WO2010059838A2 - Inhibiteurs de pde4 sélectifs pour la forme longue de pde4 pour traiter une inflammation et éviter des effets secondaires - Google Patents

Inhibiteurs de pde4 sélectifs pour la forme longue de pde4 pour traiter une inflammation et éviter des effets secondaires Download PDF

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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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PCT/US2009/065164
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WO2010059838A3 (fr
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Jasbir Singh
Mark Gurney
Alexander Kiselyov
Olefur Magnusson
Alex Burgin
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Decode Genetics Ehf
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Publication of WO2010059838A2 publication Critical patent/WO2010059838A2/fr
Publication of WO2010059838A3 publication Critical patent/WO2010059838A3/fr

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    • C07—ORGANIC CHEMISTRY
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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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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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • 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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    • C07D471/04—Ortho-condensed systems

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

La présente invention concerne des composés qui sont des inhibiteurs de la phosphodiestérase-4 (PDE4) utiles pour le traitement et la prévention d'un accident vasculaire cérébral, d'un infarctus du myocarde, de maladies et de troubles inflammatoires cardiovasculaires et de troubles du système nerveux central, ainsi que des composés avec une sélectivité pour une partie non catalytique de PDE4 et des procédés de détermination de cette sélectivité.
PCT/US2009/065164 2008-11-20 2009-11-19 Inhibiteurs de pde4 sélectifs pour la forme longue de pde4 pour traiter une inflammation et éviter des effets secondaires WO2010059838A2 (fr)

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US8791267B2 (en) 2007-11-21 2014-07-29 Decode Genetics Ehf Biaryl PDE4 inhibitors for treating inflammatory, cardiovascular and CNS disorders
US8859543B2 (en) 2010-03-09 2014-10-14 Janssen Pharmaceutica Nv Imidazo[1,2-a]pyrazine derivatives and their use for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases
WO2015048407A1 (fr) * 2013-09-26 2015-04-02 Tetra Discovery Partners, LLC Inhibiteurs hétéroaryle de la pde4
WO2016049595A1 (fr) * 2014-09-26 2016-03-31 Tetra Discovery Partners, LLC Inhibiteurs hétéroaryle de la pde4
JP2016536333A (ja) * 2013-09-04 2016-11-24 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ 免疫調節剤として有用な化合物
WO2016193110A1 (fr) 2015-05-29 2016-12-08 Koninklijke Philips N.V. Méthodes de pronostic du cancer de la prostate
US9550784B2 (en) 2012-07-09 2017-01-24 Beerse Pharmaceutica NV Inhibitors of phosphodiesterase 10 enzyme
WO2017089347A1 (fr) 2015-11-25 2017-06-01 Inserm (Institut National De La Sante Et De La Recherche Medicale) Procédés et compositions pharmaceutiques pour le traitement de mélanomes résistant aux inhibiteurs de braf
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WO2018099884A1 (fr) 2016-12-01 2018-06-07 Koninklijke Philips N.V. Scores de risque basés sur l'expression d'un variant 7 humain de phosphodiestérase 4d
US10093686B2 (en) 2012-10-25 2018-10-09 Tetra Discovery Partners, LLC Heteroaryl inhibitors of PDE4
US10385027B2 (en) 2015-03-20 2019-08-20 Mironid Limited Triazole derivatives and their use as PDE4 activators
US10604523B2 (en) 2011-06-27 2020-03-31 Janssen Pharmaceutica Nv 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives
US10611747B2 (en) 2015-11-09 2020-04-07 Forge Therapeutics, Inc. Pyrone based compounds for treating bacterial infections
US11021471B2 (en) 2017-05-10 2021-06-01 Forge Therapeutics, Inc. Antibacterial compounds
US11046660B2 (en) 2016-09-28 2021-06-29 Mironid Limited Compounds and their use as PDE4 activators
US11407740B2 (en) 2018-09-20 2022-08-09 Forge Therapeutics, Inc. Antibacterial compounds
US11560373B2 (en) 2018-04-04 2023-01-24 Mironid Limited Compounds and their use as PDE4 activators
US11731962B2 (en) 2020-03-25 2023-08-22 Blacksmith Medicines, Inc. LpxC inhibitor and methods of making

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US8791267B2 (en) 2007-11-21 2014-07-29 Decode Genetics Ehf Biaryl PDE4 inhibitors for treating inflammatory, cardiovascular and CNS disorders
US8716282B2 (en) 2009-10-30 2014-05-06 Janssen Pharmaceutica Nv Imidazo[1,2-b]pyridazine derivatives and their use as PDE10 inhibitors
US8859543B2 (en) 2010-03-09 2014-10-14 Janssen Pharmaceutica Nv Imidazo[1,2-a]pyrazine derivatives and their use for the prevention or treatment of neurological, psychiatric and metabolic disorders and diseases
US10604523B2 (en) 2011-06-27 2020-03-31 Janssen Pharmaceutica Nv 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives
US9669035B2 (en) 2012-06-26 2017-06-06 Janssen Pharmaceutica Nv Combinations comprising PDE 2 inhibitors such as 1-aryl-4-methyl-[1,2,4]triazolo-[4,3-A]]quinoxaline compounds and PDE 10 inhibitors for use in the treatment of neurological of metabolic disorders
US9550784B2 (en) 2012-07-09 2017-01-24 Beerse Pharmaceutica NV Inhibitors of phosphodiesterase 10 enzyme
US10364258B2 (en) 2012-10-25 2019-07-30 Tetra Discovery Partners, LLC Heteroaryl inhibitors of PDE4
US11401286B2 (en) 2012-10-25 2022-08-02 Tetra Discovery Partners, LLC Heteroaryl inhibitors of PDE4
US11767334B2 (en) 2012-10-25 2023-09-26 Tetra Discovery Partners, LLC Heteroaryl inhibitors of PDE4
US10626129B2 (en) 2012-10-25 2020-04-21 Tetra Discovery Partners, LLC Heteroaryl inhibitors of PDE4
US10093686B2 (en) 2012-10-25 2018-10-09 Tetra Discovery Partners, LLC Heteroaryl inhibitors of PDE4
JP2016536333A (ja) * 2013-09-04 2016-11-24 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ 免疫調節剤として有用な化合物
WO2015048407A1 (fr) * 2013-09-26 2015-04-02 Tetra Discovery Partners, LLC Inhibiteurs hétéroaryle de la pde4
WO2016049595A1 (fr) * 2014-09-26 2016-03-31 Tetra Discovery Partners, LLC Inhibiteurs hétéroaryle de la pde4
US10793531B2 (en) 2015-03-20 2020-10-06 Mironid Limited Triazole derivatives and their use as PDE4 activators
US10385027B2 (en) 2015-03-20 2019-08-20 Mironid Limited Triazole derivatives and their use as PDE4 activators
US11827938B2 (en) 2015-05-29 2023-11-28 Koninklijke Philips N.V. Methods of prostate cancer prognosis
CN108738329A (zh) * 2015-05-29 2018-11-02 皇家飞利浦有限公司 前列腺癌预后方法
WO2016193110A1 (fr) 2015-05-29 2016-12-08 Koninklijke Philips N.V. Méthodes de pronostic du cancer de la prostate
US11198909B2 (en) 2015-05-29 2021-12-14 Koninklijke Philips N.V. Risk scores based on human phosphodiesterase 4D variant 7 expression
US10875832B2 (en) 2015-11-09 2020-12-29 Forge Therapeutics, Inc. Substituted pyrimidines for treating bacterial infections
US10611747B2 (en) 2015-11-09 2020-04-07 Forge Therapeutics, Inc. Pyrone based compounds for treating bacterial infections
US10414735B2 (en) 2015-11-09 2019-09-17 Forge Therapeutics, Inc. Substituted hydroxypyrimidinones for treating bacterial infections
WO2017083431A3 (fr) * 2015-11-09 2017-08-31 Forge Therapeutics, Inc. Composés à base d'hydroxypyridinone et d'hydroxypyrimidinone pour le traitement d'infections bactériennes
WO2017089347A1 (fr) 2015-11-25 2017-06-01 Inserm (Institut National De La Sante Et De La Recherche Medicale) Procédés et compositions pharmaceutiques pour le traitement de mélanomes résistant aux inhibiteurs de braf
US11046660B2 (en) 2016-09-28 2021-06-29 Mironid Limited Compounds and their use as PDE4 activators
WO2018099884A1 (fr) 2016-12-01 2018-06-07 Koninklijke Philips N.V. Scores de risque basés sur l'expression d'un variant 7 humain de phosphodiestérase 4d
US11021471B2 (en) 2017-05-10 2021-06-01 Forge Therapeutics, Inc. Antibacterial compounds
US11560373B2 (en) 2018-04-04 2023-01-24 Mironid Limited Compounds and their use as PDE4 activators
US11407740B2 (en) 2018-09-20 2022-08-09 Forge Therapeutics, Inc. Antibacterial compounds
US11731962B2 (en) 2020-03-25 2023-08-22 Blacksmith Medicines, Inc. LpxC inhibitor and methods of making

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