WO2011041655A1 - Dérivés de la quinazolin-4-amine; et méthodes d'utilisation - Google Patents

Dérivés de la quinazolin-4-amine; et méthodes d'utilisation Download PDF

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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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quinazolin
methyl
amine
benzo
dioxol
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PCT/US2010/051090
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English (en)
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Craig J. Thomas
Bryan T. Mott
Cordelle Tanega
Min Shen
Douglas S. Auld
Andrew S. Rosenthal
David J. Maloney
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The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
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Publication of WO2011041655A1 publication Critical patent/WO2011041655A1/fr

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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

La présente invention concerne de nouveaux dérivés de la quinazolin-4-amine qui sont des inhibiteurs de la kinase Clk1, Clk2, Clk3, Clk4 ou Dyrk1A. L'invention concerne également des dérivés de la quinazolin-4-amine en tant qu'inhibiteurs sélectifs et puissants des kinases Clk1, Clk4, et Dyrk1A. Ces agents fournissent des outils utiles pour l'étude des Clk1, Clk4 et Dyrk1A et de leurs rôles respectifs dans l'épissage du pré-ARNm. L'invention concerne également des méthodes de traitement de troubles induits par la kinase Clk1, Clk2, Clk4 ou Dyrk1A par certains dérivés de la quinazolin-4-amine.
PCT/US2010/051090 2009-10-01 2010-10-01 Dérivés de la quinazolin-4-amine; et méthodes d'utilisation WO2011041655A1 (fr)

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JP2014525928A (ja) * 2011-08-19 2014-10-02 ディアクソンヒット Ｄｙｒｋ１阻害剤およびその使用
WO2016115434A1 (fr) * 2015-01-16 2016-07-21 The General Hospital Corporation Composés pour améliorer l'épissage de l'arnm
WO2018021977A1 (fr) * 2016-07-29 2018-02-01 Agency For Science, Technology And Research Modulateurs du métabolisme de la glycine et leurs utilisations
CN109721554A (zh) * 2019-01-08 2019-05-07 贵州大学 一类4-氨基喹唑啉类化合物及其制备方法和应用
CN114222741A (zh) * 2019-05-31 2022-03-22 奇斯药制品公司 作为p2x3抑制剂的吡啶并嘧啶类衍生物

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Cited By (8)

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Publication number Priority date Publication date Assignee Title
JP2014525928A (ja) * 2011-08-19 2014-10-02 ディアクソンヒット Ｄｙｒｋ１阻害剤およびその使用
WO2016115434A1 (fr) * 2015-01-16 2016-07-21 The General Hospital Corporation Composés pour améliorer l'épissage de l'arnm
US10676475B2 (en) 2015-01-16 2020-06-09 The General Hospital Corporation Compounds for improving mRNA splicing
EA037663B1 (ru) * 2015-01-16 2021-04-28 Те Дженерал Хоспитал Корпорейшн СОЕДИНЕНИЯ ДЛЯ УЛУЧШЕНИЯ СПЛАЙСИНГА мРНК
US11702417B2 (en) 2015-01-16 2023-07-18 The General Hospital Corporation Compounds for improving mRNA splicing
WO2018021977A1 (fr) * 2016-07-29 2018-02-01 Agency For Science, Technology And Research Modulateurs du métabolisme de la glycine et leurs utilisations
CN109721554A (zh) * 2019-01-08 2019-05-07 贵州大学 一类4-氨基喹唑啉类化合物及其制备方法和应用
CN114222741A (zh) * 2019-05-31 2022-03-22 奇斯药制品公司 作为p2x3抑制剂的吡啶并嘧啶类衍生物

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