WO2006115895A2 - Phenyl ethyne compounds - Google Patents

Phenyl ethyne compounds Download PDF

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Publication number
WO2006115895A2
WO2006115895A2 PCT/US2006/014517 US2006014517W WO2006115895A2 WO 2006115895 A2 WO2006115895 A2 WO 2006115895A2 US 2006014517 W US2006014517 W US 2006014517W WO 2006115895 A2 WO2006115895 A2 WO 2006115895A2
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Prior art keywords
substituted
compounds
unsubstituted
moieties
ring
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French (fr)
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WO2006115895A3 (en
Inventor
Nicholas D. Cosford
Thomas J. Seiders
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Merck and Co Inc
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Merck and Co Inc
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Priority to US11/918,993 priority Critical patent/US20090306115A1/en
Priority to AU2006240217A priority patent/AU2006240217A1/en
Priority to JP2008507795A priority patent/JP2008538562A/en
Priority to EP06740961A priority patent/EP1874724A2/en
Priority to CA002604518A priority patent/CA2604518A1/en
Publication of WO2006115895A2 publication Critical patent/WO2006115895A2/en
Publication of WO2006115895A3 publication Critical patent/WO2006115895A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
    • A01N37/34—Nitriles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
    • C07C255/51—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings containing at least two cyano groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/53—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • a novel class of compounds containing a substituted or unsubstituted phenyl ring "A” having at least one substituent which is a phenyl or heterocyclic moiety "B” linked to the phenyl A ring via an akynyl moiety.
  • inventive compounds are useful for a wide variety of applications.
  • the compounds can act to modulate physiological processes by functioning as agonists and antagonists of receptors in the nervous system.
  • Inventive compounds may also act as insecticides, and as fungicides.
  • Pharmaceutical compositions containing invention compounds also have wide utility.
  • A is phenyl, unsubstituted or substituted with one or more substituent independently selected from:
  • B is aryl or heterocycle unsubstituted or substituted with one or more substituent independently selected from:
  • Aryl refers to mononuclear and polynuclear aromatic radicals having in the range of 6 up to 14 carbon atoms, and "substituted aryl” refers to aryl radicals further bearing one or more substituents as set forth above, for example, alkylaryl moieties.
  • Heterocycle refers to ring-containing radicals having one or more heteroatoms (e.g., N, O, S) as part of the ring structure, and having in the range of 3 up to 20 atoms in the ring. Heterocyclic moieties may be saturated or unsaturated when optionally containing one or more double bonds, and may contain more than one ring.
  • heteroatoms e.g., N, O, S
  • Heterocyclic moieties include, for example, monocyclic moieties such as imidazolyl moieties, pyridinyl moieties, pyrimidinyl moieties, isothiazolyl moieties, isoxazolyl moieties, moieties, and the like, bicyclic heterocyclic moieties such as azabicycloalkanyl moieties, and oxabicycloalkyl moieties, and other non-aromatic and aromatic mon- and bi-cyclic heterocycles.
  • substituted heterocycle refers to heterocycles further bearing one or more substituents as set forth above.
  • Hydrocarbyl refers to straight or branched chain univalent and bivalent radicals derived from saturated or unsaturated moieties containing only carbon and hydrogen atoms, and having in the range of about 1 up to 12 carbon atoms.
  • exemplary hydrocarbyl moieties include alkyl moieties, alkenyl moieties, dialkenyl moieties, trialkenyl moieties, alkynyl moieties, alkadiynal moieties, alkatriynal moieties, alkenyne moieties, alkadienyne moieties, alkenediyne moieties, and the like.
  • substituted hydrocarbyl refers to hydrocarbyl moieties further bearing substituents as set forth below.
  • Alkyl refers to straight or branched chain alkyl radicals having in the range of about 1 up to 12 carbon atoms; "substituted alkyl” refers to alkyl radicals further bearing one or more substituents such as hydroxy, alkoxy, mercapto, aryl, heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amino, amide, amidine, amido, carboxyl, carboxamide, carbamate, ester, sulfonyl, sulfonamide, and the like.
  • alkenyl refers to straight or branched chain hydrocarbyl radicals having at least one carbon- carbon double bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 6 carbon atoms presently preferred), and "substituted alkenyl” refers to alkenyl radicals further bearing one or more substituents as set forth above.
  • Alkenylene refers to straight or branched chain divalent alkenyl moieties having at least one carbon-carbon double bond, and having in the range of about 2 up to 12 carbon atoms (with divalent alkenyl moieties having in the range of about 2 up to 6 carbon atoms presently preferred), and "substituted lower alkenylene” refers to divalent alkenyl radicals further bearing one or more substituents as set forth above;
  • Alkynyl refers to straight or branched chain hydrocarbyl radicals having at least one carbon- carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 6 carbon atoms presently being preferred), and "substituted alkynyl” refers to alkynyl radicals further bearing one or more substituents as set forth above.
  • Alkynylene refers to straight or branched chain divalent alkynyl moieties having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with divalent alkynyl moieties having two carbon atoms presently being preferred), and "substituted alkynylene” refers to divalent alkynyl radicals further bearing one or more substituents as set forth above.
  • Cyclohydrocarbyl refers to cyclic (i.e., ring-containing) univalent radicals derived from saturated or unsaturated moieties containing only carbon and hydrogen atoms, and having in the range of about 3 up to 20 carbon atoms.
  • cyclohydrocarbyl moieties include cycloalkyl moieties, cycloalkenyl moieties, cycloalkadienyl moieties, cycloalkatrienyl moieties, cycloalkynyl moieties, cycloalkadiynyl moieties, spiro hydrocarbon moieties wherein two rings are joined by a single atom which is the only common member of the two rings (e.g., spiro[3.4]octanyl, and the like), bicyclic hydrocarbon moieties wherein two rings are joined and have two atoms in common (e.g., bicyclo [3.2.1]octane, bicyclo [2.2.1]hept-2-ene, and the like), and the like.
  • substituted cyclohydrocarbyl refers to cyclohydrocarbyl moieties further bearing one or more substituents as set forth above;
  • Cycloalkyl refers to ring-containing radicals containing in the range of about 3 up to 20 carbon atoms, and "substituted cycloalkyl” refers to cycloalkyl radicals further bearing one or more substituents as set forth above;
  • Cycloalkenyl refers to ring-containing alkenyl radicals having at least one carbon-carbon double bond in the ring, and having in the range of about 3 up to 20 carbon atoms
  • substituted cycloalkenyl refers to cyclic alkenyl radicals further bearing one or more substituents as set forth above.
  • Halogen refers to fluoride, chloride, bromide or iodide radicals.
  • Substituted refers to the substituents recited above in connection with A and B.
  • a substituent on A or B may itself be substituted with additional substituents selected from the A and B substituents.
  • the substituent "substituted hydrocarbyl” may refer to a hydrocarbyl, such as methyl, that is further substituted with one or more of substituents (a) through (t), such as cyano.
  • the resulting substituent would be -CH 2 -CN.
  • the linker "L” may be further substituted with one or more of substituents (a) through (t).
  • L is a linking moiety which links moieties A and B.
  • L is selected from substituted or unsubstituted alkynylene moieties.
  • Presently preferred compounds of the invention are those wherein L is an unsubstituted alkynylene moiety containing two carbon atoms, i.e., ethynyl.
  • A is a moiety linked through bridging moiety L to moiety B.
  • Radicals contemplated for use in the invention are those wherein A is substituted or unsubstituted phenyl.
  • Preferred compounds of the invention are those wherein A is phenyl unsubstituted or substituted with one or more substituent independently selected from amino, alkyl, cyano, halogen, alkyl-cyano, alkyl-hydroxy, hydroxyl, alkoxy, and mercapto.
  • B is a moiety linked through bridging moiety L to moiety A.
  • Radicals contemplated for use in the invention are those wherein B is substituted or unsubstituted aryl or heterocycle.
  • preferred compounds of the invention are those wherein B is a substituted or unsubstituted aryl or heterocycle.
  • Exemplary moieties include phenyl and pyrimidinyl.
  • Especially preferred compounds are those wherein B is phenyl substituted with cyano and fluoro, for instance wherein B is substituted at the 3 position with cyano and the 5 position with fluoro, or where B is substituted at the 3 position with -O-pyridyl and the 5 position with fluoro.
  • Additional especially preferred compounds are those wherein B is pyrimidinyl substituted with a heterocycle, in particular piperidinyl.
  • R is a substituent independently selected from amino, alkyl, cyano, halogen, alkyl-cyano, alkyl- hydroxy, hydroxyl, alkoxy, and mercapto.
  • R is a substituent independently selected from amino, alkyl, cyano, halogen, alkyl-cyano, alkyl- hydroxy, hydroxyl, alkoxy, and mercapto.
  • Still further preferred compound are those of the formula:
  • R is a substituent independently selected from amino, alkyl, cyano, halogen, alkyl-cyano, alkyl- hydroxy, hydroxyl, alkoxy, and mercapto.
  • invention compounds may contain one or more chiral centers, and thus can exist as racemic mixtures.
  • Suitable stereoselective synthetic procedures for producing optically pure materials are well known in the art, as are procedures for purifying racemic mixtures into optically pure fractions.
  • invention compounds may exist in polymorphic forms wherein a compound is capable of crystallizing in different forms. Suitable methods for identifying and separating polymorphisms are known in the art.
  • compositions comprising heterocyclic compounds as described above, in combination with pharmaceutically acceptable carriers.
  • invention compounds can be converted into nontoxic acid addition salts, depending on the substituents thereon.
  • the above-described compounds (optionally in combination with pharmaceutically acceptable carriers) can be used in the manufacture of medicaments useful for the treatment of a variety of indications.
  • Pharmaceutically acceptable carriers contemplated for use in the practice of the present invention include carriers suitable for intravenous, subcutaneous, transcutaneous, intramuscular, intracutaneous, intrathecal, inhalation, intracranial, epidural, vaginal, oral, sublingual, rectal, and the like administration. Administration in the form of creams, lotions, tablets, dispersible powders, granules, syrups, elixirs, sterile aqueous or non-aqueous solutions, suspensions or emulsions, patches, and the like, is contemplated.
  • suitable carriers include emulsions, solutions, suspensions, syrups, and the like, optionally containing additives such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents, and the like.
  • suitable carriers include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • suitable carriers include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile water, or some other sterile injectable medium immediately before use.
  • Invention compounds can optionally be converted into non-toxic acid addition salts.
  • Such salts are generally prepared by reacting the compounds of this invention with a suitable organic or inorganic acid.
  • Representative salts include hydrochloride, hydrobromide, sulfate, bisulfate, methanesulfonate, acetate, oxalate, adipate, alginate, aspartate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate (tosylate), citrate, malate, maleate, fumarate, succinate, tartrate, napsylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, glucoheptan
  • Salts can also be formed with inorganic acids such as sulfate, bisulfate, hemisulfate, hydrochloride, chlorate, perchlorate, hydrobromide, hydroiodide, and the like.
  • a base salt include ammonium salts; alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, phenylethylamine, and the like; and salts with amino acids such as arginine, lysine, and the like.
  • Such salts can readily be prepared employing methods well known in the art.
  • heterocyclic compounds as described above.
  • many of the heterocyclic compounds described above can be prepared using synthetic chemistry techniques well known in the art (see Comprehensive Heterocyclic Chemistry, Katritzky, A. R. and Rees, C. W. eds., Pergamon Press, Oxford, 1984, and WO01/16121).
  • 3-alkynyl-5-bromofluorobenzene (0.1 g, 0.7 mmol), 3-iodobenzonitrile (0.2 g, 1 mmol), Palladium tetrakis(triphenylphosphine) (0.02, 0.02mol), copper (I) iodide (0.004, 0.02mol), and triethylamine (1 mL), and DMF (2.5 mL) were combined and heated to 70 0 C for 4 hours. The crude solution was filtered and purified directly on RPHPLC to yield an off white solid.
  • 3-(3-ethynyl-5-fluoro ⁇ henoxy)pyridine (0.1 g, 0.7 mmol), 3-iodobenzonitrile (0.2 g, 1 mmol), Palladium tetrakis(triphenylphosphine) (0.02, 0.02mol), copper (I) iodide (0.004, 0.02mol), and triethylamine (1 mL), and DMF (2.5 mL) were combined and heated to 70 0 C for 4 hours. The crude solution was filtered and purified directly on RPHPLC to yield an off white solid.
  • 2-piperidyl-5-bromopyrimidine (3.5 g, 15 mmol), TMS acetylene (2.1 g, 29 mmol), Palladium tetrakis(triphenylphosphine) (0.3 g, 0.3 mmol), copper (I) iodide (0.05 g, 0.3 mmol), triethylamine (10 mL), and toluene (50 mL) were combined and heated to 100 0 C for 12 hours. The solution was filtered, solvent evaporated and the crude material purified on silica (25% EtOAc/hexanes) to yield a white solid.

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Abstract

In accordance with the present invention, there is provided a novel class of heterocyclic compounds. Compounds of the invention contain a substituted or unsubstituted six membered heterocyclic ring that includes at least two nitrogen atoms. The ring additionally includes four carbon atoms. The heterocyclic ring has at least one substituent located at a ring position adjacent to a ring nitrogen atom. This mandatory substituent of the ring includes a moiety (B), linked to the heterocyclic ring via a carbon-carbon triple bond. The mandatory substituent is positioned adjacent to the ring nitrogen atom. Invention compounds are capable of a wide variety of uses. For example heterocyclic compounds can act to modulate physiological processes by functioning as agonists and antagonists of receptors in the nervous system. Invention compounds may also act as insecticides, and as fungicides. Pharmaceutical compositions containing invention compounds also have wide utility.

Description

TITLE OF THE INVENTION PHENYL ETHYNE COMPOUNDS
BRIEF DESCRIPTION OF THE INVENTION
In accordance with the present invention, there is provided a novel class of compounds containing a substituted or unsubstituted phenyl ring "A" having at least one substituent which is a phenyl or heterocyclic moiety "B" linked to the phenyl A ring via an akynyl moiety.
The inventive compounds are useful for a wide variety of applications. For example the compounds can act to modulate physiological processes by functioning as agonists and antagonists of receptors in the nervous system. Inventive compounds may also act as insecticides, and as fungicides. Pharmaceutical compositions containing invention compounds also have wide utility.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there are provided compounds having the structure
A-L-B wherein: A is phenyl, unsubstituted or substituted with one or more substituent independently selected from:
(a) halogen,
(b) substituted or unsubstituted hydrocarbyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocycle,
(e) mercapto,
(f) nitro,
(g) carboxyl, (h) carbamate, (i) carboxamide, 0) hydroxy, (k) ester,
(1) cyano,
(m) amine,
(n) amide,
(0) amidine, (p) amido,
(q) sulfonyl or
(r) sulfonamide; L is substituted or unsubstituted alkynylene; and
B is aryl or heterocycle unsubstituted or substituted with one or more substituent independently selected from:
(a) halogen,
(b) substituted or unsubstituted hydrocarbyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocycle,
(e) mercapto,
(f) nitro,
(g) -O-heterocycle, (h) -O-aryl
(1) carboxyl, (j) carbamate, (k) carboxamide, (1) hydroxy, (m) ester,
(n) cyano, (o) amine,
(p) amide,
(q) amidine,
(r) amido,
(s) sulfonyl or
(t) sulfonamide; and enantiomers, diastereomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof.
"Aryl" refers to mononuclear and polynuclear aromatic radicals having in the range of 6 up to 14 carbon atoms, and "substituted aryl" refers to aryl radicals further bearing one or more substituents as set forth above, for example, alkylaryl moieties.
"Heterocycle" refers to ring-containing radicals having one or more heteroatoms (e.g., N, O, S) as part of the ring structure, and having in the range of 3 up to 20 atoms in the ring. Heterocyclic moieties may be saturated or unsaturated when optionally containing one or more double bonds, and may contain more than one ring. Heterocyclic moieties include, for example, monocyclic moieties such as imidazolyl moieties, pyridinyl moieties, pyrimidinyl moieties, isothiazolyl moieties, isoxazolyl moieties, moieties, and the like, bicyclic heterocyclic moieties such as azabicycloalkanyl moieties, and oxabicycloalkyl moieties, and other non-aromatic and aromatic mon- and bi-cyclic heterocycles. The term "substituted heterocycle" refers to heterocycles further bearing one or more substituents as set forth above.
"Hydrocarbyl" refers to straight or branched chain univalent and bivalent radicals derived from saturated or unsaturated moieties containing only carbon and hydrogen atoms, and having in the range of about 1 up to 12 carbon atoms. Exemplary hydrocarbyl moieties include alkyl moieties, alkenyl moieties, dialkenyl moieties, trialkenyl moieties, alkynyl moieties, alkadiynal moieties, alkatriynal moieties, alkenyne moieties, alkadienyne moieties, alkenediyne moieties, and the like. The term "substituted hydrocarbyl" refers to hydrocarbyl moieties further bearing substituents as set forth below. "Alkyl" refers to straight or branched chain alkyl radicals having in the range of about 1 up to 12 carbon atoms; "substituted alkyl" refers to alkyl radicals further bearing one or more substituents such as hydroxy, alkoxy, mercapto, aryl, heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amino, amide, amidine, amido, carboxyl, carboxamide, carbamate, ester, sulfonyl, sulfonamide, and the like.
"Alkenyl" refers to straight or branched chain hydrocarbyl radicals having at least one carbon- carbon double bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 6 carbon atoms presently preferred), and "substituted alkenyl" refers to alkenyl radicals further bearing one or more substituents as set forth above. "Alkenylene" refers to straight or branched chain divalent alkenyl moieties having at least one carbon-carbon double bond, and having in the range of about 2 up to 12 carbon atoms (with divalent alkenyl moieties having in the range of about 2 up to 6 carbon atoms presently preferred), and "substituted lower alkenylene" refers to divalent alkenyl radicals further bearing one or more substituents as set forth above;
"Alkynyl" refers to straight or branched chain hydrocarbyl radicals having at least one carbon- carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with radicals having in the range of about 2 up to 6 carbon atoms presently being preferred), and "substituted alkynyl" refers to alkynyl radicals further bearing one or more substituents as set forth above. "Alkynylene" refers to straight or branched chain divalent alkynyl moieties having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms (with divalent alkynyl moieties having two carbon atoms presently being preferred), and "substituted alkynylene" refers to divalent alkynyl radicals further bearing one or more substituents as set forth above.
"Cyclohydrocarbyl" refers to cyclic (i.e., ring-containing) univalent radicals derived from saturated or unsaturated moieties containing only carbon and hydrogen atoms, and having in the range of about 3 up to 20 carbon atoms. Exemplary cyclohydrocarbyl moieties include cycloalkyl moieties, cycloalkenyl moieties, cycloalkadienyl moieties, cycloalkatrienyl moieties, cycloalkynyl moieties, cycloalkadiynyl moieties, spiro hydrocarbon moieties wherein two rings are joined by a single atom which is the only common member of the two rings (e.g., spiro[3.4]octanyl, and the like), bicyclic hydrocarbon moieties wherein two rings are joined and have two atoms in common (e.g., bicyclo [3.2.1]octane, bicyclo [2.2.1]hept-2-ene, and the like), and the like. The term "substituted cyclohydrocarbyl" refers to cyclohydrocarbyl moieties further bearing one or more substituents as set forth above;
"Cycloalkyl" refers to ring-containing radicals containing in the range of about 3 up to 20 carbon atoms, and "substituted cycloalkyl" refers to cycloalkyl radicals further bearing one or more substituents as set forth above;
"Cycloalkenyl" refers to ring-containing alkenyl radicals having at least one carbon-carbon double bond in the ring, and having in the range of about 3 up to 20 carbon atoms, and "substituted cycloalkenyl" refers to cyclic alkenyl radicals further bearing one or more substituents as set forth above.
"Azo" refers to the bivalent moiety -N=N-, wherein each bond is attached to a different carbon atom.
"Halogen" refers to fluoride, chloride, bromide or iodide radicals.
"Substituted," including the use of "substituted" in reference to substituents of A and B, refers to the substituents recited above in connection with A and B. Thus, a substituent on A or B may itself be substituted with additional substituents selected from the A and B substituents. For instance, the substituent "substituted hydrocarbyl" may refer to a hydrocarbyl, such as methyl, that is further substituted with one or more of substituents (a) through (t), such as cyano. In this example, the resulting substituent would be -CH2-CN. Similarly, the linker "L" may be further substituted with one or more of substituents (a) through (t).
Further, in accordance with the present invention, L is a linking moiety which links moieties A and B. L is selected from substituted or unsubstituted alkynylene moieties. Presently preferred compounds of the invention are those wherein L is an unsubstituted alkynylene moiety containing two carbon atoms, i.e., ethynyl.
Further, in accordance with the present invention, A is a moiety linked through bridging moiety L to moiety B. Radicals contemplated for use in the invention are those wherein A is substituted or unsubstituted phenyl. Preferred compounds of the invention are those wherein A is phenyl unsubstituted or substituted with one or more substituent independently selected from amino, alkyl, cyano, halogen, alkyl-cyano, alkyl-hydroxy, hydroxyl, alkoxy, and mercapto. Further, in accordance with the present invention, B is a moiety linked through bridging moiety L to moiety A. Radicals contemplated for use in the invention are those wherein B is substituted or unsubstituted aryl or heterocycle. Further, preferred compounds of the invention are those wherein B is a substituted or unsubstituted aryl or heterocycle. Exemplary moieties include phenyl and pyrimidinyl. Especially preferred compounds are those wherein B is phenyl substituted with cyano and fluoro, for instance wherein B is substituted at the 3 position with cyano and the 5 position with fluoro, or where B is substituted at the 3 position with -O-pyridyl and the 5 position with fluoro. Additional especially preferred compounds are those wherein B is pyrimidinyl substituted with a heterocycle, in particular piperidinyl.
Thus, preferred compounds are those of the formula:
Figure imgf000007_0001
wherein R is a substituent independently selected from amino, alkyl, cyano, halogen, alkyl-cyano, alkyl- hydroxy, hydroxyl, alkoxy, and mercapto.
Additional preferred compound are those of the formula:
Figure imgf000007_0002
wherein R is a substituent independently selected from amino, alkyl, cyano, halogen, alkyl-cyano, alkyl- hydroxy, hydroxyl, alkoxy, and mercapto.
Still further preferred compound are those of the formula:
Figure imgf000008_0001
wherein R is a substituent independently selected from amino, alkyl, cyano, halogen, alkyl-cyano, alkyl- hydroxy, hydroxyl, alkoxy, and mercapto.
Those of skill in the art recognize that invention compounds may contain one or more chiral centers, and thus can exist as racemic mixtures. For many applications, it is preferred to carry out stereoselective syntheses and/or to subject the reaction product to appropriate purification steps so as to produce substantially optically pure materials. Suitable stereoselective synthetic procedures for producing optically pure materials are well known in the art, as are procedures for purifying racemic mixtures into optically pure fractions. Those of skill in the art will further recognize that invention compounds may exist in polymorphic forms wherein a compound is capable of crystallizing in different forms. Suitable methods for identifying and separating polymorphisms are known in the art.
In accordance with another embodiment of the present invention, there are provided pharmaceutical compositions comprising heterocyclic compounds as described above, in combination with pharmaceutically acceptable carriers. Optionally, invention compounds can be converted into nontoxic acid addition salts, depending on the substituents thereon. Thus, the above-described compounds (optionally in combination with pharmaceutically acceptable carriers) can be used in the manufacture of medicaments useful for the treatment of a variety of indications.
Pharmaceutically acceptable carriers contemplated for use in the practice of the present invention include carriers suitable for intravenous, subcutaneous, transcutaneous, intramuscular, intracutaneous, intrathecal, inhalation, intracranial, epidural, vaginal, oral, sublingual, rectal, and the like administration. Administration in the form of creams, lotions, tablets, dispersible powders, granules, syrups, elixirs, sterile aqueous or non-aqueous solutions, suspensions or emulsions, patches, and the like, is contemplated.
For the preparation of oral liquids, suitable carriers include emulsions, solutions, suspensions, syrups, and the like, optionally containing additives such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents, and the like.
For the preparation of fluids for parental administration, suitable carriers include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile water, or some other sterile injectable medium immediately before use.
Invention compounds can optionally be converted into non-toxic acid addition salts. Such salts are generally prepared by reacting the compounds of this invention with a suitable organic or inorganic acid. Representative salts include hydrochloride, hydrobromide, sulfate, bisulfate, methanesulfonate, acetate, oxalate, adipate, alginate, aspartate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate (tosylate), citrate, malate, maleate, fumarate, succinate, tartrate, napsylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, benzenesulfonate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, glucoheptanoate, glycerophosphate, heptanoate, hexanoate, undecanoate, 2-hydroxyethanesulfonate,ethanesulfonate, and the like. Salts can also be formed with inorganic acids such as sulfate, bisulfate, hemisulfate, hydrochloride, chlorate, perchlorate, hydrobromide, hydroiodide, and the like. Examples of a base salt include ammonium salts; alkali metal salts such as sodium salts, potassium salts, and the like; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, phenylethylamine, and the like; and salts with amino acids such as arginine, lysine, and the like. Such salts can readily be prepared employing methods well known in the art. In accordance with another embodiment of the present invention, there are provided methods for the preparation of heterocyclic compounds as described above. For example, many of the heterocyclic compounds described above can be prepared using synthetic chemistry techniques well known in the art (see Comprehensive Heterocyclic Chemistry, Katritzky, A. R. and Rees, C. W. eds., Pergamon Press, Oxford, 1984, and WO01/16121).
The following examples are intended to illustrate but not to limit the invention in any manner, shape, or form, either explicitly or implicitly. While they are typical of those that might be used, other procedures, methodologies, or techniques known to those skill in the art may alternatively be used.
INTERMEDIATE 1
3-bromo-5-fluorobenzonitrile
Figure imgf000010_0001
3,5-dibromofluorobenzene (47g, 185 mmol), copper cyanide (16.5 g, 185 mmol), and DMF (300 mL) were heated to 1400C for 18 hours. The reaction was cooled to room temperature, extracted with EtOAc/hexanes (1:1) and washed with aqueous ammonium hydroxide three times. The crude material was purified on silica with 10% EtOAc/hexanes as the eluent to yield a white solid.
INTERMEDIATE 2
3-ethynyl-5-fluorobenzonitrile
Figure imgf000011_0001
3-bromo-5-cyanofluorobenezene (7 g, 35 mmol), TMS acetylene (5.1 g, 53 mmol), Palladium tetrakis(triphenylphosphine) (0.4 g, 0.35 mmol), copper (I) iodide (0.07 g, 0.35 mmol), and triethylamine (100 mL) were combined and heated to 40 °C for 3 hours. The solution was filtered, solvent evaporated and the crude material purified on silica (20% EtOAc/hexanes) to yield a white solid. The solid material was dissolved in THF (50 mL) and 1 equivalent of TBAF was added and the solution was stirred for 1 hour at room temperature. Methylene chloride was added and the organic layer was washed 3 times with water and evaporated to yield a colorless oil.
EXAMPLE 1
3-[(3-cyanophenyl)ethynyl]-5-fluorobenzonitrile
Figure imgf000011_0002
3-alkynyl-5-bromofluorobenzene (0.1 g, 0.7 mmol), 3-iodobenzonitrile (0.2 g, 1 mmol), Palladium tetrakis(triphenylphosphine) (0.02, 0.02mol), copper (I) iodide (0.004, 0.02mol), and triethylamine (1 mL), and DMF (2.5 mL) were combined and heated to 700C for 4 hours. The crude solution was filtered and purified directly on RPHPLC to yield an off white solid. 1HNMR 7.85 (m, IH), 7.78 (m, IH), 7.71 (m, IH), 7.65 (m, IH), 7.54 (m, IH)5 7.50 (m, IH), 7.39 (m, IH). Using methods and procedures similar to those described in Intermediates 1 and 2, and in Example 1 (above), the compounds described in Examples 2 through 16 were made.
EXAMPLE 2
3-fluoro-5-(phenylethynyl)benzonitrile
Figure imgf000012_0001
1HNMR 7.64 (s, IH), 7.55 (m, 2H), 7.48 (m, IH), 7.44 (m, 3H), 7.34 (m, IH).
EXAMPLE 3
3-[(3-aminophenyl)ethynyl]-5-fluorobenzonitrile
Figure imgf000012_0002
1H NMR 7.61 (s, IH), 7.44 (m, IH), 7.33 (m, IH), 7.18 (t, IH), 6.96 (m, IH), 6.86 (m, IH), 6.73 (m, IH).
EXAMPLE 4
3-fluoro-5-[(3-methylphenyl)ethynyl]benzonitrile
Figure imgf000013_0001
1HNMR T-Ol (s, IH), 7.46 (m, IH), 7.38-7.3 l(m, 4H), 7.25 (m, IH).
EXAMPLE 5
3 -fluoro-5 - [(3 -fluorophenyl)ethynyl]benzonitrile
Figure imgf000013_0002
1H NMR 7.64 (s, IH), 7.46 (m, IH), 7.38-7.33(m, 3H), 7.25 (m, IH), 7.15 (m, IH).
EXAMPLE 6
3- { [3 -(cy anomethyl)phenyl] ethynyl} -5-fluorobenzonitrile
Figure imgf000013_0003
1H NMR 7.64 (s, IH), 7.55 (m, 2H), 7.47 (m, IH), 7.43(m, IH), 7.38 (m, 2H), 3.80 (s, 2H).
EXAMPLE 7
3-fluoro-5- { [3-(hydroxymethyl)phenyl]ethynyl} benzonitrile
Figure imgf000014_0001
1HNMR 7.60 (s, IH), 7.57 (m, IH), 7.47 (m, 2H), 7.41 (m, 2H), 7.33 (m, IH), 4.73 (s, 2H).
EXAMPLE S
3-[(3-chlorophenyl)ethynyl]-5-fluorobenzonitrile
Figure imgf000014_0002
1H NMR 7.85 (m, IH), 7.78 (m, IH), 7.71 (m, IH)5 7.65 (m, IH), 7.54 (m, IH), 7.50 (m, IH), 7.39 (m, IH). EXAMPLE 9
3-[(3-bromophenyl)ethynyl]-5-fluorobenzonitrile
Figure imgf000015_0001
1HNMR 7.71 (m, IH), 7.63 (m, IH), 7.56 (m, IH), 7.47 (m, 2H), 7.38 (m, IH), 7.29 (m, IH).
EXAMPLE 10
3-fluoro-5-[(3-hydroxyphenyl)ethynyl]benzonitrile
Figure imgf000015_0002
1HNMR 7.62 (m, IH), 7.47 (m, IH), 7.34 (m, IH), 7.28 (m, IH), 7.12 (m, IH), 7.02 (m, IH), 6.92 (m, IH).
EXAMPLE I l
3-fluoro-5~[(2-methylphenyl)ethynyl]benzonitrile
Figure imgf000016_0001
1HNMR 7.62 (m, IH), 7.52 (m, IH), 7.47 (m, IH), 7.31 (m, 2H), 7.29 (m, IH), 7.21 (m, IH), 2.53 (s, 3H).
EXAMPLE 12
3-fluoro-5-[(4-methylphenyl)ethynyl]benzonitrile
Figure imgf000016_0002
1HNMR 7.62 (m, IH), 7.45 (m, 3H), 7.31 (m, IH), 7.21 (m, 2H), 2.40 (s, 3H).
EXAMPLE 13
3-[(2-cyanophenyl)ethynyl]-5-fluorobenzonitrile
Figure imgf000017_0001
1H NMR 7.75 (m, IH), 7.71 (m, IH), 7.66 (m, 2H), 7.58 (m, IH), 7.52 (m, IH), 7.40 (m, IH).
EXAMPLE 14
3-[(4-cyanophenyl)ethynyl]-5-fluorobenzonitrile
Figure imgf000017_0002
1HNMR 7.70 (m, 2H), 7.63 (m, 3H), 7.50 (m, IH), 7.40 (m, IH).
EXAMPLE 15
3 ,3 '-ethyne- 1 ,2-diylbis(5-fluorobenzonitrile)
Figure imgf000018_0001
1HNMR 7.65 (m, 2H), 7.48 (m, 2H), 7.41 (m, 2H).
INTERMEDIATE 3
3-(3-bromo-5-fluorophenoxy)pyridine
Figure imgf000018_0002
3,5-diluorobromoflouro (7g, 28 mmol), 3-hyrdoxypyridine (5 g, 53 mmol), potassium carbonate (10 g) and DMF (300 mL) were heated to 1400C for 18 hours. The reaction was cooled to room temperature, extracted with EtOAc/hexanes (1:1) and washed with water three times. The crude material was purified on silica with 20-40% EtOAc/hexanes as the eluent to yield a colorless oil.
INTERMEDIATE 4
3-(3-ethynyl-5-fluorophenoxy)pyridine
Figure imgf000019_0001
3-(3-bromo-5-fluorophenoxy)pyridine (7 g, 28 mmol), TMS acetylene (5.4 g, 55 mmol), Palladium tetrakis(triphenylphosphine) (1.3 g, 1.1 mmol), copper (I) iodide (0.21 g, 1.1 mmol), and triethylamine (100 mL) were combined and heated to 70 0C for 3 hours. The solution was filtered, solvent evaporated and the crude material puifϊed on silica (25% EtOAc/hexanes) to yield a white solid. The solid material was dissolved in THF (50 mL) and 1 equivalent of TBAF was added and the solution was stirred for 1 hour at room temperature. Methylene chloride was added and the organic layer was washed 3 times with water and evaporated to yield a colorless oil.
EXAMPLE 16
3-{[3-fluoro-5-(pyridin-3-yloxy)phenyl]ethynyl}benzonitrile
Figure imgf000019_0002
3-(3-ethynyl-5-fluoroρhenoxy)pyridine (0.1 g, 0.7 mmol), 3-iodobenzonitrile (0.2 g, 1 mmol), Palladium tetrakis(triphenylphosphine) (0.02, 0.02mol), copper (I) iodide (0.004, 0.02mol), and triethylamine (1 mL), and DMF (2.5 mL) were combined and heated to 700C for 4 hours. The crude solution was filtered and purified directly on RPHPLC to yield an off white solid. 1HNMR 8.5 (b, 2H), 7.6-7.8 (m, 3H), 7.49 (m, 3H), 7.05 (m, IH), 6.92 (s, IH), 6.79 (m, IH). M+ +H: 315.0. Using methods and procedures similar to those described in Intermediates 3 and 4, and in Example 16 (above), the compounds described in Examples 17 through 24 were made.
EXAMPLE 17
3~[3-fluoro-5-(phenylethynyl)phenoxy]pyridine
Figure imgf000020_0001
1HNMR 8.5 (b, 2H), 7.55 (m, 2H), 7.45 (m, 2H), 7.38 (m, 3H), 7.05 (m, IH), 6.97 (s, IH), 6.76 (m, IH). M+ +H: 290.1.
EXAMPLE 18
3 - {3 -fluoro-5- [(3 -methylphenyl)ethynyl]phenoxy } pyridine
Figure imgf000020_0002
1HNMR 8.5 (b, 2H), 7.15-7.48 (m, 6H), 7.05 (m, IH), 6.92 (s, IH), 6.74 (m, IH), 2.35 (s, 3H). M+ +H: 304.1. EXAMPLE 19
3-{3-[(3-chlorophenyl)ethynyl]-5-fluorophenoxy} pyridine
Figure imgf000021_0001
1HNMR 8.5 (b, 2H), 7.2-7.5 (m, 6H), 7.03 (m, IH), 6.92 (s, IH), 6.75 (m, IH). M+ +H: 324.
EXAMPLE 20
3 -fluoro-5 - { [3 -fluoro-5-(pyridin-3 -yloxy)phenyl] ethynyl}benzonitrile
Figure imgf000021_0002
1HNMR 7.3-7.6 (m, 4H), 7.05 (m, IH), 6.92 (s, IH), 6.79 (m, IH). M+ +H: 333.0.
EXAMPLE 21
3-{3~fluoro-5-[(2-methylphenyl)ethynyl]phenoxy}pyridine
Figure imgf000022_0001
1H NMR 8.5 (b, 2H), 7.5 (m, 3H), 7.2-7.3 (m, 3H), 7.05 (m, IH), 6.92 (s, IH), 6.74 (m, IH), 2.5 (s, 3H). M+ +H: 303.8.
EXAMPLE 22
3 - { 3 -fluoro-5 -[(4-methylphenyl)ethynyl]phenoxy } pyridine
Figure imgf000022_0002
1HNMR 8.5 (b, 2H), 7.4-7.5 (m, 4H), 7.3 (d, 2H), 7.05 (m, IH)5 6.92 (s, IH), 6.74 (m, IH), 2.4 (s, 3H). M+ +H: 303.8.
EXAMPLE 23
2-{[3-fluoro-5-(pyridin-3-yloxy)phenyl]ethynyl}benzonitrile
Figure imgf000023_0001
1HNMR 7.4-7.8 (m, 4H), 7.2 (d, 2H), 7.17 (d, IH), 7.06 (s, IH), 6.8 (d, IH). M+ +H: 314.9.
EXAMPLE 24
4-{[3-fluoro-5-(pyridin-3-yloxy)phenyl]ethynyl}benzonitrile
Figure imgf000023_0002
1H NMR 7.4-7.9 (m, 7H), 7.08 (d, IH), 6.97 (s, IH), 6.8 (d, IH). M+ +H: 315.0.
INTERMEDIATE 5
5-bromo-2-piperidin-l-ylpyrimidine
Figure imgf000024_0001
2-chloro-5-bromopyrimidine (3g, 15.5 mmol), piperidine (5.3 g, 62 mmol), and DME (30 mL) were stirred at room temperature for 1 hour. The reaction was extracted with methylenechloride and washed with water three times and the solvent evaporated to yield and off white solid.
INTERMEDIATE 6
5-ethynyl-2-piperidin-l-ylpyrimidine
Figure imgf000024_0002
2-piperidyl-5-bromopyrimidine (3.5 g, 15 mmol), TMS acetylene (2.1 g, 29 mmol), Palladium tetrakis(triphenylphosphine) (0.3 g, 0.3 mmol), copper (I) iodide (0.05 g, 0.3 mmol), triethylamine (10 mL), and toluene (50 mL) were combined and heated to 100 0C for 12 hours. The solution was filtered, solvent evaporated and the crude material purified on silica (25% EtOAc/hexanes) to yield a white solid. The solid material was dissolved in THF (50 mL) and 1 equivalent of TBAF was added and the solution was stirred for 1 hour at room temperature. Methylene chloride was added and the organic layer was washed 3 times with water and evaporated to yield a white solid. EXAMPLE 25
3-[(2-piperidin-l-ylpyrimidin-5-yl)ethynyl]benzonitrile
Figure imgf000025_0001
5-ethynyl-2-piperidin-l-ylpyrimidine (0.1 g, 0.5 mmol), 3-iodobenzonitrile (0.25 g, 1.1 mmol), Palladium tetrakis(triphenylphosphine) (0.02, 0.02mol), copper (I) iodide (0.004, 0.02mol), and triethylamine (1 mL), and DMF (2.5 mL) were combined and heated to 700C for 4 hours. The crude solution was filtered and purified directly on RPHPLC to yield an off white solid. 1H NMR 8.4 (s, 2H), 7.4-7.8 (m, 4H), 3.9 (m, 7H), 2.5 (s, 3H), 1.6-1.7 (m, 6H). M+ +H: 289.1.
Using methods and procedures similar to those described in Intermediates 5 and 6, and in Example 25 (above), the compounds described in Examples 26 through 33 were made.
EXAMPLE 26
5-(phenylethynyl)-2-piρeridin- 1 -ylpyrimidine
Figure imgf000025_0002
1HNMR 8.4 (s, 2H), 7.5 (m, 2H), 7.35 (m, 3H), 3.9 (m, 4H), 1.6-1.7 (m, 6H). M+ +H: 264.1. EXAMPLE 27
5-[(3-methylphenyl)ethynyl]-2-piperidin-l-ylpyrimidine
Figure imgf000026_0001
1H NMR 8.4 (s, 2H), 7.1-7.4 (m, 4H), 3.9 (m, 4H), 1.6-1.7 (m, 6H). M+ +H: 278.0.
EXAMPLE 28
5-[(3-chlorophenyl)ethynyl]-2-piperidin-l-ylpyrimidine
Figure imgf000026_0002
1H NMR 8.4 (s, 2H), 7.3-7.5 (m, 4H), 3.9 (m, 4H), 1.6-1.7 (m, 6H). M+ +H: 297.9.
EXAMPLE 29
5-[(3,5-dimethylphenyl)ethynyl]-2-piperidin-l-ylpyrimidine
Figure imgf000027_0001
1HNMR 8.4 (S5 2H), 7.2 (s, IH), 6.9 (s, IH), 3.9 (m, 4H), 1.6-1.7 (m, 6H).
EXAMPLE 30
5~[(3-methoxyphenyl)ethynyl]-2-piperidin- 1 -ylpyrimidine
Figure imgf000027_0002
1HNMR 8.4 (s, 2H), 7.3 (m, IH), 7.1 (m, 2H), 6.9 (m, IH), 3.9 (m, 7H), 1.6-1.7 (m, 6H). M+ +H: 294.1. EXAMPLE 31
5- { [3 -(methylthio)phenyl]ethynyl} -2-piperidin- 1 -ylpyrimidine
Figure imgf000028_0001
1HNMR 8.4 (s, 2H), 7.2-7.4 (m, 4H), 3.9 (m, 7H), 2.5 (s, 3H), 1.6-1.7 (m, 6H). M+ +H: 309.9
EXAMPLE 32
{3-[(2-piperidin-l-ylpyrimidin-5-yl)ethynyl]benzyl} amine
Figure imgf000028_0002
1HNMR 8.4 (s, 2H), 7.2-7.5 (m, 4H), 4.0 (s, 2H), 3.9 (m, 7H), 2.5 (s, 3H), 1.6-1.7 (m, 6H). M+ +H: 293.0. EXAMPLE 33
{3-[(2-piperidin-l-ylpyrimidin-5-yl)ethynyl]phenyl}acetonitrile
Figure imgf000029_0001
1HNMR 8.4 (s, 2H)5 7.2-7.5 (m, 4H), 3.9 (m, 7H), 3.77 (s, 2H), 2.5 (s, 3H), 1.6-1.7 (m, 6H). M+ +H: 289.1.
While the invention has been described in detail with reference to certain preferred embodiments thereof, it will be understood that modifications and variations are within the spirit and scope of that which is described and claimed.

Claims

WHAT IS CLAIMED IS:
1. A compound having the structure:
A-L-B wherein:
A is phenyl, unsubstituted or substituted with one or more substituent independently selected from:
(a) halogen,
(b) substituted or unsubstituted hydrocarbyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocycle,
(e) mercapto,
(f) nitro,
(g) carboxyl, (h) carbamate, (i) carboxamide, G) hydroxy,
(k) ester, (1) cyano, (m) amine, (n) amide, (o) amidine, (p) amido, (q) sulfonyl or (r) sulfonamide; L is substituted or unsubstituted alkynylene; and B is aryl or heterocycle unsubstituted or substituted with one or more substituent independently selected from:
(a) halogen,
(b) substituted or unsubstituted hydrocarbyl,
(c) substituted or unsubstituted aryl,
(d) substituted or unsubstituted heterocycle,
(e) mercapto,
(f) nitro,
(g) -O-heterocycle, (h) -O-aryl
(i) carboxyl,
(j) carbamate,
(k) carboxamide,
(1) hydroxy,
(m) ester,
(n) cyano,
(o) amine,
(p) amide,
(q) amidine,
(r) amido,
(s) sulfonyl or
(t) sulfonamide; and enantiomers, diastereomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof.
2. The compound of claim 1, wherein B is aryl.
3. The compound of claim 2, wherein B is phenyl.
4. The compound of claim 1, wherein B is heterocycle.
5. The compound of claim 4, wherein B is pyridyl.
6. A compound selected from:
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier therefor.
PCT/US2006/014517 2005-04-22 2006-04-18 Phenyl ethyne compounds Ceased WO2006115895A2 (en)

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WO2008073350A3 (en) * 2006-12-07 2008-08-14 Univ Pennsylvania Acetylene derivatives and their use for binding and imaging amyloid plaques
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US9115056B2 (en) 2007-06-29 2015-08-25 Acucela Inc. Alkynyl phenyl derivative compounds for treating ophthalmic diseases and disorders
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