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  • 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
  • C07D213/62—Oxygen or sulfur atoms
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  • C07D213/643—2-Phenoxypyridines; Derivatives thereof
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  • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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  • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
  • C07C229/50—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms being part of the same condensed ring system
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  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
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  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
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  • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
  • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
  • C07D333/78—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • 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
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  • 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
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  • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
  • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
  • C07C2603/08—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing three- or four-membered rings

Definitions

• the instant invention is concerned with tricyclic compounds containing a cyclopropyl carboxylic acid or carboxylic acid derivative fused to a bicyclic ring, including pharmaceutically acceptable salts and prodrugs thereof, which are agonists of G-protein coupled receptor 40 (GPR40) and are useful as therapeutic compounds, particularly in the treatment of Type 2 diabetes mellitus, and of conditions that are often associated with this disease, including obesity and lipid disorders.
• GPR40 G-protein coupled receptor 40
• PPAR-gamma agonism is believed to be responsible for the improved insulin sensititization that is observed in human patients who are treated with the glitazones.
• New PPAR agonists are currently being developed. Many of the newer PPAR compounds are agonists of one or more of the PPAR alpha, gamma and delta subtypes. Compounds that are agonists of both the PPAR alpha and PPAR gamma subtypes (PPAR alpha/gamma dual agonists) have been made and tested, but so far none have been approved by the regulatory authorities.
• the currently marketed PPAR gamma agonists are modestly effective in reducing plasma glucose and HemoglobinAlC.
• the currently marketed compounds do not greatly improve lipid metabolism and may actually have a negative effect on the lipid profile.
• Selective PPAR Gamma Partial Agonists SPPARM' s
• SPPARM' s Selective PPAR Gamma Partial Agonists
• the PPAR compounds represent an important advance in diabetic therapy.
• insulin secretagogues such as the sulfonylureas (e.g. tolbutamide and glipizide).
• sulfonylureas e.g. tolbutamide and glipizide
• These drugs increase the plasma level of insulin by stimulating the pancreatic ⁇ — cells to secrete more insulin.
• Insulin secretion in the pancreatic ⁇ -cell is under strict regulation by glucose and an array of metabolic, neural and hormonal signals. Glucose stimulates insulin production and secretion through its metabolism to generate ATP and other signaling molecules, whereas other extracellular signals act as potentiators or inhibitors of insulin secretion through GPCR' s present on the plasma membrane.
• Sulfonylureas and related insulin secretagogues act by blocking the ATP-dependent K+ channel in ⁇ -cells, which causes depolarization of the cell and the opening of the voltage- dependent Ca2+ channels with stimulation of insulin release.
• This mechanism is non-glucose dependent, and hence insulin secretion can occur regardless of the ambient glucose levels. This can cause insulin secretion even if the glucose level is low, resulting in hypoglycemia, which can be fatal in severe cases.
• the administration of insulin secretagogues must therefore be carefully controlled.
• the insulin secretagogues are often used as a first-line drug treatment for Type 2 diabetes.
• Dipeptidyl peptidase FV (DPP-4) inhibitors e.g., sitagliptin, vildagliptin, alogliptin, denagliptin, and saxagliptin
• DPP-4 Dipeptidyl peptidase IV
• DPP-4 is a cell surface protein with broad tissue distribution that has been implicated in a wide range of biological functions.
• DPP-4 is identical to the T cell activation marker CD26 and can cleave a number of immunoregulatory, endocrine, and neurological peptides in vitro.
• DPP-4 inhibition increases the steady state concentrations of GLP-I and GIP, resulting in improved glucose tolerance. Inactivation of these peptides by DPP-4 may also play a role in glucose homeostasis. DPP-4 inhibitors therefore have utility in the treatment of type 2 diabetes and in the treatment and prevention of the numerous conditions that often accompany type 2 diabetes, including metabolic syndrome, reactive hypoglycemia, and diabetic dyslipidemia. GLP-I has other effects that help to lower blood glucose and contribute to glucose homeostasis. GLP-I inhibits glucagon secretion from the liver.
• GPCR G-protein coupled receptors
• GPR40 agonists that are active in the islets may have the potential to restore or preserve islet function. This would be highly advantageous, because long term diabetes therapy often leads to the gradual diminution of islet activity, so that after extended periods of treatment, it is often necessary to treat type 2 diabetic patients with daily insulin injections. By restoring or preserving islet function, GPR40 agonists may delay or prevent the diminution and loss of islet function in a type 2 diabetic patient.
• the class of compounds described herein is a new class of GPR40 agonists.
• the compounds are useful in the treatment of diseases that are modulated by GPR40 agonists, including type 2 diabetes, hyperglycemia that may be associated with type 2 diabetes or pre- diabetic insulin resistance, and also obesity.
• the present invention is directed to a compound of formula I, or a pharmaceutically acceptable salt thereof, including individual diastereomers and enantiomers thereof, and mixtures of diastereomers and/or enantiomers thereof:
• Ar is selected from the group consisting of phenyl, naphthyl, a 5-6 membered monocyclic heteroaromatic ring having 1-3 heteroatoms independently selected from N, O, and S, and a benzoheteroaromatic group comprising a phenyl ring fused to a 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O and S.
• Ci_6alkyl in all instances is optionally substituted with 1-5 halogens and optionally 1 group selected from -OH and -0Ci_4alkyl optionally substituted with 1-5 halogens
• -Cs- ⁇ cycloalkyl in all instances is optionally substituted with 1-2 substituents independently selected from halogen and CH3
• the aromatic substituent groups phenyl, phenoxy, benzyl, and the 5-6 membered heteroaromatic ring having 1-3 heteroatoms independently selected from N, O and S are optionally substituted with 1-5 groups independently selected from halogen, -CN, -NO2, -OH, -C(
• X is selected from the group consisting of -O-, -S-, -S(O)-, -S(O)2-, -NR5-,
• Y is selected from the group consisting of -O-, -S-, -S(O)-, -S(O)2-, -NR5-, - C(O)-, -CR6R7. 5 -OCR6R7-, -SCR6R7-, and -CR6R7CR8R9 S
• Z is selected from the group consisting of -C(O)ORl 2 s C(O)NRl 3R14, and 5-tetrazolyl;
• Rl, R2, and R3 are each independently selected from the group consisting of H, halogen, Ci_3alkyl, and -OCi-3alkyl, wherein Ci_3alkyl, and -OCi-3alkyl are each optionally substituted with 1-3 halogens;
• Ci_6alkyl in all instances is optionally substituted with 1-5 halogens;
• R6, R7 > R8 9 R9 9 RlO 5 and Rl 1 are each independently selected from the group consisting of H, halogen, -OH, and Ci_3alkyl which is optionally substituted with 1-5 halogens;
• Rl2 is selected from the group consisting of H and Ci_7alkyl which is optionally substituted with 1-5 halogens; p is an integer from 0-3; and q is O or 1.
• Alkyl groups including the alkyl portion of other substituent groups, such as alkoxy, are linear or branched, unless otherewise defined.
• FIG. 1 is a characteristic X-ray diffraction pattern of the crystalline anhydrous free acid of Example 3.
• FIG. 2 is a typical carbon- 13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum of the crystalline anhydrous free acid of Example 3.
• CPMAS carbon- 13 cross-polarization magic-angle spinning
• NMR nuclear magnetic resonance
• FIG. 3 is a typical DSC curve of the crystalline anhydrous free acid of Example 3.
• the invention has numerous embodiments, which are summarized below.
• the invention includes the compounds as shown, and also includes individual diastereomers, enantiomers, and epimers of the compounds, and mixtures of diastereomers and/or enantiomers thereof including racemic mixtures.
• the invention also includes pharmaceutically acceptable salts of the compounds, and pharmaceutical compositions comprising the compounds and a pharmaceutically acceptable carrier.
• the compounds are especially useful in treating insulin resistance, type 2 diabetes, and dyslipidemia that is associated with type 2 diabetes and insulin resistance.
• Ci_3alkyl in all instances is optionally substituted with 1-5 halogens and optionally 1 group selected from -OH and -OCi-3alkyl optionally substituted with 1-5 halogens
• Ci-5alkyl is optionally substituted with 1-5 halogens
• -C3-6cycloalkyl in all instances is optionally substituted with 1-2 substituents independently selected from halogen and CH3, and (d) the aromatic substituent group selected from phenyl,
• 1-2 heteroatoms independently selected from O, S and N is optionally substituted with 1-2 groups independently selected from halogen, CH3, and CF3.
• Rl, R2 S and R3 are each independently selected from the group consisting of H, F, Cl, Cl-3alkyl, and CF3.
• R7, R9, and Rl 1 are each independently selected from the group consisting of H and CH3.
• Rl3 and Rl 4 are each independently selected from the group consisting of H, Ci_5alkyl, and -S(O)2Ci_5alkyl.
• X is selected from the group consisting of -O-, -S-, -S(O)-, -S(O) 2 -, -CHRl 10-,
• Rl, R2, and R3 are each independently selected from the group consisting of H, CH3, and CF3.
• R4 is selected from the group consisting of halogen, CH3, and CF3.
• R ⁇ is selected from the group consisting of H and
• R6 is selected from the group consisting of H and -OH.
• Rl 1 is selected from H and CH3.
• R i 2 is selected from the group consisting of H and Ci-5alkyl which is optionally substituted with 1-5 halogens.
• Rl 3 Js selected from the group consisting of H, Ci-3alkyl > ⁇ d -S(O)2Ci-3alkyl.
• a preferred subgroup comprises compounds of Formula I, wherein
• Ar is selected from the group consisting of phenyl, naphthyl, pyridyl, and thiazolyl, and Ar is optionally substituted with one aromatic group selected from phenyl, phenoxy, and oxadiazolyl, and is optionally substituted with 1-3 groups independently selected from halogen, -CN, -NO2, Ci-4alkyl, -OCi_2alkyl, and -OC3.6cycloal.cyl, wherein Ci-4alkyl and -OCl -2alkyl are optionally substituted with 1-5 halogens, and the substituents phenyl, phenoxy, and oxadiazolyl are optionally substituted with 1 -3 groups independently selected from halogen, -CN, -NO2, -OH, C i-3alkyl, -OCi-3alkyl, and -O(CH2)q(4-6 membered cyclic ether), wherein Ci-3alkyl is optionally substituted with 1-3 halogen
• X is selected from the group consisting of -O-, -CHRl IO-, -CH2NH-, -OCH2-, and -CH2CH2O-;
• Rl , R2, and R3 are each independently selected from the group consisting of H and CH3;
• R6 is selected from the group consisting of H and -OH;
• Rl 1 is selected from H and CH3;
• Rl 2 is H
• Rl 3 is selected from the group consisting of H, Ci-3alkyl, and -S(O)2Ci-3alkyl; Rl4 is H; p is 0; and q is O or 1.
• Ar is substituted with 1 -3 substituent groups.
• p is 0.
• Ar is selected from the group consisting of (a) phenyl, which is optionally substituted with 1-3 groups independently selected from halogen, -CN, -NO2, Ci_4alkyl, -OCl-2alkyl, and -OCs- ⁇ cycloalkyl, wherein Ci-4alkyl and -OCi_2alkyl are optionally substituted with 1 -3 halogens; and is optionally substituted with one group selected from (i) phenyl, which is optionally substituted with 1-3 substituents independently selected from halogen, -CN, -NO2, CH3, -OCH3, CF3, -OCF3, -OCHF2, -OCH2CH2OC 1 -2alkyl, and -O(CH2)q(4-6 membered cyclic ether selected from oxetane and tetrahydropyran), wherein the 4-6 membered cyclic ether is optionally substituted with 1 group selected from
• X is selected from the group consisting of -O-, -CH2O-, -CH(CH3)O-, -CH2CH2O-, -CH2NH-, and -OCH2-.
• Rl, R2, and R3 are each independently selected from the group consisting of H and CH3.
• Ar is phenyl, which is optionally substituted with 1 -3 groups independently selected from halogen, -CN, -NO2, Ci_4alkyl, CF3, -OCF3, -OCHF2, -OC 1 -2alkyl, and -O-cyclopropyl; and is optionally substituted with one group selected from (i) phenyl, which is optionally substituted with 1-3 substituents independently selected from halogen, -CN, -NO2, CH3, -OCH3, CF3, -OCF3, -OCH2CH2OCi_2alkyl, and -O(CH2)q(4-6 membered cyclic ether selected from oxetane and tetrahydropyran), wherein the 4-6 membered cyclic ether is optionally substituted with 1 group selected from CH3, and CF3; (ii) phenoxy, which is optionally substituted with 1-3 groups independently selected from CH3, CF3,
• X is selected from the group consisting of -O- and -CH2O-. In other subgroups, X is O.
• Y is O.
• Rl 3 is selected from the group consi sting of H, CH3 , and -S(O)2CH3.
• Ar is phenyl, which is optionally substituted with 1-3 groups independently selected from halogen, -CN, -NO2, Ci_4alkyl, CF3, -OCF3, -OCHF2, -OCi_2alkyl, and -O-cyclopropyl, and is optionally substituted with one phenyl group, which is optionally substituted with 1-3 substituents independently selected from halogen, -CN, -NO2, CH3, -OCH3, CF3, -OCF3, -OCH2CH2OCi-2alkyl, and -O(CH2)q(4-6 membered cyclic ether selected from oxetane and tetrahydropyran), wherein the 4-6 membered cyclic ether is optionally substituted with 1 group selected from CH3, and CF3.
• the compounds of the invention include pharmaceutically acceptable salts.
• the compounds of this invention may be used in pharmaceutical compositions comprising (a) the compound(s) or pharmaceutically acceptable salts thereof, and (b) a pharmaceutically acceptable carrier.
• the compounds of this invention may be used in pharmaceutical compositions that include one or more other active pharmaceutical ingredients.
• the compounds of this invention may also be used in pharmaceutical compositions in which the compound of Formula I or a pharmaceutically acceptable salt thereof is the only active ingredient.
• a compound of Formula I, or a pharmaceutically acceptable salt thereof, may be used in the manufacture of a medicament for the treatment of type 2 diabetes mellitus in a human or other mammalian patient.
• a method of treating type 2 diabetes comprises the administration of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound, to a patient in need of treatment.
• Other medical uses of the compounds of Formula I are described hereinafter.
• Alkyl means saturated carbon chains which may be linear or branched or combinations thereof, unless the carbon chain is defined otherwise.
• alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.
• alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched, or combinations thereof, unless otherwise defined. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2- butenyl, 2-methyl-2-butenyl, and the like.
• Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched, or combinations thereof, unless otherwise defined. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the like.
• Cycloalkyl means a saturated carbocyclic ring, having a specified number of carbon atoms. The term may also be used to describe a carbocyclic ring fused to an aryl group. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Cycloalkenyl rings comprise a double bond in the ring.
• heteroaryl examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzisoxazolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl (including S-oxide and dioxide), furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, quinazolinyl, dibenzofuranyl, and the like.
• phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, salts and/or dosage forms which are, using sound medical judgment, and following all applicable government regulations, safe and suitable for administration to a human being or an animal.
• composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
• pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
• the substituent "tetrazole” means a 2//-tetrazol-5-yl substituent group and tautomers thereof.
• Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates, racemic mixtures, single enantiomers, individual diastereomers, and mixtures of diastereomers and/or enantiomers.
• the invention is meant to comprehend all such isomeric forms of the compounds of Formula 1.
• the compounds of the instant invention have at least three asymmetric centers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. It is intended that all of the possible optical isomers, stereoisomers, and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention (i.e. all possible combinations of the asymmetric centers as pure compounds or in mixtures).
• Some of the compounds described herein may contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
• keto-enol tautomers Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers.
• An example is a ketone and its enol form, known as keto-enol tautomers.
• keto-enol tautomers The individual tautomers as well as mixtures thereof are encompassed with compounds of Formula I.
• enantiomers and other compounds with chiral centers may be synthesized by stereospecific synthesis using optically pure starting materials and/or reagents of known configuration.
• salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
• Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts in the solid form may exist in more than one crystal structure, and may also be in the form of hydrates.
• 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'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethyl enediamine, 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.
• references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
• the invention includes therapeutically active metabolites, where the metabolites themselves fall within the scope of the claims.
• the invention also includes prodrugs, which are compounds that are converted to the claimed compounds as they are being administered to a patient or after they have been administered to a patient.
• the claimed chemical structures of this application in some cases may themselves be prodrugs.
• the compounds described herein are potent agonists of the GPR40 receptor.
• the compounds, and pharmaceutically acceptable salts thereof, may be efficacious in the treatment of diseases that are modulated by GPR40 ligands, which are generally agonists. Many of these diseases are summarized below.
• One or more of the following diseases may be treated by the administration of a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to a patient in need of treatment.
• the compounds of Formula I may be used for the manufacture of a medicament for treating one or more of these diseases:
• non-insulin dependent diabetes mellitus type 2 diabetes
• hypertriglyceridemia (elevated levels of triglyceride-rich-lipoproteins);
• Preferred uses of the compounds are for the treatment of one or more of the following diseases by administering a therapeutically effective amount to a patient in need of treatment.
• the compounds may be used for manufacturing a medicament for the treatment of one or more of these diseases:
• Type 2 diabetes and specifically hyperglycemia associated with type 2 diabetes; (2) Metabolic syndrome;
• the compounds are expected to be effective in lowering glucose and lipids in diabetic patients and in non-diabetic patients who have impaired glucose tolerance and/or are in a pre-diabetic condition.
• the compounds may ameliorate hyperinsulinemia, which often occurs in diabetic or pre-diabetic patients, by modulating the swings in the level of serum glucose that often occurs in these patients.
• the compounds may also be effective in treating or reducing insulin resistance.
• the compounds may be effective in treating or preventing gestational diabetes.
• the compounds, compositions, and medicaments as described herein may also be effective in reducing the risks of adverse sequelae associated with metabolic syndrome, and in reducing the risk of developing atherosclerosis, delaying the onset of atherosclerosis, and/or reducing the risk of sequelae of atherosclerosis.
• Sequelae of atherosclerosis include angina, claudication, heart attack, stroke, and others.
• the compounds may also be effective in delaying or preventing vascular restenosis and diabetic retinopathy. Impairments in insulin and insulin-like growth factor in the brain are associated with dementia and Alzheimer's disease. See de Ia Monte et al., J. Alzheimer's Disease, 10(1): 89- 109, Sept., 2006. The compounds disclosed herein may have utility in treating, preventing, or slowing the progression of Alzheimer's disease.
• the compounds of this invention may also have utility in improving or restoring ⁇ -cell function, so that they may be useful in treating type 1 diabetes or in delaying or preventing a patient with type 2 diabetes from needing insulin therapy.
• the compounds generally may be efficacious in treating one or more of the following diseases: (1) type 2 diabetes (also known as non-insulin dependent diabetes mellitus, or NIDDM), (2) hyperglycemia, (3) impaired glucose tolerance, (4) insulin resistance, (5) obesity, (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia, (9) hypertriglyceridemia, (10) hypercholesterolemia, (1 1) low HDL levels, (12) high LDL levels, (13) atherosclerosis and its sequelae, (14) vascular restenosis, (15) abdominal obesity, (16) retinopathy, (17) metabolic syndrome, (18) high blood pressure, and (19) insulin resistance.
• type 2 diabetes also known as non-insulin dependent diabetes mellitus, or NIDDM
• hyperglycemia also known as non-insulin dependent diabetes mellitus, or NIDDM
• impaired glucose tolerance (4) insulin resistance
• obesity (6) lipid disorders
• dyslipidemia (7) dyslipidemia
• hyperlipidemia (9) hypertriglyceridemia, (10)
• One aspect of the invention provides a method for the treatment and control of mixed or diabetic dyslipidemia, hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, and/or hypertriglyceridemia, which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound having formula I.
• the compound may be used alone or advantageously may be administered with a cholesterol biosynthesis inhibitor, particularly an HMG-CoA reductase inhibitor such as lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, or itavastatin.
• the compound may also be used advantageously in combination with other lipid lowering drugs such as cholesterol absorption inhibitors (for example stanol esters, sterol glycosides such as tiqueside, and azetidinones such as ezetimibe), ACAT inhibitors (such as avasimibe), CETP inhibitors (for example torcetrapib and those described in published applications WO2005/100298, WO2006/014413, and WO2006/014357), niacin and niacin receptor agonists, bile acid sequestrants, microsomal triglyceride transport inhibitors, and bile acid reuptake inhibitors.
• cholesterol absorption inhibitors for example stanol esters, sterol glycosides such as tiqueside, and azetidinones such as ezetimibe
• ACAT inhibitors such as avasimibe
• CETP inhibitors for example torcetrapib and those described in published applications WO2005/100298,
• Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
• oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
• Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
• compounds of Formula I are administered orally.
• the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
• a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
• the total daily dosage is from about 1.0 milligrams to about 1000 milligrams.
• the total daily dose will generally be from about 1 milligram to about 500 milligrams.
• the dosage for an adult human may be as low as 0.1 mg.
• the daily dose may be as high as one gm.
• the dosage regimen may be adjusted within this range or even outside of this range to provide the optimal therapeutic response.
• Examples of doses in tablets and capsules are 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, and 750 mg.
• Other oral forms may also have the same or similar dosages.
• compositions which comprise a compound of Formula I and a pharmaceutically acceptable carrier.
• the pharmaceutical compositions of the present invention comprise a compound of Formula I or a pharmaceutically acceptable salt as an active ingredient, as well as a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
• pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
• a pharmaceutical composition may also comprise a prodrug, or a pharmaceutically acceptable salt thereof, if a prodrug is administered.
• compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration (e.g. liquid drops or spray), although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
• the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
• any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
• the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as com starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
• a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
• the compound or salt may be advantageous to formulate the compound or salt as a solution in an oil such as a triglyceride of one or more medium chain fatty acids, a lipophilic solvent such as triacetin, a hydrophilic solvent (e.g. propylene glycol), or a mixture of two or more of these, also optionally including one or more ionic or nonionic surfactants, such as sodium lauryl sulfate, polysorbate 80, polyethoxylated triglycerides, and mono and/or diglycerides of one or more medium chain fatty acids.
• an oil such as a triglyceride of one or more medium chain fatty acids, a lipophilic solvent such as triacetin, a hydrophilic solvent (e.g. propylene glycol), or a mixture of two or more of these, also optionally including one or more ionic or nonionic surfactants, such as sodium lauryl sulfate, polysorbate 80, polyethoxylated
• tablets may be coated with shellac, sugar or both.
• a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
• Compounds of formula I may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant or mixture of surfactants such as hydroxypropylcellulose, polysorbate 80, and mono and diglycerides of medium and long chain fatty acids.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g. glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
• Compounds of Formula I may be used in combination with other drugs that may also be useful in the treatment or amelioration of the diseases or conditions for which compounds of Formula I are useful.
• Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
• more than one drug is commonly administered.
• the compounds of this invention may generally be administered to a patient who is already taking one or more other drugs for these conditions.
• the compounds will be administered to a patient who is already being treated with one or more antidiabetic compound, such as metformin, sulfonylureas, and/or PPAR agonists, when the patient's glycemic levels are not adequately responding to treatment.
• one or more antidiabetic compound such as metformin, sulfonylureas, and/or PPAR agonists
• a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is preferred.
• the combination therapy also includes therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules.
• the compound of the present invention and the other active ingredients may be used in lower doses than when each is used singly.
• the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of Formula L
• Examples of other active ingredients that may be administered in combination with a compound of Formula I, and either administered separately or in the same pharmaceutical composition include, but are not limited to:
• PPAR gamma agonists and partial agonists including both glitazones and non- glitazones (e.g. pioglitazone, MCC-555, rosiglitazone, netoglitazone, T-131, and compounds disclosed in WO02/08188, WO2004/020408, WO2004/020409, and WO 2006/096514;
• biguanides such as metformin and phenformin;
• PTP-IB protein tyrosine phosphatase- IB
• dipeptidyl peptidase IV (DP-IV) inhibitors such as sitagliptin, saxagliptin, and vildagliptin;
• sulfonylureas such as tolbutamide, glimepiride, glipizide, and related materials
• ⁇ -glucosidase inhibitors such as acarbose
• agents which improve a patient's lipid profile such as (i) HMG-CoA reductase inhibitors (lovastatin, simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, and other statins), (ii) bile acid sequestrants (cholestyramine, colestipol, and dialkylaminoalkyl derivatives of a cross-linked dextran), (iii) niacin receptor agonists, nicotinyl alcohol, nicotinic acid, or a salt thereof, (iv) PPAR ⁇ agonists such as fenofibric acid derivatives (gemfibrozil, clofibrate, fenof ⁇ brate and bezafibrate), (v) cholesterol absorption inhibitors, such as for example ezetimibe, (vi) acyl CoA:cholesterol acyltransfer
• PPAR ⁇ agonists such as GW501516
• antiobesity compounds such as fenfluramine, dexfenfluramine, phentiramine, subitramine, orlistat, neuropeptide Y5 inhibitors, Mc4r agonists, cannabinoid receptor 1 (CB-I) antagonists/inverse agonists, and ⁇ 3 adrenergic receptor agonists; (1) ileal bile acid transporter inhibitors;
• agents intended for use in inflammatory conditions such as aspirin, nonsteroidal anti-inflammatory drugs, glucocorticoids, azulf ⁇ dine, and cyclo-oxygenase 2 selective inhibitors;
• GLP-I analogs such as exendins, for example exenatide (Byetta); and (r) Hydroxysterol dehydrogenase- 1 (HSD-I) inhibitors.
• HSD-I Hydroxysterol dehydrogenase- 1
• the above combinations include combinations of a compound of the present invention not only with one other active compound, but also with two or more other active compounds.
• Non-limiting examples include combinations of compounds having Formula I with two or more active compounds selected from biguanides, sulfonylureas, HMG-CoA reductase inhibitors, other PPAR agonists, PTP-IB inhibitors, DP-IV inhibitors, and anti-obesity compounds.
• Human and mouse GPR40 stable cell-lines were generated in CHO cells stably expressing NFAT BLA (Beta-lactamase).
• a human GPR40 stable cell-line was generated in HEK cells stably expressing the aequorin expressing reporter.
• the expression plasmids were transfected using lipofectamine (Life Technologies) following manufacturer's instructions. Stable cell-lines were generated following drug selection.
• FLIPR Fluorimetric Imaging Plate Reader, Molecular Devices
• GPR40/CHO NFAT BLA cells were seeded into black-wall-clear- bottom 384-well plates (Costar) at 1.4 x 10e4 cells / 20 ⁇ l medium / well.
• the cells were incubated with 20 ⁇ l / well of the assay buffer (HBSS, 0.1 % BSA, 20 mM HEPES, 2.5 mM probenecid, pH 7.4) containing 8 ⁇ M fluo-4 3 AM, 0.08 % pluronic acid at room temperature for 100 minutes. Fluorescence output was measured using FLIPR.
• Compounds were dissolved in DMSO and diluted to desired concentrations with assay buffer. 13.3 ⁇ l/well of compound solution was added.
• the assay is performed in 96-well format.
• HEK cells stably expressing human GPR40 are plated to be 60-80% confluent within 72 hours. After 72 hours, the plates are aspirated and the cells washed with inositol-free DMEM (ICN).
• the wash media is replaced with 15OuL of 3H-inositol labeling media (inositol-free media containing 0.4% human albumin or 0.4% mouse albumin, IX pen/strep antibiotics, glutamine, 25mM HEPES to which is added 3H- myo-inositol NEN #NET114A lmCi/mL, 25Ci/mmol diluted 1 :150 in loading media with a final specific radioactivity of luCi/150uL).
• the human and mouse albumin can be added after the overnight labeling step before the addition of LiCl.
• the assay is typically run the next day after 18 hours labeling. On the day of the assay, 5uL of 30OmM LiCl is added to all wells and incubated at 37 degrees for 20 mins. 0.75uL of 200X compounds are added and incubated with the cells for 60 minutes at 37 degrees. The media is then aspirated off and the assay terminated with the addition of 6OuL 1OmM formic acid. The cells are lysed for 60 mins at room temperature. 15-3OuL of lysate is mixed with 70uL/lmg YSi SPA beads (Amersham) in clear bottom Isoplates. The plates are shaken for 2 hours at room temperature. Beads are allowed to settle and the plates are counted in the Wallac Microbeta.
• the compounds in these examples all have JC50 values in the range of InM to 4 ⁇ M using the binding assay described above.
• Preferred compounds have 1C50 values in the range of InM to 10OnM.
• 6-hydroxy-2,3-dihydrobenzofuran-3-one (30 g, 0.2 mol) in DMF (375 mL) was added tert- butyldimethylsilyl chlroride (39.2 g, 0.26 mol) and triethylamine (42 mL, 0.3 mol).
• the mixture was stirred at room temperature for 2h. It was then diluted with diethyl ether (1.5 L), washed with ammonium chloride (750 mL, aq. sat.) and brine (450 mL), dired over magnesium sulfate, filtered and concentrated.
• the crude product was purified on a Biotage 65i silica gel column, eluting with ethyl acetate and hexanes (3 : 7). The final product was collected as yellow solid.
• Step 3 1 -Benzofuran-6-ol
• hydrochloric acid 323 mL, 1.0 N
• the crude product was purified on a silica gel column, eluting with ethyl acetate (1 - 30%) in heptane. The final product was collected as light brown solid.
• Solid NaOMe (6134 g) was added to a 0 0 C solution of the chloroketone 2 (7062 g) in 49 L of methanol (MeOH) in portions over 2h while maintaining the temperature at ⁇ 20 0 C.
• the slurry was aged at room temperature for Ih, at which time cyclization was determined to be complete by HPLC.
• the mixture was cooled to 0 0 C, and 2N HCl (49 L) was added while maintaining the temperature at ⁇ 20 0 C.
• the slurry was cooled to 5-10 0 C, filtered, and washed first with cold 1 : 1 MeOH/water (5 L), and then with water (16 L).
• the wet filter cake was slurry washed with isopropyl alcohol (IPA) (18 L), and then was finally washed with heptane. The filter cake was then dried under a fast stream of nitrogen. Ketone 3 was isolated as a white solid.
• IPA isopropyl alcohol
• Acetic acid (HOAc) (3.1 1 L, 3 equivalents) was added to a slurry Of NaBH 4 (1368 g) in
• the organic layer was concentrated on a rotary evaporator, and was then rinsed from the flask with toluene (6 L). Toluene (4 L) was then added, and the resulting thin slurry was filtered to remove impurities. The filtrate was concentrated on a rotary evaporator to an oil that eventually solidified to 1 -benzofuran-6-ol 4 as a pale orange solid.
• Step 2 6-f 2-(Difluoromethoxy ' )-4-rtrifluoromethyl ' )phenoxy '
• l-benzofuran-6-ol 13.4 g, 100 mmol
• 2-(difluoromethoxy)-l-fluoro-4- trifluoromethylbenzene 29.9 g, 130 mmol
• DMF 300 mL
• cesium carbonate 65.2 g, 200 mmol
• Step 3 Ethyl 4-f2-(difluoromethoxy>-4-(trifluoromethyl')phenoxy]- 1 a.6b-dihvdro-l H- cycloproparbi ⁇ Hbenzofuran- 1 -exo-carboxylate
• Step 1 A typical procedure is as follows: l-bromo-4-fluoronaphthalene (1 eq.), CuI (25.0 mol %), racemic trans-N,N'-dimethylcyclohexane-l,2-diamine (50 mol %), and NaI (2.5 equivalents) were added to a sealed tube, degassed, and dioxane was then added. The reaction mixture was again degassed, flushed with nitrogen and heated at 110 0 C for 24 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and the solid reagents were filtered off. The filtrate was concentrated to afford a residue which was purified by column chromatography (10% ethyl acetate/hexanes) to provide the desired product.
• Step 3 4- ⁇ r4-(Trifluoromethvn- 1 -naphthylloxy) - 1 a.6b-dihvdro- 1 H- cycloproparb] [ 1 ]benzofuran- 1 -exo-carboxylic acid
• the final product was purified on a ChiralPak AD-H semi-preparative column, eluting with 4-7% ethanol in heptane. MS: 385.1 (M-I).
• Step 1 To a solution of 2-fluoro-5-trifluoromethyl phenol (1080 mg, 6 mmol) in AcOH (12 mL) was added triflic acid (0.265 mL, 3 mmol) and NCS (881 mg, 6.6 mmol), and the mixture was heated to 60 0 C for 20 hours. AcOH was removed and the residue was diluted with ethyl acetate, washed with water and brine, and concentrated. The crude products were then separated by reversed-phase HPLC with MeCN/0.5%TFA in water (20-70%) as the eluent to afford the desired products.
• Step 2 Sodium chlorodifluoroacetate (178 mg, 1.17 mmol) and cesium carbonate (228 mg, 0.7 mmol) were added to a solution of 6-fluoro-2-chloro-3-trifluoromethylphenol in DMF containing 10 volume % water (1 mL), and the reaction mixture was heated for 1 h at 100 0 C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water (3X), brine (IX). The organic layer was dried over MgS ⁇ 4 and concentrated to obtain the crude product which was used in the next step without further purification.
• Step 3 4-[3-Chloro-2-( " difluoromethoxy)-4-rtrifluoromethv ⁇ phenoxy1-la.6b-dihvdro-lH- cvclopropafbi [1 lbenzofuran-1 -exo-carboxylic acid followss the method of Example 1 or Example 3. MS: 437.0 (M+l).
• Step 1 To a solution of 3-iodo-phenylboronic acid (991 mg, 4 mmol) and 1 -benzofuran-6-ol (269 mg, 2 mmol) in dichloromethane (8 mL) was added copper acetate (363 mg, 2 mmol), pyridine (0.8 mL, 10 mmol) and 4A molecular sieves (300 mg). The reaction mixture was degassed and stirred under an oxygen balloon overnight. It was then filtered and concentrated. The crude product was purified on a silica gel column, eluting with ethyl acetate (0-10%) in hexanes, to yield the desired product.
• Step 2 6-[f4'-Methoxy-2'-methylbiphenyl-3-vDoxy ⁇
• PdC ⁇ dppf 77 mg, 0.9 mmol
• K3PO4 502 mg, 2.36 mmol
• the reaction mixture was heated at 100°C for 20hr. After cooling to room temperature and normal aqueous workup, the crude product was purified on a silica gel column, eluting with ethyl acetate (0-10%) in hexanes, to yield the desired product as colorless oil.
• Step 1 To a solution of 2-fluoro-5-trifluoromethyl phenol in DMF (2 mL) was added cyclopropyl bromide (2 eq.), NaI (10 mol%) and cesium carbonate (3 eq.). The reaction mixture was heated in a pressure tube at 150 0 C overnight. The completion of the reaction was confirmed by LCMS. The reaction mixture was then diluted with ethyl acetate, washed with water and extracted with ethyl acetate (3X). The combined organic layer was dried over sodium sulfate, filtered, and concentrated to yield the crude product which was used in the next step without further purification.
• Step 2 4-[2-(CvclopropyloxyV4-(trifluoromethvnphenoxy " )-la,6b-dihvdro-lH- cvclopropa[b][l ]benzofuran-l -exo-carboxylic acid followss the method of Example 1 or Example 3. MS: 393.0 (M+l).
• Step 1 To a solution of 3-(tert-butyl)phenol (3 g, 20 mmol) in methanol (40 mL) was added iodine (5.58 g, 22 mmol) in portions, and the mixture was stirred for 48 hours at room temperature. Solvent was removed and the residue was dissolved in ethyl acetate (200 mL). The solution was washed with Na2SO3 (3X) and brine, dried over MgSO4 and concentrated. The residue was purified with a silica gel column chromatography with ethyl acetate/hexanes (10- 20%) as the eluant to afford the desired product.
• Step 2 Sodium chlorodifluoroacetate (4 g, 26.17 mmol) and cesium carbonate (5.1 g, 15.7 mmol) were added to a solution of 5 -(tert-butyl)-2-iodo-l -phenol (2.89 g, 10.47 mmol) in DMF containing 10 volume % water (22 mL), and the reaction mixture was heated for 3 days at 100 0 C in a sealed tube. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water (3X) and brine (IX). The organic layer was dried over MgS ⁇ 4 and concentrated. The residue was purified with a silica gel column chromatography with ethyl acetate/hexanes (0-10%) as the eluant to afford the desired product.
• Step 1 l-Bromo-2-chloro-4-(difluoromethoxy)benzene
• Step 1 To a solution of 2-fluoro-5-trifluoromethyl phenol in DMF (2 mL) was added iodoethane (2 eq.) and cesium carbonate (3 eq.). The reaction mixture was heated at 75 0 C overnight. The completion of the reaction was confimed by LCMS. The reaction mixture was then diluted with ethyl acetate, washed with water and extracted with ethyl acetate (3X). The combined organic layer was dried over sodium sulfate, filtered and concentrated to yield the crude product which was used in the next step without further purification.
• Step 2 Sodium chlorodifluoroacetate (2.5 eq.) and cesium carbonate (1.5 eq.) were added to a solution of 2-bromo-5-chlorophenol in DMF containing 10 volume % water, and the reaction mixture was heated for 3h at 100 0 C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water (3X), then with brine (IX). The organic layer was dried over sodium sulfate and concentrated to obtain the crude product which was used in the next step without further purification.
• Step 1 Sodium chlorodifluoroacetate (692 mg, 4.54 mmol) and cesium carbonate (888 mg, 2.73 mmol) were added to a solution of 6-fluoro-3-trifluoromethyl-4-chlorophenol in DMF containing 10 volume % water (3 mL), and the reaction mixture was heated for 1 h at 100 0 C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water (3X), brine (IX). The organic layer was dried over MgS ⁇ 4 and concentrated to obtain the crude product which was used in the next step without further purification.
• Step 1 4-fluoro-3-methoxybenzonitrile (Ig, 6.62 mmols) was dissolved in anhydrous dichloromethane (1OmL) and cooled to 0 0 C (ice-bath). To the cooled solution was added boron tribromide solution in dichloromethane (1 M, 2 eq.). The reaction mixture was stirred at 0 0 C for 5 minutes, warmed to room temperature and stirred at room temperature overnight. LCMS of the reaction mixture showed some starting material was still present. Two more equivalents of boron tribromide solution was added and the reaction was stirred at RT overnight. LCMS showed that the reaction had progressed, but some starting material was still present.
• reaction mixture was then heated at 45 0 C overnight to complete the reaction, as confirmed by LCMS.
• the reaction mixture was then poured into ice-water, warmed to RT, and extracted with ethyl acetate (3X). The combined organic layer was dried over sodium sulfate, filtered and concentrated to give the crude phenol which was used in the next step without further purification.
• Step 2 Sodium chlorodifluoroacetate (2.5 eq.) and cesium carbonate (1.5 eq.) were added to a solution of 2-fluoro-5-cyanophenol in DMF containing 10 volume % water, and the reaction mixture was heated for 3 h at 100 0 C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water (3X), then with brine (IX). The organic layer was dried over sodium sulfate and concentrated to obtain the crude product which was used in the next step without further purification.
• Step 3 4-[4-Cvano-2-(difluoromethoxy)phenoxy]-la,6b-dihvdro-lH- cvclopropaf bi ⁇ 1 Ibenzofuran- 1 -exo-carboxylic acid followss the method of Example 1 or
• Step 1 6-f2-fDifluoromethoxy)-5-methvI-4-(trifluoromethv0phenoxyl-l-benzofuran
• methyl boronic acid 12 mg, 0.2 mmol
• cesium carbonate 129 mg, 0.4 mmol
• Pd(PPhJ )4 30.5 mg, 0.026 mmol
• the mixture was degassed, flushed with nitrogen, and heated to 120 0 C for 5 hours. Solvent was removed and the residue was purified with silica gel cloumn chromatography using hexanes/ethyl acetate as the eluant (10/1) to afford the desired compound.
• Step 2 4-[2-( " DifluoromethoxyV5-methyl-4-(trifluoromethyl ' )phenoxy]-la,6b-dihvdro-lH- cvclopropafbifllbenzofuran-1-exo-carboxylic acid followss the methods of Example 1, steps 2 and 3, and Example 3, steps 3 and 4. MS: 417.0 (M+l).
• Step 1 5- ( ( 1 S.1 aR.6bS)- 4-r2-(difluoromethoxy>4-(trifluoromethv0phenoxyl - 1 a.6b-dihydro- 1 H-cvclopropaFbi [ 1 Ibenzofiiran- 1 -carbonitrile
• cyanuric chloride 89 mg, 0.48 mmol
• the reaction was stirred at room temperature for 2h. After aqueous workup, the crude product was purified on a silica gel column, eluting with ethyl acetate (0-30%) in hexanes. The final product was collected as colorless oil.
• Step 4 4- r2-(Difluoromethoxy ' )-4-f trifluoromethvOphenoxy '
• the final product was purified on a ChiralPak AD-H semi-preparative column, eluting with 4-7% ethanol in heptane. MS: 417.3 (M+l).
• Step 1. 1 -[3 -(benzyl oxy)phenoxy1 acetone
• Step 1. 1 -[3 -(benzyl oxy)phenoxy1 acetone
• Step 3 4-[2-(DifluoromethoxyV4-(trifluoromethy ⁇ phenoxy]-6b-methyl-la,6b-dihydro-lH- cvclopropafb] f 1 Ibenzofuran- 1 -exo-carboxylic acid
• the final product was purified on ChiralPak AD-H semi-preparative column, eluting with 4-7% ethanol in heptane. MS: 417.2 (M+l).
• Step 1 ⁇ -rO-iodobenzvPoxyi-l -benzofiiran To a stirred solution of l-benzofuran-6-ol (1.0 g, 7.5 rrrmol) and 3-iodobenzylbromide (2.7 g, 9.0 mmol) in DMF (10 mL) was added potassium carbonate (1.5 g, 11.0 mmol). The reaction mixture was stirred under nitrogen at room temperature for 3 days. The reaction was diluted with ethyl acetate, washed with water (2x) and brine, dried over magnesium sulfate, filtered and concentrated. The crude product was purified on a silica gel column, eluting with ethyl acetate (10-50%) in hexane. The final product was collected as a slightly yellow viscous oil.
• Step 3 4- f (3 -Iodobenzy Doxy] - 1 a.6b-dihvdro- 1 H-cvclopropafb] ⁇ 1 ]benzofuran- 1 -exo-carbox yl i c acid
• Step 3 The final product was obtained as a slightly colored solid.
• Potassium carbonate (5.28 kg) was then added. The ice water bath was removed and the batch was heated to 97°C using a steam bath. The reaction was complete after aging for 2h at 97°C, as evidenced by HPLC assay, with ⁇ 1% starting material remaining. The reaction was cooled to ambient temperature, and water (42 L) was slowly added. The batch was transferred to a 170-L extractor and extracted with MTBE (2 x 18 L). The organic layers were combined and washed with water (1 x 11 L) and brine (1 x 11 L). The MTBE solution was pumped into a 22-L flask equipped with a thermocouple, distillation apparatus, and a heating mantle. The MTBE was distilled off at 55-118°C and atmospheric pressure. The desired product was purified by distillation at 120-157 0 C and atmospheric pressure, and was isolated as a clear oil.
• the amount of water by Karl-Fischer titration was ⁇ 200 ug/mL.
• the toluene solution was filtered through a plug OfSiO 2 (5.0 kg).
• the silica was washed with toluene (14.2 L).
• the filtrate was concentrated on a rotary evaporator to yield 6-[2-(difluoromethoxy)-4- (trifluoromethyl)phenoxy]-l-benzofuran biaryl ether as a light orange oil.
• Step 1 Asymmetric Cvclopropanation to give Ethyl flR,laR,6bS " )-4-f2-(difluoromethoxy)-4- (trifluoromethyl)phenoxyi-l a.6b-dihvdro- 1 H-cvclopropaFbl T 1 lbenzofuran- 1 -carboxylate
• the phenoxybenzofuran (6.031 kg, 91.35 wt%, 92.0 Assay% purity, 26.9 ppm water by Karl Fischer titration) was rinsed into the reactor with dichloromethane (4 L). The reaction mixture was aged at rt for 0.5 h, and was then cooled to -9 to -12 0 C. Ethyl diazoacetate in dichloromethane (85 wt%, 5.64 kg, 2.63 equiv) was slowly added to the reaction mixture at -9 0 C to -12 0 C over 30 h, resulting in 96A% conversion to the desired product with a ratio of exo:endo of about 29.3: 1.
• the reaction mixture was slowly warmed to ambient temperature, and aged for 0.5 h.
• EDTA disodium salt solution (0.05M, 18 L) was added, and the reaction mixture was aged for 1 h at 20 0 C.
• the phases were separated, and the organic layer was washed with additional 0.05 M EDTA sodium salt solution (8 L).
• the desired exo product in the organic layer was assayed to be 6.17 kg (90% yield, 92.1% ee).
• the solution was concentrated and the solvent was switched to methanol (25 L, total volume) for the next step.
• Ecosorb C905 50 wt%, 2.89 kg was added to the thin slurry, and the mixture was then aged at ambient temperature for 2h, filtered through solka floe, and rinsed with toluene (23 L). The filtrate was concentrated to 29 L, and (R 3 S)-CAI, (R,S)-cis-aminoindanol (0.96 equivalents compared with the assayed amount of hydrolyzed ester) was added. The mixture was warmed to 85 0 C to dissolve all solids. The mixture was then cooled to 75 0 C, and the CAI salt began to crystallize. The mixture was aged 15 min at 75 0 C, and then heptane (13.5 L) was added over Ih.
• the mixture was allowed to slowly cool to rt.
• the mixture was filtered.
• the solid product was washed with 2:1 toluene/heptane (18 L), and was then dried under nitrogen for 5 days.
• the isolated product was 98.6% pure solid, 98.0%ee.
• the CAI salt (590Og of 98.6 wt.% product from above) was dissolved in toluene (53 L) at 85 0 C and was then cooled to 70 0 C to give a thin slurry. Heptane (18L) was added over Ih while maintaining the temperature at 65-70 0 C. The mixture was allowed to cool to rt over 3h and was then filtered. The filter cake was dried under nitrogen for 2 days. The isolated product purity was >99A% and 98.8%ee.
• Step 3 (1 R, 1 aR.6bSV4-r2-(dif1uoromethoxy>4-( trifluoromethv0phenoxy1-la.6b-dihvdro-lH- cvcloproparbi ⁇ ibenzofuran-1-carboxylic acid
• the CAI salt from the previous step was added to a IOOL cylindrical vessel which contained a mixture of MTBE (27.3 L) and 10.9 L of IN HCl (1.1 equiv.). After being stirred vigorously for 15min, the aqueous layer was allowed to settle, and the layers were separated. The organic layer was washed with 11.8 L of water. The organic layer was then solvent switched to IPA (16 L). Water (8 L) was added in one portion, and then 1% seed (obtained from earlier batches) was added. (The product crystallizes without seed if none is available.) After 15min, water (32 L) was added over Ih.
• the mixture was aged 14h, and then was filtered, washed with 2:3 IPA/water (15 L), and dried under nitrogen for 20 h.
• the product purity was 99.78 A%, 98.6%ee.
• the product is a crystalline anhydrous free acid which is characterized by the methods described below.
• the crystalline product has the same crystal morphology as the product isolated in Example 3.
• X-ray powder diffraction studies are widely used to characterize molecular structures, crystallinity, and polymorphism.
• the X-ray powder diffraction pattern of the crystalline anhydrous free acid of Example 3 made by the process described above was generated on a Philips Analytical X'Pert PRO X-ray Diffraction System with PW3040/60 console.
• a PW3373/00 ceramic Cu LEF X-ray tube K-Alpha radiation was used as the source.
• FIG. 1 shows the X-ray diffraction pattern of the crystalline anhydrous free acid of Example 3 made by the process described above.
• the crystalline anhydrous free acid exhibited characteristic diffraction peaks corresponding to d-spacings of 9.7, 6.1, and 5.6 angstroms. It was further characterized by d-spacings of 4.8, 4.4 and 4.1 angstroms. It was even further characterized by d-spacings of 3.7, 3.4, and 3.2 angstroms.
• the crystalline anhydrous free acid of Example 3 made by the process described above was further characterized by its solid-state carbon- 13 nuclear magnetic resonance (NMR) spectra.
• the solid-state carbon- 13 NMR spectrum was obtained on a Bruker DSX 500WB NMR system using a Bruker 4 mm HfXfY CPMAS probe.
• the carbon- 13 NMR spectrum utilized proton/carbon- 13 cross-polarization magic-angle spinning with variable-amplitude cross polarization, total sideband suppression, and SPINAL decoupling at 10OkHz.
• the sample was spun at 10.0 kHz, and a total of 512 scans were collected with a recycle delay of 30 seconds. A line broadening of 10 Hz was applied to the spectra before FT was performed. Chemical shifts are reported on the TMS scale using the carbonyl carbon of glycine (176.03 p.p.m.) as a secondary reference.
• FIG. 2 shows the solid-state carbon- 13 CPMAS NMR spectrum of the crystalline anhydrous free acid of the product made by the process described above.
• the crystalline anhydrous free acid exhibited characteristic signals with chemical shift values of 180.9, 153.7, 69.7, and 23.0 p.p.m. Further characteristic of the crystalline free acid are the signals with chemical shift values of 160.9, 123.5, and 31.5 p.p.m.
• the crystalline free acid is even further characterized by signals with chemical shift values of 125.8, 1 12.9, and 115.2 p.p.m.
• FIG. 3 shows the differential calorimetry scan of the crystalline anhydrous free acid.
• the crystalline anhydrous free acid exhibited an endotherm due to melting with an onset temperature of 121.0 0 C, a peak temperature of 122.8 0 C, and an enthalpy change of 64.4 J/g.
• 6- r2-Chloro-4-( " trifluoromethvOphenoxy] indan- 1 -one To a stirred solution of 6-hydroxyindan- 1-one (1.48 g, 10 mmol) in 30 ml of DMF was added 3-chloro-4-fluorobenzotrifluoride (2.46 g, 12 mmol) and cesium carbonate (8.40 g, 25 mmol). The reaction mixture was heated at 80 0 C for 12 h. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, washed with water (2x) and brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography, eluting with ethyl acetate (2 — 40%) in hexane. The final product was collected as brownish yellow oil.
• 6-r2-Chloro-4-(trifluoromethv0phenoxy1-lH-inden-l-one To a stirred solution of 6-[2-chloro- 4-(trifluoromethyl)phenoxy]indan-l-one (200 mg, 0.612 mmol) in toluene (5.0 mL) at 0 0 C under nitrogen was added triethylamine (0.104 mL, 0.734 mmol) followed by trimethylsilyl trifluoromethanesulfonate (0.140 g, 0.612 mmol). The reaction warmed to room temperature and stirred for 10 min, then was diluted with diethyl ether and saturated sodium bicarbonate.
• Example 63(a) (IR. IaR. 6bSV4-r2-Chloro-4-rtrifluoromethyl)phenoxy1-l a.6b-dihvdro- 1 H- cyclopropaf b] [1 ]benzofuran- 1 -methyl- 1 -carboxylic acid.
• LiOH (1 mL, IN aq.

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