinate;
212 Ethyl N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino] ethoxy}benzyl)-N-[(4-methylphenoxy)
213 carbonyljglycinate;
214 Ethyl N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N- {[3-(trifluoromethyl)
215 phenoxyjcarbonyl} glycinate;
216 Ethyl N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methylphenoxy)
217 carbonyljglycinate;
218 Ethyl N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- {[3-(trifluoromethyl)
219 phenoxyjcarbonyl} glycinate;
220 Ethyl N- {3-[2-(5-ethylpyridin-2-yl) ethoxyjbenzyl} -N-(phenoxycarbonyl)glycinate;
221 Ethyl N-(3-{2-[l,3-benzoxazol-2-yl (methyl) amino]ethoxy}benzyl)-N-[(3-methylphenoxy)
222 carbonyljglycinate;
223 Ethyl N-[(4-methoxyphenoxy)carbonyl]-N- {3-[2-(2-methyl-4-oxoquinazolin-3(4H)-
224 yl)ethoxy]benzyl} glycinate;
225 Ethyl N- {3-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl}-N-[(4-methylphenoxy)
226 carbonyljglycinate;
227 Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-[(3-methylphenoxy)carbonyl]glycinate;
228 Ethyl N-[(3-chlorophenoxy)carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycinate;
229 Ethyl N-[(2-chlorophenoxy)carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} glycinate;
230 Ethyl N- {3-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N-(isobutoxycarbonyl)glycinate;
231 Ethyl N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy } benzyl)-N- { [3-(trifluoromethyl)phenoxy]
232 carbonyl} glycinate;
233 Ethyl N-(2-fluorobenzoyl)-N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)glycinate;
234 Ethyl N- {4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl} -N-(2-methoxybenzoyl)glycinate;
235 N- {4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N- [(4-methoxyphenoxy)carbonyl] glycine;
236 N-{4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N-[(2-methoxyphenoxy)carbonyl]glycine; 237 N-{4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl}-N-[(4-fluorophenoxy)carbonyl]glycine;
238 N- {4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N- {[3-(trifluoromethyl)phenoxy]carbonyl]
239 glycine;
240 N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methoxyphenoxy)
241 carbonyljglycine;
242 N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-methoxyphenoxy)
243 carbonyljglycine;
244 N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(benzyloxy)carbonyl]
245 glycine;
246 N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-fluorophenoxy)
247 carbonyljglycine;
248 N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino] ethoxy }benzyl)-N- { [3-(trifluoromethyl)
249 phenoxyjcarbonyl} glycine;
250 N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino] ethoxy}benzyl)-N-[(4-methylphenoxy)
251 carbonyljglycine;
252 N-(4- {2-[ 1 ,3-benzoxazol-2-yl (methyl)amino]ethoxy}benzyl)-N-(4-methoxybenzoyl) glycine;
253 N-(4- {2-[ 1 ,3-benzoxazol-2-yl (methyl)amino]ethoxy}benzyl)-N-(3-methoxybenzoyl) glycine;
254 N-(4- {2-[ 1 ,3-benzoxazol-2-yl (methyl)amino]ethoxy}benzyl)-N-(4-methoxybenzoyl) glycine;
255 N-{3-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-[(4-methoxyphenoxy)carbonyl]glycine;
256 N-{3-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-[(2-methoxyphenoxy)carbonyl]glycine;
257 N-{3-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-[(4-fluorophenoxy)carbonyl]glycine;
258 N-{3-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl}-N-{[3-(trifluoromethyl)phenoxy]carbonyl}
259 glycine;
260 N-{3-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-[(4-methylphenoxy)carbonyl] glycine;
261 N-[(benzyloxy)carbonyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}glycine;
262 N-(3-{2-[l,3-benzothiazol-2-yl(methyl)amino] ethoxy}-4-methoxybenzyl)-N-[(4-
263 methoxyphenoxy) carbonyljglycine;
264 N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxybenzyl} -N-[(4-
265 methoxyphenoxy)carbonyl]glycine;
266 N-benzoyl-N- {4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} glycine;
267 N-{4-[2-(5-ethylpyridin-2-yl) ethoxy] benzyl} -N-(2-fluorobenzoyl)glycine;
268 N-{4-[2-(5-ethylpyridin-2-yl) ethoxy] benzyl} -N-(4-fluorobenzoyl)glycine; 269 N-benzoyl-N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy} benzyl) glycine;
270 N-(2-fluorobenzoyl)-N-(4- {2-[methyl(pyridin-2-yl)amino] ethoxy}benzyl)glycine;
271 N-{4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} -N-(2-methoxy benzoyl)glycine;
272 N-{4-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-(phenoxycarbonyl)glycine;
273 N-{4-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-[(4-methyl phenoxy)carbonyl]glycine;
274 N-{4-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-[(3-methyl phenoxy)carbonyl]glycine;
275 N-[(benzyloxy)carbonyl]-N- {4-[2-(5-ethylpyridin-2-yl)ethoxy] benzyl} glycine;
276 N-(4-{2-[methyl(pyridin-2-yl)amino]ethoxy} benzyl)-N-(phenoxycarbonyl) glycine;
277 N-[(4-methylphenoxy)carbonyl]-N-(4-{2-[methyl (pyridin-2-yl)amino]ethoxy} benzyl)
278 glycine;
279 N-[(3-methylphenoxy)carbonyl]-N-(4- {2-[methyl(pyridin-2-yl)amino] ethoxy}benzyl)
280 glycine;
281 N-[(benzyloxy)carbonyl]-N-(4- {2-[methyl(pyridin-2-yl)amino] ethoxy}benzyl)glycine;
282 N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethoxy] benzyl}-N-
283 (phenoxycarbonyl)glycine;
284 N-[(2-methoxyphenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-
285 yl)ethoxy]benzyl}glycine;
286 N-[(4-methoxyphenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl)
287 ethoxyjbenzyl} glycine;
288 N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl }-N-(phenoxycarbonyl) glycine;
289 N-[(2-methoxyphenoxy) carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]
290 benzyl} glycine;
291 N-[(4-methoxyphenoxy) carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]
292 benzyl} glycine;
293 N-[(2-chlorophenoxy) carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]
294 benzyl} glycine;
295 N-[(4-chlorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-
296 yl)ethoxy]benzyl} glycine;
297 N-[(3-chlorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)
298 ethoxyjbenzyl} glycine;
299 N- {4- [2-(2-methyl-4-oxoquinazolin-3 (4H)-yl)ethoxy] benzyl } -N- [(4-methylphenoxy)
300 carbonyljglycine; 301 N-[(4-fluorophenoxy)carbonyl]-N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl}
302 glycine;
303 N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl}-N-{[3-(trifluoromethyl)
304 phenoxyjcarbonyl} glycine;
305 N-(isobutoxycarbonyl)-N-{4-[2-(2-methyl-4-oxoquinazolin-3 (4H)-yl)ethoxy]benzyl}glycine;
306 N-[(benzyloxy)carbonyl]-N- {4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl}
307 glycine;
308 N-{4-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy] benzyl}-N-[(3-
309 methylphenoxy)carbonyl]glycine;
310 N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethoxy] benzyl}-N-{[3-
311 (trifluoromethyl)phenoxy]carbonyl} glycine;
312 N-[(3-fluorophenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzoxazin-4-yl)ethoxy]
313 benzyl} glycine;
314 N-[(2-chlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzoxazin-4-
315 yl)ethoxy] benzyl} glycine;
316 N-[(benzyloxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl)ethoxy]
317 benzyl} glycine;
318 N-[(3-methylphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-
319 yl)ethoxy] benzyl} glycine;
320 N-(isobutoxycarbonyl)-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl)ethoxy]
321 benzyl} glycine;
322 N-[(4-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-yl)ethoxy]
323 benzyl} glycine;
324 N-[(4-methylphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzoxazin-4-
325 yl)ethoxy] benzyl} glycine;
326 N-[(3-chlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzoxazin-4-
327 yl)ethoxy] benzyl} glycine;
328 N-[(2,5-dichlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzoxazin-4-yl)
329 ethoxyjbenzyl} glycine;
330 N-[(4-methoxyphenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-
331 yl)ethoxy]benzyl}glycine;
332 N-(4- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino] ethoxy}benzyl)-N-(2-fluorobenzoyl)glycine;
333 N-(4-{2-[l,3-benzothiazol-2-yl(methyl) amino] ethoxy}benzyl)-N-[(4-methoxyphenoxy)
334 carbonyljglycine; 335 N-(4- {2-[ 1 ,3-benzothiazol-2-yl (methyl) amino]ethoxy}benzyl)-N-[(4-chlorohenoxy)
336 carbonyljglycine;
337 N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy} benzyl)-N-[(3-chlorohenoxy)
338 carbonyljglycine;
339 N-(4-{2-[l,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-[(4-
340 methylhenoxy)carbonyl] glycine;
341 N-[(4-chlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzothiazin-4-yl)
342 ethoxyjbenzyl} glycine;
343 N-[(2-chlorophenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-yl)
344 ethoxyjbenzyl} glycine;
345 N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4-yl)ethoxy] benzyl} -N-(phenoxycarbonyl)
346 glycine;
347 N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino] ethoxy}benzyl)-N-[(2-chlorophenoxy)
348 carbonyljglycine;
349 N-[(2,5-dichlorophenoxy)carbonyl] -N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzothiazin-4-
350 yl)ethoxy] benzyl} glycine;
351 N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-(isobutoxycarbonyl)
352 glycine;
353 N-(isobutoxycarbonyl)-N- {4- [2-(3-oxo-2,3 -dihydro-4H- 1 ,4-benzothiazin-4-yl)ethoxy]
354 benzyl} glycine;
355 N-[(4-methylphenoxy)carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H- 1 ,4-benzothiazin-4-yl)
356 ethoxyjbenzyl} glycine;
357 N-[(3-chlorophenoxy) carbonyl]-N- {4-[2-(3-oxo-2,3-dihydro-4H-l ,4-benzothiazin-4-yl)
358 ethoxyjbenzyl} glycine;
359 N-[(3-methylphenoxy) carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4-yl)
360 ethoxyjbenzyl} glycine;
361 N-[(2-methoxyphenoxy)carbonyl]-N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4-yl)
362 ethoxyjbenzyl} glycine;
363 N-[(4-fluorophenoxy)carbonyl] -N- {4- [2-(3 -oxo-2,3 -dihydro-4H- 1 ,4-benzothiazin-4-yl)
364 ethoxyjbenzyl} glycine;
365 N-{4-[2-(3-oxo-2,3-dihydro-4H-l,4-benzothiazin-4-yl)ethoxy]benzyl}-N-{[3-
366 (trifluoromethyl)phenoxyj carbonyl} glycine;
367 N-(4- {2- [ 1 ,3-benzothiazol-2-yl(methyl)amino] ethoxy } benzyl)-N- [(2-methoxyphenoxy)
368 carbonyljglycine; 369 N-(4-{2-[l,3-benzothiazol-2-yl(methyl)amino]ethoxy} benzyl)-N-[(4-fluorophenoxy)
370 carbonyljglycine;
371 N-(4-{2-[l,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-{[3-(trifluoromethyl)
372 phenoxyjcarbonyl} glycine;
373 N-(4- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-[(2,5-
374 dichlorophenoxy)carbonyl] glycine;
375 N-(3-{2-[l,3-benzothiazol-2-yl(methyl) amino]ethoxy}-4-methoxybenzyl)-N-[(4-
376 methoxyphenoxy) carbonyl]-L-alanine;
377 N- {3-[2-(5-ethylpyridin-2-yl) ethoxy]-4-methoxybenzyl} -N- {[3-(trifluoromethyl) phenoxy]
378 carbonyl} glycine;
379 N-{3-[2-(5-ethylpyridin-2-yl) ethoxy]-4-methoxybenzyl}-N-[(4-methylphenoxy) carbonyl]
380 glycine;
381 N-{3-[2-(5-ethylpyridin-2-yl) ethoxy]-4-methoxybenzyl}-N-[(3-methylphenoxy) carbonyl]
382 glycine;
383 N-[(3-chlorophenoxy) carbonyl]-N- {3-[2-(5-ethylpyridin-2-yl)ethoxy]-4-methoxy benzyl}
384 glycine;
385 N-(3-{2-[l,3-benzothiazol-2-yl (methyl)amino]ethoxy}-4-methoxy benzyl)-N-[(4-
386 methylphenoxy)methyl] glycine;
387 N-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(4-methoxyphenoxy)carbonyl]-L-alanine;
388 N-{4-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-[(4-methyl phenoxy)carbonyl]-L-alanine;
389 N-{4-[2-(5-ethylpyridin-2-yl) ethoxy]benzyl}-N-(phenoxy carbonyl)-L-alanine;
390 N-(phenoxycarbonyl)-N-[4-(2-pyridin-2-ylethoxy)benzyl]-L-alanine;
391 N-[(2-methoxy- phenoxy)carbonyl]-N-(4-{2-[methyl (pyridin-2-yl)amino]ethoxy} benzyl)-L-
392 alanine;
393 N-[(4-methylphenoxy)carbonyl]-N-(4-{2-[methyl(pyridin-2-yl) amino] ethoxy}benzyl)-L-
394 alanine;
395 N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methoxy-
396 phenoxy)carbonyl]glycine;
397 N-(3-{2-[l,3-benzoxazol-2-yl(methyl)amino] ethoxy} benzyl)-N-[(2-methoxyphenoxy)
398 carbonyl]glycine;
399 N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino] ethoxy}benzyl)-N-[(4-fluorophenoxy)
400 carbonyl]glycine;
401 N-(3-{2-[l,3-benzoxazol-2-yl (methyl)amino]ethoxy}benzyl)-N-(isobutoxycarbonyl) glycine; 402 N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-chlorophenoxy)
403 carbonyljglycine;
404 N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl) glycine;
405 N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(benzyloxy)carbonyl]
406 glycine;
407 N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-chlorophenoxy)
408 carbonyljglycine;
409 N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methoxyphenoxy)
410 carbonyljglycine;
411 N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy} benzyl)-N-[(2-methoxyphenoxy)
412 carbonyljglycine;
413 N-(3-{2-[l,3-benzothiazol-2-yl(methyl) aminojethoxy} benzyl)-N-[(4-fluorophenoxy)
414 carbonyljglycine;
415 N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl) amino]ethoxy}benzyl)-N-(isobutoxycarbonyl)
416 glycine;
417 N-(3- {2-[ 1 ,3-benzothiazol-2-yl (methyl)amino]ethoxy}benzyl)-N-[(4-chlorophenoxy)
418 carbonyljglycine;
419 N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-(phenoxycarbonyl) glycine;
420 N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(benzyloxy)carbonyl]
421 glycine;
422 N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-chlorophenoxy)
423 carbonyl] glycine;
424 N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(4-methyl
425 phenoxy)carbonyl]glycine;
426 N-(3- {2-[ 1 ,3-benzothiazol-2-yl(methyl)amino]ethoxy}benzyl)-N- {[3-(trifluoromethyl)
427 phenoxyjcarbonyl} glycine;
428 N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl) amino]ethoxy}benzyl)-N-[(4-methylphenoxy)
429 carbonyljglycine;
430 N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N- {[3-(trifluoromethyl)
431 phenoxyjcarbonyl} glycine;
432 N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(phenoxycarbonyl)glycine;
433 N-(3- {2-[ 1 ,3-benzoxazol-2-yl(methyl)amino]ethoxy}benzyl)-N-[(3-methylphenoxy)
434 carbonyljglycine; 435 N-[(4-methoxyphenoxy)carbonyl]-N-{3-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]
436 benzyl} glycine;
437 N-{3-[2-(2-methyl-4-oxoquinazolin-3(4H)-yl)ethoxy]benzyl}-N-[(4-methylphenoxy)
438 carbonyljglycine;
439 N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-[(3-methylphenoxy)carbonyl]glycine;
440 N-[(3-chlorophenoxy)carbonyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}glycine;
441 N-[(2-chlorophenoxy)carbonyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}glycine;
442 N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-N-(isobutoxycarbonyl)glycine;
443 N-[(4-chlorophenoxy)carbonyl]-N-{3-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}glycine;
444 N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl)-N- {[3-(trifluoromethyl)phenoxy]
445 carbonyl} glycine;
446 N-[(4-fluorophenoxy)carbonyl]-N-(4- {2-[methyl(pyridin-2-yl)amino]ethoxy}benzyl) glycine;
447 Ν- [(4-methylphenoxy)carbonyl] -Ν- {4- [2-( 1 -oxido-3 -oxo-2,3 -dihydro-4Η- 1 ,4-benzothiazin-
448 4-yl)ethoxy]benzyl} glycine;
449 Ν-[(3-methylphenoxy)carbonyl]-Ν- {4-[2-(5-methyl-2-phenyl- 1 ,3-oxazol-4-
450 yl)ethoxy]benzyl}glycine;
451 N-[(4-methylphenoxy)carbonyl]-N- {4-[2-(5-methyl-2-phenyl- 1 ,3-oxazol-4-
452 yl)ethoxy]benzyl}glycine;
453 N-[(4-fluorophenoxy)carbonyl]-N- {4-[2-(5-methyl-2-phenyl- 1 ,3-oxazol-4-
454 yl)ethoxy]benzyl}glycine;
455 N-[(4-methoxyphenyl)sulfonyl]-N- {4-[2-(5-methyl-2-phenyl-l ,3-oxazol-4-
456 yl)ethoxy]benzyl}glycine;
457 N-[(2-methoxyphenoxy)carbonyl]-N-(4- {2-[methyl(pyridin-2-
458 yl)amino]ethoxy}benzyl)glycine;
459 N-[(4-methoxyphenoxy)carbonyl]-N-(4-methoxy-3- {2-[4-
460 (trifluoromethoxy)phenoxy]ethoxy}benzyl)glycine;
461 N-{3-[2-(4-?er?-butylphenoxy)ethoxy]-4-methoxybenzyl}-N-[(4-
462 methoxyphenoxy)carbonyl]glycine;
463 Ν-(4-methoxybenzoyl)-Ν-{4-[2-(5-methyl-2-phenyl-l,3-oxazol-4-yl)ethoxy]benzyl}glycine;
464 or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs,
465 prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof.
4. Pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of claim 1 together with one or more pharmaceutically acceptable carriers, excipients or diluents.
5. Pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds of claim 3 together with one or more pharmaceutically acceptable carriers, excipients or diluents.
6. A method of treating a mammal suffering from a disease or condition mediated through α, β or γ isoforms comprising administering to a mammal in need thereof a therapeutically effective amount of one or more compounds of claim 1.
7. A method of treating a mammal suffering from diabetes or associated diabetes complications comprising administering to a mammal in need thereof a therapeutically effective amount of one or more compounds of claim 1.
8. A method of treating mammal suffering from the diseases or conditions selected from the group comprising of Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis, polycystic ovarian syndrome, psoriasis, obesity, eating disorders, for improving cognitive functions in dementia and as aldose reductase inhibitors, comprising administering to the a mammal in need thereof a therapeutically effective amount of one or more compounds of claim 1.
9. A method of treating mammal suffering from the diseases or conditions selected from the group comprising of Type II diabetes, dyslipidaemia, hypertension, coronary heart disease, cardiovascular disease, atherosclerosis, diabetes nephropathy, glomerulonephritis, glomerularsclerosis, nephrotic syndrome, hypertensive nephrosclerosis, polycystic ovarian syndrome, psoriasis, obesity, eating disorders, for improving cognitive functions in dementia and as aldose reductase inhibitors, comprising administering to the a mammal in need thereof a therapeutically effective amount of one or more compounds of claim 3.
10. A method for preparing compounds of Formula VII,
Figure imgf000115_0001
(Formula I wherein X=CH, A2=CH2, A3=CHR, Y=COOH) pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof comprising the steps of: (b) reacting a compound of Formula IV
Figure imgf000116_0001
Formula IV with a compound of Formula Het-A]-OH or HeI-A1-L1 (wherein L1 is a leaving group selected from Cl, Br, I, acetate, 4-methylbenzenesulfonate, 4- bromobenzenesulfonate, 4-nitrobenzenesulfonate, methanesulfonate or trifluoromethanesulfonate) to form a compound of Formula V,
Figure imgf000116_0002
(b) treating the compound of Formula V with a compound of Formula H2NCHR5COOR28 HCI to form a compound of Formula VI, and
Figure imgf000116_0003
(c) treating the compound of Formula VI with a compound of Formula R19-Cl or R^-N=C=W to form a compound of Formula VII, wherein Het is selected from:
Figure imgf000117_0001
wherein: X1-X1 ! are each independently CH, C, CH2, N, NH, O, S, S(=O) or S(O)2; X12 and X13 are each independently CR' or N, wherein R' is hydrogen or alkyl; X14 is (CH2)χ (wherein x =0-2), NR', O, S, S(=O) or S(O)2, wherein R' is the same as defined above; X15 is CH or N; X16 and V are each independently O, NR', or S, wherein R' is the same as defined earlier; D and E are substituted or unsubstituted alkyl, aryl or a bond; R1-R5 and R1O-Rn are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino; A is N(CH3), O, C(O), NH, S or a bond; R6-R9 are each independently hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkoxy, halogen, optionally substituted amino; — is an optional double bond; R18 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, COOR2O, C(=V)R21 (wherein V is as defined earlier), OR2O, SR2O or N(R22)2 {wherein R2o is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; R21 is R2o, N(R2o)2 (wherein R2o is the same as defined above); and R22 is R20, COOR20, C(=V)R21, or S(O)qR23 (wherein V, R20 and R21 are the same as defined above and R23 is R20 except hydrogen and q is an integer 1 or 2)} ; R]9 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, COOR20, C(=V)R21, C(=V)(NR20)2, SO2R23, C(=V)NRSO2-R23, C(=V)NR'R" {wherein V, R20 and R21 are the same as defined earlier; R and R" together with nitrogen to which they are attached form a ring which contain additional one or more heteroatom(s) selected from O, S or N and the ring so formed is further substituted with SO2R23 (wherein R23 is the same as defined earlier), alkyl, aryl, heteroaryl}; R28 is substituted or unsubstituted alkyl or aryl; Z is O, S, NH, N-Me or a bond; and A1 is substituted or unsubstituted C1-4 alkylene.
11. A method for preparing compounds of Formula VIII,
Figure imgf000118_0001
pharmaceutically acceptable salts, pharmaceutically acceptable solvates, polymorphs, prodrugs, stereoisomers, tautomeric forms, N-oxides or metabolites thereof comprising: hydrolyzing a compound of Formula VII
Figure imgf000118_0002
to form a compound of Formula VIII, wherein A1-A3, Z, R, R18, and R^ are the same as defined in Claim 1, the method Het is selected from:
Figure imgf000119_0001
wherein: X1-X11 are each independently CH, C, CH2, N, NH, O, S, S(=O) or S(O)2; X12 and X13 are each independently CR' or N, wherein R' is hydrogen or alkyl; X14 is (CH2)χ (wherein x =0-2), NR', O, S, S(=O) or S(O)2, wherein R' is the same as defined above; X15 is CH or N; X16 and V are each independently O, NR', or S, wherein R' is the same as defined earlier; D and E are substituted or unsubstituted alkyl, aryl or a bond; R1-R5 and R1O-Rn are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, aryloxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, hydroxy, alkoxy, halogen, or optionally substituted amino; A is N(CH3), O, C(O), NH, S or a bond; R6-R9 are each independently hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, alkoxy, halogen, optionally substituted amino; — is an optional double bond; R18 is hydrogen, halogen, nitro, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, COOR2O, C(=V)R21 (wherein V is as defined earlier), OR2O, SR2O or N(R22)2 {wherein R2o is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl; R21 is R2o, N(R2o)2 (wherein R2o is the same as defined above); and R22 is R20, COOR20, C(=V)R21, or S(O)qR23 (wherein V, R20 and R21 are the same as defined above and R23 is R20 except hydrogen and q is an integer 1 or 2)} ; R]9 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, COOR20, C(=V)R21, C(=V)(NR20)2, SO2R23, C(=V)NRSO2-R23, C(=V)NR'R" {wherein V, R20 and R21 are the same as defined earlier; R and R" together with nitrogen to which they are attached form a ring which contain additional one or more heteroatom(s) selected from O, S or N and the ring so formed is further substituted with SO2R23 (wherein R23 is the same as defined earlier), alkyl, aryl, heteroaryl}; Z is O, S, NH, N-Me or a bond; and A1 is substituted or unsubstituted C1-4 alkylene.
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014527027A (en) * 2011-05-31 2014-10-09 レセプトス インコーポレイテッド Novel GLP-1 receptor stabilizer and modulator
US9598430B2 (en) 2013-06-11 2017-03-21 Celgene International Ii Sàrl GLP-1 receptor modulators
US9795613B2 (en) 2014-12-10 2017-10-24 Celgene International Ii Sàrl GLP-1 receptor modulators
US10214519B2 (en) 2016-09-23 2019-02-26 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10227350B2 (en) 2016-09-23 2019-03-12 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10479770B2 (en) 2016-09-23 2019-11-19 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021602A1 (en) * 1999-09-22 2001-03-29 Bristol-Myers Squibb Company Oxa- and thiazole derivatives useful as antidiabetic and antiobesity agents
US6414002B1 (en) * 1999-09-22 2002-07-02 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
WO2004004655A2 (en) * 2002-07-09 2004-01-15 Bristol-Myers Squibb Company Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method
WO2004048338A1 (en) * 2002-11-26 2004-06-10 Shenzhen Chipscreen Biosciences Ltd. Noncyclic 1,3-dicarbonyl compounds as dual ppar agonists with potent antihyperglycemic and antihyperlipidemic activity
WO2005049589A2 (en) * 2003-10-14 2005-06-02 Cadila Healthcare Limited Heterocyclic compounds for the treatment of hyperlipidemia, diabetes, obesity and similar diseases

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001021602A1 (en) * 1999-09-22 2001-03-29 Bristol-Myers Squibb Company Oxa- and thiazole derivatives useful as antidiabetic and antiobesity agents
US6414002B1 (en) * 1999-09-22 2002-07-02 Bristol-Myers Squibb Company Substituted acid derivatives useful as antidiabetic and antiobesity agents and method
WO2004004655A2 (en) * 2002-07-09 2004-01-15 Bristol-Myers Squibb Company Substituted heterocyclic derivatives useful as antidiabetic and antiobesity agents and method
WO2004048338A1 (en) * 2002-11-26 2004-06-10 Shenzhen Chipscreen Biosciences Ltd. Noncyclic 1,3-dicarbonyl compounds as dual ppar agonists with potent antihyperglycemic and antihyperlipidemic activity
WO2005049589A2 (en) * 2003-10-14 2005-06-02 Cadila Healthcare Limited Heterocyclic compounds for the treatment of hyperlipidemia, diabetes, obesity and similar diseases

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014527027A (en) * 2011-05-31 2014-10-09 レセプトス インコーポレイテッド Novel GLP-1 receptor stabilizer and modulator
US9278910B2 (en) 2011-05-31 2016-03-08 Receptos, Inc. GLP-1 receptor stabilizers and modulators
US9700543B2 (en) 2011-05-31 2017-07-11 Celgene International Ii Sàrl GLP-1 receptor stabilizers and modulators
US9598430B2 (en) 2013-06-11 2017-03-21 Celgene International Ii Sàrl GLP-1 receptor modulators
US10259823B2 (en) 2013-06-11 2019-04-16 Celgene International Ii Sàrl GLP-1 receptor modulators
US9795613B2 (en) 2014-12-10 2017-10-24 Celgene International Ii Sàrl GLP-1 receptor modulators
US10034886B2 (en) 2014-12-10 2018-07-31 Celgene International Ii Sàrl GLP-1 receptor modulators
US10214519B2 (en) 2016-09-23 2019-02-26 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10227350B2 (en) 2016-09-23 2019-03-12 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors
US10479770B2 (en) 2016-09-23 2019-11-19 Gilead Sciences, Inc. Phosphatidylinositol 3-kinase inhibitors

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