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WO2008020302A2 - Heteroaromatic quinoline-based compounds as phosphodiesterase (pde) inhibitors - Google Patents

Heteroaromatic quinoline-based compounds as phosphodiesterase (pde) inhibitors Download PDF

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Publication number
WO2008020302A2
WO2008020302A2 PCT/IB2007/002382 IB2007002382W WO2008020302A2 WO 2008020302 A2 WO2008020302 A2 WO 2008020302A2 IB 2007002382 W IB2007002382 W IB 2007002382W WO 2008020302 A2 WO2008020302 A2 WO 2008020302A2
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Prior art keywords
quinolin
methoxy
quinazoline
disorder
preparation
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PCT/IB2007/002382
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French (fr)
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WO2008020302A3 (en
Inventor
Christopher John Helal
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Pfizer Products Inc.
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Publication of WO2008020302A2 publication Critical patent/WO2008020302A2/en
Publication of WO2008020302A3 publication Critical patent/WO2008020302A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention pertains to heteroaromatic compounds that serve as effective phosphodiesterase (PDE) inhibitors.
  • PDE phosphodiesterase
  • the invention also relates to compounds which are selective inhibitors of PDE10.
  • the invention further relates to intermediates for preparation of such compounds; pharmaceutical compositions comprising such compounds; and the use of such compounds in methods for treating certain central nervous system (CNS) or other disorders.
  • CNS central nervous system
  • the invention relates also to methods for treating neurodegenerative and psychiatric disorders, for example psychosis and disorders comprising deficient cognition as a symptom.
  • Phosphodiesterases are a class of intracellular enzymes involved in the hydrolysis of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphates (cGMP) into their respective nucleotide monophosphates.
  • the cyclic nucleotides cAMP and cGMP are synthesized by adenylyl and guanylyl cyclases, respectively, and serve as secondary messengers in several cellular pathways.
  • the cAMP and cGMP function as intracellular second messengers regulating a vast array of intracellular processes particularly in neurons of the central nervous system. In neurons, this includes the activation of cAMP and cGMP-dependent kinases and subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission as well as in neuronal differentiation and survival.
  • the complexity of cyclic nucleotide signaling is indicated by the molecular diversity of the enzymes involved in the synthesis and degradation of cAMP and cGMP. There are at least ten families of adenylyl cyclases, two of guanylyl cyclases, and eleven of phosphodiesterases.
  • different types of neurons are known to express multiple isozymes of each of these classes, and there is good evidence for compartmentalization and specificity of function for different isozymes within a given neuron.
  • a principal mechanism for regulating cyclic nucleotide signaling is by phosphodiesterase-catalyzed cyclic nucleotide catabolism.
  • PDEs encoded by 21 different genes. Each gene typically yields multiple splice variants that further contribute to the isozyme diversity.
  • the PDE families are distinguished functionally based on cyclic nucleotide substrate specificity, mechanism(s) of regulation, and sensitivity to inhibitors.
  • PDEs are differentially expressed throughout the organism, including in the central nervous system. As a result of these distinct enzymatic activities and localization, different PDEs' isozymes can serve distinct physiological functions.
  • PDE10 is identified as a unique family based on primary amino acid sequence and distinct enzymatic activity. Homology screening of EST databases revealed mouse PDE10A as the first member of the PDE10 family of PDEs (Fujishige et al., J. Biol. Chem. 274:18438- 18445, 1999; Loughney, K. et al., Gene 234:109-117, 1999). The murine homologue has also been cloned (Soderling, S. et al., Proc. Natl. Acad. Sci.
  • mice PDE10A1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively.
  • the PDE 10 family of polypeptides shows a lower degree of sequence homology as compared to previously identified PDE families and has been shown to be insensitive to certain inhibitors that are known to be specific for other PDE families.
  • PDE10 also is uniquely localized in mammals relative to other PDE families. mRNA for PDE10 is highly expressed only in testis and brain (Fujishige, K. et al., Eur J Biochem. 266:1118-1127, 1999; Soderling, S. et al., Proc. Natl. Acad. Sci. 96:7071-7076, 1999;
  • PDE inhibitors A variety of therapeutic uses for PDE inhibitors has been reported including obtrusive lung disease, allergies, hypertension, angina, congestive heart failure, depression and erectile dysfunction (WO 01/41807 A2, incorporated herein by reference).
  • United States Patent Application Publication No. 2003/0032579 discloses a method for treating certain neurologic and psychiatric disorders with the selective PDE10 inhibitor papaverine.
  • the method relates to psychotic disorders such as schizophrenia, delusional disorders and drug-induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including Parkinson's disease and Huntington's disease.
  • WO2005/120514 discloses a method for treating obesity-related and metabolic syndrome-related conditions by administering a PDE10 inhibitor.
  • the present invention provides for compounds of formula I or pharmaceutical salts thereof,
  • HET 1 is selected from the group consisting of a monocyclic heteroaryl and a bicyclic heteroaryl, wherein said HET 1 may optionally be substituted with at least one R 1 ;
  • B 1 and B 2 are adjacent atoms in Het 1 wherein B 2 is carbon and B 1 is nitrogen.
  • X, Y and Z are each independently N or CR 5 , with the provisos that at least one of X, Y and Z must be CR 5 and when R 4 is O, R 4 is divalent and Z is NR 10 ; wherein each R 1 is independently selected from a group consisting of halogen, hydroxyl, cyano, (CrC 8 )alkyl, (C 2 - C 8 )alkenyl, (C 2 -C 8 )alkynyl, (Ci-C 8 )alkoxy, (C r C 8 )haloalkyl, (C- ⁇ -C 8 )haloalkoxy, (C 3 -C 8 )cycloalkyl, (5-12 membered)heterocycloalkyl, (CrC 8 )alkylthio, - NR 8 R 9 , -C(O)
  • NR 8 R 9 -NHCOR 8 , -OH, (C 6 -C 12 )aryl, (5-12 membered)heteroaryl, (C r C 8 )alkyl, (C r C 8 )alkoxy, (Ci-C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 2 -C 6 )alkenyloxy or (C 3 -C 8 )cycloalkyl;
  • R 4 is hydrogen, O, halogen, cyano, -NR 8 R 9 , -C(O)R 8 , (C r C 6 )alkyl, (C r C 6 )alkoxy, (C 3 -
  • C 12 cycloalkyl, (C r C 6 )haloalkyl, (4-12 membered)heterocycloalkyl, (C 6 -Ci 2 )aryl, -(5-12 membered)heterocycloalkyl-(C 6 -C 12 )aryl, (5-12 membered)heteroaryl, (5-12 membered)heterocycloalkyloxy, (C 6 -Ci 2 )aryloxy, (5-12 membered)heteroaryloxy, -(C 6 -
  • Ci 2 aryl-(Ci-C 6 )alkyl, or -(5-12 membered)heteroaryl-(Ci-C 6 )alkyl, wherein when R 4 is alkyl, alkoxy, cycloalkyl, haloalkyl, heterocycloalkyl, aryl, -heterocycloalkyl-aryl, heteroaryl, heterocycloalkyloxy, aryloxy, heteroaryl, heteroaryloxy, -aryl-alkyl, or -heteroaryl-alkyl, it may be optionally substituted by at least one R 7 ;
  • R 5 is independently hydrogen, halogen, -NR 8 R 9 , hydroxyl, (C r C 8 )alkyl, (CrC 8 )alkoxy, (C r C 8 )haloalkyl, (C r C 8 )hydroxyalkyl or (C 3 -C 8 )cycloalkyl; -A-
  • each R 7 is independently hydrogen, halogen, hydroxy, cyano, -COOH, - COOR 8 , -CONR 8 R 9 , -COR 8 , -NR 8 R 9 , -NHCOR 8 , -HNCOOR 8 , -HNCONHR 8 , (C r C 8 )alkyl, (C r C 8 )alkoxy, (C r C 6 )haloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 2 -C 6 )alkenyloxy, (C 3 - C 8 )cycloalkyl, (C r C 8 )hydroxyalkyl, (C 1 -C 8 )alkoxy-(C 1 -C 8 )alkyl, (C 3 -C 8 )hydroxycycloalkyl, (C 3 - C 8 )cycloalkoxy, -(C r)
  • R 10 is independently hydrogen, (C r C 8 )alkyl, (C r C 8 )haloalkyl, (Ci-C 8 )hydroxyalkyl or (C 3 -C 8 )cycloalkyl; n is 1 , 2 or 3.
  • HET 1 is selected from the group consisting of:
  • HET 1 is selected from the group consisting of
  • R is a phenyl, pyridinyl or a heterocycloalkyl having the formula:
  • R 6 is hydrogen, -COOR 8 , -CONR 8 R 9 , -COR 8 , -NR 8 R 9 , -NHCOR 8 , -OH, -HNCOOR 8 , CN, -HNCONHR 8 , (C r C 6 )alkyl or (C 1 -C 6 ) alkoxy; R 7 is defined above, and p is O or 1.
  • one or two of X, Y and Z are nitrogen. In another embodiment of the present invention, X and Z are nitrogen and Y is CH. In another embodiment of the present invention, the compound has the formula 1B:
  • R 3 is (CrC 8 )alkoxy.
  • HET 1 is selected from:
  • R 4 is a phenyl, pyridinyl or a heterocycloalkyl having the formula:
  • R 6 is hydrogen, -COOR 8 , -CONR 8 R 9 , -COR 8 , -NR 8 R 9 , -NHCOR 8 , -OH, -HNCOOR 8 , -CN, -HNCONHR 8 , (C r C 6 )alkyl or (C r C 6 )alkoxy; wherein R 7 is defined above; and p is 1.
  • R 4 is the heterocycloalkyl of Formula IA wherein R 6 is hydrogen and R 7 is phenyl.
  • X and Z are nitrogen and Y is CH.
  • Compounds of the Formula I may have optical centers and therefore may occur in different enantiomeric and diastereomeric configurations.
  • the present invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of the Formula I, as well as racemic compounds and racemic mixtures and other mixtures of stereoisomers thereof.
  • Pharmaceutically acceptable salts of the compounds of Formula I include the acid addition and base salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts.
  • Examples include, but are not limited to, the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mandelates mesylate, methylsulphate, naphthylate, 2- napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, salicylate, saccharate, stearate
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to, the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • suitable salts see Handbook of Pharmaceutical Salts: Properties,
  • compositions of Formula I may be prepared by one or more of three methods:
  • 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').
  • the compounds of the invention may also exist in unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • a currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995).
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules.
  • the compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically- labeled compounds of Formula I.
  • 'prodrugs' of the compounds of Formula I are also within the scope of the invention.
  • certain derivatives of compounds of Formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula I having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'.
  • Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association).
  • Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
  • prodrugs in accordance with the invention include, but are not limited to, (i) where the compound of Formula I contains a carboxylic acid functionality
  • metabolites of compounds of Formula I that is, compounds formed in vivo upon administration of the drug.
  • Some examples of metabolites in accordance with the invention include, but are not limited to,
  • Compounds of Formual I having a nitrogen atom in a tertiary amine functional group may be further substituted with oxygen (i.e., an N-oxide);
  • Compounds of Formula I containing one or more asymmetric carbon atoms can exist as two or more stereoisomers.
  • a compound of Formula I contains an alkenyl or alkenylene group
  • geometric cisltrans (or Z/E) isomers are possible.
  • structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur.
  • Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
  • enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of Formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to
  • the first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate.
  • Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. EHeI and S. H. Wilen (Wiley, 1994).
  • the present invention includes all pharmaceutically acceptable isotopically-labelled compounds of Formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 I and 125 I, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 O and 18 O, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of Formula I for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 O, d 6 -acetone, d 6 - DMSO.
  • Specific embodiments of the present invention include the compounds exemplified in the Examples below and their pharmaceutically acceptable salts, complexes, solvates, polymorphs, steroisomers, metabolites, prodrugs, and other derivatives thereof;
  • This invention also pertains to a pharmaceutical composition for treatment of certain psychotic disorders and conditions such as schizophrenia, delusional disorders and drug induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including Parkinson's disease and Huntington's disease, comprising an amount of a compound of formula I effective in inhibiting PDE 10.
  • this invention relates to a pharmaceutical composition for treating psychotic disorders and condition such as schizophrenia, delusional disorders and drug induced psychosis; anxiety disorders such as panic and obsessive-compulsive disorder; and movement disorders including Parkinson's disease and Huntington's disease, comprising an amount of a compound of formula I effective in treating said disorder or condition.
  • psychotic disorders and condition such as schizophrenia, delusional disorders and drug induced psychosis
  • anxiety disorders such as panic and obsessive-compulsive disorder
  • movement disorders including Parkinson's disease and Huntington's disease
  • Examples of psychotic disorders that can be treated according to the present invention include, but are not limited to, schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type.
  • Examples of movement disorders that can be treated according to the present invention include but are not limited to selected from Huntington's disease and dyskinesia associated with dopamine agonist therapy, Parkinson's disease, restless leg syndrome, and essential tremor.
  • Other disorders that can be treated according to the present invention are obsessive/compulsive disorders, Tourette's syndrome and other tic disorders.
  • this invention relates to a method for treating an anxiety disorder or condition in a mammal which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE 10.
  • This invention also provides a method for treating an anxiety disorder or condition in a mammal which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder or condition.
  • anxiety disorders examples include, but are not limited to, panic disorder; agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.
  • This invention further provides a method of treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating drug addiction.
  • a drug addiction for example an alcohol, amphetamine, cocaine, or opiate addiction
  • This invention also provides a method of treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE10.
  • a drug addiction for example an alcohol, amphetamine, cocaine, or opiate addiction
  • a “drug addiction”, as used herein, means an abnormal desire for a drug and is generally characterized by motivational disturbances such a compulsion to take the desired drug and episodes of intense drug craving.
  • This invention further provides a method of treating a disorder comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder.
  • This invention also provides a method of treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE10.
  • This invention also provides a method of treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder or condition.
  • deficiency in attention and/or cognition refers to a subnormal functioning in one or more cognitive aspects such as memory, intellect, or learning and logic ability, in a particular individual relative to other individuals within the same general age population.
  • Deficiency in attention and/or cognition also refers to a reduction in any particular individual's functioning in one or more cognitive aspects, for example as occurs in age-related cognitive decline.
  • disorders that comprise as a symptom a deficiency in attention and/or cognition are dementia, for example Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; and age-related cognitive decline.
  • dementia for example Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia
  • delirium amnestic disorder
  • post-traumatic stress disorder mental retardation
  • a learning disorder for example reading disorder, mathematics disorder, or a disorder of written expression
  • attention-deficit/hyperactivity disorder and age
  • This invention also provides a method of treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I effective in treating said disorder or episode.
  • Th is invention also provides a method of treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I effective in inhibiting PDE10.
  • mood disorders and mood episodes that can be treated according to the present invention include, but are not limited to, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post- stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia; a bipolar disorder, for example bipolar I disorder, bipolar Il disorder, and cyclothymic disorder.
  • This invention further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder or condition.
  • This invention further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE10.
  • a neurodegenerative disorder or condition refers to a disorder or condition that is caused by the dysfunction and/or death of neurons in the central nervous system.
  • the treatment of these disorders and conditions can be facilitated by administration of an agent which prevents the dysfunction or death of neurons at risk in these disorders or conditions and/or enhances the function of damaged or healthy neurons in such a way as to compensate for the loss of function caused by the dysfunction or death of at-risk neurons.
  • the term "neurotrophic agent” as used herein refers to a substance or agent that has some or all of these properties.
  • neurodegenerative disorders and conditions that can be treated according to the present invention include, but are not limited to, Parkinson's disease; Huntington's disease; dementia, for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; and multi-system atrophy.
  • the neurodegenerative disorder or condition comprises neurodegeneration of striatal medium spiny neurons in a mammal, including a human.
  • the neurodegenerative disorder or condition is Huntington's disease.
  • This invention also provides a method of treating a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, obesity, mood disorders, and neurodegenerative disorders, which method comprises administering an amount of a compound of formula I effective in treating said disorder.
  • This invention also provides a method of treating disorders selected from the group consisting of: dementia, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; age-related cognitive decline, major depressive episode of the mild, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder
  • This invention also provides a method of treating psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction which method comprises administering an amount of a compound of formula I effective in inhibiting PDE 10.
  • alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.
  • alkenyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above. Examples of alkenyl include, but are not limited to, ethenyl and propenyl.
  • alkynyl as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl.
  • alkoxy refers to an alkyl, groups linked to an oxygen atom.
  • alkylthio as used herein, unless otherwise indicated, employed herein alone or as part of another group includes any of the above alkyl groups linked through a sulfur atom.
  • halogen or "halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine.
  • haloalkyl refers to at least one halo group, linked to an alkyl group. Examples, of haloalkyl groups include, but are not limited, to trifluoromethyl, trifluoroethyl, difluoromethyl and fluoromethyl groups.
  • cycloalkyl includes non- aromatic saturated cyclic alkyl moieties wherein alkyl is as defined above.
  • examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • aryl as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl, naphthyl, indenyl, and fluorenyl. "Aryl” encompasses fused ring groups wherein at least one ring is aromatic.
  • heterocyclic refers to non-aromatic cyclic groups containing one or more heteroatoms, prefereably from one to four heteroatoms, each preferably selected from oxygen, sulfur and nitrogen.
  • heterocyclic groups of this invention can also include ring systems substituted with one or more oxo moieties.
  • non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1 ,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3- dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.
  • heteroaryl refers to aromatic groups containing one or more heteroatoms (preferably oxygen, sulfur and nitrogen), preferably from one to four heteroatoms.
  • a multicyclic group containing one or more heteroatoms wherein at least one ring of the group is aromatic is a "heteroaryl” group.
  • the heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties.
  • Heteroaryl groups containing a tertiary nitrogen may also be further substituted with oxygen (i.e., an N-oxide).
  • heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benz ⁇ thiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl,
  • substituents refers to from one to the maximum number of substituents possible based on the number of available bonding sites.
  • all the foregoing groups derived from hydrocarbons may have up to about 1 to about 20 carbon atoms (e.g. C 1 -C 2O alkyl, C 2 -C 2O alkenyl, C 3 -C 20 cycloalkyl, 3-20 membered heterocycloalkyl; C 6 -C 2O aryl, 5-20 membered heteroaryl, etc.) or 1 to about 15 carbon atoms (e.g., CrCi 5 alkyl, C 2 -Ci 5 alkenyl, C 3 -C 15 cycloalkyl, 3-15 membered heterocycloalkyl, C 6 -Ci 5 aryl, 5-15 membered heteroaryl, etc.) , or 1 to about 12 carbon atoms, or 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms.
  • carbon atoms e.g. C 1 -C 2O alkyl, C 2 -C 2O alkenyl, C 3 -
  • Neurotoxins poisoning refers to poisoning caused by a neurotoxin.
  • a neurotoxin is any chemical or substance that can cause neural death and thus neurological damage.
  • An example of a neurotoxin is alcohol, which, when abused by a pregnant female, can result in alcohol poisoning and neurological damage known as Fetal Alcohol Syndrome in a newborn.
  • Other examples of neurotoxins include, but are not limited to, kainic acid, domoic acid, and acromelic acid; certain pesticides, such as DDT; certain insecticides, such as organophosphates; volatile organic solvents such as hexacarbons (e.g. toluene); heavy metals (e.g.
  • selective PDE10 inhibitor refers to a substance, for example an organic molecule, that effectively inhibits an enzyme from the PDE10 family to a greater extent than enzymes from the PDE 1-9 families or PDE11 family.
  • a selective PDE10 inhibitor is a substance, for example an organic molecule, having a Ki for inhibition of PDE10 that is less than or about one-tenth the Kj that the substance has for inhibition of any other PDE enzyme. In other words, the substance inhibits PDE10 activity to the same degree at a concentration of about one-tenth or less than the concentration required for any other PDE enzyme.
  • a substance is considered to effectively inhibit PDE10 activity if it has a K] of less than or about 10 ⁇ M, preferably less than or about 0.1 ⁇ M.
  • a "selective PDE10 inhibitor” can be identified, for example, by comparing the ability of a substance to inhibit PDE10 activity to its ability to inhibit PDE enzymes from the other PDE families. For example, a substance may be assayed for its ability to inhibit PDE10 activity, as well as PDE1A, PDE1B, PDE1C, PDE2, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5, PDE6, PDE7, PDE8, PDE9, and PDE11.
  • treating refers to reversing, alleviating, or inhibiting the progress of the disorder to which such term applies, or one or more symptoms of the disorder.
  • the term also encompasses, depending on the condition of the patient, preventing the disorder, including preventing onset of the disorder or of any symptoms associated therewith, as well as reducing the severity of the disorder or any of its symptoms prior to onset.
  • Treating refers also to preventing a recurrence of a disorder.
  • treating schizophrenia, or schizophreniform or schizoaffective disorder also encompasses treating one or more symptoms (positive, negative, and other associated features) of said disorders, for example treating, delusions and/or hallucination associated therewith.
  • symptoms of schizophrenia and schizophreniform and schizoaffec ive disorders include disorganized speech, affective flattening, alogia, anhedonia, inappropriate affect, dysphoric mood (in the form of, for example, depression, anxiety or anger), and some indications of cognitive dysfunction.
  • mammal refers to any member of the class “Mammalia”, including, but not limited to, humans, dogs, and cats.
  • the compound of the invention may be administered either alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses.
  • suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • the pharmaceutical compositions formed thereby can then be readily administered in a variety of dosage forms such as tablets, powders, lozenges, liquid preparations, syrups, injectable solutions and the like.
  • These pharmaceutical compositions can optionally contain additional ingredients such as flavorings, binders, excipients and the like.
  • the compound of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous), transdermal (e.g. patch) or rectal administration, or in a form suitable for administration by inhalation or insufflation.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycolate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycolate
  • wetting agents
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
  • suspending agents e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats
  • emulsifying agents e.g. lecithin or acacia
  • non-aqueous vehicles e.g. almond oil, oily esters or ethyl alcohol
  • preservatives e.g
  • the composition may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in ampules or in multi-dose containers, with an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • a product solution When a product solution is required, it can be made by dissolving the isolated inclusion complex in water (or other aqueous medium) in an amount sufficient to generate a solution of the required strength for oral or parenteral administration to patients.
  • the compounds may be formulated for fast dispersing dosage forms (fddf), which are designed to release the active ingredient in the oral cavity. These have often been formulated using rapidly soluble gelatin-based matrices. These dosage forms are well known and can be used to deliver a wide range of drugs. Most fast dispersing dosage forms utilize gelatin as a carrier or structure-forming agent. Typically, gelatin is used to give sufficient strength to the dosage form to prevent breakage during removal from packaging, but once placed in the mouth, the gelatin allows immediate dissolution of the dosage form. Alternatively, various starches are used to the same effect.
  • the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compound of the invention is conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlor
  • the dosage unit may be determined by providing a valve to deliver a metered amount.
  • the pressurized container or nebulizer may contain a solution or suspension of the active compound.
  • Capsules and cartridges made e.g. from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • Aerosol formulations for treatment of the conditions referred to above are preferably arranged so that each metered dose or "puff' of aerosol contains about 20 mg to about 1000 mg of the compound of the invention.
  • the overall daily dose with an aerosol will be within the range of about 100 mg to about 10 mg.
  • Administration may be several times daily, e.g. 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
  • a proposed daily dose of the compound of the invention for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.
  • Assay methods are available to screen a substance for inhibition of cyclic nucleotide hydrolysis by the PDE 10 and the PDEs from other gene families.
  • the cyclic nucleotide substrate concentration used in the assay is 1/3 of the K m concentration, allowing for comparisons of IC 50 values across the different enzymes.
  • PDE activity is measured using a Scintillation Proximity Assay (SPA)-based method as previously described (Fawcett et al., 2000).
  • SPA Scintillation Proximity Assay
  • PDE inhibitors The effect of PDE inhibitors is determined by assaying a fixed amount of enzyme (PDEs 1-11) in the presence of varying substance concentrations and low substrate, such that the IC 50 approximates the Ki (cGMP or cAMP in a 3:1 ratio unlabelled to [ 3 H]-Iabeled at a concentration of 1/3 Km). ).
  • the final assay volume is made up to 100 ⁇ l with assay buffer [50 mM Tris-HCI pH 7.5, 8.3 mM MgCI 2 , 1 mg/ml bovine serum albumin].
  • Reactions are initiated with enzyme, incubated for 30-60 min at 30°C to give ⁇ 30% substrate turnover and terminated with 50 ⁇ l yttrium silicate SPA beads (Amersham) (containing 3 mM of the respective unlabelled cyclic nucleotide for PDEs 9 and 11). Plates are re-sealed and shaken for 20 min, after which the beads were allowed to settle for 30 minutes in the dark and then counted on a TopCount plate reader (Packard, Meriden, CT). Radioactivity units can be converted to percent activity of an uninhibited control (100%), plotted against inhibitor concentration and inhibitor IC 50 values can be obtained using the "Fit Curve' Microsoft Excel extension.
  • Step 1 of Scheme 1 is a nucleophilic displacement of a chloride with an amine.
  • Step 2 of Scheme 1 is a dealkylation reaction.
  • Step 3 of Scheme 1 is an alkylation reaction.
  • Step 1 of Scheme 2 is a Suzuki coupling reaction.
  • a palladium catalyst such as Pd 2 (dba) 3 , tricyclohexylphosphine, and cesium carbonate in dioxane at about 100 0 C affords compound 2.
  • Step 2 of Scheme 2 is a dealkylation reaction.
  • Step 3 of Scheme 1 is an alkylation reaction.
  • Step 1 of Scheme 3 is a reductive dehalogenation. Exposure of 6,7-dimethoxy-2,4- dichloroquinazoline and palladium on carbon (about 10%) in a solvent such as methanol and in the presence of a base such as triethylamine to a hydrogen atmosphere, from about 10 to 60 psi, where about 40 psi is preferred, at about room temperature, affords compound 2.
  • Step 2 of Scheme 3 is a dealkylation reaction.
  • Step 3 of Scheme 1 is an alkylation reaction.
  • Step 1 of Scheme 4 is a heterocyclization reaction.
  • a formyl source such as formamidine acetate in a solvent such as ethylene glycol monomethylether at about 13O 0 C for about 24 h affords compound 3.
  • Step 2 of Scheme 4 is a nucleophilic aromatic substitution reaction.
  • Step 3 of Scheme 4 is a dehydrative chlorination.
  • Step 4 of Scheme 4 is a Suzuki coupling reaction.
  • Treatment of compound 5 with an aryl or heteroaryl boronic acid or boronate or dialkylborane, a palladium catalyst such as Pd 2 (dba) 3 , tricyclohexylphosphine, and cesium carbonate in dioxane at about 100 0 C affords compound 6.
  • Step 5 of Scheme 4 is a dealkylation reaction.
  • Step 6 of Scheme 4 is an alkylation reaction.
  • Step 2 of Scheme 5 is an esterification.
  • Step 3 of Scheme 5 is an alkylation reaction.
  • Step 4 of Scheme 5 is a nitro reduction to an amine.
  • Step 5 of Scheme 5 is a hydrolysis.
  • Step 6 of Scheme 5 is a heterocycle forming reaction.
  • Step 7 of Scheme 5 is a dehydrative chlorination.
  • Step 8 of Scheme 5 is A) a Suzuki coupling reaction.
  • Treatment of compound 9 with an aryl or heteroaryl boronic acid or boronate or dialkylborane, a palladium catalyst such as Pd 2 (dba) 3 , tricyclohexylphosphine, and cesium carbonate in dioxane at about 100 0 C affords compound 10; or B) a nucleophilic displacement of a chloride with an amine.
  • Step 9 of Scheme 5 is a dealkylation reaction.
  • Step 10 of Scheme 5 is an alkylation reaction.
  • Step 11 of Scheme 5 is a heterocycle forming reaction.
  • Step 1 of Scheme 6 is an amide forming reaction.
  • Step 2 of Scheme 6 is a heterocycle forming reaction.
  • Treatment of compound 3 with triethyl orthoformate and anhydrous hydrogen chloride in N-methylpyrolidinone at about 120 0 C for about 24 h affords compound 4.
  • Step 3 of Scheme 6 is a dealkylation reaction.
  • Step 4 of Scheme 6 is an alkylation reaction.
  • a diazodicarboxylate such as ditertbutyl azodicarboxylate or diethylazodicarboxylate
  • triphenylphosphine in a solvent such as THF
  • Preparation 2 7-methoxy-4-(3-phenylpiperidin-1 -yl)quinazolin-6-ol: Preparation 1 (2.8 g, 8 mmol) was treated with L-methionine (1.43 g, 9.6 mmol) in methanesulfonic acid (40 mL). The mixture was heated to 120 0 C for 2 h, 14O 0 C for 5 h, then 145 0 C for 1 h. The mixture was poured onto ice, the pH was made basic by using sodium hydroxide (pH ca. 8-9), and the mixture was extracted with chloroform.
  • Preparation 3 7-methoxy-4-(3-phenylpiperidin-1-yl)-6-(prop-2-vnyloxy)quinazoline: A mixture of Preparation 2 (500 mg, 1.49 mmol), propargyl bromide (80% in toluene, 0.25 mL, 2.24 mmol) and cesium carbonate (1g, 3 mmol) in DMSO (10 mL) were stirred for 24 h. The mixture was diluted with ethylacetate (100 mL) and n-butanol (5 mL), was washed with water and brine, was dried over magnesium sulfate, was filtered, and was concentrated. Purification by silica gel chromatography afforded 355 mg (64% yield) of the title compound; MS (AP/CI): 374.5 (M+H)+.
  • Example 1 7-methoxy-4-(3-pheny ) piperidin-1-yl)-6-(2-quinolin-2- ylethoxy)quinazoline: Di-tertbutyl azodicarboxylate (92 mg, 0.4 mmol) was mixed with triphenylphosphine (131 mg, 0.5 mmol) in THF (2 mL) at room temperature for 10 min. 3-(1- Preparation 2 (67 mg, 0.2 mmol) was added followed by 2-(quinolin-2-yl)ethanol (138 mg, 0.8 mmol) and the solution was stirred at room temperature for 24 h.
  • the reaction mixture was diluted with ethyl acetate, was washed with aqueous sodium bicarbonate, water, and then brine, was dried over magnesium sulfate, was filtered, and was concentrated in vacuo.
  • the residue was dissolved in methylene chloride and was applied to a 6 mL column packed with 1 g of silica-bound p-toluene sulfonic acid (Silicycle).
  • the column was eluted by gravity with 2 column volumes (cv) of methylene chloride, 3 cv of methanol to remove reaction by-products, then was eluted with 4 cv of 1 N triethylamine in methanol to remove the product.
  • Example 2 7-methoxy-6-r3-(1 -methyl- 1 H-benzimidazol-2-ylbropoxyl-4-(3- phenylpiperidin-1-vn ⁇ uinazoline: Using Preparation 2 and 3-(1-methyl-1H-benzo[d]imidazol-2- yl)propan-1-ol, the general procedure in Example 1 was used for the synthesis of the title compound in 49% yield; 13C NMR (100 MHz, CD3OD) ⁇ ppm 163.838, 155.478, 154.670, 152.031 , 147.971 , 147.746, 143.312, 141.480, 135.632, 128.671 , 127.100, 126.891 , 122.651 , 122.404, 118.112, 111.001 , 109.648, 105.894, 105.064, 67.803, 56.624, 55.861 , 50.432, 43.104, 32.149,
  • Example 5 7-methoxy-4-(3-phenylpiperidin-1 -yl)-6-IY3-quinolin-2-ylprop-2-yn-1 - vDoxylquinazoline: 2-lodoquinoline (240 mg, 0.94 mmol) was mixed with Preparation 3 (350 mg, 0.94 mmol), copper(l) iodide (23 mg, 0.12 mmol), dichloropalladium bis(triphenylphosine) (23 mg, 0.033 mmol), triethylamine (2 mL), diisopropylamine (2 mL) in chloroform (2 mL) and methanol (2 mL). The mixture was stirred at room temperature for 24 h.
  • Example 6 7-methoxy-4-(3-phenylpiperidin-1 -yl)-6-(3-quinolin-2- ylpropoxy)quinazoline:
  • Example 5 50 mg, 0.1 mmol was mixed with Raney nickel (20 mg) in ethylacetate (10 ml). The mixture was placed under 50 psi hydrogen and was shaken at room temperature for 4 h.
  • Preparation 6 methyl 5-hvdroxy-4-methoxy-2-nitrobenzoate: Preparation 5 (15 g, 70.4 mmol) in methanol (100 mL) was treated with concentrated sulfuric acid (10 mL). The mixture was heated at reflux for 48 h. After cooling to room temperature, the methanol was removed under reduced pressure, the resulting residue was diluted with water and was extracted with ethylacetate. The organic layer was washed with water and then brine, was dried over magnesium sulfate, was filtered, and was concentrated to afford 15.4 g (96% yield) of the title compound; MS (AP/CI): 228 (M+H)+; 226 (M-H)-.
  • Preparation 8 methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate: Preparation 7 (20 g, 63 mmol) was mixed with ammonium chloride (50.6 g, 945 mmol) in methanol (200 mL) and water (50 mL), then iron poiser (35.3 g, 630 mmol) was added and the mixture was heated at 9O 0 C for 24 h. The mixture was filtered while hot through Celite and the filter cake was washed with methylene chloride and water. The aqueous and organic layers were separated and the aqueous layer was made basic with sodium bicarbonate and was extracted with methylene chloride.
  • Preparation 11 6-(benzyloxy)-4-chloro-7-methoxyquinazoline: Preparation 10 (4.85 g, 17.2 mmol) in phosphorous oxychioride (25 mL) was heated to 12O 0 C for 3 h. After cooling to room temperature, the phosphorous oxychioride was removed in vacuo, the residue was slowly added to saturated aqueous potassium carbonate and the mixture was stirred until bubbling ceased.
  • Preparation 12 6-(benzyloxy)-7-methoxy-4-phenylquinazoline:
  • Preparation 11 (1 g, 3.3 mmol) was mixed with phenylboronic acid (0.5 g, 4 mmol), Pd 2 (dba) 3 -CHCI 3 (72 mg, 0.07 mmol), tricyclohexyl phosphine (56 mg, 0.2 mmol), and cesium carbonate (1.6 g, 5 mmol) in 1 ,4-dioxane (10 mL) was heated at 100 0 C for 24 h. After cooling to room temperature, solvent was removed in vacuo. The residue was diluted with water and 1N NaOH and was extracted with chloroform.
  • Preparation 14 6-(benzyloxyV7-methoxy-4-(pyridin-4-vQquinazoline: Using 4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine and Preparation 11, the general procedure in Preparation 12 was used to synthesize the title compound in 41% yield; MS (AP/CI): 344.1 (M+H)+.
  • Preparation 15 6-(benzyloxy)-7-methoxy-4-(3-(trifluoromethyl)phenvQquinazoline: Using Preparation 11 and 3-trifluromethylphenyl boronic acid, the general procedure in Preparation 12 was used to prepare the title compound in 65% yield.; MS (AP/CI): 411.0 (M+H)+.
  • Preparation 16 7-methoxy-4-phenylquinazolin-6-ol: Preparation 12 (0.62 g, 1.8 mmol) was added to anisole (3.9 mL, 36 mmol) in trifluoracetic acid (25 mL). The mixture was heated to 75 0 C for 24 h. After cooling, the mixture was concentrated and was purified by silica gel chromatography (50:1 chloroform-methanol) to afford 430 mg (95% yield) of the title compound; MS (AP/CI) 253.1 (M+H)+.
  • Preparation 17 7-methoxy-4-(pyridin-3-v ⁇ quinazolin-6-ol: Using Preparation 13, the general procedure in Preparation 16 was used to prepare the title compound in 94% yield; MS (AP/CI): 254.1 (M+H)+.
  • Preparation 18 7-methoxy-4-(pyridin-4-yl ' )quinazolin-6-ol: Using Preparation 14, the general procedure in Preparation 16 was used to prepare the title compound in 81 % yield.; MS (AP/CI): 254.1 (M+H)+.
  • Example 8 7-methoxy-6-f3-(1-methyl-1 H-benzimidazol-2-vDpropoxy
  • p-TsCI resin Arnaut Labs
  • diisopropyl ethyl amine diisopropyl ethyl amine
  • Example 13 7-methoxy-4-pyridin-3-yl-6-(quinolin-2-ylmethoxy)quinazoline
  • Example 15 7-methoxy-4-phenyl-6-(quinolin-2-ylmethoxy)quinazoline: Using
  • Preparation 21 6-methoxyquinazolin-7-ol: 6,7-Dimethoxyquinazoline (Preparation 20, 2.3 g, 12 mmol) and L-methionine (2.1 g, 14.4 mmol) in methanesulfonic acid (60 mL) was heated as follows: 120 0 C, 1 h; 14O 0 C, 2 h; 145 0 C, 4 h; 120°C, 16 h. More L-methionine (0.5 g) was added and the mixture was heated at 145°C for 6 h and 120 0 C for 16 h.
  • Preparation 23 6-(benzyloxy)-7-methoxy-N,N-dimethylquinazolin-4-amine: Using Preparation 11 and dimethylamine, the general procedure used to synthesize Preparation 22 was used to prepare the title compound in 86% yield.; MS (AP/CI): 310.1 (M+H)+.
  • Preparation 24 6-(benzyloxyVN,N-diethyl-7-methoxyquinazolin-4-amine: Using
  • Preparation 27 6-(benzyloxyV7-methoxy-4-(piperidin-1 -vDquinazoline: Using Preparation 11 and piperidine, the general procedure in Preparation 22 was used to prepare the title compound in 89% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 24.9, 26.2,
  • Preparation 28 4-(dimethylamino)-7-methoxyquinazolin-6-ol: Using Preparation 23, the general procedure in Preparation 16 was used to prepare the title compound in 99% yield.; MS (AP/CI): 220.2 (M+H)+.
  • Preparation 29 4-(diethylamino)-7-methoxyquinazolin-6-ol: Using Preparation 24, the general procedure in Preparation 16 was used to prepare the title compound in 98% yield.; MS (AP/CI): 248.1 (M+H)+.
  • Preparation 30 4-(azetidin-1-yl)-7-methoxyquinazolin-6-ol: Using Preparation 25, the general procedure in Preparation 16 was used to prepare the title compound in 99% yield.; MS (AP/CI): 232.2 (M+H)+.
  • Preparation 31 7-methoxy-4-fpyrrolidin-1-yl)quinazolin-6-ol: Using Preparation 26, the general procedure in Preparation 16 was used to prepare the title compound in 99% yield.; MS (AP/CI): 246.3 (M+H)+.
  • Preparation 32 7-methoxy-4-(piperidin-1-v ⁇ quinazolin-6-ol: Using Preparation 27, the general procedure in Preparation 16 was used to prepare the title compound in 99% yield.; 13C NMR (101 MHz, METHANOL-D4) d ppm 24.1 , 26.4, 50.8, 56.5, 99.5, 107.0, 109.3, 136.4, 145.7, 147.6, 156.2, 161.2; MS (AP/CI): 260.3 (M+H)+
  • Preparation 33 7-methoxy-4-morpholino ⁇ uinazolin-6-ol: Using Preparation 22, the general procedure in Preparation 16 was used to prepare the title compound in 99% yield.; MS (AP/CI): 262.1 (M+H)+.
  • Preparation 36 6,7-dimethoxy-4-(pyridin-4-yl)quinazoline: Using 4-chloro-6,7- dimethoxyquinazoline and 4-pyridylboronic acid, the general procedure in Preparation 12 was used in the synthesis of the title compound in 33% yield.; MS (AP/Cl): 268.2 (M+H)+.
  • Preparation 37 6-methoxy-4-phenylquinazolin-7-ol:
  • Preparation 34 1.5 g, 5.64 mmol
  • L-methionine 1.0 g, 6.77 mmol
  • methanesulfonic acid 30 mL
  • the mixture was poured onto ice, the pH was adjusted to a range of 7-8 by using sodium hydroxide, and the mixture was extracted with methylene chloride.
  • the organic layer was dried over magnesium sulfate, was filtered, and was concentrated.
  • the residue was purified by silica gel chromatography (chloroform-methanol, 100:1 ), to afford 0.5 g (35% yield) of the title compound.; MS (AP/Cl): 253.2 (M+H)+.
  • Preparation 38 6-methoxy-4-(pyridin-3-v0quinazolin-7-ol: The same general procedure used to synthesize Preparation 7 was employed, with the change of heating temperatures and times as follows: 120°C, 16 h; then 14O 0 C, 4 h. Following work-up, the aqueous phase was extracted continuously with chloroform ("heavier-than-water" continuous extractor used) for two days. The organic layers were combined, solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (chloroform- methanol, 40:1 ). The final product was obtained in 50% yield.; MS (AP/Cl): 254.2 (M+H)+.
  • Example 27 6-methoxy-4-phenyl-7-(quinolin-2-ylmethoxy)quinazoline: Using Preparation 39 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used
  • Example 31 6-methoxy-4-pyridin-4-yl
  • Example 32 6-methoxy-7-f3-(1-methyl-1 H-benzimidazol-2-ylbropoxyl-4-pyridin-3- ylquinazoline: Using Preparation 38 and 3-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-1-ol, the general procedure in Example 1 was used for the synthesis of the title compound in 75% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 161.96, 155.55, 154.12, 153.80, 151.28, 150.93, 150.31 , 149.47, 137.28, 135.89, 133.91 , 123.98, 122.48, 122.25, 119.30, 118.98, 109.20, 108.17, 103.18, 68.32, 56.26, 29.91 , 26.73, 23.98; MS (AP/CI): 426.3 (M+H)+ ;
  • Preparation 40 6-(benzyloxy)-4-chloroquinazoline: The title compound was prepared in a manner analogous to that described for Preparation 11 , using 5-hydroxy-2-nitrobenzoic acid as the starting material in the sequence. MS (AP/CI): 271.1 , 273.1 (M+H)+.
  • Preparation 41 6-(benzyloxy)-4-phenyl ⁇ uinazoline: Using Preparation 40 and phenyl boronic acid, the general procedure in Preparation 12 was used to synthesize the title compound in 48% yield. MS (AP/CI): 313.1 (M+H)+.
  • Preparation 42 6-(benzyloxy)-4-(pyridin-3-yl)quinazoline: Using 3- (diethylboryl)pyridine and Preparation 40, the general procedure in Preparation 12 was used to synthesize the title compound in 30% yield. MS (AP/CI): 314.1 (M+H)+.
  • Preparation 43 6-(benzyloxy)-4-(pyridin-4-yl)quinazoline: Using 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine and Preparation 40, the general procedure in Preparation 12 was used to synthesize the title compound in 41% yield. MS (AP/CI): 314.1 (M+H)+.
  • Preparation 40 and 3-acetylphenyl boronic acid the general procedure in Preparation 12 was used to synthesize the title compound in 72% yield.
  • Preparation 48 4-(pyridin-4-yl)quinazolin-6-ol: Using Preparation 43, the general procedure in Preparation 16 was used to synthesize the title compound in 86% yield. MS (AP/CI): 224.1 (M+H)+.
  • Preparation 49 4-(3-(trifluoromethyl)phenyl)quinazolin-6-ol: Using Preparation 44, the general procedure in Preparation 16 was used to synthesize the title compound in 87% yield. MS (AP/CI): 291.0 (M+H)+.
  • Preparation 50 i-O-fe-hydroxyquinazolin ⁇ -vDphenvOethanone: Using Preparation 45, the general procedure in Preparation 16 was used to synthesize the title compound in 95% yield. MS (AP/CI): 265.1 (M+H)+.
  • Example 35 4-phenyl-6-(quinolin-2-ylmethoxy)quinazoline: Using Preparation 46 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 81% yield.
  • Example 36 4-pyridin-4-yl-6-(quinolin-2-ylmethoxykiuinazoline: Using Preparation 48 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 81 % yield.
  • Example 39 1 -(3-r6-(quinolin-2-ylmethoxy)quinazolin-4-v ⁇ phenyl ⁇ ethanol: A solution of Example 38 (100 mg, 0.25 mmol) in methanol (2 mL) at O 0 C was treated with sodium borohydride (19 mg, 0.5 mmol). The mixture was warmed to room temperature and was stirred for 2h. The solvent was removed in vacuo, the residue was diluted with ethyl acetate and was washed with brine, was dried (magnesium sulfate), was filtered, and was concentrated. Purification by silica gel chromatography (chloroform-methanol, 50:1 ), gave 100 mg (98% yield) of the title compound.
  • Example 40 2- ⁇ 3-f6-(quinolin-2-ylmethoxy)quinazolin-4-v ⁇ phenyl ⁇ propan-2-ol: A solution of Example 38 (100 mg, 0.25 mmol) in THF (2 mL) at -40 0 C was treated dropwise with MeMgBr (0.27 mL, 0.375 mmol, 1.4 M in toluene/THF (3:1)). The mixture was stirred at - 4O 0 C for 1h, O 0 C for 3h, was cooled back to -4O 0 C and additional MeMgBr solution (0.4 mL) was added and the mixture was stirred at O 0 C for 2h.
  • MeMgBr 0.27 mL, 0.375 mmol, 1.4 M in toluene/THF (3:1)
  • Example 41 4-phenyl-6-(2-quinolin-2-ylethoxy)quinazoline: Using Preparation 46 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 32% yield.
  • 13C NMR (101 MHz 1 CHLOROFORM-D) d ppm 38.7 (s, 1 C) 67.9 (s, 1 C) 105.3 (s, 1 C) 122.3 (s, 1 C) 124.3 (s, 1 C) 126.4 (s, 1 C) 127.0 (s, 1 C) 127.8 (s, 1 C) 129.0 (s, 1 C) 129.8 (s, 1 C) 129.9 (s, 1 C) 130.1 (s, 1 C) 130.5 (s, 1 C) 136.8 (s, 1 C) 137.6 (s, 1 C) 147.5 (s, 1 C) 148.1 (s, 1 C) 153.1 (s, 1 C) 157.9 (s, 1 C) 158.9 (
  • Example 43 4-pyridin-3-yl-6-(2-quinolin-2-ylethoxy)quinazoline: Using Preparation 47 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 47% yield.
  • 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.6 (s, 1 C) 68.0 (s, 1 C) 104.4 (s, 1 C) 122.2 (s, 1 C) 124.3 (s, 1 C) 126.4 (s, 1 C) 127.2 (s, 1 C) 127.4 (s, 1 C) 127.8 (s, 1 C) 129.0 (s, 1 C) 129.9 (s, 1 C) 130.8 (s, 1 C) 136.9 (s, 1 C) 137.2 (s, 1 C) 147.6 (s, 1 C) 148.0 (s, 1 C) 150.4 (s, 1 C) 151.0 (s, 1 C) 153.1 (s, 1 C) 158.3 (
  • Example 44 6-(2-quinolin-2-ylethoxy)-4-f3-(trifluoromethyl)phenvnquinazoline: Using Preparation 49 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 45% yield.
  • Preparation 51 7-fluoroquinazolin-4(3H)-one: A mixture of 2-amino-4-fluorobenzoic acid (1.5 g, 9.4 mmol) and formamidine acetate (2.Og, 18.8 mmol) in ethyleneglycol monomethyl ether (15 mL) was heated at 13O 0 C for 24 h. After cooling to room temperature, ca. half of the solvent was evaporated and a white solid precipitated. Aqueous ammmonia (2 mL of 30% ammonium hydroxide in 20 mL water) was added and the solid was filtered, was washed with water, was washed with hexanes, and was dried in vacuo to give 1.4 g (91% yield) of the title compound. MS (AP/CI): 165.2 (M+H)+.
  • Preparation 52 7-(benzyloxy)quinazolin-4(3H)-one: Sodium hydride (60% dispersion, 0.3 g, 7.3 mmol) was added to a solution of benzyl alcohol (0.76 mL, 7.3 mmol) in dimethylformamide (DMF 1 8 mL). Preparation 51 (300 mg, 1.8 mmol) was added and the mixture was heated to 140 0 C for 4 h. After cooling to room temperature, concentrated hydrochloric acid was added, which afforded a precipitate.
  • DMF 1 8 mL dimethylformamide
  • Preparation 54 7-(benzyloxy)-4-phenylquinazoline: Using Preparation 53 and 4- phenylboronic acid, the procedure in Preparation 12 afforded the title compound in 50% yield.
  • Preparation 57 7-(benzyloxy)-4-(4-methoxyphenyl)quinazoline: Using Preparation 53 and 4-methoxyphenylboronic acid, following the procedure in Preparation 12 afforded the title compound in 45% yield. MS (AP/CI): 343.3 (M+H)+.
  • Preparation 58 7-(benzyloxy)-4-(3-methoxyphenyl ' )quinazoline: Using Preparation 53 and 3-methoxyphenylboronic acid, following the procedure in Preparation 12 afforded the title compound in 51% yield. MS (AP/CI): 343.4 (M+H)+.
  • Preparation 59 4-phenylquinazolin-7-ol: A mixture of Preparation 54 (0.55 g, 1.76 mmol) and 10% palladium on carbon (100 mg), in methanol (20 mL) was placed under 50 psi hydrogen and was shaken for 24 h at room temperature. The mixture was filtered through
  • Preparation 60 4-(pyridin-3-vQquinazolin-7-ol: Using Preparation 55 and the general procedure from Preparation 16, the title compound was prepared in 77% yield. MS (AP/CI): 224.2 (M+H)+.
  • Preparation 61 4-(pyridin-4-v ⁇ uinazolin-7-ol: Using the mixture from Preparation 56 and the general procedure from Preparation 16, the title compound was prepared in 4% yield over two steps. MS (AP/CI): 224.2 (M+H)+.
  • Preparation 62 4-(3-methoxyphenyl)quinazolin-7-ol: Using Preparation 58, the general procedure in Preparation 59 was used to prepare the title compound in 30% yield. MS (AP/CI): 253.3 (M+H)+.
  • Preparation 63 4-(4-methoxyphenv0 ⁇ uinazolin-7-ol: Using Preparation 57, the general procedure in Preparation 59 was used to prepare the title compound in 22% yield. MS (AP/CI): 253.3 (M+H)+.
  • Example 45 4-pyridin-4-yl-7-(quinolin-2-ylmethoxy)quinazoline: Using Preparation
  • Example 46 4-phenyl-7-( ⁇ uinolin-2-ylmethoxy) ⁇ uinazoline: Using Preparation 59 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 58% yield.
  • Example 48 4-(3-methoxyphenyl)-7-(quinolin-2-ylrnethoxy)quinazoline: Using Preparation 62 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 60% yield.
  • Example 49 4-(4-methoxyphenyl)-7-(quinolin-2-ylmethoxy)quinazoline: Using Preparation 63 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 85% yield.
  • Preparation 65 6-hvdroxy-7-methoxy-3-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one: Using Preparation 64, the general procedure in Preparation 16 was used to prepare the title compound in 81% yield. MS (AP/CI): 275.0 (M+H)+.
  • Preparation 66 6-(benzyloxy)-3-ethyl-7-metho ⁇ yquinazolin-4(3H)-one: Using ethylamine, the general procedure in Preparation 64 was used to prepare the title compound in 40% yield. MS (AP/CI): 311.1 (M+H)+.
  • Preparation 67 3-ethyl-6-hvdroxy-7-metho ⁇ yquinazolin-4(3H)-one: Using Preparation 66, the general procedure in Preparation 16 was used to prepare the title compound in 72% yield. MS (AP/CI): 221.1 (M+H)+ ;l.
  • Preparation 68 6-(benzyloxyV3-isobutyl-7-methoxyquinazolin-4(3H)-one: Using isobutylamine, the general procedure in Preparation 64 was used to prepare the title compound in 16% yield. MS (AP/CI): 339.1 (M+H)+.
  • Preparation 70 6-(benzyloxy)-3-cvclopropyl-7-methoxyquinazolin-4(3H)-one: Using cyclopropylamine, the general procedure in Preparation 64 was used to prepare the title compound in 81 % yield. MS (AP/CI): 323.0 (M+H)+.
  • Preparation 71 3-cvclopropyl-6-hvdroxy-7-methoxyquinazolin-4(3H)-one: Using
  • Preparation 70 the general procedure in Preparation 16 was used to prepare the title compound in 86% yield. MS (AP/CI): 233.1 (M+H)+.
  • Preparation 72 6-(benzyloxy)-7-methoxy-3-(2-methoxyethv ⁇ quinazolin-4(3H)-one: Using 2-methoxyethylamine, the general procedure in Preparation 64 was used to prepare the title compound in 27% yield. MS (AP/CI): 341.1 (M+H)+.
  • Preparation 74 2-amino-4,5-dimethoxy-N-methylbenzamide: Methylamine (15 mL, 30 mmol, 2 M in THF) and 2-amino-4,5-dimethoxybenzoic acid in DMF (15 mL) were treated with 1-hydroxybenzotriazole (4.3g, 31.5 mmol) and dicyclohexylcarbodiimide (6.5 g, 31.5 mmol). After stirring at room temperature for 24 h, the existing solid was filtered offand was washed with chloroform. The filtrate was concentrated, was diluted with ethyl acetate, and the solution was washed with aqueous sodium bicarbonate, then was extracted with 2N HCI.
  • Methylamine 15 mL, 30 mmol, 2 M in THF
  • 2-amino-4,5-dimethoxybenzoic acid in DMF 15 mL
  • 1-hydroxybenzotriazole 4.3g, 31.5 mmol
  • Preparation 77 the general procedure in Preparation 16 was used to prepare the title compound in 95% yield. MS (AP/CI): 261.1 (M+H)+ .
  • Preparation 79 6-(benzyloxy)-3-isopropyl-7-methoxyquinazolin-4(3H)-one: Using isopropylamine the general procedure in Preparation 64 was used used to prepare the title compound in 50% yield. MS (AP/CI): 325.0 (M+H)+.
  • Preparation 80 6-hvdroxy-3-isopropyl-7-methoxyquinazolin-4(3H)-one: Using
  • Example 51 3-ethyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)-one: Using Preparation 67 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 64% yield. Diagnostic 13C NMR signals (101 MHz, CHLOROFORM-D) d ppm 15.2 (s, 1 C) 38.6 (s, 1 C) 42.3 (s, 1 C) 56.4 (s, 1 C) 61.6 (s, 1 C)
  • Example 52 3-isobutyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)-one: Using Preparation 69 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 66% yield.
  • Example 53 3-cvclopropyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)- one: Using Preparation 71 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 34% yield.
  • Example 56 3-cvclopentyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)- one: Using Preparation 78 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 56% yield.
  • Example 58 7-methoxy-3-methyl-6-r3-( 1 -methyl-1 H-benzimidazol-2- yl)propoxylquinazolin-4(3H)-one: Using Preparation 76 and 3-(1-methyl-1 H-benzo[d]imidazol- 2-yl)propan-1-ol, the general procedure in Example 1 was used for the synthesis of the title compound in 37% yield.
  • Example 59 3-cvclobutyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)- one: Using Preparation 82 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 50% yield. 13C NMR (101 MHz, CHLOROFORM- D) d ppm 15.5 (s, 1 C) 30.0 (s, 1 C) 38.5 (s, 1 C) 50.3 (s, 1 C) 56.4 (s, 1 C) 68.5 (s, 1 C)
  • Example 61 2-r2-(quinolin-6-yloxy)ethyllquinoline: Using 6-hydroxyquinoline and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 15% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.8 (s, 1 C) 67.7 (s, 1 C) 106.4 (s, 1 C) 121.5 (s, 1 C) 122.3 (s, 1 C) 122.9 (s, 1 C) 126.4 (s, 1 C) 127.2 (s, 1 C) 127.8 (s, 1 C) 128.9 (s, 1 C) 129.5 (s, 1 C) 129.9 (s, 1 C) 130.8 (s, 1 C) 135.3 (s, 1 C) 136.9 (s, 1 C) 148.0 (s, 1 C) 157.2 (s, 1 C) 159.1 (s, 1 C); MS (AP/CI): 301.3 (M+H)+ ; IC 50
  • Example 62 7-f3-(1-methyl-1 H-benzimidazol-2-yl)propoxy1quinoline: Using 7- hydroxyquinoline and 3-(1-methyl-1 H-benzo[d]imidazol-2-yl)propan-1-ol, the general procedure in Example 1 was used for the synthesis of the title compound in 35% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 24.1 (s, 1 C) 27.2 (s, 1 C) 29.9 (s, 1 C) 67.2 (s, 1 C) 108.4 (s, 1 C) 109.2 (s, 1 C) 119.3 (s, 1 C) 120.0 (s, 1 C) 122.2 (s, 1 C) 122.4 (s, 1 C) 123.8 (s, 1 C) 129.1 (s, 1 C) 135.9 (s, 1 C) 136.0 (s, 1 C) 142.5 (s, 1 C) 150.0 (s, 1 C) 150.7 (s
  • Example 64 7-r3-(1-methyl-1 H-benzimidazol-2-yl)propoxy[isoquinoline: Using 7- hydroxyisoquinoline and 3-(1-methyl-1 H-benzo[d]imidazol-2-yl)propan-1-ol, the general procedure in Example 1 was used for the synthesis of the title compound in 28% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 24.0 (s, 1 C) 27.1 (s, 1 C) 29.9 (s, 1 C) 67.2 (s, 1 C) 105.9 (s, 1 C) 109.3 (s, 1 C) 119.2 (s, 1 C) 120.4 (s, 1 C) 122.3 (s, 1 C) 122.5 (s, 1 C) 123.8 (s, 1 C) 128.3 (s, 1 C) 130.0 (s, 1 C) 131.6 (s, 1 C) 135.9 (s, 1 C) 141.4 (s, 1 C) 14
  • Example 65 6-f3-(1 -methyl-1 H-benzimidazol-2-yl)propoxy1auinoline: Using 6- hydroxyquinoline and 3-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-1-ol, the general procedure in Example 1 was used for the synthesis of the title compound in 28% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 24.0 (s, 1 C) 27.1 (s, 1 C) 29.9 (s, 1 C) 67.1 (s, 1 C) 106.2 (s, 1 C) 109.3 (s, 1 C) 119.2 (s, 1 C) 121.6 (s, 1 C) 122.3 (s, 1 C) 122.6 (s, 1 C) 129.5 (s, 1 C) 131.1 (s, 1 C) 135.1 (s, 1 C) 135.8 (s, 1 C) 142.2 (s, 1 C) 144.6 (s, 1 C) 148.2 (s, 1

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Abstract

The invention pertains to heteroaromatic compounds that serve as effective phosphodiesterase (PDE) inhibitors. The invention also relates to compounds which are selective inhibitors of PDE10. The invention further relates to pharmaceutical compositions comprising such compounds; and the use of such compounds in methods for treating certain central nervous system (CNS) or other disorders. The invention relates also to. methods for treating neurodegenerative and psychiatric disorders, for example psychosis and disorders comprising deficient cognition as a symptom. (formula I).

Description

HETEROAROMATIC QUINOLINE- BASED COMPOUNDS Field of the Invention
The invention pertains to heteroaromatic compounds that serve as effective phosphodiesterase (PDE) inhibitors. The invention also relates to compounds which are selective inhibitors of PDE10. The invention further relates to intermediates for preparation of such compounds; pharmaceutical compositions comprising such compounds; and the use of such compounds in methods for treating certain central nervous system (CNS) or other disorders. The invention relates also to methods for treating neurodegenerative and psychiatric disorders, for example psychosis and disorders comprising deficient cognition as a symptom.
Background of Invention
Phosphodiesterases (PDEs) are a class of intracellular enzymes involved in the hydrolysis of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphates (cGMP) into their respective nucleotide monophosphates. The cyclic nucleotides cAMP and cGMP are synthesized by adenylyl and guanylyl cyclases, respectively, and serve as secondary messengers in several cellular pathways.
The cAMP and cGMP function as intracellular second messengers regulating a vast array of intracellular processes particularly in neurons of the central nervous system. In neurons, this includes the activation of cAMP and cGMP-dependent kinases and subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission as well as in neuronal differentiation and survival. The complexity of cyclic nucleotide signaling is indicated by the molecular diversity of the enzymes involved in the synthesis and degradation of cAMP and cGMP. There are at least ten families of adenylyl cyclases, two of guanylyl cyclases, and eleven of phosphodiesterases. Furthermore, different types of neurons are known to express multiple isozymes of each of these classes, and there is good evidence for compartmentalization and specificity of function for different isozymes within a given neuron.
A principal mechanism for regulating cyclic nucleotide signaling is by phosphodiesterase-catalyzed cyclic nucleotide catabolism. There are 11 known families of PDEs encoded by 21 different genes. Each gene typically yields multiple splice variants that further contribute to the isozyme diversity. The PDE families are distinguished functionally based on cyclic nucleotide substrate specificity, mechanism(s) of regulation, and sensitivity to inhibitors. Furthermore, PDEs are differentially expressed throughout the organism, including in the central nervous system. As a result of these distinct enzymatic activities and localization, different PDEs' isozymes can serve distinct physiological functions. Furthermore, compounds that can selectively inhibit distinct PDE families or isozymes may offer particular therapeutic effects, fewer side effects, or both. PDE10 is identified as a unique family based on primary amino acid sequence and distinct enzymatic activity. Homology screening of EST databases revealed mouse PDE10A as the first member of the PDE10 family of PDEs (Fujishige et al., J. Biol. Chem. 274:18438- 18445, 1999; Loughney, K. et al., Gene 234:109-117, 1999). The murine homologue has also been cloned (Soderling, S. et al., Proc. Natl. Acad. Sci. USA 96:7071-7076, 1999)and N- terminal splice variants of both the rat and human genes have been identified (Kotera, J. et al., Biochem. Biophys. Res. Comm. 261:551-557, 1999; Fujishige, K. et al., Eur. J. Biochem. 266:1118-1127, 1999). There is a high degree of homology across species. The mouse PDE10A1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively. The affinity of PDE10 for cAMP (Km = 0.05 μM) is higher than for cGMP (Km = 3 μM). However, the approximately 5-fold greater Vmax for cGMP over cAMP has lead to the suggestion that PDE10 is a unique cAMP-inhibited cGMPase (Fujishige et al., J. Biol. Chem. 274:18438-18445, 1999).
The PDE 10 family of polypeptides shows a lower degree of sequence homology as compared to previously identified PDE families and has been shown to be insensitive to certain inhibitors that are known to be specific for other PDE families. United States Patent No. 6,350,603, incorporated herein by reference.
PDE10 also is uniquely localized in mammals relative to other PDE families. mRNA for PDE10 is highly expressed only in testis and brain (Fujishige, K. et al., Eur J Biochem. 266:1118-1127, 1999; Soderling, S. et al., Proc. Natl. Acad. Sci. 96:7071-7076, 1999;
Loughney, K. et al., Gene 234:109-117, 1999). These initial studies indicated that within the brain PDE10 expression is highest in the striatum (caudate and putamen), n. accumbens, and olfactory tubercle. More recently, a detailed analysis has been made of the expression pattern in rodent brain of PDE10 mRNA (Seeger, T.F. et al., Abst. Soc. Neurosci. 26:345.10, 2000)and PDE10 protein (Menniti, F.S., Stick, C.A., Seeger, T.F., and Ryan, A.M., lmmunohistochemical localization of PDE10 in the rat brain. William Harvey Research
Conference 'Phosphodiesterase in Health and Disease', Porto, Portugal, Dec. 5-7, 2001).
A variety of therapeutic uses for PDE inhibitors has been reported including obtrusive lung disease, allergies, hypertension, angina, congestive heart failure, depression and erectile dysfunction (WO 01/41807 A2, incorporated herein by reference).
The use of selected benzimidazole and related heterocyclic compounds in the treatment of ischemic heart conditions has been disclosed based upon inhibition of PDE associated cGMP activity. United States Patent 5,693,652, incorporated herein by reference.
United States Patent Application Publication No. 2003/0032579 discloses a method for treating certain neurologic and psychiatric disorders with the selective PDE10 inhibitor papaverine. In particular, the method relates to psychotic disorders such as schizophrenia, delusional disorders and drug-induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including Parkinson's disease and Huntington's disease.
WO2005/120514 discloses a method for treating obesity-related and metabolic syndrome-related conditions by administering a PDE10 inhibitor.
Summary of the Invention
The present invention provides for compounds of formula I or pharmaceutical salts thereof,
Figure imgf000004_0001
wherein HET1 is selected from the group consisting of a monocyclic heteroaryl and a bicyclic heteroaryl, wherein said HET1 may optionally be substituted with at least one R1 ;
B1 and B2 are adjacent atoms in Het1 wherein B2 is carbon and B1 is nitrogen. X, Y and Z are each independently N or CR5, with the provisos that at least one of X, Y and Z must be CR5 and when R4 is O, R4 is divalent and Z is NR10; wherein each R1 is independently selected from a group consisting of halogen, hydroxyl, cyano, (CrC8)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, (Ci-C8)alkoxy, (CrC8)haloalkyl, (C-ι-C8)haloalkoxy, (C3-C8)cycloalkyl, (5-12 membered)heterocycloalkyl, (CrC8)alkylthio, - NR8R9, -C(O)-NR8R9, and (CrC8)alkyl substituted with at least one of -OH, (CrC8)alkoxy, - SH, -(CrC8)alkylthio, -NH2, -HN(CrC8)alkyl or N((C1-C8)alkyl)((C1-C8)alkyl); R3 is independently hydrogen, halogen, cyano, -COOH, -COOR8 -CONR8R9, -COR8, -
NR8R9, -NHCOR8, -OH, (C6-C12)aryl, (5-12 membered)heteroaryl, (CrC8)alkyl, (CrC8)alkoxy, (Ci-C6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C2-C6)alkenyloxy or (C3-C8)cycloalkyl;
R4 is hydrogen, O, halogen, cyano, -NR8R9, -C(O)R8, (CrC6)alkyl, (CrC6)alkoxy, (C3-
C12)cycloalkyl, (CrC6)haloalkyl, (4-12 membered)heterocycloalkyl, (C6-Ci2)aryl, -(5-12 membered)heterocycloalkyl-(C6-C12)aryl, (5-12 membered)heteroaryl, (5-12 membered)heterocycloalkyloxy, (C6-Ci2)aryloxy, (5-12 membered)heteroaryloxy, -(C6-
Ci2)aryl-(Ci-C6)alkyl, or -(5-12 membered)heteroaryl-(Ci-C6)alkyl, wherein when R4 is alkyl, alkoxy, cycloalkyl, haloalkyl, heterocycloalkyl, aryl, -heterocycloalkyl-aryl, heteroaryl, heterocycloalkyloxy, aryloxy, heteroaryl, heteroaryloxy, -aryl-alkyl, or -heteroaryl-alkyl, it may be optionally substituted by at least one R7;
R5 is independently hydrogen, halogen, -NR8R9, hydroxyl, (CrC8)alkyl, (CrC8)alkoxy, (CrC8)haloalkyl, (CrC8)hydroxyalkyl or (C3-C8)cycloalkyl; -A-
wherein each R7 is independently hydrogen, halogen, hydroxy, cyano, -COOH, - COOR8, -CONR8R9, -COR8, -NR8R9, -NHCOR8, -HNCOOR8, -HNCONHR8, (CrC8)alkyl, (Cr C8)alkoxy, (CrC6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C2-C6)alkenyloxy, (C3- C8)cycloalkyl, (CrC8)hydroxyalkyl, (C1-C8)alkoxy-(C1-C8)alkyl, (C3-C8)hydroxycycloalkyl, (C3- C8)cycloalkoxy, -(CrCβ)alkoxy-(C3-C8)cycloalkyl, (C6-C12)aryl, (3-8 membered)heterocycloalkyl, (CrC8)alkylthio, (C5-C12)aryl, (5-12 membered)heteroaryl, (C6-C12)aryloxy, or (5-12 membered)heteroaryloxy; and when R7 is aryl or heteroaryl, it may be optional fused to the heterocycloalkyl ring to which it is attached; and when R7 is alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, alkenyloxy, cycloalkyl, hydroxyalkyl, -alkoxy-alkyl, hydroxycycloalkyl, cycloalkoxy, - alkoxy-cycloalkyl, aryl, heteroaryl, aryloxy, or heteroaryloxy, it may be optionally substituted from one to three substituents independently selected from halogen, -COOR8, -NR8R9, (C1- C8)alkyl, (CrC8)alkoxy, (CrC6)haloalkyl, (CrC8)hydroxyalkyl, (CrC8)alkoxy-(CrC8)alkyl, (C3- C8)hydroxycycloalkyl, (C3-C8)cycloalkoxy, -(CrC8)alkoxy-(C3-C8)cycloalkyl, (C6-C12)aryl (3-8 membered)heterocycloalkyl, hydroxy(3-8 membered)heterocycloalkyl, and -(CrC8)alkoxy-(3-8 membered)heterocycloalkyl, wherein R8 and R9 are each independently hydrogen, (CrC8)alkyl, (Ci-C8)alkoxy, (C2- C8)alkenyl, or (C6-C12)aryl; or R8 and R9 together with the nitrogen to which they are attached may form a heterocycloalkyl or heteroaryl group;
R10 is independently hydrogen, (CrC8)alkyl, (CrC8)haloalkyl, (Ci-C8)hydroxyalkyl or (C3-C8)cycloalkyl; n is 1 , 2 or 3.
Detailed Description of the Invention
In one e eemmbbooddiimmeernt of the present invention, HET1 is selected from the group consisting of:
Figure imgf000005_0001
optionally substituted with at least one R1.
In another embodiment of the present invention, HET1 is selected from the group consisting of
Figure imgf000006_0001
In another embodiment of the present invention, R is a phenyl, pyridinyl or a heterocycloalkyl having the formula:
Figure imgf000006_0002
wherein R6 is hydrogen, -COOR8, -CONR8R9, -COR8, -NR8R9, -NHCOR8, -OH, -HNCOOR8, CN, -HNCONHR8, (CrC6)alkyl or (C1-C6) alkoxy; R7 is defined above, and p is O or 1.
In another embodiment, one or two of X, Y and Z are nitrogen. In another embodiment of the present invention, X and Z are nitrogen and Y is CH. In another embodiment of the present invention, the compound has the formula 1B:
Figure imgf000006_0003
In another embodiment of the present invention, R3 is (CrC8)alkoxy. In another embodiment of the present invention, HET1 is selected from:
Figure imgf000006_0004
Figure imgf000007_0001
R4 is a phenyl, pyridinyl or a heterocycloalkyl having the formula:
Figure imgf000007_0002
wherein R6 is hydrogen, -COOR8, -CONR8R9, -COR8, -NR8R9, -NHCOR8, -OH, -HNCOOR8, -CN, -HNCONHR8, (CrC6)alkyl or (CrC6)alkoxy; wherein R7 is defined above; and p is 1.
In another embodiment of the present invention, R4 is the heterocycloalkyl of Formula IA wherein R6 is hydrogen and R7 is phenyl. In another embodiment of the present invention, X and Z are nitrogen and Y is CH.
Compounds of the Formula I may have optical centers and therefore may occur in different enantiomeric and diastereomeric configurations. The present invention includes all enantiomers, diastereomers, and other stereoisomers of such compounds of the Formula I, as well as racemic compounds and racemic mixtures and other mixtures of stereoisomers thereof.
Pharmaceutically acceptable salts of the compounds of Formula I include the acid addition and base salts thereof.
Suitable acid addition salts are formed from acids which form non-toxic salts.
Examples include, but are not limited to, the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mandelates mesylate, methylsulphate, naphthylate, 2- napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, salicylate, saccharate, stearate, succinate, sulfonate, stannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.
Suitable base salts are formed from bases which form non-toxic salts. Examples include, but are not limited to, the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties,
Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).
Pharmaceutically acceptable salts of compounds of Formula I may be prepared by one or more of three methods:
(i) by reacting the compound of Formula I with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of Formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or
(iii) by converting one salt of the compound of Formula I to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the resulting salt may vary from completely ionised to almost non-ionised.
The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition'). The term 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').
The compounds of the invention may also exist in unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water. A currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995). Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal iron. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'. Compounds that have the potential to form lyotropic mesophases are described as 'amphiphilic' and consist of molecules which possess an ionic (such as -CO(JNa+, -COO"K+, or -SO3 'Na+) or non-ionic (such as -N"N+(CH3)3) polar head group. For more information, see Crystals and the Polarizing Microscope by N. H. Hartshome and A. Stuart, 4th Edition (Edward Arnold, 1970). Hereinafter all references to compounds of Formula I include references to salts, solvates, multi-component complexes and liquid crystals thereof and to solvates, multi- component complexes and liquid crystals of salts thereof.
The compounds of the invention include compounds of Formula I as hereinbefore defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically- labeled compounds of Formula I.
As indicated, so-called 'prodrugs' of the compounds of Formula I are also within the scope of the invention. Thus certain derivatives of compounds of Formula I which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into compounds of Formula I having the desired activity, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association). Prodrugs in accordance with the invention can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H. Bundgaard (Elsevier, 1985).
Some examples of prodrugs in accordance with the invention include, but are not limited to, (i) where the compound of Formula I contains a carboxylic acid functionality
(-COOH), an ester thereof, for example, a compound wherein the hydrogen of the carboxylic acid functionality of the compound of Formula (I) is replaced by (CrC8)alkyl;
(ii) where the compound of Formula I contains an alcohol functionality (-OH), an ether thereof, for example, a compound wherein the hydrogen of the alcohol functionality of the compound of Formula I is replaced by (CrC6)alkanoyloxymethyl; and
(iii) where the compound of Formula I contains a primary or secondary amino functionality (-NH2 or -NHR where R ≠ H), an amide thereof, for example, a compound wherein, as the case may be, one or both hydrogens of the amino functionality of the compound of Formula I is/are replaced by (CrCi0)alkanoyl. Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.
Moreover, certain compounds of Formula I may themselves act as prodrugs of other compounds of Formula I.
Also included within the scope of the invention are metabolites of compounds of Formula I, that is, compounds formed in vivo upon administration of the drug. Some examples of metabolites in accordance with the invention include, but are not limited to,
(i) where the compound of Formula I contains a methyl group, an hydroxymethyl derivative thereof (-CH3 -> -CH2OH):
(ii) where the compound of Formula I contains an alkoxy group, an hydroxy derivative thereof (-OR -> -OH);
(iii) where the compound of Formula I contains a tertiary amino group, a secondary amino derivative thereof (-NR1R2 -> -NHR1 or -NHR2);
(iv) where the compound of Formula I contains a secondary amino group, a primary derivative thereof (-NHR1 -> -NH2); (v) where the compound of Formula I contains a phenyl moiety, a phenol derivative thereof (-Ph -> -PhOH); and
(vi) where the compound of Formula I contains an amide group, a carboxylic acid derivative thereof (-CONH2 -> COOH);
(vii) where the compound contains an aromatic nitrogen atom or an tetrtiary aliphatic amine function, an N-oxide derivative thereof.
Compounds of Formual I having a nitrogen atom in a tertiary amine functional group may be further substituted with oxygen (i.e., an N-oxide); Compounds of Formula I containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Where a compound of Formula I contains an alkenyl or alkenylene group, geometric cisltrans (or Z/E) isomers are possible. Where structural isomers are interconvertible via a low energy barrier, tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism in compounds of Formula I containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
Included within the scope of the present invention are all stereoisomers, geometric isomers and tautomeric forms of the compounds of Formula I, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof. Also included are acid addition or base salts wherein the counterion is optically active, for example, d-lactate or /-lysine, or racemic, for example, c//-tartrate or cf/-arginine.
Cisltrans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of Formula I contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer. While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate.
Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, Stereochemistry of Organic Compounds by E. L. EHeI and S. H. Wilen (Wiley, 1994).
The present invention includes all pharmaceutically acceptable isotopically-labelled compounds of Formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen, such as 2H and 3H, carbon, such as 11C, 13C and 14C, chlorine, such as 36CI, fluorine, such as 18F, iodine, such as 123I and 125I, nitrogen, such as 13N and 15N, oxygen, such as 150, 17O and 18O, phosphorus, such as 32P, and sulphur, such as 35S. Certain isotopically-labelled compounds of Formula I, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 3H, and carbon-14, i.e. 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
Substitution with heavier isotopes such as deuterium, i.e. 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
Substitution with positron emitting isotopes, such as 11C, 18F, 15O and 13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
Isotopically-labeled compounds of Formula I can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically- labeled reagent in place of the non-labeled reagent previously employed. Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6- DMSO.
Specific embodiments of the present invention include the compounds exemplified in the Examples below and their pharmaceutically acceptable salts, complexes, solvates, polymorphs, steroisomers, metabolites, prodrugs, and other derivatives thereof;
This invention also pertains to a pharmaceutical composition for treatment of certain psychotic disorders and conditions such as schizophrenia, delusional disorders and drug induced psychosis; to anxiety disorders such as panic and obsessive-compulsive disorder; and to movement disorders including Parkinson's disease and Huntington's disease, comprising an amount of a compound of formula I effective in inhibiting PDE 10.
In another embodiment, this invention relates to a pharmaceutical composition for treating psychotic disorders and condition such as schizophrenia, delusional disorders and drug induced psychosis; anxiety disorders such as panic and obsessive-compulsive disorder; and movement disorders including Parkinson's disease and Huntington's disease, comprising an amount of a compound of formula I effective in treating said disorder or condition.
Examples of psychotic disorders that can be treated according to the present invention include, but are not limited to, schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type.
Examples of movement disorders that can be treated according to the present invention include but are not limited to selected from Huntington's disease and dyskinesia associated with dopamine agonist therapy, Parkinson's disease, restless leg syndrome, and essential tremor. Other disorders that can be treated according to the present invention are obsessive/compulsive disorders, Tourette's syndrome and other tic disorders.
In another embodiment, this invention relates to a method for treating an anxiety disorder or condition in a mammal which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE 10. This invention also provides a method for treating an anxiety disorder or condition in a mammal which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder or condition.
Examples of anxiety disorders that can be treated according to the present invention include, but are not limited to, panic disorder; agoraphobia; a specific phobia; social phobia; obsessive-compulsive disorder; post-traumatic stress disorder; acute stress disorder; and generalized anxiety disorder.
This invention further provides a method of treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating drug addiction.
This invention also provides a method of treating a drug addiction, for example an alcohol, amphetamine, cocaine, or opiate addiction, in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE10.
A "drug addiction", as used herein, means an abnormal desire for a drug and is generally characterized by motivational disturbances such a compulsion to take the desired drug and episodes of intense drug craving.
This invention further provides a method of treating a disorder comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder. This invention also provides a method of treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE10.
This invention also provides a method of treating a disorder or condition comprising as a symptom a deficiency in attention and/or cognition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder or condition.
The phrase "deficiency in attention and/or cognition" as used herein in "disorder comprising as a symptom a deficiency in attention and/or cognition" refers to a subnormal functioning in one or more cognitive aspects such as memory, intellect, or learning and logic ability, in a particular individual relative to other individuals within the same general age population. "Deficiency in attention and/or cognition" also refers to a reduction in any particular individual's functioning in one or more cognitive aspects, for example as occurs in age-related cognitive decline. Examples of disorders that comprise as a symptom a deficiency in attention and/or cognition that can be treated according to the present invention are dementia, for example Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; and age-related cognitive decline.
This invention also provides a method of treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I effective in treating said disorder or episode. Th is invention also provides a method of treating a mood disorder or mood episode in a mammal, including a human, comprising administering to said mammal an amount of a compound of formula I effective in inhibiting PDE10.
Examples of mood disorders and mood episodes that can be treated according to the present invention include, but are not limited to, major depressive episode of the mild, moderate or severe type, a manic or mixed mood episode, a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post- stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder such as delusional disorder or schizophrenia; a bipolar disorder, for example bipolar I disorder, bipolar Il disorder, and cyclothymic disorder.
This invention further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in treating said disorder or condition.
This invention further provides a method of treating a neurodegenerative disorder or condition in a mammal, including a human, which method comprises administering to said mammal an amount of a compound of formula I effective in inhibiting PDE10. As used herein, and unless otherwise indicated, a "neurodegenerative disorder or condition" refers to a disorder or condition that is caused by the dysfunction and/or death of neurons in the central nervous system. The treatment of these disorders and conditions can be facilitated by administration of an agent which prevents the dysfunction or death of neurons at risk in these disorders or conditions and/or enhances the function of damaged or healthy neurons in such a way as to compensate for the loss of function caused by the dysfunction or death of at-risk neurons. The term "neurotrophic agent" as used herein refers to a substance or agent that has some or all of these properties.
Examples of neurodegenerative disorders and conditions that can be treated according to the present invention include, but are not limited to, Parkinson's disease; Huntington's disease; dementia, for example Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, and Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarct; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; and multi-system atrophy. In one embodiment of the present invention, the neurodegenerative disorder or condition comprises neurodegeneration of striatal medium spiny neurons in a mammal, including a human.
In a further embodiment of the present invention, the neurodegenerative disorder or condition is Huntington's disease.
This invention also provides a pharmaceutical composition for treating psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction, comprising an amount of a compound of formula I effective in treating said disorder or condition.
This invention also provides a method of treating a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, obesity, mood disorders, and neurodegenerative disorders, which method comprises administering an amount of a compound of formula I effective in treating said disorder.
This invention also provides a method of treating disorders selected from the group consisting of: dementia, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; age-related cognitive decline, major depressive episode of the mild, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder comprising a delusional disorder or schizophrenia; a bipolar disorder comprising bipolar I disorder, bipolar Il disorder, cyclothymic disorder, Parkinson's disease; Huntington's disease; dementia, Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke; neurodegeneration associated with cerebral infarct; hypoglycemia- induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; multi-system atrophy, paranoid, disorganized, catatonic, undifferentiated or residual type; schizophreniform disorder; schizoaffective disorder of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type, which method comprises administering an amounot of a compound of Formula I effecting in said disorders. This invention also provides a method of treating psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction which method comprises administering an amount of a compound of formula I effective in inhibiting PDE 10.
The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, and t-butyl.
The term "alkenyl", as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon double bond wherein alkyl is as defined above. Examples of alkenyl include, but are not limited to, ethenyl and propenyl. The term "alkynyl", as used herein, unless otherwise indicated, includes alkyl moieties having at least one carbon-carbon triple bond wherein alkyl is as defined above. Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl.
The term "alkoxy", as used herein, unless otherwise indicated, as employed herein alone or as part of another group refers to an alkyl, groups linked to an oxygen atom. The term "alkylthio" as used herein, unless otherwise indicated, employed herein alone or as part of another group includes any of the above alkyl groups linked through a sulfur atom.
The term "halogen" or "halo" as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine. The term "haloalkyl" as used herein, unless otherwise indicated, refers to at least one halo group, linked to an alkyl group. Examples, of haloalkyl groups include, but are not limited, to trifluoromethyl, trifluoroethyl, difluoromethyl and fluoromethyl groups.
The term "cycloalkyl", as used herein, unless otherwise indicated, includes non- aromatic saturated cyclic alkyl moieties wherein alkyl is as defined above. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
The term "aryl", as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl, naphthyl, indenyl, and fluorenyl. "Aryl" encompasses fused ring groups wherein at least one ring is aromatic.
The terms "heterocyclic", "heterocycloalkyl", and like terms, as used herein, refer to non-aromatic cyclic groups containing one or more heteroatoms, prefereably from one to four heteroatoms, each preferably selected from oxygen, sulfur and nitrogen. The heterocyclic groups of this invention can also include ring systems substituted with one or more oxo moieties. Examples of non-aromatic heterocyclic groups are aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, azepinyl, piperazinyl, 1 ,2,3,6-tetrahydropyridinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholino, thiomorpholino, thioxanyl, pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3- dioxolanyl, pyrazolinyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0jheptanyl, quinolizinyl, quinuclidinyl, 1 ,4-dioxaspiro[4.5]decyl, 1 ,4-dioxaspiro[4.4]nonyl, 1 ,4- dioxaspiro[4.3]octyl, and 1,4-dioxaspiro[4.2]heptyl.
The term "heteroaryl", as used herein, refers to aromatic groups containing one or more heteroatoms (preferably oxygen, sulfur and nitrogen), preferably from one to four heteroatoms. A multicyclic group containing one or more heteroatoms wherein at least one ring of the group is aromatic is a "heteroaryl" group. The heteroaryl groups of this invention can also include ring systems substituted with one or more oxo moieties. Heteroaryl groups containing a tertiary nitrogen may also be further substituted with oxygen (i.e., an N-oxide). Examples of heteroaryl groups are pyridinyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzσthiophenyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, dihydroquinolyl, tetrahydroquinolyl, dihydroisoquinolyl, tetrahydroisoquinolyl, benzofuryl, furopyridinyl, pyrolopyrimidinyl, and azaindolyl.
Unless otherwise indicated, the term "one or more" substituents, or "at least one" substituent as used herein, refers to from one to the maximum number of substituents possible based on the number of available bonding sites.
Unless otherwise indicated, all the foregoing groups derived from hydrocarbons may have up to about 1 to about 20 carbon atoms (e.g. C1-C2O alkyl, C2-C2O alkenyl, C3-C20 cycloalkyl, 3-20 membered heterocycloalkyl; C6-C2O aryl, 5-20 membered heteroaryl, etc.) or 1 to about 15 carbon atoms (e.g., CrCi5 alkyl, C2-Ci5 alkenyl, C3-C15 cycloalkyl, 3-15 membered heterocycloalkyl, C6-Ci5 aryl, 5-15 membered heteroaryl, etc.) , or 1 to about 12 carbon atoms, or 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms.
"Neurotoxin poisoning" refers to poisoning caused by a neurotoxin. A neurotoxin is any chemical or substance that can cause neural death and thus neurological damage. An example of a neurotoxin is alcohol, which, when abused by a pregnant female, can result in alcohol poisoning and neurological damage known as Fetal Alcohol Syndrome in a newborn. Other examples of neurotoxins include, but are not limited to, kainic acid, domoic acid, and acromelic acid; certain pesticides, such as DDT; certain insecticides, such as organophosphates; volatile organic solvents such as hexacarbons (e.g. toluene); heavy metals (e.g. lead, mercury, arsenic, and phosphorous); aluminum; certain chemicals used as weapons, such as Agent Orange and Nerve Gas; and neurotoxic antineoplastic agents. As used herein, the term "selective PDE10 inhibitor" refers to a substance, for example an organic molecule, that effectively inhibits an enzyme from the PDE10 family to a greater extent than enzymes from the PDE 1-9 families or PDE11 family. In one embodiment, a selective PDE10 inhibitor is a substance, for example an organic molecule, having a Ki for inhibition of PDE10 that is less than or about one-tenth the Kj that the substance has for inhibition of any other PDE enzyme. In other words, the substance inhibits PDE10 activity to the same degree at a concentration of about one-tenth or less than the concentration required for any other PDE enzyme.
In general, a substance is considered to effectively inhibit PDE10 activity if it has a K] of less than or about 10μM, preferably less than or about 0.1 μM. A "selective PDE10 inhibitor" can be identified, for example, by comparing the ability of a substance to inhibit PDE10 activity to its ability to inhibit PDE enzymes from the other PDE families. For example, a substance may be assayed for its ability to inhibit PDE10 activity, as well as PDE1A, PDE1B, PDE1C, PDE2, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5, PDE6, PDE7, PDE8, PDE9, and PDE11. The term "treating", as in "a method of treating a disorder", refers to reversing, alleviating, or inhibiting the progress of the disorder to which such term applies, or one or more symptoms of the disorder. As used herein, the term also encompasses, depending on the condition of the patient, preventing the disorder, including preventing onset of the disorder or of any symptoms associated therewith, as well as reducing the severity of the disorder or any of its symptoms prior to onset. "Treating" as used herein refers also to preventing a recurrence of a disorder.
For example, "treating schizophrenia, or schizophreniform or schizoaffective disorder" as used herein also encompasses treating one or more symptoms (positive, negative, and other associated features) of said disorders, for example treating, delusions and/or hallucination associated therewith. Other examples of symptoms of schizophrenia and schizophreniform and schizoaffec ive disorders include disorganized speech, affective flattening, alogia, anhedonia, inappropriate affect, dysphoric mood (in the form of, for example, depression, anxiety or anger), and some indications of cognitive dysfunction.
The term "mammal", as used herein, refers to any member of the class "Mammalia", including, but not limited to, humans, dogs, and cats.
The compound of the invention may be administered either alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed thereby can then be readily administered in a variety of dosage forms such as tablets, powders, lozenges, liquid preparations, syrups, injectable solutions and the like. These pharmaceutical compositions can optionally contain additional ingredients such as flavorings, binders, excipients and the like. Thus, the compound of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous), transdermal (e.g. patch) or rectal administration, or in a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycolate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner. The compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampules or in multi-dose containers, with an added preservative. They may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
When a product solution is required, it can be made by dissolving the isolated inclusion complex in water (or other aqueous medium) in an amount sufficient to generate a solution of the required strength for oral or parenteral administration to patients. The compounds may be formulated for fast dispersing dosage forms (fddf), which are designed to release the active ingredient in the oral cavity. These have often been formulated using rapidly soluble gelatin-based matrices. These dosage forms are well known and can be used to deliver a wide range of drugs. Most fast dispersing dosage forms utilize gelatin as a carrier or structure-forming agent. Typically, gelatin is used to give sufficient strength to the dosage form to prevent breakage during removal from packaging, but once placed in the mouth, the gelatin allows immediate dissolution of the dosage form. Alternatively, various starches are used to the same effect.
The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides. For intranasal administration or administration by inhalation, the compound of the invention is conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made e.g. from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
Aerosol formulations for treatment of the conditions referred to above (e.g. migraine) in the average adult human are preferably arranged so that each metered dose or "puff' of aerosol contains about 20 mg to about 1000 mg of the compound of the invention. The overall daily dose with an aerosol will be within the range of about 100 mg to about 10 mg. Administration may be several times daily, e.g. 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
A proposed daily dose of the compound of the invention for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.
Assay methods are available to screen a substance for inhibition of cyclic nucleotide hydrolysis by the PDE 10 and the PDEs from other gene families. The cyclic nucleotide substrate concentration used in the assay is 1/3 of the Km concentration, allowing for comparisons of IC50 values across the different enzymes. PDE activity is measured using a Scintillation Proximity Assay (SPA)-based method as previously described (Fawcett et al., 2000). The effect of PDE inhibitors is determined by assaying a fixed amount of enzyme (PDEs 1-11) in the presence of varying substance concentrations and low substrate, such that the IC50 approximates the Ki (cGMP or cAMP in a 3:1 ratio unlabelled to [3H]-Iabeled at a concentration of 1/3 Km). ). The final assay volume is made up to 100μl with assay buffer [50 mM Tris-HCI pH 7.5, 8.3 mM MgCI2, 1 mg/ml bovine serum albumin]. Reactions are initiated with enzyme, incubated for 30-60 min at 30°C to give <30% substrate turnover and terminated with 50 μl yttrium silicate SPA beads (Amersham) (containing 3 mM of the respective unlabelled cyclic nucleotide for PDEs 9 and 11). Plates are re-sealed and shaken for 20 min, after which the beads were allowed to settle for 30 minutes in the dark and then counted on a TopCount plate reader (Packard, Meriden, CT). Radioactivity units can be converted to percent activity of an uninhibited control (100%), plotted against inhibitor concentration and inhibitor IC50 values can be obtained using the "Fit Curve' Microsoft Excel extension.
The following schemes depict the preparation of the heteroaromatic quinoline-based class of compounds of this invention. Detailed Description of the Invention
Scheme 1 details the synthesis of compounds of formula 1 wherein R4 = NR8R9.
Step 1 of Scheme 1 is a nucleophilic displacement of a chloride with an amine. Treatment of 6,7-dimethoxy-4-chloroquinazoline with an amine (HNR8R9) in a solvent such as isopropanol in the presence of trialkylamine base such as diisopropylethylamine or triethylamine at a temperature about 90 0C for about 2 h affords compound 2.
Step 2 of Scheme 1 is a dealkylation reaction. Treatment of compound 2 with methanesulfonic acid and L-methionine at a temperature from about 90 to 160 0C affords compound 3.
Step 3 of Scheme 1 is an alkylation reaction. Treatment of compound 3 with an alkyl halide, a base such as cesium carbonate, in a solvent such as DMSO, or with an alcohol, a diazodicarboxylate such as ditertbutyl azodicarboxylate or diethylazodicarboxylate, and triphenylphosphine in a solvent such as THF affords compound 1.
Figure imgf000022_0001
Scheme 1 Scheme 2 details the synthesis of compounds of formula 1 wherein R4 = aryl or heteroaryl.
Step 1 of Scheme 2 is a Suzuki coupling reaction. Treatment of 6,7-dimethoxy-4- chloroquinazoline with an aryl or heteroaryl boronic acid or boronate or dialkylborane, a palladium catalyst such as Pd2(dba)3, tricyclohexylphosphine, and cesium carbonate in dioxane at about 100 0C affords compound 2. Step 2 of Scheme 2 is a dealkylation reaction. Treatment of compound 2 with methanesulfonic acid and L-methionine at a temperature from about 90 to 160 0C affords compound 3.
Step 3 of Scheme 1 is an alkylation reaction. Treatment of compound 3 with an alkyl halide, a base such as cesium carbonate, in a solvent such as DMSO, or with an alcohol, a diazodicarboxylate such as ditertbutyl azodicarboxylate or diethylazodicarboxylate, and triphenylphosphine in a solvent such as THF affords compound 1.
Figure imgf000023_0001
Scheme 2
Scheme 3 details the synthesis of compounds of formula 1 wherein R4 = H.
Step 1 of Scheme 3 is a reductive dehalogenation. Exposure of 6,7-dimethoxy-2,4- dichloroquinazoline and palladium on carbon (about 10%) in a solvent such as methanol and in the presence of a base such as triethylamine to a hydrogen atmosphere, from about 10 to 60 psi, where about 40 psi is preferred, at about room temperature, affords compound 2.
Step 2 of Scheme 3 is a dealkylation reaction. Treatment of compound 2 with methanesulfonic acid and L-methionine at a temperature from about 90 to 160 0C affords compound 3.
Step 3 of Scheme 1 is an alkylation reaction. Treatment of compound 3 with an alkyl halide, a base such as cesium carbonate, in a solvent such as DMSO1 or with an alcohol, a diazodicarboxylate such as ditertbutyl azodicarboxylate or diethylazodicarboxylate, and triphenylphosphine in a solvent such as THF affords compound 1.
Figure imgf000023_0002
Scheme 3
Scheme 4 details the synthesis of compounds wherein R4 = aryl or heteroaryl.
Step 1 of Scheme 4 is a heterocyclization reaction. Treatment of compound 2 with a formyl source such as formamidine acetate in a solvent such as ethylene glycol monomethylether at about 13O0C for about 24 h affords compound 3.
Step 2 of Scheme 4 is a nucleophilic aromatic substitution reaction. Treatment of compund 3 with benzyl alcohol and sodium hydride in DMF and heating at about 140 0C for 4 h affords compound 4.
Step 3 of Scheme 4 is a dehydrative chlorination. Treatment of compound 4 with phosphorousoxychloride at about 12O0C for about 3 h affords compound 5. Step 4 of Scheme 4 is a Suzuki coupling reaction. Treatment of compound 5 with an aryl or heteroaryl boronic acid or boronate or dialkylborane, a palladium catalyst such as Pd2(dba)3, tricyclohexylphosphine, and cesium carbonate in dioxane at about 100 0C affords compound 6. Step 5 of Scheme 4 is a dealkylation reaction. Treatment of compound 6 with trifluoroacetic acid and anisole at about 750C for about 24 h affords compound 7.
Step 6 of Scheme 4 is an alkylation reaction. Treatment of compound 7 with an alkyl halide, a base such as cesium carbonate, in a solvent such as DMSO, or with an alcohol, a diazodicarboxylate such as ditertbutyl azodicarboxylate or diethylazodicarboxylate, and triphenylphosphine in a solvent such as THF affords compound 1.
Figure imgf000024_0001
Scheme 4
Scheme 5 details the synthesis of compounds where R4 is aryl, heteroaryl, or NR8R9 (Steps 1-10) and where R4 is C=O and Z is N (Steps 1-5, 11-13). Step 1 of Scheme 5 is conversion of an aryl ether to a phenol. Treatment of compound 2 with sodium hydroxide at about 100 0C for about 3 h affords compound 3.
Step 2 of Scheme 5 is an esterification. Treatment of compound 3 with concentrated sulfuric acid in methanol followed by heating at reflux for about 48 h affords compound 4.
Step 3 of Scheme 5 is an alkylation reaction. Treatment of compound 4 with benzyl bromide and cesium carbonate in DMSO at about 230C for about 24 h affords compound 5.
Step 4 of Scheme 5 is a nitro reduction to an amine. Treatment of a solution of compound 5 in methanol and water with iron powder followed by heating to about 9O0C for about 24 h affords compound 6.
Step 5 of Scheme 5 is a hydrolysis. Treatment of compound 6 with lithium hydroxide in methanol/THF/water at about 750C for about 6 h affords compound 7.
Step 6 of Scheme 5 is a heterocycle forming reaction. Treatment of compound 7 with amidine acetate in ethyleneglycol monomethylether at about 130°C for about 24 h affords compound 8.
Step 7 of Scheme 5 is a dehydrative chlorination. Treatment of compound 8 with phosphorousoxychloride at about 12O0C for about 3 h affords compound 9. Step 8 of Scheme 5 is A) a Suzuki coupling reaction. Treatment of compound 9 with an aryl or heteroaryl boronic acid or boronate or dialkylborane, a palladium catalyst such as Pd2(dba)3, tricyclohexylphosphine, and cesium carbonate in dioxane at about 1000C affords compound 10; or B) a nucleophilic displacement of a chloride with an amine. Treatment of 9 with an amine (HNR8R9) in a solvent such as isopropanol in the presence of trialkylamine base such as diisopropylethylamine or triethylamine at a temperature about 9O0C for about 2 h affords compound 10.
Step 9 of Scheme 5 is a dealkylation reaction. Treatment of compound 10 with trifluoroacetic acid and anisole at about 750C for about 24 h affords compound 11. Step 10 of Scheme 5 is an alkylation reaction. Treatment of compound 10 with A) an alkyl halide, a base such as cesium carbonate, in a solvent such as DMSO, or B) with an alcohol, a diazodicarboxylate such as ditertbutyl azodicarboxylate or diethylazodicarboxylate, and triphenylphosphine in a solvent such as THF, affords compound 1.
Step 11 of Scheme 5 is a heterocycle forming reaction. Treatment of compound 7 with trimethyl orthoformate at about 1050C for about 2 h, followed by treatment with an amine NH2R5, affords compound 12.
Step 12 of Scheme 5 is a dealkylation reaction. Treatment of compound 12 with trifluoroacetic acid and anisole at about 750C for about 24 h affords compound 13.
Step 13 of Scheme 5 is an alkylation reaction. Treatment of compound 13 with an alcohol, a diazodicarboxylate such as ditertbutyl azodicarboxylate or diethylazodicarboxylate, and triphenylphosphine in a solvent such as THF, affords compound 1. A^J^ XOjMe — - Pti CT 1^^ ^CO2Ms
Figure imgf000025_0001
Scheme 5
Scheme 6 details an alternative route to compounds of formula 1 wherein R4 is C=O and Z is N.
Step 1 of Scheme 6 is an amide forming reaction. Treatment of compound 2 and a primary amine NH2R5 with an activating agent such as DCC followed by 1- hydroxybenztriazole in a solvent such as DMF at about 230C for about 24 h affords compound 3. Step 2 of Scheme 6 is a heterocycle forming reaction. Treatment of compound 3 with triethyl orthoformate and anhydrous hydrogen chloride in N-methylpyrolidinone at about 1200C for about 24 h affords compound 4.
Step 3 of Scheme 6 is a dealkylation reaction. Treatment of compound 4 with methanesulfonic acid and L-methionine at a temperature from about 90 to 16O0C affords compound 5.
Step 4 of Scheme 6 is an alkylation reaction. Treatment of compound 5 with an alcohol, a diazodicarboxylate such as ditertbutyl azodicarboxylate or diethylazodicarboxylate, and triphenylphosphine in a solvent such as THF, affords compound 1.
Figure imgf000026_0001
Scheme 6
The following Examples illustrate the present invention. It is to be understood, however, that the invention, as fully described herein and as recited in the claims, is not intended to be limited by the details of the following Examples. EXAMPLES
Preparation 1 : 6.7-dimethoxy-4-(3-phenylpiperidin-1-yQquinazoline: 4-chloro-6,7- dimethoxyquinazoline (15 g, 66.8 mmol) was mixed with 3-phenylpiperidine (11.8 g, 73.5 mmol) in isopropanol (300 ml_), then diisopropylethylamine (23 ml_, 133.6 mmol) was added and the mixture was heated at 900C for 2 h. After cooling to room temperature, the solvent was removed in vacuo, the residue was diluted with water and chloroform, and the mixture was made basic by adding sodium hydroxide (pH <12). The mixture was extracted with chloroform, the organic layer was washed with brine and was dried over MgSO4, was filtered, and was concentrated in vacuo. Purification by silica gel chromatography (100% chloroform to 100-1-1 chloroform/methanol/aqu. cone, ammonium hydroxide) afforded 17.5 g (75% yield) of the title compound; MS (AP/CI): 350.2 (M+H)+.
Preparation 2: 7-methoxy-4-(3-phenylpiperidin-1 -yl)quinazolin-6-ol: Preparation 1 (2.8 g, 8 mmol) was treated with L-methionine (1.43 g, 9.6 mmol) in methanesulfonic acid (40 mL). The mixture was heated to 120 0C for 2 h, 14O0C for 5 h, then 1450C for 1 h. The mixture was poured onto ice, the pH was made basic by using sodium hydroxide (pH ca. 8-9), and the mixture was extracted with chloroform. The organic extracts were washed with brine, were dried over magnesium sulfate, were filtered, and were concentrated in vacuo. The residue was purified by silica gel chromatography (100-1-0 to 100-1-1 chloroform/methanol/conc. aqu. ammonium hydroxide) to afford 1.4 g (52% yield) of the title compound; MS (AP/CI): 336.2 (M+H)+. Preparation 3: 7-methoxy-4-(3-phenylpiperidin-1-yl)-6-(prop-2-vnyloxy)quinazoline: A mixture of Preparation 2 (500 mg, 1.49 mmol), propargyl bromide (80% in toluene, 0.25 mL, 2.24 mmol) and cesium carbonate (1g, 3 mmol) in DMSO (10 mL) were stirred for 24 h. The mixture was diluted with ethylacetate (100 mL) and n-butanol (5 mL), was washed with water and brine, was dried over magnesium sulfate, was filtered, and was concentrated. Purification by silica gel chromatography afforded 355 mg (64% yield) of the title compound; MS (AP/CI): 374.5 (M+H)+.
Preparation 4: 2-fquinolin-2-yl)ethanol: Ethyl 2-quinolylacetate (8.6 g, 42.8 mmol) in diethyl ether (400 mL) was cooled to -780C and lithium aluminum hydride (1.63 g, 42.8 mmol) was added portionwise. After stirring at -78°C for 2 h, the reaction mixture was allowed to warm slowly to O0C and was then stirred for 4 h at O0C followed by stirring at room temperature overnight. After cooling back to O0C, a small amount of methanol was added to quench remaining hydride followed by sodium sulfate decahydrate (43 g). After stirring at room temperature for 1 h, the mixture was filtered and the solid was washed with chloroform and was concentrated. Purification by silica gel chromatography (2:1 ethylacetate-hexanes) gave 0.46 g (53% yield) of the title compound; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 161.53, 147.23, 137.04, 130.01 , 128.74, 127.79, 127.03, 126.39, 122.09, 61.60, 39.52; MS (AP/CI): 174.2 (M+H)+.
Example 1 : 7-methoxy-4-(3-pheny)piperidin-1-yl)-6-(2-quinolin-2- ylethoxy)quinazoline: Di-tertbutyl azodicarboxylate (92 mg, 0.4 mmol) was mixed with triphenylphosphine (131 mg, 0.5 mmol) in THF (2 mL) at room temperature for 10 min. 3-(1- Preparation 2 (67 mg, 0.2 mmol) was added followed by 2-(quinolin-2-yl)ethanol (138 mg, 0.8 mmol) and the solution was stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate, was washed with aqueous sodium bicarbonate, water, and then brine, was dried over magnesium sulfate, was filtered, and was concentrated in vacuo. The residue was dissolved in methylene chloride and was applied to a 6 mL column packed with 1 g of silica-bound p-toluene sulfonic acid (Silicycle). The column was eluted by gravity with 2 column volumes (cv) of methylene chloride, 3 cv of methanol to remove reaction by-products, then was eluted with 4 cv of 1 N triethylamine in methanol to remove the product. The solvent from the triethylamine elution was removed in vacuo and the resulting residue was purified by silica gel chromatography (50-1-0 to 50-1-1 chloroform/methanol; 50-1 chloroform/triethylamine) to afford the title compound in 30% yield; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 26.0, 32.3, 38.7, 43.2, 50.7, 56.4, 57.1 , 68.6, 105.4, 107.8, 111.8, 122.4, 126.3, 126.9, 127.2, 127.3, 127.8, 128.8, 129.1 , 129.8, 136.6, 143.7, 153.4, 155.0, 158.9, 164.3; MS (AP/CI) 491.1 (M+H)+; IC50 = 1.87 nM.
Example 2: 7-methoxy-6-r3-(1 -methyl- 1 H-benzimidazol-2-ylbropoxyl-4-(3- phenylpiperidin-1-vnαuinazoline: Using Preparation 2 and 3-(1-methyl-1H-benzo[d]imidazol-2- yl)propan-1-ol, the general procedure in Example 1 was used for the synthesis of the title compound in 49% yield; 13C NMR (100 MHz, CD3OD) Δ ppm 163.838, 155.478, 154.670, 152.031 , 147.971 , 147.746, 143.312, 141.480, 135.632, 128.671 , 127.100, 126.891 , 122.651 , 122.404, 118.112, 111.001 , 109.648, 105.894, 105.064, 67.803, 56.624, 55.861 , 50.432, 43.104, 32.149, 29.592, 26.938, 25.793, 23.692; MS (AP/CI) 508 (M+H)+ ; IC50 = 0.818 nM.
Example 3: 7-methoxy-4-(3-phenylpiperidin-1 -yl)-6-(2-pyridin-2- ylethoxy)quinazoline: Using Preparation 2 and 2-(2-pyridyl)ethanol, the general procedure in Example 1 was used for the synthesis of the title compound in 80% yield; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 26.0, 32.2, 37.9, 43.2, 50.6, 56.4, 57.3, 68.5, 105.3, 107.7, 111.8, 122.0, 124.1 , 126.9, 127.4, 128.8, 136.7, 143.7, 147.8, 149.3, 149.7, 153.3, 155.0, 158.2, 164.3; MS (AP/CI) 441.1 (M+H)+ ; IC50 = 65.6 nM.
Example 4: 7-methoxy-4-(3-phenylpiperidin-1-yl)-6-(3-pyridin-2- ylpropoxy)quinazoline: Using Preparation 2 and 3-(2-pyridyl)propanol, the general procedure in Example 1 was used for the synthesis of the title compound in 88% yield; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 25.9, 28.4, 28.9, 32.3, 34.8, 43.1 , 50.7, 56.3, 57.0, 68.5, 77.0, 77.3, 77.6, 104.9, 107.6, 111.7, 121.4, 123.2, 127.0, 127.3, 128.8, 136.6, 143.6, 148.0, 149.6, 153.2, 155.1 , 161.2, 164.2; MS (AP/CI) 455.2 (M+H)+ ; IC50 = 124 nM.
Example 5: 7-methoxy-4-(3-phenylpiperidin-1 -yl)-6-IY3-quinolin-2-ylprop-2-yn-1 - vDoxylquinazoline: 2-lodoquinoline (240 mg, 0.94 mmol) was mixed with Preparation 3 (350 mg, 0.94 mmol), copper(l) iodide (23 mg, 0.12 mmol), dichloropalladium bis(triphenylphosine) (23 mg, 0.033 mmol), triethylamine (2 mL), diisopropylamine (2 mL) in chloroform (2 mL) and methanol (2 mL). The mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with methylene chloride and was filtered through a short silica plug. The recovered reaction solvent was washed with water and then brine, was dried over magnesium sulfate, was filtered, and was concentrated. Purification by silica gel chromatography (100-1 chloroform/methanol) gave 360 mg (77% yield) of the title compound; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 26.1 , 32.4, 42.9, 51.6, 56.1 , 56.5, 57.6, 83.6, 88.3, 107.0, 107.8, 111.4, 124.0, 126.9, 127.3, 127.5, 127.7, 128.7, 129.5, 130.5, 132.4, 136.5, 142.4, 143.7, 146.1 , 148.3, 153.5, 155.0, 164.3; IC50 = 8.3 nM. Example 6: 7-methoxy-4-(3-phenylpiperidin-1 -yl)-6-(3-quinolin-2- ylpropoxy)quinazoline: Example 5 (50 mg, 0.1 mmol) was mixed with Raney nickel (20 mg) in ethylacetate (10 ml). The mixture was placed under 50 psi hydrogen and was shaken at room temperature for 4 h. The reaction mixture was filtered through Celite, was concentrated, and was purified by silica gel chromatography (100-1 chloroform/methanol) to afford 20 mg (40 % yield) of the title compound; 13C NMR (100 MHz, CDCI3) d 164.130, 151.677, 155.164, 152.794, 148.030, 143.536, 136.664, 129.725, 129.022, 128.828, 127.781 , 127.310, 127.003, 126.151 , 121.709, 111.427, 107.202, 104.899, 68.618, 56.848, 56.377, 50.753, 43.141 , 35.619, 32.306, 28.866, 25.950; MS (AP/CI) 505.3 (M+H)+ ; IC50 = 13.9 nM.
Example 7: 7-methoxy-4-(3-phenylpiperidin-1-yl)-6-(quinolin-2- ylmethoxy)quinazoline: Using Preparation 2 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 80% yield; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 25.9, 32.1 , 42.7, 51.0, 56.5, 72.6, 77.5, 106.3, 107.7, 111.6, 119.1 , 126.9, 127.0, 127.4, 127.8, 128.1 , 128.8, 129.0, 130.1, 137.5, 143.8, 147.0, 147.8, 149.1 , 153.4, 154.8, 157.5, 164.2; MS (AP/CI) 477.3 (M+H)+; IC50 = 703 nM.
Preparation 5: 5-hvdroxy-4-methoxy-2-nitrobenzoic acid: A mixture of 4,5- dimethoxy-2-nitrobenzoic acid (15 g, 66 mmol) in aqueous sodium hydroxide (6 M, 60 mL) was heated at 1000C for 3 h, was cooled to room temperature, and was poured into a mixture of concentrated hydrochloric acid and crushed ice (pH <2). The mixture was extracted with ethylacetate, was washed with brine, was dried over magnesium sulfate, was filtered, and was concentrated in vacuo to afford 14 g (99% yield) of the title compound; 13C NMR (101 MHz, Methanol-D4) d 55.82, 107.46, 114.98, 122.90, 140.33, 149.09, 151.13, 167.96; MS (AP/CI): 212 (M-H)-.
Preparation 6: methyl 5-hvdroxy-4-methoxy-2-nitrobenzoate: Preparation 5 (15 g, 70.4 mmol) in methanol (100 mL) was treated with concentrated sulfuric acid (10 mL). The mixture was heated at reflux for 48 h. After cooling to room temperature, the methanol was removed under reduced pressure, the resulting residue was diluted with water and was extracted with ethylacetate. The organic layer was washed with water and then brine, was dried over magnesium sulfate, was filtered, and was concentrated to afford 15.4 g (96% yield) of the title compound; MS (AP/CI): 228 (M+H)+; 226 (M-H)-.
Preparation 7: methyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate: Preparation 6 (15.4 g, 68 mmol), benzyl bromide (9.7 mL, 82 mmol), and cesium carbonate (44 gm, 136 mmol) in DMSO (200 mL) were stirred at room temperature for 24 h. The mixture was diluted with ethylacetate (ca. 2 L) and n-butanol (ca. 100 mL). The mixture was washed with water and brine, was dried over magnesium sulfate, was filtered, and was concentrated. The residue was purified by silica gel chromatography (1 :5 to 2:1 ethylacetate-hexanes) to afford 20.2 g (94% yield) of the title compound; MS (AP/CI): 286.1 (M+H)+ .
Preparation 8: methyl 2-amino-5-(benzyloxy)-4-methoxybenzoate: Preparation 7 (20 g, 63 mmol) was mixed with ammonium chloride (50.6 g, 945 mmol) in methanol (200 mL) and water (50 mL), then iron poweder (35.3 g, 630 mmol) was added and the mixture was heated at 9O0C for 24 h. The mixture was filtered while hot through Celite and the filter cake was washed with methylene chloride and water. The aqueous and organic layers were separated and the aqueous layer was made basic with sodium bicarbonate and was extracted with methylene chloride. The organic layers were combined and were washed with brine, were dried over magnesium sulfate, were filtered, and were concentrated to afford 15.5 g (86% yield) of the title compound; MS (AP/CI): 288.2 (M+H)+ .
Preparation 9: 2-amino-5-(benzyloxy)-4-methoxybenzoic acid: reparation 8 (15.5 g, 54 mmol) was was treated with lithium hydroxide (13 g, 540 mmol) in methanol/water/THF (1 :1 :2, 60 mL total volume). The mixture was heated at 750C for 6 h. After cooling, the methanol and THF were removed in vacuo and the aqueous layer was diluted with water, the pH was adjusted to 6/7 by using 1 N HCI, and it was extracted with ethylacetate. The organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and was concentrated to afford 13.7 g (93% yield) of the title compound; MS (AP/CI): 274.2 (M+H)+ . Preparation 10: 6-(benzyloxy)-7-methoxyquinazolin-4(3H)-one: Preparation 9 (5 g,
18.3 mmol) was mixed with amidine acetate (3.8 g, 36.6 mmol) in ethylene glycol monomethyl ether (25 mL) and the mixture was heated at 13O0C for 24 h. After cooling to room temperature, part of the solvent was removed in vacuo and ammonium hydroxide (5 mL, 30% in water) and water (50 mL) were added. The solid was filtered, was washed with water and hexanes, and was then dried under vacuum to afford 4.87 g (94% yield) of the title compound; MS (AP/CI): 283.1 (M+H)+ .
Preparation 11 : 6-(benzyloxy)-4-chloro-7-methoxyquinazoline: Preparation 10 (4.85 g, 17.2 mmol) in phosphorous oxychioride (25 mL) was heated to 12O0C for 3 h. After cooling to room temperature, the phosphorous oxychioride was removed in vacuo, the residue was slowly added to saturated aqueous potassium carbonate and the mixture was stirred until bubbling ceased. The aqueous mixture was extracted with chloroform, the organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and was concentrated to afford 5.1 g (99% yield) of the title compound; MS (AP/CI): 301.1 , 303.1 (M+H)+.
Preparation 12: 6-(benzyloxy)-7-methoxy-4-phenylquinazoline: Preparation 11 (1 g, 3.3 mmol) was mixed with phenylboronic acid (0.5 g, 4 mmol), Pd2(dba)3-CHCI3 (72 mg, 0.07 mmol), tricyclohexyl phosphine (56 mg, 0.2 mmol), and cesium carbonate (1.6 g, 5 mmol) in 1 ,4-dioxane (10 mL) was heated at 1000C for 24 h. After cooling to room temperature, solvent was removed in vacuo. The residue was diluted with water and 1N NaOH and was extracted with chloroform. The chloroform layer was washed with brine, was dried over magnesium sulfate, was filtered, and was concentrated. Purification by silica gel chromatography (2:1 ethylacetate-hexanes) afforded 0.65 g (57% yield) of the title compound; MS (AP/CI) 343.1 (M+H)+ .
Preparation 13: 6-(benzyloxyV7-methoxy-4-(pyridin-3-vDquinazoline: Using 3-(1 ,3,2- dioxaborinan-2-yl)pyridine and Preparation 11 , the general procedure in Preparation 12 was used to synthesize the title compound in 70% yield; MS (AP/CI): 344.1 (M+H)+.
Preparation 14: 6-(benzyloxyV7-methoxy-4-(pyridin-4-vQquinazoline: Using 4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine and Preparation 11, the general procedure in Preparation 12 was used to synthesize the title compound in 41% yield; MS (AP/CI): 344.1 (M+H)+.
Preparation 15: 6-(benzyloxy)-7-methoxy-4-(3-(trifluoromethyl)phenvQquinazoline: Using Preparation 11 and 3-trifluromethylphenyl boronic acid, the general procedure in Preparation 12 was used to prepare the title compound in 65% yield.; MS (AP/CI): 411.0 (M+H)+.
Preparation 16: 7-methoxy-4-phenylquinazolin-6-ol: Preparation 12 (0.62 g, 1.8 mmol) was added to anisole (3.9 mL, 36 mmol) in trifluoracetic acid (25 mL). The mixture was heated to 75 0C for 24 h. After cooling, the mixture was concentrated and was purified by silica gel chromatography (50:1 chloroform-methanol) to afford 430 mg (95% yield) of the title compound; MS (AP/CI) 253.1 (M+H)+.
Preparation 17: 7-methoxy-4-(pyridin-3-vπquinazolin-6-ol: Using Preparation 13, the general procedure in Preparation 16 was used to prepare the title compound in 94% yield; MS (AP/CI): 254.1 (M+H)+. Preparation 18: 7-methoxy-4-(pyridin-4-yl')quinazolin-6-ol: Using Preparation 14, the general procedure in Preparation 16 was used to prepare the title compound in 81 % yield.; MS (AP/CI): 254.1 (M+H)+.
Preparation 19: 7-methoxy-4-(3-(trifluoromethyl)phenyl)quinazolin-6-ol: Using
Preparation 15, the general procedure in Preparation 16 was used to prepare the title compound in 97% yield.; MS (AP/CI): 321.0 (M+H)+.
Example 8: 7-methoxy-6-f3-(1-methyl-1 H-benzimidazol-2-vDpropoxy|-4-pyridin-3- ylquinazoline: Using Preparation 17 and 3-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-1-ol as the starting materials, the general procedure in Example 1 was used for the synthesis of Example 8 with the following modifications: after silica-bound p-toluene sulfonic acid and silica gel chromatographies, the residue was treated with p-TsCI resin (Argonaut Labs), diisopropyl ethyl amine, and 4-N,N-dimethylamino yridine to remove starting benzimidazole propanol. Following silica gel chromatography (chloroform-methanol-ammonium hydroxide 50:1 :0.5), 42% yield of the title compound was obtained.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 23.9, 26.7, 29.8, 56.5, 68.1, 104.3, 107.4, 109.1, 119.0, 119.3, 122.1 , 122.4, 123.9, 133.8, 135.9, 137.2, 142.6, 149.5, 150.3, 150.4, 150.9, 153.8, 154.2, 156.6, 162.1; MS (AP/CI): 426.4 (M+H)+ ;IC50 = 1.81 nM.
Example 9: 7-methoxy-4-pyridin-3-yl-6-(2-quinolin-2-ylethoxy)quinazoline: Using Preparation 17 and Preparation 4 as the starting materials, the general procedure in Example 1 was used for the synthesis of the title compound in 63% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.5, 56.6, 68.6, 104.6, 107.4, 119.0, 122.3, 123.9, 126.4, 127.2, 127.8, 129.0, 129.8, 133.8, 136.7, 137.2, 148.1 , 149.5, 150.3, 150.4, 150.9, 153.8, 156.6, 158.5, 162.1 ; MS (AP/CI): 409.0 (M+H)+ ;IC50 = 2.85 nM. Example 10: 7-methoxy-4-pyridin-4-yl-6-(2-quinolin-2-ylethoxy)quinazoline: Using Preparation 18 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 62% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.4, 56.6, 68.6, 104.5, 107.5, 118.6, 122.3, 124.1 , 126.5, 127.2, 127.8, 128.9, 130.0, 136.9, 145.4, 149.6, 150.5, 150.6, 153.8, 156.8, 158.4, 162.5; MS (AP/CI): 409.1 (M+H)+ ;IC50 = 3.68 nM.
Example 11 : 7-methoxy-4-phenyl-6-(2-quinolin-2-ylethoxy)quinazoline: Using
Preparation 16 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 57% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.6, 56.6, 68.5, 105.7, 107.3, 122.1, 122.4, 126.3, 127.2, 127.8, 129.0, 129.0, 129.8,
129.8, 130.0, 136.6, 137.8, 148.1, 149.4, 149.9, 153.8, 156.3, 158.8, 165.3; MS (AP/CI) 408.1 (M+H)+ ;IC50 = 4.36 nM.
Example 12: 7-methoxy-6-(2-quinolin-2-ylethoxy)-4-f3- (trifluoromethyl)phenvπquinazoline: Using Preparation 19 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 46% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.4, 56.6, 68.5, 104.8, 107.4, 118.7, 122.3, 126.4, 126.6, 126.6, 126.8, 126.8, 127.2, 127.8, 129.0, 129.5, 129.8, 131.3, 131.7, 133.0, 136.7, 138.6, 149.6, 150.3, 153.7, 156.6, 158.6, 163.5; MS (AP/CI) 476.0 (M+H)+ ;IC50 = 5.08 nM. Example 13: 7-methoxy-4-pyridin-3-yl-6-(quinolin-2-ylmethoxy)quinazoline: Using
Preparation 17 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 71% yield.; 13C NMR (101 MHz, CHLOROFORM- D) d ppm 56.8, 72.6, 106.0, 107.6, 118.9, 119.2, 123.4, 127.1, 127.8, 127.9, 129.3, 130.2,
136.9, 137.5, 147.7, 149.5, 149.6, 150.4, 150.9, 154.0, 156.5, 156.7, 162.4; MS (AP/CI) 395.1 (M+H)+ ;IC50 = 166 nM.
Example 14: 7-methoxy-4-pyridin-4-yl-6-(quinolin-2-ylmethoxy)quinazoline: Using Preparation 18 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 81% yield.; 13C NMR (101 MHz, CHLOROFORM- D) d ppm 56.8, 72.6, 105.9, 107.6, 118.3, 119.0, 123.8, 127.3, 127.7, 127.9, 129.3, 130.4, 137.5, 145.0, 147.7, 149.6, 150.3, 153.9, 156.5, 156.8, 162.5; MS (AP/CI) 395.1 (M+H)+ ;IC50 = 484 nM.
Example 15: 7-methoxy-4-phenyl-6-(quinolin-2-ylmethoxy)quinazoline: Using
Preparation 16 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 96% yield.; 13C NMR (101 MHz, CHLOROFORM- D) d ppm 56.7, 72.3, 106.9, 107.5, 118.7, 119.0, 127.0, 127.8, 128.0, 128.8, 129.3, 129.5, 129.9, 130.1, 137.4, 147.8, 149.1, 149.4, 154.0, 156.2, 157.0, 165.4; MS (AP/CI) 394.1 (M+H)+ ;IC50 = 23.6 nM. Preparation 20: 6,7-dimethoxyquinazoline: A mixture of 2,4-dichloro-6, 7- dimethoxyquinazoline (5g, 19.3 mmol), triethylamine (5.6 mL), and palladium on carbon (10%, 0.5 g) in methanol (200 mL) was shaken under hydrogen (40 psi) at room temperature for 26 h. The mixture was filtered through Celite, was concentrated in vacuo, and was purified by silica gel chromatography (chloroform-methanol 100:1) to afford 2.4 g (65% yield) of the title compound.; MS (AP/CI): 191.1 (M+H)+ .
Preparation 21 : 6-methoxyquinazolin-7-ol: 6,7-Dimethoxyquinazoline (Preparation 20, 2.3 g, 12 mmol) and L-methionine (2.1 g, 14.4 mmol) in methanesulfonic acid (60 mL) was heated as follows: 1200C, 1 h; 14O0C, 2 h; 1450C, 4 h; 120°C, 16 h. More L-methionine (0.5 g) was added and the mixture was heated at 145°C for 6 h and 1200C for 16 h. After cooling to room temperature, the mixture was poured onto ice, the pH was adjusted to 7-8 with sodium hydroxide, and the aqueous mixture was extracted using chloroform in a "heavier- than-water" continuous extraction device for 72 h. The chloroform was then concentrated in vacuo and the residue was purified by silica gel chromatography (chloroform-methanol 50:1) to afford 1.2 g (57% yield) of the title compound.; MS (AP/CI): 177.2 (M+H)+ .
Example 16: 6-methoxy-7-(2-quinolin-2-ylethoxy')quinazoline: Using Preparation 21 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 38% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 158.49, 156.83, 155.80, 154.19, 151.10, 148.18, 136.74, 129.85, 129.07, 127.75, 127.20, 126.39, 122.23, 121.25, 112.50, 107.64, 104.14, 68.53, 56.41 , 38.15; MS (AP/CI): 332.2 (M+H)+;IC50 = 7.06 nM.
Example 17: 6-methoxy-7-r2-(1 -methyl- 1 H-benzimidazol-2-yl)ethoxylquinazoline: Using Preparation 21 and 2-(1-methyl-1H-benzo[d]imidazol-2-yl)ethanol, the general procedure in Example 1 was used for the synthesis of the title compound in 20% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 27.6, 30.2, 56.3, 67.7, 104.2, 107.6, 109.5, 119.4, 121.3, 122.3, 122.6, 135.9, 142.5, 148.1 , 150.8, 152.0, 154.2, 155.3, 156.9; MS (AP/CI): 335.2 (M+H)+ ;IC50 = 36.1 nM.
Example 18: 6-methoxy-7-r3-(1-methyl-1 H-benzimidazol-2-yl)propoxylquinazoline: Using Preparation 21 and 3-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-1-ol, the general procedure in Example 1 was used for the synthesis of the title compound in 79% yield.; Diagnostic 13C NMR peaks (101 MHz, CHLOROFORM-D) d ppm 156.82, 155.69, 154.20, 151.06, 148.15, 142.53, 135.92, 122.39, 122.14, 121.21, 119.31 , 109.18, 107.49, 104.03, 68.24, 56.30, 29.85, 26.73, 23.99; MS(AP/CI): 349.2 (M+H)+ ;IC50 = 7.22 nM.
Example 19: 6-methoxy-7-(quinolin-2-ylmethoxytauinazoline: Using Preparation 21 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 68% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 56.5, 72.4, 104.3, 108.5, 119.1 , 121.5, 127.0, 127.9, 129.2, 130.2, 137.5, 147.8, 148.0, 151.1, 154.1 , 155.3, 156.3, 156.9; MS (AP/CI): 318.2 (M+H)+ ;IC50 = 233 nM.
Preparation 22: 6-(benzyloxyV7-methoxy-4-morpholinoquinazoline: A solution of 6-
(benzyloxy)-4-chloro-7-methoxyquinazoline (Preparation 11 , 500 mg, 1.66 mmol), morpholine (173 uL, 1.99 mmol), and diisopropylethyl amine (580 uL, 3.32 mmol) in isopropanol (10 mL) was heated at 9O0C for 4 h. The solvent was removed in vacuo, the residue was diluted with water and chloroform, and the pH was adjusted to >12 using 1 N sodium hydroxide. The biphasic mixture was extracted with chloroform, the organic layer was washed with brine, was dried (magnesium sulfate), was filtered, and was concentrated. Purification by silica gel chromatography (chloroform-methanol, 75:1 ) gave 580 mg (99% yield) of the title compound.;
MS (AP/CI): 352.1 (M+H)+ .
Preparation 23: 6-(benzyloxy)-7-methoxy-N,N-dimethylquinazolin-4-amine: Using Preparation 11 and dimethylamine, the general procedure used to synthesize Preparation 22 was used to prepare the title compound in 86% yield.; MS (AP/CI): 310.1 (M+H)+. Preparation 24: 6-(benzyloxyVN,N-diethyl-7-methoxyquinazolin-4-amine: Using
Preparation 11 and diethylamine, the general procedure in Preparation 22 was used to prepare the title compound in 89% yield.; MS (AP/CI): 338.1 (M+H)+.
Preparation 25: 4-(azetidin-1 -yl)-6-(benzyloxy)-7-methoxyquinazoline: Using
Preparation 11 and azetidine, the general procedure in Preparation 22 was used to prepare the title compound in 85% yield.; MS (AP/CI): 322.1 (M+H)+.
Preparation 26: 6-(benzyloxy)-7-methoxy-4-(pyrrolidin-1-yl)quinazoline: Using
Preparation 11 and pyrrolidine, the general procedure in Preparation 22 was used to prepare the title compound in 87% yield.; MS (AP/CI): 336.1 (M+H)+.
Preparation 27: 6-(benzyloxyV7-methoxy-4-(piperidin-1 -vDquinazoline: Using Preparation 11 and piperidine, the general procedure in Preparation 22 was used to prepare the title compound in 89% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 24.9, 26.2,
51.1 , 56.4, 71.1 , 77.0, 106.8, 107.8, 111.5, 127.1 , 128.2, 128.9, 136.5, 146.9, 149.2, 153.4,
155.0, 164.4,MS (AP/CI): 350.1 (M+H)+.
Preparation 28: 4-(dimethylamino)-7-methoxyquinazolin-6-ol: Using Preparation 23, the general procedure in Preparation 16 was used to prepare the title compound in 99% yield.; MS (AP/CI): 220.2 (M+H)+.
Preparation 29: 4-(diethylamino)-7-methoxyquinazolin-6-ol: Using Preparation 24, the general procedure in Preparation 16 was used to prepare the title compound in 98% yield.; MS (AP/CI): 248.1 (M+H)+. Preparation 30: 4-(azetidin-1-yl)-7-methoxyquinazolin-6-ol: Using Preparation 25, the general procedure in Preparation 16 was used to prepare the title compound in 99% yield.; MS (AP/CI): 232.2 (M+H)+. Preparation 31: 7-methoxy-4-fpyrrolidin-1-yl)quinazolin-6-ol: Using Preparation 26, the general procedure in Preparation 16 was used to prepare the title compound in 99% yield.; MS (AP/CI): 246.3 (M+H)+.
Preparation 32: 7-methoxy-4-(piperidin-1-vπquinazolin-6-ol: Using Preparation 27, the general procedure in Preparation 16 was used to prepare the title compound in 99% yield.; 13C NMR (101 MHz, METHANOL-D4) d ppm 24.1 , 26.4, 50.8, 56.5, 99.5, 107.0, 109.3, 136.4, 145.7, 147.6, 156.2, 161.2; MS (AP/CI): 260.3 (M+H)+
Preparation 33: 7-methoxy-4-morpholinoαuinazolin-6-ol: Using Preparation 22, the general procedure in Preparation 16 was used to prepare the title compound in 99% yield.; MS (AP/CI): 262.1 (M+H)+.
Example 20: 7-methoxy-N,N-dimethyl-6-(2-quinolin-2-ylethoxy)quinazolin-4-amine: Using Preparation 28 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 32% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.8, 41.9, 56.3, 68.9, 106.8, 107.7, 110.6, 122.4, 126.3, 127.2, 127.8, 129.0, 129.8, 136.6, 146.9, 148.2, 149.2, 153.1 , 154.7, 159.0, 163.3; MS (AP/CI): 375.3 (M+H)+ ;IC50 = 5.73 nM.
Example 21 : 7-methoxy-4-morpholin-4-yl-6-(2-quinolin-2-ylethoxy)quinazoline: Using Preparation 33 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 24% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.6, 50.4, 56.4, 66.9, 68.8, 105.1, 107.6, 111.3, 122.4, 126.4, 127.2, 127.9, 129.0, 129.9, 136.7, 148.1 , 148.2, 152.9, 155.3, 158.8, 163.9; MS (AP/CI) 417.2 (M+H)+ ;IC50 = 12.1 nM.
Example 22: 7-methoxy-4-pyrrolidin-1 -yl-6-(2-quinolin-2-ylethoxy)quinazoline: Using Preparation 31 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 6% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 25.9, 29.9, 38.9, 50.9, 56.2, 69.1 , 107.5, 107.8, 122.5, 126.3, 127.8, 129.0, 129.7, 136.6, 146.5, 148.2, 148.7, 153.4, 159.1 ; MS (AP/CI): 401.3 (M+H)+ ; IC50 = 13.1 nM.
Example 23: 7-methoxy-4-piperidin-1 -yl-6-(2-quinolin-2-ylethoxy)quinazoline: Using Preparation 32 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 35% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 25.0, 26.1, 38.6, 51.2, 56.4, 68.6, 105.7, 107.6, 111.7, 122.5, 126.3, 127.2, 127.8, 129.0, 129.7, 136.6, 147.6, 148.2, 149.1 , 153.3, 154.9, 159.0, 164.5; MS (AP/CI): 415.3 (M+H)+; IC50 = 13.6 nM.
Example 24: N.N-diethyl-7-methoxy-6-(2-quinolin-2-ylethoxy)αuinazolin-4-amine: Using Preparation 29 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 49% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 13.4, 38.6, 45.1 , 56.3, 68.6, 106.1 , 107.7, 110.9, 122.4, 126.3, 127.2, 127.8, 129.0, 129.7, 136.6, 147.0, 148.2, 149.1, 153.0, 154.5, 159.0, 162.4; MS (AP/Cl) 403.3 (M+H)+ ; IC50 = 28.8 nM.
Example 25: 4-azetidin-1-yl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazoline: Using Preparation 30 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 25% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 17.3, 38.7, 53.4, 56.2, 68.9, 105.5, 107.7, 109.4, 122.4, 126.3, 127.2, 127.8, 129.0, 129.7, 136.6, 147.1, 147.9, 148.2, 154.0, 154.8, 158.9, 159.9; MS (AP/Cl): 387 (M+H)+ ;IC50 = 14.3 nM.
Preparation 34: 6,7-dimethoxy-4-pheny|quinazoline: Using 4-chloro-6,7- dimethoxyquinazoline and phenylboronic acid, the general procedure in Preparation 12 was used in the synthesis of the title compound in 94% yield.; MS (AP/Cl): 267.2 (M+H)+.
Preparation 35: 6,7-dimethoxy-4-(pyridin-3-yl)quinazoline: Using 4-chloro-6,7- dimethoxyquinazoline and 3-(diethylboryl)pyridine), the general procedure in Preparation 12 was used in the synthesis of the title compound in 15% yield.; MS (AP/Cl): 268.2 (M+H)+. Preparation 36: 6,7-dimethoxy-4-(pyridin-4-yl)quinazoline: Using 4-chloro-6,7- dimethoxyquinazoline and 4-pyridylboronic acid, the general procedure in Preparation 12 was used in the synthesis of the title compound in 33% yield.; MS (AP/Cl): 268.2 (M+H)+.
Preparation 37: 6-methoxy-4-phenylquinazolin-7-ol: Preparation 34 (1.5 g, 5.64 mmol) and L-methionine (1.0 g, 6.77 mmol) in methanesulfonic acid (30 mL) were heated at 12O0C, 1h; 14O0C, 2 h; 145°C, 5h; 120°C, 16h; 145°C, 5 h. After cooling to room temperature, the mixture was poured onto ice, the pH was adjusted to a range of 7-8 by using sodium hydroxide, and the mixture was extracted with methylene chloride. The organic layer was dried over magnesium sulfate, was filtered, and was concentrated. The residue was purified by silica gel chromatography (chloroform-methanol, 100:1 ), to afford 0.5 g (35% yield) of the title compound.; MS (AP/Cl): 253.2 (M+H)+.
Preparation 38: 6-methoxy-4-(pyridin-3-v0quinazolin-7-ol: The same general procedure used to synthesize Preparation 7 was employed, with the change of heating temperatures and times as follows: 120°C, 16 h; then 14O0C, 4 h. Following work-up, the aqueous phase was extracted continuously with chloroform ("heavier-than-water" continuous extractor used) for two days. The organic layers were combined, solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (chloroform- methanol, 40:1 ). The final product was obtained in 50% yield.; MS (AP/Cl): 254.2 (M+H)+.
Preparation 39: 6-methoxy-4-(pyridin-4-yl)quinazolin-7-ol: Using Preparation 36, the procedure in Preparation 38 was used to prepare the title compound in 42% yield.; MS (AP/Cl): 254.2 (M+H)+ ;IC50 = 1.87 nM.
Example 26: 6-methoxy-4-pyridin-4-yl-7-(quinolin-2-ylmethoxy)quinazoline: Using Preparation 39 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 75% yield.; 13C NMR (101 MHz, CHLOROFORM- D) d ppm 56.5, 72.4, 103.2, 109.2, 118.8, 119.1 , 124.1 , 127.0, 127.9, 129.3, 130.2, 137.5, 145.6, 147.8, 149.4, 150.5, 151.4, 153.7, 155.2, 156.1 , 162.4; MS(AP/CI): 395.2 (M+H)+ ;IC50 = 69.6 nM. Example 27: 6-methoxy-4-phenyl-7-(quinolin-2-ylmethoxy)quinazoline: Using
Preparation 37 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 85% yield.; 13C NMR (101 MHz, CHLOROFORM- D) d ppm 56.4, 72.4, 104.5, 109.0, 119.1, 119.2, 127.0, 127.9, 128.9, 129.3, 129.7, 130.0, 130.2, 137.5, 137.8, 147.8, 149.1 , 150.9, 153.7, 154.8, 156.4, 165.3; MS (AP/CI): 394.2 (M+H)+ ;IC50 = 38.7 nM.
Example 28: 6-methoxy-4-pyridin-3-yl-7-(quinolin-2-ylmethoxy)quinazoline: Using Preparation 38 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compoundin 68% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 56.5, 72.4, 103.4, 109.2, 119.1 , 119.3, 124.0, 127.0, 127.9, 129.3, 130.2, 133.9, 137.3, 137.6, 147.8, 149.3, 150.2, 150.9, 151.4, 153.8, 155.1 , 156.2, 162.1; MS (AP/CI): 395.2 (M+H)+ ;IC50 = 277 nM.
Example 29: 6-methoxy-7-[3-(1-methyl-1 H-benzimidazol-2-ylbropoxy1-4- phenylquinazoline: Using Preparation 37 and 3-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-1- ol, the general procedure in Example 1 was used for the synthesis of the title compound in 94% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d 165.17, 155.25, 154.24, 153.80, 150.79, 149.34, 137.96, 136.01 , 129.95, 129.73, 128.92, 122.35, 122.10, 119.42, 118.91, 109.15, 108.04, 104.24, 68.24, 56.21, 28.89, 26.80, 24.06 ppm; MS (AP/CI): 425.21 (M+H)+ ;IC50 = 45.6 nM.
Example 30: 6-methoxy-4-pyridin-3-yl-7-(2-quinolin-2-ylethoxy)quinazoline: Using Preparation 38 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 98% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.21 , 56.41 , 68.62, 103.31 , 108.27, 119.00, 122.22, 123.98, 126.37, 127.20, 127.77, 129.16, 129.81 , 133.93, 136.66, 137.31 , 148.19, 149.49, 150.29, 150.88, 151.35, 153.77, 155.71 , 158.47, 161.95; MS (AP/CI): 409.1 (M+H)+ ;IC50 = 64.4 nM. Example 31 : 6-methoxy-4-pyridin-4-yl-7-(2-quinolin-2-ylethoxy)quinazoline: Using
Preparation 39 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 60% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.0, 56.4, 68.6, 103.1 , 108.3, 118.6, 122.2, 124.1 , 126.5, 127.2, 127.8, 128.9, 130.0, 137.0, 145.6, 149.5, 150.5, 151.4, 153.7, 155.7, 158.3, 162.3; MS (AP/CI): 409.2 (M+H)+ ;IC50 = 80.2 nM.
Example 32: 6-methoxy-7-f3-(1-methyl-1 H-benzimidazol-2-ylbropoxyl-4-pyridin-3- ylquinazoline: Using Preparation 38 and 3-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-1-ol, the general procedure in Example 1 was used for the synthesis of the title compound in 75% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 161.96, 155.55, 154.12, 153.80, 151.28, 150.93, 150.31 , 149.47, 137.28, 135.89, 133.91 , 123.98, 122.48, 122.25, 119.30, 118.98, 109.20, 108.17, 103.18, 68.32, 56.26, 29.91 , 26.73, 23.98; MS (AP/CI): 426.3 (M+H)+ ;IC50 = 90.5 nM.
Example 33: 6-methoxy-4-phenyl-7-(2-quinolin-2-ylethoxy)quinazoline: Using
Preparation 37 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 25% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d 165.21 , 158.51, 155.34, 153.76, 150.83, 149.32, 137.94, 137.02, 130.02, 129.96, 129.74, 128.925, 127.78, 127.24, 126.52, 122.29, 118.96, 108.15, 104.41 , 68.48, 56.34, 38.05 ppm; MS (AP/CI): 408.1 (M+H)+ ;IC50 = 465 nM.
Example 34: 6-methoxy-7-r3-(1-methyl-1 H-benzimidazol-2-v0propoxyl-4-pyridin-4- ylquinazoline: Using Preparation 39 and 3-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-1-ol, the general procedure in Example 1 was used for the synthesis of the title compound in 71% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 23.8, 26.8, 30.0, 56.3, 68.3, 102.9, 108.1 , 109.3, 118.6, 119.0, 122.5, 122.7, 124.1 , 135.6, 145.7, 149.5, 150.3, 151.3, 153.6, 154.1 , 155.7, 162.2, 164.3; MS (AP/CI): 426.3 (M+H)+ ;IC50 = 43.1 nM.
Preparation 40: 6-(benzyloxy)-4-chloroquinazoline: The title compound was prepared in a manner analogous to that described for Preparation 11 , using 5-hydroxy-2-nitrobenzoic acid as the starting material in the sequence. MS (AP/CI): 271.1 , 273.1 (M+H)+.
Preparation 41 : 6-(benzyloxy)-4-phenylαuinazoline: Using Preparation 40 and phenyl boronic acid, the general procedure in Preparation 12 was used to synthesize the title compound in 48% yield. MS (AP/CI): 313.1 (M+H)+.
Preparation 42: 6-(benzyloxy)-4-(pyridin-3-yl)quinazoline: Using 3- (diethylboryl)pyridine and Preparation 40, the general procedure in Preparation 12 was used to synthesize the title compound in 30% yield. MS (AP/CI): 314.1 (M+H)+.
Preparation 43: 6-(benzyloxy)-4-(pyridin-4-yl)quinazoline: Using 4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)pyridine and Preparation 40, the general procedure in Preparation 12 was used to synthesize the title compound in 41% yield. MS (AP/CI): 314.1 (M+H)+.
Preparation 44: 6-(benzyloxy)-4-(3-(trifluoromethyl)phenyl)quinazoline: Using
Preparation 40 and 3-(trifluoromethylphenyl) boronic acid, the general procedure in Preparation 12 was used to synthesize the title compound in 86% yield. MS (AP/CI): 381.0 (M+H)+. Preparation 45: 1 -(3-(6-(benzyloxy)αuinazolin-4-yl')phenvπethanone: Using
Preparation 40 and 3-acetylphenyl boronic acid, the general procedure in Preparation 12 was used to synthesize the title compound in 72% yield. MS (AP/CI): 355.0 (M+H)+. Preparation 46: 4-phenylαuinazolin-6-ol: Using Preparation 41 , the general procedure in Preparation 16 was used to synthesize the title compound in 89% yield. MS (AP/CI):
223.1 (M+H)+.
Preparation 47: 4-(pyridin-3-vBquinazolin-6-ol: Using Preparation 42, the general procedure in Preparation 16 was used to synthesize the title compound in 70% yield. MS (AP/CI): 224.1 (M+H)+.
Preparation 48: 4-(pyridin-4-yl)quinazolin-6-ol: Using Preparation 43, the general procedure in Preparation 16 was used to synthesize the title compound in 86% yield. MS (AP/CI): 224.1 (M+H)+. Preparation 49: 4-(3-(trifluoromethyl)phenyl)quinazolin-6-ol: Using Preparation 44, the general procedure in Preparation 16 was used to synthesize the title compound in 87% yield. MS (AP/CI): 291.0 (M+H)+.
Preparation 50: i-O-fe-hydroxyquinazolin^-vDphenvOethanone: Using Preparation 45, the general procedure in Preparation 16 was used to synthesize the title compound in 95% yield. MS (AP/CI): 265.1 (M+H)+.
Example 35: 4-phenyl-6-(quinolin-2-ylmethoxy)quinazoline: Using Preparation 46 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 81% yield. 13C NMR (101 MHz, CHLOROFORM-D) d ppm 71.9 (s, 1 C) 106.3 (s, 1 C) 119.2 (s, 1 C) 124.1 (s, 1 C) 127.0 (s, 1 C) 127.8 (s, 1 C) 128.0 (s, 1 C) 128.9 (s, 1 C) 129.2 (s, 1 C) 129.6 (s, 1 C) 130.1 (s, 1 C) 130.2 (s, 1 C) 130.8 (s, 1 C) 137.3 (s, 1 C) 137.4 (s, 1 C) 147.6 (s, 1 C) 147.8 (s, 1 C) 153.3 (s, 1 C) 157.0 (s, 1 C)
157.2 (s, 1 C) 167.0 (s, 1 C); MS (AP/CI): 364.1 (M+H)+ ;IC50 = 54.6 nM.
Example 36: 4-pyridin-4-yl-6-(quinolin-2-ylmethoxykiuinazoline: Using Preparation 48 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 81 % yield. 13C NMR (101 MHz, CHLOROFORM-D) d ppm 72.1 (s, 1 C) 105.3 (s, 1 C) 119.1 (s, 1 C) 123.6 (s, 1 C) 123.9 (s, 1 C) 127.3 (s, 1 C) 127.7 (s, 1 C) 127.9 (s, 1 C) 129.3 (s, 1 C) 130.4 (s, 1 C) 131.1 (s, 1 C) 137.5 (s, 1 C) 144.8 (s, 1 C) 147.8 (s, 1 C) 150.4 (s, 1 C) 153.2 (s, 1 C) 156.8 (s, 1 C) 157.6 (s, 1 C) 164.1 (s, 1 C); MS (AP/CI): 365.1 (M+H)+ ;IC50 = 518 nM. Example 37: 4-pyridin-3-yl-6-(quinolin-2-ylmethoxy)quinazoline: Using Preparation
47 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 95% yield. 13C NMR (101 MHz, CHLOROFORM-D) d ppm 72.0 (s, 1 C) 105.5 (s, 1 C) 119.3 (s, 1 C) 123.5 (s, 1 C) 124.2 (s, 1 C) 127.1 (s, 1 C) 127.4 (S, 1 C) 127.8 (s, 1 C) 127.9 (s, 1 C) 129.2 (s, 1 C) 130.3 (s, 1 C) 131.1 (s, 1 C) 133.3 (s, 1 C) 137.0 (s, 1 C) 137.5 (s, 1 C) 147.7 (s, 1 C) 150.4 (s, 1 C) 151.0 (s, 1 C) 153.3 (s, 1 C) 156.7 (s, 1 C) 157.6 (s, 1 C) 163.9 (s, 1 C); MS (AP/CI): 365.1 (M+H)+ ; IC50 = 89.1 nM. Example 38: 1 -|3-F6-( αuinolin-2-ylmethoxy)αuinazoliπ-4-yllphenyl)ethanone: Using
Preparation 50 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 84% yield. 13C NMR (101 MHz, CHLOROFORM-
D) d ppm 71.9 (s, 1 C) 106.3 (s, 1 C) 119.2 (s, 1 C) 124.1 (s, 1 C) 127.0 (s, 1 C) 127.8 (s, 1 C) 128.0 (s, 1 C) 128.9 (s, 1 C) 129.2 (s, 1 C) 129.6 (s, 1 C) 130.1 (s, 1 C) 130.2 (s, 1 C)
130.8 (s, 1 C) 137.3 (s, 1 C) 137.4 (s, 1 C) 147.6 (s, 1 C) 147.8 (s, 1 C) 153.3 (s, 1 C) 157.0 (s, 1 C) 157.2 (s, 1 C) 167.0 (s, 1 C); MS (AP/CI): 406.1 (M+H)+ ; IC50 = 196 nM.
Example 39: 1 -(3-r6-(quinolin-2-ylmethoxy)quinazolin-4-vπphenyl}ethanol: A solution of Example 38 (100 mg, 0.25 mmol) in methanol (2 mL) at O0C was treated with sodium borohydride (19 mg, 0.5 mmol). The mixture was warmed to room temperature and was stirred for 2h. The solvent was removed in vacuo, the residue was diluted with ethyl acetate and was washed with brine, was dried (magnesium sulfate), was filtered, and was concentrated. Purification by silica gel chromatography (chloroform-methanol, 50:1 ), gave 100 mg (98% yield) of the title compound. 13C NMR (101 MHz, CHLOROFORM-D) d ppm 25.5 (s, 1 C) 70.4 (s, 1 C) 72.1 (s, 1 C) 106.5 (s, 1 C) 119.2 (s, 1 C) 124.1 (s, 1 C) 127.0 (s, 1 C) 127.1 (s, 1 C) 127.4 (s, 1 C) 127.8 (s, 1 C) 128.0 (s, 1 C) 128.7 (s, 1 C) 128.9 (s, 1 C) 130.3 (s, 1 C) 130.7 (s, 1 C) 137.2 (s, 1 C) 137.8 (s, 1 C) 147.0 (s, 1 C) 147.6 (s, 1 C) 153.3 (s, 1 C) 157.2 (s, 1 C) 157.3 (s, 1 C) 166.8 (s, 1 C); MS (AP/CI): 408.0 (M+H)+ ; IC50 = 258 nM. Example 40: 2-{3-f6-(quinolin-2-ylmethoxy)quinazolin-4-vπphenyl}propan-2-ol: A solution of Example 38 (100 mg, 0.25 mmol) in THF (2 mL) at -400C was treated dropwise with MeMgBr (0.27 mL, 0.375 mmol, 1.4 M in toluene/THF (3:1)). The mixture was stirred at - 4O0C for 1h, O0C for 3h, was cooled back to -4O0C and additional MeMgBr solution (0.4 mL) was added and the mixture was stirred at O0C for 2h. An additional 0.5 mL of MeMgBr solution was added and the mixture was stirred at room temperature for 16 h. The mixture was quenched by pouring into aqueous ammonium chloride solution, was extracted with ethyl acetate. The organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and was concentrated. Purification by silica gel chromatography (ethyl acetate- hexanes 3:2) gave 45 mg (43% yield) of the title compound. 13C NMR (101 MHz, CHLOROFORM-D) d ppm 31.9 (s, 1 C) 71.9 (s, 1 C) 72.6 (s, 1 C) 106.4 (s, 1 C) 119.3 (s, 1 C) 124.2 (s, 1 C) 126.3 (s, 1 C) 126.5 (s, 1 C) 127.0 (s, 1 C) 127.1 (s, 1 C) 127.8 (s, 1 C)
127.9 (s, 1 C) 128.0 (s, 1 C) 128.6 (s, 1 C) 129.0 (s, 1 C) 130.2 (s, 1 C) 130.7 (s, 1 C) 137.0 (s, 1 C) 137.6 (s, 1 C) 147.6 (s, 1 C) 150.2 (s, 1 C) 153.2 (s, 1 C) 157.0 (s, 1 C) 157.3 (s, 1 C) 167.2 (s, 1 C); MS (AP/CI): 421.9 (M+H)+ ; IC50 = 463 nM. Example 41 : 4-phenyl-6-(2-quinolin-2-ylethoxy)quinazoline: Using Preparation 46 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 32% yield. 13C NMR (101 MHz1 CHLOROFORM-D) d ppm 38.7 (s, 1 C) 67.9 (s, 1 C) 105.3 (s, 1 C) 122.3 (s, 1 C) 124.3 (s, 1 C) 126.4 (s, 1 C) 127.0 (s, 1 C) 127.8 (s, 1 C) 129.0 (s, 1 C) 129.8 (s, 1 C) 129.9 (s, 1 C) 130.1 (s, 1 C) 130.5 (s, 1 C) 136.8 (s, 1 C) 137.6 (s, 1 C) 147.5 (s, 1 C) 148.1 (s, 1 C) 153.1 (s, 1 C) 157.9 (s, 1 C) 158.9 (s, 1 C) 166.9 (s, 1 C); MS (AP/CI): 378.1 (M+H)+ ; IC50 = 71.1 nM. Example 42: 4-pyridin-4-y]-6-(2-quinolin-2-ylethoxy)quinazoline: Using Preparation
48 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 51% yield. 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.5 (s, 1 C) 68.0 (s, 1 C) 104.2 (s, 1 C) 122.2 (s, 1 C) 123.8 (s, 1 C) 124.1 (s, 1 C) 126.5 (s, 1 C) 127.2 (s, 1 C) 127.5 (s, 1 C) 127.8 (s, 1 C) 128.9 (s, 1 C) 130.0 (s, 1 C) 130.9 (s, 1 C) 136.9 (s, 1 C) 145.2 (s, 1 C) 147.7 (s, 1 C) 148.0 (s, 1 C) 150.6 (s, 1 C) 153.0 (s, 1 C) 158.3 (s, 1 C) 158.6 (s, 1 C) 164.1 (s, 1 C); MS (AP/CI): 379.1 (M+H)+ ; IC50 = 73.5 nM.
Example 43: 4-pyridin-3-yl-6-(2-quinolin-2-ylethoxy)quinazoline: Using Preparation 47 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 47% yield. 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.6 (s, 1 C) 68.0 (s, 1 C) 104.4 (s, 1 C) 122.2 (s, 1 C) 124.3 (s, 1 C) 126.4 (s, 1 C) 127.2 (s, 1 C) 127.4 (s, 1 C) 127.8 (s, 1 C) 129.0 (s, 1 C) 129.9 (s, 1 C) 130.8 (s, 1 C) 136.9 (s, 1 C) 137.2 (s, 1 C) 147.6 (s, 1 C) 148.0 (s, 1 C) 150.4 (s, 1 C) 151.0 (s, 1 C) 153.1 (s, 1 C) 158.3 (s, 1 C) 158.6 (s, 1 C) 163.7 (s, 1 C); MS (AP/CI): 379.1 (M+H)+ ; IC50 = 148 nM.
Example 44: 6-(2-quinolin-2-ylethoxy)-4-f3-(trifluoromethyl)phenvnquinazoline: Using Preparation 49 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 45% yield. 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.6 (s, 1 C) 67.9 (s, 1 C) 104.5 (s, 1 C) 122.2 (s, 1 C) 124.0 (s, 1 C) 126.4 (s, 1 C) 126.8 (s, 1 C) 127.2 (s, 1 C) 127.3 (s, 1 C) 127.8 (s, 1 C) 129.0 (s, 1 C) 129.5 (s, 1 C) 129.9 (s, 1 C) 130.8 (s, 1 C) 131.4 (s, 1 C) 133.1 (s, 1 C) 136.7 (s, 1 C) 138.4 (s, 1 C) 147.7 (s, 1 C) 148.1 (s, 1 C) 153.0 (s, 1 C) 158.2 (s, 1 C) 158.7 (s, 1 C) 165.0 (s, 1 C); MS (AP/CI): 446.0 (M+H)+ ; IC50 = 340 nM.
Preparation 51: 7-fluoroquinazolin-4(3H)-one: A mixture of 2-amino-4-fluorobenzoic acid (1.5 g, 9.4 mmol) and formamidine acetate (2.Og, 18.8 mmol) in ethyleneglycol monomethyl ether (15 mL) was heated at 13O0C for 24 h. After cooling to room temperature, ca. half of the solvent was evaporated and a white solid precipitated. Aqueous ammmonia (2 mL of 30% ammonium hydroxide in 20 mL water) was added and the solid was filtered, was washed with water, was washed with hexanes, and was dried in vacuo to give 1.4 g (91% yield) of the title compound. MS (AP/CI): 165.2 (M+H)+.
Preparation 52: 7-(benzyloxy)quinazolin-4(3H)-one: Sodium hydride (60% dispersion, 0.3 g, 7.3 mmol) was added to a solution of benzyl alcohol (0.76 mL, 7.3 mmol) in dimethylformamide (DMF1 8 mL). Preparation 51 (300 mg, 1.8 mmol) was added and the mixture was heated to 1400C for 4 h. After cooling to room temperature, concentrated hydrochloric acid was added, which afforded a precipitate. The precipitate was filtered off, was washed with water and with diethyl ether, was then stirred in chloroform for 2 h, was concentrated and was dried under high vacuum to give 425 mg (92% yield) of the title compound. MS (AP/CI): 253.3 (M+H)+. Preparation 53: 7-(benzyloxy)-4-chloroouinazoline: Preparation 52 (8.2 g, 32.5 mmol) in phosphorous oxychloride (50 mL) was heated at 12O0C for 3 h, was cooled to room temperature, and the phosphorous oxychloride was removed under reduced pressure. The remaining residue was added slowly to saturated aqueous potassium carbonate, When gas evolution had ceased, the mixture was extracted with chloroform, the organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and was concentrated to afford 8.5 g (97% yield) of the title compound. MS (AP/CI): 271.2, 273.2 (M+H)+.
Preparation 54: 7-(benzyloxy)-4-phenylquinazoline: Using Preparation 53 and 4- phenylboronic acid, the procedure in Preparation 12 afforded the title compound in 50% yield.
MS (AP/CI): 313.3 (M+H)+. Preparation 55: 7-(benzyloxy)-4-(pyridin-3-yl)quinazoline: Using Preparation 53 and
3-(diethylboryl)pyridine, the procedure in Preparation 12 afforded the title compound in 30% yield. MS (AP/CI): 314.3 (M+H)+.
Preparation 56: 7-(benzyloxy)-4-(pyridin-4-yl)quinazoline: Using Preparation 53 and
4-pyridylboronic acid, the procedure in Preparation 12 afforded a 2:1 mixture of the title compound and Preparation 52 that was carried on to the next step. This material was not characterized and was carried on crude to the next step.
Preparation 57: 7-(benzyloxy)-4-(4-methoxyphenyl)quinazoline: Using Preparation 53 and 4-methoxyphenylboronic acid, following the procedure in Preparation 12 afforded the title compound in 45% yield. MS (AP/CI): 343.3 (M+H)+. Preparation 58: 7-(benzyloxy)-4-(3-methoxyphenyl')quinazoline: Using Preparation 53 and 3-methoxyphenylboronic acid, following the procedure in Preparation 12 afforded the title compound in 51% yield. MS (AP/CI): 343.4 (M+H)+.
Preparation 59: 4-phenylquinazolin-7-ol: A mixture of Preparation 54 (0.55 g, 1.76 mmol) and 10% palladium on carbon (100 mg), in methanol (20 mL) was placed under 50 psi hydrogen and was shaken for 24 h at room temperature. The mixture was filtered through
Celite and was concentrated to afford 390 mg (100% yield) of the title compound. MS
(AP/CI): 223.2 (M+H)+.
Preparation 60: 4-(pyridin-3-vQquinazolin-7-ol: Using Preparation 55 and the general procedure from Preparation 16, the title compound was prepared in 77% yield. MS (AP/CI): 224.2 (M+H)+. Preparation 61 : 4-(pyridin-4-vπαuinazolin-7-ol: Using the mixture from Preparation 56 and the general procedure from Preparation 16, the title compound was prepared in 4% yield over two steps. MS (AP/CI): 224.2 (M+H)+.
Preparation 62: 4-(3-methoxyphenyl)quinazolin-7-ol: Using Preparation 58, the general procedure in Preparation 59 was used to prepare the title compound in 30% yield. MS (AP/CI): 253.3 (M+H)+.
Preparation 63: 4-(4-methoxyphenv0αuinazolin-7-ol: Using Preparation 57, the general procedure in Preparation 59 was used to prepare the title compound in 22% yield. MS (AP/CI): 253.3 (M+H)+. Example 45: 4-pyridin-4-yl-7-(quinolin-2-ylmethoxy)quinazoline: Using Preparation
61 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 45% yield. 13C NMR (101 MHz1 CHLOROFORM-D) d ppm 72.1 (s, 1 C) 108.6 (s, 1 C) 118.6 (s, 1 C) 119.3 (s, 1 C) 122.0 (s, 1 C) 124.3 (s, 1 C)
127.1 (s, 1 C) 127.9 (s, 1 C) 129.3 (s, 1 C) 130.3 (s, 1 C) 137.5 (s, 1 C) 145.0 (s, 1 C) 147.9 (s, 1 C) 150.4 (s, 1 C) 153.7 (s, 1 C) 155.5 (s, 1 C) 156.2 (s, 1 C) 163.1 (s, 1 C) 164.8 (s, 1
C); MS (AP/CI): 365.2 (M+H)+ ; IC50 = 210 nM.
Example 46: 4-phenyl-7-(αuinolin-2-ylmethoxy)αuinazoline: Using Preparation 59 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 58% yield. 13C NMR (101 MHz, CHLOROFORM-D) d ppm 71.9 (s, 1 C) 108.4 (s, 1 C) 119.0 (s, 1 C) 119.3 (s, 1 C) 121.1 (s, 1 C) 127.1 (s, 1 C) 127.9 (s, 1 C) 128.8 (s, 1 C) 129.0 (s, 1 C) 129.3 (s, 1 C) 130.1 (s, 1 C) 130.2 (s, 1 C) 130.3 (s, 1 C) 137.5 (s, 1 C) 153.6 (s, 1 C) 155.5 (s, 1 C) 156.5 (s, 1 C) 162.7 (s, 1 C) 167.5 (s, 1 C); MS (AP/CI): 364.3 (M+H)+ ; IC50 = 325 nM.
Example 47: 4-pyridin-3-yl-7-(quinolin-2-ylmethoxy)quinazoline: Using Preparation 60 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 58% yield. 13C NMR (101 MHz, CHLOROFORM-D) d ppm 71.9 (s, 1 C) 108.6 (s, 1 C) 119.0 (s, 1 C) 119.3 (s, 1 C) 121.8 (s, 1 C) 123.8 (s, 1 C)
127.2 (s, 1 C) 127.9 (s, 1 C) 128.1 (s, 1 C) 129.1 (s, 1 C) 130.4 (s, 1 C) 133.4 (s, 1 C) 137.6 (s, 1 C) 137.7 (s, 1 C) 147.6 (s, 1 C) 150.5 (s, 1 C) 151.0 (s, 1 C) 153.7 (s, 1 C) 155.5 (s, 1 C) 156.2 (s, 1 C) 163.0 (s, 1 C) 164.4 (s, 1 C); MS(AP/CI): 365.2 (M+H)+ ; IC50 = 417 nM.
Example 48: 4-(3-methoxyphenyl)-7-(quinolin-2-ylrnethoxy)quinazoline: Using Preparation 62 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 60% yield. 13C NMR (101 MHz, CHLOROFORM- D) d ppm 55.7 (s, 1 C) 71.9 (s, 1 C) 108.4 (s, 1 C) 115.2 (s, 1 C) 116.1 (s, 1 C) 119.0 (s, 1 C) 119.3 (s, 1 C) 121.1 (s, 1 C) 122.6 (s, 1 C) 127.1 (s, 1 C) 127.9 (s, 1 C) 129.0 (s, 1 C) 129.3 (s, 1 C) 129.8 (s, 1 C) 130.3 (s, 1 C) 137.5 (s, 1 C) 138.7 (s, 1 C) 147.8 (s, 1 C) 153.6 (s, 1 C) 155.4 (s, 1 C) 156.5 (s, 1 C) 160.0 (s, 1 C) 162.8 (s, 1 C) 167.4 (s, 1 C); MS (AP/CI): 394.2 (M+H)+ ; IC50 = 852 nM.
Example 49: 4-(4-methoxyphenyl)-7-(quinolin-2-ylmethoxy)quinazoline: Using Preparation 63 and 2-chloromethylquinoline, the general procedure in Preparation 3 was used for the synthesis of the title compound in 85% yield. 13C NMR (101 MHz, CHLOROFORM- D) d ppm 55.7 (s, 1 C) 71.9 (s, 1 C) 108.3 (s, 1 C) 114.3 (s, 1 C) 118.9 (s, 1 C) 119.3 (s, 1 C) 120.9 (s, 1 C) 127.0 (s, 1 C) 127.9 (s, 1 C) 129.1 (s, 1 C) 129.3 (s, 1 C) 129.8 (s, 1 C) 130.2 (s, 1 C) 131.8 (s, 1 C) 137.5 (s, 1 C) 147.8 (s, 1 C) 153.6 (s, 1 C) 155.4 (s, 1 C) 156.5 (s, 1 C)
161.5 (s, 1 C) 162.7 (s, 1 C) 167.0 (s, 1 C); MS (AP/CI): 394.3 (M+H)+ ; IC50 = 930 nM. Preparation 64: 6-(benzyloxyV7-methoxy-3-(2.2,2-trifluoroethyl)quinazolin-4(3H)-one:
A solution of Preparation 9 (300 mg, 1.1 mmol) in trimethyl orthoformate (4 mL) was heated at 1050C for 2 h. The solvent was removed in vacuo, dry toluene (6 mL) was added, followed by triflouroethylamine (865 uL, 11 mmol). The mixture was heated to 8O0C for 24 h, solvent was removed in vacuo, and the residue was purified by silica gel chromatography (chloroform- methanol, 100:1) to afford 328 mg (82% yield) of the title compound. MS (AP/CI): 365.0 (M+H)+.
Preparation 65: 6-hvdroxy-7-methoxy-3-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one: Using Preparation 64, the general procedure in Preparation 16 was used to prepare the title compound in 81% yield. MS (AP/CI): 275.0 (M+H)+. Preparation 66: 6-(benzyloxy)-3-ethyl-7-methoχyquinazolin-4(3H)-one: Using ethylamine, the general procedure in Preparation 64 was used to prepare the title compound in 40% yield. MS (AP/CI): 311.1 (M+H)+.
Preparation 67: 3-ethyl-6-hvdroxy-7-methoχyquinazolin-4(3H)-one: Using Preparation 66, the general procedure in Preparation 16 was used to prepare the title compound in 72% yield. MS (AP/CI): 221.1 (M+H)+ ;l.
Preparation 68: 6-(benzyloxyV3-isobutyl-7-methoxyquinazolin-4(3H)-one: Using isobutylamine, the general procedure in Preparation 64 was used to prepare the title compound in 16% yield. MS (AP/CI): 339.1 (M+H)+.
Preparation 69: 6-hvdroxy-3-isobutyl-7-methoχyquinazolin-4(3H)-one: Using Preparation 68, the general procedure in Preparation 16 was used to prepare the title compound in 80% yield. MS (AP/CI): 249.1 (M+H)+ ;IC50 = 1.87 nM.
Preparation 70: 6-(benzyloxy)-3-cvclopropyl-7-methoxyquinazolin-4(3H)-one: Using cyclopropylamine, the general procedure in Preparation 64 was used to prepare the title compound in 81 % yield. MS (AP/CI): 323.0 (M+H)+. Preparation 71 : 3-cvclopropyl-6-hvdroxy-7-methoxyquinazolin-4(3H)-one: Using
Preparation 70, the general procedure in Preparation 16 was used to prepare the title compound in 86% yield. MS (AP/CI): 233.1 (M+H)+. Preparation 72: 6-(benzyloxy)-7-methoxy-3-(2-methoxyethvπquinazolin-4(3H)-one: Using 2-methoxyethylamine, the general procedure in Preparation 64 was used to prepare the title compound in 27% yield. MS (AP/CI): 341.1 (M+H)+.
Preparation 73: 6-hvdroxy-7-methoxy-3-(2-methoxyethv0quinazolin-4(3H)-one: Using Preparation 72, the general procedure in Preparation 16 was used to prepare the title compound in 95% yield. MS (AP/CI): 251.1 (M+H)+.
Preparation 74: 2-amino-4,5-dimethoxy-N-methylbenzamide: Methylamine (15 mL, 30 mmol, 2 M in THF) and 2-amino-4,5-dimethoxybenzoic acid in DMF (15 mL) were treated with 1-hydroxybenzotriazole (4.3g, 31.5 mmol) and dicyclohexylcarbodiimide (6.5 g, 31.5 mmol). After stirring at room temperature for 24 h, the existing solid was filtered offand was washed with chloroform. The filtrate was concentrated, was diluted with ethyl acetate, and the solution was washed with aqueous sodium bicarbonate, then was extracted with 2N HCI. The acidic layer was made neutral (pH = 7) by addition of sodium hydroxide, then it was extracted with chloroform. This organic layer was washed with brine, was dried over magnesium sulfate, was filtered, and was concentrated. Purification by silica gel chromatography (ethyl acetate-hexanes 2:1) gave 3.5 g (53% yield) of the title compound. MS (AP/CI): 211.3 (M+H)+.
Preparation 75: 6,7-dimethoxy-3-methylquinazolin-4(3H)-one: Preparation 74 (3.5 g,
16.7 mmol) and triethyl orthoformate (8.3 mL, 50.1 mmol) in N-methyl pyrrolidinone (20 mL) were treated with 4N HCI in dioxane (2.1 mL, 84. mmol). The mixture was heated to 1200C for 24 h, was cooled to room temperature, , was diluted with water, and the pH was adjusted to ca. 7 with sodium bicarbonate. This mixture was extracted with ethyl acetate, was washed with water and then brine, was dried over magnesium sulfate, was filtered, and was concentrated. Purification by silica gel chromatography (chloroform-methanol, 80:1 ) gave 0.55 g (15% yield) of the title compound. MS (AP/CI): 221.2 (M+H)+ .
Preparation 76: 6-hvdroxy-7-methoxy-3-methylquinazolin-4(3H)-one: Using
Preparation 75, the general procedure in Preparation 21 was used to prepare the title compound in 32% yield. MS (AP/CI): 207.2 (M+H)+.
Preparation 77: 6-(benzyloxy)-3-cvclopentyl-7-methoχyquinazolin-4(3H)-one: Using cyclopentylamine, the general procedure in Preparation 64 was used to prepare the title compound in 27% yield. MS (AP/CI): 351.1 (M+H)+ .
Preparation 78: 3-cvclopentyl-6-hvdroxy-7-methoxyquinazolin-4(3H)-one: Using
Preparation 77, the general procedure in Preparation 16 was used to prepare the title compound in 95% yield. MS (AP/CI): 261.1 (M+H)+ . Preparation 79: 6-(benzyloxy)-3-isopropyl-7-methoxyquinazolin-4(3H)-one: Using isopropylamine the general procedure in Preparation 64 was used used to prepare the title compound in 50% yield. MS (AP/CI): 325.0 (M+H)+. Preparation 80: 6-hvdroxy-3-isopropyl-7-methoxyquinazolin-4(3H)-one: Using
Preparation 79, the general procedure in Preparation 16 was used to prepare the title compound in 71% yield. MS (AP/CI): 235.1 (M+H)+.
Preparation 81 : 6-(benzyloxy)-3-cvclobutyl-7-methoxyquinazolin-4(3l-0-one: Using cyclobutylamine, the general procedure in Preparation 64 was used to prepare the title compound in 65% yield. MS (AP/CI): 337.0 (M+H)+.
Preparation 82: 3-cyclobutyl-6-hvdroxy-7-methoxyquinazolin-4(3H)-one: Using
Preparation 81 , the general procedure in Preparation 16 was used to prepare the title compound in 80% yield. MS (AP/CI): 247.1 (M+H)+. Example 50: 7-methoχy-6-(2-αuinolin-2-ylethoxy)-3-(2,2,2-trifluoroethyl)αuinazolin-
4(3H)-one: Using Preparation 65 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 60% yield. 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.5 (s, 1 C) 45.1 (s, 1 C) 45.4 (s, 1 C) 45.8 (s, 1 C) 46.2 (s, 1 C)
56.5 (s, 1 C) 68.6 (s, 1 C) 107.7 (s, 1 C) 108.6 (s, 1 C) 115.1 (s, 1 C) 122.1 (s, 1 C) 122.2 (s, 1 C) 124.9 (s, 1 C) 126.3 (s, 1 C) 127.2 (s, 1 C) 127.7 (s, 1 C) 129.1 (s, 1 C) 129.8 (s, 1 C)
136.7 (s, 1 C) 144.2 (s, 1 C) 144.3 (s, 1 C) 149.2 (s, 1 C) 155.9 (s, 1 C) 158.7 (s, 1 C) 159.9 (s, 1 C); MS (AP/CI): 430.0 (M+H)+ ; IC50 = 2 nM.
Example 51 : 3-ethyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)-one: Using Preparation 67 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 64% yield. Diagnostic 13C NMR signals (101 MHz, CHLOROFORM-D) d ppm 15.2 (s, 1 C) 38.6 (s, 1 C) 42.3 (s, 1 C) 56.4 (s, 1 C) 61.6 (s, 1 C)
68.6 (s, 1 C) 107.3 (s, 1 C) 108.1 (s, 1 C) 115.8 (s, 1 C) 122.2 (s, 1 C) 126.3 (s, 1 C) 126.4 (s, 1 C) 127.2 (s, 1 C) 127.7 (s, 1 C) 129.2 (s, 1 C) 129.7 (s, 1 C) 136.6 (s, 1 C) 144.7 (s, 1 C) 145.3 (s, 1 C) 148.8 (s, 1 C) 155.3 (s, 1 C) 158.9 (s, 1 C) 160.5 (s, 1 C); MS (AP/CI): 376.1 (M+H)+ ; IC50 = 3.94 nM.
Example 52: 3-isobutyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)-one: Using Preparation 69 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 66% yield. Diagnostic 13C NMR signals (101 MHz, CHLOROFORM-D) d ppm 20.1 (s, 1 C) 28.4 (s, 1 C) 38.6 (s, 1 C) 54.3 (s, 1 C) 56.4 (s, 1 C) 68.5 (s, 1 C) 107.5 (s, 1 C) 108.1 (s, 1 C) 122.2 (s, 1 C) 126.3 (s, 1 C) 126.4 (s, 1 C) 127.2 (s, 1 C) 127.7 (s, 1 C) 127.8 (s, 1 C) 129.1 (s, 1 C) 129.8 (s, 1 C) 130.1 (s, 1 C) 136.7 (s, 1 C) 145.9 (s, 1 C) 158.9 (s, 1 C) 160.8 (s, 1 C); MS (AP/CI): 404.1 (M+H)+ ; IC50 = 7.31 nM.
Example 53: 3-cvclopropyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)- one: Using Preparation 71 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 34% yield. 13C NMR (101 MHz, CHLOROFORM- D) d ppm 6.7 (s, 1 C) 29.5 (s, 1 C) 38.5 (s, 1 C) 56.4 (s, 1 C) 68.5 (s, 1 C) 107.2 (s, 1 C) 108.1 (s, 1 C) 115.3 (s, 1 C) 122.3 (s, 1 C) 126.3 (s, 1 C) 127.2 (s, 1 C) 127.7 (s, 1 C) 129.0 (s, 1 C) 129.8 (s, 1 C) 136.8 (s, 1 C) 144.0 (s, 1 C) 145.8 (s, 1 C) 148.8 (s, 1 C) 155.3 (s, 1 C) 158.8 (s, 1 C) 161.9 (s, 1 C); MS (AP/CI): 388.1 (M+H)+; IC50 = 13.4 nM.
Example 54: 7-methoxy-3-(2-methoxyethvπ-6-(2-quinolin-2-ylethoxy)quinazolin-
4(3H)-one: Using Preparation 73 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 25% yield. Diagnostic 13C NMR signals (101
MHz, CHLOROFORM-D) d ppm 38.5 (s, 1 C) 46.9 (s, 1 C) 56.4 (s, 1 C) 59.2 (s, 1 C) 68.6 (s,
1 C) 70.3 (s, 1 C) 107.4 (s, 1 C) 108.2 (s, 1 C) 122.3 (s, 1 C) 126.4 (s, 1 C)' 127.2 (s, 1 C)
127.7 (s, 1 C) 129.0 (s, 1 C) 129.8 (s, 1 C) 136.8 (s, 1 C) 144.8 (s, 1 C) 146.5 (s, 1 C) 158.9 (s, 1 C) 160.7 (s, 1 C); MS (AP/CI): 406.1 (M+H)+ ; IC50 = 15 nM. Example 55: 7-methoxy-3-methyl-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)-one:
Using Preparation 76 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 60% yield. 13C NMR (101 MHz, CHLOROFORM-D) d ppm 34.3 (s, 1 C) 38.6 (s, 1 C) 56.4 (s, 1 C) 68.5 (s, 1 C) 107.2 (s, 1 C) 108.2 (s, 1 C) 115.5 (s, 1 C) 122.2 (s, 1 C) 126.3 (s, 1 C) 127.2 (s, 1 C) 127.7 (s, 1 C) 129.1 (s, 1 C) 129.8 (s, 1 C) 136.7 (s, 1 C) 144.8 (s, 1 C) 145.8 (s, 1 C) 148.0 (s, 1 C) 148.8 (s, 1 C) 155.3 (s, 1 C) 158.9 (s, 1 C) 161.1 (s, 1 C); MS (AP/CI): 362.2 (M+H)+ ; IC50 = 4.25 nM.
Example 56: 3-cvclopentyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)- one: Using Preparation 78 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 56% yield. 13C NMR (101 MHz, CHLOROFORM- D) d ppm 24.8 (s, 1 C) 32.3 (s, 1 C) 38.6 (s, 1 C) 55.9 (s, 1 C) 56.4 (s, 1 C) 68.5 (s, 1 C) 107.5 (s, 1 C) 108.0 (s, 1 C) 115.4 (s, 1 C) 122.2 (s, 1 C) 126.3 (s, 1 C) 127.2 (s, 1 C) 127.7 (s, 1 C) 129.1 (s, 1 C) 129.7 (s, 1 C) 136.6 (s, 1 C) 143.3 (s, 1 C) 144.1 (s, 1 C) 148.0 (s, 1 C)
148.8 (s, 1 C) 155.3 (s, 1 C) 158.9 (s, 1 C) 160.7 (s, 1 C); MS (AP/CI): 416.1 (M+H)+ ; IC50 = 34.5 nM. Example 57: 3-isopropyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazoHn-4(3H)-one:
Using Preparation 80 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 28% yield. 13C NMR (101 MHz, CHLOROFORM-D) d ppm 22.3 (s, 1 C) 36.9 (s, 1 C) 46.3 (s, 1 C) 56.4 (s, 1 C) 68.1 (s, 1 C) 107.8 (s, 1 C) 108.1 (s, 1 C) 115.4 (s, 1 C) 122.8 (s, 1 C) 126.6 (s, 1 C) 127.4 (s, 1 C) 127.5 (s, 1 C) 127.9 (s, 1 C) 131.5 (S1 1 C) 139.5 (s, 1 C) 142.9 (s, 1 C) 143.8 (s, 1 C) 148.5 (s, 1 C) 155.5 (s, 1 C) 158.6 (s, 1 C) 160.0 (s, 1 C); MS (AP/CI): 390.0 (M+H)+ ; IC50 = 42 nM.
Example 58: 7-methoxy-3-methyl-6-r3-( 1 -methyl-1 H-benzimidazol-2- yl)propoxylquinazolin-4(3H)-one: Using Preparation 76 and 3-(1-methyl-1 H-benzo[d]imidazol- 2-yl)propan-1-ol, the general procedure in Example 1 was used for the synthesis of the title compound in 37% yield. 13C NMR (101 MHz, CHLOROFORM-D) d ppm 24.1 (s, 1 C) 27.0 (s, 1 C) 29.9 (s, 1 C) 34.3 (s, 1 C) 56.4 (s, 1 C) 68.2 (s, 1 C) 106.8 (s, 1 C) 108.1 (s, 1 C) 109.1 (S, 1 C) 115.5 (s, 1 C) 119.3 (s, 1 C) 122.1 (s, 1 C) 122.3 (s, 1 C) 135.9 (s, 1 C) 142.6 (S, 1 C) 144.7 (s, 1 C) 145.8 (s, 1 C) 148.8 (s, 1 C) 154.5 (s, 1 C) 155.2 (s, 1 C) 161.1 (s, 1 C); MS (AP/CI): 379.4 (M+H)+; IC50 = 15.6 nM.
Example 59: 3-cvclobutyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)- one: Using Preparation 82 and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 50% yield. 13C NMR (101 MHz, CHLOROFORM- D) d ppm 15.5 (s, 1 C) 30.0 (s, 1 C) 38.5 (s, 1 C) 50.3 (s, 1 C) 56.4 (s, 1 C) 68.5 (s, 1 C)
107.3 (s, 1 C) 108.0 (s, 1 C) 115.3 (s, 1 C) 122.2 (s, 1 C) 126.3 (s, 1 C) 127.2 (s, 1 C) 127.7 (s, 1 C) 129.1 (s, 1 C) 129.7 (s, 1 C) 136.6 (s, 1 C) 142.9 (s, 1 C) 144.3 (s, 1 C) 148.8 (s, 1 C)
155.4 (s, 1 C) 158.9 (s, 1 C) 160.6 (s, 1 C); MS (AP/CI): 402.0 (M+H)+ ; IC50 = 42.2 nM. Example 60: 2-r2-(quinolin-7-yloxy)ethvπquinoline: Using 7-hydroxyquinoline and
Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 17% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.7 (s, 1 C) 67.6 (s, 1 C) 108.0 (s, 1 C) 118.0 (s, 1 C) 119.2 (s, 1 C) 120.4 (s, 1 C) 122.2 (s, 1 C) 123.8 (s, 1 C) 126.3 (s, 1 C) 127.2 (s, 1 C) 127.8 (s, 1 C) 129.0 (s, 1 C) 129.8 (s, 1 C) 136.3 (s, 1 C) 136.7 (s, 1 C) 149.6 (s, 1 C) 150.3 (s, 1 C) 159.1 (s, 1 C) 160.2 (s, 1 C); MS (AP/CI): 301.3 (M+H)+; IC50 = 334 nM.
Example 61 : 2-r2-(quinolin-6-yloxy)ethyllquinoline: Using 6-hydroxyquinoline and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 15% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 38.8 (s, 1 C) 67.7 (s, 1 C) 106.4 (s, 1 C) 121.5 (s, 1 C) 122.3 (s, 1 C) 122.9 (s, 1 C) 126.4 (s, 1 C) 127.2 (s, 1 C) 127.8 (s, 1 C) 128.9 (s, 1 C) 129.5 (s, 1 C) 129.9 (s, 1 C) 130.8 (s, 1 C) 135.3 (s, 1 C) 136.9 (s, 1 C) 148.0 (s, 1 C) 157.2 (s, 1 C) 159.1 (s, 1 C); MS (AP/CI): 301.3 (M+H)+ ; IC50 = 346 nM.
Example 62: 7-f3-(1-methyl-1 H-benzimidazol-2-yl)propoxy1quinoline: Using 7- hydroxyquinoline and 3-(1-methyl-1 H-benzo[d]imidazol-2-yl)propan-1-ol, the general procedure in Example 1 was used for the synthesis of the title compound in 35% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 24.1 (s, 1 C) 27.2 (s, 1 C) 29.9 (s, 1 C) 67.2 (s, 1 C) 108.4 (s, 1 C) 109.2 (s, 1 C) 119.3 (s, 1 C) 120.0 (s, 1 C) 122.2 (s, 1 C) 122.4 (s, 1 C) 123.8 (s, 1 C) 129.1 (s, 1 C) 135.9 (s, 1 C) 136.0 (s, 1 C) 142.5 (s, 1 C) 150.0 (s, 1 C) 150.7 (s, 1 C) 154.5 (s, 1 C) 160.0 (s, 1 C); MS (AP/CI): 318.3 (M+H)+ ; IC50 = 366 nM.
Example 63: 2-f2-(isoquinolin-7-yloxy)ethyriquinoline: Using 7-hydroxyisoquinoline and Preparation 4, the general procedure in Example 1 was used for the synthesis of the title compound in 21% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 159.00, 157.91 , 150.95, 140.87, 136.82, 131.77, 129.92, 128.96, 128.26, 127.82, 127.23, 126.41 , 124.27, 122.22, 120.68, 109.01 , 106.07, 67.66, 38.72; MS (AP/CI): 301.3 (M+H)+ ; IC50 = 394 nM.
Example 64: 7-r3-(1-methyl-1 H-benzimidazol-2-yl)propoxy[isoquinoline: Using 7- hydroxyisoquinoline and 3-(1-methyl-1 H-benzo[d]imidazol-2-yl)propan-1-ol, the general procedure in Example 1 was used for the synthesis of the title compound in 28% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 24.0 (s, 1 C) 27.1 (s, 1 C) 29.9 (s, 1 C) 67.2 (s, 1 C) 105.9 (s, 1 C) 109.3 (s, 1 C) 119.2 (s, 1 C) 120.4 (s, 1 C) 122.3 (s, 1 C) 122.5 (s, 1 C) 123.8 (s, 1 C) 128.3 (s, 1 C) 130.0 (s, 1 C) 131.6 (s, 1 C) 135.9 (s, 1 C) 141.4 (s, 1 C) 142.3 (s, 1 C) 151.2 (s, 1 C) 154.4 (s, 1 C) 157.7 (s, 1 C); MS (AP/CI): 318.3 (M+H)+ ; IC50 = 412 nM.
Example 65: 6-f3-(1 -methyl-1 H-benzimidazol-2-yl)propoxy1auinoline: Using 6- hydroxyquinoline and 3-(1-methyl-1H-benzo[d]imidazol-2-yl)propan-1-ol, the general procedure in Example 1 was used for the synthesis of the title compound in 28% yield.; 13C NMR (101 MHz, CHLOROFORM-D) d ppm 24.0 (s, 1 C) 27.1 (s, 1 C) 29.9 (s, 1 C) 67.1 (s, 1 C) 106.2 (s, 1 C) 109.3 (s, 1 C) 119.2 (s, 1 C) 121.6 (s, 1 C) 122.3 (s, 1 C) 122.6 (s, 1 C) 129.5 (s, 1 C) 131.1 (s, 1 C) 135.1 (s, 1 C) 135.8 (s, 1 C) 142.2 (s, 1 C) 144.6 (s, 1 C) 148.2 (s, 1 C) 154.4 (s, 1 C) 157.0 (s, 1 C); MS (AP/CI): 318.3 (M+H)+ ; IC50 = 435 nM.
The invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed, since these embodiments are intended as illustrations of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

Claims

1. A compound of formula I or a pharmaceutical acceptable salt thereof,
Figure imgf000050_0001
I wherein HET1 is selected from the group consisting of a monocyclic heteroaryl and a bicyclic heteroaryl, wherein said HET1 may optionally be substituted with at least one R1 ;
B1 and B2 are adjacent atoms in Het1 wherein B2 is carbon and B1 is nitrogen. X, Y and Z are each independently N or CR5, with the provisos that at least one of X, Y and Z must be CR5 and when R4 is O, R4 is divalent and Z is NR10; each R1 is independently selected from a group consisting of halogen, hydroxyl, cyano, (CrC8)alkyl, (C2- C8)alkenyl, (C2-C8)alkynyl, (CrC8)alkoxy, (CrC8)haloalkyl, (C1- C8)haloalkoxy, (C3-C8)cycloalkyl, (5-12 membered)heterocycloalkyl, (CrC8)alkylthio, -NR8R9 - C(O)-NR8R9, and (CrC8)alkyl substituted with at least one of: -OH, (CrC8)alkoxy, -SH, -(C1- C8)alkylthio, -NH2, -HN(CrC8)alkyl or N((CrC8)alkyl)((CrC8)alkyl); R3 is independently hydrogen, halogen, cyano, -COOH, -COOR8 -CONR8R9, -COR8, -
NR8R9, -NHCOR8, -OH, (C6-C12)aryl, (5-12 membered)heteroaryl, (CrC8)alkyl, (CrC8)alkoxy, (CrC6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C2-C6)alkenyloxy or (C3-C8)cycloalkyl;
R4 is hydrogen, O, halogen, cyano, -NR8R9, -C(O)R8, (CrC6)alkyl, (CrC6)alkoxy, (C3-
Ci2)cycloalkyl, (CrC6)haloalkyl, (4-12 membered)heterocycloalkyl, (C6-Ci2)aryl, -(5-12 membered)heterocycloalkyl-(C6-Ci2)aryl, (5-12 membered)heteroaryl, (5-12 membered)heterocycloalkyloxy, (C6-C12)aryloxy, (5-12 membered)heteroaryloxy, -(C6-
C12)aryl-(CrC6)alkyl, or -(5-12 membered)heteroaryl-(CrC6)alkyl, wherein when R4 is alky], alkoxy, cycloalkyl, haloalkyl, heterocycloalkyl, aryl, -heterocycloalkyl-aryl, heteroaryl, heterocycloalkyloxy, aryloxy, heteroaryl, heteroaryloxy, -aryl-alkyl, or -heteroaryl-alkyl, it may be optionally substituted by at least one R7;
R5 is independently hydrogen, halogen, -NR8R9, hydroxyl, (CrC8)alkyl, (Ci-C8)alkoxy, (CrC8)haloalkyl, (CrC8)hydroxyalkyl or (C3-C8)cycloalkyl; wherein each R7 is independently hydrogen, halogen, hydroxy, cyano, -COOH, -
COOR8, -CONR8R9, -COR8, -NR8R9, -NHCOR8, -HNCOOR8, -HNCONHR8, (CrC8)alkyl, (C1- C8)alkoxy, (CrC6)haloalkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C2-C6)alkenyloxy, (C3-
C8)cycloalkyl, (Ci-C8)hydroxyalkyl, (CrC8)alkoxy-(CrC8)alkyl, (C3-C8)hydroxycycloalkyl, (C3-
C8)cycloalkoxy, -(CrC8)alkoxy-(C3-C8)cycloalkyl, (C6-Ci2)aryl, (3-8 membered)heterocycloalkyl, (CrC8)alkylthio, (C5-C12)aryl, (5-12 membered)heteroaryl, (C6-C12)aryloxy, or (5-12 membered)heteroaryloxy; and when R7 is aryl or heteroaryl, it may be optional fused to the heterocycloalkyl ring to which it is attached; and when R7 is alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, alkenyloxy, cycloalkyl, hydroxyalkyl, -alkoxy-alkyl, hydroxycycloalkyl, cycloalkoxy, - alkoxy-cycloalkyl, aryl, heteroaryl, aryloxy, or heteroaryloxy, it may be optionally substituted from one to three substituents independently selected from halogen, -COOR8, -NR8R9, (C1- C8)alkyl, (Ci-C8)alkoxy, (CrC6)haloalkyl, (Ci-C8)hydroxyalkyl, (C1-C8)alkoxy-(C1-C8)alkyl, (C3- C8)hydroxycycloalkyl, (C3-C8)cycloalkoxy, -(CrC8)alkoxy-(C3-C8)cycloalkyl, (C6-C12)aryl (3-8 membered)heterocycloalkyl, hydroxy(3-8 membered)heterocycloalkyl, and -(CrC8)alkoxy-(3-8 membered)heterocycloalkyl, wherein R8 and R9 are each independently hydrogen, (CrC8)alkyl, (CrC8)alkoxy, (C2- C8)alkenyl, or (C6-Ci2)aryl; or R8 and R9 together with the nitrogen to which they are attached may form a heterocycloalkyl or heteroaryl group;
R10 is independently hydrogen, (CrC8)alkyl, (CrC8)haloalkyl, (Ci-C8)hydroxyalkyl or (C3-C8)cycloalkyl; n is 1, 2 or 3.
2. The compound of Claim 1 , wherein HET1 is selected from the group consisting of:
Figure imgf000051_0001
optionally substituted by at least one R1.
3. The compound of Claim 1 , wherein HET1 is selected from the group consisting of
Figure imgf000052_0001
4. The compound of Claim 1 , wherein R4 is a phenyl, pyridinyl or a heterocycloalkyl having the formula:
Figure imgf000052_0002
wherein R6 is hydrogen, -COOR8, -CONR8R9, -COR8, -NR8R9, -NHCOR8, -OH, -HNCOOR8, -CN, -HNCONHR8, (d-C6)alkyl or (C1-C6) alkoxy;
R7 is defined in claim 1 ; and p is O or 1.
5. The compound of Claim 1 , wherein one or two of X, Y and Z are nitrogen.
6. The compound of Claim 1 , wherein X and Z are nitrogen and Y is CH.
7. The compound of Claim 1 , wherein the compound has the formula:
Figure imgf000052_0003
8. The compound of claim 7, wherein R3 is (Ci-C8)alkoxy.
9. The compound of Claim 8, wherein HET1 is selected from:
Figure imgf000052_0004
R4 is a phenyl, pyridinyl or a heterocycloalkyl having the formula:
Figure imgf000053_0001
wherein R6 is hydrogen, -COOR8, -CONR8R9, -COR8, -NR8R9, -NHCOR8, -OH, -HNCOOR8, - CN, -HNCONHR8, (CrC6)alkyl or (C1-C6) alkoxy; R7 is defined in Claim 1 ; and p is 1.
10. The compound of Claim 9, wherein R4 is the heterocycloalkyl of Formula IA; R6 is hydrogen and R7 is phenyl.
11. The compound of Claim 8, wherein X and Z are nitrogen and Y is CH.
12. The compound of Claim 1, wherein said compound is selected from a group consisting of:
7-methoxy-4-(3-phenylpiperidin-1-yl)-6-(2-quinolin-2-ylethoxy)quinazoline;
7-methoxy-6-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]-4-(3-phenylpiperidin-1- yl)quinazoline; 7-methoxy-4-(3-phenylpiperidin-1-yl)-6-(2-pyridin-2-ylethoxy)quinazoline;
7-methoxy-4-(3-phenylpiperidin-1-yl)-6-(3-pyridin-2-ylpropoxy)quinazoline; Using
7-methoxy-4-(3-phenylpiperidin-1-yl)-6-[(3-quinolin-2-ylprop-2-yn-1-yl)oxy]quinazoline
7-methoxy-4-(3-phenylpiperidin-1-yl)-6-(3-quinolin-2-ylpropoxy)quinazoline;
7-methoxy-4-(3-phenylpiperidin-1-yl)-6-(quinolin-2-ylmethoxy)quinazoline; 7-methoxy-6-[3-(1 -methyl-1 H-benzimidazol-2-yl)propoxy]-4-pyridin-3-ylquinazoline;
7-methoxy-4-pyridin-3-yl-6-(2-quinolin-2-ylethoxy)quinazoline;
7-methoxy-4-pyridin-4-yl-6-(2-quinolin-2-ylethoxy)quinazoline;
7-methoxy-4-phenyl-6-(2-quinolin-2-ylethoxy)quinazoline;
7-methoxy-6-(2-quinolin-2-ylethoxy)-4-[3-(trifluoromethyl)phenyl]quinazoline; 7-methoxy-4-pyridin-3-yl-6-(quinolin-2-ylmethoxy)quinazoline;
7-methoxy-4-pyridin-4-yl-6-(quinolin-2~ylmethoxy)quinazoline;
7-methoxy-4-phenyl-6-(quinolin-2-ylmethoxy)quinazoline;
6-methoxy-7-(2-quinσ!iπ-2~ylethoxy)quinazoline;
6-methoxy-7-[2-(1-methyl-1H-benzimidazol-2-yl)ethoxy]quinazoline; 6-methoxy-7-[3-(1 -methyl-1 H-benzimidazol-2-yl)propoxy]quinazoline;
6-methoxy-7-(quinolin-2-ylmethoxy)quinazoline;
7-methoxy-N,N-dimethyl-6-(2-quinolin-2-ylethoxy)quinazolin-4-amine; 7-methoxy-4-morpholin-4-yl-6-(2-quinolin-2-ylethoxy)quinazoline;
7-methoxy-4-pyrroIidin-1-yl-6-(2-quinolin-2-ylethoxy)quinazoline
7-methoxy-4-piperidin-1-yl-6-(2-quinolin-2-ylethoxy)quinazoline;
N,N-diethyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4-amine; 4-azetidin-1-yl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazoline;
6-methoxy-4-pyridin-4-yl-7-(quinolin-2-ylmethoxy)quinazoline;
6-methoxy-4-phenyl-7-(quinolin-2-ylmethoxy)quinazoline;
6-methoxy-4-pyridin-3-yl-7-(quinolin-2-ylmethoxy)quina2oline;
6-methoxy-7-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]-4-phenylquinazoline; 6-methoxy-4-pyridin-3-yl-7-(2-quinolin-2-ylethoxy)quinazoline;
6-methoxy-4-pyridin-4-yl-7-(2-quinolin-2-ylethoxy)quinazoline;
6-methoxy-7-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]-4-pyridin-3-ylquinazoline;
6-methoxy-4-phenyl-7-(2-quinolin-2-ylethoxy)quinazoline;
6-methoxy-7-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]-4-pyridin-4-ylquinazoline; 4-phenyl-6-(quinolin-2-ylmethoxy)quinazoline;
4-pyridin-4-yl-6-(quinolin-2-ylmethoxy)quinazoline;
4-pyridin-3-yl-6-(quinolin-2-ylmethoxy)quinazoline;
1-{3-[6-(quinolin-2-ylmethoxy)quinazolin-4-yl]phenyl}ethanone;
1-{3-[6-(quinolin-2-ylmethoxy)quinazolin-4-yl]phenyl}ethanol; 2-{3-[6-(quinolin-2-ylmethoxy)quinazolin-4-yl]phenyl}propan-2-ol;
4-phenyl-6-(2-quinolin-2-ylethoxy)quinazoline;
4-pyridin-4-yl-6-(2-quinolin-2-ylethoxy)quinazoline;
4-pyridin-3-yl-6-(2-quinolin-2-ylethoxy)quinazoline;
6-(2-quinolin-2-ylethoxy)-4-[3-(trifluoromethyl)phenyl]quinazoline; 4-pyridin-4-yl-7-(quinolin-2-ylmethoxy)quinazoline;
4-phenyl-7-(quinolin-2-ylmethoxy)quinazoline;
4-pyridin-3-yl-7-(quino)in-2-ylmethoxy)quinazoline;
4-(3-methoxyphenyl)-7-(quinolin-2-ylmethoxy)quinazo)ine
4-(4-methoxyphenyl)-7-(quinolin-2-ylmethoxy)quinazoline; 7-methoxy-6-(2-quinolin-2-ylethoxy)-3-(2,2,2-trifluoroethyl)quinazolin-4(3H)-one;
3-ethyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quiπazolin-4(3H)-one;
3-isobutyl-7-methoxy-6-(2-quiπoliπ-2-ylethoxy)quinazolin-4(3H)-one;
3-cyclopropyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)-one;
7-methoxy-3-(2-methoxyethyl)-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)-one; 7-methoxy-3-methyl-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)-one;
3-cyclopentyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)-one;
3-isopropyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)-one; 7-methoxy-3-methy(-6-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]quinazolin-4(3H)- one;
3-cyc]obutyl-7-methoxy-6-(2-quinolin-2-ylethoxy)quinazolin-4(3H)-one;
2-[2-(quinolin-7-yloxy)ethyl]quinoline; 2-[2-(quinolin-6-yloxy)ethyl]quinoline;
7-[3-(1-methyl-1 H-benzimidazol-2-yl)propoxy]quinoline;
2-[2-(isoquinolin-7-yloxy)ethyl]quinoline;
7-[3-(1-methyl-1 H-benzimidazol-2-yl)propoxy]isoquinoline; and
6-[3-( 1 -methyl-1 H-benzimidazol-2-yl)propoxy]quinoline.
13. A pharmaceutical composition for treating psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction, comprising an amount of a compound of formula I according to claim 1 effective in treating said disorder or condition.
14. A method of treating a disorder selected from psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, obesity, and neurodegenerative disorders, which method comprises administering an amount of a compound of claim 1 effective in treating said disorder.
15. The method of claim 14, wherein said disorder is selected from the group consisting of: dementia, Alzheimer's disease, multi-infarct dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or cerebral trauma, dementia associated with Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; a learning disorder, for example reading disorder, mathematics disorder, or a disorder of written expression; attention-deficit/hyperactivity disorder; age-related cognitive decline, major depressive episode of the mild, moderate or severe type; a manic or mixed mood episode; a hypomanic mood episode; a depressive episode with atypical features; a depressive episode with melancholic features; a depressive episode with catatonic features; a mood episode with postpartum onset; post-stroke depression; major depressive disorder; dysthymic disorder; minor depressive disorder; premenstrual dysphoric disorder; post-psychotic depressive disorder of schizophrenia; a major depressive disorder superimposed on a psychotic disorder comprising a delusional disorder or schizophrenia; a bipolar disorder comprising bipolar I disorder, bipolar Il disorder, cyclothymic disorder, Parkinson's disease; Huntington's disease; dementia, Alzheimer's disease, multi-infarct dementia, AIDS-related dementia, Fronto temperal Dementia; neurodegeneration associated with cerebral trauma; neurodegeneration associated with stroke; neurodegeneration associated with cerebral infarct; hypoglycemia- induced neurodegeneration; neurodegeneration associated with epileptic seizure; neurodegeneration associated with neurotoxin poisoning; multi-system atrophy, paranoid, disorganized, catatonic, undifferentiated or residual type; schizophreniform disorder; schizoaffective disorder of the delusional type or the depressive type; delusional disorder; substance-induced psychotic disorder, psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, obesity, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; and personality disorder of the schizoid type.
16. A method of treating psychotic disorders, delusional disorders and drug induced psychosis; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction which method comprises administering an amount of the compound of claim 1 effective in inhibiting PDE10.
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