WO2013164838A1 - Heterocyclic compounds and their use for treatment of diabetes, obesity or related disorders - Google Patents

Heterocyclic compounds and their use for treatment of diabetes, obesity or related disorders Download PDF

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WO2013164838A1
WO2013164838A1 PCT/IN2013/000130 IN2013000130W WO2013164838A1 WO 2013164838 A1 WO2013164838 A1 WO 2013164838A1 IN 2013000130 W IN2013000130 W IN 2013000130W WO 2013164838 A1 WO2013164838 A1 WO 2013164838A1
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zlb
alkyl
fluorophenyl
thio
propan
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French (fr)
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Sameer Agarwal
Ranjit C. Desai
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Cadila Healthcare Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles 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
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to agonists of the G protein-coupled receptor TGR5, compositions comprising; them, methods of making the compounds and compositions and using them for the treatment of diseases TGR5 mediates or is implicated in.
  • Diabetes is a major worldwide health problem. In 2000, 171 million people were living with diabetes, and this number is projected to rise to 366 million in 2030. [Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004, 27, 1047- 53.]
  • Type II diabetes also known as non-insulin-dependent diabetes mellitus, is now internationally recognized as one of the major threats to human health in the 21st century. According to the International Diabetes Federation (IDF), diabetes is expected to cause 3.8 million deaths worldwide in 2007, roughly 6% of total world mortality, about the same as HIV/AIDS and malaria combined. Those that suffer from type II diabetes have too little insulin or cannot use insulin effectively. As a result, glucose levels build up in the blood and urine and, if left untreated, can cause life-threatening complications, including blindness, kidney failure, and heart disease. The huge human and economic costs of diabetes and associated complications prompted the research for appropriate and efficient treatments.
  • TGR5 is a novel GPCR mediating several non-genomic functional responses induced by binding of bile acids.
  • TGR5 in the literature termed GPBAR1, GPR 131, GPCR 19, M-BAR or BG37 as well, was recently identified as a G-protein coupled receptor (GPCR) responsive to bile acid (BA) (Kawamata et al., J. Biol. Chem. 2003, 278, 9435-9440; Maruyama et al, Biochem. Biophys. Res. Commun. 2002, 298, 714- 719); primarily expressed in monocytes and macrophages, lung, spleen, and the intestinal tract.
  • Bile acids are known to be key regulators of lipid, glucose and overall energy metabolism.
  • TGR5 is a G protein-coupled receptor that is activated by bile acids, resulting in an increase in cAMP levels and the subsequent modulation of energy expenditure in brown adipose tissue and muscle. Therefore, the development of a TGR5-specific agonist could lead to the prevention and treatment of various metabolic disorders related to obesity. [Thomas et al. Nature 2008, 7, 678.] Bile acid activation of the G protein-coupled receptor TGR5 has been shown to induce energy expenditure in muscle and brown fat, thereby conferring resistance to weight gain. A paper published in the current issue of Cell Metabolism (Vol. 10, Issue 3, Sept.
  • GLP-1 hormone glucagon-like peptide
  • GLP- 1 has art insulinotropic effect in the pancreas and reduces the appetite. Therefore, a small molecule that either mimics the effects of GLP-1 directly, or increases GLP-1 secretion, may be useful in treatment of the variety of conditions or disorders described above, namely diabetes mellitus.
  • the combined effects of FXR and TGR5 in metabolically-active tissues lead to a reduction of hyperglycaemia and insulin resistance.
  • TGR5 activation is followed by release of the Gas siibunit and activates the transcription of target genes by binding to cAMP response elements (CREs) contained in their promoter.
  • CREs cAMP response elements
  • BAT brown adipose tissue
  • TGR5 activation of TGR5 leads to the activation of type 2 iodothyronine deiodinase 2 (D2) which converts thyroxine (T4) to triiodothyronine (T3) and up-regulates (PPARa), uncoupling protein (UCP-1, UCP2) and PPAR-coactivator (PGC la) activity inducing beta-oxidation, oxidative phosphorylation and energy uncoupling.
  • D2 type 2 iodothyronine deiodinase 2
  • T4 triiodothyronine
  • PPARa up-regulates
  • UCP-1, UCP2 uncoupling protein
  • FXR in the liver stimulates beta-oxidation, downregulates FA synthesis. FXR also stimulates adipocyte differentiation, augmenting the production of leptin and adiponectin. These two hormones enhance energy uncoupling, b-oxidation, oxidative phosphorylation and reduce appetite. ' TGR5 and modulators of it has been the subject of a several patent applications:
  • the present invention relates to new heterocyclic compounds which are effective modulators of TGR5 agonists of structural formula I,
  • R 1 , R 2 , R 3 , R 4 , R s , R 6 , Y and Z are defined herein below and pharmaceutically acceptable salts thereof.
  • the invention further comprises compositions comprising the compounds and/or pharmaceutically acceptable salts thereof.
  • the invention also comprises use of the compounds and compositions for treating diseases or disorders in which TGR5 is a mediator or is. implicated.
  • the invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases and disorders in which TGR5 is a mediator or it's implicated.
  • the compounds are modulators or ligands of the TGR5 receptor. More particularly, the compounds are potent TGR5 agonists and may be useful for the treatment and prevention of metabolic and inflammatory diseases, in particular type II diabetes.
  • the present invention also provides compositions and combinations thereof and methods for using such compounds, compositions and combinations to treat these and related disorders.
  • All of the compounds of Formulae I disclosed herein may have quaternary ammonium ion moieties, and it is understood to one skilled in the art that these compounds may preferably be in the presence of a pharmaceutically acceptable counter ion.
  • the pharmaceutically acceptable counter ion for each of the quaternary ammonium ion moieties present in the compounds of the invention can be any pharmaceutically acceptable counter ion.
  • the source of the counter ions can be from either intermolecular sources, or, when possible, intramolecular sources.
  • each R la is independently halogen, Ci-C 4 alk:yl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-CgcycloalkyI, heterocyclyl, the group representing -R lb , -C r C 4 alkyl-R lb , or -OC1-C4 alkyl-R lb wherein
  • R l is cyano, nitro, -N(R lc ) 2 , -OR lc , -SR lc , -C(0)R lc , -C(0)OR ,c , - C(0)N(R 1C ) 2 , -S(0)N(R lc ) 2 , -S(0) 2 N(R
  • R z is an aryl or heteroaryl or heterocyclyl group, each optionally substituted with one, two, or three R Z1 groups, wherein each R Z1 independently is cyano, nitro, -R zlb ' -N(R zlb ) 2 , -O R z, b , -S R zlb , -C(O) R zlb , -C(0)0 R z,b , -C(0)N(R z, b ) 2 , -S(0)N(R z, b ) 2 , -S(0) 2 N(R zlb ) 2 , or - S(0) 2 R z,b , -OC(O) R zlb , -OC(0)0 R zlb , -OC(0)N(R zlb ) 2 , -N(R lc )C(0) R zl b , -N(R ZIb
  • each R 3b at each occurrence independently represents cyano, halogen, nitro, -N(R 3d ) 2 , -OR 3d , -SR 3d , -C(0)R 3d , -C(0)OR 3d , - C(0)N(R 3d ) 2 , -C(0)N(R 3d )-N[(C 1 -C 3 )alkyl] 3 + , -S(0)N(R 3d ) 2 , - S(0) 2 N(R 3d ) 2 , -SiO ⁇ NCR ⁇ -NKQ ⁇ alkyl ⁇ , -S(0) 2 R 3d , -OC(0)R 3d , - OC(0)OR 3d , -OC(0)N(R 3d ) 2 , -N(R 3c )C(0)R 3d , -N(R 3c )C(0)OR 3d , - N(R 3d )C(0)N(R 3d ) 2
  • R 5 and R 6 are independently selected from cyano, nitro, -R Z!
  • each R ZIb is independently Ci-C 6 alkyl, or Ci-C 6 haloalkyI.
  • R 1 may be selected from
  • Ci-C 4 alkyl independently halogen, Ci-C 4 alkyl, C1-C4 haloalkyl, C 3 -Cgcycloalkyl, heterocyclyl, the group representing -R lb , -C1-C4 alkyl-R lb , or -OC1-C4 alkyl- R lb wherein,
  • R lb at each occurrence independently represents cyano, nitro, -N(R lc ) 2 , -OR lc , - SR lc , -C(0)R lc , -C(0)OR lc , wherein each R lc is independently hydrogen, C r C 4 alkyl, or C1-C4 haloalkyl;
  • R may be selected from
  • the various groups as defined above may be selected from: "Alkyl", as well as other groups having the prefix “alk”, such as alkoxy and alkanoyl, means carbon chain which may either be linear or branched, and combinations thereof, unless the carbon chain is defined otherwise.
  • alkyl group include, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, ter/.-butyl, pentyl, hexyl etc. Where the specified number of carbon atoms permits e.g.
  • alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, Ci ⁇ is intended.
  • Cycloalkyl is the subset of alkyl and means saturated carbocyclic ring having a specified number of carbon atoms, preferably 3-6 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc.
  • a cycloalkyl group generally is monocyclic unless otherwise stated. Cycloalkyl groups are saturated unless and otherwise stated.
  • Aryl means a mono- or polycyclic aromatic ring system containing carbon ring atoms.
  • the preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
  • Heterocycle and “heterocyclyl” refer to saturated or unsaturated non-aromatic rings or ring systems containing at least one heteroatom selected from O, S, N further including the oxidized forms of sulfur, namely SO and S0 2 .
  • heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, pyridine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3- dithiane, oxathiane, thiomorpholine tetrazole, etc.
  • THF tetrahydrofuran
  • dihydrofuran 1,4-dioxane
  • morpholine 1,4-dithiane
  • 1,4-dithiane piperazine
  • piperidine pyridine
  • 1,3-dioxolane imidazoline
  • imidazolidine imidazoline
  • imidazolidine imidazoline
  • Heteroaryl means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus include heteroaryls fused to the other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic.
  • heteroaryl groups include; pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolin
  • Halogen refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred.
  • Particularly preferred compounds may be selected from: l-(4-(2-((5-(2-(3,4-dimethpxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazol- 3-yl)thio)ethoxy)-3-fluorophenyl)- 1 H- 1 ,2,4-triazole;
  • the compounds of present invention may be prepared by different synthetic schemes I wherein the groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Y and Z are as defined earlier. Synthesis of the compounds of Formulae I disclosed herein, and embodiments thereof, are not limited by these examples and schemes. One skilled in the art will know that other procedures can be used to synthesize the compounds of Formulae I disclosed herein, in combination with the processes described herein. In the descriptions below, one of ordinary skill in the art would recognize that specific reaction conditions, added reagents, solvents, and reaction temperatures can be modified for the synthesis of specific compounds that fall within the scope of this disclosure. All intermediate compounds described below, for which there is no description of how to synthesize such intermediates within these examples below, are commercially available compounds unless otherwise specified.
  • Step (I): The carboxylic acid of formula (3) may be prepared by hydrolysis of nitrile (2) with sodium or potassium hydroxide in a suitable solvent, such as methanol or ethanol.
  • Step (II): Formation of protected hydrazine (4) may be achieved by coupling of acid (3) with N-protected hydrazine using reagents such as HBTU in a suitable solvent, such as dichloromethane or DMF.
  • a suitable solvent such as DCM or toluene
  • a base such as triethylamine
  • a reagent such as bromoethanol or protected bromomethanol in a suitable solvent, such as acetone or MeCN
  • a base such as potassium carbonate
  • a suitable solvent such as " acetone or MeCN
  • a base such as potassium carbonate
  • a reagent such as bromoethanamine, protected bromoethanamine or their hydrochloride salt
  • a suitable solvent such as acetone or MeCN
  • a base such as potassium carbonate
  • a suitable solvent such as dichloromethane, DMF or MeCN
  • Example 36 2-((5-(2-(3,4-dimethoxyphenyI)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazol-3- yl)thio)-l-(4-(2-methoxyacetyI)piperazin-l-yl)ethanone.
  • Chinese Hamster Ovarian (CHO) l cells were plated in 24 well tissue culture plate at a density of 4 X 10 4 cells/well in a Nutrient Mixture F-12 HAM containing 10 % Fetal Bovine Serum, cultured for 24 hrs at 37°C/5% C0 2 , and then transfected with 50 ng of human (h) TGR5 expression plasmid (pCMV SPORT6 - hTGR5), 300 ng of cAMP-responsive element (CRE)-driven luciferase reporter plasmid (pCRE-Luc) and 100 ng of / ⁇ -galactosidase reporter vector in each well using Polyfect Transfection Reagent (QIAGEN, Cat.
  • luciferase assays 20 //L of cell lysate was mixed with 100 L of Luciferase Assay Substrate (Promega, Cat. No.: El 501) and Luminescence was measured in HIDEX Multitechnology Plate Reader.
  • 30 / L of cell lysate was mixed with 30 //L of 2X ONPG Buffer [20 mM sodium phosphate buffer - pH 7.3, 2 mM MgCl 2 , 100 mM ⁇ -mercaptoethanol, and 1.33 mg/mL o-nitrophenyl- ?-D- galactopyranoside (ONPG)] and incubated at 37°C for 2-10 mins.
  • the optical density at 415 nm was determined in SpectraMax 190.
  • the high fat diet induced obesity (DIO) in mice exhibits various features of metabolic syndrome in humans.
  • the metabolic syndrome is characterized by abdominal obesity, high triglycerides, impaired fasting glucose and hyperinsulinemia.
  • mice In OGTT, body weight of all animals are recorded and mice will receive a single dose of vehicle/ DPPIV- inhibitor administered per orally on the basis of body weight, 10-min post dosing single dose of vehicle/ test compounds are administered, 15-min post dosing blood collection is done (0 min) and glucose load (2gm/kg/10ml) administered per orally. Blood will be then collected at time points corresponding to 10, 30, 60, and 120 min after glucose load administration. At 10 min plasma is collected for insulin and GLP-1 level measurement. Serum is separated for determination of glucose levels at all time points. Glucose AUC and glucose excursion calculated using MS excel sheet and graph pad software.
  • novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
  • the compounds of Formula (I) or pharmaceutical compositions containing them are useful as antidiabetic and antiobesity compounds suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.

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Abstract

The present invention discloses agonists of the G protein-coupled receptor TGR5, compositions comprising them, methods of making the compounds and compositions and using them, methods of making the compounds and compositions and using them for the treatment of diseases TGR5 mediates or is implicated in.

Description

HETEROCYCLIC COMPOUNDS AND THEIR USE FOR TREATMENT OF DIABETES, OBESITY OR RELATED DISORDERS.
Field of the Invention
The invention relates to agonists of the G protein-coupled receptor TGR5, compositions comprising; them, methods of making the compounds and compositions and using them for the treatment of diseases TGR5 mediates or is implicated in.
Summary of the Related Art
Diabetes is a major worldwide health problem. In 2000, 171 million people were living with diabetes, and this number is projected to rise to 366 million in 2030. [Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care 2004, 27, 1047- 53.] Type II diabetes, also known as non-insulin-dependent diabetes mellitus, is now internationally recognized as one of the major threats to human health in the 21st century. According to the International Diabetes Federation (IDF), diabetes is expected to cause 3.8 million deaths worldwide in 2007, roughly 6% of total world mortality, about the same as HIV/AIDS and malaria combined. Those that suffer from type II diabetes have too little insulin or cannot use insulin effectively. As a result, glucose levels build up in the blood and urine and, if left untreated, can cause life-threatening complications, including blindness, kidney failure, and heart disease. The huge human and economic costs of diabetes and associated complications prompted the research for appropriate and efficient treatments.
TGR5 is a novel GPCR mediating several non-genomic functional responses induced by binding of bile acids. TGR5, in the literature termed GPBAR1, GPR 131, GPCR 19, M-BAR or BG37 as well, was recently identified as a G-protein coupled receptor (GPCR) responsive to bile acid (BA) (Kawamata et al., J. Biol. Chem. 2003, 278, 9435-9440; Maruyama et al, Biochem. Biophys. Res. Commun. 2002, 298, 714- 719); primarily expressed in monocytes and macrophages, lung, spleen, and the intestinal tract. Bile acids are known to be key regulators of lipid, glucose and overall energy metabolism. TGR5 is a G protein-coupled receptor that is activated by bile acids, resulting in an increase in cAMP levels and the subsequent modulation of energy expenditure in brown adipose tissue and muscle. Therefore, the development of a TGR5-specific agonist could lead to the prevention and treatment of various metabolic disorders related to obesity. [Thomas et al. Nature 2008, 7, 678.] Bile acid activation of the G protein-coupled receptor TGR5 has been shown to induce energy expenditure in muscle and brown fat, thereby conferring resistance to weight gain. A paper published in the current issue of Cell Metabolism (Vol. 10, Issue 3, Sept. 2, 2009) elaborates on a separate TGR5-regulated mechanism in the gut that drives secretion of the hormone glucagon-like peptide (GLP-1) and resulting insulin sensitization. Binding of TGR5 agonist increases cAMP stimulates the secretion of GLP-1 from intestinal endocrine cells. [Katsuma, et al, Biochem. Biophys. Res. Commun. 2005, 329(1), 386-390.1 GLP- 1 has art insulinotropic effect in the pancreas and reduces the appetite. Therefore, a small molecule that either mimics the effects of GLP-1 directly, or increases GLP-1 secretion, may be useful in treatment of the variety of conditions or disorders described above, namely diabetes mellitus. The combined effects of FXR and TGR5 in metabolically-active tissues lead to a reduction of hyperglycaemia and insulin resistance.
Upon ligand binding, TGR5 activation is followed by release of the Gas siibunit and activates the transcription of target genes by binding to cAMP response elements (CREs) contained in their promoter. In the brown adipose tissue (BAT) and muscle, activation of TGR5 leads to the activation of type 2 iodothyronine deiodinase 2 (D2) which converts thyroxine (T4) to triiodothyronine (T3) and up-regulates (PPARa), uncoupling protein (UCP-1, UCP2) and PPAR-coactivator (PGC la) activity inducing beta-oxidation, oxidative phosphorylation and energy uncoupling. [Watanabe et al, Nature 2006, 439(7075) 484-489.] FXR in the liver stimulates beta-oxidation, downregulates FA synthesis. FXR also stimulates adipocyte differentiation, augmenting the production of leptin and adiponectin. These two hormones enhance energy uncoupling, b-oxidation, oxidative phosphorylation and reduce appetite. ' TGR5 and modulators of it has been the subject of a several patent applications:
WO/2008/097976 - Heterocyclic Modulators of TGR5 for Treatment of Disease WO/2008/0 1540 - Substituted Bile Acids as TGR5 Modulators and Methods of Use WO/2008/067219 - Quinazolinone Modulators of TGR5
WO/2008/067222 - Heterocyclic Modulators of TGR5
WO/2004/067008 - Receptor Agonists
WO/2004/043468 - Screening Method
US 2006/0199795 - Receptor Agonists US 2008/0031968 - Methods for Increasing Cellular Energy Expenditure
WO/2010/014739 - Heterocyclic Modulators of TGR5
WO/2010/016846 - Heterocyclic Modulators of TGR5
WO/2010/093845 - Heterocyclic Modulators of TGR5
WO/201 1/071565 - Heterocyclic Modulators of TGR5
WO/2012/082947 - Heterocyclic Modulators of TGR5
WO/2012/149236- Heterocyclic Modulators of TGR5
SUMMARY OF THE INVENTION
The present invention relates to new heterocyclic compounds which are effective modulators of TGR5 agonists of structural formula I,
Figure imgf000004_0001
I
wherein, R1, R2, R3, R4, Rs, R6, Y and Z are defined herein below and pharmaceutically acceptable salts thereof. The invention further comprises compositions comprising the compounds and/or pharmaceutically acceptable salts thereof. The invention also comprises use of the compounds and compositions for treating diseases or disorders in which TGR5 is a mediator or is. implicated. The invention also comprises use of the compounds in and for the manufacture of medicaments, particularly for treating diseases and disorders in which TGR5 is a mediator or it's implicated.
The compounds are modulators or ligands of the TGR5 receptor. More particularly, the compounds are potent TGR5 agonists and may be useful for the treatment and prevention of metabolic and inflammatory diseases, in particular type II diabetes.
The present invention also provides compositions and combinations thereof and methods for using such compounds, compositions and combinations to treat these and related disorders.
DETAILED DESCRIPTION OF THE INVENTION
All of the compounds of Formulae I disclosed herein may have quaternary ammonium ion moieties, and it is understood to one skilled in the art that these compounds may preferably be in the presence of a pharmaceutically acceptable counter ion. The pharmaceutically acceptable counter ion for each of the quaternary ammonium ion moieties present in the compounds of the invention can be any pharmaceutically acceptable counter ion. It is also understood that the source of the counter ions can be from either intermolecular sources, or, when possible, intramolecular sources.
In accordance with one aspect of the invention compounds are provided having structure of Formula I:
Figure imgf000005_0001
I
or an isotope, enantiomer, diastereomer or pharmaceutically acceptable salt thereof, wherein:
Y is = S, SO, S02; Z is = O, C(0)N(R4), or N(R4)C(0); n is 1, 2, 3 or 4; m is 0, 1, or 2; P = 0-5; .
and wherein,
R1 is
aryl, heteroaryl, or aryl(Ci-C6)alkyl, each optionally substituted with one, two, or three Rla groups, wherein each Rla is independently halogen, Ci-C4alk:yl, C1-C4 alkoxy, C1-C4 haloalkyl, C3-CgcycloalkyI, heterocyclyl, the group representing -Rlb, -CrC4 alkyl-Rlb, or -OC1-C4 alkyl-Rlb wherein
Rl is cyano, nitro, -N(Rlc)2, -ORlc, -SRlc, -C(0)Rlc, -C(0)OR,c, - C(0)N(R1C)2, -S(0)N(Rlc)2, -S(0)2N(R|C)2, or -S(0)2Rlc, -OC(0)Rlc, -
OC(0)ORlc, -OC(0)N(Rlc)2, -N(Rlc)C(0)Rlc, -N(Rlc)C(0)ORlc, - N(Rlc)C(0)N(R,c)2, or -N(Rlc)C(=NR,c)N(Rlc)2, wherein each Rlc is independently hydrogen, Ci-C4alkyl, or C1-C4 haloalkyl;
7
- R , wherein
independently selected from is cyano, halogen, nitro,
N(Rzlb)2, -O Rzib, -S Rz,b, -C(O) Rzlb, -C(0)0 Rzib, -C(0)N(Rzlb)2, - S(0)N(Rzlb)2, -S(0)2N(Rzl )2, or -S(0)2 Rzlb, -OC(O) Rzlb, -OC(0)0 Rzlb , -OC(0)N(Rzlb)2, -N(Rlc)C(0) Rzlb, -N(Rzlb)C(0)0 Rzib, - N(RZIb)C(0)N(Rzlb)2, or -N(Rz,b)C(=N Rzlb)N(Rzlb)2, wherein each Rzl b is independently hydrogen, Ci-C6 alkyl, Ci-C6 alkoxy or Ci-C6 haloalkyl; or
Rz is an aryl or heteroaryl or heterocyclyl group, each optionally substituted with one, two, or three RZ1 groups, wherein each RZ1 independently is cyano, nitro, -Rzlb' -N(Rzlb)2, -O Rz, b, -S Rzlb, -C(O) Rzlb, -C(0)0 Rz,b, -C(0)N(Rz, b)2, -S(0)N(Rz, b)2, -S(0)2N(Rzlb)2, or - S(0)2 Rz,b, -OC(O) Rzlb, -OC(0)0 Rzlb , -OC(0)N(Rzlb)2, -N(Rlc)C(0) Rzl b, -N(RZIb)C(0)0 Rzl , -N(Rzl b)C(0)N(Rzl b)2, or -N(Rzl b)C(=N Rzlb)N(Rzlb)2, wherein each Rzlb is independently hydrogen, C C4alkyl, C1-C6 alkoxy or C C4haloalkyl; aryl, heteroaryl, heterocyclyl, 3 to 8 membered cycloalkyi, or aryl(Ci- C2)alkyl, (C^Ce) alkyl or (C[-C6) haloalkyl each optionally substituted with one, two, or three R3a groups, wherein each R3a independently represents halogen, C1-C4 alkyl, Ci-C4 haloalkyl, C3-C8 cycloalkyi, heterocyclyl, heteroaryl the groups represented by -R3b, -(C1-C4) alkyl- R3b, or -0(C,-C4) alkyl; or
(C,-C6) alkyl, (C,-C6) alkoxyl, -(Ci-C6) alkyl-N(R3b)2, -(C,-C6) alkyl- OR3b, -(C C6) alkyl-SR3b , (C3-C8)-cycloalkyl, or heterocyclyl, wherein the alkyl, cycloalkyi and heterocyclyl are each optionally substituted with 1 to 6 substituents which are each independently selected from -R3b or -(C,-C6) alkyl-R3b;
Wherein, each R3b at each occurrence independently represents cyano, halogen, nitro, -N(R3d)2, -OR3d, -SR3d, -C(0)R3d, -C(0)OR3d, - C(0)N(R3d)2, -C(0)N(R3d)-N[(C1-C3)alkyl]3 +, -S(0)N(R3d)2, - S(0)2N(R3d)2, -SiO^NCR^-NKQ^alkyl^, -S(0)2R3d, -OC(0)R3d, - OC(0)OR3d, -OC(0)N(R3d)2, -N(R3c)C(0)R3d, -N(R3c)C(0)OR3d, - N(R3d)C(0)N(R3d)2, or -N(R3d)C(=NR3d)N(R3d)2, wherein each R3d at each occurrence is independently selected from hydrogen, (C1-C4) alkyl, or (Ci-C4) haloalkyl;
independently hydrogen, Ci-C4 alkyl, C1-C4 alkoxy, Ci-C4 haloalkyl, τ S(0)2 -(Ci-C4) alkyl, -S(0)2 aryl or heteroaryl; R5 and R6 are independently selected from cyano, nitro, -RZ! b' -N(Rzl b)2, -O Rzlb, -S Rzlb, -C(O) RZi b, -C(0)0 Rzlb, -C(0)N(Rz lb)2, -S(0)N(Rzlb)2, - S(0)2N(Rzl b)2, or -S(0)2 Rzlb, -OC(O) Rzi b, -OC(0)0 Rzib , - OC(0)N(Rzl b)2, -N(Rl c)C(0) Rzl b, -N(Rz l b)C(0)0 Rz, b, - N(RZ! b)C(0)N(Rzl )2, or -N(Rzlb)C(=N Rzl b)N(Rzl b)2, wherein each RZIb is independently Ci-C6 alkyl, or Ci-C6 haloalkyI.
In a preferred embodiment,
R1 may be selected from
5 or 6 membered aryl, or 5 or 6 membered heteroaryl each optionally substituted with one, two, or three Rla groups, wherein each Rla is
independently halogen, Ci-C4alkyl, C1-C4 haloalkyl, C3-Cgcycloalkyl, heterocyclyl, the group representing -Rlb, -C1-C4 alkyl-Rlb, or -OC1-C4 alkyl- Rlb wherein,
Rlb at each occurrence independently represents cyano, nitro, -N(Rlc)2, -ORlc, - SRlc, -C(0)Rlc, -C(0)ORlc, wherein each Rlc is independently hydrogen, Cr C4alkyl, or C1-C4 haloalkyl;
R may be selected from
5 or 6 membered aryl, 5 or 6 membered heteroaryl, Ci-C6 alkyl, d-Ce alkoxy, 3 to 8 membered -cycloalkyl, each optionally substituted with one, two, or three R3a groups, wherein each R3a is independently halogen, C1-C4 haloalkyl, C3- Cgcycloalkyl, heterocyclyl, -C(0)N(R3c)2, C(0)N(R3c)-N[(Ct-C3)alkyl]3+, - S(0)2N(R3c)-N[(C,-C3)alkyl]3 +, -N(R3c)C(=NR3c)N(R3c)2, wherein each R3c is independently hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl.
In an embodiment, the various groups as defined above may be selected from: "Alkyl", as well as other groups having the prefix "alk", such as alkoxy and alkanoyl, means carbon chain which may either be linear or branched, and combinations thereof, unless the carbon chain is defined otherwise. Examples of alkyl group include, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, ter/.-butyl, pentyl, hexyl etc. Where the specified number of carbon atoms permits e.g. from C3-io, the term alkyl also includes cycloalkyl groups, and combinations of linear or branched alkyl chains combined with cycloalkyl structures. When no number of carbon atoms is specified, Ci^ is intended. "Cycloalkyl" is the subset of alkyl and means saturated carbocyclic ring having a specified number of carbon atoms, preferably 3-6 carbon atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl etc. A cycloalkyl group generally is monocyclic unless otherwise stated. Cycloalkyl groups are saturated unless and otherwise stated.
"Aryl" means a mono- or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are monocyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.
"Heterocycle" and "heterocyclyl" refer to saturated or unsaturated non-aromatic rings or ring systems containing at least one heteroatom selected from O, S, N further including the oxidized forms of sulfur, namely SO and S02. Examples of heterocycles include tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, pyridine, 1,3-dioxolane, imidazoline, imidazolidine, pyrrolidine, pyrroline, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3- dithiane, oxathiane, thiomorpholine tetrazole, etc.
"Heteroaryl" means an aromatic or partially aromatic heterocycle that contains at least one ring heteroatom selected from O, S and N. Heteroaryls thus include heteroaryls fused to the other kinds of rings, such as aryls, cycloalkyls, and heterocycles that are not aromatic. Examples of heteroaryl groups include; pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, triazinyl, thienyl, pyrimidyl, benzisoxazolyl, benzoxazolyl, benzthiazolyl, benzothiadiazolyl, dihydrobenzofuranyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolinyl, pyridazinyl, indazolyl, isoindolyl, dihydrobenzothienyl, indolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, napthyridinyl, carbazolyl, benzodioxolyl, quinoxalinyl, purinyl, furazanyl, isobenzylfuranyl, benzimidazolyl, benzofuranyl, benzothienyl, quinolyl, indolyl, isoquinolyl, dibenzofuranyl etc. For heterocyclyl and heteroaryl groups, rings and ring systems containing from 3-15 carbon atoms are included, forming 1-3 rings.
"Halogen" refers to fluorine, chlorine, bromine, iodine. Chlorine and fluorine are generally preferred.
Particularly preferred compounds may be selected from: l-(4-(2-((5-(2-(3,4-dimethpxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazol- 3-yl)thio)ethoxy)-3-fluorophenyl)- 1 H- 1 ,2,4-triazole;
1- (4-(2-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H- 1,2,4- triazol-3-yl)thio)ethoxy)-3-fluorophenyl)-lH- l,2,4-triazole;
5-(2-(5-((2-(4-( l H-1 ,2,4-triazol- 1 -yl)phenoxy)ethyl)thio)-4-(4-fluorophenyl)-4H- 1,2,4- triazol-3-yl)propan-2-yl)-2-fluorobenzonitrile;
3-((2-(2-fluoro-4-(l H-imidazol-l-yl)phenoxy)ethyl)thio)-4-(4-fluorophenyl)-5-(2-(3- methoxyphenyl)propan-2-yl)-4H- 1 ,2,4-triazole;
3-((2-(4-( lH-imidazol-l-yl)phenoxy)ethyl)thio)-4-(4-fluorophenyl)-5-(2-phenylpropan- 2-yl)-4H- l,2,4-triazole;
2- ((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazol-3- : yl)thio)-N-(4-(2-methyl-lH-imidazol-l-yl)phenyl)acetamide;
2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazol-3- yl)thio)-2-methyI-N-(4-(2-methyl-lH-imidazol-l -yl)phenyl)propanamide;
l-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazol-3- yl)thio)-N-(4-(2-methyl-lH-imidazol-l-yl)phenyl)cyclobutanecarboxamide;
N-(4-(lH-imidazol-l-yl)phenyl)-2-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-4-
(4-fluorophenyl)-4H-l,2,4-triazol-3-yl)thio)-2-methylpropanamide;
2-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazol- 3-yl)thio)-N-(4-(2-methyl- 1 H-imidazoI- 1 -yl)phenyl)acetamide;
2-((4-(4-fluorophenyl)-5-(2-(3-methoxyphenyl)propan-2-yl)-4H-l,2,4-triazol-3- : yl)thio)-2-methyl-N-(4-(2-methyl- 1 H-imidazol- 1 -yl)phenyl)propanam ide;
1- ((4-(4-fluorophenyl)-5-(2-(3-methoxyphenyl)propan-2-yl)-4H-l,2,4-triazol-3- yl)thio)-N-(4-(2-methyl-lH-imidazoI-l-yl)phenyl)cyclobutanecarboxamide;
N-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazol-3- yl)thio)ethyl)-2-(2,4,5-trifluorophenyl)acetamide;
- N-(2-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4- triazol-3-yl)thio)ethyl)-2-(2,4,5-trifluorophenyl)acetamide;
2- ((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazol-3- yl)thio)-l-(3-(trifluoromethyl)-5,6-dihydro-[l ,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)ethanone; 2- ((4-(4-fluorophenyl)-5-(2-(3-methoxyphenyl)propan-2-yl)-4H-l,2,4-triazol-3- yl)thio)-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)ethanone;
3- (2-(4-chloro-3-methoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-5-((2-(2- methoxyethoxy) ethyl)thio)-4H-l,2,4-triazole;
3-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-5-((2-(2-methoxyethoxy) ethyl)thio) -4H-l,2,4-triazole;
2-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H- l,2,4-triazol-3- y l)th io)ethoxy)ethano 1 ;
General Process for Preparation
The compounds of present invention may be prepared by different synthetic schemes I wherein the groups R1, R2, R3, R4, R5, R6, Y and Z are as defined earlier. Synthesis of the compounds of Formulae I disclosed herein, and embodiments thereof, are not limited by these examples and schemes. One skilled in the art will know that other procedures can be used to synthesize the compounds of Formulae I disclosed herein, in combination with the processes described herein. In the descriptions below, one of ordinary skill in the art would recognize that specific reaction conditions, added reagents, solvents, and reaction temperatures can be modified for the synthesis of specific compounds that fall within the scope of this disclosure. All intermediate compounds described below, for which there is no description of how to synthesize such intermediates within these examples below, are commercially available compounds unless otherwise specified.
-1
Figure imgf000010_0001
Synthesis Compounds of formula (2) are commercially available or may be prepared from known compounds using standard methodologies.
Scheme 1, Step (I): The carboxylic acid of formula (3) may be prepared by hydrolysis of nitrile (2) with sodium or potassium hydroxide in a suitable solvent, such as methanol or ethanol. Step (II): Formation of protected hydrazine (4) may be achieved by coupling of acid (3) with N-protected hydrazine using reagents such as HBTU in a suitable solvent, such as dichloromethane or DMF. Step (III): Deprotection of compound 4 under mild acidic conditions such as ethereal hydrochloric acid resulted in formation of hydrazine hydrochloride 5, known to one skilled in the art of synthetic organic chemistry. Step (IV): Substituted isothiocyanate, which may be optionally substituted suitably, may react with amino-ketone hydrochloride (5) in a suitable solvent, such as DCM or toluene, and in the presence of a base, such as triethylamine, at room temperature to yield the corresponding thiourea, which may cyclize upon treatment with HOAc or sodium hydroxide at elevated temperature to give a crucial intermediate compound of formula (6).
Scheme-2
Figure imgf000011_0001
Scheme 2, Step (I): Alkylation of triazol-2-thione (6) with a reagent such as bromoethanol or protected bromomethanol in a suitable solvent, such as acetone or MeCN, and in the presence of a base, such as potassium carbonate, may afford a compound of formula (7). Step (II): Benzylation of compound of formula (7) with a substituted benzyl bromide in a suitable solvent, such as "acetone or MeCN, and in the presence of a base, such as potassium carbonate, may afford a compound of formula (la), or, treatment of compound of formula (7) with a suitably substituted phenol in a suitable solvent, such as tetrahydrofuran, under Mitsunobu conditions, may afford a compound of formula (la). -3
Figure imgf000012_0001
Scheme 3, Step (I): Alkylation of triazol-2-thione (6) with a reagent such as bromoethanamine, protected bromoethanamine or their hydrochloride salt, in a suitable solvent, such as acetone or MeCN, and in the presence of a base, such as potassium carbonate, may afford a compound of formula (8). Step (II): Coupling of compound of formula 8 with a substituted aryl or alkyl carboxylic acid which may be optionally suitably substituted, in a suitable solvent, such as dichloromethane, DMF or MeCN, and in the presence of reagents, such as HBTU or EDC/HOBt, may afford a compound of formula (lb) and reduction of resulting compound using reagents like lithium aluminum hydride will also result in formation of compounds of general formula (lb).
Scheme-4
Figure imgf000012_0002
Scheme 4, Step (I): Alkylation of triazol-2-thione (6) with a reagent such as chloroacetic acid or substituted chloro or bromo alkyl carboxylic acid or protected carboxylic acid in a suitable solvent, such as acetone, DMF or MeCN, and in the presence of a base, such as triethylafnine, may afford a compound of formula 9. Coupling of compound of formula 9 with substituted alkyl or aryl amine which may be optionally substituted suitably, in a suitable solvent, such as dichloromethane, DMF or MeCN, and in the presence of reagents, such as HBTU or EDC/HOBt, may afford a compound of formula (I) and reduction of resulting compound using reagents like lithium aluminum hydride will also result in formation of compounds of general formula (lb).
Certain compounds as disclosed herein can be synthesized using the following general synthetic procedure set forth in Scheme 2. -5
Figure imgf000013_0001
I la or lb
Scheme 5, Reaction of thio compound (I) with a suitable oxidant, such as mCPBA, in a suitable solvent such as DCM may yield compound of formula la or lb.
The following compounds were prepared using the process described above in combination, when required, with other processes, reagents, conditions as are well known to persons skilled in the art. Such obvious modifications/alterations etc. carried out to obtain further compounds of formula (I) should, based on the disclosures herein provided in combination with the knowledge of a skilled person be considered to be within the scope of the invention.
Exam
Figure imgf000013_0002
3-(2-(3 -dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-5-((2-methoxyethyl)thio)- 4H-l,2,4-triazole
To a solution of 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)- 4H-l,2,4-triazole-3-thiol (150 mg, 0.401 mmol) in acetone was added potassium carbonate (138 mg, 1.204 mmol) and l-chloro-2-methoxyethane (46 mg, 0.481 mmol) and stirred at room temperature for 3 h. Reaction mixture was quenched with dichloro methane and extracted with brine, combined organic layers were dried over sodium sulphate and distilled the solvent under vacuum. Crude product was purified by column chromatography to afford the desired product (92 mg, 69% yield). 1H NMR (CDC13, 400 MHz): 6.90-6.84 (m, 2H), 6.67 (d, J = 8.4Hz, 1H), 6.54-6.48 (m, 4H), 3.87 (s, 3H), 3.72 (s, 3H), 3.71 (t, J = 5.6Hz, 2H), 3.40 (t, J = 5.6Hz, 2H), 3.34 (s, 3H), 1.63 (s, 6H). m/z Relative intensities = 431.9 (M)+100%. IR CHCI3 (cm"1): 669, 1028, 1258, 1464, 1603, 2855, 2928, 2959, 3019, 3424. Example 2
l-(4-(2-((5-(2-(3,4-dimethoxypheiiyl)propan-2-yl)-4-(4-fluorophenyI)-4H-l,2,4- triazol-3-yl)thio)ethoxy)phenyI)-lH-l,2,4-triazoIe
Ή NMR (CDC , 400 MHz): 8.54 (s, IH), 8.08 (s, IH), 7.61-7.54 (m, 2H), 7.09-7.03 (m, 2H), 6..90-6.85 (m, 2H), 6.68-6.66 (m, IH), 6.53- 6.50 (m, 4H), 4.41 (t, J = 6Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.48 (t, J = 6.5Hz, 2H), 1.64 (s, 6H). m/z Relative intensities = 561 (M)+100%. IR CHCI3 (cm"1): 3433, 31 17, 2926, 1647, 1602, 1464, 1252, 1 174, 1024, 841.
Example 3
3-((2-(4-(lH-pyrazol-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan-
2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazole
Ή NMR (CDCI3, 400 MHz): 7.83 - 7.82 (m, IH), 7.68 (d , J = 1.6Hz, IH), 7.60 - 7.56 (m, 2H), 7.00 - 6.97 (m, 2H), 6.90 - 6.65 (m, 2H), 6.67 - 6.65 (dd, Jl = 3.6Hz, J2 = 5.2 Hz, IH), 6.53 - 6.49 (m, 4H), 4.39 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.57 (t, J = 6.4Hz, 2H), 1.64 (s, 6H). m/z Relative intensities = 560 (M)+100%. IR CHCI3 (cm" '): 3453, 31 17, 2974, 2835, 1601, 1464, 1244, 1 153, 1026, 841.
Example 4
3-((2-(4-(lH-imidazoI-l-yI)phenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan- 2-yl)-4-(4-fluorophenyI)-4H- 1 ,2,4-triazole
Ή NMR (CDCI3, 400 MHz): 7.77 (s, IH), 7.31-7.29 (dd, Jl 2Hz, J2 = 6.5Hz, 2H), 7.21-7.19 (m, 2H), 7.04-7.01 (dd, Jl = 2.4Hz,- J2 = 6.5Hz, 2H), 6.90-6.68 (m, 2H), 6.67 (d, J = 9.2Hz, IH), 6.53-6.48 (m, 4H), 4.41 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.73 (s, 3H), 3.56 (t, J = 6.4Hz, 2H), 1.69 (s, 6H). m/z Relative intensities = 560.2 (M)+ 100%. IR CHCI3 (cm"1): 756, 1026, 1059, 1240, 1512, 1712, 1890, 3019, 3408.
Example 5
3-(2-(3,4-dimethoxyp enyl)propan-2-yl)-4-(4-fluorophenyl)-5-((2-(4-(2-methyl-lH- imidazol-l-yl)phenoxy)ethyl)thio)-4H-l,2,4-triazole
Ή NMR (CDCI3, 400 MHz): 7.21-7.18(m,2H), 7.04-7.0 (m, 3H), 6.95 (s, IH), 6.91- 6.85 (m, 2H), 6.68-6.66 (dd, Jl = 3.5Hz, J2= 6.0hz, IH), 6.65-6.47 (m, 4H), 4.42 (t, J = 6.4Hz, 2H), 3.86 (s, 3H), 3.73(s, 3H), 3.48 (t, J = 6.4Hz, 2H), 2.32 (s, 3H), 1.64 (s, 6H). m/z Relative intensities = 574.3 (M)+100%. IR CHCI3 (cm"1): 841, 1024, 1247, 1603, 2853, 2926, 2964, 3416. Example 6
3-(2-(3,4-dimethoxyphenyI)propan-2-yl)-4-(4-fluorophenyI)-5-((2-(4-(4-methyl-lH- imidazoI-l-yl)phenoxy)ethyl)thio)-4H-l,2,4-triazole
Ή NMR (CDCb, 400 MHz): 7.66(s, IH), 7.28-7.26 (m, 2H), 7.0 (d, J = 8.8Hz, 2H), 6.90 (s, IH), 6.90-6.88 (m, 2H), 6.88-6.66 (m, IH), 6.54-6.48 (m, 4H), 4.40 (t, J = 6Hz, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 3.57 (t, J = 6Hz, 2H), 2.29 (s, 3H), 1.64 (s, 6H). m/z Relative intensities = 574.2 (M)+100%. IR CHCI3 (cm"1): 843, 1026, 1246, 1603, 2853, 2928, 3071, 31 15, 3439.
Example 7
3-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-5-((2-(2-fluoro-4-(2-methyl-lH- imidazol-l-yl)phenoxy)ethyl)thio)-4-(4-fluorophenyl)-4H-l,2,4-triazole
Ή NMR (CDCb, 400 MHz): 7.22 (s, IH), 7.18 (d, J= 8.8Hz, IH), 7.06-7.05 (m, IH), 7.03-7.01 (m, 2H), 6.95-6.90 (m, 3H), 6.57-6.52 (m, 4H), 4.51 (t, J= 6.4Hz, 2H), 3.74 (s, 3H), 3.59 (t, J= 6.4Hz, 2H), 2.34 (s, 3H), 1.66 (s, 6H). m/z Relative intensities = 596.1 (M)+100%. IR CHCI3 (cm 1): 31 15, 2978, 2930, 2857, 1514, 1298, 1231, 1061, 1026, 847, 816.
Example 8
3-(2-(4-chloro-3-methoxyphenyI)propan-2-yI)-5-((2-(2-fluoro-4-(2-methyl-lH- imidazol-l-yl)phenoxy)ethyl)thio)-4-(4-fluorophenyl)-4H-l,2,4-triazole
Ή NMR (CDCb, 400 MHz): 7.22-7.17 (m, 2H), 7.06 (s, I H), 6.94-6.90 (m, 3H), 6.84- 6.81 (m, 2H), 6.57-6.52 (m, 4H), 4.47 (t, J= 6.4Hz, 2H), 3.74 (s, 3H), 3.58 (t, J= 6.4Hz, 2H), 2.27 (s, 3H), 1.66 (s, 6H). m/z Relative intensities = 596.1 (M)+ 100%. IR CHCI3 (cm"1): 31 15, 2978, 2930, 2857, 1514, 1298, 1231, 1061, 1026, 847, 816.
Example 9
3-(2-(3,4-dimethoxyphenyl)propan-2-yl)-5-((2-(3-fluoro-4-(2-methyl-lH-imidazol- l-yl) phenoxy)ethyl)thio)-4-(4-fluorophenyI)-4H-l,2,4-triazoIe
Ή NMR (DMSO-de, 400 MHz): 7.48-7.45 (dd, Jl= 12 Hz, J2 = 2.6 Hz, IH), 7.35 (t, J = 8.8 Hz, IH), 7.25-7.22 (m, 2H), 7.09 (t, J = 8.8 Hz, 2H), 6.91 (s, IH), 6.77-6.71 (m, 3H), 6.43-6.41 (m, 2H), 4.40 (t, J = 6 Hz, 2H), 3.70 (s, 3H), 3.57 (s, 3H), 3.51 (t, J = 6 Hz, 2H), 2.28 (s, 3H), 1.55 (s, 6H). m/z Relative intensities = 592.1 (M+H)+ 100%. IR CHCI3 (cm"1): 3417, 31 15, 1734, 1647, 1514. Example 10
3-((2-(4-(lH-pyrazol-l-yl)phenoxy)ethyl)thio)-5-(2-(4-chloro-3- methoxyphenyl)propan-2-yl) -4-(4-fluorophenyl)-4H-l,2,4-triazole.
Ή NMR (CDCI3, 400 MHz): 7.82 (d, J=2.4Hz, IH), 7.69 (d, J=1.6Hz, IH), 7.60-7.56 (m, 2H), 7.17 (t, J= 5.2Hz, IH), 7.00-6.97 (m, 2H), 6.93-6.87 (m, 2H), 6.56-6.51 (m, 4H), 6.44 (t, J=2 Hz, IH), 4.38 (t, J= 6.0Hz, 2H), 3.75 (s, 3H), 3.58 (t, J= 6.0Hz, 2H), 1.63 (s, 6H). m/z Relative intensities = 564 (M)+100%.
Example 11
5-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4- triazoI-3-yl) thio)ethoxy)phenyl)-lH-tetrazole
Ή NMR (DMSO-d6, 400 MHz): 7.97 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.58 Hz, 2H), 7.09 (t, J - 8.8 Hz, 2H), 6.76-6.70 (m, 3H), 6.43-6.41 (m, 2H), 4.33 (t, J = 6.6 Hz, 2H), 3.69 (s, 3H), 3.57 (s, 3H), 3.49 (t, J = 7.2 Hz, 2H), 1.55 (s, 6H). m/z Relative intensities = 562.5 (M+H)+ 100%. IR CHCI3 (cm 1): 3439, 3117, 1614, 1452.
Example 12
3-((2-(3-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-5-(2-(3,4-dimethoxyphenyl)propan- 2-yl)-4-(4-fluorophenyI)-4H-l,2,4-triazole.
Ή NMR (CDCI3, 400 MHz): 7.92 (s, IH), 7.39 - 7.34 (m, 2H), 7.22 (s, IH), 7.02 - 6.99 (m, 2H), 6.95 - 6.92 (dd, Jl = 2Hz, J2 = 8.4Hz, IH), 6.88 (t, J = 8.4Hz, 2H), 6.68 - 6.59 (m, IH), 6.53 - 6.49 (m, 4H), 4.43 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.58 (t, J = 6.4Hz, 2H), 1.64 (s, 6H). m/z Relative intensities = 560.1 (M+H)+100%. IR CHCI3 (cm-1): 3417,.2978, 2964, 1732, 1693, 1610, 1460.
Example 13
3-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-5-((2-(3-(2-methyl-lH- imidazol-l-yl)phenoxy)ethyI)thio)-4H-l,2,4-triazole.
Ή NMR (CDCI3, 400MHz): 7.37 (d, J = 8Hz, IH), 7.02 - 6.99 (m, 3H), 6.90 - 6.85 (m, 3H), 6.82 (t, J = 2Hz, IH), 6.68 - 6.66 (m, IH), 6.53 - 6.48 (m, 4H), 4.40 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.58 (t, J = 6.4Hz, 2H), 2.37 (s, 3H), 1.64 (s, 6H). m/z Relative intensities = 574.1 (M+H)+100%. IR CHCI3 (cm"1): 2976, 1604, 1446, 1386. Example 14
5-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4- triazol-3-yl) thio) ethoxy)-lH-indazole. Ή NMR (CDC , 400 MHz): 8.02 (d, J= 24 Hz, IH), 7.38 (d, J= 8.8 Hz, IH), 7.14 (d, J= 2Hz, IH), 7.04 (d, J= 8.4Hz, IH), 6.87 (t, J= 8.4Hz, 2H), 6.65 (d, J= 8.8 Hz, IH), 6.52-6.48 (m, 4H), 4.38 (t, J= 6 Hz, 2H), 3.85 (s, 3H), 3.71 (s, 3H), 3.60 (t, J= 6 Hz, 2H), 1.64 (s, 6H). m/z Relative intensities = 534.1 (M)+100%. IR CHCI3 (cm 1): 3248, 3115, 3071, 2994, 2865, 1626, 1506, 1447, 1389, 1256, 1 155, 1073, 816, 768, 654, 596.
Example 15
3-(2-(3,4-dimethoxyphenyl)propan-2-yI)-5-((2-(4-(2-ethyl-4-methyl-lH-imidazoI-l- yl) phenoxy) ethyI)thio)-4-(4-fluorophenyl)-4H-l,2,4-triazole Ή NMR (CDCI3, 400 MHz): 7.26 - 7.15 (m, 2H), 7.01 - 6.97 (m, 2H), 6.91 - 6.86 (m, 2H), 6.68 - 6.66 (dd, J, = 3.2Hz, J2 = 5.6Hz, IH), 6.63 (d, J = .8 Hz, IH), 6.54 - 6.49 (m, 4H), 4.41 (t, J = 6.4Hz, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 2.59 (t, J = 6.4Hz, 2H), 2.61 - 2.55 (q, J = 7.6Hz, 2H), 2.24 (s, 2H), 1.16 (s, 6H), 1.20 (t, J = 7.6 Hz, 3H). m/z Relative intensities: 602.3(M+) 100 %.
Example 16
5-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4- triazol-3-yl) thio)ethoxy)phenyl)-l-methyI-lH-tetrazoIe.
Ή NMR (DMSO-de, 400 MHz): 7.97 (d, J = 8.8 Hz, 2H), 7.1 1-7.06 (m, 4H), 6.76 - 6.70 (m, 3H), 6.43-6.41 (m, 2H), 4.4 (s, 3H), 4.32 (t, J= 6.2 Hz, 2H), 3.70 (s, 3H), 3.57 (s, 3H), 3.49 (t, J= 6.2 Hz, 2H), 1.55 (s, 6H). M/z Relative intensities: 576.3 (M+)100 %.
Example 17
5-(4-(2-((5-(2-(3,4-dimethoxyphenyI)propan-2-yI)-4-(4-fluorophenyl)-4H-l,2,4- triazol-3-yl) thio)ethoxy)phenyl)-2-methyl-2H-tetrazoIe. lH NMR (DMSO-d6, 400 MHz): 7.80 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 7.11-7.07 (m, 2H), 6.77-6.71 (m, 3H), 6.43-6.41 (m, 2H), 4.36 (t, J= 6.2 Hz, 2H), 4.15 (s, 3H), 3.70 (s, 3H), 3.57 (s, 3H), 3.50 (t, J= 6.2 Hz, 2H), 1.55 (s, 6H). ). m/z Relative intensities: 576.2(M+) 100 %.
Example 18
5-(4-(2-((5-(2-(benzo[d] [1, 3] dioxol-5-yl) propan-2-yl)-4-(4-fluoropheny.)-4H-l, 2,
4-triazol-3-yl) thio) ethoxy) phenyI)-l-methyI-lH-tetrazole. lH NMR (CDCI3400 MHz): 8.06-8.03 (m, 2H), 7.02-6.99 (m, 2H), 6.92-6.88 (m, 2H), 6.62 (d, J= 8.4 Hz, IH), 6.60-6.55 (m, 2H), 6.518-6.513 (m, IH), 6.43-6.40 (dd, J, = 8 Hz, J2 = 1.8 Hz, 1H), 5.93 (s, 2H), 4.42 (t, J = 6.2 Hz, 2H), 4.37 (s,3H), 3.60 (t, J = 6 Hz, 2H), 1.60 (s, 6H). m/z Relative intensities: 560.1(M+)100 %.
Example 19
3-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4- triazol-3-yl) thio)ethoxy)phenyI)-5-methyI-l,2,4-oxadiazole
Ή NMR (CDC13, 400 MHz): 7.98 (d, J = 8.8Hz, 2H), 6.99 (d, J = 8.8Hz, 2H), 6.87 (t, J = 8.8Hz, 2H), 6.66 (d, J = 8.4Hz, 1H), 6.52-6.49 (m, 4H), 4.42 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.59 (t, J = 6.8Hz, 2H), 2.63 (s, 3H), 1.57 (s, 6H). m/z Relative intensities: 575. l(M+)100 %.
Example 20
2-(4-(2-((5-(2-(3,4-dimethoxyphenyI)propan-2-yl)-4-(4-fluorop enyl)-4H-l,2,4- triazol-3-yl) thio)ethoxy)phenyl)-5-methyI-l,3,4-oxadiazole
Ή NMR (CDC13, 400 MHz): 7.95 (d, J = 8.8Hz, 2H), 7.01 (d, J = 8.8Hz, 2H), 6.88 (t, J = 8.8Hz, 2H), 6.66 (d, J = 8.8Hz, 1H), 6.53-6.48 (m, 4H), 4.44 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.58 (t, j = 6.4Hz, 2H), 2.60 (s, 3H), 1.64 (s, 6H). m/z Relative intensities: 576.1(M+)100 %.
Example 21
3-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-5-((2-(4-(4-(thiophen- 3-yl)-lH-imidazol-l-yl)phenoxy)ethyl)thio)-4H-l,2,4-triazole Ή NMR (CDC13, 400 MHz): 7.76 (d, J = lHz, 1 H), 7.62 - 7.61 (m, 1H), 7.42 - 7.41 (m, 1H), 7.38 - 7.33 (m, 4H), 7.06 - 7.03 (m, 2H), 6.91 - 6.87 (m, 2H), 6.68 - 6.66 (d, J = 7.2 Hz, 1H), 6.54 - 6.49 (m, 3H), 4.42 (d, J = 6.4 Hz, 2H), 3.85 (s, 3H), 3.37 (s, 3H), 3.58 (t, J = 6.4, 2H), 1.29 (s, 6H). ). m/z Relative intensities: 642.3 (M+) 100 %. Example 22
2-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-nuorophenyl)-4H-l,2,4- triazol-3-yI) thio)ethoxy)phenyl)-5-methyl-l,3,4-thiadiazole
'H NMR (CDC13, 400 MHz): 7.85 (d, J = 8.8Hz, 2H), 7.00 (d, J = 8.8Hz, 2H), 6.88 (t, J = 8.8Hz, 2H), 6.66 (d, J = 8.8Hz, 1H), 6.53-6.49 (m, 4H), 4.42 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.58 (t, J = 6.4Hz, 2H), 2.79 (s, 3H), 1.64 (s, 6H). m/z Relative intensities: 592.1 (60%) (M+H)+, 614.0 (100%) (M+Na)+.
Example 23
2-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4- triazol-3-yI) thio) ethoxy)phenyl)isothiazolidine 1,1-dioxide. 'Η NMR (CDC , 400 MHz): 7.26 - 7.21 (m, 2H), 6.92 - 6.85 (m, 4H), 6.67 (d, J = 8.8Hz, 1H), 6.52 - 6.49 (m, 4H), 4.33 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.72(s, 3H), 3.71 - 3.69 (m, 2H), 3.54 (t, J = 6.4Hz, 2H), 3.37 - 3.33 (m, 2H), 2.52 - 2.56 (m,2H), 1.64 (s, 6H).IR Br (cm"1): 3421, 2930, 2835, 1600, 1244, 1024. m/z Relative intensities: 613 (100%) (M)+.
Example 24
l-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4- triazol-3-yl) thio)ethoxy)phenyl)pyrro!idine-2,5-dione.
Ή NMR (CDCI3, 400 MHz): 7.17 - 7.15 (m, 2H), 7.01 - 6.89 (m, 4H), 6.88-6.86 (m, 1H), 6.66 - 6.49 (m, 4H), 3.83 (t, J = 6.4Hz, 2H), 3.85 (s, 3H), 3.72(s, 3H), 3.56 (t, J = 6.4Hz, 2H), 2.88 (s, 4H), 1.61 (m,6H). IR KBr(cm '): 3466, 31 17, 2835, 1776, 1512. m/z Relative intensities: 591 (100%) (M)+.
Example 25
5-(4-(2-((5-(2-(3,4-dimethoxyphenyI)propan-2-yI)-4-(4-fluorophenyl)-4H-l,2,4- triazol-3-yl) sulfinyl)ethoxy)phenyl)-l-methyI-lH-tetrazoIe
Ή NMR (CDCI3, 400 MHz): 8.05-8.03 (dd, J, = 6.8 Hz, J2 = 2.4 Hz, 2H), 6.98-6.95 (m, 3H), 6.88-6.83 (m, 2H), 6.67 (d, J = 8.4 Hz, 1H), 6.53-6.46 (m, 3H), 4.57-4.49 (m, 2H), 4.37 (s, 3H), 4.13-4.09 (m, 1 H), 3.92-3.87 (m, 1H), 3.85 (s, 3H), 3.71 (s, 3H), 1.72 (s, 3H), 1.68 (s, 3H). m/z Relative intensities: 592.3 (M+) 100 %.
Example 26
2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazol-3- yl)thio)-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)ethanone
2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazol-3- yl)thio)acetic acid and 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[l ,2,4]triazolo[4,3- a]pyrazine was dissolved in DMF and then cooled to 0 °C followed by addition of HBTU and DIPEA, reaction was monitored by TLC and then reaction was quenched by water and compound was extracted by ethyl acetate. Product was purified by column chromatography. Ή NMR (DMSO-ck, 400 MHz): 7.10-7.03 (m, 2H), 6.77-6.70 (m, 3H), 6.40 (d, J = 5.6 Hz, 2H), 5.03 (s, 1H), 4.84 (s, 1H), 4.24-4.19 (m, 4H), 4.05-4.00 (m, 2H), 3.72 (s, 3H), 3.60 (s, 3H), 1.53 (s, 6H). m/z Relative intensities: 606.1 (M+)100 %. Example 27
2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yI)-4-(4-fluorophenyl)-4H-l,2,4-triazol-3- yl)thio)-N-(4-(2-methyl-lH-imidazol-l-yl)phenyI)acetamide
Ή NMR (DMSO-d6, 400MHz) :- 10.5 1 (s, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.40-7.38 (dd, Jl = 6.8 Hz, J2 = 2 Hz, 2H), 7.24-7.23 (m, 1H), 7.09-7.04 (m, 2H), 6.90 (s, 1H), 6.76- 6.72 (m, 3H), 6.42-6.39 (m, 2H), 4.05 (s, 2H), 3.71 (s, 3H), 3.59 (s, 3H), 2.26 (s, 3H), 1.56 (s, 6H). m/z Relative intensities: 587.1 (M+)100 %.
Example 28
2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yI)-4-(4-fluorophenyl)-4H-l,2,4-triazol-3- yl)thio)-2-methyI-N-(4-(2-methyl-lH-imidazol-l-yi)phenyl)propanamide.
Ή NMR (DMSO-d6, 400MHz) :- 9.73 (s, 1Ή), 7.70-7.68 (dd, Jl = 6.8 Hz, J2 = 2 Hz, 2H), 7.37-7.35 (dd, Jl = 8.8 Hz, J2 =1.8 Hz, 2H), 7.245 (d, J = 1.2 Hz, 1H), 6.915 (d, J = 1.2 Hz, 1H), 6.78 (t, J = 8.8 Hz, 2H), 6.71 (d, J = 8.4 Hz, 1H), 6.55-6.51 (m, 2H), 6.36-6.33 (m, 2H), 3.65 (s,3H), 3.61 (s, 3H), 2.28 (s, 3H), 1.57 (s, 6H), 1.49 (s, 6H). m/z Relative intensities: 615.2 (M+) 100 %.
Example 29
(S)-2-(2-((5-(2-(3, 4-dimethoxyphenyl) propan-2-yl)-4-(4-fluorophenyl)-4H-l, 2, 4- triazol-3-yl)thio) acetamido)-4-methyIpentanoic acid
Ή NMR (DMSO-dg, 400 MHz): 12.61 (bs, 1 H), 8.48 (d, J = 8 Hz, 1H), 7.12-7.08 (m, 2H), 6.77-6.75 (m, 3H), 6.42-6.40 (m, 2H), 4.16 (d, J = 7.2 Hz, 1H), 3.94-3.84 (q, J = 14.8 Hz, 2H), 3.71 (s, 3H), 3.59 (s, 3H), 1.54 (s, 6H), 1.50-1.47 (m, 2H), 1.24-1.22 (m, 1H), 0.883 (d, J = 6.4 Hz, 3H), 0.818 (d, J = 6.4 Hz, 3H). m/z Relative intensities: 545.2 (M+) 100 %.
Example 30
(S)-methyl 2-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H- l,2,4-triazol-3-yl)thio)acetamido)-4-methylpentanoate.
Ή NMR (DMSO-de, 400 MHz): 8.60 (d, J = 7.6 Hz, 1H), 7.12-7.08 (m, 2H), 6.77-6.73 (m, 3H), 6.42-6.40 (m, 2H), 4.26-4.20 (m, 1H), 3.94-3.84 (m, 2H), 3.71 (s, 3H), 3.60 (d, J = 7.2 Hz, 6H), 1.54 (s, 6H), 1.49-1.48 (m, 1H), 1.24-1.22 (m, 2H), 0.88-0.81 (m, 6H). m/z Relative intensities: 559.2 (M+)100 %.
Example 31 ,
(S)-2-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4- triazol-3-yl)thio)acetamido)-3-phenyIpropanoic acid Ή NMR (DMSO-d6, 400MHz): 12.81 (bs, 1H), 8.56 (d, J = 8 Hz, 1H), 7.25-7.23 (m, 2H), 7.20-7.18 (m, 3H), 7.1 1-7.07 (m, 2H), 6.77-6.70 (m, 3H), 6.42-6.40 (m, 2H), 4.41-4.35 (m, 1H), 3.858 (d, J = 2.4 Hz, 2H), 3.71 (s, 3H), 3.60 (s, 3H), 3.05-3.00 (m, 1H), 2.88-2.73 (m, 1H), 1.54 (s, 6H). ). m/z Relative intensities: 579.3(M+)100 %. Example 32
(S)-methyl 2-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yI)-4-(4-fluorophenyI)-4H- l,2,4-triazol-3-yl)thio)acetamido)-3-phenyIpropanoate
Ή NMR (DMSO-d6, 400MHz): 8.73 (d, J = 7.6 Hz, 1H), 7.28-7.25 (m, 2H), 7.22-7.17 (m, 3H), 7.12-7.07 (m, 2H), 6.77-6.70 (m, 3H), 6.42-6.40 (m,' 2H), 4.46-4.41 (m, 1H), 3.86 (s, 2H), 3.71 (s, 3H), 3.58 (s, 6H), 3.03-2.98 (m, 1H), 2.92-2.86 (tn, 1H), 1.54 (s, 6H). ). m/z Relative intensities: 593.2(M+) 100 %.
Example 33
N-(cycIohexylmethyI)-2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4- fluorophenyl)-4H-l,2,4-triazol-3-yl)thio)acetamide.
Ή NMR (DMSO-de, 400 MHz): 8.13 (t, J = 5.6Hz, 1H), 7.10 (t, J = 8.4Hz, 2H), 6.77 - 6.71 (m, 3H), 6.42 (t, J = 8.4Hz, 2H), 3.82 (s, 2H), 3.71 (s, 3H), 3.59 (s, 3H), 2.87 (t, J = 6.4Hz, 2H), 1.61 (d, J = 1 1.2Hz, 5H), 1.53 (s, 6H), 1.37 - 1.31 (m, 1H), 1.20 -1.08 (m, 3H), 0.86 - 0.78 (m, 2H). ). m/z Relative intensities: 527.1 (M+) 100 %.
Example 34
2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazol-3- yl)thio)-N-isoperitylacetamide.
Ή NMR (DMSO-d6j 400MHz) :- 8.12 (s, 1H), 7.10 (t, J = 8.8Hz, 2H), 6.77 - 6.71 (m, 3H), 6.42 (t, J = 8.8Hz, 2H), 3.80 (s, 2H), 3.71 (s, 3H), 3.59 (s, 3H), 3.06 (d d, J, = 13.6Hz, J2 = 6.4Hz, 2H), 1.53(s, 7H), 1.28 (d d, J, = 14.4Hz, J2 = 6.8Hz, 2H), 0.84 (d, J = 6.8Hz, 6H). m/z Relative intensities: 501.3(M+)100 %.
Example 35
2-((5-(2-(3,4-dimethoxyphenyI)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazol-3- yI)thio)-l-morphoIinoethanone
Ή NMR (CDC13, 400 MHz) :- 6.91 - 6.86 (m, 2H), 6.67 (d, J = 8.8Hz, 1H), 6.59 - 6.53 (m, 2H), 6.49 - 6.47 (m, 2H), 4.19 (s, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 3.67 (t, J = 5.2Hz, 4H), 3;62 (t, J = 5.2Hz, 4H), 1.59 (s, 6H). m/z Relative intensities:
Figure imgf000021_0001
Example 36 2-((5-(2-(3,4-dimethoxyphenyI)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4-triazol-3- yl)thio)-l-(4-(2-methoxyacetyI)piperazin-l-yl)ethanone. lH NMR (CDCb, 400MHz): 6.88 (t, J = 8.4Hz, 2H), 6.67 (d, J = 8.4Hz, 1H), 6.56 (s, 2H), 6.49 (s, 2H), 4.18 (s, 2H), 4.12 (s, 2H), 3.86 (s, 3H), 3.73 (s, 4H), 3.67 - 3.52 (m, 7H), 3.43 (s, 3H), 1.58 (s, 6H). m/z Relative intensities: 572.1(M+) 100 %.
Biological studies:
In-vitro studies:
hTGR5 Reporter Gene Assay:
Chinese Hamster Ovarian (CHO) l cells were plated in 24 well tissue culture plate at a density of 4 X 104 cells/well in a Nutrient Mixture F-12 HAM containing 10 % Fetal Bovine Serum, cultured for 24 hrs at 37°C/5% C02, and then transfected with 50 ng of human (h) TGR5 expression plasmid (pCMV SPORT6 - hTGR5), 300 ng of cAMP-responsive element (CRE)-driven luciferase reporter plasmid (pCRE-Luc) and 100 ng of /^-galactosidase reporter vector in each well using Polyfect Transfection Reagent (QIAGEN, Cat. No.: 301 107) according to the manufacturer's instructions. After 4 hrs of incubation, cells were washed once with phosphate-buffered saline (PBS) and medium was exchanged to Nutrient Mixture F-12 HAM containing 0.5% Fatty acid free bovine serum albumin (FAFBSA) and ImM Sodium Pyruvate Solution. After incubation for another 18 hrs, cells were treated for 5 hrs with different concentrations of each compound. After treatment, the cells were lysed with 100 μ , of Glo Lysis buffer (Promega, Cat. No.: E2661) and subjected to Luciferase and ^-Galactosidase assays as described below.
Luciferase and /^-Galactosidase Assays.
For luciferase assays, 20 //L of cell lysate was mixed with 100 L of Luciferase Assay Substrate (Promega, Cat. No.: El 501) and Luminescence was measured in HIDEX Multitechnology Plate Reader. For galactosidase assays, 30 / L of cell lysate was mixed with 30 //L of 2X ONPG Buffer [20 mM sodium phosphate buffer - pH 7.3, 2 mM MgCl2, 100 mM β-mercaptoethanol, and 1.33 mg/mL o-nitrophenyl- ?-D- galactopyranoside (ONPG)] and incubated at 37°C for 2-10 mins. The optical density at 415 nm was determined in SpectraMax 190.
Normalized luciferase values were determined by dividing the luciferase activity by the galactosidase activity and expressed as fold induction with respect to (w.r.t.) DMSO control. TGR5 Assay Results
EC50 values determined according to the TGR5/CRE-Luciference Assay described herein (CRE-Luc). Table below display h-TGR5 CRE-Luc percentage activity of the compounds at 100 nM and Ι μΜ w.r.t. control (RG-239 at Ι μΜ) data. The following compounds in Table 1 were made by procedure described in above scheme and examples, and, where applicable, by making any necessary substituent of known material that one skilled in the art would ordinarily understand.
Figure imgf000023_0001
27 104 109
28 97 102
29 86 97
30 92 1 1 1
32 85 93
35 87 135
Evaluation of pharmacological efficacy of TGR5 agonist compounds:
The high fat diet induced obesity (DIO) in mice exhibits various features of metabolic syndrome in humans. The metabolic syndrome is characterized by abdominal obesity, high triglycerides, impaired fasting glucose and hyperinsulinemia.
In this DIO model, C57 mice of 4-6 week of age is kept on high (60%) fat diet for 4-6 weeks, when they are glucose intolerant, used for the single dose Oral Glucose Tolerance Test (OGTT) study for antidiabetic activity. On day 0 non fasting body weight of animals is recorded, grouped based on non-fasting body weights and kept on fasting for overnight, on the day of experiment animals are subjected for OGTT (oral glucose tolerance Jest). In OGTT, body weight of all animals are recorded and mice will receive a single dose of vehicle/ DPPIV- inhibitor administered per orally on the basis of body weight, 10-min post dosing single dose of vehicle/ test compounds are administered, 15-min post dosing blood collection is done (0 min) and glucose load (2gm/kg/10ml) administered per orally. Blood will be then collected at time points corresponding to 10, 30, 60, and 120 min after glucose load administration. At 10 min plasma is collected for insulin and GLP-1 level measurement. Serum is separated for determination of glucose levels at all time points. Glucose AUC and glucose excursion calculated using MS excel sheet and graph pad software.
The novel compounds of the present invention can be formulated into suitable pharmaceutically acceptable compositions by combining with suitable excipients by techniques and processes and concentrations as are well known.
The compounds of Formula (I) or pharmaceutical compositions containing them are useful as antidiabetic and antiobesity compounds suitable for humans and other warm blooded animals, and may be administered either by oral, topical or parenteral administration.

Claims

claim
Compounds of formula (I) or an isotope, enantiomer, diastereomer or pharmaceutical
Figure imgf000025_0001
Y is = S, SO, S02; Z is = O, C(0)N(R4), or N(R4)C(0); n is 1, 2, 3 or 4; m is 0, 1, or 2; p = 0-5;
and wherein, R1 is
(i) aryl, heteroaryl, or aryI(CrC6)alkyl, each optionally substituted with one, two, or three Rla groups, wherein each Rla is independently halogen, Ci-C4alkyl, C 1-C4 alkoxy, C1-C4 haloalkyl, C3-Cgcycloalkyl, heterocyclyl, the group representing -Rl b, -C1-C4 alkyl-Rl b, or -OC1-C4 alkyl-Rlb wherein Rlb is cyano, nitro, -N(Rlc)2, -ORlc, -SRlc, -C(0)Rlc, - C(0)ORlc, -C(0)N(Rlc)2, -S(0)N(R|C)2, -S(0)2N(Rlc)2, or -S(0)2Rlc, - OC(0)Rlc, -OC(0)ORlc, -OC(0)N(Rlc)2, -N(Rlc)C(0)Rlc, - N(Rlc)C(0)ORlc, -N(Rlc)C(0)N(Rlc)2, or -N(Rlc)C(=NRlc)N(Rlc)2, wherein each Rlc is independently hydrogen, Ci-C4alkyl, or C1-C4 haloalkyl;
R2 is
- Rz, wherein
(i) Rz is independently selected from is cyano, halogen, nitro, -Rzlb' - N(Rzlb)2, -O RZ!b, -S. Rzlb, -C(O) Rzlb, -C(0)0 Rzlb, -C(0)N(Rzlb)2, - S(0)N(RZIb)2, -S(0)2N(Rzlb)2, or -S(0)2 Rzib, -OC(O) Rzi b, -OC(0)0 Rz,b , -OC(0)N(Rzlb)2, -N(Rlc)C(0) Rzlb, -N(Rzlb)C(0)0 Rzlb, - N(Rzlb)C(0)N(Rzl b)2, or -N(Rzlb)C(=N Rzlb)N(Rzlb)2, wherein each Rzib is independently hydrogen, Ci-C6 alkyl, Q-C6 alkoxy or Ci-C6 haloalkyl; or
(11) R is an aryl or heteroaryl or heterocyclyl group, each optionally substituted with one, two, or three RZ1 groups, wherein each RZ1 independently is cyano, nitro, -Rzib' -N(Rzlb)2, -O Rzlb, -S Rzib, -C(O) Rzlb, -C(0)0 Rzlb, -C(0)N(Rzlb)2, -S(0)N(Rzlb)2, -S(0)2N(Rzlb)2, or - S(0)2 Rzlb, -OC(O) Rzlb, -OC(0)0 Rzlb , -OC(0)N(Rzlb)2, -N(Rlc)C(0) Rzlb, -N(Rzlb)C(0)0 Rzlb, -N(Rzlb)C(0)N(Rzlb)2, or -N(Rzlb)C(=N Rzlb)N(Rzlb)2, wherein each Rzib is independently hydrogen, Ci- C4alkyl, Ci-C6 alkoxy or Ci-Gihaloalkyl;
R3 is
aryl, heteroaryl, heterocyclyl, 3 to 8 membered cycloalkyl, or aryl(Ci- C2)alkyl, (Ci-C6) alkyl. or (Cf -C6) haloalkyl each optionally substituted with one, two, or three R3a groups, wherein each R3a independently represents halogen, Ci-C4 alkyl, Q-C4 haloalkyl, C3-C8 cycloalkyl, heterocyclyl, heteroaryl the groups represented by -R3b, -(C1-C4) alkyl- R3b, or -0(C,-C4) alkyl; or
(C,-C6) alkyl, (C C6) alkoxyl, -(CrC6) alkyl-N(R3b)2, -(CrC6) alkyl- OR3b, -(C C6) alkyl-SR3b , (C3-C8)-cycloalkyl, or heterocyclyl, wherein the alkyl, cycloalkyl and heterocyclyl are each optionally substituted with 1 to 6 substituents which are each independently selected from -R3b or -(C1-C6) alkyl-R3b; wherein, each R3b at each occurrence • independently represents cyano, halogen, nitro, -N(R3d)2, -OR3d, -SR3d, - C(0)R3d, -C(0)OR3d, -C(0)N(R3d)2, -C(0)N(R3d)-N[(C1-C3)alkyl]3 +, - S(0) (R3d)2, -S(0)2N(R3d)2, -S(0)2N(R3d)-N[(C,-C3)alkyl]3 +, -S(0)2R3d, -OC(0)R3d, -OC(0)OR3d, -OC(0)N(R3d)2, -N(R3c)C(0)R3d, - N(R c)C(0)OR3d, -N(R3d)C(0)N(R3d)2, or -N(R3d)C(=NR3d)N(R3d)2, wherein each R3d at each occurrence is independently selected from hydrogen, (C1 -C4) alkyl, or (C1-C4) haloalkyl; R4 is independently hydrogen, d-C4 alkyl, C C4 alkoxy, C,-C4 haloalkyl, -S(0)2 -{C1-C4) alkyl, -S(0)2 aryl or heteroaryl; Rs and R6 are independently selected from cyano, nitro, -Rzlb' -N(Rz, b)2, -O Rzlb, -S Rzib, -C(O) Rzlb, - C(0)0 Rzlb, -C(0)N(Rzlb)2, -S(0)N(Rzlb)2, -S(0)2N(Rzlb)2, or -S(0)2 Rzlb, -OC(O) Rzlb, -OC(0)0 Rzlb , -OC(0)N(Rzlb)2, -N(Rlc)C(0) Rzlb, -N(Rzlb)C(0)0 Rzlb, -N(Rzlb)C(0)N(Rzlb)2, or -N(Rzlb)C(=N Rzlb)N(Rzlb)2, wherein each Rzlb is independently d-C6 alkyl, or C,-C6 haloalkyl. The compound as claimed in claim 1 wherein R is selected from 5 or 6 membered aryl, or 5 or 6 membered heteroaryl each optionally substituted with one, two, or three Rla groups, wherein each Rla is independently halogen, C\- C4alkyl, C 1-C4 haloalkyl, Cs-Cecycloalkyl, heterocyclyl, the group representing -Rlb, -C C4 alkyl-Rlb, or -OC1-C4 alkyl-Rlb wherein, Rlb at each occurrence independently represents cyano, nitro, -N(Rlc)2, -ORlc, -SRlc, -C(0)Rlc, - C(0)ORI C, wherein each Rlc is independently hydrogen, C|-C4alkyl, or C1-C4 haloalkyl groups;
The compound as claimed in claim 1 wherein R3 is selected from 5 or 6 membered aryl, 5 or 6 membered heteroaryl, Ci-C alkyl, C[-C6 alkoxy, 3 to 8 membered -cycloalkyl, each optionally substituted with one, two, or three R3a groups, wherein each R3a is independently halogen, C1-C4 haloalkyl, C3- C8cycloalkyl, heterocyclyl, -C(0)N(R3c)2, C(0)N(R3c)-N[(C C3)alkyl]3+, - S(0)2N(R3c)-N[(C,-C3)alkyl]3+, -N(R3c)C(=NR3c)N(R3c)2, wherein each R3c is independently hydrogen, C 1 -C4 alkyl, or C1 -C4 haloalkyl groups.
The compound as claimed in claim 1 selected from
l-(4-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H- 1,2,4- triazol-3-yl)thio)ethoxy)-3-fluorophenyl)-lH-l,2,4-triazole;
1- (4-(2-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H- l,2,4-triazol-3-yI)thio)ethoxy)-3-fluorophenyl)-lH-l,2,4-triazole;
5-(2-(5-((2-(4-( 1 H- 1 ,2,4-triazol- 1 -yl)phenoxy)ethyl)thio)-4-(4-fluorophenyl)- 4H-l,2,4-triazol-3-yl)propan-2-yl)-2-fluorobenzonitrile;
3-((2-(2-fluoro-4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-4-(4-fluorophenyl)-5- (2-(3-methoxyphenyl)propan-2-yl)-4H-l,2,4-triazole;
3-((2-(4-(lH-imidazol-l-yl)phenoxy)ethyl)thio)-4-(4-fluorophenyl)-5-(2- phenylpropan-2-yl)-4H- 1 ,2,4-triazole;
2- ((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4- triazol-3-yl)thio)-N-(4-(2-methyl- 1 H-imidazol- 1 -yl)phenyl)acetamide;
2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H- 1,2,4- triazol-3-yl)thio)-2-methyl-N-(4-(2-methyl-lH-imidazol-l- yl)phenyl)propanamide; 1 -((5-(2-(3,4-dimethoxyphenyl)propan-2-yI)-4-(4-fluorophenyl)-4H- 1,2,4- triazol-3-yl)thio)-N-(4-(2-methyl- 1 H-imidazol- 1 - y l)pheny l)cyclobutanecarboxam ide ;
N-(4-(l H-imidazol-l-yl)phenyl)-2-((5-(2-(4-chloro-3-methoxyphenyl)propan-2- yl)-4-(4-fluorophenyl)-4H-l ,2,4-triazol-3-yl)thio)-2-methylpropanamide;
2-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4- triazol-3-yl)thio)-N-(4-(2 -methyl- 1 H-imidazol- 1 -yl)phenyl)acetamide;
2-((4-(4-fluorophenyl)-5-(2-(3-methoxyphenyl)propan-2-yl)-4H-l,2,4-triazol-3- yl)thio)-2-methyl-N-(4-(2-methyl-l H-imidazol- l-yl)phenyl)propanamide;
1- ((4-(4-fluorophenyl)-5-(2-(3-methoxyphenyl)propan-2-yl)-4H-l,2,4-triazol-3- yl)thio)-N-(4-(2 -methyl- 1 H-imidazol-1 -yl)phenyl)cyclobutanecarboxamide; N-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4- triazol-3 -y l)thio)ethyl)-2-(2,4, 5-trifl uoropheny l)acetamide;
N-(2-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H- l,2,4-triazol-3-yl)thio)ethyl)-2-(2,4,5-triflu0rophenyl)acetamide;
2- ((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyI)-4H-l,2,4- triazol-3-yl)thio)-l-(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)ethanone;
2- ((4-(4-fluorophenyl)-5-(2-(3-methoxyphenyl)propan-2-yI)-4H-l,2,4-triazol-3- yl)thio)-l -(3-(trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl)ethanone;
3- (2-(4-chloro-3-methoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-5-((2-(2- methoxyethoxy) ethyl)thio)-4H- 1 ,2,4-triazole;
3-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-5-((2-(2- methoxyethoxy) ethyl)thio) -4H-l,2,4-triazole;
2-(2-((5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-4-(4-fluorophenyl)-4H-l,2,4- triazol-3-yl)thio)ethoxy)ethanol.
The compounds of formula (I) or their pharmaceutical compositions for the treatment of diabetes and associated disorders.
Use of the compounds of formula (I) or their pharmaceutical compositions for the treatment of diabetes or its associated disorders.
A method of treating disorders caused by metabolic disorder comprising administering to a patient in need thereof an effective amount of a compound of formula (I) according to any of the preceding claims or its pharmaceutical composition according to any of the preceding claims.
A pharmaceutical composition comprising a therapeutically effective amount of formula (I) or salt thereof along with one or more additional therapeutically active compounds for the treatment of metabolic disorders.
The pharmaceutical composition as claimed in claim 8, wherein one or more additional therapeutically active compounds for the treatment of metabolic disorders are selected from insulin, insulin derivatives or mimetics, insulin secretagogues, insulin sensitizers, biguanide agents, alpha-glucosidase inhibitors, insulinotropic sulfonylurea receptor ligands, meglitinides, GLP-1 (glucagon like peptide- 1), GLP-1 analogs, DPPIV (dipeptidyl peptidase IV) inhibitors, GPR-1 19 inhibitors, sodium-dependent glucose co-transporter (SGLT2) inhibitors, PPAR modulators, non-glitazone type PPAR delta agonist, HMG-CoA reductase inhibitors, cholesterol-lowering drugs, rennin inhibitors, anti-thrombotic and anti-platelet agents or anti-obesity agents.
The pharmaceutical composition as claimed in claim 9, wherein therapeutically effective amount of formula (I) is combine with agents selected from insulin, metformin, Glipizide, glyburide, amaryl, gliclazide, meglitinides, nateglinide, repaglinide, amylin mimetics wherein amylin mimetics is selected from pramlintide; acarbose, miglitol, voglibose, Exendin-4, vildagliptin, Liraglutide, naliglutide, saxagliptin, pioglitazone, rosiglitazone, HMG-CoA reductase inhibitors, wherein HMG-CoA reductase inhibitors are selected from rosuvastatin, atrovastatin, simvastatin, lovastatin, pravastatin, fluvastatin, cerivastatin, rosuvastatin, pitavastatin; cholesterol-lowering drugs wherein cholesterol-lowering drugs are selected from fenofibrate, benzafibrate, clofibrate, gemfibrozil; cholesterol absorption inhibitors wherein cholesterol absorption inhibitors are selected from ezetimibe, eflucimibe or suitable mixture thereof.
Use of the compounds of formula (I) or their pharmaceutical compositions along with additional therapeutically active compounds as claimed in claim 8, and 10 and 14 for the treatment of metabolic disorders.
PCT/IN2013/000130 2012-03-07 2013-03-05 Heterocyclic compounds and their use for treatment of diabetes, obesity or related disorders WO2013164838A1 (en)

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WO2010093845A1 (en) * 2009-02-12 2010-08-19 Exelixis, Inc. Triazole and imidazole derivatives for use as tgr5 agonists in the treatment of diabetes and obesity
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