WO2010075273A1 - Dérivés d'hétérocycles bicycliques et leurs procédés d'utilisation - Google Patents

Dérivés d'hétérocycles bicycliques et leurs procédés d'utilisation Download PDF

Info

Publication number
WO2010075273A1
WO2010075273A1 PCT/US2009/068972 US2009068972W WO2010075273A1 WO 2010075273 A1 WO2010075273 A1 WO 2010075273A1 US 2009068972 W US2009068972 W US 2009068972W WO 2010075273 A1 WO2010075273 A1 WO 2010075273A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
alkylene
aryl
group
Prior art date
Application number
PCT/US2009/068972
Other languages
English (en)
Inventor
Unmesh G. Shah
Craig D. Boyle
Samuel Chackalamannil
Bernard R. Neustadt
Joel M. Harris
Andrew Stamford
William J. Greenlee
Santhosh Francis Neelamkavil
Original Assignee
Schering Corporation
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
Application filed by Schering Corporation filed Critical Schering Corporation
Publication of WO2010075273A1 publication Critical patent/WO2010075273A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • GPCR BACKGROUND OF THE INVENTION
  • GPCRs Receptors, including GPCRs, for which the endogenous ligand has been identified are referred to as "known" receptors, while receptors for which the endogenous ligand has not been identified are referred to as "orphan" receptors.
  • GPCRs represent an important area for the development of pharmaceutical products, as evidenced by the fact that pharmaceutical products have been developed from approximately 20 of the 100 known GPCRs. This distinction is not merely semantic, particularly in the case of GPCRs.
  • GPCRs share a common structural motif. All these receptors have seven sequences of between 22 to 24 hydrophobic amino acids that form seven alpha helices, each of which spans the membrane (each span is identified by number, i.e., transrnembrane-1 (TMM ), transmembrane-2 (TM-2), etc.).
  • TMM transrnembrane-1
  • TM-2 transmembrane-2
  • transmembrane helices are also joined by strands of amino acids between transmembrane-1 and transmembrane-2, transmembrane-3 and transmembrane-4, and transmembrane-5 and transmembrane-6 on the interior, or "intracellular” side, of the cell membrane (these are referred to as "intracellular” regions 1 , 2 and 3 (IC-1 , IC-2 and IC-3), respectively).
  • the "carboxy" (“C”) terminus of the receptor lies in the intracellular space within the cell, and the "amino" ( 11 N”) terminus of the receptor lies in the extracellular space outside of the cell.
  • GPCRs are "promiscuous" with respect to G proteins, i.e., that a GPCR can interact with more than one G protein, See, Kenakin, T., Life Sciences 43, 1095 (1988). Although other G proteins exist, currently, Gq 1 Gs, Gi, and Go are G proteins that have been identified.
  • Endogenous ligand-activated GPCR coupling with the G-protein begins a signaling cascade process (referred to as "signal transduction"). Under normal conditions, signal transduction ultimately results in cellular activation or cellular inhibition. It is thought that the IC-3 loop as well as the carboxy terminus of the receptor interact with the G protein.
  • G-protein coupled receptors Modulation of G-protein coupled receptors has been well-studied for controlling various metabofic disorders.
  • Small molecule modulators of the receptor GPR119 a G-protein coupled-receptor described in, for example, GenBank (see, e.g., accession numbers XM.sub.--066873 and AY288416), have been shown to be useful for treating or preventing certain metabolic disorders.
  • GPR119 is a G protein-coupled receptor that is selectively expressed on pancreatic beta cells. GPR119 activation leads to elevation of a level of intracellular cAMP, consistent with GPR119 being coupied to Gs. Agonists to GPR119 stimulate glucose-dependent insulin secretion in vitro and lower an elevated blood glucose level in vivo. See, e.g., International Publication Nos. WO 04/065380 and WO 04/076413, and EP 1338651 , the disclosure of each of which is herein incorporated by reference in its entirety.
  • U.S. Patent No. 7,136,426 discloses pyrazoto[3,4-d]pyrimidine ethers and related compounds as modulators of the GPR119 receptor that are useful for the treatment of various metabolic-related disorders such as type i diabetes, type Il diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperfipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia or syndrome X, The compounds are also reported as being useful for controlling weight gain, controlling food intake, and inducing satiety in mammals.
  • the promising nature of these GPCR modulators indicates a need in the art for additional small molecule GPCR modulators with improved efficacy and safety profiles. This invention addresses that need.
  • the present invention provides Compounds of Formula (I):
  • A is aryl or heteroaryl, each of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cydoalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, halo, -OH, -O-haloalkyl, -O-alkyl, -O- alkyl-OH, -O-alkyl-O-alkyl, -O-aryl, -alkylene-O-alkyl, -CN, -N(R 4 ) 2 , -C(O)H, -C(O)R 4 , - C(O)OR 4 , -C(O)N(R 4 ) 2 , -NHC(O)R 4 , -NHS(O) m R 4 , -S(O) n R 4 and -S(O) m N(R
  • aryl or heteroaryl each of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycioalkenyl, haloalkyl, hydroxyalkyl, heteroaryl, halo, -OH, -O-haloalkyl, - O-alkyI, -O-aryl, -alkylene-O-alkyl, -alkylene-S(O) 2 -alkyl, -SF 5 , -CN, -N(R 4 ) 2 , -C(O)H, - C(O)R 4 , -C(O)OR 4 , -C(O)N(R 4 ) 2 , -NHC(O)R 4 , -NHS(O) m R 4 , -S(O) n R 4 and - S(O) m
  • G is -C(R 1 )- or -N-;
  • W is a bond, -O-, -C(O)O-, -C(R 12 )-, -alkylene-O-, alkylene, -C(O)- -S(O)-, ⁇ S(O) 2 - -S(O) 2 -N(R 10 )-, -N(R 12 )-, -NHC(O)- or -C(O)-N(R 10 K such that W is other than -O- when G is -N-, and such that when G is -C(R 1 )- and W is -C(R 12 )-, these R 1 and R 12 groups can combine to form a C 1 -C 3 alkylene bridge between G and W and form a spirocycle;
  • X is a bond, -C(R 1 ) 2 -, -O-, -N(R 10 )- or -S-;
  • each occurrence of R 1 is independently H 1 alkyl, cycloalkyl, halo or -OR 7 ; wherein an alkyl group can be unsubstituted or optionally substituted with one or more of the following groups: -O-alkyl, -OH or -N(R 4 ) 2 ; and wherein any two geminal R 1 groups, together with the common carbon atom to which they are attached, can join to form a spirocyclic 3- to 6-membered cycioalkyl group, a spirocyclic 3- to 6-membered heterocycloalkyl group or a spirocyclic 3- to 6-membered heterocycloalkenyl group; and wherein any two R 1 groups present on separate ring carbon atoms can join to form an alkylene or heteroalkylene bridge between the
  • R 3 is alkyt, -(alkylene) t -alkenyl, -(alkylene) t -alkynyl, -(alkylene) r C(O)R 4 , - (alkylene)t-haloalkyl, -alkylene-O-alkyl, -alkylene-O-(alkylene) r aryl, -alkylene-S-aryl, - alkylene-N(R 4 )C(O)O-alkyl, -CH(cycloalkyl) 2 , -CH(heterocycloalkyl) 2 , -(alkylene) r aryl, - (alkylene)t-cycloalkyl, -(alkylene) t -cycfoalkenyl, -(alkylene)rheterocycloalkyl, - (alkylene)t-heterocydoalkenyl or -
  • R 9 represents from 1 to 4 optional substituents, which can be the same or different, and which are selected from alkyl, hydroxyalkyl, -(alkylene) t -O-R 13 , alkenyl, alkynyl, halo, haloalkyl, -CN, -NO 2 , -O-(alkylene) r R 13 , -S-(alkylene) t -R 13 , -N(R 13 )- (alkylene)t-R 13 , -(alkylene) r R 13 , -(alkylene) r N(R 7 ) 2 , -C(O)-(alkylene ⁇ R 13 , -C(O)O- (alkylene)rR 13 , -N(R 7 )C(OMalkylene) r R 13 , -C(O)N(R 7 )-(alkylene) t -R 13 , -OC(O)
  • R 10 is H, alkyl, aryl, Or -C(O)OR 4 , wherein an alkyl group is unsubstituted or optionally substituted with -OH or -O-alkyl;
  • R 12 is H, alkyl or aryl; each occurrence of R 13 is independently H, haloalkyl, aryl, cycloalkyl, cycloalkanoyl, cycioalkenyl, heterocycioalkyl, heterocycloalkenyl or heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyj, heterocycloalkenyl or heteroaryl group can be optionally substituted with up to 3 groups, which can be the same or different, and which are selected from alkyl, alkenyl, halo, haloalkyl, -CN, - N(R 7 ) 2 , -OH, -O-alkyl or-O-haloalkyl; each occurrence of R 14 is independently H, alkyl or aryl, or both R 14 groups, and the carbon atom to which they are attached, combine to form a cycloalkyl or heteroc
  • A is aryl or heteroary ⁇ , any of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, haio, -OH, -O-haloalkyl, -O-alkyl, -O- alkyl-OH, -O-alkyl-O-alkyl, -O-aryl, -alkylene-O-alkyl, -CN, -N(R 4 ) 2 , -C(O)H, -C(O)R 4 , - C(O)OR 4 , -C(O)N(R 4 ) 2 , -NHC(O)R 4 , -NHS(O) m R 4 , -S(O) n R 4 and -S(O) m N(R 4
  • B is aryl or heteroaryl, any of which can be optionally substituted with up to 4 groups, which can be the same or different, and are selected from: alkyl, aryl, alkenyl, cycloalkyl, cycloalkenyl, haloalkyl, hydroxyalkyl, heteroaryl, halo, -OH, -O-haloalkyl, - O-alkyl, -O-aryl, -alkylene-O-alkyl, -alkylene-S(O) 2 -alkyl, -SF 5 , -CN, -N(R 4 ) 2 , -C(O)H, - C(O)R 4 , -C(O)OR 4 , -C(O)N(R 4 ) 2) -NHC(O)R 4 , -NHS(O) m R 4 , -S(O) n R 4 and - S(O) m N(R 4
  • X is "C(R 1 ) 2 -, -O-, -N(R 10 )- or -S-; each occurrence of R 1 is independently H, alkyl, cycloalkyl, halo or -OR 7 ; R 3 is alkyl, -(alkytene) t -alkenyl, -(alkylene) r alkynyl, -(alkylene) r C(O)R 4 , -
  • (alkylene)rhaloalkyl -alkylene-O-alkyl, -alkylene-O-(alkyIene) t -aryl, -alkylene-S-aryl, - alkylene-N(R 4 )C(O)O-alkyl, -CH(cycloalkyl) 2 , -CH(heterocycIoalkyl) 2 , -(alkylene ) r aryl, - (alkylene)t-cycloalkyl, -(alkylene)rcycloalkenyl, -(alkylene) t -heterocycloalkyl, - (alkylene) t -heterocycloalkenyl or -(alkylene) t -heteroaryl, wherein an aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can
  • R 10 is H, alkyl, aryl, or -C(O)OR 4 , wherein an alkyl group is unsubstituted or optionally substituted with -OH or -O-alkyl; each occurrence of R 13 is independently H, haloalkyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl, wherein an aryl, cycloalkyl, cycioalkenyl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group can be optionally substituted with up to 3 groups, which can be the same or different, and which are selected from alkyl, halo, haloalkyl, -CN, -N(R 7 ) 2 , -OH, -O-alkyl or -O- haloalkyl; each occurrence of m is independently 1 or 2; each occurrence of n is independently O
  • the Compounds of Formulas (i) and (II) and pharmaceutically acceptable salts, solvates, esters or prodrugs thereof can be useful for treating or preventing obesity, diabetes, a diabetic complication, metabolic syndrome, a cardiovascular disease or a disorder related to the activity of a GPCR (each being a "Condition") in a patient. Also to provide by the invention are methods for treating or preventing a GPCR (each being a "Condition") in a patient. Also to provide by the invention are methods for treating or preventing a
  • the present invention provides Bicyclic Heterocycle Derivatives of Formulas (I) and (II), compositions comprising one or more Bicyclic Heterocycle Derivatives, and methods of using the Bicyclic Heterocycle Derivatives for treating or preventing a Condition in a patient.
  • a "patient” is a human or non-human mammal.
  • a patient is a human.
  • a patient is a non-human mammal, including, but not limited to, a monkey, dog, baboon, rhesus, mouse, rat, horse, cat or rabbit.
  • a patient is a companion animal, including but not limited to a dog, cat, rabbit, horse or ferret.
  • a patient is a dog. in another embodiment, a patient is a cat.
  • an obese patient refers to a patient being overweight and having a body mass index (BMI) of 25 or greater.
  • BMI body mass index
  • an obese patient has a BMI of 25 or greater
  • an obese patient has a BMI from 25 to 30.
  • an obese patient has a BMI greater than 30. in stil! another embodiment, an obese patient has a BMI greater than 40,
  • obesity-related disorder refers to: (i) disorders which result from a patient having a BMI of 25 or greater; and (ii) eating disorders and other disorders associated with excessive food intake.
  • Non-limiting examples of an obesity- related disorder include edema, shortness of breath, sleep apnea, skin disorders and high blood pressure.
  • metabolic syndrome refers to a set of risk factors that make a patient more succeptible to cardiovascular disease and/or type 2 diabetes. A patient is said to have metabolic syndrome if the patient simultaneously has three or more of the following five risk factors:
  • central/abdominal obesity as measured by a waist circumference of greater than 40 inches in a male and greater than 35 inches in a female; 2 ⁇ a fasting triglyceride level of greater than or equal to 150 mg/dL;
  • an effective amount can refer to each individual agent or to the combination as a whole, wherein the amounts of all agents administered are together effective, but wherein the component agent of the combination may not be present individually in an effective amount
  • alkyl refers to an aliphatic hydrocarbon group which may be straight or branched and which contains from about 1 to about 20 carbon atoms. In one embodiment, an alkyl group contains from about 1 to about 12 carbon atoms.
  • an alkyl group contains from about 1 to about 6 carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl.
  • An a ⁇ kyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH 2 , - NH(alkyl), -N(alkyl) 2) -NH(cycloalkyl), -O-C(O)-alkyl, -O-C(O)-aryl, -O-C(O)-cycloalkyl, -C(O)OH and -C(O)O-alkyl.
  • an alkyl group is unsubstituted.
  • an alkyl group is linear.
  • an alkyl group is branched.
  • alkenyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and contains from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms.
  • Non- limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut- 2-enyl, n-pentenyl, octenyl and decenyf.
  • An alkenyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH 2 , -NH(alkyl), -N ⁇ alkyl) 2 , -NH(cycloalkyl), -O-C(O)-alkyl, -O-C(O)-aryl, -0-C(O)- cycloalkyl, -C(O)OH and -C(O)O-alkyl.
  • an alkenyl group is unsubstituted.
  • alkynyl refers to an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and contains from about 2 to about 15 carbon atoms. In one embodiment, an alkynyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkynyl group contains from about 2 to about 6 carbon atoms.
  • Non- limiting examples of alkynyl groups include ethynyl, propynyl, 2 ⁇ butynyl and 3- methylbutynyl.
  • alkynyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH 2 , -
  • alkynyl group is unsubstituted.
  • alkylene refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond.
  • Non-timiting examples of alkylene groups include -CH 2 -, -CH 2 CH 2 -, - CH 2 CH 2 CH 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH(CH 3 )CH 2 CH 2 -, -CH(CH 3 )- and - CH 2 CH(CH 3 )CH 2 -.
  • an alkylene group has from 1 to about 6 carbon atoms.
  • an alkylene group is branched.
  • an alkylene group is linear.
  • aryl refers to an aromatic monocyclic or multicyclic ring system comprising from about 6 to about 14 carbon atoms. In one embodiment, an aryl group contains from about 6 to about 10 carbon atoms. An aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. In one embodiment, an aryl group can be optionally fused to a cycloalkyl or cycloalkanoyl group. Non-limiting examples of aryl groups include phenyl and naphthyl. in one embodiment, an aryl group is unsubstituted. In another embodiment, an aryl group is phenyl.
  • cycloalkyl refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms. In one embodiment, a cycloalkyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkyl contains from about 5 to about 7 ring atoms.
  • cycloalkyl also encompasses a cycloalkyl group, as defined above, that is fused to an aryl (e.g., benzene) or heteroaryl ring. A cycloalkyl group can be joined via a ring carbon or ring nitrogen atom.
  • a ring carbon atom of a cycloalkyl group may be functionalized as a carbonyl group.
  • An illustrative example of such a cycloalkyl group ⁇ also referred to herein as a "cycloalkanoyl" group) includes, but is not limited to, cyclobutanoyl:
  • cycloalkenyl refers to a non-aromatic mono- or multicyclic ring system comprising from about 3 to about 10 ring carbon atoms and containing at least one endocyclic double bond. In one embodiment, a cycloalkenyl contains from about 5 to about 10 ring carbon atoms. In another embodiment, a cycloalkenyl contains 5 or 6 ring atoms.
  • monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like.
  • a cycloalkenyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • a cydoalkenyl group is unsubstituted.
  • a cycloalkenyl group is a 5-membered cycloalkenyl.
  • heteroalkylene refers to group having the formula - alkylene-X-alkylene- wherein X is -O-, -S- or -NH-.
  • Non-limiting examples of heteroalkylene groups include -CH 2 OCH 2 -, -CH 2 SCH 2 -, -CH 2 N(H)CH 2 -, - CH 2 OCH 2 CH 2 -, -CH 2 SCH 2 CH 2 - and -CH 2 N(H)CH 2 CH 2 -.
  • a heteroalkylene group has from 2 to about 6 carbon atoms.
  • a heteroalkylene group has from 2 to about 3 carbon atoms.
  • heteroaryl refers to an aromatic monocyclic or multicyciic ring system comprising about 5 to about 14 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms.
  • a heteroaryl group has 5 to 10 ring atoms.
  • a heteroaryl group is monocyclic and has 5 or 6 ring atoms.
  • a heteroaryl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide,
  • heteroaryl also encompasses a heteroaryl group, as defined above, that is fused to a benzene ring.
  • heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazo ⁇ yl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1 ,2, 4-th iadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzim ⁇ dazolyl, benzothienyl, quinolinyl, imidazolyl, thien
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinoSyl, tetrahydroquinolyl and the like.
  • a heteroaryf group is unsubstituted.
  • a heteroaryl group is a 5- membered heteroaryl.
  • a heteroaryl group is a 6-membered heteroaryl.
  • heterocycloalkyl refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 10 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S or N and the remainder of the ring atoms are carbon atoms.
  • a heterocydoalkyl group can be joined via a ring carbon or ring nitrogen atom.
  • a heterocydoalkyl group has from about 5 to about 10 ring atoms.
  • a heterocycloalkyl group has 5 or 6 ring atoms. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • heterocycloalkyl any -NH group in a heterocycloalkyl ring may exist protected such as, for example, as an -N(BOC), -N(Cbz), -N(Tos) group and the like; such protected heterocycloalkyl groups are considered part of this invention.
  • heterocycloalkyl also encompasses a heterocycloalkyl group, as defined above, that is fused to an aryl (e.g., benzene) or heteroaryl ring.
  • a heterocycloalkyl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below.
  • the nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • monocyclic heterocycioalkyl rings include oxetanyl, piperidyl, pyrroiidinyl, piperazinyl, morphoiinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiopheny), lactam, lactone and the like, and ail isomers thereof.
  • a ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group.
  • An illustrative example of such a heterocycloalkyl group is pyrrolidonyl:
  • a heterocycloalkyl group is unsubstituted.
  • a heterocycloalkyl group is a 5-membered heterocycloalkyl,
  • a heterocycloalkyl group is a 6-membered heterocycloalkyl.
  • the term "heterocycloalkenyl,” as used herein, refers to a heterocycloalkyl group, as defined above, wherein the heterocycloalkyl group contains from 3 to 10 ring atoms, and at least one endocyclic carbon-carbon or carbon-nitrogen double bond.
  • a heterocycloalkenyl group can be joined via a ring carbon or ring nitrogen atom.
  • a heterocycloalkenyl group has from 5 to 10 ring atoms. In another embodiment, a heterocycloalkenyl group is monocyclic and has 5 or 6 ring atoms.
  • a heterocycloalkenyl group can optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
  • the nitrogen or sulfur atom of the heterocycloalkenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heterocycloalkenyl groups include 1 ,2,3,4- tetrahydropyridinyl, 1 ,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2- pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazoSyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl, fluoro- substituted dihydrofuranyl, 7-oxabicycto[2.2.1]heptenyl, dihydrothiophenyf, dihydrothiopyranyl, and the like.
  • a ring carbon atom of a heterocycloalkenyl group may be functionatized as a carbonyl group.
  • a heterocycloalkenyl group is unsubstituted.
  • a heterocycloalkenyl group is a 5- membered heterocycloalkenyl.
  • a heterocycloalkenyl group is a 6-membered heterocycloalkenyl.
  • Ring system substituent refers to a substituent group attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkyl-aryl, -aryl-alkyl, -alkylene-heteroaryl, - alkenylene-heteroaryl, -alkynylene-heteroaryl, hydroxy, hydroxyalkyl, haloalkyl, -O- alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, -C(O)O-alkyl, -C(O)O-ary
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • Examples of such moiety are methylenedioxy, ethylenedioxy, -C(CH 3 ) 2 ⁇ and the like which form moieties such as, for example:
  • Halo means -F, -Cl, -Br or -I. Sn one embodiment, halo refers to -F, -CI or - Br.
  • haloalkyl refers to an alkyl group as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a halogen.
  • a haloalkyl group has from 1 to 6 carbon atoms, In another embodiment, a haloalkyl group is substituted with from 1 to 3 F atoms.
  • Non- limiting examples of haloalkyl groups include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CI and -CCI 3 .
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, to provide that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • protecting groups When a functional group in a compound is termed "protected”, this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as weli as by reference to standard textbooks such as, for example, T. W. Greene et a/, Protective Groups in Organic Synthesis (1991 ), Wiiey, New York. When any variable (e.g., aryl, heterocycle, R 2 , etc.) occurs more than one time in any constituent or in Formula (I) or (II), its definition on each occurrence is independent of its definition at every other occurrence.
  • any variable e.g., aryl, heterocycle, R 2 , etc.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • a discussion of prodrugs is to provide in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • the term "prodrug” means a compound (e.g, a drug precursor) that is transformed in vivo to yleld a Bicyciic Heterocycle Derivative or a pharmaceutically acceptable salt, hydrate or solvate of the compound.
  • the transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • mechanisms e.g., by metabolic or chemical processes
  • prodrugs are to provide by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversibie Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (C 1 -C 8 )alkyl, (C 2 - C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1 ⁇
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C 1 - C 10 )alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl, -C(OH)C(O)OY 1 wherein Y 1 is H 1 ( C 1 -C 6 )alkyl or benzyl, — C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is ( C 1 -C 6 )alkyl, carboxy (C 1 -C 6 )alkyl, amino(C 1 -C 4 )alkyI or mono-N — or di
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et a/ J. Pharmaceutical Sci., 93(3), 601-611 (2004) describes the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water.
  • Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et a/, AAPS PharmSciTechours. , 5(1), article 12 (2004); and A. L. Bingham et a/, Chem. Commun., 603-604 (2001 ).
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • the Bicyc ⁇ ic Heterocycle Derivatives can form salts which are also within the scope of this invention.
  • Reference to a Bicyclic Heterocycle Derivative herein is understood to include reference to salts thereof, unless otherwise indicated.
  • salt(s) denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • a Bicyclic Heterocycle Derivative contains both a baste moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxyltc acid, zwitterions ("inner salts”) may be formed and are included within the term “salt(s)" as used herein.
  • the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt.
  • the salt is other than a pharmaceutically acceptable salt.
  • Salts of the Bicyclic Heterocycle Derivatives may be formed, for example, by reacting a Bicyclic Heterocycle Derivative with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by iyophiiization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthatenesuifonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like.
  • alkali metal salts such as sodium, lithium, and potassium salts
  • alkaline earth metal salts such as calcium and magnesium salts
  • salts with organic bases for example, organic amines
  • organic bases for example, organic amines
  • amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), and others.
  • lower alkyl halides e.g., methyl, ethyl, and butyl chlorides, bromides and iodides
  • dialkyl sulfates e.g., dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g., decyl, lauryl, and
  • esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy group of a hydroxyl compound, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, methyl, ethyl, n-propyl, isopropyt, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, C 1-4 a[kyl, or -O-C 1-4 alkyl or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesuifonyl)
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • Sterochemicaliy pure compounds may also be prepared by using chiral starting materials or by employlng salt resolution techniques.
  • some of the Bicyclic Heterocycle Derivatives may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of chiral HPLC column
  • Bicyclic Heterocycle Derivatives may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, ail keto-enol and imine-enamtne forms of the compounds are included in the invention.
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates, hydrates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4- pyridyl and 3-pyridyt).
  • Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers.
  • the chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations.
  • the use of the terms "salt”, “solvate”, “ester”, “prodrug” and the like, is intended to apply equally to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelied compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 0, 17 O, 31 P, 32 P, 35 S 1 18 F, and 36 CI, respectively.
  • Certain isotopically-labelied Pyrimidine Derivatives are useful in compound and/or substrate tissue distribution assays.
  • tritiated (i.e., 3 H) and carbon-14 (Le., 14 C) isotopes are employed for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements)
  • one or more hydrogen atoms of a Bicyclic Heterocycie Derivative is replaced with a deuterium atom.
  • lsotoptcally iabelied Bicyclic Heterocycie Derivatives can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • Polymorphic forms of the BicycHc Heterocycle Derivatives, and of the salts, solvates, hydrates, esters and prodrugs of the Bicyctic Heterocycfe Derivatives are intended to be included in the present invention.
  • the present invention provides Bicyclic Heterocycle Derivatives of Formula (I):
  • G is -CH-. in another embodiment, G is -N-. in one embodiment, W is a bond, -O- or TMalkylene-O-. in another embodiment, W is a bond.
  • W is alkylene. In another embodiment, W is -O-.
  • W is -alkylene-O-. In another embodiment, W is -C(O)O-.
  • W is -C(O)-.
  • W is -S(O) 2 -. In another embodiment, W is -S(O) 2 N(R 10 )-.
  • W is -C(O)N(R 10 )-.
  • G is -CH- and W is a bond, -O- or-alkylene-O-.
  • G is -CH- and W is a bond.
  • X is -C(R 1 ) 2 -. In another embodiment, X is -O-,
  • X is -S-
  • X is -N(R 10 )-.
  • X is -NH-.
  • Z is -C(R 1 ) 2 -. In another embodiment, Z is a single bond.
  • Z is a double bond.
  • Z is -O-. in another embodiment, Z is -S-.
  • Z is -N(R 10 )-. In another embodiment, Z is -CHR 1 -.
  • Z is -CH 2 -.
  • Z is -NH-
  • W is -C(O)O- and Z is a single bond
  • W is a bond and Z is a single bond
  • W is -C(O)O-
  • Z is a single bond
  • X is -O- .
  • W is a bond
  • Z is a single bond
  • X is -O-.
  • W is -C(O)O-
  • Z is a single bond
  • X is-NH-.
  • W is a bond
  • Z is a single bond
  • X is-NH-.
  • A is aryl
  • A is 5 or 6-membered heteroaryt.
  • A is phenyl. In still another embodiment, A is pyrimidinyl.
  • -A- is:
  • -A- is:
  • A is:
  • A is pyridyl.
  • X is -O- and A is pyrimidinyl, in another embodiment, X is -NH- and A is pyrimidinyl. In one embodiment, X is -O- and A is:
  • X is -NH- and A is:
  • Q wherein Q is H, F, methyl or -OCH 3 .
  • B is aryl. In another embodiment, B is heteroaryl. In another embodiment, B is 5 or 6-membered heteroaryl. In another embodiment, B is phenyl.
  • B is pyrimidinyl. In another embodiment, B is pyridyl.
  • B is phenyl, which is ⁇ nsubstituted or optionally substituted with up to 3 groups, each independently selected from alkyl, -CN, -S(O) 2 -alkyl, -S(O) 2 - cycloalkyl, heteroaryl and halo.
  • B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from -CN, -S(O)ralkyl and halo.
  • B is:
  • B is:
  • X is -NH- or -O-
  • B is:
  • X is -O- and B is:
  • X is -NH- and B is:
  • a and B are each independently he In another ambodiment, A and B are each independently a 5 or 6-membered heteroaryl.
  • A is a 5 or 6-membered heteroaryl and B is pyridyl.
  • -A- is:
  • X is -NH- • oorr --O0--, and -A- is:
  • X is -NH- or -O-, and -A- is:
  • A is: , wherein Q is H, halo, alkyl or -O-alkyl; and B is heteroaryl. In another embodiment, A is:
  • A is;
  • O is H, halo, alkyl or -O-alkyl; and B is:
  • A is 5 or 6-membered heteroaryl and B is phenyl.
  • A is pyrimidinyl and B is phenyl.
  • A is pyrimidinyl and B is pyridyl.
  • B is phenyl which is optionally substituted with up to 3 groups, each independently selected from alkyl, -CN, -S ⁇ O) 2 -alkyl, -S(O) 2 -cycloalkyl, heteroaryl and halo; and A is:
  • B is phenyl which is optionally substituted with up to 3 groups, each independently selected from methyl, triazoiyl, -CN 1 -Cl, -F 1 -S(O) 2 CH 3 and -S(O) 2 -cyclopropyl; and A is:
  • Q wherein Q is H, F, methyl or methoxy.
  • B is pyridyl and A is:
  • Q wherein Q is H 5 halo, alkyl or -O ⁇ alkyl.
  • X is -O 1
  • A is pyrimidinyl and B is pyridyl
  • X is -NH-
  • A is pyrimidinyl
  • B is pyridyl
  • X is -O- , A is pyrimidinyl and B is phenyl. In another embodiment, X is -NH-, A is pyrimidinyl and B is phenyl.
  • X is -0-
  • A is pyrimidinyl and B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from alkyl, -CN, -S(O) 2 -alkyl, -S(O) 2 -cycloalkyl, heteroaryl and halo.
  • X is -NH-
  • A is pyrimidinyl
  • B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from alkyl, -CN, -S(O) 2 -alkyl, -S(O) 2 -cycloalkyl, heteroaryl and halo.
  • a and B are each independently a 5 or 6-membered heteroaryf, each of which is unsubstituted or optionally substituted with one substituent, independently selected from alkyl, -CN, -S ⁇ O) 2 -alkyl, -S(O) 2 -cycloalkyl, heteroaryl and halo.
  • a and B are each independently selected from phenyl, pyridyl and pyrimidinyl, each of which is unsubstituted or optionally substituted with one substituent, independently selected from alkyl, -CN, -S(O) 2 -alkyI, -S(O) 2 - cycloalkyl, heteroaryl and halo.
  • a and B are each independently selected from phenyl, pyridyl and pyrimidinyl, each of which is unsubstituted or optionally substituted with one or more substituents, each independently selected from methyl, triazolyl, -CN, - Cl, -F, -S(O) 2 CH 3 or -S(O) 2 -cyclopropyl.
  • X is -O-
  • A is pyrimidinyl and B is pyridyl, wherein each of A and B can be optionally substituted with one substituent, independently selected from alkyl, -CN, -S ⁇ O) 2 -alkyl, -S(O) 2 -cycIoalkyl, heteroaryl and halo.
  • X is -O-
  • A is pyrimidinyl and B is pyridyl, wherein each of A and B can be optionally substituted with one or more substituents, each independently selected from methyl, triazolyl, -CN, -Cl, -F, -S(O)aCH 3 or -S(O) 2 - cyclopropyl.
  • X is -O-
  • A is pyrirnidinyl and B is pyridyl, wherein A and B are each substituted with at least one alkyl group,
  • X is -O-, A is pyrimidinyl and B is pyridyl, wherein A and B are each substituted with a methyl group.
  • X is -O-, A is pyrimidinyl and B is pyridyl.
  • X is -O-
  • A is pyrimidinyl and B is phenyl.
  • X is -O-, A is pyrimidinyl and B is pyridyl, wherein each of A and B can be optionally substituted with one substituent, independently selected from alkyl, -CN, -S(O) 2 -alkyl, -S ⁇ O) 2 -cycloalkyl, heteroaryl and halo,
  • X is -O- , A is pyrimidinyl and B is pyridyl, wherein each of A and B can be optionally substituted with one or more substituents, each independently selected from methyl, triazolyl, -CN 1 -C), -F, -S(O) 2 CH 3 Or -S(O) 2 - cyclopropyl.
  • the group B-X-A- is:
  • Q is H, halo, alkyl or -O-alkyl.
  • the group B-X-A- is:
  • the group B-X-A- is:
  • the group B-X-A- is:
  • the group B-X-A- is:
  • the group B-X-A- is:
  • group B-X-A- is: in yet another embodiment, the group B-X-A- is:
  • the group B-X-A- is:
  • group B-X-A- is:
  • the group B-X-A- is:
  • each occurrence of R 1 is selected from H 1 halo or -OH. In another embodiment, each occurrence of R 1 is H.
  • At least one occurrence of R 1 is -OH.
  • At least one occurrence of R 1 is halo.
  • At least one occurrence of R 1 is F.
  • At least one occurrence of R 2 is H, alkyl or -OH. !n another embodiment, at least one occurrence of R 2 is -OH. in still another embodiment, at least one occurrence of R 2 is alkyl.
  • At least one occurrence of R 2 is H.
  • each occurrence of R 2 is H
  • R 3 is alkyl. In another embodiment, R 3 is a linear alkyl group.
  • R 3 is a branched alkyl group.
  • R 3 is methyl. In another embodiment, R 3 is ethyl. In another embodiment, R 3 is isopropyl. In a further embodiment, R 3 is t-butyl.
  • R 3 is alke ⁇ yl
  • R 3 is alkynyl.
  • R 3 is hafoalkyl. In one embodiment, R 3 is cycloalkyl. fn another embodiment, R 3 is cyclopropyl.
  • R 3 is cyclopropyl, substituted with a methyl group.
  • R 3 is cyclobutyl
  • R 3 is cyclopentyl. In another embodiment, R 3 is cyclohexyl.
  • R 3 is aryl. tn another embodiment, R 3 is phenyl.
  • R 3 is phenyl, optionally substituted with halo.
  • R 3 is heteroaryl. In another embodiment, R 3 is 5-membered heteroaryl, in another embodiment, R 3 is 6-membered heteroaryl.
  • R 3 is oxadiazotyl.
  • R 3 is oxadiazolyl, optionally substituted with alkyl, - alkylene-0-alkyl, -alkylene-N(alkyl) 2 , cycloalkyl or alkylene-heterocycloalkyl.
  • R 3 is 4-fluorophenyt, ethyl, t-butyl, isopropyl, -
  • R 3 is:
  • W is a bond and R 3 is heteroaryl or -alkylene-O-alkyl. In another embodiment, W is a bond and R 3 is heteroaryl. In another embodiment, W is a bond and R 3 is oxadiazolyl, optionally substituted with alkyl, -alkylene-O-alkyl, -aIkylene-N(alkyI) 2 , cycioalkyl or alkylene- heterocycloalkyl.
  • W is a bond and R 3 is;
  • R 3 is -alkylene-aryl. In a further embodiment, R 3 is benzyl. In one embodiment, p and u are each 1. In another embodiment, u, p, q, r, and s are each independently O or 1.
  • p and u are each 1 , and r and s are each O.
  • q, p and u are each 1 , r and s are each O and 2 is a bond.
  • q, p and u are each 1 , r and s are each O, Z is a bond, and W is a bond.
  • q, p and u are each 1 , r and s are each O, Z is a bond, W is a bond and X is -O-.
  • q, p and ⁇ are each 1 , r and s are each 0, Z is a bond, W is a bond, X is -O-, A is a 5 or 6-membered heteroaryl, and B is phenyl or a 5 or 6- membered heteroaryl.
  • q, p and u are each 1 , r and s are each 0, Z is a bond, W is -C(O)O-, X is -O-, A is a 5 or 6-membered heteroaryl, B is phenyl or pyridyl, and R 3 is heteroaryl.
  • q, p and u are each 1 , r and s are each 0, Z is a bond, W is -C(O)O-, X is -O-, A is a 5 or 6-membered heteroaryl, B is phenyl or a 5 or 6- membered heteroaryl, each occurrence of R 1 is H, and R 3 is heteroaryl.
  • q, p and u are each 1 , r and s are each 0, Z is a bond, W is a bond, X is -O-, A is a 5 or 6-membered heteroaryl, B is phenyl or a 5 or 6- membered heteroaryl, each occurrence of R 1 and R 2 is H, and R 3 is heteroaryl,
  • q, p and u are each 1 , r and s are each 0, Z is a bond, W is a bond and X is -NH-.
  • q, p and u are each 1 , r and s are each 0, Z is a bond, W is a bond, X is -NH-, A is a 5 or 6-membered heteroaryl, and B is phenyl or a 5 or 6- membered heteroaryl.
  • q, p and u are each 1 , r and s are each 0, Z is a bond,
  • W is -C(O)O-
  • X is -NH-
  • A is a 5 or 6-membered heteroaryl
  • B is phenyl or pyridyl
  • R 3 is heteroaryl.
  • q, p and u are each 1 , r and s are each 0, Z is a bond, W is -C(O)O-, X is -NH-, A is a 5 or 6-membered heteroaryl, B is phenyl or a 5 or 6-membered heteroaryl, each occurrence of R 1 is H, and R 3 is heteroaryl.
  • q, p and u are each 1 , r and s are each 0, Z is a bond, W is a bond, X is -NH-, A is a 5 or 6-membered heteroaryl, B is phenyl or a 5 or 6- membered heteroaryl, each occurrence of R 1 and R 2 is H, and R 3 is heteroaryl.
  • the group -B-X-A- is:
  • Q is H, halo, alkyl or-O-alkyS, and the group:
  • the group -B-X-A- is:
  • the group -B-X-A- is: wherein Q is H, halo, alkyl or-O-alkyl, and the group:
  • the group -B-X-A- is: wherein Q is H, halo, alkyl or ⁇ O-alkyl, and the group:
  • the group -B-X-A- is: and the group: in still another embodiment, the group -B-X-A- is:
  • Q is H, halo, alkyl or -O-alkyl, and the group:
  • the group -B-X-A- is: and the group:
  • the present invention provides Compounds of Formula (I), wherein A, B 1 G 5 W 1 X, Z 1 R 1 , R 2 , R 3 , p, q, r, s and u are selected independently of each other.
  • a Compound of Formula (I) is in purified form.
  • a Compound of Formula (I) has the formula:
  • A is aryl or -5- or 6-membered heteroaryl, each of which can be optionally substituted with an alkyl, halo or -O-alkyl group;
  • B is aryl or heteroaryl, each of which can be optionally substituted with up to 3 groups, which can be the same or different, and are selected from: alkyl, halo, heteroaryl, -CN or ⁇ S(O) 2 alkyl;
  • W is a bond, -O-, alkylene or -alkylene-O-;
  • X is -O- or -NH-
  • R 3 is alkyl, aryl or heteroaryl, wherein an aryl or heteroaryl group can be unsubstituted or optionally substituted with an alkyl, cycloalkanoyl, cycloalkyl, hydroxyalkyl, -alkylene-N(alkyl) 2 , or -alkylene-O-alkyl group, wherein a cycloalkyl substituent can be further and optionally substituted with up to 3 groups, which can be the same or different, and are selected from alkyl, alkenyl, halo, haioalkyl, -OH or -O- alkyl.
  • A is aryl. In another embodiment, for the Compounds of Formula (Ia), A is 5 or 6- membered heteroaryl,
  • A is phenyl. In still another embodiment, for the Compounds of Formula (Ia), A is pyrimidinyl. In another embodiment, for the Compounds of Formula (Ia), -A- is:
  • B is heteroaryl
  • B is 5 or 6- membered heteroaryl. In still another embodiment, for the Compounds of Formula (Ia), B is phenyl.
  • B is pyrimidinyl
  • B is pyridyl
  • B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from alkyl, -CN 1 -S(O) 2 -alkyl, -S(O) 2 -cycloalkyl ! heteroaryl and halo.
  • B is phenyl, which is unsubstituted or optionally substituted with up to 3 groups, each independently selected from -CN, -S(O) 2 -alkyl and halo.
  • B is:
  • B is:
  • W is a bond.
  • W is alkylene. In another embodiment, for the Compounds of Formula (Ia), W is -O-.
  • W is - alkylene-O-.
  • X is -O- .
  • X is -NH-.
  • X is -O- and B is:
  • a and B are each independently heteroaryl.
  • a and B are each independently a 5 or 6-membered heteroaryl.
  • A is a 5 or 6- membered heteroaryl and B is pyridyl.
  • A is a 5 or 6- membered heteroaryl and B is substituted phenyl.
  • X is -NH- or -O-, and -A- is:
  • X is -NH- or -O-, and -A- is:
  • A is:
  • Q is H, halo, alkyl or -O-alkyl; and B is heteroaryt
  • Q is H 1 halo, alkyl or -O-alkyl; and B is pyridyl.
  • A is:
  • A is 5 or 6-membered heteroaryl and B is phenyl.
  • A is pyrimidinyl and B is phenyl.
  • A is pyrimidinyl and B is pyridyl.
  • R 3 is alkyl
  • R 3 is a linear alkyl group.
  • R 3 is a branched alkyl group. In still another embodiment, for the Compounds of Formula (Ia), R 3 is methyl.
  • R 3 is ethyl. In another embodiment, for the Compounds of Formula (Ia), R 3 is isopropyl, in a further embodiment, for the Compounds of Formula (Ia), R 3 is t-butyl. In yet another embodiment, for the Compounds of Formula (Ia), R 3 is aryl. In another embodiment, for the Compounds of Formula (Ia), R 3 is phenyl.
  • R 3 is phenyl, optionally substituted with halo.
  • R 3 is heteroaryl. In another embodiment, for the Compounds of Formula (Ia), R 3 is 5-membered heteroaryl. In another embodiment, for the Compounds of Formula (Ia), R 3 is 6-membered heteroaryl.
  • R 3 is oxadiazoiyl.
  • R 3 is oxadiazolyl, optionally substituted with alkyl, -alkylene-O-alkyl, -alkylene-N(alkyl) 2 , cycioalkyl or alkylene-heterocycloalkyl.
  • R 3 is 4- fluorophenyl, ethyl, t-butyl, isopropyl,
  • R 3 is: in another embodiment, for the Compounds of Formula (Ia), R 3 is:
  • W is a bond and R 3 is heteroaryi
  • W is a bond and R 3 is oxadiazolyl, optionally substituted with alkyl, -alkylene-O-alkyl» -alky ⁇ ene- N(alkyl) 2 , cycloalkyl or alkylene-heterocycloalkyl.
  • W is a bond and R 3 is:
  • A is 6-membered heteroaryl, which can be optionally substituted with an alkyl group;
  • B is phenyl, which can be optionally substituted with up to 2 substituents, which can be the same or different and are selected from halo and -S(O) 2 -alkyl;
  • W is a bond; and
  • X is -0-.
  • A is 6-membered heteroaryl, which can be optionally substituted with an alkyl group
  • B is phenyl, which can be optionally substituted with up to 2 substituents, which can be the same or different and are selected from halo and -S ⁇ O) 2 -alkyl
  • W is a bond
  • X is -0-
  • R 3 is heteroaryl, which can be optionally substituted with an alkyl group.
  • A is pyrimidinyl, which can be optionally substituted with an alkyl group;
  • B is phenyl, which can be optionally substituted with up to 2 substituents, which can be the same or different and are selected from halo and ⁇ S(O) 2 -alkyl;
  • W is a bond;
  • X is -O-; and
  • R 3 is heteroaryl, which can be optionally substituted with an alkyl group.
  • the present invention provides compounds of Formula (Ia), wherein A, B, W and X are selected independently of each other.
  • a compound of formula (Ia) is in purified form.
  • the present invention further provides Bicyclic Heterocycle Derivatives of Formula (II):
  • G is -CH-. In another embodiment, G is -N-. In one embodiment, W is a bond Or -C(O)O-. In another embodiment, W is a bond. In another embodiment, W is -C(O)O-.
  • W is -C(O)-. In yet another embodiment, W is -S(O) 2 -. In another embodiment, W is -S(O) 2 N(R 10 )-. In a further embodiment, W is -C(O)N(R 10 )-.
  • G is N and W is -C(O)O-.
  • G is --CH- and W is a bond.
  • X is -C(R 1 ) 2 -.
  • X is -O-.
  • X is -S-.
  • X is -N(R 10 )-.
  • X is -NH-.
  • A is aryl
  • A is 5 or 6-membered heteroaryl.
  • A is phenyl
  • A is pyrimidtnyl.
  • A is pyridyl
  • A is 5-methylpyrimidinyl
  • B is aryl
  • B is 5 or 6-membered heteroaryl.
  • B is phenyl
  • B is pyrimidinyl
  • B is pyridyl. in another embodiment, B is 2-methyS pyridyl.
  • B is 2-chloro-4-cyanophenyl.
  • B is:
  • B is:
  • a and B are each independently a 5 or 6-membered heteroaryl.
  • X is -NH- and A is pyrimidinyf. In yet another embodiment, X is -NH- and B is phenyl.
  • X is -NH-
  • A is pyrimidinyl and B is phenyl.
  • a and B are each independently a 5 or 6-membered heteroaryl, each of which can be optionally substituted with one substituent, independently selected from alkyl, aryl, -S(O) 2 -alkyl and halo.
  • a and B are each independently selected from phenyl, pyridyl and pyrimidinyl, each of which can be optionally substituted with one substituent, independently selected from alkyl, aryl, -S(O) 2 -alkyl and halo.
  • a and B are each independently selected from phenyl, pyridyl and pyrirnidinyl, each of which can be optionally substituted with one or more substituents, each independently selected from methyl, phenyl, F 5 Cl and -S(O) 2 CH 3 .
  • X is -NH-
  • A is pyrimidinyl and B is phenyl, wherein each of A and B can be optionally substituted with one substituent, independently selected from alkyl, -CN, halo and -S(O) 2 -alkyl.
  • X is -NH-
  • A is pyrimidinyl and B is phenyl, wherein each of A and B can be optionally substituted with one or more substituents, each independently selected from methyl, -CN, F, -S(O ⁇ CH 3 and Cl.
  • the group B-X-A- is:
  • each occurrence of R is selected from H, alkyl, halo or -
  • each occurrence of R 1 is H.
  • R 3 is alkyl. in another embodiment, R 3 is a linear alkyl group.
  • R 3 is a branched alkyl group.
  • R 3 is methyl
  • R 3 is ethyl. in another embodiment, R 3 is isopropyl. In a further embodiment, R 3 is t-butyl. In one embodiment, R 3 is cycloalkyl. In yet another embodiment, R 3 is aryl. In another embodiment, R 3 is phenyl. In another embodiment, R 3 is -alkylene-aryl. In another embodiment, R 3 is benzyl. In another embodiment, R 3 is heteroaryl. In another embodiment, R 3 is:
  • R 3 is alkyl or heteroaryl, wherein a heteroaryl group can be optionally substituted with an alkyl or cycloalkyl group,
  • R 3 is isopropyl or t-butyl.
  • W is -C(O)O- and R 3 is alkyl.
  • W is a bond and R 3 is heteroaryl.
  • W is -C(O)O- and R 3 is isopropyl or t-butyl.
  • W is a bond and R 3 is:
  • p and q are each 1.
  • r and s are each 1.
  • p, q, r and s are each 1.
  • the sum of p and q is 1.
  • the sum of p and q is 2. in another embodiment, the sum of p and q is 3.
  • the sum of p and q is 4. In another embodiment, the sum of p and q is 5.
  • the sum of p and q is 6.
  • the sum of r and s is 1.
  • the sum of r and s is 2.
  • the sum of r and s is 3.
  • the sum of r and s is 4.
  • the sum of r and s is 5.
  • G is N; p is 1 ; and q, r and s are each 2.
  • G is N; p is 0; q is 3; and r and s are each 2.
  • G is N; p is 0; q is 2; and r and s are each 2.
  • G is N; p and q are each 2; and r and s are each 1.
  • G is N; p and q are each 2; r is 1 ; and s is 2.
  • G is -CH-; p and q are each 2; and the sum of r and s is 1.
  • G is N; W is -C(O)O-; R 3 is alkyl; and the group B-X-A- is:
  • G is -CH-; W is a bond; R 3 is heteroaryl; and the group B-X-A- is:
  • G is N; W is -C(O)O-; R 3 is isopropyl or t-butyl; and the group B-X-A- is: tn stilf
  • G is -CH-; W is a bond; R 3 is:
  • the present invention provides compounds of Formula (Ii), wherein A 1 B 1 G, W, X 1 R 1 , p, q, r and s are selected independently of each other.
  • a compound of formula (II) is in purified form.
  • Non-t ⁇ miting examples of the Bicyclic Heterocycle Derivatives include compounds 1-100, depicted below:
  • Scheme 1 illustrates a method useful for making the compounds of formula ill, which are useful intermediates for making the Bicyclic Heterocycle Derivatives of Formula (I).
  • a and B are defined above for the compounds of formulas (I) and (II); G is ⁇ OH, -SH 1 -NHR 10 or a carbon nucleophile; and X is -S-, -O-, -C(R V or -NR 10 .
  • a dichloro aryl or heteroaryl compound of formula i can be reacted with a compound of formula ii in the presence of a base, such as potassium carbonate or sodium hydride, to provide the intermediate compounds of formula Ui.
  • a base such as potassium carbonate or sodium hydride
  • Scheme 2 illustrates a general method useful for making the Compounds of Formula (I).
  • a compound of formula iv can be coupled with a compound of formula iii in the presence of diisopropylethylamine (DIPEA) in dioxane to provide the Compounds of Formula (I).
  • DIPEA diisopropylethylamine
  • Scheme 3 illustrates an alternative method useful for making the Compounds of Formula (i).
  • R 1 , R 2 , R 3 , A, B, G, W, X, Y, Z, p, q, r, s and u are defined above for the Compounds of Formula (I).
  • a compound of formula iv can be coupled with a compound of formula i in the presence of diisopropylethylamine (DIPEA) to provide the intermediate compounds of formula v, A compound of formula v can then be reacted with a compound of formula it using the method described in Scheme 1 for coupling i and H, This provides the Compounds of Formula (i) via a two step process.
  • DIPEA diisopropylethylamine
  • Scheme 4 illustrates a method useful for making the compounds of formula (II).
  • R 1 , R 3 , A, B, G, W, X, Y 1 p, q, r and s are defined above for the compounds of formula (II).
  • a compound of formula vi can be coupled with a compound of formula i in the presence of diisopropylethylamine (DiPEA) to provide the intermediate compounds of formula vii.
  • DiPEA diisopropylethylamine
  • a compound of formula vii can then be reacted with a compound of formula ii using a Buchwald N-arylation process or the method described in Scheme 1 for coupling i and ii. This provides the compounds of formula (H).
  • Derivatives may require the need for the protection of certain functional groups (i.e., derivatization for the purpose of chemical compatibility with a particular reaction condition).
  • Suitable protecting groups for the various functional groups of the Bicyclic Heterocycle Derivatives and methods for their installation and removal may be found in Greene et ah, Protective Groups in Organic Synthesis, Wiley-lntersctence, New York, (1999).
  • Step D Synthesis of Compound 1 To a solution of Compound 1D (-0.23 mmol) in DMF (1 mL) was added
  • Step C Synthesis of Compound 2C
  • a solution of Compound 2B (2.0 g, 8.3 mmol) in a mixture of acetonitrile (8 mL), ethyl acetate (8 mL), and water (12 mL) was added sodium periodate (8.17 g, 38.17 mmol) followed by ruthenium chloride (0.1 g, 0.48 mmoi).
  • the resulting reaction was allowed to stir at room temperature for 20 hours, after which time it was diluted with dichloromethane and washed with brine solution.
  • Step D Synthesis of Compound 2D
  • 4-methylmorpholine (0.71 mL, 6.47 mmoi) followed by isopropyl chloroformate (1M in toluene, 6.5 mL, 6.5 mmol).
  • the resulting reaction was allowed to stir at room temperature for 2 hours, after which time it was washed with water and brine.
  • the combined organic extracts were dried (Na 2 SO 4 ), filtered, and concentrated in vacuo and the resulting oily residue was taken up in 30 mL DMF.
  • Compound 2E was prepared from Compound 2D using the method described in Example 1 , Step C.
  • Step G Synthesis of Compounds 2 and 3
  • a solution of Compounds 2E (0.45 g, 2.05 mmoi) and 2F (0.65 g, 2.05 mmol) and N,N-diisopropylethylamine (0.75 ml_, 4.3 mmol) in 3.5 mL dioxane and 1.0 ml_ 1- methyl-2-pyrrolidinone was heated to 170 °C and allowed to stir at this temperature for 16 hours. The reaction was cooled to room temperature, water was added and the resulting solution was extracted with ethyl acetate.
  • Compound 8 was prepared by reacting Compound 2F with Compound 6D using the method described in Example 2, Step G; LCMS: 479 (M+H) + .
  • Step B Synthesis of Compound IB To a solution of Compound 7A (150 mg, 0.5 mmol) in 2 mi_ EtOH and 2 mL
  • Step C - Synthesis of Compound 9 Compound 9 was synthesized from compound 7B using the method described in Example 2, LCMS: 480 (IvHH) + .
  • Step D was replaced with N-hydroxy-2-methoxy- acetamidine (as synthesized in EP 1479674 A1 , 2004); LCMS: 503 (M+H) + ,
  • Step A - Synthesis of Compound 19A Compound 28 (0.015 g, 0.031 mmol) was diluted with 4.0M HCl/dioxane (2.0 mL) and the resulting solution was allowed to stir for 2 hours. The reaction mixture was then concentrated in vacuo to provide Compound 19A as its hydrochloride salt, which was used without further purification.
  • Step A (heating in a microwave apparatus for 2 hours at 14O°C)
  • Compound 21 C was converted to Compound 21 D, as a yellow solid.
  • Compound 22D was prepared from Compound 22C using the method described in Example 18, Step A.
  • Step E Synthesis of Compound 25F
  • Compound 25E and 5-methyl-4,6-dichloropyrimidine were reacted using the method described in Example 18, Step A, heating by microwave at 140 °C for 1.5 hours.
  • the resulting mixture of the exo- and encfo-isomers were separated by chromatography on silica ⁇ 0-20% EtOAc/hexane), with the e ⁇ cfo-isomer (Compound 25F) eluting first.
  • Step D Compound 27D was converted to Compound 27E, which was used without further purification.
  • Step F- Synthesis of Compound 27 F Compound 27E and 5-methyl-4,6-dichloropyrimidine were reacted according to the method described in Example 18, Step A, heating by microwave at 140 °C for 1 hour. Purification using preparative TLC provided Compound 27F as a yellow oil. Step G - Synthesis of Compound 38
  • Step B Synthesis of Compound 42
  • a solution of Compound 31 A (15 mg) in 0.5 mL THF was added dimethylamine (2M in THF, 1 mL) and the resulting reaction was allowed to stir at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and the resulting residue was purified using preparative TLC (3% MeOH in CH 2 CI 2 ) to provide Compound 42.
  • LCMS 516 (M+H) + .
  • Step A Synthesis of compound 35A To a solution of 4,6-dichloro-5-methylprylmidine (0.28 g, 1.7 mmol) in 15 ml
  • Compound 46 was synthesized by reacting 35A with 2E according to the method described in Example 2, step G without using 1-methyl-2-pyrro!idine; LCMS: 465, 467 (M+Hf .
  • Compound 47 was synthesized by reacting 1E and 2E according to the method described in Example 2, step G without using i-methyl-2-pyrrolidine; LCMS: 421 (M+H) + .
  • Compound 50 was prepared from Compound 49 using the method described in Example 37; LCMS: 531 (M+H) + ,
  • Compound 51 was prepared using the method described in Example 35 and replacing 3-Chioro-4-hydroxybenzonitrile with 2-fluoro-4-methylsulfonylphenol in step A.
  • Compound 46C was synthesized from 46B using the method described in Example 2 for the synthesis of Compound 2E.
  • step A 1 Compound 2E was replaced with Compound 46C.
  • step B 1 4-(methylsulfonyl)- aniline was replaced with 2-fluoro-4-(methylsulfonyl)aniline and the reaction was conducted in dioxane using Cs 2 CO 3 and ( ⁇ )-BINAP instead of K 3 PO 4 and (o ⁇ biphenyl)PCy 2 respectively.
  • Compounds 65 and 66 were prepared using the method described in Example 35 and replacing 3 ⁇ Chloro- 4-hydroxybenzonitrile with 2-fluoro-4-methylsulfonylphenoi in step A.
  • Compound 65 LCMS: 506 (M-I-H) +
  • Compound 66 LCMS: 506 (M+H) + .
  • Compound 48A was synthesized using the method described above for the synthesis of Compound 2F.
  • Compound 49D was prepared from Compound 49C using the method described in Example 35.
  • Step D Synthesis of Compound 68
  • Compound 68 was prepared from Compound 49E using the method described in Example 2, Step D. LCMS; 518 (M+H) + .
  • Step A Synthesis of Compound 5OA
  • a solution of triethylphosphonoacetate (1.78 mL, 8.88 mmol) in 40 mL THF was added 60% NaH (0.36 g, 8.88 mmol).
  • the resulting reaction was allowed to stir for 30 minutes at 0 °C, after which time a solution of Compound 1 A (1.0 g, 4.44 mmol) in 4 mL THF was added.
  • the reaction was allowed to stir for 16 hours, during which time it was allowed to warm to room temperature on its own.
  • the reaction was then quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate (2 x 40 mL).
  • the combined organic extracts were dried (Na 2 SO 4 ) t filtered and concentrated in vacuo to provide Compound 5OA which was used without further purification.
  • Compound 5OB was converted to Compound 5OC using the method described in Example 2, Steps E and G.
  • Step D Synthesis of Compound 69
  • Trifluoroacetic acid (0.32 mL, 4.2 mmol, 4 eq) was added to a solution of Compound 51 B (0.330 g, 1.05 mmol, 1 eq) in dichloromethane 10 mL at room temperature and the resulting reaction was allowed to stir at room temperature for 4 hours then was concentrated in vacuo. The resulting residue was taken up in 1 ,4- dioxane (10 mL) and to the resulting solution was added DIPEA (0.73 mL, 4.2 mmol, 4 eq) » followed by Compound 51 C (0.297 mg, 1.05 mmol, 1 eq). The resulting reaction was heated to 110 °C and allowed to stir at this temperature for 4 hours.
  • Step C Synthesis of Compound 52D
  • a solution of Compound 52C (0.78 g, 3.0 mmol), 4,6-dichloro-5- methylpyrimidine (0.51 g, 3.1 mmof) and DiPEA (1.06 mL, 6.1 mmol) in 1 ,4-dioxane (6 mL) was sealed and heated in a microwave apparatus at 155 °C for 1 hour.
  • the reaction mixture was then cooled to room temperature and concentrated in vacuo and the residue obtained was purified using flash column chromatography on silica (0-40% EtOAc/hexanes) to provide Compound 52D.
  • Step D Synthesis of Compound 71
  • HEK293 cells expressing human GPR119 were maintained in culture flasks at 37 °C/5% CO 2 in DMEM containing 10% fetal bovine serum, 100 U/ml Pen/Strep, and 0.5 mg/ml geneticin. The media was changed to Opttmem and cells were incubated overnight at 37 °C /5% CO2. The Optimem was then aspirated and the cells were removed from the flasks using room temperature Hank's balanced saline solution (HBSS).
  • HBSS Hank's balanced saline solution
  • the cells were pelleted using centrifugation (1300 rpm, 7 minutes, room temperature), then resuspended in stimulation buffer (HBSS, 0.1 % BSA, 5 mM HEPES, 15 ⁇ M RO-20) at 2.5 x 10 6 ceils/mL. Alexa Fluor 647-anti cAMP antibody (1 :100) was then added to the cell suspension and incubated for 30 minutes.
  • a representative Bicyclic Heterocycle Derivative (6 ⁇ l at 2X concentration) in stimulation buffer containing 2% DMSO were then added to white 384 well Matrix plates. Cell suspension mix (6 ⁇ l) was added to each well and incubated with the Bicyclic Heterocycle Derivative for 30 minutes.
  • a cAMP standard curve was also created in each assay according to the kit protocol. Standard concentrations of cAMP in stimulation buffer (6 ⁇ l) were added to white 384 well plates. Subsequently, 6 ⁇ l of 1 :100 anti-cAMP antibody was added to each well. Following the 30 minute incubation period, 12 ⁇ l of detection mix (included in kit) was added to all wells and incubated for 2-3 hours at room temperature. Fluorescence was detected on the plates using an Envision instrument. The level of cAMP in each well is determined by extrapolation from the cAMP standard curve.
  • EC 50 values for various illustrative Bicyclic Heterocycle Derivatives pf the present invention were calculated and range from about 1 nM to about 20 ⁇ M.
  • Glucose was administered to the animals 30 minutes post-dosing (3 g/kg p.o.). Blood glucose was measured prior to administration of test compound and glucose, and at 20 minutes after glucose administration using a hand-held glucometer (Ascensia Elite, Bayer).
  • Derivatives of the present invention are effective in lowering blood glucose levels after glucose challenge. Uses of the Bicyclic Heterocycle Derivatives
  • the Bicyclic Heterocycle Derivatives are useful in human and veterinary medicine for treating or preventing a Condition in a patient.
  • the Bicyciic Heterocycle Derivatives can be administered to a patient in need of treatment or prevention of a Condition.
  • Bicyclic Heterocycle Derivatives are useful for treating obesity or an obesity-related disorder.
  • the invention provides methods for treating obesity or an obesity-related disorder in a patient, wherein the method comprises administering to the patient an effective amount of one or more Bicycfic Heterocycle Derivatives, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
  • the Bicyclic Heterocycle Derivatives are useful for treating diabetes in a patient. Accordingly, in one embodiment, the present invention provides a method for treating diabetes in a patient, comprising administering to the patient an effective amount of one or more Bicyclic Heterocycle Derivatives.
  • Non-limiting examples of diabetes treatable or preventable using the Bicyclic Heterocycle Derivatives include, type I diabetes (insulin-dependent diabetes mellitus), type II diabetes (non-insulin dependent diabetes mellitus), gestational diabetes, autoimmune diabetes, insulinopathies, idiopathic type I diabetes (Type 1 b), latent autoimmurnne diabetes in adults, early-onset type 2 diabetes (EOD), youth-onset atypical diabetes (YOAD), maturity onset diabetes of the young (MODY), malnutrition- related diabetes, diabetes due to pancreatic disease, diabetes associated with other endocrine diseases (such as Cushing's Syndrome, acromegaly, pheochromocytoma, glucagonoma, primary aldosteronism or somatostatinoma), type A insulin resistance syndrome, type B insulin resistance syndrome, lipatrophic diabetes, diabetes induced by ⁇ -cell toxins, and diabetes induced by drug therapy (such as diabetes induced by antipsychotic agents).
  • type I diabetes
  • the diabetes is type I diabetes. In another embodiment, the diabetes is type Il diabetes,
  • the Bicyclic Heterocycle Derivatives are useful for treating a diabetic complication in a patient. Accordingly, in one embodiment, the present invention provides a method for treating a diabetic complication in a patient, comprising administering to the patient an effective amount of one or more Bicyciic Heterocycle Derivatives.
  • Non-limiting examples of diabetic complications treatable or preventable using the Bicyclic Heterocycle Derivatives include diabetic cataract, glaucoma, retinopathy, aneuropathy (such as diabetic neuropathy, polyneuropathy, mononeuropathy, autonomic neuropathy, microaluminuria and progressive diabetic neuropathyl), nephropathy, gangrene of the feet, immune-complex vasculitis, systemic lupsus erythematosus (SLE), atherosclerotic coronary arterial disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint problems, a skin or mucous membrane complication (such as an infection, a shin spot, a candidal infection or necrobiosis lipoidica diabeticorumobesity), hyperlipidemia, cataract, hypertension, syndrome of insulin resistance, coronary artery disease, a fungal infection, a bacterial infection, and cardiomyopathy.
  • the Bicyclic Heterocycle Derivatives are useful for treating a metabolic disorder. Accordingly, in one embodiment, the invention provides methods for treating a metabolic disorder in a patient, wherein the method comprises administering to the patient an effective amount of one or more Bicyclic Heterocycle Derivatives, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof.
  • Non-limiting examples of metabolic disorders treatable include metabolic syndrome (also known as "Syndrome X”), impaired glucose tolerance, impaired fasting glucose, hypercholesterolemia, hyperiipidemia, hypertriglyceridemia, low HDL levels, hypertension, phenylketonuria, post-prandial lipidemia, a glyc ⁇ gen-storage disease, Gaucher's Disease, Tay-Sachs Disease, Niernann-Pick Disease, ketosis and acidosis.
  • the metabolic disorder is hypercholesterolemia.
  • the metabolic disorder is hyperlipidemia.
  • the metabolic disorder is hypertriglyceridemia.
  • the metabolic disorder is metabolic syndrome.
  • the metabolic disorder is low HDL levels.
  • the Bicyclic Heterocycle Derivatives are useful for treating or preventing a cardiovascular disease in a patient. Accordingly, in one embodiment, the present invention provides a method for treating a cardiovascular disease in a patient, comprising administering to the patient an effective amount of one or more Bicyclic Heterocycle Derivatives.
  • Non-iimitng examples of cardiovascular diseases treatable or preventable using the present methods include atherosclerosis, congestive heart failure, cardiac arrhythmia, myocardial infarction, atrial fibrillation, atrial flutter, circulatory shock, left ventricular hypertrophy, ventricular tachycardia, supraventricular tachycardia, coronary artery disease, angina, infective endocarditis, non-infective endocarditis, cardiomyopathy, peripheral artery disease, Reynaud's phenomenon, deep venous thrombosis, aortic stenosis, mitral stenosis, pulmonic stenosis and tricuspid stenosis.
  • the cardiovascular disease is atherosclerosis.
  • the cardiovascular disease is congestive heart failure. In another embodiment, the cardiovascular disease is coronary artery disease.
  • the present invention provides methods for treating a Condition in a patient, the method comprising administering to the patient one or more Bicyclic Heterocycle Derivatives, or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof and at least one additional therapeutic agent that is not a Bicyclic Heterocycle Derivative, wherein the amounts administered are together effective to treat or prevent a Condition.
  • Non-iirniting examples of additional therapeutic agents useful in the present methods for treating or preventing a Condition include, anti-obesity agents, antidiabetic agents, any agent useful for treating metabolic syndrome, any agent useful for treating a cardiovascular disease, cholesterol biosynthesis inhibitors, cholesterol absorption inhibitors, bile acid sequestrants, probucol derivatives, IBAT inhibitors, nicotinic acid receptor (NAR) agonists, ACAT inhibitors, choiesteryl ester transfer proten (CETP) inhibitors, low-denisity lipoprotein (LDL) activators, fish oil, water-soluble fibers, plant sterols, plant stands, fatty acid esters of plant stanols, or any combination of two or more of these additional therapeutic agents.
  • anti-obesity agents any agent useful for treating metabolic syndrome
  • any agent useful for treating a cardiovascular disease cholesterol biosynthesis inhibitors, cholesterol absorption inhibitors, bile acid sequestrants, probucol derivatives, IBAT inhibitors, nico
  • Non-limiting examples of anti-obesity agents useful in the present methods for treating a Condition include CB 1 antagonists or inverse agonists such as rimonabant, neuropeptide Y antagonists, MCR4 agonists, MCH receptor antagonists, histamine H 3 receptor antagonists or inverse agonists, metaboiic rate enhancers, nutrient absorption inhibitors, leptin, appetite suppressants and lipase inhibitors.
  • CB 1 antagonists or inverse agonists such as rimonabant, neuropeptide Y antagonists, MCR4 agonists, MCH receptor antagonists, histamine H 3 receptor antagonists or inverse agonists, metaboiic rate enhancers, nutrient absorption inhibitors, leptin, appetite suppressants and lipase inhibitors.
  • Non-limiting examples of appetite suppressant agents useful in the present methods for treating or preventing a Condition include cannabinoid receptor 1 (CBi) antagonists or inverse agonists (e.g., rimonabant); Neuropeptide Y (NPY1 , NPY2, NPY4 and NPY5) antagonists; metabotropic glutamate subtype 5 receptor (mGluR5) antagonists (e.g., 2-methyl-6-(phenyIethynyl)-pyridine and 3[(2-methyl-1 ,4-thiazol-4- yl)ethynyl]pyridine); melanin-concentrating hormone receptor (MCH1 R and MCH2R) antagonists; melanocortin receptor agonists (e.g., Melanotan-ll and Mc4r agonists); serotonin uptake inhibitors (e.g., dexfenfluramine and fluoxetine); serotonin (5HT) transport inhibitors (e.g., paroxetine, fluoxetine
  • Non-timiting examples of metabolic rate enhancers useful in the present methods for treating or preventing a Condition include acetyl-CoA carboxylase-2 (ACC2) inhibitors; beta adrenergic receptor 3 ( ⁇ 3) agonists; diacylglyceroi acyltransferase inhibitors (DGAT1 and DGAT2); fatty acid synthase (FAS) inhibitors (e.g., Cerulenin); phosphodiesterase (PDE) inhibitors (e.g., theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, rolipram and cilom ⁇ ast); thyroid hormone ⁇ agonists; uncoupling protein activators (UCP-1 ,2 or 3) (e.g., phytanic acid, 4-[(E ⁇ -2-(5,6,7,84etramethyl-2-naphthalenyl)-1-propeny
  • Non-limiting examples of nutrient absorption inhibitors useful in the present methods for treating or preventing a Condition include lipase inhibitors (e.g., oriistat, lipstatin, tetrahydrolipstatin, teasaponin and diethylumbell ⁇ feryl phosphate); fatty acid transporter inhibitors; dicarboxylate transporter inhibitors; glucose transporter inhibitors; and phosphate transporter inhibitors.
  • lipase inhibitors e.g., oriistat, lipstatin, tetrahydrolipstatin, teasaponin and diethylumbell ⁇ feryl phosphate
  • fatty acid transporter inhibitors e.g., oriistat, lipstatin, tetrahydrolipstatin, teasaponin and diethylumbell ⁇ feryl phosphate
  • dicarboxylate transporter inhibitors e.g., dicarboxylate transporter inhibitors
  • glucose transporter inhibitors e.
  • Non-limiting examples of cholesterol biosynthesis inhibitors useful in the present methods for treating or preventing a Condition include HMG-CoA reductase inhibitors, squalene synthase inhibitors, squalene epoxidase inhibitors, and mixtures thereof.
  • Non-limiting examples of cholesterol absorption inhibitors useful in the present methods for treating or preventing a Condition include ezetimibe.
  • the cholesterol absorption inhibitor is ezetimibe.
  • HMG-CoA reductase inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, statins such as iovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, cerivastatin, CI-981 , resuvastatin, rivastatin, pravastatin, rosuvastatin or L-659,699 ((E,E)-11-[3'R-(hydroxy-methyl)-4'- oxo-2'R-oxetanyl]-3,5,7R-trimethyl-2,4-undecadienoic acid).
  • Squalene synthesis inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, squalene synthetase inhibitors; squalestatin 1 ; and squalene epoxidase inhibitors, such as NB-598 ((E)-N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yf)methoxy]benzene- methanamine hydrochloride).
  • squalene synthetase inhibitors such as NB-598 ((E)-N-ethyl-N- (6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-yf)methoxy]benzene- methanamine hydrochloride).
  • BtIe acid sequestrants useful in the present methods for treating or preventing a Condition include, but are not limited to, cholestyramine (a styrene-d ⁇ vinylbenzene copolymer containing quaternary ammonium cationic groups capable of binding bile acids, such as QUESTRAN® or QUESTRAN LIGHT® cholestyramine which are available from Bristol-Myers Squibb), colestipol (a copolymer of diethy ⁇ enetriamine and 1-chloro-2,3-epoxypropane, such as COLESTID® tablets which are available from Pharmacia), coiesevelam hydrochloride (such as WelChol® Tablets (poly(allylamine hydrochloride) cross-linked with epichlorohydrin and alkylated with 1- bromodecane and ⁇ 6-bromohexyl)-trimethylammonium bromide) which are available from Sankyo), water soluble derivatives such as 3,3-
  • Suitable inorganic cholesterol sequestrants include bismuth salicylate plus montmorillonite clay, aluminum hydroxide and calcium carbonate antacids.
  • Probucol derivatives useful in the present methods for treating or preventing a Condition include, but are not limited to, AG 1-1067 and others disclosed in U.S. Patent Nos. 6,121 ,319 and 6,147,250.
  • IBAT inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, benzothiepines such as therapeutic compounds comprising a 2,3,4,5-tetrahydro-1-benzothiepine 1 ,1-dioxide structure such as are disclosed in International Publication No. WO 00/38727.
  • Nicotinic acid receptor agonists useful in the present methods for treating or preventing a Condition include, but are not limited to, those having a pyridine-3- carboxylate structure or a pyrazine-2-carboxylate structure, including acid forms, salts, esters, zwitterions and tautomers, where available.
  • nicotinic acid receptor agonists useful in the present methods include nicotinic acid, niceritrol, nicofuranose and acipimox.
  • An example of a suitable nicotinic acid product is NIASPAN® (niacin extended-release tablets) which are available from Kos Pharmaceuticals, Inc. (Cranbury, NJ).
  • nicotinic acid receptor agonists useful in the present methods for treating or preventing a Condition include, but are not limited to, the compounds disclosed in U.S. Patent Publication Nos, 2006/0264489 and 2007/0066630, and U.S. Patent Application No. 11/771538, each of which is incorporated herein by reference.
  • ACAT inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, avasimibe, HL-004, lecimibide and CL- 277082 (N-(2,4-difluorophenyl)-N-[[4-(2,2-dimethylpropyI)phenyl]-methyl]-N- heptylurea). See P. Chang er al., "Current, New and Future Treatments in Dysiipidaemia and Atherosclerosis", Drugs 2000 Jul;60(1); 55-93, which is incorporated by reference herein.
  • CETP inhibitors useful in the present methods for treating or preventing a Condition include, but are not limited to, those disclosed in International Publication No. WO 00/38721 and U.S. Patent No. 6,147,090, each of which are incorporated herein by reference.
  • LDL-receptor activators useful in the present methods for treating or preventing a Condition include, but are not limited to, include HOE-402, an imidazolidinyl- pyrimidine derivative that directly stimulates LDL receptor activity. See M. Huettinger et ai, "Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDL Receptor Pathway", Arterioscler. Thromb. 1993; 13:1005-12.
  • Natural water-soluble fibers useful in the present methods for treating or preventing a Condition include, but are not limited to, psyllium, guar, oat and pectin.
  • Fatty acid esters of plant stands useful in the present methods for treating or preventing a Condition include, but are not limited to, the sitostanol ester used in BENECOL® margarine.
  • Non-limiting examples of antidiabetic agents useful in the present methods for treating a Condition include insulin sensitizers, ⁇ -glucostdase inhibitors, DPP-IV inhibitors, insulin secretogogues, hepatic glucose output lowering compounds, antihypertensive agents, sodium glucose uptake transporter 2 fSGLT-2) inhibitors, insulin and insulin-containing compositions, and anti-obesity agents as set forth above.
  • the antidiabetic agent is an insulin secretagogue.
  • the insulin secretagogue is a sulfonylurea.
  • sulfonylureas useful in the present methods include glipizide, tolbutamide, glyburide, glimeptrtde, chlorpropamide, acetohexamide, gliamilide, gliclazide, giiquidone, glibenclamide and tolazamide.
  • the insulin secretagogue is a meglitinide.
  • meglitinides useful in the present methods for treating a Condition include repaglinide, mitiglinide, and nateglinide.
  • the insulin secretagogue is GLP- 1 or a GLP- 1 mimetic.
  • GLP-1 mimetics useful in the present methods include Byetta-Exanatide, Liraglutinide, CJC-1131 (ConjuChem, Exanatide-LAR (Amylin), BIM-51077 (Ipsen/LaRoche), ZP-10 (Zealand Pharmaceuticals), and compounds disclosed in International Publication No. WO 00/07617.
  • insulin secretagogues useful in the present methods include exendin, GIP and secretin.
  • the antidiabetic agent is an insulin sensitizer.
  • Non-limiting examples of insulin sensitizers useful in the present methods include PPAR activators or agonists, such as troglitazone, rosiglitazone, pioglitazone and englitazone; biguanidines such as metformin and phenformin; PTP- 1 B inhibitors; and glucokinase activators.
  • the antidiabetic agent is a ⁇ -Glucosidase inhibitor.
  • Non-limiting examples of ⁇ -Glucosidase inhibitors useful the present methods include miglitol, acarbose, and voglibose.
  • the antidiabetic agent is an hepatic glucose output lowering agent.
  • hepatic glucose output lowering agents useful in the present methods include Glucophage and Glucophage XR.
  • the antidiabetic agent is insulin, including all formualtions of insulin, such as long acting and short acting forms of insulin.
  • orally administrable insulin and insulin containing compositions include AL-401 from Autoimmune, and the compositions disclosed in U.S. Patent Nos. 4,579,730; 4,849,405; 4,963,526; 5,642,868; 5,763,396; 5,824,638; 5,843,866; 6,153,632; 6,191 ,105; and International Publication No. WO 85/05029, each of which is incorporated herein by reference.
  • the antidiabetic agent is a DPP-(V inhibitor.
  • Non-limiting examples of DPP-IV inhibitors useful in the present methods include sitag ⁇ ptin, saxagliptin (JanuviaTM, Merck), denagliptin, vildagliptin (GalvusTM, Novartis), alogiiptin, alogliptin benzoate, ABT-279 and ABT-341 (Abbott), ALS-2-0426 (Alantos), ARI-2243 (Arisaph), Bl-A and Bl-B (Boehringer Ingelheim), SYR-322 (Takeda), MP-513 (Mitsubishi), DP-893 (Pfizer), RO-0730699 (Roche) or a combination of sitagliptin/metformin HCl (JanumetTM, Merck), in a further embodiment, the antidiabetic agent is a SGLT-2 inhibitor.
  • Non-limiting examples of SGLT-2 inhibitors useful in the present methods include dapagliflozin and sergliflozin, AVE2268 (Sanofi-Aventis) and T-1095 (Tanabe Seiyaku),
  • Non-limiting examples of antihypertensive agents useful in the present methods for treating a Condition include ⁇ -biockers and calcium channel blockers (for example diltiazern, verapamil, nifedipine, amlopidine, and mybefradil), ACE inhibitors (for example captopril, lisinopril, enalapril, spiraprii, ceranopril, zefenopril, fosinopril, cilazoprii, and quinapril), AT-1 receptor antagonists (for example losartan, irbesartan, and valsartan), renin inhibitors and endotheiin receptor antagonists (for example sitaxsentan).
  • ⁇ -biockers and calcium channel blockers for example diltiazern, verapamil, nifedipine, amlopidine, and mybefradil
  • ACE inhibitors for example captopril, lisinopril, en
  • the antidiabetic agent is an agent that slows or blocks the breakdown of starches and certain sugars.
  • Non-limiting examples of antidiabetic agents that slow or block the breakdown of starches and certain sugars and are suitable for use in the compositions and methods of the present invention include alpha-glucosidase inhibitors and certain peptides for increasing insulin production. Atpha-glucosidase inhibitors help the body to lower blood sugar by delaylng the digestion of ingested carbohydrates, thereby resulting in a smaller rise in blood glucose concentration following meals.
  • suitable alpha-giucosidase inhibitors include acarbose; migiitol; camiglibose; certain polyamines as disclosed in WO 01/47528 (incorporated herein by reference); voglibose.
  • Non-limiting examples of suitable peptides for increasing insulin production including amlintide (CAS Reg. No. 122384-88-7 from Amylin; pramlintide, exendin, certain compounds having Glucagon-like peptide-1 (GLP- 1 ) agonistic activity as disclosed in Internationa! Publication No. WO 00/07617.
  • Additional therapeutic agents useful in the present methods for treating or preventing a Condition include, but are not limited to, rimonabant, 2-methyl- 6- ⁇ phenylethynyl)-pyridine, 3[(2-methyl-1 ,4-thiazol-4-yl)ethynyl]pyridine, Melanotan-SI, dexfenfiuramine, fluoxetine, paroxetine, fenfluramine, fluvoxamine, sertaline, imipramine, desipramine, talsupram, nomifensine, leptin, naimefene, 3- methoxynaltrexone, naloxone, nalterxone, butabindide, axokine, sibutramine, topiramate, phytopharm compound 57, Cerulenin, theophylline, pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide, roli
  • the present combination therapies for treating or preventing diabetes comprise administering a Bicyclic Heterocycle Derivative, an antidiabetic agent and/or an antiobesity agent.
  • the present combination therapies for treating or preventing diabetes comprise administering a Bicyclic Heterocycle Derivative and an antidiabetic agent. In another embodiment, the present combination therapies for treating or preventing diabetes comprise administering a Bicyclic Heterocycle Derivative and an anti-obesity agent.
  • the present combination therapies for treating or preventing obesity comprise administering a Bicycfic Heterocycle Derivative, an antidiabetic agent and/or an antiobesity agent.
  • the present combination therapies for treating or preventing obesity comprise administering a Bicyclic Heterocycle Derivative and an antidiabetic agent,
  • the present combination therapies for treating or preventing obesity comprise administering a Bicyclic Heterocycle Derivative and an anti-obesity agent.
  • the present combination therapies for treating or preventing metabolic syndrome comprise administering a Bicyclic Heterocycle Derivative and one or more additional therapeutic agents selected from: anti-obesity agents, antidiabetic agents, any agent useful for treating metabolic syndrome, any agent useful for treating a cardiovascular disease, cholesterol biosynthesis inhibitors, sterol absorption inhibitors, bile acid sequestrants, probucol derivatives, !BAT inhibitors, nicotinic acid receptor (NAR) agonists, ACAT inhibitors, cholesteryl ester transfer proten (CETP) inhibitors, low-denisity lipoprotein (LDL) activators, fish oil, water-soluble fibers, plant sterols, plant stanols and fatty acid esters of plant stanols.
  • additional therapeutic agents selected from: anti-obesity agents, antidiabetic agents, any agent
  • the additional therapeutic agent is a cholesterol biosynthesis inhibitor.
  • the cholesterol biosynthesis inhibitor is a squalene synthetase inhibitor, In another embodiment, the cholesterol biosynthesis inhibitor is a squalene epoxidase inhibitor, In still another embodiment, the cholesterol biosynthesis inhibitor is an HMG-CoA reductase inhibitor, In another embodiment, the HMG-CoA reductase inhibitor is a statin. In yet another embodiment, the statin is lovastatin, pravastatin, simvastatin or atorvastatin. in one embodiment, the additional therapeutic agent is a cholesterol absorption inhibitor, In another embodiment, the cholesterol absorption inhibitor is ezetimibe.
  • the additional therapeutic agent comprises a cholesterol absorption inhibitor and a cholesterol biosynthesis inhibitor. In another embodiment, the additional therapeutic agent comprises a cholesterol absorption inhibitor and a statin. In another embodiment, the additional therapeutic agent comprises ezetimibe and a statin. In another embodiment, the additionai therapeutic agent comprises ezetimibe and simvastatin. In one embodiment, the present combination therapies for treating or preventing metabolic syndrome comprise administering a Bicyclic Heterocycle Derivative, an antidiabetic agent and/or an antiobesity agent.
  • the present combination therapies for treating or preventing metabolic syndrome comprise administering a Bicyclic Heterocycle Derivative and an antidiabetic agent. In another embodiment, the present combination therapies for treating or preventing metabolic syndrome comprise administering a Bicyclic Heterocycle Derivative and an anti-obesity agent.
  • the present combination therapies for treating or preventing a cardiovascular disease comprise administering one or more Bicyclic Heterocycle Derivatives, and an additional agent useful for treating or preventing a cardiovascular disease.
  • the therapeutic agents in the combination may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
  • the amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts).
  • the one or more Bicyclic Heterocycle Derivatives are administered during a time when the additional therapeutic agent(s) exert their prophylactic or therapeutic effect, or vice versa.
  • the one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) are administered in doses commonly employed when such agents are used as monotherapy for treating a Condition.
  • the one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition.
  • the one or more Bicyc ⁇ c Heterocycie Derivatives and the additional therapeutic agent(s) act synergistica ⁇ y and are administered in doses lower than the doses commonly employed when such agents are used as monotherapy for treating a Condition.
  • the one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) are present in the same composition. In one embodiment, this composition is suitable for oral administration. In another embodiment, this composition is suitable for intravenous administration.
  • the one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) can act additively or synergistically. A synergistic combination may allow the use of lower dosages of one or more agents and/or less frequent administration of one or more agents of a combination therapy. A lower dosage or less frequent administration of one or more agents may lower toxicity of the therapy without reducing the efficacy of the therapy.
  • the administration of one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) may inhibit the resistance of a Condition to these agents.
  • the additional therapeutic agent when the patient is treated for diabetes or a diabetic complication, is an antidiabetic agent which is not a Bicyclic Heterocycle Derivative.
  • the additional therapeutic agent is an agent useful for reducing any potential side effect of a Bicyclic Heterocycle Derivative. Such potential side effects include, but are not limited to, nausea, vomiting, headache, fever, lethargy, muscle aches, diarrhea, general pain, and pain at an injection site.
  • the additional therapeutic agent is used at its known therapeutically effective dose. In another embodiment, the additional therapeutic agent is used at its normally prescribed dosage. In another embodiment, the additional therapeutic agent is used at less than its normally prescribed dosage or its known therapeutically effective dose.
  • the doses and dosage regimen of the other agents used in the combination therapies of the present invention for the treatment or prevention of a Condition can be determined by the attending clinician, taking into consideration the the approved doses and dosage regimen in the package insert; the age, sex and general health of the patient; and the type and severity of the viral infection or related disease or disorder.
  • the Bicyclic Heterocycle Derivative(s) and the other agent(s) for treating diseases or conditions listed above can be administered simultaneously or sequentially. This particularly useful when the components of the combination are given on different dosing schedules, e.g., one component is administered once daily and another every six hours, or when the preferred pharmaceutical compositions are different, e.g. one is a tablet and one is a capsule.
  • a total daily dosage of the one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s)can when administered as combination therapy range from about 0.1 to about 2000 mg per day, although variations will necessarily occur depending on the target of the therapy, the patient and the route of administration.
  • the dosage is from about 0.2 to about 100 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 500 mg/day, administered in a single dose or in 2-4 divided doses.
  • the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses, (n still another embodiment, the dosage is from about 1 to about 100 mg/day, administered in a single dose or in 2-4 divided doses. In yet another embodiment, the dosage is from about 1 to about 50 mg/day, administered in a single dose or in 2-4 divided doses, in a further embodiment, the dosage is from about 1 to about 20 mg/day, administered in a single dose or in 2-4 divided doses.
  • the invention provides compositions comprising an effective amount of one or more Bicyclic Heterocycle Derivatives or a pharmaceutically acceptable salt, solvate, ester, prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier.
  • compositions comprising one or more Btcyclic Heterocycle Derivatives, inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories.
  • the powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g. magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g., nitrogen.
  • a pharmaceutically acceptable carrier such as an inert compressed gas, e.g., nitrogen.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • a Bicyclic Heterocycle Derivative is administered orally.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the quantity of active compound in a unit dose of preparation is from about 0.1 to about 2000 mg. Variations will necessarily occur depending on the target of the therapy, the patient and the route of administration, in one embodiment, the unit dose dosage is from about 0.2 to about 1000 mg. In another embodiment, the unit dose dosage is from about 1 to about 500 mg. In another embodiment, the unit dose dosage is from about 1 to about 100 mg/day. In still another embodiment, the unit dose dosage is from about 1 to about 50 mg. In yet another embodiment, the unit dose dosage is from about 1 to about 10 mg.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
  • a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 1000 mg/day, 1 mg/day to about 500 mg/day, 1 mg/day to about 300 mg/day, 1 mg/day to about 75 mg/day, 1 mg/day to about 50 mg/day, or 1 mg/day to about 20 mg/day, in one dose or in two to four divided doses.
  • the two active components may be co-administered simultaneously or sequentially, or a single composition comprising one or more Bicyclic Heterocycle Derivatives and the additional therapeutic agent(s) in a pharmaceutically acceptable carrier can be administered.
  • the components of the combination can be administered individually or together in any conventional dosage form such as capsule, tablet, powder, cachet, suspension, solution, suppository, nasal spray, etc.
  • the dosage of the additional therapeutic agent can be determined from published material, and may range from about 1 to about 1000 mg per dose. In one embodiment, when used in combination, the dosage levels of the individual components are lower than the recommended individual dosages because of an advantageous effect of the combination.
  • the components of a combination therapy regimen are to be administered simultaneously, they can be administered in a single composition with a pharmaceutically acceptable carrier.
  • ком ⁇ онентs of a combination therapy regimen when the components of a combination therapy regimen are to be administered separately or sequentially, they can be administered in separate compositions, each containing a pharmaceutically acceptable carrier.
  • the present invention provides a kit comprising an effective amount of one or more Bicyclic Heterocycle Derivatives, or a pharmaceutically acceptable salt or solvate of the compound and a pharmaceutically acceptable carrier, vehicle or diluent.
  • the present invention provides a kit comprising an amount of one or more Bicycitc Heterocycle Derivatives, and an amount of one or more additional therapeutic agents, wherein the combined amounts are effective for enhancing the memory of a patient or effective for treating or preventing a cognitive disorder in a patient.
  • kits comprising comprising: (a) one or more Bicyclic Heterocycle Derivatives together in a pharmaceutically acceptable carrier in a single container, or (b) one or more Bicyclic

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention porte sur des dérivés d'hétérocycles bicycliques, sur des compositions comprenant un dérivé d'hétérocycle bicyclique et sur des procédés d'utilisation des dérivés d'hétérocycles bicycliques pour traiter ou prévenir l'obésité, le diabète, un trouble métabolique, une maladie cardiovasculaire ou un trouble lié à l'activité d'un RCPG chez un patient.
PCT/US2009/068972 2008-12-23 2009-12-21 Dérivés d'hétérocycles bicycliques et leurs procédés d'utilisation WO2010075273A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14015908P 2008-12-23 2008-12-23
US61/140,159 2008-12-23

Publications (1)

Publication Number Publication Date
WO2010075273A1 true WO2010075273A1 (fr) 2010-07-01

Family

ID=41785894

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2009/068972 WO2010075273A1 (fr) 2008-12-23 2009-12-21 Dérivés d'hétérocycles bicycliques et leurs procédés d'utilisation

Country Status (3)

Country Link
AR (1) AR074862A1 (fr)
TW (1) TW201032808A (fr)
WO (1) WO2010075273A1 (fr)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011113947A1 (fr) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combinaisons d'agonistes de gpr119 et d'inhibiteurs de dpp-iv, linagliptine, pour le traitement du diabète et d'états apparentés
WO2012040279A1 (fr) * 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
EP2485589A1 (fr) * 2009-09-04 2012-08-15 Biogen Idec MA Inc. Inhibiteurs hétéroaryles de btk
US8293729B2 (en) 2009-06-24 2012-10-23 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
US8481731B2 (en) 2009-06-24 2013-07-09 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
CN102731492B (zh) * 2011-03-30 2016-06-29 江苏恒瑞医药股份有限公司 环己烷类衍生物、其制备方法及其在医药上的应用
US9663526B2 (en) 2014-08-21 2017-05-30 Pfizer Inc. Aminopyrimidinyl compounds
US9732094B2 (en) 2013-05-11 2017-08-15 Merck Patent Gmbh Arylquinazolines
US9858291B1 (en) 2013-10-30 2018-01-02 Google Inc. Detection of related local entities
US10025830B1 (en) 2013-10-30 2018-07-17 Google Llc Aggregation of disparate entity lists for local entities
US10875848B2 (en) 2018-10-10 2020-12-29 Forma Therapeutics, Inc. Inhibiting fatty acid synthase (FASN)
US10894797B2 (en) 2018-09-18 2021-01-19 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphatase inhibitors
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders

Citations (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US968929A (en) 1909-01-28 1910-08-30 Gustave E Franquist Force-feed oiler.
WO1985005029A1 (fr) 1984-05-09 1985-11-21 Medaphore Inc. Insuline administree par voie orale et son procede de preparation
US4579730A (en) 1983-05-23 1986-04-01 Hadassah Medical Organization Pharmaceutical compositions containing insulin
US4849405A (en) 1984-05-09 1989-07-18 Synthetic Blood Corporation Oral insulin and a method of making the same
US4963526A (en) 1984-05-09 1990-10-16 Synthetic Blood Corporation Oral insulin and a method of making the same
EP0464604A2 (fr) 1990-06-29 1992-01-08 Bristol-Myers Squibb Company 1-Indolylalkyl-4-(alkoxypyrimidinyl)pipérazines
US5642868A (en) 1990-05-02 1997-07-01 The United States Of America As Represented By The Secretary Of The Navy Ceramic material
US5763396A (en) 1990-10-10 1998-06-09 Autoimmune Inc. Method of treating or preventing type 1 diabetes by oral administration of insulin
US5824638A (en) 1995-05-22 1998-10-20 Shire Laboratories, Inc. Oral insulin delivery
US5843866A (en) 1994-12-30 1998-12-01 Hampshire Chemical Corp. Pesticidal compositions comprising solutions of polyurea and/or polyurethane
WO2000007617A1 (fr) 1998-07-31 2000-02-17 Novo Nordisk A/S Utilisation de glp-1 et d'analogues pour prevenir le diabete de type ii
WO2000038727A1 (fr) 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons d'inhibiteurs de transport de l'acide biliaire ileal et de derives de l'acide fibrique utilisees dans le cadre de maladies cardio-vasculaires
WO2000038721A1 (fr) 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons d'inhibiteurs de la proteine de transfert du cholesteryle-ester et de derives de l'acide nicotinique utilisees dans le cadre de troubles cardio-vasculaires
US6121319A (en) 1997-05-14 2000-09-19 Atherogenics, Inc. Monoesters of probucol for the treatment of cardiovascular and inflammatory disease
US6147090A (en) 1998-09-17 2000-11-14 Pfizer Inc. 4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines
US6153632A (en) 1997-02-24 2000-11-28 Rieveley; Robert B. Method and composition for the treatment of diabetes
US6191105B1 (en) 1993-05-10 2001-02-20 Protein Delivery, Inc. Hydrophilic and lipophilic balanced microemulsion formulations of free-form and/or conjugation-stabilized therapeutic agents such as insulin
WO2001047528A2 (fr) 1999-12-23 2001-07-05 Centre National De La Recherche Scientifique Nouveaux inhibiteurs de glycosidases et leurs applications pharmacologiques, notamment pour traiter le diabete
EP1338651A1 (fr) 2000-12-01 2003-08-27 Yamanouchi Pharmaceutical Co. Ltd. Procede de depistage d'un remede
WO2004065380A1 (fr) 2003-01-14 2004-08-05 Arena Pharmaceuticals Inc. Derives aryles et heteroaryles tri-substitues en position 1,2,3 en tant que modulateurs de metabolisme et prophylaxie et traitement de troubles lies au metabolisme
WO2004076413A2 (fr) 2003-02-24 2004-09-10 Arena Pharmaceuticals, Inc. Derives d'aryle et heteroaryle susbtitues tenant lieu de modulateurs du metabolisme du glucose et prophylaxie et traitement de troubles associes
EP1479674A1 (fr) 2003-05-19 2004-11-24 Aventis Pharma Deutschland GmbH Dérivés d'imidazole en tant qu'inhibiteurs du facteur xa
WO2006002133A1 (fr) 2004-06-22 2006-01-05 Schering Corporation Ligands des recepteurs cannabinoides
US7136426B2 (en) 2000-12-19 2006-11-14 Denso Corporation Communication system including a wire network linked with another network via radio waves
US20060264489A1 (en) 2005-05-17 2006-11-23 Schering Corporation Heterocycles as nicotinic acid receptor agonists for the treatment of dyslipidemia
US20070066630A1 (en) 2005-05-17 2007-03-22 Anandan Palani Nitrogen-containing heterocyclic compounds and methods of use thereof
WO2007035355A2 (fr) 2005-09-16 2007-03-29 Arena Pharmaceuticals, Inc. Modulateurs du métabolisme et le traitement de troubles s’y rapportant
WO2008137435A1 (fr) * 2007-05-04 2008-11-13 Bristol-Myers Squibb Company Agonistes [6,6] and [6,7]-bicycliques du récepteur gpr 119 couplé à la protéine g
WO2009055331A2 (fr) 2007-10-22 2009-04-30 Schering Corporation Dérivés hétérocycliques bicycliques et leurs procédés d'utilisation

Patent Citations (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US968929A (en) 1909-01-28 1910-08-30 Gustave E Franquist Force-feed oiler.
US4579730A (en) 1983-05-23 1986-04-01 Hadassah Medical Organization Pharmaceutical compositions containing insulin
WO1985005029A1 (fr) 1984-05-09 1985-11-21 Medaphore Inc. Insuline administree par voie orale et son procede de preparation
US4849405A (en) 1984-05-09 1989-07-18 Synthetic Blood Corporation Oral insulin and a method of making the same
US4963526A (en) 1984-05-09 1990-10-16 Synthetic Blood Corporation Oral insulin and a method of making the same
US5642868A (en) 1990-05-02 1997-07-01 The United States Of America As Represented By The Secretary Of The Navy Ceramic material
EP0464604A2 (fr) 1990-06-29 1992-01-08 Bristol-Myers Squibb Company 1-Indolylalkyl-4-(alkoxypyrimidinyl)pipérazines
US5763396A (en) 1990-10-10 1998-06-09 Autoimmune Inc. Method of treating or preventing type 1 diabetes by oral administration of insulin
US6191105B1 (en) 1993-05-10 2001-02-20 Protein Delivery, Inc. Hydrophilic and lipophilic balanced microemulsion formulations of free-form and/or conjugation-stabilized therapeutic agents such as insulin
US5843866A (en) 1994-12-30 1998-12-01 Hampshire Chemical Corp. Pesticidal compositions comprising solutions of polyurea and/or polyurethane
US5824638A (en) 1995-05-22 1998-10-20 Shire Laboratories, Inc. Oral insulin delivery
US6153632A (en) 1997-02-24 2000-11-28 Rieveley; Robert B. Method and composition for the treatment of diabetes
US6147250A (en) 1997-05-14 2000-11-14 Atherogenics, Inc. Compounds and methods for the inhibition of the expression of VCAM-1
US6121319A (en) 1997-05-14 2000-09-19 Atherogenics, Inc. Monoesters of probucol for the treatment of cardiovascular and inflammatory disease
WO2000007617A1 (fr) 1998-07-31 2000-02-17 Novo Nordisk A/S Utilisation de glp-1 et d'analogues pour prevenir le diabete de type ii
US6147090A (en) 1998-09-17 2000-11-14 Pfizer Inc. 4-carboxyamino-2-methyl-1,2,3,4,-tetrahydroquinolines
WO2000038721A1 (fr) 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons d'inhibiteurs de la proteine de transfert du cholesteryle-ester et de derives de l'acide nicotinique utilisees dans le cadre de troubles cardio-vasculaires
WO2000038727A1 (fr) 1998-12-23 2000-07-06 G.D. Searle Llc Combinaisons d'inhibiteurs de transport de l'acide biliaire ileal et de derives de l'acide fibrique utilisees dans le cadre de maladies cardio-vasculaires
WO2001047528A2 (fr) 1999-12-23 2001-07-05 Centre National De La Recherche Scientifique Nouveaux inhibiteurs de glycosidases et leurs applications pharmacologiques, notamment pour traiter le diabete
EP1338651A1 (fr) 2000-12-01 2003-08-27 Yamanouchi Pharmaceutical Co. Ltd. Procede de depistage d'un remede
US7136426B2 (en) 2000-12-19 2006-11-14 Denso Corporation Communication system including a wire network linked with another network via radio waves
WO2004065380A1 (fr) 2003-01-14 2004-08-05 Arena Pharmaceuticals Inc. Derives aryles et heteroaryles tri-substitues en position 1,2,3 en tant que modulateurs de metabolisme et prophylaxie et traitement de troubles lies au metabolisme
WO2004076413A2 (fr) 2003-02-24 2004-09-10 Arena Pharmaceuticals, Inc. Derives d'aryle et heteroaryle susbtitues tenant lieu de modulateurs du metabolisme du glucose et prophylaxie et traitement de troubles associes
EP1479674A1 (fr) 2003-05-19 2004-11-24 Aventis Pharma Deutschland GmbH Dérivés d'imidazole en tant qu'inhibiteurs du facteur xa
WO2006002133A1 (fr) 2004-06-22 2006-01-05 Schering Corporation Ligands des recepteurs cannabinoides
US20060264489A1 (en) 2005-05-17 2006-11-23 Schering Corporation Heterocycles as nicotinic acid receptor agonists for the treatment of dyslipidemia
US20070066630A1 (en) 2005-05-17 2007-03-22 Anandan Palani Nitrogen-containing heterocyclic compounds and methods of use thereof
WO2007035355A2 (fr) 2005-09-16 2007-03-29 Arena Pharmaceuticals, Inc. Modulateurs du métabolisme et le traitement de troubles s’y rapportant
WO2008137435A1 (fr) * 2007-05-04 2008-11-13 Bristol-Myers Squibb Company Agonistes [6,6] and [6,7]-bicycliques du récepteur gpr 119 couplé à la protéine g
WO2009055331A2 (fr) 2007-10-22 2009-04-30 Schering Corporation Dérivés hétérocycliques bicycliques et leurs procédés d'utilisation

Non-Patent Citations (19)

* Cited by examiner, † Cited by third party
Title
"The Orange Book", FOOD & DRUG ADMINISTRATION
A. GENNARO: "Remington's Pharmaceutical Sciences, 18th Edition,", 1990, MACK PUBLISHING CO.
A. L. BINGHAM ET AL., CHEM. COMMUN., 2001, pages 603 - 604
ANDERSON ET AL.: "The Practice of Medicinal Chemistry", 1996, ACADEMIC PRESS
E. C. VAN TONDER ET AL., AAPS PHARMSCITECHOURS., vol. 5, no. 1, 2004, pages 12
EDWARD B. ROCHE,: "Bioreversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS
EUR. PAT. APPL., 8 January 1992 (1992-01-08), pages 464604
GREENE ET AL.: "Protective Groups in Organic Synthesis", 1999, WILEY-INTERSCIENCE
J. MED. CHEM., vol. 37, 1994, pages 2831
KENAKIN, T., LIFE SCIENCES, vol. 43, 1988, pages 1095
M. CAIRA ET AL., J. PHARMACEUTICAL SCI., vol. 93, no. 3, 2004, pages 601 - 611
M. HUETTINGER ET AL.: "Hypolipidemic activity of HOE-402 is Mediated by Stimulation of the LDL Receptor Pathway", ARTERIOSCLER. THROMB., vol. 13, 1993, pages 1005 - 12
P. CHANG ET AL.: "Current, New and Future Treatments in Dyslipidaemia and Atherosclerosis", DRUGS, vol. 60, no. 1, July 2000 (2000-07-01), pages 55 - 93, XP008010516, DOI: doi:10.2165/00003495-200060010-00005
P. GOULD, INTERNATIONAL J. OF PHARMACEUTICS, vol. 33, 1986, pages 201 - 217
P. STAHL ET AL, CAMILLE G.: "Handbook of Pharmaceutical Salts. Properties, Selection and Use", 2002, WILEY-VCH
S. BERGE ET AL., JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 66, no. 1, 1977, pages 1 - 19
T. HIGUCHI; V. STELLA: "Pro-drugs as Novel Delivery Systems", vol. 14, 1987, A.C.S. SYMPOSIUM SERIES
T. HIGUCHI; W. STELLA: "Pro-drugs as Novel Delivery Systems", vol. 14, A.C.S. SYMPOSIUM SERIES
T. W. GREENE: "Protective Groups in Organic Synthesis", 1991, WILEY

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
US8293729B2 (en) 2009-06-24 2012-10-23 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
US8481731B2 (en) 2009-06-24 2013-07-09 Boehringer Ingelheim International Gmbh Compounds, pharmaceutical composition and methods relating thereto
EP2485589A1 (fr) * 2009-09-04 2012-08-15 Biogen Idec MA Inc. Inhibiteurs hétéroaryles de btk
US9029359B2 (en) 2009-09-04 2015-05-12 Biogen Idec Ma, Inc. Heteroaryl Btk inhibitors
EP2485589A4 (fr) * 2009-09-04 2013-02-06 Biogen Idec Inc Inhibiteurs hétéroaryles de btk
WO2011113947A1 (fr) 2010-03-18 2011-09-22 Boehringer Ingelheim International Gmbh Combinaisons d'agonistes de gpr119 et d'inhibiteurs de dpp-iv, linagliptine, pour le traitement du diabète et d'états apparentés
EP3323818A1 (fr) * 2010-09-22 2018-05-23 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement de troubles associés
WO2012040279A1 (fr) * 2010-09-22 2012-03-29 Arena Pharmaceuticals, Inc. Modulateurs du récepteur gpr119 et traitement des troubles qui lui sont liés
CN103539791A (zh) * 2010-09-22 2014-01-29 艾尼纳制药公司 Gpr119 受体调节剂和对与其相关的障碍的治疗
CN103221410A (zh) * 2010-09-22 2013-07-24 艾尼纳制药公司 Gpr119受体调节剂和对与其相关的障碍的治疗
CN103539791B (zh) * 2010-09-22 2017-01-11 艾尼纳制药公司 Gpr119 受体调节剂和对与其相关的障碍的治疗
US10894787B2 (en) 2010-09-22 2021-01-19 Arena Pharmaceuticals, Inc. Modulators of the GPR119 receptor and the treatment of disorders related thereto
JP2013537242A (ja) * 2010-09-22 2013-09-30 アリーナ ファーマシューティカルズ， インコーポレイテッド Ｇｐｒ１１９レセプターのモジュレーターおよびそれに関連する障害の処置
CN103221410B (zh) * 2010-09-22 2017-09-15 艾尼纳制药公司 Gpr119受体调节剂和对与其相关的障碍的治疗
KR101871011B1 (ko) 2010-09-22 2018-06-25 아레나 파마슈티칼스, 인크. Ｇｐｒ１１９ 수용체의 조절제 및 그와 관련된 장애의 치료
CN102731492B (zh) * 2011-03-30 2016-06-29 江苏恒瑞医药股份有限公司 环己烷类衍生物、其制备方法及其在医药上的应用
WO2012170867A1 (fr) 2011-06-09 2012-12-13 Rhizen Pharmaceuticals Sa Nouveaux composes utilises comme modulateurs de gpr-119
US10383874B2 (en) 2013-05-11 2019-08-20 Merk Patent Gmbh Arylquinazolines
US10172859B2 (en) 2013-05-11 2019-01-08 Merck Patent Gmbh Arylquinazolines
US9732094B2 (en) 2013-05-11 2017-08-15 Merck Patent Gmbh Arylquinazolines
US11065253B2 (en) 2013-05-11 2021-07-20 Merck Patent Gmbh Arylquinazolines
US9858291B1 (en) 2013-10-30 2018-01-02 Google Inc. Detection of related local entities
US10025830B1 (en) 2013-10-30 2018-07-17 Google Llc Aggregation of disparate entity lists for local entities
US10980815B2 (en) 2014-08-21 2021-04-20 Pfizer Inc. Aminopyrimidinyl compounds
US9663526B2 (en) 2014-08-21 2017-05-30 Pfizer Inc. Aminopyrimidinyl compounds
US10463675B2 (en) 2014-08-21 2019-11-05 Pfizer Inc. Aminopyrimidinyl compounds
US11197867B2 (en) 2014-08-21 2021-12-14 Pfizer Inc. Aminopyrimidinyl compounds
US11007175B2 (en) 2015-01-06 2021-05-18 Arena Pharmaceuticals, Inc. Methods of treating conditions related to the S1P1 receptor
US11884626B2 (en) 2015-06-22 2024-01-30 Arena Pharmaceuticals, Inc. Crystalline L-arginine salt of (R)-2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclo-penta [b]indol-3-yl)acetic acid(Compound1) for use in S1P1 receptor-associated disorders
US11534424B2 (en) 2017-02-16 2022-12-27 Arena Pharmaceuticals, Inc. Compounds and methods for treatment of primary biliary cholangitis
US10894797B2 (en) 2018-09-18 2021-01-19 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as SRC homology-2 phosphatase inhibitors
US11034705B2 (en) 2018-09-18 2021-06-15 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as Src homology-2 phosphate inhibitors
US11459340B2 (en) 2018-09-18 2022-10-04 Nikang Therapeutics, Inc. Tri-substituted heteroaryl derivatives as Src homology-2 phosphatase inhibitors
US11518772B2 (en) 2018-09-18 2022-12-06 Nikang Therapeutics, Inc. Fused tricyclic ring derivatives as Src homology-2 phosphate inhibitors
US10875848B2 (en) 2018-10-10 2020-12-29 Forma Therapeutics, Inc. Inhibiting fatty acid synthase (FASN)
US11299484B2 (en) 2018-10-10 2022-04-12 Forma Therapeutics, Inc. Inhibiting fatty acid synthase (FASN)

Also Published As

Publication number Publication date
TW201032808A (en) 2010-09-16
AR074862A1 (es) 2011-02-16

Similar Documents

Publication Publication Date Title
EP2318404B1 (fr) Dérivés hétérocycliques bicycliques et leur utilisation comme modulateurs du gpr119
EP2414348B1 (fr) Dérivés de pipéridine et de pipérazine bicycliques en tant que modulateurs de rcpg pour le traitement de l&#39;obésité, du diabète et d&#39;autres troubles métaboliques
EP2297117B1 (fr) Dérivés hétérocycliques bicycliques et leur utilisation en tant que modulateurs de gpr119
WO2010075273A1 (fr) Dérivés d&#39;hétérocycles bicycliques et leurs procédés d&#39;utilisation
EP2382203B1 (fr) Dérivés d&#39;hétérocycles bicycliques et leurs procédés d&#39;utilisation
US9409918B2 (en) Bridged bicyclic piperidine derivatives and methods of use thereof
WO2008130584A1 (fr) Dérivés de pyrimidinone et leurs procédés d&#39;utilisation
EP2148869A1 (fr) Dérivées de pyrimidinone, et leurs méthodes d&#39;utilisation
EP2382204B1 (fr) Dérivés de pyrimidine en tant que modulateurs de rcpg pour une utilisation d&#39;un traitement de l&#39;obésité et du diabète
EP2414334A1 (fr) Dérivés d&#39;hétérocycles bicycliques pontés et leurs procédés d&#39;utilisation
WO2010009207A1 (fr) Dérivés hétérocycliques bicycliques et leur utilisation comme modulateurs de gpcr
EP2217596A2 (fr) Dérivés hétérocycliques bicycliques et leur utilisation en tant que modulateurs de l`activite du gpr 119
WO2010009208A1 (fr) Dérivés d&#39;hétérocycles bicycliques et procédés d&#39;utilisation correspondants
WO2011066137A1 (fr) Dérivés de biaryle substitué et leurs procédés d&#39;utilisation
EP2503891B1 (fr) Dérivés d&#39;éther de pyrimidine et leurs procédés d&#39;utilisation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09775518

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 09775518

Country of ref document: EP

Kind code of ref document: A1