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WO2010059838A2 - Pde4 inhibitors selective for the long form of pde4 for treating inflammation and avoiding side effects - Google Patents

Pde4 inhibitors selective for the long form of pde4 for treating inflammation and avoiding side effects Download PDF

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Publication number
WO2010059838A2
WO2010059838A2 PCT/US2009/065164 US2009065164W WO2010059838A2 WO 2010059838 A2 WO2010059838 A2 WO 2010059838A2 US 2009065164 W US2009065164 W US 2009065164W WO 2010059838 A2 WO2010059838 A2 WO 2010059838A2
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alkyl
optionally substituted
compound
phenyl
amino
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French (fr)
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WO2010059838A3 (en
Inventor
Jasbir Singh
Mark Gurney
Alexander Kiselyov
Olefur Magnusson
Alex Burgin
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Decode Genetics ehf
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Decode Genetics ehf
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Publication of WO2010059838A2 publication Critical patent/WO2010059838A2/en
Publication of WO2010059838A3 publication Critical patent/WO2010059838A3/en
Anticipated expiration legal-status Critical
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    • 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
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    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
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    • C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
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    • C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
    • C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
    • C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C07C217/86—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical containing six-membered aromatic rings
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    • C07C271/44—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
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    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
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    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
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Definitions

  • the present invention relates to compounds which are inhibitors of phosphodiesterase-4 (PDE4) useful for the treatment and prevention of stroke, myocardial infarct, cardiovascular inflammatory diseases and disorders and central nervous system disorders, to compounds with a selectivity for a non-catalytic portion of PDE4, to methods of determining this selectivity.
  • PDE4 phosphodiesterase-4
  • inhibitors are also known to inhibit all four PDE4 genes (PDE4A, PDE4B, PDE4C and PDE4D), and one possibility to explain the adverse side effects is the inability to selectively inhibit a specific gene or a specific splicing isoform (Ghavami et al. 2006. Drugs R. D. 7, 63-71).
  • inhibitors that specifically inhibit the long form of PDE4 (PDE4D7 or PDE4D5)) but do not inhibit the catalytic domain of PDE4D are expected to be clinically useful for ischemic stroke while avoiding the side effects seen with earlier PDE4 inhibitors.
  • the focus of the present invention is on inhibitors that specifically inhibit PDE4 enzymes containing regulatory domains, but do not efficiently inhibit the catalytic domain of PDE4.
  • the approach taken in the present invention is unusual in that analysis of all known PDE4 inhibitors suggests that they are competitive with cAMP and bind within the active site (Houslay et al. 2005. DDT 10, 1503-1519).
  • the compounds of the present invention are noncompetitive inhibitors of cAMP while being gene-specific inhibitors (PDE4D) and are intended to specifically inhibit long isoforms (PDE4D7).
  • the compounds Based on the target rationale and in vitro potency, a person of skill in the art would expect the compounds to be useful as antiinflammatory agents for the treatment, amelioration or prevention of inflammatory diseases and of complications arising therefrom and useful as CNS agents for amelioration of the cognitive decline in Alzheimer's disease, Parkinson's disease, the treatment of schizophrenia and depression, and neuroprotective in Huntington's disease.
  • PDE4 modulators bind to the PDE4 regulatory domains, particularly to a region of the upstream conserved region 2 (UCR2) present in all splice- isoforms of PDE4A-D [for a description of PDE4 splice-isoforms see, Houslay et al., Drug Discovery Today 10, 1503- 1509 (2005)].
  • Preferred substituents of PDE4 modulators interact with UCR2 residue Phel96 in PDE4D or Tyr274 in PDE4B and adjacent residues.
  • the binding of PDE4 modulators to UCR2 closes the regulatory domain across the PDE4 active site, thereby preventing access of cAMP.
  • PDE4 inhibitors e.g., roflumilast, that bind in the active site competitively with cAMP, do not interact with UCR2.
  • the present invention relates to compounds exhibiting PDE4 enzyme inhibition, further described in the Detailed Description of the Invention section.
  • a pharmaceutical composition comprising a compound as described herein, and a pharmaceutically acceptable carrier, excipient or diluent therefore.
  • the salt should be a pharmaceutically acceptable salt.
  • the invention relates to compounds that show preference for a regulatory segment of a PDE4 isoform over the catalytic portion of a PDE4 isoform.
  • These regulatory segment-containing PDE4 isoforms include PDE4D3, PDE4D4, PDE4D5, PDE4D7, PDE4D8, PDE4D9, PDE4D1, PDE4D2, PDE4D6, PDE4B1, PDE4B3, PDE4B4 and PDE4B2.
  • the invention relates to compounds that are PDE4 modulators.
  • the invention relates to methods for the treatment or prophylaxis of a central nervous system (CNS) disorder or a vascular disorder while minimizing at least one unwanted side effect.
  • the methods comprise administering to a mammal a therapeutically effective amount of a compound of the invention which has a ratio of binding selectivity to a regulatory domain-containing form of PDE4 of at least 100 times the binding selectivity to the catalytic portion of PDE4.
  • Examples of the side effects to be minimized include emesis, nausea and vasculopathy.
  • the invention in another aspect, relates to a method for identifying the selectivity of a potential PDE4-inhibiting compound.
  • This method includes providing at least two different isoforms of PDE4, providing cAMP substrate, providing one or more cofactors, providing an agent for detection of a reaction of cAMP substrate, determining the maximum kinetic rates of reaction of the cAMP substrate in the presence of at least two different isoforms of PDE4, providing a sample containing a test compound, determining the IC50 values of the test compound against the at least two different isoforms of PDE4 and comparing these IC50 values to determine a selectivity ratio.
  • Selective PDE4 inhibitors of the invention may be useful in improving cognition and thus useful for treating learning disorders, memory loss and other cognitive dysfunctions.
  • Selective PDE4 inhibitors of the invention are also useful for treating asthma and Chronic Obstructive Pulmonary Disease (COPD).
  • COPD Chronic Obstructive Pulmonary Disease
  • Compounds of the invention, which inhibit tumor growth and metastases, also find utility in the treatment and prevention of cancer, including esophageal cancer, brain cancer, pancreatic cancer, and colon cancer.
  • alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. A combination would be, for example, cyclopropylmethyl.
  • Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like. Preferred alkyl groups are those of C 2 0 or below; Ci to Cg are more preferred.
  • Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.
  • Ci to C 20 hydrocarbon includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. Hydrocarbon refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.
  • carbocycle (or “carbocyclyl”) is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state.
  • C3-C10 carbocycle refers to both non-aromatic and aromatic systems, including such systems as cyclopropane, benzene, cyclopentene and cyclohexene;
  • Cs-Ci 2 ) carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene.
  • Carbocycle if not otherwise limited, refers to monocycles, bicycles and polycycles.
  • Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purpose of this application, alkoxy and lower alkoxy include methylenedioxy and ethylenedioxy. Alkoxyalkyl refers to ether groups of from 3 to 8 atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an alkyl.
  • Alkoxyaryl refers to alkoxy substituents attached to an aryl, wherein the aryl is attached to the parent structure.
  • Arylalkoxy refers to aryl substituents attached to an oxygen, wherein the oxygen is attached to the parent structure.
  • Substituted arylalkoxy refers to a substituted aryl substituent attached to an oxygen, wherein the oxygen is attached to the parent structure.
  • Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy; 3,6,9-trioxadecyl; 2,6,7-trioxabicyclo[2.2.2]octane and the like.
  • the term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 196, but without the restriction of 127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups.
  • thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons has been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.
  • acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality.
  • One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Lower-acyl refers to groups containing one to four carbons.
  • the double bonded oxygen, when referred to as a substituent itself is called "oxo".
  • Aryl and heteroaryl mean (i) a phenyl group (or benzene) or a monocyclic 5- or 6-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N, or S; (ii) a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-4 heteroatoms selected from O, N, or S; or (iii) a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-5 heteroatoms selected from O, N, or S.
  • Aryl, as understood herein, includes residues in which one or more rings are aromatic, but not all need be.
  • aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
  • Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure through alkyl. Examples are benzyl, phenethyl and the like. Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl.
  • the alkyl group of an arylalkyl or a heteroarylalkyl is an alkyl group of from 1 to 6 carbons. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.
  • Heterocycle means a cycloalkyl or aryl carbocycle residue in which from one to three carbons is replaced by a heteroatom selected from the group consisting of N, O and S.
  • the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • a heterocycle maybe non- aromatic or aromatic. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic.
  • heterocyclic residues that fall within the scope of the invention include pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), morpholine, thiazole, pyridine (including 2-oxopyridine), pyridine N-oxide, pyrimidine, thiophene (i.e.
  • furan oxazole, oxazoline, oxazolidine, isoxazolidine, isoxazole, dioxane, azetidine, piperazine, piperidine, pyrrolidine, pyridazine, azepine, pyrazolidine, imidazole, imidazoline, imidazolidine, imidazolopyridine, pyrazine, thiazolidine, isothiazole, 1,2-thiazine- 1,1 -dioxide, quinuclidine, isothiazolidine, benzimidazole, thiadiazole, benzopyran, benzothiazole, benzotriazole, benzoxazole, tetrahydrofuran, tetrahydropyran, benzothiene, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, oxadiazole, triazo
  • An oxygen heterocycle is a heterocycle containing at least one oxygen in the ring; it may contain additional oxygens, as well as other heteroatoms.
  • Oxygen heterocycles found in the examples of the invention include tetrahydrofuran, benzodioxole, morpholine, isoxazole and 2,6,7-trioxabicyclo[2.2.2]octane.
  • a sulphur heterocycle is a heterocycle containing at least one sulphur in the ring; it may contain additional sulphurs, as well as other heteroatoms.
  • a nitrogen heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms.
  • substituted refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical.
  • substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl (i.e.
  • oxo is included among the substituents referred to in "optionally substituted", it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl). Additional substituents that are considered within the scope of the term, particularly for R 1 , are the are the residues of amino acids, amino acid amides, protected residues of aminoacids and their amides, and N-methylated (mono- or di-, as appropriate) amino acids and amino acid amides.
  • ete ⁇ n -a residue of an amino acid, amino acid amide refers to an amino acid etc. minus the functional groups that are considered part of the bond to the parent structure.
  • haloalkyl and “haloalkoxy” mean alkyl or alkoxy, respectively, substituted with one or more halogen atoms.
  • halogen means fluorine, chlorine, bromine or iodine. In one embodiment, halogen may be fluorine or chlorine.
  • the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include 2 H, 3 H, 13 C, 14 C, 15 N, 35 S, 18 F, and 36 Cl, respectively.
  • Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention.
  • Tritiated, i.e. H, and carbon-14, i.e., 14 C, radioisotopes are particularly preferred for their ease in preparation and detectability.
  • Radiolabeled compounds of the invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radio labeled reagent.
  • a compound is intended to include salts, solvates, co-crystals and inclusion complexes of that compound as well as any stereoisomeric form, or a mixture of any such forms of that compound in any ratio.
  • a compound as described herein including in the contexts of pharmaceutical compositions, methods of treatment, and compounds per se, is provided as the salt form.
  • the recitation "a compound of the invention” as depicted above, in which R 1 is imidazolyl would include imidazolium salts.
  • the term “compound of the invention” refers to the compound or a pharmaceutically acceptable salt thereof.
  • the compounds described herein may contain asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, in any ratio from racemic to optically pure forms.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the prefix "rac" refers to a racemate.
  • solvate refers to a compound of The invention in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice.
  • a suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered.
  • suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate.
  • solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions.
  • Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19 th Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable anions for the compounds of the present invention include acetate, benzenesulfonate (besylate), benzoate, bicarbonate, bisulfate, carbonate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, glycolate, bromide, chloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, trifluoroacetate, p-toluenesulfonate, acetamidobenzoate, adipate, alginate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, calcium edetate, camphorate, camsylate, caprate, caproate, caprylate, cinnamate,
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
  • a protecting group refers to a group, which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
  • the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere.
  • Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T. W. Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference.
  • PDED7 (D7, long form), PDE4D1 (Dl, short form), PDE4D2 (D2, supershort form), PDE4-Cat (D-Cat, catalytic form) and PDE4B1 (Bl, long form) are diagrammed.
  • Upstream conserved regions 1 (UCRl) and 2 (UCR2) are shown with horizontal lines and cross-hatched lines, respectively.
  • the conserved C-terminal domain is shown in gray, and the isoform specific N-terminal domains are unfilled (white).
  • PDE4D7 and PDE4B1 contain the Ser/Asp mutation to mimic the activated (phosphorylated) form of the enzyme [shown as vertical stripe in UCRl (horizontal lines)].
  • the catalytic domain common to all isoforms is shown as the stippled section.
  • a "long form" isoform defines a PDE4 isoform that contains a catalytic domain, upstream conserved region 1 (UCRl), upstream conserved region 2 (UCR2), and a C-terminal (C-term) domain. Long forms are exemplified by PDE4D7 and PDE4B 1 below.
  • a “short form” isoform contains the catalytic domain, UCR2 and C-term, but does not contain UCRl; the short form is exemplified by PDE4D1 below.
  • a “super-short form”isoform contains the catalytic domain, C-term and a portion of UCR2, but does not contain UCRl; the super-short form is exemplified below by PDE4D2.
  • the isoforms shown below in cartoon form are not exhaustive for these definitions, but merely exemplary.
  • a "regulatory segment” indicates a segment of PDE4 that is not the catalytic domain.
  • the term "regulatory domain-containing form” indicates any isoform of PDE4 that includes a non-catalytic domain.
  • I ⁇ mx is defined as the percent inhibition at the maximum concentration of a compound.
  • maximum concentration is defined as fifty times the IC50 of the compound in question.
  • a “mixed inhibitor” (or “full inhibitor”) of PDE4 is defined as a compound which shows selectivity for a regulatory domain-containing of PDE4 over the catalytic domain and shows an I max > 95%. These compounds show full enzyme inhibition, defined as 95-100% inhibition.
  • a "partial inhibitor” or “modulator” of PDE4 is defined as a compound which shows selectivity for a regulatory domain-containing of PDE4 over the catalytic domain and shows an I max ⁇ 95%.
  • Modulators of PDE4 are expected to exhibit an improved therapeutic ratio.
  • a “competitive inhibitor” is a compound that shows inhibition by binding to the catalytic domain.
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
  • the starting materials are either commercially available, synthesized as described in the examples or may be obtained by the methods well known to persons of skill in the art.
  • PDE4 inhibitors have been shown to be effective therapeutic agents in clinical studies. For example, administration of cilomilast and roflumilast (PDE4 inhibitors) to patients suffering from asthma and COPD showed initially excellent results, although the effect of cilomilast disappeared on long-term trial [Lipworth, Lancet 365, 167-175 (2005)]. Genetic studies have clearly demonstrated an association between PDE4D and ischemic stroke (Gretarsdottir et al. 2003. Nature Genetics. 35, 1-8). L-454,560, a selective PDE4 inhibitor has been shown to improve learning in a rat model in vivo [Huang et al. Biochemical Pharmacology 73, 1971-1981 (2007)].
  • Rolipram another selective PDE4 inhibitor, has been shown to enhance cognition in multiple rodent models [Blokland et al., Current Pharmaceutical Design 12, 2511-2523 (2006)] as well as in primates [Rutten et al., 2008, Psychopharmacology 196, 643-648 (2008)]. Rolipram also improves the outcome in two separate studies in mice in vivo in models accepted by persons of skill in the art as predictive of utility in schizophrenia [Kanes et al., Neuroscience 144. 239-246 (2007); Davis and Gould, Behav.Neurosci. 119, 595-602 (2005)].
  • Rolipram has also been shown to exhibit a neuroprotective effect in a rat model of Huntington's disease [DeMarch et al. Neurobiol.Dis. 25, 266-273 (2007)]. This suggests that PDE4 modulators will be useful for treating many CNS disorders. Selective PDE4 inhibitors (e.g. rolipram) are also useful for treating bone loss [Yao et al., J.Musculoskelet.Neuronal Interact. 7. 119-130 (2007)].
  • a PDE4 inhibitor YM976 was shown to ameliorate the effects of experimentally- induced interstitial cystitis in rats, resulting in a decrease in the frequency of urination and an increase in the volume of urine at each time of urination [Kitta et al., BJU Int. 102. 1472-1476 (2008)].
  • the compounds, compositions and methods of the present invention may be useful in treating cancer.
  • Phosphodiesterase activity has been shown to be associated with hematological malignancies [Lerner et al., Biochem.J. 393, 21-41 (2006); Ogawa et al., Blood 99, 3390-3397 (2002)].
  • the compounds may also be administered to overcome cognitive impairment induced by one or more of the following agents, alcohol, amphetamine, antipsychotic medication, anti-retroviral therapy, MDMA ( 3,4-methylenedioxy-N- methylamphetamine, cannabis, cocaine, delta-9 tetrahydrocannabinol, dexamphetamine, haloperidol, heroin and other opiates, ketamine and metamphetamine.
  • MDMA 3,4-methylenedioxy-N- methylamphetamine
  • cannabis cocaine, delta-9 tetrahydrocannabinol, dexamphetamine, haloperidol, heroin and other opiates, ketamine and metamphetamine.
  • the compounds, compositions and methods of the present invention may be employed as imaging agents and in other ways for diagnosis and/or treatment.
  • immobilization of compounds of the invention on solid support could be of utility for affinity purification and modification of compounds of the invention with chemically active groups may be used for protein labeling.
  • cholinesterase inhibitors e.g. tacrine, huperzine, donepezil
  • NMDA antagonists e.g. lanicemine, remacemide, neramexane, memantine
  • calpain inhibitors e.g. CEP-3122
  • antioxidants e.g.vitamin E, coenzyme QlO
  • agents that have shown clinical efficacy but whose mechanism is unclear e.g. dimebon.
  • Compounds of the invention may also be administered together with one or more of the following agents to improve cognition: amisulpride, atomoxetine, bromocryptine, buspirone, caffeine, chlorpromazine, clonidine, clozapine, diazepam, flumazenil, fluoxetine, galantamine, guanfacine, methylphenidate, idazoxan, modafinil, olanzapine, paroxetine, pergolide, phenserine, quetiapine, risperidone, rivastigmine, SGS742 and sulpiride.
  • the terms "methods of treating or preventing” mean amelioration, prevention or relief from the symptoms and/or effects associated with CNS or vascular disorders.
  • the term "preventing” as used herein refers to administering a medicament beforehand to forestall or obtund an acute episode.
  • the person of ordinary skill in the medical art recognizes that the term “prevent” is not an absolute term.
  • the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, and this is the sense intended in applicants' claims.
  • reference to "treatment” of a patient is intended to include prophylaxis.
  • mamal is used in its dictionary sense. Humans are included in the group of mammals, and humans would be the preferred subjects of the methods.
  • the cognitive impairment to be treated may arise from one or more of the following disorders, which may not in themselves be necessarily associated with PDE4 abnormality: acute pain, AD/HD - Attention deficit hyperactivity disorder, AIDS dementia complex, alcoholism, amphetamine addiction, amygdalo-hippocampectomy, anorexia nervosa, anterior parietal damage, antisocial behavior, antisocial personality disorder, anxiety, autism, basal ganglia lesions, bipolar disorder, borderline personality disorder, camptocormia, capgras syndrome, carcinoid syndrome, carotid endarterectomy surgery, chronic drug misuse, chronic fatigue syndrome, chronic occupational solvent encephalopathy, chronic pain, brain ischemia, coronary artery bypass surgery, critical illness requiring intensive care, dementia Alzheimer-type (DAT), dementia Lewy Body type, dementia of frontal type, dementia caused by ischemia, dental pain, developmental dyslexia, diabetes, dorsolateral frontal cortical compression, Down's Syndrome, drug abuse, dysexecutive syndrome,
  • a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration.
  • the most suitable route may depend upon the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association a compound of the invention or a pharmaceutically acceptable salt or solvate thereof ("active ingredient”) with the carrier, which constitutes one or more accessory ingredients.
  • active ingredient a pharmaceutically acceptable salt or solvate thereof
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein.
  • the pharmaceutical compositions may include a "pharmaceutically acceptable inert carrier", and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques, "Pharmaceutically acceptable carrier” also encompasses controlled release means.
  • compositions may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient must be compatible with the compound of the invention to insure the stability of the formulation.
  • the composition may contain other additives as needed, including for example lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino acids, for example alanine, glycine and betaine, and peptides and proteins, for example albumen.
  • additives including for example lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino
  • excipients for use as the pharmaceutically acceptable carriers and the pharmaceutically acceptable inert carriers and the aforementioned additional ingredients include, but are not limited to binders, fillers, dis integrants, lubricants, anti-microbial agents, and coating agents.
  • the dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
  • the precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity.
  • a dosage unit (e.g. an oral dosage unit) can include from, for example, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to 500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g.
  • compositions and their formulation For additional information about pharmaceutical compositions and their formulation, see, for example, Remington: The Science and Practice of Pharmacy, 20 th Edition, 2000.
  • the agents can be administered, e.g., by intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, topical, sublingual, intraarticular (in the joints), intradermal, buccal, ophthalmic (including intraocular), intranasaly (including using a cannula), or by other routes.
  • the agents can be administered orally, e.g., as a tablet or cachet containing a predetermined amount of the active ingredient, gel, pellet, paste, syrup, bolus, electuary, slurry, capsule, powder, granules, as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, via a micellar formulation (see, e.g. WO 97/11682) via a liposomal formulation (see, e.g., EP 736299,WO 99/59550 and WO 97/13500), via formulations described in WO 03/094886 or in some other form.
  • a micellar formulation see, e.g. WO 97/11682
  • a liposomal formulation see, e.g., EP 736299,WO 99/59550 and WO 97/13500
  • the agents can also be administered transdermally (i.e. via reservoir-type or matrix-type patches, microneedles, thermal poration, hypodermic needles, iontophoresis, electroporation, ultrasound or other forms of sonophoresis, jet injection, or a combination of any of the preceding methods (Prausnitz et al. 2004, Nature Reviews Drug Discovery 3:1 15)).
  • the agents can be administered locally, for example, at the site of injury to an injured blood vessel.
  • the agents can be coated on a stent.
  • the agents can be administered using high- velocity transdermal particle injection techniques using the hydrogel particle formulation described in U.S. 20020061336. Additional particle formulations are described in WO 00/45792, WO 00/53160, and WO 02/19989.
  • WO 96/11705 provides formulations suitable for transdermal administration.
  • the agents can be administered in the form a suppository or by other vaginal or rectal means.
  • the agents can be administered in a transmembrane formulation as described in WO 90/07923.
  • the agents can be administered non-invasively via the dehydrated particles described in U.S. 6,485,706.
  • the agent can be administered in an enteric-coated drug formulation as described in WO 02/49621.
  • the agents can be administered intranasaly using the formulation described in U.S. 5,179,079.
  • Formulations suitable for parenteral injection are described in WO 00/62759.
  • the agents can be administered using the casein formulation described in U.S. 20030206939 and WO 00/06108.
  • the agents can be administered using the particulate formulations described in U.S. 20020034536.
  • the agents can be administered by pulmonary route utilizing several techniques including but not limited to intratracheal instillation (delivery of solution into the lungs by syringe), intratracheal delivery of liposomes, insufflation (administration of powder formulation by syringe or any other similar device into the lungs) and aerosol inhalation.
  • Aerosols e.g., jet or ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry-Powder inhalers (DPIs)
  • MDIs metered-dose inhalers
  • DPIs dry-Powder inhalers
  • Aerosol formulations are stable dispersions or suspensions of solid material and liquid droplets in a gaseous medium and can be placed into pressurized acceptable propellants, such as hydrofluoroalkanes (HFAs, i.e. HFA-134a and HFA-227, or a mixture thereof), dichlorodifluoromethane (or other chlorofluorocarbon propellants such as a mixture of Propellants 11, 12, and/or 114), propane, nitrogen, and the like.
  • HFAs hydrofluoroalkanes
  • HFA-134a and HFA-227 or a mixture thereof
  • dichlorodifluoromethane or other chlorofluorocarbon propellants such as a mixture of Propellants 11, 12, and/or 114
  • propane nitrogen, and the like.
  • Pulmonary formulations may include permeation enhancers such as fatty acids, and saccharides, chelating agents, enzyme inhibitors (e.g., protease inhibitors), adjuvants (e.g., glycocholate, surfactin, span 85, and nafamostat), preservatives (e.g., benzalkonium chloride or chlorobutanol), and ethanol (normally up to 5% but possibly up to 20%, by weight). Ethanol is commonly included in aerosol compositions as it can improve the function of the metering valve and in some cases also improve the stability of the dispersion. Pulmonary formulations may also include surfactants which include but are not limited to bile salts and those described in U.S.
  • the surfactants described in U.S. 6,524,557 e.g., a Cg-Ci ⁇ fatty acid salt, a bile salt, a phospholipid, or alkyl saccharide are advantageous in that some of them also reportedly enhance absorption of the compound in the formulation.
  • dry powder formulations comprising a therapeutically effective amount of active compound blended with an appropriate carrier and adapted for use in connection with a dry-Powder inhaler.
  • Absorption enhancers which can be added to dry powder formulations of the present invention include those described in U.S. 6,632,456.
  • WO 02/080884 describes new methods for the surface modification of powders. Aerosol formulations may include U.S.
  • Pulmonary formulations containing stable glassy state powder are described in U.S. 20020141945 and U.S. 6,309,671.
  • Other aerosol formulations are described in EP 1338272A1 WO 90/09781, U. S. 5,348,730, U.S. 6,436,367, WO 91/04011, and U.S. 6,294,153 and U.S. 6,290,987 describes a liposomal based formulation that can be administered via aerosol or other means.
  • Powder formulations for inhalation are described in U.S. 20030053960 and WO 01/60341.
  • the agents can be administered intranasally as described in U.S. 20010038824.
  • Solutions of medicament in buffered saline and similar vehicles are commonly employed to generate an aerosol in a nebulizer.
  • Simple nebulizers operate on Bernoulli's principle and employ a stream of air or oxygen to generate the spray particles.
  • More complex nebulizers employ ultrasound to create the spray particles. Both types are well known in the art and are described in standard textbooks of pharmacy such as Sprowls' American Pharmacy and Remington's The Science and Practice of Pharmacy.
  • Other devices for generating aerosols employ compressed gases, usually hydrofluorocarbons and chlorofluorocarbons, which are mixed with the medicament and any necessary excipients in a pressurized container, these devices are likewise described in standard textbooks such as Sprowls and Remington.
  • the agent can be incorporated into a liposome to improve half-life.
  • the agent can also be conjugated to polyethylene glycol (PEG) chains.
  • PEG polyethylene glycol
  • Methods for pegylation and additional formulations containing PEG-conjugates i.e. PEG-based hydrogels, PEG modified liposomes
  • the agent can be administered via a nanocochleate or cochleate delivery vehicle (BioDelivery Sciences International).
  • the agents can be delivered transmucosally (i.e. across a mucosal surface such as the vagina, eye or nose) using formulations such as that described in U.S. 5,204,108.
  • the agents can be formulated in microcapsules as described in WO 88/01165.
  • the agent can be administered intra-orally using the formulations described in U.S. 20020055496, WO 00/47203, and U.S. 6,495,120.
  • the agent can be delivered using nanoemulsion formulations described in WO 01/91728A2.
  • compounds of the invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
  • the invention relates to compounds of formula:
  • R 31 is chosen from (Ci-C/Oalkoxy, amino, hydroxy, (Ci- C6)alkylamino and di(Ci-C6)alkylamino.
  • R 4 is chosen from H and F.
  • R 6 is chosen from H, (Ci-C 6 )alkyl and halogen.
  • B is an optionally substituted carbocycle. In some embodiments, B is an optionally substituted heterocycle of two or fewer rings.
  • n is zero, one or two.
  • A is an optionally substituted carbocycle. In other embodiments A is an optionally substituted heterocycle of three or fewer rings.
  • X is selected from the group consisting of N, N ⁇ O, or C-R 5 .
  • R 5 is chosen from H, halogi OH, (Ci-C 6 )alkyl, (Ci-C 6 )alkoxy, CF 3 , CN, NH 2 , CH 2 OH, CH 2 NH 2 and C ⁇ CH.
  • the compounds are of formula
  • U is S. In other embodiments, U is O.
  • V is selected from the group consisting of H, CH 3 , NH 2 , and CF 3
  • Z is selected from the group consisting of CH, C- F, C-Cl, C-Br, C-I, C-NH 2 , C-OH, C-OCH 3 , N, and N-O.
  • Y is selected from the group consisting of N, CH, CF and C-Io was alkyl.
  • R >40 is H or lower alkyl
  • R 41 is selected from the group consisting of H, alkyl, OH, NH 2 , and OCH 3 .
  • G is an optionally substituted, mono- or bicyclic aryl or heteroaryl.
  • E is an optionally substituted heterocycle or an optionally substituted carbocycle.
  • the compounds are of formula
  • R 1 is chosen from H, (Ci- C8)alkyl and halo(Ci-Cg)alkyl.
  • R 2 is chosen from H and halo.
  • Ar 1 is selected from optionally substituted phenyl and ooppttiioonnaallllyy ssuubbssttiittuutteedd hheetteerrooaarryyll.. 1
  • Ar 2 is selected from substituted phenyl and substituted heteroaryl.
  • the compounds are of formula or salt thereof wherein
  • AA is selected from N and CR 50 ;
  • DD is selected from N and CR 50 , with the proviso that both AA and DD cannot be N;
  • R 50 is selected from hydrogen, (Ci-Ce)alkyl, fluoro, hydroxyalkyl, carbonyl and amide;
  • J is a substituted 5-membered heterocycle
  • Cy 1 is selected from optionally substituted phenyl and optionally substituted heteroaryl
  • R 45 is selected independently in one or more occurrences from hydrogen, halogen and (Ci-C 6 ) alkyl;
  • R 46 is selected from (1) hydrogen, halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylamino
  • both AA and DD are CR 50 .
  • R 50 is hydrogen.
  • only one of AA or DD are nitrogen.
  • J is selected from optionally substituted 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, furane, thiophene, isoxazole, pyrazole, tetrahydrofurane, tetrahythiophene and isoxazoline; and R 46 is selected from hydroxy(Ci-C6)alkyl; hydroxy(Ci-C 6 )alkyoxy; phenyl optionally substituted with amino, halogen, hydroxy, alkylsulfonylamino or (Ci-C 6 ) alkylurea; and pyridinyl optionally substituted with amino, halogen, hydroxy, alkylsulfonylamino
  • the compounds are of
  • J is a substituted 5-membered heterocycle
  • L is selected from O, S and NR b ;
  • R a is selected from H and (Ci-C 6 ) alkyl
  • R b is selected from H and (Ci-C 6 ) alkyl
  • Cy 1 is selected from optionally substituted phenyl and optionally substituted heteroaryl
  • R 45 is selected independently in one or more occurrences from hydrogen, halogen, (Ci-C 6 ) alkyl;
  • R 46 is selected from (1) halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalky
  • J is selected from optionally substituted 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, furane, thiophene, isoxazole, pyrazole, tetrahydrofurane, tetrahythiophene and isoxazoline;
  • R 46 is selected from hydroxy(Ci- C6)alkyl; hydroxy(Ci-Ce)alkyoxy; phenyl optionally substituted with amino, halogen, hydroxy, alkylsulfonylamino or (Ci-C ⁇ ) alkylurea; and pyridinyl optionally substituted with amino, halogen, hydroxy, alkylsulfonylamino or (Ci-C ⁇ ) alkylurea.
  • the compounds are of
  • AA is selected from N and CR 50 ;
  • DD is selected from N and CR 50 , with the proviso that both AA and DD cannot be N;
  • R 50 is selected from hydrogen, (Ci-C6)alkyl, fluoro, hydroxyalkyl, carbonyl and amide;
  • Q is selected from O, NH, S, SO and SO 2 ;
  • T is selected from CONH, CH 2 NHCO, CHR d NHCO, CHR d NHSO 2 , and CHR e X a CHR c ;
  • X a is selected from O, NH, S, SO and SO 2 ;
  • R c , R d and R e are each independently selected from hydrogen, (Ci-C ⁇ ) alkyl, hydroxy(Ci-
  • Cy 1 is selected from optionally substituted phenyl and optionally substituted heteroaryl; and R 47 is selected from hydroxy(Ci-C6)alkyl, hydroxy(Ci-Ce)alkyoxy, carbocyclyl and heterocyclyl, wherein the cyclyl is optionally substituted with a substituent selected from (1) halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alky
  • AA and DD are both CR 50 .
  • R 50 is hydrogen.
  • either AA or DD are nitrogen.
  • the compounds are of
  • Q is selected from O, NH, S, SO and SO 2 ;
  • L is selected from O, S and NR b ;
  • R a is selected from H and (Ci-C 6 ) alkyl
  • R b is selected from H and (Ci-C 6 ) alkyl
  • T is selected from CONH, CH 2 NHCO, CHR d NHC0, CHR d NHSO 2 , CHR e X a CHR c , and
  • X a is selected from O, NH, S, SO and SO 2 ;
  • R c , R d and R e are each independently selected from hydrogen, (Ci-C 6 ) alkyl, hydroxy(Ci-
  • Cy 1 is selected from optionally substituted phenyl and optionally substituted heteroaryl
  • R 47 is selected from hydroxy(Ci-C 6 )alkyl, hydroxy(Ci-C 6 )alkyoxy, carbocyclyl and heterocyclyl, wherein the cyclyl is optionally substituted with a substituent selected from (1) halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyl
  • the compounds are of formula or a salt thereof wherein
  • P is chosen from nitrogen and carbon
  • Q is chosen from nitrogen and carbon, with the provisos that one of P or Q must be nitrogen, but P and Q cannot both be nitrogen;
  • R 1 is selected from hydrogen, (Ci-C ⁇ ) alkyl, haloalkyl, -CONHR 5 , lower alkoxy, alkylamino, dialkylamino, amino, -NHCOOR 2 and -OCONH 2 ;
  • W is nitrogen or CR 2 ;
  • R 2 is selected from hydrogen, (Ci-C ⁇ ) alkyl, haloalkyl and optionally substituted heterocyclyl; Y is CR 3 or nitrogen;
  • R 3 is selected from hydrogen, fluoro, hydroxyl and -OR 10 ;
  • R 10 is selected from (Ci-C ⁇ ) alkyl optionally substituted with fluoro;
  • X is selected from CR 4 , nitrogen and N + O " ;
  • R 4 is selected from hydrogen, (Ci-C ⁇ ) alkyl, halogen, amino, alkoxy and hydroxyl
  • R 5 is selected from hydrogen and (Ci-C ⁇ ) alkyl
  • q is selected from O, S(0)o -2 , NH, CH 2 and a direct bond
  • Cy 1 is selected from optionally substituted (C3-C6) carbocyclyl and optionally substituted heterocyclyl; Cy 2 is selected from optionally substituted aryl and optionally substituted heteroaryl; and
  • M is chosen from -CH 2 -, -CH 2 CH 2 -, -0-, -S(O) 0-2 , -OCH 2 , -CH 2 O, -CONH, - CONHCH 2 , -NHCO and -NHSO 2 .
  • the compounds are of formula or a salt thereof wherein
  • P is chosen from nitrogen and carbon
  • Q is chosen from nitrogen and carbon, with the provisos that one of P or Q must be nitrogen, but P and Q cannot both be nitrogen;
  • R 1 is selected from hydrogen, (Ci-C ⁇ ) alkyl, haloalkyl, -CONHR 5 , lower alkoxy, alkylamino, dialkylamino, amino, -NHCOOR 2 and -OCONH 2 ;
  • W is nitrogen or CR 2 ;
  • R 2 is selected from hydrogen, (Ci-C ⁇ ) alkyl, haloalkyl and optionally substituted heterocyclyl;
  • X is selected from CR 4 , nitrogen and N + O " ;
  • R 4 is selected from hydrogen, (Ci-C ⁇ ) alkyl, halogen, amino, alkoxy and hydroxyl
  • R 5 is selected from hydrogen and (Ci-C ⁇ ) alkyl
  • R 8 and R 9 are independently selected from hydrogen, (Ci-C ⁇ ) alkyl, (Ci-C ⁇ ) hydroxyalkyl, (C3-C6) carbocyclyl and a 3- to 6-membered heterocyclyl; or R 8 and R 9 together form a 4-6 membered ring which optionally contains a heteroatom selected from -0-, -NR 5 and S(0)o -2 ; or R 8 and R 9 together form an oxo group; q is selected from O, S(0)o -2 , NH, CH 2 and a direct bond;
  • Cy 1 is selected from optionally substituted (C3-C6) carbocyclyl and optionally substituted heterocyclyl; Cy 2 is selected from optionally substituted aryl and optionally substituted heteroaryl; and
  • M is chosen from -CH 2 -, -CH 2 CH 2 -, -0-, -S(O) 0-2 , -OCH 2 , -CH 2 O, -CONH, - CONHCH 2 , -NHCO and -NHSO 2 ,
  • the compounds are of formula or a salt thereof wherein
  • R 2 is selected from hydrogen, (Ci-C ⁇ ) alkyl, haloalkyl and optionally substituted heterocyclyl; q is selected from O, S(0)o -2 , NH, CH 2 and a direct bond; Cy 1 is an optionally substituted, mono- or bicyclic aryl or heteroaryl; and Cy 2 is an optionally substituted heterocycle or an optionally substituted carbocycle.
  • the compounds are of formula
  • R 1 is selected from hydrogen, (Ci-C ⁇ ) alkyl, haloalkyl, -CONHR 5 , lower alkoxy, alkylamino, dialkylamino, amino, -NHCOOR 2 and -OCONH 2 ;
  • W is nitrogen or CR 2 ;
  • R 2 is selected from hydrogen, (Ci-C ⁇ ) alkyl, haloalkyl and optionally substituted heterocyclyl; q is selected from O, S(0)o -2 , NH, CH 2 and a direct bond; j-k is selected from 0-N, N(R 2a )-N and N-N(R 2a );
  • R 2a is selected from hydrogen, (Ci-C ⁇ ) alkyl, haloalkyl, aminoalkyl, acyl, alkoxyalkyl, hydroxyalkyl, phenyl, heteroaryl, oxaalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylaminoalkyl, aminocarbonylalkyl, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, aryl, benzyl, heterocyclyl, and heterocyclylalkyl;
  • Cy 1 is an optionally substituted, mono- or bicyclic aryl or heteroaryl
  • Cy 2 is an optionally substituted heterocycle or an optionally substituted carbocycle.
  • the compounds are of formula
  • b is selected from the group consisting of S, O and NR 2b ;
  • R 2b is selected from hydrogen, (Ci-C ⁇ ) alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, and alkoxycarbonyl;
  • V is selected from the group consisting of H, CH 3 , NH 2 , NR 2c , OR 2d , carboxylic acid, SO 2 NH, S(O) 0-2 and CF 3 ;
  • R 2c is selected from hydrogen, (Ci-C ⁇ ) alkyl, hydroxyalkyl, haloalkyl, aminoalkyl and alkoxycarbonyl;
  • R 2d is selected from hydrogen, (Ci-C ⁇ ) alkyl, hydroxyalkyl, haloalkyl, aminoalkyl and alkoxycarbonyl; q is selected from O, S(0)o -2 , NH, CH 2 and a direct bond;
  • Y is selected from the group consisting of N, CH, CF and C-lower alkyl;
  • R 40 is H or lower alkyl;
  • R 41 is selected from the group consisting of H, alkyl, OH, NH 2 , and OCH 3 ;
  • Cy 1 is an optionally substituted, mono- or bicyclic aryl or heteroaryl
  • Cy 2 is an optionally substituted heterocycle or an optionally substituted carbocycle.
  • the compounds are of formula or a salt thereof wherein q is selected from O, S(0)o -2 , NH, CH2 and a direct bond;
  • Cy 1 is an optionally substituted, mono- or bicyclic aryl or heteroaryl
  • Cy 2 is an optionally substituted heterocycle or an optionally substituted carbocycle.
  • q is CH 2 ; M is CH 2 O; Cy 1 is optionally substituted phenyl; and Cy 2 is phenyl optionally substituted with amino or (Ci-C ⁇ ) alkylurea.
  • the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the invention is a compound of the invention wherein said compound shows preference for a regulatory segment of a PDE4 isoform over the catalytic portion of a PDE4 isoform.
  • the PDE4 isoform is selected from a regulatory domain-containing form of PDE4 and may be selected from PDE4D3, PDE4D4, PDE4D5, PDE4D7, PDE4D8, PDE4D9, PDE4D1, PDE4D2, PDE4D6, PDE4B1, PDE4B3, PDE4B4 and PDE4B2.
  • the regulatory domain-containing form of PDE4 is the long form, and is selected from PDE4D3, PDE4D4, PDE4D5, PDE4D7, PDE4D8, PDE4D9, PDE4B1, PDE4B3 and PDE4B4.
  • the PDE4 isoform is the short form, and is selected from PDE4D1 or PDE4B2.
  • the PDE4 isoform is the super-short form, and is selected from PDE4D2 or PDE4D6.
  • a compound of the invention is a PDE4 modulator wherein said modulator has an I n ⁇ x ⁇ 95%.
  • I mx is defined as the percent inhibition at the maximum concentration, and the maximum concentration is defined as a concentration at least 50-fold higher than the IC50 of the compound at the regulatory-containing domain of PDE4.
  • the modulator has an I max ⁇ 90%.
  • the invention relates to a method for treating or preventing CNS-related disorders or vascular disorders while minimizing at least one unwanted side effect comprising administering a compound of the invention having a ratio of binding selectivity to a regulatory domain-containing form of PDE4 of at least 100 times the binding selectivity to the catalytic portion of PDE4.
  • the ratio of binding selectivity to a regulatory domain-containing form of PDE4 is at least 1000 times the binding selectivity to the catalytic portion of PDE4.
  • the ratio of binding selectivity to a regulatory domain-containing form of PDE4 is at least 10,000 times the binding selectivity to the catalytic portion of PDE4.
  • the invention relates to a method of minimizing the side effect of nausea.
  • the side effect to be minimized is emesis.
  • the side effect to be minimized is vasculopathy.
  • the invention relates to a method for identifying the selectivity of a potential PDE4-inhibiting compound comprising: i. providing at least two different isoforms of PDE4, ii. providing cAMP substrate; iii. providing one or more cofactors; iv. providing an agent for detection of a reaction of cAMP substrate; v. determining the maximum kinetic rates of reaction of said cAMP substrate in the presence of said at least two different isoforms of PDE4; vi. providing a sample containing a test compound; vii. determining the IC50 values of said test compound against said at least two different isoforms of PDE4; and viii.
  • the at least two different isoforms of PDE4 are selected from PDE4D7, PDE4D1, PDE4D2, PDE4D-Cat and PDE4B1.
  • at least one of the PDE4 isoforms is selected from PDE4D7 and PDE4Bl.
  • the one or more cofactors are selected from adenylate kinase, pyruvate kinase, phosphoenolpyruvate, lactate dehydrogenase and NADH.
  • agent for detection of a reaction of cAMP substrate is detected by spectrophotometry, fluorescence or radionucleide.
  • the agent for detection of a reaction of cAMP substrate is NADH.
  • the compound is selected from the following:
  • Table 1 above lists compounds representative of embodiments of the invention. Processes for obtaining compounds of the invention are presented below. Other compounds of the invention may be prepared in analogous fashion to those whose synthesis is exemplified herein. The procedures below illustrate such methods. Furthermore, although the syntheses depicted herein may result in the preparation of enantiomers having a particular stereochemistry, included within the scope of the present invention are compounds of the invention in any stereoisomeric form, and preparation of compounds of the invention in stereoisomeric forms other than those depicted herein would be obvious to one of ordinary skill in the chemical arts based on the procedures presented herein.
  • the substituent at C8 can be introduced either before formation of the bicyclic core (S2) by Suzuki/Stille reaction allowing C-C bond formatting chemistries.
  • the intermediate S3 could be reacted by Buchwald or Cu mediated chemistries to for ether/amine linked C8 substituent (S7).
  • the substituent at the C-6 position can be introduced by a wide variety of approaches.
  • Y is an alkyl, ester, nitrile
  • S6/S7 containing alcohol alkyl halide (W)
  • W alkyl halide
  • the carbonate or -CH 2 -Br (W, S6/S7) upon reaction via organometallic coupling protocols (e.g.
  • the alcohol can be converted to a primary or secondary amine.
  • the W as acid or amine thus allows formation of amide, reverse amide, sulfonamide from acylation /sulfonation chemistries or diverse amine via reductive amine chemistry approaches.
  • the substituents containing additional functions groups allow subsequent elaboration by standard chemistries outlines above depending upon the functional groups introduced at C6. These strategies allow incorporation of acyclic, heterocyclic or heteroaryl derived substituents at the C6 / C8 position of the imidazo[l,2-a]pyridine/ imidazo[l,2-a]pyrazine core.
  • pyrozolo[l,5-a]pyridine can be obtained from 2,4-substituted pyridine (S12) via S13. N-amination of 2,4-disubstituted pyridine (S12) by 0-2- mesitylenesulfonyl hydroxyamine provides intermediate (S13). Subsequent 1,3-dipolar cycloaddition with methyl propiolate furnish the pyrozolo[l,5-a]pyridine (S14), which can subsequently be transformed into the decarboxylated product (S15) under acidic conditions.
  • substitution at C-6 position can be obtained via the ester group at C-6 position by similar approaches described above for Gl analogs.
  • the introduction of the substitutions at C-8 position to form a C-C bond can be accomplished by metal assisted cross coupling reactions.
  • the key intermediate pyrazolo[l,5-a]pyrimidine can be also obtained from S25.
  • the intermediate S25 in turn can be obtained from S18 via bromination and subsequent conversion to the ketone S24. Reaction of S25 with an orthoformate would then provide S26.
  • the final substituent can be introduced as part of formation of S24; in such case cyclization of S25 to S26 directly would yield the desired analogs.
  • Compounds of the Formula G6-a can be obtained from the intermediate 5H- pyrazolo[l,5-d][l,2,4]triazin-4-one (S26).
  • S26 2-ester pyrazole
  • S24 2-ester pyrazole
  • hydrazine By coupling of 2-ester pyrazole (S24) with hydrazine give an intermediate S25, which can be subsequently cyclized to key intermediate S26.
  • Pyrazole starting material, S24, with varying R2/R3 groups are either commercial available or can be prepared by literature procedures.
  • the introduction of substitutions at N- 5 position (G6-a) can be obtained via N-alkylation with Ari/Heti-CH 2 -halide (-Br or Cl).
  • compounds of the formula G6-b can be prepared from the intermediate 2,3-disubstituted-5,6-dihydro-pyrazolo[l,5-d][l,2,4]triazine-4,7-dione (S27). Cyclization of S25 with coupling reagents (such as CDI, triphosgene etc) afford S27, which can subsequently N-alkylation with Hetl/Arl/Rl-halide at N-5 position to provide (S28). The substitutions at C-7 position in compounds G6-b can be obtained by displacement of halogen (Cl or F) of S29 with hydroxyl, amine or thiol containing heterocyclic/aryls.
  • coupling reagents such as CDI, triphosgene etc
  • R is a substituted aryl / heteroaryl and the two biaryl groups are linked by a C-C bond
  • R may be prepared from appropriately functionalized alkoxy- aryl ether derivatives containing desirable functionalities W, where W may for example be CH, N, COH, CF, etc (Route A, Scheme Al).
  • the biaryl portion can be constructed first, typically via Suzuki or Stille coupling (Gl -> G2).
  • Y halogen or OSO 2 R (OTf, ONf) and the other reagent would be R2-B(OR) 2 or R2-SnR3' or vise versa, where R2 -halogen is coupled with Gl containing boronate/boronic acid or trialkyltin as Y.
  • A is a carbon derived substituent, e.g. CH 3 , CH 2 OH, CO 2 R", CN etc. these groups are converted to provide intermediate G3 where D is either a halogen or OTf, ONf, or OCOOR" (carbonate) such that substituent (Rl) is introduced by employing a transition-metal catalyzed coupling reactions such as Suzuki, Stille or Negishi reaction.
  • Rl which may be aryl, heterocyclic, acyclic, aliphatic, or any other desirable variety of functionality, to the central aromatic ring (Ar) by a wide rage of tether groups M.
  • the central aromatic ring (Ar) may be a biaryl ring system with a R2 group already attached, or the R2 group may be attached subsequent to that of Rl .
  • the linker group M may be a linear chain of one or more atoms consisting of C, N, O, or S.
  • the linker group M may also consist of functionalities including, but not limited to amide, sulfonamide, sulfone, or ketone.
  • halogen allows susceptibility of the aromatic halogen for nucleophilic displacement.
  • ArI group containing NO 2 , CO 2 R, ketone, CN etc. would allow formation of aryl-M-aryl(heteroaryl) intermediates.
  • the linker group M may also be subject to further elaboration.
  • sulfides may be oxidized to sulfoxides and sulfones and amines maybe subjected to alkylation or reductive amination.
  • Well known synthetic transformations can be used to create tether groups M such as ether amide, sulfonamide, and the like.
  • the functional group location in the precursor Ar and Rl groups can be used to dictate the nature and type of the linkage (e.g. alternative ethers), as mentioned above.
  • aldehyde functionality can subsequently be transformed into a suitable transition-metal catalyzed coupling reaction partner.
  • the aldehye could be used for Wittig reaction forming olefin or CH 2 CH 2 linkage to incorporate Rl.
  • substituent "A” can be various types of carbonyl (aldehyde or ketone) or imine groups.
  • Rl-MgX organometallic Rl group
  • aldehyde G9 CHO
  • the C-C bond forming reaction between the Ar and Rl groups could be accomplished by displacement of a leaving group on the Rl by a nucleophile present in the tether region M (Scheme G4) of G12.
  • M-Z is CH 2 - halide or CH 2 -O-sulfonate
  • Rl fragment can be introduced via formation of ether linkage. This allows attachment of Rl to the central aromatic ring by spacers (M) of varying lengths and compositions. (Scheme A4)
  • the Rl group could also be assembled form an acyclic intermediate to form a heterocylic or heteroaromatic ring.
  • these chemistries include formation of 5- membered heteroaryls such as oxadiazole, thiadiazole, triazole (G 17) form acyl hydrazide (G 16); thiazole from 2-halo-ketone or dipolar cycloaddition reactions from olefin or acetylic group to form 5-membered heterocycles or 5-membered heteroaryls (G18) [Scheme A5].
  • 6-membered heteroaryl or heterocyclic rings could be formed using Diels- Alder or hetero- Diels-Alder chemistries using appropriately substituted alkyl aryl ether bearing either a dienophile or a diene functionalities.
  • the necessary acyclic precursors could be synthesized by standard methods according to previously described intermediates (e.g. aldehyde, alkyl halide) schemes.
  • Rl and R2 The diverse selection of substituents present in Rl and R2 could be formed by standard functional group transformations that are well know in the art. Some of these include formation of amide, sulfonamide, ureas, imidazolone, oxazolones, carbamates from the R2, R3, or Ar ring fragments bearing appropriate amine, carboxylic acid, alcohol, or phenol groups.
  • a particularly useful aromatic ring functionalization technique, in which either the R2 or Rl rings can be employed, is the nucleophilic displacement of ortho-halo N- containing aromatic rings (G20, scheme A7). Examples of ring substrates useful in this type of transformation include 2-halo-pyridine, 2-halo-pyrimidine and 2-halo-imidazole.
  • nucleophiles (R) useful in this type of transformation include amines (primary, secondary, acyclic, or cyclic), alcohols, phenols, NH-containing heterocycle groups (imidazole, or pyrrazole) groups capable of performing nucleophilic displacement.
  • Rl group contains additional functional groups, such as amine, ester/acid /alcohols many of which may have be masked or protected during the previous chemistries, these could be used for further functional group manipulations.
  • additional functional groups such as amine, ester/acid /alcohols many of which may have be masked or protected during the previous chemistries
  • Rl functionalities may be achieved using well established synthetic procedures including, but not limited to, alkylation, reductive amination, nucleophilic displacement, cyclization, saponification, and oxidation/reduction.
  • ArI mono-cyclic may be further transformed to a bi-cyclic ring.
  • Examples of such ring transformations may be represented by elaboration of pyridine derivatives to imidazo[l,2-a]pyridine and imidazo[l,5-a]pyridine. These functional group manipulations and bicyclic ring elaborations may be accomplished at any chemically suitable point in the synthesis prior to or post incorporation of R2 or other synthetic transformations.
  • Generally compounds of the claim 2 can be prepared by shcmes x-y. Sequential introduction of substitution at the 4 and 6 positions of the benzoazoles. The introduction of the substituents at the C4 position to form a C-C bond can be accomplished by organometallic coupling protocols (e.g. Suzuki, Stille reaction) or by displacement of a halogen using metal assisted displacement with a cyclic or heterocyclic NH compound forming a C-N bond at the C4 position of the benzoazole. The atom numberings referenced in this section are shown in Gl (scheme 1).
  • the benzoazoles bearing diverse functional groups which are amenable to standard function group interconversion for example alkyl, ester, nitrile which could provide alcohol, alkyl halide could be manipulated by standard and these may include aldehyde, nitrile and esters, which allow generation of alcohol which could be converted to a carbonate or alkyl halide.
  • These functionalities allow introduction of aryl, heteroaryl substituents through C-C forming chemistries.
  • nucleophilic displacement of the alkyl halide, OTs, OTf etc. allow incorporation of substituents via C-N bond forming approach to introduce cyclic, acylic, amine derived functional groups (G7). This strategy allows incorporation of acyclic, heterocyclic or heteroaryl derived substituents at the C6 position of the benzoazole nucleus.
  • substituents at C6 or C4 could be carried in either sequence, i.e. formation of C4 substituent followed by C6 (route A, G1->G2) or vice versa (route B, G1-G5).
  • Either of these substituents may carry additional functional groups which could be further derivatized through standard functional group transformation chemistries that are well know in the art. Some of these include formation of amide, sulfonamide, ureas, imidazolone, oxazolones, and carbamates from appropriate amine, carboxylic acid, alcohols or phenol groups.
  • the Rl group contains an ortho-halo N-heterocycles (e.g 2-halo pyridine or 2-halo-pyrimidine) G8, a nucleophilic displacement of the halo (or - OTf, ONf derived from pyridin-2-one) groups.
  • these nucleophile include an amine (primary, sec. tert.; acyclic or cyclic including) or NH-containing heteroaryl (for example, substituted imidazole or pyrazole); or alcohol / thiol allowing incorporation of additional -O, -S or -N linked substituents to provide G9.
  • an appropriately functionalized pyridine can be converted to corresponding 2-OTf or 2-ONf which could then participate in similar chemistries.
  • the Rl group could also be assembled form an acyclic intermediate (Scheme A3) to form a heterocylic or heteroaromatic ring.
  • Scheme A3 acyclic intermediate
  • examples of these chemistries include formation of 5-membered heteroaryls (G12) such as oxadiazole, thiadiazole, triazole form acyl hydrazide (Gl 1); thiazole from 2-halo-ketone or dipolar cycloaddition reactions when the C4 or C6 substituent is an olefin or acetylic group (G10->G13)).
  • 6- membered heteroaryl or heterocyclic rings could be formed using Diels-Alder or hetero- Diels-Alder chemistries using appropriately substituted alkyl aryl ether bearing either a dienophile or a diene at C4 or C6 position.
  • Rl The diverse selection of substituents present in Rl could be formed by standard functional group transformations that are well know in the art. Some of these include formation of amide, sulfomanide, ureas, imidazolone, oxazolones, carbamates from the alkoxy-biaryl fragments bearing and appropriate amine, carboxylic acid, alcochols or phenol groups.
  • Rl group contains an ortho-halo pyridine or pyrimidine for example, the nucleophilic displacement of the halo (or -OTf, ONf derived from pyridone) groups. Examples of the nucleophile include an amine (primary, sec.
  • tert acyclic or cyclic including), alcohol or HN-containing heterocylic groups (for example, substituted imidazole or pyrazole).
  • HN-containing heterocylic groups for example, substituted imidazole or pyrazole.
  • Compounds of the Formula G2C can be prepared by reaction of the 2- halopyridines or 6-halopyrazine or 5-halopyrimidine Al with an aryl/heteroaryl (phenol, amine or a thiol) A2 to provide intermediate A3.
  • the functional group X COOH can then be converted to an amide by standard coupling procedures.
  • the carboxylic acid can be converted to the corresponding amine via Curtis rearrangement and subsequently converted to the amide or sulfonamides.
  • heterocyclic fragment containing a suitable functional group could optionally be further derivatized by the standard chemistries as described above for other sub-genuses, e.g., specific examples for several of these examples are provided in 2391.025A/025B and 2391.027A/027B PCT/US applications [00153] Scheme Cl
  • the carboxylic acid (A3) could be used to form an acyl hydrazide (A4) which subsequently following dehydative cyclization would provide the oxadiazole or with P2S5 or Lawson's reagent and the like, provide thiadiazole or with a suitable amine to provide a triazole, these analogs represented by G2B.
  • the acid intermediate (A3) could also serve as key intermediates to for diverse 5 and 6-memebered heterocycles and the procedures described in PCT/US2005/036558 and references cited in their analogs with published procedure in heterocyclic chemistry literature for such transformations.
  • Reaction of a bromodiester (1) with an amide, thioamide or an imidate (2) provides the azole derivative (3).
  • the hydroxyl group of (3) could be derivatized with and heterocyclic-alkyl halide (e.g. substituted benzyl bromide) or it could be used for ether formation using Cu mediated chemistries with aryl or heteroaryl halides to provide (4) where Z may be a bond.
  • tBu ester (4) could in turn be used for amide formation to provide analogs represented by G2D or the acid could be used to form an acyl hydrazide (6) which subsequently following dehydative cyclization would provide the oxadiazole or with P2S5 or Lawson's reagent and the like, provide thiadiazole or with a suitable amine to provide a triazole, these analogs represented by G2B.
  • the acid intermediate (5) could also serve as key intermediates to for diverse 5 and 6-memebered heterocycles and the procedures described in PCT7US2005/036558 and references cited in their analogs with published procedure in heterocyclic chemistry literature for such transformations.
  • the substituent at C8 can be introduced either before formation of the bicyclic core (S2) by Suzuki/Stille reaction allowing C-C bond formatting chemistries.
  • the intermediate S3 could be reacted by Buchwald or Cu mediated chemistries to for ether/amine linked C8 substituent (S7).
  • the substituent at the C-6 position can be introduced by a wide variety of approaches.
  • Y is an alkyl, ester, nitrile
  • S6/S7 containing alcohol alkyl halide (W)
  • W alkyl halide
  • the carbonate or -CH 2 -Br (W, S6/S7) upon reaction via organometallic coupling protocols (e.g.
  • the alcohol can be converted to a primary or secondary amine.
  • the W as acid or amine thus allows formation of amide, reverse amide, sulfonamide from acylation /sulfonation chemistries or diverse amine via reductive amine chemistry approaches.
  • the substituents containing additional functions groups allow subsequent elaboration by standard chemistries outlines above depending upon the functional groups introduced at C6. These strategies allow incorporation of acyclic, heterocyclic or heteroaryl derived substituents at the C6 / C8 position of the imidazo[l,2-a]pyridine/ imidazo[l,2-a]pyrazine core.
  • pyrozolo[l,5-a]pyridine can be obtained from 2,4-substituted pyridine (S12) via S13. N-amination of 2,4-disubstituted pyridine (S12) by 0-2- mesitylenesulfonyl hydroxyamine provides intermediate (S 13). Subsequent 1,3 -dipolar cycloaddition with methyl propiolate furnish the pyrozolo[l,5-a]pyridine (S14), which can subsequently be transformed into the decarboxylated product (S15) under acidic conditions.
  • Formation of the key intermediate pyrazolo[l,5-a]pyrimidine (S21) can be obtained from the pyrazole starting material (S 18). Reaction of pyrazole (S 18) with methyl chloroformate and subsequent bromination with NBS give intermediate bromomethyl pyrazole (S20). Nucleophilic substitution of tosylmethyl isocyanide (TosMIC) on the bromomethyl pyrazole (S20) followed by intramolecular transfer of the methoxycarbonyl group followed by cyclization and 1,2-elimination of p-toluenesulfinic acid to afford the pyrazolo[l,5-a] pyrimidine intermediate (S21) analogous to Mendiola, J.
  • TosMIC tosylmethyl isocyanide
  • substitution at C-6 position can be obtained via the ester group at C-6 position by similar approaches described above for Gl analogs.
  • the introduction of the substitutions at C-8 position to form a C-C bond can be accomplished by metal assisted cross coupling reactions.
  • the key intermediate pyrazolo[l,5-a]pyrimidine (S26) can be also obtained from S25.
  • the intermediate S25 in turn can be obtained from S18 via bromination and subsequent conversion to the ketone S24. Reaction of S25 with an orthoformate would then provide S26.
  • the final substituent can be introduced as part of formation of S24; in such case cyclization of S25 to S26 directly would yield the desired analogs.
  • compounds of the formula G6-b can be prepared from the intermediate 2,3-disubstituted-5,6-dihydro-pyrazolo[l,5-d][l,2,4]triazine-4,7-dione (S27). Cyclization of S25 with coupling reagents (such as CDI, triphosgene etc) afford S27, which can subsequently N-alkylation with Hetl/Arl/Rl-halide at N-5 position to provide (S28). The substitutions at C-7 position in compounds G6-b can be obtained by displacement of halogen (Cl or F) of S29 with hydroxyl, amine or thiol containing heterocyclic/aryls.
  • coupling reagents such as CDI, triphosgene etc
  • Step 1 6-Amino-5-(3-chloro-phenyl)-nicotinic acid methyl ester (2). To a 100 ml INRBF were added methyl 6-amino-5-bromonicotinate (Ig, 4.33 mmole), 40 ml toluene, 10 ml ethanol, 20 ml water, 1.37g, 13 mmole sodium carbonate and 3-chlorophenyl boronic acid (740mg, 4.73 mmole). The solution was degassed for 10 min. under argon, then the palladium tetrakis (500mg, 10%) was added. Reaction mixture was heated at 100 0 C for 6 hours.
  • methyl 6-amino-5-bromonicotinate Ig, 4.33 mmole
  • 40 ml toluene 10 ml ethanol
  • 20 ml water 1.37g, 13 mmole sodium carbonate
  • 3-chlorophenyl boronic acid 7.40mg, 4.
  • Step 2 8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridine-6-carboxylic acid methyl ester (3).
  • Step 5 4-[8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridin-6-ylmethyl]-phenylamine (D-Ol).
  • D-Ol 4-[8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridin-6-ylmethyl]-phenylamine (D-Ol).
  • a reaction mixture of compound 10 (100 mg, 0.3 mmol), 2-aminopyridine-5-boronic acid pinacol ester (73 mg, 0.33 mmol), l,5-bis(diphenylphosphino) pentane (44 mg, 0.1 mmole), allylpalladium chloride dimer (14 mg, 0.045 mmol), K 2 CO 3 (124 mg, 0.9 mmole) in DMF (2 ml)) was stirred at 90 0 C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate (3 x 10 ml), the organic portions were combined, washed with brine, dried over Na 2 SO 4 and concentrated.
  • the reaction was diluted with ethyl acetate (10 mL), washed with saturated ammonium chloride (10 mL), the aqueous wash back extracted with ethyl acetate (2 x 10 mL), and the organic extracts were combined. The organic solution was washed with brine (15 mL) and the solvent removed under vacuum. The crude material was purified by silica gel thin layer preparatory chromatography eluting with 7.5 % acetone in dichloromethanes to give D-04 (15.1 mg, 18% yield) as a yellow gum.
  • Step 1 Synthesis of ethyl 2-(4-fluorophenoxy)nicotinate: A suspension of ethyl- 2-chloronicotinate (6g, 32.32 mmole) , 4-chlorophenol (3.8 g, 33.94 mmole), cesium carbonate (1 Ig, 33.94 mmole) in 350 ml DMF was heated at 8O 0 C for 2 days. The reaction mixture was cooled down, diluted with water and extracted several time s with ethylacetate. The combined organic layers were washed with water, brine, dried over Na 2 SO 4 and concentrated down. The crude was taken into ether, hexane was added until solid precipitated out. The Suspension was filtered off, solid washed with hexane, to give 5.8 g product, 69% yield. HNMR
  • Step 3 Synthesis of N'-(4-aminobenzoyl)-2-(4-fluorophenoxy)nicotinohydrazide.
  • DMAP 628 mg, 5.15 mmole
  • EDCI 988 mg, 5.15 mmole
  • 4-aminobenzoic hydrazide 427 mg, 2.83 mmole
  • Step 4 Synthesis of 4- ⁇ 5-[2-(4-fluoro-phenoxy)-pyridin-3-yl]-[l,3,4]oxadiazol-2- yl ⁇ -phenylamine, L-085.
  • Step 5 Synthesis of l-Ethyl-3-(4- ⁇ 5-[2-(4-fluoro-phenoxy)-pyridin-3-yl]- [l,3,4]oxadiazol-2-yl ⁇ -phenyl)-urea, L-099.
  • 4- ⁇ 5-[2-(4-fluoro-phenoxy)- pyridin-3-yl]-[l,3,4]oxadiazol-2-yl ⁇ -phenylamine 200 mg, 0.57 mmole
  • ethylisocyanate 0.135 ml, 3Eq.
  • Step 7 Synthesis of 5-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-3H-[l,3,4]oxadiazol- 2-one.
  • ethyl 2-(4-fluorophenoxy)pyridine-3-carbonyl hydrazide 400 mg, 1.61 mmole
  • trichloromethylchloroformate 0.22 ml, 1.76 mmole
  • Step 8 Synthesis of 2- ⁇ 5-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-[l,3,4]oxadiazol-2- yloxyj-ethanol, L-105.
  • 5-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-3H- [l,3,4]oxadiazol-2-one. (100 mg, 0.366 mmole) and Na2CO3 (78 mg, 0.73 mmole) in 2 ml DMF was added bromoethanol (92 mg, 0.73 mmole). The reaction mixture was stirred at room temperature for 24 hours.
  • Step 1 Synthesis of 4-Hydroxy-2-methyl-thiazole-5-carboxylic acid ethyl ester: To a suspension of thioacetamide (2.4 g, 32 mmole) in 20 ml toluene was added diethylbromomalonate (8.31 g, 32 mmole). The reaction mixture was refluxed for an hour., then cooled down, and filtered off. The solid was washe with 20 ml toluene. The mother liquor was concentrated to a thick oil that was take into 20 ml water and stirred for a while. The suspension was filtered off, the solid was washed with water to afford 2g crude product, 33.8% yield. HNMR
  • Step 2 Synthesis of 4-(3-Chloro-benzyloxy)-2-methyl-thiazole-5-carboxylic acid ethyl ester: To a solution of 4-Hydroxy-2-methyl-thiazole-5-carboxylic acid ethyl ester (100 mg, 0.53 mmole) in 2 ml anhydrous DMF was added at room temperature NaH, 60% dispersion in oil (43 mg, 1.06 mmole). The reaction mixture was stirred at room temperature for 1/5 hour, then 3 -chlorobenzylbromide (110 mg, 0.53 mmole) was added. The mixture was stirred at 70°C for 5 hours.
  • Step 3 Synthesis of 4-(3-Chloro-benzyloxy)-2-methyl-thiazole-5-carboxylic acid.
  • a solution of 4-(3-Chloro-benzyloxy)-2-methyl-thiazole-5-carboxylic acid ethyl ester 50 mg, 0.17 mmole
  • the reaction mixture was stirred at room temperature, overnight.
  • Aqueous layer was extracted several times with ethylacetate. Combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated to afford 45 mg crude product.
  • Step 4 Synthesis of 4-(3-Chloro-benzyloxy)-2-methyl-thiazole-5-carboxylic acid (l-thiophen-2-yl-ethyl)-amide, L-174.
  • EDCI 31 mg, 0.155 mmole
  • HOBt 21mg, 0.155 mmole
  • l-thiophen-2-yl-ethylamine 20 mg, 0.155 mmole
  • Methods of the invention parallel the compositions and formulations.
  • the methods comprise administering to a patient in need of treatment a therapeutically effective amount of a compound according to the invention.
  • the present invention also provides a method for inhibiting phosphodiesterase 4.
  • In-vitro assay for PDE4 enzymes The in- vitro activity of PDE4 enzymes and the in-vitro potency of therapeutic agents described in the present invention was measured using a real-time, enzyme-coupled spectrophotometric assay.
  • the product of the PDE reaction, 5' - AMP can be coupled to the oxidation of NADH using three different coupling enzymes.
  • Adenylate kinase (AK) phosphorylates AMP to yield ADP in the first step.
  • Pyruvate kinase (PK) then uses ADP and phosphoenolpyruvate (PEP) to make ATP and pyruvate.
  • LDH lactate dehydrogenase
  • NADH ⁇ -nicotinamide adenine dinucleotide
  • Buffer A containing 50 mM Tris, pH 8.0, 16 mM MgCl 2 and 80 mM KCl is prepared and stored at room temperature.
  • Buffer B containing 50 mM Tris, pH 8.0 is prepared and stored at toom temperature.
  • Stock solutions of the following reagents are prepared in Buffer B and stored at -20 0 C: Adenosine-5 '-triphosphate (ATP), cyclic adenosine-5' -monophosphate (cAMP), phosphoenolpyruvate (PEP) and NADH.
  • ATP Adenosine-5 '-triphosphate
  • cAMP cyclic adenosine-5' -monophosphate
  • PEP phosphoenolpyruvate
  • An assay mix is prepared by mixing Buffer A, trichloroethylphosphine (TCEP), ATP, PEP, NADH, myokinase (MK), pyruvate kinase (PK), lactate dehydroganese (LDH) and PDE4 to a final volume of 20 mL, which is enough for a single 96-well assay plate.
  • Assay mix 180 ⁇ L
  • test article (10 ⁇ L ) in 1 : 1 DMSO/H2O mixture is pre- incubated at room temperature for 10 min. The enzymatic reaction is initiated by addition of cAMP (10 ⁇ L).
  • Final concentration of all components in the assay (200 ⁇ L/well) are as follows: 10 mM MgCl 2 , 50 mM KCl, 5 mM TCEP, 2.5% DMSO, 0.4 mM NADH, 1 mM PEP, 0.04 mM ATP, 5 units MK, 1 unit PK, 1 unit LDH and appropriate amount of PDE4.
  • Reaction progress curves are monitored in a plate reader capable of measuring light absorbance at 340 nM. A decrease in light absorbance at 340 nm is due to oxidation of NADH.
  • Positive controls containing no test article and negative controls containing no test article and no cAMP are included on every assay plate. Reaction rates are determined from the slopes of the linear portions of the progress curves. All data is percent normalized with respect to controls and presented as percent inhibition. The results of testing of representative species are shown below:
  • the figure below shows the dose response curves with PDE4D7 for three different PDE4 inhibitors: D 155947, and R- and S-rolipram. These and other compounds used in routine screening are dissolved in DMSO to a concentration of 20 mM. Using this approach, the dose range varies from IxIO 3 M to 5xlO ⁇ 16 M in a 12-point serial dilution with a dilution factor of 7. As shown in the figure below, compounds like D155947 have very shallow dose- response curves (i.e., low hillslope) such that a large concentration range is required to obtain a plateau at both ends of the curve(s).
  • Table 4 illustrates some examples of partial inhibitors of the invention. These compounds do not show full enzyme inhibition, even at concentration up to 100-10,000 times of IC50 for a regulatory domain-containing form (PDE4D7) of the human PDE4D protein. The maximum inhibition observed in these compounds is 60-90%.
  • Table 5 illustrates some examples of PDE4 inhibitors of the invention that showed full enzyme inhibition (95-100%) for a regulatory domain-containing form (PDE4D7) of the human PDE4D protein.
  • the compounds L- 009 and L-016 were dosed intravenously at a series of doses and the lowest dose that resulted in emesis was determined to be 0.0875 mg/kg for compound L-009 and 0.01mg/kg for compound L-016. Both compounds gave dose dependent change in plasma levels for blood samples taken at 2min post-dose (i.v.) and the plasma levels at the lowest emetic dose at 2min post dose were 218ng/mL for L-009 and 12.7 ng/mL for L-016. The difference in emetic threshold between the two compounds is therefore approximately 9-fold and 17-fold based on dose and plasma exposure, respectively. Thus these studies clearly show superiority of the PDE4 modulator in terms of the emetic side effect profile.

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Abstract

The present invention relates to compounds which are inhibitors of phosphodiesterase-4 (PDE4) useful for the treatment and prevention of stroke, myocardial infarct, cardiovascular inflammatory diseases and disorders and central nervous system disorders, to compounds with a selectivity for a non-catalytic portion of PDE4, to methods of determining this selectivity.

Description

PDE4 INHIBITORS SELECTIVE FOR THE LONG FORM OF PDE4 FOR TREATING INFLAMMATION AND AVOIDING SIDE EFFECTS
Field of the Invention
[0001] The present invention relates to compounds which are inhibitors of phosphodiesterase-4 (PDE4) useful for the treatment and prevention of stroke, myocardial infarct, cardiovascular inflammatory diseases and disorders and central nervous system disorders, to compounds with a selectivity for a non-catalytic portion of PDE4, to methods of determining this selectivity.
Background of the Invention
[0002] A large number of PDE4 inhibitors have been developed for a variety of clinical indications (Torphy and Page. 2000. TIPS 21, 157-159; Burnouf and Pruniaux. 2002. Curr. Pharm. Design 8, 1255-1296; Lipworth. 2005. Lancet 365, 167-175). These compounds have not reached the market because of a series of adverse side effects including emesis (Giembycz 2005. Curr. Opin. Pharm. 5, 238-244). These inhibitors are also known to inhibit all four PDE4 genes (PDE4A, PDE4B, PDE4C and PDE4D), and one possibility to explain the adverse side effects is the inability to selectively inhibit a specific gene or a specific splicing isoform (Ghavami et al. 2006. Drugs R. D. 7, 63-71).
[0003] The development of many of known PDE4 inhibitors has been guided by crystal structures of the catalytic domain of PDE4D and PDE4B (Card et al. 2005. Nat. Biotech. 23, 201-207). Their utility has been assessed primarily in in vitro assays using the catalytic domain, since the full-length enzymes are difficult to express. Unfortunately, the catalytic domain of all four PDE4 genes is completely conserved; in addition, the catalytic domain of all eleven PDE superfamily members (PDEl-PDEl 1) is highly conserved. This high degree of conservation is expected since all PDEs hydrolyze the same substrates, cAMP and/or cGMP; however this conserved structure makes it extremely difficult to create gene specific inhibitors (Ke and Wang. 2007. Curr. Top. Med. Chem. 7, 391-403). Unlike the highly conserved catalytic domain, many PDEs contain different regulatory domains that are not as highly conserved and different PDE family members use structurally distinct regulatory domains (Houslay et al. 2005. DDT 10, 1503-1519).
[0004] Genetic studies have clearly demonstrated an association between PDE4D and ischemic stroke (Gretarsdottir et al. 2003. Nature Genetics. 35, 1-8). Fine mapping of the relatively large PDE4D exonic structure has demonstrated that the disease is associated with long forms of the enzyme (PDE4D7 and PDE4D5), which contain the regulatory domains termed upstream conserved regions 1 and 2 (UCRl and UCR2). Because of the high degree of primary sequence conservation within the catalytic domain of PDE4 and the specific association of the disease with the long form of the enzyme, inhibitors that specifically inhibit the long form of PDE4 (PDE4D7 or PDE4D5)) but do not inhibit the catalytic domain of PDE4D are expected to be clinically useful for ischemic stroke while avoiding the side effects seen with earlier PDE4 inhibitors.
[0005] The focus of the present invention is on inhibitors that specifically inhibit PDE4 enzymes containing regulatory domains, but do not efficiently inhibit the catalytic domain of PDE4. The approach taken in the present invention is unusual in that analysis of all known PDE4 inhibitors suggests that they are competitive with cAMP and bind within the active site (Houslay et al. 2005. DDT 10, 1503-1519). The compounds of the present invention are noncompetitive inhibitors of cAMP while being gene-specific inhibitors (PDE4D) and are intended to specifically inhibit long isoforms (PDE4D7). Based on the target rationale and in vitro potency, a person of skill in the art would expect the compounds to be useful as antiinflammatory agents for the treatment, amelioration or prevention of inflammatory diseases and of complications arising therefrom and useful as CNS agents for amelioration of the cognitive decline in Alzheimer's disease, Parkinson's disease, the treatment of schizophrenia and depression, and neuroprotective in Huntington's disease.
[0006] PDE4 modulators bind to the PDE4 regulatory domains, particularly to a region of the upstream conserved region 2 (UCR2) present in all splice- isoforms of PDE4A-D [for a description of PDE4 splice-isoforms see, Houslay et al., Drug Discovery Today 10, 1503- 1509 (2005)]. Preferred substituents of PDE4 modulators interact with UCR2 residue Phel96 in PDE4D or Tyr274 in PDE4B and adjacent residues. The binding of PDE4 modulators to UCR2 closes the regulatory domain across the PDE4 active site, thereby preventing access of cAMP. In contrast, PDE4 inhibitors, e.g., roflumilast, that bind in the active site competitively with cAMP, do not interact with UCR2.
Summary of the Invention
[0007] The present invention relates to compounds exhibiting PDE4 enzyme inhibition, further described in the Detailed Description of the Invention section.
[0008] There is also provided, in accordance with embodiments of the invention, a pharmaceutical composition comprising a compound as described herein, and a pharmaceutically acceptable carrier, excipient or diluent therefore. When the compound is present as a salt, the salt should be a pharmaceutically acceptable salt.
[0009] In a third aspect, the invention relates to compounds that show preference for a regulatory segment of a PDE4 isoform over the catalytic portion of a PDE4 isoform. These regulatory segment-containing PDE4 isoforms include PDE4D3, PDE4D4, PDE4D5, PDE4D7, PDE4D8, PDE4D9, PDE4D1, PDE4D2, PDE4D6, PDE4B1, PDE4B3, PDE4B4 and PDE4B2.
[0010] In another aspect, the invention relates to compounds that are PDE4 modulators.
[0011] In still another aspect, the invention relates to methods for the treatment or prophylaxis of a central nervous system (CNS) disorder or a vascular disorder while minimizing at least one unwanted side effect. The methods comprise administering to a mammal a therapeutically effective amount of a compound of the invention which has a ratio of binding selectivity to a regulatory domain-containing form of PDE4 of at least 100 times the binding selectivity to the catalytic portion of PDE4. Examples of the side effects to be minimized include emesis, nausea and vasculopathy.
[0012] In another aspect, the invention relates to a method for identifying the selectivity of a potential PDE4-inhibiting compound. This method includes providing at least two different isoforms of PDE4, providing cAMP substrate, providing one or more cofactors, providing an agent for detection of a reaction of cAMP substrate, determining the maximum kinetic rates of reaction of the cAMP substrate in the presence of at least two different isoforms of PDE4, providing a sample containing a test compound, determining the IC50 values of the test compound against the at least two different isoforms of PDE4 and comparing these IC50 values to determine a selectivity ratio.
[0013] Selective PDE4 inhibitors of the invention may be useful in improving cognition and thus useful for treating learning disorders, memory loss and other cognitive dysfunctions. Selective PDE4 inhibitors of the invention are also useful for treating asthma and Chronic Obstructive Pulmonary Disease (COPD). Compounds of the invention, which inhibit tumor growth and metastases, also find utility in the treatment and prevention of cancer, including esophageal cancer, brain cancer, pancreatic cancer, and colon cancer.
[0014] These and other embodiments of the present invention will become apparent in conjunction with the description and claims that follow.
Detailed Description of the Invention
[0015] Throughout this specification the substituents are defined when introduced and retain their definitions.
[0016] Unless otherwise specified, alkyl is intended to include linear, branched, or cyclic hydrocarbon structures and combinations thereof. A combination would be, for example, cyclopropylmethyl. Lower alkyl refers to alkyl groups of from 1 to 6 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-and t-butyl and the like. Preferred alkyl groups are those of C20 or below; Ci to Cg are more preferred. Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groups of from 3 to 8 carbon atoms. Examples of cycloalkyl groups include c-propyl, c-butyl, c-pentyl, norbornyl and the like.
[0017] Ci to C20 hydrocarbon includes alkyl, cycloalkyl, polycycloalkyl, alkenyl, alkynyl, aryl and combinations thereof. Examples include benzyl, phenethyl, cyclohexylmethyl, camphoryl and naphthylethyl. Hydrocarbon refers to any substituent comprised of hydrogen and carbon as the only elemental constituents.
[0018] Unless otherwise specified, the term "carbocycle" (or "carbocyclyl") is intended to include ring systems in which the ring atoms are all carbon but of any oxidation state. Thus (C3-C10) carbocycle refers to both non-aromatic and aromatic systems, including such systems as cyclopropane, benzene, cyclopentene and cyclohexene; (Cs-Ci2) carbopolycycle refers to such systems as norbornane, decalin, indane and naphthalene. Carbocycle, if not otherwise limited, refers to monocycles, bicycles and polycycles.
[0019] Alkoxy or alkoxyl refers to groups of from 1 to 8 carbon atoms of a straight, branched or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purpose of this application, alkoxy and lower alkoxy include methylenedioxy and ethylenedioxy. Alkoxyalkyl refers to ether groups of from 3 to 8 atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an alkyl. Examples include methoxymethyl, methoxyethyl, ethoxypropyl, and the like. Alkoxyaryl refers to alkoxy substituents attached to an aryl, wherein the aryl is attached to the parent structure. Arylalkoxy refers to aryl substituents attached to an oxygen, wherein the oxygen is attached to the parent structure. Substituted arylalkoxy refers to a substituted aryl substituent attached to an oxygen, wherein the oxygen is attached to the parent structure.
[0020] Oxaalkyl refers to alkyl residues in which one or more carbons (and their associated hydrogens) have been replaced by oxygen. Examples include methoxypropoxy; 3,6,9-trioxadecyl; 2,6,7-trioxabicyclo[2.2.2]octane and the like. The term oxaalkyl is intended as it is understood in the art [see Naming and Indexing of Chemical Substances for Chemical Abstracts, published by the American Chemical Society, 196, but without the restriction of 127(a)], i.e. it refers to compounds in which the oxygen is bonded via a single bond to its adjacent atoms (forming ether bonds); it does not refer to doubly bonded oxygen, as would be found in carbonyl groups. Similarly, thiaalkyl and azaalkyl refer to alkyl residues in which one or more carbons has been replaced by sulfur or nitrogen, respectively. Examples include ethylaminoethyl and methylthiopropyl.
[0021] Unless otherwise specified, acyl refers to formyl and to groups of 1, 2, 3, 4, 5, 6, 7 and 8 carbon atoms of a straight, branched, cyclic configuration, saturated, unsaturated and aromatic and combinations thereof, attached to the parent structure through a carbonyl functionality. One or more carbons in the acyl residue may be replaced by nitrogen, oxygen or sulfur as long as the point of attachment to the parent remains at the carbonyl. Examples include acetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl, benzyloxycarbonyl and the like. Lower-acyl refers to groups containing one to four carbons. The double bonded oxygen, when referred to as a substituent itself is called "oxo".
[0022] Aryl and heteroaryl mean (i) a phenyl group (or benzene) or a monocyclic 5- or 6-membered heteroaromatic ring containing 1-4 heteroatoms selected from O, N, or S; (ii) a bicyclic 9- or 10-membered aromatic or heteroaromatic ring system containing 0-4 heteroatoms selected from O, N, or S; or (iii) a tricyclic 13- or 14-membered aromatic or heteroaromatic ring system containing 0-5 heteroatoms selected from O, N, or S. Aryl, as understood herein, includes residues in which one or more rings are aromatic, but not all need be. Thus aromatic 6- to 14-membered carbocyclic rings include, e.g., benzene, naphthalene, indane, tetralin, and fluorene and the 5- to 10-membered aromatic heterocyclic rings include, e.g., imidazole, pyridine, indole, thiophene, benzopyranone, thiazole, furan, benzimidazole, quinoline, isoquinoline, quinoxaline, pyrimidine, pyrazine, tetrazole and pyrazole.
[0023] Arylalkyl refers to a substituent in which an aryl residue is attached to the parent structure through alkyl. Examples are benzyl, phenethyl and the like. Heteroarylalkyl refers to a substituent in which a heteroaryl residue is attached to the parent structure through alkyl. In one embodiment, the alkyl group of an arylalkyl or a heteroarylalkyl is an alkyl group of from 1 to 6 carbons. Examples include, e.g., pyridinylmethyl, pyrimidinylethyl and the like.
[0024] Heterocycle means a cycloalkyl or aryl carbocycle residue in which from one to three carbons is replaced by a heteroatom selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Unless otherwise specified, a heterocycle maybe non- aromatic or aromatic. It is to be noted that heteroaryl is a subset of heterocycle in which the heterocycle is aromatic. Examples of heterocyclic residues that fall within the scope of the invention include pyrazole, pyrrole, indole, quinoline, isoquinoline, tetrahydroisoquinoline, benzofuran, benzodioxan, benzodioxole (commonly referred to as methylenedioxyphenyl, when occurring as a substituent), morpholine, thiazole, pyridine (including 2-oxopyridine), pyridine N-oxide, pyrimidine, thiophene (i.e. thiene), furan, oxazole, oxazoline, oxazolidine, isoxazolidine, isoxazole, dioxane, azetidine, piperazine, piperidine, pyrrolidine, pyridazine, azepine, pyrazolidine, imidazole, imidazoline, imidazolidine, imidazolopyridine, pyrazine, thiazolidine, isothiazole, 1,2-thiazine- 1,1 -dioxide, quinuclidine, isothiazolidine, benzimidazole, thiadiazole, benzopyran, benzothiazole, benzotriazole, benzoxazole, tetrahydrofuran, tetrahydropyran, benzothiene, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, oxadiazole, triazole, tetrazole, isatin (dioxoindole), phthalimide (dioxoisoindole), pyrrolopyridine, triazolopyridine and the dihydro and tetrahydro congeners of the fully unsaturated ring systems among the foregoing.
[0025] An oxygen heterocycle is a heterocycle containing at least one oxygen in the ring; it may contain additional oxygens, as well as other heteroatoms. Oxygen heterocycles found in the examples of the invention include tetrahydrofuran, benzodioxole, morpholine, isoxazole and 2,6,7-trioxabicyclo[2.2.2]octane. A sulphur heterocycle is a heterocycle containing at least one sulphur in the ring; it may contain additional sulphurs, as well as other heteroatoms. A nitrogen heterocycle is a heterocycle containing at least one nitrogen in the ring; it may contain additional nitrogens, as well as other heteroatoms.
[0026] As used herein, the term "optionally substituted" may be used interchangeably with "unsubstituted or substituted". The term "substituted" refers to the replacement of one or more hydrogen atoms in a specified group with a specified radical. For example, substituted alkyl, aryl, cycloalkyl, heterocyclyl etc. refer to alkyl, aryl, cycloalkyl, or heterocyclyl wherein up to three H atoms in each residue are replaced with halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, carbonyl (i.e. oxo), phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl [-C(=O)O- alkyl], alkoxycarbonylamino [ -NHC(=O)O-alkyl], alkoxycarbonylaminoalkyl [ -alkyl- NHC(=O)O-alkyl], carboxyalkylcarbonylamino [ -NHC(=O)-alkyl-COOH], carboxamido [- C(=O)NH2], aminocarbonyloxy [-OC(=O)NH2], alkylaminocarbonyl [-C(=O)NH-alkyl], dialkylaminocarbonyl [-C(=O)N(alkyl)2], aminocarbonylalkyl [-alkyl-C(=O)NH2], cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl (including cycloalkylaminoalkyl), dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, -NHC(=O)NHalkyl, -NHC(=O)NH-heterocyclyl, -alkyl-NHC(=O)N(alkyl)2, heterocyclylalkylcarbonylamino, benzyloxyphenyl, and benzyloxy. Although oxo is included among the substituents referred to in "optionally substituted", it will be appreciated by persons of skill in the art that, because oxo is a divalent radical, there are circumstances in which it will not be appropriate as a substituent (e.g. on phenyl). Additional substituents that are considered within the scope of the term, particularly for R1, are the are the residues of amino acids, amino acid amides, protected residues of aminoacids and their amides, and N-methylated (mono- or di-, as appropriate) amino acids and amino acid amides.
[0027] For the purpose of ring A, the substituents alkyl, acyl, alkoxyalkyl, hydroxyloweralkyl, phenyl, heteroaryl, benzenesulfonyl, loweralkoxy, haloalkoxy, oxaalkyl, alkoxycarbonyl, alkoxycarbonylamino, carboxamido, alkylaminocarbonyl, amino, alkylamino, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, heterocyclylalkoxy, alkylthio, sulfonylamino, alkylsulfinyl, alkylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, oxaalkyl, aminosulfonyl, amidino, guanidino, ureido, benzyloxyphenyl, and benzyloxy may be further substituted with one or two substituents from the list of substituents above. Substituents that are considered within the scope of the term, particularly for A, are the are the residues of amino acids, amino acid amides and protected residues of aminoacids and their amides, as well as the following specific residues: -CH3, -CH2CF3, -CF3, -CHO, -COOH, -CN, halogen, -OH, , -OEt, -C(=O)NH2, -C(=O)NHEt, -C(=0)NMe2 -COOCH3, -COOEt, -CH2NHC(=O)NH2, -CH(CH3)NHC(=O)NH2, -CH2NHC(=0)H, -CH2NHC(=O)CH3, -CH2C(=O)NH2, -CH2COOH, -CH2COOEt, -CH2NHC(=O)OEt, -CH2NHC(K))O-C6H5, -CH2NHC(=O)C(=O)NH2, -CH2NHC(=O)NHEt, -C(CH3)2OH, -CH2NHC(=O)N(CH3)2, -CH2NHC(=O)NHCH3, -CH2NH2, -CH(CH3)NH2, -C(CH3)2NH2, -CH2OH, -CH2CH2OH, -CH2NHSO2CH3, -CH2OC(=O)NHEt, -OCH3, -OC(O)NH2, -OCH2CH2N(CH3)2, -OCH2CH2OCH3, -NHC(=0)NH2, -NHC(=O)NHEt, -NHCH3, -NHEt, -NH(tBoc), -NHCH2COOH ("residue of glycine"), -N(CH3)CH2COOH ("residue of N-methylglycine"), -NHC(=O)NHCH2CH2C1, -NHSO2NH2, -NHEt, -N(CH3)2, -NH2, , -NH(CH3)C(=O)NH2, - NHSO2CH3, -N(SO2CH3)2, -NHC(=O)OCH3, -NHC(=O)OtBu, -NHC(=O)CH3, -SO2NH2, -NHC(=O)CH2CH2COOH, -NHC(=0)NHCH2C00H, -CH2NHCHO, -NHC(=0)NHCH2C00Et, -NHC(=O)NH(CH2)3COOEt, -NHC(=O)NH(CH2)2COOEt, -N(CH3)CH2CH2OH, -NHC(O)OEt, -N(Et)C(O)OEt, -NHC(=O)NH(CH2)2COOH, -NHC(=O)CH2N(CH3)2, -NHC(=O)NH(CH2)3COOH, -NHC(=O)CH2NH2, -NHC(=O)CH2CH2NH2, -NHC(=O)CH2NH(tBoc),
Figure imgf000010_0001
eteπn -a residue of an amino acid, amino acid amide", etc. refers to an amino acid etc. minus the functional groups that are considered part of the bond to the parent structure. For example, in the molecule BA-64 illustrated below:
Figure imgf000010_0002
after one subtracts the hydrogen that connects N,N-dimethylglycinamide to the phenyl ring, the structure of A that remains is:
Figure imgf000010_0003
This is not sensu stricto an N-methylamino acid amide, since it lacks the hydrogen on the C-terminal amide. This and similar structures that lack atoms at the points of attachment (e.g. the OH of COOH or the H OfNH2) are referred to herein as "residues" of their respective parents.
[0028] The terms "haloalkyl" and "haloalkoxy" mean alkyl or alkoxy, respectively, substituted with one or more halogen atoms. The terms "alkylcarbonyl" and "alkoxycarbonyl" mean -C(=O)alkyl or -C(O)alkoxy, respectively. [0029] The term "halogen" means fluorine, chlorine, bromine or iodine. In one embodiment, halogen may be fluorine or chlorine.
[0030] Substituents Rn are generally defined when introduced and retain that definition throughout the specification and in all independent claims.
[0031] In the characterization of some of the substituents, it is recited that certain substituents may combine to form rings. Unless stated otherwise, it is intended that such rings may exhibit various degrees of unsaturation (from fully saturated to fully unsaturated), may include heteroatoms and may be substituted with lower alkyl or alkoxy.
[0032] It will be recognized that the compounds of this invention can exist in radiolabeled form, i.e., the compounds may contain one or more atoms containing an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Radioisotopes of hydrogen, carbon, phosphorous, fluorine, and chlorine include 2H, 3H, 13C, 14C, 15N, 35S, 18F, and 36Cl, respectively. Compounds that contain those radioisotopes and/or other radioisotopes of other atoms are within the scope of this invention. Tritiated, i.e. H, and carbon-14, i.e., 14C, radioisotopes are particularly preferred for their ease in preparation and detectability. Compounds that contain isotopes 11C, 13N, 15O and 18F are well suited for positron emission tomography. Radiolabeled compounds of the invention and prodrugs thereof can generally be prepared by methods well known to those skilled in the art. Conveniently, such radiolabeled compounds can be prepared by carrying out the procedures disclosed in the Examples and Schemes by substituting a readily available radiolabeled reagent for a non-radio labeled reagent.
[0033] As used herein (particularly in the claims), and as would be understood by the person of skill in the art, the recitation of "a compound" is intended to include salts, solvates, co-crystals and inclusion complexes of that compound as well as any stereoisomeric form, or a mixture of any such forms of that compound in any ratio. Thus, in accordance with some embodiments of the invention, a compound as described herein, including in the contexts of pharmaceutical compositions, methods of treatment, and compounds per se, is provided as the salt form. Thus, for example, the recitation "a compound of the invention" as depicted above, in which R1 is imidazolyl, would include imidazolium salts. In a particular embodiment, the term "compound of the invention" refers to the compound or a pharmaceutically acceptable salt thereof.
[0034] The compounds described herein may contain asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present invention is meant to include all such possible isomers, in any ratio from racemic to optically pure forms. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The prefix "rac" refers to a racemate. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. The representation of the configuration of any carbon-carbon double bond appearing herein is selected for convenience only, and unless explicitly stated, is not intended to designate a particular configuration. Thus a carbon- carbon double bond depicted arbitrarily as E may be Z, E, or a mixture of the two in any proportion. Likewise, all tautomeric forms are also intended to be included.
[0035] The term "solvate" refers to a compound of The invention in the solid state, wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent for therapeutic administration is physiologically tolerable at the dosage administered. Examples of suitable solvents for therapeutic administration are ethanol and water. When water is the solvent, the solvate is referred to as a hydrate. In general, solvates are formed by dissolving the compound in the appropriate solvent and isolating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped under ambient conditions. Inclusion complexes are described in Remington: The Science and Practice of Pharmacy 19th Ed. (1995) volume 1, page 176-177, which is incorporated herein by reference. The most commonly employed inclusion complexes are those with cyclodextrins, and all cyclodextrin complexes, natural and synthetic, are specifically encompassed within the claims.
[0036] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases. When the compounds of the present invention are basic, salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Suitable pharmaceutically acceptable anions for the compounds of the present invention include acetate, benzenesulfonate (besylate), benzoate, bicarbonate, bisulfate, carbonate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, glycolate, bromide, chloride, isethionate, lactate, maleate, malate, mandelate, methanesulfonate, mucate, nitrate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, trifluoroacetate, p-toluenesulfonate, acetamidobenzoate, adipate, alginate, aminosalicylate, anhydromethylenecitrate, ascorbate, aspartate, calcium edetate, camphorate, camsylate, caprate, caproate, caprylate, cinnamate, cyclamate, dichloroacetate, edetate (EDTA), edisylate, embonate, estolate, esylate, fluoride, formate, gentisate, gluceptate, glucuronate, glycerophosphate, glycolate, glycollylarsanilate, hexylresorcinate, hippurate, hydroxynaphthoate, iodide, lactobionate, malonate, mesylate, napadisylate, napsylate, nicotinate, oleate, orotate, oxalate, oxoglutarate, palmitate, pectinate, pectinate polymer, phenylethylbarbiturate, picrate, pidolate, propionate, rhodanide, salicylate, sebacate, stearate, tannate, theoclate, tosylate and the like. The desired salt may be obtained by ion exchange of whatever counter ion is obtained in the synthesis of the quat. These methods are well known to persons of skill. Although pharmaceutically acceptable counter ions will be preferred for preparing pharmaceutical formulations, other anions are quite acceptable as synthetic intermediates. When the compounds contain an acidic side chain, suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine.
[0037] The graphic representations of racemic, ambiscalemic and scalemic or enantiomerically pure compounds used herein are taken from Maehr J. Chem. Ed. 62, 114- 120 (1985): solid and broken wedges are used to denote the absolute configuration of a chiral element; wavy lines and single thin lines indicate disavowal of any stereochemical implication which the bond it represents could generate; solid and broken bold lines are geometric descriptors indicating the relative configuration shown but denoting racemic character; and wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration. [0038] Terminology related to "protecting", "deprotecting" and "protected" functionalities occurs throughout this application. Such terminology is well understood by persons of skill in the art and is used in the context of processes that involve sequential treatment with a series of reagents. In that context, a protecting group refers to a group, which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable. The protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or "deprotection" occurs after the completion of the reaction or reactions in which the functionality would interfere. Thus, when a sequence of reagents is specified, as it is in the processes of the invention, the person of ordinary skill can readily envision those groups that would be suitable as "protecting groups". Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T. W. Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference.
[0039] A comprehensive list of abbreviations utilized by organic chemists appears in the first issue of each volume of the Journal of Organic Chemistry. The list, which is typically presented in a table entitled "Standard List of Abbreviations", is incorporated herein by reference.
[0040] Various isoforms of PDE4 are shown in Figure 1. PDED7 (D7, long form), PDE4D1 (Dl, short form), PDE4D2 (D2, supershort form), PDE4-Cat (D-Cat, catalytic form) and PDE4B1 (Bl, long form) are diagrammed. Upstream conserved regions 1 (UCRl) and 2 (UCR2) are shown with horizontal lines and cross-hatched lines, respectively. The conserved C-terminal domain is shown in gray, and the isoform specific N-terminal domains are unfilled (white). PDE4D7 and PDE4B1 contain the Ser/Asp mutation to mimic the activated (phosphorylated) form of the enzyme [shown as vertical stripe in UCRl (horizontal lines)]. The catalytic domain common to all isoforms is shown as the stippled section. For the purposes of this application, a "long form" isoform defines a PDE4 isoform that contains a catalytic domain, upstream conserved region 1 (UCRl), upstream conserved region 2 (UCR2), and a C-terminal (C-term) domain. Long forms are exemplified by PDE4D7 and PDE4B 1 below. A "short form" isoform contains the catalytic domain, UCR2 and C-term, but does not contain UCRl; the short form is exemplified by PDE4D1 below. A "super-short form"isoform contains the catalytic domain, C-term and a portion of UCR2, but does not contain UCRl; the super-short form is exemplified below by PDE4D2. The isoforms shown below in cartoon form are not exhaustive for these definitions, but merely exemplary. A "regulatory segment" (or "regulatory domain") indicates a segment of PDE4 that is not the catalytic domain. The term "regulatory domain-containing form" indicates any isoform of PDE4 that includes a non-catalytic domain.
[0041] The term "Iπmx" is defined as the percent inhibition at the maximum concentration of a compound. The "maximum concentration" is defined as fifty times the IC50 of the compound in question.
[0042] A "mixed inhibitor" (or "full inhibitor") of PDE4 is defined as a compound which shows selectivity for a regulatory domain-containing of PDE4 over the catalytic domain and shows an Imax > 95%. These compounds show full enzyme inhibition, defined as 95-100% inhibition.
[0043] A "partial inhibitor" or "modulator" of PDE4 is defined as a compound which shows selectivity for a regulatory domain-containing of PDE4 over the catalytic domain and shows an Imax < 95%.
[0044] Modulators of PDE4 are expected to exhibit an improved therapeutic ratio.
[0045] A "competitive inhibitor" is a compound that shows inhibition by binding to the catalytic domain.
[0046] In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here. The starting materials are either commercially available, synthesized as described in the examples or may be obtained by the methods well known to persons of skill in the art.
[0047] PDE4 inhibitors have been shown to be effective therapeutic agents in clinical studies. For example, administration of cilomilast and roflumilast (PDE4 inhibitors) to patients suffering from asthma and COPD showed initially excellent results, although the effect of cilomilast disappeared on long-term trial [Lipworth, Lancet 365, 167-175 (2005)]. Genetic studies have clearly demonstrated an association between PDE4D and ischemic stroke (Gretarsdottir et al. 2003. Nature Genetics. 35, 1-8). L-454,560, a selective PDE4 inhibitor has been shown to improve learning in a rat model in vivo [Huang et al. Biochemical Pharmacology 73, 1971-1981 (2007)]. This suggests that selective PDE4 inhibitors will be useful in treating learning disorders, memory loss (e.g. Alzheimer's disease) and other cognitive dysfunctions. Rolipram, another selective PDE4 inhibitor, has been shown to enhance cognition in multiple rodent models [Blokland et al., Current Pharmaceutical Design 12, 2511-2523 (2006)] as well as in primates [Rutten et al., 2008, Psychopharmacology 196, 643-648 (2008)]. Rolipram also improves the outcome in two separate studies in mice in vivo in models accepted by persons of skill in the art as predictive of utility in schizophrenia [Kanes et al., Neuroscience 144. 239-246 (2007); Davis and Gould, Behav.Neurosci. 119, 595-602 (2005)]. Rolipram has also been shown to exhibit a neuroprotective effect in a rat model of Huntington's disease [DeMarch et al. Neurobiol.Dis. 25, 266-273 (2007)]. This suggests that PDE4 modulators will be useful for treating many CNS disorders. Selective PDE4 inhibitors (e.g. rolipram) are also useful for treating bone loss [Yao et al., J.Musculoskelet.Neuronal Interact. 7. 119-130 (2007)].
[0048] Additionally, a PDE4 inhibitor, YM976, was shown to ameliorate the effects of experimentally- induced interstitial cystitis in rats, resulting in a decrease in the frequency of urination and an increase in the volume of urine at each time of urination [Kitta et al., BJU Int. 102. 1472-1476 (2008)]. Another PDE4 inhibitor, IC485, was shown to be equally efficacious as tolteradine tartrate, a marketed drug for treating overactive bladder, in a rodent model of obstructive bladder [Kaiho et al. BJU Int. 101, 615-20 (2008)]. These findings suggest that PDE4 inhibitors will be useful in treating symptoms of bladder overactivity, inflammation and pain.
[0049] In addition to the foregoing studies demonstrating utility in in vivo models, a number of authors have suggested connections between PDE4 inhibition and putative utilities as antidepressants [Houslay et al., Drug Discov Today 10, 1503-1519 (2005); Polesskaya et al., Biol.Psychiatr. 61, 56-64 (2007); anon. Current Qpin.Invetig.Drugs 5. 34-39 (2004)] and as anxiolytics [Zhang et al, Neuropsvchopharmacology Aug 15, 2007 Epub; Cherry et al, Biochim.Biophys.Acta 1518, 27-35 (2001)]. Rolipram has been shown in human clinical trials to ameliorate depression [Hebenstreit et al., Pharmacopsychiat. 22, 156-160 (1989)]. Other possible utilities may include Pick's disease and epilepsy.
[0050] Furthermore, the compounds, compositions and methods of the present invention may be useful in treating cancer. Phosphodiesterase activity has been shown to be associated with hematological malignancies [Lerner et al., Biochem.J. 393, 21-41 (2006); Ogawa et al., Blood 99, 3390-3397 (2002)]. The compounds may also be administered to overcome cognitive impairment induced by one or more of the following agents, alcohol, amphetamine, antipsychotic medication, anti-retroviral therapy, MDMA ( 3,4-methylenedioxy-N- methylamphetamine, cannabis, cocaine, delta-9 tetrahydrocannabinol, dexamphetamine, haloperidol, heroin and other opiates, ketamine and metamphetamine.
[0051] Furthermore, the compounds, compositions and methods of the present invention, particularly when radiolabeled as described above or labeled by methods well-known in the art with florescent and spin labels, may be employed as imaging agents and in other ways for diagnosis and/or treatment. Moreover, immobilization of compounds of the invention on solid support could be of utility for affinity purification and modification of compounds of the invention with chemically active groups may be used for protein labeling.
[0052] For many of the utilities outlined above, it maybe advantageous to administer compounds of the general invention together with cholinesterase inhibitors (e.g. tacrine, huperzine, donepezil); NMDA antagonists (e.g. lanicemine, remacemide, neramexane, memantine); calpain inhibitors (e.g. CEP-3122); antioxidants (e.g.vitamin E, coenzyme QlO) and agents that have shown clinical efficacy but whose mechanism is unclear (e.g. dimebon). Compounds of the invention may also be administered together with one or more of the following agents to improve cognition: amisulpride, atomoxetine, bromocryptine, buspirone, caffeine, chlorpromazine, clonidine, clozapine, diazepam, flumazenil, fluoxetine, galantamine, guanfacine, methylphenidate, idazoxan, modafinil, olanzapine, paroxetine, pergolide, phenserine, quetiapine, risperidone, rivastigmine, SGS742 and sulpiride.
[0053] The terms "methods of treating or preventing" mean amelioration, prevention or relief from the symptoms and/or effects associated with CNS or vascular disorders. The term "preventing" as used herein refers to administering a medicament beforehand to forestall or obtund an acute episode. The person of ordinary skill in the medical art (to which the present method claims are directed) recognizes that the term "prevent" is not an absolute term. In the medical art it is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or seriousness of a condition, and this is the sense intended in applicants' claims. As used herein, reference to "treatment" of a patient is intended to include prophylaxis.
[0054] The term "mammal" is used in its dictionary sense. Humans are included in the group of mammals, and humans would be the preferred subjects of the methods.
[0055] The cognitive impairment to be treated may arise from one or more of the following disorders, which may not in themselves be necessarily associated with PDE4 abnormality: acute pain, AD/HD - Attention deficit hyperactivity disorder, AIDS dementia complex, alcoholism, amphetamine addiction, amygdalo-hippocampectomy, anorexia nervosa, anterior parietal damage, antisocial behavior, antisocial personality disorder, anxiety, autism, basal ganglia lesions, bipolar disorder, borderline personality disorder, camptocormia, capgras syndrome, carcinoid syndrome, carotid endarterectomy surgery, chronic drug misuse, chronic fatigue syndrome, chronic occupational solvent encephalopathy, chronic pain, brain ischemia, coronary artery bypass surgery, critical illness requiring intensive care, dementia Alzheimer-type (DAT), dementia Lewy Body type, dementia of frontal type, dementia caused by ischemia, dental pain, developmental dyslexia, diabetes, dorsolateral frontal cortical compression, Down's Syndrome, drug abuse, dysexecutive syndrome, fibromyalgia, frontal lobe damage, frontal lobe excision, frontal variant frontotemporal dementia, gluten ataxia, hallucinosis, head injury, hearing loss, heart disease, heart failure, heavy social drinking, hepatic encephalopathy, heroin addiction, herpes encephalitis, hippocampal atrophy, HIV/AIDS, Huntington's disease, hydrocephalus, hypercortisolemia, hyperostosis frontalis interna, hypertension, idiopathic pain, insomnia, Korsakoff syndrome, late paraphrenia, lead exposure, left ventricular systolic dysfunction, orbitofrontal cortex lesion, liver failure, long term health effects of diving, Machado-Joseph disease, mad hatter's disease, manic depression, melancholia, mercury poisoning, mild cognitive impairment (MCI), mild cognitive impairment (MCI) of aging, motor neuron disease, multiple sclerosis, multiple system atrophy, narcolepsy, neuronal migration disorders, normal pressure hydrocephalus, obsessive compulsive disorder, organophosphate pesticide exposure, panic disorder, paraphrenia, Parkinson's disease, periventricular brain insult, personality disorder, gasoline sniffing, phenylketonuria, post-concussion syndrome, premature birth needing intensive care, premenstrual dysphoric disorder, progressive supranuclear palsy, psychopathy, psychosis, questionable dementia, renal cancer, Roifman syndrome, schizoaffective disorder, schizophrenia, seasonal affective disorder, self harm, semantic dementia, specific language impairment, social withdrawal in schizophrenia, solvent encephalopathy, spina bifida, Steele-Richardson-Olzsewski syndrome, stiff person syndrome, striatocapsular infarct, subarachnoid hemorrhage, substance abuse, tardive dyskinesia, temporal lobe excision, temporal lobe lesion, tinnitus, Tourette's syndrome, transient cerebral ischemia, traumatic brain injury, trichotillomania, tuberous sclerosis, and white matter lesions.
[0056] While it may be possible for compounds of compounds of the invention to be administered as the raw chemical, it will often be preferable to present them as part of a pharmaceutical composition. In accordance with an embodiment of the present invention there is provided a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Furthermore, when reference is made in an independent claim to a compound or a pharmaceutically acceptable salt thereof, it will be understood that claims which depend from that independent claim which refer to such a compound also include pharmaceutically acceptable salts of the compound, even if explicit reference is not made to the salts in the dependent claim.
[0057] The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration. The most suitable route may depend upon the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Such methods include the step of bringing into association a compound of the invention or a pharmaceutically acceptable salt or solvate thereof ("active ingredient") with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
[0058] Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
[0059] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide sustained, delayed or controlled release of the active ingredient therein. The pharmaceutical compositions may include a "pharmaceutically acceptable inert carrier", and this expression is intended to include one or more inert excipients, which include starches, polyols, granulating agents, microcrystalline cellulose, diluents, lubricants, binders, disintegrating agents, and the like. If desired, tablet dosages of the disclosed compositions may be coated by standard aqueous or nonaqueous techniques, "Pharmaceutically acceptable carrier" also encompasses controlled release means.
[0060] Pharmaceutical compositions may also optionally include other therapeutic ingredients, anti-caking agents, preservatives, sweetening agents, colorants, flavors, desiccants, plasticizers, dyes, and the like. Any such optional ingredient must be compatible with the compound of the invention to insure the stability of the formulation. The composition may contain other additives as needed, including for example lactose, glucose, fructose, galactose, trehalose, sucrose, maltose, raffinose, maltitol, melezitose, stachyose, lactitol, palatinite, starch, xylitol, mannitol, myoinositol, and the like, and hydrates thereof, and amino acids, for example alanine, glycine and betaine, and peptides and proteins, for example albumen.
[0061] Examples of excipients for use as the pharmaceutically acceptable carriers and the pharmaceutically acceptable inert carriers and the aforementioned additional ingredients include, but are not limited to binders, fillers, dis integrants, lubricants, anti-microbial agents, and coating agents.
[0062] The dose range for adult humans is generally from 0.005 mg to 10 g/day orally. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity.
[0063] A dosage unit (e.g. an oral dosage unit) can include from, for example, 1 to 30 mg, 1 to 40 mg, 1 to 100 mg, 1 to 300 mg, 1 to 500 mg, 2 to 500 mg, 3 to 100 mg, 5 to 20 mg, 5 to 100 mg (e.g. 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg) of a compound described herein.
[0064] For additional information about pharmaceutical compositions and their formulation, see, for example, Remington: The Science and Practice of Pharmacy, 20th Edition, 2000. The agents can be administered, e.g., by intravenous injection, intramuscular injection, subcutaneous injection, intraperitoneal injection, topical, sublingual, intraarticular (in the joints), intradermal, buccal, ophthalmic (including intraocular), intranasaly (including using a cannula), or by other routes. The agents can be administered orally, e.g., as a tablet or cachet containing a predetermined amount of the active ingredient, gel, pellet, paste, syrup, bolus, electuary, slurry, capsule, powder, granules, as a solution or a suspension in an aqueous liquid or a non-aqueous liquid, as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion, via a micellar formulation (see, e.g. WO 97/11682) via a liposomal formulation (see, e.g., EP 736299,WO 99/59550 and WO 97/13500), via formulations described in WO 03/094886 or in some other form. The agents can also be administered transdermally (i.e. via reservoir-type or matrix-type patches, microneedles, thermal poration, hypodermic needles, iontophoresis, electroporation, ultrasound or other forms of sonophoresis, jet injection, or a combination of any of the preceding methods (Prausnitz et al. 2004, Nature Reviews Drug Discovery 3:1 15)). The agents can be administered locally, for example, at the site of injury to an injured blood vessel. The agents can be coated on a stent. The agents can be administered using high- velocity transdermal particle injection techniques using the hydrogel particle formulation described in U.S. 20020061336. Additional particle formulations are described in WO 00/45792, WO 00/53160, and WO 02/19989. An example of a transdermal formulation containing plaster and the absorption promoter dimethylisosorbide can be found in WO 89/04179. WO 96/11705 provides formulations suitable for transdermal administration. The agents can be administered in the form a suppository or by other vaginal or rectal means. The agents can be administered in a transmembrane formulation as described in WO 90/07923. The agents can be administered non-invasively via the dehydrated particles described in U.S. 6,485,706. The agent can be administered in an enteric-coated drug formulation as described in WO 02/49621. The agents can be administered intranasaly using the formulation described in U.S. 5,179,079. Formulations suitable for parenteral injection are described in WO 00/62759. The agents can be administered using the casein formulation described in U.S. 20030206939 and WO 00/06108. The agents can be administered using the particulate formulations described in U.S. 20020034536.
[0065] The agents, alone or in combination with other suitable components, can be administered by pulmonary route utilizing several techniques including but not limited to intratracheal instillation (delivery of solution into the lungs by syringe), intratracheal delivery of liposomes, insufflation (administration of powder formulation by syringe or any other similar device into the lungs) and aerosol inhalation. Aerosols (e.g., jet or ultrasonic nebulizers, metered-dose inhalers (MDIs), and dry-Powder inhalers (DPIs)) can also be used in intranasal applications. Aerosol formulations are stable dispersions or suspensions of solid material and liquid droplets in a gaseous medium and can be placed into pressurized acceptable propellants, such as hydrofluoroalkanes (HFAs, i.e. HFA-134a and HFA-227, or a mixture thereof), dichlorodifluoromethane (or other chlorofluorocarbon propellants such as a mixture of Propellants 11, 12, and/or 114), propane, nitrogen, and the like. Pulmonary formulations may include permeation enhancers such as fatty acids, and saccharides, chelating agents, enzyme inhibitors (e.g., protease inhibitors), adjuvants (e.g., glycocholate, surfactin, span 85, and nafamostat), preservatives (e.g., benzalkonium chloride or chlorobutanol), and ethanol (normally up to 5% but possibly up to 20%, by weight). Ethanol is commonly included in aerosol compositions as it can improve the function of the metering valve and in some cases also improve the stability of the dispersion. Pulmonary formulations may also include surfactants which include but are not limited to bile salts and those described in U.S. 6,524,557 and references therein. The surfactants described in U.S. 6,524,557, e.g., a Cg-Ciβ fatty acid salt, a bile salt, a phospholipid, or alkyl saccharide are advantageous in that some of them also reportedly enhance absorption of the compound in the formulation. Also suitable in the invention are dry powder formulations comprising a therapeutically effective amount of active compound blended with an appropriate carrier and adapted for use in connection with a dry-Powder inhaler. Absorption enhancers which can be added to dry powder formulations of the present invention include those described in U.S. 6,632,456. WO 02/080884 describes new methods for the surface modification of powders. Aerosol formulations may include U.S. 5,230,884, U.S. 5,292,499, WO 017/8694, WO 01/78696, U.S. 2003019437, U. S. 20030165436, and WO 96/40089 (which includes vegetable oil). Sustained release formulations suitable for inhalation are described in U.S. 20010036481A1, 20030232019A1, and U.S. 20040018243A1 as well as in WO 01/13891, WO 02/067902, WO 03/072080, and WO 03/079885. Pulmonary formulations containing microparticles are described in WO 03/015750, U.S. 20030008013, and WO 00/00176. Pulmonary formulations containing stable glassy state powder are described in U.S. 20020141945 and U.S. 6,309,671. Other aerosol formulations are described in EP 1338272A1 WO 90/09781, U. S. 5,348,730, U.S. 6,436,367, WO 91/04011, and U.S. 6,294,153 and U.S. 6,290,987 describes a liposomal based formulation that can be administered via aerosol or other means. Powder formulations for inhalation are described in U.S. 20030053960 and WO 01/60341. The agents can be administered intranasally as described in U.S. 20010038824.
[0066] Solutions of medicament in buffered saline and similar vehicles are commonly employed to generate an aerosol in a nebulizer. Simple nebulizers operate on Bernoulli's principle and employ a stream of air or oxygen to generate the spray particles. More complex nebulizers employ ultrasound to create the spray particles. Both types are well known in the art and are described in standard textbooks of pharmacy such as Sprowls' American Pharmacy and Remington's The Science and Practice of Pharmacy. Other devices for generating aerosols employ compressed gases, usually hydrofluorocarbons and chlorofluorocarbons, which are mixed with the medicament and any necessary excipients in a pressurized container, these devices are likewise described in standard textbooks such as Sprowls and Remington.
[0067] The agent can be incorporated into a liposome to improve half-life. The agent can also be conjugated to polyethylene glycol (PEG) chains. Methods for pegylation and additional formulations containing PEG-conjugates (i.e. PEG-based hydrogels, PEG modified liposomes) can be found in Harris and Chess, Nature Reviews Drug Discovery 2:214-221 and the references therein. The agent can be administered via a nanocochleate or cochleate delivery vehicle (BioDelivery Sciences International). The agents can be delivered transmucosally (i.e. across a mucosal surface such as the vagina, eye or nose) using formulations such as that described in U.S. 5,204,108. The agents can be formulated in microcapsules as described in WO 88/01165. The agent can be administered intra-orally using the formulations described in U.S. 20020055496, WO 00/47203, and U.S. 6,495,120. The agent can be delivered using nanoemulsion formulations described in WO 01/91728A2.
[0068] In general, compounds of the invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
[0069] The invention relates to compounds of formula:
Figure imgf000025_0001
as described above. The disclosure of the synthesis of these compounds may be found in the US nonprovisional application filed November 20, 2008, claiming priority to provisional application 60/989,551, filed on November 21, 2007, the contents of which are incorporated herein by reference.
[0070] In accordance with some embodiments of the invention, R is chosen from H, - C(=O)NH2, -(Ci-C6)alkyl, halo(C1-C6)alkyl, (Ci-C6)alkyl-R30, (C2-C6)alkyl-R31, and saturated
4- or 5-membered heterocycle optionally substituted with methyl. In other embodiments, R 30 is chosen from -C(=O)NH2 and a 4- or 5-membered heterocycle optionally substituted with methyl. In yet other embodiments, R31 is chosen from (Ci-C/Oalkoxy, amino, hydroxy, (Ci- C6)alkylamino and di(Ci-C6)alkylamino.
[0071] In accordance with some embodiments of the invention, R4 is chosen from H and F. In accordance with some embodiments, R6 is chosen from H, (Ci-C6)alkyl and halogen.
[0072] In accordance with some embodiments of the invention, B is an optionally substituted carbocycle. In some embodiments, B is an optionally substituted heterocycle of two or fewer rings.
[0073] In accordance with some embodiments of the invention, M is chosen from direct bond, -C(R20XR21)-, -O-, -NR22-, -S(O)n-, -C(=O)-, -C(R20)(R21)C(R20)(R21)-, -C(R20)=C(R21)-, -C(R20)(R21)-O-, -C(R20)(R21)-NR22-, -C(R20)(R21)-S(O)n-, -C(R20)(R21)- C(=O)-, -O-C(R20)(R21)-, -NR22-C(R20)(R21)-, -S(O)n-C(R20)(R21)-, -C(=O)-C(R20)(R21)- and
Figure imgf000026_0001
In some embodiments, R20, R21 and R22 are each independently selected
from H and (Ci-C/Oalkyl. In still other embodiments,
Figure imgf000026_0002
is a five or six- membered ring optionally substituted with methyl and n is zero, one or two.
[0074] In accordance with some embodiments of the invention, A is an optionally substituted carbocycle. In other embodiments A is an optionally substituted heterocycle of three or fewer rings.
[0075] In accordance with some embodiments of the invention, X is selected from the group consisting of N, N→O, or C-R5. In some embodiments, R5 is chosen from H, halogi OH, (Ci-C6)alkyl, (Ci-C6)alkoxy, CF3, CN, NH2, CH2OH, CH2NH2 and C≡CH.
[0076] In accordance with some embodiments of the invention, the compounds are of formula
Figure imgf000026_0003
[0077] The disclosure of the synthesis of these compounds may be found in the US nonprovisional application filed November 20, 2008, claiming priority to provisional application 60/989,557, filed on November 21, 2007, the contents of which are incorporated herein by reference.
[0078] In accordance with some embodiments of the invention, U is S. In other embodiments, U is O. In some embodiments, V is selected from the group consisting of H, CH3, NH2, and CF3 In other embodiments, Z is selected from the group consisting of CH, C- F, C-Cl, C-Br, C-I, C-NH2, C-OH, C-OCH3, N, and N-O. In yet other embodiments, Y is selected from the group consisting of N, CH, CF and C-Io wer alkyl.
[0079] In accordance with some embodiments of the invention, R >40 is H or lower alkyl, aanndd iinn ootthheeir embodiments R41 is selected from the group consisting of H, alkyl, OH, NH2, and OCH3.
[0080] In accordance with some embodiments of the invention, G is an optionally substituted, mono- or bicyclic aryl or heteroaryl. In still other embodiments of the invention, E is an optionally substituted heterocycle or an optionally substituted carbocycle.
[0081] In accordance with some embodiments of the invention, the compounds are of formula
Figure imgf000027_0001
[0082] The disclosure of the synthesis of these compounds may be found in the US nonprovisional application filed November 20, 2008, claiming priority to provisional application 60/989,567, filed on November 21, 2007, the contents of which are incorporated herein by reference.
[0083] In accordance with some embodiments of the invention, R1 is chosen from H, (Ci- C8)alkyl and halo(Ci-Cg)alkyl. In other embodiments, R2 is chosen from H and halo.
[0084] In some embodiments, Ar1 is selected from optionally substituted phenyl and ooppttiioonnaallllyy ssuubbssttiittuutteedd hheetteerrooaarryyll.. 1 In other embodiments, Ar2 is selected from substituted phenyl and substituted heteroaryl.
[0085] In accordance with some embodiments of the invention, the compounds are of formula
Figure imgf000028_0001
or salt thereof wherein
AA is selected from N and CR50;
DD is selected from N and CR50, with the proviso that both AA and DD cannot be N;
R50 is selected from hydrogen, (Ci-Ce)alkyl, fluoro, hydroxyalkyl, carbonyl and amide;
J is a substituted 5-membered heterocycle;
Cy1 is selected from optionally substituted phenyl and optionally substituted heteroaryl;
R45 is selected independently in one or more occurrences from hydrogen, halogen and (Ci-C6) alkyl; and
R46 is selected from (1) hydrogen, halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, -NHC(=O)NHalkyl, -NHC(=O)NH-heterocyclyl, -alkyl-NHC(=O)N(alkyl)2, heterocyclylalkylcarbonylamino, benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid amides, protected residues of aminoacids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides and (2) phenyl and monocyclic heterocycle substituted with any of the foregoing. [0086] In some embodiments of the invention, both AA and DD are CR50. In further embodiments, R50 is hydrogen. In yet other embodiments, only one of AA or DD are nitrogen. In accordance with some embodiments of the invention, J is selected from optionally substituted 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, furane, thiophene, isoxazole, pyrazole, tetrahydrofurane, tetrahythiophene and isoxazoline; and R46 is selected from hydroxy(Ci-C6)alkyl; hydroxy(Ci-C6)alkyoxy; phenyl optionally substituted with amino, halogen, hydroxy, alkylsulfonylamino or (Ci-C6) alkylurea; and pyridinyl optionally substituted with amino, halogen, hydroxy, alkylsulfonylamino or (Ci-C6) alkylurea.
[0087] In accordance with some embodiments of the invention, the compounds are of
formula
Figure imgf000029_0001
or salt thereof wherein
J is a substituted 5-membered heterocycle;
L is selected from O, S and NRb;
Ra is selected from H and (Ci-C6) alkyl;
Rb is selected from H and (Ci-C6) alkyl;
Cy1 is selected from optionally substituted phenyl and optionally substituted heteroaryl;
R45 is selected independently in one or more occurrences from hydrogen, halogen, (Ci-C6) alkyl; and
R46 is selected from (1) halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, -NHC(=O)NHalkyl, -NHC(=O)NH-heterocyclyl, -alkyl-NHC(=O)N(alkyl)2, heterocyclylalkylcarbonylamino, benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid amides, protected residues of aminoacids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides and (2) phenyl and monocyclic heterocycle substituted with any of the foregoing.
[0088] In some embodiments of the invention, J is selected from optionally substituted 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, furane, thiophene, isoxazole, pyrazole, tetrahydrofurane, tetrahythiophene and isoxazoline; R46 is selected from hydroxy(Ci- C6)alkyl; hydroxy(Ci-Ce)alkyoxy; phenyl optionally substituted with amino, halogen, hydroxy, alkylsulfonylamino or (Ci-Cβ) alkylurea; and pyridinyl optionally substituted with amino, halogen, hydroxy, alkylsulfonylamino or (Ci-Cβ) alkylurea.
[0089] In accordance with some embodiments of the invention, the compounds are of
formula
Figure imgf000030_0001
or salt thereof wherein
AA is selected from N and CR50;
DD is selected from N and CR50, with the proviso that both AA and DD cannot be N;
R50 is selected from hydrogen, (Ci-C6)alkyl, fluoro, hydroxyalkyl, carbonyl and amide;
Q is selected from O, NH, S, SO and SO2;
T is selected from CONH, CH2NHCO, CHRdNHCO, CHRdNHSO2, and CHReXaCHRc;
Xa is selected from O, NH, S, SO and SO2;
Rc, Rd and Re are each independently selected from hydrogen, (Ci-Cβ) alkyl, hydroxy(Ci-
Ce)alkyl and amino(Ci-C6)alkyl;
Cy1 is selected from optionally substituted phenyl and optionally substituted heteroaryl; and R47 is selected from hydroxy(Ci-C6)alkyl, hydroxy(Ci-Ce)alkyoxy, carbocyclyl and heterocyclyl, wherein the cyclyl is optionally substituted with a substituent selected from (1) halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, -NHC(=O)NHalkyl, -NHC(=O)NH-heterocyclyl, -alkyl-NHC(=O)N(alkyl)2, heterocyclylalkylcarbonylamino, benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid amides, protected residues of aminoacids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides and (2) phenyl and monocyclic heterocycle substituted with any of the foregoing.
[0090] In some embodiments of the invention, AA and DD are both CR50. In further embodiments, R50 is hydrogen. In other embodiments, either AA or DD are nitrogen. In some embodiments of the invention, Q is NH; T is CH2NHCH2; Cy1 is selected from phenyl optionally substituted with NO2 or acyl; and R47 is selected from carbocyclyl and heterocyclyl optionally substituted with amino, halogen, hydroxy, alkylsulfonylamino or (Ci- Ce) alkylurea.
[0091] In accordance with some embodiments of the invention, the compounds are of
formula
Figure imgf000031_0001
or a salt thereof wherein
Q is selected from O, NH, S, SO and SO2;
L is selected from O, S and NRb;
Ra is selected from H and (Ci-C6) alkyl;
Rb is selected from H and (Ci-C6) alkyl;
T is selected from CONH, CH2NHCO, CHRdNHC0, CHRdNHSO2, CHReXaCHRc, and
CONHCHRC;
Xa is selected from O, NH, S, SO and SO2;
Rc, Rd and Re are each independently selected from hydrogen, (Ci-C6) alkyl, hydroxy(Ci-
C6)alkyl and amino(Ci-C6)alkyl;
Cy1 is selected from optionally substituted phenyl and optionally substituted heteroaryl; and
R47 is selected from hydroxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkyoxy, carbocyclyl and heterocyclyl, wherein the cyclyl is optionally substituted with a substituent selected from (1) halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido,
-NHC(=O)NHalkyl, -NHC(=O)NH-heterocyclyl, -alkyl-NHC(=O)N(alkyl)2, heterocyclylalkylcarbonylamino, benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid amides, protected residues of aminoacids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides and (2) phenyl and monocyclic heterocycle substituted with any of the foregoing.
[0092] In accordance with some embodiments of the invention, the compounds are of formula
Figure imgf000033_0001
or a salt thereof wherein
P is chosen from nitrogen and carbon;
Q is chosen from nitrogen and carbon, with the provisos that one of P or Q must be nitrogen, but P and Q cannot both be nitrogen;
R1 is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl, -CONHR5, lower alkoxy, alkylamino, dialkylamino, amino, -NHCOOR2 and -OCONH2; W is nitrogen or CR2;
R2 is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl and optionally substituted heterocyclyl; Y is CR3 or nitrogen;
R3 is selected from hydrogen, fluoro, hydroxyl and -OR10; R10 is selected from (Ci-Cβ) alkyl optionally substituted with fluoro; X is selected from CR4, nitrogen and N+ O";
R4 is selected from hydrogen, (Ci-Cβ) alkyl, halogen, amino, alkoxy and hydroxyl; R5 is selected from hydrogen and (Ci-Cβ) alkyl; q is selected from O, S(0)o-2, NH, CH2 and a direct bond;
Cy1 is selected from optionally substituted (C3-C6) carbocyclyl and optionally substituted heterocyclyl; Cy2 is selected from optionally substituted aryl and optionally substituted heteroaryl; and
M is chosen from -CH2-, -CH2CH2-, -0-, -S(O)0-2, -OCH2, -CH2O, -CONH, - CONHCH2, -NHCO and -NHSO2.
[0093] In accordance with some embodiments of the invention, the compounds are of formula
Figure imgf000034_0001
or a salt thereof wherein
P is chosen from nitrogen and carbon;
Q is chosen from nitrogen and carbon, with the provisos that one of P or Q must be nitrogen, but P and Q cannot both be nitrogen;
R1 is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl, -CONHR5, lower alkoxy, alkylamino, dialkylamino, amino, -NHCOOR2 and -OCONH2; W is nitrogen or CR2;
R2 is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl and optionally substituted heterocyclyl;
X is selected from CR4, nitrogen and N+ O";
R4 is selected from hydrogen, (Ci-Cβ) alkyl, halogen, amino, alkoxy and hydroxyl; R5 is selected from hydrogen and (Ci-Cβ) alkyl;
R8 and R9 are independently selected from hydrogen, (Ci-Cβ) alkyl, (Ci-Cβ) hydroxyalkyl, (C3-C6) carbocyclyl and a 3- to 6-membered heterocyclyl; or R8 and R9 together form a 4-6 membered ring which optionally contains a heteroatom selected from -0-, -NR5 and S(0)o-2; or R8 and R9 together form an oxo group; q is selected from O, S(0)o-2, NH, CH2 and a direct bond;
Cy1 is selected from optionally substituted (C3-C6) carbocyclyl and optionally substituted heterocyclyl; Cy2 is selected from optionally substituted aryl and optionally substituted heteroaryl; and
M is chosen from -CH2-, -CH2CH2-, -0-, -S(O)0-2, -OCH2, -CH2O, -CONH, - CONHCH2, -NHCO and -NHSO2,
[0094] In accordance with some embodiments of the invention, the compounds are of formula
Figure imgf000035_0001
or a salt thereof wherein
R2 is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl and optionally substituted heterocyclyl; q is selected from O, S(0)o-2, NH, CH2 and a direct bond; Cy1 is an optionally substituted, mono- or bicyclic aryl or heteroaryl; and Cy2 is an optionally substituted heterocycle or an optionally substituted carbocycle.
[0095] In accordance with some embodiments of the invention, the compounds are of formula
Figure imgf000035_0002
or a salt thereof wherein
R1 is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl, -CONHR5, lower alkoxy, alkylamino, dialkylamino, amino, -NHCOOR2 and -OCONH2; W is nitrogen or CR2;
R2 is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl and optionally substituted heterocyclyl; q is selected from O, S(0)o-2, NH, CH2 and a direct bond; j-k is selected from 0-N, N(R2a)-N and N-N(R2a);
R2a is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl, aminoalkyl, acyl, alkoxyalkyl, hydroxyalkyl, phenyl, heteroaryl, oxaalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylaminoalkyl, aminocarbonylalkyl, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, aryl, benzyl, heterocyclyl, and heterocyclylalkyl;
Cy1 is an optionally substituted, mono- or bicyclic aryl or heteroaryl; and
Cy2 is an optionally substituted heterocycle or an optionally substituted carbocycle.
[0096] In accordance with some embodiments of the invention, the compounds are of formula
Figure imgf000036_0001
or a salt thereof wherein b is selected from the group consisting of S, O and NR2b;
R2b is selected from hydrogen, (Ci-Cβ) alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, and alkoxycarbonyl;
V is selected from the group consisting of H, CH3, NH2, NR2c, OR2d, carboxylic acid, SO2NH, S(O)0-2 and CF3;
R2c is selected from hydrogen, (Ci-Cβ) alkyl, hydroxyalkyl, haloalkyl, aminoalkyl and alkoxycarbonyl;
R2d is selected from hydrogen, (Ci-Cβ) alkyl, hydroxyalkyl, haloalkyl, aminoalkyl and alkoxycarbonyl; q is selected from O, S(0)o-2, NH, CH2 and a direct bond;
Y is selected from the group consisting of N, CH, CF and C-lower alkyl; R40 is H or lower alkyl;
R41 is selected from the group consisting of H, alkyl, OH, NH2, and OCH3;
Cy1 is an optionally substituted, mono- or bicyclic aryl or heteroaryl; and
Cy2 is an optionally substituted heterocycle or an optionally substituted carbocycle.
[0097] In accordance with some embodiments of the invention, the compounds are of formula
Figure imgf000037_0001
or a salt thereof wherein q is selected from O, S(0)o-2, NH, CH2 and a direct bond;
M is chosen from CH2, CH2CH2, O, S(O)0-2, OCH2, CH2O, CONH, CONHCH2, NHCO, C=O and NHSO2;
Cy1 is an optionally substituted, mono- or bicyclic aryl or heteroaryl; and
Cy2 is an optionally substituted heterocycle or an optionally substituted carbocycle.
[0098] In some embodiments of the invention, q is CH2; M is CH2O; Cy1 is optionally substituted phenyl; and Cy2 is phenyl optionally substituted with amino or (Ci-Cβ) alkylurea.
[0099] In accordance with some embodiments, the invention is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
[00100] In accordance with some embodiments, the invention is a compound of the invention wherein said compound shows preference for a regulatory segment of a PDE4 isoform over the catalytic portion of a PDE4 isoform. In some embodiments, the PDE4 isoform is selected from a regulatory domain-containing form of PDE4 and may be selected from PDE4D3, PDE4D4, PDE4D5, PDE4D7, PDE4D8, PDE4D9, PDE4D1, PDE4D2, PDE4D6, PDE4B1, PDE4B3, PDE4B4 and PDE4B2. In some embodiments of the invention, the regulatory domain-containing form of PDE4 is the long form, and is selected from PDE4D3, PDE4D4, PDE4D5, PDE4D7, PDE4D8, PDE4D9, PDE4B1, PDE4B3 and PDE4B4. In other embodiments, the PDE4 isoform is the short form, and is selected from PDE4D1 or PDE4B2. In still other embodiments, the PDE4 isoform is the super-short form, and is selected from PDE4D2 or PDE4D6.
[00101] In accordance with one embodiment of the invention, a compound of the invention is a PDE4 modulator wherein said modulator has an In^x < 95%. Imx is defined as the percent inhibition at the maximum concentration, and the maximum concentration is defined as a concentration at least 50-fold higher than the IC50 of the compound at the regulatory-containing domain of PDE4. In other embodiments, the modulator has an Imax < 90%.
[00102] In accordance with one embodiment, the invention relates to a method for treating or preventing CNS-related disorders or vascular disorders while minimizing at least one unwanted side effect comprising administering a compound of the invention having a ratio of binding selectivity to a regulatory domain-containing form of PDE4 of at least 100 times the binding selectivity to the catalytic portion of PDE4. In another embodiment, the ratio of binding selectivity to a regulatory domain-containing form of PDE4 is at least 1000 times the binding selectivity to the catalytic portion of PDE4. In yet another embodiment, the ratio of binding selectivity to a regulatory domain-containing form of PDE4 is at least 10,000 times the binding selectivity to the catalytic portion of PDE4.
[00103] In yet another embodiment, the invention relates to a method of minimizing the side effect of nausea. In still another embodiment, the side effect to be minimized is emesis. In a further embodiment, the side effect to be minimized is vasculopathy.
[00104] In accordance with one embodiment, the invention relates to a method for identifying the selectivity of a potential PDE4-inhibiting compound comprising: i. providing at least two different isoforms of PDE4, ii. providing cAMP substrate; iii. providing one or more cofactors; iv. providing an agent for detection of a reaction of cAMP substrate; v. determining the maximum kinetic rates of reaction of said cAMP substrate in the presence of said at least two different isoforms of PDE4; vi. providing a sample containing a test compound; vii. determining the IC50 values of said test compound against said at least two different isoforms of PDE4; and viii. comparing said IC50 values to determine a selectivity ratio. [00105] In another embodiment of the invention, the at least two different isoforms of PDE4 are selected from PDE4D7, PDE4D1, PDE4D2, PDE4D-Cat and PDE4B1. In a further embodiment of the invention, at least one of the PDE4 isoforms is selected from PDE4D7 and PDE4Bl.
[00106] In still another embodiment of the invention, the one or more cofactors are selected from adenylate kinase, pyruvate kinase, phosphoenolpyruvate, lactate dehydrogenase and NADH. In yet another embodiment, agent for detection of a reaction of cAMP substrate is detected by spectrophotometry, fluorescence or radionucleide. In a further embodiment, the agent for detection of a reaction of cAMP substrate is NADH.
[00107] In some embodiments of the invention, the compound is selected from the following:
Table 1.
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
[00108] All of the compounds of the invention described herein are useful as PDE4 inhibitors. It may be found upon examination that species and genera not presently excluded are not patentable to the inventors in this application because of prior art. In this case, the exclusion of species and genera in applicants' claims are to be considered artifacts of patent prosecution and not reflective of the inventors' concept or description of their invention. The invention, in a composition aspect, is all active compounds of the invention except those that are in the public's possession. [00109] In general, compounds of the invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants that are in themselves known, but are not mentioned here.
[00110] Table 1 above lists compounds representative of embodiments of the invention. Processes for obtaining compounds of the invention are presented below. Other compounds of the invention may be prepared in analogous fashion to those whose synthesis is exemplified herein. The procedures below illustrate such methods. Furthermore, although the syntheses depicted herein may result in the preparation of enantiomers having a particular stereochemistry, included within the scope of the present invention are compounds of the invention in any stereoisomeric form, and preparation of compounds of the invention in stereoisomeric forms other than those depicted herein would be obvious to one of ordinary skill in the chemical arts based on the procedures presented herein.
Synthetic Methods
[00111] The disclosure of the synthesis of some of these compounds may be found in three US nonprovisional application filed November 20, 2008, claiming priority to provisional application numbers 60/989,551, 60/989,557 and 60/989,567, all filed on November 21, 2007, the contents of which are incorporated herein by reference.
General Synthetic Methods.
Figure imgf000074_0001
[00112] Scheme 1.
Figure imgf000075_0001
[00113] Compounds of the Formula Gl, can be prepared by reaction of the 2- aminopryridies or 2-aminopyrazine with an α-haloketone (or α-halo aldehyde) to provide the imidazo[l,2-a]pyridine (X=CH or CF)/imidazo[l,2-a]pyrazine (X=N) (S4/S5). The substituent at C8 can be introduced either before formation of the bicyclic core (S2) by Suzuki/Stille reaction allowing C-C bond formatting chemistries. Alternatively, the intermediate S3 could be reacted by Buchwald or Cu mediated chemistries to for ether/amine linked C8 substituent (S7). The substituent at the C-6 position can be introduced by a wide variety of approaches. When Y is an alkyl, ester, nitrile, following standard function group inter-conversion intermediates S6/S7 containing alcohol, alkyl halide (W) could be generated. The subsequent chemistries employed depends on the 1 -carbon functionality (Y = CH3, CHO, COOR', CN etc.) present as C6. For example, the function group alcohol may be coveted to a carbonate (W= CH-OCO2R'). The carbonate or -CH2-Br (W, S6/S7) upon reaction via organometallic coupling protocols (e.g. Suzuki, Stille reaction) allows C-C liked substituents or displacement of a halogen or tosylate (W) with a cyclic or heterocyclic -NH2, -OH, or -SH containing reagents allow formation of a C-N, C-O, or C-S bond linked substituent at C6. Alternatively, addition of a Grignard or organolithium reagent to Y=ester, allows formation of the ketone/secondary alcohol linked substituents (M = CO, C(OH)H or C(OH)R). S6/S7 intermediates (W= CH2Br or CH2OH) could be derivatized to produce ether / amine linked C6 substituents. The alcohol can be converted to a primary or secondary amine. The W as acid or amine thus allows formation of amide, reverse amide, sulfonamide from acylation /sulfonation chemistries or diverse amine via reductive amine chemistry approaches. The substituents containing additional functions groups allow subsequent elaboration by standard chemistries outlines above depending upon the functional groups introduced at C6. These strategies allow incorporation of acyclic, heterocyclic or heteroaryl derived substituents at the C6 / C8 position of the imidazo[l,2-a]pyridine/ imidazo[l,2-a]pyrazine core.
[00114] Scheme 2.
Figure imgf000076_0001
[00115] Formation of the [l,2,4]triazolo[l,5-a]pyridine (SlO, X=CH,CF)/ [l,2,4]triazolo[l,5-a]pyrazine (SlO, X=N) can be obtained from the 2-aminopryridies (S8, X=CH, CF) or 2-aminopyrazine (S8, X=N) starting material via reaction with dimethylformamide dimethyl acetal (R2= H) or dimethyl acetamide dimethyl acetal (R2= CH3) to provide intermediate S9, which following the ring closing reaction with dehydrating reagents (such as: TFAA, PPA, Ts-Cl or Ms-Cl) can provide the key triazolo- pyridine/pyrazine cores (SlO). Subsequent elaboration at C6/C8, analogous to approaches described above for Gl would provide analogs represented by G2.
Scheme 3.
Figure imgf000076_0002
[00116] Formation of pyrozolo[l,5-a]pyridine (S14) can be obtained from 2,4-substituted pyridine (S12) via S13. N-amination of 2,4-disubstituted pyridine (S12) by 0-2- mesitylenesulfonyl hydroxyamine provides intermediate (S13). Subsequent 1,3-dipolar cycloaddition with methyl propiolate furnish the pyrozolo[l,5-a]pyridine (S14), which can subsequently be transformed into the decarboxylated product (S15) under acidic conditions. The 3-ester in pyrozolo[l,5-a]pyridine (S14) could also be converted to other group (S16) by standard functional group transformations. Subsequent elaboration at C6/C8 in pyrozolo[l,5- a]pyridine (S 15 or S 16), analogous to approaches described above for Gl would provide analogs represented by G3.
[00117] Scheme 4.
Figure imgf000077_0001
[00118] Formation of the key intermediate pyrazolo[l,5-a]pyrimidine (S21) can be obtained from the pyrazole starting material (S 18). Reaction of pyrazole (S 18) with methyl chloroformate and subsequent bromination with NBS give intermediate bromomethyl pyrazole (S20). Nucleophilic substitution of tosylmethyl isocyanide (TosMIC) on the bromomethyl pyrazole (S20) followed by intramolecular transfer of the methoxycarbonyl group followed by cyclization and 1,2-elimination of p-toluenesulfinic acid to afford the pyrazolo[l,5-a] pyrimidine intermediate (S21) analogous to Mendiola, J. et.al. JOC 2004, 69, 4974-83. The substitution at C-6 position can be obtained via the ester group at C-6 position by similar approaches described above for Gl analogs. The introduction of the substitutions at C-8 position to form a C-C bond can be accomplished by metal assisted cross coupling reactions.
[00119] The key intermediate pyrazolo[l,5-a]pyrimidine (S26) can be also obtained from S25. The intermediate S25 in turn can be obtained from S18 via bromination and subsequent conversion to the ketone S24. Reaction of S25 with an orthoformate would then provide S26. When Ra =h (for S26) elaboration to final product can be achieved as described above. Alternatively, the final substituent can be introduced as part of formation of S24; in such case cyclization of S25 to S26 directly would yield the desired analogs.
[00120] Scheme 5.
Figure imgf000078_0001
[00121] Formation of the key intermediate pyrazolo[l,5-a]pyrimidine (S28) can be obtained via cyclization reaction of the pyrazole starting material (S27) with acetoacetic acid ethyl ester (or β-keto esters). A large number of starting materials of the general structure
527 are commercial available or can be prepared by published procedures. The -OH group in
528 can convert to chloride or bromide (S29) which can form C-C link substitutions in S30 via organometallic coupling protocols (e.g. Suzuki, Stille reaction). The introduction of C-6 substitution in G5 can be obtained via the methyl (R' =H) at C-6 position by similar approaches described above for Gl analogs.
[00122] Scheme 6.
Figure imgf000078_0002
[00123] Compounds of the Formula G6-a, can be obtained from the intermediate 5H- pyrazolo[l,5-d][l,2,4]triazin-4-one (S26). By coupling of 2-ester pyrazole (S24) with hydrazine give an intermediate S25, which can be subsequently cyclized to key intermediate S26. Pyrazole starting material, S24, with varying R2/R3 groups are either commercial available or can be prepared by literature procedures. The introduction of substitutions at N- 5 position (G6-a) can be obtained via N-alkylation with Ari/Heti-CH2-halide (-Br or Cl).
[00124] Alternatively, compounds of the formula G6-b, can be prepared from the intermediate 2,3-disubstituted-5,6-dihydro-pyrazolo[l,5-d][l,2,4]triazine-4,7-dione (S27). Cyclization of S25 with coupling reagents (such as CDI, triphosgene etc) afford S27, which can subsequently N-alkylation with Hetl/Arl/Rl-halide at N-5 position to provide (S28). The substitutions at C-7 position in compounds G6-b can be obtained by displacement of halogen (Cl or F) of S29 with hydroxyl, amine or thiol containing heterocyclic/aryls.
[00125] Generally compounds where R is a substituted aryl / heteroaryl and the two biaryl groups are linked by a C-C bond may be prepared from appropriately functionalized alkoxy- aryl ether derivatives containing desirable functionalities W, where W may for example be CH, N, COH, CF, etc (Route A, Scheme Al). The biaryl portion can be constructed first, typically via Suzuki or Stille coupling (Gl -> G2). In such case either Y = halogen or OSO2R (OTf, ONf) and the other reagent would be R2-B(OR)2 or R2-SnR3' or vise versa, where R2 -halogen is coupled with Gl containing boronate/boronic acid or trialkyltin as Y. When A is a carbon derived substituent, e.g. CH3, CH2OH, CO2R", CN etc. these groups are converted to provide intermediate G3 where D is either a halogen or OTf, ONf, or OCOOR" (carbonate) such that substituent (Rl) is introduced by employing a transition-metal catalyzed coupling reactions such as Suzuki, Stille or Negishi reaction. An alternative route to compounds of type G4 involves essentially reversing the order of incorporation of Rl and R2 fragments. The route B, as highlighted in Scheme Al, allows formation of G6, where the R2 fragment is introduced at later stage in the sequence, analogous to chemistries employed for G1-G2, for examples Suzuki, Stille coupling. [00126] Scheme Al
Figure imgf000080_0001
[00127] One may attach Rl, which may be aryl, heterocyclic, acyclic, aliphatic, or any other desirable variety of functionality, to the central aromatic ring (Ar) by a wide rage of tether groups M. The central aromatic ring (Ar) may be a biaryl ring system with a R2 group already attached, or the R2 group may be attached subsequent to that of Rl . The linker group M may be a linear chain of one or more atoms consisting of C, N, O, or S. The linker group M may also consist of functionalities including, but not limited to amide, sulfonamide, sulfone, or ketone. It is evident to one skilled in the art that many of these exemplified functional groups maybe attached in more than one way, for example, Ar-CEb-O-Rl or Ar- O-CH2-RI. Considering those compounds with M groups such as S or O, the heteroatom may originally be in the Ar or the Rl group. Some examples of how the two groups can then be joined are nucleophilic aromatic substitution, metal-promoted coupling, and nucleophilic displacement (Scheme A2). Chemical reactivity of the Ar and Rl groups should of course be considered when determining which partner contains the linker heteroatom, and which shall serve as the reaction partner. For example, it is well understood that in aromatic ring systems an electron-withdrawing group para- or ortho- to a leaving group (e.g. halogen) allows susceptibility of the aromatic halogen for nucleophilic displacement. Thus, ArI group containing NO2, CO2R, ketone, CN etc. would allow formation of aryl-M-aryl(heteroaryl) intermediates. The linker group M may also be subject to further elaboration. For example, sulfides may be oxidized to sulfoxides and sulfones and amines maybe subjected to alkylation or reductive amination. Well known synthetic transformations can be used to create tether groups M such as ether amide, sulfonamide, and the like. The functional group location in the precursor Ar and Rl groups can be used to dictate the nature and type of the linkage (e.g. alternative ethers), as mentioned above.
[00128] Scheme A2
Figure imgf000081_0001
[00129] The key fragments Ar and Rl could also be joined using non transition-metal catalyzed C-C bond forming coupling reactions. When A=H, Fridele-Crafts acylation or alkylation can be employed to combine the Ar and Rl groups. Given the chemical reactivity of the aromatic para-methoxy group in the Ar ring, Friedel-Crafts acylation would typically involve a suitably elaborated Rl-COCl (acid chloride) group to form compound GlO. In this case J = CO, which can be reduced to the secondary alcohol (typically with hydride-based reducing agents). If a R' MgX or other such organometallic agent is used, the J = CO group can be transformed into the tertiary alcohol with simultaneous addition of an R group. In another variation, the J = CO group can be converted into the imine or oxime using standard procedures and addition of an R'MgX-type reagent results in the tertiary amine derivative. If desired, the J = CO group can be reduced, using a number of well established methods, to the CH2 group (M). In another variation, when A=H, an aldehyde group can be introduced using either Vilsmeier reaction or using Lewis acid (TiCU, BF3, 0Et2 etc.) mediated reaction with dichloromethylmethyl. The aldehyde functionality can subsequently be transformed into a suitable transition-metal catalyzed coupling reaction partner. Alternatively the aldehye could be used for Wittig reaction forming olefin or CH2CH2 linkage to incorporate Rl. In yet another variation, substituent "A" can be various types of carbonyl (aldehyde or ketone) or imine groups. In one example, addition of a suitably elaborated organometallic Rl group (e.g. Rl-MgX) to aldehyde G9 (A = CHO) would result in GlO with J = C(H)OH. Reduction of this alcohol gives rise to Gl 1 with M = CH2. Similar types of transformations could be employed by one skilled in the art if G9 contained A = ketone or imine.
[00130] Scheme A3
Figure imgf000082_0001
[00131] Alternatively, the C-C bond forming reaction between the Ar and Rl groups could be accomplished by displacement of a leaving group on the Rl by a nucleophile present in the tether region M (Scheme G4) of G12. The activating group could be either removed to provide Z=H (Z=CO2R - decarboxylation of or Z=CN, decyanation) or these could be further transformed to other functional groups e.g. Z = CH2OH or CH2NH2. When M-Z is CH2- halide or CH2-O-sulfonate, Rl fragment can be introduced via formation of ether linkage. This allows attachment of Rl to the central aromatic ring by spacers (M) of varying lengths and compositions. (Scheme A4)
[00132] Scheme A4
Figure imgf000082_0002
[00133] The Rl group could also be assembled form an acyclic intermediate to form a heterocylic or heteroaromatic ring. Examples of these chemistries include formation of 5- membered heteroaryls such as oxadiazole, thiadiazole, triazole (G 17) form acyl hydrazide (G 16); thiazole from 2-halo-ketone or dipolar cycloaddition reactions from olefin or acetylic group to form 5-membered heterocycles or 5-membered heteroaryls (G18) [Scheme A5]. Alternatively the 6-membered heteroaryl or heterocyclic rings could be formed using Diels- Alder or hetero- Diels-Alder chemistries using appropriately substituted alkyl aryl ether bearing either a dienophile or a diene functionalities. The necessary acyclic precursors could be synthesized by standard methods according to previously described intermediates (e.g. aldehyde, alkyl halide) schemes.
[00134] Scheme A5
Figure imgf000083_0001
[00135] When the R2 group is linked to the Ar group thru a heteroatom (N), these biaryl systems could be prepared by organometallic mediated aza-coupling reactions or other nucleophilic aromatic substitution-based procedures (Scheme G6). The Ar-(N)R2 biaryl may be formed from intermediate G6 where Rl group is already in place. Alternatively, the (N)R2 ring can be added to the central Ar ring first, Rl can be attached through a variety of means using approaches described in previous schemes. Examples of (HN)R2 heteroaryl or heterocyclic rings include, but not limited to, imidazole, pyrrole, pyrazole, pyrrolidine, or triazole. The R2 functional group can be fully elaborated prior to addition of the (N)R2 to the Ar, or suitably elaborated after formation of the key C-N bond. [00136] Scheme A6
Figure imgf000084_0001
[00137] The diverse selection of substituents present in Rl and R2 could be formed by standard functional group transformations that are well know in the art. Some of these include formation of amide, sulfonamide, ureas, imidazolone, oxazolones, carbamates from the R2, R3, or Ar ring fragments bearing appropriate amine, carboxylic acid, alcohol, or phenol groups. A particularly useful aromatic ring functionalization technique, in which either the R2 or Rl rings can be employed, is the nucleophilic displacement of ortho-halo N- containing aromatic rings (G20, scheme A7). Examples of ring substrates useful in this type of transformation include 2-halo-pyridine, 2-halo-pyrimidine and 2-halo-imidazole. Additionally, other leaving groups besides halogens (X) may be used such as sulfonate esters (OTf, ONf). These displacement reactions can be carried out using alkali or tertiary amine bases, or could be mediated through the use of an organometallic reagent such as palladium or aluminum reagents. Examples of nucleophiles (R") useful in this type of transformation include amines (primary, secondary, acyclic, or cyclic), alcohols, phenols, NH-containing heterocycle groups (imidazole, or pyrrazole) groups capable of performing nucleophilic displacement.
[00138] Scheme A7
Figure imgf000084_0002
[00139] When Rl group contains additional functional groups, such as amine, ester/acid /alcohols many of which may have be masked or protected during the previous chemistries, these could be used for further functional group manipulations. A wide variety of modifications of Rl functionalities may be achieved using well established synthetic procedures including, but not limited to, alkylation, reductive amination, nucleophilic displacement, cyclization, saponification, and oxidation/reduction. Additionally, like these functional group manipulations, ArI mono-cyclic may be further transformed to a bi-cyclic ring. Examples of such ring transformations may be represented by elaboration of pyridine derivatives to imidazo[l,2-a]pyridine and imidazo[l,5-a]pyridine. These functional group manipulations and bicyclic ring elaborations may be accomplished at any chemically suitable point in the synthesis prior to or post incorporation of R2 or other synthetic transformations.
[00140] These above transformations could be carried out from alkylated phenols containing or lacking fluoro substituents in the central Ar ring. Several of these approaches are also applicable to 3 -alkoxy pyridines as the Ar ring starting materials. The non-limiting specific examples described in later schemes are meant to serve as examples of the broad scope of possible reactions. Similarly, analogs where W = CH2OH, COOH, CN, CONH2 etc. (or suitably protected precursors) could be derived by following similar chemistries (schemes A1-A7) and these functional groups could be derived form an ester or amide derived starting material.
[00141] Generally compounds of the claim 2, can be prepared by shcmes x-y. Sequential introduction of substitution at the 4 and 6 positions of the benzoazoles. The introduction of the substituents at the C4 position to form a C-C bond can be accomplished by organometallic coupling protocols (e.g. Suzuki, Stille reaction) or by displacement of a halogen using metal assisted displacement with a cyclic or heterocyclic NH compound forming a C-N bond at the C4 position of the benzoazole. The atom numberings referenced in this section are shown in Gl (scheme 1). These reactions can be performed with benzoazole derivatives bearing a variety of functionalities at the C-2 which may include V=H, CH3, a protected or derivatized amine or ether. The 2-amino group of benzoazole (V=NH2) can be converted thru intermediacy of a diazo (-N+=N) group to from V=H (for example). The substituent at the C-6 position can be introduced by a wide variety of approaches. These chemistries employed depend of the 1 -carbon functionality (CH3, CHO, COOR', CN etc.) present at the C-6. The benzoazoles bearing diverse functional groups which are amenable to standard function group interconversion, for example alkyl, ester, nitrile which could provide alcohol, alkyl halide could be manipulated by standard and these may include aldehyde, nitrile and esters, which allow generation of alcohol which could be converted to a carbonate or alkyl halide. These functionalities allow introduction of aryl, heteroaryl substituents through C-C forming chemistries. Alternatively nucleophilic displacement of the alkyl halide, OTs, OTf etc. allow incorporation of substituents via C-N bond forming approach to introduce cyclic, acylic, amine derived functional groups (G7). This strategy allows incorporation of acyclic, heterocyclic or heteroaryl derived substituents at the C6 position of the benzoazole nucleus.
[00142] Scheme Bl
Figure imgf000086_0001
[00143] Moreover, introduction of substituents at C6 or C4 could be carried in either sequence, i.e. formation of C4 substituent followed by C6 (route A, G1->G2) or vice versa (route B, G1-G5). Either of these substituents may carry additional functional groups which could be further derivatized through standard functional group transformation chemistries that are well know in the art. Some of these include formation of amide, sulfonamide, ureas, imidazolone, oxazolones, and carbamates from appropriate amine, carboxylic acid, alcohols or phenol groups. Additionally, when the Rl group contains an ortho-halo N-heterocycles (e.g 2-halo pyridine or 2-halo-pyrimidine) G8, a nucleophilic displacement of the halo (or - OTf, ONf derived from pyridin-2-one) groups. Examples of these nucleophile include an amine (primary, sec. tert.; acyclic or cyclic including) or NH-containing heteroaryl (for example, substituted imidazole or pyrazole); or alcohol / thiol allowing incorporation of additional -O, -S or -N linked substituents to provide G9. Alternatively, an appropriately functionalized pyridine can be converted to corresponding 2-OTf or 2-ONf which could then participate in similar chemistries.
[00144] Scheme B2
Figure imgf000087_0001
[00145] The Rl group could also be assembled form an acyclic intermediate (Scheme A3) to form a heterocylic or heteroaromatic ring. Examples of these chemistries include formation of 5-membered heteroaryls (G12) such as oxadiazole, thiadiazole, triazole form acyl hydrazide (Gl 1); thiazole from 2-halo-ketone or dipolar cycloaddition reactions when the C4 or C6 substituent is an olefin or acetylic group (G10->G13)). Alternatively the 6- membered heteroaryl or heterocyclic rings could be formed using Diels-Alder or hetero- Diels-Alder chemistries using appropriately substituted alkyl aryl ether bearing either a dienophile or a diene at C4 or C6 position.
[00146] Scheme B3
Figure imgf000087_0002
[00147] With an aldehyde, ketone, nitrile or an ester at C6, addition of an organometallic (Grignard or organozinc reagent) allows formation of heteroatom containing substituents where Ra or Rb bear a heteroatom. Alternatively, when C6 is C-H, Friedle-Craft acylation provide a ketone (G 17), which is subsequently transformed to sec. alcohol (via reduction), tert. alcohol (thru addition of an alkyl/aryl using RMgX or R2Zn) or sec. or tertiary amine thru mediation of an imine/oxime; or to -CH2-, providing variations at the linker position (G16).
[00148] Scheme B4
Figure imgf000088_0001
[00149] The above approaches describe means to decorate a benzoazole nucleus. On the other hand, one may also be able to start with 1,3 functionalized phenyl or heteroaryl (G20 or G22) which is then elaborated through construction of the fused five membered ring to assemble the benzoazole nucleus later stages in the synthesis of analogs corresponding to the genus I. This approach is depicted in scheme B5. Example of this strategy is also provided in some non-limiting specific example in the later section.
[00150] Scheme B5
Figure imgf000089_0001
[00151] The diverse selection of substituents present in Rl could be formed by standard functional group transformations that are well know in the art. Some of these include formation of amide, sulfomanide, ureas, imidazolone, oxazolones, carbamates from the alkoxy-biaryl fragments bearing and appropriate amine, carboxylic acid, alcochols or phenol groups. When the Rl group contains an ortho-halo pyridine or pyrimidine for example, the nucleophilic displacement of the halo (or -OTf, ONf derived from pyridone) groups. Examples of the nucleophile include an amine (primary, sec. tert; acyclic or cyclic including), alcohol or HN-containing heterocylic groups (for example, substituted imidazole or pyrazole). These displacement reactions could be carried out using alkali or tert. amine base; or could be mediated thru use of an organometallic reagent such as Pd, or Al reagent.
[00152] Compounds of the Formula G2C, can be prepared by reaction of the 2- halopyridines or 6-halopyrazine or 5-halopyrimidine Al with an aryl/heteroaryl (phenol, amine or a thiol) A2 to provide intermediate A3. The functional group X = COOH can then be converted to an amide by standard coupling procedures. Alternatively, the carboxylic acid can be converted to the corresponding amine via Curtis rearrangement and subsequently converted to the amide or sulfonamides. The heterocyclic fragment containing a suitable functional group could optionally be further derivatized by the standard chemistries as described above for other sub-genuses, e.g., specific examples for several of these examples are provided in 2391.025A/025B and 2391.027A/027B PCT/US applications [00153] Scheme Cl
Figure imgf000090_0001
[00154] The carboxylic acid (A3) could be used to form an acyl hydrazide (A4) which subsequently following dehydative cyclization would provide the oxadiazole or with P2S5 or Lawson's reagent and the like, provide thiadiazole or with a suitable amine to provide a triazole, these analogs represented by G2B. The acid intermediate (A3) could also serve as key intermediates to for diverse 5 and 6-memebered heterocycles and the procedures described in PCT/US2005/036558 and references cited in their analogs with published procedure in heterocyclic chemistry literature for such transformations.
[00155] Scheme Dl
Figure imgf000090_0002
[00156] Reaction of a bromodiester (1) with an amide, thioamide or an imidate (2) provides the azole derivative (3). The hydroxyl group of (3) could be derivatized with and heterocyclic-alkyl halide (e.g. substituted benzyl bromide) or it could be used for ether formation using Cu mediated chemistries with aryl or heteroaryl halides to provide (4) where Z may be a bond. The carboxylic acid (5), derived form the ester (4) following base or acid hydrolysis (e.g. for tBu ester (4)) could in turn be used for amide formation to provide analogs represented by G2D or the acid could be used to form an acyl hydrazide (6) which subsequently following dehydative cyclization would provide the oxadiazole or with P2S5 or Lawson's reagent and the like, provide thiadiazole or with a suitable amine to provide a triazole, these analogs represented by G2B. The acid intermediate (5) could also serve as key intermediates to for diverse 5 and 6-memebered heterocycles and the procedures described in PCT7US2005/036558 and references cited in their analogs with published procedure in heterocyclic chemistry literature for such transformations.
[00157] Scheme E1
Figure imgf000091_0001
[00158] Scheme E2.
Figure imgf000091_0002
[00159] Compounds of the Formula Gl can be prepared by reaction of the 2- aminopyridines or 2-aminopyrazine with an α-halo ketone (or α-halo aldehyde) to provide the imidazo[l,2-a]pyridine (X=CH or CF)/imidazo[l,2-a]pyrazine (X=N) (S4/S5). The substituent at C8 can be introduced either before formation of the bicyclic core (S2) by Suzuki/Stille reaction allowing C-C bond formatting chemistries. Alternatively, the intermediate S3 could be reacted by Buchwald or Cu mediated chemistries to for ether/amine linked C8 substituent (S7). The substituent at the C-6 position can be introduced by a wide variety of approaches. When Y is an alkyl, ester, nitrile, following standard function group inter-conversion intermediates S6/S7 containing alcohol, alkyl halide (W) could be generated. The subsequent chemistries employed depends on the 1 -carbon functionality (Y = CH3, CHO, COOR', CN, etc.) present as C6. For example, the function group alcohol may be coveted to a carbonate (W= CH-OCO2R'). The carbonate or -CH2-Br (W, S6/S7) upon reaction via organometallic coupling protocols (e.g. Suzuki, Stille reaction) allows C-C liked substituents or displacement of a halogen or tosylate (W) with a cyclic or heterocyclic -NH2, -OH, or -SH containing reagents allow formation of a C-N, C-O, or C-S bond linked substituent at C6. Alternatively, addition of a Grignard or organolithium reagent to Y=ester, allows formation of the ketone/secondary alcohol linked substituents (M = CO, C(OH)H or C(OH)R). S6/S7 intermediates (W= CH2Br or CH20H) could be derivatized to produce ether / amine linked C6 substituents. The alcohol can be converted to a primary or secondary amine. The W as acid or amine thus allows formation of amide, reverse amide, sulfonamide from acylation /sulfonation chemistries or diverse amine via reductive amine chemistry approaches. The substituents containing additional functions groups allow subsequent elaboration by standard chemistries outlines above depending upon the functional groups introduced at C6. These strategies allow incorporation of acyclic, heterocyclic or heteroaryl derived substituents at the C6 / C8 position of the imidazo[l,2-a]pyridine/ imidazo[l,2-a]pyrazine core.
[00160] Scheme E3.
Figure imgf000092_0001
[00161] Formation of the [l,2,4]triazolo[l,5-a]pyridine (SlO, X=CH,CF)/ [l,2,4]triazolo[l,5-a]pyrazine (SlO, X=N) can be obtained from the 2-aminopryridies (S8, X=CH, CF) or 2-aminopyrazine (S8, X=N) starting material via reaction with dimethylformamide dimethyl acetal (R2= H) or dimethyl acetamide dimethyl acetal (R2= CH3) to provide intermediate S9, which following the ring closing reaction with dehydrating reagents (such as: TFAA, PPA, Ts-Cl or Ms-Cl) can provide the key triazolo- pyridine/pyrazine cores (SlO). Subsequent elaboration at C6/C8, analogous to approaches described above for Gl would provide analogs represented by G2. [00162] Scheme E4.
Figure imgf000093_0001
[00163] Formation of pyrozolo[l,5-a]pyridine (S14) can be obtained from 2,4-substituted pyridine (S12) via S13. N-amination of 2,4-disubstituted pyridine (S12) by 0-2- mesitylenesulfonyl hydroxyamine provides intermediate (S 13). Subsequent 1,3 -dipolar cycloaddition with methyl propiolate furnish the pyrozolo[l,5-a]pyridine (S14), which can subsequently be transformed into the decarboxylated product (S15) under acidic conditions. The 3-ester in pyrozolo[l,5-a]pyridine (S14) could also be converted to other group (S16) by standard functional group transformations. Subsequent elaboration at C6/C8 in pyrozolo[l,5- a]pyridine (S 15 or S 16), analogous to approaches described above for Gl would provide analogs represented by G3.
[00164] Scheme E5.
Figure imgf000094_0001
[00165] Formation of the key intermediate pyrazolo[l,5-a]pyrimidine (S21) can be obtained from the pyrazole starting material (S 18). Reaction of pyrazole (S 18) with methyl chloroformate and subsequent bromination with NBS give intermediate bromomethyl pyrazole (S20). Nucleophilic substitution of tosylmethyl isocyanide (TosMIC) on the bromomethyl pyrazole (S20) followed by intramolecular transfer of the methoxycarbonyl group followed by cyclization and 1,2-elimination of p-toluenesulfinic acid to afford the pyrazolo[l,5-a] pyrimidine intermediate (S21) analogous to Mendiola, J. et.al. JOC 2004, 69, 4974-83. The substitution at C-6 position can be obtained via the ester group at C-6 position by similar approaches described above for Gl analogs. The introduction of the substitutions at C-8 position to form a C-C bond can be accomplished by metal assisted cross coupling reactions.
[00166] The key intermediate pyrazolo[l,5-a]pyrimidine (S26) can be also obtained from S25. The intermediate S25 in turn can be obtained from S18 via bromination and subsequent conversion to the ketone S24. Reaction of S25 with an orthoformate would then provide S26. When Ra =h (for S26) elaboration to final product can be achieved as described above. Alternatively, the final substituent can be introduced as part of formation of S24; in such case cyclization of S25 to S26 directly would yield the desired analogs. [00167] Scheme E6.
Figure imgf000095_0001
[00168] Formation of the key intermediate pyrazolo[l,5-a]pyrimidine (S28) can be obtained via cyclization reaction of the pyrazole starting material (S27) with acetoacetic acid ethyl ester (or β-keto esters). A large number of starting materials of the general structure
527 are commercial available or can be prepared by published procedures. The -OH group in
528 can convert to chloride or bromide (S29) which can form C-C link substitutions in S30 via organometallic coupling protocols (e.g. Suzuki, Stille reaction). The introduction of C-6 substitution in G5 can be obtained via the methyl (R' =H) at C-6 position by similar approaches described above for Gl analogs.
[00169] Scheme E7.
Figure imgf000095_0002
[00170] Compounds of the Formula G6-a, can be obtained from the intermediate 5H- pyrazolo[l,5-d][l,2,4]triazin-4-one (S26). By coupling of 2-ester pyrazole (S24) with hydrazine give an intermediate S25, which can be subsequently cyclized to key intermediate S26. Pyrazole starting material, S24, with varying R2/R3 groups are either commercial available or can be prepared by literature procedures. The introduction of substitutions at N- 5 position (G6-a) can be obtained via N-alkylation with Ari/Heti-CH2-halide (-Br or Cl).
[00171] Alternatively, compounds of the formula G6-b, can be prepared from the intermediate 2,3-disubstituted-5,6-dihydro-pyrazolo[l,5-d][l,2,4]triazine-4,7-dione (S27). Cyclization of S25 with coupling reagents (such as CDI, triphosgene etc) afford S27, which can subsequently N-alkylation with Hetl/Arl/Rl-halide at N-5 position to provide (S28). The substitutions at C-7 position in compounds G6-b can be obtained by displacement of halogen (Cl or F) of S29 with hydroxyl, amine or thiol containing heterocyclic/aryls.
[00172] Scheme Fl
Figure imgf000096_0001
[00173] Reaction of an aryl/heteroaryl phenol, amine, thiol with the (1) provides the intermediate (2) where M = heteroatom (O, NH, NR, S etc.). Alternatively, a NH-containing heterocyclic compound (e.g. an imidazole or benzimidazole, a pyrrolidine or piperidine etc.) would allow formation of the intermediate (2) where M-CyI is part of a cyclic fragment. Otherwise, reaction of (1) following Suzuki reaction allow introduction of an aryl or heterocyclic fragment whereby M is a bond. These diverse intermediates (2), upon reaction with hydrazine provide the intermediates (3), which could then be cyclized using phosgene or even carbon disulphide to form the bicyclic derivative (4) where R is H. The resulting thiol or hydroxyl can then be alkylated to provide the analogs (5). Cylization of an acylated intermediate of (3) or reaction with an orthoester provides the bicyclic intermediate (4) where Z- is a bond. Bromination or lithiation of (4) then allows generation of intermediate (5) [Y=Br or Li] to introduce a desired fragment providing the derivatives corresponding to G4D.
[00174] Scheme Gl
Figure imgf000097_0001
[00175] The bicyclic core of formula G5 can be prepared by cyclization of the 2- aminoazoles (example shown is for the thiadiazole) with a 2-halo ketone. Synthesis of a wide variety of the starting materials (1) is reported in the literature (Rl = H, CH3, NH2, O-alkyl, S-alkyl etc.). When R2 or R3 is an ester, reduction to aldehyde allowing elaboration with a Grignard or organolithium reagent. Reduction of ester to alcohol and conversion to bromide or carbonate provide a mean for reaction with a boronic acid or tin/zinc reagent to introduce a variety of aryl/heteroaryl groups, which could then be optionally elaborated as shown above for other series.
[00176] Scheme Hl
Figure imgf000097_0002
[00177] The starting material shown above in the scheme, when Y is COOH, CH2OH are available from pyroglatamic acid (either racemic of pure enantiomers), and these can be derivatized to prepare amide or ether derivatives (such as 3). The lactam nitrogen can then be derivatized to make N-alkyl-cycloalkyl or CH2-heterocylic or CH2-aryl derivatives, sulfonamde or N-acylated analogs. Intermediate (3) could also be used for formation of N- aryl/heteroaryl analogs using organometallic chemistry or by using reactive electrophilic reagents such reaction with 2-hano-puyridine. Otherwise, one may opt to derivative the lactam nitrogen first and then elaborate the substituent at Y via route using (2). Alternatively, and Y=OR (.g. OCH3, OEt, OAc, etc.) these inputs could be obtained by reduction of the N- derivatized imide to provide (2). This intermediate could then undergo reaction with reactive aromatic (e.g. aryl ethers), or heteroatom derived heterocyclics e.g. indole, benzimidazole etc. to provide derivative where M can be a bond, or reaction with sulfonamides/amides allowing formation of analogs with M=NHSO2. As described above depending upon additional functional groups present in the CyI and/or Cy2 fragments, additional chemistries as appropriate can be employed to prepare analogs of corresponding to the general structure with diverse substituents, e.g. CyI elaboration. Several examples of such tars formation have been described for analogs corresponding to claim 1 and 2 above.
Examples
[00178] Example 1. D-Ol
Figure imgf000098_0001
[00179] Step 1. 6-Amino-5-(3-chloro-phenyl)-nicotinic acid methyl ester (2). To a 100 ml INRBF were added methyl 6-amino-5-bromonicotinate (Ig, 4.33 mmole), 40 ml toluene, 10 ml ethanol, 20 ml water, 1.37g, 13 mmole sodium carbonate and 3-chlorophenyl boronic acid (740mg, 4.73 mmole). The solution was degassed for 10 min. under argon, then the palladium tetrakis (500mg, 10%) was added. Reaction mixture was heated at 1000C for 6 hours. TLC (20%EA/hexane) shows no SM. The reaction mixture was concentrated down to half, diluted with 20 ml water and extracted 3x 80 ml ethylacetate. Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give about 1.5 g crude. Trituration with 5% methanol in ether gave 700 mg solid (2). Mother liquor was concentrated to a solid and trituration was repeated to get a second crop of 230 mg (2). IH- NMR confirmed the structure.
[00180] Step 2. 8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridine-6-carboxylic acid methyl ester (3). A 50 ml INRB flask equipped with condenser and Dean Stark trap was loaded with 6-Amino-5-(3-chloro-phenyl)-nicotinic acid methyl ester (680 mg, 2.6 mmole) 20 ml, toluene and 1.2 g chloroacetaldehyde (50% solution in water). The mixture was heated to reflux and water was colected in the trap. After 4 hrs, TLC (EA/ hexane= 1;1) shows a new spot, Rf closer to starting material. Mixture was concentrated down, diluted with 10 ml water, neutralized to pH= 7 using saturated aq. Solution of NaHCO3 and extracted 3X 50 ml methylene chloride. Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford 500 mg product as brown solid (3), pure by IH-NMR. This material was used for the next step.
[00181] Step 3. [8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridin-6-yl]-methanol (4). To a solution of 8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridine-6-carboxylic acid methyl ester 3 (200 mg, 0.698 mmole) in 10 ml anhydrous THF was added at 00C LiBH4 (2M in THF, 2 ml). Reaction mixture was stirred at RT for 3 days. Mixture was quenched with saturated solution of NH4C1, then extracted several times with ethylacetate. Combined organic layers were washed with water, brine, dried over Na2SO4, filtered, concentrated to afford 230 mg crude. This was purified by a preparative silicagel plate (1.5 mm) using 5%MeOH/ CH2C12 to afford 150 mg product (4), pure by IH-NMR.
[00182] Step 4. Carbonic acid 8-(3-chloro-phenyl)-imidazo[l,2-a]pyridin-6-ylmethyl ester (5). To a solution of [8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridin-6-yl]-methanol (4) (100 mg, 0.387 mmole) in 2 ml anhydrous THF was added pyridine (80 ul, 0.96 mmole). The mixture was cooled to 00C and methylchloroformate was added slowly (65uL, 0.81 mmole). Reaction mixture was stirred at room temperature for 3 days. Water was added and the aqueous portion was extracted with ethyl acetate(2 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by silicagel preparative TLC plate 50%ethylacetate/ hexane as the eluent to give 80 mg of product (5) in 65 % yield.
[00183] Step 5. 4-[8-(3-Chloro-phenyl)-imidazo[l,2-a]pyridin-6-ylmethyl]-phenylamine (D-Ol). A reaction mixture of compound 5 (80 mg, 0.25 mmol), 2-aminopyridine-5-boronic acid pinacol ester 5 (62 mg, 0.27 mmol), l,5-bis(diphenylphosphino) pentane (33 mg, 0.075 mmole), allylpalladium chloride dimer (14 mg, 0.0375 mmol), K2CO3 (104 mg, 0.75 mmole) in DMF (2 ml)) was stirred at 85 0C for 8 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(2 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by silicagel preparative TLC plate 60%ethylacetate/ hexane as the eluent to give 22 mg of product D-Ol in 28 % yield. IH-NMR, MS, LCMS.
[00184] Example 2. D-02
Figure imgf000100_0001
[00185] Synthesis of 8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridine-6- carboxylic acid methyl ester and 8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridine- 6-carboxylic acid ethyl ester (6 and 7): In a microwave vial, was place 2 (990 mg, 3.76 mmole), chloroacetone (1.74 g, 19 mmole) and ethanol (15 ml). The reaction mixture was stirred at 1600C for 3 hrs on a microwave synthesizer and then cooled to room temperature. After removal of solvent under vacuum, the residue was dissolved in water and the pH was adjusted to 8-9 by addition of NaHCθ3 aq. The aqueous portion was extracted with ethyl acetate (3 x 50 ml), the organic portions were combined, washed with sat. NaHCO3 aq., brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing EtOAc/hexanes as the eluent to give 1.18 g of a mixture of 6 and 7 (-1.8: 1.5) in 53% yield. 1H-NMR (400 MHz, CDCl3).
[00186] Synthesis of [8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6-yl]- methanol (8): To a mixture of compound 6 and 7 (-1.8: 1.5) (1.18 g, 2.2 mmol) in THF(anhydrous, 60 ml), was added DIBAL-H (IM in hexane, 24 ml) dropwise at -78 oC under N2. The reaction mixture was stirred at -78°C to r.t. and r.t. for 3 hrs. The reaction mixture was diluted with ice/water, adjusted pH to acidic and then stirred at r.t for about 20 min. After pH adjusted to 8-9 by addition of NaOH aq (6N), the aqueous portion was extracted with ethyl acetate (3x 100 ml). Organic layer was washed with sat. NaHCO3 aq., brine, and dried over Na2SO4. After removal of solvent, the solid was washed with ether to give 800 mg of product 8 in 75 % yield. 1H-NMR (400 MHz, DMSO-d6)
[00187] Synthesis of 6-Bromomethyl-8-(3-chloro-phenyl)-2-methyl-imidazo[l,2- ajpyridine (9): To a mixture of compound 8 (27 mg, 0.1 mmol) in DCM (2 ml) was added PBr3 (14 mg, 0.05 mmole) at -10 oC under N2. The reaction mixture was stirred at -10 oC to r.t. and r.t for 1 hr. The reaction mixture was diluted with DCM (4 ml) and washed with diluted NaHCO3 aq., water, brine, and dried over Na2SO4. After removal of solvent, crude product 9 obtained. Crude 9 directly used in next step without further purification.
[00188] Synthesis of {4-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-phenyl}-urea (D-02): A reaction mixture of compound 9 (-0.1 mmol), A- ureidophenylboronic acid pinacol ester (26 mg, 0.1 mmol), tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), K3PO4 (42 mg, 0.2 mmole) in DME (4 ml), ethanol (1 ml) and water (1 ml) was stirred at 650C for 2 hours and then cooled to room temperature. Water (5 ml) was added and the aqueous portion was extracted with ethyl acetate (2 x 10 mL), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 4 mg of D-02 in 10% yield for two step. 1H-NMR (400 MHz, Acetone-de): 2.37 (3H, s), 3.97 (2H, s), 5.35 (2H, br), 7.20 (2H, d, J=8 Hz), 7.36 - 7.48 (5H, m), 7.64 (IH, m), 7.97 (IH, br), 8.07 (IH, m), 8.23 (IH, m), 8.33 (IH, m). MS(ESI+): 391.5 (M+ 1). LC-MS: 90 %.
Figure imgf000102_0001
[00190] Synthesis of ^[S-CS-Chloro-pheny^-ό-methoxycarbonyloxymethyl-l-methyl- imidazo[l,2-a]pyridin-3-yl]-4H-pyridine-l-carboxylic acid methyl ester (10): To a mixture of compound 8 (480 mg, 1.76 mmol) and pyridine (362 mg, 4.6 mmole) in THF (15 ml), was added methyl chloroformate (376 mg, 3.96 mmole) dropwise at -100C under N2. The reaction mixture was stirred at r.t over night. The reaction mixture was diluted with water, pH adjusted to 8-9 by addition of NaHCθ3 aq and then extracted with ethyl acetate (2x 5 ml). The organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing ethyl acetate/hexane as the eluent to give 520 mg of 10 in 63% yield. 1H-NMR (400 MHz, CDCl3)
[00191] Synthesis of {(Z)-3-[6-(6-Amino-pyridin-3-ylmethyl)-8-(3-chloro-phenyl)-2- methyl-imidazo[l,2-a]pyridin-3-yl]-but-l-enyl}-vinyl-carbamic acid methyl ester (D-03):
A reaction mixture of compound 10 (100 mg, 0.3 mmol), 2-aminopyridine-5-boronic acid pinacol ester (73 mg, 0.33 mmol), l,5-bis(diphenylphosphino) pentane (44 mg, 0.1 mmole), allylpalladium chloride dimer (14 mg, 0.045 mmol), K2CO3 (124 mg, 0.9 mmole) in DMF (2 ml)) was stirred at 900C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate (3 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 20 mg of D-03 in 14 % yield. 1H-NMR (400 MHz, DMSO-d6): 2.32 (3H, s), 3.76 (2H, s), 3.84 (3H, s), 4.90 (3H, br), 5.72 (2H, s), 6.36 (IH, d, J = 8 Hz), 6.94 (2H, br), 7.27 (IH, dd, J = 8 and 2.4 Hz), 7.36 (IH, d, J=1.6 Hz), 7.45 (IH, m), 7.50 (IH, dd, J = 8 and 8 Hz), 7.86 (IH, d, J=2.4 Hz), 7.99 (IH, m), 8.18 (IH, m), 8.21 (IH, s). MS(ESI+): 486.6 (M+l). LC-MS: 99 %.
Figure imgf000103_0001
[00193] Synthesis of S-CS-Chloro-pheny^-ό-Cό-fluoro-pyridin-S-ylmethyl)- imidazo[l,2-a]pyridine (D-04): A suspension of 5 (80 mg, 0.253 mmol), 2-fluoro-5- pyridine boronic acid (35.7 mg, 0.253 mmol), and solid potassium carbonate (104 mg, 0.759 mmol) was degassed with a nitrogen stream for 20 min. To the suspension was added palladium allyl chloride dimer (13.9 mg, 0.0380 mmol) and bis(diphenylphosphino)pentane (33.4 mg, 0.0759 mmol) and the reaction was stirred at 1000C under nitrogen overnight. The reaction was diluted with ethyl acetate (10 mL), washed with saturated ammonium chloride (10 mL), the aqueous wash back extracted with ethyl acetate (2 x 10 mL), and the organic extracts were combined. The organic solution was washed with brine (15 mL) and the solvent removed under vacuum. The crude material was purified by silica gel thin layer preparatory chromatography eluting with 7.5 % acetone in dichloromethanes to give D-04 (15.1 mg, 18% yield) as a yellow gum. IH NMR (400 MHz CDC13) d: 8.163 (d, J = 2.40 Hz, IH), 7.934- 7.865 (m, 3H), 7.689-7.610 (m, 3H), 7.429-7.357 (m, 2H), 7.066 (d, J = 1.60 Hz, IH), 6.166 (dd, J = 608.40 Hz, 602.80 Hz, IH), 4.008 (s, 3H). LCMS = 96.7%. MS(APCI+) = 338.1 (M+l).
[00194] Example 5. D-05
Figure imgf000104_0001
[00195] Synthesis of 8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2-a]pyridine-6- carboxylic acid methyl ester and 8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2- a]pyridine-6-carboxylic acid ethyl ester (11 and 12): In a microwave vial, was place 2 (1052 mg, 4 mmole), 3-bromo-2-butanone (2820 mg, 18.6 mmole) and ethanol (15 ml). The reaction mixture was stirred at 1600C for 2 hrs on a microwave synthesizer and then cooled to room temperature. After removal of solvent under vacuum, the residue was dissolved in water and the pH was adjusted to 8-9 by addition of NaHCO3 aq. The aqueous portion was extracted with ethyl acetate (3 x 50 mL), the organic portions were combined, washed with sat. NaHCO3 aq., brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing EtOAc/hexanes as the eluent to gave 600 mg of a mixture of 11 and 12 (~1 :6) in 46% yield. 1H-NMR (400 MHz, CDCl3)
[00196] Synthesis of [8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2-a]pyridin-6-yl]- methanol (13): To a mixture of compound 11 and 12 (-6: 1) (600 mg, 1.8 mmol) in THF(anhydrous, 30 ml), was added DIBAL-H (IM in Toluene, 12 ml) dropwise at -78°C under N2. The reaction mixture was stirred at -78°C to r.t. and r.t over night. The reaction mixture was diluted with ice/water, adjusted pH to acidic and then stirred at r.t for about 20 min. After pH adjusted to 8-9 by addition of NaOH aq (6N), the aqueous portion was extracted with ethyl acetate (3x100 ml). Organic layer was washed with sat. NaHCO3 aq., brine, and dried over Na2SO4. After removal of solvent, the solid was washed with ether to give 428 mg of product 13. Yield: 82 %. 1H-NMR (400 MHz, DMOS-d6)
[00197] Synthesis of 6-Bromomethyl-8-(3-chloro-phenyl)-2,3-dimethyl-imidazo[l,2- ajpyridine (14): To a mixture of compound 13 (57 mg, 0.2 mmol) in DCM (4 ml) and DMF (0.2 ml), was added PBr3 (57 mg, 0.2 mmole) at -100C under N2. The reaction mixture was stirred at -100C to r.t. and r.t for 1 hr. The reaction mixture was diluted with DCM (4 ml) and washed with diluted NaHCO3 aq., water, brine, and dried over Na2SO4. After removal of solvent, 60 mg of crude product 14 obtained. Crude 14 directly used in next step without further purification.
[00198] Synthesis of {4-[8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2-a]pyridin-6- ylmethyl]-phenyl}-urea (D-05): A reaction mixture of compound 14 (60 mg crude, 0.2 mmol), 4-ureidophenylboronic acid pinacol ester (52 mg, 0.2 mmol), tetrakis(triphenylphosphine)palladium (46 mg, 0.04 mmol), K3PO4 (84 mg, 0.4 mmole) in DME (6 mL), ethanol (1.5 mL) and water (1.5 ml) was stirred at 65°C for 2 hours and then cooled to room temperature. Water (10 mL) was added and the aqueous portion was extracted with ethyl acetate(2 x 15 mL), the organic portions were combined, washed with brine (75 mL), dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to gave 6 mg of D-05 as a solid in 7% yield for two step. 1H-NMR (400 MHz, Acetone-d6): 2.36 (3H, s), 2.45 (3H, s), 4.01 (2H, s), 5.35 (2H, br), 7.21 (2H, d, J= 8 Hz), 7.34 (IH, d, J = 2 Hz), 7.38 (IH, m), 7.42 (2H, d, J = 8 Hz), 7.45 (IH, dd, J = 8 and 8 Hz), 7.95 (IH, br), 8.04 (IH, m), 8.06 (IH, m), 8.34 (IH, m). MS(APCI+): 405.1 (M+ 1). LC-MS: 99 %.
[00199] Example 6. D-06
Figure imgf000105_0001
[00200] Synthesis of 6-Bromomethyl-8-(3-chloro-phenyl)-2,3-dimethyl-imidazo[l,2- ajpyridine (14): To a mixture of compound 13 (57 mg, 0.2 mmol) in DCM (4 ml) and DMF (0.2 ml), was added PBr3 (57 mg, 0.2 mmole) at -100C under N2. The reaction mixture was stirred at -100C to r.t. and r.t for 1 hr. The reaction mixture was diluted with DCM (4 ml) and washed with diluted NaHCθ3 aq., water, brine, and dried over Na2SO4. After removal of solvent, crude product 14 obtained. Crude 14 directly used in next step without further purification.
[00201] Synthesis of l-[8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyrrolidin-2-one (D-06): To a mixture of NaH (60 % in oil, 16 mg, 0.4 mmole) in DMF (2 ml), was added 2-pyrrolidone (34 mg, 0.4 mmole) at -100C. After reaction mixture stirring at r.t. for 10 min, compound 14 (crude, 0.2 mmol) dissolved in DMF (3 ml) was added at -100C under N2. The reaction mixture was stirred at -100C to r.t. and r.t over night. After removal of solvent under vacuum, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 10 ml), the organic portions were combined, washed with brine (75 mL), dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing ethyl acetate/hexane as the eluent gave 50 mg of D-06 as an oil in 70% yield for two step. To a solution of D-06 (50 mg) in DCM (4 ml), was added HCl in Et2O (2N, 0.2 ml), after removal of solvent, solid was washed with ether to give 37 mg of D-06 HCl salt as solid. 1H-NMR (400 MHz, CD3OD): 2.07 (2H, m), 2.45 (2H, t, J=8 Hz), 2.50 (3H, s), 2.60 (3H, s), 3.48 (2H, m), 4.67 (2H, s), 7.58 - 7.64 (3H, m), 7.74 (IH, m), 7.78 (IH, m), 8.58 (IH, m). MS(APCI+): 354 (M+l). LC-MS: 98 %.
[00202] Example 7. D-07
Figure imgf000106_0001
[00203] Synthesis of Carbonic acid 8-(3-chloro-phenyl)-2,3-dimethyl-imidazo[l,2- a]pyridin-6-ylmethyl ester methyl ester (15): To a mixture of compound 13 (57 mg, 0.2 mmol) and pyridine (79 mg, 1 mmole) in THF (2 ml), was added methyl chloroformate (76 mg, 0.8 mmole) dropwise at r.t. under N2. The reaction mixture was stirred at r.t over night. The reaction mixture was diluted with water, pH adjusted to 8-9 by addition of NaHCθ3 aq and then extracted with ethyl acetate (2x 5 ml). The organic portions were combined, washed with brine, dried over Na2SO4. After removal of solvent, 60 mg of crude product 15 obtained. Crude 15 directly used in next step without further purification.
[00204] Synthesis of 5-[8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-ylamine (D-07): A reaction mixture of compound 15 (crude, 0.15 mmol), 2-aminopyridine-5-boronic acid pinacol ester (33 mg, 0.15 mmol), 1,5- bis(diphenylphosphino) pentane (20 mg, 0.045 mmole), allylpalladium chloride dimer (7 mg, 0.023 mmol), K2CO3 (62 mg, 0.45 mmole) in DMF (1 ml)) was stirred at 90 0C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(3 x 15 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 18 mg of D-07 in 33 % yield for two step. 1H-NMR (400 MHz, Acetone-d6): 2.36 (3H, s), 2.45 (3H, s), 3.92 (2H, s), 5.22 (2H, br), 6.48 (IH, d, J = 8), 7.34 - 7.42 (3H, m), 7.46, (IH, dd, J = 8 and 8 Hz), 7.99, IH, d, J = 1.6 Hz), 8.05 (IH, s), 8.08 (IH, m), 8.35 (IH, m). MS(APCI+): 363.1 (M+ 1). LC-MS: 99 %.
Figure imgf000107_0001
[00206] Synthesis of S-CS-Chloro-pheny^-ό-Cό-fluoro-pyridin-S-ylmethyl)^^- dimethyl-imidazo[l,2-a]pyridine (D-08): A reaction mixture of compound 15 (crude, 0.15 mmol), 2-fluoro-5-pyridine-boronic acid (21 mg, 0.15 mmol), l,5-bis(diphenylphosphino) pentane (20 mg, 0.045 mmole), allylpalladium chloride dimer (7 mg, 0.023 mmol), K2CO3 (62 mg, 0.45 mmole) in DMF (1 ml)) was stirred at 90 0C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(4 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing ethyl acetate/hexane as the eluent to give 28 mg of D-08 in 51 % yield. To a solution of D-08 (28 mg) in Et2O (4 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 26 mg of D-08 HCl salt as solid. 1H-NMR (400 MHz, DMSO- d6): 2.44 (3H, s), 2.55 (3H, s), 4.19 (2H, s), 7.15 (IH, dd, J = 8 and 3Hz), 7.60 - 7.68 (3H, m), 7.76 (IH, m), 7.92 (IH, m), 8.01 (IH, m), 8.31 (IH, m), 8.79 (IH, s). MS(APCI+): 366.1 (M+l). LC-MS: 98 %.
[00207] Example 9. D-09
Figure imgf000108_0001
[00208] Synthesis of 4-[8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2-a]pyridin-6- ylmethylj-phenylamine (D-09): A reaction mixture of compound 15 (crude, 0.15 mmol), A- aminophenyl boronic acid pinacol ester (33 mg, 0.15 mmol), l,5-bis(diphenylphosphino) pentane (20 mg, 0.045 mmole), allylpalladium chloride dimer (7 mg, 0.023 mmol), K2CO3 (62 mg, 0.45 mmole) in DMF (1 ml)) was stirred at 90 0C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(4 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing ethyl acetate/hexane as the eluent to give D-09. To a solution of D-09 in DCM (3 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 19 mg of D-09 HCl salt as solid. 1H-NMR (400 MHz, DMSO- d6): 2.44 (3H, s), 2.55 (3H, s), 4.13 (2H, s), 7.11 (2H, m), 7.40 (2H, m), 7.60 - 7.68 (3H, m), 7.74 (IH, m), 7.83 (IH, m), 8.75 (IH, m). MS(APCI+): 362.1 (M+l). LC-MS: 96 %.
[00209] Example 10. D-10
Figure imgf000108_0002
[00210] Synthesis of l-{5-[8-(3-Chloro-phenyl)-2,3-dimethyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-3-ethyl-urea (D-10): To a mixture of compound D-07 (7 mg, 0.02 mmol) in pyridine (1 ml), was added ethyl isocyanate (20 mg, 0.25 mmole). The reaction mixture was stirred at r.t. for 5 days and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 6 mg of D-IO in 69 % yield. 1H-NMR (400 MHz, CD3OD): 1.18 (3H, t, J= 7.2 Hz), 2.51 (3H, s), 2.61 (3H, s), 3.20 (2H, q, J =7.2 Hz), 4.30 (2H, s), 7.28 (IH, d, J= 8Hz), 7.60 (3H, m), 7.71 (IH, m), 7.80 (IH, m), 8.22 (IH, m), 8.25 (IH, m), 8.66 (IH, s). MS(APCI+): 434.1 (M+l). LC-MS: 97 %.
[00211] Example 11. D-Il
Figure imgf000109_0001
[00212] Synthesis of Carbonic acid 8-(3-chloro-phenyl)-2-methyl-imidazo[l,2- a]pyridin-6-ylmethyl ester methyl ester (16): To a mixture of compound 8 (136 mg, 0.5 mmol) in THF (10 ml), was added NaH (60 % in oil, 50 mg, 1.25 mmole) at -10 0C and stirred at r.t. for 20 min. Methyl chloroformate (105 mg, 1.1 mmole) was added dropwise at - 20 0C under N2. The reaction mixture was stirred at r.t over night. The reaction mixture was diluted with water and extracted with ethyl acetate (2x 20 ml). The organic portions were combined, washed with brine, dried over Na2SO4. After removal of solvent, 180 mg of crude product 16 obtained. Crude 16 directly used in next step without further purification. 1H- NMR (400 MHz, CDC13)
[00213] Synthesis of 4-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethylj-phenylamine (D-Il): A reaction mixture of compound 16 (70 mg crude, 0.25 mmol), 4-aminophenyl boronic acid pinacol ester (55 mg, 0.25 mmol), 1,5- bis(diphenylphosphino) pentane (33 mg, 0.075 mmole), allylpalladium chloride dimer (14 mg, 0.038 mmol), K2CO3 (104 mg, 0.75 mmole) in DMF (2 ml)) was stirred at 90 0C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(4 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing ethyl acetate/hexane as the eluent to give 11 mg of D-Il in 13 % yield for two steps. To a solution of D-Il (11 mg) in ether (3 ml), was added HCl in Et20 (2N, 0.1 ml), solid was washed with ether to give 11 mg of D-Il HCl salt as solid. 1H-NMR (400 MHz, DMSO-d6): 2.45 (3H, s), 4.11 (2H, s), 6.85 (IH, m), 7.18 (3H, m), 7.38 (2H, d, J = 8Hz), 7.64 (3H, m), 7.78 (IH, s), 7.86 (IH, s), 8.14 (IH, s), 8.77 (IH, s), 9.70-10.0 (2H, br). MS(APCI+): 348.1 (M+l) LC-MS: 95 %.
[00214] Example 12. D-12 [00215] Example 13. D-13
Figure imgf000110_0001
[00216] Synthesis of 5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-ylamine (D-12): A reaction mixture of compound 16 (70 mg crude, 0.25 mmol), 2-aminopyridine-5-boronic acid pinacol este (55 mg, 0.25 mmol), 1,5- bis(diphenylphosphino) pentane (33 mg, 0.075 mmole), allylpalladium chloride dimer (14 mg, 0.038 mmol), K2CO3 (104 mg, 0.75 mmole) in DMF (2 ml)) was stirred at 90 0C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate(4 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 35 mg of D-12 in 40 % yield for two step. To a solution of D-12 (35 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 35 mg of D-12 HCl salt as solid. 1H-NMR (400 MHz, DMSO-d6): 2.46 (3H, s), 4.02 (2H, s), 6.98 (IH, d, J=8 Hz), 7.60 - 7.70 (3H, m), 7.82 (IH, br), 7.87 (IH, br), 7.90 (IH, m), 7.96 (IH, m), 8.04 (IH, br), 8.11 (IH, br), 8.75 (IH, br). MS(APCI+): 349.1 (M+l). LC-MS: 99 %.
[00217] Synthesis of l-{5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-3-ethyl-urea (D-13): To a mixture of compound D-12 (30 mg, 0.08 mmol) in pyridine (1 ml), was added ethyl isocyanate (57 mg, 0.8 mmole). The reaction mixture was stirred at r.t. for 5 days and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 25 mg of D-13 in 75 % yield. To a solution of D-13 (25 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 25 mg of D-13 HCl salt as solid. 1H-NMR (400 MHz, DMSO-d6): 1.09 (3H, m), 2.46 (3H, s), 3.18 (2H, m), 4.10 (2H, s), 7.37 (IH, d, J= 8 Hz), 7.65 (3H, m), 7.78 (IH, br), 7.80 - 7.88 (2H, br), 7.90 (IH, m), 8.14 (IH, m), 8.23 (IH, m), 8.77 (IH, s), 9.8 - 10.4 (IH, br). MS(APCI+): 420.1 (M+ 1). LC-MS: 99 %.
[00218] Example 14. D-14 [00219] Example 15. D-15
Figure imgf000111_0001
2-bromopropanal (17) was prepared according to reference (Aleem Gangjee, et al. J. Medi. Chem. 2005, 48, 7215-7222).
[00220] Synthesis of 8-(3-Chloro-phenyl)-3-methyl-imidazo[l,2-a]pyridine-6- carboxylic acid methyl ester and 8-(3-Chloro-phenyl)-3-methyl-imidazo[l,2-a]pyridine- 6-carboxylic acid ethyl ester (18 and 19): In a microwave vial, was place 2 (570 mg, 2.1 mmole), 2-bromopropanal (17) (1.3 g, 10 mmole) and ethanol (10 ml). The reaction mixture was stirred at 150 0C for 2 hrs on a microwave synthesizer and then cooled to room temperature. After removal of solvent under vacuum, the residue was dissolved in water and the pH was adjusted to 8-9 by addition of NaHCθ3 aq. The aqueous portion was extracted with ethyl acetate (3 x 30 ml), the organic portions were combined, washed with sat. NaHCCb aq., brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing EtOAc/hexanes as the eluent to give 400 mg of a mixture of 18 and 19 (-1 :2) in 63% yield. 1H-NMR (400 MHz, CDCl3)
[00221] Synthesis of [8-(3-Chloro-phenyl)-3-methyl-imidazo[l,2-a]pyridin-6-yl]- methanol (20): To a mixture of compound 18 and 19 (~1 :2) (700 mg, 2.2 mmol) in THF(anhydrous, 30 ml), was added DIBAL-H (IM in Toluene, 14 ml) dropwise at -78 0C under N2. The reaction mixture was stirred at -78 0C to r.t. and r.t. for 3 hrs. The reaction mixture was diluted with ice/water, adjusted pH to acidic and then stirred at r.t for about 20 min. After pH adjusted to 8-9 by addition of NaOH aq (6N), the aqueous portion was extracted with ethyl acetate (4x 80 ml). Organic layer was washed with sat. NaHCO3 aq., brine, and dried over Na2SO4. After removal of solvent, the residue was purified by column chromatography utilizing MeOH/DCM as the eluent to give 145 mg of product 20 in 24 % yield. 1H-NMR (400 MHz, CDCl3)
[00222] Synthesis of Carbonic acid 8-(3-chloro-phenyl)-3-methyl-imidazo[l,2- a]pyridin-6-ylmethyl ester methyl ester (21): To a mixture of compound 20 (110 mg, 0.4 mmol) in THF (8 ml), was added NaH (60 % in oil, 40 mg, 1 mmole) at -10 oC and stirred at r.t. for 20 min. Methyl chloroformate (86 mg, 0.9 mmole) was added dropwise at -20 oC under N2. The reaction mixture was stirred at r.t over night. The reaction mixture was diluted with water and extracted with ethyl acetate (3x 8 ml). The organic portions were combined, washed with brine, dried over Na2SO4. After removal of solvent, 130 mg of crude product 21 obtained. Crude 21 directly used in next step without further purification.
[00223] Synthesis of 5-[8-(3-Chloro-phenyl)-3-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-ylamine (D-14): A reaction mixture of compound 21 (65 mg crude, 0.2 mmol), 2-aminopyridine-5-boronic acid pinacol ester (44 mg, 0.2 mmol), 1,5- bis(diphenylphosphino) pentane (26 mg, 0.06 mmole), allylpalladium chloride dimer (11 mg, 0.03 mmol), K2CO3 (83 mg, 0.6 mmole) in DMF (2 ml)) was stirred at 90 0C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate (2 x 30 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 32 mg of D-14 in 45 % yield for two steps. To a solution of D-14 (16 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 17 mg of D-14 HCl salt as solid. 1H-NMR (400 MHz, CD30D): 2.70 (3H, s), 4.16 (2H, s), 7.01 (IH, d, J= 8 Hz), 7.58 - 7.64 (3H, m), 7.71 (IH, m), 7.83 (IH, m), 7.86 (IH, m), 7.88 (IH, m), 7.94 (IH, m), 8.71 (IH, s). MS(APCI+): 349.1 (M+l). LC- MS: 99 %.
[00224] Synthesis of l-{5-[8-(3-Chloro-phenyl)-3-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-3-ethyl-urea (D-15): To a mixture of compound D-14 (16 mg, 0.046 mmol) in pyridine (1 ml), was added ethyl isocyanate (36 mg, 0.5 mmole). The reaction mixture was stirred at r.t. for 2 days and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 16 mg of D- 15 in 83 % yield. To a solution of D-15 (16 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 16 mg of D-15 HCl salt as solid. 1H-NMR (400 MHz, CD3OD): 1.18 (3H, t, J= 7.2 Hz), 2.70 (3H, s), 3.13 (2H, q, J=7.2 Hz), 4.32 (2H, s), 7.28 (IH, d, J = 8Hz), 7.58 - 7.64 (3H, m), 7.72 (IH, m), 7.84 (IH, m), 7.88 (IH, m), 8.23 - 8.25 (2H, m), 8.74 (IH, m). MS(APCI+): 420.1 (M+l). LC-MS: 97 %.
[00225] Example 16. D-16
[00226] Example 17. D-17
Figure imgf000113_0001
[00227] Synthesis of 4-[8-(3-Chloro-phenyl)-3-methyl-imidazo[l,2-a]pyridin-6- ylmethylj-phenylamine (D-16): A reaction mixture of compound 21 (65 mg crude, 0.2 mmol), 4-aminophenyl boronic acid pinacol ester (44 mg, 0.2 mmol), 1,5- bis(diphenylphosphino) pentane (26 mg, 0.06 mmole), allylpalladium chloride dimer (11 mg, 0.03 mmol), K2CO3 (83 mg, 0.6 mmole) in DMF (2 ml)) was stirred at 90 0C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate (3 x 30 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 21 mg of D-16 in 30 % yield. To a solution of D- 16 (14 mg) in DCM (3 ml), was added HCl in Et20 (2N, 0.1 ml), solid was washed with ether to give 14 mg of D-16 HCl salt as solid. 1H-NMR (400 MHz, CD3OD): 2.68 (3H, s), 4.31 (2H, s), 7.37 (2H, d, J=7.2 Hz), 7.54 - 7.60 (5H, m), 7.67 (IH, m), 7.78 (IH, m), 7.81 (IH, m), 8.69 (IH, s). MS(APCI+): 348.1 (M+ 1). LC-MS: 99 %.
[00228] Synthesis of l-{4-[8-(3-Chloro-phenyl)-3-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-phenyl}-3-ethyl-urea (D-17): To a mixture of compound D-16 (12 mg, 0.034 mmol) in pyridine (1 ml), was added ethyl isocyanate (36 mg, 0.5 mmole). The reaction mixture was stirred at r.t. for 2 days and concentrated. The crude material was purified by column chromatography utilizing ethyl acetate/hexane as the eluent to give 12 mg of D-17 in 84 % yield. To a solution of D-17 (12 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 12 mg of D-17 HCl salt as solid. 1H-NMR (400 MHz, CD3OD): 1.13 (3H, t, J=7.2 Hz), 2.66 (3H, s), 3.20 (2H, q, J=7.2 Hz), 4.16 (2H, s), 7.24 (2H, d, J=8 Hz), 7.33 (2H, d, J= 8 Hz), 7.50 - 7.60 (3H, m), 7.68 (IH, m), 7.77 (2H, m), 8.55 (IH, m). MS(APCI+): 419.1 (M+ 1). LC-MS: 98 %. [00229] Example 18. D-18 [00230] Example 19. D-19 [00231] Example 20. D-20
Figure imgf000114_0001
[00232] Synthesis of 5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridine-2-carboxylic acid methyl ester (D-18): A reaction mixture of compound 16 (200 mg crude, 0.55 mmol), 2-(methylcarboxy) pyridine-5-boronic acid pinacol este (145 mg, 0.55 mmol), l,5-bis(diphenylphosphino) pentane (73 mg, 0.165 mmole), allylpalladium chloride dimer (30 mg, 0.082 mmol), K2CO3 (228 mg, 1.65 mmole) in DMF (3 ml)) was stirred at 90 0C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate (3 x 8 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 72 mg of D-18 in 33 % yield for two step. To a solution of D-18 (11 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 11 mg of D-18 HCl salt as solid. 1H-NMR (400 MHz, CD3OD): 2.52 (3H, s), 4.01 (2H, s), 4.39 (2H, s), 7.57 - 7.63 (3H, m), 7.72 (IH, m), 7.84 (IH, m), 8.00 (IH, m), 8.20 (IH, m), 8.26 (IH, d, J=8 Hz), 8.69, IH, m), 8.78 (IH, m). MS(APCI+): 392.0 (M+ 1). LC-MS: 98 %.
[00233] Synthesis of 2-{5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-propan-2-ol (D- 19) and l-{5-[8-(3-Chloro-phenyl)-2-methyl- imidazo[l,2-a]pyridin-6-ylmethyl]-pyridin-2-yl}-ethanone (D-20): To a mixture of compound D-18 (60 mg, 0.15 mmol) in THF (3 ml), was added MeMgBr (3 M in ether, 0.26 ml, 0.78 mmole) dropwise at -10 0C. The reaction mixture was stirred at r.t. over night. Water was added and the aqueous portion was extracted with ethyl acetate (4 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 22 mg of D- 19 in 37 % yield and 9 mg of D-20 in 16 % yield. To a solution of D- 19 (22 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 22 mg of D- 19 HCl salt as solid. For D- 19 HCl salt: 1H-NMR (400 MHz, DMSO-d6): 1.52 (6H, s), 2.46 (3H, s), 4.27 (2H, s), 7.65 (3H, m), 7.79 (IH, br), 7.94 (IH, br), 7.98 (IH, br), 8.14-8.20 (2H, m), 8.70 (IH, m), 8.88 (IH, br). MS(APCI+): 392.1 (M+l). LC-MS: 94 %.
[00234] To a solution of D-20 (9 mg) in DCM (3 ml), was added HCl in Et20 (2N, 0.1 ml), solid was washed with ether to give 9 mg of D-20 HCl salt as solid. For D-20 HCl salt:
1H-NMR (400 MHz, DMSO-d6): 2.46 (3H, s), 2.61 (3H, s), 4.27 (2H, s), 7.65 (3H, m), 7.78 (IH, br), 7.90 - 7.98 (3H, m), 8.14 (IH, m), 8.77 (IH, m), 8.84 (IH, br). MS(APCI+): 376.1 (M+l). LC-MS: 84 %. [00235] Example 21. D-21
Figure imgf000116_0001
[00236] Synthesis of N-{5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-2-dimethylamino-acetamide (D-21): To a mixture of compound D-12 (20 mg, 0.057 mmol) and dimethylaminoacetyl chloride hydrochloride (23 mg, 0.14 mmole) in DCM (2 ml), was added diisopropylethylamine (37 mg, 0.3 mmole). The reaction mixture was stirred at 40 0C for 3 days and diluted with DCM (5 ml) and sat. NaHCθ3 aq. The aqueous portion was extracted with DCM (3 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 13 mg of D- 21 in 53 % yield. To a solution of D-21 (13 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 13 mg of D-21 HCl salt as solid. 1H-NMR (400 MHz, DMSO-d6): 2.47 (3H, s), 2.85 (3H, s), 2.87 (3H, s), 4.14 (2H, s), 4.18 (2H, br), 7.65 (3H, m), 7.78 (IH, br), 7.84 (IH, dd, J= 8 and 2.4 Hz), 7.90 (IH, br), 8.00 (IH, br), 8.16 (IH, br), 8.40 (IH, d, J=2.4 Hz), 8.82 (IH, br, 10.0 (IH, br), 11.15 (IH, s), 14.0 (IH, br). MS(APCI+): 434.1 (M+l). LC-MS: 99 %.
[00237] Example 22. D-22
[00238] Example 23. D-23
Figure imgf000116_0002
[00239] Synthesis of (D-22): To a mixture of compound D-12 (40 mg, 0.115 mmol) and diisopropylethylamine (74 mg, 0.57 mmole) in DCM (3 ml), was added ethyl chloroformate (31 mg, 0.29 mmole). The reaction mixture was stirred at r.t. over night and diluted with DCM (5 ml) and sat. NaHCθ3 aq. The aqueous portion was extracted with DCM (2 x 8 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 49 mg of D-22 in 87 % yield. To a solution of D-22 (40 mg) in ether (8 ml), was added HCl in Et2O (2N, 0.15 ml), solid was washed with ether to give 50 mg of D-22 HCl salt as solid. 1H-NMR (400 MHz, DMSO-d6): 1.11 (6H, m), 2.46 (3H, s), 4.14 (4H, q, J=7.2 Hz), 4.20 (2H, s), 7.43 (IH, d, J=8 Hz), 7.64 (3H, m), 7.77 (IH, br), 7.89 (IH, dd, J=8 and 2.4 Hz), 7.95 (IH, s), 8.17 (IH, s), 8.50 (IH, d, J=2.4 Hz), 8.90 (IH, s), 14.0 (IH, br). MS(APCI+): 493.1 (M+l). LC-MS: 99 %.
[00240] Synthesis of {5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-carbamic acid ethyl ester (D-23): A reaction mixture of compound D-22 (20 mg, 0.04 mmol) in EtOH (3 ml) and NaOH aq. (2N, 1 ml) was stirred at r.t. for 4 hrs and diluted with water (5 ml). The aqueous portion was extracted with ethyl acetate (2 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 16 mg of D-23 in 95 % yield. To a solution of D-23 (16 mg) in ether (5 ml), was added HCl in Et2O (2N, 0.1 ml), solid was washed with ether to give 17 mg of D-23 HCl salt as solid. 1H-NMR (400 MHz, DMSO-d6): 1.23 (3H, t, J=7.2 Hz), 2.46 (3H, s), 4.10 (2H, s), 4.14 (2H, q, J=7.2 Hz), 7.65 (3H, m), 7.78 (3H, m), 7.91 (IH, m), 8.14 (IH, s), 8.30 (IH, br), 8.78 (IH, s), 10.25 (IH, br). MS(APCI+): 421.1 (M+l). LC-MS: 99 %.
[00241] Example 24. D-24
[00242] Example 25. D-25
Figure imgf000117_0001
[00243] Synthesis of 8-(3-Chloro-phenyl)-6-(6-fluoro-pyridin-3-ylmethyl)-2-methyl- imidazo[l,2-a]pyridine (D-24): A reaction mixture of compound 16 (220 mg crude, 0.55 mmol), 2-fluoro-5-pyridine boronic acid (78 mg, 0.55 mmol), l,5-bis(diphenylphosphino) pentane (73 mg, 0.165 mmole), allylpalladium chloride dimer (30 mg, 0.082 mmol), K2CO3 (228 mg, 1.65 mmole) in DMF (3 ml)) was stirred at 90 0C for 2 hours and then cooled to room temperature. Water was added and the aqueous portion was extracted with ethyl acetate (5 x 8 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 120 mg of D-24 in 62 % yield. To a solution of D- 24 (70 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.2 ml), solid was washed with ether to give 70 mg of D-24 HCl salt as solid. 1H-NMR (400 MHz, DMSO-d6): 2.46 93H, s), 4.17 (2H, s), 7.17 (IH, dd, J= 8 and 2.4 Hz), 7.64 (3H, m), 7.78 (IH, br), 7.93 (IH, d, J=1.6 Hz), 7.98 (IH, m), 8.14 (IH, s), 8.28 (IH, d, J = 2.8 Hz), 8.80 (IH, s). MS(APCI+): 352.0 (M+l). LC-MS: 99 %.
[00244] Synthesis of ({5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-methyl-amino)-acetic acid (D-25): A mixture of compound D-24 (50 mg, 0.13 mmol), sacosine (23 mg, 0.26 mmole) and DBU (120 mg, 0.78 mmole) was stirred at 150 0C for 1 hr. and cooled to r.t.,. A sat. NH4CI aq. was added and the aqueous portion was extracted with DCM (5 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 38 mg of D-25 in 70 % yield. To a solution of D-25 (38 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.15 ml), solid was washed with ether to give 38 mg of D-25 HCl salt as solid. 1H-NMR (400 MHz, DMSO-d6): 2.46 (3H, s), 3.17 (3H, s), 4.08 (2H, s), 4.46 (2H, s), 4.40 - 4.70 (2H, br), 7.10 (IH, br), 7.65 (3H, m), 7.78 (IH, br), 7.94 (2H, m), 8.11 (IH, m), 8.16 (IH, br), 8.83 (IH, br). MS(APCI+): 421.1 (M+l). LC-MS: 99 %.
[00245] Example 26. D-26
Figure imgf000118_0001
[00246] Synthesis of l-{5-[8-(3-Chloro-phenyl)-2-methyl-imidazo[l,2-a]pyridin-6- ylmethyl]-pyridin-2-yl}-azetidine-2-carboxylic acid (D-26): A mixture of compound D-24 (65 mg, 0.17 mmol), D,L-Azetidine-2-carboxylic acid (34 mg, 0.34 mmole) and DBU (304 mg, 2 mmole) was stirred at 150 0C for 1 hr. and cooled to r.t.,. A saturated NH4CI aq. was added and the aqueous portion was extracted with DCM (5 x 10 ml), the organic portions were combined, washed with brine, dried over Na2SO4 and concentrated. The crude material was purified by column chromatography utilizing MeOH/DCM as the eluent to give 35 mg of D-26 in 48 % yield. To a solution of D-26 (35 mg) in DCM (3 ml), was added HCl in Et2O (2N, 0.15 ml), solid was washed with ether to give 35 mg of D-26 HCl salt as solid. 1H- NMR (400 MHz, DMSO-d6): 2.40 (IH, m), 2.46 (3H, s), 2.77 (IH, m), 4.08 (2H, s), 4.12 (IH, m), 4.21 (IH, m), 5.10 (IH, m), 6.90 (IH, br), 7.65 (3H, m), 7.78 (IH, s), 7.94 (IH, s), 7.96 (IH, m), 8.11 (IH, m), 8.17 (IH, s), 8.85 (IH, s). MS(APCI+): 433.1 (M+ 1). LC-MS: 97 %.
[00247] Example 27. D-27
Figure imgf000119_0001
[00248] 5-Methyl-2H-pyrazole-3-carboxylic acid hydrazide (23): To a 20 mL vial with stir bar was added, Ethyl 3-methylpyrazole-5-carboxylate (1.56 g, 10.1 mmol), EtOH (4 mL), and hydrazine hydrate (2.46 mL, 50.6 mmol). The reaction was heated at 78 0C for 18 hours. The reaction was concentrated to afford 23 as a white solid (1.35 g, 95%), 23 was used as is in the next reaction.
[00249] 2-Methyl-7-phenyl-5H-pyrazolo[l,5-d] [l,2,4]triazin-4-one (24): Into a 50 mL round bottom flask equipped with a stir bar was added 23 (1.35 g, 9.63 mmol), DMF (25 mL), and phenyl orthoformate (2.48 mL, 14.5 mmol). The reaction was refluxed for 24 hours. The DMF was removed by blowing a stream of N2 into the hot flask. Ethyl acetate (5 mL) was added to the flask followed by H2O (5 mL). The flask was shaken and the aqueous portion discarded. This was repeated once more. The EA was concentrated. EtOH (2 mL) was added to the viscous oil, the flask was capped, and allowed to sit overnight at RT. The mixture was filtered to obtain the off-white solid that had formed overnight. The solid was washed with EtOH, collected, and dried under vacuum to give 0.37 g (17%) of off-white solid, 24. 1H-NMR (500 MHz, CDCl3) δ 13.35 (s, IH), 8.07 (dd, 2H, J= 7.5, 1.5 Hz), 7.66- 7.61 (m, 3H), 6.72 (s, IH), 2.34 (s, 3H).
[00250] 5-(4-Fluoro-benzyl)-2-methyl-7-phenyl-5H-pyrazolo[l,5-d] [l,2,4]triazin-4- one, (D-27): To a 25 mL round bottom flask equipped with a stir bar was added 24 (50.6 mg) and dry THF (2 mL). The 24 remained insoluble so dry DMF (2 mL) was added to obatin a homogeneuos solution which was cooled to 0 0C and NaH (6.4 mg) was added. The reaction was stirred at O0C for 15 min. then RT for 15 min. The mixture was then cooled to 0 0C and 4-Fluorobenzyl bromide (0.028 ml, 0.22 mmole) was added. The reaction was allowed to slowly come to RT and stir for 16 hours. 5 drops of H2O were added and the reaction concentrated. Purification by flash column chromatography (15 g Siθ2, wet-pack with hexane) using 15% EA/Hexanes afforded 40.4 mg (54%) of D-27 as a off- white solid. 1H-NMR (500 MHz, CDCl3) δ 8.12 - 8.09 (m, 2H), 7.55 - 7.49 (m, 5H), 7.04 - 6.98 (m, 3H), 5.28 (s, 2H), 2.47 (s, 3H). 13C-NMR (125 MHz, CDCl3) δ 163.7, 161.8, 154.2, 153.3, 138.6, 135.5, 132.3, 131.1, 131.0, 129.8, 129.3, 128.5, 115.8, 115.6, 106.7, 52.8, 14.2; LC/MS = 96.6%, 335.6 (ESI+).
[00251] Synthesis of L- 122.
Figure imgf000120_0001
[00252] Synthesis of ethyl 2-(3-chlorophenoxy)nicotinate: A suspension of ethyl-2- chloronicotinate (3g, 16.16 mmole) , 3-chlorophenol (2.18 g, 16.97 mmole), cesium carbonate (5.53g, 16.97 mmole) in 175 ml DMF was heated at 8O0C for 2 days. The reaction mixture was cooled down, diluted with water and extracted several times with ethylacetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated down. The crude oil was taken into 50 ml ether, hexane was added until the solution became cloudy. The solution was kept in the fridge overnight, filtered off, then the solid was washed with 10 ml hexane and dried. 1.9 g product was obtained, 40% yield. HNMR
[00253] Synthesis of 2-(3-chlorophenoxy)nicotinic acid: To a solution of ethyl 2-(3- chlorophenoxy)nicotinate (700 mg, 2.52 mmole) in a mixture of methanol/ THF= 25/ 10 ml was added NaOH, IM solution (12.6 ml, 5eq.). The reaction mixture was stirred at room temperature, overnight. The mixture was concentrated down, then acidified with 20% HCl to pH= 6. A solid precipitated out. The mixture was diluted with water, stirred for 15 minutes, filtered off. Solid was washed with water, dried to afford 600 mg product, 95% yield. HNMR
[00254] Synthesis of N'-(4-aminobenzoyl)-2-(3-chlorophenoxy)nicotinohydrazide. To a solution of 2-(3 -chlorophenoxy)nicotinic acid ( 360 mg, 1.44 mmole) in 30 ml methylene chloride was added DMAP (352 mg, 2.88 mmole), EDCI (552 mg, 2.88 mmole) and 4- aminobenzoic hydrazide (230 mg, 1.44 mmole). The reaction mixture was stirred at rt for 3 days. The mixture was concentrated down, diluted with 5 ml water, acidified with 0.5M HCl solution to pH=6, extracted several times with ethylacetate. Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrate. Crude was triturated with 20% MeOH/ether to afford 250 mg product, 45% yield. HNMR
[00255] Synthesis of 4-{5-[2-(3-Chloro-phenoxy)-pyridin-3-yl]-[l,3,4]oxadiazol-2-yl}- phenylamine, L-122. A mixture of N'-(4-aminobenzoyl)-2-(3- chlorophenoxy)nicotinohydrazide (230 mg, 0.6 mmole) in 4 ml POCI3 was heated at 110°C for one hour. The mixture was cooled to room temperature, concentrated to a thick oil, ice chips were adeed to the mixture and then a solution of NaOH, IM, dropwise to pH= 8. The suspension was filtered off, solid was washed with water and dried to give 200 mg crude. Purification was done using a silicagel preparative plate and a mixture of ethylacetate/ hexane= 1/1 to developed the plate. 30 mg product (MCLS1493-066-1) was obtained. HNMR, LC/MS
[00256] Synthesis of l-Ethyl-3-(4-{5-[2-(3-chloro-phenoxy)-pyridin-3-yl]- [l,3,4]oxadiazol-2-yl}-phenyl)-urea, L-127. To a solution of 4-{5-[2-(3-chloro-phenoxy)- pyridin-3-yl]-[l,3,4]oxadiazol-2-yl}-phenylamine (18 mg, 0.049 mmole) in 0.5 ml pyridine was added ethylisocyanate (15 ul, 3Eq.) at room temperature. The reaction mixture was stirred at room temperature for 3 days. The mixture was concentrated down to a solid residue and triturated with ethanol to afford after filtration 14 mg product, MCLS1493-121-1, 66% yield. HNMR, LC/MS
[00257] L-085 [00258] L-099 [00259] L- 105
Figure imgf000122_0001
[00260] Step 1. Synthesis of ethyl 2-(4-fluorophenoxy)nicotinate: A suspension of ethyl- 2-chloronicotinate (6g, 32.32 mmole) , 4-chlorophenol (3.8 g, 33.94 mmole), cesium carbonate (1 Ig, 33.94 mmole) in 350 ml DMF was heated at 8O0C for 2 days. The reaction mixture was cooled down, diluted with water and extracted several time s with ethylacetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated down. The crude was taken into ether, hexane was added until solid precipitated out. The Suspension was filtered off, solid washed with hexane, to give 5.8 g product, 69% yield. HNMR
[00261] Step 2. Synthesis of 2-(4-fluorophenoxy)nicotinic acid: To a solution of ethyl 2- (4-fluorophenoxy)nicotinate (1.8 g, 6.86 mmole) in 50 ml methanol was added NaOH, 2M solution (18 ml, 5eq.). The reaction mixture was stirred at 60°C for 4 hours. The mixture was concentrated down to half, extracted with ether, then acidified with 20% HCl to pH= 6. A solid precipitated out. The mixture was diluted with water, stirred for 15 minutes, filtered off. Solid was washed with water, dried to afford Ig of product, 62.5% yield. HNMR
[00262] Step 3. Synthesis of N'-(4-aminobenzoyl)-2-(4-fluorophenoxy)nicotinohydrazide. To a solution of 2-(4-fluorophenoxy)nicotinic acid ( 600 mg, 2.57 mmole) in 30 ml methylene chloride was added DMAP (628 mg, 5.15 mmole), EDCI (988 mg, 5.15 mmole) and 4-aminobenzoic hydrazide (427 mg, 2.83 mmole). The reaction mixture was stirred at rt for 2 days. The mixture was filtered off, the solid was washed with 10 ml methylenechloride and dried to give 770 mg product, 81.7% yield. HNMR
[00263] Step 4. Synthesis of 4-{5-[2-(4-fluoro-phenoxy)-pyridin-3-yl]-[l,3,4]oxadiazol-2- yl}-phenylamine, L-085. A mixture of N'-(4-aminobenzoyl)-2-(4- fluorophenoxy)nicotinohydrazide (300 mg, 0.82 mmole) in 7 ml POCI3 was heated at 110°C for 10 hours. The mixture was cooled to room temperature, concentrated to a thick oil, ice chips were adeed to the mixture and then a solution of NaOH, IM, dropwise to pH= 8. The suspension was filtered off, solid was washed with water and dried to give 250 mg crude. Trituration with 50% methanol/ ether gave 180 mg product (MCLS1428-177-1). HNMR, LC/MS
[00264] Step 5. Synthesis of l-Ethyl-3-(4-{5-[2-(4-fluoro-phenoxy)-pyridin-3-yl]- [l,3,4]oxadiazol-2-yl}-phenyl)-urea, L-099. To a solution of 4-{5-[2-(4-fluoro-phenoxy)- pyridin-3-yl]-[l,3,4]oxadiazol-2-yl}-phenylamine (200 mg, 0.57 mmole) in 2.5 ml pyridine was added ethylisocyanate (0.135 ml, 3Eq.) at room temperature. The reaction mixture was stirred at room temperature for 3 days. The mixture was concentrated down to a solid residue and triturated with ethanol to afford after filtration 58 mg product, 24% yield. HNMR, LC/MS [00265] Step 6. Synthesis of ethyl 2-(4-fluorophenoxy)pyridine-3-carbonyl hydrazide: A solution of ethyl 2-(4-fluorophenoxy)nicotinate (4.2g, 16.09 mmole), hydrazine hydrate (4g, 3.1 ml, 80 mmole) in 40 ml i-propanol was heated at 850C for 6 hours. The reaction mixture was cooled down, concentrated to half, a solid precipitated out. The suspension was filtered off, solid was washed with i-propanol, then ether to give 3 g of solid., 76% yield. HNMR
[00266] Step 7. Synthesis of 5-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-3H-[l,3,4]oxadiazol- 2-one. To a solution of ethyl 2-(4-fluorophenoxy)pyridine-3-carbonyl hydrazide (400 mg, 1.61 mmole) in 4 ml dioxane was added at room temperature, dropwise, trichloromethylchloroformate (0.22 ml, 1.76 mmole). The reaction mixture was stirred at room temperature for 1/5 hour then refluxed for 5 hrs. The reaction mixture was cooled to room temperature, concentrated to half, and filtered off. The solid was washed with water and dried to afford 450 mg white solid, 100% yield. This was used for next step without purification. HNMR
[00267] Step 8. Synthesis of 2-{5-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-[l,3,4]oxadiazol-2- yloxyj-ethanol, L-105. To a solution of 5-[2-(4-Fluoro-phenoxy)-pyridin-3-yl]-3H- [l,3,4]oxadiazol-2-one. (100 mg, 0.366 mmole) and Na2CO3 (78 mg, 0.73 mmole) in 2 ml DMF was added bromoethanol (92 mg, 0.73 mmole). The reaction mixture was stirred at room temperature for 24 hours. Mixture was concentrated down, diluted with water and extracted several times with ethylacetate. Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give 100 mg crude. Purification was done using a silicagel preparative plate and a mixture of 30 % ethylacetate/ hexane to developed the plate. 18 mg product was obtained. HNMR, LC/MS.
[00268] L- 174.
Figure imgf000124_0001
[00269] Step 1. Synthesis of 4-Hydroxy-2-methyl-thiazole-5-carboxylic acid ethyl ester: To a suspension of thioacetamide (2.4 g, 32 mmole) in 20 ml toluene was added diethylbromomalonate (8.31 g, 32 mmole). The reaction mixture was refluxed for an hour., then cooled down, and filtered off. The solid was washe with 20 ml toluene. The mother liquor was concentrated to a thick oil that was take into 20 ml water and stirred for a while. The suspension was filtered off, the solid was washed with water to afford 2g crude product, 33.8% yield. HNMR
[00270] Step 2. Synthesis of 4-(3-Chloro-benzyloxy)-2-methyl-thiazole-5-carboxylic acid ethyl ester: To a solution of 4-Hydroxy-2-methyl-thiazole-5-carboxylic acid ethyl ester (100 mg, 0.53 mmole) in 2 ml anhydrous DMF was added at room temperature NaH, 60% dispersion in oil (43 mg, 1.06 mmole). The reaction mixture was stirred at room temperature for 1/5 hour, then 3 -chlorobenzylbromide (110 mg, 0.53 mmole) was added. The mixture was stirred at 70°C for 5 hours. The mixture was cooled down, diluted with 2 ml water and extracted several times with ethyl acetate. Combined organic layers were washed with brine, dried over Na2SO4, concentrated to afford 100 mg crude. Purification was done using a silicagel preparative plate and a mixture of 20% ethylacetate/ hexane to developed the plate. 50 mg product was obtained. HNMR
[00271] Step 3. Synthesis of 4-(3-Chloro-benzyloxy)-2-methyl-thiazole-5-carboxylic acid. To a solution of 4-(3-Chloro-benzyloxy)-2-methyl-thiazole-5-carboxylic acid ethyl ester (50 mg, 0.17 mmole) in a mixture of methanol/ THF= 1/ 0.5 ml was added NaOH, IM solution (0.8 ml, 5eq.). The reaction mixture was stirred at room temperature, overnight. The mixture was concentrated down, 2 ml water was added, then acidified with IN HCl to pH= 2. Aqueous layer was extracted several times with ethylacetate. Combined organic layers were washed with brine, dried over Na2SO4, concentrated to afford 45 mg crude product. HNMR
[00272] Step 4. Synthesis of 4-(3-Chloro-benzyloxy)-2-methyl-thiazole-5-carboxylic acid (l-thiophen-2-yl-ethyl)-amide, L-174. To a solution of 4-(3-Chloro-benzyloxy)-2-methyl- thiazole-5-carboxylic acid (40 mg, 0.14 mmole) in 2 ml anhydrous THF were added: EDCI (31 mg, 0.155 mmole). HOBt (21mg, 0.155 mmole) and l-thiophen-2-yl-ethylamine (20 mg, 0.155 mmole). The reaction mixture was stirred at room temperature, overnight. The mixture was concentrated, diluted with 2 ml water and extracted several times with ethyl acetate. Combined organic layers were washed with brine, dried over Na2SO4, concentrated to afford 100 mg crude. Purification was done using a silicagel preparative plate and a mixture of 80% ethylacetate/ hexane to developed the plate. 40 mg product L- 174 was obtained, 72.7% yield.
[00273] L-101.
Figure imgf000126_0001
[00274] Compound 3 was prepared according reference (US 5264437 (1993)). A mixture of compound 1 (5.8 g, 30 mmole), 3-nitroaniline (4.9 g, 36 mmole), Cu (AcO)2 (330 mg, 1.8 mmole), N-methyl morpholine (3.3 ml, 30 mmole)) in DMF (40 ml) was stirred at 150 0C under Ar for 4 hrs. Reaction mixture was cooled to r.t. by adding ice and then the pH was adjusted to ~ 4, solid formed, and stirred at r.t. ~ 10 min. Solid was filtered and washed with water after drying, to give compound 3 (4.4 g, 57% yield) as a yellow solid. 1H NMR (DMSO-d6).
[00275] A mixture of compound 3 (3.8 g, 14.6 mmole), 4-(aminomethyl)pyridine (1.74 g, 16.2 mmole), HOBt (3.94 g, 29.2 mmole), and EDCI (5.58 g, 29.2 mmole) in DMF (80 ml) was stirred at r.t. over night. The reaction mixture was diluted with water (50 ml) and extracted with EA (2x50 ml). The EA layer was washed with water (3x50 ml), brine, and dried over Na2SO4. After removal of solvent, the solid was washed with Et20 and filtered to give compound 4 (4.3 g, 84% yield) as a yellow solid. 1H NMR (DMSO-d6).
[00276] To a solution of compound 4 (1.0 g, 2.87 mmole) in THF (20 ml), BH3 (12 ml, IM in THF) was added in 10 min at r.t. under Ar. The reaction mixture was stirred at 70 0C over night. After cooling to r.t., HCl aq. (6N, 3 ml) was added to quench reaction and then the pH was adjusted to -10 by addition of NaOH aq. (6N) with cooling (~ -10 to -20 0C). The reaction mixture was extracted with EA (3x30 ml), EA layer washed with brine and dried over Na2SO4. After removal of solvent, the residue was purified by silica gel column chromatography with EA/Hexane as eluent to give 270 mg of product L-IOl (yield: 28 %). MS(APCI+): 336.0 (M+l); LC-MS: 96 %; 1H NMR (DMSO-d6).
[00277] Synthesis of L-002.
Figure imgf000127_0001
[00278] (PR67) Synthesis of 2-(3-Acetyl-phenylamino)-nicotinic acid. A suspension of PRl (5.00 g, 25.6 mmol), l-(3-Amino-phenyl)-ethanone (4.15 g, 30.7 mmol), N-ethyl morpholine (2.96 g, 25.6 mmol) and cupric acetate (465 mg, 2.56 mmol) in DMF (35 mL) was stirred at reflux for 4 h.. Water (15 mL) was added and the solution cooled to room temperature. The pH was adjusted to 4 (litmus) using 6 N aqueous HCl. The solid that formed was filtered and washed with water (2 x 100 mL). After air drying and drying in the vacuum oven at 60 0C for 5 h, PR67 (3.96 g, 60% yield) was obtained. 1H NMR (400 MHz, DMSO- dβ) d: 10.58 (s, IH), 8.42 (d, J= 4.4 Hz, IH), 8.28-8.25 (m, 2H), 8.02 (d, J= 9.2 Hz, IH), 7.62 (d, J= 8.0 Hz, IH), 7.48 (t, J= 7.8 Hz, IH), 6.93-6.90 (m, IH), 2.60 (s, 3H) ppm.
[00279] L-002. Synthesis of 2-(3-Acetyl-phenylamino)-N-thiophen-2-ylmethyl- nicotinamide. A solution of PR67 (150 mg, 0.585 mmol), EDCI (123 mg, 0.644 mmol), HOBt (87.0 mg, 0.644 mmol) and 2-aminomethyl-thiophene (72.9 mg, 0.644 mmol) in DMF (8 mL) was stirred at room temperature for 21 h. The solvent was removed under vacuum, and the residue dissolved in ethyl acetate (20 mL). The organic solution was washed with aqueous saturated sodium bicarbonate (3 x 20 mL), water (15 mL), brine (10 mL), dried over sodium sulfate, and removed under vacuum. The residue was suspended in diethyl ether (10 mL), stirred 30 min, filtered, and washed with diethyl ether (3 mL) to give L-002 (128.2 mg, 63% yield) as a brown powder. 1H NMR (400 MHz, OMSO-d6) d: 11.00 (s, IH), 9.47 (t J = 5.6 , IH), 8.36 (dd, J= 4.6 Hz, 1.8 Hz, IH), 8.22 (t, J= 2.0 Hz, IH), 8.15 (dd, J= 7.8 Hz, 1.8 Hz, IH), 8.00-7.97 (m, IH), 7.59-7.57 (m, IH), 7.45 (t, J= 8.0 Hz, IH), 7.41 (dd, J= 5.2 Hz, 1.2 Hz, IH), 7.07 (dd, J= 3.6 Hz, 1.2 Hz, IH), 6.99-6.97 (m, IH), 6.93-6.90 (m, IH), 4.68 (d, J= 5.6 Hz, 2H), 2.59 (s, 3H) ppm. LCMS = 93.6% purity. MS(ESI-) = 350.7 (M-I)
[00280] Synthesis of L-093 and L-097.
Figure imgf000128_0001
[00281] Synthesis of (S)-5-(4-Nitro-phenoxymethyl)-pyrrolidin-2-one (PR212). A solution of toluene-4-sulfonic acid (S)-5-oxo-pyrrolidin-2-ylmethyl ester (500 mg, 1.86 mmol) and 4- nitrophenol (775 mg, 5.57 mmol) in acetonitrile (8 mL) was stirred at room temperature. To the solution was added solid potassium carbonate (1.28 g, 9.28 mmol). The reaction was stirred at room temperature for 16 h and at reflux for 24 h. The suspension was diluted with water (100 mL) and extracted into ethyl acetate (50 mL, 100 mL). The combined extracts were washed with water (2 x 100 mL) and brine (150 mL), dried over sodium sulfate, and the solvent removed under vacuum to give a mixture of product and nitrophenol. The product was purified by flash silica gel column chromatography eluting with 0-5% methanol in dichloromethane to give PR212 (339 mg, 77% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3): 8.25-8.21 (m, 2H), 7.00-6.95 (m, 2H), 5.89 (s, IH), 4.13-4.08 (m, 2H), 3.93 (t, J= 8.2 Hz, IH), 2.47-2.36 (m, 3H), 1.95-1.92 (m, IH) ppm. LCMS = 96.4% purity. MS(APCI+) = 207.1 (M-29), 237.0 (M+l).
[00282] Synthesis of (S)-I -(3 -ChIo ro-benzyl)-5-(4-nitro-phenoxymethyl)-pyrrolidin-2-one (PR213). A suspension of PR212 (330 mg, 1.40 mmol) and crushed potassium hydroxide (168 mg, 4.20 mmol) in dimethylformamide (3 mL) was stirred at room temperature for 10 min. To the deep red solution was added 3-chlorobenzylbronide (573 mg, 2.79 mmol). The solution turned orange and turbid, and was stirred for 48 h. The reaction was diluted with water and extracted with ethyl acetate (2 x 50 mL). The combined ethyl acetate was washed with water (75 mL) and brine (50 mL), dried over sodium sulfate, decanted, and the solvent removed under vacuum. The crude product was purified by flash silica gel column chromatography eluting with 20-50% ethyl acetate in hexanes to give o alkylateed product PR213 (169.0 mg, 33% yield) and the n-alkylated product (115.3 mg, 23% yield). 1H NMR (400 MHz, CDCl3): 8.20-8.17 (m, 2H), 7.23 (s, IH), 7.18-7.13 (m, 3H), 6.85-6.83 (m, 2H) 4.75 (d, J= 15.6 Hz, IH), 4.35 (d, J= 15.2 Hz, IH), 4.04-3.90 (m, 3H), 2.72-2.63 (m, IH), 2.54-2.47 (m, IH), 2.33-2.25 (m, IH), 2.07-1.98 (m, IH) ppm. 13C NMR (100 MHz, CDCl3): 21.670, 29.92, 44.83, 56.76, 69.18, 114.30, 125.91, 127.78, 127.91, 129.94, 134.60, 138.85, 142.05, 162.81, 175.46 ppm. LCMS = 92.24% yield. MS (APCI+) = 361.0 (M+l).
[00283] Synthesis of (S)-5-(4-Amino-phenoxymethyl)-l-(3-chloro-benzyl)-pyrrolidin-2- one, L-093. A suspension of PR213 (139 mg, 0.386 mmol), ammonium chloride (105 mg, 1.97 mmol), and iron powder (75 mg, 1.35 mmol) in ethanol (1.6 mL) and water (479 uL) was stirred at 85 0C for 3 h. The solvent was removed under vacuum, and the residue was diluted in water (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (30 mL), and the organic extracts were combined. The organic solution was washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, decanted, and the solvent removed under vacuum. The residue was purified by silica thin layer chromatography eluting with 5% acetone in dichloromethane to give L-093 (79.9 mg, 63 % yield) as a brown viscous oil. 1H NMR (400 MHz, CDCl3): 7.23-7.15 (m, 4H), 6.67-6.61 (m, 4H), 4.93 (d, J= 15.2 Hz, IH), 4.17 (d, J= 15.2 Hz, IH), 3.91-3.79 (m, 3H), 3.46 (s, 2H), 2.67-7.58 (m, IH), 2.49-2.41 (m, IH), 2.23-2.15 (m, IH), 2.00-1.55 (m, IH) ppm. LCMS = 92.5% purity. MS (APCI +) = 331.1 (M+l)
[00284] Synthesis of 1 - (4-[(S)-I -(3-Chloro-benzyl)-5-oxo-pyrrolidin-2-ylmethoxy]- phenyl} -3 -ethyl-urea, L-097. A solution of PR214 (63 mg, 0.19 mmol) in pyridine (1 mL) was stirred at room temperature. To the reaction was added ethyl isocyanate (41 mg, 0.57 mmol) and the reaction was stirred at room temperature for 5 h. The reaction was diluted with water (14 mL) and extracted with ethyl acetate (2 x 25 mL). The combined extracts were washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, filtered, and the solvent removed under vacuum. The residual ethyl acetate was removed by aziotrophing with dichloromethane, and the gummy solid was dried under high vacuum overnight to give L-097 (41.7 mg, 55% yield) as a tacky brown solid. 1H NMR (400 MHz, CDCl3): 7.24-7.14 (m, 6 H), 7.77-6.75 (m, 2H), 6.10 (s, IH), 4.86 (d, J= 15.6 Hz, IH), 4.55 (m, IH), 4.24 (d, J= 15.2 Hz, IH), 3.95-3.84 (m, 3H), 3.30-3.25 (m, 2H), 2.68-2.61 (m, IH), 2.51-2.44 (m, IH), 2.25-2.19 (m, IH), 2.01-1.97 (m, IH), 1.14 (t, J= 7.2 Hz, IH) ppm. LCMS = 99.2% purity. MS (APCI+) = 402.1 (M+l)
[00285] Methods of the invention parallel the compositions and formulations. The methods comprise administering to a patient in need of treatment a therapeutically effective amount of a compound according to the invention. The present invention also provides a method for inhibiting phosphodiesterase 4.
[00286] In-vitro assay for PDE4 enzymes. The in- vitro activity of PDE4 enzymes and the in-vitro potency of therapeutic agents described in the present invention was measured using a real-time, enzyme-coupled spectrophotometric assay. The product of the PDE reaction, 5' - AMP can be coupled to the oxidation of NADH using three different coupling enzymes. Adenylate kinase (AK) phosphorylates AMP to yield ADP in the first step. Pyruvate kinase (PK) then uses ADP and phosphoenolpyruvate (PEP) to make ATP and pyruvate. Pyruvate is finally reduced to lactate by lactate dehydrogenase (LDH), with the concomitant oxidation of NADH to NAD+. The dissipation of β-nicotinamide adenine dinucleotide (NADH) can be monitored spectrophotmetrically at 340 nM.
[00287] Assay description. Buffer A containing 50 mM Tris, pH 8.0, 16 mM MgCl2 and 80 mM KCl is prepared and stored at room temperature. Buffer B containing 50 mM Tris, pH 8.0 is prepared and stored at toom temperature. Stock solutions of the following reagents are prepared in Buffer B and stored at -200C: Adenosine-5 '-triphosphate (ATP), cyclic adenosine-5' -monophosphate (cAMP), phosphoenolpyruvate (PEP) and NADH. An assay mix is prepared by mixing Buffer A, trichloroethylphosphine (TCEP), ATP, PEP, NADH, myokinase (MK), pyruvate kinase (PK), lactate dehydroganese (LDH) and PDE4 to a final volume of 20 mL, which is enough for a single 96-well assay plate. Assay mix (180 μL) and test article (10 μL ) in 1 : 1 DMSO/H2O mixture is pre- incubated at room temperature for 10 min. The enzymatic reaction is initiated by addition of cAMP (10 μL). Final concentration of all components in the assay (200 μL/well) are as follows: 10 mM MgCl2, 50 mM KCl, 5 mM TCEP, 2.5% DMSO, 0.4 mM NADH, 1 mM PEP, 0.04 mM ATP, 5 units MK, 1 unit PK, 1 unit LDH and appropriate amount of PDE4. Reaction progress curves are monitored in a plate reader capable of measuring light absorbance at 340 nM. A decrease in light absorbance at 340 nm is due to oxidation of NADH. Positive controls containing no test article and negative controls containing no test article and no cAMP are included on every assay plate. Reaction rates are determined from the slopes of the linear portions of the progress curves. All data is percent normalized with respect to controls and presented as percent inhibition. The results of testing of representative species are shown below:
Table 2. Selectivity comparison between human PDE4D7 protein and catalytic domain for PDE4 modulators and inhibitors of the invention. A > 10,000-fold, B > 1,000 fold, C > 100 fold
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
[00288] In comparison, various PDE4 inhibitors cited in the literature only show up to a five-fold selectivity for the regulatory domain of PDE4 over the catalytic domain (Table 3):
Table 3. Long form versus Catalytic domain selectivity for literature PDE4 inhibitors
Figure imgf000137_0002
[00289] The figure below shows the dose response curves with PDE4D7 for three different PDE4 inhibitors: D 155947, and R- and S-rolipram. These and other compounds used in routine screening are dissolved in DMSO to a concentration of 20 mM. Using this approach, the dose range varies from IxIO 3 M to 5xlO~16 M in a 12-point serial dilution with a dilution factor of 7. As shown in the figure below, compounds like D155947 have very shallow dose- response curves (i.e., low hillslope) such that a large concentration range is required to obtain a plateau at both ends of the curve(s).
Figure imgf000138_0001
[00290] Table 4 illustrates some examples of partial inhibitors of the invention. These compounds do not show full enzyme inhibition, even at concentration up to 100-10,000 times of IC50 for a regulatory domain-containing form (PDE4D7) of the human PDE4D protein. The maximum inhibition observed in these compounds is 60-90%.
Table 4: Modulators (Partial inhibitors)
Figure imgf000138_0002
Figure imgf000139_0001
[00291] Analogs L-105, L-046, L-099, L-120, L-131, L-136, L-145 and L-146 showed maximum inhibition of < 80% in the enzyme assay utilizing a regulatory domain-containing form (PDE4D7) of the human PDE4D protein.
[00292] Table 5 illustrates some examples of PDE4 inhibitors of the invention that showed full enzyme inhibition (95-100%) for a regulatory domain-containing form (PDE4D7) of the human PDE4D protein.
Table 5: Mixed Inhibitors ( Full inhibitors)
Figure imgf000139_0002
[00293] Avoidance of the side effect of emesis can be avoided as described in the method of Robichaud, et al. (J Clin Invest. 110: 1045-1052. 2002). One or more examples of the present invention have been tested in this model and have shown decreased emesis liability. [00294] PDE4D modulator (L-009, partial) and an inhibitor (L-016, full), both analogs with essentially identical IC50 (1-2 nM) although showing different kinetic profile in the enzyme assay, were evaluated towards emesis in cynomolgus monkeys. The compounds L- 009 and L-016 were dosed intravenously at a series of doses and the lowest dose that resulted in emesis was determined to be 0.0875 mg/kg for compound L-009 and 0.01mg/kg for compound L-016. Both compounds gave dose dependent change in plasma levels for blood samples taken at 2min post-dose (i.v.) and the plasma levels at the lowest emetic dose at 2min post dose were 218ng/mL for L-009 and 12.7 ng/mL for L-016. The difference in emetic threshold between the two compounds is therefore approximately 9-fold and 17-fold based on dose and plasma exposure, respectively. Thus these studies clearly show superiority of the PDE4 modulator in terms of the emetic side effect profile.
[00295] Persons of skill in the art accept that positive results in PDE4 models are predictive of therapeutic utility as discussed above.

Claims

We claim:
1. A compound of formula:
Figure imgf000141_0001
or salt thereof wherein
A is an optionally substituted carbocycle or optionally substituted heterocycle of three or fewer rings;
B is an optionally substituted carbocycle or optionally substituted heterocycle of two or fewer rings;
R3 is chosen from H, -C(O)NH2, -(C1-C6)alkyl, halo(C1-C6)alkyl, -(Ci-C6)alkyl-R30, -(C2-
C6)alkyl-R31, and saturated 4- or 5-membered heterocycle optionally substituted with methyl;
R30 is chosen from -C(=0)NH2 and 4- or 5-membered heterocycle optionally substituted with methyl;
R31 is chosen from (Ci-C/^aikoxy, amino, hydroxy, (Ci-C6)alkylamino and di(Ci-
C6)alkylamino;
R4 is chosen from H and F;
R6 is chosen from H, (Ci-Ce)alkyl and halogen;
X is N, N→O, or C-R5;
RR55 iiss cchhoosseenn ffrroomm HH,, hhaallogen, OH, (Ci-C6)alkyl, (d-C6)alkoxy, CF3, CN, NH2 , CH2OH,
CH2NH2 and C≡CH; and
M is chosen from direct bond, -C(R20)(R21)-, -0-, -NR22-, -S(O)n-, -C(O)-,
-C(R20)(R21)C(R20)(R21)-, -C(R20)=C(R21)-, -C(R20)(R21)-O-, -C(R20)(R21)-NR22-, - C(R20)(R21)-S(O)n-, -C(R20)(R21)-C(=O)-, -O-C(R20)(R21)-, -NR22-C(R20)(R21)-,
-S(O)n-C(R20)(R21)-, -C(=O)-C(R20)(R21)- and
Figure imgf000142_0001
Figure imgf000142_0002
is a five or six-membered ring optionally substituted with methyl; and n is zero, one or two; with the provisos that: when R3 is methyl, M is CH2 and R2 is a five-membered ring heterocycle, then R1 cannot be pentamethyltetralin; when R3 is methyl, M is CH2 and R1 is a five-membered ring heterocycle, then R2 cannot be pentamethyltetralin. 2. A compound of formula:
Figure imgf000142_0003
or salt thereof wherein
U is selected from the group consisting of -S- and -O-;
V is selected from the group consisting of H, CH3, NH2, and CF3;
Z is selected from the group consisting of CH, C-F, C-Cl, C-Br, C-I, C-NH2, C-OH, C-OCH3, N, and N-O;
Y is selected from the group consisting of N, CH, CF and C-lower alkyl; R40 is H or lower alkyl;
R41 is selected from the group consisting of H, alkyl, OH, NH2, and OCH3;
G is an optionally substituted, mono- or bicyclic aryl or heteroaryl; and
E is an optionally substituted heterocycle or an optionally substituted carbocycle.
3. A compound of formula:
Figure imgf000143_0001
or salt thereof wherein
R1 is chosen from H, (Ci-Cg)alkyl and halo(d-C8)alkyl;
R2 is chosen from H and halo;
Ar1 is selected from optionally substituted phenyl and optionally substituted heteroaryl; and
Ar2 is selected from substituted phenyl and substituted heteroaryl; with the provisos that
(1) when R1 and R2 are both H, Ar2 is not 2,6-disubstituted phenyl; and
(2) when R1 is CH3 and R2 is H, Ar2 is not 2,4-diaminopyrimidin-5-yl.
4. A compound of formula
Figure imgf000143_0002
or salt thereof wherein
AA is selected from N and CR 50.
DD is selected from N and CR50, with the proviso that both AA and DD cannot be N;
R50 is selected from hydrogen, (Ci-C6)alkyl, fluoro, hydroxyalkyl, carbonyl and amide;
J is a substituted 5-membered heterocycle;
Cy1 is selected from optionally substituted phenyl and optionally substituted heteroaryl;
R45 is selected independently in one or more occurrences from hydrogen, halogen and (Ci-Cβ) alkyl; and
R46 is selected from (1) hydrogen, halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, amino sulfonyl, trityl, amidino, guanidino, ureido, -NHC(=O)NHalkyl, -NHC(=O)NH-heterocyclyl, -alkyl-NHC(=O)N(alkyl)2, heterocyclylalkylcarbonylamino, benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid amides, protected residues of aminoacids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides and (2) phenyl and monocyclic heterocycle substituted with any of the foregoing.
5. A compound or salt according to claim 4 wherein J is selected from optionally substituted 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, furane, thiophene, isoxazole, pyrazole, tetrahydrofurane, tetrahythiophene and isoxazoline; and R46 is selected from hydroxy(Ci-C6)alkyl; hydroxy(Ci-Ce)alkyoxy; phenyl optionally substituted with amino, halogen, hydroxy, alkylsulfonylamino or (Ci-Cβ) alkylurea; and pyridinyl optionally substituted with amino, halogen, hydroxy, alkylsulfonylamino or (Ci-C6) alkylurea.
6. A compound of formula
Figure imgf000144_0001
or salt thereof wherein
J is a substituted 5-membered heterocycle;
L is selected from O, S and NRb;
Ra is selected from H and (Ci-C6) alkyl; Rb is selected from H and (Ci-C6) alkyl;
Cy1 is selected from optionally substituted phenyl and optionally substituted heteroaryl; R45 is selected independently in one or more occurrences from hydrogen, halogen, (Ci-C6) alkyl; and
R46 is selected from (1) halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, -NHC(=O)NHalkyl, -NHC(=O)NH-heterocyclyl, -alkyl-NHC(=O)N(alkyl)2, heterocyclylalkylcarbonylamino, benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid amides, protected residues of aminoacids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides and (2) phenyl and monocyclic heterocycle substituted with any of the foregoing.
7. A compound or salt according to claim 6 wherein J is selected from optionally substituted 1,3,4-oxadiazole, 1,2,4-oxadiazole, 1,3,4-thiadiazole, furane, thiophene, isoxazole, pyrazole, tetrahydrofurane, tetrahythiophene and isoxazoline; R46 is selected from hydroxy(Ci-C6)alkyl; hydroxy(Ci-C6)alkyoxy; phenyl optionally substituted with amino, halogen, hydroxy, alkylsulfonylamino or (Ci-C6) alkylurea; and pyridinyl optionally substituted with amino, halogen, hydroxy, alkylsulfonylamino or (Ci-C6) alkylurea. A compound of formula
Figure imgf000146_0001
or salt thereof wherein
AA is selected from N and CR 50.
DD is selected from N and CR50, with the proviso that both AA and DD cannot be N;
R50 is selected from hydrogen, (Ci-Ce)alkyl, fluoro, hydroxyalkyl, carbonyl and amide;
Q is selected from O, NH, S, SO and SO2;
T is selected from CONH, CH2NHCO, CHRdNHC0, CHRdNHSO2, and CHReXaCHRc;
Xa is selected from O, NH, S, SO and SO2;
Rc, Rd and Re are each independently selected from hydrogen, (Ci-Cβ) alkyl, hydroxy(Ci-
Ce)alkyl and amino(Ci-C6)alkyl;
Cy1 is selected from optionally substituted phenyl and optionally substituted heteroaryl; and
R47 is selected from hydroxy(Ci-C6)alkyl, hydroxy(Ci-Ce)alkyoxy, carbocyclyl and heterocyclyl, wherein the cyclyl is optionally substituted with a substituent selected from (1) halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido,
-NHC(=O)NHalkyl, -NHC(=O)NH-heterocyclyl, -alkyl-NHC(=O)N(alkyl)2, heterocyclylalkylcarbonylamino, benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid amides, protected residues of aminoacids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides and (2) phenyl and monocyclic heterocycle substituted with any of the foregoing.
9. A compound or salt according to claim 8 wherein
Q is NH;
T is CH2NHCH2;
Cy1 is selected from phenyl optionally substituted with NO2 or acyl; and
R47 is selected from carbocyclyl and heterocyclyl optionally substituted with amino, halogen, hydroxy, alkylsulfonylamino or (Ci-C6) alkylurea.
10. A compound of formula
Figure imgf000147_0001
or a salt thereof wherein
Q is selected from O, NH, S, SO and SO2;
L is selected from O, S and NRb;
Ra is selected from H and (Ci-C6) alkyl;
Rb is selected from H and (Ci-C6) alkyl;
T is selected from CONH, CH2NHCO, CHRdNHC0, CHRdNHSO2, CHReXaCHRc, and
CONHCHRC;
Xa is selected from O, NH, S, SO and SO2;
Rc, Rd and Re are each independently selected from hydrogen, (Ci-C6) alkyl, hydroxy(Ci-
C6)alkyl and amino(Ci-C6)alkyl;
Cy1 is selected from optionally substituted phenyl and optionally substituted heteroaryl; and
R47 is selected from hydroxy(Ci-C6)alkyl, hydroxy(Ci-C6)alkyoxy, carbocyclyl and heterocyclyl, wherein the cyclyl is optionally substituted with a substituent selected from (1) halogen, haloalkyl, alkyl, acyl, alkoxyalkyl, hydroxyalkyl, hydroxyalkoxy, carbonyl, phenyl, heteroaryl, benzenesulfonyl, hydroxy, alkoxy, haloalkoxy, oxaalkyl, carboxy, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylamino, carboxyalkyl, carboxyalkoxy, carboxyalkylthio, alkoxycarbonylaminoalkyl, carboxyalkylcarbonylamino, carboxamido, aminocarbonyloxy, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, cyano, acetoxy, nitro, amino, alkylamino, dialkylamino, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkoxy, alkyl(hydroxyalkyl)amino, heterocyclylalkoxy, mercapto, alkylthio, alkylsulfonyl, alkylsulfonylamino, alkylsulfinyl, alkylsulfonyl, arylthio, arylsulfonyl, arylsulfonylamino, arylsulfinyl, arylsulfonyl, acylaminoalkyl, acylaminoalkoxy, acylamino, amidino, aryl, benzyl, heterocyclyl, heterocyclylalkyl, phenoxy, benzyloxy, heteroaryloxy, heterocyclylamino, hydroxyimino, alkoxyimino, oxaalkyl, aminosulfonyl, trityl, amidino, guanidino, ureido, -NHC(=O)NHalkyl, -NHC(=O)NH-heterocyclyl, -alkyl-NHC(=O)N(alkyl)2, heterocyclylalkylcarbonylamino, benzyloxyphenyl, benzyloxy, the residues of amino acids, amino acid amides, protected residues of aminoacids, protected residues of amino acid amides, N-methylated amino acids and N-methylated amino acid amides and (2) phenyl and monocyclic heterocycle substituted with any of the foregoing.
11. A compound of formula
Figure imgf000148_0001
or a salt thereof wherein
P is chosen from nitrogen and carbon;
Q is chosen from nitrogen and carbon, with the provisos that one of P or Q must be nitrogen, but P and Q cannot both be nitrogen;
R1 is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl, -CONHR5, lower alkoxy, alkylamino, dialkylamino, amino, -NHCOOR2 and -OCONH2; W is nitrogen or CR2;
R2 is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl and optionally substituted heterocyclyl; Y is CR3 or nitrogen;
R3 is selected from hydrogen, fluoro, hydroxyl and -OR10; R10 is selected from (Ci-Cβ) alkyl optionally substituted with fluoro; X is selected from CR4, nitrogen and N+ O"; R4 is selected from hydrogen, (Ci-Cβ) alkyl, halogen, amino, alkoxy and hydroxyl; R5 is selected from hydrogen and (Ci-Cβ) alkyl; q is selected from O, S(0)o-2, NH, CH2 and a direct bond;
Cy1 is selected from optionally substituted (C3-C6) carbocyclyl and optionally substituted heterocyclyl;
Cy2 is selected from optionally substituted aryl and optionally substituted heteroaryl; and
M is chosen from -CH2-, -CH2CH2-, -0-, -S(O)0-2, -OCH2, -CH2O, -CONH, -CONHCH2, -
NHCO and -NHSO2, with the proviso that when M is -NH or -CONH, Q is not nitrogen; and with the proviso that 4'-[(7-phenylpyrazolo[l,5-a]pyrimidin-5-yl)methyl]-[l,r-Biphenyl]-2- carbonitrile, 7-[3-(acetylethylamino)phenyl]-3-cyanopyrazolo[l,5-a]pyrimidin-5-yl-β-D-
Glucopyranosiduronic acid and 7-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-5-
(phenylmethyl)-[l,2,4]Triazolo[l,5-a]pyrimidine are excluded compounds.
12. A compound of formula
Figure imgf000149_0001
or a salt thereof wherein
P is chosen from nitrogen and carbon;
Q is chosen from nitrogen and carbon, with the provisos that one of P or Q must be nitrogen, but P and Q cannot both be nitrogen;
R1 is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl, -CONHR5, lower alkoxy, alkylamino, dialkylamino, amino, -NHCOOR2 and -OCONH2; W is nitrogen or CR2;
R2 is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl and optionally substituted heterocyclyl;
X is selected from CR4, nitrogen and N+ O";
R4 is selected from hydrogen, (Ci-Cβ) alkyl, halogen, amino, alkoxy and hydroxyl; R5 is selected from hydrogen and (Ci-Cβ) alkyl; R and R are independently selected from hydrogen, (Ci-Cβ) alkyl, (Ci-Cβ) hydroxyalkyl,
(C3-C6) carbocyclyl and a 3- to 6-membered heterocyclyl; or R8 and R9 together form a 4-6 membered ring which optionally contains a heteroatom selected from -O-, -NR5 and S(0)o-2; or R8 and R9 together form an oxo group; q is selected from O, S(0)o-2, NH, CH2 and a direct bond;
Cy1 is selected from optionally substituted (C3-C6) carbocyclyl and optionally substituted heterocyclyl;
Cy2 is selected from optionally substituted aryl and optionally substituted heteroaryl; and
M is chosen from -CH2-, -CH2CH2-, -O-, -S(O)0-2, -OCH2, -CH2O, -CONH, -CONHCH2, -
NHCO and -NHSO2, with the proviso that when M is -NH or -CONH, Q is not nitrogen; and with the proviso that 4'-[(7-phenylpyrazolo[l,5-a]pyrimidin-5-yl)methyl]-[l,r-Biphenyl]-2- carbonitrile, 7-[3-(acetylethylamino)phenyl]-3-cyanopyrazolo[l,5-a]pyrimidin-5-yl-β-D-
Glucopyranosiduronic acid and 7-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-5-
(phenylmethyl)-[l,2,4]Triazolo[l,5-a]pyrimidine are excluded compounds.
13. A compound of formula
Figure imgf000150_0001
or a salt thereof wherein
R2 is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl and optionally substituted heterocyclyl; q is selected from O, S(0)o-2, NH, CH2 and a direct bond;
Cy1 is an optionally substituted, mono- or bicyclic aryl or heteroaryl; and
Cy2 is an optionally substituted heterocycle or an optionally substituted carbocycle.
14. A compound of formula
Figure imgf000151_0001
or a salt thereof wherein
R1 is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl, -CONHR5, lower alkoxy, alkylamino, dialkylamino, amino, -NHCOOR2 and -OCONH2; W is nitrogen or CR2;
R2 is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl and optionally substituted heterocyclyl; q is selected from O, S(0)o-2, NH, CH2 and a direct bond; j-k is selected from 0-N, N(R2a)-N and N-N(R2a);
R2a is selected from hydrogen, (Ci-Cβ) alkyl, haloalkyl, aminoalkyl, acyl, alkoxyalkyl, hydroxyalkyl, phenyl, heteroaryl, oxaalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, carboxyalkyl, alkoxycarbonylaminoalkyl, aminocarbonylalkyl, aminoalkyl, (alkyl)(aryl)aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, acylaminoalkyl, aryl, benzyl, heterocyclyl, and heterocyclylalkyl;
Cy1 is an optionally substituted, mono- or bicyclic aryl or heteroaryl; and Cy2 is an optionally substituted heterocycle or an optionally substituted carbocycle.
15. A compound of formula
Figure imgf000151_0002
or a salt thereof wherein b is selected from the group consisting of S, O and NR2b;
R2b is selected from hydrogen, (Ci-Cβ) alkyl, hydroxyalkyl, haloalkyl, aminoalkyl, carboxyalkyl and alkoxycarbonyl; V is selected from the group consisting of H, CH3, NH2, NR2c, OR2d, carboxylic acid, SO2NH, S(Oy2 and CF3;
R2c is selected from hydrogen, (Ci-Cβ) alkyl, hydroxyalkyl, haloalkyl, aminoalkyl and alkoxycarbonyl;
R2d is selected from hydrogen, (Ci-Cβ) alkyl, hydroxyalkyl, haloalkyl, aminoalkyl and alkoxycarbonyl; q is selected from O, S(0)o-2, NH, CH2 and a direct bond;
Y is selected from the group consisting of N, CH, CF and C-lower alkyl; R40 is H or lower alkyl;
R41 is selected from the group consisting of H, alkyl, OH, NH2, and OCH3;
Cy1 is an optionally substituted, mono- or bicyclic aryl or heteroaryl; and
Cy2 is an optionally substituted heterocycle or an optionally substituted carbocycle.
16. A compound of formula
Figure imgf000152_0001
or a salt thereof wherein q is selected from O, S(0)o-2, NH, CH2 and a direct bond;
M is chosen from CH2, CH2CH2, O, S(O)0-2, OCH2, CH2O, CONH, CONHCH2, NHCO, C=O and NHSO2;
Cy1 is an optionally substituted, mono- or bicyclic aryl or heteroaryl; and
Cy2 is an optionally substituted heterocycle or an optionally substituted carbocycle.
17. A compound or salt according to claim 16 wherein q is CH2;
M is CH2O;
Cy1 is optionally substituted phenyl; and
Cy2 is phenyl optionally substituted with amino or (Ci-Cβ) alkylurea.
18. A pharmaceutical composition comprising a compound or salt according to any of claims 1-17 and a pharmaceutically acceptable carrier.
19. A compound or salt according to any of claims 1-17 wherein said compound shows preference for a regulatory segment of a PDE4 isoform over the catalytic portion of a PDE4 isoform.
20. A compound or salt according to claim 19 wherein the PDE4 isoform is selected from PDE4D3, PDE4D4, PDE4D5, PDE4D7, PDE4D8, PDE4D9, PDE4D1, PDE4D2, PDE4D6, PDE4B1, PDE4B3, PDE4B4 and PDE4B2.
21. A compound or salt according to claim 20 wherein the PDE4 isoform is PDE4D3, PDE4D4, PDE4D5, PDE4D7, PDE4D8, PDE4D9, PDE4B1, PDE4B3 and PDE4B4.
22. A compound or salt according to claim 20 wherein the PDE4 isoform is PDE4D1 or PDE4B2.
23. A compound or salt according to claim 20 wherein the PDE4 isoform is PDE4D2 or PDE4D6.
24. A compound or salt according to any of claims 1-17 wherein said compound or salt is a PDE4 modulator wherein said modulator has an lπmx < 95%.
25. A compound or salt according to claim 24 wherein said modulator has an Imax < 90%.
26. A method for treating or preventing CNS-related disorders or vascular disorders while minimizing at least one unwanted side effect comprising administering a compound or salt according to any of claims 1-17 having a ratio of binding selectivity to a regulatory domain- containing form of PDE4 of at least 100 times the binding selectivity to the catalytic portion of PDE4.
27. A method according to claim 26 wherein said binding selectivity to said regulatory domain-containing form is at least 1,000 times that of the catalytic portion of PDE4.
28. A method according to claim 27 wherein said binding selectivity to said regulatory domain-containing form is at least 10,000 times that of the catalytic portion of PDE4.
29. A method according to claim 26 wherein the side effect is emesis.
30. A method according to claim 26 wherein the side effect is nausea.
31. A method according to claim 26 wherein the side effect is vasculopathy.
32. A method for identifying the selectivity of a potential PDE4-inhibiting compound comprising: i. providing at least two different isoforms of PDE4, ii. providing cAMP substrate; iii. providing one or more cofactors; iv. providing an agent for detection of a reaction of cAMP substrate; v. determining the maximum kinetic rates of reaction of said cAMP substrate in the presence of said at least two different isoforms of PDE4; vi. providing a sample containing a test compound; vii. determining the IC50 values of said test compound against said at least two different isoforms of PDE4; and viii. comparing said IC50 values to determine a selectivity ratio.
33. A method according to claim 32 wherein the at least two different isoforms of PDE4 are selected from PDE4D7, PDE4D1, PDE4D2, PDE4D-Cat and PDE4B1.
34. A method according to claim 33 wherein at least one of the PDE4 isoforms is selected from PDE4D7 and PDE4B1.
35. A method according to claim 32 wherein the one or more cofactors are selected from adenylate kinase, pyruvate kinase, phosphoenolpyruvate, lactate dehydrogenase and NADH.
36. A method according to claim 32 wherein the agent for detection of a reaction of cAMP substrate is NADH.
37. A method according to claim 32 wherein the agent for detection of a reaction of cAMP substrate is detected by spectrophotometry, fluorescence or radionucleide.
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Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5594141A (en) * 1994-11-23 1997-01-14 Neurogen Corporation Certain aminomethyl biphenyl, aminomethyl phenyl pyridine and aminomethyl phenyl pyrimidine derivatives; novel dopamine receptor subtype selective ligands
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US7557143B2 (en) * 2003-04-18 2009-07-07 Bristol-Myers Squibb Company Thyroid receptor ligands
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US20070254913A1 (en) * 2006-04-19 2007-11-01 Dunn Robert F Phosphodiesterase 4 inhibitors
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