WO2007133820A2 - Diaryl triazolones as cb1 antagonists - Google Patents

Diaryl triazolones as cb1 antagonists Download PDF

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Publication number
WO2007133820A2
WO2007133820A2 PCT/US2007/060599 US2007060599W WO2007133820A2 WO 2007133820 A2 WO2007133820 A2 WO 2007133820A2 US 2007060599 W US2007060599 W US 2007060599W WO 2007133820 A2 WO2007133820 A2 WO 2007133820A2
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alkyl
substituted
compound
mono
independently chosen
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PCT/US2007/060599
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French (fr)
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WO2007133820A3 (en
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Alan J. Hutchison
Jianmin Mao
George D. Maynard
Wallace C. Pringle
He Zhao
David J. Wustrow
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Neurogen Corporation
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Publication of WO2007133820A3 publication Critical patent/WO2007133820A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • This invention relates generally to diary I triazoiones, and to the use of such compounds to treat 5 conditions responsive to cannabinoid receptor- 1 (CB l ) modulation.
  • the invention further relates to the use of such compounds as reagents for the identification of agents that bind to CBl , and as probes for the detection and loca ⁇ ization of CB l .
  • Obesity is the most common nutritional problem in developed countries. This condition is both harmful to the individual and costly to society, as it increases the likelihood of developing serious health conditions (such as cardiovascular diseases and diabetes) and complicates numerous chronic conditions such as respiratory diseases, osteoarthritis, osteoporosis, gall bladder disease and dyslipidemias. Fortunately, however, many of the conditions caused or exacerbated by obesity can be 15 resolved or dramatically improved by weight loss.
  • the present invention provides diaryl triazoiones that satisfy Formula f: y ⁇ Formula I
  • Ari and Ar 2 are independently chosen from phenyl and ⁇ -membered heteroaryl, each of which is optionally substituted, and each of which is preferably substituted with from 0 to 5 substituents independently chosen from R A ; 5 R is:
  • Ci-CsalkylsulfonyiCo-Gtalkyl mono- or di-(Ci-C s aikyl)aminoC 0 -C 4 alkyi, mono- or di-(Ci-C 8 alkyl)aminosulfonylCo-C 4 alkyl, or mono- or di-(C r
  • L is C 0 -C 3 alkylene that is optionally substituted, and is preferably substituted with from 0 to 2 substituents independently chosen from R B ;
  • 15 A is a 5- to 8-membered heterocycloalkyl group that is optionally substituted, and is preferably substituted with from 0 to 3 substituents independently chosen from R B ;
  • M is (6- to 10-membered aryl)C 0 -C 2 aikyl or (5- to 10-membered heteroaryl)C 0 -C 2 alkyl, each of which is optionally substituted, and each of which is preferably substituted with from 0 to 3 substituents independently chosen from R 8 ;
  • B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is C]-C 6 alkyl, (C 3 -C 6 cycloalky!)CcrC 2 alkyi, C r C 6 haloalkyl, C r C 6 aikoxy, C 2 -Q,alkyi ether, mono- or di-(C]-C 6 aikyl)amino, or (4- to 7-membered heterocycloalkylJCo ⁇ alkyl, each 25 of which is substituted with from 0 to 3 substituents independently chosen from R 3 ;
  • Each R A is independently chosen from:
  • Each R B is independently chosen from:
  • the present invention provides diaryl triazolones that satisfy Formula II:
  • Ar 1 and Ar 2 are independently chosen from phenyl and 6-membered heteroaryl, each of which is substituted with from 1 to 4 substituents independently chosen from R A ;
  • R is C 2 -C 8 alkyl, C 2 -C g alkcnyl, (C 3 -C]ocycloalkyl)Co-C 4 alkyl 5 C 2 -C s alkyl ether, C,-
  • R is a group of the formula -L-A-X-B or -L-X-A-B, wherein: L is Co-C 3 alkylene optionally substituted with R 13 ;
  • A is a 5- to 8-membered heterocycloalkyl group that is substituted with from O to 3 20 substituents independently chosen from R ⁇ ;
  • B is absent or cyano. such that if B is absent or cyano, then X is absent; or B is Ci-C 6 aikyl, (C r C 6 cycloalky!)C 0 -C 2 alkyI, C r C 6 haloalkyl, C r C 6 alkoxy, C 2 -C 6 alkyl ether, 25 mono- or di-(C r C 6 alkyl)amino, or 4- to 7-raembered heterocycloalkyl. each of which is substituted with from O to 3 substituents independently chosen from R B ; such that R is not morpholin-4-ylmethyl; and R A and R 5 are as described above.
  • the present invention provides diaryl triazolones that satisfy Formula III: Ar 2 o y ⁇ ⁇ Formula III
  • Ar 1 is phenyl or 6-membered heteroaryl, each of which is substituted with from 1 to 4 substituents independently chosen from R A ;
  • Ar 2 is phenyl or 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from R A ;
  • 5 R is C
  • R A and R B are as described above.
  • the present invention provides diaryl triazoiones that satisfy Formula IV:
  • Ari is 6-membered heteroaryl that is substituted with from 1 to 4 substituents independently chosen from R A ;
  • Ar 2 is phenyl or 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from R A ;
  • R is C r C s alkyl, C 2 -C s alke ⁇ yl, C 2 -C s alkynyf, (C 3 -C, 0 cycloalkyl)C 0 -C 4 alkyl, C 2 -C g alky! ether, C,-
  • Ci-Csalkyls ⁇ lfonyiQH ⁇ aikyl mono- or di ⁇ Ci-CgalkyOaminoCo-Gialkyl, mono- or di ⁇ (Ci-C 8 aikyl)aminosu3fonylCo-C 4 alky], or mono- or di-(Cr C s alkyl)aminocarbonylCo-C 4 alkyl; each of which is substituted with from 0 to 6 substituents independently chosen from R s ; or
  • R is a group of the formula -L-A-X-B or -L-X-A-B, wherein:
  • L is C 0 -Qa!ky!ene optionally substituted with R B ;
  • A is a 5- to 8-membered heterocycloalkyl group that is substituted with from 0 to 3 substituents independently chosen from R B ;
  • B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is Ci-Qalkyl, (C,-C 6 cycloaIkyl)C 0 -C 2 alkyl, C r C 6 haloalkyl, C,-C 6 alkoxy, C 2 -C 6 alkyl ether, mono- or di-(C]-C 6 alkyi)arnino, or 4- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 3 substituents independently chosen from R B ; and 30 R A and R B are as described above.
  • the present invention provides diary ⁇ triazolones that satisfy Formula V: R 2
  • R 1 is halogen, hydroxy, CpQalkyl, CpC 6 haloalkyi, CpC 6 a ⁇ koxy or CpGshaloalkoxy
  • R 2 is halogen, hydroxy, CpC 6 alkyl, C r C 6 haloalkyl, CpC 6 alkoxy, C r C 6 haloalkoxy or CpQalkoxy 5 that is substituted with a 4- to 6-membered carbocycle or heterocycle:
  • R is:
  • L is Co-C 3 alkyiene optionally substituted with R B ;
  • 15 A is a 5- to 8-membered heterocycloalky ⁇ group that is substituted with from 0 to 3 substituents independently chosen from R B ;
  • M is phenylCo-Cialkyl or (5- to 10-membered heteroaryl)Co-C 2 alkyl 3 each of which is substituted with from 0 to 3 substituents independently chosen from R B ;
  • B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is CpQalkyl, (C 3 -C 6 cycloalkyI)C 0 -C 2 alkyl, CpQhaloalkyl, CpCsalkoxy, C 2 -C 6 alkyJ ether, mono- or di-(C r C 6 alkyl)amino, or 4- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 3 substituents independently chosen from R 8 ; 25 wherein R B is as described above.
  • the present invention provides diaryl triazolones that satisfy Formula VI: Ar 2
  • Ar 2 is phenyl or 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from R A ;
  • R is:
  • L is C 0 -C 3 alkylene optionally substituted with R 6 ;
  • A is a 5- to 8-mernbered heterocycloaiky ⁇ group that is substituted with from 0 to 3 substituents independently chosen from R B ;
  • M is phenylCo-C 2 a!kyl or (5- to 1 0-membered heteroaryOQ-Qalkyl, each of which is 15 substituted with from 0 to 3 substituents independently chosen from R B ;
  • B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is C,-C 6 alky], (C 3 -C 6 cycloalkyl)C 0 -C 2 alkyl, C,-C 6 haloa!kyL C,-C 6 alkoxy, C 2 -C 6 alkyl ether, 20 mono- or di-(Cs-C ⁇ alkyl)amino, or 4- to 7-merabered heterocycloalkyl, each of which is substituted with from 0 to 3 substituents independently chosen from R B ; R A and R B are as described above; and
  • R 3 and R 4 are independently chosen from halogen, hydroxy.
  • diaiyl triazolones provided herein are CB l modulators and exhibit a K, of no greater than 2 micromolar, 1 micromolar, 500 nanomolar, 100 nanomolar or 50 nanomolar in a CB l ligand binding assay and/or have an EC 5O or IC 50 value of no greater than 1 micromolar, 100 nanomolar, 50 nanomolar or 10 nanomolar in an assay for determination of CB l agonist or antagonist activity.
  • CB l modulators as described herein are CBl antagonists and exhibit no detectable agonist activity.
  • compounds as described herein are labeled with a detectable marker (e.g., radiolabeled or fluorescein conjugated).
  • a detectable marker e.g., radiolabeled or fluorescein conjugated
  • the present invention further provides, within other aspects, pharmaceutical compositions
  • the present invention further provides methods for treating a condition responsive to CB l modulation in a patient, comprising administering to the patient a therapeutically effective amount of at least one compound as described herein.
  • Such conditions include, for example, appetite disorders, obesity, dependency disorders such as alcohol dependency and nicotine dependency, asthma, liver 5 cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, memory disorders, cognitive disorders, movement disorders, portal hypertension, fibrosis of internal organs, orthostatic hypotension and drug-induced hypotension.
  • compositions comprising (a) a First agent that is a compound as described above, (b) a second agent that is suitable for treating an appetite disorder, obesity, an addictive disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder or a movement disorder; and (c) a physiologically acceptable earner or excipient.
  • the present invention also provides packaged pharmaceutical preparations, comprising: (a) a composition comprising a compound as described above in a container; and (b) instructions for using the composition to treat one or more conditions responsive to CB l modulation.
  • the present invention provides methods for determining the presence or absence of CBl in a sample, comprising: (a) contacting a sample with a compound as described herein 20 under conditions that permit binding of the compound to CB l ; and (b) detecting a signal indicative of a level of the compound bound to CB l .
  • the invention provides methods of preparing the compounds disclosed herein, including the intermediates.
  • diaryl triazolones Such compounds may be used in vitro or in vivo in a variety of contexts as described herein.
  • 35 recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. Certain compounds are described herein using a general formula that includes
  • each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence.
  • diary! triazolones encompasses all compounds of Formula ⁇ , which compounds 5 may or may not further satisfy one or more additional other formulas provided herein, and includes pharmaceutically acceptable salts, solvates and esters of such compounds.
  • a “pharmaceutically acceptable salt” of a compound recited herein is an acid or base salt that is suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication. 10
  • Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids.
  • Specific pharmaceutically acceptable salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesuifonic, methanesulfonic, benzene sulfonic, camphors ⁇ lfonic, ethane disulfonic, 2-liydroxyethylsulfonic, nitric, benzoic, 2- 15 acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, afkanoic such as acetic, HOOC-(CH 2 ) n -COOH where n is 0-4, and the like.
  • acids such as hydrochloric, phosphoric, hydro
  • pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium.
  • pharmaceutically acceptable salts for the compounds provided herein, including 20 those listed in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, p, 1418 (1990) and in particular, the discussion and Table II appearing under the heading "Salt Formation” spanning pages 1444-45 thereof, which is incorporated herein by reference for its disclosures regarding pharmaceutically acceptable salts, or the equivalent disclosure in Remington: The Science and Practice of Pharmacy, 21 s1 ed., Lippincott Williams & Wilkins, Philadelphia, PA 25 (2005).
  • a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, isopropano! or 30 acetonitrile, is preferred.
  • prodrugs of the compounds provided herein are provided herein.
  • a “prodrug” is a compound that may not fully satisfy the structural requirements of 35 the compounds provided herein, but is modified in vivo, following administration to a patient, to produce a compound provided herein.
  • a prodrug may be an acylated derivative of a compound as provided herein.
  • Prodrugs include compounds wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, amino, or sulfhydryl group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein.
  • Prodrugs of the compounds provided herein may be 5 prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to yield the parent compounds.
  • alkyl refers to a straight or branched chain saturated aliphatic hydrocarbon. Certain aikyi groups include those having from 1 to 8 carbon atoms (CVQalkyl), from 1 to 6 carbon atoms (C r C 6 alkyl) and from 1 to 4 carbon atoms (C r C 4 alkyl). such as methyl, ethyl, 10 propyl, isopropyi, n-butyf, sec-butyl, tert-buty ⁇ , pentyl, 2-pentyi, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl or 3-methylpentyl.
  • Co-C 4 alky ⁇ refers to a single covalent bond (C 0 ) or an alkyl group having 1 , 2, 3 or 4 carbon atoms.
  • Alkylene refers to a divalent alkyl group.
  • CpQalkylene is an alkylene group having I , 2, 3 or 4 carbon atoms.
  • C 0 -C 4 alkylene refers to a single covalent bond or C
  • Alkenyl refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond.
  • Alkenyl groups include, for example, C 2 -C 8 alkenyl, C 2 - C 6 alkenyl and C 2 -C 4 alkenyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively, such as ethenyl, allyl or isopropenyl.
  • Alkynyl refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a 20 triple bond.
  • Alkynyl groups include, for example, C 2 -C 8 alkynyl, C 2 -C 6 aikynyl and C 2 -C 4 alkynyi groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.
  • a “cycloalkyl” is a saturated or partially saturated cyclic group in which all ring members are carbon, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or a partially saturated variant of any of the foregoing.
  • Certain cycloalkyl groups are C 3 -C
  • a "(C 3 -C 10 cycloalky])Co-C 4 alkyl” is a CrCjoCycbalkyi group linked via a single covalent bond or CpQalkylene.
  • alkoxy is meant an alkyl group as described above attached via an oxygen bridge.
  • Certain alkoxy groups are C r C 6 alkoxy and C r C 4 aIkoxy groups, which have from 1 to
  • Methoxy, ethoxy, propoxy, isopropoxy, ⁇ -butoxy, sec-butoxy. tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy are representative alkoxy groups.
  • Alkylthio refers to an alkyl group as described above attached via a sulfur bridge (Le., — S- alkyl).
  • Alky ⁇ sulfinyl refers to groups of the formula -(SO)-a ⁇ kyl, in which the sulfur atom is the point of attachment.
  • Representative alkySsulfinyl groups include Q-C ⁇ alkylsulf ⁇ nyl and C,- 5 C 4 alkylsulfmyl groups, which have from 1 to 6 or 1 to 4 carbon atoms, respectively.
  • Alkylsulfonyl refers to groups of the formula - ⁇ SQO-aikyl, in which the sulfur atom is the point of attachment.
  • Representative alkylsulfonyl groups include C r C 6 alkylsuifonyl and Q-
  • C 3 alkylsulfonylCo-C 4 alkyi is a C r C 8 alkylsulfonyl group linked via a single covalent bond or a C r
  • Alkanoyl groups include, for example, C 2 -C s alkanoyl, C 2 -C 6 alkanoyl and C 2 -C 4 alkanoyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.
  • Ethanoyl is C 2 alkanoy).
  • alkanone is a ketone group in which carbon atoms are in a linear or branched alkyl arrangement.
  • C 3 -C 8 alkanone refers to an alkanone having from 3 to 8 carbon atoms.
  • alkyl ether refers to a linear or branched ether substituent.
  • Representative alkyl 20 ether groups include C ⁇ -Cgalkyl ether.
  • a C 2 alkyl ether has the structure -CHi-O-CH 3 .
  • Certain alkoxycarbonyl groups include Ci-C 8 , C]-C 6 and C r C 4 alkoxycarbonyl groups, which have from 1 to 8, 6 or 4 carbon atoms, respectively, in the 25 aikyl portion of the group.
  • Ci-C 8 , C]-C 6 and C r C 4 alkoxycarbonyl groups which have from 1 to 8, 6 or 4 carbon atoms, respectively, in the 25 aikyl portion of the group.
  • Alkylami ⁇ o refers to a secondary or tertiary amine that has the general structure -NH-alkyl or -N(alkyl)(alkyl), wherein each alkyl is selected independently from alkyl, cycloaikyl and
  • (cycloalkyl)alkyl groups include, for example, mono- and di-(CrCsalkyi)amino groups, in which each C r C s alkyl may be the same or different, as well as mono- and di-(C r C 6 alkyl)ami ⁇ o
  • Alkylaminoalkyl refers to an alkylamino group linked via an alkylene group (i.e., a group having the general structure -alkylene-NH-alkyl or -aIkylene-N(alkyl)( alkyl)) in which each alkyl is selected independently from alkyl, cycloaikyl and (cycloalkyl)alkyl groups.
  • Alkylaminoafkyl groups include, for example, mono- and di-(C;-C 8 alkyl)aminoCi-C 8 alkyl.
  • “Mono- or di-(C r C s a[kyl)aminoC 0 - 35 C 4 alkyl” refers to a mono- or di-(C
  • alkyl as used in the terms “alkylamino” and “alkylaminoalkyl” differs from the definition of "alkyl” used for all other alkyl-containing groups, in the inclusion of cycloalkyl and (cycloalkyl)alkyl groups (e.g., (C 3 -C 8 cycloalkyl)Co-C 4 alkyl).
  • Csa!kyl)aminocarbonylCo-QaIkyI refers to an aminocarbonyi group in which one or both hydrogens are replaced with an independently selected Cj-Csalkyl group, and which is linked via a single covale ⁇ t bond or a C]-C 4 alkylene group.
  • aminosulfonyl refers to a sulfonamide group (i.e., -SO 2 NH 2 ).
  • “Mono- or di-(C r 10 C 8 alky[)aminosuIfony!Co-C 4 alkyI” refers to an aminosulfonyl group in which one or both hydrogens are replaced with an independently selected Ci-Cgalky! group, and which is linked via a single covending bond or a Ci- ⁇ aikyiene group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • a “ha ⁇ oalkyl” is an alkyl group that is substituted with 1 or more independently chosen
  • haioalkyl groups include, but are not limited to, mono-, di- or tri-fiuoromethyl; mono-, di- or t ⁇ -chloromethyl; mono-, di-, tri-, tetra- or penta-fluoroethyl; mono-, d ⁇ -
  • Typical haioalkyl groups are trifluoromethyi and difluoromethyi.
  • haloalkoxy refers to a haloalky! group as
  • Ci-C s haloaikoxy groups have 1 to 8 carbon atoms.
  • a "carbocycle” has from 1 to 3 fused, pendant or spiro rings, each of which has only carbon ring members.
  • a carbocycie that has a single ring contains from 3 to 8 ring members (i.e., 25 Cs-Cgcarbocycles); rings having from 4 to 6 ring members are recited in certain embodiments.
  • Carbocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members.
  • Carbocycles may be optionally substituted with a variety of substituents, as indicated.
  • a carbocycle may be a cycloalkyl group (i.e., each ring is saturated or partially saturated as described above) or an aiyl group (i.e., at least one ring within the group is aromatic).
  • 30 Phenyl groups linked via a single covending bond or CpCjalkylene group are designated phenylCo- C 4 alkyl (e.g., benzyl. 1 -phe ⁇ yl-ethyl, 1-phenyi-propyl and 2-phenyl-ethyl).
  • a pheny lCo-Gj alkoxy group is a phenyl ring linked via an oxygen bridge or via an alkoxy group having from 1 to 4 carbon atoms (e.g., phenoxy or benzoxy).
  • a “heterocycle” (also referred to herein as a “heterocyclic group”) has from 1 to 3 fused, 35 pendant or spiro rings, at least one of which is a heterocyclic ring (i.e., one or more ring atoms is a
  • heterocyclic ring comprises 1, 2, 3 or 4 heteroatoms; within certain embodiments each heterocyclic ring lias 1 or 2 heteroatoms per ring.
  • Each heterocyclic ring generally contains from 4 to 8 ring members (rings having from 4 to 6 ring members are recited in certain 5 embodiments).
  • Certain heterocycles comprise a sulfur atom as a ring member; in certain embodiments, the sulfur atom is oxidized to SO or SO 2 .
  • Heterocycles may be optionally substituted with a variety of substitue ⁇ ts, as indicated.
  • heterocycles are heteroaryl groups (i.e., at least one heterocyclic ring within the group is aromatic), such as a 5- to 10-membered heteroaryl (which may be monocyclic or bicyclic) or a 6- 10 membered heteroaryl (e.g., pyridyl or pyrimidyl).
  • Other heterocycles are heterocycloalkyl groups.
  • heterocycles may be linked by a single covending bond or via an alkylene group, as indicated, for example, by the term "(4- to S-membered heterocycle)C 0 -C 4 alkyI.”
  • Heterocycles may also be linked via an oxygen or alkoxy group, as indicated, for example, by the term "(4- to 8-membered heterocyc le)C 0 -C 4 alkoxy . ' '
  • a “substituent,” as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest.
  • a “ring substituent” may be a moiety such as a halogen, alkyl group, haioafkyi group or other group discussed herein that is covalently bonded to an atom (such as a carbon or nitrogen atom) that is a ring member.
  • substitution refers to replacing a hydrogen atom in a molecular structure with a substituent as described above, such that the 20 valence on the designated atom is not exceeded, and such that a chemically stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity) results from the substitution.
  • Groups that are "optionally substituted” are unsubstituted or are substituted by other than hydrogen at one or more available positions, typically I, 2, 3, 4 or 5 positions, by one or more suitable 25 groups (which may be the same or different).
  • Optional substitution is also indicated by the phrase "substituted with from 0 to X substituents," where X is the maximum number of possible substituents.
  • Certain optionally substituted groups are substituted with from 0 to 2, 3 or 4 independently selected substituents (i.e., are unsubstituted or substituted with up to the recited maximum number of substitutents).
  • CBl refers to the human cannabinoid receptor reported by Hoeche et al.
  • a "CB l antagonist” is a compound that detectably inhibits signal transduction mediated by
  • Such inhibition may be determined using the representative agonist-induced GTP binding assay
  • Preferred CBl antagonists have an IC 50 Of 2 ⁇ M or less in this assay, more preferably 1 ⁇ M or less, and still more preferably 500 nM or less or 100 nM or less.
  • the CB l antagonist is specific for CB l (i.e., the IC 50 value in a similar assay performed
  • CB l antagonists preferably have minimal agonist activity (i.e., induce an increase in the basal activity of CB l that is less than 5% of the increase that would be induced by one EC 50 of the agonist CP55,940, and more 5 preferably have no detectable agonist activity within the assay described in Example 14).
  • CB l antagonists for use as described herein are generally non-toxic.
  • CBl antagonists include neutral antagonists and inverse agonists.
  • a "neutral antagonist" of CB i is a compound that inhibits the activity of CBI agonist (e.g., endocannabinoids) at CB l , but does not significantly change the basal activity of the receptor (i.e., 10 within a GTP binding assay as described in Example 14 performed in the absence of agonist, CBl activity is reduced by no more than 10%, more preferably by no more than 5%, and even more preferably by no more than 2%; most preferably, there is no detectable reduction in activity).
  • CBI agonist e.g., endocannabinoids
  • An "inverse agonist" of CB l is a compound that reduces the activity of CB l below its basal
  • Inverse agonists may also inhibit the activity of agonist at CBl, and/or may inhibit binding of CB l agonist to CB l .
  • the ability of a compound to inhibit the binding of CB l agonist to the CB l receptor may be measured by a binding assay, such as the radioligand binding assay given in Example 13. The reduction in basal activity of
  • CB l produced by an inverse agonist may be determined from a GTP binding assay, such as the assay
  • a “non-competitive CB l antagonist” is a CB l antagonist that (1 ) does not detectabiy inhibit binding of CBl agonist ⁇ e.g., CP55.940) to CB l at antagonist concentrations up to 10 ⁇ M and (2) reduces the maximal functional response elicited by agonist.
  • Compounds that satisfy these two conditions may be identified using the assays provided herein. Such compounds generally do not 25 display detectable activity in the competition binding assay described in Example 13.
  • a non-competitive antagonist concentration -dependently reduces the maximal functional response elicited by agonist without altering agonist EC 50 .
  • the suppression of functional activity by a non-competitive antagonist cannot be overcome by increasing agonist concentrations (i.e., the antagonist activity is insurmountable).
  • a “therapeutically effective amount” is an amount that, upon administration to a patient, results in a discernible patient benefit (e.g., provides detectable relief from a condition being treated). Such relief may be detected using any appropriate criteria, including the alleviation of one or more symptoms of dependency or an appetite disorder, or the promotion of weight loss. In the case of appetite suppression, a therapeutically effective amount is sufficient to decrease patient appetite, as 35 assessed using patient reporting or actual food intake. Such an amount is referred to herein as an "appetite reducing amount.”
  • a therapeutically effective amount or dose generally results in a concentration of compound in a body fluid (such as blood, plasma, serum, CSF, synovial fluid, lymph,
  • the discernible patient benefit may be apparent after administration of a single dose, or may become apparent following repeated administration of the therapeutically effective dose according to a predetermined regimen, depending 5 upon the indication for which the compound is administered.
  • a "patient” is any individual treated with a compound as provided herein. Patients include humans, as well as other animals such as companion animais (e.g., dogs and cats) and livestock.
  • Patients may be experiencing one or more symptoms of a condition responsive to CBl modulation or may be free of such symptom(s) (i.e., treatment may be prophylactic in a patient considered to be at
  • diaryl triazolones of Formula I may be used in a variety of contexts, including in the treatment of appetite disorders, obesity and addictive disorders. Such compounds may also be used within in vitro assays (e.g., assays for CBl activity), as 15 probes for detection and localization of CBl and within assays to identify CB l antagonists.
  • diaryl triazolones of Formula 1 further satisfy one or more additional Formulas provided herein.
  • variables are generally as described above; in certain embodiments, such variables (where present) are as follows:
  • variables Ai"j and An are independently phenyl or pyridyl, each of which is substituted with one or two substituents independently chosen from halogen, hydroxy, cyano, amino, Q-Qalkyl, Q-Qhaloalkyl, C r C 6 alkoxy and CpC f ihaloalkoxy.
  • Representative Ar 1 groups include substituted pyridyl, such as pyridin-4-yl that is substituted at the 2-position (e.g., ⁇ yridin-4-yl that is substituted at the 2-position with halogen.
  • Ar 1 group is pyridin-4-yl that is substituted at the 2-position with a halogen, such as Cl).
  • Other representative Ar s groups include, for example, substituted phenyl, such as 2,4-disubstituted phenyl.
  • Representative R] groups include halogens, such as Cl.
  • Representative R 3 and R 4 groups include, for example, halogen, Q- Gjhaioalkyl and Q-dalkoxy, with halogen substituents preferred in certain embodiments.
  • Ar 2 groups include, for example, substituted phenyl and substituted pyridyl.
  • Ar 2 is substituted at the para position with a halogen (e.g., Cl or F), hydroxy,
  • Ar 2 is phenyl or pyridyi (e.g., pyridin-2-yl or pyridin-3-yl) that is substituted at the para position and is unsubstituted at other positions.
  • Certain Ar 2 groups satisfy the Formula:
  • R 3 is as described for Formula V, above.
  • Representative R 2 groups include, for example, halogen, Ci-C ⁇ haloalky! and CrQalkoxy.
  • one substituent of An is located para to the point of attachment and/or one substituent of Ar, is located ortho to the point of attachment.
  • R groups within Formula I and other Formulas provided comprise a group of the formula -L-A-X-B, -L-M-X-B, -L-X-A-B or -L-X-M-B, in which variables are as described above.
  • "-X-B” represents an optional substituent on the ring portion of 'A" or "M,” which substituent replaces a hydrogen on a ring member.
  • the ring "A" or "M” is unsubstituted other than by substituents chosen from R B , 15 where indicated.
  • R groups include, for example, groups of the formula -L-A-X-B or -L-X-A-B, wherein:
  • 20 L is C 0 -C 3 alkylene optionally substituted with oxo or hydroxy;
  • A is a 4- to 6-membered heterocycloalkyi group
  • B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is C
  • R groups comprise an aromatic moiety.
  • R groups include, for example, groups of the fo ⁇ nu Ia -L-M-X-B or -L-X-M-B, wherein: 30 L is Co-C 3 alkylene optionally substituted with oxo or hydroxy;
  • M is phenylCo-Cialky! or (5- to 10-membered heteroary ⁇ Co-Cialkyl, each of which is substituted with from O to 3 substituents independently chosen from oxo, hydroxy and C
  • B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is C
  • R is C 2 -C s alkyl (e.g., C 3 -C s alky! or
  • C 4 -C s a1kyl C r C s alkenyl, (C 3 -C, 0 cycloalkyf)Co-C 2 a]kyl, C 2 -C 8 haloalkyi, C 2 -C s alkyl ether, mono- or di-(Ci-C 6 alkyl)aminoCo-C 4 alky], or (4- to 8-membered heterocycloalkyi)C 0 -C 4 aIkyl.
  • R groups include, for example, C 2 -C 8 alkyi, C 2 - Cgafkenyl, (C 3 -C 7 cycloalkyl)Co-C 2 aikyl, C 2 -C s haloalkyl, C 2 -C 8 aiky! ether, and mono- and di-(C r C 6 alkyl)amtnoC 0 -C 4 alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from oxo, hydroxy, C
  • Certain such R groups 15 include alkanoyl and alkanone groups (e.g., C 2 -C 8 aikanoy! and C 3 -C 8 alkano ⁇ e).
  • R is Q-Cgalkyl, C 2 -
  • Representative R groups include, for example, Cj-Cgalkyl, C 2 -
  • R 25 independently chosen from oxo, hydroxy, C r C 4 alkyl.
  • Certain such R groups include alkanoyl and alkanone groups (e.g., Ci-Cgalkanoyl and C 3 -C s alkanone).
  • X-Q in which X is as described above; n is 1, 2 or 3; and Q is C
  • R groups include C r C s alkyt that is substituted with 1 or 2 substituents independently chosen from halogen, cyano, hydroxy, amino and oxo (e.g., CpCgalky] that is substituted with one hydroxy group or one oxo group).
  • Certain such R groups include alkanoyl and 35 alkanone groups (e.g., C 2 -C s alkanoyi and C 3 -C s alkanone).
  • diary! triazolones provided herein are CBl antagonists. Certain such compounds are non-competitive CB I antagonists, in addition, or alternatively, certain compounds provided herein are specific for CB 1.
  • CB 1 antagonist activity may be confirmed using an agonist-induced GTP binding assay, such as the assay described in Example 14, herein.
  • Such assays 10 employ a CB l -containing cell membrane preparation (e.g., a preparation of membranes of insect cells that recombinantly express CB l) to determine the effect of a test compound on CBl agonist-induced GTP binding to CB l .
  • a first cell membrane preparation comprising CBl is contacted with: (i) labeled GTP; (ii) a CB l agonist; and (iii) a test compound to yield a test membrane preparation.
  • a second cell membrane preparation comprising CB l is contacted 15 with: (i) labeled GTP; and (ii) a CB l agonist to yield a control membrane preparation.
  • the labeled GTP is preferably GTPy 33 S; a representative CB l agonist is CP55,940.
  • Such contact is performed under conditions that are suitable for GTP binding to CB I , such as the conditions described in Example 14.
  • concentrations of labeled GTP and CB l agonist used are generally concentrations that are sufficient to result in a detectable increase in the amount of labeled GTP bound to the 20 membrane preparation in the presence of CB l agonist. Such concentrations may be determined by routine experimentation; representative suitable concentrations are provided in Example 14. Generally, a range of test compound concentrations is used (e.g., ranging from I 0 "!0 M to 10 "5 M).
  • a signal that corresponds to (represents) the amount of bound, labeled GTP is detected (typically,
  • 25 unbound labeled GTP is first removed via a washing step). Tn other words, simultaneously or in either order: (i) a test signal that represents an amount of bound, labeled GTP in the test membrane preparation is detected; and (ii) a control signal that represents an amount of bound, labeled GTP in the control membrane preparation is detected.
  • the nature of the signal detected is determined by the type of label used. For example, if the GTP is radioactively labeled, the signal detected is radioactive decay
  • the CBI antagonist activity of the test compound is then determined by comparing the test signal with the control signal. A test signal that is lower than the control signal indicates that the test compound is a CB l antagonist.
  • preferred compounds are cannabinoid receptor-specific. This means that they only bind to, activate, or inhibit the activity of certain receptors other than cannabinoid
  • 35 receptors (preferably other than CB l ) with affinity constants of greater than 100 nanomolar, preferably greater than 1 micromolar, more preferably greater than 4 micromolar.
  • such compounds exhibit 200-fold greater affinity for CB l than for other cellular receptors.
  • non-can ⁇ abinoid cellular receptors include histamine receptors, bioactive peptide receptors (including NPY receptors such as NPY Y5), and hormone receptors (e.g., melanin-concentrating hormone receptors).
  • Assays for evaluating binding to such receptors are well known, and include those disclosed in US patent 6,566,367, which is incorporated herein by reference for its disclosure of NPY 5 receptor binding assays in Example 676 columns 82-83; and in PCT International Application Publication No. WO 02/094799 which is incorporated herein by reference for its disclosure of an MCH receptor binding assay in Example 2, pages 108- 109.
  • diaryl triazolones provided herein may be evaluated for certain pharmacological properties including, but not limited to, oral bioavailability (preferred compounds are orally bioavailabie to an extent allowing for therapeutically effective doses of less than 140 mg/kg, preferably 30 less than 50 mg/kg.
  • toxicity a preferred compound is nontoxic when a therapeutically effective amount is administered to a subject
  • side effects a preferred compound produces side effects comparable to placebo when a therapeutically effective amount of the compound is administered to a subject
  • serum protein binding and in -vitro and 35 in vivo half-life a preferred compound exhibits an in vivo half-life allowing for Q.I.D. dosing, preferably T.I.D. dosing, more preferably B.l.D. dosing, and most preferably once-a-day dosing).
  • Q.I.D. dosing preferably T.I.D. dosing, more preferably B.l.D. dosing, and most preferably once-a-day dosing.
  • differentia! penetration of the blood brain barrier may be desirable. Routine assays that are
  • assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers.
  • Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals 5 given the compound (e.g., intravenously).
  • Serum protein binding may be predicted from albumin binding assays.
  • Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described herein.
  • nontoxic as used herein shall be understood in a relative sense and is intended to refer to any substance that has been approved by the United States Food and Drug Administration (“FDA”) for administration to mammals (preferably humans) or, in keeping with established criteria, is susceptible to approval by the FDA for administration to mammals (preferably humans).
  • FDA United States Food and Drug Administration
  • a preferred nontoxic compound generally satisfies one or more of the following criteria: (1) does not substantially
  • a compound that does not substantially inhibit cellular ATP production is a compound that satisfies the criteria set forth in Example 16, herein.
  • cells treated as described in Example 16 with 100 ⁇ M of such a compound exhibit ATP levels that are at least 50% of
  • ATP levels that are at least 80% of the ATP levels detected in untreated cells.
  • a compound that does not significantly prolong heart QT intervals is a compound that does not result in a statistically significant prolongation of heart QT intervals (as determined by electrocardiography) in guinea pigs, minipigs or dogs upon administration of a dose that yields a serum 25 concentration equal to the EC 50 or IC 50 for the compound,
  • a dose of 0.01 , 0.05, 0.1 , 0.5, 1 , 5, 10, 40 or 50 mg/kg administered parenterally or orally does not result in a statistically significant prolongation of heart QT intervals.
  • statically significant results varying from control at the p ⁇ 0.1 level or more preferably at the p ⁇ 0.05 level of significance as measured using a standard parametric assay of statistical significance such as a student's T test.
  • a compound does not cause substantial liver enlargement if daily treatment of laboratory rodents (e.g., mice or rats) for 5- 10 days with a dose that yields a serum concentration equal to the EC 50 or IC 50 for the compound results in an increase in liver to body weight ratio that is no more than 100% over matched controls. In more highly preferred embodiments, such doses do not cause liver enlargement of more than 75% or 50% over matched controls. If non-rodent mammals (e.g., dogs) are 35 used, such doses should not result in an increase of liver to body weight ratio of more than 50%, preferably not more than 25%, and more preferably not more than 10% over matched untreated
  • Preferred doses within such assays include 0.01 , 0.05. 0.1, 0.5, 1, 5, 10, 40 or 50 mg/kg administered parenterally or orally.
  • a compound does not promote substantial release of liver enzymes if administration of twice the minimum dose that yields a serum concentration equal to the EC S o or IC 50 for the 5 compound does not elevate serum levels of ALT, LDH or AST in laboratory rodents by more than 100% over matched mock-treated controls. In more highly preferred embodiments, such doses do not elevate such serum levels by more than 75% or 50% over matched controls.
  • a compound does not promote substantial release of liver enzymes if, in an in vitro hepatocyte assay, concentrations (in culture media or other such solutions that are contacted and incubated with 10 hepatocytes m vitro) that are equal to the ECj 0 or IC 50 for the compound do not cause detectable release of any of such liver enzymes into culture medium above baseline levels seen in media from matched mock-treated control cells. In more highly preferred embodiments, there is no detectable release of any of such liver enzymes into culture medium above baseline levels when such compound concentrations are five-fold, and preferably ten-fold the ECso or IC 50 for the compound.
  • certain preferred compounds do not inhibit or induce microsomal cytochrome P450 enzyme activities, such as CYPl A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity at a concentration equal to the EC 50 or IC JO for the compound.
  • microsomal cytochrome P450 enzyme activities such as CYPl A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity at a concentration equal to the EC 50 or IC JO for the compound.
  • Certain preferred compounds are not clastogenic (e.g., as determined using a mouse
  • erythrocyte precursor cell micronucieus assay an Ames micronucleus assay, a spiral micronucleus assay or the like
  • concentration equal the EC 50 or IC 50 for the compound.
  • certain preferred compounds do not induce sister chromatid exchange (e.g., in Chinese hamster ovary cells) at such concentrations.
  • isotopically-labeled or radiolabeled such compounds may have one or more atoms replaced by an atom of the same element having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be present in the compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous. fluorine and chlorine, such as 2 H, 3 H, 1 1 C, 13 C, 14 C, 15 N. 18 O. 17 0, 3 i P, 32 P, 35 S, 18 F and 36 Cl.
  • isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous. fluorine and chlorine such as 2 H, 3 H, 1 1 C, 13 C, 14 C, 15 N. 18 O. 17 0, 3 i P, 32 P, 35 S, 18 F and 36 Cl.
  • Suitable protecting groups and methodology for protection and deprotection such as those described in Protecting Groups in Organic Synthesis by T. Greene, are well known. Compounds and intermediates requiring protection/deprotection will be readily apparent.
  • a compound provided herein may contain one or more asymmetric I O carbon atoms, so that the compound can exist in different stereoisomer ⁇ forms.
  • Such forms can be, for example, racemates or optically active forms.
  • ail stereoisomers are encompassed by the present invention. Nonetheless, it may be desirable to obtain single enantiomers (i.e., optically active forms).
  • Standard methods for preparing single enantiomers include asymmetric synthesis and resolution of the racemates. Resolution of the racemates can be accomplished, for example, by
  • Each radioisotope is preferably carbon (e.g., 14 C), hydrogen
  • Tritium iabeled compounds may also be prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas using the compound as substrate.
  • certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as
  • Preparation of radiolabeled compounds may be conveniently performed by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds.
  • the present invention also provides pharmaceutical compositions comprising one or more compounds provided herein, together with at least one physiologically acceptable earner or excipient.
  • compositions may comprise, for example, one or more of water, buffers (e.g., sodium bicarbonate, neutral buffered saline or phosphate buffered saline), ethanol. mineral oil, vegetable oil, dimethylsulfoxide. carbohydrates (e.g., glucose, rnannose, sucrose, starch, mannitol or dextrans), proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as
  • EDTA EDTA or glutathione and/or preservatives.
  • other active ingredients may (but need not) be
  • compositions may be formulated for any appropriate manner of administration, including, for example, topical, oral, nasal, rectal or parenteral administration.
  • parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, as well as any similar injection or infusion 25 technique.
  • compositions suitable for oral use are preferred. Such compositions include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
  • compositions of the present invention may be formulated as a iyophilizate.
  • compositions intended for oral use may further comprise one or more components such as
  • Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets.
  • excipients include, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic
  • binding agents e.g., starch, gelatin or acacia
  • lubricating agents e.g., magnesium stearate, stearic acid or talc. Tablets may be formed using standard techniques, including diy granulation,
  • the tablets may be uncoated or they may be coated by known techniques.
  • Formulations for oral use may aiso be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), 5 or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).
  • an inert solid diluent e.g., calcium carbonate, calcium phosphate or kaolin
  • an oil medium e.g., peanut oil, liquid paraffin or olive oil
  • Aqueous suspensions contain the active material(s) in admixture with suitable excipients, such as suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); 10 and dispersing or wetting agents (e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic aicohols such as heptadecaetbyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitoi such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters 15 derived from fatty acids and hexitoi anhydrides such as polyethylene sorbitan monooleate).
  • suspending agents
  • Aqueous suspensions may also comprise one or more preservatives, such as ethyl or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and/or one or more sweetening agents, such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredient(s) in a vegetable oil 20 (e.g., arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavoring agents may be added to provide palatable oral preparations.
  • Such suspensions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., sodium EDTA
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium EDTA, sodium bicarbonate, sodium bicarbonate
  • compositions may aiso be formulated as oil-in-water emulsions.
  • the oily phase may be a vegetable oil (e.g., olive oil or arachis oil), a mineral oil (e.g., liquid paraffin) or a mixture thereof.
  • Suitable emulsifying agents include naturally-occurring gums (e.g., gum acacia or gum tragacanth), naturally-occurring phosphatides (e.g., soy bean lecithin, and esters or partial esters derived from fatty acids and hexitoi), anhydrides (e.g., sorbitan monoleate) and condensation products 35 of partial esters derived from fatty acids and hexitoi with ethylene oxide (e.g., polyoxyethyiene sorbitan monoleate).
  • An emulsion may also comprise one or more sweetening and/or flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
  • sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
  • Formulations for topical administration typically comprise a topical vehicle combined with 5 active agent(s), with or without additional optional components.
  • Suitable topical vehicles and additional components are well known in the art, and it will be apparent that the choice of a vehicle will depend on the particular physical form and mode of delivery.
  • Topical vehicles include water; organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin; glycols (e.g., butylene, isoprene or propylene glycol); aliphatic alcohols (e.g., lanolin); mixtures of water and 10 organic solvents and mixtures of organic solvents such as alcohol and glycerin; lipid-based materials such as fatty acids, acylglycerois ⁇ including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphingolipids and waxes; protein-based materials such as collagen and gelatin; silicone-based materials (both non-volatile and volatile); and hydrocarbon -based materials such as microsponges and polymer matrices.
  • organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin
  • glycols e.g., butylene, isopren
  • a composition may further include one or more 15 components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials.
  • stabilizing agents such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials.
  • stabilizing agents such as hydroxymethylceilulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.
  • a topical formulation may be prepared in any of a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids and emulsions.
  • 25 physical appearance and viscosity of such pharmaceutically acceptable forms can be governed by the presence and amount of emulsifier(s) and viscosity adjuster(s) present in the formulation.
  • Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form; solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or
  • Creams and lotions are often similar to one another, differing mainly in their viscosity; both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • Gels can be prepared with a range of viscosities, from thick or high
  • These formulations may also contain solvents, emuisifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Liquids are thinner
  • Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
  • a pharmaceutical composition may be prepared as a sterile injectable aqueous or oleaginous
  • composition may be formulated according to the known art using suitable dispersing, wetting agents and/or suspending agents such as those mentioned above.
  • suitable dispersing, wetting agents and/or suspending agents such as those mentioned above.
  • suitable vehicles and solvents water, 1 ,3- butanediol, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils may be employed.
  • any bland fixed oil may be employed, including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectible compositions, and adjuvants such as local anesthetics, preservatives and/or buffering agents can be dissolved in the vehicle.
  • compositions may also be formulated as suppositories (e.g., for rectal
  • compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable excipients include, for example, cocoa butter and polyethylene glycols.
  • compositions for inhalation typically can be provided in the form of a solution, suspension or 20 emuision that can be administered as a dry powder or in the form of an aerosol using a conventional propellant (e.g., dichlorodifluoromethane or trichlorofiuoromethane).
  • a conventional propellant e.g., dichlorodifluoromethane or trichlorofiuoromethane.
  • compositions may be formulated for release at a pre-determined rate.
  • Instantaneous release may be achieved, for example, via sublingual administration (i.e., administration by mouth in such a way that the active ingredient(s) are rapidly absorbed via the blood vessels under sublingual administration (i.e., administration by mouth in such a way that the active ingredient(s) are rapidly absorbed via the blood vessels under sublingual administration (i.e., administration by mouth in such a way that the active ingredient(s) are rapidly absorbed via the blood vessels under
  • Controlled release formulations may be administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at a target site.
  • a controlled release formulation comprises a matrix and/or coating that delays disintegration and absorption in the gastrointestinal tract (or implantation site) and
  • One type of controlled- release formulation is a sustained-release formulation, in which at least one active ingredient is continuously released over a period of time at a constant rate.
  • the therapeutic agent is released at such a rate that blood (e.g., plasma) concentrations are maintained within the therapeutic range, but below toxic levels, over a period of time that is at least 4 hours, preferably at least 8 hours,
  • Such formulations may generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site.
  • Carriers for use within such formulations are biocompatible,
  • the formulation may also be biodegradable; preferably the formulation provides a relatively constant level of modulator release.
  • the amount of modulator contained within a sustained release formuiation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
  • Controlled release may be achieved by combining the active ingredient(s) with a matrix material that itself alters release rate and/or through the use of a controiied-release coating.
  • the release rate can be varied using methods well known in the art, including (a) varying the thickness or composition of coating, (b) altering the amount or manner of addition of plasticizer in a coating, (c) including additional ingredients, such as release-modifying agents, (d) altering the composition, 10 particle size or particle shape of the matrix, and (e) providing one or more passageways through the coating.
  • the amount of modulator contained within a sustained release formulation depends upon, for example, the method of administration (e.g., the site of implantation), the rate and expected duration of release and the nature of the condition to be treated or prevented.
  • the matrix material which itself may or may not serve a controlled-release function, is 15 generally any material that supports the active ingredient(s).
  • a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
  • Active ingredient(s) may be combined with matrix material prior to formation of the dosage Form (e.g., a tablet).
  • active ingredient(s) may be coated on the surface of a particle, granule, sphere, microsphere, bead or pellet that comprises the matrix material. Such coating may be achieved by 20 conventional means, such as by dissolving the active ingredient(s) in water or other suitable solvent and spraying.
  • additional ingredients are added prior to coating (e.g., to assist binding of the active ingredient(s) to the matrix material or to color the solution).
  • the matrix may then be coated with a barrier agent prior to application of controlled-release coating. Multiple coated matrix units may, if desired, be encapsulated to generate the final dosage form.
  • a controlled release is achieved through the use of a controlled release coating (i.e., a coating that permits release of active ingredient(s) at a controlled rate in aqueous medium).
  • the controlled release coating should be a strong, continuous film that is smooth, capable of supporting pigments and other additives, non-toxic, inert and tack-free.
  • Coatings that regulate release of the modulator include pH-independent coatings, pH-dependent coatings (which may be used to 30 release modulator in the stomach) and enteric coatings (which allow the formulation to pass intact through the stomach and into the small intestine, where the coating dissolves and the contents are absorbed by the body).
  • the coating is a hydrophobic material, preferably used in an amount effective to slow the hydration of the gelling agent following administration. Suitable hydrophobic
  • alkyl celluloses e.g., ethylcellulose or carboxymethylcellulose
  • cellulose ethers e.g., cellulose esters
  • acrylic polymers e.g., poly(acrylic acid), poly(methacrylic acid), acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxy ethyl methacrylates, cyanoethyl methacrylate, methacrylic acid alkamide copolymer, poly(methyl methacrylate), polyacrylamide, ammonio methacrylate copolymers, aminoalkyl methacrylate copolymer, poly(methacrylic acid
  • ethylcellulose 10 anhydride
  • glycidyl methacrylate copolymers glycidyl methacrylate copolymers
  • aqueous dispersions of ethylcellulose include, for example, AQUACO AT® (FMC Corp., Philadelphia,
  • Acrylic polymers include, for example, the various EUDRAGIT® (Rohm America, Piscataway, NJ) polymers, which may be used
  • Suitable plasticizers for alky] celluloses include, for example, dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and 20 triacetin.
  • Suitable plasticizers for acrylic polymers include, for example, citric acid esters such as triethyl citrate and tributyl citrate, dibutyl phthalate, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil and triacetin.
  • Controlled-release coatings are generally applied using conventional techniques, such as by spraying in the fo ⁇ n of an aqueous dispersion.
  • the coating may comprise pores or channels 25 or to facilitate release of active ingredient. Pores and channels may be generated by well known methods, including the addition of organic or inorganic material that is dissolved, extracted or leached from the coating in the environment of use.
  • pore-forming materials include hydrophilic polymers, such as hydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose), cellulose ethers, synthetic water-soluble polymers (e.g., polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone and 30 polyethylene oxide), water-soluble poiydextrose, saccharides and polysaccharides and alkali metal salts.
  • a controlled release coating may include one or more orifices, which may be formed my methods such as those described in US Patent Nos. 3.845,770; 4,034,758; 4,077,407; 4,088,864; 4,783,337 and 5,073,607.
  • Controlled-release may also be achieved through the use of transdermal patches, using conventional technology (see, e.g., US Patent No. 4,668,232).
  • 35 Further examples of controlled release formulations, and components thereof, may be found, for example, in US Patent Nos. 4,572,833; 4,587, 1 17; 4,606,909; 4,610,870; 4,684,516; 4,777,049: 4,994,276; 4,996,058; 5, 128,143; 5,202,128; 5,376,384; 5,384,133; 5,445,829; 5,510, 1 19; 5,618,560;
  • a compound provided herein may be conveniently added to food or drinking water (e.g., for administration to non-human animals including companion animals (such as dogs and cats) and livestock).
  • Animal feed and drinking water compositions may be formulated so that the animal takes in an appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to 10 feed or drinking water.
  • Compound(s) provided herein are generally administered in a therapeutically effective amount.
  • Preferred systemic doses are no higher than 50 mg per kilogram of body weight per day (e.g., ranging from about 0.001 mg to about 50 mg per kilogram of body weight per day), with oral doses generally being about 5-20 fold higher than intravenous doses ⁇ e.g., ranging from 0.01 to 40 mg per kilogram of
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage unit will vary depending, for example, upon the patient being treated and the particular mode of administration. Dosage units will generally contain from about 10 ⁇ g to about 500 mg of an active ingredient. In certain embodiments, the dosage unit contains an amount of the compound that is 20 sufficient to effect a decrease in the patient's caloric intake (i.e., an appetite-suppressing amount) following single dose administration or repeated administration according to a predetermined regimen. Optimal dosages may be established using routine testing, and procedures that are well known in the art.
  • compositions may be used for treating a condition responsive to CB 1 25 modulation.
  • Such conditions include, for example: appetite disorders (e.g., binge eating disorder, bulimia, anorexia); obesity and complications associated therewith, including left ventricular hypertrophy); weight loss or control (e.g., reducing calorie or food intake and/or appetite suppression); and addictive disorders such as: 30 alcohol dependency (e.g., alcohol abuse, addiction and/or dependency including treatment for abstinence, craving reduction and relapse prevention of alcohol intake); nicotine dependency (e.g., smoking addiction, cessation and/or dependency including treatment for craving reduction and relapse prevention of tobacco smoking); and drug dependency (e.g., chronic treatment with or abuse of drugs such as opioids, barbiturates, 35 cannabis, cocaine, amphetamines, phencyclide, hallucinogens, and/or benzodiazepines).
  • appetite disorders e.g., binge eating disorder, bulimia, anorexia
  • CNS disorders e.g., anxiety, depression, panic disorder, bipolar disorder, psychosis, schizophrenia, behavioral addiction, dementia
  • the condition responsive to CB 3 modulation is an appetite disorder, obesity, an addictive disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, portal 20 hypertension, fibrosis of internal organs, orthostatic hypotension and/or drug-induced hypotension.
  • compositions provided herein comprise a first agent that is a compound as provided herein in combination with a second agent that differs in structure from the first agent and is suitable for treating the condition of interest.
  • the second agent is not a CBl antagonist as provided herein.
  • the second agent is suitable for 25 treating an appetite disorder, obesity, an addictive disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder and/or a movement disorder.
  • Representative second agents for use within such pharmaceutical compositions include anti-obesity agents such as MCH receptor antagonists, apo-B/MTP inhibitors, l l ⁇ -hydroxy steroid dehydrogenase- 1 inhibitors, peptide YY 3 -36 or an analog thereof, MCR-4 30 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, ⁇ j adrenergic receptor agonists, dopamine agonists, meianocyte-stimulating hormone receptor analogues, 5-HT2c receptor agonists, leptin or an analog thereof, leptin receptor agonists, galanin antagonists, lipase inhibitors, bombesin agonists, neuropeptide- Y receptor antagonists, thyromimetic agents, dehydroepiandrosterone or analog thereof, glucocorticoid receptor antagonists, orexiii receptor 35 antagonists, glucagon-like ⁇ e ⁇ tide
  • Such agents include, for example, phentermine. orlistat and sibutramine (e.g., sibutramine HCl monohydrate, sold as Meridia® (Abbott Laboratories)).
  • sibutramine e.g., sibutramine HCl monohydrate, sold as Meridia® (Abbott Laboratories)
  • Representative second agents suitable for treating an addictive disorder include, for example, Methadone, LAAM (levo-alpha-acetyl-methadol), naltrexone (e.g., ReViaTM), ondansetron (e.g., 5 Zofran ® ), sertraline (e.g., Zoloft ® ), fluoxetine (e.g., Prozac ® ), diazepam (e.g., Valium ® ) and chlordiazepoxide (e.g., Librium), varenicline and buproprion (e.g., Zyban ® or Wellbutrin ® ).
  • Other representative second agents for use within the pharmaceutical compositions provided herein include nicotine receptor partial agonists, opioid antagonists and/or dopaminergic agents.
  • compositions may be packaged for treating conditions responsive to CB l
  • Packaged pharmaceutical preparations generally comprise a container holding a therapeutically effective amount of a pharmaceutical composition as described above and instructions
  • a packaged pharmaceutical preparation comprises
  • the package comprises a label bearing indicia indicating that the components are to be taken together for the treatment of an appetite disorder, obesity, an addictive disorder, asthma, liver
  • the present invention provides methods for treating a condition responsive to CB I moduiation in a patient and/or for appetite suppression.
  • the patient may be
  • a condition is "responsive to CB l modulation" if the condition or symptom(s) thereof are alleviated, attenuated, delayed or otherwise improved by modulation of CB l activity.
  • Such conditions include, for example, appetite disorders, obesity, addictive disorders, asthma, liver cirrhosis, sepsis, irritable bowel disease. Crohn's disease, depression, schizophrenia, memory disorders, cognitive
  • such methods comprise administering to the patient a therapeutically effective amount of at least one compound as provided herein.
  • the compound(s) and additional agent(s) may be present in the same
  • composition or may be administered separately in either order.
  • Representative additional agents for use in such methods include the second agents described above.
  • Suitable dosages for compounds provided herein are generally as described above. Dosages and methods of administration of any additional
  • 5 agent(s) can be found, for example, in the manufacturer's instructions or in the Physician's Desk
  • combination administration results in a reduction of the dosage of the additional agent required to produce a therapeutic effect ⁇ i.e., a decrease in the minimum therapeutically effective amount).
  • the dosage of additional agent in a combination or combination treatment method of the invention is less than the maximum dose advised by the
  • this dose is less than %, even more preferably less than Vi, and highly preferably less than VA of the maximum dose, while most preferably the dose is less than 10% of the maximum dose advised by the manufacturer for administration of the agent(s) when administered without combination administration as described herein. It will be apparent that the dose of compound as provided herein
  • Administration to the patient can be by way of any means discussed above, including oral, topical, nasal or transdermal administration, or intravenous, intramuscular, subcutaneous, intratheca], epidural, intracerebroventriicular or like injection. Orai administration is preferred in certain 20 embodiments (e.g., formulated as pills, capsules, tablets or the like).
  • Treatment regimens may vary depending on the compound used and the particular condition to be treated. In general, a dosage regimen of 4 times daily or less is preferred, with 1 or 2 times daily particularly preferred. It will be understood, however, that the specific dose ievel and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the 25 specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. Dosages are generally as described above; in general, the use of the minimum dose sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using medical or veterinary criteria suitable for the condition 30 being treated or prevented. For example, treatment of obesity is considered to be effective if it results in a statistically significant decrease in weight or BMI.
  • the present invention provides a variety of non-pharmaceutical in vitro and in vivo uses for the compounds provided herein.
  • such compounds may be labeled and used as probes for the detection and localization of CBl (in samples such as cell 35 preparations or tissue sections, preparations or fractions thereof).
  • compounds provided herein that comprise a suitable reactive group such as an aryl carbonyl, nitro or azide group
  • a suitable reactive group such as an aryl carbonyl, nitro or azide group
  • a compound 33 herein may be used as positive controls in assays for receptor activity, as standards for determining the ability of a candidate agent to bind to CB l , or as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
  • PET positron emission tomography
  • SPECT single photon emission computerized tomography
  • Detection assays including receptor autoradiography (receptor mapping) of CB l in cultured cells or tissue samples may be performed as
  • Compounds provided herein may further be used within assays for the identification of other non-competitive antagonists of CB l .
  • assays are standard competition binding assays, in which a labeled compound as provided herein is displaced by a test compound.
  • such assays 20 are performed by: (a) contacting CB l with a labeled (e.g., radiolabeled) compound and a test compound, under conditions that permit binding to CB l (b) removing unbound labeled compound and unbound test compound; (c) detecting a signal that corresponds to the amount of bound, labeled compound; and (d) comparing the signal to a reference signal that corresponds to the amount of bound labeled compound in a similar assay performed in the absence of test compound.
  • the 25 reference signal and the signal described in step (c) are generally obtained simultaneously (e.g., the assays are performed in different wells of the same plate); in addition, multiple concentrations of test compound are generally assayed. Non-competitive antagonist activity can be confirmed for test compounds that decrease the amount of bound, labeled compound using procedures described herein.
  • MS Advanced Chemistry Development, ⁇ nc; Toronto, Canada
  • Sample volume of 1 microliter is injected onto a 50x4.6mm Chromolith SpeedROD RP- 18e column (Merck KGaA, Darmstadt, Germany), and eluted using a 2 -phase linear gradient at a flow rate of 6 ml/min. Sample is detected using total absorbance count over the 220-340nm UV range.
  • the 10 elution conditions are: Mobile Phase A - 95% water, 5% MeOH with 0.05% TFA; Mobile Phase B - 5% water, 95% MeOH with 0.025% TFA.
  • the foilowing gradient is used: 0-0.5 min 10-100%B, hold at I00%B to 1.2 min, return to 10%B at 1 .21 min. Inject to inject cycle is 2.15 min.
  • Step I Synthesis of 3-chloro-N-(4-(u * ifluoromethyl)phenyl)isonicotinamide
  • Step 4 Synthesis of /er/-butyl 4-(3-(3-chloiOpyridin-4-yl)-5-oxo-4-(4-(trifluorometliyl)phenyl)-4,5- dihydro-l,2,4-triazol-] -y ⁇ )piperidine-l-carboxylate
  • Step 1 Synthesis of ethyl 2-(3-(3-chloropyridin-4-yI)-5-oxo-4-(4-(trifluoromelhyi)phenyl)-4,5- dihydro-l ,2,4-triazol-l-yl)acetate
  • This compound is prepared essentially as described in Example 2, with readily apparent 10 modification.
  • EXAMPLE 7 PREPARATION OF 5-(3-CHLOROPYRIDIN-4-YL)-2-(3,3-DIMETHYL-2-OXOBUTYL)-4-(4- ISOPROPOXYPHENYL)-2H-1 , 2,4-TRIAZOL-3(4H)-ONE AND 5-(3-CHLOROPYRID!N-4-YL)-2-(2-L IYDROXY- 3.3-DIMETHYLB ⁇ RYL)-4-(4-ISOPROPOXYPHENYL)-2H- L ,2,4-TRIAZOL-3(4 H)-ONE
  • Step I Synthesis of 5-(3-chloropyridin-4-yl)-2-(3,3-dimethyl-2-oxobutyl)-4-(4-isopiOpoxyphenyl)- 15 2H-l,2 ; 4-triazoI-3(4H)-one
  • starling matenals may be varied and additional steps employed to produce other compounds provided herein.
  • Compounds listed in Table I are prepared using such methods. All compounds in Table 1 have a K 1 of 1 micromolar or less as determined using the assay provided in Example 14, herein Mass Spectioscopy data in the column labeled "MS" is obtained as described above, and ts presented as M+l The retention time (Ret Time) is given in minutes.

Abstract

Diaryl triazolones of Formula I are provided, in which the variables are as described herein. Such compounds may be used to modulate CB1 activity in vivo or in vitro, and are particularly useful in the treatment of conditions responsive to CB1 modulation in humans, domesticated companion animals and livestock animals, including appetite disorders, obesity and addictive disorders. Pharmaceutical compositions and methods for using diaryl traizolones of Formula I to treat such disorders are provided, as are methods for using such compounds as ligands for receptor localization studies and various in vitro assays.

Description

DIARYL TRIAZOLONES AS CBl ANTAGONISTS
FIELD OF THE INVENTION
This invention relates generally to diary I triazoiones, and to the use of such compounds to treat 5 conditions responsive to cannabinoid receptor- 1 (CB l ) modulation. The invention further relates to the use of such compounds as reagents for the identification of agents that bind to CBl , and as probes for the detection and locaϊization of CB l .
BACKGROUND OF THE INVENTION
10 Obesity is the most common nutritional problem in developed countries. This condition is both harmful to the individual and costly to society, as it increases the likelihood of developing serious health conditions (such as cardiovascular diseases and diabetes) and complicates numerous chronic conditions such as respiratory diseases, osteoarthritis, osteoporosis, gall bladder disease and dyslipidemias. Fortunately, however, many of the conditions caused or exacerbated by obesity can be 15 resolved or dramatically improved by weight loss.
Once considered merely a behavioral problem (i.e., the result of voluntary hyperphagia). obesity is now recognized as a complex multifactorial disease involving defective regulation of food intake, food-induced energy expenditure and the balance between lipid and ϊean body anabolism. Both environmental and genetic factors play a role in the development of obesity. As a result, treatment 20 programs that focus entirely on behavior modification have limited efficacy and are associated with recidivism rates exceeding 95%. Pharmacotherapy is now seen as a critical component of weight loss and subsequent weight management.
Currently available prescription drugs for managing obesity generally reduce weight by inducing satiety or decreasing dietary fat absorption. Such drugs, however, often have unacceptable 25 side effects. Several, such as the older adrenergic weight-loss drugs (e.g., amphetamine, methamphetamine, and phenmetrazine), which act via dopamine pathways, are no longer recommended because of the risk of their abuse. Fenfluramine and dexfenfiuramine, both serotonergic agents used to regulate appetite, are also no longer available for use.
Thus, there exists a need for more effective agents for promoting weight loss and for reducing 30 or preventing weight-gain. In addition, there exists an unmet need for more effective agents for the treatment of alcoho! and tobacco dependence. The present invention fulfills these needs, and provides further related advantages.
SUMMARY OF THE INVENTION
The present invention provides diaryl triazoiones that satisfy Formula f: y \ Formula I
or are a pharmaceutically acceptable salt or solvate thereof, wherein:
Ari and Ar2 are independently chosen from phenyl and ό-membered heteroaryl, each of which is optionally substituted, and each of which is preferably substituted with from 0 to 5 substituents independently chosen from RA; 5 R is:
(i) hydrogen;
(ii) C|-C8alkyl, C2-Cgalkenyl, C2-C«alkynyl, (C3-CjocycJoalkyl)Co-C4alkyl3 C,-C8alkyl ether, C,-
Cgaikoxycarbonyl, Ci-CsalkylsulfonyiCo-Gtalkyl, mono- or di-(Ci-Csaikyl)aminoC0-C4alkyi, mono- or di-(Ci-C8alkyl)aminosulfonylCo-C4alkyl, or mono- or di-(Cr
10 Csalkyl)aminocarbonylCo-C4alkyl; each of which is optionally substituted, and each of which is preferably substituted with from 0 to 6 substituents independently chosen from RB; or (iii) a group of the formula -L-A-X-B, -L-M-X-B, -L-X-A-B or -L-X-M-B wherein:
L is C0-C3alkylene that is optionally substituted, and is preferably substituted with from 0 to 2 substituents independently chosen from RB; 15 A is a 5- to 8-membered heterocycloalkyl group that is optionally substituted, and is preferably substituted with from 0 to 3 substituents independently chosen from RB; M is (6- to 10-membered aryl)C0-C2aikyl or (5- to 10-membered heteroaryl)C0-C2alkyl, each of which is optionally substituted, and each of which is preferably substituted with from 0 to 3 substituents independently chosen from R8; 20 X is absent, -C(=O)-, -N(RX)C(=O)-, -C(=O)N(RX)- or -S(O2)-; wherein Rx is hydrogen or
CrC4alkyl; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is C]-C6alkyl, (C3-C6cycloalky!)CcrC2alkyi, CrC6haloalkyl, CrC6aikoxy, C2-Q,alkyi ether, mono- or di-(C]-C6aikyl)amino, or (4- to 7-membered heterocycloalkylJCo^alkyl, each 25 of which is substituted with from 0 to 3 substituents independently chosen from R3;
Each RA is independently chosen from:
(i) halogen, hydroxy, cyano, amino, nitio, aminocarbonyl, aminosulfonyl and -COOH; and (ii) Cj-Qalkyl, CrC6alkenyl, C2-C6alkynyl, (C3-C8CycloaIkyl)Co-C4alky!, C,-Qalkoxy. C1- C6alkylthio, Ci-Cβalkylsulfϊnyl, Cj-C6alkoxycarbonyl, Ci-C6aIkylsulfonylC0-C4alky], mono- or 30 di-(C]-C6aikyl)aminoCo-C4aIkyl, mono- or di-(C1-C6alkyl)aminosulfonyiCo-C4alkyI, mono- or di-(C]-Caalkyl)aminocarbonylCo-C4alkyl, phenylC0-C4aikyl, phenyl C0-C4alkoxy, (4- to 8- membered heterocycle)C0-C4alkyl and (4- to 8-membered heterocycle)Co-C4alkoxy: each of which is optionally substituted, and each of which is preferably substituted with from 0 to 6 substituents independently chosen from RB; and
2 Each RB is independently chosen from:
(i) oxo, halogen, hydroxy, cyano, amino, nitro, aminocarbony], aminosulfonyl, and -COOH; and (ii) Ci-Csalkyl, C2-Csalkenyl, C2-Csalkyny], (C3-Cscyc!oalkyI)Co-C4alkyl, CrCgalkoxy, C,- Cgalkylthio, Cj-Cgalkyisulfinyl, (CrCsaIky])sulfonylCo-C4alkyl, C2-Csalkyl ether, mono- or 5 di-(CrCgalkyl)aminoCo-C4alkyl and mono- or di-(Ci-Cgalkyl)amiπosulfonyiCo-C4alkyl; each of which is optionally substituted, and each of which is preferably substituted with from O to 6 substituents independently chosen from oxo, halogen, hydroxy, Ci-Qalkyi and Ci-Qalkoxy.
In other aspects, the present invention provides diaryl triazolones that satisfy Formula II:
Ar\ P
N" \ Formula Jl
AΓΛN'N-R or are a pharmaceutically acceptable salt or solvate thereof, wherein:
10 Ar1 and Ar2 are independently chosen from phenyl and 6-membered heteroaryl, each of which is substituted with from 1 to 4 substituents independently chosen from RA;
R is C2-C8alkyl, C2-Cgalkcnyl, (C3-C]ocycloalkyl)Co-C4alkyl5 C2-Csalkyl ether, C,-
Cgalkoxycarbonyl, CrCβalkylsulfonylQK^alkyl, mono- or di-(Ci-Csalkyl)aiτιinoCo-C4alkyI, mono- or di-(Ci-CsalkyI)aminosuifony]C0-C4alkyl, or mono- or di-(Cr
15 C8alkyl)aminocarbony]Co-C4alkyl; each of which is substituted with from O to 6 substituents independently chosen from RBJ or
R is a group of the formula -L-A-X-B or -L-X-A-B, wherein: L is Co-C3alkylene optionally substituted with R13;
A is a 5- to 8-membered heterocycloalkyl group that is substituted with from O to 3 20 substituents independently chosen from Rβ;
X is absent, -C(=O)-, -~N(RX)C(=O)-, -C(=O)N(RX> or -S(O2)-; wherein Rx is hydrogen or
Ci-Qalkyl; and
B is absent or cyano. such that if B is absent or cyano, then X is absent; or B is Ci-C6aikyl, (CrC6cycloalky!)C0-C2alkyI, CrC6haloalkyl, CrC6alkoxy, C2-C6alkyl ether, 25 mono- or di-(CrC6alkyl)amino, or 4- to 7-raembered heterocycloalkyl. each of which is substituted with from O to 3 substituents independently chosen from RB; such that R is not morpholin-4-ylmethyl; and RA and R5 are as described above.
In further aspects, the present invention provides diaryl triazolones that satisfy Formula III: Ar2 o y~ \ Formula III
30 or are a pharmaceutically acceptable salt or solvate thereof, wherein: Ar1 is phenyl or 6-membered heteroaryl, each of which is substituted with from 1 to 4 substituents independently chosen from RA; Ar2 is phenyl or 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from RA; 5 R is C|-Csalky! that is substituted with 1 or 2 substituents independently chosen from halogen, cyano, hydroxy, amino, oxo, such that R does not comprise an aminocarbonyl or carboxy group; and RA and RB are as described above.
In other aspects, the present invention provides diaryl triazoiones that satisfy Formula IV:
N \ Formula IV
AΓAN"N~R 10 or are a pharmaceutically acceptable salt or solvate thereof, wherein:
Ari is 6-membered heteroaryl that is substituted with from 1 to 4 substituents independently chosen from RA; Ar2 is phenyl or 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from RA;
15 R is CrCsalkyl, C2-Csalkeπyl, C2-Csalkynyf, (C3-C, 0cycloalkyl)C0-C4alkyl, C2-Cgalky! ether, C,-
Qalkoxycarbonyl, Ci-CsalkylsυlfonyiQH^aikyl, mono- or di^Ci-CgalkyOaminoCo-Gialkyl, mono- or di~(Ci-C8aikyl)aminosu3fonylCo-C4alky], or mono- or di-(Cr Csalkyl)aminocarbonylCo-C4alkyl; each of which is substituted with from 0 to 6 substituents independently chosen from Rs; or
20 R is a group of the formula -L-A-X-B or -L-X-A-B, wherein:
L is C0-Qa!ky!ene optionally substituted with RB; A is a 5- to 8-membered heterocycloalkyl group that is substituted with from 0 to 3 substituents independently chosen from RB;
X is absent, -C(=O)-, -N(Rx)C(=O)-5 -C(=O)N(RX)- or -S(O2)-; wherein Rx is hydrogen or 25 Ci-C4alkyl; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is Ci-Qalkyl, (C,-C6cycloaIkyl)C0-C2alkyl, CrC6haloalkyl, C,-C6alkoxy, C2-C6alkyl ether, mono- or di-(C]-C6alkyi)arnino, or 4- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 3 substituents independently chosen from RB; and 30 RA and RB are as described above. Within other aspects, the present invention provides diaryϊ triazolones that satisfy Formula V: R2
Formula V
Figure imgf000006_0001
or are a pharmaceutically acceptable salt or solvate thereof, wherein:
R1 is halogen, hydroxy, CpQalkyl, CpC6haloalkyi, CpC6aϊkoxy or CpGshaloalkoxy; R2 is halogen, hydroxy, CpC6alkyl, CrC6haloalkyl, CpC6alkoxy, CrC6haloalkoxy or CpQalkoxy 5 that is substituted with a 4- to 6-membered carbocycle or heterocycle:
R is:
(i) hydrogen;
(ii) C-Cgalkyl, C2-Qalkenyl, C2-Qalkynyl, (C3-C10cyc]oalkyl)Co-Qalkyl, C2-Csalkyl ether, C]-C8alkoxycarbonyl, CpCgalkylsulfonylCo-Qalkyl. mono- or di-(CrCsalkyI)arninoCo- 10 Qalkyl, mono- or di-(CrC8alky!)aminosuIfonyIC0-C4alky], or mono- or di-(Cr
C8alkyi)aminocarbonylC(i-C.(alkyl; each of which is substituted with from 0 to 6 substituenls independently chosen from RB; or (iii) a group of the formula -L-A-X-B, -L-M-X-B, -L-X-A-B or -L-X-M-B , wherein:
L is Co-C3alkyiene optionally substituted with RB; 15 A is a 5- to 8-membered heterocycloalkyϊ group that is substituted with from 0 to 3 substituents independently chosen from RB; M is phenylCo-Cialkyl or (5- to 10-membered heteroaryl)Co-C2alkyl3 each of which is substituted with from 0 to 3 substituents independently chosen from RB; X is absent, ~C(=O)-, -N(RX)C(=O)-, -CC=O)N(Rx)- or -S(O2)-; wherein Rx is hydrogen 20 or CpC4alkyl; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is CpQalkyl, (C3-C6cycloalkyI)C0-C2alkyl, CpQhaloalkyl, CpCsalkoxy, C2-C6alkyJ ether, mono- or di-(CrC6alkyl)amino, or 4- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 3 substituents independently chosen from R8; 25 wherein RB is as described above.
In further aspects, the present invention provides diaryl triazolones that satisfy Formula VI: Ar2
^ ,k, -R Formula Vl
Figure imgf000006_0002
or are a phaπnaceuticaliy acceptable salt or solvate thereof, wherein:
5 Ar2 is phenyl or 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from RA; R is:
(i) hydrogen;
5 (ii) Q-Qalkyl, C2-C8alkenyl, C2-Csalkyny!, (C3-Cj 0cycloa]kyl)C0-C4alkyl, C2-Csalkyl ether, C,-
Cgaikoxycarbonyl, CrCgalkylsulfonyiCo-C4aIkyl, mono- or di-(Cj-Cgalkyl)aminoCo-C4alkyl, mono- or di-(Ci-Csalkyl)aminosulfonylCo-C4alkyl! or mono- or di-(d- C8alkyl)aminocarbonylCo-C4alkyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB; or
10 (in) a group of the formula -L-A-X-B, -L-M-X-B, -L-X-A-B or -L-X-M-B , wherein:
L is C0-C3alkylene optionally substituted with R6; A is a 5- to 8-mernbered heterocycloaikyϊ group that is substituted with from 0 to 3 substituents independently chosen from RB;
M is phenylCo-C2a!kyl or (5- to 1 0-membered heteroaryOQ-Qalkyl, each of which is 15 substituted with from 0 to 3 substituents independently chosen from RB;
X is absent, -C(=O)-, -N(RX)C(=O)-, -C(=O)N(RX)- or -S(O2)-; wherein Rx is hydrogen or
C]-C4alkyi; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is C,-C6alky], (C3-C6cycloalkyl)C0-C2alkyl, C,-C6haloa!kyL C,-C6alkoxy, C2-C6alkyl ether, 20 mono- or di-(Cs-Cήalkyl)amino, or 4- to 7-merabered heterocycloalkyl, each of which is substituted with from 0 to 3 substituents independently chosen from RB; RA and RB are as described above; and
R3 and R4 are independently chosen from halogen, hydroxy. Q-Cealkyl, C|-C6haloalkyl, CrC6aikoxy or Cj-Cβhaloatkoxy.
25 Within certain aspects, diaiyl triazolones provided herein are CB l modulators and exhibit a K, of no greater than 2 micromolar, 1 micromolar, 500 nanomolar, 100 nanomolar or 50 nanomolar in a CB l ligand binding assay and/or have an EC5O or IC50 value of no greater than 1 micromolar, 100 nanomolar, 50 nanomolar or 10 nanomolar in an assay for determination of CB l agonist or antagonist activity.
30 In certain embodiments, CB l modulators as described herein are CBl antagonists and exhibit no detectable agonist activity.
Within certain aspects, compounds as described herein are labeled with a detectable marker (e.g., radiolabeled or fluorescein conjugated).
The present invention further provides, within other aspects, pharmaceutical compositions
35 comprising at least one diaiyl triazolone as described herein (e.g., a compound of Formula 1 or a pharmaceutically acceptable salt thereof) in combination with a physiologically acceptable carrier or excipient. The present invention further provides methods for treating a condition responsive to CB l modulation in a patient, comprising administering to the patient a therapeutically effective amount of at least one compound as described herein. Such conditions include, for example, appetite disorders, obesity, dependency disorders such as alcohol dependency and nicotine dependency, asthma, liver 5 cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, memory disorders, cognitive disorders, movement disorders, portal hypertension, fibrosis of internal organs, orthostatic hypotension and drug-induced hypotension.
In further aspects, methods are provided for suppressing appetite in a patient, comprising administering to the patient an appetite reducing amount of at least one compound as described herein. 10 The present invention further provides pharmaceutical compositions, comprising (a) a First agent that is a compound as described above, (b) a second agent that is suitable for treating an appetite disorder, obesity, an addictive disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder or a movement disorder; and (c) a physiologically acceptable earner or excipient.
15 The present invention also provides packaged pharmaceutical preparations, comprising: (a) a composition comprising a compound as described above in a container; and (b) instructions for using the composition to treat one or more conditions responsive to CB l modulation.
Within further aspects, the present invention provides methods for determining the presence or absence of CBl in a sample, comprising: (a) contacting a sample with a compound as described herein 20 under conditions that permit binding of the compound to CB l ; and (b) detecting a signal indicative of a level of the compound bound to CB l .
In yet another aspect, the invention provides methods of preparing the compounds disclosed herein, including the intermediates.
These and other aspects of the present invention will become apparent upon reference to the 25 following detailed description.
DETAILED DESCRIPTION
As noted above, the present invention provides diaryl triazolones. Such compounds may be used in vitro or in vivo in a variety of contexts as described herein.
TEElM INOLOGY
30 Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) ail of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon-carbon double bonds may occur in Z- and E- forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. If a compound exists in various tautomeric forms, a
35 recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. Certain compounds are described herein using a general formula that includes
7 variables (e.g., X, A, Ar,). Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence.
The term "diary! triazolones" encompasses all compounds of Formula ϊ, which compounds 5 may or may not further satisfy one or more additional other formulas provided herein, and includes pharmaceutically acceptable salts, solvates and esters of such compounds.
A "pharmaceutically acceptable salt" of a compound recited herein is an acid or base salt that is suitable for use in contact with the tissues of human beings or animals without excessive toxicity or carcinogenicity, and preferably without irritation, allergic response, or other problem or complication. 10 Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutically acceptable salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesuifonic, methanesulfonic, benzene sulfonic, camphorsυlfonic, ethane disulfonic, 2-liydroxyethylsulfonic, nitric, benzoic, 2- 15 acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, afkanoic such as acetic, HOOC-(CH2)n-COOH where n is 0-4, and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those of ordinary skill in the art will recognize further pharmaceutically acceptable salts for the compounds provided herein, including 20 those listed in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, p, 1418 (1990) and in particular, the discussion and Table II appearing under the heading "Salt Formation" spanning pages 1444-45 thereof, which is incorporated herein by reference for its disclosures regarding pharmaceutically acceptable salts, or the equivalent disclosure in Remington: The Science and Practice of Pharmacy, 21s1 ed., Lippincott Williams & Wilkins, Philadelphia, PA 25 (2005). In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. Briefly, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, the use of nonaqueous media, such as ether, ethyl acetate, ethanol, isopropano! or 30 acetonitrile, is preferred.
It will be apparent that each compound provided herein may, but need not, be foπnulated as a solvate {e.g., hydrate) or non-covaient complex. In addition, the various crystal forms and polymorphs are within the scope of the present invention. Also provided herein are prodrugs of the compounds provided herein. A "prodrug" is a compound that may not fully satisfy the structural requirements of 35 the compounds provided herein, but is modified in vivo, following administration to a patient, to produce a compound provided herein. For example, a prodrug may be an acylated derivative of a compound as provided herein. Prodrugs include compounds wherein hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein may be 5 prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved in vivo to yield the parent compounds.
As used herein, the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon. Certain aikyi groups include those having from 1 to 8 carbon atoms (CVQalkyl), from 1 to 6 carbon atoms (CrC6alkyl) and from 1 to 4 carbon atoms (CrC4alkyl). such as methyl, ethyl, 10 propyl, isopropyi, n-butyf, sec-butyl, tert-buty\, pentyl, 2-pentyi, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl or 3-methylpentyl. "Co-C4alkyϊ" refers to a single covalent bond (C0) or an alkyl group having 1 , 2, 3 or 4 carbon atoms.
"Alkylene" refers to a divalent alkyl group. CpQalkylene is an alkylene group having I , 2, 3 or 4 carbon atoms. C0-C4alkylene refers to a single covalent bond or C|-C4aikylene.
15 "Alkenyl" refers to straight or branched chain alkene groups, which comprise at least one unsaturated carbon-carbon double bond. Alkenyl groups include, for example, C2-C8alkenyl, C2- C6alkenyl and C2-C4alkenyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively, such as ethenyl, allyl or isopropenyl. "Alkynyl" refers to straight or branched chain alkyne groups, which have one or more unsaturated carbon-carbon bonds, at least one of which is a 20 triple bond. Alkynyl groups include, for example, C2-C8alkynyl, C2-C6aikynyl and C2-C4alkynyi groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.
A "cycloalkyl" is a saturated or partially saturated cyclic group in which all ring members are carbon, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl, or a partially saturated variant of any of the foregoing. Certain cycloalkyl groups are C3-C|0cyc!oalkyl, in which the 25 cycloalkyl group comprises one or more rings and contains from 3 to 10 ring members, all of which are carbon. A "(C3-C10cycloalky])Co-C4alkyl" is a CrCjoCycbalkyi group linked via a single covalent bond or CpQalkylene.
By "alkoxy," as used herein, is meant an alkyl group as described above attached via an oxygen bridge. Certain alkoxy groups are CrC6alkoxy and CrC4aIkoxy groups, which have from 1 to
30 6 or 1 to 4 carbon atoms, respectively. Methoxy, ethoxy, propoxy, isopropoxy, π-butoxy, sec-butoxy. tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy are representative alkoxy groups.
"Alkylthio" refers to an alkyl group as described above attached via a sulfur bridge (Le., — S- alkyl).
35 The term "oxo," as used herein refers to a keto group (C=O). An oxo group that is a substituent of a nonaromatic carbon atom results in a conversion of -CH2- to -C(=O}-. An oxo group that is a substituent of an aromatic carbon atom results in a conversion of -CH- to ~C(=O)- and may result in a loss of aromaticity.
"Alkyϊsulfinyl" refers to groups of the formula -(SO)-aϊkyl, in which the sulfur atom is the point of attachment. Representative alkySsulfinyl groups include Q-Cβalkylsulfϊnyl and C,- 5 C4alkylsulfmyl groups, which have from 1 to 6 or 1 to 4 carbon atoms, respectively.
"Alkylsulfonyl" refers to groups of the formula -{SQO-aikyl, in which the sulfur atom is the point of attachment. Representative alkylsulfonyl groups include CrC6alkylsuifonyl and Q-
C4alkylsulfonyl groups, which have from 1 to 6 or 1 to 4 carbon atoms, respectively. "Ci-
C3alkylsulfonylCo-C4alkyi" is a CrC8alkylsulfonyl group linked via a single covalent bond or a Cr
10 Cjalkylene group.
The term "alkanoyl" refers to an acyl group (e.g., -~{C=O)-alkyl), where attachment is through the carbon of the keto group. Alkanoyl groups include, for example, C2-Csalkanoyl, C2-C6alkanoyl and C2-C4alkanoyl groups, which have from 2 to 8, 2 to 6 or 2 to 4 carbon atoms, respectively.
"Cialkanoyl" refers to -(C=O)H, which (along with C2-Qalkanoyl) is encompassed by the term "Cr
15 Csalkanoyi." Ethanoyl is C2alkanoy).
An "alkanone" is a ketone group in which carbon atoms are in a linear or branched alkyl arrangement. "C3-C8alkanone" refers to an alkanone having from 3 to 8 carbon atoms. A C3 alkanone has the structure -CH2-(C=O)-CH3.
Similarly, "alkyl ether" refers to a linear or branched ether substituent. Representative alkyl 20 ether groups include C^-Cgalkyl ether. C2-C6alkyl ether and C2-C4alkyl ether groups, which have 2 to 8, 6 or 4 carbon atoms, respectively. A C2 alkyl ether has the structure -CHi-O-CH3.
The term "aikoxycarbonyl" refers to an alkoxy group Jinked via a carbonyi {i.e., a group having the general structure -C(=O}-O-alkyl). Certain alkoxycarbonyl groups include Ci-C8, C]-C6 and CrC4alkoxycarbonyl groups, which have from 1 to 8, 6 or 4 carbon atoms, respectively, in the 25 aikyl portion of the group. "Cialkoxycarbonyi" refers to -Cf=O)-O-CH3.
"Alkylamiπo" refers to a secondary or tertiary amine that has the general structure -NH-alkyl or -N(alkyl)(alkyl), wherein each alkyl is selected independently from alkyl, cycloaikyl and
(cycloalkyl)alkyl groups. Such groups include, for example, mono- and di-(CrCsalkyi)amino groups, in which each CrCsalkyl may be the same or different, as well as mono- and di-(CrC6alkyl)amiπo
30 groups and mono- and di-(CrC4alky])amino groups.
"Alkylaminoalkyl" refers to an alkylamino group linked via an alkylene group (i.e., a group having the general structure -alkylene-NH-alkyl or -aIkylene-N(alkyl)( alkyl)) in which each alkyl is selected independently from alkyl, cycloaikyl and (cycloalkyl)alkyl groups. Alkylaminoafkyl groups include, for example, mono- and di-(C;-C8alkyl)aminoCi-C8alkyl. "Mono- or di-(CrCsa[kyl)aminoC0- 35 C4alkyl" refers to a mono- or di-(C|-Csalkyl)amino group linked via a single covalent bond or a Cr C4alkylene group. The following are representative alkylaminoalkyl groups:
10
Figure imgf000012_0001
/~ >t> "A it will be apparent that the definition of "alkyl" as used in the terms "alkylamino" and "alkylaminoalkyl" differs from the definition of "alkyl" used for all other alkyl-containing groups, in the inclusion of cycloalkyl and (cycloalkyl)alkyl groups (e.g., (C3-C8cycloalkyl)Co-C4alkyl). 5 The term "aminocarbonyi" refers to an amide group (i.e., -Cf=O)INIiHb). "Mono- or di-(Cj-
Csa!kyl)aminocarbonylCo-QaIkyI" refers to an aminocarbonyi group in which one or both hydrogens are replaced with an independently selected Cj-Csalkyl group, and which is linked via a single covaleπt bond or a C]-C4alkylene group.
The term "aminosulfonyl" refers to a sulfonamide group (i.e., -SO2NH2). "Mono- or di-(Cr 10 C8alky[)aminosuIfony!Co-C4alkyI" refers to an aminosulfonyl group in which one or both hydrogens are replaced with an independently selected Ci-Cgalky! group, and which is linked via a single covaient bond or a Ci-^aikyiene group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
A "haϊoalkyl" is an alkyl group that is substituted with 1 or more independently chosen
15 halogens (e.g., "Ci-Cghaloalkyl" groups have from 1 to 8 carbon atoms; "Q-Qhaloalkyl" groups have from 1 to 6 carbon atoms). Examples of haioalkyl groups include, but are not limited to, mono-, di- or tri-fiuoromethyl; mono-, di- or tπ-chloromethyl; mono-, di-, tri-, tetra- or penta-fluoroethyl; mono-, dϊ-
, tri-, tetra- or penta-chloroethyl; and 1 ,2.2,2-tetrafluoro-l -trifIuoiOmethyI-ethyl. Typical haioalkyl groups are trifluoromethyi and difluoromethyi. The term "haloalkoxy" refers to a haloalky! group as
20 defined above attached via an oxygen bridge. "Ci-Cshaloaikoxy" groups have 1 to 8 carbon atoms.
A dash ("— ") that is not between two letters or numbers is used to indicate a point of attachment for a substituent. For example, -C(=O)NH2 is attached through the carbon atom.
A "carbocycle" has from 1 to 3 fused, pendant or spiro rings, each of which has only carbon ring members. Typically, a carbocycie that has a single ring contains from 3 to 8 ring members (i.e., 25 Cs-Cgcarbocycles); rings having from 4 to 6 ring members are recited in certain embodiments. Carbocycles comprising fused, pendant or spiro rings typically contain from 9 to 14 ring members. Carbocycles may be optionally substituted with a variety of substituents, as indicated. Unless otherwise specified, a carbocycle may be a cycloalkyl group (i.e., each ring is saturated or partially saturated as described above) or an aiyl group (i.e., at least one ring within the group is aromatic). 30 Phenyl groups linked via a single covaient bond or CpCjalkylene group are designated phenylCo- C4alkyl (e.g., benzyl. 1 -pheπyl-ethyl, 1-phenyi-propyl and 2-phenyl-ethyl). A pheny lCo-Gj alkoxy group is a phenyl ring linked via an oxygen bridge or via an alkoxy group having from 1 to 4 carbon atoms (e.g., phenoxy or benzoxy).
A "heterocycle" (also referred to herein as a "heterocyclic group") has from 1 to 3 fused, 35 pendant or spiro rings, at least one of which is a heterocyclic ring (i.e., one or more ring atoms is a
11 heteroatom independently chosen from oxygen, sulfur and nitrogen, with the remaining ring atoms being carbon). Typically, a heterocyclic ring comprises 1, 2, 3 or 4 heteroatoms; within certain embodiments each heterocyclic ring lias 1 or 2 heteroatoms per ring. Each heterocyclic ring generally contains from 4 to 8 ring members (rings having from 4 to 6 ring members are recited in certain 5 embodiments). Certain heterocycles comprise a sulfur atom as a ring member; in certain embodiments, the sulfur atom is oxidized to SO or SO2. Heterocycles may be optionally substituted with a variety of substitueπts, as indicated.
Certain heterocycles are heteroaryl groups (i.e., at least one heterocyclic ring within the group is aromatic), such as a 5- to 10-membered heteroaryl (which may be monocyclic or bicyclic) or a 6- 10 membered heteroaryl (e.g., pyridyl or pyrimidyl). Other heterocycles are heterocycloalkyl groups. Certain heterocycles may be linked by a single covaient bond or via an alkylene group, as indicated, for example, by the term "(4- to S-membered heterocycle)C0-C4alkyI." Heterocycles may also be linked via an oxygen or alkoxy group, as indicated, for example, by the term "(4- to 8-membered heterocyc le)C0-C4alkoxy . ' '
15 A "substituent," as used herein, refers to a molecular moiety that is covalently bonded to an atom within a molecule of interest. For example, a "ring substituent" may be a moiety such as a halogen, alkyl group, haioafkyi group or other group discussed herein that is covalently bonded to an atom (such as a carbon or nitrogen atom) that is a ring member. The term "substitution" refers to replacing a hydrogen atom in a molecular structure with a substituent as described above, such that the 20 valence on the designated atom is not exceeded, and such that a chemically stable compound (i.e., a compound that can be isolated, characterized, and tested for biological activity) results from the substitution.
Groups that are "optionally substituted" are unsubstituted or are substituted by other than hydrogen at one or more available positions, typically I, 2, 3, 4 or 5 positions, by one or more suitable 25 groups (which may be the same or different). Optional substitution is also indicated by the phrase "substituted with from 0 to X substituents," where X is the maximum number of possible substituents. Certain optionally substituted groups are substituted with from 0 to 2, 3 or 4 independently selected substituents (i.e., are unsubstituted or substituted with up to the recited maximum number of substitutents).
30 "CBl ," as used herein, refers to the human cannabinoid receptor reported by Hoeche et al.
(1991) New Biol. 3(^:880-85, as well as allelic variants thereof and homologues thereof found in other species.
A "CB l antagonist" is a compound that detectably inhibits signal transduction mediated by
CB l . Such inhibition may be determined using the representative agonist-induced GTP binding assay
35 provided in Example 14. Preferred CBl antagonists have an IC50 Of 2 μM or less in this assay, more preferably 1 μM or less, and still more preferably 500 nM or less or 100 nM or less. In certain embodiments, the CB l antagonist is specific for CB l (i.e., the IC50 value in a similar assay performed
12 using the predominantly peripheral cannabπioid receptor CB2 is greater than 2 μM and/or the IC50 ratio (CB2/CBI) is at least 10, preferably 100, and more preferably at least 1000). CB l antagonists preferably have minimal agonist activity (i.e., induce an increase in the basal activity of CB l that is less than 5% of the increase that would be induced by one EC50 of the agonist CP55,940, and more 5 preferably have no detectable agonist activity within the assay described in Example 14). CB l antagonists for use as described herein are generally non-toxic. CBl antagonists include neutral antagonists and inverse agonists.
A "neutral antagonist" of CB i is a compound that inhibits the activity of CBI agonist (e.g., endocannabinoids) at CB l , but does not significantly change the basal activity of the receptor (i.e., 10 within a GTP binding assay as described in Example 14 performed in the absence of agonist, CBl activity is reduced by no more than 10%, more preferably by no more than 5%, and even more preferably by no more than 2%; most preferably, there is no detectable reduction in activity). Neutral antagonists may, but need not, also inhibit the binding of agonist to CB 1.
An "inverse agonist" of CB l is a compound that reduces the activity of CB l below its basal
15 activity level in the absence of activating concentrations of agonist. Inverse agonists may also inhibit the activity of agonist at CBl, and/or may inhibit binding of CB l agonist to CB l . The ability of a compound to inhibit the binding of CB l agonist to the CB l receptor may be measured by a binding assay, such as the radioligand binding assay given in Example 13. The reduction in basal activity of
CB l produced by an inverse agonist may be determined from a GTP binding assay, such as the assay
20 of Example 14.
A "non-competitive CB l antagonist" is a CB l antagonist that (1 ) does not detectabiy inhibit binding of CBl agonist {e.g., CP55.940) to CB l at antagonist concentrations up to 10 μM and (2) reduces the maximal functional response elicited by agonist. Compounds that satisfy these two conditions may be identified using the assays provided herein. Such compounds generally do not 25 display detectable activity in the competition binding assay described in Example 13. In functional assays, a non-competitive antagonist concentration-dependently reduces the maximal functional response elicited by agonist without altering agonist EC50. The suppression of functional activity by a non-competitive antagonist cannot be overcome by increasing agonist concentrations (i.e., the antagonist activity is insurmountable).
30 A "therapeutically effective amount" (or dose) is an amount that, upon administration to a patient, results in a discernible patient benefit (e.g., provides detectable relief from a condition being treated). Such relief may be detected using any appropriate criteria, including the alleviation of one or more symptoms of dependency or an appetite disorder, or the promotion of weight loss. In the case of appetite suppression, a therapeutically effective amount is sufficient to decrease patient appetite, as 35 assessed using patient reporting or actual food intake. Such an amount is referred to herein as an "appetite reducing amount." A therapeutically effective amount or dose generally results in a concentration of compound in a body fluid (such as blood, plasma, serum, CSF, synovial fluid, lymph,
13 cellular interstitial fluid, tears or urine) that is sufficient to result in detectable alteration in CB l - mediated signal transduction (using an assay provided herein). The discernible patient benefit may be apparent after administration of a single dose, or may become apparent following repeated administration of the therapeutically effective dose according to a predetermined regimen, depending 5 upon the indication for which the compound is administered.
A "patient" is any individual treated with a compound as provided herein. Patients include humans, as well as other animals such as companion animais (e.g., dogs and cats) and livestock.
Patients may be experiencing one or more symptoms of a condition responsive to CBl modulation or may be free of such symptom(s) (i.e., treatment may be prophylactic in a patient considered to be at
10 risk for the development of such symptoms).
DlARYL TRI AZOLONES
As noted above, the present invention provides diaryl triazolones of Formula I that may be used in a variety of contexts, including in the treatment of appetite disorders, obesity and addictive disorders. Such compounds may also be used within in vitro assays (e.g., assays for CBl activity), as 15 probes for detection and localization of CBl and within assays to identify CB l antagonists.
In certain aspects, diaryl triazolones of Formula 1 further satisfy one or more additional Formulas provided herein. Within such Formulas, variables are generally as described above; in certain embodiments, such variables (where present) are as follows:
THE VARIABLES AR, AND AR2
20 Within certain compounds of the Formulas provided herein, the variables Ai"j and An are independently phenyl or pyridyl, each of which is substituted with one or two substituents independently chosen from halogen, hydroxy, cyano, amino, Q-Qalkyl, Q-Qhaloalkyl, CrC6alkoxy and CpCfihaloalkoxy. Representative Ar1 groups include substituted pyridyl, such as pyridin-4-yl that is substituted at the 2-position (e.g., ρyridin-4-yl that is substituted at the 2-position with halogen.
25 hydroxy, cyano, amino, C]-C6alky\, Cj-C^haloalkyl, Ci-C6alkoxy or Ci-C6haloalkoxy). One such Ar1 group is pyridin-4-yl that is substituted at the 2-position with a halogen, such as Cl). Other representative Ars groups include, for example, substituted phenyl, such as 2,4-disubstituted phenyl. Certain Ar; groups satisfy the Formula:
Figure imgf000015_0001
N N^R. or K< ^ ~R3 ,
30 in which variables are as described for Formula V and Formula VI, above. Representative R] groups include halogens, such as Cl. Representative R3 and R4 groups include, for example, halogen, Q- Gjhaioalkyl and Q-dalkoxy, with halogen substituents preferred in certain embodiments.
Representative Ar2 groups include, for example, substituted phenyl and substituted pyridyl. In certain embodiments, Ar2 is substituted at the para position with a halogen (e.g., Cl or F), hydroxy,
35 cyano, amino, CrC4alkyl, Q-C^aloalkyl, C]-C4alkoxy, Q-C^aloalkoxy, Ci-C4alkoxycarbonyl or
14 phenylQyC^aikoxy. Within certain such compounds, Ar2 is phenyl or pyridyi (e.g., pyridin-2-yl or pyridin-3-yl) that is substituted at the para position and is unsubstituted at other positions. Certain Ar2 groups satisfy the Formula:
R2--Λ \\
5 in which R3 is as described for Formula V, above. Representative R2 groups include, for example, halogen, Ci-Cβhaloalky! and CrQalkoxy.
Within certain embodiments, one substituent of An is located para to the point of attachment and/or one substituent of Ar, is located ortho to the point of attachment.
THE VARIABLE "R"
10 Certain R groups within Formula I and other Formulas provided comprise a group of the formula -L-A-X-B, -L-M-X-B, -L-X-A-B or -L-X-M-B, in which variables are as described above. Within -L-A-X-B and -L-M-X-B, "-X-B" represents an optional substituent on the ring portion of 'A" or "M," which substituent replaces a hydrogen on a ring member. Thus, if X and B are both absent in such groups, the ring "A" or "M" is unsubstituted other than by substituents chosen from RB, 15 where indicated. Alternatively, within -L-A-X-B and -L-M-X-B, if X is absent and B is not absent, then B is directly linked to a ring member of "A" or "M", If X is one of the other groups listed, that group forms a linker between the "A" or "M" ring and the B moiety.
Certain representative R groups (e.g., of Formula II, IV, V or VI) include, for example, groups of the formula -L-A-X-B or -L-X-A-B, wherein:
20 L is C0-C3alkylene optionally substituted with oxo or hydroxy;
A is a 4- to 6-membered heterocycloalkyi group; X is absent, -C(O)-, -N(RX)C(=O)-, -C(^O)N(Rx)- or -S(O2)-; wherein Rx is hydrogen or C,-
C4 alky 1; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is C|-C6alkyl, (C3- 25 C6cycloalkyl)C0-C2alkyl, Cj-C6haloalkyl, C,-C6alkoxy, Ci-Qalkyl ether, mono- or di-(C,-
Cfialkyl)amino or 4- to 7-membered heterocycloalkyi, each of which is substituted with from O to 3 substituents independently chosen from oxo, hydroxy and Ci^alkyl. Other representative R groups comprise an aromatic moiety. Such R groups include, for example, groups of the foπnu Ia -L-M-X-B or -L-X-M-B, wherein: 30 L is Co-C3alkylene optionally substituted with oxo or hydroxy;
M is phenylCo-Cialky! or (5- to 10-membered heteroary^Co-Cialkyl, each of which is substituted with from O to 3 substituents independently chosen from oxo, hydroxy and C|-Gia]kyl; X is absent, ~C(=0)-, -N(RX)C(=O>, -C(=0)N(Rx)- or -S(O2)-, wherein Rx is hydrogen or C,- C4alkyl; and
15 B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is C|-C6alkyϊ, (Cr C6cycloalkyl)C0-C2alkyi, C;-C6haloalkyl, Ci-C6alkoxy, C2-C6alkyl ether, mono- or di-(Cr CsalkyOamino, or 4- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 3 substituents independently chosen from oxo, hydroxy, and CrC4aikyl.
5 In certain embodiments of Formula II and other Formulas, R is C2-Csalkyl (e.g., C3-Csalky! or
C4-Csa1kyl), CrCsalkenyl, (C3-C, 0cycloalkyf)Co-C2a]kyl, C2-C8haloalkyi, C2-Csalkyl ether, mono- or di-(Ci-C6alkyl)aminoCo-C4alky], or (4- to 8-membered heterocycloalkyi)C0-C4aIkyl. each of which is substituted with from 0 to 4 substituents independently chosen from: (i) oxo and hydroxy; and (ii) Cp C6alkyl, (C4-C6cycloalkyl)Co-C2aIkyl, CrQ,haloaIky), CrC6alkoxy, C2-C6alkyi ether, (C1- 10 C6a]kyl)sulfonylC0-C2alkyl, and mono- or di-(Ci-C6alkyl)aminoCo-C4alkyl; each of which is substituted with 0, I or 2 oxo moieties. Representative R groups include, for example, C2-C8alkyi, C2- Cgafkenyl, (C3-C7cycloalkyl)Co-C2aikyl, C2-Cshaloalkyl, C2-C8aiky! ether, and mono- and di-(Cr C6alkyl)amtnoC0-C4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from oxo, hydroxy, C|-C4alkyl, C]-C4alkoxy and (C|-C6a!kyl)sulfonyl. Certain such R groups 15 include alkanoyl and alkanone groups (e.g., C2-C8aikanoy! and C3-C8alkanoπe).
In certain embodiments of Formulas IV, V and VI, and other Formulas, R is Q-Cgalkyl, C2-
Cgaikenyl, C2-Csaikynyl, {C3-C!ocycloalkyl)C0-C2alkyi5 C2-C8haloalky!, C2-Csalkyl ether, mono- or di-
(Ci-CsalkyOaminoCo-Cjalkyl, or (4- to 8-membered heterocycloalkyl)Co-C4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from: (i) oxo and hydroxy; and (ii) Q-
20 C6alkyl, (C4-C6cycloalky!)C0-C2aIkyI, CrC6haloalkyl, Q-C6alkoxy, C2-C6alkyϊ ether, (C,-
C6alkyl)suifonyiC[i-C2alkyi, and mono- or di-(C,-C6alkyl)aminoCo-C4alkyl; each of which is substituted with 0, 1 or 2 oxo moieties. Representative R groups include, for example, Cj-Cgalkyl, C2-
Cgaikenyl, C2-C8alkynyl, (C3-C7cycloalkyl)Co-C2alkyl, C2-Cghaloalkyl, C2-Csalkyl ether, and mono- and di-(C]-Cf,alkyI)aminoCo-C4alkyl, each of which is substituted with from 0 to 4 substituents
25 independently chosen from oxo, hydroxy, CrC4alkyl. Q-Qalkoxy and (C|-C6alkyl)sulfonyi. Certain such R groups include alkanoyl and alkanone groups (e.g., Ci-Cgalkanoyl and C3-Csalkanone).
Certain R moieties satisfy the Formula:
X-Q in which X is as described above; n is 1, 2 or 3; and Q is C|-C6alkyl, Cj-Cealkoxy, C2-C6alkyl ether, 30 (CrCιocycloalkyl)Co-C2alkyl or 4- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 3 substituents independently chosen from oxo, hydroxy and Ci-C4a!ky].
Further representative R groups include CrCsalkyt that is substituted with 1 or 2 substituents independently chosen from halogen, cyano, hydroxy, amino and oxo (e.g., CpCgalky] that is substituted with one hydroxy group or one oxo group). Certain such R groups include alkanoyl and 35 alkanone groups (e.g., C2-Csalkanoyi and C3-Csalkanone).
16 Representative diary! triazolones provided herein include, but are not limited to, those specifically described in the Examples below. It will be apparent that the specific compounds recited herein are representative only, and are not intended to limit the scope of the present invention. Further, as noted above, all compounds of the present invention may be present as a free acid or base or as a
5 pharmaceutically acceptable salt.
Within certain aspects, as noted above, diary! triazolones provided herein are CBl antagonists. Certain such compounds are non-competitive CB I antagonists, in addition, or alternatively, certain compounds provided herein are specific for CB 1. CB 1 antagonist activity may be confirmed using an agonist-induced GTP binding assay, such as the assay described in Example 14, herein. Such assays 10 employ a CB l -containing cell membrane preparation (e.g., a preparation of membranes of insect cells that recombinantly express CB l) to determine the effect of a test compound on CBl agonist-induced GTP binding to CB l . Briefly, a first cell membrane preparation comprising CBl is contacted with: (i) labeled GTP; (ii) a CB l agonist; and (iii) a test compound to yield a test membrane preparation. Simultaneously, or in either order, a second cell membrane preparation comprising CB l is contacted 15 with: (i) labeled GTP; and (ii) a CB l agonist to yield a control membrane preparation. The labeled GTP is preferably GTPy33S; a representative CB l agonist is CP55,940. Such contact is performed under conditions that are suitable for GTP binding to CB I , such as the conditions described in Example 14. The concentrations of labeled GTP and CB l agonist used are generally concentrations that are sufficient to result in a detectable increase in the amount of labeled GTP bound to the 20 membrane preparation in the presence of CB l agonist. Such concentrations may be determined by routine experimentation; representative suitable concentrations are provided in Example 14. Generally, a range of test compound concentrations is used (e.g., ranging from I 0"!0M to 10"5M).
After sufficient contact (e.g., incubation) to allow GTP binding to the membrane preparations, a signal that corresponds to (represents) the amount of bound, labeled GTP is detected (typically,
25 unbound labeled GTP is first removed via a washing step). Tn other words, simultaneously or in either order: (i) a test signal that represents an amount of bound, labeled GTP in the test membrane preparation is detected; and (ii) a control signal that represents an amount of bound, labeled GTP in the control membrane preparation is detected. The nature of the signal detected is determined by the type of label used. For example, if the GTP is radioactively labeled, the signal detected is radioactive decay
30 (e.g., via liquid scintillation spectrometry). The CBI antagonist activity of the test compound is then determined by comparing the test signal with the control signal. A test signal that is lower than the control signal indicates that the test compound is a CB l antagonist.
In certain embodiments, preferred compounds are cannabinoid receptor-specific. This means that they only bind to, activate, or inhibit the activity of certain receptors other than cannabinoid
35 receptors (preferably other than CB l ) with affinity constants of greater than 100 nanomolar, preferably greater than 1 micromolar, more preferably greater than 4 micromolar. Alternatively, or in addition, such compounds exhibit 200-fold greater affinity for CB l than for other cellular receptors. Such other
17 non-canπabinoid cellular receptors include histamine receptors, bioactive peptide receptors (including NPY receptors such as NPY Y5), and hormone receptors (e.g., melanin-concentrating hormone receptors). Assays for evaluating binding to such receptors are well known, and include those disclosed in US patent 6,566,367, which is incorporated herein by reference for its disclosure of NPY 5 receptor binding assays in Example 676 columns 82-83; and in PCT International Application Publication No. WO 02/094799 which is incorporated herein by reference for its disclosure of an MCH receptor binding assay in Example 2, pages 108- 109.
Utility of the compounds provided herein for the various diseases and disorders may be demonstrated in animal disease models that are known in the ait, such as: 10 Colombo et al. ( 1998) Life Sciences 63: 1 13-17 and Vickers and Kennett (2005) Curr. Drug,
Targets (5:215-23 -food intake and weight loss (rats)
Simiand et aJ. (1998) Behavioral Pharm. 5: 179-181 — sweet food intake (marmosets) Rowland et al. (2001) Psychopharm. 159: 1 11-16 - food intake (rats) Arnone et al. (1997) Psychopharm. 752: 104-106 - sucrose and ethanol intake (mice) 15 Colombo et al. (2004) Eur. J. Pharmacol 498: 119-23 - alcohol motivational properties (rats)
Serra et al. (2002) Eur. J. Pharmacol, 443:95-91 - alcohol deprivation effect (rats) Rubino et al. (2000) Life Sciences 22:2213-29 - opiate withdrawal syndrome (rats) Chaperon et al. ( 1998) Psychopharm. 135:324-32 - motor activity, place conditioning (rats) Abraham et al. (1993 j J. Clin. Invest. 93:776 and Milne and Piper (1995) Eur. J. Pharmacol. 20 282:243 - bronchial hyperresponsiveπess (sheep and guinea pigs)
Kadoi et al. (2005) British Journal of Anaesthesia 94(5):563-68 - septic shock (rats) Batkai et al. (2001) Nature Medicine 7(7):827-32 -vasodilation in liver cirrhosis (rats) Tsusumi et al. (2000) Biol. Pharm. Bull. (Japan) 23(5):657-59 ~ constipation (monkeys) Kapur (2001) J Pathology 194(3):277-88 - chronic intestinal pseudo- obstruction 25 (rodents)
Ϊeixeira-Clerc et. al. (2006) Natwe Medicine CB l antagonism prevents liver fibrosis (rats)
If desired, diaryl triazolones provided herein may be evaluated for certain pharmacological properties including, but not limited to, oral bioavailability (preferred compounds are orally bioavailabie to an extent allowing for therapeutically effective doses of less than 140 mg/kg, preferably 30 less than 50 mg/kg. more preferably less than 30 mg/kg, even more preferably less than 10 mg/kg, still more preferably less than 1 mg/kg and most preferably less than 0.1 mg/kg), toxicity (a preferred compound is nontoxic when a therapeutically effective amount is administered to a subject), side effects (a preferred compound produces side effects comparable to placebo when a therapeutically effective amount of the compound is administered to a subject), serum protein binding and in -vitro and 35 in vivo half-life (a preferred compound exhibits an in vivo half-life allowing for Q.I.D. dosing, preferably T.I.D. dosing, more preferably B.l.D. dosing, and most preferably once-a-day dosing). In addition, differentia! penetration of the blood brain barrier may be desirable. Routine assays that are
I S well known in the art may be used to assess these properties, and identify superior compounds for a particular use. For example, assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals 5 given the compound (e.g., intravenously). Serum protein binding may be predicted from albumin binding assays. Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described herein.
As noted above, preferred compounds provided herein are nontoxic. In general, the term
10 "nontoxic" as used herein shall be understood in a relative sense and is intended to refer to any substance that has been approved by the United States Food and Drug Administration ("FDA") for administration to mammals (preferably humans) or, in keeping with established criteria, is susceptible to approval by the FDA for administration to mammals (preferably humans). In addition, a preferred nontoxic compound generally satisfies one or more of the following criteria: (1) does not substantially
15 inhibit cellular ATP production; (2) does not significantly prolong heart QT intervals; (3) does not cause substantial ϋver enlargement, or (4) does not cause substantial release of liver enzymes.
As used herein, a compound that does not substantially inhibit cellular ATP production is a compound that satisfies the criteria set forth in Example 16, herein. In other words, cells treated as described in Example 16 with 100 μM of such a compound exhibit ATP levels that are at least 50% of
20 the ATP levels detected in untreated cells. In more highly preferred embodiments, such cells exhibit
ATP levels that are at least 80% of the ATP levels detected in untreated cells.
A compound that does not significantly prolong heart QT intervals is a compound that does not result in a statistically significant prolongation of heart QT intervals (as determined by electrocardiography) in guinea pigs, minipigs or dogs upon administration of a dose that yields a serum 25 concentration equal to the EC50 or IC50 for the compound, In certain preferred embodiments, a dose of 0.01 , 0.05, 0.1 , 0.5, 1 , 5, 10, 40 or 50 mg/kg administered parenterally or orally does not result in a statistically significant prolongation of heart QT intervals. By "statistically significant" is meant results varying from control at the p<0.1 level or more preferably at the p<0.05 level of significance as measured using a standard parametric assay of statistical significance such as a student's T test. 30 A compound does not cause substantial liver enlargement if daily treatment of laboratory rodents (e.g., mice or rats) for 5- 10 days with a dose that yields a serum concentration equal to the EC50 or IC50 for the compound results in an increase in liver to body weight ratio that is no more than 100% over matched controls. In more highly preferred embodiments, such doses do not cause liver enlargement of more than 75% or 50% over matched controls. If non-rodent mammals (e.g., dogs) are 35 used, such doses should not result in an increase of liver to body weight ratio of more than 50%, preferably not more than 25%, and more preferably not more than 10% over matched untreated
19 controls. Preferred doses within such assays include 0.01 , 0.05. 0.1, 0.5, 1, 5, 10, 40 or 50 mg/kg administered parenterally or orally.
Similarly, a compound does not promote substantial release of liver enzymes if administration of twice the minimum dose that yields a serum concentration equal to the ECSo or IC50 for the 5 compound does not elevate serum levels of ALT, LDH or AST in laboratory rodents by more than 100% over matched mock-treated controls. In more highly preferred embodiments, such doses do not elevate such serum levels by more than 75% or 50% over matched controls. Alternatively, a compound does not promote substantial release of liver enzymes if, in an in vitro hepatocyte assay, concentrations (in culture media or other such solutions that are contacted and incubated with 10 hepatocytes m vitro) that are equal to the ECj0 or IC50 for the compound do not cause detectable release of any of such liver enzymes into culture medium above baseline levels seen in media from matched mock-treated control cells. In more highly preferred embodiments, there is no detectable release of any of such liver enzymes into culture medium above baseline levels when such compound concentrations are five-fold, and preferably ten-fold the ECso or IC50 for the compound. 15 In other embodiments, certain preferred compounds do not inhibit or induce microsomal cytochrome P450 enzyme activities, such as CYPl A2 activity, CYP2A6 activity, CYP2C9 activity, CYP2C19 activity, CYP2D6 activity, CYP2E1 activity or CYP3A4 activity at a concentration equal to the EC50 or ICJO for the compound.
Certain preferred compounds are not clastogenic (e.g., as determined using a mouse
20 erythrocyte precursor cell micronucieus assay, an Ames micronucleus assay, a spiral micronucleus assay or the like) at a concentration equal the EC50 or IC50 for the compound. In other embodiments, certain preferred compounds do not induce sister chromatid exchange (e.g., in Chinese hamster ovary cells) at such concentrations.
For detection purposes, as discussed in more detai! below, compounds provided herein may be
25 isotopically-labeled or radiolabeled. For example, such compounds may have one or more atoms replaced by an atom of the same element having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be present in the compounds provided herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous. fluorine and chlorine, such as 2H, 3H, 1 1C, 13C, 14C, 15N. 18O. 170, 3 iP, 32P, 35S, 18F and 36Cl. In addition,
30 substitution with heavy isotopes such as deuterium (i.e., 2H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
PREPARATION OF DIΛRYL TRIAZOLONES
Compounds provided herein may generally be prepared using standard synthetic methods. In
35 general, starting materials are commercially available from suppliers such as Sigma-Aldrich Corp. (St.
Louis, MO), or may be synthesized from commercially available precursors using established protocols. By way of example, a synthetic route similar to that shown in any of the following Schemes
20 may be used, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon appreciated by those skilled in the art. It will be apparent that the reagents and synthetic transformations in the following Schemes can be readily modified to produce additional compounds of Formula 1. Each variable in the following Schemes refers to any group consistent with the description of the compounds provided herein.
When a protecting group is required, an optional deprotection step may be employed. Suitable protecting groups and methodology for protection and deprotection, such as those described in Protecting Groups in Organic Synthesis by T. Greene, are well known. Compounds and intermediates requiring protection/deprotection will be readily apparent.
10 Certain definitions used in the following Schemes and in the Examples include:
CDI 1 , 1 '-carbonyldiimidazole
DCM dichloromethane
DMC 2-chloro-] ,3-dimethyiimidazoltnium chloride
EtOH elhanol
15 EtOAc ethyl acetate h hour(s)
1H NMR proton nuclear magnetic resonance
Hz hertz
LCMS liquid chromatography-mass spectrometry
20 MeOH methanol
M-H mass + 1
Miπ minute(s)
MS mass spectrometry
Ms methanesulfonyi
25 rt room temperature
1BuOK potassium tø^-butoxide
TEA triethylamine
TFA trifluoroacetic acid
T
Figure imgf000022_0001
HF tetrahydrofuran
21 Scheme
O O O
Jf (COCI)2 Ji TEA
Ar1^ OH *- Arf XI Ar2-NH2 Ar1 A' 1 N11-Ar2
H 3
H2% p
1) P0CI3 , Δ ΛκrAr2 CDI Ar2 ^ Ar1 N V NH
2) H2NNH2 H ^i^
Ari
Scheme 2
OH OMs
MsCI1 TEA
Figure imgf000023_0001
N
Figure imgf000023_0002
N B oc Boc
O OMs
O
Ar2^ Ar; ^ Ar 2v
K2CO3 NA TFA N j NH ■»- N—< NBoc A N— ( NH
Figure imgf000023_0003
Figure imgf000023_0006
Ar/ ^N N
Figure imgf000023_0004
Ar1" ^N
Boc Ar1' 10
O
Rz-Ci A^N-Λ base N N-R7
Ar1- -N
11
Scheme '.
O O
Ar, -NΛ K2CO3 Ar,
NH or 1BuOK ■N^:.
R-X1 N-R
Ar1' -N
Ar1- 12 13 X1 = leaving group
Scheme 4
O O O O
Ar, -A Br- K2CO3 ^"N-Λ Λ0R^
NH 0Ry
Figure imgf000023_0005
Ar; ~N Ri Ar1-^N R1
14 15
O ON P O. Ry
LOH A^N^ VOH H DMC Ar^N^ . VN
. N. I N-< Rz Ar1-^N R1
16 17 18
22 Scheme 5 K2CO3
Figure imgf000024_0001
0
Figure imgf000024_0002
Jl
HnNNHp Ar2. Jl Ar2x N~Λ Rz-Xi
N- base
Ar1- -NHc Ar1' ~N HH X1 = leaving group
21 22 R
Scheme 6
O
K2CO3 Ar,
I NH + Br' NHBoc -N\-
NHBoc Ar/^N' Ar;
23 24
O O
TFA Jl Ar2-N^N' Ar^N^N'
-H NH, base 1N N- -R,
An H
25 An 26
X1 = leaving group
Scheme 7
O O U U Ar2. Jl O HO N-R,
NHRyRz ^ Ar2. Jl λ '
NH + r cιι^^ ^<r1A K2CQ3 , r2"N i ^\ N--7 / N EtOH [ \ N,-
Ar,' Ar1" Ar1' ^N'
27 28 29
Scheme S
O O O 0 HO
A^N-< B S K2CO3 Ar2 j; ^R, NaBH4 Ar2 ^ )
Ar1^N R^ Ar >N >N'
6 30 31 32
In certain embodiments, a compound provided herein may contain one or more asymmetric I O carbon atoms, so that the compound can exist in different stereoisomer^ forms. Such forms can be, for example, racemates or optically active forms. As noted above, ail stereoisomers are encompassed by the present invention. Nonetheless, it may be desirable to obtain single enantiomers (i.e., optically active forms). Standard methods for preparing single enantiomers include asymmetric synthesis and resolution of the racemates. Resolution of the racemates can be accomplished, for example, by
23 conventional methods such as crystallization in the presence of a resolving agent, or chromatography using, for example a chiral HPLC column.
Compounds may be radiolabeled by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. Each radioisotope is preferably carbon (e.g., 14C), hydrogen
5 (e.g., 1H), suifur (e.g., 35S) or iodine (e.g., 123I). Tritium iabeled compounds may also be prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas using the compound as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as
10 appropriate. Preparation of radiolabeled compounds may be conveniently performed by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds.
PHARMACEUTICAL COMPOSITIONS
The present invention also provides pharmaceutical compositions comprising one or more compounds provided herein, together with at least one physiologically acceptable earner or excipient.
15 Pharmaceutical compositions may comprise, for example, one or more of water, buffers (e.g., sodium bicarbonate, neutral buffered saline or phosphate buffered saline), ethanol. mineral oil, vegetable oil, dimethylsulfoxide. carbohydrates (e.g., glucose, rnannose, sucrose, starch, mannitol or dextrans), proteins, adjuvants, polypeptides or amino acids such as glycine, antioxidants, chelating agents such as
EDTA or glutathione and/or preservatives. In addition, other active ingredients may (but need not) be
20 included in the pharmaceutical compositions provided herein.
Pharmaceutical compositions may be formulated for any appropriate manner of administration, including, for example, topical, oral, nasal, rectal or parenteral administration. The term parenteral as used herein includes subcutaneous, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal and intraperitoneal injection, as well as any similar injection or infusion 25 technique. In certain embodiments, compositions suitable for oral use are preferred. Such compositions include, for example, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Within yet other embodiments, compositions of the present invention may be formulated as a iyophilizate.
Compositions intended for oral use may further comprise one or more components such as
30 sweetening agents, flavoring agents, coloring agents and/or preserving agents in order to provide appealing and palatable preparations. Tablets contain the active ingredient in admixture with physiologically acceptable excipients that are suitable for the manufacture of tablets. Such excipients include, for example, inert diluents (e.g., calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate), granulating and disintegrating agents (e.g., corn starch or alginic
35 acid), binding agents (e.g., starch, gelatin or acacia) and lubricating agents (e.g., magnesium stearate, stearic acid or talc). Tablets may be formed using standard techniques, including diy granulation,
24 direct compression and wet granulation. The tablets may be uncoated or they may be coated by known techniques.
Formulations for oral use may aiso be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), 5 or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).
Aqueous suspensions contain the active material(s) in admixture with suitable excipients, such as suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia); 10 and dispersing or wetting agents (e.g., naturally-occurring phosphatides such as lecithin, condensation products of an alkylene oxide with fatty acids such as polyoxyethylene stearate, condensation products of ethylene oxide with long chain aliphatic aicohols such as heptadecaetbyleneoxycetanol, condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitoi such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters 15 derived from fatty acids and hexitoi anhydrides such as polyethylene sorbitan monooleate). Aqueous suspensions may also comprise one or more preservatives, such as ethyl or n-propyl p- hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and/or one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredient(s) in a vegetable oil 20 (e.g., arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and/or flavoring agents may be added to provide palatable oral preparations. Such suspensions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
25 Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweetening, flavoring and coloring agents, may also be present.
30 Pharmaceutical compositions may aiso be formulated as oil-in-water emulsions. The oily phase may be a vegetable oil (e.g., olive oil or arachis oil), a mineral oil (e.g., liquid paraffin) or a mixture thereof. Suitable emulsifying agents include naturally-occurring gums (e.g., gum acacia or gum tragacanth), naturally-occurring phosphatides (e.g., soy bean lecithin, and esters or partial esters derived from fatty acids and hexitoi), anhydrides (e.g., sorbitan monoleate) and condensation products 35 of partial esters derived from fatty acids and hexitoi with ethylene oxide (e.g., polyoxyethyiene sorbitan monoleate). An emulsion may also comprise one or more sweetening and/or flavoring agents.
25 Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also comprise one or more demulcents, preservatives, flavoring agents and/or coloring agents.
Formulations for topical administration typically comprise a topical vehicle combined with 5 active agent(s), with or without additional optional components. Suitable topical vehicles and additional components are well known in the art, and it will be apparent that the choice of a vehicle will depend on the particular physical form and mode of delivery. Topical vehicles include water; organic solvents such as alcohols (e.g., ethanol or isopropyl alcohol) or glycerin; glycols (e.g., butylene, isoprene or propylene glycol); aliphatic alcohols (e.g., lanolin); mixtures of water and 10 organic solvents and mixtures of organic solvents such as alcohol and glycerin; lipid-based materials such as fatty acids, acylglycerois {including oils, such as mineral oil, and fats of natural or synthetic origin), phosphoglycerides, sphingolipids and waxes; protein-based materials such as collagen and gelatin; silicone-based materials (both non-volatile and volatile); and hydrocarbon -based materials such as microsponges and polymer matrices. A composition may further include one or more 15 components adapted to improve the stability or effectiveness of the applied formulation, such as stabilizing agents, suspending agents, emulsifying agents, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers and sustained release materials. Examples of such components are described in Martindale— The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Remington: The Science and Practice of Pharmacy, 21st ed., Lippincott 20 Williams & Wilkins, Philadelphia, PA (2005). Formulations may comprise microcapsules, such as hydroxymethylceilulose or gelatin-microcapsules, liposomes, albumin microspheres, microemulsions, nanoparticles or nanocapsules.
A topical formulation may be prepared in any of a variety of physical forms including, for example, solids, pastes, creams, foams, lotions, gels, powders, aqueous liquids and emulsions. The
25 physical appearance and viscosity of such pharmaceutically acceptable forms can be governed by the presence and amount of emulsifier(s) and viscosity adjuster(s) present in the formulation. Solids are generally firm and non-pourable and commonly are formulated as bars or sticks, or in particulate form; solids can be opaque or transparent, and optionally can contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or
30 enhance the efficacy of the final product. Creams and lotions are often similar to one another, differing mainly in their viscosity; both lotions and creams may be opaque, translucent or clear and often contain emulsifiers, solvents, and viscosity adjusting agents, as well as moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Gels can be prepared with a range of viscosities, from thick or high
35 viscosity to thin or low viscosity. These formulations, like those of lotions and creams, may also contain solvents, emuisifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product. Liquids are thinner
26 than creams, lotions, or gels and often do not contain emulsifiers. Liquid topical products often contain solvents, emulsifiers, moisturizers, emollients, fragrances, dyes/colorants, preservatives and other active ingredients that increase or enhance the efficacy of the final product.
A pharmaceutical composition may be prepared as a sterile injectable aqueous or oleaginous
5 suspension. The compound(s) provided herein, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Such a composition may be formulated according to the known art using suitable dispersing, wetting agents and/or suspending agents such as those mentioned above. Among the acceptable vehicles and solvents that may be employed are water, 1 ,3- butanediol, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils may
10 be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectible compositions, and adjuvants such as local anesthetics, preservatives and/or buffering agents can be dissolved in the vehicle.
Pharmaceutical compositions may also be formulated as suppositories (e.g., for rectal
15 administration). Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Compositions for inhalation typically can be provided in the form of a solution, suspension or 20 emuision that can be administered as a dry powder or in the form of an aerosol using a conventional propellant (e.g., dichlorodifluoromethane or trichlorofiuoromethane).
Pharmaceutical compositions may be formulated for release at a pre-determined rate.
Instantaneous release may be achieved, for example, via sublingual administration (i.e., administration by mouth in such a way that the active ingredient(s) are rapidly absorbed via the blood vessels under
25 the tongue rather than via the digestive tract). Controlled release formulations (Le., formulations such as a capsule, tablet or coated tablet that stows and/or delays release of active ingredient(s) following administration) may be administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at a target site. In general, a controlled release formulation comprises a matrix and/or coating that delays disintegration and absorption in the gastrointestinal tract (or implantation site) and
30 thereby provides a delayed action or a sustained action over a longer period. One type of controlled- release formulation is a sustained-release formulation, in which at least one active ingredient is continuously released over a period of time at a constant rate. Preferably, the therapeutic agent is released at such a rate that blood (e.g., plasma) concentrations are maintained within the therapeutic range, but below toxic levels, over a period of time that is at least 4 hours, preferably at least 8 hours,
35 and more preferably at least 12 hours. Such formulations may generally be prepared using well known technology and administered by, for example, oral, rectal or subcutaneous implantation, or by implantation at the desired target site. Carriers for use within such formulations are biocompatible,
27 and may also be biodegradable; preferably the formulation provides a relatively constant level of modulator release. The amount of modulator contained within a sustained release formuiation depends upon, for example, the site of implantation, the rate and expected duration of release and the nature of the condition to be treated or prevented.
5 Controlled release may be achieved by combining the active ingredient(s) with a matrix material that itself alters release rate and/or through the use of a controiied-release coating. The release rate can be varied using methods well known in the art, including (a) varying the thickness or composition of coating, (b) altering the amount or manner of addition of plasticizer in a coating, (c) including additional ingredients, such as release-modifying agents, (d) altering the composition, 10 particle size or particle shape of the matrix, and (e) providing one or more passageways through the coating. The amount of modulator contained within a sustained release formulation depends upon, for example, the method of administration (e.g., the site of implantation), the rate and expected duration of release and the nature of the condition to be treated or prevented.
The matrix material, which itself may or may not serve a controlled-release function, is 15 generally any material that supports the active ingredient(s). For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed. Active ingredient(s) may be combined with matrix material prior to formation of the dosage Form (e.g., a tablet). Alternatively, or in addition, active ingredient(s) may be coated on the surface of a particle, granule, sphere, microsphere, bead or pellet that comprises the matrix material. Such coating may be achieved by 20 conventional means, such as by dissolving the active ingredient(s) in water or other suitable solvent and spraying. Optionally, additional ingredients are added prior to coating (e.g., to assist binding of the active ingredient(s) to the matrix material or to color the solution). The matrix may then be coated with a barrier agent prior to application of controlled-release coating. Multiple coated matrix units may, if desired, be encapsulated to generate the final dosage form.
25 In certain embodiments, a controlled release is achieved through the use of a controlled release coating (i.e., a coating that permits release of active ingredient(s) at a controlled rate in aqueous medium). The controlled release coating should be a strong, continuous film that is smooth, capable of supporting pigments and other additives, non-toxic, inert and tack-free. Coatings that regulate release of the modulator include pH-independent coatings, pH-dependent coatings (which may be used to 30 release modulator in the stomach) and enteric coatings (which allow the formulation to pass intact through the stomach and into the small intestine, where the coating dissolves and the contents are absorbed by the body). It will be apparent that multiple coatings may be employed (e.g., to allow release of a portion of the dose in the stomach and a portion further along the gastrointestinal tract). For example, a portion of active ingredient(s) may be coated over an enteric coating, and thereby 35 released in the stomach, while the remainder of active ingredient(s) in the matrix core is protected by the enteric coating and released further down the GI tract. pH dependent coatings include, for
28 example, shellac, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, methacrylic acid ester copolymers and zein. in certain embodiments, the coating is a hydrophobic material, preferably used in an amount effective to slow the hydration of the gelling agent following administration. Suitable hydrophobic
5 materials include alkyl celluloses (e.g., ethylcellulose or carboxymethylcellulose), cellulose ethers, cellulose esters, acrylic polymers (e.g., poly(acrylic acid), poly(methacrylic acid), acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxy ethyl methacrylates, cyanoethyl methacrylate, methacrylic acid alkamide copolymer, poly(methyl methacrylate), polyacrylamide, ammonio methacrylate copolymers, aminoalkyl methacrylate copolymer, poly(methacrylic acid
10 anhydride) and glycidyl methacrylate copolymers) and mixtures of the foregoing. Representative aqueous dispersions of ethylcellulose include, for example, AQUACO AT® (FMC Corp., Philadelphia,
PA) and SURELEASE® (Colorcon, Inc., West Point, PA), both of which can be applied to the substrate according to the manufacturer's instructions. Representative acrylic polymers include, for example, the various EUDRAGIT® (Rohm America, Piscataway, NJ) polymers, which may be used
15 singly or in combination depending on the desired release profile, according to the manufacturer's instructions.
The physical properties of coatings that comprise an aqueous dispersion of a hydrophobic material may be improved by the addition or one or more plasticizers. Suitable plasticizers for alky] celluloses include, for example, dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate and 20 triacetin. Suitable plasticizers for acrylic polymers include, for example, citric acid esters such as triethyl citrate and tributyl citrate, dibutyl phthalate, polyethylene glycols, propylene glycol, diethyl phthalate, castor oil and triacetin.
Controlled-release coatings are generally applied using conventional techniques, such as by spraying in the foπn of an aqueous dispersion. If desired, the coating may comprise pores or channels 25 or to facilitate release of active ingredient. Pores and channels may be generated by well known methods, including the addition of organic or inorganic material that is dissolved, extracted or leached from the coating in the environment of use. Certain such pore-forming materials include hydrophilic polymers, such as hydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose), cellulose ethers, synthetic water-soluble polymers (e.g., polyvinylpyrrolidone, cross-linked polyvinylpyrrolidone and 30 polyethylene oxide), water-soluble poiydextrose, saccharides and polysaccharides and alkali metal salts. Alternatively, or in addition, a controlled release coating may include one or more orifices, which may be formed my methods such as those described in US Patent Nos. 3.845,770; 4,034,758; 4,077,407; 4,088,864; 4,783,337 and 5,073,607. Controlled-release may also be achieved through the use of transdermal patches, using conventional technology (see, e.g., US Patent No. 4,668,232). 35 Further examples of controlled release formulations, and components thereof, may be found, for example, in US Patent Nos. 4,572,833; 4,587, 1 17; 4,606,909; 4,610,870; 4,684,516; 4,777,049: 4,994,276; 4,996,058; 5, 128,143; 5,202,128; 5,376,384; 5,384,133; 5,445,829; 5,510, 1 19; 5,618,560;
29 5,643,604; 5,891 ,474; 5,958,456; 6,039,980; 6,143,353; 6,326,969; 6, 156,342; 6,197,347; 6,387,394; 6,399,096; 6,437,000; 6,447,796; 6,475,493; 6,491,950; 6,524,615; 6,838,094; 6,905,709; 6,923,984; 6,923,988; and 6,91 1,217; each of which is hereby incorporated by reference for its teaching of the preparation of controlled release dosage forms,
5 In addition to or together with the above modes of administration, a compound provided herein may be conveniently added to food or drinking water (e.g., for administration to non-human animals including companion animals (such as dogs and cats) and livestock). Animal feed and drinking water compositions may be formulated so that the animal takes in an appropriate quantity of the composition along with its diet. It may also be convenient to present the composition as a premix for addition to 10 feed or drinking water.
Compound(s) provided herein are generally administered in a therapeutically effective amount.
Preferred systemic doses are no higher than 50 mg per kilogram of body weight per day (e.g., ranging from about 0.001 mg to about 50 mg per kilogram of body weight per day), with oral doses generally being about 5-20 fold higher than intravenous doses {e.g., ranging from 0.01 to 40 mg per kilogram of
15 body weight per day).
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage unit will vary depending, for example, upon the patient being treated and the particular mode of administration. Dosage units will generally contain from about 10 μg to about 500 mg of an active ingredient. In certain embodiments, the dosage unit contains an amount of the compound that is 20 sufficient to effect a decrease in the patient's caloric intake (i.e., an appetite-suppressing amount) following single dose administration or repeated administration according to a predetermined regimen. Optimal dosages may be established using routine testing, and procedures that are well known in the art.
Pharmaceutical compositions may be used for treating a condition responsive to CB 1 25 modulation. Such conditions include, for example: appetite disorders (e.g., binge eating disorder, bulimia, anorexia); obesity and complications associated therewith, including left ventricular hypertrophy); weight loss or control (e.g., reducing calorie or food intake and/or appetite suppression); and addictive disorders such as: 30 alcohol dependency (e.g., alcohol abuse, addiction and/or dependency including treatment for abstinence, craving reduction and relapse prevention of alcohol intake); nicotine dependency (e.g., smoking addiction, cessation and/or dependency including treatment for craving reduction and relapse prevention of tobacco smoking); and drug dependency (e.g., chronic treatment with or abuse of drugs such as opioids, barbiturates, 35 cannabis, cocaine, amphetamines, phencyclide, hallucinogens, and/or benzodiazepines).
Other conditions responsive to CBl modulation include CNS disorders (e.g., anxiety, depression, panic disorder, bipolar disorder, psychosis, schizophrenia, behavioral addiction, dementia
30 (including memory loss, Alzheimer's disease, dementia of aging, vascular dementia, miid cognitive impairment, age-related cognitive decline, and miid neurocognitive disorder), attention deficit disorder (ADD/ADHD), stress, amnesia, cognitive disorders, memory disorders, neurodegeneration, cerebellar and spinocerebellar disorder, cranial trauma, cerebral vascular accidents, obsessive-compulsive 5 disorder, senile dementia, impulsiviry), thymic disorders, septic shock, Tourette's syndrome, Huntington's chorea, Raynaud's syndrome, peripheral neuropathy, diabetes (type 11 or non insulin dependent), glaucoma, migraine, seizure disorders, epilepsy, locomotor disorders (movement disorders induced by medicaments, dyskinesias or Parkinson's disease), respiratory disorders (such as asthma), gastrointestinal disorders {e.g., dysfunction of gastrointestinal motility or intestinal propulsion, 10 constipation, chronic intestinal pseudo-obstruction, irritable bowel syndrome, Crohn's disease), liver cirrhosis, vomiting, diarrhea, ulcer, multiple sclerosis, cardiovascular disorder, portal hypertension, fibrosis of internal organs, orthostatic hypotension (e.g., low blood pressure due to heart disease, vasovagal reaction or micturition syncope), drug-induced hypotension dystonia, endotoxemic shocks, hemorrhagic shocks, hypotension, insomnia, a disorder of the endocrine system, urinary or bladder 1 5 disorders, cancer, infectious disease, inflammation, infection, cancer, neuroinflammation (such as atherosclerosis), Guillain-Barre syndrome, viral encephalitis, cranial trauma, sepsis or a reproductive disorder. In certain embodiments, the condition responsive to CB 3 modulation is an appetite disorder, obesity, an addictive disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, portal 20 hypertension, fibrosis of internal organs, orthostatic hypotension and/or drug-induced hypotension.
Certain pharmaceutical compositions provided herein comprise a first agent that is a compound as provided herein in combination with a second agent that differs in structure from the first agent and is suitable for treating the condition of interest. In certain embodiments, the second agent is not a CBl antagonist as provided herein. In certain embodiments, the second agent is suitable for 25 treating an appetite disorder, obesity, an addictive disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder and/or a movement disorder. Representative second agents for use within such pharmaceutical compositions include anti-obesity agents such as MCH receptor antagonists, apo-B/MTP inhibitors, l l β-hydroxy steroid dehydrogenase- 1 inhibitors, peptide YY3-36 or an analog thereof, MCR-4 30 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, βj adrenergic receptor agonists, dopamine agonists, meianocyte-stimulating hormone receptor analogues, 5-HT2c receptor agonists, leptin or an analog thereof, leptin receptor agonists, galanin antagonists, lipase inhibitors, bombesin agonists, neuropeptide- Y receptor antagonists, thyromimetic agents, dehydroepiandrosterone or analog thereof, glucocorticoid receptor antagonists, orexiii receptor 35 antagonists, glucagon-like ρeρtide-1 receptor agonists, ciliary neurotrophic factors, human agouti- related protein antagonists, ghrelin receptor antagonists, histamine 3 receptor antagonists, and
31 neuromedin U receptor agonists. Such agents include, for example, phentermine. orlistat and sibutramine (e.g., sibutramine HCl monohydrate, sold as Meridia® (Abbott Laboratories)).
Representative second agents suitable for treating an addictive disorder include, for example, Methadone, LAAM (levo-alpha-acetyl-methadol), naltrexone (e.g., ReVia™), ondansetron (e.g., 5 Zofran®), sertraline (e.g., Zoloft®), fluoxetine (e.g., Prozac®), diazepam (e.g., Valium®) and chlordiazepoxide (e.g., Librium), varenicline and buproprion (e.g., Zyban® or Wellbutrin®). Other representative second agents for use within the pharmaceutical compositions provided herein include nicotine receptor partial agonists, opioid antagonists and/or dopaminergic agents.
Pharmaceutical compositions may be packaged for treating conditions responsive to CB l
10 modulation (e.g., treatment of appetite disorder, obesity and/or addictive disorder, or other disorder indicated above). Packaged pharmaceutical preparations generally comprise a container holding a therapeutically effective amount of a pharmaceutical composition as described above and instructions
(e.g., labeling) indicating that the composition is to be used for treating a condition responsive to CB l modulation in a patient. In certain embodiments, a packaged pharmaceutical preparation comprises
15 one or more compounds provided herein and one or more additional agents in the same package, either in separate containers within the package or in the same container (i.e., as a mixture). Preferred mixtures are formulated for oral administration (e.g., as pills, capsules, tablets or the like). In certain embodiments, the package comprises a label bearing indicia indicating that the components are to be taken together for the treatment of an appetite disorder, obesity, an addictive disorder, asthma, liver
20 cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder and/or a movement disorder.
METHODS OF USE
Within certain aspects, the present invention provides methods for treating a condition responsive to CB I moduiation in a patient and/or for appetite suppression. The patient may be
25 afflicted with such a condition, or may be free of symptoms but considered at risk for developing such a condition. A condition is "responsive to CB l modulation" if the condition or symptom(s) thereof are alleviated, attenuated, delayed or otherwise improved by modulation of CB l activity. Such conditions include, for example, appetite disorders, obesity, addictive disorders, asthma, liver cirrhosis, sepsis, irritable bowel disease. Crohn's disease, depression, schizophrenia, memory disorders, cognitive
30 disorders, movement disorders, portal hypertension, fibrosis of internal organs, orthostatic hypotension and drug-induced hypotension, as well as other disorders indicated above. Tn general, such methods comprise administering to the patient a therapeutically effective amount of at least one compound as provided herein.
It will be apparent that compounds provided herein may be administered alone or in
35 combination with one or more additional agents that are suitable for treating the disorder of interest. Within combination therapy, the compound(s) and additional agent(s) may be present in the same
32 pharmaceutical composition, or may be administered separately in either order. Representative additional agents for use in such methods include the second agents described above.
Suitable dosages for compounds provided herein (either alone or within such combination therapy) are generally as described above. Dosages and methods of administration of any additional
5 agent(s) can be found, for example, in the manufacturer's instructions or in the Physician's Desk
Reference. In certain embodiments, combination administration results in a reduction of the dosage of the additional agent required to produce a therapeutic effect {i.e., a decrease in the minimum therapeutically effective amount). Thus, preferably, the dosage of additional agent in a combination or combination treatment method of the invention is less than the maximum dose advised by the
10 manufacturer for administration of the agent without combination with a compound of Formula I.
More preferably this dose is less than %, even more preferably less than Vi, and highly preferably less than VA of the maximum dose, while most preferably the dose is less than 10% of the maximum dose advised by the manufacturer for administration of the agent(s) when administered without combination administration as described herein. It will be apparent that the dose of compound as provided herein
15 needed to achieve the desired effect may similarly be affected by the dose and potency of the additional agent.
Administration to the patient can be by way of any means discussed above, including oral, topical, nasal or transdermal administration, or intravenous, intramuscular, subcutaneous, intratheca], epidural, intracerebroventriicular or like injection. Orai administration is preferred in certain 20 embodiments (e.g., formulated as pills, capsules, tablets or the like).
Treatment regimens may vary depending on the compound used and the particular condition to be treated. In general, a dosage regimen of 4 times daily or less is preferred, with 1 or 2 times daily particularly preferred. It will be understood, however, that the specific dose ievel and treatment regimen for any particular patient will depend upon a variety of factors including the activity of the 25 specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. Dosages are generally as described above; in general, the use of the minimum dose sufficient to provide effective therapy is preferred. Patients may generally be monitored for therapeutic effectiveness using medical or veterinary criteria suitable for the condition 30 being treated or prevented. For example, treatment of obesity is considered to be effective if it results in a statistically significant decrease in weight or BMI.
Within separate aspects, the present invention provides a variety of non-pharmaceutical in vitro and in vivo uses for the compounds provided herein. For example, such compounds may be labeled and used as probes for the detection and localization of CBl (in samples such as cell 35 preparations or tissue sections, preparations or fractions thereof). In addition, compounds provided herein that comprise a suitable reactive group (such as an aryl carbonyl, nitro or azide group) may be used in photoaffinity labeling studies of receptor binding sites. In addition, compounds provided
33 herein may be used as positive controls in assays for receptor activity, as standards for determining the ability of a candidate agent to bind to CB l , or as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT). Such methods can be used to characterize CB l receptors in living subjects. For example, a compound may be labeled using any
5 of a variety of well known techniques (e.g., radiolabeled with a radionuclide such as tritium, as described herein), and incubated with a sample for a suitable incubation time (e.g., determined by first assaying a time course of binding). Following incubation, unbound compound is removed (e.g., by washing), and bound compound detected using any method suitable for the label employed (e.g., autoradiography or scintillation counting for radiolabeled compounds; spectroscopic methods may be
10 used to detect luminescent groups and fluorescent groups). As a control, a matched sample containing labeled compound and a greater (e.g., 10-fold greater) amount of unlabeled compound may be processed in the same manner. A greater amount of detectable ϊabel remaining in the test sample than in the control indicates the presence of CB l in the sample. Detection assays, including receptor autoradiography (receptor mapping) of CB l in cultured cells or tissue samples may be performed as
15 described by Kuhar in sections 8.1.1 to 8.1 9 of Current Protocols in Pharmacology (1998) John Wiley
& Sons, New York.
Compounds provided herein may further be used within assays for the identification of other non-competitive antagonists of CB l . In genera!, such assays are standard competition binding assays, in which a labeled compound as provided herein is displaced by a test compound. Briefly, such assays 20 are performed by: (a) contacting CB l with a labeled (e.g., radiolabeled) compound and a test compound, under conditions that permit binding to CB l (b) removing unbound labeled compound and unbound test compound; (c) detecting a signal that corresponds to the amount of bound, labeled compound; and (d) comparing the signal to a reference signal that corresponds to the amount of bound labeled compound in a similar assay performed in the absence of test compound. In practice, the 25 reference signal and the signal described in step (c) are generally obtained simultaneously (e.g., the assays are performed in different wells of the same plate); in addition, multiple concentrations of test compound are generally assayed. Non-competitive antagonist activity can be confirmed for test compounds that decrease the amount of bound, labeled compound using procedures described herein.
The following Examples are offered by way of illustration and not by way of limitation. 30 Unless otherwise specified all reagents and solvent are of standard commercial grade and are used without further purification. Using routine modifications, tine starting materials may be varied and additional steps employed to produce other compounds provided herein.
EXAMPLES
Mass spectroscopy data in the foilowing Examples is Electrospray MS, obtained in positive
35 ion mode using a Micromass Time-of-Flight LCT (Micromass, Beverly MA), equipped with a Waters
600 pump (Waters Corp.; Milford, MA), Waters 996 photodiode array detector, and a Gilson 215
34 autosampler (Gilson, Inc.; Middieton, WI). MassLynx (Advanced Chemistry Development, ϊnc; Toronto, Canada) version 4.0 software with OpenLynx Global Server™, OpenLynx™ and AutoLynx™ processing is used for data collection and analysis. MS conditions are as follows: capillary voltage = 3.5 kV; cone voltage = 30 V, desolvation and source temperature = 350 DC and 120 5 0C, respectively; mass range = 181 -750 with a scan time of 0.22 seconds and an interscan delay of 0.05 min.
Sample volume of 1 microliter is injected onto a 50x4.6mm Chromolith SpeedROD RP- 18e column (Merck KGaA, Darmstadt, Germany), and eluted using a 2 -phase linear gradient at a flow rate of 6 ml/min. Sample is detected using total absorbance count over the 220-340nm UV range. The 10 elution conditions are: Mobile Phase A - 95% water, 5% MeOH with 0.05% TFA; Mobile Phase B - 5% water, 95% MeOH with 0.025% TFA. The foilowing gradient is used: 0-0.5 min 10-100%B, hold at I00%B to 1.2 min, return to 10%B at 1 .21 min. Inject to inject cycle is 2.15 min.
EXAMPLE 1. PREPARATION OF 5-(3-CHLOROPYRIDIN-4-YL)-2-( 1 -PROPIONYLPIPERIDIN-4-YL)-4-(4- 15 (TRIFLUOROMETHYL)PHENYL)-2H- 1 ,2,4-TRIAZOL-3 (4H)-ONE
Step I . Synthesis of 3-chloro-N-(4-(u*ifluoromethyl)phenyl)isonicotinamide
F
Cl O ^
N H
Figure imgf000036_0001
To a suspension of 3-chloroisonicotinic acid (3.15 g, 20 rmnol) in anhydrous DCM (250 mL) under nitrogen at 0 0C is added oxalyl chloride (2.54 g, 20 mmol) followed by three drops of
20 anhydrous DMF. The mixture is stirred at rt for 1 h, and then added dropwise to a solution of 4- (trifluoromethyJ)benzenamine (3.22 g, 20 mmol) and TEA (4.08 g, 40 mmol) in anhydrous DCM (250 mL) under nitrogen at 0 0C over a period of 10 min. The mixture is stirred at rt overnight. After water (150 mL) is added, the organic phase is separated and the aqueous phase is extracted with DCM (2 x 200 mL). The combined organic phase is dried over anhydrous magnesium sulfate, concentrated and
25 purified by silica gel column chromatography to give the title compound as a white solid. LCMS (M+l ) 301.97. 1H NMR: (CDCl3) 7.67 (d, J = 4.4 Hz, I H); 7.73 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.4 Hz, 2H), 8.22 (S5 IH); 8.65 (d, J- 4.4 Hz, IH); 8.72 (s, I H).
Step 2. Synthesis of JV'-amino-3-chloiO-N-(4-(trifluoromethy])phenyl)isonicotinamidine
F H2N,
Figure imgf000036_0002
35 A solution of 3-chloro-N-(4-(trifluoromethyl)pheny])isonicotinamide (12.1 g, 40 mmol and phosphorus chloride (9.21 g, 44 mmol) in anhydrous benzene (250 mL) is refluxed for 4 h. After removing phosphorus oxychloride under reduced pressure, the residue is dissolved in anhydrous THF (250 mL) and added dropwise to a solution of anhydrous hydrazine (12.9 mL) in anhydrous THF (250 mL) under nitrogen at 00C. The mixture is stirred for 1 h at rt, poured into water (300 mL) and extracted with EtOAc. The organic phase is washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound as a white solid. LCMS (M+ 1 ) 314.97.
Step 3. Synthesis of 5-(3-chIoiOpyridin-4-yl)-4-(4-(trifiuoromethyl)phenyI)-2H-l ,2s4-triazol-3(4H)- one
Figure imgf000037_0001
10 N-^CI
A solution of jV'-amino-3-chloro-N-(4-(trifluoiOmethyl)phenyl)isonicotinamidine ( 13.1 g, 41.6 mmol) in anhydrous THF (600 mL) is added slowly to a solution of l , r-carbonyidiimidazole (8.1 g, 50 mmol) in anhydrous THF (600 mL) under nitrogen at 0°C over 2 h. The mixture is stirred at rt overnight. After removal of THF, the residue is purified by silica gel column chromatography to give
15 the title compound as a white yellow solid. LCMS (M+ 1) 340.94. 1H NMR: (CDCI3) 7.31 (d, J = S.4 Hz, 2H); 7.42 (d, J= 4.4 Hz, 1 H), 7.65 (d, J= 8.4 Hz, 2H), 8.63 (m, 2H); 10.67 (s, IH).
Step 4. Synthesis of /er/-butyl 4-(3-(3-chloiOpyridin-4-yl)-5-oxo-4-(4-(trifluorometliyl)phenyl)-4,5- dihydro-l,2,4-triazol-] -yϊ)piperidine-l-carboxylate
F
Figure imgf000037_0002
20 To a solution of tøV-butyl 4-hydroxypiperidine-l-carboxyiate (2 g, 10 mmol) in anhydrous
DCM (50 mL) under nitrogen at 0°C is added TEA (1.2 g, 12 mmol) followed by addition of MsCl (1.72 g, 1 5 mmol). The mixture is stirred at rt for 1 h, and concentrated to remove excess TEA and MsCl. The residue is dissolved in anhydrous acetonitrile (50 mL). 5-(3-chloropyridin-4-yI)-4-(4- (trifluoromethy!)pheny[)-2H-1.2,4-triazol-3(4H)-one (3.4 g, 10 mmol) and anhydrous potassium
25 carbonate (2.76 g, 20 mmoi) are added. The resulting mixture is refluxed for 16 h. Solids are filtered and the fϋtrate is concentrated and purified by silica gel column chromatography to give the title compound. LCMS (M+ 1) 546.02.
36 Step 5. Synthesis of 5-(3-chIoropyridin-4-y!)-2-(piperidin-4-yl)-4-(4-(trifluorometiiyJ)phenyI)-2H- l,2,4-triazoI-3(4H)-one
F
Figure imgf000038_0001
A solution of tert-butyl 4-(3-(3-chloropyridin-4-yl)-5-oxo-4-(4-(trifluoromethyl)pheny])-4,5- 5 dihydro-l,2,4-triazol-l-yl)piperidine-l-carboxylate (5.24 g, 10 mmol) in anhydrous DCM (20 mL) is treated with TFA (10 mL) at rt for 2 h. After concentration, the residue is neutraiized with saturated sodium bicarbonate and the product is extracted with DCM. The extracts are dried over anhydrous magnesium sulfate, concentrated and purified by silica gel column chromatography to give the title compound.
10 Step 6. Synthesis of 5-(3-chloropyridin-4-yl)-2-(l-propiony]pipeπdin-4-yI)-4-(4- (trifluoromethyl)phenyl)-2H-] )2,4-triazoI-3(4H)-one
F
Figure imgf000038_0002
-a
To a solution of 5-(3-chioropyridiπ-4-yl)-2-(piρeridin-4-yl)-4-(4-(trifluoromethyl)phenyl)-2H- l,2,4-triazol-3(4H)-one (42 mg, 0.1 mmol) and TEA (20 mg, 0.2 mmol) in anhydrous DCM (2 mL) at
15 0°C is added propionyl chloride (14 mg. 0.35 mmol). After stirring for 2 h at rt, the mixture is concentrated and the residue is purified by silica gel column chromatography to give the title compound. LCMS (M+ 1) 533.1.
EXAMPLE 2. PREPARA ΠON OF 5-(3-CHLOROPYRIDΓN-4-YL)-2-ISOBUTYL-4-(4-(TRIFLUOROMETHYL) 20 PHENYL)-2H- 1 ,2,4-TRIAZOL-3 (4M)-ONE
F
Figure imgf000038_0003
To a solution of 5-(3-chioropyridin-4-yl)-4-(4-(trifiuoromethyl)pheny])-2H-l ,2,4-triazol-
3(4H)-one (34 mg, 0.1 mmol) and l-bromo-2-methylpropane (17 mg, 0.12 mmol) in anhydrous
37 acetone is added anhydrous potassium carbonate (27 mg, 0.2 mmol). The mixture is heated at 65°C for 12 h. After cooling to rt, solids are removed by filtration and the filtrate is concentrated and purified by silica gel column chromatography to give the title compound. LCMS (M+ 1 ) 396.1.
EXAMPLE 3. PREPARATION OF 5-(3-CHLOROPYR[DIN-4-YL)-2-(2-OXO-2-(PIPERJDIN-1 -YL)ETHYL)-4- (4-(TRIFLUOROMETHYL)PI IENYL)-2H-1,2,4-TRIΛZOL-3(4H)-ONE
Step 1. Synthesis of ethyl 2-(3-(3-chloropyridin-4-yI)-5-oxo-4-(4-(trifluoromelhyi)phenyl)-4,5- dihydro-l ,2,4-triazol-l-yl)acetate
Figure imgf000039_0001
10 This compound is prepared essentially as described in Example 2, with readily apparent modification. LCM S (M+ 1) 426.94 .
Step 2. Synthesis of 2-(3-(3-chloropyridin-4-yl)-5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5-dihydro- l ,2,4-triazol-l -yl)acetic acid
OH
Figure imgf000039_0002
1 5 A solution of ethyl 2-(3-(3-chloropyridin-4-y!)-5-oxo-4-(4-(trifluoromethyl)phenyi)-4,5- dihydro-l ,2,4-triazol-l -yi)acetale (4.26 g, 10 mmol) in a mixed solvent of MeOH/THF/H2O (60/20/20 mL) is treated with LiOH (600 mg, 25 mmol) at rt for 16 h. The mixture is neutralized to pH ~ 3 with 3N HCl and concentrated. The residue is participated between EtOAc and water, and the organic phase is separated. The aqueous phase is extracted with EtOAc. The combined organic phase is dried
20 over anhydrous magnesium sulfate, concentrated and purified by silica gel column chromatography to give the title compound.
38 Step 3. Synthesis of 5-(3-chloropyridin-4-yl)-2-(2-oxo-2-(piperidin-l-yl)ethyl>4-(4- (trifIuoromethyI)phenyl)-2H-I ,2,4-triazol-3(4H)-one
O U O U I v
Figure imgf000040_0001
fΛJO
Figure imgf000040_0002
To a solution of 2-(3-(3-chloropyridiπ-4-yl)-5-oxo-4-(4-(tπi1uoromethyI)phenyl)-4,5-dihydro- l ,2,4-triazol-l -yt)acetic acid (40 mg, 0.1 mmol), piperidine (8.5 mg, 0.1 mmol) and triethyl amine ( 15 mg, 0.15 mmol) in dichloroethane (2 mL) is added a solution of DMC (17 mg, 0.1 mmol). The mixture is stirred at rt for 16 h, concentrated and purified by silica gel column chromatography to give the title compound. LCMS (M+ 1) 466.12.
10 EXAMPLE 4. PREPARATION OF 2 -(2-AMiNOETHYL)-S-(S-CHLOROPYRiDrN^- YL)-4-(4-
(TRIFLUOROMETl IYL)PHENYL)-2H-l32,4-TRIAZOL-3(4 H)-ONE
Step 1. Synthesis of 2-(2-(3<3-chIoropyridin-4-yI)-5-oxo-4-(4-(tπfluoromethyl)phenyl)-4,5-dihydro- 1 ,2,4-triazoI- 1 -y i)ethyl)isoindoline- 1 ,3 -dione
R F
O
Figure imgf000040_0003
15 This compound is prepared essentially as described in Example 2, with readily apparent modification. LCMS (M+ϊ ) 514.9.
Step 2. Synthesis of 2-(2-aminoethyl)-5-(3-chloropyridin-4-yl)-4-(4-(trifluoromethyi)ρhenyl)-2H- l ,2,4-triazol-3(4H)-one
Figure imgf000040_0004
20 A solution of 2-(2-(3-(3-chloropyridm-4-yl)-5-oxo-4-(4-(lrifluoromethyl)phenyl)-4,5-dihydro- l,2,4-triazol- I-yl)ethyI)isoindo!ine- I,3-dioπe (3.18 g, 6.2 mmol) and anhydrous hydrazine (1.86 g, 372 mmol) in anhydrous EtOH (60 mL) is refluxed for 4 h. Solids are removed after cooling to rt, and the filtrate is concentrated and purified by silica gel column chromatography to give the title compound.
39 LCMS (M+l ) 383.98. 1H NMR: (CDCl3) 2.44 (br s, 2H), 3.19 (t, J= 6 Hz, 2H), 4.0 l (t, J= 6 Hz, 2H), 7.3 (d, J= 8.8 Hz, 2H); 7,41 (d, J= 5.2 Hz, IH), 7.61 (d, J= 8.8 Hz, 2H), 8.6 (m, 2H).
EXAMPLE 5. PREPARATION OF 2-(3-AMΓNOPROPYL)-5-(3-CHLOROPYRIDIN-4-YL)-4-(4- (TRIFLUOROMETH YL)PHENYL)-2H- 1 ,2.4-TRIAZOL-3(4H)-ONE
Step 1. Synthesis of tert-butyl 3-{3-{3-chloropyridin-4-yl)-5-oxo-4-(4-(trifluoromethyl)phenyl)-4,5- dihydro-l,2,4-triazol-I-yi)propylcarbamate
O O HN-Y
Figure imgf000041_0001
"V
Figure imgf000041_0003
N " °
Figure imgf000041_0002
This compound is prepared essentially as described in Example 2, with readily apparent 10 modification.
Step 2. Synthesis of 2-(3-aminopiOpyl)-5-(3-chloropyridin-4-yi)-4-(4-(trifluoromethyl)phenyl)-2H- l,2,4-triazol-3(4H)-one
Figure imgf000041_0004
a ^° NH,
N-
N- ofN'
This compound is prepared essentially as described in Example 1 , with readily apparent 15 modification. LCMS (M+l ) 397.99. 1H NMR: (CDCI3) 1.82 (br s, 2H)3 2.01 (m, 2H), 2.85 (t, J= 6.8 Hz, 2H), 4.07(1, J = 6.8 Hz, 2H), 7.28 (d, J = 8 Hz, 2H); 7.39 (d, J = 5.8 Hz, I H), 7.61 (d. J = 8 Hz, 2H), 8.61 (m, 2H).
EXAMPLE 6. PREPARATION OF 2-(3-(TERT-BUTYLAMINO)-2-HYDROXYPROPYL)-5-(3 -
CHLOROPYRIDIN-4-YL)-4-(4-(TRIFLUOROMETHYL)PHENYL)-2H-] ,2,4-TRlAZOL-3(4H)-ONE
20 Step 1. Synthesis of 5-(3-chloropyridin-4-yl)-2-(oxiran-2-ylmethyl)-4-(4-(trifluoromethy!)phenyI)-2H- l ,2,4-triazol-3(4H)-one
O
Figure imgf000041_0005
This compound is prepared essentially as described in Example 2, with readily apparent modification. LCMS (M+I) 397.02.
Step 2. Synthesis of 2-(3-(tert-butylamino)-2-hydroxyρropyl)-5-(3-chloroρyridin-4-yi)-4-{4- (trifluorσmethyi)phenyl)-2H-l,2,4-tπazoI-3(4H)-one
Figure imgf000042_0001
Xl
A solution of 5-(3-chloropyridin-4-yl)-2-(oxiran-2-ylmethyl)-4-(4-{trif!uoromethyl)phenyI)- 2H-l,2,4-triazol-3(4H)-one (40 mg, 0.1 mmol) and neopentylaraine (9 mg, 0.1 mmoi) in anhydrous EtOH (60 niL) is healed at 65 °C for 24 h. The mixture is concentrated and purified by siiica gel column chromatography to give the title compound. LCMS (M+]) 453.1. 10
EXAMPLE 7. PREPARATION OF 5-(3-CHLOROPYRIDIN-4-YL)-2-(3,3-DIMETHYL-2-OXOBUTYL)-4-(4- ISOPROPOXYPHENYL)-2H-1 , 2,4-TRIAZOL-3(4H)-ONE AND 5-(3-CHLOROPYRID!N-4-YL)-2-(2-L IYDROXY- 3.3-DIMETHYLBΣRYL)-4-(4-ISOPROPOXYPHENYL)-2H- L ,2,4-TRIAZOL-3(4 H)-ONE
Step I . Synthesis of 5-(3-chloropyridin-4-yl)-2-(3,3-dimethyl-2-oxobutyl)-4-(4-isopiOpoxyphenyl)- 15 2H-l,2;4-triazoI-3(4H)-one
Figure imgf000042_0002
^ N Λ-Λ.
Figure imgf000042_0004
°-
Figure imgf000042_0003
"Cl
This compound is prepared essentially as described in Example 2, with readily apparent modification. LCMS (M+ 1 ) 428.2.
Step 2. Synthesis of 5-(3-chloropyridin-4-yl)-2-(2-hydroxy-3,3-dimethyibutyl)-4-(4-
20 isoproρoxyρhenyl)-2H-ϊ,2,4-triazol-3(4H)-oπe
O HO /
N-
N
Figure imgf000042_0005
A solution of 55-(3-chloropyridin-4-yl)-2-(3,3-dimethyl-2-oxobutyl)-4-(4-isopiOpoxyphenyl)- 2H-l,2,4-triazol-3(4H)-one (43 mg, O.I mmol) is treated with sodium borohydride (8 mg, 0.2 mmol) in MeOH (2 mL) at 0 °C for 1 h. The mixture is concentrated and purified by silica ge! column
41 chromatography to give the title compound. LCMS (M+ 1) 430.2. 1H NMR: (CDCI3) 1.03 (s, 9H), 1.31 (d, J = 5.6 Hz, 6H), 3.19 (d, J= 2.8 Hz5 I H), 3.77 (d, J= 9.2 Hz, IH), 3.93 (m, IH), 4.17 (dd, J = 14.4, 2 Hz, I H), 4.5 (m. IH), 6.81 (ά, J = 8.8 Hz, 2H); 7.03 (d, J = 8.8 Hz, 2H), 7.28 (d, J= 5.2 Hz, IH), 8.53 (d, J= 5.2 Hz, IH), 8.6) (s, IH).
EXAMPLE 8. PREPARATION OF 4,5-BIS(4-CHLOROPHENYL)-2-(3,3-DΪME'Π IYL-2-OXOBUTYL)-2H-
1,2,4-TRΪAZOLo (4H)-ONE
Step 1. Synthesis of 4s5-bis(4-chlorophenyl)-2H-l,2,4-triazol-3(4H)-one
NH U
Cl
Figure imgf000043_0001
"
10 This compound is prepared essentially as described in Example I , Step 3, with readily apparent modification. LCMS (M+ 1) 305.92.
Step 2. Synthesis of 4!5-bis(4-chloroplienyl)-2-(3,3-dimethyi-2-oxobutyl)-2H-L2,4-triazol-3(4H)-oπe
Figure imgf000043_0002
N
Figure imgf000043_0003
Cl "
This compound is prepared essentially as described in Example 7, Step 1 , with readily 15 apparent modification. LCMS (M+l) 404. 1H NMR: (CDCl3) 1.28 (s, 9H), 4.89 (s, 2H), 4.5 (m, I H), 7.79 (d. /= 8.8 Hz, 2H): 7.25 (d, J= 8.8 Hz, 2H), 7.29 (d, J= 8.8 Hz, 2H), 7.4 (d, J= 8.8 Hz, 2H).
42 EXAMPL c 9. PREPARATION or ADDITIONAL DIARYL TRIAZOLONES
Using routine modifications, the starling matenals may be varied and additional steps employed to produce other compounds provided herein. Compounds listed in Table I are prepared using such methods. All compounds in Table 1 have a K1 of 1 micromolar or less as determined using the assay provided in Example 14, herein Mass Spectioscopy data in the column labeled "MS" is obtained as described above, and ts presented as M+l The retention time (Ret Time) is given in minutes.
Table 1
Representative Diaryl Tnazolones
Ret
Compound Name Time MS
2-(1-acetyl-4-pιperιdιnyl)-4- (4-chlorophenyl)~5-(3- chloro-4-pyπdιnyl)-2,4- 1 22 431 1 dιhydro-3l-M ,2 4-tπazol-3- oπe
2-(1-butyrylpιpeπdιn-4-yl)-4-
(4-chloropheπyl)-5-(3- chloropyrιdιπ-4-yl)-2,4- 1 2 459 1 dιhydro-3H-1 ,2,4-tπazol-3- one
2-(1-butyrylpιpeπdιn-4-yi)-5- (3-chloropyπdιn-4-yl)-4-(4-
1 16 443 2 fluoropheπyl)-2,4-dihydro-
O 3H-1 2,4-triazol-3-one
Figure imgf000044_0001
N-^CI
FaC
2-(1 -bitty rylp[peπdιn-4-yl)-5- (3-chloropyrιdιn-4-yl)-4-[4- (trffϊuoromethyl)phenyl]-2,4- 1 29 493 1 dihydro-3H-1 ,2,4-tπazol-3- one
2-[(1-butyryIpipeπdιπ-4-
O yl)methyl]-5-(3- chloropyπdιn-4-yl)-4-(4- 1 18 457 2 fluoraphenyl)-2 4-dihydro- 3H-1,2,4-tπazol-3-one
Figure imgf000044_0002
43 Ret
Compound Name Time MS
2-[(2E)-but-2-en-1-ylJ-4-(4- chlorophenyl)-5-(3- ch toropyrid in-4-yl)-2 , 4- 1.22 360 1 dιhydro-3H-1 ,2,4-trϊazol-3- oπe
2-[(2E)-but-2-en-1-y[]-5-{3- chloropyπdin-4-yl}-4-(4- isopropoxyphenyl)-2,4- 1 23 384.1 dihydro-3H-1 ,2,4-tπazol-3- one
2-[(2E)-but-2-en-1-yl]-5-(3- chloropyridirι-4-y[)-4-[4-
(trifluoromethyl)phenyl]-2,4- 1.24 394.1 dihydro-3H-1 ,2,4-triazol-3- one
2-[1-(chloroacetyl)pιperidin-
Cl 4-yl]-5-(3-chloropyridin-4-
Figure imgf000045_0001
N-/ N- yl)-4-(4-fluoropheπyl)-2,4- 1 21 449.1 -"N N / 'O dihydro-3H-1 ,2,4-triazol-3- one
2-[3-(3-chloropyridin-4-yl)- 4-{4-ιsopropoxypheπyl)-5-
10 oxo-4,5-dιhydro-1 H-1 ,2,4- 1.02 416 1 triazol-1-yl]-N-
Figure imgf000045_0002
ethylacetamtde N ft O , Cl
2-[3-(3-chloropyridiπ-4-yJ)-
Figure imgf000045_0003
^Sl^ 4-(4-isopropoxypheπy[)-5- oxo-4,5-dιhydro-1 H-1 ,2,4- 0.92 430.2 tπazol-1-yl]-N- propylacetamide
Figure imgf000045_0004
2-[3-(3-chloropyridin-4-yl)-
4~(4-!sopropoxyphenyl}-5-
12 oxo-4,5-dιhydro-1 H-1 ,2,4-
1 15 442 2 triazol-1-yl]-N-
(cyclopropylmethyl)acetami de
Figure imgf000045_0005
44 Ret
Compound Name Time MS
2-[3-{3-chloropyπdiπ-4-yl)- 4-(4-ιsopropoxyphenyl)-5-
13 oxo-4,5-dιnydro-1 H-1 ,2,4- 0 92 430 2 tπazol-1-yl]-N- isopropylacetamide
Figure imgf000046_0001
2-[3-{3-chloropyπd)n-4-yl)- 4-(4-[Sopropoxyphenyi)-5-
14 oxo-4, 5-dιhydro-1 H-1, 2,4- 1 15 442 2 triazoi-1-yl]-N- cyclobutylacetamide
2-[3-(3-chloropyπdιn-4-yl)-
4-(4-!sopropoxypheπyl)-5-
15 oxo-4,5-dihydro-1 H-1 ,2,4- 0 92 456 2 tπazoi-1-yl]-N- cyclopentyiacetamide
2-[3-(3-chloropyπdιn-4-yl)-
4-(4-isopropoxyphenyl)-5-
16 oxo-4,5-dιhydro-1H-1,2,4- 0 92 470 2 trιazol-1-yl]-N- cyclohexyiacetamide
2-[3-(3-chloropyπdιn-4-yl}- 4-(4-isopropoxyphenyl)-5-
17 oxo-4,5-dιhydro-1 H-1, 2 A- 1 09 479 2 tnazol-1 -yl]-N-(pyrιdιπ-2- ylmethyi)acetam[de
2-[3-(3-chloropyrιdιn-4-yl)- 4-(4-ιsopropoxyphenyl)-5-
18 oxo-4,5-dιhydro-1 H-1 2,4- 0 91 479 2 tπazol-1-yl]-N-(pyπdιn-3- y?methyl)acetamιde
2-[3-(3-chtoropyrιdιn-4-yi)- 4-(4-ιsopropoxypheπyl)-5-
19 oxo-4 5-dihydro-1 H-1 ,2,4- 0 87 479 2 tπazol-1-yi]-N-(pyπdιn-4- yimethyl)acetamιde
Figure imgf000046_0002
45 Ret
Compound Name Time MS
2-[3-(3-chloropyridιπ-4-yl}- 4-(4-isopropoxypheπyl)-5-
20 oxσ-4,5-dihydro-1H-1 ,2,4- 0 85 493 2 triazol-1 -yl]-N-(2-pyridιπ-4- ylethyl)acetamide
2-[3-{3-chloropyπdin-4-yl)-
4-(4-isopropoxyphenyl)-5-
21 oxo-4,5-dihydro-1 H-1 ,2,4- 117 444 2 trιazol-1-y!]-N,N- diethylacetamide
2-[3-(3-chloropyridin-4-yl}- 4-(4-ϊsopropoxyphenyl)-5-
22 oxo-4, 5-dιhydro-1 H- 1 ,2,4- 1.02 416 1 triazo!-1-yl]-N,N- dimethylacetamide
2-[3-(3-chloropyridin-4-yl)-
4-{4-ιsopropoxyρhersyl)-5-
23 oxo-4,5-dihydro-1 H-1 ,2,4- 0 93 430 2 trιazol-1-yl]-N-ethy[-N- methytacetamide
2-[3-(3-ch(oropyridin-4-y[)-
4-(4-ιsopropoxypheπyl)-5-
24 oxo-4,5-dihydro-1 H-1 ,2,4-
0.93 460.2 triazol-1-yl]-N-(2- rriethoxyethyl)-N- methylacetamide
2-[3,4-bis(4-chlorophenyl)-
25 5-0X0-4, 5-dlhydro-1 H-1 ,2,4-
133 418.1 trιazol-1-yJ]-N,N- diethylacetamide
2-{f1-
O (chloroacetyl)piperidιn-4-
26 yl]methyf}-5-(3- chloropyridiπ-4-yl)-4-(4- 122 463.1 fluoropheπyl)-2,4-dihydro-
3H-1,2,4-tπazol-3-one
Figure imgf000047_0001
46 Ret
Compound Name Time MS
F3C 2-{3-(3-chloropyrιdιn-4-yl)-
5-oxo-4-[4-
Figure imgf000048_0001
(trifluoromethyl)phenyl]-4,5-
27 dihydro-1 H-1 ,2,4-triazoM- 1 33 481 1 yl}-N-{2,2- dimethylpropyl)propanamιd
Figure imgf000048_0002
2-{3-(3-chloropyridin-4-yl)-
5-oxo-4-[4-
(trifluoromethyl)ρhenyl]-4,5-
28 1 4 523 2 dihydro-1 H-1 ,2,4-tπazoi-1- y[}-N,N- dnsobutytpropanamide
FaC 2-{3-(3-chloropyridin-4-y[)-
5-oxo-4-[4-
(tπfluororrιethyl)pheπyl]-4,5-
29 dihydro-1 H-1 ,2,4-tπazol-1- 1.24 466 1
NH yl}-N-
O (cyclopropylmethyl}propana
Figure imgf000048_0003
mide
F3C o 2-{3-(3-chioropyridin-4-yl)-
Figure imgf000048_0004
V Λ 5-0X0-4- [4-
{tπfluoromethyl)phenyϊj-4,5-
JU Λ N- 1 04 466 1 dihydro-1 H-1 ,2,4-triazoM - yi}-N- cyclobutylpropanamide
FSC. 0 b
2-{3-(3-chloropyridιn-4-yl)-
5-oxo-4-[4-
(trιfluoromethyl)phenyl]-4,5-
31 1 17 467.1 dihydro-1 H-1 ,2,4-trιazo!-1- yl}-N-ethyl-N- isopropylacetamide
F3C
2-{3-(3-chloropyπdin-4-yl)-
5-oxo-4-[4-
(trif!uoromethyl)pheπyl]-4,5-
32 1 16 497 1 dihydro-1 H-1 ,2,4-tπazol-1 - yJ}-N-isopropyl-N-(2- methoxyethyljacetamide
F,C
2-{3-(3-ch!oropyπdιπ-4-yl)-
5-oxo-4-[4-
(trif luoromethyl)phenyl]-4, 5-
1 14 499 1 dιhydro-1 H-1,2,4-triazol-1- yl}-N-(2,2-dιmethoxyethyl)-
N-methylacetamide
Figure imgf000048_0005
47 Ret
Compound Name Time MS
F3C,
2-{3-(3-chlorapyridin-4-yl)-
5-oxo-4-[4-
Figure imgf000049_0001
(trifluoromethyl)phenyl]-4,5-
34 1 15 483.1 dihydro-1 H-1 ,2,4-triazol-1- yi}-N-ethyl-N-(2-
0
N^ methoxyethyl)acetamide
Cl o-
F3C
2-{3-(3-chloropyπdin-4-yl)-
5-oxo-4-[4-
(trifluoromethy[)pheny!]-4,5-
0.94 481.1 dihydro-1 H-1 ,2,4-triazot-1- yl}-N-pipeπdιπ-1- ylacetamide
Figure imgf000049_0002
2-{3-[3-{3-chloropyridin-4- r N- y])-4-(4-isopropoxyphenyl)-
36 ^r N' — \ o 5-oxo-4,5-dιhydro-1 H-1 ,2,4- 1.32 517.2 triazo[-1-yl]propyl}-1 H- ιsomdole-1 ,3(2H}-dione
Cl
Figure imgf000049_0003
^Λr 2-allyl-4-(4-ch!orophenyl)-5- (3-chloropyridιn-4-yl)-2,4-
37 -C 1 19 346 0 dihydro-3H-1 ,2,4-triazol-3- one
Figure imgf000049_0004
,0
2-allyl-5-(3-chlorapyridιn-4-
Figure imgf000049_0005
yl)-4-(4-isopropoxyphenyf)-
38 N- 2,4-dihydro-3H-1 ,2,4- 1.2 370 1 '"N tπazoi-3-one
Figure imgf000049_0006
FX
O 2-allyl-5-(3-chioropyrtdrn-4-
Figure imgf000049_0007
V >*v yl)-4-[4-
39 N A- (trifluoromethyl}phenyl]-2,4- 1 2 380 1 dιhydra-3H-1 ,2,4-triazol-3- oπe
Figure imgf000049_0008
Cl
2-but-2-yπ-1-yl-4-(4-
Figure imgf000049_0009
^ chlorophenyl)-5-(3-
40 NA'
N- chloropyridin-4-yl)-2,4- 1.19 358.0
N dihydro-3H-1 ,2,4-triazol-3- oπe
Figure imgf000049_0010
48 Re|
Name Time MS
2-but-2-yπ-1-yl-5-(3- chloropyπdιn-4-yl)-4-(4-
41 [sopropσxyphenyl)-2,4- 12 3821 dιhydro-3H-1 ,2,4-trιazol-3- one
2-but-2-yn-1-yl-5-(3- chloropyndm-4-yl}-4-[4-
42 {tπfluorσmethyl)pheπyl]-2,4- 121 3921 dιhydro-3H-1 ,2,4-tπazol-3- oπe
2-but-3-en-1-yi-4-(4- chlorophenyl)-5-(3-
43 chloropyπdιn-4-yl)-2,4- 122 3601 dιhydro-3H-1,2,4-trιazol-3- one
2-but-3-en-1-yl-5-{3- chloropyπdιn-4-yl}-4-{4-
44 [Sopropoxyphenyl)-2,4- 123 3841 dιhydro-3H-'i ,2,4-trrazoi-3- oπe
2-but-3-en-1-yl-5-(3- chloropyπdin-4-yl)-4-[4- (tπfluoromethyl)phenyl]-2,4- 123 3941 dιhydro-3H-1 ,2,4-tπazot-3- one
2-butyl-4-(4-chlorophenyl)- 5-(3-chloropyrιdιπ-4-yl)-2,4- dιhydro-3H-1,2,4-tπazol-3- 125 3621 oπe
2-butyl-5-(3-chlorαpyπdιπ-4- y!)-4-{4-!sopropoxyphenyl)- 2,4-dttnydro-3H-1,2,4- 126 3862 tπazol-3-oπe
Figure imgf000050_0001
49 Ret
Compound Name Time MS
F,C
O 2-butyi-5-(3-ch[oropyrιdin-4-
Figure imgf000051_0001
yi)-4-E4-
48 (trιfluoromethyl)phenyl]-2,4- 1 25 396 1 drhydro-3H-1 ,2,4-tnazol-3- one
Cl
O 2-ferf-butyl-4-(4-
Figure imgf000051_0002
^,A. chlorophenyl)-5-(3-
49 N A' chlorop/rrdιn-4-yl)-2τ4- 1 24 362 1 ciihydro-3H-1 ,2,4-tπazoJ-3- one
Cl
O 4-(4-chlorophenyl)-5-(3-
Figure imgf000051_0003
V chloro-4-pyπdιπyl)-2-(1 -
50 Λ fsobutyryl-4-p[peπdιπyl)-2,4- 1 27 459 1
N \ — / o dihydro-3H-1 ,2,4-tnazol-3- one
Figure imgf000051_0004
Cl
4-{4-chloropheπyl)-5-(3-
Figure imgf000051_0005
chloro-4-pyπdmyi)-2-(1 -
^ ^
51 N^' 0 propionyl-4-pipendinyl)-2,4- 1 25 445 1
O drhydro-3H-1 ,2,4-tπazol-3- one
Figure imgf000051_0006
Cl
4-(4-ch!orophenyl)-5-{3-
Figure imgf000051_0007
^ Λ - chloro-4-pyrιdιnyl)-2-[1-{2,2-
52 A N ^- dιmethylpropanoyl)-4- 1 23 473 1
N O piρeπdsnyf]-2,4-dιhydro-3H- 1 ,2,4-tπazof-3-one
Figure imgf000051_0008
Cl
4-(4-chloropheπyl)-5-(3-
Figure imgf000051_0010
1^ chloro-4-pyrιdιnyl)-2-[1-(3-
53 N^;
,N-C methylbutaπoyl)-4- 1 3 473 1
Figure imgf000051_0011
piperidinyl]-2,4-dihydro-3H- 1 ,2,4-trιazol-3-one
Figure imgf000051_0009
Cl
4-<4-chloropheπyl)-5-(3-
Figure imgf000051_0012
^K chloro-4-pyπdmyf)-2-[1-
54 (methylsulfonyl)-4- 1 16 467 1 piperfdιnyl]-2,4-dιhydro-3H- 1 2,4-trιazol-3-one
Figure imgf000051_0013
50 Ret
Compound Nc Time MS
4-(4-chloropheπy!)-5-(3- chloropyπdιn-4-yl)-2-(1- methylbutyl)-2,4-dιhydro- 135 3761 3H-1 ,2,4-tπazol-3-one
4-(4-chlorophenyl)-5-(3- chloropyπdιπ-4-yl)-2-(1- peπtanoylpipeπdιn-4-yl)- 123 4731 2,4-dιhydro-3H-1 2,4- tπazol-3-one
4-(4-chlorophenyl}-5-(3- chIoropyrιdιπ-4-yl)-2-(2,2 2- tπfluoroethyl)-24-dιhydro~ 128 3880 3H-1,2,4-trιazol-3-one
4-{4-chlorophenyl)-5-(3- chloropyrιdιn-4-yl)-2-{2,2- dιmethyJpropyl)-2,4- 135 3761 dιhydro-3H-1 ,2,4-trιazol-3- one
4-{4-chlorophenyl)-5-(3- chloropyπdιπ-4-yl)-2-{2- methyibutyl)-2,4-dihydrθ" 136 3761 3H-1 ,2,4-tπazol-3-one
4-(4-chlorophenyi)-5-{3- chloropyndιn-4-yl}-2-(2- methyiprop-2-eπ-1 -y!)-2,4- 121 3601 dιhydro-3H-1 ,2,4-tπazoi-3- one
4-(4-chloropheny[)-5-(3- chloropyπdιn-4-yl}-2-(3,3 3- {rιfluoropropyI)-2,4-dιhydro- 129 4020 3H-1 ,2 4-tnazo!-3-oπe
Figure imgf000052_0001
51 Ret
Compound Name Time MS
4-(4-chiorophenyl)-5-(3- chloropyπdiπ-4-y!)-2-(3,3-
62 dιmetriyl-2-oxobutyl)-2,4- 1 29 404 1 d[hydro-3H-1 ,2,4-tπazol-3- one
4-(4-ch!orophenyl)-5-(3- chloropyridin-4-yl)-2-(3-
63 methylbut-2-en-1-yl)-2,4- 1.25 374.1 dihydro-3H-1 ,2,4-trιazol-3- one
4-(4-chlorophenyi)-5-(3-
64 chloropyridiπ-4-yl)-2-(3-
1.35 376.1 methylbutyl)-2,4-dιhydro- 3H-1,2,4-triazo!-3-one
4-(4-chloropheny!)-5-(3- ch I o ropy rid i n-4-y I )-2-(4 -
65 metriylpeπt-3-en-1-yl)-2,4- 1.36 388.1 dihydro-3H-1 ,2,4-triazol-3- one
4-(4-chlorophenyl)-5-(3- chloropyridin-4-yl)-2-
66
Figure imgf000053_0001
(cyclobutylmethyl)-2,4- 1.26 374 1 dihydro-3H-1 ,2,4-triazof-3- one
4-{4-chloropheπyl)-5-(3- chloropyrιdiπ-4-yl)-2-
{cyclopropylmethyl)-2,4- 1.21 360 1 dιhydro-3H-1,2,4-trιazol-3- oπe
4-(4-chlorophenyl}-5-(3- ch!oropyrιdin-4-yi)-2-[(2E}- pent-2-en-1 -yl]-2,4-dιhydro- 1.26 374 1 3H-1 ,2,4-tπazol-3-one
Figure imgf000053_0002
52 Ret
Compound Name Time MS
Cl
4-(4-chloropheπyl}-5-(3-
Figure imgf000054_0001
"<SsJ^ J 1 , O chloropyrιdιn-4-y[)-2-[1 -
69 N— ( N→ (cyclobutylcarboπyl)pιpendι 1 21 471 1 n-4-yl]-2,4-d!hydro-3H- 1 ,2,4-trιazol-3-oπe
Figure imgf000054_0002
Cl
O 4-(4-chlorophenyl)-5-(3-
Figure imgf000054_0003
^, chloropyrιdιn-4-y!)-2-[1-
70 (cyclopropylcarbonyl)pιpeπ 1 19 457 1
~N
Figure imgf000054_0005
O dιn-4-yl3-2,4-dihydro-3H-
1,2,4-tnazol-3-one
Figure imgf000054_0004
C!
O F; F 4-(4-chlorophenyl)-5-(3- chloropyrιdιn-4-yl)-2-[1-
71 NΛ Λ (trιfluoraacety!)ptpeπdiπ-4- 1 22 485 1
Figure imgf000054_0007
o yl]-2 4-dιhydro-3H-1 ,2,4- tπazol-3-one
Figure imgf000054_0006
Cl
O 4-{4-chloropheny!)-5-(3-
Figure imgf000054_0008
chloropyrιdιπ-4-yl)-2-
72 N 1 23 360 1 cycJobutyl-2,4-dιhydro-3H- 1 ,2,4-tπazo!-3-one
Figure imgf000054_0009
Cl
O
Figure imgf000054_0010
1^ 4-(4-chloropheπyi)-5-{3-
N4 *o chloropyπdιn-4-yl)-2-
73 1 37 388 1 cyclohexyl-2,4-dihydro-3H- 1,2,4-trιazol-3-oπe
Figure imgf000054_0011
Cl
O
^s 4-(4-chlorophenyl)-5-(3-
Figure imgf000054_0012
N^ chloropyπdifi-4-yl)-2-
74 N 1 25 374 1 cyclopentyϊ-2,4-dihydro-3H- 1 ,2 4-tπazol-3-one
Figure imgf000054_0013
Ci
O 4-(4-chioropheπyl)-5-(3-
Figure imgf000054_0014
chioropyrιdfπ-4-y!)-2-ethyl- 2,4-dιhydro-3H-1 ,2,4- 1 17 334 0 tπazol-3-one
N^^ Cl
53 Ret
Compound Name Time MS
4-(4-chlorophenyl)-5-(3- chioropyridin-4-yl)-2- isobuty!-2,4-dihydro-3H- 1.24 362.1 1 ,2,4-tπazol-3-one
4-(4-cfιiorophenyl)-5-(3- chloropyridin-4-y[)-2-pent-2-
1 22 372 1 yn-1-yi-2,4-dιhydro-3H- 1,2,4-triazol-3-one
4-(4-chiorophenyl)-5-(3- chloropyridin-4-yϊ)-2-pent-4-
1.34 374.1 eπ-1 -yl-2,4-dihydrσ-3H- 1,2,4-triazol-3-one
4-(4-chlorophenyl)-5-(3- chloropyridιπ-4-yl}-2-pentyl- 2,4-dιhydro-3H-1,2,4- 1 36 376.1 trιazol-3-one
4-(4-chloropheπyl}-5-(3- chloropyridrπ-4-yl)~2-prap-2-
1.15 344 0 yn-1-yl-2,4-dihydro-3H- 1,2,4-triazol-3-one
4-(4-chlorophenyl)-5-(3- chloropyridin-4-yl)-2-propyl- 2,4-dihydro-3H-1 ,2,4- 1 21 348.1 triazoi-3-one
4,5-bis(4-chlorophenyl)-2- (2-ethoxyethyl)-2,4-dihydro- 1 36 377.1 3H-1,2,4-trιazol-3-one
Figure imgf000055_0001
54 Ret
Compound Name Time MS
Cl
O Ci
Figure imgf000056_0001
■Λ 4,5-bιs{4-chlorophenyl)-2- (6-chloro~4-pyπm]dtnyl)-2,4-
83 N
Figure imgf000056_0002
N 1 39 417 0 dιhydro-3H'1 ,2,4-trιazol-3-
N N- oπe
Figure imgf000056_0003
s?
Cl
Cl
4,5-bιs(4-chloropheπy!)-2-
O
Figure imgf000056_0004
^s [{1-propiony!-4-
84 Λ pιperιdιnyl)methyl]-2,4- 1 37 458 1
N
Figure imgf000056_0005
dιhydro-3H-1 ,2,4-tπazol-3- oπe
Figure imgf000056_0006
4?
Ci Cl
Figure imgf000056_0007
V X o nΛ 4,5-bιs{4-chlorophenyl)-2- [2-(methy!su!foπy[)ethyl]-
85 O O 2,4-dιhydro-3H-112,4- 1 29 411 0 trtazol-3-one
Figure imgf000056_0008
C!
O
Cl
O N
Figure imgf000056_0009
^ 4,5-bis(4-ch!orophenyl)-2- [6-(4-morpholιnyl)-4-
86 1 36 468 1 pyπmιdrnyl]-2 4-dthydro-3H-
N 1 ,2,4-tπazol-3-one
Figure imgf000056_0010
C Cl
Figure imgf000056_0011
V 4,5-bιs(4-chlorophenyi)-2-
87 A N- ethyl-2,4-dιhydro-3H-1,2,4- 1 36 333 0 tπazol-3-one
Figure imgf000056_0012
^
Cl
R
4-[3-(3-chloropyπdιn-4-yl)-
O
Figure imgf000056_0013
^. ^v 4-{4-fluorophenyl)-5-oxo-
,4 N- 4,5-d)hydro-1H-1 ,2,4- tπazol-1-yl]-N,N- 1 21 472 2
O dιethylpιpendιne-1- carboxamide
Figure imgf000056_0014
4-[3-(3-chloropyrιdιn-4-yl)-
O 4-{4-fluorophenyl)-5-oxo-
Figure imgf000056_0015
89 •uΛ HN- 4,5-dιhydro-1 H-1 ,2,4-
N- 1 23 458 2 tnazo 1-1 -y I]-N-
O propylpιperιdιne-1- carboxamide
Figure imgf000056_0016
55 Ret
Compound Name Tune MS
4-[3-(3-chloropyndin-4-yl)-
4-(4-fluorophenyl)-5-oxo-
Figure imgf000057_0001
HN
>^ 4,5-dιhydro-1 H-1 ,2,4-
90 N 1 22 458 2 tπazol-1 -y!]-N-
O ιsopropylpιpeπdιne-1 -
Figure imgf000057_0002
carboxamide
N-^^CI
4-t3-(3-chloropyndm-4-yl)- 4-(4-fluorophenyl)-5-oxo- 4,5-dιhydro-1 H-1 ,2 4- 1 27 484 2 trιazol-1 -y I]-N- cyclopentylpιpeπdιne-1 - carboxamide
O 4-[4-{4-chlorophenyl)-3-{3-
Figure imgf000057_0003
^ chloro-4-pyπdιnyl)-5-oxo-
92 uΛ HN
H, 4,5-dιhydro-1 H-1 2,4- 1 15 446 1
-H O tπazol-1-yl]-N-methyl-1- pipeπdinecarboxamide
Cl
4-{4-(4-chlorophenyl)-3-(3-
N— chloro-4-pyrιdιnyl)-5-oxo-
93 4 5-drhydro-1 H-1 ,2,4- 1 26 460 1 trtazoi-1-yl]-N,N-dιmethyl-1 - pipendinecarboxamide
4-[4-(benzyloxy)pheπy!]-5- (3-chloropyπdιn-4-yl)-2,4-
94 0 66 379 1 dιhydro-3H-1 ,2,4-tπazol-3- one
4-{I3-(3-chloropyrιdιn-4-yl)-
4-(4-fluorophenyf)-5-oxo-
4,5-dιhydro-1 H-1 ,2 4-
1 21 486 2 tπazol-1-yl]methyl}-N,N- diethylpιpeπdine-1- carboxamide
4-{[3-(3-chloropyπdιπ-4-yl)-
4-(4-fluorophenyl)-5-oxo-
4,5-dιhydro-1 H-1 ,2,4-
1 27 498 2 tπazol-1-y!jmethyl}-N- cyclopentylpιpeπdme-1- carboxamide
Figure imgf000057_0004
56 Ret
Compound Name Time MS
5-{3-chloropyrιdιn-4-y[)-2-
Figure imgf000058_0001
(1-ethylpropyl)-4-{4-
97 isopropoxyphenyi)-2,4- 1 35 400 2
Figure imgf000058_0003
dιhydro-3H-1 ,2,4-trιazol-3- one
Figure imgf000058_0002
F3C
5-(3-chloropyπdιn-4-y!)-2-
O
Figure imgf000058_0004
^ (i-ιsobutyrylpιperιdιn-4-yl)-
NA J-' 4-[4-
98
Figure imgf000058_0006
(trιfiuoramethyl)pheπyl]-2,4- 1 29 493 1
O dιhydro-3H-1 ,2,4-trιazol-3- one
Figure imgf000058_0005
F,C
5-(3-chloropyπdιn-4-yl)-2-
O
Figure imgf000058_0007
1^ (1 -pentanoylpιperιdιn-4-yi)-
4-f4-
99 L 1 W ^07 9
(trιfluoromethyl)pheny[]-2,4-
N \ — / O drhydro-3H-1 ,2,4-tπazol-3- one
Figure imgf000058_0008
5-(3-chloropyπdιπ-4-yl)-2-
{1-propiθπylpιpeπdjn-4-yl)-
100 ? N N_( N. 4-[4-
1 27 479 1
(tnfiuoronnethyl)phenyl]-2,4-
N O dιhydro-3H-1 2,4-tπazoi-3- one
Figure imgf000058_0009
F,C
5-(3-chloropyπdιn-4-yl)-2-
Figure imgf000058_0010
(2,2,2-tπf!uoroethyl)-4-[4-
101 U ' (tπfluoromethyl)phenylJ-2 4- 1 3 422 0 dιhydro3H-1 ,2,4-trιazol-3- oπe
Figure imgf000058_0011
.0.
O 5-{3-chloropyrιdιn-4-yl)-2-
Figure imgf000058_0012
(2,2-dιmethy[propyl}-4-(4~
102 ^ A N ιsopropoxypheny!)-2,4- 1 36 400 2
N dιhydro-3H-1 ,2,4-trιazol-3- one
Figure imgf000058_0013
F3C.
5-(3-chloropyrιdιn-4-yl)-2-
Figure imgf000058_0014
NN. A (2 2-dιmethylpropyl)-4-[4-
103 A N (tπfluoroιmethy!)pheriyl]-2,4- 1 36 410 1 of" dihydro-3H-1,2,4-triazol-3- one
57 Ret
Compound Name Time MS
5-(3-chloropyrιdιn-4-y[}-2-
(2-hydroxy-3,3- dιmethylbutyl)-4-(4- ιsopropoxyphenyl)-2,4- 1 32 430 2 dihydro-3H-1 ,2,4-tπazol-3- one
5-(3-chloropyπdιn-4-yl)-2- (2-hydroxy-3-pyrrolιdιn-1 - y[propyl)-4-[4-
1 17 467 1
(trιfluoromethyJ)phenyl]-2,4- dιhydro-3H-1 ,2,4-tπazol-3- one
5-(3-chloropyπdιn-4-yl)-2-
(2-hydroxy-3-th!omorpholιn-
4-ylpropyl)-4-[4-
(tπfluoromethyi)phenyl]-2,4- 1 06 499 1 dιhydro-3H-1 2,4-tnazoi-3- one
5-(3-chloropyπdιπ-4-yl)-2- (2-mβthylbuty!)-4-[4- {trιfluoromethyl)phenyl]-24- 1 37 410 1 dιhydro-3H-1 ,2,4-trιazol-3- orte
5-(3-chloropyπdm-4-yl)-2- (2-methy[prop-2~en-1 -yi)-4- [4-(trifiuoromethyl)phenyl]- 1 22 394 1 2,4-dihydro-3H-1 ,24- tπazol-3-one
5-(3-chloropyrιdιn-4-y!)-2-
(2-morpholιn-4-yl-2- oxoethyl)-4-[4-
(trif[uoromethy!)phenyl]-2,4- 1 12 467 1 d!hydro-3H-1 ,2,4-tπazol-3- one
5-{3-ch!oropyrιdιn-4-yi)-2-
(2-oxo-2-p!peπdιn-1- ylethyl)-4-[4- 1 28 465 1
*0~o (tπfluoromethyl)phenyl]-2,4- dιhydro-3H-1 2,4-tπazol-3- oπe
Figure imgf000059_0001
58 Ret
Compound Name Time MS
5-(3-chloropyπdιπ-4-yl)-2-
Figure imgf000060_0001
(3,3-dιmethyl-2-oxobutyl}-4-
1 1 1 Λ (4-fluorophenyl)-2,4- 1 25 388 1 dihyciro-3H-1 ,2,4-tπazoi-3- one
5-(3-ch!oropyrιdιn-4-yl)-2- (3,3-dιmetby!-2-oxobu£yl)-4- {4-isopropoxyphenyl)-2,4- 1 3 428 2 dιhydro-3H-1 ,2,4-tπazol-3- one
5-(3-ch!oropyπdnv4-yl)-2- (3 3-dfmethyl-2-oxobutyl)-4- [4-(trιfluoromethyl)phenyl]- 1 3 438 1 2,4-dιhydro-3H-1 ,2,4~ tπazol-3-oπe
5-(3-chloropyπdιπ-4-yi}-2- (3-methylbut-2-en-1-y[)-4- [4-{trιf]uoromethyl)pheny[]- 1 26 408 1 2 4-d!hydro-3H-1 ,2,4- tπazol-3-oπe
5-{3-chloroρyπdιn-4-yl)-2- (3-methylbutyl)-4-[4- (trιfluoromethyl)pheπyl]-2 4- 1 37 410 1 dthydro-3H-1 ,2,4-tπazol-3- one
5-(3-chloropyrιdιn-4-yl)-2- (4-methylpent-3-en-1 -yl)-4- [4-{tπfluoromethyl)phenyl]- 1 37 422 1 2,4-dιhydro-3H-1,2 4- tπazol-3-oπe
5-(3-chloropyrιdιn-4-yl)-2- (cyclobutylmethyl)-4-(4-
1 23 358 1 fluoropheπyl)-2,4-dιhydro- 3H-1 ,2,4-tπazol-3-oπe
Figure imgf000060_0002
59 Ret
Compound Name Time MS
5-{3-chloropyrιdιn-4-yi)-2- (cycJobutylmethy[)-4-(4- ιsopropoxyphenyi)-2,4- 1 26 398 2 dιhydra-3H-1 ^^-tπazol-θ- one
5-(3-chloropyπdιn-4-yl)-2- (cyclobutylmethy[)-4-[4- (trιfluoromethyl)phenyi]-2.4- 1 27 408 1 dιhydro-3H-1 ,2,4-trιazol-3- oπe
5-(3-chloropyπdιn-4-yl)-2- (cyclopropylmethyl)-4-{4-
1
Figure imgf000061_0001
20 isopropoxyphenyl)-2 4- 1 23 384 1 dιhydro-3H-1 ,2,4-trιazol-3- one
FSC
5-(3-chloropyrιdιn-4-yl)-2- (cyc[oρropylmethyl}-4-[4- (trιfluoromethyl)phenyl]-2,4- 1 23 394 1 dιhydro-3H-1 ,2,4-trιazol-3- oπe
5-{3-chloropyπdιn-4-yl)-2-
[(2E)-pent-2-en-1-yl]-4-[4-
(trιfluoromethyl)phenyl]-2,4- 1 26 408 1 dιhydro-3H-1,2,4-trιazol-3- one
5-(3-chloropyπdιπ-4-yl)-2-
[1 -(2,2- dιmethylpropanoyl)pιpendιπ
1 2 457 2
-4-yl]-4-(4-fluorophenyl)-
2,4-dιhydro-3H-1 2,4- tπazol-3-one
5-(3-chloropyrιdιn-4-yϊ)-2-
[1 -(2- βthylbutaπoyl)piperιdιπ-4-
1 29 471 2 y!]-4-(4-fluorophenyl)-2,4- dιhydro-3H-1 ,2,4-tπazol-3- oπe
Figure imgf000061_0002
60 Ret
Compound Name Time MS
5-(3-chloropyrιdιn-4-yl)-2- [1-0.3- dιmethylbutanoyl)pιpeπdrn-
125 1 29 471 2 4-y!]-4-(4-fluorophenyl)-2,4- d!hydro-3H-1 ,2,4-tπazoi-3- one
5-(3-chloropyπdin-4-yl)-2-
[1-(3-
Figure imgf000062_0001
methylbutanoyl)piperιdιn-4-
N— < H-\ X yi]-4-[4- 1 31 507 2 O (tπfluoromethyl)pheny!]-2,4- dιhydro-3H-1 ,2,4-tπazol-3- one
5-(3-ch!oropyπdιn-4-yl)-2-
[1- (cyclobuty[carbonyl)pipend! π-4-yl]-4-[4- 1 3 505 1
(trιfluoromethyl)pheπyl]-2,4- dιhydro-3H-1 ,2 4-tπazof-3- one
5-(3-chloropyrιdιn-4-yl)-2-
[1 -
(cyclobutylcarbonyOpipendi
1 18 455 2 n-4-yl]-4-(4-fluoropheπyl)-
24-dιhydro-3H-1 ,2,4- tnazol-3-one
5-{3-ch!oropyπdιπ-4-yl)-2-
[1-
(cydopentylcarbonyl)pιpeπd . „, .„. „ ιn-4-yi]-4-(4-fluoropheπyl)-
2,4-dιhydro-3H-1,2t4- tπazoi-3-one
5-(3-chforopyπdιn-4-yl)-2-
[1-
(cyclopropylcarboπyl)pιpeπ dιn-4-ylJ-4-[4- 1 27 491 1
\j \ — / Y1 (trιf!uoromethyl}phenyl]-2,4- dιhydro-3H-1 ,2,4-tπazo!-3- one
5-(3-chloropyridin-4-yl)-2-
[1 -
(cyclopropylcarbonyi)pφeπ 1 15 441 1
131 dιπ-4-yl]-4-(4-fluorophenyl)-
2,4-dιhydro-3H-1 2,4- tπazoi-3-one
Figure imgf000062_0002
61 Ret
Compound Name Time MS
5-{3-chloropyπdm-4-yl)-2-
Figure imgf000063_0001
^ [1 -(ethoxyacetyl)pιperιdιn-4-
132 •Λ N N- yl]-4-(4-fluorophenyi)-2,4- 1 23 459 1
N O dihydro-3H-1 ,2,4-tπazol-3- one
Figure imgf000063_0002
FaC
5-(3-chioropyrfdιn-4-yi)-2-
O
Figure imgf000063_0003
^ [1 -(propylsulfonyl)pιpeπdιπ-
4-yl]-4-[4-
133 i N_/ N-S
(tπfluoromethyl)phenylJ-2,4- dιhydro-3H-1,2,4-trιazol-3- one
Figure imgf000063_0004
F,C
5-(3-chloropyπdιn-4-yl}-2-
O
Figure imgf000063_0005
1^x Λ [2-(3-methoxypιperιdιn-1 - yl)-2-oxoethyl]-4-[4-
134 1 14 495 1 (tnfluoromethyl)phenyl]-2,4- dihydro-3H-1 ,2,4-tπazo!-3-
Figure imgf000063_0006
oπe
F3C
5-(3-chloropyπdιn-4-yl)-2-
Figure imgf000063_0007
%, [2-hydroxy-3-(2-methyl-1 H- ιmιdazol-1 -yl)propyl]-4-[4-
135 1 18 478 1 (tπfluoromethyl)phenyl]-2,4- dιhydro-3H-1 ,2,4-trιazol-3-
N il X
Figure imgf000063_0008
H0 N one
^^ N
FoC
5-(3-chloropyrιdιn-4-yl)-2-
O [3-(5,5-dimeEhyl-4,5- dιhydro-1 H-ιmιdazol-1-yJ)-2-
136 hydroxypropy[]-4-[4- 1 18 494 1
(trrfIuoromethyl)phenyl]-2,4- d!hydrα-3H-1 ,2,4-tπazo!-3- oπe
FX
5-(3-ch!oropyπdιn-4-yl)-2-
[3-(d!ethylamιno)»2- hydroxypropyl]-4-[4-
137 (trιfluoromethyl)phenyl]-2,4- 1 06 469 1 dιhydro-3H-1,2,4-trιazol-3- oπe
FoC,
5-(3-chloropyrιdιn-4-yl)-2-
[3-(dιmethylamιno)-2- hydroxypropyS]-4-[4-
138 (trιfluoromethyl)phenyl]-2,4- dihydro-3H-1,2 4-tπazol-3- oπe
Figure imgf000063_0009
62 Compound Name MS
5-(3-chloropyπdιn-4-yl)-2-
{[1-(2,2-
139
Figure imgf000064_0001
V dimethylpropanoyljpipeπdin
N -4-yl]methyl}-4-(4- 1 21 471 2
N fluoropheπyl)-2,4-d!hydro-
3H-1 2,4-tπazol-3-one
Figure imgf000064_0002
5-(3-chloropyπdιn-4-yl)-2- o O {[1-(2-
~N
^N X uA ethylbutanoyl)pιpeπdιn-4-
140 y!]methyl}-4-(4- 1 3 485 2
Figure imgf000064_0004
fluorophenyl)-2;4-dιhydro-
N 3H-1 ,2,4-tnazoi-3-one
Figure imgf000064_0003
5-(3-chioropyπdιn-4-yl}-2-
Figure imgf000064_0008
«1-(3,3-
Figure imgf000064_0005
N O dιmethylbutaπoyl)pιperιdιn-
141 ^ 1 26 485 2
IMA' 4-yl]methyt}-4-(4-
Figure imgf000064_0007
fiuorophenyl)-2 4-dιhydro-
N 3H-1,2,4-tnazol-3-one
Figure imgf000064_0006
5-{3-chloropyπd!n-4-yl}-2-
Figure imgf000064_0009
O {[1 -
N ^O
142 ^S^ (cyclobutylcarbonyl)pιpsrιdι
1 19 469 2 n-4-yl]methyl}-4-{4-
N
Figure imgf000064_0011
fluorophenyl)-2,4-dιhydro-
N 3H-1 ,2,4-tπazo[-3-one
Figure imgf000064_0010
5-{3-chloropyπdιn-4-yl}-2-
O {[1 -
N O
143
Figure imgf000064_0012
^A M (cyclopentyicarbonyl)pιperιd Λ „„ dH_ „
N' ιn-4-yl]methyl}-4-(4- ' ^ *^βJ ^
N
Figure imgf000064_0014
fluoropheπyl)-2,4-dιhydro-
1N 3H-1 2,4-trιazol-3one
Figure imgf000064_0013
5-{3-chloropyπdιn-4-yl)-2- {[1-(ethylsulfonyl)ptpeπdιn-
144
Figure imgf000064_0015
^ ^A 4-yi]methy[}-4-(4- 1 22 479 1
Figure imgf000064_0017
fluoropheπyl}-2 4-dιhydro-
N 3H-1 ,2,4-tπazol-3-one
Figure imgf000064_0016
63 Ret
Compound Name Time MS
F,C. 5-(3-chloropyπdιπ-4-yl}-2-
O {2-hydroxy-3-
[ιsopropyl(methyl)ainino]pro
145 py[}-4-[4- 1 07 469 1
{tnfluoromethyl)phenyl]-2,4- dιhydro-3H-1 ,2,4-tnazol-3- oπe
FSC
5-(3-chloropyπdιn-4-yl)-2-
{3-[(2,2- dιmethylpropy[)amιno]-2-
146 hyd roxy pro py l}-4-[4- 1 21 483 2
(trιfluoromettiy[)phenyl]-2,4- dιhydro-3H-1 ,2,4-tπazol-3- one
F3C
5-(3-chlαropyrιdιn-4-y!)-2- {3-[ethyl(methyl)amιnoI-2- hydroxypropyl}-4-[4-
147 1 06 455 1
(tπfluoromethyl)pheπyl]-2,4-
^f N dιhydro-3H-1,2 4-tπazol-3-
Figure imgf000065_0001
U 1 HO N- one
N^-C, /
5-{3-chloropyπdin-4-yl}-2- cyclobuty[-4-{4-
148 ιsopropoxyphenyl)-2,4- 1 22 384 1 dιhydro-3H-1 2,4-tπazol-3- one
5-(3-chloropyπdιιv4-yl)-2- cyclobutyl-4-[4-
149 (tπf!uoromethyl)pheπyl]-2 A- 1 25 394 1 dιhydro-3H-1 ,2,4-trιazol-3- one
5-(3-chloropyπdιπ-4-yl)-2- cyclohexyl-4-(4-
150 ιsopropoxyphenyl)-2,4- 1 37 412 2 dihydro-3H-1 ,2 44πazol-3- one
Figure imgf000065_0002
F3C.
/ ° 5-(3-chloropyrιdιπ-4-y!)-2- cyc!oheχyl-4-[4-
■s. ^rVo (tπfluoromethyl)pheny[]-2,4- 1 37 422 1 dιhydro-3H-1,2 4-tπazol-3- oπe
64 Ret
Compound Name Time MS
5-{3-chioropyndm-4-yi)-2- cyclopentyl-4-(4- ιsopropoxyphenyl)-2,4- 1 27 398 2 dιhydro-3H-1 ,2,4-tπazol-3- one
5-(3-chioropyπdιn-4-yl}-2- cyclopenty[-4-(4- (tπfluoromethyl)phenyl]-2,4- 1 15 408 1 dιhydro-3H-1 ,2,4-trιazol-3- one
5-(3-ch[oropyrιdιn-4-yi)-2- ethyl-4-(4- ιsopropoxyphenyl}-2,4- 1 27 358 1 dιhydro-3H-1τ2 4-tπazol-3- one
5-(3-chloropyπdιπ-4-yl)-2- ethyl-4-[4- (trιfluoromethyl)phenyl]-2,4- 1 2 368 1 dιhydro-3H-1 2,4-trιazol-3- oπe
5-{3-chloropyπdιπ-4-yl)-2- ιsobutyl-4-{4- ιsoprαpoxyphenyl)-2,4- 1 25 386 2 dihydro-3H-1 ,2,4-trιazol-3- O
Figure imgf000066_0002
ΠΘ
5-(3-chloropyπdιn-4-yl)-2- ιsobutyl-4-[4-
(trιfluoromethyl)phenyl]-2,4- 1 26 396 1 dιhydro-3H-1 ,2,4-trιazol-3- one
5-(3-chloropyrιdιn-4-yl}-2- pent-2-yn-1 -yl-4-[4-
(tπfluoromethyl)phenyl]-2,4- 1 23 406 1 dιhydro-3H-1 ,2,4-tnazol-3- one
Figure imgf000066_0001
65 Ret
Compound Name Time MS
F,C
5-(3-chloropyrid;n-4-yl)-2- pent-4-en-1-yl-4-[4- (trifluoromethy[)phenyl]-2 A- 1 35 408 1 dihydro-3H-1 ,2,4-tπazol-3- oπe
5-(3-chloropyπdιn-4-y[)-2- pentyl-4-[4-
(tnfluoromethyi}phenyl]-2,4- 1 38 410 1 dιhydro-3H-1 ,2,4-tπazol-3- oπe
5-{3-ch!σropyndιπ-4-yl)-2- prop-2-yπ-1 -yl-4-[4-
(trιfluoromethyl)pheπyi]-2,4- 1 18 378 0 dihydro-3H-1 ,2 4-tnazo[-3- one
5-(3-chloropyπdfn-4-yl)-2- propyl-4-[4-
(tπfϊuoromettiyljphenyl]^^- 1 23 382 1 dιhydro-3H-1 2φ4-tπazol-3- one
5-{3-chloropyπdιn-4-yi)-4- (4-fluorophenyl)-2-(1- hexaπoy[pιpeπdm-4-yl)-2,4- 1 3 471 2 dιhydro-3H-1 s2,4-tπazo[-3- one
5-(3-ch!oropyrfdιn-4-yl)-4- (4-fluorophenyl)-2-(1- ιsobutyrylpιpeπdιπ-4-yl)-2 4- 1 17 443 2 dihydro-3H-1 ,2,4-trιazol-3- one
5-(3-chloropyrιdιπ-4-yl)-4-
(4-fluorophenyl)-2-(1~ peπtanoyipipeπdin-4-yi)- 1 2 457 2
O 2,4-dιhydro-3H-1 ,2,4- tπazol-3-oπe
Figure imgf000067_0001
66 Ret
Compound Name Time MS
O 5-(3-ch[oropyπdιn~4-yi)-4-
Figure imgf000068_0001
^^Λ (4-fluorophenyl)-2-(1 -
166 Λ N-^ N propionytpiperidiπ-4-yl)-2,4- 1 14 429 1
O dιhydro-3H-1 ,2,4-tπazol-3- one
5-(3-chloropyrιdιπ-4-yl)-4-
Figure imgf000068_0002
(4-fluorophenyl)-2-(3-
167 N' methylbut-2-en-1 -yl)-2,4- 1 21 358.1
N dihydro-3H-1 ,2,44HaZoI-S-
Figure imgf000068_0006
one
Figure imgf000068_0003
Figure imgf000068_0004
^ 5-(3-chloropyridiπ-4-yl)-4-
\ A (4-fluorophenyl)-2-{3-
1 68 1 32 360 1 methylbutyl)-2,4-dιhydro-
N 3H-1 ,2,4-tπazol-3-one
Figure imgf000068_0005
5-(3-chloropyπdiπ-4-yl}-4-
(4-fluorophenyl)-2-[(1-
169 O hexanoylpιperidin-4- 1 32 485 2
Figure imgf000068_0007
^ ^x.
•HΛ y!)methy!]-2,4-dihydro-3H-
N
Figure imgf000068_0009
1 ,2,4-tπazof-3-one
-N
Figure imgf000068_0008
5-(3-ch!oropyrιdιn-4-yl)-4-
O N (4-fluorophenyl)-2-[(1-
Figure imgf000068_0010
170 N^ X ιsobutyrylpιpeπdιn-4- 1 17 457 2
N
Figure imgf000068_0014
y!)methy!]-2,4-dihydro-3H-
1 ,2,4-trιazof-3-one
Figure imgf000068_0011
5-{3-ch!oropyridin-4-y!)-4-
Figure imgf000068_0015
O (4-fluorophenyl)-2-t(1 -
171 O
Figure imgf000068_0012
^5, ΛJJ pentanoylpiperidin-4- 1.21 471 2 yl)methyl]-2,4-dihydro-3H- 1 ,2,4-tπazol-3-one
N
Figure imgf000068_0013
67 Ret
Compound Name Time MS
5-(3-chloropyridin-4-yl)-4-
{4-fluorophenyl)-2-[1-(2- methylpeπtaπoyl)piperidin- 1 3 471 2
4-yI]-2,4-dιhydro-3H-1,2,4- triazol-3-one
5-(3-ch!oropyrιdιn-4-yl)-4- (4-fluoropheπyl)-2-[1 -(3,3,3- trifluoropropanoyljpiperidin- 1 23 483 1 4-yl3-2,4-dihydro-3H-1 ,2,4- triazol-3-oπe
5-(3-chloropyπdιπ-4-yl)-4-
(4-fluoropheny!)-2-[1-(3- methy[butanoyl)pιperidιn-4- 1 2 457.2 yl]-2,4-dιhydro-3H-1 ,2,4- triazol-3-one
5-{3-ch!oropyπdιn-4-yl)-4- (4-fluorophenyl)-2-[1-(4- methylpentanoyi)piperidin- 1 3 471.2 4-yl]-2,4-dihydro-3H-1 ,2,4- trιazo!-3-oπe
5-(3-chloropyπdιπ-4-yl)-4-
(4-fiuorophenyl)-2-[1-
(ιsopropylsuifonyl)piperidιn- 1.23 479 1
4-yl]-2,4-dιhydro-3H-1 ,2,4- triazol-3-one
5-{3-chloropyridιn-4-y[)-4- (4-fluorophenyl)-2-[1- (methylsulfonyl)pιpeπdιπ-4- 1.2 451.1
O ° yl]-2,4-dιhydro-3H-1 ,2,4- triazoJ-3-one
5-(3-chloropyπdιn-4-yl)-4-
O
Λ (4-fluorophenyl)-2-[1-
Figure imgf000069_0001
(pιpeπdιn-1-
1 7S N-/ N- 1 22 484 2 ylcarbonyl)pipendiπ-4-yl]- 1N \ / 1O 2,4-dιhydro-3H-1 ,2,4- tπazol-3-one
Figure imgf000069_0002
Ret
Compound Name Time MS
5-(3-ch[oropyrιdιn-4-yl)-4-
Figure imgf000070_0001
(4-fluorophenyl}-2-[1 -
Figure imgf000070_0003
179 "^Vl {propylsulfonyl)pipeπdιn-4- 1 24 479 1 ylJ-2,4-dιhydro-3H-1 ,2,4- trιazol-3-one
5-(3-chloropyπdιn-4-yJ)-4- vΛ O
(4-fJuorophenyl}-2-[1-
N N- (pyrroiιdin-1-
180 A N 1 18 470 2 y!carboπyi)pιpeπdιπ-4-yl]-
N /K O 2,4-drhydro-3H-1 ,2,4- tπazol-3-one
0 F 5-(3-chloropyπdιn-4-yi)-4- (4-fl uorophe nyi)-2-[1 -
18 Ϊ Λ, N N- (trιflιιoroacetyl)pjpeπdιn-4- 1 19 469 1
-N O yl]-2 4-drhydro-3H-1 ,2,4- trιazol-3-oπe
5-(3-chloropyndιπ-4-yl)-4-
(4-fluorophenyl)-2-{[1 -(2-
182 methytpentaπoyl)pιpeπdιn- 1 31 485 2
4-ylJmettiyl}-2,4-dιhydro-
3H-1 ,2,4-tπazol-3-one
5-(3-chloropyπdιn-4-yl)-4-
(4-f[uoropheny[)-2-{[1-
(3,3,3- tπfluoropropanoyljpipeπdiπ- 1 23 497 1
4-yl]methyl}-2,4-dιhydro-
3H-1 2,4-trιazol-3-one
5-(3-chioropyπdιπ-4-yl)-4- (4-fluoropheπyl)-2-{[1 -(3- methylbutanoyl}pφeπdiπ-4- 1 2 471 2 yl]methyl}-2 4-dιhydro-3H- 1 ,2 4-tπazol-3-one
Figure imgf000070_0002
69 Ret
Compound Name Time MS
5-(3-chloropyrιdιrv4-yl)-4-
(4-fluorophenyl)-2-{ϊ1-(4-
O
185
Figure imgf000071_0001
^ J^ J[ N ~O fnethylpentanoyi)piperfdm- 1 3 485 2
4-yl]methyl}-2,4-d[hydro-
N
Figure imgf000071_0003
3H-1 ,2,4-tπazol-3-one
Figure imgf000071_0002
S=O 5-(3-chloropyπdιn-4-yl)-4- (4-fluorophenyl)-2-{[1-
186 ^Λ (ιsopropylsulfonyl)pιpeπdm- 1 24 493 1 4-yl]methy]}-2 4-dιhydro-
N 3H-1 ,2,4-tπazol-3"θne
5-(3-chloropyndιn-4-yl)-4-
(4-fluorophenyl)-2-{[1-
(pιpeπdιn-1-
1 22 498 2 ylcarbonyl)pιpeπdιn-4- yl]methyl}-2,4-dihydro-3H-
1 ,2,4-tπazoJ-3-oπe
5-(3-ch loro p yrid i π-4-y l)-4-
(4-fJuorophenyl}-2-{[1-
(propylsulfonyl)pιpeπdιn-4- 1 25 493 1 yl]methyl}-2T4-dihydro-3H-
1 ,2,4-tπazol-3-one
5-(3-chloropyπdιn-4-yi)~4-
(4-fiuoropheny!)-2-{[1-
(trιfIuoroacetyl)pιpeπc(ιn-4- 1 19 483 1 yl]methyl}-2,4-dihydro-3H-
1 ,2,4-tπazol-3-oπe
5-(3-chloropyrιdιn-4-yI)-4- (4-fluoropheny!)-2-pent-4- en-1-y!-2,4-dιhydro-3H- 1 3 358 1
1 ,2,4-tπazol-3-one
Figure imgf000071_0004
70 Ret
Compound Name Time MS
5-{3-chioropyridιn-4-yl)-4- (4-fluorophenyl)-2-pentyl-
1 34 360 1 2,4-drhydro-3H-1 ,2,4- trιazoi-3-oπe
5-(3-chloropyπdιn-4-yl)-4- (4-ιsopropoxypheπyl}-2-{1- methylbutyl)-2,4-dihydro- 1 36 400 2 3H-1 ,2,4-trrazol-3-one
5-(3-chloropyrιdιn-4-yl)-4-
(4-isopropoxyphenyl)-2-
^^^-trifluoroethyl)^^- 1.29 412 1 dιhydro-3H-1,2,4-trιazol-3- one
5-(3-chioropyrtdin-4-yl)-4- (4-isopropoxypheπyl)-2-(2-
1 36 400 2 methylbutyl)'2,4-dιhydro- 3H-1 ,2,4-tπazol-3-one
5-(3-chloropyrιdιn-4-yl)-4- {4-ιsopropoxypheπyl)-2-(2- methy[prop-2-eπ-1 -yl)-2,4- 1 22 384.1 dihydro-3H-1 ,2,4-trιazol-3- oπe
5-(3-chloropyπdιn-4-yl)-4-
(4-ιsopropoxypheπyl}-2-(2- moφholιn-4-yl-2-oxoethyl)- 1.02 458 2
2,4-dihydro-3H-1,2,4- triazol-3-one
5-<3-chloropyπdiπ-4-yl)-4- (4-ιsopropoxypheπyi)-2-(2-
N oxo-2-pipendin-1 -ylethyl)- 1 19 456 2 2,4-dιhydro-3H-1 ,2,4- trιazol-3-one
Figure imgf000072_0001
71 Ret
Compound Name Time MS
5-(3-chloropyridιn-4-yl)-4- (4-isopropoxyphβnyl)-2-{2- oxo-2-pyrroiιdιn-1 -ylethyl)- 1 09 442 2 2,4-dihydro-3H-1,2,4- trιazol-3-one
5-(3-ch!oropyrιdin-4-y[)-4-
{4-ιsopropoxyphenyl)-2-{2- oxo-2-thιomorpholin-4- 0.86 474 1 ylethyl)-2,4-dιhydro-3H-
1 ,2,4-tπazol-3-one
5-(3-chloropyridιn-4-yl)-4-
(4-ιsopropoxyphenyl)-2-
{3,3,3-trιfluoropropyf)-2,4- 1 31 426 1 dιhydrø-3H-1 ,2,4-trιazol-3- one
5-(3-chloropyπdιπ-4-yl)-4- (4-isopropoxypheπyl}-2-{3- methyϊbut-2-en-1-yl)-2,4- 1 26 398 2 dιhydro-3H-1 ,2,4-triazol-3- one
5-(3-ch!oropyrιdin-4-yi)-4- {4-ιsopropoxyphenyl)-2-(3- 1 18 400 2 methylbuEy[)-2,4-dιhydro- 3H-1 ,2,4-trrazot-3-one
5-(3-chloropyricliπ-4-yl}~4- (4-isopropoxypheπyl)-2-(4-
203 methylpent-3-en-1-yl}-2,4- 1 37 412 2 dihydro-3H-1 ,2,4-triazol-3- one
5-(3-chloropyrιdιn-4-yi)-4-
(4-isopropoxyphenyl)-2-
204 [(2E)-pent-2-en-1-yl]-2,4- 1 26 398 2 dihydro-3H-1,2,4-tnazol-3- oπe
72 Ret
Compound Name Time MS
5-(3-chloropyndin-4-yi)-4- {4-ιsopropoxyphenyl)-2-[2-
205 (2-methylpyrrolfdιπ-1-yl)-2- 093 4562 oxoethyl]-2,4-dthydra-3H- 1 ,2,4-tπazol-3-one
5-(3-chloropyπdin-4-yl)-4-
(4-ιsopropoxyphenyl)-2-[2-
206 (4-methylpιpeπdιn-1-yl)-2- 092 4702 oxoethyl]-2t4-dιhydro-3H-
1,2,4-tπazo!-3-one
5-(3-chloropyπdιn-4-yl)-4- (4-ιsopropoxyphenyl)-2-
207 pent-2-yn-1 -yl-2,4-d?hydro- 123 3961 3H-1 ,2,4-IrIaZOl-S-OiIe
5-(3-chIoropyπdιπ-4-yl)-4-
208 (4-ιsopropoxyphenyl)-2- 134 3982 pent-4-en-1-yl-2 4-d i hydro- 3H-1 ,2,4-tπazol-3-one
5-(3-chloropyπdιn-4-yl)-4- (4-isopropoxyphenyl}-2-
209 137 4002 penty[-2,4-dιhydro-3H- 1 ,2,4-trιazol-3-one
5-(3-chloropyπdιn-4-y[)-4- (4-ιsopropoxyphenyl)-2- propy!-2 4-dιhydro-3H- 122 3721 1 ,2,4-tπazol-3-one
5-(3-chloropyπdιn-4-yl}-4-
[4-(tπfluororπethyl)pheπyf]-
2-(3,3,3-tnfJuoropropyl)-2,4- 131 4361 dihydro-3H-1,2,4-tπazol-3- oπe
Figure imgf000074_0001
73 Ret
Compound Name Time MS
F3C.
5-(3-chloropyπdιn-4-yl)-4-
O
[4-(trιflLJorotnethyl)pheπyij-
Figure imgf000075_0001
2-[1 -{3,3,3-
212 1^Vl N-
Figure imgf000075_0003
Λ_ 1 17 533 1 tπfluoropropanoyl)pιpeπd[n-
^N O 4-yl3-2,4-dιhydro-3H-1 ,2,4- tπazol-3-one
Figure imgf000075_0002
Cl
Figure imgf000075_0004
1^N
6-[3 4-bιs(4-chloropheπyl}-
213 X o
HΛ 5-oxo-4,5-dthydro-1 H-1 ,2 4- 1 37 407 0
N H-V N tnazol-1-yi]nicotιnoπιtrιle
butyl 4-[3-(3-chloropyrιdιn-
4-yl)-4-(4-fluorophenyl)-5~ oxo-4,5-dιhydro-1 H-1 ,2,4- 1 25 473 2 tπazol-1-yl]pιpeπdιne-1- carboxylate
Figure imgf000075_0005
O butyl 4-{[3-(3-ch!oropyπdιn- f J O 4-yl)-4-(4-f!uorophenyl)-5- oχo-4 5-dιhydro-1 H-1 ,2,4-
215 ^ 1 27 487 2
*- — /) trιazol-1- yl]methyl}pιpeπdιne-1 - carboxylate
Cl r Γ (1 o ethyl [3-(3-chloropyπdιn-4- yl)-4-(4-ιsopropoxyphenyl)-
216 1 28 416 1
/^ JL ,N- 5-oxo-4,5-dιhydro-1 H-1 ,2,4-
1 tπazol-1 -yl]acetate
T il O ethyl {3-(3-chloropyrιdιn-4- yl)-5-oxo-4-[4-
217 {trifluoramethyl)pheny!]-4,5- 1 28 426 1
>N ) dιhydro-1 H-1 ,2,4-trιazol-1-
Figure imgf000075_0009
» I O yl}acetate
"Cl
Figure imgf000075_0006
% ethyl {4-[4-
(benzyloxy)phenyl]-3-(3-
21 8
Figure imgf000075_0007
^-^ A chioropyrιdιn-4-y!)-5-oxo- 1 32 464 1
N- 4,5-dιhydro-1 H-1 ,2,4-
N ^-ό tπazol-1-yl}acetate O
Figure imgf000075_0008
74 Ret
Compound Name Time MS ethyl 2-[3-{3-chlorαpyrιdιn- 4-y[)-4-(4- ιsopropoxyphenyl)-5-oxo- 1 3 430 1 4,5-dιhydro-1 H-1 ,2,4- tπazol-1 -yljpropaπoate
ethyl 2-{3-{3-chloropyπdιπ- 4-y!)-5-oxo-4-[4- (trιfIuoromethyl)pheπyl]-4,5- 1 31 440 1 dihydro-1 H-1 ,2,4-tπazol-1- yljpropanoate
ethyl 2-{4-[4-
(benzyloxy)pheπyl]-3-(3- chloropyndm-4-yl)-5-oxo- 1 34 478 1
4,5-dιhydro-1 H-1 ,2,4- tπazol-1-y[}propanoate
ethyl 4-[3-(3-chforopyridm- 4-yl)-4-(4-fluorophenyl)-5-
I N *K oxo-4,5-dιhydro-1H-1 ,2,4- 1 2 445 1 trιazoM-yl]pιpeπdιne-1- carboxylate
ethyl 4-[4-(4-chloropheπyl)-
3-{3-chloro-4-pyrιdιnyl)-5-
2
Figure imgf000076_0001
23 Λ oxo-4,5-dιhydro-1 H-1 ,2,4- 1 31 461 1
N^ tnazol-1-yl]-1- pipeπdinecarboxyiate
ethyl 4-{[3-(3-chloropyπdιn- 4-yl)^l-(4-fluorophenyl)-5- oxo-4,5-dιhydro-1 H-1,2 4-
224 1 2 459 1 trιazol-1 - yl]methyl}pιpeπdιne-1- carboxylate
fsobutyl 4-[3-(3- chloropyπdm-4-yl)-4-(4-
225 flLJθropheπyl)-5-oxo-4,5- 1 25 473 2 dιhydro-1 H-1,2,4-tπazol-1- yl]pιperιdιne-1 -carboxylate
Figure imgf000076_0002
75 Ret
Compound Name Time MS fsobutyl 4-[4-(4- chlorophenyl)-3-(3-chloro-4-
226
Figure imgf000077_0001
Λ o-
*K pyπd(nyl)-5-oxo-4,5- 1 37 489 1
O dιhydro-1 H-1,2,4-tπazo!-1- yl]-1 -pipendmecarboxy late
Figure imgf000077_0002
O' isobutyl 4-[[3-(3-
O ch[oropyπdιπ-4-yl)-4-(4- fluorophenyl)-5-oxo-4,5- 1 25 487 2
N — "Λ--»/ dιhydro-1 H-1 ,2,4-tπazol-1- yl|methyl}pιpeπdιne-1- carboxylate
O O isopropyl 4-[3-(3-
//
Figure imgf000077_0003
chioropyrιdιn-4-yl)-4-(4-
228 NΛ fluorophenyl)-5-oxo-4 5- 1 22 459 1
O dιhydro-1 H-1 2,4-trιazol-i- yl]pιperιdιne-1-carboxy[atβ
isopropyl 4-[4-(4-
Figure imgf000077_0004
chlorophenyl)-3-(3-chloro-4-
229 -NA υ PΛ pyπdιnyl)-5-oxo-4,5- 1 33 475 1
Figure imgf000077_0005
dιhydro-1H-1 ,2,4-trιazoi-1- yl]-1-pipeπdιπecarboxylate
isopropyl 4-{[3-(3- chioropyrιdιn-4-yl)-4-(4- fluoropheπyi)-5-oxo-4,5- dihydro-1 H-1,2,4-tnazol-1- 1 23 473 2 yl]meihyl}pιpeπdιne-1- carboxylate
methyl 4-[3-{3- chJorapyπdιn-4-yl)-1 -{3, 3- d[methy!-2-oxobutyl)-5-oxo- 1 27 428 1 1,5-dιhydro-4H-1 2,4- triazol-4-yl]benzoate
methyl 4-[3-(3-
^ A chloropyndin-4-yl)-4-(4- fluorophenyl)-5-oxo-4 5- 1 17 431 1
N \ / O dιhydro-1 H-1 2,4-tπazoJ-1- yl]pipendine-1 -carboxylate
Figure imgf000077_0006
76 Ret
Compound Name Time MS methyl 4-[4-{4-
0 chlorophenyl)-3-(3-ch[oro-4-
233 A N
Figure imgf000078_0002
M pyridιnyl)-5-oxo-4,5- 1 2 447 1
0 dιhydro-1 H-1 ,2,4-tπazol-i- yl]-1-pιpeπdιnecarboxylate
O N-(sec-butyl)-4-[3-(3-
HN- chloropyπdin-4"yl)-4-(4-
234 A N fluorophenyl)-5-oxo-4,5- 1 25 472 2
N O dιhydro-1 H-1 ,2,4-tπazoI-i- yl]piperιdine-1~carboxamιde
Figure imgf000078_0001
N-(sec-buty!}-4-{[3-(3- chloropyridιn-4-yl)-4-(4- ffuoropheny[)-5-oxo-4,5-
1.26 486 2 dihydro-1 H-1 ,2,4-triazol-1 - yl]methyl}pϊperidιne-1- carboxamide
N-(tert-butyl)-2-{3-(3- chloropyrιdιn-4-yl)-5-oxo-4- [4-(tπfluoromethyl)pheπyl]- 1 29 453 1 4,5-dihydrσ-1 H-1 ,2,4- tπazol-1 -yi}acetamιde
N-(tørt-buty!)-4-[3-{3-
HN- chloropyπdιn-4-yl)-4-(4-
237 fluoropheπyl)-5-oxo-4,5- 1 26 472 2
N X / C dιhydro-1 H-1 ,2,4-tπazo!-1- ylJpipeπdine-i-carboxaiTiide
N-(terf-butyl)-4-{[3-{3- ch!oropyrιdifi-4-yl)-4-(4- fluorophenyl)-5-oxo-4,5-
1 27 486 2 dihydro-1 H-1 ,2,4-trιazol-i- yl]methyl}pιpeπdiπe-1- carboxamide
N-{2-[3-(3-chloropyrιdιπ-4- y])-4-(4-ιsopropoxypheπyl)- 5-oxo-4,5-dihydro-1 H- 1 ,2,4- 1 26 443 2 trιazoI-1 -yl]ethyt}-2- methylpropanamide
Figure imgf000078_0003
77 Ret
Compound Name Time MS
N-{2-[3-(3-chlorσpyrιdιn-4- y[)-4-(4-isopropoxyphenyl}-
5-OXO-4, 5-dιhydro-1 H-1 ,2,4-
1 25 441 2 tπazol-1- yl]ethyl}cyclopropanecarbox amide
N-{2-[3-(3-chloropyrιdιn-4- yl)-4-(4-ιsopropoxypheπyl)-
5-0X0-4, 5-d[hydro-1 H-1 , 2,4- 1 28 457 2 tπazo!-1-yl]ethy[}-2,2- dimethylpropanamide
N-butyi-4-[3-(3- chloropyπdιn-4-yl)-4-{4- f!uoropheny[)-5-oxo-4,5- 1 25 472 2 dιhydro-1 H-1 ,2 4-tπazol-1 - yl]pspendine-1 -carboxamide
N-butyl-4-{[3-(3- chloropyrιdιπ-4-yl)-4-(4- fluorophenyl)-5-oxo-4,5-
243 ^»A ) 1 26 486 2 dιhydro-1 H-1 ,2,4-Eπazol-1- y!]methyl}pιperιdιπe-1 - carboxamide
O j — propyl 4-[3-(3-chloropyπdιn-
Figure imgf000079_0001
. j^ , — , o-7^ 4-y!)-4-(4-fluorophenyl)-5-
244 ϊ \—l U-I oxo-4,5-dihydro-1 H-1 ,2,4- 1 23 459 1
- N' \ / o tπazol-1-yl]pιpeπdιne-1- carboxylate
propyl 4-{[3-(3- chloropyrιdιn-4-yl)-4-(4-
245 ^^uA \ J f!uoropheny!)-5-oxo-4,5-
1^ w^ l } dihydro-1 H-1 ,2,4-tnazol-1- Λ Zό A lό Z yl]methyl}pιpeπdιne-1- carboxylate
fert-butyl (1 -{[3-{3- chloropyrιdιπ-4-yl)-4-(4-
246 "" ^^M Vn ιsopropoxyphenyl)-5-oxo-
Z4° ' M— ' — ' ^n 4,5-dιhydro-1 H-1 ,2,4- tπazol-1-yi]acetyl}pιpeπdjn- 4-yi)carbamate
Figure imgf000079_0002
78 Ret
Compound Name Time MS
F,C tert-butyl (3-{3-{3- ch!oropyπdrπ-4-yl)-5-oxo-4- [4-(trιfluoromethyi)phenyl]-
247 1 33 497 1 4,5-dιhydro-1 H-1,2 4- trιazol-1 - yl}propyl}carbamate
terf-buty! [3-(3- chloropyπdm-4-yi)-4-{4- ιsopropoxyphenyl)-5-oxo- 1 33 444 2 4,5-dιhydro-1H-1 2,4- tπazol-i-yljacetate
tert-butyl {3-(3- chloropyrιdιn-4-yl)-5-oxo-4-
[4-(tπfluoromethyl)phenyl]- 1 33 454 1
4,5-dιhydro-1H-1 ,2l4- tπazol-1-y!}acetate
terf-butyl {4-[4-
(benzyfoxy)pheny!]-3-(3- chloropyπdιn-4-yl}-5-oxo- 1 37 492 2
4,5-dιhydro-1 H-1,2,4- tπazol-1-y]}acetate
tø/t-butyi 3-[3-(3- ch!oropyπdιn-4-yl)-4-(4- fluoropheπyl)-5-oxo-4,5- 1 34 473 2 dιhydro-1 H-1 ,2,4-tnazol-1- yl]pιperιdine-1-carboxy[ate
tert-butyl 3-[3,4-bιs(4- chiorophenyJ)-5-oxo-4,5-
1 45 488 1 dιhydro-1 H-1,2,4-tπazol-1- ylj-1 -pipeπdmecarboxylate
tert-butyl 3-[4-(4- chlorophenyl)-3-{3-chloro-4- pyπdιnyl)-5-oxo-4,5- 1 37 489 1 dιhydro-1 H-1,2,4-trιazol-1- yl]-1 -pipendinecarboxylate
Figure imgf000080_0001
79 Ret
Compound Name Time MS
O terf-butyl 4-[3-(3-
Figure imgf000081_0001
^N 0- chloropyπciιn-4-yl)-4-(4-
254 uΛ A N fluorophenyl)-5-oxo-4,5- 1.33 473 2
N-<
N O dihydro-1 H-1 ,2,4-triazol-i - yl]piperidine-1-carboxylate
tert'buty! 4-[4-(4- chlorophenyi)-3-(3-cJiloro-4-
255 py rid i πy l)-5-oxo-4, 5- 1 35 489 1 dιhydro-1 H-1 ,2,4-tπazoi-1- yl]-1 -pipeπdiπecarboxylate
te/t-butyl 4-{[3-(3-
O chloropyπdιn-4-yl}-4-{4- fluoropheny[)-5-oxo-4,5-
1 34 487 2 dihydro-1 H-1 ,2,4-triazoϊ-1- yl]methyi}piperidine-1- carboxylate
ferf-butyl 4-{[3-(3- chloropyrιdin-4-yl)-4-(4-
Figure imgf000081_0002
isopropoxyphenyl)-5-oxo-
257 L ,N~Λ / — N 4,5-dihydro-1 H-1,2,4- 1.31 556.2
/W^N V-N N triazol-1- yt]acetyl}piperazιπe-1-
NV-CI carboxylate
ferf-butyl 4-{[3,4-bis(4- chlorophenyl)-5-oxo-4,5-
258 dihydro-1 H-1,2,4-tπazol-1- 1.46 502.2 yi]methyl}-1- piperidiπecarboxylate
terf-butyl 4-{3-(3- chloropyridin-4-yl)-5-oxo-4-
P
259 N^ [4-{trifiuoromethyi)phenyl]-
4,5-dihydro-1 H-1 ,2,4- 1 37 523 2 N ^ f 0 tπazol-1 -y!}pιpeπd ιπe-1 - carboxylate
Figure imgf000081_0003
80 Ret
Compound Name Time MS
2-(2-cyclohexyl-2-oxoethyl)~
O O 5-<2,4-dichloropheny[)-4-[4~
260 d K > (tπf!uoromethyl)phenyl]-2,4- 1.33 498 21 dιhydro-3H-1 ,2,4-tπazol-3- one
tert-butyl (3-{3-(2,4- dichlorophertyl)-5-oxo-4-[4-
261 (trifluorornethyl)phenyl]-4,5~ 1 36 474.96 dihydro-1 H- 1 ,2,4-triazol-i - yl}propy!)carbamate
2-[2-(1-adamantyl)-2- oxoethyl]-4-[4-
262 (benzyloxy)phenyl]-5-(3- cWoropyπdirv4-yl)-2,4- 1 44 555 15 dιhydro-3H-1 ,2,4-tπazol-3- one
5-{2,4-drchioropheny[)-2-
(3,3-dimethyl-2-oxobutyl}-4-
263 [4-(trifiuoromethyl)phenyl]- 1 41 472.03
2,4-dιhydro-3H-1 ,2,4- tπazo!-3-one
2-[2-(1-adamantyl)-2- oxoethyl]-5-{3- ch!oropyπdιn-4-yl)-4-(4-
264 ιsopropyipheπyl)-2,4- 1 45 491 15 dιhydro-3H-1 ,2r4-triazo!-3- one
Figure imgf000082_0001
81 Ret
Name Time MS
2-[2-(1-adamanty[)-2- oxoethyl]-5-{3- chloropyπdιπ-4-yl)-4-{4-
1 41 507 16 ιsopropoxyphenyl)-2,4- dιhydro-3H-1 ,2 4-tπazol-3- one
2-[2-(1-adamantyl)-2- oxoethyl]-4-(4-teri- butylphenyl)-5-(3- chloropyr!dιn-4-yl}-2,4- 1 45 505 16 d!hydro-3H-1 ,2,4-tπazol-3- one
5-(2,4-dschloropherty[)-2-(2- morpholιn-4-yl-2-oxoethyl)-
4-[4-
(tπfluoromethyJ)phenyl]-2,4- 1 24 500 97 dihydro-3H-1 ,2,4-tπazol-3- one
P-CH, 2-{3-(2[4-dich!oropheny[)-5- oxo-4-[4-
(trιfluoromethyJ)phenyl]-4,5-
1 29 503 04 dihydra-1 H-1 ,2 4-tπazoi-1- yl}-N-(2-methoxyethyl)-N- methytacetamide
5-(2,4-dιchlorophenyl)-2-(3- methyl-2-oxobutyl)-4-[4-
269 (tπfluoromethyl)phθnyl]-2,4- 1 28 480 14
CH, dthydro-3H-1 ,2τ4-tπazoJ-3- one
Figure imgf000083_0001
CJ
82 Ret
Compound Name Time MS
N-(3-{3-(2,4- dιchiorophenyl)-5-oxo-4-[4-
(tπfluoromethyl)pheπyϊ)-4,5-
270 dihydro-1 H-1,2 4-tnazol-1- 1 31 501 03 yl}propyl}-2- methylpropanamide
5-(2,4-dιch[orophenyl)-2-(2- hydroxy-3 3-dιmethylbutyf)-
4-E4-
271 1 32 473 93
(tπf[uoromethyl)phenyl]-2,4- dιhydro-3H-1 ,2,4-trιazo!-3- one
2-[(3-tert-butyi-1 ,2,4- oxadιazol-5-yl)methyl]-5-
(2,4-dιch!orophenyJ)-4-[4-
272 1 37 512 03
(trιf[uoromethy!)phenyl]-2,4- dihydro-3H-1 ,2,4-tπazo!-3- oπe
tert-butyl (3-{3-(2 4- dιchlorophenyl)-5-oxo-4-[4-
273 Ctrιfluoromethyl)phenyl]-4,5- 0 68 545 13 dιhydro-1 H-1,2,4-tπazol-1- yl}propyl)methylcarbamate
4-[4-(benzyloxy)phenyl] 5-
(3-chloropyπdιn-4-yl)-2-
274 (3,3-dιrτi8thy!-2-oxobutyl)- 1 23 477 08
CH3 2,4-dιhydro-3H-1 ,2,4-
O tπazol-3-one
Figure imgf000084_0001
83 Ret
Compound Name Time MS
Figure imgf000085_0001
O.
4-[4~(benzyloxy)plienyl]-5- (3-chioropyrιdin-4-yl)-2-(2-
275
Figure imgf000085_0002
A cyclohexylethyl)-2,4- 1.36 489 13
Figure imgf000085_0004
dιhydro-3H-1 ,2,4-triazo!-3- one
Figure imgf000085_0003
,u l CH, 3-(2,4-dιchlorophenyl)-N-
Λ ιsopropyl-5-oxo-4-[4-
276 r< (trif!uoromethy[)phenyl]-4,5- 1 34 458.97 CH, dihydro-1 H-1 ,2,4-triazo(e-1 - carboxamide
5-(3-ch[oropyιϊdϊn-4-yl)-2- (2"Cyclohexylethy[)-4-(4-
277 isopropylpheπyl)-2,4- 1 36 425 13 dihydro3H-1 ,2,4-tπazol-3- oπe
5-(3-chloropyridιn-4-yl)-2- (3,3-dιmethyi-2-oxobutyl)-4-
278 (4-isopropylphenyi}-2,4- 1 22 413 09 dιhydro-3H-1 ,2,4-tπazol-3- one
5-(2,4-dichlorophenyl)-2-{2- oxobuEyl)-4-[4-
279 (tπfluoromethyl)phenyl]-2,4- 1 3 444.02 dιhydro-3H-1 ,2,4-trιazol-3- oπe
Figure imgf000085_0005
84 Ret
Compound Name Time MS
5-(3-chloropyπdιr>4-yl)-2-
(2-cyclohexyl-2-oxoethyl)-4-
280 [4-(tπfluoromethyl)phenyl]- 1 24 487 23
2 4-dιhydro-3H-1 ,2,4- tπazoi-3-one
tert-butyl {3-[4-(4- chlorophenyl)-3-(2,4-
281 dιchlorophenyl)-5-oxo-4,5- 0 56 497 08 dihydro-1H-1,2,4-tπazoi-1- y[Jpropy!}carbamate
5-(2,4-dιchlorophenyl)-2-(2- oxopropyl)-4-[4-
282 (trιfluoromethyt)pheπyl]-2,4- 1 28 430 01 dιhydro-3H-1 ,2,4-trtazo!-3- one
Figure imgf000086_0001
CH,
4-(4-tert-butylphenyl)-5-(3- chloropyπdιπ-4-yl)-2-(3,3-
283 dιmethyl-2-oxobutyl)-2,4- 1 24 427 12 dιhydro-3H-1 ,2,4-tπazol-3- one
5-(3-chloropyπdιn-4-yl)-2- (2-cyclohexylethyl)-4-(4-
284 . N-^^A^J ιsopropoxyphenyl)-2,4- 1 33 441 09 dιhydro-3H-1 2,4-trιazol 3- one
Figure imgf000086_0002
85 Ret
Compound Name Time MS
4-(4-tert-bu£ylphenyl)-5-(3- chloropyrιdm-4-yi)-2-{2-
285 cyclohexy[ethyl)-2,4- 1 38 439 15 dιhydro-3H-1 ,2 4-tπazol-3- one
Figure imgf000087_0001
5-(3-ch ioropyπd ιn-4-y l)-2-
{2-hydroxy-3,3- dιmethylbutyl)-4-[4-
286 H=C 1 33 441 08
(tπfluoromethyl)pheπyl]-2,4- dιhydro-3H-1 ,2,4-tπazol-3- one
N-(3-{3-(2,4- dιchloropheπyi)-5-oxo-4-[4-
287 (tπfluoromethy!)phenyl]-4,5- 1 3 487 01 dιhydro-1 H-1 ,2,4-tπazol-1- y[}propyl)propanamιde
2-{3-(2,4-dichlorophenyl)-5- oxo-4-[4-
(trιfluoromethyl)phenyl]-4,5-
288 1 28 515 01 dιhydro-1 H-1 ,2,4-tπazol-1- yl}-N-(tetrahydro-2H-pyran-
4-y[)acetamιde
2-{3-{2,4-dιchlorophenyl}-5- oxo-4-[4-
289 (trιfliJoromethyl)pheπyl]-4,5-
1 29 503 01 dιhydro-1 H-1 ,2,4-tπazol-1- yl}-N-(2- ethoxyethyl)acetam)de
Figure imgf000087_0002
Ret
Compound Name Time MS
N-(3-{3-(3-chloropyπdιn-4- y[)-5-oxo-4-[4-
(tπfluoromethyl)phenyl]-4,5-
290 dιhydro-1 H-1 ,2,4-tπazo!-1- 1 27 508 12 yl}propy!)cyclohexanecarbo xamide
N-{3-{3-(2,4- dichlorophenyl}-5-oxo-4-[4-
(trιfluoromethyl)pheπyl]-4,5-
291 1 35 541 06 dιhydro-1 H-1 ,2,4-trιazol-1- yl}propyl)cyc!ohexanecarbo xamide
2-[2-(4-cyc[obutylpιperazιn-
1-y[)-2-oxoethyl]-5-(2,4- d)chlorophenyl)-4-[4-
292 1 17 554 25
{trιfluoromethyl)phenyl]-2,4- dιhydro-3H-1 ,2,4-tπazol-3- one
5-(3-chloropyrιdιn-4-yl)-4-
[4-
(dιfluoromethoxy}phenyi]-2-
293
(3,3-dimethyl-2-αxobutyl)- 1 28 437 08
2,4-dihydro-3H-1 ,2,4- tnazol-3-one
N-(3-{3~(2l4- dιchlorophenyl)-5-oxo-4-[4-
(tπfluoromethyl)phenyl]-4,5-
294 1 57 515 12 dιhydro-1 H-1 ,2,4-tπazol-1- yl}propyl)-N,2-
N-CK dimethylpropanamide
Cl
Figure imgf000088_0001
O
87 Ret
Compound Name Time MS
2-{3-(2,4-dιchSorophenyl)-5- oxo-4-[4-
(trifiuoromethyl)phenyl]-4,5-
295 1.3 503 03 dihydra-1 H-1 ,2,4-triazoi-1- yl}-N-(2-methoxy-1- methylethyl)acetam!de
methyl 3-{3-(2,4- dιchlorophenyl)-5-oxo-4-[4-
296 (tnfluoromethy!)pheny!j-4, 5- 1 32 459 95 dιhydro-1 H-1,2,4-tπazol-1- yljpropanoate
3~(3-{3-(2,4- dichlorophenyl)-5-oxo-4-[4-
297 (trifluoromethyl)pheπyl]-4,5- 1.29 502 01 dihydro-1 H-1,2,4-tπazo!-1- yl}propyl)-1 ,1-dimethylurea
N-(3-{3-(2T4- dichlorophenyl)-5-oxo-4-(4-
298 (tπfluoromethyl)phenyl]-4,5- 1 28 473 00 dιhydro-1 H-1 ,2,4-tπazol-1 - yl}propyl)acetamιde
N-(3-{3-(2;4- dichlorophenyl)-5-oxo-4-[4-
(tπfluoromethyl}phenyl]-4,5-
299 1.1 501 10 dιhycfro-1 H-1 ,2,4-tπazol-i- yl}propyl)-N-
N-CH, methylpropanamide
Cl
Figure imgf000089_0001
0 Ret
Compound Name Time MS
,0 N-(3-{3-(2,4- dichlorophenyl)-5-oxo-4-[4-
{tπfluoromethyl)phenyij-4,5- dR7 nft dιhydro-1 H-1,2 4-tπazol-1- 1 19 48? °8 yl}propyl)-N- methylacetamide
2-[3-(4-chlorophenyl)-3- oxopropyl]-5-(3- chloropyrιdιn-4-yl)-4-(4-
!Sopropoxypheπyl)-2,4- 1 25 496 98 dιhydro-3H-1 ,2,4-tπazol-3- one
3-(3-chloropyndin-4-yl)-5- oxo-N-propyl-4-[4-
{trιfluoromethyl)phenylj-4,5- 1 25 426 07 dιhydro1 H-1,2,4-tπazole-1- carboxamide
ethyl {3-(2,4- dichlorophenyl)-5-oxo-4-[4- (trιfluoramethyl)phenyl]-4,5- 1 31 460 00 dιhydro-1 H-1 ,2 4-tπazol-1- yl}acetate
P-CH, 2-{3-(2,4-dιch!orophenyl)-5- oxo-4-[4-
<trifluoromethyl)pheny)3-4,5- Λ 97 ΛΆQ ni dιhydra-1 H-1 2,4-tnazol-i- yl}-N-(2- methoxyethy!)acetamιcle
Figure imgf000090_0001
89 Ret
Compound Name Time MS
F. f
5-(3-chloropyπdιn-4-y[)-2-
CH, (3-methyl-2-oxobutyl)~4-[4-
305 (trιfluoromethyl)pheny[]-2,4- 1 18 447 18 dιhydro-3H~1,2 4-tπazol-3- oπe
5-(3,5-d!chloropyrιdin-2-yl)-
2-(3,3-dimethyl-2-oxobutyl)-
4-[4-
306 1 34 473 10
(tπfϊuoromethyl)pheπyl]-2,4-
O dιhydro-3H-1 ,2,4-tπazol-3- one
Figure imgf000091_0001
1-(3-{3-(2,4- dichloropheπyl)-5-oxo-4-[4-
(tπf!uoromethyl)phenyl]-4,5-
307 dιhydro-1H-1,2,4-trιazo!-1- 1 52 516 11 yl}propyl)-1 ,3,3- tπmethylurea
Figure imgf000091_0002
Cl ^
H3C Xo
N-(3-{3-(3-chIoropyndin-4- yl)-5-oxo-4-[4-
(tnfluoromethy[)pheny!]-4,5-
308 1 25 482 11
CH, dihydro-1 H-1 ,2,4-tnazol-1-
H3C -,^ / yl}propyl)~212- dimethylpropanamide
2-[(3-tert-butyl-1 2,4- oxadιazol-5~y!)methy!]-5-(3- chloropyrιdιn-4-y!)-4-[4-
309 1 27 479 07
(tπfluoromethyl)phenyl]-2,4- dιhydro-3H-1 ,2,4-trιazol-3- one
Figure imgf000091_0003
90 Ret
Compound Name Time MS
4-{4-chlorophenyi)-5-(3- chloropyndin-4-yl)-2-(2-
3 1 0 H3C hydroxy-3,3-d!methylbutyl)- 1 21 407 02
2,4-dihydro-3H-1 ,2,4- trιazol-3-oπe
5-(2,4-dιchlorophenyl)-2-{3-
[methyl(propyl)amino]propyl
}-4-[4-
31 1 25 487 15
(trιfluoromethyl)phenyl]-2,4- dιhydro-3H-1 ,2,4-tπazol-3-
N-CH3 one
tert-butyl {3-(3,5- dιchloropyπdιn-2-yl)-5-oxo-
4-[4-
312 O 1 35 433 05
(tπfluoromethyl)pheπyl]-4,5- dιhydro-1 H-1 ,2,4-tπazol-1-
O CH, yl}acetate
Figure imgf000092_0001
"Cl
.CH, 3-(3-chlorapyπdιn-4-yl)-N- isopropyl-5-oxo-4-[4-
313 N (tnfluoramethyl)phenyl]-4,5- 1 26 426 06
N-^ CH3 dιhydro-1 H-1 ,2 4-trιazoie-1- N o carboxamide
3-(3-chlorαpyπdιπ-4-yl)-N- cyclohexyl-5-oxo-4-[4-
314 N (tπfluoromethyl)phenyl]-4 5- 1 32 466 08
Figure imgf000092_0003
dihydro-1 H-1 ,2,4-:πazole-1 -
N o carboxamide
Figure imgf000092_0002
91 Ret
Compound Name Time MS
5-{3-chloropyrrdιn-4-yl)-4-
[4-
(difluoromethoxy)phenyl]-2-
{2-hydroxy-3,3- 1 19 439 04 dιmethylbutyl)-2,4-dιhydro-
3H-1,2,4-triazol-3-one
5-(3,5-dιchloropyπdιn-2-yl)- 2-(2-oxobutyl)-4-[4- {tπfluoromethyl)pheny[]-2,4- 1 29 445 08 dιhydro-3H-1 ,2,4-tπazol-3- one
5-(2,4-dichloropheny[)-2-{3-
[ethyl(methyj)amιno]propyl}-
4-[4-
1 24 473 14
(trιfluoromethyl)phenyl]-2,4- dιhydro-3H-1 ,2,4-tπazol-3- one
2-{3-{3,5-dιchloropyπdιn-2- yl)-5-oxo4-[4- (tπfluoromethyl)phenyl]-4τ5- 1 29 488 11 dihydro-1 H-1 ,2 4-triazol-1- y[}-N, N-diethylacetamide
4,5-bιs(4-chlorophenyl)-2- (2-hydroxy-3,3-
1 29 406 04 dιmethylbutyl)-2,4-dιhydro-
CH, 3H-1.2 4-tπazoi-3-one
CK
Figure imgf000093_0001
92 Ret
Compound Name Time MS
5-(3-chloropyπdιn-4-yl)-2- {2-oxobutyi)-4-[4-
320 (tπfluorofnethyl)phenyl]-2,4- 1.19 411 02 dihydro-3H-1 ,2,4-tπazol-3- one
ethyl 2-{3-{3,5- dichloropyrιdιn-2-yl)-5-oxo-
Figure imgf000094_0001
4-[4-
321 Λ CH,
1 33 475 08
V-CH3 (trifluoromethyl)phenyl]-4,5- dιhydro-1 H-1 ,2,4-triazo!-1- yljprapanoate
5-(3-chloropyπdιπ-4-yl}-4-
[4-
Figure imgf000094_0002
(dιfliioromethoxy)phenyl]-2-
322 A 1 08 466 01
(2-morphohn-4-yl-2- oxoethyl)-2,4-dιhydro-3H-
1 ,2,4-tπazo[-3"θne
N-(2-{3-(3-ch!oropyπdιn-4- yl)-5-oxo-4-[4-
(tπfiuoromethyl)pheπyl]-4,5- . __ .q . . -
323 dihydro-1 H-1 ,2,4-tr!azoI-1-
Figure imgf000094_0003
y!}ethyl)cyclohexanecarbox nr amide
Cl
5-(3-chloropyπdm-4-yl)-2- [2-{4-cyclobutylpiperazin-1 - yl)-2-oxoethyl]-4-[4-
324 (tπfluoromethy[)pheπyi]-2,4- 1.1 521 10 dιhydro-3H-1 ,2,4-tπazol-3- one
Figure imgf000094_0004
93 Ret
Compound Name Time MS
F .F
N-(2-{3-(3-chloropyndm-4-
Q
CH3 yl)-5-oxo-4-[4-
(tπf[uoromethyi)phenyl]-4,5-
1 24 468 10 d!hydro-1 H-1 ,2 4-tπazol-1- yl}ethyl)-2,2- dimethylpropaπamide
5-{3-chloropyπdm-4-yl)-4-
(4-fluorophenyl)-2-(2- hydroxy-3,3-dιmethylbu"tyl)- 1 29 391 10
2,4-dιhydro-3H-1 ,2,4- tπazoϊ-3-oπe
5-(2,4-dιcli!oiOphenyl)-2-[3- (dιmethylamιno)propyl]-4- [4-(trιfluoromethyl)phenyl]- 1 24 459 13 2,4-dιhydro-3H-1,2 4- trιazol-3-one
4-(4-chloropheny!)-5-(3- chloropyπdιn-4-yl)-2-[3- (tπfluoromethyl)pyrιdιn-2- 1 23 451 99 yl]-2 4-dihydro-3H-1 ,2,4- trrazol-3-one
2-{3-(3-chloropyrιdm-4-yl)-
5-oxo4-[4-
{tnfluoromethyl)phenyl]-4,5-
1 18 482 06 dιhydro-1 H-1 2,4-tnazol-i- yl}-N-(tetrahydro-2H-pyran-
4-yl)acetamide
N-{3-{3-(3-chloropyπdιπ-4- yl)-5-oxo-4-[4-
{tπfluorometJiyl)phenyf]-4,5-
330 1 2 510 11 dιhydro-1 H-1 ,2,4-trιazol-i- yl}propyl)tetrahydro-2H- pyran-4-carboχamιde
Figure imgf000095_0001
94 Ret
Compound Name Time MS
3-{3-(2,4-dιchlorophenyi)-5- oxo-4-[4-
331 (tπf!uoromethyl)phenyl]-4 5- 1 29 445 94 dιhydro-1 H-1 ,2 4-trιazoi-1- yljpropanojc acid
5-{2,4-dιchlorophenyl)-2-[3- (methylamino)propyl]-4-[4-
332 (trrfluorornethyl)pheny!]-2 4- 1 16 445 07 dfhydro-3H-1 ,2,4-tπazol-3- one
5-(3-chtoropyrιd!n-4-y!)-2-
(2-oxopropyl}-4-[4-
333 (tπfl uoro methyl) phenyl]-2,4- 1 16 397 05 dshydro-3H-1 ,2,4-tπazol-3- oπe
5-(3-chloropyπdιn-4-yl)-2- (3-ethyfpyrazm-2-yi)-4-[4-
334 (trιfluoromethyl)phenyl]-2 4- 1 24 447 02 dihydro-3H-1 ,2 4-trιazol-3- one
5-(2 4-dιchlorophenyl)-2- (3 3-dpmethyl-2-oxobutyl)-4-
335 [6-(trιfluoromethyl)pyπdιn-3- 1 3 473 00 yl]-2 4-dιhydro-3H-1 ,2,4- trιazol-3-oπe
Figure imgf000096_0001
-c\
95 Ret
Compound Name Time MS
5-{2,4-dιchlorophenyl)-2-(2- morpholin-4-yl-2-oxoethyl)- 4-[6-(trifluoromethyl)pyridin- 1 23 501 99 3-y|]-2,4-dιhydro-3H-1 ,2,4- tria∑ol-3-one
ethy! {3-(2,4- dιchlorophenyi)-5-oxo-4-[6-
(trifluoromethyl)pyridin-3- 1 29 460.98 ylH.S-dihydro-I H-i^^- triazo[-1-yl}acetate
4-(5-ch!oropyridin-2-yl)-5- (2,4-dichtorophenyl)-2-(3,3- dimethyl-2-oxobutyl}-2,4- 1.29 439 00 dihydro-3H-1 ,2,4-tπazol-3- one
5-{2,4-dichlorophenyl)-2- (3 , 3-dimethyJ-2-oxob utyl )-4- [5-(trif!uoromethyl)pyridin-2- 1 36 473.00 y[]-2,4-dihydro-3H-1 ,2,4- tπazol-3-one
4-(5-chloropyridiπ-2-yl)-5-
(2,4-dιchloropheπyl)-2-(2-
340 morpholiπ-4-y[-2-oxoethyl)- 1 2 468 00
2,4-dιhydro-3H-1 ,2,4- tπazol-3-one
Figure imgf000097_0001
96 Ret
Compound Name Time MS
O tert-butyl {3-(2,4- dιchlorophenyl)-5-oxo-4-[5-
34] O. CH3 (tπfluoromethyl)pyπdιn-2- 0 54 489 06 yl]-4 5-dιhydro-1H-1 ,2,4- tπazol-1-yl}acetate
5-(2,4-dichlorophenyl)-2-(2- oxobutyl)-4-[5-
342 (tπfluoromethyl)pyrιdιn-2- 0 54 445 04 yl]-2,4-dihydro-3H-1 ,2,4- tπazol-3-one
2-{3-(2,4-dιchloropheπyl}-5- oxo-4-[5-
(tπfluoromethyl)pyrιd[n-2-
343 0 76 488 08 yl]-4,5-dιhydro-1H-1 2,4- trιazol-1-y!}-N,N- diethylacetamide
5-(2,4-dιchlorophenyl}-2-(2- morpholιn-4-y!-2-oxoethyl)-
344 4-[5-(tnfluoromethyl)pyndrn- 1 28 501 98 2-yl]-2 4-dihydro-3H-1,2,4- trιazol-3-one
ethyl 2-{3-(2,4- dιchlorophenyl)-5-oxo-4-[5-
345 OχyCH3 {tnfluoromethyl)pyndirt-2- 0 72 475 05 yl]-4,5-dιhydro-1 H-1 ,2,4-
O tπazol~1-yl}propaπoate
Figure imgf000098_0001
-a
97 Ret
Compound Name Time MS
4-{3-chloropyridin-4-yl)-2-
H3C PH UX\ >^/
(2-hydroxy-3,3-
H3C Cl dimethylbutyl)-5-[4-
346 1.26 359.18
H3C (trifluorometrιy!)phenyi]-2,4- dihydro-3H-1 ,2,4-triazol-3- one
Figure imgf000099_0001
CH3 5-{2,4-dichloropheπyl)-2-
(3,3-drmethyl-2-oxobuty[)-4-
347 [6-(trifluoromethyl)pyridin-3- 1.3 473.00 yl]-2,4-dihydro-3H-1 ,2,4- triazol-3-oπe
5-(2,4-dichlorophenyl}-2-{2~ morprιolιn-4-yl-2-oxoethyi)-
348 4-[6-(trif[uoromethyl)pyridin- 1.23 501. 3-y[]-2,4-dihydro-3H-1 ,2,4- triazol-3-one
ethyl {3-(2,4- dichlorophenyl)-5-oxo-4-[6-
349 (trifluoromethyl)pyridin-3- 1.29 460.98 yl]-4,5-dihyciro-1 H-1 ,2,4- triazoi-1-yl}acetate
-Cl
Figure imgf000099_0002
EXAMPLE 10. BACULOVIRAL PREPARATIONS FOR CB l EXPRESSION
This Example illustrates the preparation of recombinant baculovirus for use in generating CBl -expressing insect cells.
The human CB l sequence has GenBank Accession Number HSU73304, and was reported by Hoehe et al. ( 1991) New Biol 3^:880-85. Human CBl (hCB l ) cDNA is amplified from a human brain cDNA library (Gibco BRL, Gaithersburg, MD) using PCR, in which the 5' primer includes the optimal Kozak sequence CCACC. The resulting PCR product is cloned into pcDNA3.1/V5-His- TOPO (Invitrogen Corp, Carlsbad, CA) using the multiple cloning site, and then subcloned into
98 pBACPAKs (BD Biosciences, Palo Alto, CA) at the Bam/Xho site to yield a hCB l bacuioviral expression vector.
The hCB l bacuioviral expression vector is co-transfected along with BACULOGOLD DNA
(BD PharMingen, San Diego, CA) into S/9 cells. The S/9 ceil culture supernatant is harvested three
5 days post-transfection. The recombinant virus-containing supernatant is serially diluted in Hink's
TNM-FH insect medium (JRH Biosciences, Kansas City, MO) supplemented with Grace's salts and with 4. ImM L-GIn, 3.3 g/L LAH. 3.3 g/L ultrafiltered yeastolate and 10% heat-inactivated fetal bovine serum (hereinafter "insect medium") and plaque assayed for recombinant plaques. After four days, recombinant plaques are selected and harvested into 1 ml of insect medium for amplification. Each 1
10 ml volume of recombinant baculovirus (at passage 0) is used to infect a separate T25 flask containing 2 x 10 S/9 cells in 5 mi of insect medium. After five days of incubation at 27 0C, supernatant medium is harvested from each of the T25 infections for use as passage 1 inoculum.
Two of seven recombinant bacuioviral clones are then chosen for a second round of amplification, using 1 ml of passage 1 stock to infect 1 x 10s cells in 100 ml of insect medium divided 15 into 2 T175 flasks. Forty-eight hours post infection, passage 2 medium from each 100 ml preparation is harvested and plaque assayed for titer. The cell pellets from the second round of amplification are assayed by affinity binding as described below to verify recombinant receptor expression. A third round of amplification is then initiated using a multiplicity of infection of 0.1 to infect a liter of S/9 cells. Seventy-two hours post-infection the supernatant medium is harvested to yield passage 3 20 bacuioviral stock.
The remaining cell pellet is assayed for affinity binding. Radioligand is 25pM-5.0nM [ H]CPSS, 940 for saturation binding and 0.SnM for competition binding (New England Nuclear Corp., Boston, MA); the hCB l -expressing baculoviral cells are used; the assay buffer contains 50 itiM Tris pH 7.4, 12OmM NaCl, 5 mM MgCl2, 0.5% BSA and 0.2 nig/ml bacitracin; filtration is carried out 25 using GF/C WHATMAN filters (presoaked in 0.3% non-fat dry milk (H2O) for 2 hours prior to use); and the filters are washed twice with 5 mL cold 5OmM Tris pH.7.4.
Titer of the passage 3 bacuioviral stock is determined by plaque assay and a multiplicity of infection, incubation time course, binding assay experiment is carried out to determine conditions for optimal receptor expression.
30 EXAMPLE 1 1. BACULOVIRAL INFECTIONS
Log-phase S/9 cells (Invitrogen Corp., Carlsbad, CA). are infected with one or more stocks of recombinant baculovirus followed by culturing in insect medium at 27 0C. Infections are carried out either only with virus directing the expression of hCBl or with this virus in combination with three G- protein subunit-expression virus stocks: I) rat Gαi2 G-protein-encoding virus stock, 2) bovine βl G- 35 protein-encoding virus stock, and 3) human γ2 G-protein-encoding virus stock, all of which are obtained from Biosignal Inc., Montreal, Canada.
99 Typical hCB l infections are conducted using Sf9 cells that are cultured in insect medium supplemented with 10% heat-inactivated fetal bovine serum (FBS) as discussed above. Higher receptor and G-prolein (Ga, Gβ, Gγ) expression can be obtained if the Sf9 cells are cultured in insect medium with 5% FBS and 5% Gibco serum-free medium (Invttrogen Corp.; Carlsbad, CA). Maximal 5 CB l expression and functional activity is achieved if the Sf9 cells are cultured in insect medium without FBS and with 10% Gibco serum-free medium. The infections are carried out at a multiplicity of infection of 0.1 : 1.0:0.5:0.5. At 72 hours post-infection, a sample of cell suspension is analyzed for viability by trypan blue dye exclusion, and the remaining S/9 cells are harvested via centrifugation (3000 rpm/ 10 min/ 4 °C).
10 EXAMPLE 12. PURIFIED RECOMBINANT INSECT CELL MEMBRANES
S/9 cell peliets are resuspended in homogenization buffer (10 mM HEPES, 250 mM sucrose, 0.5 μg/mi leupeptin, 2 μg/ml Aprotinin, 200 μM PMSF, and 2.5 mM EDTA, pH 7.4) and homogenized using a POLYTRON homogenizer (setting 5 for 30 seconds). The homogenale is centrifuged (536 x g/ 10 min/ 4 0C) to pellet the nuclei. The supernatant containing isolated membranes is decanted to a
15 clean centrifuge tube, centrifuged (48,000 X g/ 30 min, 4 0C) and the resulting pellet resuspended in 30 ml homogenization buffer. This centrifugation and resuspension step is repeated twice. The final pellet is resuspended in ice cold Dulbecco's PBS containing 5 mM EDTA and stored in frozen aliquots at -80 0C until needed. The protein concentration of the resulting membrane preparation (hereinafter V'P2 membranes") is measured using a Bradford protein assay (Bio-Rad Laboratories, Hercules, CA). 20 By this measure, a 1 -liter culture of cells typically yields 100-150 mg of total membrane protein.
EXAMPLE 13. RADIOLIGAND BINDING ASSAYS
P2 membranes are resuspended by Dounce homogenization (tight pestle) in binding buffer (50 mM Tris pH. 7.4, 12OmM NaCI, 5 mM MgCl2, 0.5% BSA and 0.2 mg/ml bacitracin).
For saturation binding analysis, membranes (10 μg) are added to polypropylene tubes
25 containing 25pM-0.5nM [~ H]CP55,940 (New England Nuclear Corp., Boston, MA). Nonspecific binding is determined in the presence of lOμM CP55,940 (Tocris Cookson Inc., Ellisville, MO) and accounts for less than 10% of tota! binding. For evaluation of guanine nucleotide effects on receptor affinity, GTPγS is added to duplicate tubes at the final concentration of 50 μM.
For competition analysis, membranes (10 μg) are added to polypropylene tubes containing
30 0.5nM [Η]CP55,940. Non-radiolabeled displacers are added to separate assays at concentrations ranging from 10"!0 M to 10"' M to yield a final volume of 0.250 mL. Nonspecific binding is determined in the presence of l OμM CP55,940 and accounted for less than 10% of total binding.
Following a one-hour incubation at rt, the reaction is terminated by rapid vacuum filtration. Samples are filtered over presoaked (0.3% non-fat dry milk for 2 hours prior to use) GF/C WHATMAN filters
35 and rinsed 2 times with 5 mL cold 5OmM Tris pH 7.4. Remaining bound radioactivity is quantified by
100 gamma counting. Kj and Hill coefficient ("nH") are determined by fitting the Hill equation to the measured values with the aid of SIGMAPLOT software (SPSS Inc., Chicago, IL).
EXAMPLE 14. AGONIST-INDUCED GTP BINDING
This Example illustrates the use of agonist-stimuϊated GTPy55S binding (''GTP binding")
5 activity to identify CBl agonists and antagonists, and to differentiate neutral antagonists from those that possess inverse agonist activity. This assay can also be used to detect partial agonism mediated by antagonist compounds. A compound being analyzed in this assay is referred to herein as a "test compound." Agonist-stimulated GTP binding activity is measured as follows: Four independent baculoviral stocks (one directing the expression of hCB l and three directing the expression of each of
10 the three subunits of a heterotrimeric G-protein) are used to infect a culture of 5/9 cells as described in
Example 1 1.
Agonist-stimulated GTP binding on purified membranes (prepared as described in Example
12) is initially assessed using the cannabinoid agonist CP55,940 to ascertain that the receptor/G- proteiπ-alpha-beta-gamma combination(s) yield a functional response as measured by GTP binding.
15 P2 membranes are resuspended by Dounce homogenization (tight pestle) in GTP binding assay buffer (50 itiM Tris pH 7.4, 120 niM NaCl5 5 mM MgCl2, 2 mM EGTA, 0.1% BSA, O.I niM bacitracin, lOOKIU/mL aprotinin, 5 μM GDP) and added to reaction tubes at a concentration of 10 μg protein/reaction tube. After adding increasing doses of the agonist CP55,940 at concentrations ranging from 10"12 M to 10"6 M, reactions are initiated by the addition of 100 pM GTPy13S. In competition
20 experiments, non-radiolabeled test compounds are added to separate assays at concentrations ranging from 10"!0 M to 10'5 M along with 1 nM CP55,940 to yield a final volume of 0.25 mL.
Following a 60-minute incubation at room temperature, the reactions are terminated by vacuum filtration over GF/C filters (pre-soaked in wash buffer, 0.1% BSA) followed by washing with ice-cold wash buffer (50 mM Tris pH 7.0, 12OmM NaCl). The amount of receptor-bound (and thereby
25 membrane-bound) GTPy55S is determined by measuring the bound radioactivity, preferably by liquid scintillation spectrometry of the washed filters. Non-specific binding is determined using 10 mM
GTPy33S and typically represents less than 5 percent of total binding. Data is expressed as percent above basal (baseline). The results of these GTP binding experiments are analyzed using
SIGMAPLOT software and ICJO determined. The IC50 may then be used to generate K, as described
30 by Cheng and Prusoff (1973) Biochem Pharmacol 22(23J:3099- 108.
Alternatively the data is analyzed as follows. First, the average bound radioactivity from negative control wells (no agonist) is subtracted from the bound radioactivity detected for each of the other experimental wells. Second, average bound radioactivity is calculated for the positive control wells (agonist wells). Then, percent inhibition for each compound tested is calculated using the
35 equation:
101 n 4 T u-i v i nn i nn F Bound radioactivity in Test Wells "]
Percent Inhibition = 100 - 100 x — — . . . — . ... ..
L Bound radioactivity in Agonist Weils J
The % inhibition data is plotted as a function of test compound concentration and test compound IC50 is determined using a linear regression in which x is ln(concentration of test compound) and y is ln(percent inhibition/(100 - percent inhibition). Data with a percent inhibition that is greater than 90% or less than 1 5% are rejected and are not used in the regression. The IC50 is c (-miercepi/slopej
Neutral antagonists are those test compounds that reduce the CP55,940-stimulated GTP binding activity towards, but not below, baseline (the level of GTP bound by membranes in this assay in the absence of added CP55,940 or other agonist and in the further absence of any test compound).
In contrast, in the absence of added CP55,940, CBl inverse agonists reduce the GTP binding 10 activity of the receptor-containing membranes below baseline. If a test compound that displays antagonist activity does not reduce the GTP binding activity below baseline in the absence of the CBl agonist, it is characterized as a neutral antagonist.
An antagonist test compound that elevates GTP binding activity above baseline in the absence of added CP55.940 in this GTP binding assay is characterized as having partial agonist activity.
15 Preferred CB l antagonists do not elevate GTP binding activity under such conditions more than 10%, more preferably less than 5% and most preferably less than 2% of the maximal response elicited by the agonist, CP55,940.
The GTP binding assay can also be used to determine antagonist selectivity towards CBl over
CB2. Agonist-stimulated GTP binding activity at CB2 is measured as described above for CBl except
20 that the Sf) cells are infected with one baculoviral stock directing the expression of hCB2 and three directing the expression of each of the three subunits of a heterotrimeric G-protein. The IC50 and K; are generated as described above for CB l .
EXAMPLE 15. SURMOUNTABILITY ASSAYS
Certain CB 3 antagonists are insurmountable with regard to the agonist induced GTPy35S
25 binding effect. To assess surmountability, P2 membranes are resuspended by Dounce homogenization (tight pestle) in GTP binding assay buffer (50 mM Tris pH 7.4, 120 niM NaCI, 5 mM MgCI2, 2 mM EGTA, lOμg/ml saponin, 0.1 % BSA, 0.1 mM bacitracin, 100KiU/mL aprotinin, 5 μM GDP) and added to reaction tubes at a concentration of 10 μg protein/reaction tube. Agonist dose-response curves (typically CP55,940) at concentrations ranging from 10"12 M to lO"3 M, are run either in the
30 absence or in the presence of a test compound at one of several doses up to IOOX the IC50 of the test compound as measured in the competition GTPyj:!S binding. The reactions are initiated by the addition of 100 pM GTPy33S to yield a final volume of 0.25 mL. Following a 90-minute incubation at it, the reactions are terminated by vacuum filtration over GF/C filters (pre-soaked in wash buffer, 0.1 % BSA) followed by washing with ice-cold wash buffer (50 mM Tris pH 7.0, 12OmM NaCl). The
102 amount of receptor-bound (and thereby membrane-bound) GTPy33S is determined by measuring the bound radioactivity, preferably by liquid scintiliation spectrometry of the washed filters. Non-specific binding is determined using 10 μM GTPγS and typically represents less than 5 percent of total binding. Data is expressed as percent above basal (baseline). The results of these GTP binding experiments 5 may be conveniently analyzed using SIGMAPLOT software. A surmountable test compound is one which shifts the EC30 of the agonist to the right (weaker) without affecting the maximum functional response of the agonist. Insurmountable antagonist test compounds have no significant effect on the hCB l agonist EC50 at concentrations roughly 10OX the IC50, but significantly reduce or eliminate the agonist stimulated GTPγ S binding response of the receptor.
10 EXAMPLE 16. MDCK CYTOTOXICITY ASSAY
This Example illustrates the evaluation of compound toxicity using a Madin Darby canine kidney (MDCK) ceil cytotoxicity assay.
1 μL of test compound is added to each weϊl of a clear bottom 96-well plate (Packard, Meriden, CT) to give final concentration of compound in the assay of 1 0 μM, 100 μM or 200 μM. 15 Solvent without test compound is added to control wells.
MDCK ceils, ATCC no. CCL-34 (American Type Culture Collection, Manassas, VA), are maintained in sterile conditions following the instructions in the ATCC production information sheet.
Confluent MDCK ceils are trypsinized, harvested, and diluted to a concentration of 0.1 x 106 cells/mL with warm (370C) medium (VITACELL Minimum Essential Medium Eagle, ATCC catalog # 30-
20 2003). 100 μL of diluted cells is added to each well, except for five standard curve control wells that contain 100 μL of warm medium without cells. The plate is then incubated at 370C under 95% O2, 5%
CO3 for 2 hours with constant shaking. After incubation, 50 μL of mammalian ceil lysis solution
(from the Packard (Meriden, CT) ATP-LITE-M Luminescent ATP detection kit) is added per well, the wells are covered with PACKARD TOPSEAL stickers, and plates are shaken at approximately 700
25 rpm on a suitable shaker for 2 min.
Compounds causing toxicity will decrease ATP production, relative to untreated cells. The ATP-LITE-M Luminescent ATP detection kit is generally used according to the manufacturer's instructions to measure ATP production in treated and untreated MDCK cells. PACKARD ATP LITE-M reagents are allowed to equilibrate to rt. Once equilibrated, the lyophilized substrate solution 30 is reconstituted in 5.5 πiL of substrate buffer solution (from kit). Lyophilized ATP standard solution is reconstituted in deionized water to give a 10 mM stock, For the five control wells, 10 μL of serially diluted PACKARD standard is added to each of the standard curve control wells to yield a final concentration in each subsequent well of 200 nM, 300 nM, 50 nM. 25 nM, and 12.5 nM. PACKARD substrate solution (50 μL) is added to all wells, which are then covered, and the plates are shaken at 35 approximately 700 rpm on a suitable shaker for 2 min. A white PACKARD sticker is attached to the bottom of each plate and samples are dark adapted by wrapping plates in foil and placing in the dark
103 for 10 min. Luminescence is then measured at 220C using a luminescence counter (e.g., PACKARD TOPCOUNT Microplate Scintillation and Luminescence Counter or TECAN SPECTRAFLUOR PLUS), and ATP levels calculated from the standard curve. ATP levels in cells treated with test compound(s) are compared to the levels determined for untreated ceils. Cells treated with 10 μM of a preferred test compound exhibit ATP levels that are at least 80%, preferably at least 90%, of the untreated cells. When a 100 μM concentration of the test compound is used, cells treated with preferred test compounds exhibit ATP levels that are at least 50%, preferably at least 80%, of the ATP levels detected in untreated cells.
104

Claims

What is claimed is:
ϊ . A compound of the formula:
At\ J?
or a pharraaceuticaliy acceptable salt or hydrate thereof, wherein:
Ar3 and Ar2 are independently chosen from phenyl and 6-membered heteroaryl, each of which is substituted with from 1 to 4 substituents independently chosen from RΛ;
R is QrCgalkyl, C2-C8alkenyl, (C.rCi0cyc]oalkyl)C0-C,a]kyl, C2-C8alkyl ether, C,-Cga]koxycarbonyl, C]-CgaIkytsu!fonylCo-C4alkyl, mono- or di-(Ci-Qalkyl)aminoC0-C4alkyl, mono- or di-(Cr C8alkyl)aminosulfonylCo-C4alkyI, or mono- or di-(Cj-Cgalkyl)aminocarbonylCo-C4aikyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB; or R is a group of the formula -L-A-X-B or -L-X-A-B, wherein: L is Co-C3alkylene optionally substituted with RB; A is a 5- to 8-membered heterocycloalkyl gi"oup that is substituted with from 0 to 3 substituents independently chosen from RB; X is absent. -C(=O)-, -N(Rx)C(O)-, -C(O)N(Rx)- or -S(O2)-; wherein Rx is hydrogen or C1-
Qalkyl; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or
B is CrQalky], (C3-Cficycloalkyi)Co-C2aIkyl, C-Qhaloaikyl, CrC«alkoxy, C2-Qalkyi ether, mono- or di-(Ci-C(salkyl)amiπo, or 4- to 7-membered heterocycloaikyl, each of which is substituted with from O to 3 substituents independently chosen from RB; such that R is not morρholin-4-ylmethyI; Each RΛ is independently chosen from:
(i) halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl and -COOH; and (U) C,-C6alkyl, C2-C6alkenyl, C2-C6alkynyi, (C3-Cgcycloalky!)Co-C4alkyl, CrC6alkoxy, C1- C6alky!thio, Ci-C6alky]sulfinyl, Ci-Coalkoxycarbonyl, Cj-C^alkylsulfonyiCo-C^alkyl. mono- or di-(C]-C6a[kyl)aminoCo-C4alkyI, mono- or di-(Ci-C6alkyl)aminosuifonylCo-C4alkyl, mono- or di-(C|-C6a]kyl)aminocarbonylC0-C4a!kyl, phenylC0-C4alkyl, phenylC0-C4alkoxy, (4- to 8- membered heterocycIe)C0-C4alkyi and (4- to 8-membered heterocycle)C0-C4alkoxy; each of which is substituted with from O to 6 substituents independently chosen from RB; and Each RB is independently chosen from:
(i) oxo, halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, and — COOH; and (ii) C,-C6alkyl, C2-Qalkenyi, CrCdalkynyl, (C3-CgcycloaIkyl)Co-C4alkyI, CrC6alkoxy, C1- Caalkylthio, Cj-C^alkylsulfinyl, (Ci-C6alkyl)sulfonylCo-C4alkyI, C2-Csa!kyf etlier, mono- or di-(C]-C6alkyl)aminoCo-C4a!kyl and mono- or di-(C|-C6atkyl)aminosulfonyICB-C4alkyl; each
105 of which is substituted with from 0 to 6 substituents independently chosen from oxo, halogen, hydroxy, Ci-C4alkyl and Cj-Qalkoxy.
2. A compound or salt or hydrate thereof according to claim 1, wherein Ar2 is substituted phenyl or substituted pyridyl,
3. A compound or salt or hydrate thereof according to claim 2, wherein Ar2 is phenyl, pyridin-2-yi or pyridin-3-yl, each of which is substituted at the para position with halogen, hydroxy, cyano, amino, Q-C^alky], Ci-Cϋhatoalkyl, Cj-C4atkoxy, d-dhaloalkoxy, Crdaikoxycarbonyl or ph eny IC0-C4al koxy .
4. A compound or salt or hydrate thereof according to any one of claims 1-3, wherein Ar i is substituted phenyl.
5. A compound or salt or hydrate thereof according to claim 4, wherein Ai-] is phenyl that is substituted at the 2-position and at the 4-position, each of which substituents of Ar2 is independently chosen from halogen, hydroxy, CrC6alkyl, Ci-C6haloalkyl, d-Cbalkoxy and Cr C6haloalkoxy.
6. A compound or salt or hydrate thereof according to any one of claims 1-3, wherein Ai"i is substituted pyridyl.
7. A compound or salt or hydrate thereof according to claim 6, wherein Af| is pyridin-4- yl that is substituted at the 2-position.
8. A compound or salt or hydrate thereof according to claim 7, wherein An is pyridiπ-4- yl that is substituted at the 2-position with halogen, hydroxy, cyano, amino, d-Cβalkyi, Ci- Cfchaloalkyl, Cj -C6afkoxy or C]-Q)haloalkoxy.
9. A compound or salt or hydrate thereof according to claim 8, wherein Aη is pyridin-4- yl that is substituted at the 2-position with a halogen.
10. A compound or salt or hydrate thereof according to any one of claims 1 -9, wherein R is C2-Cgalkyl, C2-C8alkenyl, (C3-C, 0cyc]oa!kyl)C0-C2alky!, C2-Cshaloalkyl, d-Cgalkyl ether, mono- or di-(Ci-C6alkyi)aminoCo-C4alkyl, or (4- to 8-membered heterocycloalkyl)Co-C4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from:
(i) oxo and hydroxy; and
(ii) C|-C6alkyl, (C4-C6cycloalky!)Co-C2alkyl5 CrQ,haioaIkyl, C,-C6alkoxy, C2-C6alkyl ether, (Cr
C6alkyl)su!fonylC0-C2a]kyl, and mono- or di-(Cj-Csalkyl)aminoCo-C.)alkyl; each of which is substituted with 0, 1 or 2 oxo moieties.
106
1 1. A compound or salt or hydrate thereof according to claim 10, wherein R is C2- Cgaikyl, C2-Csalkenyl, (C3-C7cycloaikyl)Co-C2alkyl, C2-C8haloalkyl, C2-C8alkyl ether, or mono- or di- {C|-Csalkyl)aminoCo-C4a!kyl, each of which is substituted with from 0 to 4 substituents independently chosen from oxo, hydroxy, C]-C4alkyl, C]-C4alkoxy and (CrCsalkyOsulforryi.
12. A compound or salt or hydrate thereof according to any one of ciaims 3-9, wherein R is a group of the formu Ia -L-A-X-B or -L-X-A-B, wherein:
L is Co-Cjalkylene optionally substituted with oxo or hydroxy;
A is a 4- to 6-membered helerocycloalkyl group;
X is absent, ™C(=O)-, -N(Rx)C(O)-, -C(K))N(Rx)- or -S(O2)-; wherein Rx is hydrogen or C1-
C4alkyl; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is Ci-Csaikyl, (C3-C6cycloalky])Co-C2alkyl, CrC6haIoalkyl, C,-C6alkoxy, CrC6alkyl ether, mono- or di-(CrC6aikyi)amino, or 4- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 3 substituents independently chosen from oxo, hydroxy, and Cj-
C4alkyl.
13. A compound of the formula:
Ar2 0
N— \
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
Ari is phenyl or 6-membered heteroaryl, each of which is substituted with from 1 to 4 substituents independently chosen from RA; Ar2 is phenyl or 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from RA; R is CrCsalkyl that is substituted with 1 or 2 substituents independently chosen from halogen, cyano, hydroxy, amino, oxo, such that R does not comprise an aminocarbonyl or carboxy group; Each RA is independently chosen from:
(i) halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl and — COOH; and (ii) Cs-C6alky!, C2-C6alkeπyl, C2-C6aIkyπyL (C3-Cscycloalkyl)Co-C4alkyl, CrC6alkoxys d- Csalkylthio, Ci-C^alkyfsulfinyl, Ci-Cύalkoxycarbonyl, Cj-CsalkyisulfonylCo^alkyl, mono- or di-(Cs-C6aIkyl)aminoCo-Cjalky], mono- or di-(Ci-C6alkyl)aminosu[fonylCo-C4alkyl, mono- or di-(CrC6alkyl)aminocarbonylCo-C4alkyl. ρhenylCo-C4aIkyl, phenylCo-C4alkoxy, (4- to 8- membered heteiOcycle)Co-CjaIkyl and (4- to 8-membered heterocycle)Co-C4alkoxy; each of which is substituted with from O to 6 substituents independently chosen from RB; and Each Rg is independently chosen from:
(i) oxo, halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, and -COOH; and
107 (ii) C-Csalky], C2-C6afkenyl, C2-C6alkynyl, (C3-Cscycloalkyl)Co'C4alky], Ci-C6a!koxy, Cr QaJkyithio, CrQalkyisulfinyl, (CrCealky^sulfonylCo-C^alkyl. C^-Qaiky! ether, mono- or di-(Ci-C6alkyl)aminoCo-C4aIkyl and mono- or di-(Ci-C(,alky!)aminosulfonylCo-C4a!kyl; each of which is substituted with from 0 to 6 substituents independently chosen from oxo, halogen, hydroxy, Cj-Qalky! and CrC4alkoxy.
14. A compound or salt or hydrate thereof according to claim 13, wherein R is CrC8alkyl that is substituted with one hydroxy group or one oxo group.
15. A compound or salt or hydrate thereof according to claim 13 or claim 14, wherein Ar1 and Ar2 are independently phenyl or pyridyl, each of which is substituted with one or two substituents independently chosen from halogen, hydroxy, cyano, amino, CrC6aikyl, C,-C6haloalkyl, C]-Ccafkoxy and C|-C6haloalkoxy.
16. A compound or salt or hydrate thereof according to claim 15, wherein one substituent of Ai'2 is located para to the point of attachment.
17. A compound or salt or hydrate thereof according to claim 15 or claim 16, wherein one substituent of Ar1 is located ortho to the point of attachment.
1 8. A compound of the formula:
Ar2N J
N— \
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
An is 6-membered heteroaryl that is substituted with from I to 4 substituents independently chosen from RA; Ar2 is phenyl or 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from RA; R is C-Cgalkyl, C2-Csalkenyl, C2-Qalkynyl, (C1-C, 0cycIoalkyl)C0-C4alkyl, C2-Csalkyl ether, C,-
CjalkoxycarbonyL Ci-CgaikylsulfonylCo-CjalkyL mono- or di-(Ci-Csalkyl)aminoCo-C4atkyL mono- or di-(C]-Csalkyl)aminosulfonylCo-C4alkyl, or mono- or di-(C]-Csalkyl)aminocarbonylC0-
C4alkyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB; or R is a group of the formula -L-A-X-B or -L-X-A-B, wherein:
L is Cfl-Qalkylene optionally substituted with RB;
A is a 5- to 8-membered heterocycloalkyl group that is substituted with from 0 to 3 substituents independently chosen from RB;
108 X is absent, -C(=O)-, -N(Rx)Cf=O)-, -Cf=O)N(Rx)- or -S(O2)-; wherein Rx is hydrogen or C,-
C4alkyl; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is Ci-C6alkyl, (C3-C6cycloalkyl)C0-C2alkyI, C|-Csha!oalkyl, C-Qaikoxy, C2-C6aSkyI ether, mono- or di-(CrC6a]kyl)amino, or 4- to 7-membered heterocycloalkyl, each of which is substituted with from O to 3 substituents independently chosen from R8; Each RA is independently chosen from:
(i) halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl and -COOH; and (ii) Cj-Cealkyl, CT-C^alkenyl, C2-C6alkynyl, (C3-CscycIoalkyl)Co-C4alkyl, Ci-Ccalkoxy, Cj- C6alkylthio, C]-C<,alkylsulfinyl, C]-C6aikoxycarbonyl, Ci-CβalkyisuIfonylCcrCjaikyl, mono- or di-(C|-Cήalkyl)aminoCo-C4alkyl, mono- or di-fCi-CόalkyOaminosulfonylQH^alky], mono- or di-fCi-C6alkyl)aminocarbony]C0-C4alkyl, pheny]C0-C4alkyl, pheny!Co-C4a]koxy, (4- to 8- membered hetei'ocycie)Co-C4alkyl and (4- to 8-membered heterocycIe)Co-C4alkoxy; each of which is substituted with from O to 6 substituents independently chosen from RB; and Each RB is independently chosen from:
(i) oxo, halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, and -COOH; and (ii) C-Qaϊkyl, C2-C6aikenyl, C2-C6alkynyi, (C,-Cscycloaikyl)C0-C4aIkyl, Q-C6alkoxy, C,- C6aikylthio, C|-C6alkylsulfmyl, (C]-C6a]kyl)su]fonylCo-C{alkyI, C2-C6alkyl ether, mono- or di-(Cj-C6alkyl)aminoCo-C4alkyl and mono- or di-(Ci-C6alkyl)aminosulfonyiCo-C4alkyl; each of which is substituted with from O to 6 substituents independently chosen from oxo, halogen, hydroxy, Ci-C4alkyl and C,-C4alkoxy,
19. A compound or salt or hydrate thereof according to claim 18. wherein Ar2 is substituted phenyl or substituted pyπdyl.
20. A compound or salt or hydrate thereof according to claim 19. wherein Ar2 is phenyl, pyridiπ-2-yl or pyridin-3-yl, each of which is substituted at the para position with halogen, hydroxy, cyano, amino, CrC,alkyl, Cj-Cjhaloalkyl, CrC4alkoxy, CrC4ha]oalkoxy, Ci-Cjaikoxycarbonyl or phenyiCo-C4alkoxy.
21. A compound or salt or hydrate thereof according to any one of claims 1 8-20, wherein Ar i is pyridin-4-yl that is substituted at the 2-position.
22. A compound or salt or hydrate thereof according to claim 21 , wherein Ai \ is pyridin- 4-yI that is substituted at the 2-position with a group selected from halogen, hydroxy, cyano, amino, CrCsalkyl, C|-C6haloalkyl, CrC6alkoxy and C1-C6ImJOaIkOXy.
23. A compound or salt or hydrate thereof according to any one of claims 18-22, wherein R is d-Cgalkyi, C2-Csalkenyl, C2-Csalkynyl, (C3-C, 0cycloalkyl)Co-C2alkyl, C2-Cghatoalkyl, C2-
109 Csalkyl ether, mono- or di-(Ci-C<salkyl)aminoCo-C4alkyl. or (4- to 8-membered heterocycfoalkyI)C<r Qalkyl, each of which is substituted with from 0 to 4 substituents independently chosen from: (i) oxo and hydroxy; and
(Ii) Ci-Ccaikyi, (C4-C6cycloalkyI)Co-C2aikyl, CrQhaioalkyl, Ci-C6a[koxy, C2-Cήalkyl ether. (Cr CealkyOsulfonylCo-C^alkyl, and mono- or di-CCpCsalky^aminoCo^alkyl; each of which is substituted with O, 1 or 2 oxo moieties.
24. A compound or salt or hydrate thereof according to claim 23, wherein R is Cr Qalkyl, C2-C8alkenyl, C2-Csalkynyl, (C3-C7cycloalky!)C0-C2a]kyl: C2-Cshaioalky], C2-C8alkyl ether, or mono- or di-(CrC(;alkyl)aminoCo-C4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from oxo, hydroxy, Cj-C4alkyi, Cj-C4alkoxy and (Q- C6alkyl)sulfonyl.
25. A compound or salt or hydrate thereof according to any one of claims 1 8-22, wherein R is a group of the formula -L-A-X-B or -L-X-A-B, wherein:
L is C0-C3alkylene optionally substituted with oxo or hydroxy;
A is a 4- to 6-membered heterocycloalkyl group;
X is absent, -C(=O>, -N(Rχ)C(=0)-, -C(O)N(Rx)- or -S(O2)-; wherein Rx is hydrogen or Cr
C4alkyl; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is Ci-Qalkyl, (C3-C6cycloalkyl)C<rC2a]kyi, C,-C6haloalkyl, CrC6aIkoxy, C2-C6alkyl ether, mono- or di-(CrC6alky])amino, or 4- to 7-membered heterocycloalkyl, each of which is substituted with from O to 3 substituents independently chosen from oxo, hydroxy, and Cj-
Qalkyi.
26. A compound of the formula:
R2
Figure imgf000111_0001
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
R] is halogen, hydroxy, C]-C6alkyl, Ci-C^haloalkyl, Ci-C^alkoxy or Ci-Cβhalσalkoxy;
R2 is halogen, hydroxy, Q-Qalkyl, Ci-Qjhaloalkyf, C]-Cf,alkoxy, C]-C6haloalko.κy or Ci-C^alkoxy that is substituted with a 4- to 6-membered carbocycle or heterocycle; R is:
(i) hydrogen;
1 10 (ii) CpCgalkyl, C2-C8alkenyl, C2-Csalkynyl, (C3-C iocycloalkyi)C0-Qaikyl, C2-Csaikyl ether, C,- Csalkoxycarbony], C]-Cga]kylsulfonylCo-C4alkyl, mono- or di-(Ci-Csalkyl)aminoCo-C4alkyt, mono- or di-(Ci-Csalkyl)aminosulfonylCo-C4alky], or mono- or di-(Cr CsaIkyl)aminocarbonylC0-C4alkyl; each of which is substituted with from 0 to 6 substituents independently chosen from RB; or
(iii) a group of the formula -L-A-X-B, -L-M-X-B, -L-X-A-B or -L-X-M-B , wherein: L is Cø-C3alkyiene optionally substituted with RB; A is a 5- to 8-membered heterocycloalkyl group that is substituted with from 0 to 3 substituents independently chosen from RB; M is phenylC0-C2alkyl or (5- to 10-membered heteroaryl)C0-C2alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from RB;
X is absent, -C(=O)-, -N(RX)C(=O)-, -C(=O)N(RX)- or -S(O2)-; wherein Rx is hydrogen or C,- C4aikyl; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is Ci-Qalky], (C3-C6cyc]oa!kyl)Co-C2aiky!, CrC6haloalky], CrC6alkoxy, C2-C6a!kyl ether, mono- or di-(Ci-C6alkyl)amino, or 4- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 3 substituents independently chosen from RB; and Each Rβ is independently chosen from:
(i) oxo, halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, and -COOH; and (ii) Ci-C«a!kyl, C2-C6alkenyl, C2-C6alkyny1, (C3-CscycIoalkyl)Co-C4alkyl, Cι-C6alkoxy, C,- Cδalkylthio, Ci-C6alkylsulf1nyl, (Ci-C<;alkyl)sulfonyiC<rC4alkyI, C2-C6alkyl ether, mono- or di-(C]-C6alkyl)aminoCo-C4alkyl and mono- or di-(Ci-Cealkyl)aminosulfony!Co-C4alkyi; each of which is substituted with from O to 6 substituents independently chosen from oxo, halogen, hydroxy, C]-C4alkyl and C[-C4alkoxy.
27. A compound or salt or hydrate thereof according to claim 26, wherein Rj is a halogen.
28. A compound or salt or hydrate thereof according to claim 26 or claim 27, wherein R2 is halogen, CrQhaloalkyl or Ci-C&alkoxy.
29. A compound or salt or hydrate thereof according to any one of claims 26-28, wherein R is Ci-Cgalkyl, C2-C8alkenyL C2-C8alkynyl, (C4-C7cycloa!kyl)C0-C2alkyi, C2-C8haioalkyi, C2-Cgalkyl ether, mono- or di-(Ci-C6aikyl)ammoCcrC4alkyl, or (4- to 8-membered heterocycloalkyl)C0-C4aIkyl, each of which is substituted with from O to 4 substituents independently chosen from:
(i) oxo and hydroxy; and
111 (ii) CrQalkyl, (C4-C6cycloa]kyI)Co-C2alkyl, C,-C6haloalkyl, C,-C6aikoxy, C2-Qalkyl ether, (C,- C6aIkyl)sulfonylCo-C2alkyl, and mono- or di-(C|-C6alkyl)aminoC0-C4aikyl; each of which is substituted with 0, 1 or 2 oxo moieties.
30. A compound or salt or hydrate thereof according to claim 29, wherein R is C1- Qalkyl, C2-C8alkenyl, C2-Cga!kynyl, (C3-C7cycloalkyI)Co-C2aIkyl, C2-C6haioalkyl, C2-Csalkyi ether, or mono- or di-(Ci-C6alkyl)aπiinoCo-C4aIkyl, each of which is substituted with from 0 to 4 substituents independently chosen from oxo, hydroxy, Cj-C^alkyi, Cj-Qalkoxy and (C\- C6alkyl)su]fonyl.
31. A compound or salt or hydrate thereof according to claim 30, wherein R is Ci-Qalkyl that is substituted with 1 or 2 substituents independently chosen from halogen, cyano, hydroxy, amino and oxo.
32. A compound or salt or hydrate thereof according to ciaim 30, wherein R is Q-Cgalkyl that is substituted with one hydroxy group or one oxo group.
33. A compound or salt or hydrate thereof according to any one of claims 26-28, wherein R is a group of the formula — L-A-X-B or -L-X-A-B, wherein:
L is C0-C3alkylene optionally substituted with oxo or hydroxy;
A is a 4- to 6-membered heterocycloalkyl group;
X is absent, -C(=O)-, -N(RX)C(=O)-, -C(=O)N(RX> or -S(O2)-; wherein Rx is hydrogen or C,-
C4alkyl; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is C,-C6alkyl, (C3-C6cycloalkyl)CD-C,alkyI, C|-C6haloalkyl, C,-C6aikoxy, C3-C6alkyl ether, mono- or di-(Ci-C6alkyl)amino, or 4- to 7-membered heterocycloalkyl, each of which is substituted with from 0 to 3 substituents independently chosen from oxo, hydroxy, and C1-
Calkyl.
34. A compound or salt or hydrate thereof according to any one of claims 26-28, wherein R is a group of the formula -L-M-X-B or -L-X-M-B, wherein:
L is Co-C3alkylene optionally substituted with oxo or hydroxy;
M is phenylCo-Cjalky] or (5- to 10-membered heteroaryl)Co-C2alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from oxo, hydroxy and Ci-Qtalkyϋ; X is absent, -C(O)-. -N(Rx)C (=0)-, -Q=O)N(Rx)- or -S(O2)-; wherein Rx is hydrogen or C,-
C4a!kyl; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is d-Csalkyl, (C3-C6cycloalkyI)C0-C2alkyi, CrC6haloalkyI, CrC6aikoxy, C2-C6alkyl ether, mono- or di-(C|-C6alkyl)amino, or 4- to 7-membered heterocycloalky!, each of which is
1 12 substituted with from O to 3 substituents independently chosen from oxo, hydroxy, and C|- C4alkyl.
35. A compound of the formuia:
Ar2
- R
INI
Figure imgf000114_0001
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
Ar2 is phenyl or 6-membered heteroaryl, each of which is substituted with from 0 to 4 substituents independently chosen from RA: R is:
(i) hydrogen;
(ii) C-Qaikyl, C2-Csa!kenyl, C2-Csalkynyϊ, (C3-C,0cycloalkyi)CQ-C^alkyl, C2-Qalkyl ether, C1- Cgalkoxycarbonyl, CrCgalkylsuIfonylQKUalkyJ, mono- or di-{Ci-Csalkyl)aminoC0-C4alkyl, mono- or di-(Cj-Cgalkyl)aminosulfonyIQj-C4alkyl, or mono- or di-(C|- C8aIky])aminocarbonylCo-Qalkyl; each of which is substituted with from 0 to 6 substituents independently chosen From R13; or
(iii) a group of the formula -L-A-X-B, -L-M-X-B, -L-X-A-B or -L-X-M-B , wherein: L is C0-C3alkylene optionally substituted with RB; A is a 5- to 8-membered heterocycloalkyi group that is substituted with from 0 to 3 substituents independently chosen from R3; M is pheny!Co-C2aIkyl or (5- to 10-membered heteroaryl)Co-C2alky!, each of which is substituted with from 0 to 3 substituents independently chosen from RB; X is absent, -C(=O)-. -N(RX)C(=O)-, -C(=O)N(RX)- or -S(O2)-; wherein Rx is hydrogen or
Ci-Calkyl; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is C,-C6alkyl, (C3-C6cycloalkyI)Co-C2alkyl, d-Qhaloalkyl, d-C6alkoxy, C2-C6alkyl ether, mono- or di-(C]-C6alkyI)amiπo, or 4- to 7-membered heterocycloalkyi, each of which is substituted with from 0 to 3 subslituents independently chosen from RB; Each RA is independently chosen from:
(i) halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl and -COOH; and
(ii) C,-Calkyl. C2-C6alkenyl, C2-C6alkynyl, (CrC8cycloafkyl)C0-C4aikyl5 CrC6alkoxy, C,-
Cealkylthio. CrC6aikylsulfmyl, C]-C6alkoxycarbonyl, C]-C6alkylsulfonylCo-C4alkyl, mono- or di-(Ci-C6alkyl)aniinoCo-C4a!kyI, mono- or di-(C]-C6aIkyi)aminosulfonyICo-C4alkyl, mono- or di-fCj-CealkyiJaminocarbonylCo-Cjalkyl, phenylCo-C+alkyl, phenylC0-C4atkoxy, (4- to 8-
113 membered heterocyc!e}Co-C4aJkyϊ and (4- to 8-membered heterocycle)Co-C4alkoxy; each of which is substituted with from 0 to 6 substituents independently chosen from RB; and Each RB is independently chosen from:
(i) oxo, halogen, hydroxy, cyano, amino, nitro, aminocarbonyl, aminosulfonyl, and -COOH: and (ii) C,-C6alkyi, C2-C6alkenyl, C2-C6alkynyl, (C3-CgcycIoaIkyl)C0-C4alkyl, CrC6alkoxy, C1- C6alkylthio, CrC6alkylsυlfinyl, (C,-C6alky!}sulfonylCo-C4alkyl, C2-Qalkyl ether, mono- or di-(C}-C6alkyl)aminoCo-C4alkyl and mono- or di-(Ci-C6aIkyl)aminosulfonylCo-C4alkyl; each of which is substituted with from O to 6 substituents independently chosen from oxo, halogen, hydroxy, CrC4alkyI and Cj-C4alkoxy; and
R1 and R4 are independently chosen from halogen, hydroxy, Cj-C6alkyl, C|-C6haloalkyl, Q-Qalkoxy or C]-C6haloalkoxy.
36. A compound or salt or hydrate thereof according to claim 35, wherein R3 and R4 are each a halogen.
37. A compound or salt or hydrate thereof according to claim 35 or claim 36, wherein R is Ci-Cgalkyl, C2-Cgalkenyl, C2-Cgalkynyl, (C4-Ci0cycloaIkyl)Co-C2aIkyi, C2-C8haloalkyl. C2-Csalky] ether, mono- or di-(Ci-C6alkyl)aminoCo-C4alkyl, or (4- to 8-membered heterocycloalkyl)Co-C4alkyl, each of which is substituted with from O to 4 substituents independently chosen from:
(i) oxo and hydroxy; and
(ii) Ci-Csalkyl, (C4-Cήcycloaikyl)Co-C2aikyl, CrC6haloalkyl, CrC6alkoxy, C2-C6alkyl ether, (C,-
C6alkyl)suIfonylCo-C?alkyl, and mono- or di-(C[-C(;a!kyl)aminoCo-C4alkyi; each of which is substituted with O, 1 or 2 oxo moieties,
38. A compound or salt or hydrate thereof according to claim 37, wherein R is Cr Cgalkyl, C2-Csalkenyl, C2-C8alkynyi, (CrC7cycloaikyl)C<rC2a]kyl, C2-C6haloalkyl, C2-Csalkyl ether, or mono- or di-(CrC6alkyl)aminoCo-C|alkyl, each of which is substituted with from O to 4 substituents independently chosen from oxo, hydroxy, C]-C4a!kyl, Ci-C4a!koxy and (C;- Cf,alky l)sιi lfonyl.
39. A compound or salt or hydrate thereof according to claim 38, wherein R is CrCgalkyl that is substituted with 1 or 2 substituents independently chosen from halogen, cyano, hydroxy, amino and oxo.
40. A compound or salt or hydrate thereof according to claim 35 or claim 36, wherein R is a group of the formula -L-A-X-B or -L-X-A-B, wherein:
L is Co-Cjalkylene optionally substituted with oxo or hydroxy; A is a 4- to 6-membered heterocycloalkyl group;
114 X is absent, -C(O)-, -N(RX)C(=O)-, -C(O)N(Rx)- or -S(O2)-; wherein Rx is hydrogen or Q-
Gialkyl; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is CrCβalkyl, (C3-C6cycloalkyl)CQ-C2alkyl, CrC6haIoaikyl, Q-C6alkoxy, QrQalkyl ether, mono- or di-(Q-C6alkyl)amino, or 4- to 7-membered heterocycloalkyl, each of which is substituted with from O to 3 substituents independently chosen from oxo, hydroxy, and Q-
Qalkyϊ.
41. A compound or salt or hydrate thereof according to claim 35 or claim 36, wherein R is a group of the formula -L-M-X-B or -L-X-M-B, wherein:
L is Co-Cjalkylene optionally substituted with oxo or hydroxy;
M is phenylCo-Ciaikyl or (5- to 10-membered heteroaryOCo-C^alkyl, each of which is substituted with from O to 3 substituents independently chosen from oxo, hydroxy and Ci^alkyl; X is absent, -C(O)-, -N(Rx)C(O)-, -C(O)N(Rx)- Or -S(O2)-; wherein Rx is hydrogen or Q-
Qalkyϊ; and
B is absent or cyano, such that if B is absent or cyano, then X is absent; or B is Q-Qaikyl, (CrC6cycloaikyI)Co-C2alkyl, Q-C6ha!oalkyl, C,-C6atkoxy, C2-C(,alkyl ether, mono- or di-(CrC6alkyl)amino, or 4- to 7-membered heterocycloalkyl, each of which is substituted with from O to 3 substituents independently chosen from oxo, hydroxy, and Q-
C4alkyl.
42. A compound or salt or hydrate thereof according to any one of claims 35-41 , wherein Ar2 is substituted phenyl or substituted pyridyl.
43. A compound or salt or hydrate thereof according to claim 42, wherein Ar2 is substituted at the para position with halogen, hydroxy, cyano, amino, Q-C4alkyl, Q-Cthaloalkyl, Q- C4alkoxy, Q-C4haloa!koxy, Q-Cjalkoxycarbonyl or ρhenylC0-C4alkoxy.
44. A pharmaceutical composition, comprising at least one compound or salt or hydrate thereof according to any one of claims 1 -43, in combination with a physiologically acceptable carrier or excipient.
45. A pharmaceutical composition according to claim 44, wherein the composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup or a transdermal patch.
46. A pharmaceutical composition, comprising:
(i) a first agent that is a compound or salt according to any one of claims 1-43;
115 (ii) a second agent that is suitable for treating an appetite disorder, obesity, an addictive disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder or a movement disorder; and
(iii) a physiologically acceptable carrier or excipient.
47. A pharmaceutical composition according to claim 46, wherein the second agent is an anti-obesity agent selected from an MCH receptor antagonist, an apo-B/MTP inhibitor, a 1 1 β-hydroxy steroid dehydrogenase- 1 inhibitor, peptide YY3-36 or an analog thereof, a MCR-4 agonist, a CCK-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a β3 adrenergic receptor agonist, a dopamine agonist, a melanocyte-stimulating hormone receptor analog, a 5-HT2c receptor agonist, Ieptin or an analog thereof, a leptin receptor agonist, a galanin antagonist, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y receptor antagonist, a thyromimetic agent, dehydroepiandrosterone or analog thereof, a glucocorticoid receptor antagonist, an orexin receptor antagonist, a glucagon-like peptide-1 receptor agonist, a ciliary neurotrophic factor, a human agouti- related protein antagonist, a ghrelin receptor antagonist, a histamine 3 receptor antagonist, or a neuromedin U receptor agonist.
48. A pharmaceutical composition according to claim 46, wherein the anti-obesity agent is phentermine, orlistat or sibutramiπe.
49. A pharmaceutical composition according to claim 46, wherein the second agent is a nicotine receptor partial agonist, an opioid antagonist or a dopaminergic agent.
50. A pharmaceutical composition according to claim 46, wherein the second agent is suitable for treating an addictive disorder, and wherein the agent is selected from methadone, LAAM, naltrexone, ondansetron, sertraline, fluoxetine, diazepam, chlordiazepoxide, varenicline and buproprion.
51. A packaged pharmaceutical preparation, comprising:
(a) a pharmaceutical composition according to claim 44 in a container; and
(b) instructions for using the composition to treat an appetite disorder, obesity, an addictive disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, portal hypertension, fibrosis of internal organs, orthostatic hypotension or drug-induced hypotension.
52. A method for treating a condition responsive to CBl modulation in a patient, in a patient, comprising administering to the patient a therapeutically effective amount of at least one compound or salt according to any one of claims 1-43.
116
53. A method according to claim 42, wherein the condition is an appetite disorder, obesity, an addictive disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease. Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, portal hypertension, fibrosis of internal organs, orthostatic hypotension or drug-induced hypotension.
54. A method according to claim 52, wherein the condition is an appetite disorder, obesity, an addictive disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease or Crohn's disease.
55. A method according to claim 54, wherein the condition is obesity, bulimia, alcohol dependency or nicotine dependency.
56. A method according to claim 55, wherein the condition is obesity.
57. A method for suppressing appetite in a patient, comprising administering to the patient an appetite reducing amount of at least one compound or salt or hydrate thereof according to any one of claims 1-43, and thereby suppressing appetite in the patient.
58. A compound or salt according to any one of claims 1 -43, wherein the compound or salt or hydrate thereof is radiolabeled.
59. A method for determining the presence or absence of CB l in a sample, comprising the steps of:
(a) contacting a sample with a compound or salt or hydrate thereof according to any one of claims 1 -43, under conditions that permit binding of the compound to CB l ; and
(b) detecting a signal indicative of a level of the compound bound to CB 1. and therefrom determining the presence or absence of CBl in the sample,
60. A method according to claim 59, wherein the compound is radiolabeled, and wherein the step of detection comprises the steps of:
(i) separating unbound compound from bound compound; and
(ii) detecting the presence or absence of bound radiolabel in the sample.
61. The use of a compound or salt or hydrate thereof according to any one of claims 1 -43 for the manufacture of a medicament for the treatment of a condition responsive to CB 1 modulation.
62. A use according to claim 61 , wherein the condition is an appetite disorder, obesity, an addictive disorder, asthma, liver cirrhosis, sepsis, irritable bowel disease, Crohn's disease, depression, schizophrenia, a memory disorder, a cognitive disorder, a movement disorder, portal hypertension, fibrosis of internal organs, orthostatic hypotension and drug-induced hypotension.
117
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WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009021740A2 (en) 2007-08-15 2009-02-19 Sanofis-Aventis Substituted tetrahydronaphthalenes, process for the preparation thereof and the use thereof as medicaments
WO2012120055A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120054A1 (en) 2011-03-08 2012-09-13 Sanofi Di- and tri-substituted oxathiazine derivates, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof
WO2012120056A1 (en) 2011-03-08 2012-09-13 Sanofi Tetrasubstituted oxathiazine derivatives, method for producing them, their use as medicine and drug containing said derivatives and the use thereof
WO2012120052A1 (en) 2011-03-08 2012-09-13 Sanofi Oxathiazine derivatives substituted with carbocycles or heterocycles, method for producing same, drugs containing said compounds, and use thereof
WO2012120053A1 (en) 2011-03-08 2012-09-13 Sanofi Branched oxathiazine derivatives, method for the production thereof, use thereof as medicine and drug containing said derivatives and use thereof

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