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WO2011041655A1 - Quinazolin-4-amine derivatives; and methods of use - Google Patents

Quinazolin-4-amine derivatives; and methods of use Download PDF

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Publication number
WO2011041655A1
WO2011041655A1 PCT/US2010/051090 US2010051090W WO2011041655A1 WO 2011041655 A1 WO2011041655 A1 WO 2011041655A1 US 2010051090 W US2010051090 W US 2010051090W WO 2011041655 A1 WO2011041655 A1 WO 2011041655A1
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Prior art keywords
quinazolin
methyl
amine
benzo
dioxol
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French (fr)
Inventor
Craig J. Thomas
Bryan T. Mott
Cordelle Tanega
Min Shen
Douglas S. Auld
Andrew S. Rosenthal
David J. Maloney
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US Department of Health and Human Services
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US Department of Health and Human Services
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • intron sequences from genes occurs via the actions of the splicesome, a protein complex that removes intervening sequences at the nuclear pre-mRNA level to afford properly coded mRNA for translation.
  • Many genes produce multiple mRNA isoforms through the actions of alternative splicing and, numerous human diseases are caused by improper splicing (e.g., degenerative diseases and cancers).
  • improper splicing e.g., degenerative diseases and cancers.
  • Modulation of kinases using small molecule inhibitors is a known approach to control numerous aspects of cell function and for the potential for the management of many diseases. Modulation of kinase activity may make it possible for the control of gene splicing.
  • kinases that alter the function of the splicesome among these are the cdc2-like kinase (Clk) family (Hanes et al., J. Mol. Biol. (1994) 244: 665-672).
  • SR serine- and arginine-rich
  • the Clk family contains four characterized isoforms (Clkl, Clk2, Clk3 and Clk4).
  • the Clks are capable of auto-phosphorylation (at serine, threonine and tyrosine residues) and phosphorylation of exogenous proteins (at serine and threonine residues).
  • the DyrklA (“dual specificity tyrosine (Y)-phosphorylation-regulated kinase 1A] gene is located on chromosome 21 and is known to be highly expressed in CNS tissues.
  • DyrklA knock-out mice are embryonic lethal and transgenic mice overexpressing DyrklA display learning and memory deficiencies.
  • the DyrklA gene is located on the Downs syndrome (DS) critical region of chromosome 21 and trisomy-driven overexpression in DS patients has been demonstrated. Further evidence has been presented that
  • DyrklA hyperphosphorylation of Tau by DyrklA is a causative factor in the early onset of Alzheimer disease in DS patients.
  • DyrklA has been implicated as an important modulator of pre- mPvNA splicing via several molecular interactions including the phosphorylation of the SR protein cyclin L2.
  • Described herein are quinazolin-4-amine derivatives, their methods of manufacture, compositions containing the quinazolin-4-amine derivatives, and methods of use of both the quinazolin-4-amine derivatives and compositions thereof.
  • a compound of formula I is provided
  • Ai and A 2 are independently chosen at each occurrence from hydrogen, methyl, and ethyl.
  • B is hydrogen, methyl, ethyl, propyl, or isopropyl; and n is 1, 2, 3, or 4;
  • Ri is a phenyl, pyridyl, 5- or 6-membered heterocycloalkyl, or a 5-membered heteroaryl group, each heterocycloalkyl or heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, each of which heterocycloalkyl or heteroaryl group is
  • n 2, 3, or 4; and B is hydrogen, methyl, ethyl, propyl, or isopropyl; and
  • Ri is mono- or di-Ci-C 4 alkylamino or amino.
  • n is 3 or 4 and Ri and B are joined to form a 5- or 6-membered heterocycloalkyl group in which one ring carbon is optionally replaced with a N, S, or O atom, which 5- or 6- membered heterocycloalkyl group is substituted with 0 or 1 substituents chosen from C 3 - Cecycloalkyl and 5- and 6-membered heterocycloalkyl.
  • G is R 2 , J is R 3 and L is hydrogen, or G is hydrogen, J is R 2 , and L is R 3 ; or G is hydrogen, J is R 3 , and L is R 2 .
  • R 2 is 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently chosen from N, O, and S, or R 2 is phenyl fused to a 5-membered saturated or partially unsaturated heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S, or R 2 is a phenyl substituted with at least one methoxy group; each of which R 2 is unsubstituted or substituted with 1, 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, cyano, Ci-C 4 alkyl, Ci-C 4 alkoxy, C 2 -C 4 alkylester; C 2 -C 4 alkanoyl, (mono- and di-Ci-C 2 alkylamino)Co-C 2 alkyl, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy, and is substituted with 0 or 1 substituents chosen from -CHO, -COOH, (C 2 -C
  • R 3 is hydrogen, halogen, hydroxyl, Ci-C 4 alkyl, Ci-C 4 alkoxy, or (C 1 -C 2 C 4 alkoxy.
  • R 2 is not a 3,5-dimethylisoxazol-4-yl group
  • Ri and R 2 are not both a furanyl group
  • Ri is not a thien-2-yl group when R 2 is a furan-3-yl group
  • Ai and A 2 are independently hydrogen, methyl, or ethyl.
  • B is hydrogen, methyl, ethyl, propyl, or isopropyl; and n is 1 or 2.
  • Ri is a 5-membered heterocycloalkyl or 5- or 6-membered heteroaryl group, each heterocycloalkyl or heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, each of which heterocycloalkyl or heteroaryl group is unsubstituted or substituted with 1, 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, Ci-C 2 alkyl, and Ci-C 2 alkoxy.
  • R 2 is 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently chosen from N, O, and S, or
  • R 2 is phenyl fused to a 5-membered saturated or partially unsaturated heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; each of which R 2 is unsubstituted or substituted with 1, 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, cyano, Ci-C 4 alkyl, Ci-C 4 alkoxy, C 2 -C 4 alkylester; C 2 -C 4 alkanoyl, mono- and di-(Ci-C 2 alkyl)amino, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy, , and is substituted with 0
  • R 3 is halogen, hydroxyl, Ci-C 4 alkyl, Ci-C 4 alkoxy, or (Ci-C 2 alkoxy)Ci-C 4 alkoxy.
  • a pharmaceutical composition comprises a compound of formula I or a salt thereof and at least one pharmaceutically acceptable carrier.
  • a method of improving spatial learning, short term memory, or working memory in a patient comprises administering an effective amount of a compound or salt of formula I to the patient.
  • a method of treating a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder in a patient comprises administering an effective amount of a compound of formula I to the patient.
  • a method of inhibiting a Clkl, Clk2, Clk4, or DyrklA kinase in vivo comprises administering an amount of a compound or salt of formula I sufficient to inhibit the kinase in vitro.
  • a method for inhibiting the phosphorylation activity of a Clkl, Clk2, Clk4, or DyrklA kinase comprises contacting a cell containing a Clkl, Clk2, Clk4, or DyrklA kinase with a solution containing a concentration of a compound or salt of formula I sufficient to inhibit the phosphorylation activity of a Clkl, Clk2, Clk4, or DyrklA kinase in vitro.
  • a method of inhibiting the splicing activity of a Clkl, Clk2, Clk4, or DyrklA kinase comprises contacting a cell containing a Clkl, Clk2, Clk4, or DyrklA kinase with a solution containing a concentration of a compound or salt of formula I sufficient to significantly alter the splicing of PKC iI TF, Tau or ⁇ -globin pre-mRNA in vitro.
  • a method for demonstrating the presence or absence of Clkl, Clk2, Clk4, or DyrklA kinase in a biological sample comprises a) contacting the biological sample with a labeled compound or salt of formula I under conditions that permit binding of the labeled compound to the Clkl, Clk2, Clk4, or DyrklA kinase; b) separating unbound labeled compound from bound labeled compound; and c) detecting the labeled compound in the biological sample, and therefrom determining the presence or absence of Clkl, Clk2, Clk4, or DyrklA kinase in the sample.
  • Fig. 1A illustrates an inhibitory dose response of a representative quinazolin- 4-amine derivative in the presence of three different ATP concentrations.
  • Fig. IB illustrates an inhibitory dose response of a representative quinazolin- 4-amine derivative in the presence of three different peptide concentrations.
  • quinazolin-4-amine derivatives that are inhibitors of Clkl, Clk2, Clk3, Clk4, or DyrklA. Also disclosed herein are quinazolin-4- amine derivatives as potent and selective inhibitors of Clkl, Clk4, and DyrklA. These agents provide useful tools for the study of Clkl, Clk4 and DyrklA and their respective roles in pre- mRNA splicing.
  • isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium and isotopes of carbon include U C, 13 C, and 14 C.
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded.
  • 2 hydrogens on the atom are replaced.
  • aromatic moieties are substituted by an oxo group
  • the aromatic ring is replaced by the corresponding partially unsaturated ring.
  • a pyridyl group substituted by oxo is a pyridone.
  • Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.
  • a stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent.
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • Alkyl includes both branched and straight chain saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms.
  • C Cialkyl means an alkyl group having from 1 to about 2 carbon atoms, e.g., methyl and ethyl, respectively.
  • Alkoxy means an alkyl group, as defined above, with the indicated number of carbon atoms attached via an oxygen bridge.
  • “Halo” or “halogen” means fluoro, chloro, bromo, or iodo.
  • “5-Membered heterocycloalkyl” means a saturated cyclic group containing from 1 to about 3 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Examples of 5-membered heterocycloalkyl groups include tetrahydrofuranyl and pyrrolidinyl groups.
  • 5-Membered heteroaryl is a stable 5-membered monocyclic ring that contains from 1 to 4, or in some embodiments from 1 to 2 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another.
  • the total number of S and O atoms in the heteroaryl group is not more than 2.
  • the total number of S and O atoms in the heteroaryl group is not more than 1.
  • such heteroaryl groups may be further substituted with carbon or non-carbon atoms or groups.
  • 5-membered heteroaryl groups include, but are not limited to, imidazolyl, oxazolyl, furanyl, thiazolyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, pyrrolyl, pyrazolyl, and thienyl.
  • Hydroxylalkyl is an alkyl group substituted with at least one hydroxyl group.
  • Phenyl fused to a 5-membered saturated or partially unsaturated heterocyclic ring means a phenyl group fused to a 5-membered saturated cyclic group that contains 1 or 2 heteroatoms independently chosen from N, O, and S, to form, for example, a 3,4- methylenedioxy-phenyl group, or a phenyl group fused to a 5-membered partially unsaturated cyclic group that contains 1 or 2 heteroatoms independently chosen from N, O, and S, to form, for example, a benzo[d][l,3]dioxolyl group.
  • Alkylester is an alkyl group as defined above attached through an ester linkage.
  • “Mono- and/ or di-alkylamino” means secondary or tertiary alkyl amino groups, wherein the alkyl groups are as defined above and have the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen.
  • the alkyl groups are independently chosen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-prop yl-amino.
  • alkyli and alkyl 2 groups are independently chosen alkyl groups, as defined as defined herein, attached through a carbamate linkage.
  • Haloalkyl means both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, generally up to the maximum allowable number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
  • Haloalkoxy indicates a haloalkyl group as defined above attached through an oxygen bridge (oxygen of an alcohol radical).
  • Compounds of formula I may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g., asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g., asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms.
  • These compounds can be, for example, racemates or optically active forms.
  • these compounds with two or more asymmetric elements these compounds can additionally be mixtures of diastereomers.
  • all optical isomers in pure form and mixtures thereof are encompassed. In these situations, the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates.
  • Racemates can also be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. All forms are contemplated herein regardless of the methods used to obtain them.
  • chiral refers to molecules, which have the property of non- superimposability of the mirror image partner.
  • “Stereoisomers” are compounds, which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • a "diastereomer” is a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis, crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
  • Enantiomers refer to two stereoisomers of a compound, which are non- superimposable mirror images of one another.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereo specificity in a chemical reaction or process.
  • a “racemic mixture” or “racemate” is an equimolar (or 50:50) mixture of two enantiomeric species, devoid of optical activity.
  • a racemic mixture may occur where there has been no stereoselection or stereo specificity in a chemical reaction or process.
  • “Pharmaceutically acceptable salts” include derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, nontoxic, acid or base addition salts thereof.
  • the salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • salts of the present compounds further include solvates of the compounds and of the compound salts.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH 2 ) n -COOH where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th
  • compositions means compositions comprising at least one active agent, such as a compound or salt of the invention, and at least one other substance, such as a carrier.
  • Pharmaceutical compositions meet the U.S. FDA's GMP (good
  • Carrier means a diluent, excipient, or vehicle with which an active compound is administered.
  • a “pharmaceutically acceptable carrier” means a substance, e.g., excipient, diluent, or vehicle, that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use.
  • “pharmaceutically acceptable carrier” includes both one and more than one such carrier.
  • a "patient” means a human or non-human animal in need of medical treatment.
  • Medical treatment can include treatment of an existing condition, such as a disease or disorder, prophylactic or preventative treatment, or diagnostic treatment.
  • the patient is a human patient.
  • Providing means giving, administering, selling, distributing, transferring (for profit or not), manufacturing, compounding, or dispensing.
  • “Treatment” or “treating” means providing an active compound to a patient in an amount sufficient to measurably reduce any symptom of a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder, e.g., cause regression of the disorder, improve short term memory or working memory, modulate insulin activity; or improve the patient' s performance on a test of spatial learning.
  • a "therapeutically effective amount" of a pharmaceutical composition means an amount effective, when administered to a patient, to provide a therapeutic benefit such as an amelioration of symptoms, e.g., an amount effective to decrease the symptoms of Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder.
  • a significant change is any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p ⁇ 0.05.
  • Compounds of formula I are useful for treating a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder in a patient.
  • Ri is a phenyl, furanyl, imidazolyl, oxadiazolyl, tetrahydrofuranyl, thiazolyl, or thienyl group, each of which is unsubstituted or substituted with 1 , 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, Ci-C 2 alkyl, and Ci-C 2 alkoxy; and R 2 is a benzo[ ⁇ i] [l,3]dioxolyl, 2,3-dihydrobenzofuranyl, benzo[ ⁇ i]oxazolyl, benzo[JJ thiazolyl, furanyl, or thienyl group, each of which is unsubstituted or substituted with 1 , 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, Ci-C 4 alkyl, Ci-C 4 alkoxy, C 2 -C 4 alkylester; C 2 -C 4 alkanoyl
  • R 3 is hydrogen
  • Ai, A 2 , and B are all hydrogen and R 3 is Ci-C 4 alkyl, Ci-C 4 alkoxy, or (Cr
  • Ai, A 2 , and B are all hydrogen and R 3 is Ci-C 4 alkyl, Ci-C 4 alkoxy, or (Ci- C 2 alkoxy)Ci-C 4 alkoxy.
  • Ri is a phenyl, furanyl, imidazolyl, oxadiazolyl, tetrahydrofuranyl, thiazolyl, or thienyl group, each of which is unsubstituted or substituted with 1 , 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, Ci-C 2 alkyl, and Ci-C 2 alkoxy and R 2 is benzo[JJ [l,3]dioxolyl, which is unsubstituted or substituted with 1 , 2, or 3 substituents independently chosen from halogen, Ci-C 2 alkyl, and Ci-C 2 alkoxy.
  • Ai and A 2 are independently hydrogen 0 or methyl; and n is 1 or 2.
  • B is hydrogen, methyl, or ethyl.
  • Ri is a furanyl, imidazolyl, oxazolyl, oxadiazolyl, tetrahydrofuranyl, thiazolyl, pyridyl, or thienyl group, each of which is unsubstituted or substituted with 1 or 2
  • R 2 is a benzo[JJ[l,3]dioxolyl, which is unsubstituted or substituted with 1 or 2 methyl or ethyl substituents; and R 3 is hydrogen or Ci-C 2 alkyl.
  • Exemplary quinazolin-4-amine derivatives include each of:
  • the compound of formula I or salt thereof is isotopically or radiolabeled.
  • quinazolin-4-amine derivatives provided by this invention and labeled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit Clkl, Clk2, Clk4, or DyrklA.
  • Labeled compounds are useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography
  • Another embodiment provides a method for demonstrating the presence or absence of Clkl, Clk2, Clk4, or DyrklA kinase in a biological sample, the method comprising: a) contacting the biological sample with a labeled compound of formula I or a salt thereof under conditions that permit binding of the labeled compound to the Clkl, Clk2, Clk4, or DyrklA kinase; b) separating unbound labeled compound from bound labeled compound; and c) detecting the labeled compound in the biological sample, and therefrom determining the presence or absence of Clkl, Clk2, Clk4, or DyrklA kinase in the sample.
  • the biological sample is derived from a mammal. In other
  • the mammal is a mouse, rat, a monkey, or a human.
  • a method of inhibiting a Clkl, Clk2, Clk4, or DyrklA kinase in vivo comprising administering an amount of a compound of formula I or a salt thereof sufficient to inhibit the kinase in vitro.
  • a method for inhibiting the phosphorylation activity of a Clkl, Clk2, Clk4, or DyrklA kinase comprises contacting a cell containing a Clkl, Clk2, Clk4, or DyrklA kinase with a solution containing a concentration of a compound of formula I or a salt thereof sufficient to inhibit the phosphorylation activity of a Clkl, Clk2, Clk4, or DyrklA kinase in vitro.
  • a method of inhibiting the splicing activity of a Clkl, Clk2, Clk4, or DyrklA kinase comprises contacting a cell containing a Clkl, Clk2, Clk4, or DyrklA kinase with a solution containing a concentration of a compound of formula I or salt thereof sufficient to significantly alter the splicing of PKC iI TF, Tau or ⁇ -globin pre- niRNA in vitro.
  • the quinazolin-4- amine derivatives can be administered as the neat chemical, but are specifically administered as a pharmaceutical composition, for example a
  • the quinazolin-4-amine derivatives may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
  • the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution.
  • Some dosage forms, such as tablets and capsules are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
  • Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
  • the carrier can be inert or it can possess pharmaceutical benefits of its own.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents.
  • Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
  • Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, and vegetable oils.
  • Optional active and/or inactive agents may be included in the pharmaceutical compositions, provided that such agents do not substantially interfere with the activity of the quinazolin-4-amine derivatives used in the pharmaceutical compositions.
  • the optional active is an additional active agent that is not a compound or salt of formula I.
  • compositions can be formulated for oral administration. These compositions contain between 0.1 and 99 weight % (wt.%) of a 2-fluorothiazole derivative and usually at least about 5 wt.% of a quinazolin-4- amine derivative. Some embodiments contain from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the quinazolin-4-amine derivatives.
  • the compounds of Formula I or a salt thereof, as well as pharmaceutical compositions comprising the compounds, are useful for treating a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorders in a patient.
  • An effective amount of a pharmaceutical composition may be an amount sufficient to (a) prevent a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder or a symptom of a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder from occurring in a patient who may be predisposed to a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder but who has not yet been diagnosed as having it; (b) inhibit the progression of a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder; and (c) cause a regression of the Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder.
  • An effective amount of a compound or pharmaceutical composition described herein will also provide a sufficient concentration of a quinazolin-4-amine derivative when administered to a patient.
  • a sufficient concentration is a concentration of the compound in the patient's body necessary to prevent or combat the disorder. Such an amount may be ascertained experimentally, for example by assaying blood concentration of the compound, or theoretically, by calculating bioavailability.
  • the amount of an active agent sufficient to modulate Clkl, Clk2, Clk4, or DyrklA in vivo may be determined in vitro with a
  • Methods of treatment include providing certain dosage amounts of a quinazolin-4-amine derivative to a patient.
  • Dosage levels of each compound of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day).
  • the amount of compound that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of each active compound. In certain embodiments 25 mg to 500 mg, or 25 mg to 200 mg of a compound of Formula I are provided daily to a patient. Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most Clkl, Clk2, Clk4, or DyrklA kinase mediated disorders, a dosage regimen of 4 times daily or less can be used and in certain embodiments a dosage regimen of 1 or 2 times daily is used.
  • the compounds of Formula I may be used to treat Clkl, Clk2, Clk4, or DyrklA kinase mediated disorders including cognitive disorders associated with splicing defects and the hyperphosphorylation of selected cellular targets. Indications such as early onset Alzheimer's disease in Down's syndrome, alteration of coagulation cascade by tissue factor (TF), modulation of insulin action, correction of mis-splicing of lamin A in Progeria, alteration of the T-cell activation and the immune response and within several inflammation models and alteration of neuronal depolarization.
  • TF tissue factor
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
  • the organic layer was dry packed and purified by flash silica column chromatography using a Biotage SP4 (0- O % MeOH in DCM gradient over 10 CV, 10% MeOH/DCM over 10 CV, collected at 254 nM) to yield 6- (benzo[d][l,3]dioxol-5-yl)quinazolin-4(3H)-one as a pure yellowish solid (1.42 g, 5.34 mmol, 40%).
  • the organic layer was concentrated in vacuo and used in the next step crude.
  • the organic layer was dry packed and purified by flash silica column chromatography using a Biotage SP4 (0-» 10 % MeOH in DCM gradient over 10 CV, 10% MeOH/DCM over 10 CV, collected at 254 nM) to yield 6-(benzo[d][l,3]dioxol-5-yl)-4-chloroquinazoline as a pure yellowish solid to be used immediately.
  • Table 1 contains exemplary substituted quinazoline intermediates produced by the Suzuki coupling procedure described above.
  • Table 1 contains exemplary quinazolin-4- amine derivatives prepared via the methods provided in Examples 1 and 2.
  • Method 1 A 7 minute gradient of 4% to 100% Acetonitrile (containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) was used with an eight minute run time at a flow rate of one mL/min.
  • Method 2 A 3 minute gradient of 4% to 100% Acetonitrile (containing 0.025%
  • trifluoroacetic acid in water (containing 0.05% trifluoroacetic acid) was used with a 4.5 minute run time at a flow rate of 1 mL/min.
  • a Phenomenex Gemini Phenyl column (3 micron, 3 x 100 mm) was used at a temperature of 50 °C.
  • Purity determination was performed using an Agilent Diode Array Detector. Mass determination was performed using an Agilent 6130 mass spectrometer with electrospray ionization in the positive mode.
  • TG003 was determined to have Kd' s of 19 nM, 95 nM and 30 nM versus Clkl, Clk2 and Clk4, respectively.
  • the Kd for TG003 versus Clk3 was 3 ⁇ .
  • TG003 had activity versus CSNK1D (150 nM), CSNK1E (300 nM), DyrklA (12 nM), DyrklB (130 nM), PIM1 (130 nM), PIM3 (280 nM) and Ysk4 (290 nM).
  • the compound 22 was found to have Kd' s of 37 nM, 50 nM and 27 nM versus Clkl, Clk4 and DyrklA, respectively.
  • the only other locus of relevant activity (below 500 nM) was found for binding to the endothelial growth factor receptor (EGFR) (230 nM).
  • Two bioluminescence assay systems were employed.
  • measurement of ATP depletion employed the Kinase-Glo assay system where a firefly luciferase detection reagent containing D-luciferin and buffer components are added to detect the remaining ATP following the kinase assay (e.g., Clk4).
  • ADP-Glo measures kinase activity by quantifying the amount of ADP formed after kinase reaction. Bioluminescent detection of ADP levels is achieved through the addition of two different detection reagents. First, a reagent that stops the protein kinase reaction and depletes the remaining ATP is added.
  • the second reagent also contains an enzyme such as pyruvate kinase that efficiently converts the ADP to ATP and the same firefly luciferase/D-luciferin components present in Kinase-Glo which generates a luminescent signal that is proportional to the concentration of ADP produced.
  • the luminescent response is inversely proportional to the kinase activity in the ATP depletion format (Kinase-Glo assay) while the luminescent response is directly proportional to kinase activity in the ADP formation format (ADP-Glo assay).
  • the two assay formats therefore show opposite luminescence signal changes in response to protein kinase inhibitors.
  • qHTS Clk4 ADP-Glo assay For the ADP-Glo kinase assay, 2 uL/well of substrate-buffer solution (100 ⁇ RS peptide, 1 ⁇ ATP, lx ADP-Glo Buffer A, mM MgCl 2 , 0.5 mM EGTA, 2.5 mM DTT, 0.01% Triton X-100, final concentrations) was dispensed into 1,536-well plates (Greiner, solid white, medium binding assay plates) with the FRD.
  • substrate-buffer solution 100 ⁇ RS peptide, 1 ⁇ ATP, lx ADP-Glo Buffer A, mM MgCl 2 , 0.5 mM EGTA, 2.5 mM DTT, 0.01% Triton X-100, final concentrations
  • the ADP product was then converted to ATP by adding 5 uL per well of ADP-Glo Reagent II to yield a total assay volume of 10 ⁇ well. Luminescence was detected after 30 min room temperature incubation with the Perkin Elmer Veilleux.
  • IB inhibitory dose response of the compound in the presence of three different peptide concentrations [50 ⁇ (filled circles), 100 ⁇ (empty circles), 200 ⁇ (empty squares)]). Additionally, while maintaining compound 22 at a constant concentration (70 nM), an examination of the dose response of ATP demonstrated a sharp decline in enzyme inhibition at high ATP concentrations (>1 mM) while an increase in the dose of the peptide did not affect the potency of the compound (data not shown). Results indicate that compounds of formula 1 are ATP competitive inhibitors of Clk4.
  • Clkl and Clk4 are highly homologous enzymes (>85% sequence identity) while Clk2 and Clk3 also share a high degree of sequence homology (>70% sequence identity). Based upon this, the X-ray structure of Clkl was utilized as the template to derive a homology model of Clk4 using MOE molecular modeling software (MOE Molecular Operating Environment, Version 2008.10; Chemical Computing Group Inc.: Montreal, Canada, 2008.
  • the spatial water maze and step-down passive avoidance models are suitable models for in vivo determinations of cognition enhancement.
  • Spatial water maze The spatial water maze has been used extensively as a test of spatial learning and memory. Rats are trained to escape from the water by swimming to a platform that is submerged just below the surface of the water. Since the platform is not visible to the animal, it has to utilize visual extra-maze cues in the area of the tank to locate the platform.
  • the water maze apparatus consists of a circular tank, 119 cm in diameter and 56 cm in height, with a black interior.
  • the tank is filled with water approximately 23-25° C. to a height of 42 cm.
  • Superimposed onto the tank are four quadrants, South, East, North and West.
  • the tank is surrounded by external visual cues, which consist of a black and white checkered wall, a black and la white striped wall, a white wall with two light fixtures, and a blue wall.
  • a black circular PLEXIGLAS platform with a black neoprene rubber top is placed in the Northeast quadrant approximately 1-2 cm below the surface of the water.
  • the submerged platform is 39 cm in height and has a diameter of 11.5 cm. Training and testing are conducted in the presence of a 60-62 dB white noise source and under dim light conditions (1.0-1.2 lux).
  • the animal's path is tracked by a video camera interfaced to an automated tracking package (Video track, CPL Systems).
  • results are given as the minimal efficacious dose of compound in mg/kg, administered IV (unless listed as PO), needed to elicit a statistically significant response.
  • Step-down Passive Avoidance In step-down passive avoidance a rat is placed on a platform located in the center of an electrified grid floor that is contained within a large (45 cmx45 cmx50 cm) white translucent Plexiglas® enclosure. The natural inclination of the rat is to step off the platform and investigate its surroundings. In day one of the experiment animals are treated with either test compound in a 50% PEG vehicle, or vehicle alone and then trained to remain on the platform for at least 120 seconds. Each time the animal steps off the platform it receives a mild foot shock of 2 mAmpsx6 sec. Following each shock the animal is removed from the box, placed in its cage for a one minute inter-trial interval, and then returned to the platform. The latency to step down on each trial, the number of trials taken to reach criterion during training and the retention latency are collected.
  • Testing is conducted approximately 24 h after training. Drug-free animals are placed on the platform in the box in which they will have been trained and the latency to step down onto the grid floor is recorded for one trial as a measure of memory retention. The animal is allowed a maximum of 120 seconds to step down and does not receive a shock upon stepping off the platform.
  • the compounds of formula I are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope.
  • the radioisotope can be selected from of at least one of carbon (specifically 14 C), hydrogen
  • radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRI International, Menlo Park, Calif.; ChemSyn
  • Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of formula I as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.

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Abstract

Disclosed herein are novel quinazolin-4-amine derivatives that are inhibitors of Clk1, Clk2, Clk3, Clk4, or Dyrk1A. Also disclosed are quinazolin-4-amine derivatives as potent and selective inhibitors of Clk1, Clk4, and Dyrk1A. These agents provide useful tools for the study of Clk1, Clk4 and Dyrk1A and their respective roles in pre-mRNA splicing. Methods of treating Clk1, Clk2, Clk4, or Dyrk1A kinase mediated disorders with certain quinazolin-4-amine derivatives are also disclosed.

Description

QUINAZOLIN-4- AMINE DERIVATIVES; AND METHODS OF USE
STATEMENT OF GOVERNMENT SUPPORT
This invention was made in part with government support from the National Institutes of Health. The government has certain rights in this invention.
CROSS REFERENCE TO RELATED APPLICATION
This application claims priority from US provisional patent application 61/ 247,632, filed October 1, 2009, which is hereby incorporated by reference in its entirety.
BACKGROUND
[0001] The removal of intron sequences from genes occurs via the actions of the splicesome, a protein complex that removes intervening sequences at the nuclear pre-mRNA level to afford properly coded mRNA for translation. Many genes produce multiple mRNA isoforms through the actions of alternative splicing and, numerous human diseases are caused by improper splicing (e.g., degenerative diseases and cancers). By manipulation of the splicesome it is theorized that gene translation can be controlled to rectify splicing abnormalities.
[0002] Modulation of kinases using small molecule inhibitors is a known approach to control numerous aspects of cell function and for the potential for the management of many diseases. Modulation of kinase activity may make it possible for the control of gene splicing. There are several reports of kinases that alter the function of the splicesome; among these are the cdc2-like kinase (Clk) family (Hanes et al., J. Mol. Biol. (1994) 244: 665-672). A major target of Clk kinases is the prominent family of serine- and arginine-rich (SR) splicing proteins, which are involved in the assembly of the splicesome and are implicated in both constitutive and alternative splicing control and selection of splicing sites.
[0003] The Clk family contains four characterized isoforms (Clkl, Clk2, Clk3 and Clk4). The Clks are capable of auto-phosphorylation (at serine, threonine and tyrosine residues) and phosphorylation of exogenous proteins (at serine and threonine residues).
Members of the Clk family have been implicated in the regulation of alternative splicing of PKC iI, TF, Tau, and β-globin pre-mRNA. These studies suggest that small molecule modulation of the Clk family of kinases may represent an important mechanism for the control of mRNA splicing. [0004] The literature reports a small molecule with low-nanomolar IC50 value versus Clkl and Clk4 (Muraki et al., J. Biol. Chem. (2004) 279: 24246-24254). The selectivity of this compound beyond the Clk family and 4 additional kinases (PKA, PKC, SRPK1 and SRPK2) is not disclosed.
[0005] Other reports of Clk inhibitors, including substituted quinolines, do not provide details of selectivity (WO2009/085226 and WO 2008/014602).
[0006] The DyrklA [dual specificity tyrosine (Y)-phosphorylation-regulated kinase 1A] gene is located on chromosome 21 and is known to be highly expressed in CNS tissues. DyrklA knock-out mice are embryonic lethal and transgenic mice overexpressing DyrklA display learning and memory deficiencies. The DyrklA gene is located on the Downs syndrome (DS) critical region of chromosome 21 and trisomy-driven overexpression in DS patients has been demonstrated. Further evidence has been presented that
hyperphosphorylation of Tau by DyrklA is a causative factor in the early onset of Alzheimer disease in DS patients. DyrklA has been implicated as an important modulator of pre- mPvNA splicing via several molecular interactions including the phosphorylation of the SR protein cyclin L2.
[0007] The literature reports a class of pyrazolidine-3,5-diones discovered via in silico screening as DyrklA inhibitors (Kim et al., Bioorg. Med. Chem. Lett. (2006) 16: 3772-3776; and Koo et al., Bioorg. Med. Chem. Lett. (2009) 19: 2324-2328). The most potent of these agents were demonstrated to have IC50 value of 0.6 μΜ and selectivity versus a panel of 15 selected kinases highly suggested that these agents were fairly promiscuous.
[0008] There remains a need in the art for new potent inhibitors of Clk, as well as potent and selective inhibitors of Clkl and Clk4. There also remains a need for potent and selective inhibitors of DyrklA.
SUMMARY OF THE INVENTION
[0009] Described herein are quinazolin-4-amine derivatives, their methods of manufacture, compositions containing the quinazolin-4-amine derivatives, and methods of use of both the quinazolin-4-amine derivatives and compositions thereof. Thus in a first aspect, a compound of formula I is provided
Figure imgf000004_0001
or a pharmaceutically acceptable salt thereof.
[0010] Within this embodiment the following conditions are met.
Ai and A2 are independently chosen at each occurrence from hydrogen, methyl, and ethyl.
B is hydrogen, methyl, ethyl, propyl, or isopropyl; and n is 1, 2, 3, or 4; and
Ri is a phenyl, pyridyl, 5- or 6-membered heterocycloalkyl, or a 5-membered heteroaryl group, each heterocycloalkyl or heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, each of which heterocycloalkyl or heteroaryl group is
unsubstituted or substituted with 1, 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, Ci-C4alkyl, and Ci-C4alkoxy.
Or, n is 2, 3, or 4; and B is hydrogen, methyl, ethyl, propyl, or isopropyl; and
Ri is mono- or di-Ci-C4alkylamino or amino.
Or, n is 3 or 4 and Ri and B are joined to form a 5- or 6-membered heterocycloalkyl group in which one ring carbon is optionally replaced with a N, S, or O atom, which 5- or 6- membered heterocycloalkyl group is substituted with 0 or 1 substituents chosen from C3- Cecycloalkyl and 5- and 6-membered heterocycloalkyl.
G is R2, J is R3 and L is hydrogen, or G is hydrogen, J is R2, and L is R3; or G is hydrogen, J is R3, and L is R2.
R2 is 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently chosen from N, O, and S, or R2 is phenyl fused to a 5-membered saturated or partially unsaturated heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S, or R2 is a phenyl substituted with at least one methoxy group; each of which R2 is unsubstituted or substituted with 1, 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, cyano, Ci-C4alkyl, Ci-C4alkoxy, C2-C4alkylester; C2-C4alkanoyl, (mono- and di-Ci-C2alkylamino)Co-C2alkyl, Ci-C2haloalkyl, and Ci-C2haloalkoxy, and is substituted with 0 or 1 substituents chosen from -CHO, -COOH, (C2-C4alkylester)C0-C2alkyl, C
C4hydroxylalkyl, (mono- and di-Ci-C4alkylcarboxamide)Co-C2alkyl, (mono- and di-Q- C4alkylcarbamate)Co-C2alkyl, and phenyl. R3 is hydrogen, halogen, hydroxyl, Ci-C4alkyl, Ci-C4alkoxy, or (C1-C2 C4alkoxy.
[0011] Further within this embodiment:
R2 is not a 3,5-dimethylisoxazol-4-yl group;
Ri and R2 are not both a furanyl group;
Ri is not a thien-2-yl group when R2 is a furan-3-yl group; and
the compound is not
6-(5-iodofuran-2-yl)-7-methoxy-N-(l-phenylethyl)quinazolin-4-amine;
6-(furan-2-yl)-7-methoxy-N-(l-phenylethyl)quinazolin-4-amine;
6-(furan-3-yl)-N-(3-methylbenzyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(2-methoxybenzyl)quinazolin-4-amine;
N-benzyl-6-(furan-3-yl)quinazolin-4-amine;
6-(furan-3-yl)-N-(pyridin-3-ylmethyl)quinazolin-4-amine;
N-(2,4-dimethoxybenzyl)-6-(furan-3-yl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-benzylquinazolin-4-amine;
6-(furan-3-yl)-N-(2-methoxybenzyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(2,4-dimethoxybenzyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(3-methylbenzyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine; or
6-(benzo[d][l,3]dioxol-5-yl)-N-(furan-2-ylmethyl)quinazolin-4-amine.
0012] In another aspect, a compound of formula I is provided
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof.
[0013] Within this embodiment the following conditions are met.
Ai and A2 are independently hydrogen, methyl, or ethyl.
B is hydrogen, methyl, ethyl, propyl, or isopropyl; and n is 1 or 2.
Ri is a 5-membered heterocycloalkyl or 5- or 6-membered heteroaryl group, each heterocycloalkyl or heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, each of which heterocycloalkyl or heteroaryl group is unsubstituted or substituted with 1, 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, Ci-C2alkyl, and Ci-C2alkoxy.
R2 is 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently chosen from N, O, and S, or
R2 is phenyl fused to a 5-membered saturated or partially unsaturated heterocyclic ring containing 1 or 2 heteroatoms independently chosen from N, O, and S; each of which R2 is unsubstituted or substituted with 1, 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, cyano, Ci-C4alkyl, Ci-C4alkoxy, C2-C4alkylester; C2-C4alkanoyl, mono- and di-(Ci-C2alkyl)amino, Ci-C2haloalkyl, and Ci-C2haloalkoxy, , and is substituted with 0
Figure imgf000006_0001
and di-C alkylcarboxamide, (mono- and di-Cj^C4alkylcarbamate Cn-C alkvk and phenyl..
R3 is halogen, hydroxyl, Ci-C4alkyl, Ci-C4alkoxy, or (Ci-C2alkoxy)Ci-C4alkoxy.
[0014] In still another aspect, a pharmaceutical composition comprises a compound of formula I or a salt thereof and at least one pharmaceutically acceptable carrier.
[0015] In yet another aspect, a method of improving spatial learning, short term memory, or working memory in a patient comprises administering an effective amount of a compound or salt of formula I to the patient.
[0016] In still another aspect, a method of treating a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder in a patient comprises administering an effective amount of a compound of formula I to the patient.
[0017] In one aspect, a method of inhibiting a Clkl, Clk2, Clk4, or DyrklA kinase in vivo comprises administering an amount of a compound or salt of formula I sufficient to inhibit the kinase in vitro.
[0018] In another aspect, a method for inhibiting the phosphorylation activity of a Clkl, Clk2, Clk4, or DyrklA kinase comprises contacting a cell containing a Clkl, Clk2, Clk4, or DyrklA kinase with a solution containing a concentration of a compound or salt of formula I sufficient to inhibit the phosphorylation activity of a Clkl, Clk2, Clk4, or DyrklA kinase in vitro.
[0019] In yet another aspect, a method of inhibiting the splicing activity of a Clkl, Clk2, Clk4, or DyrklA kinase comprises contacting a cell containing a Clkl, Clk2, Clk4, or DyrklA kinase with a solution containing a concentration of a compound or salt of formula I sufficient to significantly alter the splicing of PKC iI TF, Tau or β-globin pre-mRNA in vitro. [0020] In one aspect, a method for demonstrating the presence or absence of Clkl, Clk2, Clk4, or DyrklA kinase in a biological sample comprises a) contacting the biological sample with a labeled compound or salt of formula I under conditions that permit binding of the labeled compound to the Clkl, Clk2, Clk4, or DyrklA kinase; b) separating unbound labeled compound from bound labeled compound; and c) detecting the labeled compound in the biological sample, and therefrom determining the presence or absence of Clkl, Clk2, Clk4, or DyrklA kinase in the sample.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] The invention will be further described in connection with the accompanying drawings in which:
[0022] Fig. 1A illustrates an inhibitory dose response of a representative quinazolin- 4-amine derivative in the presence of three different ATP concentrations.
[0023] Fig. IB illustrates an inhibitory dose response of a representative quinazolin- 4-amine derivative in the presence of three different peptide concentrations.
DETAILED DESCRIPTION
[0024] Disclosed herein are novel quinazolin-4-amine derivatives that are inhibitors of Clkl, Clk2, Clk3, Clk4, or DyrklA. Also disclosed herein are quinazolin-4- amine derivatives as potent and selective inhibitors of Clkl, Clk4, and DyrklA. These agents provide useful tools for the study of Clkl, Clk4 and DyrklA and their respective roles in pre- mRNA splicing.
TERMINOLOGY
[0025] Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.
[0026] The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced items. The term "or" means "and/or". The terms "comprising", "having", "including", and "containing" are to be construed as open-ended terms (i.e., meaning "including, but not limited to"). Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as"), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention as used herein. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.
[0027] All compounds are understood to include all possible isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include UC, 13C, and 14C.
[0028] The term "substituted" means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded. When the substituent is oxo (i.e., =0), then 2 hydrogens on the atom are replaced. When aromatic moieties are substituted by an oxo group, the aromatic ring is replaced by the corresponding partially unsaturated ring. For example a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent.
[0029] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
[0030] "Alkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms. The term C Cialkyl means an alkyl group having from 1 to about 2 carbon atoms, e.g., methyl and ethyl, respectively.
[0031] "Alkoxy" means an alkyl group, as defined above, with the indicated number of carbon atoms attached via an oxygen bridge.
[0032] "Halo" or "halogen" means fluoro, chloro, bromo, or iodo. [0033] "5-Membered heterocycloalkyl" means a saturated cyclic group containing from 1 to about 3 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Examples of 5-membered heterocycloalkyl groups include tetrahydrofuranyl and pyrrolidinyl groups.
[0034] "5-Membered heteroaryl" is a stable 5-membered monocyclic ring that contains from 1 to 4, or in some embodiments from 1 to 2 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. In one embodiment, the total number of S and O atoms in the heteroaryl group is not more than 2. In one embodiment, the total number of S and O atoms in the heteroaryl group is not more than 1. When indicated, such heteroaryl groups may be further substituted with carbon or non-carbon atoms or groups. Examples of 5-membered heteroaryl groups include, but are not limited to, imidazolyl, oxazolyl, furanyl, thiazolyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, pyrrolyl, pyrazolyl, and thienyl.
[0035] "Hydroxylalkyl" is an alkyl group substituted with at least one hydroxyl group.
[0036] "Phenyl fused to a 5-membered saturated or partially unsaturated heterocyclic ring" means a phenyl group fused to a 5-membered saturated cyclic group that contains 1 or 2 heteroatoms independently chosen from N, O, and S, to form, for example, a 3,4- methylenedioxy-phenyl group, or a phenyl group fused to a 5-membered partially unsaturated cyclic group that contains 1 or 2 heteroatoms independently chosen from N, O, and S, to form, for example, a benzo[d][l,3]dioxolyl group.
[0037] "Alkylester" is an alkyl group as defined above attached through an ester linkage. The ester linkage may be in either orientation, e.g., a group of the formula - 0(C=0)alkyl or a group of the formula -(C=0)Oalkyl.
[0038] "Alkanoyl" is an alkyl group as defined above, attached through a keto (- (C=0)-) bridge. Alkanoyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms. For example a C2alkanoyl group is an acetyl group having the formula CH3(C=0)-.
[0039] "Mono- and/ or di-alkylamino" means secondary or tertiary alkyl amino groups, wherein the alkyl groups are as defined above and have the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. The alkyl groups are independently chosen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-prop yl-amino.
[0040] "Mono- or di-alkylcarboxide" is a group of the formula -(C=0)Nalkylialkyl2, where the alkyli and alkyl2 groups are independently chosen alkyl groups as defined herein, attached through a carboxamide linkage. The carboxamide linkage may be in either orientation, e.g., -NH(C=0)- or -(C=0)NH-.
[0041] "Mono- or di-alkylcarbamate" is a group of the formula
-0(C=0)Nalkylialkyl2, where the alkyli and alkyl2 groups are independently chosen alkyl groups, as defined as defined herein, attached through a carbamate linkage.
[0042] "Haloalkyl" means both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, generally up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
[0043] "Haloalkoxy" indicates a haloalkyl group as defined above attached through an oxygen bridge (oxygen of an alcohol radical).
[0044] Compounds of formula I may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g., asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. For compounds having asymmetric centers, all optical isomers in pure form and mixtures thereof are encompassed. In these situations, the single enantiomers, i.e., optically active forms can be obtained by asymmetric synthesis, synthesis from optically pure precursors, or by resolution of the racemates. Resolution of the racemates can also be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column. All forms are contemplated herein regardless of the methods used to obtain them.
[0045] All forms (for example solvates, optical isomers, enantiomeric forms, polymorphs, free compound and salts) of an active agent may be employed either alone or in combination.
[0046] The term "chiral" refers to molecules, which have the property of non- superimposability of the mirror image partner. [0047] "Stereoisomers" are compounds, which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
[0048] A "diastereomer" is a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis, crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
[0049] "Enantiomers" refer to two stereoisomers of a compound, which are non- superimposable mirror images of one another. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereo specificity in a chemical reaction or process.
[0050] Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book
Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory.
[0051] A "racemic mixture" or "racemate" is an equimolar (or 50:50) mixture of two enantiomeric species, devoid of optical activity. A racemic mixture may occur where there has been no stereoselection or stereo specificity in a chemical reaction or process.
[0052] "Pharmaceutically acceptable salts" include derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, nontoxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts.
[0053] Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)n-COOH where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., p. 1418 (1985).
[0054] "Pharmaceutical compositions" means compositions comprising at least one active agent, such as a compound or salt of the invention, and at least one other substance, such as a carrier. Pharmaceutical compositions meet the U.S. FDA's GMP (good
manufacturing practice) standards for human or non-human drugs.
[0055] "Carrier" means a diluent, excipient, or vehicle with which an active compound is administered. A "pharmaceutically acceptable carrier" means a substance, e.g., excipient, diluent, or vehicle, that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. A
"pharmaceutically acceptable carrier" includes both one and more than one such carrier.
[0056] A "patient" means a human or non-human animal in need of medical treatment. Medical treatment can include treatment of an existing condition, such as a disease or disorder, prophylactic or preventative treatment, or diagnostic treatment. In some embodiments the patient is a human patient.
[0057] "Providing" means giving, administering, selling, distributing, transferring (for profit or not), manufacturing, compounding, or dispensing. [0058] "Treatment" or "treating" means providing an active compound to a patient in an amount sufficient to measurably reduce any symptom of a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder, e.g., cause regression of the disorder, improve short term memory or working memory, modulate insulin activity; or improve the patient' s performance on a test of spatial learning.
[0059] A "therapeutically effective amount" of a pharmaceutical composition means an amount effective, when administered to a patient, to provide a therapeutic benefit such as an amelioration of symptoms, e.g., an amount effective to decrease the symptoms of Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder.
[0060] A significant change is any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p < 0.05.
CHEMICAL DESCRIPTION
[0061] Compounds of formula I are useful for treating a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder in a patient.
[0062] In addition to compounds of formula I described above, specific quinazolin-4- amine derivatives include the compounds of formula I in which the variables have the meanin s set forth below:
Figure imgf000013_0001
[0063] In addition to compounds of formula I described above, specific quinazolin-4- derivatives include the compounds of formula I in which the variables have the meanings set forth below, or example compounds of formula I in which any of the following conditions are met:
(i) wherein n is i .
(ii) Ri is a phenyl, furanyl, imidazolyl, oxadiazolyl, tetrahydrofuranyl, thiazolyl, or thienyl group, each of which is unsubstituted or substituted with 1 , 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, Ci-C2alkyl, and Ci-C2alkoxy; and R2 is a benzo[<i] [l,3]dioxolyl, 2,3-dihydrobenzofuranyl, benzo[<i]oxazolyl, benzo[JJ thiazolyl, furanyl, or thienyl group, each of which is unsubstituted or substituted with 1 , 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, Ci-C4alkyl, Ci-C4alkoxy, C2-C4alkylester; C2-C4alkanoyl, mono- and di-(Ci- C2alkyl) amino, Ci-C2haloalkyl, and Ci-C2haloalkoxy, or R2 is a furanyl or thienyl group, each substituted with 0, 1 , or 2 substituents chosen from halogen, Ci-C2alkyl, and Ci-C2alkoxy, and each substituted with 1 substituent chosen from -CHO, -COOH,
Figure imgf000014_0001
Qalkylcarboxamide^o-C^alkyk (mono- and di-Cj^C4alkylcarbamate Co-C2alkyl and, phenyl.
(iii) Ai andA2 and both hydrogen, and B are all hydrogen or methyl.
(iv) R3 is hydrogen.
(v) Ai, A2, and B are all hydrogen and R3 is Ci-C4alkyl, Ci-C4alkoxy, or (Cr
C2alkoxy)Ci-C4alkoxy.
(vi) Ai, A2, and B are all hydrogen and R3 is Ci-C4alkyl, Ci-C4alkoxy, or (Ci- C2alkoxy)Ci-C4alkoxy.
(vii) Ri is a phenyl, furanyl, imidazolyl, oxadiazolyl, tetrahydrofuranyl, thiazolyl, or thienyl group, each of which is unsubstituted or substituted with 1 , 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, Ci-C2alkyl, and Ci-C2alkoxy and R2 is benzo[JJ [l,3]dioxolyl, which is unsubstituted or substituted with 1 , 2, or 3 substituents independently chosen from halogen, Ci-C2alkyl, and Ci-C2alkoxy.
(viii) Ri is chosen from
Figure imgf000014_0002
Figure imgf000015_0001
Figure imgf000015_0002
[0064] Also included as embodiments are compounds and pharmaceutically acceptable salts of Formula I in which the following conditions are met:
Figure imgf000015_0003
Ai and A2 are independently hydrogen 0 or methyl; and n is 1 or 2. B is hydrogen, methyl, or ethyl.
Ri is a furanyl, imidazolyl, oxazolyl, oxadiazolyl, tetrahydrofuranyl, thiazolyl, pyridyl, or thienyl group, each of which is unsubstituted or substituted with 1 or 2
substituents independently chosen from halogen, CrC2alkyl, and Ci-C2alkoxy.
R2 is a benzo[JJ[l,3]dioxolyl, which is unsubstituted or substituted with 1 or 2 methyl or ethyl substituents; and R3 is hydrogen or Ci-C2alkyl.
[0065] Included as embodiments are compounds of formula I in which any of the above conditions are combined, so long as a stable compound results. For example, included herein, are compounds of formula I in which conditions (i) n is 1 and (iv) R3 is hydrogen, are both met.
[0066] Exemplary quinazolin-4-amine derivatives include each of:
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-(thiazol-2-ylmethyl)quinazolin-4-amine;
N-(2-(lH-imidazol-4-yl)ethyl)-6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(l-(2-methylthiazol-4-yl)ethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(furan-3-ylmethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(furan-2-yl)ethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((5-methylthiophen-2-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((3-methyl-l,2,4-oxadiazol-5- yl)methyl)quinazolin-4- amine ;
6-(benzo[d][l,3]dioxol-5-yl)-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((5-methylfuran-3-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(furan-2-ylmethyl)-N-methylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((2-methylfuran-3-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((l-methyl-lH-imidazol-5-yl)methyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-((tetrahydrofuran-2-yl)methyl)quinazolin-4-amine;
N-((lH-imidazol-2-yl)methyl)-6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((4-methylthiazol-2-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((5-methyl-l,3,4-oxadiazol-2- yl)methyl)quinazolin-4- amine ;
6-(benzo[d][l,3]dioxol-5-yl)-N-((2,5-dimethylfuran-3-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((3-methylthiophen-2-yl)methyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-(l-(furan-2-yl)ethyl)-N-methylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(l-(furan-2-yl)ethyl)quinazolin-4-amine;
6- (benzo[d][l,3]dioxol-5-yl)-N-(furan-2-ylmethyl)-N-methylquinazolin-4-amine;
7- (benzo[d][l,3]dioxol-5-yl)-N-((5-methylfuran-2-yl)methyl)quinazolin-4-amine;
7-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine; N-((tetrahydrofuran-2-yl)methyl)-6-(3,4,5-trimethoxyphenyl)quinazolin-4-amine;
N-(thiophen-2-ylmethyl)-6-(3,4,5-trimethoxyphenyl)quinazolin-4-amine;
N-(2-(lH-imidazol-4-yl)ethyl)-6-(3,4,5-trimethoxyphenyl)quinazolin-4-amine;
N-((5-methylfuran-2-yl)methyl)-6-(3,4,5-trimethoxyphenyl)quinazolin-4-amine;
N-((4-methylthiazol-2-yl)methyl)-6-(3,4,5-trimethoxyphenyl)quinazolin-4-amine;
5-(benzo[d][l,3]dioxol-5-yl)-6-methoxy-N-((tetrahydrofuran-2-yl)methyl)quinazolin-4- amine;
5- (benzo[d][l,3]dioxol-5-yl)-6-methoxy-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
N-methyl-N-((2-methylthiazol-4-yl)methyl)-6-(3,4,5-trimethoxyphenyl)quinazolin-4-amin^ ethyl 5-(4-(thiophen-2-ylmethylamino)quinazolin-6-yl)furan-2-carboxylate;
6- (4-methoxyphenyl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
6-(3,4-dimethoxyphenyl)-N-((tetrahydrofuran-2-yl)methyl)quinazolin-4-amine;
N-(2-(lH-imidazol-4-yl)ethyl)-6-(3,4-dimethoxyphenyl)quinazolin-4-amine;
6-(3,4-dimethoxyphenyl)-N-((5-methylfuran-2-yl)methyl)quinazolin-4-amine;
6-(3,4-dimethoxyphenyl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
6-(3,4-dimethoxyphenyl)-N-((4-methylthiazol-2-yl)methyl)quinazolin-4-amine;
6-(3,4-dimethoxyphenyl)-N-methyl-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((3-methylthiophen-2-yl)methyl)quinazolin-4- amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((l-methyl-lH-imidazol-5-yl)methyl)quinazolin-4- amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-ethyl-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
6-(4-fluorobenzo[d][l,3]dioxol-5-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
6-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
6-(2-methyl-2H-indazol-6-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
Nl-(6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-yl)-N2,N2-dimethylethane-l,2-diamine;
Nl-(6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-yl)-N3,N3-dimethylpropane-l,3-diamine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(3-morpholinopropyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(l-methylpyrrolidin-2-yl)ethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(3-(piperidin-l-yl)propyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-4-(4-(pyrrolidin-l-yl)piperidin-l-yl)quinazoline;
6-(benzo[d][l,3]dioxol-5-yl)-7-methoxy-N-methyl-N-((2-methylthiazol-4- yl)methyl)quinazolin-4- amine ;
6-(benzo[d][l,3]dioxol-5-yl)-7-methoxy-N-methyl-N-(thiophen-2-ylmethyl)quinazolin-4- amine;
Nl-(6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-yl)butane-l,4-diamine;
Nl-(6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-yl)propane-l,3-diamine;
Nl-(6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-yl)ethane-l,2-diamine;
4-((6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-ylthio)methyl)-2-methylthiazole;
N-(2-(lH-imidazol-4-yl)ethyl)-6-(benzo[d][l,3]dioxol-5-yl)-N-methylquinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(l-methyl-lH-imidazol-4-yl)ethyl)quinazolin-4-amine; 4-((lH-imidazol-5-yl)methoxy)-6-(benzo[d][l,3]dioxol-5-yl)quinazoline;
6-(benzo[d][l,3]dioxol-5-yl)-N-propyl-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(thiophen-2-yl)ethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-ethyl-N-((3-methylthiophen-2-yl)methyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(l-ethyl-lH-imidazol-4-yl)ethyl)-N-methylquinazolin-4- amine;
6 benzo[d][l,3]dioxol-5-yl)-N-ethyl-N-(2-(l-methyl-lH-imidazol-4-yl)ethyl)quinazolin-4- amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-(2-(thiophen-2-yl)ethyl)quinazolin-4-amine;
6-(2,4-dimethylthiazol-5-yl)-N-((5-methylfuran-2-yl)methyl)quinazolin-4-amine;
N-(2-(lH-imidazol-4-yl)ethyl)-6-(2,4-dimethylthiazol-5-yl)quinazolin-4-amine;
N-((lH-imidazol-2-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)quinazolin-4-amine;
6-(2,4-dimethylthiazol-5-yl)-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine;
6-(2,4-dimethylthiazol-5-yl)-N-methyl-N-((3-methylthiophen-2-yl)methyl)quinazolin-4- amine;
6-(4-methyl-2-phenyloxazol-5-yl)-N-((5-methylfuran-2-yl)methyl)quinazolin-4-amine;
N-(2-(lH-imidazol-4-yl)ethyl)-6-(4-methyl-2-phenyloxazol-5-yl)quinazolin-4-amine;
N-((lH-imidazol-2-yl)methyl)-6-(4-methyl-2-phenyloxazol-5-yl)quinazolin-4-amine;
6-(4-methyl-2-phenyloxazol-5-yl)-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine; N-methyl-6-(4-methyl-2-phenyloxazol-5-yl)-N-((3-methylthiophen-2-yl)methyl)quinazolin- 4-amine;
ethyl 2-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-3-carboxylate;
ethyl 2-(4-(2-(lH-imidazol-4-yl)ethylamino)quinazolin-6-yl)furan-3-carboxylate;
ethyl 2-(4-((lH-imidazol-2-yl)methylamino)quinazolin-6-yl)furan-3-carboxylate;
ethyl 2-(4-(methyl((3-methylthiophen-2-yl)methyl)amino)quinazolin-6-yl)furan-3- carboxylate;
6-(furan-3-yl)-N-((5-methylfuran-2-yl)methyl)quinazolin-4-amine;
N-(2-(lH-imidazol-4-yl)ethyl)-6-(furan-3-yl)quinazolin-4-amine;
N-((lH-imidazol-2-yl)methyl)-6-(furan-3-yl)quinazolin-4-amine;
6-(furan-3-yl)-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine;
6-(furan-3-yl)-N-methyl-N-((3-methylthiophen-2-yl)methyl)quinazolin-4-amine;
N-((lH-imidazol-2-yl)methyl)-6-(benzo[d][l,3]dioxol-5-yl)-N-methylquinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((5-methylfuran-2-yl)methyl)quinazolin-4-amine; N-((5-methylfuran-2-yl)methyl)-6-(2-methylfuran-3-yl)quinazolin-4-amine;
N-(2-(lH-imidazol-4-yl)ethyl)-6-(2-methylfuran-3-yl)quinazolin-4-amine;
N-((lH-imidazol-2-yl)methyl)-6-(2-methylfuran-3-yl)quinazolin-4-amine
6-(2-methylfuran-3-yl)-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine;
N-methyl-6-(2-methylfuran-3-yl)-N-((3-methylthiophen-2-yl)methyl)quinazolin-4-amine; ethyl 5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxylate;
ethyl 5-(4-(2-(lH-imidazol-4-yl)ethylamino)quinazolin-6-yl)furan-2-carboxylate;
ethyl 5-(4-((lH-imidazol-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxylate;
ethyl 5-(4-((2-methylthiazol-4-yl)methylamino)quinazolin-6-yl)furan-2-carboxylate;
ethyl 5-(4-(methyl((3-methylthiophen-2-yl)methyl)amino)quinazolin-6-yl)furan-2- carboxylate;
(5-(4-(2-(lH-imidazol-4-yl)ethylamino)quinazolin-6-yl)furan-2-yl)methanol;
(5-(4-((lH-imidazol-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)methanol;
(5-(4-((2-methylthiazol-4-yl)methylamino)quinazolin-6-yl)furan-2-yl)methanol;
(5-(4-(methyl((3-methylthiophen-2-yl)methyl)amino)quinazolin-6-yl)furan-2-yl)methanol; 5-(4-(2-(lH-imidazol-4-yl)ethylamino)quinazolin-6-yl)furan-2-carboxylic acid;
(5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)methanol;
5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxylic acid;
5-(4-(2-(lH-imidazol-4-yl)ethylamino)quinazolin-6-yl)-N-ethylfuran-2-carboxamide; N,N-dimethyl-5-(4-(methyl((3-methylthiophen-2-yl)methyl)amino)quinazolin-6-yl)furan-2- carboxamide;
(5-(4-(thiophen-2-ylmethylamino)quinazolin-6-yl)furan-2-yl)methanol;
5-(4-(thiophen-2-ylmethylamino)quinazolin-6-yl)furan-2-carboxylic acid;
(5-(4-(methyl((3-methylthiophen-2-yl)methyl)amino)quinazolin-6-yl)furan-2-yl)methyl
dimethylcarbamate;
N,N-dimethyl-5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxamide;
N-ethyl-5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxamide;
5-(4-(thiophen-2-ylmethylamino)quinazolin-6-yl)furan-2-carbaldehyde;
ethyl 5-(4-(methyl((5-methylfuran-2-yl)methyl)amino)quinazolin-6-yl)furan-2-carboxylate;
(5-(4-(methyl((5-methylfuran-2-yl)methyl)amino)quinazolin-6-yl)furan-2-yl)methanol;
5- (4-(methyl((5-methylfuran-2-yl)methyl)amino)quinazolin-6-yl)furan-2-carboxylic acid;
6- (benzo[d][l,3]dioxol-5-yl)-N-(thiazol-2-ylmethyl)quinazolin-4-amine;
2-((6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-yl)(methyl)amino)acetic acid;
6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(furan-2-yl)ethyl)-N-methylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-(l-(2-methylthiazol-4-yl)ethyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((tetrahydrofuran-2-yl)methyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((4-methylthiazol-2-yl)methyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(2-methylthiazol-4-yl)ethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-(2-(2-methylthiazol-4-yl)ethyl)quinazolin-4-amine; l-methyl-5-(4-(methyl((5-methylfuran-2-yl)methyl)amino)quinazolin-6-yl)-lH-pyrrole-2- carbonitrile;
l-(5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)ethanol;
l-(5-(4-(methyl((3-methylthiophen-2-yl)m
l-(5-(4-(thiophen-2-ylmethylamino)quinazolin-6-yl)furan-2-yl)ethanol;
(l-methyl-5-(4-(methyl((5-methylfuran-2-yl)methyl)amino)quinazolin-6-yl)-lH-pyrrol-2- yl)methanol;
l-(5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)ethanone;
6-(benzo[d][l,3]dioxol-5-yl)-N-((tetrahydro-2H-pyran-2-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(cyclohexylmethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-ethylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-propylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-neopentylquinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-(furan-2-ylmethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(tetrahydrofuran-2-yl)ethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((tetrahydrofuran-3-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(cyclopentylmethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-4-(piperidin-l-yl)quinazoline;
6-(benzo[d][l,3]dioxol-5-yl)-4-(piperazin-l-yl)quinazoline;
4- (6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-yl)morpholine;
6-(benzo[d][l,3]dioxol-5-yl)-N-ethyl-N-methylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-propylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(cyclopropylmethyl)quinazolin-4-amine;
(S)-6-(benzo[d][l,3]dioxol-5-yl)-N-((tetrahydrofuran-2-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(cyclohexylmethyl)-N-methylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-(2-(tetrahydrofuran-2-yl)ethyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((tetrahydro-2H-pyran-2-yl)methyl)quinazolin-4- amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((tetrahydro-2H-pyran-3-yl)methyl)quinazolin-4-amine;
5- (4-((tetrahydrofuran-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxylic acid;
5-(4-(neopentylamino)quinazolin-6-yl)furan-2-carboxylic acid;
5-(4-morpholinoquinazolin-6-yl)furan-2-carboxylic acid;
5-(4-(thiazol-2-ylmethylamino)quinazolin-6-yl)furan-2-carboxylic acid;
5-(4-((4-methylthiazol-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxylic acid;
(5-(4-((tetrahydrofuran-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)methanol;
(5 - (4- (neopentylamino)quinazolin- 6-yl)furan-2- yl)methanol ;
(5-(4-((4-methylthiazol-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)methanol;
N-ethyl-5-(4-((tetrahydrofuran-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxamide; N-ethyl-5-(4-(thiazol-2-ylmethylamino)quinazolin-6-yl)furan-2-carboxamide;
N-ethyl-5-(4-((4-methylthiazol-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxamide; N-ethyl-5-(4-morpholinoquinazolin-6-yl)furan-2-carboxamide;
N-ethyl-5-(4-(neopentylamino)quinazolin-6-yl)furan-2-carboxamide;
l-(5-(4-((tetrahydrofuran-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)ethanol;
l-(5-(4-((4-methylthiazol-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)ethanol;
l-(5-(4-morpholinoquinazolin-6-yl)furan-2-yl)ethanol;
l-(5-(4-(thiazol-2-ylmethylamino)quinazolin-6-yl)furan-2-yl)ethanol; (5-(4-(thiazol-2-ylmethylamino)quinazolin-6-yl)furan-2-yl)methanol;
(5-(4-morpholinoquinazolin-6-yl)furan-2-yl)methanol; or
l-(5-(4-(2-(lH-imidazol-4-yl)ethylamino)quinazolin-6-yl)furan-2-yl)ethanol..
[0067] In another aspect, the compound of formula I or salt thereof is isotopically or radiolabeled.
[0068] The quinazolin-4-amine derivatives provided by this invention and labeled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit Clkl, Clk2, Clk4, or DyrklA.
[0069] Labeled compounds are useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography
(SPECT).
[0070] Another embodiment provides a method for demonstrating the presence or absence of Clkl, Clk2, Clk4, or DyrklA kinase in a biological sample, the method comprising: a) contacting the biological sample with a labeled compound of formula I or a salt thereof under conditions that permit binding of the labeled compound to the Clkl, Clk2, Clk4, or DyrklA kinase; b) separating unbound labeled compound from bound labeled compound; and c) detecting the labeled compound in the biological sample, and therefrom determining the presence or absence of Clkl, Clk2, Clk4, or DyrklA kinase in the sample. In certain embodiments the biological sample is derived from a mammal. In other
embodiments, the mammal is a mouse, rat, a monkey, or a human.
[0071] In another embodiment, a method of inhibiting a Clkl, Clk2, Clk4, or DyrklA kinase in vivo comprising administering an amount of a compound of formula I or a salt thereof sufficient to inhibit the kinase in vitro.
[0072] In yet another embodiment, a method for inhibiting the phosphorylation activity of a Clkl, Clk2, Clk4, or DyrklA kinase comprises contacting a cell containing a Clkl, Clk2, Clk4, or DyrklA kinase with a solution containing a concentration of a compound of formula I or a salt thereof sufficient to inhibit the phosphorylation activity of a Clkl, Clk2, Clk4, or DyrklA kinase in vitro.
[0073] In another aspect, a method of inhibiting the splicing activity of a Clkl, Clk2, Clk4, or DyrklA kinase comprises contacting a cell containing a Clkl, Clk2, Clk4, or DyrklA kinase with a solution containing a concentration of a compound of formula I or salt thereof sufficient to significantly alter the splicing of PKC iI TF, Tau or β-globin pre- niRNA in vitro. PHARMACEUTICAL PREPARATIONS
[0074] The quinazolin-4- amine derivatives can be administered as the neat chemical, but are specifically administered as a pharmaceutical composition, for example a
pharmaceutical formulation comprising a quinazolin-4-amine derivative of formula I or pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier.
[0075] The quinazolin-4-amine derivatives may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers. The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
[0076] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
[0077] Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, and vegetable oils. Optional active and/or inactive agents may be included in the pharmaceutical compositions, provided that such agents do not substantially interfere with the activity of the quinazolin-4-amine derivatives used in the pharmaceutical compositions. The optional active is an additional active agent that is not a compound or salt of formula I.
[0078] The pharmaceutical compositions can be formulated for oral administration. These compositions contain between 0.1 and 99 weight % (wt.%) of a 2-fluorothiazole derivative and usually at least about 5 wt.% of a quinazolin-4- amine derivative. Some embodiments contain from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.% of the quinazolin-4-amine derivatives.
TREATMENT METHODS
[0079] The compounds of Formula I or a salt thereof, as well as pharmaceutical compositions comprising the compounds, are useful for treating a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorders in a patient. An effective amount of a pharmaceutical composition may be an amount sufficient to (a) prevent a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder or a symptom of a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder from occurring in a patient who may be predisposed to a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder but who has not yet been diagnosed as having it; (b) inhibit the progression of a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder; and (c) cause a regression of the Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder.
[0080] An effective amount of a compound or pharmaceutical composition described herein will also provide a sufficient concentration of a quinazolin-4-amine derivative when administered to a patient. A sufficient concentration is a concentration of the compound in the patient's body necessary to prevent or combat the disorder. Such an amount may be ascertained experimentally, for example by assaying blood concentration of the compound, or theoretically, by calculating bioavailability. The amount of an active agent sufficient to modulate Clkl, Clk2, Clk4, or DyrklA in vivo may be determined in vitro with a
conventional assay for Clkl, Clk2, Clk4, or DyrklA.
[0081] Methods of treatment include providing certain dosage amounts of a quinazolin-4-amine derivative to a patient. Dosage levels of each compound of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of compound that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of each active compound. In certain embodiments 25 mg to 500 mg, or 25 mg to 200 mg of a compound of Formula I are provided daily to a patient. Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most Clkl, Clk2, Clk4, or DyrklA kinase mediated disorders, a dosage regimen of 4 times daily or less can be used and in certain embodiments a dosage regimen of 1 or 2 times daily is used.
[0082] The compounds of Formula I may be used to treat Clkl, Clk2, Clk4, or DyrklA kinase mediated disorders including cognitive disorders associated with splicing defects and the hyperphosphorylation of selected cellular targets. Indications such as early onset Alzheimer's disease in Down's syndrome, alteration of coagulation cascade by tissue factor (TF), modulation of insulin action, correction of mis-splicing of lamin A in Progeria, alteration of the T-cell activation and the immune response and within several inflammation models and alteration of neuronal depolarization. It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
EXAMPLES
ABBREVIATIONS
[0083] The following abbreviations are used herein, particularly in the Example follow.
DCM Dichloromethane
DIPEA Diisopropylethylamine
DME dimethoxyethane
DMF Dimethylformamide
EtOAc Ethyl Acetate
MeOH Methanol
EXAMPLE 1. SYNTHESIS OF QUINAZOLIN-4- AMINE DERIVATIVES .
[0084] A generalized method of preparing quinazolin-4-amine derivatives is depicted in Scheme 1, below.
Figure imgf000026_0001
Figure imgf000026_0002
i. DIPEA, DMF, r.t., 2 hours; ii Pd(PPh3)4, Na2C03, DMF, 150 °C (microwave), 1 hour.
[0085] Procedure for the preparation of 6-bromo-N-(thiophen-2-ylmethyl)quinazolin- 4-amine: To a solution of 6-bromo-4-chloroquinazoline (0.3 g, 1.23 mmol) in DMF (8 mL)were added thiophen-2-ylmethanamine (0.139 g, 1.23 mmol) and Hunig's base (0.21 mL, 1.23 mmol). The reaction mixture was stirred at room temperature for 2 h. Upon completion, the reaction mixture was diluted with EtOAc (100 mL) and washed with 10% KHS04 (25 mL) and three times with 3N LiCl (3 x 30 mL). The organic layer was extracted, dried on MgS04, filtered, and concentrated in vacuo. The residue was purified directly on silica column. Gradient elution with ethyl acetate (15→75%) in hexanes provided the title compound as a colorless solid: yield (0.39 g, 1.22 mmol, 99 %).
[0086] Procedure for the preparation of 6-(benzo[d][l,3]dioxol-5-yl)-N-(thiophen-2- ylmethyl)quinazolin-4-amine: To a solution of 6-bromo-N-(thiophen-2-ylmethyl)quinazolin- 4-amine (0.1 g, 0.31 mmol) in DMF (3 mL) were added benzo[d][l,3]dioxol-5-ylboronic acid (0.078 g, 0.47 mmol), sodium carbonate (0.066 g, 0.63 mmol), and
tetrakis(triphenylphosphine)palladium(0) (0.036 g, 0.03 mmol). The reaction mixture was heated in a Biotage Initiator® microwave at 150 °C for 1 h. Upon completion, the reaction mixture was diluted with EtOAc (75 mL) and washed with NaHC03 (50 mL), three times with 3N LiCl (3 x 30 mL), and brine (30 mL). The organic layer was collected, filtered through a pad of Celite, and concentrated in vacuo. The residue was purified directly on silica column. Gradient elution with ethyl acetate (5→65%) in hexanes provided the product as a colorless solid: yield (0.065 g, 0.18 mmol, 58 %). 1H NMR (DMSO-d6) δ 4.97 (d, / = 5.53 Hz, 2H), 6.09 (s, 2H), 6.92 - 7.01 (m, 1H), 7.02 - 7.18 (m, 2H), 7.29 - 7.41 (m, 2H), 7.44 (s, 1H), 7.73 (d, / = 8.56 Hz, 1H), 8.08 (d, / = 8.46 Hz, 1H), 8.51 (d, / = 4.70 Hz, 2H), 8.99 (d, / = 4.89 Hz, 1H); 13C NMR (DMSO-J6) δ 54.88, 101.28, 107.14, 108.70, 115.04, 119.52, 120.54, 125.11, 125.79, 126.54, 127.99, 131.04, 133.21, 137.02, 142.18, 147.14, 148.11, 148.26, 154.75, 159.05. HRMS (ESI) mlz 362.0957 (M+H)+ (C20H16N3O2S requires
362.0958). Purity determination via LCMS was performed using an Agilent Diode Array Detector using a 3 minute gradient of 4% to 100% acetonitrile (containing 0.025%
trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) with a 4.5 minute run time at a flow rate of 1 mL/min and a 7 minute gradient of 4% to 100% acetonitrile
(containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) with an 8 minute run time at a flow rate of 1 mL/min. 3 minute gradient retention time = 3.050; 7 minute gradient retention time = 4.531 min. Purity was determined to be > 95% in both methods.
EXAMPLE 2. SYNTHESIS OF QUINAZOLIN-4- AMINE DERIVATIVES VIA SUZUKI COUPLING Scheme 2.
Figure imgf000027_0001
POCI3, dimethylaniline tol, Δ, 1 h
Figure imgf000027_0002
General procedure for Suzuki coupling.
[0087] To a solution of 6-bromoquinazolin-4(3H)-one (3.00 g, 13.33 mmol) in DME (18 ml) and water (1.800 ml) were added benzo[d][l,3]dioxol-5-ylboronic acid (2.65 g, 16.00 mmol), sodium carbonate (1.695 g, 16.00 mmol), tetrakis (1.540 g, 1.333 mmol). The reaction mixture was heated in the microwave for 30-60 min at 150 °C. The crude mixture was diluted in EtOAc and minimal water and filtered through Celite with EtOAc and MeOH. The filtered solution was concentrated in vacuo. The organic layer was dry packed and purified by flash silica column chromatography using a Biotage SP4 (0- O % MeOH in DCM gradient over 10 CV, 10% MeOH/DCM over 10 CV, collected at 254 nM) to yield 6- (benzo[d][l,3]dioxol-5-yl)quinazolin-4(3H)-one as a pure yellowish solid (1.42 g, 5.34 mmol, 40%).
[0088] 1H NMR (400 MHz, DMSO-d6) δ ppm,12.12 - 12.37 (1 H, m), 8.19 - 8.26 (1 H, m), 7.98 - 8.08 (2 H, m), 7.65 - 7.70 (1 H, m), 7.29 - 7.33 (1 H, m), 7.18 - 7.25 (1 H, m), 6.96 - 7.05 (1 H, m), 6.06 (2 H, s).
General procedure for Chlorination.
[0089] 6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4(3H)-one (.422 g, 1.585 mmol) was dissolved in Toluene (5 ml) at 0 °C. POCl3 (1.477 ml, 15.85 mmol) and N,N-dimethylaniline (2.009 ml, 15.85 mmol) was added and the reaction was heated at reflux for 2 h. The crude mixture was rinsed with EtOAc, cooled and concentrated in vacuo (the rotovap trap was carefully quenched). The crude product was washed with water (10 mL) and bicarbonate solution (10 mL). The organic layer was concentrated in vacuo and used in the next step crude. The organic layer was dry packed and purified by flash silica column chromatography using a Biotage SP4 (0-» 10 % MeOH in DCM gradient over 10 CV, 10% MeOH/DCM over 10 CV, collected at 254 nM) to yield 6-(benzo[d][l,3]dioxol-5-yl)-4-chloroquinazoline as a pure yellowish solid to be used immediately.
General procedure for chlorine substitution.
[0090] To 6-(benzo[d][l,3]dioxol-5-yl)-4-chloroquinazoline (.300 g, 1.054 mmol) dissolved in DMF (1 ml) was added thiophen-2-ylmethanamine (0.143 g, 1.265 mmol) and Hunig's Base (0.221 ml, 1.265 mmol). The reaction was stirred at RT for 1 h at which point LCMS indicated the reaction was complete. Slower reactions were heated at 60 °C overnight. Additional Intermediates
Table 1 contains exemplary substituted quinazoline intermediates produced by the Suzuki coupling procedure described above.
Intermediate Compound Name Analytical Data Number
ASROl-001 Ή NMR (400 MHz,
DMSO- ) δ ppm 12.12 - 12.37 (1 H, m), 8.19 - 8.26 (l H, m), 7.98 - 8.08 (2 H, m), 7.65 - 7.70 (1 H, m), 7.29 - 7.33 (1 H, m), 7.18 - 7.25 (1 H, m), 6.96 - 7.05 (1 H, m),
Figure imgf000029_0001
EXAMPLE 3. QUINAZOLIN-4- AMINE DERIVATIVES
[0091] Table 1 contains exemplary quinazolin-4- amine derivatives prepared via the methods provided in Examples 1 and 2.
[0092] Analytical analysis for several compounds was performed on an Agilent LC/MS (Agilent Technologies, Santa Clara, CA). Method 1 : A 7 minute gradient of 4% to 100% Acetonitrile (containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) was used with an eight minute run time at a flow rate of one mL/min. A Phenomenex Luna CI 8 column (3 micron, 3 x 75 mm) was used at a temperature of 50°C. Method 2: A 3 minute gradient of 4% to 100% Acetonitrile (containing 0.025%
trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) was used with a 4.5 minute run time at a flow rate of 1 mL/min. A Phenomenex Gemini Phenyl column (3 micron, 3 x 100 mm) was used at a temperature of 50 °C. Purity determination was performed using an Agilent Diode Array Detector. Mass determination was performed using an Agilent 6130 mass spectrometer with electrospray ionization in the positive mode.
Table 1.
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
EXAMPLE 4. IN VITRO COMPETITIVE BINDING ASSAYS TO DETERMINE CLK SELECTIVITY.
[0093] To assess the selectivity of compounds of Formula I 6-(benzo[d][l,3]dioxol-5- yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine (compound 22) was submitted as a representative reagent across a commercial panel of kinases. The data is first recorded as a % of kinase bound to an immobilized ligand in the presence and absence of the test reagent as compared to DMSO. Activities beyond a selected threshold are submitted for Kd
determination. For comparative purposes, the known Clkl/4 inhibitor TG003 (Muraki et al. J. Biol. Chem. (2004) 279: 24246-24254) was also profiled. The results demonstrate that both agents are selective. TG003 was determined to have Kd' s of 19 nM, 95 nM and 30 nM versus Clkl, Clk2 and Clk4, respectively. The Kd for TG003 versus Clk3 was 3 μΜ. It was also found that TG003 had activity versus CSNK1D (150 nM), CSNK1E (300 nM), DyrklA (12 nM), DyrklB (130 nM), PIM1 (130 nM), PIM3 (280 nM) and Ysk4 (290 nM). The compound 22 was found to have Kd' s of 37 nM, 50 nM and 27 nM versus Clkl, Clk4 and DyrklA, respectively. The only other locus of relevant activity (below 500 nM) was found for binding to the endothelial growth factor receptor (EGFR) (230 nM).
Figure imgf000078_0001
EXAMPLE 5. IN VITRO BIOLUMINESCENCE ASSAY CLKI , CLK3, CLK4, AND DYRKI A.
[0094] Several compounds of formula I were examined for Clk inhibition via a bioluminescent, luciferase-based assay capable of visualizing substrate (ATP) depletion and product (ADP) formation. The exemplary assays are shown below for Clk4.
[0095] Two bioluminescence assay systems were employed. In a first system, measurement of ATP depletion employed the Kinase-Glo assay system where a firefly luciferase detection reagent containing D-luciferin and buffer components are added to detect the remaining ATP following the kinase assay (e.g., Clk4). The second system, ADP-Glo measures kinase activity by quantifying the amount of ADP formed after kinase reaction. Bioluminescent detection of ADP levels is achieved through the addition of two different detection reagents. First, a reagent that stops the protein kinase reaction and depletes the remaining ATP is added. Then a second reagent is added to stop ATP degradation. In addition, the second reagent also contains an enzyme such as pyruvate kinase that efficiently converts the ADP to ATP and the same firefly luciferase/D-luciferin components present in Kinase-Glo which generates a luminescent signal that is proportional to the concentration of ADP produced. The luminescent response is inversely proportional to the kinase activity in the ATP depletion format (Kinase-Glo assay) while the luminescent response is directly proportional to kinase activity in the ADP formation format (ADP-Glo assay). The two assay formats therefore show opposite luminescence signal changes in response to protein kinase inhibitors.
[0096] qHTS Clk4 ADP-Glo assay. For the ADP-Glo kinase assay, 2 uL/well of substrate-buffer solution (100 μΜ RS peptide, 1 μΜ ATP, lx ADP-Glo Buffer A, mM MgCl2, 0.5 mM EGTA, 2.5 mM DTT, 0.01% Triton X-100, final concentrations) was dispensed into 1,536-well plates (Greiner, solid white, medium binding assay plates) with the FRD. Twenty-three nanoliter of compound and control solutions were transferred to the assay plate (as described above) followed by 0.5 uL/well Clk4-buffer solution (25 nM Clk4, lx ADP-Glo Buffer A, 2 mM MgCl2, 0.5 mM EGTA, 2.5 mM DTT, 0.01% Triton X-100 final concentration) dispensing for a total kinase reaction volume of 2.5 μΏ well. After 1 hr of room-temperature incubation, 2.5 uL ADP-Glo reagent was added and the reaction was incubated at room temperature for 45 min to stop the kinetic reaction and degrade residual ATP. The ADP product was then converted to ATP by adding 5 uL per well of ADP-Glo Reagent II to yield a total assay volume of 10 μΏ well. Luminescence was detected after 30 min room temperature incubation with the Perkin Elmer Veilleux.
[0097] qHTS Clk4 Kinase-Glo assay. Two μίΛνβϋ of substrate-buffer solution (100 μΜ RS peptide, 1 μΜ ATP, 25 mM Tris Ph.D, 10 mM MgCl2, 0.5 mM EGTA, 2.5 mM DTT, 0.01% Triton X-100 final concentration) was dispensed into 1,536-well, assay plates
(Greiner, solid white medium-binding plates) with Aurora Discovery BioRAPTR Flying Reagent Dispenser (FRD; Beckton-Dickenson, Franklin Lakes, NJ). Using a Kalypsys pin tool equipped with a 1,536-pin tool, 23 nL of compound solution was transferred to the assay plate. One uL/ well Clk4-buffer solution (25 nM Clk4, 25 mM Tris pH 7.5, 10 mM MgCl2, 0.5 mM EGTA, 2.5 mM DTT, 0.01% Triton X-100, final concentrations) was then added using the FRD yielding a total kinase reaction volume of 3 μΏ well. After 4.5 hours of room temperature incubation, 3 uL Kinase-Glo reagent was added for a final assay volume of 6 uL/ well. Luminescence was detected with the ViewLux plate reader (Perkin Elmer, Waltham, MA) after 5 min incubation using a 5 second exposure time and 2x binning. [0098] Gen Bank Accession numbers for human Clkl kinase (1195), human Clk2 kinase (1196), human C1K3 kinase (1198), human Clk4 kinase (57396) and human DyrklA kinase (1859) and the accession numbers of PKCbetall (5579), TF (2152 (F3 coagulation factor III, thromboplastin, tissue factor)), TF 7018 (TF, transferrin, involved in tissue factor pathway), Tau (4137) or β-globin (3043) pre-mRNA.
Table 2 Kinase-Glo ADP-Glo
Parameter Value Description Parameter Value Description
Reagent 2 μL· ATP/peptide Reagent 2 L ATP/peptide
Library 23 nL 0.5 nM- 46 μΜ Library 23 nL 0.6 nM- 55.2 μΜ
Controls 23 nL TG003 Controls 23 nL TG003
Reagent 1 L Clk4 Reagent 0.5 μL Clk4
Time 4.5 hrs r.t. incubation Time 1 hr r.t. incubation
Reagent 3 L Kinase-Glo Reagent 2.5 μL Deplete ATP
Read 2 sec ViewLux Time 45 min r.t. incubation
Reagent 5 μL ADP^ATP/Luc
Time 30 min r.t. incubation
Read 2 sec ViewLux
Step Notes Notes
1 100 μΜ RS peptide 1 μΜ ATP (final) 100 μΜ RS peptide 1 μΜ ATP (final) concentration in concentration in buffer: FRD dispense buffer: FRD dispense
2 Pin-tool transfer compound library for a Pin-tool transfer compound library for a (final) range (final) range of 46 μΜ to 0.5 nM οί 55.2 μΜ ΐο 0.6 ηΜ
3 Pin-tool transfer of controls Pin-tool transfer of controls
4 Clk4 at 25 nM final, FRD dispense Clk4 at 25 nM final, FRD dispense
5 Kinase reaction, room temperature Kinase reaction, room temperature incubation
incubation
6 Detection Kinase-Glo ADP-Glo Reagent I
7 Perkin Elmer ViewLux, clear filter ATP depletion, room temperature incubation
8 ADP-Glo Reagent II
9 room temperature incubation
10 Perkin Elmer ViewLux, clear filter EXAMPLE 6. IN VITRO BINDING MECHANISM DETERMINATION AT CLKI AND CLK4.
[0099] To determine the binding mechanism of the compounds of Formula I at Clkl and Clk4, the inhibitory capacity of representative compound 22 in settings that vary both compound and substrate concentrations were examined according to the protocol described in Example 5. The results are shown in Fig. 1. The dose response curve of compound 22 in the presence of three different ATP concentrations demonstrates a loss in potency when ATP levels rise (Fig. 1A, inhibitory dose response of the compound in the presence of three different ATP concentrations [1 μΜ (filled circles), 50 μΜ (empty circles), 100 μΜ (empty squares)]). Conversely, the % activity of compound 22 in the presence of varying concentrations of the peptide substrate has no affect on the compound potency (Fig. IB, inhibitory dose response of the compound in the presence of three different peptide concentrations [50 μΜ (filled circles), 100 μΜ (empty circles), 200 μΜ (empty squares)]). Additionally, while maintaining compound 22 at a constant concentration (70 nM), an examination of the dose response of ATP demonstrated a sharp decline in enzyme inhibition at high ATP concentrations (>1 mM) while an increase in the dose of the peptide did not affect the potency of the compound (data not shown). Results indicate that compounds of formula 1 are ATP competitive inhibitors of Clk4.
EXAMPLE 7. CLK B INDING MODEL.
[00100] Docking of 6-(benzo[d] [l,3]dioxol-5-yl)-N-(thiophen-2- ylmethyl)quinazolin-4- amine (compound 22) at a Clk kinase was explored. Quinazoline based small molecules have precedence as kinase inhibitors. , Examples of quinazoline the clinically approved drug erlotinib (TARCEVA), indicated for treatment of non-small cell lung and pancreatic cancer and its actions are mediated through inhibition of the EGFR tyrosine kinase (Dowell et al. Nature Rev. Drug Discovery 2005, 4, 13-14)). The structure of erlotinib bound to the ATP binding domain of EGFR (PDB code: 1M17) has been reported in the literature (Stomos et al. J. Biol. Chem. 2002, 277, 46265-46272). The inventors theorize that the relationship of the 4-anilinoquinazoline structure of erlotinib to the compounds of formula I may provide significant insight into the binding modality and mechanism of action for this class of compounds. There are no published X-ray structures of Clk4. There are structures of Clkl (PDB code: 1Z57) and Clk3 (PDB code: 2EU9). Clkl and Clk4 are highly homologous enzymes (>85% sequence identity) while Clk2 and Clk3 also share a high degree of sequence homology (>70% sequence identity). Based upon this, the X-ray structure of Clkl was utilized as the template to derive a homology model of Clk4 using MOE molecular modeling software (MOE Molecular Operating Environment, Version 2008.10; Chemical Computing Group Inc.: Montreal, Canada, 2008. Molecular docking was performed on 6-(benzo[d] [l,3]dioxol-5-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine (compound 22) within the ATP binding domain of Clkl and Clk4 to achieve an optimal binding pose using FRED (OpenEye Scientific Software, Inc.: Santa Fe, NM.
http://www.eyesopen.com/). In the crystal structure of erlotinib and EGFR, the Nl of the quinazoline heterocycle makes a critical H-bond an amide NH of the hinge region of the ATP binding pocket. This interaction is mimicked within our docking analysis of compound 22 at Clkl and Clk4. The thiophen-2-ylmethanamine moiety is oriented to fill an open pocket formed by the gatekeeper Phe241 (Phe239 in Clk4) while the benzo[d][l,3]dioxole extends toward the solvent exposed face of the hinge region.
[00101] The result of molecular docking provides evidence that inhibition is the result of binding at the kinase hinge region at the ATP binding domain
EXAMPLE 8. ANIMAL BEHAVIOR MODELS .
[0100] The spatial water maze and step-down passive avoidance models are suitable models for in vivo determinations of cognition enhancement.
[0101] Spatial water maze: The spatial water maze has been used extensively as a test of spatial learning and memory. Rats are trained to escape from the water by swimming to a platform that is submerged just below the surface of the water. Since the platform is not visible to the animal, it has to utilize visual extra-maze cues in the area of the tank to locate the platform.
[0102] The water maze apparatus consists of a circular tank, 119 cm in diameter and 56 cm in height, with a black interior. The tank is filled with water approximately 23-25° C. to a height of 42 cm. Superimposed onto the tank are four quadrants, South, East, North and West. The tank is surrounded by external visual cues, which consist of a black and white checkered wall, a black and la white striped wall, a white wall with two light fixtures, and a blue wall. A black circular PLEXIGLAS platform with a black neoprene rubber top is placed in the Northeast quadrant approximately 1-2 cm below the surface of the water. The submerged platform is 39 cm in height and has a diameter of 11.5 cm. Training and testing are conducted in the presence of a 60-62 dB white noise source and under dim light conditions (1.0-1.2 lux). The animal's path is tracked by a video camera interfaced to an automated tracking package (Video track, CPL Systems).
[0100] For the spatial water maze assay, results are given as the minimal efficacious dose of compound in mg/kg, administered IV (unless listed as PO), needed to elicit a statistically significant response.
[0101] Step-down Passive Avoidance: In step-down passive avoidance a rat is placed on a platform located in the center of an electrified grid floor that is contained within a large (45 cmx45 cmx50 cm) white translucent Plexiglas® enclosure. The natural inclination of the rat is to step off the platform and investigate its surroundings. In day one of the experiment animals are treated with either test compound in a 50% PEG vehicle, or vehicle alone and then trained to remain on the platform for at least 120 seconds. Each time the animal steps off the platform it receives a mild foot shock of 2 mAmpsx6 sec. Following each shock the animal is removed from the box, placed in its cage for a one minute inter-trial interval, and then returned to the platform. The latency to step down on each trial, the number of trials taken to reach criterion during training and the retention latency are collected.
[0102] Testing is conducted approximately 24 h after training. Drug-free animals are placed on the platform in the box in which they will have been trained and the latency to step down onto the grid floor is recorded for one trial as a measure of memory retention. The animal is allowed a maximum of 120 seconds to step down and does not receive a shock upon stepping off the platform.
EXAMPLE 9. PREPARATION OF RADIOLABELED PROBE COMPOUNDS .
[0103] The compounds of formula I are prepared as radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope can be selected from of at least one of carbon (specifically 14C), hydrogen
(specifically 3 H), sulfur (specifically 35 S), or iodine (specifically 125 I). Such radiolabeled probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Cambridge Isotope Laboratories, Inc. Andover, Mass.; SRI International, Menlo Park, Calif.; ChemSyn
Laboratories, Lexena, Kans.; American Radiolabeled Chemicals, Inc., St. Louis, Mo.; and Moravek Biochemicals Inc., Brea, Calif.
[0104] Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Such preparations are also conveniently carried out as a custom radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of formula I as substrate. In addition, certain precursors may be subjected to tritium-halogen exchange with tritium gas, tritium gas reduction of unsaturated bonds, or reduction using sodium borotritide, as appropriate.
[0105] While the invention has been described with reference to an exemplary embodiment, it will be understood by those skilled in the art that various changes can be made and equivalents can be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications can be made to adapt a particular situation or material to the teachings of the invention without departing from the essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

Claims

What is claimed is:
1. A com ound of formula I
Figure imgf000085_0001
or a pharmaceutically acceptable salt thereof, wherein
Ai and A2 are independently chosen at each occurrence from hydrogen, methyl, and ethyl;n is 1, 2, 3, or 4;
B is hydrogen, methyl, ethyl, propyl, or isopropyl; and
Ri is a phenyl, pyridyl, 5- or 6-membered heterocycloalkyl, or a 5-membered heteroaryl group, each heterocycloalkyl or heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, each of which heterocycloalkyl or heteroaryl group is unsubstituted or substituted with 1, 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, Ci-C4alkyl, and Ci-C4alkoxy; or
n is 2, 3, or 4; and
B is hydrogen, methyl, ethyl, propyl, or isopropyl;
Ri is mono- or di-Ci-C4alkylamino or amino; or
n is 3 or 4 and
Ri and B are joined to form a 5- or 6-membered heterocycloalkyl group in which one ring carbon is optionally replaced with a N, S, or O atom, which 5- or 6-membered heterocycloalkyl group is substituted with 0 or 1 substituents chosen from C3- Cecycloalkyl and 5- and 6-membered heterocycloalkyl;
where
G is R2, J is R3 and L is hydrogen; or
G is hydrogen, J is R2, and L is R3; or
G is hydrogen, J is R3, and L is R2;
R2 is 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently chosen from N, O, and S, or
R2 is phenyl fused to a 5-membered saturated or partially unsaturated heterocyclic ring
containing 1 or 2 heteroatoms independently chosen from N, O, and S, or R2 is phenyl substituted with at least one methoxy group;
each of which R2 is unsubstituted or substituted with 1, 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, cyano, Ci-C4alkyl, Cp C4alkoxy, C2-C4alkanoyl, (mono- and di-Ci-C2alkylamino)Co-C2alkyl, Q- C2haloalkyl, and Ci-C2haloalkoxy and is substituted with 0 or 1 substituents chosen from -CHO, -COOH, (C2-C4alkylester)Co-C2alkyl, Ci-C4hydroxylalkyl, (mono- and di-Ci-C4alkylcarboxamide)Co-C2alkyl, (mono- and di-Ci-C4alkylcarbamate)Co- C2alkyl, and phenyl; and
R3 is hydrogen, halogen, hydroxyl, Ci-C4alkyl, Ci-C4alkoxy, or (Ci-C2alkoxy)Ci-C4alkoxy; wherein
R2 is not a 3,5-dimethylisoxazol-4-yl group;
Ri and R2 are not both a furanyl group;
Ri is not a thien-2-yl group when R2 is a furan-3-yl group; and the compound is not
6-(5-iodofuran-2-yl)-7-methoxy-N-(l-phenylethyl)quinazolin-4-amine;
6-(furan-2-yl)-7-methoxy-N-(l-phenylethyl)quinazolin-4-amine;
6-(furan-3-yl)-N-(3-methylbenzyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(2-methoxybenzyl)quinazolin-4-amine;
N-benzyl-6-(furan-3-yl)quinazolin-4-amine;
6-(furan-3-yl)-N-(pyridin-3-ylmethyl)quinazolin-4-amine;
N-(2,4-dimethoxybenzyl)-6-(furan-3-yl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-benzylquinazolin-4-amine;
6-(furan-3-yl)-N-(2-methoxybenzyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(2,4-dimethoxybenzyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(3-methylbenzyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine; or
6-(benzo[d][l,3]dioxol-5-yl)-N-(furan-2-ylmethyl)quinazolin-4-amine.
2. A com ound of formula I
Figure imgf000086_0001
or a pharmaceutically acceptable salt thereof, wherein Ai and A2 are independently hydrogen, methyl, or ethyl;
n is 1 or 2;
B is hydrogen, methyl, ethyl, propyl, or isopropyl;
Ri is a 5-membered heterocycloalkyl or 5- or 6-membered heteroaryl group, each
heterocycloalkyl or heteroaryl group containing 1, 2 or 3 heteroatoms selected from N, O, and S, each of which heterocycloalkyl or heteroaryl group is unsubstituted or substituted with 1, 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, Ci-C2alkyl, and Ci-C2alkoxy;
R2 is 5-membered heteroaryl group containing 1, 2 or 3 heteroatoms independently chosen from N, O, and S, or
R2 is phenyl fused to a 5-membered saturated or partially unsaturated heterocyclic ring
containing 1 or 2 heteroatoms independently chosen from N, O, and S;
each of which R2 is unsubstituted or substituted with 1, 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, cyano, Ci-C4alkyl, Ci- C4alkoxy, C2-C4alkylester; C2-C4alkanoyl, mono- and di-(Ci-C2alkyl)amino, Cp C2haloalkyl, and Ci-C2haloalkoxy, and is substituted with 0 or 1 substituents chosen from -CHO, -COOH, C^- -alkylester, Cj^ hydroxylalkyk mono- and di-Cy- Qalkylcarboxamide, (mono- and di-Cj^ alkylcarbamate^o-Cqalkyk and phenyl; and
R3 is hydrogen, halogen, hydroxyl, Ci-C4alkyl, Ci-C4alkoxy, or (Ci-C2alkoxy)Ci-C4alkoxy.
3. A compound or salt of Claim 1 or 2, wherein
n is 3 or 4 and
Ri and B are joined to form a 5- or 6-membered heterocycloalkyl group chosen from
tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl, which 5- or 6- membered group is optionally substituted with 0 or 1 substituents chosen from C3- C6cycloalkyl and 5- and 6-membered heterocycloalkyl
4. A compound or salt of Claim 1 comprising a compound of the formula
Figure imgf000087_0001
5. A com ound or salt of Claim 1 or 2 comprising a compound of the formula
Figure imgf000088_0001
6. A com ound or salt of Claim 1 or 2 comprising a compound of the formula
Figure imgf000088_0002
7. A compound or salt of any one of Claims 1, 2, or 4 to 6 in which n is 1.
8. A compound or salt of Claim 1, wherein
Ri is a phenyl, furanyl, imidazolyl, oxadiazolyl, tetrahydrofuranyl, thiazolyl, pyridyl, or thienyl group, each of which is unsubstituted or substituted with 1, 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, CrC2alkyl, and Ci-C2alkoxy; and
R2 is a benzo[JJ[l,3]dioxolyl, 2,3-dihydrobenzofuranyl, benzo[<i]oxazolyl, or a
benzo[JJ thiazolyl, furanyl, or thienyl group, each of which is unsubstituted or substituted with 1, 2, or 3 substituents independently chosen from halogen, hydroxyl, amino, Ci-C4alkyl, Ci-C4alkoxy, C2-C4alkylester; C2-C4alkanoyl, mono- and di-(Ci- C2alkyl) amino, Ci-C2haloalkyl, and Ci-C2haloalkoxy; or
R2 is a furanyl or thienyl group, each substituted with 0, 1, or 2 substituents chosen from
halogen, Ci-C2alkyl, and Ci-C2alkoxy, and each substituted with 1 substituent chosen from -CHO, -COOH, (C C4alkylester Co-C2arkyl Cj-C iydioxylalkyl, (mono- or di- Cj_-C4alkylcarboxamide)Cn-C2alkyl, (mono- and di-Cj_-C4alkylcarbamate)Co-C2alkyl and, phenyl.
9. A compound or salt of Claim 1 or 2 in which Ai and A2 are both hydrogen and B is hydrogen or methyl.
10. A compound or salt of Claim 9 in which R3 is hydrogen.
11. A compound or salt of Claim 9 in which R3 is Ci-C4alkyl, Ci-C4alkoxy, or (Q- C2alkoxy)Ci-C4alkoxy.
12. A compound or salt of Claim 8, wherein R2 is benzo[JJ[l,3]dioxolyl, which is
unsubstituted or substituted with 1, 2, or 3 substituents independently chosen from halogen, Ci-C2alkyl, and Ci-C2alkoxy.
13. A compound or salt of Claim 8, wherein R2 is furanyl or thienyl, each substituted with 1 substituent chosen from -CHO, -COOH, (C2-C4alkylester)Co-C2alkyl, C^hydroxyalkyl, (mono- or di-Ci-C4alkylcarboxamide)Co-C2alkyl, (mono- and di-Ci-C4alkylcarbamate)Co- C2alkyl, and phenyl.
14. A compound or salt of Claim 8, wherein
Figure imgf000089_0001
and R2 is chosen from
Figure imgf000089_0002
Figure imgf000090_0001
A com ound of formula I
Figure imgf000090_0002
or a pharmaceutically acceptable salt thereof, wherein
Ai and A2 are independently hydrogen 0 or methyl;
n is 1 or 2;
B is hydrogen, methyl, or ethyl;
Ri is a furanyl, imidazolyl, oxazolyl, oxadiazolyl, tetrahydrofuranyl, thiazolyl, pyridyl, or thienyl group, each of which is unsubstituted or substituted with 1 or 2 substituents independently chosen from halogen, Ci-C2alkyl, and Ci-C2alkoxy; and
R2 is a benzo[JJ[l,3]dioxolyl, which is unsubstituted or substituted with 1 or 2 methyl or ethyl substituents; and
R3 is hydrogen or Ci-C2alkyl.
16. A compound of Claim 1, or a salt thereof, wherein the compound is:
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-(thiazol-2-ylmethyl)quinazolin-4-amine;
N-(2-(lH-imidazol-4-yl)ethyl)-6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(l-(2-methylthiazol-4-yl)ethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(furan-3-ylmethyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(furan-2-yl)ethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((5-methylthiophen-2-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((3-methyl-l,2,4-oxadiazol-5- yl)methyl)quinazolin-4- amine ;
6-(benzo[d][l,3]dioxol-5-yl)-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((5-methylfuran-3-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(furan-2-ylmethyl)-N-methylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((2-methylfuran-3-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((l-methyl-lH-imidazol-5-yl)methyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-((tetrahydrofuran-2-yl)methyl)quinazolin-4-amine;
N-((lH-imidazol-2-yl)methyl)-6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((4-methylthiazol-2-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((5-methyl-l,3,4-oxadiazol-2- yl)methyl)quinazolin-4- amine ;
6-(benzo[d][l,3]dioxol-5-yl)-N-((2,5-dimethylfuran-3-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((3-methylthiophen-2-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(l-(furan-2-yl)ethyl)-N-methylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(l-(furan-2-yl)ethyl)quinazolin-4-amine;
6- (benzo[d][l,3]dioxol-5-yl)-N-(furan-2-ylmethyl)-N-methylquinazolin-4-amine;
7- (benzo[d][l,3]dioxol-5-yl)-N-((5-methylfuran-2-yl)methyl)quinazolin-4-amine;
7-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine; N-((tetrahydrofuran-2-yl)methyl)-6-(3,4,5-trimethoxyphenyl)quinazolin-4-amine;
N-(thiophen-2-ylmethyl)-6-(3,4,5-trimethoxyphenyl)quinazolin-4-amine;
N-(2-(lH-imidazol-4-yl)ethyl)-6-(3,4,5-trimethoxyphenyl)quinazolin-4-amine;
N-((5-methylfuran-2-yl)methyl)-6-(3,4,5-trimethoxyphenyl)quinazolin-4-amine;
N-((4-methylthiazol-2-yl)methyl)-6-(3,4,5-trimethoxyphenyl)quinazolin-4-amine;
5-(benzo[d][l,3]dioxol-5-yl)-6-methoxy-N-((tetrahydrofuran-2-yl)methyl)quinazolin-4- amine;
5- (benzo[d][l,3]dioxol-5-yl)-6-methoxy-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
N-methyl-N-((2-methylthiazol-4-yl)methyl)-6-(3,4,5-trimethoxyphenyl)quinazolin-4-amine; ethyl 5-(4-(thiophen-2-ylmethylamino)quinazolin-6-yl)furan-2-carboxylate;
6- (4-methoxyphenyl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
6-(3,4-dimethoxyphenyl)-N-((tetrahydrofuran-2-yl)methyl)quinazolin-4-amine; N-(2-(lH-imidazol-4-yl)ethyl)-6-(3,4-dimethoxyphenyl)quinazolin-4-amine;
6-(3,4-dimethoxyphenyl)-N-((5-methylfuran-2-yl)methyl)quinazolin-4-amine;
6-(3,4-dimethoxyphenyl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
6-(3,4-dimethoxyphenyl)-N-((4-methylthiazol-2-yl)methyl)quinazolin-4-amine;
6-(3,4-dimethoxyphenyl)-N-methyl-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((3-methylthiophen-2-yl)methyl)quinazolin-4- amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((l-methyl-lH-imidazol-5-yl)methyl)quinazolin-4- amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-ethyl-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
6-(4-fluorobenzo[d][l,3]dioxol-5-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
6-(2,2-difluorobenzo[d][l,3]dioxol-5-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
6-(2-methyl-2H-indazol-6-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
Nl-(6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-yl)-N2,N2-dimethylethane-l,2-diamine;
Nl-(6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-yl)-N3,N3-dimethylpropane-l,3-diamine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(3-morpholinopropyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(l-methylpyrrolidin-2-yl)ethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(3-(piperidin-l-yl)propyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-4-(4-(pyrrolidin-l-yl)piperidin-l-yl)quinazoline;
6-(benzo[d][l,3]dioxol-5-yl)-7-methoxy-N-methyl-N-((2-methylthiazol-4- yl)methyl)quinazolin-4- amine ;
6-(benzo[d][l,3]dioxol-5-yl)-7-methoxy-N-methyl-N-(thiophen-2-ylmethyl)quinazolin-4- amine;
Nl-(6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-yl)butane-l,4-diamine;
Nl-(6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-yl)propane-l,3-diamine;
Nl-(6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-yl)ethane-l,2-diamine;
4-((6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-ylthio)methyl)-2-methylthiazole;
N-(2-(lH-imidazol-4-yl)ethyl)-6-(benzo[d][l,3]dioxol-5-yl)-N-methylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(l-methyl-lH-imidazol-4-yl)ethyl)quinazolin-4-amine;
4-((lH-imidazol-5-yl)methoxy)-6-(benzo[d][l,3]dioxol-5-yl)quinazoline;
6-(benzo[d][l,3]dioxol-5-yl)-N-propyl-N-(thiophen-2-ylmethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(thiophen-2-yl)ethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-ethyl-N-((3-methylthiophen-2-yl)methyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(l-ethyl H-imidazol-4-yl)ethyl)-N-methylquinazolin-4- amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-ethyl-N-(2-(l-methyl-lH-iinidazol-4-yl)ethyl)quinazolin-4- amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-(2-(thiophen-2-yl)ethyl)quinazolin-4-amine; 6-(2,4-dimethylthiazol-5-yl)-N-((5-methylfuran-2-yl)methyl)quinazolin-4-amine;
N-(2-(lH-imidazol-4-yl)ethyl)-6-(2,4-dimethylthiazol-5-yl)quinazolin-4-amine;
N-((lH-imidazol-2-yl)methyl)-6-(2,4-dimethylthiazol-5-yl)quinazolin-4-amine;
6-(2,4-dimethylthiazol-5-yl)-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine;
6-(2,4-dimethylthiazol-5-yl)-N-methyl-N-((3-methylthiophen-2-yl)methyl)quinazolin-4- amine;
6-(4-methyl-2-phenyloxazol-5-yl)-N-((5-methylfuran-2-yl)methyl)quinazolin-4-amine; N-(2-(lH-imidazol-4-yl)ethyl)-6-(4-methyl-2-phenyloxazol-5-yl)quinazolin-4-amine;
N-((lH-imidazol-2-yl)methyl)-6-(4-methyl-2-phenyloxazol-5-yl)quinazolin-4-amine;
6-(4-methyl-2-phenyloxazol-5-yl)-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine; N-methyl-6-(4-methyl-2-phenyloxazol-5-yl)-N-((3-methylthiophen-2-yl)methyl)quinazolin- 4-amine;
ethyl 2-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-3-carboxylate;
ethyl 2-(4-(2-(lH-imidazol-4-yl)ethylamino)quinazolin-6-yl)furan-3-carboxylate;
ethyl 2-(4-((lH-imidazol-2-yl)methylamino)quinazolin-6-yl)furan-3-carboxylate;
ethyl 2-(4-(methyl((3-methylthiophen-2-yl)methyl)amino)quinazolin-6-yl)furan-3- carboxylate;
6-(furan-3-yl)-N-((5-methylfuran-2-yl)methyl)quinazolin-4-amine;
N-(2-(lH-imidazol-4-yl)ethyl)-6-(furan-3-yl)quinazolin-4-amine;
N-((lH-imidazol-2-yl)methyl)-6-(furan-3-yl)quinazolin-4-amine;
6-(furan-3-yl)-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine;
6-(furan-3-yl)-N-methyl-N-((3-methylthiophen-2-yl)methyl)quinazolin-4-amine;
N-((lH-imidazol-2-yl)methyl)-6-(benzo[d][l,3]dioxol-5-yl)-N-methylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((5-methylfuran-2-yl)methyl)quinazolin-4-amine;
N-((5-methylfuran-2-yl)methyl)-6-(2-methylfuran-3-yl)quinazolin-4-amine;
N-(2-(lH-imidazol-4-yl)ethyl)-6-(2-methylfuran-3-yl)quinazolin-4-amine;
N-((lH-imidazol-2-yl)methyl)-6-(2-methylfuran-3-yl)quinazolin-4-amine
6-(2-methylfuran-3-yl)-N-((2-methylthiazol-4-yl)methyl)quinazolin-4-amine; N-methyl-6-(2-methylfuran-3-yl)-N-((3-methylthiophen-2-yl)methyl)quinazolin-4-amine; ethyl 5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxylate;
ethyl 5-(4-(2-(lH-imidazol-4-yl)ethylamino)quinazolin-6-yl)furan-2-carboxylate;
ethyl 5-(4-((lH-imidazol-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxylate;
ethyl 5-(4-((2-methylthiazol-4-yl)methylamino)quinazolin-6-yl)furan-2-carboxylate;
ethyl 5-(4-(methyl((3-methylthiophen-2-yl)methyl)amino)quinazolin-6-yl)furan-2- carboxylate;
(5-(4-(2-(lH-imidazol-4-yl)ethylamino)quinazolin-6-yl)furan-2-yl)methanol;
(5-(4-((lH-imidazol-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)methanol;
(5-(4-((2-methylthiazol-4-yl)methylamino)quinazolin-6-yl)furan-2-yl)methanol;
(5-(4-(methyl((3-methylthiophen-2-yl)methyl)amino)quinazolin-6-yl)furan-2-yl)methanol; 5-(4-(2-(lH-imidazol-4-yl)ethylamino)quinazolin-6-yl)furan-2-carboxylic acid;
(5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)methanol;
5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxylic acid;
5-(4-(2-(lH-imidazol-4-yl)ethylamino)quinazolin-6-yl)-N-ethylfuran-2-carboxamide;
N,N-dimethyl-5-(4-(methyl((3-methylthiophen-2-yl)methyl)amino)quinazolin-6-yl)furan-2- carboxamide;
(5-(4-(thiophen-2-ylmethylamino)quinazolin-6-yl)furan-2-yl)methanol;
5-(4-(thiophen-2-ylmethylamino)quinazolin-6-yl)furan-2-carboxylic acid;
(5-(4-(methyl((3-methylthiophen-2-yl)methyl)amino)quinazolin-6-yl)furan-2-yl)methyl
dimethylcarbamate;
N,N-dimethyl-5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxamide;
N-ethyl-5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxamide;
5-(4-(thiophen-2-ylmethylamino)quinazolin-6-yl)furan-2-carbaldehyde;
ethyl 5-(4-(methyl((5-methylfuran-2-yl)methyl)amino)quinazolin-6-yl)furan-2-carboxylate;
(5-(4-(methyl((5-methylfuran-2-yl)methyl)amino)quinazolin-6-yl)furan-2-yl)methanol;
5- (4-(methyl((5-methylfuran-2-yl)methyl)amino)quinazolin-6-yl)furan-2-carboxylic acid;
6- (benzo[d][l,3]dioxol-5-yl)-N-(thiazol-2-ylmethyl)quinazolin-4-amine;
2-((6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-yl)(methyl)amino)acetic acid;
6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(furan-2-yl)ethyl)-N-methylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-(l-(2-methylthiazol-4-yl)ethyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((tetrahydrofuran-2-yl)methyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((4-methylthiazol-2-yl)methyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(2-methylthiazol-4-yl)ethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-(2-(2-methylthiazol-4-yl)ethyl)quinazolin-4-amine; l-methyl-5-(4-(methyl((5-methylfuran-2-yl)methyl)amino)quinazolin-6-yl)-lH-pyrrole-2- carbonitrile;
l-(5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)ethanol;
l-(5-(4-(methyl((3-methylthiophen-2-yl)methyl)amino)quinazolin-6-yl)furan-2-yl)ethanol; l-(5-(4-(thiophen-2-ylmethylamino)quinazolin-6-yl)furan-2-yl)ethanol;
(l-methyl-5-(4-(methyl((5-methylfuran-2-yl)methyl)amino)quinazolin-6-yl)-lH-pyrrol-2- yl)methanol;
l-(5-(4-((5-methylfuran-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)ethanone;
6-(benzo[d][l,3]dioxol-5-yl)-N-((tetrahydro-2H-pyran-2-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(cyclohexylmethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-ethylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-propylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-neopentylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(furan-2-ylmethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(2-(tetrahydrofuran-2-yl)ethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((tetrahydrofuran-3-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(cyclopentylmethyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-4-(piperidin-l-yl)quinazoline;
6-(benzo[d][l,3]dioxol-5-yl)-4-(piperazin-l-yl)quinazoline;
4- (6-(benzo[d][l,3]dioxol-5-yl)quinazolin-4-yl)morpholine;
6-(benzo[d][l,3]dioxol-5-yl)-N-ethyl-N-methylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-propylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(cyclopropylmethyl)quinazolin-4-amine;
(S)-6-(benzo[d][l,3]dioxol-5-yl)-N-((tetrahydrofuran-2-yl)methyl)quinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-(cyclohexylmethyl)-N-methylquinazolin-4-amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-(2-(tetrahydrofuran-2-yl)ethyl)quinazolin-4-amine; 6-(benzo[d][l,3]dioxol-5-yl)-N-methyl-N-((tetrahydro-2H-pyran-2-yl)methyl)quinazolin-4- amine;
6-(benzo[d][l,3]dioxol-5-yl)-N-((tetrahydro-2H-pyran-3-yl)methyl)quinazolin-4-amine;
5- (4-((tetrahydrofuran-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxylic acid;
5-(4-(neopentylamino)quinazolin-6-yl)furan-2-carboxylic acid; 5-(4-morpholinoquinazolin-6-yl)furan-2-carboxylic acid;
5-(4-(thiazol-2-ylmethylamino)quinazolin-6-yl)furan-2-carboxylic acid;
5-(4-((4-methylthiazol-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxylic acid;
(5-(4-((tetrahydrofuran-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)methanol;
(5 - (4- (neopentylamino)quinazolin- 6-yl)furan-2- yl)methanol ;
(5-(4-((4-methylthiazol-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)methanol;
N-ethyl-5-(4-((tetrahydrofuran-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxamide;
N-ethyl-5-(4-(thiazol-2-ylmethylamino)quinazolin-6-yl)furan-2-carboxamide;
N-ethyl-5-(4-((4-methylthiazol-2-yl)methylamino)quinazolin-6-yl)furan-2-carboxamide;
N-ethyl-5-(4-morpholinoquinazolin-6-yl)furan-2-carboxamide;
N-ethyl-5-(4-(neopentylamino)quinazolin-6-yl)furan-2-carboxamide;
l-(5-(4-((tetrahydrofuran-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)ethanol;
l-(5-(4-((4-methylthiazol-2-yl)methylamino)quinazolin-6-yl)furan-2-yl)ethanol;
l-(5-(4-morpholinoquinazolin-6-yl)furan-2-yl)ethanol;
l-(5-(4-(thiazol-2-ylmethylamino)quinazolin-6-yl)furan-2-yl)ethanol;
(5-(4-(thiazol-2-ylmethylamino)quinazolin-6-yl)furan-2-yl)methanol;
(5-(4-morpholinoquinazolin-6-yl)furan-2-yl)methanol; or
l-(5-(4-(2-(lH-imidazol-4-yl)ethylamino)quinazolin-6-yl)furan-2-yl)ethanol.
17. A pharmaceutical composition comprising a compound or salt of any one of Claims 1 to 15, and at least one pharmaceutically acceptable carrier.
18. The pharmaceutical composition of Claim 17, wherein the composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a tablet, a pill, a capsule, a syrup, or a transdermal patch.
19. The pharmaceutical composition of Claim 17, containing at least one additional active agent that is not a compound or salt of Claim 1.
20. A method of improving spatial learning, short term memory, or working memory in a patient comprising administering an effective amount of a compound or salt of Claim 1 to the patient.
21. A method of treating a Clkl, Clk2, Clk4, or DyrklA kinase mediated disorder in a patient comprising administering an effective amount of a compound or salt of Claim 1 to the patient.
22. A method of inhibiting a Clkl, Clk2, Clk4, or DyrklA kinase in vivo comprising administering an amount of a compound or salt of Claim 1 sufficient to inhibit the kinase in vitro.
23. A method for inhibiting the phosphorylation activity of a Clkl, Clk2, Clk4, or DyrklA kinase comprising contacting a cell containing a Clkl, Clk2, Clk4, or DyrklA kinase with a solution containing a concentration of a compound or salt of Claim 1 sufficient to inhibit the phosphorylation activity of a Clkl, Clk2, Clk4, or DyrklA kinase in vitro.
24. A method of inhibiting the splicing activity of a Clkl, Clk2, Clk4, or DyrklA kinase comprising contacting a cell containing a Clkl, Clk2, Clk4, or DyrklA kinase with a solution containing a concentration of a compound or salt of Claim 1 sufficient to significantly alter the splicing of PKC iI TF, Tau or β-globin pre-mRNA in vitro.
25. A method for demonstrating the presence or absence of Clkl, Clk2, Clk4, or DyrklA kinase in a biological sample, said method comprising: a) contacting the biological sample with a labeled compound or salt of Claim 1 under conditions that permit binding of the labeled compound to the Clkl, Clk2, Clk4, or DyrklA kinase; b) separating unbound labeled compound from bound labeled compound; and c) detecting the labeled compound in the biological sample, and therefrom determining the presence or absence of Clkl, Clk2, Clk4, or DyrklA kinase in the sample.
26. The method of Claim 25 wherein the compound or salt of Claim 1 is isotopically or radiolabeled.
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