WO2005086661A2 - Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders - Google Patents

Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders Download PDF

Info

Publication number
WO2005086661A2
WO2005086661A2 PCT/US2005/005815 US2005005815W WO2005086661A2 WO 2005086661 A2 WO2005086661 A2 WO 2005086661A2 US 2005005815 W US2005005815 W US 2005005815W WO 2005086661 A2 WO2005086661 A2 WO 2005086661A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
phenyl
alkyl
acid
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US2005/005815
Other languages
French (fr)
Other versions
WO2005086661A3 (en
Inventor
Michelle Akerman
Jonathan Houze
Daniel C. H. Lin
Jiwen Liu
Jian Luo
Julio C. Medina
Wei Qiu
Jeffrey D. Reagan
Michael J. Schmitt
Yingcai Wang
Rajiv Sharma
Stephen J. Shuttleworth
Ying Sun
Jian Zhang
Liusheng Zhu
Jinqian Liu
Zhihua Ma
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amgen Inc
Original Assignee
Amgen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to EP05723623.4A priority Critical patent/EP1737809B1/en
Application filed by Amgen Inc filed Critical Amgen Inc
Priority to EA200601388A priority patent/EA011010B1/en
Priority to US10/591,214 priority patent/US7816367B2/en
Priority to AU2005220728A priority patent/AU2005220728B2/en
Priority to CA2558585A priority patent/CA2558585C/en
Priority to ES05723623T priority patent/ES2433466T3/en
Priority to JP2007500959A priority patent/JP5299810B2/en
Priority to BRPI0508098-3A priority patent/BRPI0508098A/en
Publication of WO2005086661A2 publication Critical patent/WO2005086661A2/en
Publication of WO2005086661A3 publication Critical patent/WO2005086661A3/en
Priority to IL177717A priority patent/IL177717A0/en
Anticipated expiration legal-status Critical
Priority to TNP2006000263A priority patent/TNSN06263A1/en
Priority to NO20064362A priority patent/NO20064362L/en
Priority to IS8542A priority patent/IS8542A/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/24—Radicals substituted by oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to compounds capable of modulating the
  • G-protein-coupled receptor GPR40 compositions comprising the compounds, and methods for their use for controlling insulin levels in vivo and for the treatment of conditions such as type II diabetes, hypertension, ketoacidosis, obesity, glucose intolerance, and hypercholesterolemia and related disorders associated with abnormally high or low plasma lipoprotein, triglyceride or glucose levels.
  • GPR40 is a member of the gene superfamily of G-protein coupled receptors
  • GPCRs are membrane proteins characterized as having seven putative transmembrane domains that respond to a variety of molecules by activating intra-cellular signaling pathways critical to a diversity of physiological functions.
  • GPR40 was first identified as an orphan receptor (i.e., a receptor without a known ligand) from a human genomic DNA fragment. Sawzdargo et al. (1997) Biochem. Biophys. Res. Commun. 239: 543-547. GPR40 is highly expressed in pancreatic ⁇ cells and insulin-secreting cell lines. of the G q family of intra-cellular signaling proteins and concomitant induction of elevated calcium levels.
  • a condition or disorder such as type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer or edema.
  • the compounds of the invention have the general formula (I): Q-L'-P-L ⁇ M-X-L ⁇ A I wherein Q is hydrogen, aryl, heteroaryl, (C ⁇ -C 6 )alkyl or (C 2 -C 6 )heteroalkyl; L 1 is a bond, (d-C ⁇ alkylene, (C 2 -C 4 )heteroalkylene, O, S(O) m , NCR 1 ), C(O)-(C 5 -C 7 )heterocycloalkylene, (C ⁇ -C 4 )alkylene-SO 2 N(R 2 ), (C ⁇ -C 4 )alkylene-N(R 2 )SO 2 or C(O)N(R ); P is an aromatic ring, a heteroaromatic ring, (C 3 -C 8 )heterocycloalkylene or (C 3 -C 8 )cycloalkylene; L 2 is a bond
  • the present invention provides a compound having the formula (lb):
  • R 21 is -H, -OH, -NHS(O 2 )CH 3 , heteroaryl, or -NH- A heteroaryl
  • R is -(C 2 .C 8 )alkyl, -(C 3 -C 8 )alkenyl, -NR R , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, c ⁇ , or C-C-R 25 ; or optionally where Z is a nitrogen atom, R is -H; R and R are independently -H, -(C ⁇ -C 5 )alkyl, or -(Ci- C 5 )oxyalkyl; R 25 is -H, -(C ⁇ -C 5 )alkyl, -hetero(C ⁇ -C 5 )alkyl, -(C r C 5 )oxyalkyl, substituted or unsubstit
  • the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula I, la, lb or II.
  • a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease atherosclerosis, kidney disease, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, thrombotic disorders, dermatopathy, dyspepsia, hypoglycemia, hypertension, cancer and edema comprising administering to a subject in need thereof a therapeutically effective amoxmt of a compoxmd of formula I, la, lb or II.
  • the invention provides methods for treating or preventing a disease or condition responsive to the modulation of GPR40 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, la, lb or II.
  • the invention provides methods for treating or preventing a disease or condition mediated, regulated or influenced by pancreatic ⁇ cells comprising administering to a subject in need thereof a therapeutically effective amoxmt of a compoxmd of formula I, la, lb or II.
  • the invention provides methods for modulating GPR40 function in a cell, comprising contacting a cell with a compound of formula I, la, lb or II.
  • the invention provides methods for modulating GPR40 function comprising contacting GPR40 with a compound of formula I, la, lb or II. [018] In another aspect, the invention provides methods for modulating circulating insulin concentration in a subject, comprising administering a compound of formula I, la, lb or II to the subject. [019] Other objects, features and advantages of the invention will become apparent to those skilled in the art from the following description and claims.
  • FIG. 1 provides a scheme for synthesis of exemplary compounds of the invention. 5. DETAILED DESCRIPTION OF THE INVENTION
  • treat are meant to include alleviating or abrogating a condition or disease and/or its attendant symptoms and alleviating.
  • prevention refers to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a subject from acquiring a condition or disease or reducing a subject's risk of acquiring a condition or disease.
  • terapéuticaally effective amount refers to that amount of the compound that will elicit the biological or medical response of a tissue, system, or subject that is being sought.
  • therapeutically effective amount includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated in a subject.
  • the therapeutically effective amount in a subject will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated.
  • the "subject” is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
  • the terms "modulate”, “modulation” and the like refer to the ability of a compoxmd to increase or decrease the function or activity of GPR40 either directly or indirectly.
  • Inhibitors are compounds that, for example, bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate signal transduction, such as, for instance, antagonists.
  • Activators are compounds that, for example, bind to, stimulate, increase, activate, facilitate, enhance activation, sensitize or up regulate signal transduction, such as agonists for instance. Modulation may occur in vitro or in vivo.
  • GPR40-mediated condition or disorder refers to a condition or disorder characterized by inappropriate, for example, less than or greater than normal, GPR40 activity.
  • a GPR40-mediated condition or disorder may be completely or partially mediated by inappropriate GPR40 activity.
  • a GPR40-mediated condition or disorder is one in which modulation of GPR40 results in some effect on the underlying condition or disease (e.g., a GPR40 modulator results in some improvement in patient well-being in at least some patients).
  • Exemplary GPR40-mediated and metabolic disorders e.g., diabetes, type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia, thrombotic disorders, metabolic syndrome, syndrome X and related disorders, e.g., cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia and edema.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (e.g., Ci. o means one to ten carbons).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like.
  • alkenyl by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C 2 .C 8 means two to eight carbons) and one or more double bonds.
  • alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl) and higher homologs and isomers thereof.
  • alkynyl by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C 2 -C 8 means two to eight carbons) and one or more triple bonds.
  • alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologs and isomers thereof.
  • alkylene by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by -CH 2 CH 2 CH 2 CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 12 or fewer carbon atoms being preferred in the present invention.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized.
  • the heteroatom(s) O, N and S may be placed at any position of the heteroalkyl group.
  • Up to two heteroatoms may be consecutive, such as, for example, -CH -NH-OCH 3 .
  • a prefix such as (C 2 -C 8 ) is used to refer to a heteroalkyl group
  • the number of carbons (2 to 8, in this example) is meant to include the heteroatoms as well.
  • a C 2 -heteroalkyl group is meant to include, for example, -CH 2 OH (one carbon atom and one heteroatom replacing a carbon atom) and -CH 2 SH.
  • a heteroalkyl group is a oxyalkyl group.
  • (C 2 .C 5 )oxyalkyl is meant to include, for example -CH 2 -O-CH (a C 3 -oxyalkyl group with two carbon atoms and one oxygen replacing a carbon atom), -CH 2 CH 2 CH 2 CH 2 OH, and the like.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH 2 -CH 2 -S-CH 2 CH 2 - and -CH2-S-CH2-CH2-NH-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.
  • heterocycloalkyl a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, _ __ 4 ⁇ rph ⁇ n ⁇ tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like.
  • cycloalkylene and “heterocycloalkylene,” by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkylene” and “heteroalkylene,” respectively.
  • cycloalkylene and heterocycloalkylene are meant to be included in the terms “alkylene” and “heteroalkylene,” respectively.
  • one or more heteroatoms can occupy positions at which the heterocycle is attached to the remainder of the molecule.
  • a cycloalkylene or heterocycloalkylene will have from 3 to 9 atoms forming the ring, more typically, 4 to 7 atoms forming the ring, and even more typically, 5 or 6 atoms will form the cycloalkylene or hetercycloalkylene ring.
  • halo or halogen
  • substituents mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.
  • terms such as “haloalkyl” are meant to include alkyl substituted with halogen atoms which can be the same or different, in a number ranging from one to (2m' + 1), where m' is the total number of carbon atoms in the alkyl group.
  • halo(C ⁇ -C 4 )alkyl is meant to include trifluoromethyl, 2,2,2-trifiuoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • haloalkyl includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m' + 1) halogen atoms).
  • perhaloalkyl means, unless otherwise stated, alkyl substituted with (2m' + 1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group.
  • perhalo(C ⁇ -C 4 )alkyl is meant to include trifluoromethyl, pentachloroethyl, l,l,l-trifluoro-2-bromo-2-chloroethyl, and the like.
  • aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
  • heteroaryl refers to aryl groups (or rings) that contain from one to four heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-pyridyl, 3 -pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyrimidinyl, 4-pyrimidinyl, 5 -pyrimidinyl, 3 -pyrid
  • aryl refers to a phenyl or naphthyl group which is unsubstituted or substituted.
  • heteroaryl refers to a pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl or quinolyl group which is unsubstituted or substituted.
  • aryl when used in combination with other terms (e.g. , aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like).
  • R', R" and R'" each independently refer to hydrogen, unsubstituted (C ⁇ -C 8 )alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(C ⁇ -C 4 )alkyl, or aryl-(C 1 -C )alkyl groups.
  • R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a " 5- - r - Dlred ⁇ nl.
  • an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the present invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyl radical will be unsubstituted.
  • alkyl is meant to include groups such as trihaloalkyl (e.g., -CF 3 and -CH 2 CF ).
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CH 2 -, -O-, -NH-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'- or a single bond, and r is an integer of from 1 to 3.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH 2 ) s -X-(CH 2 )r, where s and t are independently integers of from 0 to 3, and X is -O-, - ⁇ - ' -!- - - : i!0)2NR'-.
  • the substituent R' in -NR'- and -S(O) 2 NR'- is selected from hydrogen or unsubstituted (C ⁇ -C 6 )alkyl. Otherwise, R' is as defined above.
  • the term "heteroatom” is meant to include oxygen (O), nitrogen (N), and sulfur (S).
  • bioisostere of -CO 2 H is meant that the the substituent -CO 2 H may be optionally replaced with bioisosteric replacements such as:
  • pharmaceutically acceptable salt is meant to include a salt of the active compound which is prepared with relatively nontoxic acids or bases, depending on the particular substituents foxmd on the compound described herein.
  • a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the .
  • compoxmds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compoxmd differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention.
  • the invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the invention.
  • prodrags can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment.
  • prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility in pharmaceutical compositions over the parent drug.
  • a wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug.
  • solvate refers to a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. , ' "' 52
  • a stereomerically pure a compound having two chiral centers will be substantially free of other diastereomers of the compound.
  • a typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95%) by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound.
  • stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it.
  • Various compounds of the invention contain one or more chiral centers, and can exist as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds. This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention.
  • the compoxmds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine- 125 ( 125 I) or carbon- 14 ( 14 C).
  • Radio labled compoxmds are useful as therapeutic or prophylactic agents, research reagents, e.g., GPR40 assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
  • a class of compounds that modulate GPR40 is described herein. Depending on the biological environment (e.g., cell type, pathological condition of the subject, etc.), these compounds can modulate, e.g., activate or inhibit, the actions of GPR40. By modulating GPR40, the compounds find use as therapeutic agents capable of regulating insulin levels in a subject. The compounds find use as therapeutic agents for modulating diseases and conditions responsive to modulation of GPR40 and/or mediated by GPR40 and/or mediated by pancreatic ⁇ cells.
  • diseases and conditions include diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, cancer, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, nephropathy, thrombotic disorders, diabetic neuropathy, diabetic retinopathy, dermatopathy, dyspepsia and edema. Additionally, the compounds are useful for the treatment and/or prevention of complications of these diseases and disorders (e.g., type II diabetes, sexual dysfunction, dyspepsia and so forth).
  • complications of these diseases and disorders e.g., type II diabetes, sexual dysfunction, dyspepsia and so forth.
  • the compoxmds of the invention are believed to exert their effects by interacting with GPR40, the mechanism of action by which the compounds act is not a limiting embodiment of the invention.
  • Compounds contemplated by the invention include, but are not limited to, the exemplary compounds provided herein.
  • the present invention provides a compound having the formula (I): Q-L -P-L 2 -M-X-L 3 -A I where Q, L , P, L , M, X, L and A are defined below.
  • Q is hydrogen, aryl, heteroaryl, (C ⁇ -C 6 )alkyl or (C 2 -C 6 )heteroalkyl.
  • Q is aryl
  • Q is 4-(trifluoromethyl)phenyl or -tolyl.
  • L 1 is a bond, (C 1 -C 4 )alkylene, (C 2 -C 4 )heteroalkylene, O, S(O) m , NCR 1 ),
  • L 1 is a bond, (C ⁇ -C )alkylene
  • L 1 is a bond, O or NCR 1 ).
  • L 1 is a bond
  • P is an aromatic ring, a heteroaromatic ring, (C 3 -C 8 )heterocycloalkylene or
  • (C 3 -C 8 )cycloalkylene In certain embodiments where P is an aromatic ring, the term aromatic includes aryl. In other embodiments where P is a heteroaromatic ring, the term heteroaromatic includes heteroaryl.
  • P is an aromatic ring or a heteroaromatic ring.
  • P is a monocyclic aromatic ring or a moncyclic heteroaromatic ring.
  • P is a selected from the group consisting of benzene, naphthalene, pyrrole, pyrazole, imidazole, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, benzoxazole, triazole, oxadiazole, thiadiazole, benzooxadiazole, dibenzofuran, indole, indazole, carbazole, carboliiie, isoquinoline, quinoxaline and quinoline.
  • P can be benzene, naphthalene, pyrrole, pyrazine, pyridine, pyrimidine, pyridazine, purine, indole, carboliiie, isoquinoline, quinoxaline or quinoline.
  • P is a benzene, thiazole, or oxazole ring.
  • L 1 is a bond, O or N(R ! ) and P is an aromatic ring or a heteroaromatic ring.
  • L 2 is a bond, (C 1 -C 6 )alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O,
  • L 2 is a bond, (C 1 -C 6 )alkylene, (C 2 -C 6 )heteroalkylene, oxymethylene, O, S(0) m , N(R X ), C(O)N(R 2 ), SO 2 N(R 2 ), (C ⁇ -C 4 )alkylene-C(O)N(R 2 ), (C 2 -C 4 )alkenylene-C(O)N(R 2 ), (C ⁇ -C 4 )alkylene-SO 2 N(R 2 ) or (C 2 -C 4 )alkenylene-SO 2 N(R 2 ).
  • L 2 is (C 2 -C 6 )heteroalkylene. [076] In some embodiments, L 2 is (C 2 -C 4 )heteroalkylene. 1 1 [077] In some embodiments, L is a bond, O or N(R ) and L is (C 2 -C 6 )heteroalkylene. [078] In certain embodiments, L 2 is oxymethylene or thiomethylene. 1 9 [079] In preferred embodiments, L is a bond and L is oxymethylene or thiomethylene.
  • M is an aromatic ring, a heteroaromatic ring, (C 5 -C 8 )cycloalkylene, aryl(C ⁇ -C 4 )alkylene or heteroaryl(C ⁇ -C )alkylene.
  • aromatic includes aryl.
  • heteroaromatic includes heteroaryl.
  • M is an aromatic ring or a heteroaromatic ring.
  • M is a (C 5 -C 8 )cycloalkylene.
  • M is a monocyclic aromatic, a monocyclic heteroaromatic ring or (C 5 -C 8 )cycloalkylene.
  • M is an unsubstituted monocyclic aromatic ring or an unsubstituted monocyclic heteroaiOmatic ring.
  • M is a benzene ring or a heteroaromatic ring.
  • M is a benzene ring.
  • P is an aromatic ring or a heteroaromatic ring and M is an aromatic ring, a heteroaromatic ring or (C 5 -C 8 )cycloalkylene.
  • X is CR 3 R 4 , N(R 5 ), O or S(O) lake.
  • X is CR 3 R 4 or N(R 5 ).
  • X is CHR 3 .
  • M is a substituted or unsubstituted benzene ring and X is/?
  • M is an aromatic ring, a heteroaromatic ring or (C 5 -C 8 )cycloalkylene and X is CR 3 R 4 or 1N(R 5 ).
  • " 93 ⁇ ' P is an aromatic ring or a heteroaromatic ring and X is CR 3 R 4 or N(R 5 ).
  • L is a bond, (C ⁇ -C 5 )alkylene or (C 2 -C 5 )heteroalkylene, provided that L is not a bond when L 2 is a bond.
  • L 3 is (C ⁇ -C 5 )alkylene or (C 2 -C 5 )heteroalkylene. [096] In certain embodiments, L 3 is (Ci-C 3 )alkylene. [097] In some embodiments, L 3 is methylene. [098] In certain embodiments, L is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl. [099] In certain embodiments, X is CR 3 R 4 or N(R 5 ), and L 3 is substituted or unsubstituted methylene.
  • L 2 is (C 2 -C 4 )heteroalkylene and L 3 is (C ⁇ -C 3 )alkylene.
  • L is a bond, O or N(R ), L is (C 2 -C 4 )heteroalkylene and L is (C ⁇ -C 3 )alkylene.
  • A is -CO 2 H, tetrazol-5-yl, -SO 3 H, -PO 3 H 2 , -SO 2 NH 2 , -C(O)NHSO 2 CH 3 , -CHO, -C(O)R 6 , -C(O)NHR 6 , -C(O)NHOR 7 , thiazolidinedion-yl, hydroxyphenyl or pyridyl.
  • A is a bioisostere of -CO 2 H.
  • A is -C0 2 H or tetrazol-5-yl, -C(O)NHSO 2 CH 3 or -C(O)NHR 6 .
  • A is -CO 2 H or tetrazol-5-yl.
  • A is -CO 2 H or a salt thereof.
  • P is an aromatic ring or a heteroaromatic ring and A is -CO 2 H.
  • X is CR 3 R 4 or N(R 5 ) and A is -CO 2 H.
  • M is an aromatic ring, a heteroaromatic ring or (C 5 -C 8 )cycloalkylene and A is -CO 2 H or tetrazol-5-yl.
  • M is an aromatic ring, a heteroaromatic ring or (C 5 -C 8 )cycloalkylene
  • X is CR 3 R 4 or N(R 5 )
  • L 3 is (C 1 -C 5 )alkylene or (C 2 -C 5 )heteroalkylene and A is -CO 2 H.
  • R 1 is (C ⁇ -C 6 )alkyl, aryl(d-C 3 ) alkyl or (C 2 -C 6 )heteroalkyl. [0112] In certain embodiments, R 1 is or (C 2 -C 6 )heteroalkyl. [0113] R 2 is hydrogen, (C ⁇ -C 6 )alkyl or (C 2 -C 6 )heteroalkyl.
  • R 3 is cyano, aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, -NR 8 R 9 , -C(O)NR 10 R ⁇ , -NR 12 C(O)R 13 or -NR 12 S(O) p R 13 .
  • R is cyano, aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl or -NR 8 R 9 .
  • R is cyano, heteroaryl, (C 2 -C 6 ) alkenyl or (C 2 -C 6 )alkynyl. [0118] In certain embodiments, R is (C 2 -C 8 )alkyl, (C 3 -C 8 )alkenyl or (C 3 -C 8 )alkynyl. [0119] In some embodiments, R 3 is aryl or heteroaryl. [0120] In certain preferred embodiments, R is tetrazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxazolyl, pyrrolyl, thienyl or prop-1-ynyl.
  • R is tetrazolyl, thiazolyl, or prop-1-ynyl.
  • R 4 is hydrogen, cyano, aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -Cg)alkenyl or (C 2 -C 8 )alkynyl.
  • O ptionally, R 3 and R are combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing from zero to three heteroatoms selected from N, O and S.
  • the ring formed by combining R 3 and R 4 may be a saturated or unsaturated ring.
  • R 4 is hydrogen or methyl.
  • R is hydrogen.
  • R is cyano, aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 3 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 8 )alkynyl or -NR 8 R 9 and R 4 is hydrogen.
  • R 5 is hydrogen, aryl, heteroaryl, (C ⁇ -Cg)alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or (C 3 -C 8 )cycloalkyl.
  • R 6 is heteroaryl.
  • R 7 is hydrogen or (CrC ⁇ alkyl.
  • R 8 and R 9 are independently hydrogen, (C ⁇ -C 5 )alkyl, oxy(C ⁇ -C 5 )alkyl or carboxy(C ⁇ -C 5 )alkyl.
  • R 8 and R 9 are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S.
  • the ring formed by combining R 8 and R 9 may be a saturated, unsaturated or aromatic ring.
  • " ? ]" '' ' ! independently selected from hydrogen, aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl and (C 3 -C 8 )heterocycloalkyl.
  • R 10 and R 11 are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S.
  • the ring formed by combining R 10 and R 11 may be a saturated, unsaturated or aromatic ring.
  • R 13 is aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -C 8 )heteroalkyl, (C 3 -C 8 )cycloalkyl or
  • CR 3 R 4 and R 3 is cyano, aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or -NR 8 R 9 .
  • A is -CO 2 H
  • X is CR R and R is cyano, aryl, heteroaryl, (C ⁇ -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl or -NR 8 R 9 .
  • P and M are benzene, at least two of L , X and
  • the compounds of formula I do not include
  • compounds of formula I do not include compounds wherein P is a 1,2-azole ring when Q is aryl or heteroaryl, L 1 is a bond, M is a monocyclic aromatic ring, X is N(R 5 ), O or S(O) n , and A contains a carbonyl group.
  • compounds of formula I do not include compounds wherein P is furan or thiophene when Q is aryl, L 1 is a bond, M is an aromatic ring, X is CR 3 R 4 , O or S(O) n and A contains a carbonyl group.
  • the compounds of the invention include pharmaceutically acceptable salts, solvates or prodrugs thereof.
  • ester prodrugs are preferred.
  • divalent groups such as C(O)N(R 2 ), SO 2 N(R 2 ),(d-C 4 )alkylene-C(O)N(R 2 ) and the like, both possible orientations of the groups are permitted.
  • the carbon atom may be attached to P or to M, as shown: O O Q-L 1 -P-C-N-M-X-L 3 -A or Q-L 1 -P-N-C-M-X-L 3 -A R 2 R 2
  • the alkylene group may be attached to P or to M, as shown:
  • the present invention provides a compound having the formula (la):
  • Q is substituted or unsubstituted benzene
  • L 1 is a bond, (C ⁇ -C 4 )alkylene, O or S(O) m .
  • P is selected from the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, pyridine, pyrimidine, , resort , . '' pyri a£i ⁇ eV e ⁇ tKia' ,” l S !
  • benzimidazole indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline.
  • Q is hydrogen, aryl, heteroaryl or (C ⁇ -C 6 )alkyl
  • L 1 is a bond, (C ⁇ -C 4 )alkylene, O or S(O) m .
  • L 3 is (C ⁇ -C 5 )alkylene. In certain embodiments, L 3 is methylene.
  • R is cyano, aryl, heteroaryl, (C 2 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, -NR 8 R 9 , -C(O)NR 10 R n , -NR 12 C(O)R 13 or -NR 12 S(O) p R 13 and R 4 is hydrogen, cyano, aryl, heteroaryl, (C ⁇ -Cg)alkyl, (C 2 -C 8 )alkenyl or (C 2 -C 8 )alkynyl.
  • R is cyano, an unsubstituted aryl or heteroaryl monocyclic ring, (C 2 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, or -C(O)NR 10 R ⁇ , R 4 is hydrogen, and P is selected from the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline.
  • R is cyano, an unsubstituted aryl or heteroaryl monocyclic ring, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, -C(O)NR 10 R U , R 4 is hydrogen, and L 3 is methylene.
  • Q is aryl, heteroaryl, (C ⁇ -C 6 )alkyl or (C 2 -C 6 )heteroalkyl
  • L 1 is a bond, (C ⁇ -C 4 )alkylene, (C 2 -C 4 )heteroalkylene, S(O) m , N(R 1 ), (C ⁇ -C 4 )alkylene-SO 2 N(R 2 ), (C 1 -C 4 )alkylene-N(R 2 )SO 2 or C(O)N(R 2 )
  • P is selected from the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, indole, indazole, carbazole, carboline, isoquinoline, quinoxa
  • P is selected from the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, furan, thiophene, ' p i ine, ! y ⁇ m'e, pyrf a i erbenzothiazole, purine, benzimidazole, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline.
  • R 5 is an unsubstituted or substituted benzene.
  • the present invention provides a compound having the formula (II):
  • R 21 is -H, -OH, -NHS(O 2 )CH 3 , heteroaryl, or -NH-heteroaryl.
  • R 21 is -OH, -NHS(O 2 )CH 3 , -NH-tetrazolyl, or tetrazolyl.
  • R is tetrazolyl, pyrimidinyl, or pyridinyl.
  • R 21 is -OH, or a salt thereof.
  • R 22 is -H, -(C 2 .C 8 )alkyl, -(C 3 -C 8 )alkenyl, -NR 23 R 24 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, — c — N 5 or ⁇ C ⁇ C-R 25 _
  • R 22 is unsubstituted aryl or unsubstituted heteroaryl.
  • R 22 is substituted aryl and the substitution onto the aryl is unsubstituted -(C ⁇ -C 5 )alkyl, -(C ⁇ -C 5 )oxyalkyl, or -halo(C 1 -C 5 )alkyl.
  • R 22 is C ⁇ C-R and R 25 is -(C ⁇ -C 5 )alkyl having 0 or 1 heteroatoms.
  • R 22 is — C ⁇ CCH 3 .
  • R 23 and R 24 are independently -H, -(C C 5 )alkyl, or -(C ⁇ -C 5 )oxyalkyl.
  • R 25 is -H, -(C ⁇ -C 5 )alkyl, -hetero(C ⁇ -C 5 )alkyl, -(C ⁇ -C 5 )oxyalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 25 is -(C ⁇ -C 5 )alkyl,-(C ⁇ -C 5 )oxyalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. " " l7'3]' '' " • "" il R is -hetero(C ⁇ -C 5 )alkyl that does not contain Si. 9 [0174] In some embodiments, R is unsubstituted phenyl. [0175] In other embodiments, R 25 is a substituted phenyl. [0176] In prefened embodiments, R 25 is methyl. H -C- or -N- [0177] Z is I ' .
  • Z is nitrogen. In other embodiments, Z is carbon. [0178] L is -O-, -S-, or -N(R 26 )-. In some embodiments, L is -O-. In other embodiments, L is -S-. In other embodiments, L is -N(R 26 )-. [0179] In certain embodiments, Z is nitrogen and L is -N(R )-. [0180] R 26 is -H , -(C ⁇ -C 5 )alkyl, substituted or unsubstituted aryl(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 26 is -H , substituted or unsubstituted aryl(C ⁇ -C ⁇ 0 )alkyl or substituted or unsubstituted aryl. [0182] In some embodiments, R 26 is -H. [0183] In other embodiments, R 26 is substituted or unsubstituted phenyl.
  • Y is -CH 2 -.
  • L is -O- or -S-
  • Y is -CH 2 -, -CH 2 CH 2 -.
  • W is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • W can be a ring such as a benzene, naphthalene, pyrrole, pyrazole, imidazole, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, benzoxazole, triazole, oxadiazole, thiadiazole, benzooxadiazole, dibenzofuran, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline or quinoline., and so forth.
  • W is a substituted or unsubstituted monocyclic aryl ring or a substituted or unsubstituted monocyclic heteroaryl ring.
  • W is substituted or unsubstituted fused aryl bicyclic ring or substituted or unsubstituted fused heteroaryl bicyclic ring.
  • " '" is"a ⁇ - f err ere !fl sed aryl bicyclic ring or an 8- to 11 -membered fused heteroaryl bicyclic ring.
  • W is a substituted or unsubstituted 5- or 6-membered aryl ring or substituted or unsubstituted 5- or 6-membered heteroaryl ring.
  • the substituting group can be a halogen, substituted or unsubstituted (C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted hetero(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted halo(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted aryl(C ⁇ -C 10 )alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • W is a 5-membered ring having two or more heteroatoms.
  • W is a 5-membered ring having two or more heteroatoms.
  • R 27 is substituted or unsubstituted (C ⁇ -C 10 )alkyl, substituted or unsubstituted hetero(C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted halo(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted aryl(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • W is a substituted or unsubstituted phenyl.
  • Z is carbon and R 22 is -(C 2 -C 8 )alkyl, -(C 3 -C 8 )alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C ⁇ C-R 25 _
  • R 22 is C ⁇ C-R 5 R 2S i s -hetero(C 1 -C 5 )alkyl, L is -O- or -S-, then any heteroatom in R 25 is not Si.
  • R 21 is -OH
  • L is -O-
  • Y is -CH 2 -
  • W is
  • R 22 is C ⁇ C-R 25 ⁇ then R 25 is not -H.
  • L is -N(R 26 )-
  • Z is nitrogen
  • R 22 is a phenyl
  • R is hydrogen or a phenyl and W is a phenyl, then Y is not -C(O)-. H — C—
  • a compound of the invention can be an S-enantiomer, an R-enantiomer, or a mixture of both an S-enantiomer and an R-enantiomer.
  • a compound is an S-enantiomer.
  • R 21 is -OH; L is -O-, or -S-; and Y is -CH 2 - , or
  • W is not a 1,2-azole ring.
  • the present invention provides a compound having the formula (III):
  • R 22 , L, Y, and W are as defined with regard to formula II above.
  • R 22 is -H, -(C 2 -C 3 )alkyl, -NR 23 R 24 , or substituted or unsubstituted phenyl.
  • L is -O-, -S-, or -N(R 26 )-.
  • R 26 is -H , substituted or unsubstituted aryl(C 1 -C ⁇ o)alkyl or substituted or unsubstituted aryl.
  • W is a substituted or unsubstituted 5- or 6-membered aryl ring or substituted or unsubstituted 5- or 6-membered heteroaryl ring with the proviso if
  • R 22 is phenyl, L is -O-, -S-, or -N(R 26 )-, and W is a benzene ring then Y may not be -C(O)-.
  • L is -N(R 26 )-, and R 26 is hydrogen. l j . k b ⁇ nents, W is not a 1,2-azole ring.
  • the compound of formula III is selected from the group consisting of
  • the present invention provides a compound of formula II or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 21 is
  • R 23 and R 24 are independently -H, -(C 1 -C 5 )alkyl, or -(C ⁇ -C 5 )oxyalkyl;
  • R 25 is -H, -(C ⁇ -C 5 )alkyl,
  • W is a substituted or unsubstituted 5- or 6- membered aryl ring or substituted or unsubstituted
  • the present invention provides compounds according to formula (IN):
  • R 25 is methyl
  • L is -O- or -S- and Y is -CH 2 - or -CH 2 CH 2 -. 2 9] l -" W is a 5-membered ring selected from the group consisting of
  • R is substituted or unsubstituted (C 1 -C ⁇ 0 )alkyl, substituted or unsubstituted hetero(C 1 .C ⁇ o)alkyl, substituted or unsubstituted halo(C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted a ⁇ yl(C 1 -C ⁇ 0 )alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • R 27 is substituted phenyl.
  • R 27 is unsubstituted phenyl.
  • the present invention provides compounds according to formula (V):
  • R 21 is -OH, or a salt thereof.
  • W is substituted phenyl.
  • W is substituted with substituted or unsubstituted
  • (C 1 -C ⁇ 0 )alkyl substituted or unsubstituted hetero(C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted halo(C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted aryl(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • W is a 5-membered ring selected from the group consisting of
  • R 27 is hydrogen, substituted or unsubstituted (C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted ' er ⁇ C yl, l utet r xmsubstituted halo(CrC 10 )alkyl, substituted or unsubstituted aryl(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • a compound of formula N is a racemate.
  • the compound of formula N comprises a mixture of (S) and (R) enantiomers.
  • the present invention provides compounds having the formula (Na):
  • R 25 and W are defined in paragraph [0215] above.
  • R 25 is methyl.
  • W is a 5-membered ring selected from the group consisting of
  • R 27 is hydrogen, substituted or unsubstituted (C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted hetero(C ⁇ -C 10 )alkyl, substituted or unsubstituted halo(C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted aryl(C ⁇ -C ⁇ 0 )alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • the compound of formula VI comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula VI comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula VI comprises a mixture of S- and R-enantiomers. [0234] In certain embodiments, the present invention provides compounds according to formula (VII):
  • each R 28 is independently selected from the group consisting of substituted or unsubstituted (C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted hetero(C 1 -C ⁇ 0 )alkyl, substituted or unsubstituted halo(C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted aryl(C ⁇ -C ⁇ o)alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, the subscript q is an integer from 0 to 5, and R 25 is as defined above in paragraph [0215]. [0235] In some embodiments, the subscript q is 0, 1, or 2. 8
  • R is a methoxy, ethoxy, trihalomethyl, methyl, halo, or cyano group and the subscript q is 1 or 2.
  • R is a phenyl, methoxyphenyl, methylphenyl, trihalomethylphenyl, benzyl, phenoxy, ethoxyphenyl, cyanophenyl, halophenyl, halobenzyl, pyridyl, methoxybenyl, or pyryl group and the subscript q is 1 or 2.
  • R 25 is methyl
  • the compound of formula VII comprises a stereomerically pure S-enantiomer.
  • the compound of formula VII ⁇ " ' c tn rises ' a eTC ⁇ me cal y pu e' R-enantiomer.
  • the compound of formula VII comprises a mixture of S- and R-enantiomers.
  • the formula is selected from the group consisting of
  • the present invention provides compounds according to formula (VIII):
  • T is a direct bond, (C ⁇ -C 5 )alkylene, hetero(C ⁇ -C 5 )alkylene, O, C(O)-(C 5 -C 7 )heterocycloalkylene, (C C 4 )alkylene-SO 2 NH, or (C ⁇ -C 4 )alkylene-NHSO 2 .
  • T is a direct bond, substituted or unsubstituted (C ⁇ _C 5 )alkyl or substituted or unsubstituted hetero(C ⁇ -C 5 )alkyl.
  • Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
  • Ar is a benzene, naphthalene, pyrrole, pyrazole, imidazole, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, benzoxazole, triazole, oxadiazole, thiadiazole, benzooxadiazole, dibenzofuran, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline or quinoline.
  • R 22 is ⁇ " C ⁇ C_CH3 , [0247] In some embodiments, R 21 is -OH. [0248] In certain embodiments, T is a direct bond and Ar is a substituted or unsubstituted benzene ring. [0249] In some embodiments, W is phenyl. [0250] In other embodiments, W is a 5-membered ring selected from the group consisting of
  • R 27 is Ar-T-.
  • the compound of formula VIII comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula VIII comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula VIII comprises a mixture of S- and R-enantiomers.
  • the present invention provides compounds according to formula (IX)
  • the compound has the formula:
  • the compound is selected from the group consisting of: or a salt thereof.
  • the present invention provides compounds, for example, of formula III, IV, VI, VII, or IX, that include a bioisostere of -CO 2 H in place of
  • the invention provides compounds according to the above formulas so long as the compound is not one of the following acids, or salt thereof, including:
  • the compounds of the invention can be prepared by a variety of synthetic or semisynthetic techniques.
  • FIG. 1 and the Examples in Section 6 below provide a variety of synthesis routes to the compounds provided herein.
  • Appropriate starting materials can be prepared by techniques known or apparent to those of skill in the art or the starting materials may be commercially available.
  • One of skill in the art will understand that the synthetic routes can be modified to use different starting materials or alternative reagents and that suitable adjustments in conditions (e.g., temperatures, solvents, etc.) can be made to accomplish the desired transformations.
  • protecting groups may be necessary for the preparation of certain compounds and will n( '" t e aware- t ose'co t ⁇ b ' OTnpatible with a selected protecting group. Accordingly, the exemplary methods and the examples described herein are illustrative of the present invention and are not to be construed as limiting the scope thereof.
  • compositions suitable for pharmaceutical use comprising one or more compounds of the invention and a pharmaceutically acceptable carrier, excipient or diluent.
  • composition as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutically acceptable it is meant that the carrier or excipient is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula II, wherein R 22 comprises an alkynyl 1 containing Si, and where R , L, Y, and W are as defined above in formula II.
  • the Si atom is substituted with up to three alkyl groups.
  • R 22 is ⁇ C ⁇ C-Si ( CH 3 ) 3
  • Composition formulation may improve one or more pharmacokinetic properties (e.g., oral bioavailability, membrane permeability) of a compound of the invention (herein referred to as the active ingredient).
  • compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients.
  • the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.
  • the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or "' e ixirs'.
  • S o i ⁇ ⁇ n nfe ⁇ ied ⁇ For oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions.
  • Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbit
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents such as sucrose or saccharin.
  • flavoring agents such as sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • sweetening agents for example glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • compositions may also be administered in the form of suppositories for rectal administration of the drug.
  • a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the invention are employed.
  • topical application is also meant to include the use of mouthwashes and gargles.
  • compositions and methods of the invention may further comprise other therapeutically active compounds, as noted herein, useful in the treatment of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
  • other therapeutically active compounds as noted herein, useful in the treatment of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidos
  • the invention provides methods of treating or preventing a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.
  • the disease or condition is type II diabetes.
  • the present invention provides a method for treating a disease or condition responsive to the modulation of GPR40 comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.
  • the disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, " '" nyperl ⁇ p eiS ⁇ ray ⁇ dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
  • the disease or condition is type II diabetes.
  • the disease or condition is obesity.
  • the disease or condition is hyptertension.
  • the compound or composition is administered orally.
  • the compound or composition is administered parentally.
  • the compound or composition is administered in combination with a second therapeutic agent.
  • the second therapeutic agent is an insulin sensitizing agent, such as metformin or a thiazolidinedione, for example.
  • the invention provides methods of treating or preventing a disease or disorder responsive to modulation of GPR40 comprising administering to a subject having such a disease or disorder, a therapeutically effective amoxmt of one or more of the subject compounds or compositions.
  • the invention provides methods of treating or preventing a GPR40-mediated condition, disease or disorder comprising administering to a subject having such a condition, disease or disorder, a therapeutically effective amount of one or more of the subject compounds or compositions.
  • the invention provides methods of modulating GPR40 comprising contacting a cell with one or more of the subject compounds or compositions.
  • a cell that constitutively expresses GPR40 is contacted with one or more of the subject compounds or compositions.
  • a cell to be contacted can be made to express or overexpress GPR40, for example, by expressing GPR40 from heterologous nucleic acid introduced into the cell or, as another example, by upregulating the expression of GPR40 from nucleic acid endogenous to the cell.
  • the compounds of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal;, local) "routes' d a- - ⁇ sl:a o ⁇ - l ⁇ --t y I e formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection or implant
  • topical e.g., transdermal;, local
  • the invention also contemplates administration of the compounds of the invention in a depot formulation, in which the active ingredient is released over a defined time period.
  • a depot formulation in which the active ingredient is released over a defined time period.
  • an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses.
  • the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day.
  • a suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day.
  • the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the compounds of the invention can be combined or used in combination with other agents useful in the treatment, prevention, suppression or amelioration of the diseases or conditions for which compounds of the invention are useful, including type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular _ >( ' ⁇ rseafee ' j atte ds !
  • compositions of the invention include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound of the invention.
  • Examples of other therapeutic agents that may be combined with a compound of the invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) cholesterol lowering agents such as HMG- CoA reductase inhibitors (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and other statins), bile acid sequestrants (e.g., cholestyramine and colestipol), vitamin B 3 (also known as nicotinic acid, or niacin), vitamin B 6 (pyridoxine), vitamin B ⁇ 2 (cyanocobalamin), fibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrate and benzafibrate), probucol, nitroglycerin, and inhibitors of cholesterol absorption (e.g., beta- sitosterol and acylCoA-cholesterol acyltransferase
  • the weight ratio of the compound of the invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Combinations of a compound of the invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. [0299] In another aspect, the present invention provides a method for modulating circulating insulin concentration in a subject, comprising administering a compound or composition of the invention. ( >
  • the insulin concentration is increased. [0301] In other embodiments, the insulin concentration is decreased. [0302] In certain embodiments, a compound, or composition comprising a compound, according to formula II wherein R 22 comprises an alkylyl containing Si, and 91 where R , L, Y, and W are as defined above in formula II, may be used. [0303] In some embodiments, the Si atom is substituted with up to three alkyl groups.
  • R 22 is — C ⁇ C-Si ( CH 3 ) 3
  • (+/-)-5-[l-(4-Hydroxy-phenyl)-but-2-ynyl]-2,2-dimethyl-[l,3]dioxane-4,6- dione (1.2).
  • (+/-)-3-(4-Hydroxy-phenyl)-hex-4-ynoic acid (1.3).
  • a IL RB flask was charged with compound 1.2 (37 g), diethyl ketone (160 mL), and water (80 mL). The suspension was heated to reflux for 48h. After cooling, the aqueous layer was saturated layer was dried over MgSO 4 , filtered, and concentrated to a light brown oil which was crystallized from hot ethyl acetate:hexanes (1 :2).
  • the salt was re-suspended in 2 L of 2-propanol and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16h. A small sample of the salt was decomposed with aqueous acid and the free carboxylic acid was analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant: 0.1 % TFA in 90:10 hexanes:2-propanol) and was found to have 75% ee. The salt was re-suspended in 1.5 L of 2-propanol and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16h. This material was found to have 96% ee by chiral HPLC.
  • Example 9 [0330] The following compounds were prepared by methods similar to those described in Example 3. TABLE 4
  • Example 10 [0331] The following compounds were prepared by methods similar to those described in Examples 3-5. The carboxylic acids corresponding to 10.2 and 10.5 were prepared according to the method of Huang et al. (2003) J. Amer. Chem. Soc. 22: 6653- 6655, and Admas et al. (1973) Org. Synth. Coll. Nol. N: 107, 109, respectively. TABLE 5
  • (+/-)-3-(4-[(4-methoxyphenyI)methoxy]phenyI)-hex-4-ynoic acid (12).
  • compound 12.2 (13.8 g, 37.5 mmol) under nitrogen was added 1-propynylmagnesium bromide in THF (0.5 N, 97.5 mL) over a period of 20 minutes. After the addition was complete, the reaction mixture was stirred for 20 minutes, quenched with saturated aqueous NH 4 C1 (50 mL) and extracted with ethyl acetate (3 x 50 mL).
  • Ester 15.1 (3.19 g, 9 mmol) was taken up in glacial acetic acid (100 mL) in a 250 mL RB Flask, and the suspension was heated to reflux for 16h. The solvent was removed under reduced pressure, and the residue was re-dissolved in ethyl acetate (200 mL). The solution was washed with 1 N HCl( aq) (200 mL) and saturated brine (200 mL), dried over MgSO 4 and concentrated to a thick yellow oil, to which was added 2-methylbenyl bromide (2.57 g, 13.9 mmol), cesium carbonate (6.03 g, 18.5 mmol) and DMF (20 mL).
  • Compoxmd 15.2 was dissolved in a mixture of 24 mL methanol and 24 mL isopropanol with the aid of sonication. The solution was filtered into a 50 mL glass vial. The racemic 15.2 was resolved with chiral normal phase HPLC using a ChiralTech AD semi-preparative column (2.0 cm X 25.0 cm), eluting isocratically with hexane/isopropanol (92:8) at a flow rate 20 mL/min. Each injection contained 50 mg of ester 15 (1 mL). The absorbance at 220 nm was used for detection. Both enantiomers were collected. After 36 injections, the separated enantiomers were dried to give white solids.
  • Phosphorous oxychloride (0.72 mL, 7.8 mmol) was added dropwise to an oven-dried 100 mL pear-shaped flask charged with 18.1 (1.8 g, 7.00 mmol) and dichloromethane (20 mL). The reaction was refluxed under nitrogen atmosphere for 30 minutes and then cooled to room temperature. The reaction was washed with water (2 x 250 mL) and the combined aqueous layers were back extracted with DCM (2 x 25 mL). The combined organic layers were washed with brine and dried (Na 2 SO 4 ).
  • the reaction was stirred at 0° C for an hour, and was then allowed to gradually warm to room temperature overnight.
  • the reaction mixture was partitioned between ice water and ethyl acetate.
  • the aqueous layer was extracted 2 additional times with 25 mL ethyl acetate.
  • Saturated NaHCO 3 was then added to the aqueous layer and the aqueous layer was extracted a third time with ethyl acetate.
  • the combined organic layers were washed with saturated NaHCO 3 and concentrated under reduced pressure.
  • Example 36 [0410] The following compounds were prepared according to the methods described in Example 35. TABLE 13
  • the resulted ester was then hydrolyzed with LiOH (2.0 equiv.) in a 1 : 1 : 1 mixture of MeOH, THF, and water for 2h at 25 °C.
  • the reaction mixture was acidified with IN HCl, extracted with CH 2 C1 2 and concentrated to give the pure acid.
  • Scheme 42.2 a. TMSCHN 2 , MeOH, benzene, r.t, 1h; b. K 2 C0 3 , DMF, r.t, overnight; c. LiOH/THF, MeOH, and water, r.t, 2h.
  • the amine (60 mg, 0.15 mmol) was treated with excess formaldehyde (2 equiv.), NaBH(OAc) 3 (85 mg, 0.4 mmol) and catalytic amoxmt of AcOH in DMF overnight (14-16h) at 25 °C.
  • the product was purified by reverse phase HPLC. MS ESI m/e: 424.1 (M + H).
  • the methyl ester was hydrolyzed with LiOH (19mg, 0.45 mmol) in a 3 mL of 1 : 1 : 1 mixture of MeOH, THF, and water for 2h at 25 °C.
  • the reaction mixture was acidified with IN HCl, extracted with CH 2 C1 2 and concentrated to give the pure acid (42.14) (23 mg).
  • Example 46 The following compounds were prepared according to methods analogous to those described in Example 45: 3-(4-fluorophenyl)-3-[4-(4'-trifluoromethyl-biphenyl-3- ylmethoxy)-phenyl] -propionic acid (46.1), 3-(4-fluorophenyl)-3-[4-(4-methyl-2-p-tolyl- thiazol-5-ylmethoxy)-phenyl] -propionic acid (46.2) and 3-(4-fluorophenyl)-3- ⁇ 4-[2-(3- trifluoromethyl-phenoxy) -ethoxy] -phenyl ⁇ -propionic acid (46.3).
  • (+/-)-3- ⁇ 4-[3-(4-Chloro-2-methylphenyl)phenyl]-methoxyl)phenyl ⁇ -3-(4- fluorophenyl)-propanoic acid (47). LiOH (48 mg, 2 mmol) was added to the THF-H 2 O (1/1, 4mL) solution of compound 47.2 (104 mg, 0.2 mmol ). The reaction mixture was stirred at room temperature overnight. IN HCl( aq ) was added to acidify the mixture to pH 3 at 0 °C.
  • (+/-)-Methyl 3-(4-hydroxyphenyl)-3-(thiophen-2-yl)propanoate (52.2).
  • a 500 mL flask was equipped with a magnetic stir bar, nitrogen inlet, nitrogen outlet and placed in a room temperature water bath.
  • Compound 52.1 (5.00 g, 15.1 mmol) was added to the flask along with anhydrous THF (150 mL). After purging with nitrogen for 30 min, a solution of thiophene-2-yl-magnesium bromide in THF (1 M, 18.1 mL) was added by cannula.
  • reaction mixture was stirred for 1.5 h and quenched with aqueous NH 4 C1 (1 M, 100 mL) diluted with ethyl acetate (100 mL).
  • aqueous NH 4 C1 (1 M, 100 mL) diluted with ethyl acetate (100 mL).
  • the aqueous layer was acidified to pH ⁇ 2 with Cone. HCl and extracted with ethyl acetate (150 mL x 2).
  • the extract was washed with brine and concentrated.
  • the residue was dissolved in 100 mL of 10: 1 DMF-water heated to 100°C for 8 h.
  • the reaction was cooled and the diluted with 500 mL water and extracted with ethyl acetate (150 mL x 3).
  • (+/-)-Methyl 3-(4-hydroxyphenyl)-3-(3-methylthiophen-2-yl)propanoate (54.1).
  • a 500 mL flask was equipped with a magnetic stir bar, nitrogen inlet, nitrogen outlet and placed in a room temperature water bath.
  • Compound 52.1 (5.00 g, 15.1 mmol) was added to the flask along with anhydrous THF (150 mL). After purging with nitrogen for 30 min, a solution of 3-mefhylthiophen-2-yl-magnesium bromide in THF (1 M, 18.1 mL) was added by cannula.
  • reaction mixture was stirred for 1.5 h, quenched with aqueous NH 4 C1 (1 M, 100 mL) and diluted with ethyl acetate (100 mL).
  • the aqueous layer was acidified to pH ⁇ 2 with Cone. HCl and extracted with ethyl acetate (150 mL x 2).
  • the extract was washed with brine and concentrated.
  • the residue was dissolved in 100 mL of 10:1 DMF-water and heated to 100 °C for 8 h.
  • the reaction mixture was cooled, diluted with 500mL water, and extracted with ethyl acetate (150 mL x 3).
  • Compoxmd 60 was obtained from compound 60.3 according to the method of Example 58. 6.61
  • Example 61 [0524] The following compounds were prepared from compound 60 according to the methods described in Example 18. Table 20
  • (+/-)-3-[4-(2' -Butoxy-5'-methyl-biphenyI-4-ylmethoxy)-phenyl]-3-(l- methyl-lH-pyrazol-5-yl) pjropionic acid (63.5).
  • a 25 mL pear-shaped flask was charged with ethanol (1 mL), compound 63.3 (20 mg, 0.04 mmol), and 2N NaOH (aq ) (2 mL, 4.0 mmol). The resulting mixture was stirred overnight at room temperature.
  • the mixture was acidified to a pH of 3 with 1UST HCl and extracted with ethyl acetate (2 x 10 mL).
  • (+/-)-3-(l-Methyl-lH-pyrazol-3-yl)-3-(4-((4-methyl-2-p-tolylthia-zol-5- yl)methoxy)phenyl) propanoic acid (64.1).
  • 1H NMR (400MHz) (CDC1 3 ) ⁇ 7.84 (m, 2H); 7.12 (m, 5H); 6.89 (m, 2H); 5.92 (s, IH); 5.13 (s, 2H); 4.46 (q, IH, J 6 Hz); 3.88 s, 3H); 3.23 (m, IH); 2.98 (m, IH); 2.50 (s, 3H); 2.39 (s, 3H).
  • MS ESI (neg.) m/e: 446.2 (M - H).
  • (+/-)-3-(l-Methyl-lH-pyrazol-3-yI)-3-[4-(4'-trifluoromethyl-biphenyl-3- ylmethoxy)-phenyl]-propionic acid (64.3).
  • MS ESI (neg.) m/e: 479.2 (M - H).
  • (+/-)-3-(l-Methyl-lH-pyrazol-5-yl)-3-[4-(4'-trifluoromethyl-biphenyl-3- ylmethoxy)-phenyI]-propionic acid (64.4).
  • a cell-based aequorin assay may be employed to characterize the modulatory activity of compounds on the GPR40 signaling pathway.
  • CHO cells are transfected in a 15 cm plated containing 14 million cells with 5 ⁇ g of GPR40 expression vector and 5 ⁇ g of Aequorin expression vector (Euroscreen) using Lipofectamine 2000
  • H/HBSS Hepes
  • BSA bovine serum albumin
  • HSA fatty acid-free human serum albumin
  • Coelantrazine is added to 1 ug/mL and the cells are incubated for 2 hours at room temperature. Cells are gently mixed every 15 minutes.
  • Table 21 presents representative data (EC 50 values) obtained for exemplary compounds of the invention for the relative activation of human GPR40.
  • the stereoismers in Table 21 are as specified, i.e., S-enantiomers or
  • R-enantiomers and if not specified, are mixtures of S-enantiomers and R-enantiomers.
  • the present invention provides the S-enantiomers, the R-enantiomers, and mixtures of both S-enantiomers and R-enantiomers including racemates of each compound prepared according to the synthetic methods described herein or adapted with the necessary minor modifications from these methods. 6.66 Example 66: Insulin Secretion Assay [0550] C57/B16 mice are euthanized with carbon dioxide gas. The pancreatic bile duct is clamped proximal to the duodenum and then cannulated.
  • H/HBSS containing 0.75 mg/ml collagenase XI (Sigma) is then infused into the pancreas through the cannula.
  • the pancreas is excised and then incubated at 37°C for 13 minutes to complete enzymatic digestion.
  • the collagenase digestion is quenched in H/HBSS containing 1% BSA and washed once in the same buffer.
  • Islets can be purified using density gradient centrifugation using Histopaque (Sigma) and are hand-picked under a stereomicroscope. [0551] Islets are cultured overnight in Roswell Park Memorial Institute (RMPI) media containing 10% fetal bovine serum and 50 uM beta-mercaptoethanol. Following overnight culture, islets are incubated in Dulbecco's Modifcation of Eagle's medium (DMEM) containing 2.8 mM glucose for one hour.
  • DMEM Dulbecco's Modifcation of Eagle's medium
  • islets are incubated in DMEM containing 12.5 mM glucose and test compounds for one hour. Insulin released into the culture medium from the islets is measured using an insulin ELISA.
  • All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Emergency Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Child & Adolescent Psychology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Nutrition Science (AREA)
  • Dermatology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

The present invention provides compounds useful, for example, for modulating insulin levels in a subject and that have the general formula Q-L1-P-L2-M-X-L3-A wherein the definitions of the variables Q, L1, P, L2, M, X, L3 and A are provided herein. The present invention also provides compositions and methods for use of the compounds, for instance, for treatment of type II diabetes.

Description

COMPOUNDS, PHARMACEUTICAL COMPOSITIONS AND METHODS FOR USE IN TREATING METABOLIC DISORDERS
RELATED APPLICATIONS
[001] This application claims the benefit of United States provisional application no. 60/548,741, filed February 27, 2004, and United State provisional application no. 60/601,579, filed August 12, 2004, which are incorporated herein by reference in their entireties.
1. FIELD OF THE INVENTION
[002] The present invention relates to compounds capable of modulating the
G-protein-coupled receptor GPR40, compositions comprising the compounds, and methods for their use for controlling insulin levels in vivo and for the treatment of conditions such as type II diabetes, hypertension, ketoacidosis, obesity, glucose intolerance, and hypercholesterolemia and related disorders associated with abnormally high or low plasma lipoprotein, triglyceride or glucose levels.
2. BACKGROUND OF THE INVENTION
[003] The production of insulin is central to the regulation of carbohydrate and lipid metabolism. Insulin imbalances lead to conditions such as type II diabetes mellitus, a serious metabolic disease that afflicts around 5% of the population in Western Societies and over 150 million people worldwide. Insulin is secreted from pancreatic β cells in response to elevated plasma glucose which is augmented by the presence of fatty acids. The recent recognition of the function of the G-protein coupled receptor GPR40 in modulating insulin secretion has provided insight into regulation of carbohydrate and lipid metabolism in vertebrates, and further provided targets for the development of therapeutic agents for disorders such as obesity, diabetes, cardiovascular disease and dyslipidemia. [004] GPR40 is a member of the gene superfamily of G-protein coupled receptors
("GPCRs"). GPCRs are membrane proteins characterized as having seven putative transmembrane domains that respond to a variety of molecules by activating intra-cellular signaling pathways critical to a diversity of physiological functions. GPR40 was first identified as an orphan receptor (i.e., a receptor without a known ligand) from a human genomic DNA fragment. Sawzdargo et al. (1997) Biochem. Biophys. Res. Commun. 239: 543-547. GPR40 is highly expressed in pancreatic β cells and insulin-secreting cell lines.
Figure imgf000004_0001
of the Gq family of intra-cellular signaling proteins and concomitant induction of elevated calcium levels. It has been recognized that fatty acids serve as ligands for GPR40, and that fatty acids regulate insulin secretion through GPR40. Itoh et al. (2003) Nαtwre 422:173-176; Briscoe et al. (2003) J Biol. Chem. 278: 11303-11311; Kotarsky et α/. (2003) Biochem. Biophys. Res. Commun. 301 : 406-410. [005] The prevalence of type II diabetes, obesity, hypertension, cardiovascular disease and dyslipidemia underscores the need for new therapies to effectively treat or prevent these conditions.
3. SUMMARY OF THE INVENTION [006] Provided herein are compounds, pharmaceutical compositions and methods useful for treating or preventing a condition or disorder such as type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer or edema. [007] In one aspect, the compounds of the invention have the general formula (I): Q-L'-P-L^M-X-L^A I wherein Q is hydrogen, aryl, heteroaryl, (Cι-C6)alkyl or (C2-C6)heteroalkyl; L1 is a bond, (d-C^alkylene, (C2-C4)heteroalkylene, O, S(O)m, NCR1), C(O)-(C5-C7)heterocycloalkylene, (Cι-C4)alkylene-SO2N(R2), (Cι-C4)alkylene-N(R2)SO2 or C(O)N(R ); P is an aromatic ring, a heteroaromatic ring, (C3-C8)heterocycloalkylene or (C3-C8)cycloalkylene; L2 is a bond, (Cι-C6)alkylene, (C2-C6)heteroalkylene, O, S(O)m, N(R1), C(O)N(R2), SO2N(R2), (C C4)alkylene-C(O)N(R2), (Cι-C )alkylene-N(R2)C(O), (C2-C4)alkenylene-C(O)N(R2), (C2-C4)alkenylene-N(R2)C(O), (Cι-C4)alkylene-SO2N(R2), (Cι-C4)alkylene-N(R2)SO2, (C2-C4)alkenylene-SO2N(R2) or (C2-C4)alkenylene-N(R2)SO2; M is an aromatic ring, a heteroaromatic ring, (C5-C8)cycloalkylene, aryl(Cι-C4)alkylene or heteroaryl(Ci-C4)alkylene; X is CR3R4, N(R5), O or S(O)n; L3 is a bond, (Cι-C5)alkylene or (C2-C5)heteroalkylene, provided that L is not a bond when L is a bond; A is -CO2H, tetrazol-5-yl, -SO3H, -PO3H2, -SO2NH2, -C(O)NHSO2CH3, -CHO, -C(O)R6, -C(O)NHR6, -C(O)NHOR7, thiazolidinedion-yl, hydroxyphenyl or pyridyl; R1 is (Cι-C6)alkyl or (C2-C6)heteroalkyl; R2 is hydrogen, (Cι-C6)alkyl or (C2-C6)heteroalkyl; R3
Figure imgf000005_0001
(C2-C8)alkenyl, (C2-C8)alkynyl, -NR R , -C(O)NR10Rπ, -NR12C(O)R13 or -NR12S(O)pR13; R4 is hydrogen, cyano, aryl, heteroaryl, (C1-C8)alkyl, (C2-C8)alkenyl or (C2-C8)alkynyl, optionally R3 and R4 are combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing from zero to three heteroatoms selected from N, O and S; R5 hydrogen, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or (C3-C8)cycloalkyl; R6 is heteroaryl; R7 is hydrogen or (Cι-C5)alkyl; R8 and R9 are independently hydrogen, (Cι-C5)alkyl, oxy(C1-C5)alkyl or carboxy(Cι-C5)alkyl, optionally, R and R are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S; R10, R11 and R12 are independently selected from hydrogen, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl, optionally, R10 and R11 are combined to fonn a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S; R13 is aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl; the subscripts m and n are independently 0, 1 or 2; and the subscript p is 1 or 2; and wherein the compound is other than 3-(4-(4- methoxybenzyloxy)phenyl)pent-4-ynoic acid; β-ethenyl-4-phenylmethoxy- benzenepropanoic acid; 4-(2-quinolinylmethoxy)-β-[4-(2-quinolinylmethoxy)phenyl]- benzenepropanoic acid; N-[4-(benzoylamino)phenyl]-N-phenyl-glycine; 3-(4- (isopentyloxy)benzamido)-3-phenylpropanoate; 3-(4-isobutoxybenzamido)-3- phenylpropanoate; (R)-2-((/R,4/_)-4-isopropylcyclohexanecarboxamido)-3-phenylpropanoic acid; (R)-3-(4-(benzyloxy)phenyl)-2-(tert-butoxycarbonyl)propanoic acid; 3-(4- chlorophenyl)-3-(furan-2-carboxamido)propanoic acid; 3-(3,4-dimethoxyphenyl)-3-(furan- 2-carboxamido)propanoic acid; 3-(4-chlorobenzamido)-3-(4- (dimethylamino)phenyl)propanoic acid; 3-(2-(2-(3,4-dimethylphenoxy)ethylthio)- 1H- benzo[d]imidazol-l-yl)propanoic acid; {2-Bromo-4-[(3,4-dichloro-phenyl)- hydrazonomethyl] -6-ethoxy-phenoxy } -acetic acid; 2-(4-(2-(2-(4-chlorophenyl)furan-5 - carboxamido)ethyl)phenoxy)-2-methylpropanoic acid; 5-(3-(3,4-dimethoxyphenyl)-5-(2- fluorophenyl)-4,5-dihydropyrazol-l-yl)-5-oxopentanoic acid; 2-(2-(3-(3,4-dihydro-2Η- benzo [b] [ 1 ,4] dioxepin-7-yl)-2-methyl-4-oxo-4H-chromen-7-yloxy)acetamido)acetic acid; 3-(4'-Bromo-biphenyl-4-yl)-4-phenyl-butyric acid; 3-(4'-Bromo-biphenyl-4-yl)-3- phenylsulfanyl-propionic acid; 3-(5-(2-chloro-6-fluoro-4-(trifluoromethyl)phenoxy)-2,4- dinitrophenyl)propanoic acid; 3-(3-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)propanoic acid; 3-(4-(4-methoxybenzyloxy)phenyl)pent-4-ynoic acid; 3-(4-(4- methoxybenzyloxy)phenyl)-5-(trimethylsilyl)pent-4-ynoic acid; β,β-dimethyl-4-[[[4- ' l yl-2 4 -5-thiazolyl]methyl]thio] -benzenepropanoic acid; β- amino-4-[(4-bromo-2,5-dihydro-2-methyl-5-oxo-l-phenyl-lH-pyrazol-3-yl)methoxy]-3- methoxy-benzenepropanoic acid; or salt thereof. [008] The compounds of the invention include pharmaceutically acceptable salts, solvates or prodrugs thereof. [009] In certain embodiments, the present invention provides a compound having the formula (la):
Figure imgf000006_0001
la where Q, L , P, L , A, R and R are as defined with regard to formula I above. [010] In certain embodiments, the present invention provides a compound having the formula (lb):
Figure imgf000006_0002
lb where Q, L , P, L , A and R are as defined with regard to formula I above. [011] In another aspect, the compounds of the inventions have the general formula (II):
Figure imgf000006_0003
II H -C- or -N- wherein Z is I ' ; R21 is -H, -OH, -NHS(O2)CH3, heteroaryl, or -NH- A heteroaryl; R is -(C2.C8)alkyl, -(C3-C8)alkenyl, -NR R , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, c ^ , or C-C-R25 ; or optionally where Z is a nitrogen atom, R is -H; R and R are independently -H, -(Cι-C5)alkyl, or -(Ci- C5)oxyalkyl; R25 is -H, -(Cι-C5)alkyl, -hetero(Cι-C5)alkyl, -(CrC5)oxyalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L is -O-, -S-, or -N(R26)-; R26 is -H , -(Cι-C5)alkyl, substituted or unsubstituted aryl(Cι-Cι0)alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Y is absent or is -CH2- , - CH2CH2- , -CH=CH- , -C(O)CH2- , -C(O)CH2CH2- , -C(O)CH=CH- , -S(O2)-, -S(O2)CH2- , ''-S 2)' i ϊ -r -C -, or -C(O)-; W is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. [012] In another aspect, the invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula I, la, lb or II. [013] In another aspect, the invention provides methods for treating or preventing a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease atherosclerosis, kidney disease, ketoacidosis, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, thrombotic disorders, dermatopathy, dyspepsia, hypoglycemia, hypertension, cancer and edema comprising administering to a subject in need thereof a therapeutically effective amoxmt of a compoxmd of formula I, la, lb or II. [014] In another aspect, the invention provides methods for treating or preventing a disease or condition responsive to the modulation of GPR40 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, la, lb or II. [015] In another aspect, the invention provides methods for treating or preventing a disease or condition mediated, regulated or influenced by pancreatic β cells comprising administering to a subject in need thereof a therapeutically effective amoxmt of a compoxmd of formula I, la, lb or II. [016] In another aspect, the invention provides methods for modulating GPR40 function in a cell, comprising contacting a cell with a compound of formula I, la, lb or II. [017] In another aspect, the invention provides methods for modulating GPR40 function comprising contacting GPR40 with a compound of formula I, la, lb or II. [018] In another aspect, the invention provides methods for modulating circulating insulin concentration in a subject, comprising administering a compound of formula I, la, lb or II to the subject. [019] Other objects, features and advantages of the invention will become apparent to those skilled in the art from the following description and claims.
4. BRIEF DESCRIPTION OF THE FIGURES [020] FIG. 1 provides a scheme for synthesis of exemplary compounds of the invention. 5. DETAILED DESCRIPTION OF THE INVENTION
5.1 Abbreviations and Definitions
[021] The terms "treat", "treating" and "treatment", as used herein, are meant to include alleviating or abrogating a condition or disease and/or its attendant symptoms and alleviating. The terms "prevent", "preventing" and "prevention", as used herein, refer to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a subject from acquiring a condition or disease or reducing a subject's risk of acquiring a condition or disease.
[022] The term "therapeutically effective amount" refers to that amount of the compound that will elicit the biological or medical response of a tissue, system, or subject that is being sought. The term "therapeutically effective amount" includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated in a subject. The therapeutically effective amount in a subject will vary depending on the compound, the disease and its severity and the age, weight, etc., of the subject to be treated. [023] The "subject" is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human. [024] The terms "modulate", "modulation" and the like refer to the ability of a compoxmd to increase or decrease the function or activity of GPR40 either directly or indirectly. Inhibitors are compounds that, for example, bind to, partially or totally block stimulation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate signal transduction, such as, for instance, antagonists. Activators are compounds that, for example, bind to, stimulate, increase, activate, facilitate, enhance activation, sensitize or up regulate signal transduction, such as agonists for instance. Modulation may occur in vitro or in vivo.
[025] As used herein, the term "GPR40-mediated condition or disorder" and the like refer to a condition or disorder characterized by inappropriate, for example, less than or greater than normal, GPR40 activity. A GPR40-mediated condition or disorder may be completely or partially mediated by inappropriate GPR40 activity. However, a GPR40-mediated condition or disorder is one in which modulation of GPR40 results in some effect on the underlying condition or disease (e.g., a GPR40 modulator results in some improvement in patient well-being in at least some patients). Exemplary GPR40-mediated
Figure imgf000009_0001
and metabolic disorders, e.g., diabetes, type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia, thrombotic disorders, metabolic syndrome, syndrome X and related disorders, e.g., cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia and edema. [026] The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which is fully saturated, having the number of carbon atoms designated (e.g., Ci. o means one to ten carbons). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl and the like. [027] The term "alkenyl", by itself or as part of another substituent, means a straight or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C2.C8 means two to eight carbons) and one or more double bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(l,4-pentadienyl) and higher homologs and isomers thereof. [028] The term "alkynyl", by itself or as part of another substituent, means a straight or branched chain hydrocarbon radical, or combination thereof, which may be mono- or polyunsaturated, having the number of carbon atoms designated (i.e., C2-C8 means two to eight carbons) and one or more triple bonds. Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologs and isomers thereof. [029] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from alkyl, as exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 12 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms. [030] The terms "alkoxy," "alkylamino" and "alkylthio" (or thioalkoxy) are used in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom, an amino group, or a sulfur atom, respectively. Similarly, the
Figure imgf000010_0001
having two attached alkyl groups that can be the same or different. [031] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quatemized. The heteroatom(s) O, N and S may be placed at any position of the heteroalkyl group. Examples include -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, and -CH2-CH=N-OCH3. Up to two heteroatoms may be consecutive, such as, for example, -CH -NH-OCH3. When a prefix such as (C2-C8) is used to refer to a heteroalkyl group, the number of carbons (2 to 8, in this example) is meant to include the heteroatoms as well. For example, a C2-heteroalkyl group is meant to include, for example, -CH2OH (one carbon atom and one heteroatom replacing a carbon atom) and -CH2SH. [032] To further illustrate the definition of a heteroalkyl group, where the heteroatom is oxygen, a heteroalkyl group is a oxyalkyl group. For instance, (C2.C5)oxyalkyl is meant to include, for example -CH2-O-CH (a C3-oxyalkyl group with two carbon atoms and one oxygen replacing a carbon atom), -CH2CH2CH2CH2OH, and the like. [033] The term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified by -CH2-CH2-S-CH2CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied. [034] The terms "cycloalkyl" and "heterocycloalkyl," by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl," respectively. Thus, the terms "cycloalkyl" and "heterocycloalkyl" are meant to be included in the terms "alkyl" and "heteroalkyl," respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include l-(l,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, _ __ 4 τι rph ϊn ^^ tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 -piperazinyl, 2-piperazinyl, and the like. [035] The term "cycloalkylene" and "heterocycloalkylene," by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkylene" and "heteroalkylene," respectively. Thus, the terms "cycloalkylene" and "heterocycloalkylene" are meant to be included in the terms "alkylene" and "heteroalkylene," respectively. Additionally, for heterocycloalkylene, one or more heteroatoms can occupy positions at which the heterocycle is attached to the remainder of the molecule. Typically, a cycloalkylene or heterocycloalkylene will have from 3 to 9 atoms forming the ring, more typically, 4 to 7 atoms forming the ring, and even more typically, 5 or 6 atoms will form the cycloalkylene or hetercycloalkylene ring. [036] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl", are meant to include alkyl substituted with halogen atoms which can be the same or different, in a number ranging from one to (2m' + 1), where m' is the total number of carbon atoms in the alkyl group. For example, the term "halo(Cι-C4)alkyl" is meant to include trifluoromethyl, 2,2,2-trifiuoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Thus, the term "haloalkyl" includes monohaloalkyl (alkyl substituted with one halogen atom) and polyhaloalkyl (alkyl substituted with halogen atoms in a number ranging from two to (2m' + 1) halogen atoms). The term "perhaloalkyl" means, unless otherwise stated, alkyl substituted with (2m' + 1) halogen atoms, where m' is the total number of carbon atoms in the alkyl group. For example, the term "perhalo(Cι-C4)alkyl", is meant to include trifluoromethyl, pentachloroethyl, l,l,l-trifluoro-2-bromo-2-chloroethyl, and the like.
[037] The term "aryl" means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon substituent which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently. The term "heteroaryl" refers to aryl groups (or rings) that contain from one to four heteroatoms selected from the group consisting of N, O and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. A heteroaryl group can be attached to the remainder of the molecule through a heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1 -naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 3-pyrazolyl, 5-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,
Figure imgf000012_0001
2-pyridyl, 3 -pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 2-pyrimidinyl, 4-pyrimidinyl, 5 -pyrimidinyl, 3 -pyridazinyl, 4- pyridazinyl, 5-benzothiazolyl, 2-benzoxazolyl, 5-benzoxazolyl, benzo[c][l,2,5]oxadiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, lH-indazolyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ- carbolinyl, 1 -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 2-quinolyl, 3- quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl and 8-quinolyl. [038] Preferably, the term "aryl" refers to a phenyl or naphthyl group which is unsubstituted or substituted. Preferably, the term "heteroaryl" refers to a pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl or quinolyl group which is unsubstituted or substituted. [039] For brevity, the term "aryl" when used in combination with other terms (e.g. , aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(l-naphthyloxy)propyl, and the like). [040] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl" and "heteroaryl") is meant to include both substituted and unsubstituted forms of the indicated radical, unless otherwise indicated. Preferred substituents for each type of radical are provided below. [041] Substituents for the alkyl and heteroalkyl radicals (as well as those groups referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl) can be a variety of groups selected from: -OR', =O, =NR', =N-OR', -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR'-C(O)NR"R'", -NR'-SO2NR"R'", -NR"CO2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -SiR'R"R'", -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -CN and -NO2, in a number ranging from zero to three, with those groups having zero, one or two substituents being particularly preferred. R', R" and R'" each independently refer to hydrogen, unsubstituted (Cι-C8)alkyl and heteroalkyl, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy or thioalkoxy groups, halo(Cι-C4)alkyl, or aryl-(C1-C )alkyl groups. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a " 5- - r - Dlredτιnl.i!;; ' r"example, -NR'R" is meant to include 1 -pyrrolidinyl and 4- morpholinyl. [042] Typically, an alkyl or heteroalkyl group will have from zero to three substituents, with those groups having two or fewer substituents being preferred in the present invention. More preferably, an alkyl or heteroalkyl radical will be unsubstituted or monosubstituted. Most preferably, an alkyl or heteroalkyl radical will be unsubstituted. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups such as trihaloalkyl (e.g., -CF3 and -CH2CF ). [043] Preferred substituents for the alkyl and heteroalkyl radicals are selected from: -OR', =O, -NR'R", -SR', halogen, -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR"CO2R', -NR'-SO2NR"R'", -S(O)R', -SO2R', -SO2NR'R", -NR"SO2R, -CN and -NO2, where R' and R" are as defined above. Further preferred substituents are selected from: -OR', =O, -NR'R", halogen, -OC(O)R', -CO2R', -CONR'R", -OC(O)NR'R", -NR"C(O)R', -NR"CO2R', -NR'-SO2NR"R'", -SO2R', -SO2NR'R", -NR"SO2R, -CN and -NO2. [044] Similarly, substituents for the aryl and heteroaryl groups are varied and are selected from: -halogen, -OR', -OC(O)R', -NR'R", -SR', -R', -CN, -NO2, -CO2R', -CONR'R", -C(O)R', -OC(O)NR'R", -NR"C(O)R', -NR"C(O)2R', -NR'-C(O)NR"R'", -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR'R", -N3, -CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(Cι-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R" and R'" are independently selected from hydrogen, (C1-C8)alkyl and heteroalkyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-(Cι-C )alkyl, and (unsubstituted
Figure imgf000013_0001
[045] Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -T-C(O)-(CH2)q-U-, wherein T and U are independently -NH-, -O-, -CH2- or a single bond, and q is an integer of from 0 to 2. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CH2-, -O-, -NH-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer of from 1 to 3. One of the single bonds of the new ring so formed may optionally be replaced with a double bond. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CH2)s-X-(CH2)r, where s and t are independently integers of from 0 to 3, and X is -O-, - ^ - '-!- - - : i!0)2NR'-. The substituent R' in -NR'- and -S(O)2NR'- is selected from hydrogen or unsubstituted (Cι-C6)alkyl. Otherwise, R' is as defined above. [046] As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), and sulfur (S).
[047] As used herein, the phrase "bioisostere of -CO2H" is meant that the the substituent -CO2H may be optionally replaced with bioisosteric replacements such as:
Figure imgf000014_0001
and the like. See, e.g., The Practice of Medicinal Chemistry, Wermuth, C.G., Ed., Academic Press: New York, 1996, p. 203.
[048] The term "pharmaceutically acceptable salt" is meant to include a salt of the active compound which is prepared with relatively nontoxic acids or bases, depending on the particular substituents foxmd on the compound described herein. When a compound of the invention contains relatively acidic functionalities, a base addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When a compound of the invention contains relatively basic functionalities, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the .
"stkϊt 'ldQvvvle&Mim i'e vv i ribntoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginine and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al. (1977) J. Pharm. Sci. 66:1- 19). Certain specific compoxmds of the invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. [049] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compoxmd differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the invention. [O50] In addition to salt forms, the invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the invention. Additionally, prodrags can be converted to the compounds of the invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound of the invention which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound. [051] As used herein, "solvate" refers to a compound of the present invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate. ,'"' 52|
Figure imgf000016_0001
of the invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the invention and are intended to be within the scope of the invention. [053] Certain compounds of the invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the invention. [054] As used herein and unless otherwise indicated, the term "stereoisomer" or "stereomerically pure" means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. For example, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure a compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, more preferably greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, even more preferably greater than about 95%) by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, and most preferably greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound. It should be noted that if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing all stereoisomers of it. [055] Various compounds of the invention contain one or more chiral centers, and can exist as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds. This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms. For example, mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention. These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents. See, e.g., Jacques, J., et al, Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); Wilen, S. H., et al. (1997) Tetrahedron 33:2725; Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, '" Y, "19'62" ; Sn ilen ? F b/es of Resolving Agents and Optical Resolutions p. 268 (EX. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972). [056] The compoxmds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine- 125 (125I) or carbon- 14 (14C). Radio labled compoxmds are useful as therapeutic or prophylactic agents, research reagents, e.g., GPR40 assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention.
5.2 Embodiments of the Invention [057] In one aspect, a class of compounds that modulate GPR40 is described herein. Depending on the biological environment (e.g., cell type, pathological condition of the subject, etc.), these compounds can modulate, e.g., activate or inhibit, the actions of GPR40. By modulating GPR40, the compounds find use as therapeutic agents capable of regulating insulin levels in a subject. The compounds find use as therapeutic agents for modulating diseases and conditions responsive to modulation of GPR40 and/or mediated by GPR40 and/or mediated by pancreatic β cells. As noted above, examples of such diseases and conditions include diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, cancer, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, ketoacidosis, hypoglycemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, nephropathy, thrombotic disorders, diabetic neuropathy, diabetic retinopathy, dermatopathy, dyspepsia and edema. Additionally, the compounds are useful for the treatment and/or prevention of complications of these diseases and disorders (e.g., type II diabetes, sexual dysfunction, dyspepsia and so forth). [058] While the compoxmds of the invention are believed to exert their effects by interacting with GPR40, the mechanism of action by which the compounds act is not a limiting embodiment of the invention. [059] Compounds contemplated by the invention include, but are not limited to, the exemplary compounds provided herein. [060] In one aspect, the present invention provides a compound having the formula (I): Q-L -P-L2-M-X-L3-A I where Q, L , P, L , M, X, L and A are defined below.
[061] Q is hydrogen, aryl, heteroaryl, (Cι-C6)alkyl or (C2-C6)heteroalkyl.
[062] In preferred embodiments, Q is aryl.
[063] In further preferred embodiments, Q is 4-(trifluoromethyl)phenyl or -tolyl.
[064] L1 is a bond, (C1-C4)alkylene, (C2-C4)heteroalkylene, O, S(O)m, NCR1),
C(O)-(C5-C7)heterocycloalkylene, (CrC4)alkylene-SO2N(R2), (C1-C4)alkylene-N(R2)SO2 or C(O)N(R2).
[065] In certain embodiments, L1 is a bond, (Cι-C )alkylene,
(C2-C4)heteroalkylene, O, S(0)m, NCR1) or C(O)N(R2). [066] In certain embodiments, L1 is a bond, O or NCR1).
[067] In preferred embodiments, L1 is a bond.
[068] P is an aromatic ring, a heteroaromatic ring, (C3-C8)heterocycloalkylene or
(C3-C8)cycloalkylene. In certain embodiments where P is an aromatic ring, the term aromatic includes aryl. In other embodiments where P is a heteroaromatic ring, the term heteroaromatic includes heteroaryl.
[069] In some embodiments, P is an aromatic ring or a heteroaromatic ring.
[070] In certain embodiments, P is a monocyclic aromatic ring or a moncyclic heteroaromatic ring.
[071] In some embodiments, P is a selected from the group consisting of benzene, naphthalene, pyrrole, pyrazole, imidazole, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, benzoxazole, triazole, oxadiazole, thiadiazole, benzooxadiazole, dibenzofuran, indole, indazole, carbazole, carboliiie, isoquinoline, quinoxaline and quinoline. For example, P can be benzene, naphthalene, pyrrole, pyrazine, pyridine, pyrimidine, pyridazine, purine, indole, carboliiie, isoquinoline, quinoxaline or quinoline. In some embodiments, P is a benzene, thiazole, or oxazole ring.
[072] In preferred embodiments, L1 is a bond, O or N(R!) and P is an aromatic ring or a heteroaromatic ring.
[073] L2 is a bond, (C1-C6)alkylene, (C2-C6)heteroalkylene, oxymethylene, O,
S(O)ra, N(RX), C(O)N(R2), S02N(R2), (C1-C4)alkylene-C(O)N(R2),
Figure imgf000019_0001
(Cι-C4)alkylene-SO2N(R2), (Cι-C4)alkylene-N(R_2)SO2, (C2-C4)alkenylene-SO2N(R2) or (C2-C4)alkenylene- N(R2)SO2. [074] In certain embodiments, L2 is a bond, (C1-C6)alkylene, (C2-C6)heteroalkylene, oxymethylene, O, S(0)m, N(RX), C(O)N(R2), SO2N(R2), (Cι-C4)alkylene-C(O)N(R2), (C2-C4)alkenylene-C(O)N(R2), (Cι-C4)alkylene-SO2N(R2) or (C2-C4)alkenylene-SO2N(R2). [075] In certain embodiments, L2 is (C2-C6)heteroalkylene. [076] In some embodiments, L2 is (C2-C4)heteroalkylene. 1 1 [077] In some embodiments, L is a bond, O or N(R ) and L is (C2-C6)heteroalkylene. [078] In certain embodiments, L2 is oxymethylene or thiomethylene. 1 9 [079] In preferred embodiments, L is a bond and L is oxymethylene or thiomethylene. [080] M is an aromatic ring, a heteroaromatic ring, (C5-C8)cycloalkylene, aryl(Cι-C4)alkylene or heteroaryl(Cι-C )alkylene. In certain embodiments where M is an aromatic ring, the term aromatic includes aryl. In other embodiments where M is a heteroaromatic ring, the term heteroaromatic includes heteroaryl. [081] In some embodiments, M is an aromatic ring or a heteroaromatic ring. [082] In some embodiments, M is a (C5-C8)cycloalkylene. [083] In certain embodiments, M is a monocyclic aromatic, a monocyclic heteroaromatic ring or (C5-C8)cycloalkylene. [084] In some embodiments, M is an unsubstituted monocyclic aromatic ring or an unsubstituted monocyclic heteroaiOmatic ring. [085] In certain embodiments, M is a benzene ring or a heteroaromatic ring. [086] In preferred embodiments, M is a benzene ring. [087] In preferced embodiments, P is an aromatic ring or a heteroaromatic ring and M is an aromatic ring, a heteroaromatic ring or (C5-C8)cycloalkylene. [088] X is CR3R4, N(R5), O or S(O)„. [089] In preferred embodiments, X is CR3R4 or N(R5). [090] In further preferred embodiments, X is CHR3. [091] In certain embodiments, M is a substituted or unsubstituted benzene ring and X is/? ra to lA [092] In certain preferred embodiments, M is an aromatic ring, a heteroaromatic ring or (C5-C8)cycloalkylene and X is CR3R4 or 1N(R5). " 93 ■'
Figure imgf000020_0001
P is an aromatic ring or a heteroaromatic ring and X is CR3R4 or N(R5). [094] L is a bond, (Cι-C5)alkylene or (C2-C5)heteroalkylene, provided that L is not a bond when L2 is a bond. [095] In some embodiments, L3 is (Cι-C5)alkylene or (C2-C5)heteroalkylene. [096] In certain embodiments, L3 is (Ci-C3)alkylene. [097] In some embodiments, L3 is methylene. [098] In certain embodiments, L is a methylene substituted with a monocyclic aryl or monocyclic heteroaryl. [099] In certain embodiments, X is CR3R4 or N(R5), and L3 is substituted or unsubstituted methylene. [0100] In preferred embodiments, L2 is (C2-C4)heteroalkylene and L3 is (Cι-C3)alkylene. 1 1 [0101] In certain prefened embodiments, L is a bond, O or N(R ), L is (C2-C4)heteroalkylene and L is (Cι-C3)alkylene. [0102] A is -CO2H, tetrazol-5-yl, -SO3H, -PO3H2, -SO2NH2, -C(O)NHSO2CH3, -CHO, -C(O)R6, -C(O)NHR6, -C(O)NHOR7, thiazolidinedion-yl, hydroxyphenyl or pyridyl. [0103] In certain embodiments, A is a bioisostere of -CO2H. [0104] In certain embodiments, A is -C02H or tetrazol-5-yl, -C(O)NHSO2CH3 or -C(O)NHR6. [0105] In some embodiments, A is -CO2H or tetrazol-5-yl. [0106] In preferred embodiments, A is -CO2H or a salt thereof. [0107] In some embodiments, P is an aromatic ring or a heteroaromatic ring and A is -CO2H. [0108] In certain embodiments, X is CR3R4 or N(R5) and A is -CO2H. [0109] In preferred embodiments, M is an aromatic ring, a heteroaromatic ring or (C5-C8)cycloalkylene and A is -CO2H or tetrazol-5-yl. [0110] In certain preferred embodiments, M is an aromatic ring, a heteroaromatic ring or (C5-C8)cycloalkylene, X is CR3R4 or N(R5), L3 is (C1-C5)alkylene or (C2-C5)heteroalkylene and A is -CO2H. [0111] R1 is (Cι-C6)alkyl, aryl(d-C3) alkyl or (C2-C6)heteroalkyl. [0112] In certain embodiments, R1 is
Figure imgf000020_0002
or (C2-C6)heteroalkyl. [0113] R2 is hydrogen, (Cι-C6)alkyl or (C2-C6)heteroalkyl.
IS -
Figure imgf000021_0001
(Cι-C8)alkyl, (C2-C8)alkyl, (C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, -NR8R9, -C(O) 10Rπ, -NR12C(O)R13 or -NR12S(O)pR13. [0115] In certain embodiments, R3 is cyano, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, -NR8R9, -C(O)NR10Rπ, -NR12C(O)R13 or -NR12S(O)pR13. [0116] In some embodiments, R is cyano, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl or -NR8R9. [0117] In certain embodiments, R is cyano, heteroaryl, (C2-C6) alkenyl or (C2-C6)alkynyl. [0118] In certain embodiments, R is (C2-C8)alkyl, (C3-C8)alkenyl or (C3-C8)alkynyl. [0119] In some embodiments, R3 is aryl or heteroaryl. [0120] In certain preferred embodiments, R is tetrazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxazolyl, pyrrolyl, thienyl or prop-1-ynyl. [0121] In certain embodiments, R is tetrazolyl, thiazolyl, or prop-1-ynyl. [0122] R4 is hydrogen, cyano, aryl, heteroaryl, (Cι-C8)alkyl, (C2-Cg)alkenyl or (C2-C8)alkynyl. [[00112233]] O ( ptionally, R3 and R are combined to form a 3-, 4-, 5-, 6- or 7-membered ring containing from zero to three heteroatoms selected from N, O and S. The ring formed by combining R3 and R4 may be a saturated or unsaturated ring. [0124] In some embodiments, R4 is hydrogen or methyl. [0125] In preferred embodiments, R is hydrogen. [0126] In further preferred embodiments, R is cyano, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)alkyl, (C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl or -NR8R9 and R4 is hydrogen. [0127] R5 is hydrogen, aryl, heteroaryl, (Cι-Cg)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or (C3-C8)cycloalkyl. [0128] R6 is heteroaryl. [0129] R7 is hydrogen or (CrC^alkyl. [0130] R8 and R9 are independently hydrogen, (Cι-C5)alkyl, oxy(Cι-C5)alkyl or carboxy(C ι-C5)alkyl. [0131] Optionally, R8 and R9 are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S. The ring formed by combining R8 and R9 may be a saturated, unsaturated or aromatic ring. " ? ]"'' '!
Figure imgf000022_0001
independently selected from hydrogen, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl. [0133] Optionally, R10 and R11 are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S. The ring formed by combining R10 and R11 may be a saturated, unsaturated or aromatic ring. [0134] R13 is aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl or
(C3-C8)heterocycloalkyl. [0135] The subscripts m and n are independently 0, 1 or 2. [0136] The subscript p is 1 or 2. [0137] In some embodiments, P is an aromatic ring or a heteroaromatic ring, X is
CR3R4 and R3 is cyano, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or -NR8R9. [0138] In some embodiments, A is -CO2H, X is CR R and R is cyano, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or -NR8R9. [0139] In certain embodiments, when P and M are benzene, at least two of L , X and
L are other than CH2. [0140] In certain embodiments, the compounds of formula I do not include
3-(4-(4-methoxybenzyloxy)phenyl)pent-4-ynoic acid; β-ethenyl-4-phenylm.ethoxy- benzenepropanoic acid; 4-(2-quinolinylmethoxy)-β- [4-(2-quinolinylmethoxy)phenyl] - benzenepropanoic acid; N- [4-(benzoylamino)phenyl] -N-phenyl-glycine; 3-(4-(isopentyloxy)benzamido)-3-phenylpropanoate; 3-(4-isobutoxybenzarnido)-3- phenylpropanoate; (R)-2-((iR, R)-4-isopropylcyclohexanecarboxamido)-3 - phenylpropanoic acid; (R)-3-(4-(benzyloxy)phenyl)-2-(tert-butoxycarbonyl)propanoic acid; 3-(4-chlorophenyl)-3-(furan-2-carboxamido)propanoic acid; 3-(3,4-dimetlιoxyphenyl)-3- (furan-2-carboxamido)propanoic acid; 3-(4-chlorobenzamido)-3-(4- (dimethylamino)phenyl)propanoic acid; 3-(2-(2-(3,4-dimethylphenoxy)ethylthio)- 1H- benzo[d]imidazol-l-yl)propanoic acid; {2-Bromo-4-[(3,4-dichloro-phenyl)- hydrazonomethyl]-6-ethoxy-phenoxy} -acetic acid; 2-(4-(2-(2-(4-chlorophenyl)furan-5- carboxamido)ethyl)phenoxy)-2-methylpropanoic acid; 5-(3-(3,4-dimethoxyphenyl)-5-(2- fluorophenyl)-4,5-dihydropyrazol-l-yl)-5-oxopentanoic acid; 2-(2-(3-(3,4-dihydro-2Η- benzo[b][l,4]dioxepin-7-yl)-2-methyl-4-oxo-4H-chromen-7-yloxy)acetamido)acetic acid; 3-(4'-Bromo-biphenyl-4-yl)-4-phenyl-butyric acid; 3-(4'-Bromo-biphenyl-4-yl)-3- phenylsulfanyl-propionic acid; 3-(5-(2-chloro-6-fluoro-4-(trifluoromethyl)phenoxy)-2,4- dinitrophenyl)propanoic acid; 3-(3-(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)propanoic ,; acid; -( 4tm hόx eS y 5fphenyl)pent-4-ynoic acid; or 3-(4-(4- methoxybenzyloxy)phenyl)-5-(trimethylsilyl)pent-4-ynoic acid, salts thereof, or esters thereof. [0141] In certain embodiments, it is to be understood that compounds of formula I do not include compounds wherein P is a 1,2-azole ring when Q is aryl or heteroaryl, L1 is a bond, M is a monocyclic aromatic ring, X is N(R5), O or S(O)n, and A contains a carbonyl group. [0142] In certain embodiments, it is to be understood that compounds of formula I do not include compounds wherein P is furan or thiophene when Q is aryl, L1 is a bond, M is an aromatic ring, X is CR3R4, O or S(O)n and A contains a carbonyl group. [0143] The compounds of the invention include pharmaceutically acceptable salts, solvates or prodrugs thereof. [0144] In certain embodiments, ester prodrugs are preferred. [0145] Those of skill in art will understand that, unless otherwise indicated, divalent groups such as C(O)N(R2), SO2N(R2),(d-C4)alkylene-C(O)N(R2) and the like, both possible orientations of the groups are permitted. For example, in formula I where L2 is C(O)N(R ), the carbon atom may be attached to P or to M, as shown: O O Q-L1-P-C-N-M-X-L3-A or Q-L1-P-N-C-M-X-L3-A R2 R2 As another example, in formula I where L2 is (Cι-C4)alkylene-C(O)N(R2) in formula la, the alkylene group may be attached to P or to M, as shown:
Q-U-P- (C C4)alkylene-
Figure imgf000023_0001
[0146] In certain embodiments, the present invention provides a compound having the formula (la):
Figure imgf000023_0002
la where Q, L1, P, L3, A R3 and R4 are as defined with regard to formula I above. [0147] In some embodiments of formula la, Q is substituted or unsubstituted benzene, and L1 is a bond, (Cι-C4)alkylene, O or S(O)m. [0148] In some embodiments, P is selected from the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, pyridine, pyrimidine, , „ , . ''pyri a£iήeV e ΘtKia' ," l S!, benzimidazole, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline. [0149] In certain embodiments where P is benzene, Q is hydrogen, aryl, heteroaryl or (Cι-C6)alkyl, and L1 is a bond, (Cι-C4)alkylene, O or S(O)m. [0150] In some embodiments, L3 is (Cι-C5)alkylene. In certain embodiments, L3 is methylene. [0151] In certain embodiments, R is cyano, aryl, heteroaryl, (C2-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkynyl, -NR8R9, -C(O)NR10Rn, -NR12C(O)R13 or -NR12S(O)pR13 and R4 is hydrogen, cyano, aryl, heteroaryl, (Cι-Cg)alkyl, (C2-C8)alkenyl or (C2-C8)alkynyl. [0152] In certain embodiments, R is cyano, an unsubstituted aryl or heteroaryl monocyclic ring, (C2-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkynyl, or -C(O)NR10Rπ, R4 is hydrogen, and P is selected from the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline. [0153] In some embodiments, R is cyano, an unsubstituted aryl or heteroaryl monocyclic ring, (C3-C8)alkenyl, (C3-C8)alkynyl, -C(O)NR10RU, R4 is hydrogen, and L3 is methylene. [0154] In certain embodiments, Q is aryl, heteroaryl, (Cι-C6)alkyl or (C2-C6)heteroalkyl, L1 is a bond, (Cι-C4)alkylene, (C2-C4)heteroalkylene, S(O)m, N(R1), (Cι-C4)alkylene-SO2N(R2), (C1-C4)alkylene-N(R2)SO2 or C(O)N(R2), P is selected from the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline, R3 is cyano, an unsubstituted aromatic or heteroaromatic monocyclic ring, (C2-C8)alkyl, (C3-C8)alkenyl, (C3-C8)alkynyl, or -C(O)NR10Rn, R4 is hydrogen, and L3 is methylene. [0155] In certain embodiments, the present invention provides a compound having the formula (lb):
Figure imgf000024_0001
lb where Q, L1, P, L3, A and R5 are as defined with regard to fonnula I above. [0156] In some embodiments of formula lb, P is selected from the group consisting of benzene, naphthalene, pyrrole, imidazole, pyrazine, oxazole, thiazole, furan, thiophene, 'p i ine,! yι m'e, pyrf a i erbenzothiazole, purine, benzimidazole, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline. [0157] In certain embodiments, R5 is an unsubstituted or substituted benzene. [0158] In another aspect, the present invention provides a compound having the formula (II):
Figure imgf000025_0001
II where R21, R22, Z, L, Y and W are defined below. [0159] R21 is -H, -OH, -NHS(O2)CH3, heteroaryl, or -NH-heteroaryl. [0160] In certain embodiments, R21 is -OH, -NHS(O2)CH3, -NH-tetrazolyl, or tetrazolyl. 91 [0161] In certain embodiments, R is tetrazolyl, pyrimidinyl, or pyridinyl. [0162] In preferred embodiments, R21 is -OH, or a salt thereof. [0163] R22 is -H, -(C2.C8)alkyl, -(C3-C8)alkenyl, -NR23R24, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, — c— N 5 or ~~ C≡C-R25 _ [0164] In some embodiments, R22 is -(C2.C8)alkyl, -(C3-C8)alkenyl, -NR23R24, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ~ c= N , or —C≡C-R25 . [0165] In certain embodiments, R22 is -(C2-C3)alkyl, -NR23R24, substituted or unsubstituted phenyl, -CH=C(CH3)2, -CH2CH=CH2, or -C≡C-R25 . [0166] In other embodiments, R22 is unsubstituted aryl or unsubstituted heteroaryl.
In other embodiments, R22 is substituted aryl and the substitution onto the aryl is unsubstituted -(Cι-C5)alkyl, -(Cι-C5)oxyalkyl, or -halo(C1-C5)alkyl. [0167] In certain embodiments, R22 is C≡C-R and R25 is -(Cι-C5)alkyl having 0 or 1 heteroatoms. [0168] In preferred embodiments, R22 is — C≡CCH3 . [0169] In some embodiments, R22 is -CH=C(CH3)2, or -CH2CH=CH2. [0170] R23 and R24 are independently -H, -(C C5)alkyl, or -(Cι-C5)oxyalkyl. [0171] R25 is -H, -(Cι-C5)alkyl, -hetero(Cι-C5)alkyl, -(Cι-C5)oxyalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0172] In some embodiments, R25 is -(Cι-C5)alkyl,-(Cι-C5)oxyalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. "" l7'3]''' "• ""il
Figure imgf000026_0001
R is -hetero(Cι-C5)alkyl that does not contain Si. 9 [0174] In some embodiments, R is unsubstituted phenyl. [0175] In other embodiments, R25 is a substituted phenyl. [0176] In prefened embodiments, R25 is methyl. H -C- or -N- [0177] Z is I ' . In some embodiments, Z is nitrogen. In other embodiments, Z is carbon. [0178] L is -O-, -S-, or -N(R26)-. In some embodiments, L is -O-. In other embodiments, L is -S-. In other embodiments, L is -N(R26)-. [0179] In certain embodiments, Z is nitrogen and L is -N(R )-. [0180] R26 is -H , -(Cι-C5)alkyl, substituted or unsubstituted aryl(Cι-Cι0)alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0181] In certain embodiments, R26 is -H , substituted or unsubstituted aryl(Cι-Cι0)alkyl or substituted or unsubstituted aryl. [0182] In some embodiments, R26 is -H. [0183] In other embodiments, R26 is substituted or unsubstituted phenyl. [0184] Y is absent or is -CH2- , -CH2CH2- , -CH=CH- , -C(O)CH2- , -C(O)CH2CH2- , -C(O)CH=CH- , -S(O2)-, -S(O2)CH2- , -S(O2)CH2CH2- , -S(O2)CH=CH-, or -C(O)-. [0185] In certain embodiments, Y is -CH2- , -CH2CH2- , -CH=CH- , -C(O)CH2- , -C(O)CH2CH2- , -C(O)CH= H- , -S(O2)-, -S(O2)CH2- , -S(O2)CH2CH2- , -S(O2)CH=CH-. [0186] In some embodiments Y is -CH2-. [0187] In some embodiments L is -O- or -S-, and Y is -CH2-, -CH2CH2-. [0188] W is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. [0189] For example and without limitation, W can be a ring such as a benzene, naphthalene, pyrrole, pyrazole, imidazole, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, benzoxazole, triazole, oxadiazole, thiadiazole, benzooxadiazole, dibenzofuran, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline or quinoline., and so forth. [0190] In some embodiments, W is a substituted or unsubstituted monocyclic aryl ring or a substituted or unsubstituted monocyclic heteroaryl ring. [0191] In some embodiments, W is substituted or unsubstituted fused aryl bicyclic ring or substituted or unsubstituted fused heteroaryl bicyclic ring. In certain embodiments, " '"is"aή - f err ere !fl sed aryl bicyclic ring or an 8- to 11 -membered fused heteroaryl bicyclic ring. [0192] In other embodiments, W is a substituted or unsubstituted 5- or 6-membered aryl ring or substituted or unsubstituted 5- or 6-membered heteroaryl ring. [0193] In certain embodiments where W is a substituted aryl or heteroaryl ring, the substituting group can be a halogen, substituted or unsubstituted (Cι-Cιo)alkyl, substituted or unsubstituted hetero(Cι-Cι0)alkyl, substituted or unsubstituted halo(Cι-Cι0)alkyl, substituted or unsubstituted aryl(Cι-C10)alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0194] In some embodiments, W is a 5-membered ring having two or more heteroatoms. [0195] In certain embodiments, W is a 5-membered ring selected from the group consisting of
Figure imgf000027_0001
and R27 is substituted or unsubstituted (Cι-C10)alkyl, substituted or unsubstituted hetero(Cι-Cιo)alkyl, substituted or unsubstituted halo(Cι-Cι0)alkyl, substituted or unsubstituted aryl(Cι-Cι0)alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. H — C— [0196] In some embodiments where Z is I , R21 is -OH, L is -O-, -S-, or
-N(R26)-, and Y is -CH2- , -CH2CH2- , -CH=CH- , -C(O)CH2- , -C(O)CH2CH2- ,
-C(O)CH=CH- , or -C(O)-, then W is not furan or thiophene.
[0197] In certain embodiments, W is a substituted or unsubstituted phenyl. [0198] In some embodiments, Z is carbon and R22 is -(C2-C8)alkyl, -(C3-C8)alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C≡C-R25 _
[0199] In some embodiments where Z is carbon, W is a benzene ring, R22 is C≡C-R 5 R2S is -hetero(C1-C5)alkyl, L is -O- or -S-, then any heteroatom in R25 is not Si. [0200] In some embodiments, where R21 is -OH, L is -O-, Y is -CH2-, and W is
/?αra-methoxyphenyl, R22 is C≡C-R25 } then R25 is not -H.
[0201] In certain embodiments, where L is -N(R26)-, Z is nitrogen, R22 is a phenyl,
R is hydrogen or a phenyl and W is a phenyl, then Y is not -C(O)-. H — C—
[0202] It will be apparent that in embodiments of formula II where Z is I and
R22 is -(C2.C8)alkyl, -(C3-C8)alkenyl, -NR23R24, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, ~ c= N , or C≡C-R25 ? then the carbon at Z is a chiral carbon as shown:
Figure imgf000028_0001
Thus, a compound of the invention can be an S-enantiomer, an R-enantiomer, or a mixture of both an S-enantiomer and an R-enantiomer.
[0203] In preferred embodiments, a compound is an S-enantiomer.
[0204] In certain embodiments, R21 is -OH; L is -O-, or -S-; and Y is -CH2- , or
-CH2CH2- .
[0205] In some embodiments where Z is nitrogen, then W is not a 1,2-azole ring.
[0206] In certain other embodiments, the present invention provides a compound having the formula (III):
Figure imgf000028_0002
III or a pharmaceutically acceptable salt, hydrate or prodrug thereof, where R22, L, Y, and W are as defined with regard to formula II above.
[0207] In some embodiments, R22 is -H, -(C2-C3)alkyl, -NR23R24, or substituted or unsubstituted phenyl.
[0208] In certain embodiments, L is -O-, -S-, or -N(R26)-.
[0209] In some embodiments, R26 is -H , substituted or unsubstituted aryl(C1-Cιo)alkyl or substituted or unsubstituted aryl.
[0210] In some embodiments, Y is -CH2- , -CH2CH2- , -CH=CH- , -C(O)CH2- ,
-C(O)CH2CH2- , -C(O)CH=CH- , -S(O2)CH2- , -S(O2)CH2CH2- , -C(O)-, or
-S(O2)CH=CH- .
[0211] In some embodiments, W is a substituted or unsubstituted 5- or 6-membered aryl ring or substituted or unsubstituted 5- or 6-membered heteroaryl ring with the proviso if
R22 is phenyl, L is -O-, -S-, or -N(R26)-, and W is a benzene ring then Y may not be -C(O)-.
[0212] In some embodiments, L is -N(R26)-, and R26 is hydrogen. l j . k b < nents, W is not a 1,2-azole ring. [0214] In other embodiments, the compound of formula III is selected from the group consisting of
Figure imgf000029_0001
or a salt thereof.
[0215] In further embodiments, the present invention provides a compound of formula II or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R21 is
-OH, -NHS(O2)CH3, -NH-tetazolyl, or tetrazolyl; R22 is -(C2-C8)alkyl, -NR23R24, substituted or unsubstituted phenyl, -CH=C(CH3)2, -CH2CH=CH2, or -C≡C-R25 . R 23 and R 24 are independently -H, -(C1-C5)alkyl, or -(Cι-C5)oxyalkyl; R25 is -H, -(Cι-C5)alkyl,
-(Cι-C5)oxyalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted H — C— or — N— heteroaryl; Z is I ' ; L is -O-, -S-, or -N(R26)-; R26 is -H , -(Cι-C5)alkyl , substituted or unsubstituted aryl(Cι-C10)alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Y is -CH2- , -CH2CH2- , -CH=CH- , -C(O)CH2- ,
-C(O)CH2CH2- , -C(O)CH=CH- , -S(O2)CH2- , -S(O2)CH2CH2- , or -S(O2)CH=CH-; and W is a substituted or unsubstituted 5- or 6- membered aryl ring or substituted or unsubstituted
5- or 6- membered heteroaryl ring.
[0216] In certain embodiments, the present invention provides compounds according to formula (IN):
Figure imgf000029_0002
IV or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein R25, W, Y, and L are defined as above in paragraph [0215].
[0217] In some embodiments, R25 is methyl.
[0218] In some embodiments, L is -O- or -S- and Y is -CH2- or -CH2CH2-. 2 9] l-"
Figure imgf000030_0001
W is a 5-membered ring selected from the group consisting of
Figure imgf000030_0002
. and 97
R is substituted or unsubstituted (C1-Cι0)alkyl, substituted or unsubstituted hetero(C1.Cιo)alkyl, substituted or unsubstituted halo(Cι-Cιo)alkyl, substituted or unsubstituted aιyl(C1-Cι0)alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0220] In certain embodiments, R27 is substituted phenyl.
[0221] In other embodiments, R27 is unsubstituted phenyl.
[0222] In some embodiments, the present invention provides compounds according to formula (V):
Figure imgf000030_0003
V or a pharmaceutically acceptable salt, hydrate or prodrug thereof, where R21, R22 and W are defined as above, paragraph [0215].
[0223] In some embodiments, R21 is -OH, or a salt thereof.
[0224] In some embodiments, W is substituted phenyl.
[0225] In certain embodiments, W is substituted with substituted or unsubstituted
(C1-Cι0)alkyl, substituted or unsubstituted hetero(Cι-Cιo)alkyl, substituted or unsubstituted halo(Cι-Cιo)alkyl, substituted or unsubstituted aryl(Cι-Cι0)alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0226] In other embodiments, W is a 5-membered ring selected from the group consisting of
Figure imgf000030_0004
; and
R27 is hydrogen, substituted or unsubstituted (Cι-Cιo)alkyl, substituted or unsubstituted ' erσC yl, l utet r xmsubstituted halo(CrC10)alkyl, substituted or unsubstituted aryl(Cι-Cι0)alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0227] In certain embodiments, a compound of formula N is a racemate. In certain embodiments, the compound of formula N comprises a mixture of (S) and (R) enantiomers. [0228] In certain embodiments, the present invention provides compounds having the formula (Na):
Figure imgf000031_0001
Na 1 99 where R , R and W are defined above in formula N. [0229] In other embodiments, the compound has the formula (Nb):
Figure imgf000031_0002
Nb 1 99 where R , R and W are defined above in fonnula N. [0230] In certain embodiments, the present invention provides compounds according to formula (NI):
Figure imgf000031_0003
NI or a pharmaceutically acceptable salt, solvate or prodrug thereof, where R25 and W are defined in paragraph [0215] above. [0231] In some embodiments, R25 is methyl. [0232] In some embodiments, W is a 5-membered ring selected from the group consisting of
Figure imgf000031_0004
Figure imgf000032_0001
R27 is hydrogen, substituted or unsubstituted (Cι-Cιo)alkyl, substituted or unsubstituted hetero(Cι-C10)alkyl, substituted or unsubstituted halo(Cι-Cιo)alkyl, substituted or unsubstituted aryl(Cι-Cι0)alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
[0233] In certain embodiments, the compound of formula VI comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula VI comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula VI comprises a mixture of S- and R-enantiomers. [0234] In certain embodiments, the present invention provides compounds according to formula (VII):
Figure imgf000032_0002
VII or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein each R28 is independently selected from the group consisting of substituted or unsubstituted (Cι-Cιo)alkyl, substituted or unsubstituted hetero(C1-Cι0)alkyl, substituted or unsubstituted halo(Cι-Cιo)alkyl, substituted or unsubstituted aryl(Cι-Cιo)alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl, the subscript q is an integer from 0 to 5, and R25 is as defined above in paragraph [0215]. [0235] In some embodiments, the subscript q is 0, 1, or 2. 8
[0236] In other embodiments, R is a methoxy, ethoxy, trihalomethyl, methyl, halo, or cyano group and the subscript q is 1 or 2. 9R
[0237] In other embodiments, R is a phenyl, methoxyphenyl, methylphenyl, trihalomethylphenyl, benzyl, phenoxy, ethoxyphenyl, cyanophenyl, halophenyl, halobenzyl, pyridyl, methoxybenyl, or pyryl group and the subscript q is 1 or 2.
[0238] In other embodiments, R25 is methyl.
[0239] In certain embodiments, the compound of formula VII comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula VII ^ "' c tn rises' a eTCϋme cal y pu e' R-enantiomer. In yet other embodiments, the compound of formula VII comprises a mixture of S- and R-enantiomers. [0240] In other embodiments, the formula is selected from the group consisting of
Figure imgf000033_0001
and salts thereof. [0241] In certain embodiments, the present invention provides compounds according to formula (VIII):
Figure imgf000033_0002
VIII or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R21, R22 and W are defined in paragraph [0215] above and Ar and T are defined below. [0242] T is a direct bond, (Cι-C5)alkylene, hetero(Cι-C5)alkylene, O, C(O)-(C5-C7)heterocycloalkylene, (C C4)alkylene-SO2NH, or (Cι-C4)alkylene-NHSO2. [0243] In some embodiments, T is a direct bond, substituted or unsubstituted (Cι_C5)alkyl or substituted or unsubstituted hetero(Cι-C5)alkyl. [0244] Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
Figure imgf000034_0001
Ar is a benzene, naphthalene, pyrrole, pyrazole, imidazole, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, benzoxazole, triazole, oxadiazole, thiadiazole, benzooxadiazole, dibenzofuran, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline or quinoline. [0246] In some embodiments, R22 is ~" CΞC_CH3 , [0247] In some embodiments, R21 is -OH. [0248] In certain embodiments, T is a direct bond and Ar is a substituted or unsubstituted benzene ring. [0249] In some embodiments, W is phenyl. [0250] In other embodiments, W is a 5-membered ring selected from the group consisting of
Figure imgf000034_0002
R27 is Ar-T-. [0251] In certain embodiments, the compound of formula VIII comprises a stereomerically pure S-enantiomer. In other embodiments, the compound of formula VIII comprises a stereomerically pure R-enantiomer. In yet other embodiments, the compound of formula VIII comprises a mixture of S- and R-enantiomers.
"'"[ 252}''' 1' i '':Ά~
Figure imgf000035_0001
the compound is selected from the group consisting of:
Figure imgf000035_0002
or a salt thereof. [0253] In certain embodiments, the present invention provides compounds according to formula (IX)
Figure imgf000035_0003
IX or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein W, T and Ar are as defined above in formula VIII. [0254] In some embodiments, the compound has the formula:
Figure imgf000035_0004
, or a salt thereof. [0255] In an embodiment, the compound is selected from the group consisting of:
Figure imgf000036_0001
or a salt thereof.
[0256] In certain embodiments, the present invention provides compounds, for example, of formula III, IV, VI, VII, or IX, that include a bioisostere of -CO2H in place of
-CO2H. For illustration, compounds that include a bioisostere of -CO2H in place of the
-CO2H on examplary compoxmd 27.1, described in the examples below, can include the following:
Figure imgf000036_0002
like, without limitation, as recognized by those of skill in the art. See, e.g., The Practice of Medicinal Chemistry, Wermuth, C.G., Ed., Academic Press: New York, 1996, incorporated herein by reference in its entirety.
[0257] In certain embodiments, the invention provides compounds according to the above formulas so long as the compound is not one of the following acids, or salt thereof, including:
3-(4-(4-methoxybenzyloxy)phenyl)pent-4-ynoic acid; β-ethenyl-4-phenylmethoxy-benzenepropanoic acid;
4-(2-quinolinyhnethoxy)-β-[4-(2-quinolinylmethoxy)phenyl]-benzenepropanoic acid; N- [4-(benzoylamino)phenyl] -N-phenyl-glycine; _ "(jso eiil 3-(4-isobutoxybenzamido)-3-phenylpropanoate;
(R)-2-((7R, R)-4-isopropylcyclohexanecarboxamido)-3-phenylpropanoic acid; (R)-3-(4-(benzyloxy)phenyl)-2-(tert-butoxycarbonyl)propanoic acid; 3-(4-chlorophenyl)-3-(furan-2-carboxamido)propanoic acid; 3 -(3 ,4-dimethoxyphenyl)-3 -(furan-2-carboxamido)propanoic acid; 3 -(4-chlorobenzamido)-3 -(4-(dimethylamino)phenyl)propanoic acid; 3 -(2-(2-(3,4-dimethylphenoxy)ethylthio)- 1 H-benzo [d] imidazol- 1 -yl)propanoic acid; {2-Bromo-4-[(3,4-dichloro-phenyl)-hydrazonomethyl]-6-ethoxy-phenoxy}-acetic acid; 2-(4-(2-(2-(4-chlorophenyl)furan-5-carboxamido)ethyl)phenoxy)-2-methylpropanoic acid; 5-(3-(3,4-dimethoxyphenyl)-5-(2-fluorophenyl)-4,5-dihydropyrazol-l-yl)-5-oxopentanoic acid;
2-(2-(3-(3,4-dihydro-2Η-benzo[b][l,4]dioxepin-7-yl)-2-methyl-4-oxo-4H-chiOmen-7- yloxy)acetamido)acetic acid; 3-(4'-Bromo-biphenyl-4-yl)-4-phenyl-butyric acid; 3 -(4'-Bromo-biphenyl-4-yl)-3 -phenylsulfanyl-propionic acid;
3-(5-(2-chloro-6-fluoro-4-(trifluoromethyl)phenoxy)-2,4-dinitrophenyl)propanoic acid; 3 -(3 -(2-chloro-4-(trifluoromethyl)phenoxy)phenyl)propanoic acid; 3-(4-(4-methoxybenzyloxy)phenyl)pent-4-ynoic acid; 3-(4-(4-methoxybenzyloxy)phenyl)-5-(trimethylsilyl)pent-4-ynoic acid; β, β-dimethyl-4- [ [ [4-methyl-2- [4-(trifluoromethyl)phenyl] -5 -thiazolyl] methyl] thio] - benzenepropanoic acid; or β-amino-4-[(4-bromo-2,5-dihydro-2-methyl-5-oxo-l-phenyl-lΗ-pyrazol-3-yl)methoxy]-3- methoxy-benzenepropanoic acid.
5.2.2 Preparation of the Compounds [0258] The compounds of the invention can be prepared by a variety of synthetic or semisynthetic techniques. FIG. 1 and the Examples in Section 6 below provide a variety of synthesis routes to the compounds provided herein. Appropriate starting materials can be prepared by techniques known or apparent to those of skill in the art or the starting materials may be commercially available. One of skill in the art will understand that the synthetic routes can be modified to use different starting materials or alternative reagents and that suitable adjustments in conditions (e.g., temperatures, solvents, etc.) can be made to accomplish the desired transformations. Additionally, one of skill in the art will recognize that protecting groups may be necessary for the preparation of certain compounds and will n( '"t e aware- t ose'co tϊb ' OTnpatible with a selected protecting group. Accordingly, the exemplary methods and the examples described herein are illustrative of the present invention and are not to be construed as limiting the scope thereof.
5.2.3 Compositions [0259] In another aspect, the invention provides pharmaceutical compositions suitable for pharmaceutical use comprising one or more compounds of the invention and a pharmaceutically acceptable carrier, excipient or diluent. [0260] The term "composition" as used herein is intended to encompass a product comprising the specified ingredients (and in the specified amounts, if indicated), as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant that the carrier or excipient is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. [0261] In certain embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula II, wherein R22 comprises an alkynyl 1 containing Si, and where R , L, Y, and W are as defined above in formula II. [0262] In some embodiments, the Si atom is substituted with up to three alkyl groups. [0263] In some embodiments, R22 is ~~ C≡C-Si(CH3)3 [0264] Composition formulation may improve one or more pharmacokinetic properties (e.g., oral bioavailability, membrane permeability) of a compound of the invention (herein referred to as the active ingredient). [0265] The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. [0266] The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or
Figure imgf000039_0001
"'e ixirs'.' S o iϊ όn nfe ϊ ied^For oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with other non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,256,108; 4,166,452 and 4,265,874 to form osmotic therapeutic tablets for control release. [0267] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. [0268] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxy-ethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. _ , ι 02 ] ' ""8 Oily suspensiσ s-may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. [0270] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
[0271] The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
[0272] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
[0273] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. ""lf
Figure imgf000041_0001
compositions may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. [0275] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the invention are employed. As used herein, topical application is also meant to include the use of mouthwashes and gargles. [0276] The pharmaceutical compositions and methods of the invention may further comprise other therapeutically active compounds, as noted herein, useful in the treatment of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
5.2.4 Methods of Use
[0277] In another aspect, the invention provides methods of treating or preventing a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema, comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention. [0278] In one embodiment, the disease or condition is type II diabetes.
[0279] In another aspect, the present invention provides a method for treating a disease or condition responsive to the modulation of GPR40 comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the invention.
[0280] In some embodiments, the disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, "'"nyperlϊp eiSϊray^ dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema. [0281] In certain embodiments, the disease or condition is type II diabetes. [0282] In some embodiments, the disease or condition is obesity. [0283] In some embodiments, the disease or condition is hyptertension. [0284] In some embodiments of administering the compounds or compositions or the invention, the compound or composition is administered orally. [0285] In other embodiments, the compound or composition is administered parentally. [0286] In other embodiments, the compound or composition is administered in combination with a second therapeutic agent. [0287] In other embodiments, the second therapeutic agent is an insulin sensitizing agent, such as metformin or a thiazolidinedione, for example. [0288] In another aspect, the invention provides methods of treating or preventing a disease or disorder responsive to modulation of GPR40 comprising administering to a subject having such a disease or disorder, a therapeutically effective amoxmt of one or more of the subject compounds or compositions. [0289] In yet another aspect, the invention provides methods of treating or preventing a GPR40-mediated condition, disease or disorder comprising administering to a subject having such a condition, disease or disorder, a therapeutically effective amount of one or more of the subject compounds or compositions. [0290] In yet another aspect, the invention provides methods of modulating GPR40 comprising contacting a cell with one or more of the subject compounds or compositions. [0291] For example, in some embodiments, a cell that constitutively expresses GPR40 is contacted with one or more of the subject compounds or compositions. [0292] In certain embodiments, a cell to be contacted can be made to express or overexpress GPR40, for example, by expressing GPR40 from heterologous nucleic acid introduced into the cell or, as another example, by upregulating the expression of GPR40 from nucleic acid endogenous to the cell. [0293] Depending on the disease to be treated and the subject's condition, the compounds of the invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracistemal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal;, local) "routes' d a- -ιsl:a o ι - lι--t yI e formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. The invention also contemplates administration of the compounds of the invention in a depot formulation, in which the active ingredient is released over a defined time period. [0294] In the treatment or prevention type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema or other conditions or disorders associated with GPR40, an appropriate dosage level will generally be about 0.001 to 100 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.01 to about 25 mg/kg per day; more preferably about 0.05 to about 10 mg/kg per day. A suitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05 to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this range the dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. [0295] It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compoxmd employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. [0296] The compounds of the invention can be combined or used in combination with other agents useful in the treatment, prevention, suppression or amelioration of the diseases or conditions for which compounds of the invention are useful, including type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular _ >( 'αrseafee'j atte ds!b': rόs " t;ney- clτsease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema. Such other agents, or drugs, may be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with a compound of the invention. When a compound of the invention is used contemporaneously with one or more other drags, a pharmaceutical composition containing such other drugs in addition to the compound of the invention is preferred. Accordingly, the pharmaceutical compositions of the invention include those that also contain one or more other active ingredients or therapeutic agents, in addition to a compound of the invention. [0297] Examples of other therapeutic agents that may be combined with a compound of the invention, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) cholesterol lowering agents such as HMG- CoA reductase inhibitors (e.g., lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin and other statins), bile acid sequestrants (e.g., cholestyramine and colestipol), vitamin B3 (also known as nicotinic acid, or niacin), vitamin B6 (pyridoxine), vitamin Bι2 (cyanocobalamin), fibric acid derivatives (e.g., gemfibrozil, clofibrate, fenofibrate and benzafibrate), probucol, nitroglycerin, and inhibitors of cholesterol absorption (e.g., beta- sitosterol and acylCoA-cholesterol acyltransferase (ACAT) inhibitors such as melinamide), HMG-CoA synthase inhibitors, squalene epoxidase inhibitors and squalene synthetase inhibitors; (b) antithrombotic agents, such as thrombolytic agents (e.g., streptokinase, alteplase, anistreplase and reteplase), heparin, hirudin and warfarin derivatives, β-blockers (e.g., atenolol), β-adrenergic agonists (e.g., isoproterenol), ACE inhibitors and vasodilators (e.g., sodium nitroprusside, nicardipine hydrochloride, nitroglycerin and enaloprilat); and (c) anti-diabetic agents such as insulin and insulin mimetics, sulfonylureas (e.g., glyburide, meglinatide), biguanides, e.g., metformin (Glucophage®), α-glucosidase inhibitors (acarbose), insulin sensitizers, e.g., thiazolidinone compounds, rosiglitazone (Avandia®), troglitazone (Rezulin9), ciglitazone, pioglitazone (Actos®) and englitazone. [0298] The weight ratio of the compound of the invention to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Combinations of a compound of the invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. [0299] In another aspect, the present invention provides a method for modulating circulating insulin concentration in a subject, comprising administering a compound or composition of the invention. ( > |
" θ30U "™! '3 i4'n";sdm )b im! nts, the insulin concentration is increased. [0301] In other embodiments, the insulin concentration is decreased. [0302] In certain embodiments, a compound, or composition comprising a compound, according to formula II wherein R22 comprises an alkylyl containing Si, and 91 where R , L, Y, and W are as defined above in formula II, may be used. [0303] In some embodiments, the Si atom is substituted with up to three alkyl groups. [0304] In some embodiments, R22 is — C≡C-Si(CH3 ) 3 [0305] The following examples are offered by way of illustration and are not intended to limit the scope of the invention. Those of skill in the art will readily recognize a variety of noncritical parameters that could be modified to yield essentially similar results.
6. EXAMPLES 6.1 Example 1 [0306] This example illustrates the preparation of (3S -3-(4-Hydroxy-phenyl)-hex-
4-ynoic acid methyl ester. Scheme 1.1
Figure imgf000045_0001
1.1
[0307] 5-(4-Hydroxy-benzylidene)-2,2-dimethyI-[l,3]dioxane-4,6-dione (l.l).
Condensation with Meldrum's acid is carried out according to the method of Bigi et. al. (2001) Tetr. Lett. 42: 5203-5205. A 2L pear-shaped flask was charged with 4-hydroxybenzaldehyde (50 g, 409 mmol) and water (400 mL). The flask was placed in a water bath at 75 °C and Meldrum's acid (62 g, 430 mmol) was added as a slurry in 400 mL of water. The reaction mixture was agitated for 2h then cooled in an ice bath for 2 hours. The product was collected by filtration and rinsed with cold water. After drying thoroughly, 95 g (94%) of adduct 1.1 was obtained as a fine yellow powder.1H NMR(500MHz)(DMSO- d6) δ 9.75 (br s, IH); 8.27 (s, IH); 8.24 (d, 2H, J=10 Hz); 6.98 (d, 2H, J=10 Hz);.1.76 (s, 6H). MS ESI (pos.) m/e: 519.0 (2M + Na). Scheme 1.2
Figure imgf000046_0001
1.1 1.2
[0308] (+/-)-5-[l-(4-Hydroxy-phenyl)-but-2-ynyl]-2,2-dimethyl-[l,3]dioxane-4,6- dione (1.2). An oven-dried 3L 3-neck flask equipped with a mechanical stirrer, nitrogen inlet, nitrogen outlet and placed in a room-temperature water bath. After purging with nitrogen for 20 minutes, a solution of 1-propynylmagnesium bromide in THF (0.5 N, 600 mL) was added by cannula. In a separate oven-dried and nitrogen-flushed 500 mL RB flask, compound 1.1 (35 g, 142 mmol) was dissolved in anhydrous THF (350 mL) with gentle warming. The solution of 1.1 was then added over 15 minutes. Over the course of the addition, the reaction mixture changed to a thick, yellow suspension. After the addition was complete, the reaction mixture was stirred for 15 minutes and then quenched with aqueous NH4C1 (0.6N, 750 mL) and diluted with hexanes (800 mL). The layers were separated and the organic layer discarded. The aqueous layer was acidified to pH ~2 with saturated aqueous KHSO4 and extracted with ethyl acetate (2 x 400 mL). The combined extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a light yellow solid (37 g, 91%). !H NMR(500MHz)(acetone- 6) δ 8.26 (s, IH); 7.39 (d, 2H, J=8.5 Hz); 6.76 (d, 2H, J=8.4 Hz); 4.73 (br s, IH); 4.46 (d, IH, J=2.4 Hz); 1.82 (s, 3H); 1.81 (s, 3H); 1.64 (s, 3H). MS ESI (pos.) m/e: 599.0 (2M + Na). Scheme 1.3
Figure imgf000046_0002
1.2 1.3
[0309] (+/-)-3-(4-Hydroxy-phenyl)-hex-4-ynoic acid (1.3). A IL RB flask was charged with compound 1.2 (37 g), diethyl ketone (160 mL), and water (80 mL). The suspension was heated to reflux for 48h. After cooling, the aqueous layer was saturated
Figure imgf000047_0001
layer was dried over MgSO4, filtered, and concentrated to a light brown oil which was crystallized from hot ethyl acetate:hexanes (1 :2). After collecting and drying, the product was obtained as an off-white powder (20.3 g, 77%).1H NMR(500MHz)(DMSO-^6) δ 12.2 (s, IH); 9.27 (s, IH); 7.12 (d, 2H, J=8.5 Hz); 6.67 (d, 2H, J=8.6 Hz); 3.87 (m, IH); 2.54 (m, 2H); 1.82 (d, 3H, J=2.4 Hz). MS ESI (pos.) m/e: 205.1 (M + H); 227.1 (M + Na). Scheme 1.4
Figure imgf000047_0002
1.3 1.4
[0310] (5S)-3-(4-Hydroxy-phenyI)-hex-4-ynoic acid (1.4). A 5L RB flask was charged with compoxmd 1.3 (66.4 g, 325 mmol) and 2-propanol (1 L) and then heated to 70 °C. (IS, 2R)-l-amino-2-indanol (46.1 g, 309 mmol) was dissolved in 2-propanol (1 L) with gentle warming. The solution of amine was added to the dissolved carboxlic acid and the resulting solution was allowed to cool to room temperature. After 16h, the crystals were collected and dried. The salt was re-suspended in 2 L of 2-propanol and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16h. A small sample of the salt was decomposed with aqueous acid and the free carboxylic acid was analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant: 0.1 % TFA in 90:10 hexanes:2-propanol) and was found to have 75% ee. The salt was re-suspended in 1.5 L of 2-propanol and dissolved by heating to reflux. After allowing to cool to room temperature, the salt was collected after 16h. This material was found to have 96% ee by chiral HPLC. This material was suspended in ethyl acetate (300 mL) and water (100 mL). Saturated aqueous KHSO4 (100 mL) was added with vigorous mixing. After two clear layers were obtained, the layers were separated and the aqueous layer extracted with ethyl acetate (100 mL). The combined extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated to a light yellow oil which crystallized on drying in vacuo. Compound 1.4 was obtained as an off-white solid (23.5 g, 35%). Scheme 1.5
Figure imgf000048_0001
1.4
[0311] (3S -3-(4-Hydroxy-phenyl)-hex-4-ynoic acid methyl ester (1). Phenol 1.4
(23.5 g, 115 mmol) was dissolved in acetone (230 mL) and treated with KHCO3 (11.5 g, 115 mmol). After 15 minutes, methyl iodide (5 mL, 80 mmol) was added, and the reaction stirred at 40 °C for 14h. An additional portion of methyl iodide (3 mL, 48 mmol) was added and heating was continued for 24h. Potassium salts were removed by filtration and thoroughly rinsed with acetone. The filtrate was concentrated to an oil which was purified by filtration through a 1 cm plug of silica gel. Elution with 2.5% MeOH in dichloromethane followed by concentration provided phenol 1 (21.5 g, 85%) as a light yellow oil. 1H NMR(500MHz)(acetone- 6) δ 8.2 (br s, IH); 7.20 (d, 2H, J=9.5 Hz); 6.77 (d, 2H, J=9.0 Hz); 3.98 (m, IH); 3.60 (s, 3H); 2.65 (m, 2H); 1.78 (d, 3H, J=2.5 Hz). MS ESI (pos.) m/e: 219.1 (M + H); 241.1 (M + Na). 6.2 Example 2 [0312] This example illustrates the preparation of (3S)-3-[4-(4'-Trifluoromethyl- biphenyl-3-ylmethoxy)-phenyl]-hex-4-ynoic acid sodium salt. Scheme 2.1
Figure imgf000048_0002
[0313] 3-(4-Trifluoromethylphenyl)-benzoic acid (2.1). The Suzuki coupling was carried out according to the method of Dyer et al. (2001) Tetrahedron Letters 42: 1765- 1767. Commercially available 4-(Trifluoromethyl)phenylboronic acid (15g, 78.7 mmol) and 3-bromobenzoic acid (15. lg, 75 mmol) were suspended in 2-propanol:water (1 :4, 72 mL). 10% Pd/C (1.5g) was added followed by aqueous Na2CO3 (39 mL, 20% by wt.). The ""r ^ g ιn i e;' aS e^ ά 0C for 4 hours. The precipitate was filtered and rinsed with 20% aqueous Na2CO3 solution. The filtrate was diluted with water and acidified to pH=2. The white solid was filtered and dried in vacuo. The crude material (2.1) (19.69g) was used in the next step without further purification. Scheme 2.2
Figure imgf000049_0001
[0314] 3-(4-TrifluoromethylphenyI)-benzyl alcohol (2.2). The carboxylic acid 2.1 (13.3g, 50mmol) in anhydrous THF (lOOmL) was added dropwise to LiAlH (2.9g, 75 mmol) in anhydrous THF (150mL) at 0°C over 30 minutes. The resulting mixture was slowly warmed to room temperature and stirred for 4 hours. The reaction was slowly quenched with water (2.9mL) at 0°C, 15% NaOH aqueous solution (2.9mL) and another portion of water (8.7mL). The mixture was dried over Na2SO4 and concentrated to give a white solid (11.9g). The crude product (2.2) was used in the next step without further purification. Scheme 2.3
Figure imgf000049_0002
[0315] 3-(4-Trifluoromethylphenyι)-benzyl chloride (2.3). The alcohol 2.2 (15g, 59.5mmol) was dissolved in anhydrous dichloromethane (lOOmL). Thionyl chloride (lOmL) was slowly added dropwise to the above solution. The resulting mixture was stirred at room temperature for 24 hours. The organic solvent was removed under vacuo. The residue was then purified by flash cliromatography (SiO2 gel 60, eluted with 20% DCM in hexanes). Fractions containing the desired product 2.3 were combined and concentrated to !'"aw te sb ' O^ ' J OOMHz) (CDC13) δ 7.73 (4H, s); 7.65 (IH, s); 7.58 (IH, s); 7.52-7.28 (2H, m); 4.69 (2H, s). Scheme 2.4
Figure imgf000050_0001
[0316] t3S 3-[4-(4'-Trifluoromethyl-biphenyl-3-ylmethoxy)-phenyl]-hex-4- ynoic acid methyl ester (2.4). Benzyl chloride 2.3 (28.0 g, 103 mmol) and phenol 1 (21.5 g, 98 mmol) were dissolved in acetone (150 mL) and treated with Cs2CO3 (39.9 g, 122 mmol). The reaction was stirred at 50 °C for 16 h then filtered and concentrated to an pale yellow oil which was purified by column chromatography (silica gel, 33% to 66% dichloromethane in hexanes). Eluant containing compound 2.4 was concentrated to a colorless oil (40.0 g, 92%). Scheme 2.4
Figure imgf000050_0002
[0317] -?S 3-[4-(4'-Trifluoromethyl-biphenyl-3-yImethoxy)-phenyl]-hex-4- ynoic acid sodium salt (2). Methyl ester 2.4 was dissolved in diethyl ether (50 mL). m , „„ „ e"S ditιn me yϊsila c aϊ - θ 7 :i,g, 7 mmol) was added in one portion and the reaction mixture stirred for 48h. The precipitate was collected by filtration and recrystallized from ethyl acetate:hexanes. After drying in vacuo, the desired sodium salt was obtained as a white powder (1.3 g). 1H NMR (500MHz) (CD3OD) δ 7.82 (d, 2H, J=8.5 Hz); 7.75-7.73 (m, 3H); 7.62 (m, IH); 7.32 (d, 2H, J=8.5 Hz); 6.94 (d, 2H, J=8.5 Hz); 5.15 (s, 2H); 4.03 (m, IH); 2.52 (dd, IH, J=8.2, 14.5 Hz); 2.45 (dd, IH, J-7.0, 14.0 Hz); 1.79 (d, 3H, J=2.5 Hz). 6.3 Example 3 Scheme 3.1
Figure imgf000051_0001
3.1 3.2
[0318] 5S 3-[4-(4-Methyl-2-p-tolyl-thiazoI-5-ylmethoxy)-phenyl]-hex-4-ynoic acid methyl ester (3.2). Compoxmd 3.1 was prepared according to the method described in Example 2 starting from the commercial available 4-methyl-2-(4-methylphenyl)-l,3- thiazole-5-carboxylic acid. The chloride 3.1 (250 mg, 1.1 mmol) and phenol 1 (230 mg, 1.1 mmol) were dissolved in anhydrous DMF (5 mL). Finely powdered Cs2CO3 (650 mg, 2.2 mmol) was then added and the reaction mixture was stirred at room temperature for 14 h. The reaction was poured into water and extracted with ethyl acetate (15mL x 3). The organic phases were combined, dried over Na2SO4, and concentrated in vacuo to a residue which was used in the next step without further purification. Scheme 3.1
Figure imgf000052_0001
3.2
[0319] (S -3-[4-(4-Methyl-2-p-tolyl-thiazol-5-ylmethoxy)-phenyl]-hex-4-ynoic acid (3). Ester 3.2 was dissolved in THF/MeOH/10% NaOH(aq) (1 :1 :1) solution (15mL). After stirring at room temperature over 30 minutes, the mixture was acidified with IN HCl (aq.) until pH = 4. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over Na2SO4 and concentrated. The crude residue was triturated with 20%) ethyl acetate in hexanes (20 mL). The precipitate was filtered and compound 3 was acquired as a pale yellow powder (315 mg, 0.8 mmol). MS ESI m/e: 406 (M-H). 1H NMR (500MHz) (CDC13) δ 7.86 (2H, d, J=7.5 Hz); 7.36 (2H, d, J=9 Hz); 7.26 (2H, d, J=8 Hz); 6.96 (2H, d, J=8.5 Hz); 5.18 (2H, s); 4.1 (IH, m); 2.77 (2H, m); 2.52 (3H, s); 2.42 (3H, s); 1.86 (3H, s). 6.4 Example 4 [0320] This example illustrates the preparation of 3-{4-[2-(2,6-Dichloro- benzyl)-thiazol-4-ylmethoxy]-phenyl}-hex-4-ynoic acid. Scheme 4.1
Figure imgf000052_0002
4.1 1.3
[0321] 3-{4-[2-(2,6-Dichloro-benzyI)-thiazol-4-ylmethoxy]-phenyI}-hex-4-ynoic acid (4). Preparation of thiazole 4.1 was carried out according to the method of Bordwell et
Figure imgf000053_0001
2: 792-797. Compound 4.1 (58 mg, 0.2 mmol) and phenol 1 (43.6 mg, 0.2 mmol) were dissolved in anhydrous DMF (2 mL) and treated with finely powdered Cs2CO3 (65 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 14 hours. The reaction was poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic phases were dried over Na2SO4, concentrated in vacuo and the residue dissolved in THF/MeOH/10% NaOH(aq) (1 :1 :1) solution (6 mL). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was acidified with IN HCl(aq.) until pH = 4. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The crude residue was triturated with 20% ethyl acetate in hexanes (10 mL). The precipitate was filtered and acid 4 was acquired as a pale yellow powder (55 mg, 0.12 mmol). MS ESI m/e: 460 (M-H). 1H NMR (400MHz) (CDC13) δ 7.40-7.19 (6H, m); 6.94-6.79 (2H, m); 5.18 (2H, s); 4.73 (2H, s); 4.1-4.06 (IH, m); 2.77 (2H, m); 1.85 (3H, s). 6.5 Example 5 [0322] This example illustrates the preparation of 3-[4-(2-Methyl-5-phenyl- furan-3 -ylmethoxy)-phenyl] -hex-4-ynoic acid. Scheme 5.1
Figure imgf000053_0002
5.1 1.3
[0323] 3-[4-(2-Methyl-5-phenyl-furan-3-ylmethoxy)-phenyl]-hex-4-ynoic acid (5). The Mitsunobu reaction was carried out according to the method of Mikό et al. (2003) J. Med. Chem.46: 1523-1530. Commercially available 5.1 (37.6 mg, 0.2 mmol), PPh3 (52 mg, 0.2 mmol) and phenol 1.3 (43.6 mg, 0.2 mmol) were added to anhydrous THF (3 mL). DEAD (45 μL, 0.22 mmol) was then added dropwise. The reaction mixture was stirred at room temperature over 14 hours. The reaction was then extracted with ethyl acetate (lOmL x 3). The organic phases were combined, dried over Na2SO , and concentrated in vacuo. The resulting residue was dissolved in THF/MeOH/10% NaOH(aq) (1 :1 :1) solution (6 mL). The resulting mixture was stirred at room temperature over 30
Figure imgf000054_0001
stirred at room temperature for 30 minutes. The mixture was acidified with IN HCl(aq.) x til pH = 4. The aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over Na2SO , and concentrated in vacuo. The crude product was triturated in 20% ethyl acetate in hexanes (10 mL). The precipitate was filtered and compound 5 was obtained as a white powder (35 mg, 0.9 mmol). MS ESI m/e: 375 (M-H). 1H NMR (500MHz) (CDC13) δ 7.65 (2H, d, J=8 Hz); 7.40-7.24 (5H, m); 6.96 (2H, d, J=8.5 Hz); 6.68 (IH, s); 4.88 (2H, s); 4.1 (IH, s); 2.77 (2H, m); 2.4 (3H, s); 1.86 (3H, s). 6.6 Example 6 [0324] The following compounds were prepared by methods similar to those described in Example 2. TABLE 1
Figure imgf000054_0002
Figure imgf000054_0003
[0325] NMR and MS data for compounds 6.13 and 6.14 are as follows:
Figure imgf000055_0001
6.13
[0326] 1H NMR (400MHz) ((CD3)2SO) δ 12.4 (s, IH), 7.52 (d, 2H, J= 8.1 Hz),
7.48 (d, 2H, J= 8.1 Hz), 7.28-7.34 (m, 3H), 7.17 (s, IH), 7.08 (d, IH, J= 8.1 Hz), 6.98 (d, 2H, J= 8.2 Hz), 5.12 (s, 2H), 4.08 (q, 2H, J= 7.0 Hz), 3.95 (m, IH), 2.50-2.60 (m, 2H), 1.78 (s, 3H), 1.27 (t, 3H, J= 7.0 Hz). [M+H]+ Calculated for C27H25ClO4 : 449.1. Found 449.1.
Figure imgf000055_0002
6.14
[0327] 1H NMR (400MHz) ((CD3)2SO) δ 12.4 (s, IH), 7.52 (d, 2H, J= 8.0 Hz),
7.46 (d, 2H, J= 8.6 Hz), 7.30 (d, 2H, J= 8.8 Hz), 7.46 (d, 2H, J= 6.0 Hz), 6.98-7.01 (m, 3H), 6.91-6.98 (m, 3H), 5.13 (s, 2H), 3.92-4.04 (m, 3H), 2.61 (d, 2H, J= 7.6 Hz), 2.29 (s, 3H), 1.79 (d, 2H, J= 2.0 Hz), 1.59-1.66 (m, 2H), 1.34-1.40 (m, 2H), 0.88 (t, 3H, J= 7.6 Hz). [M+Na]+ Calculated for C30H32O4 : 471.1. Found 471.1. 6.7 Example 7 [0328] The following compounds were prepared by methods similar to those described in Example 2. TABLE 2
Figure imgf000056_0001
Figure imgf000056_0003
6.8 Example 8 [0329] The following compounds were prepared by methods similar to those described in Example 3. TABLE 3
Figure imgf000056_0004
Figure imgf000057_0002
6.9 Example 9 [0330] The following compounds were prepared by methods similar to those described in Example 3. TABLE 4
Figure imgf000057_0001
Figure imgf000057_0003
6.10 Example 10 [0331] The following compounds were prepared by methods similar to those described in Examples 3-5. The carboxylic acids corresponding to 10.2 and 10.5 were prepared according to the method of Huang et al. (2003) J. Amer. Chem. Soc. 22: 6653- 6655, and Admas et al. (1973) Org. Synth. Coll. Nol. N: 107, 109, respectively. TABLE 5
Figure imgf000058_0001
Figure imgf000058_0003
6.11 Example 11
[0332] The following compounds were prepared by methods similar to those described in Examples 3-5. TABLE 6
Figure imgf000058_0002
Figure imgf000058_0004
[0333] This example illustrates the preparation of (H-/-)-3-(4-[(4- methoxyphenyl)methoxy]- phenyl)-hex-4-ynoic acid. Scheme 12.1
Figure imgf000059_0001
[0334] 4-[(4-methoxyphenyl)methoxy]benzaldehyde (12.1). A 500 mL round bottom flask was charged with 4-hydroxybenzaldehyde (4O g, 328 mmol) and DMF (250 mL). 4-methoxybenzyl chloride (57.8 mL, 426 mmol) was added, followed by potassium carbonate (90 g, 656 mmol). The reaction mixture was stirred at room temperature for 5h then poured into ice water (2.5 L). The product was collected by filtration and rinsed with water. After drying thoroughly, 78 g (98%) of aldehyde 12.1 was obtained as a light yellow powder. 1H NMR(400MHz)(D SO-_f6) δ 9.88 (s, IH); 7.88 (d, 2H, J=8.7 Hz); 7.42 (d, 2H, J=8.8 Hz); 7.21 (d, 2H, J-8.8 Hz); 6.97 (d, 2H, J=8.6 Hz); 5.16 (s, 2H); 3.77 (s, 3H). MS ESI (pos.) m/e: 243.1 (M + H). Scheme 12.2
Figure imgf000059_0002
[0335] 5- [ [4- [(4-methoxyphenyl)methoxy] phenyl] methylene] -2,2-dimethyl-
[l,3]dioxane-4,6-dione (12.2). Condensation with Meldrxx 's acid is carried out according to the procedure of DeWolf et al. (1989) Biochemistry 28: 3833-3842. A solution of Meldrum's acid (18 g, 124 mmol) compound 12.1 (30 g, 124 mmol) in toluene (100 mL) was treated with glacial acetic acid (4 mL) and piperidine (2 mL). The reaction mixture was stirred and heated at reflux until the removal of water with a Dean-Stark trap was complete. The reaction mixture was cooled to room temperature and the resulting solid was filtered and washed with cold toluene to yield 28g (62%) of 12.2 as a bright yellow powder. pκ ι 8.32 (s, IH); 8.24 (d, 2H, J=8.9 Hz); 7.42 (d, 2H, J=8.6
Hz); 7.17 (d, 2H, J=9.0 Hz); 6.97 (d, 2H, J=8.7 Hz); 5.18 (s, 2H) 3.75 (s, 6H) 1.75 (s, 6H). Scheme 12.3
Figure imgf000060_0001
12.2 12
[0336] (+/-)-3-(4-[(4-methoxyphenyI)methoxy]phenyI)-hex-4-ynoic acid (12). To a stirring THF (120 mL) solution of compound 12.2 (13.8 g, 37.5 mmol) under nitrogen was added 1-propynylmagnesium bromide in THF (0.5 N, 97.5 mL) over a period of 20 minutes. After the addition was complete, the reaction mixture was stirred for 20 minutes, quenched with saturated aqueous NH4C1 (50 mL) and extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with water, dried over MgSO_t, filtered, and concentrated to a brown oil. A solution of this brown oil in 5:1 pyridine-water (360 mL) was heated at 100 °C for 36h. The reaction mixture was cooled to room temperature and put in an ice- water bath. Concentrated HCl was carefully added to pH ~2. The resulting suspension was extracted with ethyl acetate (200 mL x 3), dried over MgSO4, filtered, and concentrated to an off-white solid. Recrystalization from ethanol gave 9.5 g (78%) of compoxmd 12 as a white powder. 1H NMR(500MHz)DMSO- 6) δ 12.2 (s, IH); 7.37 (d, 2H, J=8.5 Hz); 7.27 (d, 2H, J=8.5 Hz); 6.95 (d, 2H, J=8.0 Hz); 6.94 (d, 2H, J=8.5 Hz); 4.99 (s, 2H); 3.95 (m, IH); 3.76 (s, 3H); 2.60 (m, 2H); 1.78 (d, 3H, J=1.5 Hz). MS ESI (neg.) m/e: 323.0 (M -1). 6.13 Example 13 [0337] This example illustrates the preparation of (5S/)-3-[4-(2-Methyl-benzyloxy)- phenyl]-hex-4-ynoic acid sodium salt. Scheme 13.1
Figure imgf000060_0002
13.1 0338] !! -*'■» ! f -3*[ h i-benzyloxy)-phenyI]-hex-4-ynoic acid methyl ester
(13.1). 2-Methylbenzyl bromide (0.98 g, 5.3 mmol) and phenol 1 (0.97 g, 4.4 n mol) were dissolved in acetone (9 mL) and treated with Cs CO3 (1.45 g, 4.4 mmol). The reaction was stirred at room temperature for 16 h then filtered and concentrated to an oil which was purified by radial chromatography (2 mm silica gel plate, 10% ethyl acetate in hiexanes). Eluant containing compound 13.1 was concentrated to a colorless oil (1.37 g, 96%). This material was analyzed by chiral HPLC (Daicel ChiralPAK AD-H column, eluant: 0.1% TFA in 95:5 hexanes:2-propanol) and was foxmd to have 94% ee. Η NMR(500MHz)(MeOH- 4) δ 7.39 (d, IH, J=7 Hz); 7.28 (d, 2H, J=8.5 Hz); 7.25-7.15 (m, 3H); 5.05 (s, 2H); 4.02 (m, IH); 3.64 (s, 3H); 2.68 (m, 2H); 2.36 (s, 3H); 1.80 ( , 3H, J=2.5 Hz). MS ESI (pos.) m/e: 323.0 (M + H); 245.1 (M + Na). Scheme 13.2
Figure imgf000061_0001
[0339] (3S -3-[4-(2-Methyl-benzyloxy)-phenyl]-hex-4-ynoic acid sodium salt
(13). 2N KOH(aq) (3.2 mL) was added to a solution of 13.1 (1.37 g, 4.25 mmol) in methanol (30 mL). The reaction was stirred at room temperature overnight and then taken up in copious water. The aqueous solution was adjusted to pH = 2.0 with IN HCl(aq) and extracted with ethyl acetate. The combined organic layers were washed with water, followed by brine. The solvent was removed under reduced pressure and the resulting residue dissolved in ethanol (4 mL) and treated with 1 equiv. of aqueous sodium bicarbonate. The solvents were removed under reduced pressure and the residue triturated with diethyl ether. After collecting by filtration and drying, sodium salt 13 (1.1 g) was obtained as a fine white powder. 1H NMR(500MHz)(D2O) δ 7.34-7.18 (m, 6H) ; 6.95 (d, 2H, J=6.5 Hz); 5.05 (s, 2H); 3.88 (m, IH); 2.47 (d, 2H, J=8.5 Hz); 2.28 (s, 3H); 1.72 (d, 3H, J=2.5 Hz). MS ESI (pos.) m/e: 309.1 (M + H); 331.0 (M + Na). [α]D = +20.6°. 6.14 Example 14 [0340] The following compounds were prepared using similar methods to those described in Example 12. TABLE 7
Figure imgf000062_0001
Figure imgf000062_0003
6.15 Example 15 [0341] This example illustrates the preparation of (3S -3-[4-(2-Methyl-benzyloxy)- phenyl]-hex-4-ynoic acid. Scheme 15.1
Figure imgf000062_0002
[0342] (+/-)- [4-(4-Methoxy-benzyloxy)-phenyl]-hex-4-ynoic acid ethyl ester
(15.1). A 100 mL RB flask was charged with compound 12 (3.00 g, 9.25 mmol), l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.67 g, 13.9 mmol), 4-dimethylaminopyridine (1.13 g, 9.25 mmol) and dichloromethane (30 mL), the mixture was stirred into a solution. After 15 min, ethyl alcohol (absolute, 1.00 mL) was added. After 2 h, the reaction was quenched with aqueous NaHCO3 (sat., 100 mL). The layers was separated, and the organic layer was washed with aqueous NaHCO3 (2 X 100 mL), dried over MgSO4 and concentrated to a white powder (3.19 g, 98%) which was used without further purification.
Figure imgf000063_0001
15.1 15.2
[0343] (+/-)- [4-(2-Methyl-benzyIoxy)-phenyl]-hex-4-ynoic acid ethyl ester (15.2).
Ester 15.1 (3.19 g, 9 mmol) was taken up in glacial acetic acid (100 mL) in a 250 mL RB Flask, and the suspension was heated to reflux for 16h. The solvent was removed under reduced pressure, and the residue was re-dissolved in ethyl acetate (200 mL). The solution was washed with 1 N HCl(aq) (200 mL) and saturated brine (200 mL), dried over MgSO4 and concentrated to a thick yellow oil, to which was added 2-methylbenyl bromide (2.57 g, 13.9 mmol), cesium carbonate (6.03 g, 18.5 mmol) and DMF (20 mL). The suspension was heated to 80 °C for overnight. After cooling, the reaction was quenched with water (200 mL) and extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with NaHCO3 (sat. 2 X 100 mL), and NaCl (sat. 3 X 100 mL), dried over MgSO4, and concentrated to a white powder (2.41 g, 79%). Scheme 15.3
Figure imgf000063_0002
15.2 15
[0344] (3S)-3-[4-(2-Methyl-benzyloxy)-phenyI]-hex-4-ynoic acid (15).
Compoxmd 15.2 was dissolved in a mixture of 24 mL methanol and 24 mL isopropanol with the aid of sonication. The solution was filtered into a 50 mL glass vial. The racemic 15.2 was resolved with chiral normal phase HPLC using a ChiralTech AD semi-preparative column (2.0 cm X 25.0 cm), eluting isocratically with hexane/isopropanol (92:8) at a flow rate 20 mL/min. Each injection contained 50 mg of ester 15 (1 mL). The absorbance at 220 nm was used for detection. Both enantiomers were collected. After 36 injections, the separated enantiomers were dried to give white solids. Analytical chiral HPLC (Chiraltech AD-H column, 0.4 cm X 25.0 cm, 8% isopropanol/hexane, 1 mL/min) indicated both
Figure imgf000064_0001
enantiomers were referred to as A (retention time = 11.5 min) and B (retention time = 15.6 min). [0345] A RB flask was charged with enantiomer A (0.65 g), ethanol (10 mL) and 2N KOH (10 mL). and was stirred for 2 h at room temperature. After acidification to pH~2 with citric acid, the product was extracted into ethyl acetate (100 mL). The organic layers were washed with saturated brine(2 X 50 mL), dried over MgSO4 and concentrated to a yellow oil (0.59 g, 42% overall). An aliquot (12.0 mg) was made into a 1 mL DMF solution, and optical rotation was measured. This enantiomer was assigned to (S) according to DeWolf Jr. et al. (1989) Biochemistry 28: 3833-3842. [0346] HNMR (400 MHz, acetone-d6) δ 7.45 (d, IH, J=7.15 Hz); 7.37 (d, 2H, J=8.66 Hz); 7.25 (d, IH, J=1.42 Hz); 7.24 (m, 2H); 7.00 (d, 2H, J=8.74 Hz); 5.11 (s, 2H); 4.05 (m, IH); 2.70 (m, 2H); 2.39 (s, 3H); 2.10 (s, IH); 1.80 (d, 3H, J-2.41). MS-ESI (neg.) m/e: 307.1 (M-H); 637.2 (2M-H). [α]D 20: +16.32 (cl.2, DMF). 6.16 Example 16 [0347] This example illustrates the preparation of 3-(4-Hydroxy-phenyl)-hex-4- ynoic acid ethyl ester. Scheme 16.1
Figure imgf000064_0002
[0348] 3-(4-Hydroxy-phenyl)-hex-4-ynoic acid ethyl ester (16). Phenol 1.2 (1.2 g, 4 mmol) was dissolved in pyridine (3 mL) and ethanol (1 mL). The mixture was heated to 90 °C for 16h and then concentrated to an oil which was purified by column chromatography (elution with 1-3%) MeOH in dichloromethane). Phenol 16 (0.88 g, 91%) was obtained as an oil. 1H NMR(500MHz)(acetone-t 6) δ 8.24 (s, IH); 7.21 (d, 2H, J=9.5 Hz); 6.78 (d, 2H, J=9.0 Hz); 4.06 (m, 2H); 3.98 (m, IH); 2.68-2.59 (m, 2H); 1.78 (d, 3H, J=2.5 Hz); 1.75 (t, 3H, J=7.0 Hz). MS ESI (pos.) m/e: 233.1 (M + H); 255.1 (M + Na). 6.17 Example 17 [0349] The following compounds were prepared by methods similar to those of Examples 12 and 15. TABLE 8
Figure imgf000065_0001
Figure imgf000066_0002
6.18 Example 18 [0350] This example illustrates the preparation of 3-{4-[5-Methyl-2-(4- trifluoromethyl-phenyl)-oxazol-4-ylmethoxy] -phenyl} -hex-4-ynoic acid. Scheme 18.1
Figure imgf000066_0001
18.1
[0351] 4,5-dimethyl-2-(4-trifluoromethyl-phenyl)-oxazole-3-oxide (18.1). A
100 mL pear-shaped flask was charged with butane-2,3-dione monooxime (2.1 g, 20.4 mmol), 4-(trifluoromethyl)benzaldehyde (3.0 mL, 22.4 mmol), and acetic acid (20 mL). The mixture was cooled to 0° C. A solution of 4N HCl in dioxane (7.0 mL, 28.0 mmol) was added dropwise to the reaction and the resultant mixture was stirred at 0° C for 20 minutes. Diethyl ether (30 mL) was added to the reaction and the mixture was allowed to warm to room temperature overnight. The solvent was removed under reduced pressure and the resulting residue was taken up in water (300 mL). Cone. NH4OH(aq) was added to adjust the pH to 9.0. The mixture was extracted with ethyl acetate (2 x 75 mL), and the combined organic layers were washed with water (100 mL), followed by saturated brine (100 mL). The organic layer was dried (Na2SO4) and the solvent removed under reduced pressure. The resulting residue was purified via radial chromatography (3% MeOH in DCM) to yield 1.8 g (35%) of 4,5-dimethyl-2-(4-trifluoromethyl-phenyl)-oxazole-3-oxide as a white solid. LC/MSD m/e: 258.1 (M+H); 1H NMR (400 MHz) (Acetone-^) δ 8.68 (d, 2H, J=8.0 Hz), 7.89 (d, 2H, J=8.0 Hz), 2.45 (s, 3H), 2.16 (s, 3H). Scheme 18.2
Figure imgf000067_0001
18.1 18.2
[0352] 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (18.2).
Phosphorous oxychloride (0.72 mL, 7.8 mmol) was added dropwise to an oven-dried 100 mL pear-shaped flask charged with 18.1 (1.8 g, 7.00 mmol) and dichloromethane (20 mL). The reaction was refluxed under nitrogen atmosphere for 30 minutes and then cooled to room temperature. The reaction was washed with water (2 x 250 mL) and the combined aqueous layers were back extracted with DCM (2 x 25 mL). The combined organic layers were washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure and the resulting residue was purified via radial cliromatography (15% diethyl ether in hexanes) to yield 216 mg (15%) of 4-chloromethyl-5-methyl-2-(4- trifluoromethyl-phenyl)-oxazole as a white solid. LC/MSD m/e: 276.0 (M+H); 1H NMR (400 MHz) (CDC13) δ 8.15 (2H, d, J=8.0 Hz), 7.73 (2H. d, J=8.0 Hz), 4.59 (2H, s), 2.48 (2H, s). Scheme 18.3
Figure imgf000067_0002
18.2 16 18.3
[0353] 3-{4-[5-Methyl-2-(4-trifluoromethyl-phenyι)-oxazol-4-ylmethoxy]- phenyl}-hex-4-ynoic acid ethyl ester (18.3). Cesium carbonate (0.51 g, 1.57 mmol) was added to a solution of 18.2 (216 mg, 0.79 mmol) and phenol 16 (220 mg, 0.79 mmol) in DMF (8 mL). The reaction was stirred at room temperature overnight and then taken up in water (500 mL). The solution was adjusted to pH = 4.0 with IN HCl(aq) and extracted with ethyl acetate (2 x 25 mL). The combined organics were washed with water, followed by brine. The solvent was removed under reduced pressure and the resulting residue was purified via radial chromatography (20% diethyl ether in hexanes) to yield 304 mg (82%>) of 3-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-hex-4-ynoic
Figure imgf000068_0001
:;ϊ / © &r?72.0 (M+H); NMR (400 MHz) (CDC13) δ 8.16 (2H, d, J=8.0 Hz), 7.73 (2H, d, J=8.0 Hz), 7.33 (2H, m), 6.99 (2H, m), 5.01 (2H, s), 4.14 (3H, m), 2.72 (2H, m), 2.48 (3H, s), 1.85 (3H, s), 1.26 (3H, t, J=8.0 Hz). Scheme 18.4
Figure imgf000068_0002
18.3 18
[0354] 3-{4-[5-Methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]- phenyl}-hex-4-ynoic acid (18). 2N KOH(aq) was added to a solution of 18.3 (304 mg, 0.65 mmol) in ethanol (5 mL). The reaction was stirred at room temperature overnight and then taken up in copious water. The aqueous solution was adjusted to pH = 2.0 with IN HCl(aq) and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were washed with water, followed by brine. The solvent was removed under reduced pressure and the resulting residue was purified via radial chromatography (40%) ethyl acetate in Hexanes + 0.1% AcOH) to yield 150 mg (52%) of compound 18 as a glass. LC/MSD m/e: 444.0 (M+H); 1H NMR (400 MHz) (acetone) d 8.21 (2H, m), 7.89 ( 2H, d, J=8.0 Hz), 7.38 (2H, m), 7.03 (2H, m), 5.06 (2H, s), 4.06 (IH, m), 2.70 (2H, m), 2.52 (3H, s), 1.81 (3H, s). 6.19 Example 19 [0355] Examples 19-22 were prepared using methods similar to those described in Example 18.
Figure imgf000068_0003
19 [0356] 3-{4-[5-Methyl-2-(4-chloro-phenyl)-oxazol-4-ylmethoxy]-phenyI}-hex-4- ynoic acid (19). LC/MSD m/e: 410.0 (M+H). 1H-NMR (400 MHz) (acetone-^) δ 8.02 (2H, m), 7.49 (2H, m), 7.35 (2H, m), 7.01 (2H, m), 5.04 (2H, s), 4.09 (IH, m), 2.77 (2H, m), 2.48 (3H, s), 1.86 (3H, s).
Figure imgf000069_0001
20
[0357] 3-{4-[5-Methyl-2-(4-methyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-hex-4- ynoic acid (16). LC/MSD m/e: 390.2 (M+H). 1H NMR (400 MHz) (CDC13) δ 7.96 (2H, m), 7.34 (2H, m), 6.70 (2H, m), 5.02 (2H, s), 4.09 (IH, m), 2.80 (2H, m), 2.47 (3H, s), 1.85 (3H, s). 6.21 Example 21
Figure imgf000069_0002
21
[0358] 3-{4-[5-Methyl-2-(4-methoxy-phenyl)-oxazol-4-ylmethoxy]-phenyl}-hex-
4-ynoic acid (21). LC/MSD m/e: 406.1 (M+H). 1H NMR (400 MHz) (acetone- 6) δ 7.89 (2H, d, J=9.0 Hz) 7.30 (2H, m), 7.09 (2H, d, J=9.0 Hz), 7.00 (2H, m), 4.97 (3H, s), 3.90 (IH, m), 3.84 (3H, s), 2.44 (3H, s), 1.79 (3H, s). 6.22 Example 22
Figure imgf000069_0003
22
[0359] 3-{4-[5-Methyl-2-(3-cyano-phenyl)-oxazol-4-ylmethoxy]-phenyl}-hex-4- ynoic acid (22). LC/MSD m/e: 401.2 (M+H). 1H NMR (400 MHz) (acetone- ) δ 8.33 (2H, m), 7.91 (IH, m), 7.79 (IH, m), 7.38 (2H, m), 7.08 (2H, m), 5.06 (2H, s), 4.06 (IH, m), 2.70 (2H, m), 2.51 (3H, s), 1.81 (3H, s). [0360] The following example illustrates the synthesis of 5-{2-[4-(2-Methyl- benzyloxy)-phenyl]-pent-3-ynyl}-lH-tetrazole.
Scheme 23.1
Figure imgf000070_0001
23.1 23.2
[0361] 3-[4-(2-Methyl-benzyIoxy)-phenyl]-hex-4-ynoic acid amide (23.2).
Carbonyl diimidazole (0.46 g, 2.84 mmol) was added to a solution of 3-[4-(2-Methyl- benzyloxy)-phenyl]-hex-4-ynoic acid (See Example 13) (0.73 g, 2.37 mmol) in anhydrous
TΗF (10 mL). The mixture was stirred at room temperature for 2 hours. Concentrated
NΗ OΗ (10 mL) was then added to the mixture, and the reaction was stirred at room temperature overnight. The reaction mixture was poured into water (300 mL) and the solution was adjusted to pH = 7 with cone. HCl. The aqueous layer was then extracted with
3 x 25 mL ethyl acetate. The combined organic layers were washed with water, followed by brine. The organic layer was then dried (Na2SO4) and concentrated under reduced pressure to yield 0.48 g (70%) of 3-[4-(2-Methyl-benzyloxy)-phenyl]-hex-4-ynoic acid amide (23.2) as a light yellow solid. LC/MSD m/e: 308.4 (M+H) Scheme 23.2
Figure imgf000070_0002
23.2 23.3
[0362] 3-[4-(2-Methyl-benzyloxy)-phenyl]-hex-4-ynenitriIe (23.3). An oven- dried 50 mL round-bottomed flask was charged with DMF (8 mL) and a stir bar. The solution was cooled to 0 °C in an ice bath. Thionyl chloride (160 μL, 1.0 mmol) was added slowly via syringe. The mixture was stirred at 0 °C for an additional 45 minutes. Nitrile ' 23'aX3W' g -'@:m- Hol) ΦafrβBb added to the mixture as a solution in DMF (2 mL). The reaction was stirred at 0° C for an hour, and was then allowed to gradually warm to room temperature overnight. The reaction mixture was partitioned between ice water and ethyl acetate. The aqueous layer was extracted 2 additional times with 25 mL ethyl acetate. Saturated NaHCO3 was then added to the aqueous layer and the aqueous layer was extracted a third time with ethyl acetate. The combined organic layers were washed with saturated NaHCO3 and concentrated under reduced pressure. The resulting residue was purified via radial chromatography (15% ethyl acetate in hexanes) to yield 203 mg (72%) of 3-[4-(2- Methyl-benzyloxy)-ρhenyl]-hex-4-ynenitrile (23.3). 1H NMR (400 MHz) (acetone-^) δ 7.44 (3H, m), 7.24 (3H, m), 7.05 (2H, m), 5.13 (2H, s), 4.09 (IH, m), 2.89 (2H, m), 2.39 (3H, s), 1.88 (3H, s). Scheme 23.4
Figure imgf000071_0001
23.3 23
[0363] 5-{2-[4-(2-Methyl-benzyloxy)-phenyl]-pent-3-ynyl}-lH-tetrazole (23). To a solution of 23.3 (200 mg, 0.51 mmol) in DMF (5 mL) was added sodium azide (35 mg, 0.54 mmol) and ammonium chloride (29 mg, 0.54 mmol). The solution was stirred at 110° C for 48 hours. The reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (2 x 25 mL). The combined organic layers were concentrated under reduce pressure, and the resulting residue was purified via HPLC to yield 5 mg (3%) of 5-{2-[4-(2- Methyl-benzyloxy)-phenyl]-pent-3-ynyl}-lH-tetrazole (23) as a film. LC/MSD m/e: 333.1 (M+Η). 1H NMR (400 MHz) (acetone-β ) δ 7.45 (IH, m), 7.34 (2H, m), 7.25 (3H, m), 7.00 (2H, m), 5.11 (2H, s), 4.17 (IH, m), 3.37 (2H, d, J=7 Hz), 2.39 (3H, s), 1.79 (3H, s). 6.24 Example 24 [0364] The following example illustrates the synthesis of 3-[4-(4-Methoxy- benzyloxy)-phenyl]-hex-4-ynoic acid thiazol-2-ylamide. Scheme 24.1
Figure imgf000072_0001
12 24
[0365] 3-[4-(4-Methoxy-benzyloxy)-phenyl]-hex-4-ynoic acid thiazol-2-ylamide
(24). A pear-shaped flask was charged with a stir bar, compound 12 (50 mg, 0.154 mmol), carbonyl diimidazole (25 mg, 0.154 mmol) and THF (4 mL). The mixture was refluxed for 1 hour, and 2-amino thiazole (16 mg, 0.154 mmol) was then added. The reaction was refluxed for 48 hours, poured into water and extracted with ethyl acetate. The organic layer was concentrated and the resulting residue was purified via HPLC to yield 1.0 mg (2%) of 3-[4-(4-Methoxy-benzyloxy)-phenyl]-hex-4-ynoic acid thiazol-2-ylamide (24) as a film. 1H NMR (400 MHz) (acetone-^) δ 7.39 (4H, m), 7.11 (IH, s), 6.95 (3H, m), 5.03 (2H, s), 3.82 (3H, s), 2.95 (2H, m), 1.79 (3H, s). 6.25 Example 25 [0366] The compoxmds in the following table were prepared using the method described in Example 24. TABLE 9
Figure imgf000072_0002
12
Figure imgf000072_0003
6.26 Example 26
[0367] The following example illustrates the preparation of 3-[4-(5-Methyl-2- phenyl-2H-[l,2,3]triazol-4-ylmethoxy)-phenyl]-hex-4-ynoic acid (26). Scheme 26.1
Figure imgf000073_0001
16 26.1 26.2
[0368] 3-[4-(5-Methyl-2-phenyl-2H-[l,2,3]triazol-4-ylmethoxy)-phenyl]-hex-4- ynoic acid ethyl ester (26.2). Cesium carbonate (107 mg, 0.33 mmol) was added to a solution of 16 (60 mg, 0.22 mmol) in DMF (5 mL). The mixture was stirred at room temperature for 5 minutes, and 4-Chloromethyl-5-methyl-2-phenyl-2H-[l,2,3]triazole (55 mg, 0.22 mmol) was added. The reaction was heated to 60° C and stirred overnight. The reaction mixture was then poured into copious water. IN ΗCl(aq) was added to adjust the pH to 4.0. The aqueous layer was extracted with ethyl acetate. The organic layer was then washed with water, followed with brine. The organic layer was dried (Na2SO4) and concentrated. The resulting residue was purified via radial chromatography (20% ethyl acetate in hexanes) to yield 60 mg (66%) of 3-[4-(5-Methyl-2-phenyl-2H-[l,2,3]triazol-4- ylmethoxy)-phenyl]-hex-4-ynoic acid ethyl ester (26.2). LC/MSD m/e: 404.2 (M+Η). Scheme 26.2
Figure imgf000073_0002
26.2 26
[0369] 3-[4-(5-Methyl-2-phenyl-2H-[l,2,3]triazol-4-ylmethoxy)-phenyl]-hex-4- ynoic acid (26). 2N KOΗ(aq) (1 mL) was added to a solution of 26.2 (68 mg, 0.17 mmol) in EtOH (2 mL). The reaction was stirred at room temperature overnight and then poured into water. The aqueous mixture was acidified to pH = 2 with IN HCl(aq), and then extracted with ethyl acetate. The organic layer was washed with water, followed by brine. The organic layer was then concentrated under reduced pressure and the resulting residue was purified via radial chromatography (20%) ethyl acetate in hexanes) to yield 60.3 mg (95%) of compound 26 as a colorless oil. LC/MSD m/e: 374.0 (M-H); 1H NMR (400 '' ) acettoιι )-δ 9( =8.0 Hz), 7.56 (2H, t, J=8.0 Hz), 7.40 (3H, t, J=8.0 Hz), 7.06 (2H, d, J=8.0 Hz), 5.28 (2H, s), 4.05 (IH, m), 2.70 (2H, m), 2.44 (3H, s), 1.80 (3H, s). 6.27 Example 27 [0370] The compoxmds in the following table were prepared using methods similar to those described in Example 26. TABLE 10
Figure imgf000074_0001
Figure imgf000074_0003
6.28 Example 28 [0371] The following example illustrates the preparation of 3-[4-(2-Methyl- benzylsulfanyl)-phenyl]-hex-4-ynoic acid (28). Scheme 28.1
Figure imgf000074_0002
28.1 [0372] 4-(2-Methyl-benzylsulfanyl)-benzaldehyde (28.1). 4-fluoro-benzaldehyde (1.16 g, 9.32 mmol) was added dropwise over 2 minutes to a solution of o-tolyl- methanethiol (1.35 g, 9.79 mmol) and Cesium carbonate (3.19 g, 9.79 mmol) in DMF (20 mL). The solution was stirred at 40 °C overnight and then poured into copious water. The pH of the solution was adjusted to 4 with IN HCl(aq), and the aqueous solution was extracted with ethyl acetate (2 x 35 mL). The combined organic layers were washed with f _ "water, ol owed bι e? ie-'colnbined organic layers were then dried (Na2SO4) and the solvent removed under reduced pressure. The resulting residue was purified via radial chromatograpliy (15% ethyl acetate in hexanes) to yield 1.29 g (54%) of 4-(2-Methyl- benzylsulfany -benzaldehyde (28.1). LC/MSD m/e: 243.0 (M+H). Scheme 28.2
Figure imgf000075_0001
28.1 28.2 [0373] 2,2-Dimethyl-5-[4-(2-methyl-benzylsulfanyI)-benzylidene]-[l,3]dioxane-
4,6-dione (28.2). Pyrrolidine (0.45 mL, 5.27 mmol) was added to a solution of aldehyde 28.1 in diethyl ether (20 mL) and the mixture was sonicated for 5 minutes. The mixture was then added to a solution of Meldrum's acid (0.73 g, 5.08 mmol) in diethyl ether (20 mL) and the resultant mixture was sonciated for 5 minutes, forming a solid. The solid was filtered, rinsed with diethyl ether, and then suspended in DCM (10 mL). p-Toluenesulfonic acid (0.97 g, 5. 10 mmol) was then added to the suspension and the suspension was sonicated until clear. The solvent was removed under reduced pressure, and the resulting residue was taken up in diethyl ether and partitioned between water and ethyl acetate. The aqueous layer was extracted 2 additional times with ethyl acetate. The combined organic layers were washed with water, dried (Na2SO4), and concentrated in vacuo to yield 1.05 g (54%) of2,2-Dimethyl-5-[4-(2-methyl-benzylsulfanyl)-benzylidene]-[l,3]dioxane-4,6- dione (28.2) as a yellow oil The resulting yellow oil was used without further purification. LC/MSD m/e: 391.1 (M+Na). Scheme 28.3
Figure imgf000075_0002
28.2 28.3 [0374] 2,2-Dimethyl-5-{l-[4-(2-methyl-benzylsulfanyl)-phenyl]-but-2-ynyI}- [l,3]dioxane-4,6-dione (28.3). An oven-dried 100 mL pear-shaped flask, fitted with an oven-dried stir bar, was charged with a 0.5 M solution of 1-propynyl magnesium bromide in •" H ( -- a 327 faetønula. The solution was cooled to 0° C, and then a solution of 28.2 (1.05 g, 2.85 mmol) in anhydrous THF (6 mL) was added over 3 minutes via cannula. The reaction was stirred at 0° C for 5 minutes and then stirred at room temperature for 1.5 hours. The reaction mixture was poured into saturated NH Cl(aq) and extracted with ethyl acetate. The combined organic layers were washed with water, followed by brine. The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified via radial chromatography (20% ethyl acetate in hexanes) followed by recrystalization from hot ethyl acetate and hexanes to yield 162 mg (15%) of2,2-Dimethyl-5-{l-[4-(2-methyl-benzylsulfanyl)-phenyl]-but-2-ynyl}- [l,3]dioxane-4,6-dione (28.3). LC/MSD m/e: 409.1 (M+H). Scheme 28.4
Figure imgf000076_0001
28.3 28 [0375] 3-[4-(2-Methyl-benzyIsulfanyϊ)-phenyl]-hex-4-ynoic acid (28). A solution of 28.3 (20 mg, 0.05 mmol) in 5:1 pyridine: water (6 mL) was heated to 80° C for 72 hours. The reaction was poured into 500 mL of water and the solution was acidified with IN HCl(aq) (65 mL). The aqueous solution was extracted with ethyl acetate and the combined organic layers were washed with water, followed by brine. The combined organic layers were then dried (Na2SO ) and concentrated in vacuo. The resultant residue was then purified via radial chromatography (30% ethyl acetate in hexanes) to yield 18 mg (quantitative) 3-[4-(2-Methyl-benzylsulfanyl)-phenyl]-hex-4-ynoic acid (28). LC/MSD m/e: 323.1 (M-H). 6.29 Example 29 [0376] The following example illustrates the preparation of 3-(4-o- Tolylmethanesulfinyl-phenyl)-hex-4-ynoic acid. Scheme 29.1
Figure imgf000077_0001
28.3 29.1
[0377] 2,2-Dimethyl-5-[l-(4-o-tolylmethanesulfinyl-phenyl)-but-2-ynyl]-
[l,3]dioxane-4,6-dione (29.1). Hydrogen peroxide (20 μL, 0.05 mmol) was added to a 0° C solution of 28.3 (20 mg, 0.05 mmol) in AcOH (2 mL). The reaction was stirred at 80° C for 1.5 hours, then cooled to room temperature and stirred for 16 hours. The reaction mixture was poured into cold water and the resulting solution was acidified to pH = 2 with 6N HCl(aq). The aqueous layer was extracted with ethyl acetate and seobutanol. The combined organic layers were concentrated to yield 10 mg (50%) of 2,2-Dimethyl-5-[l-(4- o-tolylmethanesulfinyl-phenyl)-but-2-ynyl]-[l,3]dioxane-4,6-dione (29.1). LC/MSD m/e: 383.0 (consistent with di-acid -H). Scheme 29.1
Figure imgf000077_0002
29.1 29
[0378] 3-(4-ø-TolylmethanesuIfinyl-phenyl)-hex-4-ynoic acid (29). 29.1
(10.0 mg, 0.025 mmol) was hydrolyzed using the methods described in Example 28 to yield 3.0 mg (25%>) of 3-(4-o-Tolylmethanesulfmyl-phenyl)-hex-4-ynoic acid (29). LC/MSD m/e: 339.1 (M-H); 1H NMR (400MHz) (acetone-^) δ 7.60 (2H, m), 7.49 (2H, m), 7.21 (2H, m), 7.04 (2H, m), 5.63 (2H, s), 4.17 (IH, m), 2.81 (2H, m), 2.22 (3H, s), 1.88 (3H, s). •■''6. ϊϋ3 JEx mp "'''
Figure imgf000078_0001
30
[0379] 3-(4-o-Tolylmethanesulfonyl-phenyl)-hex-4-ynoic acid (30) was prepared using methods similar to those described in Example 29.LC/MSD m/e: 357.2 (M+H); lB NMR (400MHz) (acetone-^) δ 7.69 (3H, m), 7.50 (IH, m), 7.17 (4H, m), 4.53 (2H, s), 4.22 (IH, m), 2.79 (2H, m), 2.27 (3H, s), 1.82 (3H, s). 6.31 Example 31 [0380] The following example illustrates the preparation of 3-[2-Methyl-4-
(2-methyl-benzyloxy)-phenyl]-hex-4-enoic acid (31). Scheme 31.1
Figure imgf000078_0002
31.1
[0381] 2-(2-methyl-benzyloxy)toluene (31.1). α-bromo-o-xylene (2.0 g, 10.81 mmol) was added to a solution of 2-methyl-phenol (1.06 g, 9.82 mmol) and cesium carbonate (7.99 g, 24.55 mmol) in DMF (20 mL). The reaction was stirred at 80° C overnight. The reaction mixture was acidified with 25 mL IN HCl(aq) and poured into copious water. The aqueous layer was extracted with ethyl acetate and the organic layer was dried (Na2SO ) and concentrated in vacuo. The resulting residue was purified via radial chromatography (20%> ethyl acetate in hexanes) to yield 1.82 g (88%) of 2-(2-methyl- benzyloxyjtoluene (31.1). LC MSD m/e: 213.2 (M+H). Scheme 31.2
Figure imgf000078_0003
31.1 31.2 «"[ 382}'' ' n y'- e yloxy)-5-bromotoluene (31.2). NBS (1.46 g, 8.23 mmol) was added to a solution of 31.1 (1.59 g, 7.48 mmol) in carbon tetrachloride (8 mL). The reaction was stirred at 60° C overnight and filtered to remove succinimide. The filtrate was concentrated in vacuo and purified via radial chromatography (15% diethyl ether in hexanes) to yield 0.65g (25%) of 2-(2-methyl-benzyloxy)-5-bromotoluene (31.2). LC/MSD m/e: 314.2 (M+Na).
Scheme 31.3
Figure imgf000079_0001
31.2 31.3 [0383] 2-Methyl-4-(2-methyl-benzyloxy)-benzaldehyde (31.3). A 2.5M solution of «-BuLi (2.1 mL, 5.26 mmol) in THF was added dropwise to a -78° C solution of 31.2 (1.46 g, 5.01 mmol) in THF (25 mL). The reaction was stirred at -78° C for 15 minutes and then DMF (3.3 mL) was added. Cooling was removed after 5 minutes and the reaction was allowed to warm to room temperature. The reaction was partitioned between ethyl acetate and water and the aqueous layer was extracted 1 additional time with ethyl acetate. The combined organic layers were dried (Na SO4) and concentrated. The resulting residue was purified via radial chromatography (5% ethyl acetate in hexanesO to yield 269 mg (22%) of 2-Methyl-4-(2-methyl-benzyloxy)-benzaldehyde (31.3). LC/MSD m/e: 241.2 (M+H). Scheme 31.4
Figure imgf000079_0002
31.3 31.4 [0384] 4-[2-Methyl-4-(2-methyl-benzyloxy)-phenyl]-but-3-en-2-one (31.4). 2N NaOH(aq) (0.6 mL) was added to a solution of 31.3 (100 mg, 0.42 mmol) in acetone (1 mL). The reaction was stirred at room temperature overnight and then taken up in water. The aqueous solution was acidified with IN HCl(aq) (1.5 mL) and extracted with ethyl acetate. The organic extracts were washed with brine, dried (Na2SO ), and concentrated in vacuo. The resultant residue was purified via radial chromatography (20% ethyl acetate in hexanes) to yield 74 mg (63%) of 4-[2-Methyl-4-(2-methyl-benzyloxy)-phenyl]-but-3-en-2-one
Figure imgf000080_0001
δ 7.83 (IH, d, J=16), 7.70 (IH, m), 7.46 (IH, m), 7.25 (3H, m), 6.96 (2H, m), 6.63 (IH, d, J=16 Hz). Scheme 31.5
Figure imgf000080_0002
31.4 31.5 [0385] 4-[2-MethyI-4-(2-methyl-benzyloxy)-phenyl]-but-3-en-2-ol (31.5). NaBH4 (20 mg, 0.51 mmol) was added to a 0.4 M solution of CeCl3 in MeOH (0.65 mL, 0.26 mmol), 31.4 (74 mg, 0.26 mmol), and THF (1 mL). The reaction was stirred, uncapped, until gas evolution ceased. The reaction was quenched with water (1.5 mL) and partitioned between water and diethyl ether. The aqueous layer was extracted 2 times with diethyl ether and the combined organic layers were washed with brine and concentrated in vacuo to yield 69 mg (93%) of 4-[2-Methyl-4-(2-methyl-benzyloxy)-phenyl]-but-3-en-2-ol (31.5). LC/MSD m/e: 266.3 (M-OH); 1H NMR (40O MHz) (DMSO--4) δ 7.44 (2H, m), 7.25 (3H, mO, 6.86 (2H, m), 6.75 (IH, m), 6.08 (IH, m), 5.11 (2H, s), 4.40, (IH, m), 2.38 (3H, s), 2.32 (3H, s), 1.29 (3H, m). Scheme 31.6
Figure imgf000080_0003
31.5 31.6 [0386] 3-[2-Methyl-4-(2-methyl-benzyloxy)-phenyl]-hex-4-enoic acid ethyl ester (31.6). Propionic acid (cat.) was added to a solution of 31.5 (69 mg, 0.24 mmol) in 1,1,1 - triethoxy-ethane (440 μL, 2.4 mmol). The reaction was stirred at 105° C overnight. The solvent was removed under reduced pressure and the resulting residue was purified via radial chromatography (5% ethyl acetate in hexanes) to yield 33 mg (39%) of 3-[2-Methyl- 4-(2-methyl-benzyloxy)-phenyl]-hex-4-enoic acid ethyl ester (31.6). LC/MSD m/e: 375.0 (M+Na). Scheme 31.7
Figure imgf000081_0001
31.6 31 [0387] 3-[2-Methyl-4-(2-methyl-benzyIoxy)-phenyl]-hex-4-enoic acid (31). The hydrolysis of 31.6 (33 mg, 0.094 mmol) was carried out using methods similar to those described in Example 26 to yield 5.7 mg (19%) of 3-[2-Methyl-4-(2-methyl-benzyloxy)- phenyl]-hex-4-enoic acid (31). 1H NMR (400 MHz) (acetone) d 7.44 (2H, m), 7.25 (3H, m), 6.86 (2H, m), 6.73 (IH, m), 6.10 (IH, m), 5.64 (2H, s), 4.42 (IH, m), 2.38 (3H, s), 2.32 (3H, s), 1.29 (3H, d, J=7.0 Hz). 6.32 Example 32 [0388] The following compounds were made using methods similar to those described in Examples 28 and 31. TABLE 11
Figure imgf000081_0002
32
Figure imgf000081_0003
[0389] The following example illustrates the preparation 3-[4-(3-Methoxy- benzyloxy)-phenyl]-5-methyl-hex-4-enoic acid (33). Scheme 33.1
Figure imgf000082_0001
33.1
[0390] 2-[4-(3-Methoxy-benzyloxy)-benzylidene]-malonic acid dimethyl ester
(33.1). K2CO was added to a solution of 4-hydroxybenzylidene-malonic acid dimethyl ester (6.95 mmol) and 4-methyoxybenzyl chloride (7.64 mmol) in DMF (15 ml). It was stirred at room temperature overnight. The reaction was poured into water, and the product was extracted with ethyl acetate twice. The organic layer was washed with water and saturated brine, dried over Na2SO , and concentrated in vacuo. The resulting residue was purified using silica gel column chromatography (hexane/ethyl acetate = 2/1) to give compoxmd 33.1 as a white solid (3.2 mmol). Scheme 33.2
Figure imgf000082_0002
.1 33.2
[0391] 2-{l-[4-(3-Methoxy-benzyIoxy)-phenyl]-3-methyl-but-2-enyl}-malonic acid dimethyl ester (33.2). 2-methyl-l-propenylmagnesium bromide (3 mL, 0.5 M in THF) was added dropwise to a solution of compound 33.1 (1.0 mmol) in THF. The reaction mixture was stirred at room temperature for Ihr and then quenched with saturated NH4Cl(aq) and the aqueous layer extracted with ethyl acetate twice. The combined organic layers were washed with water and saturated brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified using silica gel column chromatography (hexane/ethyl acetate = 2/1) to give compound 33.2 as a white solid (0.93 mmol). Scheme 33.3
Figure imgf000083_0001
33.2 33.3
[0392] 2-{l-[4-(3-Methoxy-benzyloxy)-phenyl]-3-methyl-but-2-eαyl}-malonic acid (33.3). To a solution of compound 33.2 (0.50g, 1.21 mmol) in THF (5 ml), methanol (5 ml) and water (2.5 ml) was added lithium hydroxide monohydrate (1.17g, 28 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was acidified with IN HCl to pH 2-3, and then extracted with ethyl acetate twice. The organic layer was washed with water and brine, dried over Na2SO , and concentrated in vacuo. The resulting residue was used for the next reaction without purification. Scheme 33.4
Figure imgf000083_0002
33.3 33
[0393] 3-[4-(3-Methoxy-benzyloxy)-phenyI]-5-methyl-hex-4-enoic acid (33). A suspension of compound 33.3 (0.136 mmol) in toluene was refluxed for 16 h. After removing the solvent, the residue was purified using silica gel column chromatography (TFA/ Dichloromethane/ ethyl acetate = 1/5/40) to give compound 33 as a white solid (0.088 mmol). MS ESI m/e: 339 (M-H) 1H NMR (500MHz) (DMSO-d6) δ 11.97 (IH, s); 7.31 (IH, t, J=10 Hz); 7.14 (2H, d, J=l l Hz); 6.99 (2H, m); 6.87 (3H, m); 5.22 (IH, m); 5.03 (2H, s); 3.75 (IH, m); 3.75 (3H, s); 2.44-2.53 (2H, m); 1.63 (3H, s); 1.62 (3H, s). 6.34 Example 34 [0394] The following compounds were made using the method described in
Example 33. TABLE 12
Figure imgf000084_0001
Figure imgf000084_0002
[0395] Compound 34.1. MS ESI m/e: 325 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 12.05 (IH, s); 7.36 (2H, d, J=10 Hz); 7.16 (2H, d, J=10 Hz); 6.94 (2H, d, J=10 HZ); 6.90 (2H, d, J=5 Hz); 5.48-5.58 (IH, m); 5.39-5.43 (IH, m); 4.98 (2H, s); 3.99-4.03 (IH, m); 3.76 (3H, s); 2.46-2.60 (2H, m); 1.64 (3H, d, J=5 HZ).
[0396] Compound 34.2. MS ESI m/e: 325 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 11.98 (IH, s); 7.38 (2H, d, J=10 Hz); 7.13 (2H, m); 6.95 (2H, m); 6.09 (2H, m); 5.63 (IH, m); 4.97 (2H, s); 4.92 (2H, d, J=10 Hz); 3.76 (3H, s); 3.03 (IH, m); 2.28-2.56 (4H, m). [0397] Compound 34.3. MS ESI m/e: 311 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 12.06 (IH, s); 7.37 (2H, d, J=10 Hz); 7.14 (2H, d, J=10 Hz); 6.92-6.95 (4H, m); 5.92 (IH, m); 5.00 (2H, m); 4.98 (2H, s); 3.76 (3H, s); 3.35 (IH, m); 2.54-2.64 (2H, m). [0398] Compound 34.4. MS ESI m/e: 325 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 12.03 (IH, s); 7.37 (2H, d, J=10 Hz); 7.09-7.19 (4H, m); 6.91-6.99 (4H, m); 4.97 (2H, s); 3.76 (3H, s); 3.63 (IH, m); 2.57-2.71 (2H, m); 2.09 (3H, s).
[0399] Compound 34.5. MS ESI m/e: 339 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 11.97 (IH, s); 7.36 (2H, d, J=10 Hz); 7.14 (2H, d, J=10 Hz); 6.94 (2H, d, J=10 Hz); 6.89 (2H, d, J=5 Hz); 5.24 (2H, d, J=10 Hz); 3.85-3.90 (IH, m); 3.76 (3H, s); 2.44-2.57 (2H, rn); 1.68 (3H, s); 1.63 (3H, d, J=10 Hz). ""[ ϋf '•=* pour.'a, .: ;; S ESI m/e: 339 (M-H). NMR (500MHz) (DMSO-d6) δ 11.97 (IH, s); 7.37 (2H, d, J=8.5 Hz); 7.10 (2H, d, m); 6.90-6.95 (4H, m); 5.23 (IH, d, J=6.5 Hz); 4.97 (2H, s); 4.29 (IH, m); 3.76 (3H, s); 2.47-2.75 (2H, m); 1.71 (3H, d, J=6 Hz); 1.56 (3H, s). [0401] Compound 34.7. MS ESI m/e: 367 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 12.18 (IH, s); 7.37 (2H, d, J=5 Hz); 7.32 (IH, m); 7.21 (2H, d, J=10 Hz); 6.92-6.95 (6H, m); 4.98 (2H, s); 4.58 (IH, m); 3.76 (3H, s); 3.01 (IH, m); 2.94 (IH, m). [0402] Compound 34.9. MS ESI m/e: 339 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 11.99 (IH, s); 7.37 (2H, m); 7.14 (2H, d, J=10 Hz); 7.04 (2H, d, J=10 Hz); 6.96 (IH, t, J=10 Hz); 6.88 (2H, d, J=10 Hz); 5.24 (2H, d, J=10 Hz); 5.00 (2H, s); 3.87 (IH, m); 3.87(3H, s); 2.45-2.55 (2H, m); 1.63 (3H, s). [0403] Compoxmd 34.10. MS ESI m/e: 323 (M-H). 1H NMR (500MHz) (DMSO- d6) δ 12.10 (IH, s); 7.25-7.32 (3H, m); 7.01 (2H, d, J=9 Hz); 6.94 (2H, d, J=10 Hz); 6.88 (IH, m); 5.05 (2H, s); 3.92-3.95 (IH, m); 3.75 (3H, s); 2.58 (2H, d, J=10 Hz); 1.77 (3H, s). [0404] Compound 34.11. MS ESI m/e:353.0 (M-H).
Figure imgf000085_0001
34.12 [0405] 1H NMR (400MHz) ((CD3)2SO) δ 11.95 (s, IH), 7.49 (d, 2H, J= 8.2 Hz), 7.15 (d, 2H, J= 8.6 Hz), 7.08-7.10 (m, 2H), 6.91-6.98 (m, 3H), 5.25 (d, IH, 9.0 Hz), 5.07 (s, 2H), 3.78-3.94 (m, 3H), 2.44-2.59 (m, 2H), 2.26 (s, 3H), 1.55-1.63 (m, 8H), 1.30-1.38 (m, 2H), 0.85 (t, 3H, J= 7.3 Hz). [M+l]+ Calculated for C3ιH36O4 : 473.3. Found 473.5. 6.35 Example 35 [0406] The following example illustrates the preparation 3-[4-(3-Methoxy- benzyloxy)-phenyl] -5-methyl-hex-4-enoic acid. Scheme 35.1
Figure imgf000086_0001
35.1 35.2
[0407] 2-[l-(4-Amino-phenyl)-but-2-ynyl]-malonic acid dimethyl ester (35.2).
Tin chloride dihydrate (46 mmol) was added to solution of compound 35.1 (15.3 mmol, prepared from commercially available dimethyl-4-nitrobenzylidinemalonate and 1- propynylmagnesium bromide according to the method in Example 33) in ethanol (200 ml). The mixture was stirred at 70 °C for 17 h. After removing solvent under reduced pressure, aqueous sodium carbonate solution was added and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with water and brine, dried over Na2SO , concentrated in vacuo. The resulting residue was filtered through short plug of silica gel, eluting with ethyl acetate. The eluant was concentrated to obtain compound 35.2 (12.8 mmol). Scheme 35.2
Figure imgf000086_0002
35.2 35.3
[0408] 2-(l-{4-[(Biphenyl-3-ylmethyl)-amino]-phenyl}-but-2-ynyl)-malonic acid dimethyl ester (35.3). A mixture of compound 35.2 (1.0 mmol), 3-(bromomethyl)biphenyl (1.3 mmol) and K2CO3 (2.0 mmol) in DMF (10 ml) was stirred at 90 °C for 19 h. After diluting with ethyl acetate, the mixture was washed with aqueous Na2CO3 and then with brine, dried over Na2SO4, and concentrated in vacuo. The resulting residue was purified using silica gel column chromatography (hexane/ethyl acetate = 2/1) to give compound 35.3. Scheme 35.3
Figure imgf000087_0001
35.3 35
[0409] 3-{4-[(Biphenyl-3-ylmethyI)-amino]-phenyI-hex-4-ynoic acid (35).
Compoxmd 35 was prepared from compound 35.3 by hydrolysis with base and decarboxylation as described in Example 33. MS ESI m/e: 368 (M-H). 1H NMR (500MHz) (DMSO- 6) δ 7.63-7.66 (2H, m); 7.51(1H, m); 7.34-7.44 (6H, m); 7.05 (2H, d, J=10 Hz); 6.60 (2H, d, J=10 Hz); 4.33 (2H, s); 3.79-3.83 (IH, m); 2.44-2.53 (2H, m); 2.09 (IH, s); 1.74 (3H, s). 6.36 Example 36 [0410] The following compounds were prepared according to the methods described in Example 35. TABLE 13
Figure imgf000087_0002
Figure imgf000087_0003
6.37 Example 37
[0411] This example illustrates the preparation of (+/-)-3-(4-[(4- methoxyphenyl)methoxy]- phenyl)-propanoic acid. Scheme 37.1
12.2 37
[0412] (+/-)-3-(4-[(4-methoxyphenyI)methoxy]phenyl)-propanoic acid (37). To a stirring ethyl acetate (lOOmL) solution of 5-[[4-[(4-methoxyphenyl)methoxy]phenyl]- methylene]-2,2-dimethyl-[l,3]dioxane-4,6-dione (200 mg, 0.543 mmol) was added EtOH (4 mL), followed by NaBH4 (62 mg, 1.63 mmol). The reaction mixture was stirred at room temperature for 15 minutes, quenched with water (5 mL), extracted with EtOAc (10 mL). The extract was washed with brine, dried over MgSO4, filtered, and concentrated to a white solid. A solution of this white solid in 3:1 pyridine-water (5 mL) was heated at 100 °C for 24h. The reaction mixture was cooled to room temperature and put in an ice-water bath. Concentrated HCl was carefully added to pH ~2. The resulting suspension was extracted with ethyl acetate (lOmL x 3), dried over MgSO4, filtered, and concentrated to an off-white solid. Preparative HPLC gave compound 37 as a white solid. MS ESI (neg.) m/e: 285.0 (M -1). 6.38 Example 38 [0413] This example illustrates the preparation of (+/-)-3-(4-[(4- methoxyphenyl)methoxy]- phenyl)-3-cyano-propanoic acid.
Figure imgf000088_0002
38 [0414] (+/-)-3-(4-[(4-methoxyphenyl)methoxy]phenyl)-3-cyano-propanoic acid
(38). To a stirred DMF (lOmL) solution of 2-[4-[(4-Methoxyphenyl)methoxy]phenyl]- acetonitrile (500 mg, 1.97 mmol) was added ethyl bromoacetate (330 μL, 2.96 mmol), followed by K2CO3 (820 mg, 5.9 mmol). The reaction mixture was stirred at room temperature for 2h, poured into ice water (100 mL), filtered, and dried to a white solid. 20 mg of this white solid in 1 :1 THF/1N NaOH in MeOH (4 mL) was stirred for 5h. The reaction mixture was concentrated, diluted with water (lOmL), washed with EtOAc (5mL x e
Figure imgf000089_0001
with 3N HCl to pH ~2, extracted with EtOAc (lOmL x 2), dried over MgSO4, filtered, and concentrated to a white solid. MS ESI (neg.) m/e: 310.0 (M -l). 6.39 Example 39 [0415] The following compounds were prepared by the methods described in Example 15 using the enantiomer with the shorter retention time from the chiral HPLC resolution.
Figure imgf000089_0002
Figure imgf000089_0003
[0416] (3S)-3-[4-(3-Methyl-benzyloxy)-phenyl]-hex-4-ynoic acid (39.1). MS-ESI (neg.) m/e: 307.1 (M-H). [α]20: +21.26 (c0.188, DMF). [0417] (3S)-3-[4-(3-Trifluoromethoxy-benzyloxy)-phenyl]-hex-4-ynoic cid (39.2). MS-ESI (neg.) m/e: 377.0 (M-H). [α]20: +18.30 (cθ.259, DMF). [0418] (3S)-3-[4-(3-chIorobenzyloxy)-phenyl]-hex-4-ynoic acid (39.3). MS-ESI (neg.) m/e: 327.1 (M-H). [α]20: +14.36 (c0.440, DMF). [0419] (3S)-3-[4-(2'-Cyano-biphenyI-4-ylmethoxy)-phenyl]-hex-4-ynoic acid (39.4). MS-ESI (neg.) m/e: 394.1 (M-H). [α]20: +16.07 (c0.331, DMF). [0420] (3S)-3-[4-(2-TirfluoromethyI-benzyloxy)-phenyl]-hex-4-ynoic acid (39.5). MS-ESI (neg.) m/e: 361.1 (M-H). [α]20: +12.80 (cθ.285, DMF). [0421] (3S)-3-[4-(4-Bromobenzyloxy)-phenyl]-hex-4-ynoic acid (39.6). MS-ESI (neg.) m/e: 371.0, 373.0 (M-H). [ ]20: +19.19 (cθ.238, DMF). [0422] (3S)-3-[4-(4-Methoxy-benzyloxy)-phenyl]-hex-4-ynoic acid (39.7). MS- ESI (neg.) m/e: 323.0 (M-H). [α]20: +23.30 (cθ.329, DMF). [0423] The following compounds were prepared by the methods described in Example 15 using the enantiomer with longer retention time from the chiral HPLC resolution. TABLE 15
Figure imgf000090_0001
Figure imgf000090_0002
[0424] (3R)-3-[4-(2-Methyl-benzyloxy)-phenyl]-hex-4-ynoic acid (40.1). 1HNMR (400 MHz, acetone-d6) δ 7.45 (d, IH, J=7.11 Hz); 7.37 (d, 2H, J=8.58 Hz); 7.26 (d, IH, J=1.62 Hz); 7.22-7.27 (m, 2H); 7.00 (d, 2H, J=8.76 Hz); 5.11 (s, 2H); 4.05 (m, IH); 3.33 (s, IH); 2.69 (m, 2H); 2.38 (s, 3H); 1.80 (d, 3H, J=2.44). MS-ESI (neg.) m/e: 307.1 (M-H). [α]20: -19.78 (cθ.286, DMF). [0425] (3R)-3-[4-(3-chlorobenzyloxy)-phenyl]-hex-4-ynoic acid (40.2). MS-ESI (neg.) m/e: 327.0 (M-H). [α]20: -20.50 (c0.158, DMF). [0426] (3R)-3-[4-(2'-Cyano-biphenyl~4-ylmethoxy)-phenyl]-hex-4-ynoic acid (40.3). MS-ESI (neg.) m/e: 394.1 (M-H). [α]20: -25.04 (c0.143, DMF). [0427] (3R)-3-[4-(2-Tirfluoromethyl-benzyloxy)-phenyl]-hex-4-ynoic acid (40.4). MS-ESI (neg.) m/e: 361.0 (M-H). [α]20: -14.69 (cθ.286, DMF). [0428] (3R)-3-[4-(4-Methoxy-benzyloxy)-phenyl]-hex-4-ynoic acid (40.5). MS- ESI (neg.) m/e: 323.0 (M-H). [α]20: -27.20 (cθ.324, DMF). 6.41 Example 41 [0429] The following compounds were prepared by the methods similar to those of Example 15.
Figure imgf000091_0001
41.1 41.2
[0430] (3S)-3-[4-(4-Methoxy-benzyloxy)-phenyl]-pent-4-ynoic acid (41.1). MS-
ESI (pos.) m/e: 333.1 (M+H). [α]20: +11.80 (cO.l 66, DMF).
[0431] (3R)-3-[4-(4-Methoxy-benzyloxy)-phenyl]-pent-4-ynoic acid (41.2). MS-
ESI (pos.) m/e: 333.1 (M+H). [α]20: -10.20 (c0.206, DMF). 6.42 Example 42 [0432] Scheme 42.1 presents a general procedure for preparation of diaryl ether compounds. Scheme 42.1
Figure imgf000091_0002
Scheme 42.1. a. ArB(OH)2, CuO(Ac)2, Et3N, DCM, 4A MS, r.t, 16h; b. LiOH/THF, MeOH, and water, r.t, 2h. 42.1 42.2 42.3
[0433] General procedure for preparation of diaryl ether compounds: A flask is charged with phenol (1.0 equiv.), Cu(OAc)2 (1.0 equiv.), arylboronic acid (1.0-3.0 equiv.), powdered 4 A molecular sieves. The reaction mixture was diluted with CH2CI2 to yield a solution approximately 0.1 M in phenol, and Et3N (5.0 equiv.) is added. After stirring the heterogeneous reaction mixture for 16h at 25 °C under ambient atmosphere, the resulting slurry is filtered and the diaryl ether is isolated from the organic filtrate by flash chromatography. The resulted ester was then hydrolyzed with LiOH (2.0 equiv.) in a 1 : 1 : 1 mixture of MeOH, THF, and water for 2h at 25 °C. The reaction mixture was acidified with IN HCl, extracted with CH2C12 and concentrated to give the pure acid.
Figure imgf000091_0003
42.4 " β434]" « ;:;:;!! !i"θ-|!4-( pii ϊ ifyloxy)-phenyl]-hex-4-ynoic acid (42.4). MS ESI m/e: 357.0 (M + H). 1H NMR (500 MHz) (CDC13) δ 7.60-7.57 (4H, m); 7.46 (2H, dd, J=8.0, 8.0 Hz); 7.39 (2H, d, J=8.5 Hz); 7.36 (IH, d, J=7.3 Hz); 7.09 (2H, d, J=8.6 Hz); 7.04 (2H, d, J=8.6 Hz); 4.2-4.1 (IH, m); 2.87 (IH, dd, J=15.8, 8.6 Hz); 2.77 (IH, dd, J=15.8, 6.7 Hz); 1.88 (3H, d, J=2.3 Hz).
Figure imgf000092_0001
42.5 [0435] 3-[4-(4-Phenoxy-phenoxy)-phenyI]-hex-4-ynoic acid (42.5). MS ESI m/e: 373.0 (M + H). 1H NMR (500 MHz) (CDC13) δ 7.37-7.32 (5H, m); 7.12 (2H, dd, J=8.0, 8.0 Hz); 7.03 (2H, d, J=7.5 Hz); 7.02 (2H, s); 6.97 (2H, d, J=8.6 Hz); 4.1 (IH, m); 2.85 (IH, dd, J=15.8, 8.6 Hz); 2.75 (IH, dd, J=15.8, 6.7 Hz); 1.87 (3H, d, J=2.3 Hz).
Figure imgf000092_0002
[0436] 3-[4-(4-Benzyloxy-phenoxy)-phenyl]-hex-4-ynoic acid (42.6). MS ESI m/e: 387.0 (M + H). lB NMR (500 MHz) (CDC13) δ 7.47 (2H, d, J=7.2 Hz); 7.42 (2H, dd, J=7.5, 7.5 Hz); 7.37 (IH, d, J=7.3 Hz); 7.33 (2H, d, J=8.7 Hz); 6.98 (4H, br. s); 6.93 (2H, d, J-9.7 Hz); 5.07 (2H, s); 4.10 (IH, m); 2.84 (IH, dd, J=15.7, 8.5 Hz); 2.75 (IH, dd, J=15.7, 6.7 Hz); 1.86 (3H, d, J=2.3 Hz).
Scheme 42.2
Figure imgf000093_0001
42.7 42.8 42.9
Figure imgf000093_0002
Scheme 42.2. a. TMSCHN2, MeOH, benzene, r.t, 1h; b. K2C03, DMF, r.t, overnight; c. LiOH/THF, MeOH, and water, r.t, 2h.
[0437] (S)-3-tert-ButoxycarbonyIamino-3-{4-[3-(4-fluoro-phenoxy)-benzyloxy]- phenyl}-propionic acid (42.11). 3-Boc-amino-3(4-hydroxyphenyl)-propanoic acid (42.7) (703 mg, 2.5 mmol) in 25mL of MeOH/Benzene (4:1) was slowly added 2.5 mL of 2M solution of trimethylsilyldiazomethane in hexane at 25 °C. The reaction mixture was stirred for lh and concentrated in vacuo to give the methyl ester. MS ESI m/e: 296.0 (M + H). To a solution of the methyl ester 42.8 (2.5 mmol) and 4-fluorophenoxybenzyl bromide 42.9 (700 mg, 2.5 mmol) in DMF (10 mL), was added K2CO3 (414 mg, 3 mmol) and the resulting mixture was stirred overnight (14~16h) at 25 °C. The solution was diluted with water (20mL0 and extracted with EtOAc twice (20 mL). The organic extraction was concentrated and the product was purified by flash chromatography. MS ESI m/e: 518.0 (M + Na). The methyl ester 42.10 (39mg, 0.08 mmol) was hydrolyzed with LiOH (10 mg, 0.25 mmol) in a 1.5 mL of 1 : 1 : 1 mixture of MeOH, THF, and water for 2h at 25 °C. The reaction mixture was acidified with IN HCl, extracted with CH2C12 and concentrated to give the pure acid (42.11). MS ESI m/e: 504.0 (M + Na). 1H NMR (400MHz) (CDC13) δ 8.5 (IH, br. s); 7.34 (IH, dd, J=8.0, 8.0 Hz); 7.24 (2H, d, J=8.8 Hz); 7.16 (IH, d, J=7.7 Hz); 7.07-6.98 (5H, m); 6.93 (2H, d, J=l 1.7 Hz); 6.92 (IH, d); 5.3 (IH, br. s); 5.03 (2H, s); 3.0- 2.8 (2H, m); 2.1-1.9 (IH, m); 1.44 (9H, s). Scheme 42.3
Figure imgf000094_0001
42.10 42.12
Figure imgf000094_0002
Scheme 42.3. a. TFA, DCM, r.t., lh; b. formaldehyde, NaBH(OAc)3, AcOH, DMF, r.t, overnight; c. LiOH/THF, MeOH, and water, r.t., 2h.
[0438] 3-Dimethylamino-3-{4-[3-(4-fluoro-phenoxy)-benzyloxy]-phenyl}- propionic acid (42.14). (S)-3-tert-Butoxycarbonylamino-3-{4-[3-(4-fluoro-phenoxy)- benzyloxy] -phenyl} -propionic acid methyl ester (42.10) (1.0 g, 2 mmol) was treated with 10 mL of 10% TFA solution in CH2C12 at 25 °C for lh. The solvent was concentrated in vacuo to give the free amine (42.12). MS ESI m/e: 418.0 (M + Na). The amine (60 mg, 0.15 mmol) was treated with excess formaldehyde (2 equiv.), NaBH(OAc)3 (85 mg, 0.4 mmol) and catalytic amoxmt of AcOH in DMF overnight (14-16h) at 25 °C. The product was purified by reverse phase HPLC. MS ESI m/e: 424.1 (M + H). The methyl ester was hydrolyzed with LiOH (19mg, 0.45 mmol) in a 3 mL of 1 : 1 : 1 mixture of MeOH, THF, and water for 2h at 25 °C. The reaction mixture was acidified with IN HCl, extracted with CH2C12 and concentrated to give the pure acid (42.14) (23 mg). MS ESI m/e: 410.2 (M + H). 1H NMR (500MHz) (CDC13) δ 9.46 (IH, br. s); 7.72 (IH, d, J=16.0 Hz); 7.51 (2H, d, J=8.7 Hz); 7.36 (IH, dd, J=8.0, 8.0 Hz); 7.17 (2H, d, J=7.0 Hz); 7.08-6.98 (5H, m); 6.94 (IH, d, J=8.2 Hz); 6.34 (IH, d, J=16.0 Hz); 5.10 (2H, s); 3.4-2.9 (2H, m); 2.73 (6H, s); 2.1-1.9 (lH, m).
Figure imgf000095_0001
Scheme 43.1
Figure imgf000095_0002
Scheme 43.1. a. HN03, HOAc, 80 °C, 3h; b. SnCI2, EtOAc/EtOH, 70 °C, 3h; c. 3- bromobenzaldehyde, DDQ, DMF, r.t, 2h; d. 4-trifluoromethylbezeneboronic acid, Pd(PPh3)4, DME, Na2C03, 80 °C, 14h; e. LiOH/THF, MeOH, and water, r.t., 2h.
[0439] 3-[2-(4'-Trifluoromethyl-biphenyl-3-yl)-benzooxazoI-5-yl]-hex-4-ynoic acid (43.3). 3-(4-Hydroxy-phenyl)-hex-4-ynoic acid methyl ester (1.32 g, 6 mmol) was treated with HNO3 (0.30 mL, 7.2 mmol) in AcOH (10 mL) at 80 °C for 3h. The solvent was concentrated in vacuo and 3-(3-nitro-4-hydroxy-phenyl)-hex-4-ynoic acid methyl ester (613 mg, 2.3 mmol) was isolated from flash chromatography. MS ESI m/e: 264.0 (M + H). The nitro group was then reduced with SnCl2 (2.62 g, 11.6 mmol) in EtOH (10 mLO and EtOAc (10 mL) at 70 °C for 3h. The reaction mixture was cooled to 25 °C, washed with saturated aqueous Na2CO3, water, brine, dried over MgSO , filtered and concentrated in vacuo. The crude product was then purified by reverse phase HPLC to give 3-(3-amino-4- hydroxy-phenyl)-hex-4-ynoic acid methyl ester (174 mg, 0.74 mmol). MS ESI m/e: 234.0 (M + H). 3-(3-amino-4-hydroxy-phenyl)-hex-4-ynoic acid methyl ester (174 mg, 0.74 mmol) and 3-bromobenzaldehyde (278 mg, 1.5 mmol) in DMF (3 mL) was treated with DDQ (204 mg, 0.9 mmol) for 2h at 25 °C. The producted was purified by reverse phase HPLC. MS ESI m/e: 398.0 (M + H). 3-[2-(3-Bromo-phenyl)-benzooxazol-5-yl]-hex-4- ynoic acid methyl ester (19.6 mg, 0.05 mmol) and trifluorophenylboronic acid (38 mg, 0.2 mmol) in DME (1 mL) and 0.2 mL of 2M solution of aqueous Na2CO3 was treated with Pd(PPh3)4 at 80 °C for 14h. The product was isolated from flash chromatography. MS ESI m/e: 464.0 (M + H). The methyl ester (7.8 mg, 0.017 mmol) was hydrolyzed with LiOH (4mg, 0.1 mmol) in a 1 mL of 1 : 1 : 1 mixture of MeOH, THF, and water for 2h at 25 °C. The reaction mixture was acidified with IN HCl, extracted with CH2C12 and concentrated to give the pure acid (7.6 mg). MS ESI m/e: 450.1 (M + H). 1H NMR (500 MHz) (CDC13) δ
Figure imgf000096_0001
); 7.91 (IH, s); 7.83 (2H, d, J=8.2 Hz); 7.82 (IH, s); 7.78 (2H, dd, J=8.0, 8.0 Hz); 7.67 (IH, dd, J=7.8, 7.8 Hz); 7.58 (2H, d, J=8.4 Hz); 7.46 (IH, dd, J=8.4, 1.5 Hz); 4.29 (IH, m); 2.94 (IH, dd, J=15.8, 8.1 Hz); 2.84 (IH, dd, J=15.8, 6.9 Hz); 1 .89 (3H, d, J=2.3 Hz). 6.44 Example 44 Scheme 44.1
Figure imgf000096_0002
Scheme 44.1. a. NaOH, EtOH, water, r.t, 3h (X = Br, Cl). 44.1 44.2 [O440] General procedure for the preparation of aryl benzyl ethers: 3-(4-Hydroxy- phenyl)-hex-4-ynoic acid in EtOH (0.4M) was added IN NaOH solution (3 equiv.) in water at 25 °C and stirred fro 5 minutes at 70 °C. ArCH2X (X = Br, Cl, 1 equiv.) in EtOH (0.2M) was slowly added, stirred for 3h at 70 °C. The reaction mixture was acidified with IN HCl and purified from reverse phase HPLC.
Figure imgf000096_0003
44.3 [0441] 3-[4-(4-Ethoxy-2-trifluoromethyl-qumolin-6-ylmethoxy)-phenyl]-hex-4- ynoic acid (44.3). MS ESI m/e: 458.0 (M + H). 1H NMR (400 MHz) (DMSO- 6) δ 12.6 (IH, br. s); 8.31 (IH, s); 8.12 (IH, d, J=8.7 Hz); 7.95 (IH, dd, J=8.7, 1.3 Hz); 7.41 (IH, s); 7.31 (2H, d, J=8.5 Hz); 7.03 (2H, d, J=8.5 Hz); 5.36 (2H, s); 4.47 (2H, q, J=8.0 Hz); 3.96 (IH, m); 2.62 (2H, d, J=7.6 Hz); 1.79 (3H, d, J=1.9 Hz); 1.21 (3H, t, J=8.0 Hz).
Figure imgf000097_0001
44.4 [0442] 3-(4-{3-[4-(3-Trifluoromethyl-pyridin-2-yl)-piperazine-l-carbonyl]- benzyloxy}-phenyl)-hex-4-ynoic acid. MS ESI m/e: 552.0 (M + H). 1H NMR (400 MHz) (DMSO-- 6) δ 12.5 (IH, br. s); 8.57 (IH, d, J=3.5 Hz); 8.12 (IH, dd, J=7.9, 1.6 Hz); 7.56- 7.48 (3H, m); 7.41 (IH, d, J=7.5 Hz); 7.30-7.25 (3H, m); 6.98 (2H, d, J=8.7 Hz); 5.16 (2H, s); 3.95 (IH, m); 3.2 (4H, m); 2.60 (2H, d, J=7.6 Hz); 2.52 (4H, m); 1.77 (3H, d, J=2.4 Hz).
Figure imgf000097_0002
44.5 [0443] 3-(4-{4-[2-(lH-Indol-3-yI)-ethylsulfamoyl]-benzyloxy}-phenyl)-hex-4- ynoic acid. MS ESI m/e: 517.2 (M + H). 1H NMR (400 MHz) (DMSO-d6) δ 12.5 (IH, br. s); 10.82 (IH, s); 7.83 (2H, d, J=8.3 Hz); 7.77 (IH, dd, J=7.8, 7.8 Hz); 7.39 (IH, d, J=8.0 Hz); 7.32 (IH, d, J=8.0 Hz); 7.29 (2H, d, J=8.7 Hz); 7.13 (IH, d, J=2.2 Hz); 7.06 (IH, dd, J=7.0, 8.0 Hz); 6.97 (2H, d, J=8.7 Hz); 5.19 (2H, s); 3.95 (IH, m); 3.02 (2H, t, J=7.6 Hz); 2.81 (2H, t, J=7.6 Hz); 2.61 (2H, d, J=8.0 Hz); 1.78 (3H, d, J=2.4 Hz). 6.45 Example 45 [0444] This example illustrates the preparation of (+/-)-3-[4-(2'-butoxy-5 '-methyl - biphenyl-4-ylmethoxy)-phenyl]-3-(4-fluorophenyl)-propionic acid (45). Scheme 45.1
Figure imgf000098_0001
45.1 45.2
Figure imgf000098_0002
45.3 45
[0445] Ethyl 3-(4-fluorophenyl)-3-(4-hydroxyphenyl)-acrylate (45.1). A solution of lithium hexamethyldisilazide (23.1 mL, IM in THF) was added to a stirred solution of ethyl (trimethylsilyl)acetate (2.53 mL, 13.9 mmol) in THF (15 mL) in 10 min. at -78 °C. The reaction mixture was further stirred at this temperature for 20 min. A solution of (4- fluorophenyl)-(4-hydroxyphenyl)-methanone (2 g, 9.2 mmol) in THF (30 mL) was slowly added to the reaction mixture. The reaction mixture was brought to 0 °C in 5 h. The reaction mixture was quenched with saturated ammonium chloride solution, extracted into ethyl acetate and washed with dilute ammonium chloride solution. The organic layer was dried over magnesium sulfate. The solvent was removed under vacuum and product was purified flash chromatography on silica gel, giving 45.1 as an oil (1.405 g). [0446] 3-(4-Fluorophenyl)-3-(4-hydroxyphenyι)-propionic acid ethyl ester
(45.2). A solution of 45.1 (385 mg) in ethanol (12 mL) and ethyl acetate (10 mL) was stirred with 10% Pd-C (50 mg) under a hydrogen atmosphere at room temperature for 3 h. The reaction mixture was filtered and concentrated to provide 45.2 (350 mg). [0447] 3-[4-(2'-Butoxy-5'-methyl-biphenyl-4-ylmethoxy)-phenyl]-3-(4- fluorophenyl)-propionic acid ethyl ester (45.3). A mixture of 45.2 (48 mg, 0.166 mmol), 4'-Bromomethyl-2-butoxy-5-methyl-biphenyl (67 mg, 0.2 mmol) and cesium carbonate (81 mg, 0.25 mmol) in DMF (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water, acidified with dilute HCl, extracted into ethyl acetate, washed with water and dried over magnesium sulfate. The residue obtained after concentration was flash chromatographed on silica gel to obtain 45.3 (71 mg). [0448] (+/-)-3-[4-(2,-Butoxy-5'-methyl-biphenyl-4-ylmethoxy)-phenyI]-3-(4- fluorophenyl)-propionic acid (45). A mixture of 45.3 (56 mg, 0.1 mmol) and 2N NaOH(aq) solution (0.31 mL, 0.62 mmol) in THF (3 mL) was stirred at room temperature overnight. "" reac' r ϊxfere as c ncentrated, treated with dilute HCl, and extracted into ethyl acetate. The organic layer washed with water and concentrated to yield product which was purified by flash chromatography to give compound 45 (40 mg). lB NMR (500 MHz, CDC13, ppm), δ 0.9 (t, 3H), 1.4 (m, 2H), 1.65 (m, 2H), 2.35 (s, 3H), 3.05 (m, 2H), 3.9 (t, 2H), 4.5 (t, IH), 5.05 (s, 2H), 6.8-7.5 (m, 15H). MS ESI (neg.) m/e: 511.0 (M-H). 6.46 Example 46 [0449] The following compounds were prepared according to methods analogous to those described in Example 45: 3-(4-fluorophenyl)-3-[4-(4'-trifluoromethyl-biphenyl-3- ylmethoxy)-phenyl] -propionic acid (46.1), 3-(4-fluorophenyl)-3-[4-(4-methyl-2-p-tolyl- thiazol-5-ylmethoxy)-phenyl] -propionic acid (46.2) and 3-(4-fluorophenyl)-3-{4-[2-(3- trifluoromethyl-phenoxy) -ethoxy] -phenyl} -propionic acid (46.3). [0450] Starting from (4-hydroxyphenyl)-phenyl-methanone, the following compounds were prepared according to methods analogous to those described in Example 45: 3-[4-(2-methyl-benzyloxy)-phenyl]-3-phenyl-propionic acid (46.4), 3-[4-(2'- butoxy-5'-methyl-biphenyl-4-ylmethoxy)-phenyl]-3-phenyl-propionic acid (46.5), 3-[4-(4- methyl-2-p-tolyl-thiazol-5-ylmethoxy)-phenyl]-3-phenyl-propionic acid (46.6), 3-phenyl-3- { 4- [2-(3-trifluoromethyl-phenoxy)-ethoxy] -phenyl} -propionic acid (46.7), 3-[4-(2'-cyano- biphenyl-4-ylmethoxy)-phenyl]-3-phenyl-propionic acid (46.8) and 3-phenyl-3-[4-(4'- trifluoromethyl-biphenyl-3-ylmethoxy)-phenyl]-propionic acid (46.9). [0451] Starting from (4-hydroxyphenyl)-pyridin-4-yl-methanone, the following compounds were prepared according to methods analogous to those described in Example 45 : 3-[4-(2'-butoxy-5'-methyl-biphenyl-4-ylmethoxy)-phenyl]-3-pyridin-4-yl- propionic acid (46.10) and 3-pyridin-4-yl-3-[4-(4'-trifluoromethyl-biphenyl-3-ylmethoxy)- phenyl] -propionic acid (46.11). 6.47 Example 47 [0452] This example illustrates the preparation of (+/-)-3-(4-[3-(4-chloro-2- methylphenyl) benzyloxy]phenyl)-3-(4-fluorophenyl)-propanoic acid (47). Scheme 47.1
Figure imgf000099_0001
45.2 47.1
Figure imgf000100_0001
47.2 47
[0453] Ethyl 3-(4-(3-iodobenzyIoxy)phenyl)-3-(4-fmorophenyl)propanoate
(47.1). Cs2CO3 (4.89g 15mmol) and l-(bromomethyl)-3-iodobenzene (4.45g, 15mmol) were added successively to a dry DMF (20 mL) solution of 45.2 (2.88g, lOmmol). The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate (200mL), washed with water (100 mL x 2) and brine (100 mL), and dried over Na2SO4. The solvent was removed under vacuum and the residue was purified by flash chromatography to give compound 47.1 as a colorless oil. MS ESI (pos.) m/e: 505.0 (M+H).
[0454] 3-(4-[3-(4-Chloro-2-methyIphenyl)benzyloxy]phenyl)-3-(4-fluorophenyl)- propanoate (47.2). CsF (96 mg, 0.6mmol), 4-chloro-2-methylphenylboronic acid (102 mg, 0.6 mmol) and Pd(PPh3)4 (70 mg, 0.06mmol) were added successively to a dry 1,2- dimethoxyethane (DME, 2 mL) solution of 47.1 (108 mg, 0.2 mmol) with stirring under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C overnight. The solvent was removed under nitrogen flow and the residue was dissolved in CH2C12 (2 mL) and purified by flash chromatography. Compoxmd 47.2 was obtained as a colorless oil. MS ESI (pos.) m/e 503.0 (M+l).
[0455] (+/-)-3-{4-[3-(4-Chloro-2-methylphenyl)phenyl]-methoxyl)phenyl}-3-(4- fluorophenyl)-propanoic acid (47). LiOH (48 mg, 2 mmol) was added to the THF-H2O (1/1, 4mL) solution of compound 47.2 (104 mg, 0.2 mmol ). The reaction mixture was stirred at room temperature overnight. IN HCl(aq) was added to acidify the mixture to pH 3 at 0 °C. The mixture was extracted with ethyl acetate (20 mL x 2), washed with water and brine, dried over Na2SO4, and purified by flash chromatography to obtain compound 47 (82 mg) as colorless oil. 1H NMR (400 MHz)(CDCl3) δ 2.22 (s, 3H), 3.05 (dd, J = 7.8, 1.1 Hz, 2H), 4.49 (t, J = 8.0 Hz, IH), 5.09 (s, 2H), 6.92-7.43 (m, 12H). MS ESI (neg.) m/e 473.0 (M-H). 6.48 Example 48 [0456] The following compounds were prepared according to the methods described in Example 47.
Figure imgf000101_0001
Figure imgf000101_0002
6.49 Example 49
[0457] This example illustrates the preparation of (+/-)-3-(4-(3-(4-
(trifluoromethyl)phenyl) benzyloxy)phenyl)-4-(diethylamino)-3-methyl-4-oxobutanoic acid. Scheme 49.1
Figure imgf000102_0001
49.1 [0458] N-Allyl-2-(4-hydroxyphenyl)propanamide (49.1). N,N'-
Carbonyldiimidazole (22.65g, 140mmol) was added to commercially available 2-(4- hydroxyphenyl)propionic acid (21g, 127mmol) in THF (lOOmL). Gentle warming and gas evolution was observed. The resulting mixture was stirred for 3 h. Allylamine (10.9 g, 190.5 mmol) and Et Ν (19.2 mL, 190.5 mmol) were added dropwise, and the mixture was stirred overnight. The reaction was quenched with water (200mL) and the organic phase was extracted with ethyl acetate (50 mLx3). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The product was purified by flash chromatography (elution with ethyl acetate). Phenol 49.1 was obtained as a white solid. MS ESI m/e: 206 (M-H). Scheme 49.2
Figure imgf000102_0002
49.2 49.1 49.3
[0459] 2-(4-(3-(4-(Trifluoromethyl)phenyl)benzyloxy)phenyl)-N- allylpropanamide (49.3). Cs2CO3 (23. lg, 71 mmol) was added to a mixture of compound 49.2 (20.33g, 64.5mmol) and phenol 49.1 (13.23g 64.5mmol) in DMF (50mL). The resulting mixture was stirred overnight. The reaction was quenched with water (500mL). The organic phase was extracted with ethyl acetate (75mLx3). The combined organic phases were dried over MgSO4 and the solvent was removed under reduced pressure. The resulting residue was purified via flash chromatography (10% Acetone in dichloromethane) to yield 15.9 g of 49.3. MS ESI m/e: 440 (M-H). Scheme 49.3
Figure imgf000103_0001
49.3 49.4
[0460] 2-(4-(3-(4-(Trifluoromethyl)phenyI)beαzyloxy)phenyl)-2-methylpent-4- enenitrile (49.4). The 3-aza-claisen reaction was carried out according to the method of Walters et al. (1991) Tetrahedron Lett. 2: 179-182. Amide 49.3 (15.9g, 36.2mmol) and PPh3 (21g, 80mmol) were dissolved in anhydrous dichloromethane (160 mL). Et3N (12g, 119.5mmol) and CC14 (18.4g, 119.5mmol) were added dropwise. The resulting mixture was stirred at room temperature overnight. The reaction was quenched with saturated brine (250 mL). The organic phase was extracted with ethyl acetate (50mLx3). The combined organic phases were dried over MgSO and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (25% ethyl acetate in hexanes) to yield 12.3 g of 49.4. 1H NMR (400MHz) (CDC13) δ 7.73 (4H, s); 7.70 (IH, s); 7.61-7.51 (3H, m); 7.41 (2H, d, J=8.9Hz); 7.05 (2H, d, J=8.9Hz); 5.76-5.72 (IH, m); 5.21-5.17 (4H, m); 2.71-2.59 (2H, m); 1.72 (3H, s). Scheme 49.4
Figure imgf000103_0002
49.4 49.5
[0461] 2-(4-(3-(4-(Trifluoromethyl)phenyl)ber-.zyIoxy)phenyl)-2-methylpent-4- enoic acid (49.5). 49.4 was added to a mixture of ethylene glycol (8 mL), H2O (0.25 mL) and KOH (750 mg). The resulting mixture was heated to 190°C for 6 h. The reaction mixture was cooled to room temperature. The aqueous phase was extracted with ethyl acetate (10 mLx3). The extracts were combined, dried over MgSO and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (10% acetone in dichloromethane) to yield 632 mg of 49.5. MS ESI m/e: 441 (M-H). ™ ,' i . Scheme 49.5
Figure imgf000104_0001
49.5 49.6 [0462] 2-(4-(3-(4-(Trifluoromethyl)phenyϊ)benzyloxy)phenyl)-N,N-diethyl-2- methylpent-4-enamide (49.6). Oxalyl chloride (57.7mg, 0.45mmol) was added dropwise to 49.5 (100 mg, 0.23 mmol) in anhydrous dichloromethane (4 mL). The resulting mixture was refluxed in a sealed tube at 50 °C overnight. The dichloromethane was removed under a stream of N2. Anhydrous ether (2 mL) was added dropwise, followed by diethyl amine (50 mg, 0.69 mmol) and Et3N (70 mg, 0.69 mmol). The mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified via flash chromatography (25% ethyl acetate in he anes). 82 mg of 49.6 was obtained. MS ESI m/e: 496 (M-H). 1H NMR (500MHz) (CDC13) δ 7.72 (4H, s); 7.69 (IH, s); 7.6-7.5 (3H, m); 7.14 (2H, d, J=8.5Hz); 7.05 (2H, d, J=8.5Hz); 5.7-5.6 (IH, m); 5.15 (2H, s); 5.03-5 (2H, m); 3.5-3.2 (2H, m); 3.0-2.9 (2H, m); 2.74-2.64 (2H, m); 1.62 (3H, s); 1.13 (3H, s); 0.72 (3H, s). Scheme 49.6
Figure imgf000104_0002
49.6 49 [0463] (+/-)-3-(4-(3-(4-(Trifluoromethyl)phenyl)benzyloxy) phenyl)-4- (diethylamino)-3-methyl-4-oxobutanoic acid (49). The oxidation reaction was carried out according to the method of Henry et al. (1993) J. Org. Chem. 58: 4745. A catalytic amoxmt of OsO was added to a solution of 49.6 (50 mg, 0.1 mmol) in acetone (4 mL), followed by an excess of Jones reagent (0.25 mL). The reaction mixture was stirred at room temperature overnight. The reaction was quenched with water (2 mL), and the aqueous phase was extracted with dichloromethane (2 mLx3). The combined organic extracts were dried over MgSO4 and removed under reduced pressure. The resulting residue was purified on reversed phase HPLC. MS ESI m/e: 514 (M-H). [0464] This example illustrates the preparation of 3-{4-[4'-(l , 1 -difluoro-ethyl)- biphenyl-3 -ylmethoxy] -phenyl } -N,N-dimethyl-succinamic acid. Scheme 50.1
Figure imgf000105_0001
49.2 50.1
[0465] [4-(4'-Trifluoromethyl-biphenyl-3-ylmethoxy)-phenyl] -acetic acid methyl ester (50.1). Compoxmd 49.2 (15.8 g, 50.1 mmol) was added to methyl 4-hydroxyphenylacetate (8.3 g 50 mmol) in DMF (30 mL), followed by Cs2CO3 (17.9 g, 55 mmol). The resulting mixture was stirred overnight. The reaction was quenched with water (300 mL). The organic phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was rinsed with saturated brine, dried over MgSO4, and concentrated under reduced pressure. The product (16.3 g) was used in the next step without further purification. MS ESI (pos.) m/e: 423 (M+Νa). Scheme 50.2
Figure imgf000105_0002
50.1 50.2
[0466] 2-{4-[4'-Trifluoromethyl-biphenyl-3-ylmethoxy]-phenyl}-succinic acid 4- fert-butyl ester 1-methyl ester (50.2). Compound 50.1 (4 g, lOmmol) in THF (12 mL) was added dropwise to LDA in THF (IM, 12 mL) at -78°C. The resulting mixture was stirred for 30 min. before tert-butyl bromoacetate (2.15 g, 11 mmol) in THF (2 mL) was added over 10 min. The reaction mixture was stirred for 2 h at -78 °C and allowed to warm slowly to 0 °C. The reaction was quenched with saturated aqueous ΝH4C1 (20 mL). The organic phase was extracted with ethyl acetate (25 mLx3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (50% ethyl acetate in hexanes) to yield 3.3 g of 50.2. MS ESI (pos.) m/e: 537 (M+Na). 1H NMR (400MHz) (CDC13) δ 7.72 (4H, s);
Figure imgf000106_0001
(2K, m); 6.98-6.97 (2H, m); 5.14 (2H, s); 4.04- 4.0 (IH, m); 3.7 (3H, s); 3.1 (IH, m); 2.63 (IK, m); 1.42 (9H, s). Scheme 50.3
Figure imgf000106_0002
50.2 50.3 [0467] 2-{4-[4'-Trifluoromethyl-biphenyl-3-ylmethoxy]-phenyl}-succinic acid 4- tert-butyl ester (50.3). Lithium hydroxide (121mg, 5mmol) was added to a solution of 50.2 in MeOH/THF/H2O (1:1:1, 90mL). The resxxlting mixtxxre was stirred at room temperature overnight. The organic solvent was removed- under reduced pressure. The reaction mixture was extracted with dichloromethane (10 mLx3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (50% ethyl acetate in hexanes) to yield acid 50.3 (860 mg). MS ESI (pos.) m/e: 523 (M+Na). lH NMR (4001MHz) (CDC13) δ 7.72 (4H, s); 7.67 (IH, s); 7.59-7.47 (3H, m); 7.29-7.25 (2H, m); 6.98-6.97 (2H, m); 5.14 (2H, s); 4.04-4.0 (IH. m); 3.1-3.053 (IH, m); 2.64-2.60 (IH, m); 1.4 (9H, s). Scheaaie 50.4
Figure imgf000106_0003
50.3 50.4 [0468] 3-{4-[4,-Trifluoromethyl-biphenyl-3-ylmethoxy]-phenyl}-N^V-diraLethyl- succinamic acid tert-butyl ester (50.4). A solution of compound 50.3 (50mg, O.lmmol) in dichloromethane (2mL) was treated with 1 -hydroxybenzotriazole (15 mg, 0.1 lmmol) and EDC (21 mg, 0.1 lmmol) sequentially. The resulting mixture was stirred for 1 h. before dimethylamine (9 mg, 0.2mmol) was added dropwise. The reaction was quenched 30 min. later with water (5 mL). The reaction mixture was extracted with dichloromethane (2 mLx3). The organic extracts were combined, dried over MgSO4 and concentrated under
Figure imgf000107_0001
(48 mg). The product was used in the next step without further purification. MS ESI (pos.) m/e: 527 (M+). Scheme 50.5
Figure imgf000107_0002
50.4 50 [0469] (+/-)-3-{4-[4'-Trifluoromethyl-biphenyl-3-ylmethoxy]-phenyl}-N^V- dimethyl-succinamic acid (50). Ester 50.4 (48mg, 0.09mmol) was dissolved in dichloromethane/TFA solution (3:1, 2 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent removed under reduced pressure, and the product was purified on reserve phase HPLC to yield acid 50 (30mg). MS ESI (pos.) m/e: 472 (M+H). 1H NMR (400MHz) (CDC13) δ 7.72 (4H, s); 7.67 (IH, s); 7.59-7.28 (3H, m); 7.2 (2H, d, J=8.6Hz); 7.0 (2H, d, J=8.6Hz); 5.13 (2H, s); 4.24-4.21 (IH, m); 3.20-3.13 (IH, m); 3.0 (3H, s); 2.95 (3H, s); 2.76-2.71 (IH, m). 6.51 Example 51 [0470] This example illustrates the preparation of 3-(4-methyl-thiazol-2-yl)-3-[4-(4'- trifluoromethyl-biphenyl-3 -ylmethoxy)-phenyl] -propionic acid. Scheme 51.1
Figure imgf000107_0003
50.3 51.1 [0471] 3-[4-(4'-Trifiuoromethyl-biphenyl-3-ylmethoxy)-phenyl]-succinamic acid tert-butyl ester (51.1). 1-hydroxybenzotriazole (225 mg, 1.65 mmol) and EDC (315 mg, 1.65 mmol) were added sequentially to compound 50.3 (750 mg, 1.5 mmol) in dichloromethane (25 mL). The resulting mixture was stirred for 1 h before ammonium hydroxide (25% in water, 630 mg, 4.5 mmol) was added dropwise. The reaction was quenched after 30 min. with water (10 mL). The reaction mixture was extracted with dichloromethane (10 mLx3). The organic extracts were combined, dried over MgSO4 and '"' COticefitra eH
Figure imgf000108_0001
The product was purified via flash chromatography (50% ethyl acetate in hexanes) to yield 51.1 (720 mg) as a white solid. MS ESI (pos.) m/e: 500 (M+H). 1H NMR (400MHz) (CDC13) δ 7.72 (4H, s); 7.68 (IH, s); 7.57-7.48 (3H, m); 7.29-7.25 (2H, m); 7.0-6.97 (2H, d, J=6,8Hz); 5.14 (2H, s); 3.91-3.88 (IH, m); 3.19-3.13 (IH, m); 2.60-2.55 (IH, m); 1.4 (9H, s). Scheme 51.2
Figure imgf000108_0002
51.1 51.2 [0472] 3-Thiocarbamoyl-3-[4-(4'-trifluoromethyl-biphenyl-3-ylmethoxy)- phenyl] -propionic acid tert-butyl ester (51.2). Lawesson's reagent (81 mg, 0.2 mmol) was added to a solution of compound 51.1 (50 mg, 0.1 mmol) in THF (2mL). The resulting mixture was stirred at room temperature for 6 h. The reaction was quenched with water (5 mL). The reaction mixture was extracted with dichloromethane (3 mLx3). The organic extracts were combined, dried over MgSO and concentrated under reduced pressure. The product was purified via flash chromatography (50% ethyl acetate in hexanes) to yield compound 51.2 (40 mg) as a clear film. MS ESI (pos.) m/e: 516 (M+H). 1H NMR (400MHz) (CDCI3) δ 7.72 (4H, s); 7.67 (IH, s); 7.51-7.48 (3H, m); 7.31-7.28 (2H, m); 7.0- 6.97 (2H, m); 5.14 (2H, s); 4.25-4.22 (IH, m); 3.51-3.46 (IH, m); 2.78-2.72 (IH, m); 1.38 (9H, s). Scheme 51.3
Figure imgf000108_0003
51.2 51.3 [0473] Ethyl 3-(4-Methyl-thiazoI-2-yl)-3-[4-(4'-trifluoromethyl-biphenyl-3- ylmethoxy)-phenyl]-propanoate (51.3). A solution of 51.2 (100 mg, 0.19 mmol) in EtOH (3 mL) was treated with chloroacetone (88mg, 0.95mmol). The resulting mixture was refluxed for 5 h. Aqueous HCl (6N, 25 μL) was added into above reaction mixture and the "re'fc iόn was at at'S C'w rnight. The solvent was removed under reduced pressure. The product was purified via flash chromatography (50% ethyl acetate in hexanes) to yield 51.3 (50mg). MS ESI (pos.) m/e: 526 (M+H). Scheme 51.4
Figure imgf000109_0001
51.3 51 [0474] (+/-)-3-(4-MethyI-thiazoI-2-yl)-3-[4-(4'-trifluoromethyl-biphenyl-3- ylmethoxy)-phenyl]-propionic acid (51). Compoxmd 51.3 (50 mg, 0.1 mmol) was dissolved in MeOH/THF/H2O (1:1:1, 3 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was acidified to PH=4 and extracted with dichloromethane (3 mLx3). The product was purified on reverse phase HPLC to yield compound 51 (40 mg). MS ESI (pos.) m/e: 498 (M+H). 1H NMR (400MHz) (DMSO) δ 7.92 (2H, d, J=8.1Hz); 7.84 (3H, d, J=8.8Hz); 7.71 (IH, t, J=5.1Hz); 7.54 (2H, d, J=7Hz); 7.29 (2H, d, J=8.7Hz); 7.09 (IH, s); 7.01 (2 H, d, J=8.7Hz); 5.18 (2H, s); 4.66 (IH, m); 3.2 (IH, m); 2.93 (IH, m); 2.33 (3H, s). 6.52 Example 52 [0475] This example illustrates the preparation of (+/-)-3-(4-((4-methyl-2-p- tolylthiazol-5-yl)methoxy)phenyl)-3-(thiophen-2-yl)propanoic acid. Scheme 52.1
Figure imgf000109_0002
1.1 52.1 [0476] 2,2-DimethyI-5-[4-(tetrahydro-pyran-2-yIoxy)-benzylidene]- [l,3]dioxane-4,6-dione (52.1). Protection of the phenol with dihydropyran was carried out based on the method given in Miyashita et al. (1977) J. Org. Chem. 42: 3772. Compound
Figure imgf000110_0001
dichloromethane (4 L). 3,4-Dihydro-2H-pyran (250 g, 3 mol) was added to the suspension followed by PPTS (5 g, 20 mmol). The reaction mixture heated to a gentle reflux (3.5 h). HPLC showed -90% completion of the reaction. The reaction was concentrated under reduced pressure to ~2L of volume. 1 L of acetone was added, and 2 L of solvent was removed under reduced pressure. 1 L of acetone was added, and 1 L of solvent was removed under reduced pressure. 0.5 L of acetone was added, and 0.5 L of solvent was removed under reduced pressure. The resulting slurry of very fine, light yellow crystals was filtered and rinsed sequentially with two 500 mL portions of acetone. The product was dried in a vacuum oven at 50 °C until no further solvent collected in the traps. Compound 52.1 (528 g) was obtained as fine, light yellow crystals. lB NMR(400MHz)(DMSO-< ) δ 8.29 (s, IH); 8.18 (d, 2H, J=8.9 Hz); 7.13 (d, 2H, J=8.9 Hz);. 5.67 (m, IH); 3.70 (m, IH); 3.60 (m, IH).1.9-1.5 (m, 12H). MS ESI (pos.) m/e: 355.1 (M + Na). Scheme 52.2
Figure imgf000110_0002
52.1 52.2 [0477] (+/-)-Methyl 3-(4-hydroxyphenyl)-3-(thiophen-2-yl)propanoate (52.2). A 500 mL flask was equipped with a magnetic stir bar, nitrogen inlet, nitrogen outlet and placed in a room temperature water bath. Compound 52.1 (5.00 g, 15.1 mmol) was added to the flask along with anhydrous THF (150 mL). After purging with nitrogen for 30 min, a solution of thiophene-2-yl-magnesium bromide in THF (1 M, 18.1 mL) was added by cannula. After the addition was complete, the reaction mixture was stirred for 1.5 h and quenched with aqueous NH4C1 (1 M, 100 mL) diluted with ethyl acetate (100 mL). The aqueous layer was acidified to pH ~2 with Cone. HCl and extracted with ethyl acetate (150 mL x 2). The extract was washed with brine and concentrated. The residue was dissolved in 100 mL of 10: 1 DMF-water heated to 100°C for 8 h. The reaction was cooled and the diluted with 500 mL water and extracted with ethyl acetate (150 mL x 3). The organic was dried with MgSO4, filtered, and concentrated on a rotary evaporator. The residue was dissolved in MeOH (200 mL) and 5 drops of cone. H2SO4 were added and the solution was refluxed for 24 h. The solution was concentrated to a residue on a rotary evaporator and purified using flash column chromatography with 30% ethyl acetate/hexanes as the eluant.
Figure imgf000111_0001
concentrated to afford 2.69 g (10.3 mmol) of 52.2 as a viscous oil. Scheme 52.3
Figure imgf000111_0002
52.2 52 [0478] (+/-)-3-(4-((4-MethyI-2-p-tolylthiazol-5-yl)methoxy)phenyl)-3-<thiophen- 2-yl)propanoic acid (52). Thiazole chloride 3.1 (108 mg, 0.457 mmol) and phenol 52.2 (100 mg, 0.381 mmol) were dissolved in DMF (1 mL) and treated with Cs2C03 ( 71 mg, 1.14 mmol). The reaction was stirred at 50°C for 16 h diluted with water (15 L) and methylene chloride (15 mL). The organic layer was washed with water, dried with MgSO , filtered, and concentrated. The residue was purified by column chromatography (silica gel, 33% to 66% ethyl acetate in hexanes). Eluant containing desired compound was- concentrated dissolved in a THF/MeOH/2N LiOH(aq) (1 :1:1) solution (2 mL). Ttie mixture was stirred at room temperature for 90 min., and the solution was poured into 0,65 N HCl (aq.) (2 mL). The aqueous phase was extracted with dichloromethane (3 x 10 mL^) and the combined organic phases were dried over Na2SO4. After filtration and drying, 1 :56 mg (0.323 mmol) of carboxylic acid 52 was obtained. 1H NMR (400MHz) (CDC13) S 7.77 (d, 2H, J= 8.1 Hz), 7.23-7.30 (m, 5H), 6.89-6.97 (m, 4H), 5.24 (s, 2H), 4.58 (t, IH, J= 7.8 Hz), 3.02 (m, IH), 2.92 (m, IH), 2.40 (s, 3H), 2.33 (s, 3H). 6.53 Example 53 [0479] This example illustrates the preparation of (+/-)-3-[4-(4'-trifluoror ιethyl- biphenyl-3-ylmethoxy)-phenyl]-3-(thiazol-2-yl)-propionic acid. Scheme 53.1
Figure imgf000111_0003
52.1 53.1 [0480] (+/-)-Methyl 3-(4-hydroxyphenyI)-3-(thiazol-2-yϊ)propanoate C53.1). A 500 mL flask was equipped with a magnetic stir bar, nitrogen inlet, nitrogen outlet and "pϊracάHn' ' ό'όrh"ϊfemperaϊxirc" a:.Br bath. Compound 52.1 (5.00 g, 15.1 mmol) was added to the flask along with anhydrous THF (150 mL). After purging with nitrogen for 30 min, a solution of thiozole-2-yl-magnesium bromide in THF (1 M, 18.1 mL) was added by cannula. After the addition was complete, the reaction mixture was stirred for 1.5 h, quenched with aqueous NH C1 (1 M, 100 mL) diluted with ethyl acetate (100 mL). The aqueous layer was acidified to pH ~2 with cone. HCl and extracted with ethyl acetate (150 mL x 2). The extract was washed with brine and concentrated. The residue was dissolved in 100 mL of 10:1 DMF-water and heated to 100 °C for 8 h. The reaction was cooled and the diluted with 500 mL water and extracted with ethyl acetate (150 mL x 3). The organic was dried with MgSO , filtered, and concentrated on a rotary evaporator. The residue was dissolved in MeOH (200 mL) and 5 drops of Cone. H2SO were added and the solution was refluxed for 24 h. The solution was concentrated to a residue on a rotary evaporator and purified using flash column chromatography with 50% ethyl acetate/hexanes as the eluant. The fractions were combined and concentrated to afford 1.90 g (7.25 mmol) of 53.1 as a viscous oil. Scheme 53.2
Figure imgf000112_0001
53.1 53 [0481] (+/-)-3-[4-(4"-Trifluoromethyl-biphenyl-3-ylmethoxy)-phenyl]-3-(thiazol- 2-yl)-propionic acid (53). Benzyl chloride 2.3 (123 mg, 0.456 mmol) and phenol 53.1 (100 mg, 0.380 mmol) were dissolved in acetone (1 mL) and treated with Cs2CO3 (371 mg, 1.14 mmol). The reaction was stined at 50 °C for 16 h, filtered and concentrated. The residue was purified by column chromatography (silica gel, 30% to 70% ethyl acetate in hexanes). Eluant containing desired compound was concentrated and dissolved in a THF/MeOH/2N LiOH(aq) (1:1 :1) solution (2 mL). The mixture was stirred at room temperature for 90 min., and the solution was poured into 0.65 N HCl (aq.) (2 mL). The aqueous phase was extracted with dichloromethane (3 x 10 mL) and the combined organic phases were dried over Na2SO4. After filtration and drying, 150 mg (0.311 mmol) of carboxylic acid 53 was obtained. 1H NMR (400MHz) (CDC13) δ 7.47-7.77 (m, 9H), 7.24-7.27 (m, 3H), 6.99-7.00 (m, 2H), 5.14 (s, 2H), 4.78 (dd, IH, J- 6.8, 4.4 Hz), 3.47 (dd, IH, J= 12.8, 6.8 Hz), 3.09 (dd, lH, J=12.8, 4.4 Hz). " •"" " ■' 6.54'""" "■Examp'lie"54'-i' [0482] This example illustrates the preparation of (+/-)-3-[4-(4'-Trifluoromethyl- biphenyl-3-ylmethoxy)-phenyl]-3-(3-methylthiophen-2-yl)-propionic acid. Scheme 54.1
Figure imgf000113_0001
52.1 54.1 [0483] (+/-)-Methyl 3-(4-hydroxyphenyl)-3-(3-methylthiophen-2-yl)propanoate (54.1). A 500 mL flask was equipped with a magnetic stir bar, nitrogen inlet, nitrogen outlet and placed in a room temperature water bath. Compound 52.1 (5.00 g, 15.1 mmol) was added to the flask along with anhydrous THF (150 mL). After purging with nitrogen for 30 min, a solution of 3-mefhylthiophen-2-yl-magnesium bromide in THF (1 M, 18.1 mL) was added by cannula. After the addition was complete, the reaction mixture was stirred for 1.5 h, quenched with aqueous NH4C1 (1 M, 100 mL) and diluted with ethyl acetate (100 mL). The aqueous layer was acidified to pH ~2 with Cone. HCl and extracted with ethyl acetate (150 mL x 2). The extract was washed with brine and concentrated. The residue was dissolved in 100 mL of 10:1 DMF-water and heated to 100 °C for 8 h. The reaction mixture was cooled, diluted with 500mL water, and extracted with ethyl acetate (150 mL x 3). The combined organic layers were dried with MgSO , filtered, and concentrated on a rotary evaporator. The residue was dissolved in MeOH (200 mL) and 5 drops of Cone. H2SO were added and the solution was refluxed for 24 h. The solution was concentrated to a residue on a rotary evaporator and purified using flash column chromatography with 30% ethyl acetate/hexanes as the eluant. The fractions were combined and concentrated to afford 2.33 g (7.25 mmol) of 54.1 as a viscous oil. Scheme 54.2
Figure imgf000113_0002
54.1 54 methylthiophen-2-yl)-propionic acid (54). Benzyl chloride 2.3 (113 mg, 0.434 mmol) and phenol 54.1 (100 mg, 0.362 mmol) were dissolved in acetone (1 mL) and treated with Cs2CO3 (371 mg, 1.14 mmol). The reaction was stirred at 50 °C for 16 h, filtered and concentrated. The residue was purified by column chromatography (silica gel, 30% to 60% ethyl acetate in hexanes). Eluant containing desired compound was concentrated and dissolved in a THF/MeOH/2N LiOH(aq) (1:1:1) solution (2 mL). The mixture was stirred at room temperature for 90 min., the solution was poured into 0.65 N HCl (aq.) (2 mL). The aqueous phase was extracted with dichloromethane (3 x 10 mL) and the combined organic phases were dried over Na2SO . After filtration and drying, 154 mg (0.311 mmol) of carboxylic acid 54 was obtained. 1H NMR (400MHz) (CDC13) δ 7.43-7.70 (m, 8H), 7.21 (d, 2H, J= 8.6 Hz), 7.05 (d, IH, J= 5.0 Hz), 6.92 (d, 2H, J= 8.6 Hz), 6.76 (d, IH, 5.0 Hz), 5.09 (s, 2H), 4.74 (t, IH, J= 7.8 Hz), 3.05 (d, 2H, J= 7.8 Hz), 2.15 (s, 3H).
6.55 Example 55 [0485] This example illustrates the preparation of methyl 3-(4-hydroxyphenyl)-3-
( 1 H-p yrrol- 1 -yl)propanoate . Scheme 55.1
Figure imgf000114_0001
55.1 [0486] 3-(4-Hydroxyphenyl)-3-(lH-pyrrol-l-yϊ)propanoic acid (55.1). At
100 °C, 2,5-dimethoxytetrahydrofuran (8.5 mmol) was added to a mixture of 3-amino-3-(4- hydroxyphenyl) propanoic acid (7.7 mmol) and sodium acetate (46 mmol) in acetic acid (34 mL). After stirring for 1 h, acetic acid was removed under reduced pressure. The residue was extracted with ethyl acetate (300 mL). The organic layer was washed with brine and dried over anhydrous Na2SO and concentrated. The residue was purified via column chromatography (10% methanol in dichloromethane) to compound 55.1. LC-MS (neg.) m/e: 230.2 (M-H). Scheme 55.2
Figure imgf000114_0002
55.1 55
Figure imgf000115_0001
Trimethysilyldiazomethane (8 mL, 2M in diethyl ether, 16 mmol) was added to a solution of compound 55.1 (7 mmol) in methanol (25 mL). After 10 min., the solvent was removed to yield methyl compound 55. MS ESI (pos.) m/e: 246.1 (M+H). 6.56 Example 56 [0488] The following compounds were prepared from compound 55 according to the methods described in Example 18. Table 17
Figure imgf000115_0002
Figure imgf000115_0003
[0489] Compound 56.1. MS ESI (neg.) m/e: 431 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 12.3 (IH, s); 7.81 (2H, d, J=8 Hz); 7.30 (4H, m); 6.99 (2H, d, J=9Hz); 6.92 (2H, m); 5.98 (2H, m); 5.56 (IH, t, J=8Hz), 5.29 (2H, s); 3.18 (2H, m); 2.44 (3H, s); 2.38 (3H, s). [0490] Compound 56.2. MS ESI (neg.) m/e: 464 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.92 (2H, m); 7.84 (3H, m); 7.72 (IH, d, J=8Hz); 7.53 (2H, m); 7.26 (2H, d, J=9Hz); 7.00 (2H, d, J=9Hz), 6.91 (2H, m); 5.55 (IH, d, J=8Hz); 5.19 (2H, s); 3.16 (2H, m). "'[ 49 ]'"
Figure imgf000116_0001
ESI (neg.) m/e: 396 (M-H). NMR (500MHz) (DMSO-d6) δ 12.37 (IH, s); 7.65-7.77 (4H, m); 7.41-7.51 (5H, m); 67.27 (2H, m); 7.01 (2H, d, J=5Hz)); 6.92 (2H, m); 5.99(2H, m), 5.56 (IH, m); 5.18 (2H, s), 3.21 (2H, m). [0492] Compound 56.4. MS ESI (neg.) m/e: 350 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 12.4 (IH, s); 7.30-7.34 (IH, t, J=8Hz); 7.26 (2H, d, J=9Hz); 7.01 (2H, m); 6.96 (2H, d, J=9Hz)); 6.90-6.92 (3H, m); 5.98 (2H, m), 5.55 (IH, t, J=8Hz); 5.07(2H, s); 3.78 (3H, s); 3.21(2H, m). [0493] Compound 56.5. MS ESI (neg.) m/e: 364 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.24-7.31 (3H, m); 6.99 (2H, m); 6.88 (3H, m); 5.97 (2H, s); 5.55 (IH, m); 5.06(2H, s), 4.04 (2H, q, J=7Hz); 3.16 (2H, m); 1.34 (3H, t, J=7Hz). [0494] Compound 56.6. MS ESI (neg.) m/e: 412 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.40-7.43 (3H, m); 7.16-7.26 (4H, m); 7.08 (IH, s); 7.03 (2H, d, J=8Hz)); 6.90-6.97 (5H, m); 5.98(2H, s), 5.54 (IH, t, J-8Hz); 5.09 (2H, s); 3.17 (2H, m) [0495] Compound 56.7. MS ESI (neg.) m/e: 396 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.70-7.71 (4H, m); 7.41-7.55 (4H, m); 7.39 (IH, m); 7.25 (2H, d, J=8Hz)); 6.98 (2H, d, J=9Hz); 6.89 (2H, s), 5.97 (2H, s); 5.55 (IH, t, J=8Hz); 5.12 (2H, s); 3.10 (2H, m). [0496] Compound 56.8. MS ESI (neg.) m/e: 421 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 8.19 (IH, s); 8.05 (IH, d, J=8Hz); 7.87 (IH, d, J=8Hz); 7.80 (2H, d, J=8Hz); 7.71 (IH, t, J=8Hz); 7.56 (2H, d, J=8Hz); 7.26 (2H, d, J=8Hz); 6.98 (2H, d, J=8Hz); 6.90 (2H, d, J=8Hz); 5.98 (2H, m); 5.55 (2H, t, J=8Hz)); 5.17 (2H, s); 3.13 (2H, m). [0497] Compound 56.9. MS ESI (neg.) m/e: 421 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.99 (IH, d, J=8Hz); 7.84 (IH, t, J=8Hz); 7.68 (IH, d, J=8Hz); 7.58-7.64 (5H, m); 7.17 (2H, d, J=8Hz); 6.96 (2H, d, J=8Hz); 6.81 (2H, m); 5.95 (2H, m); 5.55 (IH, t, J=7Hz); 5.18 (2H, s); 2.73 (2H, d, J=7Hz). 6.57 Example 57 [0498] The following compounds were prepared according to the methods described in Examples 55 and 56. Table 18
Figure imgf000117_0001
[0499] Compound 57.1. MS ESI (neg.) m/e: 431 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.81 (2H, m); 7.28-7.32 (4H, m); 7.00 (2H, d, J=8Hz); 6.92 (2H, s); 5.99 (2H, s); 5.57 (IH, m); 5.30 (2H, s); 3.23 (2H, m); 2.44(3H, s); 2.38 (3H, s). [0500] Compound 57.2. MS ESI (neg.) m/e: 464 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.93 (2H, d, J=8Hz); 7.83-7.86 (3H, m); 7.72 (IH, d, J=8Hz); 7.56 (2H, m); 7.27 (2H, d, J=9Hz); 7.01 (2H, d, J=9Hz); 6.91 (2H, m); 5.98 (2H, s); 5.55 (IH, d, J=8Hz); 3.14 (2H, m). [0501] Compound 57.3. MS ESI (neg.) m/e: 396 (M-H). 1H NMR (500MHz) (CDC13) δ 7.63-7.76 (4H, m); 7.39-7.59 (5H, m); 7.15 (2H, d, J=8Hz); 6.77 (2H, s); 6.19 (2H, s); 5.64 (IH, s); 5.13 (2H, s); 3.22-3.26 (2H, m). [0502] Compound 57.4. MS ESI (neg.) m/e: 350 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.33 (IH, t, J=8Hz); 7.25 (2H, d, J=8Hz); 7.01 (2H, m); 6.95 (2H, d, J=9Hz); 6.90 (3H, m); 5.98 (2H, s); 5.55 (IH, t, J=8Hz); 5.07 (2H, s); 3.78 (3H, s); 3.16 (2H, m). [0503] Compound 57.5. MS ESI (neg.) m/e: 412 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.40-7.43 (3H, m); 7.24-7.26 (3H, m); 7.20 (IH, m); 7.10 (IH, s); 7.03 (2H, d, J=9Hz); 6.90-6.93 (5H, m); 5.98 (2H, m); 5.55 (IH, m); 5.10 (2H, s); 3.18 (2H, m). [0504] Compound 57.6. MS ESI (neg.) m/e: 421 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.99 (IH, d, J=8Hz); 7.81(1H, m); 7.68 (IH, d, J=8Hz); 7.61-7.65 (5H, m); 6.92 (2H, m); 5.99 (2H, s); 5.56 (IH, t, J=8Hz); 5.20(2H, s); 3.19 (2H, m). s » 3.
[0505] This example illustrates the preparation of (+/-)-3-(-4-(Benzyloxy)phenyl)-3-
(lH-pyrazol-l-yl)propanoic acid (58.3). Scheme 58.1
Figure imgf000118_0001
58.1 [0506] l-(4-(Benzyloxy)benzyl)-lH-pyrazole (58.1). After a mixture of pyrazole
(7.73 mmol) and potassium hydroxide (7.73 mmol) in DMF (35 mL) was stirred at room temperature for 30 min., a solution of l-(benzyloxy)-4-(chloromethyl)benzene (6.44 mmol) in DMF (7 mL) was added dropwise. The reaction mixture was stirred at room temperature overnight and the product obtained from a standard aqueous work up. Column chromatography (1 :2 ethyl acetate / hexane) of the residue yielded compound 58.1 as a white solid. LC-MS ESI (pos.) m/e: 265 (M+Η); 1H MR (500MΗz) (DMSO-d6) δ 7.79 (IH, m); 7.46 (3H, m); 7.40 (2H, m); 7.36 (IH, m); 7.21 (2H, d, J=9Hz)); 5.27 (2H, s); 5.11 (2H, m). Scheme 58.2
Figure imgf000118_0002
58.1 58.2
[0507] l-(4-(Benzyloxy)phenyl)but-3-enyl)-lH-pyrazole (58.2). To a solution of compound 58.1 (3.41 mmol) in THF (30 mL) at -78 °C was added dropwise n-butyllithium in hexanes (3.75 mmol). The mixture was stirred for 10 min. followed by addition of allyl bromide (3.75 mmol). The reaction mixture was allowed to warm to room temperature overnight, quenched by addition of water. After extraction with ethyl acetate, the organic layer was washed with brine, dried over Na2SO4; and concentrated under reduced pressure. Column chromatography (1:3 ethyl acetate/hexane) of the residue yielded compound 58.2 as a white solid. LC-MS ESI (pos.) m/e: 305 (M+H). Scheme 58.3
Figure imgf000118_0003
58.2 58.3 " 5tf8J ^»f4- eii y phenyl)-3-(lH-pyrazol-l-yl)propanoic acid (58.3). A solution of KMnO4 (1.68 mmol) in water (19 mL) was added dropwise to a mixture of compound 58.2 (1.08 mmol), NaIO4 (2.2 mmol), acetone (6mL), and acetic acid (6mL). After stirring at room temperature for 1 h, ethylene glycol (2 mL) was added and stirred for additional 1 h. MnO2 was removed by filtration through silica gel (eluting with 1 :9 methanol: dichloromethane). After concentration under reduced pressure, the residue was purified by column cliromatography (1 :9 methanol: dichloromethane), yielding compound 58.3 (243 mg, 0.75 mmol). LC-MS ESI (pos.) m/e: 323 (M+H). Scheme 58.4
Figure imgf000119_0001
58.3 58.4 [0509] Methyl 3-(4-(benzyloxy)phenyl)-3-(lH-pyrazol-l-yl)propanoate (58.4). Compound 58.3 was esterifϊed similarly to the method discussed in connection with Scheme 55.2. Scheme 58.5
Figure imgf000119_0002
58.4 58 [0510] (+/-)-Methyl 3-(4-hydroxyphenyl)-3-(lH-pyrazo-l-l)propanoate (58). A mixture of compound 58.4 (0.37 mmol) and a small amount of Pd-C in methanol (8 mL) was stirred at room temperature under hydrogen atmosphere for 20 min. After filtration and concentration, the residue was purified by column chromatography. Compound 58 was obtained (81 mg, 0.33 mmol). LC-MS ESI (pos.) m/e: 247 (M+H). 6.59 Example 59 [0511] The following compounds were prepared from compound 58 according to the methods described in Example 18. TablejL9
Figure imgf000120_0001
Figure imgf000120_0002
[0512] Compound 59.1. MS ESI (neg.) m/e: 321 (M-H). 1H NMR (500MHz)
(DMSO-d6) δ 7.84 (IH, d, J=2Hz); 7.40-7.50 (5H, m); 7.35 (IH, m); 7.27(2H, d, J=9Hz); 6.97 (2H, d, J=9Hz); 6.24 (IH, s); 5.79 (IH, m); 5.06 (2H, s); 3.3(1H, m); 3.12 (IH, m). [0513] Compound 59.2. MS ESI (neg.) m/e: 397 (M-H). 1H NMR (500MHz)
(DMSO-d6) δ 7.85 (IH, s); 7.64-7.77 (4H, m); 7.41-7.50 (6H, m); 7.29(2H, d, J=8Hz); 7.01 (2H, d, J=9Hz); 6.24 (IH, s); 5.80 (IH, m); 5.18 (2H, s); 3.3(1H, m); 3.12 (IH, m). [0514] Compound 59.3. MS ESI (neg.) m/e: 465 (M-H). 1H NMR (500MHz)
(DMSO-d6) δ 7.93 (2H, d, J=8Hz); 7.85 (4H, m); 7.73 (IH, d, J=7Hz); 7.54(2H, m); 7.29 (IH, s); 7.28 (2H, m); 7.00 (2H, m); 6.23(1H, s); 5.80 (IH, m); 5.20 (2H, s); 3.3(1H, m); 3.14 (lH, m). ," θ515 ' » «bipo ιιI' 9: l.:;:;MS ESI (neg.) m/e: 479 (M-H). NMR (500MHz) (DMSO-d6) δ 7.92 (2H, m); 7.82-7.86 (3H, m); 7.72 (IH, m); 7.52-7.56 (2H, m); 7.36 (IH, s); 7.20 (2H, d, J=9Hz); 6.99 (2H, d, J=9Hz); 6.02 (IH, m); 5.69 (IH, m); 5.14 (2H, s); 3.3 (IH, m); 2.98 (IH, m); 2.24 (3H, s). [0516] Compound 59.5. MS ESI (neg.) m/e: 411 (M-H). 1H NMR (500MHz) (DMSO-de) δ 7.63-7.73 (4H, m); 7.36-7.52 (6H, m); 7.20 (2H, d, J=8Hz); 6.99 (2H, d, J=8Hz); 6.01 (IH, s); 5.70 (IH, m); 5.17 (2H, s); 3.3 (IH, m); 2.99 (IH, m); 2.24 (3H, s). [0517] Compound 59.6. MS ESI (neg.) m/e: 479 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.93 (2H, m); 7.84 (3H, m); 7.71 (2H, m); 7.55 (2H, m); 7.26(2H, d, J=9Hz); 7.00 (2H, d, J=9Hz); 6.00 (IH, s); 5.69 (IH, m); 5.19 (2H, s); 3.3 (IH, m); 3.05 (lH, m); 2.15 (3H, s). [0518] Compound 59.7. MS ESI (neg.) m/e: 411 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.64-7.74 (5H, m); 7.39-7.52 (5H, m); 7.26 (2H, d, J=9Hz); 6.99 (2H, d, J=9Hz); 5.99 (IH, s); 5.68 (IH, m); 5.17 (2H, s); 3.3 (IH, m); 3.06 (IH, m); 2.15 (3H, s). 6.60 Example 60 [0519] This example illustrates the preparation of ethyl 3-(4-hydroxyphenyl)-3-(5- methyloxazol-2-yl)propanoate. Scheme 60.1
Figure imgf000121_0001
60.1 [0520] 2-(4-(Benzyloxy)phenyl)-N-(prop-2-ynyl)acetamide (60.1). A mixture of 4-(benzyloxy)phenylacetic acid (20.7 mmol), 1-hydroxybenzotrizole hydrate (37 mmol), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide (37 mmol), propargylamine (20.7mmol) and N-methylmorpholine (62 mmol) in DMF (60 mL) were stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (400 mL), washed with IN HCl, water, saturated Νa2CO3 solution, brine and dried over Na2SO . After removing solvent under reduced pressure, the residue was triturated with dichloromethane. Compound 60.1 was obtained as a white solid after filtration and drying. LC-MS ESI (pos.) m/e: 280 (M+H). Scheme 60.2
60.1 60.2
[0521] 2-(4-Benzyloxy)benzyl)-5-methyl oxazole (60.2). A mixture of compound
60.1 (10.1 mmol), AuCl (1 mmol) in dichloromethane (100 mL) was stirred at room temperature overnight. Additional dichloromethane (100 L) was added and the reaction mixture was washed with NaHCO3 solution and saturated brine. After drying over Na2SO4 and concentration under reduced pressure, the residue was purified by column chromatography (1:2 ethyl acetate-hexanes) to obtain compound 60.2. LC-MS ESI (pos.) m/e: 280 (M+H). Scheme 60.3
Figure imgf000122_0002
60.2 60.3
[0522] Ethyl 3-(4-(beαzyloxy)phenyl)-3-(5-methyloxazol-2-yl)propanoate (60.3).
Compoxmd 60.3 was obtained from compound 60.2 according to the method of Example 58. Scheme 60.4
Figure imgf000122_0003
60.3 60
[0523] (+/-)-Ethyl 3-(4-hydroxyphenyI)-3-(5-methyIoxazoI-2-yl)propanoate (60).
Compoxmd 60 was obtained from compound 60.3 according to the method of Example 58. 6.61 Example 61 [0524] The following compounds were prepared from compound 60 according to the methods described in Example 18. Table 20
Figure imgf000123_0001
[0525] Compound 61.1. MS ESI (neg.) m/e: 336 (M-H). 1H NMR (500MHz) (DMSO-de) δ 7.41-7.46 (4H, m); 7.36 (IH, m); 7.17 (2H, d, J=9Hz); 6.97 (2H, d, J=9Hz); 6.73 (IH, s); 5.09 (2H, s); 4.44 (IH, m); 3.08 (IH, m); 2.71 (IH, m); 2.22 (3H, s). [0526] Compound 61.2. MS ESI (neg.) m/e: 480 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.91-7.93 (2H, m); 7.82-7.85 (3H, m); 7.72 (2H, d, J=7Hz); 7.54 (2H, m); 7.18 (2H, d, J=8Hz); 6.99 (2H, d, J=8Hz); 6.72 (IH, s); 5.17 (2H, s); 4.44 (IH, m); 3.08 (IH, m); 2.74 (IH, m); 2.21 (3H, s). [0527] Compound 61.3. MS ESI (neg.) m/e: 447 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.80 (2H, d, J=8Hz); 7.30 (2H, d, J=8Hz); 7.19 (2H, d, J=8Hz); 7.00 (2H, d, J=8Hz); 6.73 (IH, s); 5.27 (2H, s); 4.44 (IH, m); 3.10 (IH, m); 2.73 (IH, ); 2.43 (3H, s); 2.34 (3H, s); 2.21 (3H, s). [0528] Compoxmd 61.4. MS ESI (neg.) m/e: 366 (M-H). 1H NMR (500MHz) (DMSO-d6) δ 7.32 (IH, t, J=8Hz); 7.16 (2H, d, J=8Hz); 7.00(2H, m); 6.96 (2H, m); 6.89 (IH, m); 6.72 (IH, s); 5.05 (2H, s); 4.42 (IH, m); 3.76 (3H, s); 3.06 (IH, m); 2.76 (IH, m); 2.21 (3H, s). [0529] Compound 61.5. MS ESI (pos.) m/e: 500 (M+H). 1H NMR (500MHz) (DMSO-de) δ 7.50 (2H, d, J=8Hz); 7.44 (2H, d, J=8Hz); 7.11-7.18 (4H, m); 6.97 (3H, m); 6.71 (IH, s); 5.10 (2H, s); 4.43 (IH, m); 3.93 (2H, t, J=7Hz); 3.06 (IH, m); 2.70 (IH, m); 2.20 (3H, s); 1.61 (2H, m);1.36 (2H, m); 0.86 (3H, t, J=7Hz).
Figure imgf000124_0001
[0530] This example illustrates the preparation 3-(4-(3-(4-(trifluoromethyl)phenyl) benzyloxy)phenyl)-3-(isoxazol-5-yl)propanoic acid (62). Scheme 62.1
Figure imgf000124_0002
[0531] 5-(4,4-Diethoxy-l-(4-(tetrahydro-2H-pyran-2-yloxy)phenyI)but-2-ynyl)-
2,2-dimethyl-l,3-dioxane-4,6-dione (62.1). Propiolaldehyde diethyl acetal (5 g, 39 mmol) in anhydrous THF (65 mL) was cooled to -5 °C and treated with ethylmagnesium bromide (39 mmol in 14 mL of anhydrous THF) dropwise over 10 min. After 45 min., the solution of Grignard reagent was added to compound 52.1 in anliydrous THF (50 mL). After stirring 1 h, the reaction was quenched with saturated NH Cl(aq) (20 mL) and diluted with hexanes (100 mL). After mixing vigorously, the layers were separated and the organic layer discarded. The aqueous layer was acidified and extracted twice with diethyl ether. The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was used immediately without further purification. MS ESI (pos.) m/e: 478.3 (M+NH4)+. Scheme 62.2
Figure imgf000124_0003
62.1 62.2
[0532] Ethyl 6,6-diethoxy-3-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)hex-4- ynoate (62.1). Ethanolysis and decarboxylation was carried out according to the method of Example 16. Ester 62.2 was obtained as a light yellow oil (8 g). Scheme 62.3
Figure imgf000125_0001
62.2 62.3
[0533] Ethyl 3-(4-hydroxyphenyl)-3-(isoxazol-5-yl)propanoate (62.3).
Compound 62.2 (1 g, 2.5 mmol) and hydroxylamine hydrochloride (0.43 g, 6.2 mmol) were dissolved in a mixture of ethanol (10 mL) and water (1 mL). After refluxing 2 h, the reaction mixture was diluted with 200 mL of water and extracted with diethyl ether (2 x 100 mL). The combined organic layers were washed with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 5% methanol in dichloromethane eluant). Compound 62.3 was obtained as a thick oil (0.38 g). lB NMR (500MHz) (CDC13) δ 8.14 (d, J=1.5 Hz, IH); 7.12 (d, J=8.5 Hz, 2H); 6.77 (d, J=8.5, 2H); 5.98 (d, J=1.0 Hz, IH); 5.30 (s, IH); 4.64 (t, J= 8.0 Hz, IH); 4.06 (m, 2H); 3.15 (dd, J=16, 7.5 Hz, IH); 2.95 (dd, J=16, 8.0 Hz, IH); 1.17 (t, = 7.2 Hz, 3H). Scheme 62.4
Figure imgf000125_0002
62.3 62.4
[0534] Ethyl 3-(4-(3-(4-(trifluoromethyI)pheιιyl)benzyloxy)phenyι)-3-(isoxazol-
5-yl)propanoate (62.4). Compoxmd 62.3 was alkylated according to the procedure of Example 2. LC-MS ESI (pos.) m/e: 496.1 (M+H). 1H 4R (500MHz) (CDC13) δ 8.14 (s, IH); 7.70 (s, 4H); 7.66 (s, IH); 7.56 (d, J= 7.5 Hz, IH); 7.50-7.45 (m, 2H); 7.22 (d, J=8.5 Hz, 2H); 6.96 (d, J-8.5, 2H); 5.99 (s, IH); 5.12 (s, 2H); 4.67 (t, J= 7.7 Hz, IH); 4.08 (m, 2H); 3.16 (dd, J=16, 7.5 Hz, IH); 2.95 (dd, J=16, 8.0 Hz, IH); 1.17 (t, J= 7.2 Hz, 3H).
Figure imgf000126_0001
62.4 62
[0535] (+/-)-3-(4-(3-(4-(Trifluoromethyl)phenyl)benzyloxy)phenyl)-3-(isoxazol-
5-yl)propanoic acid (62). Compoxmd 62.4 was dissolved in glacial acetic acid (1 mL) and water (0.3 mL) and heated to 95 °C for 16 h. IN HCl (0.1 mL) was added and the reaction mixture was heated for another 16 h. The reaction mixture was poured into deionized water (50 mL) and extracted twice with diethyl ether. The combined organic layers were washed with saturated brine, dried over Na2SO , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 5% methanol in dichloromethane eluant). Compound 62 was obtained as a thick oil (26 mg). LC-MS ESI (pos.) m/e: 468.1 (M+H). lB NMR (500MHz) (CDC13) δ 8.14 (s, IH); 7.70 (s, 4H); 7.66 (s, IH); 7.56 (d, J= 7.5 Hz, IH); 7.50-7.45 (m, 2H); 7.22 (d, J=8.5 Hz, 2H); 6.96 (d, J=8.5, 2H); 5.99 (s, IH); 5.12 (s, 2H); 4.67 (t, J= 7.7 Hz, IH); 4.08 (m, 2H); 3.16 (dd, J=16, 7.5 Hz, IH); 2.95 (dd, J=16, 8.0 Hz, IH); 1.17 (t, J= 7.2 Hz, 3H). 6.63 Example 63 [0536] This example illustrates the preparation 3-[4-(2' -butoxy-5' -methyl -biphenyl-
4-ylmethoxy)-phenyl]-3-(l-methyl-lH-pyrazol-5-yl) propionic acid and 3-[4-(2'-butoxy-5'- methyl-biphenyl-4-ylmethoxy)-phenyl] -3 -( 1 -methyl- lH-pyrazol-3 -yl) propionic acid. Scheme 63.1
Figure imgf000126_0002
62.2 63.1 63.2
[0537] Ethyl 3-(4-hydroxyphenyl)-3-(l-methyl-lΗ-pyrazoI-5-yI)propanoate
(63.1) and ethyl 3-(4-hydroxyphenyl)-3-(l-methyl-lH-pyraz;ol-3-yι)propanoate (63.2). Compoxmd 62.2 was dissolved in abs. Ethanol (6 mL). A solution of methylhydrazine (173 mg, 3.7 mmol) in 6N HCl(aq) (0.6 mL) was added and the reaction mixture heated to reflux. After 2 h, the reaction mixture was diluted with 200 mL of water, neutralized with saturated aqueous NaHCO3, and extracted with diethyl ether (2 x 100 mL). The combined organic yef s S "e wϊs' eα'' ϊth"satxxrated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 5% methanol in dichloromethane). Compounds 63.1 and 63.2 were obtained as an inseparable mixture in a —4:5 ratio by 1H-NMR. LC-MS ESI (pos.) m/e: 275.2 (M+H). Scheme 63.2
Figure imgf000127_0001
63.3 63.4
[0538] Ethyl 3-[4-(2 '-Butoxy-5'-methyl-biphenyl-4-ylmethoxy)-ph enyl]-3-(l- methyl-lH-pyrazol-5-yl) propionic (63.3) and Ethyl 3-[4-(2'-butoxy-5'-methyl- biphenyl-4-ylmethoxy)-phenyl]-3-(l-methyI-lH-pyrazol-3-yl) propanoate (63.4). The mixture of 63.1 and 63.2 was alkylated with 4-(2-butoxy-5-methyl)phenyl)benzyl bromide according to the method of Example 2. Separation of 63.3 and 63.4 could be accomplished by flash chromatography (silica gel, 3% acetone in dichloromethane). Scheme 63.3
Figure imgf000127_0002
63.3 63.5
[0539] (+/-)-3-[4-(2' -Butoxy-5'-methyl-biphenyI-4-ylmethoxy)-phenyl]-3-(l- methyl-lH-pyrazol-5-yl) pjropionic acid (63.5). A 25 mL pear-shaped flask was charged with ethanol (1 mL), compound 63.3 (20 mg, 0.04 mmol), and 2N NaOH(aq) (2 mL, 4.0 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was acidified to a pH of 3 with 1UST HCl and extracted with ethyl acetate (2 x 10 mL). The "" 'c ϊm )irie&;re tt ι were-wSshed-' ith brine and concentrated. The resulting residue was purified via preparatory TLC (30% Acetone in dichloromethane) to yield compound 63.5 (4.0 mg). 1H NMR(400MHz)(CDCl3) δ 7.55 (d, 2H, J=2 Hz); 7.42 (d, 2H, J=2 Hz); 7.29 (m, IH); 7.19-7.08 (m, 4H); 6.95-6.86 (m, 3H); 5.98 (s, IH); 5.05 (s, 2H); 4.46 (m, IH); 3.94 (s, 3H); 3.31 (m, IH); 3.01 (m, IH); 2.33 (s, 3H); 1.67 (m, 3H); 1.40 (m, 3H); 0.90 (t, 3H, J=6 Hz). MS ESI (neg.) m/e: 497.2 (M - H). Scheme 63.4
Figure imgf000128_0001
63.4 63.6 [0540] (+/-)-3-[4-(2'-Butoxy-5'-methyl-biphenyl-4-ylmethoxy)-phenyl]-3-(l- methyl-lH-pyrazol-3-yl) propionic acid (63.6). Hydrolysis of 63.4 was carried out as described above. MS ESI (neg.) m/e: 497.2 (M - H). 6.64 Example 64 [0541] The following compounds were prepared from compounds 63.1 and 63.2 according to the methods described in Example 63.
Figure imgf000128_0002
64.1 [0542] (+/-)-3-(l-Methyl-lH-pyrazol-3-yl)-3-(4-((4-methyl-2-p-tolylthia-zol-5- yl)methoxy)phenyl) propanoic acid (64.1). 1H NMR (400MHz) (CDC13) δ 7.84 (m, 2H); 7.12 (m, 5H); 6.89 (m, 2H); 5.92 (s, IH); 5.13 (s, 2H); 4.46 (q, IH, J=6 Hz); 3.88 s, 3H); 3.23 (m, IH); 2.98 (m, IH); 2.50 (s, 3H); 2.39 (s, 3H). MS ESI (neg.) m/e: 446.2 (M - H).
Figure imgf000128_0003
64.2 yl)methoxy)phenyl) propanoic acid (64.2). MS ESI (neg.) m/e: 446.2 (M - H).
Figure imgf000129_0001
64.3 [0544] (+/-)-3-(l-Methyl-lH-pyrazol-3-yI)-3-[4-(4'-trifluoromethyl-biphenyl-3- ylmethoxy)-phenyl]-propionic acid (64.3). 1H NMR (400MHz) (CDC13) δ 7.69-7.46 (m, 8H); 7.26-6.92 (m, 5H); 5.96 (s, IH); 5.01 (s, 2H); 4.47 (m, IH); 3.91 (s, 3H); 3.25 (m, IH); 2.99 (m, IH). MS ESI (neg.) m/e: 479.2 (M - H).
Figure imgf000129_0002
64.4
[0545] (+/-)-3-(l-Methyl-lH-pyrazol-5-yl)-3-[4-(4'-trifluoromethyl-biphenyl-3- ylmethoxy)-phenyI]-propionic acid (64.4). 1H NMR (400MHz) (CHCl -rf3) δ 7.85-7.44 (m, 8H); 7.06 (d, 2H, J=6 Hz); 6.92 (s, IH); 5.10 (s, 2H); 4.46 (m, IH); 3.71 (s,
3H); 3.05 (m, IH); 2.96 (m, IH). MS ESI (neg.) m/e: 479.2 (M - H). 6.65 Example 65 Cell-based Aequorin Assay
[0546] A cell-based aequorin assay may be employed to characterize the modulatory activity of compounds on the GPR40 signaling pathway. In an exemplary assay, CHO cells are transfected in a 15 cm plated containing 14 million cells with 5 μg of GPR40 expression vector and 5 μg of Aequorin expression vector (Euroscreen) using Lipofectamine 2000
(Invitrogen). After 17-24 hours post-transfection, cells are washed with phosphate buffered saline (PBS) and detached from the tissue culture dish with 2 mL of trypsin (0.25%(w/v)).
Trypsinization is halted with 28 mL of Hanks Buffered Salt Solution containing 20 mM
Hepes (H/HBSS) and 0.01%) fatty acid-free bovine serum albumin (BSA) or 0.625% fatty acid-free human serum albumin (HSA). Coelantrazine is added to 1 ug/mL and the cells are incubated for 2 hours at room temperature. Cells are gently mixed every 15 minutes.
Compounds are dissolved in dimethyl sulfoxide for preparation of 10 mM stock solutions. p6ι s aii' containing either 0.01% BSA or 0.625% HSA. Serial dilutions of the test compounds are prepared to determine dose response. [0547] Aequorin luminescence measurements are made using an EG&G Berthold
96-well luminometer and the response is measured over a 20 second interval after cells and compounds were mixed. The area-under-curve from 2-20 seconds is plotted to determine dose reponse. The EC50 (effective concentration to reach 50% maximal response) is determined from the dose response plot.
[0548] Table 21 presents representative data (EC50 values) obtained for exemplary compounds of the invention for the relative activation of human GPR40. [0549] The stereoismers in Table 21 are as specified, i.e., S-enantiomers or
R-enantiomers, and if not specified, are mixtures of S-enantiomers and R-enantiomers. In addition, the present invention provides the S-enantiomers, the R-enantiomers, and mixtures of both S-enantiomers and R-enantiomers including racemates of each compound prepared according to the synthetic methods described herein or adapted with the necessary minor modifications from these methods. 6.66 Example 66: Insulin Secretion Assay [0550] C57/B16 mice are euthanized with carbon dioxide gas. The pancreatic bile duct is clamped proximal to the duodenum and then cannulated. H/HBSS containing 0.75 mg/ml collagenase XI (Sigma) is then infused into the pancreas through the cannula. The pancreas is excised and then incubated at 37°C for 13 minutes to complete enzymatic digestion. The collagenase digestion is quenched in H/HBSS containing 1% BSA and washed once in the same buffer. Islets can be purified using density gradient centrifugation using Histopaque (Sigma) and are hand-picked under a stereomicroscope. [0551] Islets are cultured overnight in Roswell Park Memorial Institute (RMPI) media containing 10% fetal bovine serum and 50 uM beta-mercaptoethanol. Following overnight culture, islets are incubated in Dulbecco's Modifcation of Eagle's medium (DMEM) containing 2.8 mM glucose for one hour.
[0552] For determination of insulin secretion, islets are incubated in DMEM containing 12.5 mM glucose and test compounds for one hour. Insulin released into the culture medium from the islets is measured using an insulin ELISA. [0553] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill r'ιn1;he*arM#l hFόf the ti'd'cmngs1 of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
.,,
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001

Claims

1. A compoimd having the formula (I): Q-L^P-L^M-X-L^A I or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein Q is hydrogen, aryl, heteroaryl, (Cι-C6)alkyl or (C2-C6)hetero -alkyl; L1 is a bond, (Cι-C4)alkylene5 (C2-C )heteroalkylene, O, S(O>m, NCR1), C(O)-(C5- C7)heterocycloalkylene, (Cι-C4)alkylene-SO2N(R2), (d-C4)alkylene-N(R2)SO2 or C(O)N(R2); P is an aromatic ring, a heteroaromatic ring, (C3-C8)heterocycToalkylene or (C3-C8)cycloalkylene; L2 is a bond, (Cι-C6)alkylene, (C2-C6)heteroalkylene, oxymetliylene, O, S(O)m, NCR1), C(O)N(R2), SO2N(R2), (Cι-C4)alkylene-C(O)N(R2), (Cι-C4)aLkylene-N(R2)C(O), (C2-C4)alkenylene-C(O)N(R2), (C2-C4)alkenylene-N(R2)C(O), (Cι-C-4)alkylene-SO2N(R2), (Cι-C4)alkylene-N(R2)SO2, (C2-C4)alkenylene-SO2N(R2) or (C2-C4)a-lkenylene- N(R2)SO2; M is an aromatic ring, a heteroaromatic ring, (C5-C8)cycloaUτylene, aryl(Cι-C4)alkylene or heteroaryl(C1-C4)alkylene; X is CR3R4, N(R5), O or S(O)„; L3 is a bond, (Cι-Cs)alkylene or (C2-C5)heteroalkylene, provided that L3 is not a bond when L2 is a bond; A is -CO2H, tetrazol-5-yl, -SO3H, -PO3H2, -SO2NH2, -C(O)NHS02CH3, -CHO, -C(O)R6, -C(O)NHR6, -C(O)NHOR7, thiazolidinedion-yl, hydroxyphenyl or pyridyl; R1 is (Cι-C6)alkyl, aryl(Cι-C3) alkyl or (C2-C6)heteroalkyl; R2 is hydrogen, (Cι-C6)alkyl or (C2-C6)heteroalkyl; R3 is cyano, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)alkyl, (C2-C8)alkenyl, (C3-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)alkynyl, -NR8R9, -C^NR10!?.11, -NR12C(O)R13 or
Figure imgf000156_0001
RR44 iiss hl ydrogen, cyano, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)alkenyl or (C2-C8)alkynyl; optionally, R3 and R4 are combined to form a 3-, 4-, 5-, 6- or '7-membered ring containing from zero to three heteroatoms selected from N, O and S; R5 is hydrogen, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)alkenyl-. (C2-C8)alkynyl or (C3-C8)cycloalkyl; R6 is heteroaryl; " '-" ct •' R'i' hyαrogen:Or,!(6ι-€'3)!alkyl; R8 and R9 are independently hydrogen, (Cι-C5)alkyl, oxy(Cι-C5)alkyl or carboxy(C i -C5)alkyl ; optionally, R8 and R are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S; R10, R1 and R12 are independently selected from hydrogen, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl and (C3-C8)heterocycloalkyl; optionally, R10 and R11 are combined to form a 4-, 5-, 6- or 7-membered ring containing the nitrogen atom to which they are attached and from 0 to 2 additional heteroatoms selected from N, O and S; R13 is aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)heteroalkyl, (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl; the subscripts m and n are independently 0, 1 or 2; and the subscript p is 1 or 2; and wherein the compound is other than 3-(4-(4-methoxybenzyloxy)phenyl)pent-4-ynoic acid; β-ethenyl-4-phenylmethoxy-benzenepropanoic acid; 4-(2-quinolinylmethoxy)-β- [4-(2- quinolinylmethoxy)phenyl] -benzenepropanoic acid; N- [4-(benzoylamino)phenyl] -N- phenyl-glycine; 3-(4-(isopentyloxy)benzamido)-3-phenylpropanoate; 3-(4-isobutoxybenzamido)-3-phenylpropanoate; (R)-2-((l R,4R)-4- isopropylcyclohexanecarboxamido)-3 -phenylpropanoic acid; (R)-3 -(4-(benzyloxy)phenyl)- 2-(tert-butoxycarbonyl)propanoic acid; 3 -(4-chlorophenyl)-3 -(furan-2- carboxamido)propanoic acid; 3-(3,4-dimethoxyphenyl)-3-(furan-2-carboxamido)propanoic acid; 3-(4-chlorobenzamido)-3-(4-(dimethylamino)phenyl)propanoic acid; 3-(2-(2-(3,4- dimethylphenoxy)ethylthio)-lH-benzo[d]imidazol-l-yl)propanoic acid; {2-Bromo-4-[(3,4- dichloro-phenyl)-hydrazonomethyl] -6-ethoxy-phenoxy } -acetic acid; 2-(4-(2-(2-(4- chlorophenyl)furan-5-carboxamido)ethyl)phenoxy)-2-methylpropanoic acid; 5-(3-(3,4- dimethoxyphenyl)-5-(2-fluorophenyl)-4,5-dihydropyrazol-l -yl)-5-oxopentanoic acid; 2-(2- (3-(3,4-dihydro-2Η-benzo[b][l,4]dioxepin-7-yl)-2-methyl-4-oxo-4H-chromen-7- yloxy)acetamido)acetic acid; 3-(4'-Bromo-biphenyl-4-yl)-4-phenyl-butyric acid; 3-(4'- Bromo-biphenyl-4-yl)-3-phenylsulfanyl-propionic acid; 3-(5-(2-chloro-6-fluoro-4- (trifluoromethyl)phenoxy)-2,4-dinitrophenyl)propanoic acid; 3-(3-(2-chloro-4- (trifluoromethyl)phenoxy)phenyl)propanoic acid; 3 -(4-(4-methoxybenzyloxy)phenyl)pent- 4-ynoic acid; 3-(4-(4-methoxybenzyloxy)phenyl)-5-(trimethylsilyl)pent-4-ynoic acid; β,β-dimethyl-4-[[[4-methyl-2-[4-(trifluoromethyl)phenyl]-5-thiazolyl]methyl]thio]- "' zeήepTd a c r '- hσ -[(4-bromo-255-dihydro-2-methyl-5-oxo- 1 -phenyl- 1 H- pyrazol-3-yl)methoxy]-3-methoxy-benzenepropanoic acid; or salt thereof.
2. The compound of Claim 1, wherein when P and M are benzene, at least two of L2, X and L are other than CH2
3. The compound of Claim 1, wherein when Q is aryl or heteroaryl, L1 is a bond, M is a monocyclic aromatic ring, X is N(R5), O or S(O)n, and A contains a carbonyl group, then P is not a 1,2-azole ring.
4. The compound of Claim 1, wherein when Q is aryl, L1 is a bond, M is an aromatic ring, X is CR3R4, O or S(O)n and A contains a carbonyl group, then P is other than furan or thiophene.
5. The compound of Claim 1, wherein P is selected from the group consisting of benzene, naphthalene, pyrrole, pyrazole, imidazole, pyrazine, oxazole, isoxazole, thiazole, furan, thiophene, pyridine, pyrimidine, pyridazine, benzothiazole, purine, benzimidazole, benzoxazole, triazole, oxadiazole, thiadiazole, benzooxadiazole, dibenzofuran, indole, indazole, carbazole, carboline, isoquinoline, quinoxaline and quinoline.
6. The compound of Claim 1, wherein P is selected from the group consisting of benzene, naphthalene, pyrrole, pyrazine, pyridine, pyrimidine, pyridazine, purine, indole, carboline, isoquinoline, quinoxaline and quinoline.
7. The compound of Claim 1.
8. The compound of Claim 1, wherein A is -CO2H, tetrazol-5-yl, -C(O)NHSO2CH3 or -C(O)NHR6.
9. The compound of Claim 1, wherein R3 is cyano, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or -NR8R9.
10. The compound of Claim 9, wherein R4 is hydrogen.
11. The compound of Claim 1 , wherein M is an aromatic ring, a heteroaromatic ring or (C5-C8)cycloalkylene. έ"'fe. "
Figure imgf000159_0001
1, wherein R3 is cyano, aryl, heteroaryl, (Cι-C8)al-- l, (C2-C8)alkenyl, (C2-C8)alkynyl or -NR8R9.
13. The compound of Claim 12, wherein A is -CO2H or tetrazol-5-yl.
14. The compoxmd of Claim 12, wherein A is -CO2H.
15. The compound of Claim 14, wherein X is CR3R4 or N(R5).
16. The compound of Claim 15, wherein L3 is (Cι-C5)alkylene or (C2-C5)heteroalkylene.
17. The compound of Claim 16, wherein P is an aromatic ring or a heteroaromatic ring.
18. The compound of Claim 1, wherein P is an aromatic ring or a heteroaromatic ring.
19. The compound of Claim 18, wherein X is CR3R4 or N(R5).
20. The compoxmd of Claim 19, wherein L3 is (Cι-C5)alkylene.
21. The compound of Claim 20, wherein A is -CO2H.
22. The compoxmd of Claim 21, wherein R3 is cyano, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or -NR8R9.
23. The compoxmd of Claim 22, wherein M is benzene or a heteroaromatic ring.
24. The compound of Claim 23, wherein R4 is hydrogen.
25. The compound of Claim 23, wherein L1 is a bond, O or N(R ) and L2 is (C2-C6)heteroalkylene .
1 26. The compound of Claim 24, wherein L is a bond and L is (C2-C6)heteroalkylene.
27. The compound of Claim 19, wherein M is benzene and X is para to L2.
28. The compound of Claim 27, wherein L is methylene. !i9. i / Mtø&M of β_M»28, wherein A is -CO2H.
30. The compoxmd of Claim 29, wherein R3 is cyano, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or -NR8R9.
31. The compoxmd of Claim 30, wherein L1 is a bond and L2 is oxymethylene or thiomethylene.
32. The compound of Claim 31 , wherein R is hydrogen.
33. The compound of Claim 1 , wherein Q is aryl.
1 9
34. The compound of Claim 1, wherein L is a bond and L is oxymethylene or thiomethylene.
35. The compound of Claim 1, wherein P is an aromatic ring or a heteroaromatic ring and A is -CO2H.
36. The compound of Claim 1, wherein P is an aromatic ring or a heteroaromatic ring and X is CR3R4 or N(R5).
37. The compound of Claim 1 , wherein A is -CO2H and X is CR3R4 or N(R5).
38. The compound of Claim 36, wherein X is CR3R4 and R3 is cyano, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or -NR8R9.
39. The compound of Claim 37, wherein X is CR R and R is cyano, aryl, heteroaryl, (Cι-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl or -NR8R9.
40. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient and the compound of Claim 1.
41. A method for treating a disease or condition selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, "''clfdfova xifar"&ϊs ase atϋbfσscl'έrosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema comprising administering to a subject in need thereof a therapeutically effective amount of the compound of Claim 1.
42. The method of claim 41 wherein said disease or condition is type II diabetes.
43. A method for treating a disease or condition responsive to the modulation of GPR40 comprising adminitering to a subject in need thereof a therapeutically effective amount of the compound of Claim 1.
44. The method of Claim 43 wherein said disease or condition is selected from the group consisting of type II diabetes, obesity, hyperglycemia, glucose intolerance, insulin resistance, hyperinsulinemia, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, dyslipidemia, metabolic syndrome, syndrome X, cardiovascular disease, atherosclerosis, kidney disease, ketoacidosis, thrombotic disorders, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, hypoglycemia, cancer and edema.
45. The method as in any one of Claims 41-44 wherein said compound is administered orally, parentally or topically.
46. The method of Claim 41 wherein said compound is administered in combination with a second therapeutic agent.
47. The method of Claim 46 wherein said second therapeutic agent is a metformin or a thiazolidinedione .
48. A method for modulating GPR40 function in a cell, comprising contacting a cell with the compound of Claim 1.
49. A method for modulating GPR40 function comprising contacting GPR40 with the compound of Claim 1.
50. A method for modulating circulating insulin concentration in a subject, comprising administering the compound of Claim 1 to the subject. 5ι"." •''T 'ffitϊθ '' ' here insulin concentration is increased.
52. The method of Claim 50 where insulin concentration is decreased.
PCT/US2005/005815 2004-02-27 2005-02-24 Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders Ceased WO2005086661A2 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
BRPI0508098-3A BRPI0508098A (en) 2004-02-27 2005-02-24 compounds, pharmaceutical compositions and methods for use in the treatment of metabolic disorders
EA200601388A EA011010B1 (en) 2004-02-27 2005-02-24 Compounds modulating of gpr40 receptor, pharmaceutical composition, method for treating diseases responsive to the modulation of gpr40 receptor (embodiments), method for modulating gpr40 function (embodiments) and method for modulating circulating insulin concentration
US10/591,214 US7816367B2 (en) 2004-02-27 2005-02-24 Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
AU2005220728A AU2005220728B2 (en) 2004-02-27 2005-02-24 Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
CA2558585A CA2558585C (en) 2004-02-27 2005-02-24 Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
ES05723623T ES2433466T3 (en) 2004-02-27 2005-02-24 Compounds, pharmaceutical compositions and methods for use in the treatment of metabolic disorders
JP2007500959A JP5299810B2 (en) 2004-02-27 2005-02-24 Compounds, pharmaceutical compositions and methods for use in the treatment of metabolic disorders
EP05723623.4A EP1737809B1 (en) 2004-02-27 2005-02-24 Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
IL177717A IL177717A0 (en) 2004-02-27 2006-08-27 Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
TNP2006000263A TNSN06263A1 (en) 2004-02-27 2006-08-28 Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
NO20064362A NO20064362L (en) 2004-02-27 2006-09-26 Compounds, pharmaceutical compositions and methods for use in the treatment of metabolic diseases
IS8542A IS8542A (en) 2004-02-27 2006-09-27 Substances, pharmaceutical compositions and use of substances for the manufacture of anti-metabolic drugs

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US54874104P 2004-02-27 2004-02-27
US60/548,741 2004-02-27
US60157904P 2004-08-12 2004-08-12
US60/601,579 2004-08-12

Publications (2)

Publication Number Publication Date
WO2005086661A2 true WO2005086661A2 (en) 2005-09-22
WO2005086661A3 WO2005086661A3 (en) 2006-05-04

Family

ID=34976072

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2005/005815 Ceased WO2005086661A2 (en) 2004-02-27 2005-02-24 Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders

Country Status (19)

Country Link
US (2) US7816367B2 (en)
EP (1) EP1737809B1 (en)
JP (1) JP5299810B2 (en)
KR (1) KR20070004769A (en)
CN (1) CN1946666A (en)
AR (1) AR048306A1 (en)
AU (1) AU2005220728B2 (en)
BR (1) BRPI0508098A (en)
CA (1) CA2558585C (en)
CR (1) CR8642A (en)
EA (1) EA011010B1 (en)
EC (1) ECSP066887A (en)
ES (1) ES2433466T3 (en)
IL (1) IL177717A0 (en)
IS (1) IS8542A (en)
MA (1) MA28466B1 (en)
NO (1) NO20064362L (en)
TW (1) TW200539854A (en)
WO (1) WO2005086661A2 (en)

Cited By (85)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006083477A2 (en) 2005-01-07 2006-08-10 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
WO2006097766A1 (en) * 2005-03-17 2006-09-21 Merck Sharp & Dohme Limited Arylsulfonyl benzyl ethers as 5-ht2a antagonists
WO2007056771A2 (en) 2005-11-09 2007-05-18 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
WO2006127503A3 (en) * 2005-05-20 2007-08-30 Amgen Inc Compounds, pharmaceutical compositions and methods for their use in treating metabolic disorders
WO2008030618A1 (en) 2006-09-07 2008-03-13 Amgen Inc. Benzo-fused compounds for use in treating metabolic disorders
WO2008030520A1 (en) * 2006-09-07 2008-03-13 Amgen Inc. Heterocyclic gpr40 modulators
WO2008066097A1 (en) 2006-12-01 2008-06-05 Astellas Pharma Inc. Carboxylic acid derivative
WO2008130514A1 (en) * 2007-04-16 2008-10-30 Amgen Inc. Substituted biphenyl phenoxy-, thiophenyl- and aminophenylpropanoic acid gpr40 modulators
WO2009055932A1 (en) * 2007-11-02 2009-05-07 Prometic Biosciences Inc. Substituted phenylpropionic acids as stimulators of hematopoiesis and erythropoiesis
WO2009111056A1 (en) * 2008-03-06 2009-09-11 Amgen Inc. Conformationally constrained carboxylic acid derivatives useful for treating metabolic disorders
WO2009157418A1 (en) 2008-06-25 2009-12-30 第一三共株式会社 Carboxylic acid compound
US7649110B2 (en) 2004-02-27 2010-01-19 Amgen Inc. Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
WO2010012650A1 (en) 2008-07-28 2010-02-04 Syddansk Universitet Compounds for the treatment of metabolic diseases
JP2010519306A (en) * 2007-02-22 2010-06-03 アイアールエム・リミテッド・ライアビリティ・カンパニー Compounds and methods for modulating G protein coupled receptors
EP1978948A4 (en) * 2006-02-02 2010-06-16 Wellstat Therapeutics Corp Compounds for the treatment of metabolic disorders
KR100968705B1 (en) * 2005-10-27 2010-07-06 주식회사유한양행 Novel 2-phenylpyrimidine derivatives and preparation methods thereof
EP2011788A4 (en) * 2006-04-24 2010-10-13 Astellas Pharma Inc Oxadiazolidinedione compound
WO2011046851A1 (en) 2009-10-15 2011-04-21 Eli Lilly And Company Spiropiperidine compounds and pharmaceutical use thereof for treating diabetes
WO2011052756A1 (en) 2009-10-30 2011-05-05 持田製薬株式会社 Novel 3-hydroxy-5-arylisoxazole derivative
WO2011051165A1 (en) 2009-10-28 2011-05-05 Bayer Schering Pharma Aktiengesellschaft Substituted 3-phenylpropionic acids and the use thereof
WO2011066183A1 (en) 2009-11-30 2011-06-03 Eli Lilly And Company Novel spiropiperidine compounds
WO2011069958A2 (en) 2009-12-07 2011-06-16 Nestec S.A. Low caloric fat replacers
WO2011078371A1 (en) 2009-12-25 2011-06-30 持田製薬株式会社 Novel 3-hydroxy-5-arylisothiazole derivative
US8008303B2 (en) 2005-09-16 2011-08-30 Astrazeneca Ab Biphenyl derivatives and their use in treating hepatitis C
US8030354B2 (en) 2007-10-10 2011-10-04 Amgen Inc. Substituted biphenyl GPR40 modulators
WO2011161030A1 (en) * 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
US20120004187A1 (en) * 2010-07-05 2012-01-05 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament
WO2012004269A1 (en) * 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
US8097610B2 (en) 2005-08-26 2012-01-17 Shionogi & Co., Ltd. Derivative having PPAR agonistic activity
WO2012010413A1 (en) * 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
WO2012046869A1 (en) 2010-10-08 2012-04-12 持田製薬株式会社 Cyclic amide derivative
WO2012139888A1 (en) 2011-04-13 2012-10-18 Bayer Intellectual Property Gmbh Branched 3-phenylpropionic acid derivatives and the use thereof
US8299296B2 (en) 2007-10-26 2012-10-30 Japan Tobacco Inc. Spiro compounds and pharmaceutical use thereof
US8299117B2 (en) 2010-06-16 2012-10-30 Metabolex Inc. GPR120 receptor agonists and uses thereof
WO2012147516A1 (en) 2011-04-28 2012-11-01 持田製薬株式会社 Cyclic amide derivative
WO2012147518A1 (en) 2011-04-27 2012-11-01 持田製薬株式会社 Novel 3-hydroxyisothiazole 1-oxide derivative
US8309600B2 (en) 2008-12-18 2012-11-13 Metabolex Inc. GPR120 receptor agonists and uses thereof
WO2013025424A1 (en) 2011-08-17 2013-02-21 Eli Lilly And Company A Novel 1,2,3,4-Tetrahydroquinoline Derivative Useful for the Treatment of Diabetes
WO2013102626A1 (en) * 2012-01-04 2013-07-11 Sanofi 3-[4-(phenylaminooxalylamino)phenyl]hex-4-ynoic acids, process for preparation thereof and use thereof as a medicament
WO2013128378A1 (en) 2012-02-28 2013-09-06 Piramal Enterprises Limited Phenyl alkanoic acid derivatives as gpr agonists
WO2014022528A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
EP2674417A3 (en) * 2007-11-21 2014-04-09 Decode Genetics EHF Biaryl PDE4 inhibitors for treating inflammation
WO2014073904A1 (en) 2012-11-09 2014-05-15 Lg Life Sciences Ltd. Gpr40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient
US8748462B2 (en) 2008-10-15 2014-06-10 Amgen Inc. Spirocyclic GPR40 modulators
WO2014130608A1 (en) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2014170842A2 (en) 2013-04-17 2014-10-23 Piramal Enterprises Limited Substituted alkyl carboxylic acid derivatives as gpr agonists
WO2014171762A1 (en) * 2013-04-18 2014-10-23 현대약품 주식회사 Novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative, method of preparing same and pharmaceutical composition for preventing and treating metabolic disease including same as effective ingredient
WO2015051725A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
WO2015088868A1 (en) 2013-12-13 2015-06-18 Eli Lilly And Company A novel triazolo-pyridine compound
WO2015095256A1 (en) 2013-12-19 2015-06-25 Merck Sharp & Dohme Corp. Antidiabetic substituted heteroaryl compounds
WO2015097713A1 (en) 2013-11-14 2015-07-02 Cadila Healthcare Limited Novel heterocyclic compounds
WO2015105779A1 (en) * 2014-01-10 2015-07-16 Eli Lilly And Company Isopropyl triazolo pyridine compounds
WO2015105786A1 (en) 2014-01-10 2015-07-16 Eli Lilly And Company Phenyl-triazolo-pyridine compounds
WO2015176640A1 (en) 2014-05-22 2015-11-26 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
WO2016022448A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2016022742A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2016022446A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. [5,6]-fused bicyclic antidiabetic compounds
WO2016019863A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. [7,6]-fused bicyclic antidiabetic compounds
WO2016057731A1 (en) 2014-10-08 2016-04-14 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as gpr40 agonists for the treatment of type ii diabetes
EP2963027A4 (en) * 2013-02-28 2016-07-20 Sk Chemicals Co Ltd TRICYCLIC COMPOUND AND USE THEREOF
US9499467B2 (en) 2011-04-08 2016-11-22 Caldan Therapeutics Limited Ortho-fluoro substituted compounds for the treatment of metabolic diseases
US20170296539A1 (en) * 2014-10-17 2017-10-19 Hyundai Pharm Co., Ltd. Composite preparation, containing novel 3-(4--(benzyloxy)phenyl)hex-4-inoic acid derivative and another active ingredient, for preventing or treating metabolic diseases
WO2017180571A1 (en) * 2016-04-11 2017-10-19 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as gpr40 agonists for the treatment of type ii diabetes
WO2017180457A1 (en) 2016-04-11 2017-10-19 Janssen Pharmaceutica Nv Gpr40 agonists in anti-diabetic drug combinations
WO2017190714A1 (en) 2016-05-04 2017-11-09 Universidad De La Habana Phenol compound and combination of same with a benzodiazepine fused to 1,4-dihydropyridine for treating diseases of the central nervous and vascular systems
US9856245B2 (en) 2015-08-12 2018-01-02 Janssen Pharmaceutica Nv GPR40 agonists for the treatment of type II diabetes
US9908873B2 (en) 2015-08-12 2018-03-06 Janssen Pharmaceutica Nv GPR40 agonists for the treatment of type II diabetes
US9920040B2 (en) 2015-08-12 2018-03-20 Janssen Pharmaceutica Nv GPR40 agonists for the treatment of type II diabetes
US9957219B2 (en) 2013-12-04 2018-05-01 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2018106518A1 (en) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
WO2018111012A1 (en) * 2016-12-15 2018-06-21 Il Dong Pharmaceutical Co., Ltd. Novel phenyl propionic acid derivatives and uses thereof
WO2018118670A1 (en) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
US10059667B2 (en) 2014-02-06 2018-08-28 Merck Sharp & Dohme Corp. Antidiabetic compounds
US10172814B2 (en) 2014-12-18 2019-01-08 Bayer Pharma Aktiengesellschaft Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
US10214521B2 (en) 2014-09-11 2019-02-26 Piramal Enterprises Limited Fused heterocyclic compounds as GPR120 agonists
US10227360B2 (en) 2014-02-19 2019-03-12 Piramal Enterprises Limited Compounds for use as GPR120 agonists
US10273230B2 (en) 2014-07-25 2019-04-30 Piramal Enterprises Limited Substituted phenyl alkanoic acid compounds as GPR120 agonists and uses thereof
WO2019134984A1 (en) 2018-01-08 2019-07-11 Celon Pharma S.A. 3-phenyl-4-hexynoic acid derivatives as gpr40 agonists
US10519115B2 (en) 2013-11-15 2019-12-31 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US10676458B2 (en) 2016-03-29 2020-06-09 Merch Sharp & Dohne Corp. Rahway Antidiabetic bicyclic compounds
WO2020169069A1 (en) 2019-02-21 2020-08-27 Nanjing Ruijie Pharma Co., Ltd. Novel compounds and their uses as thyroid hormone receptor agonists
US11225471B2 (en) 2017-11-16 2022-01-18 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2022269439A1 (en) * 2021-06-21 2022-12-29 Ildong Pharmaceutical Co., Ltd. Method of controlling blood sugar level and treatment of diabetes and related conditions
WO2023080741A1 (en) * 2021-11-08 2023-05-11 일동제약(주) Novel salt of phenyl propionic acid derivative, method for producing same, and pharmaceutical composition containing same
US12264171B2 (en) 2020-02-28 2025-04-01 Kallyope, Inc. GPR40 agonists

Families Citing this family (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0319069D0 (en) * 2003-08-14 2003-09-17 Glaxo Group Ltd Therapeutically useful compounds
US7262318B2 (en) * 2004-03-10 2007-08-28 Pfizer, Inc. Substituted heteroaryl- and phenylsulfamoyl compounds
JP4859665B2 (en) * 2004-03-30 2012-01-25 武田薬品工業株式会社 Alkoxyphenylpropanoic acid derivatives
US20050288340A1 (en) * 2004-06-29 2005-12-29 Pfizer Inc Substituted heteroaryl- and phenylsulfamoyl compounds
WO2007033002A1 (en) * 2005-09-14 2007-03-22 Amgen Inc. Conformationally constrained 3- (4-hydroxy-phenyl) - substituted-propanoic acids useful for treating metabolic disorders
CA2646430A1 (en) * 2006-03-14 2007-09-20 Amgen Inc. Bicyclic carboxylic acid derivatives useful for treating metabolic disorders
US7750048B2 (en) * 2006-11-15 2010-07-06 Janssen Pharmaceutica Nv GPR40 agonists
EP2272817A4 (en) * 2008-04-11 2011-12-14 Inst Med Molecular Design Inc INHIBITOR OF PAI-1
US8633245B2 (en) * 2008-04-11 2014-01-21 Institute Of Medicinal Molecular Design, Inc. PAI-1 inhibitor
NZ592603A (en) * 2008-10-21 2013-02-22 Metabolex Inc Aryl gpr120 receptor agonists and uses thereof
JP2012136438A (en) * 2009-04-22 2012-07-19 Astellas Pharma Inc Tetrazole compound
WO2012076466A2 (en) 2010-12-07 2012-06-14 Bayer Pharma Aktiengesellschaft Substituted 1-benzylcycloalkylcarboxlic acids and use thereof
GB201104153D0 (en) 2011-03-11 2011-04-27 Glaxo Group Ltd Novel compounds
WO2013057743A1 (en) * 2011-10-21 2013-04-25 Connexios Life Sciences Pvt. Ltd Process for the preparation of an aryl oxime and salts thereof
DE102012208530A1 (en) 2012-05-22 2013-11-28 Bayer Pharma AG Substituted piperidinoacetamides and their use
WO2014078610A1 (en) 2012-11-16 2014-05-22 Bristol-Myers Squibb Company Dihydropyrazole gpr40 modulators
WO2014086704A1 (en) 2012-12-03 2014-06-12 F. Hoffmann-La Roche Ag Substituted isoxazole amide compounds as inhibitors of stearoyl-coa desaturase 1 (scd1)
DE102013201104A1 (en) * 2013-01-24 2014-07-24 H.C. Starck Gmbh Process for the production of chromium nitride-containing spray powders
CN104109115B (en) * 2013-04-16 2016-11-23 中国科学院上海药物研究所 Phenylpropionic acid compound, its pharmaceutical composition, preparation method and the purposes of a kind of nitrogen heterocyclic ring link
WO2015000412A1 (en) * 2013-07-02 2015-01-08 四川海思科制药有限公司 Benzocyclobutene derivative and preparation method and pharmaceutical application thereof
CN104418801B (en) * 2013-08-19 2016-10-05 上海润诺生物科技有限公司 Benzo piperidine ring and benzo morpholine cyclics, its preparation method and medical applications
CN105198826A (en) * 2015-10-08 2015-12-30 中国药科大学 3,5-dimethyl isoxazole derivatives, preparation method of derivatives, and application of derivatives as drugs
CN109666027A (en) * 2017-10-17 2019-04-23 中国科学院上海药物研究所 GPR40 agonist compound of a kind of amide structure and application thereof
CN110092774B (en) * 2018-01-29 2022-04-08 中国科学院上海药物研究所 Aromatic propionic acid derivative, preparation method and application thereof
US10905667B2 (en) 2018-07-24 2021-02-02 Bayer Pharma Aktiengesellschaft Orally administrable modified-release pharmaceutical dosage form
AU2021225966A1 (en) * 2020-02-28 2022-09-15 Kallyope, Inc. GPR40 agonists
CN116924906A (en) * 2022-03-31 2023-10-24 广东药科大学 Novel long-acting FFA1 agonist, preparation method thereof and application thereof as medicine
JP2025110317A (en) * 2024-01-15 2025-07-28 信越化学工業株式会社 Composition for forming organic film, method for forming organic film, and method for forming pattern
KR20250173452A (en) * 2024-06-03 2025-12-10 현대약품 주식회사 Pharmaceutical composition for preventing or treating diabetes

Family Cites Families (65)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE305216B (en) * 1965-09-17 1968-10-21 Astra Apotekarnes Kem Fab
FR2359135A1 (en) 1976-07-22 1978-02-17 Hexachimie Heterocyclyl substd. phenoxy-propanolamine - with cardio:selective beta-adrenergic blocking activity
US4760089A (en) * 1985-09-09 1988-07-26 Smithkline Beckman Corporation Irreversible dopamine-β-hydroxylase inhibitors
PT85081A (en) 1986-06-19 1987-07-01 Smithkline Beckman Corp Irreversible dopamine-beta-hydroxylase inhibitors
GB8917069D0 (en) 1989-07-26 1989-09-13 Merck Sharp & Dohme Therapeutic agents
CA2135173A1 (en) 1992-05-20 1993-11-25 Bruce E. Witzel Ester derivatives of 4-aza-steroids
EP0641204B1 (en) 1992-05-20 2000-08-16 Merck & Co. Inc. 17-ethers and thioethers of 4-aza-steroids
DE4241632A1 (en) 1992-12-10 1994-06-16 Thomae Gmbh Dr K Carboxylic acid derivatives, medicaments containing these compounds and process for their preparation
US6071970A (en) 1993-02-08 2000-06-06 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
JP3894949B2 (en) 1993-06-30 2007-03-22 ザ、ウェルカム、ファンデーション、リミテッド Anti-atherosclerotic diaryl compounds
US5463063A (en) 1993-07-02 1995-10-31 Celgene Corporation Ring closure of N-phthaloylglutamines
AU4432496A (en) * 1994-12-23 1996-07-19 Dr. Karl Thomae Gmbh Piperazine derivatives, medicaments containing the same, their use and process for preparing the same
US6037367A (en) * 1995-07-14 2000-03-14 Smithkline Beecham Corporation Substituted-pent-4-ynoic acids
ATE259227T1 (en) 1995-09-18 2004-02-15 Ligand Pharm Inc TREATMENT OF NIDDM (NON-INSULIN DEPENDENT DIABETES MELLITUS) WITH RXR AGONISTS
US5795900A (en) 1995-10-03 1998-08-18 Abbott Laboratories Symmetrical bis-heteroaryl-methoxy-phenylalkyl carboxylates as inhibitors of leukotriene biosynthesis
CA2233888A1 (en) 1995-10-06 1997-04-10 Ligand Pharmaceuticals Incorporated Dimer-selective rxr modulators and methods for their use
US5771109A (en) * 1996-05-17 1998-06-23 Pixar Method and apparatus for digitizing films using a stroboscopic scanning system
JPH10316641A (en) 1997-03-14 1998-12-02 Sankyo Co Ltd Carboxylic acid derivative
WO1999011255A1 (en) 1997-08-28 1999-03-11 Ono Pharmaceutical Co., Ltd. Peroxisome proliferator-activated receptor controllers
US6645939B1 (en) * 1997-11-24 2003-11-11 Merck & Co., Inc. Substituted β-alanine derivatives as cell adhesion inhibitors
WO1999030709A1 (en) 1997-12-17 1999-06-24 Merck & Co., Inc. Integrin receptor antagonists
ATE451346T1 (en) * 1998-03-10 2009-12-15 Ono Pharmaceutical Co CARBOXYLIC ACID DERIVATIVES AND MEDICATIONS THAT CONTAIN THEM AS THE ACTIVE INGREDIENTS
MA26634A1 (en) 1998-06-04 2004-12-20 Astra Ab NOVEL 3-ARYL PROPIONIC ACID DERIVATIVES AND THE LIKE
DE19941567A1 (en) 1998-09-05 2000-04-20 Merck Patent Gmbh New liquid crystal compounds containing 3-hydroxyacrylic acid ester units, having high clear point, dielectric anisotropy and double refraction, useful e.g. in displays or (electro)optical components
EP1153017B1 (en) * 1999-02-16 2006-05-03 Aventis Pharma Limited Bicyclic compounds and their use as integrin receptor ligands
WO2000063196A1 (en) 1999-04-20 2000-10-26 Novo Nordisk A/S New compounds, their preparation and use
EP1177176B1 (en) 1999-04-28 2006-04-19 Aventis Pharma Deutschland GmbH Tri-aryl acid derivatives as ppar receptor ligands
ATE263162T1 (en) 1999-05-05 2004-04-15 Aventis Pharma Ltd UREA DERIVATIVES AND THEIR USE AS CELL ADHESION MODULATORS
US6262118B1 (en) 1999-06-04 2001-07-17 Metabolex, Inc. Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, type 2 diabetes and hyperlipidemia
GB9914977D0 (en) * 1999-06-25 1999-08-25 Glaxo Group Ltd Chemical compounds
GB9927056D0 (en) 1999-11-17 2000-01-12 Karobio Ab Thyroid receptor antagonists for the treatment of cardiac and metabolic disorders
WO2001036351A2 (en) 1999-11-19 2001-05-25 Corvas International, Inc. Plasminogen activator inhibitor antagonists related applications
JP2001242165A (en) 2000-02-25 2001-09-07 Dai Ichi Seiyaku Co Ltd Reagent for collecting blood
JP2002003368A (en) 2000-06-23 2002-01-09 Saitama Daiichi Seiyaku Kk Pharmaceutical preparation for percutaneous absorption or absorption through mucous membrane
GB0031107D0 (en) 2000-12-20 2001-01-31 Glaxo Group Ltd Chemical compounds
GB0031527D0 (en) 2000-12-22 2001-02-07 Smithkline Beecham Plc New use
CA2433573A1 (en) 2000-12-28 2002-07-11 Takeda Chemical Industries, Ltd. Alkanoic acid derivatives, process for their production and use thereof
TWI311133B (en) 2001-04-20 2009-06-21 Eisai R&D Man Co Ltd Carboxylic acid derivativeand the salt thereof
EA200400011A1 (en) 2001-06-07 2004-06-24 Эли Лилли Энд Компани MODULATORS OF RECEPTORS ACTIVATED BY PROLIFERATORS PEROXIS (PRAR)
US7345068B2 (en) * 2002-02-07 2008-03-18 Hitoshi Endou Aromatic amino acid derivatives and medicinal compositions
WO2003068959A1 (en) 2002-02-14 2003-08-21 Takeda Chemical Industries, Ltd. Novel screening method
US20030207924A1 (en) * 2002-03-07 2003-11-06 Xue-Min Cheng Compounds that modulate PPAR activity and methods of preparation
US6875780B2 (en) * 2002-04-05 2005-04-05 Warner-Lambert Company Compounds that modulate PPAR activity and methods for their preparation
EP1513817A1 (en) 2002-05-24 2005-03-16 Takeda Pharmaceutical Company Limited 1, 2-azole derivatives with hypoglycemic and hypolipidemic activity
GB0214149D0 (en) * 2002-06-19 2002-07-31 Glaxo Group Ltd Chemical compounds
EP2662211A1 (en) 2002-06-24 2013-11-13 Tufts University Silk biomaterials and methods of use thereof
AU2003261935A1 (en) 2002-09-06 2004-03-29 Takeda Pharmaceutical Company Limited Furan or thiophene derivative and medicinal use thereof
JP4594611B2 (en) * 2002-11-08 2010-12-08 武田薬品工業株式会社 Receptor function regulator
AU2003277576A1 (en) * 2002-11-08 2004-06-07 Takeda Pharmaceutical Company Limited Receptor function controlling agent
CA2521175A1 (en) 2003-04-07 2004-10-28 Kalypsys, Inc. Para-sulfonyl substituted phenyl compounds as modulators of ppars
EP1630152A4 (en) 2003-05-30 2009-09-23 Takeda Pharmaceutical CONNECTION WITH CONDENSED RING
WO2005051890A1 (en) 2003-11-19 2005-06-09 Smithkline Beecham Corporation Aminophenylcyclopropyl carboxylic acids and derivatives as agonists to gpr40
US7605171B2 (en) 2003-12-17 2009-10-20 Merck & Co., Inc. (3,4-disubstituted)propanoic carboxylates as S1P (Edg) receptor agonists
AU2004309271A1 (en) 2003-12-25 2005-07-14 Takeda Pharmaceutical Company Limited 3-(4-benzyloxyphenyl)propanoic acid derivatives
EP1698624B1 (en) 2003-12-26 2012-06-27 Takeda Pharmaceutical Company Limited Phenylpropanoic acid derivatives
JP5299810B2 (en) * 2004-02-27 2013-09-25 アムジエン・インコーポレーテツド Compounds, pharmaceutical compositions and methods for use in the treatment of metabolic disorders
US7786165B2 (en) 2004-03-15 2010-08-31 Takeda Pharmaceutical Company Limited Aminophenylpropanoic acid derivative
JP4859665B2 (en) * 2004-03-30 2012-01-25 武田薬品工業株式会社 Alkoxyphenylpropanoic acid derivatives
JP2007269630A (en) 2004-06-23 2007-10-18 Toudai Tlo Ltd Insulin secretagogue
US20060003344A1 (en) * 2004-06-30 2006-01-05 Pfizer Inc. Methods related to a single nucleotide polymorphism of the G protein coupled receptor, GPR40
JP2007284350A (en) 2004-07-27 2007-11-01 Takeda Chem Ind Ltd Diabetes treatment
EP1843766A1 (en) 2005-01-28 2007-10-17 Merck & Co., Inc. Antidiabetic bicyclic compounds
CA2593858A1 (en) 2005-01-31 2006-08-10 Min Ge Antidiabetic bicyclic compounds
US7465804B2 (en) * 2005-05-20 2008-12-16 Amgen Inc. Compounds, pharmaceutical compositions and methods for their use in treating metabolic disorders
CA2662305C (en) * 2006-09-07 2012-04-17 Amgen Inc. Heterocyclic gpr40 modulators

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BERGE ET AL., J. PHARM. SCI., vol. 66, 1977, pages 1 - 19
BORDWELL ET AL., J. AMER. CHEM. SOC., vol. 112, 1990, pages 792 - 797
DEWOLF ET AL., BIOCHEMISTRY, vol. 28, 1989, pages 3833 - 3842
DYER ET AL., TETRAHEDRON LETTERS, vol. 42, 2001, pages 1765 - 1767
MIK6 ET AL., J. MED. CHEM., vol. 46, 2003, pages 1523 - 1530
MIYASHITA ET AL., J. ORG. CHEM., vol. 42, 1977, pages 3772
See also references of EP1737809A4

Cited By (177)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7649110B2 (en) 2004-02-27 2010-01-19 Amgen Inc. Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
US8592486B2 (en) 2005-01-07 2013-11-26 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
WO2006083477A2 (en) 2005-01-07 2006-08-10 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
US8202999B2 (en) 2005-01-07 2012-06-19 Synta Pharmaceuticals Corp. Compounds for inflammation and immune-related uses
EP1846372A4 (en) * 2005-01-07 2008-12-17 Synta Pharmaceuticals Corp Compounds for inflammation and immune-related uses
WO2006097766A1 (en) * 2005-03-17 2006-09-21 Merck Sharp & Dohme Limited Arylsulfonyl benzyl ethers as 5-ht2a antagonists
US7465804B2 (en) 2005-05-20 2008-12-16 Amgen Inc. Compounds, pharmaceutical compositions and methods for their use in treating metabolic disorders
WO2006127503A3 (en) * 2005-05-20 2007-08-30 Amgen Inc Compounds, pharmaceutical compositions and methods for their use in treating metabolic disorders
US8097610B2 (en) 2005-08-26 2012-01-17 Shionogi & Co., Ltd. Derivative having PPAR agonistic activity
US8008303B2 (en) 2005-09-16 2011-08-30 Astrazeneca Ab Biphenyl derivatives and their use in treating hepatitis C
KR100968705B1 (en) * 2005-10-27 2010-07-06 주식회사유한양행 Novel 2-phenylpyrimidine derivatives and preparation methods thereof
US8178675B2 (en) 2005-11-09 2012-05-15 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
JP2009514987A (en) * 2005-11-09 2009-04-09 ウェルスタット セラピューティクス コーポレイション Compounds for the treatment of metabolic disorders
AU2006311266B2 (en) * 2005-11-09 2011-09-29 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
WO2007056771A2 (en) 2005-11-09 2007-05-18 Wellstat Therapeutics Corporation Compounds for the treatment of metabolic disorders
EP1948152A4 (en) * 2005-11-09 2010-07-07 Wellstat Therapeutics Corp Compounds for the treatment of metabolic disorders
EP1978948A4 (en) * 2006-02-02 2010-06-16 Wellstat Therapeutics Corp Compounds for the treatment of metabolic disorders
US7968552B2 (en) 2006-04-24 2011-06-28 Astellas Pharma Inc. Oxadiazolidinedione compound
EP2011788A4 (en) * 2006-04-24 2010-10-13 Astellas Pharma Inc Oxadiazolidinedione compound
AU2007292816B2 (en) * 2006-09-07 2011-11-17 Amgen Inc. Benzo-fused compounds for use in treating metabolic disorders
US8003648B2 (en) 2006-09-07 2011-08-23 Amgen Inc. Heterocyclic GPR40 modulators
US7714008B2 (en) * 2006-09-07 2010-05-11 Amgen Inc. Heterocyclic GPR40 modulators
WO2008030618A1 (en) 2006-09-07 2008-03-13 Amgen Inc. Benzo-fused compounds for use in treating metabolic disorders
AU2007293028B2 (en) * 2006-09-07 2012-05-31 Amgen Inc. Heterocyclic GPR40 modulators
WO2008030520A1 (en) * 2006-09-07 2008-03-13 Amgen Inc. Heterocyclic gpr40 modulators
WO2008066097A1 (en) 2006-12-01 2008-06-05 Astellas Pharma Inc. Carboxylic acid derivative
US8394841B2 (en) 2007-02-22 2013-03-12 Irm Llc Compounds and methods for modulating G protein-coupled receptors
JP2010519306A (en) * 2007-02-22 2010-06-03 アイアールエム・リミテッド・ライアビリティ・カンパニー Compounds and methods for modulating G protein coupled receptors
JP2010524932A (en) * 2007-04-16 2010-07-22 アムジエン・インコーポレーテツド Substituted biphenylphenoxy-, thiophenyl- and aminophenylpropanoic acid GPR40 modulators
WO2008130514A1 (en) * 2007-04-16 2008-10-30 Amgen Inc. Substituted biphenyl phenoxy-, thiophenyl- and aminophenylpropanoic acid gpr40 modulators
US8030354B2 (en) 2007-10-10 2011-10-04 Amgen Inc. Substituted biphenyl GPR40 modulators
US8299296B2 (en) 2007-10-26 2012-10-30 Japan Tobacco Inc. Spiro compounds and pharmaceutical use thereof
WO2009055932A1 (en) * 2007-11-02 2009-05-07 Prometic Biosciences Inc. Substituted phenylpropionic acids as stimulators of hematopoiesis and erythropoiesis
US8791267B2 (en) 2007-11-21 2014-07-29 Decode Genetics Ehf Biaryl PDE4 inhibitors for treating inflammatory, cardiovascular and CNS disorders
EP2674417A3 (en) * 2007-11-21 2014-04-09 Decode Genetics EHF Biaryl PDE4 inhibitors for treating inflammation
WO2009111056A1 (en) * 2008-03-06 2009-09-11 Amgen Inc. Conformationally constrained carboxylic acid derivatives useful for treating metabolic disorders
AU2009220163B2 (en) * 2008-03-06 2011-10-06 Amgen Inc. Conformationally constrained carboxylic acid derivatives useful for treating metabolic disorders
WO2009157418A1 (en) 2008-06-25 2009-12-30 第一三共株式会社 Carboxylic acid compound
JP5425772B2 (en) * 2008-06-25 2014-02-26 第一三共株式会社 Carboxylic acid compound
US8222281B2 (en) 2008-06-25 2012-07-17 Daiichi Sankyo Company, Limited Carboxylic acid compound
US8586607B2 (en) 2008-07-28 2013-11-19 Syddansk Universitet Compounds for the treatment of metabolic diseases
WO2010012650A1 (en) 2008-07-28 2010-02-04 Syddansk Universitet Compounds for the treatment of metabolic diseases
US8748462B2 (en) 2008-10-15 2014-06-10 Amgen Inc. Spirocyclic GPR40 modulators
US8598374B2 (en) 2008-12-18 2013-12-03 Metabolex, Inc. GPR120 receptor agonists and uses thereof
US8309600B2 (en) 2008-12-18 2012-11-13 Metabolex Inc. GPR120 receptor agonists and uses thereof
US8383642B2 (en) 2009-10-15 2013-02-26 Eli Lilly And Company Spiropiperidine compounds
WO2011046851A1 (en) 2009-10-15 2011-04-21 Eli Lilly And Company Spiropiperidine compounds and pharmaceutical use thereof for treating diabetes
DE102009046115A1 (en) 2009-10-28 2011-09-08 Bayer Schering Pharma Aktiengesellschaft Substituted 3-phenylpropanoic acids and their use
WO2011051165A1 (en) 2009-10-28 2011-05-05 Bayer Schering Pharma Aktiengesellschaft Substituted 3-phenylpropionic acids and the use thereof
US8455500B2 (en) 2009-10-30 2013-06-04 Mochida Pharmaceutical Co., Ltd. 3-hydroxy-5-arylisoxazole derivative
WO2011052756A1 (en) 2009-10-30 2011-05-05 持田製薬株式会社 Novel 3-hydroxy-5-arylisoxazole derivative
WO2011066183A1 (en) 2009-11-30 2011-06-03 Eli Lilly And Company Novel spiropiperidine compounds
WO2011069958A2 (en) 2009-12-07 2011-06-16 Nestec S.A. Low caloric fat replacers
US8476287B2 (en) 2009-12-25 2013-07-02 Mochida Pharmaceutical Co., Ltd. 3-hydroxy-5-arylisothiazole derivative
WO2011078371A1 (en) 2009-12-25 2011-06-30 持田製薬株式会社 Novel 3-hydroxy-5-arylisothiazole derivative
US8299117B2 (en) 2010-06-16 2012-10-30 Metabolex Inc. GPR120 receptor agonists and uses thereof
US8476308B2 (en) 2010-06-16 2013-07-02 Metabolex, Inc. GPR120 receptor agonists and uses thereof
WO2011161030A1 (en) * 2010-06-21 2011-12-29 Sanofi Heterocyclic substituted methoxyphenyl derivatives having an oxo group, method for producing same, and use thereof as gpr40 receptor modulators
US20120004165A1 (en) * 2010-06-21 2012-01-05 Sanofi Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments
US8530413B2 (en) 2010-06-21 2013-09-10 Sanofi Heterocyclically substituted methoxyphenyl derivatives with an oxo group, processes for preparation thereof and use thereof as medicaments
WO2012010413A1 (en) * 2010-07-05 2012-01-26 Sanofi Aryloxy-alkylene substituted hydroxyphenyl hexynoic acids, methods for the production thereof and use of the same as medicament
US8648038B2 (en) 2010-07-05 2014-02-11 Sanofi (2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments
US8859494B2 (en) 2010-07-05 2014-10-14 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament
WO2012004269A1 (en) * 2010-07-05 2012-01-12 Sanofi (2-aryloxy-acetylamino)-phenyl-propionic acid derivatives, method for producing same and use thereof as pharmaceuticals
US20120004187A1 (en) * 2010-07-05 2012-01-05 Sanofi Spirocyclically substituted 1,3-propane dioxide derivatives, processes for preparation thereof and use thereof as a medicament
US9040525B2 (en) 2010-10-08 2015-05-26 Mochida Pharmaceutical Co., Ltd. Cyclic amide derivative
WO2012046869A1 (en) 2010-10-08 2012-04-12 持田製薬株式会社 Cyclic amide derivative
US9499467B2 (en) 2011-04-08 2016-11-22 Caldan Therapeutics Limited Ortho-fluoro substituted compounds for the treatment of metabolic diseases
DE102011007272A1 (en) 2011-04-13 2012-10-18 Bayer Pharma Aktiengesellschaft Branched 3-phenylpropionic acid derivatives and their use
WO2012139888A1 (en) 2011-04-13 2012-10-18 Bayer Intellectual Property Gmbh Branched 3-phenylpropionic acid derivatives and the use thereof
US8629102B2 (en) 2011-04-27 2014-01-14 Mochida Pharmaceutical Co., Ltd. 3-hydroxyisothiazole 1-oxide derivatives
WO2012147518A1 (en) 2011-04-27 2012-11-01 持田製薬株式会社 Novel 3-hydroxyisothiazole 1-oxide derivative
US8765752B2 (en) 2011-04-27 2014-07-01 Mochida Pharmaceutical Co., Ltd. 3-hydroxyisothiazole 1-oxide derivatives
US8557766B2 (en) 2011-04-27 2013-10-15 Mochida Pharmaceutical Co., Ltd. 3-hydroxyisothiazole 1-oxide derivatives
WO2012147516A1 (en) 2011-04-28 2012-11-01 持田製薬株式会社 Cyclic amide derivative
US9072758B2 (en) 2011-04-28 2015-07-07 Mochida Pharmaceutical Co., Ltd. Cyclic amide derivative
WO2013025424A1 (en) 2011-08-17 2013-02-21 Eli Lilly And Company A Novel 1,2,3,4-Tetrahydroquinoline Derivative Useful for the Treatment of Diabetes
WO2013102626A1 (en) * 2012-01-04 2013-07-11 Sanofi 3-[4-(phenylaminooxalylamino)phenyl]hex-4-ynoic acids, process for preparation thereof and use thereof as a medicament
WO2013128378A1 (en) 2012-02-28 2013-09-06 Piramal Enterprises Limited Phenyl alkanoic acid derivatives as gpr agonists
WO2014022528A1 (en) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US9527875B2 (en) 2012-08-02 2016-12-27 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
KR20140060242A (en) * 2012-11-09 2014-05-19 주식회사 엘지생명과학 Gpr40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient
CN104837816A (en) * 2012-11-09 2015-08-12 株式会社Lg生命科学 GPR40 receptor agonist, method for preparing same, and pharmaceutical composition containing same as active ingredient
EP2917180A4 (en) * 2012-11-09 2016-04-27 Lg Life Sciences Ltd GPR40 RECEPTOR AGONIST, METHODS OF PREPARING THE SAME, AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME AS AN ACTIVE SUBSTANCE
RU2650506C2 (en) * 2012-11-09 2018-04-16 ЭлДжи КЕМ, ЛТД. Gpr40 receptor agonist, methods of preparing same, and pharmaceutical compositions containing same as active ingredient
KR101984629B1 (en) * 2012-11-09 2019-05-31 주식회사 엘지화학 GPR40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient
US20150291584A1 (en) * 2012-11-09 2015-10-15 Lg Life Sciences Ltd. Gpr40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
WO2014073904A1 (en) 2012-11-09 2014-05-15 Lg Life Sciences Ltd. Gpr40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient
AU2013341945B2 (en) * 2012-11-09 2018-07-12 Lg Chem, Ltd. GPR40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active ingredient
US9988379B2 (en) 2012-11-09 2018-06-05 Lg Chem, Ltd. GPR40 receptor agonist, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
US9840512B2 (en) 2013-02-22 2017-12-12 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2014130608A1 (en) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
US9643946B2 (en) 2013-02-28 2017-05-09 Sk Chemicals Co., Ltd. Tricyclic compound and use thereof
CN108017603B (en) * 2013-02-28 2021-07-23 株式会社蒂奥姆生物 Tricyclic compounds and their uses
AU2014221489B2 (en) * 2013-02-28 2018-03-08 Tiumbio Co., Ltd. Tricyclic compound and use thereof
EP2963027A4 (en) * 2013-02-28 2016-07-20 Sk Chemicals Co Ltd TRICYCLIC COMPOUND AND USE THEREOF
CN108017603A (en) * 2013-02-28 2018-05-11 株式会社蒂奥姆生物 Tricyclic compounds and their uses
WO2014170842A2 (en) 2013-04-17 2014-10-23 Piramal Enterprises Limited Substituted alkyl carboxylic acid derivatives as gpr agonists
WO2014171762A1 (en) * 2013-04-18 2014-10-23 현대약품 주식회사 Novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative, method of preparing same and pharmaceutical composition for preventing and treating metabolic disease including same as effective ingredient
US9969723B2 (en) 2013-04-18 2018-05-15 Hyundai Pharm Co., Ltd 3-(4-(benzyloxy)phenyl)hex-4-ynoic acid derivative, method of preparing same and pharmaceutical composition for preventing and treating metabolic disease including same as effective ingredient
CN105121423A (en) * 2013-04-18 2015-12-02 现代药品株式会社 Novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative, method of preparing same and pharmaceutical composition for preventing and treating metabolic disease including same as effective ingredient
CN105121423B (en) * 2013-04-18 2017-06-09 现代药品株式会社 3-(4-(Benzyloxy)phenyl)hex-4-ynoic acid derivatives, their preparation methods, and pharmaceutical compositions for preventing and treating metabolic diseases comprising the same as active ingredients
RU2628077C2 (en) * 2013-04-18 2017-08-14 Хендэ Фарм Ко., Лтд New derivative of 3-(4-(benzyloxy)phenyl)hex-4-ine acid, method for its production and pharmaceutical composition for metabolic disease prevention and treatment including it as effective ingredient
WO2015051725A1 (en) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US9932311B2 (en) 2013-10-08 2018-04-03 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US10246470B2 (en) 2013-11-14 2019-04-02 Cadila Healthcare Limited Heterocyclic compounds
US10011609B2 (en) 2013-11-14 2018-07-03 Cadila Healthcare Limited Heterocyclic compounds
WO2015097713A1 (en) 2013-11-14 2015-07-02 Cadila Healthcare Limited Novel heterocyclic compounds
US10519115B2 (en) 2013-11-15 2019-12-31 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US9957219B2 (en) 2013-12-04 2018-05-01 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2015088868A1 (en) 2013-12-13 2015-06-18 Eli Lilly And Company A novel triazolo-pyridine compound
AU2014364224B2 (en) * 2013-12-13 2017-02-16 Eli Lilly And Company A novel triazolo-pyridine compound
US9120793B2 (en) 2013-12-13 2015-09-01 Eli Lilly And Company Triazolo-pyridine compound
WO2015095256A1 (en) 2013-12-19 2015-06-25 Merck Sharp & Dohme Corp. Antidiabetic substituted heteroaryl compounds
EP3974413A1 (en) 2013-12-19 2022-03-30 Merck Sharp & Dohme Corp. Antidiabetic substituted heteroaryl compounds
US9834563B2 (en) 2013-12-19 2017-12-05 Merck Sharp & Dohme Corp. Antidiabetic substituted heteroaryl compounds
WO2015105779A1 (en) * 2014-01-10 2015-07-16 Eli Lilly And Company Isopropyl triazolo pyridine compounds
AU2015204916B2 (en) * 2014-01-10 2017-02-23 Eli Lilly And Company Isopropyl triazolo pyridine compounds
WO2015105786A1 (en) 2014-01-10 2015-07-16 Eli Lilly And Company Phenyl-triazolo-pyridine compounds
US9809592B2 (en) 2014-01-10 2017-11-07 Eli Lilly And Company Isopropyl triazolo pyridine compounds
US10059667B2 (en) 2014-02-06 2018-08-28 Merck Sharp & Dohme Corp. Antidiabetic compounds
US10227360B2 (en) 2014-02-19 2019-03-12 Piramal Enterprises Limited Compounds for use as GPR120 agonists
WO2015176640A1 (en) 2014-05-22 2015-11-26 Merck Sharp & Dohme Corp. Antidiabetic tricyclic compounds
US10000454B2 (en) 2014-05-22 2018-06-19 Merck Sharp & Dohme Antidiabetic tricyclic compounds
US10273230B2 (en) 2014-07-25 2019-04-30 Piramal Enterprises Limited Substituted phenyl alkanoic acid compounds as GPR120 agonists and uses thereof
US10968193B2 (en) 2014-08-08 2021-04-06 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
US10131651B2 (en) 2014-08-08 2018-11-20 Merck Sharp & Dohme Corp. [7,6]-fused bicyclic antidiabetic compounds
US10662171B2 (en) 2014-08-08 2020-05-26 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2016022742A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2016022446A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. [5,6]-fused bicyclic antidiabetic compounds
WO2016022448A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
WO2016019863A1 (en) 2014-08-08 2016-02-11 Merck Sharp & Dohme Corp. [7,6]-fused bicyclic antidiabetic compounds
US10100042B2 (en) 2014-08-08 2018-10-16 Merck Sharp & Dohme Corp. [5,6]—fused bicyclic antidiabetic compounds
US10214521B2 (en) 2014-09-11 2019-02-26 Piramal Enterprises Limited Fused heterocyclic compounds as GPR120 agonists
US10662170B2 (en) 2014-10-08 2020-05-26 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as GPR40 agonists for the treatment of type II diabetes
US9790198B2 (en) 2014-10-08 2017-10-17 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as GPR40 agonists for the treatment of type II diabetes
WO2016057731A1 (en) 2014-10-08 2016-04-14 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as gpr40 agonists for the treatment of type ii diabetes
US10131648B2 (en) 2014-10-08 2018-11-20 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as GPR40 agonists for the treatment of type II diabetes
US10821110B2 (en) 2014-10-17 2020-11-03 Hyundai Pharm Co., Ltd. Composite preparation, containing novel 3-(4--(benzyloxy)phenyl)hex-4-inoic acid derivative and another active ingredient, for preventing or treating metabolic diseases
US20170296539A1 (en) * 2014-10-17 2017-10-19 Hyundai Pharm Co., Ltd. Composite preparation, containing novel 3-(4--(benzyloxy)phenyl)hex-4-inoic acid derivative and another active ingredient, for preventing or treating metabolic diseases
AU2015331074B2 (en) * 2014-10-17 2018-11-15 Hyundai Pharm Co., Ltd. Composite preparation, containing novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative and another active ingredient, for preventing or treating metabolic diseases
RU2680248C1 (en) * 2014-10-17 2019-02-19 Хюндай Фарм Ко., Лтд. Combination containing new derivative 3-(4-(benzyloxy)phenyl)hex-4-in-acid and other active ingredient to activate g-protein 40 of the receptor enzyme
EP3207928A4 (en) * 2014-10-17 2018-03-14 Hyundai Pharm Co., Ltd. Composite preparation, containing novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative and another active ingredient, for preventing or treating metabolic diseases
US10172814B2 (en) 2014-12-18 2019-01-08 Bayer Pharma Aktiengesellschaft Substituted pyridyl-cycloalkyl-carboxylic acids, compositions containing them and medical uses thereof
US9908873B2 (en) 2015-08-12 2018-03-06 Janssen Pharmaceutica Nv GPR40 agonists for the treatment of type II diabetes
US9920040B2 (en) 2015-08-12 2018-03-20 Janssen Pharmaceutica Nv GPR40 agonists for the treatment of type II diabetes
US9856245B2 (en) 2015-08-12 2018-01-02 Janssen Pharmaceutica Nv GPR40 agonists for the treatment of type II diabetes
US10676458B2 (en) 2016-03-29 2020-06-09 Merch Sharp & Dohne Corp. Rahway Antidiabetic bicyclic compounds
US10195178B2 (en) 2016-04-11 2019-02-05 Janssen Pharmaceutica Nv GPR40 agonists in anti-diabetic drug combinations
WO2017180571A1 (en) * 2016-04-11 2017-10-19 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as gpr40 agonists for the treatment of type ii diabetes
WO2017180457A1 (en) 2016-04-11 2017-10-19 Janssen Pharmaceutica Nv Gpr40 agonists in anti-diabetic drug combinations
US10106553B2 (en) 2016-04-11 2018-10-23 Janssen Pharmaceutica Nv Substituted benzothiophenyl derivatives as GPR40 agonists for the treatment of type II diabetes
WO2017190714A1 (en) 2016-05-04 2017-11-09 Universidad De La Habana Phenol compound and combination of same with a benzodiazepine fused to 1,4-dihydropyridine for treating diseases of the central nervous and vascular systems
US11072602B2 (en) 2016-12-06 2021-07-27 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
WO2018106518A1 (en) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Antidiabetic heterocyclic compounds
US11731961B2 (en) 2016-12-15 2023-08-22 Ildong Pharmaceutical Co., Ltd. Phenyl propionic acid derivatives and uses thereof
JP2020502111A (en) * 2016-12-15 2020-01-23 イルドン ファーマシューティカル カンパニー リミテッド Novel phenylpropionic acid derivatives and uses thereof
US11225472B2 (en) 2016-12-15 2022-01-18 Il Dong Pharmaceutical Co., Ltd. Phenyl propionic acid derivatives and uses thereof
CN110049984A (en) * 2016-12-15 2019-07-23 日东制药株式会社 Novel phenylpropionic acid derivatives and their uses
KR102007633B1 (en) 2016-12-15 2019-08-06 일동제약(주) Novel phenyl propionic acid derivatives and uses thereof
WO2018111012A1 (en) * 2016-12-15 2018-06-21 Il Dong Pharmaceutical Co., Ltd. Novel phenyl propionic acid derivatives and uses thereof
KR20180069718A (en) * 2016-12-15 2018-06-25 일동제약(주) Novel phenyl propionic acid derivatives and uses thereof
WO2018118670A1 (en) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
US10968232B2 (en) 2016-12-20 2021-04-06 Merck Sharp & Dohme Corp. Antidiabetic spirochroman compounds
US11225471B2 (en) 2017-11-16 2022-01-18 Merck Sharp & Dohme Corp. Antidiabetic bicyclic compounds
KR20200108318A (en) * 2018-01-08 2020-09-17 셀론 파르마 에스.에이. 3-phenyl-4-hexic acid derivatives as GPR40 agonists
US20200399198A1 (en) * 2018-01-08 2020-12-24 Celon Pharma S.A. 3-phenyl-4-hexynoic acid derivatives as gpr40 agonists
WO2019134984A1 (en) 2018-01-08 2019-07-11 Celon Pharma S.A. 3-phenyl-4-hexynoic acid derivatives as gpr40 agonists
KR102705659B1 (en) 2018-01-08 2024-09-11 셀론 파르마 에스.에이. 3-Phenyl-4-hexynic acid derivatives as GPR40 agonists
US11964938B2 (en) 2018-01-08 2024-04-23 Celon Pharma S.A. 3-phenyl-4-hexynoic acid derivatives as GPR40 agonists
AU2019205093B2 (en) * 2018-01-08 2024-03-07 Celon Pharma S.A. 3-phenyl-4-hexynoic acid derivatives as GPR40 agonists
WO2020169069A1 (en) 2019-02-21 2020-08-27 Nanjing Ruijie Pharma Co., Ltd. Novel compounds and their uses as thyroid hormone receptor agonists
US12338206B2 (en) 2019-02-21 2025-06-24 Nanjing Ruijie Pharma Co., Ltd. Compounds and their uses as thyroid hormone receptor agonists
US12264171B2 (en) 2020-02-28 2025-04-01 Kallyope, Inc. GPR40 agonists
WO2022269439A1 (en) * 2021-06-21 2022-12-29 Ildong Pharmaceutical Co., Ltd. Method of controlling blood sugar level and treatment of diabetes and related conditions
WO2023080741A1 (en) * 2021-11-08 2023-05-11 일동제약(주) Novel salt of phenyl propionic acid derivative, method for producing same, and pharmaceutical composition containing same
WO2023080299A1 (en) * 2021-11-08 2023-05-11 일동제약(주) Novel salt of phenyl propionic acid derivative, method for producing same, and pharmaceutical composition containing same

Also Published As

Publication number Publication date
BRPI0508098A (en) 2007-07-17
AR048306A1 (en) 2006-04-19
US7649110B2 (en) 2010-01-19
CA2558585A1 (en) 2005-09-22
EP1737809A4 (en) 2007-10-17
ECSP066887A (en) 2006-11-24
IS8542A (en) 2006-09-27
ES2433466T3 (en) 2013-12-11
JP2007525516A (en) 2007-09-06
AU2005220728A2 (en) 2005-09-22
EA200601388A1 (en) 2007-02-27
EA011010B1 (en) 2008-12-30
NO20064362L (en) 2006-11-22
KR20070004769A (en) 2007-01-09
US20070142384A1 (en) 2007-06-21
TW200539854A (en) 2005-12-16
US20060004012A1 (en) 2006-01-05
US7816367B2 (en) 2010-10-19
JP5299810B2 (en) 2013-09-25
MA28466B1 (en) 2007-03-01
CN1946666A (en) 2007-04-11
CR8642A (en) 2008-11-28
IL177717A0 (en) 2006-12-31
CA2558585C (en) 2010-10-12
AU2005220728B2 (en) 2009-08-06
WO2005086661A3 (en) 2006-05-04
AU2005220728A1 (en) 2005-09-22
EP1737809B1 (en) 2013-09-18
EP1737809A2 (en) 2007-01-03

Similar Documents

Publication Publication Date Title
EP1737809B1 (en) Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
US7687526B2 (en) Benzo-fused compounds for use in treating metabolic disorders
US7582803B2 (en) Conformationally constrained 3-(4-hydroxy-phenyl)-substituted-propanoic acids useful for treating metabolic disorders
US7714008B2 (en) Heterocyclic GPR40 modulators
CA2607848C (en) 3-substituted (3-phenyl)-propionic acid derivatives for the treatment of metabolic disorders
EP2139843B1 (en) Substituted biphenyl phenoxy-, thiophenyl- and aminophenylpropanoic acid gpr40 modulators
JP2004517100A (en) Substituted oxazoles and thiazoles as hPPARalpha agonists
JP2009514964A (en) Compounds and compositions as PPAR modulators
MXPA06009793A (en) Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders
ZA200607579B (en) Compounds, pharmaceutical compositions and methods for use in treating metabolic disorders

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SM SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

WWE Wipo information: entry into national phase

Ref document number: 438.06

Country of ref document: BZ

WWE Wipo information: entry into national phase

Ref document number: 2007500959

Country of ref document: JP

Ref document number: 549463

Country of ref document: NZ

Ref document number: 2558585

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 177717

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2007142384

Country of ref document: US

Ref document number: 10591214

Country of ref document: US

Ref document number: 12006501677

Country of ref document: PH

Ref document number: PA/a/2006/009793

Country of ref document: MX

Ref document number: 200601388

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 2006/07579

Country of ref document: ZA

Ref document number: 200607579

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: CR2006-008642

Country of ref document: CR

WWE Wipo information: entry into national phase

Ref document number: 2005220728

Country of ref document: AU

Ref document number: 1020067019713

Country of ref document: KR

Ref document number: 5525/DELNP/2006

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: DZP2005000474

Country of ref document: DZ

WWE Wipo information: entry into national phase

Ref document number: 06096986

Country of ref document: CO

Ref document number: 2005723623

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 9637

Country of ref document: GE

ENP Entry into the national phase

Ref document number: 2005220728

Country of ref document: AU

Date of ref document: 20050224

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2005220728

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 200580012709.2

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 2005723623

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020067019713

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 10591214

Country of ref document: US

ENP Entry into the national phase

Ref document number: PI0508098

Country of ref document: BR