WO2011095997A1 - Benzamide compounds as glucokinase activators and their pharmaceutical application - Google Patents

Benzamide compounds as glucokinase activators and their pharmaceutical application Download PDF

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WO2011095997A1
WO2011095997A1 PCT/IN2011/000086 IN2011000086W WO2011095997A1 WO 2011095997 A1 WO2011095997 A1 WO 2011095997A1 IN 2011000086 W IN2011000086 W IN 2011000086W WO 2011095997 A1 WO2011095997 A1 WO 2011095997A1
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pyridin
yloxy
cyclopropanesulfonyl
isopropoxy
alkyl
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PCT/IN2011/000086
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French (fr)
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Anil Deshpande
Sachin Kandalkar
Keshav Naik
Bhavesh Dave
Debnath Bhuniya
Venkata Palle
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Advinus Therapeutics Private Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This disclosure relates to a series of benzamide compounds, their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof.
  • the disclosure also relates to process of preparation of the benzamide compounds.
  • the compounds of the present disclosure are identified as Glucokinase activators or modulators, which are beneficial for the prophylaxis, management, treatment, control of progression, or adjunct treatment of diseases and/or medical conditions where the activation of glucokinase would be beneficial, such as diabetes, metabolic syndrome, and/or diabetes-related complications including retinopathy, nephropathy, neuropathy, ischemic heart disease, arteriosclerosis, ⁇ -cell dysfunction, and as therapeutic and/or prophylactic agents for obesity.
  • Diabetes mellitus is a metabolic disorder characterized by recurrent or persistent hyperglycemia (high blood glucose) and other signs, as distinct from a single disease or condition.
  • Glucose level abnormalities can result in serious long-term complications, which include beta-cell dysfunction, glucotoxicity, cardiovascular disease, chronic renal failure, retinal damage, nerve damage (of several kinds), microvascular damage, macrovascular damage, adipocyte inflammation, vascular inflamation and obesity.
  • Glucokinase also known as hexokinase IV or D, is one of four glucose- phosphorylating enzymes called hexokinases that catalyze the first step of glycolysis, the conversion of glucose to glucose 6-phosphate (G6P), in vertebrate tissues.
  • GK functions in a dual role, with distinct functions in the pancreas and liver; (a) as a molecular glucose sensor in the insulin-producing pancreatic ⁇ -cells, and (b) as the high-capacity enzymatic step initiating the storage of glucose in the form of glycogen in the liver and uptake of glucose during hyperglycemia.
  • GK plays a central role in glucose homeostasis, through the phosphorylation of glucose in the liver, and the modulation of insulin secretion in the pancreas (Postic, C. et al (1999) J. Biol. Chem. 274: 305-315). GK also functions as a sensor in other neuroendocrine cells of the gastrointestinal tract and in various brain cells including specific cells in the hypothalamus (Jetton, T. A. et al (1994) J. Biol. Chem. 269: 3641 -3654).
  • the physiological concentration of glucose in human plasma is approximately 5.5 mM under fasting conditions, and increases to about 12 mM in the fed state. This concentration is dependent on and maintained by the activity of GK, which senses glucose and controls metabolic flux in key cell types.
  • the glucose concentration, at which GK activity is at half of its maximal velocity or V m a Xj is defined as its S0.5.
  • the S0.5 of GK for glucose lies in the middle of the physiological glucose concentration range at approximately 8 mM, allowing this enzyme to act as a molecular glucose sensor crucial for glucose homeostasis.
  • the limited tissue distribution and unique kinetic properties of GK allow it to play a critical role in pancreatic ⁇ -cell insulin secretion and hepatic glucose utilization.
  • GK differs from the other members of the mammalian hexokinase family in its unique sigmoidal kinetics with respect to glucose, a high S0.5 that lies in the physiological glucose concentration range (the other three mammalian hexokinases have S0.5 values less than 0.5 mM), the lack of product inhibition by G6P, and its tissue distribution in cell types that are thought to be responsive to changing plasma glucose levels.
  • GK mutations have a profound influence on glucose homeostasis.
  • About 2000 GK mutations that have been identified in humans result in impaired glucose-mediated insulin secretion and maturity-onset diabetes of the young type 2 (MODY-2).
  • MODY-2 impaired glucose-mediated insulin secretion and maturity-onset diabetes of the young type 2
  • Some of these mutations result in decreased accumulation of hepatic glycogen, while others decrease GK activity by reducing the stability of the enzyme or by decreasing its V max .
  • Mutations that result in activation of GK are implicated in the onset of persistent hyperinsulinemic hypoglycemia of infancy (PHI-ll).
  • Single point mutations e.g.
  • GK activity can be regulated through allosteric modulation.
  • GKAs small-molecule glucokinase activators
  • WO 2007/031739, WO 2006/125958 discloses phenyl substituted heterocyclic compounds that are glucokinase activators or modulators.
  • WO 2007/007041, WO 2008/154563, US 2009/0018Q56, WO 2009/041475 and WO 2009/046802 describe benzamide derivatives as glucokinase activators.
  • the present disclosure provides a novel class of benzamide compounds characterized as glucokinase activators or modulators, and their potential use as medicament for the prophylactic or therapeutic treatment of hyperglycemia, diabetes, obesity, dyslipidemia, metabolic syndrome and like.
  • the present disclosure relates to a series of benzamide compounds described by formula (1), their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof;
  • ring-B is a 4-12 membered saturated, unsaturated, or partially unsaturated mono or bicyclic ring containing 1- 4 hetero atoms independently selected from N, O, or S with at least one nitrogen in the ring;
  • X is selected from O or a bond;
  • ring-C is selected from an unsubstituted or a substituted cycloalkyl, an unsubstituted or a substituted heterocyclyl, an unsubstituted or a substituted heteroaryl;
  • R 1 is selected from an unsubstituted or a substituted alkyl, an unsubstituted or a substituted alkenyl, an unsubstituted or a substituted alkynyl, an unsubstituted or a substituted cycloalkyl, an unsubstituted or a substituted cycloalkylalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted arylalkyl, an unsubstituted or a substituted heterocyclyl, an unsubstituted or a substituted heterocyclylalkyl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted heteroarylalkyl;
  • R' and R° are independently selected from the group consisting of hydrogen, fluorine, OR 5 , alkyl, and perfluoroalkyl, or
  • R 3 and R 4 ring-B can be further optionally substituted with one or more substituents independently selected from halo, straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulphonyl, oxo, nitro, cyano, -COOR 5 , -C(0)NR 5 R 6 , -OR 5 , -SR 5 or -NR 5 R 6 ;
  • alkyl refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1 , 2, 3, 4, 5 or 6 carbon atoms.
  • alkylene refers to a diradical of a branched or unbranched saturated hydrocarbon chain, having 1 , 2, 3, 4, 5, 6, 7, 8, 9,10, 1 1,12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms.
  • This term is exemplified by groups such as methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), the propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -) and the like.
  • substituted alkyl refers to: 1) an alkyl group or alkylene group as defined above, having 1 , 2, 3, 4 or 5 substituents, preferably 1 , 2 or 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, heteroarylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, carboxyalkyl, -SO3H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino,
  • substituents may optionally be further substituted by 1, 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or -S(0) p R c , where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2; or 2) an alkyl group or alkylene group as defined above that is interrupted by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms independently selected from oxygen, sulfur and NR d , where R d is selected from hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl, carbonylalkyl, carboxyester, carboxyamide or sulfonyl.
  • substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or - S(0) p R c , in which R c is alkyl, aryl, or heteroaryl and p is 0, 1 , or 2;
  • alkynyl refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 2, 3, 4, 5 or 6 sites of acetylene (triple bond) unsaturation, preferably 1 triple bond.
  • alkynylene refers to a diradical of a branched or unbranched unsaturated hydrocarbon grSup preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 3, 4, 5 or 6 sites of acetylene (triple bond) unsaturation, preferably 1 triple bond.
  • cycloalkyl refers to unless otherwise mentioned, carbocyclic groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings which may be saturated or partially unsaturated.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, l,3,3-trimethylbicyclo[2.2.1]hept-2-yl, (2,3,3- trimethylbicyclo[2.2.1]hept-2-yl), or carbocyclic groups to which is fused an aryl group, for example indane, and the like.
  • substituted cycloalkyl refers to cycloalkyl groups having 1, 2, 3, 4 or 5 substituents, and preferably 1 , 2, or 3 substituents, selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -C(0)R and -S(0) p R b , where R is hydrogen, hydroxyl, alkoxy, alkyl and cyclocalkyl, heterocyclyloxywhere R b is alkyl, aryl
  • substituents may optionally be further substituted by 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, and - S(0) p R c where R c is hydrogen, alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • Haloalkyl refers to a straight chain or branched chain haloalkyl group with 1 to 6 carbon atoms.
  • the alkyl group may be partly or totally halogenated.
  • Representative examples of haloalkyl groups include but are not limited to fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, 2- fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl and the like.
  • alkoxy refers to the group R"'-0-, where R'" is optionally substituted alkyl or optionally substituted cycloalkyl, or optionally substituted alkenyl or optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein.
  • acyloxy refers to the groups -OC(0)-alkyl, -OC(0)-cycloalkyl, -OC(0)-aryl, - OC(0)-heteroaryl, and -OC(0)-heterocyclyl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF 3 , amino, substituted amino, cyano, or - S(0) p R c , where R c is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
  • Di alkylamino refers to an amino group, to which two same or different straight chain or branched chain alkyl groups with 1 to 6 carbon atoms are bound.
  • Representative examples of di alkylamino include but are not limited to dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino and the like.
  • Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds may be hydrated, solvated or N-oxides. Certain compounds may exist in multiple crystalline or amorphous forms. Also contemplated within the scope of the invention are congeners, analogs, hydrolysis products, metabolites and precursor or prodrugs of the compound. In general, unless otherwise indicated, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.
  • ring-B is selected from imidazole, oxazole, pyridine, pyrazole, pyrazine, pyrimidine, thiazole, thiazolone, thiazolopyridine, thiazolopyrimidine, benzothiazole, benzopyrimidine, thiadiazole, thiazolopyrimidine, thiazolopyridine, quinoline, isoquinoline, tetrahydrobenzothiazole, tetrahydrothiazolopyridine, tetrahydrothiazolopyrimidine, tetrahydroquinoline or tetrahydroisoquinoline;
  • R 5 and R 6 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S,
  • Another embodiment of the present invention further provides compound of formula I , or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, wherein
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, fluorine, OR 5 , alkyl and perfluoroalkyl;
  • Another embodiment provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for preventing diabetes, particularly type II diabetes, in a human demonstrating pre-diabetic hyperglycemia or impaired glucose tolerance.
  • Further embodiment of the invention provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for combined treatment or prevention of diabetes and obesity. In yet another embodiment it provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treating or preventing obesity.
  • Another embodiment of the present invention provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treatment or prevention of dyslipidemia.
  • the present invention provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treating hyperglycemia, IGT, Syndrome X, type 2 diabetes, type 1 diabetes, dyslipidemia, hyperlipidemia hypertension, for the treatment or prophylaxis of obesity, for lowering of food intake, for appetite regulation, or for regulating feeding behaviour.
  • it provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for enhancing the secretion of enteroincretins, like GLP-1 and GIP, thereby managing diseases or disorders associated with modulation of secretions of enteroincretins, like hyperglycemia, insulin resistance, impaired glucose tolerance, obesity, gastric emptying, gastroparesis, satiety, leptin resistance, dyslipidemia, wound healing, diabetic complications, such as nephropathy, retinopathy, neuropathy and cataracts.
  • enteroincretins like GLP-1 and GIP
  • diseases or disorders associated with modulation of secretions of enteroincretins like hyperglycemia, insulin resistance, impaired glucose tolerance, obesity, gastric emptying, gastroparesis, satiety, leptin resistance, dyslipidemia, wound healing, diabetic complications, such as nephropathy, retinopathy, neuropathy and cataract
  • An embodiment of the present invention also provides use of compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, in the manufacture of a medicament for the activation of Glucokinase.
  • Further embodiment provides a method of combined treatment or prevention of diabetes, obesity and dislipidemia by administering an effective amount of a compound of formula (I) of the present invention, its polymorph, stereoisomer, prodrug, solvate or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment.
  • GKAs glucokinase activators
  • Compounds of formula I may be prepared as shown in the following reaction schemes and the description thereof, as well as relevant literature procedures that may be used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working examples. Protection and deprotection in the schemes below may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and Wuts, P.G.M., Protecting Groups in Organic Synthesis, 3 rd Edition, 1999 [Wiley]).
  • the present disclosure relates to a process for the preparation of a compound of formula (I), its stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, polymorph, or solvates.
  • Methyl 3,4-dihydroxy benzoate (VII) may be reacted with halide R'-Hal under substitution reaction condition to obtain mono O-derivatized product of formula (VIII).
  • Another O- deriyatization of VIII under substitution reaction condition using compound of formula V followed by hydrolysis of ester IX under basic condition provides acid II.
  • ALK alkylene C 3.6
  • the amide coupling reaction may be carried out in the presence of solvents such as dichloromethane, dichloroethane, DMF, dimethylacetamide, THF, acetonitrile or mixture of them may be used at a temperature ranging from -5 to 150 °C.
  • the reaction may be carried out optionally in presence of catalytic amount of DMF.
  • Condition-II When R is not H, the amide coupling may be carried out by heating ester and amine either in the absence of solvent or in presence of high boiling solvent like toluene, xylene, DMSO. Amide coupling may be carried out in presence of trialkyl aluminium (Chem. Commun., 2008, 1 100-1 102).
  • Substitution reaction may be carried out using any suitable organic or inorganic bases.
  • Organic bases may be selected from a group consisting of mono, di or trialkyl amines particularly methylamine, ethylamine, dimethylamine, diethylamine or triethylamine.
  • Inorganic bases may be selected from a group consisting of alkali and alkaline earth metal hydrides, hyroxides, carbonates and bicarbonates or mixtures thereof.
  • Solvents used for this reaction may be selected from a group consisting of lower alcohols, acetone, acetonitrile, DMSO, DMF, dimethylacetamide, THF and toluene, or mixtures thereof.
  • This reaction may be carried out using strong nonnucleophilic base such as potassium -ter/-butoxide, Lithium diisopropylamide to generate a carbanion at a-carbon of sulfone group.
  • strong nonnucleophilic base such as potassium -ter/-butoxide, Lithium diisopropylamide to generate a carbanion at a-carbon of sulfone group.
  • anionic nucleophile would lead to intramolecular substitution to form the ring-C.
  • Ester hydrolysis of carboxylic acids may be carried out using general saponification conditions employing inorganic bases such as alkali and alkaline earth metal hyroxides, carbonates and bicarbonates, for example lithium hydroxide, sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and the like; in the presence of solvents such as water, methanol, ethanol, THF and diethyl ether or mixtures thereof. These reactions may be done at 0 °C to refluxing temperature.
  • inorganic bases such as alkali and alkaline earth metal hyroxides, carbonates and bicarbonates, for example lithium hydroxide, sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and the like
  • solvents such as water, methanol, ethanol, THF and diethyl ether or mixtures thereof.
  • any reactive group present such as hydroxyl, amino, carbonyl, imino and the like, may be protected during the reaction by conventional protecting groups such as trimethylsilyl, ter-butyl methyl silyl, benzyl, acetal, ketal and the like, which are cleaved again after the reaction.
  • the compounds of formula (I) may be prepared by derivatisation of formula (I) by transformations well known to those skilled in the art, e.g functional groups as R 3 or R 4 may be transformed to different functional groups such as an ester function being converted to an acid, amide, hydroxyalkyl, keto, aldehyde as well as an ester.
  • the said conversions may be carried out using reagents and conditions well documented in the literature.
  • any of the compounds of formula (I) may be converted into a pharmaceutically acceptable salt or vice versa or converting one salt form into another pharmaceutically acceptable salt form.
  • salts of compounds of formula (I) covers salts of compounds of formula (I) prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Inorganic bases salts include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene- diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as
  • therapeutically effective amount in this disclosure, it means an amount of compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, that is sufficient for effective treatment of obesity and/or type II diabetes.
  • the therapeutically effective amount or dosage of a compound according to this disclosure can vary within wide limits. The dosage will depend on individual requirements in each particular case including the specific compound(s) being administered, the manner of administration, the severity of condition being treated, as well as the patient being treated, which is readily determinable by a person skilled in the art.
  • a daily dose in the range for example, about 0.01 mg to 100 mg per kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, about 0.01. mg to 30 mg per kg body weight will generally be used.
  • a dose in the range for example, about 0.01 mg to 30 mg per kg body weight will be used.
  • the compounds and compositions of the present disclosure may be optionally employed in combination with one or more, from current or future therapy, other antidiabetic agents or anti-hyperglycemic agents, which include, for example, (a) insulin secretagogues such as sulfonylureas (e.g. Amaryl, glyburide, glimepiride, glipyride, glipizide, etc.); (b) Insulinotropic sulfonyl urea receptor ligands such as meglitinides (e.g. nateglinide, rapaglinide); (c) biguanides (e.g. metformin etc.); (d) glucagon antagonists (e.g.
  • glucosidase inhibitors e.g. acarbose, miglitol, etc.
  • glucose sensitive insulinotropic agents e.g. GLP-1 , GLP-1 mimetics e.g Exendin-4; GLP-1, GPR-1 19, GPR-40, GPR120 and like other receptor modulators chosen from small molecule or from peptides
  • insulin sensitizers e.g. rosiglitazone, pioglitazone, balaglitazone etc.
  • Dipeptidyl peptidase-IV inhibitors e.g.
  • dyslipidemic agents which include, for example: (a) fibrates (e.g. gemfibrozil, fenofibrate); (b) Niacin; (c) Statins (e.g. rosuvatatin, atorvastatin, simvastatin); (d) cholesterol absorption inhibitors (e.g. Ezetimibe); (e) bile acid sequestrants (e.g. cholestyramine) and the like.
  • fibrates e.g. gemfibrozil, fenofibrate
  • Niacin e.g. rosuvatatin, atorvastatin, simvastatin
  • Statins e.g. rosuvatatin, atorvastatin, simvastatin
  • cholesterol absorption inhibitors e.g. Ezetimibe
  • bile acid sequestrants e.g. cholestyramine
  • antihypertensive agents such as: (a) diuretics (e.g hydrochlorothiazides, mannitol, indapamide, furosemide); (b) angiotensin converting enzyme (ACE) inhibitors (e.g. captopril, enalapril); (c) Angiotensin-II receptor type-I blockers (ARB) (e.g. losartan, irbesartan); (d) rennin inhibitors (e.g aliskerin); (e) ⁇ -adrenergic receptor blockers (e.g.
  • diuretics e.g hydrochlorothiazides, mannitol, indapamide, furosemide
  • ACE angiotensin converting enzyme
  • ARB Angiotensin-II receptor type-I blockers
  • rennin inhibitors e.g aliskerin
  • ⁇ -adrenergic receptor blockers e.g.
  • the disclosure also relates to pharmaceutical composition
  • pharmaceutical composition comprising, as an active ingredient, at least one compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, and solvates thereof, wherein the pharmaceutically acceptable therapeutically active agent is selected from anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents or anti-dyslipidemic agents.
  • compositions containing the active ingredient of compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or prodrugs thereof maybe in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs; sterile injectable aqueous or oleaginous suspension; suppositories; topical use, for example creams, ointments, jellies, solutions or suspension etc including mouth washes and gargles.
  • These compositions can be manufactured by any method known in the art with the active ingredient combined with non-toxic pharmaceutically acceptable excipients.
  • HBTU 0-(benzotriazol-l-yl)-tetramethyluronium hexafluorophosphate
  • HATU 0-(7-azabenzotriazol-l-yl)-tetramethyluronium hexafluorophosphate
  • PTSA jcora-toluene sulfonic acid
  • DIAD diisopropyl azodicarboxylate
  • diastereomeric or enantiomeric products When diastereomeric or enantiomeric products are obtained as mixtures, they can be separated by conventional methods for example, chromatographic separation or fractional crystallization or through diasteriomeric salt formation. When intended, a desired enantiomer or diasteriomer can also be obtained by following appropriate enantioselective or diastereoselective reactions.
  • reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 X 150mL); this solution was washed with water followed by brine solution, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to provide a crude product which was purified by column chromatography (silica gel 100-200 mesh, 20% ethylacetate in hexanes as eluent) to provide the Product (4.2 g).
  • StepII 3-(6-CycIopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoic acid methyl ester :
  • StepIII 3-(6-Cyclopropanesulfonyl-pyridin-3-yIoxy)-5-isopropoxy-benzoic acid : To a stirred solution of 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoic acid methyl ester (2.48 g, 6.34 mmol) in tetrahydrofuran, methanol & water (3: 1 : 1, 50 mL) was added NaOH (0.76 g, 19.02 mmol) at room temperature and stirred for 8 h. After completion of reaction, organic solvent was removed under reduced pressure.
  • Step-V - Synthesis of 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2-methoxy-l- methyl-ethoxy)-benzoic acid
  • Step-I 3-Benzyloxy-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester:
  • Step-II - 3-Benzyloxy-5-isobutyl-benzoic acid methyl ester :
  • Step IV 3-(6-CycIopropanesuIfonyl-pyridin-3-yloxy)-5-isobutyl-benzoic acid methyl ester :
  • Step V 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isobutyl-benzoic acid
  • the aqueous layer was neutralized to pH ⁇ 7 using IN HC1 and was extracted with ethyl acetate (3 X 20 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate; solvent was evaporated under reduced pressure to obtain the desired product (0.35 g).
  • Step I 4-(5-Nitro-pyridin-2-yloxy)-benzoic acid methyl ester
  • Step I Synthesis of (2-tert-Butoxycarbonylamino-thiazol-4-yl)-acetic acid ethyl ester: A mixture of (2-Amino-thiazol-4-yl)-acetic acid ethyl ester (5g, 26.85 mmol) and da-tert- butoxydicarbonate (8.2g, 37.59 mmol) was heated at 80 °C in toluene for 24 hrs. Toluene was removed under vacuo and the residue was partitioned between water (100 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 ml x 2). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo to get the oily product (7.5
  • Step II Synthesis of ⁇ 2-[tert-ButoxycarbonyI-(4-methoxy-benzyl)-amino]-thiazol-4-yI ⁇ - acetic acid ethyl ester :
  • the reaction was done by the same way as mentioned in the step III.
  • the crude product was purified by column chromatography (Silica gel 60 -120 mesh, and 2-4% ethyl acetate in hexanes as eluent) to get the pure solid compound (58.51%). .
  • Step VI Synthesis of 2-(2-Amino-5-chloro-thiazol-4-yl)-2-methyl-propionic acid ethyl ester:
  • Step I 2- ⁇ 2-[tert-Butoxycarbonyl-(4-methoxy-benzyl)-amino]-5-fluoro-thiazoI-4-yl ⁇ -2- methyl-propionic acid ethyl
  • Step II 2-(2-Amino-5-fluoro-thiazol-4-yI)-2-methyl-propionic acid ethyl ester
  • reaction mixture was diluted with DCM (5 mL) & kept in an ice bath at °C followed by slow addition of 2-amino-5-fluoro-thiazole.HCL (74 mg, 0.48 mmol) in DMF (5 mL) & triethyl amine (0.138 ml, 1 mmol) in DCM (2 mL). After the addition was over the reaction mixture was continued to stirr for 4 h. at room temperature. The reaction mixture was diluted with DCM and neutralized to pH ⁇ 7 using IN aqueous HC1. The organic layer was separated; washed with wa ' ter, followed by brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the crude compound which was purified by preparative TLC or column chromatography to provide the final compound Al (60 mg).
  • the glucokinase (GK) assay is a coupled enzymatic assay.
  • GK catalyzes the first step of glycolysis, the conversion of glucose to glucose-6-phosphate (G6P) in the presence of ATP.
  • G6P in turn is converted by glucose-6-phosphate dehydrogenase (G6PD) to 6- phosphogluconate, a process that requires NAD, resulting in NADH formation. Since the GK-catalyzed step is the rate-limiting step of this coupled enzymatic process, the rate of accumulation of 6-phosphogluconate and NADH is directly proportional to the rate of glucose phosphorylation by GK.
  • the rate of the GK-catalyzed reaction can therefore be measured by monitoring the increase in NADH absorbance at 340 nm.
  • the assay is carried out according to the protocol outlined in Hariharan et al (1997), Diabetes 46: 1 1 -16. Briefly, the test compounds are incubated in a reaction mix containing 25 mM HEPES (pH 7.2), 10 mM MgCl 2 , 100 mM KC1, 5 mM ATP, 2 mM DTT, 0.5 mM NAD, 1 U/ml Leuconostoc mesenteroides G6PD, 0.3 U/ml of purified human recombinant GK, and different concentrations of glucose. Enzymatic activity is calculated from the initial reaction velocity, measured from the change in NADH absorbance as a function of time.
  • a compound is considered to be a giucokinase activator if it, in its testable range of concentrations, yields a higher rate of glucose phosphorylation than in its absence at a particular glucose concentration, for example at 5 mM glucose.

Abstract

Benzamide compounds of formula (I), their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof useful as Glucokinase activators or modulators are disclosed. The disclosure further relates to process of preparation of the benzamide compounds.

Description

BENZAMIDE COMPOUNDS AS GLUCOKINASE ACTIVATORS AND THEIR PHARMACEUTICAL
APPLICATION
Field of the invention
This disclosure relates to a series of benzamide compounds, their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof. The disclosure also relates to process of preparation of the benzamide compounds. The compounds of the present disclosure are identified as Glucokinase activators or modulators, which are beneficial for the prophylaxis, management, treatment, control of progression, or adjunct treatment of diseases and/or medical conditions where the activation of glucokinase would be beneficial, such as diabetes, metabolic syndrome, and/or diabetes-related complications including retinopathy, nephropathy, neuropathy, ischemic heart disease, arteriosclerosis, β-cell dysfunction, and as therapeutic and/or prophylactic agents for obesity.
Background of the invention
Diabetes mellitus is a metabolic disorder characterized by recurrent or persistent hyperglycemia (high blood glucose) and other signs, as distinct from a single disease or condition. Glucose level abnormalities can result in serious long-term complications, which include beta-cell dysfunction, glucotoxicity, cardiovascular disease, chronic renal failure, retinal damage, nerve damage (of several kinds), microvascular damage, macrovascular damage, adipocyte inflammation, vascular inflamation and obesity.
Type 1 diabetes, also known as Insulin Dependent Diabetes Mellitus (IDDM), is characterized by loss of the insulin-producing β-cells of the islets of Langerhans of the pancreas leading to a deficiency of insulin. Type-2 diabetes previously known as adult-onset diabetes, maturity-onset diabetes, or Non-Insulin Dependent Diabetes Mellitus (NIDDM) - is due to a combination of increased hepatic glucose output, defective insulin secretion, and insulin resistance or reduced insulin sensitivity (defective responsiveness of tissues to insulin).
Glucokinase (GK), also known as hexokinase IV or D, is one of four glucose- phosphorylating enzymes called hexokinases that catalyze the first step of glycolysis, the conversion of glucose to glucose 6-phosphate (G6P), in vertebrate tissues. GK functions in a dual role, with distinct functions in the pancreas and liver; (a) as a molecular glucose sensor in the insulin-producing pancreatic β-cells, and (b) as the high-capacity enzymatic step initiating the storage of glucose in the form of glycogen in the liver and uptake of glucose during hyperglycemia. Therefore, GK plays a central role in glucose homeostasis, through the phosphorylation of glucose in the liver, and the modulation of insulin secretion in the pancreas (Postic, C. et al (1999) J. Biol. Chem. 274: 305-315). GK also functions as a sensor in other neuroendocrine cells of the gastrointestinal tract and in various brain cells including specific cells in the hypothalamus (Jetton, T. A. et al (1994) J. Biol. Chem. 269: 3641 -3654).
The physiological concentration of glucose in human plasma is approximately 5.5 mM under fasting conditions, and increases to about 12 mM in the fed state. This concentration is dependent on and maintained by the activity of GK, which senses glucose and controls metabolic flux in key cell types. The glucose concentration, at which GK activity is at half of its maximal velocity or VmaXj is defined as its S0.5. The S0.5 of GK for glucose lies in the middle of the physiological glucose concentration range at approximately 8 mM, allowing this enzyme to act as a molecular glucose sensor crucial for glucose homeostasis. The limited tissue distribution and unique kinetic properties of GK allow it to play a critical role in pancreatic β-cell insulin secretion and hepatic glucose utilization. GK differs from the other members of the mammalian hexokinase family in its unique sigmoidal kinetics with respect to glucose, a high S0.5 that lies in the physiological glucose concentration range (the other three mammalian hexokinases have S0.5 values less than 0.5 mM), the lack of product inhibition by G6P, and its tissue distribution in cell types that are thought to be responsive to changing plasma glucose levels.
Given the role of GK as a molecular glucose sensor, it is not surprising that GK mutations have a profound influence on glucose homeostasis. About 2000 GK mutations that have been identified in humans result in impaired glucose-mediated insulin secretion and maturity-onset diabetes of the young type 2 (MODY-2). Some of these mutations result in decreased accumulation of hepatic glycogen, while others decrease GK activity by reducing the stability of the enzyme or by decreasing its Vmax. Mutations that result in activation of GK are implicated in the onset of persistent hyperinsulinemic hypoglycemia of infancy (PHI-ll). Single point mutations (e.g. V62M, D158A, Y214A, V455M, and F456V) in regions distinct from the substrate binding site of the enzyme lead to modulation of GK activity (Glaser, B. et al (1998) N. Engl. J. Med. 338: 226-230; Gloyn, A. L. (2003) Hum. Mutat. 22: 353-362; Gloyn, A. L. et al (2003) Diabetes 52: 2433-2440). These observations highlight that GK activity can be regulated through allosteric modulation. Several patent applications and publications describe the discovery of small-molecule glucokinase activators (GKAs) that allosterically modulate or activate the activity of GK (Kamata, K. et al (2004) Structure 12: 429-438; WO 2003/055482 Al ; WO 2005/123132 A2; WO 2004/002481 A2; US 6,486, 184 B2; WO 2006/040528 Al ; Fyfe, M. C. T. (2007) Diabetologia, 50: 1277-1287; McKerrecher, D. et al Bioorg. Med. Chem. Lett. 15 (2005) 2103-2106; Efanov, A. M. et al (2005) Endocrinology 146: 3696-3701 ; Printz, R. L. and Granner, D. K. (2005) Endocrinology 146: 3693-3695; Brocklehurst, K. J. et al (2004) Diabetes, 53: 535-541 ; Grimsby, J. et al (2003) Science 301 : 370-373). WO 2007/031739, WO 2006/125958 discloses phenyl substituted heterocyclic compounds that are glucokinase activators or modulators. WO 2007/007041, WO 2008/154563, US 2009/0018Q56, WO 2009/041475 and WO 2009/046802 describe benzamide derivatives as glucokinase activators.
The present disclosure provides a novel class of benzamide compounds characterized as glucokinase activators or modulators, and their potential use as medicament for the prophylactic or therapeutic treatment of hyperglycemia, diabetes, obesity, dyslipidemia, metabolic syndrome and like.
Summary of the invention
The present disclosure relates to a series of benzamide compounds described by formula (1), their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof;
Figure imgf000004_0001
wherein
ring A is a heteroaryl;
ring-B is a 4-12 membered saturated, unsaturated, or partially unsaturated mono or bicyclic ring containing 1- 4 hetero atoms independently selected from N, O, or S with at least one nitrogen in the ring; X is selected from O or a bond;
ring-C is selected from an unsubstituted or a substituted cycloalkyl, an unsubstituted or a substituted heterocyclyl, an unsubstituted or a substituted heteroaryl;
R1 is selected from an unsubstituted or a substituted alkyl, an unsubstituted or a substituted alkenyl, an unsubstituted or a substituted alkynyl, an unsubstituted or a substituted cycloalkyl, an unsubstituted or a substituted cycloalkylalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted arylalkyl, an unsubstituted or a substituted heterocyclyl, an unsubstituted or a substituted heterocyclylalkyl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted heteroarylalkyl;
R2 is selected from halogen, monohaloalkyl, dihaloalkyl, perhaloalkyl, monohaloalkoxy, dihaloalkoxy, perhaloalkoxy, cyano, nitro, alkyl, alkenyl, alkynyl, methylenedioxy, amidino, -NR5R6, -OR5, -NR5C(0)OR6, -(CR7R8)„C(0)OR5, -(CR7R8)nC(0)NR5R6, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkenyl, aryloxy, or heteroaryloxy;
R3 and R4 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, mono, di or tri substituted haloalkyl, nitrile, nitro, oxo, -NR5R6, -OR5, -S(0)pR5, -S(0)pNR5R6, -NR5S(0)pR6, - NR5C(0)R6, -OS(0)pR6, -NR5C(0)OR6, -(CR7R8)nC(0)0R5, -(CR7R8)n(C0)NR5R6, - (CR7R8)nS(0)pNR5R6, -(CR7R8)nN(R5)C(0)R5, -(CR7R8)nOR5, -C(R7R8)nNR5R6, - C(R7R8)nCO(R5) and -S(0)pC(R7R8)nC(0)OR5 ; wherein R3 and R4 are each optionally substituted with one or more substituents selected from halo, straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulfonyl, oxo, nitro, cyano, -(CR7R8)nCOOR5, -(CR7R8)nCOR5, - (CR7R8)nC(0)NR5R6 , -(CR7R8)nOR5, -SR5 or -NR5R6; or
R3 and R4 are on the same carbon atom taken together form a spiro 3- to 7-membered heterocyclyl or a spiro C3.7 cycloalkyl which is optionally substituted with one or more substituent independently selected from halo, hydroxy, Ci-4alkyl, or Ci-4alkoxy;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, or
R5 and R6 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, the said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nito, cyano, -OR5, -SR5, -NR5R6, oxo, alkylsulfonyl, -COOR5, - C(0)NR5R6, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
7 8
R' and R° are independently selected from the group consisting of hydrogen, fluorine, OR5, alkyl, and perfluoroalkyl, or
R7 and R8 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms selected from O, N or S, the said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nito, cyano, oxo, -OR5, -SR5, - NR5R6, alkylsulfonyl, -COOR5, - C(0)NR5R6, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
in addition to R3 and R4 ring-B can be further optionally substituted with one or more substituents independently selected from halo, straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulphonyl, oxo, nitro, cyano, -COOR5, -C(0)NR5R6 , -OR5, -SR5 or -NR5R6;
m = 0-3;
n = 0-4;
Ρ = 0-2;
with the proviso that when ring C contains nitrogen, the ring is not connected to sulfonyl group via the nitrogen atom.
These compounds are useful as glucokinase activators (GKAs).
Detailed description of the invention
Definitions
In the structural formulae given herein and throughout the present disclosure, the following terms have the indicated meaning, unless specifically stated otherwise. The term "optionally substituted" as used herein means that the group in question is either unsubstituted or substituted with one or more of the substituents specified. When the group in question is substituted with more than one substituent, the substituent may be same or different. The term "alkyl" refers to a monoradical branched or unbranched saturated hydrocarbon chain having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1 , 2, 3, 4, 5 or 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, t-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
The term "alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, having 1 , 2, 3, 4, 5, 6, 7, 8, 9,10, 1 1,12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, more preferably 1, 2, 3, 4, 5 or 6 carbon atoms. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2CH2-), the propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-) and the like.
The term "substituted alkyl" or "substituted alkylene" refers to: 1) an alkyl group or alkylene group as defined above, having 1 , 2, 3, 4 or 5 substituents, preferably 1 , 2 or 3 substituents, selected from the group consisting of alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, monoalkylamino, dialkylamino, arylamino, heteroarylamino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, hydroxyalkyl, keto, thiocarbonyl, carboxy, carboxyalkyl, -SO3H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, - S(0)2NRaRa, -NRaS(0) Ra and -S(0)pRb, where each Ra is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl; heterocyclyloxy where Rb is hydrogen,- alkyl, aryl, heteroaryl or heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, or -S(0)pRc, where Rc is alkyl, aryl, or heteroaryl and p is 0, 1 or 2; or 2) an alkyl group or alkylene group as defined above that is interrupted by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms independently selected from oxygen, sulfur and NRd, where Rd is selected from hydrogen, alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl, carbonylalkyl, carboxyester, carboxyamide or sulfonyl. All substituents may be optionally further substituted by alkyl, alkoxy, halogen, CF3, amino, substituted amino, cyano, or - S(0)pRc, in which Rc is alkyl, aryl, or heteroaryl and p is 0, 1 , or 2;
or 3) an alkyl or alkylene as defined above that has 1, 2, 3, 4 or 5 substituents as defined above, as well as interrupted by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 atoms as defined above. The term "alkenyl" refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1, 2, 3, 4, 5 or 6 double bond (vinyl), preferably 1 double bond. Preferred alkenyl groups include ethenyl or vinyl (-CH=CH2), 1 - propylene or allyl (-CH2CH=CH2), isopropylene (-C(CH3)=CH2), bicyclo [2.2. 1] heptene, and the like.
The term "alkenylene" refers to a diradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1, 3, 4, 5 or 6 double bond (vinyl), preferably 1 double bond.
The term "substituted alkenyl" refers to an alkenyl group as defined above having 1 , 2, 3, 4 or 5 substituents, and preferably 1 , 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, thiocarbonyl, carboxy, carboxyalkyl, S03H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0)2NRaRa, - NRaS(0)2Ra and -S(0)pRb where each Ra is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl; heterocyclyloxywhere Rb is alkyl, aryl, heteroaryl or heterocyclyl and p is 0, 1 or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 , 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(0)pRc, where Rc is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
The term "alkynyl" refers to a monoradical of an unsaturated hydrocarbon, preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 2, 3, 4, 5 or 6 sites of acetylene (triple bond) unsaturation, preferably 1 triple bond. Preferred alkynyl groups include ethynyl, (-C≡CH), propargyl (or prop-l-yn-3-yl,-CH2C≡CH), homopropargyl (or but-l-yn-4-yl, -CH2CH2C≡CH) and the like. The term "alkynylene" refers to a diradical of a branched or unbranched unsaturated hydrocarbon grSup preferably having from 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, more preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and even more preferably 2, 3, 4, 5 or 6 carbon atoms and having 1 , 3, 4, 5 or 6 sites of acetylene (triple bond) unsaturation, preferably 1 triple bond.
The term "substituted alkynyl" refers to an alkynyl group as defined above having 1, 2, 3, 4 or 5 substituents, and preferably 1, 2, or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, thiocarbonyl, carboxy, carboxyalkyl, -SO3H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0)2NRaRa, - NRaS(0)2Ra and -S(0)pRb, where each Ra is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl; heterocyclyloxy where Rb is alkyl, aryl, heteroaryl or heterocyclyl and p is 0, 1 or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(0)pRc where Rc is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
Unless otherwise constrained the alkyl, alkylene, alkenyl, alkenylene, alkynyl or alkynylene groups may optionally be substituted with 1, 2, 3 4 or 5 substituents, preferably 1, 2 or 3 substituents, selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, carboxy, carboxyalkyl, -SO3H, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0)2NRaRa, -NRaS(0)2Ra and -S(0)pRb where each Ra is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; where Rb is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl and p is 0, 1 or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 , 2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and :S(0)pRc where Rc is hydrogen, alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
The term "cycloalkyl" refers to unless otherwise mentioned, carbocyclic groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings which may be saturated or partially unsaturated. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, l,3,3-trimethylbicyclo[2.2.1]hept-2-yl, (2,3,3- trimethylbicyclo[2.2.1]hept-2-yl), or carbocyclic groups to which is fused an aryl group, for example indane, and the like.
The term "substituted cycloalkyl" refers to cycloalkyl groups having 1, 2, 3, 4 or 5 substituents, and preferably 1 , 2, or 3 substituents, selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -C(0)R and -S(0)pRb, where R is hydrogen, hydroxyl, alkoxy, alkyl and cyclocalkyl, heterocyclyloxywhere Rb is alkyl, aryl, heteroaryl or heterocyclyl and p is 0, 1 or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 , 2, or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(0)pR°, where Rc is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
Unless otherwise constrained the cycloalkyl group may optionally be substituted with 1 , 2, 3 4 or 5 substituents, preferably 1 , 2 or 3 substituents, selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, carboxy, carboxyalkyl, -SO3H, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0)2NRaRa, -NRaS(0)2Ra and - S(0)pRb where each Ra is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; where Rb is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl and p is 0, 1 or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and - S(0)pRc where Rc is hydrogen, alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
"Halo" or "Halogen", alone or in combination with any other term means halogens such as chloro (CI), fluoro (F), bromo (Br) or iodo (1).
"Haloalkyl" refers to a straight chain or branched chain haloalkyl group with 1 to 6 carbon atoms. The alkyl group may be partly or totally halogenated. Representative examples of haloalkyl groups include but are not limited to fluoromethyl, chloromethyl, bromomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, 2- fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, 3-fluoropropyl, 3-chloropropyl, 3-bromopropyl and the like.
The term "alkoxy" refers to the group R"'-0-, where R'" is optionally substituted alkyl or optionally substituted cycloalkyl, or optionally substituted alkenyl or optionally substituted alkynyl; or optionally substituted cycloalkenyl, where alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are as defined herein. Representative examples of alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, trifluoromethoxy, and the like.
The term "aminocarbonyl" refers to the group -C(0)NR'R' where each R' is independently hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or both R' groups are joined to form a heterocyclic group (e. g. morpholino). Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(0)pRc, where Rc is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
The term "acylamino" refers to the group -NR"C(0)R" where each R" is independently hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(0)pRc, where Rc is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
The term "acyloxy" refers to the groups -OC(0)-alkyl, -OC(0)-cycloalkyl, -OC(0)-aryl, - OC(0)-heteroaryl, and -OC(0)-heterocyclyl. Unless otherwise constrained by the definition, all substituents may be optionally further substituted by alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, or - S(0)pRc, where Rc is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
"Alkoxyalkyl" refers to alkyl groups as defined above wherein at least one of the hydrogen atoms of the alkyl group is replaced by an alkoxy group as defined above. Representative examples of alkoxyalkyl groups include but are not limited to methoxymethyl, methoxyethyl, ethoxymethyl and the like.
"Aryloxyalkyl" refers to the group -alkyl-O-aryl. Representative examples of aryloxyalkyl include but are not limited to phenoxymethyl, naphthyloxymethyl, phenoxyethyl, naphthyloxyethyl and the like.
"Di alkylamino" refers to an amino group, to which two same or different straight chain or branched chain alkyl groups with 1 to 6 carbon atoms are bound. Representative examples of di alkylamino include but are not limited to dimethylamino, diethylamino, methylethylamino, dipropylamino, dibutylamino and the like.
"Cycloalkylalkyl" refers to an alkyl radical as defined above which is substituted by a cycloalkyl radical as defined above. Representative examples of cycloalkylalkyl include but are not limited to cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, 1 -cyclopentylethyl, 1-cyclohexylethyl, 2-cyclopentylethyl, 2- cyclohexylethyl, cyclobutylpropyl, cyclopentylpropyl, cyclohexylbutyl and the like.
"Aminoalkyl" refers to an amino group that is attached to (Ci-6)alkylene as defined herein. Representative examples of aminoalkyl include but are not limited to aminomethyl, aminoethyl, 1 -aminopropyl, 2-aminopropyl, and the like. The amino moiety of aminoalkyl may be substituted once or twice with alkyl to provide alkylaminoalkyl and dialkylaminoalkyl respectively. Representative examples of alkylaminoalkyl include but are not limited to methylaminomethyl, methylaminoethyl, methylaminopropyl, ethylaminoethyl and the like. Representative examples of dialkylaminoalkyl include but are not limited to dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, N-methyl-N- ethylaminoethyl and the like.
The term "aryl" refers to an aromatic carbocyclic group of 6 to 20 carbon atoms having a single ring (e.g. phenyl) or multiple rings (e.g. biphenyl), or multiple condensed (fused) rings (e.g. naphthyl or anthranyl). Preferred aryls include phenyl, naphthyl and the like.
The term "arylene" refers to a diradical of an aryl group as defined above. This term is exemplified by groups such as 1,4-phenylene, 1,3-phenylene, 1 ,2-phenylene, 1,4'- biphenylene, and the like.
Unless otherwise constrained the aryl or arylene groups may optionally be substituted with 1, 2, 3 4 or 5 substituents, preferably 1 , 2 or 3 substituents, selected from the group consisting of alkyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, carboxy, carboxyalkyl, -SO3H, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, -S(0)2NRaRa, -NRaS(0)2Ra and - S(0)pRb, where each Ra is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; where Rb is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl and p is 0, 1 or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 , 2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and - S(0)pRc where Rc is hydrogen, alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
The term "arylalkyl" refers to an aryl group covalently linked to an alkylene group, where aryl and alkylene are defined herein.
"Optionally substituted arylalkyl" refers to an optionally substituted aryl group covalently linked to an optionally substituted alkylene group. Such arylalkyl groups are exemplified by benzyl, phenethyl, naphthylmethyl, and the like.
The term "aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above, and includes optionally substituted aryl groups as also defined above.
The term "arylthio" refers to the group -S-aryl, where aryl is as defined herein including optionally substituted aryl groups as also defined above.
The term "substituted amino" refers to the group -NR'R' where each R' is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, carboxyalkyl, alkoxycarbonyl, aryl, heteroaryl and heterocyclyl. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1, 2 or 3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(0)pRc, where Rc is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
The term "carboxyalkyl" refers to the groups -alkylene-C(0)OH.
The term "alkylcarboxyalkyl" refers to the groups -alkylene-C(0)ORd where Rd is alkyl, cycloalkyl, where alkyl, cycloalkyl are as defined herein, and may be optionally further substituted by alkyl, halogen, CF3, amino, substituted amino, cyano, or -S(0)pRc, in which Rc is alkyl, aryl, or heteroaryl and p is 0, 1 or 2.
The term "heteroaryl" refers to an aromatic cyclic group having 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, or 15 carbon atoms and 1 , 2, 3 or 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring. Such heteroaryl groups can have a single ring (e.g. pyridyl or furyl) or multiple condensed rings (e.g. indolizinyl, benzothiazolyl, or benzothienyl). Examples of heteroaryls include, but are not limited to, [1,2,4] oxadiazole, [1,3,4] oxadiazole, [1,2,4] thiadiazole, [1 ,3,4] thiadiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, furan, thiophene, oxazole, thiazole, triazole, triazine and the like. The term "heteroarylene" refers to a diradical of a heteroaryl group as defined above.
Unless otherwise constrained the heteroaryl or heterarylene groups can be optionally substituted with 1, 2, 3, 4 or 5 substituents, preferably 1, 2 or 3 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, thiocarbonyl, carboxy, carboxyalkyl, -SO3H, aryl, aryloxy, heteroaryl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, - S(0)2NRaR , -NRaS(0)2Ra and -S(0)pRb, where each Ra is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl heteroarylalkyl, heterocyclyl and heterocyclylalkyl; where Rb is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl, and p is 0, 1 or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1 -3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and-S(0)nRc, where Rc is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term "heteroarylalkyl" refers to a heteroaryl group covalently linked to an alkylene group, where heteroaryl and alkylene are defined herein.
"Optionally substituted heteroarylalkyl" refers to an optionally substituted heteroaryl group covalently linked to an optionally substituted alkylene group. Such heteroarylalkyl groups are exemplified by 3-pyridylmethyl, quinolin-8-ylethyl, 4-mefhoxythiazol-2-ylpropyl, and the like.
The term "heterocyclyl" refers to a saturated or partially unsaturated group having a single ring or multiple condensed rings, unless otherwise mentioned, having from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 , 2, 3 or 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring. Heterocyclic groups can have a single ring or multiple condensed rings, and include tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl, dihydropyridinyl, tetrahydroquinolinyl and the like. Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1, 2, 3, 4 or 5, and preferably 1, 2 or 3 substituents, selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, amino, aminocarbonyl, alkoxycarbonylamino, azido, cyano, halogen, hydroxy, oxo, -C(0)R where R is hydrogen, hydroxyl, alkoxy, alkyl and cyclocalkyl, thiocarbonyl, carboxy, carboxyalkyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aminocarbonylamino, heteroaryloxy, heterocyclyl, heterocyclyloxy, hydroxyamino, alkoxyamino, nitro, and -S(0)pRb, where Rb is hydrogen, alkyl, aryl, heterocyclyl or heteroaryl and p is 0, 1 or 2. Unless otherwise constrained by the definition, all substituents may optionally be further substituted by 1-3 substituents selected from alkyl, carboxy, carboxyalkyl, aminocarbonyl, hydroxy, alkoxy, halogen, CF3, amino, substituted amino, cyano, and -S(0)Rc, where Rc is alkyl, aryl, or heteroaryl and n is 0, 1 or 2.
The term "heterocyclylalkyl" refers to a heterocyclyl group covalently linked to an alkylene group, where heterocyclyl and alkylene are defined herein.
"Optionally substituted heterocyclylalkyl" refers to an optionally substituted heterocyclyl group covalently linked to an optionally substituted alkylene group.
The term "heteroaryloxy" refers to the group heteroaryl-O-.
The term "thiol" refers to the group -SH.
The term "substituted alkylthio" refers to the group -S-substituted alkyl.
The term "heteroarylthio" refers to the group -S-heteroaryl wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.
The term "sulfoxide" refers to a group -S(O).
"Substituted sulfoxide" refers to a group -S(0)R, in which R is substituted alkyl, substituted aryl, or substituted heteroaryl, as defined herein.
The term "sulfone" refers to a group -S(0)2R.
The term "substituted sulfone" refers to a group -S(0)2R, in which R is alkyl, aryl, or heteroaryl.
The compounds of the present invention may have the ability to crystallize in more than one form, a characteristic known as polymorphism, and all such polymorphic forms ("polymorphs") are encompassed within the scope of the invention. Polymorphism generally can occur as a response to changes in temperature or pressure or both, and can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics, and typically the x-ray diffraction patterns, solubility behavior, and melting point of the compound are used to distinguish polymorphs.
The compounds described herein may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), regioisomers, enantiomers or diastereomers. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated or identified compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the person skilled in the art. The compounds may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated or identified compounds.
Compounds may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, compounds may be hydrated, solvated or N-oxides. Certain compounds may exist in multiple crystalline or amorphous forms. Also contemplated within the scope of the invention are congeners, analogs, hydrolysis products, metabolites and precursor or prodrugs of the compound. In general, unless otherwise indicated, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.
"Prodrug" refers to a derivative of a drug molecule as, for example, esters, carbonates, carbamates, ureas, amides or phosphates that requires a transformation within the body to release the active drug. Prodrugs are frequently, although not necessarily, pharmacologically inactive until converted to the parent drug. Prodrugs may be obtained by bonding a promoiety (defined herein) typically via a functional group, to a drug.
"Promoiety" refers to a group bonded to a drug, typically to a functional group of the drug, via bond(s) that are cleavable under specified conditions of use. The bond(s) between the drug and promoiety may be cleaved by enzymatic or non-enzymatic means. Under the conditions of use, for example following administration to a patient, the bond(s) between the drug and promoiety may be cleaved to release the parent drug. The cleavage of the promoiety may proceed spontaneously, such as via a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a physical or environmental parameter, such as a change of temperature, pH, etc. The agent may be endogenous to the conditions of use, such as an enzyme present in the systemic circulation to which the prodrug is administered or the acidic conditions of the stomach or the agent may be supplied exogenously.
"Pharmaceutically acceptable salt" embraces salts with a pharmaceutically acceptable acid or base. Pharmaceutically acceptable acids include both inorganic acids, for example hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic, hydroiodic and nitric acid and organic acids, for example citric, fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Pharmaceutically acceptable bases include alkali metal (e.g. sodium or potassium) and alkali earth metal (e.g. calcium or magnesium) hydroxides and organic bases, for example alkyl amines, arylalkyl amines and heterocyclic amines.
Other preferred salts according to the invention are quaternary ammonium compounds wherein an equivalent of an anion (X-) is associated with the positive charge of the N atom. X- may be an anion of various mineral acids such as, for example, chloride, bromide, iodide, sulphate, nitrate, phosphate, or an anion of an organic acid such as, for example, acetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, trifluoroacetate, methanesulphonate' and p-toluenesulphonate. X- is preferably an anion selected from chloride, bromide, iodide, sulphate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate. More preferably X- is chloride, bromide, trifluoroacetate or methanesulphonate.
The present disclosure relates to compounds of formula (I), their stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof,
Figure imgf000017_0001
wherein
ring A is a heteroaryl;
ring-B is a 4-12 membered saturated, unsaturated, or partially unsaturated mono or bicyclic ring containing 1 - 4 hetero atoms independently selected from N, O, or S with at least one nitrogen in the ring;
X is selected from O or a bond;
ring-C is selected from an unsubstituted or a substituted cycloalkyl, an unsubstituted or a substituted heterocyclyl, an unsubstituted or a substituted heteroaryl;
R1 is selected from an unsubstituted or a substituted alkyl, an unsubstituted or a substituted alkenyl, an unsubstituted or a substituted alkynyl, an unsubstituted or a substituted cycloalkyl, an unsubstituted or a substituted cycloalkylalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted arylalkyl, an unsubstituted or a substituted heterocyclyl, an unsubstituted or a substituted heterocyclylalkyl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted heteroarylalkyl;
R2 is selected from halogen, monohaloalkyl, dihaloalkyl, perhaloalkyl, monohaloalkoxy, dihaloalkoxy, perhaloalkoxy, cyano, nitro, alkyl, alkenyl, alkynyl, methylenedioxy, amidino, -NR5R6, -OR5, -NR5C(0)OR6, -(CR7R8)nC(0)OR5, -(CR7R8)nC(0)NR5R6, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkenyl, aryloxy, or heteroaryloxy;
R3 and R4 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, mono, di or tri substituted haloalkyl, nitrile, nitro, oxo, -NR5R6, -OR5, -S(0)pR5, -S(0)pNR5R6, -NR5S(0)pR6, - NR5C(0)R6, -OS(0)pR6, -NR5C(0)OR6, -(CR7R8)„C(0)OR5, -(CR7R8)n(CO)NR5R6, - (CR7R8)nS(0)pNR5R6, -(CR7R8)nN(R5)C(0)R5, -(CR7R8)nOR5, -C(R7R8)nNR5R6, - C(R7R8)nCO(R5) and -S(0)pC(R7R8)nC(0)OR5 ; wherein R3 and R4 is each optionally substituted with one or more substituents selected from halo, straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulfonyl, oxo, nitro, cyano, -(CR7R8)„COOR5, -(CR7R8)nCOR5, - (CR7R8)nC(0)NR5R6 -(CR7R8)„OR5, -SR5 or -NR5R6 ; or
R3 and R4 are on the same carbon atom taken together form a spiro 3- to 7-membered heterocyclyl or a spiro C3_7cycloalkyl which is optionally substituted with one or more substituent independently selected from halo, hydroxy, Ci^alkyl, or C^alkoxy;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, or
R5 and R6 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S, the said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nito, cyano, -OR5, -SR5, - NR5R6, oxo, alkylsulfonyl, -COOR5, -C(0)NR5R6, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
R7 and R8 are independently selected from the group consisting of hydrogen, fluorine, OR5, alkyl, and perfluoroalkyl, or R7 and R8 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alky], alkenyl, alkynyl, nito, cyano, oxo, -OR5, -SR5, -NR5R6, alkylsulfonyl, - COOR5, -C(0)NR5R6, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
in addition to R3 and R4 ring-B can be further optionally substituted with one or more substituents selected from halo, straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulphonyl, oxo, nitro, cyano, -COOR5, - C(0)NR5R6 , -OR5, -SR5 or -NR5R6;
m = 0-3;
n = 0-4;
P = 0-2;
with the proviso that when ring C contains nitrogen, the ring is not connected to sulfonyl group via the nitrogen atom.
In an embodiment of the present invention it provides compound of formula I, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, wherein:
ring A is a heteroaryl having at least 1 nitrogen;
ring-B is a 4-12 membered saturated, unsaturated, or partially unsaturated mono or bicyclic ring containing 1 - 4 hetero atoms independently selected from N, O, or S with at least one nitrogen in the ring;
X is selected from O or a bond;
ring-C is selected from a cycloalkyl, a heterocyclyl or a heteroaryl;
wherein said ring C is unsubstituted or substituted with up to 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, mono, di, tri or perhaloalkyl, hydroxy, alkoxy, nitrile, oxo, amino, monoalkylamino or dialkyamino;
R1 is selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
wherein said R1 is unsubstituted or substituted with up to 4 substituents independently selected from alkyl, halogen, mono, di, tri or perhaloalkyl, nitrile, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkylcarboxy, nitro, oxo, amino, monoalkylamino or dialkyamino, -(CR7R8)nC(0)OR5, - (CR7R8)„C(0)NR5R6 or - (CR7R8)nC(0)R5;
R2 is selected from halogen, monohaloalkyl, dihaloalkyl, perhaloalkyl, monohaloalkoxy, dihaloalkoxy, perhaloalkoxy, cyano or alkyl;
R3 and R4 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, mono, di or tri substituted haloalkyl, nitrile, nitro, oxo, -NR5R6, -OR5, -S(0)pR5, -S(0)pNR5R6, -NR5S(0)pR6, - NR5C(0)R6, -OS(0)pR6, -NR5C(0)OR6, -(CR7R8)nC(0)OR5, -(CR7R8)n(CO)NR5R6, - (CR7R8)nS(0)pNR5R6, -(CR7R8)nN(R5)C(0)R5, -(CR7R8)nOR5, -C(R7R8)nNR5R6, - C(R7R8)nCO(R5) and -S(0)pC(R7R8)nC(0)OR5 ; wherein R3 and R4 is each optionally substituted with one or more substituents selected from halo, straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulfonyl, oxo, nitro, cyano, -(CR7R8)nCOOR5, -(CR7R8)nCOR5, - (CR7R8)nC(0)NR5R6 , -(CR7R8)nOR5, -SR5 or -NR5R6;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl; or
R5 and R6 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S;
R7 and R8 are independently selected from the group consisting of hydrogen, fluorine, OR5, alkyl, and perfluoroalkyl, or
R7 and R8 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S, the said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nito, cyano, oxo, -OR5, -SR5, - NR5R6, alkylsulfonyl, -COOR5, -C(0)NR5R6, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, or heteroaryl, heteroarylalkyl; in addition to R3 and R4 ring-B can be further optionally substituted with one or more substituents selected from halo, straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulphonyl, oxo, nitro, cyano, -COOR5, - C(0)NR5R6 -OR5, -SR5 or -NR5R6; m = 0-3; n = 0-4; and p = 0-2, with the proviso that when ring C contains nitrogen, the ring is not connected to sulfonyl group via the nitrogen atom.
Another embodiment of the present invention provides compound, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, wherein,
ring A is selected from oxadiazole, thiadiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoquinoline, quinoline, isothiazole, isoxazole, oxazole, thiazole, triazole or triazine;
ring-B is selected from imidazole, oxazole, pyridine, pyrazole, pyrazine, pyrimidine, thiazole, thiazolone, thiazolopyridine, thiazolopyrimidine, benzothiazole, benzopyrimidine, thiadiazole, thiazolopyrimidine, thiazolopyridine, quinoline, isoquinoline, tetrahydrobenzothiazole, tetrahydrothiazolopyridine, tetrahydrothiazolopyrimidine, tetrahydroquinoline or tetrahydroisoquinoline;
X is selected from O or a bond;
ring-C is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentanone, cyclohexanone, tetrahydrofuran, tetrahyropyran, pyrazole, imidazole, thiazole or oxazole; wherein said ring C is unsubstituted or substituted with up to 4 substituents independently selected from alkyl, halogen, mono, di, tri or perhaloalkyl, hydroxy, alkoxy, nitrile, oxo, amino, monoalkylamino or dialkyamino;
R1 is selected from alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran or tetrahyropyran;
wherein said R1 is unsubstituted or substituted with up to 4 substituents independently selected from alkyl, halogen, mono, di, tri or perhaloalkyl, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkylcarboxy, amino, monoalkylamino or dialkyamino, -(CR7R8)nC(0)OR5, - (CR7R8)nC(0)NR5R6 or -(CR7R8)nC(0)R5; R2 is selected from halogen, or alkyl;
R3 and R4 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidine, pyrrol idinealkyl, morpholine, morpholinealkyl, piperidine, piperidinealkyl, phenyl, benzyl, pyridine, pyrazole, thiazole, mono, di or tri substituted haloalkyl, nitrile, nitro, oxo, -S(0)pR5, -S(0)pNR5R6, -NR5S(0)pR6, -NR5C(0)R6, -OS(0)pR6, -NR5C(0)OR6, -(CR7R8)nC(0)OR5, -(CR7R8)n(CO)NR5R6, -(CR7R8)nS(0)pNR5R6, (CR7R8)nN(R5)C(0)R5, -(CR7R8)nOR5, -C(R7R8)nNR5R6, -C(R7R8)nCO(R5) and - S(0)pC(R7R8)nC(0)OR5 ; wherein R3 and R4 is each optionally substituted with one or more substituents selected from halo, straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulfonyl, oxo, nitro, cyano, - (CR7R8)nCOOR5, -(CR7R8)nCOR5, -(CR7R8)nC(0)NR5R6 -(CR7R8)nOR5, -SR5 or - NR5R6 ;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl or
R5 and R6 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S,
R7 and R8 are independently selected from the group consisting of hydrogen, fluorine, OR5, alkyl and perfluoroalkyl,
m = 0-3; n = 0-4; and p = 0-2, with the proviso that when ring C contains nitrogen, the ring is not connected to sulfonyl group via the nitrogen atom.
Another embodiment of the present invention further provides compound of formula I , or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, wherein
ring A is selected from pyrrole, pyrazole, pyridine, pyrazine, pyrimidine or pyridazine; ring-B is selected from imidazole, pyridine, pyrazole, pyrazine, pyrimidine, thiazole, thiazolone, thiazolopyridine, benzothiazole or thiazolopyridine;
X is selected from O or bond;
ring-C is selected from cyclopropyl, cyclobutyl or cyclopentyl;
R1 is selected from alkyl, cyclopropyl, tetrahydrofuran or tetrahyropyran;
wherein said R1 is unsubstituted or substituted with up to 4 substituents independently selected from alkyl, halogen, hydroxyl or alkoxy;
R2 is selected from halogen, or alkyl;
R3 and R4 are independently selected from the group, consisting of hydrogen, halogen, alkyl, alkenyl, cyclopropyl, pyrrolidine, pyrrol idinealkyl, morpholine, morpholinealkyl, piperidine, piperidinealkyl, phenyl, benzyl, pyridine, pyrazole, - (CR7R8)nC(0)OR5, -(CR7R8)n(CO)NR5R6, -(CR7R8)„OR5, -C(R7R8)nNR5R6 and - C(R7R8)nCO(R5); wherein R3 and R4 is each optionally substituted with one or more substituents independently selected from halo, acyl, straight chain or branched chain alkyl;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl; or R5 and R6 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S;
R7 and R8 are independently selected from the group consisting of hydrogen, fluorine, OR5, alkyl and perfluoroalkyl;
m = 0-3; n = 0-4; and p = 0-2, with the proviso that when ring C contains nitrogen, the ring is not connected to sulfonyl group via the nitrogen atom.
n embodiment of the present invention further provides compound of formula I which is: 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-(5-fluoro-thiazol-2-yl)-5-isopropoxy- benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-thiazol-2-yl-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(l -methyl-lH-pyrazol-3- yl)-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(lH-pyrazol-3-yl)- benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-thiazolo[5,4-b]pyridin-2-yl- benzamide;
3-(6-Gyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(5-morpholin-4-yl-thiazol-
2- yl)-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(5-methoxy-thiazolo[5,4- b]pyridin-2-yl)-benzamide;
3- (6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(5-pyrazol-l-yl-thiazol-2- yl)-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(l -thiazol-2-yl-lH-pyrazol- 3-yl)-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(5-methyl-4-oxo-4,5- dihydro-thiazol-2-yl)-benzamide;
N-(6-Chloro-benzothiazol-2-yl)-3-(6-cyclopropanesulfonyl-pyridin-3-yloxy)-5- isopropoxy-benzamide;
3-(6-CyclopropanesuIfonyl-pyridin-3yloxy)-5-isopropoxy-N-(6-methoxy-benzothiazol-2- yl)-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(5-isopropoxy- thiazolo[5,4-b]pyridin-2-yl)-benzamide; N-[4-(l -Acetyl-piperidin-4-yl)-thiazol-2-yl]-3-(6cyclopropanesulfonyl-pyridin-3-yloxy)- 5-isopropoxy-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-(5-ethoxy-thiazolo[5,4-b]pyridin-2-yl)-5- isopropoxy-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)- 5 -(tetrahy dro-furan -3 -y loxy) -benzam i de ;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2-methoxy-l -methyl-ethoxy)-N-(5- methoxy-hiazolo[5,4-b]pyridin-2-yl)-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2-methoxy-l-methyl-ethoxy)-N- pyrazin-2-yl-benzam ide;
2- [3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazole-4- carboxylic acid methyl ester;
3- (6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(5-vinyl-thiazol-2-yl)- benzamide;
2- [3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-(5-methoxy-thiazolo[5,4-b]pyridin-2- ylcarbamoyl)-phenoxy]-2-methyl-propionic acid tert-butyl ester;
3- (6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-(5-fluoro-thiazol-2-yl)-5-isobutyl- benzamide;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazole-4- carboxylic acid;
2- [3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazole-4- carboxylic acid amide;
3- (6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-(4-hydroxymethyl-thiazol-2-yl)-5- isopropoxy benzamide;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-(5-methoxy-thiazolo[5,4-b]pyridin-2- ylcarbamoyl)-phenoxy]-2-methyl-propionic acid;
{2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazol-4- yl}-acetic acid;
{2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]- thiazolo[5,4-b]pyridin-5-yloxy}-acetic acid;
{5-Chloro-2-[3-(6-cyclopropanesulfonyl-pyridin-3-yloxy)-5-isobutyl-benzoylamino]- thiazol-4-yl} -acetic acid;
l -{2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazol- 5-ylmethyl}-piperidine-4-carboxylic acid; 4-{2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino] thiazolo[5,4-b]pyridin-5-yloxy}-benzoic acid;
3- {2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazol-
4- yl} -propionic acid;
l -{2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazol-
5- ylmethyl}-pyrrolidine-2-carboxylic acid;
N-[4-(2-Azetidin-l-yl-2-oxo-ethyl)-5-chloro-thiazol-2-yl]-3-(6-cyclopropanesulfonyl- pyridin-3-yloxy)-5-isopropoxy-benzamide;
4- {3-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-pyrazol- 1 -ylmethyl} -benzoic acid;
1 - {2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazol-
5- yl}-piperidine-4-carboxylic acid;
{3-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-pyrazol-l- yl} -acetic acid;
{5-Chloro-2-[3-(6-cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]- thiazol-4-yl} -acetic acid;
5- Chloro-2-[3-(6-cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]- thiazole-4-carboxylic acid;
2- [3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-5-pyridin-
4- yl-thiazole-4-carboxylic acid;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]- benzothiazole-6-carboxylic acid;
{5-Chloro-2-[3-(6-yclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2-methoxy-l -methyl- ethoxy)-enzoylamino]-thiazol-4-yl} -acetic acid;
6- [3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2-methoxy-l-methyl-ethoxy)- benzoylamino]-nicotinic acid;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-(tetrahydro-furan-3-yloxy)- benzoylamino]-thiazole-4-carboxylic acid;
5- Bromo-2-[3-(6-cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]- thiazole-4.-carboxylic acid;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-4-methyl- thiazole-5-carboxylic acid;
N-(4-Carbampylmethyl-5-chloro-thiazol-2-yl)-3-(6-cyclopropanesulfonyl-pyridin-3- yloxy)-5-isopropoxy-benzamide; 2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-5-methyl- thiazole-4-carboxylic acid;
2-{5-Chloro-2-[3-(6-cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy- benzoylamino]-thiazol-4-yl}-2-methyl-propionic acid;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-4,5,6,7- tetrahydro-benzothiazol-4-yl } -acetic acid;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-4,5,6,7- tetrahydro-benzothiazole-6-carboxylic acid;
2-[3-(4-Carboxymethyl-5-chloro-thiazol-2-ylcarbamoyl)-5-(6-cyclopropanesulfonyl- pyridin-3-yloxy)-phenoxy]-2-methyl-propionic acid;
2- {2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-5- fluoro-thiazol-4-yl}-2-methyl-propionic acid;
3- (6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-[5-(l ,2-dihydroxy-ethyl)-thiazol-2-yl]-5- isopropoxy-benzamide; or
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-[4-(l,2-dihydroxy-ethyl)-thiazol-2-yl]-5- isopropoxy-benzamide.
In another embodiment of the present invention, it provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treating a disease through Glucokinase activation.
Another embodiment provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treating a disease through Glucokinase deinhibition.
Still another embodiment of the present invention provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for prophylactic or therapeutic treatment of hyperglycemia or diabetes, particularly type II diabetes.
Another embodiment provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for preventing diabetes, particularly type II diabetes, in a human demonstrating pre-diabetic hyperglycemia or impaired glucose tolerance.
Further embodiment of the invention provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for combined treatment or prevention of diabetes and obesity. In yet another embodiment it provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treating or preventing obesity.
Another embodiment of the present invention provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treatment or prevention of dyslipidemia.
Aother embodiment provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for combined treatment or prevention of diabetes, obesity and dyslipidemia.
In another embodiment of the present invention, it provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treating hyperglycemia, IGT, Syndrome X, type 2 diabetes, type 1 diabetes, dyslipidemia, hyperlipidemia hypertension, for the treatment or prophylaxis of obesity, for lowering of food intake, for appetite regulation, or for regulating feeding behaviour.
In yet another embodiment, it provides compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for enhancing the secretion of enteroincretins, like GLP-1 and GIP, thereby managing diseases or disorders associated with modulation of secretions of enteroincretins, like hyperglycemia, insulin resistance, impaired glucose tolerance, obesity, gastric emptying, gastroparesis, satiety, leptin resistance, dyslipidemia, wound healing, diabetic complications, such as nephropathy, retinopathy, neuropathy and cataracts.
An embodiment of the present invention provides a pharmaceutical composition comprising, as an active ingredient, at least one compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, and solvates thereof, together with one or more pharmaceutically acceptable carriers or excipients.
In another embodiment, it provides pharmaceutical composition comprising, as an active ingredient, at least one compound of formula (1); or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, and solvates thereof, in combination with one or more pharmaceutically acceptable therapeutically active agents.
Preferably, the pharmaceutically acceptable therapeutically active agent is selected from antidiabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents or anti-dyslipidemic agents. More preferably, the pharmaceutically acceptable therapeutically active agent is selected from insulin secretagogues like sulfonylureas selected from amaryl, glyburide, glimepiride, glipyride, glipizide; insulinotropic sulfonyl urea receptor ligands like meglitinides selected from- nateglinide, rapaglinide; biguanides like metformin, phenformin, buformin; glucagon antagonists like a peptide or non-peptide glucagon antagonist; glucosidase inhibitors like acarbose, miglitol; glucose sensitive insulinotropic agents like GLP-1, GLP-1 mimetics like exendin-4; insulin sensitizers like troglitazone, rosiglitazone, pioglitazone; dipeptidyl peptidase-IV inhibitors like sitagliptin, vildagliptin; sibutramine, orlistat, rimonabant; fibrates like gemfibrozil, fenofibrate; niacin; statins like rosuvatatin, atorvastatin, simvastatin; cholesterol absorption inhibitors like ezetimibe; bile acid sequestrants like cholestyramine; diuretics like hydrochlorothiazides, mannitol, indapamide, furosemide; angiotensin converting enzyme (ACE) inhibitors like captopril, enalapril; angiotensin-II receptor type-I blockers (ARB) like losartan, irbesartan; rennin inhibitors like aliskerin; β-adrenergic receptor blockers like atenolol, metoprolol; calcium channel blockers like amlodipine, nifedipine; aldosterone receptor antagonist like spironolactone, aldosterone synthase inhibitors like FAD286.
An embodiment of the present invention also provides use of compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, in the manufacture of a medicament for the activation of Glucokinase.
Another embodiment further provides a method of treatment of glucokinase activator mediated disease by administering a therapeutically effective amount of a compound of formula (I) of the present invention, its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof to a mammal in need of such treatment.
Further embodiment provides a method of combined treatment or prevention of diabetes, obesity and dislipidemia by administering an effective amount of a compound of formula (I) of the present invention, its polymorph, stereoisomer, prodrug, solvate or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment.
Another embodiment of the present invention provides a method of combined treatment of diabetes and obesity by administering an effective amount of a compound of formula (I) of the present invention, its polymorph, stereoisomer, prodrug, solvate or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment.
The compounds of formula I of the present invention are useful as glucokinase activators (GKAs). Compounds of formula I may be prepared as shown in the following reaction schemes and the description thereof, as well as relevant literature procedures that may be used by one skilled in the art. Exemplary reagents and procedures for these reactions appear hereinafter and in the working examples. Protection and deprotection in the schemes below may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and Wuts, P.G.M., Protecting Groups in Organic Synthesis, 3rd Edition, 1999 [Wiley]).
According to an embodiment, the present disclosure relates to a process for the preparation of a compound of formula (I), its stereoisomer, tautomer, prodrug, pharmaceutically acceptable salt, polymorph, or solvates.
General Synthesis
Scheme 1 :
Figure imgf000029_0001
Compounds of formula (II)* wherein R is hydrogen, alkyl or arylalkyl and all other symbols are defined herein above, may be reacted with compounds of formula (III) wherein all symbols are defined herein above, following amide coupling reaction conditions, optionally hydrolyzing and optionally further coupling with an amine of formula NHR5R6 to obtain compounds of formula (I), wherein all symbols are defined herein above.
Scheme 2:
Figure imgf000029_0002
Compound of formula (IV) wherein all symbols are defined herein above, may be reacted with compound of formula (V) under the condition of substitution reaction. Following this reaction conditions, optionally hydrolyzing and optionally further coupling with an amine of formula NHR5R6 to obtain compounds of formula (I), wherein all symbols are defined herein above.
Sche
Figure imgf000030_0001
Compound of formula (VI) wherein all symbols are defined herein above, may be reacted with compound of formula (Vb) under coupling reaction condition. Following this reaction conditions, optionally hydrolyzing and optionally further coupling with an amine of formula NHR5R6 to obtain compounds of formula (I), wherein all symbols are defined herein above. It will be appreciated that compounds of formula (I) may be prepared by derivatisation of other compounds of formula (I) by transformations well known to those skilled in the art. The said conversions may be carried out using reagents and conditions well documented in the literature.
Scheme 4: General route for the synthesis of compounds of formula (II), wherein X = O Substitution Reaction „ι γ Λ Jl
Figure imgf000030_0002
OH Substitution reaction
vn VIII
Figure imgf000030_0003
Methyl 3,4-dihydroxy benzoate (VII) may be reacted with halide R'-Hal under substitution reaction condition to obtain mono O-derivatized product of formula (VIII). Another O- deriyatization of VIII under substitution reaction condition using compound of formula V followed by hydrolysis of ester IX under basic condition provides acid II. Scheme: 5 General route for the synthesis of compounds of formula (II), wherein X = C.
Figure imgf000031_0001
The second phenol group of compound of formula X may be converted to aryl triflate using triflic anhydride which on coupling reaction with R2ZnX in presence of palladium catalyst (e.g. (PPh3)4Pd) can obtain compound of formula XI. Deprotection of the compound of formula XI to obtain compound of formula XII, followed by substitution reaction with V provides an ester of compound of formula XIII. The hydrolysis of an ester XIII under basic condition can provide the compound of formula II.
Scheme: 6
General route for the synthesis of compounds of formula (IV), wherein X = O
Figure imgf000031_0002
Introduction of R1 group to compound of formula X can be achieved by Mitsunobu reaction with suitable alcohol (ROM) or substitution reaction with an appropriate substrate (R'LG) to obtain compound of formula XI. The hydrolysis of an ester XI under basic condition can provide compound of formula XIV. The reaction reaction of an acid XIV with amine III, wherein all symbols are defined herein above, following an appropriate amide coupling reaction condition & subsequent deprotection can obtain desired amide of compound of formula IV. Scheme: 7
General route for the synthesis of compounds of formula (IV), wherein X = C
Figure imgf000032_0001
The hydrolysis of an ester XI under basic condition can provide compound of formula XIV. The reaction of an acid XIV with amine III, wherein all symbols are defined herein above, following an appropriate amide coupling reaction condition & subsequent deprotection can obtain desired amide of compound of formula IV.
Scheme: 8
General route for the synthesis of compounds of formula (VI), wherein X = O or C
Figure imgf000032_0002
Compound of formula XV can be obtained commercially or readily prepared by methods known in the literature or other methods used by one skilled in art. The hydrolysis of ester IV can obtain an acid of compound of formula XVI which on reaction reaction with amine III, wherein all symbols are defined herein above, following an appropriate amide coupling reaction condition can obtain compound of formula VI.
Scheme 9: Ge oalkyl.
Figure imgf000032_0003
ALK = alkylene C3.6
Compounds of formula XVII may be treated with alkyl dihalides such as l -chloro-3- bromopropane, l-chloro-3-bromopentane under substitution reaction condition to obtain compound of formula XVIII which then oxidized to obtain compound of formula XIX. Compound of formula XIX can be subjected under internal cyclization condition to obtain compound of formula V.
Scheme 10: General route for the synthesis of formula V, wherein ring C is cycloalkyl. & heterocyclyl
Figure imgf000033_0001
Compounds of formula XX may be treated with compound of formula XXI under coupling reaction conditions to obtain compound of V.
Amide Coupling Conditions: Condition-I: When R = H, the amide coupling may be carried out using any suitable amide coupling regents such as oxalyl chloride, thionyl chloride, BOP-Cl, DCC, HOBt, HOAt, HATU, EDCI, alkylchloroformate and the like in the presence of organic non-nucleophillic bases such as triethyl amine, di-isopropylethyl amine, pyridine, N-methyl pyrrolidine, Ν,Ν-dimethylaminopyridine, DBU, DABCO, N-methyl morpholine other hindered amines and pyridines. The amide coupling reaction may be carried out in the presence of solvents such as dichloromethane, dichloroethane, DMF, dimethylacetamide, THF, acetonitrile or mixture of them may be used at a temperature ranging from -5 to 150 °C. The reaction may be carried out optionally in presence of catalytic amount of DMF. Condition-II: When R is not H, the amide coupling may be carried out by heating ester and amine either in the absence of solvent or in presence of high boiling solvent like toluene, xylene, DMSO. Amide coupling may be carried out in presence of trialkyl aluminium (Chem. Commun., 2008, 1 100-1 102).
Substitution Reaction: Substitution reaction may be carried out using any suitable organic or inorganic bases. Organic bases may be selected from a group consisting of mono, di or trialkyl amines particularly methylamine, ethylamine, dimethylamine, diethylamine or triethylamine. Inorganic bases may be selected from a group consisting of alkali and alkaline earth metal hydrides, hyroxides, carbonates and bicarbonates or mixtures thereof. Solvents used for this reaction may be selected from a group consisting of lower alcohols, acetone, acetonitrile, DMSO, DMF, dimethylacetamide, THF and toluene, or mixtures thereof. The reaction may be carried out at a temperature in the range of 0 to 150 °C. Coupling Reaction : Copling reaction may be carried out using copper or palladium catalyst like Cul, CuCl, CuS04, Cu(OTf)2.C6H6, Pd(OAc)2, Pd(dba)2, Pd2(dba)3 and using appropriate ligand such as DPPF, DPEphos in presence of suitable base like sodium carbonate, potassium carbonate, cesium carbonate, TEA, DIPEA, N,N'-dimethylethylene diamine, DBU, potassium phosphate. The coupling reaction may be carried out in presence of suitable solvent like toluene, THF, Dioxane, DMF, glyme or mixture of solvent like toluene/THF at temperature in the range of 50-150 °C.
Mitsunobu Reaction: The Mitsunobu reaction between alcohol and phenol, to obtain the corresponding ether, may be carried out in THF using triphenylphosphine (TPP) and diethyl azodicarboxylate (DEAD), Di-tert-butyl azodicarboxylate (DBAD) or diisopropyl azodicarboxylate (DIAD) as reagents.
Internal Cyclization Reaction: This reaction may be carried out using strong nonnucleophilic base such as potassium -ter/-butoxide, Lithium diisopropylamide to generate a carbanion at a-carbon of sulfone group. Such anionic nucleophile would lead to intramolecular substitution to form the ring-C.
Conditions for Esterification: Ester formation, from the above mentioned carboxylic acids, may be carried out using general esterification conditions employing appropriate alcohol like methanol, ethanol and a suitable inorganic acid selected from HCl, H2S04, or thionyl chloride, or base catalysed ester formation using alkyl halide and suitable base like sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate and the like in presence of solvents such as acetone, acetonitrile, DMF, DMSO, THF and diethyl ether or mixtures thereof.
Conditions for Ester Hydrolysis: Condition I: Ester hydrolysis of carboxylic acids may be carried out using general saponification conditions employing inorganic bases such as alkali and alkaline earth metal hyroxides, carbonates and bicarbonates, for example lithium hydroxide, sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and the like; in the presence of solvents such as water, methanol, ethanol, THF and diethyl ether or mixtures thereof. These reactions may be done at 0 °C to refluxing temperature. Condition II: Estr hydrolysis of carboxylic acids particularly tetrt-b tyl esters may be carried out under acidic condition using mineral acids such as HCl, H2S04 or organic acids such as TFA or Lewis acids such as ZnBr2, CeCb-Nal in appropriate solvents such as methanol, DCM, acetonitrile. Conditions for Oxidation: Oxidation of sulfanyls to sulfonyls, may be carried out using appropriate oxidizing reagent such as H202, perbenzoic acid, mCPBA, oxone, dioxirane and the like in the presence of a solvent such as DCM, DCE, DMF, DMSO, THF and diethyl ether or mixtures thereof. Reagents like Os04, KMn04, PCC can also be used for such oxidation process.
Above mentioned conditions, for the respective functional group transformations, are only to illustrated the type of synthesis. More specific conditions for above transformations are well documented and referred in the literature (R. C. Larock in Comprehensive Organic Transformations, Wiley-VCH Publication; B. M. Trost and I. Fleming Ed. Comprehensive Organic Synthesis, Elsevier Publication)
In the reactions described in the schemes herein above, any reactive group present, such as hydroxyl, amino, carbonyl, imino and the like, may be protected during the reaction by conventional protecting groups such as trimethylsilyl, ter-butyl methyl silyl, benzyl, acetal, ketal and the like, which are cleaved again after the reaction.
It will be appreciated that the compounds of formula (I) may be prepared by derivatisation of formula (I) by transformations well known to those skilled in the art, e.g functional groups as R3 or R4 may be transformed to different functional groups such as an ester function being converted to an acid, amide, hydroxyalkyl, keto, aldehyde as well as an ester. The said conversions may be carried out using reagents and conditions well documented in the literature.
Wherever desired or necessary, in any of the above mentioned processes, any of the compounds of formula (I) may be converted into a pharmaceutically acceptable salt or vice versa or converting one salt form into another pharmaceutically acceptable salt form.
By "pharmaceutically acceptable salts" as used herein, it covers salts of compounds of formula (I) prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Inorganic bases salts include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylene- diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates. When the compound of the present disclosure is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids, such as acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are hydrochloric, maleic, phosphoric, citric, hydrobromic, sulfuric, fumaric, and tartaric acids.
By "therapeutically effective amount" in this disclosure, it means an amount of compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, that is sufficient for effective treatment of obesity and/or type II diabetes. The therapeutically effective amount or dosage of a compound according to this disclosure can vary within wide limits. The dosage will depend on individual requirements in each particular case including the specific compound(s) being administered, the manner of administration, the severity of condition being treated, as well as the patient being treated, which is readily determinable by a person skilled in the art.
In using a compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, about 0.01 mg to 100 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, about 0.01. mg to 30 mg per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, about 0.01 mg to 30 mg per kg body weight will be used.
The compounds and compositions of the present disclosure may be optionally employed in combination with one or more, from current or future therapy, other antidiabetic agents or anti-hyperglycemic agents, which include, for example, (a) insulin secretagogues such as sulfonylureas (e.g. Amaryl, glyburide, glimepiride, glipyride, glipizide, etc.); (b) Insulinotropic sulfonyl urea receptor ligands such as meglitinides (e.g. nateglinide, rapaglinide); (c) biguanides (e.g. metformin etc.); (d) glucagon antagonists (e.g. a peptide or non-peptide glucagon antagonist); (e) glucosidase inhibitors (e.g. acarbose, miglitol, etc.); (f) glucose sensitive insulinotropic agents (e.g. GLP-1 , GLP-1 mimetics e.g Exendin-4; GLP-1, GPR-1 19, GPR-40, GPR120 and like other receptor modulators chosen from small molecule or from peptides); (g) insulin sensitizers (e.g. rosiglitazone, pioglitazone, balaglitazone etc.); (h) Dipeptidyl peptidase-IV inhibitors (e.g. sitagliptin, vildagliptin, saxagliptin etc.); (i) insulin and insulin analogs; (j) SGLT-1 and SGLT-2 inhibitors (e.g. dapagliflozin, canagliflozin); (k) l l beta-HSDl inhibitors (e.g. INCB-13739, AMG 221) and the like. The said additional therapeutic agent is added in a dose range of about 0.01 mg to 100 mg per kg body weight.
The compounds and compositions of the present disclosure may also be optionally employed in combination with one or more, from current or future therapy, anti-obesity agents (e.g. sibutramine, orlistat, rimonabant etc.) and the like.
The compounds and compositions of the present disclosure may also be optionally employed in combination with one or more, from current or future therapy, dyslipidemic agents which include, for example: (a) fibrates (e.g. gemfibrozil, fenofibrate); (b) Niacin; (c) Statins (e.g. rosuvatatin, atorvastatin, simvastatin); (d) cholesterol absorption inhibitors (e.g. Ezetimibe); (e) bile acid sequestrants (e.g. cholestyramine) and the like.
The compounds and compositions of the present disclosure may also be optionally employed in combination with one or more, from current or future therapy, antihypertensive agents such as: (a) diuretics (e.g hydrochlorothiazides, mannitol, indapamide, furosemide); (b) angiotensin converting enzyme (ACE) inhibitors (e.g. captopril, enalapril); (c) Angiotensin-II receptor type-I blockers (ARB) (e.g. losartan, irbesartan); (d) rennin inhibitors (e.g aliskerin); (e) □ -adrenergic receptor blockers (e.g. atenolol, metoprolol); (f) calcium channel blockers (e.g. amlodipine, nifedipine); (g) aldosterone receptor antagonist (e.g. spironolactone); (h) aldosterone synthase inhibitors (e.g. FAD286). The said additional therapeutic agent is added in a dose range of about 0.01 mg to 100 mg per kg body weight.
The compounds and compositions of the present disclosure and the other therapeutic agents such as described above may be administered simultaneously, sequentially or separately.
The pharmaceutical compositions of the present disclosure comprise a compound of formula (I), polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic active agent in any suitable ratios.
The disclosure also relates to pharmaceutical composition comprising, as an active ingredient, at least one compound of formula (I), or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, and solvates thereof, wherein the pharmaceutically acceptable therapeutically active agent is selected from anti-diabetic agents, anti-hyperglycemic agents, anti-obesity agents, anti-hypertensive agents or anti-dyslipidemic agents.
The pharmaceutical compositions of the present disclosure comprising compounds of formula (1), polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or prodrugs thereof, may be manufactured in a manner that is known in the art, e.g. by means of conventional mixing, encapsulating, dissolving, granulating, emulsifying, entrapping, dragee making, or lyophilizing processes. These pharmaceutical preparations can be formulated with therapeutically inert, inorganic or organic carriers such as lactose, corn starch or derivatives thereof, talc, steric acid or its salts as carriers for tablets, coated tablets, dragees and hard gelatin capsules. For soft gelatin capsules suitable carriers include vegetable oils, waxes and fats. Suitable carriers for the manufacture of solutions and syrups are water, polyols, saccharose, invert sugar and glucose. Suitable carriers for injection are water, alcohols, polyols, glycerine, vegetable oils, phospholipids and surfactants. Suitable carriers for suppositories are natural or hardened oils, waxes, fats and semiliquid polyols.
The pharmaceutical preparations can also contain preserving agents, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents or antioxidants. They can also contain other therapeutically valuable substances, including additional active ingredients other than those of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or prodrugs thereof.
The pharmaceutical compositions containing the active ingredient of compound of formula (I), its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or prodrugs thereof, maybe in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs; sterile injectable aqueous or oleaginous suspension; suppositories; topical use, for example creams, ointments, jellies, solutions or suspension etc including mouth washes and gargles. These compositions can be manufactured by any method known in the art with the active ingredient combined with non-toxic pharmaceutically acceptable excipients.
While the disclosure has been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications and substitutions can be made therein without departing from the spirit and scope of the present disclosure. For example, the specific pharmacological responses observed may vary according to and depending on the particular active compound selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the results are contemplated in accordance with the objects and practices of the present disclosure.
Abbreviations
The following abbreviations are employed in the examples and elsewhere herein:
DMF: Dimethyl formamide
DMSO: Dimethyl sulfoxide
DCM: Dichloromethane
DCE: Dichloroethane
THF: Tetrahydrofuran
mCPBA: meta chloro perbenzoic acid
BOP-C1: Bis(2-oxo-3-oxazolidinyl)phosphinic chloride
DABCO: 1 ,4-Diazabicyclo[2.2.2]octane
DBU: 1 ,8-Diazabicyclo[5.4.0]undec-7-ene
DCC: Ν,Ν-Dicyclohexyl carbodiimide
EDCI: l-Ethyl-3-(3-dimetyIaminopropyl)carbodiimide
HOBT: 1 -Hydroxybenzotriazole
HOAT: 1 -Hydroxy-7-azabenzotriazole
HBTU: 0-(benzotriazol-l-yl)-tetramethyluronium hexafluorophosphate
HATU: 0-(7-azabenzotriazol-l-yl)-tetramethyluronium hexafluorophosphate PTSA: jcora-toluene sulfonic acid
TPP: triphenylphosphine
DEAD: diethyl azodicarboxylate
DIAD: diisopropyl azodicarboxylate
Examples
The disclosure is further illustrated by the following examples which in no way should be construed as being further limiting. One skilled in the art will readily appreciate that the specific methods and results described are merely illustrative. All stereoisomers of the compounds of the instant disclosure are contemplated, either in admixture or in pure or substantially pure form. The compounds of the present disclosure can have asymmetric centers at any of the carbon atoms, consequently, compounds of formula (I) can exist in enantiomeric, or diastereomeric forms, or in mixtures thereof. The processes for preparation can utilize racemates, enantiomers, or diastereomers as starting materials. When diastereomeric or enantiomeric products are obtained as mixtures, they can be separated by conventional methods for example, chromatographic separation or fractional crystallization or through diasteriomeric salt formation. When intended, a desired enantiomer or diasteriomer can also be obtained by following appropriate enantioselective or diastereoselective reactions.
Structures of the intermediates as well as the final compounds were confirmed by nuclear magnetic resonance spectra for proton (1H NMR) and LCMS.
Figure imgf000040_0001
Step I: 5-Chloro-2-(3-chloro-propyIsuIfanyl)-pyridine
A suspension of Cs2C03 (16.8 g, 51.72 mmol), and dry DMF (120 ml) was cooled to 0 °C under anhydrous condition and 5-chloro pyridine-2-thiol (5 g, 34.48 mmol) was added at one portion reaction mixtur was stirred for 10 mins. l-bromo-3-chloro propane (8.12 g, 51.72 mmol) was added drop wise at 0 °C via syringe. Reaction mixture was warmed to room temp and stirred for overnight. Reaction was monitored by TLC. On completion of reaction. 500 ml of water was added to reaction mixture and aqueous layer was extracted with ethyl acetate ( 100 ml x 3 ). Organic Layer was washed with water (350 ml), brine (250 ml), and dried over sodium sulfate. Solvent was evaporated to afford light brown colored oil as a product (7.2 g)
Ή NMR- (CDC13, 400MHz), δ 2.12-2.20 (m, 2H), 3.30 (t, J = 6.8 Hz, 2H), 3.66-3.70 (m, 2H), 7.12 (d, J = 8.5 Hz, 1H), 7.45 (dd, J = 2.4 J = 8.5 Hz, 1H), 8.38 (d, J = 2.4 Hz, 1H). MS (EI) mlz: 221.9 (M + 1).
Step II: 5-Chloro-2-(3-chloro-propane-l-sulfonyI)-pyridine
To a cool solution of 5-Chloro-2-(3-chloro-propylsulfanyl)-pyridine (7.2 g, 32.43 mmol) in 85 ml of DCM, (60%) m-chloroperbenzoic acid (18.64 g, 64.8 mmol) was added portion wise and reaction mixture was stirred for 2 hrs at 20-25 °C. Reaction was monitored by TLC. On completion of reaction reaction mixture was filtered through Buchner funnel residue was washed with DCM (30ml). Filtrate was washed with aqueous sat. sodium thiosulfate (30 ml), followed by sat. sodium bicarbonate (30ml) dried over anhydrous sodium sulfate, solvent was evaporated under reduced pressure to get a pure product (8.0 g).
Ή NMR- (CDC13, 400MHz), δ 2.28-2.34 (m, 2H), 3.59 (t, J = 7.5 Hz, 2H), 3.70 (t, J = 6.3, 2H), 7.99 (dd, J = 2.2, J = 8.3 Hz, 1H), 8.10 (d, J = 8.3 Hz, 1H), 8.73 (d, J = 2.2 Hz, 1H). MS (EI) m/z: 253.8 (M + l).
Step III: 5-Chloro-2-cyclopropanesulfonyl-pyridine
To a stirred suspension of potassium ter/-butoxide (4.24 g, 37.7 mmol) in tert-Butanol (25 ml) was added 5-Chloro-2-(3-chloro-propane-l -sulfonyl)-pyridine (8.0 g, 31.4 mmol) and stirred for 18 hours at room temperature. Reaction was monitored by TLC. On completion of reaction water (100 ml) was added to reaction mixture and extracted with Ethyl acetate (4x25 ml). Organic layer was washed with water (40 ml) followed with brine and dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to afford crude product which was purified by column chromatography (Silica gel 100-200 mesh, 22% EtOAc : hexane as eluent) to provide pure product. (4.34 g)
Ή NMR- (CDC13, 400MHz), δ 1.05-1.12 (m, 2H), 1.32-1.38 (m, 2H), 2.78 (m, 1H), 7.91 (dd, J = 2.4 J = 8.3 Hz, 1 H), 7.97 (dd, J = 0.73 J = 8.3 Hz, 1H), 8.69 (dd, J = 0.73 J = 2.4 Hz, 1H).
MS (EI) m/z: 218.0(M + l ).
Preparation 2: 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoic acid
Figure imgf000042_0001
Step I: 3-Hydroxy-5-isopropoxy benzoic acid methyl ester :
To a solution of methyl 3,5-dihydroxy benzoate (15.1 g, 90 mmol) in anhydrous DMF (200 mL) was added potassium carbonate (24.8 g, 180 mmol) followed by isopropyl bromide ( 8.44 mL, 90 mmol). The reaction mixture was then continued to stir at room temperature for 16 hours. After completion, the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (3 X 150mL); this solution was washed with water followed by brine solution, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to provide a crude product which was purified by column chromatography (silica gel 100-200 mesh, 20% ethylacetate in hexanes as eluent) to provide the Product (4.2 g).
Ή NMR- (CDC13, 400MHz), δ 1.33 (d, J = 6 Hz, 6H), 3.90 (s,3H), 4.56 (m, 1H), 5.92 (bs, 1 H), 6.60 (s, lH), 7.08-7.15 (m, 2H).
MS (EI) m/z: 210.9 (M + l).
StepII: 3-(6-CycIopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoic acid methyl ester :
To a solution of 3-hydroxy-5-isopropoxy benzoic acid methyl ester (3.1 g, 14.7 mmol) in dimethylacetamide (50 mL) was added cesium carbonate (9.0 g, 27.6 mmol) followed by 5- chloro-2-cyclopropanesulfonyl-pyridine (3 g, 13.8 mmol). The reaction mixture was then refluxed for 8 hours. After completion, the reaction mixture was cooled; solid was filtered and solvent was evaporated under reduced pressure. Residue was diluted with water (50 mL) and extracted with ethyl acetate (3 X 60 mL). The organic layer was washed with water followed by brine solution, dried over anhydrous sodium sulfate, solvent was removed under reduced pressure to provide a crude product which was purified by column chromatography (silica gel 100-200 mesh, 15% ethylacetate in hexanes as eluent ) to provide the product (4.34 g).
Ή NMR- (CDC13, 400MHz), δ 1.07-1.30 (m, 4H), 1.36 (d, J = 6 Hz, 6H), 2.79 (m,lH), 3.91 (s, 3H), 4.61 (m, 1H), 6.81 (m, 1H), 7.29 (s,lH), 7.39 (dd, J = 2.4 & 8.6 Hz 1H), 7.44 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 8.49(d, J = 2.7 Hz, 1H).
MS (El) m/z: 392.0 (M + 1 ).
StepIII: 3-(6-Cyclopropanesulfonyl-pyridin-3-yIoxy)-5-isopropoxy-benzoic acid : To a stirred solution of 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoic acid methyl ester (2.48 g, 6.34 mmol) in tetrahydrofuran, methanol & water (3: 1 : 1, 50 mL) was added NaOH (0.76 g, 19.02 mmol) at room temperature and stirred for 8 h. After completion of reaction, organic solvent was removed under reduced pressure. The residue was-washed with diethyl ether (50 mL) & then diluted with water (30 mL). The aqueous layer was neutralized to pH ~7 using IN HC1 and was extracted with ethyl acetate (3 X 50 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate; solvent was evaporated under reduced pressure to obtain the desired compound (1. 7 g). Ή NMR- (CDC13, 400MHz), δ 1.07-1.30 (m, 4H), 1.37 (d, J = 6.1 Hz, 6H), 2.80 (m,lH), 4.62 (m, 1H), 6.85 (bs, 1H), 7.35 (s, 1H), 7.41 (d, 8.6 Hz, 1H), 7.49 (s, 1H), 7.99(d, J = 8.6 Hz, 1H), 8.5 l (m, 1H).
MS (EI) mlr. 378.0 (M + 1).
Pre arations 3 and 4 were synthesized in analo ous manner of re aration 1.
Figure imgf000043_0002
Preparation 5: 3-(6-Cyclopropanesulfonyl-pyridin-3-yIoxy)-5-((S)-2-methoxy-l-methyl- ethoxy -benzoic acid
Figure imgf000043_0001
Step-I:- 3-Benzyloxy-5-hydroxy-benzoic acid methyl ester :
A clean and dry RB flask was charged with 3, 5-Dihydroxy-benzoic acid methyl ester (5 gs, 29.6 mmol) and potassium carbonate (4.5 g, 32.73 mmol) in acetone (120 ml). To this suspension was added benzyl bromide (5.34 g, 31.25 mmol) and reaction mixture was continued to stir at reflux for 3 hrs. Product formation was monitored by TLC. On completion of reaction the mixture was cooled to room temperature, filtered through Buchner funnel. The filtrate was concentrated in vacuo to get the crude product which was purified by column chromatography (silica gel 100-200 mesh, 12% ethylacetate in hexanes as eluent) to afford compound .(2.7 g)
Ή NMR (DMSO-d6, 400 MHz):- δ 3.79 (s, 3H), 5.08 (s, 2H), 6.62-6.63 (m, 1H), 6.95-6.98 (m, 2H), 7.31-7.43 (m, 5H), 9.87 (s, 1H).
MS (EI) mlz: 258.90 (M + 1).
Step- II :- 3-BenzyIoxy-5-((S)-2-methoxy-l-methyl-ethoxy)-benzoic acid methyl ester
To a mixture of 3-Benzyloxy-5-hydroxy-benzoic acid methyl ester (2.6 g, 1.3 mmol) Triphenyl phosphine (6.76 g, 25.77 mmol) and (R)-l-Methoxy-propan-2-ol (1.85 g, 20.62 mmol), in THF was added DIAD (4.16 g, 20.62 mmol) at 0°C and reaction mixture was stirred overnight at room temperature. . Product formation was monitored by TLC. On completion of reaction solvent was removed in vacuo, taken into water and extracted with ethyl acetate and dried over anhydrous sodium sulfate and concentrated in vacuo. Purified by column chromatography (silica gel 100-200 mesh, 25% ethylacetate in hexanes as eluent) to afford compound. (3.3 g)
Ή NMR (DMSO-d6, 400 MHz):- δ 1.20 (d, J = 6.4 Hz, 3H), 3.27 (s, 3H), 3.40-3.50 (m, 2H), 3.83 (s, 3H), 4.60-4.70 (m, 1H), 5.15 (s, 2H), 6.87 (s, 1H), 7.06 (s, 1H), 7.12 (s, 1H), 7.30-7.45 (m, 5H).
MS (EI) mlz: 331 .2 (M + 1 ).
Step-III:- Synthesis of 3-Hydroxy-5-((S)-2-methoxy-l-methyl-ethoxy)-benzoic acid methyl ester
3-Benzyloxy-5-((S)-2-methoxy-l-methyl-ethoxy)-benzoic acid methyl ester (3.5 g, 10.59 mmol) was taken in 20 ml THF, Palladium on carbon (10% wet, 10% w/w, 0.35 g ,) in 20 ml ethanol was added slowly, purged with argon and finally with hydrogen and reaction mixture was stirred overnight at room temperature . Product formation was monitored by TLC. On completion of reaction, filtered through sintered funnel over celite and filtrate was concentrated in vacuo, used as such without any purification. (2.53 g)
Ή NMR (CDC13, 400 MHz):- δ 1.30 (d, J = 5.6 Hz, 3H), 3.42 (s, 3H), 3.89 (s, 3H), 4.53- 4.61 (m, 2H), 4.90-5.00 (m,l H), 6.64 (s, lH), 7.10 (s, 1H), 7.17 (s, 1H).
MS (EI) m/z: 241.1 (M + 1). Step-IV:- Synthesis of 3-(6-CycIopropairesulfonyl-pyridin-3-yloxy)-5-((S)-2-methoxy-l- methyI-ethoxy)-benzoic acid methyl ester
Mixture of 3-Hydroxy-5-((S)-2-methoxy-l-methyl-ethoxy)-benzoic acid methyl ester (1.5 g, 6.25 mmol), 5-Chloro-2-cyclopropanesulfonyl-pyridine (1.62 g, 7.50 mmol), and cesium carbonate (4.07 g, 12.50 mmol) in Dimethylacetamide (25 ml) was heated at 100 °C for 8 hrs. Product formation was monitored by TLC. On completion of reaction solids were filtered and filtrate was concentrated in vacuo taken into water and extracted with ethyl acetate (50 ml x 3), The organic layer was washed with brine and dried over anhydrous sodium sulfate; solvent was evaporated under reduced pressure to obtain the titled compound (2.5 g).
Ή NMR (CDC , 400 MHz):- δ 1.06-1.1 1 (m, 2H), 1.20-1.30 (m, 2H), 1.31 (d, J = 6.4 Hz, 3H,) 2.79 (m, 1H), 3.40 (s, 3H), 3.49-3.60 (m, 2H), 3.91 (s, 3H),
4.60-4.63 (m, 1H), 6.88 (t, J = 2.4 Hz, 1 H), 7.31 -7.32 (m, 1H), 7.39 (dd, J = 2.8, J = 8.8 Hz, l H), 7.49-7.50 (m, 1H), 7.98 (d, J = 8.8 Hz, 1H), 8.49 (d, J = 3.2 Hz, 1H)
MS (EI) mlz: 422.20 (M +1).
Step-V:- Synthesis of 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2-methoxy-l- methyl-ethoxy)-benzoic acid
To a solution of 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2-methoxy-l-methyl- ethoxy)-benzoic acid methyl ester (2.6 g, 6.25 mmol), in THF: Metahnol: water (3: 1 : 1 , 50 ml) was added Lithium hydroxide monohydrate (0.79 g, 18.75 mmol) and reaction mixture was stirred overnight at room temperature Product formation was monitored by TLC. On completion of reaction, solvents was removed in vacuo, taken into water and extracted twice with diethyl ether. Aqueous layers pH was brought to ~7 with 1 N HC1. and extracted with ethyl aceatate (50 ml x 3), dried over anhydrous sodium sulfate; solvent was evaporated under reduced pressure to obtain the titled compound (2.2g).
'H NMR (CDCI3, 400 MHz):- δ 1.08-1.10 (m, 2H), 1.33 (d, J = 6.4 Hz, 3H), 1.37-1.39 (m, 2H), 2.79 (m, 1 H), 3.41 (s, 3H), 3.50-3.61 (m ,2H), 4.61-4.63 (m, 1 H), 6.89 (t, J = 2.4 Hz, 1H), 7.35-7.36 (m, 1H), 7.40 (dd, J = 3.2 Hz, J = 8.8 Hz, 1H), 7.53-7.54 (m, 1H), 7.98 (d, J = 8.8 Hz, 1H), 8.50 (d, J = 3.2 Hz, 1H).
MS (EI) mlz :- 408.10 (M+l).
Preparation 6: 3-(6-CycIopropanesulfonyl-pyridin-3-yloxy)-5-isobutyl-benzoic acid
Figure imgf000046_0001
Step-I:- 3-Benzyloxy-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester:
A reaction flask maintained at -78 °C under argon atmosphere was charged with 3- benzyloxy-5-hydroxy-benzoic acid methyl ester (Refer step-I in prep.5) (2.7 g, 10.4 mmol) in DCM (102 ml). Diisopropylethylamine (1.98 ml, 1.4 mmol) was added to above solution in a dropwise fashion and stirred for 20 minutes followed by addition of trifluoromethanesulfonic anhydride (1.89 ml, 1 1.4 mmol). Then reaction mixture was brought to room temperature and continued to stir for 30 mins. Reaction mixture was diluted with 1 N HCl, organic layer was separated, washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford product. (3.3 g)
Ή NMR (DMSO-d6, 400 MHz):- δ 3.86 (s, 3H), 5.23 (s, 2H), 7.31 -7.42 (m, 3H), 7.44-7.49 (m, 2H), 7.50-7.56 (m, 2H), 7.62-7.65 (m, 1H).
MS (EI) m/z: 391.80 (M + l).
Step-II:- 3-Benzyloxy-5-isobutyl-benzoic acid methyl ester :
A clean and dry reaction flask, maintained under nitrogen atmosphere was charged with mixture of 3-Benzyloxy-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester (1.2 g, 3.07 mmol), lithium chloride (0.390 g, 9.23 mmol) and Tetrakis(triphenyl phosphine)palladium(O) (0.17 g, 0.15 mmol) in THF (30 ml). To above solution isobutyl zinc bromide (0.5 M in THF, 0.93 g, 4.61 mmol) was added in a drop-wise fashion and refluxed for 6-8 hrs. Reaction progress was monitored by TLC. On completion the reaction mixture was concentrated in vacuo to get crude product which was purified by column chromatography (silica gel 100-200 mesh, 2% ethylacetate in hexanes as eluent) to afford pure product. (0.4 g)
Ή NMR (CDC13, 400 MHz): δ 0.93 (d, J = 6.8 Hz, 6H), 1.86-1.96 (m, 1H), 2.51 (d, J = 7.2 Hz, 2H), 3.94 (s, 3H), 5.12 (s, 2H), 7.00-7.01 (m, 1H), 7.37-7.52(m, 7H), MS (EI) mlz: 299.10 (M+l)
Step-III:- 3-Hydroxy-5-isobutyl-benzoic acid methyl ester :
In reaction flask under argon atmosphere was charged with 3-Benzyloxy-5-isobutyl-benzoic acid methyl ester (0.4 g, 1.34 mmol) in ethanol (5 ml). To this solution 10 % palladium on carbon (0.080 g, 20% w/w) was added followed by triethylsilane (1.56 g, 13.4 mmol). After 5 hrs another 10 equivalent of triethylsilane (1.56 g, 13.4 mmol) was added to reaction mixture and stirred overnight at room temperature. Reaction was monitored by TLC, on completion reaction mixture was filtered over celite through sintered funnel, filtrate was concentrated in vacuo to afford procuct. (0.27 g)
Ή NMR (CDC13, 400 MHz): δ 0.90 (d, J = 6.4 Hz, 6H), 1.84-1.91 (m, 1H), 2.46 (d, J = 7.2 Hz, 2H), 3.94 (s, 3H), 5.50(bs, 1H), 6.84-6.85 (m, 1H), 7.34-7.35 (m, 1H), 7.40(s, 1H) MS (EI) mlz : 209.0 (M+l)
Step IV:- 3-(6-CycIopropanesuIfonyl-pyridin-3-yloxy)-5-isobutyl-benzoic acid methyl ester :
A flask containing 3 -Hydroxy-5-isobutyl -benzoic acid methyl ester (0.270 g, 1.29 mmol); 5- Chloro-2-cyclopropanesulfonyl-pyridine (0.28 g, 1.29 mmol) and cesium carbonate (0.845 g, 2.59 mmol) in dimethylacetamide (5 ml) were heated at 100 °C for 6 hrs. Reaction progress was monitored by TLC and on completion; reaction mixture was diluted with water and extracted with ethyl acetate. Organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vaccuo to get the crude product which was purified by preparative TLC ( 50 % ethyl acetate in hexane as eluent) to afford the product (0.45 g)
Ή NMR (CDC13, 400 MHz): δ 0.91 (d, J = 6.4 Hz, 6H), 1.06-1.09 (m, 2H), 1.33-1.40 (m, 2H), 1.88-2.04 (m,lH), 2.54 (d, J = 7.2 Hz, 2H), 2.76-2.80 (m, lH), 3.91 (s, 3H), 7.09 (s, 1H), 7.35 (dd, J = 2.4 Hz, J = 8.8 Hz, 1H), 7.56 (s, 1H), 7.74 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 8.45 (d, J = 2.8 Hz, 1H)
MS (EI) mlz : 389.90 (M+l)
Step V :- 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isobutyl-benzoic acid
In a clean RB flask containing 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isobutyl- benzoic acid methyl ester (0.45 g, 1 .15 mmol) in tetrahedron, methanol & water (3: 1 : 1 , 5 ml) was added sodium hydroxide (0.13 g, 3.47 mmol) and stirred for 3 hrs at room temperature. Reaction was monitored by TLC & on completion solvent was removed under reduced pressure. The residue was washed with diethyl ether (10 mL) & then diluted with water (20 mL). The aqueous layer was neutralized to pH ~7 using IN HC1 and was extracted with ethyl acetate (3 X 20 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate; solvent was evaporated under reduced pressure to obtain the desired product (0.35 g).
Ή NMR (DMSO-d6, 400 MHz): δ 0.87 (d, J = 6.8 Hz, 6H), 1.05-1.1 1 (m, 4H), 1.82-1.88 (m, 1H), 2.53 (d, J = 7.6 Hz, 2H), 2.90-2.95 (m,l H), 7.24 (s, 1H), 7.44-7.45 (m,lH), 7.55 (dd, J = 2.8 Hz, J = 8.8 Hz, 1 H), 7.64 (s, l H), 8.00 (d, J = 8.8 Hz, 1H), 8.59 (d, J = 2.8 Hz, 1H). MS (EI) mlz : 375.90 (M+l)
Intermediates 7-1 to 7-33 were either obtained from commercial source or prepared as per literature method.
Figure imgf000048_0001
7-1 7-2 7-3 .4
Figure imgf000048_0002
Commercial Source US 2010/0310493 A1 WO 2007089512A1
7-5 7-8
Figure imgf000048_0003
Commercial Source Commercial Source Commercial Source Commercial Source
7-13 7-15
Figure imgf000048_0004
cial Source
US 2010/0310493 A1 Commercial Source Commer US 2010/0310493 A1
7-18
7-16
Figure imgf000048_0005
Figure imgf000049_0001
Commercial Source Commercial Source Commercial Source
7"31 7-32 7-33
Preparation 8: 2-Amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester:
Figure imgf000049_0002
Step-I: 3-Bromo-4-oxo-cyclohexanecarboxylic acid ethyl ester
To a stirred solution of N-bromosuccinimide (1.1 16g, 6.274 mmol), PTSA (108.03 mg, 0.6274 mmol) in toluene (15 ml) was added 4-oxocyclohexanecarboxylic acid ethyl ester (1.068 g, 6.274 mmol) under nitrogen atmosphere and the reaction was refluxed for 2 hrs. Toluene was evaporated under reduced pressure and the residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated; the organic layer was washed with sat. sodium bicarbonate solution followed by brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to get title the compound. (2.2 g) which was carried without purification for the next step.
Step-II: -Amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester
Thiourea (672.54 mg, 8.835 mmol) was taken in ethanol (30 ml). To this stirred solution was added 3-Bromo-4-oxo-cyclohexane carboxylic acid ethyl ester (2.2g, 8.835mmol). The reaction was refluxed for 2 hrs . The reaction mixture was allowed to cool to room temperature and ethanol was evaporated under reduced pressure, the residue was partitioned between water and Ethyl acetate . The water layer was collected and basified using sat. sodium bicarbonate solution , extracted with ethyl acetate , the organic layer was washed with brine ,dried over anhydrous sodium sulfate filtered and concentrated under reduced pressure to afford 2-Amino-4,5,6,7-tetrahydro-benzothiazole-6-carboxylic acid ethyl ester (1 -6 g) Ή NMR (400 MHZ, CDC13) : δ 1.27 (t, J = 6.8 Hz , 3H), 1.87-1.97 ( m, 1H), 2.17-2.23 (m, 1H), 2.54-2.68 (m, 2H), 2.68- 2.79 (m, 1H), 2.80-2.85 ( m, 2H), 4.172 (q, J = 6.9, 2H), 4.74 (bs, 2H) .
MS (EI) «i/z : 227.1 (M+l)
Preparation 9 was synthesized in analogous manner of preparation 8.
Figure imgf000050_0002
Pre aration 10: 5-Vinyl-thiazol-2-ylamine
Figure imgf000050_0001
Step I : (5-Vinyl-thiazol-2-yl)-carbamic acid tert-butyl ester
To a mixture of (5-Bromo-thiazol-2-yl)-carbamic acid tert-butyl ester (1.0 g, 3.58 mmol) and tributyl(vinyl)stannane (3.14 ml, 10.74 mmol) in DMF-THF (1 : 1, 24 mL) were added Pd(PPh3)4 (206.9 mg, 0.179 mmol) and LiCl (455.6 mg, 10.74 mmol), then the mixture was refluxed for 8 h under Argon atmosphere. The resulting mixture was concentrated in vacuo and the residue was dissolved in sat. NaCl, then extracted with ethyl acetate (150 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate filtered and . concentrated under reduced pressure to get crude product which was purified by column chromatography (silica gel 100-200 mesh 20% ethylacetate in hexanes as eluent) to afford pure product. (0.817 g)
Ή NMR (CDC13, 400 MHz): δ 1.58 ( s, 9H), 5.13 ( d, J = 10.7 Hz, 1H), 5.42 (d, J = 17.2 Hz, 1H), 6.718 (dd, J = 17.2Hz, 10.8Hz, 1H), 7.19 (s, 1H).
MS (EI) m/z = 227.1 (M + 1).
Step II : 5-Vinyl-thiazol-2-ylamine
In a clean RB flask containing (5-Vinyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.814 g, 3.60 mmol) in Dichloromethane (5 ml) was added trifluoroacetic acid (2.33 ml, 31.36 mmol) reaction mixture was stirred for overnight at room temperature. Reaction was monitored by TLC. On completion of reaction solvent and trifluoroacetic acid was removed under reduced pressure. The residue was diluted with ethyl acetate (50 mL). The organic layer was washed with sat. sodium bicarbonate solution (30 ml), brine and dried over anhydrous sodium sulfate; solvent was evaporated under reduced pressure to obtain the desired product (0.60 g)
Ή NMR (CDC13, 400 MHz): δ 4.98 (bs, 2H), 5.02 (d, J = 1 1 Hz, 1H), 5.16(d, J = 17.4 Hz ,
1H), 6.65 (dd, J = 17.1 Hz, 10.8Hz, 1H), 6.95(s, 1H).
MS (EI) m/z = 127.1 (M + 1).
Preparation 11 was synthesized in analogous manner of preparation 10.
Figure imgf000051_0003
Preparation 12: 2-Amino-5-methyl-thiazol-4-one
Figure imgf000051_0001
To a solution of thiourea (5 g, 65.78 mmol) in ethyl alcohol (30 mL) was added sodium acetate (13.48 g, 164.47 mmol) in one portion followed by addition of 2-bromo propionic acid (1 1.09 g, 73.02 mmol) under argon atmosphere and refluxed for 2-3 hrs. The reaction mixture was cooled to room temperature and 150 ml of water was added. Aqueous layer was extracted with ethyl acetate. The organic layer was washed brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 2-Amino-5- methyl-thiazol-4-one (1.44 g).
" H MPV (DMSO-d6, 400 MHz):- δ 1.45 (d, J = 7.2 Hz, 3H), 4.17 (q, J = 7.6 Hz 1H), 8.8 (bs, 2H).
Preparation 13: 4-(2-Amino-thiazolo[5,4-b]pyridin-5-yIoxy)-benzoic acid methyl ester
Figure imgf000051_0002
Step I :- 4-(5-Nitro-pyridin-2-yloxy)-benzoic acid methyl ester
Mixture of 2-Chloro-5-nitro-pyridine (5 g, 31.53 mmol), 4-Hydroxy-benzoic acid methyl ester (5.75 g, 37.84 mmol) and cesium carbonate (30.8 g , 94.6 mmol) in DMF (50 ml) was heated at 70 °C for 3 hrs. On completion, reaction mixture was filtered, filtrate was concentrated in vacuo, the residue was diluted with ethyl acetate (100 ml) and washed with cold solution of 1 N NaOH , water and brine (100 ml each), dried over anhydrous sodium sulfate and concentrated in vacuo to get title compound (5.3g)
MS (EI) mlr. 275.00 (M + 1).
Step- II: - 4-(5-Amino-pyridin-2-yloxy)-benzoic acid methyl ester
To a solution of 4-(5-Nitro-pyridin-2-yloxy)-benzoic acid methyl ester (5 g ) in 75 ml ethyl acetate palladium on carbon (10 % wet, 20% w/w, 1 g) was added, flask was evacuated and filled with hydrogen gas and stirred overnight at room temperature. Product formation was monitored by TLC. On completion, reaction mixture was filtered over celite pad, filtrate was concentrated in vacuo.used further as such without any purification (4.7 g).
Ή NMR (CDC13, 400 MHz):- δ 3.60 (bs, 2H), 3.89 (s, 3H), 8.30 (d, J = 8.0 Hz, 1H), 7.03- 7.06 (m, 2H), 7.1 1 (dd, J = 2.8 Hz, 8.4 Hz, 1H), 7.75 (d, J = 2.8Hz, 1H), 7.98-8.03 (m, 2H). MS (EI) mlr. 245.10 (M + 1).
Step-III :- 4-(2-Amino-thiazolo[5,4-b]pyridin-5-yIoxy)-benzoic acid methyl ester
To a solution of sodium thiocyanate (6.35 g, 78.36 mmol) in acetic acid (100 ml) at 10 °C was added 4-(5-Amino-pyridin-2-yloxy)-benzoic acid methyl ester (4.78 g, 19.59 mmol) in 10 ml acetic acid ,drop wise at same temperature. Bromine ( 3.75 g, 23.50 mmol) in 10 ml acetic acid was added. Reaction mixture was stirred overnight at room temperature. Product formation was monitored by TLC. On completion, solvent was removed in vacuo, taken into water (100 ml) and ethyl acetate ( 50 ml), layers separated, aqueous layer was basified to pH ~ 9 and extracted with ethyl acetate (100 ml x3) dried over anhydrous sodium sulphate and concentrated in vacuo. Recrystalised with methanol solids was filtered and dried to get pure compound (4 g).
Ή NMR (DMSO-d6, 400 MHz):- δ 3.84 (s, 3H), 7.01 (d, J = 8.4 Hz, 1H), 7.16 (d , J = 8.8 Hz, 2H), 7.72 (bs, 2H), 7.76 (d, J = 8.8 Hz, lH), 7.97 (d, J = 8.8 Hz, 2H)
MS (EI) mlr. 302.10 (M + 1).
Preparation 14: 2-(2-Amino-5-chloro-thiazol-4-yl)-2-methyI-propionic acid ethyl ester
Figure imgf000053_0001
Step I: Synthesis of (2-tert-Butoxycarbonylamino-thiazol-4-yl)-acetic acid ethyl ester: A mixture of (2-Amino-thiazol-4-yl)-acetic acid ethyl ester (5g, 26.85 mmol) and da-tert- butoxydicarbonate (8.2g, 37.59 mmol) was heated at 80 °C in toluene for 24 hrs. Toluene was removed under vacuo and the residue was partitioned between water (100 ml) and ethyl acetate (100 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 ml x 2). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo to get the oily product (7.5
Ή NMR (CDC13, 400 MHz) :- δ 1.22 (t,"J = 7.2 Hz, 3H), 1.55 (s, 9H), 3.73 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 6.75 (s, 1H), 9.6 (bs, 1H).
MS (EI) m/z: 287.1 (M + l ).
Step II: Synthesis of {2-[tert-ButoxycarbonyI-(4-methoxy-benzyl)-amino]-thiazol-4-yI}- acetic acid ethyl ester :
To a solution of (2-tert-Butoxycarbonylamino-thiazol-4-yl)-acetic acid ethyl ester ( 7.5 g, 26.1 1 mmol) in 100 ml of dry dichloromethane was added DBU (1 1.96 g, 78.56 mmol) followed by ? ra-methoxybenzyl chloride (6.15 g, 39.28 mmol) and the reaction mixture was stirred for 18 hrs at room temperature. The reaction was quenched with water and the layers were separated. The organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo. The residue was purified by column chromatography (silica gel 60 -120 mesh and 2-10% ethyl acetate in hexanes as eluent) to get the pure compound (8.0 g). Ή NMR (CDCI3, 400 MHz) :- δ 1.26 (t, J = 7.2 Hz, 3H), 1.52 (s, 9H), 3.69 (s, 2H), 3.78 (s, 3H), 4.18 (q, J = 7.6 Hz, 2H), 5.23 (s, 2H), 6.75 (s, 1H), 6.81 (d, J = 7.2 Hz, 2H), 7.34 (d, J = 7.2 Hz, 2H).
MS (EI) iw/z: 407.2 (M + l).
Step III: Synthesis of 2-{2-[tert-Butoxycarbonyl-(4-methoxy-benzyI)-amino]-thiazol-4- yl}-propionic acid ethyl ester :
To a solution of lithium diisopropylamide (prepared in situ) (4.24 g, 39.6 mmol) in dry THF (40 ml) was added the solution of {2-[teri-butoxycarbonyl-(4-methoxy-benzyl)-amino]- thiazol-4-yl}-acetic acid ethyl ester ( 8.0 g, 19.68 mmol) in 20 ml of dry THF in a dropwise fashion at -78 °C. The reaction mixture was continued to stir at -78 °C for 1 hour followed by the addition of methyl iodide (4.19 g, 29.52 mmol) at the same temprature. The reaction mixture was kept on stirring and slowly allowed to come to room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and diluted with ethyl acetate. The aqueous layer was extracted with ethyl acetate (50 ml x 2). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo to get the sticky compound (8.2 g). The compound was used for the next reaction without any purification.
Ή NMR (CDCI3, 400 MHz) :- δ 1 .22 (t, J = 7.2 Hz, 3H), 1.45-1 .65 (m, 12H), 3.78 (s, 3H), 3.83 (q, J = 7.6 Hz, 1H), 4.15 (q, J = 7.6 Hz, 2H), 5.21 (s, 2H), 6.68 (s, 1H), 6.80 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H).
MS (EI) mlz: 421.3 (M + l).
Step IV: Synthesis of 2-{2-[tert-Butoxycarbonyl-(4-methoxy-benzyl)-amino]-thiazol-4- yl}-2-methyl-propionic acid ethyl ester :
The reaction was done by the same way as mentioned in the step III. The crude product was purified by column chromatography (Silica gel 60 -120 mesh, and 2-4% ethyl acetate in hexanes as eluent) to get the pure solid compound (58.51%). .
'H MR (CDCI3, 400 MHz) :- δ 1.15 (t, J = 7.2 Hz, 3H), 1.51-1.59 (m, 15H), 3.77 (s, 3H), 4.09 (q, J = 7.2 Hz, 2H), 5.19 (s, 2H), 6.63 (s, 1H), 6.80 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.4 Hz, 2H).
MS (EI) m/z: 435.3 (M + 1).
Step V: Synthesis of 2-(2-Amino-thiazol-4-yl)-2-methyl-propionic acid ethyl ester:
2-{2-[tert-Butoxycarbonyl-(4-methoxy-benzyl)-amino]-thiazol-4-yl}-2-methyl-propionic acid ethyl ester (1.5g, 3.45 mmol) was refluxed in 15 ml of trifluoroacetic acid for 18 hrs. Trifluoroacetic acid was removed in vacuo and the residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 ml x 2). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo to get the solid product (0.7 g).
'HNMR (CDCI3, 400 MHz) :- δ 1.21 (t, J = 7.2 Hz, 3H), 1.52 (s, 6H), 4.14 (q, J = 7.2 Hz, 2H), 6.25 (s, 1H).
MS (EI) mlz: 215.1 (M + l).
Step VI: Synthesis of 2-(2-Amino-5-chloro-thiazol-4-yl)-2-methyl-propionic acid ethyl ester:
2-(2-Amino-thiazol-4-yl)-2-methyl-propionic acid ethyl ester (0.3 g, 1.40 mmol) was taken in 10 ml of acetonitrile and N-Chlorosuccinamide (0.224 g, 1.68 mmol) was added the reaction was stirred for 1 hr. at room temperature. After completion of reaction acetonitrile was evaporated under reduced pressure and the residue was partitioned between water (25 ml) and ethyl acetate (25 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (25 ml x 2). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo. The residue was purified by preprative TLC plate (mobile phase 40% ethyl acetate in hexane) to get the pure compound (0.3 g).
'HNMR (CDCI3, 400 MHz) :- δ 1.25 (t, J = 7.2 Hz, 3H), 1.55 (s, 6H), 4.18 (q, J = 7.2 Hz, 2H), 4.82 (bs, 2H).
MS (El) mlz: 249 Λ (M + 1).
Pre ration 15: 2-(2-Amino-5-fluoro-thiazol-4-yl)-2-methyl-propionic acid ethyl ester
Figure imgf000055_0001
Step I: 2-{2-[tert-Butoxycarbonyl-(4-methoxy-benzyl)-amino]-5-fluoro-thiazoI-4-yl}-2- methyl-propionic acid ethyl
ester
Under anhydrous condition n-BuLi (3.6 M solution in hexane, 2.55 mL, 9.20 mmol ) was added to stirred solution of Ν,Ν-Diisopropyl amine (1.29 mL, 9.20 mmol) in 10 ml dry THF at -78 °C and stirred for lhr. A solution of 2-{2-[tert-Butoxycarbonyl-(4-methoxy-benzyl)- amino]-thiazol-4-yl}-2-methyl-propionic acid ethyl ester (2.0 g, 4.60 mmol) in 10 mL of dry THF was added dropwise with the help of syringe and stirred for lhr. N- Fluorobenzenesulfonimide (2.17 g, 6.90 mmol) dissolved in 10 mL dry THF was added to reaction mixture dropwise and resulted reaction mixture was allowed to warm 0 °C within 3 hrs. Reaction mixture was poured on aq. saturated solution of NH4C1 (50 mL), mixture was then extracted with (3X50 mL) ethyl acetate; organic layer was washed with brine, dried over anhydrous sodium sulfate, sodium sulfate was filtered and washed with ethyl acetate and solvent was removed under reduced pressure. The crude material was purified by silica-gel column chromatography (4% ethyl acetate in hexane) to afford pure compound (0.5 g).
Ή NMR (CDCI3, 400 MHz) :- δ 1.19 (t, J = 7.3 Hz, 3H), 1.52 (s, 9H), 1.57-1.60 (m, 6H), 3.78 (s, 3H), 4.12 (q, J = 7.3 Hz, 2H), 5.08 (s, 2H), 6.81 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 7.8 Hz, 2H).
MS (E\) m/z: 453.3 (M + 1).
Step II : 2-(2-Amino-5-fluoro-thiazol-4-yI)-2-methyl-propionic acid ethyl ester
The reaction was done by the same way as mentioned in the preparation of 2-(2-Amino- thiazol-4-yl)-2-methyl-propionic acid ethyl ester.
Ή NMR (CDCI3, 400 MHz) :- δ 1.23 (t, J = 7.3 Hz, 3H), 1.53-1.54 (m, 6H), 4.16 (q, J = 6.9 Hz, 2H).
MS (EI) w/z: 233.1 (M + 1).
Example Al: 3-(6-CycIopropanesulfonyl-pyridin-3-yloxy)-N-(5-fluoro-thiazol-2-yI)-5- isopropoxy-benzamide
Figure imgf000056_0001
To a mixture of 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoic acid (150 mg, 0.40 mmol), 2-amino-5-fluoro-thiazole.HCL 123 mg, 0.80 mmol), HOBt (107 mg, 0.80 mmol), and EDCI.HCL (153 mg, 0.80 mmol), in DMF (10 mL), was added triethyl amine (0.17 ml, 1.20 mmol) The resulting mixture was stirred at room temperature overnight followed by dilution with water (15 mL). The reaction mixture was extracted with ethyl acetate (3 X 25 mL); organic layer was washed with water, brine, dried over sodium sulfate, and the organic solvent evaporated to get a residue which was purified by preparative TLC or column chromatography to provide the final compound Al (200 mg).
Compound (A l) can also be prepared using procedure-B
Procedure-B:
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoic acid (150 mg, 0.40 mmol) was dissolved in DCM (10 mL). To this solution was added DMF (0.05 mL) and cooled to 0 °C, followed by the addition of oxalyl chloride (0.10 mL, 1.2 mmol) under stirring. The reaction mixture was stirred at room temperature for 1-2 hours. The excess of oxalyl chloride was removed under vaccuo. The reaction mixture was diluted with DCM (5 mL) & kept in an ice bath at °C followed by slow addition of 2-amino-5-fluoro-thiazole.HCL (74 mg, 0.48 mmol) in DMF (5 mL) & triethyl amine (0.138 ml, 1 mmol) in DCM (2 mL). After the addition was over the reaction mixture was continued to stirr for 4 h. at room temperature. The reaction mixture was diluted with DCM and neutralized to pH ~7 using IN aqueous HC1. The organic layer was separated; washed with wa'ter, followed by brine, dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to get the crude compound which was purified by preparative TLC or column chromatography to provide the final compound Al (60 mg).
Ή NMR- (DMSO-d6, 400MHz), δ 1.00-1.15 (m, 4H), 1.28 (d, J = 6 Hz, 6H), 2.92 (m, lH), 4.75 (m, 1H), 7.08 (s, 1H), 7.35-7.45 (m, 2H), 7.52 (s, 1H), 7.63 (dd, J = 8.4 & 2.8 Hz, 1H), 8.00(d, J = 8.8 Hz, 1 H), 8.63(d, 2.4 Hz , 1H), 12.70 (s, 1H).
MS (EI) mlz: 478(M + 1).
Examples A2 to A22 were prepared in analogues manner of example (Al) from the appropriate intermediate that are available commercially or synthesized as above.
Figure imgf000057_0001
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-
N-( 1 -methyl- 1 H-pyrazol-3-yl)-benzamide.
Ή NMR- (DMSO-d6, 400MHz), δ 1.06-1.14 (m, 4H),
1.30 (d, J = 6 Hz, 6H), 2.94 (m, lH), 3.77 ( S, 3H), 4.76 (m,
A3 IH), 6.57( d, J = 2.4 Hz, IH), 7.00-7.03 (m, IH), 7.36 (s,
IH), 7.48 (s, IH), 7.60-7.61 (m, IH), 7.63 (dd, J = 8.8 &
2.8 Hz, IH), 8.02 (d, J = 8.8 Hz, IH), 8.63 (d, 3.2 Hz ,
IH), 10.91 (s, IH).
MS (EI) mlz: 457.1 (M + 1).
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy- N-( 1 H-pyrazol-3 -yl)-benzam ide .
Ή NMR- (DMSO-d6, 400MHz), δ 1.02-1.13 (m, 4H), 1 .28 (d, J = 6 Hz, 6H), 2.92 (m, lH), 4.74 (m, IH), 6.58(
A4
bs, IH), 6.97-7.03 (m, IH), 7.35 (s, IH), 7.46 (s, IH), 7.58- 7.61 (m, IH), 7.62-7.66 (m, IH), 8.00 (d, J = 8.8 Hz, IH), 8.14 (s, IH), 8.62 (d, 2.8 Hz , IH), 10.90 (s, IH).
MS (EI) mlz: 443.1 (M + 1).
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy- N-thiazolo[5,4-b]pyridin-2-yl-benzamide
'H NMR (400 MHz,DMSO-D6): δ 1.07-1.1 1 (m, 4H), 1.31 (d, J = 5.6 Hz, 6H), 2.93 (m, IH), 4.78 (m, IH), 7.12 (s,
A
Figure imgf000058_0001
IH), 7.49-7.52 (m, 2H), 7.59 (s, IH), 7.65 (dd, J =2.8 Hz, J
= 8.8 Hz, IH), 8.02 (d, J = 8.4 Hz, IH), 8.13 (d, J = 8.0 Hz, IH), 8.49 (d, J = 4.8 Hz, IH), 8.65 (d, J = 2.8 Hz, IH)), 13.10 (s, lH)
MS (EI) mlz: 510.90 (M + 1).
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-
O N-(5-morpholin-4-yl-thiazol-2-yl)-benzamide.
Ή NMR- (DMSO-d6, 400MHz), δ 1.02-1.12 (m, 4H),
A6 1.28 (d, J = 6 Hz, 6H), 2.90-3.03 (m, 5H), 3.65-3.74 (m,
jfr° 4H), 4.74 (m, IH), 6.71( s, IH), 7.02 (s, IH), 7.39 (s, IH),
7.50 (s, IH), 7.62 (dd, J=2.8 Hz, J=8.8 Hz, IH), 8.00 (d, J
= 8.8 Hz, IH), 8.62 (d, 2.4 Hz , IH), 12.35 (s, IH). 1.30
(s,
(m, IH),
(m, IH), IH).
Hz,
Figure imgf000059_0001
Figure imgf000060_0001
N-[4-(l -Acetyl-piperidin-4-yl)-thiazol-2-yl]-3-
(6cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy- benzamide
'H NMR (400 MHz,DMSO-D6): δ 1.05-1.15 (m, 4H), 1.30 (s, 6H), 1.38-1 .48 (m, 1 H), 1.52-1.61 (m, IH), 1.86-1.98 (m,
A 14 2H), 2.00 (s, 3H), 2.62 (t, J=13.2Hz, IH), 2.82-2.97 (m,
2H), 3.12 (t, J=12.2Hz, IH), 3.86 (d, J=13.2Hz, IH), 4.42 (d, J=12.7Hz, IH), 4.77 (bs ,1H), 6.86 (s, IH), 7.05 (s, IH), 7.44 (s, IH), 7.55 (s, IH), 7.60-7.68 (m, IH), 8.02 (d, J=8.1 Hz, IH), 8.64 (s, I H), 12.63 (s, IH)
MS (EI) mlz: 585.3 (M + 1).
3 -(6-Cyclopropanesulfony l-pyridin-3 -yloxy)-N-(5 -ethoxy- thiazolo[5,4-b]pyridin-2-yl)-5-isopropoxy-benzamide Ή NMR (400 MHz,DMSO-d6): δ 1.08-1.16 (m, 4H), 1.29- 1.40 (m, 9H), 2.95 (m, IH), 4.36 (q, J=7.1Hz, 2H), 4.79
A 15
(m, IH), 6.90 (d, J=8.8Hz, IH), 7.10 (s, IH), 7.49 (s, IH), 7.60 (s, IH), 7.67 (dd, J = 2.7 Hz, J = 8.8 Hz, lH), 8.04 (d, J = 8.8 Hz, 2H), 8.66 (d, J = 2.7 Hz, IH), 12.89 (bs, IH). MS (EI) mlz: 555.10 (M + 1).
3 -(6-Cyclopropanesulfony l-pyridin-3 -yloxy)-N-(5 - methoxy-thiazolo[5,4-b]pyridin-2-yl)-5-(tetrahydro-furan-
3-yloxy)-benzamide
Ή NMR (400 MHz,DMSO-D6): δ 1.05-1.15 (m, 4H), 1.98-2.07 (m, IH), 2.22-2.31 (m, IH), 2.93 (m, IH), 3.75- 3.80 (m, IH), 3.81-3.88 (m, 2H), 3.89-3.94 (m, 4H), 5.17-
A16
5.21 (m, lH), 6.91 (d, J=8.8 Hz, IH), 7.1 1 -7.12 (m, IH), 7.51 (s, IH), 7.56-7.58 (m, IH), 7.67 (dd, J = 8.8 ,J=2.9 Hz, IH), 8.02 (d, J=3.4 Hz IH), 8.04 (d, J=3.4 Hz, IH), 8.65 (d, J=2.9 Hz, IH), 12.85 (s,lH).
MS (EI) mlz: 569.20(M + 1). 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2- methoxy-l-methyl-ethoxy)-N-(5-methoxy-hiazolo[5,4- b]pyridin-2-yl)-benzamide
Ή NMR (400 MHz,DMSO-D6): δ 1.09-1.14 (m, 4H), 1.27 (d, J = 5.60 Hz, 3H), 2.95 (m, IH) ,3.34 (s,3H), 3.47-3.56
A 17 (m, 2H), 3.93 (s, 3H), 4.80-4.84 (m, lH), 6.95 (d, J = 8.8
Hz, IH), 7.16-7.17 (m,lH), 7.50 (s,lH), 7.63 (m, IH), 7.68 (dd, J = 2.4 Hz, J = 8.4 Hz , 1H), 8.04 (d, J = 8.8 Hz, IH), 8.08 (d, J = 8.8 Hz, 1 H),8.66 (d, J = 2.8 Hz, I H), 12.90 (s, IH).
MS (EI) m/z 569.2 (M + l).
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2- methoxy-l -methyl-ethoxy)-N-pyrazin-2-yl-benzamide Ή NMR (400 MHz,DMSO-D6): δ 1.06-1.10 (m, 4H), 1.32 (d, J = 5.60 Hz, 3H), 2.92 (m, IH), 3.27 (s, 3H), 3.45-3.53 (m, 2H), 4.80 (m, IH), 7.1 1 (t, J=2 Hz IH), 7.41 (t, J=2 Hz
A18
IH), 7.52-7.55 (m, IH), 7.63 (dd, J = 2.8 Hz, J = 8.8 Hz, IH), 8.01 (d, J = 8.8 Hz, IH), 8.41 -8.42 (m, IH), 8.46-8.48 (m, IH), 8.62 (d, J = 3.2 Hz, IH), 9.37 (d, J=1.6 Hz IH), 1 1.20 (s, lH).
MS (EI) m/z: 485.20 (M + I).
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5- isopropoxy-benzoylam ino] -th iazole-4-carboxy 1 ic acid methyl ester
'H NMR (400 MHZ,CDC13): δ 1.08-1.13 (m, 4H), 1.34 (d, J
A19 = 6.1 Hz, 6H), 2.80 (m, IH), 3.90 (s, 3H), 4.61 (m, IH),
6.77-6.79 (m, IH), 7.27 (s, IH), 7.32 (s, IH), 7.36-7.42 (m, 2H), 7.97 (d, J = 8.6 Hz, IH), 8.46 (d, J = 2.7 Hz, IH). MS (EI) m/z: 518.1 (M + 1). 3 -(6-Cyclopropanesu lfonyl-pyridin-3 -y loxy)-5 -isopropoxy-
N-(5-vinyl-thiazol-2-yl)-benzamide
Ή NMR (400 MHz,CDCl3): 61.07-1.14 (m, 2H), 1.36 (d, J
= 5.8 Hz, 6H), 1.38-1.42 ( m, 2H), 2.79 (m, IH), 4.60 (m,
IH), 5.23 (d, J =10.8 Hz, IH), 5.53 (d, J =17.1 Hz, IH),
A20 6.71 (dd, J = 17.6 Hz, 1 1 .2 Hz, IH), 6.83-6.84 (m, IH),
7.1 1 (s, IH), 7.20 (s, IH), 7.35 (s, IH), 7.44 (dd, J = 8.6 Hz,
2.7Hz, IH), 8.00 (d, J = 8.3Hz, IH), 8.51 (d, J =2.5 Hz, l H),1 1.39 (bs, IH).
MS (EI) m/z = 486.2 (M+l )
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-(5- methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-phenoxy]- 2-methyl-propionic acid tert-butyl ester
iY Ή NMR (400 MHz, CDC13): δ 1.08-1.14 (m, 2H), 1.39- 1.42 (m, 2H), 1 .44 (s, 9H), 1.61 (s, 6H), 2.80 (m, I H), 4.01
A21
(s, 3H), 6.80 (d, J = 2.4 Hz, IH), 6.81 (s, I H), 7.28 (s, IH), 7.34 (s, IH), 7.39 (dd, J = 2.6, J = 8.8 Hz, IH), 7.74 (d, J = 8.8 Hz, IH), 7.99 (d, J = 8.6 Hz, IH), 8.47 (d, J = 2.5 Hz, IH).
MS (EI) m/z: 641.3 (M + l).
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-(5-fluoro- thiazol-2-yl)-5-isobutyl-benzamide
'HNMR (DMSO-d6, 400 MHz): δ 0.87 (d, J = 6.4 Hz, 6H), 1.06-1.10 (m, 4H), 1.89-1.93 (m, IH), 2.55 (d, J = 7.6 Hz,
A22 2H), 2.90-2.94 (m, IH), 7.34 (s, IH), 7.38 (d, J = 2.4 Hz,
IH), 7.60 (dd, J = 2.8 Hz , J = 8.8 Hz, I H), 7.71 (s, IH), 7.81 (s, IH), 8.01 (d, J = 8.4 Ηζ,ΙΗ), 8.61 (d, J = 2.4 Hz, IH ), 12.70 (s, IH).
MS (EI) m/z: 476.10 (M + 1).
Example Bl : 2-[3-(6-CyclopropanesulfonyI-pyridin-3-yIoxy)-5-isopropoxy- benzoy.lamino]-thiazole-4-carboxylic acid
Figure imgf000064_0001
To a solution of 2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy- benzoylamino]-thiazole-4-carboxylic acid ethyl ester (270 mg, 0.507 mmol ) in tetrahedron, ethanol & water (3: 1 : 1 , 10 ml) was added NaOH (30 mg, 0.76 mmol ) and stirred for 2-4 h at RT. After completion of reaction, organic solvent was removed under reduced pressure. The residue was washed with diethyl ether. The aqueous layer was neutralized to pH ~7 using IN HCl and was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate; solvent was evaporated under reduced pressure to obtain the final compound Bl (180 mg)
'H NMR (400 MHz,DMSO-d6): 6 1.08-1.10 (m, 4H), 1.31 (d, J = 6 Hz, 6H), 2.95 (m ,1H), 4.79 (m , 1H), 7.10-7.1 1 (m, 1H), 7.48 (s, 1H), 7.60 (s, 1H), 7.67 (dd, J=2.8 Hz, J=8.8 Hz 1H), 8.03 (d, J = 8.8 Hz, 1H), 8.06 (s, 1H), 8.66 (d, J=3.2Hz, 1H), 13.00 (bs, 2H)
MS (El) m/z 504.10 (M + l).
Example B2 : 2-[3-(6-CyclopropanesuIfonyl-pyridin-3-yloxy)-5-isopropoxy- benzoylamino]-thiazole-4-carboxylic acid amide
Figure imgf000064_0002
In a clean Seal tube containing 2-[3-(6-Ethanesulfonyl-pyridin-3-yloxy)-5-isopropoxy- benzoylamino]-thiazole-4-carboxylic acid ethyl ester (0.35 g, 0.67 mmol) was added 25% aqueous ammonia solution (30 ml ) closed tightly and stirred for 5 hrs at room temperature. Reaction was monitored by TLC & on completion aqueous solution was extracted with ethyl acetate (3 X 20 mL). The organic layer was washed with brine and dried over anhydrous sodium sulfate; solvent was evaporated to get a residue which was purified by preparative TLC or column chromatography to provide the final compound B2 (0.21 g). Ή NMR (400 MHz,DMSO-d6): δ 1.08-1 .15 (m, 4H), 1.31 (d, J = 6.4 Hz, 6H), 2.95 (m, IH), 4.80 (m, IH), 7.1 1 (s, IH), 7.26 (bs, IH), 7.47 (s, IH), 7.56-7.62 (m, 2H), 7.67 (dd, J=2.7 Hz, J=8.8 Hz, IH), 7.88 (s, I H), 8.04 (d, J = 8 Hz, IH), 8.66 (d, J = 2.4 Hz, IH), 12.88 (s, IH). MS (EI) m/z: 503.1 (M + 1).
Example B3 : 3-(6-Cyclopropanesulfonyl-pyridin-3-yIoxy)-N-(4-hydroxymethyl-thiazol- -yl)-5-isopropoxy benzamide
Figure imgf000065_0001
To a solution of 2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy- benzoyIamino]-thiazoIe-4-carboxylic acid ethyl ester (185 mg, 0.357 mmol ) in methanol (15 ml) was added Lithium aluminium hydride (40 mg, 1.07 mmol ) and reaction was stirred for 24 h at 60-70 °C. Reaction mixture was quenched with sat sodium salfate solution and filtered through Buchner funnel.'The filtrate was concentrated in vacuo to get the crude product which was purified by column chromatography (silica gel 100-200 mesh) to afford product B3.(27 mg)
Ή NMR (400 MHz,DMSO-d6): δ 1.08-1.14 (m, 4H), 1.31 (d, J = 5.8 Hz, 6H), 2.95 (m, IH), 4.50 (d, J = 4.9 Hz, 2H), 4.78 (m, IH), 5.26 (t, J = 5.2 Hz, IH), 7.00 (s, IH), 7.08 (s, IH), 7.45 (s, IH), 7.57 (s, IH), 7.67 (dd, J=2.5 Hz, J=8.6 Hz, IH), 8.03 (d, J = 8.6 Hz, IH), 8.66 (d, J = 2.2 Hz, IH), 12.60 (bs, IH).
MS (EI) m/z: 490.2 (M + 1 ).]
Example B4 : 2-[3-(6-CyclopropanesulfonyI-pyridin-3-yloxy)-5-(5-methoxy-thiazoIo[5,4- b] pyridin-2
Figure imgf000065_0002
To a cold solution of 2 2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-(5-methoxy- thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-phenoxy]-2-methyl-propionic acid tert-butyl ester (200 mg, 0.312 mmol ) in dichloromethane (3 ml) was added dropwise trifluoroacetic acid (2 mg ) and stirred for 2 hrs at RT. After completion of reaction, acid and organic solvent was removed under reduced pressure. The residue was diluted with cold water and the aqueous layer was neutralized to pH ~7 using sat. sodium bicarbonate solution, the solid obtained was filtered and washed with water, dried under vacuum to obtained the final compound B4 (150 mg)
Ή NMR (400 MHz, DMSO-d6): δ 1.12 (m, 4H), 1.59 (s, 6H), 2.96 (m, 1H), 3.93 (s, 3H), 6.94 (d, J = 8.4 Hz, 1H), 6.99 (s, 1H), 7.43 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 8.05 (m, 2H), 8.67 (s, 1H), 12.9 (bs, 1H), 13.4 (bs, 1H).
MS (EI) m/z: 585.2 (M + 1).
Examples B5 to B31 were prepared in analogues manner of example (B1-B4) from the appropriate intermediate that are available commercially or synthesized as above.
Figure imgf000066_0001
{5-Chloro-2-[3-(6-cyclopropanesulfonyl-pyridin-3- yloxy)-5-isobutyl-benzoylamino]-thiazol-4-yl} -acetic acid
D6): δ 0.89 (d, J = 6.8 Hz, ' r ■ Ή NMR (400 MHz,DMSO- τ ΐ N 6Η), 1.09-1.12 (m, 4Η), 1.93 (m, 1H), 2.55 (d, J = 6.8
B7
Hz, 2H), 2.95 (m , 1H), 3.62 (s, 2H), 7.37 (s, 1H), 7.63
°;'s (TT°
V (dd, J = 2.8 Hz, 8.8 Hz, 1H), 7.75 (s, IH), 7.85 (s, 1H),
8.03 (d, J = 8.8 Hz, IH), 8.64(d, J = 3.2 Hz, IH), 13.00 (bs, 2H).
MS (EI) m/z: 550.00 (M + 1).
l -{2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5- isopropoxy-benzoy lam ino]-thiazol-5 -ylm ethyl } - piperidine-4-carboxylic acid
Ή NMR (400 MHz,DMSO-D6): δ 1.09-1.1 1 (m, 4H), 1.31 (d, J = 6.4 Hz, 6H), 1.51-1.57 (m, 2H), 1.77-1.80 (m
B8 ,2H), 2.02-2.04 (m ,2H), 2.16-2.18 (m , 1H), 2.77-2.80
(m, 2H),2.95 (m ,1H), 3.64 (s, 2H), 4.77 (m,lH), 7.07- 7.08 (m, IH), 7.36 (s, IH), 7.43 (s, IH), 7.54 (s, IH), 7.65 (dd, J = 2.8 Hz, J = 8.8 Hz, IH), 8.02 (d, J = 8.8 Hz, IH), 8.65 (d, J= 2.4 Hz, IH), 12.50 (bs,2H).
MS (EI) m/z 601.20(M + 1).
4-{2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5- isopropoxy-benzoylamino] thiazolo[5,4-b]pyridin-5- yloxy} -benzoic acid
Ή NMR (400 MHz,DMSO-D6): δ 1.07-1.12 (m, 4H), 1.30 (d, J = 5.6 Hz, 6H), 2.94 (m, IH), 4.79 (m ,1H), 7.12
B9
(s, IH), 7.24-7.27 (m, 3H), 7.49 (s, IH), 7.59 (s, IH), 7.66 (dd, J = 3.2 Hz, J = 8.8 Hz, IH), 7.99-8.04 (m, 3H), 8.25 (d, J = 8.8 Hz, IH), 8.65 (d, J = 2.4, IH), 12.96 (bs, IH), 13.03 (bs, IH),.
MS (EI) m/z: 647.00 (M + 1).
Figure imgf000068_0001
Figure imgf000069_0001
8.63(d, J = 2.8 Hz IH), 12.90 (s, IH).
MS (EI) m/z: 551.5 (M + 1).
5-Chloro-2-[3-(6-cyclopropanesulfonyl-pyridin-3- yloxy)-5-isopropoxy-benzoylamino]-thiazole-4- carboxylic acid
'H NMR (400 MHz,DMSO-D6): δ 1.05-1.13 (m, 2H),
B 17 1.21-1.30 (m, 2H), 1.34 (d, J = 5.9 Hz, 6H), 2.84 (m
, 1H), 4.70 (m ,1H), 6.92-6.99 (m, IH), 7.29-7.34 (m, IH), 7.40-7.46 (m, IH), 7.58-7.64 (m, IH), 7.98-8.03 (m, IH), 8.48-8.52 (m, IH),
MS (EI) m/z: 538.20 (M + 1).
H 2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5- isopropoxy-benzoylamino]-5-pyridin-4-yl-thiazole-4- carboxylic acid
0 ίΎ° Ή NMR (400 MHz,DMSO-D6): δ 1.08-1.16 (m, 4H),
1.32 (d, J = 6 Hz, 6H), 2.95 (m, IH), 4.79 (m, IH), 7.11-
B 18
7.14 (m, IH), 7.50 (bs, H), 7.54 (s, IH), 7.55 (s, IH), 7.61 (s, IH), 7.68 (dd, J=8.8, J=2.9 Hz, IH), 8.03 (d, J=8.8 Hz, IH), 8.63 (d, J=5.4 Hz, 2H), 8.67 (d, J=3.0 Hz IH), 13.20 (bs, 2H).
MS (EI) m/z: 581.2 (M+l).
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5- isopropoxy-benzoylamino]-benzothiazole-6-carboxylic acid
Ή NMR (400 MHz,DMSO-D6): δ 1.09-1.13 (m, 4H), vO" 1.33 (d, J = 6.0 Hz, 6H), 2.96 (m,lH), 4.80 (m,lH), 7.13-
B 19
7.14 (m, lH), 7.50-7.53 (m,lH), 7.60-7.63 (m,lH), 7.68 (dd, J = 3.2 Hz, J = 8.8 Hz ,1H),7.82 (d, J = 8.4 Hz, IH), 8.01 -8.05 (m, 2H), 8.65 (s, IH), 8.67 (d, J=2.9Hz, IH), 13.10 (bs, 2H).
MS (EI) m/z: 554.1 (M + l). J' ° { 5 -Chloro-2-[3 -(6-yclopropanesulfony l-pyridin-3 - yloxy)-5-((S)-2-methoxy-l-methyl-ethoxy)- enzoylamino]-thiazol-4-yl} -acetic acid
Ή NMR (400 MHz,DMSO-D6): δ 1.09-1.13 (m, 4H),
1.26 (d, J = 6.0 Hz, 3H), 2.95 (m, 1H),3.29 (s, 31H), 3.49-
B20
3.52 (m, 2H), 3.62 (s, 2H), 4.77-4.81 (m, IH), 7.13 (s,
IH), 7.45 (s, IH), 7.59 (s, IH), 7.66 (dd, J = 2.8 Hz, J =
8.8 Hz, IH), 8.03 (d, J = 8.8 Hz, IH), 8.66 (d, J = 2.8
Figure imgf000071_0001
MS (EI) mlz: 582.10 (M + 1).
6-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2- methoxy-l-methyl-ethoxy)-benzoylamino]-nicotinic acid Ή NMR (400 MHz,DMSO-D6): δ 1.08-1.12 (m, 4H), 1 .25 (d, J = 5.6 Hz, 3H), 2.93 (m, IH), 3.33 (s, 3H), 3.47-
B21 3.54 (m, 2H), 4.80-4.83 (m, IH), 7.1 1 (s, IH), 7.42 (s,
IH), 7.53 (s, IH), 7.66 (d,J = 8.8 Hz, IH), 8.04 (d, J = 8.8 Hz, IH), 8.30 (s, 2H) 8.65 (s,lH),8.80 (s, IH), 1 1.28 (s, 1H),13.26 (bs, IH).
MS (EI) mlz: 528.10 (M + 1).
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5- (tetrahydro-furan-3-yloxy)-benzoylamino]-thiazole-4- carboxylic acid
Ή NMR (400 MHz,DMSO-D6): δ 1.03-1.16 (m, 4H), 1.98-2.07 (m, IH), 2.20-2.31 (m, IH), 2.94 (m , 1H),
B22
3.80-3.95 (m, 4H), 3.65-3.95 (m, 4H), 5.19 (bs ,1H), 7.13 (s, IH), 7.52 (s, IH), 7.58 (s, IH), 7.68 (d, J=8.8 Hz IH), 8.00-8.08 (m, 2H), 8.66 (s, IH), 12.93 (bs, IH), 13.05 (bs, IH)
MS (EI) mlz: 532.0 (M + 1). 5-Bromo-2-[3-(6-cycIopropanesulfonyl-pyridin-3- yloxy)-5-isopropoxy-benzoylamino]-thiazole-4- carboxylic acid
'H NMR (400 MHz,DMSO-D6): δ 1.08-1.13 (m, 4H),
B23 1.31 (d, J = 6.4 Hz, 6H), 2.95 (m, IH), 4.78 (m, IH), 7.12
(s, IH), 7.47 (s, IH), 7.58 (s, IH), 7.67 (dd, J=8.8, J=2.9 Hz, IH), 8.03 (d, J=8.8 Hz, IH), 8.66 (d, J=2.9 Hz IH), 12.29 (bs, 2H).
MS (EI) mlz: 582.0 (M+), 584.0 (M + 2).
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5- isopropoxy-benzoylamino]-4-methyl-thiazole-5- carboxylic acid
'H NMR (400 MHz,DMSO-D6): δ 1.08-1.16 (m, 4H),
B24 1.31 (d, J = 6 Hz, 6H), 2.57 (s, 3H), 2.95 (m ,1H), 4.78
(m ,1H), 7.10-7.1 1 (m, IH), 7.46 (s, IH), 7.57 (s, IH), 7.66 (dd, J=2.8 Hz, J=8.8 Hz IH), 8.03 (d, J = 8.6 Hz, I H), 8.65 (d, J=2.7Hz, I H), 12.98 (bs, 2H)
MS (EI) mlz: 518.10 (M + 1).
N-(4-Carbamoylmethyl-5-chloro-thiazol-2-yl)-3-(6- cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy- benza
mide
Ή NMR- (DMSO-d6, 400MHz), δ 1.08-1.14 (m, 4H),
B25
1.31 (d, J =5.9Hz, 6H), 2.95 (m, lH), 3.38 (s, 2H), 4.73 (m, IH), 7.01 (s, IH), 7.39 (s, IH), 7.55 (s, I H), 7.63 (dd, J = 8.8 & 2.9 Hz, IH), 8.02(d, J = 8.8 Hz, IH), 8.64 (d, J = 2.9 Hz IH),
MS (EI) mlz: 551.1 (M + 1).
2-[3 -(6-Cyclopropanesulfonyl-pyridin-3 -yloxy)-5 - isopropoxy-benzoylamino]-5-methyl-thiazole-4-
B26 carboxylic acid
'H NMR (400 MHz,DMSO-D6): δ 1.08-1.16 (m, 4H), 1 .32 (d, J = 5.6 Hz, 6H), 2.63 (s, 3H), 2.95 (m, IH), 4.78 (m, IH), 7.09 (s, IH), 7.47 (s, IH), 7.58 (s, IH), 7.66 (d,
J=8.6 Hz, IH), 8.03 (d, J=8.6 Hz, IH), 8.66 (s, IH), 12.85 (bs, IH).
MS (EI) mlz: 518.2 (M + 1).
2-{5-Chloro-2-[3-(6-cyclopropanesulfonyl-pyridin-3- yloxy)-5-isopropoxy-benzoylamino]-thiazol-4-yl}-2- m ethyl -propionic acid
Ή NMR- (DMSO-d6, 400MHz), δ 1.06-1.14 (m, 4H),
B27 1.31 (d, J = 5.8 Hz, 6H), 1.53 (s, 6H), 2.95 (m, IH), 4.79
(m, IH), 7.07-7.1 1 (m, IH), 7.45-7.48 (m, IH), 7.56 (s, IH), 7.66 (dd, J = 8.5 & 2.7 Hz, IH), 8.03 (d, J = 8.5 Hz, IH), 8.65 (d, J = 2.7 Hz IH), 12.90 (s, IH).
MS (EI) mlz: 580.2 (M + 1).
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5- isopropoxy-benzoy lam ino] -4, 5 , 6, 7-tetrahydro- benzothiazol-4-yl} -acetic acid
1H NMR (400 MHz, DMSO-d6) : 1.06-1.15 (m, 4H), 1.31 (d, J = 5.9Hz, 6H), 1.54-1.63 (m, IH), 1.65-1.77 (m, I H) 1.81 -1.91 (m, I H), 1.92-1.21 (m, IH), 2.24 (dd, J
B28 =15.2 Hz, 10.8 Hz, IH), 2.64-2.68 (m,2H), 2.88 (dd, J =
2.8 Hz, 15.6 Hz, IH), 2.93-2.98 (m, 'lH), 3.05-3.10 (m, IH), 4.78 (m, IH), 7.07(s, IH), 7.44 (s, IH), 7.55 (s, IH), 7.65 (dd, J = 2.9 Hz, 8.8 Hz, IH), 8.02 (d, J = 8.8Hz, IH), 8.65(d, J = 2.9 Ηζ, ΙΗ), 12.22 (bs, IH), 12.52 (bs, IH).
MS (EI) mlz: 572.2 (M + l).
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5- isopropoxy-benzoylamino]-4,5,6,7-tetrahydro- benzothiazole-6-carboxylic acid
B29 1 H NMR (400 MHZ, DMSO-d6) : 1.07- 1.16 (m,
4H), 1.31 (d, J =5.8Hz, 6H), 1.83-1.90 (m, IH), 2.13-2.17
(m, I H), 2.63-2.69 (m, 2H), 2.73-2.79 (m, IH), 2.83-
2.85 (m, IH), 2.91-2.99 (m, 2H), 4.78 (m, IH), 7.08-7.09 (m, 1H), 7.44 (s, 1H), 7.56 (s, 1H), 7.66 (dd, J = 3.2
Hz,8.8 Hz, 1H), 8.03 (d, J = 8.8Hz, 1H), 8.66 (d, J = 2.5 Hz, 1H), 12.499 (bs, 2H).
MS (EI) m/z: 558.1 (M + 1).
2-[3-(4-Carboxymethyl-5-chloro-thiazol-2-ylcarbamoyl)- jj β 5-(6-cyclopropanesulfonyl-pyridin-3-yloxy)-phenoxy]-2- methyl-propionic acid
Ή NMR (400 MHz, DMSO-d6): δ 1.09 (m, 4H), 2.06 (s,
B30 6H), 2.92 (m, 1H), 3.50 (s, 2H), 6.94 (s, 1H), 7.37 (s,
1H), 7.56-7.65 (m, 2H), 8.01 (d, J = 8 Hz, 1H), 8.6 (s, 1H), 12.9 (bs, 3H).
MS (EI) m/z: 596.1 (M + l).
2-{2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5- isopropoxy-benzoylam ino] -5 -fluoro-thiazol-4-yl } -2- methyl-propionic acid
V ° Ή NMR (400 MHz, DMSO-d6): δ 1.16-1.20 (m, 4H),
1.37 (d, J = 6.4 Hz, 6H), 1.58 (s, 6H), 3.00-3.04 (m, 1H),
B31
4.82-4.88 (m, 1H), 7.15 (s, 1H), 7.51 (s, 1H), 7.61 (s, 1H), 7.74 (dd, J = 2.8 Hz, 8.0 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 8.72 (d, J = 2.4 Hz, 1 H), 12.75 (bs, 2H).
MS (EI) m/z: 564.2 (M + 1).
Example CI : 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-[5-(l,2-dihydroxy-ethyl)- thiazol-2-yl]-5-isopropoxy-benzamide
Figure imgf000074_0001
A mixture of 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(5-vinyl-thiazol- 2-yI)-benzamide (138.9 mg, 0.286 mmol), Osmium tetraoxide ( 7.27 mg, .0286 mmol), 4- methyl-4-oxidomorpholin-4-ium (50.2 mg, 0.429 mmol) in THF: Water (4: 1, 5 ml) was stirred for 3 hrs at room temperature . Reaction was monitored by TLC. On completion of the reaction, The reaction mixture was quenched with sodium thiosulfate solution (10 ml), organic solvent was evaporated under reduced pressure, the residue was partitioned between water and ethyl acetate layers, the organic layer was washed with brine, dried over anhydrous sodium sulfate, solvent was evapourated under reduced pressure to obtained crude product, which was purified by preparative TLC (5% MeOH-DCM) to afford final compound CI (60 mg)._
1HNMR (400 MHz,DMSO-d6) : δ 1 .08-1.12 ( m, 4H), 1.30 ( d, J = 5.9 Hz, 6H ), 2.95 ( m, 1 H), 3.45-3.57 (m, 2H), 4.73-4.80 (m, 2H), 4.94 ( t, J = 5.9 Hz, 1H), 5.64 ( d, J = 4.4 Hz, 1 H), 7.08 (s, 1H ), 7.36 (s, 1H), 7.44 (s, 1H), 7.55 (s, 1H), 7.65 (dd, J = 2.4 Hz, J = 8.3 Hz, 1 H), 8.02 (d, J = 8.8Hz, 1H), 8.65 (d, J =2.5 Hz, 1H), 12.5(s, 1H).
MS (EI) m/z: 520.2 (M + 1).
Examples C2 prepared in analogues manner of example (CI) from the appropriate intermediate (preparation 10)
Figure imgf000075_0001
The below list of compounds, but not limited to these, can also be synthesized following the general synthesis described above:
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Glucokinase Activity Assay:
The glucokinase (GK) assay is a coupled enzymatic assay. GK catalyzes the first step of glycolysis, the conversion of glucose to glucose-6-phosphate (G6P) in the presence of ATP. G6P in turn is converted by glucose-6-phosphate dehydrogenase (G6PD) to 6- phosphogluconate, a process that requires NAD, resulting in NADH formation. Since the GK-catalyzed step is the rate-limiting step of this coupled enzymatic process, the rate of accumulation of 6-phosphogluconate and NADH is directly proportional to the rate of glucose phosphorylation by GK. The rate of the GK-catalyzed reaction can therefore be measured by monitoring the increase in NADH absorbance at 340 nm. The assay is carried out according to the protocol outlined in Hariharan et al (1997), Diabetes 46: 1 1 -16. Briefly, the test compounds are incubated in a reaction mix containing 25 mM HEPES (pH 7.2), 10 mM MgCl2, 100 mM KC1, 5 mM ATP, 2 mM DTT, 0.5 mM NAD, 1 U/ml Leuconostoc mesenteroides G6PD, 0.3 U/ml of purified human recombinant GK, and different concentrations of glucose. Enzymatic activity is calculated from the initial reaction velocity, measured from the change in NADH absorbance as a function of time.
Compounds described in formula (I), in concentration ranges from 1.0 nM to 500 μΜ, are tested in the purified human recombinant giucokinase assay described above.
A compound is considered to be a giucokinase activator if it, in its testable range of concentrations, yields a higher rate of glucose phosphorylation than in its absence at a particular glucose concentration, for example at 5 mM glucose.
Characterization of giucokinase activators from the in vitro giucokinase assay:
Compounds of general formula (I) are tested in the in vitro GK enzymatic assay to monitor dose-dependent effect on giucokinase activation (in kinetic mode), as described above, at various glucose concentrations. The So.s of giucokinase for glucose at different concentration of each compound of interest is calculated from the following modified version of the Michaelis-Menten equation, V = Vmax [S] (So.s" + [S]"), where [S] is the glucose concentration and n is the Hill coefficient (taken as 1.7 to account for the sigmoidal kinetics of giucokinase with respect to glucose). The S0.5 is plotted against the log of the compound concentration. The change in the S0.5 of giucokinase (ASo.s) for glucose is calculated by subtracting the S0.5 at each concentration of the compound from the S0.5 in the vehicle control. The ASo.s is then normalized to a percent scale, where the S0.5 in the vehicle control is set to 0% and 0 mM glucose is set to 100%. The % ASo.s is then plotted against the log of the compound concentration. The EC50 and Emax of % change in S0.5 is obtained from the sigmoidal fit of the data. Detailed protocol has been described in our earlier patent WO- 2008/104994 which is incorporated herein by reference. Characterization data of some representative giucokinase activators of the present disclosure, which are illustrative but not limiting, are given in table I below.
The giucokinase activation data of some representative compounds of the present disclosure, which are illustrative but not to be construed as limiting the scope or spirit of the disclosure, are given in the table III below.
Table III: EC50 and Emax of GK activators
Figure imgf000084_0001
B 12 0.037 0.032 94
B 13 0.046 0.025 95
B 14 - >10 -
B 15 - 0.347 0.191 93
B 16 0.13 0.065 94
B 17 0.178 0.151 93
B 18 - >10 -
B 19 0.051 0.047 94
B20 0.138 0.058 94
B21 0.071 0.043 92
B22 0.315 0.34 89
B23 - >10 -
B24 0.5 0.33 82
B26 0.631 0.289 85
B27 - >10 -
B31 0.84 0.72 93
C2 1.9 0.53. 91
Measurement of glycogen synthesis in primary rat hepatocytes:
Primary hepatocytes are collected from male Wistar rats, and tested for viability by trypan blue exclusion. Primary hepatocytes cultures with viability greater than 95% are selected for the glycogen synthesis assay. The cells are seeded in a 48-well plate at a density of 200,000 cells/well in 250 μΐ Minimal Essential Medium (MEM) containing 10% foetal calf serum (FCS) and 1.7 μΜ insulin, and incubated for 4 hours at 37°C to allow attachment. The medium is replaced with fresh MEM containing 10% FCS, 1 .7 μΜ insulin and 10 nM dexamethasone, and the cells are incubated for 16 hours at 37°C. The medium is then replaced with fresh MEM (serum-free) containing 2
Figure imgf000085_0001
of D-[U14C]-Glucose along with 10 μΜ of the compound in a final DMSO concentration of 0.1%. The final glucose concentration is brought to 10 mM by the addition of D-Glucose (MEM already contains 5 mM glucose). The cells are incubated for 3 hours at 37°C. The cells are washed twice with 150 mM NaCl, lysed with 0.1 N NaOH, and the lysate precipitated with 8% w/v trichloroacetic acid (TCA) and 1 mg/well unlabeled glycogen as carrier. Cell debris is pelleted by centrifugation, the supernatant is removed, and the glycogen is precipitated with 63% ethanol. After another round of centrifugation, the supernatant is removed, and the pellet containing the precipitated glycogen is dried overnight. De novo synthesized glycogen is estimated in a scintillation counter (MicroBeta Trilux, Perkin Elmer), and expressed as fold increase over DMSO control.
The protocol for the glycogen assay is based on the method described in "Biochem J. 1990 Feb 15; 266(1): 91-102" with a few minor modifications. The protocol for isolation of primary rat hepatocytes is based on the method described in "Methods in Enzymology, Vol. III. pp 34-50. Ed. by S.P. Colowick and N.O. Kaplan. New York, Academic Press, 1957" with a few minor modifications.
Compounds described in formula (I), in concentration ranges from 1.0 nM to 500 μΜ, are tested in glycogen synthesis assay described above.
A compound is considered to be a glucokinase activator in a cellular environment if it demonstrates significant increase of glycogen synthesis over DMSO control as described in the above mentioned glycogen synthesis assay.
The glycogen synthesis data of some representative compounds of the present invention, which are illustrative but not limiting, is given in the follwing table.
Glycogen synthesis data
Figure imgf000086_0001

Claims

We claim:
1. A compound of for
Figure imgf000087_0001
wherein
ring A is a heteroaryl;
ring-B is a 4-12 membered saturated, unsaturated, or partially unsaturated mono or bicyclic ring containing 1 - 4 hetero atoms indep'endently selected from N, O, or S with at least one nitrogen in the ring;
X is selected from O or a bond;
ring-C is selected from an unsubstituted or a substituted cycloalkyl, an unsubstituted or a substituted heterocyclyl, an unsubstituted or a substituted heteroaryl;
R1 is selected from an unsubstituted or a substituted alkyl, an unsubstituted or a substituted alkenyl, an unsubstituted or a substituted alkynyl, an unsubstituted or a substituted cycloalkyl, an unsubstituted or a substituted cycloalkylalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted arylalkyl, an unsubstituted or a substituted heterocyclyl, an unsubstituted or a substituted heterocyclylalkyl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted heteroarylalkyl;
R2 is selected from halogen, monohaloalkyl, dihaloalkyl, perhaloalkyl, monohaloalkoxy, dihaloalkoxy, perhaloalkoxy, cyano, nitro, alkyl, alkenyl, alkynyl, methylenedioxy, amidino, -NR5R6, -OR5, -NR5C(0)OR6, -(CR7R8)nC(0)OR5, -(CR7R8)nC(0)NR5R6, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkenyl, aryloxy, or heteroaryloxy;
R3 and R4 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, mono, di or tri substituted haloalkyl, nitrile, nitro, oxo, -NR5R6, -OR5, -S(0)pR5, -S(0)pNR5R6, -NR5S(0)pR6, - NR5C(0)R6, -OS(0)pR6, -NR5C(0)OR6, -(CR7R8)„C(0)OR5, -(CR7R8)n(CO)NR5R6, - (CR7R8)nS(0)pNR5R6, -(CR7R8)nN(R5)C(0)R5, -(CR7R8)nOR5, -C(R7R8)nNR5R6, - ' C(R7R8)nCO(R5) and -S(0)pC(R7R8)nC(0)OR5 ; wherein R3 and R4 is each optionally substituted with one or more substituents selected from halo, straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulfonyl, oxo, nitro, cyano, -(CR7R8)nCOOR5, -(CR7R8)nCOR5, - (CR7R8)nC(0)NR5R6 -(CR7R8)nOR5, -SR5 or -NR5R6 ; or
R3 and R4 are on the same carbon atom taken together form a spiro 3- to 7-membered
heterocyclyl or a spiro C3.7cycIoalkyl which is optionally substituted with one or more substituent independently selected from halo, hydroxy,
Figure imgf000088_0001
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl and heterocyclylalkyl, or
R5 and R6 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S, the said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nito, cyano, -OR5, -SR5, - NR5R6, oxo, alkylsulfonyl, -COOR5, -C(0)NR5R6, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl; R7 and R8 are independently selected from the group consisting of hydrogen, fluorine, OR5, alkyl, and perfluoroalkyl, or
R7 and R8 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S, said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nito, cyano, oxo, -OR5, -SR5, -NR5R6, alkylsulfonyl, - COOR5, -C(0)NR5R6, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
in addition to R3 and R4 ring-B can be further optionally substituted with one or more substituents selected from halo, straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulphonyl, oxo, nitro, cyano, -COOR5, - C(0)NR5R6 -OR5, -SR5 or -NR5R6;
m = 0-3;
n = 0-4; p = 0-2;
with the proviso that when ring C contains nitrogen, the ring is not connected to sulfonyl group via the nitrogen atom. 2. The compound as claimed in claim 1, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof wherein:
ring A is a heteroaryl having at least 1 nitrogen;
ring-B is a 4-12 membered saturated, unsaturated, or partially unsaturated mono or bicyclic ring containing 1 - 4 hetero atoms independently selected from N, O, or S with at least one nitrogen in the ring;
X is selected from O or a bond;
ring-C is selected from a cycloalkyl, a heterocyclyl or a heteroaryl;
wherein said ring C is unsubstituted or substituted with up to 4 substituents independently selected from alkyl, alkenyl, alkynyl, halogen, mono, di, tri or perhaloalkyl, hydroxy, alkoxy, nitrile, oxo, amino, monoalkylamino or dialkyamino;
R1 is selected from alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl;
wherein said R1 is unsubstituted or substituted with up to 4 substituents independently selected from alkyl, halogen, mono, di, tri or perhaloalkyl, nitrile, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkylcarboxy, nitro, oxo, amino, monoalkylamino or dialkyamino, -(CR7R8)nC(0)OR5, - (CR7R8)nC(0)NR5R6 or - (CR7R8)nC(0)R5;
R2 is selected from halogen, monohaloalkyl, dihaloalkyl, perhaloalkyl, monohaloalkoxy, dihaloalkoxy, perhaloalkoxy, cyano or alkyl;
R3 and R4 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, mono, di or tri substituted haloalkyl, nitrile, nitro, oxo, -NR5R6, -OR5, -S(0)pR5, -S(0)pNR5R6, -NR5S(0)pR6, -
NR5C(0)R6, -OS(0)pR6, -NR5C(0)OR6, -(CR7R8)nC(0)OR5, -(CR7R8)n(CO)NR5R6, - (CR7R8)nS(0)pNR5R6, -(CR7R8)nN(R5)C(0)R5, -(CR7R8)nOR5, -C(R7R8)nNR5R6, - C(R7R8)nCO(R5) and -S(0)pC(R7R8)nC(0)OR5 ; wherein R3 and R4 is each optionally substituted with one or more substituents selected from halo, straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulfonyl, oxo, nitro, cyano, -(CR7R8)nCOOR5, -(CR7R8)„COR5, - (CR7R8)nC(0)NR5R6 -(CR7R8)nOR5, -SR5 or -NR5R6;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl; or
R5 and R6 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S;
R7 and R8 are independently selected from the group consisting of hydrogen, fluorine, OR5, alkyl, and perfluoroalkyl, or
R7 and R8 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S, the said ring system is further optionally substituted with 1 to 4 substituents independently selected from halo, alkyl, alkenyl, alkynyl, nito, cyano, oxo, -OR5, -SR5, - NR5R6, alkylsulfonyl, -COOR5, -C(0)NR5R6, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, or heteroaryl, heteroarylalkyl; in addition to R3 and R4 ; ring-B can be further optionally substituted with one or more substituents selected from halo, straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulphonyl, oxo, nitro, cyano, -COOR5, - C(0)NR5R6 , -OR5, -SR5 or -NR5R6;
m = 0-3;
n = 0-4; and
p = 0-2.
The compound : as claimed in claim 1, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof wherein ring A is selected from oxadiazole, thiadiazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoquinoline, quinoline, isothiazole, isoxazole, oxazole, thiazole, triazole or triazine;
ring-B is selected from imidazole, oxazole, pyridine, pyrazole, pyrazine, pyrimidine, thiazole, thiazolone, thiazolopyridine, thiazolopyrimidine, benzothiazole, benzopyrimidine, thiadiazole, thiazolopyrimidine, thiazolopyridine, quinoline, isoquinoline, tetrahydrobenzothiazole, tetrahydrothiazolopyridine, tetrahydrothiazolopyrimidine, tetrahydroquinoline or tetrahydroisoquinoline;
X is selected from O or a bond;
ring-C is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentanone, cyclohexanone, tetrahydrofuran, tetrahyropyran, pyrazole, imidazole, thiazole or oxazole;
wherein said ring C is unsubstituted or substituted with up to 4 substituents independently selected from alkyl, halogen, mono, di, tri or perhaloalkyl, hydroxy, alkoxy, nitrile, oxo, amino, monoalkylamino or dialkyamino;
R1 is selected from alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuran or tetrahyropyran;
wherein said R1 is unsubstituted or substituted with up to 4 substituents independently selected from alkyl, halogen, mono, di, tri or perhaloalkyl, hydroxy, alkoxy, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkylcarboxy, amino, monoalkylamino or dialkyamino,. -(CR7R8)nC(0)OR5, - (CR7R8)nC(0)NR5R6 or -(CR7R8)nC(0)R5;
R2 is selected from halogen, or alkyl;
R3 and R4 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidine, pyrrolidinealkyl, morpholine, morpholinealkyl, piperidine, piperidinealkyl, phenyl, benzyl, pyridine, pyrazole, thiazole, mono, di or tri substituted haloalkyl, nitrile, nitro, oxo, -S(0)pR5, -S(0)pNR5R6, -NR5S(0)pR6, -NR5C(0)R6, -OS(0)pR6, -NR5C(0)OR6, -(CR7R8)nC(0)OR5, -(CR7R8)n(CO)NR5R6, -(CR7R8)nS(0)pNR5R6, (CR7R8)nN(R5)C(0)R5, -(CR7R8)nORs, -C(R7R8)nNR5R6, -C(R7R8)nCO(R5) and - S(0)pC(R7R8)nC(0)OR5 ; wherein R3 and R4 is each optionally substituted with one or more substituents selected from halo, straight chain or branched chain alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycle, alkylsulfonyl, oxo, nitro, cyano, - (CR7R8)nCOOR5, -(CR7R8)nCOR5, -(CR7R8)nC(0)NR5R6 -(CR7R8)nOR5, -SR5 or - NR5R6 ; R5 and R6 are independently selected frorp the group consisting of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl or
R5 and R6 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S,
R7 and R8 are independently selected from the group consisting of hydrogen, fluorine, OR5, alkyl and perfluoroalkyl, n = 0-4; and
p = 0-2.
The compound as claimed in claim 1, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof wherein ring A is selected from pyrrole, pyrazole, pyridine, pyrazine, pyrimidine or pyridazine; ring-B is selected from imidazole, pyridine, pyrazole, pyrazine, pyrimidine, thiazole, thiazolone, thiazolopyridine, benzothiazole or thiazolopyridine;
X is selected from O or bond;
ring-C is selected from cyclopropyl, cyclobutyl or cyclopentyl;
R1 is selected from alkyl, cyclopropyl, tetrahydrofuran or tetrahyropyran;
wherein said R1 is unsubstituted or substituted with up to 4 substituents independently selected from alkyl, halogen, hydroxyl or alkoxy;
R2 is selected from halogen, or alkyl;
R3 and R4 are independently selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, cyclopropyl, pyrrolidine, pyrrol idinealkyl, morpholine, morpholinealkyl, piperidine, piperidinealkyl, phenyl, benzyl, pyridine, pyrazole, - (CR7R8)nC(0)OR5, -(CR7R8)n(CO)NR5R6, -(CR7R8)nOR5, -C(R7R8)nNR5R6 and - C(R7R8)nCO(R5); wherein R3 and R4 is each optionally substituted with one or more substituents independently selected from halo, acyl, straight chain or branched chain alkyl;
R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl; or
R5 and R6 taken together form a monocyclic or a bicyclic ring system which is saturated or partially unsaturated and optionally have additional heteroatoms independently selected from O, N or S;
R7 and R8 are independently selected from the group consisting of hydrogen, fluorine, OR5, alkyl and perfluoroalkyl;
m = 0-3;
n = 0-4; and
p = 0-2.
A compound as claimed in claim 1 which is:
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-(5-fluoro-thiazol-2-yl)-5-isopropoxy- benzamide; 3-(6-Cyclopropahesulfonyl-pyridin-3-yloxy) -5-isopropoxy-N-thiazol-2-yl-benzamide; 3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy) -5 -isopropoxy-N-( 1 -methyl- 1 H-pyrazol-3 - yl)-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy) -5 -i sopropoxy-N-( 1 H-pyrazol-3 -yl)- benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy) -5-isopropoxy-N-thiazolo[5,4-b]pyridin-2-yl- benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy) -5-isopropoxy-N-(5-morpholin-4-yl-thiazol-
2- yl)-benzamide;
3- (6-Cyclopropanesulfonyl-pyridin-3-yloxy) -5-isopropoxy-N-(5-methoxy-thiazolo[5,4- b]pyridin-2-yl)-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy) -5 -i sopropoxy-N-(5 -pyrazol- 1 -yl-thiazol-2- yl)-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy) -5-isopropoxy-N-(l -thiazol-2-yl-lH-pyrazol- 3-yl)-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy) -5 -isopropoxy-N-(5 -methyl-4-oxo-4,5 - dihydro-thiazol-2-yl)-benzamide;
N-(6-Chloro-benzothiazol-2-yl)-3-(6-cyclopropanesulfonyl-pyridin-3-yloxy)-5-- isopropoxy-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3yloxy)-5-isopropoxy-N-(6-methoxy-benzothiazol-2- yl)-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(5-isopropoxy- thiazolo[5,4-b]pyridin-2-yl)-benzamide;
N-[4-(l-Acetyl-piperidin-4-yl)-thiazol-2-yl]-3-(6cyclopropanesulfonyl-pyridin-3-yloxy)- 5-isopropoxy-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-(5-ethoxy-thiazolo[5,4-b]pyridin-2-yl)-5- isopropoxy-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)- 5-(tetrahydro-furan-3-yloxy)-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2-methoxy-l -methyl-ethoxy)-N-(5- methoxy-hiazolo[5,4-b]pyridin-2-yl)-benzamide;
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2-methoxy-l -methyl-ethoxy)-N- pyrazin-2-yl-benzamide; 2- [3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazole-4- carboxylic acid methyl ester;
3- (6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-N-(5-vinyl-thiazol-2-yl)- benzamide;
2- [3 -(6-Cyclopropanesulfony l-pyridin-3 -yloxy)-5 -(5 -methoxy-thiazolo[5 ,4-b]pyridin-2- ylcarbamoyl)-phenoxy]-2-methyl-propionic acid tert-butyl ester;
3- (6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-(5-fluoro-thiazol-2-yl)-5-isobutyl- benzamide;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazole-4- carboxylic acid;
2- [3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazole-4- carboxylic acid amide;
3- (6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-(4-hydroxymethyl-thiazol-2-yl)-5- isopropoxy benzamide;
2- [3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-(5-methoxy-thiazolo[5,4-b]pyridin-2- ylcarbamoyl)-phenoxy]-2-methyl-propionic acid;
{2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazol-4- yl} -acetic acid;
{2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]- thiazolo[5,4-b]pyridin-5-yloxy}-acetic acid;
{5-Chloro-2-[3-(6-cyclopropanesulfonyl-pyridin-3-yloxy)-5-isobutyl-benzoylamino]- thiazol-4-yl} -acetic acid;
l -{2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazol- 5-ylmethyl}-piperidine-4-carboxylic acid;
4- {2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino] thiazolo[5,4-b]pyridin-5-yloxy} -benzoic acid;
3- {2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazol-
4- yl} -propionic acid;
l-{2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-thiazol-
5- ylmethyl}-pyrrolidine-2-carboxylic acid;
N-[4-(2-Azetidin-l -yl-2-oxo-ethyl)-5-chloro-thiazol-2-yl]-3-(6-cyclopropanesulfonyl- pyridin-3-yloxy)-5-isopropoxy-benzamide;
4-{3-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-pyrazol- 1 -ylmethyl} -benzoic acid; 1 - { 2- [3 -(6-Cyclopropanesulfony l-pyridin-3 -yloxy)-5 -isopropoxy-benzoylamino]-thiazol- 5-yl}-piperidine-4-carboxylic acid;
{3-[3-(6-CyclopropanesuIfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-pyrazol-l- yl}-acetic acid;
{5-Chloro-2-[3-(6-cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]- thiazol-4-yl} -acetic acid;
5- Chloro-2-[3-(6-cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]- thiazole-4-carboxylic acid;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yIoxy)-5-isopropoxy-benzoylamino]-5-pyridin-
4- yl-thiazole-4-carboxylic acid;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]- benzothiazole-6-carboxylic acid;
{5-Chloro-2-[3-(6-yclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2-methoxy-l -methyl- ethoxy)-enzoylamino]-thiazol-4-yl}-acetic acid;
6- [3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-((S)-2-methoxy-l -methyl-ethoxy)- benzoylaminoj-nicotinic acid;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-(tetrahydro-furan-3-yloxy)- benzoylamino]-thiazole-4-carboxylic acid;
5- Bromo-2-[3-(6-cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]- thiazole-4-carboxylic acid;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-4-methyl- thiazole-5-carboxylic acid;
N-(4-Carbamoylmethyl-5-chloro-thiazol-2-yl)-3-(6-cyclopropanesulfonyl-pyridin-3- yloxy)-5-isopropoxy-benzamide;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-5-methyl- thiazole-4-carboxylic acid;
2-{5-Chloro-2-[3-(6-cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy- benzoylamino]-thiazol-4-yl}-2-methyl-propionic acid;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-4,5,6,7- tetrahydro-benzothiazol-4-yl} -acetic acid;
2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-4,5,6,7- tetrahydro-benzothiazole-6-carboxylic acid;
2-[3-(4-Carboxymethyl-5-chloro-thiazol-2-ylcarbamoyl)-5-(6-cyclopropanesulfonyl- pyridin-3-yloxy)-phenoxy]-2-methyl-propionic acid; 2- {2-[3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-5-isopropoxy-benzoylamino]-5- fluoro-thiazol-4-yl}-2-methyl-propionic acid;
3- (6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-[5-(l,2-dihydroxy-ethyl)-thiazol-2-yl]-5- isopropoxy-benzamide; or
3-(6-Cyclopropanesulfonyl-pyridin-3-yloxy)-N-[4-(l ,2-dihydroxy-ethyl)-thiazol-2-yl]-5- isopropoxy-benzamide.
6. A compound of formula (I), as claimed in any one of the claims 1 to 5, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treating a disease through Glucokinase activation.
7. A compound of formula (I), as claimed in any one of the claims 1 to 5, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treating a disease through Glucokinase deinhibition.
8. A compound of formula (I), as claimed in any one of the claims 1 to 5, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for prophylactic or therapeutic treatment of hyperglycemia or diabetes, particularly type II diabetes.
9. A compound of formula (I), as claimed in any one of the claims 1 to 5, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for preventing diabetes, particularly type II diabetes, in a human demonstrating pre-diabetic hyperglycemia or impaired glucose tolerance.
10. A compound of formula (I), as claimed in any one of the claims 1 to 5, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for combined treatment or prevention of diabetes and obesity.
11. A compound of formula (I), as claimed in any one of the claims 1 to 5, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treating or preventing obesity.
12. A compound of formula (I), as claimed in any one of the claims 1 to 5, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treatment or prevention of dyslipidemia.
13. A compound of formula (I), as claimed in any one of the claims 1 to 5, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for combined treatment or prevention of diabetes, obesity and dyslipidemia.
14. A compound of formula (1), as claimed in any one of the claims 1 to 5, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for treating hyperglycemia, IGT, Syndrome X, type 2 diabetes, type 1 diabetes, dyslipidemia, hyperlipidemia hypertension, for the treatment or prophylaxis of obesity, for lowering of food intake, for appetite regulation, or for regulating feeding behaviour.
15. A compound of formula (I), as claimed in any one of the claims 1 to 5, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, solvates and formulations thereof, for enhancing the secretion of enteroincretins, like GLP-1 and GIP, thereby managing diseases or disorders associated with modulation of secretions of enteroincretins, like hyperglycemia, insulin resistance, impaired glucose tolerance, obesity, gastric emptying, gastroparesis, satiety, leptin resistance, dyslipidemia, wound healing, diabetic complications, such as nephropathy, retinopathy, neuropathy and cataracts.
16. A pharmaceutical composition comprising, as an active ingredient, at least one compound of formula (I), as claimed in any one of the claims 1 to 5, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, and solvates thereof, together with one or more pharmaceutically acceptable carriers or excipients.
'
17. A pharmaceutical composition comprising, as an active ingredient, at least one compound of formula (1), as claimed in any one of the claims 1 to 5, or its stereoisomers, tautomers, prodrugs, pharmaceutically acceptable salts, polymorphs, and solvates thereof, in combination with one or more pharmaceutically acceptable therapeutically active agents.
18. The pharmaceutieal composition as claimed in claim 17 wherein, the pharmaceutically acceptable therapeutically active agent is selected from antidiabetic agents, anti- hyperglycemic agents, anti-obesity agents, anti-hypertensive agents or anti-dyslipidemic agents.
19. The pharmaceutical composition as claimed in claim 17 or 18 wherein the pharmaceutically acceptable therapeutically active agent is selected from insulin secretagogues like sulfonylureas selected from amaryl, glyburide, glimepiride, glipyride, glipizide; insulinotropic sulfonyl urea receptor ligands like meglitinides selected from nateglinide, rapaglinide; biguanides like metformin, phenformin, buformin; glucagon antagonists like a peptide or non-peptide glucagon antagonist; glucosidase inhibitors like acarbose, miglitol; glucose sensitive insulinotropic agents like GLP-l, GLP-1 mimetics like exendin-4; insulin sensitizers like troglitazone, rosiglitazone, pioglitazone; dipeptidyl peptidase-IV inhibitors like sitagliptin, vildagliptin; sibutramine, orlistat, rimonabant; fibrates like gemfibrozil, fenofibrate; niacin; statins like rosuvatatin, atorvastatin, simvastatin; cholesterol absorption inhibitors like ezetimibe; bile acid sequestrants like cholestyramine; diuretics like hydrochlorothiazides, mannitol, indapamide, furosemide; angiotensin converting enzyme (ACE) inhibitors like captopril, enalapril; angiotensin-II receptor type-I blockers (ARB) like losartan, irbesartan; rennin inhibitors like aliskerin; β- adrenergic receptor blockers like atenolol, metoprolol; calcium channel blockers like amlodipine, nifedipine; aldosterone receptor antagonist like spironolactone, aldosterone synthase inhibitors like FAD286.
20. Use of compound of formula (I) as claimed in any of the claims 1-5, its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof, in the manufacture of a medicament for the activation of Glucokinase.
21. A method of treatment of glucokinase activator mediated disease by administering a therapeutically effective amount of a compound of formula (I) as claimed in any of the claims 1 -5, its polymorphs, stereoisomers, pharmaceutically acceptable salt, solvate or pro-drug thereof to a mammal in need of such treatment.
22. A method of combined treatment or prevention of diabetes, obesity and dislipidemia by administering an effective amount of a compound of formula (I) as claimed in any of the claims 1 -5, its polymorph, stereoisomer, prodrug, solvate or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment.
23. A method of combined treatment of diabetes and obesity by administering an effective amount of a compound of formula (I) as claimed in any of the claims 1 -5, its polymorph, stereoisomer, prodrug, solvate or a pharmaceutically acceptable salt thereof, to a mammal in need of such treatment.
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