Pyridopyrimidine compounds and their uses

Abstract

Novel pyridopyrimidine-based compounds are found to be useful for the treatment or prevention of symptoms or manifestations associated with diseases or disorders affected by cytokine intracellular signaling.

1 - 18 . (Canceled)  
     
     
         19 . A method for inhibiting a cytokine, comprising: 
 (a) contacting the cytokine with a therapeutic compound;    (b) determining that the cellular process or activity mediated by the cytokine is inhibited;    wherein the therapeutic compound, including resolved enantiomers, diastereomers, tautomers, and salts thereof, has the following formula:                          wherein:    R 1  is selected from a member of the group consisting of hydrogen, hydroxyl, methoxyl, acylamino group, cyano group, sulfo, sulfinyl, sulfhydryl (mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino, and phosphino, phosphinyl, phospho, phosphono and —NR a R b , wherein each of R a  and R b  may be the same or different and each is selected from the group consisting of hydrogen and optionally substituted: C (1-20) alkyl, C (3-12) cycloalkyl, C 2-20) alkenyl, C (3-12) cycloalkenyl, C (2-20) alkynyl, aryl, heteroaryl, and heterocyclic group;    R 2  and R 3  are independently selected from a member of the group consisting of halo, oxo, C (1-20) alkyl, C (1-20) hydroxyalkyl, C (1-20) alkylthio, C (1-20) alkylaminoalkyl, C (1-20) aminoalkyl, C (1-20) aminoalkoxyalkenyl, C (1-20) aminoalkoxyalkynyl, C (1-20) diaminoalkyl, C (1-20) triaminoalkyl, C (2-20) tetraaminoalkyl, C (1-20) alkylamido, C (1-20) alkylamidoalkyl, C (1-20) amidoalkyl, C (1-20) acetamidoalkyl, C (2-20) alkenyl, C (2-20) alkynyl, C (1-20) alkoxy, C (1-20) alkoxyalkyl, C (1-20) dialkoxyalkyl, and —NR a R b ; and    R 4  may be hydrogen or an optionally substituted member of the group consisting of C (1-20) alkyl, C (3-12) cycloalkyl, C (2-20) alkenyl, C (3-12) cycloalkenyl, C (2-20) alkynyl, aryl, heteroaryl, and heterocyclic group.    
     
     
         20 . The method of  claim 19 , wherein step (a) is carried out in vitro.  
     
     
         21 . The method of  claim 19 , wherein said cellular process is the differentiation of naïve T cells into Th1 or T1 cells.  
     
     
         22 . The method of  claim 19 , wherein said cellular process is the differentiation of naïve T cells into Th2 or T2 cells.  
     
     
         23 . The method of  claim 19 , wherein said activity is the secretion of proinflammatory cytokines.  
     
     
         24 . The method of  claim 19 , wherein said activity is the secretion of anti-inflammatory cytokines.  
     
     
         25 . The method of  claim 19 , wherein said activity is the secretion of a cytokine selected from the group consisting of tumor necrosis factor, colony stimulating factor, interferon, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, transforming growth factor, oncostatin M, leukemia inhibiting factor, and platelet activating factor.  
     
     
         26 . The method of  claim 25 , wherein said cytokine is IL-12.  
     
     
         27 . The method of  claim 25 , wherein said cytokine is IL-4.  
     
     
         28 - 36 . (Canceled)  
     
     
         37 . The method of  claim 19 , wherein R 2  and R 3  are independently selected from a member of the group consisting of hydrogen, halo, thio, oxo, C( 1-10 )alkyl, C( 1-10 )hydroxyalkyl, C( 1-10 )alkylthio, C( 1-10 )alkylamino, C( 1-10 )alkylaminoalkyl, C( 1-10 )aminoalkyl, C( 1-10 )aminoalkoxyalkenyl, C( 1-10 )aminoalkoxyalkynyl, C( 1-10 )diaminoalkyl, C( 1-10 )triaminoalkyl, C( 2-10 )tetraminoalkyl, C( 1-10 )aminotrialkoxyamino, C( 1-10 )alkylamido, C( 1-10 )alkylamidoalkyl, C( 1-10 )amidoalkyl, C( 1-10 )acetamidoalkyl, C( 2-10 )alkenyl, C( 2-10 )alkynyl, C( 1-10 ))alkoxyl, C( 1-10 )alkoxyalkyl, and C( 1-10 )dialkoxyalkyl.  
     
     
         38 . The method of  claim 19 , wherein each of R 2  and R 3  is substituted with one or more members of the group consisting of hydroxyl, methyl, carboxyl, furyl, furfuryl, biotinyl, phenyl, naphthyl, amino group, amido group, carbamoyl group, cyano group, sulfo, sulfonyl, sulfinyl, sulfhydryl, sulfeno, sulfanilyl, sulfamyl, sulfamino, phosphino, phosphinyl, phospho, phosphono, N—OH, —Si(CH 3 ) 3 , C (1-3) alkyl, C (1-3) hydroxyalkyl, C (1-3) alkylamino, benzyldihydrocinnamoyl group, benzoyldihydrocinnamido group, optionally substituted heterocyclic group and optionally substituted carbocyclic group.  
     
     
         39 . The method of  claim 19 , wherein the heterocyclic group or carbocyclic group is substituted with one or more members of the group consisting of halo, hydroxyl, nitro, SO 2 NH 2 , C (1-6) alkyl, C 1-6) haloalkyl, C (1-6) alkoxyl, C (1-11) alkoxyalkyl, C (1-6) alkylamino, and C (1-6) aminoalkyl.  
     
     
         40 . The method of  claim 19 , wherein the heterocyclic group is a member selected from the group consisting of acridinyl, aziridinyl, azocinyl, azepinyl, benzimidazolyl, benzodioxolanyl, benzofuranyl, benzothiophenyl, carbazole, 4a H-carbazole, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, dioxoindolyl, furazanyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydro-isoquinolinyl, oxazolidinyl, oxazolyl, oxiranyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, 4-pipendonyl, piperidyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyndinyl, pyridyl, pyndyl, pyrimidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolonyl, pyrrolyl, 2H-pyrrolyl, quinazolinyl, 4H-quinolizinyl, quinolinyl, quinoxalinyl, quinuclidinyl, β-carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 2H-,6H-1,5,2-dithiazinyl, thianthrenyl, thiazolyl, thienyl, thiophenyl, triazinyl, xanthenyl and xanthinyl.  
     
     
         41 . The method of  claim 19 , wherein the carbocyclic group is a member selected from the group consisting of adamantyl, anthracenyl, benzyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hexanyl, bicyclo[2.2.2]octanyl, bicyclo[3.2.0]heptanyl, bicyclo[4.3.0]-nonanyl, bicyclo[4.4.0]decanyl, biphenyl, biscyclooctyl, cyclobutyl, cyclobutenyl, cycloheptyl, cycloheptenyl, cyclohexanedionyl, cyclohexenyl, cyclohexyl, cyclooctanyl, cyclopentadienyl, cyclopentanedionyl, cyclopentenyl, cyclopentyl, cyclopropyl, decalinyl, 1,2-diphenylethanyl, indanyl, 1-indanonyl, indenyl, naphthyl, napthlalenyl, phenyl, resorcinolyl, stilbenyl, tetrahydronaphthyl, tetralinyl, tetralonyl, and tricyclododecanyl.  
     
     
         42 . The method of  claim 19 , wherein the compound, including resolved enantiomers, diastereomers, tautomers, and salts thereof, has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         43 . The method of  claim 19 , wherein the compound, including resolved enantiomers, diastereomers, tautomers, and salts thereof, has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         44 . The method of  claim 19 , wherein the compound, including resolved enantiomers, diastereomers, tautomers, and salts thereof, has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         45 . The method of  claim 19 , wherein the compound, including resolved enantiomers, diastereomers, tautomers, and salts thereof, has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         46 . The method of  claim 19 , wherein the compound, including resolved enantiomers, diastereomers, tautomers, and salts thereof, has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         47 . The method of  claim 19 , wherein the compound, including resolved enantiomers, diastereomers, tautomers, and salts thereof, has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         48 . The method of  claim 19 , wherein the compound, including resolved enantiomers, diastereomers, tautomers, and salts thereof, has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         49 . The method of  claim 19 , wherein the compound, including resolved enantiomers, diastereomers, tautomers, and salts thereof, has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         50 . The method of  claim 19 , wherein the compound, including resolved enantiomers, diastereomers, tautomers, and salts thereof, has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         51 . The method of  claim 19 , wherein the compound, including resolved enantiomers, diastereomers, tautomers, and salts thereof, has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         52 . A method comprising the compound of  claim 19  in admixture with a pharmaceutically acceptable carrier, adjuvant or vehicle.  
     
     
         53 . A method for inhibiting a cytokine, comprising: 
 (a) contacting the cytokine with a therapeutic compound;    (b) determining that the cellular process or activity mediated by the cytokine is inhibited;    wherein the therapeutic compound, including resolved enantiomers, diastereomers, tautomers, and salts thereof, has the following formula:                          wherein:    R 1  is selected from a member of the group consisting of hydrogen, hydroxyl, methoxyl, acylamino group, cyano group, sulfo, sulfonyl, sulfinyl, sulfhydryl (mercapto), sulfeno, sulfanilyl, sulfamyl, sulfamino, phosphino, phosphinyl, phospho, phosphono and —NR a R b , wherein each of R a  and R b  may be the same or different and each is selected from the group consisting of hydrogen and optionally substituted: C (1-20) alkyl, C (3-12) cycloalkyl, C (2-20) alkenyl, C (3-12) cycloalkenyl, C (2-20) alkynyl, aryl, heteroaryl, and heterocyclic group;    R 2  and R 3  are independently selected from a unsubstituted or substituted member of the group consisting of methyl, ethyl, oxo, isopropyl, n-propyl, isobutyl, n-butyl, t-butyl, 2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxy-n-butyl, 2-methoxyethyl, 4-methoxy-n-butyl, 5-hydroxyhexyl, 2-bromopropyl, 3-dimethylaminobutyl, 4-chloropentyl, methylamino, amino-methyl, and methylphenyl; and    R 4  may be hydrogen or an optionally substituted member of the group consisting of C (1-20) alkyl, C (3-12) cycloalkyl, C (2-20) alkenyl, C (3-12) cycloalkenyl, C (2-20) alkynyl, aryl, heteroaryl, and heterocyclic group.